1080
COOMe
COOMe
Table 1. Nicholas reaction of 3 with acetylene cobalt complex
4 in the presence of a variety of acid
Zn-Cu
Products/%
HCl, MeOH
(93%)
Temp
/°C
Br
N
Br
Br
N
Entry Acid (equiv)
H
H
5
6
7a, 7b (5-:6-)
11
12
1
2
3
4
5
6
7
8
HBF4¢OEt2 (3)
BF3¢OEt2 (3)
TMSOTf (3)
Tf2NH (3)
Sc(OTf)3 (0.4)
InBr3 (0.4)
20
0
0
0
20
0
0
0
0
0
58 (1:1)
51 (1:1)
54 (1:1)
53 (1:1)
0
23 (1:1)
0
0
1) 4 (3 equiv), TMSOTf
CH2Cl2 (60%)
2) Bu3SnH, toluene
(96%)
1) MeNH2/MeOH (99%)
2) AlH3/THF (82%)
0
28
14
6
0
0
NHMe
0
COOMe
62
76
87
83
TMSOTf (0.4)
Tf2NH (0.4)
0
0
Br
N
H
Br
N
H
0
2
13
4 (2 equiv)
TMSOTf
CH2Cl2
(66%)
C-2 position and the C-5 or C-6 position of the indole product.
To our knowledge, this is the first example of the Nicholas
reaction at the C-2 position of an indole derivative. We next
performed the same reaction using one equivalent of acetylene
cobalt complex 4 and obtained a complex mixture. This
unexpected result prompted us to perform a screening of the
acid used for the reaction of methyl 3-indoleacetate (3) with
acetylene cobalt complex 4. Representative results of the
Nicholas reaction with two equivalents of acetylene cobalt
complex 4 and several acids are shown in Table 1.21,22 In the
presence of the Lewis acid BF3¢OEt2, the reaction proceeded
similarly to that of Entry 1 (Entry 2). When TMSOTf or Tf2NH
was employed as an acid, monoalkylated indole 6 was obtained
along with the dialkylated products 7a and 7b (Entries 3 and 4,
respectively). Surprisingly, when the reaction was performed in
the presence of catalytic amounts of acids such as Sc(OTf)3,
InBr3, TMSOTf, and Tf2NH, N-alkylated indole 5 was obtained
as the major product (Entries 5-8). These results implied that
product 6 might be formed through N-alkylated product 5 as an
intermediate.23 This speculation was supported in a separate
experiment, as the treatment of 5 with TMSOTf (3 equiv) gave a
mixture of compound 6 (8%), 7a and 7b (17%), and 3 (42%).24
Transformation of the acetylene cobalt complex moiety of 5, 6,
7a, and 7b to a reverse prenyl group was achieved in good yields
by reductive decomplexation with Bu3SnH, a reaction that was
developed in our laboratory.25 We thus established a procedure
for the two-step reverse prenylation at the N-1 position of the
indole nucleus, as well as the C-2 position, although the issue of
the regioselectivity has not yet been solved.
NHMe
NHMe
Bu3SnH
toluene
N
Br
Br
N
H
(85%)
H
14
Co(CO)3
Co(CO)3
deforylflustrabromine (1)
Scheme 2. Synthesis of deformylflustrabromine (1).
approach, none of the other regioisomers were obtained. As
anticipated, this indicates that the bromo substituent at the C-6
position excluded substitution at the benzene ring. The acetylene
cobalt moiety of the product was then transformed into a reverse
prenyl group by reductive decomplexation, giving 13 in
excellent yield. It is worth noting that the ester and bromo
substituents are compatible with the reaction conditions of the
sequential reverse prenylation.
We next investigated the Nicholas reaction of 6-bromo-N-
methyltryptamine (2), which was prepared from 12 in two steps,
involving N-methylamide formation and subsequent reduction
of the amide with AlH3.27 The reaction of 2 with acetylene
cobalt complex 4 was performed under optimized conditions in
66% yield. Again, it should be noted that the Nicholas reaction
appears to be unaffected in the presence of an unprotected basic
amino functional group.28 The cobalt complex of the product
smoothly underwent reductive decomplexation to provide
deformylflustrabromine (1) in 85% yield.
The above results indicate that the reactivity of the indole
benzene moiety in the Nicholas reaction is higher than we
expected. However, we envisioned that the 6-bromo substituent
of an indole derivative such as 2 would suppress the Nicholas
reaction at the benzene ring due to steric hindrance, resulting in a
regioselective reaction at the C-2 position.
We thus examined the Nicholas reaction of methyl
6-bromoindoleacetate 12, which was prepared in two steps from
methyl 3-indoleacetate (3), involving (i) 2,6-dibromination of
3 with NBS,26 and (ii) regioselective debromination of methyl
2,6-dibromoindoleacetate with a freshly prepared Zn/Cu couple
in MeOH in the presence of HCl (Scheme 2). Subsequently,
the Nicholas reaction of 12 with acetylene cobalt complex 4
(3 equiv) was carried out by treatment of TMSOTf (4 equiv) at
room temperature to provide the desired product possessing the
cobalt complex at the C-2 position in 60% yield. Using this
In summary, we have developed a new route to deformyl-
flustrabromine, a reverse prenyl indole alkaloid, by means of an
acetylene-cobalt complex. As the reverse prenylation procedure
is compatible with ester and bromo substituents, as well as basic
amino groups, this modification of indole derivatives should
facilitate an accessible route to synthesize diverse reverse-
prenylated indole compounds, not only from simple indole
derivatives, but also from naturally occurring indole alkaloids.
The generality and regioselectivity of the Nicholas reaction of
indole derivatives, as well as its application to complex terpene
indole alkaloids, are currently under investigation in our
laboratory.
This work was financially supported by a Grant-in-Aid for
Scientific Research (B) from MEXT, the Naito Foundation, and
the Nagase Science and Technology Foundation.
Chem. Lett. 2011, 40, 1079-1081
© 2011 The Chemical Society of Japan