Hf(OTf)4-Catalyzed regioselective N -aminomethylation of indoles and related NH-containing heterocycles

Article abstract of DOI:10.1021/jo1006043

Figure presented Under Lewis acidic conditions using Hf(OTf)₄, the aminomethylation of an indole derivative with a typical N,O-acetal preferentially produced kinetically favored N-aminomethylated indole derivatives instead of thermodynamically favored 3-aminomethylated indoles.

Full text of DOI:10.1021/jo1006043

pubs.acs.org/joc
temperature the aminomethyl substituent was mainly intro-
Hf(OTf)4-Catalyzed Regioselective
N-Aminomethylation of Indoles and Related
NH-Containing Heterocycles
duced onto the nitrogen atom (N-alkylation) on indole.3-5
We also reported the Hf(OTf)4-doped Me3SiCl-catalyzed
C-alkylation of indoles with N,O-acetals having either a
cyano group or an ester group and recognized a preferential
introduction of the substituent onto the C3-position in
indole.6 However, during ongoing studies on the aminometh-
ylation of nitrogen-containing heterocycles with the N,
O-acetals, we found an unprecedented result: Hf(OTf)4 pro-
moted the regioselective N-alkylation of an indole derivative,
preferentially producing the kinetically favored N-amino-
methylated indole derivative at room temperature instead of
the thermodynamically favored 3-aminomethylated indole.
With but two exceptions, aminomethylation of a 3-protected
indole under Lewis acidic conditions or an N-underivatized
indole derivative under basic conditions, this type of highly
regioselective N-aminomethylation of an indole derivative
in the presence of a catalytic amount of a Lewis acid has
not been reported. The success of N-alkylation under Lewis
acidic conditions enables the use of indoles having a base-
sensitive functional group, which is applied to the practical
preparation of some biologically active substances such as
isogramine. Herein, we report the unconventional results
of this unique N-aminomethylation of indoles and related
NH-containing heterocycles.
Norio Sakai,* Kazuyori Shimamura, Reiko Ikeda, and
Takeo Konakahara
Department of Pure and Applied Chemistry,
Faculty of Science and Technology, Tokyo University of
Science (RIKADAI), Noda, Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
Received March 30, 2010
Initially, a series of N,O-acetals 2a-g having several
amino groups were prepared via the reaction of a secondary
amine, methanol, and paraformaldehyde in the presence of a
dehydrating reagent such as K2CO3 and Na2SO4.7 When the
reaction of indole (1a) with the N,O-acetal 2a was then
carried out in the presence of Hf(OTf)4 in CH2Cl2, N-
aminomethylation was cleanly completed within 5 min to
lead to the selective preparation of indole 3aa in 76% yield
with formation of 3-substituted indole 4aa and 1,3-disubsti-
tuted indole 5aa (run 1 in Table 1).7 Thus, to improve the
regioselectivity of the aminomethylation, we then per-
formed the reaction using several different Lewis/Brønsted
acids. When HfCl4 was used instead of Hf(OTf)4, both the
product yield and selectivity were reduced (run 2). In the
presence of AgOTf, however, the yield of 3-aminomethy-
lated indole was increased (run 3). With no reference to a
Under Lewis acidic conditions using Hf(OTf)4, the amino-
methylation of an indole derivative with a typical N,
O-acetal preferentially produced kinetically favored
N-aminomethylated indole derivatives instead of thermo-
dynamically favored 3-aminomethylated indoles.
Aminoalkylation is one of the most efficient and practical
methods for introduction of a nitrogen-containing func-
tional group onto an aromatic compound, especially an
electron-rich heterocycle such as indole and pyrrole.1 In this
context, a number of researchers have previously reported
that a common aminomethylation of an indole derivative
with an N,O-acetal and N,N-aminal in the presence of a typi-
cal Lewis acid regioselectively took place on the 3-position
(C-alkylation)2 and that under basic conditions or at low
(3) (a) Swaminathan, S.; Ranganathan, S.; Sulochana, S. J. Org. Chem.
1958, 23, 707. (b) Swaminathan, S.; Narasimhan, K. Chem. Ber. 1966, 99,
889. (c) Love, B. E.; Nguyen, B. T. Synlett 1998, 1123. (d) Love, B. E. J. Org.
Chem. 2006, 72, 630.
(4) Selected papers for N-alkylation of indoles with electrophiles in the
presence of a base: (a) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
1973, 499. (b) Bergman, J.; Norrby, P.-O.; Sand, P. Tetrahedron 1990, 46,
6113. (c) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
(d) Bombrun, A.; Casi, G. Tetrahedron Lett. 2002, 43, 2187. (e) Shieh, W.-C.;
Dell, S.; Bach, A.; Repic, O.; Blacklock, T. J. J. Org. Chem. 2003, 68, 1954.
(f) Burley, G. A.; Davies, D. L.; Griffith, G. A.; Lee, M.; Singh, K.
J. Org. Chem. 2010, 75, 980.
(5) Fridkin, G.; Boutard, N.; Lubell, W. D. J. Org. Chem. 2009, 74, 5603.
(6) (a) Sakai, N.; Hamajima, T.; Konakahara, T. Tetrahedron Lett. 2002,
43, 4821. (b) Sakai, N.; Hirasawa, M.; Hamajima, T.; Konakahara, T. J. Org.
Chem. 2003, 68, 483. (c) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron
Lett. 2006, 47, 631. (d) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T.
Synlett 2007, 2675. (e) Sakai, N.; Asano, J.; Shimano, Y.; Konakahara, T.
Tetrahedron 2008, 64, 9208. (f) Sakai, N.; Asano, J.; Kawada, Y.; Konakahara,
T. Eur. J. Org. Chem. 2009, 917.
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996. (b) Joule,
J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science Ltd.: Oxford,
2000. (c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044. (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005,
1199.
(2) Selected papers and review for C-alkylation of indole and pyrrole with
an acetal, an aminal, and a hemiacetal: (a) Heaney, H.; Papageorgiou, G.;
Wilkins, R. F. J. Chem. Soc., Chem. Commun. 1988, 1161. (b) Heaney, H.;
Papageorgiou, G.; Wilkins, R. F. Tetrahedron Lett. 1988, 29, 2377.
(c) Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F.; Eyley,
S. C. Tetrahedron Lett. 1989, 30, 1433. (d) Katritzky, A. R.; Yang, Z.; Lam,
J. N. Tetrahedron 1992, 48, 4971. (e) Heaney, H.; Papageorgiou, G.; Wilkins,
R. F. Tetrahedron 1997, 53, 2941. (f) Gong, Y.; Kato, K. J. Fluorine Chem.
2001, 108, 83. (g) DeNinno, M. P.; Eller, C.; Etienne, J. B. J. Org. Chem. 2001,
66, 6988. (h) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G. Tetrahedron Lett.
2004, 45, 3673. (i) Lindquist, C.; Ersoy, O.; Somfai, P. Tetrahedron 2006, 62,
3439. (j) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409.
(7) See the experimental details in the Supporting Information.
DOI: 10.1021/jo1006043
r
Published on Web 05/10/2010
J. Org. Chem. 2010, 75, 3923–3926 3923
2010 American Chemical Society

