Palladium-Catalyzed Regio- and Chemoselective Reactions of 2-Bromobenzyl Bromides: Expanding the Scope for the Synthesis of Biaryls Fused to a Seven-Membered Sultam

Article abstract of DOI:10.1002/ejoc.201501032

Speedy access to biaryls fused to seven-membered sultams was achieved by starting from readily accessible N-alkylbenzenesulfonamides and 2-bromobenzyl bromides. The protocol features a domino reaction and proceeds through an N-benzylation followed by an intramolecular direct C-H arylation that occurs ortho to the sulfonamide group. A palladium-catalyzed domino reaction of N-alkylbenzenesulfonamides and 2-bromobenzyl bromides gives biaryls fused to a seven-membered sultam. This approach employs readily accessible substrates and provides speedy access to fused-ring compounds.

Full text of DOI:10.1002/ejoc.201501032

FULL PAPER
DOI: 10.1002/ejoc.201501032
Palladium-Catalyzed Regio- and Chemoselective Reactions of 2-Bromobenzyl
Bromides: Expanding the Scope for the Synthesis of Biaryls Fused to a Seven-
Membered Sultam
Joydev K. Laha,*[a] Shubhra Sharma,[a] and Neetu Dayal[a]
Keywords: Heterocycles / Sulfonamides / Fused-ring systems / Domino reactions / Regioselectivity
Speedy access to biaryls fused to seven-membered sultams
protocol features a domino reaction and proceeds through an
was achieved by starting from readily accessible N-alkyl- N-benzylation followed by an intramolecular direct C–H
benzenesulfonamides and 2-bromobenzyl bromides. The
arylation that occurs ortho to the sulfonamide group.
Introduction
The sulfonamide functional group has long been recog-
nized as an important pharmacophore because of its dis-
tinct ability to improve pharmacological potency and phar-
macokinetic profiles.[1] Recently, biaryls that contain an or-
tho-sulfonamide functionality (e.g., 1 and 2) have been iden-
tified as potent and selective ETA (endothelin-A receptor)
antagonists for use in the treatment of congestive heart fail-
ure (Figure 1).[2] Besides pharmacophoric activity, the bulky
ortho-sulfonamide group can restrict the rotation of the aryl
group along the biaryl C–C axis, which results in atropiso-
mers (e.g., in 1). Biaryls embedded in cyclic sulfonamides
(i.e., biaryl sultams; e.g., 3 and 4) have emerged as privi-
leged structures in drug discovery because of their diverse
enzyme inhibitory activity and active role in selective sero-
tonin reuptake inhibition.[3–5] The structural simplicity of
biaryl sultams belies their preparative complexity, and the
quest for an efficient and convergent synthesis has capti-
vated the attention of synthetic organic chemists.
Towards this endeavor, biaryls that are fused to five-,
six-, or seven-membered sultams and polycyclic sultams
have been synthesized, but often with notable difficulty.[6]
In particular, biaryls that are fused to a seven-membered
sultam have been prepared with limited success. The reper-
toire of methods for the preparation of these biaryl sultams
mainly includes palladium-catalyzed intramolecular direct
arylations of 2-bromobenzenesulfonamide derivatives
(Scheme 1).[7] Previously, we reported the competitive for-
mation of seven-membered biaryl sultams during the prepa-
Figure 1. Biaryl sulfonamides that contain an ortho-sulfonamide
group and biaryl sultams.
ration of dihydrophenanthridines and dibenzoazepines.[8]
Recently, our group also developed a palladium-catalyzed
intramolecular oxidative coupling strategy that involves
C(sp2)–H double bonds for the synthesis of five-,[9] six-,[10]
and seven-membered[10] (hetero)biaryl sultams by using
AgOAc as a mild oxidant. Subsequently, Youn et al. re-
ported the competitive formation of seven-membered biaryl
sultams in the ortho-C–H hydroxylation of N-sulfonylben-
zylamines by using K2S2O8 as a strong oxidant.[11] The lim-
ited substrate scope, the preparation of elaborate precursors
for intramolecular direct arylations, and the competitive
formation of byproducts obviate the need to develop an al-
ternative approach to prepare these compounds. Recently,
we unveiled an important discovery, in which a nucleophilic
ring-opening of a heterobiaryl sultam could provide reason-
able access to heterobiaryl sulfonamides.[9] Expedient access
to biaryls fused to seven-membered sultams could provide
ample opportunities to compare their reactivity with (het-
ero)biaryl sultams towards nucleophilic ring-opening reac-
tions. Herein, we describe the exclusive synthesis of seven-
membered biaryl sultams from readily accessible N-alkyl-
ated benzenesulfonamides and 2-bromobenzyl bromides by
employing an intramolecular direct arylation reaction.
[a] Department of Pharmaceutical Technology (Process
Chemistry), National Institute of Pharmaceutical Education
and Research,
S. A. S. Nagar, Punjab 160062, India
E-mail: jlaha@niper.ac.in
http://www.niper.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501032.
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Scheme 1. Approaches to biaryl sultams that contain a seven-membered ring.
110 °C for 18 h gave biaryl sultam 4 in 60% yield (Table 1,
Entry 1). A noticeable amount (30%) of N-benzylated
product 7 could account for the quantitative conversion of
reactants into products. When the ligand was changed from
PPh3 to PCy3 (Cy = cyclohexyl), the yield of 4 further im-
proved to 70% (Table 1, Entry 2). The palladium(0) species
Pd(PPh3)4 had a deleterious effect compared with that of
Pd(OAc)2 and PCy3 (Table 1, Entry 3). Palladium plays a
catalytic role in the reaction, as no biaryl sultam 4 was ob-
tained from a reaction of 5a and 6a without Pd(OAc)2
(Table 1, Entry 4). A detailed investigation to determine the
optimized conditions by varying different reaction param-
eters ultimately secured the combination that produced the
most acceptable yield (70%) of biaryl sultam 4.
