Synthesis of 4-halophosphaisocoumarins via halocyclization of 2-(1-alkynyl)phenylphosphonates

Article abstract of DOI:10.1016/j.tet.2005.08.032

A series of 4-halophosphaisocoumarins were prepared with high regioselectivity in good to excellent yields under mild conditions by the reaction of 2-(1-alkynyl)phenylphosphonic acid diesters with I₂ in CHCl₃ or ICl in CH₂Cl₂, or by the reaction of 2-(1-alkynyl)phenylphosphonic acid monoesters with NBS or NCS in DMF. Whether the alkynylphosphonates could cyclize or not was affected by the substituents, reaction solvents and electrophiles. A rationale for this reaction is discussed.

Full text of DOI:10.1016/j.tet.2005.08.032

Tetrahedron 61 (2005) 10303–10308
Synthesis of 4-halophosphaisocoumarins via halocyclization of
2-(1-alkynyl)phenylphosphonates
Ai-Yun Penga,b and Yi-Xiang Dingb,
*
aSchool of Chemistry & Chemical Engineering, Sun Yat-sen University, 135 Xingangxi Lu, Guangzhou 510275, China
bShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 21 June 2005; revised 1 August 2005; accepted 2 August 2005
Abstract—A series of 4-halophosphaisocoumarins were prepared with high regioselectivity in good to excellent yields under mild
conditions by the reaction of 2-(1-alkynyl)phenylphosphonic acid diesters with I2 in CHCl3 or ICl in CH2Cl2, or by the reaction of 2-(1-
alkynyl)phenylphosphonic acid monoesters with NBS or NCS in DMF. Whether the alkynylphosphonates could cyclize or not was affected
by the substituents, reaction solvents and electrophiles. A rationale for this reaction is discussed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
iodocyclization reaction showed very high 6-endo-dig5
regioselectivity and the yields of 2 were dependent on
the substituents of the substrates and the strength of the
electrophiles. We think it is necessary to further study the
cyclization of phosphonates to C–C triple bond with other
electrophiles and synthesize more type of phosphaiso-
coumarins for future bioassays. Herein, we wish to present a
detailed study on the halocyclization of 2-(1-alkynyl)-
phenylphosphonates with I2, ICl, NBS and NCS, respect-
ively, and discuss the plausible mechanisms in this paper.
4-Chloroisocoumarins 1 are effective irreversible inhibitors
of serine proteases1 and potent inhibitors of amyloid peptide
production.2 Since there is a remarkable similarity in
bioactivities between the carbon species and their phos-
phorus counterparts,3 one would anticipate that phosphorus
4-chloroisocoumarin analogs 2–4 might have potential
bioactivities similar to those of the 4-chloroisocoumarins
reported herein (Fig. 1).
2. Results and discussion
We first examined the reaction of 2-(phenylethynyl)
phenylphosphonate 5a with 2.0 equiv of iodine in several
different organic solvents at room temperature. It was
obvious that the reaction was highly dependent on the type
of solvent used (Table 1, entries 1–5). In CH3CN and DMF,
the diiodide 6a was the major product (entries 1, 2); in
benzene, a ketone byproduct 7a was isolated (entry 3)
(Fig. 2). Fortunately, when the reaction was run in CHCl3 or
CH2Cl2, the desired product 2a was produced in good yield
(entries 4, 5).
Figure 1. 4-Chloroisocoumarins and 4-haolophosphaisocoumarins.
In a recent communication, we described the synthesis of
4-iodophosphaisocoumarins 2 via iodocyclization of 2-(1-
alkynyl)phenylphosphonic acid diesters with I2 or ICl.4
However, the bromo- and chlorophosphaisocoumarins 3 and
4 remain unknown compounds as yet. On the other hand,
during the course of preparing 2, we found that this
To explore the scope of this reaction, other 2-(1-alkynyl)
phenylphosphonic acid diesters 5 with a variety of
substituents were allowed to react with I2 in CHCl3 or
with ICl in CH2Cl2 and the results are summarized in
Table 1. I2 was efficient in most cases and a series of
4-iodophosphaisocoumarins were obtained in good to
excellent yields. However, 5c with an H group on the
Keywords: Synthesis; Phosphonates; Alkynes; 4-Halophosphaisocoumar-
ins; Halocyclization.
