Synthesis of N-methyl secondary amines

Article abstract of DOI:10.1081/SCC-120018703

A diverse set of N-methyl secondary amines are obtained in high yields by an expedient reductive alkylation of commercially available methanolic methylamine.

Full text of DOI:10.1081/SCC-120018703

This article was downloaded by: [University of Hawaii at Manoa]
On: 21 November 2013, At: 01:12
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of N-Methyl Secondary Amines
Hephzibah J. Kumpaty a , John S. Williamson b & Sukanta Bhattacharyya c
a Department of Chemistry , University of Wisconsin–Whitewater , Wisconsin, USA
b Department of Medicinal Chemistry , School of Pharmacy , The University of Mississippi ,
Mississippi, USA
c Argonaut Technologies , Foster City, California, USA
Published online: 15 Aug 2006.
To cite this article: Hephzibah J. Kumpaty , John S. Williamson & Sukanta Bhattacharyya (2003) Synthesis of N-Methyl
Secondary Amines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:8, 1411-1416, DOI: 10.1081/SCC-120018703
To link to this article: http://dx.doi.org/10.1081/SCC-120018703
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1411–1416, 2003
Synthesis of N-Methyl Secondary Amines
Hephzibah J. Kumpaty,1 John S. Williamson,2 and
Sukanta Bhattacharyya3,
*
1Department of Chemistry, University of
Wisconsin–Whitewater, Wisconsin, USA
2Department of Medicinal Chemistry,
School of Pharmacy, The University of Mississippi,
Mississippi, USA
3Argonaut Technologies, Foster City, California, USA
ABSTRACT
A diverse setof N-methyl secondary amines are obtained in high
yields by an expedient reductive alkylation of commercially available
methanolic methylamine.
Key Words: Reductive alkylation; Methylamine; Titanium(IV)
isopropoxide; Sodium borohydride.
*Correspondence: Sukanta Bhattacharyya, Argonaut Technologies, 1101 Chess
Drive, Foster City, CA 94404, USA; Fax: þ650-655-4329; E-mail:
sbhattacharyya@ argotech.com.
1411
DOI: 10.1081/SCC-120018703
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1412
Kumpaty, Williamson, and Bhattacharyya
Amines and their derivatives are proven synthetic targets because of
their versatile applications.[1] A recentreport [2] claims that about 25% of
the registered drugs are based on amines. In connection with our ongoing
studies[3] on reductive amination reactions,[4] we have earlier described[5]
a method for the preparation of N-methyl secondary amines by reductive
amination of carbonyl compounds using a combination of titanium(IV)
isopropoxide and sodium borohydride. A mixture of methylamine
hydrochloride and triethylamine has been employed as the source of
nucleophilic methylamine. The method conveniently avoids the use of
gaseous methylamine, however, the overall reaction was slow.
As a sequel to this work, we reasoned that a more convenient trans-
formation might be achieved using a commercially available solution of
methylamine in methanol. We report herein the results of this investigation
leading to a rapid, high-yielding protocol for the preparation of N-methyl
secondary amines. The efficacy of the protocol has been evaluated on a
varied set of carbonyl compounds and the results were compared with
our reported[5] data. The starting aldehydes and ketones were reacted
with a commercially available methanol solution of methylamine (2 M)
for 5–6 h in the presence of titanium(IV) isopropoxide, followed by the
addition of solid sodium borohydride. The reaction mixture was allowed
to stir for a further period of 2 h and quenched with water. The reaction is
possibly proceeding through the formation of the titanium(IV) complex 1
(Sch. 1) as an intermediate,[5] which is reduced either directly or via
transient iminium species. Titanium(IV) isopropoxide has been utilized[5,6]
as a mild reagent compatible with a variety of potentially acid-sensitive
functional groups that include acetal, lactam, acetonide and tert-butyl-
dimethylsilyl ether.
The results are collated in the Table 1. The carbonyl substrates used in
this study contained a number of other functional groups such as chloro,
methoxy, cyano, nitro, and urethane. In the case of the N-methylamines
derived from aldehydes, the pure products were isolated by simple diethyl
ether extraction. For the products derived from ketonic substrates,
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of N-Methyl Secondary Amines
1413
Table 1. Synthesis of N-methylamine.
Product aminea
Entry
1
Carbonyl compound
% Yieldb
85
2
3
88
70
4
5
95
82
6
7
85
80
8
9
88
92
90
10
11
92
(continued )

