Palladium-catalyzed regiocontrolled domino synthesis of N-sulfonyl dihydrophenanthridines and dihydrodibenzo[c, e]azepines: Control over the formation of biaryl sultams in the intramolecular direct arylation

Article abstract of DOI:10.1021/jo501910q

A palladium-catalyzed domino N-benzylation/intramolecular direct arylation involving sulfonanilides and 2-bromobenzyl bromides has been developed for the first time, providing a workable access to N-sulfonyl dihydrophenanthridines in good to excellent yields. Under the optimized conditions, the formation of 5,6-dihydrophenanthridines was largely controlled over the formation of biaryl sultams containing a seven member ring. The optimized condition was found extendable to the regiocontrolled domino formation of N-sulfonyl-6,7-dihydro-5H-dibenzo[c,e]azepines over the biaryl sultam formation. Using an appropriate substrate, a biaryl sultam has been obtained exclusively.

Full text of DOI:10.1021/jo501910q

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Article
Palladium-Catalyzed Regiocontrolled Domino Synthesis of N-Sulfonyl
Dihydrophenanthridines and Dihydrodibenzo[c,e]azepines: Control over
the Formation of Biaryl Sultams in the Intramolecular Direct Arylation
Joydev K. Laha, Neetu Dayal, Roli Jain, and Ketul Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501910q • Publication Date (Web): 23 Oct 2014
Downloaded from http://pubs.acs.org on October 27, 2014
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Palladium-Catalyzed Regiocontrolled Domino Synthesis of N-Sulfonyl
Dihydrophenanthridines and Dihydrodibenzo[c,e]azepines: Control over the Formation
of Biaryl Sultams in the Intramolecular Direct Arylation
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Joydev K. Laha,* Neetu Dayal, Roli Jain, and Ketul Patel
Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062
INDIA
Email: jlaha@niper.ac.in
Abstract.
R
control over
N
R
SO2R
Me
NHSO2R
n
up to 98%
(for n = 0)
R
Pd-catal.
n = 0, 1 or 2
O
regiocontrolled
S
Domino Reaction
+
O
N
R
Ph
Br
exclusive
n
R
R
(for n = 1 or 2)
Br
control over
SO2R
N
R
up to 76%
(for n = 1)
A palladiumꢀcatalyzed domino Nꢀbenzylation/intramolecular direct arylation involving
sulfonanilides and 2ꢀbromobenzyl bromides has been developed for the first time providing a
workable access to Nꢀsulfonyl dihydrophenanthridines in good to excellent yields. Under the
optimized conditions, the formation of 5,6ꢀdihydrophenanthridines was largely controlled
over the formation of biaryl sultams containing a seven member ring. The optimized
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condition was found extendable to the regiocontrolled domino formation of Nꢀsulfonylꢀ6,7ꢀ
dihydroꢀ5Hꢀdibenzo[c,e]azepines over the biaryl sultam formation. Using an appropriate
substrate, a biaryl sultam has been obtained exclusively.
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Introduction
Phenanthridines (1) and structurally related phenanathridinones (2) are largely found in
natural sources, exhibiting various biological activities including antibiotic, antiꢀ
inflammatory, and anticancer activity (Figure 1).1 In contrast, dihydrogenated
phenanthridines at the 5ꢀ and 6ꢀpositions viz. 5,6ꢀdihydrophenanthridines (3), are reported to
be poorly natural abundant,2 and often exhibit distinct biological properties compared to the
phenanthridines owing to the absence of electrophilic C=N bond.3 Compared to the diverse
biological profiles of phenanthridines, the biological activity of dihydrophenanthridines4 is
least investigated probably because of poor accessibility to this skeleton. For example, a
dihydrophenanthridine 4 has recently been identified as bradykinin B1 antagonist.5
Figure 1. Dihydrophenanthridine and its structurally related compounds
MeO
N
O
N
N
N
Phenanthridine (1)
H
SO2
Cl
Bradykinin B1 antagonist (4)
Cl
X
N
H
Phenanthridinone (2, X = CO)
Dihydrophenanthridine ( , X = CH2)
3
The synthesis of the two important skeletons 1 and 2 merits extensive discussion.6 However,
less attention has been paid to the synthesis of dihydrophenanthridines 3 or its derivatives.
The available procedure includes biommetic approach,7 PictetꢀSpengler cyclizations,8 domino
CꢀC/CꢀN reactions,9 palladiumꢀcatalyzed intramolecular direct arylations,10 palladiumꢀ
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catalyzed crossꢀcoupling of aryl stannanes with aryl iodides,11 and baseꢀmediated
intramolecular radicalꢀcyclizations (Scheme 1).12 The use of elaborated precursors in many of
these approaches, apparently limited substrate scope in the palladiumꢀcatalyzed reactions,10
and inefficiency of precursors containing a Nꢀsulfonyl group in the radical cyclizations12 are
particularly noteworthy. Several other methods describing the synthesis of
dihydrophenanthridines often produce the product contaminated with phenanthridines,
generated in situ by oxidation of dihydrophenanthridines.13
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Scheme 1: Approaches to 5,6ꢀdihydrophenanthridines or its derivatives
Previous appr oaches
1
NAD(P)H model, hydrogenation7
R
X
N
H/X
Pictet-Spengler
cycl.8
Pd-catal.10,11
RHN
base12
or
or
N
R
Domino C-C/C-N
(R = EWG)
bond form 9
This work
Domino reaction from easily accessible
starting materials
Fast, wide scope
Easy isolation
direct arylation
H
Br
Domino
+
NHSO2R
Br
N
n
Pd-catal.
SO2R
n
Dihydrophenanthridines (n = 0)
Dibenzoazepines (n = 1)
N-benzylation
A Domino reaction is a process involving two or more bondꢀforming transformations that
occur under one reaction condition without adding additional reagents and catalysts, and
subsequent reactions result as a consequence of the functionality formed in the previous
step.14 Transitionꢀmetalꢀcatalyzed reactions have expanded the scope of domino reactions for
the rapid assembly of molecular scaffolds that are medicinally important.15 The development
of a transitionꢀmetalꢀcatalyzed regiocontrolled domino reaction from a set of substrates that
are capable of forming more than one domino product represents a significant challenge. A
regiocontrolled domino reaction to the synthesis of 5,6ꢀdihydrophenanthridine using readily
available substrates is yet to be realized. Our continued effort to develop domino synthesis of
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fused nitrogen heterocycles16 and recent experiences in the synthesis of (NH)ꢀ
phenanthridinone (3)17 led us to explore a domino synthesis of dihydrophenanthridines.
Herein, we report first example of a palladiumꢀcatalyzed regiocontrolled domino reaction
involving sulfonanilides and 2ꢀbromobenzyl bromide providing an expedient access to Nꢀ
sulfonyl dihydrophenanthridines with diverse substitution patterns and its application to the
synthesis of Nꢀsulfonyl ꢀ6,7ꢀdihydrodibenzo[c,e]azepines in good to excellent yields.
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Results and Discussion
Previously, we demonstrated regioselective Nꢀbenzylation of indoles16c and Cꢀbenzylation of
primary benzamides18 over arylations using 2ꢀboromobenzyl bromide as one of the coupling
partners under palladiumꢀcatalyzed conditions. Based on our previous experiences,
sulfonanilides and 2ꢀbromobenzyl bromides were chosen as the two coupling partners for the
synthesis of dihydrophenanthridines in the current investigation. The reasons for choosing a
sulfonyl group protected anilines as one of coupling partners were two folds: a) to prevent the
undesired in situ oxidation of dihydrophenanthridines,13 b) ease of preparation of starting
sulfonanilides together with facile deprotection, if necessary. At the outset, we were inclined
upon a condition that could offer both Nꢀbenzylation followed by intramolecular direct
arylation. Our investigation on finding an optimized condition for the reaction of
sulfonanilide 5 and 2ꢀbromobenzyl bromide (6) ultimately secured a reagent blend consisting
of Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2.5 equiv), and dioxane (200 mM) at 110
0C for 16 h, which afforded compound 710 in 78% yield (Table 1, entry 1). Interestingly, a
competitive domino product 8, a biaryl sultam containing a seven member ring obtained by
intramolecular arylation of 9 on the benzensulfonyl ring, was also isolated in 20% yield.
