Unusual dimerization of N-protected bromomethylindoles using phenylmagnesium chloride

Article abstract of DOI:10.1016/j.tetlet.2005.08.068

A novel dimerization of N-protected bromomethylindoles involving an exchange reaction with phenylmagnesium chloride is reported.

Full text of DOI:10.1016/j.tetlet.2005.08.068

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6983–6985
Unusual dimerization of N-protected bromomethylindoles using
phenylmagnesium chloride
Arasambattu K. Mohanakrishnan,* Neelamegam Ramesh and Chandran Prakash
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 17 June 2005; revised 8 August 2005; accepted 17 August 2005
Abstract—A novel dimerization of N-protected bromomethylindoles involving an exchange reaction with phenylmagnesium chlo-
ride is reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In continuation of our interest on the synthesis of carba-
zole-based alkaloids,1 we wanted to develop a viable
procedure for the arylation of N-protected bromome-
thylindoles2 as the existing procedure is applicable only
to electron rich arenes.3 Numerous developments have
been achieved recently using transition metal mediated
carbon–carbon bond formation.4 Nevertheless, these
developments are yet to be adapted to the indole system.
In continuation of our efforts to explore the synthetic
utility of N-protected bromomethyl indoles using transi-
tion metal complexes as catalysts,5 the Ni(II)-mediated
coupling reaction of bromo compound 1a0 was carried
out with phenylmagnesium chloride. However, the reac-
tion failed to produce the expected benzylindole 3
Ni(dppp)Cl2/ THF
SPh
Br
PXhMgCl
SPh
N
RT, N2 atm.
N
5 h
SO2Ph
SO2Ph
1a'
3
PhS
SPh
N
N
SO2Ph
SO2Ph
2a
Scheme 1.
1
(Scheme 1). Careful analysis of the H NMR and 13C
NMR spectra confirmed the product as dimer 2a in
50% yield. Recently, Qian and Negishi observed6 a sim-
ilar dimerization during the Pd-mediated coupling of
benzyl bromide with phenylethynylzinc bromide. Repe-
tition of the coupling reaction using freshly prepared
4-methoxyphenylmagnesium bromide also afforded the
self-dimerization product 2a in 52% yield.
reaction did not afford the dimerization product 2a, only
the starting bromo compound 1a0 was recovered.
Next, the bromo compound 1a0 was reacted with phe-
nylmagnesium chloride in the absence of the Ni(II)/
Pd(0) complex at 0–10 ꢁC under a nitrogen atmosphere
for 5 h to afford the dimerized product 2a in 60% yield.
Obviously, the reaction of bromo compound 1a0 with
PhMgCl led to the formation of indolylmethyl Grignard
4 via Grignard exchange (Scheme 2), which reacts with
more bromomethylindole 1a0 to form the dimer 2a.
In order to gain an insight into the mechanism of the
dimerization, the coupling reaction of bromo compound
1a0 was carried out in the presence of Ni(II)/Pd(0) with-
out the addition of the Grignard reagent. However, the
SPh
MgCl
PhMgCl
1a'
1a'
2a
N
Keywords:
Dimerization.
Bromomethylindoles;
Phenylmagnesium
chloride;
SO2Ph
4
*
Corresponding author. Tel.: +91 44 24451108; fax: +91 44
22352494; e-mail: mohan_67@hotmail.com
Scheme 2.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.068

