Synthesis of sulfur heterocycles via domino metal-mediated reactions

Article abstract of DOI:10.1080/10426507.2016.1255621

Two methodologies to access S-heterocycles and mixed N,S-heterocycles via metal-mediated domino reactions are described. One involves a cyclocarbopalladation/cross-coupling domino process and leads to benzene-fused five- or six-membered sulfur heterocycles with a stereo defined tetrasubstituted exocyclic double bond. The other consists in a three-component domino reaction between 2-aminophenyl disulfide, copper cyanide, and an electrophile to access N-substituted 2-amino benzothiazoles. Preliminary results in the use of the second method to access N-substituted 2-imino benzothiazoles are also reported.

Full text of DOI:10.1080/10426507.2016.1255621

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Synthesis of Sulfur Heterocycles via Domino Metal-Mediated Reactions
Thomas Castanheiro, Jean Suffert, Morgan Donnard,* and Mihaela Gulea*
Laboratoire d’Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Faculté
de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France
Address correspondence to Morgan Donnard or Mihaela Gulea, Laboratoire d’Innovation
Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du
Rhin, 67401 Illkirch Cedex, France. Email: donnard@unistra.fr, gulea@unistra.fr
Abstract
Two methodologies to access S-heterocycles and mixed N,S-heterocycles via metal-mediated
domino reactions are described. One involves a cyclocarbopalladation / cross-coupling domino
process and leads to benzene-fused five- or six-membered sulfur heterocycles with a
stereodefined tetrasubstituted exocyclic double bond. The other consists in a three-component
domino reaction between 2-aminophenyl disulfide, copper cyanide, and an electrophile to access
N-substituted 2-amino benzothiazoles. Preliminary results in the use of the second method to
access N-substituted 2-imino benzothiazoles are also reported.
GRAPHICAL ABSTRACT
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Keywords
Sulfur heterocycles; domino reactions; palladium catalysis; copper-mediated reaction; sulfides,
thiocyanates
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INTRODUCTION
Domino reactions involving transition metal catalysts or reagents represent a powerful tool in
the synthesis of heterocyclic molecules. They provide a step-economic access to complex
molecules from simple starting materials.1 The impact of S-heterocyclic compounds in
pharmaceutical industry is significant,2 therefore the search for efficient diversity-oriented
syntheses to provide this type of compounds represents a topical subject.
One of the objectives of our laboratory is to develop new efficient syntheses of small and
medium sulfur heterocycles based on metal-mediated domino reactions, starting from readily
accessible pre-organized sulfur-containing substrates. This communication summarizes our
recent results in this topic. We have developed two types of metal-mediated domino processes
for the synthesis of S- or mixed N,S-heterocycles from simple acyclic substrates containing a
sulfur function. The first one involves a palladium-catalyzed reactions in sulfides series and the
second one a copper-mediated S-cyanation of 2-amino-benzene disulfide.
RESULTS AND DISCUSSION
Synthesis of S-heterocycles via Pd-catalyzed domino reactions
Original benzene-fused 5- or 6-membered S-heterocycles 2-12 bearing a stereodefined
tetrasubstituted exocyclic double bond have been obtained via the cyclocarbopalladation/cross-
coupling (Stille or Suzuki-Miyaura) domino reaction starting from propargyl sulfides 1a-d or
ynethioethers 1e (Scheme 1, Table 1).3 The different precursors 1a-d have been reacted in the
presence of Pd(PPh3)4 catalyst with 2-furyl, 2-thienyl, allyl, and vinyl tributylstannanes as Stille
coupling partners, and led to the desired products 2a-e, 3a, 4a, and 5a, respectively (Table 1,
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entries 1-8). The yields were moderate due in particular to the difficulty in the product isolation
using stannanes. Cyclocarbopalladation/Suzuki-Miyaura cascade reaction was then investigated.
By using electron-rich or electron-poor arylboronic acids, as well as vinyl, allyl, and cyclopropyl
derivatives as coupling partners, the reaction worked well, and sulfur heterocycles 3b-e and 4d-
12d have been obtained in good yields (Table 1, entries 9-21).
