Highly efficient asymmetric conjugate hydrocyanation of aromatic enones by an anionic chiral phosphate catalyst

Article abstract of DOI:10.1002/ejoc.201300406

Chiral keto nitriles (β-cyano ketones) have been prepared by a facile and efficient asymmetric conjugate hydrocyanation of poorly active chalcone-type enones with benzophenone cyanohydrin. Using in situ generated 5-10 mol-% of sodium (S)-6,6′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diyl phosphate as catalyst and 5-10 mol-% of 2-tert-butylphenol as an additive, high yields and excellent enantioselectivities were obtained within 2 h in toluene at 80 °C. The development of catalysts, optimization of the reaction parameters, and substrate scope are reported. On the basis of the experimental results, HCN is shown to be the real cyanide source and a mechanism is proposed to explain the origin of the enantioselectivity with the chiral-anion-modified nucleophile HCN. The asymmetric conjugate hydrocyanation of poorly reactive chalcone-type enones with benzophenone cyanohydrin using an anionic chiral phosphate catalyst has been achieved in high yields (72-96 %) and excellent enantioselectivities (92-98 % ee). It is proposed that the chiral anion modifies HCN, the real nucleophile, in the transition state through hydrogen bonding. Copyright

Full text of DOI:10.1002/ejoc.201300406

FULL PAPER
DOI: 10.1002/ejoc.201300406
Highly Efficient Asymmetric Conjugate Hydrocyanation of Aromatic Enones
by an Anionic Chiral Phosphate Catalyst
Yao-Feng Wang,[a] Wei Zeng,[a] Muhammad Sohail,[a] Jiyi Guo,[a] Shaoxiang Wu,[a] and
Fu-Xue Chen*[a]
Keywords: Asymmetric catalysis / Chirality / Hydrocyanation / Enones / Nitriles
Chiral keto nitriles (β-cyano ketones) have been prepared by
a facile and efficient asymmetric conjugate hydrocyanation
of poorly active chalcone-type enones with benzophenone
cyanohydrin. Using in situ generated 5–10 mol-% of sodium
(S)-6,6Ј-di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diyl phosphate
as catalyst and 5–10 mol-% of 2-tert-butylphenol as an addi-
tive, high yields and excellent enantioselectivities were ob-
tained within 2 h in toluene at 80 °C. The development of
catalysts, optimization of the reaction parameters, and sub-
strate scope are reported. On the basis of the experimental
results, HCN is shown to be the real cyanide source and a
mechanism is proposed to explain the origin of the enantio-
selectivity with the chiral-anion-modified nucleophile HCN.
Introduction
Nitrile is an important building block for both natural
products[1a] and pharmaceuticals[1b] as well as a versatile
functionality undergoing diverse transformations in organic
synthesis.[1c–1e] The enantioselective introduction of cyanide
into various substrates has been at the forefront of research
for a long time.[2a] The asymmetric nucleophilic addition
of cyanide to carbonyls and carbonyl derivatives has been
established and comprehensively reviewed.[2b–2f] However,
the synthesis of secondary or tertiary nitriles (2) by the
asymmetric addition of cyanide to a C=C double bond (1)
is less well explored (Scheme 1)[3a,3b] and only a few studies
have been reported involving α,β-unsaturated imides and
alkylidene malonates.[4a–4c,5]
Scheme 1. Strategies used for the asymmetric 1,4-hydrocyanation
of enones.
Shibasaki and co-workers demonstrated a highly enan-
tioselective 1,4-hydrocyanation of α,β-unsaturated N-acyl-
pyrroles[6a] and enones[6b,6c] with tert-butyldimethylsilyl cy-
anide (TBSCN) in the presence of 2,6-dimethylphenol and
bifunctional gadolinium and SrII complexes of d-glucose-
derived chiral ligands (Scheme 1). They observed an inter-
esting asymmetric rearrangement of 1,2-adduct cyano-
hydrins into 1,4-adduct β-cyano ketones.[6b,6c] Subsequently,
the challenging 1,4-addition of cyanide to enones received
increasing interest from chemists working in the field of
asymmetric catalysis. Ohkuma and co-workers described
the chiral RuII-catalyzed asymmetric hydrocyanation of α,β-
unsaturated ketones with trimethylsilyl cyanide (TMSCN)
and MeOH (Scheme 1).[7] In addition to metal-containing
catalysts, organocatalysts[8] have also found roles in asym-
metric conjugate cyanide addition.[9] Deng and co-workers
disclosed the enantioselective 1,4-addition of cyanide with
acetone cyanohydrin (4; see Table 1 for structure) to enones
catalyzed by a cinchona-derived phase-transfer catalyst
(PTC).[10a] Most recently, by using a similar methodology,
Shibata and co-workers demonstrated the first enantioselec-
tive synthesis of tertiary nitriles through conjugate hydrocy-
anation of enones featuring the β-trifluoromethyl group.[10b]
However, the examples involve the use of noble metals, re-
quire high catalyst loading, or long reaction times. Pre-
viously, only moderate enantioselectivity (up to 72% ee)
was achieved in the asymmetric conjugate addition of
TMSCN to poorly reactive chalcone analogues.[11] Herein,
we report the highly efficient asymmetric conjugate hydro-
[a] Department of Applied Chemistry, School of Chemical
Engineering & the Environment, Beijing Institute of
Technology,
5
South Zhongguancun Street, Haidian District, Beijing
100081, China
Fax: +86-10-68918296
E-mail: fuxue.chen@bit.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300406.
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Asymmetric Conjugate Hydrocyanation of Aromatic Enones
cyanation of aromatic enones with benzophenone cyano-
hydrin catalyzed by an anionic chiral phosphate catalyst.
Subsequently, the effect of substituents at the 3,3Ј- and
6,6Ј-positions of the catalyst on the enantioselectivity and
catalytic activity was investigated. All the 3,3Ј-disubstituted
catalysts (7a–c) showed poor chiral inductivity (Table 2, en-
tries 1–3). In contrast, the 6,6Ј-disubstituted catalysts (7d,e)
led to excellent enantioselectivities of 93–95% ee. Moreover,
the adamantyl catalyst 7d exhibited greater activity than the
corresponding aryl catalyst 7e (entry 4 vs. 5). The result
with 7f, bearing substituents at both the 3,3Ј- and 6,6Ј-posi-
tions (entry 6), demonstrated that substitution at the 3,3Ј-
positions does not benefit catalyst efficiency in this reac-
tion.
Results and Discussion
Our work commenced with a preliminary survey of the
reaction conditions using chalcone (1a) as the model sub-
strate in the presence of the sodium salt of (S)-6,6Ј-di(1-
adamantyl)-BINOL-derived phosphate (7d), which was pre-
pared in situ by mixing equimolar amounts of 7d with so-
dium amide in toluene for 1 h. As shown in Table 1, a series
of other cyanide sources were screened. In general, chalcone
cyanohydrin (5; 76% ee) and benzophenone cyanohydrin
Table 2. Effect of catalyst structure on the asymmetric conjugate
(6; 86% ee) were found to be superior to silyl cyanide rea- hydrocyanation of chalcone (1a).[a]
gents (52–67% ee) in this reaction (entries 2 and 3 vs. 1 and
4), whereas 3 and 4 gave no conversion (entries 5 and 6). Of
the cyanide reagents, 6 exhibited the best enantioselectivity
(86% ee) and highest yield (72%, entry 3). Furthermore,
with in situ generated HCN, 2a was isolated in a compar-
able 85% ee (entry 7). Modifying the operation by adding
6 at 80 °C instead of at room temperature dramatically in-
creased the catalyst efficiency, giving 95% ee and 94% yield
(entry 8).
