2-Acyloxy-4,6-dimethoxy-1,3,5-triazine - A new reagent for ester synthesis

Article abstract of DOI:10.1055/s-1999-3448

2-Acyloxy-4,6-dimethoxy-1,3,5-triazines obtained in reaction between carboxylic acid and 2-chloro-4,6-dimethoxy-1,3,5-triazine were used as acylating agents for the synthesis of esters from primary, secondary, and tertiary alcohols. Because of mild acylation conditions the method could be applied to esterification of labile alcohols with aromatic and aliphatic (also α-branched) acids in good yields.

Full text of DOI:10.1055/s-1999-3448

PAPER
593
2-Acyloxy-4,6-dimethoxy-1,3,5-triazine – A New Reagent for Ester Synthesis
Janina E. KamiÒska,* Zbigniew J. KamiÒski, Józef Góra
Institute of General Food Chemistry, Technical University of £ódü, ul. Stefanowskiego 4/10, 90-924 £ódü, Poland
Fax +48(42)6362860; Email:jekamins@snack.p.lodz.pl
Institute of Organic Chemistry, Technical University of £ódü, ul. Øwirki 36, 90-924 £ódü, Poland
Received 2 October 1998
cording to KamiÒski's procedure.6 Preliminary alcoholy-
Abstract: 2-Acyloxy-4,6-dimethoxy-1,3,5-triazines obtained in re-
ses were performed on 2-benzoyloxy-4,6-dimethoxy-
1,3,5-triazine in solution of the appropriate alcohol (pro-
panol, isopropanol, tert-butanol) at room temperature
action between carboxylic acid and 2-chloro-4,6-dimethoxy-1,3,5-
triazine were used as acylating agents for the synthesis of esters
from primary, secondary, and tertiary alcohols. Because of mild
acylation conditions the method could be applied to esterification of (Method A). We have found that even without transester-
labile alcohols with aromatic and aliphatic (also a-branched) ac-
ification catalysts, primary and secondary alcohols were
acylated at acceptable rates (2–4 days), while tertiary al-
cohols require longer reaction time or higher temperature.
Searching for catalysts able to increase the rate of alcohol-
ysis of 2-acyloxy-4,6-dimethoxy-1,3,5-triazines we have
tested acids, bases, amines, metal alkoxides, transition
metal salts, organotin compounds and others.7 All com-
pounds tested were added at a quantity of 5 mol% of acy-
loxytriazine. Progress of alcoholysis of 2-benzoyloxy-
4,6-dimethoxy-1,3,5-triazine with cyclohexanol was
monitored by GC and compared to esterification without
catalyst. As the most efficient catalyst we found magne-
sium bromide and 4-(N,N-dimethylamino)pyridine, fre-
quently used as the esterification catalyst. The increase in
the rate of acylation in the presence of magnesium
bromide (5 mol%) was sufficient to substantially reduce
the excess of alcohol used (important when alcohol is not
easily available). Following the general procedure (Meth-
od A or C) we have obtained benzoates 2a–i, 2-ethylhex-
anoates 2j–m, and trimethylacetate 2n in 44–92% yield
(see Table). Esters were purified by distillation or column
chromatography. Purity was checked by GC and identity
confirmed by comparison of physical parameters for
known compounds with literature data and inspecting H
NMR spectra.
ids in good yields.
Key words: transesterification, alcoholysis, catalyst, magnesium
bromide
Although numerous general methods of ester formation
are well known, there are still cases when results achieved
in these ways are not satisfactory. In recent years much at-
tention has been paid to syntheses based on transesterifi-
cations,1 and the best results are usually obtained when the
reaction is irreversible. This is the case when vinyl esters
act as acylating agents, because the vinyl alcohol formed
is rapidly converted into the more stable keto tautomer,
shifting the transesterification equilibrium in the desired
direction. Especially difficult is the esterification of alco-
hols and/or acids, which are labile in acidic or basic medi-
um (allyl or tertiary alcohols, sterically hindered a-
substituted acids, and substrates containing other func-
tional groups too sensitive to stand conditions employed
in typical esterification procedures). Therefore we decid-
ed to check the possibility of application of 2-acyloxy-
4,6-dimethoxy-1,3,5-triazines as acyl donors in ester bond
formation as an alternative to classic esterification meth-
ods.
