Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes

Article abstract of DOI:10.1021/acs.joc.6b02678

A highly efficient enantioselective hydrogenation of 1,2-dicyanoalkenes catalyzed by the complex of rhodium and f-spiroPhos has been developed. A series of 1,2-dicyanoalkenes were successfully hydrogenated to the corresponding chiral 1,2-dicyanoalkanes under mild conditions with excellent enantioselectivities (up to 98% ee). This methodology provides efficient access to the asymmetric synthesis of chiral diamines.

Full text of DOI:10.1021/acs.joc.6b02678

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Article
Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes
Meina Li, Duanyang Kong, Guofu Zi, and Guohua Hou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02678 • Publication Date (Web): 13 Dec 2016
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Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes
Meina Li, Duanyang Kong, Guofu Zi and Guohua Hou*
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University,
Beijing 100875, China
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E-mail: ghhou@bnu.edu.cn.
Abstract: A highly efficient enantioselective hydrogenation of 1,2-dicyanoalkenes catalyzed by
the complex of rhodium and f-spiroPhos has been developed. A series of 1,2-dicyanoalkenes were
successfully hydrogenated to the corresponding chiral 1,2-dicyanoalkanes under mild conditions
with excellent enantioselectivities (up to 98% ee). This methodology provides efficient access to
the asymmetric synthesis of chiral diamines.
Introduction
Chiral 1,2-dicyanoalkanes are an important class of compounds in organic synthesis and high
valuable intermediates for synthesis of many biologically active compounds and pharmaceuticals
(Figure 1).1 They have been regarded as versatile synthetic intermediates due to their readily
conversions to other useful chiral building blocks, such as chiral diamines,2 dicarboxylic acids,3
4
diamides and various heterocycles (pyrrolidines, succinimides, and pyrroles),5 which are highly
valuable structures for natural and biologically active molecules. Although some significant
approaches have been developed in the synthesis of racemic 1,2-dicyanoalkanes, such as the
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Michael addition of lithium cyanide to vinyl sulfones,6 1,2-dicyanation of alkynes followed by the
reduction of the corresponding dicyanoalkenes,7 and the tandem double Michael addition of
trimethylsilyl cyanide to nitroalkenes,8 there is no asymmetric synthesis of chiral
1,2-dicyanoalkanes reported up to now. Therefore, development of an efficient method for
asymmetric catalytic synthesis of chiral 1,2-dicyanoalkanes is of importance and remains
challenging.
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Figure 1. Key Structural Elements in Chiral Pharmaceuticals and Biologically Active Compounds
Derived from Chiral 1,2-Dicyanoalkanes.
Asymmetric catalytic hydrogenation has been developed as one of the most efficient,
environmentally friendly, atom-economic approaches to generate enantiomerically enriched
products from prochiral substrates,9 and great progress on its application in industry has also been
made.10 Many transition-metal catalysts were developed and exhibited high activity and
enantioselectivity in the asymmetric hydrogenation of various prochiral substrates including
olefins, ketones and imines.9 However, to the best of our knowledge, the asymmetric
hydrogenation of 1,2-dicyanoalkenes for straightforward synthesis of the corresponding chiral
1,2-dicyanoalkanes has not yet been explored so far.11 The challenges imposed by both the linear
geometry of the cyano group, which keeps a coordinated catalyst away from the C=C bond, and
the strong binding affinity to transition-metal complexes resulting in catalyst deactivation.11c, 12
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Thus, the asymmetric hydrogenation of 1,2-dicyanoalkenes remains challenging and efficient
catalysts suitable for this class of substrates are scarce and highly desirable.
8
9
Recently, we reported the asymmetric hydrogenation of nitroolefins, imines, unsaturated nitriles
and carboxylic acids using f-spiroPhos, a chiral ferrocenyl diphosphine ligand containing the
privileged spirobiindane skeleton developed by Zhou and coworkers,13 and excellent
enantioselectivity and activity were achieved.14 Herein, we wish to tackle the challenging
1,2-dicyanoalkene substrates in asymmetric hydrogenation and report the first, highly efficient and
enantioselective hydrogenation of 1,2-dicyanoalkenes, which provides a straightforward route to
prepare chiral 1,2-dicyanoalkanes (Scheme 1) .
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Scheme 1. Rh-Catalyzed Asymmetric Hydrogenation of 2-Aryl-1,2-dicyanoalkenes.
Results and Discussion
The investigation initially began with the hydrogenation of (E)-2-phenyl-1,2-dicyanoalkene 1a
o
as the model substrate under 10 atm of H2 in CH2Cl2 at 40 C for 1 hour using the catalyst
generated in situ by [Rh(COD)Cl]2 and (R,R)-f-spiroPhos. Although a full conversion was
observed, only moderate enantioselectivity, 77% ee was achieved. To our delight, by decreasing
the reaction temperature to 25 oC the enantioselectivity could be dramatically increased to 90% ee
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without any erosion of conversion (Table 1, entries 1 and 2). However, a lower temperature would
result in an incomplete conversion and decreased enantioselectivity (entry 3). Subsequently,
several other chiral diphosphorus ligands illustrated in figure 2 including (S)-BINAP,
(S,R)-DuanPhos, (R)-JosiPhos, (S)-f-Binaphane and (R)-DM-SegPhos were evaluated and the
results revealed that all of them exhibited extremely lower activities and moderate
enantioselectivities in this reaction (entries 48). The solvent effect was also investigated and it
had significant influence on the conversion and enantioselectivity. While in THF this
hydrogenation could accomplish with moderate enantioselectivity (entry 9), in some other solvents
such as DME, 1,4-dioxane and toluene both incomplete conversions and lower enantioselectivitis
were provided (entries 1012). The polar solvent MeOH was not suitable for this transformation
and extremely low activity was observed (entry 13).
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Table 1. Rh-Catalyzed Asymmetric Hydrogenation of (E)-2-Phenyl-1,2-dicyanoalkene (1a),
Optimizing the Reaction Conditions.a
entry
ligand
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
T (oC)
40
conv. (%)b
ee (%)c
77
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(S)-f-Binaphane
(S)-Binap
>99
>99
65
1
2
3
4
5
6
25
90
0
82
25
28
52
25
trace
3
ND
41
(R)-DM-SegPhos
25
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(S,R)-DuanPhos
(R)-JosiPhos-1
CH2Cl2
CH2Cl2
THF
25
25
25
25
25
25
25
6
27
63
71
54
71
34
ND
7
12
8
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
(R,R)-f-spiroPhos
>99
45
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toluene
DME
10
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12
95
dioxane
MeOH
77
trace
13
a
Unless
otherwise
mentioned,
all
reactions
were
carried
out
with
a
[Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of 0.5 : 1.1 : 100, 10 atm of H2, 1 h. b Determined
1
c
by H NMR spectroscopy or GC analysis. Determined by HPLC analysis using a chiral
stationary phase or chiral GC analysis.
