A One-Pot Procedure for the Regiocontrolled Synthesis of Allyltriazoles via the Pd-Cu Bimetallic Catalyzed Three-Component Coupling Reaction of Nonactivated Terminal Alkynes, Allyl Carbonate, and Trimethylsilyl Azide

Article abstract of DOI:10.1021/jo035292b

A one-pot procedure for the regiocontrolled synthesis of both 2-allyl- and 1-allyl-1,2,3-triazoles via the three-component coupling (TCC) reaction between nonactivated terminal alkynes, allyl carbonate, and trimethylsilyl azide (TMSN₃) under a

Full text of DOI:10.1021/jo035292b

A On e-P ot P r oced u r e for th e Regiocon tr olled Syn th esis of
Allyltr ia zoles via th e P d -Cu Bim eta llic Ca ta lyzed
Th r ee-Com p on en t Cou p lin g Rea ction of Non a ctiva ted Ter m in a l
Alk yn es, Allyl Ca r bon a te, a n d Tr im eth ylsilyl Azid e
Shin Kamijo,† Tienan J in,‡ Zhibao Huo,‡ and Yoshinori Yamamoto*,†,‡
Research Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for
Advanced Materials, and Department of Chemistry, Graduate School of Science, Tohoku University,
Sendai 980-8578, J apan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received September 3, 2003
A one-pot procedure for the regiocontrolled synthesis of both 2-allyl- and 1-allyl-1,2,3-triazoles
via the three-component coupling (TCC) reaction between nonactivated terminal alkynes,
allyl carbonate, and trimethylsilyl azide (TMSN3) under a palladium and copper bimetallic cat-
alyst has been developed. To accomplish the regioselective synthesis of the allyltriazoles, proper
choice of two different catalyst systems is needed. The combination of Pd2(dba)3‚CHCl3-
CuCl(PPh3)3-P(OPh)3 catalyzes the formation of 2-allyl-1,2,3-triazoles, while the combination of
Pd(OAc)2-CuBr2-PPh3 promotes the formation of 1-allyl-1,2,3-triazoles. The cooperative activity
of palladium and copper catalysts plays an important role in the present transformations. Most
probably, the palladium catalyst works as a catalyst for generating reactive azide species,
π-allylpalladium azide complex and allyl azide. The copper catalyst probably behaves as an activator
of the C-C triple bond of the starting terminal alkynes by forming a copper-acetylide intermediate
and thereby promotes the [3 + 2]-cycloaddition reaction between the reactive azide species and
the copper-acetylide to form the triazole framework.
In tr od u ction
a backbone of a bidentate phosphine ligand, and several
new compounds have been synthesized.3 Because of their
potent usefulness, several synthetic methods have been
developed for the construction of triazole frameworks.
Among them, 1,3-dipolar cycloaddition reactions are a
powerful tool for the formation of a wide variety of cyclic
compounds.4 1,2,3-Triazoles are in general prepared
through the coupling reaction between alkynes and
azides.1,4 In the standard procedure for the synthesis of
triazoles, it is usually required that starting alkynes and/
or azides are substituted with an activating electron-
withdrawing functional group, and the reaction is often
conducted at high temperatures for a prolonged time. The
thermal cycloaddition reaction between terminal alkynes
and azides causes another problem with regard to the
regioselectivity of the derived triazoles: a mixture of 1,4-
substituted- and 1,5-substituted-1,2,3-triazoles is pro-
duced in most cases. The recent advances in triazole
synthesis using a catalytic amount of copper salt have
settled the above issues to some extent.5 Thus, it occurred
to us that the employment of a transition-metal catalyst
may overcome the above-mentioned problems: both the
acceleration of the coupling reaction between alkynes and
1,2,3-Triazoles are an important class of compounds
because of their wide utilities.1 They have been consid-
ered as an interesting component from the viewpoint of
biological activity and are seen in many drugs.2 Triazole
heterocycles have also found broad use in industrial
applications such as dyes and brighteners for fibers;
corrosion inhibitors for many metals and alloys; light
stabilizers for organic materials and polymers; and
agrochemicals as herbicides, fungicides, and antibacterial
agents.1b More recently, triazoles have been utilized as
* To whom correspondence should be addressed.
† Institute of Multidisciplinary Research for Advanced Materials.
‡ Department of Chemistry.
(1) For 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 Compre-
hensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 5, pp 669-732. (c) Sheradsky, T.; In
The Chemistry of the Azido Group; Patai, S., Ed.; Interscience: London,
1971; 377-382. (d) Abu-Orabi, S. T.; Atfah, M. A.; J ibril, I.; Mari’i, F.
M.; Ali, A. A.-S. J . Heterocycl. Chem. 1989, 26, 1461-1468.
(2) (a) Buckle, D. R.; Rockell, C. J . M. J . Chem. Soc., Perkin Trans.
1 1982, 627-630. (b) Buckle, D. R.; Outred, D. J .; Rockell, C. J . M.;
Smith, H.; Spicer, B. A. J . Med. Chem. 1983, 26, 251-254. (c) Buckle,
D. R.; Rockell, C. J . M.; Smith, H.; Spicer, B. A. J . Med. Chem. 1986,
29, 2262-2267. (d) Alvarez, R.; Vela´zquez, S.; San-Fe´lix, A.; Aquaro,
S.; Clercq, E. D.; Perno, C.-F.; Karlsson, A.; Balzarini, J .; Camarasa,
M. J . J . Med. Chem. 1994, 37, 4185-4194. (e) Genin, M. J .; Allwine,
D. A.; Anderson, D. J .; Barbachyn, M. R.; Emmert, D. E.; Garmon, S.
A.; Graber, D. R.; Grega, K. C.; Hester, J . B.; Hutchinson, D. K.; Morris,
J .; Reischer, R. J .; Ford, C. W.; Zurenko, G. E.; Hamel, J . C.; Schaadt,
R. D.; Stapert, D.; Yagi, B. H. J . Med. Chem. 2000, 43, 953-970.
(3) (a) Rheingold, A. L.; Liable-Sands, L. M.; Trofimenko, S. Angew.
Chem., Int. Ed. 2000, 39, 3321-3324. (b) Trofimenko, S.; Rheingold,
A. L.; Incarvito, C. D. Angew. Chem., Int. Ed. 2003, 42, 3506-3509.
(4) For reviews on 1,3-dipolar cycloadditions, see: (a) Carruthers,
W.; Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford,
1990; pp 269-331. (b) Gothelf, K. V.; J ørgensen, K. A. Chem. Rev. 1998,
98, 863-909. (c) L’abbe´, G. Chem. Rev. 1969, 69, 345-363.
10.1021/jo035292b CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/20/2004
2386
J . Org. Chem. 2004, 69, 2386-2393

Regiocontrolled Synthesis of Allyltriazoles
TABLE 1. Effects of Cu Ca ta lyst a n d P Liga n d on th e
F or m a tion of th e 2-Allyltr ia zole 2a a
SCHEME 1. Regiocon tr olled Syn th esis of
Allyltr ia zoles via th e Th r ee-Com p on en t Cou p lin g
Rea ction
yield, %b
entry
Cu catalyst
P ligand
2a
3a
1
2
3
4
5
6
7
CuCl (20 mol %)
CuBr (20 mol %)
Cul (20 mol %)
CuCl(PPh3)3 (20 mol %)
Ph-CtC-Cu (20 mol %) dppp (10 mol %) 78
dppp (10 mol %) 15
dppp (10 mol %) 31
dppp (10 mol %) 12
49
61
39
0
0
51
dppp (10 mol %) 73 (66)
CuBr2 (20 mol %)
none
dppp (10 mol %)
dppp (10 mol %) complex
mixture
0
8
9
10
11
12
13
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (5 mol %)
CuCl(PPh3)3 (5 mol %)
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
dppp (10 mol %) 75 (68)
dppp (10 mol %) 34
dppp (10 mol %) 48
dppb (10 mol %) 44
dppe (10 mol %) 52
(p-MeO-C6H4)3P 45
(20 mol %)
0
13
21
0
21
20
14
CuCl(PPh3)3 (10 mol %)
(p-CF3-C6H4)3P
15
49
azide compounds and the selective formation of the
substituted triazoles might be observed under a transi-
tion-metal catalyst.
(20 mol %)
15
16
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
Bu3P (20 mol %) 45
22
0
(2-furyl)3P
(20 mol %)
P(OPh)3
(20 mol %)
none
63
Previously, we reported the regioselective formation of
2-allyltriazoles via the three-component coupling (TCC)
reaction between activated alkynes conjugated with an
electron-withdrawing group (EWG), allyl methyl carbon-
ate, and TMSN3 in the presence of a catalytic amount of
Pd2(dba)3‚CHCl3 and 1,3-bis(diphenylphosphino)propane
(dppp), as shown in eq 1 (Scheme 1).6 A wide range of
activated alkynes can be used as a substrate in this
protocol; however, nonactivated alkynes did not afford
any desired allyltriazoles. The limitation of the starting
alkynes is apparently the major drawback in this allyl-
triazole synthesis via the palladium-catalyzed TCC reac-
tion strategy. A dramatic change occurred when a
catalytic amount of a Cu salt was introduced to the
reaction mixture.7 In the TCC reaction of phenylacetylene
1a , a nonactivated terminal alkyne, under the combina-
tion of Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3 catalyst,
gave 2-allyl-4-phenyl-1,2,3-triazole 2a in a high yield; the
Pd-Cu bimetallic catalyst efficiently promoted the 2-al-
lyltriazole-forming reaction from a nonactivated terminal
alkyne (eq 2, Scheme 1).8 Later on, it was found that
1-allyltriazoles were regioselectively synthesized by the
proper choice of Pd, Cu, and phosphine ligand. We herein
17
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
83 (83)
30
0
18
22
a
The reaction of phenylacetylene 1a with allyl methyl carbonate
(1.2 equiv) and TMSN3 (1.2 equiv) was carried out in the presence
of Pd2(dba)3‚CHCl3 (2.5 mol %), P ligand, and Cu catalyst in AcOEt
(0.5 M) at 100 °C for 12 h. The yield was calculated by 1HNMR
b
or GC analysis. The isolated yield is shown in parentheses.
report a detailed investigation of the regiocontrolled
synthesis of 2-allyl-1,2,3-triazoles (eq 2, Scheme 1) and
1-allyl-1,2,3-triazoles (eq 3, Scheme 1) via the Pd-Cu
bimetallic catalyzed TCC reaction between nonactivated
terminal alkynes, allyl carbonate, and TMSN3.
