Useful reagents for introduction of Boc and Fmoc protective groups to amines: Boc-DMT and Fmoc-DMT

Article abstract of DOI:10.1055/s-2006-942389

New amino-protecting reagents, Boc-DMT and Fmoc-DMT, were prepared, and found to be useful for the introduction of Boc and Fmoc groups into amines. Both the reagents can protect various amines including amino acids in good yield in aqueous media. Since the reagents are neither unstable nor irritating, they are practically useful. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942389

SHORT PAPER
1931
Useful Reagents for Introduction of Boc and Fmoc Protective Groups to
Amines: Boc-DMT and Fmoc-DMT
U
seful Reagents fo
a
r
Introduct
z
ionof the te
u
rt-Butoxyca
h
r
bonyl to A
m
i
ines to Hioki,a,b Mizuho Kinugasa,a Michiko Kishimoto,a Miho Fujiwara,a Shohei Tani,a,b Munetaka Kunishima*a,b
a
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishiku, Kobe 651-2180, Japan
High Technology Research Center, Kobe Gakuin University, Nishiku, Kobe 651-2180, Japan
b
Fax +81(78)9745689; E-mail: kunisima@pharm.kobegakuin.ac.jp
Received 6 January 2006; revised 23 February 2006
MeO
N
MeO
N
(Boc)2O or Fmoc-Cl
base
Abstract: New amino-protecting reagents, Boc-DMT and Fmoc-
DMT, were prepared, and found to be useful for the introduction of
Boc and Fmoc groups into amines. Both the reagents can protect
various amines including amino acids in good yield in aqueous me-
dia. Since the reagents are neither unstable nor irritating, they are
practically useful.
N
N
N
N
OH
O
O R
CH2Cl2
O
MeO
MeO
R = t-Bu, fluorenylmethyl
Scheme 1 Preparation of the N-protecting reagents containing the
dimethoxytriazinyloxy group.
Key words: protecting groups, amines, amino acids, triazine, ac-
tive carbonate ester
can be stored over a year in a refrigerator without notice-
able decomposition. Based on the reaction yields, the use
of polar solvents such as methanol and acetonitrile is pref-
erable to tetrahydrofuran for the N-protection of several
aliphatic amines with Boc-DMT. The reaction with amino
acid esters in methanol, which is cheaper than acetonitrile,
afforded the desired products in good yields. The reac-
tions of free amino acids were carried out in methanol–
water mixtures due to the low solubility of the substrates
in methanol. As shown in Table 1, all reactions were com-
plete within an hour to afford the products in good yields.
Recently we have introduced a novel N-protecting re-
agent, benzyl 4,6-dimethoxy-1,3,5-triazinyl carbonate (Z-
DMT), which features a 4,6-dimethoxy-1,3,5-triazinyl-
oxy moiety as the leaving group.1 This reagent was devel-
oped based on the property of 2-acyloxy-4,6-dimethoxy-
1,3,5-triazine, which exclusively undergoes aminolysis
over methanolysis, even in methanol, as shown in dehy-
drocondensing reactions using 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride (DMT-
MM).2 Various amines were protected using Z-DMT in
high yields in protic solvents such as water, methanol, and
their mixture, without racemization and dimerization,
which are common problems observed in reactions using
benzyl chloroformate (Z-Cl).3 Furthermore, storage and
handling of Z-DMT are easy, since it is non-irritating and
more stable than Z-Cl. Because the reagent can be pre-
pared by reusing 4,6-dimethoxy-1,3,5-triazin-2-ol (HO-
DMT), a co-product of the condensation reaction using
DMT-MM, our methodology is desirable from both envi-
ronmental and economic perspectives.4,5 In this paper, we
describe the preparation of tert-butyl 4,6-dimethoxy-
1,3,5-triazinyl carbonate (Boc-DMT; Scheme 1) and 9-
fluorenylmethyl 4,6-dimethoxy-1,3,5-triazinyl carbonate
(Fmoc-DMT; Scheme 1), and their usefulness as N-pro-
tecting reagents having similar characteristics as that of Z-
DMT.
