Strecker-type reaction catalyzed by carboxylic acids in aqueous media

Article abstract of DOI:10.1055/s-0029-1216805

Carboxylic acid catalyzed Strecker-type reactions were successfully carried out by simply mixing aldehydes, amines, tributyltin cyanide and carboxylic acid in aqueous media at room temperature, to afford α-aminonitriles in high yields. Georg Thieme Verlag

Full text of DOI:10.1055/s-0029-1216805

PAPER
2035
Strecker-Type Reaction Catalyzed by Carboxylic Acids in Aqueous Media
A
queous Streck
h
er-Type
R
ea
e
ction
C
ata
l
n
g
oxylic
A
cidsfeng Xie,a,b Guilong Li,c Gang Zhao,*c Jide Wang*a,b
a
School of Sciences, Xi’an Jiaotong University, Xi’an 710049, P. R. of China
b
College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R. of China
Fax +86(991)8582807; E-mail: awangjd@xju.edu.cn
c
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: Zhaog@mail.sioc.ac.cn
Received 16 December 2008; revised 19 February 2009
(Bu3SnCN) in water, the carboxylic acid might be regen-
erated, thus the Strecker-type reaction catalyzed by car-
boxylic acid could be achieved (Scheme 2). Herein, we
would like to describe the Strecker reaction catalyzed by
carboxylic acids in an aqueous media.
Abstract: Carboxylic acid catalyzed Strecker-type reactions were
successfully carried out by simply mixing aldehydes, amines, tribu-
tyltin cyanide and carboxylic acid in aqueous media at room tem-
perature, to afford a-aminonitriles in high yields.
Key words: Strecker reaction, a-aminonitriles, tributyltin cyanide,
carboxylic acid, aqueous media
R2
HN
carboxylic acid (1 equiv)
SnBu3
R1CHO + R2NH2
+
MeCN, r.t.
The Strecker reaction is one of the most efficient and
straightforward methods for the synthesis of a-aminoni-
triles,1 which are very important intermediates for the syn-
thesis of a-amino acids and various nitrogen-containing
heterocycles, such as thiadiazoles, imidazoles, etc.2 Gen-
erally, the classical Strecker reaction takes place through
nucleophilic addition of cyanide anions on imines, using
various kinds of catalysts or promoters, such as polymeric
scandium triflamide, BiCl3, NiCl2, RuCl3, Pr(OTf)3,
Yb(OTf)3, silica sulfuric acid, [HP(HNCH2CH2)3N]NO3,2c,3
Lanthanide-PYBOX complexes, chiral N,N¢-dioxide,
Al(salen)/triphenylphosphine oxide, iodine, and Montmo-
rillonite KSF clay, 4 etc. The Strecker reaction in ionic liq-
uids has also been reported.5 Additionally, several
modifications of the Strecker reaction have been reported,
which use a variety of cyanating agents such as a-trimeth-
ylsiloxynitriles, tributyltin cyanide or diethyl phosphoro-
cyanidate, under a variety of reaction conditions.6
Amongst these, tributyltin cyanide has been successfully
used by S. Kobayashi et al. as a safe cyanide source for the
Strecker reaction – the reagent is stable, easily handled
and more effective in the nucleophilic addition reactions
under mild conditions than hydrogen, sodium or potassi-
um cyanides.
R1
Scheme 1
In an initial experiment using pure water as solvent and
benzoic acid (20 mol%) as catalyst, the Strecker-type re-
action of benzaldehyde (0.2 mmol), aniline (0.2 mmol),
and tributyltin cyanide (0.22 mmol) was studied
(Table 1). To our delight, a moderate yield (67%) of the
desired a-amino nitrile 4a was produced (entry 1). There-
fore, several other carboxylic acids were then investigated
for this reaction. A number of dicarboxylic acids were
found to be highly efficient for promoting the Strecker re-
action (entries 5–7). For example, the acid A6 provided 4a
in a yield of 93% (entry 6). When 2,2¢-(4-methylbenzene-
sulfonamido)diacetic acid (A7) was utilized as a catalyst,
a quantitative yield was obtained. This is presumably due
to the fact that this dicarboxylic acid is more soluble in
water and thus functions not only as a catalyst but proba-
bly also as a surface-active agent. Decreasing the amount
of the catalyst A7 to 15 mol% resulted in a lower yield
(81%, entry 8). Compared with the results obtained using
water as solvent, similar Strecker reactions performed in
acetonitrile were also conducted. As shown in Table 1, a
yield of only 29% of 4a was obtained when the solvent
water was replaced with acetonitrile (entry 9). It is appar-
ent that at least one equivalent of acid A7 was needed in
order to promote the Strecker reaction and provide com-
parably good results in acetonitrile (99% yield, entry 11).
