Gold(I)-catalyzed addition of diphenyl phosphate to alkynes: Isomerization of kinetic enol phosphates to the thermodynamically favored isomers

Article abstract of DOI:10.1002/anie.201001799

(Chemical Equation Presented) Gold, gold, or... gold? It depends on the (gold) catalyst whether the product of thermodynamic or kinetic control is formed in an unprecedented hydrophosphoryloxylation approach to enol phosphates (see scheme). A third catalyst, [(C₆F₅) ₃PAuOTf], was found to be exceedingly effective for the previously unknown isomerization of kinetic enol phosphates to the thermodynamically favored isomers. Tf=trifluoromethanesulfonyl; R=alkyl, cyclohexyl, Ph.

Full text of DOI:10.1002/anie.201001799

Communications
DOI: 10.1002/anie.201001799
Gold Catalysis
Gold(I)-Catalyzed Addition of Diphenyl Phosphate to Alkynes:
Isomerization of Kinetic Enol Phosphates to the Thermodynamically
Favored Isomers**
Phil Ho Lee,* Sundae Kim, Aeri Park, Bathoju Chandra Chary, and Sunggak Kim*
Dedicated to Professor Masakatsu Shibasaki
The conversion of carbonyl compounds into enol phosphates
is of a great synthetic importance, since enol phosphates are
versatile intermediates which undergo various synthetically
useful transformations.[1] A general method for the prepara-
tion of enol phosphates involves the quenching of lithium
enolates with dialkyl phosphorochloridates.[2] The major issue
in this transformation is selectivity (kinetic versus thermody-
namic). In particular, the more substituted thermodynamic
enol derivatives from unsymmetrical ketones normally pre-
dominate under thermodynamic conditions but do not form
Scheme 1. Formation of kinetic enol phosphates and the thermody-
exclusively, which is a serious problem in organic synthesis.
Thus, the preparation of thermodynamic enol phosphates
namically more stable isomers. L1 and L2 are ligands.
with high selectivity is of synthetic importance and still a very
challenging problem.[2b,3] Herein, we report the gold-cata-
lyzed addition of diphenyl phosphate to terminal alkynes as
an unprecedented approach for the preparation of both
kinetic and thermodynamic enol phosphates (Scheme 1).[4,5]
We also disclose the gold-catalyzed isomerization of enol
phosphates, produced under kinetic control, to the much less
accessible thermodynamically favored enol phosphates.
To examine the feasibility of the hydrophosphoryloxyla-
tion of alkynes, we began our study with the catalyst
[Ph3PAuCl]/AgOTf.[6] We found that the reaction was very
sensitive to the solvent. Among the solvents tested, toluene
gave the best result. When the reaction was carried out with
1-octyne and diphenyl phosphate in dichloromethane, nitro-
methane, acetonitrile, or ethanol at room temperature for
15 h, it did not proceed to give an observable amount of the
product, whereas the reaction in toluene afforded the
thermodynamic enol phosphate product 2 in 48% yield
along with the Markovnikov addition product 1 (10%).
Evidently, 2 was produced by the isomerization of 1.
Encouraged by this preliminary result, we carried out
several experiments to control selectivity by the fine-tuning of
the ligands attached to gold. The reaction did not occur in the
presence of a catalytic amount of AuCl3, AuCl3/AgOTf, or
AuCl3/AgPF6 (Table 1, entries 1–3), and [(NHC)AuCl] com-
=
plexes (NHC N-heterocyclic carbene) were totally ineffec-
tive (entries 4 and 5).[7] Of various silver cocatalysts exam-
ined, AgPF6 was the most effective. When it was used in
combination with the catalyst [Ph3PAuCl], enol phosphate 1
was formed selectively in 88% yield (Table 1, entry 11).
AgBF4 was slightly less effective (Table 1, entry 8). Somewhat
surprisingly, the selectivity was completely reversed with
[(C6F5)3PAuCl]/AgOTf,[8] which produced the thermody-
namic product 2 in 88% yield without any of the anti-
Markovnikov product (Table 1, entry 12). Apparently, the
reaction proceeded through the addition of diphenyl phos-
phate to alkynes in a Markovnikov fashion, followed by
isomerization. To check the possibility of catalysis by a protic
acid, we attempted the reaction in the presence of triflic acid
(5 mol%) in toluene at room temperature and at 1108C.
Under these conditions, the reaction did not proceed (Table 1,
entry 13).
