Rapid access to pyrimido[5,4-c]isoquinolines via a sulfur monoxide extrusion reaction

Article abstract of DOI:10.1021/ol0627146

The scope of a sulfur monoxide extrusion reaction of pyrimido[4,5-b][1,4] benzothiazepines leading to pyrimido[5,4-c]isoquinolines was investigated. Thus, selective oxidation followed by nucleophilic displacement of the oxidized side chain sulfur group an

Full text of DOI:10.1021/ol0627146

ORGANIC
LETTERS
2007
Vol. 9, No. 4
571-574
Rapid Access to
Pyrimido[5,4-c]isoquinolines via a Sulfur
Monoxide Extrusion Reaction
Renzhong Fu, Xianxiu Xu, Qun Dang, Feng Chen, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, Jilin UniVersity,
75 Haiwai Street, Changchun, Jilin 130012, PRC
xbai@jlu.edu.cn
Received November 6, 2006
ABSTRACT
The scope of a sulfur monoxide extrusion reaction of pyrimido[4,5-b][1,4]benzothiazepines leading to pyrimido[5,4-c]isoquinolines was investigated.
Thus, selective oxidation followed by nucleophilic displacement of the oxidized side chain sulfur group and subsequent extrusion reaction of
sulfur monoxide in the ring, which can be conducted in a two-step sequence or in a one-pot procedure, produced novel pyrimido[5,4-c]-
isoquinolines, a class of compounds with potential biological and pharmaceutical applications.
Isoquinoline derivatives are well-known to exhibit diverse
biological activities.1 Consequently, there is a continuing
interest in developing efficient methodologies to access
pyrimidine-fused heterocyclic scaffolds both by our labora-
tory2 and by others. 3 Previously, we reported that arylthio-
pyrimido[4,5-b][1,4]benzothiazepines 2 could be prepared
from a simple pyrimidine building block 1 via Bischler-
Napieralski-like reactions (Scheme 1).2e To expand the scope
of applications, it is envisioned that pyrimido[5,4-c]isoquino-
lines 5 should be readily accessible from benzothiazepines
2 following a synthetic strategy outlined in Scheme 2. This
new strategy entails the selective oxidation of the aryl sulfide
substituent in 4-arylthiopyrimido[4,5-b][1,4]benzothiazepines
2 to its corresponding sulfone, whereas the ring sulfur is
oxidized to the sulfoxide. This is then followed by a one-
pot transformation to the final pyrimido[5,4-c]isoquinoline
derivatives 5 via displacement of the newly oxidized side
chain sulfur with various nucleophiles and sulfoxide extru-
sion to contract the central ring. This strategy complements
a previous report on the preparation of pyrimido[5,4-c]-
isoquinolines via sulfur monoxide extrusion of 4-aminopy-
* Phone: +86-431-85188955. Fax: +86-431-85188900.
(1) (a) Jayaraman, M.; Fox, B. M.; Hollingshead, M.; Kohlhagen, G.;
Pommier, Y.; Cushman, M. J. Med. Chem. 2002, 45, 242-249. (b)
Goldberg, D. R.; Butz, T.; Cardozo, M. G.; Eckner, R. J.; Hammach, A.;
Huang, J.; Jakes, S.; Kapadia, S.; Kashem, M.; Lukas, S.; Morwick, T. M.;
Panzenbeck, M.; Patel, U.; Pav, S.; Peet, G. W.; Peterson, J. D.;
Prokopowicz, A. S., III; Snow, R. J.; Sellati, R.; Takahashi, H.; Tan, J.;
Tschantz, M. A.; Wang, X.-J.; Wang, Y.; Wolak, J.; Xiong, P.; Moss, N.
J. Med. Chem. 2003, 46, 1337-1349. (c) Griffin, R. J.; Fontana, G.; Golding,
B. T.; Guiard, S.; Hardcastle, I. R.; Leahy, J. J. J.; Martin, N.; Richardson,
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569-585. (d) Goldbrunner, M.; Loidl, G.; Polossek, T.; Mannschreck, A.;
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Scheme 1. Synthesis of Pyrimido[4,5-b][1,4]benzothiazepines
(2) (a) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem.
2006, 8, 381-387. (b) Che, X.; Zheng, L.; Dang, Q.; Bai, X. Tetrahedron
2006, 62, 2563-2568. (c) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X.
J. Comb. Chem. 2005, 7, 813-815. (d) Yang, J.; Che, X.; Dang, Q.; Wei,
Z.; Gao, S.; Bai, X. Org. Lett. 2005, 7, 1541-1543. (e) Fu, R.; Xu, X.;
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10.1021/ol0627146 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/20/2007

