Copper catalyzed cross-coupling of iodobenzoates with bromozinc- difluorophosphonate

Article abstract of DOI:10.1021/ol3006425

A copper-catalyzed cross-coupling of iodobenzoates with bromozinc-difluorophosphonate, generated from diethyl bromodifluoromethylphosphonate and zinc in dioxane, is reported. The notable features of this reaction are its high reaction efficiency, excellen

Full text of DOI:10.1021/ol3006425

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1938–1941
Copper Catalyzed Cross-Coupling
of Iodobenzoates with Bromozinc-
difluorophosphonate
Zhang Feng, Fei Chen, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xgzhang@mail.sioc.ac.cn
Received March 13, 2012
ABSTRACT
A copper-catalyzed cross-coupling of iodobenzoates with bromozinc-difluorophosphonate, generated from diethyl bromodifluoro-
methylphosphonate and zinc in dioxane, is reported. The notable features of this reaction are its high reaction efficiency, excellent functional
group compatibility, and operational simplicity. This protocol provides a useful and facile access to aryldifluorophosphonates of interest in
life science.
Owing to the unique properties of the fluorinated func-
tional groups that often lead to pronounced activity en-
hancement of pharmaceuticals and agrochemicals,1 fluor-
ined compounds have gained extensive attention. Among
them, aryldifluorophosphonates constitute a distinct class
of fluorinated compounds. Because the difluoromethylene
group (CF2) can act as an isopolar-isosteric substitute for
oxygen, and replacement of the phosphoryl ester oxygen
with CF2 leads to a nonhydrolyzable phosphate mimetic,2
such difluorinated structures exhibit significant bioactiv-
ities as protein tyrosine phosphatase (PTP) inhibitors and
have been used as valuable tools for drug discovery and
development.3 However, compared to the fluorination4
and trifluoromethylation5 of organic substrates, strategies
for incorporation of the CF2 group into organic molecules
has been less explored.6 Generally, aryldifluorophospho-
nates can be prepared by difluorination of unstable
benzilic R-oxophosphonates with DAST,7electrophilic
fluorination of phosphonates,3a,8 and copper-mediated
cross-coupling between aryl halides and metalated
difluoromethylphosphonates.9 Despite the utility of these
methods, the requirement of multiple steps, functional
group incompatibility, and use of expensive fluorinated
(1) For recent reviews, see: (a) Smart, B. E. J. Fluorine Chem. 2001,
109, 3. (b) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93. (c) Special
issue on “Fluorine in the Life Sciences”: ChemBioChem 2004, 5, 557. (d)
(5) For a review, see: Tomashenko, O. A.; Grushin, V. V. Chem. Rev.
2011, 111, 4475.
€
Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (e) Purser,
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Rev. 2006, 106, 3868. (b) Burke, T. R., Jr.; Lee, K. Acc. Chem. Res. 2003,
36, 426. (c) Zhang, Z.-Y. Acc. Chem. Res. 2003, 36, 385. For selected
recent papers, see: (d) Hikishima, S.; Hashimoto, M.; Magnowska, L.;
Bzowska, A.; Yokomatsu, T. Bioorg. Med. Chem. Lett. 2010, 18, 2275.
(e) Mandal, P. K.; Liao, W. S.-L.; McMurray, J. S. Org. Lett. 2009, 11,
3394. (f) Mitra, S.; Barrios, A. M. ChemBioChem 2008, 9, 1216.
(4) For selected reviews, see: (a) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470. (b) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160.
(c) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929.
(6) For selected examples, see: (a) Zhang, X.; Xia, H.; Dong, X.; Jin,
J.; Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2003, 68, 9026. (b) Chu,
L. L.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11, 2197. (c) Hu, J.; Zhang,
W.; Wang, F. Chem. Commun. 2009, 7465. (d) Li, Y.; Hu, J. Angew.
Chem., Int. Ed. 2005, 44, 5882. (e) Fujikawa, K.; Fujioka, Y.; Kobayashi,
A.; Amii, H. Org. Lett. 2011, 13, 5560. (f) 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.
(7) (a) Smyth, M. S.; Burke, T. R. Tetrahedron Lett. 1994, 35, 551.
(b) Solas, D.; Hale, R. L.; Patel, D. V. J. Org. Chem. 1996, 61, 1537.
(8) Taylor, S. D.; Kotoris, C. C.; Dinaut, A. N.; Chen, M.-J.
Tetrahedron 1998, 54, 1691.
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1997, 53, 815.
r
10.1021/ol3006425
Published on Web 03/21/2012
2012 American Chemical Society

