Synthesis of highly functionalized bis(4H-chromene) and 4H-benzo[g]chromene derivatives via an isocyanide-based pseudo-five-component reaction

Article abstract of DOI:10.1021/jo9005427

(Chemical Equation Presented) The reactive intermediates generated by the addition of alkyl, aryl, and alicyclic isocyanides to dialkyl acetylenedicarboxylates were trapped by 2,5-dihydroxycyclohexa-2,5-diene-1,4- dione or 2-hydroxynaphthalene-1,4-dione t

Full text of DOI:10.1021/jo9005427

Synthesis of Highly Functionalized
Bis(4H-chromene) and 4H-Benzo[g]chromene
Derivatives via an Isocyanide-Based
Pseudo-Five-Component Reaction
Ahmad Shaabani,* Rahim Ghadari, Afshin Sarvary, and
Ali Hossein Rezayan
Department of Chemistry, Shahid Beheshti UniVersity,
P.O. Box 19396-4716, Tehran, Iran
a-shaabani@cc.sbu.ac.ir
FIGURE 1. Some biologically active chromenes and isochromenes.
ReceiVed March 11, 2009
Recently, the synthesis of particular groups of naturally
occurring pyranonaphthoquinones, such as pentalongin A,5-7
dehydroherbarin B,8 several 1,3-disubstituted-3,4-dehydropy-
ranonaphthoquinones C,9 and 3-arylpyranonaphthoquinones
D10,11 have been reported. The biological activities of these
compounds were investigated too.12 For example, pentalongin
A is a natural product, which is reported in Rwanda and Kenya
for the treatment of malaria and skin diseases (Figure 1). These
compounds have been synthesized via multistep approach in
the presence of transition metal catalysts under sensitive
conditions.8,9 Compounds E and F were used as antimultire-
sistant hospital bacteria, too. These compounds were semisyn-
thetically obtained from lapachol.13
Multicomponent reactions (MCRs), due to their productivity,
simple procedures, convergence, and facile execution, are one
of the best tools in combinatorial chemistry. Therefore, the
design of novel MCRs, especially isocyanide-based multicom-
ponent reactions (IMCRs), have attracted great attention from
research groups working in areas such as drug discovery, organic
synthesis, and materials science.14-20
It has been shown that alkyl or aryl isocyanide add to dialkyl
acetylenedicarboxylate to generate zwitterionic species, which
serve as intermediates in many different reactions. Recently,
these highly reactive zwitterionic intermediates have been
The reactive intermediates generated by the addition of alkyl,
aryl, and alicyclic isocyanides to dialkyl acetylenedicarboxy-
lates were trapped by 2,5-dihydroxycyclohexa-2,5-diene-1,4-
dione or 2-hydroxynaphthalene-1,4-dione to produce highly
functionalized bis(4H-chromene)- and 4H-benzo[g]chromene-
3,4-dicarboxylate derivatives in fairly good yields in CH3CN
at room temperature. These compounds are closely related
to the ring systems pentalongin, dehydroherbarin, 1,3-
disubstituted-3,4-dehydropyranonaphthoquinones, and 3-
arylpyranonaphthoquinones, which have a broad spectrum
of biological activity.
(5) De Kimpe, N.; Van Puyvelde, L.; Schripsema, J.; Erkelens, C.; Verpoorte,
R. Magn. Reson. Chem. 1993, 31, 329–330.
(6) Kesteleyn, B.; Van Puyvelde, L.; De Kimpe, N. J. Org. Chem. 1999, 64,
438–440.
(7) Kesteleyn, B.; De Kimpe, N.; Van Puyvelde, L. Synthesis 1999, 1881–
1883.
(8) Kesteleyn, B.; De Kimpe, N.; Van Puyvelde, L. J. Org. Chem. 1999, 64,
1173–1179.
(9) Nguyen Van, T.; Kesteleyn, B.; De Kimpe, N. Tetrahedron 2001, 57,
4213–4219.
(10) Aldersley, M. F.; Christi, S. H.; Dean, F. M.; Douglas, M. E.; Ennis,
D. S. J. Chem. Soc., Perkin Trans. 1 1990, 2163–2174.
(11) Aldersley, M. F.; Dean, F. M.; Hamzah, A. S. Tetrahedron Lett. 1986,
27, 255–258.
The chromene moiety often appears as an important structural
component in both biologically active and natural compounds.
