7-Alkyl indole synthesis via a convenient formation/alkylation of lithionitrobenzenes and an improved Bartoli reaction

Article abstract of DOI:10.1055/s-2002-19346

A more convenient and efficient method for metalation/alkylation of nitrobenzenes to give 2-substituted nitrobenzenes was developed. Their conversion to 7-alkylindoles using the Bartoli reaction with vinyl magnesium bromide was performed with an improved protocol.

Full text of DOI:10.1055/s-2002-19346

LETTER
143
7-Alkyl Indole Synthesis via a Convenient Formation/Alkylation of
Lithionitrobenzenes and an Improved Bartoli Reaction
7
-Alkyl Indole Synthe
s
i
is via
c
C
onvenie
h
F
ormation
a
/Alkylation
e
of
L
ithioni
l
trobenzenes C. Pirrung,* Michael Wedel, Yan Zhao
Department of Chemistry, Levine Science Research Center, Duke University, Durham, North Carolina 27708-0317, USA
Fax 1(919)6601591; E-mail: pirrung@chem.duke.edu
Received 5 September 2001
in THF to a solution of the nitrobenzene at –40 °C. Due to
the low solubility of vinyl Grignards in THF at low tem-
perature, this protocol results in heterogeneous reaction
mixtures.
Abstract: A more convenient and efficient method for metalation/
alkylation of nitrobenzenes to give 2-substituted nitrobenzenes was
developed. Their conversion to 7-alkylindoles using the Bartoli re-
action with vinyl magnesium bromide was performed with an im-
proved protocol.
This letter reports novel reaction conditions that enable
2-lithionitrobenzene to be generated and used at the
much more convenient –78 °C. Alkylation with reactive
electrophiles provides the 2-alkylnitrobenzenes in excel-
lent yields. They are converted by excess vinyl magne-
sium bromide in dimethoxyethane to the indoles in good
yields.
Key words: nitroarenes, lithiation, allylations, alkylations
For a natural product synthetic library, we require a family
of 7-alkylindoles. We hoped to gain these compounds
from 2-alkylnitrobenzenes using the fascinating Bartoli
reaction. Ready access to diverse 2-alkylnitrobenzenes
was essential to this plan. A reasonable route to these
compounds is via alkylation of a 2-metalated nitroben-
zene.
Initial experiments were conducted as reported originally
by Köbrich and Buck, by addition at –78 °C of phenyllith-
ium in ether to a solution of 2-bromonitrobenzene in THF.
The resulting 2-lithionitrobenzene was alkylated after 2 h
with prenyl bromide to give 2-prenylnitrobenzene in 48%
yield. Simple variation of reaction conditions did not im-
prove this result, so more detailed studies were undertak-
en. Quenching the reaction (NH4Cl) after 5 min and
capillary gas chromatography analysis showed that metal-
halogen exchange is rapid: no starting materials remain,
but many products are obtained, including 2-nitrobiphe-
nyl. This product may arise from the reaction of 2-lithio-
nitrobenzene with bromobenzene, suggesting that mini-
