A versatile one-pot synthesis of 4-aryl-1,5-disubstituted 1,2,3-triazoles via 1,3-dipolar cycloaddition followed by Negishi reaction under new conditions

Article abstract of DOI:10.1055/s-2006-958435

Several derivatives of 4-aryl-1,5-disubstituted 1,2,3-triazole were synthesized in good yields via 1,3-dipolar cycloaddition followed by Negishi reaction under new conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958435

LETTER
31
A Versatile One-Pot Synthesis of 4-Aryl-1,5-disubstituted 1,2,3-Triazoles
via 1,3-Dipolar Cycloaddition Followed by Negishi Reaction under
New Conditions
Versatile
One-Pot
t
S
ynthe
s
sis of 4-
A
u
ryl-1, 5-disub
s
stituted 1,
h
2,3-Triazole
i
s
Akao,*a Takayuki Tsuritani,a Satoshi Kii,a Kimihiko Sato,a Nobuaki Nonoyama,a Toshiaki Mase,a
Nobuyoshi Yasudab
a
Process Research, Preclinical Development, Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
Fax +81(29)8772024; E-mail: atsushi_akao@merck.com
b
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 2 August 2006
R
5
Ar2
catalysts
X
R
Abstract: Several derivatives of 4-aryl-1,5-disubstituted 1,2,3-tri-
azole were synthesized in good yields via 1,3-dipolar cycloaddition
followed by Negishi reaction under new conditions.
Ar2
Ar1
M
R
M
N3 Ar1
Ar1
N
4
1
N
3 N
N
2
N
N
Key words: triazole, Negishi reaction, 1,3-dipolar cycloaddition,
XANTPHOS, zinc, cross-coupling
Scheme 1 Synthesis of 1,2,3-triazole by 1,3-dipolar cycloaddition
followed by cross-coupling reaction
1,2,3-Triazole substructures are emerging as valuable
pharmacophores.1,2 Among these, 4-aryl-1,5-disubstitut-
ed-1,2,3-triazole is a useful structure for development of
pharmaceutical agents;3 therefore, it is important to devel-
op efficient synthetic methods for this compound.
However, direct cross-coupling of the 4-metallo-1,2,3-tri-
azole intermediates has not yet been reported.
Here, we report a highly effective synthetic method for 4-
aryl-1,5-disubstituted 1,2,3-triazole by 1,3-dipolar cyclo-
addition followed by direct Negishi reaction under new
conditions.
N-Alkylation is a simplistic approach to synthesize sub-
stituted 1,2,3-triazoles. However, regioselectivity in this
reaction is generally poor.4 1,3-Dipolar cycloaddition of
organic azides and alkynes is a direct route to 1,2,3-tri-
azoles.5–7 Sharpless et al. reported a selective synthesis
of 1,4-disubstituted 1,2,3-triazoles via copper-catalyzed
1,3-dipolar cycloaddition,2 and of 1,5-disubstituted 1,2,3-
triaozoles by ruthenium-catalyzed 1,3-dipolar cyclo-
addition.8
First, 1,3-dipolar cycloaddition was investigated using
alkynylmetal (Li, Mg and Zn) reagents (Table 1). 1,3-Di-
polar cycloaddition of azide 2a and alkynyllithium 1a pro-
duced triazole in mediocre yield (entry 1). As reported by
Sharpless et al.6 and Akimova et al.,11 however, 1,3-dipo-
lar cycloaddition using alkynylmagnesium halide 1b gave
the desired product in near-quantitative yield (entry 2).
To improve functional group compatibility, less reactive
alkynylzinc halides prepared in situ were examined. With
1.05 equivalents of propynylzinc chloride, the yield was
lower (entry 3). The use of dialkylzinc and zincate were
also examined, but the reaction was unsuccessful (entries
4 and 5). However, with 3 equivalents propynylzinc
chloride, the reaction proceeded well and the product was
obtained in good yield (entry 6).
