N-acyl and N-alkoxycarbonyl derivatives of 1H-1,2,3-triazolo-[4,5-c] pyridine; preparation and application

Article abstract of DOI:10.1002/jhet.5570430223

The N-acylating and N-alkoxycarbonylation ability of the N-substituted 1,2,3-triazolo[4,5-c]pyridines 1a-e have been investigated. The alkoxycarbonyl triazolopyridine derivatives (1c-e) were readily prepared in 81-96% yield (the corresponding tetrafluoroborate > 95%). Triazolo[4,5-c]pyridine (1) has been shown to work as a good leaving group by the formation of amido- and carbamate protected derivatives of primary amines. The method was also successful for the N-tert-butoxycarbonyl (N-BOC) protection of the amino acid, phenylalanine. The synthetic transformations are facilitated by the one-pot preparation of 1a-e followed by the direct reaction with the amines or amino acid. The present method thus offers an efficient and convenient protocol for the in situ preparation of triazolopyridine reagents to be used directly for the protection of amines and amino acids. N-Acyl- and N-alkoxycarbonyl triazolopyridines (1a-e) were readily prepared in 4 steps from 4-aminopyridine (4) by amine protection, pyridine nitration, nitro reduction and diazotizations/cyclizations. All reactions offer the advantages of rapid conversions in high yields under very mild conditions.

Full text of DOI:10.1002/jhet.5570430223

Mar-Apr 2006
417
N-Acyl and N-Alkoxycarbonyl Derivatives of 1H-1,2,3-Triazolo-
[
4,5-c]pyridine; Preparation and Application
*
Jarle Holt and Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology, NTNU
N-7491 Trondheim, Norway
(
Anne.Fiksdahl@chem.ntnu.no)
X
N
N
NH
N
2
NH-
N
X
X NH
i) Ac O / Bz O/
in situ
2
N
2
2
NO2
H /Pd/C
NH
R
NH2
ClCO
2
R
prep.
2
R
NH-X
N-acylation
N-alkoxy-
ii) N
2
O
5
/SO
2
N
NOBF
2 min
N
HBF4
4
nitration
carbonylation
triazolopyridine
derivative
2 min
X = Ac, Bz, CO Me, CO Et, CO tBu
R = i-Pr, Bn
2
2
2
The N-acylating and N-alkoxycarbonylation ability of the N-substituted 1,2,3-triazolo[4,5-c]pyridines
a-e have been investigated. The alkoxycarbonyl triazolopyridine derivatives (1c-e) were readily prepared
1
in 81-96 % yield (the corresponding tetrafluoroborate > 95 %). Triazolo[4,5-c]pyridine (1) has been shown
to work as a good leaving group by the formation of amido- and carbamate protected derivatives of
primary amines. The method was also successful for the N-tert-butoxycarbonyl (N-BOC) protection of the
amino acid, phenylalanine. The synthetic transformations are facilitated by the one-pot preparation of 1a-e
followed by the direct reaction with the amines or amino acid. The present method thus offers an efficient
and convenient protocol for the in situ preparation of triazolopyridine reagents to be used directly for the
protection of amines and amino acids. N-Acyl- and N-alkoxycarbonyl triazolopyridines (1a-e) were readily
prepared in 4 steps from 4-aminopyridine (4) by amine protection, pyridine nitration, nitro reduction and
diazotizations/cyclizations. All reactions offer the advantages of rapid conversions in high yields under
very mild conditions.
J. Heterocyclic Chem., 43, 417 (2006).
Introduction.
The use of N-acylbenzotriazole (3-Ac, see Scheme 1) as
an effective neutral acylating agent for the preparation of
primary, secondary and tertiary amides has been reported
by Katritzky et al. [11]. As an alternative to N-acyl-
imidazole several advantages have been reported for the
N-acylbenzotriazoles. They are stable crystalline non-
volatile storable intermediates and allow the acyl group to
be introduced and removed easily by simple work-up
procedures.
Katritzky et al. have demonstrated the synthetic
auxiliary properties of benzotriazole [12]. Due to the
activation of the carbon to which the triazole is attached, a
series of synthetic transformations can be performed. The
reaction principle have been applied for the C-acylation of
sulfones in the preparation of ꢀ-ketosulfones [13], of alkyl
cyanides to ꢁ-substituted ꢀ-ketonitriles [14] and for the
synthesis of ꢀ-dicarbonyl compounds [15], as well as for
regiospecific C-acylation of heterocycles [16]. 1,2,3-
Triazolo[4,5-b]pyridine (2) has also been studied for its
acylation and alkoxycarbonylation abilities [6].