mizing their concentrations could improve the reaction.
This was accomplished by simultaneous, separate addi-
tion of phenyllithium and prenyl bromide in THF to a 2-
bromonitrobenzene solution at –78 °C. With this varia-
tion, using equimolar amounts of each reagent, the alkyla-
tion product is obtained in 63% yield. Superior results
were gained by adding the alkyl halide quickly. The lim-
iting reagent was the bromide, as it is the most expensive
reactant. Metalation (2 equiv phenyllithium, 2 equiv 2-
bromonitrobenzene, 5 min, –78 °C) and alkylation with 1
equiv 1-bromo-3-methyl-2-butene (3 h) proceeds in quan-
titative yield. Similar reaction conditions were then ap-
plied to several other reactive alkyl halides. For 4-bromo-
3-nitrotoluene and 2-bromo-3-nitrotoluene, it was neces-
sary to also add TMEDA (2 equiv) to the lithium reagent
to obtain the highest yields in the alkylation step. Yields
for alkylation products purified by silica gel chromatog-
raphy are essentially quantitative, as summarized in the
Table. These reactions were so successful, alkylation by
less reactive alkyl halides was also examined. However,
2-lithionitrobenzene is alkylated with n-butyl bromide in
only 29% yield.
The generation of organometallic derivatives containing
nitro groups is challenging. Ready electron transfer reac-
tions to the nitro group preclude generation of Grignard
reagents from nitro-containing halides and magnesium.
One solution to this problem has been offered by Köbrich
and Buck,1 who reported that 2-bromonitrobenzene un-
dergoes metal-halogen exchange with phenyllithium in
THF to yield 2-lithionitrobenzene, which reacts with car-
bon dioxide as the electrophile. At –100 °C, the 2-lithio-
nitrobenzene is stable (1 h), and the acid is obtained in
97% yield. At even slightly higher temperature (–80 °C),
the acid is obtained in only 61% yield due to decomposi-
tion of the lithium reagent. The low-temperature reaction
conditions can also be applied to 4-bromo-3-nitrotoluene
(80%) and 2-bromo-3-nitrotoluene (92%) to obtain the
acids. Despite the inconvenience of conducting the reac-
tion at –100 °C, this process has been further used in
synthesis,2 including reactions with other electrophiles:
N-methyl-4-piperidone (85%),3 sorbal,4 and a formyl
pyrrole (54%).5 However, only reactions with carbonyl
electrophiles have been reported.
The Bartoli reaction involves a novel mechanism based on
addition of a vinyl Grignard to the oxygen of an interme-
diate nitroso compound.6 While powerful in that it con-
verts 2-substituted nitrobenzenes directly to 7-substituted
indoles, it exhibits variable efficiency. It has generally
been performed by adding 3 molar equiv (required by its
stoichiometry) of a commercial Grignard reagent solution
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0143,0145,ftx,en;S07601ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

