A study of the scope and regioselectivity of the ruthenium-catalyzed [3 + 2]-cycloaddition of azides with internal alkynes

Article abstract of DOI:10.1021/jo061688m

[3 + 2]-Cycloadditions of alkyl azides with various unsymmetrical internal alkynes in the presence of Cp*RuCl(PPh₃)₂ as catalyst in refluxing benzene have been examined, leading to 1,4,5-trisubstituted-1,2,3-triazoles. Whereas alkyl

Full text of DOI:10.1021/jo061688m

the work by the Sharpless group on so-called “click” reactions,4
whereby heteroatom links between molecules can be generated
under mild conditions, it was found that cycloadditions of
terminal alkynes with alkyl azides catalyzed by Cu(I) can be
conducted at room temperature and are highly regioselective.5,6
This methodology was also independently discovered by Meldal
et al. at about the same time.7 Thus, cycloadditions of alkynes
1 with azides 2 under conditions such as those shown in Scheme
1 lead exclusively to 4-substituted-1,2,3-triazoles 3 in high
yields. This type of copper catalysis, however, does not promote
the cycloadditions of internal alkynes. Mechanistic studies have
demonstrated that these reactions involve terminal copper
acetylides and proceed via a stepwise non-concerted process.5b
More recently, it was discovered that the reaction of terminal
alkynes with alkyl azides is catalyzed by Cp*RuCl(PPh3)2 in
refluxing benzene to afford exclusively the 1,5-disubstituted-
1,2,3-triazoles 4 (Scheme 1).8 In contrast to the click reactions
promoted by copper, the ruthenium complex was also reported
to catalyze the cycloaddition reaction of internal alkynes,
although only a single case which involved a symmetrical
system was described (eq 1).
A Study of the Scope and Regioselectivity of the
Ruthenium-Catalyzed [3 + 2]-Cycloaddition of
Azides with Internal Alkynes
Max M. Majireck and Steven M. Weinreb*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
smw@chem.psu.edu
ReceiVed August 14, 2006
[3 + 2]-Cycloadditions of alkyl azides with various unsym-
metrical internal alkynes in the presence of Cp*RuCl(PPh3)2
as catalyst in refluxing benzene have been examined, leading
to 1,4,5-trisubstituted-1,2,3-triazoles. Whereas alkyl phenyl
and dialkyl acetylenes undergo cycloadditions to afford
mixtures of regioisomeric 1,2,3-triazoles, acyl-substituted
internal alkynes react with complete regioselectivity. In
addition, propargyl alcohols and propargyl amines were
found to react with azides to afford single regioisomeric
products.
It was suggested that this transformation probably occurs by
initial coordination of the alkyne and azide with catalyst 5 to
afford intermediate 6, which then undergoes cyclotrimerization
to afford metallacycle 7 or 8 (Scheme 2). The formation of the
former metallacycle 7 seems most likely due to unfavorable
steric interactions in isomer 8. Reductive elimination of this
intermediate then leads to the 1,2,3-triazole and regenerates the
catalyst. No rationale was presented, however, for the preference
for the observed formation of the 1,5-disubstituted triazole
system 4 when using terminal alkynes. As part of our recent
interest in 1,2,3-triazoles,9 we decided to explore the generality
and scope of the Ru-catalyzed cycloadditions of alkyl azides
with internal alkynes.
Initial experiments were conducted with benzyl azide and
commercially available alkynes to form 1,4,5-trisubstituted-
1,2,3-triazoles (A and/or B) as outlined in Table 1. The reactions
were all run with 10 mol % of ruthenium catalyst 5 in refluxing
benzene. In the majority of cases, the cycloadditions proceeded
to completion within 2.5 h using ∼1.5 equiv of acetylene relative
1,2,3-Triazoles are nitrogen heteroarenes which have found
a range of important applications in the pharmaceutical and
agricultural industries.1 The most widely used method for
synthesis of 1,2,3-triazoles has involved the thermal 1,3-dipolar
cycloaddition of organic azides with alkynes pioneered by
Huisgen.2 However, there are major problems commonly
associated with this methodology, including the need for long
reaction times and high temperatures, as well as the formation
of regioisomeric mixtures of products when using unsymmetrical
alkynes. It was recently reported that it is possible to impart
some regioselectivity into these thermal cycloadditions by
utilizing sterically or electronically biased alkynes.3 As part of
(1) For reviews of 1,2,3-triazoles, see: (a) Fan, W.-Q.; Katritzky, A. R.
In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 4, pp
1-126. (b) Dehne, H. In Methoden der Organischen Chemie (Houben-
Weyl); Schaumann, E., Ed.; Thieme: Stuttgart, 1994; Vol. E8d, pp 305-
405. (c) Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. ReV. 2005, 74,
339.
(2) For reviews, see: (a) L’Abbe, G. Chem. ReV. 1969, 69, 345. (b)
Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; p 559. (c) Sha, C.-K.; Mohanakrishnan, A. K. In
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.;
Wiley: New York, 2002; p 623.
(4) For reviews of “click chemistry”, see: (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004. (b) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(5) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Himo, F.; Lovell, T.; Hilgraf,
R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J.
Am. Chem. Soc. 2005, 127, 210. (c) Chan, T. R.; Hilgraf, R.; Sharpless, K.
B.; Fokin, V. V. Org. Lett. 2004, 6, 2853.
(6) For recent improved experimental procedures, see: (a) Lee, B.-Y.;
Park, S. R.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett. 2006, 47, 5105. (b)
Reddy, K. R.; Rajgopal, K.; Kantam, M. L. Synlett 2006, 957.
(7) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
(3) See for example: (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem.
1994, 59, 6184. (b) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J.
Org. Lett. 2005, 7, 1469. (c) Li, Z.; Seo, T. S.; Ju, J. Tetrahedron Lett.
2004, 45, 3143.
(8) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(9) Yap, A. H.; Weinreb, S. M. Tetrahedron Lett. 2006, 47, 3035.
10.1021/jo061688m CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/05/2006
8680
J. Org. Chem. 2006, 71, 8680-8683

SCHEME 1
with a propargyl amine (entry 13). It should also be noted that
attempted cycloaddition of benzyl azide with phenyl trimeth-
ylsilyl acetylene provided a complex mixture of products.
The cycloaddition of benzhydryl azide11 with methyl phenyl
acetylene was also examined. This secondary azide reacts more
slowly than does benzyl azide, but affords the same ratio of
adducts A/B (entry 15). In the case of highly hindered, tertiary
adamantyl azide, the reaction is extremely slow and provides a
single product of type B, but only in very low yield (entry 16).
We have shown that the reaction of internal alkynes with
azides catalyzed by Cp*RuCl(PPh3)2 (5) is a general process.
These cycloadditions proceed under mild conditions, affording
1,4,5-trisubstituted-1,2,3-triazoles in good yields. Depending
upon the alkyne substitution pattern, the reactions can be highly
regioselective. At present, however, we are unable to offer a
compelling mechanistic rationale for these regiochemical results.
SCHEME 2
Experimental Section
General Procedure for Ru-Catalyzed Cycloadditions. A
mixture of azide (1.0 equiv, 0.5 mmol), alkyne (1.2-5.0 equiv),
Cp*RuCl(PPh3)2 (0.1 equiv, 0.05 mmol), and 2.5 mL of anhydrous
benzene was refluxed at 80 °C for 2.5-40 h. The progress of the
reaction was monitored by TLC. The mixture was then cooled and
evaporated under reduced pressure. The product was purified by
flash column chromatography using a mixture of ethyl acetate and
hexanes. Ratios of regioisomers (see Table 1) were determined on
the crude reaction mixture by 1H NMR integration prior to
chromatography. Numbers of structures below refer to Table 1.
