cycloadditions and condensations as essential tools in spiropyrazoline synthesis
TRANSCRIPT
at SciVerse ScienceDirect
European Journal of Medicinal Chemistry 63 (2013) 347e377
Contents lists available
European Journal of Medicinal Chemistry
journal homepage: http: / /www.elsevier .com/locate/ejmech
Mini-review
Cycloadditions and condensations as essential tools in spiropyrazolinesynthesis
Sureshbabu Dadiboyena a,b,*
aMedicinal Chemistry, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USAbMississippi State University, Mississippi State, MS 39762, USA
a r t i c l e i n f o
Article history:Received 16 July 2012Received in revised form12 January 2013Accepted 15 January 2013Available online 6 March 2013
Keywords:SpiropyrazolinesSpiroisoxazolinesPyrazolinesHeterocyclesCycloadditionsCondensationsRegioselectivity
* Medicinal Chemistry, Torrey Pines Institute for MVillage Parkway, Port St. Lucie, FL 34987, USA. Fax: þ
E-mail addresses: [email protected], dadibo
0223-5234/$ e see front matter � 2013 Elsevier Mashttp://dx.doi.org/10.1016/j.ejmech.2013.01.059
a b s t r a c t
Heterocycles with potential bioactive properties are of greater interest to researchers engaged in theareas of natural product synthesis and heterocyclic methodology. Several FDA (Food and Drug Admin-istration) approved pharmaceutical drugs incorporate a heterocyclic motif in their core structure. Spi-roisoxazolines and spiropyrazolines belong to the class of five membered heterocycles that have receivedgreater attention over the past four decades. Spiropyrazolines structurally resemble naturally occurringspiroisoxazolines, have extra nitrogen in place of isoxazoline oxygen, and offer the viability to constructuseful analogs for the exploration of possible bioactivity. As of today, no reports on the construction ofthese spiropyrazolines were available and the current review is aimed at providing a comprehensivediscussion of the protocols applied in the synthesis of functionalized spiropyrazolines.
� 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
The exploitation of a small molecule to a desirable extent is avaluable contribution in the field of synthetic organic and medici-nal chemistry. Bioactive heterocyclic compounds are of potentialinterest to researchers engaged in the areas of natural productsynthesis and heterocyclic methodology [1e9]. In addition to thepotential bioactive properties rendered by these heterocycliccompounds, they are actively sought in the agrochemical andpharmaceutical sectors [6,7,10e15]. A few examples of the phar-maceutical drugs that incorporated a heterocyclic scaffold includecelecoxib (celebrex) 1 [14], rimonabant 2 [16e18], raloxifene 3 [15],lipitor 4 [19,20], and cialis 5 [21e23]. Of the several heterocycles,five membered isoxazole (isoxazoline) and pyrazole (pyrazoline)based motifs have garnered greater attention and are convenientlyaccessed in few steps [24e36]. These five membered heterocyclesexhibited several biological properties including antiviral [37,38],antitubulin [39,40], anti-inflammatory [41], antibacterial [42,43],antifungal [44,45], and antidepressant activity [46]. However, whenan isoxazoline or pyrazoline is joined to another ring at one carbon
olecular Studies, 11350 SW1 601 979 [email protected].
son SAS. All rights reserved.
atom, they are termed as spiroisoxazolines and spiropyrazolines[28,29,32,47,48].
The spirocyclic molecular framework is of substantial interest tomedicinal chemists [49e51], and the synthesis of these spirocyclesis a daunting task, due to the non-availability of the convenientprotocols and starting materials. Spiroisoxazolines and spiropyr-azolines belong to the class of five membered heterocyclic com-pounds, and an array of methodologies were designed andexecuted adopting various synthetic pathways [47,48,e52e62].While the major structural core of several bromotyrosinated nat-ural products 6e11 is spiroisoxazoline [49e59], spiropyrazolineswith extra nitrogen (in place of isoxazoline oxygen) present theflexibility to synthesize additional analogs for the investigation ofpossible bioactivity (Fig. 1) [31,48,53,54]. In general, the spiropyr-azolines have a basic structure derived from the pyrazoline and areexemplified by unique spiro junction at the C-5 position of a pyr-azoline [47,48]. These spiropyrazoline based templates are attrac-tive targets for synthesis based upon the intriguing spirocyclicskeleton rendered with potential bioactive applications.
A variety of methods exist for the synthesis of the functionalizedspiropyrazolines. General and classical syntheses of the spiropyr-azolines rendered protocols based on 1,3-dipolar cycloaddition[1,6,61e65] or condensation as an essential step [66e71]. Spi-ropyrazolines with several sites for modification present the
NN
CF3
CH3
SH2N
O O
1 CelebrexS
O
HO
ON
OH
3 Raloxifene
NN
O
O
H
OO
NH
5 Cialis
NN
CH3
O
HN N
Cl
Cl Cl
2 Rimonabant
ON
OMeBr Br
OH
O
HN
n NH O
NO
OMeBr Br
HO
6 n = 2, aerothionin7 n = 3, homoaerothionin
ON
BrOMe
Br
HN
O
O
Br
Br
HN
O
OOH
10 epi-fistularin-3
OHOH
HO
Br BrOMe
ON
OBr
11 calafianin
HN
O
O
NH
O
ON
BrO
O
NO
Isoxazoline
NHN
Structural
Resemblance
Pyrazoline
NHN
Spiropyrazoline
NHNX
X = heteroatom
Spiro-pyrazoline
N
F
NH
O
OH
OH OH O
4 Lipitor
ON
OMeBr Br
O
HN
8 aerophobin 1
HO
NNH
ON
OMeBr Br
O
HN
9 purealidin Q
HO
Br
O NMe
MeBr
Fig. 1. Bioactive heterocyclic compounds of natural and synthetic origin.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377348
flexibility to construct additional analogs of biomedical interest[48] and also serve as essential precursors in the synthesis ofcyclopropane derivatives [72,73]. To date, there exist no reviewreports that provided a discussion on the synthesis of these mol-ecules and the current review is aimed at providing a compre-hensive overview of practical methodologies used to constructspiropyrazolines of biomedical interest. In addition to the spi-ropyrazoline synthesis, a discussion on the synthesis of cyclopro-pane derivatives is also provided (wherever required). The contentsare discussed in four sections: (a) condensation reactions, (b) 1,3-dipolar cycloadditions, (c) related 1,3-dipolar cycloadditions, and(d) reactions of spiropyrazolines.
2. Condensation reactions
Condensation reaction is an example of organic reaction,wherein two molecules or moieties interact and unite to form onesingle molecule [14,27,66e68]. During the condensation process,they are normally associated with a loss of a small molecule such asH2O, HCl, or AcOH [31,66,69e71]. These condensations find supe-rior place in organic synthesis and are actively sought in the syn-thesis of heterocyclic rings of varied sizes. In this section, a briefoverview of condensation reactions applied to synthesize variousspiropyrazolines is provided.
Indole-2,3-dione (isatin) 12 is a valuable precursor in organicsynthesis and find several applications in chemistry and biology[74e77]. In presence of a base, these indole-2,3-diones reactedwitha-tetralone [78] (or) substituted acetophenones [79e82], and fur-nished the a,b-unsaturated carbonyl intermediates 13e15. Thesynthesized intermediates 13e15 following reacted with hydrazine(or) phenylhydrazine under ethanol reflux conditions to afford the
desired spiropyrazolines 16e19 in moderate yields (Scheme 1)[78e82].
In another report, Aoyagi and coworkers treated 3-phenacylideneindolin-2-ones 20 with hydrazine hydrate and iso-lated several spiro[indoline-3,30-(50-pyrazolin)]-2-ones 21 [82]. Thesynthesized spiropyrazolines on following treatment with aceticanhydride furnished the 20-acetyl analogs 22/23 in high yields. Ofrecent, Alizadeh and Zohreh utilized the ketene aminals as essentialintermediates and synthesized several spiropyrazolines incorpo-rated with an indole-2,3-dione motif [83]. The required keteneaminals 25were conveniently prepared through the reaction of 1,1-bis(methylthio)-2-nitroethylene with diamines or ammonia. Onepot reaction of 1,1-bis(methylthio)-2-nitroethylene (ketene aminal)25, hydrazine hydrate and isatin 24 (1:2:2) proceeded to comple-tion and the desired spirooxindoleepyrazolines 26were isolated inhigh yields (Scheme 2) [83].
Similar to isatin, indenoquinoxalines 27 also find potential ap-plications in organic synthesis and exhibited several bioactiveproperties such as antimetabolism and antitubercular properties[84,85]. Indenoquinoxaline and indenopyridopyrazine derivedspiropyrazolines (31 and 32) were prepared through the conden-sation of chalcones and hydrazine in acidic conditions [81]. Thechalcone intermediates 29 and 30were prepared in two convenientsteps that involved a base treatment under solvent free conditionsand following dehydration using glacial AcOH and HCl. The chal-cones 29e30 upon condensation with hydrazine hydrate underethanol reflux conditions furnished the desired spiropyrazolines31/32 in excellent yields (Scheme 3) [81].
Additional report that utilized the condensation as a key step wasreported by Youssef and coworkers [86]. The desired spiropyrazo-lines 36aec incorporated an essential benzothienopyridazine motif.
NH
O
O
R
C6H5NHNH2/ EtOH
NH
OR
NN
R = H, 5-F, 6-F44-59%
3 examples
NH
O
O
CH3
O
NH
NH
O
NHN
NH
O
NHN
R = H, Br, Cl, OMe
R R
52-92%
CH3
O
OHR1
R2
R3
NH
OOOHR1
R2
R3
C6H5NHNH2
alc. KOHNH
NN
O HO R1
R2
R3
R1 = H, Br; R2 = OEt, OnBu; R3 = H, NO2
72- 87%
8 examples
O
a) Et2NH/EtOHb) HCl (or) AcOH NH2NH2/ PhNHNH2 (or)
4 examples 3 examples
12
13
14
15
16
17 18
19
O
O
R
R
R = H, Br, Cl, OMe R = H, Cl, OMe
Scheme 1. Synthesis of isatin derived spiropyrazolines.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 349
Diazotization and following coupling of ethyl 2-amino-4,5,6,7-tetrahydrobenzo-[b]thiophene-3-carboxylate 33 with acetylace-tone, ethyl cyanoacetate and malononitrile provided the interme-diate precursors 34. The synthesized intermediates 34 upon reflux insodium ethoxide underwent cyclization and furnished a few ben-zothienopyridazines 35aec. The benzothienopyridazines 35aec inpresence of hydrazine hydrate underwent oxidative cyclizationand the final products 36aec were isolated in moderate yields(Scheme 4) [86].
Recently, Karpenko and coworkers reported an elegant syn-thesis of spiropyrazoline based triazinones 41aeo via cyclocon-densation-Dimroth-like rearrangement reaction [87]. Triazino-annulated quinazoline based heterocycles are known to exhibitinteresting medicinal and biological applications [88e91]. Cyclo-condensation of 4-hydrazinoquinazolines 37 with different heter-oaryl substituted 2,4-diketoesters in glacial acetic acid generatedthe corresponding 3-acylmethyl derivatives 40. The synthesized 3-acylmethyl derivatives 40 on following condensationwith excess of
NO
R2
R1
O
N2H4N
O
R2
NNH
R1
31-70%
R2 = H, Me, Allyl, Ac, BnR1 = Me, Ph
2021
NO2
S
SMe
Me+ N2H4
R2
NR1
O
O
EtOH,60-
R1 = H, Me, PMB, Bn; R2 = H, NO2, Br
24 25
Scheme 2. Synthesis of indole
hydrazine hydrate furnished a series of spiropyrazolines 41aeo inhigh yields (Scheme 5) [87].
3. 1,3-Dipolar cycloaddition reactions
1,3-dipolar or [2 þ 3]-dipolar cycloadditions represent one ofthe most useful strategies applied in the construction of bioactiveheterocycles of pharmaceutical significance [1,6,14]. Resulted fromthe pioneering work of Rolf Huisgen [63e65], cycloadditions findpotential applications in synthetic organic and medicinal chem-istry, and is often a determining step in the regioselective con-struction of novel heterocycles [14,27,31e33]and several naturalproducts [28,29,56e58]. In general, a 1,3-dipolar reaction involvean interaction of a dipolarophile with suitable 1,3-dipole in aconcerted manner leading to the cyclization process. A fewexamples of 1,3-dipoles applied in the synthesis of spiropyrazo-lines include nitrile imines [47,48,61,62,92,93] or diazoalkanes[94e97] or related diazo derivatives [98] or diaziridines [99] and
Ac2ON
O
R2
NN
H3C
Ac86-98%
22
H2O
R2
NR1
O
HN
HNNO2
NN
OH N
R1
R2
r.t., 12h
8 examples
76% 26
NO
R2
NN Ac
(or)
23
based spiropyrazolines.
N
N
O
R2
R2
R2 = H, MeR3 = H, Br, Cl, OMe
H3C
O
R3
HNMe2/ r.t. /15-30 minsolvent free
N
NR2
R2
O
R3
AcOH/ HCl
70-80oC, 30 min
a) N2H4 H2O/ EtOH, reflux, 1hrb) Cyclization
N
NR2
R2
NHN
R3
80-95%
8 examples 8 examples
N
N
N
O
R1 = H, Br, Cl
H3C
O
R1
HNMe2/ r.t. /15-30 minsolvent free
N
N
N
O
R1
AcOH/ HCl
70-80oC, 30 min
a) N2H4 H2O/ EtOH, reflux, 1hrb) Cyclization
N
N
N
NHN
R1
83-89%
3 examples 3 examples
27
28
29
30
31
32
Scheme 3. Spiropyrazolines bearing an indenoquinoxaline or indenopyridopyrazine motif.
S
CO2Et
NH2NaNO2/ H+
CH2
R2R1
S
CO2Et
N NR2
R1(a) R1 = R2 = COMe (b) R1 = R2 = CO2Et(c) R1 = R2 = CN
NaOEt
SN
N
O R1R2
NH2NH2
alc./piperidineS
NN
ONNR1
R2
78-100% 34-100%
35-71%
33 34 35a-c
36a-c
3 examples
(a) R1 = R2 = CH3 (b) R1 = OH, R2 = NH2(c) R1 = R2 = NH2
+
Scheme 4. Synthesis of benzothienopyridazine derived spiropyrazolines.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377350
the usual dipolarophile for this process is an alkene or alkyne. Thissection will emphasize on the synthesis of spiropyrazolines thatutilized nitrile imines or diazoalkanes or diaziridines as suitabledipoles.
3.1. Nitrile imines
Nitrile imines are examples of efficient 1,3-dipoles employed in1,3-dipolar cycloadditions and are generated in situ from the
NH
N
NNH2
O
R CO2Me
OH
NH
N
NNO
R CO2Me
AcOH, reflux,1-24h
R = Ph, 2-ClPh,
HN
NH2
NNH
O
N NR
15 examples
37
38 39
41a-o
H
Scheme 5. Synthesis of triazinoquin
corresponding hydrazonyl halides in presence of a base [14,31e33].Batra and coworkers reported a versatile BayliseHillman adductbased cycloaddition methodology and synthesized a series of spi-ropyrazolines bearing quinolin-2-one and pyrrolidin-2-one motifs[47]. Treatment of substituted 2-nitrobenzaldehyde with ethylacrylate delivered an essential intermediate 42 which, followingreacted with several in situ generated nitrile imines 43 and fur-nished the intermediate pyrazolines 44 as a syn isomer. The syn-thesized pyrazolines upon reductive cyclization (In/HCl) process
N
N
NN
OO
R
N
N
NN
OO R
49-79%
4-MePh, 4-OMePh, 3-NO2Ph, 4-NO2Ph, 2-FPh, 4-FPh, 2,5-F2Ph,4-ClPh, 3-BrPh, 4-BrPh, thiophen-2-yl, furan-2-yl, benzo[b]furan-2-yl
N2H4 H2O (4eq.)
i-PrOH, reflux, 5-8h
54-91%40
azoline based spiropyrazolines.
R1
CO2EtOH
NO2
TEA/Ether
36-44%
NCl
N
R2
+ R1 NN
OHH
R2
In/HClTHF/H2O, 70 oC
71-96%
NH
O
HO NN
R1R2
R1 = H, 3,4-(OMe)2R2 = H, 2-F, 4-Cl, 4-Me, 2-thienyl
6 examples'Syn'
HCl
Cl
TEA/EtherN
N
R2
MeO2C
NO2
In/HClTHF/H2O, 70 oC
50-77%NH
O
NNR
R2 = H, 4-Cl, 4-Me, 2-thienyl
4 examples'Syn'
CO2Me
NO2
73-97%
Reagents and Conditions: (a) DABCO, THF/H2O, r.t. then NaBH4, r.t. 5 min.
-78oC ->r.t.
Cl Cl
42 43
44
45a-e
46
47
48a-d
Cl
NO2
OEtO
43
Scheme 6. Synthesis of quinolin-2-one derived spiropyrazolines.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 351
furnished the targeted spiropyrazolines 45aee in good yields.Additional 1,3-dipolar cycloadditions and following reductive cy-clizations of reduced BayliseHillman adducts 46 also furnished thespiropyrazolines 48aed in high yields (Scheme 6).
Similar to the quinolin-2-ones, 2-pyridone derived structuralmotifs are also of potential interest to chemical biologists as theyconstitute the structural core of several naturally occurring com-pounds including nothapodytine-B, akanthomycin, and sempervi-lam [100e102]. 2-Pyridone based BayliseHillman adducts 51 wereconveniently synthesized in few steps from the corresponding al-dehydes 49. The synthesized adducts 51 on following 1,3-dipolarreaction with several hydrazonyl chlorides 43 resulted in theisolation of pyrrolidine-spiropyrazolines 52aes as a single diaste-reomer (Scheme 7) [102].
