Palladium-catalyzed cross-coupling of benzylzinc reagents with 2-bromo-3,3,3-trifluoropropene

Article abstract of DOI:10.1080/00397911.2019.1663540

α-Trifluoromethyl alkenes can be used as peptide isosteres, moreover, the pre-installed vinyl group make it possible that transformation to diverse fluorine-containing unities. However, the cross-coupling of benzyl group with α-trifluoromethyl alkenes has yet to be developed. In this report, we describe a general method for the cross-coupling of benzylzinc reagents with 2-bromo-3,3,3-trifluoropropene (BTP) to afford diverse α-trifluoromethylalkene derivatives by using Pd(TFA)₂ as catalyst. This method takes advantage of cheap industrial available fluorine building blocks and easily prepared benzylzinc reagents to generate α-trifluoromethylalkene derivatives, which features with mild reaction conditions, wide substrate scope and feasibility of product transformations.

Full text of DOI:10.1080/00397911.2019.1663540

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Palladium-catalyzed cross-coupling of benzylzinc
reagents with 2-bromo-3,3,3-trifluoropropene
An-Jun Wang, Yue-Guang Lou, Liang Zhao, Fei-Hu Gou, Lian Wang, Yanbo Yu,
Jiwei Gu & Chun-Yang He
To cite this article: An-Jun Wang, Yue-Guang Lou, Liang Zhao, Fei-Hu Gou, Lian Wang,
Yanbo Yu, Jiwei Gu & Chun-Yang He (2019): Palladium-catalyzed cross-coupling of
benzylzinc reagents with 2-bromo-3,3,3-trifluoropropene, Synthetic Communications, DOI:
10.1080/00397911.2019.1663540
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https://doi.org/10.1080/00397911.2019.1663540
Palladium-catalyzed cross-coupling of benzylzinc reagents
with 2-bromo-3,3,3-trifluoropropene
Ã
Ã
An-Jun Wang , Yue-Guang Lou , Liang Zhao, Fei-Hu Gou, Lian Wang, Yanbo Yu,
Jiwei Gu , and Chun-Yang He
Key Laboratory of Biocatalysis and Chiral Drug Synthesis of Guizhou Province, Generic Drug Research
Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, China
ABSTRACT
ARTICLE HISTORY
Received 15 August 2019
a-Trifluoromethyl alkenes can be used as peptide isosteres, moreover,
the pre-installed vinyl group make it possible that transformation to
diverse fluorine-containing unities. However, the cross-coupling of ben-
zyl group with a-trifluoromethyl alkenes has yet to be developed. In this
report, we describe a general method for the cross-coupling of benzyl-
zinc reagents with 2-bromo-3,3,3-trifluoropropene (BTP) to afford diverse
a-trifluoromethylalkene derivatives by using Pd(TFA)2 as catalyst. This
method takes advantage of cheap industrial available fluorine building
blocks and easily prepared benzylzinc reagents to generate a-trifluoro-
methylalkene derivatives, which features with mild reaction conditions,
wide substrate scope and feasibility of product transformations.
KEYWORDS
Trifluoromethylation; BTP;
benzylzinc reagents;
palladium-catalyzed
GRAPHICAL ABSTRACT
Pd(TFA)2 (2.5 mol%)
X-Phos (5 mol%)
THF, 90 oC, 8 h
Br
ZnBr
+
R
R
CF3
F3C
up to 90% yield
Introduction
Due to the unique properties of fluorine atom (small size, high electronegativity, inert-
ness of C-F bonds), fluorinated compounds are of paramount importance in pharma-
ceuticals, agrochemicals, and materials science.[1–7] During the last 10 years, the demand
for fluorinated molecules is rapidly increasing. Therefore, it is of great importance to
develop novel and effective synthetic methods for the construction of fluorine-contain-
ing organic compounds.[8–21]
2-Bromo-3,3,3-trifluoropropene (BTP) is a readily available versatile organo-fluorine
building block, which has been widely used in various coupling/addition reactions under
various conditions.[22–25] The pre-installed vinyl group make it possible that
CONTACT Chun-Yang He
hechy2002@163.com
Key Laboratory of Biocatalysis and Chiral Drug Synthesis of
Guizhou Province, Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University,
Zunyi, 563003, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Ã
Both author contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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A.-J. WANG ET AL.
Figure 1. Diversity transformation of 3,3,3-trifluoropropene containing structures.
transformation to diverse fluorine-containing unities (Figure 1).[26–29] More important,
a-trifluoromethyl alkenes can be used as peptide isosteres,[30–33] which are important
medicinally relevant moieties in pharmacologically active compounds. Therefore, it is of
great interesting to introduce such structure into organic compounds. However, to the
best of our knowledge, the cross-coupling of benzyl group with a-trifluoromethyl alkenes
has yet to be developed. Alkylzinc reagents are important alkylmetal reagents, which can
be easily prepared therefore have many applications in organic synthesis.[34–36] Inspired
by our previous reports,[37] we envision that the cross-coupling of benzylzinc reagents
with 2-bromo-3,3,3-trifluoropropene via palladium catalyst is also feasible. As part of our
ongoing studies on the development of green strategies for fluoroalkylation,[38–40] herein,
we present an efficient protocol to construct trifluoromethyl substituted terminal alkenes
by the cross-coupling of benzylzinc reagents with BTP. The resulting products can be well
suited to obtain diverse fluorinated compounds by subsequent simple transformations.
Results and discussion
To begin this study, (4-(tert-butyl)benzyl)zinc bromide (1a) and 2-bromo-3,3,3-trifluor-
opropene 2 (2.0 equiv.) were chosen as model substrates to test the transformation of
this protocol. After initial failures, we found that the combination of Pd(OAc)2 (2.5 mol
%) with PPh3 in THF at 110 ꢀC provide product 3a with 16% yield (Table 1, entry 1).
Inspired by this result, a variety of different phosphine ligands were screened, to our
delight, the yield increased to 71% when X-Phos was used (Table 1, entries 2–5). After
a survey of the solvents utilized, other solvents, such as MeCN, DMF, Dioxane and
DMA were less effective compared to THF (Table 1, entries 6–9) and no reaction
occurred when DMSO was used. Comparable yield can still be obtained when the reac-
tion performed at 90 ꢀC, and the reactivity decreased dramatically when the temperature
further decreased to 80 ꢀC (Table 1, entries 11-12). Then, under these conditions, a

