One-pot, three-component condensation of 2-hydroxybenzaldehyde derivatives, primary amines with alkyl isocyanides to N-alkyl-2-(2-hydroxyphenyl)-2-imino-acetamides

Article abstract of DOI:10.2478/s11532-010-0054-7

One-pot, three-component condensation of 2-hydroxybenzaldehyde derivatives, primary amines with alkyl isocyanides is reported. N-alkyl-2-(2-hydroxyphenyl)-2-iminoacetamide derivatives are generated presumably via the preliminary formation of N, N′-disubstituted benzo[b]furan-2,3-diamines and subsequent oxidation with molecular oxygen.

Full text of DOI:10.2478/s11532-010-0054-7

Cent. Eur. J. Chem. • 8(4) • 2010 • 899–905
DOI: 10.2478/s11532-010-0054-7
Central European Journal of Chemistry
One-pot, three-component condensation
of 2-hydroxybenzaldehyde derivatives,
primary amines with alkyl isocyanides to
N-alkyl-2-(2-hydroxyphenyl)-2-imino-acetamides
Research Article
Mehdi Ghandi*, Parham Asgari, Abuzar Taheri, Alireza Abbasi
School of Chemistry, College of Science, University of Tehran,
P.O. Box 14155 6455 Tehran, Iran
Received 10 January 2010; Accepted 23 March 2010
Abstract: One-pot, three-component condensation of 2-hydroxybenzaldehyde derivatives, primary amines with alkyl isocyanides is
reported. N-alkyl-2-(2-hydroxyphenyl)-2-iminoacetamide derivatives are generated presumably via the preliminary formation of N,
N’-disubstituted benzo[b]furan-2,3-diamines and subsequent oxidation with molecular oxygen.
Keywords: Ugi reaction • Three-component • 2-Hydroxybenzaldehyde derivatives
© Versita Sp. z o.o.
1. Introduction
Smiles rearrangement in place of the traditional Mumm
acyl transfer. Utilization of electron deficient o- and
Multicomponent reactions (MCRs) [1-5] in general and p-phenols, salicylic derivatives and heteroaromatic
isocyanide-based multicomponent reactions (IMCRs) phenols as the acidic surrogate in 4-CR leading to
[6-10] in particular have attracted the attention of N-arylamides associated with Smiles rearrangement
chemist’s during the past years. These reactions has been reported [20].
are well defined and suited for combinational library
Utilization of bifunctional starting materials, in which
synthesis due to the fact that products are formed in the participating functional groups of two components
one-pot reactions [11-12]. The most popular IMCR is of the 4CC reaction are present in one structure, is
probably the Ugi reaction, in which a carboxylic acid, another strategy to increase scaffold diversity. The
a primary amine, an aldehyde, and an isocyanide react Reaction of bifunctional starting materials, such
in a one-pot manner to afford an N-substituted acyl as 2-(2-formylphenoxy)acetic acid or levulinic acid
aminoamide containing four independently varying containing either an aldehyde or a ketone and carboxylic
groups [13]. The Brönsted properties of carboxylic acid functional groups in Ugi three-component
acids in Ugi MCR allow faster imine formation and condensation (3CC) reactions to lactam structures
addition of the moderately nucleophilic isocyanide to has been previously reported [21,22]. These results
the activated iminiums. Subsequent trapping of the prompted us to explore the 3CC of primary amines,
nitrilium intermediate by carboxylate followed by the and isocyanides with a bifunctional starting material,
irreversible acyl transfer step, known as the Mumm containing aldehyde and hydroxy functional groups.
rearrangement [14], associated with the Ugi reaction Herein, we report the direct synthesis of novel N-alkyl-
seems to be responsible for the displacement of 2-(2-hydroxyphenyl)-2-iminoacetamide
derivatives
various equilibria. In a recently disclosed novel Ugi-type via one-pot, three component condensation of
process, phenols have been used instead of carboxylic 2-hydroxybenzaldehyde derivatives, primary aliphatic,
acids [15-20]. These reactions involve an irreversible aromatic or heteroaryl amines with alkyl isocyanides in
acetonitrile.
