Rh(I)-Catalyzed Reaction of Trifluoromethylketone N-Tosylhydrazones and Arylboronates

Article abstract of DOI:10.1002/cjoc.201500889

Rh(I)-Catalyzed synthesis of 1,1-difluoro-2,2-diarylalkenes from trifluoromethylketone N-tosylhydrazones and arylboronates is presented in this communication. This new synthetic method is based on the Rh(I)-carbene migratory insertion followed by β-fluori

Full text of DOI:10.1002/cjoc.201500889

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DOI: 10.1002/cjoc.201500889
Rh(I)-Catalyzed Reaction of Trifluoromethylketone
N-Tosylhydrazones and Arylboronates
Zhikun Zhang,a Weizhi Yu,a Qi Zhou,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 State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Rh(I)-Catalyzed synthesis of 1,1-difluoro-2,2-diarylalkenes from trifluoromethylketone N-tosylhydrazones and
arylboronates is presented in this communication. This new synthetic method is based on the Rh(I)-carbene migra-
tory insertion followed by β-fluoride elimination. In one particular case the protonation occurs instead of β-fluoride
elimination, affording 2,2-diaryl trifluoroethane product.
Keywords Rh(I)-catalysis, metal carbene, migratory insertion, β-fluoride elimination
Introduction
conceived that transition-metal-catalyzed cross-coupling
of CF3-bearing N-tosylhydrazones with organboron
compounds should also give 1,1-difluoroolefins
(Scheme 1c).[5] Herein we report the Rh(I)-catalyzed
reaction of trifluoromethylketone N-tosylhydrazones
and arylboronates, which constitutes a new method for
the synthesis of 1,1-difluoro-2,2-diarylalkenes.
Owing to the distinct properties of fluorine, organ-
ofluorine compounds have found wide applications in
various fields, ranging from material science to phar-
maceutical chemistry and biological science.[1] As a re-
sult, significant efforts have been devoted to the devel-
opment of efficient synthetic methods toward fluo-
rine-containing organic compounds.[2] Among them, the
synthesis based on transition-metal-catalyzed reaction
has attracted much attentions in the past decade.
Scheme 1 Synthesis of 1,1-difluoroolefins from the cross-cou-
pling with CF3-bearing N-tosylhydrazones
On the other hand, diazo compounds or their equiv-
alents, such as N-tosylhydrazones have emerged as a
new type of cross-coupling partners in transition-metal-
catalyzed reactions.[3] The key process of this type of
transformations is the formation of metal carbene spe-
cies and the subsequent migratory insertion. As an ap-
plication of this type of coupling reactions in the syn-
thesis of fluorine-containing compounds, we and others
have demonstrated that CF3-bearing N-tosylhydrazones
or diazo-compounds are versatile building blocks for the
synthesis of trifluoromethyl[4a-4d] and difluoromethyl-
ene[4e] compounds. For example, we have previously
reported the Pd-catalyzed cross-coupling of CF3-bearing
N-tosylhydrazones with benzyl bromides for the synthe-
sis of trifluoromethylated trisubstituted olefins (Scheme
1a).[4a] Subsequently, we have demonstrated the Cu(I)-
catalyzed cross-coupling of trifluoromethylketone
N-tosylhydrazones and terminal alkynes to give 1,1-di-
fluoroolefins. The transformation is proposed to un-
dergo carbene migratory insertion and β-fluoride elimi-
nation (Scheme 1b).[4e] As the continuation of our inter-
ests in carbene-based cross-coupling reactions, we have
Experimental
General procedure for the Cu(I)-catalyzed reaction
Under N2 atmosphere, [Rh(COD)Cl]2 (3.0 mg, 0.006
mmol, 3 mol%), LiOtBu (40 mg, 0.5 mmol), and
N-tosylhydrazone 1 (0.26 mmol) were successively
added to a flame-dried 10 mL Schlenk tube. The reac-
tion flask was degassed three times with N2, and dry
MeOH (2.0 mL) was added using syringe. Then a solu-
tion of arylboronate 2 (0.2 mmol) in 1.0 mL MeOH was
added dropwise in 20 min through syringe. The reaction
*
E-mail: wangjb@pku.edu.cn
Received December 21, 2015; accepted January 18, 2016; published online March 14, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500889 or from the author.
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473

