Regioselective synthesis of 1-(2,2-dimethoxyethyl)-1,2,3-triazoles by copper(I)-catalyzed [3+2] cyclization of 2-azido-1,1-dimethoxyethane with alkynes

Article abstract of DOI:10.1016/j.tetlet.2007.09.069

1-(2,2-Dimethoxyethyl)-1,2,3-triazoles are regioselectively prepared by copper(I)-catalyzed [3+2] cyclizations of 2-azido-1,1-dimethoxyethane with alkynes.

Full text of DOI:10.1016/j.tetlet.2007.09.069

Tetrahedron Letters 48 (2007) 7923–7925
Regioselective synthesis of 1-(2,2-dimethoxyethyl)-
1,2,3-triazoles by copper(I)-catalyzed [3+2]
cyclization of 2-azido-1,1-dimethoxyethane with alkynes
Muhammad Sher,a,b Helmut Reinkea and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 14 July 2007; revised 10 September 2007; accepted 11 September 2007
Available online 15 September 2007
Abstract—1-(2,2-Dimethoxyethyl)-1,2,3-triazoles are regioselectively prepared by copper(I)-catalyzed [3+2] cyclizations of 2-azido-
1,1-dimethoxyethane with alkynes.
Ó 2007 Elsevier Ltd. All rights reserved.
2-Azido-1,1-dimethoxyethane (ADE) represents a small,
but versatile C2-building block containing a masked
aldehyde and a masked amino group. It can be readily
prepared by reaction of 1-chloro- or 1-bromo-2,2-
dimethoxyethane with sodium azide.1,2 Despite its struc-
tural simplicity and potential synthetic usefulness, there
are only a few reports related to the reactions of ADE.
The reaction of ADE with p-toluenesulfonic acid in
acetone and water afforded azidoacetic aldehyde.3 Two
pyrroles were prepared by TiCl4-mediated condensation
of ADE with silyl enol ethers and subsequent reductive
cyclization.4 We reported the synthesis of functionalized
2-alkylidenepyrrolidines and pyrroles based on Me3-
SiOTf-catalyzed reactions of ADE with 1,3-bis(silyl enol
ethers) and subsequent cyclization by the Staudinger–
aza-Wittig reaction.2 The Staudinger–aza-Wittig reac-
tion of 2-azido-1,1-diethoxyethane with 1,3-dicarbonyl
compounds afforded 3-(1-aza-3,3-diethoxypropyl)alk-2-
en-1-ones, which were subsequently transformed into a
variety of functionalized pyrroles.5 The Staudinger–
aza-Wittig reaction of ADE with aldehydes was
reported to give iminoacetals.1 Herein, we report what
are, to the best of our knowledge, the first [3+2] cyclo-
addition reactions of ADE. These reactions provide a
convenient approach to 1-(2,2-dimethoxyethyl)-1,2,3-
triazoles. To the best of our knowledge, only one exam-
ple of this type of molecule has been reported so far.6 It
has been previously reported that acetals, aldehydes and
ketones are inert during the formation of triazoles by
[3+2] cyclizations.7 We believe that the triazoles
reported herein will be useful synthetic building blocks
in organic and medicinal chemistry. In fact, 1,2,3-tri-
azoles are emerging as powerful pharmacophores.8
Our starting point was the reaction of ADE (1) with
dimethyl acetylenedicarboxylate. The reaction of an
ethanol solution of the starting materials in a pressure
tube (2 h, 120 °C) afforded 1,2,3-triazole 3a in excellent
yield (Scheme 1). The structure of 3a was independently
confirmed by X-ray crystal structure analysis (Fig. 1).9
The thermal [3+2] cyclization of azides with terminal
alkynes often suffers from low regioselectivities.10 1,4-
Disubstituted 1,2,3-triazoles can be regioselectively pre-
pared by copper(I)-catalyzed [3+2] cyclization of azides
with terminal alkynes.11 The reaction of ADE (1) and
methyl propynoate (2b), dissolved in a 1:1 mixture of
OMe
+
N
OMe
OMe
N3
N
OMe
N
i
1
CO2Me
MeO2C
MeO2C
CO2Me
2a
3a (85%)
*
Scheme 1. Synthesis of 1,2,3-triazole 3a. Reagents and conditions: (i)
EtOH, 2 h, 120 °C.
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.069