Recently, it was found that carboxylic acids are efficient
promoters for the allylation of aldehydes and imines with
tributylallyltin under mild reaction conditions.7 In all of
these reactions at least one equivalent of carboxylic acid
is necessary due to the production of the corresponding tin
ester of the carboxylic acid (Scheme 1). In our subsequent
studies to develop carboxylic acid-catalyzed reactions, we
considered that in the presence of the acid HCN, generat-
ed from carboxylic acid and tributyltin cyanide
However, we did not achieve satisfactory results (Table 2,
entries 1–8) when using other aldehydes and amines as
substrates; for example, p-anisaldehyde (37%, entry 1),
m-anisaldehyde (17%, entry 3), p-chlorobenzaldehyde
(39%, entry 5) and p-anisidine (13%, entry 7), all provid-
ed low yields. These results could be understood by the
fact that, except for catalyst A7, the starting materials and
products (generally, all are solid) are all insoluble in wa-
ter. Therefore, as we observed, the reaction took place
SYNTHESIS 2009, No. 12, pp 2035–2039
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216805; Art ID: F25408SS
© Georg Thieme Verlag Stuttgart · New York

2036
Z. Xie et al.
PAPER
R3CO2H
R3CO2
H2O
R2
H
R2
H
R3CO2H
N
HN
R1CHO
+
R2NH2
R1
1
2
R1
R3CO2
I
II
R2
HN
H
HCN
H3O
R1
CN
4
Bu3SnCN
3
Bu3SnOH
5
Scheme 2
completely heterogeneously in pure water. Good to high substrates, the Strecker-type reaction also proceeded
yields were obtained when a mixed solvent system (H2O– smoothly and provided moderate to very high yields of the
MeCN, 9:1) was used. Compared with the results obtained corresponding a-amino nitriles (entries 5, 14 and 15). Un-
using water as a solvent, the yields obtained by using fortunately, when the aliphatic amine of benzylamine was
mixed solvent were greatly increased (57%, entry 2; 67%, used as a substrate, none of the desired a-amino nitrile
entry 4; 86%, entry 6; 92%, entry 8).
was observed (entry 20).
With the optimal reaction conditions established (A7 as While the exact mechanism of the carboxylic acid-cata-
catalyst and H2O–MeCN, 9:1 as solvent), the scope of the lyzed Strecker-type reaction is not currently clear, a pos-
reaction was explored (Table 3). It is obvious that the car- sible mechanism was proposed (Scheme 2). It is known
boxylic acid A7 is an efficient catalyst for the Strecker- that the ability of water to dissociate an oxygen acid and
type reaction. For example, moderate to excellent yields to solvate the proton is much stronger than that of aceto-
were obtained in the cases of aromatic aldehydes (entries nitrile.8 Here, the carboxylic acid was hydrolyzed by wa-
1–7, 11 and 13). a-Furaldehyde also gave the desired a- ter to produce a carboxylate anion and a hydronium ion,
amino nitrile 4l in a moderate yield (65%, entry 12). In the which would react with tributyltin cyanide to give the
case of aliphatic aldehydes, such as butyraldehyde (78%, tributyltin hydroxide, HCN and regenerate carboxylic
entry 8), isobutyraldehyde (84%, entry 9), and cyclohex- acid at the same time. On the other hand, the carboxylic
anecarbaldehyde (86%, entry 10), the Strecker-type reac- acid could activate imine I by forming iminium II, which
tion catalyzed by carboxylic acid A7 in aqueous media can then be subjected nucleophilic attack by CN– to pro-
was also efficient. When aromatic amines were used as vide the a-amino nitrile 4. Therefore, in the presence of
Table 1 Development of the Strecker Reaction Catalyzed by Carboxylic Acids
Ph
HN
catalyst
Bu3SnCN
PhCHO
+
PhNH2
+
solvent, r.t.