Compounds 1A,12 1B,13 3A,14 4A,13,15 and 9B12 have been previ-
ously prepared.
to azide, giving good yields of products. In reactions which were
slower, however, the amount of alkyne was increased, as was
the reaction time. In cases where regioisomers were formed,
NMR integration of the crude reaction mixture prior to
chromatographic separation was utilized to determine product
ratios. The regiochemistry of the purified products was then
1-Benzyl-4-methyl-5-phenyl-1H-[1,2,3]triazole (entry 1A) and
1-Benzyl-5-methyl-4-phenyl-1H-[1,2,3]triazole (entry 1B). Benzyl
azide (67 mg, 0.50 mmol), prop-1-ynylbenzene (125 mg, 1.08
mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). The products
were obtained as a yellow oil (42 mg of 1A) and a white solid (78
mg of 1B) in a total yield of 95%. 1A: 1H NMR (300 MHz, CDCl3)
δ 7.46-7.44 (m, 3H), 7.30-7.25 (m, 3H), 7.20-7.15 (m, 2H),
7.07-7.03 (m, 2H), 5.45 (s, 2H), 2.34 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 142.1, 135.9, 135.1, 129.9, 129.7, 129.3, 129.1, 128.5,
127.7, 52.5, 11.1; LRMS-ES+ m/z (relative intensity) 250 (MH+,
65); HRMS-ES+ (C16H15N3) calcd 250.1344 (MH+), found 250.1349.
1
established by H NMR NOE experiments. In the cases of
phenyl alkyl acetylenes (entries 1 and 2), moderate regioselec-
tivity was observed in favor of isomers B. With unsymmetrical
methyl propyl acetylene (entry 7), the A/B ratio was about 1/2.
In the case of hindered methyl t-butyl acetylene, the cycload-
dition proved to be quite slow, and although only one regio-
isomeric triazole B was detected, the yield was low.
1
1B: H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 2H), 7.49-
7.21 (m, 8H), 5.57 (s, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 145.4, 135.3, 132.0, 129.6, 129.5, 129.1, 128.7, 128.1, 127.59,
127.57, 52.5, 9.6; LRMS-ES+ m/z (relative intensity) 250 (MH+,
65); HRMS-ES+ (C16H15N3) calcd 250.1344 (MH+), found 250.1349.
1-Benzyl-5-phenyl-4-propyl-1H-[1,2,3]triazole (entry 2A) and
1-Benzyl-4-phenyl-5-propyl-1H-[1,2,3]triazole (entry 2B). Benzyl
azide (67 mg, 0.50 mmol), pent-1-ynylbenzene (110 mg, 0.76
mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). Both products
were obtained as yellow oils (14 mg of 2A; 96 mg of 2B) in a
total yield of 80%. 2A: 1H NMR (300 MHz, CDCl3) δ 7.44-7.01
(m, 10H), 5.41 (s, 2H), 2.61 (t, J ) 7.5 Hz, 2H), 1.67 (sextet, J )
7.6 Hz, 2H), 0.87 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 146.3, 136.1, 130.2, 129.6, 129.3, 129.2, 129.1, 128.4, 128.0,
127.8, 52.4, 27.5, 23.3, 14.3; LRMS-ES+ m/z (relative intensity)
A few unsymmetrical disubstituted alkynes which bear a
carbonyl group were also investigated (entries 3, 4, 11, and 12),
and in all cases, the cycloadditions were totally regioselective,
affording only triazole isomers A. It should be noted that thermal
(uncatalyzed) cycloadditions of electron-deficient alkynes with
azides usually produce mixtures of regioisomeric products,2b
although isomers such as A usually predominate, presumably
for polarity reasons. It has recently been found that, if these
thermal reactions are conducted in water, isomers of type A
are produced cleanly with both terminal and internal alkynes.3c
We were surprised to find that propargylic alcohols undergo
Ru-catalyzed cycloadditions to afford exclusively 1,2,3-triazoles
of type B (entries 5 and 14). On the other hand, in the case of
a homopropargyl alcohol (entry 10), the regioselectivity is low
and is similar to that found with a simple dialkyl acetylene (cf.
entry 7). Moreover, the alkynyl acetal in entry 6 showed no
regioselectivity in the cycloaddition, which would seem to
preclude any type of heteroatom-metal coordination.10 The
same high regioselectivity in favor of triazole B was observed
(11) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2110.
