Aerobic Copper-Mediated Domino Three-Component Approach to 2-Aminobenzothiazole Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b00967

An unprecedented three-component reaction involving a 2,2′-diaminodiaryl disulfide, copper cyanide, and an electrophile is described. This transformation is based on an oxidative copper-mediated S-cyanation as a key step and involves a cyanation/cyclization/acylation domino sequence enabling a rapid and efficient synthesis of diversely substituted 2-aminobenzothiazole derivatives. Notably, this reaction proceeds via an original mechanism involving an intermolecular migration of the acyl group.

Full text of DOI:10.1021/acs.orglett.6b00967

Letter
pubs.acs.org/OrgLett
Aerobic Copper-Mediated Domino Three-Component Approach to
2‑Aminobenzothiazole Derivatives
Thomas Castanheiro, Jean Suffert, Mihaela Gulea,* and Morgan Donnard*
́ ́ ́
Laboratoire d’Innovation Therapeutique (UMR 7200), Faculte de Pharmacie, Universite de Strasbourg, CNRS, 74 Route du Rhin,
67401 Illkirch, France
S
* Supporting Information
ABSTRACT: An unprecedented three-component reaction involving a 2,2′-
diaminodiaryl disulfide, copper cyanide, and an electrophile is described. This
transformation is based on an oxidative copper-mediated S-cyanation as a key step
and involves a cyanation/cyclization/acylation domino sequence enabling a rapid
and efficient synthesis of diversely substituted 2-aminobenzothiazole derivatives.
Notably, this reaction proceeds via an original mechanism involving an
intermolecular migration of the acyl group.
mong the various copper-mediated reactions,1 aerobic
oxidative cross-couplings represent a powerful method for
atom without specific preliminary protection. In our specific
case, the nitrogen will then induce a cyclization on the newly
formed thiocyanate that would drive to an amide that could
subsequently be quenched by an electrophile, reaching diversely
substituted 2-aminobenzothiazole derivatives (Scheme 1). The
A
the construction of carbon−carbon and carbon−heteroatom
bonds.2 These transformations have been widely investigated
during the last 15 years and led to elegant syntheses of simple
to complex molecules. However, if only very few examples of
their incorporation into domino multicomponent reactions
(MCRs)3,4 are reported, none of them includes a cyclization
step leading to polycyclic compounds. This strategy would be
particularly attractive, as aerobic copper-mediated reactions
generally take place under mild reaction conditions, do not
require specific precursors such as aromatic halides, and are
tolerant of a large number of functional groups. Moreover, the
involvement of aerobic copper-mediated cross-coupling as a key
step in MCRs will complement the copper-catalyzed domino
reactions approach,5 providing efficient atom- and step-
economic accesses to a large diversity of cyclic and heterocyclic
structures.
Scheme 1. Proposed Domino 3CR To Access 2-
Aminobenzothiazole Derivatives
Due to their pharmacological importance,6 2-aminobenzo-
thiazoles represent a major class of heterocycles, and their
synthesis7 still attracts a major attention from the organic
chemistry community. For instance, this motif can be found in
drugs used to treat diabetes, epilepsy, Alzheimer’s disease, or
viral infections. The most emblematic representative of this
class of compound is undoubtedly riluzole, which is a classical
treatment of amyotrophic lateral sclerosis (ALS), a lethal
neurodegenerative disease.
Our group has recently reported the aerobic copper-
mediated cyanation of thiols/disulfides to obtain aromatic
thiocyanates.8 This reaction is performed in the presence of
CuCN in acetonitrile and requires the use of TMEDA as
ligand.9 To extend its synthetic applicability, we have
envisioned that this method could be integrated in a domino
three-component (3CR) sequence involving aromatic thiols or
disulfides bearing an amino group at the ortho position. If it has
already been established that 2-aminophenyl thiocyanate can
cyclize to produce 2-aminobenzothiazole,10 this aerobic method
allows selective cyanation of the sulfur atom over the nitrogen
overall transformation is challenging as competitive reactions
(for example, the mono- or diacylation of the aniline when the
electrophile is an acyl chloride11 or the direct reaction of CuCN
with the electrophile12) would prevent access to the desired
product.