Hamme and Dadiboyena reported an elegant methodology to-ward the construction of spiropyrazoline regioisomers thatinvolved a tandem intramolecular cyclization/methylationsequence [48]. The methodology involved a 1,3-dipolar reaction offunctionalized alkene derivative 53 with in situ generated nitrileimines 54. The synthesized pyrazolines 55 on following intra-molecular cyclization/methylation pathway furnished the desiredcarbocyclic spiropyrazolines 56e57 as a mixture of diastereomers.A plausible mechanism involved the O-methylation of the gener-ated spiropyrazoline enolates 60e61. The methodology wasimproved further by repositioning the ester moiety to a remotelocation relative to the pyrazoline ring 59. Repositioning of theelectrophilic ester to a remote location potentially reduced thesteric environment and the desired spiropyrazolines 56e57 wereisolated in higher yields (Scheme 8) [28,48].
R1 = H, 2-F, 4-Cl, 2,6-diCl, 4-MeR2 = OEt, Me; R3 = H, 2-F, 4-Cl, 4-Me
R1 H
O
R1CN
OO
R2
R1
O
R2TFA/H2SO4
(4:1)
35-69%49
50
3 steps
Scheme 7. Synthesis of pyrrolidin-2
Mernyak and coworkers synthesized a few steroidal derivedspiropyrazolines via a 1,3-dipolar reaction of hydroxymethylideneprecursors 63 with in situ generated nitrile imine 64. The observedcycloaddition was highly diastereoselective and the spiropyrazo-lines 65a,b were isolated in high yields (Scheme 9) [93].
Additional 1,3-dipolar reactions of substituted 2-arylmethylene-1,3-indanediones 66 and 6-arylmethylidenecyclopenta[1,2-c]pyr-azoles 68 with nitrile imines generated in situ 69/70 proceeded tocompletion and the resultant spiropyrazolines 71e72were isolatedas a single regioisomer (Scheme 10) [103,104].
Butenolide and 5-oxazolone based structural motifs displayseveral important applications in the construction of novel spi-roheterocyclic systems [105,106]. 1,3-dipolar reaction of these 3-arylidenebutenolide 73 or 5-oxazolone 74 dipolarophiles withdiarylnitrile imine 75 resulted in cyclization and the targeted spi-ropyrazolines 76/77were isolated as a single regioisomer [107,108].Likewise, cycloaddition of substituted nitrile imine 80 with anisoxazolinone 78 or a pyrazolinone 79 also furnished the spi-ropyrazolines 81/82 as sole product (Scheme 11) [109].
In another study,Ragunathanandcoworkersutilized severalbulkydipolarophiles and demonstrated the scope of 1,3-dipolar cycloaddi-tion process [110e115]. The bulky dipolarophiles included 9-methyleneanthrone 83, tetraphenylfulvene 84 and 9-benzalfluorene85 which, following 1,3-dipolar cycloaddition with nitrile iminegenerated in situ 75, furnished the spiropyrazolines 86e88 as a singleregioisomer. However, in case of 2,3,4,5-tetraphenylfulvene subst-ituted with a phenyl group 84c, the reaction failed to undergocompletion due to the steric hindrance imposed by the phenyl groupat C6 of the fulvene molecule (Scheme 12) [110e115].
NCl
N
R3H
Cl
anhyd. C6H6reflux, 5d
HN
R2
O
O
R1
NN
Cl
R3
19 examples
NH
O
51
43
52a-s34-66%
-one derived spiropyrazolines.
N
Cl
N
OCH CH O
CH
OH+
CH Cl
(C H ) NNN
OOCH CH
CH
OR
RR
R
R R
NN
O
OCH
KOt-Bu, Toluene;
+
(CH ) SO , Δ
NN
O
OCHR
R
R
R
R
R
N
Cl
N
OCH
OCH CH
OH+
CH Cl
(C H ) N NN
OCH
OCH CH
O
R
RR
R
RR
KOt-Bu, Toluene;
(CH ) SO , ΔR = H, Cl
R = H, Br, Cl
R = H, ClR = H, Br, Cl
67-85%
(55-80%)
R = H, Br, Cl
71-78%
R = H
(CH ) SO , (CH ) SO ,
55
NN
O
O
NNKOt-Bu, Toluene;
+N
N
O
O
OOCH CH
CH
O
60 61
K
KR
RR
R
R
R
R
R
R
59
NNKOt-Bu, Toluene;
(CH ) SO , Δ
OCH
OCH CH
OR
RR
53 54 55
5657
58 5459
NN
O
OCH
NN
O
OCHR
R
R
R
R
R
5657
Δ Δ
Scheme 8. Spiropyrazolines via intramolecular cyclization/methylation.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377352
Chromanone and thiochromanone based structural motifs areprevalent features for several natural products and bioactive het-erocyclic compounds [116e119]. The existence of an exocyclicdouble bond (a,b-enones) rendered these scaffolds as suitablepartner for cycloaddition studies [120,121]. In addition to thesemotifs, tetralones and flavanones also find potential utility asdipolarophiles in 1,3-dipolar cycloaddition studies [122]. 1,3-dipolar reaction of these dipolarophiles 89e91 with substitutedarylnitrile imines 75/92a,b resulted in the isolation of the desiredspiropyrazoline 93e97 in high yields (Scheme 13) [112e115,121,122].
In a similar fashion, additional chromanone and thio-chromanones (a,b-enones) 98aed reacted with phenylhydrazonylchloride 75 and the requisite spiropyrazolines 99aedwere isolatedin high yields. However, these cycloadducts were relatively unsta-ble and following anodic fluorination process furnished the ringfragmented pyrazoles 100aed [61]. Additional 1,3-dipolar reactionsof 98a,b with bis-nitrile imine 101 (in 2:1 molar ratio) resulted in
RO
O
CHOH
RO
O
CH2O, Na2CO3
acetone, 24h
62 63
Scheme 9. Synthesis of sp
the isolation of bis-spiropyrazoline-5,30-chroman-4-ones and bis-spiropyrazoline-5,30-thiochroman-4-ones 102aed respectively.The bis-nitrile imine has two 1,3-dipole sites and thus formation ofa bis-spiropyrazoline system is expected (Scheme 14) [62].
As an extension, oxothiopyrano[2,3-b]pyridine based 3-benzylidenes 104a,b were treated with diphenyl nitrile imine 75and 4-oxothiopyrano[2,3-b]pyridine derived spiropyrazolines wereisolated in modest yields 105a,b [123]. Molecules incorporatedwith a 4-oxothiopyrano[2,3-b]-pyridine unit 103a,b were reportedas potential antihypertensive agents (Scheme 15) [124,125].
Girgis and coworkers synthesized a few bisspiro[naphthalene-2(1H),30-(3H)pyrazol]-1-ones 112e114 and studied the issuesassociated with regioselectivity [126]. The intermediate bisnap-thalenones 109 and bisylidenes 110were prepared via treatment of4,40-(alkanediylbisoxy)bisbenzaldehydes 106 and 2,20-(alka-nediylbisoxy)-bisbenzaldehydes 107, with 3,4-dihydro-(2H)-nap-thalen-1-one 108 in ethanolic KOH solution. The bisnapthalenones109 upon cycloaddition process with nitrile imines generated in
OEtO
NCl
NH
Me
Et3N, toluene, reflux(or)
AgOAc, toluene, r.t RO
O
NN
CO2Et
Me
R = (a) Me, (b) Bn78-81%
64
65a-b
iropyrazoline-steroids.
O
O
H
R1
(C2H5)3N, toluene
O
ON N
R1
R2
16 examples50-90%
R1 = H, OCH3, CH3, NO2R2 = H, OCH3, CH3, NO2Cl
NN
H+
PhR2
O
R1 = H, OMe; R2 = Me, Ph, 4-ClPh, 4-NH2SO2Ph
R2NHNH2
NNR2
H
5 examples
+
R3
N
Cl
NH
TEA
NNR2
H
NN
R3
R1 = Ph; R2 = Me, 4-ClPhR3 = Me, COMe
66
67 68
69
70
71
72
71-85%
R1 R1
R2
R1
R1
R1
Scheme 10. Synthesis of indanedione and spirocyclopenta[c]-pyrazole derived spiropyrazolines.
Cl
NN
H+TEA/ CHCl3
R1 = H, Me, OMe, NMe2, Cl, NO2R2 = Ph, 4-ClPh, 4-MePh
62- 78%
OO
H
R1
OO
NN
H
R1
6 examples
O
N
O
H
R2 O
N
O
NN
R2 H
3 examples
(or) (or)
NNO
NOO
(or) TEA/ CH2Cl2+
Cl
NN
H
Br
NNO
NOO
(or)N N
PhBrN N
Ph
73 74 75 76 77
78 79 80 8281
58- 72%
Scheme 11. Spiropyrazolines synthesis via 1,3-dipolar cycloaddition.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 353
situ 111 furnished the dicycloadducts as major isomers 113 alongwith the formation of monoadducts 112 in minor amounts. How-ever, similar cycloadditions of bisylidenes 110 with nitrile imines111 proceeded to completion and the desired dicycloadducts 114 asa single regioisomer. Although not specified, the formation of one
O
HR1
TEA, r.t
O
NNR1
53-87%
3 examples
HR4CHCl3 (or) C6H6
83
85
86a-c
(a) R1 = Ph,(b) R1 = 4-MePh,(c) R1 = 4-NMe2Ph NTEA, r.t
57-90%
CHCl3 (or) C6H6
75
Scheme 12. Spiropyrazolines f
regioisomer 114 is owed to the ortho-alkoxy group effect, adjacentto the olefinic ylidene proton (Scheme 16) [126].
g-Substituted a-methylene-g-butyrolactones 116, a prevalentfeature for several natural products [127] are conveniently syn-thesized via Reformatsky reaction of a-bromomethylacrylic acid
Ph Ph
HR3
PhPh Ph Ph
PhPh
N NR3
HPh
N NR4
HPh
3 examples
3 examples
84a-c
87a-c
88a-c
(a) R3 = H,(b) R3 = Me,(c) R3 = Ph
ClN
H
75
TEA, r.t
56-92%
CHCl3 (or) C6H6
R4 = Ph, 4-ClPh, 4-MePh
rom bulky dipolarophiles.
R2 = H, 4-Me, 4-NO2, 4-OMe, 4-NMe2, 4-Cl, 3-F
O
H
R2 O
N N
R2
7 examples
O PhO
O H
Me
ONN
H
Me
O
O NN
Ph
R3
5 examples
89
90
93
9594
TEA, r.t
51-76%CHCl3 (or) C6H6
TEA, r.t
79%CHCl3 (or) C6H6
75
R3 = H, 4-Cl, 4-Me, 4-OMe, 4-NO2, 4-NMe2, 4-F
R1 75
R1 = H
TEA, r.t
59-84%CHCl3 (or) C6H6
ClN
NH
75
R1 = Ph
X
O H
RR = H, Me; X = C, O, S; R1 = Me, Ph
X
O
R
NNR1
ONO2HX
O
Ph
NNMe
HNO2
R1 N N CMe N N C NO2O NO2
5 examples91a-c
92b92a
9796
+
Scheme 13. Spiropyrazolines from various bulky dipolarophiles.
X
O H Cl
NNH
TEA / C6H6,reflux
X
O
N N
R
R = H, 4-Cl
R
X = O, S
75
98a: R = H, X =O98b: R = Cl, X =O98c: R = H, X =S98d: R = Cl, X =S
79-83% 4 examples
N N
Ph
Ph
R
O
F
O
(C2H5)4NF.4HF
58-88%
100a: R =H100b: R =Cl
-2e, -H+
isolated
NN
Ph
Ph
R
H
O46-88%
100c-d
R = H, 4-Cl
X = S
X = O
X
HO
+N
NN
N
R
R
X
ONN
R
HN N
R
X
O
H
R = H, ClX = O, S
Et3N
dry C6H6, reflux
62-75%
4 examples
98a-d99a-d
98a-b101
102a-d
Scheme 14. Chromanone and thiochromanone derived spiropyrazolines.
N S
O
ArCHO
N S
O
Ar
H
+
ClN
NH
TEA/C6H6
N S
ONN
ArAr = Ph, 4-ClPh103a-b
104a-b75
105a-b
57-60%
Scheme 15. 4-Oxothiopyrano[2,3-b]pyridine derived spiropyrazolines.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377354
AOHC CHO +
Oalc. KOH
AOO
61-87%+ N
Cl
NH
R
TEA/ C6H6
AON
N
OR
ANN
OR
NN
OR
+
minor major
a) R = H; A = 4-O(CH2)2O-4'b) R = H; A = 4-O(CH2)3O-4'c) R = H; A = 4-O(CH2)4O-4'd) R = Cl; A = 4-O(CH2)2O-4'
11-16% 65-73%
AOHC CHO alc. KOH
AOO
61-87%
TEA/ C6H6
a) R = H; A = 2-O(CH2)2O-2'b) R = H; A = 2-O(CH2)4O-2'c) R = Cl; A = 2-O(CH2)2O-2'
57-76%
106108
109
111
113a-d112a-d
107
108
110
111
4 examples
ANN
OR
NN
OR
major114a-c
3 examples
Scheme 16. Synthesis of mono- and bis-spiropyrazoline cycloadducts.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 355
115with substituted aldehydes [128]. An example that involved theapplication of g-substituted a-methylene-g-butyrolactones in spi-ropyrazoline synthesis were reported by Savage and coworkers[129]. The synthesized lactones 116 following reacted with nitrileimine 117 in a 1,3-dipolar fashion and furnished the spiropyrazo-lines 118 as a single isomer. However, in few cases, a mixture ofdiastereomers were isolated and the generation of a diastereomericmixture relied on the substituent employed by the lactone. Whilethe formation of an anti isomer presumably involved a transaddition (to the bulky R substituent), the syn isomer resulted fromthe cis addition (Scheme 17) [130].
In another report, 3-ethylidene-1-indanone was applied as asuitable dipolarophile and an array of spiropyrazoline derivativeswere prepared. 3-ethylidene-1-indanone 122 reacted several nitrileimines 121 in a 1,3-dipolar fashion and the corresponding
O
OH
Br
RCHOSnCl2/Amberlyst
THF/ H2Oreflux, 18h
O
O
R
R = (a) CH3, (b) Ph, (c) tBu, (d) 2,6-Cl2C6H3 N NO
anti
115 116a-d
+
Major
Me
R = Me, Ph, tBu,
Scheme 17. Synthesis of sp
spiropyrazolines 123 were isolated in modest yields (Scheme 18)[131].
3.2. Diaziridines
Diaziridines belong to the group of three-membered heterocy-clic ring systems and are considered as dinitrogen analogs foraddition reactions [99]. Limited reports documented the applica-tion of diaziridines as the reactions require activated substratessuch as ketenes, cyclopropenones and isocyanates to promote thereaction [132e135].
One report that documented the application of diaziridines inthe 1,3-dipolar cycloaddition process were reported by He andcoworkers [99a]. The methodology involved the gold(I) promotedapplication of diaziridine as a suitable 1,3-dipole with several
anhyd. THF, r.t.N N
N NO
O
O
R R
43-66%
Syn
Minor
C N N Me
Me
O
O
R
Me
2,6-Cl2C6H3 R = Me, Ph
117 118
iropyrazoline lactones.
NO
R1
ClHN
H3CO
Et3N, r.t. NO
R1
N+
R2
R1 = Me, Ph, PhNH, 2-C4H3O,2-C4H3S, 2-C10H7; R2 = H, Cl
R2Benzene, reflux
12-16hr
O
NN Me
O R1
R2
57-64%6 examples
119
121 122 123
NO
R1
Br HN
R2120
(or)
Scheme 18. Spiropyrazolines from 3-ethylidene-1-indanone.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377356
alkyne derivatives. The researchers envisioned a tandem eventwherein, a diaziridine would undergo ring fragmentation andfollowing react with alkynes in a concerted fashion to yield a spi-ropyrazoline. Treatment of substituted diaziridines 125 with phe-nylacetylene 124 in presence of Ph3AuNTf2 (10 mol%) provided aspiropyrazoline 126 as one isomer. Additional reactions of 125witharyl and aliphatic alkynes 127/128 proceeded in a similar fashionand a series of spiropyrazolines 129e130 were isolated in highyields. It was observed that electron deficient substrates resulted inthe higher isolated yields of spiropyrazolines. A plausible mecha-nism involved gold(I) promoted opening of the diaziridine ring 131and following insertion of an alkyne 133. The intermediate alkyne133 upon gold (I) intramolecular hydroamination pathway led tothe isolation of the spiropyrazoline cycloadduct 135 (Scheme 19)[99a].
3.3. Diazoalkanes and diazo derivatives
Diazoalkanes and related compounds are essential precursorsthat have found an array of potential applications in organic syn-thesis and methodology [136,137]. Reaction of a,b-enones andrelevant diazo based dipolarophiles is an efficient approach for thesynthesis of a wide variety of spiropyrazolines/spiro-1-pyrazolines.The synthesized spiro-1-pyrazolines have a tendency to undergospontaneous isomerization to yield the analogous spiro-2-pyrazolines [138].
