Reaction between isocyanides, dialkyl acetylenedicarboxylates and 2-hydroxy-1-aryl-2-(arylamino)ethanones: One-pot synthesis of highly functionalized 2-aminofurans

Article abstract of DOI:10.1055/s-0029-1217951

A facile synthesis of highly functionalized 2-aminofuran derivatives by the multicomponent reaction of alkyl isocyanides, dialkyl acetylenedicarboxylates and 2-hydroxy-1-aryl-2-(arylamino)ethanone is described. The reaction is characterized by mild condit

Full text of DOI:10.1055/s-0029-1217951

2676
LETTER
Reaction between Isocyanides, Dialkyl Acetylenedicarboxylates and
2-Hydroxy-1-aryl-2-(arylamino)ethanones: One-Pot Synthesis of Highly
Functionalized 2-Aminofurans
One-Pot Synthesis of
H
o
ighly Funct
h
a
minofuran
m
s
mad Hossein Mosslemin, Mohammad Anary-Abbasinejad,* Hossein Anaraki-Ardakani
Department of Chemistry, Islamic Azad University, Yazd Branch, P.O. Box 89195-155, Yazd, Iran
Fax +98(351)8211109; E-mail: mohammadanary@yahoo.com
Received 26 May 2009
esters in the presence of 2-hydroxy-1-aryl-2-(arylami-
Abstract: A facile synthesis of highly functionalized 2-aminofuran
derivatives by the multicomponent reaction of alkyl isocyanides, di-
alkyl acetylenedicarboxylates and 2-hydroxy-1-aryl-2-(arylami-
no)ethanone is described. The reaction is characterized by mild
no)ethanone derivatives, already prepared by the reaction
of the requisite aniline with arylglyoxal monohydrate de-
rivatives,23 in order to trap the active zwitterionic interme-
conditions, high selectivity, and tolerance to various functional diate. Thus, we reacted cyclohexyl isocyanide with
groups.
dimethyl acetylenedicarboxylate (DMAD) and 2-hy-
droxy-1-(4-nitrophenyl)-2-(4-nitrophenylamino)ethanone
(3a) in dichloromethane at room temperature. We antici-
pated the isocyanide–DMAD intermediate to be protonat-
ed by one of the NH or OH protons followed by the
addition of the conjugate base of 3a to the nitrilium cation
6 and finally afford oxazine derivatives 9,15,16 but after
separation of the product and elucidation of its structure
by elemental and spectral data we found that 2-amino-
furan derivative 4a had been produced (Scheme 1).24
The 1H NMR spectrum of 4a consisted of a multiplet for
the cyclohexyl ring (d = 1.28–2.15 ppm), a multiplet for
CH of cyclohexyl (d = 3.62 ppm) and two singlets for
methoxy groups (d = 3.94 ppm and 3.78 ppm) supported
by the absorptions at 1729 and 1677 cm–1 in the IR spec-
trum. A fairly broad doublet (d = 8.89 ppm, 3JHH = 8.0 Hz)
was observed for the NH proton and the phenyl protons
exhibited characteristic signals in the aromatic region of
the spectrum. The 1H decoupled 13C NMR spectrum of 4a
showed 16 distinct resonances, consistent with the pro-
posed structure.
