In situ Generation and Utilization of CO: An Efficient Route towards N-Substituted Saccharin via Carbonylative Cyclization of 2-Iodosulfonamides

Article abstract of DOI:10.1055/s-0036-1588422

The present protocol demonstrates the synthesis of N-substituted saccharines via carbonylative cyclization of 2-iodosulfonamides using a Pd(OAc) ₂ /Xantphos catalyst system and phenyl formate as a CO source. A variety of saccharin derivatives is synthesized under milder reaction conditions.

Full text of DOI:10.1055/s-0036-1588422

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
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S. P. Chavan et al.
Letter
Synlett
In situ Generation and Utilization of CO: An Efficient Route
towards N-Substituted Saccharin via Carbonylative Cyclization of
2-Iodosulfonamides
Sujit P. Chavana
Adithyaraj K.b
Bhalchandra M. Bhanage*a
O
O
O
O
Pd(OAc)2 (3 mol%)
Xantphos (6 mol%)
O
S
S
X
R
N
R
N
H
H
OR1
Et3N (2 equiv), toluene
80 °C, 18 h
O
a Department of Chemistry, Institute of Chemical Technology,
N. Parekh Marg, Matunga, Mumbai-400019, India
bm.bhanage@gmail.com
up to 92% isolated yield
R = phenyl, benzyl, cyclopentyl
and heterocycles
R1 = Ph, Me, Et
bm.bhanage@ictmumbai.edu.in
b Integrated Science Education & Research Centre (ISERC), Visva
Bharati University, Santiniketan 731235, West Bengal, India
In situ generation & utilization of CO
Safer process
High functional group tolerance
Gram-scale synthesis
X = I, Br
Received: 25.02.2017
Accepted after revision: 20.04.2017
Published online: 18.05.2017
reported.13 Transition-metal-catalyzed carbonylation is an
effective way to synthesize a large range of carbonyl com-
pounds using carbon monoxide.14 The carbonylative C–H
activation of 4-methyl-N-(perfluorophenyl)benzenesulfon-
amide for the synthesis of the corresponding saccharin us-
ing Pd(OAc)2 as catalyst and two equivalent AgOAc as an ad-
ditive under 1 atmosphere pressure of CO has been report-
ed by Yu and co-workers.15 However, the reaction was
performed on a very small scale (0.125 mmol) and the gen-
eral applicability of the reaction was not explored.
DOI: 10.1055/s-0036-1588422; Art ID: st-2017-d0143-l
Abstract The present protocol demonstrates the synthesis of N-sub-
stituted saccharines via carbonylative cyclization of 2-iodosulfonamides
using a Pd(OAc)2/Xantphos catalyst system and phenyl formate as a CO
source. A variety of saccharin derivatives is synthesized under milder re-
action conditions.
Key words carbonylative cyclization, palladium catalysis, CO surro-
gate, phenyl formate, N-substituted saccharin.
