CuX2-mediated halolactonization reaction of monoesters of 1,2-allenyl phosphonic acids and their suzuki cross-coupling reaction

Article abstract of DOI:10.1021/jo802051r

CuX₂-mediated (X = Cl, Br) halolactonization of monoesters of 1,2-allenyl phosphonic acids is presented.The reaction proceeded smoothly under the mild condition for differently substituted allenic substrates giving the 4-halo-2,5-dihydro[1,2]ox

Full text of DOI:10.1021/jo802051r

CuX2-Mediated Halolactonization Reaction of Monoesters of
1,2-Allenyl Phosphonic Acids and Their Suzuki Cross-Coupling
Reaction
Fei Yu,† Xiongdong Lian,† Jinbo Zhao,† Yihua Yu,‡ and Shengming Ma*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China, and Shanghai Key
Laboratory of Functional Magnetic Resonance Imaging, Physics Department, East China Normal
UniVersity, Shanghai 200062, People’s Republic of China
masm@mail.sioc.ac.cn
ReceiVed September 16, 2008
CuX2-mediated (X ) Cl, Br) halolactonization of monoesters of 1,2-allenyl phosphonic acids is presented.
The reaction proceeded smoothly under the mild condition for differently substituted allenic substrates
giving the 4-halo-2,5-dihydro[1,2]oxaphosphole 2-oxides in good yields. The Suzuki cross-coupling
reaction of these bromides and even chlorides with organic boronic acids under the catalysis of
PdCl2(Sphos)2 afforded 4-substitueted-2,5-dihydro[1,2]oxaphosphole 2-oxides in moderate to good yields.
Introduction
organophosphorous derivatives.5 Methods have been developed
using the allenic phosphonates or phosphonic acids: for example,
Macomber and co-workers have disclosed cyclization of allenic
phosphonic acids with different electrophiles (eq 1),6 which
provides a convenient method for the preparation of 1,2-oxaphos-
phol-3-enes. Subsequent reports7 from other groups showed that
the 2,5-dihydro[1,2]oxaphosphole 2-oxide derivatives would be
formed directly via dialkyl phosphonates by treating with certain
electrophilic reagents, such as Cl+, I+, SO2Cl2, etc.
The phosphorus-containing compounds are always attractive due
to their various biological activities1 and catalytic properties.2 So
far, the phosphorylated heterocycles and related compounds have
shown their superiorities and are already widely used in the field
of agrochemistry and pharmaceuticals such as pesticides, insecti-
cides, fungicides, bactericides, and growth regulators.3 Phospho-
nateshavebetterphysiologicalstabilitybecausethecarbon-phosphorus
bond is not susceptible to enzymatic degradation by phosphatases,
and have better cell permeability due to the more lipophilic nature
of the phosphonate esters.4 Among them the oxaphospholenes had
been extensively studied not only for their potential biological
activities but also as useful precursors for the synthesis of
* Corresponding author. Fax: (+86) 21-64167510.
† Chinese Academy of Sciences.
‡ East China Normal University.
We have previously described a convenient and efficient method
for the synthesis of ꢀ-halobutenolides. Both ꢀ-chloro- and ꢀ-bro-
mobutenolides can be obtained in high to excellent yields by the
(1) (a) Mader, M. M.; Bartlett, P. A. Chem. ReV. 1997, 97, 1281. (b)
Brassfield, H. A.; Jacobsen, R. A.; Verkade, J. G. J. Am. Chem. Soc. 1975, 97,
4143. (c) Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem. 1994, 59, 2976.
(d) Morita, I.; Kunimoto, K.; Tsuda, M.; Tada, S. I.; Kise, M.; Kimura, K. Chem.
Pharm. Bull. 1987, 35, 4144. (e) Stewart, J. D.; Liotta, L. J.; Benkovic, S. J.
Acc. Chem. Res. 1993, 26, 396. (f) Collard, J.; Benezra, C. Tetrahedron Lett.
1982, 23, 3725.
(2) For reviews, see: (a) Brunel, J. M.; Buono, G. Top. Curr. Chem. 2002,
220, 79. (b) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(3) (a) Cupta, H. C. L. Insecticides: Toxicology and Uses; Agrotech
Publishing Academy Press: Udaipur, India, 1999, 51211. (b) Matsumara, F.
Tocicology of Insecticides, 2nd ed.; Plenum Press: New York, 1985; pp 62-
90.