Key words: alkyl isocyanide, dialkyl acetylenedicarboxylate, mul-
ticomponent reaction, 2-aminofuran
Substituted furans play an important role in organic chem-
istry, not only as key structural units in many natural prod-
ucts and important pharmaceuticals1 but also as useful
building blocks in synthetic chemistry.2
Multicomponent reactions (MCRs) have been attracting
much interest from synthetic chemists because they pro-
vide simple one-pot routes for the synthesis of complex
molecules from simple and easily available starting mate-
rials. These processes do not require separation and puri-
fication of intermediates and so save time, energy and raw
materials. Due to the unique reactivity of the isocyanide
functional group, isocyanide-based MCRs (I-MCRs) are
among the most versatile, in terms of the number and va-
riety of compounds that can be generated.3–6 A recently
developed class of I-MCRs is the reaction of isocyanides
with electron-deficient acetylenes in the presence of an
electrophile. Addition of isocyanides to acetylene diesters
is well known to produce a reactive zwitterionic interme-
diate, which further reacts with electrophiles to afford a
wide variety of carbo- and heterocycles. A wide variety of
electrophiles has been applied to trap isocyanide–dimeth-
yl acetylenedicarboxylate (DMAD) intermediate; among
them are carbon electrophiles such as aldehydes,7,8 quino-
nes,7 1,2-diketones,9 1,2,3-tricarbonyl compounds,10 imi-
nes,11 isocyanates,12 and hydrogen electrophiles such as
pyrrole,13 amides,14 4-hydroxycoumarine,15 phenols,16
phthalic anhydride,17 and isatoic anhydride.18 This class of
reactions has also been used for the synthesis of 2-amino-
furan derivatives.7,19 In the course of our studies on the
reaction of acetylene diesters with isocyanides in the pres-
ence of acidic organic compounds,13–15,20–22 we decided to
investigate the reaction of isocyanides with acetylene di-
Although the mechanism of this reaction has not been es-
tablished, a plausible rationalization can be advanced to
explain product formation (Scheme 1). It is reasonable to
assume that zwitterionic intermediate 5 produced by reac-
tion between cyclohexyl isocyanide and DMAD adds to
carbonyl group of 3a resulting in the formation of 2,5-di-
hydrofuran derivative 8, which undergoes aromatization
to furan ring by losing of a molecule of N-(4-nitrophe-
nyl)formamide.
To explore the scope and limitations of this reaction fur-
ther, we extended our studies to the reaction of various di-
alkyl acetylenedicarboxylates and alkyl isocyanides with
2-hydroxy-1-aryl-2-(arylamino)ethanones. As indicated
in Table 1, the reactions proceeded very efficiently in rel-
atively good yields.
In conclusion, we have developed a simple and efficient
method for the preparation of functionalized 2-amino-
furans of potential synthetic and pharmacological interest.
This method has the advantage that, not only is the reac-
SYNLETT 2009, No. 16, pp 2676–2678
Advanced online publication: 04.09.2009
DOI: 10.1055/s-0029-1217951; Art ID: D13409ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Highly Functionalized 2-Aminofurans
2677
O
Ar
Ar'
N
HNR
O
E
E
9
R
H
N
N+
C
H
N
O–
O
H
E
HO
O
Ar
Ar
R
N+
E
E
Ar'
Ar'
C
6
7
3a
–
H
+
NC
R
N
E
E
HO
O
Ar
Ar'
E
1
R
N
5
2
R = c-Hex
E = CO2Me
Ar = Ar' = 4-O2NC6H4
E
E
8
O
H
–
H
N
Ar
E
E
HNR
Ar'
O
4a
Scheme 1 Reaction between cyclohexyl isocyanide, DMAD and 2-hydroxy-1-(4-nitrophenyl)-2-(4-nitrophenylamino)ethanone
(7) Nair, V.; Unni Vinod, A.; Abhilash, N.; Rajeev Menon, S.;
Santhi, V.; Luxmi Varma, R.; Viji, S.; Mathew, S.; Srinivas,
R. Tetrahedron 2003, 59, 10279.
(8) Yadav, J. S.; Subba Reddy, B. V.; Shubashree, S.; Sadashiv,
K.; Krishna Rao, D. J. Mol. Catal. A.: Chem. 2007, 272, 128.
(9) Nair, V.; Menon, R. S.; Deepthi, A.; Devi, B. R.; Biju, A. T.
Tetrahedron Lett. 2005, 46, 1337.
(10) Nair, V.; Deepthi, A. Tetrahedron Lett. 2006, 47, 2037.
(11) Nair, V.; Vinod, A. U. J. Org. Chem. 2001, 66, 4427.
(12) Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Bijanzadeh, H. R.
Chem. Month. 2008, 139, 49.
(13) Anary-Abbasinejad, M.; Mosslemin, M. H.; Anaraki-
Ardakani, H.; Tahan, S. J. Chem. Res. 2006, 306.
(14) Anary-Abbasinejad, M.; Mosslemin, M. H.; Tahan, S.;
Anaraki-Ardakani, H. J. Chem. Res. 2006, 170.
(15) Anary-Abbasinejad, M.; Anaraki-Ardakani, H.; Rastegari,
F.; Hassanabadi, A. J. Chem. Res. 2007, 602.