Chromene fragments occur in alkaloids, flavonoids, tocopherols,
and anthocyanins. Moreover, functionally substituted chromenes
have played increasing roles in synthetic approaches to promis-
ing compounds in the field of medicinal chemistry.1-4
(12) Nguyen Van, T.; De Kimpe, N. Tetrahedron 2003, 59, 5941–5946.
(13) Machado, T. B.; Pinto, A. V.; Pinto, M. C. F. R.; Leal, I. C. R.; Silva,
M. G.; Amaral, A. C. F.; Kuster, R. M.; Netto-dosSantos, K. R. Int. J. Antimicrob.
Agents. 2003, 21, 279–284.
(14) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(15) Weber, L. Curr. Med. Chem. 2002, 9, 1241–1253.
(16) Schreiber, S.-L. Science 2000, 287, 1964–1969.
(17) Orru, R. V. A.; Greef, M. Synthesis 2003, 1471–1499.
(18) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.sEur. J. 2000,
6, 3321–3329.
* To whom correspondence should be addressed. Fax +982122431663. Phone:
+982129902800.
(1) Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.;
Nasybullin, R. F.; Stepanov, N. O.; Nikishin, G. I. Tetrahedron Lett. 2006, 47,
7629–7633.
(2) Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.;
Hammond, M. L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468–1472.
(3) Stachulski, A. V.; Berry, N. G.; Low, A. C. L.; Moores, S. L.; Row, E.;
Warhurst, D. C.; Adagu, I. S.; Rossignol, J.-F. J. Med. Chem. 2006, 49, 1450–
1454.
(4) Gesson, J. P.; Fonteneau, N.; Mondon, M.; Charbit, S.; Ficheux, H.;
Schutze, F. US patent 6,965,039 B2, 2005.
(19) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(20) Zhu, J.; Bienayme´, H. Multicomponent Reactions; Wiley-VCH: Wein-
heim, Germany, 2005.
4372 J. Org. Chem. 2009, 74, 4372–4374
10.1021/jo9005427 CCC: $40.75 2009 American Chemical Society
Published on Web 04/27/2009

TABLE 1. Bis(4H-chromene)-3,4-dicarboxylate Derivatives 4a-j
SCHEME 1. Synthesis of
Bis(4H-chromene)-3,4-dicarboxylate Derivatives 4a-j
captured by suitable CH acids,21-24 NH acid-like amides,25 and
OH acids like carboxylic acids26,27 and oxime28 substrates.
As part of our continuing interest in the development of new
synthetic methods in heterocyclic compounds and isocyanide-
based multicomponent reactions,29-35 in the present work we
wish to report the reaction of alkyl, aryl, and alicyclic isocya-
nides with dialkyl acetylenedicarboxylates in the presence of
2,5-dihydroxycyclohexa-2,5-diene-1,4-dione in CH3CN at room
temperature (Scheme 1).
In a pilot experiment, 2,5-dihydroxycyclohexa-2,5-diene-1,4-
dione, dimethyl acetylenedicarboxylate, and cyclohexyl isocya-
nide in CH3CN were stirred at room temperature. After
completion of the reaction (after 24 h), the precipitated product
was separated from the reaction mixture by filtration and was
washed with n-hexane to afford product 4a in 86% yield.
To explore the scope and limitations of this reaction, we
extended the procedure to various alkyl, aryl, and alicyclic
isocyanides and various dialkyl acetylenedicarboxylates with
2,5-dihydroxycyclohexa-2,5-diene-1,4-dione.
entry
product
R1
R2
yield (%)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
cyclohexyl
Me
Me
Me
Me
Me
Me
Et
86
70
73
62
83
70
82
75
65
70
tert-butyl
1,1,3,3-tetramethylbutyl
ethoxycarbonylmethyl
benzyl
2,6-dimethylphenyl
cyclohexyl
benzyl
Et
2,6-dimethylphenyl
2,6-dimethylphenyl
Et
4j
tBu
SCHEME 2. Proposed Pathway
As indicated in Table 1, the reactions proceed very efficiently
and led to the formation of the corresponding highly function-
alized bis(4H-chromene)-3,4-dicarboxylate derivatives 4a-j in
excellent yields at room temperature, without any undesirable
byproducts.
The structure of compounds 4a-j was deduced from their
1
IR, mass, H NMR, 13C NMR, and HMQC for 4a and 10i
spectral data. For example, the 1H NMR spectrum of 4a
exhibited a multiplet for the cyclohexyl ring δ 1.35-1.96 (20H,
m, 10CH2 of 2cyclohexyls), two singlets identified as two
methoxy groups (12H, 4OCH3, δ 3.66 and 3.71), a broad singlet
at δ 3.79 (2H, br s, 2CH-NH of 2cyclohexyls), a singlet at δ
4.64 (2H, s, 2CH-CO2Me), and a broad singlet at δ 8.57 for
agreement with proposed structure. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate
m/z values.