Some substituted 1,2,3-triazolopyridines (1,2) are
analgesic, antipyretic, antiasthmatic or useful as inflam-
mation inhibitors [1,2] while others have been patented
for their anxiolytic antidepressant properties [3] and
herbicidal activity [4]. The 1,2,3-triazolo[4,5-c]pyridine
(
1) is a commercially available fine chemical, but to our
knowledge, only to a very high price. Substituted 1,2,3-
triazolopyridines (1,2) have previously been prepared by
amine substitution of a chloroaminopyridine followed by
diazotization and cyclization [1,5]. Diazotization of ethyl
2
-aminopyridyl-3-carbamate with isoamyl nitrite in acetic
acid has been reported to give the ethyl 3-carbamate
derivative of 1,2,3-triazolo[4,5-b]pyridine (2) [6] while
1
,2,3-benzotriazole (3) has been synthesized in high
yields by diazotization of o-phenylenediamine with
sodium nitrite in acetic acid solution followed by
cyclization [7-10].
HN
N
HN
N
The high reactivity of these acylating agents is caused
by the relative weakness of the “amide” bond; the
aromatic character of the heterocycle makes the -:N-C=O
less delocalized and therefore less stabilized compared to
regular amides. Triazolopyridine (1) is expected to be an
H
N
N
N
N
N
N
N
1
2
3
1
,2,3-triazolo[4,5-c]pyridine 1,2,3-triazolo[4,5-b]pyridine benzotriazole

4
18
J. Holt and A. Fiksdahl
Vol 43
Scheme 1
N-acylamine
amine
sulfone
O
Ms
RC
HN
N
ꢀ-ketosulfone
N
N
N
N
N
MsCl, pyr
RCOOH
Et
N
N
alkylnitriles
ketone
ꢀ
-ketonitrile
3
N
benzotriazole
ꢀ
-diketone
3
3-Ms
3-Ac
heterocycles
C-acylation
O
Ms
RC
HN
N
N
N
N
N
N
N
N
MsCl, pyr
RCOOH
Et N
R'NH2
R'NHCOR
3
N
N
N
1
1-Ms
1-Ac
even better leaving group than benzotriazole 3 due to the
diazonium intermediate afforded the non-derivatised
triazolopyridine (1) in quantitative yield. However, by
less vigorous diazotization conditions, using iso-amyl
nitrite and tetrafluoroboric acid in ethanol or nitrosonium
tetrafluoroborate in acetonitrile, the carbamates 7c-e were
readily converted to the alkoxycarbonyl triazolopyridines
(1c-e) and isolated as the corresponding tetrafluoroborates
in > 95 % yield. Respectively, the “free” triazolopyridine
derivatives (1c-e) were prepared in 81-96 % yield by
acetic acid and iso-amyl nitrite [6] for characterization.
The N-acyltriazolopyridines (1a,b) were correspondingly
obtained by iso-amyl nitrite/tetrafluoroboric acid or
nitrosonium tetrafluoroborate diazotization of the amides
ꢀ
-electron-deficient character of the pyridine moiety.
We have investigated the corresponding N-acylating
and N-alkoxycarbonylation properties of the triazolo-
pyridine derivatives 1a-e aiming at the formation of
amido- and carbamate protected derivatives of primary
amines and BOC amino acids. The method was also
applied on one amino acid for the preparation of the N-
tert-butylcarbonyl (BOC) derivative. The diazotization
reactions of 3,4-diaminopyridine derivatives (7a-e) for the
preparation of the 1,2,3-triazolopyridine derivatives (1a-e)
have been studied. The key substrates for our syntheses of
1
a-e are 4-substituted 3-nitropyridines, which have now
7
a,b. The hydrolysis product 1 was readily prepared by
been readily available through an improved nitration
method [17,18].
heating crystalline 1a in sulfuric acid (2 %).
In general, either iso-amyl nitrite/tetrafluoroboric acid or
nitrosonium tetrafluoroborate could be used for the
diazotization and cyclization of 7a-e to the triazolo
3
,4-Diaminopyridine, which is a suitable substrate for
the preparation of unsubstituted 1,2,3-triazolopyridine (1)
5], has also readily been prepared by the improved
[
1
products 1a-e. H nmr of the crude products showed
nitration method, affording higher yields [19] compared
to previous methods [20].
quantitative and spontaneous formation of the cyclic
products 1a-e by both methods. The triazolopyridines 1a-e
are formed as tetrafluoroborates. Our experience was,
however, that especially the amido products 1a,b were
sensitive to moisture due to water in the tetrafluoroboric
acid solution. We observed that the amidotriazolo
compounds 1a,b were less stable than the carbamates 1c-e,
using the tetrafluoroboric acid/iso-amyl nitrite reaction
conditions, since 1a,b easily hydrolyzed to triazolopyridine
1 during work-up from the tetrafluoroboric acid solution.
