Stille carbonylation of N-protected bromomethylindoles

Article abstract of DOI:10.1016/j.tetlet.2005.05.010

A variety of N-protected indolylmethylbromides are carbonylated using 5 mol % Pd(PPh₃)₂Cl₂ under Stille conditions in the presence of an alcohol to afford the corresponding methyl/ethyl esters.

Full text of DOI:10.1016/j.tetlet.2005.05.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4577–4579
Stille carbonylation of N-protected bromomethylindoles
Arasambattu K. Mohanakrishnan* and Neelamegam Ramesh
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 9 March 2005; revised 28 April 2005; accepted 4 May 2005
Abstract—A variety of N-protected indolylmethylbromides are carbonylated using 5 mol % Pd(PPh3)2Cl2 under Stille conditions in
the presence of an alcohol to afford the corresponding methyl/ethyl esters.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Indole and its myriad of derivatives are important frag-
ments of a large number of natural products of both
marine and terrestrial origin, and hence continue to cap-
ture the attention of synthetic organic chemists. Re-
cently, Gribble has extensively reviewed1 the various
developments involved in the synthesis of indoles.
methylindoles under Stille conditions11 using a Pd
catalyst.
As a model study, bromo compound 1a was carbonyl-
ated using 5% Pd(PPh3)2Cl2 as a catalyst under CO
atmosphere at room temperature.
In general, most substituted indoles are prepared
through lithiation protocols.2 The fact that N-protected
methylindole can be easily allyl brominated using NBS
led to the syntheses of a variety of substituted indoles.
In particular, the synthetic elaboration of bromomethyl-
indoles has been thoroughly exploited in order to
prepare different types of indole-based natural prod-
ucts.3–5 The bromomethylindoles can be smoothly dis-
placed by a variety of nucleophiles such as CN, OH,
(EtO)3P, PPh3, SPh, NR2, N3, etc.6 They can also be
easily displaced by stabilized carbanions derived from
diethylmalonate, ethyl acetoacetate, phenylacetonitrile,
etc.7 Srinivasan and co-workers have reported PdCl2-
mediated arylation of bromomethylindoles.8 Bromome-
thylindoles have also been used to synthesize b and
c-carboline derivatives.9
Workup followed by column chromatographic purifica-
tion afforded methyl ester 2a0 in 62% yield (Scheme 1).
The carbonylation reaction was then tested with a
variety of bromomethylindoles, 1a–l and the results
are presented in Table 1.
The bromo compound 1a was also converted into the
corresponding ethyl ester (entry 2) without any appre-
ciable change in yield. During the carbonylation of bro-
momethylindole 1b (entry 3), both bromides underwent
simultaneous carbonylation to afford bisester 2b. The
bis(dibromomethyl)indole 1l afforded the corresponding
bisester 2l (entry 13) in a reasonable yield. The carbonyl-
ations of bromomethylindoles 1f–h containing a vinyl
ester moiety led to the respective products in diminished
yields (entries 7–9). The relatively unexplored bromo-
methylindoles 1i and 1j were also carbonylated to afford
the corresponding esters 2i and 2j in 77% and 52%
yields, respectively.
In an ongoing project, we required several 2-indolyl-
methyl esters as starting materials. To our surprise, there
were only a few reports which described the synthesis of
indolylmethyl acetates.10 All these methods involved
multi-step procedures and gave only low yields. Since
numerous bromomethylindoles were easily available,
we decided to investigate the carbonylation of bromo-
5% Pd(PPh3)2Cl2
CO (atmosphere)
SPh
Br
SPh
CO2Me
N
THF-MeOH (6:1)
RT, 10 h
N
SO2Ph
SO2Ph
Keywords: Bromomethylindoles; Stille carbonylation; Pd catalyst;
Indolylmethyl esters.
62%
1a
2a'
*
Corresponding author. Tel.: +91 44 24451108; fax: +91 44
22352494; e-mail: mohan_67@hotmail.com
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.010

