Expedient synthesis of substituted (diphenylphosphinoylmethyl)benzenes

Article abstract of DOI:10.1021/jo062114k

An efficient protocol for the synthesis of structurally diverse (diphenylphosphinoylmethyl)benzenes is described. The reaction employs readily available carboxylic acids, chlorodiphenylphosphine, and water as the reagents. A 97% reduction in the reaction

Full text of DOI:10.1021/jo062114k

SCHEME 1. Protocols for the Synthesis of
(Diphenylphosphinoylmethyl)benzene Adducts
Expedient Synthesis of Substituted
(Diphenylphosphinoylmethyl)benzenes
Sean P. Bew,* Rebecca A. Brimage, David L. Hughes,
Laurent Legentil, Sunil V. Sharma, and Martin A. Wilson
School of Chemical Sciences & Pharmacy, UniVersity of East
Anglia, Norwich, NR4 7TJ, U.K.
s.bew@uea.ac.uk
ReceiVed October 12, 2006
An efficient protocol for the synthesis of structurally diverse
(diphenylphosphinoylmethyl)benzenes is described. The
reaction employs readily available carboxylic acids, chlo-
rodiphenylphosphine, and water as the reagents. A 97%
reduction in the reaction times and substantially higher yields
of products result, up to a 60% increase, if the reactions are
performed under microwave irradiation. The first examples
of transition-metal-catalyzed reactions applied to 4-bromo-
1,3-bis(diphenylphosphinoylmethyl)benzene are also re-
ported.
ethyl)benzene adducts had not been reported.10 We report in
this Note a convenient, straightforward microwave-mediated
method that affords, after a simple workup and purification
procedure, structurally diverse (diphenylphosphinoylmethyl)-
benzene adducts in good to high yields and, compared to
conventional heating protocols, significantly reduced reaction
times.
Our interest in (diphenylphosphinoylmethyl)benzene as well
as 1,2- and 1,3-bis(diphenylphosphinoylmethyl)benzene adducts
stems from a series of ongoing research projects. Critical to
their use for us was their synthesis in reasonable quantities
(∼0.5-2 g) from cheap and commercially available starting
materials. A few examples will serve to illustrate current
protocols for the synthesis of (diphenylphosphinoylmethyl)-
benzene, 1,2-, or 1,3-bis(diphenylphosphinoylmethyl)benzenes:
(i) Negishi couplings employing substoichiometric amounts of
nickel or palladium catalysts between aryl halides and orga-
nozinc reagents derived from iodomethyldiphenylphosphine
oxide (Scheme 1a); (ii) nucleophilic displacement reactions
between aryl Grignard reagents and iodomethyldiphenylphos-
phine oxides (Scheme 1b); (iii) Michaelis-Arbuzov reaction
processes between R,R′-dibromo-meta-xylene and methyl diphe-
nylphosphinite (Scheme 1c); (iv) SN2 displacements using
At first sight, (diphenylphosphinoylmethyl)benzenes appear
as unreactive and or unexciting chemical entities, but in fact,
they have been used in a wide spectra of interesting and diverse
reactions. They have, for example, been employed as key
reagents and or catalysts in novel podands for the complexation
of ammonium cations,1 ligands for the hydroformylation of
alkenes,2 hydrogen-bonding hosts,3 ligands for metal-ion
extraction,4 analogues of methadone,5 precursor ligands to caged
platinacycles,6 precursors of PCP pincer ligands,7 and synthesis
of coordination complexes8 and as key reagents within the
Ramburg-Ba¨cklund reaction.9 Surveying the literature, we were
surprised that the application of microwave irradiation for the
efficient and expedient synthesis of (diphenylphosphinoylm-
* To whom correspondence should be addressed. Phone: + 44 (0)1603
593142. Fax: + 44 (0)1603 592003.
(1) Kruszynski, R.; Wieczorek, W. Heteroat. Chem. 2004, 15, 233-
240.
(2) Clark, H. J.; Wang, R.; Alper, R. J. Org. Chem. 2002, 67, 6224-
6225.
(3) Ashton, P. R.; Calcagno, P.; Spencer, N.; Harris, K. D. M.; Philp,
D. Org. Lett. 2000, 2, 1365-1368.
(4) Tan, T.-C.; Gan, X.-M.; Stanchfield, J. L.; Duesler, E. N.; Paine, R.
