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Synthetic Communications: AnInternational Journal for RapidCommunication of SyntheticOrganic ChemistryPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/lsyc20

A High Throughput Synthesis ofN,N-Dimethyl Tertiary AminesSukanta Bhattacharyya a ba Department of Chemistry , The University ofMississippi , MS , 38677b Argonaut Technologies , 887 Industrial Road, SuiteG, San Carlos , CA , 94070Published online: 04 Dec 2007.

To cite this article: Sukanta Bhattacharyya (2000) A High Throughput Synthesis ofN,N-Dimethyl Tertiary Amines, Synthetic Communications: An International Journalfor Rapid Communication of Synthetic Organic Chemistry, 30:11, 2001-2008, DOI:10.1080/00397910008087249

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SYNTHETIC COMMUNICATIONS, 30(1 I), 2001-2008 (2000)

A HIGH THROUGHPUT SYNTHESIS OF N,N- DIMETHYL TERTIARY AMINES

Sukanta Bhattacharyya*

Department of Chemistry, The University of Mississippi, MS 38677

ABSTRACT: N,N-dimethyl tertiary amines are obtained in high yields by titanium(IV) isopropoxide mediated reductive amination of carbonyl compounds with a commercially available methanol solution of dimethylamine.

The tertiary amines are important synthetic targets because of their versatile utility as medicinal agents and agrochemicals. A recent report' claims about 25% of the registered drugs contain a tertiary amine functionality. The noteworthy applications of N,N-dimethyl tertiary amines include: as ligands2 in catalytic asymmetric transformations; as modifiers' for reversed phase chromatography and as buffers4 in sequential analysis of proteins and peptides. The methods described' for the synthesis of N,Ndimethyl tertiary amines mostly involve a large excess of gaseous dimethylamine at elevated temperatures and pressures. These protocols suffer from major limitations such as low product yields and formation of quaternary salts. Moreover, secondary alkylating agents cannot be used due to the preponderant elimination reactions and many of these methods are covered as patents.6

'Currenf Address : Argonaut Technologies, 887 Industrial Road, Suite G, San Carlos, CA 94070

200 1

Copyright 0 2000 by Marcel Dekker, Inc. www.dekker.com

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The reductive amination of carbonyl compounds that allows a rapid access to

diversity mines is one of the widely used reactions in synthetic organic

~hemistry.~ The synthetic protocol involves the formation of an imine or iminium

intermediate upon exposure of a carbonyl compound to a primary or secondary

amine followed by in situ reduction to an alkylated amine. In connection with our

ongoing studies on reductive amination reactions, we have recently described' a

method for the preparation of N,N-dimethyl tertiary amines by reductive

amination of carbonyl compounds using a combination of titanium(1V)

isopropoxide and sodium borohydride. A mixture of dimethylamine hydrochloride

and triethylamine has been employed as the source of nucleophilic dimethylamine.

Though the method conveniently avoids the use of gaseous dimethylmine, the

reactions were slow, the overall reaction time being 19-20 h.

0

1 NaBH, , rA., 1.5 h H,C,NMe2

R,' 'R2

Scheme 1

As a sequel to this work, we reasoned that a more convenient, fast transformation

may be achieved using a commercially available solution of dimethylamine in

methanol. Indeed, this has been the case. Herein, the results of this investigation

leading to a rapid, high-yielding protocol for the preparation of N,N-dimethyl

tertiary amines are reported.

The relevance of this protocol has been evaluated on a structurally varied set of

carbonyl compounds. The aldehydes and the ketones were reacted with a

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N,N-DIMETHYL TERTIARY AMINES 2003

commercially available methanol solution of dimethylamine (2 M) for 4-5 h in the

presence of titanium(1V) isopropoxide. The reaction mixture was then treated with

sodium borohydride, stirred for 1.5 h and quenched with water. The reaction is

possibly proceeding through the formation of

dimethylaminocarbinolatotitanium(1v) complex 1 (scheme 1) as an intermediate,*

which is reduced either directly or via transient iminium species. Titanium(1V)

isopropoxide has been as a mild reagent compatible with a vareity of

potentially acid-sensitive functional groups such as acetals, lactams, acetonide and

tert-butyldimethylsilyl ethers.