Although carbon monoxide is an inexpensive and com-
monly employed C1 source; its flammability and toxicity
creates serious difficulties in handling. In recent years, sev-
eral CO surrogates have been examined for various carbon-
ylation processes.16 The substoichiometric use of aryl for-
mates for in situ generation and utilization CO is reliable
and has shown its efficacy for carbonylative cyclizations.17
The saccharin framework is a key structural motif in
several biologically active compounds such as ipsapirone,
CU-CPD103, supidimide, and repinotan (Figure 1).1 Saccha-
rin derivatives serves as inhibitors of serine proteases,2 an-
algesics,3 aldehyde dehydrogenase inhibitors,4 human mast
cell tryptase inhibitors,5 human leukocyte elastase (HLE)
inhibitors,6 and 5-HT1a antagonists.7 A number of synthetic
pathways for the production of N-substituted saccharin de-
rivatives has been well documented in the literature.8
O
O
O
O
S
S
N
N
H
NH
O
Oxidative cyclization of N-substituted o-methylarene-
sulfonamides using different catalyst systems such as
H5IO6-CrO3, PhI(OAc)2/I2, W lamp or PhI(OAc)2/I2, Hg lamp
have been reported for the synthesis of N-substituted sac-
charins.9 Dolenc and co-workers extended the methodology
to access amino acid derivatives of saccharin using the
H5IO6-CrO3 catalytic system.10 In addition, the synthesis of
N-substituted saccharins has been explored by direct ortho
lithiation of arylsulfonamides.11 Functionalization of sac-
charin using phenylboronic acid or triarylbismuth as arylat-
ing agents with stoichiometric amounts of copper catalyst
has been reported.12 Recently, the synthesis of N-substitut-
ed saccharines via intermolecular oxidative C–H imidation
of arenes with saccharin using hypervalent iodine(III) as an
oxidant under transition-metal-free conditions has been
O
Saccharin
Repinotan
O
O
O
O
S
N
O
S
N
NH
O
O
O
Boc
CU-CPD103
Supidimede
N
O
O
N
N
O
N
N
O
S
N
Ipsapirone
O
Figure 1 Bioactive saccharine derivatives
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
S. P. Chavan et al.
Letter
Synlett
Recently, we have demonstrated the efficacy of phenyl for-
mate as a CO source in palladium-catalyzed carbonylative
cyclization of N-substituted 2-iodobenzamides and 2-iodo-
anilides for the synthesis of phthalimides and benzoxazi-
nones, respectively.18 In the present work, the
Pd(OAc)2/Xantphos-catalyzed carbonylation of 2-iodoben-
zenesulfonamides for the synthesis of saccharin derivatives
is presented (Scheme 1). To the best of our knowledge, the
carbonylative synthesis of saccharine derivatives using a CO
surrogate has been not reported.
Table 1 Screening of Reaction Parametersa
H
O
N
S
I
O
O
O
[Pd] catalyst (3 mol%)
ligand (P/Pd = 4)
1a
S
+
N
Et3N (2 equiv)
solvent, 80 °C, 18 h
O
O
3a
R
H
O
2a–c
O
Entry Formate
Catalyst
Ligand
Solvent
Yield (%)b
O
O
Pd(OAc)2 (3 mol%)
Xantphos (6 mol%)
O
O
S
S
X
R
1
2
HCO2Me
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PhCN)2
PdCl2(PPh3)2
PdCl2
Ph3P
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
34
30
67
60
65
70
94
10
72
86
64
84
N
R
N
+
H
OR1
H
Et3N (2 equiv), toluene
80 °C, 18 h
HCO2Et
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
HCO2Ph
Ph3P
O
3
Ph3P
3a–o
1a–r
2a–c
4
P(tBu)3·HBF4
dppp
R = phenyl, benzyl, cyclopentyl
and heterocycles
R1 = Ph, Me, Et
5
X = I, Br
6
dppf
Scheme 1 General reaction scheme for saccharine synthesis
7
Xantphos
–
8
9
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Initially, we investigated the Pd(OAc)2/Ph3P-catalyzed
carbonylative cyclization of N-phenylbenzenesulfonamide
1a to produce N-phenylsaccharin 3a (2-phenylbenzo[d]iso-
thiazol-3(2H)-one 1,1-dioxide) using different CO surro-
gates and Et3N as a base at 80 °C for 18 hours (Table 1 en-
tries 1–3). Phenyl formate was found to be a better CO
source than alkyl formates presumably because of the high-
er decomposition energies of alkyl formates compare to
aryl formates.19 Using phenyl formate as the CO source, we
next studied the effect of different phosphine ligands on
the cyclization of 1a. Use of P(tBu)3·HBF4 gave a 60% yield of
3a, while bidentate ligands such as 1,3-bis(diphenylphos-
phino)propane (dppp), 1,1-bis(diphenylphosphino)ferro-
cene (dppf) provided 3a in 65% and 70% yields, respectively
(Table 1, entries 4–6). 4,5-Bis(diphenylphosphino)-9,9-di-
methylxanthene (Xantphos) proved to be the best ligand for
this transformation and provided a 94% yield of 3a (Table 1,
entry 7). Reaction in the absence of ligand resulted in a poor
yield (Table 1, entry 8). It has been observed that the cata-
lyst precursor has a vital role in coupling reactions.20 Hence,
we screened various palladium precursors such as
PdCl2(PhCN)2, PdCl2(PPh3)2, PdCl2, and Pd(dba)2 (Table 1, en-
tries 9–12). To investigate the role of solvent, experiments
were carried out using polar and nonpolar solvents, where-
in it was observed that nonpolar solvents are most effective
(Table 1, entries 13–16). Reacting at higher temperatures
led to a drop in yield, and a small amount of dehalogenated
material was detected by GC–MS (Table 1, entry 17).
