Enantioselective, NHC-catalyzed annulations of trisubstituted enals and cyclic n-sulfonylimines via α,β-unsaturated acyl azoliums

Article abstract of DOI:10.1002/anie.201204145

All aboard please! A new reaction of enals and cyclic sulfonylimines, as the nucleophiles(!), is the first highly enantioselective NHC-catalyzed annulation of trisubstituted enals. The catalytically generated α,β-unsaturated acyl azolium undergoes a reaction with the enamine tautomer of the imine via an aza-Claisen rearrangement as the key C-C bond-forming step. High yields and enantioselectivities were achieved using β-, α,β-, and β,β'-substituted enals.

Full text of DOI:10.1002/anie.201204145

Angewandte
Chemie
DOI: 10.1002/anie.201204145
NHC Catalysis
Enantioselective, NHC-Catalyzed Annulations of Trisubstituted Enals
and Cyclic N-Sulfonylimines via a,b-Unsaturated Acyl Azoliums**
Alberto G. Kravina, Jessada Mahatthananchai, and Jeffrey W. Bode*
The combination of N-heterocyclic carbene (NHC) catalysts
with a,b-unsaturated aldehydes has emerged as one of the
À
most powerful methods for enantioselective C C bond
forming reactions via the catalytic generation of reactive
intermediates.[1] From this single substrate class, NHC catal-
ysis provides access to nucleophiles including acyl anion
equivalents,[1e] homoenolate equivalents,[1b] and ester enolate
surrogates,[1f] as well as the electrophilic acyl azoliums and
a,b-unsaturated acyl azoliums.[1a] Dozens of new C C, C N,
À
À
À
À
C S, and C O bond forming reactions have been reported
using the unique chemistry of these catalytically generated
species, most of them with good yields, outstanding enantio-
selectivities, and simple reaction methods.
Despite the versatility of enantioselective NHC-catalyzed
reactions, they are restricted to simple enals. The a- and b,b’-
substituted enals are usually unreactive, and only a few
successful annulations with these substrates have been
reported.[2] This limitation parallels the development of
enantioselective, secondary-amine catalyzed reactions of
a,b-unsaturated aldehydes and ketones, which until 2005
were restricted to a-unsubstituted substrates.[3] Herein we
disclose a new NHC-catalyzed, highly enantioselective annu-
lation that makes two significant advances in the substrate
scope: 1) it permits, for the first time, highly enantio- and
diastereoselective annulations of a- and b,b’-substituted enals
and 2) it demonstrates the utility of cyclic sulfonylimines as
nucleophiles in highly enantioselective NHC-catalyzed reac-
tions (Scheme 1). Previously, these saccharine-derived cyclic
imines had proven to be electrophiles[4] for NHC-catalyzed g-
lactam formation via homoenolates, but only with poor
enantioselectivity.[5]
Scheme 1. An enantioselective annulation of trisubstituted enals and
cyclic N-sulfonylimines.
associates with the highly electrophilic ketone of the acyl
azolium followed by a sigmatropic rearrangement.[12] The
ability of a,b-unsaturated acyl azoliums to also serve as
acceptors in conjugate addition reactions[13] implies that they
should also be outstanding partners for other nucleophiles,
but catalytic reactions involving nucleophiles that cannot also
give 1,2-addition products have not been successful to date;
the scope of the annulations has remained limited to activated
ketones[8,14] and N-unprotected enamines.[15]
The potential for cyclic sulfonylimine 5 to serve as
a nucleophile through enamine generation is apparent from
facile the H–D[16] exchange of the CH3 group, but only a single
report of its use as a nucleophile has appeared.[17] To test their
potential for NHC-catalyzed aza-Claisen annulations, we
combined imine 5 and cinnamaldehyde in the presence of an
NHC precatalyst, oxidant 7,[18] and base (Table 1). Azolium
salts 10 and 11, which have been used in NHC-catalyzed
annulations with 1,3-diketones,[8a,13c] were unreactive. Achiral
azolium salts bearing N-mesityl groups, in contrast, delivered
the desired annulation product contaminated with a small
amount of homoenolate addition product 9 (entry 4). In the
absence of oxidant, only homoenolate product 9 was detected
(entry 5). Chiral N-mesityl substituted triazolium salt 1,[19]
used together with Hꢀnigꢁs base,[2a,20] proved to be an
outstanding catalyst for the annulation, affording the desired
dihydropyridinone[21] product exclusively in 99% ee. The use
of stronger bases such as DBU or other chiral azolium salts
(i.e. 14), led to diminished yield and byproducts (entries 6 and
8).
