Heterobimetallic Ir-Sn catalysis: Aza-Friedel-Crafts reaction of N-sulfonyl aldimines

Article abstract of DOI:10.1016/j.tet.2013.01.074

The heterobimetallic complex [Ir(COD)(SnCl₃)Cl(μ-Cl)] ₂ catalyzes the aza-Friedel-Crafts reaction of 1,3,5- trimethoxybenzene, as well as substituted indoles with N-sulfonyl aldimines leading to the formation of diarylamines and triarylmethanes in good yields. The symmetrical triarylmethanes were also obtained from diarylamines and suitable nucleophiles via simultaneous cleavage of sp³ C-N bond and elimination of 1,3,5-trimethoxybenzene.

Full text of DOI:10.1016/j.tet.2013.01.074

Tetrahedron 69 (2013) 2816e2826
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heterobimetallic IreSn catalysis: aza-FriedeleCrafts reaction of
N-sulfonyl aldimines
,
Paresh Nath Chatterjee a b, Arnab Kumar Maity a, Swapna Sarita Mohapatra c,
,
Sujit Royc
*
a Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
b Department of Chemistry, National Institute of Technology, Meghalaya, Bijni Complex, Laitumkhrah, Shillong 793003, India
c Organometallics and Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The heterobimetallic complex [Ir(COD)(SnCl3)Cl(m-Cl)]2 catalyzes the aza-FriedeleCrafts reaction of 1,3,5-
Received 21 November 2012
Received in revised form 16 January 2013
Accepted 21 January 2013
trimethoxybenzene, as well as substituted indoles with N-sulfonyl aldimines leading to the formation of
diarylamines and triarylmethanes in good yields. The symmetrical triarylmethanes were also obtained
from diarylamines and suitable nucleophiles via simultaneous cleavage of sp3 CeN bond and elimination
of 1,3,5-trimethoxybenzene.
Available online 1 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Heterobimetallic catalysis
Iridium
Tin
Aza-FriedeleCrafts reaction
N-Sulfonyl aldimine
Diarylamines
Triarylmethanes
Indoles
Arene
1. Introduction
lactams4i towards carbonecarbon and carboneheteroatom bond
formation. As an extension of our contributions in the field of
Heterobimetallic catalysts are known to display unique re-
activity in comparison to the mononuclear ones. It is because of the
fact that the inclusion of two metals in a single scaffold often results
in selective substrate binding, cooperative activation of the sub-
strate and higher catalytic efficiency.1 Thus the successful design of
homogeneous heterobimetallic catalysts is an area of enduring in-
terest.2 Obviously, the success of such bimetallic catalysis truly
depends on the stereoelectronic features of and around the two
metals, and their ability to communicate during substrate binding
and activation. In numerous studies carried out in our laboratory,
we have found that dual-reagent combination of d8/d10 transition
metal (Cu, Ir, Rh and Pd) and main group metal, tin, can act as ef-
ficient catalysts for the activation of small organic molecules.3 Quite
recently, we have illustrated the unique reactivity of hetero-
bimetallic catalysts bearing [IreSn] motif, which are capable of
activating electrophiles, such as benzylic alcohols,4a,b,e,g propargylic
heterobimetallic catalysis, we were encouraged to explore the re-
activity of aldimines within the [IreSn] domain using our in-house
designed [Ir(COD)(SnCl3)Cl(m
-Cl)]2 catalyst (here after IrIIIeSnCl3).
The Lewis or Brønsted acid catalyzed addition of arenes and
heteroarenes to imines is known as the aza-FriedeleCrafts reaction
(AFCR). The transition metal5aem catalyzed or organocatalytic5a,nez
AFCR is a synthetically powerful strategy for the construction of
carbonecarbon bond, providing functionalized amines, which are
potential starting materials for many biologically active compounds,
in a completely atom-economical way. Additionally, Lewis acidic
metal salts catalyzed AFCR and other catalytic and stoichiometric
protocols are also known in the literature.6 Stopping the Friedele
Crafts reaction of aromatic aldimines 1 seems at the intermediate
benzylic amine 2 stage is often difficult, since such amines are sus-
ceptible towards the second FriedeleCrafts reaction under the acidic
reaction conditions, resulting into triaryl/heteroaryl methanes
(TRAMs) 3 (Scheme 1). Motifs bearing triarylmethanes and their
heterocyclic analogues display varied and interesting applications as
bioactive compounds, prodrugs, pharmaceuticals, and dyes.7 They
also constitute the backbone of dendrimers, and NLOs.8
alcohols,4f,g allylic alcohols,4h ethers,4d aldehydes,4c and
g-hydroxy
* Corresponding author. Tel.: þ91 674 2676021; fax: þ91 674 2306303; e-mail
addresses: sroy@iitbbs.ac.in, sujitroy.chem@gmail.com (S. Roy).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.074

P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
2817
Scheme 1. Synthesis of triarylmethanes 3 from aromatic aldimines 1 through intermediate 2 by Lewis acid catalyzed FriedeleCrafts reaction.
Wereporthere IrIIIeSnCl3 catalyzed AFCRthat allows the selective
preparation of functionalized diarylamines using N-sulfonyl aldi-
mines and highly electron-rich arenes and heteroarenes (1,3,5-
trimethoxybenzene and indole derivatives, respectively) as the
coupling partners. Structurally diverse symmetrical and un-
symmetrical TRAMs could also be synthesized through IrIIIeSnCl3
catalyzed cleavage of sp3 carbonenitrogen bond of 2.9 Moreover,
symmetrical TRAMs were obtained when both N-sulfonyl group and
required to fully comprehend the nature of such a synergy. Both
aldimine 1a and 1,3,5-trimethixybenzene remained un-reacted in
absence of [Ir(COD)(SnCl3)Cl( -Cl)]2 catalyst (entry 9).
