Copper-mediated oxidative cross-coupling reaction of terminal alkynes with α-silyldifluoromethylphosphonates: An efficient method for α,α-difluoropropargylphosphonates

Article abstract of DOI:10.1021/ol301113v

A copper-mediated oxidative cross-coupling reaction of terminal alkynes with readily available α-silyldifluoromethylphosphonates under mild conditions has been developed. This method allows for an efficient synthesis of a series of synthetically useful α,α-difluoropropargylphosphonates with excellent functional group compatibility.

Full text of DOI:10.1021/ol301113v

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2870–2873
Copper-Mediated Oxidative Cross-
Coupling Reaction of Terminal Alkynes
with r-Silyldifluoromethylphosphonates:
An Efficient Method for
r,r-Difluoropropargylphosphonates
Xueliang Jiang,† Lingling Chu,† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China and College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University,
2999 North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received April 25, 2012
ABSTRACT
A copper-mediated oxidative cross-coupling reaction of terminal alkynes with readily available R-silyldifluoromethylphosphonates under mild
conditions has been developed. This method allows for an efficient synthesis of a series of synthetically useful R,R-difluoropropargylphos-
phonates with excellent functional group compatibility.
Phosphonates are of great importance by virtue of their
similarity to phosphates.1 Inrecentyears, there has beenan
increasing interest in the development of fluorinated
phosphonates2 due to the unique properties that fluorine
imparts on organic molecules.3 Amongthem, difluoropho-
sphonates have gained special attention because of their
potentialasanaloguesof biologicallyimportant phosphate
esters and utilization in the design and development of new
drugs.4
† Shanghai Institute of Organic Chemistry
‡ Donghua University
(1) Engel, R. Chem. Rev. 1977, 77, 349.
Generally, difluorophosphonates can be prepared by
direct electrophilic fluorination of phosphonate carba-
nions5 or DAST-promoted nucleophilic fluorination of
R-oxophosphonates.6 The addition of a phosphonodi-
fluoromethyl radical onto alkenes, alkynes, and unsatu-
rated ketones has also been developed.7 Furthermore, the
nucleophilic displacement,8 nucleophilic addition,9 or
transtion-metal-mediated cross-coupling reaction10 of
metalated difluoromethylphosphonates ((EtO)2P(O)CF2M;
M = Li, ZnBr, MgCl, CdBr) has been extensively inves-
tigated. Although these methods have been widely used in
(2) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868.
(3) For recent reviews, see: (a) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, 2004. (b) Uneyama, K. Organofluorine
Chemistry; Blackwell: Oxford, U.K., 2006. (c) Ojima, I. Fluorine in
Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chichester,
U.K., 2009. (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(e) Hird, M. Chem. Soc. Rev. 2007, 36, 2070. (f) Kirk, K. L. Org. Process
Res. Dev. 2008, 12, 305. (g) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(h) Ritter, S. K. Chem. Eng. News 2012, 90, 10.
(4) (a) Halazy, S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991,
113, 315. (b) Hebel, D.; Kirk, K. L.; Kinjo, J.; Kovacs, T.; Lesiak, K.;
ꢀ
Balzarini, J.; De Clercq, E.; Torrence, P. F. Bioorg. Med. Chem. Lett.
1991, 1, 357. (c) Ye, B.; Burke, T. R., Jr. Tetrahedron 1996, 52, 9963. (d)
Gautier-Lefebvre, I.; Behr, J.-B.; Guillerm, G.; Ryder, N. S. Bioorg.
Med. Chem. Lett. 2000, 10, 1483. (e) Cox, R. J.; Hadfield, A. T.; Mayo-
Martin, M. B. Chem. Commun. 2001, 1710. (f) Yokomatsu, T.; Murano,
T.; Akiyama, T.; Koizumi, J.; Shibuya, S.; Tsuji, Y.; Soeda, S.; Shimeno,
H. Bioorg. Med. Chem. Lett. 2003, 13, 229. (g) Cushman, M.; Sambaiah,
T.; Jin, G.; Illarionov, B.; Fischer, M.; Bacher, A. J. Org. Chem. 2004, 69,
601. (h) Mandal, P. K.; Liao, W. S. L.; McMurray, J. S. Org. Lett. 2009,
11, 3394.
€
(5) (a) Differding, E.; Duthaler, R. O.; Krieger, A.; Ruegg, G. M.;
Schmit, C. Synlett 1991, 395. (b) Taylor, S. D.; Kotoris, C. C.; Dinaut,
A. N.; Chen, M.-J. Tetrahedron 1998, 54, 1691. (c) Hum, G.; Lee, J.;
Taylor, S. D. Bioorg. Med. Chem. Lett. 2002, 12, 3471. (d) Ladame, S.;
ꢀ ꢀ
Willson, M.; Perie, J. Eur. J. Org. Chem. 2002, 2640.
r
10.1021/ol301113v
Published on Web 05/15/2012
2012 American Chemical Society