To illustrate the interest of our method for the synthesis of biologically active molecules,
we have decided to prepare compound 13 as a potential selective estrogen-receptor modulator
(SERM), due to its structural similitudes with the anticancer agent Tamoxifen (Scheme 2). Two
routes have been attempted starting from S-(2-bromo-5-methoxybenzyl) thioacetate: route 1
involved the transformation of OMe into OH group (12e into 12f) after the domino reaction, but
the desired product 12f was isomerized into isothiochromene 12f’ under the acidic conditions
due to the use of BBr3; route 2 consisted in a three-steps sequence (OMe into OH
transformation, S-alkylation, and O-alkylation) to obtain the appropriate precursor for the Pd-
catalyzed cyclization/Suzuki domino process. Targeted product 13 was thus obtained in 42%
overall yield.
Synthesis of N,S-heterocycles via Cu-mediated domino reactions involving thiocyanates
Diversely N-substituted 2-amino-benzothiazole derivatives have been synthesized via a
domino sequence involving an oxidative copper-mediated S-cyanation of 2-amino-benzene
disulfides 14 as the key-step. First we developed an efficient access to aromatic thiocyanates by
using copper cyanide (CuCN) as the cyanating agent of thiols/disulfides.4,5 We then integrated
this transformation in a domino three-component process involving aromatic disulfides bearing
an amino group at the ortho position.6 The reactions have been performed between a 2,2′-
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diaminodiphenyl disulfide 14a-c, CuCN, and an electrophile, under air, in acetonitrile, and with
the use of TMEDA as the copper ligand (Scheme 3, Table 2). Aromatic and aliphatic acyl
chlorides (Table 2, entries 1-13), Boc anhydride, menthyl chloroformate, and phenyl isocyanate
(entries 14-17) have been successfully used as electrophiles to access variously N-substituted 2-
amino-benzothiazoles 15-28.
We proposed two mechanisms to describe this domino process: one consisted in S-cyanation by
CuCN at first, then cyclization via nitrogen nucleophilic attack of the thiocyanate carbon, and
final N-acylation of the exocyclic nitrogen, and the second consisted at first in the N-acylation of
the 2-aminoaryl disulfide, then S-cyanation followed by cyclization, and finally an acyl transfer
from the endocyclic nitrogen to the exocyclic nitrogen. Several experiments6 let us conclude that
the transformation takes place via the second mechanism and that the final nitrogen-to-nitrogen
acyl transfer is intermolecular (Scheme 4).
To extend the synthetic applicability of our method we also have envisioned to access 2-
imino derivatives by using N-protected 2-aminoaryl disulfides as precursors (Scheme 5). When
reacting N-benzoyl starting substrate 29 with copper cyanide and 2,5-difluorobenzoyl chloride,
only the N,N-diacylated disulfide 30 was obtained (Scheme 6). On the other hand, when the N-
tosylated substrate 31 was used in reaction with CuCN and benzoyl chloride, the domino process
led to a mixture of products. Among them, the desired (N-tosyl-benzothiazol-ylidene)benzamide
32 was isolated in low yield (25%), as well as a little amount of ditosylated 2-
iminobenzothiazole 33 (Scheme 6). It is worth noting that when substrate 31 was placed under
standard reaction conditions (CuCN/TMEDA) in the absence of an electrophile, product 33 was
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obtained in mixture with 2-amino benzothiazole 34 and isolated in 23% yield. The structures of
the obtained compounds 30, 32 and 33 have been confirmed by X-ray analysis (Scheme 6).
CONCLUSIONS
In conclusion, we developed two methodologies to synthesize S-heterocycles and mixed
N,S-heterocycles via metal-mediated domino reactions: one involves a cyclocarbopalladation/
cross-coupling domino process and leads to benzene-fused five- or six-membered sulfur
heterocycles (benzothiolanes and isothiochromanes) with a stereodefined tetrasubstituted
exocyclic double bond; the other consists in a three-component domino reaction between 2-
amino phenyl disulfide, copper cyanide, and an electrophile to access N-substituted 2-amino or
2-imino benzothiazoles. Current studies are focused on exploiting these methods to access more
complex, highly functionalized sulfur heterocycles, with potential biological properties.
