COMMUNICATION
hydroacylation reactions have been described, as both kinet-
ic resolutions and desymmetrisations,[13] there are no exam-
ples of the corresponding intermolecular reactions. Herein,
we describe an effective alkyne-based kinetic resolution and
demonstrate that both a- and b-substituted S-chelating alde-
hydes can be converted to the corresponding enones with
high levels of selectivity.
Our initial investigation focused on the combination of 3-
(ethylthio)butanal (7a) and phenylacetylene to obtain the
unsaturated ketone 8a (Table 1). Reactions were performed
QuinoxP*[16] gave good reactivity, but diminished selectivi-
ties relative to Me-Duphos (Table 1, entries 5 and 6). By
using a preformed catalyst incorporating Me-Duphos, and
performing the reaction at 08C, the product was isolated in
40% yield with 85:15 e.r. (Table 1, entry 7). Finally, the use
of the diphosphine Duanphos, recently used in ketone and
ketoxime hydroacylation,[17,18] delivered material with 86:14
e.r. in 45% yield (Table 1, entry 8). Both Me-Duphos and
Duanphos were then evaluated against the b-phenyl-substi-
tuted aldehyde 7b in combination with phenylacetylene;
Me-Duphos was found to generate the most effective cata-
lyst for the aryl-substituted aldehyde, delivering the ketone
product (8b) in 47% yield with an e.r. of 94:6 (Table 1, en-
tries 9 and 10). The two most successful reactions in this
series, employing Duanphos for the Me-substituted aldehyde
(Table 1, entry 8), and Me-Duphos for the aryl aldehyde
(Table 1, entry 9), were used to calculate representative se-
lectivity factors for the process; s=13 and 45, for the respec-
tive reactions.[19]
Table 1. Hydroacylation between rac-b-substituted aldehydes 7a, 7b and
phenylacetylene.[a]
Next we explored the generality of the reaction against a
variety of b-substituted thioaldehydes 7b–f and acetylenes
(Table 2). The substituted aldehydes were easily prepared
by a Et3N-catalysed 1,4-addition of ethane thiol to the ap-
propriate enal. All reactions were performed at 08C by
using acetone as solvent. Both the ethyl- and pentyl-substi-
tuted aldehydes were combined with phenylacetylene em-
ploying a Duanphos catalyst and performed similarly to the
parent methyl aldehyde (91:9 and 88:12 e.r., respectively;
Table 2, entries 2 and 3). For the remaining entries, which all
feature aryl-substituted aldehydes, Me-Duphos catalysts
were used. The results in Table 2, entries 4 and 5 demon-
strate that a second aryl-substituted aldehyde, as well as a
heteroaryl derivative, can be combined with phenylacetylene
with good yields and selectivities. The next five entries illus-
trate that variation in the acetylene is also possible, with n-
alkyl, tert-alkyl, cycloalkyl- and silyl-substituted examples all
delivering the expected ketone products with high selectivi-
ties.
Having established an effective protocol for the kinetic
resolution of b-substituted aldehydes, we turned our atten-
tion to the corresponding a-substituted substrates (Table 3).
Reaction of the a-phenyl-substituted aldehyde (9a) with
phenylacetylene was achieved by using a Me-Duphos-con-
taining catalyst and delivered the enone product in 39%
yield with an e.r. of 94:6 (Table 3, entry 1). The calculated
selectivity factor for this reaction is s=34.[19] Pleasingly, this
level of selectivity demonstrated that the same catalyst
system was effective for both the a- and b-substituted alde-
hydes. The remaining examples in Table 3 illustrate that var-
iation of both the aldehyde and acetylene substituents is
possible, while still maintaining high yields and selectivities.
The exception is the tert-butyl-substituted aldehyde (9c),
which although delivering the enone product in reasonable
yield (43%), resulted in a reduced e.r. of 84:16 (Table 3,
entry 3). As with the b-substituted aldehydes, all reactions
with the a-substituted aldehyde substrates were performed
at 08C.
Entry
R1
Ligand
Solvent[b]
Yield [%][c]
e.r.[d]
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me-Duphos
Et-Duphos
iPr-Duphos
Me-BPE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
acetone
DCE
acetone
45
39
0
82:18
75:25
–
–
69:31
79:21
85:15
86:14 (s=13)
94:6 (s=45)
86:14
0
Tangphos
36
47
40
45
47
45
QuinoxP*
Me-Duphos
Duanphos
Me-Duphos
Duanphos
7[e]
8[e,f]
9[e,f]
10[e]
Ph
[a] Conditions: aldehyde (2.0 equiv), alkyne (1 equiv), [RhACTHUNGTRENNUG(nbd)2]ACHTUNTGERN[NUNG BF4]
(5 mol%), ligand (5 mol%), solvent, RT, 12 h. Catalysts activated by H2.
[b] DCE=dichloroethane. [c] Isolated yields. [d] The enantiomeric ratio
(e.r.) was determined by chiral HPLC. [e] Preformed catalyst (5 mol%)
was used and the reaction was performed at 08C. [f] Selectivity factors
(s) were calculated by using conversions and e.r. values of the ketone
products.
in DCE at room temperature and employed 5 mol% of a
chiral Rh-catalyst, generated in situ from the combination
of a diphosphine ligand and [RhACHTNUTRGENNUG(nbd)2]ACHTUNTGREN[NUGN BF4] (nbd=norbor-
nadiene) followed by hydrogenation. Several chiral biden-
tate phosphine ligands were employed, commencing with
Me-Duphos, which was the optimal ligand in our enantiose-
lective allene hydroacylation chemistry. When using Me-
Duphos, ketone 8a was obtained with a promising 82:18 e.r.
and in a good yield (Table 1, entry 1).[14] Alternative Duphos
ligands gave lower selectivity and/or reactivity (Table 1, en-
tries 2 and 3); for example, with the bulky iPr-Duphos only
starting material was recovered. The related, ethylene-
bridged diphosphine, Me-BPE, was also investigated, but
gave no reaction (Table 1, entry 4). Both Tangphos[15] and
Chem. Eur. J. 2010, 16, 10950 – 10954
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10951