Gold(I)-catalyzed stereoselective synthesis of alkenyl phosphates by hydrophosphoryloxylation

Article abstract of DOI:10.1002/chem.201103304

A pinch of gold will do: Alkenyl phosphates, useful substrates in many cross-coupling reactions, can be synthesized by gold-catalyzed hydrophosphoryloxylation of terminal alkynes. The use of [Au(IPr)(OH)] as a pre-catalyst in a silver-free protocol permit

Full text of DOI:10.1002/chem.201103304

DOI: 10.1002/chem.201103304
Gold(I)-Catalyzed Stereoselective Synthesis of Alkenyl Phosphates by
Hydrophosphoryloxylation
Pierrick Nun,[a] Jonathan D. Egbert,[a] Marꢀa-Josꢁ Oliva-Madrid,[a, b] and
Steven P. Nolan*[a]
In recent decades, late-transition-metal-mediated cross-
coupling reactions have become one of the most important
[1]
À
tools to create C C bonds in organic synthesis. Significant
efforts have been devoted to developing catalytic systems,
to expand the scope of useful substrates in these couplings.
A significant goal is to develop systems that do not require
Scheme 1. Previous protocols leading to the formation of kinetic and
aryl iodide or bromide, which represent the most common
electrophilic moieties in Pd-catalyzed reactions.[2] Among
the alternatives, we can cite the use of vinyl and aryl tri-
flates[3] due to their excellent leaving group ability. Never-
theless, the synthesis of triflates is expensive and corrosive,
making alternatives attractive. As a coupling partner, alken-
yl phosphates have been proven reactive in most metal-cata-
lyzed cross-coupling reactions, such as Stille,[4,8] Suzuki–
Miyaura,[5] Negishi,[6] Kumada,[7] Sonogashira,[8] and Mizoro-
ki–Heck.[9]
Alkenyl phosphate synthesis most often involves the con-
version of carbonyl compounds into enolates by base-pro-
moted proton extraction followed by reaction with dialkyl
phosphorochloridates.[10] In addition to a simple synthesis,
the selectivity between kinetic and thermodynamic alkenyl
phosphates presents a significant challenge, which is difficult
to solve using organic synthesis.[10b,11]
Gold complexes have emerged as powerful catalytic tools
enabling numerous synthetic transformations.[12] Among a
panoply of reagents, alkynes currently exist as the most
prevalent substrates.[13] It is therefore not surprising that re-
cently, Lee et al.[14] reported the gold(I)-catalyzed addition
of diphenyl phosphates to terminal alkynes for the selective
preparation of alkenyl phosphates using various phosphane-
bearing gold centres in conjunction with silver salts as acti-
vators (Scheme 1). The choice of reaction conditions and
thermodynamic alkenyl phosphates.[14]
catalytic system allow preparation of either the kinetic or
thermodynamic product. Surprisingly, even though the reac-
tion proved to be quite efficient with phosphane ligands,
even at high catalyst loadings, the authors found no activity
when N-heterocyclic carbenes[15] (NHC) were used as li-
gands.
In the course of studies focusing on the chemistry of orga-
nogold complexes, we recently described the synthesis and
characterization of an NHC-gold(I) hydroxide complex,
[Au
azol-2-ylidene),[16] acting as a pre-catalyst and generating the
corresponding active catalyst [Au
(IPr)]+ by protonolysis-ac-
ACHTUNGTREN(NUNG IPr)(OH)] 1 (IPr=1,3-bis-(2,6-diisopropylphenyl)imid-
AHCTUNGTRENNUNG
tivation using a Brønsted acid in situ. This procedure avoids
the use of silver additives such as AgPF6, AgBF4, AgOTf,
AgNTf2, or AgSbF6 that are known to be light- and mois-
ture-sensitive, as well as expensive and toxic compounds.
This pre-catalyst was previously applied to the hydration of
alkynes at low catalyst loading.[17] Consequently, we decided
to investigate this new catalytic system toward the hydro-
phosphoryloxylation of different terminal alkynes for the se-
lective preparation of kinetic alkenyl phosphates (Markovni-
kov addition product).
To optimize the reactions conditions, 1-hexyne, with a
short sterically unencumbered alkyl chain, was chosen as the
model substrate to be reacted with diphenyl phosphate. Re-
sults of the catalyst generation protocol and subsequent
transformation of 1-hexyne are summarized in Table 1. The
[a] Dr. P. Nun, Dr. J. D. Egbert, M.-J. Oliva-Madrid, Prof. S. P. Nolan
EaStCHEM School of Chemistry
reaction was carried out with [AuACTHUNTGRNEUNG(IPr)(OH)] (1, 5 mol%) in
University of St Andrews
toluene at 508C, using comparable conditions to those de-
scribed by Lee et al. Unsurprisingly, without any acid activa-
tion, no reaction occurs and the starting material is isolated
unchanged (Table 1, entry 1). When 1 is activated by a
St Andrews, KY 16 9ST (UK)
E-mail: snolan@st-andrews.ac.uk
[b] M.-J. Oliva-Madrid
Visiting researcher from:
Departamento de Quꢀmica Inorgꢁnica
Facultad de Quꢀmica, Universidad de Murcia
Apartado 4021, 30071 Murcia (Spain)
Brønsted acid (HX) to generate [AuACTHUNTGRNEUNG(IPr)]X, relative conver-
sion to either the kinetic or the thermodynamic alkenyl
phosphate is dependent on the nature of X. With HNTf2 no
new product is observed (Table 1, entry 2), whereas with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103304.
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Chem. Eur. J. 2012, 18, 1064 – 1067

