Gold(I)-catalyzed hydration of alkynylphosphonates: Efficient access to β-ketophosphonates

Article abstract of DOI:10.1002/ejoc.201400066

A general, efficient, and highly regioselective protocol with the use of a gold(I) complex catalytic system for the transformation of alkynylphosphonates into the corresponding β-ketophosphonates has been successfully developed. This method produces a variety of β-ketophosphonates with the advantages of mild reaction conditions, high functional-group tolerance, and excellent yields. An efficient and mild gold-catalyzed hydration process for the regioselective synthesis of β-ketophosphonates directly from alkynylphosphonates is described. Twenty-two examples with yields of 85-97 % are reported. Different substituents including substituted aryl, alkyl, chloro, ester, sulfonoxyl, and phthalimide groups are tolerated; XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, Tf = trifluoromethylsulfonyl. Copyright

Full text of DOI:10.1002/ejoc.201400066

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400066
Gold(I)-Catalyzed Hydration of Alkynylphosphonates: Efficient Access to
β-Ketophosphonates
Longyong Xie,[a] Rui Yuan,[a] Ruijia Wang,[a] Zhihong Peng,[a] Jiannan Xiang,*[a] and
Weimin He*[a]
Keywords: Synthetic methods / Gold / Hydration / Phosphonates / Alkynes / Ketophosphonates
A general, efficient, and highly regioselective protocol with
the use of a gold(I) complex catalytic system for the transfor-
mation of alkynylphosphonates into the corresponding β-
ketophosphonates has been successfully developed. This
method produces a variety of β-ketophosphonates with the
advantages of mild reaction conditions, high functional-
group tolerance, and excellent yields.
β-Ketophosphonate derivatives are extremely valuable
carbonyl compounds that exhibit a variety of biological ac-
tivities[13] and outstanding metal-complexing abilities.[14]
They also serve as useful building blocks in organic synthe-
sis,[15] especially as intermediates for the formation of α,β-
unsaturated carbonyl compounds[16] and chiral β-
hydroxy[17] and β-amino[18] phosphonic acids. To date, there
have been numerous reported methods for the synthesis of
β-ketophosphonate derivatives,[19] but there are still calls for
novel methods, especially those that are performed under
mild conditions with high functional-group tolerance. On
the basis of our continuing interest in the construction of
various α-functionalized carbonyl compounds through
gold-catalyzed reactions,[12,20] herein we present a mild and
highly efficient method for the synthesis of β-ketophos-
phonates.
Introduction
Over the past several decades, gold catalysis has emerged
to become a powerful tool enabling the creation of numer-
ous novel organic transformations.[1] Among these gold-fa-
cilitated transformations, those concerning the catalytic hy-
dration of unactivated alkynes have received much atten-
tion, as they can yield the corresponding Markovnikov
products with complete atom economy under mild reaction
conditions and with the use of water as a cheap and safe
oxygen resource. The first example of the gold-catalyzed hy-
dration of alkynes was reported in 1991 by Fukuda and
Utimoto.[2] Twenty years later, there was a breakthrough in
this field with the independent discovery of efficient gold-
catalyzed hydration reactions by the groups of Hayashi,[3]
Laguna,[4] Schmidbaur,[5] Nolan,[6] Hammond,[7] Corma,[8]
and others.[9] Various types of alkyne substrates have been
used with gold catalysts[10] in hydration reactions, and the
corresponding dialkyl or alkylaryl ketones were ob-
tained.[11] It is surprising, however, that examples of the
gold-catalyzed hydration of α-heteroatom-substituted alk-
ynes are still limited. Very recently, we first reported the
gold-catalyzed hydration of haloalkynes to synthesize α-
halomethyl ketones.[12] To further explore and expand the
utility of gold catalysis in hydration reactions and to pro-
vide potential access to important α-functionalized carb-
onyl compounds, it is necessary to broaden the scope of α-
substituted alkynes.