Results and Discussion
Our study largely focused on developing the synthesis of
N-alkylated biaryl sultams that contain a seven-membered
ring, which could then be subjected to a nucleophilic ring-
opening reaction to obtain biaryl sulfonamides, which are
structurally related to BMS-207940 (1; a potent and selec-
tive endothelin-A receptor antagonist). N-Alkylbenzene-
sulfonamides and 2-bromobenzyl bromide were judiciously
chosen as the two starting coupling partners because:
(a) these substrates are readily accessible, (b) their use
would avoid the formation of dibenzoazepines, which oc-
curred in our previous study that used N-aryl-substituted
sulfonylbenzylamines and 2-bromobenzyl bromide as the
two coupling partners, and (c) an anticipated domino reac-
Notably, the reaction of 5a and 6a follows a domino se-
tion between these substrates could enable the formation of quence that involves N-benzylation followed by an intramo-
the desired biaryl sultams. lecular direct arylation of the benzenesulfone ring, and any
Our optimization study thus commenced with readily competitive formation of N-arylated product from the first
available N-methylbenzenesulfonamide (5a) and 2-bromo- step is controlled under the optimized conditions. Import-
benzyl bromide (6a). Heating of a mixture of the reactants antly, the intramolecular direct arylation in our study is
in the presence of 10 mol-% of Pd(OAc)2, 20 mol-% of complementary to the direct arylations reported in the lit-
PPh3, and Cs2CO3 (3 equiv.) in 1,4-dioxane (200 mm) at erature,[7] in which direct arylation occurs at the benzyl
Table 1. Optimization study for the synthesis of 4 from 5a and 6a.[a]
Entry
Pd source
Ligand
Base
Yield [%][b]
4
7
1
2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
–
PPh3
PCy3
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
60
70
0
30
15
85
83
3[c]
4[d]
PCy3
0
[a] Reagents and conditions: 5a (0.5 mmol), 6a (0.6 mmol), Pd source (0.05 mmol), ligand (0.10 mmol), base (1.5 mmol), 1,4-dioxane
(200 mm), 110 °C, 18 h. [b] Isolated yield. [c] Pd(PPh3)4 (0.10 mmol) was employed. [d] No Pd source was used.
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Synthesis of Biaryls Fused to a Seven-Membered Sultam
ring. The one-pot synthesis of 4 by employing the reaction direct arylation exclusively occurring at the more hindered
of 5a and 6a in the presence of Cs2CO3 followed by the ortho position to the sulfonamide group. Because of the
addition of 10 mol-% of Pd(OAc)2 and 20 mol-% of PPh3 acidic proton ortho to the electron-withdrawing group, di-
also gave 4 in comparable yield.
rect arylation occurred ortho to the sulfonamide unit.[12] On
Next, we investigated the scope of the substrates that the other hand, the benzenesulfonamide with a methoxy
could participate in the domino reaction. N-Alkylbenz- group in meta position yielded biaryl sultam 14 in 67%
enesulfonamides 5a–5m were readily prepared in nearly yield as a result of the cyclization occurring in para posi-
quantitative yields by the reaction of the corresponding alk- tion. In addition, a methyl group in meta position of benz-
ylamines and sulfonyl chlorides, which were commercially enesulfonamide 5i gave a mixture of inseparable isomers,
available. N-Alkylbenzenesulfonamides 5b–5e, which have a and biaryl sultam 15 was afforded in an isomeric ratio of
substituent in para position, worked successfully under the 2:3. The CF3 group in ortho position of N-alkyl-substituted
optimized conditions to yield biaryl sultams 8–11 in 55– sulfonamide 5j also afforded sultam 16, albeit in moderate
72% yield (Table 2). N-Alkylbenzenesulfonamides 5f and yield (45%). The reaction between 5a and 5-bromo-6-(bro-
5g, which have electron-withdrawing groups in meta posi- momethyl)benzo[d][1,3]dioxole (6b) yielded sultam 17 in
tion, produced biaryl sultams 12 and 13 as a result of the 64% yield. A slightly different trend was observed in the
Table 2. Synthesis of various substituted biaryl sultams that contain a seven-membered ring.[a]
[a] Reagents and conditions: 5a–5m (0.5 mmol), 6a or 6b (0.6 mmol), Pd source (0.05 mmol), PCy3 (0.10 mmol), Cs2CO3 (1.5 mmol), 1,4-
dioxane (200 mm), 110 °C, 18 h. [b] PPh3 was used instead of PCy3.
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synthesis of 18 and 19 compared with that of 9 and 10. both 7 and 22 under the optimized conditions yielded 4
Sluggish reaction was observed with N-propyl- and N-but- along with a significant amount of unreacted 22 (Equa-
ylbenzensulfonamides 5k and 5l under the optimized reac- tion 2). The higher reactivity of 7, largely because of the
tion conditions, which delivered biaryl sultams 18 and 19 acidic ortho-hydrogen atom α to the sulfonyl group, facili-
in 45–60% yield. Gratifyingly, employing the less reactive tates the intramolecular direct arylation of the benzenesulf-
PPh3 ligand instead of PCy3 turned out to be more efficient one ring.
and yielded 18 and 19 in 81 and 64% yield, respectively.
