Catalytic enantioselective intermolecular hydroacylation: Rhodium-catalyzed combination of β-S-aldehydes and 1,3-disubstituted allenes

Full text of DOI:10.1021/ja8069133

Published on Web 12/03/2008
Catalytic Enantioselective Intermolecular Hydroacylation: Rhodium-Catalyzed
Combination of ꢀ-S-Aldehydes and 1,3-Disubstituted Allenes
James D. Osborne,† Helen E. Randell-Sly,‡ Gordon S. Currie,§ Andrew R. Cowley,† and
Michael C. Willis†,*
Department of Chemistry, UniVersity of Oxford, Chemical Research Laboratory, Mansfield Road, Oxford, U.K.,
Department of Chemistry, UniVersity of Bath, Bath, U.K., and AstraZeneca, Alderley Park, Macclesfield, Cheshire, U.K.
Received September 1, 2008; E-mail: michael.willis@chem.ox.ac.uk
Table 1. Allene Hydroacylation: Ligand Evaluationa
Transition metal catalyzed alkene hydroacylation is an attractive
method for the preparation of ketone derivatives; it is an atom
economic process, employs readily available substrates, and can
be achieved using relatively low catalyst loadings.1 Intramolecular
variants, particularly those leading to the formation of cyclopen-
tanones, have been extensively studied,2 and highly enantioselective
entry
ligand
yield (%)b
ee (%)c
variants have been developed.3 Intermolecular reactions are more
challenging, due mainly to competitive metal-catalyzed reductive
decarbonylation.4 One successful strategy to achieve these difficult
transformations has been to stabilize the key acyl-metal intermedi-
ates using chelation control.5 Although this has resulted in a number
of useful reactions, the scope of these processes is still relatively
narrow, with a particular limitation being the ability to routinely
use disubstituted alkenes.6 Given these difficulties it is not surprising
that there is only a single report of enantioselective intermolecular
hydroacylation, which, although efficient in terms of yield, offers
only variable enantioselectivity.7 Allenes have been demonstrated
to provide useful reactivity in a growing number of transition metal
catalyzed processes,8 including enantioselective transformations,9
although their use in hydroacylation reactions is virtually unex-
plored.10 In this communication, we demonstrate that, by exchang-
ing alkenes for allenes as substrates, an efficient and highly
enantioselective catalytic intermolecular hydroacylation process can
be achieved.
Recent results from our laboratories have established that ꢀ-S-
substituted aldehydes are useful substrates in intermolecular Rh-
catalyzed alkene and alkyne hydroacylation reactions, although,
again, reactions with 1,1- or 1,2-disubstituted alkenes were generally
unsuccessful.11 We reasoned that employing 1,3-disubstituted
allenes in intermolecular hydroacylation reactions should allow
access to substituted nonconjugated enone products. This should
provide a transformation potentially amenable to asymmetric
catalysis, while avoiding the need to employ poorly reactive
disubstituted alkenes as substrates (reactions 1 and 2). In following
such an approach, the inherent axial chirality of 1,3-disubstituted
allenes would need to be considered.
1
2
3
4
4
5
6
7
8
6
68
67
71
60
62
65
32
58
71
34
30
80
5
6d
a Conditions: aldehyde (1.0 equiv), allene (2.0 equiv),
[Rh(COD)2]BF4 (10 mol%), ligand (10 mol%), acetone, 55 °C, 16 h.
b Isolated yields. c Determined by chiral HPLC. d Reaction performed at
40 °C for 24 h.
Catalysts were generated in situ from [Rh(COD)2]BF4 and the
appropriate diphosphine ligand. We selected ligands that had been
successfully employed in enantioselective intramolecular
reactions;2b Chiraphos (4), Binap (5), and Me-DuPhos (6). Although
all three ligands generated effective catalysts, the complex incor-
porating Me-DuPhos displayed the highest levels of both reactivity
and selectivity, delivering enone 3 in 71% yield and with a 71%
ee (entries 1-3). Encouraged by these results we explored the Et-
i
and Pr-Duphos ligands (7 and 8); however, both generated less
selective catalysts (entries 4 and 5). These initial ligand evaluations
had been performed at 55 °C for 16 h. Simply reducing the
temperature to 40 °C and running the reaction for 24 h allowed the
product to be isolated with an improved 80% ee and only a slightly
reduced yield (entry 6).