4578
A. K. Mohanakrishnan, N. Ramesh / Tetrahedron Letters 46 (2005) 4577–4579
Table 1. Preparation of indolylmethyl esters via Stille carbonylation
Entry Bromo compounds12
Esters13
Yield (%),
mp (ꢁC)
Entry Bromo compounds12 Esters13
Yield (%),
mp (ꢁC)
SPh
Br
SPh
CO2Et
CO2Et
CO2Me
Br
CO2Me
1
62 (114–116)
8
45 (142)
45 (150)
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1a
2a'
2g
1g
CO2Me
CO2Me
CO2Me
Br
SPh
CO2Et
SPh
Br
2
61 (90)
9
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1a
2a"
1h
2h
Br
CO2Me
Br
Br
CO2Me
CO2Me
3
58 (122–124) 10
77 (88)
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
2b
1b
2i
1i
Me
Br
Me
CO2Me
N
N
4
58 (120–122) 11
52 (88–90)
58 (70)
N
N
COPh
COPh
MeO2C
N
Br
SO2Ph
SO2Ph
1j
2j
1c
2c
CN
Br
CN
Br
Me
SO2Ph
CO2Me
Me
CO2Me
CO2Et
5
6
47 (96)
12
13
N
N
N
SO2Ph
SO2Ph
SO2Ph
1k
2k
2d
1d
MeO
MeO
CO2Me
CO2Me
Br
Br
CO2Et
Br
CO2Me
50 (118)
58 (138)
N
N
N
N
SO2Ph
SO2Ph
SO2Ph
SO2Ph
1l
2l
1e
2e
CO2Me
CO2Me
Br
CO2Me
N
7
42 (150)
N
SO2Ph
SO2Ph
1f
2f
Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org.
Lett. 2003, 11, 1899–1902.
In summary, we have synthesized several indolylmethyl
esters involving hitherto unexplored Stille carbonylation
of the corresponding N-protected bromomethylindoles.
The synthetic utility of these esters will be explored in
due course.
3. (a) Gribble, G. W.; Allen, R. W.; Lehoullier, C. S.; Eaton,
J.; Easton, N. R.; Slayton, R. I.; Sibi, M. P. J. Org. Chem.
1981, 46, 1025–1026; (b) Gribble, G. W.; Saulnier, M. G.;
Sibi, M. P.; Obaza-Nutaitis, J. A. J. Org. Chem. 1984, 49,
4518–4523.
4. Sha, C.-K.; Yang, J. F. Tetrahedron 1992, 48, 10645–
10654.
Acknowledgements
5. Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem.
1995, 60, 1939–1946.
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.
6. (a) Nagarathnam, D.; Vedachalam, M.; Srinivasan, P. C.
Synthesis 1983, 156–157; (b) Macor, J. E.; Newman, M.
E.; Ryan, K. Tetrahedron Lett. 1989, 30, 2509–2512; (c)
Nagarathnam, D. Synthesis 1992, 743–745; (d) Nagarath-
nam, D.; Johnson, M. E. Tetrahedron Lett. 1993, 34,
3215–3218; (e) Nagarathnam, D. Synthesis 1992, 743–745;
(f) Nagarathnam, D. J. Heterocycl. Chem. 1992, 29, 953–
958.
References and notes
1. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045–
1075.
2. (a) Sundberg, R. J.; Russell, H. F. J. Org. Chem. 1973, 38,
3324–3330; (b) Katritzky, A. R.; Akutagawa, K. Tetrahe-
dron Lett. 1985, 26, 5935–5938; (c) Katritzky, A. R.;
Akutagawa, K. J. Am. Chem. Soc. 1986, 108, 6808–6809;
(d) Inagaki, S.; Nishigava, Y.; Sugiura, T.; Ishihara, H. J.
Chem. Soc., Perkin Trans. 1 1990, 179–180; (e) Inagaki, S.;
Naruse, Y.; Ito, Y. J. Org. Chem. 1991, 56, 2256–2258; (f)
7. Nagarathnam, D.; Srinivasan, P. C. Synthesis 1982, 926–
927.
8. Rajeswaran, W. G.; Srinivasan, P. C. Synthesis 1992, 835–
836.
9. (a) Mohanakrishnan, A. K.; Srinivasan, P. C. Tetrahedron
Lett. 1996, 37, 2659–2662; (b) Mohanakrishnan, A. K.;
Srinivasan, P. C. Synth. Commun. 1995, 25, 2415–2424.

