Catalytic generation of activated carboxylates from enals: A product-determining role for the base

Article abstract of DOI:10.1021/ol051269w

(Chemical Equation Presented) N-Heterocycle carbenes generated in situ from imidazolium or triazolium salts and bases react with enals, leading to the catalytic generation of homoenolates. The fate of these intermediates is determined by the catalytic base: strong bases such as ^tBuOK lead to carbon-carbon bond formation, while weaker bases allow protonation of the homoenolate and subsequent generation of activated carboxylates. This discovery, along with the design of a new triazolium precatalyst, enables the catalytic, atom-economical redox esterification of enals.

Full text of DOI:10.1021/ol051269w

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3873-3876
Catalytic Generation of Activated
Carboxylates from Enals: A
Product-Determining Role for the Base
Stephanie S. Sohn and Jeffrey W. Bode*
Department of Chemistry and Biochemistry, UniVersity of California-Santa Barbara,
Santa Barbara, California 93101
bode@chem.ucsb.edu
Received May 30, 2005
ABSTRACT
N-Heterocycle carbenes generated in situ from imidazolium or triazolium salts and bases react with enals, leading to the catalytic generation
t
of homoenolates. The fate of these intermediates is determined by the catalytic base: strong bases such as BuOK lead to carbon
−carbon
bond formation, while weaker bases allow protonation of the homoenolate and subsequent generation of activated carboxylates. This discovery,
along with the design of a new triazolium precatalyst, enables the catalytic, atom-economical redox esterification of enals.
Although the vast majority of carboxylic acid derivatives
are prepared via the intermediacy of activated carboxylates,
a general, catalytic method for their transient generation has
not emerged.1 This is suprising, as catalytic methods could
both improve the efficiency of these widespread reactions
and provide a mechanistic basis for control of the absolute
stereochemistry of the products.
In the course of our ongoing studies on novel methods
for the N-heterocyclic carbene (NHC)-catalyzed2 generation
of activated carboxylates via internal redox reactions (Scheme
1),3,4 we were attracted to readily available R,â-unsaturated
aldehydes as substrates for redox esterification.5 Our initial
atempts to effect this transformation led to a surprising result.
While all evidence suggested that a variety of NHC catalysts
reacted with enals to give i, carbon-carbon bond formation
products predominated, and protonation was not observed,
even when protic solvents were employed (Scheme 2). To
determine if the observed preference for carbon-carbon bond
formation was due to slow protonation of the postulated
homoenolate ii or arose from reversible protonation, we
conducted experiments in tBuOD at 60 °C. Remarkably, no
deuterium incorporation at the â-position was observed,
implying that carbon-carbon bond formation, rather than
protonation, is the preferred fate of catalytically generated
(1) (a) For catalytic methods for the esterifications of carboxylic acids,
see: Otera, J. Esterification: Methods, Reactions, and Applications; Wiley
& Sons: New York, 2003. (b) Ishihara, K. Nakagawa, S.; Sakakura, A. J.
Am. Chem. Soc. 2005, 127, 4168-4169.
Scheme 1. Catalytic Generation of Activated Carboxylates via
Internal Redox Reactions
(2) For NHC-catalyzed transesterifications, see: (a) Grasa, G. A.; Sing,
E.; Nolan, S. P. Synthesis 2004, 971-985. (b) Nyce, G. W.; Glauser, T.;
Conor, E. F.; Mo¨ck, A.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem.
Soc. 2003, 125, 3046-3056. (c) Movassaghi, M.; Schmidt, M. A. Org.
Lett. 2005, 7, 2453-2456.
(3) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-
8127.
(4) For the catalytic generation of activated carboxylates from R-chlo-
roaldehydes, see: Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am.
Chem. Soc. 2004, 126, 9518-9519.
10.1021/ol051269w CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/10/2005