*
Corresponding author. Tel.: C86 21 54925334; fax: C86 21 64166128;
e-mail: dingyx@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.032

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A.-Y. Peng, Y.-X. Ding / Tetrahedron 61 (2005) 10303–10308
Table 1. Synthesis of phosphaisocoumarins via iodocyclization of 5a
Entry
R1
R2
Solvent
Product(s)
Yield (%)b
1
2
3
4
5
6
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3O
C6H5
C6H5
C6H5
C6H5
C6H5
n-C4H9
H
CH3CN
DMF
PhH
6a
6a
2aC7a
2a
2a
2b
2cC6c
2c
2dC7d
2d
2eC7e
2e
2f
2g
2h
2i
2i
85
65
35C15
80
83
70
4C65
35
64C30
78
67C25
80
64
76
46
0
82
93
CH2Cl2
CHCl3
CHCl3
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CHCl3
7
8b
9
H
4-EtC6H4
4-EtC6H4
C6H5
10c
11
12c
13
14
15
16
17b
18
C6H5
n-C4H9
Cyclopropyl
CH2OCH3
SiMe3
SiMe3
C6H5
2j
a All reactions were conducted at room temperature with 2.0 equiv of I2 in solvent for 12 h and the solvent was used as received unless otherwise specified.
b The reaction was carried out at room temperature with 1.2 equiv of ICl in CH2Cl2 under N2 for 10 h.
c In this reaction, the solvent CHCl3 was distilled from calcium hydride.
acetylenic moiety (R2ZH) gave the diiodide as the major
product (entry 7). A bulky SiMe3 group (entry 16) totally
halted the reaction and the starting material 5i was
completely recovered under these conditions. Use of the
strong electrophile ICl instead of I2 afforded the desired
products 2c and 2i in moderate yields for 5c and 5i (entries 8
and 17). It is also worth mentioning that for the reactions of
Scheme 1. The reaction of 5a with NBS in CHCl3.
5d and 5e (entries 9 and 11), the corresponding a-ketone
byproducts 7d and 7e resulting from water attacking onto
Cl.8 It has been reported that iodocyclization of alkenyl-
phosphonic acid diesters could proceed smoothly, while
the iodonium intermediates were also isolated (entries 9 and
11);4 the a-ketone byproducts could be reduced substan-
under the similar conditions, bromocyclization of the same
substrates only led to dibromides.9 Although Shibuya and
tially when the above reactions were carried out in
anhydrous CHCl3 (entries 10 and 12) (Fig. 2).
co-workers at last synthesized phostones by bromocycliza-
tion of alkenylphosphonic acid monoesters, they did not
extend it to the chlorocyclization reactions.10 The weak
nucleophilicity of phosphonyl group and the lower
reactivity of alkynes towards electrophilic reagents than
that of alkenes might add more challenge to our proposed
halocyclization reactions.
We then investigated the reaction of 2-(phenylethynyl)
phenylphosphonic acid monoester 8a with NBS. When
using CHCl3 as the solvent, the reaction of 8a with 2.0 equiv
of NBS at room temperature for 24 h afforded only a trace
amount of the cyclization product 3a. However, we were
pleased to see that when using DMF as the solvent, the
reaction of 8a with NBS gave 3a as the single product in
74% isolated yield (Table 2, entry 1). We thought that the
solvents had a large effect on the reaction largely because
the solvent DMF could act as a Lewis base to enhance the
nucleophilicity of the phosphonyl oxygen.11
Figure 2. The structures of 6 and 7.
