Efficient synthesis of functionalized 2,5-dihydrofurans and 1,5-dihydro-2H-pyrrol-2-ones by reaction of isocyanides with activated acetylenes in the presence of hexachloroacetone

Article abstract of DOI:10.1007/s00706-007-0810-3

Isocyanides react smoothly with dimethyl acetylenedicarboxylate in the presence of hexachloroacetone to produce dimethyl 5-[alkyl(aryl)imino]-2,2- bis(trichloromethyl)-2,5-dihydro-furan-3,4-dicarboxylates in high yields. When the reaction was performed wi

Full text of DOI:10.1007/s00706-007-0810-3

Monatsh Chem 139, 625–628 (2008)
DOI 10.1007/s00706-007-0810-3
Printed in The Netherlands
Efficient synthesis of functionalized 2,5-dihydrofurans
and 1,5-dihydro-2H-pyrrol-2-ones by reaction of isocyanides
with activated acetylenes in the presence of hexachloroacetone
Issa Yavari, Maryam Sabbaghan, Zinatossadat Hossaini
Chemistry Department, Tarbiat Modares University, Tehran, Iran
Received 19 August 2007; Accepted 20 September 2007; Published online 29 April 2008
# Springer-Verlag 2008
Abstract Isocyanides react smoothly with dimethyl
acetylenedicarboxylate in the presence of hexachloro-
acetone to produce dimethyl 5-[alkyl(aryl)imino]-
2,2-bis(trichloromethyl)-2,5-dihydro-furan-3,4-di-
carboxylates in high yields. When the reaction was
performed with dibenzoylacetylene, 3-benzoyl-1-
alkyl-4-chloro-5-hydroxy-5-phenyl-1,5-dihydro-2H-
pyrrol-2-ones were obtained.
compound assemblies, to accomplish the synthesis
of highly complex natural products.
Results and discussion
The reactivity of nucleophilic carbenes such as iso-
cyanides towards dimethyl acetylenedicarboxylate
(DMAD) is well recognized [3]. The initially formed
zwitterionic intermediate, from DMAD and an iso-
cyanide, has been shown to undergo further reaction
with different electrophilic reagents, leading to a va-
riety of complex heterocycles. These reactions have
been the subject of detailed investigation by a num-
ber of research groups [1–6]. As part of our current
studies on the development of new routes in hetero-
cyclic systems [7], we describe a simple synthesis of
trichloromethylated iminofuranes and pyrrol-2-ones
by reaction of isocyanides with activated acetylenes
in the presence of hexachoroacetone (HCA) [8]. Thus,
tert-butyl isocyanide (1a) and DMAD undergo a
smooth reaction in the presence of HCA in dry CH2Cl2
at room temperature to produce dimethyl 5-(tert-butyl-
imino)-2,2-bis(trichloromethyl)-2,5-dihydrofuran-
3,4-dicarboxylate (2a) in 95% yield (Scheme 1) [9].
The structures of 2a–2e were deduced from their IR,
1H NMR, and 13C NMR spectra. The mass spectra
of these compounds displayed molecular ion peaks
at the appropriate m=z values.
Keywords Three-component reaction; Isocyanide; Hexa-
chloroacetone; Iminofurane; 2,5-Dihydrofurans.
Introduction
Isocyanides are the only class of stable organic com-
pounds with a formally divalent carbon. Owing to its
reactivity the isocyanide group differs fundamentally
from other functional groups [1]. A classic theme in
the chemistry of isocyanides is heterocyclic syn-
thesis [2]. Multi-component reactions (MCRs), by
virtue of their convergence, facile execution, and
generally high yields of products, have attracted
much attention from the point of combinatorial
chemistry. Of pivotal importance in this area are the
isocyanide based MCRs such as the versatile Ugi
and Passerini reactions [1, 2]. MCRs have been used
to create diversity oriented and biased combinatorial
Correspondence: Issa Yavari, Chemistry Department,
Tarbiat Modares University, Tehran, Iran. E-mail: yavarisa@
modares.ac.ir
1
The H NMR spectrum of 2a in CDCl3 shows
three singlets for tert-butyl (ꢀ ¼ 1.39 ppm) and me-

