Synthesis of (Z)-1,2-dihydro-1-tosylbenzo[b]azepin-3-ones by two-step, one-pot gold-catalyzed tandem heterocyclization/Petasis-Ferrier rearrangement of 2-(N-(prop-2-ynyl)-N-tosylamino)benzaldehydes

Article abstract of DOI:10.1016/j.tet.2013.04.069

A two-step, one-pot synthetic method that relies on gold(I)-catalyzed tandem heterocyclization/Petasis-Ferrier rearrangement and Br?nsted acid-assisted debenzoxylation of 2-(N-(prop-2-ynyl)-N-tosylamino)benzaldehydes to prepare (Z)-1,2-dihydro-1-tosylbenzo[b]azepin-3-ones efficiently is reported. The reactions proceed rapidly under mild and operationally straightforward conditions for a wide variety of aldehyde substrates containing electron-withdrawing, electron-donating, and sterically demanding functional groups and afforded the corresponding benzo-fused azaheterocyclic products in moderate to excellent yields.

Full text of DOI:10.1016/j.tet.2013.04.069

Tetrahedron 69 (2013) 5558e5565
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (Z)-1,2-dihydro-1-tosylbenzo[b]azepin-3-ones by
two-step, one-pot gold-catalyzed tandem heterocyclization/
PetasiseFerrier rearrangement of 2-(N-(prop-2-ynyl)-N-tosylamino)
benzaldehydes
y
y
*
Ella Min Ling Sze, Ming Joo Koh , Yen Min Tjia , Weidong Rao, Philip Wai Hong Chan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step, one-pot synthetic method that relies on gold(I)-catalyzed tandem heterocyclization/Peta-
siseFerrier rearrangement and Brønsted acid-assisted debenzoxylation of 2-(N-(prop-2-ynyl)-N-tosyla-
mino)benzaldehydes to prepare (Z)-1,2-dihydro-1-tosylbenzo[b]azepin-3-ones efficiently is reported.
The reactions proceed rapidly under mild and operationally straightforward conditions for a wide variety
of aldehyde substrates containing electron-withdrawing, electron-donating, and sterically demanding
functional groups and afforded the corresponding benzo-fused azaheterocyclic products in moderate to
excellent yields.
Received 29 November 2012
Received in revised form 1 April 2013
Accepted 15 April 2013
Available online 18 April 2013
Keywords:
Aldehydes
Cyclization
Ó 2013 Elsevier Ltd. All rights reserved.
Gold
Homogeneous catalysis
Nitrogen-containing heterocycles
1. Introduction
The 1H-benzo[b]azepine ring system is found in many phar-
maceutically important compounds (Fig. 1).1e6 It is therefore not
surprising to find the development of new methods to access this
member of the N-heterocyclic family of compounds has received
and continues to receive an immense amount of attention.7 While
this has led to a myriad of elegant works to the benzo-fused ni-
trogen ring motif, there remains a need for novel approaches for
their construction, with control of substitution patterns, from
starting materials that are readily accessible, atom economical, and
low cost.
Gold-catalyzed alkyne cycloisomerizations have emerged as one
of the most efficient and convenient strategies for heterocyclic
synthesis in recent years.7a,8e11 For example, recently we reported
one method to prepare benzo[b]oxepin-3(2H)-ones that relied on
gold-mediated heterocyclization/PetasiseFerrier rearrangement of
2-(prop-2-ynyloxy)benzaldehydes (Scheme 1, Eq. 1).9 In the course
of this study, the steric interactions between the substituent at the
Me
O
Me2N
HO
Me
N
H
Cl
N
N
N
O
O
Me
O
O
Me
O
N
H
Me
N
H
Cl
N
Tolvaptan 3
OPC-312602
OPC-518034
CO2H
N
N
O
Me
O
H
O
Cl
F
N
N
O
NMe2
H
O
OMe
VA1064836
RWJ-6760705
* Corresponding author. Tel.: þ65 6316 8760; fax: þ65 6791 1961; e-mail
address: waihong@ntu.edu.sg (P.W.H. Chan).
Fig. 1. Structures of pharmaceutically important compounds containing the 1H-benzo
[b]azepine motif.
y
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.069

E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
5559
Table 1
position ortho to the ethereal group on the salicylaldehyde ring
Optimization of the reaction conditionsa
with that of the acetylenic side chain in the substrate was found to
dramatically enhance reactivity. This mode of reactivity was also
found to differ to that previously reported for reactions of alkynyl
tethered aldehydes catalyzed by gold complexes, which were
shown to preferentially undergo carbonyl metathesis.10 Building on
our earlier findings, we reasoned that substrates in which the
ethereal oxygen atom is replaced by a protected amine functional
group might also occupy a similar conformation and, therefore,
exhibit comparable reactivities. As part of an ongoing program
exploring the utility of gold catalysis in heterocyclic synthesis,11 we
herein describe a tandem heterocyclization/PetasiseFerrier rear-
rangement of 2-(N-(prop-2-ynyl)-N-tosylamino)benzaldehydes
with the aid of gold(I) catalysis (Scheme 1, Eq. 2). Achieved without
the need for a substituent at the ortho position of the aniline moiety
in the substrate to promote reactivity, this two-step, one-pot pro-
cess provides a synthetic route to (Z)-1,2-dihydro-1-tosylbenzo[b]
azepin-3-ones in 34e87% yield for a wide variety of substrates
under mild and operationally simplistic conditions.
i) catalyst (5 mol %)
BnOH (1.2 equiv)
solvent, r.t.
CHO
O
N
ii) p-TsOH.H2O
N
Ts
1a
Ts
(20 mol %)
air,
Δ
2a
Cy Cy
P
AuCl
i-Pr
F3C
PAuCl
3
i-Pr
i-Pr
4
5
Entry
Catalyst
Solvent
Timeb (h)
Yieldc (%)
1
3
3
3
3
3
3
3
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(CH2Cl)2
(CH2Cl)2
MeCN
1/5
1/5
5/d
1/5
81
57
55
68
20
43
50
16
19
26
dh
7
13
36
dh
34
53
32
dh
29
30
31
dh
dh
dh
2d
3d
4e
5f
1/5
6
7
8
9
1/2g
1/2
t-Bu
t-Bu
23/2
24/2
1/2
23/d
24/2
1/5
1/5
24/d
1/5
1/5
1/5
24/d
1/5
1/5
P
MeNO2
PhMe
THF
Au
SbF6
C
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Me
1,4-Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
R3
R2
3
AuCl
R1
X = O
i) 3 (5 mol %)
AuCl/AgSbF6
AuCl/AgOTf
AuCl3
AuCl3/AgSbF6
AuCl3/AgOTf
Ph3PAuCl
Ph3PAuCl/AgSbF6
Ph3PAuCl/AgOTf
Ph3PAuNTf2
(1)
(2)
O
O
BnOH (1.2 equiv)
previous
work
R1
O
CHO
R2
CH2Cl2, air or N2(g)
r.t., 1-24 h
ref 9
21-99% yield
X
ii) p-TsOH.H2O
(20 mol %)
R3
R3
R1
air, 40 °C, 5 or 6 h
X = NTs
1
this work
N
R2
1/5
Ts
4
5
24/d
24/d
20/d
2
Scheme 1. Gold(I)-catalyzed synthesis of benzo[b]oxepin-3(2H)-ones and (Z)-1,2-
dihydro-1-tosylbenzo[b]azepin-3-ones.
TfOH
a
All reactions were performed with 0.3 mmol of 1a and 5 mol % of catalyst at
room temperature followed by 20 mol % of p-TsOH$H2O at reflux.
b
Isolated yields.
c
The first value indicates the initial reaction time and the second value indicates
the reaction time after the addition of p-TsOH$H2O.
2. Results and discussion
d
Reaction conducted under atmospheric conditions.
Following our success of using Au(I) complex 3 to effect the
tandem heterocyclization/PetasiseFerrier rearrangement of 2-
(prop-2-ynyloxy)benzaldehydes,9 we chose this metal catalyst
and 2-(N-(prop-2-ynyl)-N-tosylamino)benzaldehyde 1a as the
model substrate to establish the reaction conditions (Table 1).
This study revealed treating 1a with 5 mol % of 3 and 1.2 equiv of
BnOH in CH2Cl2 at room temperature under a nitrogen gas at-
mosphere for 1 h followed by p-TsOH$H2O (20 mol %) at 40 ꢀC for
5 h under atmospheric conditions gave the best result (entry 1).