We next studied the bromocyclization reaction of 5a. Under
the similar conditions used for the iodocyclization of 5a, the
reaction of 5a with 2.0 equiv of NBS in CHCl3 at room
temperature for 48 h did not lead to any cyclization products
but rather to an unidentified product (Scheme 1). This result
was not surprising. Iodocyclization of unsaturated com-
pounds is one of the most important procedures to construct
various heterocycles containing N, O, S atoms.6 However,
there are far fewer reports about bromocyclization
reactions7 and especially chlorocyclization reactions,7a,b
probably because of the stability of the corresponding
halonium intermediates decreasing in the order of IOBrO
To explore the scope of this bromocyclization reaction, a
series of 2-(1-alkynyl)phenylphosphonic monoesters 8 were

A.-Y. Peng, Y.-X. Ding / Tetrahedron 61 (2005) 10303–10308
Table 2. Synthesis of phosphaisocoumarins via bromo- and chlorocyclization of 8a
10305
Entry
R1
R2
NXS
Product
Yield (%)b
1
2
3
4
5
6
7
8
H
Cl
Cl
Cl
Cl
Cl
CH3O
H
Cl
Cl
Cl
Cl
Cl
C6H5
C6H5
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
4e
4f
74
84
85
73
4-EtC6H4
Cyclopropyl
n-C4H9
CH2OCH3
C6H5
85
Trace
51
73
66
69
C6H5
C6H5
9
10
11
12
13
14
4-EtC6H4
Cyclopropyl
n-C4H9
CH2OCH3
C6H5
73
Trace
Trace
Trace
CH3O
4g
a All reactions were conducted at room temperature with 2.0 equiv of NBS or NCS in DMF for 24 h.
b Isolated yield.
allowed to react with NBS or NCS in DMF at room
temperature and the results are summarized in Table 2.
Apparently, the substituents and electrophiles have large
effects on the reaction. The substrates 8a–d with aryl and
cyclopropyl groups on the acetylenic moiety could react
with both NBS and NCS to give the desired products in good
to excellent yields (entries 1–4, 8–11). The substrate 8f with
an electron-withdrawing methoxymethyl group did not
participate in either bromo- or chlorocyclization reaction
(entries 6 and 13). The reaction of 8e having a n-butyl group
on the acetylenic moiety with NBS produced the desired
product 3e in 85% yield (entry 5), but most of the starting
material 8e was recovered even after extended exposure to
NCS under the same conditions (entry 12). Moreover, the
reaction of 8g bearing an electron-donating methoxy group
on the benzene with NBS gave the product 3g only in 51%
yield (entry 7), and the chlorocyclization of 8g did not
proceed at all under our conditions (entry 14). It is also
worth mentioning that no 5-exo-dig5 cyclization products
were detected in each case. The bromo- and chlorocycliza-
tion products are assigned as 3 and 4 based on comparison
by the following factors: (1) the longer bond lengths of C–P
and P–O would make the phosphonyl oxygen much closer to
the farther position of the triple bonds; (2) the tetrahedral
phosphonates might further increase the ring strain and
lower the stabililty of the corresponding five-membered-
ring products. Thus, the substrates (e.g., 8e and 8g), bearing
groups that can better stabilize the benzylic cations B other
than intermediates C, did not proceed the chlorocyclization
reactions smoothly (Table 2, entries 12, 14). By way of
contrast, the substituents have fewer effects on the iodo- and
bromocyclization than on the chlorocyclization, probably
because iodonium ions compete more effectively with open
carbocations than bromonium ions, chloronium ions
compete less effectively,8 and it is difficult for open
carbocations B to form the desired cyclization products.
