Four-component coupling reactions of silylacetylenes, allyl carbonates, and trimethylsilyl azide catalyzed by a Pd(0)-Cu(I) bimetallic catalyst. Fully substituted triazole synthesis from seemingly internal alkynes

Article abstract of DOI:10.1016/j.tetlet.2003.11.070

Fully substituted triazoles were synthesized via the four-component coupling reaction of unactivated silylacetylenes, two equivalents of allyl carbonates, and trimethylsilyl azide in the presence of a Pd(0)-Cu(I) bimetallic catalyst. Various trisubstituted 1,2,3-triazoles were obtained in good yields. The reaction most probably proceeds through the [3+2] cycloaddition reaction between the alkynylcopper species and azide followed by the cross-coupling reaction between the vinylcopper intermediate and π-allylpalladium complex.

Full text of DOI:10.1016/j.tetlet.2003.11.070

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 689–691
Four-component coupling reactions of silylacetylenes, allyl
carbonates, and trimethylsilyl azide catalyzed by a Pd(0)–Cu(I)
bimetallic catalyst. Fully substituted triazole synthesis from
seemingly internal alkynes
Shin Kamijo,a Tienan Jinb and Yoshinori Yamamotoa,b,
*
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 4 October 2003; revised 31 October 2003; accepted 14 November 2003
Abstract—Fully substituted triazoles were synthesized via the four-component coupling reaction of unactivated silylacetylenes, two
equivalents of allyl carbonates, and trimethylsilyl azide in the presence of a Pd(0)–Cu(I) bimetallic catalyst. Various trisubstituted
1,2,3-triazoles were obtained in good yields. The reaction most probably proceeds through the [3+2] cycloaddition reaction between
the alkynylcopper species and azide followed by the cross-coupling reaction between the vinylcopper intermediate and p-allylpal-
ladium complex.
Ó 2003 Elsevier Ltd. All rights reserved.
In recent years, triazole forming reactions1 have received
much attention and new conditions were developed for
the 1,3-dipolar cycloaddition reaction2 between alkynes
and azides. The thermal cycloaddition is a traditional
procedure for this purpose, but there exist several
drawbacks inherent in this protocol.1 The major prob-
lem arises due to the low reactivity of the substrates,
therefore the installation of an electron withdrawing
group is usually required to activate the alkynes. The
recent investigations on the copper-catalyzed cycload-
dition made it possible to use unactivated terminal
alkynes as a starting material.3 Terminal alkynes are
activated by forming a copper-acetylide species. How-
ever, a problem still remains since the copper-catalyzed
method is applicable only to terminal alkynes. We
herein report the synthesis of triazoles4 from seemingly
internal alkynes through a four-component coupling
(FCC) reaction. The reaction of the silylacetylenes 1,
allyl carbonates 2, and trimethylsilyl azide in the pres-
ence of a bimetallic catalyst, Pd(0)–Cu(I), gave the 1,4,5-
trisubstituted triazoles 3, the formal [3+2] cycloaddition
products between allyl azide and internal alkynes,
R1CBC(allyl), in good yields (Eq. 1).
1
2
2.5 mol% Pd (dba) ·CHCl
3
R
SiMe R
2
1
2
3
20 mol% P(OEt)
10 mol% CuCl
3
+
1
R
OCO Me 2a
2
N
N
o
dioxane, 100
C
N
+
3
TMS
N
3
ð1Þ
The results are summarized in Table 1. When a mixture of
1-phenyl-2-(trimethylsilyl)acetylene 1a, allyl methyl car-
bonate 2a, and TMSN3 in 1,4-dioxane was stirred at
100 °C for 8 h in the presence of 2.5 mol %
Pd2(dba)3ÆCHCl3, 20 mol % P(OEt)3, and 10 mol % CuCl,
1,5-diallyl-4-phenyl-1,2,3-triazole 3a was formed in 77%
yield (Table 1, entry 1). The choice of the bimetallic
catalyst, Pd2(dba)3ÆCHCl3–CuCl, and phosphine ligand,
P(OEt)3, is essential in order to obtain the desired triazole
3a, and formation of the triazole was not observed in the
absence of any of these components in the catalytic sys-
tem. We investigated the reactivity of the arylacetylenes
1b–f. The alkynes bearing electron donating groups 1b
and 1c at the para-position of the phenyl ring gave the
Keywords: Triazole; Four-component coupling; Palladium catalyst;
Copper catalyst; Bimetallic catalyst; p-Allylpalladium complex; TMS-
azide.
