Synthesis of monosubstituted phosphinic acids: Palladium-catalyzed cross-coupling reactions of anilinium hypophosphite [8]

Full text of DOI:10.1021/ja005721c

510
J. Am. Chem. Soc. 2001, 123, 510-511
Table 1. Influence of Conditions on the Yield of
Phenylphosphinate
Synthesis of Monosubstituted Phosphinic Acids:
Palladium-Catalyzed Cross-Coupling Reactions of
Anilinium Hypophosphite
Jean-Luc Montchamp* and Yves R. Dumond
solventa
CH3CN
benzene
dioxane
THF
dry DMF
reagent DMF
reagent DMF, in air Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN, in air
CH3CN
CH3CN
CH3CN
base
catalystb
yieldc
Department of Chemistry, Box 298860
Texas Christian UniVersity, Fort Worth, Texas 76129
entry equiv of 4
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.1
1.1
2.0
2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
i
i
i
i
i
i
i
i
ii
iii
91
68
53
85
96
87
86
97
92
96
ReceiVed October 23, 2000
Functionalized monoarylphosphinic acids are valuable inter-
mediates for the preparation of medicinal compounds and
synthetic intermediates, but methods to access them are currently
limited.1 During studies aimed at the preparation of biologically
active phosphinic acids, we required new methods for phosphorus-
carbon bond formation under mild conditions. Despite recent
advances in the palladium-catalyzed formation of carbon-
heteroatom bonds,2 the direct preparation of monosubstituted
phosphinic acids via palladium-catalyzed cross-coupling has not
been described previously. Herein, we report the novel palladium-
catalyzed cross-coupling reaction of hypophosphite salts with
aromatic halides, which addresses the following factors: (1)
selective formation of monosubstituted products, (2) wide ap-
plicability, (3) functional group tolerance, (4) convenient reaction
conditions, and (5) avoidance of hazardous anhydrous hypophos-
phorous acid. In principle, such preparation of monosubstituted
phosphinic acids 1 is most atom-efficient because it uses the direct
alkylation of environmentally benign H3PO2 or its salts (eq 1).
Et3N
Et3N
Et3N
9
2
2
2
2
1.1
1.1
1.2
10
11
12
13
14
15
Et3N i + 10% BHT 96
Et3N
Et3N
pyr.
i
i
i
i
86
81
78
38
none
a Reactions in DMF were conducted at 85 °C, all others were at the
reflux temperature. Reaction times: entries 1-7, 12-24 h; entries
8-11, 8 h; entries 12-15, 3-6 h. HPLC grade CH3CN was used. PhI
concentration was 0.2 M. b Catalyst: i, Pd(PPh3)4; ii, Cl2Pd(PPh3)2; iii,
Pd(OAc)2 + 4 PPh3. BHT ) 2,6-di-tert-butyl-4-methylphenol. c Yields
were determined by 31P NMR analysis of the crude reaction mixtures.
coupling between anhydrous H3PO2 and a steroidal dienyl triflate.5
Schwabacher has developed an elegant cross-coupling of aryl
iodides with methyl- or tert-butylhypophosphites prepared in situ.6
However, these reactions were limited to using reactive iodides
under strickly anaerobic and anhydrous conditions, because alkyl
hypophosphites rapidly decompose thermally or in the presence
of moisture or air.6
The preparation of phosphonate diesters and disubstituted
phosphinate esters via cross-coupling was reported relatively early
on, but is limited to nucleophiles which contain only one P-H
bond.3 In contrast, hypophosphorus derivatives are powerful
reducing agents with two reactive P-H bonds, leading to the
potential for unwanted disubstitution and reduction products (2
and 3, respectively, eq 1). Indeed, a number of substrates have
been reduced with sodium hypophosphite or H3PO2, in the
presence of transition metals such as palladium.4 At the outset,
we expected the competing catalytic transfer hydrogenation
pathway to be the most difficult problem.
To avoid the problems associated with handling anhydrous
H3PO2, we developed a safer reagent. Anilinium hypophosphite
4, a cheap, highly crystalline, high-melting, and nonhygroscopic
salt, was found to be most convenient.7,8 Initial investigations
focused on the reaction of 4 with iodobenzene using Pd(PPh3)4
(2 mol %) as the catalyst (Table 1). Several solvents are
satisfactory, but acetonitrile and anhydrous DMF are the most
suitable. Remarkably, no special precautions are necessary, and
phenylphosphinic acid is still obtained in good yield using reagent
grade DMF (entry 6), even in the presence of air (entry 7). Various
palladium catalysts delivered consistently high yields, and the
presence of a radical inhibitor had no effect (Table 1, entries
8-11), while no product was observed without catalyst. Finally,
the influence of the base was briefly probed, and pyridine was
found to be equivalent to triethylamine (Table 1, entry 14 vs 13),
while in the absence of added base (Table 1, entry 15), the yield
was lowered but a significant amount of product was still
produced.
