Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium

Article abstract of DOI:10.1002/anie.201605380

Although important progress has been made in the fluoroalkylation reactions, the transition-metal-catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd-catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.

Full text of DOI:10.1002/anie.201605380

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605380
German Edition: DOI: 10.1002/ange.201605380
Carbonylation
Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium
Hai-Yang Zhao, Zhang Feng, Zhiji Luo, and Xingang Zhang*
Abstract: Although important progress has been made in the
fluoroalkylation reactions, the transition-metal-catalyzed car-
bonylative fluoroalkylation reaction remains challenging so
far. Herein, we report the first example of a Pd-catalyzed
carbonylation of difluoroalkyl bromides with (hetero)arylbor-
onic acids under one atmosphere pressure of CO. The reaction
can also be extended to the aryl potassium trifluoroborate salts.
The advantages of this protocol are synthetic simplicity, broad
substrate scope, and excellent functional group compatibility.
The resulting difluoroalkyl ketones can serve as versatile
building blocks for the synthesis of various useful fluorinated
compounds.
probably occur, which is a classic technique to prepare
fluoroalkyl metal complexes.[8] As a result, it is very difficult
to control the catalytic cycle to obtain the desired fluorinated
products. Nevertheless, herein, we describe the discovery and
development of the reaction that can meet these challenges.
We began this study by examining the feasibility of
palladium-catalyzed carbonylation of difluoroalkyl bromides
with arylboronic acids (Scheme 1). The choice of difluor-
Scheme 1. Pd-catalyzed carbonylation of difluoroalkyl bromides with
arylboronic acids.
The past several decades have witnessed the development of
transition-metal-catalyzed cross-coupling reactions and their
wide application in the pharmaceuticals, fine chemicals, and
functional materials. These cross-coupling strategies, how-
ever, are generally not ready to be adapted to the construction
of a carbon-fluorocarbon (C-Rf) bond with high predictability
and generality,[1] because the unique properties of fluorine
atom(s) can dramatically influence the stability and reactivity
of fluoroalkyl transition-metal complexes, leading to some
unexpected reactions.[2] Given the importance of fluorinated
compounds in medicinal chemistry and material sciences,[3]
introduction of fluorinated substituents into organic mole-
cules through transition-metal catalysis of the cross-coupling/
fluoroalkylations has emerged as one of the most attractive,
efficient, and environmentally benign strategies to access
fluorinated compounds.[1] One of the challenges belonging to
this theme is the transition-metal catalyzed carbonylative
fluoroalkylation reaction. Although numerous of carbonyla-
tion reactions have been developed since Heck and co-
workers reported their pioneering work of the Pd-catalyzed
carbonylation of aryl halides in the 1970s,[4,5] no example of
transition-metal-catalyzed carbonylative fluoroalkylation
reaction has been reported yet. The reason is that compared
with their hydrocarbon counterparts the stronger s-bonds
between fluoroalkyl groups and transition metals (Rf-M) are
less prone to undergo carbonyl insertion.[6] To date, only few
examples of carbon monoxide (CO) inserting into a M-Rf
bond to produce a fluoroacyl complex (M-C(O)Rf) have been
documented.[7] In addition, once the M-C(O)Rf complexes are
formed, their decarbonylation to generate the (CO)M-Rf will
oalkyl bromides, a type of inexpensive and widely available
compounds, as the model substrate is because the unique
properties of difluoromethylene group (CF2) often lead to
profound changes in physical, chemical, and biological
properties of organic molecules.[9] Although the targeting
difluoroalkyl ketones are valuable intermediates and building
blocks in the synthesis of various useful fluorinated com-
pounds, the existing methods to prepare difluoroalkyl ketones
are limited to substrate scope, functional group compatibility,
and requirement of a stepwise procedure thus lowering the
reaction efficacy. Therefore, it is also highly demanding to
develop new, efficient and green methods to prepare such
a valuable structural motif with high functional group
tolerance.