(12) (a) Olsen, C. E. Acta Chem. Scand. 1973, 27, 2983. (b) Olsen, C.
E. Acta Chem. Scand. B 1975, 29, 953.
(13) Cottrell, I. F.; Hands, D.; Houghton, P. G.; Humphrey, G. R.; Wright,
S. H. B. J. Heterocycl. Chem. 1991, 28, 301.
(14) (a) Prager, R. H.; Razzino, P. Aust. J. Chem. 1994, 47, 1375. (b)
Cwiklicki, A.; Rehse, K. Arch. Pharm. Pharm. Med. Chem. 2004, 337,
156.
(10) See for example: Na, Y.; Chang, S. Org. Lett. 2000, 2, 1887.
(15) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 8, 1314.
J. Org. Chem, Vol. 71, No. 22, 2006 8681

TABLE 1. Preparation of 1,4,5-Trisubstituted-1,2,3-triazoles via Ru-Catalyzed Cycloadditions of Azides with Internal Alkynes
equiv of
entry
R1
R2
R3
alkyne
time (h)
% yield
A:B ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
Me
Me
Bu
Et
Me
Pr
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CHPh2
1-adamantyl
2.0
1.5
2.0
1.5
1.5
1.5
3.0
2.0
5.0
1.5
1.2
1.5
1.5
1.5
3.0
5.0
2.5
2.5
2.5
2.5
5.0
2.5
16
95
80
85
100
70
75
75
85
15
90
90
90
70
80
65
10
38:62
13:87
100:0
100:0
0:100
50:50
32:68
N/A
0:100
23:77
100:0
100:0
0:100
0:100
33:67
0:100
CO2Et
COMe
CH2OH
CH(OEt)2
Pr
Et
t-Bu
6.0
36
CH2CH2OH
CO2Me
COMe
CH2NEt2
CMe2OH
Me
8.0
2.5
2.5
2.5
5.0
20
Me
Et
Ph
Ph
Me
40
278 (MH+, 100); HRMS-ES+ (C18H20N3) calcd 278.1657 (MH+),
0.05 mmol). The products were obtained as a yellow oil (45 mg of
6A) and a clear oil (80 mg of 6B) in a total yield of 75%. 6A: 1H
NMR (400 MHz, CDCl3) δ 7.42-7.40 (m, 3H), 7.26-7.20 (m,
5H), 7.04-7.01 (m, 2H), 5.60 (s, 1H), 5.43 (s, 2H), 3.71-3.64
(m, 2H), 3.59-3.52 (m, 2H), 1.12 (t, J ) 7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.8, 135.7, 130.4, 129.8, 129.1, 128.9,
128.5, 127.8, 127.2, 96.8, 61.9, 52.3, 15.4; LRMS-ES+ m/z (relative
intensity) 338 (MH+, 100); HRMS-ES+ (C20H24N3O2) calcd
338.1869 (MH+), found 338.1855. 6B: 1H NMR (300 MHz, CDCl3)
δ 7.73-7.70 (m, 2H), 7.50-7.33 (m, 8H), 5.82 (s, 2H), 5.64 (s,
1H), 3.66-3.56 (m, 2H), 3.43-3.35 (m, 2H), 1.09 (t, J ) 7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 146.6, 136.5, 131.2, 131.1,
128.9, 128.8, 128.6, 128.3, 128.2, 96.2, 63.6, 53.7, 15.2; LRMS-
ES+ m/z (relative intensity) 338 (MH+, 100); HRMS-ES+
(C20H24N3O2) calcd 338.1869 (MH+), found 338.1855.