Similarly, when NꢀTsꢀ1ꢀnapthylamine 1019 was reacted with substituted 2ꢀbromobenzyl
bromide 11, the two domino products 12 and 13 were obtained in 78 and 19% yields,
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respectively (entry 2). The synthesis of biaryl sultam containing a seven member ring has
been reported though limited to a few reports.20 However, the formation of biaryl sultam was
uncovered in the previous palladiumꢀcatalyzed intramolecular direct arylation.10 Clearly, the
conditions developed by us is incongruent from the conditions reported earlier and the results
are quite different.10 Nevertheless, the intramolecular direct arylation on the aniline ring was
largely controlled over the biaryl sultam formation under the optimized conditions.
Furthermore, we envisaged that the formation of biaryl sultam could be avoided completely
by using NꢀMs anilines. To our delight, reaction of compound 1421 and 6 gave
dihydrophenanthridine 1522 in 96% yield (entry 3). Compound 14 exhibited similar reactivity
with a different coupling partner 1623 affording 15 in 95% yield (entry 4). Interestingly, when
NꢀTosyl 2,6ꢀdimethylaniline 1724 was subjected to reaction with 6 under the optimized
condition, intramolecular arylation occurred exclusively on the benzenesulfonyl ring leading
to the formation of biaryl sultam 18 albeit in poor yield (entry 5, 32% yield).
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Table 1: Optimization studya
R6
Br
R
R
+
X
R3
NHPG
R2
N-Ts aniline (5)
N-Ts 1-naphthylamine (10)
14
6 R,R = H,H; X = Br
11 R,R = -O-CH2O-; X = Br,
16 R,R = H,H; X = OTs
N-Ms aniline (
)
N-Ts 2,6-dimethylaniline (17)
reagents and
conditions
R3
Br
R2
SO2
R6
H
N
O
S
N
H
N
R
Me
O
7
R = Ts
15 R = Ms
9
Me
8
R2,R3,R6 = H,H,H
18 R2,R6 = Me,Me, R3 = H
O
O
Me
Br
N
N
SO2
Me Ts
N
19
O
Ts
12
O
Me
13
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Entry Reagents and conditions
Substrates DHP ( %)b Sultam (%)b
6
7
1
Pd(OAc)2, PPh3, Cs2CO3, 5 + 6
7 (78%)
8 (20%)
8
9
2
dioxane, 110 °C, 16 h
10 + 11
14 + 6
14 + 16
17 + 6
12 (78%)
15 (96%)
15 (95%)
13 (19%)
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3
4
5c
18 (32%)
a
Sulfonanilide (0.5 mmol), 2ꢀbromobenzyl bromide (0.5 mmol), Pdꢀsource (10 mol%), ligand (20 mol%), base
(1.25 mmol), solvent (0.2 M), temp, 16 h; b Isolated yield; c NꢀTsꢀbenzylꢀ2,6ꢀdimethyl aniline 19 formed in 65%
yield.
We next investigated the formation of dihydrophenanthrdines using other NꢀTosyl or Nꢀ
Mesyl derivatives of anilines under the optimized condition. The sulfonalides 20-32 were
prepared by reacting anilines and sulfonyl chlorides.25 Under the optimized condition, the
sulfonanilides 20,26 21,27 and 2228 containing an electronꢀdonating or withdrawing group at
the 2ꢀposition exhibit similar reactivity with 6 affording dihydrophenanthridines 33-35 in
excellent yields (Table 2). While the sulfonanilide 2329 containing a substituent at the 4ꢀ
position sustained similar reactivity with 6 yielding dihydrophenanthridine 36 in 92% yield,
compound 2430 afforded dihydrophenanthridine 37 in somewhat reduced yield. Interestingly,
3ꢀsubstituted sulfonanilides 25 and 2627 formed only one regioisomer of
dihydrophenanthridines 38 and 39, resulted from intramolecular direct arylation occurred
exclusively at the paraꢀposition to the concerned group. However, 3ꢀnitro sulfonanilides 2727
or 2831 exerted good regiocontrol in the formation of regioisomeric dihydrophenanthridines
(40 and 41) or (42 and 43), which upon silica chromatography furnished pure
dihydrophenanthridines. A complete regioselectivity was observed in the synthesis of 44 that
resulted from intramolecular direct arylation occured exclusively at the orthoꢀposition to the
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NO2 group. The sulfonanilides with a methylenedioxy (ꢀOCH2Oꢀ) group in aniline,
5
6
benzenesulfonyl, or both rings also reacted with 6 or 11 regioselectively resulting in
7
8
dihydrophenanthridines 45-48 in excellent yields.
A
triꢀmethoxy substituted
9
dihydrophenanthridine 49 was synthesized from 31,32 which indicated intramolecular direct
arylation occurred at the orthoꢀ to a methoxy group. The application of this protocol was also
extended to the synthesis of dihydrobenzo[c]phenanthridine 50. A complete regiocontrol
observed in the synthesis of many NꢀTosyl dihydrophenanthridines reported herein is
particularly noteworthy. In addition, mild reaction conditions make the protocol especially
attractive.
