Cu(II)-mediated C-S/N-S bond formation via C-H activation: Access to benzoisothiazolones using elemental sulfur

Article abstract of DOI:10.1021/ol5027156

A copper-mediated C-S/N-S bond-forming reaction via C-H activation that uses elemental sulfur has been developed. The addition of TBAI was found to be crucial for the success of this transformation. The method is scalable, shows excellent functional group tolerance, and is compatible with heterocycle substrates, providing efficient and practical access to benzoisothiazolones. The direct diversification of the benzoisothiazolone products into a variety of sulfur-containing compounds is also demonstrated.

Full text of DOI:10.1021/ol5027156

Letter
pubs.acs.org/OrgLett
Cu(II)-Mediated C−S/N−S Bond Formation via C−H Activation:
Access to Benzoisothiazolones Using Elemental Sulfur
Fa-Jie Chen,† Gang Liao,† Xin Li,† Jun Wu,*,† and Bing-Feng Shi*,†,‡
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A copper-mediated C−S/N−S bond−forming
reaction via C−H activation that uses elemental sulfur has
been developed. The addition of TBAI was found to be crucial
for the success of this transformation. The method is scalable,
shows excellent functional group tolerance, and is compatible
with heterocycle substrates, providing efficient and practical access to benzoisothiazolones. The direct diversification of the
benzoisothiazolone products into a variety of sulfur-containing compounds is also demonstrated.
n recent years, copper-catalyzed/mediated functionalization
of C−H bonds to form C−C, C−N, and C−O bonds has
unactivated C−H bonds is an appealing transformation but has
not been reported to the best of our knowledge.
I
attracted significant attention.1,2 In contrast, copper-catalyzed
direct C−S bond formation has remained relatively undevel-
oped.3−8 This could be due to catalyst poisoning by sulfur species
or the susceptibility of sulfur toward oxidative decomposition or
oligomerization.3 So far, only a few examples of sulfenylation of
unactivated arene C−H bonds have been reported.6−8 In 2006,
Yu reported the first copper-mediated C−H thioetherification of
2-phenylpyridine substrates with PhSH and MeSSMe as the
sulfur sources in moderate yields.6 Qing reported a copper-
mediated methylthiolation of arylpyridines using DMSO as the
sulfur source.7 In 2012, the Daugulis group reported a copper-
promoted sulfenylation of benzoic acid derivatives with disulfides
employing a removable 8-aminoquinoline directing group
(Scheme 1a).8 These established sulfenylation methods,
Benzoisothiazolones are well-known five-membered sulfur-
and nitrogen-containing heterocycles that are ubiquitous in
agrochemicals and pharmaceuticals. It has been shown that
certain benzoisothiazolones and their derivatives possess anti-
HIV and antifungal activities.10 In view of their biological and
synthetic importance, a number of methods have been developed
to access these compounds.11 However, these procedures
generally require multiple synthetic steps and/or use highly
toxic and corrosive reagents. Therefore, the development of an
efficient and environmentally benign protocol, by which a diverse
library of benzoisothiazolones could be prepared from readily
available starting materials, would be highly desirable.
Herein, we report the first example of copper-mediated C−S/
N−S bonds formation via C−H activation that uses elemental
sulfur (Scheme 1b). This protocol uses readily available
benzamide starting materials and provides a straightforward
means of preparing a variety of benzoisothiazolones. We have
also demonstrated that the corresponding benzoisothiazolones
are versatile intermediates for the synthesis of aryl sulfides, aryl
sulfoxides, saccharins, and other sulfur-containing organic
compounds.
Scheme 1. Copper-Mediated C−H Activation/C−S Bond
Formation
As part of our ongoing research in developing novel C−H
functionalization reactions for the synthesis of heterocycles,12 we
became interested in the use of our newly developed bidentate
directing group derived from (pyridin-2-yl)isopropylamine
(PIP-amine) for such transformations.13−15 Therefore, we
commenced our studies by attempting to couple benzamide 1
with S8 in the presence of Cu(OAc)2 and Ag2CO3 under aerobic
conditions. Gratifyingly, the desired product 2 was obtained in
10% yield in DMF (Table 1, entry 1). TBAI is commonly
employed as an efficient additive in C−S bond-forming
however, suffer from some limitations, including restricted
substrate scope; the use of odorous sulfur sources, such as thiols
and disulfides; and the formation of undesired toxic byproducts.