Sakai et al.
JOCNote
TABLE 1. Examination of the Aminomethylation of Indole
TABLE 3. N-Aminomethylation of Indoles a,b
yielda (%)
run
acid (5 mol %)
time (min)
3aa
4aa
5aa
1
2
3
4
5
6
7
8
9
Hf(OTf)4
HfCl4
AgOTf
Cu(OTf)2
Zn(OTf)2
In(OTf)3
Yb(OTf)3
TfOHb
5
30
30
30
30
30
30
30
30
(76)
31
13
47
55
72
75
64
5
6
9
45
19
9
3
5
8
87
2
5
16
11
4
6
8
7
3
Me3SiCl
aNMR(isolated) yield. b0.2 equiv of TfOH was used.
TABLE 2. N-Alkylation of Indole with Several N,O-Acetals
aIsolated yield. bThe term “b” in 3ba denotes a sort of indole, and the
term “a” in 3ba corresponds to a sort of N,O-acetal 2 shown in Table 2.
We next examined the effect of an amine moiety on the N,
O-acetal for the aminomethylation of indole (1a) (Table 2).
For instance, in the case of the N,O-acetals having an acyclic
amino group, the corresponding N-aminomethylated pro-
ducts 3a-c were regioselectively produced in good yields.
Use of N,O-acetals having a cyclic amino moiety slightly
reduced the yields of N-aminomethylated indoles 3 (entries
4 and 5). N,O-Acetal 2f with an unsymmetrical amine
produced good selectivity and practical yield. However, in
the case of the N,O-acetal 2g derived from N-methylaniline,
the yield of product 3ag was drastically decreased. This may
have been due to the phenyl group retarding conversion into
the corresponding Mannich base.
To further extend the generality of this reaction, the
reaction of N,O-acetals 2a-g with a variety of indoles was
carried out under optimal conditions (Table 3). With the
exception of N,O-acetal 2g, most N-aminomethylations of
indoles with a substituted group, such as a methoxy, a bro-
mine, a nitro, or a Boc-protected amino group, proceeded
smoothly to produce the corresponding derivatives in mode-
rate to good yields. Unfortunately, in the cases of 2-sub-
stituted indoles, the yields of N-aminomethylated derivatives
3fb and 3ga were drastically reduced; in particular, use of
2-phenylindole did not give the desired product 3fb due to the
steric repulsion between a relatively bulky isopropyl group
and a 2-substituted group. On the other hand, when amino-
methylation of an indole possessing a TBS-protected OH
aIsolated yield.
sort of metal cation, when the number of the triflate anion
was increased, both the yield and selectivity were drasti-
cally improved (runs 4-7). Thus, when 20 mol % of TfOH
was used as a catalyst, the similar reaction proceeded
smoothly to produce the N-aminomethylated indole as a
major product with high regioselectivity (run 8). These
results imply that the triflate anion species or TfOH func-
tions as a key promoter of this unique aminomethylation.
On the other hand, use of Me3SiCl gave 3-aminomethylated
indole 4 as a major product as well as the conventional
results (run 9).2 From the viewpoints of the handling of the
catalyst and the reactivity, the reaction conditions shown
in run 1 were the optimal conditions for the present amino-
methylation.
3924 J. Org. Chem. Vol. 75, No. 11, 2010