Under these conditions, (Z)-1,2-dihydro-1-tosylbenzo[b]azepin-3-
one 2a was furnished in 81% yield. The structure of the nitrogen-
containing ring product was determined by 1H NMR spectro-
scopic measurements and X-ray crystallographic analysis (see
Fig. 2).12 On the other hand, repeating the reaction under atmo-
spheric conditions or these latter conditions with both the Lewis
and Brønsted acid catalysts co-currently present was found to
result in lower yields of 57 and 55%, respectively (entries 2 and 3).
Likewise, lower product yields were obtained on introducing
e
Reaction conducted with 50 mg of CaSO4.
f
ꢀ
Reaction conducted with 50 mg of 4 A MS.
g
First step carried out in (CH2Cl)2 at 80 ꢀC for 1 h.
No reaction based on 1H NMR spectroscopy and TLC analysis of the crude
h
mixture.
ꢀ
CaSO4 or 4 A molecular sieves (MS) to remove water from the
reaction conditions or conducting the first step at 80 ꢀC in 1,2-
dichloroethane (entries 4e6). A survey of other solvent systems
and gold catalysts was also found to provide no improvements
(entries 7e24). Changing the solvent from dichloromethane to
1,2-dichloroethane, MeCN, MeNO2, toluene or 1,4-dioxane gave
2a in low yields of 7e50% or, in the case of THF, the recovery of
Fig. 2. ORTEP drawing of 1-tosyl-1H-benzo[b]azepin-3(2H)-one (2a) with thermal
ellipsoids at 50% probability levels.12

5560
E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
the substrate (entries 7e12). A similar outcome was found when
the reaction was carried out with gold(I) complexes 4, 5, AuCl,
AuPPh3Cl, AuPPh3NTf2, and AuCl3 and combination of these cat-
alysts with AgOTf or AgSbF6 (entries 13e24). A final control ex-
periment with TfOH in place of gold(I) complex 3 as the catalyst
leading to the recovery of 1a in near quantitative yield
additionally provided evidence that the cationic Au(I) complex is
the catalytically active species (entry 25).
To define the scope of the present procedure, we next turned
our attention to the reactions of a series of 2-(N-(prop-2-ynyl)-N-
tosylamino)benzaldehydes and the results are summarized in
Table 2. Overall, these experiments showed that with the Au(I)
Table 2
Tandem heterocyclization/PetasiseFerrier rearrangement of 1ber catalyzed by 3a
Entry
Substrate
Time (h)
Product
Yieldb (%)
CHO
1
2
1
R¼OMe
R¼Cl
55
59
O
N
N
Ts
Ts
22
R
R
2b-c
1b-c
CHO
3
4
23
1
R¼CF3
56
80
O
R
R
N
R
R
N
Ts
Ts
R¼OMe
1d-e
2d-e
CHO
5
22
R¼Cl
71
O
N
N
6
7
2
3
R¼Br
60
58
Ts
Ts
R¼Me
1f-h
2f-h
MeO
MeO
MeO
MeO
CHO
O
8
9
3
1
67
87
N
N
Ts
Ts
1i
1j
2i
Me
CHO
Me
O
N
N
Ts
Ts
Me
Me
2j
CHO
O
O
10
11
24
65
63
N
N
Ts
Ts
2k
2l
1k
1l
CHO
O
O
O
O
3
N
N
Ts
Ts
R
R
CHO
12
13
1
2
R¼Me
R¼Cl
60
O
O
35c
N
N
Ts
Ts
2m-n
1m-n
R
CHO
14
15
22
22
R¼Me
R¼Ph
76
N
N
Ts
34c
R
Ts
1o-p
2o-p

E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
5561
Table 2 (continued )
Entry
Substrate
Time (h)
24
Product
Yieldb (%)
16
R¼Ms
77
CHO
O
N
R
2q-r
N
R
1q-r
17
25
R¼p-Ns
75
a
Unless otherwise stated, reactions were performed in CH2Cl2 (3 mL) with 0.3 mmol of 1 and 5 mol % of catalyst at room temperature for the stated amount of time followed
by 20 mol % of p-TsOH$H2O at reflux for 5 h.
b
Isolated yields.
c
Side product additionally obtained that could not be identified by NMR spectroscopic analysis.
complex 3 as the catalyst, the reaction conditions were found
to be broad and a variety of (Z)-1,2-dihydro-1-tosylbenzo[b]aze-
pin-3-ones could be isolated in 34e87% yield. Starting 2-
BnO
CHO
p-TsOH.H2O
O
O
N
N
aminobenzaldehydes with
a pendant electron-donating or
N
Ts
Ts
Ts
electron-withdrawing group at the position ortho to the amino
moiety on the aniline ring were found to react well, giving the
corresponding products 2b and 2c in 55 and 59% yields, re-
spectively (entries 1 and 2). Similarly, the presence of an electron-
donating or electron-withdrawing group or a benzo-fused ring at
various positions on the 2-aminobenzaldehyde ring was found to
have no influence on the course of the reaction (entries 3e13). In
these transformations, the corresponding (Z)-1,2-dihydro-1-
tosylbenzo[b]azepin-3-ones 2dem were obtained in 56e87%
yield. The only exception was that of 1n in which the position
adjacent or ortho to the aldehyde moiety on the aromatic ring is
occupied by a Cl substituent (entry 13). In this reaction, the cor-
responding nitrogen-containing ring product 2n was furnished in
a lower yield of 35%. Substrates containing an acetylene moiety
with a pendant Me (1o) or Ph (1p) group were also investigated
under the standard conditions (entries 14 and 15). In these ex-
periments, cycloisomerization of 1o was found to give the corre-
sponding benzo-fused adduct 2o in 76% yield whereas a lower
product yield of 34% was obtained for the analogous cyclization of
1p to 2p. This method was also applicable to Ms- and 4-Ns-pro-
tected starting materials 1q and 1r (entries 16 and 17). Under the
standard conditions, these latter reactions gave the corresponding
N-sulfonyl protected heterocycles 2q and 2r in 77 and 75% yields,
respectively.
A plausible mechanism for the present Au(I)-mediated cyclo-
isomerization reactions is illustrated in Scheme 2. In a manner
similar to that proposed in our earlier work,9 this could initially
involve in situ formation of the hemiacetal A from reaction of BnOH
with 1 in the presence of the Lewis acidic catalyst. This is followed
by activation of the acetylene bond of this newly formed hemiacetal
species by gold(I) complex 3. This results in cyclization of the
pendant aniline group to the alkyne moiety and formation of the
putative vinyl gold intermediate B. PetasiseFerrier rearrangement
of this aurated azaheterocyclic intermediate involving cyclo-
reversion to furnish the enolic gold complex C that subsequently
undergoes cyclization would then deliver the organogold species
D.13 Protodeauration followed by p-TsOH$H2O-mediated deben-
zoxylation provides 2 and regeneration of the gold(I) catalyst. We
surmise the gradual decrease in product yields as the steric demand
of the substituent ortho to the aldehyde moiety in the substrate
increases on going from 1a/1m/1n would be consistent with
typical reactivities found in a hemiacetal forming step. A similar
rationale could be applied to account for the gradual decrease in
product yield as the steric bulk of the pendant group at the acet-
ylenic carbon center increases on going from 1a/1o/1p. It might
be anticipated that the formation of a vinyl gold intermediate of the
type B may not be expected to be as efficient as steric interactions
2a
E
1a
3 = [Au]+
+ BnOH
OBn
BnO
[Au]
O
OH
N
Ts
N
D
A[Au]+
Ts
BnO
H
BnO
O
HO
[Au]
N
[Au]
N
Ts
Ts
C
B
Scheme 2. Proposed mechanism.
between the metal catalyst and the geminal functional group in-
crease as the steric bulk of the latter increases.
3. Conclusion
In summary, an efficient synthetic route to (Z)-1,2-dihydro-1-
tosylbenzo[b]azepin-3-ones based on rearrangement of 2-(N-
(prop-2-ynyl)-N-tosylamino)benzaldehydes has been reported.
The two-step, one-pot method to this member of the N-heterocy-
clic family of compounds was achieved under mild conditions and
shown to be applicable to a wide variety of 2-aminobenzaldehyde
substrates containing electron-withdrawing, electron-donating,
and sterically encumbered functional groups. This contrasts to our
earlier works in the analogous gold(I)-mediated cycloisomerization
of 2-(prop-2-ynyloxy)benzaldehydes to benzo[b]oxepin-3(2H)-
ones,9 which were found to require a substituent at the position
ortho to the ethereal group on the substrate to enhance reactivity.
