Cu(I)-Catalyzed Three-Component Coupling of Trifluoromethyl KetoneN-Tosylhydrazones, Alkynes and Azides: Synthesis of Difluoromethylene Substituted 1,2,3-Triazoles

Article abstract of DOI:10.1002/cjoc.201600888

A CuI-catalyzed three-component coupling of trifluoromethyl ketone N-tosylhydrazones, alkynes and azides has been developed. The reactionrepresents a straightforward method to access difluoromethylene substituted 1,2,3-triazoles. Mechanistically, it has been proposed that the reaction follows a pathway involving the formation of Cu(I)triazolide intermediate, Cu(I) carbene formation, migratory insertion, and β-fluoride elimination. Thetransformation is featured by mild conditions, wide substrate scope and high efficiency.

Full text of DOI:10.1002/cjoc.201600888

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DOI: 10.1002/cjoc.201600888
Cu(I)-Catalyzed Three-Component Coupling of Trifluoromethyl
Ketone N-Tosylhydrazones, Alkynes and Azides: Synthesis
of Difluoromethylene Substituted 1,2,3-Triazoles
Zhikun Zhang,a Qi Zhou,a Weizhi Yu,a Tianjiao Li,a Yan Zhang,a and Jianbo Wang*,a,b
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
b The State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
A CuI-catalyzed three-component coupling of trifluoromethyl ketone N-tosylhydrazones, alkynes and azides has
been developed. The reaction represents a straightforward method to access difluoromethylene substituted
1,2,3-triazoles. Mechanistically, it has been proposed that the reaction follows a pathway involving the formation of
Cu(I) triazolide intermediate, Cu(I) carbene formation, migratory insertion, and β-fluoride elimination. The trans-
formation is featured by mild conditions, wide substrate scope and high efficiency.
Keywords Cu(I)-catalysis, metal carbene, migratory insertion, β-fluoride elimination, triazole
Introduction
we reported a Cu(I)-catalyzed three-component cou-
pling of N-tosylhydrazones, alkynes and azides (Scheme
1a).[5] The Cu(I) triazolide intermediate A has been
proposed to react the in situ-generated diazo compounds
to form Cu(I) carbene species. We further conceived
that the intermediate A can react with other diazo com-
pounds, such as CF3-bearing diazo-compounds, to gen-
erate Cu(I) carbene intermediate (Scheme 1b). Accord-
ing to the previous reports,[4e-4f,6] the Cu(I) carbene mi-
gratory insertion will be followed by β-fluoride elimina-
tion to afford 1,1-difuoroolefins as the products.
Owing to their unique properties, the organofluorine
compounds have found wide applications in various
fields, ranging from material sciences, pharmaceutical
chemistry and biological sciences.[1] Therefore, signifi-
cant attentions and efforts have been devoted to the de-
velopment of efficient synthetic methods toward fluo-
rine-containing organic compounds.[2] Among them, the
synthesis based on transition-metal-catalyzed reaction
has attracted increasing attentions in the past decade.
On the other hand, transition-metal-catalyzed cross
coupling reactions involving migratory insertion of
metal carbene have been extensively studied by our
group and other groups recently.[3] The key process of
this type of transformations is the formation of metal
carbene species and the subsequent migratory insertion.
The process has been proved to be a versatile method to
construct C－C bonds and C－X bonds. One of the
major current focuses in this field is the finding of new
organometallic species from which the metal carbene
intermediate can be generated. Another focus is the ap-
plication of this novel type of coupling reactions for the
synthesis of functional organic compounds, such as flu-
orine-containing compounds.
Scheme 1 Cu(I)-catalyzed three-component reaction involving
triazolide copper carbene intermediate
R1
N
N
N
Ar
NNHTs
ref. [5]
CF3
(a)
(b)
R1 N3
+
Ar
R1
R2
R1
N
N
N
Cu(I)
Base
N
N
N
R2
R3
[Cu]
NNHTs
R2
A
R3
R2
This work
F
F
Experimental
In this context, we and others have previously
demonstrated that CF3-bearing N-tosylhydrazones or
diazo-compounds are versatile building blocks for the
synthesis of compounds containing trifluoromethyl
groups[4a-4d] and difluoromethylene groups.[4e-4f] In 2015,
General procedure for the Cu(I)-catalyzed reaction
Under nitrogen atmosphere, CuI (7.6 mg, 0.04 mmol,
20 mol%), LiOtBu (32 mg, 0.4 mmol, 2.0 equiv.) CF3-
bearing N-tosylhydrazones (1, 0.20 mmol) were succes-
*
E-mail: wangjb@pku.edu.cn; Tel.: 0086-010-62757248, Fax: 0086-010-62751708
Received December 14, 2016; accepted January 26, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600888 or from the author.
