Organocatalytic enantioselective strecker reaction of imines containing a thiazole moiety by using a cinchona-based squaramide catalyst

Article abstract of DOI:10.1002/ejoc.201402764

An organocatalytic enantioselective Strecker reaction was developed for the synthesis of α-amino nitriles that contain a thiazole moiety by using a cinchona-based squaramide catalyst. The corresponding products were obtained in good to excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee) by starting from aromatic-substituted imines. In addition, two trifunctional squaramides with amino acid residues were synthesized, and good enantioselectivities (up to 89% ee) were achieved when they were employed in the model reaction.

Full text of DOI:10.1002/ejoc.201402764

FULL PAPER
DOI: 10.1002/ejoc.201402764
Organocatalytic Enantioselective Strecker Reaction of Imines Containing a
Thiazole Moiety by Using a Cinchona-Based Squaramide Catalyst
Hai-Xiao He[a] and Da-Ming Du*[a]
Keywords: Synthetic methods / Asymmetric catalysis / Organocatalysis / Enantioselectivity / Nitrogen heterocycles / Schiff
bases
An organocatalytic enantioselective Strecker reaction was
ties (up to 98% ee) by starting from aromatic-substituted
developed for the synthesis of α-amino nitriles that contain a
imines. In addition, two trifunctional squaramides with
thiazole moiety by using a cinchona-based squaramide cata- amino acid residues were synthesized, and good enantio-
lyst. The corresponding products were obtained in good to
excellent yields (up to 99%) with excellent enantioselectivi-
selectivities (up to 89% ee) were achieved when they were
employed in the model reaction.
Strecker reactions of heterocyclic imines have been reported
that employ tertiary amine-squaramide catalysts. After the
pioneering report of organocatalysis by the Rawal
group,[10a] chiral squaramides have been successfully em-
ployed in various asymmetric reactions in recent years.[10]
Our group has also reported on a series of efficient enantio-
selective reactions that were catalyzed by a squaramide or-
ganocatalyst.[11] Herein, we report the first highly enantio-
selective Strecker reaction by using cinchona-based squar-
amide organocatalysts (see Figure 1).
Introduction
The Strecker reaction[1] (cyanation of imines) is one of
the most direct and viable methods for the asymmetric syn-
thesis of natural and unnatural α-amino acids and their de-
rivatives.[2] The products, α-amino nitriles, can readily be
converted into α-amino acids, 1,2-diamines, and 2-amino
alcohols, all of which are valuable building blocks for the
syntheses of biologically active compounds. Therefore,
stereoselective Strecker reactions that provide chiral amino
nitriles are of great interest. A large number of recent efforts
have resulted in the establishment of highly efficient and
general protocols that provide reliable access to a wide
range of optically active α-amino nitriles.[3]
Results and Discussion
Most of the reported catalytic enantioselective Strecker
reactions use common aldimines[4] and ketoimines[5] as sub-
strates. However, the utilization of heterocyclic imines or
imines that contain heterocyclic amino counterparts has
been rarely reported. It is well known that heterocyclic com-
pounds play an important role in the structures of many
natural products and medically important synthetic mo-
lecules.[6] In particular, compounds that contain a benzothi-
azole moiety exhibit a wide spectrum of significant bio-
logical activities.[7] The development of a facile method for
the synthesis of α-amino acid derivatives that contain a
benzothiazole moiety is an interesting task for our group.
Although many catalysts such as organocatalysts[8] and
metal catalysts[9] have been successfully used in the asym-
metric Strecker reaction, no similar enantioselective
Enantioselective Strecker Reaction of Imine with TMSCN
We began with the addition reaction of trimethylsilyl
cyanide (TMSCN, 2) to imine 1a, which contains a benzo-
thiazole moiety, by using 5 mol-% cinchona-based squar-
amide II as the catalyst. This model reaction proceeded well
at room temperature for 24 h in CH2Cl2, and the corre-
sponding adduct 3a was obtained with very low enantio-
selectivity (43% ee), albeit in 99% yield (see Table 1, En-
try 2). Next, several other organocatalysts were prepared
and evaluated in this model reaction. Cinchona-based
squaramide catalysts I–IV all gave product 3a in excellent
yields with low to moderate enantioselectivities (16–45% ee,
see Table 1, Entries 1–4). Quinine-based thiourea V gave the
corresponding adduct 3a in 99% yield with 23% ee (see
Table 1, Entry 5). Squaramides VI and VII, which were de-
rived from (1S,2S)-1,2-diaminocyclohexane, afforded the
product in high yields, but the enantioselectivities were also
very low (99 and 90% yield, 16 and 9% ee, respectively, see
Table 1, Entries 6 and 7). To improve the enantioselectivity
of the product, two trifunctional squaramides, each with an
[a] School of Chemical Engineering and Environment, Beijing
Institute of Technology,
5 South Zhongguancun Street, Beijing 100081, P. R. China
E-mail: dudm@bit.edu.cn
http:/www.bit.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402764.
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Organocatalytic Enantioselective Strecker Reaction
Figure 1. The screened organocatalysts.
amino acid residue, were developed and evaluated. Squar- Table 1. Screening of catalysts for the enantioselective Strecker re-
action of imine 1a with TMSCN.[a]
amide VIII, derived from l-phenylalanine and quinine, was
used to give the corresponding adduct 3a in 85% yield with
59% ee (see Table 1, Entry 8). Squaramide IX, derived from
l-valine and quinine, afforded a better yield and enantio-
selectivity (87% yield, 76% ee; see Table 1, Entry 9). When
this reaction was performed at –15 °C in the presence of
either squaramide catalyst VIII or IX, better enantio-
selectivities (71 and 89% ee, respectively) were obtained (see
Table 1, Entries 10 and 11), but the yields were lower than
those obtained at room temperature. Because squaramide
II is an effective catalyst at –15 °C,[11h] we performed this
reaction at –15 °C by using 5 mol-% of squaramide II, and
the corresponding adduct 3a was obtained in 99% yield
with 95% ee (see Table 1, Entry 12). In the absence of a
catalyst, adduct 3a was obtained as a racemate in 82% yield
(see Table 1, Entry 13). From the above evaluation, squar-
amide II was identified as the optimal catalyst.
Entry
Catalyst
Time [h]
% Yield[b]
% ee[c]
1
2
3
4
5
6
7
8
I
II
III
IV
V
24
24
24
24
24
24
24
24
24
48
48
24
24
90
99
99
97
99
99
90
85
87
60
70
99
82
45
43
16
–38
23
16
9
59
76
71
89
95
0
VI
VII
VIII
IX
VIII
IX
II
9
10[d]
11[d]
12[d]
13
With these initial results, we continued to optimize the
reaction parameters. To improve the enantioselectivity of
the Strecker reaction, we initially focused on the influence
–
of the solvent. Common solvents such as CH2Cl2, CHCl3, [a] Unless otherwise noted, reactions were carried out by using im-
ine 1a (23.8 mg, 0.1 mmol) and TMSCN (2, 19.8 mg, 0.2 mmol) in
tetrahydrofuran (THF), CCl4, ClCH2CH2Cl, and PhMe
were evaluated as the reaction was carried out at room tem-
perature (90–99% yield, 55–88% ee; see Table 2, Entries 2–
CH2Cl2 (1 mL) at room temperature. [b] Isolated yield after purifi-
cation by column chromatography. [c] Determined by HPLC analy-
sis using Daicel Chiralpak AD-H column. [d] Reactions were car-
6). The best result was obtained by using THF as the sol-
vent. Next, we varied the loading of catalyst II to 5, 20,
and 30 mol-% (see Table 2, Entries 7–9), but the screening
ried out at –15 °C.
results from earlier showed that 10 mol-% was the best cata- and 45 °C in THF, the enantioselectivity was lower than
lyst loading (see Table 2, Entry 3). When the reaction was that obtained at room temperature (see Table 2, Entries 10–
carried out with a catalyst loading of 10 mol-% at 0, –15, 12).
