A direct lithiation route to 2-acyl-1-(phenylsulfonyl)indoles

Article abstract of DOI:10.1081/SCC-120004854

2-Acyl-1-(phenylsulfonyl)indoles (3, 7-9) are prepared in 75-84% yield from 1-(phenylsulfonyl)indoles (1, 5) in one operation by treatment of the latter with s-butyllithium followed by inverse quenching of the C-2 lithioindoles with carboxylic acid anhydr

Full text of DOI:10.1081/SCC-120004854

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A DIRECT LITHIATION ROUTE TO 2-ACYL-1-
(PHENYLSULFONYL)INDOLES
Jun Jiang a & Gordon W. Gribble b
a Department of Chemistry , Dartmouth College , Hanover, NH, 03755, U.S.A.
b Department of Chemistry , Dartmouth College , Hanover, NH, 03755, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Jun Jiang & Gordon W. Gribble (2002) A DIRECT LITHIATION ROUTE TO 2-ACYL-1-
(PHENYLSULFONYL)INDOLES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:13, 2035-2040, DOI: 10.1081/SCC-120004854
To link to this article: http://dx.doi.org/10.1081/SCC-120004854
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SYNTHETIC COMMUNICATIONS, 32(13), 2035–2040 (2002)
A DIRECT LITHIATION ROUTE TO
2-ACYL-1-(PHENYLSULFONYL)INDOLES
*
Jun Jiang and Gordon W. Gribble
Department of Chemistry,
Dartmouth College, Hanover, NH 03755, USA
ABSTRACT
2-Acyl-1-(phenylsulfonyl)indoles (3, 7–9) are prepared in
75–84% yield from 1-(phenylsulfonyl)indoles (1, 5) in one
operation by treatment of the latter with s-butyllithium fol-
lowed by inverse quenching of the C-2 lithioindoles with car-
boxylic acid anhydrides (6).
Key Words: 2-Acylindoles;
2-Lithioindoles;
Acylation;
Lithiation; Carboxylic acid anhydrides
2-Acylindoles are important intermediates in the synthesis of various
fused indoles such as furo[3,4-b]indoles[1] and pyrrolo[3,4-b]indoles,[2] and
they are alkaloids in their own right.[3] In our previous work in this area we
have prepared these ketones by the C-2 lithiation of a 1-(phenylsulfonyl)in-
dole, quenching with an aldehyde, and oxidation with active manganese
dioxide.[1a–e,2b,4] Alternatively, the 2-lithioindole can be treated with tri-
methylsilyl chloride and the resulting C-2 silylated indole subjected to an
ipso-desilylation Friedel–Crafts acylation reaction with an acid chloride or
anhydride to furnish the C-2 ketone.[5] For example, as summarized in
*Corresponding author. E-mail: grib@dartmouth.edu
2035
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

2036
JIANG AND GRIBBLE
Scheme 1 both methods afford the C-2 ketone 3 in 55–58% yield from
3-methyl-1-(phenylsulfonyl)indole (1).
Scheme 1.
Although these methods are often satisfactory, they do involve two
steps and occasionally the oxidation with manganese dioxide is erratic and
proceeds poorly if at all. We now describe a one-pot method that affords the
2-acylindoles usually in higher yields. Thus, lithiation of 1-(phenylsulfonyl)-
indoles 1 and 5 with s-BuLi followed by inverse quenching with excess
carboxylic acid anhydride 6 affords the desired ketones 3 and 7–9 in very
good yield as shown in Scheme 2. Our results are summarized in Table 1 in
comparison with the two-step methods depicted in Scheme 1 (Methods A
and B, respectively).
Table 1. Preparation of 2-Acylindoles 3, 7–9 from 1 and 5
Yield, %
Product Method Aa Method Bb Method Cc
Indole
6, R0
1
1
1
5
Me
Ph
n-C5H11
Me
3
7
8
9
55%
47%
–
58%
–
57%
–
81%
84%
75%
76%
81%
aMethod A: 1) s-BuLi; 2) RCHO; 3) MnO2.
bMethod B: 1) s-BuLi; 2) TMSCl; 3) (RCO)2O, AlCl3.
cMethod C: (Present method; Scheme 2) 1) s-BuLi; 2) (RCO)2O.

