Expedient synthesis of highly substituted pyrroles via tandem rearrangement of α-diazo oxime ethers

Article abstract of DOI:10.1021/ja300552c

An efficient rhodium-catalyzed synthesis of 2H-azirines and pyrroles has been developed. Novel rearrangement of α-oximino ketenes derived from α-diazo oxime ethers provides 2H-azirines bearing quaternary centers and allows for subsequent rearrangement to highly substituted pyrroles in excellent yields.

Full text of DOI:10.1021/ja300552c

Communication
pubs.acs.org/JACS
Expedient Synthesis of Highly Substituted Pyrroles via Tandem
Rearrangement of α-Diazo Oxime Ethers
Yaojia Jiang, Wei Chuen Chan, and Cheol-Min Park*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
bearing quaternary centers required for the subsequent
rearrangement.
ABSTRACT: An efficient rhodium-catalyzed synthesis
of 2H-azirines and pyrroles has been developed. Novel
rearrangement of α-oximino ketenes derived from α-diazo
oxime ethers provides 2H-azirines bearing quaternary
centers and allows for subsequent rearrangement to highly
substituted pyrroles in excellent yields.
Wolff rearrangement, among the fundamental reactions of
diazo compounds, has found broad applications in organic
synthesis.14 Ketenes generated by metal-catalyzed or thermal/
photochemical activation of diazo compounds have proven as
versatile intermediates in various transformations including
nucleophilic addition, cycloaddition, ring contraction, and
homologation.15 However, to the best of our knowledge, no
examples of 2H-azirine synthesis via Wolff rearrangement have
been reported. In conjunction with our recent studies on the
chemistry of α-diazo oxime ethers,16 we investigated the
feasibility of metal-mediated cascade rearrangement leading to
formation of 2H-azirine-2-carboxylic esters (eq 2) and sub-
sequent rearrangement to pyrroles by introduction of vinyl
groups on α-diazo oxime ethers (eq 1).
yrroles1 are among the most important heterocycles that
2
Pare frequently found in natural products,
pharmaceut-
icals,3 and functional materials.4 These utilities continue to
drive the interest in the development of new synthetic methods
for pyrroles which include cycloaddition reactions,5 multi-
component coupling reactions,6 and transition metal-mediated
reactions.7 Padwa and co-workers reported synthesis of pyr-
roles via rearrangement of 2-vinyl-2H-azirines.8 Inspired by the
report, we aimed to develop a synthetic method for 2H-azirines
and pyrroles based on novel rearrangement of α-dizao oxime
ethers (eq 1).
Our attempts began with a reaction on α-diazo-β-keto
oxime ether 1a employing Cu(OTf)2 as catalyst (Scheme 1).17
Scheme 1. Selectivities of Catalysts between Wolff
a
Rearrangement and 2-Alkoxy-2H-azirine
2H-Azirines represent a highly valuable class of compounds
found in natural products and synthetic intermediates.9 Derived
from the high ring strain present in these smallest heterocycles,
their unique reactivity allows for 2H-azirines to serve as a
versatile source of nitrenes, electrophiles, dienophiles, and di-
polarophiles in various reactions.10 These reactions lead to the
development of efficient synthetic platforms for various
nitrogen containing heterocycles including pyrroles, indoles,
pyrazolo[1,5-a]pyridines, isoxazoles, and piperidines.11 De-
spite their broad utility, the availability of synthetic methods
for 2H-azirines is rather limited, primarily relying on the
Neber reaction12 and thermal/photochemical rearrangement
of vinyl azides.13 The efficiency of these reactions is, however,
highly variable and dependent on substrates due to the sensi-
tive nature of 2H-azirines that promotes further activation and
subsequent decomposition. Also, these reactions typically
require stoichiometric reagents and harsh reaction conditions.
With the tandem synthesis of pyrroles in mind, we first set out
to develop catalytic and neutral conditions for 2H-azirines
a
OTf = trifluoromethanesulfonate, OBz = benzoate. Yields determined
by NMR vs standard.