COMMUNICATION
Table 1. Optimization of reaction conditions.
Table 2. Gold(I) catalyzed synthesis of alkenyl phosphates.[a,b]
Phosphate
T
[8C]
Product
Yield
[%]
1
2
3
diphenyl
dibenzyl
dibutyl
50
70
70
83[a]
76[a]
68[a]
2a
2b
2c
Entry
HX
[Au]/HX
[mol%]
T
[8C]
Conv.
[%]
Kinetic/
Thermodynamic
G
1
2
3
4
5
6
–
5
5
5
5
5
1
0.1
0.1
50
50
50
50
25
50
50
70
50
50
0
0
–
–
[a] Reaction time: 14 h; [b] 1 mol% catalyst loading.
HNTf2
TfOH
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
100
100
<20
100
82
100
50
0
8:92 (E/Z 1:0.3)
1:0
1:0
1:0
1:0
1:0
1:0
–
action with respect to the phosphate selection, we carried
out reactions with different phosphates and [Au(IPr)(OH)]/
HBF4 in toluene. As observed with our model substrate,
when HBF4 is used in combination with the catalyst [Au-
AHCTUNGTRENNUNG
7[a]
8[a]
9[a]
10
0.01
[Au] 0 HX 5
AHCTUNGTREG(NNNU IPr)(OH)] 1, the kinetic alkenyl phosphates (Markovnikov
products) form selectively in good yields (Table 2). 1-
Hexyne, when reacted with diphenyl phosphate in the pres-
[a] Reaction time: 24 h.
ence of [AuACHTNUTRGNE(UNG IPr)(OH)]/HBF4 (1 mol%) gave the desired
HOTf and HBF4 all the starting material is converted
(Table 1, entries 3 and 4). However, the kinetic and thermo-
dynamic products with HOTf form in an 8 to 92 mixture
(Table 1, entry 3). Conversely, complete selectivity for the
kinetic product is obtained with HBF4 (Table 1, entry 4).
Lowering the reaction temperature to 258C hinders the con-
version significantly (Table 1, entry 5). A blank reaction
without gold, in the presence of HBF4 (5 mol%) gave no
product and suggests that the reaction does not proceed by
simple acid catalysis and that gold activation of the alkyne is
necessary.
product in 83% isolated yield (Table 2, entry 1). The reac-
tivity of both dibenzyl phosphate and dibutyl phosphate was
examined using the same substrate. In both cases, the reac-
tions required additional heating to 708C for comparable
conversion in the same time as the less sterically demanding
diphenyl phosphate (Table 2, entries 2 and 3).
Also explored, was the extent to which the alkyne could
be varied. The reaction was conducted with several terminal
alkynes with various length n-alkyl chains and diphenyl
phosphate. Using 0.1 mol% loading the five-carbon deriva-
tive gives good but decreased reactivity compared with the
four-carbon derivative (Table 3, entry 1). Transitioning to
the much longer eight-carbon chain, results in more moder-
ate reactivity (Table 2, entry 2). This reaction was also car-
ried out at 708C with an extremely low catalyst loading,
0.01 mol%, and the desired product was isolated in 38%
yield. Using the much more sterically encumbered tert-butyl
still gives the desired alkenyl phosphate, however 1 mol%
catalyst loading is required for an efficient reaction. An
88% yield was obtained after 14 h at 508C (Table 2,
entry 3). The reaction still proceeds with 0.1 mol% catalyst
loading but after 24 h at the same temperature only 20%
conversion is observed. Even at very low catalyst loading
(0.01 mol%) the reaction between the tert-butyl substituted
alkyne and diphenyl phosphate proceeds. Although sluggish,
after 40 h 28% conversion is achieved. Alkynes with elec-
tron-withdrawing halides have good conversion with
1 mol% catalyst loading. Treatment of 5-chloro-1-pentyne
and 6-chloro-1-hexyne with diphenyl phosphate using
1 mol% of 1 in toluene at 508C (Table 3, entries 4 and 5),
gave the corresponding alkenyl phosphates in 77 and 82%
yields respectively.
The minimal amount of 1 required was investigated to
eliminate the use of excessive gold catalyst. In contrast to
the [AuACHTUNGTRENNUNG(PR3)Cl] activated by silver system, which requires
5 mol% [Au], complex 1 gives full conversion with much
lower loadings. With 1 mol% loading full conversion occurs
within 14 h at 508C (Table 1, entry 6). With 0.1 mol% cata-
lyst loading, full conversion occurs within 24 h, although a
slight elevation in temperature to 708C is required (Table 1,
entry 7). With extremely low catalyst loading (0.01 mol%)
and the moderate temperature of 508C, a respectable 50%
conversion occurs in 24 h (Table 1, entry 9). Additional reac-
tions were conducted with IPrAuCl (5 mol%) as catalyst
and AgBF4 or AgOTf (5 mol%) as co-catalyst and the best
result using this protocol provided an 80% conversion of
the thermodynamic phosphate product after overnight stir-
ring at 508C with 5 mol% each of IPrAuCl and AgOTf.
These results highlight the higher reactivity of IPrAuOH in
combination with acids and the superior selectivity of the
protocol, allowing the preparation of either kinetic or ther-
modynamic alkenyl phosphates as a function of the nature
of the activating acid.
We next turned our attention to the direct preparation of
various kinetic alkenyl phosphates through hydrophosphory-
loxylation (Table 2). To further explore the scope of the re-
The addition of diphenyl phosphate to activated alkynes,
such as ethyl propiolate and ethyl phenylpropiolate, gives
trans addition in
a regio- and stereoselective manner
Chem. Eur. J. 2012, 18, 1064 – 1067
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www.chemeurj.org
1065

