An intramolecular [2 + 2] cycloaddition of ketenimines via palladium-catalyzed rearrangements of N-allyl-ynamides

Article abstract of DOI:10.1021/ol3013233

A cascade of Pd-catalyzed N-to-C allyl transfer-intramolecular ketenimine-[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.

Full text of DOI:10.1021/ol3013233

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3214–3217
An Intramolecular [2 þ 2] Cycloaddition
of Ketenimines via Palladium-Catalyzed
Rearrangements of N-Allyl-Ynamides
Kyle A. DeKorver, Richard P. Hsung,* Wang-Ze Song, Xiao-Na Wang, and
Mary C. Walton
Division of Pharmaceutical Sciences and Department of Chemistry,
University of Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received May 12, 2012
ABSTRACT
A cascade of Pd-catalyzed N-to-C allyl transferꢀintramolecular ketenimineꢀ[2 þ 2] cycloadditions of N-allyl ynamides is described. This tandem
sequence is highly stereoselective and the [2 þ 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene
substitutions, leading to bridged and fused bicycloimines.
Throughout our studies on palladium catalyzed N-to-C
allyl transfers1 of N-allyl ynamides2ꢀ4 to ketenimines,5 we
have anticipated the possibility of effecting an intramolecu-
lar ketenimine-[2 þ 2] cycloaddition with tethered alkenes
[Scheme 1]. Seminal work on cycloadditions involving
ketenes6 and keteniminium ions has been extensively
undertaken by Marko,7 Snider,8 Brady,9 and recently by
11
Minehan,10 giving rise to cyclobutanones through fusedꢀ
and/or crossedꢀ[2 þ 2]12 pathways. For our own designs,
we imagined that ketenimino-Pd-π-allyl complexes prepared
(5) 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, pp 701ꢀ720. (e) Alajarin, M.; Vidal, A.; Tovar, F.
Targets Heterocycl. Syst. 2000, 4, 293.
(6) For a review, see: Snider, B. B. Chem. Rev. 1988, 88, 793.
(7) Marko, I.; Ronsmans, B.; Hesbain-Frisque, A.-M.; Dumas, S.;
Ghosez, L. J. Am. Chem. Soc. 1985, 107, 2192.
(8) For leading references, see: (a) Snider, B. B.; Hui, R. A. H. F.;
Kulkarni, Y. S. J. Am. Chem. Soc. 1985, 107, 2194. (b) Lee, S. Y.;
Kulkarni, Y. S.; Burbaum, B. W.; Johnston, M. I.; Snider, B. B. J. Org.
Chem. 1988, 53, 1848.
(9) Brady, W. T.; Giang, Y. F. J. Org. Chem. 1985, 50, 5177.
(10) Tran, V.; Minehan, T. Org. Lett. 2011, 13, 6588.
(1) (a) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.;
Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899. (b) DeKorver, K. A.;
Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org. Lett. 2010, 12, 1840. (c)
DeKorver, K. A.; Johnson, W. L.; Zhang, Y.-S.; Zhang, Y.; Lohse,
A. G.; Hsung, R. P. J. Org. Chem. 2011, 76, 5092.
(2) For current leading reviews on ynamides, see: (a) DeKorver,
K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P.
Chem. Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840.
(3) 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.
(4) For ynamide papers published since February 2012, see: (a) Saito,
N.; Ichimaru, T.; Sato, Y. Org. Lett. 2012, 14, 1914. (b) Kerr, D. J.;
Miletic, M.; Chaplin, J. H.; White, J. M.; Flynn, B. L. Org. Lett. 2012,
14, 1732. (c) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.;
Malacria, M.; Aubert, C.; Gandon, V. Chem.;Eur. J. 2012, 18, 4337.
(d) Jin, X.; Yamaguchi, K.; Mizuno, N. Chem. Commun. 2012, 48, 4974.
(e) Tchabanenko, K.; Sloan, C.; Bunetel, Y.-M.; Mullen, P. Org. Biomol.
Chem. 2012, 10, 4215.
(11) For more examples of fusedꢀ[2 þ 2] ketene cycloadditions, see:
(a) Snider, B. B.; Hui, R. A. H. F.; Kulkarni, Y. S. J. Am. Chem. Soc.
1985, 107, 2194. (b) Zhang, W.; Collins, M. R.; Mahmood, L.; Dowd, P.
Tetrahedron Lett. 1995, 36, 2729.
(12) For recent crossed keteneꢀ[2 þ2] cycloadditions, see: (a)
ꢀ
McCaleb, K. L.; Halcomb, R. L. Org. Lett. 2000, 2, 2631. (b) Belanger,
ꢀ
^
B.; Leevesque, F.; Paquet, J.; Barbe, G. J. Org. Chem. 2005, 70, 291.
r
10.1021/ol3013233
Published on Web 06/05/2012
2012 American Chemical Society