Thus, identifying a generally useful and operationally convenient
sulfur source is crucial for expanding the practical utility of this
class of reactions. Elemental sulfur (S8) is inexpensive, readily
available, and nonodorous.9 Therefore, the use of elemental
sulfur as a sulfur source in copper-catalyzed sulfenylation of
Received: September 15, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of the Reaction Conditions
a
Figure 1. Benzamide substrate scope. Reaction conditions: substrate
(0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), Ag2O (0.5 mmol), S8 (0.4
mmol), and TBAI (0.2 mmol) in CH2Cl2 (1.0 mL) under air at 90 °C for
18 h. Isolated yield.
Isolated yield on 0.2 mmol scale in 2.0 mL of solvent unless
b
otherwise noted. PIP = (pyridin-2-yl)isopropyl. 0.2 equiv of
Cu(OAc)2·H2O was used. 1.0 mL of CH2Cl2 was used.
c
reactions.3 5d Indeed, in the present reaction, the addition of 1
e,
protocol with heterocyles (Figure 2). Gratifyingly, a wide range
of heterocycles including pyridines, thiophenes and benzothio-
equiv of TBAI slightly improved the yield of 2 (entry 2). The
desired product was obtained in 11% yield in the absence of silver
salt (entry 3), while the use of Ag2O led to modest improvement
(25%, entry 4). Cu(OAc)2·H2O proved to be the best promoter
among various copper sources that were examined (entries 6−9).
No desired product was observed in the absence of copper salt
(entry 10). The yield improved to 59% when the reaction was
conducted in CH2Cl2 (entry 11). After further screening the
desired product 2 could be obtained in 89% yield under the
following optimized conditions: 1.0 equiv of Cu(OAc)2·H2O, 2.5
equiv of Ag2O, 2.0 equiv of S8 and 1.0 equiv of TBAI in CH2Cl2
(0.2 M) under air at 90 °C for 18 h (entry 15). Both TBAI and
Ag2O are crucial for the efficiency of this transformation (entries
16−20). The connectivity of benzoisothiazolone 2 was
confirmed by single-crystal X-ray diffraction (Figure S1,
Supporting Information).
After identifying the optimized conditions, we next explored
the substrate scope of this transformation. Both electron-rich and
-deficient benzamides proceeded well to afford substituted
benzoisothiazolones in moderate to high yields (Figure 1).
Trifluoromethyl substituents in the ortho, meta, and para
positions gave the desired products in high yields (3−5).
Generally, substrates bearing electron-withdrawing groups
(−CF3, 5; −CO2Me, 9; −CN, 10; and −NO2, 11) gave higher
yields than those bearing electron-donating groups (−OMe, 6;
−Me, 7; and −OAc, 8). This qualitative trend suggests the
electrophilic aromatic substitution (SEAr) pathway was unlikely
to be operative. It is worth noting that all halides, fluoride,
chloride, bromide, and iodide, remained intact under the
standard reaction conditions, affording the desired products in
moderate to high yields (12−16). m-Alkoxy substrate partially
led to the sulfenylation adjacent to oxygen (19b), possibly
indicating that coordination of the alkoxy substituent stabilizes
the aryl−copper intermediates.
Figure 2. Scope of heteraryl benzamide. Reaction conditions: substrate
(0.2 mmol), Cu(OAc)2·H2O (0.2 mmol), Ag2O (0.5 mmol), S8 (0.4
mmol), and TBAI (0.2 mmol) in CH2Cl2 (1.0 mL) under air at 90 °C for
18 h. Isolated yield.
phenes, were all tolerated under the reaction conditions,
furnishing the heteroaryl-fused isothiazolones in good yields.
Notably, 2-fluoroisonicotinamide reacted at the kinetically more
acidic C−H bond (21b). This observation can be rationalized by
invoking a concerted metalation/deprotonation (CMD) path-
way. 5-Nitrothiophene-2-PIP-carboxamide gave thioether 30,
presumably due to the presence of a strong electron-withdrawing
In light of the biological importance of the heteroaryl-fused
isothiazolones, we further investigated the compatibility of this
B
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Letter
group. Interestingly, benzothiophene-2-PIP-carboxamide pre-
dominantly gave the free thiol product 31b in 64% yield.
