Carbocyclization cascades of allyl ketenimines via aza-Claisen rearrangements of N-phosphoryl-N-allyl-ynamides

Article abstract of DOI:10.1021/ol300366e

A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein-Wagner rearrangements and polyene-type cyclizations en route to fused bi-and tricyclic frameworks are featured.

Full text of DOI:10.1021/ol300366e

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1768–1771
Carbocyclization Cascades of Allyl
Ketenimines via Aza-Claisen
Rearrangements of
N-Phosphoryl-N-allyl-ynamides
Kyle A. DeKorver,* Xiao-Na Wang, Mary C. Walton, and Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53705, United States
dekorver@wisc.edu; rhsung@wisc.edu
Received February 14, 2012
ABSTRACT
A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl
ynamides is described. Interceptions of the cationic intermediate via MeerweinꢀWagner rearrangements and polyene-type cyclizations en route
to fused bi- and tricyclic frameworks are featured.
We recently reported a new class of ynamides1ꢀ3 bearing
a phosphoryl group as the required electron-withdrawing
component.4 Most notably, it was demonstrated that N-
phosphoryl-N-allyl ynamides 1 [for EWG = PO(OR)2]
could undergo a thermal 3-aza-Claisen rearrangement5,6
togenerate allyl ketenimine7 intermediates 2 in situ without
suffering a subsequent facile 1,3-shift observed in related
N-sulfonylsystems [1f4 whenEWG = ArSO2], leading to
an effective formation of structurally unique quaternary
nitriles 58,9 (Scheme 1). While such a 1,3-sulfonyl shift can
be of immense interest,10 it precluded us from developing a
useful carbocyclization of allyl ketenimines 4.8,9 Conse-
quently, in lieu of a 1,3-phosphoryl shift, we envisioned
that carbocyclizations of 2 could take place to afford
cyclopentenyl zwitter ionic intermediates 6, which would
allow us to construct cyclopentenimine derivatives 7 via a
(3) For ynamide papers published since May 2011, see: (a) Lu, Z.;
Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem. 2011, 76, 8524. (b)
Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew Chem., Int. Ed.
2011, 50, 8931. (c) Greenaway, R. L.; Campbell, C. D.; Holton, O. T.;
Russell, C. A.; Anderson, E. A. Chem.;Eur. J. 2011, 17, 14366. (d)
Aikawa, K.; Hioki, Y.; Shimizu, N.; Mikami, K. J. Am. Chem. Soc. 2011,
133, 20092. (e) Schotes, C.; Mezzetti, A. J. Org. Chem. 2011, 76, 5862. (f)
Dassonneville, B.; Witulski, B.; Detert, H. Eur. J. Org. Chem. 2011,
2836. (g) Nissen, F.; Detert, H. Eur. J. Org. Chem. 2011, 2845. (h)
Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Narayan
Karad, S.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 15372. (i) Kitamura,
T.; Hasan Morshed, M.; Tsukada, S.; Miyazaki, Y.; Iguchi, N.; Inoue,
D. J. Org. Chem. 2011, 76, 8117. (j) Vasu, D.; Hung, H.-H.; Bhunia, S.;
Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2011, 50, 6911.
(k) Smith, D. L.; Goundry, W. R. F.; Lam, H. W. Chem. Commun. 2012,
48, 1505. (l) Dateer, R. B.; Shaibu, B. S.; Liu, R.-S. Angew. Chem., Int.
Ed. 2012, 51, 113. (m) Beveridge, R. E.; Batey, R. A. Org. Lett. 2012, 14,
540. (n) Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.; Wang, G.; Deng, Y.;
Lai, G. Org. Lett. 2012, 14, 38. (o) Laouiti, A.; Rammah, M. M.;
Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org. Lett. 2012, 14,
6. (p) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756.
(4) DeKorver, K. A.; Walton, M. C.; North, T. D.; Hsung, R. P. Org.
Lett. 2011, 13, 4862.
(1) For current leading reviews on ynamides, see: (a) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (b)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(2) For leading reviews on the synthesis of ynamides, see: (a) Tracey,
M. R.; Hsung, R. P.; Antoline, J. A.; Kurtz, K. C. M.; Shen, L.; Slafer,
B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations; Weinreb, S. M., Ed. Georg Thieme Verlag KG:
Stuttgart, Germany, 2005; Chapter 21.4. (b) Mulder, J. A.; Kurtz, K. C. M.;
Hsung, R. P. Synlett 2003, 1379.
(5) For leading reviews on aza-Claisen rearrangements, see: (a)
Majumdar, K. C.; Bhayyacharyya, T.; Chattopadhyay, B.; Nandi,
R. K. Synthesis 2009, 2117. (b) Nubbemeyer, U. Top. Curr. Chem.
2005, 244, 149.
r
10.1021/ol300366e
Published on Web 03/13/2012
2012 American Chemical Society