Inspection of the literature revealed only three publications
dealing with the cross-coupling of hypophosphorus com-
pounds, but these provided little or no discussion of the possible
reductive pathways.5,6 Holt reported a single example of cross-
(1) Typically, monoaryl phosphinic acids are prepared from the corre-
sponding dichlorophosphines. For a discussion, see: Bennett, S. N. L.; Hall,
R. G. J. Chem. Soc. Trans. 1 1995, 1145. The Ciba Geigy group reported an
alternative two-step synthesis of phosphinic acids, based on the masking of a
P-H bond and cross-coupling with 10% Pd(PPh3)4.
(2) Reviews: (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (b)
Baran˜ano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem. 1997, 1, 287. See
also references cited in: (c) Harris, M. C.; Buchwald, S. L. J. Org. Chem.
2000, 65, 5327. (d) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1,
1307. (e) Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T. J. Org. Chem.
2000, 65, 4776. (f) Oshidi, T.; Imamoto, T. J. Am. Chem. Soc. 1992, 114, 3975.
(3) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron Lett.
1980, 21, 3595. (b) Hirao, T.; Masunaga, T.; Yamada, N. Bull. Chem. Soc.
Jpn. 1982, 55, 909. (c) Xu, Y.; Zhang, J. Synthesis 1984, 778. (d) Xu, Y.; Li,
Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1983, 377. (e) Xu, Y.; Li, Z.; Xia,
J.; Guo, H.; Huang, Y. Synthesis 1984, 781.
The reaction displays a remarkably broad scope for a single
set of conditions, and these results are summarized in Table 2.
Aryl iodides, bromides, and triflates, as well as benzylic chlorides,
all undergo cross-coupling in moderate to excellent yields. The
monophosphinic acid product could be obtained conveniently, and
(6) (a) Lei, H.; Stoakes, M. S.; Schwabacher, A. W. Synthesis 1992, 1255.
(b) Schwabacher, A. W.; Stefanescu, A. D. Tetrahedron Lett. 1996, 37, 425.
(7) See Supporting Information for details. This salt has been reported in
the literature: Schmidt, H. Chem. Ber. 1948, 81, 477.
(8) Other reagents can be used: Montchamp, J.-L.; Dumond, Y. R.
Unpublished results. (a) Triethylammonium and N-ethylpiperidinium hypo-
phosphites give slightly lower yields than 4, and are less convenient to handle.
Ammonium and sodium hypophosphites can also react but require experimental
modifications. (b) In situ generated (TMSO)2PH also undergoes the reaction.
(4) (a) Johnstone, R. A. W.; Wilby, A. H. Chem. ReV. 1985, 85, 129. (b)
Boyer, S. K.; Bach, J.; McKenna, J.; Jagdmann, E., Jr. J. Org. Chem. 1985,
50, 3408.
(5) Holt, D. A.; Erb, J. M. Tetrahedron Lett. 1989, 30, 5393.
10.1021/ja005721c CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/22/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 3, 2001 511
Scheme 1. Postulated Mechanism
Table 2. Cross-Coupling Reactions of Anilinium Hypophosphitea
31P NMR yield, %b
(isolated yield, %)
entry
Ar-X
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
21
22
23
24
25
26
27
C6H5-I
C6H5-I
CH3CN
DMF
97
96 (89)
96 (91)
93 (74)
98 (87)
92
2-MeC6H4-I
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
4-CH3COC6H4-I
3-MeC6H4-I
more convenient when oxidative addition into the C-X bond is
facile. The amount of reduction through transfer hydrogenation
becomes much more significant when the rate of oxidative
addition in the C-X bond is slow. For example, substrates
undergoing oxidative addition readily gave high yields of cross-
coupled product, while in the case of the deactivating electron-
donating methoxy substituent, reduction competed to produce
anisole in 49% yield (Table 2, entry 2 vs 11 vs 12). As little
as 0.2 mol % Pd(PPh3)4 gave a quantitative yield of PhPO2H2
(Table 2, entry 27). On the other hand, ortho substitution con-
siderably slows down, or even suppresses, the reaction (Table 2,
entry 26).
A possible mechanism is presented in Scheme 1. Oxidative
additions into the C-X and P-H bonds are two competitive
processes. When oxidative addition into C-X is facile, little
reduction is observed, but when it is slow, reduction becomes
dominant. Since the base has little influence, and formation of a
hypophosphite dianion is unlikely, the P(III) form of 4 is
presumably the reactive species,8b and the reaction proceeds
through a phosphonium intermediate.10
4-O2NC6H4-I
4-MeOC6H4-I
4-MeOC6H4-I
2-BrC6H4-I
48
91 (85)c
65
3-ClC6H4-I
C6H5-Br
95 (94)
81
4-MeOC6H4-Br
4-MeOC6H4-Br
4-ClC6H4-Br
4-HOOCC6H4-Br
naphthyl-2-Br
C6H5-OTf
51
85c
75
quant.