(4) (a) Racha, S.; Vargeese, C.; Vemishetti, P.; El-Subbagh, H. I.; Abushanab,
E.; Panzica, R. P. J. Med. Chem. 1996, 39, 1130. (b) Reist, E. J.; Sturm, P. A.;
Pong, R. Y.; Tanga, M. J.; Sidwell, R. W. Synthesis of Acyclonucleoside
Phosphonates for Evaluationas Antiviral AgentsIn Nucleotide Analogues as
AntiViral Agents; Martin, J. C., Ed.; American Chemical Society: Washington,
DC, 1989; pp 17-34.
(5) (a) Hah, J.; Lee, B.; Lee, S.; Lee, H. Tetradron Lett. 2003, 44, 5811. (b)
Macomber, R. S.; Guttadauro, M.; Pinhas, A. R.; Bauer, J. K. J. Org. Chem.
2001, 66, 1480. (c) Minami, T.; Motoyoshiya, J. Synthesis 1992, 333.
1130 J. Org. Chem. 2009, 74, 1130–1134
10.1021/jo802051r CCC: $40.75 2009 American Chemical Society
Published on Web 01/05/2009

Halolactonization Reaction of 1,2-Allenyl Phosphonic Acids
TABLE 1. Preparation of the Starting Materials 3a-n
entry
R1
R2
R3
yield of 2 (%)
yield of 3 (%)
1
2
3
4
5
6
7
8
n-Bu
Bn
allyl
Me
Me
Me
Me
Et
Me
Me
Me
Me
Et
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
(1g)
(1h)
(1i)
(1j)
(1k)
(1l)
(1m)
(1n)
72 (2a)
51 (2b)
98 (2c)
81 (2d)
52 (2e)
32 (2f)
74 (2g)
80 (2h)
96 (2i)
78 (2j)
73 (2k)
62 (2l)
63 (2m)
66 (2n)
93 (3a)a
85 (3b)b
75 (3c)c
81 (3d)c
82 (3e)c
66 (3f)c
55 (3g)c
57 (3h)c
85 (3i)c
42 (3j)c,d
64 (3k)b
69 (3l)b
99 (3m)b
99 (3n)b
2-methylallyl
n-C6H13
n-Bu
n-Bu
Me
n-Bu
n-Bu
allyl
-(CH2)4-
-(CH2)5-
-(CH2)5-
9
Me
H
H
H
H
Et
n-Pr
H
H
H
10
11
12
13
14
Me
n-Bu
H
Me
Me
a The reaction was conducted in H2O under reflux overnight. b The reaction was conducted in H2O at 80 °C overnight. c The reaction was conducted
in a mixed solvent of H2O and MeOH in a ratio of 1:1 under reflux. d 55% of 2j was recovered.
reaction of 2,3-allenoic acids or ester with CuX2 in aqueous
acetone.8 Subsequent metal-mediated coupling reactions9 made the
ꢀ-bromobutenolides an important class of building blocks for the
introduction of different types of R′ at the ꢀ-position (eq 2).
TABLE 2. CuCl2-Mediated Chlorocyclization Reaction of Ethyl
(2-Methylocta-2,3-dien-4-yl)phosphonate 3a
entry
CuCl2 (equiv)
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
2
3
4
5
4
4
4
4
4
4
4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
THF
80
80
80
80
60
100
40
reflux
60
60
48
66
75
75
88
41
81
70
76
69
77
To complement our earlier work in this area,10 we examined
the CuX2-mediated cyclization reaction of monoesters of 2,3-
allenic phosphonic acids. To avoid using the relatively active
eletrophiles such as I2, Br2, Cl2, etc., the reaction with CuX2
may be much easier to handle and should have better substituent
compatibility.8,11 Herein we present our recent results on halo-
lactonization of monoesters of 1,2-allenyl phosphonic acids with
CuX2 and the subsequent of Pd-catalyzed Suzuki cross-coupling
reaction of the corresponding bromides or even chlorides with
Sphos as the ligand.
9
10
11
CH3CN
toluene
60
of diethyl 1,2-allenyl phosphonates 2 with excess NaOH,12
which, in turn, were afforded by the reaction of propargylic
alcohols 1 with P(OEt)2Cl (Table 1).13
Results and Discussion
CuX2-Mediated Halolactonization Reaction of Monoe-
sters of 1,2-Allenyl Phosphonic Acids 3. Our initial study
began with the reaction of the monoester of 1,2-allenyl
phosphonic acid 3a with CuCl2 (Table 2). The reaction of 3a
with 2 equiv of CuCl2 in DMF at 80 °C for 12 h smoothly
afforded 3-butyl-4-chloro-2-ethoxy-5,5-dimethyl-2,5-dihydro-
[1,2]oxaphosphole 2-oxide 4a in 48% yield (entry 1, Table 2).