Thus, exposure of 1a to Cu(OTf)2 in 1,2-dichloroethane
(DCE) at 60 °C resulted in formation of two products in
low yields that were identified as 2a and 2a′. Compound 2a
appears to arise from the desired cascade rearrangement,
Received: January 21, 2012
Published: February 14, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
while 2a′ results from N−O insertion.18 With the result in
hand, we proceeded with screening of various metal salts
(see the Supporting Information). Use of Ag(OBz) which is
frequently employed in the Wolff rearrangement gave im-
provement in yield, while the selectivity between the cascade
rearrangement and N−O insertion remained unsatisfactory.
To our delight, exposure of 1a to 2 mol % of Rh2(OAc)4 led
to exclusive formation of 2a in nearly quantitative yield.19
Examination of solvent effects on the rearrangement revealed
that the reaction is well tolerated in various solvents (see the
Supporting Information).
the rearrangement, various types of substituents for each of the
three sites (R1, R2, and R3) were examined. For R1 adjacent to
the oxime ethers, alkyl groups were well tolerated (2b and 2c).
Also, substrates with alkenyl, alkynyl, and aryl substituents
smoothly reacted to give the corresponding 2H-azirine-2-
carboxylic esters in excellent yields (2d−g). Examination of the
electronic effect of R1 by varying substituents on phenyl groups
revealed little impact on the reaction efficiency; 92% and 96%
for 4-methoxyphenyl (2f) and 4-nitrophenyl (2g) compounds,
respectively. Furthermore, the substrate with heteroaryl group
such as 2-furyl group afforded 2h in 87% yield.
Next, we turned our attention to the influence of R2
undergoing migration (Table 1, 2i−q). Examination of various
R2 revealed the efficiency of the reaction in the order of
secondary, vinyl ≈ primary followed by tertiary alkyl groups: 2j,
94%; 2l, 74%; 2i, 66%; 2k, 33%. For those with low yields, the
major byproducts were the corresponding N−O insertion
products (Table 1, footnote). For 1k, additional byproduct 2k″
was isolated in 18% yield that results from 1,5-hydride shift
from the methyl ether.20,21 To examine the potential
isomerization of (E)- and (Z)-alkenes during migration, 1l
and 1m were subjected to the reaction conditions. Gratifyingly,
both substrates gave the corresponding isomers with complete
retention of geometry (Table 1, 2l and 2m). Moreover, 1n with
a cyclohexene moiety also produced 2n in 82% yield. Next, we
examined the influence of migrating groups when R2 = aryl/
heteroaryl groups. While the substrates with phenyl (1o) and
2-furyl (1q) groups afforded the expected products 2o and 2q
(44% and 60%, respectively) along with N−O insertion
products 2o′ and 2q′ (44% and 31%, respectively), 1p bearing
more electron-rich 4-methoxyphenyl group gave 2p in higher
yield (70%) along with byproduct 2p″ (21%) formed via 1,5-
hydride shift20 (Table 1, footnote). A brief examination of the
alkoxy group (OR3) of oxime ethers showed that both electron-
deficient (1r) and phenyl (1s) groups are also well tolerated to
afford the corresponding esters in excellent yields.
With the optimal conditions in hand, we next examined the
substrate scope of 2H-azirine formation (Table 1). Consistent
a
Table 1. Substrate Scope
With the efficient synthetic protocol for 2H-azirines in hand,
we explored the viability of tandem rearrangement to pyrroles
(Table 2). The study by Padwa and co-workers demonstrated
that 2-vinyl-2H-azirines undergo rearrangement to furnish
pyrroles via nitrenes.8 We reasoned that the rhodium catalysis
in the formation of 2-vinyl-2H-azirines may be further exploited
in the synthesis of pyrroles in tandem fashion. We were
delighted to find that exposure of α-diazo oxime ether 3a to
2 mol % Rh2(OAc)4 in refluxing toluene provided tetrasub-
stituted pyrrole 4a in 90% yield. Encouraged by this result, we
examined the substrate scope of the reaction. As shown in
Table 2, this protocol offers highly flexible synthesis of pyrroles
with various substituents. While substrates with alky groups on
vinyl substituents required refluxing toluene (4a, 4n, and 4l),
those with aryl groups for R3 gave the corresponding pyrroles at
60 °C in excellent yields (4b−h).
a
The reported yields in parentheses are of the isolated products.