reagents or a large excess of copper restrict their wide-
spread synthetic applications. From the point of view
of new practical and environmentally benign processes, a
transition-metal-catalyzed reaction would be an attractive
alternative.
Given that a carboxylate ester is important and synthe-
tically useful as well as can function as a directing group,
we began this study by choosing methyl 2-iodobenzoate 1a
as a model substrate to test our hypothesis. Initially,
according to Shibuya’s conditions,9b a room temperature
reaction of 1a with bromozinc-difluorophosphonate 2,
generated from diethyl bromodifluoromethylphosphonate
and zinc in DMF, in the presence of catalytic amount of
CuBr (10 mol %) was investigated (Table 1, entry 1).
However, only a trace amount of desired product 3a was
observed. Considering that ethereal solvents benefit the
formation of 2,12 and diamine ligands can stabilize the
soluble copper complexes by chelation and increase elec-
tron density at the copper center, we assumed that the use
of dioxane as a solvent and 1,10-phenanthroline (phen) as
a ligand may prevent decomposition of I to a difluoropho-
sphonate radical13 and improve the reaction efficiency. As
expected, a 72% yield (determined by 19F NMR) of 3 was
afforded, when the reaction was carried out in dioxane
with CuBr (10 mol %) and phen (20 mol %) at 50 °C
(Table 1, entry 2). With a further increase in reaction
temperature to 60 °C, a higher yield (94%, determined
by 19F NMR) was provided (Table 1, entry 3). The absence
of copper failed to give any desired product (Table 1, entry 4),
thus implying that a copper catalyst was involved in the
catalytic cycle. Encouraged by these results, a variety of
copper catalysts and solvents were examined. Among the
copper catalysts tested, CuI was found to be the optimum
catalyst, providing 3a in 95% isolated yield (Table 1, entry 9),
although other copper catalysts, such as CuBr2, CuCl,
CuCl2, and Cu(OAc)2, underwent the reaction smoothly
(Table 1, entries 5À8). These findingsclearly demonstrated
that the present reaction is not sensitive to the nature of
copper catalysts. However, the choice of solvent is crucial
for the reaction efficiency. DMF and DMA led to a trace
amount of 3a, even in the presence of phen (Table 1, entries
10À11), which is in sharp contrast to previous results.9b
Other solvents, suchasDMPU, DMSO, and diglyme, were
less effective than dioxane (Table 1, entries 12À14).
The absence of phen led to a diminished yield (Table 1,
entry 16), indicating that a diamine ligand also plays an
important role in the copper catalytic cycle.
Several years ago, Shibuya and co-workers developed a
copper-mediated cross-coupling of aryl iodides with bro-
mozinc-difluorophosphonate for the synthesis of aryldi-
fluorophosphonates.9b This reaction is significant and
useful but requires a stoichiometric amount of CuBr. An
attempt to reduce the loading of CuBr proved that copper
could not catalyze the reaction, and a single electron
transfer (SET) mechanism via a difluorophosphonate
radical was proposed for this copper mediated cross-
coupling.9b In our continuing efforts to develop transi-
tion-metal-catalyzed reactions for introduction of fluori-
nated functional groups into organic molecules,10 we
hypothesized that if installing a directing group ortho to
the iodide to chelate and direct delivery of organocopper
complex I,11 the oxidative addition of copper to the
aryl iodides would be facilitated, and thus the copper-
catalyzed cross-coupling of aryl iodides with meta-
lated difluoromethylphosphonate would be possible
(Scheme 1). Herein, we present the first example of
copper-catalyzed cross-coupling of iodobenzoates with
bromozinc-difluorophosphonate. This reaction provides
a convenient protocol for the preparation of aryldifluor-
ophosphonates with high efficiency and excellent func-
tional group compatibility.
Scheme 1. Cross-Coupling of Aryl Iodides with Bromozinc-
difluorophosphonate
On the basis of the above observations, methyl 4-iodo-
benzoate 5 was also tested (Scheme 2). However, no more
than a 20% yield of desired product 6 was observed, when
(11) The organocopper complex I has been characterized; see:
(a) Sprague, L. G.; Burton, D. J.; Guneratne, R. D.; Bennett, W. E.
J. Fluorine Chem. 1990, 49, 75. (b) Yokomatsu, T.; Suemune, K.;
Murano, T.; Shibuya, S. J. Org. Chem. 1996, 61, 7207.
(12) Burton, D. J.; Ishihara, T.; Maruta, M. Chem. Lett. 1982, 755.
(13) The organocopper complex I decomposes slowly in DMF to give
many products via a difluorophosphonate radical and carbene process
at room temperature. See ref 11b.
(14) General procedure for copper-catalyzed cross-coupling of iodo-
benzoates with bromozinc-difluorophosphonate: To a stirred suspen-
sion of Zn dust (1.0 mmol) in dioxane (2 mL) was added
bromodifluoromethanephosphonate (1.0 mmol) under N2. After stir-
ring for 3 h at 60 °C, the resulting mixture was cooled to room
temperature, and CuI (0.1 equiv) and phen (0.2 equiv) were added.
The reaction mixture was then stirred at the same temperature for
30 min, and iodobenzoate 1 (0.5 mmol) was added. The reaction was
warmed to 60 °C and stirred for 24À48 h.
(10) (a) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132,
12850. (b) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.;
Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (c) Fan, S.; Chen, F.;
Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 5918. (d) Fan, S.; Yang, J.;
Zhang, X. Org. Lett. 2011, 13, 4374. (e) Fan, S.; He, C.-Y.; Zhang, X.
Chem. Commun. 2010, 46, 4926. (f) Chen, F.; Feng, Z.; He, C.-Y.; Wang,
H.-Y.; Guo, Y.-L.; Zhang, X. Org. Lett. 2012, 14, 1176.
Org. Lett., Vol. 14, No. 7, 2012
1939

