Benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate as N-protecting reagent

Article abstract of DOI:10.1246/cl.2002.66

A new active carbonate ester, benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate (Z-DMT), was prepared, and found to be a useful reagent for the introduction of benzyloxycarbonyl group into amines. Since Z-DMT is neither unstable nor irritating, it is practically useful.

Full text of DOI:10.1246/cl.2002.66

66
Chemistry Letters 2002
Benzyl 4,6-Dimethoxy-1,3,5-triazinyl Carbonate as N-Protecting Reagent
Kazuhito Hioki,y Miho Fujiwara,y Shohei Tani,yz and Munetaka Kunishimaꢀyz
yFaculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180
zHigh Technology Research Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180
(Received October 1, 2001; CL-010964)
A new active carbonate ester, benzyl 4,6-dimethoxy-1,3,5-
Z-DMT was synthesized in 87% yield by treatment of 4,6-
dimethoxy-2-hydroxy-1,3,5-triazine (HO-DMT; 1 equiv) with Z-
Cl (1 equiv) and triethylamine (1 equiv) in dry chloroform at rt.6
Z-DMT is not irritating to the eye and nose, and can be stored over
several months in a refrigerator without marked decomposition.
triazinyl carbonate (Z-DMT), was prepared, and found to be a
useful reagent for the introduction of benzyloxycarbonyl group
into amines. Since Z-DMT is neither unstable nor irritating, it is
practically useful.
Table 1. The N-benzyloxycarbonylation of amines with Z-
DMT
Among numerous N-protecting groups, urethane-type pro-
tecting groups represented by benzyloxycarbonyl (Z), t-butox-
ycarbonyl (Boc), and 9-fluorenylmethoxycarbonyl (Fmoc) are
most widely known and used in general organic synthesis. For the
introduction of Z group, benzyl chloroformate (Z-Cl) is generally
used for many practical purposes because of its reactivity and
costs.1 However, the chloroformate is irritating and unstable, and
serious side reactions sometimes occur leading to the formation of
dipeptides during N-benzyloxycarbonylation of amino acids.2
Although other benzyloxycarbonyl donors like mixed carbonates
with phenols or N-hydroxy compounds, and various heterocycles
possessing Z group have been studied, they have not found much
application partly because of laborious preparation, cost, or lower
reactivity of the reagents.3 Thus, a more practical and effective
reagent for benzyloxycarbonylation of amines is required.
Recently, we have introduced 4-(4,6-dimethoxy-1,3,5-tria-
zin-2-yl)-4-methylmorpholinium chloride (DMT-MM) as a new
condensing reagent for the synthesis of amides or esters.4 Most
importantly, DMT-MM allows to condense carboxylic acids and
amines in commercial methanol under atmospheric conditions.
The reaction involves an intermediate acyloxytriazine, which
exclusively undergoes aminolysis over methanolysis even in
methanol. The high amide/ester selectivity can be attributed to the
moderate reactivity of the triazinyl esters allowing them to be
isolated.5 Based on this fact, we expected that the ester activating
ability of the dimethoxytriazinyl group is applicable to carbonate
esters for protection of amino groups. In this paper we describe
development of benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate
(Z-DMT) as a new N-protecting reagent.
Z-DMT/equiv Solvent Time Yield/%
R NH2
1.1
30 min
90
THF
NH2
1.2
1.2
1.2
THF
MeOH 40 min
CH3CN 30 min
30 min
91
92
92
NH2
1.1
60 min
THF
83
NH
MeOHa
30 min
COOMe
NH2
1.2
85
HO
MeOHa
15 min
COOEt
NH2
1.2
90
a2 eq of Et3N was used.
Table 1 summarizes N-bezyloxycarbonylation of simple
amines by Z-DMT. Sterically hindered cyclohexylamine or
secondary amine as well as primary one readily underwent N-