1
of their IR, H NMR, 31P NMR spectrum with those of 2.4
We rationalized our results by plausible mechanisms shown
in Scheme 2. Electrophilic addition of I2, ICl, NBS or NCS
to the C–C triple bond might form the corresponding
intermediates A, B or C; their stabilities and the
nucleophilicity of the phosphonyl oxygen play crucial
roles in determining whether the alkynylphosphonates will
cyclize or not. Intramolecular nucleophilic attack by the
phosphonyl oxygen onto the position 2 of A or C would give
the desired products 2, 3 or 4. Alternatively, the phosphonyl
oxygen might also attack onto the position 1 of A or B to
give the five-membered-ring products. However, all the
examined substrates showed high regioselectivity for six-
membered-ring products, indicating that the 5-exo-dig
process was very disadvantageous for 2-(1-alkynyl)phenyl-
phosphonates. The above regioselectivity might be caused
Scheme 2. Plausible mechanisms of the halocyclization of 2-(1-alkynyl)
phenylphosphonates.

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A.-Y. Peng, Y.-X. Ding / Tetrahedron 61 (2005) 10303–10308
3. Conclusions
4.4.2. Diethyl 2-((E)1,2-diiodovinyl)phenylphosphonate
(6c). Red oil. 1H NMR (300 MHz, CDCl3): d 7.83–7.93 (m,
1H), 7.33–7.53 (m, 2H), 7.11–7.23 (m, 2H), 4.00–4.19 (m,
4H), 1.25–1.34 (m, 6H); MS (EI), m/z (%): 365 [(MKI)C,
86], 336 (30), 309 (100), 291 (10), 182 (46), 165 (23), 153
(43), 136 (26), 118 (21); IR (film, cmK1): n 3058, 2980,
1592, 1466, 1391, 1243, 1140, 1081, 1049, 1024, 970.
In conclusion, a series of 4-iodophosphaisocoumarins were
prepared with high regioselectivity in good yields via
iodocyclization of 2-(1-alkynyl)phenylphosphonic acid
diesters with I2 in CHCl3 or ICl in CH2Cl2, and 4-bromo-
and 4-chlorophosphaisocoumarins were synthesized by the
reaction of 2-(1-alkynyl)phenylphosphonic acid monoesters
with NBS and NCS in DMF. These halocyclization
reactions have been much affected by the substituents of
the substrates, reaction solvents and electrophiles, which
could be rationalized by the proposed mechanisms in this
paper.
4.4.3. {5-Chloro-2-[2-(4-ethyl-phenyl)-2-oxo-ethyl]-
phenyl}-phosphonic acid diethyl ester (7d). Pale yellow
1
oil. H NMR (300 MHz, CDCl3): d 7.90–7.98 (m, 3H),
7.19–7.50 (m, 4H), 4.66 (s, 2H), 3.96–4.11 (m, 4H), 2.72 (q,
JZ7.5 Hz, 2H), 1.20–1.27 (m, 9H); MS (EI), m/z (%): 394
(MC, 1), 291 (2), 254 (6), 178 (6), 150 (49), 133 (100), 105
(92), 77 (39); IR (film, cmK1): n 2969, 1686, 1606, 1478,
1384, 1250, 1221, 1182, 1106, 1019, 971. Anal. Calcd
for C20H24ClO4P: C, 60.82; H, 6.14. Found: C, 61.03; H,
6.18.
4. Experimental
4.1. General
NMR spectra were all recorded on a Varian Mercury 300
spectrometer using CDCl3 as the solvent. The H NMR
4.4.4. [5-Chloro-2-(2-oxo-2-phenyl-ethyl)-phenyl]-phos-
phonic acid diethyl ester (7e). Pale yellow oil. H NMR
1
1
spectra used CDCl3 (with TMS) as the internal reference at
7.27 ppm. 31P NMR spectra used the 85% H3PO4 as the
external reference. MS spectra were determined using a
HP5989A mass spectrometer. IR spectra were measured on
a Y-Zoom Cursor instrument. Starting materials 5 and 8
were prepared as described previously.11
(300 MHz, CDCl3): d 7.51–8.06 (m, 7H), 7.24–7.29 (m,
1H), 4.73 (s, 2H), 4.03–4.17 (m, 4H), 1.25 (dt, J1Z7.2 Hz,
J2Z2.4 Hz, 6H); MS (EI), m/z (%): 366 (MC, 6), 261 (1),
228 (2), 187 (4), 165 (2), 105 (100), 77 (28); IR (film, cmK1): n
2982, 1691, 1598, 1478, 1384, 1330, 1250, 1217, 1150, 1019,
969; HRMS (EI): calcd for C18H20ClO4P (MC): 366.07877.
