Approach to green chemistry of DMT-MM: Recovery and recycle of coproduct to chloromethane-free DMT-MM

Article abstract of DOI:10.1016/S0040-4039(02)00546-4

A simple procedure for the isolation of 2-hydroxy-4,6-dimethoxy-1,3,5-triazine (HO-DMT), a coproduct arising from dehydrating condensation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) has been established. HO-DMT can be recycled by treatment with POCl₃ to give 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), which is further converted to DMT-MM. Alternatively, reaction with triflic anhydride followed by addition of N-methylmorpholine gives DMT-MM triflate.

Full text of DOI:10.1016/S0040-4039(02)00546-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3323–3326
Approach to green chemistry of DMT-MM: recovery and
recycle of coproduct to chloromethane-free DMT-MM
Munetaka Kunishima,* Kazuhito Hioki, Ayako Wada, Hiroko Kobayashi and Shohei Tani
Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180,
Japan
Received 26 December 2001; revised 13 March 2002; accepted 15 March 2002
Abstract—A simple procedure for the isolation of 2-hydroxy-4,6-dimethoxy-1,3,5-triazine (HO-DMT), a coproduct arising from
dehydrating condensation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) has been estab-
lished. HO-DMT can be recycled by treatment with POCl to give 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), which is further
3
converted to DMT-MM. Alternatively, reaction with triflic anhydride followed by addition of N-methylmorpholine gives
DMT-MM triflate. © 2002 Elsevier Science Ltd. All rights reserved.
Although the formation of by-products resulting from
undesirable side reactions can be avoided by improving
reaction conditions, formation of coproducts, i.e.
accompanying reactions leading to a desired product, is
inevitable. Unless isolation and conversion of such
coproducts into other useful compounds are very easy,
they become waste materials. To be useful on an indus-
trial scale, it is particularly important to avoid column
chromatography in the isolation procedure. Thus,
development of effective and efficient methods for
recovery and reuse of coproducts is highly desirable
from both an environmental and economic perspective.
rate it from typical organic products by extraction,
would seem to make isolation of HO-DMT from a
protic as well as aportic reaction mixture difficult. In
this communication, we report a simple procedure for
isolation of HO-DMT and regeneration of DMT-MM
from it.
As shown in Chart 1, HO-DMT can be readily recov-
ered by filtration from the reaction mixture of a dehy-
drating condensation.
A
methanolic solution of
cinnamic acid and phenylethanamine (0.1 mol/L each)
was treated with DMT-MM for 2.5 h. The resulting
Recently, we have introduced 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride (DMT-
1
MM) as a new dehydrating condensing agent that
enables us to carry out amidation of carboxylic acid in
protic solvents such as water, MeOH, EtOH, and i-
2
PrOH. Condensation using DMT-MM gives 2-
hydroxy-4,6-dimethoxy-1,3,5-triazine (HO-DMT) as a
coproduct along with the formation of the desired
product. For a good example of salvage of HO-DMT,
we developed a method for converting it to benzyl
4
,6-dimethoxy-1,3,5-triazinyl carbonate (Z-DMT),
which is a promising new N-benzyloxycarbonylating
agent. To make this or other salvage pathways useful,
3
it is necessary to establish a convenient procedure for
recovery of HO-DMT. However, the high water solu-
bility of HO-DMT, which makes it very easy to sepa-
Keywords: triazines; condensations; amides.
*
Corresponding author. Tel.: +81-78-974-1551; fax: +81-78-974-5689;
e-mail: kunisima@pharm.kobegakuin.ac.jp
Chart 1. Recovery of HO-DMT from the reaction mixture.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00546-4