+ NNBn Cbz
10 mol% ca
Toluene,50-70o
35-89%Catalyst: Ph3AuCl/ AgOTf, Ph3AuNTf2
NNBn CbzR2
Toluene, 18h, 70oC
N NBn
Cbz
R2
73-85%
Ph3AuNTf2
R2 = 3-Thiophenyl, Bn, 5-Methoxynapthyl, Cyclopentyl, 2-butyl
5 examples
NNBn Cbz
Mechanism:
Au+PPh3
NN
Cbz
Bn
Au+PPh3
R2
H +
R2H
Ph3PAu+
124 125
125
128
130
131 132
Scheme 19. Diaziridine based synthes
Licandro and coworkers reported the 1,3-dipolar reactions ofalkenylalkoxycarbene chromium complexes and synthesized a fewspiropyrazoline complexes 138 and 140 [97]. The exo-methylenebased chromium complexes 136 reacted with diazomethane in a1,3-dipolar fashion and furnished novel spiropyrazolines 138. Theexistence of an exo-methylene unit in 137 implied that the reactionis not chemoselective and the addition of dipole occurred at boththe carbonecarbon and carbonemetal double bond. With thepurpose of synthesizing additional Cr(CO)5 carbene complexes,alkene 139 was treated with Me3SiCHN2 (trimethylsilyldiazo-methane) which, because of its steric constraints, were expected todemonstrate selectivity for the exo carbonecarbon double bond.The reaction was carried out by heating the exo-methylene withMe3SiCHN2 under reflux conditions. The spiropyrazolines 140weregenerated as an inseparable mixture of three diastereomers(Scheme 20).
In another report, Ong and coworkers reported the synthesis ofa few organometallic iron complexes utilizing 1,3-dipolar cyclo-addition chemistry [94]. The alkene 141 was prepared by treatingtricarbonyl[4-methoxy-1-methylenecyclohexadienyl]iron hexa-fluorophosphate with triethylamine in THF. The synthesized alkene141 upon 1,3-dipolar reactionwith ethyl diazoacetate furnished thespiropyrazolines as a mixture of diastereomers 142 and 143. Thereaction was completely regio- and stereoselective and an attemptto access cyclopropane derivatives was unsuccessful as the 142e143 failed to undergo nitrogen elimination (Scheme 21).
talyst
18hC
N NBn
Cbz
Toluene, 18h, 70oC
N NBn
Cbz
73-95%
Ph3AuNTf2
R1
R1
R1 = H, Me, Br, OMe, Ph, CF3
6 examples
N BnN
Cbz
N NBn
Cbz
R2AuPPh3
N NBn
Cbz
R2H
H+
126
127
129
133 134 135
is of spiropyrazoline derivatives.
O(OC)5Cr
R2
R1 CH2N2
- 5oC, 10 min
O
R2
R1
NN
(OC)5Cr
air/ lightEt2O, rt
O
NN
R1 = Me, R2 = HR1-R2 = -(CH2)4-R1 = R2 = Me
R1-R2 = -(CH2)4-
O(OC)5Cr Me Me3SiCHN2
n-Hexane68oC, 6h
O(OC)5Cr Me
NN
52%Me3Si
136
137138
139 140
42%
74%3 examples
Inseparable mixture of3 diastereomers
Scheme 20. Synthesis of spiropyrazoline based chromium complexes.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 357
Bouillon and coworkers demonstrated the synthesis of 3-(2,2,2-trifluoroethylidene)-lactams and concomitant 1,3-dipolarcycloadditions utilizing diazomethane as a suitable dipole [139].3-(2,2,2-Trifluoroethylidene)-lactams 146 were prepared from thecorresponding 3-trifluoroacetyl-substituted lactams 144 viareduction and following dehydration of the generated alcohols.Treatment 3-trifluoroacetyl-substituted lactams 144 with sodiumborohydride in methanol resulted in the efficient generation ofalcohols 145 as a diastereomeric mixture. The generated di-astereomers 145 on following dehydration in presence of P2O5furnished the methylenes as an E-isomer 146. 1,3-Dipolarreaction of the synthesized alkenes 146 with diazomethaneresulted in regioselective annulation and furnished the spiropyr-azoline 147 as a single diastereomer. The spiropyrazoline 147 onfollowing heating furnished a cyclopropane analog 148 in 72%yield (Scheme 22).
Coffen and Bender developed a cycloaddition methodology andsynthesized a spiropyrazoline 151 incorporated with a quininemotif [140]. 6-Methoxyquinoline-4-carboxaldehyde 149 uponcondensation with 3-quinuclidinone [141e143] in presence of so-dium ethoxide, furnished a 60-methoxy-7-oxo-8-rubene 150. Thesynthesized rubene 150 possesses a double bond at C8eC9 positionand following treatment with diazomethane generated a
OMe
CH2
Fe(CO)3
OMe
CH2
Fe(CO)3Ethyl Diazoace
81%
141a 141b
(1.2:1) ratio
Scheme 21. Synthesis of a few spi
Nn
O
Me
F3CO
NaBH4
MeOH, 0-25oCNn
O
Me
F3COH
H
80-95% Nn
O
Me
F3C
P2O5
68-84%
H
n = 1-3
144145 14
Scheme 22. Synthesis of sp
spiropyrazoline 151 in high yields. Likewise, Chamissonin 152 alsoreacted with diazomethane and furnished a few spiropyrazolines153a,b in good yields [144]. Additional treatment of ethyladamantylidene-cyanoacrylate [145] 154 and substituted chiralenaminones 157aec [146e149] with diazomethane generated afew spiropyrazolines 155 and 158e159 in moderate yields. Theadamantine based spiropyrazolines [150e152] 155a/155b serve assuitable examples of sterically strained models for physical organicstudies (Scheme 23) [145e149].
Himmelreich and coworkers synthesized a few spiropyrazolinesincorporated with camphor or a borneol unit. These camphor orborneol derived spiropyrazolines 162 were prepared through a 1,3-dipolar reaction of an olefin 161 in presence of diazomethane [153].The heterocyclic ring with an azo group was optically active and theobserved rotatory strength was unusually high for ketones 162compared to the alcohols 163. In a similar fashion, 3-diazopiperidine-2-one [154] 166 reacted with electron deficient dipolarophiles andfurnishedseveral spiropyrazolines167 inhighyields. The synthesizedspiropyrazolines 167 on following nitrogen extrusion furnished thecyclopropane analogs 168 in very high yields (Scheme 24) [153,154].
A facile methodology to access ring fused alkylidenecyclopro-panes through Wittig olefination of bicyclo[n.1.0]alkanone N,O-hemiacetals were reported by Tokuda and coworkers [155]. 1,3-
tate
OMe
Fe(CO)3
OMe
Fe(CO)3+
NN
NN
H CO2EtHCO2Et142 143
ropyrazoline iron complexes.
CH2N2/ ether
0-25oCN O
Me
NNF3C
H
n = 1
160-170oCN O
Me
F3CH
46% 72%6 147 148
iropyrazoline-lactams.
N
MeO
O H
+
N
O
NaOEt
N
MeO
H
NO CH2N2
N
MeON
ONN
H
ROO
O
OR
R = H, Ac
CH2N2
ROO
O
OR
NN
X
O
MeO2C
NMe
Me
X = N-Boc, N-Bz, O
KCN, AcOH
r.t X
O
MeO2C
NN
NC
X
O
MeO2C
CN CH2N2, ether
0oC
3 examples
34%
TEA, Et2O
CH2N2
3 weeks
NN
NCCO2Et
CN
EtO2CN
HN
NCCO2Et
149150 151
152a-b 153a-b154 155a 155b
156a-c 157a-c
90% 88%
64%
X
O
MeO2C
NN+
NC
major minor(3:2)
(158:159)
overall43-67%
Scheme 23. Spiropyrazolines bearing 60-methoxy-7-oxo-8-rubene, chamissonin, adamantine and chiral enaminone motifs.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377358
Dipolar cycloaddition of alkylidenecyclopropanes 169 with diazo-methane furnished several spiropyrazolines 170 which, followingthermolysis resulted in ring enlargement and a series of cyclo-butanes 171 were isolated in excellent yields. The diazomethanebased 1,3-dipole approached the double bond stereospecificallyfrom the less hindered exo-direction. A plausible mechanisminvolved the formation of a diradical 173 (denitrogenation)which, following rearrangement resulted in the fragmentation of acyclopropane and generated the ring enlarged derivatives 171(Scheme 25).
9-Diazoxanthenes are interesting 1,3-dipoles utilized in organicsynthesis andhave the ability to undergo various addition reactions inorganic synthesis. The greater reactivity of 9-diazoxanthenes is owedto the electron donating ability of the g-pyranyl moiety on to its diazofunction. Addition of 9-diazoxanthene 174 to dimethyl acetylenedi-carboxylate in a 1,3-dipolar fashion generated a spiropyrazoline; 4,5-dicarbomethoxyspiro[3H-pyrazole-3,90-xanthene] 175 in 82% yield[156]. Thermal and photochemical extrusion of nitrogen of 175resulted in the isolationof apyranderivative176or its tautomer(s)177a,b than desired cyclopropane analog 178. However, cycloaddition of9-diazoxanthene 174 with methyl acrylate proceeded to completionand generated a spiropyrazoline 179 which, following nitrogenextrusion furnished the spiro[2-carbomethoxycyclopropane-1,90-xanthene] 181 and its isomer 3-carbomethoxy-spiro[2]-pyrazoline-5,90-xanthene 180. Similar to 9-diazoxanthene, substituted styrenes
O Oa) diethyl oxalateb) CH2O CH2N2
160 161
H2NNH2
OHO
Alumina
toluene, 1.5hreflux
NH
NH2
O
iso-amyl nitrite
CHCl3, AcOH15 min.
R = OMe, Me, H; R1 = Me, H
164 165quantitative 60%
Scheme 24. Synthesis of piperidinone an
182 also reacted rapidly to give spiropyrazolines 183a,-b andconcomitant cyclopropanes 184. The greater reactivity of styrenes isowed to the electron-rich or electron-deficient substituents mountedon the styrene ring. While the electron-deficient substituentsaccelerated the rate of the 1,3-dipolar reaction, electron-richsubstituents retarded the reaction to a greater extent (Scheme 26)[156].
Pocar and coworkers reported the synthetic application of 5-amino-1-aryl-4,5-dihydro-4-methylene-1,2,3-triazoles. These tri-azolyl derivatives with an exocyclic olefin are stable, highly reactiveand exhibited a low tendency to undergo isomerization process[157].1,3-Dipolar cycloaddition of these triazolyl dipolarophiles 185with excess of diazomethane derivatives furnished the spiropyr-azoline cycloadducts as single diastereomers 186. However, addi-tional reactions of triazolyl dipolarophiles 188 with diazoethaneresulted in the isolation of spiropyrazolines as a mixture of epimers189. The synthesized spiropyrazolines 186/189 upon thermolysisresulted in the extrusion of nitrogen and provided several cyclo-propane analogs 187/190. Additional reaction of alkene 191 withdiazopropane generated a spiropyrazoline 192 that following ringcontraction yielded a cyclopropane 193. Presence of two methylsubstituents or aryl moieties resulted in a greater stability of theisolated spiropyrazolines. These triazolyl based olefins were highlyreactive and acted as an electron deficient center. The cycloadditionwas highly regiospecific as the incoming 1,3-dipole approached
ON
NN
NNaBH4
HO
162 163
NH
N
O
N[2+3]
NH
O
NN
R1 R
O
NH
OR1
R
O
67-95% 75-99%
166167 168
d camphor derived spiropyrazolines.
R1R2
xx = 1, 2
CH2N2, ether, r.t
3 daysx
NNR2
R1
o-Xylene, heat
-N2 x
R1R2
x
H2CN
N
x
NNR2
R1
-N2
x
R2R1
xx = 1, 2
Mechanism
169 170
171
172 170 173 171
95-99% 85-98%
R1 R2
R1 = H, Me, CH2-CH=CH2; R2 = CO2Me, CO2Et
R1 R2
Δ
Scheme 25. Spiropyrazolines from alkylidenecyclopropanes and bicyclo[5.1.0]oct-8-ylidenes.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 359
from the less-hindered diastereotopic side of the olefin leading tothe formation of an exo-adduct (Scheme 27) [157].
The macrolide antibiotic erythromycin A and corresponding 3-ketolides were found to display activity against erythromycin-resistant strains [158,159]. The SAR studies of these 3-ketolidesrevealed that a cyclic carbamate group at C-11,12 on the ketolideis a requisite for displaying such pathogenic activity [160]. Hu andcoworkers reported the synthetic modifications of the ketolideanalogs bearing a C-12 pyrazolinyl moiety [161]. The ketolide pre-cursor 195 required for the cycloaddition protocol was prepared infew steps from the starting material 194. Treatment of the olefin
O
N2
CO2Me
CO2Me
O
NN CO2Me
CO2Me
Thermal/ photochem
elimination
O
CO2MeO2C
Expected prod"Not Observe
O
N2CO2Me
O
NN
CO2Me
waming/ he
H
O
N2
O
NN
CH2+
R = 4-OMe, 4-Br, 4-Me, 3-Br, 4-H, 4-Cl
R
174 175
174 179
174182
18
82%
quantitative(1:1.65) rat
Scheme 26. 9-Diazoxanthene and st
195 with several diazo derivatives furnished the intermediate spi-ropyrazolines 196aed in excellent yields. Removal of the C-9,11hydroxyl protecting group in presence of PPTS (pyridinium p-tol-uenesulfonate) generated the intermediate diols 197aed thatfollowing DesseMartin periodinane oxidation and benzyl depro-tection steps furnished the final products in moderate yields 198aed [161]. The synthesized spiropyrazolines were prone to undergospontaneous isomerization from D1-pyrazolinyl 196 to the analo-gous D2-pyrazoline 197. The tautomerism is likely to be induced bythe p-toluenesulfonic acid being ionized from pyridinium p-tolue-nesulfonate (PPTS) (Scheme 28) [162].
ical
H-Migration
O
H
CO2MeMeO2C
57%
O
CO2MeMeO2C
O
CO2MeMeO2C
(or)
H
H
Me
uctd"
ating
O
CO2MeH
H H
+O
NHN
CO2Me
O
H
H H
R
O
NN
R
H -N2
R
176
177a
177b
178
181 180
3a 183b
184
6 examples
io
27-73%
yrene derived spiropyrazolines.
N NN
H NR1
NO2
H2C
N NN
H NR1
NO2
NN
R1 = NMe2, NEt2, Morpholino, Piperidino
N NN
H NR1
YH2C R2R3CN2
N NN
H NR1
Y
NN
R1 = NMe2, NEt2, Morpholino, PiperidinoR2 = H, Me; R3 = H, Me; Y = Cl, NO2
N NN
H NR1
NO2110oCEther:CH2Cl2
R2
R3110oC
inseparable mixtureof epimers (~1:1)
N NN
H NR1
NO2
R2
R3
R4
R5
epimer ratio4:1
N NN
H N
NO2
H2C Me2HCN2
N NN
H N
NO2
NN
N NN
H N
NO2Ether:CH2Cl2Me
Me
MeMe
MeMe
MeMe
185186
187
188 189 190
191 192 193
56-93% 68-95%
4 examples 4 examples
61-80%33-70%
22%82%
CH2N2
MeMe
Scheme 27. Triazole derived spiropyrazoline and spirocyclopropane derivatives.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377360
Jonckers and coworkers reported the synthesis of 20-deoxy-20-spirocyclopropylcytidine as a new and selective inhibitor of thehepatitis C virus NS5B polymerase [72]. The olefin 200 utilized inthe cycloaddition based methodology were accessed in a few stepsfrom the precursor uridine 199. The N3-atom of the pyrimidine 200was benzoylated and the target was achieved through a 1,3-dipolarcycloaddition of diazomethane on the vinylic precursor 201, andthe spiropyrazolines were isolated as a mixture of isomers 202 a,b.The spiropyrazoline mixture 202 a,b upon further light inducednitrogen extrusion process provided a cyclopropane analog 203 in84% isolated yield (Scheme 29).
Robins and Samano described an efficient synthesis of 20-deox-yadenosine-20-spirocyclopropane and corresponding spirocyclopro-pane analog via 1,3-dipolar cycloaddition strategy [73]. Treatment of30,50-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diy1)-20-deoxy-20-methyleneadenosin 204 with excess of diazomethane resulted inannulation and a mixture of 20-deoxynucleoside-20-spiropyrazoline
O
O
HOOMe
O
HOO
O
O
HO
OHOMe
N
O
O
OOMe
O
O
O
BnON
O
HO
HOOMe
O
O
O
BnON
NHN
Clarithromycin
4 steps
R
PPTS
MeCN, H2O
R = H, Me, CO2Et, CO2Me
194
195
197a-dPyrazoline ring Tautomerism
Scheme 28. Synthesis and tautomeris
diastereomers 205 and 206 were isolated. The diazomethaneapproached from the less hindered a-face of the olefin and fur-nished 205 as a major isomer. Benzophenone-sensitized photolysisof the spiropyrazoline derivatives in acetonitrile/benzene (1:1) fur-nished the 20-spironucleoside 207 in excellent yields. In case ofspiropyrazolines protected with TBDMS group, deprotection wasachieved using (TBAF/THF) to give 20-deoxyadenosine-20-spi-rocyclopropane in 90% yield (Scheme 30) [73].
Msaddek and Hamidi treated (E)-benzylidene-N-arylsuccini-mide 208 and (E)-benzylidene-N-arylmethylsuccinimide 209 with2-diazopropane and synthesized several spiropyrazoline racemates210/211 [163]. (E)-Benzylidene-N-arylsuccinimide 208 and (E)-benzylidene-N-arylmethylsuccinimide 209 intermediates wereprepared via condensation of araldehydes with correspondingylides. The intermediates 208e209 upon 1,3-dipolar cycloadditionin presence of diazopropane furnished the desired spiropyrazolines210/211 in good yields. Irradiation of the cycloadducts 210 at 0e5 �C
RCHN2/ Et2O
O
O
OOMe
O
O
O
BnON
a) Dess-Martin Periodinane/ DCMb) MeOH/ reflux
70-98%NN
R
O
O
HOOMe
O
O
O
HON
NHN
RR = H, Me, CO2Et, CO2Me
32-38%
196a-d
198a-d
m of spiropyrazoline-macrolides.