4. Experimental section
4.1. General
All reactions were performed under a nitrogen atmosphere
unless otherwise stated. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received. Gold complexes 3e5 and PPh3AuNTf2 were purchased
from commercial sources and used as received; they can also be
prepared following the literature procedures.14e16 Solvents were
purified following standard literature procedures. Analytical thin
layer chromatography (TLC) was performed using pre-coated silica

5562
E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
gel plates. Visualization was achieved by UV light (254 nm). Flash
chromatography was performed using silica gel and gradient sol-
vent system (EtOAc/n-hexane as eluent). 1H and 13C NMR spectra
were measured on Bruker Avance 300 and 400 MHz spectrometers.
Chemical shifts (ppm) were recorded with tetramethylsilane (TMS)
as the internal reference standard. Multiplicities are given as: br s
(broad singlet), s (singlet), br d (broad doublet), d (doublet), t
(triplet), dd (doublet of doublets), dt (doublet of triplets), br m
(broad multiplet) or m (multiplet). The number of protons (n) for
a given resonance is indicated by nH and coupling constants are
reported as a J value in hertz (Hz). Infrared spectra were recorded
on a Shimadzu IR Prestige-21 FTIR spectrometer. All samples were
examined as a thin film between NaCl salt plates. Solid samples
were examined as a thin film between NaCl salt plates using
chloroform as the solvent. High-resolution mass spectra (HRMS)
were obtained using a Q-TOF LC/HRMS mass spectrometer using
simultaneous electrospray (ESI) or a DART TOF mass spectrometer.
1697, 1585, 1356, 1161 cmꢁ1; HRMS (ESI) calcd for C18H18NO4S
(MþþH): 344.0957, found: 344.0965.
4.4.3. N-(2-Chloro-6-formylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1c). Yield 88%; 0.166 g; yellow solid; mp
128e129 ꢀC; Rf (25% EtOAc/n-hexane) 0.58; 1H NMR (300 MHz,
CDCl3):
d
10.22 (s, 1H), 7.94 (dd, 1H, J¼1.5, 6.3 Hz), 7.57e7.62 (m,
3H), 7.45 (t, 1H, J¼7.8 Hz), 7.28 (d, 2H, J¼8.1 Hz), 4.92 (dd, 1H, J¼2.4,
18.0 Hz), 4.29 (dd, 1H, J¼2.4, 18.0 Hz), 2.42 (s, 3H), 2.27 (t, 1H,
J¼2.1 Hz); 13C NMR (75 MHz, CDCl3):
d 189.8, 144.5, 139.1, 137.3,
136.4, 135.7, 135.3, 130.4, 129.9, 127.5, 127.0, 77.0, 75.0, 40.2, 21.6; IR
(neat): 3304, 1694, 1597, 1584, 1449, 1358, 1165 cmꢁ1; HRMS (ESI)
35
calcd for C17
H
ClNO3S (MþþH): 348.0461, found: 348.0458.
15
4.4.4. N-(2-Formyl-5-(trifluoromethyl)phenyl)-4-methyl-N-(prop-2-
yn-1-yl)benzenesulfonamide (1d). Yield 35%; 0.0798 g; white solid;
mp 140e141 ꢀC; Rf (25% EtOAc/n-hexane) 0.56; 1H NMR (300 MHz,
CDCl3):
d
10.42 (s, 1H), 8.12 (d, 1H, J¼8.1 Hz), 7.73 (d, 1H, J¼8.1 Hz),
7.47 (d, 2H, J¼8.3 Hz), 7.30 (d, 2H, J¼8.1 Hz), 7.07 (s, 1H), 4.48 (br s,
4.2. General experimental procedure for the preparation of 2-
(N-(prop-2-ynyl)-N-tosylamino)benzaldehydes (1a)e(1r)
2H), 2.44 (s, 3H), 2.21 (t, 1H, J¼2.4 Hz); 13C NMR (75 MHz, CDCl3):
d
188.9, 145.2, 141.4, 138.6, 135.4 (1C, d, JC,F¼33.1 Hz), 133.8, 129.8,
129.2, 128.0, 125.9 (1C, q, JC,F¼3.6 Hz), 124.6, 121.0, 76.3, 75.4, 41.6,
21.6; IR (neat): 3306, 1701, 1362, 1327, 1167 cmꢁ1; HRMS (ESI) calcd
for C18H15F3NO3S (MþþH): 382.0725, found: 382.0724.
Propargyl bromide (0.27 mL, 3 mmol, 1.5 equiv) was added to
a solution of 2-(tosylamino)benzaldehyde (2 mmol) and K2CO3
(0.829g, 6 mmol, 3 equiv) in acetone (20 mL). The resulting reaction
mixture was stirred at reflux under atmospheric conditions for 4 h.
On cooling to room temperature, the reaction mixture was filtered
through Celite and the filtrate was concentrated under reduced
pressure and purified by silica gel flash column chromatography
(9:1 n-hexane/EtOAc as eluent) to give the title compound.
4.4.5. N-(2-Formyl-5-methoxyphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1e). Yield 15%; 0.0364 g; pale yellow liquid; Rf
(50% EtOAc/n-hexane) 0.37; 1H NMR (400 MHz, CDCl3):
d 10.16 (s,
1H), 7.80 (d, 1H, J¼8.8 Hz), 7.58 (d, 2H, J¼8.4 Hz), 7.29 (d, 2H,
J¼8.0 Hz), 6.98 (dd,1H, J¼2.4, 8.8 Hz), 6.46 (d,1H, J¼2.4 Hz), 4.45 (br
s, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 2.20 (t, 1H, J¼2.4 Hz); 13C NMR
4.3. General procedure for the preparation of 1-tosyl-1H-
benzo[b]azepin-3(2H)-ones (2a)e(2r)
(100 MHz, CDCl3):
d 189.0, 164.1, 144.5, 142.9, 134.8, 130.5, 129.7,
129.1, 128.2, 114.9, 114.3, 74.8, 55.7, 41.9, 21.6; IR (neat): 3306,
1684 cmꢁ1; HRMS (ESI) calcd for C18H18NO4S (MþþH): 344.0957,
found: 344.0967.
Benzyl alcohol (0.36 mmol) was added to a dichloromethane
(3 mL) solution containing 3 (11.6 mg, 5 mol %), and 1 (0.3 mmol) at
room temperature. The reaction mixture was monitored by TLC
analysis until no more starting material could be observed. At this
point, p-TsOH$H2O (11.4 mg, 20 mol %) was added to the reaction
mixture. The reaction mixture was then stirred at reflux under at-
mospheric conditions for 5 h. On cooling to room temperature, the
reaction mixture was concentrated under reduced pressure and the
crude product was purified by silica gel flash column chromatog-
raphy (9:1 n-hexane/EtOAc as eluent) to give the title compound.
4.4.6. N-(4-Chloro-2-formylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1f). Yield 20%; 0.0276 g; white solid; mp
90e92 ꢀC; Rf (25% EtOAc/n-hexane) 0.50; 1H NMR (300 MHz,
CDCl3):
d
10.29 (s, 1H), 7.96 (d, 1H, J¼2.4 Hz), 7.52 (d, 2H, J¼8.4 Hz),
7.46 (dd, 1H, J¼2.7, 8.6 Hz), 7.31 (d, 2H, J¼8.1 Hz), 6.88 (d, 1H,
J¼8.4 Hz), 4.44 (br s, 2H), 2.43 (s, 3H), 2.20 (t, 1H, J¼2.6 Hz); 13C
NMR (75 MHz, CDCl3): d 188.7, 144.9, 139.3, 137.2, 135.7, 134.2, 134.1,
129.9, 129.8, 128.5,128.0, 76.6, 75.2, 41.6, 21.6; IR (neat): 3306,1694,
35
1597, 1477, 1360, 1163 cmꢁ1; HRMS (ESI) calcd for C17
H ClNO3S
15
4.4. Characterization data
(MþþH): 348.0461, found: 348.0455.
4.4.1. N-(2-Formylphenyl)-4-methyl-N-(prop-2-yn-1-yl)benzene-
4.4.7. N-(4-Bromo-2-formylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1g). Yield 58%; 0.485 g; pale orange solid; mp
106e107 ꢀC; Rf (25% EtOAc/n-hexane) 0.37; 1H NMR (300 MHz,
sulfonamide (1a). Yield 80%; 0.281 g; white solid; mp 79e81 ꢀC; Rf
(25% EtOAc/n-hexane) 0.23; 1H NMR (400 MHz, CDCl3):
d 10.39 (s,
1H), 7.99e7.97 (m, 1H), 7.51e7.47 (m, 4H), 7.28e7.26 (m, 2H),
6.91e6.89 (m,1H), 4.47 (br s, 2H), 2.42 (s, 3H), 2.20 (t,1H, J¼2.4 Hz);
CDCl3):
d
10.29 (s, 1H), 8.07 (d, 1H, J¼2.3 Hz), 7.59 (dd, 1H, J¼2.3,
8.5 Hz), 7.48 (d, 2H, J¼8.2 Hz), 7.28 (d, 2H, J¼8.1 Hz), 6.78 (d, 1H,
13C NMR (100 MHz, CDCl3):
d 190.2, 144.6, 141.0, 135.9, 134.4, 134.3,
J¼8.5 Hz), 4.44 (br s, 2H), 2.42 (s, 3H), 2.22 (t, 1H, J¼2.2 Hz); 13C
129.7,129.2, 128.5,128.4,128.0, 76.9, 74.9, 41.7, 21.6; IR (neat): 3306,
1695, 1597, 1356, 1165 cmꢁ1; HRMS (ESI) calcd for C17H16NO3S
(MþþH): 314.0851, found: 314.0866.
NMR (75 MHz, CDCl3): d 188.7, 144.9, 139.9, 137.2, 137.1, 134.0, 131.5,
130.0, 129.9, 128.0, 123.6, 76.6, 75.2, 41.6, 21.6; IR (neat): 3304,1692,
1597, 1478, 1358, 1163 cmꢁ1; HRMS (ESI) calcd for C17
H
BrNO3S
79
15
(MþþH): 391.9956, found: 391.9974.
4.4.2. N-(2-Formyl-6-methoxyphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1b). Yield 65%; 0.451 g; white solid; mp
146e147 ꢀC; Rf (50% EtOAc/n-hexane) 0.54; 1H NMR (400 MHz,
4.4.8. N-(2-Formyl-4-methylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1h). Yield 87%; 0.0541 g; yellow solid; mp
102e105 ꢀC; Rf (25% EtOAc/n-hexane) 0.43; 1H NMR (300 MHz,
CDCl3):
3H, J¼7.6 Hz), 6.80 (d, 1H, J¼8.1 Hz), 4.44 (br s, 2H), 2.43 (s, 3H),
2.40 (s, 3H), 2.18 (s, 1H); 13C NMR (75 MHz, CDCl3):
190.4, 144.4,
139.6, 138.5, 135.5, 135.0, 134.7, 129.7, 128.9, 128.4, 128.0, 74.7, 41.8,
21.6, 21.1; IR (neat): 3306, 1688, 1599, 1493, 1354, 1163 cmꢁ1
CDCl3):
d
10.40 (s, 1H), 7.58 (dd, 1H, J¼0.6, 7.8 Hz), 7.47 (d, 2H,
J¼8.0 Hz), 7.41 (t, 1H, J¼8.0 Hz), 7.24 (d, 2H, J¼8.0 Hz), 7.00 (dd, 1H,
J¼1.0, 8.2 Hz), 4.84 (dd, 1H, J¼2.4, 17.2 Hz), 4.23 (dd, 1H, J¼2.4,
17.2 Hz), 3.27 (s, 3H), 2.40 (s, 3H), 2.18 (t, 1H, J¼2.6 Hz); 13C NMR
d
10.32 (s, 1H), 7.79 (s, 1H), 7.52 (d, 2H, J¼8.2 Hz), 7.27 (d,
d
(100 MHz, CDCl3):
d 191.1, 156.5, 143.7, 138.1, 136.4, 130.2, 129.3,
128.2, 127.5, 119.5, 116.5, 76.8, 74.1, 55.2, 39.9, 21.5; IR (neat): 3306,
;

E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
5563
35
HRMS (ESI) calcd for C18H18NO3S (MþþH): 328.1007, found:
1163 cmꢁ1; HRMS (ESI) calcd for C17
found: 348.0468.
H
ClNO3S (MþþH): 348.0461,
15
328.1010.
4.4.9. N-(2-Formyl-4,5-dimethoxyphenyl)-4-methyl-N-(prop-2-yn-
1-yl)benzenesulfonamide (1i). Yield 66%; 0.481 g; orange solid; mp
159e161 ꢀC; Rf (50% EtOAc/n-hexane) 0.42; 1H NMR (300 MHz,
4.4.15. N-(But-2-yn-1-yl)-N-(2-formylphenyl)-4-methylbenzenesulf-
onamide (1o). Yield 61%; 0.406 g; yellow solid; mp 129e130 ꢀC; Rf
(25% EtOAc/n-hexane) 0.31; 1H NMR (300 MHz, CDCl3):
d 10.38 (s,
CDCl3):
d
10.14 (s, 1H), 7.59 (d, 2H, J¼8.1 Hz), 7.44 (s, 1H), 7.30 (d, 2H,
1H), 8.03e7.99 (m, 1H), 7.55e7.46 (m, 4H), 7.30e7.27 (m, 2H),
6.97e6.94 (m, 1H), 4.42 (br s, 2H), 2.45 (s, 3H),1.63 (t, 3H, J¼2.3 Hz);
J¼7.8 Hz), 6.38 (s, 1H), 4.48 (br s, 2H), 3.95 (s, 3H), 3.65 (s, 3H), 2.44
(s, 3H), 2.25 (t, 1H, J¼2.6 Hz); 13C NMR (75 MHz, CDCl3):
d
189.0,
13C NMR (75 MHz, CDCl3):
d 190.3, 144.3, 141.5, 136.1, 135.0, 134.2,
153.6, 149.5, 144.5, 135.4, 134.9, 129.6, 129.4, 128.2, 111.1, 108.9, 76.7,
74.8, 56.2, 56.0, 42.1, 21.6; IR (neat): 3304, 1682, 1597, 1512, 1358,
1163 cmꢁ1; HRMS (ESI) calcd for C19H20NO5S (MþþH): 374.1062,
found: 374.1053.
129.6, 129.0, 128.6, 128.3, 128.1, 83.0, 72.4, 42.5, 21.6, 3.3; IR (neat):
1694, 1597, 1483, 1352, 1163 cmꢁ1; HRMS (ESI) calcd for C18H18NO3S
(MþþH): 328.1007, found: 328.1006.
4.4.16. N-(2-Formylphenyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)
benzenesulfonamide (1p).17 Yield 64%; 0.248 g; orange solid; mp
109e111 ꢀC; Rf (25% EtOAc/n-hexane) 0.24; 1H NMR (300 MHz,
4.4.10. N-(2-Formyl-4,6-dimethylphenyl)-4-methyl-N-(prop-2-yn-1-
yl)benzenesulfonamide (1j). Yield 79%; 0.510 g; pale orange solid;
mp 120e122 ꢀC; Rf (50% EtOAc/n-hexane) 0.80; 1H NMR (400 MHz,
CDCl3):
d
10.52 (s, 1H), 8.02 (dd, 1H, J¼1.7, 7.4 Hz), 7.57 (d, 2H,
CDCl3):
d
9.82 (s, 1H), 7.60e7.56 (m, 3H), 7.30e7.26 (m, 3H), 4.79
J¼8.1 Hz), 7.52e7.44 (m, 2H), 7.25e7.15 (m, 7H), 7.05 (d, 1H,
(dd,1H, J¼2.5,17.9 Hz), 4.18 (dd,1H, J¼2.4,17.8 Hz), 2.41 (s, 3H), 2.35
J¼7.2 Hz), 4.71 (s, 2H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3):
(s, 3H), 2.25 (t, 1H, J¼2.5 Hz), 2.03 (s, 3H); 13C NMR (100 MHz,
d
190.2, 114.5, 141.5, 136.0, 135.9, 135.4, 131.5, 129.8, 129.2, 128.8,
CDCl3):
d
190.9, 144.3, 139.6, 139.4, 138.0, 136.6, 136.5, 136.0, 130.0,
128.6, 128.4, 128.3, 128.1, 121.9, 86.5, 82.5, 42.8, 21.6.
127.2, 127.1, 77.3, 74.8, 41.3, 21.6, 21.0, 17.7; IR (neat): 3304, 1686,
1597, 1354, 1161 cmꢁ1; HRMS (ESI) calcd for C19H20NO3S (MþþH):
342.1164, found: 342.1149.