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45
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48
49
50
51
52
53
54
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58
59
60
Table 2: Synthesis of various substituted 5,6-dihydrophenanthridines
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Br
O
4
5
6
R
+
O
NHPG
Br
20-32
6, 11
7
8
Pd(OAc)2, PPh3, Cs2CO3
dioxane, 110 °C, 16 h
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
32
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36
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R
N
33-50
PG
R
N
R
N
N
R
Ms
Ms
Ms
33 R = Me (94%)
34 R = F (92%)
35 R = CF3 (90%)
38 R = CO2Et (71%)
39 R = Me (80%)
36 R = Cl (92%)
37 R = NO2 (72%)
O
O
O
NO2
O
O2N
N
N
PG
N
PG
44 (84%)
Ts
PG = Ms
45 PG = Ms (91%)
46 PG = Ts (90%)
40 3-NO2 (15%), 41 1-NO2 (82%)
PG = Ts
42 3-NO2 (80%), 43 1-NO2 (14%)
R'
OMe
R'
MeO
MeO
R
R
N
N
Ms
Ts
N
49 (75%)
50 (95%)
Ts
47 R,R = H,H; R',R' = -O-CH2-O- (88%)
R,R = R,R = -O-CH2-O- (89%)
'
'
48
During the course of our current investigation, we also uncovered that the protocol described
herein could be extended to the synthesis of 6,7ꢀdihydroꢀ5Hꢀdibenzo[c,e]azepines. While the
several elegant syntheses of dibenzo[c,e]azepines have been reported,33 to the best of our
knowledge, a domino synthesis is unprecedented. When NꢀTs benzylamine 5124 was
subjected to reaction with 6 under the optimized condition, dibenzoazepine 5233f and biaryl
sultam 53 were obtained in 42 and 53% yields, respectively (Table 3). It is important to
mention here that unlike in dihydrophenanthridine synthesis, the biaryl sultam 53 was found
to be the major product in the synthesis of dibenzoazepine 52. About a fourꢀfold increase in
the ratio of biaryl sultam to dibenzoazepine was observed when NꢀTs benzhydrylamine 5434
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was reacted with 6 affording dibenzoazepine 55 and biaryl sultam 56 in 14 and 58% yields,
respectively. A complete regiocontrol was observed in the reaction of 51 and 11 leading to
the formation of biaryl sultam 57 exclusively. While an attempted reaction of 5835 and 11 to
form an eight member ring was unsuccessful, only biaryl sultam 59 was isolated in 78%
yield. Interestingly, the presence of an electronꢀwithdrawing group on the benzylamine ring
facilitates the the intramolecular direct arylation largely on the benzylamine ring. Thus,
heating a reaction of NꢀTs 3ꢀtrifluoromethylbenzylzmine 60 and 6 in the presence of
Pd(OAc)2, PPh3, and Cs2CO3 in toluene at 130 ºC for 16 h gave dibenzoazepine 61 and biaryl
sultam 62 in 58 and 40% yields, respectively. Notably, intramolecular direct arylation
occurred at the paraꢀ to the CF3 group in benzylamine ring. Further improvement in the
regioselectivity was demonstrated in the synthesis of optically pure dibenzoazepine 64. Thus,
when NꢀTs αꢀmethylbenzylamine 63 and 6 were allowed to react, dibenzoazepine 64 and
biaryl sultam 65 were obtained in 53 and 30% isolated yields, respectively. Gratifyingly, Nꢀ
Ms 3ꢀtrifluoromethylbenzylamine 66 gave dibenzoazepine 67 resulted from intramolecular
direct arylation occurred exclusively at the paraꢀ to the CF3 group in benzylamine ring
Notably, a palladiumꢀcatalyzed intramolecular oxidative coupling involving double C(sp2)ꢀH
bonds to the synthesis of (NH)ꢀbiaryl sultam containing a seven member ring was reported by
us recently.17
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19
20
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22
23
24
25
26
27
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30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3: Regioselective Synthesis of N-Sulfonyl 6,7-dihydro-5H-dibenzo[c,e]azepines
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Pd(OAc)2, PPh3, Cs2CO3
Products
Substrates
dioxane or toluene, 110 or 130 0C, 16 h
5
Me
6
7
8
9
O
NHTs
S
N
and
O
R
N
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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60
Ts
51 R = H
R
R
54 R = Ph
53 R = H (53%)
56 R = Ph (58%)
52 R = H (42%)
55 R = Ph (14%)
+ 6
Me
NHTs
n
O
O
O
S
N
O
51
58
n = 1
n = 2
Ph
n
57
n = 1 (68%)
11
+
59 n = 2 (78%)
Me
O
S
N
O
and
NHPG
F3C
60 PG = Ts
66 PG = Ms
N
F3C
PG
61 PG = Ts (58%)
67 PG = Ms (76%)
F3 C
+ 6
62 (40%)
Me
and
O
NHTs
Me
S
O
N
N
63
Ts
Ph
Me
+ 6
65 (30%) Me
64 (53%)
In line with the mechanism proposed by Fagnou36 and Echavarren37 for intramolecular direct
arylation, we also propose the involvement of a similar catalytic cycle as illustrated in
Scheme 2. Subsequent to oxidative insertion of palladium (0) into the carbonꢀbromide bond
of Nꢀbenzylated intermediate 68, two pathways may be followed in the transformation of 69
to the dihydrophenanthridines or dibenzoazepines. In the first pathway, the carbonate may act
as an external base at the CꢀH bond (Ha) cleaving transition state via 70 to form the
biarylpalladium(II) intermediate 72, which would reductively eliminate to give the observed
product and regenerate the catalyst. Alternatively, exchange of bromide with carbonate in 69
could give a species 71, which would undergo a concerted metalationꢀdeprotonation to give
the same intermediate 72 of the other pathway.
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Subsequent to oxidative insertion into the carbonꢀbromide bond, 69 could form biaryl sultam
following two similar pathways as demonstrated above. The external base will abstract
proton (Hb) via transition state 73 to form the biarylpalladium(II) intermediate 74, which
would reductively eliminate to give the biaryl sultam and regenerate the catalyst.
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While dihydophenanthridine 7 is the major product when n = 0 in Scheme 2, biaryl sultam 53
is the major product obtained in the synthesis of dibenzoazepine 52. This reverse
regioselectivity observed in the synthesis of dibenzoazepine 52 can be rationalized as
follows. When n = 0, concerted metalationꢀdeprotonation in 70 may be favored compared to
that in 73, which could drive the formation of energetically favorable six membered
dihydrophenanthridine ring. However, the presence of more acidic Hb proton in 73 could
facilitate the intramolecular arylation of 73 compared to 70 when n = 1 in Scheme 2.
Scheme 2: Proposed mechanism for the intramolecular direct arylation
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O
L
O
Pd
Br
O
Br
L
+
H
NHTs
Br
N-benzylation
n
O
O
N
S
n
L
Pd
L
Me
Br
70
Br
Hb
Base-assisted
intermolecular
O
S O
Hb
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Me
and/or
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O
7
(n = 0)
N
N
N
n
52 (n = 1)
S
Me
S
Me
n
L
O
n
Ha
O
Ha
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O
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Pd
72
O
69
68
H
O
N
S
n
O
O
L
Pd
L
O
H
Br
O
71
Me
O
N
n
Base-assisted
intramolecular
S
Me
O
73
n
N
SO2
8
(n = 0)
53 (n = 1)
Pd
74
Me
Finally, the synthesis of phenanthridines was achieved by deprotecting
dihydrophenantridines, exemplified with a dihydrophenanthrdine 50. Thus, treatment of 50
with TBAF in acetonitrile at reflux gave nearly quantitative deprotection of Ms group
affording 75 in 95% yield.6h
TBAF.3H2O, MeCN, reflux
eq 1
N
N
Ms
50
75 (95%)
In conclusion, a palladiumꢀcatalyzed domino reaction involving sulfonanilides with 2ꢀ
bromobenzyl bromides to the synthesis of Nꢀsulfonylꢀ5,6ꢀdihydrophenanthridines has been
developed, which opens an expedient access to 5,6ꢀdihydrophenanthridines with wide
substrate scope. The optimized condition was also found beneficial to the domino synthesis
of 6,7ꢀdihydroꢀ5Hꢀdibenzo[c,e]azepines that are otherwise obtained in several steps using
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literature procedures. Considering the reaction profiles of NHꢀTs amines with 6, the
formation of biaryl sultam was favoured as we moved from NHꢀTs aniline 5 to NHꢀTs
aliphatic amine 51, and biaryl sultam 59 became the exclusive product when NHꢀTs aliphatic
amine 58 was used.
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EXPERIMENTAL
General. Unless noted otherwise, all reagents and solvents were purchased from commercial
sources and used as received. All palladiumꢀcatalyzed reactions were performed in a screwꢀ
cap sealed tube. The 1H and 13C NMR spectra were obtained in CDCl3 as solvent using a 400
MHz spectrometer with Me4Si as an internal standard. Coupling constants (J values) are
reported in Hz. Column chromatography was performed using silica gel (60ꢀ120, 100ꢀ200, or
230ꢀ400 mesh). High Resolution Mass Spectra (HRMS) were obtained using Electron Spay
Ionisation (ESI) technique and as TOF mass analyser. All melting points were taken using a
melting point apparatus equipped with a calibrated thermometer and are uncorrected. New
compounds were characterized by melting point, H & 13C NMR, IR, and HRMS data.
1
Compounds 5, 6, and 11 were purchased from commercial vendors.
