Highly selective gem -difluoroallylation of organoborons with bromodifluoromethylated alkenes catalyzed by palladium

Article abstract of DOI:10.1021/ja4114825

A first example of Pd-catalyzed gem-difluoroallylation of organoborons using 3-bromo-3,3-difluoropropene (BDFP) in high efficiency with high α/γ-substitution regioselectivity has been developed. The reaction can also be extended to substituted BDFPs and has advantages of low catalyst loading (0.8 to 0.01 mol %), broad substrate scope, and excellent functional group compatibility, thus providing a facile route for practical application in drug discovery and development.

Full text of DOI:10.1021/ja4114825

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Communication
Highly Selective gem-Difluoroallylation of Organoborons with
Bromodifluoromethylated Alkenes Catalyzed by Palladium
Qiao-Qiao Min, Zengsheng Yin, Zhang Feng, Wen-Hao Guo, and Xingang Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Jan 2014
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Highly Selective gem-Difluoroallylation of Organoborons with
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Bromodifluoromethylated Alkenes Catalyzed by Palladium
Qiao-Qiao Min, Zengsheng Yin, Zhang Feng, Wen-Hao Guo, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
Supporting Information Placeholder
ly useful methods to access such valuable structures are rare.12 We
ABSTRACT:
A
first example of Pd-catalyzed gem-
chose 3-bromo-3,3-difluoropropene (BDFP) as the starting rea-
gent for gem-difluoroallylation because it is readily and commer-
cially available,13 and a transition-metal-catalyzed cross-coupling
between the low cost BDFP and widely available organometallics
difluoroallylation of organoborons using 3-bromo-3,3-
difluoropropene (BDFP) in high efficiency with high α/γ-
substitution regioselectivity has been developed. The reaction can
also be extended to substituted BDFPs, and has advantages of low
catalyst loading (0.8 mol % to 0.01 mol %), broad substrate scope,
and excellent functional group compatibility, thus providing a
facile route for practical application in drug discovery and
development.
would thus provide
a
cost-efficient access to gem-
difluoroallylated structures that can be applied in the synthesis of
bioactive compounds. In this study, we focused our research on
addressing three crucial issues: (1) regiochemical selectivity, i.e.,
α-substitution vs γ-substitution (Scheme 1a), (2) efficient catalytic
system that can suppress undesired defluorination side reaction
resulted from gem-difluoroallylated products14 (Scheme 1b), and
(3) efficient and practical processes with broad substrate scope.
As a result, we disclose the first example of highly selective Pd-
catalyzed gem-difluoroallylation of organoborons with BDFP.
The reaction can also be extended to substituted BDFPs. The no-
table advantages of this reaction are its high efficiency and regi-
oselectivity (α/γ up to >37:1), low catalyst loading (0.8 mol % to
0.01 mol % Pd), applicability for large scale production (10 gram),
broad substrate scope, and excellent functional group compatibil-
ity.
The importance of fluorinated compounds in agrochemicals,
pharmaceuticals, and materials science1 has triggered an explo-
sion of research efforts in developing new and efficient methods
to introduce fluorinated functional groups into organic molecules.
Over the past few years, although considerable progresses have
been achieved in fluorination and trifluoromethylation of organic
substrates,2 to date, strategies for introduction of a difluorometh-
ylene (CF2) group into organic molecules have been less ex-
plored3 despite the unique properties and important biological
activity of compounds containing CF2.4 For instance, CF2 is usu-
ally considered as a bioisostere of the oxygen or a carbonyl
group,5 which leads to increased dipole moments, enhanced acidi-
ty of its neighboring group and conformational changes.6 In par-
ticular, the introduction of a CF2 onto the aromatic rings can dra-
matically improve the metabolic stability and oral bioavailability
of biological active compounds.7 Generally, such a structural
moiety is achieved by conversion of carbonyl group with DAST
or Deoxofluor.8 But the intrinsic limitations of this method, such
as the important functional groups incompatibility and the use of
expensive and toxic fluorinated reagents, significantly restrict its
widespread synthetic applications. To address these issues, one
alternative approach is to directly introduce a functionalized CF2
group into the organic molecules catalyzed by transition-metal.
