the adventures of a reactive intermediatestoltz2.caltech.edu/seminars/2006_tadross.pdf · the...
TRANSCRIPT
Pamela TadrossStoltz Group Literature Presentation
Noyes 1478 PM, May 15, 2006
BenzyneThe Adventures of a
Reactive Intermediate
Cl
NaNH2
NH3 (l)
NH2NH2
+
Nearly 1:1 ratio!
History and Structure
Nu-
Nu
E
E+
Polar Reactions Pericyclic Reactions
O+ O
NPh
NN
Methods of Generation+N2
-O2C
TMS
OTf
Cl
Overview
Applications to Natural Product Synthesis
PhN3
Cl
NaNH2NH3 (l), -38 °C
NH2 OCH3
Cl
OCH3
NEt2
Cl LiNEt2NEt2
NEt2
+
Unusual Rearrangements of Substituted Benzenes
Gilman, Wittig, and Roberts observed strange behavior in reactions of halobenzenes in the 1940s and 1950s
F C6H5Li
Li
G. Wittig, Naturwissenschafter 1942, 30, 696.
LiNEt2
J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.
H. Gilman, S. Avakian, J. Am. Chem. Soc. 1945, 67, 349.F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334.
NH3 (l), -38 °C
NH3 (l), -38 °C
THF, -78 °C
Wittig's ExplanationClose but no cigar...
FC6H5Li
F
Li
zwitterionic intermediate
C6H5Li
Li
G. Wittig, Naturwissenschafter 1942, 30, 696.
- LiF
THF, -78 °C
John D. Roberts: The Right Place at the Right Time
Cl LiNEt2NEt2
NEt2
+NH3 (l), -38 °C
Reactions are very rapid even at -38 °C
No reaction occurs when there is no hydrogen adjacent to the leaving halogen
The entering amino group is never more than one carbon away from the position occupied by the leaving halogen
no p-aminotoluene formed
The starting halides and the resulting anilines are not isomerized under reaction conditions
Br
LiNEt2NH3 (l), -38 °C
No Reaction
J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.
ClNH3 (l), -38 °C
Cl NEt2 NH3 (l), -38 °C NEt2
Further Mechanistic Evidence...
NH2
NH2 NH2
Cl
Cl
Cl
% % %
45
40
none
55 none
52
62
8
38
substrate
product
J. D. Roberts, C. W. Vaughan, L. A. Carlsmith, D. A. Semenow, J. Am. Chem. Soc. 1956, 78, 611-14.
The Classic 14C Labeling Experiment
Cl
NaNH2
NH3 (l)
NH2
The Hypothesis: If one started with chlorobenzene-1-14C, equal amounts of aminobenzenes with the 14C at C-1 and C-2 would be formed.
NH2
+
Nearly 1:1 ratio!
Roberts' Proposed Intermediate:
BENZYNE!
"These facts as well as the orientation data for various substituents can be accomodated by an elimination-addition mechanism involving at least transitory existence of an electrically neutral "benzyne" intermediate."
J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.
Further Support from Wittig and Huisgen
O+ O
Wittig finds that benzyne can participate in Diels-Alder reactions as a dienophile:
Huisgen reports that arynes generated from different precursors have identical reactivity:
F
Li
F
MgBr
N2+
CO2-
SO2
NN
O
O
k1
k2
k1/k2 = constant
G. Wittig, L. Pohmer, Angew. Chem. 1955, 67(13), 348.
R. Huisgen, R. Knorr, Tetrahedron Lett. 1963, 1017.
Cl
NaNH2
NH3 (l)
NH2NH2
+
Nearly 1:1 ratio!
History and Structure
Nu-
Nu
E
E+
Polar Reactions Pericyclic Reactions
O+ O
NPh
NN
Methods of Generation+N2
-O2C
TMS
OTf
Cl
Overview
Applications to Natural Product Synthesis
PhN3
Generation of BenzyneEarlier basic and harsh methods give way to recent neutral and mild methods of aryne generation
F
Li
F
MgBr
N2+
CO2-
SO2
NN
X
X1
X2
NN
N
NH2
TMS
OTf
I
TMS
Ph
X
OTf
Bu4NFstrong base
Pb(OAc)2
heat
n-BuLiBu4NF
Iodonium Triflate: T. Kitamura, M. Yamane, J. Chem. Soc., Chem. Commun. 1995, 983. Silyl Triflate: Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211. Benztriazole: C. D. Campbell, C. W. Rees, J. Chem. Soc. (C) 1969, 742. Halo Triflate: T. Matsumoto, T. Hosoya, M. Katsuki, K. Suzuki, Tet. Lett.