Results and Discussion
Our initial work focused on diethyl (phenylethynyl)phos-
phonate (1a), which was subjected to a solution of
[21]
Ph3PAuNTf2
(2.5 mol-%, Tf = trifluoromethylsulfonyl)
and H2O (1–5 equiv.) in 1,2-dichloroethane (DCE), and the
reaction was then run for 12 h at room temperature. Diethyl
(2-oxo-2-phenylethyl)phosphonate (2a) was obtained in
73% yield according to NMR spectroscopy (Table 1, en-
try 1). Then, we tuned the steric and electronic properties
of the gold catalyst (Table 1, entries 2–9). Gratifyingly, the
use of XPhosAuNTf2 (2.5 mol-%, XPhos = 2-dicyclohex-
ylphosphino-2Ј,4Ј,6Ј-triisopropylbiphenyl) bearing a bulky
ligand in DCE resulted in a sharp increase in the yield
(Table 1, entry 8). Other gold catalysts worked equally well
(Table 1, entries 6, 7, and 9). In the presence of 1.75 and
1 mol-% XPhosAuNTf2, the catalytic hydration of 1a gave
2a in 76 and 51% yield, respectively, as determined by
[a] State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan
University,
Changsha 410082, People’s Republic of China
E-mail: wmhe@hnu.edu.cn
jnxiang@hnu.edu.cn
http://cc.hnu.cn/index.php?option=com_content&task=
view&id=2050&Itemid=230
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400066.
2668
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2668–2671

Gold(I)-Catalyzed Hydration of Alkynylphosphonates
NMR spectroscopy (Table 1, entries 10 and 11). In addition with substrates bearing bioactive groups such as piperonyl
to DCE, methanol and THF afforded the products as well, and thienyl also proceeded smoothly (see 2i and 2j). If or-
albeit in lower yields (Table 1, entries 12–16). To confirm tho-substituted (phenylethynyl)phosphonates such as di-
that gold was the true catalyst of the reaction, a series of ethyl [2-oxo-2-(o-tolyl)ethyl]phosphonate and diethyl [2-(2-
control experiments were performed. No hydration product bromophenyl)-2-oxoethyl]phosphonate were used, only
was detected if the reaction was performed under similar trace amounts of the desired products were observed, likely
conditions without a gold catalyst (Table 1, entries 17–19). due to steric hindrance. Many synthetically important sub-
Therefore, the optimized reaction conditions are the follow- stituent groups including alkyl (see 2k), chloro (see 2l), ester
ing: alkynylphosphonate (1 equiv.), H2O (3 equiv.), XPho- (see 2m), sulfonoxyl (see 2n), silyl ether (see 2o), and phthal-
sAuNTf2 (2.5 mol-%) in DCE at room temperature for 12 h imide groups (see 2p) were well tolerated with excellent
(Table 1, entry 8).
yields of the desired isolated products. Interestingly, the
presence of bulky groups (cyclopropyl, cyclohexenyl, and
cyclohexyl groups) in the 3-position of the alkylalkyne had
no negative effect on the efficiency of the transformation
(see 2q–s). By using other phosphonates as substrates, this
alkyne hydration strategy was extended to access the corre-
sponding β-ketophosphonates (see 2t–v).
Table 1. Screening of the optimized reaction conditions.[a]
Entry Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
Ph3PAuNTf2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
CH3OH
THF
CH3CN
DMF
DCE
DCE
DCE
73
82
65
61
85
90
92
98[d]
98
76[e]
51[f]
86
85
72
–
[c]
(RO)3PAuNTf2
Cy3PAuNTf2
Et3PAuNTf2
IPrAuNTf2
MePhosAuNTf2
SPhosAuNTf2
XPhosAuNTf2
BrettphosAuNTf2
XPhosAuNTf2
XPhosAuNTf2
XPhosAuNTf2
XPhosAuNTf2
XPhosAuNTf2
Conclusions
In summary, we developed a simple method for the gold-
catalyzed regioselective hydration of alkynylphosphonates.
