Highly efficient and mild synthesis of variously 5-substituted-4-carbaldehyde-1,2,3-triazole derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01923-2

Synthesis of variously 5-substituted-4-carbaldehyde-1,2,3-triazole derivatives 2 was accomplished by reacting sodium azide with α,β-acetylenic aldehydes 1 in DMSO at room temperature. Therefore, the reaction remains basic avoiding the generation of the hazardous explosive HN₃, resulting in a safe process. This mild and general reaction was instantaneous and was essentially quantitative.

Full text of DOI:10.1016/S0040-4039(01)01923-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9117–9118
Highly efficient and mild synthesis of variously
-substituted-4-carbaldehyde-1,2,3-triazole derivatives
5
Michel Journet,* Dongwei Cai,* Jason J. Kowal and Robert D. Larsen
Department of Process Research, Merck Research Laboratories, PO Box 2000, RY800-B267, Rahway, NJ 07065-0900, USA
Received 20 August 2001; revised 10 October 2001; accepted 15 October 2001
Abstract—Synthesis of variously 5-substituted-4-carbaldehyde-1,2,3-triazole derivatives 2 was accomplished by reacting sodium
azide with a,b-acetylenic aldehydes 1 in DMSO at room temperature. Therefore, the reaction remains basic avoiding the
generation of the hazardous explosive HN , resulting in a safe process. This mild and general reaction was instantaneous and was
3
essentially quantitative. © 2001 Elsevier Science Ltd. All rights reserved.
The 1H-1,2,3-triazole heterocyclic entity is a very inter-
esting component in terms of biological activity. Indeed,
the 1,2,3-triazole moiety is present in a number of drugs
such as the b-lactam antibiotic Tazobactam or the
cephalosporine Cefatrizine just to name a few. As part
of an ongoing program in our laboratories, we became
interested in preparing a 1,2,3-triazole aldehyde deriva-
tive as a key building block in the synthesis of a drug
with an activated triple bond has been investigated
primarily with acetylenic esters. Surprisingly, upon
5
checking the literature, we found very few examples of
the cycloaddition between azides and acetylenic alde-
5
b,6
hydes,
and the synthesis of 1,2,3-triazole-4-carbalde-
7
hydes had not been studied extensively. A recent
example was reported using an acetylenic silyl ketone run
at high temperatures in refluxing toluene for several
1
2
8
candidate. The 1,3-dipolar cycloaddition reaction is a
well-established and general method for the construction
of five-membered ring heterocycles. In particular, addi-
tion of azides to acetylenes has been a method of choice
hours albeit in moderate yields. Subsequent desilylation
provided 4-carbaldehyde-1,2,3-triazoles, however lack-
ing substitution at the 5-position. In our case it was also
important to use sodium azide instead of an alkyl azide
since no substitution on the nitrogen was desired. Also,
3
for the synthesis of 1,2,3-triazoles. Consequently, per-
6b,c
forming reactions with azides has become a useful tool
the reportedly used hydrazoic acid
for us for obvious safety reasons.
was not an option
4
in industrial organic synthesis. Cycloaddition of azides
H
R
O
1
) 1 equiv n-BuLi; THF; -40 ºC
O
H
1) 1.1 equiv NaN ; DMSO; r.t.
3
R
R
2) 2 equiv DMF; -40 ºC to r.t.; 0.5h
2) Hydrolysis
N
N
(a)
1
N
H
2
3) "Reverse" 10% aq. KH PO (4 equiv);
2
4
MTBE; 5 ºC
Entry
R
Yield (%)
(Ref. 9)
a
b
c
d
e
f
Ph
TBSO(CH2)3
THPO(CH2)2
THPOCH2
(a)
Position of the triazole NH is arbitrarily assigned since
we cannot differentiate reliably between NH tautomers.
>
98
TBSOCH2
n-C H
4
9
Scheme 1.
*
0
Corresponding authors. Fax: (732)594-1499; e-mail: michel journet@merck.com; dongwei cai@merck.com
–
–
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01923-2

