Heteroaryldifluoromethylation of organoborons catalyzed by palladium: Facile access to aryl(heteroaryl)difluoromethanes

Article abstract of DOI:10.1021/ol502121m

A first example of Pd-catalyzed heteroaryldifluoromethylation of organoborons with bromodifluoromethylated heteroarenes has been described. The use of phosphine ligand PAd₂(n-Bu)·HI is critical for the reaction efficiency. With use of this ligand, a wide range of aryl(heteroaryl)-difluoromethanes were obtained with high efficiency. The notable features of this reaction are its broad substrate scope and excellent functional group compatibility, thus providing a facile protocol for application in drug discovery and development.

Full text of DOI:10.1021/ol502121m

Letter
pubs.acs.org/OrgLett
Heteroaryldifluoromethylation of Organoborons Catalyzed by
Palladium: Facile Access to Aryl(Heteroaryl)difluoromethanes
Yu-Lan Xiao, Bo Zhang, Zhang Feng, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A first example of Pd-catalyzed heteroaryldi-
fluoromethylation of organoborons with bromodifluoromethy-
lated heteroarenes has been described. The use of phosphine
ligand PAd2(n-Bu)·HI is critical for the reaction efficiency.
With use of this ligand, a wide range of aryl(heteroaryl)-
difluoromethanes were obtained with high efficiency. The notable features of this reaction are its broad substrate scope and
excellent functional group compatibility, thus providing a facile protocol for application in drug discovery and development.
enzoxazole, benzothiazole, and their derivatives are a class
of prominent structural motifs found in numerous
palladium-catalyzed heteroaryldifluoromethylation of organo-
borons with bromodifluoromethylated benzoxazole, (benzo)-
thiazoles, and benzoimidazole in the presence of phosphine
ligand, PAd2(n-Bu)·HI that has been rarely utilized for
fluoroalkylation.10 The reaction proceeds under mild reaction
conditions with excellent functional group compatibility, and is
applicable to a wide range of organoborons, including
arylboronic acids, boronates, and potassium trifluoroborate
salts, thus providing a facile access to a series of aryl-
(heteroaryl)difluoromethanes. An especially significant feature
of this protocol is the successful heteroaryldifluoromethylation
of bioactive compounds, thus providing a useful protocol for
drug discovery and development.
We began this study by choosing 2-(bromodifluoromethyl)-
benzo[d]oxazole 1a7b,e and phenyl boronic acid 2a as model
substrates (Table 1). Initially, the reaction was tested with 5
mol % of Pd(OAc)2 and a range of phosphines in the presence
of K2CO3 (2.0 equiv) in dioxane at 80 °C (Table 1, entries 1−
10). It was found that the reaction was very sensitive to the
phosphine ligands, good yield (64% determined by 19F NMR)
of 3a was obtained when bidentate ligand XantPhos (5 mol %)
was used (Table 1, entry 9). This finding is in accordance with
our previous results, in which only XantPhos that bound Pd
with a large bite angle showed good reactivity.9c,11 To our
delight, however, the bulky ligand cataCXium HI [PAd2(n-Bu)·
HI]10 provided 3a in even much higher yield (95% determined
by 19F NMR, Table 1, entry 10). We assumed that this is
attributed to the formation of an active T-shaped palladium
complex (Ph)(CF2HetAr)Pd[PAd2(n-Bu)] that benefits the
reductive elimination.12 But the extremely sterically hindered
ligand BrettPhos13 failed to afford the desired product (Table 1,
entry 8). Similar negative results were also found by using other
phosphine ligands (Table 1, entries 1−7). The choice of
solvent is also critical for the reaction efficiency (for details, see
B
pharmaceuticals and agrochemicals.1 Conceptually, introduc-
tion of a difluoromethylene group (CF2) or a functionalized
difluoromethylated group (CF2R) onto such heteroarene
motifs could lead to the discovery of some interesting bioactive