Notably, the functional groups of this study were well toler-
ated under the optimized reaction conditions, which could
enable further synthetic manipulations. Compared with pre-
vious studies,[7] the current protocol demonstrates a wide
substrate scope for the preparation of these biaryl sultams,
(2)
and the yields from this study are either comparable or bet-
ter than the overall yields obtained from multiple steps.[7]
A plausible mechanism for the domino reaction is de-
N-Benzyl-substituted biaryl sultam 20 was prepared to
picted in Scheme 2.
A base-mediated N-benzylation
demonstrate the ready accessibility of a biaryl fused to a
seven-membered NH-free sultam. Debenzylation (unopti-
mized) of 20 by using H2 (50 psi) in the presence of 10 mol-
% Pd/C in methanol gave NH-free biaryl sultam 21 (Equa-
tion 1). A single-crystal X-ray structure was obtained for
compound 20 (Figure 2).[13]
of 5a with 2-bromobenzyl bromide gives 7 followed by the
oxidative insertion of palladium(0) into the aryl bromide
moiety to lead to the formation of 23. A concerted
metalation–deprotonation (CMD) reaction could form bi-
aryl palladium(II) intermediate 25, which upon reductive
elimination gives 4 with the concomitant release of palla-
dium(0).
(1)
Scheme 2. Plausible mechanism for the intermolecular domino re-
action.
Figure 2. ORTEP diagram of 20.
Conclusions
In the course of our study, we had the opportunity to
compare the reactivity of 7 with that of N-benzyl-2-bromo-
The expedient synthesis of the seven-membered biaryl
N-methylbenzenesulfonamide (22),[7b] which could demon- sultams from N-alkylated benzenesulfonamides and 2-bro-
strate the relative ease of the intramolecular direct arylation mobenzyl bromides has been developed. Although the pro-
on the benzenesulfone versus the benzyl ring. Under our tocol described herein complements a reported procedure,
optimized reaction conditions, the intramolecular direct our protocol features a domino reaction from readily ac-
arylation of 7 or 22 independently gave 4 in comparable cessible substrates, which provides speedy access to biaryl
yields. However, a competition experiment that involved sultams that are difficult to prepare by other methods. The
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Synthesis of Biaryls Fused to a Seven-Membered Sultam
H), 2.44 (s, 3 H), 1.54–1.44 (m, 2 H), 0.87 (t, J = 7.4 Hz, 3 H) ppm.
13C NMR: δ = 143.3, 136.9, 129.6, 127.1, 44.9, 22.9, 21.5,
11.1 ppm. HRMS: calcd. for C10H16NO2S [M + H]+ 214.0902;
found 214.0900.
palladium-catalyzed regio- and chemoselective reaction of
2-bromobenzyl bromides with N-alkylbenzenesulfonamides
is especially noteworthy. Our protocol offers facile access to
biaryl sultams that have a seven-membered ring and a free
NH group, which is needed for late-stage diversification in
drug discovery. The nucleophilic ring-opening reaction of
the prepared biaryl sultams to synthesize biaryls with an
ortho-sulfonyl group is currently under investigation.
N-Butyl-4-methylbenzenesulfonamide (5d): Viscous oil (111 mg,
98%). IR (neat): ν = 3284, 2959, 2873, 1426, 1325, 1160, 1094,
˜
815 cm–1. 1H NMR: δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.32 (d, J =
8.0 Hz, 2 H), 4.78 (s, 1 H), 2.94 (q, J = 6.7 Hz, 2 H), 2.44 (s, 3 H),
1.48–1.41 (m, 2 H), 1.34–1.24 (m, 2 H), 0.85 (t, J = 7.4 Hz, 3 H)
ppm. 13C NMR: δ = 143.2, 137.0, 129.6, 127.1, 42.9, 31.5, 21.5,
Experimental Section
19.6, 13.5 ppm. HRMS: calcd. for C11H18NO2S [M
228.1058; found 228.1054.
+
H]+
General Methods: Unless noted otherwise, all reagents and solvents
were purchased from commercial sources and used as received. All
palladium-catalyzed reactions were performed in a screw-cap se-
4-Chloro-N-methylbenzenesulfonamide (5e): Off-white solid
(101 mg, 98%); m.p. 60–62 °C. IR (KBr): ν = 3304, 2917, 1663,
˜
1
aled tube. The H and 13C NMR spectroscopic data were recorded
1477, 1395, 1159 cm–1. 1H NMR: δ = 7.82 (d, J = 8.6 Hz, 2 H),
7.52 (d, J = 8.7 Hz, 2 H), 4.57 (s, 1 H), 2.69 (d, J = 5.4 Hz, 3 H)
ppm. 13C NMR: δ = 143.4, 135.7, 129.7, 127.2, 29.2, 21.5 ppm.
HRMS: calcd. for C7H9ClNO2S [M + H]+ 206.0043; found
206.0041.
with a 400 MHz spectrometer. CDCl3 was used as the solvent along
with Me4Si as the internal standard. Coupling constants (J) are
reported in Hz. Column chromatography was performed on silica
gel (100–200 mesh). High-resolution mass spectra were obtained by
using electron-spray ionization and a TOF mass analyzer. All melt-
ing points were recorded with a melting-point apparatus equipped
with a calibrated thermometer. New compounds were charac-
terized by melting point, 1H NMR, 13C NMR, IR, and HRMS
analyses. Compound 6a was purchased from a commercial vendor.
