EDTA-catalyzed synthesis of 3,4-dihydroquinoxalin-2-amine derivatives by a three-component coupling of one-pot condensation reactions in an aqueous medium

Article abstract of DOI:10.1016/j.tet.2010.09.050

This paper describes a simple and efficient one-pot synthetic approach for the preparation of biologically interesting 3,4-dihydroquinoxalin-2-amine derivatives using EDTA-catalyzed three-component reactions of o-phenylenediamines, carbonyl compounds, and isocyanides in an aqueous medium. This method is of great value because of its environmentally benign character, high yields, and ease of handling.

Full text of DOI:10.1016/j.tet.2010.09.050

Tetrahedron 66 (2010) 8938e8944
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
EDTA-catalyzed synthesis of 3,4-dihydroquinoxalin-2-amine derivatives by
a three-component coupling of one-pot condensation reactions in an
aqueous medium
*
Srinivasa Rao Kolla, Yong Rok Lee
School of Chemical Engineering and Technology, Yeungnam University, Kyongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2010
Received in revised form 11 September 2010
Accepted 14 September 2010
Available online 18 September 2010
This paper describes a simple and efficient one-pot synthetic approach for the preparation of biologically
interesting 3,4-dihydroquinoxalin-2-amine derivatives using EDTA-catalyzed three-component reactions
of o-phenylenediamines, carbonyl compounds, and isocyanides in an aqueous medium. This method is of
great value because of its environmentally benign character, high yields, and ease of handling.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
o-Phenylenediamine
3,4-Dihydroquinoxalin-2-amines
Ethylenediaminetetraaceticacid
Three-component reactions
1. Introduction
Among the various classes of nitrogen-containing heterocyclic
compounds, quinoxalines display a broad spectrum of biological
Multicomponent reactions (MCRs) are generally defined as re-
actions where more than two starting materials react to form
a product. Generally, there are three different possible classification
schemes of MCRs according to reaction mechanism, components
involved, or intrinsic variability.1 The development of new MCRs is
an interesting research topic in applied areas of organic, medicinal,
and pharmaceutical chemistry.2 MCRs have attracted considerable
interest owing to their exceptional synthetic efficiency. Hundreds
of MCRs have recently been described. These reactions play a piv-
otal role in the synthesis of natural and unnatural products because
of their importance of therapeutic and pharmacological uses.
Isocyanide-based multicomponent reactions (IMCRs) are par-
ticularly interesting as they are more versatile and diverse than
other MCRs.3 The great potential of isocyanides for the development
of multicomponent reactions lies in the diversity of bond forming
processes available, functional group tolerance, and the high levels
of chemo-, regio-, and stereoselectivity often observed. Moreover,
there is virtually no restriction on the nature of the nucleophiles
and electrophiles in IMCRs. MCRs involving isocyanides have
emerged as valuable tools for the preparation of structurally diverse
chemical libraries of drug-like heterocyclic compounds.4
activity.5,6 Quinoxalines play an important role as a basic skeleton
for the design of a number of antibiotics, such as echinomycin,
actinomycin, and leromycin, compounds with reported inhibition
of the growth of gram-positive bacteria and activity against various
transplantable tumors.7,8 Furthermore, quinoxaline derivatives
show very interesting biological properties (antibacterial, antiviral,
anticancer, antifungal, antihelmintic, insecticidal).9,10 Nevertheless,
development of an effective method for the synthesis of quinoxa-
lines remains an important challenge. Accordingly, a number of
synthetic strategies have been reported for the preparation of
substituted quinoxalines.11e16
To the best of the authors’ knowledge, there is no report on the
synthesis of 3,4-dihyroquinoxaline-2-amines using ethylenedi-
aminetetraaceticacid (EDTA). From known, reported reactions,
a system based on FeII and EDTA in the presence of ascorbic acid and
oxygen was used for the biomimetic hydroxylation of organic sub-
strates.17 EDTA was used in combination with PdCl2 as a catalyst for
the synthesis of biaryl compounds.18 Additionally, the above com-
bination of PdCl2eEDTA was found to be an effective catalyst for the
SuzukieMiyaura cross-coupling.19 EDTA also has the significantly
superior ability to bind the Tc-tricarbonyl core [Tc(CO)3].20 The
combination of 1.0 mM of EDTA in 10% glycerol was used for the
preparation of cell extracts of Rhodococcus erythropolis SC 13845.21
Reported herein is a general and convenient method for the
synthesis of 3,4-dihyroquinoxaline-2-amine derivatives 4 via the
* Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.050

S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
8939
three-component condensation of o-phenylenediamine (1), ke-
tones 2, and isocyanides 3 in the presence of a catalytic amount of
EDTA in aqueous medium at 80 ꢀC or room temperature in good to
excellent yields (Scheme 1).
organic chemistry in recent years.24 Water as a solvent is not only
inexpensive and environmentally benign, but also gives completely
new reactivities.25 However, no combination of catalyst and eth-
ylenediamine (20 mol %) in water at 80 ꢀC for 12 h has provided any
adducts. The use of ethylenediamine dihydrochloride and ethyl-
enediamine diacetate gave products in 66 and 74% yields, re-
spectively. Similarly, o,o-dipheylmethylammonium acetic acid and
o,o-dipheylmethylammonium trifluoroacetic acid provided ad-
ducts in 70 and 76% yields, respectively. When we used ammonium
acetate and acetic acid as catalysts, 4a was produced in 57 and 86%
yields, respectively. Interestingly, the best yield (95%) was obtained
in the presence of 20 mol % EDTA.