N
NH
O
OOHO
HO OH
N
NH
O
OOOSi
Si OO
BzCl, Hunig's base
DCM, r.t., 12h86%
N
N
O
OOOSi
Si OO
CH2N2, ether
r.t., 48h, 84%
N
N
O
OOOSi
Si OO NN
N
N
O
OOOSi
Si OO NN+
hv, C6H5CH3/MeCNBenzophenone, r.t.,
3h, 84%
N
N
O
OOOSi
Si OO
3 steps
O
O
O O
199 200201
202a 202b203
Scheme 29. Spiropyrazoline and concomitant spiropcyclopropane synthesis.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 361
led to the isolation of gem-dimethylcyclopropane analogs 212(Scheme 31) [163].
Shanmugam and coworkers reported a versatile BayliseHillmanadduct based cycloaddition methodology and synthesized an arrayof spiropyrazoline derivatives (spirooxindolepyrazolines) stereo-selectively [164]. The desired 3-spiropyrazole-2-oxindoles 214were accessed via 1,3-dipolar reaction of BayliseHillman adducts213 with several diazo derivatives. Treatment of the bromo allylderivative of 1-methyl isatin 213 in acetonitrile with Me2S, diethylazodicarboxylate (DEAD) and K2CO3 afforded the 3-spiropyrazole-2-oxindole 214 in 73% yield. Additional reactions of substitutedBayliseHillman adducts with diazo compounds afforded the cor-responding spiropyrazolines in good yields. Bromo allyl basedBayliseHillman adducts substituted with electron deficient formyland fluorine groups favored the cycloaddition process than electronrich substituents. Additionally, Bennett and coworkers also studiedthe regiospecific behavior of enedicarbonyl compounds 215 bytreating them with several diazoalkanes of specific interest [165].Treatment of the acrylates 215 with diazomethane proceeded in a1,3-dipolar fashion and provided the spiropyrazolines 216 inmodest yields. The synthesized spiropyrazolines 216 upon heatingresulted in denitrogenation and generated the corresponding spi-rocyclopropane analogs 217. Additional reaction of acrylate withphenyldiazomethane also furnished the requisite spirocyclopr-opane as a single diastereomer (Scheme 32) [164,165].
In another report, Aoyagi and coworkers [82] treated 3-phenacylideneindolin-2-ones 20 with diazomethane and isolated
O
OR1
RO
CH2
B
CH2N2/Ether O
OR1
ROB
NN
+
Reagents and Conditions: (a) hv/PhC(O)Ph/MeCN/C6H6; (b)PhO(S)Cl/DMAP/MeCN; (f) Bu3SnH/AIBN/C6H6/
204205
(a-d): R = R1 = TPDS; (e): R = R1 = H; (f) R = TBDMS, R1 = H(a) B = adenin-9-yl, (b) B = uracil-1-yl, (c) B = 3-N-benzoylurac
88%
Scheme 30. Synthesis of 20-deoxyn
a few spiropyrazolines 218a,b. The synthesized spiropyrazolinesupon thermal heating resulted in nitrogen extrusion and the cor-responding cyclopropane analogs 219a,b were isolated in highyields. However, cycloaddition of 3-(a-nitro)ethylidene-indolin-2-one 220 with diazomethane and following treatment withalumina resulted in the elimination of a nitro group and a meth-ylated spiropyrazoline 222 was isolated (Scheme 33).
Liebscher and coworkers studied the 1,3-dipolar cycloadditionsof 5-alkylidene-1,3-dioxane-4-ones 223 and 5-benzylidene-1,3-dioxan-4-ones 230 as suitable precursors toward the stereo-selective synthesis of cyclopropane derivatives [166e168]. Themethodology involved the application of 5-alkylidene-1,3-dioxane-4-ones and 5-benzylidene-1,3-dioxan-4-ones which, followingcycloaddition with diazomethane furnished several spiropyrazo-lines (224, 227 and 228) [167,168]. The synthesized spiropyrazo-lines 224 upon irradiation resulted in the extrusion of nitrogen anda few cyclopropane analogs 225 were isolated. A few 5-arylidene-1,3-dioxanones 226 were found to be less reactive, required pro-longed reaction times, and furnished the spiropyrazolines as amixture of diastereomers 227a,b. Additional cycloaddition re-actions of ethylidene derivative 223a with trimethylsilyldiazo-methane and ethyl diazoacetate at higher temperature conditionsgenerated the cycloadducts; 1-spiropyrazolines 228a and 2-spiropyrazolines 228b respectively [168].
As an extension, enantiomerically pure benzylidene-b-lactones230 were treated with diazomethane in a 1,3-dipolar fashion and afew spiropyrazolines 231 were isolated as a single diastereomer.
O
OR1
ROB
NN
O
OR1
ROB
NH3/MeOH (c) TBAF/THF; (d) TBDMSCl/imidazole/DMF; (e)
206 207
conditions
; (g) R = TBDMS, R1 = C(S)OPhil
7 examples4%
a-f
63-92%
ucleoside-20-spiropyrazolines.
N
H
R2
O
O
R1
NMe
MeN
Et2O, -78oC
N
O
O
R1
NN
R2
Me
Me
N
O
O
R1
MeMe
hv0-5oC
H
R2
N
H
R2
O
O
R1
NMe
MeN
Et2O, -78oC
N
O
O
R1
NN
R2
Me
Me
Me Me
R1 = R2 = H, OMe4 examples
4 examplesR1 = R2 = H, OMe
40-80%
40-65%
45-75%208 210212
209 211
Scheme 31. Spiropyrazolines from substituted (E)-benzylidene-N-succinimides.
NO
R1
R2
Z1Br
+ N N Z3Z3Me2CO3, K2CO3
MeCN, r.t.N
O
R1
R2
NN
Z1
Z3
Z3
66-91%
R1 = Me, Propargyl, BenzylR2 = H, CHO, FZ1 = CO2Me, CNZ2 = CO2Et, CO2CHMe2, COCMe3
NH
O
XEtO2C
RCHN2
NH
O
NN
X
RCO2Et
NH
OXCO2Et
R
X = H; R = H, Ph
68%
213
214
215216
217
13 examples
62%
Scheme 32. Synthesis of 3-spiropyrazole-2-oxindole derivatives.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377362
The configuration at the pyrazoline ring of the spiro-b-lactonewereopposite to those of the spiro-1,3-dioxanone. When observed, thedipole (diazomethane) approached from the top-face of the diox-anone and the presence of symmetrically placed 4-methyl grouphampered the attack from the b-face (Scheme 34).
Another following report from this group demonstrated theapplicability of 5-ylidene-1,3-dioxane-4-ones and a few opticallyactive trans-3-amino-2-pyrrolidones 233 were isolated via hydro-genolytic ring transformation of the intermediate spiropyrazolines.The spiropyrazolines 224 accessed via 1,3-dipolar cycloadditionunderwent reductive NeN cleavage and provided a novel route tosynthesize 4-substituted trans-3-amino-2-pyrrolidones 233 dia-stereoselectively (Scheme 35) [167].
HN
O
CH3
O
CH2N2
HN
O
NN CH3
O
HN
O
Me
CH2N2HN
O
NNNO2
NOM
55%
20a 218b
220221
NN
(or)
2
HN
O
O
(or)
20b
90-92%
Scheme 33. Synthesis of spirop
Yet another report documented the application of a-alkylideneor d-lactones as suitable templates in the construction of a-spi-rocyclopropyl-g-butyrolactones [168]. The intermediate spiropyr-azolines on following N2 elimination provided a useful route toaccess a-amino-a-(u-hydroxyalkyl)-g-butyrolactams. Treatment ofoptically pure a-alkylidenelactones 234 with diazomethane(method A) or trimethylsilyldiazomethane (method B) proceededsmoothly and furnished several spiropyrazolines 235a,b. However,when 234 were substituted with dibenzylaminopropylidene, thereaction resulted in the deprotection of TMS group to provide 237.The synthesized spiropyrazolines 235a,b on following light irradi-ation resulted in the isolation of a-spirocyclopropyllactones 236a,bas a single isomer (Scheme 36) [168].
HN
Oheat
60-80%
O
Al2O3/C6H6
2e
HN
O
NN
Me82%
219b
222
HN
OO
18b
HN
OCH3
O219a
(or)
yrazole-2-oxindole analogs.
quantitatived.r. > 95:5
hv, 330 nm
quantitatived.r. > 95:5
O O
R2
O
R1
R3CHN2R1 = Me, Et, i-Pr, Ph, 3-OMePh,R2 = t-Bu, c-Hex, R3 = H, Me, TMS
O O
R2
O
NN
R1 HR3
Et2O, 0-20oCC6H6/ MeCN
O O
R2
O
R1 R3
O O
tBu
O
R1
R1 = Me, Et, i-Pr, Ph, 3-OMePh
O O
tBu
OEt2O,0oC-r.t, 20h
CH2N2 O O
tBu
ONN
NNH
R1 R1H
+
73-80%
O O
tBu
O
MeDCM, 10 kbar
EtOOCCHN2O O
tBu
O
NN
Me HEtO2C
TMSCCHN2O O
tBu
O
NN
Me HTMS
H
223 224 225
226227a 227b
228a223a 228b
O O
R2
O
3N HCl/ THF, 78%
MeSCl/ DCM/ NaHCO3
1-3h, 0oC-r.t.
OO CH2N2/ Et2O
0oC-r.t., 20h
OO
NN
H
229
230231
48-99%40-99%
94%97%
89%98%
Scheme 34. Spiropyrazolines from 5-alkylidene-1,3-dioxane-4-ones and 4-benzylidene-b-lactones.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 363
Bernabe and coworkers reported an elegant methodology to-ward the enantioselective synthesis of (þ)-(1R,2S)-allocoronamicacid (ACC) 244 via intermediate generation of a spiropyrazoline as akey precursor [169,170]. The diketopiperazine 239 required for themethodology was accessed from the corresponding (Z)-phenyl 4-propylidene-5(4H)-oxazolone 238. Benzoyl deprotection andfollowing Boc-protection/acylation furnished the protected dike-topiperazines 241a,b. 1,3-Dipolar reaction of diketopiperazines241a,b with diazomethane furnished a spiropyrazoline as a singlediastereoisomer 242a,b which, following photolysis generated afew cyclopropanes 243a,b in excellent yields. Acid hydrolysis ofspirocyclopropane 243a resulted in the isolation of the desired(þ)-(1R,2S)-allocoronamic acid 244 in 66% yield [169,170].
As an addition, asymmetric synthesis of 1-amino-2-phenylcyclopropanecarboxylic acid 249 via diastereoselectivecyclopropanation of highly functionalized homochiral olefin de-rivatives 246 were achieved [171]. Treatment of (Z)-2-methyl-4-benzylideneoxazolone 245 with L-proline and following cycliza-tion furnished a diketopiperazine 246 in 72% yield. 1,3-Dipolar re-action of the diketopiperazine with diazomethane, and followingphotolysis generated a cyclopropane analog 248. Acid hydrolysis ofthe synthesized cyclopropane 248 gave the corresponding (þ)-1-amino-2-phenylcyclopropanecarboxylic acid 249 in high yields(Scheme 37).
a,b,a,g-Unsaturated ketones are potential intermediates in thesynthesis of styryl derived spiropyrazolines and a few examples
R = Me, Et, i-Pr, Ph,
O O
tBu
OO
R
CH2N2O O
tBu
OO
NNR
H
H2/ Raney NI
223 224
Scheme 35. Application of spiropyrazoline precur
include 2-cinnamylidene-1-indanones, -1-tetralones, and benzo-suberones [139]. Chromanone, and flavanone derivatives 250reacted with trans-cinnamaldehydes 251 and generated the cor-responding exocyclic olefins 252 in 66e83% yields. 1,3-dipolar re-action of diazomethane with (E)- and (Z)-isomers of an exocyclicolefin 252 generated the spiropyrazolines 253 wherein, themethylene unit of the diazomethane was connected to the b-car-bon atom of a,b-enone. Additional cycloadditions of E-2-Arylidene-1-indanones 254 [172], a,b-unsaturated ketones 255, and 2-arylidene-1-benzosuberones 258/259 [173,174] with diazo-methane proceeded in a similar fashion and generated the desiredtrans-spiropyrazolines 256e257/260e261 in good yields. Theoutcome of the cycloaddition was completely regio- and stereo-selective (with respect to the six and seven-membered rings) andthe presence of a bulky 1-napthyl or 2-napthyl group had no in-fluence on the overall cycloaddition process (due to the freerotation of the napthyl group). However, the presence of a 1-napthyl group at 2-position imposed a greater effect (strong ste-ric hindrance originated from the very hindered rotation) andfailed to furnish the cycloaddition products [139,172e174]. Addi-tional reactions of Z-3-arylidene-1-thioflavanones 262 withdiazomethane and following denitrogenation of the cycloadduct263 furnished a methylene analog. The formation of a methyleneanalog 264 could have originated from that regioisomer, whereinthe methylene unit was linked to the b-carbon atom of the pre-cursor (Scheme 38) [95].
O O
tBu
OONH2R
H NH2
NH
NH2
O
R
NH
O
R NH2
232a 232b 233
62-96%
sors to access trans-3-amino-2-pyrrolidones.
O O
R O O
NN
O O
NN
HR
TMSH
RMethod A: Et2O/ -20-0oCMethod B: toluene, reflux, 2h
Method A: Et2O/ -20-0oCMethod B: toluene, reflux, 2h
CH2N2
R = Bn2NMe
O O
NN
Me
Bn2N OO
MeMe
OO
R =OBn
OHMe
NBn2
4 examples
2 examples
76%
62-92%
87-89%
TMSCHN2DCM/hexane10 Kbar, 48h
hv/ MeCN
68-95%
hv/MeCN
43%
O O
O O
TMS H
R
R
H
234
235a
235b
236a
236b
237
Scheme 36. Spiropyrazoline based cycloaddition reactions to a-alkylidene or d-lactones.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377364
Boukamcha and coworkers studied the cycloaddition reactionsof 2,5-dibenzylidene-cyclopentanone 265 with diazopropane[175e177]. In addition to the expected bis-cycloaddition products266/267 (1:9 ratio), a new spiro-(1,3,4)-oxadiazole 268was isolatedin high yields. The formation of a new spiro-oxadiazole 268 isascribed to the inverse addition of dipole on to the carbonylgroup. The minor syn cycloadduct 266 were relatively unstablewhich, following spontaneous transformation generated an ethyl-idene 269. The synthesized gem-dimethyl spiropyrazoline diaste-reomer 267 (major cycloadduct) upon treatment in anhydrous
NO
O
Ph
a) NaOH, S-ProlineH2O-acetone, r.t. 24hb) Ac2O, r,t,, 12h
NN
Bz
O
OH
Reagents and conditions: (a) Glycine-methylester hydrochloride, TEA, Et2O, r.tr.t., 12h; (d) CH2N2, benzene, r.t., 3 or 8d; (e) hv, benzene, 7h (f) 1). 6N HCl-AcO
a
NN
R
O
OH
NN
eN
N
R
O
OH
f
(3'S, 4'S, 7aS) (1'R, 2'S, 7aS)R = AcR = Boc
R = AcR = Boc
238239
242a-b 243a-b
NO
Me
O a) NaOH, S-ProlineH2O-acetone, r.t. 12h;b) Ac2O, r.t. 48h N
N
Ac
O
OH
Ph CH2N2
C6H6, r.t. 3
6N HCl-AcOH
24h, 70% NH3
CO2H
Cl
245246
249
50% 35%
quantitative 66%
72%70%
Scheme 37. Synthesis of allocoronamic acid and 1-amino-2-phenylcyclo
dichloromethane resulted in the photochemical extrusion of ni-trogen and provided a bis-cyclopropane analog 270 (Scheme 39)[175e177].
Kopf and coworkers studied the chlorination reactions of thesynthesized spiropyrazoline diastereomers [178]. The spiropyr-azoline diastereomers (4:1 or 5:1 ratio) were accessed via 1,3-dipolar cycloaddition of the substituted arylidenes 271aef inpresence of diazomethane. Treatment of these major isomers272aef with excess chlorine generated the dichlorinated products274aef in 63e84% yields. However, in case of spiropyrazolines
NN
H
O
OH
. 12h; (b) Ac2O, 130oC, 12h; (c) TEA, DMAP, (tBuCO2)2O, CH2Cl2 (argon),H, 100oC, 2d; 2). Amberlite CG-120 (Na+ form)
b (or) c NN
R
O
OH
d
CO2H
NH2 HCl
R = AcR = Boc
(+)-allocoronamic acid(1R, 2S)
240 241a-b
244
dN
N
Ac
O
OH
NN
Phhv, C6H6, 7h
NN
Ac
O
OH
Ph
247 248
75%
90%
propanecarboxylic acid via spiropyrazoline intermediate formation.