Sakai et al.
JOCNote
TABLE 4. N-Aminomethylation of N-Containing Heterocyclesa
FIGURE 1. Time-course of thermal conversion of indole derivative
3aa into indole derivatives 4aa, 5aa, and indole (1a) in the presence
of 5 mol % of Hf(OTf)4 by NMR monitoring.
aIsolated yield.
substituent, or of 3-methylated indole was conducted, the
aminomethyl group was easily introduced onto the nitrogen
atom. Moreover, the present method could be applied to
the quantitative N-aminomethylation of 7-azaindole and
benzimidazole.
TABLE 5. Comparison of N- and C-Alkylation in the Reaction of Indole
(1a) and N,O-Acetal 2a in the Presence of Me3SiXa
When the reaction of other nitrogen-containing hetero-
cycles such as pyrrole, pyrazole, imidazole, and carbazole
with several N,O-acetals was performed with 5 mol % of
Hf(OTf)4, it was found that unlike conventional reports
using a typical silyl chloride, such as Me3SiCl as a promoter,
N-aminomethylation proceeded selectively to produce the
desired derivatives 6-9 in good to excellent yields (Table 4).
To better understand the reaction pathway for amino-
methylation, a time-course of thermal rearrangement of the
aminomethyl moiety on the isolated indole 3aa was moni-
tored by 1H NMR in CD2Cl2 at room temperature (Figure 1).
The gradual conversion of indole 3aa into 3-aminomethy-
lated indole 4aa, 1,3-diaminomethylated indole 5aa, and
indole (1a) was directly observed, and after 6 h, the reaction
reached equilibrium (4aa, 12%; 5aa, 14%; 1a, 15%; 59% of
3aa remained). Thus, the results of the present study show
that isomerization from kinetically favored indole 3aa into
thermodynamically favored 4aa via a consecutive dissociation-
recombination of the aminomethyl group proceeded slowly
under these conditions.8,9 Also, the formation of 1,3-disub-
stituted indole 5aa shows that the shift of the aminomethyl
group occurred intermolecularly.10 Moreover, to understand
product yielda (%)
run
Me3SiX
3aa
4aa
5aa
1a
1
2
Me3SiOTf
Me3SiCl
46
9
4
37
2
16
46
38
aNMR yield.
an effect of a counteranion of the Mannich base generated
from the N,O-acetal 2, aminomethylation of indole (1a)
with the acetal 2a was performed with Me3SiOTf or Me3SiCl
in the presence of N,N-diisopropylethylamine (DIPEA) as
a scavenger of an acid (Table 5).11 Interestingly, the one
Me3SiOTf mainly produced N-aminomethylated product
3aa, and the other Me3SiCl gave C-aminomethylated indole
4aa as a major product. The results imply that a softness
of the in situ generated electrophile controls regioselectivity
of this aminomethylation. In short, the alkylating reagent
with a harder triflate anion favored N1-alkylation, and
the iminium salt with a chloride ion, which is a softer anion
than the triflate anion, provided C3-alkylation product
predominantly.9,12
(8) (a) When isolated product 3aa was treated with 2 equiv of Me3SiCl in
CH2Cl2 at room temperature for 72 h, no shift of the aminomethyl group was
observed.
(9) Several groups reported that regioselective N1- or C3-alkylation of
NH-containing heterocycles depends on a softness of the leaving group of an
electrophile; see: (a) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi,
H.; Eguchi, S. J. Chem. Soc., Perkin Trans. 1 1990, 111. (b) Epling, G. A.;
Kumar, A. Synlett 1991, 347. (c) Bourak, M.; Gallo, R. Heterocycles 1990,
31, 447.
(10) When isolated product 3aa in the presence of 20 mol % of Hf(OTf)4
was vigorously stirred in CH2Cl2 at room temperature, product 4aa was
obtained in 68% yield.
In summary, we have found that Hf(OTf)4 promotes
aminomethylation of indole derivatives, preferentially affording
J. Org. Chem. Vol. 75, No. 11, 2010 3925

Sakai et al.
JOCNote
the kinetically favored N-aminomethylated indole derivatives
(N-alkylation product) instead of the thermodynamically
favored 3-aminomethylated indoles (C-alkylation product).
This method could be successfully extended to the N-alkyla-
tion of pyrroles and other related NH-containing hetero-
cycles. Further studies by our group on the detailed reaction
mechanism of this type of aminomethylation are currently
ongoing.
at room temperature. The reaction was quenched with a satu-
rated aqueous solution (2 mL) of Na2CO3. The combined
organic layer was dried over MgSO4 and evaporated under
reduced pressure. The crude product was purified by silica gel
column chromatography (hexane/AcOEt) to afford the corre-
sponding product.
N-((1H-Indol-1-yl)methyl)-N-ethylethanamine (3aa): colorless
oil; IR (neat) 3040, 2933, 1459 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 1.06 (t, 6H, J = 7 Hz), 2.60 (q, 4H, J = 7 Hz), 4.87 (s,
2H), 6.49 (d, 1H, J = 3 Hz), 7.09 (t, 1H, J = 7.5 Hz), 7.16 (d, 1H,
J = 3 Hz), 7.19 (t, 1H, J = 7.5 Hz), 7.46 (d, 1H, J = 7.5 Hz), 7.61
(d, 1H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 12.2, 44.9,
64.1, 101.4, 109.9, 119.4, 120.7, 121.5, 128.2, 128.6, 136.8; MS
(ESI) m/z 225 (Mþ þ Naþ); HRMS (ESI) calcd for C13H18N2Na
225.1368, found 225.1383.
N-((1H-Pyrrol-1-yl)methyl)-N-ethylethanamine (6a): colorless
oil; IR (neat) 3104, 2937, 1490 cm-1; 1H NMR (300 MHz, CDCl3)
δ1.09 (t, 3H, J= 7 Hz), 2.54 (q, 2H, J=7Hz), 4.72(s, 1H), 6.14(t,
1H, J = 2 Hz), 6.68 (t, 1H, J = 2Hz); 13C NMR (75 MHz, CDCl3)
δ 12.5, 45.0, 65.8, 107.8, 121.2; MS (ESI) m/z 153(Mþ þ H);
HRMS (FAB) calcd for C9H17N2 153.1392, found 153.1417.
Experimental Section
General Procedure for the Hf(OTf)4-Catalyzed Aminomethy-
lation of a Nitrogen-Containing Heterocycle with an N,O-Acetal.
To a freshly distilled CH2Cl2 solution (2 mL) was successively
added an N,O-acetal 2 (70.3 mg, 0.600 mmol), indole (70.3 mg,
0.600 mmol), and Hf(OTf)4 (23.2 mg, 0.0300 mmol) under a
nitrogen atmosphere. The resulting solution was stirred for 0.1 h
(11) When the reaction was conducted with another proton scavenger
such as N,O-bis(trimethylsilyl)acetamide, the desired reaction did not
proceed.
(12) The reviewer commented that a shift of the aminomethyl group
occurs from a kinetically favored one (N-alkylation) to a thermodynamically
favored one (C-alkylation) in the presence of the catalyst. However, we have
no observation from the thermodynamic product to the kinetic one through a
series of experiments (eq 1).
Acknowledgment. This work was partially supported by a
grant from the Japan Private School Promotion Foundation
supported by MEXT. We deeply thank Dow Corning Toray
Co., Ltd. for the gift of Me3SiCl. We thank the reviewers for
useful comments and are grateful for Mr. Kosuke Tamura
for his assistance in obtaining IR, HRMS, and NMR
spectra.
Additionally, the same reviewer pointed out the disproportion that the case
using Me3SiCl did not undergo the thermal conversion (see ref 8). It seems
that a relatively moderate Lewis acid Me3SiCl does not lead to regeneration
of the iminium species through a cleavage of the C-N bond.
Supporting Information Available: Experimental details and
spectroscopic data of the prepared compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3926 J. Org. Chem. Vol. 75, No. 11, 2010