N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition/decarboxylation of silyl dienol ethers with α,β-unsaturated acid fluorides

Article abstract of DOI:10.1021/ja111067j

Herein we report the first all-carbon N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition. The reaction proceeds with α,β-unsaturated acid fluorides and silyl dienol ethers and produces 1,3-cyclohexadienes with complete diastereocontrol (dr >20:1) while demonstrating a new type of reaction cascade exploiting α,β-unsaturated acyl azoliums.

Full text of DOI:10.1021/ja111067j

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N-Heterocyclic Carbene-Catalyzed (4 þ 2) Cycloaddition/
Decarboxylation of Silyl Dienol Ethers with r,β-Unsaturated Acid
Fluorides
Sarah J. Ryan, Lisa Candish, and David W. Lupton*
School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
S Supporting Information
b
Table 1. Selected Optimization Studies
ABSTRACT: Herein we report the first all-carbon N-hetero-
cyclic carbene-catalyzed (4 þ 2) cycloaddition. The reaction
proceeds with R,β-unsaturated acid fluorides and silyl dienol
ethers and produces 1,3-cyclohexadienes with complete
diastereocontrol (dr >20:1) while demonstrating a new type
of reaction cascade exploiting R,β-unsaturated acyl azoliums.
ransformations that rapidly generate complexity are integral
T
to the assembly of challenging molecular architectures.1 In
entry
cat. (mol %)a
base/solvent
3a:6ab
yield of 3a (%)c
this regard, cycloadditions are peerless in advancing chemical
synthesis.2 This is exemplified by the (4 þ 2) Diels-Alder cycloaddi-
tions of pyrones.3 In addition to reacting with predictable stereo- and
regioselectivity, the bicyclic products (i.e., 1) undergo decarboxylation
to produce 1,3-cyclohexadienes 2, which are valuable for further
elaboration (eq 1).3 We postulated that olefins, when conjugated to
acyl azoliums (i.e., I),4 should possess the electronic and steric
requirements appropriate to a dienophile in a (4 þ 2) cycloaddition.
This reaction, when followed by lactonization and decarboxylation,5
would provide 1,3-cyclohexadienes6 that are isomeric to those from
pyrone Diels-Alder reactions . Herein we report the realization of
this concept with the first all-carbon N-heterocyclic carbene (NHC)-
catalyzed (4 þ 2) cycloaddition (eq 2).7
1
2
3
4
5
6
7
8
A1 (20)
A1 (10)
A1 (10)d
A2 (10)
B (10)
KOtBu/Toluene
KOtBu/THF
THF
KOtBu/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
THF
3:1
>95:5
77:23
3:1
13
70
44
48
-
10e
tracee
-
C (10)
-
D1 (10)
D2 (10)f
-
>95:5
76
a All catalysts were generated using using equimolar base, except
as noted. b Ratio determined by 1H NMR analysis. c Isolated yield
following flash column chromatography. d Generated from the imida-
1
zolium and isolated from KCl. e Conversion as judged by H NMR
analysis. f Generated by reduction of the corresponding thiourea.
Subsequent to that work, these intermediates have been impli-
cated in various transformations.4 We recently developed a
conceptually distinct strategy in which NHC-mediated substitu-
tion provides acyl azoliums, while concurrently liberating groups
active in bond-forming cascades.9 In the context of a (4 þ 2)
cycloaddition, this strategy would allow cascade activation of
R,β-unsaturated acid 4 and TMS enol ether 5, providing inter-
mediates I and II, which could then form cycloadduct III (eq 2).
To test this hypothesis, IMes-substituted NHC A1 (20 mol %)
was exposed to substrates 4a and 5a (eq 3). Gratifyingly, these
conditions resulted in the formation of cyclohexadiene 3a in 13%
yield along with R,β-unsaturated dienol ester 6a (Table 1,
entry 1).10 Standard optimization showed that coordinating sol-
vents and decreased catalyst loading provided 3a in an improved
yield of 70% with only a trace of ester 6a (Table 1, entry 2).
In 2004, Bode4a and Rovis4b reported approaches to acyl
azoliums via the reaction of NHCs8 with redox-active aldehydes.
Received: December 9, 2010
Published: March 10, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja111067j J. Am. Chem. Soc. 2011, 133, 4694–4697
|