144
M. C. Pirrung et al.
LETTER
comparable to the original procedure. These reaction con-
ditions were then applied to the 2-substituted nitroben-
zenes prepared by earlier alkylation reactions, leading to
the desired indoles in 37–57% yields.
Table Alkylation of Nitrobenzenes
The method described here for the production of lithioni-
trobenzene is much more convenient to conduct than that
previously described, encouraging its wider application in
organic synthesis. The alkylation of this carbanion pro-
ceeds in high yield only with allylic and benzylic halides,
however. The use of these 2-alkylnitrobenzenes in the
modified Bartoli reaction procedure gives 7-alkylindoles
in quite good efficiency and only two reaction steps.
Nitrobenzene
Alkylhalide
Nitrobenzene Indole
yield (%)
yield (%)
100
50a
53a
100a
100
57
Formation/Alkylation of Lithionitrobenzenes; General
Procedure
Phenyllithium (2.3 mmol) was dissolved in THF (25 mL) under ar-
gon and the solution cooled to -78 °C [EtOH / N2(l)]. 2-Bromo-5-
methyl-nitrobenzene (2.3 mmol) dissolved in THF (5 mL) was add-
ed drop wise via a syringe. After 5 min, prenylbromide (1.15 mmol)
was added all at once followed by TMEDA (2.3 mmol). The solu-
tion was kept at -78 °C for 3 h. After quenching with saturated
NH4Cl (20 mL) the aqueous phase was extracted with Et2O (2 20
mL). The combined ethereal extracts were filtered through cotton
wool and evaporated under reduced pressure. The residue was puri-
fied by silica gel chromatography (hexanes–EtOAc, 9:1), yielding
5-methyl-2-prenyl-nitrobenzene as a brown oil (236 mg, 100%). 1H
NMR (CDCl3): 1.70 (s, 3 H), 1.73 (s, 3 H), 2.38 (s, 3 H), 3.56 (d,
J = 7.2 Hz, 2 H), 5.23 (m, 1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.30 (dd,
J = 8.1, 1.8 Hz, 1 H), 7.67 (s, 1 H). 13C NMR (CDCl3): 18.26,
21.01, 26.08, 31.28, 122.14, 124.94, 131.39, 133.64, 133.79,
134.42, 137.20, 149.31. HRMS (EI): C12H15NO2, Calcd.: 205.1102,
found: 205.1109.
100
99
37
41
43
100
100
49
a Known compound; unknown compounds characterized by NMR and
MS
Bartoli Reaction; Genaral Procedure
Vinyl magnesium bromide (4.8 mmol, 1 M solution in THF) and
DME (3 mL) were cooled under argon to -40 °C (EtOH/dry ice). 2-
Farnesylnitrobenzene (0.8 mmol) dissolved in THF (2 mL) was
added drop wise via a syringe. The solution was kept at -40 °C until
TLC and GC showed no remaining starting material (2 h). After
quenching with saturated NH4Cl (20 mL), the aqueous phase was
extracted with ether (3 20 mL). The combined ethereal extracts
were filtered through cotton wool and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel chro-
matography (hexanes–EtOAc, 9:1), yielding 7-farnesylindole as a
yellow wax (106 mg, 41%). 1H NMR (CDCl3): 1.64 (s, 6 H), 1.72
(d, J = 1.2 Hz, 3 H), 1.85 (d, J = 1.2 Hz, 3 H), 2.11 (m, 8 H), 3.63
(d, J = 6.9 Hz, 2 H), 5.15 (m, 2 H), 5.48 (m, 1 H), 6.59 (dd, J = 3.3,
2.1 Hz, 1 H), 7.07 (m, 2 H), 7.19 (dd, J = 3.3, 2.7 Hz, 1 H), 7.56 (dd,
J = 7.5, 0.6 Hz, 1 H). 13C NMR (CDCl3): 16.47, 16.74, 18.31,
26.12, 26.88, 27.15, 31.15, 40.00, 40.13, 103.16, 118.93, 120.19,
121.73, 122.35, 124.01, 124.12, 124.53, 127.99, 131.57, 135.32,
135.61, 137.27. HRMS (EI): C23H31N, Calcd.: 321.2456, found:
321.2456.
Under traditional Bartoli reaction conditions, the addition
of vinyl magnesium bromide solution to 2-prenyl ni-
trobenzene produces 7-prenylindole in 50% yield after
chromatography. Because of the heterogeneity of these re-
action mixtures, the solubility of vinyl Grignard at –40 °C
in a variety of ethereal solvents, including diglyme, 1,3-
dioxolane, and dimethoxyethane (glyme, DME), was ex-
amined. Equal volumes of 1,3-dioxolane and the Grig-
nard/THF solution are required to achieve solubility,
whereas only half volumes of either diglyme or DME are
required. Because of the volatility of the latter, it was cho-
sen for further study. Two other modifications were made.
As the reaction requires a 3 fold excess of the Grignard
over the nitrobenzene, the nitrobenzene was added to the
Grignard solution in the mixed ethereal solvent to main-
tain the Grignard in excess throughout the reaction. In
classical Grignard chemistry, this would constitute nor-
mal addition; inverse addition has become the norm in the
modern era when so many reagents are purchased. The
Grignard was also used in a 6 fold excess. These modifi-
cations make the reaction easier to conduct and give high-
er yields in several other Bartoli reactions performed in
our lab. In this case, they lead to 7-prenylindole in a yield
Acknowledgement
Financial support was provided by American Diabetes Association,
the Diabetes Action Research and Education Foundation, and CaP
CURE. The assistance of L. LaBean in administrative support of
this work is appreciated.
Synlett 2002, No. 1, 143–145 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
7-Alkyl Indole Synthesis via a Convenient Formation/Alkylation of Lithionitrobenzenes
145
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