Found: 366.07821.
4.2. General procedure for the halocyclization of 5 by I2
4.5. General procedures for the preparation of 3 and 4
A mixture of 5 (0.50 mmol) and I2 (1.00 mmol) was
dissolved in CHCl3 (5.0 mL). After stirring at room
temperature for 12 h, the reaction mixture was then diluted
with EtOAc and washed with 5% aqueous Na2S2O3. The
organic phase was washed with brine, dried (Na2SO4), and
evaporated in vacuo. The residue was chromatographed on
silica gel using hexane/EtOAc as eluent to give the
corresponding product 2.
A mixture of 8 (0.50 mmol), NBS (1.00 mmol) or NCS
(1.00 mmol) was dissolved in DMF (5.0 mL). After stirring
at room temperature for 24 h, the reaction mixture was then
diluted with EtOAc and washed with 5% aqueous Na2S2O3.
The organic phase was washed with brine, dried (Na2SO4),
and evaporated in vacuo. The residue was chromatographed
on silica gel using hexane–EtOAc (5/1–2/1) as eluent to
give the corresponding product 3 or 4. The isolated yield
and the physical data for 3 and 4 are as follows:
4.3. General procedure for the halocyclization of 5 by ICl
To the substrate 5 (0.10 mmol) was added ICl (0.12 mmol)
in CH2Cl2 (1.2 mL), and the resulting mixture was stirred in
the dark under nitrogen at room temperature for 10 h. The
reaction mixture was then diluted with EtOAc and washed
with 5% aqueous Na2S2O3. The organic phase was washed
with brine, dried (Na2SO4), and evaporated in vacuo. The
residue was chromatographed on silica gel using hexane/
EtOAc as eluent to give the product 2.
4.5.1. 1-Ethoxy-3-phenyl-4-bromobenzo[c][1,2]oxa-
phosphinine 1-oxide (3a). White solid, mp 109–110 8C.
Yield: 74%. H NMR (300 MHz, CDCl3): d 7.92–8.01 (m,
2H), 7.71–7.88 (m, 3H), 7.45–7.56 (m, 4H), 4.25–4.31 (m,
2H), 1.36 (t, JZ6.9 Hz, 3H); 31P NMR (121 MHz, CDCl3):
d 9.94; MS (EI), m/z (%): 364 (MC, 97), 336 (100), 279 (9),
257 (12), 239 (38), 229 (1), 165 (19), 105 (54), 77 (43); IR
(KBr, cmK1): n 2992, 1608, 1446, 1268, 1234, 1070, 1019,
970. Anal. Calcd for C16H14BrO3P: C, 52.62; H, 3.87.
Found: C, 52.55; H, 3.88.
1
For the characterization data of compounds 2 in Table 1, see
the Supporting information of Ref. 4.
4.4. Characterization data for compounds 6a, 6c, 7d, and
7e listed in Table 1
4.5.2. 7-Chloro-1-ethoxy-3-phenyl-4-bromobenzo[c][1,2]
oxaphosphinine 1-oxide (3b). White solid, mp 109–110 8C.
