Development of a simple system for dehydrocondensation using solid-phase adsorption of a water-soluble dehydrocondensing reagent (DMT-MM)

Article abstract of DOI:10.1248/cpb.52.1223

It has been indicated that hydrophilic solid powder to which aqueous solution of a novel dehydrocondensing reagent DMT-MM is adsorbed becomes a simple solid-phase dehydrocondensing reagent of low cost. Reaction in a liquid-liquid biphasic system on the surface of a solid phase with a large area was accelerated by suspending this powder in a dichloromethane solution of a carboxylic acid and an amine to be condensed. The reaction was rapid with a high yield despite the heterogeneity of the system. Like general solid-phase reagents, a hydrophobic carboxamide alone could be isolated at a relatively high purity only by filtration of the resulting suspension of reaction mixture.

Full text of DOI:10.1248/cpb.52.1223

October 2004
Chem. Pharm. Bull. 52(10) 1223—1226 (2004)
1223
Development of a Simple System for Dehydrocondensation Using
Solid-Phase Adsorption of a Water-Soluble Dehydrocondensing Reagent
(DMT-MM)
Yasunobu WATANABE,a Takako FUJI,a Kazuhito HIOKI,a,b Shohei TANI,a,b and
Munetaka KUNISHIMA*,a,b,c
a Faculty of Pharmaceutical Sciences, Kobe Gakuin University; b High Technology Research Center, Kobe Gakuin
University; and c PRESTO, JST; Nishi-ku, Kobe 651–2180, Japan.
Received June 29, 2004; accepted August 3, 2004; published online August 11, 2004
It has been indicated that hydrophilic solid powder to which aqueous solution of a novel dehydrocondensing
reagent DMT-MM is adsorbed becomes a simple solid-phase dehydrocondensing reagent of low cost. Reaction in
a liquid–liquid biphasic system on the surface of a solid phase with a large area was accelerated by suspending
this powder in a dichloromethane solution of a carboxylic acid and an amine to be condensed. The reaction was
rapid with a high yield despite the heterogeneity of the system. Like general solid-phase reagents, a hydrophobic
carboxamide alone could be isolated at a relatively high purity only by filtration of the resulting suspension of re-
action mixture.
Key words carboxamide; heterogeneous system; condensing agent; solid-supported reagent
A novel triazine type dehydrocondensing reagent, 4-(4,6- but actually, it is a liquid–liquid biphasic system on the sur-
dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo- face of the solid phase. Since the interface area should be
ride (DMT-MM), developed in our laboratory is a quaternary equivalent to the surface area of the solid phase, the contact
ammonium compound with 1,3,5-triazino residue bound to area of the two phases is markedly larger than that in simple
4-methylmorpholine.1) This compound dissolves very well in liquid–liquid biphasic systems, suggesting that the reaction
water and alcohol, but is almost insoluble in general aprotic between DMT–MM in the aqueous phase and carboxylic
organic solvents.2) It is characteristic of DMT-MM to synthe- acid in the organic phase proceeds rapidly. Since HO-DMT
size carboxamides at high yields only by addition of it to and methylmorpholine hydrochloride generated by the reac-
mixtures of carboxylic acids and amines. The reaction pro- tion should remain in the aqueous phase adsorbed to the
ceeds not only in general neutral aprotic solvents but also in solid phase, hydrophobic carboxamides alone may be ob-
protic solvents, such as water and alcohol, independent of the tained by filtration of the suspension followed by rinsing the
solubility of DMT-MM.3) Automation and simplification of solid with an organic solvent (Fig. 1).
the dehydrocondensation for combinatorial synthesis is
We performed a dehydrocondensation of 3-phenylpropi-
expected because of the simple and efficient reaction charac- onic acid and benzylamine. The solid-phase material we
teristics of DMT-MM, for which it is most common to obtain employed was Extrelut®, which is often used for extraction.
