Facile synthesis of 4-H-pyran derivatives bearing indole skeleton via [3+3] cyclization of 3-indolyl-3-oxopropanenitriles with dialkyl acetylenedicarboxylates and isocyanides

Article abstract of DOI:10.1002/cjoc.201400155

An efficient multicomponent reaction of 3-indolyl-3-oxopropanenitriles with dialkyl acetylenedicarboxylates and isocyanides under mild conditions leading to highly functionalized 6-(indol-3-yl)-4H-pyrans in moderate to good yields has been developed. An e

Full text of DOI:10.1002/cjoc.201400155

COMMUNICATION
DOI: 10.1002/cjoc. 201400155
Facile Synthesis of 4-H-Pyran Derivatives Bearing Indole
Skeleton via [3＋3] Cyclization of 3-Indolyl-3-oxopro-
panenitriles with Dialkyl Acetylenedicarboxylates
and Isocyanides
Ping Song,a Lili Zhao,b and Shunjun Ji*,b
a Analytic and Testing Center, Soochow University, Suzhou, Jiangsu 215123, China
b Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology,
Soochow University, Suzhou, Jiangsu 215123, China
An efficient multicomponent reaction of 3-indolyl-3-oxopropanenitriles with dialkyl acetylenedicarboxylates
and isocyanides under mild conditions leading to highly functionalized 6-(indol-3-yl)-4H-pyrans in moderate to
good yields has been developed.
Keywords isocyanides, indole, [3+3] cyclization, dialkyl acetylenedicarboxylates, pyran derivatives
Introduction
dyes, etc.[3] For example, Melatonin (Ic, Figure 1)[3e]
and compounds (Id, Figure 1)[3h] possessing both es-
sential units showed a good antifungal and antibacterial
activity. Therefore, it is interesting to construct mole-
cules bearing pyran and indole skeleton.
Pyran derivatives widely exist in natural products
with important biological activities. Among these com-
pounds, chromene moiety was an important structural
component in biologically active and natural alkaloids,
such as flavonoids.[1,2] Pirarubicin (Ia, Figure 1) is a
commonly used antineoplastic agents and cytotoxic
drugs,[1a] HA 14-1 (Ib, Figure 1) is an antagonist of the
antiapoptotic Bcl-2 proteins.[1b] Indole units exist in a
variety of molecular structures, which widely exist in
the field of pharmaceuticals, pesticides, fragrances,
During past decades, isocyanides based multicom-
ponent reactions (IMCRs) have attracked great attention
for their synthetic value and applications.[4] The isocya-
nide had the ability to undergo facile α-addition with a
nucleophile and an electrophile, which made it a popu-
lar reactant for the development of novel MCRs.[5] In
2007, we have reported the synthesis of 3-(2-furanyl)-
indole derivative by multi-component reactions of iso-
cyanides, 3-cyanoacetyl indole, and aromatic aldehydes
(Scheme 1).[6] As a continuation of our works on iso-
cyanide based reactions,[6,7] especially 1,3-dipolar cy-
clization of CO2 with zwitterionic species generated
from isocyanide[8] as well as 3-cyanoactetyl indoles
based reactions,[6,9] herein, we demonstrate an one-pot
three-component reaction of isocyanides, dialkyl acety-
lenedicarboxylates and N-alkyl 3-cyanoactetyl indoles
to give the desired 4-H-pyran derivatives bearing indole
skeleton in moderate to good yields under mild condi-
tions.
O
O
HO
O
CN
O
OH
O
OH
Br
O
O
O
O
O
OH
O
NH2
Ib: HA 14-I
O
O
NH2
Ia: Pirarubicin
R
O
N
NC
HN
H2N
O
CN
O
H3CO
N
N
H
H
Experimental
Id
Ic: Melatonin
General
Figure 1 Select important compounds bearing pyran or/and
indole skeleton.
Melting points were recorded on an Electrothermal
*
E-mail: shunyi@suda.edu.cn, shunjun@suda.edu.cn; Tel.:0086-0512-65880307; Fax: 0086-0512-65880307
Received March 17, 2014; accepted April 21, 2014; published online May 22, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400155 or from the author.
Chin. J. Chem. 2014, 32, 381—386
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
381