β-Ketophosphonates were prepared in high yields under
milder conditions than with other catalytic systems. No-
tably, functional groups such as halogen atom, ester, sul-
fonoxyl, silyl ether, and phthalimide groups were readily
carried through the hydration reaction, which allowed sub-
sequent elaboration of the products.
9
10
11
12
13
14
15
16
17
18
19
XPhosAuNTf2
XPhosAuNTf2
–
–
–
–
AgSbF6 (r.t. to 85 °C)[g]
AgNTf2 (r.t. to 85 °C)[g]
[g]
HNTf2
Experimental Section
[a] In a vial; [1a] = 0.1 m. Cy = cyclohexyl, IPr = 1,3-bis(2,6-diisop-
ropylphenyl)-2,3-dihydro-1H-imidazole, MePhos = 2-(dicyclohex-
General Procedure for the Synthesis of 2a–v: To a solution of alk-
ynylphosphonate (0.3 mmol) in DCE (3 mL) was added H2O
(0.9 mmol, 16.2 mg) and XPhosAuNTf2 (0.0075 mmol, 6.7 mg).
The reaction mixture was stirred at room temperature, and the pro-
gress of the reaction was monitored by TLC. The reaction typically
took 12 h. Upon completion of the reaction, the mixture was con-
centrated, and the residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate) to afford 2a–v.
ylphosphino)-2Ј-methylbiphenyl, SPhos
= 2-(dicyclohexylphos-
phino)-2Ј,6Ј-dimethoxybiphenyl, BrettPhos = dicyclohexyl[3,6-di-
methoxy-2Ј,4Ј,6Ј-tris(1-methylethyl)-1,1Ј-biphenyl-2-yl]phosphine.
1
[b] Estimated by H NMR spectroscopy by using diethyl phthalate
as an internal reference. [c] R = 2,4-(tBu)2Ph. [d] Yield of isolated
product was 96%. [e] 1.75 mol-% XphosAuNTf2 was used; 19% of
1a remained unreacted. [f] 1 mol-% XPhosAuNTf2 was used; 45%
of 1a remained unreacted. [g] 10 mol-% catalyst was used.
Supporting Information (see footnote on the first page of this arti-
cle): General information; general procedures for the synthesis of
2a–v; spectral data for 2a–v; references; and 31P NMR, H NMR,
1
and 13C NMR spectra of 2a–v.
After optimizing the reaction conditions, we explored the
substrate scope, and the results are illustrated in Table 2.
The outcome of this hydration reaction was found to be
only slightly influenced by the electronic properties of the
diethyl (phenylethynyl)phosphonates, and a variety of β-
ketophosphonates substituted with electron-donating or
electron-withdrawing groups were readily synthesized in ex-
cellent yields (see 2b–h). The bromine atom was compatible
with this reaction sequence by providing a handle for fur-
ther functionalization (see 2f and 2h). The conversion rate
of 1c and 1d were slow under the optimized conditions, and
10% of the substrates was recovered after the reaction was
Acknowledgments
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (grant number 21302048), the Specialized
Research Fund for the Doctoral Program of Higher Education
(grant number 20130161120035), the China Postdoctoral Science
Foundation (grant number 2013M540625), the Hunan Provincial
Natural Science Foundation of China (grant number 14JJ7028),
and the Department of Science and Technology Foundation of Hu-
allowed to run overnight. It is remarkable that reactions nan Province (grant number 2010FJ306).
Eur. J. Org. Chem. 2014, 2668–2671
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2669

L. Xie, R. Yuan, R. Wang, Z. Peng, J. Xiang, W. He
SHORT COMMUNICATION
Table 2. Substrate scope.[a,b]
[a] [1] = 0.1 m. [b] Yield of isolated product. [c] 90% conversion of 1. [d] Ts = p-tolylsulfonyl, TBDPS = tert-butyldiphenylsilyl, Phth =
phthalyl. [e] 93% conversion of 1.