by N-to-C allyl transfers of N-allyl ynamides 1 could also
participate in fusedꢀ or, more rarely, crossedꢀ[2 þ 2]
cycloadditions to afford highly substituted bicycloimines 2
or 3 via intermediates 5 or 6.
π-system and the bulky c-hexyl group into a pseudoequa-
torial position, diastereomeric transition states 10 and 100
can be envisioned. The A1,3 strain between the c-hex group
and imine disfavored 100, leading to 8 as the exclusive
product with the imine anti to the c-hexyl.
Scheme 1. Intramolecular Ketenimineꢀ[2 þ 2] Cycloadditions
Figure 1. X-ray of 8 and diastereoselectivity rationale.
During our pursuit of this endeavor, Tu13 demonstrated
beautifully the feasibility of carrying out intramolecular
crossedꢀ[2 þ 2] cycloadditions using ketenimines gener-
ated in situ by extrusion of N2 from N-tosyl azides in
a retro-[3 þ 2] manner.2a,14 In their work, the resulting
bicycloimines were immediately hydrolyzed to ketones,
and the crossed cycloaddition was the exclusive pathway.
Our findings deviate significantly from theirs, and we
report herein our successful development of highly diastereo-
selective crossed and fused ketenimineꢀ[2 þ 2] cycloaddi-
tions from N-allyl ynamides.
We quickly discovered that, in fact, γ-branched N-allyl
ynamide 7 featuring an oxygen tethered styryl moiety
cleanly underwent the desired Pd-catalyzed rearrange-
mentꢀintramolecular [2 þ 2] cycloaddition sequence to
give bridged bicycloimine 8 in 80% yield as a single diaster-
eomer [Scheme 2].15 It is noteworthy that cycloadduct 9
from a fusedꢀcycloaddition pathway was not observed.
The substrate scope proved to be exceptional, tolerating
an array of propargylic substituents and tethered olefins
[Table 1]. Styryl-tethered ynamide 11 led to bicycle 14
in near-quantitative yield [entry 1]. By utilizing crotyl-
tethered ynamides 12aꢀc, cycloadducts 15aꢀc were iso-
lated in good yields, though a competing carbocyclization1a,16
involving the Pd-π-allyl moiety was also observed in 10ꢀ20%
yield [entries 2ꢀ4; see Scheme 4].
Gratifyingly, styryl-tethered ynamide 13 featuring an
N-Ts linkage could also be used to afford 16 in quantitative
yield as a 9:1 mixture of diastereomers [entry 9]. Interest-
ingly, NOE of 1615 implied a switch of stereoselectivity.
Subsequently, X-ray analysis showed that the once pro-
pargylicphenyl was indeed syn tothe imine in 16[Figure2],
opposite to the observed stereochemistry in the oxygen-
tethered system employing a similarly sized propargylic
c-hex moiety [see Figure 1].
It is noteworthy that such a selectivity switch was not
observed in Tu’s study.13 The switch in diastereoselectivity
for the crossed cycloaddition with N-Ts tethered ynamides
is likely a result of a gauche interaction between the phenyl
and the N-sulfonyl moiety as shown in 170 [Figure 2].
Instead, the cycloaddition favored chair-flipped 17 with
the phenyl pseudoaxial, explaining the formation of 16
with the imine and phenyl syn as the major diastereomer.
In Table 1, we revealed that a competing carbocycliza-
tion was operational to give cyclopentenimines in 10ꢀ20%
yield with several of the γ-branched ynamides. Upon
attempting to carry out cycloadditions with tethered cis
alkenes, this reaction dichotomy was exemplified [Scheme
3]. As anticipated, ynamide 18 bearing a tethered trans-
olefin afforded the desired crossed cycloadduct 20 in
g95% yield. However, the cis-olefin tethered analogue
21 [10:1 cis/trans] gave cyclopentenimine 24 in 55% yield
with only a trace amount of cycloadduct 20 observed,
Scheme 2. Discovery of a Crossed Ketenimineꢀ[2 þ 2]
Unlike in Tu’s system,13 the directly resulting imine was
isolable by silica gel column chromatography and also
crystalline, allowing for unambiguous determination of
its structure by single crystal X-ray analysis [Figure 1].
By orienting the alkene to engage the orthogonal imine
(13) Li, B.-S.; Yang, B.-M.; Wang, S.-H.; Zhang, Y.-Q.; Cao, X.-P.;
Tu, Y.-Q. Chem. Sci 2012, 3, 1975.
(14) For a recent review, see: Meldal, M.; Tornoe, C. W. Chem. Rev.
2008, 108, 2952.
(15) See Supporting Information.
(16) DeKorver, K. A.; Wang, X.-N.; Walton, M. C.; Hsung, R. P.
Org. Lett. 2012, 14, 1768.
Org. Lett., Vol. 14, No. 12, 2012
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Table 1. Crossed Ketenimineꢀ[2 þ 2] Cycloadditionsa
Scheme 3. A Dichotomy Based on Olefin Geometry
Scheme 4. Crossedꢀ[2 þ 2] versus Carbocyclization
a Reaction conditions: 5 mol % pd(PPh3)4, Tol [concn = 0.1 M],
70 °C 2 h. b Isolated yields. c g20:1 dr by 1H NMR unless otherwise
noted. d 10ꢀ20% cyclopentenimine. e 9:1 dr as measured by 1H NMR.
70 °C with 5 mol % Pd(PPh3)4, a 1:1 mixture of cycload-
duct 31and cyclopentenimine 32was isolated in 61% yield,
arising from the competing fusedꢀ[2 þ 2] cycloaddition
and carbocyclization. Fortunately, fused cycloadduct 31
crystallized cleanly from the mixture, allowing us to con-
firm its structure by X-ray analysis. The cycloaddition was
highlydiastereoselective, giving31withthe imine syn tothe
c-hexyl as a single diastereomer through 33 to minimize
A1,2 strain suffered in 330.
Figure 2. Switch in diastereoselectivity with N-Ts tether.
which likely arose from the trans impurity in the starting
ynamide and not from reaction of the cis alkene. Clearly,
the cis olefin geometry would have disfavored the cycload-
dition transition state 22, and instead the carbocyclization
through 23 ensued.
Scheme 5. Discovery of a Fusedꢀ[2 þ 2] Cycloaddition
Furthermore, when t-Bu-substituted ynamide 24 was
subjected to the reaction conditions, the desired cycloadduct
25 was isolated in only 22% yield; however cyclopentenimine
26 was obtained in 57% yield [Scheme 4]. This further
illustrates the necessity for the cycloaddition to occur through
the highly organized transition state 28, as disfavorable steric
interactions clearly favor carbocyclization through 29.
Next, we wished to assess how an unsubstituted allyl
group serving as the cycloaddition partner would behave
under the reaction conditions, as Pd-catalyzed deallylation
was also possible [Scheme 5]. Additionally and notably,
Tu found unsubstituted alkenes to be unreactive in their
system.13 Interestingly, when ynamide 30 was heated to
Similar to what has been well documented for keteneꢀ
[2 þ 2] cycloadditions,6 we found that tethered internally
substituted alkenes also favored the formation of fused
cycloadducts in our system [Table 2]. Ynamides 34aꢀd
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Org. Lett., Vol. 14, No. 12, 2012