2-Bromobenzyl 4-methylbenzenesulfonate (16).23 A mortar was charged with anhydrous
K2CO3 (414 mg, 3 mmol), pꢀtoluenesulfonyl chloride (285 mg, 1.5 mmol), and 2ꢀ
bromobenzyl alcohol (187 mg, 1 mmol), then grinded with a pestle for 5 min. After
completion of the reaction, excess tosyl chloride was quenched by the addition of powdered
KOH (5 mmol) and a few drops of tertꢀbutanol to accelerate the disappearance of tosyl
chloride. The reaction mixture was washed with ether (3 x 20 mL). The combined organic
layer was evaporated under reduced pressure to obtain an offꢀwhite solid that was used in the
next step (256 mg, 75%). mp 47ꢀ49 °C; IR (KBr, cm−1): 3430, 1593, 1360, 1171, 1032; H
1
NMR: δ 7.86 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (d, J
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= 8.1 Hz, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 5.16 (s, 2H), 2.47 (s, 3H); 13C
NMR: δ144.9, 132.9, 132.9, 132.8, 130.4, , 130.3, 129.8, 128.0, 127.6, 123.3, 71.0, 21.6;
HRMS calcd for C14H14BrO3S [M+H]+ 340.9847, found 340.9844.
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Typical Procedure for Sulfonylation of Anilines (10, 14, 17, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32). Following a literature procedure,25 a mixture of aniline (1.5 mmol), 4ꢀ
toluenesulfonyl chloride or methane sulphonyl chloride (1 mmol) and silica gel [1 g (60–120
mesh)] was stirred at room temperature. The progress of the reaction was monitored by TLC.
After completion of the reaction, EtOAc (5 mL) was added and the mixture was filtered
through a sintered funnel. Concentration of the filtrate followed by chromatography [silica,
EtOAc−hexanes = 1:9] gave the sulfonanilides.
Typical Procedure for Sulfonylation of Aliphatic amines (51, 54, 58, 60, 63, 66).
Following a literature procedure,34 a solution of benzylamine (1 mmol) and triethylamine (3
mmol) in CH2Cl2 (10 mL) was treated with 4ꢀmethylbenzeneꢀ1ꢀsulfonyl chloride (1 mmol) in
small portions at 0 0C. The resulting solution was stirred at room temperature for 4ꢀ6 h. Water
(50 mL) was added and the aqueous layer was extracted with dichloromethane (3 x 20 mL).
The combined organic layer was dried (Na2SO4) and concentrated, which upon
chromatography [silica, EtOAc−hexanes = 1:9] gave the sulfonanilides.
General Procedure for the Synthesis of N-Sulfonyl-5,6-dihydrophenanthridines. A
mixture of sulfonanilides (0.5 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), PPh3 (26 mg, 0.10
mmol), and Cs2CO3 (1.25 mmol) in dioxane (2.5 mL) was purged with nitrogen for 5ꢀ10 min.
2ꢀBromobenzyl bromide (0.5 mmol) was added and the mixture was heated at 110 ○C for 16
h in a screwꢀcap sealed tube. Water (20 mL) was added and the aqueous layer was extracted
with EtOAc (3 x 20 mL). The combined organic layer was dried (Na2SO4) and concentrated,
which upon chromatography [silica, EtOAc−hexanes = 1:9 to 1:4] gave the
dihydrophenanthridines.
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Desulfonylation of dihydrophenanthridine 50. A solution of dihydrophenanthridine 50 (77
mg, 0.25 mmol) in acetonitrile (2 mL) was treated with tetrabutylammonium fluoride
trihydrate (157 mg, 0.50 mmol) and then the reaction mixture was refluxed for 6 h. After
completion, the mixture was diluted with H2O and extracted with EtOAc. The organic layer
was dried (Na2SO4) and concentrated, which upon chromatography [silica, EtOAc−hexanes =
1:9] gave the phenanthridine 756h (54 mg, 95%).
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2-Methyl-6-phenyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-dioxide (8). White solid
(40 mg, 20 %). mp 111ꢀ113 °C; IR (KBr, cm−1): 3423, 2923, 2335, 1593, 1445, 1340, 1162,
1
1039; H NMR: δ 7.87 (d, J = 8.0 Hz, 1H), 7.56ꢀ7.55 (m, 2H), 7.49ꢀ7.47 (m, 3H), 7.42ꢀ7.34
13
(m, 4H), 7.30ꢀ7.29 (m, 2H), 4.35 (s, 2H), 2.56 (s, 3H); C NMR: δ 144.1, 142.4, 140.8,
139.4, 134.0, 133.4, 130.5, 130.2, 129.6, 129.5, 129.3, 129.2, 129.0, 128.4, 127.7, 127.2,
126.8, 121.7, 55.9, 21.6; HRMS calcd for C20H18NO2S [M + H]+ 336.1058, found 336.1055.
5-Tosyl-5,6-dihydrobenzo[c][1,3]dioxolo[4,5-j]phenanthridine (12). Pale yellow solid
(167 mg, 78%). mp 147ꢀ149 °C; IR (KBr, cm−1): 3395, 2923, 1591, 1481, 1347, 1161, 1035;
1H NMR: δ 8.72 (d, J = 8.56 Hz, 1H), 7.85 (d, J = 6.0 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.56ꢀ
7.50 (m, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.69 (s, 1H), 6.61 (s, 1H),
13
5.95 (s, 2H), 5.17 (d, J = 16.4 Hz, 1H), 4.46 (d, J = 16.4 Hz, 1H), 2.27 (s, 3H); C NMR: δ
147.5, 147.3, 143.0, 133.9, 133.5, 131.6, 131.3, 129.2, 128.5, 128.1, 127.7, 127.3, 126.6,
126.5, 126.4, 126.4, 121.1, 107.0, 104.0, 101.1, 50.9, 21.3; HRMS calcd for C25H20NO4S
[M+H]+ 430.1113, found 430.1110.
2-Methyl-6-(naphthalen-1-yl)-6,7-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2
d]benzo[f][1,2]thiazepine 5,5-dioxide (13). Pale yellow solid (41 mg, 19%). mp 252ꢀ254
°C; IR (KBr, cm−1): 3431, 2923, 2252, 1595, 1505, 1335, 1224, 1161, 1035; 1H NMR: δ 8.41
(d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.2 Hz,
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1H), 7.60ꢀ7.54 (m, 2H), 7.44ꢀ7.37 (m, 3H), 7.28 (d, J = 7.2 Hz, 1H), 7.03 (s, 1H), 6.9 (s, 1H),
13
6.06 (d, J = 8.5 Hz, 2H), 4.24 (s, 2H), 2.54 (s, 3H); C NMR: δ 148.7, 148.3, 144.1, 139.3,
7
8
9
139.2, 134.8, 134.5, 134.0, 132.3, 130.4, 128.9, 128.7, 128.0, 127.2, 127.0, 126.6, 125.4,
124.1, 123.7, 110.5, 108.9, 101.8, 56.6, 21.7; HRMS calcd for C25H20NO4S [M+H]+
430.1113, found 430.1112.
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6-(2,6-Dimethylphenyl)-2-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine
5,5-dioxide
(18). White solid (58 mg, 32%). mp 210ꢀ212 °C; IR (KBr, cm−1): 3414, 2913, 1598, 1449,
1
1315, 1190, 1159, 1030, 769; H NMR: δ 8.0 (d, J = 8.0 Hz, 1H), 7.59ꢀ7.55 (m, 2H), 7.51ꢀ
13
7.47 (m, 2H), 7.45ꢀ7.40 (m,2H), 7.19ꢀ7.13 (m,3H) 4.8 (s, 2H), 2.47 (s,3H), 1.81 (s, 6H); C
NMR: δ 143.4, 140.7, 139.8, 139.1, 138.9, 135.4, 134.0, 130.6, 130.0, 129.4, 129.2, 128.9,
128.8, 128.7, 128.5, 126.0, 54.3, 21.6, 19.4; HRMS calcd for C22H22NO2S [M+H]+ 364.1371,
found 364.1365.
