5. results and discussion thc two-carbon synthon, nmsm...
TRANSCRIPT
5. Results and Discussion
5.1. Nitroketene-NJ-acctals: Introduction
Thc two-carbon synthon, N-methyl-N-[(El)-l-(metl1ylsulfanyl)-2-nitro-l-
ethenyllanline (1~-mcthyl-1~-methyl-2-nitroethylene, NMSM) 76s (Figure 1.6), a
nitroketene-N,S-acetiil, is a versatile molccu~e.~" It is embodied with threc functional
groups on ethylene motif, viz., alkylamine, methylsulfanyl and nitro, each one of
which is amenable for synthetic exploitation and functional group manipulation. With
an excellent electron-withdrawing nitro group in place, the nitro-ethylene substructure
in 76a is a guod Michael acceptor. The methylsulfanyl group is an electron donor and
is also a good leaving group. Utilizing well established methods, the methylsulfanyl
group in 76a can be replaced with a varicty of nucleophiles, by substitution
nucleophilic vinyl (SNV) mechanism.
NMSM Ranitidine
76a 77
Figure 1.6
The ethylene moiety in NMSM 76a is a polarized push-pull alkene with
electron flow cmanating from methylamino I methylsulfanyl to nitro group. Due to
polarization, the C1 in NMSM 76a exhibits electrophilic characteristics and the C2
exhibits nucleophilic charactcristics. Molecules of the type NMSM 76a are synthetic
equivalents of nitroacetic acid where the ester is masked as ketene-N,S-acetal. Also,
NMSM 76a is a synthetic equivalent of the amino acid glycine, which can be realized
by reduction of nitro group and release of masked acid. Above qualities make NMSM
768 a multi-faceted building block ready to be exploited to build organic molecules of
diverse structures." As an example, NMSM 7611 is a starting material in the
manufacture of anti-ulcer (histamine H2 receptor antagonists) bulk drugs ranitidine
7782 and nizatidine."
We reasoned that since nitroketene dithioacetals have electrophilic and
nucleophilic carbons at adjacent (CI and C2) positions they can be condensed with
bifunctional molecules having nucleophilic and electrophilic centres in 1 -4-position so
that a six-membcr ring can be generated. In the present thesis, we describe realization
of this concept for a convenient combinatorial synthesis of several 2-alkylamino-3-
nitro-4H-chromenes and their further transformation to 2-alkylamino-4-aryl-3-nitro-
411-chromenes, non-natural hybrid amino acids as well as four DOPA isomers. The
4H-chromencs and 4-aryl-4H-chromencs are heterocyclic molecules of current
interest as they exhibit cytotoxic properties and thus evaluated as anticancer
5.2. Synthesis of nitroketene SJ-acetal81
Thc starting material for our work is nitroketene N,S-acetals, e.g. 76. The N,S-
acetals were prepared from the S,S-acetal, ],I-bis(methy1thio)-2-nitroethene 81. The
S.S-acetal, 81 was prepared in bulk scale in two stcps following thc procedure
described by Rao and ~akthikumar.'~
KOH Me2S0, MeOH CHINO2 + CJ, _ /=iS 2 K+ benzene - OoC, 3 h 02N S 02N SMe 45%
rt, 2 h, 85%
78 79 80 81
Scheme 1.27
Condensation of nitromethane 78 with carbon disulfide 79 in presencc of
concentrated potassium hydroxide in dry methanol resulted in the formation of
dipotassium salt of nitroketene dithioacetate 80 in moderate yield. The unstable salt
needed storage at 0-5 "C in dark. Methylation of the salt 80 with dimethyl sulfate in
benzene: furnished 1,l-bis(methy1thio)-2-nitroethene 81 in excellent yield (Scheme
1.27). The dimethyl nitroketene dithioacetal 81 exhibited physical (mp -. 127 "C) and
spectral (IR, 'H NMR, "C NMR) properties, matching those of thc authentic sample.
The methyl groups in 81 appeared as two singlets at 2.53 and 2.54 ppm indicating
restricted rotation around the double bond at room temperature even though the bond
between C1 and C2 has single bond character due to push-pull characteristics of the
molecule. This feature of 81 is similar to the one found in Nfl-dimethylfomamide
(DMF), where in two singlets for NMe group are observed in the NMR spectrum
recorded at room temperature."
5.3. Synthesis of nitroketene NJ-acetals 76a-g
MeCN
SMe 3-28 h SMe
82a, 76s: R = Me
82b, 76h: R = 11-Bu
82c, 76c: R = Ph
82d, 76d:R = Bn
82e, 76c: R = (CH2)2Ph
82f,76f: R = (CH2)2CbH40Me-p
82g, 76g: R = CH(CII3)Ph
Scheme 1.28
NMSM 76s is cornmemially available. Other N,S-acetals 76b-g were to bc
prepared in the laboratory. We have convened the nitroketene S,S-acetal 81 into
various nitroketene N,S-acctals 76b-g in good yield by trcating with primary amines
82b-g in acetonitrile reflux (Scheme 1.28, Tablc 1. All the Ar,S-acetals 76b-g
prepared in this study were assigned E-configuration based on the literature
precedence, wherein it was found by X-ray crystallographic studies that E-
configuration is preferred over ~ - c o n f i ~ r a t i o n . ~ ~ The hydrogen bonding interactions
between hydrogen of the NH and negatively charged oxygen of the NOZ dictate the
stable E-geometry. Due to polarized nature of the molecules, thcre is some single
bond character between C1 and C2 of 76a-g, which makes free rotation around C1
and C2 possible.
Table 1.1: Synthesis of nitroketenc N,S-acetal 76a-g from S.S-acetal 81 and primary amines 82b-g in acetonitrile reflux.
Entry Primary am,ne Product nilroketene T~me Yleld N,S acetal (hl 1%)
PhNH, 0,N NHPh
62c 76c
SMe BnNH, 02NANHBn
82d 76d
SMe
SMe 5 MeOC,H,(CH,),NH, 3.5 87
SMe 6 C6H,CH(CH3)NH2 5 50
Among the N,S-acetals prepared in the present study (Tilble 1.1) 76f, having
methoxyphenylethylarnine moiety is a new compound. We present below spectral
characterization details of this compound as a representative example.
5.3.1. Characterization of A'-(4-mcth0xyphenethyI)-N-I(0-1-(methylsny1)-2-
nitro-1-ethenyllamine 76f
Figure 1.7
Thc N,S-acctal 76f (Figure 1.7) was obtained as a yellow colored solid, mp
107 "C. Thc UV spectrum of 76f showed two absorptions at 354 nm (log & = 4.2) and
275 nm (log r: = 3.6). The i,,,,, at Iongcr wavelength was due to the push-pull system
involving NHCH2CH2Ph, C=C and the nitro group. The h,,,,, at 275 nm was due to the
nitroethylcne moiety. The IR spectrum displayed a band at 3187 cm" for the olefinic
C-H strctching. 1571 cm" and 1342 cm" fbr thc nitro group. The ' H NMR spectrum
(Figure 1.8) displayed singlets for SMc, OMe and olefinic hydrogens at 6 2.41, 3.66
and 6.55 ppm respcctively. The aromatic hydrogens appeared as two broad AB tqpc
doublcts at 6 6.8 and 7.1 ppm; CH: protons attached to the aromatic ring appeared as
a triplet at 2.9 ppm and CH2 attached to N H group appeared as a quartet at 3.62 ppm.
The NH proton appearcd downfield at 6 10.5 pprn as a broad singlet, indicating the
hydrogen bonding interaction between NH and NO2 group, which confirms the
assigned E-stercochemistry for the double bond. The ')c NMR spectrum (Figure 1.9)
displayed four signals in the aliphatic region out of which two were for SMe (6 14.2)
and OMe (6 55.2) and rest were for two methylenes (6 34.5 and 55.2). Two olefinic
carbons Cl and C2 appeared at 6 158.6 and 8 106.2 respectively.
Literature study reveals that molecules containing arylethylamine moiety
exhibit profound biological activity because they mimic dopamine. Some molecules
with phenylethylamine core are used for the treatment of Parkinson's disease." In the
light of this background nitroketene N,S-acetals 76e and 76f having phenylethylamine
moiety could show significant biological activity. However, due to lack of facilities
we did not carryout biological evaluation.
Figure 1.9 75 MHz (CDCI,) ')c NMR spectrum of N-(4-methoxyphenethyl). N-[(E)-l-(methylsulfanyl)-2-nitro-I-ethenyl]amine 76f.
I
E I
!! I
-
- - L ,. 1 -- Figure 1.8 300 MHz (CDCI3) 'H NMR spectrum of N-(4-methoxyphenethyl)- N-[(a- I -(mcthylsulfanyl)-2-nitro- I -ethcnyl]am~ne 76f
5.4. Synthesis of amino acid containing nitroketcne NS-acetals 86a-g
With the experience gained from the preparation of the N,S-acctals, we
ventured into the synthesis of the amino acid substituted nitroketenc N,S-acetals. Such
amino acids could become starting materials for the synthesis of Ranitidine like
molecules and increase water solubility of the drug molccule.
SOCI, - +
H N COOH MeOH, rt CI H,N yCOOMe Et,N H,NyCOOMe v - R 12-17 h k R
-
Scheme 1.29
The amino actd esters 85a-g nccdcd for this work were prepared by treating
corresponding commercially available amino acids 83a-g with thionyl chloride,
methanol according according to the procedure described by Meyers and coworkers
(Scheme 1.29)." All the amino acid esters 85a-g were characterized by spectral data,
which matched with thc reported values." Specific rotation for each amino acid ester
was detemined to check if racemization occurred during esterification. The a~ values
matched with the reported values indicating that raceimizatior, did not occur at this
stage.
COOMe COOMe 2:;
02N\=/Me + H,N< - SMe R 4-24 h SMe
50-88%
81 85a-g 86a-g
85a, 86s: R = H
85b, 86h: R =Me
85c, 86c: R = CH2Ph
85d, R6d: R = CH(CHJ)~
85e, 86e: R = CH~CH(CIII)I
85f, 86f: R = CH(CHJ)CHICHJ
85g, 86g: R = CH~(CRH~N)
Scheme 1.30
Ncxt we reacted S,S-acctal 81 with amino acid methyl esters 85a-g in
acetonitrile reflux to furnish corresponding nitroketene N,S-acetals 86a-g (Schcme
1.30). Yields of the product, reaction time, enantiomeric excess (ce) determined on
the basis of chiral HPLC and the optical rotation values obtained in each reaction is
given in Table 1.2.