Eur. J. Org. Chem. 2014, 6190–6199
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H.-X. He, D.-M. Du
FULL PAPER
Table 2. Optimization of the reaction conditions.[a]
the solvent in the presence of 5 mol-% of catalyst II with
0.2 mmol EtOH as the additive at –15 °C.
Table 3. Optimization of the reaction conditions in CH2Cl2.[a]
Entry Solvent
T
[°C]
Time Loading
%
% ee[c]
[h]
[mol-%]
Yield[b]
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
24
48
48
48
48
48
72
72
72
48
48
48
10
10
10
10
10
10
5
20
30
10
10
10
99
99
99
92
99
90
99
99
99
99
63
99
43
81
88
73
55
83
63
59
79
85
53
40
Entry
T
[°C]
Time
[h]
Loading
[mol-%]
%
%
Yield[b]
ee[c]
CCl4
1
2
3
4
5
6
7
8
r.t..
–15
–15
–15
–15
–15
0
–30
–15
–15
–15
–30
–15
24
24
24
24
24
24
24
24
4
10
5
10
15
2
1
5
5
5
5
5
99
99
99
99
90
84
99
74
99
99
90
80
86
43
95
90
93
95
84
79
97
96
96
96
98
97
(CH2Cl)2
PhMe
THF
THF
THF
THF
THF
THF
9
10
11
12
–15
45
9[d]
10[e]
11[f]
12[d]
13[g]
[a] Reactions were carried out by using imine 1a (23.8 mg,
0.1 mmol) and TMSCN (2, 19.8 mg, 0.2 mmol) in the solvent
(1 mL). [b] Isolated yield after purification by column chromatog-
raphy. [c] Determined by HPLC analysis using Daicel Chiralpak
AD-H column.
4
12
24
24
5
5
[a] Reactions were carried out by using imine 1a (23.8 mg,
0.1 mmol) and TMSCN (2, 19.8 mg, 0.2 mmol) in CH2Cl2 (1 mL).
[b] Isolated yield after purification by column chromatography.
[c] Determined by HPLC analysis using Daicel Chiralpak AD-H
column. [d] EtOH (0.2 mmol) was used as additive. [e] iPrOH
(0.2 mmol) was used as additive. [f] H2O (0.2 mmol) was used as
additive. [g] EtOH (0.1 mmol) and TMSCN (2, 9.9 mg, 0.1 mmol)
was used.
Because the reaction performed at –15 °C for 24 h in
CH2Cl2 afforded a better result than that obtained after
48 h in THF, CH2Cl2 was still considered the best reaction
medium. Subsequently, the effect of the catalyst loading was
further investigated in CH2Cl2. For this study, five different
loadings (5, 10, 15, 2, and 1 mol-%) of catalyst II were
evaluated and compared as the reaction was carried out at
After the optimal reaction conditions were established,
–15 °C for 24 h (see Table 3, Entries 2–6). A catalyst loading we explored the scope of the substrates. The results are
of 5 mol-% gave the best results (99% yield, 95% ee, see shown in Table 4. Imines 1b, 1c, and 1d, which are derived
Table 3, Entry 2). A further increase or reduction in the cat- from aromatic aldehydes that contain a 4-F, 2-Cl, and 4-Br
alyst loading compromised the enantioselectivity and yield. substituent, respectively, underwent
a reaction with
When the reaction was carried out at 0 °C with a catalyst TMSCN to afford the corresponding adducts 3b–3d in 95–
loading of 5 mol-%, the enantioselectivity decreased to 99% yield with high to excellent enantioselectivities (86–
79% ee (see Table 3, Entry 7). However, when the reaction 95% ee, see Table 4, Entries 2–4). Imines 1e, 1f, 1g, and 1h,
temperature was lowered to –30 °C, the enantioselectivity which contain electron-donating substituents [2-MeO, 4-
slightly improved relative to that obtained at –15 °C, but CH3, 4-MeO, and 3,4-(MeO)2, respectively], afforded the
the Strecker product was obtained in a lower 74% yield (see corresponding products 3e–3h in 80–97% yield with excel-
Table 3, Entry 8). A series of additives were then examined. lent enantioselectivities (93–98% ee, see Table 4, Entries 5–
In general, the reaction rate greatly improved by the ad- 8). Imines 1i, 1j, and 1k, which are derived from 1-naph-
dition of 0.2 mmol of EtOH, iPrOH, or H2O (see Table 3, thaldehyde and heteroaromatic aldehydes, were also good
Entries 9–11), and the enantioselectivities slightly increased substrates, and the desired products 3i–3k were obtained in
to 96% ee. The same excellent yields were obtained with the high to excellent yields and with high to excellent enantio-
addition of EtOH and iPrOH, whereas the reaction with selectivities (92–99% yield, 90–96% ee, see Table 4, En-
0.2 mmol H2O as an additive afforded the product in a tries 9–11). Imines 1l–1p incorporated different substituents
lower 90% yield (see Table 3, Entry 11). When the reaction (i.e., 6-Cl, 6-Me, or 6-MeO) on the benzothiazole ring. The
was carried out at –30 °C for 24 h, the corresponding prod- desired products 3l–3p were obtained in high yields with
uct 3a was obtained in 80% yield with 98% ee (see Table 3, excellent enantioselectivities (90–94% yield and 92–97% ee,
Entry 12). Furthermore, when 0.1 mmol TMSCN was used see Table 4, Entries 12–16). Imines 1q and 1r, each derived
with 0.1 mmol EtOH as an additive, the desired product from a small-ring heteroaromatic amine, afforded the de-
was obtained in 86% yield and 97% ee (see Table 3, En- sired products 3q and 3r in excellent yields (up to 99%) but
try 13). With regard to the yield and enantioselectivity, we without any enantioselectivity (see Table 4, Entries 17 and
identified that the optimal conditions involved CH2Cl2 as 18). Under the optimal reaction conditions, common imines
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Organocatalytic Enantioselective Strecker Reaction
Table 4. Substrate scope of the enantioselective Strecker reaction.[a] 1s and 1t afforded the corresponding products 3s and 3t in
high yields but with poor enantioselectivities (93% yield,
7% ee and 90% yield, 17% ee, respectively; see Table 4, En-
tries 19 and 20). The above results indicate that the benzo-
thiazole ring in the heterocyclic imine is crucial to achieve
the high asymmetric induction. There may be a π-π interac-
tion between the benzene ring of the benzothiazole unit and
the bis(trifluoromethyl)phenyl moiety of the squaramide, or
a hydrogen-bonding interaction may occur between the aro-
matic C–H of the benzothiazole unit and the C–F of the
CF3 group.
The absolute configuration of product 3b was ascer-
tained as (S) on the basis of X-ray crystal structure analysis
(see Figure 2).[12] The absolute configuration of the other
products were assigned by analogy.
Figure 2. X-ray crystal structure of product 3b.
Mechanistic Aspects of the Enantioselective Strecker
Reaction of Imine with TMSCN
To discover the role of the squaramide and the tertiary
amine moieties of the catalyst, we designed two control ex-
periments and employed different catalysts (see Scheme 1).