1991, 32, 6735. Diazonium Carboxylate: L. Friedman, F. M. Logullo, J. Am. Chem. Soc. 1963, 85, 1792. Fluoro Magnesium and Fluoro Lithium: R. W. Hoffmann, Dehydrobenzene and Cycloalkanes, Academic Press, New York, 1967. Benzothiadiazol-1,1-dioxide: G. Wittig, R. W. Hoffmann, Org. Synth., Coll. Vol.
V, 60, 1971.
0 °C
Mg orRMgX
0 °C
-20 °C
OTf
Cl
NaNH2
NH3 (l)
NH2NH2
+
Nearly 1:1 ratio!
History and Structure
Nu-
Nu
E
E+
Polar Reactions Pericyclic Reactions
O+ O
NPh
NN
Methods of Generation+N2
-O2C
TMS
OTf
Cl
Overview
Applications to Natural Product Synthesis
PhN3
Polar Reactions of BenzyneBenzyne reacts as both nucleophile and electrophile
Nu-
Nu NuE++ +
E E
Nu-
Nu
+ E+Nu
E
Regiochemistry of Nucleophilic Additions to BenzyneEWG
δ+
δ−
+ Nu-
EWG
Nu
EDG
δ+
δ−+ Nu-
EDGNu
Harold Hart; in Chemistry of Triple Bonded Functional Groups; Saul Patai, Ed.; The Chemistry of Functional Groups, Supplement C2; Wiley: Chichester, UK, 1994, 1017-1134.
Additions of Carbon Nucleophiles
MgBr
MgBr
E+E = H, CHO, CO2H, RX
Grignard reagents:
Organolithium reagents:
NORLi
NO LiR
E+NO
R
E
H+
OHO
R
E
Copper-lithium reagents:
NO
1. R2CuLi2. E+
NO
E
R
H+
OHO
E
R
H. Hart, A. Saednya, Synth. Commun. 1988, 18, 749.
E
P. D. Pansegrau, W. F. Rieker, A. I. Meyers, J. Am. Chem. Soc. 1988, 110, 7178.M. E. Jung, G. T. Lowen, Tetrahedron Lett. 1986, 27, 5319.
E = H, CHO, CO2H, RX
E = H, CHO, CO2H, RX
Synthesis of Substituted Indoles
FN
R
Br tBuLi, THF, -110 °C E+
NR
LiN
RN
R
E
R = Me, allyl
DIBAL[NiCl2(dppp)]PhMe, 20 °C N
H
E R E+ E YieldMe H2O H 75%Me PhCHO PhC(H)OH 69%allyl Bu3SnCl SnBu3 52%Me Bu3SnCl SnBu3 67%N
R
E
F
NBr
tBuLi, THF, -110 °C
N
E
E+
pTsOH, PhMe110 °C
N
E
E = Br: 59%E = CO2Et: 65%
J. Barluenga, F. J. Fananas, R. Sanz, Y. Fernandez, Chem. Eur. J. 2002, 8(9), 2034.
Stabilized Carbon Nucleophiles
OMe
R1
R2
Br+ R3 CN NaNH2
OMe
R1
R2
CN
R3
H3O+
O
R1
R2
R3
O
S. P. Khanapure, E. R. Biehl, J. Org. Chem. 1990, 55, 1471.
+R CN
CN
R
Li
Cl
Li R
N Li
CN
R
LiH+
CN
R
Alternative Pathway: C-C Insertion
J. H. Waggenspack, L. Tran, S. Taylor, L. K. Leung, M. Morgan, A. Deshmukh, S. P. Khanapure, E. R. Biehl, Synthesis, 1992, 765.