Zhang et al.
Table 1 Optimization of reaction conditionsa
COMMUNICATION
tube was then immersed in a 70 ℃ oil bath. The reac-
tion was heated with stirring for 4 h. Upon cooling
down to room temperature, the reaction solution was
filtered through a short plug of silica gel (eluted with
petroleum ether∶EtOAc＝5∶1). Removal of solvent
and silica gel column chromatographic separation af-
forded the pure 1,1-difluoro-2,2-diarylethene product.
Entry Catalyst (x mol%)
Ar-B T/℃ Solvent (3a/4a)b/%
Results and Discussion
1
None
2a 60
2a 60
2a 70
2b 70
2c 70
2d 70
2d 70
2e 70
Dioxane N.R.
Dioxane N.R.
MeOH 30/0
MeOH 25/0
MeOH 57/0
MeOH 50/0
MeOH 70/0
MeOH 0/78
The initial experiment was carried out at 60 ℃ with
CF3-bearing N-tosylhydrazone 1a and (p-phenyl)-
phenyl boronic acid 2a as substrates, LiOt-Bu as the
base and dioxane as the solvent. However, no product
could be detected (Table 1, Entry 1). The addition of
CuI as the catalyst to the reaction system also did not
give the coupling product and the starting materials
were recovered unchanged (Table 1, Entry 2). This
might be attributed to the fact that transmetalation of
boronate with Cu(I) catalyst is not efficient under the
current reaction conditions. Then Rh(I) catalysts were
examined. To our delight, the expected 1,1-difluoro-2,2-
diarylethene product was obtained in 30% isolated yield
(Table 1, Entry 3). However, most of the boronic acid
was directly protonated to give biphenyl as the side
product.
2
CuI (20)
3
[Rh(COD)Cl]2 (3)
[Rh(COD)Cl]2 (3)
[Rh(COD)Cl]2 (3)
[Rh(COD)Cl]2 (3)
[Rh(COD)Cl]2 (3)
[Rh(COD)Cl]2 (3)
4
5
6
7c
8c
a All the reactions were carried out in 0.2 mmol scale, 1a∶2＝
1.3∶1; solvent (3 mL). b Isolated yields. c The borate was added
dropwise in 20 min.
fluoroolefin could be detected (Eq. 1).
Next, we examined the reaction with pinacol
(p-phenyl)phenylboronate 2b, but only 25% yield of the
product was obtained (Table 1, Entry 4). In this case, the
boronate 2b was largely remained unchanged due to its
stability and low reactivity. The reaction with more re-
active boronate 2c gave the product with improved yield
(Table 1, Entry 5). In this case, the protonation byprod-
uct was still formed in small amount. We then tried to
add the boronate 2c dropwise by using a syringe, but the
poor solubility of 2c resulted in the failure of the ex-
periment. Then we turned to the boronate substrate 2d,
which has high solubility in methanol. Under the same
reaction conditions as mentioned above, a 50% yield of
the coupling product could be obtained (Table 1, Entry
6). By slowly adding 2d, the yield of the cross-coupling
products could be improved to 70% (Table 1, Entry 7).
Surprisingly, the reaction with boronate 2e as the
substrate gave the pronation product 4, and no 1,1-di-
With the optimized reaction conditions in hand, the
substrates scope of this cross-coupling reaction was in-
vestigated with a series of CF3-bearing N-tosylhy-
drazones and arylboronates. As illustrated in Scheme 3,
the N-tosylhydrazone 1a could react with a series of
arylboronates to afford corresponding 1,1-difluoroolefin
products in moderate yields. Notably, the boronates
bearing ortho-substituted aryl moiety also gave the cou-
pling products (3d, 3e). N-Tosylhydrazones bearing
electron-donating p-methoxy group could afford the
1,1-difluoroolefin products, albeit in diminished yields
(3k, 3l). The reaction with boronates bearing hetero
aromatic moiety and m-acetamido substituted phenyl
group also worked well (3h, 3i). Interestingly, as shown
in Eq. 1, the reaction with arylboronates bearing elec-
tron-withdrawing substituent did not afford the corre-
sponding 1,1-difluoroolefin product. Instead, CF3-
bearing products were isolated. When the boronate with
aromatic moiety bearing moderately electron-with-
Scheme 2 The boronic acid and boronates employed for the
reaction condition optimization
O
Ph
B(OH)2
Ph
B
O
2b
2a
O
O
Ph
B
Me
B
O
O
2c
2d
O
OHC
B
O
2e
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 473—476