Additional reactions of 1 with a variety of ketones and several
isocyanides were carried out to establish generality in the presence
of 20 mol % of EDTA in water. The results are summarized in Table 2.
All reactions were highly regioselective with no other side reactions
observed. For example, the 1H NMR of compound 4b showed the
H
N
R1
NH2
NH2
O
+
-
C
EDTA (20 mol%)
R2
+
+
R2
N
R3
H2O, 80 o
C
R1
N
N R3
3
or r.t
H
2
1
4
Scheme 1.
2. Results and discussion
Recently, Brønsted acids and bases have demonstrated their
potential to serve as active catalysts for a variety of synthetically
useful reactions in organic chemistry.22 In particular, this lab de-
veloped a new and useful methodology for preparing a variety of
benzopyrans using ethylenediamine diacetate (EDDA) as effective
Brønsted acid and base catalysts.23 As a part of an ongoing study
into the synthetic efficacy of utilizing Brønsted acid and base cat-
alysts, reactions of o-phenylenediamine (1) with acetone and tert-
butyl isocyanide were first investigated using several Brønsted acid
and base catalysts in water (Table 1). Presently, the development of
environmental friendly techniques is one of the priority goals of
chemical research, with water emerging as a versatile solvent for
characteristic peaks of a methylene and methyl group at
(m) and 0.90 (t, J¼6.6 Hz). The other methyl peaks appeared at
1.45 and 1.27 as singlets. To investigate the scope and limitation of
d 1.61e1.46
d
this cycloaddition, three-component reactions with benzaldehyde
and acetophenone were carried out. Treatment of 1 with 2f and 3a
afforded the product 4f in 20% yield, whereas that with 2g gave no
product. Interestingly, molecules with spirocyclic analogs were
produced in good yields. However, the products of 4e, 4l, and 4q
were obtained in somewhat lower yield due to steric hindrance of
the cycloheptanone. Three-component coupling reactions with
benzyl isocyanide were also successful at room temperature. Re-
action of 1 with acetone (2a) and benzyl isocyanide (3d) afforded
product 4r in 92% yield, whereas that with cyclohexanone (2d) gave
adduct 4s in 82%.
A possible reaction mechanism is suggested in Scheme 2. The
authors contend that the EDTA could act as a Brønsted acid and
base catalyst. The carbonyl group could be protonated by EDTA,
which could facilitate formation of an iminium cation. Nucleophilic
addition of isocyanide 3 to iminium intermediate 5, followed by
intramolecular cyclization, gave intermediate 7, which could then
be isomerized to final product 4.
In summary, a one-pot, three-component condensation reaction
of aromatic amines, various carbonyl compounds, and isocyanides
was successfully applied to the synthesis of 3,4-dihydroquinoxa-
line-2-amine derivatives. This method further allows preparation
of a class of structurally unique spirocyclic molecules. This meth-
odology offers several advantages, including high product yield,
ease of experimental procedure, environmentally benign character,
and amenability to large-scale operations.
Table 1
Reaction of 1 with 2a and 3a under several catalystsa
H
NH2
NH2
N
O
catalyst
C
N
+
+
H2O
80 oC
N
N
1
H
2a
3a
4a
Entry
1
Catalyst
Time
12
Yieldb
d
0
2
3
12
4
0
H2N
NH2
H3N+
Cl-
+NH3
-Cl
66
74
H3N+
AcO-
+NH3
-OAc
4
5
6
6
70
76
3. Experimental
3.1. General
-OAc
+
NH3
All experiments were carried out in the aqueous layer. Merck,
pre-coated silica gel plates (Art. 5554) with a fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck). All 1H and 13C NMR
spectra were recorded on a Bruker Model ARX (300 and 75 MHz,
respectively) spectrometer in CDCl3 as the solvent chemical shift. IR
spectra were recorded on a Jasco FTIR 5300 spectrophotometer.
HRMS spectra were carried out at the Korea Basic Science Institute
on a Jeol JMS-700 spectrometer.
6
6
+
-OCOCF3
NH3
7
8
NH4OAc
AcOH
5
3
57
86
HOOCH2C
HOOCH2C
CH2COOH
CH2COOH
3.2. General procedure for the preparation of substituted
3,4-dihydroquinoxalin-2-amine
N
N
9
4
95
a
All reactions were carried out with 20 mol % catalyst in water at 80 ꢀC.
Yields of product 4a after column chromatography.