This project was supported by the University of Strasbourg (IDEX grant for T.C.) and the Centre
National de la Recherche Scientifique (CNRS). We thank Dr. Lydia Karmazin (analytical
department of the University of Strasbourg) for X-ray analyses.
ACKNOWLEDGMENTS
This project was supported by the University of Strasbourg (IDEX grant for T.C.) and the Centre
National de la Recherche Scientifique (CNRS). We thank Dr. Lydia Karmazin (analytical
department of the University of Strasbourg) for X-ray analyses.
Supplemental Materials
Crystallographic data for the structural analysis of compounds 23a, 30, 32, and 33 have been
deposited at the Cambridge Crystallographic Data Center. Summary of Data CCDC 1486722
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(product 32), Formula: C21H16N2O3S2, Unit Cell Parameters: a 8.1931(4) b 17.0832(7) c
13.8481(6) P21/c; Summary of Data CCDC 1486723 (product 30), Formula: C40H24F4N2O4S2,
Unit Cell Parameters: a 10.6893(10) b 11.2057(10) c 15.9469(15) P-1; Summary of Data CCDC
1486724 (product 23a), Formula: C11H12N2O1S1, Unit Cell Parameters: a 22.535(3) b 8.1096(11)
c 24.573(3) Pbca; Summary of Data CCDC 1486725 (product 33), Formula: C21H18N2O4S3, Unit
Cell Parameters: a 7.8455(4) b 8.0210(4) c 33.0465(15) P21/c.
Copies of the information may be obtained free of charge from The Director, CCDC, 12 Union
Road, Cambridge CB2 1 EZ, UK (Fax: + 44-1223-336033; email: deposit@ccdc.cam.ac.uk or
www.ccdc.can.ac.uk).
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REFERENCES
1. For recent reviews on this topic, see: (a) Liao, Q.; Yang, X.; Xi, C. J. Org. Chem., 2014, 79,
8507-8515; (b) Michelet, V. Top. Curr. Chem., 2015, 357, 95-132; (c) de Meijere, Armin;
von Zezschwitz, P.; Brase, S. Acc. Chem. Res., 2005, 38, 413-422; (d) Vlaar, T.; Ruijter, E.;
Orru, R. V. A. Adv. Synth. Catal., 2011, , 8 9 8 e hinchilla, Naj ra, C. Chem.
Rev. 2014, , 78 826 f) Ohno, H. Asian J. Org. Chem. 2013, 2, 8 28 (g) Ball, C. J.;
Willis, M. C. Eur. J. Org. Chem. 2013, 2
2. Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem., 2014, 57, 2832-2842.
3. Castanheiro, T.; Donnard, M.; Gulea, M.; Suffert, J. Org. Lett., 2014, 16, 3060-3063.
4. Castanheiro, T.; Gulea, M.; Donnard, M.; Suffert, J. Eur. J. Org. Chem., 2014, 2014, 7814-
7817.