the preparation of a variety of difluorophosphonates, they
are limited by some combination of expensive reagents, the
incompatibility of functional groups, and restricted syn-
thetic applications. The current synthetic methods have
been applied mainly for the preparation of alkyldifluor-
ophosphonates and aryldifluorophosphonates. A method
for the construction of functionalized difluorophospho-
nate derivatives such as R,R-difluoropropargylphospho-
nates has not been well developed.
into organic molecules. Recently, the copper-mediated
oxidative trifluoromethylation developed by our group
has facilitated the direct and efficient synthesis of a wide
range of trifluoromethylated compounds.11 Specifically,
this protocol allows the direct installation of a trifluoro-
methyl group in place of CÀH bonds without the need for
prefunctionalized substrates.11a,c,e Encouraged by these
results, we anticipated that a similar copper-mediated
CÀH oxidation protocol might allow for the preparation
of difluorophosphonate analogues. Herein, we describe
the first example of a copper-mediated oxidative cross-
coupling reaction of teminal alkynes with R-silyldifluor-
omethylphosphonates (Scheme 1c). This reaction provides
a novel and direct methodology for the preparation of R,R-
difluoropropargylphosphonates bearing a wide range of
functional groups by employing readily available R-
silyldifluoromethylphosphonates.
To test our hypothesis, the initial investigation focused
on the reaction of phenylacetylene 1a with (EtO)2P(O)-
CF2SiMe312a 2a under the optmized conditions of copper-
mediated trifluoromethylation of terminal alkynes.11a
However, when the reaction was run using stoichiometric
amounts of CuI, 1,10-phenthroline, and KF under air
none of the desired product, 3a, was observed. Instead
dimer 4a and (EtO)2P(O)CF2H 5a were obtained (Table 1,
entry 1). Lowering the reaction temperature did not inhibit
the decomposition of (EtO)2P(O)CF2SiMe3 2a and the
formation of homocoupling product 4a (entry 1).
To achieve this transformation, we evaluated a series of
oxidantsand foundthata significant amountof the desired
product 3a was observed when the reaction was carried out
with PhI(OAc)2 (entries 2À5). Since the base is known to
have a profound effect on transmetalations and cross-
coupling reactions, we investigated the influence of the
base. It was found that t-BuOK gave the highest yield of
product 3a (entries 6À10). Switching to other bases such as
K2CO3, K3PO4, or t-BuONa led to a dramatic decrease in
yield (entries 6À10). Various copper salts were found to
mediate this transformation, while CuI proved to be better
than other copper salts (entries 11À14). Considering
the effectiveness of PhI(OAc)2 as the oxidant, a series of
other hypervalent iodine reagents such as PhI(OPiv)2 and
R,R-Difluoropropargylphosphonates were originally
recognized as a new type of difluorophosphonate by
Hammond in 1996.6c These compounds would be highly
useful as versatile synthetic intermediates to various bio-
logically important difluorophosphonates through conver-
sion of the triple bond into other functional groups.6c,d,10d,e
Hammond first reported the preparation of R,R-difluor-
opropargylphosphonates via nucleophilic fluorination
of R-ketophosphonates, but this method required the use of
limitedly stable R-ketophosphonates and a large excess of
the fluorinating reagent (Scheme 1a).6c,d Later, Burton
and co-workers developed a copper-mediated cross-
coupling reaction of propargyl halides and (EtO)2P(O)-
CF2ZnBr, providing an alternative method for the
preparation of these compounds (Scheme 1b).10d,e A path-
way involving (EtO)2P(O)CF2Cu species generated in situ
was proposed for this copper-mediated cross-coupling
reaction. This method is useful and practical but requires
prefunctionalized alkynyl substrates and metalated
difluoromethylphosphonates. Therefore, the development
of direct and efficient methods for the preparation of R,
R-difluoropropargylphosphonates is still highly desirable.
Scheme 1. Preparation of R,R-Difluoropropargylphosphonates
(8) (a) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J. Org.
Chem. 1993, 58, 6174. (b) Vinod, T. K.; Hayes Griffith, O.; Keana,
J. F. W. Tetrahedron Lett. 1994, 35, 7193. (c) Berkowitz, D. B.; Sloss,
D. G. J. Org. Chem. 1995, 60, 7047. (d) Matulic-Adamic, J.; Haeberli, P.;
Usman, N. J. Org. Chem. 1995, 60, 2563. (e) Berkowitz, D. B.; Bhuniya,
D.; Peris, G. Tetrahedron Lett. 1999, 40, 1869.
(9) (a) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemaker, R. K.
J. Org. Chem. 1996, 61, 4666. (b) Piettre, S. R.; Girol, C.; Schelcher,
C. G. Tetrahedron Lett. 1996, 37, 4711. (c) Blades, K.; Lapotre, D.;
Percy, J. M. Tetrahedron Lett. 1997, 38, 5895. (d) Blades, K.; Percy, J. M.
Tetrahedron Lett. 1998, 39, 9085.
Fluoroalkyl cross-coupling has been proven to be
an efficient strategy to introduce the fluoroalkyl moiety
^
(6) (a) Smyth, M. S.; Burke, T. R., Jr. Tetrahedron Lett. 1994, 35, 551.
(b) Solas, D.; Hale, R. L.; Patel, D. V. J. Org. Chem. 1996, 61, 1537. (c)
Benayoud, F.; Hammond, G. B. Chem. Commun. 1996, 1447. (d) Wang,
Z.; Gu, Y.; Zapata, A. J.; Hammond, G. B. J. Fluorine Chem. 2001, 107,
127.
(10) (a) Weiming, Q.; Burton, D. J. Tetrahedron Lett. 1996, 37, 2745.
(b) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S. J. Org. Chem.
1996, 61, 7207. (c) Yokomatsu, T.; Murano, T.; Suemune, K.; Shibuya,
S. Tetrahedron 1997, 53, 815. (d) Zhang, X.; Burton, D. J. Tetrahedron
Lett. 2000, 41, 7791. (e) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2002,
116, 15. (f) Feng, Z.; Chen, F.; Zhang, X. Org. Lett. 2012, 14, 1938.
(11) (a) Chu, L. L.; Qing, F. L. J. Am. Chem. Soc. 2010, 132, 7262. (b)
Chu, L. L.; Qing, F. L. Org. Lett. 2010, 12, 5060. (c) Chu, L. L.; Qing,
F. L. J. Am. Chem. Soc. 2012, 134, 1298. (d) Jiang, X. L.; Chu, L. L.;
Qing, F. L. J. Org. Chem. 2012, 77, 1251. (e) Chu, L. L.; Qing, F. L. Org.
Lett. 2012, 14, 2106.
(7) (a) Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676. (b) Li,
A.-R.; Chen, Q.-Y. Synthesis 1996, 606. (c) Lequeux, T.; Lebouc, F.;
Lopin, C.; Yang, H.; Gouhier, G.; Piettre, S. R. Org. Lett. 2000, 3, 185.
(d) Ozouf, P.; Binot, G.; Pommelet, J.-C.; Lequeux, T. P. Org. Lett. 2004,
ꢁ
6, 3747. (e) Sene, A.; Diab, S.; Hienzsch, A.; Cahard, D.; Lequeux, T.
Synlett 2009, 981.
Org. Lett., Vol. 14, No. 11, 2012
2871

Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Copper-Mediated Oxidative Cross-Coupling Reaction
of Terminal Alkynes with R-Silyldifluoromethylphosphonatesa
yield
(%)b
entry
[Cu]
base
KF
oxidant
1c
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
air
none
trace
trace
trace
22
KF
DDQ
3
KF
Ag2CO3
4
KF
Cu(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OPiv)2
PhI(O2CCF3)2
DDQ
5
KF
6
K3PO4
K2CO3
t-BuOLi
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
none
none
trace
36
7
8
9
10
11
12
13
14
15
16
17
18d
19e
20
21f
22g
71
[Cu(OTf)]2 C6H6
53
3
CuCl
CuBr
Cu(OAc)2
CuI
60
68
44
54
CuI
11
CuI
98
CuI
CuI
DDQ
97
DDQ
19
/
DDQ
none
none
none
CuI
DDQ
CuI
DDQ
a Reaction conditions: 1a (0.1 mmol), 2a (3.0 equiv), copper salt (1.0
equiv), phen (1.0 equiv), base (4.0 equiv), oxidant (2.0 equiv), DMF (1.0
mL), ethanol-ice bath (À15 °C). b Yield was determined by 19F NMR
using fluorobenzene as an internal standard. c The reaction was con-
ducted at 80 °C or À15 °C. d 1.5 equiv of DDQ. e In the absence of 1,10-
phenanthroline. f All reagents were mixed simultaneouly. g 1a was pre-
mixed with CuI, 1,10-phenanthroline, and t-BuOK followed by addition
of 2a and DDQ
a Reaction was conducted on a 0.4 mmol scale under the optimal
conditions of entry 18 in Table 1. Isolated yield.
DMF at À15 °C followed by the addition of (EtO)2P(O)-
CF2SiMe3 2a and DDQ (entry 22). These results prompted
us to hypothesize that (EtO)2P(O)CF2Cu species might be
involved in this process. (EtO)2P(O)CF2Cu species, which is
most commonly generated from (EtO)2P(O)CF2ZnBr, has
been generally suggested as the key intermediate in the
copper-mediated cross-coupling reaction of metalated
difluoromethylphosphonates.10 However, to the best of
our knowledge, the use of (EtO)2P(O)CF2SiMe3 as the
precursor to the (EtO)2P(O)CF2Cu species has not been
reported, despite the availability, stability, convenience of
handling, and wide applications of R-silyldifluorophospho-
nates as equivalents of difluorinated carbonions.12 Further
studies will be needed to support the possibility of (EtO)2P-
(O)CF2Cu intermediates.
PhI(O2CCF3)2 were examined (entries 15À16). However,
when the reactions were conducted with PhI(OPiv)2 or
PhI(O2CCF3)2 much lower yields were obtained compared
to when PhI(OAc)2 was used (entries 10, 15À16). Interest-
ingly, the best yield of 3a was obtained when t-BuOK and
DDQ were employed as the base and oxidant (entry 17).
This result was surprising to us because DDQ was found to
be completely ineffective when used in combination with
KF (entry 2). Decreasing the quantity of DDQ from 2.0 to
1.5 equiv had no significant effect on the yield of product
3a (entry 18). Both copper salts and ligands were essential
for this transformation (entries 19À20).
With the optimal reaction conditions in hand, we next
examined the substrate scope of the oxidative cross-coupling
The mode of addition of reagents was critical to achieving
a high yield of product 3a: (EtO)2P(O)CF2SiMe3 2a should
be injected into the mixture of CuI, 1,10-phenanthroline,
t-BuOK, and DMF at À15 °C, followed by the addition
of phenylacetylene 1a and DDQ (entries 17À18). When all
of the reagents were mixed simultaneously, no product
was observed (entry 21). Moreover, no detectable amount
of products was formed when phenylacetylene was added
to the mixture of CuI, 1,10-phenanthroline, t-BuOK, and
(12) (a) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard,
J. A. K. Tetrahedron 1996, 52, 165. (b) Martynov, B. I.; Stepanov,
A. A. J. Fluorine Chem. 1997, 85, 127. (c) Kolomeitsev, A. A.; Kadyrov,
A. A.; Szczepkowska-Sztolcman, J.; Milewska, M.; Koroniak, H.;
€
Bissky, G.; Barten, J. A.; Roschenthaler, G.-V. Tetrahedron Lett.
2003, 44, 8273. (d) Alexandrova, A. V.; Beier, P. J. Fluorine Chem.
2009, 130, 493. (e) Kosobokov, M. D.; Dilman, A. D.; Struchkova, M. I.;
Belyakov, P. A.; Hu, J. J. Org. Chem. 2012, 77, 2080.
2872
Org. Lett., Vol. 14, No. 11, 2012

