Suzuki-Miyaura cross-coupling of benzylic phosphates with arylboronic acids

Article abstract of DOI:10.1021/ol0517271

(Chemical Equation Presented) Suzuki-Miyaura cross-coupling of benzylic phosphates with arylboronic acids was investigated. Optimum conditions employed the simple catalytic system of palladium(II) acetate (1 mol %) and triphenylphosphine (4 mol %) with either potassium phosphate or potassium carbonate as the base and toluene as the solvent at 90°C. Using the developed conditions, a series of structurally diverse diarylmethanes were prepared.

Full text of DOI:10.1021/ol0517271

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4875-4878
Suzuki−Miyaura Cross-Coupling of
Benzylic Phosphates with Arylboronic
Acids
Mark McLaughlin*
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
mark_mclaughlin@merck.com
Received July 21, 2005
ABSTRACT
Suzuki
catalytic system of palladium(II) acetate (1 mol %) and triphenylphosphine (4 mol %) with either potassium phosphate or potassium carbonate
as the base and toluene as the solvent at 90 C. Using the developed conditions, a series of structurally diverse diarylmethanes were prepared.
−Miyaura cross-coupling of benzylic phosphates with arylboronic acids was investigated. Optimum conditions employed the simple
°
Owing to its robust nature and practicality, the Suzuki-
Miyaura cross-coupling reaction has become a cornerstone
of organic synthesis.1 Recent advances have significantly
broadened the scope of the reaction, allowing previously
unreactive substrates such as aryl chlorides2 and sulfonates3
to participate efficiently. Moreover, as a result of intense
research into the reactivity and stability of various catalyst
systems, it is now possible to conduct such reactions using
low catalyst loadings and often under mild conditions.4
Additionally, the area of alkyl halide cross-coupling has
recently witnessed important developments.5 Traditionally,
this type of reaction was problematic when applied to
nonactivated alkyl substrates due to reduced rates of oxidative
insertion of transition metals into alkyl halide bonds (versus
aryl or vinyl systems), slow reductive elimination of the
cross-coupled product from the catalyst and competing
reaction pathways, such as the usually facile â-hydride
elimination. On the other hand, the cross-coupling of simple
benzylic substrates, still involving activation of an sp3-
hybridized carbon atom, is not complicated by the possibility
of interfering â-hydride elimination and should, therefore,
be a straightforward process. Despite this fact, the Suzuki-
Miyaura cross-coupling of benzylic substrates is relatively
underdeveloped and has generally been limited to the use
of benzylic halides as the electrophilic component.6
In a recent report by Kuwano, the scope of electrophilic
substrates for benzylic Suzuki-Miyaura cross-couplings was
expanded to include benzylic carbonates.7 The activation of
benzylic alcohols toward nucleophilic displacement via the
intermediacy of phosphate esters is well documented,8
although cross-coupling of such phosphates with arylboronic
acids has not been previously explored.9 Hence, the Suzuki-
(1) Reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-
2483. (b) Suzuki, A. Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2.
(c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (d) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11-59. (e) Hassan, J.; Sevignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 58, 9633-9695. (f) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695. (g) Bellina,
F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419-2440.
(2) For a review on Pd-catalyzed couplings of aryl chlorides, see: Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(3) For example, see: Baxter, J. M.; Steinhuebel, D.; Palucki, M.; Davies,
I. W. Org. Lett. 2005, 7, 215-218.
(4) (a) Walker, S. D.; Barder, T.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871-1876. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685-4696.
(5) For a recent review of alkyl halide cross-couplings, see: Frisch, A.
C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688.
(6) For some recent examples of Suzuki-Miyaura cross-coupling of
benzylic halides, see: (a) Chowdhury, S.; Georghiou, P. E. Tetrahedron
Lett. 1999, 40, 7599-7603. (b) Langle, S.; Abarbri, M.; Duchene, A.
Tetrahedron Lett. 2003, 44, 9255-9258. (c) Chahen, L.; Doucet, H.; Santelli,
M. Synlett 2003, 1668-1672. (d) Nobre, S. M.; Monteiro, A. L. Tetrahedron
Lett. 2004, 45, 8225-8228.
(7) Kuwano, R.; Yokogi, M. Org. Lett. 2005, 7, 945-947.
10.1021/ol0517271 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/06/2005