R = Ph: 40%R = 3-FC6H4: 80%R = 3-MeOC6H4: 70%
ROMe
Br
NC CO2Et
LDA
CNO
OEtR
OMeLi O-
OEt
CN
Li+
OEt
O
Li
CN
ROMe
More Stabilized Carbanions
ROMe OH
CN
OMe OMeRR R = H: 36%
R = OMe: 38%
B. M. Bahwal, S. P. Khanapure, H. Zhang, E. R. Biehl, J. Org. Chem. 1991, 56, 2846.
CO2H
RBr S
CN
LDA+
CO2H
R
Anthraquinone Synthesis:
S
CN
R
NHO
S
Basic Skeleton of Ergot and Aristolactam Alkaloids:
A. Wang, E. R. Biehl, J. Chem. Soc., Perkin Trans. 1 1998, 1461.R = OMe: 77%R = Me: 57%
OMeR
Reactions of Enolates with Arynes
OOO
Br
NaNH2t-BuONa+
O
O
OOOHO
AcOO
Li
NH3
O
Facile access to strained aromatic polycyclic compounds
83%
M. A. Zouaoui, A. Mouaddib, B. Jamart-Gregoire, S. Ianelli, M. Nardelli, P. Caubere J. Org. Chem. 1991, 56, 4078.
Br
+NHAr
O LiTMP
NAr
O-Li++
NAr
O-Li+Li
NAr
O-Li+
NHAr
O
NHAr
O
A. R. Deshmukh, T. Long, E. R. Biehl, J. Org. Chem. 1992, 57, 667.A. R. Deshmukh, H. Zhang, T. L. Duc, E. R. Biehl, J. Org. Chem. 1992, 57, 2485.
+
69:9
Total Synthesis of Dynemicin A
OMOM
OMOM
BrMeO2C CO2Me
Li
NLi
OMOM
OMOM
CO2Me
CO2MeCO2Me
O
OMe
MOMO
MOMO
MOMO
MOMO
CO2Me
OMeO
OMOM
OMOM
CO2Me
CO2Me
H+
71%
THF, -78 °C
OMOM
OMOM
CO2Me
CO2Me
stepsHNOH
OH
O
O OH
MeCO2H
OMeH
O
H
dynemicin A
M. D. Shair, T. Y. Yoon, K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc. 1996, 118, 9509.
K. C. Nicolaou, S. A. Snyder, Dynemicin A. Classics in Total Synthesis II; Wiley-VCH: Weinheim, 2003; 75-108.
Total Synthesis of Fredericamycin AOMe
OMeMeO
Br
MeO2C CO2Me
NLi
OMe
MeOOMe
OMe
MeOOMe
CO2Me
CO2MeCO2Me
CO2Me
+
steps steps
OO
OMe
MeOOMe
OMe
MeOOMe
OMeO
O OMe
O
O
O
OMe
MeOOMe
OMeO
O
steps
HN
O HO O
O
OH
O
OMe
HO
O
fredericamycin A
Y. Kita, K. Higuchi, Y. Yoshida, K. Iio, S. Kitagaki, K. Ueda, S. Akai, H. Fujioka, J. Am. Chem. Soc. 2001, 123, 3214.
58%
C-C σ-Bond Insertion Reactions
TMS
OTfEtO
O O+
CsF (2.5 equiv)MeCN (0.2 M)80 °C, 1.5 h EtO
O O
Ph
+
O
O OEt
EtO
O O Cs+
EtO2C
OO
OOEt
Cs+
H+H+
U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 5340.
R R
O OTMS
OTf+
KF (3 equiv)18-crown-6 (3 equiv)
THF, room temp.
R
R
O
O
R = OEt: 71%R = Ph: 68%R = Me: 56%R, R = —O(CH2)8O—: 61%
H. Yoshida, M. Watanabe, J. Ohshita, A. Kunai, Chem. Commun. 2005, 3292.
Averufin
O
OOR
RO
BrOR
O
O+ LiTMPO
O OR
O
O
RO
OR
O
O
O
O
OR
RO
ORsteps
O
O
O
O
OH
HO
OH
averufinC. A. Townsend, S. G. Davis, S. B. Christensen, J. C. Link, C. P. Lewis, J. Am. Chem. Soc. 1981, 103, 6885.