However, these difluoroalkylation processes still remain challeng-
Scheme 1. Transition-Metal-Catalyzed Cross-Coupling
Between 3-Bromo-3,3-difluoropropene and Organometal-
lics.
We began our study with the reaction of air stable (4-(tert-
butyl)phenyl)boronic acid 1a and 3-bromo-3,3-difluoropropene 2
in the presence of Pd-catalyst (Table 1). After screening the reac-
tion conditions, we found a 77% yield of a mixture of 3a and 4a
with α-substitution 3a as major product (3a/4a = 6.2:1) was ob-
tained when the reaction was carried out with 1a (1 mmol), 2 (2
equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2 (5 mol%), and PPh3 (10
mol%) in dioxane at 80 oC (Table 1, entry 1). Notably, no defluor-
ination of 3a was observed under these reaction conditions. This
is in sharp contrast to previous results, in which the defluorination
of gem-difluoroallylated compounds frequently occurred.14 The
reaction was also found very sensitive to the bases (Table 1, en-
ing, and only a handful of examples have been developed so far.9,
10
As part of ongoing study in transition-metal-catalyzed reactions
for introduction of fluorinated functional groups into organic mol-
ecules,11 herein we demonstrate the feasibility of Pd-catalyzed
gem-difluoroallylation.
(CF2CH=CH2) is extremely appealing due to the versatile synthet-
ic utility of the carbon-carbon double bond. However, synthetical-
The
gem-difluoroallyl
group
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tries 2-5) and solvents. K2CO3 and dioxane were the optimal
matic boronic acids bearing either electron-rich or electron-
choice. Other bases and solvents led to either lower yields or poor
regioselectivities. No product was obtained when polar solvents,
such as DMF, DMSO, and CH3CN, were used due to the for-
mation of uncertain byproducts from BDFP (see Supporting In-
formation). To our delight, a low catalyst loading of Pd(PPh3)4
(0.2 mol %) showed a beneficial effect on both reaction efficiency
and regioselectivity (94% yield, 3a/4a = 10:1) (Table 1, entry 8).
Switching Pd(PPh3)4 to Pd2(dba)3 dramatically increased the α/γ
(3a/4a) regioselectivity (3a/4a = 20:1) (Table 1, entry 9). Im-
portantly, even the amount of catalyst loading was reduced to 0.05
mol % in combination of 1.2 equiv of 2, high yield of 3a was still
afforded while maintaining high levels of regioselectivity (Table 1,
entry 11). Finally, the optimal reaction conditions were identified
by increasing the amount of K2CO3 to 3.0 equiv with utilization of
0.48 equiv of H2O (Table 1, entry 12), providing 3a in high yield
with excellent regioselectivity (3a/4a = 20:1) (for details see Sup-
porting Information). It is noteworthy that this reaction could be
successfully conducted under air in wet solvent, thus featuring an
operational simplicity advantage of the present process. It should
be mentioned that even BDFP 2 was treated with 2.5 equiv of 1a
under optimized reaction conditions (Table 1, entry 12), only 5%
yield (determined by 19F NMR) of defluorinated side product
fluoroolefin was observed, and 90% yield of desired product 3a
still could be obtained with high α/γ regioselectivity (3a/4a > 20:1)
(for details see Supporting Information).
deficient substituents all led to 3 in high yields with high to excel-
lent α/γ regioselectivities (3a-m). Importantly, in many cases the
Pd2(dba)3 loading can be reduced to 0.2 mol % without compro-
mising the reaction efficiency and α/γ regioselectivities (3g-i, 3k-
m). However, in the case of 3-nitrophenyl boronic acid, a dramat-
ically decreased yield (44% determined by 19F NMR) of 3j was
observed. Further improvement of the reaction efficiency by em-
ploying Pd(PPh3)4 (0.4 mol %) in conjunction with catalytic
amount of CuI (6 mol %) provided 3j in good yield (70%) with
high regioselectivity (3j/4j = 13:1). The steric effect of the aro-
matic boronic acids did not interfere with the reaction. The phenyl
substituent at the para, meta, and ortho position of the phenyl
boronic acid afforded the corresponding products 3 in high effi-
ciency with high α/γ regioselectivity (3b-d). Notably, even steri-
cally hindered mesitylboronic acid previously demonstrated to be
a challenging substrate for fluoroalkylation was also a competent
coupling partner (3f), thus demonstrating the generality of the
present reaction.