626
I. Yavari et al.
Scheme 1
Scheme 2
1
2H-pyrrol-2-ones 5 (Scheme 3) [11]. The H NMR
thoxy (ꢀ ¼ 3.85 and 3.90 ppm) protons. The 13C NMR
spectrum of 2a exhibites twelve signals in agreement
with the proposed structure. Partial assignments of
these resonances are given in the Experimental sec-
spectrum of 5a showed two singlets arising from tert-
butyl (ꢀ ¼ 1.29 ppm) and hydroxy (ꢀ ¼ 6.14 ppm)
protons, along with the aromatic protons. The 13C
NMR spectrum of 5a shows fifteen distinct reso-
nances in agreement with the proposed structure.
A plausible mechanism for the formation of 5
is proposed in Scheme 4. The initial event is the
formation of 1,3-dipolar intermediate 3 from the iso-
cyanide and DBA which is subsequently attacked by
HCA to produce 7 [8a]. In the presence of moisture,
intermediate 7 is transformed to 8, which undergoes
cyclization reaction to generate 9. Intermediate 9,
rearranges to 5, via the open-chain structure 10.
In conclusion, we described a convenient route to
bis-trichloromethylated iminofuranes, from isocya-
nides and DMAD in the presence of HCA. The func-
tionalized iminofuranes, reported in this work may
1
tion. The H NMR and 13C NMR spectra of 2b–2e
are similar to those for 2a except for the alkylimino
moieties, which show characteristic resonances in
appropriate regions of the spectrum.
A tentative mechanism for this transformation is
proposed in Scheme 2. It is conceivable that, the ini-
tial event is the formation of 1,3-dipolar intermediate
3 from the isocyanide and DMAD [3], which is sub-
sequently attacked by HCA to produce 4. Intermedi-
ate 4 undergoes cyclization reaction to generate 2.
The reaction of alkyl isocyanides with dibenzoyl-
acetylene (DBA) [10] in the presence of HCA in
CH2Cl2 at room temperature led to 3-benzoyl-1-
(tert-butyl)-4-chloro-5-hydroxy-5-phenyl-1,5-dihydro-
Scheme 3

Efficient synthesis of functionalized 2,5-dihydrofurans
627
Scheme 4
(s, MeO) ppm; 13C NMR (125.7MHz, CDCl3): ꢀ ¼ 29.4
(CMe3), 53.1 (OMe), 53.2 (OMe), 56.2 (C–N), 98.0 (2CCl3),
99.7 (C–O), 141.2, 142.0 (2C), 147.7 (C¼N), 160.6, 160.7
be considered as potentially useful synthetic inter-
mediates. When the reaction was performed in the
presence of DBA, functionalized pyrrol-2-ones were
obtained. The advantage of the present procedure is
that the reaction is performed under neutral condi-
tions by simple mixing of the starting materials. The
procedure described here provides an acceptable
one-pot method for the preparation of functionalized
iminofuranes and pyrrol-2-ones.
þ
(2C¼O) ppm; MS (EI, 70eV): m=z (%) ¼ 489 (M ꢂ, 2), 474
(25), 320 (40), 260 (25), 58 (100), 41 (50).
Dimethyl 5-(cyclohexlimino)-2,2-bis(trichloromethyl)-2,5-
dihydrofuran-3,4-dicarboxylate (2b, C16H17Cl6NO5)
Yellow oil, yield 0.66 g (65%); IR (KBr): ꢁꢀ¼ 1734, 1690,
1
1420, 1273cmꢁ1; H NMR (500MHz, CDCl3): ꢀ ¼ 1.25 (m,
2CH2), 1.27 (m, 2CH2), 1.31 (m, CH2), 3.62 (m, N–CH), 3.64
(s, OMe), 3.77 (s, OMe) ppm; 13C NMR (125.7 MHz, CDCl3):
ꢀ ¼ 24.5 (CH2), 24.7 (2CH2), 25.7 (2CH2), 51.2, 53.1 (2OMe),
53.8 (C–N), 95.0 (2CCl3), 99.8 (C–O), 134.5, 135.3 (2C),
159.5 (C¼N), 160.9, 161.2 (2C¼O) ppm.
