Supporting information
Synthesis of novel series of malonamides derivatives via a fivecomponent reaction
Abbas Rahmati*, Tahmineh Kenarkoohi, Mahdi Ahmadi-Varzaneh
Department of Chemistry, University of Isfahan, P. O. Box 81746 - 73441, Isfahan,
Iran.
Abstract
A one-pot, five-component condensation reaction of isocyanide, Meldrum’s acid, arylidene
malononitrile and two amine molecules in CH2Cl2 at ambient temperature to give malonamide
derivatives, is described.
Keywords Malonamide. Isocyanide. Multi-component reactions (MCRs)
Materials and methods
All chemicals were purchased and used without any further purification. All melting
points are measured in open glass-capillaries using Electrotermal 9100 apparatus. IR
spectra were recorded on an FT Infrared Spectroscope instrument JASCO, FT/IR6300 model as KBr discs. The 1H and
13
C NMR spectra were recorded on a Bruker-
AVANCE 400 MHz instrument using DMSO-d6 as deuterated solvent. Elemental
analyses were performed using a Heraeus CHNS Rapid analyzer and are reported in
percent atomic abundance.
*
Corresponding author. Email: a.rahmati@sci.ui.ac.ir
General procedure for the synthesis of malonmaides (5a-o):
A mixture of an isocyanide (1 mmol), arylidene malononitrile (1 mmol), Meldrum’s
acid (1 mmol), and an amine (2 mmol) in 3 mL of CH2Cl2 was stirred for 2 h at room
temperature. After reaction completion, based by TLC (EtOAc:n-hexene, 1:2), the
reaction mixture was filtered, and the separated solid washed with CH2Cl2 (5 mL), and
in some cases with additional EtOH or MeOH (5 mL). Pure product was isolated
without the need of crystallization.
N1,N3-dibenzyl-2-(3,3-dicyano-1-(cyclohexylamino)-2-p-tolylpropylidene)
malonamide (5a)
White powder (83%); IR (KBr): 3286, 3063, 3030, 2928, 2853, 1652, 1634, 1546,
1448 cm-1; 1H NMR (400 MHz, DMSO-d6) δ: 1.08-1.19 (m, 10H, 5CH2 of
cyclohexyl), 2.30 (s, 3H, CH3), 3.40 (m, 1H, NCH of cyclohexyl (this signal has been
overlaped by water signal in DMSO solvent)), 4.00 (dd, 2J = 15.6 Hz, 3J = 5.6 Hz, 1H,
CHAHBNH), 4.09 (d, 3J = 11.6 Hz, 1H, CH(CN)2), 4.20-4.27 (m , 2H, CH2NH), 4.31
(d, 3J = 11.6 Hz, 1H, CHPh), 4.38 (dd, 2J = 15.6 Hz, 3J = 5.6 Hz, 1H, CHAHBNH),
6.74-7.32 (m, 14H, CHarom), 7.91 (d, 3J = 8.0 Hz, 1H, NH-cyclohexyl), 8.05 (t, 3J =
5.6 Hz, 1H, NHamid), 8.10 (t, 3J = 5.6 Hz, 1H, NHamid) ppm. 13C NMR (100 MHz,
DMSO-d6) δ: 20.7, 24.4, 24.5, 25.2, 32.0, 32.2, 41.8, 42.2, 47.4, 49.2, 56.4, 126.5,
126.5, 126.7, 126.9, 127.9, 128.1, 128.2, 128.5, 135.5, 135.6, 138.8, 139.2, 167.1,
167.6, 170.7 ppm. Anal. Calcd for C35H37N5O2: C, 75.11; H, 6.66; N, 12.51. Found:
C, 75.29; H, 6.69; N, 12.48.