underwent the tandem aza-Claisen rearrangementꢀ
carbocyclization to give 9b, presumably through a tertiary
carbocation intermediate.
Scheme 1. A Carbocyclization of Allyl Ketenimines
While it is also possible that deprotonation could lead to
1-amido dienes that then tautomerized to the observed
cyclopentenimines, the idea of a 1,2-H shift was enticing.
We therefore wondered if other MeerweinꢀWagner shifts
could occur following the initial aza-Claisen rearrange-
ment and carbocyclization (Scheme 3). To explore this
possibility, N-prenyl ynamide 10 was heated to 135 °C,
with the hopes of demonstrating a 1,2-methyl shift through
the formation of cyclopentenimine 14. Unfortunately, 14
was not observed. Instead, a 1:1 tautomeric mixture of 13a
and 13b was isolated in 90% yield causedby deprotonation
R to the enamide instead of the desired methyl shift.
Remarkably, when air was bubbled through the tauto-
meric mixture at rt in CHCl3, a [4 þ 2] cycloaddition of
2-amido diene 13b with O2 ensued to first give endoperoxide
1,2-H shift, or more powerfully, nucleophilic trapping11ꢀ13
of 6. We report herein our success in intercepting these
intermediates.
Scheme 3. Attempts at a 1,2-Alkyl Shift: An Unexpected [4 þ 2]
Scheme 2. Feasibility of the Carbocyclization
Our first success with an ynamide-initiated thermal
carbocyclization was the rearrangement of ynamide 8a
to R,β-unsaturated cyclopentenimine 9a in 50% yield
(Scheme 2). We were fascinated with this discovery, as it
implied that a 1,2-H shift through zwitter ionic intermedi-
ate 6 may be in operation. Furthermore, ynamide 8b also
(6) (a) DeKorver, K. A.; North, T. D.; Hsung, R. P. Synlett 2010,
2397. (b) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.;
Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899.
(7) For reviews on the chemistry of ketenimines, see: (a) Krow, G. R.
Angew. Chem., Int. Ed. Engl. 1971, 10, 435. (b) Gambaryan, N. P. Usp.
Khim. 1976, 45, 1251. (c) Dondoni, A. Heterocycles 1980, 14, 1547. (d)
Barker, M. W.; McHenry, W. E. In The Chemistry of Ketenes, Allenes
and Related Compounds; Patai, S., Ed.; Wiley-Interscience: Chichester,
U.K., 1980; Part 2, pp701ꢀ720. (e) Alajarin, M.; Vidal, A.; Tovar, F.
Targets Heterocycl. Syst. 2000, 4, 293.
(8) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai,
H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092.
(9) DeKorver, K. A.; Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org.
Lett. 2010, 12, 1840.
(10) For leading references on synthetic applications of nitriles, see:
(a) Fleming, F. F.; Liu, W. Eur. J. Org. Chem. 2009, 699. (b) Fleming,
F. F.; Wei, G.; Steward, O. W. J. Org. Chem. 2008, 73, 3674. (c)
Mermerian, A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949.
(11) For related carbocyclizations of ynol ethers, see: (a) Sosa, J. R.;
Tudjarian, A. A.; Minehan, T. G. Org. Lett. 2008, 10, 5091. (b)
Tudjarian, A. A.; Minehan, T. G. J. Org. Chem. 2011, 76, 3576.
(12) Hanessian, S.; Tremblay, M.; Marzi, M.; Del Valle, J. R. J. Org.
Chem. 2005, 70, 5070.
16 that subsequently fragmented to the isolated ene-dione
15. While this could be a radical fragmentation, although
the reaction conditions involved no base, it is very likely
another example of a KornblumꢀDeLaMare process.14,15
The idea of pursuing [4 þ 2] cycloadditions with in situ
generated 2-amido dienes was intriguing; however we were
still very interested in intercepting the zwitter ionic inter-
mediates through either MeerweinꢀWagner rearrange-
ments or nucleophilic trappings. To explore the former,
we prepared ynamides 17 and 21 bearing a tethered
(13) For related examples of intercepted Nazarov cyclizations, see:
(a) Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed.
2000, 39, 1970. (b) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221. (c)
Wang, Y.; Schill, B. D.; Arif, A. M.; West, F. G. Org. Lett. 2003, 5, 2747.
(d) Huang, J.; Leboeuf, D.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133,
6307. (e) For a recent review, see: Grant, T. N.; Rieder, C. J.; West, F. G.
Chem. Commun. 2009, 5676.
(14) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73,
880.
(15) For recent examples, see: (a) Tang, Y.; Cole, K. P.; Buchanan,
G. S.; Li, G.; Hsung, R. P. Org. Lett. 2009, 11, 1591. (b) Buchanan, G. S.;
Cole, K. P.; Tang, Y.; Hsung, R. P. J. Org. Chem. 2011, 76, 7027.
Org. Lett., Vol. 14, No. 7, 2012
1769