Inspired by our recent work on palladium-catalyzed
difluoroalkylation of arylboronic acids with bromodifluoroa-
cetate 2a,[10a] we focused our initial study on the Pd-catalyzed
carbonylation reaction of 2a with arylboronic acid 1a under
1 atmosphere pressure of CO (Table 1). In addition, 2a is low-
cost and widely available and can provide a good platform for
downstream transformations. After carefully examining the
catalytic system, we found that 14% of carbonylation product
3a could be obtained with utilization of PdCl2(PPh3)3
(5 mol%), Xantphos (10 mol%), Cs2CO3 (2.0 equiv) and
1 atm of CO in dioxane at 808C (entry 1). Surprisingly,
compound 3a could also be produced in 6% yield in the
absence of CO (entry 2). This unusual finding is noteworthy
as no carbonylation reaction has been previously reported
through such a mode. The decomposition of 2a is likely to
occur under the current reaction conditions and generate CO
as the carbonyl source for the following carbonylation
reaction. Stimulated by this unprecedented result, a survey
of reaction parameters, such as palladium sources, ligands,
bases, and solvents, with 2a as a self-serve CO source was
conducted (for details see the Supporting Information). The
combination of PdCl2(PPh3)2, Xantphos, and dioxane
[*] H.-Y. Zhao, Z. Feng, Z. Luo, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605380.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Representative results for optimization of Pd-catalyzed carbon-
ylation of 2a with 1a.[a]
Table 2: Pd-catalyzed carbonylation of arylboronic acids 1 with bromo-
difluoroacetate 2a.[a]
Entry
[Pd]
Base
Additive
3a/4a
Yield [%][b]
1
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Cs2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
–
–
–
14/<1
6/ 6
16/ 31
35/64
81/trace
92 (87)/6
2[c]
3[c]
4[c]
5
Cu(hfac)2
Cu(hfac)2
Cu(hfac)2
6[d]
[a] Reaction conditions (unless otherwise specified): 1a (0.5 mmol,
1.0 equiv), 2a (2.0 equiv), dioxane (2 mL), 24 h. [b] Determined by
19F NMR using fluorobenzene as internal standard and number in
parenthesis is isolated yield. [c] Reaction ran in the absence of CO.
[d] Molecular sieves (3 ꢀ) were added.
remained the optimal choice and K3PO4 afforded 3a in
a slightly higher yield (16%) along with 31% yield of
byproduct difluoroacetylated arene 4a (entry 3). Taking into
account the fact that the copper salt can facilitate the
transmetalation step thus benefiting the reaction efficiency,[11]
a variety of copper salts were examined (for details see the
Supporting Information). When Cu(hfac)2 [hfac =
hexafluoroacetylacetone monoanion] was employed, an
increased yield of 3a (35%) was provided, accompanied by
a significantly increased amount of byproduct 4a (64%)
(entry 4). The facile production of 4a appears to compete
with the desired carbonylation reaction, which is limited by
the relatively slow release of CO from 2a. Accordingly,
additional CO (1 atm) was used to suppress this competitive
reaction and afforded 3a in a high yield (81%; entry 5).
Finally, the optimal reaction conditions were identified by
addition of 3 ꢀ molecular sieves (MS), providing 3a in 87%
yield upon isolation (entry 6). No product or poor yield of 3a
was obtained without palladium catalyst or Xantphos,[12] thus
demonstrating the critical role of PdCl2(PPh3)2/Xantphos in
promotion of the reaction (for details see the Supporting
Information).
Upon the identification of viable reaction conditions,
a variety of arylboronic acids were examined in this trans-
formation (Table 2). Generally, arylboronic acids bearing
either electron-rich or electron-deficient substituents all
undergo the reaction smoothly, providing 3 with high
efficiency. The steric effect of the arylboronic acids does not
interfere with the reaction. Sterically hindered substrates,
such as ortho-phenyl substituted phenyl boronic acid and (2,5-
dimethylphenyl)boronic acid, afford the corresponding prod-
ucts with good yields (3c and 3d). Meanwhile, this reaction
exhibits high tolerance to functional groups: many versatile
functional groups, including base or nucleophile sensitive
moieties (ester, formyl, enolizable ketone, nitrile, thioether,
siyl, and bromide) show excellent compatibility to the
reaction (3k–3m, 3o–3t). It is noteworthy that the phenol
derived substrate furnishes the corresponding product 3u in
[a] Reaction conditions (unless otherwise specified): 1 (0.5 mmol,
1.0 equiv), 2a (2.0 equiv), PdCl2(PPh3)2 (5 mol%), Xantphos (10 mol%),
Cu(hfac)2 (5 mol%), 3 ꢀ molecular sieves, dioxane (2 mL), 24 h.