6984
A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 6983–6985
It is also clear that the self-dimerization of bromo com-
Me
Me
MgBr/THF
pound 1a0 is not catalyzed by Ni or Pd.
i)
SPh
SPh
Me
1a'
Me
Me
In order to verify the proposed Grignard exchange, bro-
mo compound 1a0 was reacted with isopropylmagne-
sium bromide at room temperature. Acidic workup of
the reaction mixture followed by mass spectral analysis
indicated the formation of isopropylmethyl indole 5
[M+, 421 (10%)] and 1-phenylsulfonyl-3-phenylthio-2-
methylindole 6 [M+, 379 (15%)], Scheme 3. The forma-
tion of 5 can be visualized through nucleophilic attack
and compound 6 can be formed only through Grignard
exchange. The formation of the latter compound con-
firmed that bromomethylindole 1a0 underwent Grignard
exchange.
N
ii) H
N
SO2Ph
SO2Ph
5
6
Scheme 3.
At this point it is worthwhile mentioning that the at-
tempted formation of Grignard 4 from bromo com-
pound 1a0 in the presence of Mg in dry THF under
reflux was found to be unsuccessful. Even though aryl
Grignards have been generated via exchange reactions
Table 1. Dimerization of N-protected bromomethyl indoles using PhMgCl
Entry bromo/chloroindole8
Conditions
Dimerized product9
Yielda (%)/mp
SPh
SPh
SO2Ph
N
1
1.2equiv PhMgCl, rt, 3 h
1.2equiv MeOC 6H4MgBr, rt, 5 h
1.2equiv PhMgCl, rt, 5 h
60 (220 ꢁC)
X
52
N
N
SO2Ph
1a' X = Br
1a" X = Cl
48
PhO2S
PhS
2a
CN
CN
Br
SO2Ph
N
2
3
1.2equiv PhMgCl, rt, 8 h
20 (230 ꢁC)
48 (268 ꢁC)
N
N
SO2Ph
PhO2S
NC
1b
2b
Me
Me
Br
SO2Ph
N
N
1.2equiv PhMgCl, rt, 5 h
1.2equiv PhMgCl, rt, 7 h
N
SO2Ph
PhO2S
43
1c' X = Br
1c" X = Cl
Me
Ph
2c
O
N
Br
N
4
5
1.2equiv PhMgCl, rt, 5 h
42(liquid)
N
N
Ph
O
Ph
O
1d
2d
Br
N
SO2Ph
1.2equiv PhMgCl, rt, 10 h
40 (230 ꢁC)
N
SO2Ph
PhO2S
1e
2e
Br
SO2Ph
N
N
N
6
7
1.2equiv PhMgCl, rt, 5 h
1.2equiv PhMgCl, rt, 10 h
58 (148 ꢁC)
71 (208 ꢁC)
PhO2S
SO2Ph
2f
Br
1f
Br
Br
SO2Ph
N
N
N
SO2Ph
PhO2S
Br
2g
1g
CO2Me
SO2Ph
N
CO2Me
Br
N
N
8
1.2equiv PhMgCl, rt, 6 h
48 (148 ꢁC)
PhO2S
SO2Ph
MeO2C
1h
2h
a Isolated yield after column chromatography.