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Table 2. gem-Difluoroallylation of Organoboronic Acids 1
with 3-Bromo-3,3-difluoropropene 2.a
F
F
Pd2(dba)3 (0.4 mol %)
K2CO3 (3.0 equiv)
B(OH)2
R
BrF2C
R
+
R
+
H2O (0.48 equiv)
F
F
dioxane, 80 o
C
2
F
3
1
4
F
F
F
F
F
Table 1. Representative Results for Optimization of Pd-
F
F
F
F
Catalyzed
Cross-Coupling
between
(4-(tert-
Ph
Me
Me
Butyl)phenyl)boronic Acid 1a
and 3-Bromo-3,3-
Ph
difluoropropene 2.a
tBu
Ph
3a
3b
3c
3d
3e
93% (20:1)
85% (16:1)
87% (16:1)
83% (15:1)
92% (18:1)
F
F
F
F
F
F
F
F
F
F
Me
Me
NO2
3jd,e
MeO
OMe
Me
BnO
MeO
OMe
3hc
3fb
3gc
3ic
3a+4a Yield
(%), 3a/4a b
entry
[Pd] (mol %)
Base (equiv)
78% (17:1)
87% (28:1)
71% (24:1)
82% (16:1)
70% (13:1)
F
F
F
F
F
F
F
F
1c
2c
3c
4c
5c
6
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (0.4)
Pd(PPh3)4 (0.2)
Pd2(dba)3 (0.4)
Pd2(dba)3 (0.1)
Pd2(dba)3 (0.05)
Pd2(dba)3 (0.4)
Cs2CO3 (1.5)
K2CO3 (1.5)
Na2CO3 (1.5)
KOAc (1.5)
K3PO4 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (3.0)
77, 6.2:1
78, 6.4:1
26, 5.9:1
11, only 3a
28, 5.9:1
75, 3.2:1
97, 9.4:1
94, 10:1
F
F
CO2Et
HO
EtS
EtO2C
3kc,e
OHC
3lc,e
3mc,e
3nb
3oc
68% (19:1)
82% (28:1)
78% (13:1)
60% (10:1)
80% (15:1)
F
F
F
F
F
F
F
F
F
F
S
Br
7
Br
3pb
3q
3r
3s
3t
90% (20:1)
67% (12:1)
74% (20:1)
93% (17:1)
8
60% (8:1)
F
F
F
F
F
F
F
F
9
89, 20:1
O
10d
11d
12e
77, 20:1
N
Ph
73, 20:1
3uc
3vf
72% (8:1)
3wb
3xb
90% (20:1)
92% (26:1)
72% (15:1)
92 (93), 20:1
aReaction conditions (unless otherwise specified): 1a (1.0
aReaction conditions (unless otherwise specified): 1 (1 mmol),
o
mmol, 1.0 equiv), 2 (1.5 equiv), dioxane (5 mL), 80 C, 24 h un-
2 (1.5 mmol), dioxane (5 mL) under air for 24 h. All reported
yields are combined isolated yields of 3 and 4. The ratio of 3/4 in
der N2. bDetermined by 19F NMR using trifluoromethylbenzene as
internal standard and number in parenthesis is isolated yield. The
ratio of 3a/4a was determined by 19F NMR before working up.
b
parentheses was determined by 19F NMR before working up. 1.5
mmol of 1 and 1.0 mmol of 2 were used. c0.2 mol % of Pd2(dba)3
was used. d0.4 mol % of Pd(PPh3)4 and 6 mol % of CuI were used.
e2.0 mmol of 2 was used. f0.2 mol % of Pd(PPh3)4 was used.
d
cUsing 2.0 equiv of 2, 10 mol % PPh3. Using 1.2 equiv of 2.
eUsing 0.48 equiv of H2O, and reaction was conducted under air.