Table 1. Effect of different cyanide sources on the asymmetric con-
jugate hydrocyanation of chalcone (1a).[a]
Entry
Acid
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
(R)-7a
7b
72
85
30
94
55
64
–11
14
8
95
93
11
7c
7d
7e
7f
[a] Reaction conditions: After stirring the mixture of chiral acid
(0.02 mmol. 20 mol-%) and NaNH2 (0.02 mmol. 20 mol-%) in tolu-
ene (0.6 mL) at room temp. for 1 h, 1a (20.8 mg, 0.1 mmol), 2-tBu-
PhOH (0.02 mmol. 20 mol-%), and toluene (0.5 mL) were added at
room temperature followed by benzophenone cyanohydrin
(0.2 mmol, 2.0 equiv.) at 80 °C and stirring for 2 h at 80 °C under
argon. [b] Isolated yield. [c] Determined by HPLC analysis on Chi-
ralpak AS-H.
Entry
Cyanide
Yield [%][b]
ee [%][c]
1
2
3
4
TMSCN
95
22
72
67
76
86
52
–
–
85
95
To optimize the reaction conditions, different solvents
were screened. It was found that toluene is the best choice
in terms of catalytic activity and enantioselectivity (Table 3,
entry 1). A poor yield and ee were obtained in polar
CH3CN (entry 2), dioxane and THF gave traces of products
as a racemic mixture (entries 3 and 4), and no conversion
was observed with CH2Cl2 as the solvent (entry 5).
(Ϯ)-5
6
TBSCN
60
5
3
4
n.r.
n.r.
60
6
7[d]
8[e]
HCN
6
94
[a] Reaction conditions: After stirring the mixture of 7d
(0.02 mmol, 20 mol-%) and NaNH2 (0.02 mmol, 20 mol-%) in tolu-
ene (0.6 mL) at room temp. for 1 h, 1a (20.8 mg, 0.1 mmol), 2-tBu-
PhOH (0.02 mmol, 20 mol-%), and toluene (0.5 mL) were added at
room temperature followed by cyanide reagent (0.2 mmol,
2.0 equiv.) at room temp. and stirring for 2 h at 80 °C under argon.
[b] Isolated yield. [c] Determined by chiral HPLC analysis on Chi-
ralpak AS-H. [d] The HCN solution was generated from equimolar
amounts of TMSCN and MeOH. [e] Benzophenone cyanohydrin
(6) was added at 80 °C.
The cation and precursor have significant effects on cata-
lyst efficiency. Thus, a series of metal salts of 7d were exam-
ined. The sodium salt of 7d gave only moderate enantio-
selectivity with an equimolar amount of 7d and NaOH
(Table 4, entry 1), whereas with NaH or NaNH2 the
enantioselectivity was increased to 94 and 95% ee, respec-
tively (entries 2 and 3). This implies that trace amounts of
water generated in situ would be disadvantageous to the
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Y.-F. Wang, W. Zeng, M. Sohail, J. Guo, S. Wu, F.-X. Chen
FULL PAPER
Table 3. Effect of solvent on the asymmetric conjugate hydrocyan-
Table 4. Effect of cation on the asymmetric conjugate hydrocyan-
ation of chalcone (1a).[a]
ation of chalcone (1a).[a]
Entry
Solvent
Yield [%][b]
ee [%][c]
Entry
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
toluene
CH3CN
dioxane
THF
94
59.5
8.5
4.3
n.r.
95
2.1
0
0
–
1
2
3
4
5
6
7
NaOH
NaH
NaNH2
KOH
85
72
94
51
89
68
63
13
17
72
94
95
72
32
27
–6
22
51
CH2Cl2
tBuLi
Cs2CO3
Sr(OiPr)2
NaNH2
NaNH2
[a] Reaction conditions: After stirring the mixture of 7d
(0.02 mmol, 20 mol-%) and NaNH2 (0.02 mmol, 20 mol-%) in sol-
vent (0.6 mL) at room temp. for 1 h, 1a (20.8 mg, 0.1 mmol), 2-
tBuPhOH (0.02 mmol, 20 mol-%), and solvent (0.5 mL) were
added at room temperature followed by benzophenone cyano-
hydrin (0.2 mmol, 2.0 equiv.) at 80 °C followed by stirring for 2 h
at 80 °C under argon. [b] Isolated yield; n.r.: no reaction. [c] Deter-
mined by HPLC analysis on Chiralpak AS-H.
8[d,e]
9[d,f]
[a] Reaction conditions: After stirring the mixture of 7d
(0.02 mmol, 20 mol-%) and base (0.02 mmol, 20 mol-%) in toluene
(0.6 mL) at room temp. for 1 h, 1a (0.1 mmol), 2-tBuPhOH
(0.02 mmol, 20 mol-%), and toluene (0.5 mL) were added at room
temperature followed by benzophenone cyanohydrin (0.2 mmol,
2.0 equiv.) at 80 °C and stirring for 2 h at 80 °C under argon. [b]
Isolated yield. [c] Determined by chiral HPLC analysis on Chi-
ralpak AS-H. [d] 5 mol-% catalyst loading. [e] 15-Crown-5 (5 mol-
%) was added. [f] Poly(ethylene glycol dimethyl ether) (MW. 250,
5 mol-%) was added.
enantioselectivity. Accordingly, KOH gave a similar ee to
NaOH, but a lower yield (entry 4). In addition, catalyst
generated from NaNH2 showed higher activity than NaH
(entry 3 vs. 2). Other alkali-metal ions such as Li+ and Cs+
afforded poorer results (entries 5 and 6). Note, the major
product had the opposite absolute configuration when alka-
line-earth-metal ion Sr2+ was used (entry 7). Moreover, the
yield and ee of the product decreased markedly to 13 and
22%, respectively, in the presence of 15-crown-5, which can
specifically and efficiently trap the sodium ion (entry 8),
whereas a 17% yield and 51% ee were obtained in the pres-
ence of poly(ethylene glycol dimethyl ether) (DM-PEG,
MW. 250), which can coordinate Na+ (entry 9).
Table 5. Effect of additives on the asymmetric conjugate hydro-
cyanation of chalcone (1a).[a]
Entry Additive
Yield [%][b]
ee [%][c]
Moreover, phenolic additives were found to be vital for
good conversion, that is, no reaction occurred in the ab-
sence of a protonic additive. Phenol and electron-rich phen-
ols had similar effects on enantioselectivity (Table 5, en-
tries 1–4) although bulky substituents reduced the yield (en-
tries 2–4). Electron-deficient substituents caused a marked
decrease in both the yield and ee (entry 5), and carboxylic
acid and alcohol inhibited the conversion completely (en-
tries 6 and 7). Thus, an appropriate acidic strength is im-
portant for optimal catalyst efficiency. The chiral phenolic
additives (R)- and (S)-BINOL were also used in this reac-
tion (entries 8 and 9); although the configuration of the ad-
ditives was reversed, the products had almost the same
enantioselectivity. This implies that the additive is not in-
volved in the stereochemistry-determining transition state.
We also investigated the effect of catalyst loading, con-
centration, and temperature on catalyst efficiency. When the
1
2
3
4
5
6
7
8
9
2-tBuC6H4OH
PhOH
2,6-iPr2C6H3OH
2-Ad-4-BuC6H3OH
4-O2NC6H4OH
PhCO2H
iPrOH
(R)-BINOL
(S)-BINOL
94
72
47
8
17
n.r.
n.r.
47
43
95
96
91
90
78
–
–
94
93
[a] Reaction conditions: After stirring the mixture of 7d
(0.02 mmol, 20 mol-%) and NaNH2 (0.02 mmol, 20 mol-%) in tolu-
ene (0.6 mL) at room temp. for 1 h, 1a (20.8 mg. 0.1 mmol), addi-
tive (0.02 mmol, 20 mol-%), and toluene (0.5 mL) were added at
room temperature followed by benzophenone cyanohydrin
(0.2 mmol, 2.0 equiv.) at 80 °C and stirring for 2 h at 80 °C under
argon. Ad = 1-adamantyl. BINOL = 1,1Ј-binaphthalene-2,2Ј-diol.