,a98 [e1aos-s'~ pahuap au!analjo uo!letua)oeaeqo aql uo uo!ssnJs!p molaq a ~ ! 9 am aldruexa aa!)e)uasa~da~ e
s v ~umouy !ou am sl!un Ssg mqdo~dCI~ pm jsg au!bna[os! 'as8 aulonal uroy panpap
P98 PSB
d l Y
sanlen uo!la)o~ lea!$do pun ssaaxa Juauo!iueua Jpyl '8-BSX sJaisa p ! ~ o ou!me pug 18 IIQ~~B-S'S woy 8-698 [BI~JE-S'N aualayoJl!u pa~ni!lsqns p!Je ou!uV :Z'L a l q U
5.4.1. Characterization of methyl (ZS)-4-methyl-2-[(E)-I-(rnethylrulfanyl)-Z-
nltro-1-ethenyl]amlnopentanoate 86c
j N 0 2 MeS NH
f l O M e H,C CH,
86e
Figure 1,10
The UV spectrum of the nitroketcne N,S-acetal 86e (F iy r c 1.10) showed
characteristic A,,,,, at 354 nm (log c = 4.1) assignable to the N,S-acetal moiety. The IR
spectrum displayed bands at 3153 em" for the olefinic CH stretching, 1563 cm" and
1336 cm" for the nitro group. The 'H NMR spectrum (Figure 1.1 1) displayed a signal
at S 0.99 ppm as doublet for six mcthyl hydrogens. The CH proton belonging to the
amino acid portion appearcd as AB quartet at S 4.45 and 4.46 ppm. The SMe and estcr
Me appeared as singlets at S 2.48 and 3.76 ppm respectively. The olefinic proton
displayed u signal at 6 6.6 ppm as a singlet and thc NH proton appeared at 10.5 pprn
as a broad singlet. The "C NMR spectrum (Figure 1.12) displayed signals for the
SMe (8 14.2), ivopropyl (6 21.4, 22.1 and 41.2), methylene (6 24.1), methine (6 55.3),
OMe (6 52.4) and CO (6 170.6) groups. In addition, characteristic signals for the C1
and C2 of olefin appeared at 6 163.4 and 106.9 ppm respectively.
KG-11-44 - 8 9
- PRI
? 5 C C m m--
Figure 1.11. 300 MHz (CDC13) 'H NMR spectrum of methyl 4-methyl-2-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 86e.
(methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 86e.
B y carrying out the chiral HPLC analysis using Daicel A D - H column (4.6 x
250mm) and using acetonitrile (ACN) and isopropyl alcohol (IPA) as the eluent we
found ee of the nitroketene N,S-acetals 86b-e, 86g and dc of 86f. In all the cases 1.0
mg of the sample was dissolved in 1.0 mL of 1:l ACN: IPA (95:s) mixture, out of
whichW.0 pL was injected into HPLC having a flow rate 0.5 mL I min. Betentton time
at which the minor and the major enantiomer separated was calculated by maintaining
the pressure max 14 Kgf 1 cm2 and at column temperature of 25 "C. As an example,
retention times for diasteromers of 86b were found to be 6.6 rnin (minor isomer) and
7.0 rnin (major isomer; Figure 1 . I 3).
Preparation of isolcucine substituted nitroketcne N,S-acetal 86f is interesting
because of the gcneration of diastereomers. There exists one chiral center in the amino
acid which does not get disturbed in the process of N,S-acetal preparation. The "C
NMR spcctrutn of the isolated product 86f showed that it is a single product.
Howcver, both normal and chiral HPLC (Figure 1.14) analysis showed that
diatereomcric excess was 89%. The rctention times for two diastereomers were found
to be 6.9 min (minor enantiomer) and 6.6 rnin (major enantiolncr).
Thc optical rotations of the product N,S-acetals 86b-f were measured and they
are given in Table 1.2. Since HPLC analysis revealed the presence of two enantiomers
in each case, we conclude that raceimization to ccrtain extent has taken place during
SNV substitution of SMe with amino group of amino acid esters. Reported optical
rotation values are for the samples obtained from thc reaction.
Sincc raceimization took place in acetonitrile, we tried thc SsV reaction of
leucine ester and N,S-acetal 86c in polar protic solvent MeOH and polar aprotic
solvent like DMF. In the carlier case reaction was not going to completion cvcn after
48 h reflux. In the later casc yield was low and there was complete raceimization.
In conclusion, we described synthesis and characterization of N,S-acctals 869-
g incorporating amino acid esters. Further experiments are required to find
experimental conditions where raceimization during the SNV reaction can be arrested.
1 Run RrpoH I -A 0 7 o a )
11.M W 49447.19 17Y57 UJZ W
Tmk
Figure 1.13: HPLC diagram for alanine substituted nitroketene N,S-acetal 86b.
Dala Graph - -. .- -
lo IT Mm ,,. -wfun Anr I
O ' 1
00
/. .____ , -- , - ~ , 8 l 4 6 6 7 ~ , , ~
Mln*
Run Report D*IPtDIA OYnm)
R L WatlmTLnr M HliLhl lnUPqlon I 6.617 4 I 7 2 6 S I W W
m" 2 6.m) 2 i l359 66920 1.13 81
w.47 81
T d
Figure 1.14: HPLC diagram for isoleucine substituted nitroketene N,S-acetal 86f.
m8624 1131924 IW.W
5.5. Synthesis and characterizatlon of 3-nitro-4H-chromenes 87
DBU (10 mol%) aCHO + g N 0 2 MeOH - /
OH MeS NHMe " l7 93% NHMe
Schemc 1.31
As noted earlier, nitroketcne N,S-acetals 76a-g possess nucleophilic CI and
electrophilic C2 carbons. We reasoned that nitroketenc N.S-ace~als 76a-g would react
with 2-hydroxybenzaldehyde 18a (salicylaldehyde), which possesses a nucleophilic
phenolic hydroxyl and an electrophilic aldehyde, located in 1.4 positions. Thus
condensation of nitroketene N,S-acetal 76a with salicylaldehyde 18a would provide
henzpyrans 87s (Schemc 1.3 1 ).
We conducted the rcaction of 2-hydroxybenzaldehyde 18a with NMSM 76a in
THF using piperidine (I .0 mol equiv) as a base (entry I, Table 1.3). After stimng at 8
h at rt, a faintly yellow color solid separated from the reaction medium in 85% yield.
However, the reaction was not clean. Same reaction was tried with catalytic amount
(10 mol%) of pipcridine (entry 2, Table 1.3), which provided clean product 87a.
cventhough it took 72 h for completion. The solid was filtcred and recrystallized from
dichloromethane and hexane to generate crystalline product (mp 152-153 'C). The
micro analysis and mass spectra showed that the molecular formula of compound 87a
was Cl lH12N203S The UV spectrum showed absorption A,, at 352 nm (log E = 4.0)
and 279 nm (log c = 3.0), which indicated the presence of nitroketene acetal moiety.
Absorption at longer wavelengh was due to conjugation running from lone pair of
electrons on the oxygen of the pyran ring to the nitro group. The IR spectrum showed
intense bands at 161 I (C=C), 1470 and I372 cm" (N02). The 'H NMR spectrum
(Figure I. IS) displayed a singlet for SMe at 1.8 pprn, a doublet at 3.24 pprn (J = 5.1
Hz) for NMe, a singlet at 5.49 ppm for CH and well defined peaks between 7.1 and
7.5 ppm for I,2-disubstituted benzene and a broad singlet for NH at 10.3 pprn
assignable for the structure of N-methyl-N-[4-(methyIsulfanyl)-3-nitro-4H-2-
chromenyllamine 87a. The "C NMR spectrum (Figure 1.16) exhibited three signals
at b 12.2, 28.0, and 40.3 ppm for three aliphatic carbons. Four quaternary carbons and
four aromatic CH type carbons in the aromatic region supported thc structure.
---1O. . - I pL.I
!igurc 1.15 3 0 0 M H 1 (CDCh) 'H NMR rpatrum of V-mcthy~-A'-[C (rnethylsulfanyl)-3-n1tro-4H-2-chromenyl]am1ne 87a
- 7 - 7 - - 7 - . - - I I% 101 $4 d
Figure 1.16 75 MHz (CDCI,) "C NMR spectrum of N-methyl-N-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]amn 87a.
Thc structure of the product 87a was confirmed unambiguously from the
analysis of single crystal X-ray (Figurc 1.17) diffraction datil (depos~ted with
Cambridge Crystallographic Data Centre. CCDC; deposition No. 261071). The X-ray
structure showed that SMe goup takes pseudo axial orientation and the pyan ring
adapts an envelope conformation. Thc nitro group is coplanar with the chromenc
system.
Figure 1.17: The single ctrystal X-ray structure of N-me thy^. N-[4-(methylsulfanyl)-3-nitro-1H-2-chromcnyl]amine 87s.
Condensation of salicylaldehyde 18a with NMSM 76a is a highly atom
economic reaction formed by click, spl~t and add routc (CSA) (vide infia). 3-Nitro-
4H-chromene 87a incorporates functional groups NHMe, NO2, SMe, en01 ether and
an enamine, each one of which is amenable for further functional group
transformations.
Having found a facile synthesis of pharmacologically relevant 4H-chromene
87a, we next attempted various reaction conditions to optimize yields and to find
facile reaction conditions by taking CSA condensation of 2-hydroxybenzaldehyde 18a
and NMSM 76a to form 4H-chromene 87a as a test case. Details of optimization of
base 1 solvents 1 conditions for 3-nitro-4H-chromene 87a formation from nitrokctene
N,S.acetal76a and 2-hydroxybenzaldehyde 18s are gathered in Table 1.3.
Table 1.3: Synthesis of 3-nitro-4H-chromene 87a from NMSM 76a and 2-hydroxybenzaldchyde 18a using different bases f conditions, ;;;;vz;; E F 7 7 ! T ; ) 7
Pipcridine (I .O)
Reactions were conducted at reflux temperature of the solvent used, The reaction was conducted under microwave irradiation (2.45 GHz; 400 W, 2 min).' No reaction.: extensive decomposition of 76 took place. d ~ ~ e l d with respect to recovered NMSM.
2
3
4
5
6
7
8
9
I :p
We attempted CSA condensation with secondary amine like pyrolidine (entry
4) and morpholine (entry 5) in THF or teniary amine like DBU ( I , %
diazabicyclo[5.4.0]undec-7-ene; entry 6), Et3N (entry 7) and DABCO (1,4-
diazabicyclo[2.2.2]octane; entry 8) in THF only to find that the yields were lower and
longer reaction time in each case. The reaction with pyridine (entry 3) in THF at rt or
Piperidinc (0. 1)
Pyridine ( I .0)
Pyrrolidine (0.1) .-
Morpholine (I .O)
THF
THF
-- 72
72
DBU (0.1) ; THI:
90
. 3"
15 ! 20
EtlN (1.0)
DABCO (I .O)
NaH(I.O)
NaH (1.0)
K ~ C O I ( I .O)
54
43
T H I : , 48
144
96
9
5
7
THF
THF
THF
DMF
Acetone
THF
38
70
75'
71
45 ,
192
at reflux temperature did not yield 87a. The abovc experiments revcaled that CSA
reaction worked well with DBU (0.1 equiv)-in MeOH (entry 17) to provide desircd
product in 93% yield and the reaction was also clean. With inorganic bases like NaH
(1.0 equiv) 1 THF (entry 9 ) or NaH (1.0 equiv) in DMF (entry 10). K2C03 1 acetonc
(entry 18) or two-phase reaction with aqueous K2C03. TBAB, DCM (entry 13), the
reaction yields were moderate. Howevcr the condensation was facile with K2C03 (0.1
equiv) in water to provide the 4JI-chromenc 87a in 85% yield (entry 18). The reaction
was slow or did not take place in KF I neutral alumina (entry 15) under microwave
condition or with besic alumina (entry 14) under neat condition. Since the product has
a chiral ccntre, we attempted the condensation with proline (entry 16), proline methyl
ester (entry 17) and proline benzylester (entry 18) in MeOH. Though the product
formation took place in all these cases in moderate to good yield and there was no
chiral induction in the product.