NC
H
N
NC
O
O
NH HN
N1,N3-dibenzyl-2-(3,3-dicyano-1-(cyclohexylamino)-2-(4-methoxyphenyl)propyl
idene)malon amide (5b)
White powder (75%); IR (KBr): 3302, 3062, 3030, 2930, 2853, 1666, 1633, 1544,
1455 cm-1; 1H NMR (400 MHz, DMSO-d6) δ: 0.94-1.69 (m, 10H, 5CH2 of
cyclohexyl), 3.40 (m , 1H, NCH of cyclohexyl (this signal overlaped with water
signal in DMSO solvent)), 3.75 (s, 3H, OCH3), 4.22-4.41 (m, 4H, 2 × CH2NH and 2H
of PhCHCH(CN)2), 6.71-7.44 (m, 14H, CHarom), 7.89 (d, 3J = 8.0 Hz, 1H, NHcyclohexyl), 8.04 (t, 3J = 5.6 Hz, 1H, NHamid), 8.10 (t, 3J = 5.8 Hz, 1H, NHamid) ppm.
C NMR (100 MHz, DMSO-d6) δ: 24.37, 24.44, 25.19, 31.97, 32.25, 41.78, 42.13,
13
47.42, 49.43, 54.91, 56.51, 113.29, 126.47, 126.68, 126.92, 127.93, 128.14, 129.33,
130.47, 138.78, 139.17, 158.08, 167.16, 167.63, 170.81 ppm. Anal.Calcd for
C35H37N5O3: C, 73.02; H, 6.48; N, 12.16. Found: C, 73.25; H, 6.51; N, 12.22.
OMe
NC
H
N
NC
O
O
NH HN
N1,N3-dibenzyl-2-(2-(2,4-dichlorophenyl)-3,3-dicyano-1-(cyclohexylamino)propyl
idene)malonamide (5c)
white powder (58%); IR (KBr) cm-1: 3280, 3086, 3032, 2927, 2853, 1664, 1647,
1545, 1452; 1H NMR (400 MHz, DMSO-d6) δ: 1.05-1.62 (m, 10H, 5CH2 of
cyclohexyl), 3.98 (dd, 2J = 15.6 Hz, 3J = 5.2 Hz, 1H, CHAHBNH), 4.17 (d, 3J = 11.6
Hz, 1H, CH(CN2)), 4.22-4.27 (m , 2H, CH2NHgroups), 4.41 (dd, 2J = 15.2 Hz, 3J = 6.4
Hz, 1H, CHA´HB´NH), 4.73 (d, 3J = 11.6 Hz, 1H, CHPh),
6.77-7.59 (m, 13H,
13CHarom), 7.71 (d, 3J = 8.0 Hz, 1H, NH-cyclohexyl), 8.19 (t, 3J = 6.0 Hz, 1H,
NHamid), 8.28 (t, 3J = 6.0 Hz, 1H, NHamid) ppm. 13C NMR (100 MHz, DMSO-d6) δ:
24.48, 24.52, 25.11, 31.87, 31.93, 41.95, 42.26, 46.43, 47.87, 56.17, 126.49, 126.55,
126.74, 126.97, 127.96, 128.16, 128.65, 131.03, 132.15, 134.48, 134.72, 138.75,
139.07, 166.61, 166.91, 168.63 ppm. Anal.Calcd for C34H33Cl2N5O2: C, 66.45; H,
5.41; N, 11.40. Found: C, 66.52; H, 5.32; N, 11.29.
Cl
Cl
NC
H
N
NC
O
O
NH HN
2-(3,3-dicyano-1-(cyclohexylamino)-2-(3,4-dimethoxyphenyl)propylidene)-N1,N3-dip-tolylmalonamide (5d)
White powder (68%); IR (KBr) cm-1: 3278, 3124, 3075, 2930, 2854, 1671, 1632,
1516, 1455, 1337, 1249; 1H NMR (400 MHz, DMSO-d6) δ: 0.97-1.65 (m, 10H, 5CH2
of cyclohexyl), 2.20 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 3.70 (s, 3H,
OCH3), 4.24 (d, 3J = 11.4 Hz, 1H, CH(CN)2), 4.37 (d, 3J = 11.4 Hz, 1H, CHPh), 6.827.45 (m, 11H, CHarom), 7.98 (d, 3J = 7.9 Hz, 1H, NH-cyclohexyl), 9.70 (s, 2H,
2NHamid),
13
C NMR (100 MHz, DMSO-d6) δ: 20.35, 20.39, 24.31, 24.38, 25.13,
31.96, 32.18, 47.41, 49.63, 55.25, 55.34, 57.98, 111.30, 111.88, 119.04, 120.15,
129.05, 129.17, 130.49, 132.43, 132.60, 135.91, 136.20, 147.60, 148.04, 165.11,
165.67, 170.59 ppm. Anal.Calcd for C36H39N5O4: C, 71.38; H, 6.49; N, 11.56. Found:
C, 71.49; H, 6.47; N, 11.60.