Resu lts a n d Discu ssion
Syn th esis of 2-Allyl-1,2,3-tr ia zoles via th e TCC
Rea ction u n d er P d 2(d ba )3‚CHCl3-Cu Cl(P P h 3)3-P -
(OP h )3 Bim eta llic Ca ta lyst. After the discovery of the
unique effect of Cu salt on the indole synthesis,7 we
investigated the effect of Cu salts and ligands on the
regioselective formation of either isomer of the two
allyltriazoles. First, the effect of Cu catalysts on the TCC
reaction of phenylacetylene 1a , allyl methyl carbonate,
and TMSN3 was surveyed under the standard conditions,
Pd2(dba)3‚CHCl3-dppp catalyst. The representative re-
sults of the TCC reaction performed with various Cu
additives are summarized in Table 1. The Cu(I) salts such
as CuCl, CuBr, and CuI gave a mixture of the corre-
sponding 2-allyltriazole 2a and 1-allyltriazole 3a (entries
1-3). CuCl(PPh3)3 promoted the TCC reaction efficiently
and produced the 2-allyltriazole 2a selectively in a high
yield (entry 4). Copper(I) phenylacetylide also showed
comparable reactivity to CuCl(PPh3)3 (entry 5). In con-
trast, CuBr2 did not afford the 2-allyltriazole 2a at all,
and the 1-allyltriazole 3a was produced as a single
product (entry 6). The reaction without Cu salt resulted
(5) For copper-catalyzed synthesis of 1,2,3-triazoles, see: (a) Ros-
tovtsev, 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) Wang, Q.; Chan,
T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J . Am.
Chem. Soc. 2003, 125, 3192-3193. (d) Lo¨ber, S.; Rodriguez-Loaiza, P.;
Gmeiner, P.; Org. Lett. 2003, 5, 1753-1755. (e) Pe´rez-Balderas, F.;
Ortega-Mun˜oz, M.; Morales-Sanfrutos, J .; Hera´ndez-Mateo, F.; Calvo-
Flores, F. G.; Calvo-As´ın, J . A.; Isac-Garc´ıa, J .; Santoyo-Gonza´lez, F.
Org. Lett. 2003, 5, 1951-1954.
(6) Kamijo, S.; J in, T.; Huo, Z.; Yamamoto, Y. Tetrahedron Lett.
2002, 43, 9707-9710.
(7) The utilization of a Pd-Cu bimetallic catalyst for the synthesis
of indoles has been reported; see: (a) Kamijo, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 1780-1782. (b) Kamijo, S.; Yamamoto, Y. J .
Org. Chem. 2003, 68, 4764-4771.
(8) Kamijo, S.; J in, T.; Huo, Z.; Yamamoto, Y. J . Am. Chem. Soc.
2003, 125, 7786-7787.
J . Org. Chem, Vol. 69, No. 7, 2004 2387

Kamijo et al.
TABLE 2. Effect of P Liga n d a n d Cu Ca ta lyst on th e
F or m a tion of th e 1-Allyltr ia zole 3a a
regioselective transformation (entry 18). Other reaction
parameters, such as palladium sources and solvents,
were also studied. As for the palladium sources, we
examined Pd2(dba)3‚CHCl3, Pd(OAc)2, and π-allylpalla-
dium chloride dimer. Among them, Pd2(dba)3‚CHCl3
afforded the highest yield of the desired product 2a .
AcOEt was the solvent of choice; nonpolar solvents such
as toluene and octane decreased the yield of 2a , and polar
solvents such as THF, 1,2-dichloroethane, CH3CN, and
DMF gave a mixture of 2a and 3a . The best result for
the synthesis of 2-allyltriazole 2a was obtained by
carrying out the TCC reaction under Pd2(dba)3‚CHCl3 (2.5
mol %)-CuCl(PPh3)3 (10 mol %)-P(OPh)3 (20 mol %)
catalyst in AcOEt at 100 °C, as indicated in eq 2.
The TCC reactions using various simple terminal
alkynes 1 substituted with aryl, alkyl, alkenyl, and
alkynyl groups gave the corresponding 2-allyltriazoles 2
in the range of 50-83% yields. The bulkiness of the
starting alkyne did not exert a significant influence on
the reaction progress, and the reaction took place chemose-
lectively at the terminal alkyne moiety to afford the
corresponding products when conjugated enynes and
diyne were utilized as a starting material. The reaction
of (triisopropylsilyl)acetylene 1m also furnished the
corresponding 2-allyltriazole 2m in 31% yield. A substi-
tuted allylic carbonate could be used in the 2-allyltriazole
forming reaction; the TCC reaction of 1a , cinnamyl
methyl carbonate, and TMSN3 under the usual reaction
conditions gave the corresponding 2-allyltriazole 2p in
72% yield (eq 4). It should be noted that no γ-addition
yield, %b
entry
P ligand
Cu catalyst
2a
3a
1c
2c
3c
4c
5c
dppp (10 mol %)
P(OPh)3 (20 mol %)
(2-furyl)3P (20 mol %) CuBr2 (20 mol %)
PPh3 (20 mol %)
none
CuBr2 (20 mol %)
CuBr2 (20 mol %)
0
5
10
0
51
47
50
72
CuBr2 (20 mol %)
CuBr2 (20 mol %)
no
reaction
6d
7d
8d
9d
PPh3 (20 mol %)
PPh3 (20 mol %)
PPh3 (20 mol %)
PPh3 (20 mol %)
CuBr2 (5 mol %)
CuCl2 (5 mol %)
Cu(OMe)2 (5 mol %) 18
CuBr (5 mol %)
Ph-CtC-Cu
Cu powder
(5 mol %)
0
8
85 (88)
60
54
60
(38)
32
15
(5)
0
10d PPh3 (20 mol %)
11d PPh3 (20 mol %)
12d PPh3 (20 mol %)
none
complex
mixture
a
The reaction of phenylacetylene 1a with allyl methyl carbonate
(1.2 equiv) and TMSN3 (1.2 equiv) was carried out in the presence
of Pd2(dba)3‚CHCl3 (2.5 mol %), P ligand, and Cu additive at 100
b
°C. The yield was calculated by 1HNMR or GC analysis. The
isolated yield is shown in parentheses. c The reaction was con-
d
ducted in AcOEt (0.5 M) for 10 h. The reaction was conducted
in toluene (0.5 M) for 5 h.
in formation of a complex mixture of unidentified prod-
ucts, probably due to rapid oligomerization of the termi-
nal alkyne 1a under the palladium catalyst (entry 7). At
this stage, we focused on the selective synthesis of
2-allyltriazole 2a , and CuCl(PPh3)3 was chosen for further
investigations. The amount of CuCl(PPh3)3 exerted a
great influence on regioselectivity of the allyltriazoles.
