Efficient synthesis of 6-amino-8-aryl-2-methyl-1,2,3,4- tetrahydroisoquinoline-5,7-dicarbonitrile under solvent-free conditions

Article abstract of DOI:10.1080/00397910902965970

A series of 6-amino-8-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,7- dicarbonitriles were prepared in good yields under solvent-free conditions by multicomponent reactions of aromatic aldehyde, malononitrile, and 1-methylpiperidin-4-one in the presence of sodium hydroxide (NaOH). The structures of the products were characterized by infrared, ¹H NMR spectra, elemental analysis, and high-resolution mass spectrometery (HRMS).

Full text of DOI:10.1080/00397910902965970

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Efficient Synthesis of 6-
Amino-8-aryl-2-methyl-1,2,3,4-
tetrahydroisoquinoline-5,7-dicarbonitrile
Under Solvent-Free Conditions
Liangce Rong a b , Lijiu Gao a , Hongxia Han a , Hong Jiang b , Yisi Dai
a & Shujiang Tu a b
a College of Chemistry and Chemical Engineering , Xuzhou Normal
University , Xuzhou , China
b Key Laboratory of Biotechnology for Medicinal Plants , Xuzhou ,
Jiangsu , China
Published online: 29 Dec 2009.
To cite this article: Liangce Rong , Lijiu Gao , Hongxia Han , Hong Jiang , Yisi Dai & Shujiang Tu (2009)
Efficient Synthesis of 6-Amino-8-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbonitrile
Under Solvent-Free Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:2, 289-294, DOI: 10.1080/00397910902965970
To link to this article: http://dx.doi.org/10.1080/00397910902965970
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Synthetic Communications1, 40: 289–294, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902965970
EFFICIENT SYNTHESIS OF 6-AMINO-8-ARYL-2-METHYL-
1,2,3,4-TETRAHYDROISOQUINOLINE-5,7-
DICARBONITRILE UNDER SOLVENT-FREE CONDITIONS
Liangce Rong,1,2 Lijiu Gao,1 Hongxia Han,1 Hong Jiang,2
Yisi Dai,1 and Shujiang Tu1,2
1College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, China
2Key Laboratory of Biotechnology for Medicinal Plants, Xuzhou,
Jiangsu, China
A series of 6-amino-8-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbonitriles were
prepared in good yields under solvent-free conditions by multicomponent reactions of
aromatic aldehyde, malononitrile, and 1-methylpiperidin-4-one in the presence of sodium
1
hydroxide (NaOH). The structures of the products were characterized by infrared, H
NMR spectra, elemental analysis, and high-resolution mass spectrometery (HRMS).
Keywords: Aromatic aldehyde; isoquinoline; malononitrile; 1-methylpiperidin-4-one; solvent-free
conditions
Because of increasing environmental concerns and the regulatory constraints
faced in the chemical and pharmaceutical industries, the development of environ-
mentally benign organic reactions has become a crucial area in modern organic
chemical research.[1] In recent years, solvent-free organic reactions[2] have caused
great interest because they have many advantages, such as high efficiency and selec-
tivity, easy separation and purification, mild reaction conditions, and reduction of
waste produced. Many articles about solvent-free reactions have been reported.[3]
The isoquinoline backbone appears in numerous natural products, and most of
them contain different kinds of bioactivities.[4] So, the isoquinoline family has
received increased interest.[5] The development of efficient synthetic methods for iso-
quinoline and related derivatives has continuously attracted the attention of many
chemists. Multicomponent reactions (MCRs), an important subclass of tandem reac-
tions,[6] are one-pot processes in which three or four easily accessible components
react to form a single product that incorporates essentially all the carbon atoms
of the starting materials.[7] The development of MCRs to prepare heterocyclic
Received December 1, 2008.
Address correspondence to Liangce Rong, College of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou 221116, China. E-mail: lcrong2005@yahoo.com
289