[b] Gram-scale synthesis.
good yield without observation of the dicarbonylated side
product, which is in sharp contrast to the previously reported
results using phenols as nucleophiles for the carbonylation
reaction.[5a] The heteroaromatic boronic acids, such as
dibenzo[b,d]thiophene, carbazole, and pyridine containing
substrates are also applicable to the reaction (3v–3y), thus
highlighting the advantages of the current process further. It is
also possible to prepare compounds 3 on a gram-scale. For
examples, yields as high as ~ 90% were obtained for the gram-
scale synthesis of 3e and 3 f, thus offering a reliable and
practical access to the highly functionalized fluorinated
molecules.
To demonstrate the generality of this catalytic system,
bromodifluoroacetamides (2b–2e) were explored (Table 3).
Good yields and high functional group compatibility were still
observed. Importantly, the amino acid containing difluoroa-
cetamides undergo the reaction smoothly, leading to the
corresponding products with high efficiency (5e and 5 f). It
should be mentioned that thioethers usually poison the
palladium catalyst and inhibit the catalysis reaction,[13] but
the methionine residue does not influence the reaction
efficiency (5 f). This transformation is also highly relevant to
the drug discovery and development, in light of the impor-
tance of a,a-difluoroalkyl ketone based peptide in the
medicinal chemistry, for example, a,a–difluoroketone
A79285 being an excellent inhibitor of HIV-1 aspartic pro-
tease.[14]
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Considering that phosphonyldifluoromethyl group
importance and utility of this protocol have also been
(CF2PO(OEt)2) is an attractive structural motif in the
medicinal chemistry, in which the difluoromethylene group
(CF2) can function as a bioisostere for an oxygen atom,[15] we
then extended the substrate scope of the difluoroalkyl
bromides to bromodifluoromethylphosphonate 2 f just with
minor modification (5g–5k). The advantages of the current
process can also be featured by the carbonylation of
bromodifluoromethylbenzoxazole and its derivatives (5l–
5p).[16] But in these cases, Pd(OAc)2 instead of PdCl2(PPh3)2
in the absence of copper and molecular sieves additives
exhibits good activity. Since benzoxazole and its derivatives
highlighted by the rapid synthesis of diverse difluorome-
thylenated molecules from the building blocks 3e or 3 f. As
shown in Scheme 2b, the carbonyl group can be easily
converted into vinyl through the Wittig reaction. Decarbox-
ylation of 3 f to difluoromethyl ketone 7, an important
building block for the synthesis of the difluoroalkylated
compounds, proceeds smoothly. What is more, excellent yield
of diol 8 is also produced through the reduction of both
carbonyl and ester moiety of 3 f. Importantly, the condensa-
tion of hydrazines with 3e affords the biologically active
compounds 4,4-difluoropyrzaol-5-ones 9a and 9b with high
efficiency. Finally, application of current process can also
efficiently synthesize fluorinated peptiod 11 in only one step
with the yield of 90%, which may have potential interest in
the discovery of new bioactive molecules (Scheme 2c). The
late-stage difluoroalkylation of Fenofibrateꢁ, a drug against
cardiovascular disease,[17] is also successfully performed
(Scheme 2d), thus featuring the applicability of this protocol
in the medicinal chemistry further.
Table 3: Pd-catalyzed carbonylation of arylboronic acids 1 with difluor-
oalkyl bromides 2.[a]
To gain the mechanistic insight into the current reaction,
several experiments were conducted, as shown in Scheme 3.