1
found 278.1638. 2B: H NMR (300 MHz, CDCl3) δ 7.74-7.70
(m, 2H), 7.48-7.21 (m, 8H), 5.58 (s, 2H), 2.72 (t, J ) 6.3 Hz,
2H), 1.43 (sextet, J ) 8.1 Hz, 2H), 0.87 (t, J ) 7.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 145.2, 135.7, 133.9. 132.2, 129.4, 129.1,
128.7, 128.1, 127.51, 127.47, 52.5, 25.6, 22.3, 14.4; LRMS-ES+
m/z (relative intensity) 278 (MH+, 100); HRMS-ES+ (C18H20N3)
calcd 278.1657 (MH+), found 278.1638.
1-Benzyl-5-phenyl-1H-[1,2,3]triazole-4-carboxylic Acid Ethyl
Ester (entry 3A). Benzyl azide (67 mg, 0.50 mmol), phenylpro-
pynoic acid ethyl ester (165 mg, 0.95 mmol), and Cp*RuCl(PPh3)2
(40 mg, 0.05 mmol). The product was obtained as an off-white
solid (131 mg) in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.50-
7.41 (m, 3H), 7.28-7.18 (m, 5H), 7.01-6.98 (m, 2H), 5.44 (s,
2H), 4.29 (q, J ) 7.2 Hz, 2H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 161.3, 141.7, 137.5, 135.0, 130.5, 130.2, 129.2,
128.9, 128.8, 127.9, 126.4, 61.4, 52.6, 14.5; LRMS-ES+ m/z
(relative intensity) 308 (MH+, 100); HRMS-ES+ (C18H17N3O2)
calcd 308.1399 (MH+), found 308.1377.
1-(1-Benzyl-5-phenyl-1H-[1,2,3]triazol-4-yl)-ethanone (entry
4A). Benzyl azide (67 mg, 0.50 mmol), 4-phenylbut-3-yn-2-one
(110 mg, 0.76 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol).
The product was obtained as a yellow oil (140 mg) in 100% yield:
1H NMR (400 MHz, CDCl3) δ 7.51-7.43 (m, 3H), 7.29-7.25 (m,
3H), 7.23-7.21 (m, 2H), 7.04-7.02 (m, 2H), 5.43 (s, 2H), 2.69
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.1, 144.2, 140.0, 135.1,
131.0, 130.1, 129.3, 129.1, 128.9, 128.0, 126.4, 52.4, 28.5; LRMS-
ES+ m/z (relative intensity) 300 (M + Na+, 95); HRMS-ES+
(C17H16N3O) calcd 278.1293 (MH+), found 278.1312.
(3-Benzyl-5-phenyl-3H-[1,2,3]triazol-4-yl)methanol (entry 5B).
Benzyl azide (67 mg, 0.50 mmol), 3-phenylprop-2-yn-1-ol (100
mg, 0.75 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). The
product was obtained as an off-white solid (93 mg) in 70% yield:
1H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.39-7.23 (m,
8H), 5.62 (s, 2H), 4.69 (s, 2H), 3.83 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 146.6, 135.4, 132.6, 130.9, 129.4, 129.2, 128.8, 128.7,
128.1, 128.0, 52.9, 52.7; LRMS-ES+ m/z (relative intensity) 266
(MH+, 100); HRMS-ES+ (C16H16N3O) calcd 266.1293 (MH+),
found 266.1273.
1-Benzyl-5-methyl-4-propyl-1H-[1,2,3]triazole (entry 7A) and
1-Benzyl-4-methyl-5-propyl-1H-[1,2,3]triazole (entry 7B). Benzyl
azide (67 mg, 0.50 mmol), hex-2-yne (125 mg, 1.5 mmol), and
Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). Both products were obtained
as clear oils (25 mg of 7A; 56 mg of 7B) in 75% total yield. 7A:
1H NMR (400 MHz, CDCl3) δ 7.35-7.32 (m, 3H), 7.17-7.15 (m,
2H), 5.48 (s, 2H), 2.60 (t, J ) 7.4 Hz, 2H), 2.09 (s, 3H), 1.70 (q,
J ) 7.5 Hz, 2H), 0.95 (t, J ) 7.4 Hz, 3H); 13C NMR (300 MHz,
CDCl3) δ 146.0, 135.5, 129.3, 128.6, 127.50, 127.47, 52.3, 27.5,
23.2, 14.2, 8.3; LRMS-ES+ m/z (relative intensity) 216 (MH+, 100);
HRMS-ES+ (C13H17N3) calcd 216.1501 (MH+), found 216.1495.