molecules. This is because the CF2 group2 can functionalize as a
bioisostere of the oxygen or a carbonyl group,3 and can
dramatically improve the metabolic stability and change
physiochemical properties of biologically active molecules.4
Traditionally, the CF2 group can be generated by reaction of
carbonyl groups with aminosulfur trifluorides.5 However, the
drawbacks of these reactions, such as important functional
group incompatibility and use of expensive and toxic
fluorinated reagents, significantly limit their widespread
synthetic applications. In this context, the use of readily
available difluoromethylated sources as starting materials for
further transformations would be an attractive alternative.6
Recently, bromodifluoromethylated benzoxazole, benzothia-
zoles, and their derivatives have emerged as one of the useful
difluoromethylated building blocks for the preparation of
fluorinated heteroarene derivatives.7 However, most of the
reported examples are limited to the nucleophilic heteroaryldi-
fluoromethylation of electrophiles, such as aldehydes.7a,b To
date, due to the lack of general and efficient strategies, there are
rare examples of using bromodifluoromethylated heteroarene as
electrophiles for carbon−carbon bond formation,8 and the use
of transition-metal-catalyzed cross-coupling processes to
construct Ar−CF2HetAr systems remains challenging.9
Hence, it is of great interest to develop new strategies and
efficient methods to prepare such important fluorinated
structures.
Very recently, we developed an efficient method for direct
difluoroalkylation of arenes through a palladium-catalyzed
process that linked difluoroalkyl halides (Rf-Br, Rf = CF2P(O)-
(OEt)2, CF2CO2Et) and arylboronic acids, which represents an
efficient strategy to access fluorinated arenes.9c Inspired by this
preliminary study, herein we describe the first example of
Received: August 4, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502121m | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Representative Results for Optimization of Pd-
Catalyzed Cross-Coupling between 1a and 2a
Scheme 1. Pd-Catalyzed Cross-Coupling between 1a and
Aryl Boronic Acids
a
a
b
entry
L (x)
PPh3 (10)
temp (°C)
yield (%)
1
80
80
80
80
80
80
80
80
80
80
70
60
70
70
70
70
ND
2
PCy3·HBF4 (10)
Pt-Bu3·HBF4 (10)
DavePhos (10)
RuPhos (10)
ND
3
ND
4
trace
trace
trace
trace
NR
5
6
XPhos (10)
7
SPhos (10)
8
BrettPhos (10)
XantPhos (5)
9
64
10
11
12
13
14
PAd2(n-Bu)·HI (10)
PAd2(n-Bu)·HI (10)
PAd2(n-Bu)·HI (10)
PAd2(n-Bu)·HI (7.5)
PAd2(n-Bu)·HI (5)
PAd2(n-Bu)·HI (5)
none
95
95 (90)
90
95 (90)
92 (90)
NR
c
15
16
NR
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol), 2a
b
(1.5 equiv), dioxane (2 mL), 7 h. NMR yield determined by 19F
NMR using fluorobenzene as an internal standard (isolated yield in
parentheses). Reaction run in the absence of Pd(OAc)2.
c
a
Reaction conditions (unless otherwise specified): 1a (0.5 mmol), 2
b
(1.5 equiv), dioxane (3.5 mL), 7 h. Pd(PPh3)4 (5 mol %), XantPhos
(5 mol %). Reaction carried out on a gram scale.
c
Supporting Information). Dioxane is the optimum reaction
media. The nonpolar solvent toluene also furnished 3a in high
yield (85% determined by 19F NMR). But other solvents, such
as DMF and DMSO, led to no product. Finally, the optimal
reaction conditions were identified by decreasing the loading
amount of PAd2(n-Bu)·HI to 5 mol % with utilization of
Pd(OAc)2 (5 mol %), K2CO3 (2.0 equiv) in dioxane at 70 °C
(Table 1, entry 14). The use of 1/1 ratio of Pd/PAd2(n-Bu)·HI
also suggested that a heteroaryldifluoromethylpalladium bro-
mide dimer {(HetArCF2)Pd(Br)[PAd2(n-Bu)]}2 formed from
the oxidative addition of RCF2−Br bond to Pd(0)Ln was
generated during the reaction.12 Yet the absence of palladium
catalyst or phosphine ligand resulted in no product, thus
demonstrating the essential roles of both palladium and
phosphine ligand for the catalytic cycle (Table 1, entries 15
and 16).
