Novel synthesis of difluoromethyl-containing 1,4-disubstituted 1,2,3-triazoles via a click-multicomponent reaction and desulfanylation strategy

Article abstract of DOI:10.1002/adsc.201000791

Fourteen difluoromethyl-containing 1,4-disubstituted 1,2,3-triazoles were synthesized via a novel copper-catalyzed click-multicomponent reaction of 2,2-difluoro-2-phenylsulfanylethanol, sodium azide and terminal alkynes in the presence of N-(p-toluenesulf

Full text of DOI:10.1002/adsc.201000791

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DOI: 10.1002/adsc.201000791
Novel Synthesis of Difluoromethyl-Containing 1,4-Disubstituted
1,2,3-Triazoles via a Click–Multicomponent Reaction and
Desulfanylation Strategy
Jian Zhang,a Jingjing Wu,a Li Shen,a Guanyi Jin,a and Song Caoa,*
a
Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy, East China
University of Science and Technology, Shanghai, 200237, Peopleꢀs Republic of China
Fax : (+86)-21-6425-2603, phone: (+86)-21-6425-2945; e-mail: scao@ecust.edu.cn
Received: October 20, 2011; Published online: March 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000791.
Abstract: Fourteen difluoromethyl-containing 1,4-
disubstituted 1,2,3-triazoles were synthesized via a
novel copper-catalyzed click-multicomponent reac-
tion of 2,2-difluoro-2-phenylsulfanylethanol, sodium
azide and terminal alkynes in the presence of N-
(p-toluenesulfonyl)imidazole, tetrabutylammonium
iodide and triethylamine, followed by reductive
cleavage of the phenylsulfanyl group using tributyl-
tin hydride and azobisisobutyronitrile.
The development of difluoromethyl-containing
scaffolds has gained a real interest especially in the
organic and pharmaceutical areas due to their unique
chemical and physiological properties.[6] It was report-
ed that some 1,2,3-triazoles bearing a CF2H unit ex-
hibit herbicidal or protein kinase inhibitive bioactivity
(Figure 1).[7] Up till now, several different methods for
the preparation of CF2H-containing compounds have
been developed such as direct fluorination (using flu-
orine gas, hydrogen fluoride, fluorinating agents),[8]
the usage of simple reactive fluoro-containing build-
ing blocks and the nucleophilic, radical, and electro-
philic (phenylsulfonyl)difluoromethylations.[9] More
recently, we reported a general and efficient synthesis
strategy for the construction of the functionalized
small molecules having a terminal CF2H group.[10] In
Keywords: azides; click chemistry; desulfanylation;
difluoromethyl group; multicomponent reactions
1,4-Disubstituted 1,2,3-triazole derivatives have found continuation of our interest in the synthesis of new di-
widespread applications in various different areas in- fluoromethyl compounds, herein we report a concise
cluding bioconjugations, polymer, surface science, pes- and practical strategy for the synthesis of difluoro-
ticides and pharmaceuticals.[1] The most popular methyl-containing 1,4-disubstituted 1,2,3-triazole de-
method for the construction of the 1,2,3-triazole rivatives via a novel CuI-catalyzed click–multicompo-
framework is the Cu(I)-catalyzed azide-alkyne 1,3-di- nent reaction based on fluoro-containing building
polar cycloaddition.[2] Multicomponent reactions have blocks (CMR-FBB), followed by reductive cleavage
been proven to be a practical and efficient method to of the phenylsulfanyl group (Scheme 1).
access complex structures from simple building
According to the literature, 1,4-disubstituted 1,2,3-
blocks.[3] Compared to the classical step-by-step for- triazoles can be prepared in excellent yields by the
mation of individual bonds for the target compounds, one-pot three-component 1,3-dipolar cycloaddition of
multicomponent reactions (MCRs) take advantage of
the simultaneous formation of several bonds in a
single step. Recently, the combination of click chemis-
try and MCR (click–multicomponent reaction, CMR)
has aroused great interest in the chemical community
this is because the new reaction possesses the advan-
tages of both click reaction and multicomponent reac-
tion.[4] However, a survey of the literature revealed
that there were only a few reports on the preparation
of 1,2,3-triazole derivatives via click-MCR chemistry
Figure 1. Two examples of bioactive 1,2,3-triazoles bearing a
CF2H group.
protocols.[5]
580
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Adv. Synth. Catal. 2011, 353, 580 – 584