Song, Zhao & Ji
COMMUNICATION
Scheme 1 Multi-component reactions involving isocyanides
and 3-cyanoacetyl indole
when utilizing DCM as the solvent (Table 1, Entry 4).
The definite structure of compound 4a was determined
by mass spectra, 1H and 13C NMR, and IR spectroscopic
data, as well as X-ray single crystal diffraction (Figure
2). Further screening the solvents such as EtOH, MeOH,
CH3CN and the ratio of the substrates and the reaction
temperature, the optimal reaction conditions were ob-
served. The reaction of 1a (1.0 equiv.) with 2a (2.0
equiv.) and 3a (1.0 equiv.) led to the desired product 4a
in 68% yield at room temperature (Table 1, Entry 6).
Our previous work
CN
O
H
R1 NC
+
R3
R2
+
O
N
H
R1
HN
O
R2
Table 1 Attempted three-component coupling reaction using
tert-butyl isocyanide 1a, dimethyl but-2-ynedioate 2a and
3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitrile (3a)a
CH3COONH4 (20 mol%)
EtOH reflux
CN
R3
N
H
CN
O
CN
This work
O
CH2Cl2
NC
MeO2C
CO2Me
+
+
r.t., 24 h
N
R1
R2O2C
+
CO2R2
2a
+
R4
NC
1a
N
3a
R3
CO2Me
MeO2C
NC
CO2R2
H
R2O2C
NC
N
H
N
CH2Cl2
r.t., 48 h
O
R1
O
R4
N
N
4a
R3
Entry Solvent Temp./℃
DMAD (equiv.)
Yieldb/%
digital melting point apparatus and were uncorrected. IR
spectra were recorded on a Varian FT-1000 spectropho-
tometer using KBr optics. 1H NMR and 13C NMR spec-
tra were recorded on a Varian INOVA 300 or 400 MHz
(1H NMR) and 75 or 100 MHz (13C NMR) spectrumeter
using CDCl3 or DMSO-d6 as solvent and TMS as inter-
nal standard. High resolution mass spectra were ob-
tained using GCT-TOF instrument with EI or ESI
source.
1
2
3
4
5
6
7
8
EtOH
MeOH
MeCN
DCM
DCM
DCM
DCM
DCM
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
1
10
27
35
45
54
68
66
36
1
1
1
1.5
2
2.5
1
a Reaction conditions: tert-butyl isocyanide 1a (0.5 mmol), di-
methyl but-2-ynedioate (DMAD) 2a, 3-(1-methyl-1H-indol-3-yl)-
3-oxopropanenitrile 3a (0.5 mmol), solvent (3.0 mL), 48 h. b Iso-
lated yields.
Typical procedure for the synthesis of 4
To a mixture of dialkyl acetylenedicarboxylates
(1.0 mmol) and (1-alkyl-1H-indol-3-yl)-3-oxopropane-
nitriles (0.5 mmol) in 4 mL CH2Cl2, 0.5 mmol isocya-
nide was added, then the mixture was stirred at room
temperature for 48 h. Upon reaction completion (moni-
tored by TLC), the solvent was removed under reduced
pressure and the residue was purified by column chro-
matography (silica gel, Merck 300－400 mesh) using
petroleum ether-acetone (20∶1－10∶1) as eluent.
With the optimal conditions in hand, we examined
the scope of the reaction. The results were summarized
in Table 2 and Table 3. When N-benzyl 3-cyanoactetyl
indole and N-(4-methoxyphenyl) 3-cyanoactetyl indole
were applied to the reaction, the desired products 4b and
4d could be obtained in 89% and 85% yields, respec-
tively (Table 2, Entries 2 and 4). When N-hexyl
3-cyanoactetyl indole was involved in this reaction, the
desired product 4c was obtained in 62% yield (Table 2,
Entry 3). The substituents in aromatic ring of 3-cyano-
actetyl indole showed little difference in reactivity re-
gardless of their electron-donating or electron-with-
drawing nature (Table 2, Entries 5－8).
Results and Discussion
Our study was initiated by the reaction of tert-butyl
isocyanide 1a with dimethyl but-2-ynedioate (DMAD)
2a and 3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitrile
3a.[10] To our delight, the [3＋3] cyclization product 4a
could be (Table 1, Entries 1－4) obtained in 45% yield
382
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 381—386

Facile Synthesis of 4-H-Pyran Derivatives Bearing Indole Skeleton via [3＋3] Cyclization
Table 2 Reaction of isocyanides with DMAD and N-alkyl 3-cyanoactetyl indolesa,b
CO2Me
CN
MeO2C
NC
O
H
N
R1
O
CH2Cl2
R1
R4
NC
+
+
CO2Me
MeO2C
r.t., 48 h
N
R4
1
2a
R3
N
R3
3
4
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
NC
MeO2C
NC
MeO2C
NC
MeO2C
NC
H
N
H
H
N
H
N
N
O
O
O
O
N
N
N
N
4c, 62%
4d, 85%
4b, 89%
4a, 68%
OCH3
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
NC
MeO2C
NC
MeO2C
NC
MeO2C
NC
H
N
H
N
H
H
N
N
O
O
O
O
Br
MeO
N
N
Br
N
N
CF3
4e, 77%
4f, 70%
4g, 70%
4h, 73%
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
NC
MeO2C
NC
MeO2C
NC
MeO2C
NC
H
N
H
N
H
N
H
N
O
O
O
O
N
N
N
N
4k, 40%
4l, 68%
4j, 58%
4i, 51%
OCH3
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
NC
MeO2C
NC
MeO2C
NC
MeO2C
NC
H
N
H
N
H
H
N
N
O
O
O
O
Br
MeO
N
N
Br
N
N
CF3
4m, 44%
4n, 60%
4o, 50%
4p, 56%
a The reactions were carried out at room temperature for a specific time using 1 (0.5 mmol), 2 (1.0 mmol), 3 (0.5 mmol), and solvent (4.0
mL, DCM). b Isolated yield.
Chin. J. Chem. 2014, 32, 381—386
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
383