Table 1. Optimization of Copper-Catalyzed Cross-Coupling of
Methyl 2-Iodobenzoate 1a with Bromozinc-difluorophospho-
nate 2a
Scheme 3. Copper-Catalyzed Cross-Coupling of Iodobenzoates 1
with Bromozinc-difluorophosphonatea
temp
yield
(%)b
entry
CuX
CuBr
solvent
(°C)
1c
2
DMF
25
50
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
trace
72
CuBr
CuBr
none
CuBr2
CuCl
CuCl2
Cu(OAc)2
CuI
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
3
94
4
NR
94
5
6
88
7
89
8
80
9
98 (95)
trace
trace
39
10
11
12
13
14
15d
16c
17e
CuI
CuI
DMA
CuI
DMPU
DMSO
diglyme
dioxane
dioxane
dioxane
CuI
20
CuI
48
CuI
90
CuI
79
CuI
85
a Reaction conditions (unless otherwise specified): 1a (0.5 mmol), 4
(2.0 equiv), Zn (2.0 equiv), solvent (2 mL), 24 h. b NMR yield determined
by 19F NMR using fluorobenzene as an internal standard (isolated yield
in parentheses). c Reaction run in the absence of phen. d Using 0.1 equiv
of phen. e Using 1.5 equiv of 4 and 1.5 equiv of Zn.
a Reaction conditions (unless otherwise specified): 1 (0.5 mmol), 4
(2.0 equiv), Zn (2.0 equiv), CuI (0.1 equiv), phen (0.2 equiv), in dioxane
(2 mL) at 60 °C.bUsing 0.4 equiv of CuI and 0.4 equiv of phen. cReaction
run in 2-g scale.
groups, including ester, nitro, amide, bromide, and iodide,
thus providing opportunities for further transformations.
2-g-scale reactions of 3k and 3m were also performed in
good yields (3k, 64% yield; 3m, 70% yield), indicating the
good reliability of the process. Importantly, the heterocycle,
pyridine, was also a suitable substrate, although 0.4 equiv of
CuI was required (Scheme 3, 3n), which is in sharp contrast
to previous results that nitrogen-containing heterocycles
could not furnish the corresponding products.15
0.2 equiv of CuI and 0.2 equiv of phen were used. Further
screening of different 1,10-phenanthroline derivatives and
bipyridyl ligands led to similar results (see Table S1 in the
Supporting Information), thus suggesting that the ortho-
effect of the carboxylate ester in the substrates is essential
to the reaction efficiency.
To further demonstrate the utility of this protocol,
transformations of 3k and 3m were conducted. As shown
in Scheme 4, the phenylation of 3k and alkynylation of 3m
provide rapid access to diversified aryldifluorophospho-
nates. Furthermore, the triple CÀC bond in compound 3m
offers a unique and highly valuable opportunity for further
synthetic transformations of interest in drug discovery and
development.
Scheme 2. Cross-Coupling of Methyl 4-Iodobenzoate 5 with
Bromozinc-difluorophosphonate 2
To gain some mechanistic insights into the present
reaction, the following experiments were performed
(Table 2). The reaction carried out in the absence of
ambient light had little influence on the reaction efficiency
(Table 2, entry 2). The addition of nitrobenzene (1.0 equiv)
Under the optimum reaction conditions (Table 1,
entry 9),14 the substrate scope of the cross-coupling of
iodobenzoates 1 with bromozinc-difluorophosphonate 2,
generated from diethyl bromodifluoromethylphosphonate
and zinc in dioxane, was examined, and the representative
results are illustrated in Scheme 3.
(15) Cockerill, G. S.; Easterfield, H. J.; Percy, J. M.; Pintat, S.
J. Chem. Soc., Perkin Trans. 1 2000, 2591.
(16) (a) Wakselman, C.; Tordeux, M. J. Chem. Soc., Chem. Commun.
1987, 1701. (b) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13,
5464.
The present method allowed the preparation of aryldi-
fluorophosphonates containing a range of functional
1940
Org. Lett., Vol. 14, No. 7, 2012