N-(2-Bromobenzyl)-N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide (19). White
solid (143 mg, 65%). mp 133ꢀ135 °C; IR (KBr, cm−1): 3434, 2923, 1596, 1437, 1339, 1154,
1024, 861; 1H NMR: δ 7.75 (d, J = 8.2 Hz, 2H),7.70 (dd, J = 7.7, 1.7 Hz, 1H), 7.40 (dd, J =
8.0, 1.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.13ꢀ7.08 (m, 2H),
13
6.96 (d, J = 7.6 Hz, 2H), 4.89 (s, 2H), 2.47 (s, 3H), 1.81 (s, 6H); C NMR: δ 143.3, 139.6,
138.3, 135.6, 135.4, 133.0, 132.6, 130.0, 129.6, 129.6, 128.9, 128.3, 128.2, 128.0, 127.6,
127.5, 124.9, 52.9, 21.5, 18.7; HRMS calcd for C22H23BrNO2S [M+H]+ 444.0633, found
444.0631.
Ethyl 3-(methylsulfonamido)benzoate (25). White solid (194 mg, 80%). mp 112ꢀ114 °C;
IR (KBr, cm−1): 3246, 2999, 1699, 1339, 1153; 1H NMR: δ 7.97 (s, 1H), 7.86 (d, J = 7.6 Hz,
1H), 7.65 (bs.,1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.84 Hz, 1H), 4.40 (q, J = 7.0 Hz,
13
2H), 3.05 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H); C NMR: δ 166.2, 137.4, 131.8,129.8, 126.1,
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124.9, 121.6, 61.6, 39.5, 14.2; HRMS calcd for C10H14NO4S [M+H]+ 244.0644, found
244.0640.
6
7
8
9
N-(Benzo[d][1,3]dioxol-5-yl)methanesulfonamide (29). White solid (204 mg, 95%). mp
10
11
12
13
14
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18
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1
106ꢀ108 °C; IR (KBr, cm−1): 3240. 2901, 1614, 1460, 1342, 1124, 1037, 991; H NMR: δ
6.84 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.70ꢀ6.68 (m, 2H), 5.98 (s, 2H), 2.97 (s,
3H); 13C NMR: δ 148.4, 146.1, 130.2, 116.2, 108.5, 105.0, 101.6, 38.8; HRMS calcd for
C8H10NO4S [M+H]+ 216.0331, found 216.0334.
N-(Benzo[d][1,3]dioxol-5-yl)-4-methylbenzenesulfonamide (30). White solid (268 mg,
92%). mp 130ꢀ132 °C; IR (KBr, cm−1): 3290, 2904, 1492, 1347, 1160, 936; 1H NMR: δ 7.62
(d, J = 8 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.71 (bs., 1H), 6.68 (s, 1H), 6.61 (d, J = 8.0 Hz,
1H), 6.43 (dd, J = 8.2, 2.1 Hz, 1H), 5.92 (s, 2H), 2.38 (s, 3H); 13C NMR: δ 148.0, 145.9,
143.8, 135.8, 130.1, 129.6, 127.3, 116.8, 108.2, 105.5, 101.5, 21.5; HRMS calcd for
C14H14NO4S [M+H]+ 292.0644, found 292.0649.
4-Methyl-5-(methylsulfonyl)-5,6-dihydrophenanthridine (33). White solid (128 mg, 94%).
1
mp 128ꢀ130 °C; IR (KBr, cm−1): 3829, 3412, 2928, 2346, 1330, 1150, 960, 762; H NMR: δ
7.84 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.3 Hz, 1H), 7.37ꢀ7.27 (m, 4H),
13
5.06 (d, J = 16.6 Hz, 1H), 4.48 (d, J = 16.5 Hz, 1H) 2.56 (s, 3H), 2.13 (s, 3H); C NMR: δ
138.6, 134.9, 132.9, 132.4, 131.5, 131.1, 128.8, 128.5, 127.9, 126.2, 123.8, 122.1, 50.5, 37.7,
19.6; HRMS calcd for C15H16NO2S [M+H]+ 274.0902, found 274.0897.
4-Fluoro-5-(methylsulfonyl)-5,6-dihydrophenanthridine (34). White solid (127 mg, 92%).
mp 154ꢀ156 °C; IR (KBr, cm−1): 3417, 2912, 1561, 1460, 1338, 1152, 964; H NMR: δ 7.84
1
(d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.48ꢀ7.34 (m, 4H), 7.18 (t, J = 8.9 Hz, 1H), 4.79
(s, 2H), 2.62 (s, 3H); 13C NMR: δ 159.0 (J = 252 Hz), 133.2, 132.7, 130.7 (J = 3 Hz), 129.1,
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128.8, 128.4 (J = 9 Hz), 126.1, 124.1, 119.8, 116.3, 116.1, 49.7, 39.2 ; HRMS calcd for
C14H13FNO2S [M+H]+ 278.0651, found 278.0661.
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8
9
5-(Methylsulfonyl)-4-(trifluoromethyl)-5,6-dihydrophenanthridine (35). White solid (147
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1
mg, 90%). mp 140ꢀ143 °C; IR (KBr, cm−1): 3416, 2933, 1610, 1497, 1319, 1159, 967; H
NMR: δ 8.00 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.54 (t, J
= 7.8 Hz, 1H), 7.47ꢀ7.39 (m, 2H), 7.34 (d, J = 7.2 Hz, 1H), 5.01 (d, J = 16.8 Hz, 1H), 4.56 (d,
J = 16.8 Hz, 1H), 2.37 (s, 3H); 13C NMR: δ 133.7, 133.3, 132.7, 130.8, 129.5 (J = 31 Hz ),
129.4, 129.0, 128.3, 128.2 (J = 5 Hz), 127.8, 126.2, 124.8 (J = 273 Hz), 124.0, 49.7, 38.8;
HRMS calcd for C15H13F3NO2S [M+H]+ 328.0619, found 328.0618.
2-Chloro-5-(methylsulfonyl)-5,6-dihydrophenanthridine (36). Pale yellow semiꢀsolid (135
mg, 92%); IR (KBr, cm−1): 3746, 2923, 2361, 1440, 1339, 1155, 965, 779; H NMR: δ 7.81
1
(d, J = 2.36 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H) 7.47ꢀ7.42 (m, 2H),
7.35ꢀ7.32 (m, 2H), 4.82 (s, 2H), 2.28 (s, 3H); 13C NMR: δ 134.2, 133.4, 132.0, 131.2, 130.1,
129.2, 129.0, 128.6, 126.2, 124.1, 123.8, 49.3, 37.8; HRMS calcd for C14H13ClNO2S [M+H]+
294.0356, found 294.0366.
5-(Methylsulfonyl)-2-nitro-5,6-dihydrophenanthridine (37). Yellow solid (109 mg, 72%).
mp 162ꢀ164 °C; IR (KBr, cm−1): 3730, 3423, 2924, 2343, 1739, 1459, 1340, 1152; H NMR:
1
δ 8.75 (s, 1H), 8.23 (dd, J = 8.8, 2.5 Hz, 1H), 7.93ꢀ7.90 (m, 2H), 7.54 (td, J = 7.4, 1.4 Hz,
13
1H), 7.49 (td, J = 7.4, 1.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 4.91 (s, 2H), 2.43 (s, 3H); C
NMR: δ 146.5, 141.2, 131.9, 130.5, 130.0, 129.4, 128.1, 126.2, 124.1, 123.3, 119.5, 49.1,
38.8; HRMS calcd for C14H13N2O4S [M+H]+305.0596, found 305.0590.
Ethyl 5-(methylsulfonyl)-5,6-dihydrophenanthridine-3-carboxylate (38). White solid
(118 mg, 71%). mp 144ꢀ146 °C; IR (KBr, cm−1): 3246, 2999, 1698, 1588, 1474, 1339, 1153,
972; 1H NMR: δ 8.35 (s, 1H), 8.07 (dd, J = 8.0, 1.7 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.85 (d,
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J = 7.4 Hz, 1H), 7.49ꢀ7.41 (m, 2H), 7.36 (d, J = 7.0 Hz, 1H), 4.85 (s, 2H), 4.41 (q, J = 7.1 Hz,
2H), 2.29 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR: 165.6, 135.7, 133.6, 132.6, 130.8,
130.4, 129.6, 129.0, 128.9, 128.6, 126.2, 124.2, 124.1, 61.3, 49.3, 38.0, 14.3; HRMS calcd
for C17H18NO4S [M+H]+ 332.0957, found 332.0950.