the use of stoichometric reagents or proton sources, our
studies highlight a mechanistically revealing and product-
determing role for the catalytic base.
Scheme 2. Reaction Pathways of Catalytically Generated
Activated Carboxylates
The conversion of cinnamaldehyde to ethyl hydrocin-
namate illustrates the role of the heterocyclic precatalyst in
the success of this transformation (Table 1). Thiazolium salts
Table 1. Catalysts and Conditions for Redox Esterificationa
catalyst
(mol %)
temp
(°C)
conversionb
(%)
yieldc
(%)
homoenolates. These observations temporarily stymied the
development of a truly catalytic method for redox esterifi-
cations but contributed to our discovery that such catalytically
generated homoenolates undergo facile carbon-carbon bond-
forming reactions for the synthesis of γ-lactones and γ-lac-
tams.6,7
Recently, Scheidt and Chan communicated a solution to
the protonation of catalytically generated homonenolates
using excess phenol as an added proton source.8 While this
protocol nicely achieved protonation of homoenolate equiva-
lents generated under our usual conditions, the requirements
of excess phenol, 5 equiv of the alcohol, and high temper-
atures limit its utility as a practical alternative to traditional
coupling reagent-based esterifications. Prompted by this
entry
1
2
3
4
5
6
7
8
9
4 (10)
5 (10)
6 (15)
7 (10)
8 (10)
9a (10)
9a (5)
9a (5)
9a (2)
9a (5)
9b (5)
40
40
40
40
40
40
40
60
60
60
60
15
trace
80
trace
98
99
90
99
95
89
59
89
86
60
69
89
10d
11
99
a All reactions were performed on a 0.2 mmol scale. DIPEA )
diisopropylethylamine; Mes ) 2,4,6-trimethylphenyl. b Determined by GC
analysis of unpurified reaction mixtures. c Isolated yield following chro-
matography. d Performed with 1.2 equiv of EtOH.
Scheme 3. Heterocyclic Precatalysts for the Catalytic
Generation of Activated Carboxylates from Cinnamaldehyde
4 and 5 provided small amounts of the desired saturated ester,
along with conspicuous amounts of the unsaturated ester and
other byproducts. Imidazolium salt 6 (IMes-HCl) offered
significant advantages, but tended to produce the unsaturated
acid as a byproduct, possibly due to slow turnover of the
catalyst-bound activated carboxylate. Although triazolium salt
7, previously described by Rovis,4 was unproductive (entry
4), methoxyphenyl analogue 8 was effective (entry 5), but
with a limited range of substrates. Further studies on catalyst
synthesis and screening identified triazolium precatalyst 9a
as uniquely active, effecting redox esterifications of cinna-
maldehyde overnight with as little as 2 mol % of the salt
and 5 mol % DIPEA as the only added reagents.10 The
counterion had no noticible effect (entry 11), although the
chloride salt was hygroscopic while the tetrafluoroborate
report, we now disclose our ongoing efforts in this area,
namely, the combination of substoichiometric amounts of
triazolium precatalyst 9 and diisopropylethylamine (DIPEA)
as a highly effective catalyst system for the direct conversion
of R,â-unsatured aldehydes to saturated esters (eq 1).9 In
addition to providing a practical esterification process without
(7) Glorius has independently reported a related method: Burstein, C.;
Glorius, F. Angew. Chem. Int. Ed. 2004, 43, 6205-6208.
(8) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908.
(9) For the organocatalytic, asymmetric conjugate reduction of R,â-
unsaturated aldehydes to the saturated aldehydes in the presence of a hydride
donor, see: (a) Ouellet, S. G.; Tuttle, J. B.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32-33. (b) Yang, J. W.; Hechavarria Fonseca, M.
T.; List, B. L. Angew. Chem., Int. Ed. 2004, 43, 6660-6662. (c) Yang, J.
W.; Hechavarria Fonseca, M. T.; Vignola, N.; List, B. L. Angew. Chem.,
Int. Ed. 2005, 44, 108-110.
(5) For a metal-mediated redox esterification of cinnamaldehyde, see:
de Vries, J. G.; Roelfes, G.; Green, R. Tetrahedron Lett. 1998, 39, 8329-
8332.
(6) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370-14371. (b) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131-
3134.
3874
Org. Lett., Vol. 7, No. 18, 2005

Triazolium precatalyst 9 (5 mol %), in conjuction with
10 mol % DIPEA, promoted the esterification of a wide
variety of unsaturated aldehydes. Primary and secondary
alcohols (Table 2, entries 1-4), as well as phenols (entry
5), are competent nucleophiles. Both electron-rich and
electron-deficient cinnamaldehydes (entries 4-8) serve as
precursors to catalytically generated activated carboxylates,
as do a broad range of aliphatic-substituted enals (entries
9-12). Intramolecular esterifications are also possible, as
illustrated by the clean formation of lactone 34 (entry 14).
In preliminary investigations, we have found that â,â-
disubstituted enals are viable substrates (entry 8). Only
R-substituted unsaturated aldehydes proved to be recalcitrant
to esterifications with this catalyst system.11
Table 2. Catalytic Esterifications of R,â-Unsaturated
Aldehydes
The choice, and presence, of the amine base is critical to
the success of the reaction and serves as a catalytic proton
shuttle. Given that sufficient proton sources, including the
alcohol substrate, are present in the reaction mixtures, the
key role of the protonated amine was not immediately
obvious. However, a clear correlation between the success
of the reaction and the pKa of the conjugate acid emerged.
While weaker amine bases, including NEt3 and DIPEA, give
excellent conversion (Table 3, entries 1 and 2), strong bases,
Table 3. Effect of the Amine Base of Catalytic Esterificationsa
X
pKa of conjugate acid relative yield
entry (mol %)
base
in THF13
(%)b
1
2
3
4
5
6
7
5
5
5
5
5
NEt3
DIPEA
DBU
P2-t-Bu
KOtBu
KOtBu
DIPEA
12.5
∼13
99
99
15
>5
>5
75
99
16.8
20.9
29.4c
20
20
a Reaction conditions: X mol % of 9b, 10 mol % of base, 0.2 mmol of
enal, 1 M THF, 3 equiv of ROH, 60 °C, 15 h. b Relative yield of ester to
starting material and other products, as determined by 1H NMR or GC
analysis of unpuried reaction mixtures. c In DMSO.
including DBU, KOtBu, and the phosphazine base P2-tBu,
show little if any products arising from protonation of the
catalytically generated homoenolate species. We also con-
sidered that the triazolium salt itself could effect protonation,
a pathway that would not be available in systems with strong
bases that completely and irreversibly deprotonate the
heterocyclic salt. Upon conducting the esterification in the
presence of excess salt relative to KOtBu (entry 6), we again
observed esterification products, raising the intriguing pos-
sibility that the heterocyclic salt serves as the catalytic proton
shuttle.12
a Reaction conditions: 5 mol % of 9a, 10 mol % of DIPEA, 1.0 mmol
of enal, 1 M THF, 3 equiv of ROH, 60 °C, 24 h. b Isolated yield following
chromatography. c Performed with 2 equiv of geraniol. d Performed with 1
equiv of 15. e Performed with 10 mol % of 9b, 15 mol % of DIPEA.
required no special handling. Esterifications with 9a or 9b
and DIPEA produced no benzoin, Stetter, or lactone products
and are far more efficient and selective than other combina-
tions of heterocyclic salts and bases we have examined.
Importantly, in contrast to other NHC precursors, the
triazolium precatalysts are readily deprotonated by weaker
bases (DIPEA, NEt3), a feature critical to the success of the
overall catalytic process.
(10) (a) Synthesis of related azolium catalysts has been described:
Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkins Trans. 1 1998, 1891-
1893. (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005,
70, 5725-5728. We are grateful to Prof. Rovis for a preprint of this work.
Org. Lett., Vol. 7, No. 18, 2005
3875