1
two NH groups (2H, br s, 2CH-NH). The H-decoupled 13C
NMR spectrum of 4a showed 14 distinct resonances in
Although the mechanism of this reaction has not been
established experimentally, the formation of these heterocycles
can be rationalized by initial Michael-type vinylisonitrilium
cation 5.23,36-38 Then, the positively charged ion might be
attacked by the anion of the 2,5-dihydroxycyclohexa-2,5-diene-
1,4-dione, which leads to the keteneimine 7. Such an addition
product may isomerize under the reaction conditions employed
to produce the fused heterocyclic systems 4a-j (Scheme 2).
The versatility of this multicomponent reaction with respect
to the CH acid component was also studied (Scheme 3). As
indicated in Scheme 3 and Table 2, 2-hydroxynaphthalene-1,4-
dione 9 and dialkyl acetylenedicarboxylates 2 with various
isocyanides 1 in CH3CN led to the formation of 4H-ben-
zo[g]chromene-3,4-dicarboxylate derivatives 10a-i in good
yields at ambient temperature.
(21) Nair, V.; Vinod, A. U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma,
R. L.; Viji, S.; Mathewa, S.; Srinivas, R. Tetrahedron 2003, 59, 10279–10286.
(22) Teimouri, M. B.; Bazhrang, R.; Bazhrangh, V.; Nouri, A. Tetrahedron
2006, 63, 3016–3020.
(23) Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin Trans. 1 2002,
2343–2346.
(24) Yavari, I.; Esnaashari, M. Synthesis 2005, 1049–1051.
(25) Adib, M.; Sayahi, M. H.; Aghaaliakbari, B.; Bijanzadeh, H. R.
Tetrahedron 2005, 61, 3963–3966.
(26) Alizadeh, A.; Oskueyan, Q.; Rostamnia, S.; Ghanbari-Niaki, A.;
Mohebbi, A. R. Synthesis 2008, 2929–2932.
(27) Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006, 1592–1594.
(28) Alizadeh, A.; Rostamnia, S. Synthesis 2008, 57–60.
(29) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Org. Chem.
2008, 73, 3925–3927.
(30) Shaabani, A.; Rezayan, A. H.; Rahmati, A.; Sarvary, A. Synlett 2007,
1458–1460.
(31) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Tetrahedron
Lett. 2008, 49, 1469–1472.
(32) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007,
48, 6137–6141.
The reaction proceeded under mild conditions and was
compatible with a wide range of functional groups. Two
(33) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R.
Org. Lett. 2008, 10, 2581–2584.
(34) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Rahmati, A.; Khavasi, H. R.
Catal. Commun. 2008, 9, 1082–1086.
(35) Shaabani, A.; Soleimani, E.; Sarvary, A.; Rezayan, A. H. Bioorg. Med.
Chem. Lett. 2008, 18, 3968–3970.
(36) Nair, V.; Vinod, A. U.; Ramesh, R.; Menon, R. S.; Varma, R. L.;
Mathew, S.; Chiaroni, A. Heterocycles 2002, 58, 147–151.
(37) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, UK, 1992.
(38) Yavari, I.; Zare, H.; Mohtat, B. Mol. DiVersity 2006, 10, 247–250.
J. Org. Chem. Vol. 74, No. 11, 2009 4373

SCHEME 3. Synthesis of
4H-Benzo[g]chromene-3,4-dicarboxylate Derivatives 10a-i
1,4-dione (0.14 g, 1.0 mmol) and dimethyl acetylenedicarboxylate
(0.28 g, 2.0 mmol) in CH3CN (5 mL) was added a solution of
cyclohexyl isocyanide (0.22 g, 2.0 mmol) in CH3CN (2 mL) at
room temperature over 5 min. The mixture was then stirred for
24 h. After completion of the reaction, the precipitated product was
separated from the reaction mixture by filtration and was washed
with 5 mL of n-hexane. The desired product was obtained as a
brownish red powder (0.55 g, yield 86%). Mp 257-258 °C; IR
(KBr) (νmax/cm-1) 2933, 2859, 1751, 1673, 1602, 1446; MS, m/z
(%) 456 (M+ - 14, 5), 396 (50), 344 (30), 284 (100), 252 (40), 77
TABLE 2. 4H-Benzo[g]chromene-3,4-dicarboxylate Derivatives
10a-i
1
(35), 55 (65), 57 (70); H NMR (300 MHz, CDCl3) δH (ppm)
1.35-1.96 (20H, m, 10CH2 of 2cyclohexyl), 3.66 (6H, s, 2O-CH3),
3.71 (6H, s, 2O-CH3), 3.79 (2H, br s, CH-NH), 4.64 (2H, s,
2CH-CO2Me), 8.57 (2H, br s, 2CH-NH); 13C NMR (75 MHz,
CDCl3) δC (ppm) 24.3, 25.4, 33.5, (C-cyclohexyl), 35.2
(CH-CO2Me), 50.3 (CH-NH), 51.2, 52.8 (2O-CH3), 70.7, 117.7,
147.8, 158.3 (C-alkene), 169.1, 172.2, 176.9 (3CdO). Anal. Calcd
for C32H38N2O12: C, 59.81; H, 5.96; N, 4.36. Found: C, 59.76; H,
5.84; N, 4.28.
