La(O-i-Pr)3 catalyzed three-component condensation reaction: A convenient synthesis of N,N-dialkyl-α-cyanoamines

Article abstract of DOI:10.1081/SCC-120012986

In the presence of 10 mol% of La(O-i-Pr)₃, a three-component condensation reaction of aldehyde, secondary amine and trimethylsilylcyanide proceeded smoothly to afford N,N-dialkyl-α-cyanoamine in good yield.

Full text of DOI:10.1081/SCC-120012986

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La(O-i-Pr)3 CATALYZED THREE-COMPONENT
CONDENSATION REACTION: A CONVENIENT SYNTHESIS
OF N,N-DIALKYL-α-CYANOAMINES
Peipei Sun a , Changtao Qian b , Limin Wang a & Ruifang Chen a
a State Key Laboratory of Organometallic Chemistry , Shanghai Institute of Organic
Chemistry , Chinese Academy of Sciences , 354 Fenglin Lu, Shanghai, 200032, China
b Department of Chemistry , Nanjing Normal University , Nanjing, 210097, China
Published online: 16 Aug 2006.
To cite this article: Peipei Sun , Changtao Qian , Limin Wang & Ruifang Chen (2002) La(O-i-Pr)3 CATALYZED THREE-
COMPONENT CONDENSATION REACTION: A CONVENIENT SYNTHESIS OF N,N-DIALKYL-α-CYANOAMINES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:19, 2973-2978, DOI:
10.1081/SCC-120012986
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 2973–2978, 2002
La(O-i-Pr)3 CATALYZED
THREE-COMPONENT CONDENSATION
REACTION: A CONVENIENT SYNTHESIS
OF N,N-DIALKYL-a-CYANOAMINES
*
Peipei Sun, Changtao Qian, LiminWang,
and Ruifang Chen
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
ABSTRACT
In the presence of 10 mol% of La(O-i-Pr)3, a three-component
condensation reaction of aldehyde, secondary amine and
trimethylsilylcyanide proceeded smoothly to afford N,N-dialkyl-
a-cyanoamine in good yield.
Key Words: La(O-i-Pr)3; Three-component condensation;
One-pot synthesis; N,N-dialkyl-a-cyanoamine
During recent years, the use of lanthanide(III) compounds as
catalysts or promoters in organic synthesis have attracted great interest.[1]
Very recently, we have reported a series of organic reactions catalyzed
*Corresponding author. Current address: Department of Chemistry, Nanjing
Normal University, Nanjing, 210097, China. E-mail: qianct@pub.sioc.ac.cn
2973
DOI: 10.1081/SCC-120012986
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2974
SUN ET AL.
by rare earth metals, such as ene reaction,[2a] one-pot synthesis of amino
phosphonates,[2b] imino Diels–Alder reaction,[2c] [2 þ 2] cycloaddition
reaction,[2d] Biginelli reaction[2e] as well as the addition of silyl ketene acetals
to nitrones.[2f ]
Bifunctional a-amino nitriles are versatile intermediates in organic
synthesis. It also exhibit a valuable dual reactivity, which has been utilized
in a broad range of synthetic applications.[3] One of the important methods
for the synthesis of amine derivatives is athree-component condensation in the
presence of Lewis acid.[4] However, many Lewis acids are deactivated or
sometimes decomposed by nitrogen containing reactants. In other cases, more
than stoichiometric amounts of the Lewis acids are needed because the acids
are trapped by nitrogen.[4b,5] The reaction of organometallic nucleophiles
with imines or acylimines prepared from aldehydes and primary amines or
carbamates is an useful method for the preparation of bifunctional amine
derivatives. But it is not suitable for the synthesis of N,N-disubstituted amine
derivatives. Herein, we wish to report a convenient synthesis of N,N-dialkyl-
a-cyanoamines from one-pot condensation of aldehydes, secondary amines
and trimethylsilylcyanide using La(O-i-Pr)3 as catalyst (Sch. 1).
At first, several kinds of Lewis acids were examined in the model reac-
tion (R¼Ph, R1¼R2¼CH2Ph), and the results are summarized in Table 1.
Traditional Lewis acids, such as ZnCl2 and SnCl2 cannot catalyze this
three-component condensation reaction at all. Among all the lanthanide
catalysts screened, La(O-i-Pr)3 showed the better catalytic activity. In the
presence of 10 mol% of La(O-i-Pr)3, the condensation reaction of benzalde-
hyde, dibenzylamine and trimethylsilylcyanide proceeded smoothly to afford
N,N-dibenzyl-a-cyanoamine with 78% yield in 10 h at 40ꢀC. Increasing the
catalyst amount did not show an evidently better effect. On the other hand,
the lower reaction temperature (<20ꢀC) would lead to the decrease of the
yield. THF was found to be a superior solvent than any others.
Several other aldehydes and secondary amines were examined under
the optimal reaction conditions: (10 mol% La(O-i-Pr)3 at 40ꢀC in THF).[6]
The result are listed in Table 2. To most of the substrates we used, the
reaction can be completed in 8–15 h and give the products in good yields.
The electron-donating and electron-withdrawing groups on the benzene ring
of aromatic aldehydes did not affect the yields of the products. But the
reaction of aliphatic aldehyde was rather difficult. For the a,b-unsaturated
Scheme 1.

