Synthesis of functionalised 2,5-diaminofurans by reaction of isocyanides, acetylenic esters and acid anhydrides

Article abstract of DOI:10.3184/174751912X13333688963253

The reaction between two equivalents of an isocyanide, a dialkyl acetylenedicarboxylates and an acid anhydride at room temperature provides a simple and efficient one-pot route for the synthesis of 2,5-diaminofuran derivatives in high yields. The reaction is characterised by mild conditions, short reaction time and tolerance to various functional groups.

Full text of DOI:10.3184/174751912X13333688963253

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 261
MAY, 261–263
Synthesis of functionalised 2,5-diaminofurans by reaction of isocyanides,
acetylenic esters and acid anhydrides
Alireza Hassanabadia*, Mohammad H. Mossleminb, Mohammad Anary-Abbasinejadc and
Sharminehsadat Ghalehbandyb
aDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
cDepartment of Chemistry, Rafsanjan Vali-e-Asr University, Rafsanjan, PO Box 77176, Iran
The reaction between two equivalents of an isocyanide, a dialkyl acetylenedicarboxylates and an acid anhydride at
room temperature provides a simple and efficient one-pot route for the synthesis of 2,5-diaminofuran derivatives in
high yields. The reaction is characterised by mild conditions, short reaction time and tolerance to various functional
groups.
Keywords: multicomponent reactions, isocyanides, diaminofurans, dialkyl acetylenedicarboxylates, acid anhydrides
Isocyanides, as the only class of stable organic compounds
with a two-valence carbon atom, are very reactive species and
react with many functional groups by different mechanisms.
On the basis of valence-bond theory, the isocyanide function-
ality can be shown as two resonance forms I and II
(Scheme 1). Isocyanides have carbenic character on the basis
of resonance form I and nucleophilic character on the basis of
form II. In most addition reactions of isocyanides both the
nucleophile and electrophile add to the α-carbon atom, and no
species is added to the nitrogen.
to have formed over 24h at room temperature in the presence
of aliphatic carboxylic acids,17 while when acid anhydrides are
used, the reaction is faster and produces comparable yields.
Compounds 4a–j are known and their structures were
deduced by comparison of spectroscopic data with authentic
samples.17 Compounds 4k–o were new and their structures
were deduced by elemental and spectroscopic analysis. The 1H
NMR spectrum of compound 4k was simple and exhibited
two sharp singlets, which were due to two methoxy groups
protons (δ 3.71 and 3.84 ppm) and one NH group (δ 6.62 ppm,
disappeared with addition of D2O) and one sharp line (δ
1.32 ppm ) for the protons of the three methyl groups of tert-
butyl. Cyclohexyl fragments protons resonated as multiplets at
δ 0.91–2.11 and a multiplet at δ 4.13–4.35 ppm.
The Ugi four-component reaction (U-4CR)1–3 and Passerini
three component reaction (P-3CR)4 are among the most impor-
tant isocyanide-based multi-component reactions (IMCRs).
U-4CR and P-3CR describe the reaction of isocyanides with
carboxylic acids in the presence of imines or aldehydes,
respectively.
The 13C NMR spectrum of compound 4k showed 19 distinct
resonances in agreement with the proposed structure. The
signals at 85.9, 115.2, 137.8, 160.2, 163.7, 165.1 and 172.0
ppm are related to furan ring carbons and three carbonyl
groups. The IR spectrum showed an absorption bond at
3332 cm−1 for the NH group. The carbonyl stretching vibra-
tions were observed as strong absorption bonds at 1730, 1683
and 1671 cm−1. The molecular ion peak at 462 in the mass
spectrum of compound 4k supported the 2:1:1 adduct of
cyclohexyl isocyanide, acid anhydride and dimethyl acetyl-
enedicarboxylate.
Recently, a wide variety of electrophiles have been applied
to trap isocyanide-dimethyl acetylenedicarboxylates (DMAD)
intermediates, among them are carbon electrophiles such
as aldehydes, imines, quinonids,5 1,2-diketones,6 1,2,3-tricar-
bonyl compounds,7 isocyanates,8 and hydrogen electrophiles
such as pyrrole,9 amides,10 hydroxy coumarine,11 phenols,12
phthalic anhydride13 and isatoic anhydride.14 Treatment of an
isocyanide-DMAD zwitterion with aromatic carboxylic acids
has been reported to produce unsaturated amides.15 The reac-
tion of an isocyanide-DMAD adduct with aromatic-substituted
acetic acids has been reported to afford 2,5-diaminofuran
derivatives in the presence of two equivalents of an isocya-
nide.16 The reaction between two equivalents of an isocyanides,
aliphatic carboxylic acids and dialkyl acetylenedicarboxylates
has been reported to afford 2,5-diaminofuran derivatives.17
In the context of our previous work on IMCRs,9–11,17–21 we
nowreport the results of our investigations on the reaction of
isocyanides and dialkyl acetylenedicarboxylates (DAADs) in
the presence of acid anhydrides.
A reasonable mechanism for the formation of compound 4
is presented in Scheme 3.
On the basis of the well established chemistry of isocya-
nides1–3,16 it is reasonable to assume that compound 4 is pro-
duced by initial formation of a highly reactive 1:1 zwitterionic
intermediate 5 by the Michael-type addition reaction of the
alkyl isocyanide 1 with the dialkyl acetylenedicarboxylate 2,
which adds to the carbonyl group of the acid anhydride 3
leading to species 6 and 7. The addition of carboxylate anion 7
on nitrilium cation 6 affords intermediate 8 which then
rearranges to unsaturated imide 9. Cycloaddition of another
molecule of isocyanide to imide 9 leads to dihydrofuran
intermediate 10. Attack by adventitious water at the ketone
carbonyl followed by loss of the carboxylic acid which forms
the furan derivative 4.
Results and discussion
The reaction of alkyl isocyanides (2 equiv.) with dialkyl
acetylenedicarboxylates (1 equiv.) in the presence of acid
anhydrides (1 equiv.) in dichloromethane for 8 h at room
temperature, affords 2,5-diaminofuran derivatives 4a–o in high
yields (Scheme 2 and Table 1). Derivatives 4 have been reported
Scheme 1 Two resonance forms.
Scheme 2
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