[b] Isolated yield; n.r.: no reaction. [c] Determined by chiral HPLC
analysis on Chiralpak AS-H.
catalyst loading was reduced to 5 mol-% at the same con- sult was achieved with 5 mol-% catalyst loading (entry 3 vs.
centration of 1a, 2a was generated in moderate yield and a 1). No further increase in enantioselectivity was observed
slightly reduced enantioselectivity (Table 6, entry 2 vs. 1). above 0.17 m chalcone. A decrease in the reaction tempera-
However, at a higher concentration of 1a, a comparable re- ture led to lower yields (entries 5 and 6) and poor results
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Asymmetric Conjugate Hydrocyanation of Aromatic Enones
were also obtained when the temperature was increased (en- Table 7. Asymmetric conjugate hydrocyanation of enones 1a–s.[a]
tries 7 and 8). Therefore the optimal reaction conditions are
as follows: 5 mol-% of the sodium salt of 7d as catalyst,
5 mol-% of 2-tBuPhOH as the additive, and stirring for 2 h
at 80 °C in toluene.
Table 6. Further optimization of the reaction conditions.
Entry Product R1
R2
Yield
[%][b]
ee [%][c]
1
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
91
91
95
93
93
96
94
93
94
72
90
90
91
95
93
93
96
93
91
91
95(R)
94(S)
2[d]
3
96(R)
96(R)
94(R)
95(R)
97(R)
94(R)
97(R)
96(R)
92(R)
98(R)[f]
93(R)
96(R)
93(R)[g]
95(R)
92(R)
94(R)
94(R)
95(R) [f]
4
5
6
Entry[a]
T [°C]
Conc. [m][b]
Yield [%][c]
ee [%][d]
4-MeOC6H4 3-BrC6H4
Ph
Ph
4-MeC6H4
7[e]
8[e]
9[e]
10[e]
11[e]
12[e]
13
14
15
16
17
18
19
20
4-MeOC6H4
4-MeC6H4
Ph
1[e]
2
3
4
5
6
7
8
80
80
80
80
60
70
90
100
0.09
0.09
0.17
0.33
0.17
0.17
0.17
0.17
94
68
91
80
64
82
68
64
95
91
95
89
94
95
57
47
2-MeOC6H4 Ph
3-MeOC6H4 Ph
4-MeOC6H4 Ph
4-FC6H4
3-FC6H4
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3 Ph
4-BrC6H4
tBu
Ph
Ph
Ph
Ph
[a] Reaction conditions: After stirring the mixture of 7d
(0.005 mmol, 5 mol-%) and base (0.005 mmol, 5 mol-%) in toluene
(0.1 mL) at room temp. for 1 h, 1a (0.1 mmol), 2-tBuPhOH
(0.005 mmol, 5 mol-%), and toluene (volume according to indi-
cated concentration) were added at room temperature followed by
benzophenone cyanohydrin (0.2 mmol, 2.0 equiv.) at 80 °C and
stirring for 2 h at 80 °C under argon. [b] Concentration of 1a. [c]
Isolated yield. [d] Determined by chiral HPLC analysis on Chi-
ralpak AS-H. [e] 20 mol-% catalyst loading.
Ph
Ph
Ph
cHex
[a] Reaction conditions: After stirring the mixture of 7d
(0.005 mmol, 5 mol-%) and base (0.005 mmol, 5 mol-%) in toluene
(0.1 mL) at room temp. for 1 h,
1 (0.1 mmol), 2-tBuPhOH
(0.005 mmol, 5 mol-%), and toluene (volume according to indi-
cated concentration) were added at room temperature followed by
benzophenone cyanohydrin (0.2 mmol, 2.0 equiv.) at 80 °C and
stirring for 2 h at 80 °C under argon. [b] Isolated yield. [c] Deter-
mined by HPLC analysis on Chiralpak AS-H unless otherwise
noted. [d] The sodium salt of (R)-7d was used. [e] 10 mol-% 2-
tBuPhOH and 10 mol-% sodium salt of 7d in toluene. [f] Deter-
mined by HPLC analysis on a Chiralcel OD-H column. [g] Deter-
mined by HPLC analysis on a Chiralpak AD-H column.
Under the optimized conditions, the substrate scope of
the anionic chiral phosphate catalyzed reaction was exam-
ined and the results are listed in Table 7. In general, all the
chalcone analogues exhibited excellent enantioselectivities
(92–98% ee) and the exclusive formation of 1,4-adducts in
yields of up to 96% (Table 7, entries 1–18). Chalcone deriv-
atives with electron-withdrawing substituents on either aro-
matic ring (1b–e, 1l–q) were smoothly converted into keto
nitriles with excellent enantioselectivities (92–97% ee, en- ether could be converted into 2a, but decomposed into
tries 3–6 and 13–18). However, an electron-donating Me or chalcone in the case of the cyanohydrin (Scheme 2, a). Con-
MeO substituent on either aromatic ring of chalcone (1f–k) sequently, both rearrangement from cyanohydrin to ni-
lowered the reactivity compared with 1a as a result of the trile[6b,6c] and competition between reversible 1,2-addition
σ/n–π conjugate effect. With 10 mol-% catalyst loading, the and thermodynamic irreversible conjugate addition[11b,11c]
corresponding products were obtained in yields of 72–94% can be ruled out. The above result (Table 1, entry 7) and
and 95–98% ee (entries 7–12). The bulky β-alkyl-substi- previous reports in the literature (Scheme 1)[6,7,10] indicate
tuted enones (1r,s) were also converted with excellent that the reaction is an asymmetric conjugate 1,4-hydrocyan-
enantioselectivities (94 and 95% ee, entries 19 and 20). The ation with HCN.
absolute configuration of 2e was determined to be R by
Furthermore, enantiopure chalcone cyanohydrin (+)-5
comparing the sign of the optical rotation with the litera- was prepared[2g] and used in the model reaction under the
ture.[11d] The absolute configurations of the other nitriles optimized reaction conditions.[13] To our surprise, 2a was
were assigned by analogy. To obtain (S)-2a, (R)-BINOL- produced in 0% ee from (+)-5 in 100% ee (Scheme 2, b).
derived phosphoric acid (R)-7d was used (entry 2).[12]
This proves that 1,4-hydrocyanation with cyanohydrin pro-
The mechanism of this efficient asymmetric synthesis of ceeds stepwise with HCN rather than by the proposed
chiral nitriles has been investigated. In the absence of chalc- Meerwein–Ponndorf–Verley-type synergetic cyanide trans-
one (1a), neither cyanohydrin 5 nor its O-trimethylsilyl fer.[2b,14]
Eur. J. Org. Chem. 2013, 4624–4633
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Y.-F. Wang, W. Zeng, M. Sohail, J. Guo, S. Wu, F.-X. Chen
FULL PAPER
Scheme 2. Control experiments.
Figure 1. Proposed mechanism for the hydrocyanation of enones with a chiral anionic catalyst.
Recently, a range of chiral anions[15] generated from acid tathesis of basic D and acid 7Ј recycles the active catalyst A
precursors such as amino acids,[16] binaphthol (BINOL),[17] together with recovered phenol in a proton shuttle.
and phosphoric acids[18] demonstrated magic chiral induc-
tion capabilities. They operated as a Lewis base, Brønsted
base, or ion-pair model.[19] The facial selectivity of the C=C
bond in the conjugate 1,4-hydrocyanation is definitely con- Conclusions
trolled by the chiral phosphate anion in the transition state.
