TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions

Article abstract of DOI:10.1021/acs.orglett.6b01937

By the formal extension of the Passerini reaction to thiocarbonyl derivatives, the straightforward preparation of thiophthalides is disclosed. This method involves the intermediate formation of a sulfanyl-phthalide and a titanium tetrachloride mediated is

Full text of DOI:10.1021/acs.orglett.6b01937

Letter
pubs.acs.org/OrgLett
TiCl ‑Mediated Preparation of Thiophthalide Derivatives via Formal
4
Thio-Passerini Reactions
Sudipta Ponra, Aude Nyadanu, Laurent El Kaïm,* Laurence Grimaud,* and Maxime R. Vitale*,†
†
‡
,‡
,§,∥
†
PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, Paris, 75005, France
‡
́
LSO (UMR 7652), Ecole Polytechnique - ENSTA ParisTech, Universite
́
Paris-Saclay, 91120, Palaiseau, France
§
∥
Ecole Normale Super
́
ierure, PSL Research Univerity, Dep
́
artement de Chimie and Sorbonne Universites
́
, UPMC Univ Paris 06,
ENS, CNRS, PASTEUR, 24, rue Lhomond, 75005 Paris, France
*
S Supporting Information
ABSTRACT: By the formal extension of the Passerini
reaction to thiocarbonyl derivatives, the straightforward
preparation of thiophthalides is disclosed. This method
involves the intermediate formation of a sulfanyl-phthalide
and a titanium tetrachloride mediated isocyanide insertion
reaction. When tert-butyl thiol is used, thanks to the
deprotection of the tert-butyl group, a thiophthalide resulting
from a 1,5-Mumm rearrangement is isolated. Owing to the
multifaceted activity of TiCl , all steps may conveniently be
4
performed in one pot, starting directly from 2-formylbenzoic
acids, tert-butyl thiol, and various isocyanides.
hrough the years, sulfur-based skeletons have been
far overlooked chemical space, the development of new synthetic
methods is highly desirable.
T
identified as leading constituents of numerous pharma-
ceuticals, partly due to the fact that sulfur−lone pair interactions
In this context, as part of our continuing interest in isocyanide
1
,2
10
may serve as key conformational control elements. Noticeably,
compared to their oxygen and nitrogen analogues, the 1,3-
dihydro-benzo[c]thiophene derivatives as well as their 1-keto
analogs, thiophthalides, represent a relatively ignored class of
sulfur-containing heterocycles in medicinal chemistry. Yet,
talsupram (Lu 5-003), one of the most studied members of
this family, has been identified as a very potent norepinephrine
reuptake inhibitor, while other 1,3-dihydro-benzo[c]thiophenes
have similarly showed interesting psychotropic activities (Figure
based multicomponent reactions, we decided to study
straightforward access to 1,3-dihydro-benzo[c]thiophenone
(thiophthalide) derivatives by means of an unprecedented
11,12
formal thio-Passerini reaction (Scheme 1).
Whereas the
Scheme 1. Our Strategy for the Construction of
Thiophthaliddes via a Thio-Passerini Type Coupling
3
−6
1
). Thiophthalides, on the other hand, are equally stimulating
targets considering that some of them display antithrombotic,
7
,8
anticonvulsant, and analgesic properties.
Whereas these compounds are typically synthesized through
multistep processes or by nucleophilic additions onto
3
,4,7,9
thiophthalic anhydride,
the restricted available methods
for their preparation have most likely hampered their use in
medicinal chemistry. Accordingly, in order to allow a more
thorough evaluation of the pharmacological potential of this so
formation of phthalides from isocyanides and 2-formyl benzoic
13
acid was originally described by Passerini, the development of a
thio-variant of this transformation has, to the best of our
knowledge, never been reported. Actually, the achievement of
this goal was definitely not trivial considering the lack of any
14
reliable access to stable thioaldehydes. For this reason, we
Figure 1. 1,3-Dihydro-benzo[c]thiophene and thiophtalide containing
biologically relevant molecules.
Received: July 4, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01937
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
designed an original strategy in which, starting from 2-formyl
benzoic acid and the appropriate thiol partner, the in situ
generation of a thiocarbenium species A would allow the
required isocyanide insertion reaction (Scheme 1). Based on this
hypothesis and by the careful selection of the S-protecting group,
we anticipated that the formation of the targeted thiophthalide C
could be achieved via a Mumm 1,5-acyl transfer triggered by the
in situ S-deprotection of intermediate B (Scheme 1).