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M. Kunishima et al. / Tetrahedron Letters 43 (2002) 3323–3326
Table 1. Dehydrating condensation of carboxylic acids and amines with DMT-MM
DMT-MM or DMT-MM (TfO)
RCOOH+R%NH ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁ RCONHR%
2
Run
RCOOH
R%NH2
Condensing agent
Solvent
Conditions
Yielda (%)
88
1
2
3
4
5
6
7
8
PhCHꢂCHCOOH
PhCHꢂCHCOOH
Ph(CH ) COOH
Ph(CH ) NH
Ph(CH ) NH
Ph(CH ) NH
Ph(CH ) NH
Ph(CH ) NH
Ph(CH ) NH
H-Phe-OMe
H-Phe-OMe
DMT-MM
DMT-MM (TfO)
DMT-MM
DMT-MM (TfO)
DMT-MM
DMT-MM (TfO)
DMT-MM
MeOH
MeOH
CH Cl
Rt, 2.5 h
Rt, 2.5 h
Rt, 1 h
Rt, 1 h
Rt, 1 h
Rt, 1 h
Rt, 1 h
Rt, 1 h
2
2
2
2
2
2
2
2
b
96
2
2
83
84
88
87
94
98
2
2
2 2
2
2
2
2
2
Ph(CH ) COOH
CH Cl
2
2
2 2
2
PhCOCOOH
PhCOCOOH
Boc-Leu-OH
Boc-Leu-OH
CH Cl
2
2
2
CH Cl
2
2
2
CH CN
3
DMT-MM (TfO)
CH CN
3
a
Isolated yield.
b
HO-DMT (93% yield) and sodium triflate (88% yield) were recovered.
mixture was concentrated by a rotary evaporator to
about one-fifth of its original volume to precipitate a
white solid, which was collected by suction to give
almost pure HO-DMT in 71% yield. An additional
HO-DMT (11%) was recovered from the filtrate by
further concentration followed by washing of the result-
ing residue with acetone. The amide was obtained from
the resulting acetone washings by general workup in
unstable and decomposes considerably during isolation,
we attempted to convert HO-DMT directly to DMT-
MM (TfO) without isolation of the intermediate. We
found that treatment of HO-DMT with triflic anhy-
dride in CH Cl2 followed by addition of NMM
2
7
afforded DMT-MM (TfO) in a good yield (Eq. (3)).
An equimolar amount of triflate ion arising from triflic
anhydride during the reaction could be recovered as
7
8
8% yield (Table 1, run 1). When condensation is
sodium triflate, which can be converted into triflic
8
conducted in other low-boiling organic solvents, HO-
DMT can be isolated from a concentrated crude
residue in a similar manner.
anhydride.
In contrast to the original DMT-MM, DMT-MM
(
TfO) appears to be soluble in organic solvents to some
We have developed two procedures for recycling HO-
DMT to DMT-MM. Chlorination of the hydroxyl
extent. However, the reactivity of DMT-MM (TfO) as
a dehydrating condensing agent is similar to that of the
original DMT-MM which has a chloride counter ion.
As shown in Table 1, all the reactions took place in
good to excellent yields in both polar and nonpolar
solvents. Both HO-DMT and a triflate (as its sodium
salt) resulting from reactions using DMT-MM (TfO)
could be also recovered in 93 and 88% yields, respec-
tively (run 2).
group of HO-DMT with POCl and diethylaniline gave
3
2
-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in 90%
4
yield, which was quantitatively converted to DMT-
MM by coupling with N-methylmorpholine (NMM)
1
a
(
Eq. (1)). Alternatively, HO-DMT was treated with
triflic anhydride to give 4,6-dimethoxy-2-trifluoro-
methylsulfonyl-1,3,5-triazine (TfO-DMT) in 49% yield,
and then coupled with NMM to give [DMT-MM
(
TfO)] in 87% yield, with triflate instead of chloride as
When DMT-MM is suspended at room temperature in
organic solvents, especially CH Cl or CHCl , it readily
6
the counter anion (Eq. (2)). Since TfO-DMT is
2
2
3
Me N
O
MeO
N
POCl3
MeO
N
MeO
N
Me
N
N
N
N
N,N-diethylaniline
N
N
NMM
y. 98%
N+
(1)
(2)
O
OH
Cl
reflux, 3 h
y. 90%
MeO
MeO
MeO
HO-DMT
CDMT
DMT-MM
MeO
MeO
N
MeO
N
Me
N
N
(CF SO ) O
N
NMM
THF, rt
3
2 2
N
N+
O
OH
N
OTf
CH2Cl2, rt
N
N
TfO–
MeO
MeO
MeO
HO-DMT
TfO-DMT, 49%
DMT-MM(TfO), y. 87%
(y. 43% from HO-DMT)
NMM
Me
(
CF3SO2)2O
DMT-MM(TfO) + TfO–
y. 87%
N+
HO-DMT
[TfO-DMT]
O
H
CH2Cl2, rt, 1 h
rt, 1 h
(3)
y. 88% as TfONa

