Esterification of carboxylic acids with alcohols by 4-(4,6-dimethoxy- 1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM)

Article abstract of DOI:10.1055/s-1999-2828

Reaction of carboxylic acids with DMTMM in methanol, ethanol, or isopropyl alcohol in the presence of N-methylmorpholine affords the corresponding esters. The esterification can take place with an equimolar alcohol in THF.

Full text of DOI:10.1055/s-1999-2828

LETTER
1255
Esterification of Carboxylic Acids with Alcohols by 4-(4,6-Dimethoxy-
1,3,5-triazin-2-yl)-4-methyl-morpholinium Chloride (DMTMM)
Munetaka Kunishima,a* Jun Morita,a Chiho Kawachi,a Fumiaki Iwasaki,b Keiji Terao,c and Shohei Tania
aFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan
bTokuyama Corp., 40 Wadai, Tsukuba-City, Ibaraki 300-4247, Japan
cWacker Chemicals East Asia Ltd., 2-14-1 Nishi-Waseda, Shinjuku-ku, Tokyo 169-0051, Japan
Fax +81-78-974-5689; E-mail: kunisima@pharm.kobegakuin.ac.jp
Received 7 June 19998
acyloxytriazines (3) faster than carboxylic acids (1), addi-
tion of NMM as a tertiary amine to form an ammonium
carboxylate is essential to the reaction. Thus, the reaction
proceeded with a catalytic amount (0.1 equiv) of NMM in
85% yield whereas only low yield (32%) of the ester was
formed with recovery of 1a (49%) without NMM under
similar conditions (runs 2, 3). The best yield was obtained
by using 2 equiv of DMTMM with 1.2 equiv of NMM
(93%, run 4).4
Abstract: Reaction of carboxylic acids with DMTMM in methanol,
ethanol, or isopropyl alcohol in the presence of N-methylmorpho-
line affords the corresponding esters. The esterification can take
place with an equimolar alcohol in THF.
Key words: esterification, condensation, triazines, carboxylic acids
and derivatives
Although there are a variety of methods available for the
preparation of esters,1 development of a more general,
convenient, and economical approach is still desired. Re-
cently, we have found that 4-(4,6-dimethoxy-1,3,5-triaz-
in-2-yl)-4-methylmorpholinium chloride (DMTMM)
could be quantitatively synthesized from 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT), and was an effective,
new condensing agent for the preparation of amides.2,3
Here, we report the esterification of carboxylic acids with
alcohols by DMTMM.
It is noteworthy that the reaction proceeds in a flask open
to the atmosphere by using commercial MeOH without
drying (run 5). Aliphatic (1a), aromatic (1c, 1f), a,b-unsat-
urated (1b), and a-branched (1d, 1e) carboxylic acids
were found to undergo esterification. Trimethylacetic acid
(1g) was allowed to couple with benzyl alcohol (3 equiv)
in a moderate yield by a stepwise procedure, where an
acid was treated with DMTMM and NMM followed by
addition of an alcohol (run 16). The ethyl esters (2b, 2g)
and the isopropyl ester (2c) were also obtained by under-
taking the reaction in either EtOH (runs 7, 8, 13) or i-
PrOH (run 9) whereas no ester was formed in t-BuOH un-
der similar conditions. The amount of alcohols was al-
lowed to decrease to a stoichiometric amount by using
THF as a solvent (run 11).
N-Methylmorpholine (NMM) was added to a mixture of
3-phenylpropionic acid 1a and DMTMM in dry methanol
at room temperature, followed by stirring for 4 h under ni-
trogen which gave the methyl ester (2a) in 75% yield as
seen in Table 1 (run 1). The reaction is most likely to pro-
ceed by a mechanism illustrated in Scheme 1. Since car-
boxylate anions would attack DMTMM to generate
Table 1. Condensation of carboxylic acids with alcohols by DMTMMa
time yield (%)c
alcoholb
run
carboxylic acid
DMTMM NMM
product
(eq)
(eq)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph(CH2)2COOH (1a)
MeOH (solvent)
MeOH (solvent)
MeOH (solvent)
MeOH (solvent)
MeOH (solvent)d
MeOH (2.0 eq)e
EtOH (solvent)
EtOH (solvent)
i-PrOH (solvent)
MeOH (solvent)
PhCH2OH (1.1 eq)e
MeOH (solvent)
EtOH (solvent)
MeOH (solvent)
MeOH (solvent)
PhCH2OH (3.0 eq)e
1.1
1.2
1.2
2.0
2.0
2.0
1.2
2.0
2.0
2.0
3.0
1.2
2.0
1.2
2.4
3.0
1.1
0.1
0
Ph(CH2)2COOMe (2a)
4 h
5 h
5 h
1.5 h
1.5 h
22 h
4 h
1.5 h
5 h
75
85
32
93
87
67
60
95
72
99
89
94
96
83
64
34
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
1.2
1.2
2.0
0.1
1.2
1.2
1.2
3.0
1.2
1.2
1.2
2.2
3.0
Ph(CH2)2COOEt (2b)
2b
Ph(CH2)2COOPri (2c)
PhCH=CHCOOMe (2d)
PhCH=CHCOOCH2Ph (2e)
p-O2N-C6H4COOMe (2f)
Ph2CHCOOEt (2g)
Boc-Leu-OMe (2h)
p-MeOOCC6H4COOMe (2i)
t-BuCOOCH2Ph (2j)
PhCH=CHCOOH (1b)
1b
p-O2N-C6H4COOH (1c)
Ph2CHCOOH (1d)
Boc-Leu-OH (1e)
2 h
22 h
2.5 h
2 h
5 h
15 p-HOOCC6H4COOH (1f)
16 t-BuCOOH (1g)
4 h
25 hf
a All reactions were conducted at room temperature. b The alcohol was used as a solvent. c Isolated yield. d Reaction
was conducted in commercial MeOH without drying, see text. e Reaction was conducted in THF as a solvent. f After
treatment of the acid with DMTMM and NMM for 1 h, benzyl alcohol was added, and the resulting solution was
stirred for 24 h.
Synlett 1999, No. 8, 1255–1256 ISSN 0936-5214 © Thieme Stuttgart · New York