Cephalotaxine
O
ON
OMe
H
HOH
O
O Cl
N
OMeO
DME, 50 °C
O
O
N
OMeO
cephalotaxine
O
ON
OMe
H
O
DIBALPhH, 25 °C
16%
R = CH2OCH3
M. F. SemmeIhack, B. P. Chong, L. D. Jones, J. Am. Chem. Soc. 1972, 94, 8629.
35%
KCPh3
Additions of Nitrogen NucleophilesPreparation of alkylated anilines:
Cl LiNH3
NH2
Preparation of indoles:
N
Ph HPh+ N Ph
HPh
N
PhHPh
NH
Ph
Ph
N
Ph+ N
Ph
HN
Ph
50%
A. G. Giumanini, J. Org. Chem. 1971, 37, 513.
F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334.
V. Nair, K. H. Kim, J. Org. Chem. 1975, 40, 3784.
HN Ph
14%
Preparation of Acridones
N
OMe
O
Li+
N
CO2Me
N
O
M. Watanabe, A. Kurosaki, S. Furukawa, Chem. Pharm. Bull. 1984, 32, 1264.
CO2Me
NLi
O
BrOMe
+ LiICA
N
O
O
LiICA = NLi
acronycine, 41%
M. Watanabe, A. Kurosaki, S. Furukawa, Chem. Pharm. Bull. 1984, 32, 1264.
Total Synthesis of γ-Licorane
MeOCl
NH2MeO
NH2 NHMeO
NO
Br
OO
NLi
NO
OO
O
O N
O
O
O N
H HH
γ-licorane
40%
Two benzyne cyclization reactions complete the skeleton...
H. Ilda, S. Aoyagi, C. Kibayashi, J. Chem. Soc. Perkin Trans. 1, 1975, 2502.N. Ueda, T. Tokuyama, T. Sakan, Bull. Chem. Soc. Japan, 1966, 39, 2012.
Competitive Cyclization Reactions
NHO
RO
Br
ROOR
NaHDMSO
NO
RO
ROOR
N
RO
HO
ROOR
20%
N
RO
HOOR
OR30%
ortho cyclizationamine cyclization
ORO
N
ROOR
2%
N
ROOR
HOOR
CH2SOMe
para cyclization
S. V. Kessar, S. Batra, S. S. Ghandi, Indian J. Chem. 1970, 8, 468. S. V. Kessar, R. Randhawa, S. S. Ghandi, Tetrahedron Lett. 1973, 2923. S. V. Kessar, S. Batra, U. K. Nadir, S. S. Ghandi, Indian J. Chem. 1975, 13, 1109.
T. Kametani, S. Shibuya, K. Kigasawa, M. Hiiragi, O. Kusama, J. Chem. Soc. C 1971, 2712. T. Kametani, K. Fukumoto, T. Nakano, Tetrahedron 1972, 28, 4667.M. S. Gibson, G. W. Prenton, J. M. Walthew, J. Chem. Soc. C 1970, 2234. I. Ahmad, M. S. Gibson, Can. J. Chem. 1975, 53, 3660.
CH2SOMe
aporphine
dibenzindolizine
morphinandienone
Ortho Cyclizations of Imines and Anilines
Cl N NH2
NH2
N N
NH2
N
S. V. Kessar, D. Pal, M. Singh, Tetrahedron 1973, 29, 177.S. V. Kessar, Acc. Chem. Res. 1978, 11, 283.
> 90%
NMeO
OMe
O
O
chlerythrine
NMeO
MeO
OH
OMe
fagaronineS. V. Kessar, M. Singh, P. Balakrishnan, Indian J. Chem. 1974, 12, 323. J. P. Gillespie, L. G. Amros, F. R. Stermitz, J. Org. Chem. 1974, 39, 3239
Synthesis of Benzophenanthridine Alkaloids
Cl HN NH2 N NH
S. V. Kessar, Acc. Chem. Res. 1978, 11, 283.
Cl
NaNH2
NH3 (l)
NH2NH2
+
Nearly 1:1 ratio!