Scheme 2. Strategy to Access Pyrimido[5,4-c]isoquinolines
Scheme 3. Sequential Selective Oxidation of
Pyrimido[4,5-b][1,4]benzothiazepines 2 by m-CPBA
rimidothiazepines.4 It is recognized that the scope of this
sulfur monoxide extrusion reaction was not fully explored,
especially with regard to a one-pot variation of the reaction.
Sulfur extrusion reactions are often reported for organic
sulfides, sulfoxides, and sulfones, and only a few complex
molecules were prepared through their applications.5 On the
other hand, direct extrusions of sulfur monoxide6 are less
common, compared to the well-documented extrusion reac-
tions of sulfide and sulfur dioxide.7 Herein, we report the
details of our investigation on the scope of the nucleophilic
aromatic substitution-sulfur monoxide extrusion approach
to pyrimido[5,4-c]isoquinolines outlined in Scheme 2.
The existence of two sulfur atoms in compounds 2 presents
a challenge for selective or sequential oxidation of the
4-sulfide group and the ring sulfur atom. Previously, we
demonstrated that the arylsulfide group in 4-phenylthiopy-
rimido[4,5-b][1,4]benzothiazepine 2 could be selectively
oxidized to its corresponding sulfoxide 6 (Scheme 3) in good
yield.2e To explore the feasibility of sequential selective
oxidation, various oxidation conditions were applied to 2.1
(R1 ) R2 ) H) as outlined in Scheme 3. Compound 2.1
could be selectively converted to 6, 7, 8, 3.1, and 9 by
controlling the stoichiometry of m-CPBA and the reaction
temperature. Treatment of compound 2.1 with 1.2 equiv of
m-CPBA at 0 °C provided the side chain sulfoxide 6 in 77%
yield. Increasing m-CPBA to 2.2 equiv and elevating the
reaction temperature to ambient gave a mixture of two
compounds (7 and 8) which could not be separated via flash
column chromatography. Further increase of m-CPBA to 3.6
equiv at room temperature resulted in sulfone-sulfoxide 3.1
in 60% isolated yield. Sulfone-sulfone product 9 could be
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572
Org. Lett., Vol. 9, No. 4, 2007