In addition, regioselective syntheses of 1,4,5-trisubstitut-
ed 1,2,3-triazoles have been reported.9 Yamamoto et al.
reported the synthesis of 5-allyl-1,4-disubstituted 1,2,3-
triazoles by a cross-coupling reaction between p-allylpal-
ladium complexes and 5-copper-1,2,3-triazoles prepared
in situ.10 Sharpless et al. reported nucleophilic substitution
reactions of 4-magnesio-1,2,3-triazoles, prepared from
alkynylmagnesium bromides and organic azides, to yield
1,4,5-trisubstituted 1,2,3-triazoles.6 Wu et al. reported the
synthesis of 5-aryl-1,4-disubstituted 1,2,3-triazoles by a
cross-coupling reaction between 5-iodo-1,2,3-triazoles
and arylboronic acids.7
3-Phenylpropynylzinc reagents were also systematically
investigated (entries 7–10). With mono- or dialkylzinc
reagents, the reactions were sluggish (entries 7 and 8), but
the use of zincates substantially improved the yields
(entries 9 and 10).
It is expected that 1,3-dipolar cycloaddition of organic
azides and alkynylmetals, followed by cross-coupling of
the resulting 4-metallo-1,2,3-triazole species with aryl-
halides, may be developed as a particularly streamlined
and regioselective synthesis method for 4-aryl-1,5-disub-
stituted 1,2,3-triazoles (Scheme 1).
In summary, the best result was obtained by using
alkynylmagnesium bromide. Alkynyllithiums were not
effective. Reactions using alkynylzinc reagents were
slow, but the yields were acceptable in some cases.
Cross-coupling of 4-metallo-1,2,3-triazole species was
then investigated. Initially, Kumada–Tamao reactions
were examined, but due to the narrow compatibility of this
method with reactive functional groups, the focus was
moved to the more versatile Negishi reaction. The reac-
SYNLETT 2007, No. 1, pp 0031–0036
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958435; Art ID: U09406ST
© Georg Thieme Verlag Stuttgart · New York

32
A. Akao et al.
LETTER
Table 1 1,3-Dipolar Cycloaddition of Mg, Li, and Zn Species
M
R
M = Li, R = Ph
M = MgBr, R= Me
1a
1b
ZnCl2
R
F
XZn
XZn
R
N
N3
F
N
N
2a
R
F
H+
H
N
N
N
R = Ph
R = Me
3a
3b
Entry
1 (equiv)
1a (1.05)
1b (1.05)
1b (1.05)
1b (1.05)
1b (1.05)
1b (3.00)
1a (1.05)
1a (1.05)
1a (1.05)
1a (1.05)
ZnCl2 (equiv)
Temp (°C)
Time (h)
24
Yield of 3 (%)a
1
2
0
r.t.
r.t.
40
22
96
57
29
34
75
9
0
2.5
7
3
1.05
0.53
0.35
3.00
1.05
0.53
0.35
0.26
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
5
24
6
24
7
24
8
24
17
74
73
9
24
10
24
a Yields determined by HPLC.
tion conditions were optimized as shown in Table 2 and and BIPHEP17 were found to be ineffective (entries 1–3).
Figure 1. Since the best yields of 4-metallo-1,2,3-triazole The reaction using DPPF was a slight improvement (entry
species were obtained by 1,3-dipolar cycloaddition using 4), but more bulky ligands such as DtBPF16,18 shut down
a magnesium reagent, 4-zincio-1,2,3-triazoles were pre- the reaction (entry 5).19 Negishi et al. reported that
pared by in situ transmetalation of 4-magnesio-1,2,3-tri- DPEPHOS was an effective bidentate ligand for Negishi
azoles with ZnCl2. The subsequent Negishi reactions were reactions.20 However, the yield obtained from the reaction
carried out by adding bromobenzene and catalysts to the using DPEPHOS was mediocre (entry 6). Recently,
4-zincio-1,2,3-triazole mixture, producing the desired XANTPHOS has been found to be an excellent ligand for
product 5 along with the uncoupled product 3. When typ- a variety of palladium-mediated cross-coupling reac-
ical palladium catalysts were used, 10 mol% of catalyst tions.21 When this ligand was used for our reaction (entry
was required, but yields were moderate (entries 1–4).12 Fu 7), the reaction proceeded smoothly even with 1 mol% of
et al. reported that Pd(Pt-Bu3)2 functioned as a good cata- Pd2(dba)3.22 The XANTPHOS ligand was also applied to
lyst for Negishi reactions,13 but the use of this catalyst did the Kumada–Tamao reaction, but this was not as effective
not improve the yield in this case (entries 5 and 6). Vari- as the Negishi reaction (53% yield).23
ous ligands for the palladium catalyst were also screened
Hayashi et al. reported that the use of bidentate ligands to
form complexes with larger P–Pd–P angles results in
(entries 7–10). Monodentate phosphines (PPh3, Pt-Bu3
and X-PHOS14) were found to be ineffective (entries 7–9).