protection in good yield. HO-DMT formed as a co-product was
easily removed by simple extraction with water. Since Z-DMT
undergoes aminolysis faster than either hydrolysis or alcoholysis,
N-benzyloxycarbonylation can be conducted in a protic solvent.
For example, reaction of polar compounds, amino acid ester
hydrochlorides, occurred smoothly in methanol.
Ph
Cl
O
MeO
N
OH
O
O
MeO
N
Ph
O
As shown in Table 2, reaction of various amino acids also
took place in good yields in either water or aqueous methanol.7
When Z-Cl is used for the protection of amino acids, dimerization
via the activation of the carboxyl group often becomes a serious
side reaction.8 By contrast, in the benzyloxycarbonylation of
glycine with Z-DMT, the dimerization did not occur to a
discernible extent (< 1%). Since HO-DMT is the co-product
formed in dehydrating condensation using DMT-MM as well as
in the present reaction, Z-DMT salvaging HO-DMT is economic-
al and environmentally friendly, and therefore, a useful and stable
alternative to Z-Cl.
N
N
N
N
O
CHCl3, rt
OMe
OMe
Z-DMT
R2
N
R1R2NH
O
Ph
R1
O
MeO
N
N
N
OH
HO-DMT
MeO
Scheme 1.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
Table 2. The protection of amino acids
67
4
a) M. Kunishima, C. Kawachi, J. Morita, K. Terao, F. Iwasaki,
and S. Tani, Tetrahedron, 55, 13159 (1999). b) M. Kunishima,
C. Kawachi, K. Hioki, K. Terao, and S. Tani, Tetrahedron, 57,
1551 (2001).
a
Z-DMT
/equiv
Base
Yield
/
Amino acid
Solvent
/equiv
5
6
a) J. E. Kaminska, Z. J. Kaminski, and J. Gora, Synthesis,
1999, 593. b) Z. J. Kaminski, J. Prakt. Chem., 332, 579
(1990).
94
1.1
1.0
1.0
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.0
1.2
Ala
Gly
Et3N; 1.1
Et3N; 1.1
H2O
H2O
95
H2O
70
Phe
Et3N; 1.0
For the synthesis of Z-DMT: freshly distilled Z-Cl (904 mg,
5.30mmol) was added to a solution of HO-DMT (1.0g,
6.36 mmol) and triethylamine (536 mg, 5.30mmol) in
chloroform (200 mL) at rt. After stirring for 1 h at rt, the
solution was washed three times with water (100 mL) and
dried over magnesium sulfate and evaporated. The title
compound was obtained as colorless viscous oil (1.34 g, 87%
yield). The reagent was used for following experiments
without further purification.
For general procedures for N-protection: to a solution of an
amino acid (0.5 mmol) in water (1 mL) containing triethy-
lamine (1.0mmol), Z-DMT (0.75 mmol) in methanol (1 mL)
was added at rt. After stirring for 1 h, most of the methanol
was evaporated and the resulting aqueous solution was
acidified with 1 N hydrochloric acid to pH 1 to 2. The aqueous
solution was extracted with ethyl acetate, and the combined
extracts were washed with water, dried, and evaporated. The
amino acid derivatives were isolated by either recrystalliza-
tion or column chromatography.
H2O
88
Phe
Et3N; 1.1
Phe
NaHCO3; 1.5
Et3N; 1.0
92
aq. MeOH
H2O
74
N-phenylGly
Thr
82
aq. MeOH
aq. MeOH
aq. MeOH
aq. MeOH
aq. MeOH
aq. MeOH
aq. MeOH
NaHCO3; 2.0
Et3N; 2.0
79
Thr
88
Ser
NaHCO3; 2.0
Et3N; 3.0
7
80
87b
Tyr
Met
NaHCO3; 2.0
Et3N; 2.0
70
Glu
67
Gln
Et3N; 2.0
aThe concentration of aq. MeOH was prepared to ca. 50
.
bn.m.r. yield.
7
References and Notes
1
2
3
‘‘Amino Acid Derivatives,’’ ed. by G. C. Barrett, Oxford
University Press, New York (1999), pp 7-19.
S. Romani, L. Moroder, G. Bovermann, and E. Wunsch,
¨
Synthesis, 1985, 738.
E. Wunsch, W. Graf, O. Keller, W. Keller, and G. Wersin,
¨
Synthesis, 1986, 958. See also references therein.
8
a) ‘‘Peptide–Structure and Functions, Proc. 8th Am. Peptide
Symp. 1983,’’ ed. by V. J. Hruby and D. H. Rich, Pierce
Chem. Company, Rockford, Illinois 1984, pp 55–64. b) S.
Iguchi, K. Kawasaki, and Y. Okada, Int. J. Peptide Protein
Res., 30, 695 (1987).