290
L. RONG ET AL.
Scheme 1. Synthesis of tetrahydroisoquinoline.
compounds and other compounds has become an important area of research in
organic, combinatorial, and medicinal chemistry.[8]
As part of our current studies on the development of new routes in organic
synthesis,[9] in this article, we report an efficient MCRs to prepare 6-amino-8-aryl-
2-methyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbonitrile under solvent-free condi-
tions using a heating method.
The synthesis was very simple: The aromatic aldehyde 1, malononitrile 2, and
1-methylpiperidin-4-one 3 were added in a mortar in the presence of 0.1 g NaOH as
catalyst. The mixture was heated to 70ꢀC, and the reaction was completed within
25 min with good yields (Scheme 1).
The results of reactions are listed in Table 1. As shown in Table 1, the corre-
sponding products were obtained in 85–97% yields. Different kinds of substituted
benzaldehydes, bearing either electron-releasing (such as CH3-) or electron-
withdrawing substituents (such as F-, Cl-, Br-), were all created smoothly in the
reactions. The structure of 4 was confirmed by infrared (IR), 1H NMR, and
elemental analysis and was further ascertained by high-resolution mass spectrometry
(HRMS).
In conclusion, we have successfully developed an efficient and facile method to
prepare a series of 6-amino-8-aryl-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,7-
dicarbonitrile via MCRs of aromatic aldehydes, malononitrile, and 1-methylpiperidin-
4-one under solvent-free conditions. Because it avoids use of toxic organic solvent, this
new protocol has the advantages of good yields, lower cost, reduced environmental
impact, and convenient procedure.
Table 1. Synthetic results of compounds 4
Entry
Ar
Product
Mp (ꢀC)
Yield (%)
1
2
C6H5
4a
4b
4c
4d
4e
4f
236–237
239–240
205–206
191–194
222–225
235–237
218–220
243–246
188–190
196–199
90
95
93
85
96
92
97
89
90
93
4-CH3C6H4
3,4-(CH3O)2C6H3
3,4-(CH3)2C6H3
4-BrC6H4
3
4
5
6
4-FC6H4
4-ClC6H4
7
4g
4h
4i
8
3-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
9
10
4j

SYNTHESIS OF 1,2,3,4-TETRAHYDROISOQUINOLINE
291
EXPERIMENTAL
Melting points were determined on an XT-5 microscopic melting-point spec-
trometer and are uncorrected. IR spectra were recorded on a Fourier transform
(FT)–IR-8101 spectrometer. 1H NMR spectra were obtained from solution in
dimethyl sulfoxide (DMSO-d6) with Me4Si as internal standard using a Bruker-400
spectrometer. Microanalyses were carried out using a Perkin-Elmer 2400 II analyzer.
HRMS spectra were obtained with a Bruker microTOF-Q 134 instrument.
General Procedure for the Synthesis of 6-Amino-8-aryl-2-methyl-1,2,3,
4-tetrahydroisoquinoline-5,7-dicarbonitrile
The mixture of aromatic aldehydes 1 (2 mmol), malononitrile 2 (5 mmol),
1-methylpiperidin-4-one 3 (2 mmol), and 0.1 g NaOH was put in a reaction flask
at 70ꢀC for about 25 min. After completion, the reaction mixture was poured into
water and then washed with water thoroughly. The product was filtered, dried,
and recrystallized from 95% ethanol.
Selected Data
6-Amino-2-methyl-8-phenyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbo-
nitrile (4a). IR (KBr) v: 3390, 3316, 3173, 2947, 2844, 2778, 2215, 1655, 1567, 1462,
1271, 1134, 720, 694 cmꢁ1; 1NMR (400 MHz, DMSO-d6) d: 2.17 (3H, s, NCH3), 2.58
(2H, t, J ¼ 5.6 Hz, J ¼ 6.0 Hz, CH2), 2.92 (4H, t, J ¼ 6.8 Hz, J ¼ 10.4 Hz, 2CH2), 6.52
(2H, s, NH2), 7.29 (2H, dd, J ¼ 1.6 Hz, J ¼ 1.6 Hz, ArH), 7.50–7.52 (3H, m, ArH).
Anal. calcd. for C18H16N4: C, 74.98; H, 5.59; N, 19.43. Found: C, 74.71; H, 5.54;
N, 19.50. HRMS m=z calculated for C18H16N4 [M þ H]: 289.1453; found: 289.1451.
6-Amino-2-methyl-8-p-tolyl-1,2,3,4-tetrahydroisoquinoline-5,7-dicarbo-
nitrile (4b). IR (KBr) v: 3467, 3360, 3239, 2944, 2840, 2760, 2214, 1635, 1570, 1456,
1
1287, 823 cmꢁ1; NMR (400 MHz, DMSO-d6) d: 2.18 (3H, s, NCH3), 2.39 (3H, s,
CH3), 2.58 (2H, t, J ¼ 6.0 Hz, J ¼ 6.0 Hz, CH2), 2.92 (4H, t, J ¼ 4.4 Hz, J ¼ 6.0 Hz,
2CH2), 6.49 (2H, s, NH2), 7.18 (2H, d, J ¼ 8.0 Hz, ArH), 7.32 (2H, d, J ¼ 8.0 Hz,
ArH). Anal. calcd. for C19H18N4: C, 75.47; H, 6.00; N, 18.53. Found: C, 75.71; H,
5.92; N, 18.65. HRMS m=z calculated for C19H18N4 [M þ H]: 303.1610; found:
303.1614.
6-Amino-8-(3,4-dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoqui-
noline-5,7-dicarbonitrile (4c). IR (KBr) v: 3397, 3360, 3138, 2956, 2842, 2777,
1
2215, 1655, 1520, 1464, 1242, 1141, 1022, 821 cmꢁ1; H NMR (400 MHz, DMSO-
d6) d: 2.20 (3H, s, NCH3), 2.59 (2H, dd, J ¼ 6.0 Hz, J ¼ 6.0 Hz, CH2), 2.90–3.02
(4H, m, 2CH2), 3.76 (3H, s, OCH3), 3.82 (3H, s, OCH3), 6.47 (2H, s, NH2), 6.81
(1H, dd, J ¼ 2.0 Hz, J ¼ 2.0 Hz, ArH), 6.89 (1H, d, J ¼ 2.4 Hz, ArH), 7.07 (1H, d,
J ¼ 8.0 Hz, ArH). Anal. calcd. for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08. Found:
C, 68.81; H, 5.82; N, 16.16. HRMS m=z calculated for C20H20N4O2 [M þ H]:
349.1700; found: 349.1699.
6-Amino-8-(3,4-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line-5,7-dicarbonitrile (4d). IR (KBr) v: 3460, 3352, 3287, 2940, 2854, 2792, 2214,