acceleration of reductive elimination to form the coupling
Organ et al. reported that N-heterocyclic carbene-class
product.24 In this case, reactions using catalysts with
ligands such as IPr were effective for Negishi reactions.15
smaller P–Pd–P bite angles (less than 92°)25,26 did not
However, IPr was found to be ineffective in this case
proceed (entries 1–3), while reactions using catalysts
with larger bite angles (DPPF: 96°, DPEPHOS: 102°,
(entry 10).
The use of palladium catalysts containing bidentate XANTPHOS: 111°)25 proceeded with conversion rates
ligands was then examined (Table 3). DPPE, (S)-BINAP that were seemingly dependent on bite angle (entries 4,
Synlett 2007, No. 1, 31–36 © Thieme Stuttgart · New York

LETTER
Versatile One-Pot Synthesis of 4-Aryl-1,5-disubstituted 1,2,3-Triazoles
33
Table 2 Studies of Catalysts for the Negishi Reaction
ZnCl2
(1.1 equiv)
F
F
ClZn
BrMg
N
N
N
N
N
N
R1
R1
R1 = H 4a
R1 = F 4b
PhBr (6)
F
F
catalyst
Ph
H
+
N
N
N
N
THF
65 °C, 12 h
N
N
R1
R1
R1 = H 5a
R1 = F 5b
R1 = H 3b
R1 = F 3c
Entry
Substrate 4
Catalyst (mol%)a
Yield of 5 (%)b
Yield of 3 (%)b
1
2
4a
4b
4a
4b
4a
4b
4b
4b
4b
4a
Pd(PPh3)4 (2)
0
64
41
62
24
67
0
86
10
48
0
Pd(PPh3)4 (10)
3
PdCl2(dppf)·CH2Cl2 (2)
PdCl2(dppf)·CH2Cl2 (10)
Pd(Pt-Bu3)2 (2)
4
5
68
16
80
77
81
87
6
Pd(Pt-Bu3)2 (10)
7
Pd2(dba)3 (1), PPh3 (4)
Pd2(dba)3 (1), Pt-Bu3 (4)
Pd2(dba)3 (1), X-PHOS (2)
Pd2(dba)3 (1), IPr (2)
8
1
9
1
10
0
a Pd2(dba)3 and the appropriate ligand were mixed for at least 1 h prior to use.
b Determined by HPLC.
6 and 7). From these results, it may be suggested that rized in Table 4. The new conditions were applicable to
acceleration of the reductive elimination step is critical in bromoaryls, including those bearing reactive functional
these reactions.
groups such as ketone 7, ester 8, or lactone 9 (entries
2–4). For 7, the yield was moderate, probably due to
deprotonation of the a-proton of the ketone. Reactions
The scope and limitations of this strategy for construction
of 4-aryl-1,5-disubstituted-1,2,3-triazoles are summa-
Table 3 Negishi Reaction Using Catalysts Containing Bidentate Ligands
Entry
Substrate 4
Bidentate ligand
(mol%)a
Bite angle (P–Pd–P) Yield of 5 (%)b
Yield of 3 (%)b
1
2
3
4
5
6
7
4b
4b
4b
4b
4b
4b
4a
DPPE
85°
92°
0
0
76
83
81
55
79
53
10
BIPHEP
(S)-BINAP
DPPF
92°
0
96°
20
1
DtBPF
104°16
102°
111°
DPEPHOS
XANTPHOS
30
90
a 1 mol% of Pd2(dba)3 and 2 mol% of the appropriate ligand were mixed for at least 1 h prior to use.
b Determined by HPLC.
Synlett 2007, No. 1, 31–36 © Thieme Stuttgart · New York

34
A. Akao et al.
LETTER
Table 4 Application of XANTPHOS Catalyst in 1,3-Dipolar Cycloaddition Followed by Negishi Reactiona,27,28
Pd2(dba)3 (1 mol%)
ZnCl2
XANTPHOS (2 mol%)
BrMg
ClZn
R2
H
R1
R1
R1
R1
+
N
N
N
N
N
N
N
N
R2Br
N
N
N
N
4
5
3
Entry
1
Substrate4 R2Br
Temp
(°C)
Time
(h)
Coupling product
Yield of 5 Yield of 3
(%)b
(%)b
4a
4a
PhBr
6
65
12
90
10
N
F
N
N
5a
2
65
12
51
19
O
O
Br
7
N
F
N
N
5c
3
4
4a
4b
55
60
17
13
81
70
11
14
EtO2C
EtO2C
Br
8
N
F
N
N
N
5d
O
O
Br
O
O
9
F
N
N
F
5e
5
4a
55
12
79
15
N
N
Br
N
F
10
N
N
5f
a Pd2(dba)3 and XANTPHOS were mixed for at least 1 h prior to use.
b Determined by HPLC.
with the heteroaromatic compound 10 also proceeded
efficiently (entry 5). Notably, the acidic proton of 2-meth-
ylpyridine did not disturb the coupling reaction.
iPr
PPh2
PPh2
In conclusion, various 4-aryl-1,5-disubstituted-1,2,3-tri-
azoles were synthesized effectively by 1,3-dipolar
cycloaddition followed by Negishi reaction catalyzed by
1 mol% of Pd2(dba)3 and 2 mol% of XANTPHOS. This
methodology is applicable to many types of substrate and
will contribute to the development of pharmaceutical
agents. Further reports on the application of XANTPHOS
in Negishi reactions will be published in the near future.
PCy2
iPr
iPr
Ph2P PPh2
BIPHEP
X-PHOS
(S)-BINAP
PPh2
PPh2
PPh2
PtBu2
PtBu2
Fe
Fe
PPh2
DPPF
iPr
DtBPF
DPPE
iPr
N
N
Acknowledgment
O
O
We are grateful to the editor of SYNLETT and a referee for very
valuable advice.
iPr iPr
IPr
Ph2P
PPh2 Ph2P
PPh2
DPEPHOS
XANTPHOS
Figure 1 Ligands for the Negishi reaction
Synlett 2007, No. 1, 31–36 © Thieme Stuttgart · New York

LETTER
Versatile One-Pot Synthesis of 4-Aryl-1,5-disubstituted 1,2,3-Triazoles
35
(16) Bite angle as a cis-coordinating ligand: Mann, G.; Shelby,
Q.; Roy, A. H.; Hartwig, J. F. Organometallics 2003, 22,
2775.
(17) Ogasawara, M.; Yoshida, K.; Hayashi, T. Organometallics
2000, 19, 1567.
References and Notes
(1) Bourne, Y.; Kolb, H. C.; Radić, Z.; Sharpless, K. B.; Taylor,
P.; Marchot, P. Proc. Natl. Acad. Sci. U. S. A. 2004, 101,
1449.
(2) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radić, Z.;
Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 1053.
(18) Hamman, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369.
(19) It is known that DPPF generally behaves as a cis-coordinat-
ing ligand. However, DtBPF has been reported to behave as
a trans-coordinating ligand; this may be the reason for the
shut-down of our Negishi reaction. See: (a) Dekker, G. P. C.
M.; Elsevier, C. J.; Vrieze, K.; van Leeuwen, P. W. N. M.
Organometallics 1991, 11, 1598. (b) Zuideveld, M. A.;
Swennenhuis, B. H. G.; Boele, M. D. K.; Guari, Y.; van
Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.; Goubitz,
K.; Fraanje, J.; Lutz, M.; Spek, A. L.; van Leeuwen, P. W.
N. M. J. Chem. Soc., Dalton Trans. 2002, 2308.
(20) (a) Shi, J.-C.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825.
(b) Schöpfer, U.; Schlapbach, A. Tetrahedron 2001, 57,
3069. (c) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E. J. Am.
Chem. Soc. 2003, 125, 13636. (d) Shi, J.-C.; Negishi, E. J.
Organomet. Chem. 2003, 687, 518. (e) Qian, M.; Negishi,
E. Tetrahedron Lett. 2005, 46, 2927. (f) Qian, M.; Negishi,
E. Synlett 2005, 1789. (g) Negishi, E.; Shi, J.-C.; Zeng, X.
Tetrahedron 2005, 61, 9886. (h) Tan, Z.; Negishi, E.
Angew. Chem. Int. Ed. 2006, 45, 762.
(21) (a) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587. (b) Wu, L.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(c) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem.
Int. Ed. 2005, 44, 403. (d) Cacchi, S.; Fabrizi, G.;
Goggiamani, A.; Parisi, L. M.; Bernini, R. J. Org. Chem.
2004, 69, 5608. (e) Anderson, K. W.; Mendez-Perez, M.;
Priego, J.; Buchwald, S. L. J. Org. Chem. 2003, 68, 9563.
(f) Karnenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
(g) Guari, Y.; van Es, D. S.; Reek, J. N. H.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Tetrahedron Lett. 1999, 40,
3789. (h) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 10251. (i) Harris, M. C.; Geis, O.;
Buchwald, S. L. J. Org. Chem. 1999, 64, 6019. (j) Yin, J.;
Buchwald, S. L. Org. Lett. 2000, 2, 1101. (k) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (l)Ali,
M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560.
(m) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.;
Beslin, P. Tetrahedron 2005, 61, 5253.
(22) The results of the Negishi reaction under new conditions
using simple substrates are as follows. Negishi reactions
were conducted using 1 mol% of Pd2(dba)3 and 2 mol%
XANTPHOS in THF–NMP (2:1) at 70 °C for 12–19 h. Zinc
reagents were prepared by transmetalation from the
corresponding Grignard reagents. Negishi reactions of
bromobenzene with phenyl-, vinyl- and propynylzinc
chloride produced coupling products in almost quantitative
yields. A Negishi reaction of chlorobenzene and phenylzinc
chloride produced biphenyl in 78% yield. Further results
from reactions using a variety of zinc reagents and halides
will be reported.
(3) (a) Kawamoto, H.; Ito, S.; Satoh, A.; Nagatomi, Y.; Hirata,
Y.; Kimura, T.; Suzuki, G.; Sato, A.; Ohta, H. WO
2005085214, 2005. (b) Kawamoto, H.; Ito, S.; Satoh, A.;
Nagatomi, Y.; Hirata, Y.; Kimura, T.; Suzuki, G.; Sato, A.;
Ohta, H. WO 2006004142, 2006. (c) Timpe, C.; Borghese,
A.; Coffey, D. S.; Footman, P. K.; Pedersen, S. W.; Reutzel-
Edens, S. M.; Tameze, S. L.; Weber, C. WO 2005042515,
2005. (d) Amegadzie, A. K.; Gardinier, K. M.; Hembre, E.
J.; Hong, J. E.; Jungheim, L. N.; Muehl, B. S.; Remick, D.
M.; Robertson, M. A.; Savin, K. A. WO 2003091226, 2003.
(e) Tullis, J. S.; Van Rens, J. C.; Natchus, M. G.; Clark, M.
P.; De, B.; Hsieh, L. C.; Janusz, M. J. Bioorg. Med. Chem.
Lett. 2003, 13, 1665. (f) Tullis, J. S.; Van Rens, J. C.; Clark,
M. P.; Blass, B. E.; Natchus, M. G.; De, B. WO 2002088113,
2002. (g) Tullis, J. S.; Van Rens, J. C.; Clark, M. P.; Blass,
B. E.; Natchus, M. G.; De, B. WO 2002088108, 2002.
(4) Gold, H. Justus Liebigs Ann. Chem. 1965, 688, 205.
(5) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984, 1–176. (b)Padwa,
A. In Comprehensive Organic Synthesis, Vol. 4; Trost, B.
M., Ed.; Pergamon: Oxford, 1991, 1069–1109. (c) Fan, W.-
Q.; Katritzky, A. R. In Comprehensive Heterocyclic
Chemistry II, Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996, 101–126.
(d) Himbert, G.; Frank, D.; Regitz, M. Chem. Ber. 1976,
109, 370. (e) Fridman, S. G.; Lisovska, N. M. Zap. Inst.
Khim., Akad. Nauk Ukr. R.S.R., Inst. Khim. 1940, 6, 353.
(f) Boyer, N. M.; Mack, C. H.; Goebel, N.; Morgan, L. R. Jr.
J. Org. Chem. 1958, 23, 1051. (g) Akimova, G. S.;
Chistokletov, V. N.; Petrov, A. A. Zh. Org. Khim. 1965, 1,
2077.
(6) Krasiꢀski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004,
6, 1237.
(7) (a) Deng, J.; Wu, Y.-M.; Chen, Q.-Y. Synthesis 2005, 2730.
(b) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314.
(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) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71,
8680.
(10) Kamijo, S.; Jin, T.; Yamamoto, Y. Tetrahedron Lett. 2004,
45, 689.
(11) (a) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh.
Org. Khim. 1967, 3, 968. (b) Akimova, G. S.; Chistokletov,
V. N.; Petrov, A. A. Zh. Org. Khim. 1967, 3, 2241.
(c) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh.
Org. Khim. 1968, 4, 389.
(12) (a) Tsuji, J. In Palladium Reagents and Catalysts: New
Perspectives for the 21st Century; Tsuiji, J., Ed.; Wiley:
Chichester, 2004, 327–351. (b) Knochel, P.; Perea, J. J. A.;
Jones, P. Tetrahedron 1998, 54, 8275.
(23) The reaction was conducted with magnesium species 4a and
bromobenzene(6) in the presence of 1 mol% of Pd2(dba)3
and 2 mol% XANTPHOS at 65 °C for 12 h.
(13) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(14) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(15) (a) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M.
G. Org. Lett. 2005, 7, 3805. (b) Hadei, N.; Kantchev, E. A.
B.; O’Brien, C. J.; Organ, M. G. J. Org. Chem. 2005, 70,
8503.
(24) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
(25) Van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.;
Dierkes, P. Chem. Rev. 2000, 100, 2741.
(26) Ogasawara, M.; Yoshida, K.; Hayashi, T. Organometallics
2000, 19, 1567.
Synlett 2007, No. 1, 31–36 © Thieme Stuttgart · New York

36
A. Akao et al.
LETTER
(27) Typical Procedure for 1,3-Dipolar Cycloaddition
Followed by Negishi Reaction.
6.2%
4.7%
N
8.1%
4.3%
N
3.0%
17.7%
To a stirred solution of 8.4 wt% propynylmagnesium
bromide(1a) in THF (d = 0.9339 g/cm–3, 1.35 mL, 0.742
mmol) was added azide 2a (95 mg, 0.693 mmol) in THF (0.1
mL), and the flask was washed with THF (2 × 0.1 mL). After
stirring for 2 h at r.t., 1.41 M ZnCl2 in THF solution (0.54
mL, 0.762 mmol) was added to the resulting yellow slurry.
The resulting red solution was stirred for 1 h, and then
bromobenzene (6; 73 mL, 0.693 mmol) and an active
palladium catalyst solution prepared by mixing Pd2(dba)3
(6.3 mg, 0.00693 mmol) and XANTPHOS (8.0 mg, 0.0138
mmol) in THF (0.38 mL) for 2 h (this pre-mixing step is
important in ensuring that the Negishi reaction proceeds
smoothly) were added. After degassing, the mixture was
stirred at 60–65 °C for 12 h. The mixture was then cooled to
r.t., and the reaction mixture was added to 15% aq NH4Cl (5
mL), stirred for 10 min, and extracted with THF (10 mL and
5 mL); the volume was then adjusted to 25 mL using THF.
HPLC analysis showed that product 5a (158 mg assay) was
obtained in 90% overall yield from 2a, and protonated
triazole 3a was also recovered (12 mg assay, 10% recovery).
(28) Spectroscopic Data for Products (Figure 2).
Compound 5a: IR (KBr): 3055, 2926, 1605, 1580, 1562,
1519, 1464, 1444, 1415, 1383, 1367, 1297, 1237, 1157,
1117, 1092, 1072, 1041, 1010 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.77 (br d, J = 8.0 Hz, 2 H), 7.52–7.47 (m, 4 H),
7.39 (br t, J = 7.5 Hz, 1 H), 7.29–7.25 (m, 2 H), 2.47 (s, 3 H).