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3-Methyl-5-(methylsulfonyl)-5,6-dihydrophenanthridine (39). White solid (109 mg, 80%).
mp 130ꢀ132 °C; IR (KBr, cm−1): 3248, 2929, 1610, 1494, 1316, 772; 1H NMR: δ 7.78 (d, J =
7.7 Hz, 1H), 7.73(d, J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.42 (td, J = 7.3, 1.1 Hz, 1H), 7.37ꢀ7.31
(m, 2H), 7.21 (d, J = 7.2 Hz, 1H), 4.82 (s, 2H), 2.44 (s, 3H), 2.28 (s, 3H); 13C NMR: δ 139.1,
135.7, 131.6, 131.4, 128.7, 128.5, 128.2, 127.0, 126.0, 123.9, 123.3, 49.6, 37.6, 21.3; HRMS
calcd for C15H16NO2S [M+H]+ 274.0902, found 274.0908
5-(Methylsulfonyl)-1-nitro-5,6-dihydrophenanthridine (40). Pale yellow solid (124 mg,
82%). mp 174ꢀ176 °C; IR (KBr, cm−1): 3730, 2928, 2368, 1527, 1340, 1154; 1H NMR: δ 7.99
(dd, J = 8.2, 1.24 Hz, 1H), 7.71 (dd, J = 1.24, 8.0 Hz, 1H), 7.52ꢀ7.39 (m, 5H), 4.86 (s, 2H),
2.16 (s, 3H); 13C NMR: δ 138.4, 133.1, 131.0, 129.9, 129.0, 128.4, 126.8, 126.5, 126.1,
123.8, 123.0, 49.8, 38.5; HRMS calcd for C14H13N2O4S [M+H]+ 305.0596, found 305.0595.
5-(Methylsulfonyl)-3-nitro-5,6-dihydrophenanthridine (41). Pale yellow solid (45 mg,
1
15%). mp 200ꢀ202 °C; IR (KBr, cm−1): 3426, 2923, 1333, 1155; H NMR: δ 8.57 (s, 1H),
8.24 (dd, J = 8.0, 2.3 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.88ꢀ7.86 (m, 1H), 7.53ꢀ7.47 (m,
13
2H), 7.40ꢀ7.38 (m, 1H), 4.89 (s, 2H), 2.36 (s, 3H); C NMR: δ 136.5, 135.4, 132.8, 130.6,
129.4, 129.3, 126.4, 124.8, 124.6, 123.1, 122.2, 49.1, 38.5; HRMS calcd for C14H13N2O4S
[M+H]+ 305.0596, found 305.0590.
3-Nitro-5-tosyl-5,6-dihydrophenanthridine (42). Pale yellow solid (152 mg, 80%). mp
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156ꢀ158 °C; IR (KBr, cm−1): 3730, 2928, 2368, 1527, 1340, 1154 cmꢀ1; H NMR: δ 8.69 (s,
1H), 8.20 (dd, J = 8.6, 2.3 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29ꢀ
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7.27 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H),
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6.78 (d, J = 8.0 Hz, 2H), 4.93 (s, 2H), 2.19 (s, 3H); C NMR: δ 147.2, 143.6, 136.7, 136.3,
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134.4, 132.2, 129.8, 129.1, 128.7, 128.1, 127.0, 126.4, 124.4, 123.8, 123.5, 122.1, 49.4, 21.3;
HRMS: calcd for C20H17N2O4S [M+H]+ 381.0909, found 381.0904.
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1-Nitro-5-tosyl-5,6-dihydrophenanthridine (43). Pale yellow solid (27 mg, 14%). mp 140ꢀ
142 °C; IR (KBr, cm−1): 3736, 2917, 2346, 1519, 1353, 1163; 1H NMR: δ 7.98 (d, J = 8.4 Hz,
1H), 7.87 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.24 (t, J = 7.5
Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.92ꢀ6.86 (m, 4H), 6.69 (d, J = 7.8 Hz, 1H), 4.88 (s, 2H),
2.14 (s, 3H); 13C NMR: δ 148.1, 143.4, 138.6, 134.4, 132.4, 131.4, 129.0, 128.8, 128.0,
127.7, 126.6, 126.5, 126.3, 125.4, 124.5, 122.8, 50.0, 21.3; HRMS: calcd for C20H17N2O4S
[M+H]+ 381.0909, found 381.0911.
1-Nitro-6-tosyl-5,6-dihydro-[1,3]dioxolo[4,5-b]phenanthridine (44). Yellow solid (178
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mg, 84%). mp 220ꢀ222 °C; IR (KBr, cm−1): 3423, 2923, 1731, 1354, 1166, 939, 713; H
NMR: δ 8.06 (dd, J = 8.0, 1.5 Hz, 1H), 7.66 (dd, J = 8.0, 1.2 Hz, 1H ), 7.45 (t, J = 8.1 Hz,
1H), 6.99 (d, J = 8.3 Hz, 2H ), 6.87 (d, J = 8.0 Hz, 2H ), 6.60 (s, 1H), 6.20 (s, 1H), 5.94 (s,
2H), 4.73 (s, 2H), 2.25 (s, 3H); 13C NMR: δ 148.5, 147.6, 143.6, 138.2, 134.6, 131.5, 129.9,
128.7, 127.6, 127.3, 127.2, 126.8, 124.8, 123.1, 120.4, 107.2, 105.6, 101.5, 50.0, 21.3;
HRMS calcd for C21H17N2O6S [M+H]+ 425.0807, found 424.0812.
6-(Methylsulfonyl)-6,7-dihydro-[1,3]dioxolo[4,5-a]phenanthridine (45). White solid (138
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mg, 91%). mp 166ꢀ168 °C; IR (KBr, cm−1): 3432, 2913, 1439, 1324, 1151, 968; H NMR: δ
8.1 (d, J = 8.4 Hz, 1H), 7.42 (td, J = 7.3, 1.6 Hz, 1H), 7.37 (td, J = 7.4, 1.3 Hz, 1H), 7.34 (d,
J = 7.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.16 (s, 2H), 4.82 (s,
13
2H), 2.27 (s, 3H); C NMR: δ 146.9, 144.2, 131.8, 129.6, 128.6, 128.5, 128.5, 126.7, 126.0,
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121.3, 113.7, 107.7, 101.8, 49.8, 37.5; HRMS calcd for C15H14NO4S [M+H]+ 304.0644,
found 304.0648.
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6-Tosyl-6,7-dihydro-[1,3]dioxolo[4,5-a]phenanthridine (46). White solid (170 mg, 90%).
mp 130ꢀ132 °C; IR (KBr, cm−1): 2901, 1593, 1436, 1340, 1239, 1158, 1049, 940; 1H NMR: δ
7.51 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.12ꢀ7.06 (m, 3H), 6.96 (d, J = 6.5 Hz,
2H), 6.82 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 6.04 (s, 2H), 4.80 (s, 2H), 2.15 (s,
3H); 13C NMR: δ 146.7, 143.6, 142.8, 134.4, 131.1, 129.9, 128.3, 128.1, 127.8, 127.2, 127.1,
126.0, 125.9, 121.5, 114.6, 107.4, 101.6, 50.2, 21.3; HRMS calcd for C21H18NO4S [M+H]+
380.0957, found 380.0954.
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5-Tosyl-5,6-dihydro-[1,3]dioxolo[4,5-j]phenanthridine (47). White solid (168 mg, 88%).
