Journal of the American Chemical Society
Article
a
As for β-aryl N,N-Me2-α,β-unsaturated amides, both
electron-donating groups (3baa−3caa) and electron-with-
drawing groups (3daa−3gaa) were well acceptable at the
para position of the aryl substituent (83−99%, 98−99% ee). It
was noted that α,β-unsaturated amide containing a para-
methoxyl-phenyl group (1ca) led to slightly lower yield (3caa,
83%). Aryls containing either an ortho-substituent or a meta-
substituent did not affect both the yield and the enantiose-
lectivity (3haa−3iaa, 94−95%, 98% → 99% ee). 2-Naphathyl
was also well tolerated at the β-position of α,β-unsaturated
amide (3jaa, 97%, 99% ee). Moreover, substrates with a β-
heteroaryl, such as 2-furanyl, 2-thienyl, and 2-benzofuranyl,
generated the corresponding products in uncompromising
yield and enantioselectivity (3kaa−3maa, 86−98%, 96−97%
ee).
The β-substituent was further extended from an aryl group
to an alkyl group. Various alkyls, including methyl, linear alkyls,
α-branched alkyl, β-branched alkyl, γ-branched alkyl, and
cycloalkyls, were well acceptable at the β-position without any
detrimental effect on both the yield and the enantioselectivity
(3naa−3vaa, 72−97%, 87−98% ee). The conjugate hydro-
phosphination of a α,β,γ,δ-unsaturated amide underwent 1,4-
addition smoothly without generation of a 1,6-addition
product (3waa, 97%, 91% ee). Then, several functional groups,
such as alkyl chloride, ester, diphenyl phosphine oxide, ether,
and silyl ether, were installed into the β-alkyl group of the
substrates (1a′a−1h′a) to test the compatibility of this
methodology. Satisfyingly, these functional groups did not
disturb both the yield and the enantioselectivity significantly
(3a′aa−3h′aa, 82−99%, 84−95% ee). Furthermore, both the
yield and the enantioselectivity were not sensitive to the length
of the alkyl chain (3a′aa, 3g′aa, and 3h′aa). The absolute
configuration of 3aea was determined to be R by its
transformation to a known compound (for details, see the
Supporting Information). The absolute configurations of other
products (3) were assigned tentatively by analogy as shown in
Table 2.
Then, the nucleophile in the present 1,4-conjugate hydro-
phosphination was extended from symmetric diphenylphos-
phine (2a) to unsymmetrical diarylphosphines (2b, 2c), which
may result in a catalytic asymmetric dynamic kinetic resolution
reaction21 as shown in Table 3. With (R,R)-Ph-BPE as the
ligand, the addition of mesitylphenylphosphine (2b) to N,N-
dimethyl-acrylamide (4a) occurred smoothly at −20 °C,
providing the product 5ab in 98% yield with 98% ee. The
dynamic kinetic resolution of 2,3,5,6-tetramethylphenylphe-
nylphosphine (2c) also proceeded in excellent results at −20
°C (5ac, 93%, 94% ee). The absolute configuration of 5ac was
assigned analogically by the exact structure of 5ab, which was
determined unambiguously through X-ray diffraction of its
single crystals. Subsequently, in the kinetic dynamic resolution
of 2b with β-substituted α,β-unsaturated amides, (R,R)-BDPP
was identified as the best ligand. Seven examples were
presented in Table 3 with the corresponding products obtained
at 10 °C in moderate isolated yields with moderate
diastereoselectivity but excellent enantioselectivity (3nab,
3oab−3pab, 3e′ab−3f′ab, and 3h′ab, 72−84%, 5/1 dr to
16/1 dr, 92−96% ee). The absolute configuration of 3nab was
determined by X-ray analysis, and the stereochemistry in the
other five products was assigned by analogy.
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
(R)-BINAP
(R)-SEGPHOS
(R,R)-Ph-BPE
(R,R)-BDPP
(R,R)-QUINOXP*
(R)-(S)-JOSIPHOS
(R,R)-WALPHOS
(R,RP)-TANIAPHOS
(R,RP)-TANIAPHOS
(R,RP)-TANIAPHOS
(R,RP)-TANIAPHOS
(R,RP)-TANIAPHOS
base
yield (%)
ee (%)
1
2
3
4
5
6
7
Barton’s Base
Barton’s Base
Barton’s Base
Barton’s Base
Barton’s Base
Barton’s Base
Barton’s Base
Barton’s Base
DBU
50
86
70
84
70
86
58
98
88
86
0
−4
−34
3
5
65
37
−17
96
96
96
d
8
9
10
11
TMG
iPr2NEt
e
12
Barton’s Base
32
75
a
b
1ab: 0.1 mmol, 2a: 0.15 mmol. Determined by 1H NMR analysis of
reaction crude mixture using CH2Br2 as an internal standard.
c
d
Determined by chiral-stationary-phase HPLC analysis. 1ab: 0.2
e
mmol, 2a: 0.3 mmol. 48 h. Isolated yield. 0 °C. TMG =
tetramethylguanidine.
effective, indicating the relatively higher pKa of the proton in
HPPh2 (entry 11). Moreover, it was found that this reaction
was very sensitive to reaction temperature as significantly
extenuated yield was observed at 0 °C, suggesting the weak
electrophilicity of α,β-unsaturated amide 1ab (entry 12).
Under the optimized reaction conditions (entry 8), both
HPPhiPr and HPiPr2 were tried. However, only trace product
was observed in the case of HPPhiPr, and no reaction occurred
in the case of HPiPr2.
2. Investigation of the Substrate Scope. By using the
reaction conditions described in entry 8 in Table 1, the
substrate scope of α,β-unsaturated amides was studied (Table
2). Several α,β-unsaturated amides prepared from different
secondary amines were competent substrates, which generated
corresponding products uniformly in high yields with excellent
enantioselectivity (3aaa−3aga, 84−98%, 94−98% ee). Defi-
nitely, the Weinreb amide (3aea) would allow easy further
structure elaboration. Interestingly, the reaction of substrates
derived from primary amines, which contain an acidic N-H
moiety, proceeded in decreased yields but with excellent
enantioselectivity (3aha−3aia, 68−80%, 94−95% ee). Nota-
bly, the α,β-unsaturated amide of ammonia bearing two N-H
units also served as a suitable substrate (3aja, 79%, 92% ee).
The robustness of the present catalytic asymmetric hydro-
phosphination was demonstrated by a 1.0 mmol scale reaction
of 2aj, which furnished 269 mg of 3aja in 78% yield with 91%
ee. These two types of amide containing an N-H moiety would
be easily further derivatized to afford diversified amides.
3. Insights into the Reaction Mechanism and
1
Proposed Reaction Pathway. H NMR experiments were
employed to explore the reactive species in the present
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX