Palladium-catalyzed cross coupling of Grignard reagents with in situ-derived enol phosphates

Article abstract of DOI:10.1016/S0040-4039(02)01600-3

A useful, one-pot protocol has been developed for the conversion of enolizable ketones to alkylated or arylated olefins by Pd-catalyzed cross coupling of in situ-generated enol phosphate intermediates with Grignard reagents.

Full text of DOI:10.1016/S0040-4039(02)01600-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7111–7114
Palladium-catalyzed cross coupling of Grignard reagents with
in situ-derived enol phosphates
Joseph A. Miller*
DSM Pharmaceuticals, Inc., 5900 NW Greenville Boulevard, Greenville, NC 27834, USA
Received 20 June 2002; accepted 8 July 2002
Abstract—A useful, one-pot protocol has been developed for the conversion of enolizable ketones to alkylated or arylated olefins
by Pd-catalyzed cross coupling of in situ-generated enol phosphate intermediates with Grignard reagents. © 2002 Elsevier Science
Ltd. All rights reserved.
The Pd- and Ni-catalyzed cross coupling of enol
acid (B:H) would not be acidic enough to protonate the
Grignard reagent coupling partner. For this reason, we
explored the deprotonation of various ketones utilizing
sterically hindered Grignard reagents. As shown in
Table 1, i-PrMgCl, t-BuMgCl, and 2-mesitylmagne-
sium bromide (MesMgBr) are all effective bases for
conversion of b-tetralone to its enol phosphate. On the
other hand, only MesMgBr proved to be effective for
selective deprotonation of the a-tetralone substrate.
Finally, the even more sterically bulky Grignard
1
2
triflates and -phosphates with organometallic reagents
is becoming an increasingly important synthetic tool.
When viable, coupling reactions utilizing enol phos-
phates are preferred relative to use of the corresponding
triflates because the former are generally less expensive,
easier to prepare, and more stable. While Pd-catalyzed
coupling of enol phosphates with certain alkyl Grig-
nard reagents (e.g. Me SiCH MgCl) is known in the
3
2
2
c
literature, there have been no examples reported of
this reaction using aryl Grignard reagents. With this in
mind, we briefly screened reaction conditions for this
coupling reaction and found that it can proceed readily.
As shown in Eq. (1), coupling of the diphenyl enol
phosphate derived from cyclohexanone with phenyl-
magnesium chloride in the presence of a palladium
reagent 2,4,6-tri-t-butylphenylmagnesium bromide
4
(
TTBP–MgBr) proved necessary to use for efficient
conversion of a simple dialkyl ketone (i.e. cyclohex-
anone) to its enol phosphate derivative.
With viable conditions in hand for preparing enol
phosphates in situ from the corresponding ketones
using hindered Grignard reagents, we examined the
possibility of a ‘one-pot process’ for converting ketones
into alkylated/arylated olefins via their enol phosphate
catalyst affords 1-phenylcyclohexene in 81% yield after
3
1
1
h at 65°C. The process is indeed catalyzed by Pd; no
-phenylcyclohexene is produced in the absence of the
Pd catalyst.
(1)
The synthetic utility of this reaction could be markedly
enhanced if the preparation of the enol phosphate and
its subsequent Pd-catalyzed cross coupling could be
carried out as a ‘one-pot process’ from the ketone
substrate (i.e. ketone “ enol phosphate “ arylated
olefin). In order to do this, the enol phosphate would
need to be produced using a base (B:) whose conjugate
intermediates. As shown in Table 2 (entry 1), sequential
treatment of a mixture of a-tetralone and ClPO(OPh)
2
with MesMgBr produced the corresponding enol phos-
phate. This solution was treated with the Pd catalyst
and then PhMgCl was added at 65°C to give the
1-phenyl-3,4-dihydronaphthalene product in high yield
(85% isolated).
Several features of this reaction sequence are notewor-
thy (Table 2). First, a broad scope with respect to
ketone substrates and Grignard reagents used in the
*
0
Fax: 252-707-2568; e-mail: joe.miller@dsm.com
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01600-3

