Efficient solvent-free synthesis of benzothiazine-fused pyrrolo[3,4-c]coumarins: Cycloaddition reactions between coumarin-based dihydrobenzothiazoles and isocyanides

Article abstract of DOI:10.1002/hlca.201300310

A new and unusual synthesis of benzothiazine-fused pyrrolo[3,4-c]coumarins, involving the ring-opening of coumarin-based dihydrobenzothiazoles and subsequent [4+1] cycloaddition reaction with isocyanides, was described. Thus, simple heating of various 3-(2,3-dihydro-2-methylbenzo[d]thiazol-2-yl)coumarins with isocyanides produced the title compounds in good yields under solvent-free conditions. Copyright

Full text of DOI:10.1002/hlca.201300310

Helvetica Chimica Acta – Vol. 97 (2014)
847
Efficient Solvent-Free Synthesis of Benzothiazine-Fused
Pyrrolo[3,4-c]coumarins: Cycloaddition Reactions between Coumarin-Based
Dihydrobenzothiazoles and Isocyanides
by Mehdi Khoobia)b), Ali Ramazani*c), Mohammad Mahdavid), Alireza Foroumadia),
Saeed Emami ), Sang Woo Joo* ), Katarzyna Slepokura ), Tadeusz Lis ), and Abbas Shafiee* )
b
e
f
f
d
´
a) Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
b) Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of
Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
c) Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran
(phone: þ 98-241-5152572; fax: þ 98-241-5152477; e-mail: aliramazani@gmail.com)
d) Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran 14176, Iran
e) School of Mechanical Engineering, Yeungnam University, Gyeongsan 712 – 749, Republic of Korea
(e-mail: swjoo@yu.ac.kr)
f) Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., PL-50-383 Wrocław
A new and unusual synthesis of benzothiazine-fused pyrrolo[3,4-c]coumarins, involving the ring-
opening of coumarin-based dihydrobenzothiazoles and subsequent [4 þ 1] cycloaddition reaction with
isocyanides, was described. Thus, simple heating of various 3-(2,3-dihydro-2-methylbenzo[d]thiazol-2-
yl)coumarins with isocyanides produced the title compounds in good yields under solvent-free
conditions.
Introduction. – Cycloaddition reactions are an important route to the formation of
cyclic compounds from acyclic substrates. A [4 þ 1] cycloaddition reaction of a
conjugated 1,3-p system with isocyanides is a straightforward and attractive method for
the construction of five-membered compounds, such as furan and pyrrole derivatives
(X ¼ O and N, Scheme 1) [1]. Quai et al. reported the reaction of a,b-unsaturated
carbonyl compounds with isocyanides to afford quite unstable furan-2-imines, which
are oxidized quickly by triplet O2 leading to 5-hydroxy-N-substituted-2H-pyrrole-2-
ones [2].
Nair and co-workers described the reaction of in situ generated quinone methides
from 4-hydroxycoumarin with various aldehydes, which underwent reaction with
isocyanides to produce furocoumarins [3].
Scheme 1. [4 þ 1] Cycloaddition Reaction of Conjugated 1,3-p Systems with Isocyanides
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 97 (2014)
Coumarins (2H-1-benzopyran-2-ones) and their annulated derivatives are an
important class of compounds, as they display a wide spectrum of biological activities
[4]. Especially polycyclic coumarin derivatives have been shown to be potent inhibitors
of tumor induction by carcinogenic polycyclic aromatic hydrocarbon [5]. Pyrrolo-
annulated benzopyranones were found to possess promising biological features such as
antitumor activity, reversal of multidrug resistance (MDR), and HIV-1 integrase
inhibition activity [6]. Lamellarins are pyrrolo-annulated benzopyranone alkaloids
isolated from mollusks and ascidians. Of the family of lamellarins, Lam-D is one of the
most potent lead candidates for cancer chemotherapy. There is substantial evidence
that Lam-D is an inhibitor of topoisomerase I and a potent pro-apoptotic agent [7]. In
the light of the significance of pyrrolo-annulated coumarin systems and their diverse
pharmacological properties, there has been a continuous effort to develop new,
convenient, and versatile methods for modification of this class of compounds.
Results and Discussion. – As part of our continuing efforts on the development of
efficient routes for the preparation of biologically active coumarin-based compounds
[8][9], we have now synthesized new benzothiazine-fused pyrrolo[3,4-c]coumarins
using a simple reaction between 3-(dihydrobenzothiazol-2-yl)coumarins and isocya-
nides without using any solvent or catalyst.
Recently, we have studied the synthesis and biological activities of new coumarin
derivatives of type 1 containing the 2-methylbenzothiazole motif. These compounds
were easily prepared in excellent yields using the standard protocol developed in our
laboratory [9].
Considering the ring-opening ability of the dihydrobenzothiazole derivatives 1 and
generation of intermediate A [10], our attention was directed to develop a [4 þ 1]
cycloaddition reaction of this 1,3-conjugated system with isocyanides. As far as we
know, there is no report on the reaction of 3-imino-substituted coumarin with
isocyanides. We initiated our studies with dihydrobenzothiazole 1a, which, upon
treatment with a 1.5 equiv. of cyclohexyl isocyanide 2a, afforded the product 3a in 77%
yield (Scheme 2).
Product 3a was characterized on the basis of its spectroscopic data. The IR spectrum
showed a strong absorption band at 1721 cmꢀ1, which is characteristic for the coumarin
C¼O group. In the 1H-NMR spectrum, the aromatic H-atoms of coumarin and benzene
rings appeared at 7 – 8 ppm and the HꢀN resonated at 4.93 ppm (exchangeable by
D2O) [3]. Also, two CH2 H-atoms of the benzothiazine ring were observed as a singlet
Scheme 2. Synthesis of Densely Functionalized Pyrrole Derivatives 3a