The generality of the reaction was successfully tested under the
optimized conditions with various N-sulfonyl aldimines 1 and
1,3,5-trimethoxybenzene and indole derivatives, giving rise to
corresponding functionalized diarylamines 2 (Tables 3 and 4). The
m
N-tosyl aldimines
1 bearing electron-donating and electron-
1,3,5-trimethoxybenzene of
2
work as leaving groups under
withdrawing substituents on the phenyl ring reacted smoothly
with 1,3,5-trimethoxybenzene at room temperature to provide
corresponding coupling products, 2a, and 2cei, in good yields,
along with small amount of corresponding TRAMs 3 (Table 3, en-
tries 1e3, 5, and 7,8). When the protecting group in aldimine was
changed from N-Ts to N-SO2Ph, the substrate 1k reacted equally
well with 1,3,5-trimethoxybenzene, providing 2i in 84% yield (Table
3, entry 8). On the other hand, the reactions of N-tosyl aldimines 1
with indole derivatives at the same reaction conditions increase the
amount of corresponding TRAMs 4, instead of getting the desired
amines 2 as major products. This problem was overcome by de-
creasing the reaction temperature from room temperature to 10 ꢀC.
At the modified reaction conditions, different N-tosyl aldimines 1
coupled with indole derivatives to give the desired 3-indolyl
methanamine derivatives 2jep in good yields, along with small
IrIIIeSnCl3 catalysis in the presence of nucleophiles, like indoles, fu-
rans, thiophenes,1,3-dimethoxybenzene, and4-methoxythiophenol.
2. Results and discussions
At first we attempted the AFCR of various N-protected aldimines
1 of 4-chlorobenzaldehyde with 1,3,5-trimethoxybenzene in the
presence of 1 mol % of IrIIIeSnCl3 catalyst and in 1,2-dichloroethane
(C2H4Cl2) as the solvent at room temperature (Table 1). Along with
the minor TRAM product 3a, the major coupling products 2a and 2b
were formed in 85% and 50% yields for aldimines 1a and 1b, re-
spectively (entries 1 and 2). But aldimines 1c and 1d slowly hy-
drolyzed into corresponding aldehyde and amines instead of giving
any coupling product with trimethoxybenzene (entries 3 and 4).
Table 1
IrIIIeSnCl3 catalyzed AFCR of 1,3,5-trimethoxybenzene with different N-protected aldimines 1a
#
eR group
Yield of 2b (%)
Yield of 3ab (%)
1
2
3
4
eTs, 1a
2a, 85
2b, 50
0
0
5
<5
0
eCOPh, 1b
eCH2Ph, 1c
ePh, 1d
0
a
Unless otherwise mentioned, general reaction conditions: 1 (0.5 mmol), 1,3,5-trimethoxybenzene (0.5 mmol), IrIIIeSnCl3 catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
b
Initial catalyst screening included a number of heterobimetallic
catalysts bearing [IreSn] motif (Table 2). The efficiency of the cat-
alyst [Ir(COD)(SnCl3)Cl( -Cl)]2 was highest in comparison to other
heterobimetallic catalysts (entries 1e5). It was also observed that
cationic iridium(I) species like [Ir(COD)(MeCN)2]PF6 had negligible
amount of bisindole addition products 4 (Table 4). The AFCR of
indoles with N-tosyl aldimines 1 was found to be general with
electron-donating and electron-withdrawing substituents on
either indoles or N-tosyl aldimines (Table 4, entries 1e5). Notably,
2-(thiophen-2-yl)-1H-indole coupled with aldimines 1e and 1i at
room temperature producing 93% and 90% of the desired products,
2o and 2p, respectively (Table 4, entries 6 and 7), without giving
any bisindole addition products 4f, and 4g. Aromatic systems like
toluene, anisole, dimethoxybenzene derivatives, thiophenes, and
m
catalytic activity (entry 6). Individually [Ir(COD)(m-Cl)]2 was in-
active, while SnCl4 was poorly active (entries 7 and 8). The above
facts suggested a bimetallic synergism in the IrIIIeSnCl3 motif,
which promotes the AFCR of aldimines. However, further work is

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P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
Table 2
AFCR of 1,3,5-trimethoxybenzene with 1a: catalyst screeninga
#
Catalyst
Yield of 2ab (%)
85
65
60
5
<5
<5
0
15
0
Yield of 3ab (%)
1
2
3
4
5
6
7
8
9
[Ir(COD)(SnCl3)Cl(
m
m
-Cl)]2
-Br)]2
[Ir(COD)(MeSnCl2)Cl( -Cl)]2
5
<5
<5
0
0
0
0
<5
0
[Ir(COD)(SnBr3)Br(
m
[IrCl(CO)(PPh3)2(SnCl4)]
[Ir(COD)2(SnCl3)]2
[Ir(COD)(MeCN)2]PF6
[Ir(COD)(
SnCl4
No catalyst
m-Cl)]2
a
Unless otherwise mentioned, general reaction conditions: 1a (0.5 mmol), 1,3,5-trimethoxybenzene (0.5 mmol), catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
b
Table 3
IrIIIeSnCl3 catalyzed AFCR of 1,3,5-trimethoxybenzene with N-sulfonyl aldimines 1a
#
1
Aldimine, 1
Time (min)
Yield of 2b (%)
Yield of 3b (%)
25
2
25
3
40

P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
2819
Table 3 (continued )
#
Aldimine, 1
Time (min)
Yield of 2b (%)
Yield of 3b (%)
4
30
5
35
6
30
7
45
8
30
a
Unless otherwise mentioned, general reaction conditions: 1 (0.5 mmol), 1,3,5-trimethoxybenzene (0.5 mmol), IrIIIeSnCl3 catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
b
furans did not couple with aldimines 1 to produce the corre-
TRAMs can also be achieved from aldimines 1 by first acid-
catalyzed hydrolysis (which produces aldehydes), followed by
acid-catalyzed FriedeleCrafts reaction of corresponding aldehydes
via an intermediacy of benzyl alcohols.10 During the study it was
observed that 1a slowly hydrolyzed to 4-chlorobenzaldehyde
(monitored vide TLC) in absence of any arene or heteroarene at
80 ꢀC using IrIIIeSnCl3 catalyst. Subsequent addition of 2-methyl-
thiophene (2 equiv) in the reaction mixture, under same reaction
conditions, resulted a complete conversion of the aldehyde to
corresponding TRAM 4h (Scheme 2).