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1414
Kumpaty, Williamson, and Bhattacharyya
Table 1. Continued.
Product aminea
Entry
12
Carbonyl compound
% Yieldb
93
13
14
90
90
15
16
88
92
aThe products were characterized by comparison of their 1H, 13C NMR and
GC-mass spectral data with the reported[5] data.
bYields are of isolated and pure products.
the crude N-methyl amines were extracted with hydrochloric acid (2 M)
to separate the neutral materials. Unlike many reported reductive
amination[4] protocols, the present method works well with enolizable
carbonyl compounds. The neutral nonaqueous reaction conditions,
simple isolation of the products with high yields, and the convenient
use of a commercially available solution of methylamine are the notable
features of the present method. This protocol should provide an
easy access to other amines bearing functionalized motifs due to the
compatibility of titanium(IV) isopropoxide with a variety of acid-sensitive
functional groups.
In summary, an expedient, high throughput access to various
N-methyl secondary amines is reported via reductive amination of
carbonyl compounds with
a commercially available solution of
methylamine in methanol using titanium(IV) isopropoxide and sodium
borohydride.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Synthesis of N-Methyl Secondary Amines
EXPERIMENTAL SECTION
1415
General Procedure for the Reductive Amination of
Aldehydes with Methylamine
Titanium(IV) isopropoxide (2 mL, 6.6 mmol) was added to a com-
mercially available solution of methylamine in methanol (2 M, 7.5 mL)
followed by the addition of the starting aldehyde (5 mmol). The reaction
mixture was stirred at ambient temperature for 5 h, after which sodium
borohydride (0.2 g, 5 mmol) was added and the resulting mixture was
further stirred for another period of 2 h. The reaction was then quenched
by the addition of water (1 mL), the resulting inorganic precipitate was
filtered and washed with diethyl ether (20 mL). The organic layer was
separated and the aqueous part was further extracted with diethyl ether
(20 mL ꢀ 2). The combined ether extracts were dried (K2CO3) and
concentrated in vacuo to give N-methyl secondary amines in high purity.
General Procedure for the Reductive Amination of
Ketones with Methylamine
For the reductive amination of ketones, the same general procedure
was used except that the combined diethyl ether extracts were next
extracted with hydrochloric acid (2 M, 10 mL ꢀ 2) to separate the neutral
materials. The acidic aqueous solution containing the N-methylated
amine hydrochloride saltwas made alkaline (pH ¼ 10) by slow
addition of (10%, w/v) aqueous NaOH and extracted with diethyl
ether (20 mL ꢀ 2). The combined organic extracts were dried (K2CO3)
and concentrated in vacuo to give pure N-methylated alkylamines.
REFERENCES
1. For some leading references, see: Statistical investigation into the
structural complementarity of natural products and synthetic
compounds: Henkel, T.; Brunne, R.M.; Mueller, H.; Reichel, F.
Angew. Chem. Int. Ed. 1999, 38, 643; Main, B.G.; Tucker, H.
Medicinal Chemistry, 2nd Ed.; Genellin, C.R., Roberts, S.M., Ed.;
Academic Press: New York, 1993; p. 187; Kukhar, V.P.; Svistunova,
N. Yu.; Soloshonok, V.A.; Solodenko, V.A. Russ. Chem. Rev. (Engl.
Transl.) 1993, 62, 284; Kirschbaum, J. Analytical Profiles of

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1416
Kumpaty, Williamson, and Bhattacharyya
Drug Substances; Florey, K., Ed.; Academic Press: New York, 1983;
Vol. 12, p. 1.
2. Brown, A.R.; Rees, D.C.; Rankovic, Z.; Morphy, J.R. J. Am. Chem.
Soc. 1997, 119, 3288; see Ref. 10 cited therein.
3. For example, see: Bhattacharyya, S. Tetrahedron Lett. 1994, 35, 2401;
Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928; Bhattacharyya, S.;
Neidigh, K.A.; Avery, M.A.; Williamson, J.S. Synlett 1999, 1781.
4. For some recent reviews on reductive aminations see: (a) Whitesell,
J.K. Comprehensive Organic Synthesis; Trost, B.M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 6, p.724; (b) Hutchins, R.O.;
Hutchins, M.K. Comprehensive Organic Synthesis; Trost, B.M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, p. 25; (c)
Gribble, G.W. Reductions in Organic Synthesis; Abdel-Majid, A.F.,
Ed.; ACS Symposium Series 641, American Chemical Society:
Washington, DC, 1996; p. 167; (d) Abdel-Majid, A.F. Reductions in
Organic Synthesis; ACS Symposium Series 641, American Chemical
Society: Washington, DC, 1996; p. 201.
5. Neidigh, K.A.; Avery, M.A.; Williamson, J.S.; Bhattacharyya, S.J.
Chem. Soc. Perkin Trans. 1 1998, 2527.
6. Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zueger, M. Synthesis 1982, 138.
Received in the Netherlands June 15, 2002