1
7B: H NMR (400 MHz, CDCl3) δ 7.33-7.29 (m, 3H), 7.16-
7.14 (m, 2H), 5.47 (s, 2H), 2.46 (t, J ) 7.6 Hz, 2H), 2.28 (s, 3H),
1.36 (q, J ) 7.6 Hz, 2H), 0.84 (t, J ) 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 141.7, 135.9, 133.6, 129.3, 128.6, 127.4, 52.3, 24.9,
22.1, 14.1, 11.0; LRMS-ES+ m/z (relative intensity) 216 (MH+,
100); HRMS-ES+ (C13H17N3) calcd 216.1501 (MH+), found
216.1495.
1-Benzyl-4,5-diethyl-1H-[1,2,3]triazole (entry 8). Benzyl azide
(67 mg, 0.50 mmol), hex-3-yne (82 mg, 1.0 mmol), and Cp*RuCl-
(PPh3)2 (40 mg, 0.05 mmol). The product was obtained as a yellow
oil (90 mg) in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-
7.27 (m, 3H), 7.15-7.11 (m, 2H), 5.45 (s, 2H), 2.62 (q, J ) 7.6
Hz, 2H), 2.51 (q, J ) 7.7 Hz, 2H), 1.26 (t, J ) 7.6 Hz, 3H), 0.94
(t, J ) 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 146.7, 135.9,
134.4, 129.3, 128.5, 127.4, 52.2, 18.9, 16.3, 14.6, 13.7; LRMS-
ES+ m/z (relative intensity) 216 (MH+, 100); HRMS-ES+
(C13H18N3) calcd 216.1501 (MH+), found 216.1500.
1-Benzyl-4-diethoxymethyl-5-phenyl-1H-[1,2,3]triazole (entry
6A) and 1-Benzyl-5-diethoxymethyl-4-phenyl-1H-[1,2,3]triazole
(entry 6B). Benzyl azide (67 mg, 0.50 mmol), (3,3-diethoxyprop-
1-ynyl)benzene (155 mg, 0.76 mmol), and Cp*RuCl(PPh3)2 (40 mg,
8682 J. Org. Chem., Vol. 71, No. 22, 2006

1-Benzyl-5-tert-butyl-4-methyl-1H-[1,2,3]triazole (entry 9B).
Benzyl azide (67 mg, 0.50 mmol), 4,4-dimethylpent-2-yne (245
mg, 2.5 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). The
product was obtained as a clear oil (17 mg) in 15% yield: 1H NMR
(400 MHz, CDCl3) δ 7.32-7.27 (m, 3H), 6.99-6.97 (m, 2H), 5.73
(s, 2H), 2.50 (s, 3H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
140.5, 140.1, 137.2, 129.2, 128.1, 126.5, 54.2, 31.9, 30.9, 15.0;
LRMS-ES+ m/z (relative intensity) 230 (MH+, 55); HRMS-ES+
(C14H20N3) calcd 230.1657 (MH+), found 230.1647.
2-(3-Benzyl-5-ethyl-3H-[1,2,3]triazol-4-yl)-propan-2-ol (entry
14B). Benzyl azide (67 mg, 0.50 mmol), 2-methylhex-3-yn-2-ol
(83 mg, 0.74 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol).
The product was obtained as an off-white solid (96 mg) in 80%
yield: 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 3H), 7.14-
7.12 (m, 2H), 5.83 (s, 2H), 3.48 (s, 1H), 2.71 (q, J ) 7.5 Hz, 2H),
1.51 (s, 6H), 1.26 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 144.6, 138.1, 137.7, 129.0, 128.0, 127.5, 69.8, 54.2, 31.2, 20.7,
14.8; LRMS-ES+ m/z (relative intensity) 246 (MH+, 100); HRMS-
ES+ (C14H20N3O) calcd 246.1606 (MH+), found 246.1604.