sponding amines 2 in the above mentioned reaction conditions.
During the study of IrIIIeSnCl3 catalyzed AFCR of N-sulfonyl
aldimines 1, it was observed that TRAMs 3 or 4 with 1,3,5-
trimethoxybenzene or indole moieties, respectively, was obtained
as minor products via a side reaction. We were also delighted to
find that the isolated AFCR coupling products 2 undergo further
FriedeleCrafts reaction producing TRAMs (4aee, 5a and 5b) as
the sole products when the reaction temperature was elevated
(Table 5). The IrIIIeSnCl3 catalyst can activate sp3 CeN bond of
compounds 2jen to give symmetrical bisindolyl-aryl methanes
4aee, while reacting with indole derivatives at room temperature
(Table 5, entries 1e5). Not only aromatic nucleophiles, but carbon
nucleophiles like allylTMS or dibenzoylmethane were equally good
to afford diarylmethane derivatives 5a and 5b in good yields via
FriedeleCrafts type substitution reaction with 2a or 2i (entries
6e9) when heated at 80 ꢀC. It is noteworthy to mention that,
While extending the scope of IrIIIeSnCl3 catalyzed sp3 CeN bond
activation, followed by a new CeC bond formation, we had yet an-
other interesting observation. Different outcome was observed when
AFCR product 2c reacted with 2 equiv of anisole and 2 equiv of
1,3-dimethoxybenzene separately at 80 ꢀC, providing an un-
symmetrical TRAM 3h and a symmetrical TRAM 3i, respectively
(Scheme 3). TRAM 3i can only be obtained via an unusual loss

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P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
Table 4
IrIIIeSnCl3 catalyzed AFCR of indole derivatives with N-sulfonyl aldimines 1a
#
1
Aldimine, 1
Time (min)
Yield of 2b (%)
Yield of 4b (%)
20
2
20
25
20
30
3
4
5
6c
30
4f, 0%
7c
35
4g, 0%
a
Unless otherwise mentioned, general reaction conditions: 1 (0.5 mmol), indole derivatives (0.5 mmol), IrIIIeSnCl3 catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
Room temperature.
b
c

P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
2821
Table 5
IrIIIeSnCl3 catalyzed synthesis of symmetrical and unsymmetrical TRAMs from 2a
#
1
Substrate, 2
Product, 4 or 5
Temp, time, yieldb (%)
rt, 1 h, 83
2
3
4
5
rt, 1 h, 88
rt, 1.5 h, 85
rt, 1 h, 89
rt, 1.5 h, 80
6
80 ꢀC, 2 h, 70
7
80 ꢀC, 2 h, 74
(continued on next page)

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P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
Product, 4 or 5
Table 5 (continued )
#
Substrate, 2
Temp, time, yieldb (%)
8
80 ꢀC, 2 h, 78
9
80 ꢀC, 2 h, 77
a
Unless otherwise mentioned, general reaction conditions: 2 (0.5 mmol), nucleophile (0.5 mmol), IrIIIeSnCl3 catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
b
Scheme 2. IrIIIeSnCl3 catalyzed formation of TRAM 4h by the hydrolysis of 1a, followed by FriedeleCrafts reaction.
Scheme 3. IrIIIeSnCl3 catalyzed synthesis of symmetrical and unsymmetrical TRAMs, 3h and 3i, from 2c: dependence of arene.
of 1,3,5-trimethoxybenzene under acidic environment. Here we
propose that our in-house developed Lewis acidic IrIIIeSnCl3
catalyst is capable of coordinating to highly electron rich 1,3,5-
trimethoxybenzene, thus withdraws pi-electrons from the aromatic
ring. This interaction subsequently weakens the sp3 carbone1,3,5-
trimethoxybenzene bond and facilitate the nucleophilic attack to
sp3 carbon centre. At this moment we areyetto establish the nature of
such electronic interaction between highly electron rich 1,3,5-
trimethoxybenzene and Lewis acidic IrIIIeSnCl3 unit but the possi-
bility of such communication cannot be ruled out. The specific role of
iridium and tin towards the 1,3,5-trimethoxybenzene activation
process is now ongoing in our laboratory. In this context, it is im-
portant to mention that in the year 2000 Castellani et al. reported
a very similar kind of interaction of Lewis acidic Sc(OTf)3 with 1,3,5-
trimethoxybenzene leading to hydrogen/deuterium exchange.11 It is
also unambiguous that the IrIIIeSnCl3 catalyst activates the CeN bond
via an interactionwith either Lewis basic nitrogen or oxygen centre of
NHSO2R group. The generality of this reaction involving the dis-
placement of 1,3,5-trimethoxybenzene moiety is described in Table 6
and it was observed that symmetrical TRAMs were obtained in good

P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
2823
Table 6
IrIIIeSnCl3 catalyzed synthesis of symmetrical TRAMs from 2a
#
1
Substrate, 2
Product, 4 or 5
Time, yieldb (%)
1 h, 88
1 h, 82
1 h, 85
1 h, 85
1 h, 88
1 h, 80
2
3
4
5
6
7
2 h, 85
(continued on next page)

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P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
Product, 4 or 5
Table 6 (continued )
#
Substrate, 2
Time, yieldb (%)
8
2 h, 80
9
2 h, 86
10
2 h, 84
11
2 h, 79
12
1 h, 87
a
Unless otherwise mentioned, general reaction conditions: 2 (0.5 mmol), nucleophile (1.0 mmol), IrIIIeSnCl3 catalyst (0.005 mmol), C2H4Cl2 (2 mL).