2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) reacts
under mild conditions with carboxylic acids yielding so
called ”superactive esters”.2 Aminolysis of these esters is
a very efficient method for amide bond formation.3,4 Pre-
sumably, during aminolysis of 2-acyloxy-4,6-dimethoxy-
1,3,5-triazine, the driving force of the reaction is the tau-
tomerization of 2-hydroxy-4,6-dimethoxy-1,3,5-triazine
formed as a temporary intermediate, into more stable keto
form.5 Although acylating ability of acyloxytriazines in
amide bond formation is already recognized, their poten-
tial in the esterification reaction remains unexplored.
Herein we report results of our study on alcoholysis of 2-
benzoyloxy-, 2-(2-ethylhexanoyloxy)- and 2-trimethylac-
etoxy-4,6-dimethoxy-1,3,5-triazine with variety of alco-
hols.
R = Ph, 3-heptyl, t-Bu; R′OH see Table
Scheme
All triazinyl esters were obtained from the corresponding
acids (benzoic, 2-ethylhexanoic, and trimethylacetic) ac-
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594
J. E. KamiÒska et al.
PAPER
Table Synthesis of Esters by Alcoholysis of 2-Acyloxy-4,6-dimethoxy-1,3,5-triazines
20
R
R′OH
Method/
Cat.
Time
Yielda
Bp
(°C/Torr)
nD
Lit. bp or
mp, nD20 or
[a]D
1H NMR, (CDCl3)
d, (ppm), J (Hz)
2
a
or [a]D
[d]
2
[%]
84
Ph
PrOH
A/MgBr2
A/MgBr2
A/MgBr2
96–8/8
1.5006
1.4995
1.4958
113/148
1.50039
0.92 (t, 3H, J 7.5), 1.68
(sextet, 2H, J 7.5), 4.18
(t, 2H, J 7.5), 7.33
(m, 2H), 7.42 (m, 1H),
7.95 (m, 2H)
b
c
Ph
Ph
BuOH
2
3
92
85
108–10/8
105–8/8
108/1010
1.497511
0.88 (t, 3H, J 7.25), 1.37
(m, 2H), 1.65 (m, 2H),
4.23, (t, 2H, J 6.5), 7.32
(m, 2H), 7.41 (m, 1H),
7.93 (m, 2H)
iBuOH
109/811
1.02 (d, 6H, J 6.75), 2.08
(septet, 1H, J 6.75), 4.10
(d, 2H, J 6.75), 7.43
(m, 2H), 7.53 (m, 1H),
8.05 (m, 2H)
1.491812
d
e
Ph
Ph
iPrOH
A/MgBr2
A/MgBr2
4
4
82
62
1.4970
1.4959
1.494813
1.26 (d, 6H, J 6.25), 5.16
(septet, 1H, J 6.25), 7.31
(m, 2H), 7.43 (m, 1H),
7.94 (m, 2H)
sBuOH
100–3/8
114–7/2014
1.494815
0.97 (t, 3H, J 7.25), 1.33
(d, 3H, J 6.25), 1.72
(m, 2H), 5.09 (sextet, 1H,
J 6.25), 7.44 (m, 2H), 7.52
(m, 1H), 8.04 (m, 2H)
f
Ph
C/MgBr2
5
85
1.4961
1.5215
1.4887
0.98, 1.08 (2d, 6H, J 6.8),
1.29 (d, 3H, J 6.8), 1.94
(octet, 1H, J 6.8), 5.0
(quintet, 1H, J 6.8), 7.46
(m, 2H), 7.54 (m, 1H),
8.05 (m, 2H)
(25°C)20
g
Ph
Ph
A/DMAP
B/MgBr2
C/MgBr2
1
64
43
52
146–8/8
144/810
1.23–1.62 (m, 6H), 1.77
(m, 2H), 1.92 (m, 2H),
5.03 (m, 1H), 7.41
(m,2H), 7.51 (m, 1H),
8.06 (m, 2H)
1.522310
11
8
21
h
C/MgBr2
10
56
mp 54–55
[a]D
[a]D20 –90.6
(0.953,
0.80 (d, 3H, J 6.75), 0.91
(d, 3H, J 7.0), 0.94 (d, 3H,
J 6.5), 1.12 (m, 3H), 1.56
(m, 2H), 1.73 (m, 2H),
1.96, 1.98 (d septet, 1H,
J 7.0), 2.13 (m, 1H), 4.93,
4.95 (dt, 1H, J 11), 7.44
(m, 2H), 7.54 (m, 1H),
8.06 (m, 2H)
–94.2
(1.19,
C6H6)
C6H6)16
mp 5517
i
Ph
C/MgBr2
B/MgBr2
6
6
44
24
124–6/1.4
102–4/1.2