After screening some reaction conditions, it was observed that
the temperature is important, cyclic product 4a was isolated in
88% yield in DMF at 60 °C by applying 4 equiv of CuCl2 (entry
5, Table 2). When other solvents were used, no better results
can be achieved (entries 8-11, Table 2).
With the optimized reaction conditions in hand, we studied
the reaction of differently substituted monoesters of 1,2-allenyl
phosphonic acids under the optimized conditions (Table 3). The
bromolactonization products 5 were also smoothly formed from
the reaction of the monoester of 1,2-allenyl phosphonic acid 3
Preparation of the Starting Materials 3. The monoesters
of 1,2-allenyl phosphonic acids 3 were prepared from hydrolysis
(6) (a) Macomber, R. S.; Krudy, G. A.; Seff, K.; Rendon-Diazmiron, L. E.
J. Org. Chem. 1983, 48, 1425. (b) Macomber, R. S. J. Am. Chem. Soc. 1977,
99, 3072. (c) Macomber, R. S. J. Org. Chem. 1977, 42, 3297. (d) Macomber,
R. S. J. Org. Chem. 1978, 43, 1832. (e) Macomber, R. S.; Kennedy, E. R. J.
Org. Chem. 1976, 41, 3191.
(7) (a) Smadja, W. Chem. ReV. 1983, 83, 263. (b) Angelov, C. M. Phosphorus
Sulfur 1983, 15, 177. (c) Angelov, C. M.; Christov, C. Z. Synthesis 1984, 8,
664. (d) Augelov, C. M.; Vachkov, K. V. Tetrahedron Lett. 1981, 22, 2517. (e)
Alabugin, I. V.; Brel, V. K.; Chekhlov, A. N.; Zefirov, N. S.; Stang, P. J.
Tetrahedron Lett. 1994, 35, 8275. (f) Enchev, D. D. Heteroat. Chem. 2005, 16,
156. (g) Angelov, C. M.; Christov, C. Z. Heterocycles 1983, 20, 219.
(8) (a) Ma, S.; Wu, S. J. Org. Chem. 1999, 64, 9314. (b) Ma, S.; Wu, S.
Tetrahedron Lett. 2001, 42, 4075. (c) Ma, S.; Wu, S. Chem. Commun. 2001,
441. (d) Ma, S.; Xie, H. Org. Lett. 2000, 2, 3801.
(9) (a) Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393. (b) Ma, S.;
Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137. (c) Ma, S.; Shi, Z. Chin. J. Chem.
2001, 19, 1280.
(10) (a) Ma, S.; Yu, F.; Zhao, J. B. Synlett 2007, 583. (b) Yu, F.; Lian, X. D.;
Ma, S. Org. Lett. 2007, 9, 1703.
(11) (a) Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817. (b)
Ma, S.; Wei, Q. Eur. J. Org. Chem. 2000, 1939.
(12) Rabinowitz, R. J. Am. Chem. Soc. 1960, 82, 4564.
(13) Altenbach, H.; Korff, R. Tetrahedron Lett. 1981, 22, 5175.
J. Org. Chem. Vol. 74, No. 3, 2009 1131

Yu et al.
Acids. Next we studied the Suzuki cross-coupling reaction14 of
4-bromo-3-butyl-2-ethoxy-5,5-dimethyl-2,5-dihydro[1,2]oxaphos-
phole 2-oxide 5a with phenyl boronic acid (Table 4). Our initial
experiments were conducted using Pd(PPh3)4, PdCl2(PPh3)2, or
PdCl2(PhCN)2 as the catalyst; however, the cross-coupling product
6a was formed in very low isolated yield (entries 1-5, Table 4).15
Recently, Buchwald et al. developed a very practical and efficient
catalyst system based on the ligand: Sphos.16 We also have
achieved the activation of the C-Cl bond of R-chloroalkylidene-
ꢀ-lactones and furnished the Suzuki cross-coupling reaction in the
presence of PdCl2(Sphos)2.17 When we used the preprepared
PdCl2(Sphos)217 (5 mol %) as the catalyst, the yield of 6a was
improved significantly (entries 6-8, Table 4). The best result was
obtained by conducting the reaction in refluxing toluene for 1 h
affording 6a in 96% yield (entry 8, Table 4).
In addition, the cross-coupling reaction of the carbon-
chlorine bond in 3-butyl-4-chloro-2-ethoxy-5,5-dimethyl-2,5-
dihydro[1,2]oxaphosphole 2-oxide 4a with 2.5 equiv of Ph-
B(OH)2 could also proceed smoothly to afford 6a in 89% yield
under the catalysis of PdCl2(Sphos)2 for 10 h (Scheme 2).
