Lewis Acid-Mediated Reactions of Alkyl Azides with α,β- Unsaturated Ketones

Article abstract of DOI:10.1021/ol0355130

(Matrix presented) Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt reaction, but this reaction does not proceed when α,β-unsaturated ketones are used. In this study, alk

Full text of DOI:10.1021/ol0355130

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ORGANIC
LETTERS
2003
Vol. 5, No. 21
3899-3902
Lewis Acid-Mediated Reactions of Alkyl
Azides with r,â-Unsaturated Ketones
D. Srinivasa Reddy, Weston R. Judd, and Jeffrey Aube´*
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Malott Hall,
Room 4070, UniVersity of Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received August 11, 2003
ABSTRACT
Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt
reaction, but this reaction does not proceed when r,â-unsaturated ketones are used. In this study, alkyl azides were reacted with enones in
the presence of Lewis acids to give enaminones (vinylogous amides), which formally involve a ring contraction reaction. The mechanism and
scope of this reaction is discussed.
The chemistry of alkyl azides encompasses 1,3-cycloaddition
or radical reactions as well as polar chemistry in which the
Scheme 1
azide plays the role of either electrophile or nucleophile.1
About 10 years ago, we discovered that alkyl azides undergo
Lewis acid-mediated reactions with ketones to give the
corresponding lactams (the azido-Schmidt reaction; Scheme
1).2 This reaction entails the initial addition of azide to an
activated carbonyl group in a 1,2 fashion. In contrast, we
(1) For reviews and some recent leading references, see: (a) Banthorpe,
D. V. In The Chemistry of the Azido Group; Patai, S., Ed.; John Wiley &
Sons: London, 1971; pp 397-440 (b) Abramovich, R. A.; Kyba, E. P. In
The Chemistry of the Azido Group; Patai, S., Ed.; John Wiley & Sons:
London, 1971; pp 221-329. (c) Kyba, E. P. In Azides and Nitrenes:
ReactiVity and Utility; Scriven, E. F. V., Ed.; Academic: Orlando, 1984;
pp 2-34. (d) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297-
368. (e) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521-
5522. (f) Tingoli, M.; Tiecco, M.; Chianelli, D.; Balducci, R.; Temperini,
A. J. Org. Chem. 1991, 56, 6809-6813. (g) Clive, D. L. J.; Etkin, N.
Tetrahedron Lett. 1994, 35, 2459-2462. (h) Wang, Q.; Chan, T. R.; Hilgraf,
R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003,
125, 3192-3193. (i) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2113-2116. (j) Evans, D. A.; Britton, T. C.; Ellman, J. A.;
Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011-4030. (k) Mertens, A.;
Lammertsma, K.; Arvanaghi, M.; Olah, G. A. J. Am. Chem. Soc. 1983,
105, 5657-5660. (l) Khouki, M.; Vaultier, M.; Carrie´, R. Tetrahedron Lett.
1986, 27, 1031-1034.
have been unable to obtain Schmidt type ring expansion
products from R,â-unsaturated ketones in either an inter- or
intramolecular sense.2d In this paper we report that Lewis
acids activate enones toward a facile [3 + 2] cycloaddition
pathway, affording 1,2,3-triazolines. These intermediates are
not observed, but in many cases rearrange in situ to furnish
enaminones in an overall ring contraction process.
This investigation began by examining the reactions of
2-cyclohexenone with simple alkyl azides. Thus, treatment
of cyclohexenone with benzyl azide in the presence of
TMSOTf afforded enaminone 1 as a crystalline material in
(2) (a) Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Aube´, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992,
57, 1635-1637. (c) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman,
C.; Milligan, G. L.; Aube´, J. J. Am. Chem. Soc. 2000, 122, 7226-7232.
(d) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995,
117, 10449-10459. (e) Wrobleski, A.; Aube´, J. J. Org. Chem. 2001, 66,
886-889.
10.1021/ol0355130 CCC: $25.00 © 2003 American Chemical Society
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68% yield (Scheme 2). The assigned structure was confirmed
by X-ray crystallography.3
and the present method could provide an alternative route
to these useful materials.
Scanning a variety of Lewis acids for the above transfor-
mation, it was found that the first choice of TMSOTf was
best, although BF3‚Et2O and TFA also gave the same
product. Other Lewis acids such as TiCl4, triflic acid,
MeAlCl2, and Yb(OTf)3 resulted in less than 10% conversion.
Using TMSOTf, we then examined the reaction of cyclo-
hexenone with a variety of alkyl azides (Table 1). The alkyl
Scheme 2