[*] Prof. Dr. P. H. Lee, Dr. S. Kim, A. Park
Department of Chemistry, Kangwon National University
Chuncheon 200-701 (Republic of Korea)
Fax: (+82)33-253-7582
E-mail: phlee@kangwon.ac.kr
Homepage: http://indium.kangwon.ac.kr
B. C. Chary, Prof. Dr. S. Kim
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: sgkim@ntu.edu.sg
[**] P.H.L. acknowledges financial support from the National Research
Foundation of Korea (NRF) through the NRL Program, an NRFgrant
funded by the Korean government (MEST; 2009-0087013), and the
2nd phase BK 21 program. S.K. acknowledges financial support
from Nanyang Technological University.
To explore the scope of the reaction with respect to the
alkyne substrate, we carried out further reactions in toluene
with [Ph3PAuCl]/AgPF6 (5 mol%; Table 2). The reaction of
3-phenyl-1-propyne proceeded well without the Friedel–
Crafts cyclization (Table 2, entry 2). 3-Cyclohexyl-1-propyne
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001799.
6806
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 6806 –6809

Angewandte
Chemie
Table 1: Reaction optimization.[a]
the desired products in good yields; however, these reactions
required heating at 608C (Table 2, entries 8–10). Diphenyl
phosphate underwent a clean regioselective addition to
benzylthioacetylene (Table 2, entry 11). Similarly, the addi-
tion of diphenyl phosphate to activated alkynes, such as ethyl
propiolate and ethyl phenylpropiolate, occurred by trans
addition in a regio- and stereoselective manner (Table 2,
entries 12 and 13). Dialkyl and alkyl, aryl-substituted alkynes
were much less reactive than terminal and activated alkynes
and required heating at reflux (1108C) for a long period of
time (Table 2, entries 14 and 15).
We next turned our attention to the direct preparation of
thermodynamic enol phosphates through hydrophosphory-
loxylation and subsequent isomerization with the
[(C6F5)3PAuCl]/AgOTf catalyst. The present method was
effective with both 3-phenyl-1-propyne and 5-phenyl-1-pen-
tyne: the corresponding enol phosphates were formed
selectively at room temperature (Table 3, entries 3 and 4).
Entry
Catalyst
Yield [%]
1
2
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
AuCl3
<1
<1
<1
0
0
0
0
0
0
AuCl3/AgOTf[b]
[b]
AuCl3/AgPF6
[(IPr)AuCl]/AgPF6
[(IMes)AuCl]/AgPF6
[Ph3PAuCl]/AgOTf
[Ph3PAuCl]/AgSbF6
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgAsF6
[Ph3PAuCl]/AgNTf2
[Ph3PAuCl]/AgPF6
[(C6F5)3PAuCl]/AgOTf
TfOH
0
10
<1
72
12
<1
88
4
48 (1:3.8)[c]
0
0
14 (1:3.7)[c]
0
0
88 (1:3)[c]
0
0
[a] Reactions were carried out with 5 mol% of the Au catalyst and
5 mol% of the Ag cocatalyst. [b] The reaction was carried out with
15 mol% of the Ag cocatalyst. [c] E/Z ratio. [d] Reactions were carried
out with TfOH (5 mol%) at RT for 24 h and at 1108C for 10 h. IPr=N,N’-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IMes=N,N’-bis(2,4,6-tri-
methylphenyl)imidazol-2-ylidene, Tf=trifluoromethanesulfonyl.
Table 3: Preparation of thermodynamically favored enol phosphates.[a]
Entry
R
Yield [%]
1
n-C5H11
c-C6H11
Ph
Ph(CH2)2
Cl(CH2)2
86 (1:35;[b] 1:2.6[c])
93 (1:17; 1:1.8)
87 (0:100; 1:3.6)
85 (1:25; 1:2)
2[d]
3
reacted smoothly with diphenyl phosphate in the presence of
[Ph3PAuCl]/AgPF6 to provide the desired product in 80%
yield (Table 2, entry 4). A chloro and a bromo group on the
propargylic carbon atom were tolerated under these reaction
conditions (Table 2, entries 5 and 6). The reaction of 5-chloro-
1-pentyne gave the Markovnikov addition product selectively
in 78% yield (Table 2, entry 7). Phenylacetylene and deriv-
atives containing substituents with diverse electronic proper-
ties on the aromatic ring, such as a trifluoromethyl or n-pentyl
group, all reacted smoothly with diphenyl phosphate to afford
4
5
86 (1:17; 1:2.6)
[a] Reactions were carried out with 5 mol% of the Au catalyst and
5 mol% of the Ag cocatalyst at room temperature for 24 h. [b] Ratio of
kinetic and thermodynamic isomers. [c] E/Z ratio. [d] The reaction was
carried out at 808C for 24 h.