3f was also performed without affecting the reaction efficiency,
thus demonstrating the good reliability of the present reaction
(3f).
The reaction was not restricted to 2-(bromodifluoromethyl)-
benzo[d]oxazole 1a, as other heteroaryldifluoromethyl bro-
mides were also suitable substrates (Scheme 2). Benzoxazole
bearing a methyl or a chloride group underwent the reaction
smoothly (4a and 4b). The bromodifluoromethylated
Scheme 2. Pd-Catalyzed Cross-Coupling between
Heteroaryldifluoromethyl Bromides 1 and Aryl Boronic
a
Acids
To demonstrate the substrate scope of this method, a variety
of arylboronic acids were examined (Scheme 1). Overall,
moderate to high yields of 3 were obtained through the present
Pd-catalyzed cross-coupling process between 1a and arylbor-
onic acids 2, in which aromatic boronic acids bearing electron-
rich groups furnished their corresponding products in higher
yields than those substrates bearing electron-deficient groups. A
variety of versatile functional groups, including base or
nucleophile sensitive functional groups, such as formyl,
enolizable ketone, alkoxycarbonyl, cyano, nitro, and thioether,
were compatible with the reaction (3i−3m and 3o). Most
remarkably, bromide was also tolerated quite well (3n). But in
this case, the utilization of Pd(PPh3)4 (5 mol %) and XantPhos
(5 mol %) instead of Pd(OAc)2 (5 mol %) and PAd2(n-Bu)·HI
showed good activity (3n). Thus, this palladium-catalyzed
process provide a good platform for downstream trans-
formations. In addition, the sterically hindered substrates 2d
and 2e did not interfere with the reaction efficiency, providing
3d and 3e respectively, in high yields. A gram scale synthesis of
a
Reaction conditions (unless otherwise specified): 1 (0.5 mmol), 2
b
(1.5 equiv), dioxane (3.5 mL), 7 h. Pd(PPh3)4 (5 mol %), XantPhos
(5 mol %).
B
dx.doi.org/10.1021/ol502121m | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzothiazole, thiazole, and benzoimidazole were also appli-
cable to the present cross-coupling reactions, providing their
corresponding products with high efficiency (4c−h). Notably,
oxadiazole substituted difluoromethyl bromide was also a
competent coupling partner, with a good yield being obtained
(4i).
method led to difluoroalkylated, biologically active molecules
with high efficiency, thus providing a facile route for application
in drug discovery and development. The phosphine ligand
PAd2(n-Bu)·HI used in this study has been rarely utilized for
fluoroalkylation, but showed good activity, offering a new
opportunity for further study in other derived fluoroalkylation
reactions. Further studies to uncover the mechanism as well as
other derivative reactions are now in progress in our laboratory.
The heteroaryldifluoromethylation of arylboronic acids can
also be extended to aryl boronates 5 (Scheme 3a). This is
ASSOCIATED CONTENT
* Supporting Information
Scheme 3. Heteroaryldifluoromethylation of Organoborates
and Potassium Trifluoroborate Salts
■
S
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
■
*E-mail: xgzhang@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
1a (0.5 mmol), 5 (1.5 equiv), Pd(PPh3)4 (5 mol %), XantPhos (5
■
b
mol %), K2CO3 (2.0 equiv), dioxane (3.5 mL), 7 h. 1a (0.5 mmol), 6
(1.5 equiv), Pd(PPh3)4 (5 mol %), XantPhos (5 mol %), K2CO3 (2.0
equiv), dioxane (3.5 mL), H2O (100 μL) 7 h.
