A novel domino condensation-intramolecular nucleophilic cyclization approach towards annulated thiochromenes

Article abstract of DOI:10.1016/j.tetlet.2013.07.040

A one-pot protocol towards previously unreported derivatives of thiochromeno [2′,3′:4,5] imidazo[2,1-a]isoquinoline via a domino reaction of isoquinoline-derived iminium salts and α-mercapto benzaldehydes is elaborated.

Full text of DOI:10.1016/j.tetlet.2013.07.040

Tetrahedron Letters 54 (2013) 5172–5173
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Tetrahedron Letters
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A novel domino condensation–intramolecular nucleophilic
cyclization approach towards annulated thiochromenes
⇑
Leonid G. Voskressensky , Ekaterina A. Sokolova, Alexey A. Festa, Alexey V. Varlamov
Organic Chemistry Department of the Peoples’ Friendship University of Russia, 6, Miklukho-Maklaya St., Moscow 117198, Russia
a r t i c l e i n f o
a b s t r a c t
A one-pot protocol towards previously unreported derivatives of thiochromeno [20,30:4,5] imidazo[2,1-
Article history:
Received 13 May 2013
Revised 22 June 2013
Accepted 5 July 2013
Available online 15 July 2013
a]isoquinoline via a domino reaction of isoquinoline-derived iminium salts and
hydes is elaborated.
a-mercapto benzalde-
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Domino-reaction
Thiochromene
ortho-Mercaptobenzaldehyde
Condensation
Imidazoquinoline
Critical objectives in modern organic chemistry and drug dis-
covery are the improvement of efficiency, avoidance of toxic re-
agents, reduction of waste and the responsible treatment of
resources.1 Domino reactions have emerged as a powerful tool
for the effective creation and expansion of molecular diversity.2
Carbon–carbon and carbon–heteroatom bond-forming reactions
are crucial to organic synthesis. Domino processes are important
for generating high levels of diversity and complexity giving rise
to complex structures by simultaneous formation of two or more
bonds from simple substrates. These advantages are of particular
interest in pharmaceutical research for the construction of libraries
of biologically active compounds. Thus, developing new, environ-
mentally benign domino reactions is an important topic of green
chemistry.3
We recently reported a new domino pathway towards previ-
ously unknown chromeno [20,30:4,5] imidazo[2,1-a]isoquinolines
B based on the reaction of isoquinoline derived cycloiminium salts
A with salicylic aldehydes (Scheme 1).4
Herein, we present a novel reaction which provides an easy
access towards functionalized thiochromeno [20,30:4,5] imi-
dazo[2,1-a]isoquinoline derivatives, which, to the best of our
knowledge have not been described. Thiochromene derivatives
and their fused analogues are of interest because they represent
an important class of heterocycles, many of which exhibit useful
biological activities, and some have been tested and applied as
drugs.5To our disappointment the ortho-mercaptobenzaldehydes
1, prerequisite for the present study, were not commercially avail-
able and we had to plan their synthesis. A careful literature search6
revealed, that the only procedure compatible with the presence of
NO2 and Br substituents in 1 is that involving nucleophilic dis-
placement of an ortho-halogen atom in the corresponding benzal-
dehyde as described earlier.7 The choice of the substituents is
R
H
OH
Na2CO3
O
+
N
MeOH-H2O
Cl
R
A
N
N
N
O
B
(3-76%)
Scheme 1. Previously reported domino reaction of salicylic aldehyde.
O
O
1) Na2S, DMF
Ar, rt, 1 h
SH
F
2) H3O+
R
R
1a
R=NO2, 60%
1b R=Br, 80%
⇑
Corresponding author. Tel.: +7 495 955 07 57; fax: +7 495 955 07 79.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
Scheme 2. Preparation of thiosalicylic aldehydes.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.040