5. Castanheiro, T., Suffert, J., Donnard, M., Gulea, M. Chem. Soc. Rev., 2016, 45, 494-505.
6. Castanheiro, T.; Suffert, J.; Gulea, M.; Donnard, M.; Org. Lett., 2016, 18, 2588-2591.
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Graphic for Table of Contents Synthesis of Sulfur Heterocycles via Domino Metal-mediated
Reactions
Thomas Castanheiro, Jean Suffert, Morgan Donnard,* and Mihaela Gulea*
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Table 1. Cyclocarbopalladation/cross-coupling domino reactions in sulfides series
Entry m, n
R1
Starting Coupling Conditionsa R2
Product Yield
(%)
sulfide partner
R2-Y
1
m = 0, n
TMS
TMS
TMS
TMS
Et
R2-
2-Furyl
65
1a
1a
1a
1a
1b
1c
1d
1e
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
2a
= 1
SnBu3
2
m = 0, n
= 1
R2-
2-Thienyl
Vinyl
77
3a
SnBu3
R2-
3
m = 0, n
= 1
51
4a
SnBu3
4
m = 0, n
= 1
R2-
Allyl
62
5a
SnBu3
R2-
5
m = 0, n
= 1
2-Furyl
2-Furyl
2-Furyl
2-Furyl
Ph
52
2b
SnBu3
6
m = 0, n
= 1
Ph
R2-
81
2c
SnBu3
R2-
7
m = 1, n
= 1
Et
61
2d
SnBu3
8
m = 1, n
= 0
Me
Et
R2-
59
2e
SnBu3
R2-
9
m = 0, n
= 1
66
3b
B(OH)2
10
11
12
13
14
15
16
17
18
19
m = 0, n
= 1
m = 1, n
= 1
m = 1, n Me
= 0
m = 1, n Et
= 1
m = 1, n
= 1
m = 1, n Et
= 1
m = 1, n Et
= 1
m = 1, n Et
= 1
Ph
R2-
Ph
79
3c
B(OH)2
R2-
Et
Ph
91
3d
B(OH)2
R2-
Ph
30
3e
B(OH)2
R2-
4-F-C6H4
4-CF3O-C6H4
83
4d
B(OH)2
Et
R2-
86
5d
B(OH)2
R2-
4-CO2Me-
C6H4
3-NO2-C6H4
69
6d
B(OH)2
R2-
86
7d
B(OH)2
R2-
3-CF3-C6H4
67
8d
B(OH)2
m = 1, n
= 1
m = 1, n
= 1
Et
R2-
2,4-
(MeO)2C6H3
Vinyl
60
9d
B(OH)2
R2-BF3K
Et
64
10d
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20
21
m = 1, n Et
= 1
m = 1, n Et
= 1
R2-BF3K
Allyl
73
55
1d
1d
B
B
11d
12d
R2-
B(OH)2
Cyclopropyl
aConditions A: C6H6, 115 °C (MW), 3 h; Conditions B: MeTHF/H2O (98/2), K3PO4 ,130 °C
(MW), 3 h
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Table 2. Aerobic Cu-mediated domino approach to 2-aminobenzothiazole derivatives
Entry Starting
disulfide
’
EX
R
Product Yield (%)
1
H
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
RC(O)Cl
Boc2O
Ph
73
82
72
61
80
37
49
76
77
60
61
69
86
93
71
50
55
65
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14b
14b
14c
14a
14a
14a
14b
15a
16a
17a
18a
19aa
20a
21a
22a
23aa
24a
25a
15b
16b
15c
26a
27a
28a
26b
2
H
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
2,5-F2-C6H4
4-CN-C6H4
2-Thienyl
Et
3
H
4
H
5
H
6
H
7
H
8
H
9
H
iPr
10
11
11
12
13
14
15
16
17
H
Cyclohexyl
Cyclopropyl
Ph
H
Cl
Cl
CF3
H
4-Me-C6H4
Ph
OtBu
H
ROC(O)Cl
PhNCO
OMenthyl
NHPh
H
Cl
Boc2O
OtBu
aanalyzed by X-ray crystallography
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Scheme 1. Synthesis of S-heterocycles by cyclocarbopalladation/cross-coupling domino
reactions
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Scheme 2. Synthesis of a potentially bioactive molecule 13, analogue of Tamoxifen
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Scheme 3. Synthesis of 2-aminobenzothiazole derivatives by Cu-mediated domino reaction
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Scheme 4. Proposed sequence for the overall domino transformation
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Scheme 5. Approach to 2-iminobenzothiazole derivatives
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CuCN
ArC(O)Cl
standard conditions
S)2
S)2
C(O)Ph
N
NHC(O)Ph Ar = 2,5-F2-C6H3
30
(80%)
29
C(O)Ar
30
CuCN
PhC(O)Cl
standard conditions
S)2
Ts
S
N
C(O)Ph
N
S
N
+
N
NHTs
32
(25%)
31
33
(< 10%)
Ts
Ts
CuCN
standard conditions
S
+
NH2
N
33
(23%)
H
33
34
32
Scheme 6. Reactions with N-protected 2-aminoaryl disulfides 29 and 31; X-ray structures of
products 30, 32, 33
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