A. K. Mohanakrishnan, N. Ramesh / Tetrahedron Letters 46 (2005) 4577–4579
4579
10. (a) Samizu, K.; Ogasawara, K. Synlett 1994, 499–500; (b)
Chillin, A.; Rodighiero, P.; Guiotto, A. Synthesis 1998,
309–312; (c) Arcadi, A.; Cacchi, S.; Fabrizi, F.; Marinelli,
F. Synlett 2000, 3, 394–396.
11. Cowel, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193–
4198.
12. The required bromocompounds 1a–l were prepared via the
allylic bromination of the corresponding methylindoles
using NBS in the presence of a catalytic amount of
benzoyl peroxide in CCl4 under reflux.
13. All the esters gave satisfactory spectral and analytical
data.
(s, 3H), 4.30 (s, 2H), 6.98–7.03 (m, 3H), 7.06–7.15 (m, 3H),
7.24 (t, J = 7.36 Hz, 1H), 7.37–7.40 (m, 3H), 7.50 (t, J =
6.3 Hz, 1H), 7.80 (t, J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz,
1H). MS (EI) m/z (%): 437 (M+, 28%), 378 (42), 237 (100).
Elemental anal. calcd for C23H19NO4S2: C, 63.14; H, 4.38;
N, 3.20; S, 14.66. Found: C, 63.08; H, 4.52; N, 3.17; S,
14.53.
Data for 2b: mp 122–124 ꢁC; IR (KBr) mmax: 1739, 1712,
1
1384, 1195 cmꢀ1. H NMR (300 MHz, CDCl3): d 3.71 (s,
3H), 3.93 (s, 3H), 4.74 (s, 2H), 7.30–7.33 (m, 2H), 7.45 (t,
J = 7.9 Hz, 2H), 7.53–7.55 (t, J = 7.3 Hz, 1H), 7.89 (d,
J = 7.4 Hz, 2H), 8.02–8.09 (m, 2H). 13C NMR (75.5 Mz,
CDCl3): d 32.87, 51.62, 52.29, 113.42, 114.05, 122.15,
124.42, 125.35, 126.83, 129.37, 134.06, 138.43, 140.49,
164.84, 169.77. MS (EI) m/z (%): 388 (M+1, 40%), 329 (23).
Elemental anal. calcd for C19H17NO6S: C, 58.91; H, 4.42;
N, 3.62; S, 8.28. Found: C, 59.11; H, 4.57; N, 3.58; S, 8.32.
Data for 2g: mp 142 ꢁC; IR (KBr) mmax: 1743, 1712, 1369,
Typical experimental procedure for 2a0: A two-necked
flask containing bromo compound 1a (0.5 g, 1.09 mmol),
PdCl2(PPh3)2 (40 mg, 0.06 mmol), and K2CO3 (0.16 g,
1.16 mmol) was evacuated. To this, dry THF (30 mL) and
MeOH (5 mL) were added via syringe. The reaction
mixture was then purged with dry carbon monoxide gas
for 5 min, then stirred under a carbon monoxide atmos-
phere at room temperature for 10 h. The reaction mixture
was diluted with water (50 mL) and extracted with ethyl
acetate (2 · 20 mL). The combined extract was washed
with water (10 mL) and dried (Na2SO4). Removal of the
solvent followed by column chromatographic purification
(silica gel, EtOAc–hexane 1:5) afforded 2a0 as a colorless
solid (0.42 g, 62%); mp 114–116 ꢁC; IR (KBr) mmax: 1740,
1172 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.32 (t,
.
J = 7.36 Hz, 3H), 3.72 (s, 3H), 4.23–4.28 (m, 4H), 6.52
(d, J = 16.1 Hz, 1H), 7.29–7.33 (m, 3H), 7.41–7.44 (m, 2H),
7.53 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 16.1 Hz, 1H), 7.77–
7.79 (m, 1H), 7.83 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 6.8 Hz,
1H). MS (EI) m/z (%): 427 (M+, 13%), 286 (77), 182 (36),
154 (95). Elemental anal. calcd for C22H21NO6S: C, 61.81;
H, 4.95; N, 3.28; S, 7.50. Found: C, 61.73; H, 5.02; N, 3.22;
S, 7.58.
1365, 1172 cmꢀ1 1H NMR (400 MHz, CDCl3): d 3.58
.