X R1
O
+
HCHO
HR2
10% KOH/EtOH
r.t. 3h68-93%
X R1
O H
H
R2
X = O, S; R1 = H, Ph; R2 = H, OMe, NO28 examples
CH2N2
4oC, 48h71-86%
X R1
ON N
H
H R2
8 examples250 251 252 253
OH
R1
O
NN
R
R1 = 4-Me, 2-OMe, 3-OMe, 4-OMe, 4-F, 2-Cl, 3-Cl, 4-Cl8 examples
254 256
X R2
O H
Ar CH2N2
X = CH2, S, O; R2 = H, Ph; Ar = Ph, 3-i-PrPh, 4-NO2Ph,4-OMePh, 4-BrPh, 1-Napthyl, 2-Napthyl
12 examples255
257
S Ph
O
Ar
H
CH2N2
S
ON N
PhH
Hcis
Ar
Htrans
-N2
S Ph
O
Ar1
Me73-83% 51-74%
9 examples 5 examplesAr = 2-MeC6H4, 3-MeC6H4, 4-MeC6H4,4-iPr-C6H4, 2-Cl-C6H4
X R2
NN
H
Hcis
Htrans
Ar
O69-93%
262263 264
OH
R CH2N2
O NN
H R
Hcis
Htrans
71-87% OH
ArCH2N2
O NN
HAr
Hcis
Htrans
82-87%12 examples 2 examples
Ar = 1-Napthyl, 2-NapthylR = 2-Me, 4-Me, 4-iPr, 2-OMe, 3-OMe,4-OMe, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br, 4-CN
258 260259 261
CH2N2
74-86%
Scheme 38. Synthesis of six and seven membered spiropyrazoline ring systems.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 365
substituted with chlorine 272b, a tetrachloro derivative 275 wasgenerated that following nitrogen extrusion afforded a cyclopro-pane analog 276. Likewise, other spiropyrazolines 274aef under-went nitrogen elimination process and the desired cyclopropanes277aef were isolated in excellent yields (Scheme 40) [178].
O
Me2CN2
ONN NMe
Me
H HHHa
b
ONNMe
Me
H HHa
b
10%
90%
265
266
267
Scheme 39. Bis-spiropyrazolines from
Martin and coworkers synthesized several novel spiropyrazo-lines 279a,b and concomitant cyclopropane analogs via a 1,3-dipolar reaction of several a,b-unsaturated 2-arylidene-1-tetralones 278a,b with excess of diazopropane [175,179]. The twofaces of 2-arylidene-1-tetralones are sterically equivalent and a
NMe
Me
NN
H
MeMe NN
NNMe
Me
H HHa
bPh Me
Me
90%
O NN
MeMe
Me2CN2 0oC
DCM
ONNMe
MeH H
HHa
b iPr
spontaneously
0-10oC57%
74%
hv/ DCM92%
a
OMe
MeH H
HHa
b Me
Me
c
269
268
270
Δ
2,5-dibenzylidenecyclopentanone.
O
Ar Ar
n n = 0,1
CH2N2
O
n
NN
NN
Ar
O
n
NN NN
Ar
Ar
+
ArAr = a) Ph, b) 4-ClC6H4, c) 4-OMeC6H4
major
minor
Cl2O
n
NN
NN
Ar
ArClH
ClH
ON
N
NN
Ar
Ar
Cl2, 0oC
ON
N
NN
Ar
ArClCl Cl
Cl 60oC
O
Ar
Cl
ClCl
Cl
HH
Ar
n = 0,1Ar = Ph, 4-ClC6H4
O
n
NN
NN
Ar
ArClH
ClH
EtOH
60oC
O
n
Cl
H
H
Ar
H
ClArH
86-91%Ar = 4-ClPh
3 examples271a-c; n = 0271d-f; n = 1
272a-f
273a-f
274a-f
272b
275
276
274a-f277a-f
Cl2, 0-60oC
(4:1) or (5:1)ratio
63-84%
Scheme 40. Spiropyrazolines from cyclohexanone and cyclopentanone.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377366
possible diazopropane attack would result in the generation ofenantiomers as a racemic mixture. Additional reactions of the tet-ralone 281a,b with excess of diazopropane also gave spiropyrazo-lines 282/283 as a mixture of diastereomers. Although, the mixtureof diastereomers were generated due to the attack of diazopropaneon both faces of the dipolarophile, it preferentially attacked on theless hindered face leading to the formation of a major cycloadduct.The synthesized spiropyrazoline adducts 279, 282a,b on irradiationin dry dichloromethane led to the isolation of spiro-gem-dime-thylcyclopropanes 280 and 284 which, represented a prevalentfeature for many natural products (Scheme 41) [179].
O
R
R = H, OMeTetralones
CH2Cl2, 0oC
N NMe
Me
O
O
R
R = H, OMeTetralones
CH2Cl2, 0oC
N NMe
Me
Me
major
O
Me
CH2Cl2, hv58-65%
278a-b 279a-
281a-b
69-72%
18-82%(4:1) ratio
Scheme 41. Spiropyrazolines from a,b-u
Toth and coworkers reported the synthesis and acid promotedstructural properties of a few spiropyrazoline isomers [180]. Thesynthesized flavanone and chalcone derived spiro-1-pyrazolines287/288 isomerized to the corresponding spiro-2-pyrazolines289/290 on long standing in CDCl3 solution. As the spiro-1-pyrazoline 287/288 / spiro-2-pyrazoline 289/290 rearrangementis an acid catalyzed process, the observed tautomerism wereaccelerated to a greater extent with the addition of trace amountsof acid (preferably trifluoroacetic acid) to the CDCl3 solution. In caseof chalcones 291/292, addition of a small amount of trifluoroaceticacid (TFA) to the CDCl3 solution of the cis 293 and the trans isomer
NN
R
ONN
R
CH3(a)CH3(b)
Me
ONN
R
CH3(a)
CH3(b)+
Me
CH2Cl2, hv
-N2
R
O
R
-N2
b
280a-b
282a-b 283a-b
284a-b
43-54%
nsaturated 2-arylidene-1-tetralones.
X R
HO
X R
H
O
CH2N2X R
ON N
HH+ X R
ON N
H
H
CH2N2X R
ON N
H+ X R
ON N
H
H H
X = O, S; R = H, Ph
X = O, S; R = H, Ph
HO
CH2N2
ON N
H
ON N
H
H
n n n
n = 0, 2
O H
hv
R
CH2N2
TFA
TFA
285
286
287
288
289
290
291 293295
ON N O
N NH
n n
294
296
RR
R R
R
R = H, Cl
H H
292
Scheme 42. Acid catalyzed tautomerism of spiropyrazolines.
O
S
CO2PMB
OCH2N2
(1:7)
O
S
CO2PMB
NN
HO
O
S
CO2PMB
NN
HO
+
hv
O
S
CO2PMBH
O
56%
28%
O
S
CO2PMB
E-isomer
Z-isomer
O
CH2N2
28%
O
S
CO2PMB
NN
HO
+
O
SNN
HO
N NPMBO2C
inseparable mixture
hv
O
S
CO2PMBH
O
PMB = para-methoxybenzyl
O
S
HO
N NPMBO2C
+71%inseparable
mixture
297
298a
298b
299
300
301a
301b
302a
302b
minor
major
Scheme 43. Spiropyrazolines from 6-spirocyclopropyl penems.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 367
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377368
294 lead to the conversion of cis to trans 295 and trans to cis isomers296 respectively (Scheme 42) [181,182].
Guest and coworkers reported the synthesis of 6-spirocyclopropyl penems that rendered 1,3-dipolar cycloadditionreaction as an essential step [183]. Treatment of E-furylmethylenepenem 297 with diazomethane proceeded slowly and a mixture ofspiropyrazolines 298a,b (resulted from a, and b-attack of theexocyclic bond)were isolated. Thermolysis of themajor isomer 298bresulted in the extrusion of nitrogen and a spirocyclopropane analog299was isolated inmodest yields. Delivery of the dipole to themoresterically hindered b-face resulted from the consequence of a func-tional group reagent directing effect that involved the penem sulfuratom. Similar reaction with Z-furylmethylene penem 300 furnishedan inseparable mixture of a pyrazoline 301a and an adduct 301barising from the addition to diazomethane to both the exo- and endo-cyclic double bond. Thermal denitrogenation of the inseparablemixture gave the corresponding spirocyclopropyl penem 302a andpenem 302b as an inseparable mixture (Scheme 43).
Another report to synthesize additional 3-methylenecephamanalogs were reported by Baldwin and coworkers [184]. These 3-methylenecephams are useful members and belong to the class ofcephalosporins [185]. 1,3-Dipolar reaction of 3-methylenecepham303 with excess diazomethane proceeded smoothly and amixture of b-cycloaddition products 304a,b were isolated in 10:1ratio. The reaction was completely stereoselective and the
N
S
O
VHN H H
H CO2PNB
CH2N2V
(10:1)
N
S
O
VHN H H
H CO2PNB
CH2N2
N
S
O
VHN H H
H CO2PNBN N
N
S
O
VHN H H
H CO2MeN N
+
(20:1)
O O
O
D
PNB = p-NitrobenzylV = Phenoxyacetyl
303
305
n n
n
n = 0,1
306a
306b
N
SHN
O
O
CO2RMe
R1CN2
N
SHN
O
O
CO2RMeN
N
R1R1
O
R = CO2CCl3; R1 = Ph, H
311
31
314
Scheme 44. Spiropyrazolines from 3-met
formation of a minor methyl ester 304b is owed to the unexpectedtransesterification occurred during the cycloaddition process.When compared to sulfides 303, the ratio of formation of thesulfoxide based cycloadducts 306a,b were in 20:1 ratio. While thethermolysis of the sulfides 304a,b failed to furnish the cyclopro-panes, the sulfoxides 306a readily underwent nitrogen extrusionand furnished the cyclopropane 307 and a vinyl analog 308. Aplausible mechanism for the formation of vinyl analog involved a1,2-hydrogen shift and following nitrogen elimination process.AcCleKI promoted reduction of the sulfoxide analogs readily fur-nished the sulfides 309 and 310.
Yet another report from Jaszberenyi and coworkers documentedthe cycloadditions of diazomethane and diphenyldiazomethane toexo-2-methylenecephalosporins 311 [186]. 2-Methylenecephal-osporins were readily accessible through the Mannich reaction ofcephalosporin sulfoxides or sulfones [185]. These sulfoxide or sul-fone bearing cephalosporins reacted with diazomethane ordiphenyldiazomethane and furnished the 2-spirocyclopropylceph-alosporins 312 and 313 via the intermediate formation of labilespiropyrazolinocephams 314 and 315 [187,188]. Although the spi-ropyrazolines were not isolated, the formation of cyclopropyl ringevidenced the intermediate generation of the spiropyrazolines(Scheme 44) [186].
6-Acetylmethylenepenicillinic acid 316 serve as an inhibitorfor many of the chromosomally and R-factor mediated b-
N
S
O
HN H H
H CO2PNBN N N
S
O
VHN H H
H CO2MeN N
+
MF, 150oCN
S
O
VHN H H
H CO2PNB
O
N
S
O
VHN H H
H CO2PNBH
O
+
N
S
O
VHN H H
H CO2PNB
N
S
O
VHN H H
H CO2PNBH
AcCl -KI AcCl - KI
304a 304b
n n
307 308
309 310
N
SHN
O
O
CO2RMe
NNR1
R1
N
SHN
O
CO2RMe N
SHN
O
O
CO2RMe
R1
R1
R1
R1
+
2 313
315
Δ
hylenecephams and cephalosporins.
S Me
MeAlloc
O
R
S Me
MeAlloc
O
R
R, S diastereomers
S Me
MeCO2CH2CH=CH2
O
R
CH2N2/ Ether
0oC
S Me
MeCO2CH2CH=CH2
O62-70%
NN
RH
R = SO2Ph, SO2Me,SOMe (R)
S Me
MeCO2CH2CH=CH2
O
R
CH2N2/ Ether
0oCS Me
MeCO2CH2CH=CH2
O62-72%
NHN
R = COMe, CO2Me
RS Me
MeCO2CH2CH=CH2
O
NN
RH
cat. Pd(O)
cat. Pd(O) S Me
MeCO2Na
O
NHN
R
S Me
MeCO2Na
O
NN
RH
60-90%
60-90%
(or)
318
318
318
319320
321 322323
S Me
MeCO2H
O
R
R = COMe
S(O)nR1
S Me
MeCO2H
O
RX
R = COR1, X = CH2N2R = S(O)nR1, X = CH2N2
316 317
68-72%
Scheme 45. Spiropyrazolines from diethyl methylsulfinylmethylphosphonate.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 369
lactamases. Likewise, 6-methoxymethylenepenicillinic acid 317was found to irreversibly inactivate RTEM-2 3-lactamase fromEscherichia coli [189e193]. Sulfur substituted 6-methylenederived penicillins are of greater interest due to the variabilityinherent in the sulfur oxidation levels. Moreover, the electrondeficient methylene function would present a possibility forsynthesizing new structures via 1,3-dipolar cycloaddition [194].Habich and Metzer utilized the pure olefins (or) olefinic mixture(R,S diastereomers, 1:1) 318 and performed the cycloadditionprocess with diazomethane as a suitable dipole. 1,3-Dipolar re-action of these olefins 318 with diazomethane in ether at 0 �Cyielded the spiropyrazolinepencillinates 319/322. Although, thecycloaddition occurred in a regio- and stereochemical manner,the sulfomethylene derivatives 319 added exactly in the oppo-site sense to the carbomethylene congeners 322 (Scheme 45)[195].
NO
OH
NO
a) MsClb) NaHCO3, MeOH
to
Z
NO TBS
OTBS a) LDA, MeI, PhSeBrb) H2O2, pyridine
NO TBS
OTBS
NO
E
CH2N2/Et
6h, 0o
d.r. 82:18
CH2N2/Ether
CH2Cl23d, r.t
NO
NN
NO
NN
+
324325
329 330
326327a 327b
93%
97%
73%
Scheme 46. Spiropyrazolines from optic
Similar to penicillinate and structural analogs, monocyclic b-1actams are useful pharmacophores [196] and have the ability toserve as precursors for b-amino acids [197]. Although, several ex-amples of mono- [198e202] and bicyclic-b-lactams [203e206]were available, cycloadditions to the olefinic bond are of greaterinterest to organic and medicinal chemists. Liebscher and co-workers documented the synthesis of new optically active a-alky-lidene-b-lactams and concomitant 1,3-dipolar cycloadditions [207].Mesylation of the hydroxyl derivative 324 and following treatmentwith NaHCO3 in MeOH resulted in elimination and furnished a Z-olefin in moderate yields 325. The generated Z-isomer 325 uponreflux in toluene furnished the corresponding E-isomer 326 alongwith the Z-isomer as diastereomers. The synthesized E- and Z-isomers 325 and 326 reacted slowly with diazomethane and pro-vided the spiropyrazoline diastereomers 327 and 328 in high yields.The observed stereoselectivity was of the order of same magnitude
DBUluene/ reflux N
ON
O+
E Z
(1:1)
NO
Z
NO TBS
OTBSNN
H
NO TBS
OTBSNN+
d.r. 87:13
her
C
d.r. 85:15
CH2N2/Ether
CH2Cl23d, r.t
H
NO
NN
NO
NN+
326 325
331a 331b
325328a 328bquantitative
55%
ally active a-alkylidene-b-1actams.
SN2
OCO2CH2Ph Cu(AcAc)2
N2
O O
S S
CO2tBuCO2
tBu
O
OMe NHN
SN2
OCO2CH2Ph
S
OCO2CH2Ph
Cu(AcAc)2
O
NH2 NHN
H2NOC
S
OCO2CH2Ph
NHN
MeO2C MeO2C
332
334333
336
332 335
Cu(AcAc)2
O
OMe
mixture of diastereomers26% and 38%
75%
Scheme 47. Spiropyrazolines from 6-diazopenams and 7-diazocephams.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377370
as the cycloaddition of diazomethane to the methylene-b-lactam.Similar cycloadditions of protected butyrolactone 330 with diazo-methane also proceeded smoothly and furnished the desired spi-ropyrazoline diastereomers 331a,bwith preference of anti-additionwith respect to the CH2OTBS substituent (Scheme 46) [207].
In addition, Campbell and coworkers also reported the cyclo-addition reactions of 6-diazopenams and 7-diazocephams andsynthesized several spiropyrazolines [208]. The penam 332 with adiazo group underwent 1,3-dipolar cycloaddition with methylacrylate (with or without Cu(AcAc)2), and furnished the spiropyr-azoline 334 as a single regioisomer. Additional reaction of penam332 with acrylamide also gave the spiropyrazoline 335 as a singleisomer. The isolation of one isomer is resultant of the attack fromthe less hindered a-face during the cycloaddition process. However,a mixture of diastereomers 336 was generated, when methylacrylate was allowed to react with a cepham 333. In the formationof spiropyrazolines, initial cycloaddition afforded the 1-pyrazolineswhich, following prototropic rearrangement gave the isomericproducts rather providing cyclopropanes (Scheme 47) [208].
Recently, chiral spiro-b-lactams were synthesized utilizing 6-diazopenicillanates as the suitable precursors [209]. The 6-diazopenicillanates 338 were synthesized through the treatmentof the amine 337 with ethylnitrite at room temperature. The syn-thesized diazopenicillanates 338 on following cycloaddition withan array of electron deficient dipolarophiles resulted in annulationand furnished the spiropyrazolines 339a,b as a mixture of di-astereomers (3:1 ratio). It was observed that the nature of estersignificantly enhanced the isolated yields. The formation of a majordiastereomer resulted from the less sterically hindered a-side ofthe b-lactam. Similar cycloadditions of 6-diazopenicillanates 338with methyl propiolate and dimethyl acetylenedicarboxylate undervaried reactions conditions gave the b-lactams 340/341 as single
N
SH
CO2R1
HH2N
O
EtONO, CH2Cl2
r.t., 6h
R1 = Bn, CHPh2R2 = CN, CO2Et, CO2Me, COMe
N
SH
CO2R1
N2
O80-90% 8 e
3
N
SH
CO2R1
N2
O
+CO2Me CO2Me
(or)
CO2MeR1 = Bn, CHPh2
r.t./ microw
14-73%4 example
337 338
338
Scheme 48. Synthesis of chiral spiro-b-
product. However, performing the reactions at 45e50 �C had agreater influence on the cycloaddition process and the productswere isolated in higher yields (Scheme 48) [209].
