Synthesis of 2H-1,2-oxaphosphorin 2-oxides

Article abstract of DOI:10.1016/S0022-328X(01)01207-4

Two novel heterocyclic dienes, 2-ethoxy-3-phenyl-2H-oxo-1,2-oxaphosphorin 2-oxide (3) and 5-bromo-2-ethoxy-3-phenyl-2H-oxo-1,2-oxaphosphorin 2-oxide (4), are described. They were prepared in four steps starting from 2-ethoxy-3-phenyl-1,2-oxaphos-phorinane 2-oxide (12a,b) (trans and cis) by a bromination-dehydrobromination sequence. Free radical bromination of 12a, b with NBS/AIBN furnished two isomeric bromides 13a,b. Isomer 13b gave 2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin 2-oxide (14) on treatment with LiCl/DMF. Isomer 13a underwent C-OEt bond cleavage followed by HBr elimination to give the phosphonic acid 17. Treatment of 14 with NBS/AIBN afforded isomeric 5-bromo-2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin 2-oxides (15a,b) and 5,5-dibromo-2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin 2-oxide (18), separated by chromatography. Dehydrobromination of 15a,b, and 18 with an excess of Et₃N in toluene at 80-95 °C provided the target dienes 3 and 4, respectively.

Full text of DOI:10.1016/S0022-328X(01)01207-4

Journal of Organometallic Chemistry 646 (2002) 153–160
www.elsevier.com/locate/jorganchem
Synthesis of 2H-1,2-oxaphosphorin 2-oxides
Alexandre M. Polozov a,b,1, Sheldon E. Cremer b,*
a A.M. Butlero6 Research Chemical Institute, Kazan State Uni6ersity, Kremle6skaya 18, Kazan 420111, Russia
b Department of Chemistry, Marquette Uni6ersity, PO Box 1881, Milwaukee, WI 53201-1881, USA
Received 27 June 2001; accepted 4 September 2001
Abstract
Two novel heterocyclic dienes, 2-ethoxy-3-phenyl-2H-oxo-1,2-oxaphosphorin 2-oxide (3) and 5-bromo-2-ethoxy-3-phenyl-2H-
oxo-1,2-oxaphosphorin 2-oxide (4), are described. They were prepared in four steps starting from 2-ethoxy-3-phenyl-1,2-oxaphos-
phorinane 2-oxide (12a,b) (trans and cis) by a bromination–dehydrobromination sequence. Free radical bromination of 12a,b with
NBS/AIBN furnished two isomeric bromides 13a,b. Isomer 13b gave 2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin
2-oxide (14) on treatment with LiCl/DMF. Isomer 13a underwent CꢀOEt bond cleavage followed by HBr elimination to give the
phosphonic acid 17. Treatment of 14 with NBS/AIBN afforded isomeric 5-bromo-2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphos-
phorin 2-oxides (15a,b) and 5,5-dibromo-2-ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin 2-oxide (18), separated by chro-
matography. Dehydrobromination of 15a,b, and 18 with an excess of Et3N in toluene at 80–95 °C provided the target dienes 3
and 4, respectively. © 2002 Elsevier Science B.V. All rights reserved.
Keywords: Phosphorus heterocycles; 2H-1,2-Oxaphosphorin 2-oxide; Bromination; Synthesis; Dehydrobromination
Due to our interest in the physico-chemical proper-
ties of non-stabilized phosphorous a-pyrone analogs,
we undertook synthesis of two 3-phenyl-2H-oxo-1,2-
1. Introduction
Analogs of a-pyrone have been of considerable inter-
oxaphosphorin 2-oxides 3 and 4. The synthetic pathway
est to synthetic chemists because of their biological
allowed isolation of several 5,6-dihydro-3-phenyl-2H-
properties [1–7]. The activity of a-pyrones as HIV
1,2-oxaphosphorin 2-oxide derivatives which may serve
protease inhibitors sparked additional interest in the
as valuable synthetic intermediates.
investigation of these compounds [1,2]. Sulfur and sele-
nium intracyclic analogs of a-pyrone exhibited strong
photobiological activity [8]. Furthermore, pyrones are
valuable substrates in the Diels–Alder reaction as pre-
2. Results and discussion
cusors for more complex systems [6,7,9–13]. By con-
trast, only two phosphorus analogs of a-pyrone (1 and
2) have been previously synthesized [14,15]; important
steric or electronic effects accounted for their stability.