More examples of the Suzuki coupling of 4-halo-2-ethoxy-
5,5-dimethyl-2,5-dihydro[1,2]oxaphosphole with phenyl boronic
acid to afford the coupling products 6 in high yields were shown
in Table 5. The structure of 6h was further confirmed by the
single-crystal X-ray diffraction study.18
TABLE 3. CuX2-Mediated Halocyclization Reaction of Monoesters
of 1,2-Allenyl Phosphonic Acids 3
entry
R1
R2
R3
X
yield (%)
1
2
3
4
5
6
7
8
n-Bu
(3a)
Bn
(3b)
allyl
(3c)
2-methylallyl
(3d)
n-C6H13
(3e)
n-Bu
(3f)
n-Bu
(3g)
Me
(3h)
Me
Me
(3a)
(3b)
(3c)
(3d)
(3e)
(3f)
(3g)
(3h)
(3i)
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
88 (4a)
84 (5a)
68 (4b)
69 (5b)
77 (4c)
Me
Me
Me
Et
Me
Me
Me
Et
82 (5c)
82 (4d)
66 (5d)
83 (4e)
80 (5e)
73 (4f)
73 (5f)
84 (4g)
76 (5g)
73 (4h)
94 (5h)
38; 23 (4i)a
36; 26 (5i)a
17; 12 (4j)a
15; 20 (5j)a
9
10
11
12
13
14
15
16
17
18
19
20
-(CH2)4-
-(CH2)5-
-(CH2)5-
n-Bu
(3i)
n-Bu
(3j)
Me
Et
n-Pr
H
(3j)
The reactions of 4-bromo-3-butyl-2-ethoxy-5,5-dimethyl-2,5-
dihydro[1,2]oxaphosphole 2-oxide 5a with various different
organic boronic acids were also examined (Table 6). Both
electron-donating (entries 1-5, Table 6) and electron-withdraw-
ing (entries 6-9, Table 6) aryl boronic acids could smoothly
react with 5a to afford the products 6 in high yields. n-Butyl
boronic acid reacted with 5a to afford product 6x in 58% yield
(entry 10, Table 6).
a Two diastereoisomers were isolated.
SCHEME 1
SCHEME 2
Conclusion
In conclusion, we have developed a convenient and efficient
method for the synthesis of 4-bromo- or 4-chloro-2,5-
dihydro[1,2]oxaphosphole 2-oxides in high yields by the reaction
of monoesters of 1,2-allenyl phosphonic acids with CuX2.
PdCl2(Sphos)2 was shown to be an excellent catalyst for the Suzuki
cross-coupling reaction of these products with organic boronic acids
to afford 4-substituted-2,5-dihydro[1,2]oxaphosphole 2-oxides in
moderate to excellent yields. It should be a very useful synthetic
strategy for construction of relatively more complex phosphorus-
containing compounds and provide a possibility for finding
potentially bioactive hits in medicinal chemistry. Further studies
in this area are being conducted in our laboratory.
with CuBr2 (Table 3). With fully substituted substrates 3, the
halolactonization products 4 or 5 could be smoothly prepared
in good yields (entries 1-18, Table 3). When R3 is H, the yield
is relatively lower (entries 19 and 20, Table 3). It should be
noted that two diastereoisomers were formed as a mixture when
R2 was different from R3 (entries 17-20, Table 3). However,
no reaction was observed with 1-monosubstituted substrates 3k,
3l, 3m, and 3,3-disubstituted substrate 3n, possibly owing to
the low electron density and, thus, low reactivity of the allene
moieties toward CuX2.
A plausible mechanism was proposed for this CuX2-mediated
halolactonization reaction (Scheme 1): in the presence of CuX2,
the 1,2-allenyl phosphonic acids undergo an oxy-metalation to
generate a five-membered intermediate M2, which undergoes
a C-X bond formation reaction to afford product 4 or 5 in the
presence of another molecule of CuX2 with the generation of
two molecules of CuX.
Experimental Section
Synthesis of Starting Materials:
Synthesis of Diethyl 1,2-Allenyl Phosphonates 2a-n.
Compounds 2a-n were prepared from Horner-Mark [2,3]-
sigmatropic rearrangement of propargylic alcohols 1 with
P(OEt)2Cl.13
(14) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Miyaura, N. Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: New York, 2004; Chapter 2. (d) Suzuki, A. Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E. I., Ed.; Wiley Interscience: New
York, 2002; Chapter III.2.2.