When this reaction was conducted at –15 °C with
squaramide catalyst X, almost no adduct was produced
after 24 h. However, when 1,4-diazabicyclo[2.2.2]octane
(DABCO) was used as the catalyst under the same condi-
tions, the corresponding product rac-3a was obtained in
98% yield. This result indicates that the tertiary amine unit
is the actual catalyst of this reaction, and the role of the
squaramide unit is to provide hydrogen-bonding interac-
tions to stabilize the transition state. On the basis of pre-
vious reports in the literature,[5d,5f] we proposed a possible
mechanism for this tertiary amine-squaramide catalyzed
enantioselective Strecker reaction (see Figure 3). Squar-
amide organocatalyst II activates heteroaromatic imine 1a
through a double hydrogen-bonding interaction between
the two NH groups of the squaramide catalyst and the two
N atoms of heteroaromatic imine 1a. The basic quinuclidine
moiety of the squaramide catalyst activates the HCN that
is generated in situ from TMSCN. The nucleophilic cyanide
group then attacks the C=N double bond of imine 1a from
the most favored re face through a transition state that leads
to amino nitrile product 3a [(S) configuration] with excel-
lent enantioselectivity, as observed in the investigation.
To demonstrate the value of this method, some synthetic
transformations were performed (see Scheme 2). Addition
[a] Reactions were carried out by using imine 1 (0.1 mmol) and
TMSCN (2, 19.8 mg, 0.2 mmol) with EtOH (0.2 mmol) in CH2Cl2
(1 mL) at –15 °C. [b] Isolated yield after purification by column
chromatography. [c] Determined by HPLC analysis.
Eur. J. Org. Chem. 2014, 6190–6199
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H.-X. He, D.-M. Du
FULL PAPER
Scheme 1. Control experiments for the formation of rac-3a.
Scheme 2. The synthetic transformations of 3a (TEA = triethylamine, DIPEA = N,N-diisopropylethylamine).
product 3a is a versatile synthetic organic intermediate and
can be converted into important chiral compounds. When
3a, phenyl isothiocyanate, and a catalytic amount of trieth-
ylamine in N,N-dimethylformamide (DMF) was heated at
reflux, thiourea derivative 4 and tautomer 4Ј were afforded
in 71% total yield. Product 4 was obtained with excellent
enantioselectivity (up to 99% ee). It is interesting that when
we performed the same reaction in toluene, product 4Ј was
obtained as the sole product in 95% yield. Product 3a could
also be reduced by treatment with LiAlH4 to afford the cor-
responding amine, which readily underwent a reaction with
triphosgene to afford imidazolidinone 5 without the loss of
stereochemical purity.
Conclusions
In summary, we have developed an efficient enantioselec-
tive Strecker reaction between imines that contain a benzo-
thiazole moiety and TMSCN by using a cinchona-based
squaramide catalyst. A variety of imines that have electron-
Figure 3. Proposed mechanism for the enantioselective Strecker re-
action of imine 1a with TMSCN (2).
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Organocatalytic Enantioselective Strecker Reaction
4-methylpentanamide (0.422 g, 1.0 mmol). After stirring at room
temperature for 48 h, chromatography on a silica gel column (meth-
anol/ethyl acetate 1:10) directly afforded squaramide catalyst IX
withdrawing and -donating substituents at different posi-
tions of the aromatic ring were investigated, and the corre-
sponding products were obtained in good to excellent yields
(up to 99%) with excellent enantioselectivities (up to
98% ee). Further studies of squaramide-catalyzed asym-
metric reactions and the enantioselective syntheses of other
useful chiral molecules are currently underway in our labo-
ratory.
(0.619 g, 85% yield) as a yellow solid; m.p. 210–212 °C. [α]2D5
=
–148.4 (c = 1.0, CH2Cl2). 1H NMR (400 MHz, [D6]DMSO): δ =
10.53 (s, 1 H), 10.03 (s, 0.3 H), 9.31–8.91 (m, 1.4 H), 8.79 (d, J =
4.0 Hz, 1 H), 8.42 (s, 1 H), 8.21 (br. s, 1 H), 8.08 (s, 2 H), 7.97 (d,
J = 9.2 Hz, 1 H), 7.75 (s, 1 H), 7.63 (s, 1 H), 7.60 (br. s, 1 H), 7.43
(d, J = 7.6 Hz, 1 H), 7.36 (s, 0.3 H), 5.99 (br. s, 1 H), 5.67 (br. s, 1
H), 5.06 (br. s, 2 H), 4.64 (s, 1 H), 3.96 (s, 3 H), 3.40–3.20 (m, 3
H), 2.72 (br. s, 1 H), 2.31–2.15 (m, 2 H), 1.58 (br. s, 3 H), 0.95–
0.91 (m, 6 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.7,
184.0, 180.3, 176.4, 169.0, 162.5, 157.4, 147.5, 144.1, 143.1, 141.1,
Experimental Section
General Methods: Commercially available compounds were used
without further purification. Solvents were dried according to stan-
dard procedures. Column chromatography was carried out by using
silica gel (200–300 mesh). Melting points were measured on a XT-
2
1
131.3 (q, JC,F = 32.7 Hz), 131.2, 124.7, 123.0 (q, JC,F
=
–271.1 Hz), 122.0, 121.2, 117.8, 117.1, 114.5, 102.3, 61.2, 59.6, 55.6,
40.8, 21.0, 20.6, 18.4, 16.6, 13.9 ppm. IR (KBr): ν = 3268, 3085,
˜
2964, 2880, 1796, 1378, 1329, 1191, 1032, 999, 934, 881, 849, 825,
701, 689, 620 cm–1. HRMS (ESI): calcd. for C37H38F6N5O4 [M +
H]+ 730.28225; found 730.28080.
1
4 melting point apparatus. The H NMR spectroscopic data were
recorded with a Varian Mercury-plus 400 MHz or Bruker Avance
400 MHz spectrometer, and the 13C NMR spectroscopic data were
recorded at 100 MHz. Infrared spectra were obtained with a Per-
kin–Elmer Spectrum One FTIR spectrometer. High resolution
mass spectra (electron spray ionization) were measured with a
Bruker APEX IV Fourier-Transform mass spectrometer. Optical
rotations were measured on a WZZ-3 polarimeter, and the indi-
cated concentrations are reported in units of g100 mL–1. The enan-
tiomeric excess values (ee) of the products were determined by chi-
ral HPLC analysis using an Aglient HP 1200 instrument (n-hexane/
2-propanol mixture as eluent). The squaramide catalysts I–IV, VI,
and VII were prepared according to a literature procedure.[11]
General Procedure for the Enantioselective Strecker Reaction of
Imines with TMSCN: Imine 1 (0.1 mmol), TMSCN (2, 19.8 mg,
0.2 mmol), catalyst II (3.2 mg, 0.005 mmol), and EtOH (0.2 mmol)
in CH2Cl2 (2 mL) was stirred at –15 °C for 4–48 h. After the reac-
tion reached completion, the components of the mixture were di-
rectly separated by chromatography on a silica gel column (petro-
leum ether/ethyl acetate, 5:1), and pure product 3 was obtained.