b
Byproduct: 1-(2-methoxy-3-phenyl-2H-azirin-2-yl)butan-1-one 2i′
c
(29%). Byproducts: 1-(2-methoxy-3-phenyl-2H-azirin-2-yl)-2,2-dime-
thylpropan-1-one 2k′ (46%); 2,2-dimethyl-1-(3-phenyl-2H-azirin-2-
yl)propan-1-one 2k″ (18%). Byproduct: (E)-1-(2-methoxy-3-phenyl-
2H-azirin-2-yl)hex-2-en-1-one 2l′ (18%). Byproduct: (2-methoxy-3-
d
Mechanistically, we propose that the rearrangement proceeds
through ketene intermediate C. Thus, rhodium-catalyzed
formation of carbenoid B promotes migration of the vinyl
substitutent to the carbenoid center resulting in formation of
ketene C. Attack of the oxygen atom of the oxime ether moiety
on the ketene leads to formation of ylides D/E that further
undergo rearrangement to afford 2H-azirine-2-carboxylic ester
F. Rhodium−nitrene complex G formed via ring-opening of F
undergoes C−H insertion to afford pyrrole H.
e
phenyl-2H-azirin-2-yl)(phenyl)methanone 2o′ (44%) obtained as an
inseparable mixture with 2o (yields were determined by NMR).
f
Byproduct: (4-methoxyphenyl)(3-phenyl-2H-azirin-2-yl)methanone
g
2p″ (21%). Byproduct: furan-2-yl(2-methoxy-3-phenyl-2H-azirin-2-yl)-
methanone 2q′ (31%).
with the results in the optimization studies, reactions smoothly
proceeded to afford 2H-azirine-2-carboxylic esters in good to
excellent yields. To probe electronic and steric influences on
To probe the presence of ketenes as intermediates in the
reaction pathway as shown in Scheme 2, we demonstrated that
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Communication
Table 2. Synthesis of Pyrroles via Tandem Reaction of
α-Diazo Oxime Ethers
ASSOCIATED CONTENT
* Supporting Information
■
a
S
Experimental procedures and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
cmpark@ntu.edu.sg
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Paul A. Wender. We
gratefully acknowledge Nanyang Technological University Start
Up Grant and Tier 1 Grant RG 25/09 for the funding of this
research.
REFERENCES
■
(1) Comprehensive Heterocyclic Chemistry II; Fan, W. Q.; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 2.
a
The reported yields in parentheses are of the isolated products.
Toluene, 110 °C. DCE, 60 °C. (E)-3-(3-Cyclohexyl-2-methoxy-
b
c
d
(2) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2007,
2H-azirin-2-yl)-1-phenylprop-2-en-1-one 4 h′ (19%) obtained as
108, 264. (b) Grube, A.; Kock, M. Org. Lett. 2006, 8, 4675. (c) Fujita,
M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita, J.; van
̈
byproduct.
Soest, R. W. M.; Fusetani, N. J. Am. Chem. Soc. 2003, 125, 15700.
(d) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (e) Boger,
D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 54.
̈
Scheme 2. Proposed Reaction Mechanism of the
Rearrangement
(3) Lohray, B. B.; Lohray, V. Pure Appl. Chem. 2005, 77, 179.
(4) (a) Berlin, A.; Vercelli, B.; Zotti, G. Polym. Rev. (Philadelphia, PA,
U.S.) 2008, 48, 493. (b) Gabriel, S.; Cec
Cossement, D.; Hecq, M.; Ruth, N.; Jer
Mater. 2007, 19, 2364. (c) Novak, P.; Muller, K.; Santhanam, K. S. V.;
́
ius, M.; Fleury-Frenette, K.;
́
o
̂
me, R.; Jer me, C. Chem.
́ ̂
o
́
̈
Haas, O. Chem. Rev. 1997, 97, 207.
(5) (a) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products;
Wiley: New York, 2002; Vol. 59. (b) St. Cyr, D. J.; Arndtsen, B. A.
J. Am. Chem. Soc. 2007, 129, 12366.
(6) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev.
2010, 39, 4402. (b) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238.
(c) Fontaine, P.; Masson, G. r.; Zhu, J. Org. Lett. 2009, 11, 1555.
(d) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465.
(e) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 126, 468.
(7) (a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 9585. (b) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou,
K. Angew. Chem., Int. Ed. 2011, 50, 1338. (c) Mizuno, A.; Kusama, H.;
Iwasawa, N. Angew. Chem., Int. Ed. 2009, 48, 8318.
the ketene independently prepared from carboxylic acid 5
spontaneously undergoes rearrangement to afford 2t in 85%
(eq 3).