a,b-unsaturated acyl azoliums may be generated by
internal redox reactions of ynals,[6] by nucleophilic additions
to acyl fluorides or esters,[7] or from a,b-unsaturated alde-
hydes in conjunction with an external oxidant.[8] Studies from
ourselves[9,10] and Lupton[11] have shown that these electro-
philic reactive species can undergo annulation reactions by
a Coates–Claisen process in which the nucleophile pre-
[*] A. G. Kravina, J. Mahatthananchai, Prof. Dr. J. W. Bode
Laboratorium fꢀr Organische Chemie, Department of Chemistry
and Applied Biosciences, ETH Zꢀrich
Wolfgang Pauli Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bode.ethz.ch/
[**] We are grateful to the ETH-Zꢀrich for supporting this research. We
thank Benedikt Wanner for a preliminary investigation and Dr. Bernd
Schweizer (X-ray structure analysis) and the MS services at ETH-
Zꢀrich.
These conditions were adopted for further studies of the
reaction scope. With respect to the enal partners, the reaction
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204145.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Reaction optimization.
Table 2:
Entry
NHC
Base
[O]
Conversion [%]
8/9
1
2
3
4
5
6
7
8
10
11
12
13
13
1
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
DBU
DBU
iPr2NEt
iPr2NEt
7
7
7
7
n/a
7
7
0
–
–
trace
27
91
100
47
100
18
1.0:0
1.0:0.1
0:1.0
1.0:0
1.0:0
1.0:0.1
1
14
7
tolerated all tested E-enals including cinnamaldehyde, its
derivatives (with electron-donating and electron-withdrawing
groups), aliphatic and alkenyl side chains (18–20, Table 2).
Saccharine-derived cyclic sulfonylimines bearing either aro-
matic or aliphatic substituents were competent reactions
partners in good (23, 24) to excellent (21, 22) enantioselec-
tivity. Sulfonylimine 15 (X = O, R1 = H) was also found to be
successful under these reaction conditions (25, 26). In many
cases, the desired product crystalized from the crude reaction
mixture; purification by chromatography was not required.
The failure of trisubstituted enals to participate in NHC-
catalyzed annulations is a long-standing limitation of the
substrate scope. We were therefore pleased to find that (E)-a-
methyl-cinnamaldehyde, (E)-a-methyl-pentenal, and gera-
nial participated in this reaction (Table 3). Unlike disubsti-
tuted enals, highly substituted enals generally required
a much longer reaction time and/or higher catalyst loading,
which we attributed to a change in the rate-determining step
À
from C C bond formation to oxidative formation of the
sterically congested a,b-unsaturated acyl azoliums.[22] None-
theless, the coupling with cyclic saccharine-derived sulfony-
limines proved to be high yielding and highly diastereoselec-
tive, albeit moderate in enantioselectivity (27–29). Sulfonyli-
mine 15 (X = O, R1 = H) was a better substrate, affording the
desired product in good yield, d.r., and ee (31, 32).
[a] Reaction conditions: 0.1m PhCH3 at 408C for 12–72 h. [b] Yield refers
to isolated products after recrystallization. [c] Yield refers to isolated
products after chromatography. [d] The absolute configuration of (R)-19
was established by X-ray analysis; others were assigned by analogy.
Mechanistically, we propose that the combination of enal
and chiral N-mesityl triazolium salt 1 led to the formation of
the Breslow intermediate (I, Scheme 2), which is oxidized to
form the key a,b-unsaturated acyl azolium (II).[23] Tautome-
rization between the imine and the enamine occurred readily
with base, and the enamine was intercepted by II to form
hemiaminal III. Alternatively, N-acylation of the imine, which
increased the acidity of the adjacent proton, could occur first
followed by a base-mediated deprotonation directly to III. In
either case, the hemiaminal engaged in a Stork-Hickmott-
Stille-type annulation[24] via a “tight-ion-pair/aza-Claisen-
type” transition state.[15] This step determined the absolute
stereochemistry of the product and has the same sense of
asymmetric induction as observed in all our prior annulations
by this reaction mode.[12,15] The subtle details of the stereo-
chemical induction of a related reaction has been recently
outlined.[10] Lactam formation followed the protonation of
enolate IV and effected catalyst turnover to complete the
catalytic cycle.
An unresolved question was the stereochemical course of
protonation of enolate IV.[25] NHC-mediated enantioselec-
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Table 3:
Scheme 2. A proposed catalytic cycle for enantioselective, NHC-cata-
lyzed annulations of enals and cyclic N-sulfonylimines.
