A general synthesis of 1-(dialkylaminomethyl)indoles

Article abstract of DOI:10.1055/s-1998-1883

1-(N,N-Dialkylamino)methylindoles are prepared from the corresponding 1-(dialkylaminomethyl)benzotriazoles by treatment with indole and base. The aminoalkylation proceeds in high yield with good regioselectivity.

Full text of DOI:10.1055/s-1998-1883

October 1998
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A General Synthesis of 1-(Dialkylaminomethyl)indoles
Brian E. Love* and Binh T. Nguyen
Department of Chemistry, East Carolina University, Greenville, NC 27858, USA
Fax (252) 328-6210; E-mail: loveb@mail.ecu.edu
Received 25 August 1998
Abstract: 1-(N,N-Dialkylamino)methylindoles are prepared from the
corresponding 1-(dialkylaminomethyl)benzotriazoles by treatment with
indole and base. The aminoalkylation proceeds in high yield with good
regioselectivity.
aminomethylindoles 2 as the major products in close analogy to what is
observed with Grignard reagents. Indeed, reaction of N-lithioindole
(generated by treatment of indole with n-butyl lithium at low
temperature) with 1-dimethylaminobenzotriazole 1a produced
isogramine 2a in 79% crude yield, contaminated by only a small amount
(ca. 10-15%) of gramine 3a. Similar reactions using 1b-f produced the
corresponding indoles 2b-f in yields ranging from 87% to quantitative.
The products, as with 2a, were contaminated by only small amounts
(10-15%) of the isomeric 3-aminomethylindoles.
The dimethylaminomethyl group has proven to be a useful nitrogen
1
2
protecting group for indoles as well as other heterocycles. It is able to
direct metallation at C-2 of the indole ring, and can be removed using
1b
1a
sodium borohydride, or in certain cases, with sodium methoxide.
While the regioselectivity of reactions of metalloindoles is known to
Preparation of 1-(N,N-dimethylamino)methylindole ("isogramine") 2a
10,11
depend on the electrophile
as well as other experimental
(Scheme 1) is typically accomplished by reaction of indole with
11,12
3
conditions,
the nature of the counterion has also been shown to be
dimethylamine and formaldehyde. Though this method produces 2a in
quite important. For example, the potassium salt of indole shows a much
greater preference for N-alkylation than does the corresponding lithium
salt.
54.6% yield after purification by distillation (83% yield based on
consumed indole), in our hands the reaction proved capricious,
1b
11
frequently producing significant quantities of the isomeric 3-(N,N-
dimethylamino)methylindole (gramine) 3a from which separation was
difficult. Since we required significant amounts of 2a as part of an
ongoing synthetic effort, we investigated other methods of preparing 2a
as well as analogs of this compound.
Accordingly, in order to improve the regioselectivity of the
aminomethylation reaction, we investigated the use of potassium t-
butoxide as a base in place of n-butyllithium. Yields for these reactions
were comparable to those obtained using butyllithium. Though the
amount of C-aminomethylated product remained essentially the same,
the greater ease of handling of potassium t-butoxide relative to n-
butyllithium favored the use of the alkoxide. Product ratios for the
reactions of 1 with indole and potassium t-butoxide are shown in
13
Scheme 1. Changes in solvent and order of addition of reagents failed
to produce significant improvements in the ratio of 2:3, and in some
instances gave 3 as the major product.
As the yields of indoles 2a-g were quite good, application of this
methodology to the preparation of other structurally similar indoles was
also investigated. Contemplating eventual removal of the
(dialkylamino)methyl groups by reductive methods, we investigated the
preparation of benzyl substituted compounds 5 (Scheme 2). While these
compounds could be prepared from benzotriazoles 4, the products were
contaminated with significant amounts of the corresponding 3-
aminoalkylated compounds. We currently do not have an explanation
for the lower regioselectivity of these reactions relative to other
reactions run under similar conditions.
Scheme 1
Katritzky and coworkers have demonstrated that 1-(dialkylamino-
methyl)benzotriazoles 1 (which are easily prepared by reaction of
4
Scheme 2
benzotriazole, aldehydes and amines) are effective aminomethylating
5,6
agents.
For example, reaction of 1 with Grignard reagents and
organozinc reagents has been shown to be an excellent method of
preparing tertiary amines. Other reactions in which 1-(dialkylamino-
Benzylic compounds such as 7 (Scheme 3) could, however, be prepared
by condensation of the appropriate benzotriazole with indole in THF.
Virtually none of the corresponding 3-substituted compound was found
to contaminate compound 7. Furthermore, unlike indoles 2, 7 was a
7
methyl)benzotriazoles act as sources of iminium ions have also been
5,8
reported.
Though Katritzky has shown that reaction of 1-(dialkylaminomethyl)-
benzotriazoles with indole in the presence of Lewis acids produces 3-
(dialkylaminomethyl)indoles, we reasoned that reaction of an
solid which readily recrystallized from ethanol, thus making purification
14
very facile.
Another solid, 1-(dimethylamino)methylindole-3-
9
carboxaldehyde 8, which possesses an electron-withdrawing group at C-
organometallic derivative of indole with
1
should produce
3, could also be prepared by this method, but generally required more

