One-pot synthesis of unsymmetrical aryl methylphosphinates by insertion of dichlorophosphines into the O-Me bond of anisoles

Article abstract of DOI:10.1016/S0040-4039(01)01197-2

This letter describes a new one-pot method for the synthesis of unsymmetrical aryl methylphoshinates by insertion of phosphorus moiety into the O-Me bond of anisoles. These products are very difficult to obtain with other reported methods requiring several steps.

Full text of DOI:10.1016/S0040-4039(01)01197-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6121–6124
One-pot synthesis of unsymmetrical aryl methylphosphinates by
insertion of dichlorophosphines into the OꢀMe bond of anisoles
Graziano Baccolini* and Carla Boga
Dipartimento di Chimica Organica, Universita`, Viale Risorgimento 4, I-40136 Bologna, Italy
Received 21 June 2001; accepted 4 July 2001
Abstract—This letter describes a new one-pot method for the synthesis of unsymmetrical aryl methylphoshinates by insertion of
phosphorus moiety into the OꢀMe bond of anisoles. These products are very difficult to obtain with other reported methods
requiring several steps. © 2001 Elsevier Science Ltd. All rights reserved.
Since the last century, the Friedel–Crafts type reaction
using PCl3 and AlCl3 has been an excellent method for
the direct attachment of a phosphorus atom to an
aromatic ring to give aryldichlorophosphines or
diarylchlorophosphines. However, this reaction is very
sensitive to the type of substituents present on the
aromatic ring1,2 and often the literature gives conflicting
results.3,4 In particular, it is reported4a that anisole,
upon treatment with phosphorus trichloride and alu-
minum chloride, afforded p-anisylphosphonous dichlo-
ride (A) but in very poor yields and with large amounts
of undistillable residues while in some cases it gave
phenyl dichlorophosphite (B) but always in poor yields.
In addition, it is reported4a,b that this phosphonation
reaction fails completely when thioanisoles are used
(Scheme 1).
formation of heterocyclic compounds related to 2 or of
other unexpected products. In fact, we found that
varying the reagent ratios and the reaction conditions
we have been able to obtain, as prevalent product
(30–40% yield), the benzooxadiphosphole systems 4 and
5 (Scheme 3) using a ratio of 3a:AlCl3:PCl3 of 1:0.6:7
OPCl2
OCH3
undistillable
products
PCl3
+
fresh AlCl3
B
PCl3
comm. AlCl3
OCH3
undistillable
products
+
In contrast to these reported results, in the past years,
we discovered5 that the reaction of PCl3 and AlCl3 with
thioanisoles 1 gave, unexpectedly, the new fused-
bicyclic system6 2 (fused 1,2,3-benzothiadiphosphole) in
good yields (see Scheme 2).
PCl2
A
Scheme 1.
Recently, analyzing the above reported4 data on
anisoles and our results5 on thioanisoles we decided to
reinvestigate the reaction of anisoles with the couple
PCl3/AlCl3, in order to verify whether the reported3,4
large amounts of undistillable residues and the conflict-
uality of the reported results might be due to the
SMe
1) AlCl3, PCl3
2) H2O
X
X
P
P
S
S
X
2 (50%)
1
a, X = Me
b, X = H
Keywords: phosphorylations; insertions; Lewis acids.
* Corresponding author. Tel.: 390512093616; fax: 390512093654;
e-mail: baccolin@ms.fci.unibo.it
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01197-2

6122
G. Baccolini, C. Boga / Tetrahedron Letters 42 (2001) 6121–6124
X
X
X
P
OMe
0.6 AlCl3
7 PCl3
0.6 AlCl3
1 PCl3
1)
1)
X
X
P
O
O
O
O
Me
P
4
2) H2O
2) H2O
X
O
O
P
P
O
O
X
3
6
5
Scheme 3.
R
O
O
and refluxing for about 20–25 h without solvent. After
several studies to understand the structure of the other
by-products, we found7,8 that, when the reaction is
carried out in appropriate reaction conditions, an unex-
pected ‘insertion’ of the phosphorus moiety into the
OꢀMe bond of anisole 3 occurs, to give compound 6 as
the major product (Scheme 3). The best selective forma-
tion of 6 (50–70% yield) was obtained with anisole 3:
AlCl3:PCl3 ratio of 1:0.6:1, at 70–80°C for 7–10 h in an
atmosphere of dry nitrogen and without solvent.