[a] Reaction conditions: 0.1m PhCH3 at 408C for 1–8 days; E-enals were
used in these reactions. [b] Yield refers to isolated products after
chromatography. [c] The configuration of 30 was established by X-ray
analysis; others were assigned by analogy.
tive[26] and diastereoselective[27] protonation reactions have
been described, and we first considered catalyst control of the
stereoselectivity. To probe this issue, we subjected methacro-
lein (33) to the standard conditions of our enantioselective
annulation with 5. The reaction smoothly afforded expected
product 34, but as a racemic mixture. Based on our proposed
catalytic cycle, this result indicated that protonation of
enolates (such as IVa, Scheme 3b) is not stereoselective.
The high diastereomeric ratio observed for all the products in
Table 3 is, therefore, an outcome of diastereoselective proto-
nation. Stereoinduction arose from the stereocenter formed
after the rearrangement of hemiaminal III. For the observed
trans-products, such as 27, a stereochemical model shown in
Scheme 3c, based on minimizing A1,3 (1,3-allylic) strain,
rationalizes the stereochemical course of protonation.[28]
In summary, we have disclosed a new class of NHC-
catalyzed annulations of cyclic sulfonylimines operating
through the catalytic generation of a,b-unsaturated acyl
azoliums. These studies both extend the scope of highly
enantioselective NHC-catalyzed reactions to cyclic imines
bearing both aliphatic and aromatic substituents and offer, for
the first time, the opportunity for stereoselective annulations
using trisubstituted enals. By demonstrating that there is no
mechanistic limitation to NHC-catalyzed annulations of more
substituted substrates and that diastereocontrol can arise
Scheme 3. A stereochemical probe and proposed stereochemical
models for protonation of enolates IVa–c.
from substrate-directed protonation, rather than catalyst-
directed protonation, these studies will provide the founda-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[12] a) J. Kaeobamrung, J. Mahatthananchai, P. Zheng, J. W. Bode, J.
Am. Chem. Soc. 2010, 132, 8810 – 8812; b) J. Mahatthananchai, J.
Kaeobamrung, J. W. Bode, ACS Catal. 2012, 2, 494 – 503.
[13] a) M. Merski, C. A. Townsend, J. Am. Chem. Soc. 2007, 129,
15750 – 15751; b) S. J. Ryan, A. Stasch, M. N. Paddon-Row, D. W.
Lupton, J. Org. Chem. 2012, 77, 1113 – 1124; c) R. C. Samanta, B.
Maji, S. De Sarkar, K. Bergander, R. Frçhlich, C. Mꢀck-
Lichtenfeld, H. Mayr, A. Studer, Angew. Chem. 2012, 124,
5325 – 5329; Angew. Chem. Int. Ed. 2012, 51, 5234 – 5238.
[14] a) Z. Q. Zhu, J. C. Xiao, Adv. Synth. Catal. 2010, 352, 2455 –
2458; b) Z.-Q. Zhu, X.-L. Zheng, N.-F. Jiang, X. Wan, J.-C. Xiao,
Chem. Commun. 2011, 47, 8670 – 8672; c) Z.-Q. Rong, M.-Q. Jia,
S.-L. You, Org. Lett. 2011, 13, 4080 – 4083; d) F.-G. Sun, L.-H.
Sun, S. Ye, Adv. Synth. Catal. 2011, 353, 3134 – 3138; e) C. Yao,
D. Wang, J. Lu, T. Li, W. Jiao, C. Yu, Chem. Eur. J. 2012, 18,
1914 – 1917.
[15] B. Wanner, J. Mahatthananchai, J. W. Bode, Org. Lett. 2011, 13,
5378 – 5381.
[16] See the Supporting Information for details.
[17] X.-F. Xiong, H. Zhang, J. Peng, Y.-C. Chen, Chem. Eur. J. 2011,
17, 2358 – 2360.
[18] M. S. Kharasch, B. S. Joshi, J. Org. Chem. 1957, 22, 1439 – 1443.
[19] a) For a Review of the chemistry of N-mesityl catalysts, see P.-C.
Chiang, J. W. Bode, TCI Mail. 2011, 149, 2 – 17; b) for their
syntheses: J. R. Struble, J. W. Bode, Org. Synth. 2010, 87, 362 –
376.
tion for further advances in substrate scope and reactivity in
NHC-catalyzed processes.