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N,N-DIALKYL-a-CYANOAMINES
2975
Table 1. Optimal Reaction Conditions of the Three-Component Condensation
Reaction (R¼Ph, R1¼R2¼CH2Ph)
Temp.
(ꢀC)
Time
(h)
Yielda
(%)
Entry
1
2La(O-i-Pr)
3
4
5
6
7
8
9
10
11
12SnCl
Catalyst
Solv.
THF
THF
THF
Toluene
2Cl2
La(O-i-Pr)3
20
40
60
40
14
10
10
10
12CH
12Et
10
10
10
12THF
15
15
67
78 (62b,79c)
3
La(O-i-Pr)3
La(O-i-Pr)3
La(O-i-Pr)3
La(O-i-Pr)3
Sm(O-i-Pr)3
Yb(O-i-Pr)3
La(OTf)3
LaCl3
77
64
51
71
72
70
72
2
40
Refluxing
2O
40
40
40
40
40
40
THF
THF
THF
8
ZnCl2
THF
THF
0
0
2
b
c
aIsolated yields. 5 mol% catalyst. 20 mol% catalyst.
a
Table 2. The Results of the Condensation Reaction Catalyzed by La(O-i-Pr)3
Time
(h)
Yieldb
(%)
Entry
R
R1
R2
1
2PhCH
3
4
5
6
7
8
9
10
Ph
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
(CH3)2CH
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
(CH3)2CH
10
10
15
8
8
8
78
81
72
75
82
65
80
45
¼CH
p-CH3OC6H4
p-O2NC6H4
p-BrC6H4
2-pyridin
2,4-di-Cl-C6H3
Ph
8
15
1278
10
10
15
10
10
Ph
CH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2
PhCH¼CH
p-BrC6H4
3)2CH
Ph
p-BrC4H6
72
64
trace
71
11
12(CH
13
14
PhCH2
PhCH2
PhCH2
PhCH2
CH3
CH3
76
a10 mol% cat., 40ꢀC, THF. Isolated yields.
b