4.4.17. N-(2-Formylphenyl)-N-(prop-2-yn-1-yl)methanesulfonamide
(1q). Yield 83%; 0.407 g; white solid; mp 120e123 ꢀC; Rf (50%
EtOAc/n-hexane) 0.40; 1H NMR (300 MHz, CDCl3):
d 10.32 (s, 1H),
4.4.11. N-(3-Formylnaphthalen-2-yl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1k). Yield 21%; 0.0871 g; orange solid; mp
117e120 ꢀC; Rf (50% EtOAc/n-hexane) 0.63; 1H NMR (400 MHz,
7.99 (d, 1H, J¼7.6 Hz), 7.73e7.65 (m, 2H), 7.57e7.52 (m, 1H), 4.49 (br
s, 2H), 3.07 (s, 3H), 2.48 (t, 1H, J¼2.3 Hz); 13C NMR (75 MHz, CDCl3):
d
189.9, 141.2, 135.2, 134.9, 129.6, 129.6, 128.6, 77.9, 75.2, 41.6, 39.1;
CDCl3):
d
10.50 (s,1H), 8.55 (s,1H), 8.04e8.01 (m,1H), 7.72e7.69 (m,
IR (neat): 3304, 2126, 1695, 1595, 1483, 1352, 1155 cmꢁ1; HRMS
1H), 7.64e7.59 (m, 2H), 7.56 (d, 2H, J¼8.3 Hz), 7.43 (s,1H), 7.30e7.28
(ESI) calcd for C11H12NO3S (MþþH): 238.05379, found: 238.05480.
(m, 2H), 4.50e4.62 (br m, 2H), 2.47 (s, 3H), 2.21 (t, 1H, J¼2.42 Hz);
13C NMR (100 MHz, CDCl3):
d
190.4, 144.5, 136.4, 135.5, 134.7, 132.7,
4.4.18. N-(2-Formylphenyl)-4-nitro-N-(prop-2-yn-1-yl)benzene-
132.2, 131.1, 129.9, 129.7, 129.2, 128.8, 128.2, 128.0, 127.9, 77.2, 74.7,
42.1, 21.7; IR (neat): 3304, 1694, 1593, 1356, 1163 cmꢁ1; HRMS (ESI)
calcd for C21H18NO3S (MþþH): 364.1007, found: 364.1027.
sulfonamide (1r). Yield 62%; 0.189 g; yellow solid; mp 159e162 ꢀC;
Rf (50% EtOAc/n-hexane) 0.66; 1H NMR (400 MHz, CDCl3):
d 10.31 (s,
1H), 8.34e8.31 (m, 2H), 8.04e8.02 (m, 1H), 7.88e7.85 (m, 2H),
7.59e7.52 (m, 2H), 7.03e7.01 (m, 1H), 4.56 (br s, 2H), 2.27 (t, 1H,
4.4.12. N-(6-Formylbenzo[d][1,3]dioxol-5-yl)-4-methyl-N-(prop-2-
yn-1-yl)benzenesulfonamide (1l). Yield 68%; 0.303 g; brown solid;
mp 113e114 ꢀC; Rf (25% EtOAc/n-hexane) 0.26; 1H NMR (300 MHz,
J¼2.5 Hz); 13C NMR (100 MHz, CDCl3):
d 189.4, 150.5, 143.8, 139.8,
135.5, 134.6, 130.0, 129.8, 129.4, 129.0, 124.2, 76.6, 75.4, 42.2; IR
(neat): 3304, 1697, 1595, 1533, 1481, 1366, 1350, 1171 cmꢁ1; HRMS
(ESI) calcd for C16H13N2O5S (MþþH): 345.05536, found: 345.05452.
CDCl3):
d
10.08 (s, 1H), 7.59 (d, 2H, J¼8.2 Hz), 7.38 (d, 1H, J¼0.5 Hz),
7.30 (d, 2H, J¼8.1 Hz), 6.41 (d, 1H, J¼1.3 Hz), 6.07 (s, 2H), 4.31e4.54
(m, 2H), 2.45 (s, 3H), 2.22 (t, 1H, J¼2.5 Hz); 13C NMR (75 MHz,
4.4.19. 1-Tosyl-1H-benzo[b]azepin-3(2H)-one (2a).18 Yield 73%;
0.0682 g; pale yellow solid; mp 151e152 ꢀC; Rf (25% EtOAc/n-hex-
CDCl3):
d 188.6, 152.4, 148.6, 144.6, 137.3, 134.8, 131.4, 129.8, 128.1,
108.7, 106.8, 102.7, 76.9, 75.0, 42.1, 21.6; IR (neat): 3302, 1689, 1597,
1481, 1356, 1165 cmꢁ1; HRMS (ESI) calcd for C18H16NO5S (MþþH):
358.0749, found: 358.0761.
ane) 0.20; 1H NMR (400 MHz, CDCl3):
d
7.69 (d, 1H, J¼6.4Hz), 7.47 (t,
1H, J¼7.4 Hz), 7.40e7.31 (m, 4H), 7.14 (d, 2H, J¼7.6 Hz), 6.73 (d, 1H,
J¼12.4 Hz), 5.73 (d, 1H, J¼12.4 Hz), 4.85 (d, 1H, J¼16.8 Hz), 3.94 (d,
1H, J¼16.8 Hz), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 196.4,
4.4.13. N-(2-Formyl-3-methylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1m). Yield 71%; 0.348 g; white solid; mp
112e113 ꢀC; Rf (33% EtOAc/n-hexane) 0.46; 1H NMR (400 MHz,
144.0, 140.6, 138.7, 137.0, 133.1, 132.4, 131.3, 130.3, 129.5, 129.3,
128.5, 127.1, 58.9, 21.6.
CDCl3):
d
10.57 (s, 1H), 7.49 (d, 2H, J¼8.4 Hz), 7.22e7.32 (m, 4H),
4.4.20. 9-Methoxy-1-tosyl-1H-benzo[b]azepin-3(2H)-one
Yield 55%; 0.0578 g; yellow solid; mp 201e203 ꢀC; Rf (50% EtOAc/n-
hexane) 0.63; 1H NMR (400 MHz, CDCl3):
(2b).
6.69 (d,1H, J¼8.0 Hz), 4.30e462 (br m, 2H), 2.59 (s, 3H), 2.40 (s, 3H),
2.19 (t, 1H, J¼2.4 Hz); 13C NMR (100 MHz, CDCl3):
d
192.9, 144.5,
d
7.71 (d, 2H, J¼8.0 Hz),
142.2, 141.7, 134.5, 134.2, 132.9, 132.7, 129.7, 128.1, 126.1, 76.9, 74.8,
7.36 (t, 1H, J¼8.0 Hz), 7.29 (d, 2H, J¼7.6 Hz), 7.05 (d, 1H, J¼8.0 Hz),
6.99e6.93 (m, 2H), 5.94 (d, 1H, J¼12.4 Hz), 4.63 (dd, 1H, J¼1.2,
18.4 Hz), 3.97 (d, 1H, J¼18.0 Hz), 3.85 (s, 3H), 2.44 (s, 3H); 13C NMR
42.0, 21.6, 21.3; IR (neat): 3306, 1695, 1597, 1466, 1354, 1163 cmꢁ1
;
HRMS (ESI) calcd for C18H18NO3S (MþþH): 328.1007, found:
328.0996.
(100 MHz, CDCl3): d 198.6, 156.7, 143.9, 140.5, 137.5, 135.4, 129.6,
129.5,129.4,128.0,124.1,114.4, 59.7, 55.9, 21.6; IR (neat): 1672,1597,
1574, 1472, 1346, 1159 cmꢁ1; HRMS (ESI) calcd for C18H18NO4S
(MþþH): 344.0957, found: 344.0952.
4.4.14. N-(3-Chloro-2-formylphenyl)-4-methyl-N-(prop-2-yn-1-yl)
benzenesulfonamide (1n). Yield 46%; 0.0861 g; white solid; mp
104e106 ꢀC; Rf (25% EtOAc/n-hexane) 0.26; 1H NMR (300 MHz,
CDCl3):
d
10.36 (s,1H), 7.57 (d, 2H, J¼8.3 Hz), 7.50e7.48 (m, 1H), 7.39
4.4.21. 9-Chloro-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2c). Yield
59%; 0.0409 g; yellow solid; mp 173e175 ꢀC; Rf (25% EtOAc/n-
(t, 1H, J¼8.0 Hz), 7.29 (d, 2H, J¼8.0 Hz), 7.01e6.99 (m, 1H), 4.51 (br s,
2H), 2.45 (s, 3H), 2.23 (t, 1H, J¼2.4 Hz); 13C NMR (75 MHz, CDCl3):
hexane) 0.15; 1H NMR (300 MHz, CDCl3):
d 7.56e7.63 (m, 3H), 7.37
d
189.5, 144.4, 140.2, 135.8, 135.4, 134.0, 133.0, 131.8, 129.6, 129.2,
(t, 1H, J¼7.8 Hz), 7.27 (d, 3H, J¼7.8 Hz), 6.79 (d, 1H, J¼12.6 Hz), 5.76
128.0, 77.4, 74.6, 41.8, 21.6; IR (neat): 3306, 1707, 1584, 1452, 1354,
(d, 1H, J¼12.6 Hz), 4.78 (dd, 1H, J¼1.2, 18.6 Hz), 4.05 (d, 1H,

5564
E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
J¼18.6 Hz), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
197.8, 144.4,
131.1, 130.4, 128.4, 117.5, 116.3, 62.4, 59.7, 59.4, 24.8; IR (neat): 1665,
1603, 1518, 1354, 1163 cmꢁ1; HRMS (ESI) calcd for C19H20NO5S
(MþþH): 374.1062, found: 374.1048.