L. G. Voskressensky et al. / Tetrahedron Letters 54 (2013) 5172–5173
5173
R4
washed with MeOH and dried in air to yield compounds 2 (Scheme
3).8 The structures of compounds 2 were determined similar to
compounds B: the 1H spectra of the following compounds are char-
acterized by a singlet signal of the methylene group at 4.49–
5.08 ppm and an absence of the C-1 proton of the isoquinoline ring.
The mass spectra of the compounds 2 confirmed the presence of a
sulfur atom. The structures are also confirmed by the data of 13C, IR
spectra and elemental analysis.
We presume that compound 2 is the product of an anionic dom-
ino-reaction, starting with condensation of thiosalicylic aldehyde
and isoquinolinium salt A to produce the styryl derivative C. The
base-catalysed deprotonation of the thiophenol SH yields zwitter-
ion D. This then undergoes two consecutive nucleophilic cycliza-
tions, followed by a [1,4] proton shift to yield the pentacycle 2
(Scheme 4).
R3
O
R2
SH
20 mol% Na2CO3
MeOH-H2O-THF
N+ R1
reflux, 1 h
R
Cl-
1a,b
N
R3 R2
A
R4
R1
N
N
R
S
1
2
3
4
2a
2b
2c
2d
2e
R=NO2, R =H, R =H, R =H, R =H; 66%
R=NO2, R =H, R =H, R =H, R =OH; 29%
R=NO2, R =H, R =H, R =OH, R =H; 22%
R=NO2, R =Me, R =H, R =H, R =H; 21%
Although the yields of the polycyclic thiochromenes were mod-
erate, the simplicity of the procedure and the molecular complex-
ity gained make this reaction very attractive. Further studies aimed
at the optimization of the reaction conditions as well as at explor-
ing the scope and limitations of this procedure are underway and
will be reported in due course.
1
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
R=Br, R =H, R =H, R =H, R =OH; 30%
Scheme 3. The reaction of isoquinolinium salts with thiosalicylic aldehydes.
Product 2e was obtained without the addition of THF.
Acknowledgment
R3 R2
Financial support of the Russian Foundation for Basic Research
(Grant # 12-03-93000-Viet_a) is gratefully acknowledged.
R4
R1
Cl
SH
+
A
N
R
O
Supplementary data
C
S
H
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
040.
R
R4
R4
OH
R3
R3
H2O
R2
R1
R2
References and notes
R1
N
S
D
N
1. Schreiber, S. L. Science 2000, 287, 1964–1969.
2. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Tietze, L. F.; Brasche, G.;
Gericke, K. Domino Reactions in Organic Synthesis; Wiley–VCH: Weinheim, 2006.
pp. 160–185.
N
N
S
3. (a) Barry, B. T.; Dennis, G. H. Chem. Rev. 2009, 109, 4439–4486; (b) Candeias, N.
R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M. P. Eur. J. Org. Chem. 2009, 1859–1863.
4. (a) Voskressensky, L. G.; Festa, A. A.; Sokolova, E. A.; Varlamov, A. V. Tetrahedron
2012, 68, 5498–5504; (b) Safarov, S.; Voskressensky, L. G.; Bizhko, O. V.;
Kulikova, L. N.; Khrustalev, V. N. Acta Crystallogr. 2010, E-66, 710.
5. (a) Geissler, J. F.; Roesel, J. L.; Meyer, T.; Trinks, U. P.; Traxler, P.; Lydon, N. B.
Cancer Res. 1992, 52, 4492–4498; (b) Nakazumi, H.; Ueyama, T.; Kitao, T. J.
Heterocycl. Chem. 1984, 21, 193–196; (c) Wang, H.; Bastow, K. F.; Cosentino, L.
M.; Lee, K. J. Med. Chem. 1996, 39, 1975–1980; (d) Holshouser, M. H.; Loeffler, L.
J.; Hall, I. H. J. Med. Chem. 1981, 24, 853–858; (e) Brown, M. J.; Carter, P. S.;
Fenwick, A. E.; Fosberry, A. P.; Hamprecht, D. W.; Hibbs, M. J.; Jarvest, R. L.;
Mensah, L.; Milner, P. H.; O’Hanlon, P. J.; Pope, A. J.; Richardson, C. M.; West, A.;
Witty, D. R. Bioorg. Med. Chem. Lett. 2002, 12, 3171.
6. For a survey of synthetic approaches towards thiosalicylic aldehydes, see: Niu,
Q.; Xu, X.; Sun, H.; Li, X. Chin. J. Chem. 2012, 30, 2495–2500. and references
therein.
7. (a) Korobov, M. S.; Minkin, V. I.; Nivorozhkin, L. E. J. Org. Chem. USSR 1975, 11,
826–831; (b) Reinhard, E.J., Kolodziej, S.A., Anderson, D.R., Stehle, N.W., Vernier,
W.F., Lee L.F., Hegde, S.G. U.S. Patent, 2004/0127, 519.
R
R
R4
R3
R4
H
R2
R3
R2
R1
R1
N
[1,4]-shift
N
N
S
S
N
2
R
R
Scheme 4. A mechanistic proposal for the domino process.
8. 10-Nitro-8H-thiochromeno [20,30:4,5] imidazo[2,1-a]isoquinoline (2a). Yield
220 mg (66%), yellow solid, mp 268–269 °C (dec); 1H NMR (400 MHz,
CDCl3 + CF3CO2H): d = 4.68 (s, 2H, H-8), 7.56 (d, J = 8.9 Hz, 1H, H-12), 7.83 (d,
J = 6.9 Hz, 1H, H-5), 7.95–7.97 (m, 1H, H-2), 8.00–8.02 (m, 1H, H-3), 8.09–8.12
(m, 2H, H-6, H-1), 8.19 (dd, J = 8.9, 2.1 Hz, 1H, H-11) 8.35 (s, 1H, H-9), 8.45 (d,
J = 8.3 Hz, 1H, H-4); 13C NMR (100 MHz, CDCl3 + CF3CO2H): d = 25.8, 100.0,
116.3, 116.9, 118.9, 119.3, 122.8, 123.3, 123.4, 125.2, 126.0, 128.6, 128.8, 131.5,
133.6, 135.4, 139.2, 146.9; IR (KBr) 1517, 1335 cmꢀ1; EI MS: m/z (%) = 334 (12),
333 (100) [M]+, 287 (22), 286 (46), 143 (12), 129 (11), 128 (22), 71 (12), 43 (17),
42 (11); C18H11N3O2S (333.36): Calcd C, 64.85, H, 3.33, N, 12.60; found C, 64.72,
H, 3.45, N, 12.53.
determined by the possibility of further modification of the target
molecules by cross- and aza-coupling reactions.
The targets 1a and 1b were obtained in 60% and 80% yields as
judged by LC–MS analysis and were used without any further puri-
fication due to their instability (Scheme 2).
In a typical experiment the isoquinolinium salt (1 mmol),
20 mol % of sodium carbonate and 1.2 mmol of thiosalicylic
aldehyde in a mixture of MeOH–H2O–THF were stirred vigorously
under reflux for 1 h. The resulting precipitate was filtered off,