Ph
CN
1a
2a
3
4a
Entry
Catalyst
Catalyst loading (mol%) Solvent
Yield (%)
67
1
2
PhCO2H (A1)
20
20
20
20
20
20
20
15
20
40
100
H2O
p-NO2C6H4CO2H (A2)
H2O
82
3
p-MeC6H4SO2NHCH2CO2H (A3)
p-MeC6H4SO3H (A4)
H2O
72
4
H2O
72
5
maleic acid (A5)
H2O
82
6
BnN(CH2CO2H)2 (A6)
H2O
93
7
p-MeC6H4SO2N(CH2CO2H)2 (A7)
p-MeC6H4SO2N(CH2CO2H)2 (A7)
p-MeC6H4SO2N(CH2CO2H)2 (A7)
p-MeC6H4SO2N(CH2CO2H)2 (A7)
p-MeC6H4SO2N(CH2CO2H)2 (A7)
H2O
100
81
8
H2O
9
MeCN
MeCN
MeCN
29
10
11
48
99
Synthesis 2009, No. 12, 2035–2039 © Thieme Stuttgart · New York

PAPER
Aqueous Strecker-Type Reaction Catalyzed by Carboxylic Acids
2037
Table 3 The Strecker-Type Reaction Catalyzed by Carboxylic Acid
A7
Table 2 Effect of Solvents on the Strecker-Type Reaction Cata-
lyzed by Carboxylic Acid A7
R2
R2
HN
R1
HN
A7 (20 mol%)
A7 (20 mol%)
R1CHO
+
R2NH2
+ Bu3SnCN
R1CHO
R2NH2
+
Bu3SnCN
+
H2O–MeCN (9:1), r.t.
CN
solvent, r.t.
R1
4a–s
CN
1
2
3
1
2
3
4b–e
Entry R1
R2
Product Yield (%)
Entry R1
R2
Solvent
H2O
ProductYield
(%)
1
2
Ph
Ph
4a
4b
4c
4d
4e
4f
99
57
67
86
92
92
58
78
84
86
1
2
3
4
5
6
7
8
p-MeOC6H4
p-MeOC6H4
Ph
Ph
4b
37
57
17
67
39
86
13
92
p-MeOC6H4
m-MeOC6H4
p-ClC6H4
Ph
Ph
H2O–MeCNa 4b
H2O 4c
H2O–MeCNa 4c
H2O 4d
H2O–MeCNa 4d
H2O 4e
H2O–MeCNa 4e
3
Ph
m-MeOC6H4 Ph
m-MeOC6H4 Ph
4
Ph
5
p-MeOC6H4
p-ClC6H4
p-ClC6H4
Ph
Ph
Ph
6
p-BrC6H4
2,4-Cl2C6H3
MeCH2CH2
Me2CH
Ph
Ph
Ph
Ph
Ph
7
4g
4h
4i
p-MeOC6H4
p-MeOC6H4
8
Ph
9
a Solvent ratio: H2O–MeCN, 9:1.
10
c-C6H11
4j
H3O+ in the aqueous media, as shown in Table 2, the equi-
librium between carboxylic acid, H3O+, and HCN, might
keep the catalytic cycle working. As supporting evidence
for this mechanism, we isolated the side-product
Bu3SnOH from the reaction mixture after workup using
silica gel chromatography. In conclusion, a carboxylic
acid-catalyzed Strecker-type reaction has been success-
fully developed. As expected, the reaction proceeded
smoothly in aqueous media to afford the corresponding a-
amino nitriles in moderate to quantitative yields under
mild reaction conditions.
