N-aminomethylation vs. C-aminomethylation of indole and pyrrole with an N,O-acetal controlled by the hardness of a counter ion of an iminium compound

Article abstract of DOI:10.1246/cl.131116

Under relatively strong Lewis acidic conditions (a softer counter ion) using TMSOTf and TMSI, the aminomethylation of indole or pyrrole with a typical N,O-acetal preferentially produced the kinetically favored N-aminomethylated indole or pyrrole derivative. Use of a relatively weak Lewis acid (a harder counter ion), such as TMSCl and TMSBr, preferentially produced the thermodynamically favored C-aminomethylated indole and pyrrole derivative.

Full text of DOI:10.1246/cl.131116

Received: November 29, 2013 | Accepted: December 21, 2013 | Web Released: December 28, 2013
CL-131116
N-Aminomethylation vs. C-Aminomethylation of Indole and Pyrrole with an N,O-Acetal
Controlled by the Hardness of a Counter Ion of an Iminium Compound
Norio Sakai,* Hidetoshi Okano, Kazuyori Shimamura, and Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510
(
E-mail: sakachem@rs.noda.tus.ac.jp)
Under relatively strong Lewis acidic conditions (a softer
counter ion) using TMSOTf and TMSI, the aminomethylation
of indole or pyrrole with a typical N,O-acetal preferentially
produced the kinetically favored N-aminomethylated indole or
pyrrole derivative. Use of a relatively weak Lewis acid (a harder
counter ion), such as TMSCl and TMSBr, preferentially
produced the thermodynamically favored C-aminomethylated
indole and pyrrole derivative.
Table 1. Selective aminomethylation of indole with an N,O-
acetal by organosilicon Lewis acids
NR2
N
TMSX
1 or 0.2 equiv)
H
(
N
+
+
N
CH Cl , rt, 0.5 h
R N
H
2
2
2
NR2
1
2
OMe
NR2 = cyclo-C H10N)
(
5
Product ratioa,c
Conversion
Because indole and pyrrole constitute the basic skeleton of
natural products and biologically active substances, developing
the regioselective introduction of a functional group onto these
skeletons with an ambident nucleophilic point remains a
fundamentally important and central pursuit in organic synthe-
Entry TMSX
a,b
3d
/%
1
2
1
2
3
4
TMSCl
TMSBr
TMSI
86 (63)
85 (81)
96 (77)
95 (90)
8 (14) 77 (59) 15 (27)
19 (19) 65 (59) 16 (22)
36 (52) 53 (23) 11 (25)
1
,2
3
sis. Among these efforts, aminoalkylation with imines, N,O-
TMSOTf
60 (62) 37 (20)
3 (18)
acetals, or N,N-aminals6 in the presence of a Lewis acid
constitutes a straightforward and practical method to achieve this
goal. Thus far, the common aminomethylation of indole or
pyrrole derivatives with N,O-acetals in the presence of a typical
organosilicon Lewis acid such as chlorotrimethylsilane (TMSCl)
regioselectively took place at either the 3- or 2-position (C-
aminomethylation), respectively.6 However, as an unconven-
tional example, we reported that with a Lewis acid, Hf(OTf)4
promoted the regioselective N-aminomethylation of an indole
derivative, preferentially producing the kinetically stable N-
aminomethylated indole derivative instead of the thermodynami-
4,5
a0.2 equiv of TMSX is in parentheses. Based on indole. Ratio
b
c
d
was calculated by NMR. Compound 3: 1,3-disubstituted
indole.
e,6f