OMe
1 AlCl3
1 RPCl2
P
1)
Me
2) H2O
X
X
3a, b
7a, b (8a, b)
a, X = Me
b, X = H
7, R= Ph
8, R= Cyclohexyl
A suggested mechanism, depicted in Scheme 4, for this
phosphorus insertion reaction was also reported.7 The
insertion of the P moiety is explained by the attack of
a molecule of PCl3 on the anisole–AlCl3 complex and
subsequent migration of the methyl group on the same
P atom giving the intermediate A%. Subsequent nucleo-
philic attack of free anisole on phosphonium salt A% gives
B% which, after quenching with water, gives phosphonate
6.
O
R
OMe
P
O
X
O
X
H P
O
Ph
10a, b (11a, b)
Now, analyzing the above results, we decided to investi-
gate the reaction of anisoles 3 with the couple RPCl2/
AlCl3, in order to verify whether the insertion of the P
moiety into the OꢀMe bond of anisole may occur also
with dichlorophosphines RPCl2. In this manner it should
be possible to obtain in a one-pot procedure racemic
methylphosphinates such as 7 or 8 (see Scheme 5), which
10, R= Ph
11, R= Cyclohexyl
9
Scheme 5.
are very difficult to obtain with simple procedures. In
fact, it should be noted that the aryl methylphenylphos-
phinates 7 are known but their synthesis9 requires
complex procedures involving several steps, as described
in Scheme 6, while compounds 8 are still unknown.
-
AlCl4
Cl
Cl
Cl
Cl
Cl
+
P
P
O
Me
Me
Me
AlCl3
O
O
X
When we used RPCl2 with R=cyclohexyl, the reaction
led to the formation of the corresponding aryl cyclo-
hexylmethylphoshinates (8a,b) in good yields. When we
used PhPCl2 we obtained a good formation of 7a (50%)
but small amounts of 7b (20%). In this case the formation
A’
X
X
3.AlCl3 complex
- MeCl
MeOH
PhPCl2
PhPClMe
PhP(O)HMe
PCl5
OH
X
-
AlCl4
Cl
+
O
P
O
H2O
6
Me
X
X
PhP(O)ClMe
7
B’
Scheme 4.
Scheme 6.

G. Baccolini, C. Boga / Tetrahedron Letters 42 (2001) 6121–6124
6123
of phosphinoxide 9 (40%) is preferred due to the com-
petitive attack on the para position of anisole. The best
selective formation of 7 or 8 was obtained with anisole
3a:AlCl3:RPCl2 ratio of 1:1:1, at room temperature for
30–35 h or at 60°C for 4–6 h in an atmosphere of dry
nitrogen and without solvent. Compounds 10 or 11
were obtained in small amounts as by-products. When
we used a ratio of anisole 3:AlCl3:RPCl2 of 2:1:1, we
obtained a good formation of diarylphosphonate 10 or
11 (45–60%). In all cases, the structures were assigned
by comprehensive spectral data.10
ture and the reaction was monitored both by TLC and
GC–MS analyses. After about 30–35 h the reaction mix-
ture was diluted with 25 mL of dichloromethane, then it
was quickly treated with water and extracted. The
organic layer was dried with anhydrous Na2SO4 and the
solvent was removed. A quick flash chromatography of
the residue gave compounds 7a in 50% yield.
