Communication
problem in this reaction was the compatibility of the highly re-
active secondary alcohol with a comparatively less reactive
alkyne moiety; thus it was decided to synthesise 2-carbonyl in-
doles. Because of the high nucleophilicity of the indole C-3 po-
sition, it has always been challenging to achieve the alkylation
at N-1 in preference to C-3 position. Numerous reports are
available in the literature describing a metal-catalysed C-3 alk-
ylation but very few of them are for the alkylation at C-2 or
N-1 position.[9] To avoid the complications initially we blocked
C-3 position of the indole.
idants were screened. The best results were obtained when
Pd(OAc)2 was used in presence of Cs2CO3 (2 equiv) in DMF at
758C with the highest yield of 95% (entry 15). This annulation
reaction with other bases/oxidants, such as AgOAc, K2CO3,
Cu(OAc)2, KOH and KOtBu, gave lower yields compared to
Cs2CO3 (entries 9–14). Among several Pd catalysts screened,
[Pd(CH3CN)2Cl2] (entry 16) and [Pd(PPh3)2Cl2] (entry 17) gave
77% and 93% yield, respectively. It is worth mentioning that
a decrease in catalyst and base loadings lowered the rate of re-
action, although the rate and yields of the reaction were unaf-
fected when a higher catalyst and base loading were used.
The reaction was sluggish at room temperature, and 758C was
found to be the optimum temperature.
To verify our hypothesis depicted in Scheme 1, ketone 9a
and alkyne ester 10a were treated with various metal catalysts
in combination with different types of bases and oxidants. Pre-
liminary studies were performed with the aim to find a suitable
catalyst to promote the reaction between 9a and 10a. Since
the annulation reactions of alkyne compounds are known
mostly with Pd(OAc)2 as a metal catalyst, we also chose it as
our initial screening catalyst.
The substrate scope of the reaction was examined by pre-
paring various pyrroloindole derivatives (Scheme 2). Both elec-
tron-withdrawing and -donating substituents on the benzene
ring were well tolerated and gave high yields of pyrroloindole
derivatives. Heteroaryls, like furan-, thiophene- and naphtha-
lene-substituted internal alkynes also reacted quite well and
gave high yields. The structure of pyrroloindole derivative was
unambiguously established by single-crystal X-ray analysis of
compound 11 n (Figure 2).[10]
Initially the reaction was performed using Pd(OAc)2 (5 mol%)
and CuCl2 as oxidant in DMF at 758C (Table 1); however, it
Table 1. Optimisation of the annulation reaction.[a]
Entry Catalyst
Base/Oxidant Solvent
Yield [%]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuCl2
CuCl
CuBr
PIDA
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
K2CO3
Cu(OAc)2
KOH
DMF
DMF
DMF
DMF
NR
NR
NR
NR
NR
NR
NR
22
28
44
47
61
trace
trace
95
77
93
1,4-dioxane
toluene
acetonitrile
CH3CN/1,4-dioxane (1:1)
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
toluene
Figure 2. X-ray crystal structures of 11 n and 18a. Nitrogen (green) and
oxygen (red).
9
Initially, with an anticipation that the indole C-3 position
would interfere in the reaction due to its higher nucleophilicity,
we carried out all the reactions using C-3 substituted indoles.
Just out of curiosity, later the annulation reaction was per-
formed on C-3 unsubstituted indoles. Surprisingly, the reaction
went smoothly to afford desired pyrroloindoles in excellent
yields. No C-3 alkylation products were observed in these
cases.
10
11
12
13
14
15
16
17
18
19
KOtBu
Cs2CO3
[Pd(CH3CN)2Cl2] Cs2CO3
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
[Pd(PPh3)2Cl2]
Cs2CO3
Cs2CO3
Cs2CO3
48
46
At this stage, we also became interested in the outcome of
the reaction between the indoline derivative 9d’ and alkyne
esters 10d and 10e following the same reaction conditions. In-
terestingly, indoline 9d’ on independent reactions with alkyne
esters 10d and 10e generated pyrroloindoles 11 j and 11 n, re-
spectively (Scheme 3), first by palladium-catalysed aromatisa-
tion of indoline to indole[11] and subsequent reaction with
alkyne ester.
[a] Unless specified, reactions were carried out by treating 9a (0.3 mmol)
and 10a (0.3 mmol) with catalyst (5 mol%) and base (2 equiv) in solvent
(2 mL) at 758C. NR=no result; PIDA=phenyliodine diacetate.
failed to afford the desired product and the starting material
was recovered. Uses of other oxidants, such as CuCl, CuBr and
phenyliodine diacetate (PIDA), were also unsuccessful. To our
delight, treatment of the mixture of ketone 9a and alkyne
ester 10a with Pd(OAc)2 (5 mol%) and AgOAc (2 equiv) in
CH3CN/dioxane (1:1) at 758C afforded compound 11 a in 22%
yield. Encouraged by this result, various solvents and bases/ox-
Furthermore, it was observed that pyrrolo[1,2-a]indole deriv-
atives 11 converted to more stable compounds 12 when kept
in CDCl3 at room temperature for 5 min in the NMR tube
(Scheme 4). These structures of 12 were established by spec-
troscopic data. A similar rearrangement was also observed
Chem. Eur. J. 2016, 22, 106 – 110
107
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim