Unusual mechanistic course of some NHC-mediated transesterifications

Article abstract of DOI:10.1021/ol900257t

During experiments on the transesterification of vinyl benzoate with ethanol mediated by IPr and IMes, unexpected species were observed and characterized that call into question the accepted mechanism of the NHC-mediated transesterification of vinyl ester

Full text of DOI:10.1021/ol900257t

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1643-1646
Unusual Mechanistic Course of Some
NHC-Mediated Transesterifications
Luca Pignataro,*,† Teresa Papalia,‡ Alexandra M. Z. Slawin,§ and
Stephen M. Goldup*,
Dipartimento di Chimica Organica e Industriale, UniVersita` degli Studi di Milano, Via
Venezian 21, I-20133 Milano, Italy, Dipartimento di Chimica Organica e Biologica,
UniVersita` degli Studi di Messina, Salita Sperone 31 (Vill. S. Agata), 98166 Messina,
Italy, School of Chemistry, UniVersity of St. Andrews, Purdie Building, St. Andrews,
Fife KY16 9ST, U.K., and School of Biological and Chemical Sciences, Queen Mary
UniVersity of London, Mile End Road, London E1 4NS, U.K.
luca.pignataro@unimi.it; s.m.goldup@qmul.ac.uk
Received February 6, 2009
ABSTRACT
During experiments on the transesterification of vinyl benzoate with ethanol mediated by IPr and IMes, unexpected species were observed and
characterized that call into question the accepted mechanism of the NHC-mediated transesterification of vinyl esters.
N-Heterocyclic carbenes (NHCs), first prepared as early as
19681 and isolated by Arduengo and co-workers in 1991,2
have attracted considerable interest as both ligands for
transition metals3,4 and organocatalysts.3,5,6 In 2002 the
groups of Hedrick and Waymouth7a and Nolan8a simulta-
neously reported the application of NHCs to acyl transfer
reactions: several structurally simple and easy-to-prepare
NHCs were described to catalyze the transesterification of
vinyl, methyl, and ethyl esters with primary and secondary
alcohols in excellent yields. The scope of NHC-catalyzed
acyl transfer has since been extended to “living”
polymerizations,7b amidation of esters with aminoalcohols,9
synthesis of phosphorus esters,8d and through the use of chiral
NHCs, kinetic resolution of racemic secondary alcohols.10,11
Despite these successes, the mechanism of NHC-promoted
transesterification remains unclear. The formation of an acyl-
imidazolium species12 is generally accepted by analogy with
† Universita` degli Studi di Milano.
‡ Universita` degli Studi di Messina.
§ University of St. Andrews.
Queen Mary University of London.
(1) (a) Wanzlick, H.-W.; Scho¨nherr, H.-J. Angew. Chem. 1968, 80, 154.
¨
(b) Ofele, K. J. Organomet. Chem. 1968, 12, P42-P43.
(2) Arduengo, A. J., III.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361–363.
(3) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-
VCH: Weinheim, 2006
.
(4) (a) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768–2813. (b) Glorious, F. N-Heterocyclic Carbenes in
Transition Metal Catalysis. Top. Organomet. Chem. 2007, 21, 1–218
.
(7) (a) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.;
Hedrick, J. L. Org. Lett. 2002, 4, 3587–3590. (b) Nyce, G. W.; Glauser,
T.; Connor, E. F.; Mo¨ck, A.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem.
Soc. 2003, 125, 3046–3056.
(5) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107,
5606–5655. (b) Marion, N.; D´ıez-Gonzalez, S.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2988–3000. (c) Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534–541
.
(8) (a) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002, 4,
3583–3586. (b) Grasa, G. A.; Gu¨veli, T.; Singh, R.; Nolan, S. P. J. Org.
Chem. 2003, 68, 2812–2819. (c) Singh, R.; Kissling, R.; Letellier, M.-A.;
Nolan, S. P. J. Org. Chem. 2004, 69, 209–212. (d) Singh, R.; Nolan, S. P.
(6) For recent reviews on organocatalysis, see: (a) Lelais, G.; MacMillan,
D. W. C. New Frontiers in Asymmetric Catalysis; Wiley-VCH: Weinheim,
2007; pp 313-358. (b) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta
2006, 39, 79–87. (c) List, B. Chem. Commun. 2006, 8, 819–824. (d)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH; Weinheim,
2005. (e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–
Chem. Commun. 2005, 43, 5456–5458
.
(9) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453–2456
.
(10) (a) Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem.
Commun. 2004, 23, 2770–2771. (b) Suzuki, Y.; Muramatsu, K.; Yamauchi,
K.; Morie, Y.; Sato, M. Tetrahedron 2006, 62, 302–310.
5175
.
10.1021/ol900257t CCC: $40.75
Published on Web 03/09/2009
2009 American Chemical Society