Novel Synthesis of Difluoromethyl-Containing 1,4-Disubstituted 1,2,3-Triazoles
Scheme 1. Synthesis of CF2H-containing 1,4-disubstituted 1,2,3-triazoles via a click–multicomponent reaction and desulfany-
lation strategy.
Scheme 2. Synthesis of 2,2-difluoro-2-phenylsulfanylethanol.
alkyl or aryl halides, sodium azide, and terminal al- (OH) in hand, we turned our efforts to use it as one
kynes.[11] Some other click–multicomponent reactions of the components to prepare the 1,4-disubstituted
involved the use of organic azides as one of the com- 1,2,3-triazoles via a three-component cycloaddition
ponents.[12] Compared to sodium azide, organic azides reaction. To the best of our knowledges, this is the
are relatively safe, however, some organic azides of first example of using an alcohol as substrate in the
low molecular weight could be unstable and hard to click–multicomponent reaction.
handle, thus, the search for an efficient method that
avoids the isolation of organic azides is not only late to give the organic azide via nucleophilic substi-
highly desirable but also necessary.
tution.[4] In order to avoid the isolation of unstable,
It is reported that the azide ion reacts with the tosy-
In this communication, we firstly designed and syn- toxic or sensitive organic azides and the use of expen-
thesized a novel difluoro-containing building block, sive iodide, as a first step, we performed this one-pot
2,2-difluoro-2-phenylsulfanylethanol (2). The synthet- click reaction of sodium azide and phenylacetylene
ic pathway for compound 2 is outlined in Scheme 2. with three different types of alcohols (1-butanol,
The ethyl 2,2-difluoro-2-(phenylthio)acetate (1) was phenyl methanol, 2,2-difluoro-2-phenylsulfanylethanol
readily prepared by the reaction of ethyl bromodi- 2) to check the potential and compatibility of cop-
fluoroacetate and thiophenol according to the litera- per(I) iodide as a catalyst in the TsIm/TBAI/TEA
ture,[13] and the intermediate 1 could easily be re- system using DMF as a solvent. To our delight, the re-
duced by LiAlH4 to give corresponding alcohol 2. It action was found to be simple and efficient, giving the
should be mentioned that the reaction time of the re- corresponding products 1,4-disubstituted 1,2,3-tria-
duction should not exceed 10 min, otherwise, the hy- zoles in good to high yields. (Scheme 3)
drodefluorination takes place and a mixture of 2 and
Generally, the catalyst plays a particularly impor-
tant role in the click reaction. Therefore, 2,2-difluoro-
the defluorinated compound is obtained.[14]
With the new difluorinated building block which 2-phenylsulfanylethanol (2), sodium azide and phenyl-
contains an inactive group (PhS) and a reactive group acetylene were selected as representative reactants
Scheme 3. The reactions of n-butyl alcohol, benzyl alcohol, 2 with sodium azide and phenylacetylene.
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Table 1. Effect of catalysts on the one-pot reaction.
celerate the formation of the by-product diphenyl di-
sulfide.
Catalyst[a]
Time [h]
Yield [%][b]
Finally, in order to obtain 1,4-disubstituted 1,2,3-tri-
azoles bearing a terminal difluoromethyl group, we
attempted to remove the protecting group (PhS)
using Bu3SnH/AIBN as the reducing agent.[15] The re-
moval of the PhS group from 4a was used as a model
reaction to investigate the effect of the amount of
Bu3SnH on the desulfanylation reaction. The results
are listed in Table 3. We were delighted to find that
the reaction proceeded much faster than other report-
ed desulfanylations.[10,16] Treatment of 4a with 3 equiv-
alents of Bu3SnH in the presence of a catalytic
amount of AIBN in refluxing toluene for only 40 min
could afford desired product 5a in 92% yield
(entry 4).
To survey the generality and scope of the method, a
variety of alkynes were examined under the opti-
mized conditions (Table 4 and Scheme 1). In all cases,
both the new click three-component reaction and de-
sulfanylation proceeded smoothly to give the corre-
sponding 1,4-disubstituted 1,2,3-triazoles bearing a
terminal difluoromethyl group in good to high yields.
In summary, we have reported a novel and efficient
protocol for the synthesis of CF2H-containing 1,4-dis-
ubstituted 1,2,3-triazoles by a Cu(I)-catalyzed one-pot
three-component reaction of PhSCF2CH2OH, sodium
azide and terminal alkynes, followed by the cleavage
of phenylsulfanyl group. We also provided a simple
approach for the synthesis of 1,2,3-triazole derivatives
from easily available alcohols. Furthermore, this new
strategy, click–multicomponent reaction based on a
fluoro-containing building block (CMR-FBB), will be
a useful tool for one-pot synthesis of fluoro-contain-
ing 1,2,3-triazole derivatives with high efficiency.
none
CuCl
CuBr
CuI
>12
2
2
1
0
56
70
81
0
CuSO4·5H2O
>10
[a]
10 mmol% of catalysts were used.
Isolated yield.
[b]
Table 2. Effect of temperature and time on the one-pot reac-
tion.
Entry
Temperature [8C]
Time [h]
Yield[a] [%]
1
2
3
4
5
6
7
8
100
100
100
100
60