* E-mail: ghandi@khayam.ut.ac.ir
899

One-pot, three-component condensation of 2-hydroxybenzaldehyde
derivatives,primary amines with alkyl isocyanides to
N-alkyl-2-(2-hydroxyphenyl)-2-imino- acetamides
2. Experimental Procedure
(22), 126 (44), 77 (100), 83 (90); C, H, N-analysis calcd.
All commercially available chemicals and reagents for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99; found: C,
were used without further purification. Melting points 71.01; H, 6.98; N, 12.51.
were determined with an Electrothermal model 9100 2.1.4. N-tert-butyl-2-(2-hydroxyphenyl)-2-(pyridin-2-
apparatus and were uncorrected. IR spectra were
ylimino)acetamide (1d).
1
recorded on a Shimadzu 4300 spectrophotometer. Brown crystal, mp.: 175-1770C; H NMR: δ = 1.29 (s,
1
The H and 13C NMR spectra were recorded in CDCl3 9H), 5.42 (s, 1H), 6.87-8.17 (m, 8H), 13.24 (s, 1H);
on a Bruker DRX-500 AVANCE spectrometer. Chemical 13C NMR: δ = 28.7, 52.9, 112.7, 116.9, 117.8, 118.1,
shifts (δ) are reported in ppm and are referenced to 119.9, 122.9, 123.8, 125.0, 126.7, 129.5, 136.5, 139.8,
the NMR solvent. Mass spectra of the products were 158.0; IR (KBr): vmax (cm-1): 3322 (NH and OH), 1667
obtained with a HP (Agilent technologies) 5937 Mass (C=O); MS (EI, 70 eV): m/z 297 (M+, 2), 204 (16), 100
Selective Detector. Elemental analyses were carried (100), 77 (80); C, H, N-analysis calcd. for C17H19N3O2;
out by a CHN-O-Rapid Heraeus elemental analyzer C, 68.67, H, 6.44, N, 14.13; found: C, 68.37; H, 6.04;
(Wellesley, MA).
N, 14.59.
2.1.5. N-cyclohexyl-2-(2-hydroxyphenyl)-2-(pyrimidin-
2-ylimino)acetamide (1e).
2.1. General procedure for the synthesis of 1a-q
Aniline (0.093 g, 1.0 mmol) and cyclohexyl isocyanide Yellow crystal, mp.: 193-1950C; 1H NMR: δ = 0.86-1.63
(0.109 mL, 1.0 mmol) were successively added to (m, 10H), 3.81-3.83 (m, 1H), 4.22 (d, J = 9 Hz, 1H),
a solution of salicylaldehyde (0.122 g, 1.0 mmol) in 6.89-8.48 (m, 7H), 12.03 (s, 1H); 13C NMR: δ = 25.2,
acetonitrile (10 mL). The resulting solution was refluxed 26.1, 34.5, 57.3, 111.5, 112.6, 119.2, 119.9, 129.3,
with stirring for 6 h. The solvent was then removed under 131.4, 134.2, 139.3, 162.2, 164.1, 189.9; IR (KBr):
reduced pressure and the residue was recrystalized
from methanol to afford 1a-q.
2.1.1. N-cyclohexyl-2-(2-hydroxyphenyl)-2-
v
max (cm-1): 3311 (NH and OH), 1665 (C=O); MS (EI, 70
eV): m/z 324 (M+, 3), 231 (21), 126 (43), 77 (100); C, H,
N-analysis calcd. for C18H20N4O2; C, 66.65; H, 6.21; N,
17.27; found: C,66.23; H, 6.32; N, 17.44.
(phenylimino)acetamide (1a).