The Cu additive could be reduced from 20 to 10 mol %
without loss of the regioselectivity (entry 8), but a
mixture of 2a and 3a was formed when the amount of
the Cu catalyst was further decreased to 5 mol % (entry
9). We next examined the effect of phosphine ligand on
the regioselectivity. The TCC reaction proceeded smoothly
with the addition of 10 mol % dppp and gave 2a
selectively in a high yield, as shown in entry 8. However,
decrease of the amount of the phosphine ligand caused
low regioselectivity. When the amount of dppp was
reduced from 10 to 5 mol %, a mixture of 2a and 3a was
formed (entry 10). Among other bidentate phosphine
ligands we tested, 1,4-bis(diphenylphosphino)butane (dppb)
furnished 2a as a sole product (entry 11), whereas 1,2-
bis(diphenylphosphino)ethane (dppe) did not improve the
ratio of 2a and 3a (entry 12). Monodentate phosphine
ligands such as (p-MeO-C6H4)3P, (p-CF3-C6H4)3P, and
Bu3P resulted in formation of a mixture of 2a and 3a
(entries 13-15). The intensive investigation revealed that
the use of tri(2-furyl)phosphine efficiently promoted the
TCC reaction and afforded the desired 2-allyltriazole 2a
as a sole product (entry 16). Among the phosphine ligands
we examined, triphenyl phosphite exhibited the highest
catalytic activity and the 2-allyltriazole 2a was isolated
in 83% yield (entry 17). Without addition of the phos-
phine ligand, no regioselectivity was observed, which
clearly proves the effect of P(OPh)3 ligand in the present
product was detected in this case. The structure of the
product, 2-allyl-4-(p-dimethylamino)phenyl-1,2,3-triazole,
was confirmed unambiguously by the X-ray crystal-
lographic analysis (see Supporting Information for de-
tails).
Syn th esis of 1-Allyl-1,2,3-tr ia zoles via th e TCC
Rea ction u n d er P d (OAc)2-Cu Br 2-P P h 3 Bim eta llic
Ca ta lyst. We next turned our attention to the regiocon-
trolled preparation of 1-allyltriazoles 3a and started to
optimize the reaction conditions. We have already found
that the addition of CuBr2 afforded 1-allyltriazole 3a as
a single product; thus, we examined the effect of a variety
of phosphine ligands under the Pd2(dba)3‚CHCl3-CuBr2
bimetallic catalyst in the first place. The results are
summarized in Table 2. As mentioned in the previous
section, the addition of dppp afforded the 1-allyltriazole
3a in a moderate yield (entry 1). The monodentate
phosphine ligands such as P(OPh)3 and (2-furyl)3P fur-
nished a mixture of 2a and 3a (entries 2 and 3). Among
them, PPh3 promoted the TCC reaction most efficiently
and gave the desired product 3a as a single product with
a high chemical yield (entry 4). The reaction without
addition of phosphine ligand resulted in recovery of the
starting alkyne 1a and allyl methyl carbonate (entry 5).
2388 J . Org. Chem., Vol. 69, No. 7, 2004

Regiocontrolled Synthesis of Allyltriazoles
TABLE 3. Syn th esis of th e 1-Allyltr ia zoles 3 via th e
We then performed the TCC reaction using the Pd2(dba)3‚
CHCl3-PPh3 catalyst with addition of some Cu salts to
reconfirm their catalytic activity. The amount of the
CuBr2 could be reduced from 20 to 5 mol % without loss
of the regioselectivity and the yield of 3a (entry 6). The
other Cu(II) catalysts, such as CuCl2 and Cu(OMe)2,
produced a mixture of 2a and 3a (entries 7 and 8). The
Cu(I) catalysts, such as CuBr and Cu(I) phenylacetylide,
did not improve the ratio of the products (entries 9 and
10). Cu powder afforded 3a as a sole product, though the
yield of 3a was low (entry 11). Of course, without addition
of Cu catalyst, the reaction gave only a complex mixture
of unidentified products due to oligomerization of the
terminal alkyne 1a (entry 12). Other reaction param-
eters, such as palladium sources, solvents, and reaction
temperature, were also studied. As for the palladium
sources, Pd2(dba)3‚CHCl3, Pd(PPh3)4, Pd(OAc)2, and π-al-
lylpalladium chloride dimer were examined, and all
the palladium catalysts showed a comparable reactivity.
Among them, Pd(OAc)2 was chosen because of the con-
venience for the product purification. As for the sol-
vents, toluene, THF, 1,2-dichloroethane, AcOEt, and
CH3CN, were examined. Again, all the solvents gave
similar chemical yields of the desired product 3a . Among
them, toluene was chosen because it seemed that only
3a was obtained and almost no side products were
produced by the use of this solvent judging from the crude
reaction mixture. The reaction temperature could be
lowered for the formation of the 1-allyltriazole 3a , and
the reaction proceeded smoothly even at 80 °C. Further-
more, we found that the total amount of the catalysts
could be reduced. The best result for the synthesis of the
1-allyltriazole 3a was obtained by running the TCC
reaction under Pd(OAc)2 (2 mol %)-CuBr2 (2 mol %)-
PPh3 (8 mol %) catalyst in toluene at 80 °C, as depicted
in eq 3.