* Corresponding author. Tel.: +81-22-217-6581; fax: +81-22-217-6784;
e-mail: yoshi@yamamoto1.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.070

690
S. Kamijo et al. / Tetrahedron Letters 45 (2004) 689–691
Table 1. Four-component coupling reaction between 1, 2a, and
a
TMSN3
resulted in formation of a mixture of unidentified products
(Table 2, entry 3). The disilane 1m produced 3i in 44%
yield (Table 2, entry 4). The installation of two alkynyl
groups on the Si atom 1n dramatically increased the
reactivity and 3i was obtained in 63% isolated yield in 4 h
(Table 2, entry 5). This means that the two alkynyl groups
of the dialkynylsilyl molecule 1n can be utilized in the
FCC reaction. The tetra(alkynyl)silane 1o was not as
reactive as 1n (Table 2, entry 6). The introduction of allyl
1p and phenyl 1q groups was less effective (Table 2,
entries 7 and 8).
Entry
R1
1
Time, h Triazole 3 Yield,
b
%
1
2
3
4
5
6
7
8
9
Ph
1a
1b
1c
1d
1e
1f
8
5
3a
3b
3c
3d
3e
3f
77
67
75
66
71
57
69
51
27c
4-MeO–C6H4
4-Me2N–C6H4
4-MeO2C–C6H4
4-Cl–C6H4
5
13
10
15
5
4-NC–C6H4
Isopropenyl
t-Bu
1g
1h
1i
3g
3h
3i
24
24
CH3(CH2)5
a The reaction of the alkyne (R2 ¼ Me) 1 (0.5 mmol), allyl methyl
carbonate 2a (1.2 mmol), and TMSN3 (0.6 mmol) was conducted in
the presence of Pd2(dba)3ÆCHCl3 (12.5 lmol), P(OEt)3 (100 lmol),
and CuCl (50 lmol) in 1,4-dioxane (1 mL) at 100 °C for the time
indicated in this table.
We further conducted the reaction of the substituted
allyl carbonates 2b–d with TMSN3 and di(phenylethy-
nyl)dimethylsilane 1r. The mono-substituted allyl car-
bonates, such as cinnamyl 2b and methallyl carbonate
2c, furnished the corresponding triazoles 3j and 3k in
70% and 51% yields, respectively (Eqs. 2 and 3). The
prenyl carbonate 2d afforded the desired triazole 3l in a
lower yield (Eq. 4). It should be noted that no c-addi-
tion products were detected in the reactions of 2b and
2d.
b Isolated yield.
c NMR yield.
corresponding triazoles 3b and 3c in good yields,
respectively (Table 1, entries 2 and 3). The alkynes 1d–f
having electron withdrawing groups also produced the
corresponding triazoles 3d–f in good to moderate yields
(Table 1, entries 4–6). The conjugated enyne 1g afforded
the desired triazole 3g in 69% yield (Table 1, entry 7).
Bulky 1-(tert-butyl)-2-(trimethylsilyl)acetylene 1h gave
the corresponding product 3h in 51% yield, though a
longer reaction time was required (Table 1, entry 8).
In contrast, the reaction of a simple alkylacetylene such
as 1-(trimethylsilyl)-1-octyne 1i was sluggish and gave
the desired triazole 3i only in a low yield (Table 1, entry 9).