We next transferred our optimized conditions to aryl aldehyde
9, with the expectation that the reduced mobility of the substrate
would have a beneficial effect on the enantioselectivity of the
process. Pleasingly, this proved to be the case, with the reaction
between aldehyde 9 and allene 2 delivering the enone product in
92% ee (Table 2, entry 1). Variation of the alkyl-substituent of the
allene, from pentyl to hexyl, butyl, and ethyl, had minimal impact
on the efficiency or enantioselectivity of the process (entries 2-4).
However, the smaller methyl-substituted allene delivered only a
moderately selective reaction (entry 5). Reaction with the benzyl-
phenyl-substituted allene was again highly selective (entry 6). We
To assess the potential of the proposed asymmetric transformation
we studied the combination of ꢀ-MeS-propanal (1) and racemic
phenyl-pentyl-substituted allene 2, leading to enone 3 (Table 1).12
† University of Oxford.
‡ University of Bath.
§ AstraZeneca.
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17232 J. AM. CHEM. SOC. 2008, 130, 17232–17233
10.1021/ja8069133 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Allene Hydroacylation: Allene Scopea
In summary, by employing 1,3-disubstituted allenes and ꢀ-S-
aldehydes, we have developed the first efficient and highly
enantioselective intermolecular carbon-carbon double-bond hy-
droacylation process. Preliminary experiments suggest a dynamic
kinetic asymmetric transformation is in operation; a detailed
mechanistic study is underway.
entry
R1
R2
R3
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Pent
Hex
But
Et
Me
Bn
Hex
Et
Hex
Et
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ph
81
88
83
76
93
77
95
94
79
89
56
64
25
92
94
93d
91
60
93
94
90
96
96
90
89
94
Acknowledgment. This work was supported by the EPSRC and
AstraZeneca.
Supporting Information Available: Experimental procedures and
full characterization for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
4-F3C-C6H4
4-F3C-C6H4
3,5-F3C-C6H4
3,5-F3C-C6H4
4-Me-C6H4
4-Me-C6H4
Ph
9
References
10
11
12
13
Hex
Et
Hex
(1) Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Tetrahedron Lett. 1972, 1287.
(2) Selected examples: (a) Fairlie, D. P.; Bosnich, B. Organometallics 1988,
7, 936. (b) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 946. (c)
Gable, K. P.; Benz, G. A. Tetrahedron Lett. 1991, 32, 3473. (d) Sattelkau,
T.; Eilbracht, P. Tetrahedron Lett. 1998, 39, 9647. (e) Morgan, J. P.; Kundu,
K.; Doyle, M. P. Chem. Commun. 2005, 3307.
(3) Selected examples: (a) James, B. R.; Young, C. G. J. Chem. Soc., Chem.
Commun. 1983, 1215. (b) Bosnich, B. Acc. Chem. Res. 1998, 31, 667, and
references therein. (c) Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.;
Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.;
Suemune, H. J. Org. Chem. 2000, 65, 5806, and references therein. (d)
Kundu, K.; McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem. Soc. 2005,
127, 16042.
(4) Examples: (a) Schwartz, J.; Cannon, J. B. J. Am. Chem. Soc. 1974, 96,
4721. (b) Vora, K. P.; Lochow, C. F.; Miller, R. G. J. Organomet. Chem.
1980, 192, 257. (c) Marder, T. B.; Roe, D. C.; Milstein, D. Organometallics
1988, 7, 1451. (d) Kondo, T.; Tsuji, Y.; Watanabe, Y. Tetrahedron Lett.
1987, 28, 6229. (e) Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem.
Soc. 1998, 120, 6965. (f) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am.
Chem. Soc. 2007, 129, 2082. (g) Shibahara, F.; Bower, J. F.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 14120. (h) Omura, S.; Fukuyama, T.;
Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094.
(5) (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640. (b) Jun, C.-H.; Lee,
D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem., Int. Ed. 2000, 39, 3070. (c)
Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (d)
Imai, M.; Tanaka, M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.;
Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. J. Org. Chem.