Song, Zhao & Ji
COMMUNICATION
the three components reactions instead of tert-butyl
isocyanide. It was found that the desired products could
be obtained in moderate to good yields (Table 2 and
Table 3).
Replacing the conjugate acceptor with diethyl
but-2-ynedioate 2b in the reaction furnished highly
functionalized
6-(1-alkyl-1H-indol-3-yl)-4H-pyrans
4q－4x in 50%－69% yields (Table 3, Entries 1－8).
Based on the above results and literature reports,[11,12]
a plausible mechanism was proposed as shown in
Scheme 2. The reaction of isocyanide 1 and dialkyl
acetylenedicarboxylate 2 in situ leads to the formation
of zwitterionic intermediate 5, which could be proto-
nated by OH of 3' to give intermediates 6 and 7. Sub-
sequently, ketenimine 8 could be formed by the reaction
of enolate 6 with the nitrilium ion 7. After tautomeriza-
tion under the employed reaction conditions and cycli-
zation, pyran derivative 4 is formed.
Figure 2 Crystal structure of compound 4a.
Then cyclohexyl isocyanide could also be used to
Table 3 Reaction of isocyanides with diethyl but-2-ynedioate and N-alkyl 3-cyanoactetyl indolesa,b
CO2Et
EtO2C
CN
O
H
N
R1
NC
CH2Cl2
O
R1 NC
+
EtO2C
CO2Et
+
r.t., 48 h
1
2b
N
N
R3
R3
3
4
CO2Et
CO2Et
CO2Et
CO2Et
EtO2C
NC
EtO2C
NC
EtO2C
NC
EtO2C
NC
H
N
H
N
H
N
H
N
O
O
O
O
N
N
N
N
4q, 52%
4s, 65%
4r, 66%
OCH3
CO2Et
4t, 69%
CO2Et
CO2Et
CO2Et
EtO2C
NC
EtO2C
NC
EtO2C
NC
EtO2C
NC
H
N
H
N
H
H
N
N
O
O
O
O
N
N
N
N
4u, 55%
4w, 50%
4v, 53%
OCH3
4x, 62%
a The reactions were carried out at room temperature for a specific time using 1 (0.5 mmol), 2 (1.0 mmol), 3 (0.5 mmol), and solvent (4.0
mL, DCM). b Isolated yield.
384
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 381—386

