Copper-mediated fluoroalkylation of aryl iodides enables facile access to diverse fluorinated compounds: The important role of the (2-Pyridyl)sulfonyl group

Article abstract of DOI:10.1021/ol3029737

The (2-pyridyl)sulfonyl group was found to be a multifunctional group in the preparation of structurally diverse fluorinated products. It not only facilitates the copper-mediated (or catalyzed) cross-coupling reaction between α-fluoro sulfone 4a and aryl iodides, but also enables further transformations of the coupling products 2.

Full text of DOI:10.1021/ol3029737

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Mediated Fluoroalkylation of Aryl
Iodides Enables Facile Access to Diverse
Fluorinated Compounds: The Important
Role of the (2-Pyridyl)sulfonyl Group
Yanchuan Zhao, Bing Gao, Chuanfa Ni, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
jinbohu@sioc.ac.cn
Received October 29, 2012
ABSTRACT
The (2-pyridyl)sulfonyl group was found to be a multifunctional group in the preparation of structurally diverse fluorinated products. It not only
facilitates the copper-mediated (or catalyzed) cross-coupling reaction between R-fluoro sulfone 4a and aryl iodides, but also enables further
transformations of the coupling products 2.
Fluorinated organic compounds have received increas-
ing attention during the past years because of their indis-
pensable role in the progress of various fields. This is
largely due to the beneficial changes that fluorine imparts
to organic molecules.1 As arylꢀfluoroalkyl linkages are
widely found in pharmaceuticals, fluoroalkylated aromatics
are of intense synthetic interest,2 and in this context, copper-
mediated (or catalyzed) processes are generally employed to
prepare fluoroalkylated aromatics. It is now possible to
efficiently install trifluoromethyl (CF3), difluoromethyl
(CF2H), and functionalized difluoromethyl groups [CF2X,
X = C(O)R, P(O)(OEt)2] onto aromatic rings via copper-
mediated (or catalyzed) fluoroalkylations.3 However, the
introduction of a fluoromethyl (CH2F) or functionalized
fluoromethyl (CFR1R2) group by copper-mediated process
remains an interesting challenge possibly due to the de-
creased stability of the corresponding organocopper species.
The only example of copper-mediated monofluoroalkyla-
tion of aryl iodides was reported by Burton and co-workers
in 1999 using [(EtO)2P(O)CHFBr], while the yield was
strongly dependent on the electronic nature of the sub-
strates.4 Therefore, it is highly desired to develop a new
€
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(b) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.;
ꢀ
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Wiley: Chichester, 2009. (c) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008. (d) Uneyama,
K. Organofluorine Chemistry; Blackwell: Oxford, 2006.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Schlosser, M. Angew. Chem., Int. Ed. 2006,
45, 5432. (c) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
(3) (a) For a recent review, see: Tomashenko, Q. A.; Grushin, V. V.
Chem. Rev. 2011, No. 111, 4475. (b) Hu, J.; Zhang, W.; Wang, F. Chem.
Commun. 2009, 7465 and references cited therein. (c) Davis, C. R.;
Burton, D. I. Fluorinated Organocopper Reagents. In The Chemistry
of Organocopper Compounds; Rappoport, Z., Marek, I., Eds.; Wiley:
Chichester, 2009. (d) Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu,
J. J. Org. Chem. 2010, 75, 5505 and references cited therein. (e) Fujikawa,
K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560.
(f) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524. (g) Feng,
Z.; Chen, F.; Zhang, X. Org. Lett. 2012, 14, 1938. (h) Qi, Q.; Shen, Q.; Lu,
L. J. Am. Chem. Soc. 2012, 134, 6548. (i) Oishi, M.; Kondo, H.; Amii, H.
Chem. Commun. 2009, 1909. (j) Novak, P.; Lishchynskyi, A.; Grushin,
V. V. J. Am. Chem. Soc. 2012, 134, 16167. (k) Novak, P.; Lishchynskyi, A.;
Grushin, V. V. Angew. Chem., Int. Ed. 2012, 51, 7767.
(4) Zhang, X.; Qiu, W. M.; Burton, D. J. Tetrahedron Lett. 1999, 40,
2681.
r
10.1021/ol3029737
XXXX American Chemical Society