A variety of versatile functional groups (nitro, ester, aldehyde,
alcohol, thioether, and vinyl) were quite well-tolerated (3j-p).
To ascertain the substrate scope of this method, a wide range of
aryl boronic acids were then examined (Table 2). Generally, aro-
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Most remarkably, the successfully selective formation of 3q-r
with intact bromide provided a good platform for further func-
tionalization. Heteroaromatic rings are a prominent structural
motif found in numerous pharmaceuticals and agrochemicals.
Boronic acids derived from dibenzo[b,d]thiophene, carbazole, and
dibenzo[b,d]furan all underwent gem-difluoroallylation smoothly
(3t-v). Most importantly, N-containing heterocycle carbazole
furnished its gem-difluoroallylated product 3u in 90% yield with
high regioselectivity (3u/4u
= 20:1). However, pyridine-
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containing boronic acids were not suitable substrates. Furthermore,
the reaction was not restricted to the (hetero)aryl boronic acids,
vinyl boronic acids were also suitable substrates, and provided
linear and branched gem-difluoromethylenated dienes in high
efficiency with high to excellent α/γ regioselectivities (3w-x).
aReaction conditions (unless otherwise specified): 1 (1.3 mmol),
5 (1.0 mmol), dioxane (5 mL) under air for 10 h. All reported
yields are isolated yields, the number in parentheses is the ratio of
In spite of substantial progress in fluoroalkylation of organic
molecules, efficient method that enables low catalyst loading to
practically synthesize fluorinated compounds has received rare
attention. In this context, grams scale synthesis of gem-
difluoroallylated arenes 3 with utilization of 0.1 mol % to 0.01
mol % of Pd catalyst was conducted to demonstrate the synthetic
utility of the protocol further (Scheme 2). As shown in Scheme 2a,
gram-scale synthesis of 3o and 3r in the presence of 0.05 mol %
Pd2(dba)3 proceeded smoothly with high α/γ regioselectivity, thus
offering a reliable and practical access to highly functionalized
difluoromethylenated structure. Most excitingly, a 10-gram-scale
reaction with Pd-catalyst loading as low as 0.01 mol % afforded
3a in 80% yield with high regioselectivity (α/γ = 10:1) (Scheme
2b). To the best of our knowledge, this is the first example of
transition-metal-catalyzed fluoroalkylation of organic molecules
by using as low as 0.01 mol % catalyst in a practical manner.
b
α/γ. 0.4 mol % of Pd(PPh3)4 and 3.0 mmol of KOH were used.
c1.0 mmol of 1 and 1.3 mmol of 5 were used.
The gem-difluoroallylation of organoboronic acids can also be
extended to organoborates without affecting the reaction efficien-
cy (Scheme 3). High yield of 3a with a slightly decreased α/γ
regioselectivity (3a/4a = 13:1) was obtained by reaction of aryl-
borate 7 with BDFP 2 (Scheme 3a). Furthermore, aryl potassium
trifluoroborate salt 8 also underwent the reaction smoothly in high
yield (90%) with excellent regioselectivity (3a/4a > 20:1)
(Scheme 3b) (for details see Supporting Information). However,
the Burke’s MIDA esters afforded poor yields.
Scheme 3. gem-Difluoroallylation of Organoborates and
Potassium Trifluoroborate Salt.
Scheme 2. Grams-Scale Synthesis of gem-Difluoroallylated
Arenes with Low Catalyst Loading.a
aAll reported yields are combined isolated yields of 3 and 4, and
the number in parentheses is the ratio of 3/4.
The substituted BDFPs15 were also applicable to the reaction.