Miyaura cross-coupling of benzylic phosphates was evaluated
and the results are described herein.
both starting materials suffered extensive decomposition in
these instances (Table 1, entries 3 and 4). A low conversion
and assay yield was also obtained with the poorly soluble
PdCl2 (Table 1, entry 13). These examples aside, good yields
were observed using various Pd sources in conjunction with
both mono- and diphosphine ligands (Table 1, entries 6-10)
and also with a heterocyclic carbene ligand (Table 1, entry
11).
Although several of the intially screened catalyst systems
afforded high yields of 3, the simple and least expensive
combination of Pd(OAc)2/PPh3 was chosen for further
optimization (Table 2). The effect of the Pd/PPh3 ratio was
The benzylic phosphates required for the present study
were readily prepared in high yield from the corresponding
alcohols by treatment with diethyl chlorophosphate in the
presence of triethylamine with catalytic DMAP.10 Initially,
the Suzuki-Miyaura cross-coupling reaction between diethyl
benzyl phosphate 1 and phenylboronic acid 2 was investigat-
ed using a variety of palladium sources and ligands (Table 1).
Table 1. Investigation of Various Pd Sources and Ligandsa
Table 2. Optimization of Pd(OAc)2/PPh3 Catalyzed Reactiona
entry
Pd source (mol %)
ligand (mol %)
assay yield %
1
2
3
4
5
6
7
8
none
none
0
99
6
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
[PdCl(allyl)]2 (1)
PdCl2(Ph3P)2 (1)
Pd2dba3 (1)
PPh3 (4)
P(o-Tol)3 (4)
PCy3 (4)
dppb (1)
dppPt (1)
dppf (1)
PPh3 (4)
none
Ph3P (4)
IPrHCl (2)
PPh3 (2)
PPh3 (2)
mol %
entry Pd(OAc)2
mol %
PPh3
mol %
assay
base (mol %) PhB(OH)2 yield %
31
55
99
97
99
86
95
94
80
32
1
2
3
4
5
6
7
8
9
0.5
1
2
0.5
1
1
1
1
1
1
2
4
2
4
4
4
4
4
K3PO4 (200)
K3PO4 (200)
K3PO4 (200)
K3PO4 (200)
K3PO4 (200)
K3PO4 (110)
K3PO4 (110)
K2CO3 (110)
none
150
150
150
150
150
150
110
110
110
52
85
93
88
99
99
99
96
31
9
10
11
12
13
Pd2dba3 (1)
PdCl2(MeCN)2 (1)
PdCl2 (1)
a Reaction conditions: 1.0 mmol of 1, 1.5 mmol of 2 and 2.0 mmol of
K3PO4 with the indicated quantities of catalyst/ligand in toluene (3 mL) at
90 °C for 16 h. Assay yield determined by LC versus a purified standard.
(dppPt ) 1,5-bis(diphenylphosphino)pentane and IPrHCl ) 1,3-bis(2,6-
diisopropylphenyl)imidazolium chloride).
a Reaction conditions: 1.0 mmol of 1 with the indicated quantities of 2,
catalyst/ligand and base in toluene (3 mL) at 90 °C for 16 h. Assay yield
determined by LC versus a purified standard.
studied and clear differences between 1:2 and 1:4 ratios were
observed.
The general conclusion from this initial screen was that
the reaction appeared quite facile, affording high assay yields
of diphenylmethane 3 under the influence of several catalytic
systems. These results contrast with those of Kuwano for
the Suzuki-Miyaura cross-coupling of benzylic carbonates,
where a specific catalyst system was essential to the success
of the reaction.7 In the present work, attempted cross-
coupling of diethyl benzyl phosphate 1 in the absence of
any catalyst/ligand gave zero conversion of either starting
material, indicating that the benzylic phosphate was otherwise
stable to the reaction conditions (Table 1, entry 1). Low assay
yields were obtained with the bulkier monophosphine ligands
P(o-Tol)3 and PCy3 in combination with Pd(OAc)2, while
Table 3. Solvent Compatibilitya
entry
solvent
temp (°C)
assay yield %
1
2
3
4
5
6
7
toluene
DMF
MeCN
i-PrOH
1,2-DME
THF
22
90
80
80
80
55
55
<1
99
97
97
97
40
38
(8) For recent examples, see: (a) Chung, J. Y. L.; Cvetovich, R.; Amato,
J.; McWilliams, J. C.; Reamer, R.; DiMichele, L. J. Org. Chem. 2005, 70,
3592-3601. (b) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen,
D. M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer,
R.; Volante, R.; Grabowski, E. J. J.; Dolling, U. H.; Reider, P. J.; Okada,
S.; Kato, Y.; Mano, E. J. Org. Chem. 1999, 64, 9658-9667.
(9) The Suzuki-Miyaura cross-coupling of enol phosphates is known:
(a) Huffman, M. A.; Yasuda, N. Synlett 1998, 471-473. (b) Nan, Y.; Yang,
Z. Tetrahedron Lett. 1999, 40, 3321-3324. (c) Lepifre, F.; Buon, C.; Rabot,
R.; Bouyssou, P.; Coudert, G. Tetrahedron Lett. 1999, 40, 6373-6376.
(10) Full details of the phosphate preparations may be found in
Supporting Information.
t-BuOMe
a Reaction conditions: 1.0 mmol of 1, 1.1 mmol of 2 and 1.1 mmol of
K3PO4 with 1 mol % Pd(OAc)2/4 mol % PPh3 using the indicated solvent/
temperature for 16 h. Assay yield determined by LC versus a purified
standard.
Reactions employing a 1:2 Pd/PPh3 ratio consistently
became black after only 15 min at 90 °C. However, despite
4876
Org. Lett., Vol. 7, No. 22, 2005

