A facile and efficient direct aldol addition of simple thioesters

Article abstract of DOI:10.1021/ol060413q

Simple thioesters undergo direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂ and i-Pr₂NEt using untreated, reagent-grade CH₂Cl₂ under atmospheric conditions. The reactions proceed extrem

Full text of DOI:10.1021/ol060413q

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1503-1506
A Facile and Efficient Direct Aldol
Addition of Simple Thioesters
Julianne M. Yost, Guoqiang Zhou, and Don M. Coltart*
Department of Chemistry and the Center for Chemical Biology, Duke UniVersity,
Durham, North Carolina 27708
don.coltart@duke.edu
Received February 16, 2006
ABSTRACT
Simple thioesters undergo direct aldol addition to aldehydes in the presence of MgBr2‚OEt2 and i-Pr2NEt using untreated, reagent-grade
CH2Cl2 under atmospheric conditions. The reactions proceed extremely rapidly and in excellent yield.
The aldol reaction is among the most important chemical
reactions. Substantial effort has gone into its development
using preformed enolates, resulting in a remarkable level of
regio- and stereochemical control.1 However, the desire to
develop milder and operationally simplified chemical meth-
ods has spawned a renewed interest in the direct aldol
reaction,1a without reliance on preformed enolates. While
only a limited number of reports have appeared,1a,2 initial
investigations into these in situ enolization approaches clearly
establish their potential.
The majority of this research, for both metal-assisted and
organocatalytic processes, focuses on the use of ketone- and,
to a lesser extent, aldehyde-based nucleophiles.1a However,
owing to the inherent advantages of carboxylate-derived
nucleophiles in aldol addition reactions, such as obviating
the issue of regioselectivity of deprotonation and the iterative
potential of the process, it is extremely desirable to develop
related procedures based on these systems.
magnesium halide catalyzed aldol reactions of chiral N-
acyloxazolidinones and N-acylthiazolidinethiones,2a,b as well
as those of achiral N-acylthiazolidinethiones with a chiral
Ni(II) bis(oxazoline) catalyst.2c In addition, copper-catalyzed
decarboxylative enolization of malonic acid half thioesters
has been demonstrated by Shair and co-workers, in both an
asymmetric and nonasymmetric sense.2d,e
We were intrigued by the possibility of using readily
accessible, simple thioesters in the direct aldol addition
reaction. Our inspiration for this derives from Nature’s use
of thioesters, typically in the form of acetyl coenzyme A, in
carbon-carbon bond-forming processes. Here, Nature’s
choice of thioesters over oxoesters is undoubtedly a deliberate
one and may well be connected to the increased acidity of
the thioester R-proton,3 compared to that of the corresponding
oxoester. The sophistication of Nature’s aldol processes
overcomes the need for prior enolate formation, lending
simplicity and elegance to this important carbon-carbon
bond-forming reaction. Of course, mimicking the direct
nature of this reaction in the laboratory in a synthetic context
would be advantageous in terms of procedural simplification
and, potentially, reduced cost and environmental impact.
From a practical point of view, the use of simple thioesters
for such a direct aldol addition is desirable for a number of
reasons. For instance, they are readily accessible from
inexpensive, commercially available thiols, or are themselves
Recently, a small number of examples along these lines
have appeared. Evans and co-workers have begun to explore
(1) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; 2 Vols. (b) Carreira, E. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Heidelberg, 1999; Vol. 3, pp 997-1065.
(2) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392-393. (b) Evans, D. A.; Downey, C. W.; Shaw,
J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127-1130. (c) Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706-8707.
(d) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125,
2852-2853. (e) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise,
A. D.; Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284-7285.
(3) The pKa of the thioester R-proton has been reported to be 2 units
less than that of a corresponding oxoester. See: Bordwell, F. G.; Fried, H.
E. J. Org. Chem. 1991, 56, 4218-4223.
10.1021/ol060413q CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/07/2006