T. Inorg. Chem. 2001, 40, 2910-2913.
(5) Shelver, W. H.; Schreibman, M.; Tanner, N. S.; Rao, V. S. J. Med.
Chem. 1974, 17, 120-124.
(6) Lindner, E.; Khanfar, M.; Steimann, M. Eur. J. Inorg. Chem. 2001,
2411-2419.
(10) Chiarello, J.; Jo´ullie, M. M. Synth. Commun. 1988, 18, 2211-2223.
Renard, P.-Y.; Vayron, P.; Lederc. E.; Valleix, A.; Mioskowski, C. Angew.
Chem., Int. Ed. 2003, 42, 2389-2392. Brown, K. M.; Lawrence, N. J.;
Liddle, J.; Muhammad, F.; Jackson, D. A. Tetrahedron Lett. 1994, 35,
6733-6736. Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.;
Kabachnik, M. I. Synthesis 1986, 198-208. Renard, P.-Y.; Vayron, P.;
Mioskowski, C. Org. Lett. 2003, 5, 1661-1664.
(7) Beletskaya, I. P.; Chuchurjukin, A. V.; Dijkstra, H. P.; van Koten,
G.; van Klink, G. P. M. Tetrahedron Lett. 2000, 41, 1075-1079.
(8) Gan, X.-M.; Bond, E. M.; Cai, C.; Duesler, E. N.; Paine, R. T. Inorg.
Chem. 2000, 39, 4591-4598.
(9) Lawrence, N. J.; Muhammad, F. Tetrahedron 1998, 54, 15361-
15370.
10.1021/jo062114k CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/09/2007
J. Org. Chem. 2007, 72, 2655-2658
2655

SCHEME 2. Generic Reaction Protocol Reported by
Sartori and Mosler
SCHEME 4. Low-Yielding Synthesis of 5
SCHEME 5. Efficient Synthesis of 1 Using Microwave
Irradiation
SCHEME 3. Low-Yielding Synthesis of 1 Using Modified
Sartori and Mosler Reaction Conditions
nylphosphine (8 equiv). Both test reactions afforded less than
5% of the desired products, returning instead the unreacted
carboxylic acids.
lithiated diphenylphosphine oxides and alkyl halides (Scheme
1d) and similarly SN2 displacements using Grignard-derived
diphenylphosphine oxides on alkyl halides (Scheme 1e). In 1980,
Sartori and Mosler reported the synthesis of a series of
(diphenylphosphinoylmethyl)benzenes via a high-temperature
(180 °C) and time-consuming 100 h reaction process that
employed carboxylic acids, chlorodiphenylphosphine, and water
(Scheme 2).11 More recently, Ishibashi et al. reported the
synthesis of 2,2,2-trifluoroethyldiphenylphosphine oxide via an
almost identical process, employing trifluoroacetic acid, chlo-
rodiphenylphosphine, and water via a procedure that also
required a high reaction temperature (180 °C) but a slightly
shorter reaction time (80 h).12
It is interesting to note that although the Sartori and Mosler
methodology was reported over 25 years ago its utilization, as
judged by citations, by the synthetic chemistry community has
been largely nonexistent,13 a fact that may be attributed to the
very long, highly inconvenient reaction times and the relatively
poor yields of the resulting (diphenylphosphinoylmethyl)-
benzenes.
We considered the Sartori and Mosler process to have a
number of merits: viz., in the majority of cases, the starting
materials are cheap and readily available; the protocol is
straightforward and uncomplicated, with no requirement for the
use of anhydrous solvents, an inert atmosphere, or expensive
catalysts; and the reaction process appears to be versatile with
the capacity to afford multigram quantities of products. For our
use, it was important that the aryl ring not directly connected
to the phosphorus be equipped with a halogen “handle”. With
this in mind, we attempted the synthesis of 1 (Scheme 3) using
a procedure similar to that reported by Sartori and Mosler.