108, 3351–3378; g) A. S. K. Hashmi, M. Rudolph, Chem. Soc.
[1] a) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. Int. Ed.
2006, 45, 7896–7936; Angew. Chem. 2006, 118, 8064–8105; b)
R. A. Widenhoefer, X. Han, Eur. J. Org. Chem. 2006, 4555–
4563; c) L. Zhang, J. Sun, S. A. Kozmin, Adv. Synth. Catal.
2006, 348, 2271–2296; d) A. Fürstner, P. W. Davies, Angew.
Chem. Int. Ed. 2007, 46, 3410–3449; Angew. Chem. 2007, 119,
3478–3519; e) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180–
3211; f) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008,
Rev. 2008, 37, 1766–1775; h) R. Skouta, C.-J. Li, Tetrahedron
2008, 64, 4917–4938; i) S. M. Abu Sohel, R.-S. Liu, Chem. Soc.
Rev. 2009, 38, 2269–2281; j) P. Belmont, E. Parker, Eur. J. Org.
Chem. 2009, 6075–6089; k) S. P. Nolan, Acc. Chem. Res. 2010,
43, 91–100; l) S. Wang, G. Zhang, L. Zhang, Synlett 2010, 692–
706; m) A. S. K. Hashmi, Angew. Chem. Int. Ed. 2010, 49,
5232–5241; Angew. Chem. 2010, 122, 5360–5369; n) C. Aubert,
L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau, Chem.
2670
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2668–2671

Gold(I)-Catalyzed Hydration of Alkynylphosphonates
Rev. 2011, 111, 1954–1993; o) M. Bandini, Chem. Soc. Rev. [13] a) C. Balg, S. P. Blais, S. Bernier, J. L. Huot, M. Couture, J.
2011, 40, 1358–1367; p) A. Corma, A. Leyva-Pérez, M. J. Sab-
ater, Chem. Rev. 2011, 111, 1657–1712; q) T. de Haro, C. Nev-
ado, Synthesis 2011, 2530–2539; r) H. Huang, Y. Zhou, H. Liu,
Beilstein J. Org. Chem. 2011, 7, 897–936; s) N. Krause, C. Win-
ter, Chem. Rev. 2011, 111, 1994–2009; t) H. A. Wegner, M. Au-
zias, Angew. Chem. Int. Ed. 2011, 50, 8236–8247; Angew. Chem.
Lapointe, R. Chênevert, Bioorg. Med. Chem. 2007, 15, 295–
304; b) S. K. Perumal, S. A. Adediran, R. F. Pratt, Bioorg.
Med. Chem. 2008, 16, 6987–6994.
[14] a) F. A. Cotton, R. A. Schunn, J. Am. Chem. Soc. 1963, 85,
2394–2402; b) D. J. McCabe, E. N. Duesler, R. T. Paine, Inorg.
Chem. 1985, 24, 4626–4629.
2011, 123, 8386–8397; u) M. Rudolph, A. S. K. Hashmi, Chem. [15] a) A. Kondoh, H. Yorimitsu, K. Oshima, Chem. Asian J. 2010,
Commun. 2011, 47, 6536–6544; v) J. Xiao, X. Li, Angew. Chem.
Int. Ed. 2011, 50, 7226–7236; Angew. Chem. 2011, 123, 7364–
7375; w) H. V. Adcock, P. W. Davies, Synthesis 2012, 44, 3401–
3420; x) C. C. J. Loh, D. Enders, Chem. Eur. J. 2012, 18, 10212–
10225; y) M. Rudolph, A. S. K. Hashmi, Chem. Soc. Rev. 2012,
41, 2448–2462.