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Table 1. Optimization of palladium-catalyzed cross-coupling of (4-(tert-butyl)benzyl)zinc bromide
(1a) with 2-bromo-3,3,3-trifluoropropene (2).a
Entry
Pd
L
Temp. (ꢀC)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd(dppf)Cl2
PdCl2
PPh3
Xantphos
DPPM
110
110
110
110
110
110
110
110
110
110
90
80
90
90
90
90
90
THF
THF
THF
THF
THF
MeCN
DMA
Dioxane
DMF
DMSO
THF
THF
THF
THF
THF
THF
THF
16
9
7
DPPP
Nr
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
71
16
37
60
44
Nr
75
40
42
56
34
55
87(81)
9
10
11
12
13
14
15
16
17
Pd(TFA)2
aReaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0 equiv.), 2a (2.0 equiv.), solvent (2.0 mL).
bNMR yield determined by 19F NMR using fluorobenzene as an internal standard (isolated yield in parentheses).
variety of catalyst systems were tested, only moderate yield was obtained when
Pd(PPh3)4, Pd2(dba)3 or Pd(dppf)Cl2 were used (Table 1, entries 13–15), the yield fur-
ther increased to 87% when the catalyst switch to Pd(TFA)2 (Table 1, entry 17).
The optimized cross-coupling conditions were applied to a series of different benzyl-
zinc substrates. As summarized in Table 2, the reaction proceeds in moderate to high
yield with benzylzinc agents bearing electron-withdrawing, electron-neutral and elec-
tron-donating substituents on the aromatic ring. Alkyl or dialkyl substituted benzylzinc
reagents undergo the desired transformation smoothly (3a–b). Fluoro or chloro substi-
tuted benzylzinc reagents were also suitable substrates, providing compound 3c–e in
moderate to good yields. Benzylzinc reagents with methoxyl, ester or cyano on the aro-
matic ring proceeded this reaction well (3f–i). Additionally, heteroaromatic was also tol-
erated in this reaction to give the desired product in good yield (Table 2, 3j–k).
Experiments
General procedure for the palladium-catalyzed cross-coupling of benzylzinc reagents (1)
with 2-bromo-3,3,3-trifluoropropene (2): To a 25 mL of Schlenk tube were added
Pd(TFA)2 (2.5 mg, 2.5 mol %), X-Phos (7.2 mg, 5 mol %). The reaction tube was evac-
uated and backfilled with argon for three times, then THF (2.0 mL), benzylzinc reagent
1 (solution, 0.3 mmol, 1.0 equiv) and 2-bromo-3,3,3-trifluoropropane 2 (0.6 mmol, 2.0
equiv) were added subsequently. The Schlenk tube was screw capped and put into a
preheated oil bath (90 ꢀC). After stirring for 8 h, the reaction mixture was cooled to
room temperature, diluted with EtOAc (50 mL) and filtered with a pad of Celite. The

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A.-J. WANG ET AL.
Table 2. Palladium-catalyzed cross-coupling of benzylzinc reagents with 2-bromo-3,3,3-
trifluoropropene.a
Pd(TFA)2 (2.5 mol%)
X-Phos (5 mol%)
THF, 90 oC, 8 h
Br
ZnBr
+
R
R
CF3
F3C
1
2
3
F
CF3
CF3
CF3
CF3
t-Bu
Cl
F
3a, 84%
3c, 55%
3d, 65%
3b, 78%
3f, 90%
MeO
NC
MeO
CF3
CF3
CF3
CF3
3h, 85%
O
3e, 85%
3g, 81%
O
N
CF3
CF3
CF3
NC
Cl
N
3k, 80%
3j, 85%
3i, 86%
aReaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), THF (2.0 mL).
filtrate was washed with water (15mL), dried over anhydrous Na2SO4, filtered and concen-
trated. The residue was purified with silica gel chromatography to give the pure product.
Conclusion
In conclusion, this communication demonstrates a general approach for palladium-cata-
lyzed cross-coupling of benzylzinc reagents with 2-bromo-3,3,3-trifluoropropene. This
protocol used cheap industrial fluorine building blocks and easily prepared alkylzinc
reagents to generate a-trifluoromethylalkene derivatives. This transformation features
synthetic simplicity, mild reaction conditions and high functional group tolerance, pro-
viding a facile route for applications in medicinal chemistry.
Funding
The National Natural Science Foundation of China [No. 81760624, 21702241, 21762053], Young
Elite Scientists Sponsorship Program by Cast of the China Association for Science and
Technology [No. 2015-41], the Programs of Guizhou Province [No. 2017-1225, 2018-1427] are
warmly acknowledged for funding this work.
ORCID
Jiwei Gu
Chun-Yang He
http://orcid.org/0000-0002-4908-7544
http://orcid.org/0000-0002-0599-7335

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