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J. A. Miller / Tetrahedron Letters 43 (2002) 7111–7114
a
Table 1. Preparation of enol phosphates from ketones using sterically hindered Grignard reagents
Pd-catalyzed cross coupling portion of the process (aryl
and alkyl) are tolerated. Second, the enol phosphate
intermediate can be derived from diethyl- or
diphenylchlorophosphate with similar results (compare
entries 4 and 5). Third, organolithium reagents (e.g.
PhLi; entry 2) also function efficiently in the cross
coupling portion of this ‘one-pot process’.
catalyzed dehydration) for carrying out this same
ketone “ arylated/alkylated olefin transformation. For
example, Scheme 1 compares these two methodologies
for conversion of b-tetralone into 2-phenyl-3,4-dihy-
dronapthalene. While this new enol phosphate based
route (‘Route B’) affords the product in high yield (91%
isolated), the ‘classical’ chemistry (‘Route A’) gives this
same product in low yield (29%) along with a signifi-
cant amount (47%) of starting material indicative of
competing enolization of the ketone by the phenyl
Finally, this new methodology can offer a useful alter-
native to ‘classical’ methodology (i.e. addition of a
Grignard reagent to a carbonyl group, followed by acid
3
Grignard reagent. At least in the case of readily eno-
lized ketone substrates, the chemistry described herein
can clearly be advantageous to ‘classical’ methods.
Acknowledgements
We thank Professor B. M. Trost (Stanford University),
Dr. Tamim Braish (Pfizer Inc.) and Dr. Frank Urban
(
Pfizer Inc.) for helpful discussions concerning this
Scheme 1.
chemistry.

J. A. Miller / Tetrahedron Letters 43 (2002) 7111–7114
7113
a
Table 2. Examples of Pd-catalyzed cross coupling of Grignard reagents with in situ-derived enol phosphates
References
organometallic reagents: (a) Pd/R Al: Takai, K.; Sato, M.;
Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984, 57,
3
1
. (a) For Ni-catalyzed cross coupling of an enol triflate with
an aryl Grignard reagent, see: Busacca, C. A.; Eriksson,
M. C.; Fiaschi, R. Tetrahedron Lett. 1999, 40, 3101; (b)
For a review of enol triflate chemistry, including Ni- and
Pd-catalyzed cross coupling reactions, see: Ritter, K. Syn-
thesis 1993, 735.
108; (b) Ni/R Al: Fukamiya, N.; Oki, M.; Aratani, T.
Chem. Ind. (London) 1981, 606; (c) Ni- or Pd/
3
Me SiCH MgCl: Hayashi, T.; Fujiwa, T.; Okamoto, Y.;
3
2
Katsuro, Y.; Kumada, M. Synthesis 1981, 1001; (d) Ni/
RMgX: Sofia, A.; Karlstrom, E.; Itami, K.; Backvall, J. J.
Org. Chem. 1999, 64, 1745; (e) Ni/RZnX: Wu, J.; Yang, Z.
2. See the following representative references for Ni- or Pd-
catalyzed cross coupling of enol phosphates with
J. Org. Chem. 2001, 66, 7875; (f) Pd/R Mn: Fugami, K.;
Oshima, K.; Utimoto, K. Chem. Lett. 1987, 2203.
n

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J. A. Miller / Tetrahedron Letters 43 (2002) 7111–7114
3. These results were obtained by GC analysis of a reaction dichlorobis(triphenylphosphine)palladium (0.140 g;
1
sample (containing tridecane as an internal standard)
quenched in a mixture of 1 M sodium citrate (aq.) and
ether.
. Stuermann, M.; Weidenbruch, M.; Klinkhammer, K. W.;
Lissner, F.; Marsmann, H. Organometallics 1998, 17, 4425.
mol%) and warmed to 65°C. Phenylmagnesium chloride
(11.5 mL; 24.0 mmol; 2.08 M in THF) was added over 5–10
min to the reaction mixture, resulting in a gentle reflux of
the solvent. After stirring at 65°C for 30 min, the mixture
was cooled to room temperature and poured into a mixture
of 3N HCl (30 mL) and pentane (30 mL). The phases were
separated, and the aqueous portion was extracted with
pentane (25 mL). The combined organic phase was washed
sequentially with 3N HCl (15 mL), 3N NaOH (twice, using
15 mL each extraction), and brine (20 mL). The resulting
4
5
. Representative
procedure
(1-phenyl-3,4-dihydronaph-
thalene; Table 2, entry 1): A solution of 2-mesitylmagne-
sium bromide in THF (20.0 mL of 1.02 M solution; 20.4
mmol; Aldrich) was added over 10–15 min to a solution
containing a mixture of 1-tetralone (2.66 mL; 20.0 mmol)
and diphenyl chlorophosphate (4.56 mL; 22.0 mmol). The
resultant solution was stirred at 0°C for 30 min, allowed to
warm to room temperature, and then stirred for an addi-
tional 30 min. The reaction mixture was then treated with
organic phase was dried (MgSO ), concentrated, and then
4
distilled using a Kugelrohr apparatus (oven temp.=120–
150°C; 0.1 torr) to provide 3.51 g of 1-phenyl-3,4-dihy-
dronaphthalene (85% yield based on 1-tetralone).