the apparent decomposition of the catalyst in these reactions,
reasonably high assay yields were observed with catalyst
loadings >1 mol % (Table 2, entries 2 and 3). On the other
hand, reactions using a 1:4 Pd/PPh3 ratio generally remained
yellow throughout and provided the highest assay yields
(Table 2, entries 4 and 5). In terms of catalyst loading, entry
4 indicates that as little as 0.5 mol % Pd was required for
high conversion. No attempt was made to employ catalyst
loadings lower than 0.5 mol %.
acid 2. Indeed, lowering the amount of 2 to 110 mol %
furnished equivalent yields of 3 as when 150 mol % of 2
was used (Table 2, entries 6 and 7).
With respect to the base, K2CO3 and K3PO4 afforded
similar assay yields for this reaction (Table 2, entries 7 and
8). In both cases it was determined that using 110 mol % of
base maintained the reaction efficiency. The assay yield was
seriously affected when the reaction was performed in the
absence of added base (Table 2, entry 9).
Table 5. Cross-Coupling of Various Benzylic Phosphates with
Phenylboronic Acida
Table 4. Cross-Coupling of Diethyl Benzyl Phosphate with
Various Arylboronic Acidsa
a Reaction conditions: 1.0 mmol of benzylic phosphate, 1.1 mmol of 2
and 1.1 mmol of K3PO4 with 1 mol % Pd(OAc)2/4 mol % PPh3 in toluene
at 90 °C for 16 h. Assay yield determined by LC versus a purified standard.
Isolated yield determined after workup and chromatographic purification.
b Yield in parentheses refers to isolated material.
a Reaction conditions: 1.0 mmol of 1, 1.1 mmol of boronic acid and
1.1 mmol of K3PO4 with 1 mol % Pd(OAc)2/4 mol % PPh3 in toluene at
90 °C for 16 h. Assay yield determined by LC versus a purified standard.
Isolated yield determined after workup and chromatographic purification.
b Yield in parentheses refers to isolated material.
After establishing the optimum catalyst system for this
cross-coupling, the reaction was examined using different
solvents. As shown in Table 3, using the standard catalyst
system in toluene at room temperature led to zero conversion
after 24 h (Table 3, entry 1).11 At elevated temperatures (80-
90 °C), the reaction proceeded smoothly in a range of
solvents (Table 3, entries 2-5). The use of THF or MTBE
at 55 °C led to lower conversions (Table 3, entries 6 and 7).
Throughout these optimization experiments, the extent of
homocoupling of phenylboronic acid was quantitatively
monitored and found to be negligible (consuming <3 mol
% of boronic acid). From this observation it became apparent
that the cross-coupling would likely retain high conversion
of the phosphate 1 with reduced quantities of phenylboronic
(11) When this particular reaction mixture was then heated to 90 °C, a
97% assay yield was obtained.
Org. Lett., Vol. 7, No. 22, 2005
4877