To validate our approach to 2-aminobenzothiazoles via S-
cyanation/cyclization, we first performed the reaction between
2,2′-diaminodiphenyl disulfide 1 and copper cyanide under
similar reaction conditions to those we reported previously
without the presence of an electrophile (Scheme 2). The
reaction drove to the expected product 4a in a decent yield of
57%. Notably, it appeared that the reaction needed around 1 h
to reach completion at 60 °C, and a longer reaction time drove
the degradation of the newly formed 2-aminobenzothiazole and
thus to an erosion of the yield proportional to the additional
time. It appeared also that the reaction could not be performed
Received: April 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
desired product 4g was obtained in a low 37% yield. The use of
a heterocyclic acid chloride such as thiophene-2-carbonyl
chloride allowed us to obtain the corresponding amino-
benzothiazole 4h in an average 49% yield. Then the reaction
was extended to aliphatic acyl chlorides such as isobutyryl
chloride and propionyl chloride and led to products 4i and 4j in
good (77% and 76%) yields. Yields of the three-component
reaction appeared to be slightly decreased when cyclic acid
chlorides such as cyclohexanecarbonyl chloride and cyclo-
propanecarbonyl chloride were used and led to the
corresponding 2-aminobenzothiazoles 4k and 4l in 60% and
61% yields, respectively. The reaction was then extended to
other substrates bearing different substituents on the aromatic
ring. For instance, when 2-amino-4-chlorophenyl disulfide 2
was used as the starting material, the desired products 4m and
4n were obtained in good yields of 69% and 86%, respectively.
The reaction appeared to be even more efficient when
performed with a starting material encompassing a poorer
aromatic ring. Thus, starting from 2-amino-4-(trifluoromethyl)-
thiophenol 313 and using benzoyl chloride as electrophile, the
corresponding product 4o was obtained in an excellent 93%
yield. Two particular cases (Scheme 3) have been identified
Scheme 2. Copper-Mediated Domino Three-Component
Reaction Using Acid Chlorides as Electrophiles
Scheme 3. Three-Component Reactions Leading to Valuable
Side Products 5 and 6
a
b
The thiol was used as the precursor instead of the disulfide. Reaction
performed without RC(O)Cl and stopped after 1 h.
at room temperature as only the cyanation step took place to
reach the 2-aminophenyl thiocyanate as the only product. In a
second attempt, the three-component reaction was investigated
by adding an acid chloride as reagent. Pleasingly, by reacting
disulfide 1 with CuCN in the presence of benzoyl chloride, we
obtained the desired product 4b in 73% yield (Scheme 2). In
that case, 3 h was required to have a complete conversion at 60
°C. In contrast to the reaction without an acid chloride (vide
supra), it appeared during our investigation that this trans-
formation can be performed at room temperature, but 7 h is
then required to reach complete conversion of the starting
material into 4b in a similar yield.
Diversely substituted benzoyl chlorides such as p-Me, p-
OMe, p-Br, and 2,5-difluoro derivatives were then investigated
and furnished, respectively, products 4c, 4d, 4e, and 4f in good
yields (61−80%). We succeeded in the isolation of a single
crystal of 4f and obtained its structure by X-ray diffraction
(Figure 1).
during the scope and limitation study. First, when substrate 1
was cyanated in the presence of methyl 5-chloro-5-oxopenta-
noate as the electrophile, the expected product 4p was obtained
together with the benzothiazine derivative 5 (48% and 32%,
respectively). As reported previously by Bolm et al., instead of
going through an S-cyanation (CN is not incorporated in the
final structure), this side product 5 is the result of the oxidative
copper-mediated cyclization of the sulfur nucleophile at the α
position of the amide carbonyl group.14 The second particular
result was obtained with cinnamoyl chloride as the electrophile.
In this case, the tricyclic compound 615 was obtained along
with the expected product 4q. The new side product 6 comes
from the 1,4-addition of the exocyclic nitrogen of the newly
formed 2-aminobenzothiazole on the cinnamoyl double bond
and subsequent oxidation under the reaction conditions.