Colorless crystal, mp.: 183-1850C; H NMR: δ = 0.84- 2.1.6. N-tert-butyl-2-(2-hydroxyphenyl)-2-(pyrimidin-2-
1
1.65 (m, 10H), 3.80-3.82 (m, 1H), 5.45 (d, J = 8.0
ylimino)acetamide (1f).
Hz, 1H), 6.93-7.55 (m, 9H), 13.31 (s, 1H); 13C NMR: Bright yellow crystal, mp.: 187-1890C; 1H NMR: δ =1.45
δ = 24.8, 25.6, 32.8, 48.5, 116.7, 118.5, 119.4, 121.7, (s, 9H), 4.21 (s, 1H), 6.89-8.48 (m, 7H), 12.03 (s, 1H);
126.5, 129.7, 131.1, 134.3, 149.6, 162.5, 168.5; IR 13C NMR: δ = 28.8, 52.6, 111.5, 112.59 ,119.2, 119.9,
(KBr): vmax (cm-1): 3320 (NH and OH), 1673 (C=O); MS 129.3, 131.4, 134.2, 138.4, 162.2, 191.0; IR (KBr):
(EI, 70 eV): m/z 322 (M+, 2), 196 (84), 126 (45), 77
v
max(cm-1):3270(NHandOH),1680(C=O);MS(EI,70eV):
(100); C, H, N-analysis calcd. for C20H22N2O2; C, 74.51, m/z 298 (M+, 4), 205 (11), 93 (71), 77 (100); C, H,
H, 6.88, N, 8.69; found: C, 74.81; H, 6.39; N, 8.99.
2.1.2. N-tert-butyl-2-(2-hydroxyphenyl)-2-
(phenylimino)acetamide (1b).
N-analysis calcd. for C16H18N4O2; C, 64.41; H, 6.08; N,
18.78; found: C, 64.86; H, 6.23; N, 18.34.
2.1.7. N-tert-butyl-2-(2-hydroxyphenyl)-2-
1
Brown crystal, mp.: 175-1770C; H NMR: δ = 1.14 (s,
(benzylimino)acetamide (1g).
9H), 5.19 (s, 1H), 6.91-7.69 (m, 9H), 13.27 (s, 1H); 13C Bright brown crystal, mp.: 79-810C; H NMR: δ = 1.46
NMR: δ = 28.8, 53.0,118.6 ,119.5 ,121.9 ,122.5 ,126.4, (s, 9H), 4.83 (bs, 3H), 6.75-7.70 (m, 9H), 11.54 (s, 1H);
129.3 ,129.6 ,131.2, 134.3 ,146.8 ,162.5 ,168.5; IR 13C NMR: δ = 28.8, 44.9, 52.9, 112.7, 118.1, 119.1,
(KBr): vmax (cm-1): 3321 (NH and OH), 1670 (C=O); MS 122.9, 123.8, 125.0, 158.0, 166.9; IR (KBr): vmax (cm-1):
(EI, 70 eV): m/z 296 (M+, 2), 196 (46), 100 (65), 77 (60), 3303 (NH and OH), 1675 (C=O); MS (EI, 70 eV): m/z
57( 100); C, H, N-analysis calcd. for C18H20N2O2; C, 310 (M+, 3), 210 (32), 145 (44), 77 (100), 57 (90); C, H,
72.95; H, 6.80; N, 9.45; found: C,72.63; H, 7.02; N, 9.11. N-analysis calcd. for C19H22N2O2 ; C, 73.52; H, 7.14; N,
1
2.1.3. N-cyclohexyl-2-(2-hydroxyphenyl)-2-(pyridin-2-
ylimino)acetamide (1c).
9.03 ; found: C, 73.07; H, 7.44; N, 9.38.
2.1.8. N-tert-butyl-2-(2-hydroxyphenyl)-2-
(methylimino)acetamide (1h).