2.1. Bromination–dehydrobromination of phostone (5)
Prior work in our laboratory on the synthesis of
2-ethoxy-1,2-dioxaphosphorinane 5 (phostone) and its
derivatives [16–18] suggested the use of 5 as a starting
material. Bromination–dehydrobromination of 5 was
expected to provide the cyclic diene, 2-ethoxy-2H-1,2-
oxaphosphorin 9 (Scheme 1).
Free radical bromination of 5 with NBS in the
presence of AIBN in CCl4 was unsuccessful. However,
5 was brominated by treatment with LDA in bromine–
THF (Scheme 2) to give a 1:1 mixture of monobro-
* Corresponding author.
E-mail addresses: apolozov@medichem.com (A.M. Polozov),
sheldon.e.cremer@marquette.edu (S.E. Cremer).
1 Present address: MediChem Life Sciences, 2501 Davey Road,
Woodridge, IL 60517, USA.
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01207-4

154
A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
Scheme 1.
mides 6a,b (1:1.7 cis and trans isomers) and dibromide
10 after purification. The monobromide and dibromide
were easily separated by flash-chromatography. Their
structures were supported by NMR spectroscopy (31P,
1H, 13C) and GC-MS. Attempted sequential addition of
LDA and Br2 was less successful, resulting in a mixture
of 5, 6 and 10 in a 64:23:10 ratio, respectively.
Attempted dehydrobromination 6 in the presence of
KO-t-Bu or DBU at room temperature did not yield
any product. When DBU–THF was used at 60 °C for
12 h, a complex mixture of five products was obtained
(l 31P-NMR, ppm (content): 16.0 (1), 13.64 (2), 8.0
(7.4), 7.1 (8.7)). Only a small amount of compound 7
was observed by GC-MS. Conditions involving KO-t-
Bu–DMSO (room temperature, 12 h) also gave a com-
plex mixture containing only a small amount of the
desired product by GC-MS. An attempt to use LiCl as
a dehydrobromination agent led to exocyclic C–O
cleavage to give 11 (Scheme 3). The 13C-NMR spec-
trum of this phosphonic acid is very similar to that of
6.
isomers (12b, 13b) were upfield relative to the trans
isomers (12a, 13a).
Each of the individual isomers of 13 partially isomer-
ized to give 13% of the other isomer by GC (injector
temperature 260 °C). The mechanism for the isomer-
ization is not clear. In addition, the invariant 13a/13b
ratio obtained during the bromination reaction of 12a,b
(vide infra) was anticipated since bromination would
give the same free radical intermediate. For 13b (cis
isomer) the further transformation to 2-ethoxy-5,6-di-
hydro-3-phenyl-2H-1,2-oxaphosphorin
occurred.
14
(9%)
Attempts to dehydrobrominate 13 with conventional
reagents such as potassium tert-butoxide in (THF or
DMSO) or DBU in THF were unsuccessful. Elimina-
tion was achieved (Scheme 5) by treatment of the major
cis isomer 13b with LiCl–Li2CO3 in DMF using condi-
tions reported for dehydrohalogenation of a,a-dihalo-
carboxylates [19] and 1,2-dibromocyclohexane [20].
Heating 13b with LiCl (twofold excess) and Li2CO3 (0.5
equivalents) in DMF at 80 °C for 1.5 h gave 14 in only
28% yield (after water-workup and chromatography).
In contrast to the observed low yield for the dehydro-
halogenation of a,a-dihalocarboxylates using LiCl in
the absence of Li2CO3 [18], we were able to increase the
yield (57%) of 14. Similar to the results employing
LiCl–Li2CO3, two water-soluble byproducts (31P-
NMR, l 11.2, 9.3 ppm) were observed in the reaction
mixture. The structure of 14 was confirmed by elemen-
tal analysis, GC-MS and 1H- and 13C-NMR data
(Table 1).