1124
LETTERS
SYNLETT
vigorous reaction conditions (heating at reflux overnight) and thus is
perhaps best prepared by other methods.
(2) (a) Katritzky, A. R.; Rewcastle, G. W.; Vazquez de Miguel, L. M.
J. Org. Chem. 1988, 53, 794. (b) Katritzky, A. R.; Rewcastle, G.
W.; Fan, W. Q. J. Org. Chem. 1988, 53, 5685.
15
(3) Swaminathan, S.; Narasimhan, K. Chem. Ber. 1966, 99, 889.
(4) (a) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Org. Prep. Proced.
Int. 1989, 21, 135. (b) Katritzky, A. R.; Rachwal S.; Rachwal, B.
J. Chem. Soc. Perkin Trans. 1 1987, 799. (c) Bachman, G. B.;
Heisey, L. V. J. Am. Chem. Soc. 1946, 68, 2496.
(5) (a) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron
1991, 47, 2683. (b) Katritzky, A. R.; Lan, X.; Fan, W.-Q. Synthesis
1994, 445.
(6) 1-(Dialkylaminomethyl)benzotriazoles
contaminated with small amounts of the corresponding 2-
(dialkylaminomethyl)benzotriazoles. As these isomeric
(2)
are
typically
compounds display essentially the same reactivity, the presence of
both isomers is not detrimental to the success of the reaction. For a
discussion of this isomerism, see: Katritzky, A. R.;
Yannakopoulou, K.; Kuzmierkiewicz, W.; Aurrecoechea, J. M.;
Palenik, G. J.; Koziol, A. E.; Szczesniak, M. J. Chem. Soc. Perkin
Trans. 1 1987, 2673, Katritzky, A. R.; Yannakopoulou, K.
Heterocycles 1989, 28, 1121, and reference 18.
Scheme 3
In summary,
a
short, efficient method of preparing 1-
(dialkylaminomethyl)indoles has been developed, which proceeds in
high yield and utilizes readily available reagents. Products are easily
distinguished from the isomeric 3-(dialkylaminomethyl)indoles as well
(7) (a) Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.;
Urogdi, L. J. Chem. Soc. Perkin Trans. 1 1989, 225;
(b) Katritzky, A. R.; Strah, S.; Belyakov, S. A. Tetrahedron 1998,
54, 7167.
16
as the starting 1-(dialkylaminomethyl)benzotriazoles by proton NMR.
The ability of indole derivatives 2 to undergo lithiation at C-2 as well as
methods for removal of the dialkylaminomethyl groups are currently
under investigation.
(8) Katritzky, A. R.; Rachwal S.; Rachwal, B.; Steel, P. J. J. Org.
Chem. 1992, 57, 4932.
(9) Katritzky, A. R.; Yang, Z.; Lam, J. N. Tetrahedron 1992, 48, 4971.
(10) Epling, G. A.; Kumar, A. Synlett 1991, 347.
Experimental Section
(11) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.;
THF was dried over sodium metal and freshly distilled prior to use. 1-
(Dialkylaminomethyl)benzotriazoles were prepared according to
Eguchi, S. J. Chem. Soc. Perkin Trans. 1 1990, 111.
4,7
4a,17-20 18
7
literature procedures.
Benzotriazoles 1,
4
and 6 are all
(12) Bourak, M.; Gallo, R. Heterocycles 1990, 31, 447.
21
known compounds, and 1a, b & d are commercially available.
(13) Percentages for compounds 2c, f & g may be slightly inaccurate
due to partial overlap of the methylene signal of 3 with a small
signal from residual THF.
General Experimental Procedure:
1
(14) mp: 120-5 (EtOH); H NMR (200 MHz, CDCl ): δ 7.7-7.0 (m, 10
3
Potassium t-butoxide was placed in a dry flask, suspended in freshly
distilled THF, and cooled in an ice bath under nitrogen. A THF solution
of one equivalent of indole was added via syringe, followed by a THF
solution of one equivalent of the 1-(dialkylaminomethyl)benzotriazole.
The stirred solution was removed from the bath and allowed to come to
room temperature over two hours. The solution was diluted with ether,
washed four times with water, and once with a saturated NaCl solution.
The ether layer was dried over magnesium sulfate, and the solvent
removed under reduced pressure to give the product which typically did
not require further purification. (Note: some 1-(dialkylaminomethyl)-
indoles 2 were observed to slowly rearrange to the corresponding 3-
(dialkylaminomethyl)indoles 3 upon standing at room temperature for
several months).
H), 6.55 (d, J = 3.5 Hz, 1H), 5.79 (s, 1H), 3.8-3.6 (m, 4H) 2.6-2.3
13
(m, 4H); C NMR (50 MHz, CDCl ): δ 137.8, 136.4, 128.6,
3
128.5, 128.4, 127.6, 125.5, 121.6, 120.9, 119.7, 109.8, 102.5,
78.8, 66.8, 50.6.
(15) Love, B. E.; Raje, P. S. Heterocycles 1993, 35, 1259.
(16) The methylene resonance in
1 typically had a value of
approximately 5.5 ppm, which shifted to 4.8 ppm in the products
2. In the isomeric 3-substituted indoles 3 this signal was shifted
even further upfield to approximately 3.8 ppm and was
accompanied by the disappearance of the C-3 proton signal at
1
approximately 6.5 ppm. Complete H NMR data (200 MHz,
CDCl ) for products 2 are as follows: 2a: 7.64 (d, J= 7.9 Hz, 1H),
3
7.56 (d, J= 8 Hz, 1H), 7.5-7.1 (m, 3H), 6.50 (d, J= 3.2 Hz, 1H),
4.67 (s, 2H), 2.25 (s, 6H); 2b: 7.64 (d, J= 7.6 Hz, 1H), 7.46 (d, J=
7 Hz, 1H), 7.4-7.0 (m, 3H), 6.52 (d, J= 2.5 Hz, 1H), 4.93 (s, 2H),
2.8-2.5 (m, 4H), 1.9-1.6 (m, 4H); 2c: 7.63 (d, J= 7 Hz, 1H), 7.46
(d, J= 7 Hz, 1H), 7.4-7.0 (m, 3H), 6.50 (d, J= 3.2 Hz, 1H), 4.81 (s,
2H), 2.7-2.4 (m, 4H), 1.7-1.5 (m, 4H), 1.5-1.2 (m, 2H); 2d: 7.62
(d, J= 8 Hz, 1H), 7.47 (d, J= 8 Hz, 1H), 7.3-7.0 (m, 3H), 6.53 (d,
J= 3.2 Hz, 1H), 4.78 (s, 2H), 3.8-3.6 (m, 4H), 2.6-2.4(m, 4H); 2e:
7.60 (d, J= 8 Hz, 1H), 7.45 (d, J= 8 Hz, 1H), 7.3-7.0 (m, 3H), 6.48
(d, J= 3 Hz, 1H), 4.82 (s, 2H), 2.7-2.5 (m, 1H), 2.24 (s, 3H),1.9-
1.5 (m, 5H), 1.4-1.0 (m, 5H); 2f: 7.60 (d, J= 8 Hz, 1H), 7.45 (d, J=
Acknowledgement
Acknowledgement is made to the donors of The Petroleum Research
Fund, administered by the ACS, for support of this research.
References
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3688.

October 1998
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