In summary, wc found that the condensation reaction worked well with 0.1
equiv. of piperidine in THF (entry 2) or DBU in MeOH (entry 19) or K2CO1 in water
(entry 20) in each case at room temperature. An yellow solid precipitated and was
obtained by simple filtration. Out of the above reagents and solvents, use of 0.1
equivalent of DBU in McOH (entry 17) appeared to be most appropriate to generalize
the transformation. Employing K?COI-H?O (entry 18) combination needs further fine
tuning when substituted 2-hydroxybenzaldehydcs or substituted NMSM employed.
To generalize CSA condensation, we needed a variety of 2-
hydroxybenzaldehydes, which were prepared by following the published procedures
(Scheme 1.32). Among them, the 2-hydroxybcnzaldehydes 18b, 18f-j were prepared
from corresponding phenols ~ d a Reimer-Tiemann rea~t ion . '~ 2,4-
Dihydroxybenzaldehyde required for the preparation of 18k. 18m, 181 was made from
resorcinol by employing Vilsmeir Hack f o r m y ~ a t i o n . ~ ~ Selective benzylation of C4
hydroxy group in 2,4-dihydraxybcnzaldehyde with benzyl chloride in presence of
NaHCO, (1.1 equiv) and K1 (1.0 equiv) in CH3CN reflux furnished 4-benzyloxy-2-
hydroxybenzaldehyde 18k.~' 2,4-Dihydroxybenzaldehyde was treated with dimethyl
sulfate, NaOH to get 4-methoxy-2-hydroxybenzaldehyde 18m.'~ In the same manner
4-allyloxy-2-hydroxybenzaldehyde 181 was prepared by reacting 2 4 -
dihydr~x~benzaldehyde with allylbromide in presence of K2CO3 in acetone under
reflux."' 2-~~d~~xy-6-methoxybenzaldehyde I8d was prepard in two steps starting
from resorcinol dimethylether.Yv In the first step, resorcinol dimethylether was
transformed into 2,6-dimcthoxybenzaldehyde using n-BuLi and DMF. In the second
step, monodemcthylation with EtSH in the presence Nall in DMF furnished the 2-
hydroxy-6-rnethoxybenzaldehydc 18d.""'
18a.k 78a 87a-k
Ma, 87a: R1= R2 =R3 -R4 = 11
18b. 87b: R1 = R3 = R4 = H, R2 = Br
18c, 87c: RI = R2 = R3 = H, R4 = OMe
18d, 87d: R1 = OMe, R2 = R3 = R4 = H
18e, 87e: R1 = R3 = R4 = H, R2 =Me
18f, 87f: R1 = R3 = R4 = H, R2 = Et
18g, 87g: RI = R3 = R4 = H, R2 = r-Bu
18h, 87h: RI = R3 = R4 = H, R2 = OMe
18i, 87i: RI = R3 = R4 = H, R2 = C1
18j, 87j: RI = Mc, R2 = CI, R3 = R4 = H
18k, 87k: R1 = R? = R4 = H, R3 = OCH2Ph
Scheme 1.32
Above ten different 2-hydroxybenzaldehydes 18b-k were smoothly condensed
with NMSM 76a under optimized condition to furnish 4II-chromenes 87b-k in 75-
93% yield (Scheme 1.32; Table 1.4).
Table 1.4: Synthesis of 3-nitro-4H-chromenes 87a-k from substituted salicylaldehydes 18a-k.
a,' &NO> NHMe
I11 17, (17 h 83%)
& &NO2
NHMe
1 Ld 87d (12h 88%)
"a:"u&No> I I
NHHe
18, 1171 112 h, 89%)
OH
NHMe
l a b 87b (18 h 78%)
CH, 3Ms
cl&cHo c l ~ N O p \ I I
' OH NHMe
1 01 VJ (17 n 78%)
10 PnCH20 PhCH>O NHMI
1Ik 87k (18 h 82%)
11
NHMe NHMe
lam atm (O %I
13
PhCOO PhCOO NHMB
cl&No, 1 1
NHMs
Spectral data of 4H-chromenes 87a-k matched well with the parent
compound, Complete 'k NMR spectral assignments for the above 4H-chromenes
87a-k are given in Table 1.5. The structure of 87e'" was also confirmed
unambiguously by single crystal X-ray analysis and the X-ray crystal structure is
given in Figure 1.18.
--. 1
Figure 1.18: The single crystal X-ray structure of .V- methyl-N-[6-methyl-4-(methylsulfanyl)-3-nitro.4H-2- chromenyllamine 87c.
Table 1.5: Comparison of "C NMR spectral 6 valucs of 3-nitro-4H-chromenes.
--'r- 3-Nitro-lH-Chromenes
34.5 (c);' 55.8 (OMe); 15.9 (Me); 70.5 (CH*), 136.1 (C), 127.4 (2 x CH), 128.7 (2 x CH), 128.3 (CH).
Condensations of 3-methoxy, 4-methoxy, 5-methoxy and 6-methoxy-2-
hydroxybenzaldehydes lac, 18k, 18h, 18d with NMSM 76a to provide corresponding
4H-chromenes 87c, 87k, 87h, 87d were of interest, because they could eventually
lead to dihydroxphenyl alanine (DOPA) isomers. While the CSA reaction of three 2-
hydroxybenzaldehyde namely 18c, lad, 18h worked well, condensation of 4-
methoxy-2-hydroxybenzaldehyde 18m and 4-benzoyloxy-2-hydroxybenzaldehyde
with NMSM 76a did not take place. Only product isolated in low yield appeared to be
that of a polymer derived from KMSM 76a. It is understandable that 4-methoxy-2-
hydroxybenzaldehyde 18m did not participate in the condensation because of the low
electrophilic nature of the carbonyl carbon. To circumvent the difficulty 4-allyloxy-2-
hydroxybenzaldehyde 181 was treated with NMSM 76s. The CSA reaction provided
corresponding 4H-chromene 871 in low yield 59%. Moreover subsequent
desulfurization reaction did not take place at rt and the chromenc 871 charred when
the reaction was conducted at higher temperature. So, we nccdcd to find an alternative
for this condensation. We were happy to find that the condensation of 4-benzyloxy-2-
hydroxybenzaldehyde worked well to yield 82% of N-[7-(benzyloxy)-4-
(methylsulfanyl)-3-nitro-4H-2-chromcnyl]-A1-mcthylamine 18k. From this study it has
been concluded that subtle changes in electronic nature of the aromatic ring gets
reflected in the 4H-chromene formations.
5.5.1. Mechanism for the formation of 3-nitroJH-chromenes
O,N-NHMe + aCHO - aoqNO, C
SMe OH MeOH, rt s N M e
87s
Scheme 1.33
Plausible mechanism for the formation of 411-chromene 870 from NMSM 760
and 2-hydroxybenzaldehyde I8a is given in Scheme 1.33. Thc conversion appears to
follow four major steps namely i. Michael addition, where the anion gencrated from
2-hydroxyhenzaldchyde 180 adds to NMSM 76a in conjugate manner (rate
determining step, rds). ii, nitroaldol condensation to provide the pyran ring (steps 1
and 2: click; rds in the case of 2-hydroxy benzaldehydes with C4-OMe), iii.
dehydration and dethiomethylation (split) to generate intermediate benzpyrilium
cation. iv. thiomethyl anion present in the solution adds on to the benzpyrilium cation
forming 3-nitro-411-chromene 87a (add). Thus thc mechanism of the reaction follows
click, split and add (CSA) route.
The yield of the 4/f-chromene was relatively high for 2-hydroxybenzaldehyde
having electron donating substituent present on C5 carbon (para to hydroxy) 87e-h
compared to those with electron withdrawing substitucnt 87b, 871. This result
indicates that nucleophilic attack of the phenolate anion on C1 of the NMSM 760
could be the rate-determining step. Methoxy group para to aldehyde retards thc
intramolecular nitroaldol condensation. thereby allowing the intermediate to react
with NMSM 76a ugain to generate polymeric product. Quenching of the benzpyilium
cation with methylthiolate anion augers wcll for the replacement of SMe with other
nucleophiles.
5.6. Synthesis of 3-nitro-4H-chromenes 88a-f from dlfferent nitroketene NJ-
acctal76b-g
SMe
59-83% NHR
l e a 76b-g 88a.f
76b, 88s: R = n-Bu
76c, 88b: R = Ph
76d, 88c: R = Bn
76e, 88d: R = (CH2)zPh
76f, 88e: R = (CH2)2C6H40Me-p
76g, 88f: R = CH(CH3)Ph
Scheme 1.34
In continuation of thc studies on CSA reaction, wc ncxt focused on changing
substitution on the amino goup from methyl to alkyl aryl groups (Schemc 1.34).
The condensation reaction of all worked well under optimized conditions (DBU in
MeOH) at rt to generate a combinntorial library of 4H-chromenes 87a-f in good yields
(Tablc 1.6).
Table 1.6: Synthesis of 3-nitro-411-chromencs 88a-f from diffcrcnt nitroketene N,S- acctals 76b-g and 2-hydroxybcnzaldehyde 18%
E~~~ Nnmketna 3.Nllrc-4H.
6"tly Nltmkelsna 3.Nnm4H.
N S.as~lal chmmene
N,S.BCBUI chmmene
(Ilme yield) illme, yleldj
3
NHBn Ma*,,
2 MeS AND' NHPh NO' NHPh
By achieving the synthesis of 4H-chromenes 88d and 88e we have now
incorporated physiologically active arylcthylaminc unit into 4H-chromene (Table 1.6,
entry 4 and S), The spectral values (IR, 'H, I3c NMR spectra) of above 4H-chromene
88a-88f matched well with the parent compound 87% The structure of 88c was
confirmed unambiguously by single crystal X-ray analysis (Figure 1 . 1 9 ) . ' ~ ~
NO
McS ~ N ; ~ ~ H 2 ) , c s H , o M e &NO'
NHICHJ2C.H.0Me
S,Me
6654a/4x3,N02 I II I / 708,8a.0.2\
NHR
Table 1.7: Comparison of "C NMR spectral chemical shift ( 8 ) value of 3- nitc*H-chromencs
Carbon atom
number
2
3 - 4
4a
5
6
7
8
I 8a
I SMe
PEA = Phenylethylamine: PMPEA = p-Methoxy phenylethylamine ' 41.2 (CH!), 3 1.5 (CHI), 19.9 (CH2). 12.2 (CHI); 134.7 (C), 126.3 (2 x CH), 129.4 (2 x CH), 123.1 (CH); ' 45.5 (CH2), 136.0 (C), 127.3 (2 x CH), 129.2 (2 x CH), 126.2 (CH); 43.0 (C'HI), 40.3 (CH*), 137.4 (C), 128.6 (2 x CH), 128.9 (2 x CH), 126.1 (CH): " 43.2 (CHI), 40.3 (CH2), 129.3 (C), 129.7 (2 x CH), 114.3 (2 x CH), 158.6 (CH), 55.2 (OMe).
88a @Sf. 3-Nitro-4H-Chromenes
R - Bu" 88a
159.4
105.5
40.3
122.4
129.1
R-
88b
156.9
106.6'
40.1
122.1
129.0
88e 159.3
105.9 I
40.3
122.4
129.1 ".
128.2
128.7
115.6
127.1
128.2
I 15.6
148.8--
12.2
126.1 126.6
159.3
105.6
36.1 .
126.1
128.6
115.6
148.8
12.2
128.7
115.6
159.4
105.6 -- - . . . -
35.2 -- --
128.8
115.7
148.8
13.6
122.4
129.1
148.7 148.8
122.4
129.1
12.1 12.2
1
./\ 1 I Figure 1.19. Thc s~ngle crystal X-ray structure of A'-bcnzyl-N- [4-(methylsulfanyl)-3-n1tro-4H-2-chromcnyl]m1ne 86c.
5.7. Synthesis of 3-nitro-4H-chromenes 89b-g having amino acid unit
SMe NH 41 -62%
88b-g 18a 89b-g
86h, 89b: R = Me
86c, 89c: R = CH2Ph
86d, 89d: R = CH(CHa)2
86e, 89e: R = CH2CH(CH1)2
86f, 89f: R = CH(CH))CH2CH,
86g, 898: R = CHI(CIH~N)
Scheme 1.35
After realizing the synthesis of n-nlkyllaryl 2-amino-411-chromcne, we
focused on the synthesis and characterization of amino acid substituted 4H-chromenes
89b-g with an objective to determine if there is any chiral induction arising from
amino acid portion to the newly generated stereogenic centre at C4. Thus, the
nitroketene N,S-acetals possessing amino acid residues of alanine 86b, phenylalanine
86c, valine 86d, leucine 86e, isoleucine 86f and tryptophan 86g, on treatment with 2-
hydroxybenzaldehyde 18a under optimized conditions yielded the CSA products 89b-
g as inseparable mixture of diastereomers (Scheme 1.35). The glycine substituted
nitroketene N,S-acetal X6a. howcvcr failed tn undcrgo this condensation reaction,
possibly, becausc of the acidic nature of thc active methylene proton in the glycinc
unit. The chiral HPLC analysis showed the presencc of four products - two pairs of
enantiomers - for each compound. The yiclds of the product and the diastereomer~c
cxcess of the major isomer are given in the form of Table 1.8.
Table 1.8: Synthesis of 3-n1tro-4H-chromcncs 89b-g from amino acid containing nitrokctenc N,S-acetal 86b-g.
All thc six amino acid substitu~ed 3-nitro-4H-chromenes 89b-g were
5-nltro.4H. Enlw chromene de(%)
(t~me, y~eld)
characterized by physical, analytical and spectroscopic data. From thc "C NMR
3-n~tro-4K En'ry chrornene de(%)
(time yleld)
spectra, it was found that the product formed was a diastereomeric mixture. The
diastereomeric ratio and diastcreomeric excess was calculated from the 'k NMR
spectra. The diastereomeric excess was found to be maximum for phenylalanine
substituted 3-nitro-4H-chromene 89c. The yield of the 4H-chromenes 89b-g and
diasterwmeric excess are presented (Table 1.8). The I3c NMR spectral peaks due to
the major product were extracted from the spectra and the data is given in the form of
Table 1.9. As a representative example 'H and "C NMR spectra of 89e are given in
Figure 1.20 and Figure I .21.
Table 1.9: Comparison of "C NMR 6 value of amino acid substituted 3-nitro-4H-
22.7 (CH1); "0.2 (CH), 15.5 (CHI), 24.7 (CHI), 11.2 (CHI); 51.1 (CHl), 106.7 (C), 122.6 (CH), 116.5 (CH), I2O.O(CH), 117.5 (CH), 110.3 (CH).
gbff $URkf#RRE&AWREE8ia I=== .:::: ,,,,,,,,,.,,. $ 139 "! m ... m
I
I
I
BI
.. . - , - - - - -- -
~ i ~ u r i 1-20 300 MH: (CDCI~) 'H R M R spectrum (methylsulfanyl)-3-n1tro-4H-2-chromenyl]am~nopentanoate 89e
I s rn n L Figure 1.21 75 MHz (CDCla) "C NMR spectrum of methyl 4-methyl-2-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 89e.
5.8. Synthesis of 2:1 adducts 90a-f
aCHO+ ~ ~ ' 2 N a z H F
OH MeS N H R reflux, 800C
76a, 87a. 90a: R = Mc
76b, 88a, 90b: R = n-Bu
76c, 88b, 90c: R = Ph
76d, 88c, 90d: R - CH2Ph
76c, 88d, 90e: R = 11-(CH2)2Ph
76f, 88e, 901: R = (CH2)2CbH40Me-p
Scheme 1.36
When we conducted the CSA reaction of 2-hydroxybenzaldehyde 18a with
NMSM 768 in NaH-THF reflux, we isolated a minor amount of the adduct 90a (4%
yield) along with the major product 87a in 75% yicld (Scheme 1.36). Thc 'H NMR
spectrum of the minor product indicated its formation by the reaction of two
molecules of NMSM 768 and one molecule of 2-hydroxybenzaldehyde 18a. The
product however could not he cleaned from contaminants. On the other hand, in the
reaction of N.5-acetal possessing N-benzyl group 76d, the minor product 90d was
formed in 24% yield (Scheme 1.36). The UV spectrum of 90d showed ),,,, 378 nm
(log E = 4.5), 354 run (log c = 4.7) and a shoulder at 280 nm. Two longer wavelength
bands indicated the presence of two nitroketerie acetal moieties. The IR spectrum
exhibited bands at 1556 and 1370 cm", which are assignable for nitro group. 'H NMR
spectrum (Figure 1.22) displayed a singlet at 6 2.69 ppm assignable to SMe. One of
the two methylenes occurred as doublet at 6 4.8 ppm with a coupling constant of 5.7
Hz and the other occurred at 6 4.9 ppm as doublet of doublet with a coupling constant
of 15.0 Hz and 5.4 Hz assignable to diastereotopic benzylic hydrogens. A singlet at 6
6.55 ppm for benzylic hydrogen and broad singlets at 6 11.0 and 11.5 ppm for two
NH protons indicated the formation of 2:l adduct. The "C NMR spectrum (Figure
1.23) showed signals in the aliphatic region for one SMe, one methine and two
benzylic methylene carbons. Based on HMBC correlations we assigned that the signal
at 161.57 ppm is due to the quaternary carbon of side chain N,S-acetal and 160.32
ppm is due to the quaternary carbon preqcnt in pyran ring where NH-benzyl g o u p is
attached.
-. .,-- . 1. ,. , . , --"".'T' I 8 8 ? , , ,
10 s I a 6 4 a z ~ p p m
'It< 74 Figure 1.22 300 MHz (CDCln) 'H N M R spectrum of M-benzyl-4-[(a-2- (benzy1amino)-2-(methylsulfany1)-I -nitro-I-ethenyl]-3-nitro-4H-2- chromenamine 90d.
80 $0 IW IW m m m w o p
Flgure 1.23 75 MHz (CDCI3) "C NMR spectrum of M-benzyl-4-[(m-2. (benzy1amino)-2-(methy1sulfanyl)-l -nitro- l -ethenyl]-3-nitro-4H-2- chromenamine 90d.
Similar to 1 :l CSA udduct, (see Scheme 1.33) 2: 1 adducl 90 could be formed
through bcnzpyrilium cation (Schemc 1.37). This intermediate is quenched by one or
more unit of N,S-acctal 76. This was confirmed by treating parent 4H-chromene X7a
with nitroketene N,S-acetal 76a in presence of NaH in THF and the reaction yielded
thc 2: 1 adduct 9Ua. Wc found that 2:l adduct formation betwccn NMSM derivatives
76a-f and 2-hydroxyhenzaldehyde 18a is quite general. when conducted in NaH I
THF rcflux. Four more NMSM derivatives were reacted w ~ t h I8a to provide the 2:1
adducts in 4-24% yield formed in each case as minor pr~~ducts (Table 1.10).
Spectroscopic analysis confirmed the assigned structure of the adducts and they
matchcd well with the parent compound 90a (Table 1.1 1).
O N N H R + acHO SMe OH -
76a.f 18a
O Z N y N H R SMe
NO, - W N O 2 NHR
NHR s d H R +
Scheme 1.37
Table 1.10: Synthesis of 3-nitro-4/f-chromenes (2:l adduct) 90a-f ffom different substituted nitroketcne N,S-acetal 76a-f.
3 NO,
@
NHPh
Enlry 2 1 adducl Y'e'd in) IS)
Table 1.11: Comparison of "C FJMR 8 value of 3-nitro-4H-chromenes
Entry I llducl Time yield ih) 1%)
NHCH, I NHCH>Ph
5.9. Reaction of 3-nitro-4H-chromene 87a with high boiling thiols 91s-e
EtOH
+ RSH - NHMe
9-18 h 75-93%
87a Ola-e Q2a-e
91a, 92a: R = ChHs
91 b, 92b: R = 4-CH3ChH4
91c, 92c: R = 4-CICoH4
91d, 92d: R - ~- (CH~) ICHI
91e, 92e: R = n-(CHj)7Ctl1
Scheme 1.38
According to the proposed mechanism for the formation of 4H-chromenes 87
(Scheme 1.33) the benzpyilium cation is the key intermediate. We reasoned that it
should be possible to quench this intermediate with different nucleophiles to prepare
products of structural diversity. Accordingly, 3-nitro-411-chromene 87a was treated
with three-equivalents of high boiling aromatic thiols like thiophcnol 91% 4-methyl
thiophenol 91b, 4-chloro thiophenol 91c and aliphatic thiols like butane 91d and
octane thiols 91e in ethanol retlux to provide C4-substituted 411-chromenes 92a-e in
excellent yield (Scheme 1.38, Table 1.12). Before concluding ethanol as solvent, we
tried the reaction of 87a with butane thiol 91d in THF. However, the reaction
provided 92d as the only product in 62% yield. For efficient conversion of 87a into
92d, the reaction needed three equivalents of thiols 91d. With one or two equivalents,
the reaction was slow, cven after 24 h in EtOH reflux as starting material 87a was
only partly converted to product 92d.
Table 1,12: Synthesis of 3-nitro-4/{-cliromene 87s from high boiling thiols 91a-c
2
NHMe
3
NHCH,
4
NHMe
5 19 93
NHMe
920
A!! the five thiol substituted 3-citro-41f-chromenes 9211-e were characterized
by analytical and spectra! data which matched well with the parent 4fI-chromene 87a.
The I3c NMR spectral data for the fivc compounds arc given in the form of Table
1.13. Apart from the characteristic singlet for benzylic proton at about 6 5.6 ppm in
'H NMR spectra, the newly made 4H-chromenes 92a-e displayed appropriate signals
due to C4 side chain. As a representative example 'H and "C NMR Spectra of 92d
are given in Figure 1.24 and Figure 1.25.