Additional reactions of 6-diazopenicillanates 338 with N-substituted-maleimides gave a diastereomeric mixture of spi-ropyrazoline-b-lactams 342a,b [207,208]. The formation of a majorspiropyrazoline diastereomer is attributed to the selective additionof the dipolarophile to sterically less hindered a-side of the b-lac-tam (characteristic endo selectivity). The synthesized major dia-stereomer 342a upon microwave irradiation at 250 �C in 1,2,4-trichlorobenzene furnished a mixture of cyclopropane derivatives344a,b in 3:1 ratio. The mechanism for the formation of cyclopro-panes plausibly involved the generation of an open-chain biradicalintermediates 343a,b followed by ring closure to generate a three-membered cyclopropane ring (Scheme 49) [209].
Tomilov and coworkers studied the 1,3-dipolar reactions ofdiazo-2-methylenecyclopropane generated in situ with methylmethacrylate as an active dipolarophile [210]. The nitrosourea 346required for the synthesis were conveniently synthesized in fewsteps from the 2-methylenecyclopropanecarboxylic acid 345.Treatment of the nitrosoureawith MeONa resulted in the evolutionof nitrogen and generated a diazo derivative 347 that followingcycloaddition with methyl methacrylate provided the 6-methoxycarbonyl-6-methyl-1-methylene-4,5-diazospiro[2,4]hept-4-enes as a mixture of anti and syn isomers 348a,b. The synthesizedpyrazolines 348a,b upon thermal denitrogenation and concomitantcycloaddition with diazomethane afforded the isomeric methyl-1-methyldispiro[2.0.2.1]heptanes-1-carboxylates 351a,b in 90% yield.
In another report, the generation and following trapping ofdiazospiropentane with unsaturated compounds were reported[211]. The intermediate diazospiropentane 353 generated from theN-nitroso-N-spiropentylurea 352, following reacted with methyl
R2
N
SH
CO2R1O
N
SH
CO2R1O
NHN
NHNR1
R2
+
xamples
~ (3:1)
3-85%
N
SH
CO2R1O
NN
MeO2C
N
SH
CO2R1O
NN
MeO2C
(or)
CO2Meave
s
339a339b
340 341
lactams from 6-diazopenicillanates.
N
SH
CO2R1
N2
O
R1 = Bn, CHPh2R2 = Ph, Me
r.t. or MW+ N
O
O
R2
N
S
CO2R1O
NN
NO
O R2
H +N
S
CO2R1O
NN H
NR2O
O
N
S
CO2R1O
NN
NO
O R2
H
MW250oC, 2 min
1,2,4-trichlorobenzene
R1 = CHPh2; R2 = Ph, Me
N
S
CO2R1O
HN
O
O
R2H
+
N
S
CO2R1O
HN
O
O
R2
H
64-90% (3:1)
N
S
CO2R1O
HN
O
O
R2
H
H
+
N
S
CO2R1O
HN
O
O
R2
H
H
H
H
338
342a342b
342a
343a
343b
344a
334b
Scheme 49. Reactions of 6-diazopenicillanates with N-substituted-maleimides.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 371
methacrylate in a 1,3-dipolar fashion to generate the 8-methoxycarbonyl-8-methyl-6,7-diazadispiro[2.1.4.0]non-6-onesas a mixture of isomers 354a,b. The synthesized spiropyrazolinesupon pyrolysis afforded the 1-methoxycarbonyl-1-methyldispiro[2.1.2.0]heptane 355a,b. Similar treatment of the diazospir-opentane 353 with 3,3-dimethylcyclopropene gave the correspo-nding spiropyrazoline isomers 356a,b with spiropentane fragmentin 1.1:1 ratio (Scheme 50).
HO2C 5 steps H2NOCNNO
MeONa
-30oC N2
N N
CO2MeMe
N N
MeCO2Me
+ anti
Syn
Me
CO2Me
CO2Me
Me
+anti
Syn
CH2N2/etherPd(OAc)4
345 346347
348a
348b
349a
349b
MeONa/ NaOH N2
MeO O
35%352
353
N(NO)CONH2
(1.1:1) ra
Scheme 50. Synthesis of spiropyraz
3.4. Related 1,3-dipolar cycloadditions
Namboothiri and coworkers reported the application ofBestmann-Ohira reagent (BOR) as a suitable cycloaddition partnerand synthesized several spiropyrazolines [98]. The methodologyinvolved the treatment of chalcones 357 with Bestmann-Ohira re-agent (BOR) [212e214] 358 under K2CO3 in EtOH conditions. Underthese conditions, the cycloaddition proceeded diastereoselectively
MeMeO
O
[2+3]N N
CO2MeMe N N
MeCO2Me+
anti Syn
Me
CO2Me
CO2Me
Me
Syn
NN
NN
+
Me
CO2Me
CO2Me
Me
+
anti
Syn
90%
348a 348b
350a
350b
anti
351a
351b
N N
Me
CO2Me
N N
CO2Me
Me
+MeO2C Me
Me CO2Me
+300-310oC
MeMe NN
Me Me
NN
Me Me
+
354a
354b
355a
355b
356a 356b
70%
90%
tio
olines and spirocyclopropanes.
O
Ar
n
+
OP
N2
OEtOEt
OK2CO3/ EtOH
O
n
NHN
ArP
OEt
OEtO
Ar = H, 4-OMePh,4-ClPh, 2-thienyl70- 91%
OP
NOEtOEt
N
OP
NOEtOEt
N
O
O
Ar
n
OEtOO
n
NN
ArP
OEt
OEtO
EtOH
O
n
NHN
ArP
OEt
OEtO
Mechanism
EtO
n = 0,1
6 examples
357 358
359
360361
362
Scheme 51. Bestmann-Ohira reagent (BOR) as a suitable dipole in spiropyrazoline synthesis.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377372
and furnished several spiropyrazoline phosphonates 359 in highyields. A plausible mechanism involved the reaction of the gener-ated diazophosphonate anion 360 with an alkene 357 in aconcerted fashion to generate an initial cycloadduct 361 which,following protonation furnished the desired spiropyrazolines 362(Scheme 51) [98].
Abdou and coworkers reported the chemistry of 2-diazonio-1,3-dioxo-2,3-dihydro-1H-inden-2-ide that have the ability to undergoaddition reactions with alkylidenephosphoranes and relevantphosphonium salts [215]. 1,3-Dipolar cycloaddition reaction of 2-diazo-1,3-indandione 363 with vinyltriphenylphosphonium bro-mide 364a resulted in the isolation of a phosphonium salt 365 inexcellent yields. Similar treatment of 363 with diethyl cyanome-thylphosphonate 364b under reflux conditions generated amixtureof spiropyrazoline phosphonates 369 and 370 in moderate yields(Scheme 52) [215].
Reddy and coworkers documented the synthesis of spirote-trahydrothiapyranopyrazolines via 1,3-dipolar cycloaddition reac-tion [216]. Treatment of cis-2,6-diphenyltetrahydrothiapyranilidene371 with nitrile imines generated in situ proceeded smoothly andthe desired spiropyrazolines 373 and 374 were isolated in highyields. The mode of cyclization was found to be dependent on theelectronegativity exercised by the substituent R employed by theolefin (Scheme 53) [216].
Jedlovska and coworkers reported the cycloaddition reactions ofnitrile imines with several arylidene dipolarophiles 375e376 suchas chromanone, thiochromanone, tetralone and flavanone [217].
O
O
N N + PPh3BrLiH, THF
O
O
N N
NC P(OEt)2O
LiOH/H2O/CHCl3
O
O
N NLi
P(OEtNC
O
363
363
364a
364b
368
quantitative
Scheme 52. Synthesis of spiropy
The nitrile imines generated in situ from the correspondinghydrazones (chloramines-T) [218] reacted with several dipolar-ophiles in a regio- and diastereoselective fashion and provided thetrans-spiropyrazolines 377e379. Similar cycloadditions of flava-nones 380 afforded the anti spiropyrazolines 381, despite the ex-istence of a chiral center at C-2 position. The presence of stericinteraction with an axial phenyl group directed the attack of the1,3-dipole from the sterically less hindered side (i.e. opposite to theC-2 phenyl group) (Scheme 54) [217].
In another report, 3,3-methylene-5,5-dimethyl-2-pyrrolidinones382 reacted with nitrile imines and the spiropyrazolines 383 wereisolated in moderate yields. When observed, the dipolarophile 382substituted with hydrogen, acetyl, 1,1-dimethyleneethoxycarbonyland 1-methyethenyl groups, the cycloaddition was completelyregioselective and theproducts383were isolated inmoderate tohighyields. Although the cycloadditionwas regioselective, the reaction ofC-(5-nitro-2-furyl)-N-methyl nitrilimine385with384 resulted in theisolation of spiropyrazoline 386 and an unexpected deacetylatedproduct 387 in 68% and 21% yields (suggesting a competitive deace-tylation over cycloaddition). This observation was further evidencedthrough the reaction of C-4-nitrophenyl-N-methyl nitrilimine 388with 1-acetyl-3,3-methylene-5,5-dimethylpyrrolidin-2-one384, anda deacetylated spiropyrazoline 389 was the only product isolated(Scheme 55) [219,220].
Alkyl azides and alkenes bearing electron deficient groups un-derwent a sequence of reactions that involved intermolecular 1,3-dipolar cycloaddition, isomerization and another intermolecular
O
O
NHN
PPh3Br
O
O
NHN
O
O
NN
CH2PhPhCHO
OH
)2 OH
O
O
NN
NHH
P(OEt)2O
+
O
O
NNEt
P(OEt)2O
CN
38% 33%
365
366
367
369 370
razolinephosphonate esters.
SPh Ph
R1H
S
NN
S
NN
R1
R2
Chloramine-T
Et2O
R1 = Ph, CO2EtR2 = H, 4-Cl
68- 71%4 examples
Chloramine-T
Et2O72-74%
R2
R1 = H; R2 = H, 4-Cl
2 examples
R1
S
H
R1
R1
R1 = Ph
NN
H
HR2
371
372372
373374
Scheme 53. Synthesis of spirotetrahydrothiapyranopyrazolines.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 373
1,3-dipolar cycloaddition to provide an array of spiropyrazolines[221]. However, when allyl azides (instead of alkyl azides) reactedwith electron deficient alkenes 390 in high concentration, Michaeladducts were formed in major amounts along with the isolation ofminor spiropyrazolines 395. The formation of cyclized spiropyr-azoline 395 resulted from the reaction of an allyl azide and threemolecules of methyl vinyl ketone. Additional reactions ofsubstituted azides with methyl vinyl and ethyl vinyl ketones also
N
OR1 C N
HNR2 R3
N
ORNN
R3
R2
N
OAc
+ C NHN Me
OO2N Chloramine-T
EtOH, reflux
65-86%
N
OAc
+ C NHN Me
Ch
EtO2N
382383
384385
384
388
Scheme 55. Pyrrolidin-2-one deriv
X
O
Ph
O
Ph(or)CH
NR1HN R2
Chloramine-TMeOH, refluxX = O,S
R1 = 5-nitro-2-furanyl, 4-nitrophenylR2 = Me, Ph
O
O
PhCH
NR1HN R2
Chloramine-TMeOH, reflux
3
Ph
52-91%
71-78%
375376
380 381
Scheme 54. Spiropyrazolines from chromanone,
proceeded smoothly and the corresponding spiropyrazolines395aei were isolated in acceptable yields (Scheme 56) [221].
4. Reactions of spiropyrazolines
Tomilov and coworkers studied the reactions of spiro[pyr-azolinecyclopropane] 396 with N-aminopthalimide. When thesetwo substrates were allowed to react in presence of Pb(OAc)4,
1 R1 = H, COMe, Boc, 1-methylethenyl; R3 = Me, PhR2 = Ph, 5-NO2-2-furyl, 4-NO2-2-furyl, 4-NO2C6H4,3-NO2C6H4, 4-ClC6H4, 5-NO2C6H4,
N
OAcNN
MeN
OHNN
Me
+OO
O2NO2N21%68%
loramine-T
OH, reflux
N
OHNN
Me
66%
O2N
386 387
389
unexpected(3.4:1)
ed spiropyrazoline synthesis.
O
O
(or)N N
H Ph
R2
R1 S
ON N
H Ph
R2
R1
ON N
H Ph
R2
R1
O
ON N
H Ph
R2
R1R1 = 5-nitro-2-furanyl, 4-nitrophenylR2 = Me, Ph
examples 2 examples3 examples
Ph
2 examples
377 378 379
(or)
thiochromanone, tetralone and flavanones.
RN3
NN
NR
RNH
NN
RNH
N NHMe
OMe
O
Me
OMe
OMe
O
Me
O Me
O
RN
N NH Me
O
Me
O
H
N
HO Me Me
ONN
H
Me
ON
HO R2 R2
ONN
H
R2
O RR1
R1 = Me, Et; R2 = benzyl, Pr, Tosyl,CH2=CHCH2, CH2=C(CH3)CH2,CH2=CHCH2CH2, CH3CH=CHCH2 9 examples
30-36%
390391 392
393 394
395
395a-i
OMe
Scheme 56. Spiropyrazolines from alkyl azides and methyl vinyl ketones.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377374
azimine isomers 397 and 398 were generated [222]. Of the tworegioisomers 397 and 398, the latter 398 underwent quick nucle-ophilic substitution and generated a N-{3-acetoxyspiro[1-pyrazolinio-5,10-cyclopropane]}-N-phthalimidoamide 399. Theacetoxy derivative 399 on following treatments with methanol andsodium azide provided more stable products 400e401 substitutedwith a methoxy and azide group (Scheme 57).
In another report, reactions of spirocyclopropane containingpyrazolines with several electrophilic reagents were studied [223].The researchers investigated the protonation, acylation, andbromination of cyclopropane containing pyrazolines with the aimof revealing the mutual effect of the small ring and the azo group.Treatment of a pyrazoline 402 with gaseous HCl at 0 �C resulted inthe cleavage of a cyclopropane ring to generate a 1,5-additionproduct 403. Similar reaction of a pyrazoline 402 with benzylbromide followed the same pattern and furnished a bromoe-thylpyrazoline 404. Additional treatment of 5-bromospiro(1-
N N
BrH + NH2PhthN
Pb(OAc)4
CH2Cl2, -20-30oCN N
BrH
N
PhthN
±+
N N
AcOH
N
PhthN
±MeOH
N N
MeOH
N
PhthN
±
396397
399400
Scheme 57. Reactions o
N NHCl
0oCNH
N
Cl
HCl
NN N
N3HCl
0oCN N
H H
ClCl
402403
NaN3
4408409
Scheme 58. Reactions of spirocyclopropane-
pyrazoline-3,10-cyclopropane) 405 with equimolar amount ofgaseous HCl resulted in the ring fragmentation and afforded thecorresponding chloro- and bromo-derived pyrazole 406 and 407/409 derivatives. Further, these spiropyrazolines with no substitu-tion at N-1 position have the ability to undergo acylation andgenerate the acylated products (Scheme 58).
Kostikov and coworkers studied the reactions of a few spi-ropyrazoline derivatives with chlorinating agents [224]. The re-searchers treated 40-arylspiro[1,2,3,4-tetrahydronapthalene-2,30-(10-pyrazolin)]-1-ones 410aec with N-chlorosuccinimide and iso-lated a few chlorinated spiropyrazolines 411aec in modest yields.These chlorinated spiropyrazolines upon heating resulted in thenitrogen elimination and a mixture of stereoisomeric cyclopro-panes 412e413were isolated. However, a few pyrazolines 410a,b inpresence of excess chlorine gave the corresponding dichlorinatedderivatives 414a,b which, following nitrogen extrusion furnishedthe cyclopropanes 415a,b in moderate yields (Scheme 59) [224].
Phth =
HNO ON N
BrH
N
PhthN
±AcO
N N
AcOH
N
PhthN
±
NaN3 N N
N3H
N
PhthN
±
398 399
401
f spiropyrazolines.
PhCH2Br
- 5oC N N
Br
N
Br HCl
50- 0oCN N
H H
BrN N
H H
Cl+ XX
X = Br or Cl X = Br or Cl
404
05 406 407
pyrazolines with electrophilic reagents.
O NNO NN Cl
H110oC
O Cl
H
O H
Cl+25-46% 51-61%
(~9:1)
R R R RR = H, Cl, Me
O NN O NN Cl
Cl 110oCO Cl
Cl24% 19-55%
(~9:1)
R RR
R = H, Cl
excess Cl2
410a-c 411a-c 412a-c 413a-c
410a-b 414a-b 415a-b
N-chlorosuccinimde
Scheme 59. Chlorination reactions of spiropyrazoline derivatives.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 375
5. Conclusions
In conclusion, spiropyrazolines are structurally very useful ex-amples of five membered spiroheterocyclic compounds. Thestructural resemblance of spiropyrazolines to spiroisoxazolines,offer the feasibility to construct structurally useful analogsrendered with potential bioactive properties. The spiropyrazolineshave a basic molecular structure derived from the correspondingpyrazoline and are exemplified by a unique spiro junction at the C-5position of a pyrazoline ring. Important advances in the synthesis offunctionalized spiropyrazolines are summarized in detail, withclassification in to four types: (a) condensation reactions, (b) 1,3-dipolar cycloadditions, (c) related 1,3-dipolar cycloadditions, (d)reactions of spiropyrazolines.