To
a solution of o-phenylenediamine (1 mmol), ketone
b
(2 mmol), and isocyanide (1 mmol) in 5 mL of water was added

8940
S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
Table 2
Additional reactions of 1 with several ketones and isocyanidesa
Entry
Diamine
Ketone
Isocyanide
Time (h)
1
Product
Yielda,b (%)
H
N
O
-C N+
1
86
4b
4c
3a
2b
2c
N
N
H
H
N
O
O
2
3
3a
3a
1
1
82
81
N
N
H
H
N
4d
4e
N
N
H
2d
2e
O
H
N
4
5
3a
3a
2
3
77
NH2
NH2
N
N
H
O
1
H
N
20c
H
4f
2f
O
N
N
H
H
N
6
3a
12
4g
0
2g
N
N
H
H
N
-C N+
7
8
2a
2b
2
4
92
85
4h
4i
N
N
H
3b
H
N
3b
N
N
H
H
N
4j
4k
4l
9
2c
3b
3b
2
2
90
95
N
N
H
H
N
10
2d
N
N
H
H
N
11
2e
3b
12
74c
N
N
H

S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
8941
Table 2 (continued)
Entry
Diamine
Ketone
Isocyanide
Time (h)
Product
Yielda,b (%)
H
N
12
2a
3
93
82
80
86
-C N+
N
N
H
3c
4m
4n
4o
H
N
13
14
15
2b
2c
2d
3c
3c
3c
2
2
1
N
N
H
H
N
N
N
H
H
N
N
N
H
4p
H
N
16
17
2e
2a
3c
2
2
72
N
N
H
4q
4r
H
N
92c
+
-C
N
N
N
H
3d
H
N
18
2d
3d
3
82c
N
N
H
4s
a
All new compounds were characterized by 1H and 13C NMR, HRMS, and IR spectroscopy.
Yield of isolated product.
Reaction carried at room temperature.
b
c
EDTA
R1
H
+
N
NH2
NH2
OH
C-
N+
R3
3
R2
+
+
R1 R2
NH2
5
2
1
Iminium Cation
R1
H
R1
R2
H
N
R1
H
N
R2
N
-H+
R2
R3
R3
+N
N
4
N
H
N
H
N
NH2
R3
6
7
Scheme 2. Proposed mechanism for the formation of product 4.
EDTA (20 mol %). The resulting mixture was heated at 80 ꢀC or room
temperature until the completion of the reaction, as indicated by
TLC (ethyl acetate/n-hexane). Extracted with ethyl acetate then
washed with satd NaHCO3 followed by brine. The organic layer was
dried on Na2SO4, removed the solvent by rotary evaporator, and the
crude product was purified by silica gel column chromatography
using EtOAc/n-hexane as eluent to give products.
3.2.1. Compound 4a. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), acetone 2a (120 mg, 2 mmol), and tert-butyl
isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added 20 mol %
of EDTA (58.5 mg). The reaction mixture was heated at 80 ꢀC for 2 h.
After completion of the reaction the crude mixture was extracted
with ethyl acetate (2ꢁ25 mL) then washed with satd NaHCO3
(5 mL) and followed by brine. Dried over Na2SO4 and removed the

8942
S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
solvent by rotary evaporator followed by column chromatography
removed the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (9.4:0.6)
gave product 4e (220 mg, 77%) as a solid. Mp 113e115 ꢀC; 1H NMR
on silica gel using hexane/ethylacetate (9:1) gave product 4a
(220 mg, 95%) as a solid. Mp 88e90 ꢀC; 1H NMR (300 MHz):
d
7.03
(1H, m), 6.80e6.70 (2H, m), 6.52 (1H, m), 4.18 (1H, br s), 3.42 (1H, br
s), 1.46 (9H, s) 1.25 (6H, s); 13C NMR (75 MHz):
157.4, 135.4, 134.7,
(300 MHz):
(1H, br s), 3.77 (1H, br s), 1.77e1.70 (4H, m), 1.58e1.52 (8H, m), 1.45
(9H, s); 13C NMR (75 MHz):
158.9, 135.8, 134.6, 123.9, 122.6, 119.5,
d 7.01 (1H, m), 6.80e6.69 (2H, m), 6.53 (1H, m), 4.25
d
123.8, 122.5, 119.3, 113.4, 51.5, 50.4, 28.9, 26.0; IR (KBr):
n
3438,
d
3370, 3047, 2869, 1619, 1585, 1511, 1229, 748 cmꢂ1; HRMS (EI) calcd
113.9, 56.1, 51.7, 36.4, 30.8, 29.2, 23.1; IR (KBr): n 3761, 3466, 2924,
for C14H21N3: 231.1735. Found: 231.1736.
1603, 1510, 1220, 1115, 745 cmꢂ1; HRMS (EI) calcd for C18H27N3:
285.2205. Found: 285.2201.
3.2.2. Compound 4b. To
a solution of o-phenylenediamine 1
(108 mg, 1 mmol), 2-butanone 2b (150 mg, 2 mmol), and tert-butyl
isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added 20 mol %
of EDTA (58.5 mg). The reaction mixture was heated at 80 ꢀC for 1 h.
