Palladium-catalyzed α-arylation of benzylic phosphine oxides

Article abstract of DOI:10.1021/ol403124g

A novel approach to prepare diarylmethyl phosphine oxides from benzyl phosphine oxides via deprotonative cross-coupling processes (DCCP) is reported. The optimization of the reaction was guided by High-Throughput Experimentation (HTE) techniques. The Pd(OAc)₂/Xantphos-based catalyst enabled the reaction between benzyl diphenyl or dicyclohexyl phosphine oxide derivatives and aryl bromides in good to excellent yields (51-91%).

Full text of DOI:10.1021/ol403124g

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Benzylic Phosphine Oxides
Sonia Montel, Tiezheng Jia, and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A novel approach to prepare diarylmethyl phosphine oxides from benzyl phosphine oxides via deprotonative
cross-coupling processes (DCCP) is reported. The optimization of the reaction was guided by High-Throughput
Experimentation (HTE) techniques. The Pd(OAc)2/Xantphos-based catalyst enabled the reaction between benzyl diphenyl
or dicyclohexyl phosphine oxide derivatives and aryl bromides in good to excellent yields (51−91%).
ability of the requisite halogenated diarylmethanes or protected
diarylmethanols. Diarylmethanes can also serve as precursors,
but a three-step synthesis under harsh reaction conditions is
needed to obtain the desired products (Scheme 1).9b In this
Letter, the first examples of palladium-catalyzed direct α-
arylation of benzyl phosphine oxides are reported.
Recently, transition-metal-catalyzed cross-coupling reactions
with phosphorus compounds have emerged as a powerful route
to construct P−C bonds.10 In contrast, few examples of α-
arylation of phosphorus compounds have been reported to
date. These involve the deprotonation of significantly more
acidic protons on (RO)2P(O)CH2−EWG (EWG = keto,
cyano, or sulfonyl) compared to those of benzyl diphenylphos-
phine oxide, where the pKa in DMSO is around 29.11 Hagadorn
and Hlavinka developed a method to deprotonate (MeO)2P-
(O)Me using Zn(tmp)212 and coupled it with bromobenzene in
a palladium-catalyzed process.
rganophosphorus compounds, such as phosphine oxides,
Oexhibit a wide range of applications in medicinal
chemistry,1 biochemistry,2 agrochemistry,3 material science,4
catalysis (as catalysts and as ligands),5 and organic synthesis
(from Arbuzov to Wadsworth−Horner−Emmons reactions).
They are also known flame-retardants6 and metal extractants.7
Considering these diverse applications, it is not surprising that
the synthesis of organophosphorus compounds has attracted
much attention.
Among organophosphorus compounds, α-diarylmethyl
phosphine oxides exhibit particularly interesting properties.8
Surprisingly, very few methods have been reported for their
synthesis. Classical methods involve the use of Michaelis−
Arbuzov or Michaelis−Becker reactions (Scheme 1).9 These
approaches, however, suffer from limited commercial avail-
Scheme 1. Synthesis of Diarylmethyl Phosphine Oxides
Recently, our research group has introduced methods for the
functionalization of weakly acidic sp3-hybridized C−H bonds
(pKa’s 28−35 in DMSO) of diarylmethanes, sulfoxides,
sulfones, amides, and amine derivatives via deprotonative
cross-coupling processes (DCCP).13 Encouraged by the success
of these reactions, we focused our effort on the cross-coupling
of benzyl phosphine oxides with aryl bromides. To initiate these
investigations, six bases [LiN(SiMe3)2, NaN(SiMe3)2, KN-
(SiMe3)2, LiOtBu, NaOtBu, and KOtBu], four solvents [CPME
(cyclopentyl methyl ether), dioxane, THF, and toluene], two
palladium sources [Pd(OAc)2 and Pd(dba)2], and two ligands
[NiXantphos (L1, Table 1) and N-(dicyclohexylphosphino)-2-
2′-tolylindole (L2)] were chosen based on our previous
experience.12 These initial variables were tested using micro-
scale High-Throughput Experimentation (HTE) techniques
(see Supporting Information for details). An interesting cation
effect was observed: the catalysis only proceeded smoothly
Received: October 30, 2013
Published: December 2, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of α-Arylation of
Benzyldiphenylphosphine Oxide with 4-tert-Butyl
Bromobenzene
Scheme 2. Substrate Scope of Aryl Bromides in Pd-Catalyzed
α-Arylation with Benzyldiphenylphosphine Oxide (1a)
a
1a: 3.42 mmol, 2a: 6.84 mmol, NaOtBu: 6.84 mmol, CPME: 34 mL.
NaOtBu was replaced by NaH. 48 h, 0.2 M.
catalyst/
ligand/
mol %
b
c
temp/
°C
a
entry
catalyst
ligand
base
yield /%
1
2
3
4
5
6
7
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L3
L4
L4
L4
L4
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaOtBu
10/20
10/20
10/20
10/20
10/20
5/10
80
80
30
42
48
56
88
bromides containing electron-donating, electron-withdrawing,
and sterically hindered substituents exhibited good to excellent
yields. Bromobenzene 2b underwent coupling in 79% yield
while electron-donating 4-tert-butyl and 4-methoxy bromoben-
zene led to the desired products (3a and 3c) in 90% and 91%
yield, respectively. The cross-coupling reactions proceeded
smoothly between 1a and aryl bromides bearing electron-
withdrawing groups, such as 4-fluoro (2d) and 4-chloro (2f)
bromobenzene generating the arylation products in 83% and
54% yield respectively. With the 3-bromobenzotrifluoride 2e,
the use of NaOtBu did not afford the expected product.
Instead, the product underwent P−C bond cleavage leading
exclusively to the 1-benzyl-3-(trifluoromethyl)benzene and tert-