To uncover further the scope of the three-component
reaction, other types of electrophiles were investigated (Table
2). First, Boc anhydride was used to obtain 2-amino-
benzothiazoles bearing a carbamate function on the exocyclic
nitrogen. The reaction appeared to work moderately well and
furnished under classical conditions the desired product 7 in
49% yield. However, the addition of 20% of DMAP as
activating agent of the (Boc)2O allowed a significant increase in
the yield to 71% (entry 1). The same reaction conditions were
then applied to 6,6′-disulfanediylbis(3-chloroaniline) 2 and
drove to the corresponding product 8 in a similar 65% yield
When the reaction was preformed using p-cyanobenzoyl
chloride as the electrophile, an electron-poor acyl chloride, the
Figure 1. ORTEP view of the X-ray structure of 4f (R1 = 4.4%).
B
DOI: 10.1021/acs.orglett.6b00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Domino Three-Component Reaction Using Other
Electrophiles
Scheme 4. Synthesis of 4b Starting from N,N′-Diacylated
2,2′-Diaminodiphenyl Disulfide 13
We then examined the intramolecular or intermolecular
mode of the final N-acylation when the starting material is the
N,N′-diacylated 2,2′-diaminodiaryl disulfide. For this purpose,
we undertook a crossover experiment by placing under the
cyanation conditions an equimolecular mixture of N,N′-
diacylated 2,2′-diaminodiaryl disulfides 13 and 14 (Scheme
1
5). At the end of the reaction, the analysis (by H NMR and
entry
disulfide
EX
product
Scheme 5. Crossover Experiment Starting from Disulfides 13
and 14 and CuCN
a
1
2
3
4
5
6
1
2
1
1
1
1
Boc2O
Boc2O
TsCl
7
a
8
9
(Me)2NC(S)Cl
PhNCO
10
11
12
L-menthylOC(O)Cl
a
20% of DMAP were added to the reaction mixture.
(entry 2). Attempts using tosyl chloride as electrophile
remained, with or without DMAP, unsuccessful and systemati-
cally led to the degradation of the starting material without
formation of the desired compound 9 (entry 3). The use of
dimethylcarbamothioic chloride under normal conditions
allowed us to obtain the corresponding aminobenzothiazole
bearing a thiourea 10 in a modest 37% yield (entry 4). These
species are known to be very good ligands of copper,16
suggesting that a part of the newly formed product stayed
coordinated to copper complexes present in the reaction
mixture. Unfortunately, different attempts to release compound
10 to increase the yield of the reaction were unsuccessful.
When the reaction was performed using phenyl isocyanate as
electrophile, the desired product 11 bearing a urea was
obtained in 55% yield (entry 5). Finally, the use of L-menthyl
chloroformate as a chiral electrophile allowed us to obtain the
2-aminobenzothiazole 12 bearing a menthyl carbamate in a
moderate 50% yield that can mainly be explained by the
sensitivity of the product that led to a degradation of it during
the purification process (entry 6).
For a better understanding of the overall process and to
propose a reasonable mechanism, we performed some
additional experiments. In light of the side products 5 and 6
obtained during our investigations, we presumed that the first
step of the reaction could be the acylation of the aniline moiety
of the starting material. Therefore, we first set out to determine
if the N,N′-diacylated 2,2′-diaminodiphenyl disulfide 13 can act
as the precursor of product 4b (Scheme 4).
LC/MS) of the resulting mixture clearly showed crossover
products 4b, 4c, 4m, and 4n in an almost equimolar ratio (see
the Supporting Information). This result confirmed that the
exocyclic nitrogen acylation takes place via an intermolecular
process.
Finally, a last experiment reacting substrate 1, CuCN, and
benzoyl chloride was monitored over time by TLC. After 10
min, the starting material 1 was partially transformed into the
N-acylated disulfide 13. After an additional 20 min, product 4b
appeared, but remaining 1 and 13 were still detected. It
appeared that the N-acylated product seemed to undergo the S-
cyanation faster than the nonacylated product. Then the
cyclization involving the attack of a less nucleophilic amide
group on the thiocyanate could take place, presumably helped
by the fact that it is an intramolecular process.