Dedicated to Professor Xikui Jiang on the occasion of his 90th birthday.
Chin. J. Chem. 2017, XX, 1—5
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Zhang et al.
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increased to 1.3 equiv., the isolated yield of 4a was di-
minished to 43%. However, by increasing the amount of
alkyne 2a and azide 3a to 1.3 equiv., the isolated yield
of 4a could be improved to 83%. Thus, this was selected
as the standard condition for the following experiments.
With the optimized conditions in hand, the substrate
scope was investigated with a series of CF3-bearing
N-tosylhydrazones, alkynes and azides. Firstly, the
functional group compatibility of N-tosylhydrazones
was studied. As shown in Scheme 2, we found different
types of CF3-bearing N-tosylhydrazones could tolerate
this condition to afford the final coupling products. This
transformation is not sensitive to steric effect, as shown
by the reaction with ortho-methyl substituted aryl
N-tosylhydrazones 1c. The yield of coupling product 4c
was only slightly diminished. In general, the electronic
effect of aryl ring of N-tosylhydrazones did not show
obvious influence on the yields. However, the reaction
with the N-tosylhydrazone 1j bearing electron-rich het-
eroaromatic ring afforded the corresponding product 4j
in low yield, which may be attributed to the instability
of the in situ-generated diazo compound. The structure
of 4i was confirmed by X-ray crystallography.[7] The
alkyl substituted N-tosylhydrazones also gave the cor-
responding products (4k－4m), while the yields are
only moderate.
sively added to a flame-dried 10 mL Schlenk tube. The
reaction flask was degassed three times with nitrogen
and dry dioxane (2.0 mL) was added using a syringe.
Then alkyne 2 (1.3 equiv., 0.26 mmol) and azide 3 (1.3
equiv., 0.26 mmol) were added by microsyringe, suc-
cessively. If the alkynes or azides were solid, they
should be added before degassing. At last, the reaction
tube was immersed in 65 ℃ bath oil. The reaction was
heated with stirring for 4 h, and it was then cooled to
room temperature and filtered through a short plug of
silica gel [V(petroleum ether) ∶ V(acetone) ∶
V(dichloromethane)＝3∶1∶1 as eluents]. Solvent was
then removed in vacuo to leave a crude mixture, which
was purified by silica gel column to afford pure product
triazoles 4, 5 and 6.
Results and Discussion
According to previous reaction conditions,[5] the ini-
tial experiment was carried out at 65 ℃ with 0.2 mmol
CF3-bearing N-tosylhydrazone 1a and terminal alkyne
2a and benzyl azide 3a as substrates in the ratio of 1∶
1∶1, LiOtBu (2.0 equiv.) as the base and dioxane (2.0
mL) as the solvent. To our delight, 73% isolated yield of
product 4a was obtained through silica gel chromatog-
raphy. When the amount of N-tosylhydrazone 1a was
Scheme 2 Substrate scope of CF3-bearing N-tosylhydrazones 1a－1m
Bn
N
CuI (20 mol%)
N
F
N
LiOtBu (2 equiv.)
NNHTs
CF3
R3
BnN3
+
Ph
+
R3
dioxane (2 mL)
65 oC
Ph
3a
2a
F
1a 1m
4a 4m
Ph
Ph
Ph
Ph
Ph
Ph
Br
N
MeO
N
N
F
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Me
F
F
F
F
F
F
F
F
F
F
F
F
4f, 68%
4e, 64%
4c, 62%
4d
, 56%
4a, 83%
4b, 79%
Ph
N
Ph
Ph
I
F3C
N
N
N
N
N
N
N
N
Ph
Ph
Ph
F
F
F
F
F
F
4i, 79%
4g
, 74%
4h, 61%
Ph
Ph
N
Ph
Ph
N
N
N
N
N
N
N
O
F
N
N
N
N
Et
Ph
Ph
Ph
Ph
F
F
F
F
F
F
F
4l, 48%
4m, 58%
4j, 42%
4k
, 57%
2
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Chin. J. Chem. 2017, XX, 1—5

Synthesis of Difluoromethylene Substituted 1,2,3-Triazoles
Next, the substrate scope of alkynes was surveyed
with various terminal alkynes. The terminal alkynes
substituted by various aryl and alkyl groups can tolerate
the reaction conditions, affording the corresponding
products in good to moderate yields (Scheme 3). Nota-
bly, the alkynes bearing electron-rich aromatic substit-
uents afforded the products in good yields (5a－5c, 5h),
while these bearing electron-withdrawing substituents
gave low yields of the products (5f－5g). The reaction
with alkyne 2i, which bears heteroaromatic substituent,
also afforded the coupling product 5i in moderate yield.