commercially available. They are also stable and easily
handled, yet they undergo a number of important transforma-
tions under very mild conditions including reduction, hy-
drolysis, and direct amidation.
Table 1. Investigation of the Effect of the Thiol on Thioester
Reactivity in the MgI2-Promoted Direct Aldol Reactiona
To explore the possibility of using simple thioesters to
develop a direct aldol addition reaction, we investigated the
reaction of S-benzyl thioacetate4 (1) with benzaldehyde under
a variety of conditions using several different metal salts
based on Zn, Cu, and Ni. In no case was there any indication
of a reaction between the thioester and aldehyde. However,
we eventually found that the aldol addition could be
promoted by MgI2, and after screening a variety of solvents
and amine bases, we settled on the use of i-Pr2NEt in CH2Cl2.
Coincidentally, these conditions had previously been reported
to provide moderate to high yields for the direct aldol reaction
between ketones and aromatic aldehydes, and modest yields
with certain oxoesters and benzaldehyde.5
In the presence of MgI2 and i-Pr2NEt, 1 reacted with
benzaldehyde in CH2Cl2 to give the corresponding â-hydroxy
thioester (2) in 95% isolated yield in only 25 min (see
Scheme 1).6 In comparison to oxoester substrates, the yield
Scheme 1. MgI2-Promoted Direct Aldol Reaction of Thioester
1 and Oxoester 3 with Benzaldehydea
a Conducted under Ar by combining 1 molar equiv of thioester, 1.2 molar
equiv of benzaldehyde, and 1.2 molar equiv of MgI2 in CH2Cl2 (concn, 0.2
M), followed by addition of 1.3 molar equiv of i-Pr2NEt.
nature of the reaction in the cases of 5-7, we were unable
to establish a clear preference for either thioester in the aldol
addition. However, competition experiments involving 5-7
with benzaldehyde showed a slight preference for the
formation of 10 over 11 and 12. On this basis, and the fact
that it is commercially available, 5 was chosen for subsequent
studies. Significantly, a competition experiment between 5
and acetophenone gave a 3:1 mixture of the corresponding
â-hydroxy ketone to 10, demonstrating that the reactivity of
a simple thioester in the direct aldol reaction is comparable
to that of a highly reactive ketone.
While the direct aldol demonstrated above is rapid and
highly efficient, our attempts to conduct it catalytically using
5, 7, or 9 were unsuccessful. This was as expected in the
case of 5, given the presumed thermodynamic preference of
MgI2 for interaction with the â-hydroxy thioester product
over either 5 or benzaldehyde. For 7 and 9, however, there
is a somewhat greater possibility that the MgI2/â-hydroxy
thioester complex would be able to exchange with the starting
thioester, given the availability of additional oxygen atoms
in the thiol component for coordination, albeit through a
seven-membered ring. Efforts to facilitate this exchange via
in situ silylation of the product through addition of TMSCl2a-c
showed no indication of catalysis.
a Conducted under Ar by combining 1 molar equiv of thioester,
1.2 molar equiv of benzaldehyde, and 1.2 molar equiv of MgI2 in
CH2Cl2 (concn 0.2 M), followed by addition of 1.3 molar equiv of
i-Pr2NEt.
of addition product from 1 was significantly higher (cf. 60
to 72% for the oxoesters5), with a somewhat shorter reaction
time. The superior reactivity of the thioester was confirmed
via a competition experiment between 1 and O-benzyl acetate
(3) with benzaldehyde, in which 92% conversion to 2 was
observed after 30 min, with no corresponding â-hydroxy
oxoester (4) detected. Reaction of 3 with benzaldehyde in
the presence of MgI2 and i-Pr2NEt gave 46% yield of 4 after
20 h (see Scheme 1).
We next investigated the effect of the thiol component of
the thioester on its reactivity. Thus, thioesters 5-9 (see Table
1) were subjected to the conditions described above. Re-
markably, thioesters 5-7 provided the aldol product nearly
quantitatively within only 20 min. Given the extremely rapid
The majority of methods for effecting the direct aldol
addition reported recently employ catalytic amounts of the
activating component, be it a metal or organic molecule.1a,2
When organic molecules are used to promote a reaction, it
is generally desirable that they be used catalytically, given
the time, effort, and cost often associated with their prepara-
(4) All thioesters used in this work, with the exception of commercially
available 5, 8, 9, and 29, were prepared via acylation of the corresponding
commercially available thiols. See the Supporting Information.
(5) Wei, H.-X.; Li, K.; Zhang, Q.; Jasoni, R. L.; Hu, J.; Pare´, P. W.
HelV. Chim. Acta 2004, 87, 2354-2358.
(6) A control experiment in which MgI2 was omitted gave only starting
material after 2 days. Likewise, omission of base gave no product.
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Org. Lett., Vol. 8, No. 7, 2006

To test this, 5 was combined with benzaldehyde, i-Pr2NEt,
and MgBr2‚OEt2 in untreated, reagent-grade CH2Cl27 under
atmospheric conditions. Significantly, not only was the
reaction highly efficient, giving a 96% yield of product, but
it remained extremely facile, taking only 30 min to go to
completion. No increase in yield or decrease in reaction time
was observed when the reaction was conducted using dry
CH2Cl2 under an Ar atmosphere. When MgI2 was used in
this manner, reaction yields were lower than when anhydrous
conditions were employed.
Table 2. MgBr2·OEt2-Promoted Direct Aldol Addition between
5 and Various Aldehydes Using Untreated Solvent under
Atmospheric Conditionsa
Using these conditions, we investigated the scope of the
reaction with a variety of aldehydes (see Table 2). In all
cases, reaction times were short and yields were excellent.
Significantly, the reaction could be conducted using an
aldehyde having a single R-proton (entry 8) with only a small
amount (<4%) of the self-addition product produced. In this
case, best results were obtained when the thioester was used
in a 1.5-fold excess, relative to the aldehyde.
The effect of R-substitution on the thioester was examined
via the direct aldol addition between benzaldehyde and each
of S-phenyl thiopropionate (29) and S-phenyl-R-benzyloxy
thiopropionate (30) (see Scheme 2). In both cases, the
Scheme 2. MgBr2‚OEt2-Promoted Direct Aldol Reaction of
R-Substituted Thioesters with Benzaldehydea
a Conducted under atmospheric conditions by combining 1 molar
equiv of 5, 1.2 molar equiv of aldehyde, and 1.4 molar equiv of
MgBr2‚OEt2 in untreated, reagent-grade CH2Cl2 (concn 0.2 M),
followed by addition of 2.0 molar equiv of i-Pr2NEt.
a Conducted under atmospheric conditions by combining 1 molar equiv
of 5, 1.2 molar equiv of aldehyde, and 1.4 molar equiv of MgBr2‚OEt2 in
untreated, reagent-grade CH2Cl2 (concn 0.2 M), followed by addition of
2.0 molar equiv of i-Pr2NEt.
reaction gave an excellent yield of the respective diastereo-
meric products in a reasonably short time.
tion. For a transition-metal-mediated process, a catalytic
mode of action is also generally desirable for reasons
typically associated with cost and toxicity of the metal, along
with downstream purification requirements of the products,
especially in pharmaceutical applications.
Last, we probed the issue of reversibility of the addition
reaction. Thus, 10 was combined with MgBr2‚OEt2 (1.4
molar equiv), i-Pr2NEt (2.0 molar equiv), and 6 (1 molar
equiv). A 1:1 mixture of 10 to 11 was obtained from this
experiment, suggesting that the addition process is reversible
under these conditions. The corresponding experiment in
which 5 was added to a mixture containing 11, MgBr2‚OEt2,
and i-Pr2NEt was also conducted and gave a similar result.
These results indicate that, to develop an asymmetric varient
of this reaction, it will be necessary to trap the kinetic product
in a manner similar to that reported by Evans.2a-c Investiga-
tions in this regard are ongoing.
The catalytic requirement of a process is diminished when
one uses promoters that are themselves readily accessible,
very inexpensive, and environmentally benign. Along these
lines, given the extremely rapid nature of the reaction with
thioester 5, we wondered about the possibility of substituting
MgBr2‚OEt2 for MgI2. This compound is commercially
available and very inexpensive and, like MgI2, generates no
toxic byproducts on aqueous workup. While the reaction with
MgBr2‚OEt2 would be expected to be slower, we hoped that
this would be more than compensated for, not only by the
low cost of the reagent, but also by allowing us to conduct
the reactions open to the atmosphere using untreated, reagent
grade solvent.
In conclusion, we have developed a mild and efficient
direct aldol reaction using simple thioesters. The reaction is
conducted using inexpensive MgBr2‚OEt2 in untreated,
(7) Aldrich. ACS reagent grade, g99.5%.
Org. Lett., Vol. 8, No. 7, 2006
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reagent grade solvent under atmospheric conditions and
produces innocuous byproducts on workup. To our knowl-
edge, this is the first report of a direct aldol addition involving
simple thioesters. The superior reactivity of thioesters over
oxoesters in this reaction was established via competition
experiments and is fundamental to the facility of this
procedure. Given the operational simplicity of the reaction
and the accessibility of thioesters,4 we expect that this method
will meet with wide application. Work is currently ongoing
to develop an asymmetric variant of the reaction through
incorporation of a recoverable chiral auxiliary, and we are
also exploring other modes of incorporating heteroatoms into
the starting thioesters, in both the thiol region (cf. 7 and 9)
and at the R-position (cf. 30), to investigate the development
of a catalytic asymmetric process using a metal possessing
chiral ligands. Additionally, we have begun to explore the
use of thioesters in the context of several other reactions.
Acknowledgment. We thank Dr. Anna Gromova and
Drew Schwartz for their assistance in conducting certain
experiments.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060413Q
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Org. Lett., Vol. 8, No. 7, 2006