OMe
MeO
H
N
NC
NC
O
O
NH HN
2-(3,3-dicyano-1-(cyclohexylamino)-2-(phenyl)propylidene)-N1,N3-bis(2hydroxyphenyl)malonamide (5e)
white powder (57%); IR (KBr) cm-1: 3537, 3299, 3272, 3081, 2929, 2854, 1640,
1601, 1545, 1497; 1H NMR (400 MHz, DMSO-d6) δ: 0.95-1.63 (m, 10H, 5CH2 of
cyclohexyl), 4.41 (d, 3J = 11.4 Hz, 1H, CH(CN)2), 4.84 (d, 3J = 11.4 Hz, 1H, CHPh),
6.61-8.06 (m, 13H, 13CHarom and 1H, NH-cyclohexyl), 9.49 (s, 1H, NHamid), 9.56 (s,
1H, NHamid), 9.81 (bs, 2H, 2OH) ppm.
13
C NMR (100 MHz, DMSO-d6) δ: 24.32,
24.40, 25.13, 31.92, 32.22, 47.40, 50.88, 56.75, 114.29, 114.37, 114.90, 116.36,
118.66, 118.85, 119.44, 120.51, 120.94, 123.78, 124.03, 126.18, 126.96, 127.92,
128.13, 138.51, 146.64, 146.89, 165.64, 166.40, 170.42 ppm. Anal.Calcd for
C32H31N5O4: C, 69.93; H, 5.69; N, 12.74. Found: C, 70.09; H, 5.67; N, 12.80.
H
N
NC
NC
O
O
NH HN
OH HO
2-(3,3-dicyano-1-(cyclohexylamino)-2-(4-methoxyphenyl)propylidene)-N1,N3-bis(2hydroxyphenyl)malonamide (5f):
white powder (53%); IR (KBr) cm-1: 3529, 3277, 3076, 3001, 2930, 2854, 1658,
1633, 1539, 1513, 1455, 1248; 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.64 (m, 10H,
5CH2 of cyclohexyl), 3.68 (s, 3H, OCH3), 4.34 (d, 3J = 11.2 Hz, 1H, CH(CN)2), 4.77
(d, 2J = 11.6 Hz, 1H, CHPh), 6.63-7.98 (m, 13H, CHarom and 1H, NH-cyclohexyl),
9.47 (s, 1H, NHamid), 9.54 (s, 1H, NHamid), 9.82 (bs, 2H, OH) ppm. 13C NMR (100
MHz, DMSO-d6) δ: 24.35, 24.43, 25.15, 31.97, 32.24, 47.35, 50.02, 54.83, 56.93,
113.32, 114.90, 118.68, 118.84, 120.53, 120.88, 123.77, 123.99, 126.26, 126.69,
129.12, 130.44, 146.64, 146.84, 157.95, 165.72, 166.50, 170.73 ppm; Anal.Calcd for
C33H33N5O5: C, 68.38; H, 5.74; N, 12.08. Found: C, 68.21; H, 5.71; N, 12.05.
OCH3
H
N
NC
NC
O
O
NH HN
OH HO
2-(1-(tert-butylamino)-3,3-dicyano-2-(4-methoxyphenyl)propylidene)-N1,N3-bis(2hydroxyphenyl)malonamide (5g):
white powder (61%); IR (KBr) cm-1: 3555, 3303, 3260, 2970, 2931, 2886, 1643,
1607, 1540, 1519, 1500, 1456, 1254; 1H NMR (400 MHz, DMSO-d6) δ: 1.11 (s, 9H,
C(CH3)3), 3.68 (s, 3H, OCH3), 4.35 (d, 3J = 11.6 Hz, 1H, CH(CN)2), 4.42 (d, 3J = 11.6
Hz, 1H, CHPh), 6.63-7.99 (m, 13H, CHarom and 1H, NH-t-butyl), 9.45 (s, 1H, NHamid),
9.51 (s, 1H, NHamid), 9.81 (bs, 1H, OH), 9.89 (bs, 1H, OH) ppm. 13C NMR (100 MHz,
DMSO-d6) δ: 28.33, 49.77, 50.55, 54.80, 57.24, 113.28, 114.90, 114.96, 118.70,
118.87, 120.59, 120.89. 123.81, 123.99, 126.25, 126.69, 129.11, 130.60, 146.71,
146.83, 157.88, 165.79, 166.63, 171.27 ppm. Anal.Calcd for C31H31N5O5: C, 67.26;
H, 5.64; N, 12.65. Found: C, 67.13; H, 5.66; N, 12.62.