11
12
Ph
Ph
4k
4l
81
65
O
13
14
15
16
17
18
19
20
p-MeC6H4
Ph
4m
4n
4o
4p
4q
4r
4s
–
69
54
100
82
77
81
39
–
Ph
p-ClC6H4
p-MeOC6H4
p-FC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
PhCH2
Me2CH
Ph
Ph
Solvents and reagents were purified using standard methods. Petro-
leum ether (PE) refers to the fraction boiling in the range 60–90 °C.
Flash column chromatography was performed on silica gel (300–
400 mesh, Qingdao, China). Melting points were measured on a
Mettler FP62 or WRS-1A apparatus and are uncorrected. 1H and 13C
NMR spectra were taken on EM-360A or Bruker AM-300 300 MHz
spectrometers with TMS as an internal standard (d = 0.00 ppm).
LRMS were obtained on a HP-5989A mass spectrometer. HRMS
were performed on Finigan MAT8403 mass spectrometer.
Ph
p-MeOC6H4
Ph
with 1 M HCl. The white precipitate was filtered and washed with
ice-water (5 mL) to afford the product A7.
Yield: 1.18 g (87%); white solid; mp 191–193 °C (Lit.10 yield 61%,
mp 193–194 °C).
(Toluene-4-sulfonylimino)diacetic Acid (A7)
Diethyl iminodiacetate9 (1.17 g, 6.19 mmol) and Et3N (0.71 g, 7.03
mmol) were dissolved in CHCl3, and TsCl (1.18 g, 6.20 mmol) was
added under cooling with an ice bath. The mixture was stirred at r.t.
for 24 h, then the organic layer was washed with H2O (3 × 5 mL),
dried (Na2SO4), and concentrated. The residue was purified by
chromatography over silica gel (PE–EtOAc, 95:5) to give pure es-
ter.
IR (KBr): 3415, 2948, 2552, 1720, 1660, 1367, 1255, 1157, 1093,
816, 777 cm–1.
1H NMR (D2O, 300 MHz): d = 2.23 (s, 3 H), 3.97 (s, 4 H), 7.24 (d,
J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H).
Strecker-Type Reaction; Typical Procedure
A mixture of benzaldehyde (21.2 mg, 0.2 mmol), aniline (18.6 mg,
0.2 mmol), Bu3SnCN (69.5 mg, 0.22 mmol) and (toluene-4-sulfo-
nylimino)diacetic acid (A7; 11.32 mg, 0.04 mmol) in either H2O (1
mL) or H2O–MeCN (1 mL, v/v = 9:1), was stirred at r.t. for 24 h.
The reaction was quenched with sat. aq NaHCO3 (3 mL) and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layer was dried over Na2SO4 and concentrated under
reduced pressure to furnish the crude product, which was purified
Yield: 1.66 g (80%).
1H NMR (CDCl3, 300 MHz): d = 1.14 (t, J = 7.2 Hz, 6 H), 2.35 (s,
3 H), 4.05 (q, J = 7.2 Hz, 4 H), 4.13 (s, 4 H), 7.21 (d, J = 8.4 Hz,
2 H), 7.65 (d, J = 8.4 Hz, 2 H).
The ester (1.66 g, 4.83 mmol) and NaOH (0.58 g, 14.50 mmol) in
H2O (10 mL) were refluxed until hydrolysis was complete (indicat-
ed by TLC). The mixture was cooled to r.t. and acidified to pH 3.0
Synthesis 2009, No. 12, 2035–2039 © Thieme Stuttgart · New York

2038
Z. Xie et al.
PAPER
by silica gel chromatography (typical eluent: PE–EtOAc, 25:1), to
afford 4a (41.6 mg, 100%). Tributyltin hydroxide (5) was recovered
by eluting with MeOH.