292
L. RONG ET AL.
1683, 1570, 1456, 1272, 1146, 826 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) d: 2.18 (3H,
s, NCH3), 2.27 (3H, s, CH3), 2.29 (3H, s, CH3), 2.57 (2H, t, J ¼ 5.6 Hz, J ¼ 5.6 Hz,
CH2), 2.91 (4H, t, J ¼ 2.0 Hz, J ¼ 5.2 Hz, 2CH2), 6.50 (2H, s, NH2), 6.99 (1H, d,
J ¼ 7.6 Hz, ArH), 7.06 (1H, s, ArH), 7.27 (1H, d, J ¼ 7.6 Hz, ArH). Anal. calcd.
for C20H20N4: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.81; H, 6.42; N, 17.66.
HRMS m=z calculated for C20H20N4 [M þ H]: 317.1766; found: 3317.1767.
6-Amino-8-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-
5,7-dicarbonitrile (4e). IR (KBr) v: 3464, 3346,3237, 2946, 2846, 2804, 2215, 1683,
1
1569, 1456, 1276, 1013, 830 cmꢁ1; H NMR (400 MHz, DMSO-d6) d: 2.19 (3H, s,
NCH3), 2.58 (2H, t, J ¼ 6.0 Hz, J ¼ 6.0 Hz, CH2), 2.92 (4H, t, J ¼ 5.2 Hz, J ¼ 5.6 Hz,
2CH2), 6.57 (2H, s, NH2), 7.29 (2H, dd, J ¼ 6.0 Hz, J ¼ 1.6 Hz, ArH), 7.72 (2H, d,
J ¼ 6.0 Hz, J ¼ 1.6 Hz, ArH). Anal. calcd. for C18H15BrN4: C, 58.87; H, 4.12; N,
15.26. Found: C, 58.81; H, 4.02; N, 15.36. HRMS m=z calculated for C18H15BrN4
[M þ H]: 367.0558; found: 367.0561.
6-Amino-8-(4-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,
7-dicarbonitrile (4f). IR (KBr) v: 3395, 3312, 3180, 2952, 2849, 2779, 2216, 1685,
1
1575, 1461, 1238, 1160, 839 cmꢁ1; H NMR (400 MHz, DMSO-d6) d: 2.19 (3H, s,
NCH3), 2.58 (2H, t, J ¼ 5.6 Hz, J ¼ 6.0 Hz, CH2), 2.92 (4H, t, J ¼ 5.2 Hz, J ¼ 5.6 Hz,
2CH2), 6.55 (2H, s, NH2), 7.35 (2H, d, J ¼ 4.4 Hz, ArH), 7.37 (2H, d, J ¼ 1.6 Hz,
ArH). Anal. calcd. for C18H15FN4: C, 70.57; H, 4.94; N, 18.29. Found: C, 70.65;
H, 4.87; N, 18.36. HRMS m=z calculated for C18H15FN4 [M þ H]: 307.1359;
found: 307.1357.
6-Amino-8-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,
7-dicarbonitrile (4g). IR (KBr) v: 3452, 3344, 3225, 2946, 2846, 2800, 2216, 1639,
1
1568, 1455, 1277, 1091, 833 cmꢁ1; H NMR (400 MHz, DMSO-d6) d: 2.19 (3H, s,
NCH3), 2.58 (2H, t, J ¼ 5.6 Hz, J ¼ 5.6 Hz, CH2), 2.92 (4H, t, J ¼ 6.4 Hz, J ¼ 8.4 Hz,
2CH2), 6.60 (2H, s, NH2), 7.36 (2H, d, J ¼ 8.4 Hz, ArH), 7.59 (2H, d, J ¼ 8.4 Hz,
ArH). Anal. calcd. for C18H15ClN4: C, 66.98; H, 4.68; N, 17.36. Found: C, 66.85;
H, 4.74; N, 17.26. HRMS m=z calculated for C18H15ClN4 [M þ H]: 323.1063;
found: 323.1054.
6-Amino-8-(3-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,
7-dicarbonitrile (4h). IR (KBr) v: 3410, 3364, 3237, 3063, 2946, 2807, 2213, 1634,
1568, 1458, 1279, 1134, 946, 714 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) d: 2.19 (3H,
s, NCH3), 2.59 (2H, t, J ¼ 6.0 Hz, J ¼ 6.4 Hz, CH2), 2.91 (4H, t, J ¼ 5.2 Hz,
J ¼ 6.4 Hz, 2CH2), 6.58 (2H, s, NH2), 7.27–7.30 (1H, m, ArH), 7.45 (1H, s, ArH),
7.55–7.58 (2H, m, ArH). Anal. calcd. for C18H15ClN4: C, 66.98; H, 4.68; N, 17.36.
Found: C, 66.88; H, 4.60; N, 17.41. HRMS m=z calculated for C18H15ClN4
[M þ H]: 323.1063; found: 323.1058.
6-Amino-8-(2-chlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-5,
7-dicarbonitrile (4i). IR (KBr) v: 3347, 3235, 2970, 2852, 2797, 2214, 1646, 1566,
1456, 1279, 1091, 741 cmꢁ1 1H NMR (400 MHz, DMSO-d6) d: 2.19 (3H, s,
;
NCH3), 2.59 (2H, t, J ¼ 5.6 Hz, J ¼ 5.6 Hz, CH2), 2.91 (4H, t, J ¼ 6.0 Hz, J ¼ 6.4 Hz,
2CH2), 6.59 (2H, s, NH2), 7.28 (1H, d, J ¼ 5.6 Hz, ArH), 7.48 (1H, s, ArH), 7.55
(2H, d, J ¼ 5.2 Hz, ArH). Anal. calcd. for C18H15ClN4: C, 66.98; H, 4.68; N,