OCH3
H
N
NC
NC
O
O
NH HN
OH HO
2-(1-(tert-butylamino)-2-(4-chlorophenyl)-3,3-dicyanopropylidene)-N1,N3-bis(2hydroxyphenyl)malonamide (5h):
white powder (48%); IR (KBr) cm-1: 3375, 3304, 3067, 2965, 2758, 2590, 1654,
16.02, 1532, 1495, 1457, 746; 1H NMR (400 MHz, DMSO-d6) δ: 1.11 (s, 9H,
C(CH3)3), 4.44 (d, 3J = 11.4 Hz, 1H, CH(CN)2), 4.73 (d, 2J = 11.4 Hz, 1H, CHPh),
6.36-8.02 (m, 12H, 12CHarom), 7.85 (bs, 1H, NH-t-butyl), 9.45 (s, 1H, NHamid), 9.57
(s, 1H, NHamid), 9.84 (s, 1H, OH), 9.89 (s, 1H, OH) ppm.
13
C NMR (100 MHz,
DMSO-d6) δ: 28.27, 49.88, 50.67, 55.99, 114.90, 118.70, 118.88, 120.49, 121.02,
123.82, 124.12, 126.07, 126.66, 127.93, 129.91, 131.32, 137.75, 146.64, 146.93,
165.53, 166.25, 170.51 ppm. Anal.Calcd for C30H28ClN5O4: C, 64.57; H, 5.06; N,
12.55. Found: C, 64.72; H, 5.08; N, 12.49.
Cl
H
N
NC
NC
O
O
NH HN
OH HO
2-(1-(tert-butylamino)-3,3-dicyano-2-phenylpropylidene)-N1,N3-dibenzylmalonamide
(5i):
white powder (65%); IR (KBr) cm-1: 3296, 3063, 3028, 2931, 2871, 1651, 1545,
1453; 1H NMR (400 MHz, DMSO-d6) δ: 1.15 (s, 9H, C(CH3)3), 3.98 (dd, 2J = 15.8
Hz, 3J = 5.4 Hz, 1H, CHAHBNH), 4.04 (d, 3J = 11.6 Hz, 1H, CH(CN2)), 4.16-4.25 (m,
2H, 1H of CHAHBNH and 1H of CHA´HB´NH), 4.36 (d, 3J = 11.2 Hz, 1H, CHPh),
4.46 (dd, 2J = 15.4 Hz, 3J = 6.6 Hz, 1H, CHA´HB´NH), 6.71-7.40 (m, 15H, 15CHarom),
7.72 (bs, 1H, NH-t-butyl), 8.06 (t, 3J = 6.0 Hz, 1H, NHamid), 8.06 (t, 3J = 6.0 Hz, 1H,
NHamid) ppm. 13C NMR (100 MHz, DMSO-d6) δ: 28.34, 41.80, 42.14, 49.83, 50.62,
56.61, 126.46, 126.59, 126.68, 126.96, 127.88, 128.06, 128.14, 128.28, 138.71,
138.75, 139.20, 167.10, 167.65, 171.01 ppm. Anal.Calcd for C32H33N5O3: C, 73.96;
H, 6.40; N, 13.48. Found: C, 74.24; H, 6.42; N, 13.43.