4-Methylphenyl methyl(phenyl)phosphinate (7a): mp 65–
67°C (lit.9 66–67°C), Rf=0.20 (light petroleum:ethyl ace-
tate=1:1), 1H NMR (300 MHz, CDCl3)
l (ppm):
7.90–7.80 (m, 2H), 7.60–7.40 (m, 3H), 7.05–6.95 (m, 4H),
2
2.26 (s, 3H, p-CH3), 1.84 (d, 3H, JP–H=14.4 Hz, PCH3);
13C NMR (75.56 MHz, CDCl3) l (ppm): 148.5 (d, 1C,
J=9.0 Hz), 134.2 (s, 1C), 132.5 (d, 1C, J=2.3 Hz), 131.3
(d, 2C, J=10.6 Hz), 130.1 (s, 2C), 128.6 (d, 2C, J=13.0
Hz), 120.4 (d, 2C, J=4.5 Hz), 115.6 (d, 1C, J=75.7 Hz),
20.7 (s, 1C), 16.0 (d, 1C, J=102.2 Hz); 31P NMR (120.75
MHz, CDCl3) l (ppm): 41.8 (m); MS (70 eV, EI): m/z
(%): 246 (M+, 52), 245 (M+−1, 100), 139 (67), 91 (20), 77
(49), 41 (3); HRMS: calcd for C14H15O2P: 246.0810.
Found: 246.0808; calcd C, 68.29; H, 6.14; found C, 68.32,
H, 6.12.
In conclusion we have found that insertion of the
phosphorus moiety into the OꢀMe bond of anisoles can
occur also with RPCl2. In this manner the reaction
permits to obtain in a one-pot reaction at room temper-
ature racemic methylphosphonates which are very
difficult to obtain with other reported methods.
Acknowledgements
4-Methylphenyl cyclohexyl(methyl)phosphinate (8a): 60%
yield as greasy solid, Rf=0.13 (light petroleum:ethyl ace-
tate=6:4), H NMR (300 MHz, CDCl3) l (ppm): 7.15–
Investigation supported by University of Bologna
(funds for selected research topics A.A. 1999–2001),
Ministero dell’ Universita` e della Ricerca Scientifica e
Tecnologica (MURST, Roma), Consiglio Nazionale
delle Ricerche (CNR, Roma).
1
7.05 (m, 4H), 2.31 (s, 3H, p-CH3), 2.14–2.00 (m, 2H),
1.92–1.78 (m, 3H), 1.78–1.68 (m, 1H), 1.47 (d, 3H,
2JP–H=13.0 Hz, PCH3), 1.50–1.20 (m, 5H); 13C NMR
(75.56 MHz, CDCl3) l (ppm): 148.6 (d, 1C, J=9.1 Hz),
134.0 (s, 1C), 130.1 (s, 2C), 120.2 (d, 2C, J=3.8 Hz), 38.5
(d, 1C, J=96.2 Hz), 26.0 (d, 2C, J=14.9 Hz), 25.7 (s,
1C), 25.4 (dd, 2C, J=8.0 Hz, J=2.9 Hz), 20.6 (s, 1C),
10.7 (d, 1C, J=87.3 Hz); 31P NMR (120.75 MHz,
CDCl3) l (ppm): 57.3 (m); MS (70 eV, EI): m/z (%): 252
(M+, 91), 197 (M+− 55, 99), 170 (84), 155 (100), 108 (35),
91 (46); HRMS: calcd for C14H21O2P: 252.1279. Found:
252.1275; calcd C, 66.65; H, 8.39; found C, 66.60; H,
8.37.
References
1. Michaelis, A. Chem. Ber. 1879, 12, 1009.
2. Fild, M.; Schmutzler, R. In Organic Phosphorus Com-
pounds; Kosolapoff, G.; Maier, L., Eds.; Wiley-Inter-
science, 1972; Vol. 4, p. 79.
3. (a) Michaelis, A. Justus Liebigs Ann. Chem. 1896, 294, 1;
(b) Kunz, P. Chem. Ber. 1894, 27, 2559–2565.
4. (a) Miles, J. A.; Beeny, M. T.; Ratts, K. W. J. Org.
Chem. 1975, 40, 343–347; (b) Sime´on, F.; Jaffre`s, P.;
Villemin, D. Tetrahedron 1998, 54, 10111–10118.
5. (a) Baccolini, G.; Mezzina, E.; Todesco, P. E.; Foresti, E.