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1
at 4.37 ppm. The H-decoupled 13C-NMR spectrum of 3a exhibited 22 signals. For
example, the CH2 group of the benzothiazine ring which absorbed at 56.5 ppm was
confirmed with DEPT spectra. The mass spectrum of 3a displayed a molecular-ion
peak at m/z 402, and a fragmention peak at m/z 319, indicating the loss of the cyclohexyl
group. Furthermore, an X-ray crystallographic study was carried out on compound 3a,
after recrystallization from MeCN (Fig.).
Several examples of this prototype reaction which confirm the synthetic utility of
this protocol are outlined in the Table.
To explain the formation of the products, we propose a reaction mechanism, which
is outlined in Scheme 3. On the basis of the well-established chemistry of isocyanides
[11], it is reasonable to assume that cycloaddition of the initially generated
intermediate A and isocyanide 2 leads to compound B. The formation of the
benzothiazine scaffold certainly involves a complex multistep sequence of events and
probably proceeds by intramolecular addition of the SH group to alkene. It is
conceivable that compound B can tautomerize under the reaction condition to an
intermediate C. In the next step, the intramolecular addition of SH to the exocyclic
group C¼C results in the formation of compounds D, which is converted to compound
E by tautomerization. Finally, compound 3 can be formed after further tautomerization
and air oxidation and aromatization.
Conclusions. – We have introduced a new and unusual synthetic procedure to
prepare benzothiazine-fused pyrrolo[3,4-c]coumarins involving the ring opening of
coumarin-based dihydrobenzothiazoles and subsequent [4 þ 1] cycloaddition reaction
with isocyanides. The present method offers the advantages that the reaction is
Figure. X-Ray structure of compound 3a with the atom numbering scheme and the intramolecular CꢀH ···
O/N contacts (dashed lines). Displacement ellipsoids are shown at the 50% probability level.

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Table. Synthesis of Benzothiazine-Fused Pyrrolo[3,4-c]coumarins 3a – 3h
Compound
R
R’
Yield [%]a)
3a
3b
3c
3d
3e
3f
3g
3h
H
Cyclohexyl
Cyclohexyl
77
73
74
70
77
67
68
64
6-Br
8-MeO
H
8-MeO
H
Cyclohexyl
tBu
tBu
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
8-MeO
6-Br
a) Yield of isolated product.
Scheme 3. Proposed Mechanism for the Formation of the Title Compounds 3