Nearly quantitative yields of all the crude products 1a-e
were obtained using nitrosonium tetrafluoroborate, as
Results and Discussion.
Preparation of Triazolopyridine Derivatives 1a-e.
The acyl- and alkoxycarbonyl triazoles 1a-e were
readily available from 4-aminopyridine (4) via 7a-e in
four steps, as shown in Scheme 2. The nitration of 4-
aminopyridine (4) was carried out after protection of the
-amino group by acyl or alkoxycarbonyl groups to give
a,b and 6c-e, respectively [19,21]. Methyl carbamate 6c
has also been prepared by nitration of methyl 4-
pyridylcarboxylate (5) followed by diazotization of the
hydrazide intermediate and Curtius rearrangement in
methanol [22]. The amides (7a,b) and carbamates (7c-e)
were obtained by selective reduction of the nitro group
in quantitative yield by catalytic hydrogenation. As
expected, traditional diazotization (sodium nitrite, sulfuric
acid) of the methyl carbamate 7c and cyclization of the
4
6
1
shown by H nmr. To avoid hydrolysis of the triazolo
derivatives 1a-e we therefore preferred the milder
nitrosonium tetrafluoroborate method.
The cyclization of 7a-e to the triazolo compounds 1a-e
1
could easily be followed by H nmr. Due to the
deshielding effect of the triazolo moiety, unusual high
pyridine proton frequencies were in particular observed

Mar-Apr 2006
N-Acyl and N-Alkoxycarbonyl Derivatives of 1H-1,2,3-Triazolo[4,5-c]pyridine
419
for H-2 for the tetrafluoroborates of 1a-e. This is demon-
strated by the pyridine chemical shift of H-2 of 1c tetra-
fluoroborate; ꢀ 9.89 in deuterochloroform and 10.33 in d6-
acetone, respectively. The ir spectra of the triazolo
derivatives were also characteristic as shown by the high
frequency strong carbonyl absorptions at approximately
borates of the cyclic triazolopyridines 1a-e by addition of
nitrosonium tetrafluoroborate, the immediate reactions with
the subsequently added iso-propylamine or benzylamine
1
were complete within few minutes, as shown by H nmr.
The amine derivatives 8a-j were isolated in 72 - 84 % yield
by flash chromatography without extraction (Table 1). We
observed that the in situ prepared triazolopyridine tetra-
fluoroborate reagents (1c-e tetrafluoroborates) were more
reactive than the “free” triazolopyridine reagents (1c-e),
due to the activation by protonation of the triazolopyridine
in order to improve its leaving group ability.
Katritzky’s method [11] (Scheme 1) is based on the
non-derivatised benzotriazole substrate and involves an
additional benzotriazole mesylation step (3 to 3-Ms)
before acylation (3-Ms to 3-Ac) and eventually the
-1
1
(
800 cm , most predominant for the methyl carbamate
1c).
We experienced that the methoxy- and ethoxycarbonyl
derivatives 1c,d could be purified by flash chroma-
tography and that the crystalline products 1c,d could be
stored at room temperature for weeks. The tert-butyl
carbamate 1e and the acyl compounds 1a,b were however
less stable and could neither be stored nor isolated by
chromatography.
Scheme 2
NH
2
i) Ac
ii) N
nitration
2
O / Bz
2
O
NHAc / Bz
NO
2
O
5
/SO
2
2
X
X
HN
N
N
N
N
N
NH
2
diazotization,
NOBF4 or
acylation,
alkoxy-
carbonylation
H
>
2
/Pd/C
99 %
i) ClCO R
2
4
6a,b
ii) N
2
O
5
/SO
2
N
nitration
HBF
4
/ iAmONO
HBF4
CO R
2
CO Me
HN
2
triazolopyridine
7a-e
NO2
1a-e
i) N
2 5 2
O /SO ,nitration
1, 6, 7
X = H
ii) N H
2
4
1a, 6a, 7a X = Ac
b, 6b, 7b X = Bz
1c, 6c, 7c X = CO Me
N
N
iii) diazotization
iv) Curtius rearr.
heat, -N ,ROH
2
1
6c-e
5
2
1d, 6d, 7d X = CO Et
2
1
e, 6e, 7e X = CO tBu
2
N-Acylation and N-Alkoxycarbonylation.
reaction with the substrate to be modified. By preparation
of both the mesyltriazolopyridine 1-Ms and benzotriazole
Due to their high reactivity, the prepared triazolo-
pyridines 1a-e were used immediately for the derivatization
of amines. For synthetic use we thus developed a
convenient method for the in situ preparation of 1a-e
followed by the direct reaction with amines (Scheme 3).