Fmoc-DMT was obtained in 95% yield as colorless crys-
tals by treatment of HO-DMT with 9-fluorenylmethyl
chloroformate in dichloromethane in the presence of tri-
ethylamine. The reagent was found to be stable for over a
year at room temperature. Although Fmoc-DMT was
slightly soluble in methanol (9.5 mM), the N-protecting
reactions of several amines were carried out in methanol
using a suspension of Fmoc-DMT to afford the desired
products in good yield within 30 minutes. However we
employed acetonitrile as a solvent because the solubility
of Fmoc-DMT in acetonitrile at 25 °C (331 mM) is higher
than that in methanol. In the case of free amino acids,
which are difficult to dissolve in acetonitrile, the use of
acetonitrile–water mixtures was found to be effective. As
shown in Table 1, all of the substrates were readily pro-
tected in good yields.
Boc-DMT was obtained in 68% yield as a colorless oil by
treatment of HO-DMT with di-tert-butyl dicarbonate in
dichloromethane in the presence of a catalytic amount of
pyridine. The reagent is soluble in common organic sol-
vents, such as hexane, tetrahydrofuran, acetonitrile, and
methanol, but insoluble in water. As a note, the reagent
In summary, we have described the usefulness of two nov-
el N-protecting reagents, Boc-DMT and Fmoc-DMT,
which feature the leaving ability of a triazinyloxy group.
Protecting reactions by Boc-DMT and Fmoc-DMT were
completed in relatively short times (15–60 min) in aque-
ous media without detectable side-reactions such as
dimerization and racemization.3
SYNTHESIS 2006, No. 12, pp 1931–1933
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Advanced online publication: 08.05.2006
DOI: 10.1055/s-2006-942389; Art ID: F00206SS
© Georg Thieme Verlag Stuttgart · New York

1932
K. Hioki et al.
SHORT PAPER
Table 1 N-Protection Reactions of Boc-DMT and Fmoc-DMT
Amine
Boc-DMTa
Time (min)
Fmoc-DMTb
Time (min)
Solventc
MeCN
Yield (%)d
91
Solventc
Yield (%)d
94
15
aq MeCN
40
NH2
THF
MeOH
MeCN
60
60
15
58e
73
85
aq MeCN
15
88
NH2
THF
MeCN
60
15
78e
98
aq MeCN
MeOH
30
30
92
97
NH
MeOH
30
15
30
89
COOMe
NH2⋅HCl
COOEt
NH2⋅HCl
MeOH
91 (96)
98
aq MeCN
aq MeCN
15
75
99
96
HO
aq MeOH
H3C
COOH
NH2
COOH
aq MeOH
aq MeOH
30
30
85f
88
aq MeCN
aq MeCN
20
30
96
92
H2N
COOH
NH2
aq MeOH
aq MeOH
30
30
92
85
aq MeCN
aq MeCN
65
30
94
92
H
N
COOH
OH
COOH
NH2
aq MeOH
aq MeOH
30
60
82
79
aq MeCN
aq MeCN
40
35
89
74
COOH
NH2
HO
COOH
NH2
HO
aq MeOH
aq MeOH
60
60
80 (91)
74 (92)
aq MeCN
aq MeCN
75
30
99
79
HOOC
COOH
NH2
O
COOH
H2N
S
NH2
COOH
aq MeOH
30
98
aq MeCN
60
94
NH2
a Reagent (1.5 equiv), unless noted otherwise.
b Reagent (1.2 equiv).
c aq MeOH and aq MeCN represent a mixture of H2O–MeOH (1:1) and H2O–MeCN (1:2), respectively.
d Isolated yields. The yield determined by NMR is shown in parentheses.
e Reagent (1.1 equiv).
f Reagent (2.0 equiv).