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M. Sher et al. / Tetrahedron Letters 48 (2007) 7923–7925
conditions. The structure of products 3b–k was
confirmed by 2D NMR experiments.
The acetal group of 1-(2,2-dimethoxyethyl)-1,2,3-tri-
azoles 3 can be further functionalized as exemplified
by the following experiment. The reaction of 3c with
tosylhydrazine in the presence of hydrochloric acid
and subsequent treatment with thionyl chloride13 affor-
ded 1,2,3-thiadiazole 5 (Scheme 3).14
Acknowledgement
Financial support by the state of Mecklenburg-
Vorpommern is gratefully acknowledged.
Figure 1. Ortep plot of 3a.
N
OMe
OMe
References and notes
OMe
N
i
N
R
+
R
N3
OMe
1. Katritzky, A. R.; Yang, Z.; Cundy, D. J. Heteroatom
Chem. 1994, 5, 103–106.
2b-k
3b-k
1
2. Bellur, E.; Go¨rls, H.; Langer, P. J. Org. Chem. 2005, 70,
4751–4761.
3. Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457–3465.
Scheme 2. Synthesis of 1,2,3-triazoles 3b–k. Reagents and conditions:
(i) Cu/CuSO4 (5 mol %), H2O, t-BuOH, 2 h, 110 °C.
water and tert-butanol (2 h, 110 °C), gave 1-(2,2-dimeth-
oxyethyl)-1,2,3-triazole 3b in excellent yield (Scheme 2,
Table 1).12 Likewise, the cyclization of ADE with alky-
nes 2c–k afforded the 1-(2,2-dimethoxyethyl)-1,2,3-tri-
azoles 3c–k. All products were formed in excellent
yields and with very good regio- and chemoselectivity.
It is noteworthy that a number of different functional
groups (acetal, hydroxyl, amino and trimethylsilyl
groups) proved to be compatible with the reaction
4. Bertschy, H.; Meunier, A.; Neier, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 777–780.
5. Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 2151–
2154.
6. Saalfrank, R. W.; Weiss, B.; Wirth, U.; Peters, K.; von
Schnering, H. G. Z. Naturforsch. B 1989, 44, 587–
597.
7. (a) Lo¨ber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org.
Lett. 2003, 5, 1753–1755; (b) Barral, K.; Moorhouse, A.
D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811; (c) de
Oliveira, R. N.; Sinou, D.; Srivastava, R. M. J. Carbohydr.
Chem. 2006, 25, 407–425.
8. (a) Bourne, Y.; Kolb, H. C.; Radic, Z.; Sharpless, K. B.;
Taylor, P.; Marchot, P. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 1449–1454; (b) Lewis, W. G.; Green, L. G.;
Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
1053–1057.
9. CCDC 657500 contains all crystallographic details of this
publication and is available free of charge at www.ccdc.cam.
ac.uk/conts/retrieving.html or can be ordered from the
following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; fax:
(+44)1223 336 033; or deposit@ccdc.cam.ac.uk.
10. Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; pp 1–176.
11. (a) Tornoe, C. W.; Meldal, M. In 17th American Peptides
Symposium Proceedings Book. Peptides: The Wave of the
Future; Lebl, M., Houghten, R. A., Eds.; Peptidotriazoles:
Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions on Solid-
phase; American Peptide Society and Kluwer Academic:
San Diego, 2001; pp 263–264; (b) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057–3064; (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V.
V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596–2599; (d) Krasinski, A.; Fokin, V. V.; Sharpless, K.
B. Org. Lett. 2004, 6, 1237–1240; (e) Moses, J. E.;
Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–1262.
12. Typical procedure: Phenylacetylene (500 mg, 4.89 mmol)
and 2-azido-1,1-dimethoxyethane (705 mg, 5.38 mmol)
were suspended in a 1:1 mixture of water and tert-butanol
Table 1. Products and yields
a
3
R
%
b
c
d
e
f
CO2Me
Ph
4-(nBuO)C6H4
CH2Ph
(CH2)2OH
CH(OH)Et
CH(OH)cHex
C(OH)Me2
N(Me)CH2Ph
SiMe3
84
75
76
80
82
85
89
84
72
88
g
h
i
j
k
a Yields of isolated products.
N
OMe
OMe
N
ii
N
N
N
Ts-NHNH2
i
N
N
NHTs
Ph
Ph
3c
4
N
S
N
N
N
N
Ph
5 (60%)
Scheme 3. Synthesis of 1,2,3-thiadiazole 5. Reagents and conditions:
(i) concd HCl, EtOH, reflux, 12 h; (ii) SOCl2, neat, 20 °C, 2 h.