protocol for the copper-mediated fluoroalkylation of aryl
iodides to introduce a fluoromethyl or functionalized
fluoromethyl group in terms of both synthetic and me-
chanistic aspects.5
methyl 4-iodobenzoate (5a) as a model substrate. Et2Zn
was added to a solution of fluoroiodomethyl sulfone
(4aꢀd) in DMF at room temperature, and CuI and 5a
were added subsequently. The results are illustrated in
Table 1. It was found that sulfone 4b bearing a phenyl
moiety displayed low reactivity under the current reaction
conditions (Table 1, entry 1), and the product yield was
We envisioned that the stability and/or reactivity of
(monofluoroalkyl)copper intermediates could be tuned
by introducing an intramolecular coordinating group, as
organocuprates bearing a neighboring N-atom were re-
ported to react with a variety of electrophiles efficiently.6
Based on our experience on the nucleophilic fluoroalkyla-
tion and olefination with fluoroalkyl 2-pyridyl sulfones,7
we assumed that [(2-pyridyl)sulfonyl]fluoromethylcopper
species (1) could serve as a good monofluoroalkylat-
ing agent to react with aryl iodides, since the (2-pyridyl)-
sulfonyl group may act as an intramolecular ligand by
coordinating to copper catalyst with its nitrogen atom
(Scheme 1, step a). Furthermore, given the versatile
chemical behaviors of the fluoroalkyl 2-pyridyl sulfones
in fluoroalkylations and fluoroolefinations,7 the copper-
mediated coupling products 2 could be further trans-
formed into structurally diverse monofluorinated organic
compounds (Scheme 1, step b).
Table 1. Survey of Reaction Conditionsa
entry
R
x
y
ligand
phen
yieldf (%)
1
Ph
1.2
1.2
1.2
1.2
1.2
2.0
1.2
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.2
0.3
0.3
34
23
2b
3
Ph
2-Py
BT
90
4
trace
trace
87
5
TBT
2-Py
2-Py
2-Py
2-Py
2-Py
6
7c
8
>95 (92)
48
Scheme 1. Copper-Mediated Monofluoroalkylation Assisted by
the Multifunctional (2-Pyridyl)sulfonyl Group
9d
10d,e
80
90 (80)
a Unless otherwise stated, the reactions were run on a 0.25 mmol scale
in DMF (3 mL) at rt. b 1,10-Phenanthroline (20%) was added as a ligand.
c [2-PySO2CFHCu] species was prepared at ꢀ15 °C. d The reaction was
heated to 60 °C after 5a was added. e NMP was used as a solvent instead
of DMF. f Yield of coupling product based on the amount of 5a, which
was determined by 19F NMR spectroscopy using PhCF3 as an internal
standard; data in parentheses refers to the yield of isolated coupling
product.
At the onset of our investigation, we speculated that the
reactive species [2-PySO2CHFCu] used in the cross-coupling
reaction with aryl iodides could be prepared by a transme-
talation between CuI and [2-PySO2CHF]ZnX, and the latter
species could be furnished by metalꢀhalide exchange be-
tween the corresponding iodide (2-PySO2CHFI) (4a) and
Et2Zn under mild conditions.8 Furthermore, other structu-
rally similar compounds RSO2CHFCI (R ¼ 2-Py) species
were also prepared and used to examine their reactivity in the
copper-mediated monofluoroalkylation (Scheme 2).
similar to that for the reported monofluoroalkylation with
[(EtO)2P(O)CHFCu].4 It is surprising that the reactions
with nitrogen-containing heteroaryl sulfones 4c and 4d
(with BT and TBT groups substituted at sulfur atom,
respectively) only gave a trace amount of the correspond-
ing products (Table 1, entries 4 and 5). The addition of
1,10-phenanthroline, which was shown to be very effective
in promoting the copper-catalyzed trifluoromethylation,3
did not improve the yield (Table 1, entry 2). To our delight,
the reaction employing 2-pyridyl sulfone (4a) gave much
better results (entries 3 and 6ꢀ10). The coordination of the
Scheme 2. Synthesis of Different Fluoroiodomethyl Sulfones 4
(5) Although palladium-catalyzed monofluoroalkylation of aryl halides
(or boronic acids) with R-fluoro ketones (or enolates) and esters are known,
further transformations of the corresponding monofluorinated products
are limited. See: (a) Guo, C.; Wang, R.-W.; Guo, Y.; Qing, F.-L. J. Fluorine
Chem. 2012, 133, 86. (b) Guo, C.; Yue, X.; Qing, F.-L. Synthesis 2010, 1837.
(c) Guo, Y.; Twamley, B.; Shreeve, J. M. Org. Biol. Chem. 2009, 7, 1716.
(d) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(6) Dieter, R. K. N-Functionalized Organocuprates. In The Chemistry of
Organocopper Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester,
2009 and references cited therein.
(7) (a) Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444.
(b) Zhao, Y.; Gao, B.; Hu, J. J. Am. Chem. Soc. 2012, 134, 5790.
(c) Prakash, G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A. Angew. Chem.,
Int. Ed. 2011, 50, 2559. (d) Zhao, Y.; Zhang, L.; Xu, G.; Zheng, J.; Hu, J.
Sci. Sin. Chim. 2011, 41, 1833.
With a series of different fluoroiodomethyl sul-
fones 4aꢀd in hand, we first examined their reactivity
in the Cu(I)-mediated cross-coupling reaction using
B
Org. Lett., Vol. XX, No. XX, XXXX