indole derivatives, respectively. Compound 3 was characterized
as the 1,3-disubstituted indole derivative. The hardness of a
counter ion directly controlled the product ratio of the amino-
methylated indole. In other words, when the strength of the
Lewis acid increased, the product ratio of the kinetically stable
1-aminomethylated indole 1 increased, but the formation of the
thermodynamically stable 3-aminomethylated indole 2 remark-
ably decreased. Interestingly, when this aminomethylation was
also subjected to the conditions with a catalytic amount
(0.2 equiv) of a Lewis acid, a similar tendency for the product
ratio was observed. Moreover, this tendency was maintained
7
cally stable 3-aminomethylated indole. Therefore, we antici-
pated that in this aminomethylation the hardness (basicity) of a
counter anion of the iminium compound, which is derived from
an N,O-acetal, would control the product ratio of the N-
aminomethylation vs. the C-aminomethylation of an indole, and
actually attempted the regioselective aminomethylation of either
indole or pyrrole with an N,O-acetal in the presence of an
organosilicon Lewis acid series (e.g., TMSCl, TMSBr, TMSI,
and TMSOTf). Thus, we have obtained new results, in which an
iminium intermediate with a softer counter anion (a weakly
basic anion) undertook an aminomethylation onto the harder
nitrogen position of indole or pyrrole; to a certain extent, these
results correlated with the principle of the hard and soft acids
1
1
when the reaction time was prolonged.
Then, when the aminomethylation of pyrrole was performed
with the same organosilicon Lewis acids, a similar tendency
toward the product ratio was observed (Table 2). As the strength
of four types of organosilicon Lewis acids increased, the product
ratio of N-aminomethylated pyrrole 4 increased more than that
of C-aminomethylated pyrrole 5. The formation of a mixture
of 1,2-disubstituted pyrrole 6 and 2,5-disubstituted pyrrole 7
was also observed. Unfortunately, neither compound could be
cleanly isolated from the mixture. When the aminomethylation
was conducted with 0.2 equiv of a Lewis acid series, contrary to
expectations, cases with TMSCl and TMSBr afforded disubsti-
tuted pyrroles as a major product. However, the cases with TMSI
and TMSOTf produced N-aminomethylated pyrrole 4 with a
relatively high selectivity.
8
,9
and bases (HSAB). In this letter, we report these results.
Initially, the regioselective aminomethylation of indole with
an N,O-acetal, 1-(methoxymethyl)piperidine, prepared from
piperidine, methanol, and paraformaldehyde in the presence of
7
both K2CO3 and Na2SO4, was performed with four types of
organosilicon Lewis acids (1 equiv) at room temperature in
CH2Cl2; the results are summarized in Table 1.10 In all cases,
indole was consumed within 30 min to produce three types
of indole derivatives 1, 2, and 3. Compounds 1 and 2 were
characterized as the N-aminomethylated and C-aminomethylated
To understand the effect to regioselectivity of a counter
anion of each iminium compound, several control experiments
Chem. Lett. 2014, 43, 501–503 | doi:10.1246/cl.131116
© 2014 The Chemical Society of Japan | 501