Synthesis 2006, No. 12, 1931–1933 © Thieme Stuttgart · New York

SHORT PAPER
Useful Reagents for Introduction of Boc and Fmoc to Amines
1933
HO-DMT was prepared according to our procedures, as previously
described.4 Other chemicals and solvents were obtained from com-
mercial sources and were used without further purifications. H
NMR spectra were taken on a Bruker DPX-400 spectrometer. Melt-
ing points were measured with a Yanaco melting point apparatus
and are uncorrected. IR data were recorded on a Thermo Nicolet
AVATAR 360 FT-IR instrument. Microanalyses were performed at
the Center for Organic Elemental Microanalysis, Kyoto University
Graduate School of Pharmaceutical Sciences.
Reaction of Boc-DMT with Amino Acids
To a solution of glycine (0.5 mmol) in H2O (1 mL) containing Et3N
(1.0 mmol) at r.t. was added Boc-DMT (1.0 mmol) in MeOH (1
mL). After stirring for 30 min, the reaction mixture was concentrat-
ed to remove most of the MeOH. The resulting aqueous solution
was acidified to pH 3–4 using 20% citric acid, and was then extract-
ed with EtOAc (2 × 30 mL). The combined extracts were washed
with H2O (30 mL), dried over MgSO4 and concentrated. Recrystal-
lization of the residue using EtOAc–hexane gave Boc-glycine (74
mg, 85%).
1
tert-Butyl 4,6-Dimethoxy-1,3,5-triazinyl Carbonate (Boc-DMT)
To a suspension of 4,6-dimethoxy-1,3,5-triazin-2-ol (HO-DMT;
10.0 g, 63.8 mmol) in CH2Cl2 (255 mL), at r.t. under a N2 atmo-
sphere, were added di-t-butyl dicarbonate (13.3 g, 60.7 mmol), fol-
lowed by pyridine (480 mg, 6.1 mmol). After stirring for 24 h at r.t.,
the solvent was removed by evaporation. The residue was treated
with Et2O (200 mL), and the resulting precipitate was removed by
filtration. The filtrate was concentrated, and the residual oil was pu-
rified using a short column of silica gel (90 mm diameter × 30 mm
in length and activated charcoal 5 mm in length; hexane–EtOAc,
7:3) to give Boc-DMT as a colorless oil (10.6 g, 68%).
IR (KBr): 1056, 1028, 959, 883, 860, 787, 736, 677 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H, t-Bu), 3.86–4.02 (m,
2 H, CH2), 5.06 (br s, 1 H, NH).
Reactions with other amino acids were carried out similarly as de-
scribed above. In each case, the products were confirmed using
spectroscopic data of commercial products.
Reaction of Fmoc-DMT with Amines or Amino acids
To a solution of phenylalanine (0.13 mmol) in H2O (1 mL) contain-
ing Na2CO3 (0.26 mmol) at r.t. was added Fmoc-DMT (0.156
mmol) in MeCN (1 mL). After stirring for 30 min, most of the
MeCN was removed by evaporation under reduced pressure. The
resulting aqueous solution was acidified with 20% citric acid to pH
3–4, and then extracted with EtOAc (30 mL). The extracts were
washed with H2O (2 × 15 mL) and brine (20 mL), dried over
MgSO4, concentrated, and then subjected to recrystallization using
EtOAc–hexane to afford Fmoc-phenylalanine (46.2 mg; 92%); mp
179–182 °C.
1H NMR (400 MHz, CDCl3): d = 1.57 (s, 9 H, t-Bu), 4.05 (s, 6 H,
OMe).
Anal. Calcd for C10H15N3O5: C, 46.69; H, 5.88. Found: C, 46.64; H,
5.87.
9-Fluorenylmethyl 4,6-Dimethoxy-1,3,5-triazinyl Carbonate
(Fmoc-DMT)
To a solution of 4,6-dimethoxy-1,3,5-triazin-2-ol (HO-DMT; 668
mg, 4.3 mmol) in CH2Cl2 (180 mL), at r.t. under a N2 atmosphere,
were added 9-fluorenylmethyl chloroformate (1.0 g, 3.9 mmol) and
Et3N (391 mg, 3.9 mmol). After stirring for 1 h at r.t. the reaction
mixture was washed with H2O (2 × 50 mL), dried over MgSO4, and
concentrated. Recrystallization of the residue using EtOAc–hexane
gave the desired product as colorless crystals (1.39 g, 95%); mp
100–103.5 °C.