phosphoryl-substituted ynamide 35,17 were assigned by
NOE analysis.15
Table 2. Fused Ketenimineꢀ[2 þ 2] Cycloadditionsa
We have showcased here a highly diastereoselec-
tive cascade of Pd-catalyzed N-to-C allyl transferꢀ
intramolecularꢀ[2 þ 2] cycloadditions to afford highly
substituted bicycloimines from N-allyl ynamides. The
alkene substitution pattern played an imminent role in
favoring either the fused or crossed cycloaddition path-
way, leading to fused or bridged cycloadducts. Also
uncovered is a competing carbocyclization pathway when
hindered alkenes or sterically demanding propargylic sub-
stituents were employed, giving rise to R,β-unsaturated
cyclopentenimines. Applications and a further mechanistic
understanding of these unique cycloaddition manifolds are
currently underway.
a Reaction conditions: 5 mol % pd(PPh3)4, Tol [concn = 0.1 M],
70 °C 2 h. b Isolated yields. c g20:1 dr by 1H NMR unless otherwise
noted. d 10ꢀ20% cyclopentenimine. e 9:1 dr as measured by 1H NMR.
Acknowledgment. We thank the NIH [GM066055]
for funding. K.A.D. thanks the American Chemical
Society for a Division of Medical Chemistry Predoctoral
Fellowship. We thank Dr. Victor G. Young of the
University of Minnesota for providing X-ray structural
analysis.
featuring a variety of propargylic substituents gave
fused cycloadducts 36aꢀd in good yields with excellent
diastereoselectivity. Further supporting the switch to a
fusedꢀcycloaddition pathway, the imine carbon NMR
signal for the fused cycloadducts was consistently 3ꢀ5
ppm upfield from the imine signal in the related bridged
systems [194ꢀ195 ppm vs 198ꢀ199 ppm]. The rela-
tive stereochemistries of 36a and 37, derived from the
Supporting Information Available. Experimental pro-
cedures as well as NMR spectra and characterizations for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) DeKorver, K. A.; Walton, M. C.; North, T. D.; Hsung, R. P.
Org. Lett. 2011, 13, 4862.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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