Experimental
Dibenzoylacetylene was prepared according to Ref. [9]. Other
chemicals were purchased from Fluka and used without
further purification. Melting points were measured on an
Electrothermal 9100 aparatus. Elemental analyses for the C,
H, and N were performed using a Heraeus CHN–O-Rapid
analyzer. The results agreed favorably with the calculated val-
ues. Mass spectra were recorded on a FINNIGAN-MAT 8430
spectrometer operating at an ionization potential of 70eV. IR
spectra were measured on a Shimadzu IR-460 spectrometer.
1H and 13C NMR spectra were measured with a BRUKER
DRX-500 AVANCE spectrometer at 500.1 and 125.8MHz.
Dimethyl 5-[(2,6-dimethylphenyl)imino]-2,2-bis(trichloro-
methyl)-2,5-dihydrofuran-3,4-dicarboxylate
(2c, C18H15Cl6NO5)
Yellow powder, mp 140–142ꢀC; yield 0.96 g (90%); IR (KBr):
ꢁꢀ¼ 1737, 1715, 1426, 1276 cmꢁ1; 1HNMR(500 MHz,CDCl3):
ꢀ ¼ 2.22 (s, 2CH3), 3.97 (s, OMe), 4.03 (s, OMe), 6.99 (t,
3
3JHH ¼ 6.9 Hz, CH), 7.07 (t, JHH ¼ 7.5 Hz, 2CH) ppm; 13C
NMR (125.7MHz, CDCl3): ꢀ ¼ 18.5 (2Me), 53.8, 53.9
(2OMe), 97.7 (2CCl3), 100.1 (C–O), 124.6 (CH), 127.4 (2C),
128.0 (2CH), 141.5, 143.0,145.7 (3C), 147.0 (C¼N), 160.5,
160.8 (2C¼O) ppm; MS (EI, 70 eV): m=z (%) ¼ 538 (Mþ, 30),
537 (42), 420 (88), 418 (100), 121 (42), 119 (100), 117 (90).
General procedure for the preparation of 2,5-dihydrofurans 2
To a stirred solution of 0.28 g DMAD (2mmol) and 0.52g
HCA (2mmol) in 10 cm3 CH2Cl2 was added 2 mmol of the
alkyl(aryl) isocyanide at room temperature. The reaction mix-
ture was then stirred for 24h. The solvent was removed under
reduced pressure and the viscous residue was purified by col-
umn chromatography on silica gel (Merck 230–400 mesh)
using n-hexane-EtOAc as eluent to give the product.
Dimethyl 5-[(1,1,3,3-tetrabuthyl)imino]-2,2-bis(trichlorometh-
yl)-2,5-dihydrofuran-3,4-dicarboxylate (2d, C18H23Cl6NO3)
Yellow oil, yield 0.92 g (80%); IR (KBr): ꢁꢀ¼ 1742, 1736,
1
1430, 1270 cmꢁ1; H NMR (500 MHz, CDCl3): ꢀ ¼ 1.00 (s,
CMe3), 1.47 (s, 2CH3), 1.55 (s, CH2), 3.89 (s, OMe), 3.95 (s,
OMe) ppm; 13C NMR (125.7 MHz, CDCl3): ꢀ ¼ 29.9 (2CH3),
31.9 (CMe3), 32.3 (C), 53.5, 53.6 (2OMe), 55.9 (CH2), 60.1
(C–N), 98.5 (2CCl3), 99.9 (C–O), 141.7, 142.2 (2C), 147.1
(C¼N), 161.0, 161.2 (2C¼O) ppm; MS (EI, 70eV): m=z
(%) ¼ 474 (25), 395 (20), 322 (20), 121 (18), 119 (62), 117
(100), 57 (30).