3-Fluoro-N-methylbenzenesulfonamide (5f): Off-white solid (92 mg,
97%); m.p. 61–63 °C. IR (KBr): ν = 3291, 2924, 1472, 1330, 1225,
˜
1155, 1085 cm–1. 1H NMR: δ = 7.69 (td, J = 7.7, 1.4 Hz, 1 H), 7.59
(td, J = 8.2, 2.2 Hz, 1 H), 7.57–7.51 (m, 1 H), 7.31 (ddt, J = 8.2,
2.5, 0.8 Hz, 1 H), 4.71 (d, J = 4.3 Hz, 1 H), 2.71 (d, J = 5.3 Hz, 3
H) ppm. 13C NMR: δ = 163.7 (d, J = 250 Hz), 140.9 (d, J = 28 Hz),
131.0 (d, J = 8 Hz), 122.9 (d, J = 3 Hz), 120.0 (d, J = 221 Hz),
114.7 (d, J = 24 Hz), 29.3 ppm. HRMS: calcd. for C7H9FNO2S [M
+ H]+ 190.0338; found 190.0334.
General Procedure for the Synthesis of Sulfonamides 5a–5m: A solu-
tion of benzenesulfonyl chloride (1 equiv.) in anhydrous CH2Cl2
(5 mLmmol–1) was treated with the alkylamine (1.2 equiv.) drop-
wise at 0 °C. The resulting solution was stirred at room temperature
for 15 min, and water (20 mL) was then added. The aqueous layer
was extracted with CH2Cl2 (3ϫ 20 mL). The combined organic
layers were dried with Na2SO4 and concentrated. The residue was
triturated with hexane to provide a solid that was used in the next
step without further purification.
N-Methyl-3-nitrobenzenesulfonamide (5g): Off-white solid (104 mg,
97%); m.p. 102–104 °C. IR (KBr): ν = 3306, 3080, 2925, 1400,
˜
1333, 1171 cm–1. 1H NMR: δ = 8.72 (t, J = 1.8 Hz, 1 H), 8.46 (ddd,
J = 8.2, 2.3, 1.1 Hz, 1 H), 8.21 (td, J = 7.8, 1.4 Hz, 1 H), 7.77 (t,
J = 8.2 Hz, 1 H), 4.68 (s, 1 H), 2.75 (d, J = 5.3 Hz, 3 H) ppm. 13C
NMR: δ = 141.3, 132.7, 130.5, 127.2, 122.4, 29.3 ppm. HRMS:
calcd. for C7H9N2O4S [M + H]+ 217.0283; found 217.0278.
General Procedure for the Synthesis of Biaryl Sultams 4 and 8–20:
To a screw-cap sealed tube was added a mixture of the sulfonamide
(0.5 mmol), Pd(OAc)2 (10 mol-%), the ligand (20 mol-%), and
Cs2CO3 (3 equiv.) in dioxane (2.5 mL). The system was purged with
nitrogen for 5–10 min, and 2-bromobenzyl bromide (0.6 mmol) was
added. The reaction mixture was heated at 110 °C for 18 h, and
water (20 mL) was then added. The aqueous layer was extracted
with EtOAc (3ϫ 20 mL). The combined organic layers were dried
with Na2SO4 and concentrated to give a residue, which upon col-
umn chromatography (silica; EtOAc/hexanes, 1:9 to 1:4) gave the
biaryl sultam.
3-Methoxy-N-methylbenzenesulfonamide (5h): Viscous oil (97 mg,
97%). IR (neat): ν = 3294, 2942, 2839, 1478, 1316, 1157, 1038 cm–1.
˜
1H NMR: δ = 7.46–7.43 (m, 1 H), 7.42 (s, 1 H), 7.40–7.38 (m, 1
H), 7.12 (td, J = 7.2, 2.0 Hz, 1 H), 4.82 (s, 1 H), 3.86 (s, 3 H), 2.66
(d, J = 5.5 Hz, 3 H) ppm. 13C NMR: δ = 160.0, 139.8, 130.1, 119.3,
119.1, 111.8, 55.6, 29.3 ppm. HRMS: calcd. for C8H12NO3S [M +
H]+ 202.0538; found 202.0533.
N,3-Dimethylbenzenesulfonamide (5i): Viscous oil, (91 mg, 98%).
IR (neat): ν = 3435, 1446, 1322, 1155, 1097 cm–1. 1H NMR: δ =
˜
N-Methylbenzenesulfonamide (5a): Viscous oil (83 mg, 98%). IR
7.67–7.65 (m, 2 H), 7.43–7.39 (m, 2 H), 4.30 (br. s, 1 H), 2.66 (d,
J = 5.4 Hz, 3 H), 2.43 (s, 3 H) ppm. 13C NMR: δ = 139.3, 138.5,
133.5, 128.9, 127.5, 124.3, 29.3, 21.3 ppm. HRMS: calcd. for
C8H12NO2S [M + H]+186.0589; found 186.0581.
(neat): ν = 3584, 3292, 2924, 2854, 1633, 1447, 1311, 1157,
˜
1093 cm–1. 1H NMR: δ = 7.88 (d, J = 7.3 Hz, 2 H), 7.59 (t, J =
7.2 Hz, 1 H), 7.5 (t, J = 7.5 Hz, 2 H), 5.03 (s, 1 H), 2.64 (d, J =
5.3 Hz, 3 H) ppm. 13C NMR: δ = 138.7, 132.7, 129.1, 127.2,
29.2 ppm. HRMS: calcd. for C7H10NO2S [M + H]+ 172.0432;
found 172.0430.
