Cobalt Catalyzed C-H and N-H Bond Annulation of Sulfonamide with Terminal and Internal Alkynes

Article abstract of DOI:10.1021/acs.orglett.5b03142

Chelate assisted cobalt catalyzed C-H and N-H annulation of aryl sulfonamide with terminal and internal alkynes is reported. Very high regioselectivity and excellent functional group tolerance were achieved using oxygen as a co-oxidant. The reaction is scalable under mild conditions.

Full text of DOI:10.1021/acs.orglett.5b03142

Letter
pubs.acs.org/OrgLett
Cobalt Catalyzed C−H and N−H Bond Annulation of Sulfonamide
with Terminal and Internal Alkynes
Deepti Kalsi and Basker Sundararaju*
Fine Chemical Laboratory, Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India
S
* Supporting Information
ABSTRACT: Chelate assisted cobalt catalyzed C−H and N−
H annulation of aryl sulfonamide with terminal and internal
alkynes is reported. Very high regioselectivity and excellent
functional group tolerance were achieved using oxygen as a co-
oxidant. The reaction is scalable under mild conditions.
unctional groups such as sulfonamide, sulfonylurea, and
naturally unavailable cyclic sultam are common motifs in
many drugs and medicinal compounds and play a significant
role in their bioactivity.1 Common drugs such as glibenclamide,
sultiame, and COX-II inhibitors Piroxicam, Ampiroxiam, and
Celecoxib possess a sulfonyl moiety, which displays potential
activity across a variety of biological targets (Figure 1).2
systems based on noble metal catalysts are efficient with
internal alkynes, but lack in reactivity with terminal alkynes.4d
The concept of utilizing a bidentate directing group for chelate
assisted C−H bond functionalization was first introduced by
Daugulis6 and later explored by Chatani7 and others8 for
various C−C and C−X bond formations with various transition
metals.9 Very recently, Daugulis showed an elegant method for
the annulation of benzamide10a using a simple, commercially
available cobalt(II) precursor along with a carboxylate base and
Mn(III) as a cocatalyst under mild conditions.10 In
continuation of our constant effort on the utilization of first
row, late transition metals as a catalyst11,12 for C−H bond
functionalization,13 we herein report the first cobalt catalyzed
C−H bond annulation of sulfonamide via C−H and N−H
activation with terminal and internal alkynes.
F
We began our investigation by screening various cobalt
precursors; among them, cobalt(II) acetate gave a good yield
with sulfonamide 1a and phenyl acetylene 2a using
trifluoroethanol as a solvent under 1 atm of oxygen at 100
°C for 24 h (Table 1, entries 1−4). Changing the solvent from
trifluoroethanol to tert-amyl alcohol completely stopped the
reaction (entry 5). Control experiments revealed that [Co],
[Mn], and NaOPiv were necessary to obtain the annulated
product in good yield (entries 6−8). Changing the base from
NaOPiv to AgOPiv did not improve the yield (entry 9). A
similar yield was obtained when the reaction was carried out at
a slightly lower temperature for 36 h, whereas a drop in yield
was observed when the reaction was performed under air.
With the optimized conditions in hand, the scope for various
substituted sulfonamides featuring 8-aminoquinoline is pre-
sented in Table 2. Electron-rich substrates gave good to
excellent yields, whereas electron-deficient substrates gave
moderate yields (3ba−3fa). Sulfonamides containing a meta-
substituent gave a mixture of C6 and C2 functionalized
regioisomers in a 1.7:1 ratio (3ga). The sterically hindered
substituent did not give any annulated product, even at high
temperature (1i). When sulfonamide 1j was employed, no sign
Figure 1. Drugs featuring biologically active benzosultam and
sulfonamide motif.
Straightforward synthesis of these structural motifs in particular
for annulated benzosultam are relatively rare. Very few
examples have been reported of C−H bond functionalization3
using sulfonamide as a directing group,4 unlike in traditional
methods which require multistep synthesis or the prefunction-
alization of arene.5 Recently, noble metals such as PdII, RhIII,
and RuII have been utilized for the preparation of sultam
derivatives using sulfonamide as a directing group.4 To the best
of our knowledge, utilization of a cheap, abundant base metal as
a catalyst for the functionalization of sulfonamide has not been
reported in the literature. Furthermore, the reported catalytic
Received: October 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Cobalt Catalyzed Annulation of
Sulfonamide
Table 2. Scope of Sulfonamides
a
b
entry
conditions
standard conditions
yield (%)
1
70
50
55
10
n.r.
n.r.
n.r.
n.r.
35
60
70
50
2
CoBr2 (10 mol %) as [Co] source
CoCl2·6H2O (10 mol %) as [Co] source
Co(acac)3 as a [Co] source
tAmOH was used as a solvent
without [Co] cat.
3
4
5
6
7
without Mn(III)
8
without NaOPiv
9
AgOPiv instead of NaOPiv
at 80 °C for 24 h
at 80 °C for 36 h
10
11
12
performed under air instead of O2
a
Standard reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol),