obtained in high yield by employment of a large excess (9
equiv) of m-CPBA The conditions identified for the selective
conversion of 2.1 to 3.1 were applied to other substrates
(2.2-2.7) and gave the corresponding sulfone-sulfoxides
3.2-3.7 in good yields (Table 1).
because several examples were reported for the conversion
of benzothiazepines to quinolines most likely via the well-
known Eschenmoser sulfur extrusion reaction mechanism.5a,8
Under thermal conditions (such as prolonged refluxing in
toluene or xylene), no sulfur extrusion was observed for
sulfide 10. Addition of triphenylphosphine was shown to
promote the Eschenmoser sulfur extrusion reactions,5g,8 but
it did not help the sulfur extrusion in 10. Next, the sulfoxide
4.1 was subjected to the thermal sulfur extrusion reaction
conditions (refluxing in toluene), and to our delight, it was
smoothly converted to the desired pyrimidoquinoline 5.1 in
excellent yield (entry 1, Table 2). This thermal sulfur
Table 1. Conversion of Compounds 2 to 3
entry
2
R1
R2
3
yield (%)
1
2
3
4
5
6
7
2.1
2.2
2.3
2.4
2.5
2.6
2.7
H
Me
Cl
MeO
H
H
H
H
H
H
Me
F
Me
3.1
3.2
3.3
3.4
3.5
3.6
3.7
60
55
55
53
59
52
55
Table 2. Stepwise Preparation of
Pyrimido[4,5-b][1,4]benzothiazepines from Sulfoxide 3
Me
entry
3
R1
R2
4a
yield (%)
5b
yield (%)
The introduction of a sulfoxide or a sulfone substituent at
the 4-position in compounds 3, 6, and 9 enables the
introduction of various nucleophiles in the final scaffold of
pyrimido[5,4-c]isoquinoline thus providing a diversification
point. To test the feasibility of sequential displacement of
the oxidized side chain sulfur followed by sulfur extrusion
to form the desired pyrimidoisoquinoline skeleton, n-butyl
amine was selected as the nucleophile. Both side chain
sulfoxide and sulfones in compounds 3, 6, and 9 could be
replaced by n-butylamine to give desired products 4, 10, and
11 in excellent yields when the substrate was treated with 3
equiv of n-butylamine in methylene chloride at room
temperature (Scheme 4). With substrates 4, 10, and 11 in
1
2
3
4
5
6
3.1
3.2
3.3
3.4
3.5
3.6
H
Me
Cl
MeO
H
H
H
H
H
H
Me
F
4.1
4.2
4.3
4.4
4.5
4.6
90
85
80
80
88
92
5.1
5.2
5.3
5.4
5.5
5.6
94
92
80
82
90
90c
a Reactions were conducted in CH2Cl2 with 3 equiv of n-BuNH2 at room
temperature. bReactions were conducted in refluxing toluene under nitrogen
c
for 0.3 h unless otherwise noted. Reaction was run for 24 h.
monoxide extrusion condition was applied to other sulfoxides
4.2-4.6 and produced pyrimidoquinolines 5.2-5.6 in excel-
lent yields (Table 2). The extrusion of sulfur monoxide was
surprisingly facile. For example, sulfoxide 4.1 underwent
extrusion even at room temperature, albeit at a slower rate.
A solution of 4.1 in chloroform standing at room temperature
after 2 days generated about 50% of 5.1. Encouraged by the
successful extrusion reactions of 4.1-4.6, sulfone 11 was
subjected to the same reaction conditions, but like sulfide
10, it also proved to be unsuitable for the extrusion reaction
even after prolonged heating (Scheme 4).
Scheme 4. Exploration of Stepwise Nucleophilic
Substitution-Sulfur Extrusion Reactions
It is logical to explore a one-pot procedure by combining
the nucleophilic replacement and sulfoxide extrusion because
one-pot procedures are often developed for efficient synthesis
of various heterocycles.9 When substrate 3 was subjected to
an excess (3 equiv) of the corresponding nucleophiles in
refluxing toluene, the desired substituted pyrimidoisoquino-
lines 5 were obtained. As demonstrated by the results in
Table 3, all the employed amines (NH3, primary and
secondary amines, even those with demanding steric proper-
ties) worked quite well in this one-pot procedure to give the
desired heterocycles. The reaction proceeded faster, and
yields were even higher when strong nucleophiles were used
(8) (a) Sakurai, O.; Ogiku, T.; Takahashi, M.; Hayashi, M.; Yamanaha,
T.; Horikawa, H.; Iwasaki, T. J. Org. Chem. 1996, 61, 7889-7894. (b)
Mitchell, R. H. Tetrahedron Lett. 1973, 14, 4395-4398. (c) Lee, H. K.;
Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173-2174.
(9) (a) Xie, F.; Cheng, G.; Hu, Y. J. Comb. Chem. 2006, 8, 286-288.
(b) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org.
Chem. 2006, 71, 3634-3635. (c) Georgiou, T.; Tofi, M.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2006, 8, 1945-1948. (d) Koeller, K. M.;
Wong, C.-H. Chem. ReV. 2000, 100, 4465-4493.
hand, the sulfur extrusion reactions were explored (Scheme
4). First, the sulfide extrusion reaction of 10 was investigated
Org. Lett., Vol. 9, No. 4, 2007
573