N-Methyl-2-(trifluoromethyl)benzenesulfonamide (5j): Off-white so-
lid (117 mg, 98%); m.p. 82–83 °C. IR (KBr): ν = 3336, 2947, 1442,
˜
1398, 1314, 1275, 1166 cm–1. 1H NMR: δ = 8.25–8.22 (m, 1 H),
7.91–7.88 (m, 1 H), 7.76–7.69 (m, 2 H), 4.68 (br. s, 1 H), 2.75 (d,
J = 5.3 Hz, 3 H) ppm. 13C NMR: δ = 137.4, 132.7, 132.3, 132.1,
128.5 (q, J = 6 Hz), 127.7, 124.3 (q, J = 276 Hz), 29.3 ppm. HRMS:
calcd. for C8H9F3NO2S [M + H]+ 240.0306; found 240.0305.
N,4-Dimethylbenzenesulfonamide (5b): White solid (98 mg, 98%);
m.p. 70–71 °C. IR (KBr): ν = 3270, 2917 , 1454, 1317, 1156 cm–1.
˜
1H NMR: δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H),
4.85 (s, 1 H), 2.64 (d, J = 5.3 Hz, 3 H), 2.44 (s, 3 H) ppm. 13C
NMR: δ = 143.4, 135.7, 129.7, 127.2, 29.2, 21.5 ppm. HRMS:
calcd. for C8H12NO2S [M + H]+ 186.0589; found 186.0586.
N-Propylbenzenesulfonamide (5k): Viscous oil, (96 mg, 97%). IR
4-Methyl-N-propylbenzenesulfonamide (5c): Off-white solid
(neat): ν = 3293, 3066, 2936, 2877, 1447, 1317, 1153, 1092,
˜
(103 mg, 97%); m.p. 90–93 °C. IR (KBr): ν = 3423, 2970, 1503, 754 cm–1. 1H NMR: δ = 7.90–7.88 (m, 2 H), 7.58 (tt, J = 7.3,
˜
1
1393, 1161, 1035, 745 cm–1. H NMR: δ = 7.78 (d, J = 8.3 Hz, 2
1.2 Hz, 1 H), 7.56–7.51 (m, 2 H), 4.72 (t, J = 5.6 Hz, 1 H), 2.94 (q,
J = 7 Hz, 2 H), 1.54–1.45 (m, 2 H), 0.88 (t, J = 7.4 Hz, 3 H) ppm.
H), 7.33 (d, J = 8.4 Hz, 2 H), 4.68 (s, 1 H), 2.91 (q, J = 6.8 Hz, 2
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13C NMR: δ = 140.0, 132.5, 129.1, 127.0, 44.9, 22.9, 11.0 ppm.
HRMS: calcd. for C9H14NO2S [M
200.0740.
128.4, 128.3, 56.0, 39.0 ppm. HRMS: calcd. for C14H13ClNO2S [M
+ H]+ 294.0356; found 294.0346.
+
H]+ 200.0745; found
1-Fluoro-6-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide
(12): Off-white solid (120 mg, 87%); m.p. 140–142 °C. IR (KBr): ν
˜
N-Butylbenzenesulfonamide (5l): Viscous oil (104 mg, 98%). IR
= 3351, 3088, 2817, 1448, 1338, 1186, 704 cm–1. 1H NMR: δ = 7.82
(dd, J = 7.6, 0.4 Hz, 1 H), 7.60–7.57 (m, 1 H), 7.56–7.51 (m, 1 H),
7.51–7.44 (m, 4 H), 4.06 (s, 1 H), 3.53 (s, 1 H), 2.86 (s, 3 H) ppm.
13C NMR: δ = 160.3 (J = 250.9 Hz), 136.7, 134.0, 133.7, 130.5,
130.1 (J = 4.8 Hz), 129.7 (J = 8.5 Hz), 129.5, 128.9, 126.3, 126.2,
123.4 (J = 3.5 Hz), 121.1, 120.8, 56.0, 39.1 ppm. HRMS: calcd. for
C14H13FNO2S [M + H]+ 278.0651; found 278.0644.
1
(neat): ν = 3285, 2933, 2873, 1447, 1324, 1161, 1094, 755 cm–1. H
˜
NMR: δ = 7.91–7.88 (m, 2 H), 7.59 (tt, J = 7.4, 1.2 Hz, 1 H), 7.56–
7.50 (m, 2 H), 4.79 (br. s, 1 H), 2.93 (t, J = 7.0 Hz, 2 H), 1.47 (q,
J = 6.8 Hz, 2 H), 1.33 (q, J = 7.3 Hz, 2 H), 0.85 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR: δ = 139.9, 132.5, 129.0, 127.0, 42.9, 31.5 ppm.
HRMS: calcd. for C10H16NO2S [M + H]+ 214.0902; found
214.0900.
6-Methyl-1-nitro-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide
N-Benzylbenzenesulfonamide (5m): Off-white solid (121 mg, 98%);
(13): Off-white solid (120 mg, 79%); m.p. 173–175 °C. IR (KBr): ν
˜
m.p. 122–124 °C. IR (KBr): ν = 3330, 2929, 1447, 1325, 1150, 1060,
˜
= 3435, 3084, 2924, 1531, 1439, 1345, 1170 cm–1. 1H NMR: δ =
8.23 (dd, J = 7.8, 1.3 Hz, 1 H), 8.05 (dd, J = 8.3, 1.3 Hz, 1 H), 7.73
(t, J = 8.0 Hz, 1 H), 7.53–7.42 (m, 3 H), 7.23 (d, J = 7.2 Hz, 1 H),
4.19 (d, J = 11.8 Hz, 1 H), 3.70 (d, J = 11.5 Hz, 1 H), 2.91 (s, 3 H)
ppm. 13C NMR: δ = 150.3, 137.5, 135.3, 132.8, 132.5, 130.8, 130.5,
130.3, 129.7, 129.3, 128.0, 127.9, 56.01, 39.12 ppm. HRMS: calcd.
for C14H13N2O4S [M + H]+ 305.0596; found 305.0590.