From this study we have shown that C4 SMe group can be readily replaced
with soft nucleophiles. Since thiopheno! replaced SMe group readily, it was of interest
to study the reaction of patent 4Ij-chromene 87a with phenols.
I J Figure 1.24 300 MHz (CDCI1) ' H NMR spectrum of N-[4-(hutylsulfany1)-3- nitro-4H-2-chromenyll-N-methylaminc 92d.
"i30.7(C),128.3 (2 x CH), 137.2 (2 x CH), 128.5 (CH); 127.1 (C), 128.5 (2 x CH), 137.0 (2 x CH), 119.3 (C-CHI), 21.2 (CHI); 135.8 (C), 128.5 (2 x CH), 138.4 (2 x CH), 129.7 (C); 21.4 (CH?), 29.9 (CH?), 22.0 (CHI), 13.5 (CH3); ' 31.7 (CHz), 30.2 (CHz), 29.4 (CH?), 29.1 (CHz), 29.0 (2 x CH); 28.0 (CH?), 22.5 (CHz), 14.1 (CH3).
Tablc 1.13: Comparison of "C NMR 6 value of thiol substituted 3-nitro- 4//-chromenes Carbon
atom
No
2
3
4
. 4a
5
6
i: Xa
NHMe
92a-c. - 3-Nitro-4H-chromenes
R = Pha
92a
159.9 -
105.4
45.6
122.7
129.2
125.9
129.2
148.5
R = P ~ C H ?
92b
159.9
166.1
45.5
1 2 2 . ~ -
129.2
125.8.
129.1
1 1 ~ ~
y78f 27.6
R = PhCI'
92c
159.7
l 0 i 5
45.9
122.7
129.2
126.0
128.8
115.5
148.6
27.7
R - (cH~),
C ~ 1 " 9 2 d
159.9
106.8
39.8 --
123.3
129.0 --
, 126.0
128.6
R = (CH?),
CHqr92e
160.0
106.2
39.9
123.3
129.1
126.1
148.6
28.0
- 148.6
28.0
5.10. Treatment of 3-nitro-4H-chromene 87a with phenols
path c
NHMe
93 87a 140 95a 1,4-sub$tItut1on 1,2-substitut~on
path a
Q
94
(ether)
Scheme 1.39
Three reaction products are possible from the rcaction of phenol 14e and 4H-
chromcnc 87a. i. SNI substitution provides 94, an ether; ii. C2 electrophilic aromatic
substitution product 95a; iii. C4 electrophilic substitution product 93 (Scheme 1.39).
In contrast to the reaction of 3-nitro-411-chromene 87a with thiophenol 91a, which
yielded substitution product 92a, the reaction wi:h phenol 14e in EtOH medium
yielded the regio-selective electrophilic ring substitution product 95a exclusively
(Scheme 1.39). Employing bases like NaH 1 THF or KzC03 I CH,COCHJ or NaOMe I
MeOH provided only lower yield of 95a, but there was no trace of substitution
product 93. When the reaction was carried out with sodium acetate, the reaction was
fast but it was not clean and the overall yield was poor. Thus, best yield of the product
95a was obtained with three equivalent of phenol 14e in ethanol reflux. In all cases,
the product crystallized out from the reaction mixture.
NHR X
87a, 88a-c 14e. i 95a-n
87a: R = Me: 14e: X = Y = Z = H; 95a: R = Me, X = Y = Z - II 87a: R = Me; 14f: X = CH3. Y = Z = H; 95b: R = Me, X -Me. Y = Z = H
R7a: R = Me; 14g, 9%: X = C1, Y = Z = H; 9%: R = Me, X = CI, Y 2 = H
87a: R = Me: 14h, 95d: Y =CHI, X = Z = H; 95d: R = Me, Y =CHI, X = Z = H
87a: R = Me; 14i. 95e: Z = CIIJ, X - Y = H; 95e : R Me, Z = CHI, X = Y = H
88a: R = n-Bu; 14e, 95f: X = Y = Z = H; 95C: R - n-Bu, X - Y = Z = I f
88a: R = n-Bu; 14f, 95g: X =- CH,, Y = Z = H; 95g: n-Bu, X = CHI, Y = Z = H
88s: R = n-Bu; 14g, 95h: X = CI, Y = Z = H; 95h: R = n-Bu, X = C1, Y = Z = H
88b: R - Ph; 14e. 95i: X = Y = Z = H; 95i: R = Ph, X = Y =I, = H
8Xh: R = Ph; 14f, 95j: X = CHI, Y = Z = H; 95j: R = Ph, X = CH3, Y = Z = I f
88b: R - Ph: 14g, 95k: X = Cl, Y = Z = H; 95k: R - Ph, X = CI, Y = Z = H
88c: R = Bn; 14e, 951: X = Y = Z = H; 951: R = Bn, X = Y = Z - H
88c: R = Bn; 14f. 95m: X = CHI, Y = 2 = H; 95m: R = Bn, X = CH3, Y = Z = H
88c: R = Bn; 14g, 9511: X = CI, Y = Z = H; 9%: R = Bn, X = C1, Y = Z = H
Scheme 1.40
The product formation was ascertained by the analysis of 'H and "C NMR
spectra. The 'H NMR spectrum (Figure 1.26) showed a doublet at 6.8 ppm for IH
assignable to aromatic hydrogen next to phenolic hydroxyl group. Similarly, the I3c NMR spectrum (Figure 1.27) displayed a quaternary carbon at 124.7 pprn. As a
comparison the C2 quaternary carbon in 2-methylphenol 14i occurs at 124.0 pprn. If
the substitution were para to hydroxyl as in 93, the 'k NMR spectrum should have
displayed four peaks instead of six as observed. The fact that all the six carbons arc
observed rules out the possibility of ether 94 as a structure of the product.
Substitution of phenol 14e in ortho-carbon shows that electrophilic aromatic
substitution at C2 has taken place exclusively. Hydrogen bonding interaction with
nitro group could be responsible for generating single regioisomer. Such substitution
reaction did not take place with anisole or catechol dimethylether, pointing out the
dccisive role of phenolic hydroxyl g o u p in the product formation.
Present 4-aryl-4H-chromsne synthesis is by two high yielding steps tiom
commercially available 2-hydro~ybenzaldeh~de 18a, nitroketene N,S-acetuls 76 and
phenols 14. In both the steps product crystallized out of the rcaction mixture making
thc reaction attractivc in terms of scale up. As noted in the earlier section 4-aryl-4H-
chromenes 17 are prepared from electron rich phenols 14, reactive aryl aldehydes 15
and malononitrile 16. Eventhough earlier method is a single step process it could not
bc extended to generate 2-hydroxyaryl substituted 4H-chromenes.
To tcst thc gcncrality of electrophilic ring substitution, we prepared a library
of 4-aryl-3-nitro-4H-chromenes 9Sa-n by taking three different phcnols 14e-g. Each
one of them wcre treated with four different NH-substituted 3-nitro-411-chromenes
87a, 88a-c to furnish twelve 4-aryl-3-nitro-4H-chromencs 95a-c and 95f-n in good
yields (Scheme 1.40). In cach case, the substitution was exclusive to C2 position of
phenol. Othcr than these three phenols, we canicd out reactions using ortho and mcta-
cresol 14h & 14i with the parent 3-nitro-4H-chromcncs 87a to yield two isomeric 4-
aryl-3-nitro-411-chromenes 95d, 9Se. The yield of the products arc givcn in the form
of Table 1.14.
Some of the phenol substituted compounds exhibit atropisomcrism due to
restricted rotation around C-C single bond possibly due to strong hydrogen bonding
stabilization between the hydroxyl and the nitro g o u p of the chromene moiety. The
operation of atropisomerism was evidenced by observation of two sets of pcaks from
' H and "C spectra. The 'H NMR spectra of each one of the 4-aryl-3-nitro-4H-
chromenn displayed a characteristic singlet for the brnzylic proton at about 5.4 ppm.
The "C values assigned for the 4H-chromene 95s-n are given in Table 1 . I 5.
We conducted a reaction where two steps namely CSA condensation of 2-
hydroxybenzaldehyde 18s with NMSM 76a followed by electrophilic substitution to
generate 4-aryl-4H-chromene 95a, can be combined in one-pot reaction. Towards this
objective we conducted the reaction by taking one equivalent of 2-
hydroxybenzaldehyde 188, one equivalent of NMSM 76a and 1 . 1 equivalent of
phenol 14e in the presence of 0.1 equivalent of NaOAc in water. This reaction
furnished 4-aryl-4H-chromene 95a in 81% yield after recrystallization using EtOH
Table 1.14: Various 4-aryl-3-nitro-4H-chromcnes 95a-n prcparcd from phenols 14e-g and 87s.
951 (14 h. 45%)
10
NHPh
95j (17 h 64%)
E~~~~ 4.A'yl-3.n1lro.4H. chromene
Entry 4 . ~ , ~ ~ . 3 . ~ , ~ ~ ~ . ~ ~ . chromene
En,ry 4-An/1.3-nlro-4H. chromrns
NHMe
951 (12 h. 88%) 95f(12 h, 63%) 96k (16 h 40%)
\ NHMe \
QSb(19h 73%) 95% (12 h. 73%) 951 112 h 87%)
' OH OH OH
, NO, , NO,
NHCH,Ph
95c (29 h. 51%) e l h ( l 3 h 43%) vsm (16 n. 46%)
I - ... I Figure 1.26: 300 MHz (DMSO-d6) 'H NMR spectrum of 2-[2-(methy1amtno)- 3-nitro-411-4-chromenyl]phenol 9%.
I . * " . , , Z2PEOP:kL% 8 5 5 5 E$E3%g$leE " I
I m 'd
Figure 1.27. 75 MHz (DMSO-d6) "C NMR spectrum of 2-[2-(methylam~no)- m
3-nttro-41f-4-chromenyl]phenol95a.
Tal r-
le 1.15: Comparison of "C NMR 6 value of 4-aryl-3-nitro-4H-chromenes.
1
- R-CH>
X = H 9Sa
I SO S
llK>X
371
I311 2
12'1 ll
I!?!
I 2 7 7
1158
147 4
- 1545
1247
129 I
1188
1279
1156
4.Aryl-3.n~tro4il.c111~~m~1ic, ,.
37 U
R=CHI X-CHt 951,
15'44
1596
1169
372 8
125.2
124 7
R-Bu X-CI 95h
ISYO
llih.2
I 376
R=CHI X-CI 9%
159 1
11163
370 374 j
' R-Ph X-H 951
ISh9
If lR! '
374
' R-Ph X-CHI 95,
I 5 6 9
15'0
l l lX3
37 4
2 4
R-Bu X-H 9Sf
37 h
RrPli X=CI PSk
lShh
1117.7
- - .. R-Bu
X=CII1 9
1289 ' 1 2 q 3 1 I 2 8 4
374
R=B, X z t l 951
158.5
1589
107 1
1082
3
127 1
127 0
127 K
l l X R
145 1 1474
I 5 2 3
1546
1243
I30 I
1303
1343
128 0
I28 4
I 1 5 6
1 15 8
2 9 1 I
1
1 I I 13011
I 5 9 9 / 159 1
I202
l ? b 4
I284
1181
1483
l S 3 b i
1250
1299
1212
I 2 8 4
1157
1249
I2701
1 1 7 0 ,
1473
1514
1217
1288
1318
1277
1154
372
R-ll, X-CH3 95m
IS90
107 1
1072
..-- l i lh8
4 1 s
2
R-0, X-CI 95"
1587
, 1067
1592
I l l6 8
l i ib 9
372
I!X I I I!9!!4
I2Y l I 1291 i 129 I
1 1277
125 !