2-(Phenylamino)pentanenitrile (4h)11b
IR (film): 3371, 2962, 2932, 2874, 2232, 1604, 1505, 1465, 1313,
1260, 1155, 751, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.94 (t, J = 7.2 Hz, 3 H), 1.56 (m,
2 H), 1.85 (m, 2 H), 3.68 (d, J = 9.6 Hz, 1 H), 4.13 (dd, J = 7.2, 9.6
Hz, 1 H), 6.62 (d, J = 8.4 Hz, 2 H), 6.79 (m, 1 H), 7.17 (t, J = 7.5
Hz, 2 H).
Tributyltin Hydroxide (5)12
IR (film): 2955, 2923, 2854, 1073, 878, 773, 672 cm–1.
1H MNR (CDCl3, 300 MHz): d = 0.89–0.94 (t, J = 7.5 Hz, 9 H),
1.08–1.14 (m, 4 H), 1.25–1.38 (m, 8 H), 1.55–1.63 (m, 6 H), 1.86
(br, 1 H).
3-Methyl-2-(phenylamino)butanenitrile (4i)11b
IR (film): 3375, 2967, 2931, 2876, 2230, 1604, 1505, 1467, 1315,
1271, 1155, 751, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.18 (t, J = 7.5 Hz, 6 H), 2.17 (m,
1 H), 3.78 (d, J = 9.6 Hz, 1 H), 4.03 (dd, J = 6.0, 9.6 Hz, 1 H), 6.70
(d, J = 8.7 Hz, 2 H), 6.85 (t, J = 7.5 Hz, 1 H), 7.25 (t, J = 7.5 Hz,
2 H).
MS (EI, 70 eV): m/z (%) = 309 (2) [M + 2], 175 (6), 57 (27), 44
(100).
2-Phenyl-2-(phenylamino)acetonitrile (4a)11a
IR (film): 3372, 2923, 2230, 1602, 1503, 751, 693 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.05 (d, J = 8.4 Hz, 1 H), 5.40 (d,
J = 8.4 Hz, 1 H), 6.76 (d, J = 9.0 Hz, 2 H), 6.89 (t, J = 7.5 Hz, 1 H),
7.26 (t, J = 7.8 Hz, 2 H), 7.44 (m, 3 H), 7.58 (m, 2 H).
2-Cyclohexyl-2-(phenylamino)acetonitrile (4j)11a
IR (film): 3382, 2929, 2852, 2224, 1605, 1507, 1446, 748, 688 cm–1.
2-(4-Methyloxyphenyl)-2-(phenylamino)acetonitrile (4b)4f
IR (film): 3365, 2934, 2839, 2230, 1604, 1511, 1307, 1253, 1180,
1031, 836, 752, 693 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.18–1.28 (m, 6 H), 1.71–1.97 (m,
7 H), 3.79 (d, J = 9.0 Hz, 1 H), 4.13 (dd, J = 7.2, 9.0 Hz, 1 H), 6.70
(d, J = 7.5 Hz, 2 H), 6.85 (m, 1 H), 7.24 (t, J = 7.5 Hz, 2 H).
1H NMR (CDCl3, 300 MHz): d = 3.83 (s, 3 H), 3.99 (d, J = 8.1 Hz,
1 H), 5.34 (d, J = 8.1 Hz, 1 H), 6.76 (d, J = 9.0 Hz, 2 H), 6.95 (m,
3 H), 7.27 (d, J = 9.0 Hz, 2 H), 7.49 (d, J = 9.0 Hz, 2 H).
2-(Naphthalene-2-yl)-2-(phenylamino)acetonitrile (4k)11e
IR (film): 3368, 3054, 2237, 1602, 1503, 816, 750, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.10 (d, J = 8.4 Hz, 1 H), 5.39 (d,
J = 8.4 Hz, 1 H), 6.78 (d, J = 7.2 Hz, 2 H), 6.90 (m, 1 H), 7.27 (t,
J = 7.5 Hz, 2 H), 7.56 (m, 3 H), 7.90 (m, 3 H), 8.10 (s, 1 H).