Stirring a mixture of 4-bromobenzoic acid, water (3 equiv of
each), and chlorodiphenylphosphine (4 equiv) at ambient
temperature (30 min) and subsequently at 100 °C for 2 h
afforded a very low 5% yield of 1, the majority of the mass
balance comprising unreacted 4-bromobenzoic acid. Concerned
that the electron-withdrawing properties of the bromine atom
may be having an adverse effect on the progress of the reaction,
we undertook two “test” reactions (employing the same reaction
conditions used for 4-bromobenzoic acid, i.e., ambient temper-
ature for 30 min then 100 °C for 2 h) using: (a) benzoic acid,
water (3 equiv of each), and chlorodiphenylphosphine (4 equiv)
and (b) phthalic acid, water (6 equiv of each), and chlorodiphe-
Employing the higher temperature (180 °C) and longer
reaction time conditions (100 h) reported,13 we repeated the
reaction outlined in Scheme 3. Chlorodiphenylphosphine (4
equiv) was added dropwise to a mixture of 4-bromobenzoic acid
and water (3 equiv of each) at ambient temperature. The
resulting mixture was warmed slowly to 80 °C then to 180 °C
over 3 h and held at this temperature for 100 h. Quenching the
reaction afforded, after purification, a 44% yield of 1. With this
positive result in hand, we repeated one of our test reactions.
Utilizing the higher temperature and longer reaction time
protocol recounted and phthalic acid as the starting material,
we attempted the synthesis of 5 (Scheme 4). After workup, a
very poor 7% yield of the desired 1,2-bis(diphenylphosphinoyl-
methyl)benzene (5) was afforded.
Microwave irradiation is often employed to heat and drive
chemical reactions; one of the advantages of using microwaves
in chemical synthesis is the often dramatic reduction in reaction
times that are observed.14 The possibility that focused microwave
irradiation may result in a significant shortening of the very
long reaction times reported by Sartori and Mosler intrigued
us. Microwave irradiating a mixture of 4-bromobenzoic acid
(1 equiv), chlorodiphenylphosphine (3 equiv of each), and water
(2 equiv) at 150 °C for 4 h afforded 1 in a mediocre 34% yield.
However, when the reaction was repeated at 180 °C, 1 was
isolated in a significantly improved 74% yield after only 3 h.
Repeating the reaction at 180 °C but further reducing the
reaction time to 90 min (cf. 100 h), we again isolated a 74%
yield of 1. A 60% yield increase, compared to the conventional
Sartori and Mosler procedure (cf. 44% yield), was achieved via
a 97% reduction in the reaction time (Scheme 5). Further
reduction of the irradiation reaction time to 30 min returned a
43% yield of 1, which is essentially identical to that of Sartori
and Mosler but was achieved via a 99.5% reduction in the
reaction time. An X-ray crystal structure of 1 confirmed that
the potentially labile bromine was still intact (see Figure 1 in
the Supporting Information).
With a reliable and robust procedure in place, we probed the
versatility of the procedure applying it to a range of aryl
monocarboxylic acids (Table 1). This study confirmed that
unsubstituted arylcarboxylic acids (entry 2), 2-substituted car-
boxylic acids (entry 3), as well as 2-napthoic acid, a bicyclic
arylcarboxylic acid (entry 4, Table 1), afforded the desired
products 2-4 in 79%, 71%, and 68% yields, respectively.
(11) Sartori, P.; Mosler, G. Phosphorus Sulfur Rel. Elem. 1980, 8, 115-
119.
(12) Kobayashi, T.; Eda, T.; Tamura, H.; Ishibashi, H. J. Org. Chem.
2002, 67, 3156-3159.
(13) SCOPUS has nine citations in the intervening period since the
publication in 1980.
(14) de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. AdV. Org. Synth. 2005,
1, 119-171.
2656 J. Org. Chem., Vol. 72, No. 7, 2007

TABLE 1. Substrates Utilized in the Synthesis of
(Diphenylphosphinoylmethyl)benzenes
SCHEME 7. Sonogashira, Stille, and Suzuki
Transformations Applied to 7
entry
carboxylic acid
yield or result
1
2
4-bromobenzoic acid
benzoic acid
74%
79%
3
2-toluic acid
71%
4
2-napthoic acid
68%
5
phthalic acid
62%
6
7
8
9
10
11
12
13
14
15
16
4-bromoisophthalic acid
5-hydroxyisophthalic acid
2-methoxybenzoic acid
2-iodobenzoic acid
monomethyl phthalate
trimellitic anhydride
salicylaldehyde
2,4-dinitrobenzoic acid
phthalamic acid
anthranilic acid
54%
many products
decomposition
decomposition
no product
no product
decomposition
no product
no product
no product
no product
4-cyanobenzoic acid
SCHEME 6. Synthesis of 4-Bromo-1,3-bis(diphenylphos-
phinoylmethyl)benzene 7
(entry 10), anhydride (entry 11), aldehyde (entry 12), nitro (entry
13), amide (entry 14), amine (entry 15), or nitrile (entry 16)
afforded none of the desired adducts, and in many cases,
decomposition of the starting materials was observed.