Yield: 84%. H NMR (300 MHz, CDCl3): d 7.83–7.96 (m,
1
4.4.1. Diethyl 2-((E)1,2-diiodo-2-phenylvinyl)phenyl-
phosphonate (6a). Red oil. H NMR (300 MHz, CDCl3):
2H), 7.65–7.74 (m, 3H), 7.46–7.48 (m, 3H), 4.26–4.36 (m,
2H), 1.38 (t, JZ6.9 Hz, 3H); 31P NMR (121 MHz, CDCl3):
d 14.24; MS (EI), m/z (%): 400 (97), 398 (MC, 75), 372
(100), 273 (16), 263 (10), 199 (10), 163 (14), 105 (28), 77
(25); IR (KBr, cmK1): n 2999, 1594, 1467, 1385, 1285,
1246, 1160, 1069, 1009, 973. Anal. Calcd for C16H13-
BrClO3P: C, 48.09; H, 3.29. Found: C, 48.11; H, 3.18.
1
d 8.20–8.23 (m, 2H), 7.50–7.88 (m, 7H), 3.97–4.11 (m, 4H),
1.28 (t, JZ6.9 Hz, 6H); MS (EI), m/z (%): 441 [(MKI)C,
5], 412 (2), 385 (2), 241 (82), 213 (28), 185 (100), 167 (22),
105 (19), 77 (25); IR (film, cmK1): n 3062, 2924, 1596,
1450, 1209, 1146, 1099, 1019, 934.

A.-Y. Peng, Y.-X. Ding / Tetrahedron 61 (2005) 10303–10308
10307
4.5.3. 7-Chloro-1-ethoxy-3-(4-ethylphenyl)-4-bromo-
benzo[c][1,2]oxaphosphinine 1-oxide (3c). White solid,
mp 121–122 8C. Yield: 85%. 1H NMR (300 MHz, CDCl3):
d 7.82–7.94 (m, 2H), 7.64–7.67 (m, 3H), 7.28–7.30 (m, 2H),
4.25–4.35 (m, 2H), 2.72 (q, JZ7.8 Hz, 2H), 1.37 (t, JZ
6.9 Hz, 3H), 1.29 (t, JZ7.8 Hz, 3H); 31P NMR (121 MHz,
CDCl3): d 8.34; MS (EI), m/z (%): 426 (MC, 78), 428 (100),
400 (69), 385 (55), 319 (12), 291 (9), 255 (11), 189 (23), 105
(14), 77 (18); IR (KBr, cmK1): n 2965, 1592, 1461, 1281,
1268, 1158, 1065, 1028, 1018, 974. Anal. Calcd for
C18H17BrClO3P: C, 50.55; H, 4.01. Found: C, 50.45; H,
3.93.
5H), 7.46–7.49 (m, 3H), 4.25–4.35 (m, 2H), 1.37 (t, JZ
6.9 Hz, 3H); 31P NMR (121 MHz, CDCl3): d 12.19; MS
(EI), m/z (%): 354 (MC, 70), 326 (100), 269 (8), 233 (4),
199 (8), 163 (13), 105 (39), 77 (36); IR (KBr, cmK1): n
2979, 1601, 1467, 1387, 1285, 1268, 1161, 1011, 969. Anal.
Calcd for C16H13Cl2O3P: C, 54.11; H, 3.69. Found: C,
54.12; H 3.49.
4.5.9. 7-Chloro-1-ethoxy-3-(4-ethylphenyl)-4-chloro-
benzo[c][1,2]oxaphosphinine 1-oxide (4c). White solid,
mp 105–107 8C. Yield: 69%. 1H NMR (300 MHz, CDCl3):
d 7.84–7.92 (m, 2H), 7.66–7.75 (m, 3H), 7.29–7.32 (m, 2H),
4.25–4.35 (m, 2H), 2.73 (q, JZ7.8 Hz, 2H), 1.36 (t, JZ
6.9 Hz, 3H), 1.29 (t, JZ7.5 Hz, 3H); 31P NMR (121 MHz,
CDCl3): d 8.30; MS (EI), m/z (%): 382 (MC, 100), 354 (85),
339 (82), 319 (19), 290 (11), 255 (15), 189 (14), 105 (12), 77
(18); IR (KBr, cmK1): n 2966, 1599, 1468, 1290, 1269,
1161, 1075, 1011, 972. Anal. Calcd for C18H17Cl2O3P: C,
56.42; H, 4.47. Found: C, 56.36; H, 4.54.