Isolated yields.
b
yields using varieties of nucleophiles, like indoles (entries 1e6), fu-
4. Experimental section
4.1. General remarks
rans (entries 7, 8 and 11), thiophenes (entries 9 and 10), and 4-
methoxythiophenol (entry 12). The exact mechanism of 1,3,5-
trimethoxybenzene activation by IrIIIeSnCl3 catalyst is underway.
NMR spectra were recorded on Bruker-AC 200 MHz and Bruker-
Avance II 400 MHz spectrometer at 300 K. 1H NMR spectra were
recorded at 200 MHz and 400 MHz. Chemical shifts are reported in
parts per million (ppm) from tetramethylsilane with the solvent
resonance as the internal standard (deuterochloroform:
3. Conclusion
In conclusion, we have developedtheAFCRof N-sulfonyl aromatic
aldimines with highly electron-rich arenes and heteroarenes cata-
lyzed by the in-house designed heterobimetallic [Ir(COD)(SnCl3)
d
7.26 ppm). 13C NMR spectra were recorded at 100 MHz and
Cl(
m
-Cl)]2 complex. Additionally, this bimetallic catalyst also allows
54.6 MHz with complete proton decoupling. Chemical shifts are
reported in parts per million (ppm) from tetramethylsilane with
the solvent resonance as the internal standard (deuterochloroform:
the formation of symmetrical and unsymmetrical TRAMs via a con-
secutive FriedeleCrafts reaction pathway. The formation of sym-
metrical TRAMs via the sp3 CeN bond cleavage along with
elimination of 1,3,5-trimethoxybenzene is yet another discrete out-
come of this study. Asymmetric version of the AFCR with N-sulfonyl
aldimines is underway.
d
77.0 ppm). Elemental analyses were carried out using a CHNS/O
Analyzer PerkineElmer 2400 Series II instrument.
All reactions were carried out under an argon atmosphere in
flame-dried glassware using Schlenk techniques. Chromatographic

P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
2825
purifications were done using either 60e120 or 100e200 mesh silica
gel. For reaction monitoring, pre-coated silica gel 60 F254 TLC sheets
were used. Petroleum ether refers to the fraction boiling in the range
60e80 ꢀC. 1,2-Dichloroethane (DCE) was dried and distilled prior to
use. IrCl$xH2O, 1,5-cyclooctadiene and tin tetrachloride were com-
(s, 2H), 7.14 (d, 1H, J¼9.2 Hz), 7.26e7.32 (m, 4H), 7.48e7.56 (m, 3H),
7.87 (d, 2H, J¼7.2 Hz), 8.07 (d, 1H, J¼9.2 Hz).
13C NMR (CDCl3, 100 MHz):
d ppm 46.9, 55.3, 55.9, 91.3, 109.6,
126.9,127.6,128.1,128.5,131.3,132.0,134.7,141.3,158.6,160.9,166.2.
DEPT-135: ppm 46.9, 55.3, 55.9, 91.3, 126.9, 127.6, 128.1, 128.5,
131.3.
d
mercially available. [Ir(COD)(
literature procedure12 and the heterobimetallic catalysts [Ir(COD)
(SnCl3)Cl(
-Cl)]2,4a [Ir(COD)(SnBr3)Br( -Br)]2,13 [Ir(COD)(MeSnCl2)
Cl(
-Cl)]2,13 [IrCl(CO)(PPh3)2(SnCl4)],14 and [Ir(COD)2(SnCl3)]15 were
m-Cl)]2 was prepared according to the
Anal. Calcd for C23H22ClNO4 (411.12): C, 67.07; H, 5.38; N, 3.40.
Found: C, 66.97; H, 5.30; N, 3.52.
m
m
m
prepared according to the literature procedure. N-Sulfonyl aldimines
1aek and 2-(thiophen-2-yl)-1H-indole were also prepared accord-
ing to the literature (see Supplementary data).
4.5.2. N-(m-Tolyl(2,4,6-trimethoxyphenyl)methyl)-toluenesulfona-
mide (2g). 1H NMR (CDCl3, 200 MHz):
d ppm 2.27 (s, 3H), 2.31
(s, 3H), 3.63 (s, 6H), 3.75 (s, 3H), 5.89 (s, 2H), 6.08 (d, 1H, J¼10.8 Hz),
6.22 (d, 1H, J¼10.8 Hz), 6.95e7.12 (m, 6H), 7.50 (d, 2H, J¼8.2 Hz).
13C NMR (CDCl3, 54.6 MHz):
d ppm 21.3, 21.4, 51.5, 55.3, 55.6,
4.2. Representative procedure for the AFCR of 1,3,5-
trimethoxybenzene with N-tosyl aldimine 1a catalyzed by
[Ir(COD)(SnCl3)Cl(m-Cl)]2
90.7, 108.8, 123.4, 126.8, 127.2, 127.4, 127.7, 128.6, 137.4, 137.7, 141.2,
142.4, 157.9, 160.9.