Gratifyingly, the reaction with enyne (2j) and the al-
kynes (2k－2n) bearing different alkyl substituents, also
afforded the expected products in moderate yields.
plored. It was found that the reaction with a series of
azides could afford the corresponding products in mod-
erate to good yields (Scheme 4). The transformation was
not significantly influenced by the electronic properties
of the aryl ring. However, the transformation is sensitive
to the steric effect. For example, the sterically hindered
substrate 3d only gave the product in moderate yield.
The reaction bearing heteroaromatic azide 3f also af-
forded the product, albeit in low yield. This may be at-
tributed to the fact that the pyridine moiety coordinates
to the catalyst to influence the reaction. Moreover, the
alkyl azide 3g gave the expected product 6g smoothly.
Furthermore, to show the potential application of
this transformation, we scaled up this reaction to 10
mmol. And it gave the product smoothly, albeit in
Furthermore, the substrate scope of azides was ex-
Scheme 3 Substrate scope of terminal alkynes 2a－2n
Bn
N
CuI (20 mol%)
N
F
NNHTs
LiOtBu (2 equiv.)
N
R3
F
R2
+
BnN3
+
Ph
Bn
R2
CF3
dioxane (2 mL)
65 oC
2a 2n
3a
1a
5a 5n
Bn
N
Bn
N
Bn
Bn
Bn
Bn
N
N
N
N
N
N
N
F
N
F
N
F
N
F
N
F
N
N
N
N
N
N
F
Ph
N
N
Ph
Ph
Ph
Ph
Ph
F
Ph
F
F
F
F
F
F
F
Me
N
Me
OMe
N
Br
N
CO2Me
CF3
Me
5c, 70%
F
5g, 48%
5f, 65%
5a, 86%
5b, 84%
5e, 76%
5d, 61%
Bn
N
N
Bn
F
N
Bn
Bn
N
N
Bn
Ph
F
Bn
N
N
N
N
N
N
Bn
Ph
N
N
N
N
N
F
N
N
F
N
F
Ph
F
Ph
F
Ph
F
F
Ph
TMS
Ph
F
F
F
F
S
F
5n, 59%
, 71%
5j, 40%
5m
OMe
5k, 42%
5l, 60%
5i, 71%
5h, 86%
Scheme 4 Substrate scope of terminal azides 3a－3g
Chin. J. Chem. 2017, XX, 1—5
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Zhang et al.
COMMUNICATION
Scheme 5 Proposed reaction mechanism
elimination with the regeneration of Cu(I) catalyst
(Scheme 5, path a). Alternatively, the Cu(I) triazolide
intermediate A may be in equilibrium with its protonat-
ed counterpart 8 (Scheme 5, path b). To verify such pos-
sibility, triazolide 8 was prepared and subjected to the
standard reactions. However, triazolide 8 remains un-
changed, which indicates path b can be ruled out.
diminished yield (Eq. 1).
Conclusions
In summary, we have developed an efficient and re-
gioselective method for the synthesis of difluorometh-
ylene substituted 1,4,5-trisubstituted 1,2,3-triazoles.[8,9]
The reaction is featured by mild conditions, wide sub-
strate scope, and good yields. Mechanistically, this reac-
tion follows a pathway involving [2＋3] cycloaddition
(click reaction), Cu(I) carbene formation, migratory
insertion, and β-fluoride elimination. This reaction fur-
ther demonstrates the application of CF3-bearing
N-tosylhydrazones in the synthesis of fluorine-contain-
ing organic compounds.
For gaining insights into the mechanism of this
transformation, control experiments were conducted as
shown in Eq. 2. In order to substantiate the reaction se-
quence, 1a and 2a were subjected to the reaction first
for 4 h, the azide 3a was added to the reaction system.
Under such conditions, the triazole product could not be
obtained, but only 1,1-difluoroenyne 7 was detected.[4e]
The results support our initial assumption shown in
Scheme 1 that the alkyne reacts first with azide to form
the Cu(I) triazolide intermediate A, which further reacts
with the in situ generated diazo substrate.