After completion of the reaction the crude mixture was extracted
with ethyl acetate (2ꢁ25 mL) then washed with satd NaHCO3
(5 mL) and followed by brine. Dried over Na2SO4 and removed the
solvent by rotary evaporator followed by column chromatography
on silica gel using hexane/ethylacetate (9.4:0.6) gave product 4b
3.2.6. Compound 4f. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), benzaldehyde 2f (106 mg, 1 mmol), and tert-
butyl isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was stirred at
room temperature for 3 h. After completion of the reaction the
crude mixture was extracted with ethyl acetate (2ꢁ25 mL) then
washed with satd NaHCO3 (5 mL) and followed by brine. Dried
over Na2SO4 and removed the solvent by rotary evaporator fol-
lowed by column chromatography on silica gel using hexane/
ethylacetate (9:1) gave product 4f (56 mg, 20%) as a solid. Mp
(211 mg, 86%) as a solid. Mp 96e98 ꢀC; 1H NMR (300 MHz):
d 7.00
(1H, m), 6.80e6.67 (2H, m), 6.49 (1H, m), 4.14 (1H, br s), 3.47 (1H, br
s), 1.61e1.46 (2H, m), 1.45 (9H, s), 1.27 (3H, s) and 0.90 (3H, t,
118e120 ꢀC; 1H NMR (300 MHz):
m), 6.81e6.72 (2H, m), 6.49 (1H, m), 4.66 (1H, s), 3.99 (1H, br s),
3.73 (1H, br s), 1.35 (9H, s); 13C NMR (75 MHz):
153.1, 139.9, 135.1,
134.8, 129.2, 128.8, 128.1, 124.5, 123.0, 119.7, 113.2, 57.6, 52.0, 29.0;
d 7.37e7.30 (5H, m), 7.09 (1H,
J¼6.6 Hz); 13C NMR (75 MHz):
d 156.6, 135.0, 134.7, 123.7, 122.5,
118.9, 112.9, 53.5, 51.5, 31.2, 29.0, 24.1, 7.8; IR (KBr):
n
3751, 3451,
d
3349, 2965, 1613, 1514, 1267, 748 cmꢂ1; HRMS (EI) calcd for
C15H23N3: 245.1892. Found: 245.1896.
IR (KBr):
n 3434, 3059, 2965, 1689, 1566, 1518, 1452, 1325, 1219,
1018, 761 cmꢂ1; FAB-HRMS m/z [MþH]þ calcd for C18H22N3:
3.2.3. Compound 4c. To
a
solution of o-phenylenediamine
1
280.1814. Found: 280.1817.
(108 mg, 1 mmol), cyclopentanone 2c (170 mg, 2 mmol), and tert-
butyl isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was heated at
80 ꢀC for 1 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and re-
moved the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (9.4:0.6)
gave product 4c (211 mg, 82%) as a solid. Mp 105e107 ꢀC; 1H NMR
3.2.7. Compound 4h4c. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), acetone 2a (120 mg, 2 mmol), and cyclohexyl
isocyanide 3b (110 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was heated at
80 ꢀC for 2 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and re-
moved the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (8.5:1.5)
gave product 4h (237 mg, 92%) as a solid. Mp 82e84 ꢀC; 1H NMR
(300 MHz):
(1H, br s), 3.61 (1H, br s), 1.80e1.68 (8H, m) 1.46 (9H, s); 13C NMR
(75 MHz): 157.1, 136.0, 135.0, 123.7, 122.2, 119.4, 113.6, 61.5, 51.4,
36.8, 28.9, 24.0; IR (KBr): 3461, 3298, 2959, 1591, 1516, 1216,
744 cmꢂ1; HRMS (EI) calcd for C16H23N3: 257.1892. Found 257.1895.
d 7.00 (1H, m), 6.80e6.74 (2H, m), 6.50 (1H, m), 4.16
d
(300 MHz):
d
7.06 (1H, d, J¼7.2 Hz), 6.82e6.72 (2H, m), 6.54 (1H, m),
n
4.28 (1H, br s), 4.04 (1H, m), 3.46 (1H, br s), 2.07e2.04 (2H, m),
1.72e1.60 (4H, m), 1.50e1.38 (2H, m), 1.28 (6H, s), 1.20e1.09 (2H,
m); 13C NMR (75 MHz):
d
158.0, 135.3, 134.7, 123.5, 122.6, 119.5,
113.5, 50.6, 48.3, 33.0, 25.9, 25.8, 24.7; IR (KBr): 3758, 3396, 2931,
2851, 2355, 1529, 1418, 1211, 743 cmꢂ1
3.2.4. Compound 4d. To
a solution of o-phenylenediamine 1
n
(108 mg, 1 mmol), cyclohexanone 2d (200 mg, 2 mmol), and tert-
butyl isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was heated at
80 ꢀC for 1 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and re-
moved the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (9.4:0.6)
gave product 4d (220 mg, 81%) as a solid. Mp 106e108 ꢀC; 1H NMR
.
3.2.8. Compound 4i. To
a solution of o-phenylenediamine 1
(108 mg,1 mmol), 2-butanone 2b (150 mg, 2 mmol), and cyclohexyl
isocyanide 3b (110 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was heated at
80 ꢀC for 4 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and re-
moved the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (8.5:1.5)
(300 MHz):
(1H, br s), 4.10 (1H, br s), 1.82e1.78 (2H, m), 1.63e1.55 (4H, m), 1.45
(9H, s) 1.40e1.18 (4H, m); 13C NMR (75 MHz):
157.4, 135.5, 133.9,
d 7.01 (1H, m), 6.81e6.71 (2H, m), 6.59 (1H, m), 4.32
d
gave product 4i (231 mg, 85%) as a liquid. 1H NMR (300 MHz):
d 7.02
123.6, 122.2, 119.3, 113.6, 51.5, 51.4, 31.6, 28.9, 25.0, 20.7; IR (KBr):
n
(1H, d, J¼7.2 Hz), 6.80e6.68 (2H, m), 6.50 (1H, d, J¼7.2 Hz), 4.23 (1H,
br s), 4.05 (1H, m), 3.51 (1H, br s), 2.08e2.00 (2H, m), 1.70e1.37 (8H,
m), 1.30 (3H, s), 1.24e1.10 (2H, m), 0.90 (3H, t, J¼7.5 Hz); 13C NMR
3435, 2928, 2859, 1612, 1574, 1512, 1219, 741 cmꢂ1; HRMS (EI) calcd
for C17H25N3: 271.2048. Found: 271.2046.
(75 MHz):
d 157.5, 135.1, 134.9, 123.5, 122.8, 119.2, 113.2, 53.9, 48.5,
3.2.5. Compound 4e. To
a solution of o-phenylenediamine 1
33.2, 31.1, 25.9, 24.9, 24.0, 7.9; IR (Neat):
n 3455, 3363, 2927, 2852,
(108 mg, 1 mmol), cycloheptanone 2e (225 mg, 2 mmol), and tert-
butyl isocyanide 3a (83 mg, 1 mmol) in 5 mL of water was added
20 mol % of EDTA (58.5 mg). The reaction mixture was heated at
80 ꢀC for 2 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and
2353, 1612, 1578, 1515, 1453, 1196, 746 cmꢂ1; HRMS (EI) calcd for
C17H25N3: 271.2048. Found: 271.2052.
3.2.9. Compound 4j. To
a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cyclopentanone 2c (170 mg, 2 mmol), and

S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
8943
cyclohexyl isocyanide 3b (110 mg, 1 mmol) in 5 mL of water was
50.6, 32.0, 31.8, 29.3, 26.3; IR (KBr):
2364, 1609, 1509, 1223, 739 cmꢂ1
n
3756, 3459, 3364, 2956,
added 20 mol % of EDTA (58.5 mg). The reaction mixture was
heated at 80 ꢀC for 2 h. After completion of the reaction the crude
mixture was extracted with ethyl acetate (2ꢁ25 mL) then washed
with satd NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4
and removed the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (4:1) gave
product 4j (255 mg, 90%) as a solid. Mp 148e150 ꢀC; 1H NMR
.
3.2.13. Compound 4n. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), 2-butanone 2b (150 mg, 2 mmol), and 1,1,3,3-
tetramethyl butyl isocyanide 3c (140 mg, 1 mmol) in 5 mL of water
was added 20 mol % of EDTA (58.5 mg). The reaction mixture was
heated at 80 ꢀC for 2 h. After completion of the reaction the crude
mixture was extracted with ethyl acetate (2ꢁ25 mL) then washed
with satd NaHCO3 (5 mL) and followed by brine. Dried over
Na2SO4 and removed the solvent by rotary evaporator followed by
column chromatography on silica gel using hexane/ethylacetate
(19:1) gave product 4n (247 mg, 82%) as a solid. Mp 51e53 ꢀC; 1H
(300 MHz):
d 7.05 (1H, m), 6.80e6.72 (2H, m), 6.53 (1H, m), 4.24
(1H, m), 4.06 (1H, m), 3.64 (1H, br s), 2.06e2.02 (2H, m), 1.78e1.61
(10H, m), 1.50e1.38 (2H, m), 1.25e1.08 (4H, m); 13C NMR (75 MHz):
d
157.8, 136.1, 135.1, 123.5, 122.4, 119.6, 113.7, 61.7, 48.3, 36.8, 33.0,
25.8, 24.7, 23.9; IR (KBr): n 3429, 3264, 2931, 2855, 2354, 1568, 1511,
1311, 1200, 742 cmꢂ1; HRMS (EI) calcd for C18H25N3: 283.2048.
Found: 283.2050.
NMR (300 MHz):
d
7.00 (1H, d, J¼7.2 Hz), 6.78e6.68 (2H, m), 6.50
(1H, d, J¼7.2 Hz), 4.21 (1H, br s), 3.48 (1H, br s), 1.55 (6H, s), 1.50
(2H, s), 1.26 (3H, s), 1.01 (9H, s), 0.96e0.86 (5H, m); 13C NMR
3.2.10. Compound 4k. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cyclohexanone 2d (200 mg, 2 mmol), and
cyclohexyl isocyanide 3b (110 mg, 1 mmol) in 5 mL of water was
added 20 mol % of EDTA (58.5 mg). The reaction mixture was
heated at 80 ꢀC for 2 h. After completion of the reaction the crude
mixture was extracted with ethyl acetate (2ꢁ25 mL) then washed
with satd NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4
and removed the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (4:1) gave
product 4k (282 mg, 95%) as a solid. Mp 103e105 ꢀC; 1H NMR
(75 MHz): d 151.9, 130.7, 130.2, 119.2, 118.0, 114.4, 108.5, 51.2, 49.0,
48.1, 27.2, 26.5, 24.5, 24.4, 19.5, 3.2; IR (KBr):
n 3462, 3354, 3046,
2955, 1616, 1512, 1224, 745 cmꢂ1; HRMS (EI) calcd for C19H31N3:
301.2518. Found 301.2516.
3.2.14. Compound 4o. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cyclopentanone 2c (170 mg, 2 mmol), and
1,1,3,3-tetramethyl butyl isocyanide 3c (140 mg, 1 mmol) in 5 mL
of water was added 20 mol % of EDTA (58.5 mg). The reaction
mixture was heated at 80 ꢀC for 2 h. After completion of the re-
action the crude mixture was extracted with ethyl acetate
(2ꢁ25 mL) then washed with satd NaHCO3 (5 mL) and followed by
brine. Dried over Na2SO4 and removed the solvent by rotary
evaporator followed by column chromatography on silica gel using
hexane/ethylacetate (19:1) gave product 4o (251 mg, 80%) as
(300 MHz):
d 7.03 (1H, m), 6.82e6.72 (2H, m), 6.61 (1H, m), 4.40
(1H, m), 4.13 (1H, br s), 4.05 (1H, m), 2.06e2.02 (2H, m), 1.83e1.80
(2H, m), 1.72e1.60 (8H, m), 1.49e1.39 (4H, m); 1.25e1.09 (4H, m);
13C NMR (75 MHz):
d 158.2, 135.6, 134.0, 123.4, 122.4, 119.6, 113.7,
51.8, 48.4, 33.0, 31.6, 25.8, 25.1, 24.8, 20.8; IR (KBr):
n 3396, 2927,
2853, 2352, 1511, 1295, 1168, 739 cmꢂ1; HRMS (EI) calcd for
C19H27N3: 297.2205. Found 297.2202.
a liquid. 1H NMR (300 MHz):
6.51 (1H, m), 4.21 (1H, br s), 3.61 (1H, br s), 1.87 (2H, s), 1.75e1.68
(8H, m), 1.52 (6H, s), 1.01 (9H, s); 13C NMR (75 MHz):
156.8, 136.4,
135.1, 123.9, 122.2, 119.6, 113.8, 61.7, 55.7, 52.3, 36.9, 31.9, 31.8, 29.2,
d 7.02 (1H, m), 6.79e6.71 (2H, m),
d
3.2.11. Compound 4l. To
a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cycloheptanone 2e (225 mg, 2 mmol), and
cyclohexyl isocyanide 3b (110 mg, 1 mmol) in 5 mL of water was
added 20 mol % of EDTA (58.5 mg). The reaction mixture was stirred
at room temperature for 12 h. After completion of the reaction the
crude mixture was extracted with ethyl acetate (2ꢁ25 mL) then
washed with satd NaHCO3 (5 mL) and followed by brine. Dried over
Na2SO4 and removed the solvent by rotary evaporator followed by
column chromatography on silica gel using hexane/ethylacetate
(4:1) gave product 4l (230 mg, 74%) as a semi solid. Mp 42e46 ꢀC;
24.1; IR (Neat): n 3466, 3365, 2954, 2872, 2358, 1614, 1582, 1514,
1223, 745 cmꢂ1; HRMS (EI) calcd for C20H31N3: 313.2518. Found:
313.2517.
3.2.15. Compound 4p. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cyclohexanone 2d (200 mg, 2 mmol), and
1,1,3,3-tetramethyl butyl isocyanide 3c (140 mg, 1 mmol) in
5 mL of water was added 20 mol % of EDTA (58.5 mg). The
reaction mixture was heated at 80 ꢀC for 1 h. After completion
of the reaction the crude mixture was extracted with ethyl ac-
etate (2ꢁ25 mL) then washed with satd NaHCO3 (5 mL) and
followed by brine. Dried over Na2SO4 and removed the solvent
by rotary evaporator followed by column chromatography on
silica gel using hexane/ethylacetate (19:1) gave product 4p
1H NMR (300 MHz):
d
7.02 (1H, d, J¼7.2 Hz), 6.81e6.70 (2H, m), 6.55
(1H, dd, J¼7.2 and 1.5), 4.34 (1H, m), 4.03 (1H, m), 3.82 (1H, br s),
2.04e2.01 (2H, m), 1.76e1.71 (4H, m), 1.57e1.41 (12H, m), 1.26e1.11
(4H, m); 13C NMR (75 MHz):
d 159.4, 134.4, 123.3, 122.5, 119.5, 113.7,
56.0, 48.1, 36.1, 32.9, 30.5, 25.8, 24.6, 22.8; IR (Neat):
n 3454, 3046,
2922, 2855, 2347, 1578, 1506, 1189, 1096, 741 cmꢂ1; HRMS (EI) calcd
for C20H29N3: 311.2361. Found 311.2359.
(282 mg, 86%) as a liquid. 1H NMR (300 MHz):
d 7.00 (1H, m),
6.81e6.71 (2H, m), 6.59 (1H, m), 4.35 (1H, br s), 4.11 (1H, br s),
1.88 (2H, s), 1.81e1.58 (5H, m), 1.51 (6H, s), 1.42e1.21 (5H, m),
3.2.12. Compound 4m4a. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), acetone 2a (120 mg, 2 mmol), and 1,1,3,3-
tetramethyl butyl isocyanide 3c (140 mg, 1 mmol) in 5 mL of
water was added 20 mol % of EDTA (58.5 mg). The reaction
mixture was heated at 80 ꢀC for 3 h. After completion of the re-
action the crude mixture was extracted with ethyl acetate
(2ꢁ25 mL) then washed with satd NaHCO3 (5 mL) and followed
by brine. Dried over Na2SO4 and removed the solvent by rotary
evaporator followed by column chromatography on silica gel
using hexane/ethylacetate (9.4:0.6) gave product 4m (267 mg,
1.00 (9H, s); 13C NMR (75 MHz):
d
157.0, 135.8, 134.0, 123.6,
122.1, 119.4, 113.7, 55.5, 51.7, 51.5, 31.7, 31.6, 29.3, 25.1, 20.8; IR
(Neat):
n 3470, 3404, 2936, 2864, 2355, 1613, 1580, 1515, 1359,
1222, 744 cmꢂ1; HRMS (EI) calcd for C21H33N3: 327.2674. Found:
327.2679.