(entries 4, 14, and 25, Table 3). Although other weak
nucleophiles were also used to test the scope of the reaction,
such as phenylmethanethiol (entries 7, 8, 26, and 27, Table
3) or butan-1-ol (entries 9 and 10, Table 3), the reactions
were more difficult. In these cases, pyridine has been added
as the base catalyst to promote the nucleophilic substitution.
Therefore, other alkoxides and sulfides could be assumed
to give the expected pyrimidoisoquinoline analogues under
the same conditions.
Table 3. One-Pot Preparation of Pyrimido[5,4-c]isoquinolinesa
In summary, an efficient strategy for the conversion of
4-arylthiopyrimido[4,5-b][1,4]benzothiazepines to pyrimido-
[5,4-c]isoquinoline derivatives was demonstrated. Keys to
this synthesis of pyrimido[5,4-c]isoquinolines are selective
oxidation of the two sulfur atoms present in 4-arylthiopy-
rimido[4,5-b][1,4]benzothiazepines and one-pot conversion
of selective displacements of the 4-arylsulfonyl groups and
a sulfur monoxide extrusion reaction. This synthetic strategy
expands the scope of 4-arylthiopyrimido[4,5-b][1,4]benzo-
thiazepines to access novel heterocyclic scaffolds of py-
rimido[5,4-c]isoquinoline. Moreover, various nucleophiles
were readily introduced via the displacement of the 4-aryl-
sulfonyl groups thereby generating additional structural
diversification. It is demonstrated herein that this new
strategy provides a convenient methodology to access these
biologically interesting scaffolds of pyrimido[5,4-c]isoquino-
lines with high structural diversity.
entry
5
R1
R2
nucleophile
time (h) yield (%)
1
2
3
4
5
6
7
8
9
5.1
5.7
5.8
5.9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
n-BuNH
BnNH
i-PrNH
PhNH
NH2
pyrrolidin-1-yl
BnS
BnS
n-BuO
n-BuO
n-BuNH
BnNH
i-PrNH
PhNH
pyrrolidin-1-yl
n-BuNH
i-PrNH
NH2
n-BuNH
BnNH
i-PrNH
pyrrolidin-1-yl
0.3
0.3
0.3
3
0.3
0.3
4
94
93
90
55
80b
82
27
66c
0
H
H
H
H
H
H
H
H
H
Me
5.10
5.11
5.12
5.12
5.13
5.13
5.2
5.14 Me
5.15 Me
5.16 Me
5.17 Me
3.5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4
21d
93
90
88
60
83
89
83
93b
91
92
85
88
92
88
68
32
69c
0.3
0.3
0.3
4
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
4
5.3
5.18 Cl
5.19 Cl
Cl
5.4
MeO
5.20 MeO
5.21 MeO
5.22 MeO
5.23 Me
5.24 Me
5.25 Me
5.26 Me
5.26 Me
Acknowledgment. This work was supported by grants
(#20572032 and #20232020) from the National Natural
Science Foundation of China and Changchun Discovery
Sciences, Ltd. We must thank a reviewer of Organic Letters
who made valuable suggestions in our last submission.
Me BnNH
Me i-PrNH
Me PhNH
Me BnS
5
4
Me BnS
a Reactions were conducted in refluxing toluene with 3 equiv of
Supporting Information Available: Experimental details
nucleophiles under nitrogen. bAmmonia saturated methanol was utilized.
1
and H and 13C NMR and LC-MS-ELSD spectra for key
c20 equiv of pyridine was used as the base. Reactions were conducted in
d
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
refluxing butan-1-ol with 20 equiv of pyridine as the base.
(entries 1-3, 5, 6, 11-13, and 15-24, Table 3) compared
to weak nucleophiles such as, for example, aromatic amines
OL0627146
574
Org. Lett., Vol. 9, No. 4, 2007