J. Chem. Soc., Chem. Commun. 1988, 304–305; (b) Bac-
colini, G.; Mezzina, E.; Todesco, P. E. J. Chem. Soc.,
Perkin Trans. 1 1988, 3281–3283; (c) Baccolini, G.;
Beghelli, M.; Boga, C. Heteroatom Chem. 1997, 8, 551–
556; (d) Gang, W.; Wasylishen, R. E.; Power, W. P.;
Baccolini, G. Can. J. Chem. 1992, 72, 1229–1235.
6. For a recent review on fused rings, see: Tebby, J. C. In
Comprehensive Heterocyclic Chemistry II; Katrizky, A.
R.; Rees, C. W. E.; Scriven, F. V.; Jones, G., Eds.
Bicyclic systems with ring junction, phosphorus, arsenic,
antimony, or bismuth atoms; Pergamon Press: New
York, 1996; Vol. 8, pp. 864–888.
7. Baccolini, G.; Boga, C. Synlett 1999, 822–824.
8. Baccolini, G.; Bazzocchi, M.; Boga, C. Eur. J. Org.
Chem. 2001, 2229–2233.
9. Dunn, E. J.; Purdon, J. G.; Bannard, R. A. B.; Albright,
K.; Buncel, E. Can. J. Chem. 1988, 66, 3137–3142.
10. Typical procedure: p-Methylanisole (3b) (0.007 mol),
AlCl3 (1.2 g, 0.009 mol), and dichlorophenylphosphine
(0.007 mol) were placed in a dried apparatus, filled with
dry nitrogen. The mixture was stirred at room tempera-
Phenyl cyclohexyl(methyl)phosphinate (8b): greasy solid,
40% yield, Rf=0.20 (light petroleum:ethyl acetate=1:1),
1H NMR (300 MHz, CDCl3) l (ppm): 7.38–7.25 (m, 2H),
7.24–7.10 (m, 3H), 2.15–2.00 (m, 2H), 1.95–1.80 (m, 2H),
2
1.80–1.70 (m, 1H), 1.49 (d, 3H, JP–H=13.0 Hz, PCH3),
1.60–1.10 (m, 6H); 13C NMR (75.56 MHz, CDCl3) l
(ppm): 151.0 (d, 1C, J=9.1 Hz), 129.7 (s, 2C), 124.5 (s,
1C), 120.6 (d, 2C, J=4.1 Hz), 38.6 (d, 1C, J=96.3 Hz),
26.1 (d, 2C, J=14.9 Hz), 25.7 (d, 1C, J=1.2 Hz), 25.5
(dd, 2C, J=7.2 Hz, J=3.0 Hz), 10.9 (d, 1C, J=87.2 Hz);
31P NMR (120.75 MHz, CDCl3) l (ppm): 58.1 (m); MS
(70 eV, EI): m/z (%): 238 (M+, 66), 183 (M+−55, 100), 141
(82), 94 (37), 77 (74), 41 (69); HRMS: calcd for
C13H19O2P: 238.1123. Found: 238.1120; calcd C, 65.53;
H, 8.04; found C, 65.50; H, 8.07.
(4-Methoxyphenyl)phenylphosphine oxide (9): mp 68–
70°C, lit. 1169–70°C, 1H NMR (300 MHz, CDCl3) l
(ppm): 8.06 (d, 1H, 1JP–H=481 Hz), 7.80–6.90 (m, 9H),
3.85 (s, 3H, OCH3), 31P NMR (120.75 MHz, CDCl3) l
(ppm): 21.7 (dm, 1JP–H=481 Hz); MS (70 eV, EI): m/z
(%): 232 (M+, 100), 231 (M+−1, 92), 155 (13), 154 (14),
139 (7), 108 (45), 92 (10), 77 (29); HRMS: calcd for
C13H13O2P: 232.0653. Found: 232.0656; calcd C, 67.24;
H, 5.64; found C, 67.20; H, 5.67.

6124
G. Baccolini, C. Boga / Tetrahedron Letters 42 (2001) 6121–6124
Bis(4-methylphenyl) phenylphosphonate (10a): greasy solid,
J=1.8 Hz), 20.6 (s, 2C); 31P NMR (120.75 MHz, CDCl3)
l (ppm): 26.7 (m); MS (70 eV, EI): m/z (%): 344 (M+, 71),
289 (M+−55, 26), 155 (20), 108 (100), 91 (21), 55 (42), 41
(31); HRMS: calcd for C20H25O3P: 344.1541. Found:
344.1539; calcd C, 69.75; H, 7.32; found C, 69.70; H,
7.30.
