Generation and reactions of 2,3-dilithio-N-methylindole. Synthesis of 2,3-disubstituted indoles

Article abstract of DOI:10.1016/S0040-4039(01)00332-X

Generation of 2,3-dilithio-N-methylindole (7) from 2,3-diiodo-N-methylindole (6) and subsequent reaction with various electrophiles (NH₄Cl, DMF, ClCO₂Me, CO₂, phthalic anhydride) affords the corresponding 2,3-disubstituted indoles in good to excellent yields (41-99%).

Full text of DOI:10.1016/S0040-4039(01)00332-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2949–2951
Generation and reactions of 2,3-dilithio-N-methylindole.
Synthesis of 2,3-disubstituted indoles
Yanbing Liu and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 6 February 2001; revised 14 February 2001; accepted 16 February 2001
Abstract—Generation of 2,3-dilithio-N-methylindole (7) from 2,3-diiodo-N-methylindole (6) and subsequent reaction with various
electrophiles (NH4Cl, DMF, ClCO2Me, CO2, phthalic anhydride) affords the corresponding 2,3-disubstituted indoles in good to
excellent yields (41–99%). © 2001 Elsevier Science Ltd. All rights reserved.
The metallation and subsequent reaction of heterocy-
cles is a powerful tactic in synthesis,1 and the genera-
tion and utility of lithioindoles has been used by many
investigators to elaborate indoles.2,3 Several years ago
we attempted to generate 2,3-dilithio-N-(phenylsul-
fonyl)indole (2).4 Surprisingly, this species underwent
facile indole ring fragmentation at temperatures down
to and even below −100°C, to afford the stable lithium
2-(N-lithiophenylsulfonamido)phenylacetylide (3). Sub-
sequent trapping of 3 with electrophiles (aq. NH4Cl,
TMSCl, ClCO2Et) afforded the corresponding products
in good yields (66–82%).4 Products with an intact
indole ring were obtained in low yield (<20%).
with saturated aqueous NH4Cl afforded N-methylin-
dole (8)9 in 99% yield. Evidence for the formation of
dilithioindole 7, rather than monolithiated iodinated
intermediates, was revealed by direct injection of the
lithiated reaction mixture into a gas chromatograph.
This showed the presence of only 8 and no iodinated
N-methylindoles. Quenching dilithioindole 7 with DMF
(10 equiv.) gave 2,3-diformyl-N-methylindole (9)10 in
82% yield. A similar reaction with methyl chlorofor-
mate gave 2,3-bis(methoxycarbonyl)-N-methylindole
(10)12 in 75% yield. Likewise, reaction of 7 with gaseous
CO2 gave N-methyl-2,3-indole dicarboxylic acid (11)14
in 66% yield.
We now report that the N-methyl analogue of 2 is
stable at low temperatures and can be trapped with
electrophiles to give 2,3-disubstituted indoles. This
chemistry is summarized in Scheme 1. We synthesized
2,3-diiodo-N-methylindole (6) in two steps from indole
(4). Thus, the Bergman procedure5 gave 2-iodoindole
(5)6 in 90% yield. Treatment of 5 with I2/KOH/DMF
followed by methyl iodide in the presence of tetra-n-
butylammonium hydrogen sulfate gave 67,8 in 91%
yield. The dilithio species 7 was generated with excess
tert-butyllithium (5–10 equiv.) at −78°C (THF, 20 min).
Quenching the resulting bright yellow solution at −78°C
In view of our long interest in employing lithiated
indoles as a synthetic route to the anticancer ellipticine
alkaloid family and related benzo[b]carbazoles,3,16 we
quenched dilithioindole 7 with phthalic anhydride. This
afforded
5-methyl-5H-benzo[b]carbazole-6,11-dione
(12)17 in 41% yield. Work is currently underway to
adapt this latter reaction to a synthesis of pyridocarba-
zolequinones and pyridocarbazoles such as ellipticine.
Unfortunately, attempts to achieve bis-electrophilic
reactions with TMSCl and methyl iodide have led to
Li
Li
I
t-BuLi
Li
-100°C
N
N
Li
N
I
THF
SO2Ph
SO2Ph
SO2Ph
2
3
1
Keywords: 2,3-dilithio-N-methylindole; 2,3-diiodo-N-methylindole; lithiation; benzo[b]carbazole-6,11-dione.
* Corresponding author. Tel.: +1-603-646-3118; fax: +1-603-646-3946; e-mail: grib@dartmouth.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00332-X