entry
product
R1
cyclohexyl
1,1,3,3-tetramethylbutyl
ethoxycarbonylmethyl
2,6-dimethylphenyl
cyclohexyl
1,1,3,3-tetramethylbutyl
ethoxycarbonylmethyl
2,6-dimethylphenyl
2,6-dimethylphenyl
R2
yield (%)
Typical Procedure for the Preparation of Product 10a. To a
magnetically stirred solution of 2-hydroxynaphthalene-1,4-dione
(0.17 g, 1.0 mmol) and dimethyl acetylenedicarboxylate (0.14 g,
1.0 mmol) in CH3CN (5 mL) was added a solution of cyclohexyl
isocyanide (0.11 g, 1.0 mmol) in CH3CN (2 mL) at room
temperature over 5 min. The mixture was then stirred for 24 h.
After completion of the reaction, the precipitated product was
separated from the reaction mixture by filtration and was washed
with 5 mL of n-hexane. The desired product was obtained as a
brownish red powder (0.38 g, yield 89%). Mp 177-178 °C; IR
(KBr) (νmax/cm-1) 2936, 2859, 1732, 1680, 1637, 1598; MS, m/z
(%) 456 (M+ - 14, 5), 396 (50), 344 (30), 284 (100), 252 (40), 77
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
Me
Me
Me
Me
Me
Me
Et
89
75
60
77
84
74
62
74
64
Et
tBu
substituents in the products can be varied independently of each
other. Owing to the great diversity of substitution patterns, this
reaction may be used in the production of combinatorial
libraries. Representative examples of this reaction are shown
in Tables 1 and 2.
In conclusion, we have developed an efficient synthetic
approach for the synthesis of the highly functionalized bis(4H-
chromene)- and 4H-benzo[g]chromene-3,4-dicarboxylate deriva-
tives from readily available substrates in fairly good yields. The
advantages of the present procedure are the following: the
reaction is performed by a simple mixing of the starting
materials, neutral reaction conditions, easy workup procedure,
and displaying good functional groups tolerance. We hope this
approach may be of value to others seeking novel synthetic
fragments with unique properties for medicinal chemistry.
1
(35), 55 (65), 57 (70); H NMR (300 MHz, CDCl3) δH (ppm)
1.42-2.08 (10H, m, 5CH2 of cyclohexyl), 3.67 (3H, s, O-CH3),
3.74 (3H, s, O-CH3), 3.86 (1H, br s, CH-NH), 4.74 (1H, s,
CH-CO2Me), 7.27-8.15 (4H, m, arom), 8.64 (1H, br s, CH-NH);
13C NMR (75 MHz, CDCl3) δC (ppm) 24.4, 24.4, 25.4, 33.4, 33.7,
(C-cyclohexyl), 35.0 (CH-CO2Me), 50.7 (CH-NH), 51.3, 52.7
(2O-CH3), 72.3, 114.2, 123.8, 129.8, 130.0, 131.8, 135.1, 135.4,
156.9, 158.2 (C-alkene, C-arom), 169.3, 172.9, 177.7, 177.9
(4CdO). Anal. Calcd for C23H23NO7: C, 64.93; H, 5.45; N, 3.29.
Found: C, 64.88; H, 5.49; N, 3.32.
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti University.
Supporting Information Available: Experimental proce-
1
dures and characterization data of products, IR, mass, H, and
13C NMR. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experimental Section
Typical Procedure for the Preparation of Product 4a. To a
magnetically stirred solution of 2,5-dihydroxycyclohexa-2,5-diene-
JO9005427
4374 J. Org. Chem. Vol. 74, No. 11, 2009