1H NMR (400 MHz, CDCl3): d = 4.06 (s, 6 H, OMe), 4.34 (t, J = 7.4
Hz, 1 H, CH), 4.57 (d, J = 7.4 Hz, 2 H, CH2), 7.33 (td, J = 1.2, 7.5
Hz, 2 H), 7.42 (ddd, J = 0.6, 1.2, 7.5 Hz, 2 H), 7.64 (ddd, J = 0.8,
1.9, 7.5 Hz, 2 H), 7.77 (td, J = 0.8, 7.5 Hz, 2 H).
IR (KBr): 1676, 1538, 1435, 1341, 1230, 1038, 740 cm–1.
1H NMR (400 MHz, CD3OD): d = 2.94 (dd, J = 9.5, 13.9 Hz, 1 H,
PhCH2), 3.21 (dd, J = 4.8, 13.9 Hz, 1 H, PhCH2), 4.14 (br t, J = 7.1
Hz, 1 H, Ar2CH), 4.22 (dd, J = 7.1, 10.4 Hz, 1 H, OCH2), 4.29 (dd,
J = 7.2, 10.4 Hz, 1 H, OCH2), 4.42 (dd, J = 4.8, 9.5 Hz, 1 H, BnCH),
7.17–7.31 (m, 7 H, Ph, fluorene), 7.37 (t, J = 7.5 Hz, 2 H, fluorene),
7.59 (d, J = 7.5 Hz, 2 H, fluorene), 7.77 (d, J = 7.5 Hz, 2 H, fluo-
rene).
References
(1) Hioki, K.; Fujiwara, M.; Tani, S.; Kunishima, M. Chem.
Lett. 2002, 1, 66.
Anal. Calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C,
63.32; H, 4.67; N, 11.01.
(2) (a) Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.;
Iwasaki, F.; Tani, S. Tetrahedron 1999, 55, 13159.
(b) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani,
S. Tetrahedron 2001, 57, 1551.
(3) (a) Amino Acid Derivatives, A Practical Approach; Oxford
University Press: New York, 1999. (b) Nájera, C. Synlett
2002, 1388; and references cited therein.
Reaction of Boc-DMT with Lipophilic Amines
To a solution of Boc-DMT (386 mg, 1.5 mmol) in MeCN (3.0 mL)
at r.t. was added phenethylamine (121 mg, 1.0 mmol). After stirring
for 15 min at r.t., the resulting precipitate was removed by filtration.
The filtrate was concentrated under reduced pressure, then re-dis-
solved in EtOAc (30 mL), and washed with H2O (2 × 15 mL) and
brine (20 mL), successively. The organic layer was dried over
MgSO4, concentrated under reduced pressure, and then purified us-
ing silica gel column chromatography (hexane–EtOAc, 85:15) to
afford tert-butyl phenethylcarbamate (203 mg, 91%).
(4) Kunishima, M.; Hioki, K.; Wada, A.; Kobayashi, H.; Tani,
S. Tetrahedron Lett. 2002, 43, 3323.
(5) (a) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani,
S. Tetrahedron 2001, 57, 1551. (b) Kunishima, M.;
Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.; Tani, S.
Tetrahedron 1999, 55, 13159.
IR (KBr): 3349, 2977, 2931, 1693, 1523, 1365, 1249, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 9 H, t-Bu), 2.78 (t, J = 7.0
Hz, 2 H, PhCH2), 3.29–3.43 (m, 2 H, NHCH2), 4.48–4.67 (m, 1 H,
NH), 7.16–7.24 (m, 3 H, Ph), 7.27–7.32 (m, 2 H, Ph).
Reactions with other lipophilic amines were carried out similarly as
described above.
Synthesis 2006, No. 12, 1931–1933 © Thieme Stuttgart · New York