Palladium-catalyzed α-arylation of benzylic phosphonates

Article abstract of DOI:10.1021/ol5002413

A new synthetic route to access diarylmethyl phosphonates is presented. The transformation enables the introduction of aromatic groups on benzylic phosphonates via a deprotonative cross-coupling process (DCCP). The Pd(OAc) ₂/CataCXium A-based catalyst afforded a reaction between benzyl diisopropyl phosphonate derivatives and aryl bromides in good to excellent isolated yields (64-92%).

Full text of DOI:10.1021/ol5002413

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Benzylic Phosphonates
Sonia Montel, Ludovic Raffier, Yuying He, and Patrick J. Walsh*
Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, University of Pennsylvania,
Department of Chemistry, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A new synthetic route to access diarylmethyl phosphonates is presented. The transformation enables the
introduction of aromatic groups on benzylic phosphonates via a deprotonative cross-coupling process (DCCP). The Pd(OAc)2/
CataCXium A-based catalyst afforded a reaction between benzyl diisopropyl phosphonate derivatives and aryl bromides in good
to excellent isolated yields (64−92%).
hosphonates and their derivatives are a class of organo-
phosphorus compounds that exhibit a wide range of
reported. Classical preparations include Michaelis−Arbuzov or
Michaelis−Becker reactions,6 which are dependent on the
limited availability of the starting diarylmethyl halides. Recently,
a Friedel−Crafts type reaction has been developed by
Chakravarty et al. starting from diethyl (hydroxy(aryl)methyl)-
phosphonates to obtain diethyl (diarylmethyl)phosphonates
(Figure 2A).7 The products were obtained in good yields,
although the scope suffers from the usual limitations of
Friedel−Crafts reactions. To date, some examples of α-
arylation of activated phosphonates have been reported.8
They involved the deprotonation of relatively acidic methylene
C−H’s (pKa around 17 in DMSO) sandwiched between
phosphonates and a second electron-withdrawing group
(Figure 2B−D). One example of palladium-catalyzed α-
arylation of dimethyl methylphosphonate in 70% yield has
been reported by Hagadorn and Hlavinka using Zn(tmp)2 as
the base (Figure 2E).9 This approach employs an irreversible
deprotonation, rather than a reversible deprotonation em-
ployed in our work.10 In this Letter, we disclose the first general
palladium-catalyzed direct α-arylation of dialkyl benzyl
phosphonates (Figure 2F). These substrates (pKa = 27.6 in
DMSO) are around 10 orders of magnitude less acidic than
those in Figure 2B−D, making their arylation considerably
more challenging.
P
applications in medicinal1 and agricultural chemistry.2 They are
also flame retardants, metal extractants,3 and reagents in the
Horner−Wadsworth−Emmons (HWE) reaction.4 Given the
interest in phosphonates, and their applications as reagents to
prepare a host of useful molecules (Figure 1),5 there is a
significant demand for their synthesis.
Despite the widespread use of dialkyl (diarylmethyl)phos-
phonates, only a few methods for their synthesis have been
Our group is interested in the functionalization of weakly
acidic sp3 C−H bonds via deprotonative cross-coupling
processes (DCCP). Substrates employed to date include
diarylmethanes, sulfoxides, sulfones, amides,11 12 and most
’
recently phosphine oxides.13 Encouraged by the utility of
phosphonates, and the lack of general methods to α-arylate
weakly acidic members of these compounds, we set out to
develop the arylation of benzylic phosphonates. Based on our
Figure 1. Examples of interesting molecules obtained from dialkyl
(diarylmethyl)phosphonates.
Received: January 22, 2014
Published: February 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of α-Arylation of Benzyl Diisopropyl
Phosphonate with Bromobenzene, 4-Methoxy
Bromobenzene, and 4-Fluoro Bromobenzene
a
base
(equiv)
temp
(°C)
concn
(mol/L)
yield
(%)
entry
R
ligand
1
H
L1
L2
L1
L2
L1
L2
L1
L2
L1
L1
3
3
3
3
3
3
3
3
2
3
80
80
80
80
80
80
80
80
80
50
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
85%
84%
99%
98%
99%
79%
99%
88%
70%
24%
2
H
3
H
4
H
5
OMe
OMe
F
6
7
8
F
9
H
10
H
a
1
Yields determined by H NMR of the crude reaction mixtures using
CH2Br2 as the internal standard.
Figure 2. α-Arylation and Friedel−Crafts type reaction of
was chosen as the more suitable ligand for this reaction.