Dimethyl 5-(tert-butylimino)-2,2-bis(trichloromethyl)-2,5-
dihydrofuran-3,4-dicarboxylate (2a, C14H15Cl6NO5)
Colorless crystals, mp 141–144ꢀC; yield 0.80 g (95%);
IR (KBr): ꢁꢀ¼ 1736, 1698, 1427, 1270 cmꢁ1
;
1H NMR
(500 MHz, CDCl3): ꢀ ¼ 1.39 (s, CMe3), 3.85 (s, MeO), 3.90

628
I. Yavari et al.
(AB system, JAB ¼ 15Hz, CH2), 6.10 (s, OH), 7.22 (t, 3JHH
¼
¼
Dimethyl 5-[(2-ethoxy-2-oxo)imino]-2,2-bis(trichloromethyl)-
2,5-dihydrofuran-3,4-dicarboxylate (2e, C14H13Cl6NO7)
Red oil, yield 0.76g (75%); IR (KBr): ꢁꢀ¼ 1740, 1736, 1429,
3
3
8.2 Hz, CH), 7.31 (d, JHH ¼ 8.8 Hz, CH), 7.44 (t, JHH
3
7.2 Hz, CH), 7.50 (m, 4CH), 7.64 (d, JHH ¼ 7.3Hz, 2CH),
3
8.01 (d, JHH ¼ 7.3 Hz, CH) ppm; 13C NMR (125.7 MHz,
1
3
1271 cmꢁ1; H NMR (500MHz, CDCl3): ꢀ ¼ 1.29 (t, JHH
¼
¼
3
CDCl3): ꢀ ¼ 28.5 (CH3), 31.8 (CMe3), 31.9 (C), 32.0 (CH3),
51.3 (C), 56.8 (CH2), 90.6 (C–O), 125.4 (2CH), 126.1 (C),
128.1 (2CH), 128.4 (2CH), 129.2 (2CH), 129.6 (CH), 130.4
(CH), 134.1 (C), 136.9 (C), 141.3 (C–Cl), 171.2, 180.5
(2C¼O) ppm; MS (EI, 70 eV): m=z (%) ¼ 320 (5), 119 (64),
117 (66), 84 (86), 82 (90), 58 (14), 48 (100).
7.1 Hz, CH3), 3.89 (s, OMe), 3.96 (s, OMe), 4.24 (q, JHH
7.1 Hz, OCH2), 4.41 (s, CH2) ppm; 13C NMR (125.7 MHz,
CDCl3): ꢀ ¼ 14.6 (CH3), 51.0 (C–N), 53.8, 53.9 (2OMe), 61.7
(OCH2), 98.0 (2CCl3), 99.8 (C–O), 138.4, 146.4 (2C), 155.3
(C¼N), 160.1, 160.7, 168.9 (3C¼O) ppm; MS (EI, 70eV):
m=z (%) ¼ 519 (Mþ, 2), 368 (60), 317 (60), 121 (80), 119
(100), 117 (100), 59 (40).
References
General procedure for the preparation of 1,5-dihydro-2H-
pyrrol-2-ones 5
¨
1. a) Domling A, Ugi I (2000) Angew Chem Int Ed Eng
¨
39:3169; b) Domling A (2006) Chem Rev 106:17
2. Marcaccini S, Torroba T (1993) Org Prep Preced Int
25:141
To a stirred solution of 0.48g DBA (2mmol) and 0.52g HCA
(2mmol) in 10cm3 CH2Cl2 was added 2 mmol alkyl(aryl) iso-
cyanide at room temperature. The reaction mixture was then
stirred for 24 h. The solvent was removed under reduced pres-
sure and the viscous residue was purified by precipitation in
Et2O to give 5.