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Table 2. Scope in Regard to Silyl Dienol Ether 5a
Scheme 1. Derivatization of Cyclohexadienes 3a, 3b, and 3e
Scheme 2. Mechanistic Rationale
a Isolated yield following column chromatography. b dr determined by
1H NMR analysis.
Table 3. Scope in Regard to Acyl Fluoride 4a
smoothly, providing dihydrophenanthrene 3f and annulated
cycloheptene 3g in good yields. Alkyl groups at R2 could be
included, providing cyclohexadienes 3h and 3i in good yield with
excellent diastereoselectivity (>20:1).13
a Isolated yield following column chromatography. b dr determined by
1H NMR analysis
The nature of the R,β-unsaturated acid fluoride 414 was
investigated through the introduction of electron-releasing,
electron-withdrawing, heteroaromatic, and olefinic groups
(Table 3). Again, the reaction proved flexible, forming products
3j-r in good yields with excellent sterocontrol.
The transformation was highly sensitive to the nature of the
catalyst. For example, use of NHC A1 under salt-free conditions
increased the amount of O-acylation, as did use of the more
sterically demanding IDip-substituted NHC A2 (Table 1, entries 3
and 4). Imidazolinium-derived NHC B, triazolium-derived C, and
benzimidazole-derived D1 all proved unsuitable for this reaction
(Table 1, entries 5-7). These catalyst modifications suggested that
dialkyl imidazolium-derived NHCs should display ideal nucleophili-
city11 and bulk. This proved to be the case, with an optimal yield
obtained using NHC D2 (Table 1, entry 8).
Exploration of the scope of the (4 þ 2) cycloaddition/
decarboxylation commenced with an examination of the func-
tional group tolerance at R1 (Table 2). Electron-poor aromatics
gave 1,3-cyclohexadiene 3b in good yield, while alkyl groups at R1
were accommodated, with i-Pr-containing 3d prepared in 94%
yield. Unfortunately, electron-rich substrates (i.e., 5c) were not
suited to the conditions. Similarly, acyclic dienolates and alde-
hyde-derived substrates were incompatible, providing the O-acy-
lated proucts.12 The incorporation of additional degrees of
unsaturation into the substrate gave triene 3e in 98% yield, while
polycyclic substrates and those containing larger rings reacted
The synthetic potential of the 1,3-cyclohexadienes was next
investigated. As expected, they proved to be competent sub-
strates for aromatization, providing highly substituted tetrahy-
dronapthalene 7a and naphthalene 7e, and also acted as dienes in
the Diels-Alder reaction, providing structurally rich tricyclic
compounds 8a and 8b (Scheme 1).15
Mechanistically, we believe that the reaction commences with
nucleophilic substitution of the acyl fluoride by the NHC
followed by desilylation to generate I and II.16 On the basis of
the stereochemistry of compounds 3h, 3i, and 3q, we propose
that the annulation occurs via a concerted pathway with an endo
orientation in the transition state (eq 6). When the reaction was
performed using cis-cinnamoyl fluoride (cis-4a) and dienol silyl
ether 5h, unfavorable steric interactions in the endo transition
state retarded the cycloaddition, and exclusive O-acylation
occurred (eq 7). An alternate explanation for the annulation
involves a stepwise vinylogous Michael/aldol sequence.17 To
explore the nature of the annulation, kinetic isotope effect (KIE)
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Scheme 3. Crossover Studies
’ ACKNOWLEDGMENT
We acknowledge financial support from the ARC
(DP0881137) and Monash University (Research Accelerator
Program), helpful discussions with Professor Tomislav Rovis
(Colorado State University), and donation of catalysts (not
discussed).
’ REFERENCES
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V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006,
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studies using natural abundance techniques18 were undertaken.
While the precision was modest (eq 8), positive KIEs at C6 and
C7, implicates a concerted (4 þ 2) cycloaddition as the turnover-
limiting step (Scheme 2).19 These data, together with the endo
selectivity and the documented reactivity of related dienolates,20
indicate that a concerted reaction is most likely.
A concerted endo-selective (4 þ 2) cycloaddition results in a
trans arrangement between the acyl azolium and the alkoxide
(i.e., trans-III). However, lactonization and decarboxylation
presumably occur via cis-III. Mechanistically, such an isomeriza-
tion can occur by either an intermolecular proton transfer or a
retro-aldol/aldol sequence.21 To investigate these scenarios, a
crossover experiment involving (R-D)-4a and 4m was under-
taken (Scheme 3). If proton transfer were required, then
scrambling of the deuterium across the two cyclohexadiene
products would have been expected. In the event, complete
deuterium retention (formation of 7D-3a and no 7D-3m)
indicated that the trans-III f cis-III isomerization likely occurs
via a retro-aldol/aldol sequence.
To summarize, we have reported the first all-carbon NHC-
catalyzed (4 þ 2) cycloaddition. The reaction proceeds with a