4.5.4. 7-Chloro-4-bromo-3-cyclopropyl-1-ethoxy-
benzo[c][1,2]oxaphosphinine 1-oxide (3d). White solid,
1
mp 82–83 8C. Yield: 73%. H NMR (300 MHz, CDCl3): d
7.72–7.79 (m, 2H), 7.57–7.61 (m, 1H), 4.15–4.26 (m, 2H),
2.40–2.50 (m, 1H), 1.36 (t, JZ6.9 Hz, 3H), 1.16–1.24 (m,
1H), 0.95–1.04 (m, 3H); 31P NMR (121 MHz, CDCl3): d
9.05; MS (EI), m/z (%): 362 (MC, 30), 364 (39), 336 (38),
255 (100), 237 (24), 220 (13), 209 (23), 175 (13), 139 (10),
99 (6), 75 (4); IR (KBr, cmK1): n 2988, 1600, 1465, 1392,
1284, 1266, 1161, 1062, 1018, 970. Anal. Calcd for
C13H13BrClO3P: C, 42.95; H, 3.60. Found: C, 43.01; H,
3.59.
4.5.10. 4,7-Dichloro-3-cyclopropyl-1-ethoxy-benzo[c][1,
2]oxaphosphinine 1-oxide (4d). White solid, mp 62–
63 8C. Yield: 73%. H NMR (300 MHz, CDCl3): d 7.59–
1
7.81 (m, 3H), 4.15–4.26 (m, 2H), 2.33–2.43 (m, 1H), 1.35 (t,
JZ6.9 Hz, 3H), 1.16–1.24 (m, 1H), 0.94–1.04 (m, 3H); 31P
NMR (121 MHz, CDCl3): d 9.05; MS (EI), m/z (%): 318
(MC, 72), 320 (47), 290 (100), 255 (94), 237 (27), 220 (15),
209 (37), 175 (21), 139 (15), 99(9), 75(10); IR(KBr, cmK1):n
2955, 1612, 1467, 1380, 1266, 1220, 1156, 1070, 1025, 988.
Anal. Calcd for C13H13Cl2O3P: C, 48.93; H, 4.11. Found: C,
48.83; H 4.58.
4.5.5. 3-Butyl-4-bromo-7-chloro-1-ethoxy-benzo[c][1,2]
oxaphosphinine 1-oxide (3e). Pale yellow oil. Yield:
85%. H NMR (300 MHz, CDCl3): d 7.72–7.81 (m, 2H),
1
7.57–7.61 (m, 1H), 4.22–4.27 (m, 2H), 2.69–2.78 (m, 2H),
1.62–1.70 (m, 2H), 1.23–1.46 (m, 5H), 0.95 (t, JZ7.2 Hz,
3H); 31P NMR (121 MHz, CDCl3): d 12.39; MS (EI), m/z
(%): 380 [(MC2)C, 100], 378 (MC, 77), 352 (26), 323 (52),
271 (90), 229 (64), 101 (6), 75 (7); IR (film, cmK1): n 2959,
1609, 1466, 1389, 1287, 1273, 1081, 1033, 971. Anal. Calcd
for C14H17BrClO3P: C, 44.30; H, 4.51. Found: C, 44.64; H,
4.47.
References and notes
¨
1. Powers, J. C.; Asgian, J. L.; Ekici, O.D.; James, K. E. Chem.
4.5.6. 7-Methoxy-1-ethoxy-3-phenyl-4-bromobenzo[c][1,
2]oxaphosphinine 1-oxide (3g). White solid, mp 125–
126 8C. Yield: 51%. 1H NMR (300 MHz, CDCl3): d
7.88–7.94 (m, 1H), 7.70–7.74 (m, 2H), 7.35–7.47 (m, 4H),
7.21–7.25 (m, 1H), 4.22–4.32 (m, 2H), 3.92 (s, 3H), 1.37 (t,
JZ7.2 Hz, 3H); 31P NMR (121 MHz, CDCl3): d 10.37; MS
(EI), m/z (%): 394 (MC, 100), 396 (96), 366 (94), 351 (50),
269 (4), 259 (16), 195 (4), 105 (31), 77(34); IR(KBr, cmK1):n
2985, 1598, 1486, 1280, 1261, 1154, 1030, 1020, 948. Anal.