Acknowledgement
The project is supported by National Basic Research
Program of China (973 Program, No. 2015CB856600)
and NSFC (Nos. 21472004 and 21332002).
The proposed reaction mechanism is shown in
Scheme 5. The Cu(I) triazolide intermediate A reacts
with in situ generated diazo compound 1a' to form Cu(I)
carbene C, followed by migratory insertion of the Cu(I)
carbene to form a new Cu(I) species D. At last, the in-
termediate D gives the product 4a through β-fluoride
References
[1] For selected recent reviews on organofluorine chemistry, see: (a)
Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH, Weinheim, 2004; (b) Gladysz, J. A.; Cur-
ran, D. P.; Horváth, I. T. Handbook of Fluorous Chemistry, Wiley-
VCH, Weinheim, 2005; (c) Horváth, I. T. Fluorous Chemistry,
4
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Chin. J. Chem. 2017, XX, 1—5

Synthesis of Difluoromethylene Substituted 1,2,3-Triazoles
Springer-Verlag, Berlin, 2011; (d) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881; (e) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470; (f) Ni, C.; Hu, J. Chem. Soc. Rev. 2016, 45,
5441; (g) Zhang, K.; Xu, X.; Qing, F. Chin. J. Org. Chem. 2015, 35,
556; (h) He, J.; Lou, S.; Xu, D. Chin. J. Org. Chem. 2016, 36, 1218.
[2] For most recent reviews on the synthesis of fluorine-containing or-
ganic compounds, see: (a) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem.
Rev. 2015, 115, 683; (b) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem.
Rev. 2015, 115, 731; (c) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115,
765; (d) Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513; (e)
Zhu, W.; Wang, J.; Wang, S.; Gu, Z.; Aceña, J. L.; Izawa, K.; Liu, H.;
Soloshonok, V. A. J. Fluorine Chem. 2014, 167, 37; (f) Chen, P.; Liu,
G. Synthesis 2013, 45, 2919; (g) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214; (h) Liu, H.; Gu, Z.; Jiang, X.
Adv. Synth. Catal. 2013, 355, 617; (i) Studer, A. Angew. Chem., Int.
Ed. 2012, 51, 8950; (j) Wu, X.-F.; Neumann, H.; Beller, M. Chem.
Asian J. 2012, 7, 1744; (k) Liu, T.; Shen, Q. Eur. J. Org. Chem. 2012,
6679; (l) Macé, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2479; (m)
García-Monforte, M. A.; Martínez-Salvador, S.; Menjón, B. Eur. J.
Inorg. Chem. 2012, 4945; (n) Tomashenko, O. A.; Grushin, V. V.
Chem. Rev. 2011, 111, 4475; (o) Zheng, Y.; Ma, J.-A. Adv. Synth.
Catal. 2010, 352, 2745; (p) Zheng, H.; Huang, Y.; Wen, Z. Tetrahe-
dron Lett. 2016, 57, 1397; (q) Xiong, H.-Y.; Pannecoucke, X.; Bes-
set, T. Chem. Eur. J. 2016, 22, 1; (r) Chachignon, H.; Cahard, D.
Chin. J. Chem. 2016, 34, 445; (s) For a special issue on organofluo-
rine chemistry in Chin. J. Chem.: http://onlinelibrary.wiley.com/doi/
10.1002/cjoc.v34.5/issuetoc; (t) Ni, C.; Zhu, L.; Hu, J. Acta Chim.
Sinica 2015, 73, 90; (u) Xu, J.; Chen, P.; Ye, J.; Liu, G. Acta Chim.
Sinica 2015, 73, 1294; (v) Fan, X.; Zhao, H.; Zhu, C. Acta Chim.
Sinica 2015, 73, 979; (w) Xiao, Y.; Pan, Q.; Zhang, X. Acta Chim.
Sinica 2015, 73, 383; (x) Zheng, J.-F.; Xie, Z.-Q.; Chen, X.-J.;
Huang, P.-Q. Acta Chim. Sinica 2015, 73, 705.
Xu, H. Chin. J. Org. Chem. 2015, 35, 1820; (k) Zhang, M.; Chen, B.;
Ge, C.; Liu, R.; Gao, J.; Jia, Y. Chin. J. Org. Chem. 2016, 36, 1636.