Table 1 Reaction of Alkyl Isocyanides, Dialkyl Acetylenedicar-
boxylates and 2-Hydroxy-1-aryl-2-(arylamino)ethanone
4
a
b
c
d
e
f
R
E
Ar¢
Ar
Yield (%)a
Cy
CO2Me
4-O2NC6H4
4-O2NC6H4
Ph
4-O2NC6H4
4-O2NC6H4
3-O2NC6H4
3-O2NC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
89
90
91
89
91
88
85
t-Bu CO2Me
Cy CO2Et
t-Bu CO2Me
Cy CO2Et
4-ClC6H4
4-O2NC6H4
4-BrC6H4
Ph
t-Bu CO2Me
t-Bu CO2Me
g
a Isolated yields.
(16) Yavari, I.; Djahaniani, H.; Nasiri, F. Tetrahedron 2003, 59,
9409.
(17) Shaabani, A.; Teimouri, M. B.; Bijanzadeh, H. R. J. Chem.
Res. 2002, 381.
(18) Shaabani, A.; Teimouri, M. B.; Mirzaei, P.; Bijanzadeh,
H. R. J. Chem. Res. 2003, 82.
(19) Alizadeh, A.; Rostamnia, S.; Zhu, L. Z. Synthesis 2008,
1788.
tion performed under neutral conditions, but also the sub-
stances can be mixed without any further manipulation.
The simplicity of this procedure makes it an interesting al-
ternative to other approaches.
(20) Anary-Abbasinejad, M.; Ghanea, F.; Anaraki-Ardakani, H.
Synth. Commun. 2009, 39, 544.
References and Notes
(21) Anary-Abbasinejad, M.; Anaraki-Ardakani, H.; Ghanea, F.
Monatsh. Chem. 2009, 140, 397.
(1) Dean, F. A. Naturally Occurring Oxygen Ring Compounds;
Butterworth: London, 1963.
(2) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(3) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53.
(4) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(5) Nair, V.; Menon, R. S.; Sreekumar, V. Pure Appl. Chem.
2005, 77, 1191.
(22) Anary-Abbasinejad, M.; Moslemine, M. H.; Anaraki-
Ardakani, H. J. Fluorine Chem. 2009, 130, 368.
(23) Synthesis of 3a as a Typical Route for the Preparation of
2-Hydroxy-1-aryl-2-(arylamino)ethanone Derivatives:
A solution of 4-nitroaniline (10 mmol) and 4-nitrophenyl-
glyoxal monohydrate (10 mmol) in EtOH (20 mL) was
(6) Dömling, A. Chem. Rev. 2006, 106, 17.
Synlett 2009, No. 16, 2676–2678 © Thieme Stuttgart · New York

2678
M. H. Mosslemin et al.
LETTER
refluxed for 3 h. The solution was cooled in ice-water bath.
The precipitate was filtered of to afford pure 3a as yellow
crystals; mp 150–151 °C. IR (KBr): 3645 (OH), 3390 (NH),
1690 (C=O) cm–1. MS (%): m/z = 317 (7) [M+]. Anal. Calcd
for C14H11N3O6 (317): C, 53.00; H, 3.49; N, 13.24. Found: C,
53.12; H, 3.52; N, 13.08. 1H NMR (500.1 MHz, CDCl3): d =
5.96 (d, 3JHH = 6.5 Hz, 1 H, CH), 6.64 (d, 3JHH = 6.5 Hz, 1 H,
NH), 6.84 (d, 3JHH = 9.0 Hz, 2 H, 2 × CH of Ar), 7.96 (d, 3JHH
= 9.0 Hz, 2 H, 2 × CH of Ar), 8.18 (d, 3JHH = 8.7 Hz, 2 H, 2
OCH2CH3), 6.73 (d, 3JHH = 7.9 Hz, 1 H, NH), 7.39–7.58 (5
H, m, Ar). 13C NMR (125.7 MHz, CDCl3): d = 14.47, 14.81
(2 × OCH2CH3), 24.90, 25.78, 33.82 (5 × CH2 of Cy), 52.07
(CHN), 60.42, 60.55 (2 × OCH2CH3), 89.43, 118.26, 124.40,
124.71, 135.41, 138.35, 146.39, 162.41 (CAr), 164.75
(CO2Et), 165.81 (CO2Et). 4d: yellow crystals (yield: 0.32 g,
89%); mp 95–97 °C. IR (KBr): 3335 (NH), 1735, 1679
(C=O) cm–1. MS (%): m/z = 365 (5) [M+]. Anal. Calcd for
C18H20ClNO5 (365): C, 59.10; H, 5.51; N, 3.83. Found: C,
59.22; H, 5.41; N, 3.72. 1H NMR (500.1 MHz, CDCl3): d =