This work was financially supported by the National Basic
Research Program of China (2015CB931900), the National
Natural Science Foundation of China (Nos. 21172242 and
21332010), and SIOC.
noteworthy, as the aromatic pinacol ester can be easily accessed
through Ir-catalyzed C−H borylation.14 Thus, this trans-
formation provides a good opportunity for direct fluorination
of biologically active molecules for drug discovery and
development. What is more, aryl potassium trifluoroborate
salt 6 also underwent smooth reaction, thus highlighting the
good generality of the present reaction (Scheme 3b).
The utility of this reaction can also be demonstrated by
heteroaryldifluoromethylation of biologically active molecules.
As shown in Scheme 4, treatment of the estrone-derived
REFERENCES
■
(1) (a) Kazimierczuk, Z.; Andrzejewska, M.; Kaustova, J.; Klimesova,
V. Eur. J. Med. Chem. 2005, 40, 203. (b) Hernan
́
dez-Luis, F.;
quez, G.; Soria-
́
ez-Mulia, L. Eur. J. Med.
Hernan
Arteche, O.; Hernan
Chem. 2010, 45, 3135. (c) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359.
́
dez-Campos, A.; Castillo, R.; Navarrete-Vaz
́
́
dez-Hernandez, M.; Yep
́
(2) For selected reviews, see: (a) Qiu, X.-L.; Xu, X.-H.; Qing, F.-L.
Tetrahedron 2010, 66, 789. (b) Meanwell, N. A. J. Med. Chem. 2011,
54, 2529.
(3) (a) Blackburn, C. M.; England, D. A.; Kolkmann, F. J. Chem. Soc.,
Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Kent, D. E.;
Kolkmann, F. J. Chem. Soc. Perkin Trans. I 1984, 1119. (c) Kitazume,
T.; Kamazaki, T. Experimental Methods in Organic Fluorine Chemistry;
Gordon and Breach Science: Tokyo, 1998.
Scheme 4. Heteroaryldifluoromethylation of Biologically
Active Molecules
(4) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Burgey, C. S.;
Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Dale Lewis, S.; Lucas,
B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.;
Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J.
C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.;
McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.;
Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J.
J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P.
J. Med. Chem. 2003, 46, 461. (c) Li, J.; Chen, S. Y.; Murphy, B. J.;
Flynn, N.; Seethala, R.; Slusarchyk, D.; Yan, M.; Sleph, P.; Zhang, H.;
Humphreys, W. G.; Ewing, W. R.; Robl, J. A.; Gordon, D.; Tino, J. A.
Bioorg. Med. Chem. Lett. 2008, 18, 4072. (d) Lynch, C. L.; Willoughby,
C. A.; Hale, J. J.; Holson, E. J.; Budhu, R. J.; Gentry, A. L.; Rosauer, K.
G.; Caldwell, C. G.; Chen, P.; Mills, S. G.; MacCoss, M.; Berk, S.;
Chen, L.; Chapman, K. T.; Malkowitz, L.; Springer, M. S.; Gould, S. L.;
DeMartino, J. A.; Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver,
G.; Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Eminic, E. A. Bioorg. Med. Chem. Lett. 2003,
13, 119.
arylboronic acid 7 with bromodifluoromethylated thiazole 1e
afforded heteroaryl difluoromethylated compound 8 with high
efficiency. Although the reaction of arylboronate 9 with 1a
furnished its difluoroalkylated estrone 10 in a reasonable yield,
the success of this transformation provides the possibility for
sequential C−H borylation/heteroaryldifluoromethylation of
biologically active molecules.
In conclusion, we have disclosed the first example of Pd-
catalyzed heteroaryldifluoromethylation of organoborons with
bromodifluoromethylated heteroarenes. The reaction allowed
heteroaryldifluoromethylation of a wide range of organoborons,
including arylboronic acids, boronates, and potassium trifluor-
oborate salts under mild reaction conditions. Application of the
(5) For selected examples of difluorination of carbonyl group with
fluorinated reagents, see: (a) Middleton, W. J.; Bingham, E. M. J. Org.
