Direct synthesis of 6-sulfonylated phenanthridines via silver-catalyzed radical sulfonylation-cyclization of 2-isocyanobiphenyls

Article abstract of DOI:10.1016/j.tetlet.2018.07.024

A convenient and straightforward synthesis of 6-sulfonylated phenanthridines via silver-catalyzed sequential radical insertion, cyclization and aromatization of 2-isocyanobiphenyls is reported. The protocol does not require a phenanthridine scaffold as a substrate and presents a highly regioselective synthesis of 6-alkyl/arylsulfonyl phenanthridines. The protocol utilizes readily available and easy to handle sodium sulfinates as sulfonating agents and potassium persulfate as an oxidant to afford good to excellent yields of the desired products in a one-pot operation at room temperature.

Full text of DOI:10.1016/j.tetlet.2018.07.024

Accepted Manuscript
Direct synthesis of 6-sulfonylated phenanthridines via silver-catalyzed radical
sulfonylation-cyclization of 2-isocyanobiphenyls
Manjula Singh, Arvind K. Yadav, Lal Dhar S. Yadav, Rana Krishna Pal Singh
PII:
S0040-4039(18)30884-0
https://doi.org/10.1016/j.tetlet.2018.07.024
TETL 50133
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
10 June 2018
5 July 2018
8 July 2018
Please cite this article as: Singh, M., Yadav, A.K., Yadav, L.D.S., Singh, R.K.P., Direct synthesis of 6-sulfonylated
phenanthridines via silver-catalyzed radical sulfonylation-cyclization of 2-isocyanobiphenyls, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.024
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Direct synthesis of 6-sulfonylated phenanthridines via Leave this area blank for abstract info.
silver-catalyzed radical sulfonylation-cyclization of
2-isocyanobiphenyls
Manjula Singh, Arvind K. Yadav, Lal Dhar S. Yadav, Rana Krishna Pal Singh

1
Tetrahedron Letters
journal homepage: www.els evier.com
Direct synthesis of 6-sulfonylated phenanthridines via silver-catalyzed radical sulfonylation-
cyclization of 2-isocyanobiphenyls
Manjula Singha, Arvind K. Yadavb, Lal Dhar S. Yadavb*, Rana Krishna Pal Singha*
aElectrochemical laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India
bGreen Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
∗ Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533; E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav)
ARTICLE INFO
ABSTRACT
A convenient and straightforward synthesis of 6-sulfonylated phenanthridines via silver-catalyzed
sequential radical insertion, cyclization and aromatization of 2-isocyanobiphenyls is reported. The
protocol does not require a phenanthridine scaffold as a substrate and presents a highly regioselective
synthesis of 6-alkyl/arylsulfonyl phenanthridines. The protocol utilizes readily available and easy to
handle sodium sulfinates as sulfonating agents and potassium persulfate as an oxidant to afford good to
excellent yields of the desired products in a one-pot operation at room temperature.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Cyclization
Isonitriles
Phenanthridines
Radical reaction
Sodium sulfinates
Sulfonylation
Sulfur-containing fragments are useful building blocks of
numerous natural products, bioactive molecules and organic
materials, thus C-S bond formation is an important step in
various synthetic sequences.1,2 Particularly, sulfonylated
heterocycles constitute an important class of compounds that
with sulfonic acid chloride and potassium cyanide in 13-31%
yields.20e
In view of the above discussion and our recent work on practical
synthetic routes involving radicals,20d, 21 we envisaged the insertion
of sulfonyl radicals into isocyanides followed by cyclization and
aromatization cascade to give 6-sulfonylated phenanthridines
(Scheme 1b).
feature in many natural
products,
pharmaceuticals
Heterocycles containing
and
a
biologically active compounds.3
sulfonyl group have found a wide range of applications in
medicinal chemistry,4 organic synthesis3c,5 and material science.6
Consequently, the development of more convenient and efficient
(a) Previous work
6- Sulfenyl-20a-c and 6-thiocyanatophenanthridines20d
R2
methods
for the introduction of a sulfonyl group into
heterocycles has attracted considerable attention of synthetic
chemists.7 In general, sulfonylated heterocycles have been
synthesized mainly in two ways:
Ph-S-S-Ph/ R3-SH
R1
R2
oxidant
N
S-Ph/R3
(i) By the cyclization of various pre-sulfonated substrates8 and
(ii) The sulfonation of already prepared heterocycles.9
C-S bond formation
R1
R2
NC
metal-free
The phenanthridines heterocyclic scaffold is the basic
constituent of many natural products, bioactive alkaloids,
pharmaceuticals and functional materials.10 In particular, C-6
diversely substituted phenanthridines have shown a variety of good
biological activities,11 hence numerous methods are available for
their synthesis.12 Following the elegant approach of Nanni and
co-workers,13 a general strategy involving sequential radical
addition, cyclization and aromatization of 2-isocyanobiphenyls
NH4SCN, air (O2)
R1
visible light, eosinY
N
SCN
C-S bond formation
(b) Present work
6-Sulfonylated phenanthridines
R2
R2
AgNO3 (cat.)
K2S2O8 (oxidant)
R1
R3SO2Na
R1
R3
has emerged for the synthesis of 6-subsituted phenanthridines. In
15a,16
DMF, rt, N2, 2 h
this method various alkyl,14 aryl,15 haloalkyl,
acyl,17 P-
N
S
O2
NC
cenered,18 silyl,19 and S-centred radicals have been utilized to
access a wide range of 6-substituted phenanthridines.12 As regards
the sulfur–containing functionalities, only 6-sulfenyl and 6-
thiocyanatophenanthridines have been synthesized via radical
sulfonylation-cyclization cascade reaction of 2-isocyanobiphenyls.
(Scheme 1a).20a-d However, a few 6-sulfonylated phenanthridines
have been synthesized by the reaction of phenanthridine 5-oxide
C-S bond formation
Scheme 1. Cyclization of 2-isocyanobiphenyls triggered by sulfur-
centered radicals.