Figure 2. Structures of the Ligands Screened.
Encouraged by the promising result obtained in the hydrogenation of
(E)-2-phenyl-1,2-dicyanoalkene 1a, we then prepared a variety of (E)-1,2-dicyanoalkene 1 and
applied them to the asymmetric hydrogenation under the optimized reaction conditions. As the
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results revealed in table 2, the electronic properties of the substituent at the meta- or para-position
of the aromatic ring had no obvious influence on the enantioselectivity. For example, substrates
bearing regardless of electron-withdrawing substituents (F, 1b and Br, 1c) or electron-donating
substituents ( MeO, 1d and Me, 1e) at the para-position of the aromatic ring could be smoothly
hydrogenated to produce the corresponding chiral 1,2-dicyanoalkanes with full conversions and
high enantioselectivities (entries 25). Despite a slightly higher hydrogen pressure needed for the
full conversion, substrates with a MeO (1i) or Me group (1j) at the ortho-position as well as the
1-naphthyl substrate 1k provided much higher enantioselecitivities, up to 98% ee, which could
presumably be attributed to the steric hindrance (entries 911). However, electron-withdrawing
substituents at the ortho-position, such as F or Cl group, resulted in lower enantioselecitivities, 88%
ee (entry 78). Notably, the alkyl substrate 1l could be smoothly hydrogenated to provide the
corresponding product 2l with 96% ee (entry 12).
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Table 2. Rh-Catalyzed Asymmetric Hydrogenation of (E)-2-Aryl-1,2-dicyanoalkene 1.a
entry
1
R
product
2a
con (%)b
ee (%)c
90
(E)-C6H5 (1a)
>99(98%)
>99(99%)
>99(98%)
>99(97%)
>99(99%)
>99(97%)
>99(98%)
2d
3e
(E)-4-FC6H4 (1b)
(E)-4-BrC6H4 (1c)
(E)-4-MeOC6H4 (1d)
(E)-4-MeC6H4 (1e)
(E)-3-MeC6H4 (1f)
(E)-2-ClC6H4 (1g)
89
2b
88
2c
4d
5
86
2d
93
2e
6d
7f
90
2f
88
2g
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8 f
(E)-2-FC6H4 (1h)
>99(97%)
89
96
98
93
96
2h
2i
9d
(E)-2-MeOC6H4 (1i)
(E)-2-MeC6H4 (1j)
(E)-1-napthyl (1k)
(E)-nHexyl (1l)
>99(96%)
>99(96%)
>99(99%)
>99(98%)
10d
11d
12
2j
2k
2l
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a
Unless
otherwise
mentioned,
all
reactions
were
carried
out
at
a
[Rh(COD)Cl]2/(R,R)-f-spiroPhos/substrate ratio of 0.5:1.1:100 in CH2Cl2 at 10 atm of H2 and
b
1
25 °C for 1 h. Conversion, determined by H NMR spectroscopy or GC analysis; data in
c
d
parentheses are isolated yields. Determined by chiral GC analysis or HPLC analysis. 7 h, 30
atm of H2. e 24 h, 30 atm of H2. f 12 h, 50 atm of H2.
It was found that the Z-isomers of 1,2-dicyanoalkenes were also obtained in high yields together
with the E-isomers in the synthesis of the substrates. We further investigated the asymmetric
hydrogenation of (Z)-2-phenyl-1,2-dicyanoalkene 1a using Rh/(R,R)-f-spiroPhos catalyst under
the optimized reaction conditions. However, only moderate enantioselectivity, 73% ee, was
obtained with an opposite configuration, which indicated the geometric structure of the substrate
had an obvious effect on the coordination of the C=C double bond to the metal center. (Z)- and
(E)-Substrates coordinated to the catalyst from the opposite enantioface, which resulted in the
hydrogenation products with opposite configuration.11d,14e-g According to the research of halide
effects in rhodium catalysts by Lautens and Fagnou,15 we changed the metal precursor with the
[Rh(COD)2]BF4. Gratifyingly, the ee value of the hydrogenation product 2a was increased to 90 %
still with a complete conversion (table 3, entry 1). Based on this promising result, a series of
(Z)-1,2-dicyanoalkene 1 were successfully hydrogenated to afford the desired products with
comparable results with those obtained from (E)-substrates. As the results showed in table 3, the
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electronic properties of substituents on the phenyl ring of the substrate had a very little effect on
the enantioselectivities. Electron-donating substituents at the identical position of phenyl ring
generally could give a little higher enantioselectivity than electron-withdrawing ones. For instance,
the substrates with a Me or MeO at para-position of the phenyl ring provided 91% ee, whereas the
substrates bearing an electron-withdrawing F or Br substituent afforded the corresponding
products with 89% and 88% ee, respectively (entries 25). The sterically hindered
ortho-substituted substrates, 1h1k, could also be completely hydrogenated with higher
enantioselectivities of up to 95% ee (entries 8, 10 and 11), compared with those provided by the
corresponding meta- or para-substituted substrates. Both the 1-naphthyl and 2-naphthyl substrate
1l and 1m afforded the products 2l and 2m with high ee values. However, the 2-furyl and
2-thienyl substrates 1n and 1o only provided moderate enantioselectivities, 65% and 57% ee,
respectively (entries 14 and 15).
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Table 3. Rh-Catalyzed Asymmetric Hydrogenation of (Z)-2-Aryl-1,2-dicyanoalkene 1.a
entry
R
product
2a
con (%)b
ee (%)c
90
1
2
3
4
5
6
7
>99(98%)
>99(97%)
>99(99%)
>99(98%)
>99(98%)
>99(99%)
>99(99%)
(Z)-C6H5 (1a)
89
(Z)-4-FC6H4 (1b)
(Z)-4-BrC6H4 (1c)
(Z)-4-MeOC6H4 (1d)
(Z)-4-MeC6H4 (1e)
(Z)-3-MeC6H4 (1f)
(Z)-3-MeOC6H4 (1g)
2b
88
2c
91
2d
91
2e
88
2f
87
2g
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>99(98%)
>99(99%)
>99(98%)
>99(98%)
>99(99%)
>99(98%)
>99(98%)
>99(96%)
92
85
95
90
86
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65
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(Z)-2-MeOC6H4 (1h)
(Z)-2-ClC6H4 (1i)
(Z)-2-MeC6H4 (1j)
(Z)-2-FC6H4 (1k)
(Z)-1-napthyl (1l)
(Z)-2-napthyl (1m)
(Z)-2-furyl (1n)
2h
2i
9d
10e
11
12e
13
14e
15e
2j
2k
2l
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2m
2n
2o
(Z)-2-thienyl (1o)
a
Unless
otherwise
mentioned,
all
reactions
were
carried
out
at
a
[Rh(COD)2]BF4/(S,S)-f-spiroPhos/substrate ratio of 1.0:1.1:100 in CH2Cl2 at 10 atm of H2 and
b
1
60 °C for 8 h. Conversion, determined by H NMR spectroscopy or GC analysis; data in
c
d
parentheses are isolated yields. Determined by chiral GC analysis or HPLC analysis. 36 h, 50
atm of H2, 60 °C. e 24 h, 50 atm of H2, 60 °C.