A plausible mechanism is presented in Figure 1. Cyano- An efficient asymmetric conjugate hydrocyanation of po-
hydrin 6 first decomposes into HCN and associates with orly reactive chalcone analogues with benzophenone
the in situ generated phosphate A, the real catalyst, to form cyanohydrin has been achieved by using an (S)-BINOL-de-
the negative-charged intermediate B and BЈ. Subsequently, rived anionic chiral phosphate catalyst. In the presence of
the HCN nucleophile, modified by the chiral anion through 5–10 mol-% of the sodium phosphate 7d, the corresponding
hydrogen bonding,[8e,8f] undergoes asymmetric conjugate β-cyano ketones were obtained with excellent enantio-
addition to the enone 1 to give cyano-enolate C, which is selectivities (92–98% ee) and in up to 96% yield within 2 h.
acidified by the phenol additive to afford the hydrocyan- The chiral-anion-modified HCN nucleophile determines
ation product 2 and sodium phenolate D. The following me- the stereochemical outcome through a hydrogen-bonding
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Asymmetric Conjugate Hydrocyanation of Aromatic Enones
by silica gel chromatography using PE/EtOAc (10:1, v/v) as eluent
to yield (S)-6,6Ј-di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diol as a
white solid (1.670 g, 3.01 mmol, 60 % yield), m.p. 207–209 °C;
interaction. This protocol, using chiral anion catalysts, may
provide a new general route for asymmetric catalysis.
[α]1D7 = +108.0 (c = 0.100, CHCl3). H NMR (500 MHz, CDCl3):
1
δ = 1.79–1.85 (m, 12 H, CHCH2CH), 2.00 (s, 12 H, CCH2CH),
2.15 [s, 6 H, CH(CH2)3], 7.17 (d, J = 9.0 Hz, 2 H, ArH), 7.37–7.43
(m, 4 H, ArH), 7.80 (s, 2 H, ArH), 7.97 (d, J = 9.0 Hz, 2 H,
ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 29.0, 36.1, 36.8,
43.1, 110.7, 117.5, 123.5, 124.0, 125.7, 129.5, 131.4, 131.6, 147.0,
152.3 ppm.
Experimental Section
1
General: The H (300 MHz, 400 MHz) and 13C NMR (100 MHz)
spectra were recorded in CDCl3 with Bruker Avance 300, Bruker
Avance 400 and Varian Mercury 400 spectrometers. The 1H and
13C NMR spectra are internally referenced to tetramethylsilane (δ
= 0.0 ppm) and CDCl3 (δ = 77.0 ppm), respectively. IR spectra were
recorded with a Bruker ALPHA FTIR spectrometer. The elemental
analyses were performed with an Elementar Vario MICRO CUBE
instrument. All melting points were determined with an XT4A
melting point apparatus. Enantiomeric excesses were determined
by HPLC with a Shimadzu LC-20A apparatus with Chiralpak AS-
H, OD-H, and AD-H columns. Optical rotations were measured
with a Krüss P8000 polarimeter. High-resolution mass spectrome-
try were recorded with a Bruker Apex IV FTMS. Analytical TLC
was performed on F254 precoated silica gel plate. Column
chromatography was performed on silica gel (200–300 mesh). Pe-
troleum ether (PE) has a boiling point in the range 60–90 °C. All
reactions were performed in oven-dried glassware under a positive
pressure of argon using typical vacuum-line techniques unless
otherwise noted. Solvents were dried according to standard pro-
cedures and transferred by syringe into the reaction vessel though
a rubber septum. Enones 1a–q[20] and binaphthyls 7a–c and 7e–f
were prepared following literature procedures.[21]
(S)-6,6Ј-Di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diol (555 mg,
1 mmol) was dissolved in pyridine (3 mL) in a 50 mL Schlenk tube
and phosphorous oxychloride (185 μL, 2 mmol, 2.0 equiv.) was
added dropwise at room temperature. After stirring the resulting
solution at room temperature for 10 h, H2O (3 mL) was added and
the resulting mixture was stirred at room temperature for an ad-
ditional 6 h. CH2Cl2 was added and all the pyridine was removed
by reverse extraction with 1 m HCl. The organic phase was dried
with Na2SO4 and concentrated. The crude solid was purified by
flash silica gel chromatography with CH2Cl2/MeOH (5:1, v/v) as
eluent to yield (S)-6,6Ј-di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diyl-
phosphoric acid (7d) as a white solid (555 mg, 0.9 mmol, 90%
1
yield), m.p. Ͼ300 °C; [α]2D1 = +264.7 (c = 0.100, CHCl3). H NMR
(400 MHz, [D6]DMSO): δ = 1.75 (s, 12 H, CHCH2CH), 1.95 (s, 12
H, CCH2CH), 2.07 [s, 6 H, CH(CH2)3], 7.21–7.23 (m, 2 H, ArH),
7.41–7.42 (m, 4 H, ArH), 7.87 (s, 2 H, ArH), 8.01 (d, J = 8.8 Hz,
2 H, ArH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 28.5, 35.9,
36.4, 42.7, 121.6, 122.4, 123.4, 124.3, 126.0, 130.0, 130.3, 130.8,
147.1, 149.3 ppm. 31P NMR (162 MHz, [D6]DMSO): δ = 3.5
(s) ppm.
(R)-(3,3Ј-Diphenyl-1,1Ј-binaphthyl-2,2Ј-diyl)phosphoric Acid (7a):
Yield 48%. [α]2D1 = –144.1 (c = 0.136, CHCl3) [ref.[21b] [α]2D7 = –283.5
(c = 0.99, CHCl3) for the R enantiomer]. 1H NMR (400 MHz, [D6]-
DMSO): δ = 7.15 (d, J = 8.4 Hz, 2 H, ArH), 7.33–7.37 (m, 2 H,
ArH), 7.40–7.43 (m, 2 H, ArH), 7.47–7.54 (m, 6 H, ArH), 7.83 (d,
J = 6.8 Hz, 4 H, ArH), 8.12 (d, J = 8.4 Hz, 2 H, ArH), 8.19 (s, 2
H, ArH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 28.5, 35.9,
36.4, 42.7, 121.6, 122.4, 123.4, 124.3, 126.0, 130.0, 130.3, 130.8,
147.1, 149.3 ppm. 31P NMR (162 MHz, [D6]DMSO): δ = 3.0
(s) ppm.
(S)-{6,6Ј-Bis[3,5-bis(trifluoromethyl)phenyl]-1,1Ј-binaphthyl-2,2Ј-
diyl}phosphoric Acid (7e): Yield 46%. [α]2D1 = +197.3 (c = 0.100,
CHCl3). 1H NMR (400 MHz, [D6]DMSO): δ = 7.38–7.58 (m, 4 H,
ArH), 7.88 (d, J = 4.2 Hz, 2 H, ArH), 8.10 (s, 2 H, ArH), 8.23 (s,
J = 4.4 Hz, 2 H, ArH), 8.48–8.67 (m, 6 H, ArH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 119.8, 121.4, 122.5, 124.8 (q, J =
124.8 Hz), 125.2, 125.4, 127.5, 127.8, 131.2, 131.9 (q, J = 33.0 Hz),
133.0, 133.1, 142.5, 150.1, 151.3 ppm. 31P NMR (162 MHz, [D6]-
DMSO): δ = 3.5 (s) ppm. HRMS: calcd. for C36 H18F12O4P
773.0762 [M – H]–; found 773.0746.
(S)-[3,3Ј-Di(2-naphthyl)-1,1Ј-binaphthyl-2,2Ј-diyl]phosphoric Acid
(7b): Yield 50%. [α]2D1 = +232.9 (c = 0.146, CHCl3) [ref.[21d] [α]2D5
=
–265.0 (c = 0.20, CHCl3) for the R enantiomer]. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.11 (d, J = 8.4 Hz, 2 H, ArH), 7.28–
7.31 (m, 2 H, ArH), 7.44–7.47 (m, 2 H, ArH), 7.53–7.55 (m, 4 H,
ArH), 7.97–7.99 (m, 6 H, ArH), 8.20 (d, J = 8.0 Hz, 2 H, ArH),
8.21 (s, 2 H, ArH), 8.30 (d, J = 8.4 Hz, 2 H, ArH), 8.49 (s, 2 H,
ArH) ppm. 31P NMR (162 MHz, [D6]DMSO): δ = 1.7 (s) ppm.