The results obtained for a representative group of carbonyl compounds are

summarized in the Table 1. In case of the amines derived fiom aldehydes, the pure

products were isolated by simple diethyl ether extraction. For the products derived

fiom ketonic substrates; the crude N,N-dimethyl amines were extracted with

hydrochloric acid (2 M) to separate the neutral materials. In contrast to the existing

acid mediated reductive amination' protocols, the present method also works well

with enolizable carbonyl compounds. The reaction conditions were found to be

tolerant to a number of functional groups such as chloro, methoxy, cyano, nitro,

and urethane. The notable advantages of the present method include: the neutral

non-aqueous reaction conditions, simple work-up, no chromatograhic separation,

high-yielding transformations and the use of relatively safe and inexpensive

reagents with no special handling techniques. Moreover, because of the

compatibility of titanium(1V) isopropoxide with a variety of acid-sensitive

functional groups including acetonide, tert-butyldimethylsilyl ether and acetals this

method can provide an easy access to analogous tertiary amines bearing

hctionalized motifs.

In summary, an expedient, high throughput access to various N,N-dimethyl

tertiary amines is reported via reductive amination of carbonyl compounds with a

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Table 1. Preparation of N,N-Dimethyl Tertiary Amines from Aldehydes and Ketones

Entry Substrate Product Amine' Yieldb bp "Cil'orr (%) or mp "CIUt]

1

2

3

4

5

6

7

8

9

10

11

12

13

14

PhCHO

o-CICmCHO

pBrC&CHO

pNCCmCHO

m - MeOC& CH 0 p-02NCmCHO

PhCH2CHO

PhCH2CH2CHO

Me(CH2)gCHO

PhCOMe

oo EtoOCN>O

90

94

96

95

95

95

92

90

88

80

l82/760[ 185/760]"

200-202c[203]12

206-208d[209]"

253-254d[255]'3

103/10[105/13]14

176- 1 78d[ 1781"

2 12/760[2 15/760]' I

l7?[ 178- 1801"

l48/760[ 150/760]15

140" 138- 139]l6

85 156/760[159/760]17

87 130/760[133/760]'8

79 185" 186-187]16

78 g

a All products were routinely characterized by their IR, IH NMR and physical constant data and comparison with the data reported in the literature or authentic compounh. bYields are of isolated and purified products. HCl salt. HBr salt. Methiodide derivative. Picrate. Anal Calcd. for Cl&&02: C 59.95, H 10.06, N 13.99; Found: C 59.84, H 10.12. N 13.69.

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N,N-DIMETHYL TERTIARY MINES 2005

commercially available solution of dimethylamine in methanol using titanium(1V)

isopropoxide and sodium borohydride. Further studies towards adaptation of this

protocol to parallel synthesis of diversity amines are currently underway.

Experimental Section

General Procedure for the Reductive Amination of Aldehydes with

Dimethylamine:

Titanium(1V) isopropoxide (3 mL, 10 mmol) was added dropwise to a

commercially available solution of dimethylamine in methanol (2 M, 10 mL)

followed by the addition of the starting aldehyde (5 mmol). The reaction mixture

was stirred at ambient temperature for 4-5 h, after which sodium borohydride

(0.19g, 5 mmol) was added and the resulting mixture was further stirred for

another period of 1.5 h. The reaction was then quenched by the addition of water

(1 mL), the resulting inorganic precipitate was filtered, washed with diethyl ether

(20 mL) and the aqueous filtrate was extracted with diethyl ether (20 mL x 2). The

combined ether extracts were dried (K2CO3) and concentrated in vucuo to give

N,N-dimethyl tertiary mines in high purity.

General Procedure for the Reductive Amination of Ketones with

Dimethylamine:

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 x 2) to separate the neutral materials. The acidic

aqueous solution containing the mine hydrochloride salt was made alkaline

(pH-10) by slow addition of (lo%, w/v) aqueous NaOH and extracted with diethyl

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ether (20 mL x 2). The combined organic extracts were dried (K2CO3) and

concentrated in vumo to give pure N,Ndimethylated alkylamines.

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