Interestingly, Xantphos proved to be a better ligand for the α-
arylation of phosphine oxides.13 Note that attempts to reduce
the amount of base or the temperature resulted in a drop in the
yield (entries 9 and 10).
phosphonates.
previous observations in the arylation of phosphine oxides,13
our investigations were initiated using six bases [LiOt-Bu,
NaOt-Bu, KOt-Bu, LiN(SiMe3)2, NaN(SiMe3)2, and KN-
(SiMe3)2], two palladium sources [Pd(OAc)2 and Pd(dba)2],
two ligands [CataCXium A (L1)14 and Xantphos (L2),15
Figure 3], and four solvents [CPME (cyclopentyl methyl
The optimized reaction conditions in Table 1 were then used
to determine the substrate scope of aryl bromides 2a−j
(Scheme 1). Bromobenzene underwent a reaction to give 3a in
91% isolated yield. It is noteworthy that an 88% yield was
obtained when the reaction was carried out with 1 g of
phosphonate 1a and bromobenzene, indicating that the catalyst
and conditions are scalable. Reaction with 4-tert-butyl
bromobenzene afforded compound 3b in 82% yield. No
difficulty was noted with electron-donating groups, such as 4-
methoxy bromobenzene and 4-bromo-N,N-dimethylaniline,
which resulted in the formation of products 3c and 3d in
86% and 82% yield, respectively. Reaction with electron-
withdrawing groups also proceeded well. With 4-fluoro
bromobenzene, 3e was isolated in 82% yield. Similar reactivity
was observed with 4-chloro bromobenzene, although a longer
reaction time was required to reach complete conversion.
Sterically hindered 2-methyl bromobenzene and 1-bromo-
naphthalene afforded products 3g and 3h both in 89% isolated
yield. Finally, introduction of heteroaromatics 5-bromobenzo-
furan and 5-bromo-N-methyl indole were achieved in 80% and
71% yield, respectively.
The substrate scope of the diisopropyl benzyl phosphonate
was then studied (Scheme 2). The benzyl group in 1a was
replaced with 4-methoxybenzyl (1b), 4-fluorobenzyl (1c), 2-
methylbenzyl (1d), and 3-methylpyridyl (1e) groups. In each
case, the substrate was coupled with neutral, electron-rich, and
electron-poor aryl bromides (bromobenzene, 4-methoxy
bromobenzene, and 4-fluoro bromobenzene). Phosphonate
1b, possessing a 4-methoxybenzyl group, afforded coupled
products 3c, 3k, and 3l in 60−82% yield. It is noteworthy that a
longer reaction time and/or a higher temperature was required
for these substrates, probably due to the lower acidity of the
benzylic protons of 1b. Compounds 3e, 3l, and 3m were
Figure 3. Structures of CataCXium A (L1) and Xantphos (L2).
ether), 1,4-dioxane, THF, and DME], using microscale (10
μmol) High-Throughput Experimentation (HTE) techniques
(see Supporting Information).
From this microscale screen, two hits were obtained with
NaOt-Bu, Pd(OAc)2 and CataCXium A (L1, Figure 3) or
Xantphos (L2, Figure 3) in CPME at 80 °C. On laboratory
scale (0.2 mmol), these two systems led to the desired arylation
product in 85% and 84% yield, respectively (Table 1, entries 1−
2). Changing the concentration from 0.1 to 0.2 M resulted in
an increase in the yields to 99% and 98%, respectively (entries
3−4). To differentiate these two catalysts, reactions with an
electron-rich and -poor aryl bromide were tested. While
CataCXium A (L1) generated the desired products in 99%
yield with 4-methoxy bromobenzene and with 4-fluoro
bromobenzene (entries 5 and 7), the use of Xantphos (L2)
resulted in a drop in the yield to 79% and 88%, respectively
(entries 6 and 8). Based on these results, CataCXium A (L1)
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Organic Letters
Letter
Scheme 1. Substrate Scope of Aryl Bromides 2a−j in Pd-
Catalyzed α-Arylation of Diisopropyl Benzyl Phosphonate
Scheme 2. Substrate Scope of Diisopropyl Benzyl
Phosphonate in the Pd-Catalyzed α-Arylation with Aryl
1a
Bromides
a
b
1a: 3.90 mmol, 1.0 g. 32 h reaction time.
obtained from 4-fluoro benzyl phosphonate (1c) in 77−84%
yield. Sterically hindered 2-methyl benzyl phosphonate (1d)
afforded 3g, 3n, and 3o in 73−92% yield. A longer reaction
time and a higher temperature were, however, needed to reach
complete conversion. Finally, coupling products 3p−r were
obtained from 3-pyridyl containing phosphonate 1e in 67−84%
yield after 24 h or 48 h of reaction time.
a
32 h reaction time. b 24 h reaction time, 110 °C. c 24 h reaction time.