Anal. Calcd for C24H27NO5S (441.16): C, 65.28; H, 6.16; N, 3.17.
Found: C, 65.40; H, 6.09; N, 3.26.
A 10 mL Schlenk flask equipped with a magnetic bar was
charged with [Ir(COD)(SnCl3)Cl( -Cl)]2 (0.005 mmol), 1,3,5-
m
4.5.3. N-((4-Chlorophenyl)(2,4,6-trimethoxyphenyl)methyl)benzene-
trimethoxybenzene (0.5 mmol), N-tosyl aldimine 1a (0.5 mmol)
and 1,2-dichloroethane (2 mL). The flask was degassed, flushed
with argon. The reaction was allowed to continue at room tem-
perature, and monitored by TLC. After completion, solvent was
removed under reduced pressure and the mixture was subjected to
column chromatography over silica gel (eluent: gradient mixture of
EtOAc/petroleum ether) to afford the functionalized amine product
2a in 85% isolated yield.
sulfonamide (2i). 1H NMR (CDCl3, 400 MHz):
d ppm 3.61 (s, 6H), 3.73
(s, 3H), 5.88 (s, 2H), 6.08 (d, 1H, J¼10.8 Hz), 6.29 (d, 1H, J¼10.8 Hz),
7.15e7.26 (m, 6H), 7.35 (t, 1H, J¼7.4 Hz), 7.63 (d, 2H, J¼7.2 Hz).
13C NMR (CDCl3, 100 MHz):
d ppm 51.2, 55.6, 55.8, 90.8, 108.3,
127.0, 128.1, 128.2, 128.4, 132.2, 132.5, 140.3, 140.6, 157.9, 161.3.
DEPT-135: ppm 51.2, 55.6, 55.8, 90.8, 127.0, 128.1, 128.2, 128.4,
132.2.
d
Spectral data of compounds 2a,5j 2c,5j 2d,5j 2e,5j 2f,5j 2h,5j 2j,5g
2k,5g 2l,5s 2m,5v 2n,5s 3a,5j 3b,16 3c,5j 3e5j and 3g5j were in excel-
lent agreement with those in the literature.
Anal. Calcd for C22H22ClNO5S (447.09): C, 58.99; H, 4.95; N, 3.13.
Found: C, 59.08; H, 4.82; N, 3.22.
4.5.4. N-((4-Bromophenyl)(2-(thiophen-2-yl)-1H-indol-3-yl)
methyl)-toluenesulfonamide (2o). 1H NMR (CDCl3, 200 MHz):
d ppm
4.3. Representative procedure for the synthesis of TRAM 4a
from functionalized amine 2j catalyzed by [Ir(COD)(SnCl3)
Cl(m-Cl)]2
2.25 (s, 3H), 5.37 (d, 1H, J¼7.6 Hz), 6.07 (d, 1H, J¼7.6 Hz), 6.83 (d, 2H,
J¼8.0 Hz), 6.90e7.42 (m, 13H), 8.09 (br, 1H).
13C NMR (CDCl3, 54.6 MHz):
d ppm 21.5, 53.5, 100.0, 111.2, 119.4,
120.7,121.5,123.2,126.1,126.4,126.5,126.7,128.1,128.8,129.1,129.5,
131.6, 132.7, 136.0, 136.4, 139.7, 142.7.
Anal. Calcd for C26H21BrN2O2S2 (536.02): C, 58.10; H, 3.94; N,
5.21. Found: C, 58.23; H, 3.88; N, 5.15.
A 10 mL Schlenk flask equipped with a magnetic bar was charged
with [Ir(COD)(SnCl3)Cl( -Cl)]2 (0.005 mmol), indole (0.5 mmol),
m
functionalized amine 2j (0.5 mmol) and 1,2-dichloroethane (2 mL).
The flask was degassed, flushed with argon. The reaction was
allowed to continue at room temperature, and monitored by TLC.
After completion, solvent was removed under reduced pressure and
the mixture was subjected to column chromatography over silica gel
(eluent: gradient mixture of EtOAc/petroleum ether) to afford the
symmetrical TRAM 4a in 83% isolated yield.
4.5.5. N-((2-(Thiophen-2-yl)-1H-indol-3-yl)(m-tolyl)methyl)-tolue-
nesulfonamide (2p). 1H NMR (CDCl3, 200 MHz):
d ppm 2.24 (s, 3H),
2.29 (s, 3H), 5.43 (d, 1H, J¼8.0 Hz), 6.18 (d, 1H, J¼8.0 Hz), 6.79 (d, 2H,
J¼8.0 Hz), 6.93e7.33 (m, 13H), 8.26 (br, 1H).
13C NMR (CDCl3, 54.6 MHz):
d ppm 21.4, 21.5, 53.9, 111.1, 111.6,
119.6, 120.3, 122.8, 124.3, 126.2, 126.3, 126.5, 126.6, 127.9, 128.0,
128.3, 128.4, 128.5, 129.5, 133.1, 136.1, 136.6, 138.2, 140.4, 142.5.
Anal. Calcd for C27H24N2O2S2 (472.13): C, 68.61; H, 5.12; N, 5.93.
Found: C, 68.76; H, 5.00; N, 5.82.
4.4. Representative procedure for the synthesis of TRAM 4a
from functionalized amine 2a catalyzed by [Ir(COD)(SnCl3)
Cl(m-Cl)]2
A 10 mL Schlenk flask equipped with a magnetic bar was charged
with [Ir(COD)(SnCl3)Cl( -Cl)]2 (0.005 mmol), indole (1.0 mmol),
4.5.6. 2-((4-Bromophenyl)(4-methoxyphenyl)methyl)-1,3,5-
trimethoxybenzene (3h). 1H NMR (CDCl3, 400 MHz):
d ppm 3.61 (s,
m
functionalized amine 2a (0.5 mmol) and 1,2-dichloroethane (2 mL).