reaction between terminal alkynes 1 and R-silyldifluoro-
methylphosphonates 2 (Scheme 2). A variety of aryl alkynes
bearing electron-donating and electron-withdrawing groups
can be transformed into the desired products in moderate
yields (3bÀ3j). Many functional groups, including cyano,
ester, and nitro, were well-tolerated in the reaction (3f,
3hÀ3i). Notably, chloro or bromo containing substrates
were compatible with the reaction, enabling further trans-
formations via transition-metal-catalyzed cross-coupling re-
actions (3dÀ3e). The heterocyclic alkyne as well as the
aliphatic alkyne was also effective in this reaction, producing
the desired products in moderate yields (3lÀ3m).
In summary, a copper-mediated oxidative cross-
coupling reaction between terminal alkynes and R-silyldi-
fluoromethylphosphonates was developed, affording a
series of synthetically useful R,R-difluoropropargylpho-
sphonates in moderate yields. Due to the high functional
group tolerance and mild conditions of our methodology,
and the potential of difluorophosphonates as biologically
activeagents, we expect this procedure willbe useful for the
synthesis of this class of compounds.
Acknowledgment. National Natural Science Founda-
tion of China (21072028, 20832008) and National Basic
Research Program of China (2012CB21600) are gratefully
acknowledged for funding this work.
The reaction scope was also investigated with respect to
the R-silyldifluoromethylphosphonate coupling partner
under the optimized conditions (Scheme 2). A series of
different R-silyldifluoromethylphosphonates, including
diisopropyl difluoro(trimethylsilyl)methylphosphonate 2b,
dibutyl difluoro(trimethylsilyl)methylphosphonates 2c, and
O,O-diethyl difluoro(trimethylsilyl)methylphosphonothioate
2d, are effective, and all reactions afforded the corresponding
products in moderate yields (3nÀ3p).
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
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. 11, 2012
2873