Condensation reactions find very useful applications in thesynthesis of pyrazoles and related spiropyrazoline ring systems.Although, condensations are widely utilized to synthesize pyrazolesand pyrazolines, very few reports have documented the synthesis ofspiropyrazolines. On the other hand, 1,3-dipolar cycloadditions andrelated 1,3-dipolar cycloadditions have the ability to alleviate theissues related to regio- and stereoselectivity and the requisite spi-ropyrazolines can be accessed in few steps. The synthesized spi-ropyrazolines (reactions of dipolarophiles with diazomethane)serve as useful templates in the synthesis of cyclopropanes andsubstituted penicillinic acids. Inspite of these potential utilities, veryless attention has been paid toward the synthesis of these spi-ropyrazolines. Nonetheless, these condensations and cycloadditionshave the ability to furnish some very interesting spirocyclic mo-lecular frameworks. In view of the increasing significance of spi-ropyrazolines, we speculate that the development of novel syntheticprotocols incorporating the condensations and cycloadditions willpresent the future insight to this area.
References
[1] W.H. Pearson, A. Padwa, in: Synthetic Applications of 1,3-Dipolar Cycload-dition Chemistry toward Heterocycles and Natural Products, vol. 59, Inter-science, John Wiley & Sons, 2002, pp. 1e900.
[2] K.C. Majumdar, S.K. Chattopadhyay, in: Heterocycles in Natural ProductSynthesis, Wiley-VCH, 2011.
[3] K.C. Nicolaou, S. Jason, Chem. Soc. Rev. 38 (2009) 2993.[4] M. Juhl, D. Tanner, Chem. Soc. Rev. 38 (2009) 2983.[5] C.A. Carson, M.A. Kerr, Chem. Soc. Rev. 38 (2009) 3051.[6] P. Caramella, P. Grunanger, in: A. Padwa (Ed.), 1,3-Dipolar Cycloaddition
Chemistry, vol. 1, Interscience, London, 1984, p. 291.[7] J. Elguero, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.), Comprehensive
Heterocyclic Chemistry II, vol. 3, Pergamon, Oxford, 1996, p. 1.[8] P. Grunanger, P. Vita-Finzi, in: E.C. Taylor, A. Weissberger (Eds.), The
Chemistry of Heterocyclic Compounds, vol. 49, John Wiley & Sons, New York,1991, pp. 125e264.
[9] J.J. Li, in: Heterocyclic Chemistry in Drug Discovery, Wiley, NY, 2013.[10] T.,D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, S. Docter,
M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S. Rogers, D.J. Rogier,S.S. Yu, G.D. Anderson, E.G. Burton, J.N. Cogburn, S.A. Gregory, C.M. Koboldt,W.E. Perkins, K. Seibert, A.W. Veenhuizen, Y.Y. Zhang, P.C. Isakson, J. Med.Chem. 40 (1997) 1347.
[11] J.B. Patel, J.B. Malick, A.I. Salama, M.E. Goldberg, Pharmacol. Biochem. Behav.23 (1985) 675.
[12] C.B. Vicentini, D. Mares, A. Tartari, M. Manfrini, G. Forlani, J. Agric. FoodChem. 52 (2004) 1898.
[13] I. Shinkai, in: I. Shinkai (Ed.), Comprehensive Heterocyclic Chemistry II:A Review of the Literature 1982e1995: The Structure, Reactions, Synthesis,and Uses of Heterocyclic Compounds, vol. 3, Pergamon, Oxford, UK, 1996, pp.1e75.
[14] For a review on celecoxib, see: S. Dadiboyena, A.T. Hamme II Curr. Org. Chem.16 (2012) 1390.
[15] For a review on raloxifene, see: S. Dadiboyena Eur. J. Med. Chem. 51 (2012) 17.[16] M. Segal, Cannabinoids and analgesia, in: R. Mechoulam (Ed.), Cannabinoids
as Therapeutic Agents, CRC Press, Boca Raton, FL, 1986, pp. 105e120.[17] S.R. Donohue, C. Halldin, V.W. Pike, Tetrahedron Lett. 49 (2008) 2789.[18] R. Lan, Q. Liu, P. Fan, S. Lin, S.R. Fernando, D. McCallion, R. Pertwee,
A. Makriyannis, J. Med. Chem. 42 (1999) 769.[19] H.A. Deshmukh, H.M. Colhoun, T. Johnson, P.M. McKeigue, D.J. Betteridge,
P.N. Durrington, J.H. Fuller, S. Livingstone, V. Charlton-Menys, A. Neil,N. Poulter, P. Sever, D.C. Shields, A.V. Stanton, A. Chatterjee, C. Hyde,R.A. Calle, D.A. Demicco, S. Trompet, I. Postmus, I. Ford, J.W. Jukema,M. Caulfield, G.A. Hitman, J. Lipid Res. 53 (2012) 1000.
[20] J.B. Schwartz, Clin. Pharmacol. Ther. 85 (2009) 198.[21] A. Daugan, P. Grondin, C. Ruault, A.C. Le Monnier de Gouville, H. Coste,
J. Kirilovsky, F. Hyafil, R. Labaudinière, J. Med. Chem. 46 (2003) 4525.[22] N.K. Terrett, Bioorg. Med. Chem. Lett. 6 (1996) 1819.[23] B.J. Sung, K. Yeon Hwang, Y. Ho Jeon, J.I. Lee, Y.S. Heo, J. Hwan Kim, J. Moon,
J. Min Yoon, Nature 425 (2003) 98.[24] S. Dadiboyena, J. Xu, A.T. Hamme II, Tetrahedron Lett. 48 (2007) 1295.[25] J. Xu, A.T. Hamme II, Synlett (2008) 919.[26] S. Dadiboyena, A. Nefzi, Tetrahedron Lett. 53 (2012) 2096.[27] For a review on valdecoxib, see: S. Dadiboyena, A. Nefzi Eur. J. Med. Chem. 45
(2010) 4697.[28] E.D. Ellis, J. Xu, E.J. Valente, A.T. Hamme II, Tetrahedron Lett. 50 (2009) 5516.[29] E. McClendon, A.O. Omollo, E.J. Valente, A.T. Hamme II, Tetrahedron Lett. 50
(2009) 533.[30] A.T. Hamme II, J. Xu, J. Wang, T. Cook, E. Ellis, Heterocycles 65 (2005) 2885.[31] For reviews on pyrazoles, see: (a) S. Dadiboyena, A. Nefzi, Eur. J. Med. Chem.
46 (2011) 5258;(b) S. Dadiboyena, A.T. Hamme, Curr. Org. Chem. 16 (2012) 1390.
[32] S. Dadiboyena, E.J. Valente, A.T. Hamme II, Tetrahedron Lett. 50 (2009) 291.[33] S. Dadiboyena, E.J. Valente, A.T. Hamme II, Tetrahedron Lett. 51 (2010) 1341.[34] Y.-R. Liu, J.-Z. Luo, P.-P. Duan, J. Shao, B.-X. Zhao, J.-Y. Miao, Bioorg. Med.
Chem. Lett. 22 (2012) 6882.[35] Y. Li, D. Hong, P. Lu, Y. Wang, Tetrahedron Lett. 52 (2011) 4161.[36] L. Bianchi, A. Carloni-Garaventa, M. Maccagno, G. Petrillo, C. Scapolla,
C. Tavani, Tetrahedron Lett. 53 (2012) 6394.[37] Y.-S. Lee, B.H. Kim, Bioorg. Med. Chem. Lett. 12 (2002) 1395.[38] S. Srivastava, L.K. Bajpai, S. Batra, A.P. Bhaduri, J.P. Maikhuri, G. Gupta,
J.D. Dhar, Bioorg. Med. Chem. 7 (1999) 2607.[39] D. Simoni, G. Grisolia, G. Giannini, M. Roberti, R. Rondanin, L. Piccagli,
R. Baruchello, M. Rossi, R. Romagnoli, F.P. Invidiata, S. Grimaudo, M.K. Jung,E. Hamel, N. Gebbia, L. Crosta, V. Abbadessa, A. Di Cristina, L. Dusonchet,M. Meli, M. Tolomeo, J. Med. Chem. 48 (2005) 723.
[40] J. Kaffy, R. Pontikis, D. Carrez, A. Croisy, C. Monneret, J.-C. Florent, Bioorg.Med. Chem. 14 (2006) 4067.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377376
[41] J.J. Talley, D.L. Brown, J.S. Carter, M.J. Graneto, C.M. Koboldt, J.L. Masferrer,W.E. Perkins, R.S. Rogers, A.F. Shaffer, Y.Y. Zhang, B.S. Zweifel, K. Seibert,J. Med. Chem. 43 (2000) 775.
[42] H.H. Lee, B.F. Cain, W.A. Denny, J. Org. Chem. 54 (1989) 428.[43] R.M. Claramunt, J. Elguero, Org. Prep. Proced. Int. 23 (1991) 273.[44] F.H. Havaldar, P.S. Fernandes, J. Ind. Chem. Soc. 65 (1988) 691.[45] S.P. Sachchar, A.K. Singh, J. Ind. Chem. Soc. 62 (1985) 142.[46] D.M. Bailey, P.E. Hansen, A.G. Hlavac, E.R. Baizman, J. Pearl, A.F. De Felice,
M.E. Feigenson, J. Med. Chem. 28 (1985) 256.[47] V. Singh, V. Singh, S. Batra, Eur. J. Org. Chem. (2008) 5446.[48] S. Dadiboyena, A.T. Hamme II, Tetrahedron Lett. 52 (2011) 2536.[49] P.R. Berquist, R.J. Wells, Chemotaxonomy of the Porifera: the development
and current status of the field, in: P.J. Scheuer (Ed.), Marine Natural Products:Chemical and Biological Perspectives, vol. 5, Academic Press, New York,1993, pp. 1e50.
[50] (a) P.R. Berquist, R.J. Wells, in: P.J. Scheuer (Ed.), Marine Natural Products,vol. V, Academic Press, New York, 1983. (Chapter 1);(b) G.M. Konig, A.D. Wright, Heterocycles 36 (1993) 1351.
[51] (a) R.D. Encarnacion, E. Sandoval, J. Malmstrom, C. Christophersen, J. Nat.Prod. 63 (2000) 874;(b) F. Perron, K.F. Albizati, Chem. Rev. 89 (1989) 1617.
[52] K. Goldenstein, T. Fendert, P. Proksch, E. Winterfeldt, Tetrahedron 56 (2000)4173.
[53] M.F.A. Adamo, S. Chimichi, F. De Sio, D. Donati, P. Sarti-Fantoni, TetrahedronLett. 43 (2002) 4157.
[54] J.J. Harburn, N.P. Rath, C.D. Spilling, J. Org. Chem. 70 (2005) 6398.[55] M.F.A. Adamo, D. Donati, E.F. Duffy, P. Sarti-Fantoni, J. Org. Chem. 70 (2005)
8395.[56] M.A. Marsini, Y. Huang, R. Van De Water, T.R.R. Pettus, Org. Lett. 9 (2007)
3229.[57] T. Ogamino, S. Nishiyama, Tetrahedron 59 (2003) 9419.[58] S. Bardhan, D.C. Schmitt, J.A. Porco Jr., Org. Lett. 8 (2006) 927.[59] For a review on spiro-isoxazolines, see: G.P. Savage Curr. Org. Chem. 14
(2010) 1478.[60] J.E. Aho, P.M. Pihko, T.K. Rissa, Chem. Rev. 105 (2005) 4406.[61] K. Dawood, T. Fuchigami, J. Org. Chem. 70 (2005) 7537.[62] K. Dawood, Tetrahedron 61 (2005) 5229.[63] R. Huisgen, Angew. Chem. Int. Ed. Engl. 2 (1963) 565.[64] R. Huisgen, Angew. Chem. Int. Ed. Engl. 2 (1963) 633.[65] R. Huisgen, R. Grashey, R. Sauer, in: S. Patai (Ed.), Chemistry of Alkenes,
Interscience, London, 1964, p. 806.[66] C.W. Bird, G.W.H. Cheesemen, R.C. Brown, S.F. Dyke, in: C.W. Bird,
G.W.H. Cheesemen (Eds.), Aromatic and Heteroaromatic Chemistry, 1973,pp. 98e122.
[67] J.J. Li, E.J. Corey, in: Name Reactions in Heterocyclic Chemistry II (Compre-hensive Name Reactions), Wiley, NY, 2011.
[68] J.J. Li, in: Name Reactions: A Collection of Detailed Mechanisms and SyntheticApplications, fourth ed., Springer, New York.
[69] K.R.A. Abdellatif, M.A. Chowdhury, Y. Dong, Q.-H. Chen, E.E. Knaus, Bioorg.Med. Chem. 16 (2008) 3302.
[70] A. Zarghi, S. Kakhgi, A. Hadipoor, B. Daraee, O.G. Dadrass, M. Hedayati, Bio-org. Med. Chem. Lett. 18 (2008) 1336.
[71] A. Gadad, M.B. Palkar, K. Anand, M.N. Noolvi, T.S. Boreddy, J. Wagwade,Bioorg. Med. Chem. 16 (2008) 276.
[72] T.H.M. Jonckers, T.-I. Lin, C. Buyck, S. Lachau-Durand, K. Vandyck, S. Van Hoof,L.A.M. Vandekerckhove, L. Hu, J.M. Berke, L. Vijgen, L.L.A. Dillen,M.D. Cummings, H. de Kock, M. Nilsson, C. Sund, C. Rydegard, B. Samuelsson,A. Rosenquist, G. Fanning, K.V. Emelen, K. Simmen, P. Raboisson, J. Med.Chem. 53 (2010) 8150.
[73] V. Samano, M.J. Robins, J. Am. Chem. Soc. 114 (1992) 4007.[74] H.G. Lindwall, J.S. McLennan, J. Am. Chem. Soc. 54 (1932) 4739.[75] B.E. Bayoumy, S.E. Bahaie, A.E.A. Rahman, J. Ind. Chem. Soc. 61 (1984) 520.[76] S.K. Bhattacharya, A. Chakraborti, Indian J. Exp. Biol. 36 (1998) 118.[77] H. Pajouhesh, R. Parson, F.D. Popp, J. Pharm. Sci. 72 (1983) 318.[78] A. Dandia, R. Joshi, V. Sehgal, C.S. Sharma, M. Saha, Heterocycl. Commun. 2
(1996) 281.[79] M.N. Ibrahim, M.F. El-Messmary, M.G.A. Elarfi, Eur. J. Chem. 7 (2010) 55.[80] M.D. Ankhiwala, J. Ind. Chem. Soc. 67 (1990) 432.[81] J. Azizian, M. Shaabanzadeh, F. Hatamjafari, M.R. Mohammadizadeh, Arkivoc
xi (2006) 47.[82] H. Otomasu, T. Tanaka, M. Aoyagi, Chem. Pharm. Bull. 24 (1976) 782.[83] A. Alizadeh, N. Zohreh, Synlett 23 (2012) 428.[84] A. Gazit, H. App, G. McMahon, J. Chen, A. Levitzki, F.D. Bohmer, J. Med. Chem.
39 (1996) 2170.[85] U. Sehlstedt, P. Aich, J. Bergman, E.I. Vallberg, B. Norden, A. Graslund, J. Mol.
Biol. 278 (1998) 3156.[86] R.A.M. Faty, A.M. Gaafar, A.M.S. Youssef, J. Chem. Pharm. Res. 3 (6) (2011) 222.[87] A.V. Karpenko, S.I. Kovalenko, O.V. Shishkin, Tetrahedron 65 (2009) 5964.[88] M.A.E. Shaban, M.A.M. Taha, E.M. Sharshira, Adv. Heterocycl. Chem. 52
(1991) 110.[89] E.S.H. El Ashry, N. Rashed, A. Moushaad, E. Ramadan, Adv. Heterocycl. Chem.
61 (1994) 267.[90] S.G. Abdel-Hamide, J. Ind. Chem. Soc. 74 (1997) 613.[91] E. Bansal, T. Ram, S. Sharma, M. Tyagi, A.P. Rani, K. Bajaj, R. Tyagi, B. Goel,
V.K. Srivastava, J.N. Guru, A. Kumar, Ind. J. Chem. Sect. B 40 (2001) 307.
[92] A. Kerbel, J. Vebrel, M. Roche, B. Laude, Tetrahedron Lett. 31 (1990) 4145.[93] E. Mernyak, E. Kozma, A. Hetenyi, L. Mark, G. Schneider, J. Wolfling, Steroids
74 (2009) 520.[94] C.W. Ong, T.-L. Chien, Organometallics 15 (1996) 1323.[95] A. Levai, Org. Prep. Proced Int. 34 (2002) 425.[96] A. Bartels, P.G. Jones, J. Liebscher, Synthesis (1998) 1645.[97] C. Baldoli, P.D. Buttero, E. Licandro, S. Maiorana, A. Papagni, A. Zanotti-Ger-
osa, J. Organomet. Chem. 476 (1994) C27.[98] D. Verma, S. Mobin, I.N.N. Namboothiri, J. Org. Chem. 76 (2011) 4764.[99] (a) D.A. Capretto, C. Brouwer, C.B. Poor, C. He, Org. Lett. 13 (2011) 5842;
(b) N.N. Makhova, V.Y. Petukhova, V.V. Kuznetsov, Arkivoc i (2008) 128;(c) A. Nabeya, Y. Tamura, I. Kodama, Y. Iwakura, J. Org. Chem. 38 (1973) 3758.