insolubility by binding the basic structure of DMT-MM to Extrelut®, with high water retentivity, is widely used as a
solid-phase carriers.4) However, in general, there are prob- liquid–liquid extraction column filler,10—12) and has been
lems in the synthesis of polymer-support reagent, such as reported to be used for organic chemical reaction in
reduction of the reaction efficiency and increases in cost and columns.13,14) Dichloromethane solution of the carboxylic
waste.5,6) Since the dehydrocondensation using a solid-sup- acid and amine was added to the solid phase adsorbed with
port reagent must be carried out in heterogeneous systems an aqueous solution of two equivalents of DMT-MM, and a
with the solid and liquid phases,7) reduction of the reaction reaction was performed at room temperature by standing
rate is also a problem. We developed a simple, efficient, and after 5 min of stirring. The reaction suspension was filtered
economic method using monomeric DMT-MM, which solved with suction, and the solid material was washed with
the problems of solid-phase reagents.
dichloromethane. The yield of carboxamides was 91% and
The major compounds generated by synthesis of carbox- 100% with a reaction at room temperature for 10 min and
amides using DMT-MM are the target compounds, 2-hy- 30 min, respectively, indicating that the reaction was suffi-
droxy-4,6-dimethoxy-1,3,5-triazine (HO-DMT),8) and meth- ciently rapid compared to that in the simple homogeneous
ylmorpholine hydrochloride derived from the condensing system with methanol (Table 1, runs 1, 2, 6). As the control,
reagent. Since the latter two compounds are water-soluble,
they can be separated from the hydrophobic carboxamides by
extraction. Based on the solubility of DMT-MM in water and
organic solvents described above, we examined the reaction
in the heterogeneous system with a suspension of solid-phase
carriers adsorbed with an aqueous solution of DMT-MM in
an organic solvent that is immiscible with water. Carboxylic
acids and amines as the reaction substrates were dissolved in
the organic solvent, and then mixed with the solid phase. The
Fig. 1. Dehydrocondensation by DMT-MM in a Liquid–Liquid Biphasic
reaction system is apparently a solid–liquid biphasic system, System on a Solid Surface
* To whom correspondence should be addressed. e-mail: kunisima@pharm.kobegakuin.ac.jp
© 2004 Pharmaceutical Society of Japan

1224
Vol. 52, No. 10
an amidation was performed in
a
simple water– tion of carboxylic acids and amine-conjugated acids as the
dichloromethane biphasic system without the solid phase by substrates was suppressed, and both the rate of addition of
the same procedures, and the yield at room temperature for carboxylic acid to DMT-MM and the rate of aminolysis of
30 min was markedly low (61%) (run 3). These results indi- activated ester intermediates were reduced, resulting in the
cated that the reaction was accelerated by adsorption of the reduction of the yield. However, since the yield remained at
aqueous phase to the solid phase. In the system without the 39% with silica gel 60N even when using Et3N/hydrochlo-
solid phase, the yield was 76% with dichloromethane alone ride buffer at pH 9, it was suggested that the nature of solid-
and 31% with water alone. This may be because DMT-MM is phase materials are also an important factor, though the
only sparsely soluble in dichloromethane and because self- details are unknown.
decomposition of DMT-MM occurs by an intramolecular
Based on these results, syntheses of other hydrophobic
nucleophilic demethylation caused by chlorine ions.2) In carboxamides were examined. As shown in Table 3, an aque-
water, since 3-phenylpropionic acid as the substrate is hardly ous solution of 1.1 eq of DMT-MM was adsorbed to Alumina
soluble, the reaction at room temperature for 30 min may B, and a reaction was performed in dichloromethane. After
have been insufficient (runs 4, 5).
addition of ether to the reaction mixture, filtration, and rins-
Experiments were performed with solid powder materi- ing of the solid substances with ether were performed, and
als15) shown in Table 2 by the same procedures. To evaluate the mixture of the filtrate and rinsing solution was con-
the characteristics of these solid phases accurately, 1.1 eq of densed, providing carboxamides with a sufficiently high
DMT-MM was used. The reaction with Alumina N or Celite®
Table 1. Reaction Acceleration in a Liquid–Liquid Biphasic System on
proceeded almost quantitatively at room temperature for
30 min. The yield by the reaction with diatomaceous earth
the Surface of Extrelut®
was 90%, while that with silica gel 60N was very low (35%).