1-Benzhydryl-4-methyl-5-phenyl-1H-[1,2,3]triazole (entry 15A)
and 1-Benzhydryl-5-methyl-4-phenyl-1H-[1,2,3]triazole (entry
15B). Benzhydryl azide11 (105 mg, 0.50 mmol), prop-1-ynylbenzene
(175 mg, 1.5 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol).
Both products were obtained as yellow solids (30 mg of 15A; 70
mg of 15B) in 65% overall yield. 15A: 1H NMR (300 MHz, CDCl3)
δ 7.50-7.48 (m, 3H), 7.34-7.31 (m, 6H), 7.24-7.19 (m, 6H), 6.55
(s, 1H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.3, 139.4,
135.7, 130.2, 129.8, 129.5, 129.0, 128.8, 128.5, 128.1, 66.2, 11.1;
LRMS-ES+ m/z (relative intensity) 326 (MH+, 100); HRMS-ES+
(C22H20N3) calcd 326.1657 (MH+), found 326.1666. 15B: 1H NMR
(400 MHz, CDCl3) δ 7.74-7.72 (m, 2H), 7.48-7.45 (m, 2H),
7.42-7.34 (m, 7H), 7.29-7.25 (m, 4H), 6.85 (s, 1H), 2.40 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 145.2, 138.2, 132.0, 130.0, 129.2,
129.0, 128.9, 128.7, 128.1, 127.8, 66.8, 10.0; LRMS-ES+ m/z
(relative intensity) 326 (MH+, 100); HRMS-ES+ (C22H20N3) calcd
326.1657 (MH+), found 326.1666.
2-(3-Benzyl-5-methyl-3H-[1,2,3]triazol-4-yl)-ethanol (entry
10A) and 2-(1-Benzyl-5-methyl-1H-[1,2,3]triazol-4-yl)-ethanol
(entry 10B). Benzyl azide (67 mg, 0.50 mmol), pent-3-yn-1-ol (130
mg, 1.5 mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). The
products were obtained as an inseparable mixture (99 mg) in 90%
1
overall yield. 10A + 10B: H NMR (400 MHz, CDCl3) δ 7.33-
7.27 (m, 3H major + 3H minor), 7.14-7.12 (m, 2H major + 2H
minor), 5.55 (s, 2H major), 5.44 (s, 2H minor), 3.92 (t, J ) 5.9
Hz, 2H minor), 3.72 (t, J ) 6.1 Hz, 2H major), 2.81 (t, J ) 5.9
Hz, 2H minor), 2.72 (t, J ) 6.1 Hz, 2H major), 2.20 (s, 3H major),
2.04 (s, 3H minor); 13C NMR (75 MHz, CDCl3) major peaks δ
142.2, 135.5, 134.8, 132.2, 129.4, 129.3, 129.1, 128.8, 128.7, 127.8,
127.6, 65.0, 60.7, 52.7, 52.2, 30.1, 26.5, 14.1, 10.7; LRMS-ES+
m/z (relative intensity) 218 (MH+, 100); HRMS-ES+ (C12H15N3-
ONa) calcd 240.1113 (M + Na+), found 240.1095.
1-Benzyl-5-butyl-1H-[1,2,3]triazole-4-carboxylic Acid Methyl
Ester (entry 11A). Benzyl azide (67 mg, 0.50 mmol), hept-2-ynoic
acid methyl ester (80 mg, 0.61 mmol), and Cp*RuCl(PPh3)2 (40
mg, 0.05 mmol). The product was obtained as a yellow oil (114
mg) in 90% yield: 1H NMR (400 MHz, CDCl3) δ 7.34-7.32 (m,
3H), 7.17-7.15 (m, 2H), 5.53 (s, 2H), 3.92 (s, 3H), 2.85 (t, J )
8.0 Hz, 2H), 1.31-1.22 (m, 6H), 0.82 (t, J ) 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 162.4, 143.3, 136.9, 134.9, 129.5, 129.0,
127.6, 52.5, 52.3, 30.7, 23.4, 22.9, 14.0; LRMS-ES+ m/z (relative
intensity) 296 (M + Na+, 100); HRMS-ES+ (C15H19N3O2) calcd
296.1375 (M + Na+), found 296.1377.