(8) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc. 1975, 97,
4682.
(9) (a) Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 2592.
(b) Salomon, C. E.; Williams, D. H.; Faulkner, D. J. J. Nat. Prod. 1995,
58, 1463. (c) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53,
2103.
(10) (a) Padwa, A. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: Orlando, FL, 2010; Vol. 99, p 1.
(b) Gilchrist, T. L.; Alves, M. J. In Organic Azides; John Wiley & Sons
Ltd.: Chichester, U.K., 2010; p 167. (c) Palacios, F.; de Retana, A. M.
O.; de Marigorta, E. M.; de los Santos, J. M. Eur. J. Org. Chem. 2001,
2001, 2401. (d) Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.;
Santos, J. M. d. l. Org. Prep. Proced. Int. 2002, 34, 219. (e) Singh, G. S.;
D’Hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080. (f) e Melo,
T. M. V. D. P.; Amd’Ar, G. Curr. Org. Synth. 2004, 1, 275.
(11) (a) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett.
2010, 12, 3736. (b) Candito, D. A.; Lautens, M. Org. Lett. 2010, 12,
3312. (c) Padwa, A.; Stengel, T. Tetrahedron Lett. 2004, 45, 5991.
In summary, we have described development of highly
efficient synthesis of 2H-azirine-2-carboxylic esters with
quaternary centers and tandem synthesis of pyrroles. Novel
rearrangement of α-oximino ketenes generated from α-diazo
oxime ethers via the Wolff rearrangement results in formation
of 2H-azirine-2-carboxylic esters in excellent yields. This
reaction allowed us to further develop a tandem reaction for
highly substituted pyrroles via cascade rearrangement of α-diazo
oxime ethers.
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(d) Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.;
Jung, D. K.; Sexton, C. J.; Boyd, F. L. Jr.; Peel, M. R. Tetrahedron
2003, 59, 9001. (e) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang,
J. G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.;
Chamberlain, S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753. (f) Brahma,
S.; Ray, J. K. J. Heterocycl. Chem. 2008, 45, 311. (g) Alves, M. J.; Gil
Fortes, A.; Lemos, A.; Martins, C. Synthesis 2005, 2005, 555.
(h) Timen, A. S.; Fischer, A.; Somfai, P. Chem. Commun. 2003,
1150. (i) Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058.
(12) Rappoport, Z.; Liebman, J. F. The Chemistry of Hydroxylamines,
Oximes and Hydroxamic Acids; Wiley: Hoboken, NJ, 2008; Vol. 2.
(13) (a) Banert, K. In Organic Azides; John Wiley & Sons, Ltd:
Chichester, U.K., 2010; p 113. (b) Sjoholm Timen
Somfai, P. Tetrahedron Lett. 2003, 44, 5339.
́
, Å.; Risberg, E.;
̈
(14) (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2002, 2193. (b) Tidwell,
T. T. Angew. Chem., Int. Ed. 2005, 44, 5778.
(15) (a) Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512.
(b) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2008, 74,
415. (c) Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
125, 13624. (d) Dalton, A. M.; Zhang, Y.; Davie, C. P.; Danheiser,
R. L. Org. Lett. 2002, 4, 2465. (e) de Lucas, N. C.; Netto-Ferreira,
J. C.; Andraos, J.; Scaiano, J. C. J. Org. Chem. 2001, 66, 5016.
(16) Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed.
2010, 49, 7963.
(17) Preparation of α-diazo β-keto oxime ethers. For details, see ref
16 and the Supporting Information.
(18) (a) Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130,
8602. (b) Manning, J. R.; Davies, H. M. L. Tetrahedron 2008, 64, 6901.
(19) (a) P. Marsden, S.; Pang, W.-K. Chem. Commun. 1999, 1199.
(b) Collomb, D.; Doutheau, A. Tetrahedron Lett. 1997, 38, 1397.
(c) Karady, S.; Amato, J. S.; Reamer, R. A.; Weinstock, L. M.
Tetrahedron Lett. 1996, 37, 8277.
(20) Qi, X.; Jiang, Y.; Park, C.-M. Chem. Commun. 2011, 47, 7848.
(21) Plausible mechanism for the formation of 2k″.
4107
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