M. Sher et al. / Tetrahedron Letters 48 (2007) 7923–7925
7925
(5 mL each). To this mixture was added copper turning
(50 mg) and an aqueous solution of copper sulfate (1 M,
5 mol %) and the mixture was heated at 110 °C for 2 h.
After cooling, the reaction mixture was diluted with water
(20 mL). The precipitated product was filtered off and
washed with cold water (20 mL) and subsequently with
petroleum ether to give 3c as a colourless solid (851 mg,
75%). 1H NMR (300 MHz, CDCl3): d = 2.99 (s, 6H,
OCH3), 4.06 (d, 3J = 5.2 Hz, CH2), 4.24 (t, 3J = 5.2 Hz,
CH), 6.81–7.01 (m, 3H, Ph), 7.31–7.40 (m, 2H, Ph), 7.41
(s, 1H, CH). 13C NMR (100 MHz, CDCl3): d = 51.9
(CH2), 55.1 (OCH3), 102.7 (CH), 120.8, 15.6, 128.0, 130.5
116 (19), 75 (100), 47 (18). Elemental Anal. Calcd for
C12H15N3O2 (233.27): C, 61.79; H, 6.48; N, 18.03. Found:
C, 61.75; H, 6.44; N, 17.78.
13. Katritzky, A. R.; Tymoshenko, D. O.; Nikonov, G. N.
J. Org. Chem. 2001, 66, 4045–4046.
14. 5-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1,2,3-thiadiazole
(5).
Colourless solid, yield: 60%; 1H NMR (300 MHz,
DMSO-d6): d = 7.36–5.51 (m, 3H, Ph), 7.85–7.88 (m, 2
H, Ph), 9.44 (s, 1H, CH), 9.44 (s, 1H, CH). 13C NMR
(100 MHz, DMSO): d = 121.3 (CH), 125.5 (CHPh), 128.9
(C), 129.0 (CHPh), 129.1 (C), 129.2, (CHPh), 138.7 (CH),
~
147.9 (C). IR (KBr): m ¼ 2996 (m), 2894 (s), 1466 (s),
~
(CHPh), 132.3, 147.8 (C). IR (KBr): m ¼ 3126 (s), 2996 (m),
1364 (m), 1222 (s), 1124 (s), 1079 (s), 1018 (s), 924 (s), 772
(s), 836 (s), 768 (s), 693 (s), 542 (m) cmꢀ1. Elemental Anal.
Calcd for C10H7N5S (229.26): C, 52.39; H, 3.08; N, 30.50.
Found: C, 52.67; H, 3.44; N, 30.11.
2894 (s), 1466 (s), 1364 (m), 1222 (s), 1124 (s), 1079 (s),
1018 (s), 924 (s), 772 (s), 836 (s), 768 (s), 693 (s), 542
(m) cmꢀ1. MS (EI, 70 eV): m/z (%): 233 (M+, 16), 173 (13),