The relative difficulty of protonating the catalytically
generated homoenolates vis-a`-vis carbon-carbon bond form-
ing pathways is most evident when IMes-HCl is used as the
catalyst (Scheme 4). Heating a solution of cinnamaldehyde,
Scheme 5. Postulated Catalytic Cycle for Catalytic Redox
Esterifications of Enals
Scheme 4. Effect of Catalytic Base on the Fate of
Catalytically Generated Homoenolate Equivalents
this postulated catalytic cycle and disfavor a concerted
hydride shift mechanism.
15 mol % IMes-HCl, 10 mol % KOtBu, 3 equiv of EtOH in
THF leads to lactone dimer 35 as the major isolated product;
less than 5% saturated ester is formed. In contrast, the
identical experiment performed with 10 mol % DIPEA gives
the unsaturated ester in 60% yield, with only a trace of the
lactone dimer.
This process is likely to be mechanistically similar to our
previous reports of catalytically generated homoenolates and
activated carboxylates with N-heterocyclic carbenes (Scheme
5).14,15 Studies with deuterated substrates and solvents support
In summary, we have identified a critical and product-
determining role for the catalytic amine base in the chemistry
of homoenolates generated catalytically from enals and
N-heterocyclic carbenes. In addition to revealing the unique
properties of these transient intermediates, these findings
were critical to the development of a catalytic method for
the generation of activated carboxylates from R,â-unsaturated
aldehydes under mild conditions that requires no additional
coupling reagents or additives and produces no reaction
byproducts.
(11) We postulate that the allylic strain inherent to the key homoenolate
equivalent inhibits protonation at the â-position by impeding the formation
of a fully conjugated system.
Acknowledgment. This work has been supported by the
National Science Foundation (CAREER Award to J.W.B.),
the Camille and Henry Dreyfus Foundation, and the Uni-
versity of California. We thank Evie Rosen and Justin Struble
for experimental assistance.
Supporting Information Available: Experimental pro-
cedures, characterization data, and deuterium labeling studies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We have shown, by deuterium labeling experiments, that the catalyst reacts
with R-methylcinnamaldehyde to give A (or its geometric isomer). This
process, however, is unproductive and does not promote the formation of
any products other than the deuterated aldehyde.
OL051269W
(14) The apparently related conversion of â-formyl acrylic acid to
succinic acid by aqueous cyanide ion has been described: (a) Nowak, R.
M. J. Org. Chem. 1963, 28, 1182-1187. (b) Franzen, V.; Fikentscher, L.
Liebigs Ann. 1959, 623, 68-73.
(15) For a similar overall transformation via the stoichiometric inter-
mediacy of TMS cyanohydrins, see: Kawabata, H.; Hayashi, M. Tetrahe-
dron Lett. 2002, 43, 5645-5647.
(12) Triazolium salts 9a and 9b undergo rapid proton exchange even in
1
the absence of base. For example, H NMR spectra of 9 in CD3OD show
rapid exchange of the C2 proton with deuterium.
(13) (a) Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito, I.;
Koppel, I. A. J. Org. Chem. 2002, 67, 1873-1881. (b) Bordwell, F. G.
Acc. Chem. Res. 1988, 21, 456-463.
3876
Org. Lett., Vol. 7, No. 18, 2005