Table 1. Reaction of Cyclohexenone with Various Azides
entry
R
yield (%) product (Z/E ratio)
1
2
3
4
5
6
7
PhCH2CH2-
93
83
76
69
62
77
20
2 (2:1)
3 (2:1)
4 (3:2)
5 (1:1)
6 (1:1)
7 (2:1)
8 (2:1)
Reactions of azides and enones are known to produce ring-
contracted products or ring-expanded lactams thermally via
triazoline intermediates.4 There have also been reports on
ring-contraction of enamines and enol ethers using arylsul-
fonyl azides.5 In general, such reactions usually require
heating to ca. 100 °C for 1,3-dipolar cycloaddition. In the
present case, temperatures of 0 °C to rt are sufficient to
activate the carbonyl group toward cycloaddition. Enami-
nones are versatile building blocks for the construction of
various heterocycles6 and natural products7 and are often
endowed with useful pharmacological properties.8 Enami-
nones are generally prepared from 1,3-diketones and amines,6a,9
n-C6H13
-
trans-PhCHdCHCH2-
EtO2CCH2CH2-
p-MeO(C6H4)CH2-
Cl(CH2)3-
c-C6H11
-
azides examined gave smooth ring contraction to furnish
enaminones 2-7 in ca. 60-90% yields with the exception
of azidocyclohexane (entry 7).
1
The Z,E ratio of each product was determined using H
NMR of the crude material. In general, the isomers were
not separable, and enaminones with Z double-bond geometry
were favored over the E isomers. The geometry was assigned
based on spectroscopic (IR and 1H NMR) trends throughout
the series (Figure 1). To wit, the isomer that had the lower
(3) Coincidently, a single crystal of the minor isomer (E)-1 was picked
from the mixture of E,Z isomers for X-ray analysis.
(4) (a) Schultz, A. G.; McMahon, W. G. J. Org. Chem. 1984, 49, 1676-
1678. (b) Schultz, A. G.; Ravichandran, R. J. Org. Chem. 1980, 45, 5008-
5009. (c) Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Hseu, T.-H. J. Chem.
Soc., Chem. Commun. 1984, 492-494. (d) Sha, C.-K.; Ouyang, S.-L.; Hsieh,
D.-Y.; Chang, R.-C.; Chang, S.-C. J. Org. Chem. 1986, 51, 1490-1494.
(e) Benati, L.; Calestani, G.; Montevecchi, P. C.; Spagnolo, P. J. Chem.
Soc., Perkin Trans. 1 1995, 1381-1385. (g) Hansen, P. E.; Undheim, K. J.
Chem. Soc., Perkin Trans. 1 1975, 305-308. (h) Benati, L.; Montevecchi,
P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1991, 71-77. (i) Benati,
L.; Montevecchi, P. C.; Spagnolo, P.; Foresti, E. J. Chem. Soc., Perkin
Trans. 1 1992, 2845-2850. (j) Molander, G. A.; Bibeau, C. T. Tetrahedron
Lett. 2002, 43, 5385-5388.
(5) (a) Wohl, R. A. HelV. Chim. Acta 1973, 56, 1826-1828. (b) Wohl,
R. A. Tetrahedron Lett. 1973, 3111-3114. (c) Semenov, V. P.; Andreeva,
T. D.; Ogloblin, K. A. Zh. Org. Khim. 1988, 24, 217-220. (d) Semenov,
V. P.; Mishin, M. A.; Ogloblin, K. A. Zh. Org. Khim. 1988, 24, 2384-
2388. (e) Semenov, V. P.; Ogloblin, K. A. Zh. Org. Khim. 1987, 23, 898-
899. (f) Semenov, V. P.; Ogloblin, K. A. Zh. Org. Khim. 1988, 24, 2389-
2397. (g) Xu, Y.; Wang, Y.; Zhu, S. Synthesis 2000, 513-516.
(6) (a) Greenhill, J. V. Chem. Soc. ReV. 1977, 6, 277-294. (b) Lue, P.;
Greenhill, J. V. AdV. Heterocycl. Chem. 1997, 67, 207-343. (c) Cimarelli,
C.; Palmieri, G. Recent Res. DeVel. Org. Chem. 1997, 1, 179-189.
(7) Michael, J. P.; De Koning, C. B.; Gravestock, D.; Hosken, G. D.;
Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly,
S. C.; Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979-988.
(8) (a) Scott, K. R.; Rankin, G. O.; Stables, J. P.; Alexander, M. S.;
Edafiogho, I. O.; Farrar, V. A.; Kolen, K. R.; Moore, J. A.; Sims, L. D.;
Tonnu, A. D. J. Med. Chem. 1995, 38, 4033-4043. (b) Edafiogho, I. O.;
Alexander, M. S.; Moore, J. A.; Farrar, V. A.; Scott, K. R. Curr. Med.
Chem. 1994, 1, 159-175. (c) Edafiogho, I. O.; Moore, J. A.; Alexander,
M. S.; Scott, K. R. J. Pharm. Sci. 1994, 83, 1155-1170.
Figure 1. Characteristic spectral data of (Z)- and (E)-1.
field NH proton and a higher field olefinic proton was
assigned as the Z isomer.10 In addition, the Z isomer has a
lower νCdO compared to that measured for the E isomer.
Intramolecular hydrogen bonding in the Z isomer could be
responsible for the dramatic difference in the spectral data
of the Z and E isomers.11
(9) (a) Azzaro, M.; Geribaldi, S.; Videau, B. Synthesis 1981, 880-881.
(b) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983, 902-903.
(c) Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante, M. E. F.
Synthesis 1998, 1019-1022. (d) Stefane, B.; Polanc, S. New J. Chem. 2002,
26, 28-32.
(10) (a) Zhuo, J.-C. Magn. Reson. Chem. 1997, 35, 311-322. (b). Zhuo,
J. C.; Schenk, K. HelV. Chim. Acta 1997, 80, 2137-2147.
3900
Org. Lett., Vol. 5, No. 21, 2003