Pd-Catalyzed Suzuki Cross-Coupling of 4-Halo-2,5-
dihydro[1,2]oxaphosphole 2-Oxides with Organic Bronic
(15) Maiyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
1132 J. Org. Chem. Vol. 74, No. 3, 2009

Halolactonization Reaction of 1,2-Allenyl Phosphonic Acids
TABLE 4. The Suzuki Coupling Reaction of 4-Bromo-3-butyl-2-ethoxy-5,5-dimethyl-2,5-dihydro[1,2]oxaphosphole 2-Oxide 5a with Phenyl
Boronic Acid
entry
Pd complex (mol %)
base (equiv)
solvent
T (°C)
time (h)
yield of 6a (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4 (3)
Pd(PPh3)4 (3)
Pd(PPh3)4 (3)
PdCl2(PPh3)2 (3)
PdCl2(PhCN)2 (3)
PdCl2(Sphos)2 (3)
PdCl2(Sphos)2 (3)
PdCl2(Sphos)2 (5)
Na2CO3a (2)
b
reflux
100
100
100
100
100
reflux
reflux
22
8
24
24
24
2
5c
K3PO4 ·3H2O (2)
K3PO4 ·3H2O (1)
K3PO4 ·3H2O (2)
K3PO4 ·3H2O (2)
K3PO4 ·3H2O (2)
K3PO4 ·3H2O (2)
K3PO4 ·3H2O (2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
34
29
24
trace
84
89
96
1
1
a Aqueous solution (2 M). b Toluene:EtOH ) 4:1. c Cycloisomerzation product 7a (9%) was also isolated.
TABLE 5. The Suzuki Cross-Coupling Reaction of
4-Halo-2-ethoxy-5,5- dimethyl-2,5-dihydro[1,2]oxaphosphole 2-Oxide
5 with Phenyl Boronic Acid
TABLE 6. The Suzuki Cross-Coupling Reaction of
4-Bromo-3-butyl-2-ethoxy-5,5-dimethyl-2,5-dihydro[1,2]oxaphosphole
2-Oxide 5a with Different Organic Bronic Acids
entry
R1
Bn
allyl
n-C6H13 Et
n-Bu
Me
Bn
allyl
n-C6H13 Et
n-Bu
R2
R3
X
time (h) yield of 6 (%)
RB(OH)2
1a
2a
3a
4a
5a
6b
7b
8b
9b
10b
Me
Me
Me
Me
Et
Br (5b)
Br (5c)
Br (5e)
Br (5g)
Br (5h)
Cl (4b)
Cl (4c)
Cl (4e)
Cl (4f)
Cl (4h)
4
7
1
2
1
9
9
9
1
9
96 (6b)
80 (6c)
77 (6e)
81 (6g)
81 (6h)
91 (6b)
65 (6c)
73 (6e)
73 (6f)
61 (6h)
entry
R
equiv
time (h)
yield of 6 (%)
1
2
3
4
5
6
7
8
9
10
p-methylphenyl
p-methoxyphenyl
m-methoxyphenyl
o-methoxyphenyl
benzo[1,3]dioxol-5-yl
m-nitrophenyl
p-acetylphenyl
cyclopropyl
hex-1(E)-en-1-yl
n-butyl
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.5
1.5
1
1
2
2
91 (6o)
71 (6p)
66 (6q)
93 (6r)
90 (6s)
69 (6t)
47 (6u)
84 (6v)
90 (6w)
58 (6x)
-(CH2)5-
-(CH2)5-
Me
Me
Me
Me
Et
2
20
20
64
48
68
-(CH2)5-
-(CH2)5-
Me
a 1.5 equiv of PhB(OH)2 was used. b 2.5 equiv of PhB(OH)2 was
used.
JPC ) 5.7 Hz), 29.7 (d, JPC ) 6.3 Hz), 27.8 (d, JPC ) 8.0 Hz),
21.5, 19.1 (d, JPC ) 6.9 Hz), 15.7 (d, JPC ) 6.1 Hz), 13.3 (d, JPC
) 1.1 Hz); 31P NMR (121.5 MHz, CDCl3) δ 20.2; IR (neat, cm-1)
1959, 1444, 1379, 1245, 1028; MS m/z 260 (M+, 4.90), 218 (M+
- C3H6, 56.41), 79 (100); HRMS (ESI) m/z calcd for C13H25O3PNa
[M+ + Na] 283.1434, found 283.1433.