2-(Benzothiazol-2-ylamino)-2-phenylacetonitrile (3a): Following the
general procedure afforded compound 3a (26.2 mg, 99% yield) as
a yellow solid; m.p. 153–155 °C. HPLC analysis (Daicel Chiralpak
AD-H column; n-hexane/2-propanol, 80:20; flow rate: 1.0 mL
min–1; detection at 254 nm): tR = 8.2 (minor enantiomer) and
7.3 min (major enantiomer); 96% ee. [α]2D5 = –32.4 (c = 0.84,
Synthesis of Squaramide Catalysts VIII and IX
(S)-2-{2-[3,5-Bis(trifluoromethyl)phenylamino]-3,4-dioxocyclobut-
1-enylamino}-N-[(S)-(6-methoxyquinolin-4-yl)(8-vinylquinuclidin-2-
yl)methyl]-3-phenylpropanamide (VIII): To a solution of 3-[3,5-
bis(trifluoromethyl)phenylamino]-4-methoxycyclobut-3-ene-1,2-
dione (0.339 g, 1.0 mmol) in CH2Cl2 (10 mL) was added (S)-2-
amino-N-[(S)-(6-methoxyquinolin-4-yl)(8-vinylquinuclidin-2-
yl)methyl]-3-phenylpropanamide[13] (0.470 g, 1.0 mmol). After stir-
ring at room temperature for 48 h, chromatography on a silica gel
column (methanol/ethyl acetate, 1:10) directly afforded squaramide
catalyst VIII (0.637 g, 82 % yield) as a yellow solid; m.p. 190–
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 1
H, ArH), 7.62–7.59 (m, 3 H, ArH), 7.46–7.44 (m, 3 H, ArH), 7.35
(t, J = 7.6 Hz, 1 H, ArH), 7.18 (t, J = 7.8 Hz, 1 H, ArH), 6.21 (s,
1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.7, 151.4,
132.9, 129.8, 129.4, 127.3, 126.2, 123.0, 121.0, 120.2, 117.5,
49.4 ppm. IR (KBr): ν = 3343, 3158, 2956, 2731, 1955, 1723, 1594,
˜
1566, 1536, 1496, 1454, 1444, 1313, 1288, 1267, 1215, 1128, 1069,
1016, 924, 911, 845, 763, 753, 725, 695 cm–1. HRMS (ESI): calcd.
for C15H12N3S [M + H]+ 266.07464; found 266.07398.
1
191 °C. [α]2D5 = –157.6 (c = 1.0, CH2Cl2). H NMR [400 MHz, di-
2-(Benzothiazol-2-ylamino)-2-(4-fluorophenyl)acetonitrile (3b): Fol-
lowing the general procedure afforded compound 3b (28.0 mg, 99%
yield) as a yellow solid; m.p. 122–123 °C. HPLC analysis (Daicel
Chiralpak IB column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 7.5 (minor enantiomer)
and 6.3 min (major enantiomer); 95% ee. [α]2D5 = –31.3 (c = 1.92,
methyl sulfoxide-d6 ([D6]DMSO)]: δ = 10.58 (s, 1 H), 9.15 (s, 1 H),
8.81 (d, J = 4.0 Hz, 1 H), 8.23 (d, J = 6.0 Hz, 1 H), 8.07 (s, 2 H),
7.99 (d, J = 8.8 Hz, 1 H), 7.76 (s, 1 H), 7.63 (s, 2 H), 7.42 (d, J =
9.2 Hz, 1 H), 7.27–7.23 (m, 5 H), 6.00–5.73 (m, 2 H), 5.12–5.00 (m,
3 H), 3.95 (s, 3 H), 3.50–3.27 (m, 4 H), 3.07–3.02 (m, 1 H), 2.84
(br. s, 2 H), 2.32 (br. s, 1 H), 1.70–1.50 (m, 4 H), 0.83–0.75 (m, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 187.8, 183.8,
180.3, 176.4, 168.6, 162.5, 157.4, 147.5, 144.1, 141.1, 135.9, 131.4,
1
CH2Cl2). H NMR (400 MHz, CD3COCD3): δ = 7.79–7.73 (m, 3
H, ArH), 7.61 (d, J = 8.0 Hz, 1 H, ArH), 7.37–7.33 (m, 1 H, ArH),
7.31–7.25 (m, 2 H, ArH), 7.19–7.15 (m, 1 H, ArH), 6.40 (s, 1 H,
CH) ppm. 13C NMR (100 MHz, CD3COCD3): δ = 166.0, 164.9 (d,
2
131.31 (q, JC,F = 32.7 Hz), 131.27, 129.8, 128.0, 126.5, 123.1 (q,
1JC,F = –271.1 Hz), 121.2, 117.7, 114.4, 102.3, 57.4, 55.6, 54.4, 40.9,
4
1JC,F = –245.1 Hz), 153.7, 133.2, 132.2 (d, JC,F = 3.0 Hz), 131.6
30.5, 30.0, 27.1, 21.1, 18.6 ppm. IR (KBr): ν = 3275, 3033, 2944,
˜
(d, 3JC,F = 8.6 Hz), 127.8, 124.3, 122.9, 121.5, 119.8, 117.8 (d, 2JC,F
2869, 1796, 1683, 1604, 1552, 1511, 1473, 1378, 1330, 1279, 1244,
1231, 1182, 1135, 1031, 999, 933, 882, 851, 831, 748, 733, 700, 682,
620 cm–1. HRMS (ESI): calcd. for C41H38F6N5O4 [M + H]+
778.28225; found 778.28223.
= 21.9 Hz), 49.9 ppm. IR (KBr): ν = 3343, 3071, 2958, 2897, 2242,
˜
1890, 1596, 1564, 1539, 1510, 1486, 1456, 1441, 1414, 1316, 1287,
1235, 1206, 1161, 1121, 1084, 1015, 937, 925, 860, 817, 806, 749,
724, 654 cm–1. HRMS (ESI): calcd. for C15H11FN3S [M + H]+
284.06522; found 284.06605.
(S)-2-{2-[3,5-Bis(trifluoromethyl)phenylamino]-3,4-dioxocyclobut-
1-enylamino}-N-[(S)-(6-methoxyquinolin-4-yl)(8-vinylquinuclidin-2-
yl)methyl]-4-methylpentanamide (IX): To a solution of 3-[3,5-bis(tri-
fluoromethyl)phenylamino]-4-methoxycyclobut-3-ene-1,2-dione
2-(Benzothiazol-2-ylamino)-2-(2-chlorophenyl)acetonitrile (3c): Fol-
lowing the general procedure afforded compound 3c (28.4 mg, 95%
(0.339 g, 1.0 mmol) in CH2Cl2 (10 mL) was added (S)-2-amino-N- yield) as a yellow solid; m.p. 144–145 °C. HPLC analysis (Daicel
[(S)-(6-methoxyquinolin-4-yl)(8-vinylquinuclidin-2-yl)methyl]- Chiralpak IB column; n-hexane/2-propanol, 80:20; flow rate:
Eur. J. Org. Chem. 2014, 6190–6199
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6195

H.-X. He, D.-M. Du
FULL PAPER
1.0 mLmin–1; detection at 254 nm): tR = 7.1 (minor enantiomer)
90 % yield) as a yellow solid; m.p. 128–130 °C. HPLC analysis
(Daicel Chiralpak IB column; n-hexane/2-propanol, 80:20; flow
and 6.2 min (major enantiomer); 94% ee. [α]2D5 = –18.9 (c = 1.85,
CH2Cl2). 1H NMR (400 MHz, [D6]DMSO): δ = 9.24 (d, J = rate: 1.0 mLmin–1; detection at 254 nm): tR = 9.7 (minor enantio-
7.2 Hz, 1 H, NH), 7.86 (d, J = 6.8 Hz, 1 H, ArH), 7.78 (d, J = mer) and 8.2 min (major enantiomer); 97% ee. [α]2D5 = –18.8 (c =
8.0 Hz, 1 H, ArH), 7.63 (d, J = 8.0 Hz, 1 H, ArH), 7.58 (d, J =
0.96, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J =
8.0 Hz, 1 H, ArH), 7.54–7.47 (m, 2 H, ArH), 7.36 (t, J = 7.8 Hz, 8.4 Hz, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 1 H, ArH), 7.49 (d, J =
1 H, ArH), 7.15 (t, J = 7.6 Hz, 1 H, ArH), 6.54 (d, J = 7.2 Hz, 1 8.8 Hz, 2 H, ArH), 7.34 (t, J = 7.6 Hz, 1 H, ArH), 7.17 (t, J =
H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.6, 151.2, 7.6 Hz, 1 H, ArH), 6.92 (d, J = 8.8 Hz, 2 H, ArH), 6.10 (s, 1 H,
133.6, 131.3, 130.9, 130.5, 130.4, 129.5, 127.7, 126.2, 122.9, 121.0,
CH), 5.73 (br. s, 1 H, NH), 3.81 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.8, 160.6, 151.4, 131.0, 128.7, 126.2,
124.8, 122.8, 121.0, 120.1, 117.7, 114.7, 55.4, 48.9 ppm. IR (KBr):
120.2, 116.9, 47.5 ppm. IR (KBr): ν = 3157, 2963, 2926, 2850, 1730,
˜
1593, 1534, 1508, 1472, 1444, 1262, 1218, 1097, 1071, 1051, 1019,
934, 802, 768, 758, 724, 704, 657 cm–1. HRMS (ESI): calcd. for ν = 3345, 3055, 2999, 2959, 2936, 2839, 2254, 1895, 1611, 1597,
˜
C15H11ClN3S [M + H]+ 300.03567; found 300.03618.
