Reductive methylation using decaborane in methanol

Article abstract of DOI:10.1081/SCC-100106199

Amines (primary and secondary) were methylated to the corresponding tertiary amine using 37% formaldehyde and decaborane in methanol at room temperature under nitrogen in high yields.

Full text of DOI:10.1081/SCC-100106199

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REDUCTIVE METHYLATION USING DECABORANE IN
METHANOL
Yeon Joo Jung a , Jong Woo Bae a , Choon-Ock Maing Yoon a , Byung Woo Yoo b & Cheol
Min Yoon c
a Department of Life Science and Biotechnology , Graduate School of Biotechnology,
Korea University , Seoul, 136-701, S. Korea
b Department of Chemistry , Korea University , Chochiwon, Chungnam, 339-700, S. Korea
c Department of Life Science and Biotechnology , Graduate School of Biotechnology,
Korea University , Seoul, 136-701, S. Korea
Published online: 22 Aug 2006.
To cite this article: Yeon Joo Jung , Jong Woo Bae , Choon-Ock Maing Yoon , Byung Woo Yoo & Cheol Min Yoon (2001)
REDUCTIVE METHYLATION USING DECABORANE IN METHANOL, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:22, 3417-3421, DOI: 10.1081/SCC-100106199
To link to this article: http://dx.doi.org/10.1081/SCC-100106199
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SYNTHETIC COMMUNICATIONS, 31(22), 3417–3421 (2001)
REDUCTIVE METHYLATION
USING DECABORANE
IN METHANOL
Yeon Joo Jung,1 Jong Woo Bae,1
1
Choon-OckMaing Yoon, Byung Woo Yoo,2
and Cheol Min Yoon1,
*
1Department of Life Science and Biotechnology,
Graduate School of Biotechnology,
Korea University, Seoul, 136-701, S. Korea
2Department of Chemistry, Korea University,
Chochiwon, Chungnam, 339-700, S. Korea
ABSTRACT
Amines (primary and secondary) were methylated to the
corresponding tertiary amine using 37% formaldehyde and
decaborane in methanol at room temperature under nitrogen
in high yields.
The methylation of amines has been achieved by numerous methods.1
Especially, the reductive methylation has been known as one of the powerful
methods for the methylation of amine. These reagents of the reductive
methylation are triethylsilane/37% aqueous formaldehyde,2 formic acid/30%
*Corresponding author.
3417
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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JUNG ET AL.
aqueous formaldehyde involving irradiation,3 sodium borohydride/
trifluoroacetic acid/paraformaldehyde,4 trimethyl orthoformate/sulfuric
acid,5 sodium borohydride/zinc chloride/paraformaldehyde,6 and sodium
cyanoborohydride/aqueous formaldehyde.7,8 However, these methods have
some limitations such as high temperature, strong acidic condition, toxicity
or low yield.
As a continuous study on decaborane as a mild, quite stable and
nontoxic reducing agent, it was found that primary or secondary amines
were reductively methylated to the corresponding tertiary amine using deca-
borane in the presence of 37% aqueous formaldehyde in methanol at room
temperature (Scheme 1). The reaction condition is mild and the reaction is
efficient.
Scheme 1.
The amount of 37% formaldehyde and decaborane used in the reac-
tion depended on the starting amines. 3 equiv. of formaldehyde and 60 mole
% of decaborane was used for dimethylation of primary amines, and
1.5 equiv. of the formaldehyde and 30 mole % of decaborane was used
for the monomethylation of secondary amines.9 When 37% formaldehyde
was added to the solution of 2-methylindoline in methanol (entry 7), the
conversion of the amine into the intermediate (carbinolamine) was observed
by TLC using a solution of ethyl acetate and hexane (1 : 10). In all the
reactions, decaborane was added after stirring the solution of formaldehyde
and amines in methanol for a while (30 min). Otherwise, the yields were
reduced probably due to the possible competitive reductive etherification
of formaldehyde.10 The yield of the reaction was generally high, but the
yield of the electron sufficient amines is relatively low compared to that of
the other amines due to the adduct formation with decaborane (or its
decomposed stuff) (entries 3, 9, 10). The further studies with other reductive
amination reaction in situ are underway.

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REDUCTIVE METHYLATION
3419
In conclusion, amines (primary and secondary) were reductively
methylated into the corresponding tertiary amines efficiently using 37%
formaldehyde and decaborane in methanol.
EXPERIMENTAL
Silica gel 60 (230–400 mesh, Merck) was used for column chromato-
graphy, and silica gel 60F254 plates (0.25 mm, Merck) were used for TLC.
Melting point was determined using a Electrothermal IA 9100 (15 v,
1
50/60 Hz, 40 W) and are uncorrected. H-NMR spectra were recorded on
a VARIAN at 300 MHz. Elemental analyses were performed on a EAGER
200 analyser. All reagents and substrates were purchased from commercial
sources and used without further purification.
GENERAL PROCEDURE FOR
N-METHYLATION
A representative procedure is as follows (entry 5 of Table 1): A sol-
ution of 2-methylindoline (0.097 ml, 0.751 mmol) and 37% aqueous formal-
dehyde (0.084 ml, 1.126 mmol) in methanol (4 ml) was stirred for 30 min at
room temperature under nitrogen. To the solution was added decaborane
(27.53 mg, 0.225 mmol) and then the resulting solution was stirred at r.t. The
reaction was followed by tlc using a solution of ethyl acetate and hexane
(1 : 10). After 30 min, the reaction mixture was then concentrated under
reduced pressure and chromatographed on silica gel using a solution of
ethyl acetate and hexane (1 : 30) as an eluent to give N-methyl-2-methylindo-
line as a light yellow syrup in quantitative yield.
Methyl 4-(dimethylamino)benzoate (entry 1): yield 94%; white solid
1
110.9 mg (m.p.: 90.4); H-NMR (CDCl3, 300 MHz): d 7.90 (d, J ¼ 7.9 Hz,
2H), 6.65 (d, J ¼ 7.9 Hz, 2H), 3.85 (s, 3H), 3.31 (s, 6H); Anal. Calcd for
C10H13NO2, C, 67.02; H, 7.31; N, 7.82. Found, C, 67.01; H, 7.29; N, 7.83.
N-Methyl-N-isopropyl-(4-nitrophenyl)amine (entry 5): yield 97%;
1
yellow syrup. 105 mg; H-NMR (CDCl3, 300 MHz): d 8.11 (d, J ¼ 9.3 Hz,
2H), 6.67 (d, J ¼ 9.3 Hz, 2H), 4.22 (q, J ¼ 6.4 Hz, 1H), 2.88 (s, 3H), 1.24 (d,
J ¼ 6.4 Hz, 6H); Anal. Calcd for C10H14N2O2, C, 61.84; H, 7.27; N, 14.42.
Found, C, 61.67; H, 7.45; N, 14.59.
Methyl 4-(N-methyl-N-isopropylamino)benzoate (entry 8): yield 94%;
1
colorless oil 104 mg; H-NMR (CDCl3, 300 MHz): d 7.89 (d, J ¼ 7.1 Hz,
2H), 6.70 (d, J ¼ 7.0 Hz, 2H), 4.19 (q, J ¼ 6.6 Hz, 1H), 3.85 (s, 3H), 2.80

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JUNG ET AL.
Table 1. The Reductive Methylation Using Decaborane

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REDUCTIVE METHYLATION
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(s, 3H), 1.19 (d, J ¼ 6.6 Hz, 6H); Anal. Calcd for C12H17NO2, C, 69.54; H,
8.27; N, 6.76. Found, C, 69.33; H, 8.44; N, 6.73.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation Grants
(KRF-99-2000).
REFERENCES
1. Klyuev, M.V.; Khidekel, M.L. Russ. Chem. Rev. (Eng. Transl.) 1980,
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2. Luke, R.W.A.; Boyce, P.G.T.; Dorling, E.K. Tetrahedron Lett. 1996,
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3. Barbry, D.; Torchy, S. Synth. Commun. 1996, 26, 3919.
4. Gribble, G.W.; Nutaitis, C.F. Synthesis 1987, 709.
5. Padmanabhan, S.; Reddy, N.L.; Durant, G. J. Synth. Commun. 1997,
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6. Bhattacharyya, S. Synth. Commun. 1995, 25, 2061.
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9. A little excess amount of formaldehyde (2 equiv.) and decaborane
(40 mole %) in the case of entry 4 compared to that of other secondary
amines (entries 3 and 5–9) was used to complete the reaction.
10. Lee, S.H.; Park, Y.J.; Yoon, C.M. Tetrahedron Lett. 1999, 40, 6049.
Received in Japan October 17, 2000

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