Firstly, to identify whether a fluoroalkyl radical pathway is
involved in the reaction, a-cyclopropylstyrene 14 was added
in the reaction of 2a with arylboronic acid under the standard
[a] Reaction conditions (unless otherwise specified): 1 (0.5 mmol,
1.0 equiv), 2a (2.0 equiv), PdCl2(PPh3)2 (5 mol%), Xantphos (10 mol%),
Cu(hfac)2 (5 mol%), 3 ꢀ molecular sieves, dioxane (2 mL), 24 h. [b] Pd-
(OAc)2 (5 mol%), Xantphos (10 mol%), dioxane (2 mL), 24 h. [c] With-
out 3 ꢀ molecular sieves. [d] 10 mol% of IPr·HCl was used.
are a prominent structural motif present in numerous
pharmaceuticals and agrochemicals, this method is a valuable
strategy for the discovery of new interesting bioactive
compounds. In addition, aryldifluoromethyl bromide is suit-
able substrate, providing the corresponding products 5q and
5r in moderate yields. Remarkably, the unactivated 1-bromo-
1,1-difluoroalkane is also viable in the reaction, but a rela-
tively electron-rich N-heterocyclic carbene ligand N,N-
bis(2,6-diisopropylphenyl)imidazole-2-ylidene, IPr) is used
to promote the reaction (5s).
Scheme 2. Transformations of compounds 3 and synthesis of biologi-
cally active molecules.
reaction conditions (Scheme 3a). A ring-expanded product
15 was obtained in 33% yield, suggesting that a single
electron transfer (SET) pathway via a difluoroalkyl radical is
involved in the reaction process. The formation of radical
intermediate was further confirmed by the ESR study of
reaction of 2a with spin-trapping agent phenyl tert-butyl
nitrone (PBN) (see the Supporting Information). Thus, both
The reaction can also be extended to aryl potassium
trifluoroborate salts. Even higher yields of 3a and 3g were
obtained when 1a’ and 1g’ were examined (Scheme 2a). The
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
results clearly demonstrate that a free fluoroalkyl radical is
involved in the reaction. Secondly, the carbonylation of
bromodifluoroacetamide 2b can also employ methanol as the
nucleophile (Scheme 3b), thus suggesting that a fluoroacyl
palladium complex may be involved in the catalytic cycle. To
rule out the possibility that radical carbonylations without
palladium also produce esters, the reaction between 2b and
methanol in the absence of palladium catalyst was conducted
(Scheme 3c). However, no ester 17 was observed when the
reaction was irradiated by blue LED in the presence of
a photocatalyst Ir(bpy)3, but the difluoroalkyl radical [Et2NC-
(O)CF2C] was indeed generated.[18] Thus, this result demon-
strates that the palladium is essential for the current carbon-
ylation reaction and a fluoroacyl palladium complex may be
generated in the reaction process.
BrCF2CO2Et can serve as a CO source and a coupling partner.
We believe that the current reaction not only provides us
a new view to understand transition-metal-catalyzed carbon-
ylative fluoroalkylation reaction but also is useful for the drug
discovery and development. Further studies to reveal the
detailed mechanism as well as other derivative reactions are
now in progress in our laboratory.[21]
Acknowledgements
This work was financially supported by the National Basic
Research Program of China (973 Program; grant numbers
2012CB821600 and 2015CB931900), the National Natural
Science Foundation of China (grant numbers 21425208,
21332010, and 21421002), the Strategic Priority Research
Program of the Chinese Academy of Sciences (grant number
XDB20020000), and SIOC.
Keywords: arylboronic acids · carbonylation · cross-coupling ·
difluoroalkyl bromides · palladium
[1] For selected reviews of transition-metal-catalyzed fluoroalkyla-
tions, see: a) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473,
470; b) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111,
4475; c) T. Besset, C. Schneider, D. Cahard, Angew. Chem. Int.
Ed. 2012, 51, 5048; Angew. Chem. 2012, 124, 5134; d) M.-C.
Belhomme, T. Besset, T. Poisson, X. Pannecoucke, Chem. Eur. J.
2015, 21, 12836.
Scheme 3. Mechanistic studies.
[2] a) D. T. Rosevear, F. G. A. Stone, J. Chem. Soc. A 1968, 164;
b) H. D. Empsall, M. Green, F. G. A. Stone, J. Chem. Soc. Dalton
Trans. 1972, 96; c) A. J. Mukhedker, M. Green, F. G. A. Stone, J.
Chem. Soc. A 1969, 3203.
[3] For recent reviews, see: a) B. E. Smart, J. Fluorine Chem. 2001,
109, 3; b) K. Mꢂller, C. Faeh, F. Diederich, Science 2007, 317,
1881; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320.