2-(3-Methyloxyphenyl)-2-(phenylamino)acetonitrile (4c)11a
IR (film): 3364, 2924, 2852, 2230, 1602, 1504, 1318, 1257, 1157,
1047, 785, 751, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.82 (s, 3 H), 4.06 (d, J = 8.4 Hz,
1 H), 5.38 (d, J = 8.4 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 2 H), 6.87–6.97
(m, 2 H), 7.11 (m, 1 H), 7.13 (d, J = 8.1 Hz, 1 H), 7.26 (dd, J = 7.5,
8.1 Hz, 2 H), 7.36 (t, J = 8.1 Hz, 1 H).
2-(Furan-2-yl)-2-(phenylamino)acetonitrile (4l)4f
IR (film): 3368, 3054, 2925, 2230, 1604, 1501, 1249, 1015, 750,
692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.21 (d, J = 8.7 Hz, 1 H), 5.49 (d,
J = 8.7 Hz, 1 H), 6.41 (dd, J = 1.8, 3.0 Hz, 1 H), 6.58 (dd, J = 1.8,
3.0 Hz, 1 H), 6.78 (d, J = 7.5 Hz, 2 H), 6.91 (m, 1 H), 7.24–7.30 (m,
2 H), 7.47 (d, J = 0.9 Hz, 1 H).
2-(4-Chlorophenyl)-2-(phenylamino)acetonitrile (4d)11a
IR (film): 3363, 2924, 2230, 1603, 1492, 1262, 1093, 1015, 752,
691 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.05 (d, J = 8.7 Hz, 1 H), 5.39 (d,
J = 8.7 Hz, 1 H), 6.75 (d, J = 7.5 Hz, 2 H), 6.91 (m, 1 H), 7.27 (t,
J = 7.5 Hz, 2 H), 7.41 (d, J = 7.8 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 2 H).
2-(Phenylamino)-2-(p-tolyl)acetonitrile (4m)4f
IR (film): 3365, 2926, 2230, 1605, 1502, 1266, 1091, 750, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 2.30 (s, 3 H), 4.02 (d, J = 8.4 Hz,
1 H), 5.27 (d, J = 8.4 Hz, 1 H), 6.66 (d, J = 7.8 Hz, 2 H), 6.78 (t,
J = 7.5 Hz, 1 H), 7.12–7.19 (m, 4 H), 7.37 (d, J = 8.1 Hz, 2 H).
2-(4-Methyoxyphenylamino)-2-phenylacetonitrile (4e)11a
IR (film): 3348, 3034, 2934, 2834, 2230, 1513, 1453, 1244, 1180,
1033, 822, 744, 698 cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.80 (s, 3 H), 3.85 (d, J = 8.4 Hz,
1 H), 5.34 (d, J = 8.4 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 6.88 (d,
J = 8.7 Hz, 2 H), 7.47 (m, 3 H), 7.62 (m, 2 H).
2-(4-Chlorophenylamino)-2-phenylacetonitrile (4n)11a
IR (film): 3365, 3030, 2230, 1601, 1498, 1089, 817, 758, 698 cm–1.
1H NMR (CDCl3, 300 MHz): d = 4.09 (d, J = 8.4 Hz, 1 H), 5.39 (d,
J = 8.4 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H),
7.45 (m, 3 H), 7.56 (m, 2 H).
2-(4-Bromophenyl)-2-(phenylamino)acetonitrile (4f)11d
IR (film): 3385, 2926, 2235, 1603, 1503, 1265, 1074, 1012, 746,
704, 693 cm–1.
2-(4-Methoxyphenylamino)-3-methylbutanenitrile (4o)
Brown oil.
1H NMR (CDCl3, 300 MHz): d = 4.05 (d, J = 8.7 Hz, 1 H), 5.39 (d,
J = 8.7 Hz, 1 H), 6.75 (d, J = 7.5 Hz, 2 H), 6.89 (m, 1 H), 7.26 (t,
J = 7.5 Hz, 2 H), 7.46 (d, J = 7.8 Hz, 2 H), 7.58 (d, J = 7.8 Hz, 2 H).