The relationship between the yield and specific surface
area S (m2/g) was examined for each solid phase. The reac-
tions with Celite®, of the smallest specific surface area of
Run
Solvent
Time
Solid phase
Yield (%)a)
0.93 m2/g, and with Alumina N, of a more than 200-fold
larger specific surface area than that of Celite®, proceeded
quantitatively, while the yield with silica gel 60N, of the
largest specific surface area of 650ꢀ50 m2/g, was lowest,
indicating that there was no correlation between the specific
surface area and yield. However, the results shown in Table 1
demonstrated that the solid-phase carriers were clearly effec-
tive, indicating that solid substances with a specific surface
area of at least 1 m2/g have sufficient acceleration effects.
Since there was no correlation between the specific surface
area and the yield, the relationship between the yield and pH
of the solid phases was examined. Silica gel was weakly
acidic, and the remaining solid phases were weakly basic. To
evaluate the effects of pH, experiments using Alumina A (pH
4.5) and Alumina B (pH 10) with the same specific surface
area were performed using the same procedures, and the
yield was 78% and 99%, respectively. The yield by the reac-
tion with Extrelut® in phosphate buffer at pH 5, even when
performed with two equivalents of DMT-MM, was reduced
to 79%, showing that the yield was reduced at an acidic pH
as predicted. The correlation between pH and the yield
agreed well with the acidification of the solution by genera-
tion of morpholine hydrochloride as the dehydrocondensa-
1
2
3
4
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2
H2O
MeOH
10 min
30 min
30 min
30 min
30 min
3 h
Extrelut®
Extrelut®
none
none
none
91
100
61
76
31
5
6b)
none
96
a) Determined by GC. b) Data cited from ref. 3.
Table 2. Relationship of the Yield of Dehydrocondensation on a Solid
Surface to Specific Surface Area and pH of the Solid
Specific surface area S
Solid phase
Extrelut®
Diatomaceous Earth
Molecular Sieves 3A, Powder
Molecular Sieves 4A, Powder
Alumina A
Yield (%)
pH
10a)
(m2/g)
88
90
83
86
78
99
99
98
35
43d)
1.18a)
1.54b)
2.02b)
—
10.11c)
11.93c)
12.19c)
4.5a)
200a)
200a)
200a)
0.93b)
650a)
650a)
Alumina N
7.5a)
Alumina B
10a)
Celite®
9.43c)
6.37c)
6.37c)
Silica Gel 60N
Silica Gel 60N
a) The value described in the catalog. b) Measured by BET method. c) The pH
tion with DMT-MM proceeded. In other words, the dissocia- of 10% suspension of the solid. d) Two equivalent of DMT-MM was used.
Table 3. Convenient Synthesis of Lipophilic Amides in a Biphasic System on Alumina Ba)
Carboxylic acid
Amine
Product
Yieldb)
Ph(CH2)2CO2H
PhCHꢁCHCO2H
PhCO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
PhCO2H
PhCH2NH2
Ph(CH2)2CONHCH2Ph
PhCHꢁCHCONH(CH2)2Ph
PhCONH-c-C6H11
Ph(CH2)2CONEt2
Ph(CH2)2CONH(CH2)2OH
PhCO-Ser-OMe
99%
94%
87%
Ph(CH2)2NH2
c-C6H11NH2
Et2NH
HO(CH2)2NH2
H-Ser-OMe·HCl
H-Ser-OMe·HCl
93%c)
94%d)
100%e)
83%f)
PhCO2H
PhCO-Ser-OMe
a) The reaction procedure: see the typical experiment. b) Isolated yield. c) Two equivalent of DMT-MM was used. d) Carboxylic acid/amine/DMT-MMꢁ1 : 3 : 2. e)
Carboxylic acid/amine/DMT-MMꢁ1 : 5 : 2. NMM was used as a neutralizer. The reaction was performed for 3 h. f) Carboxylic acid/amine/DMT-MMꢁ1 : 3 : 2. NMM was used
as a neutralizer. The reaction was performed for 24 h.

October 2004
1225
purity by NMR.