2-ACYL-1-(PHENYLSULFONYL)INDOLES
2037
Inverse quenching of the C-2 lithioindole with 5–10 equivalents of
carboxylic acid anhydride was superior to either quenching with lesser quan-
tities of acid anhydride or with acid chlorides, and better than a direct
quenching (normal addition) with acid anhydrides. Thus, reaction of 1
with s-BuLi followed by inverse quenching with acetyl chloride (10 equiva-
lents) gave only recovered starting material, presumably resulting from
rapid enolization of the acid chloride. Direct quenching of the C-2 lithio
species from 1 with acetic anhydride gave 3 in only 38% yield. A similar
reaction with hexanoic anhydride gave 8 in 48% yield, whereas the inverse
quenching procedure afforded 8 in 75% yield.
The availability of acid anhydrides makes this one-step procedure an
attractive alternative to the two-step methods for the synthesis of 2-acyl-1-
(phenylsulfonyl)indoles shown in Scheme 1.
Scheme 2.
EXPERIMENTAL
Melting points were determined with a Mel-Temp Laboratory Device
apparatus, and are uncorrected. Elemental analyses were done by Atlantic
Microlab Inc. High resolution mass spectra (HRMS) were carried out at the
Mass Spectrometry Laboratory, School of Chemical Sciences, University of
Illinois at Urbana Champaign. Infrared spectra were recorded on a BioRad
1
FT-IR Infrared Spectrophotometer, and 13C and H NMR spectra were
recorded on a Varian XL-300 Fourier-transform NMR spectrometer.
Tetrahydrofuran (THF) was distilled from sodium/benzophenone.
3-Methyl-1-(phenylsulfonyl)-2-(trimethylsilyl)indole (4): To a À70ꢀC
stirred solution of 3-methyl-1-(phenylsulfonyl)indole (1) (3.26 g, 12.0 mmol)
in dry THF (100 mL) was added a solution of s-butyllithium (1.3 M in

2038
JIANG AND GRIBBLE
cyclohexane, 14.0 mmol) dropwise via syringe. The reaction mixture was
stirred at À 70ꢀC for 2 h and allowed to warm to r.t. for 4 h. The dark
brown reaction mixture was recooled to À 70ꢀC and treated with freshly
distilled trimethylsilyl chloride (1.47 g, 13.5 mmol) and stirred overnight.
The mixture was quenched by aqueous ammonium chloride (250 mL). The
organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 Â 100 mL) and the combined organic layer was washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The resulting
oil was purified by flash chromatography (10% ethyl acetate in hexanes) and
the desired product 4 was obtained as a white solid (3.0 g, 8.8 mmol, 73%).
Recrystallization (MeOH) gave 4 as colorless crystals which was identical
1
(TLC, 13C NMR, H NMR) to what was obtained by us before:[6] m.p.
94–94.5ꢀC (Lit.[6] m.p. 93–94ꢀC; IR (KBr) vmax 2944, 1444, 1385, 1174,
1106, 837, 725 cmÀ1; UV (EtOH) lmax 216, 220, 224, 284, 296 (sh) nm:
1H NMR (CDCl3) d 7.95–7.98 (m, 1H), 7.55–7.58 (m, 2H), 7.16–7.43
(m, 6H), 2.35 (s, 3H), 0.54 (s, 9H); 13C NMR (CDCl3) d 139.5, 138.2,
138.0, 133.7, 133.6, 133.2, 128.7, 126.6, 125.5, 123.7, 119.2, 115.6, 12.1,
2.6; MS m/z 343 (Mþ), 328 (100%), 264, 236, 202, 186, 160, 125, 73.
Anal. Calcd for C18H22NO2SSi: C, 62.94; H, 6.16; N, 4.08; S, 9.33.
Found: C, 62.88; H, 6.19; N, 4.06; S, 9.38.
2-Hexanoyl-3-methyl-1-(phenylsulfonyl)indole (8). (General Procedure):
To a À70ꢀC stirred solution of 3-methyl-1-(phenylsulfonyl) indole (1)
(1.09 g, 4.0 mmol) dissolved in dry THF (25 mL) was added a solution of
s-butyllithium (1.3 M in cyclohexane, 4.5 mmol) dropwise via syringe. The
reaction mixture was stirred at À 70ꢀC for 2 h and allowed to warm to r.t.
for 4 h. The dark brown reaction mixture was recooled to À 70ꢀC and then
was added to a stirred solution of hexanoic anhydride (4.2 mL, 20.0 mmol)
in dry THF (25 mL) at À 70ꢀC via a cannula. And the mixture was stirred
overnight. The mixture was quenched by aqueous sodium bicarbonate
(250 mL) and the mixture was refluxed for 3 h to remove the excessive anhy-
dride. The organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (3 Â 50 mL) and the combined organic layer was washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The resulting
oil was purified by flash chromatography (10% ethyl acetate in hexanes) to
give an oil (1.25 g, 88% pure, 75% yield) which contains 12% starting
material according to 1H NMR. The analytical sample was obtained as
white crystals by recrystallization (ethyl acetate/hexanes) which was identi-
1
cal (TLC, 13C NMR, H NMR) to what was obtained by us before:[6] m.p.
75–77ꢀC (Lit.[6] m.p. 76–77ꢀC; IR (KBr) nmax 2945, 2862, 1675 (C¼O), 1560,
1449, 1369, 1171, 1100, 944, 577 cmÀ1; UV (EtOH) lmax 214, 244, 271 (sh),
1
276, 288 nm: H NMR (CDCl3) d 8.04–8.07 (m, 1H), 7.45–7.64 (m, 2H),
7.23–7.46 (m, 6H), 3.02 (t, 2H, J ¼ 7.5 Hz), 2.20 (d, 3H, J ¼ 1.8 Hz),