2950
Y. Liu, G. W. Gribble / Tetrahedron Letters 42 (2001) 2949–2951
I
I
1. n-BuLi
1. KOH, I2
2. MeI
2. CO2
N
H
I
N
H
N
n-Bu4NHSO4
3. t-BuLi
4. (CH2I)2
Me
91%
4
5
6
90%
t-BuLi
THF
-78°C
CHO
CHO
Li
Li
NH4Cl
H2O
DMF
82%
N
N
N
Me
Me
99%
Me
8
9
7
ClCO2Me
75%
CO2
66%
O
O
41%
O
CO2H
CO2H
CO2Me
CO2Me
N
O
N
Me
Me
11
N
10
Me
O
12
Scheme 1.
mixtures of products. For example, reaction of 7 with
excess methyl iodide afforded a 60:40 (GC–MS) mix-
ture of 1,2,3-trimethylindole and a dimethylindole.
Reaction of 7 with a,a%-dibromo-o-xylene and 1,4-
dibromobutane led to complex reaction mixtures and
the apparent formation of an unidentified indole dimer.
References
1. (a) Gschwend, H. W.; Rodriguez, H. R. Org. React.
1979, 26, 1–360; (b) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science: Oxford, 2000.
2. (a) Shirley, D. A.; Roussel, P. A. J. Am. Chem. Soc. 1953,
75, 375; (b) Sundberg, R. J.; Russell, H. F. J. Org. Chem.
1973, 38, 3324–3330; (c) For reviews, see: Sundberg, R. J.
Indoles; Academic Press: San Diego, CA, 1996; Gawley,
R. E.; Rein, K. In Comprehensive Organic Synthesis, Vol.
1; Pergamon Press: Oxford, 1991; pp. 459–485.
3. (a) Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982,
47, 757–761; (b) Saulner, M. G.; Gribble, G. W. J. Org.
Chem. 1982, 47, 2810–2812; (c) For reviews of our work,
see: Gribble, G. W. Adv. Heterocyclic Nat. Prod. Synth.
1990, 1, 43–94; Gribble, G. W. Synlett 1991, 289–300.
4. Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48,
607–609.
In conclusion, the substitution of the electron-donating
methyl group for the electron-withdrawing phenylsul-
fonyl group prevents indole ring fragmentation of 2,3-
dilithioindole and allows for bis-electrophilic reactions
of this novel species.19,20 Finally, it should be noted that
Winter has described the synthesis of a stable dimeric
2,3-dialuminated indole.21
Acknowledgements
5. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57,
2495–2497.
This work was supported by the National Institutes of
Health (GM58601), for whose support we are grateful.