Received: May 28, 2012
Published online: && &&, &&&&
Keywords: acyl azolium · enantioselectivity ·
.
homogeneous catalysis · N-heterocyclic carbenes ·
N-sulfonyl imine
[1] For recent reviews of NHC catalysis: a) P.-C. Chiang, J. W. Bode
in N-Heterocyclic Carbenes, The Royal Society of Chemistry,
London, 2011, pp. 399 – 435; b) V. Nair, R. S. Menon, A. T. Biju,
C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc. Rev.
2011, 40, 5336 – 5346; c) A. Grossmann, D. Enders, Angew.
Chem. 2012, 124, 320 – 332; Angew. Chem. Int. Ed. 2012, 51, 314 –
325; d) D. T. Cohen, K. A. Scheidt, Chem. Sci. 2012, 3, 53 – 57;
e) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511 – 3522;
f) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth. Catal. 2012, 354,
1617 – 1639; g) J. Douglas, G. Churchill, A. D. Smith, Synthesis
2012, 44, 2295 – 2309.
[2] a) S. S. Sohn, J. W. Bode, Org. Lett. 2005, 7, 3873 – 3876; b) A.
Chan, K. A. Scheidt, Org. Lett. 2005, 7, 905 – 908; c) C. Burstein,
S. Tschan, X. Xie, F. Glorius, Synthesis 2006, 2418 – 2439;
d) H. U. Vora, T. Rovis, J. Am. Chem. Soc. 2010, 132, 2860 –
2861; e) X. Fang, X. Chen, H. Lv, Y. R. Chi, Angew. Chem. 2011,
123, 11986 – 11989; Angew. Chem. Int. Ed. 2011, 50, 11782 –
11785.
[20] J. Kaeobamrung, M. C. Kozlowski, J. W. Bode, Proc. Natl. Acad.
Sci. USA 2010, 107, 20661 – 20665.
[21] For other recent approaches to dihydropyridinones: a) M. He,
J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128, 8418 –
8420; b) X. Huang, S. Broadbent, C. Dvorak, S.-H. Zhao, Org.
Process Res. Dev. 2010, 14, 612 – 616; c) T.-Y. Jian, P.-L. Shao, S.
Ye, Chem. Commun. 2011, 47, 2381 – 2383; d) L. Hao, Y. Du, H.
Lv, X. Chen, H. Jiang, Y. Shao, Y. R. Chi, Org. Lett. 2012, 14,
2154 – 2157; e) C. Simal, T. Lebl, A. M. Z. Slawin, A. D. Smith,
Angew. Chem. 2012, 124, 3713 – 3717; Angew. Chem. Int. Ed.
2012, 51, 3653 – 3657.
[3] a) K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2005, 127, 10504 –
10505; b) H. D. King, Z. Meng, D. Denhart, R. Mattson, R.
Kimura, D. Wu, Q. Gao, J. E. Macor, Org. Lett. 2005, 7, 3437 –
3440; c) Pihko et al. recently demonstrated the utility of this
class of substrates in complex-molecule synthesis: E. K. Kemp-
painen, G. Sahoo, A. Valkonen, P. M. Pihko, Org. Lett. 2012, 14,
1086 – 1089.
[22] J. Mahatthananchai, J. W. Bode, Chem. Sci. 2012, 3, 192 – 197.
[23] A competitive experiment between imine 5 and MeOH with
aldehyde 6 afforded a 1:2 ratio of 8 and the corresponding
methyl ester product (see the Supporting Information). This
confirms the involvement of species II and provides a support for
the proposed catalytic cycle.
[24] a) G. Stork, R. A. Kretchmer, R. H. Schlessinger, J. Am. Chem.
Soc. 1968, 90, 1647 – 1648; b) P. W. Hickmott, G. Sheppard, J.
Chem. Soc. C 1971, 2112 – 2115; c) K. Paulvannan, J. R. Stille, J.
Org. Chem. 1992, 57, 5319 – 5328.
[25] For computational studies regarding NHC-bound enolates, see
a) Ref. [20]; b) Y. Reddi, R. B. Sunoj, Org. Lett. 2012, 14, 2810 –
2813; c) S. E. Allen, J. Mahatthananchai, J. W. Bode, M. C.
Kozlowski, J. Am. Chem. Soc. 2012, 134, 12098 – 12103.
[26] a) N. T. Reynolds, T. Rovis, J. Am. Chem. Soc. 2005, 127, 16406 –
16407; b) X.-N. Wang, H. Lv, X.-L. Huang, S. Ye, Org. Biomol.
Chem. 2009, 7, 346 – 350; c) C. Concellꢂn, N. Duguet, A. D.
Smith, Adv. Synth. Catal. 2009, 351, 3001 – 3009.