(S)-{3,3Ј-Bis[3,5-bis(trifluoromethyl)phenyl]-6,6Ј-di(1-adamantyl)-
1,1Ј-binaphthyl-2,2Ј-diyl}phosphoric Acid (7f): Yield 76%. [α]2D1
=
1
+219.3 (c = 0.100, CHCl3). H NMR (400 MHz, [D6]DMSO): δ =
1.71 (s, 12 H, CHCH2CH), 1.89 (s, 12 H, CCH2CH), 2.02 [s, 6 H,
CH(CH2)3], 7.09 (d, J = 4.6 Hz, 2 H, ArH), 7.39 (d, J = 4.6 Hz, 2
H, ArH), 7.96 (d, J = 6 Hz, 2 H, ArH), 8.13 (s, 2 H, ArH), 8.22
(s, 2 H, ArH), 8.79 (s, 4 H, ArH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 28.7, 36.3, 36.7, 42.9, 120.9, 121.1, 121.2, 122.9, 125.2
(q, J = 181.3 Hz), 125.3, 125.4, 130.5 (q, J = 32.9 Hz), 130.6, 131.5
(q, J = 18.5.0 Hz), 131.8, 141.2, 146.9, 147.0, 147.9 ppm. 31P NMR
(162 MHz, [D6]DMSO): δ = 3.9 (s) ppm. HRMS: calcd. for
C56H44F12O4P 1039.2816 [M – H]–; found 1039.2791.
(S)-{3,3Ј-Bis[3,5-bis(trifluoromethyl)phenyl]-1,1Ј-binaphthyl-2,2Ј-
diyl}phosphoric Acid (7c): Yield 95%. [α]2D1 = +280.9 (c = 0.220,
CH3OH) [ref.[21e] [α]2D6 = –197.5 (c = 0.97, CHCl3) for the R enanti-
1
omer]. H NMR (400 MHz, [D6]DMSO): δ = 7.13–7.48 (m, 6 H,
ArH), 8.12–8.30 (m, 6 H, ArH), 8.79 (s, 4 H, ArH) ppm. 31P NMR
(162 MHz, [D6]DMSO): δ = 1.1 (s) ppm.
(S)-6,6Ј-Di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diylphosphoric Acid General Procedure for the Asymmetric Conjugate Hydrocyanation
(7d): Concentrated H2SO4 (0.8 mL) was added dropwise to a stirred
solution of (S)-BINOL (1.431 g, 5.0 mmol) and 1-adamantanol
(1.522 g, 10.0 mmol) in CH2Cl2 (25 mL) at 0 °C over 5 min. After
stirring for 30 min at 0 °C, the ice bath was removed. The resulting
suspension was stirred at room temperature for a further 6 h before
aqueous NaOH (5%) was added to neutralize the H2SO4 and thus
quench the reaction. The resulting mixture was extracted twice by
CH2Cl2. The combined organic layers were washed with brine and
dried with Na2SO4 and concentrated. The crude solid was purified
of Aromatic Enones with (S)-7d: The catalyst solution was gener-
ated before use by stirring solution of (S)-7d (12.5 mg,
a
0.02 mmol) and NaNH2 (0.7 mg, 0.02 mmol) in toluene (0.4 mL) at
room temperature for 1 h. The resulting catalyst solution (100 μL,
0.005 mmol, 5 mol-%) was added to a mixture of 1 (0.1 mmol) and
2-tBuPhOH (0.75 mg, 0.05 mmol, 5 mol-%) in toluene (0.5 mL) at
room temperature followed by the addition of Ph2C(OH)CN (6,
41.8 mg, 0.2 mmol, 2.0 equiv.) at 80 °C under argon. After stirring
for 2 h at 80 °C, the solvent was evaporated under reduced pressure
Eur. J. Org. Chem. 2013, 4624–4633
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4629

Y.-F. Wang, W. Zeng, M. Sohail, J. Guo, S. Wu, F.-X. Chen
FULL PAPER
and the crude product purified by column chromatography with
silica gel (PE/EtOAc) to give the product (R)-2.
CHCHAHBCO), 3.80 (s, 3 H, OCH3), 4.49 (dd, J = 7.6, 6.4 Hz, 1
H, CHCHAHBCO), 6.891–6.92 (m, 2 H, ArH), 7.32–7.37 (m, 3 H,
ArH), 7.70–7.72 (m, 1 H, ArH), 7.84–7.83 (m, 1 H, ArH), 8.03–
4-Oxo-2,4-diphenylbutanenitrile (2a): White solid; yield 21.4 mg,
91% (PE/EtOAc = 15:1, v/v), 95% ee, m.p. 121–123 °C (ref.[11c]
8.04 (m, 1 H, ArH) ppm. IR (neat): ν = 1685, 2240 cm–1. The enan-
˜
tiomeric excess was determined by HPLC on Chiralpak AS-H (n-
hexane/2-propanol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor) =
15.3 min, tR(major) = 18.4 min.
120–122 °C); [α]2D8 = +28.0 (c = 0.100, CH2Cl2) [ref.[11d] [α]1D7
=
–20.0 (c = 0.100, CH2Cl2, 71% ee) for the S enantiomer; ref.[7]
[α]2D4 = +18.2 (c = 0.98, CH2Cl2, 92% ee) for the R enantiomer].
1H NMR (400 MHz, CDCl3): δ = 3.52 (dd, J = 18.0, 6.0 Hz, 1 H,
CHCHAHBCO), 3.74 (dd, J = 18.0, 8.0 Hz, 1 H, CHCHAHBCO),
4.57 (dd, J = 8.0, 6.0 Hz, 1 H, CHCHAHBCO), 7.34–7.50 (m, 7 H,
ArH), 7.58–7.62 (m, 1 H, ArH), 7.92–7.94 (m, 2 H, ArH) ppm. IR
4-(4-Methoxyphenyl)-4-oxobutanenitrile (2f): White solid; yield
24.9 mg, 94% (PE/EtOAc = 10:1, v/v), 97% ee, m.p. 79–83 °C
1
(ref.[22b] m.p. 62 °C); [α]1D7 = +32.7 (c = 0.100, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 3.45 (dd, J = 17.7, 6.1 Hz, 1 H,
CHCHAHBCO), 3.67 (dd, J = 17.7, 8.0 Hz, 1 H, CHCHAHBCO),
(neat): ν = 1681, 2236 cm–1. The enantiomeric excess was deter-
˜
3.86 (s,
3 H, OCH3), 4.56 (dd, J = 7.9, 6.1 Hz, 1 H,
mined by HPLC on Chiralpak AS-H (n-hexane/2-propanol, 70:30,
1.0 mLmin–1, 254 nm), tS(minor) = 10.7 min, tR(major) = 14.8 min.
CHCHAHBCO), 6.91–6.94 (m, 2 H, ArH), 7.26–7.44 (m, 5 H,
ArH), 7.89–7.91 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 32.0, 44.2, 55.6, 114.0, 120.8, 127.5, 128.3, 128.8,
(S)-2a: Yield 21.4 mg, 91% yield, 94% ee. Chiralpak AS-H (n-hex-
ane/2-propanol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor)
=
129.3, 130.5, 135.5, 164.1, 193.1 ppm. IR (neat): ν = 1666,
˜
10.6 min, tR(major) = 14.7 min; [α]2D8 = +28.7 (c = 0.100, CH2Cl2).