262 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Reaction of alkyl isocyanides with dialkyl acetylenedi-
mixture of dialkyl acetylenedicarboxylate (1.0 mmol) in dichloro-
methane (2 mL) at room temperature. The reaction mixture was then
stirred for 8 h. The solvent was removed and the residue was purified
by silica gel column chromatography using hexane–ethyl acetate (3:1)
as eluent. The solvent was removed under reduced pressure to afford
the product.
Dimethyl 2-[cyclohexyl(2,2-dimethyl propionyl)amino]-5-(cyclo-
hexylamino)furan-3,4-dicarboxylate (4k): Yellow oil, (85%); IR (KBr)
(νmax, cm−1): 3332 (NH), 1730, 1683 and 1671 (carbonyl groups).
Anal. Calcd for C25H38N2O6: C, 64.91; H, 8.28; N, 6.06. Found: C,
64.82; H, 8.45; N, 5.92%. MS (m/z, %): 462 (M+, 5). 1H NMR (500.1
MHz, CDCl3): δ 0.91–2.11 (20H, 10 CH2 of cyclohexyl), 1.32 (9H, s,
3 CH3), 3.71 (3H, S, OCH3) and 3.84 (3H, s, OCH3), 4.13–4.35 (2H,
m, 2CH of cyclohexyl), 6.62 (1H, s, NH). 13C NMR (125.7 MHz,
CDCl3): δ 28.1 (3CH3), 24.5, 25.5, 25.7, 26.4, 33.1, 33.9 (10 CH2 of
cyclohexyl groups), 51.4 and 51.8 (2 NCH), 52.8 and 55.7 (2 OCH3),
81.3 (C), 85.9, 115.2, 137.9, 160.2 (4C of furan ring), 163.7, 165.1
and 172.0 (3 C=O).
Diethyl 2-[cyclohexyl(2,2-dimethyl propionyl)amino]-5-(cyclo-
hexylamino)furan-3,4-dicarboxylate (4l): Yellow oil, (87%); IR (KBr)
(νmax, cm−1): 3335 (NH), 1728, 1680 and 1673 (carbonyl groups).
Anal. Calcd for C27H42N2O6: C, 66.10; H, 8.63; N, 5.71. Found: C,
65.87; H, 8.49; N, 5.90%. MS (m/z, %): 490 (M+, 7). 1H NMR (500.1
MHz, CDCl3): δ 1.27 (3H, t, J = 7Hz, CH3) and 1.34 (3H, t, J = 7 Hz,
CH3), 0.88–2.04 (20H, 10 CH2 of cyclohexyl), 1.30 (9H, s, 3 CH3),
4.07–4.42 (2H, m, 2CH of cyclohexyl), 4.25 (4H, m, 2 OCH2), 6.74
(1H, s, NH). 13C NMR (125.7 MHz, CDCl3): δ 14.3 and 14.9 (2 CH3),
28.1 (3CH3), 24.3, 25.7, 25.7, 26.4, 33.4, 33.8 (10 CH2 of cyclohexyl
groups), 51.5 and 51.8 (2 NCH), 60.1 and 61.9 (2 OCH2), 81.3 (C),
85.8, 115.3, 138.0, 160.4 (4C of Furan ring), 163.6, 165.4 and 172.2
(3 C=O).
carboxylates and acid anhydrides
Entry
R
R'
R“
Product
Yield/%a
Found From ref.17
1
2
tert-Bu
tert-Bu
Me
Et
Me
Me
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
93
92
92
95
89
92
94
90
88
90
85
87
90
88
91
95
95
90
94
90
93
95
90
85
88
–
3
tert-Bu t-Bu
4
Cy
tert-Bu
tert-Bu
Me
Me
Et
5
6
Et
7
tert-Bu t-Bu
Et
Et
8
Cy
tert-Bu
Cy
Cy
Cy
tert-Bu
Cy
Cy
Me
Me
Me
Me
Et
Et
t-Bu
Et
9
CF3
CF3
t-Bu
t-Bu
CF3
CF3
CF3
10
11
12
13
14
15
–
–
–
–
Cy, cyclohexyl.
a Isolated yield.
In summary, we report here the reaction between two equiv-
alents of an isocyanide, a dialkyl acetylenedicarboxylate and
an acid anhydride for the synthesis of functionalised 2,5-
diaminofuran derivatives. The procedure has advantages
including the use of simple starting materials, short reaction
times, easy work-up and good yields. Also not only is the reac-