Yellow crystal, mp.: 149-1510C; 1H NMR: δ = 1.21-1.88
(m, 10H), 3.00 (bs, 2H), 6.89-8.16 (m, 8H), 13.24 (s, Bright brown crystal, mp.: 90-920C; 1H NMR: δ = 1.24 (s,
1H); 13C NMR: δ = 25.2, 26.1, 34.5, 57.3, 112.6, 117.0, 9H), 3.54 (s, 3H), 5.20 (s, 1H), 7.19-8.18 (m, 4H), 13.27
117.9, 118.1 ,119.1, 122.9, 123.8, 125.0, 126.7, 129.5, (s, 1H); 13C NMR: δ = 28.8, 44.9, 52.9, 112.7, 118.1,
136.4, 139.8, 158.0; IR (KBr): vmax (cm-1): 3323 (NH and 119.1, 122.9, 123.8, 125.0, 158.0, 166.9; IR (KBr): vmax
OH), 1664 (C=O); MS (EI, 70 eV): m/z 323 (M+, 3), 225 (cm-1): 3291 (NH and OH), 1670 (C=O); MS (EI, 70
900

M. Ghandi, P. Asgari, A. Taheri, A. Abbasi
eV): m/z 234 (M+, 2), 141 (32), 72 (100), 77 (65); C, H, 8H), 13.35 (s, 1H); 13C NMR: δ = 28.7, 29.6, 37.6, 60.7,
N-analysis calcd. for C13H18N2O2 ; C, 66.64; H, 7.74; N, 110.6, 118.6, 120.2, 121.9, 126.4, 133.3, 136.4, 146.5’
11.96; found: C, 66.99; H, 7.31; N, 12.35.
2.1.9. N-cyclohexyl-2-(2-hydroxy-3-methoxyphenyl)-2-
(phenylimino)acetamide (1i).
161.4, 162.2, 167.6; IR (KBr): vmax (cm-1): 3296 (NH
and OH), 1658 (C=O); MS (EI, 70 eV): m/z 400 (M+,
3), 172 (47), 126 (36), 77 (100); C, H, N-analysis calcd.
Bright brown crystal, mp.: 169-1710C; 1H NMR: δ =1.20- for C20H21BrN2O2; C, 59.86; H, 5.27; N, 6.98; found: C,
1.86 (m, 10H), 3.05-3.07 (m, 1H), 3.95 (s, 3H), 5.42 60.01; H, 4.88; N, 6.66.
(s, 1H), 6.87-7.42 (m, 8H), 13.79 (s, 1H); 13C NMR:
2.1.14. N-tert-butyl-2-(5-bromo-2-hydroxyphenyl)-2-
(phenylimino)acetamide (1n).
δ = 25.3 , 26.1 ,34.4, 56.5, 57.4, 115.5, 116.7, 118.7,
122.0, 122.5, 126.4, 129.4, 146.6, 149.2, 153.0, 162.7, Colorless crystal, mp.: 235-2370C; H NMR: δ =1.13
158.8; IR (KBr): vmax (cm-1): 3296 (NH and OH), 1658 (s, 9H), 2.44 (s, 1H), 6.82-7.52 (m, 8H), 13.47 (s, 1H);
(C=O); MS (EI, 70 eV): m/z 352 (M+, 4), 226 (9), 126 13C NMR: δ = 28.6, 52.6, 110.6, 118.6, 120.2, 121.9,
(45), 77 (100); C, H, N-analysis calcd. for C21H24N2O3; 126.4, 129.2, 133.3, 136.4, 146.5, 161.4, 162.2, 167.6;
C, 71.57; H, 6.86; N, 7.95; found: C,71.99; H, 6.44; N, IR (KBr): vmax (cm-1): 3323 (NH and OH), 1631 (C=O);
1
7.65.
MS (EI, 70 eV): m/z 375 (M+, 3), 153 (89), 100 (70),
77 (100); C, H, N-analysis calcd. for C18H19BrN2O2; C,
57.61; H, 5.10; N, 7.47; found: C, 57.11; H, 4.51; N,
2.1.1.0 N-tert-butyl-2-(2-hydroxy-3-methoxyphenyl)-2-
(phenylimino)acetamide (1j).