750 cm–1. 1H NMR: δ = 7.91–7.88 (m, 2 H), 7.61 (tt, J = 8.4,
2.3 Hz, 1 H), 7.55–7.51 (m, 2 H), 7.30–7.27 (m, 3 H), 7.23–7.19 (m,
2 H), 4.77 (t, J = 5.1 Hz, 1 H), 4.18 (d, J = 6.3 Hz, 2 H) ppm. 13C
NMR: δ = 139.9, 136.1, 132.7, 129.1, 128.7, 127.9, 127.8, 127.1,
47.3 ppm. HRMS: calcd. for C13H14NO2S [M + H]+ 248.0745;
found 248.0745.
N-(2-Bromobenzyl)-N-methylbenzenesulfonamide (7): Off-white so-
3-Methoxy-6-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Di-
oxide (14): Off-white solid (97 mg, 67%); m.p. 135–140 °C. IR
lid (133 mg, 78%); m.p. 66–68 °C. IR (KBr): ν = 3400, 2950, 2843,
˜
1454, 1345, 1053, 747 cm–1. 1H NMR: δ = 7.90–7.88 (m, 2 H),
7.68–7.54 (m, 5 H), 7.36 (dt, J = 7.5, 1.0 Hz, 1 H), 7.18 (dt, J =
7.8, 1.6 Hz, 1 H), 4.34 (s, 2 H), 2.72 (s, 3 H) ppm. 13C NMR: δ =
137.5, 134.9, 132.8, 129.8, 129.3, 129.2, 127.9, 127.4, 123.4, 53.5,
35.0 ppm. HRMS: calcd. for C14H15BrNO2S [M + H]+ 340.0007;
found 340.0001.
(KBr): ν = 3400, 2923, 2852, 1604, 1478, 1337, 116 cm–1. 1H NMR:
˜
δ = 7.55 (d, J = 6.4 Hz, 1 H), 7.53 (s, 1 H), 7.52–7.47 (m, 1 H),
7.45–7.38 (m, 3 H), 7.25 (dd, J = 8.3, 2.8 Hz, 1 H), 3.94 (s, 3 H),
3.80 (s, 2 H), 2.91 (s, 3 H) ppm. 13C NMR: δ = 159.4, 140.7, 135.9,
133.3, 131.5, 131.1, 130.1, 129.6, 128.4, 128.3, 119.4, 112.1, 56.2,
55.8, 39.0 ppm. HRMS: calcd. for C15H16NO3S [M
290.0851; found 290.0848.
+
H]+
2,6-Dimethyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide (8):
Off-white solid (98 mg, 72%); m.p. 112–114 °C. IR (KBr): ν =
˜
1,6-Dimethyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide and
3,6-Dimethyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide
1
3284, 2923, 2853, 1461, 1335, 1160 cm–1. H NMR: δ = 7.90 (d, J
= 7.9 Hz, 1 H), 7.53–7.47 (m, 2 H), 7.44–7.42 (m, 3 H), 7.38 (d, J
= 8.0 Hz, 1 H), 3.77 (s, 2 H), 2.88 (s, 3 H), 2.53 (s, 3 H) ppm. 13C
NMR: δ = 144.0, 140.9, 139.3, 133.5, 132.0, 130.5, 130.1, 129.4,
128.9, 128.8, 128.3, 127.6, 56.2, 38.9, 21.6 ppm. HRMS: calcd. for
C15H16NO2S [M + H]+ 274.0902; found 274.0901.
Mixture (15): Off-white solid (102 mg, 75%); m.p. 147–150 °C. IR
(KBr): ν = 3400, 2923, 2852, 1463, 1338, 1163, 749 cm–1. 1H NMR:
˜
δ = 7.86 (d, J = 7.7 Hz, 1 H), 7.80 (s, 0.6 H), 7.59 (d, J = 7.7 Hz,
1 H), 7.50–7.36 (m, 9 H), 4.01 (d, J = 11.4 Hz, 1 H), 3.76 (s, 1 H),
3.42 (d, J = 11.3 Hz, 1 H), 2.87 (s, 2 H), 2.78 (s, 3 H), 2.49 (s, 2
H), 2.42 (s, 3 H) ppm. 13C NMR: δ = 140.9, 138.9, 138.7, 137.4,
137.1, 136.5, 135.6, 135.0, 134.6, 133.9, 133.7, 133.4, 130.2, 130.1,
130.0, 129.8, 129.4, 128.1, 128.7, 128.7, 128.5, 128.3, 127.8, 125.2,
56.2, 39.0, 29, 21.1, 20.8 ppm. HRMS: calcd. for C15H16NO2S [M
+ H]+ 274.0902; found 274.0892.