After the spontaneous and complete conversion of the non-
cyclic precursors 7a-e to the corresponding tetrafluoro-
3
1
-Ms by the Katritzky method [11], the triazolopyridine
-Ms was, as expected, less stable than 3-Ms. Similarly to
the acyltriazolopyridines (1a,b) 1-Ms had to be used for
synthetic purposes immediately and could not be properly
characterised or stored. Compared to the Katritzky
methodology (in Scheme 1), following our protocol
Table 1
Protection of iso-propyl- and benzylamine with triazolopyridine reagents 1a-e (see Scheme 3).
Triazolopyridine
Amine
Product
Conversion/Yield [a]
[ref]
1
1
1
1
1
a
b
c
iso-propylamine
benzylamine
iso-propylamine
benzylamine
iso-propylamine
benzylamine
iso-propylamine
benzylamine
8a; X = Ac, R = i-Pr
8b; X = Ac, R = Bn
8c; X = Bz, R = i-Pr
8d; X = Bz, R = Bn
>99 % / 76 %
>99 % / 72 %
>99 % / 72 %
>99 % / 73 %
>99 % / 76 %
>99 % / 84 %
>99 % / 73 %
>99 % / 73 %
>99 % / 74 %
>99 % / 73 %
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
8e; X = CO
2
Me, R = i-Pr
Me, R = Bn
2
Et, R = i-Pr
8f; X = CO
8g; X = CO
8h; X = CO
2
d
e
2
Et, R = Bn
iso-propylamine
benzylamine
8i; X =CO
8j; X = CO
2
t-Bu, R = i-Pr
2
t-Bu, R = Bn
1
[
a] Conversion is based on H nmr of crude product reaction mixture. Yields are calculated after chromatography.

4
20
J. Holt and A. Fiksdahl
Vol 43
Scheme 3
X
N
HN
N
N
in situ
R NH
2
N
N
H
N
prep.
NOBF4
7a-e
R
X
+
N-acylation
2
min
N
N
N-alkoxycarbonylation
HBF4
2
min
8a-j
1
1
a-e
8a
8c
8e
8g
8i
R = i-Pr, X = Ac
R = i-Pr, X = Bz
R = i-Pr, X = CO Me
R = i-Pr, X = CO Et
R = i-Pr, X = CO t-Bu
8b R = Bn, X = Ac
8d R = Bn, X = Bz
8f R = Bn, X = CO Me
8h R = Bn, X = CO Et
8j R = Bn, X = CO t-Bu
2
2
2
2
2
2
(
Scheme 2,3), the N-acyl or the N-alkoxycarbonyl groups
carbamate (N-BOC) protection of the amino acid
phenylalanine (9a). The protection reactions of iso-propyl-
and benzylamines were complete within few minutes and
the amides and carbamates 8a-j, were isolated in 72 -84 %
yield. Longer reaction time was needed for the amino acid
since L-phenylalanine was converted to the BOC protected
amino acid (76 %) in 4 days.
The synthetic transformations were facilitated by
development of the in situ preparation method of 1a-e to
offer the advantages of a one-pot procedure. N-Acyl- and
N-alkoxycarbonyl-1,2,3-triazolo[4,5-c]pyridine (1a-e) were
readily prepared in 4 steps from 4-aminopyridine (4) by
amine protection, pyridine nitration, nitro reduction and
diazotization/cyclization.
Our strategy thus offers an efficient and convenient
protocol for the in situ preparation of triazolopyridine
reagents to be used directly for the protection of amines.
All reactions are performed quickly in high yields under
very mild conditions. The triazolopyridine method may
have a synthetic potential for a series of transformations
and may represent a supplement to the benzotriazole
methodology.
have already been introduced, and the acyl- and
alkoxycarbonyl triazoles (1a-e) can be made directly by
diazotization and cyclization. For our purposes the
mesylated intermediate (1-Ms) can thus be left out.
Protective groups are important in amino acid chemistry.
Carbamates are in particular used as protective groups for
amino acids to minimize racemization in peptide synthesis.
Since the tert-butoxy carbamate (BOC) group, is
extensively used for amino acid protection, the tert-butoxy
carbonyl (BOC)-triazolopyridine method was applied on
one amino acid to demonstrate the versatility of the
method. In a similar manner as above for the primary
amines, L-phenylalanine ethyl ester 9a (Scheme 4) was
reacted with BOC-triazolopyridine 1e, prepared in situ, to
give the BOC protected amino acid 9b. The reaction was
slower than the previous ones (8a-j) and full conversion to
the BOC amino acid 9b, was obtained in 4 days, as shown
1
by H nmr of the reaction mixture. After chromatography
7
protected amino acid 9b was not lost during the reaction.