History and Structure
Nu-
Nu
E
E+
Polar Reactions Pericyclic Reactions
O+ O
NPh
NN
Methods of Generation+N2
-O2C
TMS
OTf
Cl
Overview
Applications to Natural Product Synthesis
PhN3
Diels-Alder Reactions of Arynes
O+ O
G. Wittig, L. Pohmer, Angew. Chem. 1955, 67, 348.
+ O
PhPh
PhPh
Ph
Ph Ph
Ph
O
PhPh
PhPh
-CO
95%
C. D. Campbell, C. W. Rees, Proc. Chem. Soc. 1964, 296.
88%
O
O+ O
O
36%
-CO2
G. Wittig, R. W. Hoffmann, Chem. Ber. 1962, 95, 2718.
+
R
R
R = H, CH3, CO2Me, NO2, CH2Cl, CH2OH, CH(OMe)2, CN, etc.
Yields 6-75%
E. C. Kornfeld, P. Barney, J. Blankley, W. Faul, J. Med. Chem. 1965, 8, 342.
Total Synthesis of the Gilvocarcins
OOBn
OBn
H MeOBn
TfO
IOBn
O OMe+ n-BuLi
OOBn
OBn
H MeOBn
OBn
O
OMe
OOBn
OBn
H MeOBn
OBnOMe
OH OOH
OH
H MeOH
OHOMe
O
O
OMe
R
gilvocarcin M: R = Megilvocarcin V: R = vinylgilvocarcin E: R = Et
THF, -78 °C10 min
88%
O
OMe
OR OH OR
OMe
O
OR OMe OR
OH
OMe
Head-to-head Product Head-to-tail Product
T. Matsumoto, T. Hosoya, K. Suzuki, J. Am. Chem. Soc, 1992, 114, 3568.T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J. Am. Chem. Soc. 1994, 116, 1004.
Application to the Synthesis of Aporphinoid Natural Products
N
O
MeO
MeO
lysicamine
N
O
O
O
duguenaine
N
O
MeO
OMeO
alkaloid PO-3
NH
OOMeO
MeO
norcepharadione B
N
OOMeO
MeO
cepharadione B
N
OOMeO
MeO
MeOOMe
pontevedrine
N. Atanes, L. Castedo, E. Guitian, C. Saa, J. M. Saa, R. Suau, J. Org. Chem. 1991, 56, 2984.H. Guinaudeau, M. Lebouef, A. Cave, J. Nat. Prod. 1983, 46, 761.
M. Shamma, The Isoquinoline Alkaloids; Academic Press: New York, 1972.
Norcepharadione B, Cepharadione B, and Pontevedrine
NR3
OOMeO
MeO
R1
R2
+
NR3
OOMeO
MeONR3
OOMeO
MeOaromatization
R1
R2R1
R2
NR3
OOMeO
MeO
R1
R2
R1 = R2 = R3 = H: norcepharadione BR1 = R2 = OMe, R3 = Me: pontevedrineR1 = R2 = H, R3 = Me: cepharadione B
N. Atanes, L. Castedo, E. Guitian, C. Saa, J. M. Saa, R. Suau, J. Org. Chem. 1991, 56, 2984.
Yields 20% - 68%
Total Syntheses of Nitidine and Fagaronine
N
O
O
OR3
CO2R4
R5O
R5O
+
O
ON
R1
R2
R5O
R5OO
R3
R1
R2-CO2
CO2R4
N
CO2R4
R1
R2R5O
R5OO
R3
Δ
N
MeO
MeO
R1
R2R1 = OH, R2 = OMe: fagaronineR1 + R2 = -OCH2O-: nitidine
D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 1992, 57, 5911.
40%
Total Synthesis of Protoberberines: Corydaline
N
MeO
MeOOMe
OMe
H
H
N
O
OMeO
MeO
+OMe
N
O
OMeO
MeO
OMe
OMe
N
O
OMeO
MeO
OMe
N O
OMe
OMe-CO
MeO
MeO
OMe
OMe
32% corydaline
C. Saa, E. Guitian, L. Castedo, R. Suau, J. M. Saa, J. Org. Chem. 1986, 51, 2781.A. Cobas, E. Guitian, L. Castedo, J. Org. Chem. 1992, 57, 6765.
single regioisomer
Total Synthesis of the Lycorines: Intramolecular Aryne Diels-Alder Reactions
O
HN
Br LDA
N
OLi
N
OH
N
O
Yields 61% - 91%
N
O
O
HOOH
H H
lycorine
N
O
O
O
hippadine
N
O
O
O
OHkalbretorine
N
Cl
O
O
anhydrolycorinium chloride
N
Cl
O
O
OH
ungeremineC. Gonzalez, D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 1995, 60, 6318.