1563, 1541, 1512, 1465, 1453, 1444, 1420, 1295, 1271, 1252, 1209,
1182, 1126, 1081, 1031, 934, 911, 852, 816, 757, 728, 657 cm–1
.
2-(Benzothiazol-2-ylamino)-2-(4-bromophenyl)acetonitrile (3d): Fol-
lowing the general procedure afforded compound 3d (34.0 mg, 99%
yield) as a white solid; m.p. 150–152 °C. HPLC analysis (Daicel
Chiralpak IB column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 8.4 (minor enantiomer)
and 7.1 min (major enantiomer); 86% ee. [α]2D5 = –4.8 (c = 0.54,
HRMS (ESI): calcd. for C16H14N3OS [M + H]+ 296.08521; found
296.08532.
2-(Benzothiazol-2-ylamino)-2-(3,4-dimethoxyphenyl)acetonitrile
(3h): Following the general procedure afforded compound 3h
(26.0 mg, 80 % yield) as a white solid; m.p. 103–105 °C. HPLC
analysis (Daicel Chiralpak IB column; n-hexane/2-propanol, 90:10;
flow rate: 1.0 mLmin–1; detection at 254 nm): tR = 28.3 (minor
enantiomer) and 25.1 min (major enantiomer); 98% ee. [α]2D5 = –5.7
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.62 (t, J = 7.8 Hz, 2
H, ArH), 7.56 (d, J = 8.4 Hz, 2 H, ArH), 7.46 (d, J = 8.4 Hz, 2 H,
ArH), 7.35 (t, J = 7.8 Hz, 1 H, ArH), 7.19 (t, J = 7.6 Hz, 1 H,
ArH), 6.20 (s, 1 H, CH), 5.84 (br. s, 1 H, NH) ppm. 13C NMR
(100 MHz, CD3COCD3): δ = 165.9, 153.6, 135.4, 134.0, 133.2,
131.3, 127.8, 124.8, 124.3, 122.9, 121.5, 119.5, 50.0 ppm. IR (KBr):
1
(c = 0.53, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.68 (d, J =
8.0 Hz, 1 H, ArH), 7.63 (d, J = 7.6 Hz, 1 H, ArH), 7.37 (t, J =
7.8 Hz, 1 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.05 (d, J = 2.0 Hz,
1 H, ArH), 6.90 (d, J = 8.4 Hz, 1 H, ArH), 6.13 (s, 1 H, CH), 5.56
(br. s, 1 H, NH), 3.90 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 163.6, 151.5, 150.2, 149.6, 131.1,
126.3, 125.1, 123.0, 121.0, 120.2, 119.9, 117.6, 111.4, 110.2, 56.1,
ν = 3312, 3071, 3009, 2889, 2249, 1676, 1595, 1541, 1488, 1455,
˜
1442, 1400, 1265, 1212, 1125, 1073, 1012, 937, 855, 806, 751,
724 cm–1. HRMS (ESI): calcd. for C15H11BrN3S [M + H]+
343.98516; found 343.98565.
2-(Benzothiazol-2-ylamino)-2-(2-methoxyphenyl)acetonitrile (3e):
Following the general procedure afforded compound 3e (28.0 mg,
95 % yield) as a white solid; m.p. 165–167 °C. HPLC analysis
(Daicel Chiralpak IB column; n-hexane/2-propanol, 80:20; flow
rate: 1.0 mLmin–1; detection at 254 nm): tR = 10.7 (minor enantio-
mer) and 7.4 min (major enantiomer); 94% ee. [α]2D5 = +23.5 (c =
0.68, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J =
8.0 Hz, 1 H, ArH), 7.60 (d, J = 7.6 Hz, 1 H, ArH), 7.47 (d, J =
7.6 Hz, 1 H, ArH), 7.42 (t, J = 8.0 Hz, 1 H, ArH), 7.35 (t, J =
7.6 Hz, 1 H, ArH), 7.16 (t, J = 7.6 Hz, 1 H, ArH), 7.03–6.99 (m,
1 H, ArH), 6.22 (s, 1 H, CH), 5.99 (br. s, 1 H, NH), 3.96 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.1, 156.9, 151.4,
131.3, 130.9, 129.2, 126.0, 122.5, 121.2, 121.0, 120.8, 119.8, 117.7,
56.0, 49.2 ppm. IR (KBr): ν = 3442, 3318, 2964, 2937, 2839, 1725,
˜
1596, 1537, 1517, 1456, 1443, 1270, 1230, 1204, 1157, 1141, 1070,
1020, 857, 804, 758, 726 cm– 1 . HRMS (ESI): calcd. for
C17H16N3O2S [M + H]+ 326.09577; found 326.09601.
2-(Benzothiazol-2-ylamino)-2-(naphthalen-1-yl)acetonitrile (3i): Fol-
lowing the general procedure afforded compound 3i (28.9 mg, 92%
yield) as a yellow solid; m.p. 201–202 °C. HPLC analysis (Daicel
Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 9.9 (minor enantiomer)
and 7.4 min (major enantiomer); 95% ee. [α]2D5 = +34.3 (c = 1.51,
1
CH2Cl2). H NMR (400 MHz, CD3COCD3): δ = 8.11–7.99 (m, 5
H, ArH), 7.75 (d, J = 7.6 Hz, 1 H, ArH), 7.70 (d, J = 8.0 Hz, 1 H,
1
2
ArH), 7.64–7.56 (m, 3 H, ArH), 7.38 (dt, J = 1.2 Hz, J = 7.8 Hz,
111.4, 55.7, 45.9 ppm. IR (KBr): ν = 3188, 2976, 2842, 1946, 1905,
˜
1
2
1 H, ArH), 7.19 (dt, J = 1.0 Hz, J = 7.8 Hz, 1 H, ArH), 7.06 (s,
1 H, CH), 5.61 (s, 1 H, NH) ppm. 1 3 C NMR (100 MHz,
CD3COCD3): δ = 166.0, 153.8, 136.0, 133.2, 132.3, 132.1, 131.0,
130.8, 129.2, 128.4, 128.1, 127.8, 127.1, 124.8, 124.3, 123.0, 121.5,
1783, 1720, 1593, 1528, 1496, 1466, 1444, 1433, 1290, 1255, 1209,
1108, 1071, 1023, 917, 842, 796, 751, 724 cm–1. HRMS (ESI): calcd.
for C16H14N3OS [M + H]+ 296.08521; found 296.08531.