48 h reaction time.
d
Scheme 3. α-Arylation of Diethyl Benzylphosphonate 1f with
Bromobenzene
Replacement of the isopropyl moieties of 1a has also been
considered. Ethoxy groups are among the most commonly
employed substituents on the phosphorus atom in phosphonate
chemistry. We, therefore, applied our α-arylation conditions to
diethyl benzylphosphonate 1f (Scheme 3). Unfortunately, the
coupling did not proceed smoothly. Only a 30% yield of the
product was obtained, along with the formation of a byproduct,
tert-butyl ethyl benzylphosphonate BP1 (∼ 20% yield), and
some degradation of the starting material. Changing the base
did not solve the problem, as degradation was observed with all
bases employed. Only the nature of the major byproduct
formed differed: tert-butyl ethyl benzylphosphonate BP1 when
tert-butoxide bases (Li, Na, K) were employed and diethyl (1-
phenylpropyl)phosphonate BP2 when the MN(SiMe3)2 (M =
Li, Na, K) bases were used. Formation of BP2 presumably also
gives rise to BP3, but this charged species was not isolated.
After extensive optimization, slow addition of sodium tert-
butoxide to the reaction media (0.1 mL/h, see Supporting
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Organic Letters
Letter
1993, 58, 7009. (c) Rout, L.; Regati, S.; Zhao, C.-G. Adv. Synth. Catal.
2011, 353, 3340.
Information for details) avoided the degradation of the diethyl
benzylphosphonate 1f and decreased the formation of the
byproduct BP1. The product 3s was isolated in 64% yield.
In summary, we have developed the first Pd-catalyzed α-
arylation of benzylic phosphonates with aryl bromides. Despite
the perceived similarity between phosphine oxides and
phosphonates, different catalysts gave the best results for each
substrate class. For phosphonates, the combination of Pd-
(OAc)2, CataCXium A, and NaOt-Bu in CPME enabled access
to useful diarylmethyl phosphonates in good to excellent yields
through a deprotonative cross-coupling process.
(9) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26, 4105.
(10) Biellmann, J.-F.; Ducep, J.-B. Org. React. 1982, 27, 1.
(11) (a) Zhang, J.; Belomo, A.; Creamer, A. D.; Dreher, S. D.; Walsh,
P. J. J. Am. Chem. Soc. 2012, 134, 13765. (b) Bellomo, A.; Zhang, J.;
Trongsiriwat, N.; Walsh, P. J. Chem. Sci. 2013, 4, 849. (c) Jia, T.;
Bellomo, A.; El Baina, K.; Dreher, S. D.; Walsh, P. J. J. Am. Chem. Soc.
2013, 135, 3740. (d) Zheng, B.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 15,
1690. (e) McGrew, G. I.; Temaismithi, J.; Carroll, P. J.; Walsh, P. J.
Angew. Chem., Int. Ed. 2010, 49, 5541. (f) McGrew, G. I.; Stanciu, C.;
Zhang, J.; Carroll, P. J.; Dreher, S. D.; Walsh, P. J. Angew. Chem., Int.
Ed. 2012, 51, 11510. (g) Zheng, B.; Jia, T.; Walsh, P. J. Org. Lett. 2013,
15, 4190. (h) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El Baina, K.;
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B.; Jia, T.; Walsh, P. J. Adv. Synth. Catal. 2014, 356, 165.
(12) Some of these substrates have also proven useful in allylic
substitution reactions. See: (a) Sha, S.-C.; Zhang, J.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2013, 135, 17602. (b) Zhang, J.; Stanciu,
C.; Wang, B.; Hussain, M. M.; Da, C.-S.; Carroll, P. J.; Dreher, S. D.;
Walsh, P. J. J. Am. Chem. Soc. 2011, 133, 20552.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and full characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(13) Montel, S.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 16, 130.
(14) Sergeev, A. G.; Zapf, A.; Spannenberg, A.; Beller, M.
Organometallics 2008, 27, 297.
(15) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Acc.
Chem. Res. 2001, 34, 895.
■
Corresponding Author
*E-mail: pwalsh@sas.upenn.edu.
Notes
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. L.R. thanks the “Region Rhone-Alpes” for
its Explor’Pro fellowship. We thank Dr. Simon Berritt for his
help at the UPenn High-Throughput Experimentation Center.
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