2-Methyl-6-propyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Diox-
ide (9): Semisolid (102 mg, 68%). IR (neat): ν = 3436, 2925, 2854,
˜
1458, 1335, 1160, 1015, 753 cm–1. 1H NMR: δ = 7.90 (d, J = 8.0 Hz,
1 H), 7.50–7.48 (m, 2 H), 7.43–7.41 (m, 3 H), 7.36 (d, J = 8.0,
1.1 Hz, 1 H), 3.86 (s, 2 H), 3.27 (t, J = 7.4 Hz, 2 H), 2.52 (s, 3 H),
1.75–1.65 (m, 2 H), 1.00 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR: δ =
143.6, 140.9, 139.1, 134.0, 133.9, 130.3, 130.0, 129.2, 128.9, 128.4,
126.8, 53.3, 53.3, 21.5, 21.0, 11.2 ppm. HRMS: calcd. for
C17H20NO2S [M + H]+ 302.1215; found 302.1211.
6-Methyl-4-(trifluoromethyl)-6,7-dihydrodibenzo[d,f][1,2]thiazepine
5,5-Dioxide (16): Off-white solid (74 mg, 45%); m.p. 82–85 °C. IR
1
(KBr): ν = 3340, 2925, 2853, 1455, 1359, 1312, 1176, 763 cm–1. H
˜
NMR: δ = 8.00 (dd, J = 6.8, 2.2 Hz, 1 H), 7.82–7.77 (m, 2 H), 7.54
(dt, J = 7.3, 1.6 Hz, 1 H), 7.48–7.41 (m, 3 H), 3.81 (s, 2 H), 3.02
(s, 3 H) ppm. 13C NMR: δ = 143.3, 142.0, 135.0, 133.1, 132.0,
129.6, 129.5, 129.2, 128.5, 127.5 (q, J = 7 Hz), 123.8 (q, J =
273 Hz), 120.6, 55.6, 39.3 ppm. HRMS: calcd. for C15H13F3NO2S
[M + H]+ 328.0619; found 328.0617.
6-Butyl-2-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide
(10): Off-white solid (86 mg, 55%); m.p. 127–128 °C. IR (KBr): ν
˜
1
= 3301, 2952, 2866, 1465, 1330, 1165, 1094, 773 cm–1. H NMR: δ
= 7.87 (d, J = 7.8 Hz, 1 H), 7.48–7.46 (m, 2 H), 7.41–7.39 (m, 3
H), 7.33 (td, J = 8.0, 0.9 Hz, 1 H), 3.83 (s, 2 H), 3.26 (t, J = 7.4 Hz,
2 H), 2.49 (s, 3 H), 1.70–1.59 (m, 2 H), 1.44–1.35 (m, 2 H), 0.95 (t,
J = 7.4 Hz, 3 H) ppm. 13C NMR: δ = 143.6, 140.9, 139.1, 134.0,
133.9 130.3, 130.0, 129.2, 128.8, 128.4, 126.8, 53.2, 51.3, 29.7, 21.5,
6-Methyl-6,7-dihydro-[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2d]benzo[f]-
[1,2]thiazepine 5,5-Dioxide (17): Off-white solid (96 mg, 64%); m.p.
1
160–162 °C. IR (KBr): ν = 3428, 3232, 2917, 1604, 1440 cm–1. H
˜
20.0, 13.7 ppm. HRMS: calcd. for C18H22NO2S [M
316.1371; found 316.1367.
+
H]+
NMR: δ = 8.01 (dd, J = 8.2, 0.9 Hz, 1 H), 7.71 (dt, J = 8.1, 1.3 Hz,
1 H), 7.56–7.52 (m, 2 H), 6.93 (d, J = 7.7 Hz, 2 H), 6.06 (s, 2 H),
3.66 (s, 2 H), 2.86 (s, 3 H) ppm. 13C NMR: δ = 148.6, 148.1, 139.4,
134.7, 134.5, 133.2, 129.6, 128.0, 127.5, 127.2, 110.6, 108.9, 101.7,
55.8, 38.8 ppm. HRMS: calcd. for C15H14NO4S [M + H]+
304.0644; found 304.0643.
2-Chloro-6-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Diox-
ide (11): Off-white solid (95 mg, 65%); m.p. 150–152 °C. IR (KBr):
1
ν = 3289, 2927, 1443, 1386, 1168 cm–1. H NMR: δ = 7.95 (d, J =
˜
8.3 Hz, 1 H), 7.62 (d, J = 2.0 Hz, 1 H), 7.57–7.50 (m, 2 H), 7.50–
7.43 (m, 3 H), 3.81 (s, 2 H), 2.90 (s, 3 H) ppm. 13C NMR: δ = 6-Propyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide (18):
141.0, 139.6, 139.4, 133.4, 133.3, 130.4, 129.8, 129.6, 129.6, 128.9,
Off-white solid (116 mg, 81%); m.p. 92–95 °C. IR (KBr): ν = 3153,
˜
7890
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7885–7891

Synthesis of Biaryls Fused to a Seven-Membered Sultam
1
2969, 2858, 1460, 1360, 1176, 1012, 768 cm–1. H NMR: δ = 8.02 greatly appreciate the financial support from the Department of
(dd, J = 7.9, 1.1 Hz, 1 H), 7.71 (dt, J = 7.6, 1.2 Hz, 1 H), 7.61 (dd,
J = 7.6, 0.9 Hz, 1 H), 7.56 (dt, J = 7.5, 1.1 Hz, 1 H), 7.50–7.46 (m,
2 H), 7.44–7.43 (m, 2 H), 3.87 (s, 2 H), 3.27 (t, J = 7.4 Hz, 2 H),
1.75–1.66 (m, 2 H), 0.99 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR: δ =
140.8, 139.1, 136.7, 133.8, 132.9, 130.1, 129.7, 129.3, 129.0, 128.5,
128.3, 126.7, 53.4, 53.2, 21.0, 11.2 ppm. HRMS: calcd. for
C16H18NO2S [M + H]+ 288.1058; found 288.1048.