NC
H
N
NC
O
O
NH HN
2-(1-(tert-butylamino)-3,3-dicyano-2-p-tolylpropylidene)-N1,N3-dibenzylmalonamide
(5j):
white powder (77%); IR (KBr) cm-1: 3298, 3067, 3036, 2970, 2871, 1653, 1545,
1453; 1H NMR (400 MHz, DMSO-d6) δ: 1.13 (s, 9H, C(CH3)3), 2.30 (s, 3H, CH3),
3.94-4.47 (m, 6H, 4H of 2 × CH2NH, 1H of CH(CN2) and 1H, CHPh), 6.71-7.28 (m,
14H, 14CHarom), 7.64 (bs, 1H, NH-t-butyl), 8.05 (t, 3J = 6.0 Hz, 1H, NHamid), 8.09 (t,
3
J = 5.6 Hz, 1H, NHamid) ppm.
13
C NMR (100 MHz, DMSO-d6) δ: 20.72, 28.36,
41.81, 42.14, 49.79, 50.24, 56.61, 126.48, 126.51, 126.67, 126.97, 127.95, 128.14,
128.16, 128.47, 135.50, 135.73, 138.81, 139.23, 167.17, 167.73, 171.18 ppm.
Anal.Calcd for C33H35N5O2: C, 74.27; H, 6.61; N, 13.12. Found: C, 73.88; H, 6.57; N,
13.20.
NC
H
N
NC
O
O
NH HN
2-(1-(tert-butylamino)-3,3-dicyano-2-(4-methoxyphenyl)propylidene)-N1,N3-dibenzyl
malonamide (5k):
white powder (73%); IR (KBr) cm-1: 3289, 3064, 3031, 2928, 2834, 1662, 1650,
1544, 1513, 1453, 1251; 1H NMR (400 MHz, DMSO-d6) δ: 1.15 (s, 9H, C(CH3)3),
3.75 (s, 3H, OCH3), 3.94-4.48 (m, 6H, 4H of 2 × CH2NH, 1H of CH(CN2) and 1H,
CHPh), 6.70-7.30 (m, 14H, 14 CHarom), 7.65 (bs, 1H, NH-t-butyl), 8.04 (t, 3J = 5.8
Hz, 1H, NHamid), 8.08 (t, 3J = 6.0 Hz, 1H, NHamid) ppm. 13C NMR (100 MHz, DMSOd6) δ: 28.35, 41.76, 42.12, 49.78, 49.81, 54.88, 56.84, 113.25, 126.47, 126.66, 126.95,
127.93, 128.13, 129.31, 130.66, 138.80, 139.22, 158.02, 167.22, 167.73, 171.32 ppm.
Anal.Calcd for C33H35N5O3: C, 72.11; H, 6.42; N, 12.74. Found: C, 71.94; H, 6.45; N,
12.80.
OCH3
NC
H
N
NC
O
O
NH HN
2-(1-(tert-butylamino)-2-(4-chlorophenyl)-3,3-dicyanopropylidene)-N1,N3-dibenzyl
malonamide (5l):
white powder (58%); IR (KBr) cm-1: 3296, 3064, 3029, 2973, 2874, 1654, 1545,
1494, 1458, 697; 1H NMR (400 MHz, DMSO-d6) δ: 1.14 (s, 9H, C(CH3)3), 3.93-4.47
(m, 6H, 4H of 2 × CH2NH, 1H of CH(CN2) and 1H, CHPh), 6.70-7.39 (m, 14H,
14CHarom), 7.76 (bs, 1H, NH-t-butyl), 8.07 (t, 3J = 6.4 Hz, 1H, NHamid), 8.15 (t, 3J =
6.0 Hz, 1H, NHamid) ppm. 13C NMR (100 MHz, DMSO-d6) δ: 28.27, 41.80, 42.15,
49.91, 49.99, 56.53, 126.40, 126.53, 126.70, 126.92, 127.96, 128.16, 130.14, 131.44,
137.68, 138.71, 139.14, 166.97, 167.42, 170.58 ppm. Anal.Calcd for C32H32ClN5O2:
C, 69.37; H, 5.82; N, 12.64. Found: C, 69.03; H, 5.84; N, 12.61.