P d -Cu Bim eta llic Ca ta lyzed TCC Rea ction a
a
The reaction of the terminal alkynes1 (R′ ) H in eq 3), allyl
methyl carbonate (1.2 equiv), and TMSN3 (1.2 equiv) was con-
ducted in toluene (0.5 M) under a catalytic amount of Pd(OAc)2 (2
mol %), PPh3 (8 mol %), and CuBr2 (2 mol %) at 80 °C for the time
b
shown in Table 3. Isolated yield. c The starting material 1e was
d
Since the optimum reaction conditions for the regiose-
lective synthesis of 1-allyltriazoles 3 were in hand, we
conducted the TCC reaction by employing various non-
activated terminal alkynes 1. The results are sum-
marized in Table 3. The TCC reaction of phenylacetylene
1a with allyl methyl carbonate and TMSN3 was com-
pleted in 3 h and the corresponding 1-allyltriazole 3a was
isolated in 88% yield (entry 1). The arylacetylenes
bearing an electron-withdrawing methoxycarbonyl group
1b, 1c, and 1d on the aromatic ring gave the correspond-
ing 1-allyltriazoles 3b, 3c, and 3d in good to high yields
(entries 2-4). The substituent position on the aromatic
ring did not exert a significant influence on the reaction
progress. The reaction of p-cyanophenylacetylene 1e did
not reach completion, and the corresponding 1-allyltria-
zole 3e was obtained in 41% yield along with the recovery
of the starting alkyne 1e (entry 5). On the other hand,
the reaction of the arylacetylene 1f having an electron-
donating methoxy group at the para-position on the
aromatic ring proceeded smoothly to give the 1-allyltria-
zole 3f in a high yield (entry 6). The reaction of alky-
lacetylenes such as 1-octyne 1g and tert-butylacetylene
1h furnished the desired products 3g and 3h in good
yields, although prolonged reaction times were required
(entries 7 and 8). The reaction of 4-pentyn-1-ol 1i,
containing a hydroxy functional group, produced the
corresponding 1-allyltriazole 3i in 75% yield (entry 9).
recovered in 17% yield. After the reaction was completed, the
crude mixture was treated with AcOH. e The starting material 1j
was recovered in 22% yield. f The reaction was conducted under
Pd(OAc)2 (4 mol %)-PPh3 (16 mol %)-CuBr2 (4 mol %) catalyst.
g
Cinnamyl methyl carbonate was used instead of allyl methyl
carbonate.
In this case, the treatment of the crude mixture with an
acid was necessary prior to the isolation to cleave the
silyl ether formed during the reaction. The reaction of
6-chloro-1-hexyne 1j, containing halide moiety, did not
reach completion and the desired 1-allyltriazole 3j was
formed in 38% yield together with the recovery of the
staring alkyne 1j (entry 10). The reaction of 1-ethynyl-
cyclohexene 1k proceeded chemoselectively at the ter-
minal alkyne moiety and the desired 1-allyltriazole 3k
was formed in 71% yield (entry 11). The reaction of the
conjugated diyne 1l also took place at the terminal alkyne
moiety to give the 1-allyltriazole 3l (entry 12). Even a
bulky silylacetylene 1m reacted to give the expected
product 3m in 85% yield (entry 13). The 1-allyltriazole-
forming reaction was applicable for the substrates having
two reactive sites in one molecule, such as 1,4-diethy-
nylbenzene 1n and 1,7-octadiyne 1o, and the correspond-
ing products 3n and 3o were obtained in moderate yields,
respectively (entries 14 and 15). A substituted allylic
carbonate could be used in the 1-allyltriazole-forming
reaction instead of allyl methyl carbonate; the TCC
J . Org. Chem, Vol. 69, No. 7, 2004 2389

Kamijo et al.
TABLE 4. Cou p lin g Rea ction of 1a w ith Cin n a m yl Azid e u n d er Va r iou s Con d ition sa
conditions
NMR yield, %
2p 3p
88
entry
Pd catalyst
Cu catalyst
P ligand
1b
2b
3b
4b
5c
6c
7c
8c
Pd(OAc)2 (2 mol %)
CuBr2 (2 mol %)
CuBr2 (2 mol %)
CuBr2 (2 mol %)
PPh3 (8 mol %)
0
0
0
0
53
99
4
PPh3 (8 mol %)
PPh3 (8 mol %)
P(OPh)3 (20 mol %)
Pd(OAc)2 (2 mol %)
Pd2(dba)3‚CH Cl3 (2.5 mol %)
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
CuCl(PPh3)3 (10 mol %)
51
0
0
0
79
77
16
P(OPh)3 (20 mol %)
P(OPh)3 (20 mol %)
Pd2(dba)3‚CH Cl3 (2.5 mol %)
11
a
b
The reaction of 1a and cinnamyl azide (1.2 equiv) was carried out under the conditions indicated in Table 4. The reaction was
conducted in toluene at 80 °C for 20 h. c The reaction was conducted in AcOEt at 100 °C for 48 h.
reaction of 1a , cinnamyl methyl carbonate, and TMSN3
under the standard reaction conditions afforded the
corresponding 1-allyltriazole 3p in 75% yield (entry 16).
It should be noted that only R-addition product was
detected in this case. The structures of the 1-allyltriazoles
3 were determined by the analysis of their spectroscopic
data. The position of the allyl group of 3a was confirmed
by performing NOE experiments9 and the comparison
with the NMR spectra of its regioisomer, 2-allyltriazole
2a .
Mech a n istic Con sid er a tion s: Th e Roles of P d
a n d Cu Ca ta lysts a n d P h osp h in e Liga n d . To eluci-
date the roles of palladium and copper complexes and
phosphine ligand in the catalyst systems for the prep-
aration of 1-allyltriazoles and 2-allyltriazoles, the cou-
pling reaction between phenylacetylene 1a and cinnamyl
azide was investigated under several conditions (eq 5,
Table 4). The coupling reaction under the standard
catalytic conditions for the 1-allyltriazole synthesis,
Pd(OAc)2-CuBr2-PPh3, gave the expected 1-allyltriazole
3p in 88% yield as the sole product (entry 1). This result
corresponds well with the outcome of the TCC reaction
of 1a , cinnamyl methyl carbonate, and TMSN3, as re-
ported in entry 16 of Table 3, where 3p was obtained in
75% isolated yield. On the contrary, the reaction between
phenylacetylene 1a and trimethylsilyl azide did not
proceed under Pd(OAc)2-CuBr2-PPh3 catalyst conditions
and recovery of the starting acetylene 1a was observed.
The coupling reaction under CuBr2 catalyst alone re-
sulted in formation of 3p in a moderate yield (entry 2),
whereas the combination of CuBr2 and PPh3 afforded
3p quantitatively (entry 3). It is clear that Cu catalyst
promotes the [3 + 2]-cycloaddition reaction between the
terminal alkyne and allyl azide to form the triazole
skeleton. It is known that the PPh3 reduces Cu(II) to
generate Cu(I),10 and that Cu(I) is the active catalyst in
the Cu-catalyzed triazole-forming reaction reported re-
cently by other research groups.5 These observations
account well for the fact that CuBr2-PPh3 catalyst gave
a higher yield of 3p than CuBr2 alone.11 However, we
cannot exclude the possibility of the [3 + 2]-cycloaddition
reaction between an alkyne and a π-allylpalladium azide
intermediate under the copper catalyst, since the reaction
also proceeded smoothly under Pd(OAc)2-CuBr2-PPh3
catalyst. At least we can point out that both allyl azide
and a π-allylpalladium azide intermediate did not react
efficiently with an alkyne in the absence of the copper
catalyst (entry 4). The role of the palladium catalyst
would be to generate active azide species, allyl azide and
a π-allylpalladium azide intermediate, judging from a
blank test of the TCC reaction; the recovery of the
starting alkyne and allyl methyl carbonate was observed
when the TCC reaction was conducted under CuBr2-
PPh3 catalyst without the addition of Pd(OAc)2. We then
examined the coupling reaction of 1a with cinnamyl azide
under the standard catalytic conditions for the synthesis
of 2-allyltriazoles, Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3.
The reaction gave the expected 2-allyltriazole 2p in 51%
yield (entry 5). The same product 2p has been obtained
via the TCC reaction of 1a , cinnamyl methyl carbonate,
and TMSN3, as shown in eq 4. The reaction between
phenylacetylene 1a and trimethylsilyl azide did not
proceed under Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3
catalyst conditions and the starting acetylene 1a
was recovered. In the case of the coupling reactions of
1a with cinnamyl azide under the copper catalyst, both
CuCl(PPh3)3 and CuCl(PPh3)3-P(OPh)3 promoted the
formation of the 1-allyltriazole 3p in good yields without
affording the 2-allyltriazole 2p (entries 6 and 7). The
coupling reaction under Pd2(dba)3‚CHCl3-P(OPh)3 cata-
(9) The geometry of 1-allyl-4-phenyl-1,2,3-triazole 3a was estab-
lished by NOE experiments. Irradiation of the HA proton on the triazole
ring gave the enhancement of both HB and HC protons. The enhance-
ment between HB and HC protons was not observed.
(10) (a) J ardine, F. H.; Rule, L.; Vohra, A. G. J . Chem. Soc. (A) 1970,
238-239. (b) Reichle, W. T. Inorg. Chim. Acta 1971, 5, 325-332.
(11) It is reported that a terminal alkyne reduces Cu(II) to generate
Cu(I); see: Tsuda, T.; Hashimoto, T.; Saegusa, T. J . Am. Chem. Soc.
1972, 94, 658-659.
2390 J . Org. Chem., Vol. 69, No. 7, 2004

Regiocontrolled Synthesis of Allyltriazoles
SCHEME 2. Isom er iza tion betw een th e
2-Allyltr ia zole 2a a n d 1-Allyltr ia zole 3a
Taken together, a proposed mechanism for the regio-
controlled formation of allyltriazoles via the TCC reaction
is illustrated in Scheme 3. The copper-acetylide species
A would be formed from the simple terminal alkynes 1
and Cu(I)X complex (X ) Cl or Br) with generation of
HX at the initial stage of the catalytic cycle.5,12 As a
coupling partner for A, two reactive azide species can be
conceivable, π-allylpalladium azide complex B13 and allyl
azide C.14 The π-allylpalladium azide complex B is
formed via the reaction of Pd(0), allyl methyl carbonate,
and TMSN3 with the extrusion of CO2 and TMSOMe.