acyl-transfer reactions mediated by nitrogen nucleophiles,8,10
while computational studies13 indicate that the role of the
NHC in catalysis is to assist proton transfer from the alcohol
to the carbonyl oxygen through a hydrogen-bonded complex.
The isolation and characterization of an IMes-MeOH
hydrogen-bonded complex is invoked in support of the latter
mechanism.9 However, little or no direct experimental
evidence has been provided in support of either hypothesis.
Here we report experimental observations on the mecha-
nism of transesterification of vinyl esters, obtained during
preliminary studies on the applicability of such reactions in
the active template synthesis of interlocked architectures,14
which run contrary to either of these mechanistic proposals.
In initial experiments (Scheme 1) the transesterification of
vinyl benzoate with ethanol promoted by a stoichiometric
Figure 1. X-ray crystal structure of adduct 4b with thermal
ellipsoids (50% probability). Chloride counterion, solvent molecules,
and hydrogen atoms are omitted for clarity.
and secondary alcohols.10a Intrigued by the unusual products
isolated and in an effort to determine if these species play a
significant role in the NHC-mediated transesterification of
vinyl esters, possibly providing an explanation for the
disparate yields previously reported, we investigated the
Scheme 1. Reaction of Carbenes 2 with Vinyl Benzoate
1
reaction between IPr and vinyl benzoate by H NMR.
When vinyl benzoate was added to IPr (2a) that had been
generated in d8-THF (Figure 2a), near quantitative conversion
amount of in situ generated IPr (2a) proved sluggish, with little
formation of ethyl benzoate observed when the reaction was
quenched with ethereal HCl after 2 h. Despite the low
conversion to product, 1H NMR analysis of the crude reaction
mixture indicated complete consumption of the vinyl ester, with
the major component being an unknown imidazolium-derived
compound. Intriguingly, when vinyl benzoate was added to a
solution of carbene 2a and the reaction quenched with ethereal
HCl after 2 h, the major product in near quantitative yield was
the same unknown species, which proved stable enough to be
purified by column chromatography and was tentatively as-
signed as adduct 4a. This assignment was confirmed by single
crystal X-ray analysis of analogous compound 4b, prepared in
a similar manner using 1b (Figure 1).15
A brief survey of previous reports on the use of vinyl esters
as acyl-transfer agents in the NHC-mediated acylation of
alcohols7,8,10,11 reveals extremely variable yields: from near
quantitative in the case of the IMes-mediated reaction
between vinyl acetate and BnOH7a to between 4% and 44%
in the case of NHC-mediated reactions between vinyl acetate
1
Figure 2
.
Partial H NMR spectra (400 MHz, d8-THF, 300 K) of
(a) IPr (2a), (b) IPr + vinyl benzoate (adduct 3a), (c) IPr + vinyl
benzoate + EtOH after 3.5 h, and (d) adduct 4a.
(11) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347–1349.
(12) For other reports on acyl-imidazolium and thiazolium species, see:
(a) Davies, D. H.; Hall, J.; Smith, E. H. J. Chem. Soc., Perkin Trans. 1
1989, 837–838. (b) Ohta, S.; Hayakawa, S.; Okamoto, M. Tetrahedron Lett.
1984, 25, 5681–5684.
to a new imidazolium species (Figure 2b) was observed
within 1 h. This species could not be isolated, but it proved
1
stable enough to be characterized by H and 13C NMR as
(13) Lai, C.-L.; Lee, H. M.; Hu, C.-H. Tetrahedron Lett. 2005, 46, 6265–
6270.
adduct 3a, although evidence of decomposition was observed
after 5 h. When EtOH (1 equiv) was added to a freshly
prepared solution of adduct, slow conversion from ethanol
(14) Aucagne, V.; Berna´, J.; Crowley, J. D.; Goldup, S. M.; Ha¨nni, K. D.;
Leigh, D. A.; Lusby, P. J.; Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi,
A.; Walker, D. B. J. Am. Chem. Soc. 2007, 129, 11950–11963.
1644
Org. Lett., Vol. 11, No. 7, 2009