3.2.16. Compound 4q. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cycloheptanone 2e (225 mg, 2 mmol), and
1,1,3,3-tetramethyl butyl isocyanide 3c (140 mg, 1 mmol) in 5 mL of
water was added 20 mol % of EDTA (58.5 mg). The reaction mixture
was heated at 80 ꢀC for 2 h. After completion of the reaction the
crude mixture was extracted with ethyl acetate (2ꢁ25 mL) then
washed with satd NaHCO3 (5 mL) and followed by brine. Dried over
Na2SO4 and removed the solvent by rotary evaporator followed by
93%) as a solid. Mp 56e58 ꢀC; 1H NMR (300 MHz):
d 7.02 (1H, m),
6.80e6.70 (2H, m), 6.52 (1H, m), 4.23 (1H, br s), 3.41 (1H, br s),
1.88 (2H, s), 1.51 (6H, s), 1.24 (6H, s), 1.01 (9H, s); 13C NMR
(75 MHz):
d 157.1, 135.8, 134.9, 124.0, 122.5, 119.5, 113.7, 55.8, 52.3,

8944
S.R. Kolla, Y.R. Lee / Tetrahedron 66 (2010) 8938e8944
column chromatography on silica gel using hexane/ethylacetate
Acknowledgements
(19:1) gave product 4q (246 mg, 72%) as a solid. Mp 78e80 ꢀC; 1H
NMR (300 MHz):
d
7.00 (1H, m), 6.80e6.70 (2H, m), 6.54 (1H, m),
This work was supported by grant No. RTI04-01-04 from the
Regional Technology Innovation Program of the Ministry of
Knowledge Economy (MKE).
4.26 (1H, br s), 3.78 (1H, br s), 1.89 (2H, s), 1.78e1.70 (4H, m),
1.57e1.52 (8H, m), 1.50 (6H, s), 1.01 (9H, s); 13C NMR (75 MHz):
d
158.2, 135.8, 134.4, 123.7, 122.3, 119.3, 113.8, 55.8, 55.6, 52.1, 36.2,
31.7, 30.7, 29.2, 23.0; IR (KBr): 3465, 3371, 2919, 2363, 1613, 1511,
1366, 1211, 1074, 738 cmꢂ1; HRMS (EI) calcd for C22H35N3: 341.2831.
Found 341.2828.
References and notes
1. Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley: Weinheim, 2005.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115.
3. Domling, A. Chem. Rev. 2006, 106, 17.
3.2.17. Compound 4r. To
a solution of o-phenylenediamine 1
4. Some exampleswith isocyanides (a)Li, J.; Liu, Y.; Li, C.; Jia, X. Tetrahedron Lett. 2009,
50, 6502; (b) Heravi, M. M.; Baghernejad, B.; Oskooie, H. A. Tetrahedron Lett. 2009,
50, 767; (c) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem.
2008, 10, 323; (d) Fujiwara, S.-i.; Asanuma, Y.; Shin-ike, T.; Kambe, N. J. Org. Chem.
2007, 72, 8087; (e) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47,
3031; (f) Shaabani, A.; Teimouri, M. B.; Arab Ameri, S. Tetrahedron Lett. 2004, 45,
(108 mg, 1 mmol), acetone 2a (116 mg, 2 mmol), and benzyl iso-
cyanide 3d (117 mg, 1 mmol) in 5 mL of water was added 20 mol %
of EDTA (58.5 mg). The reaction mixture was stirred at room tem-
perature for 2 h. After completion of the reaction the crude mixture
was extracted with ethyl acetate (2ꢁ25 mL) then washed with satd
NaHCO3 (5 mL) and followed by brine. Dried over Na2SO4 and re-
moved the solvent by rotary evaporator followed by column
chromatography on silica gel using hexane/ethylacetate (4:1) gave
product 4r (244 mg, 92%) as a solid. Mp 152e154 ꢀC; 1H NMR
€
8409; (g) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647.
5. Toshima, K.; Takano, R.; Ozawa, T.; Matsumura, S. Chem. Commun. 2002, 212.
6. Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 541.
7. Bailly, C.; Echepare, S.; Gago, F.; Waring, M. Anticancer Drug Des. 1999, 14, 291.
8. Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem. Commun. 2003, 2286.
9. Cheeseman, G. W. H.; Cookson, R. F. In The Chemistry of Heterocyclic Compounds,
2nd ed.; Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, NY, 1979; Vol. 35,
pp 1e27.
10. Porter, A. E. A. In Comprehensive Heterocyclic Chemistry; Katrizky, A. R., Rees, C.
W., Eds.; Pergamon: New York, NY, 1984; Vol. 3, p 157.
11. Corona, P.; Vitale, G.; Loriga, M.; Paglietti, G. II Farmaco 2000, 55, 77.
12. Hassan, S. Y.; Khattab, S. N.; Bekhit, A. A.; Amer, A. Bioorg. Med. Chem. Lett. 2006,
16, 1753.