Y. Liu, G. W. Gribble / Tetrahedron Letters 42 (2001) 2949–2951
2951
1
6. Compound 5 (90%): Mp 77°C (decomposed into tar) (lit.5
1550, 1500, 1461, 1344, 1228 cm−1; H NMR (acetone-d6)
l 8.33 (d, 1H, J=8.0 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.51
(m, 1H), 7.40 (m, 1H), 4.25 (s, 3H).
1
mp 98–99°C); H NMR (CDCl3) l 8.1 (s, br, 1H), 7.55
(m, 1H), 7.34 (m, 1H), 7.16–7.08 (m, 2H), 6.74 (m, 1H);
13C NMR (CDCl3) l 138.9, 129.8, 122.5, 120.5, 119.4,
112.9, 110.3, 74.9. HRMS m/z calcd for C8H6IN (M+):
242.9545; found: 242.9542.
15. Baiocchi, L.; Giannangeli, M. J. Heterocyclic Chem.
1988, 25, 1905–1909.
16. Gribble, G. W.; Silva, R. A.; Saulnier, M. G. Synth.
Commun. 1999, 29, 729–747 and previous papers.
17. Compound 12 (41%): Mp 207–208°C (lit.18 mp 206–
208°C); IR (film) wmax 2922, 2856, 1656, 1594, 1517, 1394,
1
7. Compound 6 (91%): Mp 64–65°C (lit.8 mp 76–78°C); H
NMR (CDCl3) l 7.41 (m, 1H), 7.29 (m, 1H), 7.23–7.14
(m, 2H), 3.90 (s, 3H); 13C NMR (DMSO-d6) l 137.9,
130.9, 122.5, 120.6, 120.3, 110.9, 99.7, 71.6, 35.9.
1233 cm−1; H NMR (CDCl3) l 8.49 (d, 1H, J=8.0 Hz),
1
8. Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.;
Pe´rez, M.; Garc´ıa-Mart´ın, M. A.; Gonza´lez, J. M. J. Org.
Chem. 1996, 61, 5804–5812. This paper describes a syn-
thesis of 6 from 2-trimethylsilyl-N-methylindole.
8.24 (d, 1H, J=7.5 Hz), 8.20 (d, 1H, J=7.5 Hz), 7.75–
7.71 (m, 2H), 7.51 (m, 2H), 7.43 (m, 1H), 4.29 (s, 3H).
18. Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J. Tetra-
hedron 1994, 50, 4811–4828.
9. Compound 8 (99%): Oil; IR (film) wmax 3056, 2933, 1611,
19. General procedure: A solution of 6 (0.050 g, 0.13 mmol)
in dry THF (10 mL) was cooled to −78°C and treated
dropwise with tert-butyllithium (5–10 equiv. of 1.7 M
pentane solution). The resulting bright yellow solution
was stirred for 20 min at −78°C and then treated with the
electrophile (1.3 mmol; in the case of phthalic anhydride,
0.13 mol). The reaction was allowed to warm to room
temperature, poured into water, and extracted with ethyl
acetate. The organic phase was dried (MgSO4), and con-
centrated in vacuo to afford the crude product. Flash
chromatography over silica gel gave the purified products
in the yields indicated.
20. For other examples of dilithio heterocycles, see (a) Ried,
W.; Bender, H. Chem. Ber. 1956, 89, 1574–1577; (b)
Zaluski, M.-C.; Robba, M.; Bonhomme, M. Bull. Soc.
Chim. Fr. 1970, 1838–1846; (c) Srogl, J.; Janda, M.;
Stibor, I.; Procha´zkova´, H. Z. Chem. 1971, 11, 464; (d)
Janda, M.; Srogl, J.; Stibor, I.; Nemec, M.; Vopatrna´, P.
Synthesis 1972, 545–547; (e) Cugnon de Sevrivourt, M.;
Robba, M. Bull. Soc. Chim. Fr. 1977, 142–144; (f)
Feringa, B. L.; Hulst, R.; Rikers, R.; Brandsma, L.
Synthesis 1988, 316–318.
1506, 1456, 1422, 1317, 1239, 1150, 1072, 1006, 741 cm−1
.
1H NMR (CDCl3) l 7.65 (m, 1H), 7.35 (d, 1H, J=8.5
Hz), 7.27–7.21 (m, 1H), 7.15–7.11 (m, 1H), 7.07 (d, 1H,
J=3.0 Hz), 6.50 (d, 1H, J=3.0 Hz), 3.81 (s, 3H). This
material was identical to a commercial sample of N-
methylindole by NMR and TLC.
10. Compound 9 (82%): Mp 161°C (lit.11 mp 158°C); IR
(film) wmax 2920, 2848, 2365, 1679, 1653, 1478, 1386, 1345,
1
1134, 1015, 898, 749 cm−1; H NMR (acetone-d6) l 10.77
(s, 1H), 10.74 (s, 1H), 8.39 (d, 1H, J=8.1 Hz), 7.72 (d,
1H, J=8.7 Hz), 7.58–7.53 (t of d, 1H, J=0.6, 8.1 Hz),
7.43–7.38 (t, 1H, J=8.1 Hz), 4.22, (s, 3H).
11. Dupas, G.; Duflos, J.; Que´guiner, G. J. Heterocyclic
Chem. 1980, 17, 93–96.
12. Compound 10 (75%): Oil (lit.13 mp 35°C); IR (film) wmax
2956, 2356, 1706, 1528, 1472, 1439, 1400, 1372, 1250,
1217, 1156, 1106, 1028 cm−1 1H NMR (acetone-d6) l
;
8.08 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.39 (m,
1H), 7.30 (m, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H).
13. Acheson, R. M.; Vernon, J. M. J. Chem. Soc. 1962,
1148–1157.
14. Compound 11 (66%): Mp 205–207°C (dec.) (lit.15 mp
208–209°C (dec.)); IR (film) wmax 3144, 2356, 1700, 1600,
21. Reck, C. E.; Bretschneider-Hurley, A.; Hegg, M. J.;
Winter, C. H. Organometallics 1998, 17, 2906–2911.
.
.