Synthesis of Monoesters of 1,2-Allenyl Phosphonic Acids
3a-n. Compounds 3a-n were prepared by the hydrolysis of the
diethyl 1,2-allenyl phosphonates 2 with excess NaOH.12
Synthesis of the Monoethyl Ester of (2-Methylocta-2,3-
dien-4-yl)phosphonic Acid (3a). Typical procedure II: A
solution of diethyl (2-methylocta-2,3-dien-4-yl)phosphonate 2a
(12.566 g, 47.2 mmol) and NaOH (11.596 g, 289.9 mmol) in 300
mL of H2O was stirred under reflux overnight. After extraction
with ethyl acetate, the aqueous phase was acidified with 1 N HCl
and extracted with ether. The organic layer was washed with water,
dried over anhydrous Na2SO4, and evaporated to afford 10.227 g
(93%) of 3a: liquid; 1H NMR (300 MHz, CDCl3) δ 10.56 (br s, 1
H), 4.09-3.96 (m, 2 H), 2.18-2.03 (m, 2 H), 1.74 (d, J ) 7.2 Hz,
6 H), 1.49-1.23 (m, 7 H), 0.89 (t, J ) 6.9 Hz, 3 H); 13C NMR
(CDCl3, 75.4 MHz) δ 206.4 (d, JPC ) 6.3 Hz), 97.9 (d, JPC ) 17.3
Synthesis of Diethyl (2-Methylocta-2,3-dien-4-yl)phospho-
nate (2a). Typical procedure I: To a solution of 2-methylocta-
3-yn-2-ol 1a (4.255 g, 30.4 mmol) and Et3N (6 mL, d ) 0.726
g/cm3, 4.32 g, 42.9 mmol) in THF (110 mL) was added a solution
of P(OEt)2Cl (7.117 g, 45.5 mmol) in THF (50 mL) dropwise at
-78 °C. After the addition the resulting mixture was warmed to rt
and then heated under reflux. After complete conversion of the
corresponding propargylic alcohol as monitored by TLC (petroleum
ether/ether ) 1:1), the mixture was filtered off. Evaporation of the
solvent and flash chromatography on silica gel (eluent: petroleum
ether/ether ) 1:1) afforded 5.699 g (72%) of 2a: liquid; 1H NMR
(300 MHz, CDCl3) δ 4.10-4.00 (m, 4 H), 2.15-2.07 (m, 2 H),
1.74 (d, J ) 6.3 Hz, 6 H), 1.45-1.25 (m, 10 H), 0.89 (t, J ) 6.9
Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz) δ 206.1 (d, JPC ) 5.7
Hz), 97.1 (d, JPC ) 16.7 Hz), 91.1 (d, JPC ) 188.0 Hz), 61.3 (d,
(16) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(17) Ma, S.; Jiang, X.; Cheng, X.; Hou, H. AdV. Synth. Catal. 2006, 348,
2114.
(18) For the crystal data for 6h, see the Supporting Information.
J. Org. Chem. Vol. 74, No. 3, 2009 1133

Yu et al.
Hz), 92.0 (d, JPC ) 193.3 Hz), 61.8 (d, JPC ) 6.3 Hz), 30.1 (d, JPC
) 6.9 Hz), 28.0 (d, JPC ) 8.6 Hz), 21.9, 19.5 (d, JPC ) 7.5 Hz),
16.1 (d, JPC ) 6.9 Hz), 13.8; 31P NMR (121.5 MHz, CDCl3) δ
23.4; IR (neat, cm-1) 1958, 1450, 1377, 1230, 1046; MS m/z 233
(M+ + 1, 21.38), 232 (M+, 9.69), 217 (M+ - CH3, 6.25), 190
(M+ - C3H6, 47.13), 79 (100); HRMS (EI) m/z calcd for
C11H21O3P [M+] 232.1228, found 232.1222.