S. P. Nolan et al.
Table 3. Gold(I) catalyzed synthesis of alkenyl phosphates.
alyst loading as indicated in Table 2. The solvent was removed
under vacuum and the crude product purified by silica-gel
column chromatography (EtOAc/pentane 2:8) to afford hex-
1-en-2-yl diphenyl phosphate (2a) as
a colorless liquid
(138 mg, 83%). 1H NMR (400 MHz, CDCl3): d=7.37–7.33
(m, 4H, m-H), 7.25–7.18 (m, 6H, o-H+p-H), 4.94–4.92 (m,
1H, CH alkene), 4.60–4.59 (m, 1H, CH alkene), 2.22–2.18 (m,
2H, CH2-C), 1.45–1.41 (m, 2H, CH2), 1.33–1.26 (m, 2H,
R1; R2
mol%
0.10
T
t
Product
Yield
[%]
[8C] [h]
3
CH2), 0.86 ppm (t, JHH =7.2 Hz, 3H, CH3); 31P NMR (162 Hz,
1
2
3
4
5
n-C5H11; H
n-C8H17; H
tBu; H
70
14
73
CDCl3): d=À18.1 ppm (s, OP(O)
(100 MHz, CDCl3): d=156.1 (s, C alkene), 150.7 (d, JCP
10.2 Hz, i-C, PhO), 129.9 (s, m-CH, PhO), 125.6 (s, p-CH,
(OPh)2); 13C NMR
ACHTUNGTRENNUNG
3a
2
=
0.1
70
70
50
50
18
64
PhO), 120.2 (d, 3JCP =6.6 Hz, o-CH, PhO), 98.1 (d, JCP
=
3
0.01
1.0
48 3b
14
38
5.7 Hz, CH2 alkene), 34.1 (d, 3JCP =7.4 Hz, CH2 aliphatic),
28.4 (s, CH2 aliphatic), 22.0 (s, CH2 aliphatic), 13.9 ppm (s,
CH3); HRMS (ESI): m/z: calcd for C18H21O4P: 332.1177;
found: 332.1170.
88
0.01
40 3c
28[a]
Cl
(CH2)3; H 1.0
50
50
14
77
82
3d
Acknowledgements
Cl(CH2)4; H 1.0
E
24
3e
Support of this work by the ERC (Advanced Researcher
Grant to S.P.N.) and EPSRC is gratefully acknowledged. We
6
CO2Et; H
1.0
50
14
74
thank the Ministerio de Educaciꢃn
y Ciencia (Spain),
FEDER (CTQ2007-60808/BQU), and Fundaciꢃn Sꢄneca
(04539/GERM/06) for financial support to M.J.O.M. S.P.N. is
a Royal Society Wolfson Research Merit Award holder.
3 f
7
8
CO2Et; Ph
1.0
50
50
14
72
3g
Keywords: alkenyl phosphates · alkyne activation ·
gold · gold catalysis · homogeneous catalysis
n-C6H9; H
0.01
20
96[a]
3h
[a] % conversion from 31P NMR spectroscopy.
(Table 3, entries 6 and 7).[18] Finally, a reaction was conduct-
ed using the di-terminal alkyne, 1,7-octadiyne. The reaction
with phosphate occurs at both alkyne moieties. With ex-
tremely low (0.01 mol%) catalyst loading 1,7-octadiyne
reacts nearly quantitatively with diphenyl phosphate in 20 h
at 508C (Table 3, entry 8).
In conclusion, we have developed a straightforward silver-
free method for the synthesis of alkenyl phosphates with
high selectivity catalyzed by cationic gold(I) complexes gen-
erated in situ through the reaction between pre-catalyst [Au-
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the case of sterically unencumbered substrates quantitative
conversion can be realized with extremely low (0.01 mol%)
catalyst loadings.
Experimental Section
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ACHTUNGTRENNUNG
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Gold(I)-Catalyzed Synthesis of Alkenyl Phosphates
COMMUNICATION
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Received: October 19, 2011
Published online: December 19, 2011
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