Co(OAc)2·4H2O (0.03 mmol), NaOPiv (0.6 mmol), Mn(OAc)3·
2H2O (0.6 mmol), CF3CH2OH (0.2 M), O2 (1 atm), 100 °C.
b
Isolated yield; Q = quinoline.
of product formation was observed, which may be due to
difficulty in the formation of a six-membered metallocycle, or it
may indicate that the presence of an acidic C−H proton
between SO2− and Ph− terminating the reaction completely.
Nevertheless, the currently developed cobalt catalytic system
seems to be the best catalyst for the annulation of sulfonamides
especially with terminal alkynes with very high regioselectivity.
Next, we investigated the scope of various terminal and
internal alkynes (Scheme 1). Electron-rich and -deficient 3- and
4-substituted phenyl acetylenes underwent the reaction
smoothly with good yields as a single regioisomer (Scheme 1,
4cb−4ce). Aliphatic terminal alkynes including cyclopropyl-
and cyclopentyl-substituted alkynes, which are known to be less
reactive for annulation, expedited product formation in a facile
manner along with the small amount of β-substituted
compound as a minor isomer (Scheme 1, 4cf−4ci). Terminal
alkynes with phenyl or larger substituents give a single
regioisomer whereas a smaller substituent gives a mixture of
regioisomers, which may possibly be due to steric factors.
Furthermore, we undertook the challenge of employing
functionalized terminal alkynes 2j−k under optimized reaction
conditions with 1c and the annulation progressed smoothly in
good yield (Scheme 1, 4cj−4ck). The reaction can also be
extended to other internal alkynes. Symmetrical alkynes such as
diaryl- and dialkyl-substituted acetylenes were efficiently used
for cyclization in good yield (Scheme 1, 4cl−4cm). Unsym-
metrical alkyne 2n was exposed to our reaction conditions, and
it gave a highly regioselective product in moderate yield.
A gram scale reaction was performed with the objective of
evaluating the feasibility of this catalytic process by exercising
1c (1.0 g, 2.93 mmol) and 2a (644 μL, 5.86 mmol) using 10
mol % of [Co], 2 equiv of NaOPiv, and 2 equiv of Mn(OAc)3·
2H2O in trifluoroethanol at 100 °C for 24 h, which gave 3ca in
85% yield (Scheme 2). Intermolecular competition experiments
were performed using 8-aminoquinoline protected benzamide
and sulfonamide with phenyl acetylene 2a under our optimized
conditions favoring annulation with a benzamide over
sulfonamide, confirming the ease of cyclometalation with a
a
Standard reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol),
Co(OAc)2·4H2O (0.03 mmol), NaOPiv (0.6 mmol), Mn(OAc)3·
2H2O (0.6 mmol), CF3CH2OH (0.2 M), O2 (1 atm), 100 °C.
b
c
Isolated yield. Mixture of regioisomer (C6/C2) obtained in 1.7:1
ratio.
benzamide over an attenuated sulfonamide (Scheme 3a). In
addition, we conducted a competitive reaction with electron-
rich and -poor terminal alkynes with 1c, which somewhat favors
toward electron-rich alkynes in a 1.4:1 ratio of 4cc and 4ce,
suggesting that the cyclometalation is possibly irreversible in
nature (Scheme 3b).
Given the efficacy of the versatile cobalt catalyzed C−H
annulation of sulfonamides, a plausible mechanism was
proposed based on our experimental observations and relevant
reports with cobalt(II) (Scheme 4).10a Initial coordination of 8-
B
DOI: 10.1021/acs.orglett.5b03142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Scope of Alkynes
Scheme 4. Proposed Mechanism
B. Reductive elimination of B led to 3 and regenerated the
active catalyst upon oxidation of Co(I) using a Mn(III)
cocatalyst. Nevertheless, the possibility of proceeding via a
radical pathway cannot be overlooked at this stage.
In conclusion, we have developed an unprecedented cobalt
catalyzed C−H/N−H annulation of sulfonamide with various
terminal alkynes and internal alkynes via bidentate chelate
assisted C−H bond activation. The annulation reaction possibly
involved a Co(II)/Co(III) catalytic system and O2 as a terminal
oxidant along with Mn(III) a cocatalyst. We have shown
excellent regioselectivity in particular, with terminal alkynes in
good yield. Further studies probing the reaction mechanism
and stoichiometric experiments are currently in progress.
a
All reactions were carried out under Oxygen (1 atm) with 1c (0.3
mmol), 2 (0.6 mmol), Co(OAc)2·4H2O (0.03 mmol), NaOPiv (0.6
mmol), Mn(OAc)3·2H2O (0.6 mmol) in CF3CH2OH (0.2 M) at 100
°C for 24 h; Q = quinoline.
Scheme 2. Gram Scale Synthesis of 3ca
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03142.
Experimental details and complete spectra of all newly
synthesized compounds (PDF)
Scheme 3. Intermolecular Competitive Experiments
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: basker@iitk.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by the Indian Institute of
Technology Kanpur through initiation grant (IITK/CHM/
20130187) and DAE-BRNS (BRNS/CHM/2014110) for the
young scientist research fund award to B.S. is gratefully
acknowledged. D.K. wishes to thank IITK for her fellowship.
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DOI: 10.1021/acs.orglett.5b03142
Org. Lett. XXXX, XXX, XXX−XXX