Calcd for C17H16BrO4P: C, 51.67; H, 4.08. Found: C, 51.90;
H, 4.37.
Rev. 2002, 102, 4639–4750 and references therein.
2. Bihel, F.; Quelever, G.; Lelouard, H.; Petit, A.; Alves da Costa,
C.; Pourquie, O.; Checler, F.; Thellend, A.; Pierre, P.; Kraus,
J.-L. Bioorg. Med. Chem. 2003, 11, 3141–3152.
3. (a) Dillon, K. B.; Mathey, F.; Nixon FRS, J. F. Phosphorus:
The Carbon Copy; Wiley: Chichester, 1998. (b) Quin, L. D. A
Guide to Organophosphorus Chemistry; Wiley: New York,
2000; Chapter 11.
4. Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2004, 6, 1119–1121.
5. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
6. For the leading references, see: (a) review: Frederickson, M.;
Grigg, R. Org. Prep. Proced. Int. 1997, 29, 33–62. (b) Flynn,
B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3,
651–654. (c) Knight, D. W.; Redfern, A. L.; Gilmore, J.
J. Chem. Soc., Perkin Trans. 1 2002, 622–628. (d) Rossi, R.;
Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron
2003, 59, 2067–2081. (e) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936–5942. (f) Barluenga, J.; Trincado, M.; Rubio,
4.5.7. 1-Ethoxy-3-phenyl-4-chlorobenzo[c][1,2]oxa-
phosphinine 1-oxide (4a). White solid, mp 100–101 8C.
Yield: 73%. H NMR (300 MHz, CDCl3): d 7.76–7.91 (m,
1
5H), 7.46–7.60 (m, 4H), 4.21–4.33 (m, 2H), 1.35 (t, JZ
7.2 Hz, 3H); 31P NMR (121 MHz, CDCl3): d 14.28; MS
(EI), m/z (%): 320 (MC, 80), 292 (100), 235 (15), 199 (9),
165 (17), 105 (49), 77 (51); IR (KBr, cmK1): n 2995, 1609,
1446, 1388, 1268, 1235, 1159, 1020, 967. Anal. Calcd for
C16H14ClO3P: C, 59.92; H, 4.40. Found: C, 59.70; H, 4.25.
´
E.; Gonzalez, M. J. Angew. Chem., Int. Ed. 2003, 42,
2406–2409. (g) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am.
Chem. Soc. 2003, 125, 15748–15749. (h) Yue, D.; Larock,
R. C. Org. Lett. 2004, 6, 1037–1040.
4.5.8. 7-Chloro-1-ethoxy-3-phenyl-4-chlorobenzo[c][1,2]
oxaphosphinine 1-oxide (4b). White solid, mp 138–139 8C.
Yield: 66%. H NMR (300 MHz, CDCl3): d 7.67–7.92 (m,
7. (a) Krafft, G. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
1981, 103, 5459–5466. (b) Nagarajan, A.; Balasubramanian,
T. R. Indian J. Chem., Sect. B 1988, 27, 380. (c) Steinmann,
1

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10. Yokomatsu, T.; Shioya, Y.; Iwasawa, H.; Shibuya, S.
Heterocycles 1997, 46, 463–472.
8. Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.;
Wiley: New York, 2001; Chapter 15.
9. Zhao, Y.-F.; Yan, S.-J.; Zhai, C. J. Org. Chem. 1985, 50,
2136–2140.
11. Peng, A.-Y.; Ding, Y.-X. J. Am. Chem. Soc. 2003, 125,
15006–15007.