1259
1169
147 1
153 3
1229
1290
130.9
1272
1169
36 8
37.2
1 ~ x 4
125?
I27 I
127 7
I I X ' I
I455
1474
IS23
IS4.h
124 1
124 7
1290
1294
1343
127 7
1279
l l S 5
1157
1!6!
I 2 7 9
1218
1473
1547
1244
I29 S
1245
1280
1188
3
37 1
. 1252
? ? 4
1172
i475 /
IS37
123 h
129 0
1319
I282
1157
I25 5
I 2 6 2
1280
1189
1454
1472
1524
1517
124.0
129 6
1298
127.2
1283
12R h
111.4
1156
1289
I 2 5 2
I25 7 - 127 X
1 2 7 0 1
1157
11611
1474
1546
IS62
124.7
I29 I
12Y?
1188
I28 I
1152
115.6
24 .9 I 2 2 5
1291
5
1277
127.9
111.7
1188
1454
147.3
1522
1546
I 2 4 3
I 2 9 9
1300
1344
l ? & I
128 4
1154
1156
1288 1 I 2 5 0
I?'?
1169
118.7
1472
153.3
1236
I:8 8
1314
117 7
I 1 5 3
1156
A z i n e gOAc rt, 16 h, 57%
NO2
,' 0' NHMe /
0 NHMe
Scheme 1.41
The parent 4-aryl-4H-chromcnc 95a was converted to its acetylatcd derivative
96 with acetic anhydride and pyridine (Scheme 1.41). The 'H and "C NMR spectra of
the acetylated product 96 showed two sets of signals confirming atropisomerisrn due
lo restricted rotation around C-C single bond. X-ray crystal structure of the acetylated
derivative 96 ( F i p r c I .28) further conf ined the assigned structurc. The X-ray crystal
structurc displayed cxistence of stabilizing hydrogen bond interaction between
oxygen of NO2 and NH of N H M ~ . " " The X-ray crystal structure also showed that thc
aryl ring occupies pseudo-axial orientation with acetyl group projecting into the space
above the plane of 4H-chromene moiety.
I 1
Figure 1.28: The single crystal X-ray structure of 2-[2- (mefhylamino)-3-nitro-4H-4-chromenyl]phenyl acetate 96.
Atler demonstrating facile aromatic substitution of phenols to provide 4-aryl-
4H-chromene, we turned our attention towards the synthesis of bis-chromene by
reaction with 1,2-, 1,3- and 1,4-dihydroxybenzene derivatives.
OH
NaOAc NHMe EtOH, reflux
8 h 82% 97 87a 98
Scheme 1.42
Reactlon of 1,3-dihydroxybcnzene, 1,4-dihydroxybenzcnc in presence or
absence of NaOAc provided only a no no substitution product 97 and 98 respectively
(Scheme 1.42). Eventhough TLC and column chromatography indicated presence of
bis-chromene in minor quantities, they could not bc isolated and characterized (less
than 3%). The 'H and "C NMR spectra of 98 are given in Figure 1.29 and Figure
1.30.
:-c r m m . !!E!Eif3iig ?
? I
Figure 1.29 300 MHz (DMSO-d6) 'H NMR spectrum of 2-[2-(methy1amlno)-3- nltro-4/~-4-chromeny1]-1,4-ben~ened10l 98
OH
87a 90 100
Scheme 1.43
The reaction of parent 4H-chromcnc 87a (2.0 equiv), 1,2-dihydroxybcnzene
( I .O equiv) provided two products (Scheme 1.43). A major product (30%; higher R,
value in silica gel TLC) is the monosubstitution product 99 and the minor (25%)
being bis-chromene 100. Formation of his-chromene 100 was confirmed on the basis
of ESI-MS, which exhibited MtH signal at 519.1526. The 'H and "C NMR spectra
of 99 matched well with 4-aryl-4H-chromene 95a. Several attempts to increase yields
of bis-chromenc by changing reaction conditions like usc of higher boiling solvents
like isopropanol or using NaOAc did not help.
HO
EtOH NHMe NHMe
reflux
87a 101
Scheme 1.44
The reaction of 4/f-chromene 87a with phloroglucinol (1,3,5-
trihydroxyhcnzene) did not yield desirable tris-4-aryl-4fI-chromene 101 (Scheme
1.44) and the starting matcrial was recovered even after 24 h reflux in EtOti with or
without NaOAc.
- 12 h, 92% 8 h, 74%
NHMe
EtOH. reflux 12 h, 89%
103 Scheme 1.45
Reaction of parent 4H-chromene 87a with I-naphthol, 2-naphthol and 8-
hydroxy quinoline in ethanol reflux leads to the formation of 4-aryl-3-nitro-4H-
chrornenes 102-104 respectively in quantitative yields (Scheme 1.45). In each case,
only one regioselectivc product was formed. Thc structure of the product was
confirmed by HMBC correlations between C4H and quaternary carbon next to aryl
OH. It is intercsting to note the regiochemical outcvmc of the reaction of 87a with I -
naphthol. Both C2 and C4 substituted products are possible from this reaction.
Isolation of single regioisomer 102 shows that the substitution is highly influenced by
hydrogen bonding interaction of CH with NO2. The ' H and "C NMR spectra of 103
arc given in Figure 1.31 and Figure 1.32.
8
:a ,, WF SCW461PPR%BRtEi$~@% 1. ----l..--..O.....l*l
I
I
E 8 I 1 n
Figure 1.31 300 MH7 (DMSO-dh) 'H NMR spectrum of I-[2-(meth~l~mlno)-3- n1tro-4il-4-chrornenyI]-2-naphthol 103
l
a E 8 f i iR0Im:Z2Y3ZP:U 5 5 i jafiggac&ggm:snp
/ I
I T I ' ' "
Figure 1.32 75 MHz (DMSO-d6) "C NMR spectrum of 1-[2-(methylam~no)- 3-n1tro-4H-4-chromenyl]-2-naphthol 103
5.1 1 . Reaction of 4H-chromene with electron rich aromatic compounds
Having succeeded in displacing thiomethyl group in 4H-chromene with
phenols. it was our next endeavor to rcplace thiomethyl group with electron rich
aromatic compounds to preparc different 4-aryl-411-chromcnc dcrivatives.
NHMe 10 h, 92%
87a 105 108
Scheme 1.46
As a part of this effort we reacted the 4H-chromene 87a (1.0 cquiv) with NJ-
dimethylaniline 105 (1.0 equiv) and the reaction provided 4-aryl-4H-chromene 106 in
near quantitative yield (Scheme 1.46). The regiochemistry in the substitution of NJ-
dimethylaniline was ascertained from ' H NMR spectmrn (Figure 1.33), which showed
AA'BB' quartet for hydrogens on N,N-dimethylanilino ring. The "C NMR spectrum
(Figure 1.34) displayed signals for four aromatic carhons of NJ-dimethylaniline
portion, confirming assigncd structure.
H,C.N.CH,
0 NHMe
- .-L' . I . . . - -- - - . - . f.
Figure 1.33 300 \{Hz (CDCI! - DSlSO-d,) H SMR spcctrum of .I?-methyl-4-
r- .--,-- - ? ,- -- _ _ _ _ ,. ? --- 7 Flgure 1.34 75 MHz (CDCI3 + DMSO-db) "C NMR spectrum of hZ-methyl-4- [4-(dimethylam1no)phenyl]-3-nltro-4H-2-chromenam1ne 106.
EtOH - reflux 6 h, 93% &""' 0 NHMe
Scheme 1.47
Reaction of 4H-chromene 87a with indole 107 was facile and provided indole
substituted 411-chromenc 108 (Scheme 1.47). Substitution on indole took place, as
anticipated, at C3 position. This fact was ascertained by the presence of quaternary
carbon signals st 111.7 ppni in the "C NMR spcctrum (Figure 1.36) of 108. In
addition the 'H NMR spectrum (Figure 1.35) did not show a signal at 6.5 ppm, which
would have appeared if there was a hydrogen on C3 of indole.
I I
Figure 1.35 400 MHz (DMSO-db) 'H NMR spectrum of N-[4-(llf-3-indoly1)-3- nitro-4H-2-chromenyll-N-methylamine 108.
F' 0 NHMe
$*,
A h I .
, , ; , L I 1 O * I 1 6 1 1 L P P
kl W
I
I - 7 , I- 11. >.. ,.. 1.1 1.0 LI. 1.0 10 'I . 20 0 -
Figure 1.36 100 MHz (DMSO-d(,) "C NMR spectrum of N-[4-(1 H-3-indolyl)- 3-nitro-4H-2-chromenyI]-N-n1cthylamine 108.
reflux
87a 109 110
Scheme 1.48
The reaction of 4H-chromene (1.0 equiv) 87a with pyrole (3.0 equiv) 109
provided C2 substituted product 110 (Scheme 1.48) and this fact was ascertained from
'H NMR, which exhibited three broad and one sharp singlet between 5.2 and 6.8 ppm.
In addition "C spectra showed a quaternary carbon at 134.5 ppm assignable for C2' in
pyrole ring.
mNo2 NHMe
113
CX- NHMe -+ NHMe E~OH, refux EtOH, reflux NHMe
87a
Scheme 1.49
Reaction with other electron rich heterocyclic aromatic compound like
thiophene (3.0 equiv), furan (3.0 equiv) or imidazole (3.0 equiv) did not provide any
substitution product 111-113 (Scheme 1.49). In all the cases the starting material was
rccovered as such
NHMe 115
NHMe
87r
Scheme 1.50
Similarly the reaction with marginally electron rich aromatic compounds like
anisole, 1,3-dimethoxy benzene and o, p-directing chlorobenzene also did not provide
substitution products 114-116 (Scheme 1.50), indicating that electron rich nature of
aromdtlL nng and thc hydrogen bondlng ~nterdct~on of Ot-l with nltlo group dre
rcqulrementr tor the arnmat~c elcctroph~l~c suhst~tut~on redct~on
5.12. Attempted substitution reaction with nucleophiles like alkoxide, prinlarj
amine, azidc and cyanide
NaCN EtOH or NaCN MeOH or
NaCN THF+DMF ' rl NaN, DMFor NaN, DMSO or
-X--
NHMe
118 87a 117
Scheme 1.51
Slnce benzpynl~um catlon IS generated from 4H-chromene 87a by ellrn~ndtlon
of methylth~oldte anlon, we reasoned that t h ~ s lntermcd~ate ~ o u l d be quenched w~!h
products 117-119 (Schcmc 1 51) Rcact~on In each cdsc was conducted both under
S h l and ShZ cond~t~ons only to find that thc reartlon d ~ d not take place, to prov~de
mean~ngful productr In all the ca$er there was an extens~ve decompos~tlon of 4H-
chromene 87a and no lsolahle product could be reallzed S ~ n c e thc nucleoph~les llke
cyan~de, a z ~ d e and alkox~de cdn behave ds bases, ahstract~ng NH proton to generate
anlon IS a competing reactlon Once the anlon gets generated the ~ntermed~dte could
undergo heterocyclic nng opening and d~s~ntegratc the molecule
C,H,NH, EtOH or Benzene or
A A THF, r t
EtOH or Benzene
C,H,CH,NH, EtOH or Benzene or THF, rt
120
Scheme 1.52
When the reaction of 87a was conducted with a primary amine namely.
benzylamine only product isolated was the imine 120, which got generated i ~ ~ s i t u
from 2-hydroxybenzaldehyde and benzylamine (Scheme I . 5 2 ) . In this case the 4H-
chromene 87a possibly undergoes retro-CSA reaction to salicylaldehyde which
condenses with benzylamine. Alternatively it is also possible that the initial
substitution leads to amino product which undergoes decomposition. This reaction
was found to be general for other primary amines like butylamine and aniline. In both
the cases the only isolable products were bidentate ligands 121 & 122 (Scheme 1.52).