Scheme 2. Scope of the TiCl -Promoted Isocyanide Insertion
into Thiophthalides 1a−b
4
With this plan in mind, we initially surveyed the practicability
of the insertion reaction of isocyanides into an in situ generated
1
5,16
thiocarbenium A.
For this purpose, 3-phenylsulfanyl-
1
7
phthalide 1a was prepared and submitted to a stoichiometric
amount of a variety of Lewis acids in the presence of a slight
excess (1.2 equiv) of tert-butylisocyanide 2a in dichloromethane
at room temperature (Table 1). Among the various Lewis acids
Table 1. Optimization Studies of the Isocyanide Insertion into
Thiophthalides
between 1b and tert-butylisocyanide 2a afforded the isochrome-
none 3ba in a lower 50% yield, as a result of the competitive
cleavage of the tert-butyl group leading to the corresponding free-
amino compound 3ba′ (12% yield).
On the other hand, we were quite pleased to observe that the
S-cyclohexyl phthalide 1c, in the reaction with 2b, progressed to
an approximately 2 to 1 mixture of the isochromenone 3cb and
the ultimately targeted thiophthalide 4b (Scheme 3). This result
a
entry
solvent
Lewis acid
BF .OEt
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
CH Cl2
2
2
2
2
2
2
1
1
1
1
1
1
1
0
0
2
3
2
CH Cl2
GaCl3
2
CH Cl2
In(OTf)3
Zn(OTf)2
AlCl3
0
2
CH Cl2
0
Scheme 3. Conversion of Phthalide 1c into Thiophthalide 4b
via the Intermediary Formation of Isochromenone 3cb
2
CH Cl2
13
0
2
CH Cl2
TiCl(Oi-Pr)3
TiCl4
2
CH Cl2
76
16
41
18
0
2
CHCl3
TiCl4
b
1,2-DCE
TiCl4
1
1
1
1
0
1
2
3
Et O
2
TiCl4
THF
TiCl4
CH CN
TiCl4
0
3
Toluene
TiCl4
39
a
b
Isolated yield. DCE: 1,2-dichloroethane.
seemed to confirm that the involvement of a subsequent S-
1
8
tested, only two allowed the desired insertion product to be
deprotection/Mumm rearrangement sequence was an attainable
19,20
obtained, in the form of the tautomeric thio-isochromenone 3aa
task
and somehow endorsed our thio-Passerini approach to
(
Table 1, entries 5 and 7). As observed by Chatani and co-
thiophthalides. Interestingly, we could also demonstrate that
workers in the specific context of the isocyanide insertion into
symmetrical thioketals, the best yields were achieved using
titanium tetrachloride (Table 1, entry 7) but, in opposition to
TiCl is a suitable promoter of this subsequent process. Indeed,
4
the high yielding formation of 4b from 3cb could be achieved
using 1 equiv of this Lewis acid in dichloromethane at room
temperature over a 24-h period (Scheme 3).
16
their study, GaCl gave no insertion product (Table 1, entry 2).
3
Whereas other solvents were tested (Table 1, entries 8−13),
none provided superior results compared to that obtained with
To optimize this thio-Passerini-like process and to capitalize
on the ability of TiCl to both promote the isocyanide insertion
4
dichloromethane, in which the use of TiCl led to the formation
of 3aa in good 76% isolated yield (Table 1, entry 7). All attempts
step and the subsequent rearrangement of isochromen-1-ones,
various S-protecting groups were then evaluated for the direct
preparation of thiophthalide 4b. For this purpose, sulfanylph-
thalides 1b−d and cyclohexylisocyanide 2b were submitted to 2
4
to perform the reaction with catalytic amounts of Lewis acids
18
failed to give better yields.
With the optimized reaction conditions in hand, sulfanylph-
equiv of TiCl in dichloromethane at room temperature (Table
4
thalides 1a and 1b were reacted with a set of several isocyanides
2). After 2 h, the reaction was consistently quenched and, after
purification, the yield of thiophthalide 4b and that of the
corresponding isochromenone were determined. As we could
expect, the overall efficiency of this transformation was highly
dependent on the capacity of the S-protecting group to stabilize
the positive charge resulting from the carbon−sulfur bond
rupture event. While phthalide 1b, which possesses a linear alkyl
chain, failed to give 4b, its cyclohexyl-substituted counterpart 1c
only partially afforded 31% of the targeted thiophthalide.