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mp 145ꢀ147 °C; IR (KBr, cm−1): 2914, 1732, 1595, 1480, 1342, 1159, 1032 ; H NMR: δ
7.77 (dd, J = 7.8, 1.8 Hz, 1H), 7.42 (dd, J = 7.1, 2.1 Hz, 1H), 7.36 (td, J = 7.4, 1.9 Hz, 2H),
6.98 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 6.52 (s, 1H), 5.92 (s, 2H),
4.73 (s, 2H), 2.23 (s, 3H); 13C NMR: δ 147.5, 147.3, 142.9, 135.3, 134.8, 130.7, 128.3, 128.0,
127.7, 127.5, 127.1, 125.5, 125.3, 123.2, 106.6, 103.6, 101.1, 49.7, 21.3; HRMS calcd for
C21H18NO4S [M+H]+ 380.0957, found 380.0955.
6-Tosyl-6,7-dihydrobis([1,3]dioxolo)[4,5-a:4',5'-j]phenanthridine (48). White solid (188
mg, 89%). mp 196ꢀ198 °C; IR (KBr, cm−1): 3434, 2901, 2372, 1596, 1452, 1344, 1159, 1037,
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934; H NMR: δ 7.30 (d, J = 8.4 Hz, 2H), 7.06ꢀ7.02 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H ), 6.82
(s, 1H), 6.80 (s, 1H), 6.59 (s, 1H), 6.06 (s, 2H), 5.93 (s, 2H), 4.72 (s, 2H), 2.25 (s, 3H); 13C
NMR: δ 147.1, 146.9, 146.6, 143.0, 134.7, 129.3, 128.3, 127.2, 125.5, 122.1, 121.4, 114.7,
106.8, 106.6, 106.5, 101.5, 101.0, 50.1, 21.3; HRMS calcd for C22H18NO6S [M+H]+
424.0855, found 424.0854.
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1,2,3-Trimethoxy-5-tosyl-5,6-dihydrophenanthridine (49). White solid (159 mg, 75%). mp
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108ꢀ110 °C; IR (KBr, cm−1): 3434, 2928, 2379, 1593, 1348, 1166, 1086, 946; H NMR: δ
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7.67 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.06ꢀ6.99 (m, 3H), 6.91 (d, J = 8.2 Hz, 2H), 6.69 (d, J
= 8.0 Hz, 2H), 4.73 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.69 (s, 3H), 2.16 (s, 3H); 13C NMR: δ
152.6, 151.2, 142.8, 142.0, 134.4, 132.8, 130.9, 129.2, 128.3, 127.2, 126.9, 126.7, 126.3,
125.8, 117.8, 107.6, 61.2, 60.7, 56.2, 50.4, 21.2; HRMS calcd for C23H24NO5S [M+H]+
426.1375, found 426.1371.
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5-(Methylsulfonyl)-5,6-dihydrobenzo[c]phenanthridine (50). Pale yellow solid (147 mg,
95%). mp 170ꢀ172 °C; IR (KBr, cm−1): 3427, 2925, 1741, 1333, 1151, 957; 1H NMR: δ 8.60
(d, J = 8 Hz, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.95 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.63 (t, J =
6.9, 1H), 7.57ꢀ7.50 (m, 2H), 7.44ꢀ7.42 (m, 2H), 5.26 (d, J = 16.5 Hz, 1H), 4.65 (d, J = 16.5
13
Hz, 1H), 2.20 (s, 3H); C NMR: δ 134.1, 133.2, 132.4, 132.3, 131.2, 129.0, 128.9, 128.8,
128.1, 127.4, 126.9, 126.6, 126.6, 126.3, 123.9, 121.4, 50.7, 37.2; HRMS calcd for
C18H16NO2S [M+H]+ 310.0902, found 310.0912.
6-Benzyl-2-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-dioxide (53). White solid
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(92 mg, 53%). mp 186ꢀ188 °C; IR (KBr, cm−1): 3735, 2923, 2346, 1333, 1160, 957; H
NMR: δ 7.97 (d, J = 7.9 Hz, 1H), 7.50 ꢀ7.32 (m, 10 H), 7.25 (d, J = 7.4 Hz, 1H), 4.45 (s, 2H),
3.70 (s, 2H), 2.53 (s, 3H); 13C NMR: δ 7.97 (d, J = 7.9 Hz, 1H), 7.50 ꢀ7.32 (m, 10 H), 7.25 (d,
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J = 7.4 Hz, 1H), 4.45 (s, 2H), 3.70 (s, 2H), 2.53 (s, 3H); C NMR: δ 143.9, 140.8, 139.3,
135.9, 133.6, 133.5, 130.5, 130.0, 129.3, 128.9, 128.8, 128.7, 128.6, 128.4, 127.9, 127.1,
54.9, 52.7, 21.6; HRMS calcd for C21H20NO2S [M+H]+ 350.1215, found 350.1216.
5-Phenyl-6-tosyl-6,7-dihydro-5H-dibenzo[c,e]azepine (55)
Offꢀwhite solid (30 mg, 14%). mp 145ꢀ147 °C; IR (KBr, cm−1): 3319, 2922, 1599, 1454,
1338, 1157; 1H NMR: δ 7.44 (d, J = 8.3 Hz, 2H), 7.19ꢀ7.16 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H),
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7.07 ꢀ7.04 (m, 6H), 6.78 (d, J = 8.2 Hz, 2H), 6.39 (s, 1H), 4.52 (s, 2H), 2.38 (s, 3H);13C
NMR: δ 142.9, 138.8, 138.0, 137.1, 129.2, 129.2, 128.3, 128.2, 127.8, 127.5, 127.3, 126.9,
65.9, 49.8, 21.4; HRMS calcd for C27H24NO2S [M+H]+426.1528, found 426.1521.
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6-Benzhydryl-2-methyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-dioxide (56)
White solid (123 mg, 58%). mp173ꢀ175 °C; IR (KBr, cm−1): 3435, 2926, 2852, 1594, 1443,
1319, 1164; 1H NMR: 7.89 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 4.6 Hz, 2H), 7.40ꢀ7.27 (m, 13H),
7.18 (d, J = 7.3 Hz, 1H), 6.82 (s, 1H), 3.61 (s, 2H), 2.44 (s, 3H);13C NMR: δ 143.4, 140.6,
139.1, 138.3, 134.6, 134.1, 130.1, 129.8, 129.1, 129.0, 129.0, 128.6, 128.3, 128.1, 127.6,
126.3, 64.8, 48.6, 21.5; HRMS calcd for C27H24NO2S [M+H]+426.1528, found 426.1524.
6-Benzyl-2-methyl-6,7-dihydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]benzo[f][1,2]thiazepine
5,5-dioxide (57). White solid (131 mg, 68%). mp 214ꢀ216 °C; IR (KBr, cm−1): 3401, 2835,
1597, 1481, 1333, 1227, 1162, 1037, 949; 1H NMR: δ 7.95 (d, J = 8.4 Hz, 1H), 7.44ꢀ7.31 (m,
7H), 6.95 (s, 1H), 6.70 (s, 1H), 6.03 (s, 2H), 4.42 (s, 2H), 3.58 (s, 2H), 2.51 (s, 3H); 13C
NMR: δ 148.4, 148.0, 143.9, 139.3, 135.9, 134.6, 133.1, 130.2, 128.7, 128.6, 128.5, 127.9,
127.3, 127.2, 110.4, 108.8, 101.6, 54.5, 52.3, 21.6; HRMS calcd for C22H20NO4S [M+H]+
394.1113, found 394.1111.