With gram quantities of 7 in hand, its transformation via
transition-metal-mediated processes into a subset of chemically
diverse 1,3-bis(diphenylphosphinoylmethyl)benzene analogues
was investigated. Utilizing standard reaction conditions, 7
underwent Sonogashira couplings with O-THP-protected pro-
pargyl alcohol or phenylacetylene, affording the desired alkynes
8 and 9 in 90% and 88% yields, respectively. Curiously, all
attempts at coupling trimethylsilylacetylene to 7 using typical
Sonogashira conditions failed to afford any of the expected
trimethylsilylalkyne-derived product. During the course of our
studies, we observed the tenacious capacity of 1,3-bis(diphe-
nylphosphinoylmethyl)benzenes to hydrogen bond to water and/
or amines (in our case, diisopropylamine), a property that has
been previously observed by Philp et al.3 and is clearly evident
Exemplifying this methodology and for the purposes of our
research, we specifically required 1,2- and 1,3-bis(diphenylphos-
phinoylmethyl)benzene adducts. Utilizing phthalic acid as our
starting material, the synthesis of 1,2-bis(diphenylphosphinoyl-
methyl)benzene 5 was attempted. After microwave irradiation
(180 °C, 90 min), workup, and purification, the previously
unattainable 1,2-bis(diphenylphosphinoylmethyl)benzene 5 was
afforded in an unoptimized 62% yield (entry 5, Table 1; see
Figure 2 in the Supporting Information for the X-ray crystal
structure of 5). Particularly noteworthy, repeating this reaction
at 180 °C (i.e., no warming to 80 °C first) employing a
conVentional oil bath failed to afford any of 5, even after the
reaction time was considerably extended (36 h).
1
in the H NMR of, for example, 8 and 9. Subjecting 7 and
Our requirement for a 1,3-bis(diphenylphosphinoyl)benzene
adduct that contained a bromine atom compelled us to inves-
tigate the potential of 6 (4-iodoisophthalic acid is not com-
mercially available) as a possible starting material for the
synthesis of 7 (Scheme 6). Subjecting 4-bromoisophthalic acid
(6) to the same reaction conditions and quantities of chlo-
rodiphenylphosphine and water (3 equiv of each) utilized
previously for the synthesis of 3, we isolated a 54% yield of
the desired 4-bromo-1,3-bis(diphenylphosphinoyl)benzene ad-
duct 7 as a white solid (entry 6, Table 1). Undertaking a larger-
scale synthesis of 8, we efficiently transformed multigram
quantities (2 g) of 6 into 7 in an excellent 92% yield.
vinyltri-n-butylstannane to typical Stille coupling reaction
conditions afforded the vinyl derivative 10 in a 51% yield, and
subsequent dihydroxylation of the alkene afforded 11 which after
sodium periodate cleavage returned aldehyde 12 (Scheme 7) in
a 76% yield. Utilizing a palladium(0)-mediated reaction process,
the pinacolboronate 13 was readily synthesized, but not isolated,
from 7 and bis(pinacolato)diboron. Subsequent attempts at
utilizing 13 via Suzuki coupling procedures were plagued by
incomplete reactions and or the formation of byproducts
resulting from the decomposition of the organopalladium(II)
intermediate derived from oxidative addition of 13 to the
catalyst. Negating this, we switched to coupling 7 with
arylboronic acids. The Suzuki coupling between 7 and para-
vinylphenylboronic acid was investigated. Using standard reac-
tion conditions, we synthesized styrene adduct 14 in an
unoptimized but satisfactory 56% yield. Transmetalating the
bromine atom on 7 with 2 equiv of n-BuLi at -78 °C followed
by quenching of the presumably formed lithiated species with
isobutanal afforded a complex mixture comprising 7, 1,3-bis-
(diphenylphosphinoylmethyl)benzene, and polar compounds that
were in our hands inseparable and unidentifiable.