neighboring 2-pyridyl group to a metal catalyst is exten-
sively involved in transition-metal-catalyzed reactions.9
Although the exact role of the 2-pyridyl group in the
current reaction has not been fully elucidated at the cur-
rent stage, we believe that it could accelerate the rate of
transmetalation between [RSO2CHF]ZnX species and
CuI, and enhance the reactivity of [RSO2CHFCu] species
by electron-donation from nitrogen to copper. It should be
mentioned that only 0.3 mmol of Et2Zn was needed for the
full conversion of 0.5 mmol of 2-PySO2CFIH in the
current reaction, which suggests that [2-PySO2CHF]2Zn
(rather than [2-PySO2CHF]ZnEt) is probably involved in
the current reaction. Furthermore, it was found that
generation of [2-PySO2CHFCu]10 species at low tempera-
ture (ꢀ15 °C) further improved the yield, and we could
isolate the product 2a in 92% yield under the optimized
reaction conditions (Table 1, entry 7). Moreover, the reac-
tion could also proceed smoothly with catalytic amount
of CuI (30%) at elevated temperature (60 °C) without
significant loss of the product yield (Table 1, entry 10). It
should be noted that no ligand is needed in our catalytic
reaction, which is different from the recently developed
copper-catalyzed fluoroalkylations in the presence of
catalytic amount of copper.3a,g,i This result suggests the
(2-pyridyl)sulfonyl group may serve as an “intramolecular
ligand” in the current reaction.
Scheme 3. Copper-Mediated or -Catalyzed Fluoromethylation
of Aryl Iodidesa
Considering the low cost of CuI and mild reaction
conditions when employing a stoichiometric amount
of copper, we first examined the substrate scope of
the copper-mediated cross-coupling reaction between 2-
PySO2CFHI 4a and aryl iodides 5 by using reaction condi-
tions as described in Table 1, entry 7 as standard (reactant
ratio 4a:5 = 2:1). As shown in Scheme 3, the reactions
with iodoarenes containing either electron-withdrawing
[including ester (5a), nitro (5bꢀ5d), cyano (5e)] or elec-
tro-donating groups [including methoxyl (5i and 5j)] af-
forded the desired products in 76ꢀ92% yields. The reac-
tion tolerates several reactive functionalities, such as hy-
droxyl (5o), aldehydes(5mand5n), andketones(5land 5p).
Bromo- and chloro-substituted iodoarenes (5g, 5h,
and 5q) reacted selectively at the arylꢀI bond. It should
be mentioned that, in the reaction with 2-(allyloxy)iodo-
benzene (5k), no cyclized product 3-methyl-2,3-dihydro-
benzofuran was observed. This result suggests that the
involvement of aryl radicals (possibly generated from cleav-
age of CꢀI bond) in the current copper-mediated cross-
coupling reaction with 4a is unlikely. Moreover, the cata-
lytic version of this reaction (as those for Table 1, entry 10)
a Copper-mediated process: 4a (0.5 mmol), ArI 5 (0.25 mmol), CuI
(0.5 mmol), Et2Zn (0.3 mmol) in DMF (3 mL) at rt for 8 h, isolated
yield is reported. b Copper-catalyzed process: 4a (0.5 mmol), ArI 5
(0.25 mmol), CuI (0.075 mmol), Et2Zn (0.3 mmol) in NMP (3 mL)
at 60 °C for 8 h, isolated yield is reported. c The reaction was heated to
60 °C. d CuI (0.65 mmol) was employed in the reaction.
also proceeded smoothly to give the products in satisfac-
tory yields (5a,d,i,j,n,pꢀr). It is striking that even the acetyl
(5p) and formyl group (5n) are tolerated in the current
copper-catalyzed reaction.
Taking advantage of the versatile chemical behavior of
the 2-pyridylsulfonyl group, the present copper-mediated
fluoroalkylation with 4a was further used to prepare a
variety of structurally diverse and potentially useful fluori-
nated compounds (as shown in Scheme 4).7 Biologically
active 3-fluoromethyl-3-deoxylestrone (7) was obtained
with satisfactory yield in two steps from the correspond-
ing iodide (6) by our CuI-mediated cross-coupling with
2-PySO2CHFI and subsequent desulfonylation with
(8) Knochel, P. Synlett 1995, 393.
(9) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) Garcia-Rubia, A.; Gomez Arrayas, R.; Carretero, J. C. Angew.
Chem., Int. Ed. 2009, 48, 6511. (c) Garcı
´
a-Rubia, A.; Urones, B.;
ꢀ
ꢀ
Gomez Arrayas, R.; Carretero, J. C. Chem.;Eur. J. 2010, 16, 9676.
ꢀ
a-Rubia, A.; Fernandez-Ibanez, M. A.; Gomez Arrayas, R.;
ꢀ
ꢀ~
ꢀ
ꢀ
(d) Garcı
´
Carretero, J. C. Chem.;Eur. J. 2011, 17, 3567. (e) Llamas, T.; Gomez
Arrayas, R.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 3329.
(f) Esquivias, J.; Gomez Arrayas, R.; Carlos Carretero, J. Angew.
Chem., Int. Ed. 2007, 46, 9257.
(10) The “copper reagent” exhibited a broad 19F NMR signal
at ꢀ216 ppm, and the signal gradually decreased after aryl iodide
was added.
(11) (a) Wnuk, S. F.; Robins, M. J. J. Am. Chem. Soc. 1996, 118,
2519. (b) Wnuk, S. F.; Rios, J. M.; Khan, J.; Hsu, Y. L. J. Org. Chem.
2000, 65, 4169.
Org. Lett., Vol. XX, No. XX, XXXX
C