to ethyl benzoate was observed (1 h, 2%; 7 h, 10%; 24 h,
20%) accompanied by slow degradation to a complex
mixture of imidazolium-containing byproducts and proto-
nated adduct 4a (1H NMR spectrum of 4a shown in Figure
2d). Formation of product ceased once all of adduct 3a had
been consumed. The same results were obtained when in
situ generated IPr was added to a solution of vinyl benzoate
and EtOH, indicating that formation of adduct 3a takes place
at a significantly higher rate than the transesterification
reaction. On the other hand, when a large excess (15 equiv)
of ethanol was added to preformed 3a, full conversion to
EtOBz was obtained within 50 min. When the transesteri-
fication of vinyl benzoate with EtOH was repeated in the
presence of a catalytic amount of IPr (1 mol %), rapid
formation of adduct 3a was again clearly observed by NMR.
As in the stoichiometric experiment, a slow transesterification
process was observed (4 h, 11%). Once again, when after
8 h all of 3a had disappeared, the reaction stopped (16%
final conversion). Finally, when adduct 4a was treated with
1 equiv of EtOK in d8-THF, formation of 3a took place much
more quickly than the transesterification process. Taken
together, these results indicate that adduct 3a plays a central
role in the IPr-promoted transesterification between vinyl
benzoate and EtOH, whereas adduct 4a is inactive to acyl
transfer under the reaction conditions.
Scheme 2. Possible Mechanisms of Formation for Adduct 3
alkoxide 5 may tautomerize to give the Breslow intermediate
commonly invoked in the NHC-mediated benzoin reaction
(7).17 Enol 6 can then undergo C-acylation18 to give
intermediate 7 and regenerate acetaldehyde (pathway b).
C-O migration of the benzoyl19 group gives adduct 3 via
intermediate 8. Adduct 4 is then simply the product of
protonation of adduct 3. It should be noted that acetaldehyde
is regenerated in this process, and thus only a trace amount
of acetaldehyde need be present to initiate the reaction.
In light of the above results it seems clear that the IMes
and IPr-mediated transesterifiction of vinyl esters are far more
complicated than has previously been thought, with adducts
3 being important intermediates in the process. Two roles
that can be envisaged for these species are shown: an
intermediate that becomes activated by trace amounts of free
carbene or an active species in its own right (Scheme 3a
When the transesterification of vinyl benzoate in the presence
of a catalytic quantity (1%) of IMes (2c)7,8 was monitored by
1H NMR, rapid formation of analogous adduct 3c was
observed. The lifetime of adduct 3c was extremely short:
after 5 min adduct 4c was the only identifiable IMes-derived
species remaining. However, in the presence of 2c the
transesterification process was significantly faster than with
2a, and a conversion of 31% was obtained despite the short
lifetime of 3c.
Scheme 3. Possible Mechanisms of the NHC-Mediated
Transesterification Reaction of Vinyl Benzoate and EtOH
Thus, apart from the obvious kinetic differences, the
transesterification reaction between vinyl benzoate and EtOH
mediated by IMes (2c) appears to proceed in a fashion
analogous to that mediated by IPr (2a). However, 1H NMR
analysis of the reaction mediated by carbene ItBu (2d)
indicated that in this case the reaction may proceed differ-
ently. When vinyl benzoate was added to carbene 2d (1%)
in d8-THF, no formation of adducts 3d or 4d was observed
by 1H NMR. However, addition of EtOH led to rapid
transesterification (14% maximum conversion), with a small
amount of adduct 4d detected after 2 h of reaction.
Two plausible mechanisms for the formation of adduct 3
are envisaged (Scheme 2), both initiated by attack of the
NHC on trace amounts of acetaldehyde.16 The simplest
mechanism then involves O-acylation of alkoxide 5 by vinyl
benzoate followed by deprotonation of adduct 4 by the
acetalydehyde enolate byproduct to give observed product
3 and regenerate acetaldehyde (pathway a). Alternatively,
and b, respectively). In cycle a, adduct 3 reverts to acyl-
imidazolium species 9, which is then attacked by EtOH to
(15) Protonated Breslow-type intermediates have been observed in NHC-
mediated Baylis-Hillman reactions (Hsu, J.-C.; Yen, Y.-H.; Chu, Y.-H.
Tetrahedron Lett. 2004, 45, 4673-4676; Schrader, W.; Handayani, P. P.;
Burstein, C.; Glorius, F. Chem. Commun. 2007, 7, 716-718) and character-
ized crystallographically in the NHC-mediated addition of R-hydroxypro-
pargylsilanes to aldehydes: Reynolds, T. E.; Stern, C. A.; Scheidt, K. A.
Org. Lett. 2007, 9, 2581-2584.
(16) Trace acetaldehyde required to initiate this process may be fomed
via an acyl-imidazolium species normally postulated. As suggested by one
of the reviewers, this same acyl-imidazolium species may also be responsible
for the acylation of 5 or 6, and this represents a valid variation on either
pathway a or pathway b.
(17) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
Org. Lett., Vol. 11, No. 7, 2009
1645

give the product ester and regenerate the carbene. Alterna-
tively, cycle b is far simpler, with direct displacement of
the benzoyl group from adduct 3 to give product and enol
6, which then reacts with 1 equiv of vinyl benzoate to
regenerate adduct 3 once again.
Scheme 4. IPr-Mediated Transesterification of Alkenyl Acetates
In both proposed mechanisms it seems likely that the
reaction rate is significantly retarded by formation of adducts
3: in cycle a, adducts 3 can be considered catalyst rest states,
1
which by H NMR appear to be the dominant form of the
catalyst, whereas in cycle b, in which adducts 3 are the active
species, they can be expected to be significantly less reactive
than corresponding, charged, acyl-imidazolium species 9.
Thus, the acetaldehyde formed during the NHC-mediated
transesterification of vinyl esters plays a significant and
almost certainly deleterious role in the process. Further,
addition of excess acetaldehyde to adduct 3a in d8-THF led
to rapid discoloration (dark red to pale orange) and complete
consumption of adduct 3a to give a complex mixture of
unidentified products, implying that the acetaldehyde also
plays a role in catalyst decomposition.
Lin et al. reported that the acetaldehyde produced in the
vanadium(V)-mediated transesterification of vinyl acetate
leads to reduced yields due to acetaldehyde-induced catalyst
degradation.20 The authors found that the use of isopropenyl
acetate led to significantly improved yields. However, in our
hands, addition of isopropenyl acetate to a solution of carbene
2a in d8-THF led to little or no consumption of either
compound. This appears to indicate that the displacement
of the acetone enolate from the vinyl ester is either slow or
that the position of the equilibrium lies significantly to the
left. When a catalytic amount (1 mol %) of IPr was added
to a solution of isopropenyl acetate and EtOH in d8-THF,
conversion of EtOH to EtOAc was slow (3% in 18 h),
implying that the former is the case. In contrast, in the
presence of catalytic IPr (1 mol %), the reaction between
vinyl acetate and EtOH proceeds to 33% conversion of EtOH
to EtOAc in less than 30 min, at which time adduct 11 is
the major imidazolium-derived species, leading us to believe
that vinyl acetate reacts with IPr in a fashion similar to that
for vinyl benzoate: addition of vinyl acetate to IPr in d8-
THF gives rise to the rapid formation of a new imidazolium-
derived species characterized in situ as adduct 10. Addition
of HCl to a solution of 10 gave protonated adduct 11.
In conclusion, we have identified new and unexpected
species formed in the IPr- and IMes-catalyzed transesteri-
fication of vinyl esters that imply that the reaction mechanism
is significantly different from those proposed so far for this
kind of process. It is not possible to distinguish between the
two proposed mechanisms on the basis of our results, and
investigations are ongoing. However, a literature report on
the kinetic resolution of racemic secondary alcohols by a
chiral NHC reveals different ee’s when methyl acetate (0%
ee) is used as the acylating agent in place of vinyl acetate
(29% ee)11,21 under similar conditions. Although not con-
clusive, this may imply that these reactions do not proceed
via the same final bond-forming step, as would be the case
if the acylating agent in both cases were an acyl-imidazolium
species, which is consistent with the mechanism proposed
in Scheme 3b. We believe that the information reported here
will be helpful in order to develop a deeper understanding
of the NHC-promoted transesterification of vinyl esters and
should be seen as a consideration for the continued develop-
ment of NHC catalysts for the kinetic resolution of racemic
secondary alcohols.
Acknowledgment. The authors are grateful for the gener-
ous support of Profs. D. A. Leigh (University of Edinburgh)
and P. Bonaccorsi (Universita` degli Studi di Messina). We
thank the EPSRC National Mass Spectrometry Service
Centre (Swansea, U.K.) for mass spectra data. S.M.G. thanks
the Leverhulme Trust for an Early Career Fellowship.
Supporting Information Available: Experimental details
and data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Compound 6 may also undergo O-acylation to give adduct 3
directly.
OL900257T
(19) Based on the proposed mechanism of benzil rearrangement in the
presence of an NHC: Lachmann, B.; Steinmaus, H.; Wanzlick, H. W.
Tetrahedron 1971, 27, 4085–4090.
(21) This may also be attributed to the MeOAc requiring a reaction
temperature of -20 instead of -78 °C as required for vinyl acetate.
(20) Lin, M.-H.; RajanBabu, T. V. Org. Lett. 2000, 2, 997–1000.
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