Rh(I)-Catalyzed Reaction of Trifluoromethylketone N-Tosylhydrazones and Arylboronates
Scheme 3 The substrate scope of the reaction
NNHTs
CF2
[Rh(COD)Cl]2
O
O
LiOtBu (2.5 equiv.)
MeOH, 70 oC
B
CF3
+
Y
X
Y
X
3a - 3l
1a, X = H
1b, X = OMe
2d - 2m
CF2
CF2
CF2
Me
Me
3a, 47%
3b, 63%
3c, 70%
CF2 Me
CF2 OMe
CF2
tBu
3f, 68%
3d, 57%
CF2
3e, 41%
CF2
CF2
O
H
N
Me
O
OMe
3g, 55%
3h, 45%
3i, 59%
CF2
CF2
CF2
MeO
Me
F
MeO
Cl
3j,34%
3l, 38%
3k, 40%
drawing substituent was employed, the reaction afforded
a mixture of CF3-bearing product and 1,1-difluoroolefin.
Apparently, the chemo-selectivity of the reaction is de-
pendent on electronic nature of substrates.
sively follow path a.
Scheme 4 Proposed reaction mechanism
CF2
O
According to our previous study on Cu(I)-catalyzed
reaction involving β-fluoride elimination,[4e] we propose
the following reaction mechanism (Scheme 4). Firstly,
aryl rhodium species is generated through transmetalla-
tion. The aryl rhodium species then reacts with the in
situ generated diazo compounds to afford the Rh(I) car-
bene intermediate B, which is followed by migratory
insertion to generate intermediate C. From intermediate
C the catalytic cycle can be completed in two ways:
β-fluoride elimination (path a) and protonation of car-
bon rhodium bond (path b). The path a gives the
1,1-difluoroolefin product, and path b gives the
CF3-bearing product D. In path a, we suggest that rho-
dium fluoride is formed, which undergoes transmetalla-
tion with arylboronate.[6]
To verify the possible involvement of path b in the
reaction mechanism, (2,2,2-trifluoroethane-1,1-diyl)di-
benzene 5 was subjected to the identical reaction condi-
tions. The 1,1-difluoroolefin product 3a was not de-
tected (Eq. 2). The result does not support the involve-
ment of path b in the reaction mechanism. The forma-
tion of 1,1-difluoroolefin product 3a seems to exclu-
LiOt-Bu
+
Ph
B
Ph
Ph
O
1a
Rh(I)F
transmetallation
3a
-F elimination
path a
(RO)2BOt-Bu
LiOt-Bu
Rh(I)
path b
Rh
Ph
CF3
Ar
CF3
Ar
HOtBu
Ph Rh
NNHTs
CF3
A
Ph
D
Ph
C
LiOt-Bu
dediazoniation
migratory insertion
N2
Ph
Rh
Ph
CF3
Ph
CF3
B
Chin. J. Chem. 2016, 34, 473—476
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475

Zhang et al.
COMMUNICATION
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easier to associate with fluoride.
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Conclusions
In summary, we have demonstrated a new method to
synthesize 1,1-difluoro-2,2-diaryl olefins or 2,2-diaryl
trifluoroethanes.[9] The chemo-selectivity of the reaction
is dominated by the electronic nature of the substrates.
Mechanistically, this reaction follows a pathway in-
volving transmetallation, carbene formation, migratory
insertion, and β-fluoride elimination or protonation.
This reaction further demonstrates the application of
CF3-bearing N-tosylhydrazones in the synthesis of fluo-
rine-containing organic compounds.
Acknowledgement
The project is supported by the National Basic Re-
search Program of China (973 Program, No.
2012CB821600) and the National Natural Science
Foundation of China (Nos. 21472004, 21332002).
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Chin. J. Chem. 2016, 34, 473—476