(Scheme 2). Remarkably, the 3-amino-4-thio-isochromen-1-
ones 3 were consistently obtained in good to excellent yields and
thereby demonstrated the efficiency of this original isocyanide
insertion process. While the reaction of 3-phenylsulfanyl-
phthalide 1a well tolerated the use of either aliphatic or aromatic
isocyanides 2b−d, we were satisfied to witness that the desired
isocyanide insertion process could straightforwardly be extended
to the S-alkyl substituted phthalide 1b. Notably, the reaction
B
DOI: 10.1021/acs.orglett.6b01937
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Optimization of the S-Protecting Group Allowing the
Direct Synthesis of Thiophthalides from Phthalides
Table 3. One-Pot Sequential Three-Component Thio-
Passerini-like Preparation of Carboxamide Thiophthalides 4
entry
substrate, R
3xx, yield
4b (yield)
entry substrates
R1
R2
4x, yield
n
1
2
3
4
5
1b, C H
3bb, 93%
3cb, 69%
3db, 0%
3eb, 10%
3fb, 0%
−
1
2
25
1
2
5a, 2a
5a, 2b
5a, 2c
5a, 2d
5a, 2f
5a, 2h
5a, 2i
5a, 2j
5b, 2b
5c, 2a
H
tBu
Cy
Bn
4a, 69%
4b, 78%
4c, 58%
4d, 75%
4f, 64%
4h, 79%
4i, 45%
4j, 58%
4b′, 64%
4a″, 72%
1c, Cy
31%
65%
82%
76%
a
1d, PMB
1e, Bn
H
3
H
t
1f, Bu
4
H
2,6-(Me) -C H
2
6
3
a
5
H
2-Naphthyl
nPent
PMB = p-methoxybenzyl.
6
H
Conversely, the p-methoxybenzyl-, the benzyl-, or the tert-butyl-
substituted phthalides 1d, 1e, and 1f led straightforwardly to 4b
in 65%, 82%, and 76% yield, respectively. While the benzyl
mercaptan 1e gave an incomplete conversion, 1f was selected for
the remainder of our studies.
7
H
1,1,3,3-(Me)4‑Bu
8
H
-(CH
Cy
) -3,4-(MeO) -C H
2 2 2 6 3
2
1
9
Me
OMe
t
10
Bu
Pleasingly, this direct preparation of thiophthalides 4 from the
S-(tert-butyl)-substituted phthalide 1f could be efficaciously
extended to the use of a wide range of isocyanides 2a−i (Scheme
isocyanide 2 (1.5 equiv) and extra TiCl (2 equiv), the desired
4
thiophthalides 4 were reliably obtained in respectable yields,
comparable to those obtained starting directly from S-(tert-
butyl)-substituted phthalides (Table 2).
Considering the reaction mechanism which may be at stake, as
other Lewis acids triggered Passerini couplings, the starting or
the in situ generated phthalide D is likely activated by TiCl to
form a transient thiocarbenium E which is attacked by the
isocyanide (Scheme 5). The resulting nitrilium F is then trapped
4
). Indeed, independently of the aliphatic or aromatic nature of
22
Scheme 4. Scope of This Formal Thio-Passerini
Thiophthalide Synthesis
4
Scheme 5. Mechanistic Proposal
the isocyanide partner, the expected thiophthalides were reliably
obtained with satisfactory yields. Of note, this method was also
amenable to the functionalization of the aromatic moiety of the
starting phthalides, considering that 1g and 1h similarly afforded
the desired thiophthalides 4b′ and 4b″ in good 74% and 80%
yield, respectively.
intramolecularly by the carboxylate group leading to the
oxycarbenium G. As witnessed by the typical dark blue-green
color of the reaction mixture, a tautomeric equilibrium most
probably engenders pyrylium H, in which the relative stability
To push the boundaries of this formal thio-Passerini process,
we envisioned the development of an even more straightforward
preparation of thiophthalides 4 by means of a one-pot reaction
sequence. After some optimization, we could demonstrate that
the transiently required phthalides 1f, 1g, or 1h could be easily
generated in situ, in dichloromethane at room temperature, by
entails the use a stoichiometric amount of TiCl . Depending on
4
the starting thiol which is used, 3-amino-4-thio-isochromen-1-
ones 3 are obtained or, upon higher loading of TiCl and the use
4
t
of BuSH, the subsequent thiol dealkylation followed by a
Mumm 1,5-acyl transfer promotes the formation of thiophtha-
19,23
lides 4.