In addition, the hydrogenation on a gram scale using a lower catalyst loading was also
explored. Using a loading of 0.2 mol% Rh-(R,R)-f-spiroPhos catalyst the asymmetric
hydrogenation of (E)-1e could still be accomplished to produce the product 2e with maintained
enantioselectivity, 93% ee (Scheme 2).
Scheme 2. Asymmetric Hydrogenation of the Substrate 1e under Lower Catalyst Loading.
Finally, we attempted to apply this method to the asymmetric synthesis of chiral 1,4-diamines,
which was regarded as a very important class of building blocks in pharmaceutical synthesis and
used extensively as chiral auxiliaries and catalysts. 16 The hydrogenation product 2i with 96% ee
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value could be readily further reduced to afford the chiral 1,4-diamine with unchanged excellent
enantioselectivity (Schem 3).17
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Scheme 3. Synthesis of 1,4-Diamine 3 from the Hydrogenation Product 2i.
Conclusions
In conclusion, we have developed a highly enantioselective hydrogenation of a series of
1,2-dicyanoalkenes including both E and Z-isomers to produce chiral 1,2-dicyanoalkanes with
excellent enantioselectivities (up to 98% ee) and good activity (TON up to 500) using the complex
of rhodium and f-spiroPhos as catalyst under mild reaction conditions. Moreover, this method is
also successfully applied to the synthesis of a chiral 1,4-diamine with an excellent
enantioselectivity.
Experimental Section
General Information: All the air or moisture sensitive reactions and manipulations were
performed by using standard Schlenk techniques and in a nitrogen-filled glovebox. DME, THF,
1,4-dioxane and toluene were distilled from sodium benzophenone ketyl. CH2Cl2 was distilled
from calcium hydride. Anhydrous MeOH was distilled from magnesium. 1H NMR spectra were
recorded on a 400 MHz spectrometer. 13C NMR (proton-decoupled) spectra were obtained at 100
MHz. CDC13 was the solvent used for the NMR analysis, with tetramethylsilane as the internal
standard. Chemical shifts were reported upfield to TMS (0.00 ppm) for 1H NMR. Optical rotation
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was determined using a polarimeter. HRMS were recorded on a mass spectrometer with APCI or
ESI.
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General procedure for the synthesis of compound 1: Under a nitrogen atmosphere benzoyl
chloride (25.0 mmol, 1.0 equiv) was slowly added at room temperature to a stirred suspension of
copper (I) cyanide (50.0 mmol 2.0 equiv) in dry acetonitrile (80 mL). After about 4 hours of
refluxing the resulting clear solution was cooled to room temperature and concentrated in vacuo.
The residue was washed with ether, filtrated and concentrated in vacuo again. After additional
distillation (0.12 mbar, 65 – 80 °C) the product benzoyl cyanide was obtained as a colorless
solid.18 The corresponding benzoyl cyanide (9.1 mmol) was placed in a 100 mL round bottom flask,
then Ph3P=CHCN (13.59 mmol, 1.5 equiv) and toluene (20 mL) was added. The reaction mixture
was stirred at 80 °C until no starting material was detected by TLC. Then the reaction mixture was
cooled to room temperature and concentrated in vacuo. The residue was purified by
chromatography on silica gel (PE:EA = 50:1 – 5:1) to give compound 1.17
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2-Phenylfumaronitrile (1a): Purification by column chromatography (PE:EA = 10:1) afforded the
1
product as a white solid; MP: 48-50 oC; 0.98 g, yield: 28%; H NMR (400 MHz, CDCl3) δ =
7.94-7.91 (m, 2H), 7.59-7.52 (m, 3H), 6.14 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 133.7,
133.3, 130.3, 128.8, 116.9, 115.2, 108.0; TOF-HRMS Calcd. for C10H5N2 [M-H+]: 153.0458,
found 153.0458.7a
2-(4-Fluorophenyl)fumaronitrile (1b): Purification by column chromatography (PE:EA = 10:1)
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afforded the product as a white solid; MP: 64-66 oC; 0.91 g, yield: 30%; H NMR (400 MHz,
CDCl3) δ = 7.89-7.86 (m, 2H), 7.18-7.13 (m, 2H), 6.05 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz)
δ: 164.9 (d, 1JC-F = 255.0 Hz), 131.8, 130.7, 130.6, 126.0, 125.9, 116.9, 116.7, 116.0, 114.5, 107.1.
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TOF-HRMS Calcd. for C10H6N2F [M+H+]: 173.0509, found 173.0511.
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afforded the product as a white solid; MP: 62-64 oC; 1.05 g, yield: 30%; H NMR (400 MHz,
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CDCl3) δ = 7.79-7.77 (d, J = 8.8 Hz, 2H), 7.68-7.66 (d, J = 8.8 Hz, 2H), 6.17(s, 1H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 132.8, 131.9, 129.5, 128.6, 127.7, 115.9, 114.4, 107.9.
TOF-HRMS Calcd. for C10H4N2Br [M-H+]: 230.9563, found 230.9564.7b
2-(4-Methoxyphenyl)fumaronitrile (1d): Purification by column chromatography (PE:EA = 10:1)
1
afforded the product as a white solid; MP: 82-86 oC; 1.05 g, yield: 35%; H NMR (400 MHz,
CDCl3) δ = 7.93-7.91 (m, 2H), 7.00-6.98 (m, 2H), 5.94 (s, 1H), 3.87 (s, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 163.6, 132.7, 130.8, 122.9, 117.1, 115.9, 115.4, 104.3, 56.2. TOF-HRMS
Calcd. for C11H9N2O [M+H+]: 185.0709, found 185.0709.7b
2-(p-Tolyl)fumaronitrile (1e): Purification by column chromatography (PE:EA = 20:1) afforded
the product as light yellow solid; MP: 94-97 oC; 0.81 g, yield: 27%; 1H NMR (400 MHz, CDCl3) δ
= 7.83 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.06 (s, 1H), 2.43 (s, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 143.8, 132.8, 130.0, 128.1, 127.1, 116.4, 114.9, 106.0, 105.9, 21.6.
TOF-HRMS Calcd. for C11H9N2 [M+H+]: 169.0760, found 169.0759.
2-(m-Tolyl)fumaronitrile (1f): Purification by column chromatography (PE:EA = 10:1) afforded
the product as a light yellow solid; MP: 75-79 oC; 0.84 g, yield: 28%; 1H NMR (400 MHz, CDCl3)
δ = 7.74-7.69 (m, 2H), 7.44-7.37 (m, 2H), 6.10 (s, 1H), 2.43 (s, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 140.4, 134.3, 134.2, 130.4, 130.1, 127.9, 124.4, 115.3, 114.8, 107.6, 21.9. TOF-HRMS
Calcd. for C11H9N2 [M+H+]: 169.0760, found 169.0758.
2-(2-Chlorophenyl)fumaronitrile (1g): Purification by column chromatography (PE:EA = 20:1)
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afforded the product as light yellow liquid; 0.78 g, yield: 26%; H NMR (400 MHz, CDCl3) δ =
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7.55-7.42 (m, 4H), 6.36 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 132.9, 132.8, 131.9, 130.7,
130.5, 129.0, 127.7, 115.1, 114.8, 113.2. TOF-HRMS Calcd. for C10H6N2Cl [M+H+]: 189.0214,
found 189.0215.
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2-(2-Fluorophenyl)fumaronitrile (1h): Purification by column chromatography (PE:EA = 30:1)
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afforded the product as a white solid; MP: 88-90 oC; 0.63 g, yield: 21%; H NMR (400 MHz,
CDCl3) δ = 7.54-7.46 (m, 2H), 7.25-7.14 (m, 2H), 6.24-6.23 (m, 1H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 160.8 (d, 1JC-F = 255.0 Hz), 134.3, 134.2, 130.8, 128.4, 125.4, 118.2, 118.1, 117.3, 117.1,
114.6, 113.9, 112.6, 112.4. TOF-HRMS Calcd. for C10H6N2F [M+H+]: 173.0509, found 173.0511.
2-(2-Methoxyphenyl)fumaronitrile (1i): Purification by column chromatography (PE:EA = 10:1)
1
afforded the product as a white solid; MP: 58-60 oC; 1.14 g, yield: 38%; H NMR (400 MHz,
CDCl3) δ = 7.53-7.48 (m, 2H), 7.09-7.00 (m, 2H), 6.17 (s, 1H), 3.94 (s, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 157.0, 133.7, 131.1, 130.1, 121.1, 119.3, 116.1, 114.2, 111.9, 111.8, 55.7.
TOF-HRMS Calcd. for C11H9N2O [M+H+]: 185.0709, found 185.0708.7b
2-(o-Tolyl)fumaronitrile (1j): Purification by column chromatography (PE:EA = 20:1) afforded
1
the product as light yellow liquid; 0.9 g, yield: 30%; H NMR (400 MHz, CDCl3) δ = 7.43-7.31
(m, 4H), 6.27 (s, 1H), 2.45 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 136.2, 134.2, 131.5, 131.3,
129.7, 128.9, 126.7, 115.5, 113.6, 19.6. TOF-HRMS Calcd. for C11H9N2 [M+H+]: 169.0760, found
169.0759.
2-(Naphthalen-1-yl)fumaronitrile (1k): Purification by column chromatography (PE:EA = 20:1)
1
afforded the product as a light yellow solid; MP: 128-131 oC; 0.78 g, yield: 26%; H NMR (400
MHz, CDCl3) δ = 8.06-8.04 (m, 1H), 7.96-7.94 (m, 2H), 7.66-7.57 (m, 4H), 6.45 (s, 1H),
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13C{1H}NMR (CDCl3, 100 MHz) δ: 133.7, 133.5, 132.6, 129.6, 129.1, 128.3, 128.0, 127.6, 127.3,
125.2, 123.6, 116.1, 114.3, 113.7. TOF-HRMS Calcd. for C14H9N2 [M+H+]: 205.0760, found
205.0760.
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2-Hexylfumaronitrile (1l): Purification by column chromatography (PE:EA = 20:1) afforded the
product as light yellow liquid; 0.25 g, yield: 21%; 1H NMR (400 MHz, CDCl3) δ = 5.96 (s, 1H),
2.59 (t, J= 7.44 Hz, 2H), 1.62-1.69 (m, 2H), 1.33-1.39 (m, 6H), 0.88-0.91 (m, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 137.6, 116.7, 114.0, 112.7, 34.2, 31.8, 28.8, 28.0, 22.9, 14.5. The analytical
data are consistent with the literature.7a
2-Phenylmaleonitrile (1a): Purification by column chromatography (PE:EA = 5:1) afforded the
product as a white solid; MP: 90-92 oC; 2.03 g, yield: 58%; 1H NMR (400 MHz, CDCl3) δ =
7.67-7.65 (m, 2H), 7.58-7.53 (m, 1H), 7.51-7.50 (m, 2H), 6.39 (s, 1H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 133.5, 132.9, 129.9, 129.7, 126.7, 114.7, 114.2, 107.4. TOF-HRMS Calcd. for C10H5N2
[M-H+]: 153.0458, found 153.0458.7a
2-(4-Fluorophenyl)maleonitrile (1b): Purification by column chromatography (PE:EA = 5:1)
1
afforded the product as a white solid; MP: 112-115 oC; 1.89 g, yield: 63%; H NMR (400 MHz,
CDCl3) δ = 7.62-7.59 (m, 2H), 7.15-7.11 (m, 2H), 6.27 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz)
δ: 165.3 (d, 1JC-F = 255.0 Hz), 132.2, 129.1, 129.0, 126.2, 126.1, 117.2, 117.0, 114.6, 114.0, 107.3.
TOF-HRMS Calcd. for C10H6N2F [M+H+]: 173.0509, found 173.0510.
2-(4-Bromophenyl)maleonitrile (1c): Purification by column chromatography (PE:EA = 30:1)
1
afforded the product as a white solid; MP: 107-110 oC; 2.06 g, Yield: 59%; H NMR (400 MHz,
CDCl3) δ = 7.65 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 6.39 (s, 1H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 133.0, 132.4, 128.8, 128.0, 127.9, 114.4, 113.7, 107.8. TOF-HRMS Calcd. for
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C10H4N2Br [M-H+]: 230.9563, found 230.9563.7b
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2-(4-Methoxyphenyl)maleonitrile (1d): Purification by column chromatography (PE:EA = 5:1)
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afforded the product as a white solid; MP: 114-117 oC; 1.56 g, yield: 52%; H NMR (400 MHz,
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CDCl3) δ = 7.65 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.21 (s, 1H), 3.88 (s, 3H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 163.4, 132.7, 128.6, 122.4, 115.2, 115.1, 114.3, 103.9, 55.7.