M. Kunishima et al. / Tetrahedron Letters 43 (2002) 3323–3326
3325
Chart 2. NMR analysis for the stability of DMT-MM (TfO) in CDCl . (a) DMTM arising from DMT-MM by demethylation.
3
(
b–d) DMT-MM (TfO) after 15 min (b), 6 h (c), and 100 h (d) at rt.
undergoes demethylation at the morpholinium nitro-
gen by attack of chloride anion, and chloromethane,
References
1c
which is an undesirable air pollutant, evolves. Since
the demethylation appears to be slower than the reac-
tion of DMT-MM with carboxylic acids, these
organic solvents can be employed for condensation
using DMT-MM. A small amount of chloromethane,
however, would be formed in most condensation reac-
1. (a) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.;
Tani, S. Tetrahedron Lett. 1999, 40, 5327–5330; (b) Kun-
ishima, M.; Morita, J.; Kawachi, C.; Iwasaki, F.; Terao,
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1,2
tions conducted in less-polar organic solvents.
In
2. Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani,
contrast with DMT-MM, DMT-MM (TfO) is quite
S. Tetrahedron 2001, 57, 1551–1558.
stable in CHCl , presumably due to the lower nucle-
ophilicity of triflate ion than that of chloride. Thus,
3. Hioki, K.; Fujiwara, M.; Tani, S.; Kunishima, M. Chem.
Lett. 2002, 66–67.
4. For regeneration of CDMT from HO-DMT: According
3
when DMT-MM (TfO) was suspended in CDCl at
3
room temperature, no decomposition was observed by
NMR analysis even after 100 h, as illustrated in
Chart 2. Other analogues that circumvent the evolu-
tion of chloromethane were prepared by counter ion
exchange; DMT-MM nitrate or perchlorate were
obtained by treatment with AgNO or LiClO , respec-
to the literature describing chlorination of heterocyclic
5
alcohols, a mixture of HO-DMT (5.0 g, 31.8 mmol) and
N,N-diethylaniline (9.5 g, 636 mmol) dissolved in phos-
phoryl chloride (89 mL) was refluxed for 3 h. After
removal of the excess phosphoryl chloride at 35°C/45
mmHg, the residue was poured into ice-water and stirred
for 50 min. The resulting mixture was extracted with
3
4
tively.
CHCl , and the organic layer was washed successively
3
DMT-MM is one of several promising dehydrating
condensing candidates that are attractive to industry
because of the synthetic advantages that they offer,
which are superior to other dehydrating condensing
agents such as carbodiimides. HO-DMT is widely
formed as a coproduct in reactions using not only
with HCl, NaHCO , and brine. Purification of the crude
material by silica gel column chromatography gave
CDMT (5.0 g) in 90% yield.
3
5. Robins, R. K.; Revankar, G. R.; O’Brien, D. E.;
Springer, R. H.; Novinson, T.; Albert, A.; Senga, K.;
Miller, J. P.; Streeter, D. G. J. Heterocyclic Chem. 1985,
22, 601–634.
6. The abbreviations DMT-MM and DMT-MM (TfO) refer
to the chloride and the triflate salts, respectively.
7. For direct formation of DMT-MM (TfO) from HO-
DMT: Triflic anhydride (9.90 g, 35.0 mmol) was added
dropwise to a solution of HO-DMT (5.0 g, 31.8 mmol) in
9
3
DMT-MM but also CDMT, Z-DMT, and
a
10
cyclodextrin-based artificial acyltransferase.
Thus,
the present procedures for isolation and reuse of HO-
DMT, which are environmentally friendly and eco-
nomically favorable, should become very useful in
future.

3
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M. Kunishima et al. / Tetrahedron Letters 43 (2002) 3323–3326
CH Cl (318 mL) under nitrogen at room temperature.
4H), 4.02–4.11 (m, 2H), 4.18 (s, 6H), 4.48–5.58 (m, 2H).
Anal. calcd for C H F N O S: C, 33.85; H, 4.39.
Found. C, 33.55; H, 4.16%.
2
2
After stirring the mixture for 1 h, NMM (7.10 g, 70.0
mmol) was added dropwise to the solution, and then the
mixture was allowed to react for another 1 h. The solvent
was evaporated, and the residue was dissolved in MeOH
1
1
17
3
4
6
8. (a) Haszeldine, R. N.; Kidd, J. M. J. Chem. Soc. 1954,
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N. J. Chem. Soc. 1957, 4069–4079.
(
100 mL), and then Et O (400 mL) was added to give
2
1
0.8 g (87% yield) of DMT-MM (TfO). The resulting
organic layer including 4-methylmorpholinium triflate
was concentrated, and treated with 1 M NaOH in MeOH
followed by evaporation. The residue was dissolved in
acetone followed by filtered, and the filtrate was poured
9. (a) Kaminski, Z. J. Tetrahedron Lett. 1985, 26, 2901–
2904; (b) Kaminski, Z. J. Int. J. Peptide Protein Res.
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into CH Cl2 to give a precipitate, which was recrystal-
2
lized from acetone to give sodium triflate (5.32 g, 88%
yield). DMT-MM (TfO): colorless needles; mp 156–
1
59°C, IR (KBr) 1634, 1541, 1487, 1391, 1276, 1133, 1031
−
1 1
cm ; H NMR (CD OD) l 3.52 (s, 3H), 3.79–3.92 (m,
3