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These results show that, under Lewis acid activation, the
enones are more activated for 1,3-dipolar cycloaddition than
for nitrogen insertion into the carbonyl group. The mecha-
nism formulated in Scheme 3 involves Lewis acid-mediated
Table 2. Reactions of Benzyl Azide with Various Enones
Scheme 3
regioselective 1,3-dipolar cycloaddition12 of the alkyl azide
onto the enone olefin as the first step to give the triazoline
intermediate. Under the reaction conditions, the unstable
triazoline intermediate undergoes decomposition to produce
a zwitterionic species that can exist in either one of the two
conformations (A or B). In conformer A, 1-2 bond migration
onto the leaving diazonium species in an antiperiplanar
fashion followed by 1,3-hydrogen shift leads to the ring-
contracted exocyclic enaminone. In contrast, migration of
the alkyl group in B onto the axial diazonium species results
in formation of an endocyclic enaminone.
Various enones were then surveyed toward their reaction
with benzyl azide in the presence of TMSOTf (Table 2).
Many examples gave ring-contraction products (enaminones)
as occurred with cyclohexenone (entries 2-4 and 8).
Cyclopentenone gave two different products in 81% overall
yield, with the endocyclic enaminone 9 being the major one
and the aziridine derivative 1013 being the minor one. Another
a Compounds were identified in crude NMR but not isolated. b Crude
yield; stereochemistry unassigned.
manifold is possible for ketones bearing an additional
substituent at the R carbon (see C in Scheme 3). Entries 5-7
show products with new quaternary centers in which the
intermediates formed during ring contraction were mecha-
nistically prohibited from forming enaminones via 1,3-H
shift. In the case of (+)-pulegone, a diastereomeric mixture
of â-diketones 19 and 2014 was isolated in 50% yield (entry
(13) Formation of aziridine 10 can be explained by the following
mechanism.
(11) Gilli, P.; Bertolasi, V.; Pretto, L.; Lycka, A.; Gilli, G. J. Am. Chem.
Soc. 2002, 124, 13554-13567.
(12) (a) Huisgen, R.; Szeimies, G.; Moebius, L. Chem. Ber. 1966, 99,
475-490. (b) Broeckx, W.; Overbergh, N.; Samyn, C.; Smets, G.; L’Abbe,
G. Tetrahedron 1971, 27, 3527-3534. (c) Texier, F.; Carrie, R. Bull. Soc.
Chim. Fr. 1971, 4119-4128.
Org. Lett., Vol. 5, No. 21, 2003
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7) in which the imine obtained from methyl migration was
hydrolyzed to give â-diketones under the reaction conditions.
Also note that imines obtained in entries 5 and 6 were not
isolated in pure form due to their instability. We also tried
the reaction of benzyl azide with an acyclic enone, which
gave enaminone 22 as the only isolated product (entry 9).
In contrast, reaction of benzyl azide with methyl crotonate
gave no desired product under the same conditions. Our
experimental results showed that “path a” is favored over
“path b” in our proposed mechanism (see Scheme 3) in all
cases except cyclopentenone, which can be attributed to the
strain factor in going from a 5- to a 4-membered ring. It is
noteworthy that a formal Schmidt lactam product 13 (from
ring expansion) was observed only in the case of naphtho-
quinone out of all the substrates tried.
kinds of double-bond reactivity are possible. Our study shows
that azides react with Lewis acid-activated enones in the well-
known [3 + 2] cycloaddition mode rather than in the Schmidt
reaction mode. Furthermore, these reactions occur at tem-
peratures well below those needed for analogous thermal
reactions. Finally, we have established a range of further
reactions possible for the 1,2,3-triazolines formed, at least
one of whichsring contraction to afford enaminonessis
likely to be of some synthetic interest. Further studies of
alternative modes of azide reactivity are underway in these
laboratories.
Acknowledgment. We thank the National Institutes of
Health (GM-49093) for the support of this work and Doug
Powell for the X-ray crystallographic structure.
This study establishes why enones fail in the Schmidt
reactions of alkyl azides. Unlike simple carbonyls, which
have only one mode of reactivity, enones can react at the
carbonyl group in a 1,2 fashion or at the double bond. In
the latter case, 1,4-addition (i.e., conjugate addition) or other
Supporting Information Available: Experimental details
and characterization data for all new compounds and details
pertaining to the X-ray structure of compound 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Reusch, W.; Anderson, D. F.; Johnson, C. K. J. Am. Chem. Soc.
1968, 90, 4988-4993.
OL0355130
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