2004, 69, 1144. (e) Tanaka, T.; Tanaka, M.; Suemune, H. Tetrahedron
Lett. 2005, 46, 6053. (f) Tanaka, K.; Shibata, Y.; Suda, T.; Hagiwara, Y.;
Hirano, M. Org. Lett. 2007, 9, 1215.
a Conditions: aldehyde (1.0 equiv), allene (2.0 equiv), [Rh(R,R)-
Me-DuPhos)]ClO4 (10 mol.%), acetone, 45 °C, 24 h. Catalyst generated
in situ from [Rh(R,R)-Me-DuPhos)(nbd)]ClO4 and H2. b Isolated yields.
c Determined by chiral HPLC. d Absolute configuration determined from
X-ray structure. See the Supporting Information for further details. All
other configurations assigned by analogy.
Scheme 1. Enantioselective Hydroacylation: Nonracemic Allene
also explored variation of the electronics of the aromatic allene
substituent; both electron-withdrawing (4-CF3, 3,5-di-CF3) and
electron-donating (4-Me) groups could be introduced with minimal
effect on the enantioselectivity of the processes, although the
more electron-rich allene was less reactive (entries 7-12). The final
example in Table 2 demonstrates the transformation remains highly
enantioselective when an achiral allene is employed, with the
indicated trisubstituted allene delivering the expected enone with
94% ee (entry 13). Unfortunately, trisubstituted allenes displayed
significantly reduced reactivity, so although good enantioselectivity
could be maintained, the yields were low (25% for this example).13
To begin to explore the nature of the observed asymmetric
processes, we repeated an example from Table 2 (entry 4) but
employed a single equivalent of racemic allene; after 48 h, the
adduct was obtained in 77% yield, with 88% ee. We also reacted
aldehyde 9 with enantiomerically enriched allene 2 using both
enantiomers of the catalyst (Scheme 1). Catalyst control was
observed in both reactions, with the two enantiomers of catalyst
delivering enantiomeric products. Importantly, allenes recovered
from both reactions had significantly reduced ee’s, with the (R,R)-
catalyst returning allene with -31% ee, and the (S,S)-catalyst
delivering allene with 33% ee.14,15 These reactions establish that
the process is not a simple kinetic resolution of the allene; a dynamic
kinetic asymmetric transformation, involving racemization of the
allene during the reaction, is a more likely explanation.
(6) For methods that do allow the use of substituted alkenes, see: refs 4d,f,g,h
and 5d,e,f.
(7) Stemmler, R. T.; Bolm, C. AdV. Synth. Catal. 2007, 349, 1185.
(8) (a) Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, 2004. (b) Ma, S. Chem. ReV. 2005, 105, 2829.
(9) Selected recent examples: (a) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2007, 129, 14148. (b) Burks, H. E.; Liu, S.; Morken,
J. P. J. Am. Chem. Soc. 2007, 129, 8766. (c) LaLonde, R. L.; Sherry, B. D.;
Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (d) Trost,
B. M.; Simas, A. B. C.; Plietker, B.; Ja¨kel, C.; Xie, J. Chem.sEur. J. 2005,
11, 7075.
(10) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1999, 72, 303.
(11) (a) Willis, M. C.; McNally, J. S.; Beswick, P. J. Angew. Chem., Int. Ed.
2004, 43, 340. (b) Willis, M. C.; Randell-Sly, H. E.; Woodward, R. L.;
Currie, G. S. Org. Lett. 2005, 7, 2249. (c) Willis, M. C.; Randell-Sly, H. E.;
Woodward, R. L.; McNally, S. J.; Currie, G. S. J. Org. Chem. 2006, 71,
5291. (d) Moxham, G. L.; Randell-Sly, H. E.; Brayshaw, S. K.; Woodward,
R. L.; Weller, A. S.; Willis, M. C. Angew. Chem., Int. Ed. 2006, 45, 7618
For an intramolecular example, see: (e) Bendorf, H. D.; Colella, C. M.;
Dixon, E. C.; Marchetti, M.; Matukonis, A. N.; Musselman, J. D.; Tiley,
T. A. Tetrahedron Lett. 2002, 43, 7031.
(12) Single regio- and geometrical isomers were observed in all cases.
(13) Trialkyl-substituted allenes delivered no hydroacylation products when
combined with aldehyde 9.
(14) Both reactions illustrated in Scheme 1 were performed for 24 h. However,
there was an observable difference in the rates of the two processes, with
the (S,S)-catalyst delivering slower reactions. Comparative times to achieve
60% conversion: (R,R)-catalyst 11 h; (S,S)-catalyst 17 h.
(15) We have established that there is no product racemization under the standard
reaction conditions.
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J. AM. CHEM. SOC. VOL. 130, NO. 51, 2008 17233