Synthesis of benzo-γ-sultams via the Rh-catalyzed aromatic C-H functionalization of diazosulfonamides

Article abstract of DOI:10.1039/c4cc00250d

An efficient synthesis of 1-aryl-benzo-γ-sultams, 1-aryl-1,3-dihydrobenzo[c]isothiazole-2,2-dioxides, was achieved in 65-99% yields via the Rh-catalyzed intramolecular aromatic C-H functionalization of N,N-diaryl diazosulfonamides with 0.5 mol% Rh₂(oct)₄ as the catalyst. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00250d

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Synthesis of benzo-c-sultams via the Rh-catalyzed
aromatic C–H functionalization of
diazosulfonamides†
Cite this: Chem. Commun., 2014,
50, 3616
Received 11th January 2014,
Accepted 4th February 2014
Zhanhui Yang and Jiaxi Xu*
DOI: 10.1039/c4cc00250d
www.rsc.org/chemcomm
An efficient synthesis of 1-aryl-benzo-c-sultams, 1-aryl-1,3-dihydro- (2, Y = CH, R1 = NO2, X = F)11 and an intramolecular oxidative
benzo[c]isothiazole-2,2-dioxides, was achieved in 65–99% yields via substitution of hydrogen from N-nitroaryl (or pyridinyl)alkanesulfo-
the Rh-catalyzed intramolecular aromatic C–H functionalization of namides (2, Y = CH, R1 = 3-NO2) under strongly basic conditions
N,N-diaryl diazosulfonamides with 0.5 mol% Rh2(oct)4 as the catalyst.
(Conditions B, eqn (1)).13b Notably, these approaches are not applic-
able to substrates with two aryl groups at the nitrogen atom of
Recently, sultams have attracted increasing attention in synthetic sultams, because of the facile N–S bond cleavage under the strongly
and medicinal chemistry1 because of their wide spectrum of bio- basic or nucleophilic conditions. Other approaches include the
activities, such as antiviral, antimicrobial, antileukemic, anticancer, intramolecular Ullmann-type coupling of 2-chlorobenzylsulfon-
enzyme inhibition, etc.2 In the continuation of our work on the amide (3) by heating with K2CO3 and copper–bronze powder in
preparation of sulfonic acid derivatives,3 now we focus our attention N,N-dimethylaniline (Conditions a, eqn (2)) and intramolecular
on the benzo-g-sultams, namely 1,3-dihydrobenzo[c]isothiazole-2,2- cyclization of sodium 2-aminobenzylsulfonate (4) in refluxing POCl3
dioxides (1). In the pharmaceutical field, benzosultams 1 were (Conditions b, eqn (2)).13c However, these approaches also suffer
designed as a key structural motif in ORL1-receptor antagonists from the use of toxic reagents and harsh conditions. Recently, Zard
used for the treatment of pain and various CNS disorders.4 In the reported a radical-based route using N-aryl ethenesulfonamides (5)
synthetic field, benzosultams 1 undergo thermal extrusion of SO2 to and xanthates (6) with a stoichiometric radical initiator lauroyl
form reactive 1-azadiene-type intermediates aza-ortho-xylylenes,5 peroxide, with low to moderate yields and unavoidable side-
which are building blocks for the construction of heterocyclic reactions in most cases14 (eqn (3), Scheme 1). However, all reported
systems, such as 1,2,3,4-tetrahydroquinolines,6 benzimidazoles,7
perimidines,7 benzoxazoles,7 5,6-dihydro-4H-thiopyrans,8 and
3,4-dihydrothiophenes,8 2-vinylanilines or imines,6b,9 2-aminobenzyl
derivatives,10 ortho-aminobenzophenones,11 etc. Moreover the
modification of the benzosultam backbone was reported as well.12
In contrast to the importance, only limited synthetic approaches
toward the benzo-g-sultams 1 have been reported since 1963 (eqn (1),
Scheme 1).11,13 The first approach, introduced by Bunnett,13a
involves the generation of benzyne intermediates from
N-20-chloroaryl alkanesulfonamides (2, X = Cl) under extremely
strong basic conditions (Conditions A, eqn (1)), affording
desired 1-alkyl products in low to moderate yields along with
byproducts. The harsh conditions significantly limit its application.