A. K. Mohanakrishnan et al. / Tetrahedron Letters 46 (2005) 6983–6985
6985
between aryl iodides and phenylmagnesium chloride,7 to
our knowledge, this is the first time Grignard exchange
has been observed with benzylic, or more specifically,
an indolylmethyl system.
Lett. 2004, 45, 6959–6962; (e) Chang, C.; Huang, Y.; Hong,
F. Tetrahedron 2005, 61, 3835–3837; (f) Kuwano, R.;
Yokogi, M. Org. Lett. 2005, 7, 945–947.
5. Mohanakrishnan, A. K.; Ramesh, N. Tetrahedron Lett.
2005, 46, 4577–4579.
6. Qian, H.; Negishi, E. Tetrahedron Lett. 2005, 46, 2927–
2930.
The unusual dimerization reaction was then tested with
a variety of bromomethylindoles 1a–h and the results
are described in Table 1. The dimerization was found
to be facile irrespective of the position of the bromo-
methyl unit. The rate and yield of the dimerization were
found to be somewhat decreased with the corresponding
N-protected chloromethylindoles (entries 1 and 3). The
presence of a cyano group at the 3-position significantly
lowers the yield of the dimerization process (entry 2). In
contrast, the presence of a methyl ester at the indole-3-
position allowed the dimerization to proceed smoothly
to afford the product 2h in 48% yield (entry 8).
7. For generation of aryl Grignards using phenylmagnesium
chloride, see: (a) Collibee, S. E.; Yu, J. Tetrahedron Lett.
2005, 46, 4453–4455; (b) Sapountzis, I.; Dube, H.; Lewis,
R.; Gommermann, N.; Knochel, P. J. Org. Chem. 2005, 70,
2445–2454.
8. The required bromo/chloro compounds (1a–h) were pre-
pared via bromination/chlorination of the corresponding
methylindoles using NBS/NCS in the presence of a catalytic
amount of benzoyl peroxide in CCl4 at reflux.
9. All the dimeric indole derivatives 2a–h gave satisfactory
spectral and analytical data.
Typical experimental procedure for 2a: 1-Phenylsulfonyl-3-
phenylthio-2-bromomethylindole 1a0 (0.5 g, 1.09 mmol)
dissolved in dry THF (10 mL) was stirred at 0-10 ꢁC under
a nitrogen atmosphere. To this, phenylmagnesium chloride
(0.65 mL, 2M in THF) was added slowly. The reaction
mixture was slowly raised to room temperature and stirred
for 5 h. Then it was quenched with saturated ammonium
chloride solution (10 mL), extracted with ethyl acetate
(2 · 20 mL) and the extracts were combined and dried
(Na2SO4). Removal of the solvent followed by column
chromatographic purification (silica gel, hexane–EtOAc;
9:1) afforded 2a as a colourless solid (0.42g, 52%); mp
In conclusion, we have observed an unusual Grignard
exchange reaction of N-protected bromomethylindoles
with aryl and isopropylmagnesium bromides. Using
the observed Grignard exchange phenomena, a novel
dimerization of N-protected bromomethyl indoles was
achieved in reasonable yields. Investigations are under-
way to utilize the Grignard exchange technique to syn-
thesize various indole analogs.
1
220 ꢁC; H NMR (400 MHz, CDCl3): d 3.77 (s, 4H), 6.65–
Acknowledgements
6.68 (m, 4H), 6.92–6.94 (m, 6H), 7.16 (t, J = 7.8 Hz, 2H),
7.24 (t, J = 7.3 Hz, 2H), 7.27–7.32 (m, 2H), 7.37 (t,
J = 16.1 Hz, 4H), 7.51–7.53 (m, 2H), 7.73 (d, J = 7.3 Hz,
4H), 8.22 (d, J = 8.3 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3): d 28.1, 113.7, 115.6, 120.3, 124.4, 125.2, 125.4,
126.3, 126.5, 128.7, 129.5, 130.9, 134.1, 136.6, 137.3, 138.8,
144.6. Anal. Calcd for C42H32N2O4S4: C, 66.64; H, 4.26; N,
3.70; S, 16.94. Found: C, 66.30; H, 4.40; N, 3.92; S, 16.81.
Data for 2b: mp 2 30ꢁC; 1H NMR (400 MHz, CDCl3): d
4.27 (s, 4H), 7.37 (t, J = 7.1 Hz, 2H), 7.42–7.44 (m, 2H),
7.49 (t, J = 8.1 Hz, 4H), 7.55 (d, J = 7.8 Hz, 2H), 7.61 (t,
J = 7.4 Hz, 2H), 7.86 (d, J = 7.8 Hz, 4H), 8.25 (d,
J = 8.8 Hz, 4H). 13C NMR (100.6 MHz, CDCl3): d 28.9,
96.5, 112.9, 115.1, 119.5, 125.1, 126.5 (2C), 127.1, 129.8,
134.8, 135.9, 137.6, 146.7. Anal. Calcd for C32H22N4O4S2:
C, 65.07; H, 3.75; N, 9.49; S, 10.86. Found: C, 65.31; H,
3.91; N, 9.35; S, 10.67.
We thank UGC, New Delhi (F.12-140/2001 SR-1), for
the financial support. Financial support to the Depart-
ment by DST-FIST is also acknowledged.
References and notes
1. (a) Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem.
1995, 60, 1939–1946; (b) Mohanakrishnan, A. K.; Bala-
murugan, R. Tetrahedron Lett. 2005, 37, 2659–2662.
2. (a) Nagarathnam, D.; Vedachalam, M.; Srinivasan, P. C.
Synthesis 1983, 156–157; (b) Nagarathnam, D. Synthesis
1992, 743–745; (c) Nagarathnam, D. J. Heterocycl. Chem.
1992, 29, 953–958.
3. (a) Rajeswaran, W. G.; Srinivasan, P. C. Synthesis 1992,
835–836; (b) Rajeswaran, W. G.; Srinivasan, P. C. Indian J.
Heterocycl. Chem. 1992, 2, 89–91.
4. (a) Chowdhury, S.; Georghiou, P. E. Tetrahedron Lett.
1999, 40, 7599–7603; (b) Langle, S.; Abarbri, M.; Duchene,
A. Tetrahedron Lett. 2003, 44, 9255–9258; (c) Nobre, S. M.;
Monteiro, A. L. Tetrahedron Lett. 2004, 45, 8225–8228; (d)
Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Tetrahedron
Data for 2g: mp 2 08ꢁC; 1H NMR (400 MHz, CDCl3): d
3.65 (s, 4H), 7.25–7.43 (m, 10H), 7.51–7.53 (m, 2H), 7.77 (d,
J = 7.3 Hz, 4H), 8.22 (d, J = 8.3 Hz, 2H); 13C NMR
(100.6 MHz, CDCl3): d 28.2, 104.8, 115.6, 120.3, 124.9,
126.3, 127.9, 129.4, 129.9, 130.1, 134.7, 136.7, 139.1. Anal.
Calcd for C30H22Br2N2O4S2: C, 51.59; H, 3.17; N, 4.01; S,
9.18. Found: C, 51.51; H, 3.41; N, 4.16; S. 8.98.