TOF-HRMS Calcd. for C11H9N2O [M+H+]: 185.0709, found 185.0709.7b
2-(p-Tolyl)maleonitrile (1e): Purification by column chromatography (PE:EA = 10:1) afforded
the product as light yellow solid; MP: 134-136 oC; 1.74 g, yield: 58%; 1H NMR (400 MHz, CDCl3)
δ = 7.55 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.33 (s, 1H), 2.43 (s, 3H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 144.0, 133.2, 130.3, 127.1, 126.6, 114.9, 114.2, 105.9, 21.5. TOF-HRMS
Calcd. for C11H9N2 [M+H+]: 169.0760, found 169.0759.
2-(m-Tolyl)maleonitrile (1f): Purification by column chromatography (PE:EA = 5:1) afforded the
product as a light yellow solid; MP: 127-130 oC; 1.89 g, yield: 63%; 1H NMR (400 MHz, CDCl3)
δ = 7.45-7.39 (m, 2H), 7.38-7.37 (m, 2H), 6.35 (s, 1H), 2.42 (s, 3H). 13C{1H}NMR (CDCl3, 100
MHz) δ: 140.1, 134.2, 133.8, 129.9, 129.3, 127.9, 125.9, 124.4, 116.9, 107.7, 21.9. TOF-HRMS
Calcd. for C11H9N2 [M+H+]: 169.0760, found 169.0759.
2-(3-Methoxyphenyl)maleonitrile (1g): Purification by column chromatography (PE:EA = 10:1)
afforded the product as a light yellow solid; MP: 86-88 oC; 0.75 g, yield: 25%; 1H NMR (400 MHz,
CDCl3) δ = 7.36-7.32 (m, 1H), 7.18-7.15 (m, 1H), 7.05-7.03 (m, 2H), 6.30 (s, 1H), 3.78 (s, 3H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 160.3. 133.3, 131.1, 130.8, 119.0, 118.5, 114.7, 114.1, 112.0,
107.7, 55.6. TOF-HRMS Calcd. for C11H9N2O [M+H+]: 185.0709, found 185.0709.
2-(2-Methoxyphenyl)maleonitrile (1h): Purification by column chromatography (PE:EA = 5:1)
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afforded the product as a light yellow solid; MP: 146-149 oC; 1.44 g, yield: 48%; H NMR (400
MHz, CDCl3) δ = 7.68-7.66 (m, 1H), 7.51-7.47 (m, 1H), 7.04 (t, J = 8.0 Hz, 2H), 7.02 (d, J = 8.4
Hz, 1H), 6.98 (s, 1H), 3.96 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 158.8, 133.7, 131.4, 130.6,
121.4, 118.8, 115.6, 114.9, 112.0, 111.2, 56.0. TOF-HRMS Calcd. for C11H9N2O [M+H+]:
185.0709, found 185.0709.7b
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2-(2-Chlorophenyl)maleonitrile (1i): Purification by column chromatography (PE:EA = 10:1)
afforded the product as a white solid; MP: 70-74 oC; 1.68 g, yield: 56%; H NMR (400 MHz,
1
CDCl3) δ = 7.53-7.26 (m, 4H), 6.43 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 132.8, 132.6,
131.4, 131.3, 130.6, 129.5, 127.9, 115.0, 113.9, 113.8. TOF-HRMS Calcd. for C10H6N2Cl [M+H+]:
189.0214, found 189.0214.
2-(o-Tolyl)maleonitrile (1j): Purification by column chromatography (PE:EA = 10:1) afforded
1
the product as a white solid; MP: 63-67℃; 1.77 g, yield: 59%; H NMR (400 MHz, CDCl3) δ =
7.36-7.32 (m, 1H), 7.24-7.18 (m, 3H), 6.02 (s, 1H), 2.42 (s, 3H). 13C{1H}NMR (CDCl3, 100 MHz)
δ: 136.4, 134.3, 131.7, 131.6, 130.8, 128.9, 127.0, 114.3, 114.1, 113.3, 20.3. TOF-HRMS Calcd.
for C11H9N2 [M+H+]: 169.0760, found 169.0759.
2-(2-Fluorophenyl)maleonitrile (1k): Purification by column chromatography (PE:EA = 20:1)
afforded the product as a white solid; MP: 105-108 oC; 1.71 g, yield: 57%; H NMR (400 MHz,
1
CDCl3) δ = 7.66-7.61 (m, 1H), 7.50-7.45 (m, 1H), 7.28-7.24 (m, 1H), 7.18-7.13 (m, 1H),
6.62-6.61 (m, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 160.8 (d, 1JC-F = 255.0 Hz), 134.3, 134.2,
130.8, 128.4, 125.4, 117.3, 117.1, 114.6, 112.6, 112.4. TOF-HRMS Calcd. for C10H6N2F [M+H+]:
173.0509, found 173.0511.
2-(Naphthalen-1-yl)maleonitrile (1l): Purification by column chromatography (PE:EA = 10:1)
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afforded the product as a light yellow liquid; 1.62 g, yield: 54%; 1H NMR (400 MHz, CDCl3) δ =
8.09-7.93 (m, 3H), 7.66-7.54 (m, 4H), 6.32 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 133.6,
133.2, 132.6, 129.4, 129.1, 128.8, 128.2, 128.0, 127.2, 125.2, 123.4, 114.9, 114.3, 114.0.
TOF-HRMS Calcd. for C14H9N2 [M+H+]: 205.0760, found 205.0759.
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2-(Naphthalen-2-yl)maleonitrile (1m): Purification by column chromatography (PE:EA = 10:1)
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afforded the product as a light yellow solid; MP: 147-151 oC; 1.74 g, yield: 58%; H NMR (400
MHz, CDCl3) δ = 8.22 (s, 1H), 7.96-7.88 (m, 3H), 7.64-7.59 (m, 3H), 6.47 (s, 1H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 134.9, 133.3, 132.7, 129.8, 129.4, 129.3, 129.1, 127.9, 127.8, 127.1, 120.8,
114.9, 114.2, 106.8. TOF-HRMS Calcd. for C14H9N2 [M+H+]: 205.0760, found 205.0760.
2-(Furan-2-yl)maleonitrile (1n): Purification by column chromatography (PE:EA = 10:1)
afforded the product as a light yellow liquid; 1.62 g, yield: 54%; 1H NMR (400 MHz, CDCl3) δ =
7.70 (s, 1H), 7.22-7.21 (m, 1H), 6.65-6.64 (m, 1H), 5.80 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz)
δ: 147.4, 146.2, 120.2, 118.4, 114.7, 114.2, 113.4, 100.9. TOF-HRMS Calcd. for C8H4N2ONa
[M+Na+]: 167.0215, found 167.0212.
2-(Thiophen-2-yl)maleonitrile (1o): Purification by column chromatography (PE:EA = 10:1)
1
afforded the product as a light yellow liquid; 1.8 g, yield: 60%; H NMR (400 MHz, CDCl3) δ =
7.58-7.57 (m, 2H), 7.18-7.17 (m, 1H), 6.11 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 134.9,
134.7, 133.6, 128.9, 126.5, 115.9, 115.7, 102.1. TOF-HRMS Calcd. for C8H4N2SNa [M+Na+]:
182.9987, found 182.9988.