80
120
150
6
8
30
60
81
78
10
60
74
53
10
12
10
10
10
10
[a]
Isolated yield.
Table 3. Effect of the amount of Bu3SnH on the desulfanyla-
tion reaction.
Entry[a]
Bu3SnH (equiv.)
Time [h]
Yield[b] [%]
1
2
3
4
1
1.5
2
3
3
1.5
0.7
59
71
89
92
3
[a]
10 mmol% of AIBN was used.
Isolated yield.
[b]
for further investigation of the effect of the copper
salt on this one-pot reaction. In the absence of the
catalyst, the reaction could not proceed well even
after a prolonged reaction time. Several other copper
salts were screened in our model reaction and the re-
sults are shown in Table 1. It was found that CuI ex-
hibited high catalytic activity in terms of reaction
Experimental Section
All reagents were of analytical grade, and were obtained
from commercial suppliers and used without further purifi-
cation. Toluene was dried by standard methods prior to use.
Melting points were measured in an open capillary using a
Bꢂchi melting point B-540 apparatus and are uncorrected.
time as well as yields of the products. However, cop- 1H NMR and 13C NMR spectra were recorded on a Bruker
AM-400 spectrometer (400 MHz and 100 MHz, respectively)
using TMS as internal standard, The 19F NMR spectra were
obtained using a Bruker AM-400 spectrometer (376 MHz).
CDCl3 was used as the NMR solvent in all cases except
compound 5j. Gas chromatography-mass spectra (GC-MS)
were recorded on an HP 5973 MSD with a 6890 GC. High-
resolution mass spectra (HR-MS) were recorded under elec-
tron impact conditions using a MicroMass GCT CA 055 in-
strument and recorded on a MicroMass LCTTM spectrome-
ter. Compounds 1,[13] 3e–k,[17] 3l–n[18] were synthesized ac-
per(II) sulfate pentahydrate had no observable cata-
lytic effect on the reaction.
Using the same substrates, the effects of the reac-
tion temperature and time were also examined in the
presence of CuI. Generally, the yield was significantly
affected by both reaction time and reaction tempera-
ture. As shown in Table 2, the reaction proceeded
smoothly in DMF at 1008C for 10 h, yielding the ex-
pected product in 81% yield. A further increase in
temperature would lead to a decrease in yield and ac- cording to literature procedures.
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Novel Synthesis of Difluoromethyl-Containing 1,4-Disubstituted 1,2,3-Triazoles
Table 4. Synthesis of 1,4-disubstituted 1,2,3-triazoles bearing terminal difluoromethyl group via click three-component reac-
tion, followed by cleavage of the phenylsulfanyl group.
Entry
R
Yield[a] [%] of 4
Yield[a] [%] of 5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
C6H5
p-CH3C6H4
m-CH3C6H4
p-CH3OC6H4
C6H5OCH2
p-FC6H4OCH2
o-CH3C6H4OCH2
p-CH3C6H4OCH2
p-(CH3)3CC6H4OCH2
4-CH3-2,6-di-(CH3)3CC6H2OCH2
(naphthalen-1-yloxy)methyl
C6H5CONHCH2
p-CH3C6H4CONHCH2
3,5-di-CH3C6H3CONHCH2
81
85
84
82
80
75
81
83
82
84
80
75
78
76
92
92
91
88
87
80
92
91
90
89
85
80
82
84
[a]
Isolated yield.
KF/H2O (15 mg/0.15 mL) for 4 h and extracted with EtOAc
(15 mL ꢃ 3). The organic layer was washed successively
with water (20 mL) and brine (20 mL), and dried over anhy-
drous MgSO4. After solvent removal, the crude product was
purified by chromatography to give desired product 5.
2,2-Difluoro-2-(phenylthio)ethanol (2)
A solution of the ethyl 2,2-difluoro-2-(phenylthio)acetate
(1) (9.28 g, 40 mmol) in dry THF (40 mL) was added drop-
wise to a suspension of lithium aluminium hydride (2.28 g,
60 mmol) in dry THF (40 mL) at 08C under an argon atmos-
phere. The reaction mixture was then stirred at 08C for
10 min and quenched with H2O (10 mL). The resulting sus-
pension was stirred for 10 more minutes and filtered. The
filtrate was diluted with ethyl acetate, washed successively
with H2O and brine, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure to leave the crude
product. The resultant crude residue was purified by chro-
matography to obtain compound 2 as yellow liquid; yield:
80%; GC-MS: m/z=190, 159, 110, 77.
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (Grant No. 21072057), the
National Basic Research Program of China (973 Program,
2010CB126101), Shanghai Foundation of Science of Technol-
ogy (09391911800), and the Shanghai Leading Academic
Discipline Project (B507)
General Procedure for the Preparation of 4a–n
To a stirred solution of 2 (0.38 g, 2 mmol) in 10 mL DMF,
TsIm (0.88 g, 4 mmol), sodium azide (0.38 g, 4 mmol), TBAI
(0.03 g, 0.06 mmol), and TEA (0.58 mL,4 mmol) were added
successively. The mixture was stirred for 10 h at 1008C.
Then, the mixture was cooled to room temperature, 3
(1.8 mmol) and CuI (0.04 g, 0.2 mmol) were added to the so-
lution. The reaction was continued for 1–3 h (TLC), and
quenched with H2O (10 mL). The resulting suspension was
filtered and the filtrate was diluted with CH2Cl2, washed
successively with H2O and brine, dried over anhydrous
MgSO4, concentrated under reduced pressure to leave the
crude product. The resultant crude residue was purified by
chromatography to give the pure product 4.
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