Reaction with secondary amine like piperidine leads to undetectable products.
5.13. Substitution of SMc in 4H-chromene 87a with hydride
Next attempt on synthetic modification of 4H-chromene 87a was SMe group
replacement with hydrogen so that thc latent amino acid component can be revcalcd.
In this quest we treated 4H-chromene with various reducing agents. Reduction of 4H-
chromene with Raney Nickel proved to be most difficult reaction to encounter in
present rcscarch.
- reflux, 15 h, 11% NHMe
87a 124
Scheme 1.53
Upfront we thought reductive removal of SMe group is a facile reaction with
Kancy nickel. This reaction, however was most dimcult to handle. Not only reaction
was dependent on the batch of Raney nickel, it also did not yield desired product.
Rancy nickel reaction was conducted in EtOH, EtOH-THF, THF and iPrOH-THF at
rt. Only in one case we isolated a dimeric product 124 in I I% yield (Scheme 1.53).
The NMR spectrum of this molecule was remarkably similar to the parent 4H-
chromene 87a, the signal due to SMc was missing. A singlet at 4.84 ppm for two
hydrogens, two doublets and two triplets in the aromatic region for eight hydrogens
and a broad quartet at 10.27 ppm for two hydrogens along with a doublet at 2.85 ppm
for two hydrogen's endorsed the proposed structure. The "C NMR spectrum
exhibited two signals at 27.52 ppm and 38.94 ppm along with eight signals in the
aromatic region.
dNo2 a:-';. NHMe
rt, 2 h, 12%
87a 125
Scheme 1.54
In one of the runs, thc reaction provided M-methyl-2H-2.3-chromenediaminc
125 in 12% yield (Scheme 1.54). The product however. could not bc isolated in pure
form. The ' H NMR spectrum showed a singlet at 6 3.1 ppm for NHMe, a singlet at 6
6.2 ppm for C2H and multiplct for aromatic hydrogens. "C NMR spectrum displayed
a sibmal for CH, group at 6 33.2 ppm and for CH at 6 102.2 ppm apari from the
aromatic and olefinic carbon signals. In thc abscncc of complete spectral data the
structure assigned is tentative.
mN02 0 0
127
t BF,. Et,O MeOH, fl
NHMe
871 Scheme 1.55
Reductive removal of SMe in 4H-chromene 878 did not take place with H2.
5% Pd-C in presence or absence of acetic acid. Similarly hydride reducing agents like
NaBH4 in MeOH, NaBH4 in EtOH, NaBH4, BF3.Et20 in THF (BH,), LAH in dry
diethyl ether at -78 'C or at room temperature did not yield any tangible products
(Scheme 1.55).
HgCI,, EtOH &No2 or M 4
NHMe reflux, 1 h, 44%
871 127
Scheme 1.56
As a part of our studies on reductive removal of SMe group from 87a, we
e~nployed HgCl2 in EtOH or catalytic amount of HC1 in dry MeOH to remove SMe
group (Scheme 1.56).In4 Only product isolated in low yield was known 3-nitro-
coumarin 127. Spectral data of 3-nitro-coumarin matched well with that of reported
data. "I5
i-HF XNo2+ aHrzi 0 O C , 0.5 h
127 128 129
Scheme 1.57
The NaBH4-BFj.Et20 rcaction provided two products in low yield. One of
which was 2-(2-nitroethy1)phcnol 128"'~ and other one was 2-(3-hydroxy-2-
nitropropy1)phenol 129, which is unknown (Scheme 1.57). From above experiments
we concluded that elimination of MeSH takes plclce to producc nitmstyrene motif
initially. If reduction of double bond follows in preference to reduction of the NO2
group, decarboxylation occurs to provide 2-phenyl-l -nitroethane 128.
The failure of hydrogcnation (metal bound hydrogen) as well as reduction
with hydride donors (both nucleophilic and electrophilic) prompted us to rethink on
the ways to reductively remove C4-SMe. We reasoned that if the SMe was removed
reductively undcr acidic or basic condition, concomitant decarboxylation was a clear
possibility. Therefore we came to an understanding that the SMe removal must be
carried under radical or neutral reaction conditions. As a first choice we employed,
tri-n-butyltin hydride (TBTH) in the presence of 2.2'-azobisisobutyronitrile
(AIBN) ."~ This reaction proved to be inconsistent and not reproducible: when it
worked, a maximum of 82% yield of 126 could be generated. Afier enormous amount
of synthetic effort employed for this seemingly simple transformation, we were elated
to find that SMe removal did takes place when 4H-chromene was heated with
thiophenol in a sealed tube at 163 'C in a pre-heated oil bath. If the reaction was
conducted in open vessel at least five times more thiophenol was required for
complete conversion to 126a (88%) (Scheme 1 S8).
TBTH, AIBN benzene, reflux dNO2 0,s h, 82Oh or
CBH6SH, 163 0C NHMe 2.5 h, 88%
878 126a
Scheme 1.58
The U V spectrum of 1269 showed a A,,,, at 351 nm (log c = 4.5) indicating the
intact nature of nitroketene N,O-acetal moiety. Thc IR spectrum cxhibitcd bands for
the nitro goup at 1475 ern.', 1373 cm'l and olefinic C=C stretching at 1658 cm.'.
Besides, ' H NMR spectrum (Figure 1.37) showed a doublet for NHMe at 3.22 ppm (J
= 5.1 Hz) and a s in~le t for C4 methylene at 2.98 ppm, two doublets and four triplets
between 7.2-7.4 ppm for aromatic hydrogens and a singlet at 10.5 ppm for NH. The
"C NMR spectrum (Figure 1.38) showed two signals at 25.0 ppm (CH2) and 27.0
pprn (CHI). In addition, four methine and four quaternary carbon rcsonancc in the
aromatic region confirmed the structure.
1
: l a ' ? I R e B ..-*h*.b- ! Eii: s i ! % - -
a
--,,d Figure 1.37 300 MHz (CCb CDCI,) 'H NMR spectrum of N-methyl-N-(3- n1tro-4H-2-chromenyl)am1ne 126r
- - - - - - -. - m . -5- - . 2 - -> I#
Figure 1.38 75 MHz (CCI4.CDCI,) "C NMR spectrum of N-methyl-N-(3-nttro- 4H-2-chromenyl)am1nc 126a.
R1 SMe
H,C
R3 NHMe MeOH
R3 R4 reflux, 7-9 h R4
7242% 87a, 87c, 87d, 87h, 87k 126a-e
87a, 126a: R1 = R2 = R3 = R4 = H
87d, 126b: RI = OMc, R2 = R3 = R4 = H
87h, 126c: RI = R3 = R4 = H, R2 = OMe
87k, 126d: R1 = R2 = R4 = H, R3 = OCHzCbHS
87c, 126e: R1 = R2 = R3 =H, R4 = OMe
Scheme 1.59
Mechanistically this transformation could go through the formation of methyl
phenyl sulfide to generate a carbanion intermediate, which gets quenched by the
protic solvent. Employment of thiophenol for the above transformation required
stringent condition of heating the reaction mixture in obnoxiously smelling thiophenol
rcflux. Therefore, there was a requirement to find an alternative for this
transfonation.
As an option, the biornirnetic hydride donor, Hantzsch diester appeared to be a
suitable reagent to this tran~fonnation.'"~ Hantzsch diester prepared over a century
ago, mimics biological hydride donors like NADH and NADPH. It is acquiring
increased attention in recent ycars as a selective and mild reducing agent operating at
neutral conditions.""
Table 1.16: Displacement SMc in 3-nitro-4H-chrornenes 87a, 87c, 87d, 87h, 87k using Hantzsch dicster.
Entry Substrate Product Time yield (h) (%)
SMe
OMe SMe
2
3 Me0&N02 NHMe
87h
SMe
&NO_ 7 74
0 NHMe
126b
phAO mNo2 0 NHMe 1 82
pNO\ 0 NHMe 72
OMe
We were happy to find that Hantzsch dicstcr in MeOH rcflux, converted 87a
to 126a in 4 h and in 82% yield (Scheme 1.59). Reductive removal of SMe from 4H-
chromene 87a by this method was proved to be general. We conductcd this
transformation on five different substrates and in cach case 4H-chromenes were
obtained in good yield (Tablc 1.16). The "C NMR spectral values for all five
compounds are given in the form of Table 1.17.
SMe . ,- C,H,SH
-0 -0 NHMe "-
163OC
871 126f
Scheme 1.60
At this point it is worth noting an experiment conducted on the benzyl ether
87k with thiophenol reflux (Scheme 1.60). Surprisingly this reaction did not yield any
tangible product. Moreover, similar to corresponding benzyl ether 87k, ally1 ether 871
also did not work indicating labile nature of the substrate. Reductive removal of SMe,
however, worked with Hantzsci diester (entry 4; Table 1.16).
5.14. Synthesis of lactones of ortho-tyrosine 1328 and DOPA isomers 132b-e
pNH2 a N H 2
COOH OH 0 0
ortho-Tyrosine ortho-Tyosine lactone N-Acetyl-ortho-tyrosine lactone
130 131 132a
Figure 1.39
ortho-Tyrosine 130 (Figure 1.39) is a natural amino acid synthesized in the
body from phenylalanine."O Sometimes it is formed through non-enzymatic free
radical hydroxylation of phenylalanine under conditions of oxidative stress.'" ortho-
Tyrosine is also formed during radiolytic oxidation of proteins. During limited
radiolysis, its cancentration increases gradually in proteins as a function of absorbed
dose."2 So ortho-tyrosine is proposed as marker for the identification irradiated
protein-rich food."' Patients affected with Diabetes mellitus and chronic kidney
diseases produce ortho-tyosinc in larger quantities, level of which in urine is uscd for
detection of these diseases.22 A few synthetic procedures for ortho-tyrosine are known
but are tedious to conduct.l14 In view of'the difficult~es In literature methods and due
to the fact that scarce amount of ortho-tyrosine available from natural sources design
we embarked to convert 4H-chromene 87a into ortho-tyosine lactone. For this
purpose we needed to reduce the nitro g o u p to the amino g o u p and hydrolyse the
enamine to the lactone carbonyl."' It should be noted that owing to push-pull nature,
reduction of the nitro g o u p in nitroketene dithioacetal 81 is generally difficult.