60% yield, Rf=0.80 (light petroleum:ethyl acetate=1:1),
1H NMR (300 MHz, CDCl3) l (ppm): 8.00–7.88 (m, 2H,
arom.), 7.65–7.55 (m, 1H, arom.), 7.55–7.45 (m, 2H,
arom.), 7.15–7.05 (m, 8H, arom.), 2.29 (s, 6H, CH3); 13C
NMR (75.56 MHz, CDCl3) l (ppm): 148.1 (d, J=7.7
Hz), 134.6 (s), 133.1 (d, J=3.1 Hz), 132.3 (d, J=10 Hz),
130.1 (s), 128.6 (d, J=15.6 Hz), 126.9 (d, J=192.2 Hz),
120.3 (d, J=4.6 Hz), 20.7 (s); 31P NMR (120.75 MHz,
CDCl3) l (ppm): 12.16 (t, JPH=13.5 Hz, P); MS (70 eV,
EI): m/z (%): 338 (M+, 96), 337 (M+−1, 100), 231 (44),
198 (24), 108 (17), 91 (80), 65 (47); HRMS: calcd for
C20H19O3P: 338.1072. Found: 338.1074; calcd: C, 71.00;
H, 5.66; found C, 71.05; H, 5.64.
Bis(4-methylphenyl) cyclohexylphosphonate (11a): greasy
solid, 55% yield, Rf=0.73 (light petroleum:ethyl acetate=
6:4), 1H NMR (300 MHz, CDCl3) l (ppm): 7.20–6.95 (m,
8H), 2.27 (s, 6H, CH3), 2.25–2.00 (m, 3H), 2.00–1.80 (m,
2H), 1.80–1.70 (m, 1H), 1.70–1.45 (m, 2H), 1.40–1.15 (m,
3H); 13C NMR (75.56 MHz, CDCl3) l (ppm): 148.3 (d,
2C, J=9.5 Hz), 134.3 (s, 2C), 130.0 (s, 4C), 120.1 (d, 4C,
J=4.1 Hz), 35.9 (d, 1C, J=141.5 Hz), 25.9 (d, 2C,
J=17.1 Hz), 25.64 (d, 2C, J=6.6 Hz), 25.60 (d, 1C,
Diphenyl cyclohexylphosphonate (11b): 50% yield, mp:
62–63°C, lit.12 62°C, Rf=0.81 (light petroleum:ethyl ace-
1
tate=1:1), H NMR (300 MHz, CDCl3) l (ppm): 7.40–
7.20 (m, 4H), 7.20–7.05 (m, 6H), 2.30–2.00 (m, 3H),
1.95–1.80 (m, 2H), 1.80–1.45 (m, 3H), 1.45–1.20 (m, 3H);
13C NMR (75.56 MHz, CDCl3) l (ppm): 150.5 (d, 2C,
J=9.7 Hz), 129.6 (s, 2C), 124.9 (d, 4C, J=1.1 Hz), 120.5
(d, 4C, J=4.3 Hz), 36.0 (d, 1C, J=141.5 Hz), 25.9 (d,
2C, J=17.1 Hz), 25.74 (d, 2C, J=4.9 Hz), 25.62 (d, 1C,
J=1.6 Hz); 31P NMR (120.75 MHz, CDCl3) l (ppm):
27.0 (m); MS (70 eV, EI): m/z (%): 316 (M+, 78), 261
(M+−55, 31), 140 (22), 94 (100), 55 (50), 41 (40); HRMS:
calcd for C18H21O3P: 316.1228. Found: 316.1224; calcd
C, 68.34; H, 6.69; found: C, 68.30; H, 6.67.
11. Curci, R.; Piepoli, A. M. Boll. Sci. Fac. Chim. Ind.
Bologna 1969, 27, 237–243.
12. Muller, E.; Padeken, G. Chem. Ber. 1967, 100, 521–532.
.