SYNTHESIS OF 1,2,3,4-TETRAHYDROISOQUINOLINE
293
17.36. Found: C, 66.79; H, 4.64; N, 17.43. HRMS m=z calculated for C18H15ClN4
[M þ H]: 323.1063; found: 323.1052.
6-Amino-8-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line-5,7-dicarbonitrile (4j). IR (KBr) v: 3434, 3343, 3237, 2944, 2840, 2750, 2214,
1647, 1565, 1457, 1280, 1093, 873 cmꢁ1; 1H NMR (400 MHz, DMSO-d6) d: 2.20 (3H,
s, NCH3), 2.58 (2H, t, J ¼ 6.0 Hz, J ¼ 6.4 Hz, CH2), 2.94 (4H, t, J ¼ 6.8 Hz,
J ¼ 6.0 Hz, 2CH2), 6.65 (2H, s, NH2), 7.35 (1H, dd, J ¼ 2.0 Hz, J ¼ 2.0 Hz, ArH),
7.72 (1H, d, J ¼ 2.0 Hz, ArH), 7.79 (1H, d, J ¼ 8.4 Hz, ArH). Anal. calcd. for
C18H14Cl2N4: C, 60.52; H, 3.95; N, 15.68. Found: C, 60.65; H, 4.00; N, 15.53.
HRMS m=z calculated for C18H15Cl2N4 [M þ H]: 357.0674; found: 357.0679.
ACKNOWLEDGMENTS
We thank the Natural Science Foundation of Jiangsu Education Department
(No. 08KJB150017) and the Pei Yu Foundation (No. 07PYL06) of Xuzhou Normal
University for financial support.
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