1.2 mmol) was stirred at 60 °C in 2 mL of DMF for 12 h. After
12 h, ether (50 mL) was added. The reaction mixture was washed
with brine (three times) and dried over Na2SO4. After evaporation,
the residue was subjected to column chromatography on silica gel
(petroleum ether/ether acetate ) 3/1) to afford 80 mg (84%) of
1
5a: liquid; H NMR (300 MHz, CDCl3) δ 4.22-4.05 (m, 2 H),
2.42-2.20 (m, 2 H), 1.79-1.61 (m, 1 H), 1.60-1.42 (m, 1 H),
1.56 (s, 3 H), 1.52 (s, 3 H), 1.41-1.27 (m, 5 H), 0.93 (t, J ) 7.2
Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz) δ 143.5 (d, JPC ) 47.7
Hz), 128.4 (d, JPC ) 152.5 Hz), 86.3 (d, JPC ) 4.0 Hz), 63.1 (d,
JPC ) 6.9 Hz), 29.3 (d, JPC ) 1.7 Hz), 27.5, 27.4 (d, JPC ) 3.5
Synthesis of the Monoethyl Ester of (2-Methylhepta-2,3,6-
trien-4-yl)phosphonic Acid (3c). Typical procedure III: A
solution of diethyl (2-methylhepta-2,3,6-trien-4-yl)phosphonate 2c
(9.318 g, 38.8 mmol) and NaOH (9.644 g, 241.1 mmol) in a mixed
solvent of 240 mL of H2O and 240 mL of MeOH was stirred under
reflux for 3 days. After extraction with ethyl acetate, the aqueous
phase was acidified with 1 N HCl and extracted with ether. The
organic layer was washed with water, dried over anhydrous
Na2SO4, and evaporated. Then the residue was diluted again with
ether, washed with water, dried over anhydrous Na2SO4, and
evaporated to afford 6.284 g (75%) of 3c. This compound was
used for the cyclization reaction directly. 3c: liquid; 1H NMR (300
MHz, CDCl3) δ 5.84-5.65 (m, 1 H), 5.09-4.95 (m, 2 H),
4.11-3.94 (m, 2 H), 2.84 (dd, J ) 11.1, 6.9 Hz, 2 H), 1.70 (d, J
) 6.9 Hz, 6 H), 1.27 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75.4
MHz) δ 207.3 (d, JPC ) 6.0 Hz), 134.9 (d, JPC ) 7.5 Hz), 116.0,
Hz), 26.7 (d, JPC ) 1.7 Hz), 22.4, 16.4 (d, JPC ) 5.7 Hz), 13.6; 31
P
NMR (121.5 MHz, CDCl3) δ 32.6; IR (neat, cm-1) 1621, 1461,
1368, 1257, 1147, 1080; MS m/z 313 (M+(Br81) + 1, 1.53), 311
(M+(Br79) + 1, 1.09), 242 (M+(Br81) - C3H6 - C2H4, 57.84), 240
(M+(Br79) - C3H6 - C2H4, 58.76), 43 (100); HRMS (EI) m/z calcd
for C11H20O379BrP [M+] 310.0333, found 310.0323.
PdCl2(Sphos)2-Catalyzed Suzuki Cross-Coupling Reac-
tion of 4-Halo-2-ethoxy-2,5-dihydro[1,2]oxaphosphole 2-Ox-
ides with Organic Boronic AcidssSynthesis of 4-Substituted-
2,5-dihydro[1,2]oxaphosphole 2-Oxides:
Synthesis of 3-Butyl-5,5-dimethyl-2-ethoxy-4-phenyl-2,5-
dihydro[1,2]oxaphosphole 2-Oxide (6a). Typical procedure
VI: A mixture of 4-bromo-3-butyl-5,5-dimethyl-2-ethoxy-2,5-
dihydro[1,2]oxaphosphole 2-oxide 5a (95 mg, 0.31 mmol), phenyl
boronic acid (54 mg, 0.45 mmol), K3PO4 ·3H2O (160 mg, 0.60
mmol), and PdCl2(Sphos)217 (15 mg, 5 mol%) was stirred under
reflux in 2 mL of toluene. When the reaction was complete as
monitored by TLC, ether (50 mL) was added. The reaction was
washed with brine (three times) and dried over Na2SO4. After
evaporation, the residue was subjected to column chromatography
on silica gel (petroleum ether/ether acetate ) 3/2) to afford 90 mg
98.9 (d, JPC ) 15.9 Hz), 90.5 (d, JPC ) 195.5 Hz), 62.1 (d, JPC
)
6.6 Hz), 32.8 (d, JPC ) 9.4 Hz), 19.3 (d, JPC ) 6.9 Hz), 16.0 (d,
JPC ) 6.7 Hz); 31P NMR (121.5 MHz, CDCl3) δ 22.1; IR (neat,
cm-1) 1961, 1642, 1445, 1377, 1211; MS m/z 216 (M+, 5.97),
187 (M+ - C2H5, 19.42), 91 (100); HRMS (EI) m/z calcd for
C10H17O3P [M+] 216.0915, found 216.0923.