IR (film): 3355, 2966, 2934, 2876, 2230, 1515, 1466, 1244, 1180,
1036, 822 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.17 (t, J = 6.6 Hz, 6 H), 2.13 (m,
1 H), 3.55 (d, J = 9.9 Hz, 1 H), 3.76 (s, 3 H), 3.95 (dd, J = 6.0, 9.9
Hz, 1 H), 6.70 (d, J = 9.0 Hz, 2 H), 6.82 (d, J = 9.0 Hz, 2 H).
13C NMR (CDCl3, 75 MHz): d = 18.3, 19.2, 31.7, 54.1, 55.7, 115.0,
115.0, 116.2, 116.2, 119.1, 139.1, 153.9.
2-(2,4-Dichlorophenyl)-2-(phenylamino)acetonitrile (4g)11f
1H NMR (CDCl3, 300 MHz): d = 4.02 (d, J = 8.4 Hz, 1 H), 5.67 (d,
J = 8.4 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 2 H), 6.92 (m, 1 H), 7.27 (m,
2 H), 7.36 (dd, J = 2.4, 8.4 Hz, 1 H), 7.50 (d, J = 1.8 Hz, 1 H), 7.67
(d, J = 8.4 Hz, 1 H).
LRMS (EI): m/z (%) = 204 (45) [M+], 161 (100).
IR (film): 3373, 2925, 2230, 1603, 1503, 1265, 1104, 1049, 742,
691 cm–1.
HRMS (EI): m/z calcd for C12H16N2O: 204.1263; found: 204.1266.
2-(4-Fluorophenylamino)-2-phenylacetonitrile (4p)11c
IR (film): 3363, 2919, 2230, 1608, 1511, 1225, 822, 747, 697 cm–1.
Synthesis 2009, No. 12, 2035–2039 © Thieme Stuttgart · New York

PAPER
Aqueous Strecker-Type Reaction Catalyzed by Carboxylic Acids
2039
1H NMR (CDCl3, 300 MHz): d = 3.99 (d, J = 8.4 Hz, 1 H), 5.35 (d,
J = 8.4 Hz, 1 H), 6.69–6.73 (m, 2 H), 6.93–6.99 (m, 2 H), 7.43–7.47
(m, 3 H), 7.56–7.59 (m, 2 H).
(3) (a) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron
Lett. 1996, 37, 9221. (b) De S, K.; Gibbs, R. A. Tetrahedron
Lett. 2004, 45, 7407. (c) De S, K. Synth. Commun. 2005, 35,
653. (d) De S, K.; Gibbs, R. A. Synth. Commun. 2005, 35,
961. (e) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett 1997,
115. (f) Chen, W.-Y.; Lu, J. Synlett 2005, 2993.
2-(4-Bromophenylamino)-2-phenylacetonitrile (4q)11c
IR (film): 3370, 2919, 2230, 1594, 1494, 1073, 814, 751, 697 cm–1.
(g) Fetterly, B. M.; Jana, N. K.; Verkade, J. G. Tetrahedron
2006, 62, 440.
1H NMR (CDCl3, 300 MHz): d = 4.12 (d, J = 8.1 Hz, 1 H), 5.35 (d,
J = 8.1 Hz, 1 H), 6.62–6.65 (d, J = 8.4 Hz, 2 H), 7.32–7.35 (d,
J = 8.4 Hz, 2 H), 7.43–7.45 (m, 3 H), 7.54–7.57 (m, 2 H).
(4) (a) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153.
(b) Jiao, Z.; Feng, X.; Liu, B.; Chen, F.; Zhang, G.; Jiang, Y.
Eur. J. Org. Chem. 2003, 3818. (c) Kim, S. S.; Kwak, J. M.
Tetrahedron 2006, 62, 49. (d) Royer, L.; De, S. K.; Gibbs,
R. A. Tetrahedron Lett. 2005, 46, 4595. (e) Martinez, R.;
Ramon, D. J.; Yus, M. Tetrahedron Lett. 2005, 46, 8471.
(f) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas,
M. Tetrahedron 2004, 60, 1767.
2-(p-Toluidino)-2-phenylacetonitrile (4r)11c
IR (film): 3356, 3037, 2911, 2230, 1612, 1520, 1453, 1291, 1124,
803, 747, 692 cm–1.