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performed under neutral conditions and the substances can be mixed under solvent-
free conditions, and without any promoters such as acids, Lewis acids, or transition-
metal complexes. The products are polycyclic molecules of potential synthetic and
pharmacological interest.
This work is funded by the Grant 2011-0014246 of the National Research Foundation of Korea. The
authors thank University of Zanjan, Tehran University of Medical Sciences, and University of Wrocław
for the support and guidance.
Experimental Part
General. IR Spectra: Nicolet FT-IR Magna 550 spectrometer; KBr disks; ˜n in cmꢀ1 1H-NMR
.
Spectra: Bruker 400 or 500 MHz instruments; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
HP 5937, mass selective detector (Agilent technologies); in m/z. Elemental analyses: CHN-Rapid
Heraeus elemental analyzer, the results of elemental analyses (C, H, N) were within ꢁ 0.4% of the
calculated values.
General Procedure. A mixture of 3-(2-methyl-2,3-dihydrobenzo[d]thiazol-2-yl)-2H-chromen-2-ones
1 (2 mmol) and the appropriate isocyanide 2 (3 mmol) was stirred at 1308 for 3 h in a sealed tube. The
mixture was cooled to r.t. and the residue was purified by column chromatography (CC) with hexane/
AcOEt 1:2. The product was recrystallized from hexane/AcOEt 1:1.
14-(Cyclohexylamino)[1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-6(7H)-one (3a).
Red solid. M.p. 217 – 2198. IR: 3332 (NH), 1721 (C¼O). 1H-NMR (CDCl3): 0.90 – 1.03 (m, 5 H);
1.37 – 1.58 (m, 5 H); 2.54 (m, 1 H); 4.37 (s, 2 H); 4.93 (s, 1 H); 7.29 – 7.32 (m, 4 H); 7.42 (t, J ¼ 7.7, 1 H ) ;
7.60 (d, J ¼ 7.7, 1 H); 8.30 (d, J ¼ 7.3, 1 H); 8.46 (d, J ¼ 8.2, 1 H). 13C-NMR (CDCl3): 23.8; 24.1; 25.2; 32.6;
56.5; 100.0; 112.0; 116.7; 117.0; 122.6; 123.5; 124.1; 126.6; 126.7; 127.1; 127.7; 129.4; 129.8; 130.7; 133.8;
150.3; 158.1. ESI-MS: 402 (85, Mþ), 319 (100), 305 (51), 280 (48). Anal. calc. for C24H22N2O2S (402.50): C
71.62, H 5.51, N 6.96; found: C 71.41, H 5.86, N 6.69.
2-Bromo-14-(cyclohexylamino)[1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-6(7H)-
one (3b). Yellow solid. M.p. 222 – 2248. IR: 3328 (NH), 1720 (C¼O). 1H-NMR (CDCl3): 0.87 – 0.97 (m,
5 H); 1.39 – 1.54 (m, 5 H); 2.09 (s, 1 H); 4.36 (s, 2 H); 5.13 (s, 1 H); 7.26 (d, J ¼ 8.5, 1 H); 7.33 (t, J ¼ 7.5,
1 H); 7.44 (t, J ¼ 7.5, 1 H); 7.48 (d, J ¼ 8.5, 1 H); 7.62 (d, J ¼ 7.5, 1 H); 8.42 (d, J ¼ 8.5, 1 H); 8.48 (s, 1 H).
Anal. calc. for C24H21BrN2O2S (481.40): C 59.88, H 4.40, N 5.82; found: C 59.56, H 4.22, N 5.61.
14-(Cyclohexylamino)-4-methoxy[1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-6(7H)-
one (3c). Yellow solid. M.p. 188 – 1908. IR: 3326 (NH), 1723 (C¼O). 1H-NMR (CDCl3): 0.92 – 1.04 (m,
5 H); 1.34 – 1.48 (m, 5 H); 2.48 (m, 1 H); 3.94 (s, 3 H); 4.39 (s, 2 H); 5.01 (s, 1 H); 6.91 (d, J ¼ 7.5, 1 H);
7.23 (t, J ¼ 7.5, 1 H); 7.44 – 7.58 (m, 5 H); 8.44 (d, J ¼ 8.5, 1 H). Anal. calc. for C25H24N2O3S (432.53): C
69.42, H 5.59, N 6.48; found: C 69.21, H 5.80, N 6.69.
14-[(tert-Butyl)amino][1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-6(7H)-one (3d).
1
Yellow solid. M.p. 231 – 2338. IR: 3332 (NH), 1715 (C¼O). H-NMR (CDCl3): 0.81 (s, 9 H); 4.06 (d,
J ¼ 1.5, 1 H); 4.67 (d, J ¼ 1.5, 1 H); 4.80 (s, 1 H); 7.28 – 7.32 (m, 4 H); 7.40 (t, J ¼ 7.6, 1 H); 7.62 (d, J ¼ 7.6,
1 H); 8.36 (d, J ¼ 8.0, 1 H); 8.50 (d, J ¼ 7.6, 1 H). Anal. calc. for C22H20N2O2S (376.47): C 70.19, H 5.35, N
7.44; found: C 70.34, H 5.13, N 7.18.
14-[(tert-Butyl)amino]-4-methoxy[1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-6(7H)-
one (3e). Yellow solid. M.p. 204 – 2068. IR: 3330 (NH), 1722 (C¼O). Anal. calc. for C23H22N2O3S
(406.50): C 67.96, H 5.46, N 6.89; found: C 67.73, H 5.71, N 6.66.
14-[(1,1,3,3-Tetramethylbutyl)amino][1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]benzothiazin-
6(7H)-one (3f). Yellow solid. M.p. 169 – 1718. IR: 3335 (NH), 1720 (C¼O). 1H-NMR (CDCl3): 0.86 (s,
9 H); 0.95 (s, 6 H); 1.40 (s, 2 H); 4.04 (d, J ¼ 1.5, 1 H); 4.62 (s, 1 H); 4.68 (d, J ¼ 1.5, 1 H); 7.29 – 7.33 (m,
4 H); 7.42 (t, J ¼ 7.3, 1 H); 7.62 (d, J ¼ 7.3, 1 H); 8.31 (d, J ¼ 7.8, 1 H); 8.48 (d, J ¼ 7.3, 1 H). 13C-NMR
(CDCl3): 27.2; 28.7; 30.1; 31.5; 55.8; 60.4; 100.1; 114.7; 116.8; 117.3; 123.5; 124.3; 124.5; 126.6; 127.4; 128.5;
128.8; 129.4; 131.5; 134.3; 150.4; 158.2. Anal. calc. for C26H28N2O2S (432.58): C 72.19, H 6.52, N 6.48;
found: C 72.32, H 6.33, N 6.69.