N
NH
Br
O
N
NO
HOOCOOC N
NH
O
HOOCN
NH
HOOCH
Intramolecular Diels-Alder: Lysergic Acid
LDA-30 °C
lysergic acid30%B. Gomez, E. Guitian, L. Castedo, Synlett, 1992, 903.
Pseudopterosin A and E Aglycon
OMeOMe
Me
O
OBr
O
OMe
OMeOMe
Me
O
OMe
OMeOMe
Me
+
58
42
Me Me
MeH
Me OHOH
Me
pseudopterosin A and E aglycon
K. R. Buszek, D. L. Bixby, Tetrahedron Lett. 1995, 36, 9129.
71%
Mansonone I and F
O
BrBr
MeO
Me
O
OO
Me
O
MeO
Me
O
OO
Me
n-BuLi
O
O
O
O
MeMe
MeO
61%
O
OO
Me
Me
Me
OH O
OO
Me
Me
Me
mansonone I mansonone F
W. Best, D. Wege, Aust. J. Chem. 1986, 39, 647.
H2SO4EtOH
[2 + 2] Cycloadditions of Arynes
R
R+
N2+
CO2-
In the absence of a reactive partner:
apparent [2 + 2] cycloaddition product
R
R
With other olefins:biphenylene also seen as side product in most aryne reactions!
R
RR
R
Proposed Mechanism
Problem: [2 + 2] cycloadditions are not allowed thermally!
R
R
+ R
RR
RR
R
R
R
R R
stepwise addition
Best yields and regiochemical control with R = electron-donating groups
Facile Access to Benzocyclobutenes
R1
R2
Br
OMeMeO+ NaNH2
R1
R2OMe
OMe
R1 R2 YieldH
OMeOMe
HCl
HH
OMeOMe
H
63%76%68%56% (+8% other regioisomer)76%
Rationalizing RegiochemistryOMe
MeO δ−
δ+
OMeMeO
δ−δ+
OMeMeO
OMe
OMe
OMeMeO
OMeOMe
R. V. Stevens, G. S. Bisacci, J. Org. Chem. 1982, 47, 2393.L. S. Liebeskind, L. J. Lescosky, C. M. McSwain Jr., J. Org. Chem. 1989, 54, 1435.
R1
R2OMe
OMeH3O+
R1
R2 O
Hydrolysis to benzocyclobutenones:
OMeMeO
Br
Total Synthesis of Taxodione
MeO OMe+
1. NaNH2
2. H3O+
OMeMeO
OO
O
HO
HH
taxodioneR. V. Stevens, G. S. Bisacchi, J. Org. Chem. 1982, 47, 2396.
Li
OMeOMe
OH
OMeOMe
O
XylopinineCO2
-
N2+
OAc+
OAc
N
MeO
MeOΔ
NMeO
MeO
N
MeO
MeO
T. Kametani, T. Kato, K. Fukumoto, Tetrahedron 1974, 30, 1043.
OMe
OMe
OMe
OMe OMeOMe
N
MeO
MeO
OMeOMe
xylopinine
t-BuOKt-BuOH
Δ
[2 + 2] Aryne Cycloadditions in Steroid Synthesis
OMeOMe
I O
O
MeO2C+
K2CO3, Me2CO
> 93%
OMeO2C
O
Δ> 85%
OMeO2C
O
OO H
HMeO2C
O
H H
HMeO2C
O
Steroids obtained in 5 steps from 1,3-butadiene in overall yields of 27-33%
P. Y. Michellys, P. Maurin, L. Toupet, H. Pellissier, M. Santelli, J. Org. Chem. 2001, 66, 115.
single diastereomer
1,3-Dipolar Cycloadditions of Arynes
NO
NNN
NO
ONN
O
diazoalkanes
nitrile oxides
azides
nitrones
+
O N
N NN
NO
NN
EtO2C
F. Minisci, A. Quilico, Chimica e Industria 1964, 46, 428
R. Huisgen, R. Knorr, Naturwiss. 1961, 48, 716.
55%
G. A. Reynolds, J. Org. Chem. 1964, 29, 3733.G. Wittig, R. W. Hoffmann, Chem. Ber. 1962, 95, 2718.
88%
R. Huisgen, R. Knorr, Naturwiss. 1961, 48, 716.
92%
Some early examples...