Chem. 1980, 45, 2883. (b) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.;
Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048. (c) Solas, D.;
C
dx.doi.org/10.1021/ol502121m | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Hale, R. L.; Patel, D. V. J. Org. Chem. 1996, 61, 1537. (d) Kobayashi,
S.; Yoneda, A.; Fukuhara, T.; Hara, S. Tetrahedron 2004, 60, 6923.
(e) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc.
2010, 132, 18199. (f) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D.
R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell,
D.; Couturier, M. J. Org. Chem. 2010, 75, 3401.
(6) For transition metal mediated difluoroalkylation, see: (a) Taguchi,
T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.;
Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103. (b) Sato, K.; Omote,
M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509. (c) Qiu,
W.; Burton, D. J. Tetrahedron Lett. 1996, 37, 2745. (d) Yokomatsu, T.;
Murano, T.; Suemune, K.; Shibuya, S. Tetrahedron 1997, 53, 815.
(e) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(f) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood,
K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090.
(g) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon,
D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc.
2012, 134, 1494. (h) Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara,
Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52,
3949.
(7) (a) Burkholder, C.; Dolbier, W. R., Jr.; Medebielle, M. J. Org.
Chem. 1998, 63, 5385. (b) Dolbier, W. R., Jr.; Burkholder, C. R.;
Medebielle, M. J. Fluorine Chem. 1999, 95, 127. (c) Ge, F.; Wang, Z.;
Wan, W.; Lu, W.; Hao, J. Tetrahedron Lett. 2007, 48, 3251. (d) Yang,
X.; Wang, Z.; Fang, X.; Yang, X.; Wu, F.; Shen, Y. Synthesis 2007,
1768. (e) Jiang, H.; Yuan, S.; Cai, Y.; Wan, W.; Zhu, S.; Hao, J. J.
Fluorine Chem. 2012, 133, 167.
(8) (a) Ma, G.; Wan, W.; Hu, Q.; Jiang, H.; Wang, J.; Zhu, S.; Hao, J.
Chem. Commun. 2014, 50, 7527. (b) Jiang, H.; Lu, W.; Yang, K.; Ma,
G.; Xu, M.; Li, J.; Yao, J.; Wan, W.; Deng, H.; Wu, S.; Zhu, S.; Hao, J.
Chem.Eur. J. 2014, DOI: 10.1002/chem.201402205.
(9) For transition metal catalyzed difluoroalkylation, see: (a) Feng,
Z.; Chen, F.; Zhang, X. Org. Lett. 2012, 14, 1938. (b) Feng, Z.; Xiao,
Y.-L.; Zhang, X. Org. Chem. Front. 2014, 1, 113. (c) Feng, Z.; Min, Q.-
Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53,
1669. (d) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.; Zhang, X. J. Am.
Chem. Soc. 2014, 136, 1230. (e) Ge, S.; Chaladj, W.; Hartwig, J. F. J.
Am. Chem. Soc. 2014, 136, 4149. (f) Guo, C.; Wang, R.-W.; Qing, F.-L.
J. Fluorine Chem. 2012, 143, 135.
(10) (a) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589.
(b) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39,
4153.
(11) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
́ ́
12644. (b) Bakhmutov, V. I.; Bozoglian, F.; Gomez, K.; Gonzalez, G.;
Grushin, V. V.; Macgregor, S. A.; Martin, E.; Miloserdov, F. M.;
Novikov, M. A.; Panetier, J. A.; Romasho, L. V. Organometallics 2012,
31, 1315.
(12) (a) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc.
2008, 130, 15549. (b) Sergeev, A. G.; Zapf, A.; Spanneberg, A.; Beller,
M. Organometallics 2008, 27, 297.
(13) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679.
(14) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890.
D
dx.doi.org/10.1021/ol502121m | Org. Lett. XXXX, XXX, XXX−XXX