10
11
12
13
14
15
16
17c
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
mesitylene 90
benzene
DMF
80
68
56
82
THF
toluene
a Reaction conditions: 1a (1.0 mmol), 2 (1.5 mmol), catalyst (3 mol %), li-
gand (6 mol %) and Et3N (3 mmol) in solvent (1 mL), 18 h, 80 °C.
b GC yields.
c At 100 °C.
With the optimized reaction conditions in hand, a range
of 2-iodosulfonamides was subjected to carbonylative cy-
clization to generate the corresponding saccharins in good
to excellent yields (Scheme 2).21 Using 2-iodosulfonamides
bearing various substituents on the N-aryl group revealed
that the steric and electronic properties of the substituents
had little effect on reaction resulting in the formation of
3b–k in very good yield. 2-Iodobenzenesulfonamides bear-
ing N-cyclopentyl, N-benzyl, and N-benzyl substituents led
to the corresponding N-substituted saccharine derivatives
being formed in good to moderate yields (3l–n). Finally, the
N-3-thiophenyl substrate furnished 3o in good yield.
To illustrate the practical utility of the protocol, a gram-
scale reaction was performed. Thus, cyclization of 1a (1.5 g)
provided 3a in 86% isolated yield (Scheme 3). Efforts were
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
S. P. Chavan et al.
Letter
Synlett
H
O
H
N
O
N
S
I
S
I
O
O
O
O
Pd(OAc)2 (3 mol%)
Xantphos (6 mol%)
1a
S
1a
O
1.8 g
5.01 mmol
N
O
Pd(OAc)2 (3 mol%)
Xantphos (6 mol%)
S
H
Et3N (2 equiv)
toluene, 80 °C, 18 h
O
H
N
O
Et3N (2 equiv)
toluene, 80 °C, 18 h
3a
O
O
O
H
2a
3a
O
1.1 g
86% yield
4.30 mmol
2a
0.9 g
7.5 mmol
O
O
S
N
O
O
O
O
S
S
N
N
O
Scheme 3 Gram-scale synthesis of N-phenyl saccharine
O
O
O
O
3a, 92%
3b, 55%
3c, 90%
H
O
N
Pd(OAc)2 (3 mol%)
Xantphos (6 mol%)
S
O
O
O
O
S
O
O
R
2a
O
S
S
Et3N (2 equiv)
toluene
N
N
O
Br
N
1p–r
O
O
S
N
O
1p; R = H, 100 °C, 24 h
1q; R = p-OMe, 100 °C 24 h
1r; R = p-CN, 100 °C, 24 h
O
O
O
O
S
3d, 78%
3e, 86%
3f, 82%
N
R
H
R
O
O
O
O
S
N
3a
4a–c
O
O
O
S
N
Cl
S
3a; 60% 4a; 32%
3c; 42% 4b; 54%
3g; 36% 4c; 50%
N
CN
F
O
O
O
Scheme 4 Carbonylative cyclization of 2-bromosulfonamide
3g, 82%
3h, 90%
3i, 78%
O
O
O
O
S
O
O
S
O
O
S
N
Cl
N
N
Acknowledgment
O
O
O
S.P.C. is grateful to the CSIR, New Delhi for providing a Senior Research
Fellowship.