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4-Methoxy-14-[(1,1,3,3-tetramethylbutyl)amino][1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]ben-
zothiazin-6(7H)-one (3g). Yellow solid. M.p. 143 – 1458. IR: 3328 (NH), 1720 (C¼O). Anal. calc. for
C27H30N2O3S (462.60): C 70.10, H 6.54, N 6.06; found: C 70.33, H 6.21, N 6.27.
2-Bromo-14-[(1,1,3,3-tetramethylbutyl)amino][1]benzopyrano[3’,4’:3,4]pyrrolo[2,1-c][1,4]ben-
zothiazin-6(7H)-one (3h). Yellow solid. M.p. 179 – 1818. IR: 3334 (NH), 1718 (C¼O). Anal. calc. for
C26H27BrN2O2S (511.47): C 61.05, H 5.32, N 5.48; found: C 61.29, H 5.09, N 5.26.
X-Ray Crystallography. Yellow-brown single crystals of 3a were obtained from MeCN soln. by slow
evaporation at r.t. over several days. The yellow-brown single crystals were filtered, washed with cold
MeCN, and dried at r.t. (m.p. 2168). Compound 3a: C24H22N2O2S, Mr 402.50; yellow-brown block, crystal
dimensions, 0.40 ꢂ 0.32 ꢂ 0.26 mm3; orthorhombic; space group, Pbca; a ¼ 7.267(2) ꢂ, b ¼ 18.636(4) ꢂ,
c ¼ 28.259(4) ꢂ, V¼ 3827.1(14) ꢂ3, T¼ 100(2) K, Z ¼ 8, 1calc ¼ 11.397 g/cm3, m ¼ 0.19 mmꢀ1 (for MoKa,
l ¼ 0.71073 ꢂ); F(000) ¼ 1696, reflections collected, 28350; reflections independent, 7480 [Rint ¼ 0.022];
reflections observed, 6031 [I > 2s(I)]; q range, 2.62 – 38.468, h, k, l range, ꢀ 10 ꢃ h ꢃ 11, ꢀ 28 ꢃ k ꢃ 26,
ꢀ 39 ꢃ l ꢃ 41, full-matrix least-squares on F2, parameters, 266; restraints, 0; R1 ¼ 0.046, wR2 ¼ 0.115 [F2 >
2s (F2)], GoF ¼ S ¼ 1.09, largest difference in peak and hole, D1max and D1min, 0.54 and ꢀ 0.36 e/ꢂ3; resp.
CCDC-851379 contains supplementary crystallographic data for this article. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif or by e-mailing deposit@ccdc.cam.ac.uk.
The crystallographic measurement was performed on a k-geometry Xcalibur PX four-circle
diffractometer with graphite-monochromatized MoKa radiation (w and f scans). Data were corrected
for Lorentz and polarization effects. Data collection, cell refinement, and data reduction and analysis
were carried out with the Xcalibur PX software, CRYSALIS CCD, and CRYSALIS RED, resp. (Oxford
Diffraction Ltd., Abingdon, England, 2009). Empirical absorption correction was applied to the data
with the use of CRYSALIS RED. The structure was solved by direct methods with the SHELXS-97
program, and refined using SHELXL-97 [12] with anisotropic thermal parameters for non-H-atoms. All
H-atoms were found in difference Fourier maps, and were refined isotropically. In the final refinement
cycles, all C-bonded H-atoms were treated as riding atoms in geometrically optimized positions, with
CꢀH of 0.95 – 1.00 ꢂ, and with Uiso(H) ¼ 1.2Ueq(C). The figure was drawn using DIAMOND program
(ver. 3.0d, K. Brandenburg, Crystal Impact GbR, Bonn, Germany, 2005).
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Received August 7, 2013