Regiochemical Controlor the lack thereof...
R2
R1
OTf
Br
NPh
t-Bu
O
n-BuLiTHF
+
ON t-Bu
PhR1
R2
+ NO
Ph
R1
R2t-Bu
A B
R1 R2 %A %BOMOM
Met-BuTMSTBS
HHH
MeMe
9123765
12
063148982
T. Matsumoto, T. Sohma, S. Hatazaki, K. Suzuki, Synlett, 1993, 843.
R
N
Ph
t-BuO+
R
δ+
δ−
R
δ+
δ−
N
Ph
t-BuO
N
Ph
t-BuO ON t-Bu
PhR
NO
Ph
R
t-Bu
R = EWG
R = EDG
Regiochemical rationale:
Steric effects also influence the regiochemistry!
EWG
EDG
Food for Thought...
Arynes are highly reactive intermediates that can participate in a wide variety of polar and pericyclic reactions
Since their discovery in 1953, the synthetic power of arynes has barely been explored - there is an immense amount of uncharted territory!
C-C (and maybe even C-H) σ-bond insertions seem to hold the most potential
Insertion into strained ring systems (e.g. β-lactams, β-oxonitriles)
Transition metal catalyzed reactions of arynes (especially Pd and Ni) have only recently been investigated - opportunity to control aryne reactivity
There is a need for better control of regiochemistry in aryne reactions
There is a need for better understanding and control of aryne reactivity pathways (e.g. [2 + 2] vs. ene vs. Diels-Alder)
M. A. Bennett, E. Wenger, Chem. Ber. 1997, 130, 1029.D. Pena, S. Escudero, D. Perez, E. Guitian, L. Castedo, Angew. Chem. Int. Ed. Engl. 1998, 37, 2659.D. Pena, D. Perez, E. Guitian, L. Castedo, Org. Lett. 1999, 1, 1555.K. V. Radhakrishnan, E. Yoshikawa, Y. Yamamoto, Tetrahedron Lett. 1999, 121, 5827.D. Pena, D. Perez, E. Guitian, L. Castedo, J. Org. Chem. 2000, 65, 6944.D. Pena, D. Perez, E. Guitian, L. Castedo, Synlett 2000, 7, 1061.E. Yoshikawa, Y. Yamamoto, Angew. Chem. Int. Ed. Engl. 2000, 39, 173.E. Yoshikawa, K. V. Radhakrishnan, Y. Yamamoto, Tetrahedron Lett. 2000, 41, 729.
Handy Reviews and Books
Books: R. W. Hoffmann; Dehydrobenzene and Cycloalkynes; Academic Press: New York, 1967. J. D. Roberts; The Right Place at the Right Time; J. I. Seeman, Ed.; Profiles, Pathways, and Dreams Series; American Chemical Society: Washington, DC, 1990.
Review Articles: T. L. Gilchrist; Arynes. In The Chemistry of Triple-bonded Functional Groups, Supplement C; S. Patai and Z. Rappoport, Eds.; The Chemistry of Functional Groups Series; John Wiley and Sons: New York, 1983; Volume 1, pp. 383-419. H. Hart; Arynes and Heteroarynes. In The Chemistry of Triple-bonded Functional Groups, Supplement C; S. Patai, Ed.; The Chemistry of Functional Groups Series; John Wiley and Sons: New York, 1983; Volume 2, pp. 1017-1134. L. Castedo; E. Guitian; Synthesis of Natural Products via Arynes. In Studies in Natural Products Chemistry; Atta-ur- Rahman, Ed.; Stereoselective Synthesis (Part B) Series; Elsevier: Amsterdam,1989; Volume 3, pp. 417-454. M. Winkler; H. H. Wenk; W. Sander; Arynes. In Reactive Intermediate Chemistry; R. A. Moss, M. S. Platz, M. Jones Jr., Eds.; Wiley-Interscience: New York, 2004; pp. 741-794. H. Pellissier, M. Santelli; The Use of Arynes in Organic Synthesis, Tetrahedron 2003, 59, 710-730.