tion performed under neutral conditions but also the substances
can be mixed without any activation or modification.
Diethyl 2-[tert-butyl(trifluoroacetyl)amino]-5-(tert-butylamino)furan-
3,4-dicarboxylate (4m): Yellow oil, (90%); IR (KBr) (νmax, cm−1): 3333
(NH), 1737, 1689, (carbonyl groups). Anal. Calcd for C20H29F3N2O6:
C, 53.33; H, 6.49; N, 6.22. Found: C, 53.50; H, 6.32; N, 6.12%. MS
1
(m/z, %): 450 (M+, 5). H NMR (500.1 MHz, CDCl3): δ 1.29 (3H, t,
Experimental
J = 7Hz, CH3) and 1.31 (3H, 2 t, J = 7 Hz, CH3), 1.51 (9H, s,
tert-butyl) and 1.58 (9H, s, tert-butyl), 4.15 (4H, m, 2 OCH2), 6.93
(1H, s, NH). 13C NMR (125.7 MHz, CDCl3): δ 14.2 and 14.7
(2 CH3), 28.0, 30.7 (methyl groups of 2 tert-butyl), 53.4 and 64.0
(2 NC), 60.0 and 61.7 (2 OCH2), 86.4, 114.9, 135.1, 157.7 (4C of
Furan ring), 162.5 and 165.4 (two ester carbonyl carbons), 117.1 (d,
J = 281 Hz, CF3), 157.7 (q, J = 36 Hz, COCF3).
Ditert-butyl2-[cyclohexyl(trifluoroacetyl)amino]-5-(cyclohexylamino)
furan-3,4-dicarboxylate (4n): Yellow oil, (88%); IR (KBr) (νmax, cm−1):
3336 (NH), 1732, 1680, (carbonyl groups). Anal. Calcd for
C28H41F3N2O6: C, 60.20; H, 7.40; N, 5.01. Found: C, 60.35; H, 7.50;
N, 5.15%. MS (m/z, %): 558 (M+, 3). 1H NMR (500.1 MHz, CDCl3):
Elemental analyses were performed using a Heraeus CHN-O-Rapid
analyser. Mass spectra were recorded on a finnigan-MAT 8430 mass
spectrometer operating at an ionisation potential of 70 eV. IR spectra
were recorded on a Shimadzu IR-470 spectrometer. 1H and 13C NMR
spectra were recorded on Bruker DRX-500 Avance spectrometer on
solution in CDCl3 using TMS as internal standard. The chemicals used
in this work were purchased from Fluka (Buchs, Switzerland) and
were used without further purification.
General procedure
To a magnetically stirred solution of an isocyanide (2.0 mmol) and an
acid anhydride (1 mmol) in dichloromethane (15 mL) was added a
Scheme 3 Suggested mechanism for formation of compound 4.

JOURNAL OF CHEMICAL RESEARCH 2012 263
References
δ 0.89–2.05 (20H, 10 CH2 of cyclohexyl), 1.41 (9H, s, tert-butyl) and
1.48 (9H, s, tert-butyl), 4.10–4.38 (2H, m, 2CH of cyclohexyl), 7.16
(1H, s, NH). 13C NMR (125.7 MHz, CDCl3): 28.57 and 29.11 (methyl
groups of 2 tert-butyl), δ 24.9, 25.3, 25.5, 26.8, 32.7, 33.8 (10 CH2
of cyclohexyl groups), 51.6 and 51.9 (2 NCH), 80.6 and 82.4
(2 OC), 85.9, 115.1, 135.8, 158.1, (4C of Furan ring), 163.0 and 165.2
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Diethyl 2-[cyclohexyl(trifluoroacetyl)amino]-5-(cyclohexylamino)
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165.4 (two ester carbonyl carbons), 117.5 (d, J = 280 Hz, CF3), 157.1
(q, J = 36 Hz, COCF3).
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Received 16 December 201;accepted 28 February 2012
Paper 1101043 doi: 10.3184/174751912X13333688963253
Published online: 10 May 2012

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