6 % yield was obtained. The optical purity of the BOC
Scheme 4
EXPERIMENTAL
NH
2
Ph
OEt
Chemicals: Nitrosonium tetrafluoroborate (Sigma), tetra-
BOC
O
O
N
N
O-tBu
fluoroboric acid and iso-propylamine (Acros), iso-amyl nitrite
in situ prep.of
L-Phe 9a
HN
1
13
N
7e
and benzylamine (Fluka); solvents: pro analysi quality. H/ C
nmr: Bruker Avance DPX 300 and 400 MHz spectrometers,
chemical shifts are reported in ppm downfield from tetramethyl
silane. Hexafluorobenzene was correspondingly used as
BOC-triazolopyridine
Ph
OEt
alkoxy-
carbonylation
76 %
O
N
HBF
4
1
e
9b
1
9
reference for F nmr. J values are given in Hz. ms: Finnigan
MAT 95 XL (EI / 70 eV). ir: Nicolet 20SXC FT-IR spectro-
photometer. All melting points are uncorrected, measured by
Griffin apparatus. Elemental analysis was measured by an
Elementar Vario III instrument at the Institute of Chemical
Technology, Prague. Flash chromatography: Silica (sds, 60 Å,
Conclusion.
The N-acylating and N-alkoxycarbonylation ability of the
,2,3-triazolopyridine derivatives 1a-e were studied. The
1
alkoxycarbonyl triazolopyridine derivatives (1c-e) were
readily prepared in 81-96 % yield and the corresponding
tetrafluoroborates in > 95 % yield. 1,2,3-Triazolo[4,5-
c]pyridine (1) has been shown to work as a good leaving
group in the acylation and alkoxycarbonylation of amines.
The method was also successful for the N-tert-butyl
4
0-63 μm). The intermediates 6a-e and 7a-e were prepared by
nitration and reduction according to the literature [21,33-35].
Triazolopyridine Derivatives (1a-e).
Tetrafluoroborates were prepared for characterization by the
following general diazotization procedure: A solution of 7a-e

Mar-Apr 2006
N-Acyl and N-Alkoxycarbonyl Derivatives of 1H-1,2,3-Triazolo[4,5-c]pyridine
421
(
100 mg, 0.47-0.66 mmol), tetrafluoroboric acid (43-63 mg, 1.05
%), 150 (13), 135 (53), 119 (15), 107 (100), 91 (12), 80 (26);
HRMS: calcd for C H N O ; 178.04908, observed 178.04917.
equivalent) and iso-amyl nitrite (58-81 mg, 1.05 equiv.) in
7
6
4
2
ethanol (1 ml) was stirred at 0 °C for approx. 15 minutes. The
product 1a-e were afforded as tetrafluoroborates, pure by H
1
1-Ethoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1d)
Tetrafluoroborate.
nmr. The acyl (1a,b) and the tert-butyl carbamate (BOC, 1e)
products easily hydrolyzed into the non-derivatised triazolo-
pyridine 1 by extraction and isolation and were therefore
prepared in situ (see below) and used directly in the next step
without further purification. Only methoxy- and ethoxycarbonyl-
triazolopyridine (1c,d) were fully characterized as their
respective tetrafluoroborates, while the “free” methoxy, ethoxy
and tert-butoxy triazolopyridine derivatives (1c,d,e) were
characterized after preparation by acetic acid and iso-amyl
nitrite [6]. For synthetic use, all compounds 1a-e were prepared
in situ and reacted directly with the amines, see general N-
acylation/N-alkoxycarbonylation procedure below.
1
This compound was prepared from 7d, pure by H nmr
(quantitative conversion, > 95 % isolated yield); mp 143.5-144.5
°C (pentane); ir (potassium bromide) 3066w, 1771s, 1635s,
1613s, 1558m, 1498m, 1323s, 1109s, 1070s, 1018s, 958m, 838m,
786s, 713m cm ; H nmr (300 MHz, d -dimethyl sulfoxide): ꢀ
1.60 (t, J 7.1, 3H), 4.75 (q, J 7.1, 2H), 8.30 (d, J 6.1, 1H, H-2),
8.88 (d, J 6.1, 1H, H-6), 9.85 (s, 1H, H-5); C nmr (75 MHz, d6-
dimethyl sulfoxide): ꢀ 13.9, 65.9, 109.6, 136.8, 142.2, 143.0,
145.1, 147.5; F nmr (376 MHz, d -dimethyl sulfoxide) ꢀ -148.1.