2-ACYL-1-(PHENYLSULFONYL)INDOLES
2039
1.68–1.77 (m, 2H), 1.33–1.40 (m, 4H), 0.87–0.94 (m, 3H); 13C NMR
(CDCl3) d 199.2, 137.3, 136.5, 135.5, 134.0, 132.0, 128.9, 127.4, 126.2,
125.0, 120.9, 116.3, 115.3, 45.1, 31.6, 24.6, 22.7, 14.2, 9.5; MS m/z 370
(Mþþ1), 369 (Mþ), 298, 271, 228, 172, 158 (100%), 130, 102, 77. Anal.
Calcd for C21H23NO3S: C, 68.27; H, 6.27; N, 3.79; S, 8.68. Found: C,
68.35; H, 6.37; N, 3.81; S, 8.84.
2-Acetyl-3-methyl-1-(phenylsulfonyl)indole (3): This was prepared
from 1 in 81% yield by the general method, using 10 equivalents of acetic
anhydride. The product was obtained as white needles, m.p. 115–117ꢀC
(Lit.[1a] m.p. 115.5–117ꢀC). The spectra characteristics matched literature
data;[1a] 13C NMR(CDCl3) d 195.8, 137.6, 136.9, 135.4, 134.1, 132.1,
128.9, 127.8, 127.4, 125.2, 121.1, 116.5, 32.4, 9.7.
2-Benzoyl-3-methyl-1-(phenylsulfonyl)indole (7): This was prepared
from 1 in 84% yield by the general method, using 5 equivalents of benzoic
anhydride. The product was obtained as a white solid, m.p. 139–140ꢀC
(Lit.[1a] m.p. 140.5–141ꢀC). The spectra characteristics matched literature
data.[1a]
2-Acetyl-1-(phenylsulfonyl)indole (9): This was prepared from 5 in
76% yield by the general method, using 10 equivalents of acetic anhydride.
The product was obtained as white needles, m.p. 90–91ꢀC (Lit.[4] m.p.
89–90ꢀC). The spectra characteristics matched literature data.[4]
ACKNOWLEDGMENTS
This investigation was supported by the National Institutes of Health
(GM58601), for which support we are grateful.
REFERENCES
1. (a) Gribble, G.W.; Keavy, D.J.; Davis, D.A.; Saulnier, M.G.; Pelcman, B.;
Barden, T.C.; Sibi, M.P.; Olson, E.R.; BelBruno, J.J. J. Org. Chem.
1992, 57, 5878–5891; (b) Gribble, G.W.; Silva, R.A.; Saulnier, M.G.
Synth. Commun. 1999, 29, 729–747; (c) Gribble, G.W.; Saulnier,
M.G.; Sibi, M.P.; Obaza-Nutaitis, J.A. J. Org. Chem. 1984, 49,
4518–4523; (d) For reviews of our earlier work in this area, see
Gribble, G. W. Adv. Heterocycl. Nat. Prod. Syn. 1990, 1, 43–94;
Gribble, G.W. Synlett 1991, 289–300; (e) Miki, Y.; Hachiken, H.
Synlett 1993, 333–334.

2040
JIANG AND GRIBBLE
2. (a) For a review, see Sha, C.-K. Adv. Nitrogen Heterocycl. 1996, 2,
147–178; (b) Gribble, G.W.; Pelkey, E.T.; Simon, W.M.; Trujillo, H. A.
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(b) Weisbach, J.A.; Douglas, B. Chem. Ind. 1966, 233–236; (c)
Kutney, J.P. Heterocycles 1977, 8, 813–830; (d) Gribble, G.W. In
Rodd’s Chemistry of Carbon Compounds, 2nd Supplement to 2nd
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5. Ketcha, D.M.; Lieurance, B.A.; Homan, D.F.J.; Gribble, G.W. J. Org.
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6. Pelkey, E.T.; Gribble, G.W. Unpublished Results; E.T. Pelkey, Ph.D.
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Received in the USA July 24, 2001