[100] E.F.V. Scriven, in: A.R. Katritzky, C.W. Rees (Eds.), Comprehensive Hetero-cyclic Chemistry, vol. 2, Pergamon, Oxford, 1984.
[101] A.D. Elbein, R.J. Molyneux, in: S.W. Pelletier (Ed.), Alkaloids: Chemical andBiological Perspectives, vol. 5, Wiley, New York, NY, 1981, pp. 1e54.
[102] V. Singh, G.P. Yadav, P.R. Malik, S. Batra, Tetrahedron 64 (2008) 2979.[103] S. Boudriga, M. Askri, R. Gharbi, M. Rammah, K. Ciamala, J. Chem. Res. (S)
(2003) 204.[104] H.A. Albar, M.S.I. Makki, H.M. Faidallah, J. Chem. Res. (S) (1997) 40.[105] For review on butenolides see: Y.S. Rao Chem. Rev. 64 (1964) 354.[106] N.G. Argyropoulos, C.E. Argyropoulou, J. Heterocycl. Chem. 21 (1984) 1397.[107] M. Shanmugasundaram, R. Raghunanthan, E.J.P. Malar, Heteroatom Chem. 9
(1998) 517.[108] R. Raghunathan, P.V.R. Naidu, Ind. J. Chem. Sect. B 28B (1989) 966.[109] G. Bruno, F. Nicolo, A. Rotondo, F. Foti, F. Risitano, G. Grassi, Acta Crystallogr.
Sect. C C60 (2004) o879.[110] D.N. Dhar, R. Ragunathan, Tetrahedron 40 (1984) 1585.[111] M. Shanmugasundaram, S. Manikandan, R. Kumareswaran, R. Raghunathan,
Ind. J. Chem. 40B (2001) 707.[112] R. Raghunathan, M. Shanmugasundaram, S. Bhanumathi, E. Padma Malar,
J. Heteroat. Chem. 9 (1998) 327.[113] S. Manikandan, R. Raghunathan, J. Chem. Res. (S) (2001) 424.[114] R. Krishna, D. Velmurugan, R. Murugesan, M. Shanmuga Sundaram,
R. Raghunathan, Acta Crystallogr. C55 (1999) 1676.[115] R. Krishna, D. Velmurugan, M. Shanmugasundaram, R. Raghunathan,
K. Sekar, S.S. Sundararaj, H.K. Fun, Cryst. Res. Technol. 37 (2002) 135.[116] F. Cottiglia, B. Dhanapal, O. Sticher, J. Heilmann, J. Nat. Prod. 67 (2004) 537.[117] J. Mutanyatta, B. Matapa, D.D. Shushu, B.M. Abegaz, Phytochemistry 62
(2003) 797.[118] T. Kataoka, S. Watanabe, E. Mori, R. Kadomoto, S. Tanimura, M. Kohno,
Bioorg. Med. Chem. 12 (2004) 2397.[119] T. Ishikawa, Y. Oku, T. Tanak, T. Kumamoto, Tetrahedron Lett. 40 (1999) 3777.[120] F. Neumann, D. Martina, C.D. Buchecker, Tetrahedron Lett. (1975) 1763.[121] J.H. Rigby, P.Ch. Kierkus, J. Am. Chem. Soc. 111 (1989) 4125.[122] G. Toth, B. Balazs, A. Levai, L. Fisera, E. Jedlovska, J. Mol. Struct. 508 (1999) 29.[123] K.M. Dawood, J. Heterocycl. Chem. 42 (2005) 221.[124] A.D. Settimo, A.M. Marini, F.D. Primofiore, S. Settimo, C.L. Salerno, G. Motta,
G. Pardi, P.L. Ferrarini, J. Heterocycl. Chem. 37 (2000) 379.[125] P.L. Ferrarini, C. Mori, M. Badwaneh, V. Calderone, R. Greco, C. Manera,
A. Martinelli, P. Niera, G. Saccomanni, Eur. J. Med. Chem. 35 (2000) 815.[126] A.S. Girgis, F.H. Osman, F.A. El-Samahy, I.S. Ahmed-Farag, Chem. Pap. 60
(2006) 237.[127] S.M. Pereira, G.P. Savage, G.W. Simpson, R.J. Greenwood, M.F. Mackay, Aust. J.
Chem. 46 (1993) 1401.[128] K. Ramarajan, K. Ramalingam, D.J. O’Donnell, K.D. Berlin, Org. Synth. 61
(1983) 56.[129] J.B.F. Dunstan, G.M. Elsey, R.A. Russell, G.P. Savage, G.W. Simpson,
E.R.T. Tiekin, Aust. J. Chem. 51 (1998) 499.[130] S.F. Martin, B. Dupre, Tetrahedron Lett. 24 (1983) 1337.[131] H.M. Dalloul, Chin. J. Chem. 29 (2011) 751.[132] Y.S. Syroeshkina, V.V. Kuznetsov, V.V. Kachala, N.N. Makhova, J. Heterocycl.
Chem. 46 (2009) 1195.[133] A.P. Molchanov, D.I. Sipkin, Y.B. Koptelov, J. Kopf, R.R. Kostikov, Russ. J. Org.
Chem. 40 (2004) 67.[134] Y.B. Koptelov, S.P. Saik, A.P. Molchanov, Chem. Heterocycl. Compd. 44 (2008)
860.[135] H. Ortega, S. Ahmed, H. Alper, Synthesis 23 (2007) 3683.[136] M.P. Doyle, M. Anthony, T. Ye, Modern Catalytic Methods of Organic Synthesis
with Diazo Compounds: From Cyclopropane to Ylides, Wiley, NY, 1998.[137] H. Zollinger, Diazo Chemistry II. Aliphatic, Inorganic and Organometallic
Compounds, VCH, Weinheim, Germany, 1995.[138] A. Levai, A. Simon, A. Jenei, G. Kalman, J. Jeko, G. Toth, Arkivoc xii (2009) 161.[139] J.-P. Bouillon, Z. Janousek, H.G. Viehe, B. Tinant, J.-P. Declercq, J. Chem. Soc.
Perkin Trans. 1 (1996) 1853.[140] D.R. Bender, D.L. Coffen, J. Org. Chem. 33 (1968) 2504.[141] C.A. Grob, A. Kaiser, Helv. Chim. Acta 46 (1963) 2646.[142] A.T. Nielsen, J. Org. Chem. 31 (1966) 1053.[143] G.R. Clemo, E. Hoggarth, J. Chem. Soc. (1939) 1241.[144] T.A. Geissman, R.J. Turley, S. Murayama, J. Org. Chem. 31 (1966) 2269.[145] T. Sasaki, S. Eguchi, Y. Hirako, Tetrahedron 32 (1976) 437.[146] M. Skof, J. Svete, B. Stanovnik, L. Golic, S. Grdadolnik, L. Selic, Helv. Chim. Acta
81 (1998) 2332.[147] S. Pirc, S. Recnik, M. Skof, J. Svete, L. Golic, A. Meden, B. Stanovnik,
J. Heterocycl. Chem. 39 (2002) 411.
S. Dadiboyena / European Journal of Medicinal Chemistry 63 (2013) 347e377 377
[148] M. Skof, S. Pirc, S. Recnik, J. Svete, B. Stanovnik, L. Golic, L. Selic, J. Heterocycl.Chem. 39 (2002) 957.
[149] J. Svete, Arkivoc vii (2006) 35.[150] B.R. Ree, J.C. Martin, J. Am. Chem. Soc. 92 (1970) 1660.[151] P.V.R. Schleyer, V. Buss, R. Gleiter, J. Am. Chem. Soc. 93 (1971) 3927.[152] D.A. Lightner, T.C. Chang, J. Am. Chem. Soc. 96 (1974) 3015.[153] G. Snatzke, J. Himmelreich, Tetrahedron 23 (1967) 4337.[154] I.S. Hutchinson, S.A. Matlin, A. Mete, Tetrahedron 58 (2002) 3137.[155] M.A. Chowdhury, H. Senboku, M. Tokuda, Tetrahedron Lett. 44 (2003) 3329.[156] G.W. Jones, K.T. Chang, H. Shechter, J. Am. Chem. Soc. 101 (1979) 3906.[157] D. Pocar, A. Regola, L.M. Rossi, P. Trimarco, M. Ballabio, Gazz. Chim. Ital. 111
(1981) 325.[158] R.P. Bax, R. Anderson, J. Crew, P. Fletcher, T. Johnson, E. Kaplan, B. Knaus,
K. Kristinson, M. Malek, L. Strandberg, Nat. Med. (NY) 4 (1998) 545.[159] C. Agouridas, A. Denis, J. Auger, Y. Benedetti, A. Bonnefoy, F. Bretin, J. Chantot,
A. Dussarat, C. Fromentin, S. Dambrieres, S. Lachaud, P. Laurin, O. Martret,V. Loyau, N. Tessot, J. Pejac, S. Perron, Bioorg. Med. Chem. Lett. 9 (1999) 3075.
[160] S. Pal, Tetrahedron 62 (2006) 3171.[161] L. Hu, Q.-L. Song, Z.-J. Huang, P.-H. Sun, C. Zhuo, Y. Wang, S. Xiao, W.-M. Chen,
Eur. J. Med. Chem. 45 (2010) 5943.[162] Y.-T. Wang, L. Hu, W.-M. Chen, A.-X. Hu, Q.-L. Song, D. Guan, Lett. Org. Chem.
6 (2009) 306.[163] N.B. Hamadi, M. Msaddek, J. Chem. Res. (2007) 121.[164] K. Selvakumar, V. Vaithiyanathan, P. Shanmugam, Chem. Commun. 46 (2010)
2826.[165] G.B. Bennett, R.B. Mason, M.J. Shapiro, J. Org. Chem. 43 (1978) 4383.[166] A. Bartels, J. Liebscher, Tetrahedron: Asymmetry 5 (1994) 1451.[167] A. Bartels, J. Liebscher, Synth. Commun. 29 (1999) 193.[168] A. Otto, B. Ziemer, J. Liebscher, Synthesis (1999) 965.[169] D.O. Adams, S.F. Yang, Proc. Natl. Acad. Sci. U. S. A. 76 (1979) 170.[170] C. Alcaraz, A. Herrero, J.L. Marco, E. Fernandez-Alvarez, M. Bernabe, Tetra-
hedron Lett. 33 (1992) 5605.[171] M.D. Fernandez, M.P. de Frutos, J.L. Marco, E. Fernandez-Alvarez, M. Bernabe,
Tetrahedron Lett. 30 (1989) 3101.[172] A. Levai, T. Patonay, J. Heterocycl. Chem. 36 (1999) 747.[173] G. Toth, A. Szollosy, A. Levai, G. Kotovych, J. Chem. Soc. Perkin Trans. II (1986)
1895.[174] A. Levai, A.M.S. Silva, T. Patonay, J.A.S. Cavaleiro, J. Heterocycl. Chem. 36
(1999) 1215.[175] K.B. Ali, N. Boukamcha, A. Khemiss, M.-T. Martin, J. Chem. Res. (2005) 498.[176] M.F. Neumann, C.D. Buchecker, Tetrahedron Lett. 21 (1980) 671.[177] F. Neumann, M. Miesch, E. Lacroix, Tetrahedron Lett. 30 (1989) 3533.[178] A.P. Molchanov, A.A. Eremeeva, J. Kopf, R.R. Kostikov, Chem. Heterocycl.
Compd. 44 (2008) 435.[179] L. Gouiaa, N. Boukamcha, M.-T. Martin, A. Khemiss, Heterocyl. Commun. 10
(2004) 227.[180] G. Toth, A. Levai, Z. Dinya, G. Snatzke, Tetrahedron 47 (1991) 8119.[181] G. Toth, A. Levai, H. Duddeck., Mag. Res. Chem. 30 (1992) 235.[182] G. Toth, A. Levai, A. Szollosy, H. Duddeck, Tetrahedron 49 (1993) 863.[183] J.H. Bateson, A.W. Guest, Tetrahedron Lett. 34 (1993) 1799.[184] J.E. Baldwin, J. Pitlik, Tetrahedron Lett. 31 (1990) 2483.[185] P.V. Demarco, R. Nagarajan, in: E.H. Flynn (Ed.), Cephalosporins and Peni-
cillins, Chemistry and Biology, Academic Press, New York, 1972, pp. 330e360. (Chapter 8).
[186] J. Cs Jaszberenyi, I. Petrikovics, E.T. Gunda, S. Hosztafi, Acta Chim. Acad. Sci.110 (1982) 81.
[187] G.E. Gotowski, C.J. Daniels, R.D.G. Cooper, Tetrahedron Lett. (1971) 3429.[188] R.D.G. Cooper, P.V. Demarco, J.C. Cheng, N.D. Jones, J. Am. Chem. Soc. 91
(1969) 1408.[189] M. Arisawa, R.L. Then, J. Antibiot. 35 (1982) 1578.[190] P. Angehrn, M. Arisawa, J. Antibiot. 35 (1982) 1584.[191] M. Arisawa, S. Adam, Biochem. J. 211 (1983) 447.[192] M. Arisawa, R.L. Then, J. Antibiot. 36 (1983) 1372.[193] M. Arisawa, R.L. Then, Biochem. J. 209 (1983) 609.[194] D.G. Brenner, J. Org. Chem. 50 (1985) 18.[195] D. Habich, K. Metzer, Heterocycles 24 (1986) 289.[196] W. Dfirckheimer, J. Blumbach, R. Lattrell, K.H. Scheunemann, Angew. Chem.
Int. Ed. Engl. 24 (1985) 180.[197] M.S. Manhas, D.R. Wagle, J. Chiang, A.K. Bose, Heterocycles 27 (1988) 1755.[198] H.-H. Otto, S. Gtirtler, S. Ruf, M. Johner, Pharmazie 51 (1996) 811.[199] H.-H. Otto, H.-J. Bergmann, R. Mayrhofer, Arch. Pharm. 319 (1986) 203.[200] R.M. Adlington, A.G.M. Barrett, P. Quayle, A. Walker, M.J. Betts, J. Chem. Soc.
Perkin Trans. 1 (1983) 605.[201] K. Tanaka, H. Yoda, K. Inoue, A. Kaji, Synthesis (1986) 66.[202] Y. Kawashima, M. Sato, Y. Hatada, J. Goto, Y. Yamane, K. Hatayama, Chem.
Pharm. Bull. 39 (1991) 3202.[203] S. Adam, W. Arnold, P. Schnholzer, Tetrahedron 39 (1983) 2485.[204] Y.L. Chen, C.-W. Chang, K. Hedberg, Tetrahedron Lett. 27 (1986) 3449.[205] S. Coulton, I. Francois, J. Chem. Soc. Perkin Trans. 1 (1991) 2699.[206] M. Ohno, K. Okano, Y. Kyotani, H. Ishihama, S. Kobayashi, J. Am. Chem. Soc.
105 (1983) 7186.[207] S. Anklam, J. Liebscher, Tetrahedron 54 (1998) 6369.[208] M.M. Campbell, R.G. Harcus, S.J. Ray, Tetrahedron Lett. 16 (1979) 1441.[209] B.S. Santos, S.C.C. Nunes, A.A.C.C. Pais, M.V.D. Teresa, P.E. Melo, Tetrahedron
68 (2012) 3729.[210] Y.V. Tomilov, I.P. Klimento, E.V. Shulishov, O.M. Nefedov, Russ. Chem. Bull. 49
(2000) 1207.[211] Y.V. Tomilov, E.V. Shulishov, G.P. Okonnishnikova, O.M. Nefedov, Mendeleev
Commun. 7 (1997) 200.[212] P.Y. Rajendra, R.A. Lakshmana, L. Prasoona, K. Murali, K.P. Ravi, Bioorg. Med.
Chem. Lett. 15 (2005) 5030.[213] Z. Ozdemir, H.B. Kandilici, B. Gumusel, U. Calis, A.A. Bilgin, Eur. J. Med. Chem.
42 (2007) 373.[214] H.M. Hassaneen, N. Elwan, H.M. Hassaneen, Synth. Commun. 32 (2002) 3047.[215] W.M. Abdou, M.D. Khidre, R.E. Khidre, Eur. J. Med. Chem. 44 (2009) 526.[216] D.B. Reddy, A.S. Reddy, A. Padmaja, Synth. Commun. 29 (1999) 4433.[217] E. Jedlovska, A. Levai, G. Toth, B. Balazs, L. Fisera, J. Heterocycl. Chem. 36
(1999) 1087.[218] K.L. Rai, A. Hassner, Synth. Commun. 19 (1989) 2799.[219] E. Jedlovska, L. Fisera, J. Heterocycl. Chem. 41 (2004) 677.[220] E. Jedlovska, L. Fisera, Chem. Heterocycl. Compd. 31 (1995) 1183.[221] C.-H. Yang, L.-T. Lee, J.-H. Yang, Y. Wang, G.-H. Lee, Tetrahedron 50 (1994)
12133.[222] Y.V. Tomilov, I.V. Kostyuchenko, E.V. Shulishov, B.B. Averkiev, M.Y. Antipin,
Russ. Chem. Bull. 49 (2000) 1919.[223] Y.V. Tomilov, I.V. Kostyuchenko, G.P. Okonnishikova, E.V. Shulishov,
E.A. Yogodkin, O.M. Nefedov, Russ. Chem. Bull. 49 (2000) 472.[224] A.P. Molchanov, Y.S. Korotkov, R.R. Kostikov, Russ. J. Org. Chem. 42 (2006) 1146.