NH-1,2,3-triazoles from azidomethyl pivalate and carbamates: Base-labile N-protecting groups

Article abstract of DOI:10.1055/s-2005-918944

NH-1,2,3-triazoles have been prepared via the copper(I)-catalyzed 1,3-dipolar cycloaddition between terminal alkynes and three N-protected organic azides, azidomethyl pivalate, azidomethyl morpholine-4-carboxylate, and azidomethyl N,N-diethylcarbarnate. T

Full text of DOI:10.1055/s-2005-918944

LETTER
2847
NH-1,2,3-Triazoles from Azidomethyl Pivalate and Carbamates:
Base-Labile N-Protecting Groups
N
H
-1, 2,3-
o
Triazoles
f
ro
n
m
A
zidomethyl Piv
C
alate and
C
arbam
.
ates Loren, Antoni Krasiński, Valery V. Fokin, K. Barry Sharpless*
The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC-315,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Fax +1(858)7845672; E-mail: sharples@scripps.edu
Received 17 August 2005
Dedicated to the memory of Dr. Anne-Ghosez Giese.
H
N
N
N
R2
Abstract: NH-1,2,3-triazoles have been prepared via the copper(I)-
catalyzed 1,3-dipolar cycloaddition between terminal alkynes and
three N-protected organic azides, azidomethyl pivalate, azido-
methyl morpholine-4-carboxylate, and azidomethyl N,N-diethyl-
carbamate. These organic azides were easily prepared on 0.1-mol
scale in one or two steps from inexpensive commercially available
materials. The cleaving properties of N-substituents in the resulting
1,2,3-triazole products with aqueous sodium hydroxide vary from
<10 minutes at room temperature in the case of N-methyl pivalate,
to 24 hours at room temperature in the case of N-methyl morpho-
line-4-carboxylate, to 24 hours at 85 °C in the case of N-methyl
diethylcarbamate.
N
N
N
R1
R1
H
H
A
B
Figure 1
Here we introduce three new organic azides as precursors
to base-labile protected NH-triazoles using copper(I)-
catalyzed dipolar cycloaddition and note their require-
ments for deprotection, which results in water soluble by-
products and simplified product purification. Further
highlights of this work are the inexpensive starting
materials and the suitability for large-scale syntheses.
Thus, we have addressed the issues of chemical synthesis
connected to NH-triazoles in one concerted effort using a
click chemistry approach.9
Key words: triazoles, click chemistry, azides, protecting groups,
alkynes, cycloaddition, heterocycles
Classically, the synthesis of N-unsubstituted 1,2,3-tri-
azole heterocycles A (simply termed NH-triazoles in the
following) is exemplified by alkyne cycloaddition with
hydrazoic acid1 or sodium azide.2 Related methods in-
volve organic azides with removable protecting group
substituents on nitrogen; an attractive feature since the in-
cipient heterocycle allows potential structural elaboration
that would otherwise be interrupted by the NH moiety. In
particular, tropylium (1,3,5-cycloheptatriene),3 methoxy-
benzyl,4 and SEM [(trimethylsilyl)ethoxymethyl] azides5
have been used in this manner, but often suffer from high
cost or requisite harsh cleaving conditions to reveal the
parent heterocycle. Under thermal cycloaddition condi-
tions, conjugated electron-withdrawing groups on the
alkyne component are essential for high yields or conver-
sions,6 and with hydrazoic acid, associated hazards can
jeopardize the safety of large-scale syntheses. The cop-
per(I)-catalyzed ‘click reaction’ is ideally suited for syn-
thesis of 1,4-disubstituted 1,2,3-triazoles B,7 but to date is
not optimized with sodium azide for the synthesis of NH-
triazoles. Recently, trimethylsilyl azide was demonstrated
as a viable precursor in the synthesis of NH-triazoles me-
diated by copper. However, it does not have the benefit of
an isolable N-substituted (protected) triazole intermediate
and likely involves hydrazoic acid as the reactive species.8
The preparation of azidomethyl pivalate (1), azidomethyl
morpholine-4-carboxylate (3a) and azidomethyl N,N-di-
ethylcarbamate (3b) was achieved on 0.1-mol scale in
either one or two steps, commencing with commercially
available substrates (Scheme 1). Treatment of chloro-
methyl pivalate with aqueous sodium azide under hetero-
geneous conditions afforded 1 in analytically pure form
upon work-up. Similarly, 2a and 2b, which were prepared
by the addition of chloromethyl chloroformate to two
equivalents of morpholine or diethyl amine, respectively,
afforded 3a and 3b in high yield and purity, requiring only
simple work-up for purification. These azides are easy to
handle, stable liquids that have shelf lives in excess of
several months at room temperature. Additionally, they
tolerate neat heating to 80 °C without any significant
decomposition.
Azides 1 and 3a,b underwent facile cycloaddition with
commercially available alkyl- and aryl-substituted
alkynes using the standard copper(II) sulfate/sodium
ascorbate conditions,7a resulting in 1,4-disubstituted
1,2,3-triazoles 4a–k, 5a–k and 6a–l in moderate to excel-
lent yields (Scheme 2).10 In most cases the resulting tri-
azoles were isolated in pure form by filtration after
precipitation with water from the crude reaction mixtures.
However, when the resulting products were oils, aqueous
work-up with ethyl acetate or diethyl ether was employed.
Product purification was not required except for the
SYNLETT 2005, No. 18, pp 2847–2850
0
3
.1
1
.2
0
0
5
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918944; Art ID: Y06505ST
© Georg Thieme Verlag Stuttgart · New York