139.0, 137.2, 136.5, 136.4, 136.3, 132.7, 130.7, 130.0, 129.7, 128.0, 59.7,
21.6; IR (neat): 1672, 1362, 1167 cmꢁ1; HRMS (ESI) calcd for
35
C17
H
ClNO3S (MþþH): 348.0461, found: 348.0464.
15
4.4.28. 7,9-Dimethyl-1-tosyl-1H-benzo[b]azepin-3(2H)-one
4.4.22. 1-Tosyl-8-(trifluoromethyl)-1H-benzo[b]azepin-3(2H)-one
(2d). Yield 56%; 0.0212 g; yellow liquid; Rf (25% EtOAc/n-hexane)
(2j). Yield 87%; 0.0897 g; brown liquid; Rf (50% EtOAc/n-hexane)
0.74; 1H NMR (400 MHz, CDCl3):
d
7.40 (d, 2H, J¼8.2 Hz), 7.18 (d, 3H,
0.29; 1H NMR (300 MHz, CDCl3):
d
7.96 (s,1H), 7.63 (d,1H, J¼8.1 Hz),
J¼8.1 Hz), 6.92 (s, 1H), 6.53 (d, 1H, J¼12.6 Hz), 5.43 (d, 1H,
7.46 (d, 1H, J¼8.1 Hz), 7.40 (d, 2H, J¼8.3 Hz), 7.19 (d, 2H, J¼8.2 Hz),
6.79 (d, 1H, J¼12.6 Hz), 5.87 (d, 1H, J¼12.5 Hz), 4.87 (br s, 1H), 3.99
J¼12.5 Hz), 4.84 (dd, 1H, J¼1.4, 18.4 Hz), 3.94 (d, 1H, J¼18.4 Hz), 2.49
(s, 3H), 2.38 (s, 3H), 2.32 (3H, s); 13C NMR (100 MHz, CDCl3):
d 198.0,
(br s, 1H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
195.7, 144.5,
144.0, 140.6, 139.9, 138.7, 137.5, 134.9, 134.8, 133.9, 130.9, 129.6,
128.5, 127.7, 60.0, 21.6, 20.8, 19.5; IR (neat): 1661, 1597, 1354,
1163 cmꢁ1; HRMS (ESI) calcd for C19H20NO3S (MþþH): 342.1164,
found: 342.1167.
139.3, 138.7, 137.0, 135.3, 133.3, 133.0, 132.6, 131.3, 129.8, 127.5 (1C,
d, JC,F¼3.7 Hz), 127.2, 125.0 (1C, d, JC,F¼3.7 Hz), 58.8, 21.6; IR (neat):
1674, 1616, 1339, 1167 cmꢁ1; HRMS (ESI) calcd for C18H15F3NO3S
(MþþH): 382.0725, found: 382.0727.
4.4.29. 1-Tosyl-1H-naphtho[2,3-b]azepin-3(2H)-one
65%; 0.0481 g; yellow solid; mp 187e190 ꢀC; Rf (50% EtOAc/n-
hexane) 0.80; 1H NMR (400 MHz, CDCl3):
8.15 (s, 1H), 7.91 (d, 1H,
(2k). Yield
4.4.23. 8-Methoxy-1-tosyl-1H-benzo[b]azepin-3(2H)-one
Yield 80%; 0.0283 g; yellow solid; mp 109e112 ꢀC; Rf (50% EtOAc/n-
hexane) 0.34; 1H NMR (400 MHz, CDCl3):
(2e).
d
d
7.38 (d, 2H, J¼8.0 Hz),
J¼7.9 Hz), 7.87e7.84 (m, 2H), 7.63e7.55 (m, 2H), 7.35 (d, 2H,
J¼8.2 Hz), 7.14 (d, 2H, J¼8.0 Hz), 6.89 (d, 1H, J¼12.5 Hz), 5.74 (d, 1H,
J¼12.5 Hz), 4.96 (d, 1H, J¼17.6 Hz), 4.03 (d, 1H, J¼17.7 Hz), 2.37 (s,
7.25e7.28 (m, 1H), 7.16 (d, 2H, J¼8.4 Hz), 6.94 (dd,1H, J¼2.4, 8.4 Hz),
6.70 (d, 2H, J¼12.4 Hz), 5.65 (d, 1H, J¼12.4 Hz), 4.86 (d, 1H,
J¼17.2 Hz), 3.95 (d, 1H, J¼23.2 Hz), 3.92 (s, 3H), 2.39 (s, 3H); 13C
3H); 13C NMR (100 MHz, CDCl3):
d 197.1, 143.9, 140.8, 137.1, 134.8,
NMR (100 MHz, CDCl3):
d
196.0, 161.6, 144.0, 140.7, 140.3, 136.9,
134.1, 134.0, 132.3, 131.0, 129.6, 128.5, 128.5, 128.3, 128.2, 127.7,
127.3, 59.0, 21.6; IR (neat): 1668, 1358, 1165 cmꢁ1; HRMS (ESI) calcd
for C21H18NO3S (MþþH): 364.1007, found: 364.1000.
134.6, 129.5, 127.2, 127.0, 125.2, 115.0, 114.8, 58.7, 55.8, 21.6; IR
(neat): 1663, 1605, 1558, 1506, 1356, 1341, 1165 cmꢁ1; HRMS (ESI)
calcd for C18H18NO4S (MþþH): 344.0957, found: 344.0951.
4.4.30. 5-Tosyl-5H-[1,3]dioxolo[40,50:4,5]benzo[1,2-b]azepin-7(6H)-
4.4.24. 7-Chloro-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2f). Yield
71%; 0.0249 g; yellow solid; mp 133e135 ꢀC; Rf (25% EtOAc/n-
one (2l). Yield 63%; 0.0453 g; yellow solid; mp 198e200 ꢀC; Rf (25%
EtOAc/n-hexane) 0.11; 1H NMR (400 MHz, CDCl3):
d 7.38 (d, 2H,
hexane) 0.52; 1H NMR (300 MHz, CDCl3):
d
7.66 (d, 1H, J¼8.7 Hz),
J¼8.3 Hz), 7.17 (s, 2H), 7.15 (s, 1H), 6.70 (s, 1H), 6.54 (d, 1H,
J¼12.5 Hz), 6.09 (d, 2H, J¼11.1 Hz), 5.62 (dd, 1H, J¼0.9, 12.5 Hz), 4.83
(d, 1H, J¼1.3, 17.6 Hz), 3.92 (d, 1H, J¼17.6 Hz), 2.38 (s, 3H); 13C NMR
7.44 (dd, 1H, J¼2.4, 8.4 Hz), 7.37 (d, 2H, J¼8.4 Hz), 7.31 (d, 1H,
J¼2.4 Hz), 7.18 (d, 2H, J¼8.1 Hz), 6.63 (d, 1H, J¼12.6 Hz), 5.77 (d, 1H,
J¼12.3 Hz), 4.88 (d, 1H, J¼17.1 Hz), 3.93 (d, 1H, J¼17.1 Hz), 2.39 (s,
(100 MHz, CDCl3):
d 196.2, 149.6, 147.7, 144.0, 140.1, 136.9, 134.2,
3H); 13C NMR (75 MHz, CDCl3):
d
195.9, 144.3, 138.8, 137.2, 136.8,
129.5, 128.1, 127.2, 126.8, 110.9, 110.9, 102.6, 59.1, 21.6; IR (neat):
1668, 1591, 1487, 1342, 1157 cmꢁ1; HRMS (ESI) calcd for C18H16NO5S
(MþþH): 358.0749, found: 358.0749.
134.2, 133.7, 132.3, 131.8, 131.1, 130.6, 129.7, 127.2, 58.9, 21.6; IR
(neat): 1672, 1597, 1483, 1358, 1167 cmꢁ1; HRMS (ESI) calcd for
35
C17
H
ClNO3S (MþþH): 348.0461, found: 348.0462.
15
4.4.31. 6-Methyl-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2m). Yield
60%; 0.0608 g; yellow solid; mp 153e155 ꢀC; Rf (33% EtOAc/n-
4.4.25. 7-Bromo-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2g). Yield
60%; 0.0472 g; orange solid; mp 149e152 ꢀC; Rf (25% EtOAc/n-
hexane) 0.37; 1H NMR (400 MHz, CDCl3):
d 7.41e7.46 (m, 3H), 7.31
hexane) 0.43; 1H NMR (300 MHz, CDCl3):
d
7.58 (d, 2H, J¼1.2 Hz),
(t,1H, J¼7.6 Hz), 7.22 (d, 1H, J¼7.6 Hz), 7.18 (d, 2H, J¼8.0 Hz), 6.93 (d,
1H, J¼12.8 Hz), 5.78 (dd, 1H, J¼1.2, 12.8 Hz), 4.83 (dd, 1H, J¼1.6,
18.0 Hz), 3.95 (d, 1H, J¼18.0 Hz), 2.38 (s, 3H), 2.37 (s, 3H); 13C NMR
7.46 (s, 1H), 7.36 (d, 2H, J¼8.3 Hz), 7.17 (d, 2H, J¼8.1 Hz), 6.62 (d, 1H,
J¼12.6 Hz), 5.76 (d, 1H, J¼12.5 Hz), 4.86 (d, 1H, J¼16.6 Hz), 3.92 (d,
1H, J¼17.3 Hz), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
195.8,
(100 MHz, CDCl3): d 197.9, 143.9, 139.6, 139.3, 137.6, 136.6, 131.6,
144.3, 138.7, 137.7, 136.8, 135.3, 134.1, 134.0, 132.0, 130.5, 129.7, 127.1,
130.7,130.6,129.6, 129.3,127.7,127.1, 60.1, 21.6, 20.8; IR (neat): 1676,
1595, 1470, 1356, 1163 cmꢁ1; HRMS (ESI) calcd for C18H18NO3S
(MþþH): 328.1007, found: 328.0997.
122.1, 58.8, 21.6; IR (neat): 1676, 1481, 1356, 1165 cmꢁ1; HRMS (ESI)
79
calcd for C17
H
BrNO3S (MþþH): 391.9956, found: 391.9942.
15
4.4.26. 7-Methyl-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2h). Yield
58%; 0.0190 g; orange solid; mp 138e140 ꢀC; Rf (50% EtOAc/n-
4.4.32. 6-Chloro-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2n). Yield
35%; 0.0120 g; yellow solid; mp 118e120 ꢀC; Rf (25% EtOAc/n-
hexane) 0.41; 1H NMR (300 MHz, CDCl3):
d
7.58 (d, 1H, J¼8.1 Hz),
hexane) 0.46; 1H NMR (400 MHz, CDCl3):
d
7.60 (d, 1H, J¼8.0 Hz),
7.36 (d, 2H, J¼8.2 Hz), 7.29 (s, 1H), 7.14 (t, 3H, J¼7.9 Hz), 6.67 (d, 1H,
J¼12.5 Hz), 5.71 (d, 1H, J¼12.5 Hz), 4.86 (d, 1H, J¼17.3 Hz), 3.93 (d,
1H, J¼17.0 Hz), 2.39 (s, 3H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3):
7.49e7.36 (m, 4H), 7.22e7.17 (m, 3H), 5.84 (d, 1H, J¼12.8 Hz), 4.87
(dd,1H, J¼1.2,18.0 Hz), 3.99 (d,1H, J¼18.0 Hz), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 196.7, 144.3, 140.5, 137.3, 136.1, 135.2, 131.1,
d
196.6, 143.9, 140.7, 138.5, 137.1, 136.2, 133.4, 132.2, 132.1, 130.2,
130.8, 130.5, 129.9, 129.8, 128.8, 127.1, 59.8, 21.6; IR (neat): 1676,
1456,1356,1165 cmꢁ1; HRMS (ESI) calcd for C17
348.0461, found: 348.0474.
H
ClNO3S (MþþH):
35
129.5, 129.3, 127.2, 59.1, 21.6, 20.9; IR (neat): 1670, 1497, 1354,
1163 cmꢁ1; HRMS (ESI) calcd for C18H18NO3S (MþþH): 328.1007,
found: 328.1008.
15
4.4.33. 4-Methyl-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2o). Yield
76%; 0.0515 g; pale yellow solid; mp 123e125 ꢀC; Rf (25% EtOAc/n-
4.4.27. 7,8-Dimethoxy-1-tosyl-1H-benzo[b]azepin-3(2H)-one
(2i). Yield 67%; 0.0503 g; yellow solid; mp 157e159 ꢀC; Rf (50%
hexane) 0.19; 1H NMR (400 MHz, CDCl3):
d
7.75 (d, 1H, J¼8.0 Hz),
EtOAc/n-hexane) 0.44; 1H NMR (300 MHz, CDCl3):
d
7.32 (d, 2H,
7.43 (dt, 1H, J¼1.5, 7.8 Hz), 7.27 (dt, 1H, J¼1.1, 7.5 Hz), 7.21 (d, 2H,
J¼8.4 Hz), 7.16 (dd, 1H, J¼1.2, 7.6 Hz), 7.05 (d, 2H, J¼8.0 Hz), 6.80 (s,
1H), 4.63 (s, 2H), 2.33 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz,
J¼8.40 Hz), 7.20 (s, 1H), 7.12 (d, 2H, J¼8.1 Hz), 6.69 (s, 1H), 6.58 (d,
1H, J¼12.3 Hz), 5.59 (d, 1H, J¼12.6 Hz), 4.83 (br d, 1H, J¼17.1 Hz),
3.95 (s, 3H), 3.91 (obscured d,1H), 3.87 (s, 3H), 2.35 (s, 3H); 13C NMR
CDCl3):
d 195.4, 143.7, 136.6, 135.9, 133.6, 133.3, 130.9, 129.1, 128.8,
(75 MHz, CDCl3): d 199.3, 154.1, 151.9, 147.2, 143.7, 140.1, 136.2, 132.7,
128.0, 127.5, 127.0, 127.0, 43.3, 24.8, 21.5; IR (neat): 1663,1628,1599,

E.M.L. Sze et al. / Tetrahedron 69 (2013) 5558e5565
5565
1356, 1167 cmꢁ1; HRMS (ESI) calcd for C18H18NO3S (MþþH):
Reimann, D.; Gross, P. Cardiovasc. Res. 2001, 51, 403; (d) Wong, L. L.; Verbalis, J.
G. Cardiovasc. Res. 2001, 51, 391.
2. Yamamura, Y.; Ogawa, H.; Yamashita, H.; Chihara, T.; Miyamoto, H.; Nakamura,
S.; Onogawa, T.; Yamashita, T.; Hosokawa, T.; Mori, T.; Tominaga, M.; Yabuuchi,
Y. Br. J. Pharmacol. 1992, 105, 787.
3. Yamamura, Y.; Nakamura, S.; Ito, S.; Hirano, T.; Onogawa, T.; Yamashita, T.;
Yamada, Y.; Tsujimae, K.; Aoyama, M.; Kotosai, K.; Ogawa, H.; Yamashita, H.;
Kondo, K.; Tominaga, M.; Tsujimoto, G.; Mori, T. J. Pharmacol. Exp. Ther. 1998,
287, 860.
4. Nakamura, S.; Yamamura, Y.; Itoh, S.; Hirano, T.; Tsujimae, K.; Aoyama, M.;
Kondo, K.; Ogawa, H.; Shinohara, T.; Kan, K.; Tanada, Y.; Teramoto, S.; Sumida,
T.; Nakayama, S.; Sekiguchi, K.; Kambe, T.; Tsujimoto, G.; Mori, T.; Tominaga, M.
Br. J. Pharmacol. 2000, 129, 1700.
328.1007, found: 328.1001.
4.4.34. 4-Phenyl-1-tosyl-1H-benzo[b]azepin-3(2H)-one (2p). Yield
38%; 0.0267 g; brown solid; mp 118e121 ꢀC; Rf (25% EtOAc/n-
hexane) 0.46; 1H NMR (400 MHz, CDCl3):
d
7.83 (d, 1H, J¼8.1 Hz),
7.54 (t, 1H, J¼7.5 Hz), 7.49e7.45 (m, 1H), 7.39 (d, 2H, J¼7.7 Hz), 7.34
(d, 2H, J¼8.2 Hz), 7.30e7.23 (m, 4H), 7.10 (d, 3H, J¼8.1 Hz), 6.66 (s,
1H), 4.84 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 193.5,
143.7, 137.0, 136.5, 136.4, 132.3, 132.0, 131.1, 129.5, 129.0, 128.9,
128.3,128.0,127.5,127.1,127.0, 44.7, 21.5; IR (neat): 1626,1597,1447,
1350, 1167 cmꢁ1; HRMS (ESI) calcd for C23H20NO3S (MþþH):
390.1164, found: 390.1161.