Brown crystal, mp.: 180-1820C; H NMR: δ = 1.20 (s, 7.98.
1
2.1.15. N-cyclohexyl-2-(5-bromo-2-hydroxyphenyl)-2-
(pyridin-2-ylimino)acetamide (1o).
9H), 3.98 (s, 3H), 5.43 (s, 1H), 6.88-7.40 (m, 8H), 13.79
(s, 1H); 13C NMR: δ = 28.8, 53.0, 118.6, 119.5, 121.9,
122.5, 126.4, 129.3, 129.6, 131.2, 134.3, 146.8, 162.5, Yellow crystal, mp.: 209-2110C; 1H NMR: δ = 1.22-1.88
168.5; IR (KBr): vmax (cm-1): 3296 (NH and OH), 1658 (m, 10H), 3.01-3.03 (m, 1H), 3.73 (dd, J = Hz, 1H),
(C=O); MS (EI, 70 eV): m/z 326 (M+, 2), 226 (24), 100 6.93-7.55 (m, 7H), 13.31 (s, 1H); 13C NMR: δ = 18.9,
(65), 77 (100); C, H, N-analysis calcd. for C19H22N2O3; 25.2, 34.6, 57.4, 110.9, 113.0, 117.9, 119.6, 119.9,
C, 69.92; H, 6.79; N, 8.58; found: C, 69.51; H, 6.39; N, 122.8, 124.1, 125.4, 129.4, 131.9, 135.2, 139.9, 157.0;
8.99.
IR (KBr): vmax (cm-1): 3315 (NH and OH), 1670 (C=O);
MS (EI, 70 eV): m/z 402 (M+, 2), 274 (22), 126 (44), 83
(100), 77 (70); C, H, N-analysis calcd. for C19H20BrN3O2;
2.1.11. N-cyclohexyl-2-(2-hydroxy-3-methoxyphenyl)-
2-(pyridin-2-ylimino)acetamide (1k).
Yellow crystal, mp.: 154-1560C; H NMR: δ =1.20-1.86 C, 56.73; H, 5.01; N, 10.45; found: C, 56.32; H, 5.25;
1
(m, 10H), 3.05-3.07 (m, 1H), 3.15 (bs, 1H), 3.98 (s, 3H), N, 10.69.
6.86-8.18 (m, 7H), 13.22 (s, 1H); 13C NMR: δ = 25.3,
2.1.16. N-tert-butyl-2-(5-bromo-2-hydroxyphenyl)-2-
(pyridin-2-ylimino)acetamide (1p).
26.1, 34,4, 56.5, 77,2, 77.5, 77.7, 111.6, 112.6, 117.1,
118.2, 118.6, 119.0, 122.9, 124.1, 124.9, 136.4,139.9, Brown crystal, mp.: 218-2200C; H NMR: δ = 1.28 (s,
147.8, 149.4; IR (KBr): vmax (cm-1): 3514 (NH and OH), 9H), 3.75 (s, 1H), 6.93-8.56 (m, 7H), 13.51 (s, 1H); 13C
1637 (C=O); MS (EI, 70 eV): m/z 353 (M+, 2), 126 NMR: δ = 30.9, 55.2, 108.9, 110.0, 119.7, 119.8, 121.0,
(53), 106 (100), 77 (78); C, H, N-analysis calcd. for 123.4,130.9, 135.7, 136.8, 139.0, 149.5, 161.3, 163.89;
C20H23N3O3; C, 67.97 ; H, 6.56; N, 11.89; found: C, IR (KBr): vmax (cm-1): 3343 (NH and OH), 1680 (C=O)
1
67.53; H, 6.99; N, 11.45.
cm-1; MS (EI, 70 eV): m/z 375 (M+, 3), 196 (89), 100
(70), 77 (100); C, H, N-analysis calcd. for C17H18BrN3O2;
C, 54.27; H, 4.82; N, 11.17; found: C, 54.53; H, 4.66;
2.1.12. N-tert-butyl-2-(2-hydroxy-3-methoxyphenyl)-2-
(pyridin-2-ylimino)acetamide (1l).