2848
J. C. Loren et al.
LETTER
O
O
NaN3 (1.5 equiv)
O
Cl
O
N3
H2O
90 °C, 12 h
74%
1
O
O
O
0 °C → r.t.
NaN3 (1.5 equiv)
+
R
H
R
O
N3
Cl
O
Cl
R
O
Cl
CH2Cl2
0.5 h
H2O
r.t., 12 h
R =
O
N
2a 99%
2b 97%
3a 98%
3b 90%
N
Scheme 1 Synthesis of azidomethyl pivalate (1) and carbamates (3a,b).
aniline derivatives 4c, 5c and 6c, which were accompa- groups (sodium chloride, formaldehyde, and secondary
nied by unavoidable baseline materials that were easily amine or pivalic acid) remain in solution and do not im-
separated by column chromatography. The N-methyl pede product isolation. Although the reactions proceed
pivalate and carbamate protected triazoles are stable with complete conversion of starting material, the moder-
solids, and in solution at room temperature are unreactive ate isolated yields of 7b (60–66%) suggest some water
towards aqueous acid.11
solubility of the desired product. Furthermore, the sequen-
tial preparation of 7b from 3a and phenylacetylene was
performed on a 0.1 mol scale (15.8 g based on 3a), which
resulted in 10.7 g of isolated product (87% over two
steps), an improvement over the smaller scale synthesis.
This scalable feature coupled with the ease of product
isolation/purification makes this method attractive for
NH-triazole synthesis on multi-gram scale.
CuSO4·5H2O
(0.05 equiv)
O
O
sodium ascorbate
(0.30 equiv)
N
R
O
N
N
R
O
N3
+
R'
t-BuOH-H2O 2:1
R'
r.t., 1–2 d
R =
1
4a–k
5a–k
O
N
1) NaOH (2.2 equiv)
3a
Ph
MeOH–H2O 1:1,
r.t., <10 min
O
very mild
O
N
N
N
3b
6a–l
N
2) 1 M HCl
(2.2 equiv)
4b
R' substituents found in Table 1.
Scheme 2 Copper(I)-catalyzed formation of protected NH-1,2,3-
triazoles.10
1) NaOH (2.2 equiv)
MeOH–H2O 1:1,
r.t., 24 h
Ph
Ph
O
moderate
N
O
N
N
HN
N
Phenylacetylene and its resulting NH-triazole, 4-phenyl-
NH-1,2,3-triazole (7b), were chosen for our initial pro-
tecting group investigations. After screening a variety of
cleavable azide/triazole substituents, N-methyl pivalate
emerged as an attractive candidate,12 which was cleaved
from the triazole with diluted aqueous sodium hydroxide
at room temperature in only a few minutes. In order to im-
prove the stability of the protecting group, we examined
N-mono- and N,N-disubstituted azidomethyl carbam-
ates.13 The azidomethyl pivalate 1 and carbamates 3a,b
were ultimately chosen because their cleavage could be
achieved with aqueous sodium hydroxide under very mild
(in less than 10 min at r.t. for 4b), moderate (in 24 h at r.t.
for 5b), and harsh (24 h at 85 °C for 6b) conditions
(Scheme 3). Product 7b was isolated in pure form by fil-
tration after neutralization with aqueous HCl and precipi-
tation with water, thus the by-products of the protecting
N
N
O
2) 1 M HCl
(2.2 equiv)
5b
7b
1) NaOH (2.2 equiv)
MeOH–H2O 1:1,
85 °C, 24 h
Ph
O
strong
N
O
N
N
N
2) 1 M HCl
(2.2 equiv)
6b
Scheme 3 Requirements for the hydrolysis step in the synthesis of
4-phenyl-NH-1,2,3-triazole (7b).
The deprotection conditions optimized for 7b were ap-
plied to the cognate aryl and alkyl derivates 4a–k, 5a–k,
and 6a–l in order to explore substrate scope (Table 1). In
nearly every case the desired product was obtained in
Synlett 2005, No. 18, 2847–2850 © Thieme Stuttgart · New York

LETTER
NH-1,2,3-Triazoles from Azidomethyl Pivalate and Carbamates
2849
moderate to good yield under all three (time and tempera- Table 1 Deprotection of Aryl and Alkyl Derivatives 4a–k, 5a–k,
and 6a–l
ture) conditions. However, certain functional groups such
as the nitrile in 6d, were not tolerant to heating in the
O
NaOH
N
N
presence of sodium hydroxide. Additionally, the methyl
esters 4k, 5k and 6k were quantitatively converted into
their carboxylic acid products 7k. The synthesis of 4,5-
dimethoxymethyl-NH-1,2,3-triazole 7l was achieved un-
der neat thermal conditions (80 °C, 5 d) with 3b and 1,4-
dimethoxybut-2-yne followed by treatment with aqueous
sodium hydroxide, and incidentally demonstrates the ther-
mal stability of the azidomethyl N,N-diethylcarbamate.
HN
N
R
O
N
N
MeOH:H2O
R'
R'
R =
4a–k
5a–k
6a–l
7a–l
N
N
O
In summary, the set of organo-azides presented here,
azidomethyl pivalate, azidomethyl morpholine-4-carbox-
ylate and azidomethyl N,N-diethylcarbamate enable a
facile route to NH-1,2,3-triazoles from base-labile pro-
tected precursors prepared via the copper(I)-catalyzed
click reaction with terminal alkynes. The safe, easy and
inexpensive preparation of these protected azides makes
them attractive alternatives to hydrazoic acid for cyclo-
addition with alkynes and suitable for large-scale syn-
theses. Furthermore, their stability to aqueous acid and 7c
varying conditions for alkaline deprotection provide con-
trol over neighboring functional group selection and a
range of reaction/work up conditions. The pivalate and
carbamate moieties validated here for azide and 1,2,3-tri-
Number Product (R¢)
Yield (%)d from
4a
5b
6c
7a
7b
83
63
93
N
N
N
OMe
HN
60
–
62
–
66
63
0
N
HN
N
N
N
NH2
HN
7d
86
97
79
92
N
CN
HN
7e
98
F3C
O2N
azole are worth testing as protecting groups for other
nitrogen-containing functionalities.
N
N
HN
7f
70
60
76
N
N
N
Azidomethyl Pivalate (1)
Sodium azide (13.7 g, 0.21 mol) was added to a suspension of
chloromethyl pivalate (21.2 g, 0.14 mol) in H2O (25 mL) and stirred
vigorously at 90 °C for 12 h. Subsequently, the reaction was diluted
with H2O (25 mL). The organic layer was separated, filtered
HN
7g
69
60
–
82
98
N
HN
N
7h
96
CF3
through a pad of anhyd MgSO4 and evaporated under vacuum to
N
1
N
yield a clear liquid (16.4 g, 74%). H NMR (300 MHz, CDCl3):
d = 5.12 (s, 2 H), 1.24 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 177.99, 74.32, 38.91, 26.93. IR: 2976 (C–H), 2104 (N3), 1739
HN
CF3
(C=O) cm–1.
7i
75
85
96
OH
N
N
N
HN
General Experimental Procedures for the Copper(I)-Catalyzed
1,4-Disubstituted 1,2,3-Triazole Formations:
[4-(4-Methoxyphenyl)-1,2,3-triazol-1-yl]methyl Pivalate (4a)
Azidomethyl pivalate (0.31 g, 2.0 mmol) and 4-ethynylanisole
(0.26 mL, 2.0 mmol) were suspended in 1:1 H2O–t-BuOH (6 mL).
To this was added CuSO4·5H2O (0.02 mL of 5 M solution, 0.1
mmol, 5 mol%) and sodium ascorbate (0.12 g, 0.6 mmol). The mix-
ture was stirred at r.t. for 24 h, at which time TLC (silica, hexane–
EtOAc 4:1) indicated complete conversion. The reaction mixture
was partitioned between EtOAc and H2O. The organic layer was
washed with 5% aq NH4OH (2 × 10 mL), and brine, dried over
MgSO4, filtered, and the solvent was removed under vacuum to
yield an off-white solid (0.46 g, 81%). Mp 89–90 °C. 1H NMR (300
MHz, CDCl3): d = 7.93 (s, 1 H), 7.75 (d, J = 8.7 Hz, 2 H), 6.94 (d,
J = 8.7 Hz, 2 H), 6.24 (s, 2 H), 3.82 (s, 3 H), 1.18 (s, 9 H). 13C NMR
(75 MHz, CDCl3): d = 177.84, 159.71, 148.02, 127.06, 122.58,
120.05, 114.18, 69.65, 55.23, 38.71, 26.73. EMS: m/z calcd for
C15H19N3O3: 290.1 [M + H]+, 312.1 [M + Na]+; found: 290.0 [M +
H]+, 312.0 [M + Na]+.
7j
58
72
–
–
OEt
OEt
N
HN
7k
65
75
COOH
OMe
N
N
HN
7l
–
–
78
N
HN
N
MeO
a Reaction conditions for 4a–k: NaOH (2.2 equiv), MeOH–H2O, r.t.,
30 min.
b Reaction conditions for 5a–k: NaOH (2.2 equiv), MeOH–H2O, r.t.,
24 h.
c Reaction conditions for 6a–l: NaOH (2.2 equiv), MeOH–H2O,
85 °C, 24 h, sealed vial.
d No yield (–) indicates reaction was not performed.
Synlett 2005, No. 18, 2847–2850 © Thieme Stuttgart · New York

2850
J. C. Loren et al.
LETTER
General Experimental Procedure for N-Methyl Pivalate
Removal (NH-1,2,3-Triazole Formation) as Exemplified for
4-(4-Methoxyphenyl)-NH-1,2,3-triazole (7a)
(7) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Torrnøe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(8) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004,
3789.
(9) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(10) Suporting information (experimental procedures, yields and
characterizations for compounds 4a–k, 5a–k, 6a–l) is
available from the authors upon request . Aryl and alkyl
alkyne groups (R¢) are found in Table 1.
(11) The ease of synthesis of N,N-disubstituted azidomethyl
carbamate from secondary amines suggests that polymer-
supported azidomethyl carbamates can be prepared and be
converted to N-anchored triazoles. The latter would be
cleavable under basic, rather than acidic conditions reported
earlier. See: Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-
Kauhaluoma, J. J. Comb. Chem. 2003, 5, 826.
(12) The pivaloyloxymethyl (POM) group, introduced by means
of pivaloyloxymehtyl chloride, is a nitrogen-protecting
group in nucleoside base chemistry. It was also used to a
limited extent as a base-labile protecting group for nitrogen
atoms in heterocycles such as imidazoles, tetrazoles,
pyrroles and indoles. See: (a) Rasmussen, M.; Leonard, N.
J. J. Am. Chem. Soc. 1967, 89, 5439. (b) Araki, L.;
Harusawa, S.; Yamaguchi, M.; Yonezawa, S.; Taniguchi,
N.; Lilley, D. M. J.; Zhaob, Z.; Kuriharaa, T. Tetrahedron
Lett. 2004, 45, 2657. (c) Kalindjian, S. B.; Buck, I. M.;
Davies, J. M. R.; Dunstone, D. J.; Hudson, M. L.; Low, C.
M. R.; McDonald, I. M.; Pether, M. J.; Steel, K. I. M.; Tozer,
M. J.; Vinter, J. G. J. Med. Chem. 1996, 39, 1806.
(d) Dhanak, D.; Reese, C. B. J. Chem. Soc., Perkin Trans.
1986, 1, 2181.
To a solution of [4-(4-methoxyphenyl)-1,2,3-triazol-1-yl]methyl
pivalate (4a, 0.29 g, 1 mmol) in MeOH (2.2 mL) was added NaOH
(1 M aq solution, 2.2 mL). The reaction was stirred at r.t. for 30 min
and subsequently neutralized with HCl (1 M aq solution, 2.2 mL)
and diluted with H2O (20 mL). The resulting precipitate was fil-
tered, washed with H2O (10 mL) and dried under vacuum to yield
the product in pure form. White solid (0.14 g, 83%). Mp 165–
1
166 °C. H NMR (300 MHz, CDCl3): d = 8.00 (s, 1 H), 7.70 (d,
J = 8.5 Hz, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H). EMS: m/z
calcd for C9H9N3O3: 176.0 [M + H]+, 198.0 [M + Na]+; found: 175.9
[M + H]+, 197.9 [M + Na]+.
Acknowledgment
The authors thank the National Institutes of General Medical
Science, National Institutes of Health (GM28384 and GM48870),
the Skaggs Foundation and the W. M. Keck Foundation for finan-
cial support.
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(13) Azidomethyl N-tert-butyl carbamate was also studied. It is
quantitatively removed from the 1,2,3-triazole nitrogen
under conditions similar to the morpholine 4-carboxymethyl
group. However N,N¢-di-tert-butyl urea byproduct
complicated product purification.
Synlett 2005, No. 18, 2847–2850 © Thieme Stuttgart · New York