Having optimized the cross-coupling between diethyl
benzyl phosphate and phenylboronic acid, the reaction was
then tested using a variety of alternative substrates. First,
diethyl benzyl phosphate was reacted with a series of
substituted arylboronic acids (Table 4).
As shown, the reaction was broadly successful, affording
good yields with a range of electron-neutral and electron-
rich arylboronic acids, including the more sterically encum-
bered 2-substituted arylboronic acids. With respect to
electron-deficient arylboronic acids, both the 4-chloro- and
4-trifluoromethyl-substituted boronic acids performed well.
However, 3-nitrobenzeneboronic acid gave a lower yield.12
The cross-coupling was also tested using a series of
substituted benzylic phosphates (Table 5). Once again, the
yield of product diarylmethanes was generally good regard-
less of the electronic/steric nature of the substituents.
the phosphate 27 and phenylboronic acid 2 underwent
significant conversion; however, no cross-coupled product
28 was observed. Not unexpectedly, â-hydride elimination
was facile under these conditions and the major product was
styrene 29 (identified by comparison with an authentic
sample). In an attempt to suppress â-hydride elimination,
the reaction using 27 was attempted using the widely
applicable Buchwald Pd(OAc)2/SPhos catalyst system, known
to promote Suzuki-Miyaura cross-couplings at room tem-
perature.4 Indeed, when this catalyst system was applied to
the room-temperature coupling of phenylboronic acid 2 with
diethyl benzyl phosphate 1, a 47% assay yield of diphenyl-
methane 3 was obtained after 24 h (vs 0% conversion using
PPh3 as a ligand at room temperature (Table 3, entry 1).
However, application of these conditions to secondary
phosphate 27 gave none of the desired cross-coupled product
28.
In conclusion, the Suzuki-Miyaura cross-coupling reac-
tion of benzylic phosphates and arylboronic acids was
investigated. This relatively facile reaction was efficiently
catalyzed by the simple combination of palladium acetate
and triphenylphosphine. The generality of this cross-coupling
was demonstrated using a variety of substrates and afforded
high yields of the expected diarylmethanes, a substructure
prevalent in numerous pharmacologically active substances.13
Acknowledgment. The author would like to acknowledge
Robert A. Reamer for assistance with the interpretation of
NMR data.
Figure 1. Attempted cross-coupling with phosphate 27.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
The possibility of introducing asymmetry to this process
prompted investigation of a secondary phosphate substrate
27 (Figure 1). Under the developed standard conditions, both
OL0517271
(12) Electron-deficient arylboronic acids are less nucleophilic and
undergo transmetalation at a slower rate than electron-neutral and electron-
rich arylboronic acids. Additionally, electron-deficient arylboronic acids are
prone to homocoupling. For a report, see: Wong, M. S.; Zhang, X. L.
Tetrahedron Lett. 2001, 42, 4087-4089.
(13) For example, see: Long, Y.-Q.; Jiang, X.-H.; Dayam, R.; Sanchez,
T.; Shoemaker, R.; Sei, S.; Neamati, N. J. Med. Chem. 2004, 47, 2561-
2573.
4878
Org. Lett., Vol. 7, No. 22, 2005