from multistep procedures and poor functional group
tolerance.12 In our case, direct introduction of the
(2-pyridylsulfonyl)fluoromethyl group in the presence
of the formyl group smoothly gave the precursor of an
intramolecular JuliaꢀKocienski olefination. Simple treat-
ment of the product with t-BuOK in DMF furnished the
desired monofluoroalkene with an eight-member ring in
80% yield (Scheme 4, b).7a Moreover, the fluorinated sul-
finates are important precursors for fluorinated sulfonic
acids and fluorinated sulfones, which found wide applica-
tion in modern functional materials and biologically active
compounds.13 Monofluorinated sulfinate could be easily
generated by a t-BuSNa-mediated depyridination and
could be trapped in situ with CH3I to furnish the corre-
sponding methyl sulfone (10) in 85% yield (Scheme 4, c).7c
Inconclusion, acopper-mediatedmonofluoroalkylation
of aryl iodides has been successfully developed using
fluoroiodomethyl 2-pyridyl sulfone 4a. With this method,
a wide range of aryl iodides bearing various functional
groups were efficiently converted into the desired mono-
fluoroalkylated products employing either stoichiometric
or catalytic amount of copper. The method is amenable to
the late-stage fluoromethylation of biologically active
molecules (as demonstrated in Scheme 4, a). Not only does
the presence of the (2-pyridyl)sulfonyl group play a crucial
role in the copper-mediated cross-coupling reaction, it
also facilitates further transformations of the obtained
products, such as desulfonylation, intramolecular Juliaꢀ
Kocienski olefination, and depyridination.
Scheme 4. Synthetic Application of the Products of the Copper-
Mediated Cross-Coupling Reactions
Bu3SnH and AIBN (Scheme 4, a).11 The method thus
enabled a quick access to fluoromethylarenes from the
corresponding iodoarenes. Moreover, JuliaꢀKocienski
olefination is generally employed to stereoselectively con-
struct alkenes; however, for designing an intramolecular
version of JuliaꢀKocienski olefination, the introduc-
tion of the heterosulfone functional group often suffers
Acknowledgment. This work was supported by the Na-
tional Basic Research Program of China (2012CB821600,
2012CB215500), the National Natural Science Founda-
tion of China (20825209, 20832008), and the Chinese
Academy of Sciences.
(12) (a) Aıssa, C. J. Org. Chem. 2005, 71, 360. (b) Giesbrecht, H. E.;
Knight, B. J.; Tanguileg, N. R.; Emerson, C. R.; Blakemore, P. R.
Synlett 2010, 374.
(13) (a) Olah, G. A.; Prakash, G. K. S.; Sommer, J.; Molnar, A.
Superacid Chemistry, 2nd ed.; Wiley: New York, 2009. (b) Lawrence, R. M.;
Biller, S. A.; Dickson, J. K.; Logan, J. V. H.; Magnin, D. R.; Sulsky, R. B.;
DiMarco, J. D.; Gougoutas, J. Z. B.; Beyer, D.; Kunselman, S.; Taylor, C.;
Lan, S.-J.; Ciosek, C. P.; Harrity, T. W.; Jolibois, K. G.; Slusarchyk, L. K. D.
A. J. Am. Chem. Soc. 1996, 118, 11668. (c) Enders, D.; Saeidian, H.;
Mirjafary, Z.; Iffland, D.; Raabe, G.; Rusink, J. Synlett 2009, 2872 and
references cited therein.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX