An alternative approach to aldol reactions: Gold-catalyzed formation of boron enolates from alkynes

Article abstract of DOI:10.1021/ja102129c

A new method for enolate generation via the gold-catalyzed addition of boronic acids to alkynes is reported. The formation of boron enolates from readily accessible ortho-alkynylbenzeneboronic acids proceeds rapidly with 2 mol % PPh³AuNTf²

Full text of DOI:10.1021/ja102129c

Published on Web 04/09/2010
An Alternative Approach to Aldol Reactions: Gold-Catalyzed Formation of
Boron Enolates from Alkynes
Cindy K o¨ rner, Pavel Starkov, and Tom D. Sheppard*
Department of Chemistry, UniVersity College London, Christopher Ingold Laboratories, 20 Gordon Street,
London, WC1H 0AJ, U.K.
Received March 12, 2010; E-mail: tom.sheppard@ucl.ac.uk
The aldol reaction is one of the most well established and widely
used methods for the formation of carbon-carbon bonds. However,
Scheme 1. Gold-Catalyzed Boron Enolate Formation/Aldol
Reaction
1
without natural substrate bias, the chemoselective formation of an
enolate from one carbonyl component in the presence of another
is extremely challenging. Therefore, the most commonly employed
2
solution is the use of a preformed enolate or enolate equivalent.
A method for the direct generation of an enolate from a non-
carbonyl precursor would provide a more elegant approach, but
such methods are rare and generally incompatible with the presence
3
of enolizable aldehydes. In this communication, we describe the
first catalytic method for the generation of enolates from unactivated
alkynes. The conditions are extremely mild, and the enolate can
be generated even in the presence of aldehydes prone to self-
condensation.
a
b
2
c
1 mol % PPh AuNTf , CH Cl , rt, 1 h. R CHO, CH Cl , rt, 2 h. 10
3
2
2
2
2
2
mol % CuSO
4
2 2
·5H O, H O, 60 °C, 16 h.
We envisaged that a boron enolate could be obtained by the gold-
4
5
catalyzed addition of a boronic acid to an alkyne. To demonstrate
Scheme 2. Transformation of Aldol Products 3 via Oxidation,
Suzuki Reaction, or Chan-Lam Coupling
this concept, we prepared ortho-alkynylbenzene boronic acid 1a
in two steps from bromoiodobenzene. Treatment of 1a with 1 mol
6
7
2
%
2
PPh
3
AuNTf
led to the rapid formation of isolable boron enolate
1
8
(R ) Bu) in 85% yield (Scheme 1). There was no evidence for
the formation of products via 5-exo-dig cyclization in contrast to
9
the Au-catalyzed cyclization of the corresponding carboxylic acids.
Selective formation of the six-membered ring in our case may be
8
due to possible aromatic stabilization present in 2. Boron enolate
2
underwent aldol reaction with butyraldehyde at room temperature
to give the cyclic boronate 3a as a mixture of separable diastere-
oisomers. Gratifyingly, in a one-pot procedure where the boron
enolate was generated in the presence of the aldehyde, the aldol
product 3a was obtained in 87% isolated yield (80:20 dr) over two
steps.
a
2
b
1
Cl
-2 mol % PPh
2
3
AuNTf
, rt, 30 min. Ac O, pyridine, rt, 2 h. 3 mol % (PPh
ArI, CH Cl , 37 °C, 10 h. 5 mol % Cu(OAc)
2
, R CHO, CH
2
Cl
2
, rt, 1-12 h. mCPBA,
c
d
CH
2
2
3
)
2
PdCl , CsF,
O, MeOH, 40 °C, 10 h.
2
e
2
2
2
·H
2
To determine the stereochemistry of the products, we then
prepared cyclic boronate 3b (75:25 dr), which underwent protode-
1
0
17
borylation to give the known alcohols 4 (75:25 dr). The major
diastereoisomer was found to be anti-4, derived from trans-3b.
first examples of intramolecular Chan-Lam coupling reactions
18
employing aliphatic alcohols. Excellent isolated yields of the final
products were obtained over two or three steps. In each case, the
1
Careful comparison of the H NMR spectra of the cyclic boronate
1
3
a with that of 3b indicated that trans-3a was the major product in
diastereoisomers were assigned by comparison of the H NMR
spectra of the cyclic boronates 3c-i with 3a-b. Importantly, no
change in diastereomeric ratio was observed during the post-aldol
transformations.
1
1
11
the reaction of boronic acid 1a.
The one-pot enolate formation/aldol reaction was found to be
applicable to a range of alkynes and aldehydes (Scheme 2 and Table
1
). The mild enolate formation conditions were even compatible
The above reactions demonstrate that the gold-catalyzed addition
of a boronic acid to an alkyne is a feasible method for accessing
boron enolates for use in aldol reactions. We were also keen to
explore intermolecular boron enolate formation as this would allow
the use of catalytic quantities of boronic acid. Pleasingly, on stirring
with acetaldehyde which is prone to self-condensation in the
12
presence of acid or base. In some cases, the cyclic boronates 3a-i
were prone to retro-aldol reaction and could not be isolated via
chromatography. However, the cyclic boronate provides a useful
handle for further transformations, and the crude reaction products
could be used directly in subsequent steps. Multistep sequences
were developed for direct conversion of the boronic acids 1a-e
into phenols/acetates (5 or 6), biaryls (7), or 2,3-dihydrobenzo-
1
9
aldehyde 9 (Scheme 3) with 2 mol % PPh
3 2
AuNTf and 30 mol
% of commercially available boronic acid 10, a slow reaction took
2
0
place over the course of 3 days to give enone 11 as the sole
product in 50% isolated yield. In this case, as expected, complete
selectivity for Markovnikov addition of the boronic acid to the
alkyne is observed. Enone 11 could potentially be produced via a
1
3
14
15
furans (8) via oxidation, Suzuki-Miyaura coupling, or
Chan-Lam coupling, respectively. These latter reactions are the
1
6
5
968 9 J. AM. CHEM. SOC. 2010, 132, 5968–5969
10.1021/ja102129c  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Gold-Catalyzed Enolate Formation/Aldol Reactions
Followed by Oxidation, Suzuki-Miyaura, or Chan-Lam Coupling
by aldehydes present in the reaction mixture. Intramolecular enolate
formation/aldol reactions provide access to a range of functionalized
scaffolds in excellent yield, after subsequent transformation of the
boronic acid. We have also demonstrated the feasibility of a
combined gold/boronic acid catalyzed aldol condensation reaction.
Further work is underway to explore the scope of this novel
approach to enolate chemistry.
Acknowledgment. We are grateful to Dr. Abil Aliev (UCL)
for technical assistance with the NMR studies. Financial support
for this work was provided by the EPSRC (Advanced Research
Fellowship to T.D.S. and a PhD studentship to P.S.), and the DAAD
(
scholarship to C.K.).
Supporting Information Available: Detailed experimental proce-
dures and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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JA102129C
J. AM. CHEM. SOC. 9 VOL. 132, NO. 17, 2010 5969