The
treatment
of
3-cyclohexyl-1-propyne
with
[(C6F5)3PAuCl]/AgOTf in toluene at 808C for 24 h provided
the thermodynamic enol phosphate in 93% yield (Table 3,
entry 2). When 5-chloro-1-pentyne was subjected to the
reaction conditions, the thermodynamic enol phosphate was
obtained in 86% yield (Table 3, entry 5). In all cases, the ratio
of the thermodynamic to the kinetic isomer was at least 17:1.
Finally, we examined the previously unknown conversion
of kinetically formed enol phosphates into the thermody-
namically favored enol phosphates. [(C6F5)3PAuOTf] was
found to be slightly more efficient than [(C6F5)3PAuCl]/
AgOTf for the isomerization (Table 4, entries 1 and 2). The
kinetic enol phosphate derived from 2-butanone and diethyl
chlorophosphate was completely isomerized in toluene at
708C to the thermodynamic product in 87% yield within 2 h
(Table 4, entry 1). Furthermore, the isomerization was also
complete in 15 h at room temperature (Table 4, entry 3). To
check whether a protic acid participates in the isomerization,
we repeated the reaction in the presence of allyltrimethylsi-
lane (10 mol%). We observed a similar result, indicative of
the sole participation of [(C6F5)3PAuOTf] (Table 4, entry 4).[9]
Additional acyclic kinetic enol phosphates underwent smooth
isomerization to afford the thermodynamically favored
Table 2: Preparation of kinetic enol phosphates.[a]
Entry
R1
R2
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
7
8
n-C6H13
PhCH2
Ph(CH2)3
c-C6H11CH2
ClCH2
BrCH2
Cl(CH2)3
Ph
H
H
H
H
H
H
H
H
RT
RT
RT
RT
RT
RT
RT
60
9
9
9
17
15
16
7
12
17
8
88
87
81
80
70
92
78
88
80
95
98
84
78
72
69
9
4-CF3-C6H4
4-nPent-C6H4
PhCH2S
H
Ph
Et
H
H
H
CO2Et
CO2Et
Et
60
60
10
11
12
13
14
15
RT
RT
60
110
110
2
10
10
15
10
Me
Ph
[a] Reactions were carried out with 5 mol% of the Au catalyst and
5 mol% of the Ag cocatalyst.
Angew. Chem. Int. Ed. 2010, 49, 6806 –6809
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6807

Communications
Table 4: Isomerization of kinetic enol phosphates to the thermodynami-
cally favored enol phosphates with [(C6F5)3PAuOTf].[a]
Experimental Section
Typical procedure: 1-Octyne (66.0 mg, 0.6 mmol) was added to a
suspension of [Ph3PAuCl] (12.4 mg, 0.025 mmol), AgPF6 (6.3 mg,
0.025 mmol), and diphenyl phosphate (125.0 mg, 0.5 mmol) in toluene
(2 mL) at room temperature by using a V Vial, and the resulting
mixture was stirred at room temperature for 9 h. The solvent was then
removed under reduced pressure, and the crude product was purified
by silica-gel column chromatography (EtOAc/hexane 1:5) to give
oct-1-en-2-yl diphenyl phosphate (159.0 mg, 88%) as a colorless
liquid. IR (film): n˜ = 3071, 2931, 2859, 1940, 1864, 1783, 1726, 1659,
Entry
Reactant
T [8C]
t [h]
Product
Yield [%][b]
1
70
70
RT
70
2
2
15
2
87 (0:100)[c]
84 (1:25)
87 (1:36)
90 (1:29)
2[d]
3
4[e]
5
6
7
8
70
2
4
3
3
96 (0:100)
86 (1:26)
88 (1:34)
90 (1:21)
1560, 1591, 1490, 958, 688 cmÀ1 1H NMR (400 MHz, CDCl3, 258C,
;
TMS): d = 7.37–7.33 (m, 4H), 7.25–7.19 (m, 6H), 4.93 (t, J = 2.2 Hz,
1H), 4.59 (t, J = 2.0 Hz, 1H), 2.19 (t, J = 7.6 Hz, 2H), 1.44 (quint, J =
7.4 Hz, 2H), 1.31–1.19 (m, 6H), 0.87 ppm (t, J = 6.9 Hz, 3H);
70
13C NMR (100 MHz, CDCl3, 258C, TMS): d = 155.9 (d, JC,P
=
9.5 Hz), 150.5 (d, JC,P = 7 Hz), 129.8, 125.5, 120.1 (d, JC,P = 5 Hz),
98.0 (d, JC,P = 4 Hz), 34.3 (d, JC,P = 5.4 Hz), 31.5, 28.4, 26.1, 22.5,
14.1 ppm; HRMS (EI): m/z calcd for C20H25O4P: 360.1490 [M]+;
found: 360.1488.