2-Methyl-6-phenethyl-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-dioxide (59). White
solid (142 mg, 78%). mp 100ꢀ102 °C; IR (KBr, cm−1): 3421, 2922, 1598, 1455, 1333, 1162,
1088, 750; 1H NMR: δ 7.92 (d, J = 7.9 Hz, 1H), 7.50ꢀ7.46 (m, 2H), 7.43ꢀ7.40 (m, 2H), 7.36ꢀ
7.31 (m, 3H), 7.28ꢀ7.26 (m, 3H), 6.14 (s, 2H), 3.82 (s, 2H), 3.54 (t, J = 7.5 Hz, 2H), 2.99 (t, J
= 7.9 Hz, 2H), 2.52 (s, 3H); 13C NMR: δ 143.7, 140.8, 139.0, 138.7, 134.1, 133.7, 130.4,
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130.1, 129.3, 128.9, 128.9, 128.6, 128.4, 126.7, 126.5, 53.9, 53.5, 35.0, 21.5; HRMS calcd
for C22H22NO2S [M+H]+ 364.1371, found 364.1365.
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4-Methyl-N-(3-(trifluoromethyl)benzyl)benzenesulfonamide (60)
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Offꢀwhite solid (312 mg, 95%). mp101ꢀ103°C; IR (KBr, cm−1): 3428, 2933, 1631, 1475,
1330, 1169, 1074; 1H NMR: δ 7.74 (d, J = 8.1 Hz, 2H), 7.50ꢀ7.48 (m, 2H), 7.45 (t, J = 7.4
Hz, 1H), 7.39 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H), 5.35 (bs, 1H), 4.21 (s, 2H), 2.43 (s, 3H); 13C
NMR: δ 143.7, 137.5, 136.7, 131.2, 131.0, 129.7, 129.5, 129.1, 127.0, 125.2 (q, J = 270 Hz),
124.5 (q, J = 3 Hz), 46.6, 21.4; HRMS calcd for C15H15F3NO2S [M+H]+ 330.0776, found
330.0770.
6-Tosyl-3-(trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (61)
White solid (120 mg, 58%). mp186ꢀ188 °C; IR (KBr, cm−1): 3444, 2924, 1597, 1462, 1330,
1157, 1087; 1H NMR: δ 7.74 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.0, 1.0 Hz, 1H), 7.52 (d, J =
8.0 Hz, 1H), 7.47ꢀ7.34 (m, 4H), 7.27 (d, J = 7.8 Hz, 2H), 7.22 (s, 1H), 4.19 (s, 2H), 4.13 (s,
2H), 2.38 (s, 3H);13C NMR: δ 143.9, 139.1, 135.9, 132.3, 132.0, 130.2, 130.1, 129.8, 129.7,
129.2, 129.1, 128.3, 128.0, 127.4, 126.5 (q, J = 4 Hz), 125.6 (q, J = 4 Hz), 125.1 (q, J = 270
Hz), 48.9, 48.5, 21.4; HRMS calcd for C22H19F3NO2S [M+H]+ 418.1089, found 418.1084.
2-Methyl-6-(3-(trifluoromethyl)benzyl)-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-
dioxide (62)
White solid (83 mg, 40%). mp 168ꢀ170 °C; IR (KBr, cm−1): 3434, 2924, 1599, 1447, 1329,
1165, 1074; 1H NMR: δ 7.97 (d, J = 7.9 Hz, 1H), 7.68ꢀ7.65 (m, 2H), 7.61 (d, J = 7.7 Hz,
1H), 7.54ꢀ7.49 (m, 3H), 7.42ꢀ7.37 (m, 3H), 7.28 (d, J = 7.4 Hz, 1H), 4.52 (s, 2H), 3.72
(s,2H), 2.53 (s, 3H);13C NMR: δ 144.1, 140.7, 139.2, 137.1, 133.3, 133.3, 131.8, 131.5 (q, J =
32 Hz), 130.6, 130.0, 129.4, 129.3, 129.0, 128.9, 128.0 (q, J = 270 Hz), 127.0, 125.2 (q, J = 3
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Hz), 124.8 (q, J = 3 Hz), 54.5, 53.0, 21.6; HRMS calcd for C22H19F3NO2S [M+H]+418.1089,
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(S)-5-Methyl-6-tosyl-6,7-dihydro-5H-dibenzo[c,e]azepine (64). White solid (96 mg, 53%).
mp 179ꢀ181 °C; IR (KBr, cm−1): 3428, 2931, 1596, 1449, 1335, 1161; 1H NMR: δ 7.78 (d, J
= 8.0 Hz, 2H), 7.49ꢀ7.35 (m, 6H), 7.30 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.91 (d,
J = 7.5 Hz, 1H), 5.01 (q, J = 7.0 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 3.55 (d, J = 11.8 Hz,
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1H), 2.42 (s, 3H), 0.97 (d, J = 7.0 Hz, 3H); C NMR: δ 143.2, 140.8, 138.6, 137.3, 136.3,
133.1, 129.7, 129.6, 129.4, 129.1, 128.5, 128.4, 128.1, 127.6, 127.1, 59.1, 49.0, 23.9, 21.5;
HRMS calcd for C22H22NO2S [M+H]+ 364.1371, found 364.1378.
(S)-2-methyl-6-(1-phenylethyl)-6,7-dihydrodibenzo[d,f][1,2]thiazepine 5,5-dioxide (65).
White solid (54 mg, 30%). mp 148ꢀ150 °C; IR (KBr, cm−1): 3399, 2924, 1736, 1599, 1447,
1328, 1166, 753; 1H NMR: δ 8.00 (d, J = 7.9 Hz, 1H), 7.52ꢀ7.46 (m, 4H), 7.42ꢀ7.33 (m, 6H),
7.08 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 6.9 Hz, 1H), 3.72 (d, J = 12.0 Hz, 1H), 3.53 (d, J = 12.0
Hz, 1H), 2.52 (s, 3H), 1.60 (d, J = 7.0 Hz, 3H); 13C NMR: δ 143.5, 140.6, 139.9, 139.2,
135.1, 134.1, 130.3, 129.8, 129.0, 128.9, 128.9, 128.5, 128.1, 127.7, 127.6, 126.3, 56.4, 46.2,
21.5, 15.7; HRMS calcd for C22H22NO2S [M+H]+ 364.1371, found 364.1378.
N-(3-(Trifluoromethyl)benzyl)methanesulfonamide (66)
Offꢀwhite solid (240 mg, 95%). mp 66ꢀ68 °C; IR (KBr, cm−1): 3336, 2929, 1330, 1161, 975;
1H NMR: δ 7.60 (s, 1H), 7.57ꢀ7.54 (m, 2H), 7.50 (t, J = 7.6Hz, 1H), 5.28 (bs, 1H), 4.36 (s,
2H), 2.87 (s, 3H); 13C NMR: δ 137.9, 131.6 (q, J = 36 Hz), 131.2, 129.3, 125.2 (q, J = 270
Hz), 124.8 (q, J = 4 Hz), 124.5 (q, J = 4 Hz), 46.5, 40.9 ; HRMS calcd for C9H11F3NO2S
[M+H]+ 254.0463, found 254.0460.
6-(Methylsulfonyl)-3-(trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (67)
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White solid (96 mg, 76%). mp 133ꢀ135 °C; IR (KBr, cm−1): 3421, 2923, 1621, 1327, 1160;
1H NMR: δ 7.79 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56ꢀ7.54 (m,
2H), 7.49ꢀ7.46 (m, 2H), 4.20 (s, 4H), 2.82 (s, 3H);13C NMR: δ 144.2, 139.1, 132.8, 132.2,
130.9, 130.5, 129.9, 129.5, 128.8, 128.5, 126.7 (q, J = 4 Hz), 126.1 (q, J = 4 Hz), 125.1 (q, J
= 271 Hz), 48.8, 48.6, 37.4; HRMS calcd for C16H15F3NO2S [M+H]+ 342.0776, found
342.0770.
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Acknowledgement. We thank the Council of Scientific and Industrial Research, New Delhi
for financial support.
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Supporting Information Available. H and C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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