3j, 83%
3k, 87%
3l, 87%
O
O
S
N
O
O
S
N
O
O
S
N
S
Supporting Information
O
O
Supporting information for this article is available online at
O
CN
3m, 90%
3n, 90%
3o, 80%
https://doi.org/10.1055/s-0036-1588422.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Scheme 2 Substrate scope for the synthesis of N-substituted saccha-
rines. a Reagents and conditions: 1a–o (1 mmol), 2a (1.5 mmol),
Pd(OAc)2 (3 mol%), Xantphos (6 mol%), Et3N (3 mmol) in toluene (1
mL), 18 h, 80 °C.
References and Notes
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benzenesulfonamide as staring material, but this resulted
in poor to moderate yields of the desired products along
with dehalogenated products (Scheme 4).
In conclusion, the use of phenyl formate for in situ gen-
eration of CO proved to be an effective and safe alternative
to high-pressure carbonylation for the synthesis of N-sub-
stituted saccharin derivatives via carbonylative cyclization
of 2-iodobenzenesulfonamides. The methodology tolerates
a variety of functional groups and gives N-substituted sac-
charin derivatives in good to excellent yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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S. P. Chavan et al.
Letter
Synlett
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(21) General Experimental Procedure for the Synthesis of N-Sub-
stituted Saccharins
An oven-dried Schlenk tube was charged with Pd(OAc)2 (6.7 mg,
0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), 2-iodosulfon-
amide (1.0 mmol), phenyl formate (1.5 mmol), and Et3N (3
mmol) under nitrogen, and the reaction mixture was stirred at
80 °C for 18 h. The reaction mixture was then diluted with
EtOAc (10 mL) and aq NaHCO3 (10 mL), and the aqueous phase
was further extracted with EtOAc (3 × 20 mL). The combined
organic layers washed with brine, dried over Na2SO4, filtered,
and the solvent was removed under reduced pressure. The
crude residue was purified by column chromatography on silica
gel (120–200 mesh) using EtOAc–PE as eluents to give the cor-
responding N-substituted saccharin 3a–o.
Compound 3a: isolated as white solid; 238 mg (92%). 1H NMR
(500 MHz, CDCl3): δ = 8.16 (d, J = 7.6 Hz, 1 H), 8.02–7.98 (m, 1
H), 7.95–7.86 (m, 2 H), 7.59–7.52 (m, 5 H). 13C NMR (126 MHz,
CDCl3): δ = 158.3, 137.6, 135.0, 134.4, 130.1, 129.9, 128.7, 128.6.
127.1, 125.6, 121.2.
Compound 3h: isolated as white solid; 249 mg (90%). 1H NMR
(500 MHz, CDCl3): δ = 8.15 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.4 Hz,
1 H), 7.95–7.86 (m, 2 H), 7.54–7.49 (m, 1 H), 7.36 (d, J = 7.6 Hz, 1
H), 7.30 (dt, J = 9.1, 2.2 Hz, 1 H), 7.24–7.20 (m, 1 H). 13C NMR
(126 MHz, CDCl3): δ = 163.9, 161.9, 158.0, 137.4, 135.2, 134.6,
131.0, 130.9, 130.1, 130.0, 126.8, 125.7, 124.0, 124.0, 121.2,
117.2, 117.1, 116.0, 115.8.
1
Compound 3m: isolated as white solid; 245 mg (90%). H NMR
(500 MHz, CDCl3): δ = 8.04 (d, J = 7.6 Hz, 1 H), 7.91 (d, J = 7.4 Hz,
1 H), 7.86–7.78 (m, 2 H), 7.50 (d, J = 7.3 Hz, 2 H), 7.37–7.29 (m, 3
H), 4.90 (s, 2 H). 13C NMR (126 MHz, CDCl3): δ = 158.8, 137.7,
134.7, 134.4, 134.3, 128.7, 128.6, 128.2, 127.2, 125.2, 121.0,
42.6.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D