In the light of those results, we can reasonably assume that
the mechanism of the three-component reaction involves the
following steps (Scheme 6): (I) N,N′-diacylation of the starting
2,2′-diaminodiaryl disulfide; (II) oxidative copper-mediated S-
cyanation by CuCN; (III) cyclization via nitrogen nucleophilic
attack of the thiocyanate carbon; (IV) intermolecular acyl
transfer to the exocyclic nitrogen.
In conclusion, we have developed a synthetic strategy
involving for the first time an aerobic copper-mediated coupling
reaction and a cyclization step in a domino multicomponent
process starting from three simple precursors (2,2′-diamino-
diaryl disulfide, copper cyanide, and an electrophile) under mild
reaction conditions. Notably, the specific reaction mechanism
that has emerged from the different experiments that were
conducted during this study can undoubtedly explain how the
Indeed, under our cyanation conditions, substrate 13 led to
the same product 4b as that obtained from 1 in the three-
component process (see Scheme 2) and in a similar 80% yield.
Furthermore, in addition to the 2-aminobenzothiazole 4b, the
corresponding N-benzoyl-2-thiocyanatoaniline was isolated
(31% yield) when the reaction was performed at room
temperature.
C
DOI: 10.1021/acs.orglett.6b00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Biol. 2010, 14, 371. (d) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A.
Angew. Chem., Int. Ed. 2011, 50, 6234. (e) Choudhury, L. H.; Parvin,
T. Tetrahedron 2011, 67, 8213. (f) de Graaff, C.; Ruijter, E.; Orru, R.
V. A. Chem. Soc. Rev. 2012, 41, 3969. (g) Eckert, H. Molecules 2012,
Scheme 6. Proposed Mechanism Based on Experimental
Observations
17, 1074. (h) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
̈
3083. (i) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev.
2014, 114, 8323.
(5) For a review on domino copper-catalyzed reactions, see: Liao, Q.;
Yang, X.; Xi, C. J. Org. Chem. 2014, 79, 8507.
(6) For selected recent examples, see: (a) Namani, V.; Goud, B. B.
K.; Kumari, Y. B.; Kumbham, R.; Balakrishna, K.; Bhima, B. Asian J.
Chem. 2015, 27, 4575. (b) Nooka Raju, D.; Subhadra Devi, D. V. R.;
Grace Aghastina, D.; Govinda Rao, K.; Sathish Kumar, K. World J.
Pharm. Pharm. Sci. 2015, 4, 1815. (c) Cho, H. Y.; Ul Mushtaq, A.; Lee,
J. Y.; Kim, D. G.; Seok, M. S.; Jang, M.; Han, B. W.; Kim, S.; Jeon, Y.
H. FEBS Lett. 2014, 588, 2851. (d) Chikhale, R.; Menghani, S.; Babu,
R.; Bansode, R.; Bhargavi, G.; Karodia, N.; Rajasekharan, M. V.;
Paradkar, A.; Khedekar, P. Eur. J. Med. Chem. 2015, 96, 30.
(7) For selected recent examples, see: (a) Zhao, N.; Liu, L.; Wang, F.;
Li, J.; Zhang, W. Adv. Synth. Catal. 2014, 356, 2575. (b) Koppireddi,
S.; Komsani, J. R.; Avula, S.; Pombala, S.; Vasamsetti, S.; Kotamraju, S.;
Yadla, R. Eur. J. Med. Chem. 2013, 66, 305. (c) Ma, D.; Lu, X.; Shi, L.;
Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem., Int. Ed. 2011, 50, 1118.
(d) Morofuji, T.; Shimizu, A.; Yoshida, J. Chem. - Eur. J. 2015, 21,
3211. (e) Toulot, S.; Heinrich, T.; Leroux, F. R. Adv. Synth. Catal.