[4] a) A. Schoenberg, I. Bartoletti, R. F. Heck, J. Org. Chem. 1974,
39, 3318; b) A. Schoenberg, R. F. Heck, J. Org. Chem. 1974, 39,
3327; c) A. Schoenberg, R. F. Heck, J. Am. Chem. Soc. 1974, 96,
7761.
[5] For selected recent reviews, see: a) A. Brennfꢂhrer, H. Neu-
mann, M. Beller, Angew. Chem. Int. Ed. 2009, 48, 4114; Angew.
Chem. 2009, 121, 4176; b) R. Grigg, S. P. Mutton, Tetrahedron
2010, 66, 5515; c) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc.
Rev. 2011, 40, 4986; d) X.-F. Wu, H. Neumann, M. Beller, Chem.
Rev. 2013, 113, 1.
On the basis of the present results and previous
reports,[5,10] a plausible reaction mechanism was proposed.
The reaction was initiated by a Pd0Ln-promoted single
electron transfer (SET) pathway to generate the difluoroalkyl
radical [RCF2C] A and [BrPd(I)Ln] B. A subsequently reacted
with B to provide [BrPdLnCF2R] C. After insertion of CO
into s bond of palladium species C (BrPdLn-CF2R), the key
intermediate difluoroalkylacyl palladium complex [BrPdLn-
(CO)CF2R] D was provided. D underwent transmetalation
with arylboronic acids, followed by the reductive elimination
to deliver carbonylated products and regenerate Pd0Ln.
However, an alternative pathway through the formation of
D between [BrPd(I)Ln] B and difluoroalkylacyl radical that
was derived from the reaction of difluoroalkyl radical [RCF2C]
A with CO cannot be ruled out.[19]
In conclusion, the first example of transition-metal-
catalyzed carbonylative fluoroalkylation reaction has been
described. The reaction undergoes smoothly under mild
reaction conditions in the presence of 1 atm of CO with
high efficiency, broad substrate scope, and excellent func-
tional group compatibility. Applications of the method
efficiently lead to diverse fluorinated compounds, thus
featuring its importance and usefulness. The remarkable
function of Xantphos in the current catalytic system is
probably because of its wide bite angle,[12a,b] but it might not
always be the key contributing factor.[12d,20] A self-serve CO
system for the carbonylation reaction is found, in which
[6] a) R. B. King, S. L. Stafford, P. M. Treichel, F. G. A. Stone, J. Am.
Chem. Soc. 1961, 83, 3604; b) K. J. Klabunde, R. Campostrini, J.
Fluorine Chem. 1989, 42, 93; c) J. G. Cordaro, R. G. Bergman, J.
Am. Chem. Soc. 2004, 126, 16912; For the carbonylative
transformation of organofluorinated compounds without for-
mation of RCO-Rf bond, see: d) T. Fuchikami, A. Yamanouchi,
I. Ojima, Synthesis 1984, 766; e) H. Amii, Y. Kishikawa, K.
Kageyama, K. Uneyama, J. Org. Chem. 2000, 65, 3404; f) T.
Kobayashi, T. Nakagawa, H. Amii, K. Uneyama, Org. Lett. 2003,
5, 4297.
[7] a) C. R. Jablonski, Inorg. Chem. 1981, 20, 3940; b) C. J. Bour-
geois, R. P. Hughes, T. L. Husebo, J. M. Smith, I. M. Guzei, L. M.
Liable-Sands, L. N. Zakharov, A. L. Rheingold, Organometallics
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
2005, 24, 6431; c) J. Yuan, R. P. Hughes, A. L. Rheingold,
Blackburn, Chem. Ind. 1981, 134; d) G. M. Blackbum, D. E.
Organometallics 2011, 30, 1744.
Kent, F. Kolkmann, J. Chem. Soc. Perkin Trans. 1 1984, 1119;
e) Z. Feng, F. Chen, X. Zhang, Org. Lett. 2012, 14, 1938.
[16] For transition-metal-catalyzed difluoroalkylation with bromodi-
fluoromethyl benzoxazole, see: a) Y.-L. Xiao, W.-H. Guo, G.-Z.
He, Q. Pan, X. Zhang, Angew. Chem. Int. Ed. 2014, 53, 9909;
Angew. Chem. 2014, 126, 10067; b) Y.-L. Xiao, B. Zhang, Z.
Feng, X. Zhang, Org. Lett. 2014, 16, 4822.
[8] a) W. R. McClelian, J. Am. Chem. Soc. 1961, 83, 598; b) R. B.
Kin, M. B. Bisnette, J. Organomet. Chem. 1964, 2, 15; c) P. J.
Brothers, A. K. Burrell, G. R. Clark, C. E. F. Rickard, W. R.
Roper, J. Organomet. Chem. 1990, 394, 615; d) H. Huang, R. P.
Hughes, A. L. Rheingold, Organometallics 2010, 29, 1948 and
ref. [6c].
[9] a) K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b) D.
OꢃHagan, Chem. Soc. Rev. 2008, 37, 308.
[17] N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem. Educ.
2010, 87, 1348.
[10] a) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang, X. Zhang, Angew.
Chem. Int. Ed. 2014, 53, 1669; Angew. Chem. 2014, 126, 1695;
b) Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo, X. Zhang, J. Am.
Chem. Soc. 2014, 136, 1230.
[11] a) M. B. Thathagar, J. Beckers, G. Rothenberg, J. Am. Chem.
Soc. 2002, 124, 11858.
[12] For selected reviews on Xantphos, see: a) P. C. J. Kamer,
P. W. N. M. Van Leeuwen, J. N. H. Reek, Acc. Chem. Res. 2001,
34, 895; b) P. W. N. M. Van Leeuwen, Z. Freixa in Modern
Carbonylation Methods (Ed.: L. Kollar), Wiley-VCH, Wein-
heim, 2008, p. 1; For selected Pd/Xantphos catalyzed carbon-
ylation reactions, see: c) J. R. Martinelli, D. A. Watson, D. M. M.
Freckmann, T. E. Barder, S. L. Buchwald, J. Org. Chem. 2008,
73, 7102; d) F. M. Miloserdov, V. V. Grushin, Angew. Chem. Int.
Ed. 2012, 51, 3668; Angew. Chem. 2012, 124, 3728.
[13] N. Munakata, M. Reinhard, Appl. Catal. B 2007, 75, 1.
[14] a) A. M. Silva, R. E. Cachau, H. L. Sham, J. W. Erickson, J. Mol.
Biol. 1996, 255, 321; b) D. Schirlin, S. Baltzer, J. M. Altenburger,
C. Tarnus, J. M. Remy, Tetrahedron 1996, 52, 305.
[18] A difluoroalkyl radical can be initiated by irradiation of 2b with
blue LED in the presence of photocatalyst Ir(bpy)3, see the
Supporting Information Scheme S2a. Also, see: J. D. Nguyen,
J. W. Tucker, M. D. Konieczynska, C. R. J. Stephenson, J. Am.
Chem. Soc. 2011, 133, 4160.
[19] S. Sumino, A. Fusano, T. Fukuyama, I. Ryu, Acc. Chem. Res.
2014, 47, 1563.
[20] V. I. Bakhmutov, F. Bozoglian, K. Gomez, G. Gonzalez, V. V.
Grushin, S. A. Macgregor, E. Martin, F. M. Miloserdov, M. A.
Novikov, J. A. Panetier, L. V. Romashov, Organometallics 2012,
31, 1315.
[21] While this manuscript was under review, the following paper was
published: T. L. Andersen, M. W. Frederiksen, K. Domino, T.
Skrydstrup, Angew. Chem. Int. Ed. 2016, DOI: 10.1002/
anie.201604152; Angew. Chem. 2016, DOI: 10.1002/
ange.201604152.
Received: June 2, 2016
[15] a) T. R. Burke, K. Lee, Acc. Chem. Res. 2003, 36, 426; b) V. D.
Romanenko, V. P. Kukhar, Chem. Rev. 2006, 106, 3868; c) G. M.
Revised: June 30, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Carbonylation
H.-Y. Zhao, Z. Feng, Z. Luo,
X. Zhang*
&&&& — &&&&
Carbonylation of Difluoroalkyl Bromides
Catalyzed by Palladium
Insertion of CO: A palladium-catalyzed
carbonylation reaction of difluoroalkyl
halides into ketones was developed (see
picture). The resulting difluoroalkyl
ketones can serve as versatile building
blocks for the synthesis of useful fluori-
nated compounds.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!