Attempting to employ either a starting material containing a
“free” phenol-OH group (entry 7, Table 1) or its O-TBDMS
variant afforded a complex, unidentifiable mixture of com-
pounds. Employing the aryl methyl ether containing 2-meth-
oxybenzoic acid as the starting material (entry 8) failed to return
any of the desired diphenylphosphinoylmethyl adduct. Instead,
a complex polar mixture of compounds was returned, none of
1
which, as judged by H NMR, appeared to contain the methyl
group located on the ether. Likewise, the utilization of 2-iodo-
benzoic acid (entry 9) resulted in the thermally labile C-I bond
decomposing under the reaction conditions. Probing the pos-
sibility of using starting materials that contained a methyl ester
We have developed the first efficient microwave-mediated,
short reaction time protocol for the synthesis of structurally
diverse (diphenylphosphinoylmethyl)benzenes. Using our im-
J. Org. Chem, Vol. 72, No. 7, 2007 2657

was purified by column chromatography on silica gel (3% methanol
proved procedure, the synthesis of the previously unreported
4-bromo-1,3-bis(diphenylphosphinoyl)benzene (7) has been
accomplished. The transformation and elaboration of 7 via
transition-metal-mediated procedures affording functionalized
(diphenylphosphinoylmethyl)benzenes has been accomplished.
The products of these reactions would not be available using
the original Sartori and Mosler reaction conditions. Furthermore,
we have elucidated the structures of 1 and 5 using X-ray crystal
analysis. The ease with which it is now possible to synthesize
multigram quantities of these entities should ensure their
applications within the synthetic, pharmaceutical, agrochemical,
and material chemistry arenas.
in DCM) to afford 115 as a white solid in a 74% yield (503 mg).
1
Uncorrected melting point: mp > 250 °C. H NMR (400 MHz,
CDCl3): δ 3.60 (d, 2H), 6.98-7.01 (m, 2H), 7.44-7.49 (m, 4H),
7.52-7.56 (m, 2H), 7.67-7.72 (m, 4H). 13C NMR (75 MHz,
CDCl3): δ 132.7, 131.9 (d JPC ) 9.1), 131.7 (d JPC ) 5.7), 131.1,
130.3, 128.6, 120.9, 37.4. IR (KBr) ν 2941, 1590, 1492, 1485, 1440,
1436, 1418, 1407, 1312 cm-1. m/z (CI/NH3) 374.1 (79Br, 52%),
373.1 (81Br, 50%), 293.2 (92), 126.2 (32), 114.2 (39), 112.1 (63),
106.0 (88), 98.1 (100), 96.1 (69), 94.1 (64), 84.1 (48), 78.1 (42),
72.1 (39). HRMS calcd for C19H1679BrOP 371.0195, found 371.0195.
Acknowledgment. S.P.B. would like to acknowledge the
support of UEA, EPSRC, the Dovetrust for financial support,
and the EPSRC national mass spectroscopy service at Swansea.
Experimental
Compound 1. Chlorodiphenylphosphine (1 mL, 5.46 mmol) was
added dropwise to a process vial charged with 4-bromobenzoic acid
(360 mg, 1.82 mmol) and water (65 µL, 3.64 mmol, CARE
hydrogen chloride evolved). The vial was capped, and the mixture
was heated at 80 °C for 30 min, then at 180 °C for 1.5 h (microwave
irradiation, Biotage Emrys Creator, reactions conducted at a constant
180 °C with a maximum of 300 W energy input). The vial was
allowed to cool to ambient temperature, and the residue was
suspended in DCM (15 mL), washed with 10% aqueous sodium
carbonate (3 × 15 mL) and water (15 mL), dried over magnesium
sulfate, filtered, and concentrated to dryness in vacuo. The product
Supporting Information Available: Details and results (includ-
ing the CIF files) of the crystallographic analysis of compounds 1
and 5, the synthesis of 2-5, 7-12, and 14, and NMR spectral data
for 1-5, 7-12, and 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO062114K
(15) Knoth, W. H., Jr.; Mrowca, J. J. Aromatic phosphine oxides by
reaction of diarylhalophosphine and benzylic halide. U.S. patent 3975447,
1976.
2658 J. Org. Chem., Vol. 72, No. 7, 2007