N-Cyclohexylbenzamide3): Colorless crystals. mp 145—146 °C (CH2Cl2/
1
hexane). IR (KBr) cmꢂ1: 3313, 1627, 1535. H-NMR (CDCl3) : 1.15—1.29
In general, marked reduction of the reaction rate is the
major problem in heterogeneous reaction systems. To solve
this problem, use of a phase transfer catalyst,16—18) use of an
excessive amount of reagents,19—23) and improvement of stir-
ring efficiency24,25) are performed. In this study, the interface
area of two phases was increased by performing reactions in
the water–dichloromethane biphasic system on the surface of
solid phases, and reaction acceleration and improvement of
the yield were achieved. We also succeeded in simplification
of purification procedures utilizing the solubility of the reac-
tion products in water and dichloromethane. Thus, the use-
fulness of our system is comparable to that of polymer
reagents even though a simple monomer reagent is used. In
other words, since the system is liquid–liquid biphasic in
reaction but solid–liquid biphasic in operation, highly pure
carboxamides could be obtained only by filtration. Although
carboxamides must be lipophilic in order that this method is
effective, it will be applicable to various compounds because
(3H, m,), 1.38—1.49 (2H, m), 1.63—1.78 (3H, m), 2.02—2.06 (2H, m),
3.94—4.03 (1H, m), 5.94 (1H, br s), 7.40—7.50 (3H, m), 7.73—7.76 (2H, m).
N,N-Diethyl-3-phenylpropanamide3): Colorless oil. IR (neat) cmꢂ1: 1642.
1H-NMR (CDCl3) d: 1.10 (3H, t, Jꢁ7.1 Hz), 1.11 (3H, t, Jꢁ7.1 Hz), 2.59
(2H, t, Jꢁ7.8 Hz), 2.98 (2H, t, Jꢁ7.7 Hz), 3.22 (2H, q, Jꢁ7.2 Hz), 3.37 (2H,
q, Jꢁ7.1 Hz), 7.17—7.30 (5H, m). MS m/z: 205 (Mꢃ).
N-(2-Hydroxyethyl)-3-phenylpropanamide3): Colorless needles. mp
72.5—73.5 °C (AcOEt/hexane). IR (KBr) cmꢂ1: 3296, 1647, 1559. 1H-NMR
(CDCl3) d: 2.48 (2H, t, Jꢁ7.7 Hz), 2.94 (2H, t, Jꢁ7.6 Hz), 3.31—3.36 (2H,
m), 3.61 (2H, t, Jꢁ5.0 Hz), 6.15 (1H, br s), 7.16—7.18 (3H, m) , 7.21—7.27
(2H, m).
N-Benzoylserine Methyl Ester35) Alumina B powder (3 g) was added
to aqueous solution (1 ml) of DMT-MM (0.4 mmol, 2 eq) and H-Ser-OMe
hydrochloride (1.0 mmol, 5 eq), N-methylmorpholine (1.0 mmol, 5 eq) and
mixed by shaking the reaction flask at intervals until all solution was ad-
sorbed. A dichloromethane solution of a benzoic acid (50 mM, 4 ml, 1 eq)
was added to the solid substance obtained and the resulting mixture was
stirred at room temperature for 3 h. After addition of 2 M HCl (1 ml) and
ether, the mixture was filtered by suction through a glass filter filled with a
small amount of Celite®. The organic layer was concentrated. The product
was purified by preparative TLC. Colorless needles. mp 84—85 °C. IR
1
the amide residue is originally hydrophobic. DMT-MM can (KBr) cmꢂ1: 3438, 3322, 1751, 1628. H-NMR (CDCl3) d: 2.51 (1H, br),
be synthesized at low cost,1,26) and the solid materials used in
3.83 (3H, s), 4.05—4.09 (2H, m), 4.88 (1H, dt, Jꢁ7.1, 3.6 Hz), 7.08 (1H,
br), 7.43—7.47 (2H, m), 7.51—7.55 (1H, m), 7.82—7.85 (2H, m).
this study can be purchased at low cost and are reusable.27)
Therefore, the present method is considered economic and
practical.