2240 cm–1. The enantiomeric excess was determined by HPLC on
Chiralpak AS-H (n-hexane/2-propanol, 70:30, 1.0 mLmin–1,
254 nm), tS(minor) = 15.6 min, tR(major) = 23.7 min.
4-(4-Fluorophenyl)-4-oxobutanenitrile (2b): White solid; yield
24.1 mg, 95% (PE/EtOAc = 15:1, v/v), 96% ee, m.p. 97–99 °C
(ref.[4c] m.p. 102 °C); [α]1D7 = +34.0 (c = 0.100, CH2Cl2). H NMR
1
4-(4-Methylphenyl)-4-oxobutanenitrile (2g): White solid; yield
23.2 mg, 93% (PE/EtOAc = 15:1, v/v), 94% ee, m.p. 71–72 °C
(ref.[22a] m.p. 71–73 °C); [α]2D2 = +16.0 (c = 0.100, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3), 3.49 (dd, J =
23.6, 8.0 Hz, 1 H, CHCHAHBCO), 3.71 (dd, J = 23.6, 10.4 Hz, 1
H, CHCHAHBCO), 4.56–4.60 (m, 1 H, CHCHAHBCO), 7.27–7.29
(m, 2 H, ArH), 7.32–7.52 (m, 5 H, ArH), 7.82–7.85 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 31.8, 44.3,
120.6, 127.4, 128.1, 128.3, 129.2, 129.4, 133.2, 135.3, 144.8,
(400 MHz, CDCl3): δ = 3.47 (dd, J = 17.9, 6.0 Hz, 1 H,
CHCHAHBCO), 3.70 (dd, J = 17.9, 8.1 Hz, 1 H, CHCHAHBCO),
4.55 (dd, J = 8.0, 6.0 Hz, 1 H, CHCHAHBCO), 7.12–7.16 (m, 2 H,
ArH), 7.32–7.34 (m, 5 H, ArH), 7.94–7.98 (m, 2 H, ArH) ppm. 13
C
=
2
NMR (100 MHz, CDCl3): δ = 32.0, 44.5, 116.1 (d, JC-F
21.9 Hz), 120.5, 127.5, 128.5, 129.3, 130.8 (d, 3JC-F = 9.4 Hz), 132.2
4
1
(d, JC-F = 3.0 Hz), 135.2, 166.2 (d, JC-F = 255.4 Hz), 193.1 ppm.
IR (neat): ν = 1675, 2241 cm–1. The enantiomeric excess was deter-
˜
mined by HPLC on Chiralpak AS-H (n-hexane/2-propanol, 70:30,
194.1 ppm. IR (neat): ν = 1677, 2241 cm–1. The enantiomeric excess
was determined by HPLC on Chiralpak AS-H (n-hexane/2-prop-
anol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor) = 9.5 min, tR(major)
= 13.2 min.
˜
1.0 mLmin–1, 254 nm), tS(minor) = 11.2 min, tR(major) = 14.9 min.
4-(4-Chlorophenyl)-4-oxobutanenitrile (2c): White solid; yield
25.1 mg, 93% (PE/EtOAc = 10:1, v/v), 96% ee, m.p. 110–112 °C
(ref.[22a] m.p. 116–118 °C); [α]1D7 = +32.7 (c = 0.100, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 3.46 (dd, J = 17.9, 6.0 Hz, 1 H,
CHCHAHBCO), 3.69 (dd, J = 17.9, 8.0 Hz, 1 H, CHCHAHBCO),
4.54 (dd, J = 7.8, 6.1 Hz, 1 H, CHCHAHBCO), 7.26–7.45 (m, 7 H,
ArH), 7.84–7.87 (d, J = 8.7 Hz, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 32.0, 44.6, 120.6, 127.6, 128.6, 129.3, 129.4,
2-(4-Methylphenyl)-4-oxo-4-phenylbutanenitrile (2h): White solid;
yield 23.4 mg, 94% (PE/EtOAc = 15:1, v/v), 97% ee, m.p. 120–
123 °C (ref.[11c] m.p. 129–131 °C); [α]1D7 = +30.0 (c = 0.100, CH2Cl2)
[ref.[11d] [α]1D7 = –8.0 (c = 0.100, CH2Cl2, 72% ee) for the S enanti-
1
omer]. H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H, CH3), 3.49
(dd, J = 17.9, 6.1 Hz, 1 H, CHCHAHBCO), 3.70 (dd, J = 17.9,
7.9 Hz, 1 H, CHCHAHBCO), 4.53 (dd, J = 7.8, 6.2 Hz, 1 H,
CHCHAHBCO), 7.19 (d, J = 8.0 Hz, 2 H, ArH), 7.31 (d, J =
8.0 Hz, 2 H, ArH), 7.44–7.48 (m, 2 H, ArH), 7.57–7.61 (m, 1 H,
129.6, 134.1, 135.2, 140.6, 193.6 ppm. IR (neat): ν = 1675,
˜
2242 cm–1. The enantiomeric excess was determined by HPLC on
Chiralpak AS-H (n-hexane/2-propanol, 70:30, 1.0 mLmin–1,
254 nm), tS(minor) = 13.7 min, tR(major) = 19.0 min.
ArH), 7.90–7.93 (m, 2 H, ArH) ppm. IR (neat): ν = 1682,
˜
2241 cm–1. The enantiomeric excess was determined by HPLC on
Chiralpak AS-H (n-hexane/2-propanol, 70:30, 1.0 mLmin–1,
254 nm), tS(minor) = 9.3 min, tR(major) = 10.9 min.
4-(4-Bromophenyl)-4-oxobutanenitrile (2d): White solid; yield
29.2 mg, 93% (PE/EtOAc = 15:1, v/v), 94% ee, m.p. 120–123 °C
(ref.[22a] m.p. 122–124 °C); [α]1D7 = +29.3 (c = 0.100, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 3.45 (dd, J = 17.9, 5.9 Hz, 1 H,
CHCHAHBCO), 3.680 (dd, J = 17.9, 8.0 Hz, 1 H, CHCHAHBCO),
4.53 (dd, J = 7.9, 6.1 Hz, 1 H, CHCHAHBCO), 7.25–7.43 (m, 5 H,
ArH), 7.58–7.61 (d, J = 8.4 Hz, 2 H, ArH), 7.78–7.75 (d, J =
8.4 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.9,
44.5, 120.5, 127.5, 128.5, 129.3, 129.4, 129.6, 132.2, 134.4, 135.1,
2-(2-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2i): White solid;
yield 19.1 mg, 72% (PE/EtOAc = 10:1, v/v), 96% ee, m.p. 84–86 °C
(ref.[11c] m.p. 84–86 °C); [α]1D7 = 63.3 (c = 0.100, CH2Cl2) [ref.[11d]
[α]1D7 = –34.0 (c = 0.100, CH2Cl2, 63% ee) for the S enantiomer].
1H NMR (400 MHz, CDCl3): δ = 3.50 (dd, J = 17.9, 4.9 Hz, 1 H,
CHCHAHBCO), 3.65 (dd, J = 17.9, 9.0 Hz, 1 H, CHCHAHBCO),
193.7 ppm. IR (neat): ν = 1675, 2242 cm–1. The enantiomeric excess
˜
3.87 (s,
3 H, OCH3), 4.78 (dd, J = 9.0, 4.8 Hz, 1 H,
was determined by HPLC on Chiralpak AS-H (n-hexane/2-prop-
CHCHAHBCO), 6.91–7.02 (m, 2 H, ArH), 7.31–7.33 (m, 1 H,
anol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor)
tR(major) = 15.1 min.
=
12.4 min,
ArH), 7.45–7.51 (m, 3 H, ArH), 7.57–7.61 (m, 1 H, ArH), 7.93–
7.95 (m, 2 H, ArH) ppm. IR (neat): ν = 1678, 2243 cm–1. The enan-
˜
tiomeric excess was determined by HPLC on Chiralpak AS-H (n-
hexane/2-propanol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor) =
13.9 min, tR(major) = 24.6 min.