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2976
SUN ET AL.
aldehyde, the reaction took place perfectly in 1,2-position, and the carbon–
carbon double bond was not affected (Entries 2and 10, Table 2).
In summary, we have found a novel and convenient method for
the synthesis of N,N-dialkyl substituted a-cyanoamines by a Lewis acid
catalyzed three-component condensation reaction. It has some noteworthy
features, such as good yields and operational simplicity. It also enlarged the
application sale of rare earth metal in organic synthesis.
EXPERIMENTAL
General procedure for the synthesis of N,N-diphenyl-a-cyanoamines: To
a suspension of La(O-i-Pr)3 (0.1 mmol, 10 mol%) in THF (5 mL) were added
cinnamaldehyde (1 mmol) and dibenzylamine (1 mmol). After stirred at
40ꢀC for 1 h, trimethylsilylcyanide (1.2mmol) was added. The reaction
mixture was stirred at 40ꢀC for 10 h. Water was added and the product
was extracted with diethyl ether. The organic layer was combined and
dried with anhydride Na2SO4. After evaporated in vacuo, the residue was
chromatographed on silica gel to afford the desired product with 78% yield.
Compound (1): M.p. 92–93ꢀC. H NMR (CDCl3): ꢀ ¼ 7.25–7.59 (m,
1
15H), 4.91 (s, 1H), 3.88 (d, J ¼ 13.4 Hz, 2H), 3.41 (d, J ¼ 13.4 Hz, 2H).
13C-NMR (CDCl3): ꢀ ¼ 136.15, 135.21, 131.35, 128.78, 128.73, 128.12,
128.55, 127.16, 126.58, 121.11, 114.37, 77.15, 76.89, 76.10, 55.38. MS: m/z
(%) ¼ 312(M þ, 6), 91 (100), 286 (5), 235 (6). 221 (54), 194 (16), 149 (5), 116
(17), 65 (12). Anal. Calcd. for C22H20N2: C, 84.57; H, 6.47; N, 8.97. Found:
C, 84.48; H, 6.67; N, 8.75.
Compound (2): M.p. 112–113ꢀC. H NMR (CDCl3): ꢀ ¼ 7.24–7.41 (m,
1
15H), 6.94 (d, J ¼ 16.1 Hz, 1H), 6.08 (dd, J ¼ 4.3, 16.1 Hz, 1H), 4.51 (m, 1H),
4.01 (d, J ¼ 13.6 Hz, 2H), 3.43 (d, J ¼ 13.6 Hz, 2H). 13C NMR (CDCl3):
ꢀ ¼ 137.82, 135.37, 134.75, 128.78, 128.72, 128.63, 128.54, 127.63, 126.78,
122.71, 115.37, 77.45, 77.03, 76.60, 55.28, 55.26. IR (KBr): ꢁ ¼ 3062, 2920,
2228, 1494, 1377, 1295, 1123, 913, 739 cmꢁ1. MS: m/z (%) ¼ 338 (Mþ, 8), 91
(100), 311 (12), 247 (32), 220 (40), 222 (20), 142 (12), 115 (27), 65 (9).
Anal. Calcd. for C24H22N2: C, 85.21; H, 6.51; N, 8.28. Found: C, 84.98;
H, 6.61; N, 8.15.
Compound (3): M.p. 91–92ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.48 (d, J ¼ 0.52,
2H), 6.90 (d, J ¼ 8.78, 2H), 6.93–7.49 (m, 10H), 4.84 (s, 1H), 3.38 (d,
J ¼ 13.4 Hz, 2H), 3.87 (d, J ¼ 13.4 Hz, 2H), 3.78 (s, 3H, OCH3). 13C-NMR
(CDCl3): ꢀ ¼ 137.75, 135.27, 134.11, 128.56, 128.11, 128.32, 128.44, 127.15,
126.13, 121.14, 114.75, 77.78, 77.08, 75.80, 55.96. Anal. Calcd. for
C23H22ON2: C, 80.66; H, 6.49; N, 8.18. Found: C, 84.88; H, 6.61; N, 8.35.