2.2. Bromination–dehydrobromination of phenyl
phostone (12)
The presence of the phenyl substituent in 3-phenyl-2-
oxo-1,2-oxaphosphorinane 12a,b (trans and cis isomers
previously assigned [18] by X-ray and NMR spec-
troscopy) permitted facile introduction of a bromo
substituent via AIBN-initiated bromination with 1.5
equivalents of NBS in refluxing CCl4 to give 13a,b
(Scheme 4).
Although the 12b(cis)/12a(trans) ratio was varied
from 3.2:1 to 0.7:1, a constant 2.1:1 ratio of 13b:13a
was observed in the 31P-NMR spectra. The 12b/12a
ratio did not change over the course of the reaction
(GC, 31P-NMR). The isomers of 13 were separated by
flash chromatography to give 25% of 13a and 65% of
13b (overall 90% yield). The structure of 13 was sup-
ported by elemental combustion analysis, GC-MS and
NMR spectral data (Table 1). Comparison of 31P-
NMR and 13C-NMR data of 13a,b with that of 12a,b
allowed a tentative stereo-assignment of the former pair
of isomers. The phosphorus chemical shifts in the cis
Scheme 2.
Scheme 3.

A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
155
Scheme 4.
Table 1
NMR data for the phostone derivatives 3, 4, 12, 13, 14, 15 and 18
Compound
31P-NMR (CDCl3)
13C-NMR (CDCl3)
C-3 (1JCP
a
)
C-4 (2JCP
)
C-5 (3JCP
)
C-6 (2JCP
)
C-7 (2JCP
)
3
4
10.9
7.6
125.9 (166)
127.8 (168)
43.1 (126)
43.0 (125)
58.4 (141)
58.2 (140)
131.3 (165)
132.7 (164)
132.6 (160)
127.8 (163)
135.3 (3.6)
138.6 (3.4)
30.1 (4.9)
28.9 (6.1)
38.1 (2.2)
35.9 (3.9)
141.7 (5.1)
139.9 (2.9)
140.0 (3.6)
143.3 (bs)
105.6 (20.6)
101.7 (22.8)
27.1 (3.7)
27.1 (4.9)
24.8 (4.3)
23.8 (6.5)
27.9 (10.5)
41.5 (9.3)
41.9 (9.7)
52.6 (9.8)
144.5 (13.4)
141.8 (15.1)
68.9 (4.9)
70.0 (7.2)
69.6 (5.5)
70.2 (7.1)
65.4 (5.7)
70.8 (6.7)
69.6 (5.5)
75.6 (7.0)
134.3 (11.3)
134.4 (11.3)
136.5 (6.1)
135.6 (8.5)
138.7 (bs)
12a (trans)
12b (cis)
13a (trans)
13b (cis)
14
15a
15b
18
26.5
22.4
16.7
14.0
11.6
10.0
9.9
138.5 (bs)
135.7 (10.1)
134.4 (10.5)
134.2 (9.0)
132.3 (8.6)
8.2
a C-7 is the ipso carbon of the phenyl substituent.
Scheme 5.
converted to 14 upon treatment with NaH followed by
EtI. The two water-soluble by-products observed for
the reaction 13b(cis) with LiCl were likely compounds
16 and 17.
Treatment of the minor isomer with LiCl 13a(trans)
for 2 h led to 2-hydroxy-5,6-dihydro-3-phenyl-2H-1,2-
oxaphosphorin 2-oxide 17 (31P-NMR, l 9.3 ppm) along
with a small amount (10%) of 14 and a product of
unknown structure (8%, l 10.7 ppm); the latter was
transformed to 17 upon further heating. This suggested
that the reaction of 13a generated the intermediate
bromophosphinic acid 16, which underwent subsequent
elimination to give 17 (Scheme 5). The structure of 17
was supported by 1H and 13C-NMR spectral data
which were very similar to ester 14. Compound 17 was
2.3. Bromination–dehydrobromination of 5,6-dihydro-
3-phenyl-2H-1,2-oxaphosphorin 2-oxide (14)
Treatment of 14 with NBS (1.05 equivalents)–AIBN
in refluxing CCl4 gave an approximate ratio 1.5:0.7:1 of
15a:15b:18 with an overall yield (48%) (Scheme 6).