the high reaction efficiency, excellent functional group
compatibility, and the ease of conducting such reactions,
this protocol provides a useful and facile access to aryldi-
fluorophosphonates of interest in life science.
Scheme 4. Transformations of 3k and 3m
Table 2. Effects of Additives on Copper-Catalyzed Cross-
Coupling of Iodobenzoate with Bromozinc-difluorophosphonate
previously demonstrated to be an inhibitor of SET steps16
had a negligible impact on the yield of this reaction
(Table 2, entry 3). While the addition of a radical scavenger
TEMPO (1.0 equiv) or a radical initiator AIBN (0.2 equiv)
led to diminished yields (Table 2, entries 4À5), this is
probably because organocopper complex I is prone to
decompose to difluorophosphonate radical.13 The addi-
tion of a radical initiatior or a scavenger could accelerate
the decomposition of the key intermediate I and affect the
copper catalytic cycle illustrated in Scheme 1; as a result,
lower yields of 3a were observed. Thus, on the basis of
these preliminary results, a pure SET mechanism via a
difluorophosphonate radical is not involved in the present
copper catalytic cycle, and the proposed mechanism shown
in Scheme 1 is possible. Further studies of the detailed
mechanism are in progress.
entry
additive (equiv)
yield (%)a
1
2
3
4
5
ambient light
dark
98
94
95
55
55
PhNO2 (1.0)
TEMPO (1.0)
AIBN (0.2)
a NMR yield determined by 19F NMR using fluorobenzene as an
internal standard.
Acknowledgment. The National Basic Research Pro-
gram of China (973 Program (No. 2012CB821600)), the
NSFC (Nos 20902100, 20832008, 21172242), and SIOC
are greatly acknowledged for funding this work.
In conclusion, the first example of copper-catalyzed
cross-coupling of iodobenzoates with bromozinc-difluor-
ophosphonates has been demonstrated. The directing
group benzoate ester and solvent effect play important
roles in the reaction efficiency. Application of the method
leads to diversified aryldifluorophosphonates. Because of
Supporting Information Available. Detailed experimen-
tal procedures, and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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