HRMS (ESI): m/z calcd for C15H13N3F [M + H]+: 254.1094;
found: 254.1091.
F
F
N
N
N
N
F
5a
5b
O
5.7%
24.5%
4.2%
4.8%
3.6% 21.4%
3.3%
EtO2C
F
F
N
N
N
N
N
N
5c
5d
O
5.8%
1.6%
3.7%
2.2%
N
O
F
F
N
N
N
N
4.6%
N
N
F
5e
5f
Figure 2 NOE
1365, 1312, 1279, 1222, 1176, 1160, 1106, 1011 cm–1. 1H
NMR (500 MHz, CDCl3): d = 8.16 (br d, J = 8.0 Hz, 2 H),
7.87 (br d, J = 8.0 Hz, 2 H), 7.51–7.49 (m, 2 H), 7.29–7.26
(m, 2 H), 4.41 (q, J = 7.0 Hz, 2 H), 2.50 (s, 3 H), 1.42 (t,
J = 7.0 Hz, 3 H). HRMS (ESI): m/z calcd for C18H17N3O2F
[M + H]+: 326.1305; found: 326.1306.
Compound 5e: IR (KBr): 3060, 2977, 1749, 1617, 1523,
1444, 1347, 1271, 1227, 1152, 1109, 1054, 1029, 1013
cm–1. 1H NMR (500 MHz, CDCl3): d = 8.00 (br s, 1 H), 8.00
(d, J = 7.5 Hz, 1 H), 7.92 (br d, J = 7.5 Hz, 1 H), 7.57 (m, 1
H), 7.15–7.09 (m, 2 H), 5.39 (s, 2 H), 2.47 (d, J = 1.6 Hz, 3
H). HRMS (ESI): m/z calcd for C17H12N3O2F2 [M + H]+:
328.0898; found: 328.0896.
Compound 5f: IR (KBr): 2984, 2928, 1606, 1518, 1495
1466, 1443, 1415, 1383, 1351, 1294, 1257, 1235, 1156,
1116, 1091, 1007 cm–1. 1H NMR (500 MHz, CDCl3):
d = 8.85 (br s, 1 H), 8.10 (br d, J = 7.8 Hz, 1 H), 7.52–7.49
(m, 2 H), 7.33–7.26 (m, 3 H), 2.65 (br s, 3 H), 2.48 (s, 3 H).
HRMS (ESI): m/z calcd for C15H14N4F [M + H]+: 269.1202;
found: 269.1205.
Compound 5b: IR (KBr): 3052, 1610, 1526, 1495, 1460,
1442, 1278, 1260, 1151, 1110, 1006 cm–1. 1H NMR (500
MHz, CDCl3): d = 7.80–7.77 (m, 2 H), 7.55 (m, 1 H), 7.49–
7.46 (m, 2 H), 7.37 (m, 1 H), 7.11–7.04 (m, 2 H), 2.39 (d,
J = 1.6 Hz, 3 H). HRMS (ESI): m/z calcd for C15H12N3F2
[M + H]+: 272.0999; found: 272.1001.
Compound 5c: IR (KBr): 3083, 1685, 1609, 1574, 1509,
1466, 1435, 1406, 1362, 1295, 1261, 1183, 1157, 1113,
1092, 1009 cm–1. 1H NMR (500 MHz, CDCl3): d = 8.07 (br
d, J = 8.3 Hz, 2 H), 7.90 (br d, J = 8.3 Hz, 2 H), 7.51–7.48
(m, 2 H), 7.29–7.26 (m, 2 H), 2.65 (s, 3 H), 2.51 (s, 3 H).
HRMS (ESI): m/z calcd for C17H15N3OF [M + H]+:
296.1199; found: 296.1202.
Compound 5d: IR (KBr): 3087, 2986, 2944, 2904, 1696,
1657, 1611, 1563, 1518, 1474, 1448, 1432, 1410, 1390,
Synlett 2007, No. 1, 31–36 © Thieme Stuttgart · New York

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