The flask was degassed, flushed with argon. The reaction was
allowed to continue at 80 ꢀC, and monitored by TLC. After comple-
tion, solvent was removed under reduced pressure and the mixture
was subjected to column chromatography over silica gel (eluent:
gradient mixture of EtOAc/petroleum ether) to afford the symmet-
rical TRAM 4a in 88% isolated yield.
6H), 3.79 (s, 3H), 3.81 (s, 3H), 5.94 (s, 1H), 6.16 (s, 2H), 6.79 (d, 2H,
J¼8.8 Hz), 7.05 (d, 2H, J¼8.4 Hz), 7.13 (d, 2H, J¼8.8 Hz), 7.33 (d, 2H,
J¼8.4 Hz).
13C NMR (CDCl3, 100 MHz):
d ppm 43.8, 55.1, 55.2, 55.6, 91.5,
113.1, 118.8, 130.0, 130.4, 130.7, 135.2, 143.9, 157.5, 158.9, 160.1.
Anal. Calcd for C23H23BrO4 (442.08): C, 62.31; H, 5.23. Found: C,
62.40; H, 5.18.
Spectral data of compounds 4a,5j 4b,6h 4c,5j 4d,17 4e,18 4i19 and
4j20 were in excellent agreement with those in the literature.
4.5.7. (4-Bromophenyl)-bis-(2,4-dimethoxy-phenyl)methane
(3i). 1H NMR (CDCl3, 400 MHz):
d ppm 3.69 (s, 6H), 3.79 (s, 6H),
4.5. Spectral and analytical data of new products
5.95 (s, 1H), 6.37 (dd, 2H. J¼2.2 and 8.4 Hz), 6.46 (d, 2H, J¼2.2 Hz),
6.66 (d, 2H, J¼8.4 Hz), 6.92 (d, 2H, J¼8.4 Hz), 7.34 (d, 2H, J¼8.4 Hz).
4.5.1. N-((4-Chlorophenyl)(2,4,6-trimethoxyphenyl)methyl)benza-
13C NMR (CDCl3, 100 MHz):
d ppm 42.0, 55.5, 55.9, 98.9, 103.8,
119.6, 124.8, 130.5, 131.1, 131.2, 144.1, 158.2, 159.6.
mide (2b). 1H NMR (CDCl3, 400 MHz):
d
ppm 3.89 (s, 9H), 6.25

2826
P.N. Chatterjee et al. / Tetrahedron 69 (2013) 2816e2826
1999, 99, 3379; (d) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248,
Anal. Calcd for C23H23BrO4 (442.08): C, 62.31; H, 5.23. Found: C,
62.25; H, 5.39.
2365; (e) Kamijo, S.; Yamamoto, Y. In Multimetallic Catalysts in Organic Syn-
thesis; Shibasaki, M., Yamamoto, Y., Eds.; Wiley-VCH: Weinheim, Germany,
2004; pp 1e52.
4.5.8. (4-Chlorophenyl)-bis-(5-methyl-2-thienyl)methane (4h). 1H
NMR (CDCl3, 200 MHz): d ppm 2.36 (s, 6H), 5.59 (s, 1H), 6.52 (s, 4H),
3. (a) Kundu, A.; Prabhakar, S.; Vairamani, M.; Roy, S. Organometallics 1999, 18,
2782; (b) Kundu, A.; Roy, S. Organometallics 2000,19,105; (c) Sinha, P.; Kundu, A.;
Roy, S.; Prabhakar, S.; Vairamani, M.; Sankar, A. R.; Kunwar, A. C. Organometallics
2001, 20,157; (d) Banerjee, M.; Roy, S. Chem. Commun. 2003, 534; (e) Banerjee, M.;
Roy, S. Org. Lett. 2004, 6, 2137; (f) Banerjee, M.; Roy, S. J. Mol. Catal. A: Chem. 2006,
246, 231; (g) Roy, U. K.; Roy, S. J. Organomet. Chem. 2006, 691, 1525; (h) Das, D.;
Pratihar, S.; Roy, U. K.; Mal, D.; Roy, S. Org. Biomol. Chem. 2012,10, 4537; (i) Das, D.;
Pratihar, S.; Roy, S. Org. Lett. 2012, 14, 4870; (j) Roy, U. K.; Roy, S. Chem. Rev. 2010,
110, 2472 and the references there in.
7.15e7.25 (m, 4H).
13C NMR (CDCl3, 54.6 MHz):
d ppm 15.4, 47.2, 124.7, 125.9, 128.7,
129.7, 132.8, 139.4, 142.4, 144.7.
Anal. Calcd for C17H15ClS2 (318.03): C, 64.03; H, 4.74. Found: C,
64.14; H, 4.71.
4. (a) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127, 6162; (b)
Podder, S.; Choudhury, J.; Roy, S. J. Org. Chem. 2007, 72, 3129; (c) Podder, S.;
Choudhury, J.; Roy, U. K.; Roy, S. J. Org. Chem. 2007, 72, 3100; (d) Podder, S.; Roy,
S. Tetrahedron 2007, 63, 9146; (e) Choudhury, J.; Roy, S. J. Mol. Catal. A: Chem.
2008, 279, 37; (f) Chatterjee, P. N.; Roy, S. J. Org. Chem. 2010, 75, 4413; (g)
Chatterjee, P. N.; Roy, S. Tetrahedron 2011, 67, 4569; (h) Chatterjee, P. N.; Roy, S.