156
A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
Scheme 6.
Increase of amount of NBS (1.5 equivalents) resulted
diene 3 decomposed in a few weeks at room tempera-
ture. The bromominated diene 4 was more stable which
permitted the longer storage of this material.
in only the single isomer 15a and 18 (crude ratio 1:1.7)
with an enhanced yield (73%). Compound 18 and the
isomers 15a,b were all separated by chromatography.
Isomers 15a,b were easily equilibrated in the presence
of Et3N or pyridine at room temperature to afford a
15b:15a mixture (1.6:1). Similar to other cases, chro-
matography altered the 15a:15b ratio to 1:3. The nearly
identical NMR data of 15a,b isomers prevented isomer
assignments.
Similar to the GC-MS behavior of isomer 13b, we
observed dehydrobromination upon injection of iso-
mers 15a,b to give diene 3. The ratio of 15:3 varied
from one injection to another, and the individual iso-
mers of 15 were not separated. Moreover, the dibro-
mide 18 cleanly dehydrobrominated during the
injection to give the diene 4 as the only observable
peak.
2.4. Diels–Alder reactions of 2H-1,2-oxaphosphorin
2-oxides
Acyclic phosphorus-containing dienes are known to
be good reactants in the Diels–Alder reaction [21,22].
The cyclic mesityl-2,4-butadienylphostinate underwent
Diels–Alder addition with maleic anhydride or
dimethyl acetylenedicarboxylate, but only under forcing
conditions, which caused decomposition of the postu-
lated adducts [14]. The diene 3 was anticipated to react
with tetracyanoethylene dienophile. However, this reac-
tion failed to afford any cycloadduct under the conven-
tional conditions at 75 °C in THF or in the presence of
BF3·OEt2 (one equivalent) or LiClO4 (25%) in CH2Cl2
Attempted dehydrobromination of bromide 15a with
potassium tert-butoxide, DBU or LiCl–Li2CO3, did
not produce diene 3 as indicated by 31P- and 13C-NMR
spectroscopy. The lack of dehydrobromination in the
presence of LiCl was attributed to nucleophilic substitu-
tion of Br by Cl; a pair of new compounds (l 10.0, 9.8
ppm: 19a,b) was observed (Scheme 7). The MS peaks of
isomeric chlorides 19a,b (1.5:1; isomer assignment un-
known) in the GC-MS along with a peak of the diene 3
(30%, thermal dehydrohalogenation) supported this as-
sumption. The GC-MS data indicated that one isomer
of the 19 underwent elimination much faster than the
other. The structure of 19 was also supported by its
13C-NMR spectrum which was similar to that of bro-
mide analogs 15.
Scheme 7.
Ultimately, dehydrobromination of 15 was achieved
upon heating with an excess of Et3N in toluene at
95 °C, producing 3 in 71% yield (Scheme 4). Likewise,
dehydrobromination of 18 at 80 °C gave 4 in 54% yield
(Scheme 8). Similar to 13a, the treatment of dibromide
18 with LiCl–Li2CO3 in DMF led to both elimination
and C–O cleavage to render the phosphonic acid 20
Scheme 8.
1
which was characterized in the crude mixture. The H-
and 13C-NMR features of the heterocyclic ring in 20
were close to that of 4.
1
The H-NMR spectrum of diene 3 is especially inter-
esting as all the coupling constants in this molecule are
well resolved and readily assigned (Fig. 1).
The cyclic dienes were sufficiently stable upon chro-
matography with silica gel. However, after isolation
Fig. 1. Coupling constants (in MHz) from 1H-NMR spectrum of
diene 3.

A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
157
under ultrasound radiation at room temperature. This
suggested that the electron withdrawing properties of
the phosphorus and phenyl groups decreased the elec-
tron donor capability of this fragment.
In conclusion, the first non-stabilized 2-oxo-1,2-
oxaphosphorinane-3,5-diene derivatives 3 and 4 were
synthesized in four steps from the phenyl phostone 12.