[27] a) A. Kena Diba, C. Noll, M. Richter, M. T. Gieseler, M.
Kalesse, Angew. Chem. 2010, 122, 8545 – 8547; Angew. Chem.
Int. Ed. 2010, 49, 8367 – 8369; b) T. Jousseaume, N. E. Wurz, F.
Glorius, Angew. Chem. 2011, 123, 1446 – 1450; Angew. Chem.
Int. Ed. 2011, 50, 1410 – 1414.
[4] For other reactions of these electrophiles, see: a) Y.-Q. Wang, C.-
B. Yu, D.-W. Wang, X.-B. Wang, Y.-G. Zhou, Org. Lett. 2008, 10,
2071 – 2074; b) X.-Y. Chen, R.-C. Lin, S. Ye, Chem. Commun.
2012, 48, 1317 – 1319; c) T. Nishimura, A. Noishiki, G. Chit Tsui,
T. Hayashi, J. Am. Chem. Soc. 2012, 134, 5056 – 5059.
[5] a) M. Rommel, T. Fukuzumi, J. W. Bode, J. Am. Chem. Soc.
2008, 130, 17266 – 17267; b) P. Zheng, C. A. Gondo, J. W. Bode,
Chem. Asian J. 2011, 6, 614 – 620.
[6] a) K. Zeitler, Org. Lett. 2006, 8, 637 – 640; b) Y.-M. Zhao, Y.
Tam, Y.-J. Wang, Z. Li, J. Sun, Org. Lett. 2012, 14, 1398 – 1401.
[7] a) S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2009,
131, 14176 – 14177; b) L. Candish, D. W. Lupton, Org. Lett. 2010,
12, 4836 – 4839.
[8] a) S. De Sarkar, A. Studer, Angew. Chem. 2010, 122, 9452 – 9455;
Angew. Chem. Int. Ed. 2010, 49, 9266 – 9269; b) A. Biswas, S. D.
Sarkar, R. Frohlich, A. Studer, Org. Lett. 2011, 13, 4966 – 4969;
c) A. Biswas, S. De Sarkar, L. Tebben, A. Studer, Chem.
Commun. 2012, 48, 5190 – 5192. Ref. [8a] includes two racemic
examples of annulation with a- and b,b’-substituted enals.
[9] J. Mahatthananchai, P. Zheng, J. W. Bode, Angew. Chem. 2011,
123, 1711 – 1715; Angew. Chem. Int. Ed. 2011, 50, 1673 – 1677.
[10] E. Lyngvi, J. W. Bode, F. Schoenebeck, Chem. Sci. 2012, 3, 2346 –
2350.
[28] a) H. E. Zimmerman, Acc. Chem. Res. 1987, 20, 263 – 268;
b) H. E. Zimmerman, W.-H. Chang, J. Am. Chem. Soc. 1959, 81,
3634 – 3643; c) J. R. Mohrig, R. E. Rosenberg, J. W. Apostol, M.
Bastienaansen, J. W. Evans, S. J. Franklin, C. D. Frisbie, S. S. Fu,
M. L. Hamm, C. B. Hirose, D. A. Hunstad, T. L. James, R. W.
King, C. J. Larson, H. A. Latham, D. A. Owen, K. A. Stein, R.
Warnet, J. Am. Chem. Soc. 1997, 119, 479 – 486.
[11] Lupton concluded that the Coates–Claisen mechanism is
operative in certain substrate classes based on the observation
of a 1,2-addition byproduct and a cross-over experiment: a) S. J.
Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2011, 133,
4694 – 4697; b) L. Candish, D. W. Lupton, Org. Biomol. Chem.
2011, 9, 8182 – 8189; c) L. Candish, D. W. Lupton, Chem. Sci.
2012, 3, 380 – 383.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
NHC Catalysis
A. G. Kravina, J. Mahatthananchai,
J. W. Bode*
&&&& — &&&&
Enantioselective, NHC-Catalyzed
Annulations of Trisubstituted Enals
and Cyclic N-Sulfonylimines via
a,b-Unsaturated Acyl Azoliums
All aboard please! A new reaction of enals
and cyclic sulfonylimines, as the nucleo-
philes(!), is the first highly enantioselec-
tive NHC-catalyzed annulation of trisub-
stituted enals. The catalytically generated
a,b-unsaturated acyl azolium undergoes
a reaction with the enamine tautomer of
the imine via an aza-Claisen rearrange-
À
ment as the key C C bond-forming step.
High yields and enantioselectivities were
achieved using b-, a,b-, and b,b’-substi-
tuted enals.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!