Tetrahedron 2012, 68, 3776; (i) Maity, A. K.; Roy, S. J. Org. Chem. 2012, 77, 2935.
5. (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626
and the references there in; (b) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J.
Am. Chem. Soc. 1998, 120, 4548; (c) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc.
2000, 122, 976; (d) Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930; (e) Temelli, B.;
4.5.9. (4-Bromophenyl)-bis-(2,5-dimethyl-3-furyl)methane (4k). 1H
NMR (CDCl3, 200 MHz):
5.69 (s, 2H), 7.06 (d, 2H, J¼8.6 Hz), 7.38 (d, 2H, J¼8.6 Hz).
13C NMR (CDCl3, 54.6 MHz):
ppm 11.7, 13.6, 37.5, 107.2, 119.9,
d ppm 2.13 (s, 6H), 2.21 (s, 6H), 4.87 (s, 1H),
d
121.5, 129.9, 131.3, 143.1, 145.5, 149.5.
Anal. Calcd for C19H19BrO2 (358.06): C, 63.52; H, 5.33. Found: C,
63.48; H, 5.42.
ꢀ
Unaleroglu, C. Tetrahedron Lett. 2005, 46, 7941; (f) Esquivias, J.; Arrayas, R. G.;
Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 629; (g) Jia, Y.-X.; Xie, J.-H.; Duan,
H.-F.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 1621; (h) Alonso, I.; Esquivias, J.;
Arrayas, R. G.; Carretero, J. C. J. Org. Chem. 2008, 73, 6401; (i) Yu, X.; Lu, X.
4.5.10. 2-(1-(4-Chlorophenyl)but-3-enyl)-1,3,5-trimethoxybenzene
(5a). 1H NMR (CDCl3, 400 MHz):
d
ppm 2.93 (t, 2H, J¼6.4 Hz), 3.73
ꢀ
(s, 6H), 3.79 (s, 3H), 4.64 (t, 1H, J¼8.0 Hz), 4.88 (d, 1H, J¼10.0 Hz),
4.99 (d, 1H, J¼16.8 Hz), 5.67e5.77 (m, 1H), 6.11 (s, 2H), 7.17 (d, 2H,
J¼8.0 Hz), 7.25 (d, 2H, J¼8.0 Hz).
Tetrahedron Lett. 2011, 52, 2076; (j) Thirupathi, P.; Kim, S. S. J. Org. Chem. 2010,
75, 5240; (k) Liu, J.; He, T.; Wang, L. Tetrahedron 2011, 67, 3420; (l) Huang, T.; Li,
C.-H. Tetrahedron Lett. 2000, 41, 6715; (m) Kadam, S. T.; Thirupathi, P.; Kim, S. S.
Tetrahedron 2009, 65, 10383; (n) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8,
4939; (o) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett. 2007, 9,
4065; (p) Nakamura, S.; Sakurai, Y.; Nakashima, H.; Shibata, N.; Toru, T. Synlett
2009, 1639; (q) Enders, D.; Seppelt, M.; Beck, T. Adv. Synth. Catal. 2010, 352,
1413; (r) Sun, F.-L.; Zheng, X.-J.; Gu, Q.; He, Q.-L.; You, S.-L. Eur. J. Org. Chem.
2010, 47; (s) Xu, F.; Huang, D.; Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75,
8677; (t) Ube, H.; Fukuchi, S.; Terada, M. Tetrahedron: Asymmetry 2010, 21, 1203;
(u) Chauhan, P.;Chimni, S. S. Eur. J. Org. Chem. 2011,1636; (v)Xing, C.-H.;Liao, Y.-X.;
Ng, J.; Hu, Q.-S. J. Org. Chem. 2011, 76, 4125; (w) Ingle, G. K.; Mormino, M. G.;
Wojtas, L.; Antilla, J. C. Org. Lett. 2011,13, 4822; (x) He, Y.; Lin, M.; Li, Z.; Liang, X.; Li,
G.; Antilla, J. C. Org. Lett. 2011, 13, 4490; (y) Righi, M.; Bartoccini, F.; Lucarini, S.;
Piersanti, G. Tetrahedron 2011, 67, 7923; (z) Wang, B.-L.; Zhang, J.-X.; Li, N.-K.; Liu,
G.-G.; Shen, Q.; Wang, X.-W. Tetrahedron Lett. 2011, 52, 4671.
13C NMR (CDCl3, 100 MHz):
d ppm 36.3, 38.6, 55.2, 55.6, 91.0,
112.9, 115.1, 127.6, 129.3, 130.6, 138.0, 143.6, 158.9, 159.6.
DEPT-135: ppm 36.3, 38.6, 55.2, 55.6, 91.0,115.1,127.6,129.3,138.0.
d
Anal. Calcd for C19H21ClO3 (332.12): C, 68.57; H, 6.36. Found: C,
68.69: H, 6.30.
4.5.11. 2-((4-Chlorophenyl)(2,4,6-trimethoxyphenyl)methyl)-1,3-
diphenylpropane-1,3-dione (5b). 1H NMR (CDCl3, 400 MHz):
d ppm
3.65 (s, 6H), 3.69 (s, 3H), 5.84 (d, 1H, J¼11.6 Hz), 5.92 (s, 2H), 6.76 (d,
1H, J¼11.6Hz), 7.07 (d, 2H, J¼8.4 Hz), 7.24e7.32 (m, 4H), 7.36e7.44 (m,
3H), 7.49 (t,1H, J¼7.2 Hz), 7.82 (d, 2H, J¼7.6 Hz), 7.94 (d, 2H, J¼7.6 Hz).