2013, 355, 3263.
overall process passed over the diverse challenges that were
exposed previously. This method represents a new, efficient
access to various 2-aminobenzothiazole derivatives.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8) (a) Castanheiro, T.; Gulea, M.; Donnard, M.; Suffert, J. Eur. J.
Org. Chem. 2014, 2014, 7814. (b) Castanheiro, T.; Suffert, J.;
Donnard, M.; Gulea, M. Chem. Soc. Rev. 2016, 45, 494.
(9) In the presence of copper under aerobic conditions, it has been
reported that TMEDA can act as methylene or formyl source. In our
case, we have never observed side products resulting from the reaction
of the starting aminothiol with TMEDA. See: Zhang, L.; Peng, C.;
Zhao, D.; Wang, Y.; Fu, H.-J.; Shen, Q.; Li, J.-X. Chem. Commun. 2012,
48, 5928.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00967.
X-ray data for 4f (CIF)
Full experimental and characterization details for all
compounds; X-ray crystallographic data for molecule 4f;
data to support the crossover experiment(PDF)
(10) Erian, A. W.; Sherif, S. M. Tetrahedron 1999, 55, 7957.
(11) (a) Wang, L.; Wang, Y.; Chen, M.; Ding, M. W. Adv. Synth.
Catal. 2014, 356, 1098. (b) Masu, H.; Sakai, M.; Kishikawa, K.;
Yamamoto, M.; Yamaguchi, K.; Kohmoto, S. J. Org. Chem. 2005, 70,
1423.
(12) For a relevant example, see the reaction of CuCN with an acid
chloride to form an acyl cyanide: Santelli, M.; El Abed, D.; Jellal, A. J.
Org. Chem. 1986, 51, 1199.
(13) In the previous study (ref 8a), it was shown that under the
reactions conditions the thiol is instantaneously transformed into
disulfide.
(14) Zou, L. H.; Priebbenow, D. L.; Wang, L.; Mottweiler, J.; Bolm,
C. Adv. Synth. Catal. 2013, 355, 2558.
(15) Notably, compound 6 is the first example for the synthesis of
this regioisomer coming from the formal condensation of acetylenic
acids and 2-aminobenzothiazoles. For the synthesis of the other
regioisomer, see: Wahe, H.; Mbafor, J. T.; Nkengfack, A. E.; Fomum,
Z. T.; Cherkasov, R. A.; Sterner, O.; Doepp, D. ARKIVOC 2003,
No. xv, 107.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gulea@unistra.fr.
*E-mail: donnard@unistra.fr.
Notes
The authors declare no competing financial interest.
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 Barbara Schaeffer-Lamure
(mass analyses) and Dr. Lydia Karmazin (X-ray analyses) from
the analytical department of the University of Strasbourg. We
are also grateful to Dr. Nicolas Girard from the Faculty of
Pharmacy of the University of Strasbourg for fruitful
discussions.
(16) Gallagher, W. P.; Vo, A. Org. Process Res. Dev. 2015, 19, 1369.
REFERENCES
■
(1) For a complete review on copper-catalyzed cross-coupling
reactions, see: Copper-Mediated Cross-Coupling Reactions; Evano, G.,
Blanchard, N., Eds.; John Wiley & Sons: Hoboken, 2014.
(2) For a review of aerobic copper-catalyzed reactions, see: Allen, S.
E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev.
2013, 113, 6234.
(3) (a) Li, J.; Neuville, L. Org. Lett. 2013, 15, 6124. (b) Zhai, L.; Li,
Y.; Yin, J.; Jin, K.; Zhang, R.; Fu, X.; Duan, C. Tetrahedron 2013, 69,
10262. (c) Kim, J.; Stahl, S. J. Org. Chem. 2015, 80, 2448.
(4) For selected reviews on multicomponent reactions, see: (a)
Multicomponent Reactions; Zhu, J., Bienayme, H., Eds; Wiley-VCH:
Weinheim, 2005. (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
51. (c) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem.
D
DOI: 10.1021/acs.orglett.6b00967
Org. Lett. XXXX, XXX, XXX−XXX