4-(3-Bromophenyl)-2-(4-methoxyphenyl)-4-oxobutanenitrile
(2e):
White solid; yield 32.9 mg, 96% (PE/EtOAc = 15:1, v/v), 95% ee,
m.p. 94–97 °C (ref.[11c] m.p. 97–98 °C); [α]2D2 = +14.0 (c = 0.100,
CH2Cl2) [ref.[11d] [α]1D7 = –9.4 (c = 0.574, CH2Cl2, 66% ee) for the
S enantiomer]. 1H NMR (400 MHz, CDCl3): δ = 3.45 (dd, J =
18.0, 6.4 Hz, 1 H, CHCHAHBCO), 3.65 (dd, J = 18.0, 7.6 Hz, 1 H,
2-(3-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2j): White solid;
yield 23.9 mg, 90% (PE/EtOAc = 10:1, v/v), 92% ee, m.p. 107–
109 °C (ref.[22a] m.p. 106–108 °C); [α]1D7 = 20.7 (c = 0.100, CH2Cl2)
4630
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4624–4633

Asymmetric Conjugate Hydrocyanation of Aromatic Enones
[ref.[11d] [α]1D7 = –6.0 (c = 0.100, CH2Cl2, 67% ee) for the S enanti-
omer]. 1H NMR (400 MHz, CDCl3): δ = 3.50 (dd, J = 18.0, 6.0 Hz,
1 H, ArH), 7.67–7.79 (m, 1 H, ArH), 7.94–7.96 (m, 2 H, ArH) ppm.
IR (neat): ν = 1686, 2247 cm–1. The enantiomeric excess was deter-
˜
1
H, CHCHAHBCO), 3.72 (dd,
J
=
18.0, 8.0 Hz,
1
H, mined by HPLC on Chiralpak AD-H (n-hexane/2-propanol, 70:30,
CHCHAHBCO), 3.82 (s, 3 H, OCH3), 4.55 (dd, J = 8.0, 6.0 Hz, 1 1.0 mLmin–1, 254 nm), tS(minor) = 7.2 min, tR(major) = 8.2 min.
H, CHCHAHBCO), 6.86–6.88 (m, 1 H, ArH), 6.96–7.02 (m, 2 H,
ArH), 7.28–7.32 (m, 1 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.58–
2-(4-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (2o): White solid;
yield 25.1 mg, 93% (PE/EtOAc = 15:1, v/v), 95% ee, m.p. 110–
7.62 (m, 1 H, ArH), 7.92–7.94 (m, 2 H, ArH) ppm. IR (neat): ν =
˜
113 °C (ref.[22a] m.p. 116–118 °C); [α]2D2 = +39.3 (c = 0.100,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 3.51 (dd, J = 18.0,
6.4 Hz, 1 H, CHCHAHBCO), 3.71 (dd, J = 18.0, 7.2 Hz, 1 H,
CHCHAHBCO), 4.55–4.58 (m, 1 H, CHCHAHBCO), 7.35–7.40 (m,
4 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.58–7.62 (m, 1 H, ArH),
7.90–7.93 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
31.4, 44.3, 120.3, 128.1, 128.9, 129.0, 129.5, 133.8, 134.1, 134.5,
1680, 2238 cm–1. The enantiomeric excess was determined by
HPLC on Chiralpak AS-H (n-hexane/2-propanol, 70:30,
1.0 mLmin–1, 254 nm), tS(minor) = 13.2 min, tR(major) = 20.0 min.
2-(4-Methoxyphenyl)-4-oxo-4-phenylbutanenitrile (2k): White solid;
yield 23.9 mg, 90%, after flash chromatography (PE/EtOAc = 10:1,
v/v), 98% ee, m.p. 112–114 °C (ref.[11c] m.p. 111–113 °C); [α]1D7
=
135.6, 194.6 ppm. IR (neat): ν = 1677, 2241 cm–1. The enantiomeric
23.3 (c = 0.100, CH2Cl2) [ref.[11d] [α]1D7 = –12.2 (c = 0.654, CH2Cl2,
˜
1
excess was determined by HPLC on Chiralpak AS-H (n-hexane/2-
propanol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor) = 9.9 min,
tR(major) = 12.5 min.
70% ee) for the S enantiomer]. H NMR (400 MHz, CDCl3): δ =
3.49 (dd, J = 17.9, 6.3 Hz, 1 H, CHCHAHBCO), 3.69 (dd, J = 17.9,
7.7 Hz, 1 H, CHCHAHBCO), 3.80 (s, 3 H, OCH3), 4.52 (dd, J =
7.4, 6.5 Hz, 1 H, CHCHAHBCO), 6.89–6.91 (m, 2 H, ArH), 7.33–
7.36 (m, 2 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.57–7.61 (m, 1 H,
2-(2,4-Dichlorophenyl)-4-oxo-4-phenylbutanenitrile (2p): White so-
lid; yield 29.2 mg, 96% (PE/EtOAc = 15:1, v/v), 92% ee, m.p. 89–
91 °C (ref.[11c] m.p. 90–91 °C); [α]2D2 = +59.3 (c = 0.100, CH2Cl2)
[ref.[11d] [α]1D7 = –36.0 (c = 0.100, CH2Cl2, 64% ee) for the S enanti-
omer]. 1H NMR (400 MHz, CDCl3): δ = 3.52 (dd, J = 18.0, 4.7 Hz,
ArH), 7.91–7.93 (m, 2 H, ArH) ppm. IR (neat): ν = 1679,
˜
2250 cm–1. The enantiomeric excess was determined by HPLC on
Chiralpak OD-H (n-hexane/2-propanol, 85:15, 1.0 mLmin–1,
254 nm), tS(minor) = 27.1 min, tR(major) = 29.3 min.
1
H, CHCHAHBCO), 3.67 (dd, J = 18.0, 9.2 Hz, 1 H,
CHCHAHBCO), 4.88 (dd, J = 9.0, 4.7 Hz, 1 H, CHCHAHBCO),
7.33–7.36 (m, 1 H, ArH), 7.45–7.50 (m, 3 H, ArH), 7.59–7.63 (m,
2-(4-Fluorophenyl)-4-oxo-4-phenylbutanenitrile (2l): White solid;
yield 23.0 mg, 91% (PE/EtOAc = 15:1, v/v), 93% ee, m.p. 99–
102 °C (ref.[22a] m.p. 97–101 °C); [α]1D7 = 30.0 (c = 0.100, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 3.51 (dd, J = 17.9, 6.5 Hz, 1 H,
CHCHAHBCO), 3.71 (dd, J = 17.9, 7.2 Hz, 1 H, CHCHAHBCO),
4.55–4.59 (m, 1 H, CHCHAHBCO), 7.05–7.11 (m, 2 H, ArH), 7.39–
7.49 (m, 4 H, ArH), 7.58–7.62 (m, 1 H, ArH), 7.91–7.93 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.2, 44.5, 116.3 (d,
2 H, ArH), 7.93–7.95 (m, 2 H, ArH) ppm. IR (neat): ν = 1680,
˜
2245 cm–1. The enantiomeric excess was determined by HPLC on
Chiralpak AS-H (n-hexane/2-propanol, 90:10, 1.0 mLmin–1,
254 nm), tS(minor) = 15.9 min, tR(major) = 17.6 min.
2-(4-Bromophenyl)-4-oxo-4-phenylbutanenitrile (2q): White solid;
yield 29.4 mg, 93% (PE/EtOAc = 15:1, v/v), 94% ee, m.p. 117–
118 °C (ref.[22a] m.p. 122–124 °C); [α]2D2 = +14.7 (c = 0.100,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 3.50 (dd, J = 18.0,
6.5 Hz, 1 H, CHCHAHBCO), 3.71 (dd, J = 18.0, 7.3 Hz, 1 H,
CHCHAHBCO), 4.53–4.57 (m, 1 H, CHCHAHBCO), 7.32–7.33 (m,
2 H, ArH), 7.46–7.53 (m, 4 H, ArH), 7.59–7.62 (m, 1 H, ArH),
7.90–7.92 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
31.4, 44.3, 120.2, 122.5, 128.1, 128.9, 129.3, 132.4, 134.1, 134.3,
3
2JC-F = 21.7 Hz), 120.5, 128.1, 128.9, 129.4 (d, JC-F = 8.3 Hz),
1
131.1 (d, 4JC-F = 3.3 Hz), 134.0, 135.6, 162.5 (d, JC-F = 247.1 Hz),
194.5 ppm. IR (neat): ν = 1679, 2241 cm–1. The enantiomeric excess
˜
was determined by HPLC on Chiralpak AS-H (n-hexane/2-prop-
anol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor)
tR(major) = 14.2 min.
= 10.0 min,
2-(3-Fluorophenyl)-4-oxo-4-phenylbutanenitrile (2m): White solid;
yield 24.1 mg, 95% (PE/EtOAc = 15:1, v/v), 96% ee, m.p. 99–
100 °C; [α]1D7 = +28.7 (c = 0.100, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 3.52 (dd, J = 17.9, 6.5 Hz, 1 H, CHCHAHBCO), 3.73
(dd, J = 17.9, 7.2 Hz, 1 H, CHCHAHBCO), 4.57–4.60 (m, 1 H,
CHCHAHBCO), 7.06–7.02 (m, 1 H, ArH), 7.18–7.15 (m, 1 H,
ArH), 7.26–7.22 (m, 1 H, ArH), 7.34–7.40 (m, 1 H, ArH), 7.46–
135.6, 194.3 ppm. IR (neat): ν = 1677, 2241 cm–1. The enantiomeric
˜
excess was determined by HPLC on Chiralpak AS-H (n-hexane/
2-propanol, 70:30, 1.0 mLmin–1, 254 nm), tS(minor) = 12.5 min,
tR(major) = 15.5 min.
2-(tert-Butyl)-4-oxo-4-phenylbutanenitrile (2r): White solid; yield
19.7, 91% (PE/EtOAc = 15:1, v/v), 94% ee, m.p. 116–118 °C;
[α]3D1 = 46.7 (c = 0.10, CH2Cl2) [ref.[7] [α]2D7 = 43.7 (c = 1.01, CH2Cl2,
7.50 (m, 2 H, ArH), 7.59–7.63 (m, 1 H, ArH), 7.92–7.94 (m, 2 H,
4
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.6 (d, JC-F
=
1
64% ee)]. H NMR (400 MHz, CDCl3): δ = 1.13 [s, 9 H, (CH3)3],
1.9 Hz), 44.3, 114.9 (d, 2JC-F = 22.8 Hz), 115.5 (d, 2JC-F = 20.9 Hz),
3.15–3.21 (m, 2 H, CHCHAHBCO, NCCHCHAHBCO), 3.37 (dd,
J = 18.0, 10.0 Hz, 1 H, NCCHCHAHBCO), 7.48–7.52 (m, 2 H,
4
3
120.1, 123.3 (d, JC-F = 3.1 Hz), 128.1, 128.9, 130.9 (d, JC-F
=
=
3
1
ArH), 7.60–7.63 (m, 1 H, ArH), 7.96–7.98 (m, 2 H, ArH) ppm. 13
C
8.3 Hz), 134.1, 135.6, 137.6 (d, JC-F = 7.4 Hz), 163.0 (d, JC-F
247.2 Hz), 194.3 ppm. IR (neat): ν = 1691, 2244 cm–1. C H FNO
˜
NMR (100 MHz, CDCl3): δ = 27.4, 32.9, 36.9, 37.8, 121.1, 128.1,
128.8, 133.8, 136.1, 195.8 ppm. The enantiomeric excess was deter-
mined by HPLC on Chiralpak AS-H (n-hexane/2-propanol, 90:10,
1.0 mLmin–1, 254 nm), tS(minor) = 11.8 min, tR(major) = 14.6 min.
16 12
(253.27): calcd. C 75.88, H 4.78, N 5.53; found C 75.72, H 4.84, N
5.61. The enantiomeric excess was determined by HPLC on Chi-
ralpak AS-H (n-hexane/2-propanol, 70:30, 1.0 mLmin–1, 254 nm),
tS(minor) = 9.2 min, tR(major) = 12.8 min.
2-Cyclohexyl-4-oxo-4-phenylbutanenitrile (2s): White solid; yield
22.3, 91% (PE/EtOAc = 15:1, v/v), 95% ee, m.p. 138–140 °C;
[α]3D1 = 8.0 (c = 0.100, CH2Cl2) [ref.[7] [α]2D8 = 5.8 (c = 1.03, CH2Cl2,
2-(2-Chlorophenyl)-4-oxo-4-phenylbutanenitrile (2n): White solid;
yield 25.1 mg, 93% (PE/EtOAc = 15:1, v/v), 93% ee, m.p. 100–
102 °C (ref.[11c] m.p. 100–102 °C); [α]2D2 = 70.0 (c = 0.100, CH2Cl2)
[ref.[11d] [α]1D7 = –35.9 (c = 0.668, CH2Cl2, 53% ee) for the S enanti-
omer]. 1H NMR (400 MHz, CDCl3): δ = 3.53 (dd, J = 18.0, 4.5 Hz,
1
96% ee)]. H NMR (400 MHz, CDCl3): δ = 1.19–1.29 (m, 5 H, c-
C6H11), 1.57–1.89 (m,
6 H, c-C6H11), 3.21–3.29 (m, 2 H,
CHCHAHBCO, CHCHAHBCO), 3.38 (dd, J = 19.2, 9.2 Hz, 1 H,
H, CHCHAHBCO), 3.68 (dd, J = 18.0, 9.4 Hz, 1 H, CHCHAHBCO), 7.43–7.50 (m, 2 H, ArH), 7.58–7.62 (m, 1 H,
1
CHCHAHBCO), 4.93 (dd, J = 9.4, 4.5 Hz, 1 H, CHCHAHBCO), ArH), 7.94–7.96 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
7.26–7.38 (m, 2 H, ArH), 7.42–7.50 (m, 3 H, ArH), 7.58–7.62 (m,
CDCl3): δ = 25.8, 25.9, 26.0, 29.2, 31.5, 32.6, 38.5, 39.0, 121.0,
Eur. J. Org. Chem. 2013, 4624–4633
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4631

Y.-F. Wang, W. Zeng, M. Sohail, J. Guo, S. Wu, F.-X. Chen
FULL PAPER
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CCDC-886595 contains the supplementary crystallographic
data for (R)-6,6Ј-di(1-adamantyl)-1,1Ј-binaphthyl-2,2Ј-diol, the
precursor for phosphoric acid (R)-7d. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
See the Supporting Information.
128.1, 128.9, 133.8, 136.0, 195.6 ppm. The enantiomeric excess was
determined by HPLC on Chiralpak OD-H (n-hexane/2-propanol,
90:10, 1.0 mLmin–1, 254 nm), tS(minor) = 10.5 min, tR(major) =
12.4 min.
[11]
[12]
Supporting Information (see footnote on the first page of this arti-
1
cle): HPLC chromatograms, H and 13C NMR spectra of the final
products.
Acknowledgments
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The financial support from the Beijing Institute of Technology
(grant number 2011cx01008 and others) and the National Natural
Science Foundation of China (NSFC) (grant number 20972016) are
acknowledged.
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Received: March 18, 2013
Published Online: June 5, 2013
Eur. J. Org. Chem. 2013, 4624–4633
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4633