9
118
M. Journet et al. / Tetrahedron Letters 42 (2001) 9117–9118
Herein, we wish to report the efficient preparation of
variously 5-substituted-4-carbaldehyde-1,2,3-triazole
Industrial Organic Synthesis’ at The BACS Conference
Europe 98.
5. (a) Huisgen, R.; Szeimies, C.; Knorr, R. Chem. Ber. 1965,
98, 4014; (b) Looker, J. J. J. Org. Chem. 1965, 30, 638; (c)
Khetan, S. K.; George, M. V. Can. J. Chem. 1967, 45,
1993.
derivatives under mild conditions. Since the ease of the
azide cyclization is governed by polarization of the
acetylene, we thought that a,b-acetylenic aldehydes
would be highly reactive towards sodium azide. There-
fore, we first designed an efficient synthesis of a,b-
acetylenic aldehydes 1 by simple formulation of
6. (a) Hu3 ttel, R. Ber. 1941, 74B, 1680; (b) Sheehan, J. C.;
Robinson, C. A. J. Am. Chem. Soc. 1951, 73, 1207; (c)
Birkofer, L.; Richtzenhain, K. Chem. Ber. 1979, 112,
2829.
9
acetylides with DMF. As expected, they reacted
instantaneously with sodium azide in DMSO at room
temperature to give the corresponding triazoles 2 in
essentially quantitative yield (Scheme 1). In addition, it
is noteworthy that the reaction remains basic avoiding
7. Rearrengements of 1H-1,2,3-triazole-4-carbaldehydes to
replace the 1-aryl substituent have been studied started
from the known 1-phenyl-1,2,3-triazole-4-carbaldehyde
(Ref. 6a): (a) L’abb e´ , G.; Bruynseels, M.; Delbeke, P.;
Toppet, S. J. Heterocyclic Chem. 1990, 27, 2021; (b)
L’abb e´ , G.; Bruynseels, M. J. Chem. Soc., Perkin Trans.
1 1990, 1492.
8. Degl’Innocenti, A.; Scafato, P.; Capperucci, A.; Barto-
letti, L.; Mordini, A.; Reginato, G. Tetrahedron Lett.
1995, 36, 9031.
the generation of the hazardous explosive HN , result-
3
ing in a safe process. The mode of addition as well as
good mixing were important to achieve a clean reac-
tion. Indeed, acetylenic aldehydes 1a–f must be reverse-
1
0
added into a vigorously stirred DMSO solution
1
1
containing 1.1 equiv. of sodium azide leading to the
1
2
1,2,3-triazole aldehydes 2a–f.
9
. Journet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D.
General procedure: To a vigorously stirred solution of
Tetrahedron Lett. 1998, 39, 6427.
1
0
dissolved sodium azide (3.57 g, 55 mmol) in DMSO
110 mL) was added a DMSO solution of the aldehyde
(50 mmol in 35 mL of DMSO) over 10 min maintain-
10. Starvation of azide during addition led to decomposition.
We believe that in the absence of sodium azide, the
triazole aldehyde anion added onto 1 triggering its poly-
merization.
11. Since the excess azide in the waste stream can be a
potential hazard, 1.0 equiv. of azide can be used still
leading to a quantitative yield of the triazole and keeping
the azide level 530 ppm into the aqueous. Sodium azide
was assayed by reverse phase HPLC: C-18 Metachem
inertsil ODS-3 column (250×4.6 mm, 5 mm) with a flow
rate of 0.75 mL/min (UV detection @ 200 nm). Elution:
gradient using a 10/90 mixture of CH CN/H O (0.1%
(
1
ing the temperature between 20 and 25°C over an
ice-water bath. The resulting reaction mixture was
stirred at room temperature for 30 min and was poured
into a vigorously stirred biphasic solution prepared
from a 15% aqueous solution of KH PO (300 mL, 300
2
4
mmol) and MTBE (350 mL) at room temperature.
Layers were separated and the organic extract was
washed with water (2×250 mL). Combined aqueous
layers were back extracted with MTBE (100 mL). Com-
bined organic layers were dried over MgSO4, filtered
and concentrated to give the crude triazole aldehyde
derivative in >98% yield with no purification needed.
3
2
H PO ) to 30/70 in 20 min. t for azide was 7.35 min.
3
4
R
1
12. H NMR (400 MHz, CDCl ) for 1,2,3-triazole aldehydes
3
2. Compound 2a: registry no. 2579-22-8. Compound 2b:
l 10.22 (s, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.16 (t, J=7.0
Hz, 2H), 1.96 (quin., J=7.0 Hz, 2H), 0.89 (s, 9H), 0.07 (s,
6H). Compound 2c: l 10.23 (s, 1H), 4.65 (br s, 1H),
References
4.05–4.12 (m, 1H), 3.79–3.86 (m, 2H), 3.50–3.53 (m, 1H),
1
2
. (a) Cai, D.; Journet, M.; Larsen, R. D. US Patent
,051,707; (b) Cai, D.; Journet, M.; Kowal, J.; Larsen, R.
D. US Patent 6,051,717.
. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John
Wiley and Sons: NY, 1984.
. L’abb e´ , G. Chem. Rev. 1969, 69, 345.
3.34–3.38 (m, 2H), 1.63–1.78 (m, 2H), 1.49–1.56 (m, 4H).
Compound 2d: l 10.24 (s, 1H), 5.21 (br d, J=15.3 Hz,
1H), 5.03 (d, J=15.3 Hz, 1H), 4.74 (br t, J=3.8 Hz, 1H),
3.98–4.03 (m, 1H), 3.57–3.63 (m, 1H), 1.84–1.90 (m, 2H),
1.56–1.65 (m, 4H). Compound 2e: l 10.23 (s, 1H), 5.13 (s,
2H), 0.95 (s, 9H), 0.17 (s, 6H). Compound 2f: l 10.23 (s,
1H), 3.07 (t, J=7.7 Hz, 2H), 1.70 (quin., J=7.6 Hz, 2H),
1.35 (hex., J=7.7 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H).
6
3
4
. Peer, M. (Dynamit Nobel GmbH) ‘Performing Haz-
ardous Reactions with Sodium Azide: A Useful Tool in