2-(Benzothiazol-2-ylamino)-2-p-tolylacetonitrile (3f): Following the
general procedure afforded compound 3f (27.0 mg, 97% yield) as
a yellow solid; m.p. 153–155 °C. HPLC analysis: (Daicel Chiralpak
IB column; n-hexane/2-propanol, 80:20; flow rate: 1.0 mLmin–1;
detection at 254 nm): tR = 7.1 (minor enantiomer) and 6.3 min
119.9, 48.8 ppm. IR (KBr): ν = 3166, 3055, 2967, 2713, 1964, 1932,
˜
1894, 1775, 1593, 1569, 1530, 1511, 1456, 1446, 1397, 1377, 1355,
1248, 1206, 1071, 1037, 1018, 922, 862, 811, 798, 776, 751,
724 cm–1. HRMS (ESI): calcd. for C19H14N3S [M + H]+ 316.09029;
found 316.09077.
1
(major enantiomer); 93% ee. [α]2D5 = –14.5 (c = 0.69, CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.0 Hz, 1 H, ArH), 7.60
(d, J = 8.0 Hz, 1 H, ArH), 7.47 (d, J = 8.0 Hz, 2 H, ArH), 7.37–
7.32 (m, 1 H, ArH), 7.24 (d, J = 8.0 Hz, 2 H, ArH), 7.19–7.15 (m,
1 H, ArH), 6.13 (s, 1 H, CH), 5.70 (br. s, 1 H, NH), 2.37 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.7, 151.4, 140.0,
131.0, 130.1, 129.9, 127.2, 126.2, 122.9, 121.0, 120.2, 117.6, 49.2,
2-(Benzothiazol-2-ylamino)-2-(furan-2-yl)acetonitrile (3j): Following
the general procedure afforded compound 3j (25.2 mg, 99% yield)
as a yellow solid; m.p. 139–140 °C. HPLC analysis (Daicel Chi-
ralpak IB column; n-hexane/2-propanol, 90:10; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 11.9 (minor enantiomer)
and 10.5 min (major enantiomer); 90% ee. [α]2D5 = +95.9 (c = 2.08,
1
21.2 ppm. IR (KBr): ν = 3309, 2963, 2922, 2244, 1598, 1536, 1455,
˜
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 1
1443, 1262, 1205, 1069, 1019, 930, 852, 813, 753, 724 cm–1. HRMS
H, ArH), 7.58 (d, J = 8.0 Hz, 1 H, ArH), 7.43 (d, J = 1.2 Hz, 1 H,
(ESI): calcd. for C16H14N3S [M + H]+ 280.09029; found 280.08946.
1
2
ArH), 7.34 (dt, J = 1.2 Hz, J = 7.6 Hz, 1 H, ArH), 7.18–7.14 (m,
2-(Benzothiazol-2-ylamino)-2-(4-methoxyphenyl)acetonitrile (3g): 1 H, ArH), 6.60 (d, J = 3.6 Hz, 1 H, ArH), 6.38 (dd, 1J = 3.4 Hz, 2J
Following the general procedure afforded compound 3g (26.5 mg,
= 1.8 Hz, 1 H, ArH), 6.27 (s, 1 H, CH) ppm. 13C NMR (100 MHz,
6196
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6190–6199

Organocatalytic Enantioselective Strecker Reaction
CDCl3): δ = 163.4, 151.1, 144.8, 144.2, 131.0, 126.2, 123.0, 121.0,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.3, 155.8, 145.4,
120.1, 115.9, 111.0, 110.3, 43.1 ppm. IR (KBr): ν = 3169, 3146, 132.8, 132.0, 129.6, 129.3, 127.2, 120.4, 117.7, 113.9, 105.2, 55.8,
˜
3117, 2958, 2765, 1948, 1719, 1671, 1594, 1537, 1517, 1455, 1445,
1380, 1311, 1276, 1240, 1222, 1149, 1129, 1070, 1014, 900, 880,
853, 831, 755, 725 cm–1. HRMS (ESI): calcd. for C13H10N3OS [M
+ H]+ 256.05391; found 256.05353.
49.3 ppm. IR (KBr): ν = 3344, 3011, 2961, 2929, 2823, 2248, 1602,
˜
1569, 1540, 1495, 1470, 1452, 1437, 1282, 1266, 1226, 1207, 1057,
1031, 870, 830, 821, 744, 695 cm–1. HRMS (ESI): calcd. for
C16H14N3OS [M + H]+ 296.08521; found 296.08523.
2-(Benzothiazol-2-ylamino)-2-(thiophen-2-yl)acetonitrile (3k): Fol-
2-(4-Methoxyphenyl)-2-(6-methylbenzothiazol-2-ylamino)aceto-
lowing the general procedure afforded compound 3k (25.2 mg, 93% nitrile (3o): Following the general procedure afforded compound
yield) as a yellow solid; m.p. 118–119 °C. HPLC analysis (Daicel
Chiralpak IB column; n-hexane/2-propanol, 85:15; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 9.0 (minor enantiomer)
and 7.8 min (major enantiomer); 96% ee. [α]2D5 = –11.3 (c = 0.53,
3o (27.8 mg, 90% yield) as a white solid; m.p. 132–133 °C. HPLC
analysis (Daicel Chiralpak IB column; n-hexane/2-propanol, 80:20;
flow rate: 1.0 mL min–1; detection at 254 nm): tR = 9.1 (minor
enantiomer) and 7.8 min (major enantiomer); 96% ee. [α]2D5 = –13.3
1
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 1
(c = 0.86, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.47 (t, J =
1
2
1
2
H, ArH), 7.53 (dd, J = 0.8 Hz, J = 8.0 Hz, 1 H, ArH), 7.33–7.28 8.4 Hz, 3 H, ArH), 7.35 (s, 1 H, ArH), 7.12 (dd, J = 1.0 Hz, J =
1
2
(m, 3 H, ArH), 7.15–7.11 (m, 1 H, ArH), 6.93 (dd, J = 3.6 Hz, J
8.2 Hz, 1 H, ArH), 6.89 (d, J = 8.8 Hz, 2 H, ArH), 6.03 (s, 1 H,
= 4.8 Hz, 1 H, ArH), 6.56 (br. s, 1 H, NH), 6.32 (d, J = 0.8 Hz, 1 CH), 3.78 (s, 3 H, OCH3), 2.39 (s, 3 H, CH3) ppm. 13C NMR
H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.6, 151.0, (100 MHz, CDCl3): δ = 163.4, 160.4, 149.0, 132.6, 130.9, 128.6,
135.0, 130.9, 127.8, 127.6, 127.1, 126.1, 122.9, 121.0, 119.9, 117.0,
127.3, 124.8, 120.9, 119.4, 117.8, 114.5, 55.3, 48.8, 21.2 ppm. IR
45.0 ppm. IR (KBr): ν = 3156, 2955, 2846, 2751, 1703, 1594, 1536,
(KBr): ν = 3343, 2996, 2956, 2916, 2835, 2255, 1896, 1879, 1750,
˜
˜
1517, 1456, 1445, 1359, 1312, 1280, 1214, 1129, 1069, 905, 852,
841, 755, 723 cm–1. HRMS (ESI): calcd. for C13H10N3S2 [M +
H]+ 272.03107; found 272.03172.
1604, 1600, 1542, 1509, 1463, 1442, 1420, 1310, 1296, 1273, 1248,
1219, 1202, 1183, 1036, 833, 813, 740, 709, 691 cm–1. HRMS (ESI):
calcd. for C17H16N3OS [M + H]+ 310.10086; found 310.10124.