-1
1
6
1
3
1
9
6
Anal. Calcd. for C H BF N O : C, 34,32; H, 3,24; N, 20,01.
8
9
4
4
2
Found: C, 33.98; H, 3,23; N, 19,75.
1
-Acetyl-1H-1,2,3-triazolo[4,5-c]pyridine (1a) Tetrafluoroborate.
1-Ethoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1d).
Free 1d was prepared according to literature [6] to give 96 %
1
This compound was prepared from 7a, pure by H nmr
1
1
(quantitative conversion); H nmr (300 MHz, d -dimethyl
yield, pure by H nmr; mp 170-171 °C; ir (potassium bromide)
6
sulfoxide): ꢀ 3.01 (s, 3H), 8.46 (d, J 6.2, 1H, H-5), 8.60 (d, J
3159m, 2989m, 1790s, 1710s, 1593m, 1514m, 1477m, 1401w,
13
-1 1
6
.2, 1H, H-6), 9.86 (s, 1H, H-2); C nmr (100 MHz, d -dimethyl
1366m, 1319w, 1231s, 1062s, 837w, 795w, 772w cm ; H nmr
(300 MHz, deuteriochloroform): ꢀ 1.61 (t, J 7.1, 3H), 4.74 (q, J
7.1, 2H), 8.04 (dd, J 1.0, 5.7, 1H, H-2), 8.78 (d, J 5.7, 1H, H-6),
6
1
9
sulfoxide): ꢀ 12.6, 111.1, 135.8, 139.7, 142.4, 143.1, 170.0. F
nmr (376 MHz, d -dimethyl sulfoxide) ꢀ -148.8.
6
1
3
9
.56 (d, J 1.0, 1H, H-5); C nmr (75 MHz, deuteriochloroform):
1-Benzoyl-1H-1,2,3-triazolo[4,5-c]pyridine (1b) Tetrafluoroborate.
ꢀ
13.8, 65.5, 107.7, 135.6, 142.4, 144.2, 147.6, 147.9; ms: m/z
1
+
This compound was prepared from 7b, pure by H nmr
192 (M , 25 %), 164 (6), 136 (100), 120 (54), 105 (2), 92 (61),
80 (12); HRMS: calcd for C H N O ; 192.0647 observed
1
(quantitative conversion);
H nmr (400 MHz, deuterio-
8
8
4
2
chloroform): ꢀ 7.38 (m, 2H, Ph-H), 7.52 (m, 1H, Ph-H), 7.86 (d,
192.06419.
J 7.2, 2H), 8.33 (d, J 6.8, 1H, H-5), 8.60 (d, J 6.8, 1H, H-6), 9.81
1
3
1-tert-Butoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1e)
Tetrafluoroborate.
(
1
s, 1H, H-2); C nmr (100 MHz, deuteriochloroform): ꢀ 110.7,
28.4, 129.0, 129.3, 133.5, 135.1, 138.5, 140.0, 140.6, 169.8. F
1
9
1
nmr (376 MHz, d -dimethyl sulfoxide) ꢀ -148.3.
This compound was prepared from 7e, pure by H nmr
6
1
(
quantitative conversion, > 95 % isolated yield); H nmr (300
1
-Methoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1c)
MHz, d -dimethyl sulfoxide): ꢀ 1.72 (s, 9H), 8.35 (d, J 6.4, 1H,
6
Tetrafluoroborate.
13
H-5), 8.84 (d, J 6.4, 1H, H-6), 9.97 (s, 1H, H-2); C nmr (100
1
This compound was prepared from 7c, pure by H nmr
quantitative conversion). 1c tetrafluoroborate precipitated
MHz, deuteriochloroform): ꢀ 27.7, 89.9, 111.8, 135.9, 141.7,
1
9
(
142.8, 146.0, 149.4; F nmr (376 MHz, d -dimethyl sulfoxide) ꢀ
6
quantitatively from the reaction solution and could be
recrystallized (> 95 %); mp 156-157 °C (acetone). ir (potassium
bromide) 3274s, 3147m, 3087m, 2969w, 1800s, 1644s, 1618m,
-148.9.
1
-tert-Butoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1e).