The key intermediates and isomers were isolated and
characterized by NMR spectroscopy; GC-MS, and ele-
mental combustion analysis.
evaporated, the residue was extracted with CH2Cl2
(3×5 ml), and the organic phase washed with water (5
ml) and dried over Na2SO4. After evaporation of the
solvent, the crude product was purified by flash chro-
matography on SiO2 (EtOAc–hexanes, 1:1, then
EtOAc) to give a 1:1.7 mixture of 6a/6b (0.39 g, 16%)
and 10 (0.55 g, 17%) as yellowish oils.
6: Rf=0.37 (EtOAc); tR=18.9 min; 31P-NMR
1
l(content): 16.8 (6a), 14.5 (6b), (6a:6b, 1:1.7); H-NMR
l(6a:6b, 1:1.7): 4.45–4.18 (m, 4H), 3.95–3.86 (m, 1H),
2.63–2.14 (m, 2H), 2.11–1.68 (m, 2H), 1.47 (dt, 3 H,
3JHH=7.1, 4JHP=0.6), 1.38 (dt, 3 H, 3JHH=7.1,
4JHP=0.4); 13C-NMR (6a) l: 69.52 (d, 2JCP=5.7),
3. Experimental
2
1
63.26 (d, JCP=6.2), 36.64 (d, JCP=141.5), 32.46 (d,
3
3
3.1. General
2JCP=0.9), 24.50 (d, JCP=5.4), 16.21 (d, JCP=3.8);
13C-NMR (6b) d: 69.65 (d, JCP=6.6), 63.99 (d, JCP
=
2
2
1
2
All reactions were carried out in flame-dried glass-
ware under a nitrogen atmosphere. NMR spectra were
recorded on a GE OMEGA 300 MHz NMR spectrom-
eter. CDCl3 was used as the solvent in all cases unless
6.6), 36.20 (d, JCP=140.4), 33.55 (d, JCP=5.0), 26.97
3
3
(d, JCP=5.6), 16.21 (d, JCP=3.8). MS m/e (relative
intensity) 244 ([M+], 7), 242 ([M+], 6), 217 (45), 215
(46), 163 (43), 135 (100), 108 (25), 106 (24), 71 (18), 55
(70), 41 (37).
1
stated otherwise. Chemical shifts for H- and 13C- (75
MHz) NMR were reported in ppm relative to TMS and
to 85% H3PO4 for 31P-NMR (121 MHz). Coupling
constants, J, are given in Hz. Two-dimensional NMR
spectra (COSY, HETCOR and DEPT) supported the
structural assignments for all new isolated compounds.
GC-MS data were obtained on a Hewlett–Packard
5890A gas chromatograph-5970 series mass selective
detector: capillary column DB-1, 0.25 mm; id 30 m;
injection temperature 260 °C; determinant temperature
265 °C; initial temperature 100 °C for 5 min then
10 °C min−1; final temperature 250 °C. Elemental
analyses were performed by Quantitative Technologies
Inc., NJ. HR-MS were performed by the Washington
University Resource for Biomedical and Bio-Organic
Mass Spectrometry, St. Louis, MO. Melting points
were determined with a Thomas–Hoover capillary
melting point apparatus and are uncorrected. TLC
(Aldrich) plates were developed by iodine. All chemi-
cals were purchased from the Aldrich Chemical Co. and
used without further purification. Preparative flash
chromatography was performed with Acros silica gel
(0.035–0.075 mm). The preparation of 5 and 12 was
previously described [18].
10: Rf=0.20 (EtOAc–hexanes, 1:1); tR=15.1 min;
31P-NMR l: 8.7; 1H-NMR l: 4.51–4.25 (m, 4H), 3.04–
2.77 (m, 2H), 2.22–2.07 (m, 1H), 1.93–1.77 (m, 1H),
1.42 (dt, 3H, 3JHH=7.1, 4JHP=0.8); 13C-NMR l:
70.02 (d, 2JCP=8.3), 66.22 (d, 2JCP=7.1), 53.03 (d,
3
1JCP=145.9), 45.92 (bs), 25.86 (d, JCP=3.2), 16.38 (d,
3JCP=2.9). MS m/e (relative intensity) 324 ([M+], 1),
322 ([M+], 2), 320 ([M+], 1), 297 (13), 295 (24), 293
(12), 243 (33), 241 (32), 215 (55), 213 (56), 186 (24), 135
(34), 133 (51), 53 (100), 47 (42).