butyl diphenylphosphinate, Ph2PO(O-tBu). Formation of this
byproduct was suppressed by using a non-nucleophilic base,
NaH, which led to α-arylation product 3e in 71% yield. In the
case of more sterically demanding 2-bromotoluene and 1-
bromonaphthalene, longer reaction times and higher reaction
concentrations (from 0.1 to 0.2 M) were necessary, providing
3g and 3h in 51 and 66% yield, respectively. The scalability of
the cross-coupling was evaluated by performing the reaction
with 4-tert-butyl bromobenzene on a 3.42 mmol (1.0 g) scale
leading to the desired product 3a in 83% yield.
We next turned to the substrate scope of benzyldiphenyl-
phosphine oxides (Scheme 3). In this study, diphenylphosphine
oxides possessing 4-methoxybenzyl (1b) or 4-fluorobenzyl (1c)
were coupled with aryl bromides containing electron-donating
and -withdrawing groups. Under our optimized conditions,
products were isolated in 61−87% yields. In addition,
(naphthalen-1-ylmethyl)diphenylphosphine oxide (1d) and
(2-methylbenzyl)diphenylphosphine oxide (1e) furnished the
products 3g and 3h in 85% and 78% yield respectively. These
yields are significantly better than those obtained in Scheme 2
for the synthesis of these products. Finally, diphenyl(phenyl-
(pyridine-3-yl)methyl)phosphine oxide 3n, an example of
heterocycle-containing substrates, was isolated in 75% yield
80
80
110
110
110
b
85
b
5/10
90
a
Yield determined by 1H NMR integration of the crude reaction
mixture using 0.1 mmol of CH2Br2 as the internal standard. Isolated
yield after chromatographic purification.
b
when NaN(SiMe3)2 or NaOtBu was utilized as a base. In
contrast, the potassium and lithium bases were totally
ineffective (less than 5% yield). The leading results from the
screen were NaN(SiMe3)2, Pd(dba)2/NiXantphos, or Pd-
(OAc)2/NiXantphos as the catalyst in CPME. On laboratory
scale, unfortunately, these conditions led to 3a in only 30% and
42% yield, respectively (Table 1, entries 1 and 2). As the choice
of ligand is very important in DCCP, 23 mono- and bidentate
ligands were screened using NaN(SiMe3)2 as a base and
Pd(OAc)2 as a catalyst in CPME at 80 °C (see Supporting
Information for details). Among those, CataCXium A (L3) and
Xantphos (L4) gave the best results. On laboratory scale,
Xantphos proved to be more effective, producing 3a in 56%
yield (Table 1, entry 4 vs 2−3). However, unreacted 1a was
present. To push the reaction to completion, the temperature
was increased from 80 to 110 °C, leading to the desired
product 3a in 88% crude yield (entry 5). A decrease in the
palladium/Xantphos loading from 10/20 mol % to 5/10 mol %
was successfully achieved, and the arylated product 3a was
isolated in 85% yield (entry 6). We observed some degradation
of 1a with NaN(SiMe3)2. Therefore, NaOtBu was employed
and led to an increased yield of the desired product 3a (90%
yield) (entry 7).
With the optimal conditions in hand, the substrate scope of
aryl bromides in the arylation of benzyldiphenylphosphine
oxide (1a) was investigated (Scheme 2). In general, aryl
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Organic Letters
Letter
Scheme 3. Substrate Scope of Benzyldiphenylphosphine
Oxides in Pd-Catalyzed α-Arylations with Aryl Bromides
Scheme 4. α-Arylation of Benzyldicyclohexylphosphine
Oxide with 4-tert-Butyl Bromobenzene
Scheme 5. Reduction of the Phosphine Oxide 3a to
Phosphine 4a
In summary, we have developed the first α-arylation of
benzyl phosphine oxide derivatives with aryl bromides. The
combination of Pd(OAc)2 and Xantphos under basic
conditions catalyzed the reaction, providing access to these
useful compounds in good yield. NaOtBu or NaH bases
enabled the deprotonation of the weakly acidic α-protons of
phosphine oxides and promoted the transmetalation to
palladium. This work broadens the scope of weakly acidic
substrates that can be employed in deprotonative cross-
coupling processes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures, characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pwalsh@sas.upenn.edu.
Notes
when NaH was utilized as the base. It is noteworthy that this
compound has been demonstrated to be a potent inhibitor of
the Kv1.5 potassium channel and a possible treatment for atrial
fibrillation.8a The prior synthesis provided only a 2% yield of
this biologically interesting compound, whereas the yield was
significantly improved employing our method.
Dialkyl phosphine oxides are less acidic than their diaryl
analogues and, therefore, are more challenging to prepare.
Nonetheless, many important ligands used in transition-metal-
catalyzed reactions possess bulky P-alkyl substituents.14 We,
therefore, decided to apply our method to prepare benzyl
phosphine oxides bearing bulky alkyl substituents. As shown in
Scheme 4, benzyldicyclohexylphosphine oxide underwent
DCCP with 2a to give the desired product in 84% yield
using sodium hydride as a base.
The α-diarylmethyl phosphine oxides prepared herein can be
envisioned as precursors for the synthesis of new phosphine
ligands. Unfortunately, using trichlorosilane and triethylamine
to reduce the phosphine oxide moiety resulted in no reaction.
In contrast, the reaction proceeded smoothly with a catalytic
amount of Ti(OiPr)4 and triethoxysilane, furnishing the
expected phosphine 4a in 91% yield (Scheme 5).15
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation [CHE-1152488]
and National Institutes of Health (NIGMS 104349) for
financial support.
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