t
submitting 2-formyl benzoic acids 5a−c (1.1 equiv) to BuSH (1
To conclude, we developed two original procedures for the
preparation of a large variety of thiophthalides starting from
easily accessible sulfanyl-phthalides or directly from the
equiv) in the presence of 0.2 equiv of TiCl and 4 Å molecular
4
sieves (Table 3). Upon the subsequent addition of the desired
C
DOI: 10.1021/acs.orglett.6b01937
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
corresponding 2-formyl benzoic acid derivatives. This process,
which was proven to implicate the intermediary formation of
valuable 4-sulfanyl-isochromenone, features the multifaceted
11867−11878. (d) Inami, T.; Kurahashi, T.; Matsubara, S. Chem.
Commun. 2011, 47, 9711−9713. (e) Tatsuta, K.; Fukuda, T.; Ishimori,
T.; Yachi, R.; Yoshida, S.; Hashimoto, H.; Hosokawa, S. Tetrahedron
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Chim. Acta 2013, 96, 1894−1904. (g) Kobayashi, K.; Shigemura, Y.;
Ezaki, K. Heterocycles 2015, 91, 526−536.
24
activity of TiCl . Formally, these new entries to thiophthalides
4
are based on the coupling between a thiocarbonyl surrogate, an
isocyanide, and a carboxylic acid and, in so doing, represent the
first examples of formal thio-Passerini reactions.
(10) (a) El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
4
2
4, 7961−7964. (b) El Kaïm, L.; Grimaud, L. Eur. J. Org. Chem. 2014,
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ASSOCIATED CONTENT
Supporting Information
Dos Santos, A.; El Kaïm, L.; Gamez-Montejo, R.; Grimaud, L. Angew.
Chem., Int. Ed. 2013, 52, 7194−7197. (d) Martinand-Lurin, E.; Dos
Santos, A.; El Kaïm, L.; Grimaud, L.; Retailleau, P. Chem. Commun.
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01937.
2
014, 50, 2214−2217.
11) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126−129. For
reviews, see: (b) Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140.
c) Kazemizadeh, A. R.; Ramazani, A. Curr. Org. Chem. 2012, 16, 418−
50.
12) For reviews on isocyanide-based multicomponent reactions, see:
(a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168−3210.
(b) Domling, A. Chem. Rev. 2006, 106, 17−89. (c) Domling, A.; Wang,
W.; Wang, K. Chem. Rev. 2012, 112, 3083−3135. (d) Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Viley-VCH: Weinheim, 2005.
(
Experimental procedures, analytical data, and NMR
spectra for all compounds are reported (PDF)
(
4
(
AUTHOR INFORMATION
Corresponding Authors
■
̈
̈
̈
*
*
*
E-mail: laurent.elkaim@ensta-paristech.fr.
E-mail: laurence.grimaud@ens.fr.
E-mail: maxime.vitale@chimie-paristech.fr.
́
(
13) (a) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964−969.
For applications, see: (b) Falck, J. R.; Manna, S. Tetrahedron Lett. 1981,
Notes
22, 619−620.
(14) Thioaldehydes are very unstable compounds; see: (a) Collier, S. J.
The authors declare no competing financial interest.
Science of Synthesis 2004, 27, 177. (b) Metzner, P. Synthesis 1992, 1992,
185−1199.
15) For reviews on isocyanide insertion reactions, see: (a) Qiu, G.;
1
(
ACKNOWLEDGMENTS
This work has been realized within the framework and with the
financial support of the IDEX referenced as ANR-10-IDEX-
■
Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257−5269. (b) Isocyanide
Chemistry: Applications in Synthesis and Material Science; Nenajdenko, V.,
Ed.; Wiley-VCH: Weinheim, 2012.
0
001-02 PSL★. A.N. thanks the Ecole Polytechnique for a
fellowship, and all the authors thank PSL★, Chimie ParisTech,
ENS, and ENSTA ParisTech for financial support.
(16) For a related precedent dealing with the Lewis acid promoted
insertion of isocyanides into dithioketal, see: Tobisu, M.; Ito, S.;
Kitajima, A.; Chatani, N. Org. Lett. 2008, 10, 5223−5225.
(17) For a seminal preparation of 1a from 2-formylbenzoic acid, see:
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