Facile Synthesis of 4-H-Pyran Derivatives Bearing Indole Skeleton via [3＋3] Cyclization
Scheme 2 Proposed mechanism
CN
O
R4
N
R3
3
HO
CN
R4
R1
R1
+ N
N
-
CO2R2
O
R3
3'
+
N
C
C
-
CN
C
R1
+
N
CH
CO2R2
R4
+
+
H
CO2R2
-
1
N
CO2R2
CO2R2
CO2R2
R3
2
5
7
6
R1
CO2R2
N
CO2R2
C
R2O2C
NC
R2O2C
NC
H
C
R2O2C
O
N
R1
O
R1
CO2R2
N
OH
CN
R4
R4
R4
N
N
N
R3
R3
R3
4
9
8
43; (b) Doshi, J. M.; Tian, D. F.; Xing, C. G. J. Med. Chem. 2006,
49, 7731; (c) Vitorino, J.; Sottomayor, M. J. J. Mol. Struct. 2010,
975, 292.
Conclusions
In summary, we have described a simple, atom-
economical, catalyst-free and efficient approach for the
preparation of 6-(1-alkyl-1H-indol-3-yl)-4H-pyrans de-
rivatives in moderate to good yields under very mild
conditions. Considering the advantages such as no prior
activation, readily available starting materials as well as
simple operations and the potential bioactivites of
6-(1-alkyl-1H-indol-3-yl)-4H-pyrans derivatives, this
approach could be useful in organic synthesis and
pharmaceutical chemistry.
[2] Janjua, N. K.; Shaheen, A.; Yaqub, A.; Perveen, F.; Sabahat, S.;
Mumtaz, M.; Jacob, C.; Ba, L. A.; Mohammed, H. A. Spectrochim.
Acta Part A 2011, 79, 1600.
[3] (a) Gribble, G. W. Comprehensive Heterocyclic Chemistry II, Eds.:
Katritzky, A. R.; Ress, C. W.; Scriven, E. F. V.; Bird, C. W., Perga-
mon Press, Oxford, 1996, p. 270; (b) Indoles, Ed.: Sundberg, R. J.,
Academic Press, London, 1996; (c) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893; (d) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (e) Paredes, S. D.;
Korkmaz, A.; Manchester, L. C.; Tan, D. X.; Reiter, R. J. J. Exp. Bot.
2009, 60, 57; (f) Kenda, B.; Quesnel, Y.; Ates, A.; Michel, P.; Turet,
L.; Mercier, J. WO2006128693, 2006; (g) Nandakumar, A.; Thiru-
murugan, P.; Perumal, P. T.; Vembu, P.; Ponnuswamy, N. M.;
Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252; (h) Nandaku-
mar, A.; Thirumurugan, P.; Perumal, P. T.; Vembu, P.; Ponnuswamy,
N. M.; Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252; (i) Gao,
X.; Gong, H.; Men, P.; Zhou, L.; Ye, D. Chin. J. Chem. 2013, 31,
1164.
Acknowledgement
We gratefully acknowledge the National Natural
Science Foundation of China (Nos. 21172162,
21372174), the Ph.D. Programs Foundation of Ministry
of Education of China (No. 2013201130004), the
Scientific Research Foundation for the Returned
Overseas Chinese Scholars, PAPD, and Soochow
University for financial support.
[4] (a) Lygin, A. V.; Meijere, A. D. Angew. Chem., Int. Ed. 2010, 49,
9094; (b) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
3083; (c) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem.,
Int. Ed. 2011, 50, 6234.
[5] (a) Millich, F. Chem. Rev. 1972, 72, 1; (b) Dömling, A.; Ugi, I. An-
gew. Chem., Int. Ed. 2000, 39, 3168; (c) Dömling, A. Chem. Rev.
2006, 106, 17; (d) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013,
42, 5257; (e) Lang, S. Chem. Soc. Rev. 2013, 42, 4867.
References
[1] (a) Bartzatt, R. L. Physiol. Chem. Phys. Med. NMR NMR 2008, 40,
Chin. J. Chem. 2014, 32, 381—386
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
385

Song, Zhao & Ji
COMMUNICATION
[6] Sun, C.; Ji, S.-J.; Liu, Y. Tetrahedron Lett. 2007, 48, 8987.
[7] (a) Wang, X.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2013, 15, 1954; (b)
Wang, X.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2013, 15, 4246; (c) Wang,
R.; Xu, X.-P.; Meng, H.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2013, 69,
1600; (d) Wang, R.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2013, 69,
10836; (e) Wang, R.; Wang, S.-Y.; Ji, S.-J. Org. Biomol. Chem.
2014, 12, 1735; (f) Zhu, T.-H.; Wang, S.-Y.; Wang, G.-N.; Ji, S.-J.
Chem.-Eur. J. 2013, 19, 5850; (g) Zhu, T.-H.; Wang, S.-Y.; Tao,
Y.-Q.; Wei, T.-Q.; Ji, S.-J. Org. Lett. 2014, 16, 1260; (h) Zhu, T.-H.;
Xu, X.-P.; Cao, J.-J.; Wei, T.-Q.; Wang, S.-Y.; Ji, S.-J. Adv. Synth.
Catal. 2014, 356, 509; (i) Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.; Xu,
X.-P.; Wang, S.-Y.; Ji, S.-J. ACS Catal. 2014, 4, 49.
4a' in 70% yield.
CN
O
CH2Cl2
r.t.
NC
+
MeO2C
CO2Me
CN
+
N
2a
1a
H
3a'
O
N
C
N
MeO2C
CO2Me
4a' 70%
[8] Zhao, L.-L.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. Chem. Commun. 2013,
49, 2569.
[9] (a) Zhu, S.-L.; Ji, S.-J.; Su, X.-M.; Sun, C.; Liu, Y. Tetrahedron Lett.
2008, 49, 1777; (b) Zhu, S.-L.; Ji, S.-J.; Zhao, K.; Liu, Y. Tetrahe-
dron Lett. 2008, 49, 2578.
[11] For review see: De Moliner, F.; Banfi, L.; Riva, R.; Basso, A. Comb.
Chem. High Throughput Screen 2011, 14, 782.
[12] (a) Teimouri, M. B.; Bazhrang, R.; Eslamimanesh, V.; Nouri, A.
Tetrahedron 2006, 62, 3016; (b) Shaabani, A.; Soleimani, E.; Sar-
vary, A.; Rezayan, A. H. Bioorg. Med. Chem. Lett. 2008, 18, 3968.
[10] The reaction of 1a with 2a and 3a' afforded the ketenimine product
(Pan, B.; Qin, X.)
386
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 381—386