2
Tetrahedron
optimized (Table 1, entry 1 vs 14 and 15), which indicated that
the silver catalyst played a key role in the reaction and its optimum
amount required was 15 mol%. The screening of various solvents
showed DMF to the best among DMSO, EtOH, CH3NO2, THF,
CH3CN, and toluene (Table 1, entries 16-21).The reaction was
quenched on addition of a well known radical scavenger TEMPO
(2,2,6,6-tetramethylpiperidyl-1-oxyl) (4 equiv) at the beginning,
which indicates that a radical intermediate is involved in the
reaction (Table 1, entry 22).
Table1
Optimization of reaction conditionsa
Entry
Solvent
Catalyst (mol%)
Oxidant (equiv)
Yield (%)b
Table 2
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
CH3NO2
THF
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
Fe2O3 (15)
CuI (15)
K2S2O8 (2)
TBHP (2)
86
35
44
62
53
30
75
Substrate scope for the synthesis of 6-sulfonylated
phenanthridines from 2-isocyanobiphenylsa
2
3
DTBP (2)
4
(NH4)2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (1)
K2S2O8 (3)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
5
6
7
FeCl3 (15)
AgOAc (15)
CuCl (15)
8
42
9
28
55
O
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 (15)
-
Ph
Ph
Ph
Ph
26
Ph
N
S
O2
N
S
N
S
O2
O2
AgNO3 (15)
AgNO3(15)
AgNO3 (10)
AgNO3 (20)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
AgNO3 (15)
68
86
67
3a, 86%
3b, 90%
3c, 93%
O
Ph
Ph
N
S
O2
N
S
O2
N
S
O2
86
3d, 92%
3e, 89%
3f, 95%
82
F
25
18
Ph
N
S
O2
O
N
S
N
S
O2
O2
-
3g, 88%
3h, 68%
3i, 81%
CH3CN
Toluene
DMF
-
Cl
CF3
-
Cl
Ph
S
O2
22
Tracesc
Ph
Ph
N
N
S
O2
N
S
O2
a
Reaction conditions: A mixture of 2-isocyanobiphenyl 1a (0.25 mmol),
sodium sulfinate 2a (0.25 mmol), catalyst, and K2S2O8 (1-3 equiv) in
solvent (3 mL) was stirred for 2 h under N2 .
3j, 82%
3k, 76%
3l, 82%
O
b Yield of isolated product 3a after column chromatography.
c
Cl
Reaction was quenched on addition of TEMPO (4 equiv) at the
beginning.
N
S
O2
N
S
O2
N
S
O2
In order to realize our envisaged, synthetic strategy and
optimize the reaction conditions, we began the investigation
with the silver-catalyzed reaction of isocyanobiphenyl 1a
sodium sulfinate 2a, using K2S2O8 as an oxidant in DMF at
room temperature (Table 1). 6-sulfonylated phenanthridine 3a
was obtained in an excellent yield of 86% in just 2 h. Next,
different organic and inorganic oxidants, such as tert-butyl
hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), and
(NH4)2S2O8 were tested in place of K2S2O8, but among them
K2S2O8 was found to be the best (Table 1, entries 1-4). The
optimum amount of the oxidant was found to be 2 equiv
because on decreasing the amount, the yield was considerably
decreased, while on increasing the amount no change in the
yield was observed (Table 1 entries 12 and 13). Among the
tested catalysts AgNO3 proved to be the best and gave a
maximum yield of the desired product 3a (Table 1, entries 1vs
5-10). In the absence of a catalyst, the yield was poor (Table 1,
Entry 11). Subsequently, quantitative catalyst loading was
3m, 74%
3n, 90%
3o, 89%
O
O
Ph
Ph
S
O2
N
S
O2
N
3p + 3p' = 88% (ratio 3:1),
respectively
a For experimental procedure, see ref. 22.
b Yields of pure isolated products 3 (for the characterization data of
all products, see Supplementary data).
c Compounds 3a, 3h and 3n are known.20e
Employing the optimized reaction conditions, we explored
the generality and scope of the protocol across a wide range of
2-isocyanobiphenyls 1 and sodium sulfinates 2 incorporating
various functionalities, such as CH3, CH3O, F, Cl and CF3. The
reaction shows splendid tolerance for both electron donating

3
and electron-withdrawing groups and the substrates produce the
desired 6-sulfonylated phenanthridines 3 in good to excellent
yields irrespective of differences in their electronic and steric
properties (Table 2). 2-Isocyanobiphenyls 1 and sodium
sulfinates 2 bearing an electron-donating group in their aromatic
rings appeared to react faster and afford slightly higher yields of
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5
Highlights
Direct synthesis of 6-alkyl/arylsulfonyl
•
•
•
•
phenanthridines.
Silver-catalyzed sulfonylation with
sodium sulfinates.
Sulfonyl radical triggered cyclization-
aromatization of 2-isocyanobiphenyls.
Use of K2S2O8 as a radical surrogate
and oxidant.