As shown in Table 3, branched BDFP derivatives including phe-
nyl and alkyl-substituted substrates underwent the gem-
difluoroallylation in high efficiency with excellent α/γ regioselec-
tivity (6a-g). Again, important functional groups were compatible
with the reaction conditions (6c-e, 6g). It was found that the linear
substituted BDFPs were more reactive than BDFP, and resulted in
some undesired defluorinated compounds and other uncertain
byproducts. To our delight, decreasing the reaction temperature
and using Pd(PPh3)4 (0.4 mol %) as a catalyst could afford gem-
difluoallylated products in moderate yields (6h-i). Importantly, no
branched products (γ-substitution) were observed during the reac-
tion. We reasoned that this is probably due to the steric effect of
the substituents. It should be pointed out that bisubstituted BDFP
was also a suitable substrate, providing 6j in synthetically useful
yield. This is noteworthy, as it is difficult to prepare such fluori-
nated molecule otherwise.
aCombined isolated yield of α and γ substitutions, and the number
in parentheses is the ratio of α/γ.
The usefulness of this protocol can also be featured by the late-
stage gem-difluoroallylation of bioactive natural product. This
offered a unique and highly valuable opportunity for drug discov-
ery and development, because the unique structure of gem-
difluoroallyl group not only provides a platform to use CF2 as a
bioisostere of the oxygen or a carbonyl group,5 but also makes it
possible to further modify the bioactive compounds through trans-
formation of double bond. As shown in Scheme 3c, treatment of
arylborate 9 derived from estrone with BDFP on a gram-scale
afforded gem-difluoroallylated compound 10 in 88% yield with
high regioselectivity (α/γ = 15:1). Subsequently, dihydroxylation
of 10 afforded modified bioactive compound 11 in high efficiency.
While previous preparation of aryl gem-difluorodiols required
electrochemical fluorination, and only low yield of desired prod-
uct was provided,16 thus highlighting the advantages of the pre-
Table 3. gem-Difluoroallylation of Organoboronic Acids 1
with Substituted BDFPs 5.a
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(g) Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y. Sella, E.; Shabat,
D.; Baran, P. S. Angew. Chem. Int. Ed. 2013, 52, 3949.
sent process. In addition, the successful use of aromatic pinacol
esters as the coupling partners also provides the possibility for
sequential C-H borylation/gem-difluoroallylation reactions. This
is because aromatic pinacol esters are readily available through Ir-
catalyzed C-H borylation.17
(4) (a) Hertel, L. W.; Kroin, J. S.; Missner, J. W.; Tustin, J. M. J. Org.
Chem. 1988, 53, 2406. (b) Akahoshi, F.; Ashimori, A.; Sakashita, H.;
Yoshimura, T.; Eda, M.; Imada, T.; Nakajima, M.; Mitsutomi, N.;
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In conclusion, we have demonstrated a first example of Pd-
catalyzed gem-difluoroallylation of organoborons with 3-bromo-
3,3-difluoropropene. The reaction allowed gem-difluoroallylation
of a wide range of organoborons including (hetero)aryl and vinyl
boronic acids, borates, and potassium trifluoroborate salt with low
catalyst loading under mild and operationally simple conditions.
This reaction can also be extended to substituted BDFPs. Applica-
tion of the method led to modified fluorinated bioactive com-
pounds in a highly efficient and practical manner. Because of the
unique structure of gem-difluoroallyl group and the advantages of
this protocol, such as practicality with low catalyst loading, high
regioselectivity and excellent functional group compatibility, we
believed that this protocol should be useful for drug discovery and
development. Further studies to uncover the mechanism as well as
other derivative reactions are now in progress in our laboratory.
9
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Dube, P.; Frost, H. N.; Paquin, J.-F. Angew. Chem., Int. Ed. 2010, 49,
1123, and ref 12c.
(15) The substituted BDFP 5 are not commercially available and were
prepared according to the literature, see: (a) Nihei, T.; Iwaio, N.; Matsuda,
T.; Kitazume, T. J. Org. Chem. 2005, 70, 5912. (b) Gonzalez, J.; Foti, C.
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ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* xgzhang@mail.sioc.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by the National Basic Re-
search Program of China (973 Program) (No. 2012CB821600),
the National Natural Science Foundation of China (Nos 21172242
and 21332010), and SIOC.
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