Yellow crystal, mp.: 204-2060C; 1H NMR: δ =1.21 (s, 9H), N, 11.01.
2.1.17. N-tert-butyl-2-(2-hydroxy-5-nitrophenyl)-2-
(phenylimino)acetamide (1q).
118.2, 119.0, 122.9, 124.9, 136.4, 139.9, 147.8, 149.4; IR Bright brown crystal, mp.: 183-1850C; H NMR: δ =
(KBr): vmax (cm-1): 3290 (NH and OH), 1650 (C=O); MS 1.51 (s, 9H), 5.41 (s, 1H), 7.30-8.75 (m, 8H), 14.49
(EI, 70 eV): m/z 327 (M+, 4), 204 (14), 106 (56), 77 (100); (s, 1H); 13C NMR: δ = 28.8, 52.8, 118.3, 118.5, 118.8,
C, H, N-analysis calcd. for C18H21N3O3; C, 66.04; H, 6.47; 121.7, 128.5, 128.8, 128.8, 130.1, 140.4, 147.1, 161.0,
3.15 (s, 1H), 3.98 (s, 3H), 6.86-8.18 (m, 7H), 13.22 (s,
1H); 13C NMR: δ = 28.7, 52.9, 56.6, 111.5, 112.6, 117.1,
1
N, 12.84; found: C, 66.48; H, 6.04; N, 12.44.
2.1.13. N-cyclohexyl-2-(5-bromo-2-hydroxyphenyl)-2-
167.4; IR (KBr): vmax (cm-1): 3289 (NH and OH), 1673
(C=O); MS (EI, 70 eV): m/z 341 (M+, 2), 241 (21), 100
(78), 77 (100); C, H, N-analysis calcd. for C18H19N3O4 ;
(phenylimino)acetamide (1m).
1
Colorless crystal, mp.: 222-2240C; H NMR: δ = 1.23 C, 63.33; H, 5.61; N, 12.31; found: C, 62.98; H, 5.90;
(s, 10H), 3.05-3.07 (m, 1H), 5.12 (s, 1H), 6.73-7.42 (m, N, 12.22.
901

One-pot, three-component condensation of 2-hydroxybenzaldehyde
derivatives,primary amines with alkyl isocyanides to
N-alkyl-2-(2-hydroxyphenyl)-2-imino- acetamides
3. Results and Discussion
2-hydroxybenzaldehyde derivatives, amines and
alkylisocyanides(Scheme1). Obtaining1a-q(Scheme1)
In the model experiment, the reaction smoothly went was a surprising outcome. Our surprise was tempered
to completion when the imine, obtained from reaction when a literature search disclosed that the similar
of salicylaldehyde with aniline, was treated with compound III, has been employed as an important
cyclohexyl isocyanide in CH3CN, and heated to reflux intermediate for preparing fungicides (Scheme 2) [24].
for 6 h. After evaporation of solvent under reduced Compound III has been prepared from the reaction of
pressure, the recrystalized solid from methanol alkyl (2-hydroxyphenyl)-oxoacetates II with a proper
was identified as 1a on the basis of analytical data amount of methylamine (Scheme 2) [24]. Compounds
(Scheme 1). The IR spectrum of 1a showed peaks at II had been obtained in turn through the photo-Fries
3514, and 1637 cm-1 due to –OH, and –C=O groups, rearrangement of alkyl phenyl oxalates I as a minor
respectively. The 1H NMR spectrum of 1a exhibited product (Scheme 2) [25]. Therefore, the serendipitious
the characteristic multiplets at δ: 0.84-1.65 (10H) and outcome of 1a-q deserves some consideration.