5. Xiang, M. A.; Rybczynski, P. J.; Patel, M.; Chen, R. H.; McComsey, D. F.; Zhang, H.-
C.; Gunnet, J. W.; Look, R.; Wang, Y.; Minor, L. K.; Zhong, H. M.; Villani, F. J.;
Demarest, K. T.; Damianob, B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2007,
17, 6623.
6. Yea, C. M.; Allan, C. E.; Ashworth, D. M.; Barnett, J.; Baxter, A. J.; Broadbridge, J.
D.; Franklin, R. J.; Hampton, S. L.; Hudson, P.; Horton, J. A.; Jenkins, P. D.; Penson,
4.4.35. 1-(Methylsulfonyl)-1H-benzo[b]azepin-3(2H)-one
ꢁ
A. M.; Pitt, G. R. W.; Riviere, P.; Robson, P. A.; Rooker, D. P.; Semple, G.; Shep-
(2q). Yield 77%; 0.0726 g; pale yellow solid; mp 122e125 ꢀC; Rf
pard, A.; Haigh, R. M.; Roe, M. B. J. Med. Chem. 2008, 51, 8124.
(50% EtOAc/n-hexane) 0.40; 1H NMR (400 MHz, CDCl3):
d 7.66e7.64
7. For selected recent examples: (a) Kothandaraman, P.; Huang, C.; Susanti, D.;
Rao, W.; Chan, P. W. H. Chem.dEur. J. 2011, 17, 10081; (b) Cho, H.; Iwama, Y.;
Sugimoto, K.; Mori, S.; Tokuyama, H. J. Org. Chem. 2010, 75, 627; (c) Ghosh, D.;
Thander, L.; Ghosh, S. K.; Chattopadhyay, S. K. Synlett 2008, 3011; (d) Yama-
moto, H.; Pandey, G.; Asai, Y.; Nakano, M.; Kinoshita, A.; Namba, K.; Imagawa,
H.; Nishizawa, M. Org. Lett. 2007, 9, 4029; (e) Cropper, E. L.; White, A. J. P.; Ford,
A.; Hii, K. K. J. Org. Chem. 2006, 71, 1732; (f) Lautens, M.; Tayama, E.; Herse, C. J.
(m, 1H), 7.52e7.42 (m, 3H), 7.30 (d, 1H, J¼12.5 Hz), 6.39 (d, 1H,
J¼12.5 Hz), 4.78 (d, 1H, J¼14.5 Hz), 3.96 (d, 1H, J¼14.5 Hz), 2.86 (s,
3H); 13C NMR (100 MHz, CDCl3):
d 196.5, 141.8, 138.7, 133.4, 132.3,
131.6,129.8,129.4, 128.6, 58.6, 41.0; IR (neat): 1670,1611,1487,1352,
1157 cmꢁ1; HRMS (ESI) calcd for C11H12NO3S (MþþH): 238.05444,
found: 238.05379.
ꢂ
Am. Chem. Soc. 2005, 127, 72; (g) Ortiz-Marciales, M.; Rivera, L. D.; De Jesus, M.;
Espinosa, S.; Benjamin, J. A.; Casanova, O. E.; Figueroa, I. G.; Rodríguez, S.;
Correa, W. J. Org. Chem. 2005, 70, 10132; (h) Qadir, M.; Cobb, J.; Sheldrake, P. W.;
Whittall, N.; White, A. J. P.; King, K. H.; Horton, P. N.; Hursthouse, M. B. J. Org.
Chem. 2005, 70, 1545; (i) Dolman, S. J.; Schrock, R. R.; Hoveyada, A. H. Org. Lett.
2003, 5, 4899; (j) Omar-Amrani, R.; Thomas, A.; Brenner, E.; Schneider, R.; Fort,
Y. Org. Lett. 2003, 5, 2311; (k) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett.
2002, 4, 2691.
4.4.36. 1-((4-Nitrophenyl)sulfonyl)-1H-benzo[b]azepin-3(2H)-one
(2r). Yield 75%; 0.0517 g; pale yellow solid; mp 169e172 ꢀC; Rf (50%
EtOAc/n-hexane) 0.54; 1H NMR (400 MHz, CDCl3):
d 8.19 (d, 2H,
J¼8.8 Hz), 7.73 (d, 1H, J¼7.9 Hz), 7.61 (d, 2H, J¼8.8 Hz), 7.56e7.52
(m, 1H), 7.46 (dt, 1H, J¼0.9, 7.5 Hz), 7.37e7.35 (m, 1H), 6.74 (d, 1H,
J¼12.5 Hz), 5.72 (d, 1H, J¼12.5 Hz), 4.90 (d, 1H, J¼17.4 Hz), 4.02 (d,
8. For selected general reviews on gold catalysis: (a) Rudolph, M.; Hashmi, A. S. K.
Chem. Soc. Rev. 2012, 41, 2448; (b) Garayalde, D.; Nevado, C. ACS Catal. 2012, 2,
1462; (c) Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 6536; (d) Krause,
ꢂ
N.; Winter, C. Chem. Rev. 2011, 111, 1994; (e) Corma, A.; Leyva-Perez, A.; Sabater,
1H, J¼17.5 Hz); 13C NMR (100 MHz, CDCl3):
d 195.0, 150.2, 145.1,
M. J. Chem. Rev. 2011, 111, 1657; (f) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T.
Chem. Commun. 2009, 5075; (g) Abu Sohel, S. M.; Liu, R.-S. Chem. Soc. Rev. 2009,
38, 2269; (h) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351; (i)
Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (j) Hashmi, A. S. K. Chem.
140.6, 137.7, 133.4, 132.0, 131.8, 130.3, 129.5, 129.2, 128.3, 124.1, 58.9;
IR (neat): 1670, 1609, 1533, 1487, 1368, 1348, 1171 cmꢁ1; HRMS (ESI)
calcd for C16H13N2O5S (MþþH): 345.05469, found: 345.05452.
ꢂ
ꢂ
Rev. 2007, 107, 3180; (k) Jimenez-Nunẽz, E.; Echavarren, A. M. Chem. Commun.
2007, 333; (l) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896; (m) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271.
9. Sze, E. M. L.; Rao, W.; Koh, M. J.; Chan, P. W. H. Chem.dEur. J. 2011, 17, 1437.
10. For selected examples of gold-catalyzed carbonyl metathesis: (a) Escribano-
Acknowledgements
ꢂ
Custa, A.; Lopez-Carrillo, V.; Janssen, D.; Echavarren, A. M. Chem.dEur. J. 2009,
This work is supported by College of Science Start-up Grant from
Nanyang Technological University and a Science and Engineering
Research Council Grant (092 1010053) from A*STAR, Singapore. We
thank Dr. Yongxin Li of this Division for providing the X-ray crys-
tallographic data reported in this work.
15, 5646; (b) Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137; (c) Baskar, B.; Bae, H.
J.; An, S. E.; Cheong, J. Y.; Rhee, Y. H.; Duschek, A.; Kirsch, S. F. Org. Lett. 2008, 10,
2605; (d) Bae, H. J.; Baskar, B.; An, S. E.; Cheong, J. Y.; Thangadurai, D. T.; Hwang,
I.-C.; Rhee, Y. H. Angew. Chem., Int. Ed. 2008, 47, 2263; (e) Jin, T.; Yamamoto, Y.
Org. Lett. 2007, 9, 5259; (f) Schelwies, M.; Dempwolff, A. L.; Rominger, F.;
ꢂ
ꢂ~
Helmchen, G. Angew. Chem., Int. Ed. 2007, 46, 5598; (g) Jimenez-Nunez, E.;
Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
2006, 45, 5452.
Supplementary data
11. For selected examples by us, see Refs. 7a, 9 and: (a) Rao, W.; Sally; Koh, M. J.;
Chan, P. W. H. J. Org. Chem. 2013, 78, 3183; (b) Rao, W.; Koh, M. J.;
Kothandaraman, P.; Chan, P. W. H. J. Am. Chem. Soc. 2012, 134, 10811; (c) Rao, W.;
Susanti, D.; Chan, P. W. H. J. Am. Chem. Soc. 2011, 133, 15248; (d) Kothandaraman,
P.; Rao, W.; Foo, S. J.; Chan, P. W. H. Angew. Chem., Int. Ed. 2010, 49, 4619; (e) Rao,
W.; Chan, P. W. H. Chem.dEur. J. 2008, 14, 10486.
1H and 13C NMR spectra for all starting materials and products.
This material is available free of charge via the internet at http://
www.sciencedirect.com. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.04.069.
12. CCDC 906092 (2a) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141.
ꢂ
14. Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127,
References and notes
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18. Hannah, E. D.; Peaston, W. C.; Proctor, G. R. J. Chem. Soc. C 1968, 1280.
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ꢂ