General procedure for asymmetric hydrogenation of 1: A stock solution was made by mixing
[Rh(COD)Cl]2 with (R,R)-f-spirophos in a 1:2.2 molar ratio in CH2Cl2 at room temperature for 20
min in a nitrogen-filled glovebox. An aliquot of the catalyst solution (1.0 mL, 0.001 mmol) was
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transferred by syringe into the vials charged with different substrates (0.1 mmol for each) in
anhydrous CH2Cl2 (2.0 mL). The vials were subsequently transferred into an autoclave which
hydrogen gas was charged. The reaction was then stirred under H2 (10 atm) at room temperature
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o
for 7 h for the substrates 1 or 60 C 8 h for the substrates 1. The hydrogen gas was released
slowly and carefully. The solution was passed through a short column of silica gel to remove the
metal complex. The ee values of products 2 or 2 were determined by GC analysis on a chiral
stationary phase. The crude products 2j, 2l, 2m were concentrated and purified by column
chromatography and the ee values were determined by HPLC analysis on a chiral stationary
phase.
(+)-2-Phenylsuccinonitrile (2a): 19.1 mg, yield 98%; 90% ee; [α]D20 = +30.2 (c = 0.5, CH2Cl2);
GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min,
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programmed 100 C - 1 C/min - 200 C - 50 min; tR = 77.9 min (minor), tR = 78.3 min (major).
(2a): 18.9 mg, yield 97%; 90% ee; [α]D20 = +30.0 (c = 0.5, CH2Cl2); GC condition: Supelco
gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100 oC - 1
oC/min - 200 C - 50 min; tR = 77.9 min (minor), tR = 78.4 min (major). H NMR (400 MHz,
CDCl3) δ = 7.46-7.41 (m, 5H), 4.16 (t, J = 6.9 Hz, 1H), 3.03-2.91 (m, 2H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 132.8, 130.3, 130.2, 127.8, 118.3, 115.7, 34.7, 25.3. TOF-HRMS Calcd. for C10H9N2
[M+H+]:157.0760, found 157.0759.7a, 19
o
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(+)-2-(4-Fluorophenyl)succinonitrile (2b): 21.5 mg, yield 99%; 89% ee; [α]D20 = +46.0 (c = 0.5,
CH2Cl2); GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
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mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 67.3 min (minor), tR = 68.2 min
(major). (2b): 21.1 mg, yield 97%; 89% ee; [α]D20 = +46.2 (c = 0.5, CH2Cl2); GC condition:
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Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100
oC - 1 oC/min - 200 oC - 50 min; tR = 67.2 min (major), tR = 68.7 min (minor). 1H NMR (400 MHz,
CDCl3) δ = 7.42-7.39 (m, 2H), 7.17-7.13 (m, 2H), 4.16 (t, J = 6.8 Hz, 1H), 3.02-2.90 (m, 2H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 163.1 (d, 1JC-F = 249.0 Hz), 129.2, 129.1, 128.0, 127.9, 117.5,
116.9, 116.6, 115.0, 33.3, 24.7. TOF-HRMS Calcd. for C10H6N2F [M-H+]: 173.0520, found
173.0521.
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(+)-2-(4-Bromophenyl)succinonitrile (2c): 28.7 mg, yield 98%; 88% ee; [α]D20 = +27.6 (c = 0.5,
CH2Cl2); GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
o
o
o
mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 77.9 min (minor), tR = 78.3 min
(major). (2c): 29.0 mg, yield 99%; 88% ee; [α]D20 = +27.7 (c = 0.5, CH2Cl2); GC condition:
Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed
100 oC - 1 oC/min - 200 oC - 50 min; tR = 77.9 min (minor), tR = 78.4 min (major). 1H NMR (400
MHz, CDCl3) δ = 7.61-7.58 (m, 2H), 7.31-7.28 (m, 2H), 4.14 (t, J = 6.8 Hz, 1H), 3.01-2.90 (m,
2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 132.8, 131.1, 128.9, 123.9, 117.3, 114.9, 33.5, 24.5.
TOF-HRMS Calcd. for C10H6N2Br [M-H+]: 232.9719, found 232.9719.
(+)-2-(4-Methoxyphenyl)succinonitrile (2d): 22.5 mg, yield 97%; 86% ee; [α]D20 = +33.4 (c =
0.5, CH2Cl2); GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2
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1.0 mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 85.5 min (minor), tR = 86.4
min (major). (2d): 22.8 mg, yield 98%; 91% ee; [α]D20 = +35.6 (c = 0.5, CH2Cl2); GC condition:
Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100
oC - 1 oC/min - 200 oC - 50 min; tR = 85.6 min (minor), tR = 86.7 min (major). 1H NMR (400 MHz,
CDCl3) δ = 7.31 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 4.12 (t, J = 6.9 Hz, 1H), 3.82 (s, 3H),
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2.99-2.87 (m, 2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 160.4, 128.5, 124.1, 118.1, 115.4, 115.0,
55.4, 33.3, 24.9. TOF-HRMS Calcd. for C11H11N2O [M+H+]: 187.0865, found 187.0867.
(+)-2-(p-Tolyl)succinonitrile (2e): 21.0 mg, yield 99%; 93% ee; [α]D20 = +36.9 (c = 0.5, CH2Cl2);
GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min,
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programmed 100 C - 1 C/min - 200 C - 50 min; tR = 68.7 min (minor), tR = 69.6 min (major).
(2e): 20.8 mg, yield 98%; 91% ee; [α]D20 = +36.2 (c = 0.5, CH2Cl2); GC condition: Supelco alpha
DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100 oC - 1 oC/min
o
- 200 C - 50 min; tR = 68.8 min (minor), tR = 69.8 min (major).1H NMR (400 MHz, CDCl3) δ =
7.23-7.16 (m, 4H), 4.05 (t, J = 6.9 Hz, 1H), 2.93-2.81 (m, 2H), 2.30 (s, 3H). 13C{1H}NMR (CDCl3,
100 MHz) δ: 139.6, 130.3, 129.2, 127.0, 117.9, 115.3, 33.7, 24.7, 21.1. TOF-HRMS Calcd. for
C11H9N2 [M-H+]:169.0771, found 169.0772.
(+)-2-(m-Tolyl)succinonitrile (2f): 20.6 mg, yield 97%; 90% ee; [α]D20 = +45.9 (c = 0.5, CH2Cl2);
GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min,
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programmed 100 C - 1 C/min - 200 C - 50 min; tR = 77.0 min (minor), tR = 77.3 min (major).