Later, Wojciechowski developed an intramolecular SNAr reaction
strategy using N-fluoronitroaryl (or pyridinyl) alkanesulfonamides
State Key Laboratory of Chemical Resource Engineering, Department of Organic
Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing
100029, P. R. China. E-mail: jxxu@mail.buct.edu.cn; Fax: +86 10 64435565
† Electronic supplementary information (ESI) available: Experimental procedures for
the preparation of intermediates 7 and products 1, analytical data and copies of 1H
and 13C NMR spectra of intermediates 7 and products 1. See DOI: 10.1039/c4cc00250d
Scheme 1 Approaches toward benzo-g-sultams.
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Table 1 Optimization of conditionsa
Table 2 Rh-catalyzed synthesis of benzo-g-sultamsa
Entry Cat.
Cat. (mol%) Solventb Time (h) Yieldc (%)
1
2
3
4
5
6
7
8
Rh2(OAc)4
Rh2(oct)4
1
1
1
1
1
1
1
1
1
1
0.5
0.25
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
DCM
DCE
DCE
11
0.5
13
3
1
2
24
40
46
20
0.5
6
28d
99
91
71
79
Cu(acac)2
Cu(OAc)2ꢀH2O
Cu(OTf)2
(CuOTf)2C6H6
Co(TDMPP)
PhCOOAg
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
Rh2(oct)4
50
o1e
0 f
9
90
99
99
99
10
11
12
a
a
Reactions were conducted on a 0.25 mmol scale in 5 mL of solvent. The
yields were obtained by chromatography on silica gel. b Reaction performed
on a 0.07 mmol scale. c Reaction performed on a 0.12 mmol scale.
All the reactions were conducted on a 0.25 mmol scale in 5 mL of
b
c
solvent. All the solvents were dried prior to use. Isolated yield by
chromatography on silica gel. Recovery of 7a was 50%. Recovery of
7a was 79%. Recovery of 7a was 44%.
d
e
f
caused by the ylide formation from the rhodium carbenoid and the
methods are limited to N-unsubstituted or N-alkyl benzo-g-sultams. methoxy group.17a The functionality-tolerance was also tested. The
Therefore, synthesis of N-aryl-benzo-g-sultams (1) under mild condi- installments of halo-atoms are well-tolerated, regardless of fluoro-,
tions with good functionality-tolerance still remains a big challenge. chloro-, or bromo-atoms, on the aryl rings, with the formation of the
The metal-catalyzed direct C–H functionalization with diazo desired benzosultams 1d, 1e, and 1f in satisfactory yields of 80%,
compounds as starting materials has been proved as a powerful tool 85%, and 73%, respectively. The presence of the halogens makes it
for constructing C–C bonds in synthetic chemistry.15 Of great possible to further modify the aryl rings to access more complex
importance is the intramolecular version of the reactions, which structures. The impact of substituted positions on the aryl rings was
always give cyclic products that may possess bioactivities. However, also assessed. With 3,5-dimethyl and 3,5-dimethoxy attached, the
very limited attention has been paid to the intramolecular C–H diazosulfonamides 7g and 7h, especially 7h, exhibit a highly con-
functionalization with diazosulfonyl compounds16—a useful trans- gested feature between the two aryl rings and the sulfonyl group (See
formation to form a thia-ring.17 We found that the aromatic C–H 1H NMR in ESI†); however, the formation of benzosultams 1g and 1h
functionalization within N-aryl diazosulfonamides 7 leads to benzo- proceeds smoothly in 68% and 67% yields, respectively. The regio-
sultams 1 in a clean and efficient fashion. To the best of our selectivities of the C–H functionalization were initially investigated
knowledge, this is the first example that employs diazosulfonamides, with N-phenyl-N-(o-tolyl) diazosulfonamide 7i as a model, and three
a new class of compounds of the diazo family, to efficiently construct inseparable products 1i, 10i and 100i were obtained in a total yield of
designed target molecules.