Science and Technology (DST), New Delhi.
[1]
a) A. Kalgutkar, R. Jones, A. Sawant in RSC Drug Discovery
Series No. 1: Metabolism, Pharmacokinetics, and Toxicity of
Functional Groups (Ed.: D. A. Smith), RSC Publishing, Cam-
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lor, Comprehensive Medicinal Chemistry, Pergamon Press, Ox-
ford, 1990, vol. 2, chapter 7.1.
6-Butyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide (19):
Semisolid (96 mg, 64%). IR (CH Cl ): ν = 3280, 2927, 1447, 1336,
˜
2
2
[2]
[3]
a) N. Murugesan, Z. Gu, P. D. Stein, S. Bisaha, S. Spergel, R.
Girotra, V. G. Lee, J. Lloyd, R. N. Misra, J. Schmidt, J. Med.
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U. Többen, C. Chung, S. Pampou, N. Southall, D. Vidovic´, S.
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Austin, D. W. Landry, D. H. Smith, D. S. Auld, Bioorg. Med.
Chem. Lett. 2008, 18, 329–335.
1172, 758, 580 cm–1. 1H NMR: δ = 8.02 (dd, J = 7.9, 1.1 Hz, 1 H),
7.72 (dt, J = 7.5, 1.3 Hz, 1 H), 7.63 (dd, J = 7.7, 1.1 Hz, 1 H), 7.57
(dt, J = 7.6, 1.4 Hz, 1 H), 7.53–7.47 (m, 2 H), 7.46–7.42 (m, 2 H),
3.87 (s, 2 H), 3.30 (t, J = 7.4 Hz, 2 H), 1.70–1.62 (m, 2 H), 1.47–
1.35 (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR: δ = 140.8,
139.1, 136.7, 133.8, 132.9, 130.1, 129.7, 129.3, 129.0, 128.5, 128.3,
126.7, 53.2, 51.5, 29.9, 13.7 ppm. HRMS: calcd. for C17H21NO2S
[M + H]+ 302.1215; found 302.1210.
6-Benzyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-Dioxide (20):
White solid (67 mg, 40%); m.p. 123–124 °C. IR (KBr): ν = 3340,
˜
[4]
[5]
Y. Xie, G. Gong, Y. Liu, S. Deng, A. Rinderspacher, L.
Branden, D. W. Landry, Tetrahedron Lett. 2008, 49, 2320–2323.
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K. D. Dykstra, F. P. DiNinno, T. A. Blizzard, M. L. Ham-
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a) D. K. Rayabarapu, A. Zhou, K. O. Jeon, T. Samarakoon, A.
Rolfe, H. Siddiqui, P. R. Hanson, Tetrahedron 2009, 65, 3180–
3188; b) C. B. Bheeter, J. K. Bera, H. Doucet, Adv. Synth. Ca-
tal. 2012, 354, 3533–3538.
1
2924, 2856, 1445, 1385, 1332, 1168, 1068, 761 cm–1. H NMR: δ =
8.09 (dd, J = 7.8, 1.0 Hz, 1 H), 7.73 (dt, J = 7.6, 1.2 Hz, 1 H),
7.63–7.57 (m, 2 H), 7.51–7.49 (m, 2 H), 7.45–7.34 (m, 6 H), 7.26
(d, J = 7.3 Hz, 1 H), 4.48 (s, 2 H), 3.73 (s, 2 H) ppm. 13C NMR: δ
= 140.7, 139.4, 136.4, 135.8, 133.6, 133.1, 130.0, 129.8, 129.3, 129.0,
128.7, 128.5, 128.5, 128.2, 127.9, 126.9, 55.0, 52.7 ppm. HRMS:
calcd. for C20H17NO2S [M + H]+ 336.1058; found 336.1058.
[6]
[7]
6,7-Dihydrodibenzo[d,f][1,2]thiazipine 5,5-Dioxide (21): Off-white
solid (49 mg, 40%); m.p. 130–132 °C. IR (KBr): ν = 3453, 2924,
˜
1
1591, 1348, 1128 cm–1. H NMR: δ = 8.09 (dd, J = 7.7, 1.1 Hz, 1
[8] J. K. Laha, N. Dayal, R. Jain, K. Patel, J. Org. Chem. 2014,
79, 10899–10907.
H), 7.74 (dt, J = 7.6, 1.3 Hz, 1 H), 7.63–7.57 (m, 2 H), 7.55–7.54
(m, 1 H), 7.53–7.47 (m, 3 H), 5.10 (br. s, 1 H), 4.11 (d, J = 2.4 Hz,
2 H) ppm. 13C NMR: δ = 140.9, 138.9, 137.3, 133.2, 132.4, 130.3,
130.1, 129.7, 129.2, 129.0, 128.4, 126.2, 47.5 ppm. HRMS: calcd.
for C13H12NO2S [M + H]+ 246.0589 found 246.0593.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra, X-ray diffraction study
[12] D. G. Cuadrado, P. D. Mendoza, A. A. C. Braga, F. Maseras,
A. M. Echavarren, J. Am. Chem. Soc. 2007, 129, 6880–6886.
[13] CCDC-1407554 (for 20) contains the supplementary crystallo-
graphic data for the paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
of 20, and references.
Acknowledgments
We thank Mr. Kamal Verma, Indian Institute of Technology (IIT),
Ropar for his assistance with the X-ray crystallographic studies. We
Received: August 7, 2015
Published Online: November 13, 2015
Eur. J. Org. Chem. 2015, 7885–7891
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7891