To demonstrate the synthetic utility of this method, the
reaction was performed on 5 mmol scale, producing
benzoisothiazolone 2 in 80% yield (eq 1, 1.08 g).
and 7s revealed that electron-deficient arenes reacted with higher
relative rates (Figure S3a, Supporting Information). Addition of
1 equiv of radical scavengers, such as TEMPO and 1,1-
diphenylethylene, did not inhibit the reaction (Figure S3b,
Supporting Information). Addition of 1 equiv hydroquinone
substantially reduced the yield but still did not completely
suppress the reaction. These experiments suggest that the
transformation does not proceed via radical intermediates. The
intermolecular KIE between 1 and d4-1 gave a value of 2.6,
indicating that C−H cleavage could potentially be the rate-
limiting step (Figure S3c, Supporting Information). Although
the exact role of TBAI is unclear at this point, we speculated that
TBAI could play a role as a S8 activator and increase the solubility
of sulfur in dichloromethane.5d,19
The synthetic versatility of the products can be exploited
through the diverse transformations shown in Figure 3, allowing
On the basis of these mechanistic studies and earlier
precedents,20,21 a plausible mechanism appears to involve
Cu(II)-mediated, disproportionative C−H activation followed
by sulfur-atom transfer to form Cu(III) intermediate B.22,23
Subsequent N−S reductive elimination leads to benzoisothiazo-
lone 2 and Cu(OAc) (Figure 4).21 Finally, Cu(OAc) is oxidized
by Ag2O/air to regenerate Cu(II), which would finish the
catalytic cycle. A detailed mechanism remained to be
elucidated.24
Figure 3. Versatile transformations of benzoisothiazolone 2 to various
sulfur-containing compounds. Conditions: (a) MeMgBr, THF, rt, 2 h;
(b) NaBH4, EtOH, 0 °C to rt, overnight; (c) NaBH4, EtOH, 0 °C to rt,
30 min; then BnBr, Et3N, overnight; (d) 4-methylbenzenethiol, CH2Cl2,
rt, 12 h; (e) H5IO6, CrO3 (cat.), CH3CN, rt, 3 h; (f) 2,4,6-trichloro-
1,3,5-triazine, 30% H2O2, CH3CN, rt, 1 h; (g) TMSCF3, KF, DMF, 80
°C, overnight; (h) NaBH4, EtOH, 0 °C to rt, 30 min; then p-
MeOPhCOCl, overnight.
Figure 4. Plausible reaction mechanism.
In conclusion, we have developed the first copper-mediated
C−S/N−S bond-forming reaction via C−H activation that uses
elemental sulfur as the sulfur source. The presence of a
stoichiometric amount of TBAI is crucial for the success of this
transformation. This reaction is scalable and tolerates a wide
range of functional groups, providing an efficient means of
accessing biologically important benzoisothiazolones. In addi-
tion, heterocyclic substrates are compatible with this protocol,
which allows synthesis of a variety of unique heteroaryl-fused
isothiazolones. The versatility of the benzoisothiazolone moiety
renders this protocol highly attractive for both synthetic and
medicinal chemistry.
access to various sulfur-containing compounds. Treatment of
benzoisothiazolone 2 with MeMgBr gave thioether 32 in 89%
yield.16 Reduction of 2 by NaBH4 gave thiophenol 33 in 84%
yield. Oxidation of 2 with 30% H2O2 in the presence of 2,4,6-
trichloro-1,3,5-triazine selectively afforded sulfoxide 37 in 74%
yield.17 Saccharin derivative 36 was obtained in 97% yield by the
oxidation of 2 with H5IO6 in the presence of catalytic CrO3.18
Notably, trifluoromethylthiolation product 38 was obtained in
68% yield when 2 was reacted with Ruppert’s reagent and KF,
providing a new route to aryl trifluoromethylthioarenes. Other
sulfur-containing compounds, such as benzyl thioether 34,
disulfide 35, and thioester 39 could also be produced by the
transformation of benzoisothiazolone 2. Although the PIP group
could not be directly cleaved from the benzoisothiazolone
products, it can be easily removed from sulfur-containing
benzamides, such as 34, by treatment with KOH and CuCl2 in
EtOH (eq 2).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data for all new compounds, and X-
ray data for 2 (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
To gain further insight into the reaction mechanism, additional
experiments were conducted (Figure S3, Supporting Informa-
tion). An intermolecular competition experiment between 5s
*E-mail: wujunwu@zju.edu.cn.
*E-mail: bfshi@zju.edu.cn.
C
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Letter
(13) (a) Li, X.; Liu, Y.-H.; Gu, W.-J.; Li, B.; Chen, F.-J.; Shi, B.-F. Org.
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(14) For pioneering work on the use of bidentate auxiliaries, see:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Basic Research Program of
China (2015CB856600), the NSFC (21422206, 21272206), the
Fundamental Research Funds for the Central Universities
(2014QNA3008), Qianjiang Project (2013R10033), and Special
Fund for Agro-Scientific Research in the Public Interest of China
(201403030) is gratefully acknowledged. We thank Dr. Keary M.
Engle (California Institute of Technology) for helpful
suggestions and comments.
(17) Bahrami, K.; Khodaei, M. M.; Sohrabnezhad, S. Tetrahedron Lett.
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