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N,N-DIALKYL-a-CYANOAMINES
2977
Compound (4): M.p. 96–97ꢀC. 1H NMR (CDCl3): ꢀ ¼ 8.31 (d, J ¼ 8.83,
2H), 7.82 (d, J ¼ 9.44, 2H), 7.31–7.45 (m, 10H), 5.08 (s, 1H), 3.90
(d, J ¼ 13.34 Hz, 2H), 3.51 (d, J ¼ 13.36 Hz, 2H). 13C NMR (CDCl3):
ꢀ ¼ 138.77, 136.27, 135.75, 128.96, 128.32, 128.56, 128.43, 127.75, 126.12,
121.75, 114.14, 77.25, 77.07, 74.50, 55.21. Anal. Calcd. for C22H19O2N3:
C, 73.92; H, 5.37; O, 8.95; N, 11.76. Found: C, 73.83; H, 5.16; N, 11.45.
Compound (5): M.p. 98–100ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.56 (d,
J ¼ 8.61 Hz, 2H), 7.48 (d, J ¼ 8.45 Hz, 2H), 7.05–7.36 (m, 10H), 4.67 (s,
1H), 3.69 (d, J ¼ 13.39 Hz, 2H), 3.24 (d, J ¼ 13.34 Hz, 2H). 13C NMR
(CDCl3): ꢀ ¼ 138.66, 137.27, 136.75, 129.76, 128.32, 128.66, 128.15,
127.14, 126.76, 121.65, 114.11, 78.10, 76.25, 74.10, 54.35. Anal. Calcd. for
C22H19N3Br: C, 73.92; H, 5.37; N, 11.76. Found: C, 67.52; H, 4.90; N, 7.16.
Compound (6): M.p. 93–95ꢀC. H NMR (CDCl3): ꢀ ¼ 7.35–7.51 (m,
1
14H), 4.91 (s, 1H), 3.85 (d, J ¼ 13.3 Hz, 2H), 3.31 (d, J ¼ 13.1 Hz, 2H).
13C NMR (CDCl3): ꢀ ¼ 137.22, 137.77, 136.15, 129.15, 128.33, 128.11,
128.75, 127.55, 126.65, 121.66, 115.12, 77.45, 75.15, 74.25, 53.01.
Anal. Calcd. for C21H20N2: C, 83.95; H, 6.72; N, 9.33. Found: C, 83.76;
H, 6.57; N, 9.12.
Compound (7): M.p. 114–115ꢀC. H NMR (CDCl3): ꢀ ¼ 7.51 (d, J ¼
1
1.63 Hz, 1H), 7.31 (dd, J ¼ 8.4, 1.6 Hz, 1H), 7.22 (d, J ¼ 8.4 Hz, 1H),
7.03–7.32(m, 10H), 4.57 (s, 1H), 3.61 (d, J ¼ 13.39 Hz, 2H), 3.18 (d, J ¼
13.34 Hz, 2H). 13C NMR (CDCl3): ꢀ ¼ 138.17, 136.25, 134.88, 128.75, 128.22,
128.77, 127.50, 127.15, 77.25, 76.23, 76.15, 75.33, 74.21. Anal. Calcd. for
C22H18Cl2N2: C, 69.29; H, 4.77; N, 7.35. Found: C, 69.11; H, 4.43; N, 7.16.
Compound (8): M.p. 86–87ꢀC. H NMR (CDCl3): ꢀ ¼ 7.15–7.55 (m,
1
5H), 4.81 (m, 1H), 0.91–1.01 (m, 12H), 1.78 (m, 2H). Anal. Calcd. for
C13H16N2: C, 77.94; H, 8.07; N, 13.99. Found: C, 77.78; H, 7.92; N, 14.06.
Compound (9): M.p. 87–88ꢀC. H NMR (CDCl3): ꢀ ¼ 7.25–7.55 (m,
1
5H), 4.81 (s, 1H), 2.51 (m, 4H), 1.61–1.46 (m, 6H). Anal. Calcd. for
C13H16N2: C, 77.94; H, 8.07; N, 13.9. Found: C, 77.78; H, 7.92; N, 14.06.
Compound (10): M.p. 111–112ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.21–7.35 (m,
5H), 6.85 (d, J ¼ 15.58 Hz, 1H), 6.02(dd, J ¼ 3.1 Hz, 15.3 Hz, 1H), 4.42(m,
1H), 2.48 (m, 4H), 1.43–1.52 (m, 6H). Anal. Calcd. for C15H18N2: C, 79.59;
H, 8.03; N, 12.38. Found: C, 79.51; H, 7.92; N, 12.18.
Compound (11): M.p. 94–95ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.52(d,
J ¼ 8.31 Hz, 2H), 7.38 (d, J ¼ 8.43 Hz, 2H), 4.62 (s, J ¼ 3.1 Hz, 15.3 Hz,
1H), 4.42(m, 1H), .248 (m, 4H), 1.43–1.52(m, 6H). Anal. Calcd. for
C13H15BrN2: C, 55.92; H, 5.43; N, 10.04. Found: C, 55.78; H, 5.23; N, 9.91.
Compound (12): M.p. 88–90ꢀC. H NMR (CDCl3): ꢀ ¼ 1.66 (m, 1H),
1
0.81 (d, J ¼ 6.8 Hz, 3H), 0.72(d, J ¼ 6.1 Hz, 3H), 3.82(m, 1H), 3.61 (d, J ¼
13.10 Hz, 2H), 3.21 (d, J ¼ 12.85 Hz, 2H), 7.02–7.31 (m, 10H). Anal. Calcd.
for C19H22N2: C, 81.96; H, 7.98; N, 10.06. Found: C, 81.74; H, 7.68; N, 9.90.

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SUN ET AL.
Compound (13): M.p. 90–91ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.02–7.31
(m, 10H), 4.89 (s, 1H), 3.45 (d, J ¼ 13.60 Hz, 2H), 1.15 (m, 3H). Anal.
Calcd. for C16H16N2: C, 81.31; H, 6.84; N, 11.86. Found: 81.11; H, 6.71;
N, 11.91.
Compound (14): M.p. 97–99ꢀC. 1H NMR (CDCl3): ꢀ ¼ 7.03–7.31
(m, 5H), 4.58 (m, 1H), 7.53 (d, J ¼ 7.51 Hz, 2H), 7.42 (d, J ¼ 8.10 Hz, 2H),
3.45 (d, J ¼ 13.25 Hz, 2H), 1.14 (m, 3H). Anal. Calcd. for C16H15BrN2:
C, 60.96; H, 4.81; N, 8.89. Found: C, 60.76; H, 4.61; N, 8.61.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China and the
State Key Project of Basic Research (Project 973) (No. G2000048007) for
their financial supports.
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Received in the USA September 18, 2001