(2f): 21.0 mg, yield 99%; 88% ee; [α]D20 = +45.0 (c = 0.5, CH2Cl2); GC condition: Supelco
gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100 oC - 1
o
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oC/min - 200 C - 50 min; tR = 77.5 min (minor), tR = 77.9 min (major). H NMR (400 MHz,
CDCl3) δ = 7.25-7.12 (m, 4H), 4.04 (t, J = 6.9 Hz, 1H), 2.93-2.82 (m,2H), 2.31 (s, 3H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 139.7, 132.1, 130.3, 129.6, 127.8, 124.3, 117.9, 115.3, 34.0,
24.8, 21.4. TOF-HRMS Calcd. for C11H9N2 [M-H+]:169.0771, found 169.0771.
(+)-2-(2-Chlorophenyl)succinonitrile (2g): 22.3 mg, yield 98%; 88% ee; [α]D20 = +96.3 (c = 0.5,
CH2Cl2); GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
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mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 84.9 min (major), tR = 86.4 min
(minor). (2i): 23.5 mg, yield 99%; 85% ee; [α]D20 = +95.6 (c = 0.5, CH2Cl2); GC condition:
Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed
100 oC - 1 oC/min - 200 oC - 50 min; tR = 84.9 min (major), tR = 86.3 min (minor). 1H NMR (400
MHz, CDCl3) δ = 7.69-7.66 (m, 1H), 7.47-7.38 (m, 3H), 4.66 (t, J = 5.6 Hz, 1H), 3.10-2.94 (m,
2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 132.5, 131.1, 130.4, 129.8, 129.4, 128.2, 117.3, 115.1,
31.6, 22.7. TOF-HRMS Calcd. for C10H6N2Cl [M-H+]:189.0224, found 189.0226.
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(+)-2-(3-Methoxyphenyl)succinonitrile (2g): 23.0 mg, yield 99%; 87% ee; [α]D20 = +45.2 (c =
0.5, CH2Cl2); GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2
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2.0 mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR =72.8 min (minor), tR = 73.8
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min (major). H NMR (400 MHz, CDCl3) δ = 7.37-7.33 (m, 1H), 6.98-6.93 (m, 3H), 4.14 (t, J =
6.8 Hz, 1H), 3.82 (s, 3H), 2.97-2.95 (m, 2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 160.4, 133.6,
130.8, 119.3, 117.9, 115.4, 114.9, 113.1, 55.5, 34.0, 24.6. TOF-HRMS Calcd. for C11H11N2O
[M+H+]:187.0865, found 187.0867.20
(+)-2-(2-Fluorophenyl)succinonitrile (2h): 21.1 mg, yield 97%; 89% ee; [α]D20 = +59.1 (c = 0.5,
CH2Cl2); GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
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mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 74.2 min (minor), tR = 74.6 min
(major). (2k): 21.3 mg, yield 98%; 90% ee; [α]D20 = +59.8 (c = 0.5, CH2Cl2); GC condition:
Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed
100 oC - 1 oC/min - 200 oC - 50 min; tR = 73.6 min (minor), tR = 73.8 min (major). 1H NMR (400
MHz, CDCl3) δ = 7.43 (t, J = 7.6 Hz, 1H), 7.31-7.30 (m, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.03 (t, J =
9.4 Hz, 1H), 4.34 (t, J = 6.4 Hz, 1H), 2.94-2.82 (m, 2H). 13C{1H}NMR (CDCl3, 100 MHz) δ:
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159.6 (d, JC-F = 247.0 Hz), 129.2, 129.1, 128.0, 127.9, 117.5, 116.9, 116.6, 115.0, 33.3, 24.7.
131.8, 131.7, 129.2, 129.1, 125.5, 125.4, 119.5, 119.4, 116.9, 116.4, 116.2, 114.9, 28.5, 28.4, 23.1,
23.0. TOF-HRMS Calcd. for C10H6N2F [M-H+]: 173.0520, found 173.0521.
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(+)-2-(2-Methoxyphenyl)succinonitrile (2i): 22.4 mg, yield 96%; 96% ee; [α]D20 = +106.7 (c =
0.5, CH2Cl2); GC condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2
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1.0 mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 81.2 min (minor), tR = 81.9
min (major). (2h): 22.8 mg, yield 98%; 92% ee; [α]D20 = +105.2 (c = 0.5, CH2Cl2); GC condition:
Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed
100 oC - 1 oC/min - 200 oC - 50 min; tR = 81.3 min (minor), tR = 82.1 min (major). 1H NMR (400
MHz, CDCl3) δ = 7.49 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.95
(d, J = 8.3 Hz, 1H), 4.51 (t, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.04-2.92 (m, 2H). 13C{1H}NMR
(CDCl3, 100 MHz) δ: 155.9, 130.9, 128.7, 121.4, 120.2, 118.0, 115.7, 111.1, 55.6, 29.2, 22.2.
TOF-HRMS Calcd. for C11H11N2O [M+H+]:187.0865, found 187.0867.
(+)-2-(o-Tolyl)succinonitrile (2j): 20.4 mg, yield 96%; 98% ee; [α]D20 = +132.2 (c = 0.5, CH2Cl2);
GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min,
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programmed 100 C - 1 C/min - 200 C - 50 min; tR = 67.6 min (major), tR = 68.1 min (minor).
(2j): 20.8 mg, yield 98%; 95% ee; [α]D20 = +131.6 (c = 0.5, CH2Cl2); GC condition: Supelco
o
alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0 mL/min, programmed 100 C - 1
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oC/min - 200 C - 50 min; tR = 67.4 min (minor), tR = 68.2 min (major). H NMR (400 MHz,
CDCl3) δ = 7.41-7.40 (m, 1H), 7.24-7.18 (m, 3H), 4.28 (t, J = 6.9 Hz, 1H), 2.92-2.81 (m, 2H),
2.32 (s, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 135.6, 132.1, 131.1, 130.2, 128.1, 128.0, 118.7,
115.8, 31.4, 23.9, 19.7. TOF-HRMS Calcd. for C11H9N2 [M-H+]: 169.0771, found 169.0772.
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(+)-2-(Naphthalen-1-yl)succinonitrile (2k): 25.5 mg, yield 99%; 93% ee; [α]D20 = +52.0 (c = 0.5,
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CH2Cl2); HPLC condition: Lux 5u Cellulose-2 (250 × 4.60mm), ipa : hex = 35:65, 1mL/min, 254
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nm; tR = 10.7 min (major), tR = 14.6 min (minor). (2l): 25.5 mg, yield 99%; 86% ee; [α]D
=
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+45.0 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-2 (250 × 4.60mm), ipa : hex = 35:65,
1mL/min, 254 nm; tR = 10.5 min (minor), tR = 14.0 min (major). 1H NMR (400 MHz, CDCl3) δ =
7.95-7.85 (m, 2H), 7.83-7.79 (m, 2H), 7.67-7.54 (m, 3H), 4.94 (t, J = 6.7 Hz, 1H), 3.20-3.06 (m,
2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 133.7, 130.1, 129.4, 128.8, 127.3, 127.1, 126.2, 125.9,
125.1, 120.5, 117.5, 114.8, 30.8, 23.1. TOF-HRMS Calcd. for C14H11N2 [M+H+]: 207.0916, found
207.0914.