1.45 (s, 9 H, CMe3), 3.73 (s, 3 H, OMe), 3.87 (s, 3 H, OMe),
6.81 (s, 1 H, NH), 7.37 (d, 3JHH = 8.6 Hz, 2 H, 2 × CH of Ar),
7.46 (d, 3JHH = 8.6 Hz, 2 H, 2 × CH of Ar). 13C NMR (125.7
MHz, CDCl3): d = 30.12 (CMe3), 51.63 (CMe3), 53.12
(OMe), 53.25 (OMe), 89.03, 114.27, 121.85, 126.39,
128.59, 132.33, 140.70, 162.00 (CAr), 165.30 (CO2Me),
166.26 (CO2Me). 4e: yellow crystals (yield: 0.39 g, 91%);
mp 101–103 °C. IR (KBr): 3410 (NH), 1722, 1675 (C=O)
cm–1. MS (%): m/z = 430 (7) [M+]. Anal. Calcd for
× CH of Ar), 8.23 (d, 3JHH = 8.7 Hz, 2 H, 2 × CH of Ar). 13
NMR (125.7 MHz, CDCl3): d = 81.92 (CHN), 113.56,
124.20, 126.33, 131.12, 138.47, 140.14, 151.08, 151.13
(CAr), 192.67 (C=O).
C
(24) To a magnetically stirred solution of dialkyl acetylene-
dicarboxylate (2 mmol) and 2-hydroxy-1-aryl-2-(aryl-
amino)ethanone (2 mmol) in CH2Cl2 (10 mL) was added a
solution of alkyl isocyanide (2 mmol) in CH2Cl2 (5 mL)
dropwise at r.t. over 10 min. The mixture was then allowed
to stir for 24 h. The solvent was removed under reduced
pressure, and the residue was separated by column
C22H26N2O7 (385): C, 61.39; H, 6.09; N, 6.51. Found: C,
61.46; H, 6.14; N, 6.43. 1H NMR (500.1 MHz, CDCl3): d =
1.36–2.05 (m, 10 H, 5 × CH2 of Cy), 1.30 (t, 3JHH = 7.1 Hz,
3 H, OCH2CH3), 1.39 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 3.72
(m, 1 H, CHN), 4.24 (q, 3JHH = 7.2 Hz, 2 H, OCH2CH3), 4.42
(q, 3JHH = 7.2 Hz, 2 H, OCH2CH3), 6.76 (d, 3JHH = 7.9 Hz, 1
H, NH), 7.60 (d, 3JHH = 8.9 Hz, 2 H, 2 × CH of Ar), 8.20 (d,
3JHH = 8.9 Hz, 2 H, 2 × CH of Ar). 13C NMR (125.7 MHz,
CDCl3): d = 14.42, 14.82 (2 × OCH2CH3), 24.87, 25.78,
33.80 (5 × CH2 of Cy), 52.06 (CHN), 60.42, 62.55 (2 ×
OCH2CH3), 89.52, 118.26, 124.71, 124.22, 135.55, 138.35,
146.39, 162.06 (CAr), 164.58 (CO2Et), 165.38 (CO2Et). 4f:
yellow crystals (yield: 0.35 g, 88%); mp 99–101 °C. IR
(KBr): 3335 (NH), 1735, 1679 (C=O) cm–1. MS (%): m/z =
409 (5) [M+]. Anal. Calcd for C18H20BrNO5(409): C, 52.70;
H, 4.91; N, 3.41. Found: C, 52.62; H, 4.80; N, 3.62. 1H NMR
(500.1 MHz, CDCl3): d = 1.46 (s, 9 H, CMe3), 3.75 (s, 3 H,
chromatography (silica gel; hexane–EtOAc, 5:1) to afford
the pure title compounds. 4a: yellow crystals (yield: 0.35 g,
89%); mp 172–173 °C. IR (KBr): 3385 (NH), 1729, 1677
(C=O) cm–1. MS (%): m/z = 402 (7) [M+]. Anal. Calcd for
C20H22N2O7 (402): C, 59.70; H, 5.51; N, 6.96. Found: C,
59.82; H, 5.60; N, 6.82. 1H NMR (500.1 MHz, CDCl3): d =
1.25–2.06 (m, 10 H, 5 × CH2 of Cy), 3.74 (m, 1 H, CHN),
3.78 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 6.73 (d, 3JHH = 7.9
Hz, 1 H, NH), 7.61 (d, 3JHH = 9.0 Hz, 2 H, 2 × CH of Ar),
8.21 (d, 3JHH = 9.0 Hz, 2 H, 2 × CH of Ar). 13C NMR (125.7
MHz, CDCl3): d = 24.91, 25.77, 33.80 (5 × CH2 of Cy),
52.13 (CHN), 51.80 (OMe), 53.41 (OMe), 89.23, 118.26,
124.40, 124.71, 135.41, 138.35, 146.39, 162.01 (CAr),
164.85 (CO2Me), 165.81 (CO2Me). 4b: yellow crystals
(yield: 0.33 g, 90%); mp 173–174 °C. IR (KBr): 3420 (NH),
1730, 1675 (C=O) cm–1. MS (%): m/z = 376 (5) [M+]. Anal.