Table 2. Selective aminomethylation of pyrrole with an N,O-
acetal by organosilicon Lewis acids
Table 3. Aminomethylation of indole with an N,O-acetal in the
presence of MeOH
NR2
N
TMSX (1 equiv)
N
H
TMSX (1 equiv)
H
MeOH (10 equiv)
N
N
N
+
+
+
+
H
NR2
N
CH Cl , rt, 0.5 h
CH Cl , rt, 0.5 h
2
2
2
2
R N
R N
2
H
NR2
2
NR2
4
5
1
2
OMe
NR = c-C H10N
OMe
NR = c-C H10N
2
5
2
5
Product ratioa,c
Product ratiob
Conversion
Conversion
Entry TMSX
Entry
TMSX
TMSCl
TMSBr
TMSI
TMSOTf
b
a,b
6 + 7d
a
3c
/
%
4
5
/%
1
2
1
2
3
4
TMSCl
TMSBr
TMSI
100 (93)
98 (94)
5 (11) 83 (38) 12 (51)
15 (30) 68 (23) 17 (47)
89 (100) 46 (70) 32 (19) 22 (11)
98 (100) 68 (75) 26 (16) 6 (9)
1
2
3
99
91
99
99
ND
ND
3
100
100
95
ND
ND
2
TMSOTf
4
ND
100
c
ND
a
c
.2 equiv of TMSX is in parentheses. bBased on pyrrole.
Ratio was calculated by NMR. A mixture of 1,2-disubstituted
a
0
Based on indole. Ratio was calculated by NMR. Compound
3: 1,3-disubstituted indole.
d
pyrrole 6 or 2,5-disubstituted pyrrole 7.
resulted into preferential N-aminomethylation at the harder
nitrogen atom on indole and pyrrole.
Also, when aminomethylation of indole was carried out in
the presence of excess methanol (10 equiv) in the hopes that
strong solvation would separate the iminium cation from the
counter anion, the aminomethylation was completed within 0.5 h
TMSX (1 equiv)
8
.63
N
N
C
X
3
CDCl , rt, 0.5 h
X = Cl
OMe
H
H
8
.49
to selectively produce thermodynamically stable indole 2
X = Br
14
(
Table 3). These results showed that the electrophilicity of
each iminium compound became identical by the insertion of
1
5
methanol between the iminium cation and the counter anion.
8
.36
In the selective aminomethylation of either indole or pyrrole
having an ambident nucleophilic position with an N,O-acetal in
the presence of organosilicon Lewis acid series, we observed a
X = I
1
6
new tendency. As the hardness of a counter ion on an iminium
salt decreased, the kinetically stable N-aminomethylated prod-
ucts preferentially formed (N-aminomethylation), and, in turn, as
the hardness of a conjugate anion on an iminium salt increased, a
thermodynamically stable 3- or 2-aminomethylated indole or
pyrrole preferentially formed (C-aminomethylation). Also, we
observed that each counter anion undertook a strong interaction
with the methylene protons of the iminium intermediate.
7
.99
X = TfO
Figure 1. Observation of the chemical shift of the methylene
protons on each iminium compound by H NMR.
1
were then examined. First, a chemical shift of the corresponding
methylene peak of each iminium compound, generated in situ
from the N,O-acetal and Lewis acid, was measured by H NMR
This work was partially supported by a grant from the Japan
Private School Promotion Foundation supported by MEXT. The
authors thank Mr. Hiroaki Hori (Tokyo University of Science)
for his assistance with the experiments. The authors also thank
Shin-Etsu Chemical Co., Ltd., for the gift of chlorosilane.
1
(Figure 1). In all cases, a single peak derived from the
methylene proton was observed at 8.0­8.6 ppm. The observed
shift was in agreement with the results of the chemical shifts of
+
¹
diethylmethyleneammonium salts, Et N =CH X (X = Cl, Br,
2
2
1
2,13
I, and OTf) in CD3CN by Mayr and Würthwein.
Based on
References and Notes
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1
2
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¹
¹
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position carbon on indole or pyrrole, respectively. In turn, in
¹
¹
cases with relatively soft counter anions, such as TfO and I ,
the methylene moiety became an even harder electrophile, which
502 | Chem. Lett. 2014, 43, 501–503 | doi:10.1246/cl.131116
© 2014 The Chemical Society of Japan

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¹
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¹
¹
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15 One reviewer pointed out that the presence of excess
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8
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7
8
such as CH CN, dioxane, and toluene, the same result to the
3
product ratio shown in Table 1 was observed in each case.
The only case with MeOH that has a strong solvation led to a
selective C-aminomethylation. Consequently, we assume
that solvation of the iminium intermediate by a protic
solvent, MeOH affected the product ratio.
9
For selected papers of regioselective reaction with ambifuc-
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0 General procedure for the aminomethylation of indole or
16 When the aminomethylation of indole with an N,O-acetal
was performed with Brønsted acids, the same tendency to the
product ratio was observed; TfOH: 1:2:3 = 76:20:4, HCl
¹1
(4 mol L in dioxane): 1:2:3 = 1:98:1. In this context, we
cited a related paper, in which alkylation and dimerization of
indole could be controlled by removal of protic acids, see:
M. J. Earle, R. A. Fairhurst, H. Heaney, Tetrahedron Lett.
1991, 32, 6171.
1
Chem. Lett. 2014, 43, 501–503 | doi:10.1246/cl.131116
© 2014 The Chemical Society of Japan | 503