(S)-2-Hexylsuccinonitrile (2l): 20.1 mg, yield 98%; 96% ee; [α]D20 = -62.0 (c = 0.5, EtOH); GC
condition: Supelco gamma DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 3.0 mL/min,
programmed 100 oC - 2 oC/min - 190 oC - 30 min; tR = 35.6 min (minor), tR = 35.7 min (major). 1H
NMR (400 MHz, CDCl3) δ = 2.91 (s, 1H), 2.72 (s, 2H), 1.76-1.77 (m, 2H), 1.55-1.57 (m, 1H),
1.46-1.47 (m, 1H), 1.24-1.30 (s, 6H), 0.87-0.89 (m, 3H). 13C{1H}NMR (CDCl3, 100 MHz) δ:
119.5, 116.2, 32.0, 31.9, 29.0, 27.2, 23.0, 21.6, 14.5, 1.56. The analytical data are consistent with
the literature.21
(+)-2-(Naphthalen-2-yl)succinonitrile (2m): 25.2 mg, yield 98%; 92% ee; [α]D20 = +51.4 (c =
0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-2 (250 × 4.60mm), ipa : hex = 35:65, 1mL/min,
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254 nm; tR = 9.9 min (major), tR = 11.0 min (minor). H NMR (400 MHz, CDCl3) δ = 7.94-7.87
(m, 4H), 7.58-7.56 (m, 2H), 7.45-7.43 (m, 1H), 4.32 (t, J = 6.8 Hz, 1H), 3.10-2.99 (m, 2H).
13C{1H}NMR (CDCl3, 100 MHz) δ: 132.6, 132.5, 129.2, 128.7, 127.4, 127.1, 126.6, 126.5, 126.3,
123.2, 117.1, 114.5, 33.6, 24.0. TOF-HRMS Calcd. for C14H11N2 [M+H+]: 207.0916, found
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207.0915.
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CH2Cl2); GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
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mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 43.3 min (minor), tR = 44.5 min
(major). 1H NMR (400 MHz, CDCl3) δ = 7.46 (s, 1H), 6.52-6.42 (m, 2H), 4.32 (t, J = 6.7 Hz, 1H),
3.06 (d, J = 6.7 Hz, 2H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 144.8, 144.5, 116.2, 115.5, 111.7,
28.8, 22.1. TOF-HRMS Calcd. for C8H6N2ONa [M+Na+]: 169.0372, found 169.0374.
(+)-2-(Thiophen-2-yl)succinonitrile (2o): 19.4 mg, yield 96%; 57% ee; [α]D20 = +54.8 (c = 0.5,
CH2Cl2); GC condition: Supelco alpha DexTM 225 column (30 m × 0.25 mm × 0.25 µm), N2 1.0
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o
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mL/min, programmed 100 C - 1 C/min - 200 C - 50 min; tR = 63.7 min (minor), tR = 65.1 min
(major). 1H NMR (400 MHz, CDCl3) δ = 7.37-7.36 (m, 1H), 7.21-7.20 (m, 1H), 7.05-7.02 (m, 1H),
4.47 (t, J = 6.7 Hz, 1H), 3.04-3.02 (m, 1H). 13C{1H}NMR (CDCl3, 100 MHz) δ: 134.0, 128.2,
128.1, 127.6, 117.6, 115.6, 29.9, 25.5. TOF-HRMS Calcd. for C8H6N2SNa [M+Na+]: 185.0143,
found 185.0146.
General procedure for the synthesis of 1,4-diamines: To a stirring solution of the hydrogenation
product (0.2 mmol) in MeOH (3 mL) Boc2O (0.8 mmol) and NiCl2•6H2O (0.8 mmol) were first
added, then NaBH4 (3.2mmol) was added portionwise at 0 oC over 1 h. The mixture was stirred at
room temperature until no starting material was detected by TLC and carefully quenched with
H2O. The aqueous layer was extracted with ethyl acetate, dried over MgSO4. After the solvent was
removed in vacuo, the residue was purified by silica gel column chromatography using petroleum
ether/ AcOEt as an eluent.17
1,4-Bis((tert-butoxycarbonyl)amino)-2-(4-methoxyphenyl)butane (3): 25.5 mg, yield: 65%; 96%
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ee; [α]D = -8.8 (c = 0.5, CH2Cl2); HPLC condition: Lux 5u Cellulose-2 (250 × 4.60mm), ipa :
hex = 10:90, 1mL/min, 254 nm; tR = 8.4 min (major), tR = 9.9 min (minor). 1H NMR (CDCl3, 400
MHz) δ: 7.22-6.85 (m, 4H),4.65 (s, 1H), 4.45 (s, 1H), 3.81(s, 3H), 3.46-3.45 (m, 1H), 3.30-3.25
(m, 2H), 3.10-3.06 (m, 1H), 2.88-2.83 (m, 1H), 2.03 (s, 1H), 1.86-1.81 (m, 1H), 1.41-1.38(m,
18H) . 13C{1H}NMR (CDCl3, 100 MHz) δ: 158.1, 156.5, 156.4, 131.4, 130.2, 128.3, 128.2, 121.6,
111.2, 79.5, 79.4, 55.9, 45.4, 39.1, 36.8, 33.4, 31.5, 28.9, 28.8, 19.7, 1.5. TOF-HRMS Calcd. for
C21H35N2O5 [M+H+]: 395.2540, found 395.2539.
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ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Grant Nos. 21672024, 21272026,
and 21472013), the Ministry of Education of China (the Fundamental Research Funds for the
Central Universities, Program for Changjiang Scholars and Innovative Research Team in
University), and Beijing Municipal Commission of Education for generous financial support.
SUPPORTING INFORMATION
NMR, GC and HPLC spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
REFERENCES
[1] (a) Finke, P. E.; Meurer, L. C.; Oates, B. et al. Bioorg. Med. Chem. Lett. 2001, 11, 265. (b)
Macfarlane, D. E.; Manzel, L. J. Immunol. 1998, 160, 1122. (c) Young, W. B.; Rai, R.; Shrader, W.
D.; Burgess-Henry, J.; Hu, H.; Elrod, K. C.; Sprengeler, P. A.; Katz, B. A.; Sukbuntherng, J.;
Mordenti, J. Bioorg. Med. Chem. Lett. 2006, 16, 2034. (d) Meyers, M. J.; Sun, J.; Carlson, K. E.;
Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 4230.
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