1.5332
1.4551
1.70 (d, 3H, J 6.75), 6.22
(q, 1H, J 6.75), 6.35
(m, 2H), 7.35–7.50
(m, 4H), 8.02 (m, 2H)
j
3-heptyl
B/MgBr2
6
41
0.81–0.90 (2t, 6H), 1.20–
1.30 (m, 4H), 1.48–1.60
(m, 4H), 1.57 (d, 3H,
J 6.75), 2.24 (m, 1H), 6.0
(q, 1H, J 6.75), 6.31
(m, 2H), 7.36 (s,1H)
Synthesis 1999, No. 4, 593–596 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2-Acyloxy-4,6-dimethoxy-1,3,5-triazine
595
Table (continued)
20
R
R′OH
Method/
Cat.
Time
Yielda
Bp
(°C/Torr)
nD
Lit. bp or
mp, nD20 or
[a]D
1H NMR, (CDCl3)
d, (ppm), J (Hz)
2
or [a]D
[d]
11
[%]
69
k
3-heptyl-
C/MgBr2
98–100/
1.5
1.4492
0.86–0.92 (2t, 6H, J 6.8),
1.26–1.80 (m, 18H), 2.20
(m, 1H), 4.75–4.83 (m, 1H)
i
3-heptyl-
iPrOH
C/MgBr2
4
73
88–90/19
1.4140
0.89 (2t, 6H, J 7.5), 1.24
(d, 6H, J 6), 1.22–1.29
(m, 4H), 1.48–1.61 (m, 4H),
2.20 (m, 1H), 5.03 (septet,
1H, J 6)
m
n
3-heptyl
tBuOH
C/MgBr2
C/none
5
1
46
60
1.4170
1.4417
[a]D
–75.3
(2.49,
MeOH)
0.89 (2t, 6H, J 7.5), 1.20–
1.37 (m, 4H), 1.37–1.70
(m, 4H), 1.45 (s, 9H), 2.13
(m, 1H)
tBu
126–8/17
124.5/
0.75 (d, 3H, J 7), 0.85–0.91
(m, 8H), 1.19 (s, 9H), 1.20–
1.55 (m,3H), 1.60–1.75
(m, 2H), 1.80–2.01 (m, 2H),
4.63 (double t, 1H, J 10,J 5)
13.518
20
1.441
(25°C)19
[a]D25 –83.1
(MeOH)19
a
isolated yields of pure products
Although treatment of carboxylic acids with CDMT in the The advantage of our method is also the convenient and
presence of N-methylmorpholine usually give high yield efficient means for the purification of esters due to weak
of numerous acyloxytriazines, it is always advantageous basicity of 1,3,5-triazine ring which simplifies the remov-
to avoid purification and handling these highly reactive al of co-product 3 simply by washing with acid solution.
derivatives 1. Therefore, as proof of preparative utility of Hence in some cases it is possible to obtain esters of ana-
our method, esters 2f–i, and 2k–n were synthesized start- lytical purity (>98% by GC).
ing from corresponding carboxylic acids in a two-step
procedure using crude triazinyl ester followed by immedi-
ate treatment with alcohol (Method C). We found crucial
to wash out thoroughly the side products from the crude
Melting points were measured on a Buchi capillary melting point
apparatus and are uncorrected. Optical rotation was measured on
Rudolph Autopol IV apparatus in 1 dm cell. Proton NMR spectra
triazine ester, because alcoholysis carried out directly in
the mixture obtained during activation procedure was
slower, and hence the yields of esters went down (proba-
bly due to catalyst deactivation by the excess of N-meth-
ylmorpholine hydrochloride). Thus, the more convenient
two-step ”one pot” procedure without isolation of acylox-
ytriazine 1 (Method B), following standard workup and
distillation or flash chromatography, gave esters 2g, 2i,
and 2j in moderate overall yield (24–43%).
