Organic Letters
Letter
fully developed in a multistep process prior to indole
formation. Nenitzescu indole synthesis (type 7) (Scheme
2c),12 which involved the construction of both rings, derived
the benzene ring from a cyclohexane or benzoquinone
derivative generally after the pyrrole ring was built and
required multiple steps before full-fledged indoles were
created. Likewise, the Kanematsu process implemented an
intramolecular Diels−Alder reaction to construct both rings of
indoles (type 9) (Scheme 2d).13 The Kanematsu strategy
required the assembly of all necessary carbon and nitrogen
fragments in one advanced intermediate. Herein we report a
novel strategy for the synthesis of highly functionalized indoles
that constructs both the benzene and the pyrrole rings in one
step by a K2CO3-catalyzed condensation of fumaronitrile with
1,3-diketones. This unprecedented protocol synthesizes
indoles by the cleavage of a C(sp3)−C(sp2) bond in 1,3-
diketones and the simultaneous formation of five new bonds
one carbon−nitrogen bond and four carbon−carbon bonds.
During our investigation on alkene functionalization, we
serendipitously discovered that fumaronitrile underwent
condensation with 2,4-pentanedione in the presence of
K2CO3 to generate 2,5-dimethylindole-4,6,7-tricarbonitrile in
81% yield based on the molar equivalence of fumaronitrile
(Scheme 3). The structure of the new product was confirmed
molecules generate C-4/C-9 and C-6/C-7 carbons of the
phenyl ring. The phenyl C-8 is derived from the nitrile carbon
of fumaronitrile that also forms the C-4/C-9 carbon diad. The
remaining nitrile nitrogen at the C-8 carbon, along with two
carbons of the three-carbon fragment from 2,4-pentanedione,
forms the pyrrole ring.
Further optimization of the reaction condition with the
correct stoichiometry of 2,4-pentanedione and fumaronitrile in
a 1:2 molar ratio revealed that the transformation could be
catalyzed by 10 mol % K2CO3 at 40 °C in 48 h, which afforded
the indole product in 86% yield (Table 1, entry 1). The
a
Table 1. Optimization of Reaction Conditions
entry
variation in reaction conditions
none
yield (%)
1
86 (83)
2
3
4
5
6
7
8
9
10
11
12
13
14
100 mol % K2CO3, 24 h
THF instead of dioxane
DMSO instead of dioxane
hexanes instead of dioxane
100 mol % KHCO3, 80 °C, 24 h
100 mol % Na2CO3, 80 °C, 24 h
100 mol % K3PO4, 80 °C, 24 h
100 mol % BaCO3, 80 °C, 24 h
100 mol % CaCO3, 80 °C, 24 h
100 mol % Li2CO3, 80 °C, 24 h
100 mol % SrCO3, 80 °C, 24 h
100 mol % Et3N instead of K2CO3
100 mol % DBU instead of K2CO3
78
78
37
19
80
66
67
0
7
0
0
47
0
Scheme 3. Discovery of a Novel Indole Synthesis Method
a
1
Reactions were run on a 0.10 mmol scale in 0.5 mL of solvent. H
NMR yields are based on pyrene as an internal standard. The value in
parentheses is the isolated yield from the 1.0 mmol scale reaction.
reaction also affords the indole product in THF in a
comparable yield (entry 3). Other polar and nonpolar solvents
like DMSO and hexanes formed the expected product in lower
yield (entries 4 and 5). The indole product 1 was also formed
in significant amounts, albeit at higher temperature, when
K2CO3 was replaced with stoichiometric amounts of KHCO3,
Na2CO3, and K3PO4 (entries 6−8). Other bases such as
BaCO3, CaCO3, Li2CO3, and SrCO3 either did not form or
generated the indole product 1 in trace amounts (entries 9−
12). Replacing K2CO3 with 1 equiv of Et3N generated product
1 in 47% (entry 13). However, 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base did not form the indole product 1 (entry
14).
The optimized conditions were used to evaluate the scope of
the reaction with respect to 1,3-diketones, especially
considering substitution patterns and steric factors on 1,3-
diketones (Scheme 4). The reaction proceeded well with
symmetric 1,3-diketones containing linear, sterically accessible
alkyl groups, such as Me, Et, and i-Bu, and afforded the
substituted indole products (1, 2, 4, and 5) in 52−83% yield.
1,3-Diketone bearing a sterically hindered t-Bu group
generated the corresponding indole product (3) in only
moderate yield. A symmetric 1,3-diketone with an alkene
substituent can also be condensed with fumaronitrile to
produce an indole (5) containing alkenyl side chain on both
the pyrrole and benzene rings.14
Figure 1. X-ray crystal structure of 2,5-dimethylindole-4,6,7-
tricarbonitrile (1). Selected bond lengths (Å), angles (deg), and
hydrogen bonds: N1−C10 = 1.149(3); N2−C11 = 1.141(3); N3−
C13 = 1.149(3); N4−C9 = 1.371(3); N4−C2 = 1.386(3). N1−C10−
C8 = 177.0(3); N2−C11−C7 = 178.1(2); N3−C13−C5 = 178.9(3);
C9−N4−C2 = 108.8(2). N4···N1 = 2.996(3). N4−H4···N1 =
173(3).
by single-crystal X-ray crystallography (Figure 1). Analysis of
the X-ray structure revealed that the indole product would
require the insertion of two fumaronitrile molecules between
carbon 2 and carbon 3 of 2,4-pentanedione with the cleavage
of the 2C(sp2)−3C(sp3) bond, the formation of one C−N and
four C−C bonds (shown in red), and the loss of two H2O
molecules. Upon C2−C3 bond cleavage, the three-carbon
fragment of 2,4-pentanedione remains on the pyrrole side,
whereas the remaining two-carbon acyl fragment goes to the
phenyl ring. Therefore, the benzene ring of the indole 1 is
constructed by five carbons from two molecules of
fumaronitrile and the carbonyl carbon of the acyl fragment
derived from 2,4-pentanedione. In particular, the acyl carbon
forms C-5, and the four vinylic carbons of two fumaronitrile
B
Org. Lett. XXXX, XXX, XXX−XXX