Ph
SiMe2
2.5 mol% Pd2(dba)3·CHCl3
20 mol% P(OEt)3
1r
2
Ph
+
+
Ph
10 mol% CuCl
Ph
OCO2Me 2b
N
N
Ph
dioxane
120 oC, 2 h
N
3j
TMS N3
70%
ð2Þ
ð3Þ
It occurred to us that modification of the silyl group
might increase the reactivity of the alkylacetylenes.5 The
FCC reaction of the alkynes 1j–q having a variety of
substituents on the Si atom was carried out under the
usual conditions (Table 2). The fluorosilane 1j showed a
slight increase of the yield (Table 2, entry 1). To our
surprise, the introduction of the methoxy group in 1k
increased the reactivity and 3i was produced in 51% yield
(Table 2, entry 2). On the other hand, the silanol 1l
Ph
SiMe
2.5 mol% Pd (dba) ·CHCl
3
1r
2
2
3
2
20 mol% P(OEt)
10 mol% CuCl
3
+
+
Ph
N
OCO Me
2c
2
N
dioxane
N
o
150 C, 2 h
3k
51%
TMS
N
3
Table 2. Effect of the silyl group on the triazole formationa
Entry
[CH3(CH2)5–CBC]SiMeR2
1
Time, h
Triazole 3
Yield, %b
1
[CH3(CH2)5–CBC]SiMe2F
1j
24
3
3i
3i
3i
3i
3i
3i
3i
3i
39
51
2
[CH3(CH2)5–CBC]SiMe2OMe
[CH3(CH2)5–CBC]SiMe2OH
[CH3(CH2)5–CBC]SiMe2–SiMe3
[CH3(CH2)5–CBC]2SiMe2
[CH3(CH2)5–CBC]4Si
[CH3(CH2)5–CBC]SiMe2(CH2CH2@CH2)
[CH3(CH2)5–CBC]SiMe2Ph
1k
1l
3
3
Mixture
4
1m
1n
1o
1p
1q
14
4
44
5c
6e
7
63d
36
3
24
24
46
20f
8
a Unless otherwise noted, the reaction of the alkyne 1 (0.5 mmol), 2a (1.2 mmol), and TMSN3 (0.6 mmol) was conducted in the presence of
Pd2(dba)3ÆCHCl3 (12.5 lmol), P(OEt)3 (100 lmol), and CuCl (50 lmol) in 1,4-dioxane (1 mL) at 100 °C for the time indicated in this table.
b NMR using p-xylene as an internal standard except when otherwise indicated.
c The di(alkynyl)silane 1n (0.25 mmol) was used as the starting material.
d Isolated yield.
e The tetra(alkynyl)silane 1o (0.125 mmol) was used as the starting material.
f The alkyne 1q was recovered in 32% yield.

S. Kamijo et al. / Tetrahedron Letters 45 (2004) 689–691
691
+
R
TMS
CuX·Ln
Acknowledgements
1
path (b)
path (a)
We thank the faculty members in the Instrumental
Analysis Center at Tohoku University for the mea-
surements of NMR spectra, mass spectra, and elemental
analyses.
TMSX
N
3
Pd N
3
E
R
Cu·Ln
B
A
R
N
CuLn
R
CuLn
References and notes
N
N
N
Pd
N
N
1. Reviews on 1,2,3-triazoles, see: (a) Dehne, H. In Methoden
der Organischen Chemie (Houben-Weyl); Schumann, E.,
Ed.; Thieme: Stuttgart, 1994; Vol. E8d, pp 305–405; (b)
Wamhoff, H. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 5, pp 669–732.
F
C
Pd OMe
Pd OMe
D
D
R
2. Reviews on 1,3-dipolar cycloaddition reactions, see: (a)
Little, R. D.; Chan, D. M. T. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp 239–314; (b) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon:
Oxford, 1990.
N
N
N
CuOMe + Pd(0)
CuOMe + 2 Pd(0)
3
Scheme 1. Proposed mechanism for the formation of triazoles 3.