Calcd for C18H20N2O7 (376): C, 57.44; H, 5.36; N, 7.44.
Found: C, 57.55; H, 5.29; N, 7.49. 1H NMR (500.1 MHz,
CDCl3): d = 1.51 (s, 9 H, CMe3), 3.78 (s, 3 H, OMe), 3.96 (s,
3 H, OMe), 6.96 (s, 1 H, NH), 7.61 (d, 3JHH = 8.8 Hz, 2 H,
2 × CH of Ar), 8.22 (d, 3JHH = 8.8 Hz, 2 H, 2 × CH of Ar).
13C NMR (125.7 MHz, CDCl3): d = 29.75 (CMe3), 51.43
(CMe3), 53.05 (OMe), 53.10 (OMe), 89.56, 117.46, 123.87,
124.38, 134.93, 138.26, 145.89, 161.87 (CAr), 164.53
(CO2Me), 165.50 (CO2Me). 4c: yellow oil (yield: 0.31 g,
91%). IR (KBr): 3345 (NH), 1732, 1672 (C=O) cm–1. MS
(%): m/z = 385 (2) [M+]. Anal. Calcd for C22H27NO5 (385):
C, 68.55; H, 7.06; N, 3.63. Found: C, 68.63; H, 7.12; N, 3.60.
1H NMR (500.1 MHz, CDCl3): d = 1.27–2.12 (m, 10 H, 5 ×
CH2 of Cy), 1.23 (t, 3JHH = 7.1 Hz, 3 H, OCH2CH3), 1.32 (t,
3JHH = 7.1 Hz, 3 H, OCH2CH3), 3.74 (m, 1 H, CHN), 4.13 (q,
3JHH = 7.1 Hz, 2 H, OCH2CH3), 4.26 (q, 3JHH = 7.1 Hz, 2 H,
OMe), 3.88 (s, 3 H, OMe), 6.81 (s, 1 H, NH), 7.32 (d, 3JHH
=
8.6 Hz, 2 H, 2 × CH of Ar), 7.44 (d, 3JHH = 8.6 Hz, 2 H, 2 ×
CH of Ar). 13C NMR (125.7 MHz, CDCl3): d = 30.34
(CMe3), 51.66 (CMe3), 53.15 (OMe), 53.29 (OMe), 87.04,
112.18, 124.23, 126.22, 127.44, 131.79, 138.78, 162.05
(CAr), 163.38 (CO2Me), 164.32 (CO2Me). 4g: yellow
crystals (yield: 0.28 g, 85%); mp 78–80 °C. IR (KBr): 3345
(NH), 1740, 1679 (C=O) cm–1. MS (%): m/z = 332 (5) [M+ +
1]. Anal. Calcd for C18H21NO5 (331): C, 65.24; H, 6.39; N,
4.23. Found: C, 65.44; H, 6.35; N, 4.36. 1H NMR (500.1
MHz, CDCl3): d = 1.48 (s, 9 H, CMe3), 3.77 (s, 3 H, OMe),
3.91 (s, 3 H, OMe), 6.82 (s, 1 H, NH), 7.24–7.66 (m, 5 H,
Ar). 13C NMR (125.7 MHz, CDCl3): d = 30.14 (CMe3),
51.46 (CMe3), 52.95 (OMe), 53.69 (OMe), 88.52, 113.18,
124.23, 126.22, 127.44, 129.79, 140.23, 162.05 (CAr),
163.30 (CO2Me), 166.12 (CO2Me).
Synlett 2009, No. 16, 2676–2678 © Thieme Stuttgart · New York