Reductive elimination of Pd(0) from B furnishes allyl
azide C. According to the formation of two reactive azide
species, two reaction pathways could be proposed to reach
the final products, 1-allyltriazoles 3 and 2-allyltriazoles
2, respectively. The formation of 1-allyltriazoles 3 is
rationalized as follows. In path a, [3 + 2]-cycloaddition
would take place between the copper-acetylide A and
allyl azide C to afford the copper-containing intermediate
D.5,15 The protonolysis of the C-Cu bond of D by terminal
alkynes 1 or HX produces the 1-allyltriazoles 3 and
regenerates A or Cu(I)X catalyst. Alternatively, in path
b, [3 + 2]-cycloaddition between the copper-acetylide A
and the π-allylpalladium azide complex B would produce
the palladium and copper-containing intermediate E.16
The protonolysis of the C-Cu bond of E and reductive
elimination of Pd(0) produce the corresponding 1-allyl-
triazoles 3. The formation of 2-allyltriazoles 2 is ex-
plained as follows. One plausible pathway is isomeriza-
tion of the 1-allyltriazoles 3, formed during the TCC
reaction, under the conditions for the 2-allyltriazole
lyst resulted in formation of a mixture of 2p and 3p in
low yields (entry 8). Of course, the recovery of the starting
alkyne and allyl methyl carbonate was observed when
the TCC reaction was conducted under CuCl(PPh3)3-
P(OPh)3 catalyst without the addition of Pd2(dba)3‚CHCl3.
Here again, the palladium catalyst would work as a
generator of reactive azide species, allyl azide and a
π-allylpalladium azide intermediate. The copper catalyst
would behave as a promoter of the [3 + 2]-cycloaddition
reaction between a terminal alkyne and active azide
species to form the triazole framework, but it does not
control the regiochemistry of the allyl group. The phos-
phine ligand, P(OPh)3, most probably plays a key role in
controlling the position of allyl group on the triazole ring.
synthesis
[Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3]
through the π-allylpalladium intermediates E′, F ′, and
G′. Oxidative addition of the Pd(0)-P(OPh)3 complex
would form E′, which would be in equilibrium with G′
through intervention of the (η3-allyl)(η5-triazoyl)palla-
dium complex F ′.17 Reductive elimination of Pd(0)-
P(OPh)3 from the intermediate G′ furnishes the 2-allyl-
triazoles 2 as the final product. To confirm the involvement
of π-allylpalladium intermediates E′-G′, we conducted
the reaction between 1-trimethylsilyl-4-phenyl-1,2,3-tri-
We further investigated the possibility of isomerization
between the 2-allyltriazole 2a and 1-allyltriazole 3a
(Scheme 2). Neither 2a nor 3a was isomerized under
Pd(OAc)2-CuBr2-PPh3 catalyst at 80 °C for 3 h and the
starting material was recovered in both cases. On the
other hand, isomerization from the 1-allyltriazole 3a to
the 2-allyltriazole 2a occurred under Pd2(dba)3‚CHCl3-
CuCl(PPh3)3-P(OPh)3 catalyst and the ratio of 3a to 2a
reached to 77:23 after heating at 100 °C for 10 h (eq 6);
the ratio was determined by GC. The isomerization took
place also in the presence of Pd2(dba)3‚CHCl3-P(OPh)3
catalyst and the ratio of 3a to 2a reached to 13:87 (eq 7).
These results clearly indicate that the isomerization from
1-allyltriazoles to 2-allyltriazoles proceeds under the
standard sets of the catalyst for the 2-allyltriazole
forming reaction, Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3,
and the nature of the phosphine ligand plays an impor-
tant role for the determination of the position of the allyl
group on the triazole ring. The perfect isomerization
(3a :2a ) ∼0:100) did not take place within 10 h, the
reaction time observed in the TCC reaction of phenyl-
acetylene 1a , allyl methyl carbonate, and TMSN3 in the
presence of Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3 cata-
lyst, which produces 2a exclusively. This difference
suggests intervention of other pathways to furnish 2-al-
lyltriazoles 2. One possibility is the direct formation of
2-allyltriazoles through the coupling reaction between the
alkyne and the π-allylpalladium azide complex under the
Cu catalyst.
(12) For generation of a copper-acetylide species under similar
conditions, see: (a) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 2535-2538. (b) Koradin, C.; Gommermann, N.;
Polborn, K.; Knochel, P. Chem. Eur. J . 2003, 9, 2797-2811. (c) Wei,
C.; Li, C.-J .; J . Am. Chem. Soc. 2002, 124, 5638-5638. (d) Zhang, J .;
Wei, C.; Li, C.-J . Tetrahedron Lett. 2002, 43, 5731-5733. (e) Kno¨pfel,
T. F.; Carreira, E. M. J . Am. Chem. Soc. 2003, 125, 6054-6055.
(13) (a) Busetto, L.; Palazzi, A.; Inorg. Chim. Acta 1975, 13, 233-
238. (b) Shaw, B. L.; Shaw, G. J . Chem. Soc. (A) 1971, 3533-3535.
(14) Tornøe and co-workers have reported in ref 5b that the coupling
reaction between the terminal alkyne and trimethylsilyl azide did not
occur in the presence of CuI catalyst. We also confirmed that the
reaction between phenylacetylene and trimethylsilyl azide did not take
place at all under the two bimetallic catalyst conditions, Pd(OAc)2-
CuBr2-PPh3 and Pd2(dba)3‚CHCl3-CuCl(PPh3)3-P(OPh)3.
(15) For copper-acetylide in cycloaddition reactions, see: (a) Kinu-
gasa, M.; Hashimoto, S. J . Chem. Soc., Chem. Commun. 1972, 466-
467. (b) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J . Org. Chem.
1995, 60, 4999-5004. (c) Lo, M. M.-C.; Fu, G. C. J . Am. Chem. Soc.
2002, 124, 4572-4573. (d) Shintani, R.; Fu, G. C. J . Am. Chem. Soc.
2003, 125, 10778-10779.
(16) For reactions involving a π-allylpalladium azide complex, see:
(a) Kamijo, S.; J in, T.; Yamamoto, Y. J . Am. Chem. Soc. 2001, 123,
9453-9454. (b) Kamijo, S.; Yamamoto, Y. J . Am. Chem. Soc. 2002,
124, 11940-11945. (c) Kamijo, S.; J in, T.; Yamamoto, Y. J . Org. Chem.
