Hydroacylation of activated ketones catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja060833a

N-heterocyclic carbenes derived from triazolium salts are effective catalysts between 10 and 15 mol % for the hydroacylation of activated ketones. The reducing equivalent is generated via the interaction of a nucleophilic carbene species and an aromatic aldehyde. The subsequent alcohol product can undergo an acylation event with the resulting acyl heteroazolium intermediate formed in situ between the NHC and the aldehyde. This unprecedented multiple bond-forming reaction can accommodate aromatic aldehydes as the hydride source and various electron-deficient ketones. Preliminary mechanistic evidence indicates that the reduction and acylation steps are sequential operations. The intramolecular variant of this organocatalytic reaction affords benzofuranones in good yield. Copyright

Full text of DOI:10.1021/ja060833a

Published on Web 03/21/2006
Hydroacylation of Activated Ketones Catalyzed by N-Heterocyclic Carbenes
Audrey Chan and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received February 3, 2006; E-mail: scheidt@northwestern.edu
Direct methods for the selective oxidation of σ bonds are
powerful bond-forming strategies in organic synthesis. One establish-
ed approach to selectively oxidize C-H bonds utilizes transition
metals capable of undergoing oxidative addition pathways.1 The
rhodium(I)-catalyzed intramolecular hydroacylations of alkenes,
reported from many laboratories including Bosnich, Larock, Jun,
Brookhart, Shair, Fu, and Morehead, functionalize aldehydic C-H
bonds for the synthesis of carbocycles.2 Interestingly, the develop-
ment of analogous catalytic hydroacylation processes involving
aldehydes and carbonyl π systems has not received the same atten-
tion.3 We have been interested in developing approaches in which
an organic molecule promotes multiple bond-forming steps in a
single catalytic cycle.4 Herein, we report the hydroacylation of R-keto
esters (2) with aldehydes (1) catalyzed by N-heterocyclic carbenes
(eq 1). In this process, the carbene facilitates selective catalytic
oxidation of a C-H bond with concomitant reduction of a ketone.
(path B). We envisioned that this Cannizzaro-type10 reducing equiv-
alent could be harnessed to reduce ketones.11 The resulting alcohol
(4) produced after a reduction step can undergo an acylation event
with the acyl iminium species formed in situ (III), thus promoting
catalyst turnover and yielding an overall hydroacylation process
catalyzed by an organic molecule. Importantly, the aldehdye and
activated ketone are separate components, thereby providing for a
metal-free reaction with broader potential reaction scope than the
related Al(III)-promoted Tishchenko disproportionation reaction.12
To explore this transformation, a protic solvent (MeOH) was
employed to decouple the reduction and acylation events (Scheme
2). After examining various heteroazolium salts and potential ketone
Scheme 2. Protic and Aprotic Reaction Conditions with Keto
Ester 1
electrophiles, the combination of R-keto ester (2a) with benzalde-
hyde (1a) in the presence of 15 mol % triazolium salt 5 and DBU
produces methyl mandalate (6) in excellent yield (96%).13 Gratify-
ingly, the use of an aprotic solvent, such as dichloromethane, and
10 mol % 5 affords the hydroacylation product (78%, 7), which is
the product expected from path B in Scheme 1.
The interaction of N-heterocyclic carbenes5 with aldehydes has
been extensively employed in the development of carbonyl anions,
mainly in the additions of these Umpolung species6 to aldehydes
(benzoin reaction)7 and conjugate acceptors (Stetter reaction).8 A
common premise in these processes is that the tetrahedral inter-
mediate (I) resulting from the addition of the NHC to an aldehyde
usually generates a “Breslow intermediate” structure (II, path A,
Scheme 1).9 However, an alternative course potentially involves
Table 1. Examination of Aldehydes in Hydroacylation
entry
R
compd
yield (%)
Scheme 1. Proposed Reaction Pathway
1
2
3
4
5
6
7
Ph
7
8
9
10
11
12
13
78
77
71
72
70
73
0
4-MeO-Ph
4-F-Ph
4-Me-Ph
2-Naphthyl
2-Furyl
Ph(CH2)2
A survey of aldehydes for this process (Table 1, eq 3), indicates
that aromatic substituents afford high yields of the corresponding
products. The process is tolerant of electron rich aldehydes, while
the yields are generally lower when electron-deficient systems are
employed. To date, the use of enolizable aldehydes yields pre-
dominantly benzoin products.
We have also examined the scope of the reaction with regard to
the activated ketone component (Table 2, eq 4). Substituted aromatic
keto esters provide the desired esters resulting from overall hydro-
acylation in good yield when dichloromethane is used as the solvent.
By switching the media to ethanol, the corresponding alcohols are
the collapse of this intermediate to afford an acyl heteroazolium
species (III) with concomitant formation of a hydride equivalent
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10.1021/ja060833a CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of NHC-Catalyzed Reduction/Hydroacylation
process occurs via separate reduction and acylation steps in which
the organocatalyst is responsible for two key bond-forming steps
of the catalytic cycle. Further investigations of the generality of
this catalytic process and the development of asymmetric variants
are currently ongoing and will be reported in due course.
Acknowledgment. Support has been generously provided by North-
western University, the PRF (Type-G), Abbott Laboratories, Amgen, 3M,
and Boehringer-Ingelheim (New Investigator Awards). A.C. is the recipient
of a Dow Fellowship. We thank FMCLithium, Sigma-Aldrich, and BASF
for reagent support, Troy Reynolds (NU) for assistance with X-ray crys-
tallography, and Dr. Steve Wittenberger (Abbott) for helpful discussions.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Protic solvent reactions employed 1a and aprotic solvent reaction used
1b. b Aldehyde 1a was used. c Performed at 40 °C.
produced directly in the reaction along with the benzoic ester.
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products with enolizable keto esters. For less active ketones (e.g.,
entry 8), only protic conditions are successful in the reduction, and
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the operative reaction pathway in Scheme 1. The experiment using
deuterium-labeled benzaldehyde and 4-methyl benzaldehyde in CH2-
Cl2 generates all potential products (7, 10, and 28-29). This obser-
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keto ester (2a) in the presence of 5 and DBU affords the hydro-
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(13) The use of N,N′-dimethylbenzimidazolium iodide as a precatalyst affords
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(14) The heteroazolium-catalyzed benzoin reaction has been shown to be
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This NHC-catalyzed hydroacylation is also successful in an
intramolecular manifold (eq 5). The exposure of 31 to 5 delivers
the benzofuranone 32 in moderate yield under aprotic conditions.
In summary, we have demonstrated that hydroacylations of
activated ketones can be catalyzed by N-heterocyclic carbenes. This
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