Cl
NC
H
N
NC
O
O
NH HN
2-(1-(tert-butylamino)-3,3-dicyano-2-p-tolylpropylidene)-N1,N3-dip-tolylmalonamide
(5m):
white powder (72%); IR (KBr) cm-1: 3294, 3126, 3033, 2973, 2867, 1675, 1638,
1543, 1518, 1452; 1H NMR (400 MHz, DMSO-d6) δ: 1.11 (s, 9H, C(CH3)3), 2.19 (s,
3H, CH3), 2.21 (s, 3H, CH3), 2.24 (s, 3H, CH3), 4.16 (d, 3J = 11.2 Hz, 1H, CH(CN)2),
4.42 (d, 3J = 11.6 Hz, 1H, CHPh), 7.02-7.46 (m, 12H, 12CHarom), 7.45 (bs, 1H, NH-tbutyl), 9.67 (s, 1H, NHamid), 9.70 (s, 1H, NHamid) ppm. 13C NMR (100 MHz, DMSOd6) δ: 20.34, 20.39, 20.59, 28.27, 49.87, 50.25, 58.42, 119.04, 119.06, 127.92, 128.62,
129.04, 129.16, 132.41, 132.57, 135.36, 135.71, 135.89, 136.22, 165.05, 165.70,
171.01 ppm. Anal.Calcd for C33H35N5O2: C, 74.27; H, 6.61; N, 13.12. Found: C,
74.51; H, 6.63; N, 13.16.
H
N
NC
NC
O
O
NH HN
2-(1-(tert-butylamino)-3,3-dicyano-2-(3,4-dimethoxyphenyl)propylidene)-N1,N3-diptolylmalonamide (5n):
white powder (56%); IR (KBr) cm-1: 3307, 3124, 3036, 2967, 2835, 1676, 1633,
1516, 1453, 1245; 1H NMR (400 MHz, DMSO-d6) δ: 1.13 (s, 9H, C(CH3)3), 2.20 (s,
3H, CH3), 2.25 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 4.15 (d, 3J =
10.1 Hz, 1H, CH(CN)2), 4.39 (d, 3J = 11.2 Hz, 1H, CHPh), 6.82-7.47 (m, 11H, 11
CHarom), 7.71 (bs, 1H, NH-t-butyl), 9.62 (s, 1H, NHamid), 9.71 (s, 1H, NHamid) ppm.
C NMR (100 MHz, DMSO-d6) δ: 20.36, 20.40, 28.28, 49.88, 50.17, 55.23, 55.32,
13
58.45, 111.29, 111.84, 119.08, 119.11, 120.18, 129.05, 129.15, 130.64, 132.40,
132.57, 135.93, 136.22, 147.55, 148.00, 165.24, 165.73, 171.02 ppm; Anal.Calcd for
C34H37N5O4: C, 70.45; H, 6.43; N, 12.08. Found: C, 70.49; H, 6.44; N, 12.05.
OCH3
OCH3
H
N
NC
NC
O
O
NH HN
2-(1-(tert-butylamino)-3,3-dicyano-2-p-tolylpropylidene)-N1,N3-bis(4methoxyphenyl)malonamide (5o):
white powder (62%); IR (KBr) cm-1: 3299, 3134, 3065, 2966, 2885, 1671, 1638,
1512, 1459, 1245; 1H NMR (400 MHz, DMSO-d6) δ: 1.12 (s, 9H, C(CH3)3), 2.22 (s,
3H, CH3), 3.67 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.12 (d, 3J = 11.4 Hz, 1H,
CH(CN)2), 4.41 (d, 3J = 11.4 Hz, 1H, CHPh), 6.80-7.49 (m, 12H, 12 CHarom), 7.72
(bs, 1H, NH-t-butyl), 9.59 (s, 1H, NHamid), 9.62 (s, 1H, NHamid) ppm. 13C NMR (100
MHz, DMSO-d6) δ: 20.60, 28.29, 49.86, 20.32, 55.12 (ovrlap of two signal), 58.29,
113.78, 113.88, 120.65, 127.95, 128.59, 131.57, 131.90, 135.42, 135.67, 155.30,
155.38, 164.95, 165.58, 171.01 ppm; Anal.Calcd for C33H35N5O4: C, 70.07; H, 6.24;
N, 12.38. Found: C, 69.92; H, 6.25; N, 12.31.
H
N
NC
NC
O
O
NH HN
H3CO
OCH3