Reactions in the heterogeneous system have synthetic
Acknowledgements We thank Mr. N. Kubota (MARUO CALUCIUM
CO., LDT.) who measured the specific surface area of solid powder materi-
als.
advantages, such as simplification of purification proce-
dures,28,29) recycling of expensive catalysts,30,31) and expres-
sion of a novel reaction selectivity,32) which is not observed
in the homogeneous system. For example, we are developing
a substrate-specific amidation using a cyclodextrin as an
inverse phase transfer catalyst.33) The major problem of this
reaction is also reduction of the reaction rate in the heteroge-
neous system. We are further evaluating the acceleration of
this substrate-specific reaction by the present solid-phase
adsorption system.
References and Notes
1) Kunishuima M., Kawachi C., Iwasaki F., Terao K., Tani S., Tetrahe-
dron Lett., 40, 5327—5330 (1999).
2) Kunishuima M., Kawachi C., Morita J., Terao K., Iwasaki F., Tani S.,
Tetrahedron, 55, 13159—13170 (1999).
3) Kunishuima M., Kawachi C., Hioki K., Terao K., Tani S., Tetrahedron,
57, 1551—1558 (2001).
4) Masala S., Taddei M., Org. Lett., 1, 1355—1357 (1999).
5) Kirschning A., Monenschein H., Wittenberg R., Angew. Chem. Int.
Ed., 40, 650—679 (2001).
6) Ley S. V., Baxendale I. R., Bream R. N., Jackson P. S., Leach A. G.,
Longbottom D. A., Nesi M., Scott J. S., Storer R. I., Taylor S. J., J.
Chem. Soc., Perkin Trans. 1, 2000, 3815—4195 (2000).
7) Desai M. C., Stephens Stramiello L. M., Tetrahedron Lett., 34, 7685—
7688 (1993).
8) Although the stable structure of HO-DMT would be its tautomer, 4,6-
dimethoxy-1,3,5-triazn-2(1H)-one,9) we use the enol form for conve-
nience.
9) Glowka M. L., Bertolasi V., Acta Cryst., C34, 149—151 (1987).
10) Charles M., Martin B., Ginies C., Etievant P., Coste G., Guichard E., J.
Agric. Food Chem., 48, 70—77 (2000).
Experimental
General Methods DMT-MM was prepared from 2-chloro-4,6-dime-
thoxy-1,3,5-triazine (CDMT) and N-methylmorpholine according to the
method reported previously.2) CDMT was prepared from 2,4,6-trichloro-
1,3,5-triazine.26) All other solvents and chemicals were obtained from com-
mercial sources and used as received unless otherwise noted. Chemical
1
shifts of H- (400 MHz) and 13C-NMR spectra were recorded in ppm (d)
downfield from TMS as an internal standard. Preparative thin-layer chro-
matography (TLC) was performed on Merck precoated silica gel plates.
General Procedure for Condensation of Carboxylic Acids and Amines
Using Solid-Phase Adsorption System N-Benzyl-3-phenylpropanam-
ide3): Alumina B powder (3 g) was added to DMT-MM solution (220 mM,
1 ml), and mixed by shaking the reaction flask at intervals until all solution
was adsorbed. A dichloromethane solution of a 3-phenylpropionic acid
(100 mM, 2 ml) was added to the solid substance obtained, and a dichloro-
methane solution of a benzylamine (100 mM, 2 ml) was added. The mixture
was stirred at room temperature for 30 min (when Extrelut® was used, the
mixture was left standing for 25 min after 5 min of stirring because the mate-
rial was crushed by stirring), and after addition of ether, filtration with suc-
tion was performed with a glass filter filled with a small amount of Celite®.
Almost pure carboxamide was obtained by concentration of the filtrate.34)
Colorless crystals. mp 83—84 °C (CH2Cl2/hexane). IR (KBr) cmꢂ1: 3290,
1638, 1541. 1H-NMR (CDCl3) d: 2.52 (2H, t, Jꢁ7.6 Hz), 3.00 (2H, t,
Jꢁ7.6 Hz), 4.40 (2H, d, Jꢁ5.7 Hz), 5.60 (1H, br s), 7.13—7.32 (10H m).
MS m/z: 239 (Mꢃ).
11) Allen D. L., Scott K. S., Oliver J. S., J. Anal. Toxicol., 23, 216—218
(1999).