Previously Rajappa and coworkers tried Zn- Ac20 i AcOH for reduction of the
nitro group to N-acetylamino group enroute to the synthesis of N-acetyldipeptides
derivatives."' Basavaiah and coworkers employed the Pe 1 AcOH for this type of
reduction."' When we employed Fe-AcOH for reduction of 4H-chromene 87a the
reaction was not clean at room temperature or at reflux. Then, we switched over Zn-
AcOH, however. this reaction was also not clean and no meaningful product could bc
Isolated
dNO2 Z z
NHMe AcOH. ri, h Ol"rNH2 0 0 42%
u O A N H M e AcOH, 110 1 h, 69%
126a
Scheme 1.61
When we employed Fe or Zn and AcOH on parent 4If-chromene 871, the
reaction provided known enamine 133 as the only isolable product (Scheme 1 .61) . "~
We were gratified to find that Zn- AczO 1 AcOH reduction on 4H-chromene 126a at
110 "C (oil bath temperature) provided 68% of N-acetyl orrho-tyrosine lactone 132a
(Figure 1.38, Scheme 1.61). It is possible that, with Zn-AcOH as a reducing agent at
certain stage of reduction of nitro group, enamino styrene double bond gets generated
which is stabilired by conjugation with aromatic p u p and carbonyl goup . However
in Ac20 medium, the reaction gets diverted by acetylation which does not allow
enamine to he generated, instead acetyl amino group gets generated. The Fe-AcOH /
Ac2O did not provide amino ac~d in good yield and also the reaction was not clean.
Therefore we adopted Zn-AcOH 1 Ac20 as a general reducing reagent for this
transfetmation.
The ortho-tyrosinc derivative 132a was characterized on the basis of analytical
and spectroscopic data. The IR spectrum showed a lactone carbonyl band at 1765 cm"
and thc secondary amide stretching band at 3290 cm'l. In addition, bands due to the
nitro group were absent. The ' H NMR spectrum (Figure 1.40) showed a singlet at 6
2.1 1 ppm for acetyl, a triplet and a doublet of doublet at 2.02 and 3.49 ppm for
prochiral hydrogens and doublet of triplet at 4.7 ppm for C3H. A broad singlet for NH
was present at 6.6 ppm. "C NMR spcctrum (Figure 1.41) in conjugation with DEPT-
135 spcctrum revealed the presence of one methylene, one methyl, four methines and
Sour quaternary carbons. The two carbonyl groups for lactone and amide appeared at
168.6 and 170.2 ppm respectively.
1 I 1 .I Figure 1.40 300 MHz (CDCI3) 'H NMR spectrum of NI-(2-0x0-3,4-dihydro- 2H-3-chromenyl)acetamide 132a.
1 I Figure 1.41 75 MHz (CDC13) IJC NMR spectrum of NI-(2-0x0-3,4-dihydro- 2ff-3-chromenyl)acctamide 132a.
Figure 1.42
It was our next task to extcnd the newly discovered procedure for conversion
of nitroketene 0,s-acetals 126 to the conespondicg amino acids, towards the
synthesis of dihydroxphcnylalanine (DOPA) isomers.
DOPA is an essential amino acid. It has a role in neur~transmittance."~
Dopamine generated from DOPA act at synapse when the communication is required.
Natural levodopa is used as a prodrug to increase dopamine levels for the treatment of
Parkinson's disease since it is able to cross blood brain barrier whereas dopamine
itself cannot.'20 During Parkinson's disease dopamine producing nerve cells in the
basal ganglia degenerate, which causes tremor, rigidity and akinesia. L-DOPA, which
is converted to dopamine in the brain, compensates for the lack of doparnine and
normalizes motor behavior.'*' Lactones of DOPA isomers, of which we identified
four (Figure 1.42; 133~-d) as synthetic targets, have not been characterized fully.
Literature survey on DOPA isomcrs revealed few reports on their syntl~csis."~ In
1954, Lamhooy reported thc synthesis of four isomers of DOPA.'^' In 1970 Ueno and
coworkers reported an enzymatic synthesis of DOPA isomer 133c from resorcinol and
5-methyl-L-cysteine using P-tyrosinasc c n ~ y n e . ' * ~ The structure was assigned based
on 60 MHz NMR spectrum and mass spectral date. The isomer 133b is known in
patent literaturc. It was synthesized starting from 2,3-dimethoxy bcnzaldehyde,
nitroethane and butyl arnine.''s
Zn, Ac,O R 2 ~ N 0 2 Ac%
R3 0 N H M ~ l lO°C, 0.5-1 h 61-68% R3 0 0
R4 R2@NHAc R4
126b-e 132b-e
126b, 132b: RI = OMe, R2 = R3 = R4 = H
126c, 132c: RI = R3 = R4 = H, R2 = OMe
126d, 132d: R1 = R2 = R4 = H. R3 = OCH2C6Hs
126e, 132e: R1 = R2 = R3 =H, R4 = OMe
Scheme 1.62
Zn-AcOH 1 Ac20 reduction of the isomeric methoxy 1 benzyloxy-4-
(methylsulfanyl)-3-nitro-4H-2-chromenyl]--methylami1e 126b-c provided
corresponding lactones of DOPA isomers 132b-e in the protected form (Scheme 1.62;
Table 1.18). Each one of them exhibited spectral data characteristic of the amino acid
and also in tandem with the lactone of ortho-tyrosine. Presence of OMe group at peri-
position, not surprisingly, influenced the diastercotopic C4 hydrogen in 132b. The 'H
NMR spectrum displayed a chemical shift difference of 1.2 ppm between two C4-
hydrogcns. Large chemical shift difference between diastereotopic C4 hydrogen
indicates the interaction of one of the two with lone pair of electrons on OMe through
hydrogen bonding interaction. The I3c NMR spectral values for all four compounds
are given in the form of Table 1.19.
Table 1.18: Treatment o f 126b-g with xinc, AczO and AcOH to get 132b-g.
Entry Subsrate Product T~me Yleld (h) ( % I
1 hNo2 hNHAc 68
0 NHMe 0 0
126b 132b
M e O m N O , M e O m N H A c 2 1 62
0 NHMe 0 0
3 mNo2 0.5 61 PhCH,O 0 NHMe PhCH20
4 1 68
OMe OMe
126e I320
Table 1.19: Cornpanson of "C NMR spectral values for DOPA
128.7 (2 r CH), 128.2 (CH); 55.6 (OMe).
5.15. Synthesis of novel non-natural hybrid amino acids 135 & 137
108
Scheme 1.63
AAer establishing a facile synthesis of ortho-tyrosine 132a and DOPA isomers
132b-e, our next task was to convert 4H-chromene 108 into hybrid non-natural amino
acids (Scheme 1.63). For example, the compound 135 has both tryptophan and
tyrosine units incorporated into the structure. Initially, the 4H-chromene having indole
substituent 108 was subjected to reduction with Zn-AcOH or Fe-AcOH and we found
that the reaction was more clean wit11 Zn-AcOH. The Zn-AcOH reduction provided
thc enamine 134 in 32% yield (Figure 1.43 and Figure 1.44). On the other hand, the
Zn-AcOH I AczO reduction prov~ded required hybrid acctylated amino acid 135 in
65% yield.
The NMR spectroscopy of the N-acetyl amino acid 135 (Figure 1.45 and
Figure 1.46) shows signals due lo both indole as well as coumarin. Interestingly from
this reaction a single isomer was isolated to which we assigned trans stercochemistry
based upon the largc coupling constant of 13.2 Hz between C3H and C4H. The C3
NH appeurcd as doublet with a coupling constant of 8.7 Hz due to coupling with C3H
- - .- -, - - - * - - - -_._- __ _ Figure 1.43 300 MHz (CDCI, + DMSO-4) 'H NMR spectrum of 3-amino-4- (1K3-indolyl)-2H-2-chromenonc 134.
Figure 1.44 75 MH7. (CDCI, + DMSO-d6) "C NMR spectrum of 3-am1no-4- ( 1 H-3-indolyI)-2H-2-chromenone 134.
1 - 8 1 -- 1 0 * 1 7 * 6 4 1 PP
Flgure 1.45 300 MHz (CDCI,) 'H NMR spectrum of N1-[4-(lH-3-lndolyl)-2- oxo-3,4-dihydro-2H-3-chmrnenyl]acetamide 135.
-.-. - -T- r 7-7-
r o im rm i w ro .o .D 10 ppm
Figure 1.46 75 MHz (CDCI?) " C NMR spectrum of NI-[4-(1H-3-1ndolyl)-2- oxo-3,4-dihydro-2H-3-chromenyl]acetamide 135.
l l D D C , 1 h llOGC, 1 h NHAc 40% 62'K
\ 0 0
95a
Scheme 1.64
As a next effort we converted C4 phenol substituted 4H-chromene 958 to the
cr~rresponding amino acid 137 or the enamine 136. Like in previous case, the Zn-
AcOH reduction provided enamine 136 (Scheme 1.64, Figures 1.47 and 1.48) and Zn-
Ac20 I AcOH reduction provided N-acetyl amino acid 137 (Scheme 1.64, Figures
1.49 and 1.50). From "C NMR spectrum (Figure 1.50) we concluded both cis- and
trans- isomer were formed in 6:5 ratio. Interestingly, the cis- isomer crystallized as a
white solid during fractional crystallization and its structure was confirmed by single
crystal X-ray (Figure 1.51) analysis (Deposited with CCDC; deposition No. 698176).
e -. 6 I - _ ---- .. C-.A
Figure 1.47 300 MHz (DMSO-d6) ' H NMR spectrum of 3-ammo-4-(2- hydroxypheny1)-211-2-chromenone 136.
I .d II Figure 1.48 75 MHz (DMSO-d6) I3c NMR spectrum of 3-amino-4-(2- hydroxypheny1)-2H-2-chromenone 136.
I II I 4 2 rl Figure 1.49 300 MHz (CDCI3) 'H NMR spectrum of NI-[4-(2-hydroxypheny1)- 2-oxo-3,4-dihydro-2H-3-chromenyl]acetamide 137.
I
- - - 1 L - _ . - Figure 1.50 75 MHz (CDCI,) C NMR spectrum of NI-[4-(2-hydroxypheny1)- 2-oxo-3,4-dihydro-2H-3-chromenyl]acetam1de 137.
Figure 1.51: Single crystal XRD structure of N1- [4-(2. hydrox~hcnyl)-2-ox0-3.4-dihydro-2H-3-chromenyl] ucctarnide 137.
5.16. Reduction of enamino double bonds in 134 & 136 by high pressure
hydrogenation
q H,, 10% Pd-C - q MeOH, 80 PI mN~e2 48 h, 82%
0 0 0 0
Scheme 1.65
Scheme 1.66
We attempted to reduce the endo double bond in compound 134 or in 136 by
high pressure hydrogenation using Hz, 10% Pd-C in MeOH. The reduction of the
double bond did not take place, Instead the reaction provided a good yield of N,N-