range of silyl dienol ethers and R,β-unsaturated acid fluorides,
providing 1,3-cyclohexadienes in good yields with excellent
diastereoselectivity. Mechanistic investigations suggest that the
(4 þ 2) cycloaddition proceeds in a concerted fashion with a
preference for endo orientation of the coupling partners. The
catalytic cycle is completed by isomerization via a retro-aldol/
aldol sequence, lactonization, and then decarboxylation. These
studies expound a new class of NHC-catalyzed transformation
involving R,β-unsaturated acyl azoliums22 and will contribute to
further advances in nucleophilic organocatalysis. The application
of this reaction in total synthesis and investigations into the
mechanism using theoretical and experimental approaches are
ongoing.
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data, NMR
b
(7) For NHC-catalyzed hetero-Diels-Alder reactions, see: (a) He,
M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b) He,
M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. (c) Zhang,
Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.—Eur. J. 2008, 14, 8473. (d) He, M.;
Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817. (e) Huang, X.-L.; He,
L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009, 48, 192. (f)
Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20661.
spectra, and detailed experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
david.lupton@monash.edu
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COMMUNICATION
(8) For reviews of NHC catalysis, see: (a) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Marion, N.; Díez-
Gonzꢀalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (c)
Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (d)
Moore, J. L.; Rovis, T. Top. Curr. Chem. 2009, 290, 77. (e) Phillips, E. M.;
Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55.
(9) (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009,
131, 14176. (b) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836.
(10) The lack of reactivity of 6a is surprising when compared with
previous studies using R,β-unsaturated enol esters (see ref 9a) and
supports the interpretation of Bode, at least with certain substrates. See:
(a) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am.
Chem. Soc. 2010, 132, 8810. (b) Mahatthananchai, J.; Zheng, P.; Bode,
J. W. Angew. Chem., Int. Ed. 2011, 50, 1673.
(11) For a review discussing NHC nucleophilicity, see: Dr€oge, T.;
Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940.
(12) When the reaction was performed with aldehyde-derived TMS
dienol ethers or those derived from acyclic ketones, O-acylation occurred.
(13) The assignments of 3h, 3i, and 3q were based on nuclear
Overhauser effect (NOE) correlations and comparison to related 1,3-
cyclohexadienes. See: (a) K€undig, E. P.; Bernardinelli, G.; Liu, R.; Ripa,
A. J. Am. Chem. Soc. 1991, 113, 9676. (b) K€undig, E. P.; Ripa, A.;
Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 1071. The
assignments of silyl ethers 5h and 5i were based on NOE correlations.
(14) Acyl fluorides are essential for this reaction; with acyl chlorides
or cyanides, no reaction occurs.
(15) The stereochemistry was assigned by analogy to related Diels-
Alder reactions of substituted cyclopentadienes. See: Letourneau, J. E.;
Wellman, M. A.; Burnell, D. J. J. Org. Chem. 1997, 62, 7272.
(16) For related reactivity, see ref 9 and: (a) Bappert, E.; M€uller, P.;
Fu, G. C. Chem. Commun. 2006, 2604. (b) Poisson, T.; Dalla, V.;
Papamicael, C.; Dupas, G.; Marsais, F.; Levacher, V. Synlett 2007, 381.
(17) For a review, see: Denmark, S. E.; Heemstra, J. R., Jr.; Beutner,
G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
(18) (a) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995,
117, 9357. For studies using low conversion, as in eq 8, see: (b) Frantz,
D. E.; Singleton, D. A. J. Am. Chem. Soc. 2000, 122, 3288. (c) Denmark,
S. E.; Pham, S. M.; Stavenger, R. A.; Su, X.; Wong, K.-T.; Nishigaichi, Y. J.
Org. Chem. 2006, 71, 3904.
(19) Further details are given in the Supporting Information.
(20) For studies with related 1-dienolates implicating a concerted
mechanism, see: (a) Bienayme, H.; Longeau, A. Tetrahedron 1997,
53, 9637. For 2-dienolates that are reported to react via concerted
mechanisms, see: (b) Tricotet, T.; Br€uckner, R. Eur. J. Org. Chem.
2007, 1069.
(21) Isomerization by intramolecular proton transfer is not possible
on the basis of conformational analysis. For related lactonizations in
which retro-aldol/aldol sequences have been invoked, see: Henry-Riyad,
H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett. 2006, 8, 4363. In
addition, it is noteworthy that because ester 6a forms with retention of
the enolate geometry (on the basis of NOE analysis), isomerization of II
prior to cycloaddition is unlikely to occur.
(22) For other C-C bond-forming reactions of R,β-unsaturated
acyl azoliums, see refs 9a, 9b, and 10a as well as: (a) De Sarkar, S.; Studer,
A. Angew. Chem., Int. Ed. 2010, 49, 9266. (b) Zhu, Z.-Q.; Xiao, J.-C. Adv.
Synth. Catal. 2010, 352, 2455.
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