6. (a) Mi, X.; Luo, S.; He, J.; Cheng, J.-P. Tetrahedron Lett. 2004, 45, 4567; (b) Ke, B.; Qin,
Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005, 46,1751; (c) Zhao, J.-L.; Liu, L.;
Zhang, H.-B.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synlett 2006, 96; (d) Macleod, P. D.; Li,
Z.; Feng, J.;Li, C.-J. Tetrahedron Lett. 2006, 47, 6791; (e)Liu,C.-R.;Li, M.-B.;Yang,C.-F.;
Tian, S.-K. Chem. Commun. 2008, 1249; (f) Li, B.-Y.; Li, Z.-L.; Meng, X.-B. Carbohydr.
Res. 2010, 345,1708; (g) Macleod, P. D.; Li, Z.; Li, C.-J. Tetrahedron 2010, 66,1045; (h)
Yang, H.; Cui, B.; Wu, G.; Miao, Z.; Chen, R. Tetrahedron 2012, 68, 4830; (i)
Jaratjaroonphong, J.; Krajangsri, S.; Reutrakul, V. Tetrahedron Lett. 2012, 53, 2476.
13C NMR (CDCl3, 100 MHz):
d ppm 41.4, 55.4, 55.8, 60.9, 91.2,
110.7, 128.2, 128.4, 128.7, 128.8, 129.0, 129.8, 131.6, 132.8, 133.4,
137.4, 137.5, 141.6, 158.8, 160.3, 194.6, 195.7.
Anal. Calcd for C31H27ClO5 (514.15): C, 72.30; H, 5.28. Found: C,
72.18; H, 5.35.
€
7. (a) Wulff, H.; Miller, M. J.; Hansel, W.; Grissmer, S.; Cahalan, M. D.; Chandy, K. G.
Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8151; (b) McNaughton-Smith, G. A.; Rigdon,
G. C.; Stocker, J. W. (Icagen, Inc., U.S.A.). PCT Int. Appl. WO-2000050026, 2000;
[CAN 133, 187954]. (c) Lacroix, R.; Poupelin, J. P.; Lacroix, J.; Reynouard, F.;
Combescot, C. Ann. Pharm. Fr. 1979, 37, 131; (d) Poupelin, J. P.; Saint-Ruf, G.;
Foussard-Blanpin, O.; Narcisse, G.; Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med.
Chem. 1978, 13, 67; (e) Manzoni, C.; Lovati, M. R.; Bonelli, A.; Galli, G.; Sirtori, C. R.
Eur. J. Pharmacol. 1990, 190, 39; (f) Finer, J. T.; Chabala J. C.; Lewis, E. (Cytokinetics,
Inc., U.S.A.). PCT Int. Appl. WO-2002056880, 2005; [CAN 137,124985]. (g) Mibu, N.;
Yokomizo, K.; Uyeda, M.; Sumoto, K. Chem. Pharm. Bull. 2003, 51, 1325; (h) Oclarit,
J. M.; Ohta, S.; Kamimura, K.; Yamaoka, Y.; Shimizu, T.; Ikegami, S. Nat. Prod. Lett.
1994, 4, 309.
4.5.12. (p-Tolylmethylene)bis((4-methoxyphenyl)sulfane)(5c). 1H NMR
(CDCl3, 200 MHz): d ppm 2.25 (s, 3H), 3.72 (s, 6H), 5.07 (s, 1H), 6.71 (d,
4H, J¼8.8 Hz), 6.99 (d, 2H, J¼8.0 Hz), 7.10 (d, 2H, J¼8.0 Hz), 7.22 (d, 4H,
J¼8.8 Hz).
13C NMR (CDCl3, 54.6 MHz):
d ppm 21.3, 55.3, 62.8, 114.4, 125.1,
127.8, 129.1, 135.8, 137.2, 137.6, 159.9.
Anal. Calcd for C22H22O2S2 (382.11): C, 69.07; H, 5.80. Found: C,
68.94; H, 5.84.
8. (a) Shagufta, S. K. D.; Panda, G. Tetrahedron Lett. 2005, 46, 3097 and references
cited therein; (b) Sanguinet, L.; Twieg, R. J.; Wiggers, G.; Mao, G.; Singer, K. D.;
Petschek, R. G. Tetrahedron Lett. 2005, 46, 5121; (c) Baker, L. A.; Sun, L.; Crooks,
R. M. Bull. Korean Chem. Soc. 2002, 23, 647.
Acknowledgements
9. For other catalytic protocols of TRAM synthesis, please see: (a) Liu, C.-R.; Li, M.-B.;
Yang, C.-F.; Tian, S.-K. Chem.dEur. J. 2009, 15, 793; (b) Kato, Y.; Yen, D. H.;
Fukudome, Y.; Hata, T.; Urabe, H. Org. Lett. 2010, 12, 4137; (c) Thirupathi, P.;
Neupane, L. K.; Lee, K.-H. Tetrahedron 2011, 67, 7301 and Refs.5f and 5i.
10. Barbero, M.; Cadamuro, S.; Dughera, S.; Magistris, C.; Ventutello, P. Org. Biomol.
Chem. 2011, 9, 8393 and the references there in.
We thank DST (financial support to S.R., INSPIRE fellowship to
S.S.M.), CSIR (fellowship to P.N.C.), and UGC (fellowship to A.K.M.).
Supplementary data
11. Castellani, C. B.; Perotti, A.; Scrivanti, M.; Vidari, G. Tetrahedron 2000, 56, 8161.
12. Walter, R.; Kirchner, S.; Franz, R. U.S. Patent 6,399,804, 2002.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.074.
13. Choudhury, J.; Krishna Kumar, D.; Roy, S. J. Organomet. Chem. 2007, 692, 5614.
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