3. Cu-catalyzed triazole synthesis, see: (a) Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599; (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–
3064; (c) Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.;
Wong, C.-H. J. Am. Chem. Soc. 2002, 124, 14397–14402;
(d) Wang, Q.; Chan, R. C.; Hilgraf, R.; Fokin, V. V.;
Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003,
Ph
SiMe2
2.5 mol% Pd2(dba)3·CHCl3
20 mol% P(OEt)3
1r
2
+
+
Ph
10 mol% CuCl
OCO2Me
2d
N
N
dioxane
150 oC, 2 h
N
3l
34%
TMS N3
€
125, 3192–3193; (e) Lober, S.; Rodriguez-Loaiza, P.;
Gmeiner, P. Org. Lett. 2003, 5, 1753–1755; (f) Perez-
ð4Þ
ꢀ
~
Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.;
Hernandez-Mateo, F.; Valvo-Flores, F. G.; Calvo-Asın, J.
A proposed mechanism for the FCC reaction is illus-
trated in Scheme 1. The copper-acetylide species A would
be formed from alkynes 1 and CuCl with extrusion of
TMSCl at the initial stage of the catalytic cycle.6 At this
point, two pathways are conceivable to reach the final
products 3. In the path (a), [3+2] cycloaddition4 between
the copper-acetylide A and the p-allylpalladium azide
complex B,7 which is generated in situ from Pd(0), allyl
carbonate 2a, and TMSN3, would give the intermediate
C. The cross-coupling reaction8 between the vinylcopper
derivative C and the p-allylpalladium methoxide D9
would form the triazole 3 with regeneration of the Pd(0)–
Cu(I) bimetallic catalyst. Alternatively in the path (b),
[3+2] cycloaddition would take place between A and allyl
azide E,3 which is formed by reductive elimination of B,
to give the intermediate F. The successive cross-coupling
reaction between F and D would afford the triazole 3.
There might be an equilibrium between C and F. Need-
less to say, a more detailed investigation is needed to
clarify the mechanism of the FCC reaction.
ꢀ
ꢀ
ꢀ
ꢀ
A.; Isac-Garcıa, J.; Santoyo-Gonzalez, F. Org. Lett. 2003,
5, 1951–1954.
4. (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahe-
dron Lett. 2002, 43, 9707–9710; (b) Kamijo, S.; Jin, T.;
Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
7786–7787.
5. (a) Hirayabayashi, K.; Mori, A.; Kawashima, J.; Sufuro,
M.; Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65,
5342–5349, and references cited therein; (b) Denmark, S.
E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835–846, and
references cited therein.
6. Transmetallation between Si and Cu, see: (a) Ito, H.;
Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedon Lett.
1997, 38, 3977–3980; (b) Nishihara, Y.; Ikegashira, K.;
Mori, A.; Hiyama, T. Chem. Lett. 1997, 1233–1234; (c)
Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.;
Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780–1787;
(d) Nishihara, Y.; Takemura, M.; Mori, A.; Osakada, K.
J. Organomet. Chem. 2001, 620, 282–286.
7. p-Allylpalladium azide complexes in catalytic reactions,
see: (a) Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 11940–11945; (b) Kamijo, S.; Jin, T.; Yamam-
oto, Y. J. Org. Chem. 2002, 67, 7413–7417.
Irrespective of the precise mechanism, we are now in a
position to synthesize a wide variety of triazoles 3 through
the FCC reaction, which are formal [3+2] cycloaddition
products of seemingly internal alkynes, not easily avail-
able in a single step via the previously known procedures.
In addition, we have disclosed that the introduction of
two alkynyl groups on the Si atom increased the reactivity
of the starting alkyne. Further studies on the synthetic
application of this novel reaction and the mechanistic
detail are underway in our laboratory.
8. Reviews on the transition metal-catalyzed cross-coupling
reaction, see: (a) Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; (b) Brandsma, L.; Vasilevsky, S. F.;
Verkruijsse, H. D. Application of Transition Metal Cata-
lysts in Organic Synthesis; Springer: Berlin, 1998; (c)
Organocopper Reagents; Taylor, R. J. K., Ed.; Oxford
University: Oxford, 1994.
9. This is generated from 2a and the Pd(0) catalyst.