DOI: 10.1002/chem.201604035
Communication
&
Synthetic Methods
Traceless Rhodium-Catalyzed Hydroacylation Using Alkyl
Aldehydes: The Enantioselective Synthesis of b-Aryl Ketones
+
+
[a]
¨
chelating aldehydes are useful substrates for a series of
tandem catalytic processes that deliver traceless hydroacyla-
tion products (Scheme 1a).[8] Herein, we report the develop-
ment of chemistry that allows S-chelating alkyl aldehydes to
give traceless products by a hydroacylation-conjugate addition
sequence, which ultimately replaces the S-substituent with
a stereochemically defined aryl group (Scheme 1b).
Abstract: A one-pot three-step sequence involving Rh-cat-
alyzed alkene hydroacylation, sulfide elimination and Rh-
catalyzed aryl boronic acid conjugate addition gave prod-
ucts of traceless chelation-controlled hydroacylation em-
ploying alkyl aldehydes. The stereodefined b-aryl ketones
were obtained in good yields with excellent control of
enantioselectivity. Good variation of all three reaction
components is possible.
Methods based on CÀH functionalization are revolutionizing
synthetic chemistry, and are allowing non-conventional discon-
nections to become routine in synthesis planning. The synthe-
sis of ketones and enones using alkene and alkyne hydroacyl-
ation reactions, respectively, provides powerful illustrations of
this concept.[1] Despite the significant advances that have been
achieved in metal-catalyzed hydroacylation, processes based
on the use of rhodium catalysts are limited by competing re-
ductive-decarbonylation pathways.[2] The use of chelation-con-
trolled strategies, with the incorporation of the chelating
group on either the aldehyde[3] or the alkene/alkyne,[4] has
become an established and useful approach to deliver highly
efficient transformations that proceed under mild conditions,
often with high levels of selectivity.[5] Although there are
a number of examples of metal-catalyzed intermolecular hy-
droacylation reactions that do not require the use of a chelate,
these processes usually have strict substrate requirements in
their own right.[6] For the benefits accrued from a chelation-
controlled approach, there is also a penalty to pay, in that the
additional coordinating group used to control reactivity is also
present in the product. One approach to address this limitation
has been to develop methods for the in situ removal, or deri-
vatization of these substituents.[7] Intermolecular hydroacyl-
ation methods based on S-chelating substrates are some of
the most general processes reported, with aryl-, heteroaryl-, al-
kenyl- and alkyl-substituted aldehydes all proving to be excel-
lent reaction partners.[3k–n] To extend the utility of these meth-
ods, our laboratory has shown that alkenyl- and aryl-derived S-
Scheme 1. Traceless hydroacylation using S-chelating aldehydes.
To begin our investigation, we established optimal condi-
tions for the three independent steps of our proposed se-
quence: Rh-catalyzed alkene hydroacylation, sulfide elimination
and Rh-catalyzed conjugate addition. A catalyst generated in
situ from the commercially available precatalyst [Rh(nbd)2BF4]
(nbd=norbornadiene) and the ligand bis(dicyclohexylphosphi-
no)methane (dcpm) proved to be efficient for the combination
of 1-octene and aldehyde 1a,[9] enabling the formation of
ketone 2a in 99% yield (Scheme 2, Eq. (1)). Two complementa-
ry sets of conditions were identified for the conversion of b-
sulfide 2a into enone 3a, with the first involving treatment
with a mixture of potassium carbonate and methyl trifluorome-
thanesulfonate, affording the corresponding enone 3a in 92%
yield in 1 h at 558C; the second method employed copper(I) 3-
methylsalicylate (CuMeSal), which required a longer reaction
time, but with the benefit of tolerating a greater range of func-
tional groups [Eq. (2)]. Finally, of the many ligands reported for
the rhodium-catalyzed 1,4-addition of aryl boronic acids to
enones,[10] catalysts generated from dienes L1 and L2 both de-
livered enantiomerically enriched ketone 4a in good yields
with excellent selectivities [Eq. (3)].[11]
[a] A. Bouisseau,+ M. Gao,+ Prof. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA (UK)
We next directed our attention to combining these three in-
dividual steps into a one-pot procedure (Table 1). We initially
explored the feasibility of both rhodium catalysts being pres-
ent from the start of the reaction. However, by using this ap-
[+] These authors contributed equally to this work.
Supporting information and ORCID from the author for this article are
Chem. Eur. J. 2016, 22, 1 – 6
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