1-(1-Benzyl-5-ethyl-1H-[1,2,3]triazol-4-yl)-ethanone (entry 12A).
Benzyl azide (67 mg, 0.50 mmol), hex-3-yn-2-one (73 mg, 0.75
mmol), and Cp*RuCl(PPh3)2 (40 mg, 0.05 mmol). The product was
obtained as a yellow oil (105 mg) in 90% yield: 1H NMR (400
MHz, CDCl3) δ 7.35-7.28 (m, 4H), 7.18-7.16 (m, 2H), 5.51 (s,
2H), 2.89 (q, J ) 7.5 Hz, 2H), 2.67 (s, 3H), 0.95 (t, J ) 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 194.4, 143.9, 142.7, 134.9,
129.5, 129.0, 127.6, 52.0, 28.1, 17.3, 12.6; LRMS-ES+ m/z (relative
intensity) 252 (M + Na+, 100); HRMS-ES+ (C13H15N3ONa) calcd
252.1113 (MH+), found 252.1113.
1-Adamantan-1-yl-5-methyl-4-phenyl-1H-[1,2,3]triazole (en-
try 16B). 1-Azidoadamantane (95 mg, 0.50 mmol), prop-1-
ynylbenzene (305 mg, 2.63 mmol), and Cp*RuCl(PPh3)2 (40 mg,
0.05 mmol). The product was obtained as a yellow oil (13 mg) in
10% yield: 1H NMR (400 MHz, CDCl3) δ 7.64-7.61 (m, 2H),
7.48-7.44 (m, 2H), 7.38-7.37 (m, 1H), 2.62 (s, 3H), 2.44 (d, J )
3.0 Hz, 6H), 2.30 (m, 3H), 1.83 (t, J ) 3.1 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 146.8, 132.3, 128.9, 128.5, 127.9, 62.3, 42.0, 36.4,
30.1, 12.4; LRMS-ES+ m/z (relative intensity) 293 (M+, 100);
HRMS-ES+ (C19H23N3) calcd 293.1892 (MH+), found 293.1888.
Acknowledgment. We are grateful to the National Institutes
of Health (CA-034303) for financial support of this research.
We also thank Amy Yap for conducting some preliminary
experiments, and Dr. G. Jia for providing information on
preparation of the ruthenium catalyst 5.
(3-Benzyl-5-methyl-3H-[1,2,3]triazol-4-ylmethyl)diethy-
lamine (entry 13B). Benzyl azide (67 mg, 0.50 mmol), but-2-
ynyldiethylamine (85 mg, 0.75 mmol), and Cp*RuCl(PPh3)2 (40
mg, 0.05 mmol). The product was obtained as a yellow oil (90
mg) in 70% yield: 1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m,
3H), 7.17-7.15 (m, 2H), 5.85 (s, 2H), 3.36 (s, 2H), 2.42 (q, J )
7.1 Hz, 4H), 2.29 (s, 3H), 0.95 (t, J ) 7.1 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 143.1, 136.2, 130.9, 129.1, 128.3, 127.6, 52.3, 46.7,
45.9, 11.7, 10.7; LRMS-ES+ m/z (relative intensity) 259 (MH+,
100); HRMS-ES+ (C15H23N4) calcd 259.1923 (MH+), found
259.1907.
Note Added after ASAP Publication. Table 1 had an
incorrect ratio in the version published October 5, 2006; the
correct version was published October 5, 2006.
Supporting Information Available: Copies of proton and
carbon NMR spectra of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061688M
J. Org. Chem, Vol. 71, No. 22, 2006 8683