were run on Bruker 250 MHz in CDCl3 using the residual solvent
signal as the internal standard. All chemicals were reagent grade
and were used without additional purification. Benzoic acid and
CH2Cl2 were purchased from POCH-Gliwice, 2-ethylhexanoic acid
and N-methylmorpholine from Fluka, anhyd magnesium bromide,
4-(N,N-dimethylamino)pyridine and 2-acetylfuran from Aldrich. 1-
(2-Furyl)ethanol was obtained from 2-acetylfuran by reduction with
NaBH4 in MeOH at 0–5 °C. Kieselgel 60H (Merck) was used for
flash chromatography and mixture of hexane and acetone in various
proportions as eluent. TLC was performed on precoated silica gel
plates (Merck) which were visualized with UV light or I2 vapors.
In conclusion we established that carboxylic acids activat-
ed by 2-chloro-4,6-dimethoxy-1,3,5-triazine acylate pri-
mary, secondary, and tertiary alcohols. Acylation
proceeds under mild reaction conditions, so the method is
found to be useful for synthesis of esters of alcohols labile
in acidic medium or at elevated temperature (1-(2-fur-
yl)ethanol), as well as for esterification of a-branched car-
boxylic acids (2-ethylhexanoic, trimethylacetic acid). The
general procedure C allows ester synthesis directly from
appropriate carboxylic acid via crude triazinyl ester 1.
Butyl Benzoate (2b); Typical Procedure
Alcoholysis of Acyloxytriazines (Method A)
To a solution of 2-benzoyloxy-4,6-dimethoxy-1,3,5-triazine (1.3 g,
5 mmol) in CH2Cl2 (10 mL), butanol (3.7 g, 50 mmol) and MgBr2
(0.1 g, 0.5 mmol) were added at r.t. Progress of transesterification
was followed by TLC. When the spot of benzoyloxytriazine disap-
peared, the mixture was diluted with CH2Cl2 (50 mL) and washed
succesively with sat. NaHSO4 (2 x 30 mL), NaHCO3 (3 x 30 mL)
and H2O (1 x 50 mL). Extract was dried (MgSO4) and solvent evap-
orated. Residue was distilled under reduced pressure (bp 108–110/
8 Torr) yielding pure butyl benzoate (0.761 g, 92%).
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Two-Step Synthesis of Esters 2f–n; Typical Procedure
1-(2-Furyl)ethyl 2-Ethylhexanoate (2j) (Method B)
Acknowledgement
Research was financially supported by Komitet BadaÒ Naukowych,
Grant 3 T09A 067 08.
To a stirred solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (7.2
g, 50 mmol) in CH2Cl2 (70 mL) cooled to 0 °C, N-methylmorpho-
line (5.8 mL, 52 mmol) was added dropwise, followed by 2-ethyl-
hexanoic acid (7.2 g, 50 mmol) dissolved in CH2Cl2 (30 mL). After
2 h stirring at 0–5 °C, 1-(2-furyl)ethanol (22.4 g, 200 mmol) and
MgBr2 (0.5 g, 2.5 mmol) were added. The mixture was left at r.t. Af-
ter 6 days (the spot of 2-ethylhexanoyloxytriazine disappeared on
TLC) the mixture was washed successively with NaHSO4 (2 x 100
mL), NaHCO3 (2 x 100 mL), H2O (100 mL) and dried (MgSO4). Af-
ter solvent evaporation the residue was distilled under reduced pres-
sure yielding 1-(2-furyl)ethyl 2-ethylhexanoate (4.9 g, 41%), bp
102–104 °C/ 1.2 Torr.
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distilled under reduced pressure (bp 88–90 °C/19 Torr) yielding 6.8
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Synthesis 1999, No. 4, 593–596 ISSN 0039-7881 © Thieme Stuttgart · New York