5, 398–409; b) Y. Zhou, G. Wang, Y. Saga, R. Shen, M. Goto,
Y. Zhao, L.-B. Han, J. Org. Chem. 2010, 75, 7924–7927; c) Y.
Zhou, S. Yin, Y. Gao, Y. Zhao, M. Goto, L.-B. Han, Angew.
Chem. Int. Ed. 2010, 49, 6852–6855; Angew. Chem. 2010, 122,
7004–7007; d) C.-K. Pei, L. Wu, Z. Lian, M. Shi, Org. Biomol.
Chem. 2012, 10, 171–180; e) Y. Li, S. Das, S. Zhou, K. Junge,
M. Beller, J. Am. Chem. Soc. 2012, 134, 9727–9732; f) W. De-
brouwer, T. S. A. Heugebaert, K. Van Hecke, C. V. Stevens, J.
Org. Chem. 2013, 78, 8232–8241; g) W. Yang, Y. Yu, T. Zhang,
M. M. Hansmann, D. Pflästerer, A. S. K. Hashmi, Adv. Synth.
Catal. 2013, 355, 2037–2043.
[2] Y. Fukuda, K. Utimoto, J. Org. Chem. 1991, 56, 3729–3731.
[3] a) E. Mizushima, K. Sato, T. Hayashi, M. Tanaka, Angew.
Chem. Int. Ed. 2002, 41, 4563–4565; Angew. Chem. 2002, 114,
4745–4747; b) C. Zhang, D.-M. Cui, L.-Y. Yao, B.-S. Wang,
Y.-Z. Hu, T. Hayashi, J. Org. Chem. 2008, 73, 7811–7813.
[4] a) R. Casado, M. Contel, M. Laguna, P. Romero, S. Sanz, J.
Am. Chem. Soc. 2003, 125, 11925–11935; b) S. Sanz, L. A.
Jones, F. Mohr, M. Laguna, Organometallics 2007, 26, 952–
957.
[16] a) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863–927;
b) S. V. Pronin, A. Martinez, K. Kuznedelov, K. Severinov,
H. A. Shuman, S. A. Kozmin, J. Am. Chem. Soc. 2011, 133,
12172–12184; c) S. Müller, T. Mayer, F. Sasse, M. E. Maier,
Org. Lett. 2011, 13, 3940–3943; d) A. S. K. Hashmi, T. Wang,
S. Shi, M. Rudolph, J. Org. Chem. 2012, 77, 7761–7767.
[17] a) M. Kitamura, M. Tokunaga, R. Noyori, J. Am. Chem. Soc.
1995, 117, 2931–2932; b) M. Á. Chávez, S. Vargas, A. Suárez,
E. Álvarez, A. Pizzano, Adv. Synth. Catal. 2011, 353, 2775–
2794.
[18] A. Ryglowski, P. Kafarski, Tetrahedron 1996, 52, 10685–10692.
[19] a) A. J. Poss, R. K. Belter, J. Org. Chem. 1987, 52, 4810–4812;
b) T. Calogeropoulou, G. B. Hammond, D. F. Wiemer, J. Org.
Chem. 1987, 52, 4185–4190; c) E. J. Corey, S. C. Virgil, J. Am.
Chem. Soc. 1990, 112, 6429–6431; d) S. D. Guile, J. E. Saxton,
M. Thornton-Pett, J. Chem. Soc. Perkin Trans. 1 1992, 1763–
1767; e) M. R. R. S. Todd, A. H. Davidson, WO 9322321, 1993
[Chem. Abstr. 1994, 120, 245504]; f) T. J. Baker, D. F. Wiemer,
J. Org. Chem. 1998, 63, 2613–2618; g) G. P. Luke, C. K. Seek-
amp, Z.-Q. Wang, B. L. Chenard, J. Org. Chem. 2008, 73,
6397–6400; h) K. M. Maloney, J. Y. L. Chung, J. Org. Chem.
2009, 74, 7574–7576; i) R. R. Milburn, K. McRae, J. Chan, J.