methylcyclopentylidine and methylcyclobutylidine, re-
spectively, reasoning that the added ring strain should
favor ring expansion through zwitter ions 20 (Scheme 4).
When 17 was heated to 135 °C, spirocycles 18 resulting
from elimination dominated; however bicycle 19a was also
isolated in 10% yield representing a successful ring expan-
sion. Moreover, ynamide 21 with increased ring strain
yielded ring-expansion product 23 in 84% yield and spiro-
cycle 22 was not observed.
Wagner rearrangements, we wanted to explore the possibility
of using the aza-Claisen rearrangement to initiate a carbocy-
clization cascade with tethered carbon nucleophiles. Gratify-
ingly, ynamide 27 featuring a m-methoxyphenyl moiety
tethered to the allyl fragment cleanly underwent the required
3-aza-Claisen rearrangement followed by carbocyclization
and FriedelꢀCraft electrophilic aromatic substitution to give
30a and 30b as a 1:1 mixture of trans and cis isomers without
any competing alkyl shifts (Scheme 6).
Scheme 4. Ring Expansion through MeerweinꢀWagner Shift
Scheme 6. FriedelꢀCraft Trapping of Cationic Intermediate
We also, rather unexpectedly, discovered a Meerweinꢀ
Wagner ring contraction when pursuing the carbocycliza-
tion of ynamide 24a bearing a tethered methylcyclohexene
(Scheme 5). In addition to the anticipated 5,6-fused bicycle
19a resulting from a 1,2-H shift, 5,5-spirocycle 26a was
isolated as the major product in 53% yield. It is possible
that A1,2 strain promoted the CꢀC bond of the fused
cyclohexane ring to adopt a pseudoaxial position in
The ability to intercept these cationic intermediates with
aryl nucleophiles was exciting and propelled us into ex-
ploring other nucleophilic trappings. Inspired by the
abundance of beautiful work using terpenes in cationic
polyene cascades16,17 we decided to investigate the possi-
bility of an ynamide-initiated carbocyclization cascade
with terpene-derived ynamides (Scheme 7).
Scheme 5. Ring Contraction through MeerweinꢀWagner Shift
Starting from commercially available geranylamine 31,
a simple two-step protocol involving phosphorylation and
Cu-catalyzed amidative cross-coupling gave ynamide 32 in
82% overall yield. When 32 was heated to 135 °C for 12 h,
5,5-cis-fused bicycle 36 bearing an exocyclic olefin was
isolated in 55% yield as a single diastereomer. Of note, the
cis-fused bicyclic core in 36 is prominent in triquinane18
natural products. In addition to 36, tricycle 37 featuring
four contiguous stereocenters and three all-carbon qua-
ternary centers was isolated in 38% yield as a single
diastereomer. The geometry of both products was deter-
mined by NOE analysis.
(16) For reviews on polyene cyclizations, see: (a) Johnson, W. S. Acc.
Chem. Res. 1968, 1, 1. (b) Johnson, W. S. Angew. Chem., Int. Ed. 1976,
15, 9. (c) For a key account, see: Johnson, W. S.; Telfer, S. J.; Cheng, S.;
Schubert, U. J. Am. Chem. Soc. 1987, 109, 2517.
(17) Also see: (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc.
1955, 77, 5068. (b) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D.
Helv. Chim. Acta 1955, 38, 1890. (c) Stadler, P. A.; Eschenmoser, A.;
Schinz, H.; Stork, G. Helv. Chim. Acta 1957, 40, 2191.
25-CC-ax, thereby allowing the 1,2-alkyl shift to compete.
This notion was furthered by our experimentation with
methyl-terminated ynamide 24b, where the expected 1,2-H
shift dominated to give 19b in 75% yield and only 3% of
the spirocycle 26b.
After successfully completing several examples of inter-
cepting the zwitter ionic intermediates via Meerweinꢀ
1770
(18) For a review on triquinane synthesis: Mehta, G.; Srikrishna, A.
Chem. Rev. 1997, 97, 671.
Org. Lett., Vol. 14, No. 7, 2012

shown in either 34a or 34b, which followed by elimination
would give 36. Mechanistically more intriguing is the
formal [4 þ 2] cycloaddition to afford 37, which must arise
through the olefin approach shown in 34a, followed by
enamide addition to the resulting tertiary carbocation.
The described carbocyclization cascade worked equally
well with methyl-terminated ynamide 38. After 12 h, 5,
5-cis-fused bicycle 39 was isolated as a 9:1 mixture of endo
and exo olefin isomers, as well as tricycle 40 as a single
diastereomer.
Scheme 7. Ynamide Initiated Cationic Polyene Cascade
We have showcased here a tandem aza-Claisenꢀ
carbocyclization for the synthesis of R,β-unsaturated cy-
clopentenimines from N-phosphoryl-N-allyl ynamides.
Furthermore, we have demonstrated the ability to inter-
cept the zwitter ionic intermediates through Meerweinꢀ
Wagner ring expansions and contractions, as well as with
tethered carbon nucleophiles to afford bi- and tricyclic
scaffolds. Applications of these carbocyclization cascades
in total synthesis are currently underway.
Acknowledgment. We thank NIH [GM066055] for
funding. K.A.D. thanks the American Chemical Society
for a Division of Medical Chemistry Predoctoral Fellow-
ship. We thank Dr. Vic Young and Mr. Gregory T. Rohde
of the University of Minnesota for providing X-ray struc-
tural analysis. The authors would also like to thank one of
the referees for providing valuable mechanistic suggestions.
Supporting Information Available. Experimental pro-
cedures as well as NMR spectra, and characterizations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The divergence in reaction pathways leading to the bi-
and tricylic products was interesting. As one might ima-
gine, after the initial carbocyclization, the second olefin
may add to the carbocation through the facial approach
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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