1256
M. Kunishima et al.
LETTER
MeO
N
Me
N+
N
N
O
Me
H
Cl-
N+
O
MeO
DMTMM
O
O
OMe
N
R2OH
O
O
R1
N
N
O
R1
OR2
R1
O–
R1
OH
2
OMe
1
3
OMe
N
N
N
HO
Me
N
O
OMe
NMM
Scheme 1
(3) Though Kaminski et al. also reported the formation of
DMTMM, its ability as a condensing agent was found to be
poor, probably due to decomposition of DMTMM by
demethylation giving 4-(4,6-dimethoxy-1,3,5-triazin-2-
yl)morpholine either before or during the reaction, see: ref 2,
and Kaminski, Z. J.; Paneth, P.; Rudzinski, J. J. Org. Chem.
1998, 63, 4248.
(4) For a typical procedure: to a solution of 1a (0.20 mmol) and
DMTMM (0.40 mmol) in 1 mL methanol, dried over
molecular sieves overnight, was added NMM (0.24 mmol) at
rt under nitrogen. After stirring for 1.5 h, the solvent was
evaporated, and the residue was extracted with ether.
Purification by preparative TLC (hexane : AcOEt = 2 : 1)
afforded 2a5 (0.186 mmol) in 93%. colorless oil; 1H NMR
(CDCl3) d 2.63, (t, J = 7.9 Hz, 2H), 2.95, (t, J = 7.9 Hz, 2H),
3.66 (s, 3H), 7.17-7.22 (m, 3H), 7.25-7.31 (m, 2H); IR (neat)
3023, 2952, 1737 cm-1 ; MS m/z 164 (M+).
The present method proceeds under weak basic conditions
in inexpensive alcohols and, therefore, appears to be com-
plementary to the acidic Fischer esterification. In addi-
tion, the reaction is technically very easy and simple.
Since DMTMM can be quantitatively prepared from
CDMT that is either commercially available or prepared
from inexpensive cyanuric chloride,6 the present reaction
is economically advantageous.
References and Notes
(1) For reviews on esterification, see: Ogliaruso, M.; Wolfe, J. F.
The Chemistry of Functional Grou; Patai, S., Ed.; Wiley:
Chichester; Suppl. B, Part 1, pp 411. Sutherland, I. O.
Comprehensive Organic Chemistry; Barton, D. H. R.; Ollis,
W. D., Ed.; Pergamon Press: Oxford, 1979; Vol. 2, pp 869.
Sandler, S. R.; Karo, W. Organic Functional Group
Preparations, Wasserman, H. H., Ed.; Academic Press: New
York, 1983; Vol. 1, 2nd ed. pp 288. Mulzer, J. Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 6, pp 323.
(5) Halfpenny, P. R.; Horwell, D. C.; Rees, D. C. Synthesis 1990,
517.
(6) Cronin, J. S.; Ginah, F. O.; Murray, A. R.; Copp, J. D. Synth.
Commun. 1996, 26, 3491.
(2) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Tetrahedron Lett. in press.
Article Identifier:
1437-2096,E;1999,0,08,1255,1256,ftx,en;Y11299ST.pdf
Synlett 1999, No. 8, 1255–1256 ISSN 0936-5214 © Thieme Stuttgart · New York