2002, 67, 7413-7417. (d) Reference 6. (e) Reference 8.
(17) Analogous complexes, (η3-allyl)(η5-cyclopentadienyl)palladium
complex, have been synthesized; see: Tatsuno, Y.; Yoshida, T.; Otsuka,
S. Inorg. Synth. 1979, 19, 221-223.
J . Org. Chem, Vol. 69, No. 7, 2004 2391

Kamijo et al.
SCHEME 3. Mech a n ism for th e Regiocon tr olled F or m a tion of 2-Allyltr ia zoles 2 a n d 1-Allyltr ia zoles 3
azole 4 and allyl methyl carbonate in the presence of a
catalytic amount of Pd2(dba)3‚CHCl3 and P(OPh)3 at 100
°C for 10 h (eq 8). The corresponding 2-allyltriazole 2a
dium complex F under the reaction conditions [Pd2(dba)3‚
CHCl3-CuCl(PPh3)3-P(OPh)3] for the formation of 2-
allyltriazoles. The protonolysis of the C-Cu bond of G
and reductive elimination of Pd(0) afford the 2-allyltri-
azoles 2 directly as the final product. There might be an
equilibrium between the intermediates D and E in the
presence of the Pd(0)-P(OPh)3 complex.
Con clu sion s
We developed a novel one-pot procedure for the regio-
controlled synthesis of allyltriazoles via the Pd-Cu
bimetallic catalyzed TCC reaction of nonactivated ter-
minal alkynes 1, allyl carbonate, and TMSN3. The
selective formation of 2-allyltriazoles 2 is attained by
conducting the reaction under Pd2(dba)3‚CHCl3-
CuCl(PPh3)3-P(OPh)3 catalyst. The selective synthesis
of 1-allyltriazoles 3 are accomplished by running the
reaction under Pd(OAc)2-CuBr2-PPh3 catalyst. The
cooperative activity of Pd and Cu catalysts plays an
important role for the construction of the triazole frame-
work, and the nature of phosphine ligand controls the
position of allyl group on the triazole ring. We are now
was obtained as a major product along with formation
of the 1-allyltriazole 3a . The reaction of unprotected
phenyltriazole 4′ under the same conditions also showed
almost the same result. The other possible pathway is
the direct formation of 2-allyltriazoles 2 through the
palladium and copper-containing intermediates E, F , and
G formed by the coupling of the copper-acetylide A and
the π-allylpalladium azide complex B. The intermediate
E would be in equilibrium with the intermediate G
through intervention of the (η3-allyl)(η5-triazoyl)palla-
2392 J . Org. Chem., Vol. 69, No. 7, 2004

Regiocontrolled Synthesis of Allyltriazoles
mmol), and CuBr2 (2.2 mg, 0.01 mmol) were added phenyl-
acetylene 1a (55 µL, 0.5 mmol), allyl methyl carbonate (68 µL,
0.6 mmol), and TMSN3 (80 µL, 0.6 mmol) under an Ar
atmosphere. The reaction mixture was stirred at 80 °C for 3 h
in a tightly capped 5-mL microvial. After consumption of 1a ,
the mixture was cooled to room temperature and filtered
in a position to synthesize regioselectively either 1-allyl-
or 2-allyl-1,2,3-triazoles just by choosing the proper
catalyst system.
Exp er im en ta l Section
through
a
short Florisil pad with Et2O (∼100 mL) and
R ep r esen t a t ive P r oced u r e for t h e Syn t h esis of 2-
Allyltr ia zoles (2) via th e TCC Rea ction . To an AcOEt
solution (1 mL) of Pd2(dba)3‚CHCl3 (13.0 mg, 0.0125 mmol) and
CuCl(PPh3)3 (44.3 mg, 0.05 mmol) were added P(OPh)3 (26 µL,
0.1 mmol), phenylacetylene 1a (55 µL, 0.5 mmol), allyl methyl
carbonate (68 µL, 0.6 mmol), and TMSN3 (80 µL, 0.6 mmol)
under an Ar atmosphere. The reaction mixture was stirred at
100 °C for 10 h in a tightly capped 5-mL microvial. After
consumption of 1a , the mixture was cooled to room tempera-
ture and filtered through a short Florisil pad with Et2O (∼100
mL) and concentrated. The residue was purified by a silica
gel column chromatography (n-hexane/AcOEt ) 50:1 to 20:1)
to afford 2-allyl-4-phenyl-1,2,3-triazole 2a in 83% yield (77.0
mg).
concentrated. The residue was purified with a silica gel column
chromatography (n-hexane/AcOEt ) 20:1 to 2:1) to afford
1-allyl-4-phenyl-1,2,3-triazole 3a in 88% yield (81.3 mg).
Ack n ow led gm en t. We thank the members in the
Instrumental Analysis Center at Tohoku University for
the measurements of mass spectra, elemental analyses,
NMR spectra, and X-ray crystallography.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and NMR spectra of the 2-allyltriazoles 2a , 2m , and 2p
and the 1-allyltriazoles 3a -p and crystallographic data of
2-allyl-4-(p-dimethylaminophenyl)-1,2,3-triazole. This material
is available free of charge via the Internet at http://pub.acs.org.
Rep r esen ta tive P r oced u r e for th e Syn th esis of 1-Al-
lyltr ia zoles (3) via th e TCC Rea ction . To a toluene solution
(1 mL) of Pd(OAc)2 (2.3 mg, 0.01 mmol), PPh3 (10.5 mg, 0.04
J O035292B
J . Org. Chem, Vol. 69, No. 7, 2004 2393