[4] (a) Wang, X.; Xu, Y.; Deng, Y.; Zhou, Y.; Feng, J.; Ji, G.; Zhang, Y.;
Wang, J. Chem. Eur. J. 2014, 20, 961; (b) Jiménez-Aquino, A.; Vega,
J. A.; Trabanco, A. A.; Valdés, C. Adv. Synth. Catal. 2014, 356,
1079; (c) Emer, E.; Twilton, J.; Tredwell, M.; Calderwood, S.; Colli-
er, T. L.; Liegault, B.; Taillefer, M.; Gouverneur, V. Org. Lett. 2014,
16, 6004; (d) Zhang, Z.; Feng, J.; Xu, Y.; Zhang, S.; Ye, Y.; Li, T.;
Wang, X.; Chen, J.; Zhang, Y.; Wang, J. Synlett 2015, 26, 59; (e)
Zhang, Z.; Zhou, Q.; Yu, W.; Li, T.; Wu, G.; Zhang, Y.; Wang, J. Org.
Lett. 2015, 17, 2474; (f) Zhang, Z.; Yu, W.; Zhou, Q.; Li, T.; Zhang,
Y.; Wang, J. Chin. J. Chem. 2016, 34, 473.
[5] Zhang, Z.; Zhou, Q.; Ye, F.; Xia, Y.; Wu, G.; Hossain, M. L.; Zhang,
Y.; Wang, J. Adv. Synth. Cat. 2015, 357, 2277.
[6] Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu, J. J. Am. Chem. Soc.
2013, 135, 17302.
[7] CCDC1512004 (4i) contains the supplementary crystallographic da-
ta for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[8] For the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles through
CuI-triazolide intermediate, see: (a) Wu, Y. M.; Deng, J.; Li, Y.;
Chen, Q. Y. Synthesis 2005, 1314; (b) Zhang, X.; Hsung, R. P.; Li, H.
Chem. Commun. 2007, 2420; (c) Li, L.; Zhang, G.; Zhu, A.; Zhang,
L. J. Org. Chem. 2008, 73, 3630; (d) Gerard, B.; Ryan, J.; Beeler, A.
B.; Jr. Porco, J. A. Tetrahedron 2006, 62, 6405; (e) Yang, D.; Fu, N.;
Liu, Z.; Li, Y.; Chen, B. Synlett 2007, 278; (f) Li, L.; Hao, G.; Zhu,
A.; Fan, G.; Zhang, L.; Zhang, L. Chem. Eur. J. 2013, 19, 14403; (g)
Wang, W.; Wei, F.; Ma, Y.; Tung, C.-H.; Xu, Z. Org. Lett. 2016, 18,
4158; (h) Wei, F.; Wang, W.; Ma, Y.; Tung, C.-H.; Xu, Z. Chem.
Commun. 2016, 52, 14188; (i) Wang, W.; Peng, X.; Wei, F.; Tung,
C.-H.; Xu, Z. Angew. Chem., Int. Ed. 2016, 55, 649.
[9] For recent reports on the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles, see: (a) Spiteri, C.; Moses, J. E. Angew. Chem., Int.
Ed. 2010, 49, 31; (b) Zhou, Y.; Lecourt, T.; Micouin, L. Angew.
Chem., Int. Ed. 2010, 49, 2607; (c) Worrell, B. T.; Ellery, S. P.;
Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52, 13037; (d) Ding, S.;
Jia, G.; Sun, J. Angew. Chem., Int. Ed. 2014, 53, 1877; (e) Thomas, J.;
John, J.; Parekh, N.; Dehaen, W. Angew. Chem., Int. Ed. 2014, 53,
10155; (f) Li, W.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 14186.
[3] For reviews of transition-metal catalyzed cross-coupling reactions
involving diazo compounds, see: (a) Zhang, Y.; Wang, J. Eur. J. Org.
Chem. 2011, 1015; (b) Barluenga, J.; Valdés, C. Angew. Chem., Int.
Ed. 2011, 50, 7486; (c) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012,
41, 560; (d) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46,
236; (e) Liu, Z.; Wang, J. J. Org. Chem. 2013, 78, 10024; (f) Xia, Y.;
Zhang, Y.; Wang, J. ACS Catal. 2013, 3, 2586; (g) Shang, X.; Liu, Z.
2015, 35, 522; (h) Zeng, S.; Xu, S.; Wang, Y.; Yu, M.; Zhu, L.; Yao,
X. Chin. J. Org. Chem. 2015, 35, 827; (i) Fu, Z.; Li, Z.; Xiong, Q.;
Cai, H. Chin. J. Org. Chem. 2015, 35, 984; (j) Zhang, W.; Dai, J.;
(Cheng, F.)
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