1H NMR (CDCl3, 300 MHz): d = 2.27 (s, 3 H), 3.90 (d, J = 8.1 Hz,
1 H), 5.37 (dd, J = 3.3, 8.1 Hz, 1 H), 6.68–6.71 (dd, J = 3.3, 8.4 Hz,
2 H), 7.06–7.10 (dd, J = 3.3, 8.4 Hz, 2 H), 7.42–7.46 (m, 3 H),
7.58–7.60 (m, 2 H).
(5) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Srinivas, M.;
Vishnumurthy, P. New J. Chem. 2003, 27, 462.
(6) (a) Nagayama, S.; Kobayashi, S. Angew. Chem. Int. Ed.
2000, 39, 567. (b) Obora, Y.; Baleta, A. S.; Tokunaga, M.;
Tsuji, Y. J. Organomet. Chem. 2002, 660, 173. (c) Ishitani,
H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2000, 122, 762.
(7) (a) Li, G.-l.; Zhao, G. J. Org. Chem. 2005, 70, 4272. (b) Li,
G.-l.; Zhao, G. Synlett 2005, 2540. (c) Li, G.-l.; Zhao, G.
Org. Lett. 2006, 8, 633.
(8) Bordwell, F. G. Acc. Chem. Res. 1998, 21, 456.
(9) St-Denis, Y.; Chan, T. H. Can. J. Chem. 2000, 78, 776.
(10) Formanovskii, A. A.; Mikhura, I. B.; Sokolovskii, S. A.;
Murakhovskaya, A. S.; Terent’ev, P. B.; Sharbatyan, P. A.
Chem. Heterocycl. Compd. (Engl. Transl.) 1988, 24, 930.
(11) (a) McEwen, W. E.; Grossi, A. V.; MacDonald, R. J.;
Stamegna, A. P. J. Org. Chem. 1980, 45, 1301.
2-(4-Methoxyphenyl)-2-(4-methoxyphenylamino)acetonitrile
(4s)11c
IR (film): 3352, 3000, 2933, 2836, 2230, 1609, 1515, 1464, 1247,
1178, 1032, 824 cm–1.
1H NMR (CDCl3, 300 MHz): d = 3.72 (d, J = 8.4 Hz, 1 H), 3.77 (s,
3 H), 3.84 (s, 3 H), 5.28 (d, J = 8.4 Hz, 1 H), 6.75 (d, J = 8.4 Hz,
2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.96 (d, J = 8.1 Hz, 2 H), 7.51 (d,
J = 8.1 Hz, 2 H).
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20862015, 20762009, 20562011), the Program for New
Century Excellent Talents in University (NCET-04-0987) and the
Specialized Research Fund for the Doctoral Program of Higher
Education (No.20050755003) for financial support.
(b) Neelakantan, L.; Hartung, W. H. J. Org. Chem. 1959, 24,
1943. (c) Barnikow, G.; Hagen, A.; Hagen, V.; Goeres, E.;
Richter, D.; Fichtner, K. Pharmazie 1983, 38, 449. (d) El-
Ahl, A.-A. S. Synth. Commun. 2003, 33, 989. (e) Lee, B. S.;
Mahajan, S.; Janda, K. D. Tetrahedron Lett. 2005, 46, 807.
(f) Van Daele, G. Patent US 4246429 1980, 63.
References
(12) Brown, J. M.; Chapman, A. C.; Harper, R.; Mowthorpe, D.
J.; Davies, A. G.; Smith, P. J. J. Chem. Soc., Dalton Trans.
1972, 338.
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(2) (a) Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem.
Int. Ed. 1998, 37, 3186. (b) Kobayashi, S.; Busujima, T.;
Nagayama, S. Chem. Commun. 1998, 981. (c) Surendra, K.;
Krishnaveni, N. S.; Mahesh, A.; Rao, K. R. J. Org. Chem.
2006, 71, 2532. (d) De S, K. J. Mol. Catal. A: Chem. 2005,
225, 167.
Synthesis 2009, No. 12, 2035–2039 © Thieme Stuttgart · New York