3. Nair VJ, Rajesh C, Vinod AU, Bindu S, Sreekanth AR,
Mathess JS, Balagopal L (2003) Acc Chem Res 36:899
4. Teimouri MB, Shaabani A, Bazhrang R (2006) Tetrahe-
dron 62:1845
5. Esmaeili AA, Zendegani H (2005) Tetrahedron 61:4031
6. Nair V, Vinod AU, Abhilash N, Menon RS, Santhi V, Varma
RL, Viji S, Mathew S, Srinivas R (2003) Tetrahedron
59:10279
3-Benzoyl-1-(tert-butyl)-4-chloro-5-hydroxy-5-phenyl-1,5-
dihydro-2H-pyrrol-2-one (5a, C21H20Cl6NO3)
Pale yellow powder, mp 139–142ꢀC; yield 0.68 g (92%); IR
(KBr): ꢁꢀ¼ 3390, 1672, 1604, 1367 cmꢁ1; 1H NMR (500MHz,
7. a) Yavari I, Sabbaghan M, Hossaini Z (2006) Synlet:2501;
b) Yavari I, Djahaniani H (2006) Tetrahedron Lett 47:2953;
c) Yavari I, Moradi L (2006) Tetrahedron Lett 47:1627;
d) Yavari I, Djahaniani H (2005) Tetrahedron Lett 46:7491
8. Hexachloroacetone was introduced as a source of positive
chlorine: Laskovics FM, Schulman EM (1977) Tetrahe-
dron Lett 18:759 and dichlorocarbene: Grant FW, Cassie
WB (1960) J Org Chem 25:1443; Grant FW, Cassie WB
(1960) J Org Chem 25:2263, and has been used for the
preparation of amides: Panetta CA, Casanova TG (1970)
3
CDCl3): ꢀ ¼ 1.29 (s, CMe3), 6.14 (s, OH), 7.23 (t, JHH
¼
3
7.7 Hz, CH), 7.26 (d, JHH ¼ 7.6Hz, CH), 7.34 (m, 3CH),
3
3
7.45 (d, JHH ¼ 7.3 Hz, CH), 7.50 (t, JHH ¼ 7.7 Hz, 2CH),
3
7.64 (d, JHH ¼ 7.2 Hz, 2CH) ppm; 13C NMR (125.7 MHz,
CDCl3): ꢀ ¼ 28.8 (CMe3), 52.2 (C), 90.2 (C–O), 124.9
(2CH), 125.6 (C), 127.7 (2CH), 128.0 (2CH), 129.0 (2CH),
129.2 (CH), 130.0 (CH), 133.4, 135.5 (2C), 140.7 (C–Cl),
170.5, 179.9 (2C¼O) ppm; MS (EI, 70eV): m=z (%) ¼ 278
(10), 117 (20), 105 (66), 77 (40), 58 (100), 42 (40).
J
Org Chem 35:2423 and alkyl trichloroacetates:
3-Benzoyl-4-chloro-5-hydroxy-5-phenyl-1-(1,1,3,3-tetramethyl-
butyl)-1,5-dihydro-2H-pyrrol-2-one (5b, C25H28ClNO3)
Pale yellow powder, mp 126–129ꢀC; yield 0.80 g (85%); IR
(KBr): ꢁꢀ¼ 3380, 1667, 1606, 1364 cmꢁ1; 1H NMR (500MHz,
CDCl3): ꢀ ¼ 0.98 (s, CMe3), 1.05 (s, CH3), 1.36 (s, CH3), 1.85
Freedlander RS, Bryson TA, Dunlap RB, Schulman EM,
Lewis CA (1981) J Org Chem 46:3519
9. a) Skattebøl L, Jones ERH, Whiting MC (1963) Org Synth
Coll vol 4:792; b) Bowden K, Heilbron IM, Jones ERH,
Weedon BC (1946) J Chem Soc:39