Free 1e was prepared from 7e and nitrosonium tetrafluoro-
-
1
1
552m, 1474s, 1437m, 1369m, 1253s, 1090s, 943m, 911s cm ;
1
H nmr (400 MHz, d -dimethyl sulfoxide): ꢀ 4.30 (s, 3H), 8.38
borate and added triethyl amine to give 81 % yield of free 1e,
pure by H nmr; mp 87-88 °C; ir (potassium bromide) 3004m,
6
1
(d, J 6.1, 1H, H-5), 8.89 (d, J 6.1, 1H, H-6), 9.89 (s, 1H, H-2);
correspondingly in d -acetone: ꢀ 4.37 (s, 3H), 8.88 (d, J 6.8,
2989m, 1782m, 1709s, 1601w, 1364s, 1321w, 1255m, 1222m,
1152m, 1092m, 1040m, 930w, 828w cm ; H nmr (400 MHz,
6
1
3
-1
1
1
H, H-5), 9.25 (d, J 6.8, 1H, H-6), 10.33 (s, 1H, H-2); C nmr
(
1
ꢀ
75 MHz, d -dimethyl sulfoxide): ꢀ 56.0, 110.6, 135.8, 140.6,
deuteriochloroform): ꢀ 1.79 (s, 9H), 7.98 (dd, J 0.8, 5.6, 1H, H-
2), 8.74 (d, J 5.6, 1H, H-6), 9.52 (s, 1H, H-5); C nmr (100
MHz, deuteriochloroform): ꢀ 27.9, 88.0, 108.1, 135.9, 142.9,
6
19
13
42.4, 145.4, 148.2; F nmr (376 MHz, d -dimethyl sulfoxide)
6
-148.5.
Anal. Calcd. for C H BF N O : C, 31.61; H, 2.65; N, 21.07.
144.5, 146.5, 147.7.
7
7
4
4
2
Found: C, 31.67; H, 2.54; N, 20.85.
1
-Methylsulfonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1-Ms).
This compound was made according to the procedure for N-
1
-Methoxycarbonyl-1H-1,2,3-triazolo[4,5-c]pyridine (1c).
Free 1c was prepared according to literature [6] to give 92 %
yield, pure by H nmr; mp 139-140 °C; ir (potassium bromide)
(1-methanesulfonyl)benzotriazole (3-Ms) [11] in 30 % yield.
1
The compound was unstable and could not be isolated for full
1
3
1
106m, 3000w, 2972w, 1794s, 1626m, 1475m, 1448m, 1377s,
330m, 1256s, 1213s, 1181s, 1062s, 922m, 844m, 759m, 587m
characterization; H nmr (300 MHz, deuteriochloroform): 3.54
(s, 3H), 7.86 (dd, J 5.80, 1H), 8.69 (d, J 5.80, 1H), 9.47 (d, J 1.0,
-
1
1
13
cm ; H nmr (300 MHz, deuteriochloroform): ꢀ 4.28 (s, 3H),
1H); C nmr (75 MHz, deuteriochloroform): ꢀ 43.1, 106.6,
8
1
1
.03 (dd, J 1.1, 5.7, 1H, H-2), 8.78 (d, J 5.7, 1H, H-6), 9.60 (d, J
135.8, 141.9, 144.8, 147.9. IR (film): 3651, 3422, 2254, 1598,
1
3
-1
.1, 1H, H-5); C nmr (75 MHz, d -dimethyl sulfoxide): ꢀ 56.2,
1386, 1255, 1194, 1179, 967, 734 cm ; ir (potassium bromide)
6
+
-1
08.4, 136.5, 143.3, 145.1, 148.6, 149.3; ms: m/z 178 (M , 51
1598w, 1386m, 1193s, 1179s cm ;

4
22
J. Holt and A. Fiksdahl
Vol 43
1
H-1,2,3-Triazolo[4,5-c]pyridine (1).
N-Alkoxycarbonylation of L-phenylalanine Ethyl Ester 9a.
A solution of 7c (120 mg, 0.72 mmol), in water (6 ml) was drop-
L-Phenylalanine ethyl ester N-tert-butyl carbamate (9b) [36]
was prepared from L-phenylalanine ethyl ester hydrochloric salt
9a and tert-butoxycarbonyltriazolopyridine 1e (prepared in situ
from 7e) as described above for the amine derivatives 8i and 8j.
However, larger excess of BOC-triazolopyridines 1e (2
equivalents) was used and the reaction was performed in the
presence of triethyl amine (2 equivalents). Four days reaction
time was needed to obtain 76 % yield after flash chroma-
tography (20 % ethyl acetate in hexane). The product was
characterized according to literature [37].
wise added sulfuric acid (conc. 0.1 ml). The mixture was stirred,
cooled to 0 °C and drop-wise added a solution of sodium nitrite (124
mg, 1.8 mmol, 2.5 equivalents) in water (3 ml) during 10 minutes.