(300 MHz):
(2H, m), 6.57 (1H, dd, J¼7.2 and 1.5 Hz), 4.63 (3H, br s), 3.52 (1H, br
s), 1.31 (6H, s); 13C NMR (75 MHz):
158.9, 139.0, 135.1, 134.8, 128.8,
128.2, 127.6, 123.7, 123.3, 119.7, 113.8, 51.0, 45.3, 26.0; IR (KBr):
d
7.36e7.26 (5H, m), 7.09 (1H, d, J¼6.0 Hz), 6.85e6.74
d
n
3340, 3292, 3026, 2964, 2920, 2370, 1606, 1568, 1528, 1486, 1210,
908, 747 cmꢂ1; HRMS m/z (Mþ) calcd for C17H19N3: 265.1579. Found
265.1578.
13. Thakuria, H.; Das, G. J. Chem. Sci. 2006, 118, 425.
14. Woo, G. H. C.; Snyder, J. K.; Wan, Z.-K. Prog. Heterocycl. Chem. 2002, 14, 279.
15. Mizuno, T.; Wei, W.-H.; Eller, L. R.; Sessler, J. L. J. Am. Chem. Soc. 2002, 124, 1134.
16. Crossley, M. J.; Johnston, L. A. Chem. Commun. 2002, 1122.
17. Brodie, B. B.; Axelrod, J.; Shore, P. A.; Udenfriend, S. J. Biol. Chem. 1954, 208, 741.
18. Ram, R. N.; Singh, V. Tetrahedron Lett. 2006, 47, 7625.
3.2.18. Compound 4s. To a solution of o-phenylenediamine 1
(108 mg, 1 mmol), cyclohexanone 2d (196 mg, 2 mmol), and
benzyl isocyanide 3d (117 mg, 1 mmol) in 5 mL of water was
added 20 mol % of EDTA (58.5 mg). The reaction mixture was
stirred at room temperature for 3 h. After completion of the re-
action the crude mixture was extracted with ethyl acetate
(2ꢁ25 mL) then washed with satd NaHCO3 (5 mL) and followed
by brine. Dried over Na2SO4 and removed the solvent by rotary
evaporator followed by column chromatography on silica gel
using hexane/ethylacetate (4:1) gave product 4s (250 mg, 82%) as
19. Korolev, D. N.; Bumagin, N. A. Tetrahedron Lett. 2005, 46, 5751.
20. Rattat, D.; Eraets, K.; Cleynhens, B.; Knight, H.; Fonge, H.; Verbruggen, A.
Tetrahedron Lett. 2004, 45, 2531.
21. Patel, R. N.; Chu, L.; Mueller, R. Tetrahedron: Asymmetry 2003, 14, 3105.
22. (a) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44,
1758; (b) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1995, 34, 1059; (c) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245; (d)
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
23. (a) Lee, Y. R.; Choi, J. H.; Yoon, S. H. Tetrahedron Lett. 2005, 46, 7539; (b) Lee, Y. R.;
Lee, W. K.; Noh, S. K.; Lyoo, W. S. Synthesis 2006, 853; (c) Lee, Y. R.; Kim, D. H.
Synthesis 2006, 603; (d) Lee, Y. R.; Kim, J. H. Synlett 2007, 2232; (e) Wang, X.; Lee, Y.
R. Tetrahedron Lett. 2007, 48, 6275; (f) Wang, X.; Lee, Y. R. Synthesis 2007, 3044; (g)
Lee, Y. R.; Xia, L. Synthesis 2007, 3240; (h) Lee, Y. R.; Li, X.; Kim, J. H. J. Org. Chem.
2008, 73, 4313; (i)Lee, Y. R.;Xia, L. Tetrahedron Lett. 2008, 49, 3283; (j) Xia, L.; Lee, Y.
R. Synlett 2008, 1643; (k) Lee, Y. R.; Hung, T. V. Tetrahedron 2008, 64, 7338.
24. (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816; (b) Breslow, R.
Acc. Chem. Res. 1991, 24, 159.
25. (a) Grieco, P. A. Organic Synthesis in Water; Blackie Academic and Professional:
London, 1998; (b) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley:NewYork,NY,1997;(c)Li,C.-J. Chem. Rev. 2005,105, 3095;(d)Delair, P.;Luche,
J.-L. J. Chem. Soc., Chem. Commun. 1989, 398; (e) Ponaras, A. A. J. Org. Chem.1983, 48,
3866; (f) Coates, R. M.; Rogers, B. D.; Hobbs, S. J.; Curran, D. P.; Peck, D. R. J. Am. Chem.
Soc. 1987, 109, 1160; (g) Mattes, H.; Benezra, C. Tetrahedron Lett. 1985, 26, 5697.
a solid. Mp 165e167 ꢀC; 1H NMR (300 MHz):
d 7.35e7.26 (5H, m),
7.08 (1H, d, J¼7.5 Hz), 6.87e6.75 (2H, m), 6.64 (1H, dd, J¼7.2 and
1.8 Hz), 4.75 (1H, br s), 4.62 (2H, s), 4.19 (1H, s), 1.89e1.86 (2H, d,
J¼9.3 Hz), 1.73e1.55 (4H, m), 1.46e1.38 (3H, m), 1.24e1.17 (1H,
m); 13C NMR (75 MHz):
d 159.0, 139.1, 135.3, 134.3, 128.8, 128.2,
127.6, 123.7, 123.1, 119.8, 114.0, 52.2, 45.6, 31.7, 25.2, 20.8; IR (KBr):
n
3448, 3399, 3019, 2933, 2856, 1610, 1574, 1524, 1485, 1294, 1242,
741 cmꢂ1; HRMS m/z (Mþ) calcd for C20H23N3: 305.1892. Found
305.1889.