94% with the ratio not determined. This observation encouraged
The optimization of the reaction of 7a to 1a was conducted and is us to do further studies on the aromatic C–H functionalization
presented in Table 1. Rh2(oct)4 worked better than Rh2(OAc)4 at the selectivity.
same catalyst loading (1 mol%) and gave an excellent yield of 99%
To get more knowledge on the regioselectivity of the aromatic
(entries 1 and 2). The copper catalysts, such as Cu(acac)2, Cu(OAc)2ꢀ C–H insertion, we synthesized a set of N-aryl-N-( p-chlorophenyl)-
H2O, Cu(OTf)2, and CuOTf, were also able to catalyze the reaction, diazosulfonamides 7j–n and subjected them to the standard con-
but either long time was necessitated (entry 3) or lower yields were ditions. In most cases the two regiomers can be isolated by column
obtained (entries 4ꢁ6). The selected cobalt and silver catalysts chromatography. The isolated yields and the ratios are presented in
showed no activity (entries 7 and 8). The solvent screening revealed Table 3. It is observed that the aromatic C–H functionalization
that DCE (1,2-dichloroethane) was the most appropriate. At a catalyst occurs at the more electron-rich aromatic rings. Since there is no
loading of 0.5 mol%, Rh2(oct)4 still exhibited high activity. However, distinct difference in the electronic density between phenyl and
further lowering of the catalyst loading to 0.25 mol% led to a long p-tolyl rings, the ratios of 1j :10j and 1k :10k are 46 : 54 and 49 : 51,
reaction time without any loss of yield.
respectively, with very slight preference for the electron-rich C–H
With the optimized conditions, we tried to synthesize a series of functionalization products 10j and 10k. Increasing the electron-
N-aryl substituted benzosultam derivatives 1 (Table 2). This work density of the other aryl ring can obviously enhance the content
commenced with the reaction of symmetric N,N-diaryl diazosulfon- of the electron-rich C–H functionalization products, giving the
amides 7. The presence of donating groups such as methoxy and ratios of 1l :10l and 1m :10m as 39 : 61 and 36 : 64, respectively. In
methyl groups on the diazosulfonamides 7b and 7c does not affect the presence of two strongly electron-donating methoxy groups in
the reactivities, giving rise to the desired products 1b and 1c in 65% diazosulfonamide 7n, the electron-rich C–H functionalization pro-
and 94% yields, respectively. The lower yield of 1b is presumably duct 10n is generated preferentially with the ratio of 1n :10n as
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Table 3 Regio-selectivity in the Rh-catalyzed formation of benzo-g-
Notes and references
sultamsa
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a
Reactions were conducted on a 0.25 mmol scale in 5 mL of solvent. The
yields were obtained by chromatography on silica gel. The ratios were
determined by the 1H NMR of the crude mixtures. Reactions performed
b
c
on a 0.08 mmol scale. Reaction performed on a 0.14 mmol scale.
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In the reaction of diazosulfonamide 7o, which incorporates both
p-chloro- and o-methyl phenyl rings, the C–H functionalization
prefers to occur at the electron-deficient ring, rather than the
electron-rich phenyl ring. This unexpected result is presumably
caused by the steric effect of the o-methyl group. Surprisingly, the
1H and 13C NMR spectra of product 1o reveal that it consists of two
diastereomers with a ratio of 47 : 53 (see ESI†). We assumed that
because of the steric hindrance between the o-methyl group and
the sulfonyl group, the o-methylphenyl ring cannot freely rotate
around the C–N bond. With respect to diazosulfonamide 7p,
it follows the general rule that the C–H functionalization
predominantly takes place at the more electron-rich a-position
of the b-naphthyl ring, giving inseparable products 1p and 1p0
with a ratio of 15: 85.
In conclusion, we have successfully realized the synthesis of
N-aryl substituted benzo-g-sultams via the Rh-catalyzed intra-
molecular aromatic C–H functionalization of N,N-diaryl diazo-
sulfonamides. This method benefits from the advantages of
mild and clean conditions, high efficiency, and low catalyst
loading. Notably, this report provides the first example of
diazosulfonamides, a new class of compounds in the diazo
family, and also makes them suitable materials for the pre-
paration of N-aryl substituted benzo-g-sultams that are not
accessible by previous methods. Further studies on the proper-
ties of diazosulfonamides are in progress.
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The project was supported by The National Basic Research
Program of China (No. 2013CB328905) and the National Natural
Science Foundation of China (No. 21372025 and 21172017).
3618 | Chem. Commun., 2014, 50, 3616--3618
This journal is ©The Royal Society of Chemistry 2014