3.80-3.82 (1H) due to cyclohexyl and -CH-Ph protons,
It is quite evident that obtaining products 1a-q
respectively. A doublet and a singlet appeared at δ: supportstheformationofN-alkyl-3-(aryllamino)-benzo[b]
5.45 (J = 8 Hz, 1H) and 13.31 (1H) for -NH and –OH furan-2-carboxamides I as fleeting intermediates and
groups, respectively. The 13C NMR displayed four peaks their subsequent reaction with molecular oxygen. The
at δ: 24.8 to 48.5 and nine peaks at δ: 116.7 to 146.9 following evidence could explain the reaction pathway
due to aliphatic and aromatic carbons, respectively. for the formation of 1a-q.
Finally, two characteristic peaks appeared at δ: 162.5
and 168.5 for –C=N and –C=O groups, respectively. long as the reaction is carried out under atmosphere.
The MS (EI) spectrum revealed the molecular ion peak
(2) Implementation of the reaction of salicylaldehyde,
(1) The reproduceability of 1a-q is guaranteed as
at m/z 322 corresponding to the molecular weight aniline and cyclohexyl isocyanide under argon
of 1a. The microelemental analysis of compound 1a atmosphere afforded a complex mixture of products,
was consistent with the molecular structure. Our later amongst which 1a was not identified. This experiment
studies revealed that 1a could be prepared via a one- clearly indicates the key role of molecular oxygen in the
pot experiment if aniline, and cyclohexyl isocyanide are formation of 1a.
added successively to a solution of salicylaldehyde in
CH3CN. This experiment clearly indicates the implication
of salicylaldehyde-aniline imine in the reaction.
We then examined the scope of the amines that
could participate in the coupling of cyclohexyl isocyanide
or tert-butyl isocyanide with 2-hydroxybenzaldehyde
derivatives through one-pot experiments (Scheme 2).
The results are presented in Table 1. Three types
of 2-hydroxybenzaldehyde derivatives worked with
moderate to good efficiency, affording the desired
products (Table 1). Inspection of the results, shown
in Table 1, reveals that the reactions tolerate aniline
affording the corresponding products in good yields
(entries 1, 2, 9, 10, 13, 14, 17). On the other hand,
utilization of heteroaryl amines leads to the formation of
the relevant products, albeit with notably lower yields in
some cases (entries 3-6, 11, 12, 15, 16). However, when
aliphatic amines such as benzyl amine or methyl amine Scheme 1.Synthesis of compounds 1a-q.
were used, the reaction became sluggish, affording
NCH3
products in poor yields of 10% and 12%, respectively
OCOCO2R
hv
COCO2R
CH3NH2
CONHCH3
(entries 7 and 8). Synthesis of 1j enabled the single
crystal X-ray analysis to be performed. As shown in
Fig. 1, the structure of 1j was further confirmed [23].
At the beginning of this study, we expected
OH
OH
I
II
III
to
obtain
the
N-alkyl-3-(aryllamino)-benzo[b]
Scheme 2.
furan-2-carboxamides
I
from the reaction of Scheme 2.Structural similarity of III (obtained from II and I) with 1a
902

M. Ghandi, P. Asgari, A. Taheri, A. Abbasi
Table 1.Results of the synthesized 1a-q
Yielda
(%)
Entry
R1
R2
R3
R4
Product
O3
1
2
3
C6H11
(CH3)3C
C6H11
H
H
H
H
H
H
1a
1b
1c
83
75
58
O2
N2
O1
N1
N
N
N
N
4
5
6
(CH3)3C
C6H11
H
H
H
H
H
H
1d
1e
1f
36
44
40
N
N
(CH3)3C
Figure 1.X-ray crystal structure of 1j.
7
8
9
(CH3)3C
(CH3)3C
C6H11
H
H
H
H
H
1g
1h
1i
15
14
81
CH3-
R
N
NO2
CH3O
N C
N
O
N
NO2
(a)
10
11
(CH3)3C
C6H11
CH3O
CH3O
H
H
1j
82
48
+
R = OH
OH
1k
N
N
OH
NH2
O
12
13
14
15
(CH3)3C-
C6H11
CH3O-
H
1l
1m
1n
1o
45
80
79
75
H
(b)
N
(c)
H
H
H
Br
Br
Br
+
R = H
O
OH
(CH3)3C
C6H11
C
NO2
NO2
NO2
N
N
HN
O
H2O
16
17
(CH3)3C
(CH3)3C
H
H
Br
1p
1q
63
53
N
N
H
N
O2
NO2
O
OH
aIsolated products.