12) Fenske M., J. Chromatogr. B., 692, 238—240 (1997).
13) Kunugi A., Tsuji C., Tabei K., Chem. Pharm. Bull., 36, 2661—2664
(1988).
14) Kunugi A., Tabei K., J. Chromatogr., 398, 320—322 (1987).
15) For Solid materials: Extrelut® was obtained from Merck Inc. Diatoma-
ceous Earth, Molecular Sieves 3A (Powder), Molecular Sieves 4A
(Powder) and Celite® was obtained from Nacalai Tesque, Inc. Alumina
N, Alumina A, and Alumina B was obtained from ICN Pharmaceuti-
cals, Inc. Silica gel 60N was obtained from Kanto Chemical co., Inc.
16) Makosza M., Pure Appl. Chem., 72, 1399—1403 (2000).
17) Rabinovitz M., Cohen Y., Halpern M., Angew. Chem. Int. Ed. Engl.,
25, 960—970 (1986).
18) Dehmlow E. V., Angew. Chem. Int. Ed. Engl., 16, 493—505 (1977).
19) Stewart J. M., Young J. D., “Solid Phase Peptide Synthesis,” W. H.
Freeman and Company, San Francisco, 1969, pp. 27—64.
20) Makosza M., Chesnokov A., Tetrahedron, 56, 3553—3558 (2000).
21) Beller M., Krauter J. G. E., Zapf A., Angew. Chem. Int. Ed. Engl., 36,
772—774 (1997).
N-Phenethylcinnamamide3): Colorless needles. mp 126—127 °C (CH2Cl2/
hexane). IR (KBr) cmꢂ1: 3301, 1651, 1615, 1544. 1H-NMR (CDCl3) d: 2.89
(2H, t, Jꢁ6.9 Hz), 3.66 (2H, td, Jꢁ6.8, 6.1 Hz), 5.74 (1H, br s), 6.34 (1H, d,
Jꢁ15.6 Hz), 7.22—7.35 (8H, m), 7.47—7.49 (2H, m), 7.62 (1H, d, Jꢁ
15.6 Hz). MS m/z: 251 (Mꢃ).
22) Solaro R., D’Antone S., Chiellini E., J. Org. Chem., 45, 4179—4183

1226
Vol. 52, No. 10
Haag R., Angew. Chem. Int. Ed., 41, 3964—4000 (2002).
(1980).
23) Makosza M., Jonczyk A., Org. Synth., 55, 91—95 (1976).
24) Gobbi A., Landini D., Maia A., Petricci S., J. Org. Chem., 63, 5356—
5361 (1998).
29) Curran D. P., Angew. Chem. Int. Ed., 37, 1174—1196 (1998).
30) de Wolf E., van Koten G., Deelman B.-J., Chem. Soc. Rev., 28, 37—41
(1999).
25) Tomoi M., Ford W. T., J. Am. Chem. Soc., 103, 3821—3828 (1981).
26) Cronin J. S., Ginah F. O., Murray A. R., Copp J. D., Synth. Commun.,
26, 3491—3494 (1996).
31) Herrmann W. A., Kohlpaintner C. W., Angew. Chem. Int. Ed. Engl., 32,
1524—1544 (1993).
32) Prinz T., Keim W., Driessen-Holscher B., Angew. Chem. Int. Ed. Engl.,
35, 1708—1710 (1996).
27) For recycling experiment of solid materials, Alumina B was quantita-
tively recovered from the reaction mixture, preparing N-benzyl-3- 33) Unpublished results.
phenylpropanamide under the same conditions described in Table 2, 34) The product was sometimes contaminated with a small amount of HO-
by filtration, followed by washed with water, and dry in vacuo. The de-
hydrocondensation of 3-phenylpropionic acid and benzylamine by use
of the recovered Alumina B proceeded quantitatively (yield 100%).
28) Tzschucke C. C., Markert C., Bannwarth W., Roller S., Hebel A.,
DMT, which can be removed by filtration after dissolved in ether.
35) Ranganathan D., Vaish N. K., Shah K., J. Am. Chem. Soc., 116,
6545—6557 (1994).