74 (71)d
81
65
74
4-MeO2CC6H4-OTf
naphthyl-1-OTf
C6H5CH2Cl
4-MeOC6H4CH2Cl
4-CH2dCHC6H4CH2Cl
4-NCC6H4-Cl
4-NCC6H4-Cl
2,6-(Me)2C6H3-Br
C6H5-I
81 (66)
60 (46)
55 (34)
0
71c
<2
CH3CN
quant.e
The influence of the phosphine ligand was briefly investigated,
with the hope of controlling the partitioning between transfer
hydrogenation and cross-coupling. Using Pd(OAc)2/dppp (2 and
2.2 mol %, respectively) in place of Pd(PPh3)4 was a superior
alternative and decreased the competing reduction (Table 2, entries
7 vs 8, 12 vs 13, and 24 vs 25). With this catalyst system, even
the activated 4-chlorobenzonitrile reacted in 71% yield, while no
product formed with Pd(PPh3)4. Further studies will be conducted
along these promising leads.
a All reactions were conducted at 80-85oC and reaction times were
not optimized: entries 1, 2, 4, 5, 6, 10, and 15, 2-6 h; entries 21-23,
7-9 h; all other entries, 18-24 h. 2 equiv of 4 was used in CH3CN,
1.2 equiv of 4 was used in DMF. b Reduction products constitute the
mass balance. In all instances, yield of Ar2P(O)OM was <2%. c 2 mol
% Pd(OAc)2 + 2.2 mol % Ph2P(CH2)3PPh2 (dppp) was used as the
catalyst. d Isolated as the butyl ester (see ref 9). e 0.2 mol % Pd(PPh3)4
was employed.
In conclusion, a straightforward synthesis of monosubstituted
phosphinic acids has been developed, based on the Pd-catalyzed
reaction between anilinium hypophosphite and various aromatic
electrophiles. Efforts to optimize the catalyst and to broaden the
scope of this novel reaction to unactivated chlorides and alkenyl
or allylic partners are currently underway in our laboratory.
in better than 95% purity after solvent removal, acidification, and
extraction.9 Several generalizations can be made about this novel
cross-coupling. Excellent selectivity is observed for the formation
of monosubstituted over disubstituted phosphinates. The reaction
does not require the use of strictly anhydrous, degassed, solvents
and proceeds well even in the presence of small amounts of
moisture.
Even functionalities which can be reduced easily under phase-
transfer hydrogenation4 are tolerated, although the reaction time
becomes important to avoid reduction of the product when an
excess of 4 is employed. The best results are obtained when the
reaction is conducted in DMF at 85 °C with a slight molar excess
of 4 (1.1-1.2 equiv), but refluxing CH3CN and 2 equiv of 4 is
Acknowledgment. The authors thank the donors of the Petroleum
Research Fund, administered by the ACS (34334-G1), and the Robert
A. Welch Foundation (P-1435) for support of this research. We also thank
Mr. Mendes-Rojas and Prof. W. Watson for the X-ray of anilinium
hypophosphite 4.
Supporting Information Available: Experimental procedures, rep-
resentative spectral data, and crystallographic data for 4 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(9) In a typical experiment (Table 2, entry 2), iodobenzene (2 mmol),
hypophosphite 4 (2.2 mmol), and Et3N (6 mmol) were dissolved in anhydrous
DMF (10 mL). Pd(PPh3)4 (0.04 mmol) was added, and the solution was heated
to 85 °C under N2. The reaction mixture was then concentrated in vacuo,
acidified with aqueous KHSO4 (1 M, saturated with NaCl), and extracted with
EtOAc. Drying over MgSO4 and concentration gave phenyl phosphinic acid
in 89% yield and >98% purity. The crude acid can also be esterified; see:
Dumond, Y. R.; Baker, R. L.; Montchamp, J. L. Org. Lett. 2000, 2, 3341.
JA005721C
(10) Intermediacy of phosphonium ions during cross-coupling has been
observed previously: (a)Martorell, G.; Garc´ıas, X.; Janura, M.; Saa´, J. M. J.
Org. Chem. 1998, 63, 3463. (b) Hinkle, R. J.; Stang, P. J.; Kowalski, M. H.
J. Org. Chem. 1990, 55, 5033. (c) Tunney, S. E.; Stille, J. K. J. Org. Chem.
1987, 52, 748.