A
B
Scheme 3.
Scheme 3.Proposed mechanism for the formation of C.
(3) The 2-Hydroxy group present in salicylaldehyde
has a vital role in the formation of 1a, since the reaction
of benzaldehyde, primary amine and isocyanide has
been reported to afford an indole derivative [26].
(4) That 1a might have been formed via the reaction
of isocyanide with imine and subsequent reaction with
water and oxidation of the obtained N-cyclohexyl-
2-(2-hydroxyphenyl)-2-(phenylamino) acetamide to
N-cyclohexyl-2-(2-hydroxyphenyl)-2-(phenylimino)
acetamide does not seem to be a plausible pathway.
The formation of 1a in dry acetonitrile rules out the
implication of water. Moreover, implementation of the
reaction in acetonitrile and water leads to a complex
mixture of products.
(5) The final note, worth emphasizing, is the
recently reported three-component condensation
of salicylaldehyde, various o-aminophenols, and
2,6-dimethylphenylisocyanide affording 2-imino-1,4-
benzoxazines (Scheme 3, pathway a) [27]. To cast
light on the importance of the hydroxyl group of the
Scheme 4.Proposed mechanim for the formation of 1a
903

One-pot, three-component condensation of 2-hydroxybenzaldehyde
derivatives,primary amines with alkyl isocyanides to
N-alkyl-2-(2-hydroxyphenyl)-2-imino- acetamides
F would finally afford N-tert-butyl-2-(2-hydroxyphenyl)-2-
(phenylimino)acetamide 1a. There are several reports in
the literature for the fast conversion of iminolactones to
2-aminofurans. These quite unstable intermediates then
undergo oxidation with triplet oxygen with mechanisms
similar to that depicted in Scheme 4 [28-30].
o-aminophenols in the formation of the benzoxazines,
the authors have run the reaction with salicylaldehyde-
p-nitroaniline Schiff base under nitrogen atmosphere.
Isolation of t he 2-oxoacetamide derivative as the
sole product has convinced the authors that the
presence of the hydroxyl group of the o-aminophenol
is a requirement for the generation of the benzoxazines
(Scheme 3, pathway b) [27]. Although no explanation
for the formation the 2-oxoacetamide derivative C
has been suggested by the authors, we believe that it
has been driven from the reaction of intermediate A
with triplet oxygen probably during work-up, followed
by hydrolysis of the 2-aryliminoacetamide derivative
4. Conclusion
In conclusion, N-alkyl-2-(2-hydroxyphenyl)-2-imino-
-acetamides containing three independently varying
groups in one reaction were successfully prepared
and identified through the 3CC of primary aromatic or
heteroarylamines and isocyanides with bifunctional
starting materials, such as 2-hydroxybenzaldehyde
derivatives. It seems likely that products have been
resulted from the preliminary formation of N-cyclohexyl-
B
during column chromatography (Scheme 3,
pathway c).
To rationalize the reaction mechanism, it is
postulated that treatment of salicylaldehyde with aniline
leads to the formation of imine and nucleophilic attack
of isocyanide to imine furnishes the iminolactone A
as is shown in Scheme 4. Tautomerization of A to the
fleeting 2-aminofuran B, and subsequent reaction with
triplet oxygen affords hydroperoxide C. The formation of
molozonide D followed by fragmentation to E and then to
3-(phenylamino)-benzo[b]furan-2-carboxamide
and
subsequent oxidation with triplet oxygen.
Acknowledgement
The authors wish to thank the Research Council of the
University of Tehran for financial support of this research.
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