The reaction mixture was left stirring at 0 °C for 1 hour and refluxed
for 3 hours. The pH was adjusted to 5-6 by addition of a saturated
sodium carbonate solution. An off-white crystalline product, pure by
1
H nmr, was obtained after extraction, drying and evaporation of the
solvent (85 mg, 99 %). 1 was also quantitatively prepared from
triazolo carbamate 1c by heating in 2 % sulfuric acid for 20 minutes;
mp 186-187 °C; ir (potassium bromide) 3414m, 1625m, 1457w,
Acknowledgements.
-1
1
1
323w, 1139s, 995m, 620s cm ; H nmr (300 MHz, d -dimethyl
6
Financial support from the Research Council of Norway is
gratefully acknowledged.
sulfoxide): ꢀ 7.89 (d, J 5.9, 1H, H-5), 8.49 (d, J 5.9, 1H, H-6), 9.47 (s,
13
1
H, H-1); C nmr (75 MHz, d -dimethyl sulfoxide): ꢀ 107.5, 139.0,
6
+
140.0, 141.7, 142.4; ms: m/z 120 (M , 100 %), 92 (81), 65 (48), 52
(
20); HRMS: calcd for C H N 120.04360, observed 120.04329.
REFERENCES AND NOTES
5
4
4
N-Acylation and N-Alkoxycarbonylation of Primary Amines by
[
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1
a-e, Prepared in situ.
(
[
The amides and carbamates 8a-j [23-32] were prepared from iso-
6
propylamine or benzylamine, respectively, and 1a-e, prepared in situ
from 7a-e, by the following general procedure: The appropriate 3-
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[
(
[
[
(
[
[
(
20 % ethyl acetate in hexane) without previous extraction and
DD 273630 (1989); Chem. Abstr. 112, 235324 (1989).
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(1940).
characterized in accordance with literature data [23-39].
1
N-iso-Propylacetamide 8a [23]: (76 %); H nmr (300 MHz,
[
11] A. R. Katritzky, H.-Y. He and K. Suzuki, J. Org. Chem., 65,
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deuteriochloroform): ꢀ 5.34 (br, 1H), 4.06 (hept, J 6.6, 1H), 1.95
8
(
s, 3H), 1.15 (d, J 6.6, 6H).
N-Benzylacetamide 8b [24]: (72 %); H nmr (300 MHz,
deuteriochloroform): ꢀ 7.24-7.31 (m, 5H), 6.53 (br, 1H), 4.35
1
(
[
(d, J 5.5, 2H), 1.95 (s, 3H).
N-iso-Propylbenzamide 8c [25, 38]: (72 %).
N-Benzylbenzamide 8d [26, 39]: (73 %).
[
Org. Chem., 68, 4932 (2003).
1
Methyl N-iso-propylcarbamate (8e) [27]: (76 %); H nmr (400
MHz, deuteriochloroform): ꢀ 1.15 (d, J 6.4, 6H), 3.65 (s, 3H),
.80 (m, 1H), 4.49 (br., 1H).
Methyl N-benzylcarbamate (8f) [28]: (84 %); H nmr (300
MHz, deuteriochloroform): ꢀ 7.27 (m, 5H), 5.19 (br, 1H), 4.33
d, J 5.8, 2H), 3.67 (s, 3H).
Ethyl N-iso-propylcarbamate (8g) [29]: (73 %); H nmr (300
MHz, deuteriochloroform): ꢀ 1.15 (d, J 6.5, 6H), 1.24 (t, J 7.1,
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[
3
1
[
(
[
[
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3
H), 3.81 (m, 1H), 4.11 (q, J 7.1, 2H), 4.55 (br, 1H).
1
Ethyl N-benzylcarbamate (8h) [30]: (73 %); H nmr (300
2
MHz, deuteriochloroform): ꢀ 7.27 (m, 5H), 5.18 (br, 1H), 4.32
[
(d, J 5.9, 2H), 4.11 (q, J 7.1, 2H), 1.23 (t, J 7.1, 3H).
1
tert-Butyl N-iso-propylcarbamate (8i) [31]: (74 %); H nmr
400 MHz, deuteriochloroform): ꢀ 4.35 (br, 1H), 3.76 (m, 1H),
[
(
1
.46 (s, 9H), 1.14 (d, J 6.4, 6H).
tert-Butyl N-benzylcarbamate (8j) [32]: (73 %); H nmr (300
MHz, deuteriochloroform): ꢀ 7.28 (m, 5H), 4.89 (br, 1H), 4.30
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[
1
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(

Mar-Apr 2006
N-Acyl and N-Alkoxycarbonyl Derivatives of 1H-1,2,3-Triazolo[4,5-c]pyridine
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[
[
[
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