CuX2-Mediated Halocyclization of Monoesters of 1,2-
Allenyl Phosphonic AcidssSynthesis of 4-Halo-2-ethoxy-
2,5-dihydro[1,2]oxaphosphole 2-Oxides:
1
(96%) of 6a: liquid; H NMR (300 MHz, CDCl3) δ 7.40-7.25
Synthesis of 3-Butyl-4-chloro-5,5-dimethyl-2-ethoxy-2,5-
dihydro[1,2]oxa-phosphole 2-Oxide(4a).10b Typical procedure
IV: A mixture of the monoethyl ester of (2-methylocta-2,3-dien-
4-yl)phosphonic acid 3a (69 mg, 0.30 mmol) and CuCl2 (162 mg,
1.2 mmol) was stirred at 60 °C in 2 mL of DMF for 12 h. After
12 h, ether (50 mL) was added. The reaction mixture was washed
with brine (three times) and dried over Na2SO4. After evaporation,
the residue was subjected to column chromatography on silica gel
(petroleum ether/ether acetate ) 3/1) to afford 70 mg (88%) of
4a: liquid; 1H NMR (300 MHz, CDCl3) δ 4.11 (dq, J ) 6.9, 9.3
Hz, 2 H), 2.42-2.18 (m, 2 H), 1.60-1.45 (m, 2 H), 1.51 (s, 3 H),
1.47 (s, 3 H), 1.38-1.24 (m, 2 H), 1.30 (t, J ) 6.9 Hz, 3 H), 0.88
(t, J ) 7.5 Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz) δ 150.6 (d,
JPC ) 50.6 Hz), 124.7 (d, JPC ) 157.7 Hz), 85.4 (d, JPC ) 2.9
Hz), 63.1 (d, JPC ) 6.3 Hz), 29.4 (d, JPC ) 1.7 Hz), 26.8 (d, JPC
) 2.9 Hz), 26.2 (d, JPC ) 2.3 Hz), 25.4 (d, JPC ) 9.2 Hz), 22.4,
16.5 (d, JPC ) 5.7 Hz), 13.6; 31P NMR (121.5 MHz, CDCl3) δ
32.7; IR (neat, cm-1) 1630, 1464, 1368, 1272, 1151, 1042; MS
m/z 269 (M+(37Cl) + 1, 28.14), 267 (M+(35Cl) + 1, 81.43), 240
(M+(37Cl) - C2H4, 4.91), 238 (M+(35Cl) - C2H4, 12.79), 226
(M+(37Cl) - C3H6, 19.15), 224 (M+(35Cl) - C3H6, 49.73), 43 (100);
HRMS (EI) m/z calcd for C11H20O335ClP [M+] 266.0839, found
266.0844.
(m, 3 H), 7.09-7.00 (m, 2 H), 4.18-4.04 (m, 2 H), 2.17-1.82
(m, 2 H), 1.45-1.38 (m, 8 H), 1.15 (t, J ) 7.5 Hz, 3 H), 1.20-1.06
(m, 2 H), 0.72 (t, J ) 7.2 Hz, 3 H); 13C NMR (CDCl3, 75.4 MHz)
δ 161.1 (d, JPC ) 24.7 Hz), 133.7 (d, JPC ) 21.9 Hz), 128.4, 128.2,
127.8 (d, JPC ) 1.7 Hz), 125.9 (d, JPC ) 155.4 Hz), 85.9 (d, JPC
)
9.3 Hz), 62.4 (d, JPC ) 6.3 Hz), 30.3 (d, JPC ) 2.3 Hz), 27.3 (d,
JPC ) 2.9 Hz), 26.7 (d, JPC ) 1.7 Hz), 25.4 (d, JPC ) 12.7 Hz),
22.3, 16.5 (d, JPC ) 5.7 Hz), 13.5; 31P NMR (121.5 MHz, CDCl3)
δ 38.5; IR (neat, cm-1) 1637, 1598, 1465, 1264, 1232, 1149, 1044;
MS m/z 309 (M+ + 1, 24.22), 308 (M+, 27.83), 307 (M+ - 1,
21.48), 293 (M+ - CH3, 17.83), 279 (M+ - C2H5, 13.16), 266
(M+ - C3H6, 100); HRMS (EI) m/z calcd for C17H25O3P [M+]
308.1541, found 308.1534.
Acknowledgment. Financial support from the State Key Basic
Research & Development Program (2009CB825300), National
Natural Science Foundation of China (20732005 and 20423001),
and Shanghai Municipal Committee of Science and Technology
is greatly appreciated.
Supporting Information Available: Typical experimental
procedure, analytical data for all new products not listed in the
text, 1H, 13C NMR, and 31P spectra of all new compounds, and cif
file of 6h. This material is available free of charge via the Internet
at http://pubs.acs.org.
Synthesis of 4-Bromo-3-butyl-5,5-dimethyl-2-ethoxy-2,5-
dihydro[1,2]oxaphosphole 2-Oxide (5a). Typical procedure
V: A mixture of the monoethyl ester of (2-methylocta-2,3-dien-
4-yl)phosphonic acid 3a (71 mg, 0.31 mmol) and CuBr2 (269 mg,
JO802051R
1134 J. Org. Chem. Vol. 74, No. 3, 2009