100
100
Received: March 26, 2010
Revised: June 16, 2010
Published online: August 4, 2010
[a] Reactions were carried out with 5 mol% of the catalyst
[(C6F5)3PAuOTf]. [b] The ratio of the reactant to the product is given in
parentheses. [c] The E/Z ratio for this reaction was 1:2. [d] The reaction
was carried out with [(C6F5)3PAuCl] (5 mol%) and AgOTf (5 mol%).
[e] The reaction was carried out in the presence of allyltrimethylsilane
(10 mol%).
Keywords: alkynes · gold · homogeneous catalysis ·
isomerization · phosphates
.
[1] See, for example: a) J. Wu, Z. Yang, J. Org. Chem. 2001, 66, 7875;
b) J. A. Miller, Tetrahedron Lett. 2002, 43, 7111; c) F. L. Galbo,
E. G. Occhiato, A. Guarna, C. Faggi, J. Org. Chem. 2003, 68,
6360; d) J. Y. Onishi, T. Takuwa, T. Mukaiyama, Chem. Lett.
2003, 32, 994; e) E. G. Occhiato, F. L. Galbo, A. Guarna, J. Org.
Chem. 2005, 70, 7324; f) U. S. Larsen, L. Martiny, M. Begtrup,
Tetrahedron Lett. 2005, 46, 4261; g) A. L. Hansen, J.-P. Ebran,
T. M. Gogsig, T. Skrydstrup, Chem. Commun. 2006, 4137;
h) A. L. Hansen, J.-P. Ebran, M. Ahlquist, P.-O. Norrby, T.
Skrydstrup, Angew. Chem. 2006, 118, 3427; Angew. Chem. Int.
Ed. 2006, 45, 3349; i) A. L. Hansen, J.-P. Ebran, T. M. Gogsig, T.
Skrydstrup, J. Org. Chem. 2007, 72, 6464; j) J.-P. Ebran, A. L.
Hansen, T. M. Gogsig, T. Skrydstrup, J. Am. Chem. Soc. 2007,
129, 6931; k) P. Cheruku, S. Gohil, P. G. Andersson, Org. Lett.
2007, 9, 1659; l) G. Cahiez, O. Gager, V. Habiak, Synthesis 2008,
2636; m) S. Protti, M. Fagnoni, Chem. Commun. 2008, 3611;
n) A. T. Lindhardt, T. M. Gogsig, T. Skrydstrup, J. Org. Chem.
2009, 74, 135; o) D. Gauthier, S. Beckendorf, T. M. Gogsig, A. T.
Lindhardt, T. Skrydstrup, J. Org. Chem. 2009, 74, 3536; p) P. G.
Steel, T. M. Wood, Synthesis 2009, 3897.
isomers (Table 4, entries 5 and 6). The isomerization of cyclic
kinetic enol phosphates to the thermodynamically preferred
isomers proceeded cleanly but required higher reaction
temperatures for completion (Table 4, entries 7 and 8).
Mechanistically, the isomerization reaction would proceed
via the oxocarbenium intermediate A, the deprotonation of
which could yield the more thermodynamically stable enol
phosphate 2 (Scheme 2).[10]
[2] For examples of enolate formation, see: a) H. B. Mekelburger,
C. S. Wilcox in Comprehensive Organic Synthesis, Vol. 2 (Ed.:
B. M. Trost), Pergamon, Oxford, 1991, pp. 99 – 131; b) D. L.
Boger in Modern Organic Synthesis, TSRI, La Jolla, 1999,
pp. 147 – 206; c) W. Carruthers, I. Coldham in Modern Methods
of Organic Synthesis, Cambridge University Press, Cambridge,
2004, pp. 9 – 19.
[3] M. E. Krafft, R. A. Holton, Tetrahedron Lett. 1983, 24, 1345.
[4] The ruthenium-catalyzed addition of diphenylphosphinic acid
(Ph2P(O)OH) to terminal alkynes was reported previously;
however, the reaction was unsuccessful with diphenyl phosphate
((PhO)2P(O)OH): R. Hua, M. Tananka, Chem. Lett. 1998, 431.
[5] For reviews on metal-catalyzed reactions of alkynes, see: a) T. E.
Mꢀller, M. Beller, Chem. Rev. 1998, 98, 675; b) F. Alonso, I. P.
Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079; c) C. Bruneau,
P. H. Dixneuf, Angew. Chem. 2006, 118, 2232; Angew. Chem. Int.
Ed. 2006, 45, 2176; d) Y. Yamamoto, J. Org. Chem. 2007, 72,
7817.
Scheme 2. Proposed mechanism of the isomerization reaction.
In summary, we have developed a gold(I)-catalyzed
hydrophosphoryloxylation of alkynes with diphenyl phos-
phate, whereby the catalyst [Ph3PAuCl]/AgPF6 affords the
kinetic enol phosphates exclusively, whereas the catalyst
[(C6F5)3PAuCl]/AgOTf gives the thermodynamically favored
enol phosphates with high selectivity. Furthermore, kinetic
enol phosphates were isomerized to the thermodynamically
favored isomers with [(C6F5)3PAuOTf]. Further studies on the
isomerization of alkenyl derivatives with [(C6F5)3PAuCl]/
AgOTf are underway.
6808 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 6806 –6809

Angewandte
Chemie
[6] For reviews on gold catalysis, see: a) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int.
Ed. 2006, 45, 7896; b) A. S. K. Hashmi, Chem. Rev. 2007, 107,
3180; c) A. S. K. Hashami, Chem. Soc. Rev. 2008, 37, 1766; d) Z.
Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239; e) A. Arcadi,
Chem. Rev. 2008, 108, 3266; f) N. Patil, Y. Yamamoto, Chem.
Rev. 2008, 108, 3395; g) H. C. Shen, Tetrahedron 2008, 64, 3885;
h) J. Muzart, Tetrahedron 2008, 64, 5815; i) R. Skouta, C.-J. Li,
Tetrahedron 2008, 64, 4917; j) A. S. K. Hashmi, M. Rudolph,
Chem. Soc. Rev. 2008, 37, 1766.
[7] a) P. de Fremont, N. M. Scott, E. D. Stevens, S. P. Nolan,
Organometallics 2005, 24, 2411; b) R. Dorta, E. D. Stevens,
N. M. Scott, C. Costabile, L. Cavallo, C. D. Hoff, S. P. Nolan, J.
Am. Chem. Soc. 2005, 127, 2485.
[8] a) C. Nieto-Oberhuber, S. Lopez, A. M. Echavarren, J. Am.
Chem. Soc. 2005, 127, 6178; b) S. Shin, Bull. Korean Chem. Soc.
2005, 26, 1925; c) C. Nieto-Oberhuber, M. P. Munoz, S. Lopez, E.
Jimenez-Nunez, C. Nevado, E. Herrero-Gomez, M. Raducan,
A. M. Echavarren, Chem. Eur. J. 2006, 12, 1677; d) C. Lim, J.-E.
Kang, J.-E. Lee, S. Shin, Org. Lett. 2007, 9, 3539; e) H. J. Bae, B.
Baskar, S. E. An, J. Y. Cheong, D. T. Thangadurai, I.-C. Hwang,
Y. H. Rhee, Angew. Chem. 2008, 120, 2295; Angew. Chem. Int.
Ed. 2008, 47, 2263; f) M.-Z. Wang, M.-K. Wong, C.-M. Che,
Chem. Eur. J. 2008, 14, 8353; g) S. S. Gunatilleke, A. M. Barrios,
J. Inorg. Chem. 2008, 102, 555; h) B. Baskar, H. J. Bae. S. E. An,
J. A. Cheong. Y. H. Rhee, A. Duschek, S. F. Kirsch, Org. Lett.
2008, 10, 2605.
[9] We found that triflic acid was effective for the isomerization of
kinetic enol phosphonates to the thermodynamically favored
isomers. For example, the treatment of but-1-en-2-yl diethyl
phosphate with triflic acid (5 mol%) in toluene at room
temperature for 1 h afforded the thermodynamic enol phos-
phate. Studies on the triflic acid catalyzed isomerization of enol
derivatives are under way and will be reported in due course.
[10] a) Y. Peng, L. Cui, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2009,
131, 5062; b) G. Li, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2008,
130, 3740; c) C. H. M. Amijs, V. Lepez-Carrillo, A. M. Echavar-
ren, Org. Lett. 2007, 9, 4021; d) J. Zhao, C. O. Hughes, F. D.
Toste, J. Am. Chem. Soc. 2006, 128, 7436; e) L. Zhang, S. Wang, J.
Am. Chem. Soc. 2006, 128, 1442; f) A. Buzas, F. Gagosz, Org.
Lett. 2006, 8, 515.
Angew. Chem. Int. Ed. 2010, 49, 6806 –6809
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6809