Tedrow, R. Larsen, M. Faul, Tetrahedron Lett. 2009, 50, 870–
872; j) W. Wei, J.-X. Ji, Angew. Chem. Int. Ed. 2011, 50, 9097–
9099; Angew. Chem. 2011, 123, 9263–9265; k) X. Li, G. Hu, P.
Luo, G. Tang, Y. Gao, P. Xu, Y. Zhao, Adv. Synth. Catal. 2012,
354, 2427–2432.
[5] a) P. Roembke, H. Schmidbaur, S. Cronje, H. Raubenheimer,
J. Mol. Catal. A: Chem. 2004, 212, 35–42; b) H. Schmidbaur,
A. Schier, Organometallics 2010, 29, 2–23.
[6] a) N. Marion, R. n. S. Ramón, S. P. Nolan, J. Am. Chem. Soc.
2009, 131, 448–449; b) P. Nun, S. Dupuy, S. Gaillard, A. Poater,
L. Cavallo, S. P. Nolan, Catal. Sci. Technol. 2011, 1, 58–61; c)
P. Nun, R. S. Ramón, S. Gaillard, S. P. Nolan, J. Organomet.
Chem. 2011, 696, 7–11.
[7] W. Wang, B. Xu, G. B. Hammond, J. Org. Chem. 2009, 74,
1640–1643.
[8] a) A. Leyva, A. Corma, J. Org. Chem. 2009, 74, 2067–2074; b)
J. Oliver-Meseguer, J. R. Cabrero-Antonino, I. Domínguez, A.
Leyva-Pérez, A. Corma, Science 2012, 338, 1452–1455.
[9] a) A. Almássy, C. E. Nagy, A. C. Bényei, F. Joó, Organometal-
lics 2010, 29, 2484–2490; b) N. Ghosh, S. Nayak, A. K. Sahoo,
J. Org. Chem. 2010, 76, 500–511; c) M. Lein, M. Rudolph,
S. K. Hashmi, P. Schwerdtfeger, Organometallics 2010, 29,
2206–2210; d) C. E. Czégéni, G. Papp, Á. Kathó, F. Joó, J.
Mol. Catal. A 2011, 340, 1–8; e) E. Tomás-Mendivil, P. Y. Toul-
lec, J. Díez, S. Conejero, V. Michelet, V. Cadierno, Org. Lett.
2012, 14, 2520–2523; f) X. Xu, S. H. Kim, X. Zhang, A. K.
Das, H. Hirao, S. H. Hong, Organometallics 2013, 32, 164–171;
g) E. Tomás-Mendivil, P. Y. Toullec, J. Borge, S. Conejero, V.
Michelet, V. Cadierno, ACS Catal. 2013, 3, 3086–3098.
[10] A. S. K. Hashmi, Science 2012, 338, 1434.
[11] For a recent example of gold-catalyzed alcoholysis, see: M. C.
Blanco Jaimes, C. R. N. Böhling, J. M. Serrano-Becerra,
A. S. K. Hashmi, Angew. Chem. Int. Ed. 2013, 52, 7963–7966;
Angew. Chem. 2013, 125, 8121–8124.
[12] L. Xie, Y. Wu, W. Yi, L. Zhu, J. Xiang, W. He, J. Org. Chem.
2013, 78, 9190–9195.
[20] a) W. He, L. Xie, Y. Xu, J. Xiang, L. Zhang, Org. Biomol.
Chem. 2012, 10, 3168–3171; b) L. Xie, Z. Liang, D. Yan, W.
He, J. Xiang, Synlett 2013, 24, 1809–1812; c) C. Wu, Z. Liang,
D. Yan, W. He, J. Xiang, Synthesis 2013, 45, 2605–2611.
[21] N. Mézailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133–
4136.
Received: January 15, 2014
Published Online: March 17, 2014
Eur. J. Org. Chem. 2014, 2668–2671
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2671