2-(6-Chlorobenzothiazol-2-ylamino)-2-phenylacetonitrile (3l): Fol-
lowing the general procedure afforded compound 3l (27.0 mg, 90%
yield) as a yellow solid; m.p. 109–110 °C. HPLC analysis (Daicel
Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 8.6 (minor enantiomer)
and 7.7 min (major enantiomer); 92% ee. [α]2D5 = –47.2 (c = 0.50,
2-(6-Methoxybenzothiazol-2-ylamino)-2-(4-methoxyphenyl)aceto-
nitrile (3p): Following the general procedure afforded compound
3p (29.5 mg, 91% yield) as a white solid; m.p. 111–112 °C. HPLC
analysis (Daicel Chiralpak IB column; n-hexane/2-propanol, 80:20;
flow rate: 1.0 mLmin–1; detection at 254 nm): tR = 11.5 (minor
enantiomer) and 9.9 min (major enantiomer); 97% ee. [α]2D5 = –29.3
1
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.60–7.54 (m, 4 H, (c = 1.55, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.46 (d, J =
ArH), 7.46–7.45 (m, 3 H, ArH), 7.31 (dd, 1J = 2.0 Hz, 2J = 8.8 Hz,
8.8 Hz, 1 H, ArH), 7.42 (d, J = 8.8 Hz, 2 H, ArH), 7.04 (d, J =
1 H, ArH), 6.18 (s, 1 H, CH), 5.64 (br. s, 1 H, NH) ppm. 13C NMR 2.4 Hz, 1 H, ArH), 6.89–6.82 (m, 3 H, ArH), 6.30 (br. s, 1 H, NH),
(100 MHz, CDCl3): δ = 164.2, 149.8, 132.4, 132.1, 129.7, 129.3, 5.98 (s, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3) ppm.
128.0, 127.1, 126.6, 120.54, 120.51, 117.5, 49.3 ppm. IR (KBr): ν =
13C NMR (100 MHz, CD3COCD3): δ = 162.3, 160.3, 155.7, 145.4,
˜
3152, 3063, 2959, 2745, 1963, 1894, 1711, 1589, 1559, 1534, 1515,
1450, 1405, 1305, 1269, 1219, 1183, 1064, 1055, 928, 857, 822, 791,
761, 697 cm–1. HRMS (ESI): calcd. for C15H11ClN3S [M + H]+
300.03567; found 300.03654.
131.9, 128.6, 124.7, 120.2, 117.9, 114.5, 113.7, 105.2, 55.7, 55.2,
48.8 ppm. IR (KBr): ν = 3364, 3320, 3018, 2959, 2938, 2837, 2246,
˜
2050, 1896, 1604, 1584, 1568, 1539, 1515, 1482, 1469, 1438, 1340,
1303, 1258, 1226, 1183, 1118, 1097, 1057, 1028, 878, 831, 821, 792,
738, 728, 708 cm–1. HRMS (ESI): calcd. for C17H16N3O2S [M +
H]+ 326.09577; found 326.09558.
2-(6-Methylbenzothiazol-2-ylamino)-2-phenylacetonitrile (3m): Fol-
lowing the general procedure afforded compound 3m (25.9 mg,
93 % yield) as a yellow solid; m.p. 128–130 °C. HPLC analysis
(Daicel Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow
rate: 1.0 mLmin–1; detection at 254 nm): tR = 10.0 (minor enantio-
mer) and 8.4 min (major enantiomer); 96% ee. [α]2D5 = –48.0 (c =
2-Phenyl-2-(thiazol-2-ylamino)acetonitrile (3q): Following the gene-
ral procedure afforded compound 3q (21.2 mg, 99% yield) as a
white solid; m.p. 169–171 °C. HPLC analysis (Daicel Chiralpak
AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 8.1 (minor enantiomer)
and 7.0 min (major enantiomer); 0% ee. 1H NMR (400 MHz,
1
0.82, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.59–7.57 (m, 2
H, ArH), 7.52 (d, J = 8.0 Hz, 1 H, ArH), 7.43–7.42 (m, 3 H, ArH),
7.38 (s, 1 H, ArH), 7.15 (d, J = 8.0 Hz, 1 H, ArH), 6.17 (s, 1 H, CDCl3): δ = 7.60–7.58 (m, 2 H, ArH), 7.47–7.44 (m, 3 H, ArH),
CH), 5.75 (br. s, 1 H, NH), 2.41 (s, 3 H, CH3) ppm. 13C NMR 7.03 (d, J = 3.2 Hz, 1 H, ArH), 6.62 (d, J = 3.2 Hz, 1 H, ArH),
(100 MHz, CD3COCD3): δ = 165.4, 151.7, 136.1, 134.0, 133.3, 5.84 (s, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.7,
131.2, 131.0, 129.3, 128.9, 122.9, 121.1, 120.0, 50.6, 22.2 ppm. IR
138.7, 132.9, 129.7, 129.3, 127.3, 117.5, 109.1, 50.3 ppm. IR (KBr):
(KBr): ν = 3356, 2919, 2247, 1602, 1588, 1565, 1536, 1498, 1453, ν = 3159, 3115, 3038, 2953, 2238, 1955, 1804, 1743, 1602, 1546,
˜
˜
1254, 1215, 1200, 1073, 1032, 926, 813, 746, 697 cm–1. HRMS
(ESI): calcd. for C16H14N3S [M + H]+ 280.09029; found 280.09028.
1511, 1488, 1451, 1334, 1315, 1227, 1157, 1074, 1058, 938, 920,
746, 730, 694, 628, 609 cm–1. HRMS (ESI): calcd. for C11H10N3S
[M + H]+ 216.05899; found 216.05876.
2-(6-Methoxybenzothiazol-2-ylamino)-2-phenylacetonitrile (3n): Fol-
lowing the general procedure afforded compound 3n (27.7 mg, 94%
yield) as a yellow solid; m.p. 168–170 °C. HPLC analysis (Daicel
Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 12.1 (minor enantiomer)
and 10.5 min (major enantiomer); 96% ee. [α]2D5 = –55.2 (c = 0.50,
2-(4-Chlorophenyl)-2-(1,3,4-thiadiazol-2-ylamino)acetonitrile (3r):
Following the general procedure afforded compound 3r (24.7 mg,
99% yield) as a white solid; m.p. 107–109 °C. HPLC analysis
(Daicel Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow
rate: 1.0 mLmin–1; detection at 254 nm): tR = 6.9 (minor enantio-
mer) and 7.7 min (major enantiomer); 0% ee. 1H NMR (400 MHz,
CD3COCD3): δ = 8.76 (s, 1 H, ArH), 7.96 (s, 1 H, NH), 7.72 (d, J
= 8.4 Hz, 2 H, ArH), 7.55 (d, J = 8.4 Hz, 2 H, ArH), 6.28 (s, 1 H,
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 4.4 Hz, 2
H, ArH), 7.55 (d, J = 8.8 Hz, 1 H, ArH), 7.45–7.43 (m, 3 H, ArH),
1
2
7.12 (d, J = 2.4 Hz, 1 H, ArH), 6.94 (dd, J = 2.4 Hz, J = 8.8 Hz,
1 H, ArH), 6.16 (s, 1 H, CH), 5.53 (br. s, 1 H, NH), 3.83 (s, 3 H, CH) ppm. 13C NMR (100 MHz, CD3COCD3): δ = 167.9, 146.3,
Eur. J. Org. Chem. 2014, 6190–6199
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6197

H.-X. He, D.-M. Du
FULL PAPER
136.7, 134.8, 131.2, 131.0, 119.4, 50.7 ppm. IR (KBr): ν = 3319,
1-(Benzothiazol-2-yl)-4-imino-3,5-diphenylimidazolidine-2-thione
(5): A solution of Strecker adduct 3a (0.71 mmol, 190 mg) in anhy-
drous THF (2.0 mL) was added to a suspension of LiAlH4
˜
3089, 2961, 2698, 2241, 1902, 1783, 1600, 1503, 1490, 1444, 1408,
1288, 1272, 1235, 1200, 1094, 1043, 1017, 936, 893, 875, 824, 805,
751, 714 cm–1. HRMS (ESI): calcd. for C10H8ClN4S [M + H]+ (3.0 mmol, 117 mg) in anhydrous THF (15 mL) at 0 °C. The reac-
251.01527; found 251.01476.
tion mixture was warmed to room temperature and stirred over-
night. AcOEt (15 mL) and water (6 mL) were sequentially added
dropwise to the reaction mixture until a white solid was formed.
The mixture was filtered, and the filtrate was dried with Na2SO4.
The solvent was removed in vacuo to give the crude amine, which
was dissolved in anhydrous CH2Cl2 (6 mL). To this solution was
added diisopropylamine (0.45 mL, 2.25 mmol) dropwise at 0 °C.
After 15 min, a solution of triphosgene (267 mg, 0.9 mmol) in an-
hydrous CH2Cl2 (3 mL) was added dropwise, and the reaction mix-
ture was warmed to room temperature and then stirred overnight.
The reaction mixture was diluted with CH2Cl2 (10 mL), and the
resulting mixture was washed with water (10 mL) and brine
(20 mL) and then dried with Na2SO4. The solvent was removed in
vacuo. The crude residue was purified by chromatography on a
silica gel column (CH2Cl2/MeOH, 40:1) to afford the correspond-
ing imidazolidinone 5 (176 mg, 84% yield) as a white solid; m.p.
276–278 °C. HPLC (Daicel Chiralpak AD-H column; n-hexane/2-
propanol, 80:20; flow rate: 1.0 mLmin–1; detection at 254 nm): tR
= 24.3 (minor enantiomer) and 9.4 min (major enantiomer);
98% ee. [α]2D5 = +123.6 (c = 0.50, CH2Cl2). 1H NMR (400 MHz,
[D6]DMSO): δ = 8.00 (s, 1 H, NH), 7.88 (dd, 1J = 0.8 Hz, 2J =
8.0 Hz, 1 H, ArH), 7.52 (d, J = 8.0 Hz, 1 H, ArH), 7.37–7.24 (m,
2-Phenyl-2-(p-toluidino)acetonitrile (3s): Following the general pro-
cedure afforded compound 3s (19.2 mg, 93% yield) as a white solid;
m.p. 107–109 °C. HPLC analysis (Daicel Chiralpak IB column; n-
hexane/2-propanol, 80:20; flow rate: 1.0 mLmin–1; detection at
254 nm): tR = 12.5 (minor enantiomer) and 8.6 min (major enantio-
mer); 7% ee. [α]2D5 = +8.6 (c = 1.23, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.58–7.56 (m, 2 H, ArH), 7.43–7.41 (m, 3 H, ArH),
7.06 (d, J = 8.0 Hz, 2 H, ArH), 6.68 (d, J = 8.4 Hz, 2 H, ArH),
5.36 (s, 1 H, CH), 3.91 (br. s, 1 H, NH), 2.27 (s, 3 H, CH3) ppm.
IR (KBr): ν = 3332, 3057, 3026, 2921, 2242, 1877, 1617, 1521, 1494,
˜
1450, 1321, 1302, 1287, 1243, 1195, 1129, 1095, 1074, 1029, 922,
877, 821, 805, 752, 697 cm–1.
N-[Cyano(phenyl)methyl]-4-methylbenzenesulfonamide (3t): Follow-
ing the general procedure afforded compound 3t (26.1 mg, 90%
yield) as a white solid; m.p. 153–155 °C. HPLC analysis (Daicel
Chiralpak AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 15.3 (minor enantiomer)
and 11.2 min (major enantiomer); 17% ee. [α]2D5 = –2.0 (c = 0.60,
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.4 Hz, 2
H, ArH), 7.46–7.43 (m, 2 H, ArH), 7.42–7.39 (m, 3 H, ArH), 7.36
(d, J = 8.0 Hz, 1 H, ArH), 5.48 (d, J = 8.4 Hz, 1 H, CH), 5.14 (d,
J = 8.8 Hz, 1 H, NH), 2.46 (s, 3 H, CH ) ppm. IR (KBr): ν = 3254,
1
2
6 H, ArH), 7.21–7.17 (m, 1 H, ArH), 5.76 (dd, J = 9.2 Hz, J =
2.8 Hz, 1 H, CH), 4.07 (t, J = 9.4 Hz, 1 H, CH), 3.25 (dd, 1J =
9.2 Hz, 2J = 2.4 Hz, 1 H, CH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 157.2, 156.8, 148.9, 141.2, 131.7, 128.6, 127.5, 125.6,
˜
3
3060, 3036, 2938, 2860, 1913, 1599, 1491, 1454, 1439, 1334, 1303,
1184, 1159, 1092, 1055, 942, 902, 835, 808, 760, 699, 673 cm–1.
125.5, 122.8, 121.3, 120.1, 58.5, 46.9 ppm. IR (KBr): ν = 3233,
˜
Synthetic Transformations of Product 3a
3120, 2980, 2851, 1722, 1598, 1524, 1485, 1444, 1399, 1336, 1275,
1251, 1145, 1082, 1048, 1017, 988, 944, 930, 855, 798, 766, 752,
726, 702 cm–1. HRMS (ESI): calcd. for C16H14N3OS [M + H]+
296.08521; found 296.08567.
1-(Benzothiazol-2-yl)-4-imino-3,5-diphenylimidazolidine-2-thione
(4): A mixture of 3a (0.1 mmol) and phenyl isothiocyanate
(0.1 mmol) in DMF (10 mL) that contained a catalytic amount of
Et3N (4 drops) was heated at reflux for 24 h and then cooled to
room temperature. The reaction mixture was added to CH2Cl2
(20 mL), and the resulting mixture was washed with water (2ϫ
100 mL). The organic phase was washed with brine, dried with
Na2SO4, and concentrated in vacuo. The residue was purified by
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate, 5:1), and compounds 4 and 4Ј were obtained as a yellow solid
(28.4 mg, 71% yield); m.p. 217–219 °C. HPLC analysis (Daicel Chi-
ralpak AD-H column; n-hexane/2-propanol, 80:20; flow rate:
1.0 mLmin–1; detection at 254 nm): tR = 18.4 (minor enantiomer)
and 7.2 min (major enantiomer); 99% ee. [α]2D5 = +120.3 (c = 0.70,
CH2Cl2). HRMS (ESI): calcd. for C22H17N4S2 [M + H]+
401.08891; found 401.08910.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the HPLC chromatograms, 1H and 13C NMR spec-
tra of all new products.
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant number
21272024).
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(0.1 mmol) in PhMe (10 mL) that contained a catalytic amount of
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(s, 1 H, NH), 8.02 (d, J = 7.2 Hz, 1 H, NH), 7.65–7.53 (m, 6 H,
ArH), 7.49–7.34 (m, 8 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.7, 168.0, 157.1, 147.1, 136.1, 132.2, 131.0, 129.9,
129.8, 129.4, 129.3, 128.4, 126.5, 125.2, 124.9, 121.4, 121.2,
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˜
1680, 1636, 1594, 1544, 1502, 1482, 1442, 1399, 1371, 1345, 1316,
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6198
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6190–6199

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Received: June 17, 2014
Published Online: August 21, 2014
Eur. J. Org. Chem. 2014, 6190–6199
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6199