3.3. 3-Bromo-2-hydroxy-3-phenyl-1,2-oxaphos-
phorinane 2-oxide (11)
A mixture of 6 (50 mg, 0.2 mmol), LiCl (17 mg, 0.4
mmol) and DMF (5 ml) was heated at 80 °C for 6 h.
31P-NMR (DMF) l: 8.2; 13C-NMR (DMF) l: 66.03 (d,
2
2JCP=4.1), 43.60 (d, 1JCP=136.1), 33.22 (d, JCP
2.4), 24.98 (d, JCP=2.7).
=
3
3.4. 3-Bromo-2-ethoxy-3-phenyl-1,2-oxaphosphorinane
2-oxide (13a,b)
A solution of 12a:12b (1:0.7), (1.46 g, 6.08 mmol),
NBS (1.62 g, 9.1 mmol, 1.5 equivalents), and AIBN
(0.15 g, 0.9 mmol, 0.15 equivalents) in CCl4 (15 ml) was
stirred and refluxed for 3.0 h. The residue was cooled at
0 °C and the succinimide was removed by filtration.
The solvent was evaporated in vacuo and the residue
13a:13b (1:2.1 by 31P-NMR) was chromatographed on
SiO2 (EtOAc–hexane, 1:1) to give 13a (0.49 g, 25%)
and 13b(cis) (1.26 g, 65%) as colorless oils (total 90%).
13a: Rf=0.36 (EtOAc–hexanes, 1:1); tR=19.0 min;
31P-NMR l: 16.7; 1H-NMR l: 7.80–7.75 (m, 2H),
7.40–7.27 (m, 3H), 4.53–4.27 (m, 4H), 3.05–2.93 (m,
3.2. 3-Bromo-2-ethoxy-3-phenyl-1,2-oxaphosphorinane
2-oxide (mixture 6a,b) and 3,3-dibromo-2-ethoxy-3-
phenyl-1,2-oxaphosphorinane 2-oxide (10)
An LDA solution (11 mmol) in THF (10 ml) was
slowly added over 10 min to a solution of phostone 5
(1.64 g, 10 mmol) and bromine (1.60 g, 10 mmol) at
−78 °C. Immediate decoloration was observed. After
stirring for 30 min the mixture was quenched with
saturated NaHCO3 (5 ml) at −78 °C and then allowed
to warm to room temperature (r.t.). The THF was

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A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
1H), 2.79–2.64 (m, 1H), 2.37–2.22 (m, 1H), 1.89–1.78
(m, 1H), 1.42 (dt, 3H, 3JHH=7.1, 4JHP=0.4); 13C-NMR
l: 138.69 (bs), 128.47 (two peaks are overlapped), 127.89
LiCl (1.20 g, 28.3 mmol). The mixture was stirred at
80 °C for 2.0 h. The DMF was evaporated under high
vacuo at 40 °C, then water (20 ml) was added, and the
water phase was extracted by ether (3×20 ml). The
organic phase was washed by brine (10 ml) and dried
over Na2SO4. After evaporation of the solvent, the crude
product was purified by flash chromatography on SiO2
(EtOAc–hexanes, 1:1, then EtOAc) to give 14 (1.90 g,
57%) as a colorless oil identical to the product obtained
from method A above.
3
2
2
(d, JCP=5.8), 69.56 (d, JCP=5.5), 65.45 (d, JCP
=
1
3
7.4), 58.44 (d, JCP=141.3), 38.13 (d, JCP=2.2), 24.76
3
3
(d, JCP=4.3), 16.41 (d, JCP=5.4); MS m/e (relative
intensity) 320 ([M+], 0.6), 318 (M+, 0.6), 239 (100), 211
(19), 209 (13), 195 (25), 131 (56), 129 (72), 103 (27), 91
(43), 77 (36), 51 (19); Anal. Calc. for C12H16BrO3P: C,
45.16; H, 5.05; Found: 45.68; H, 5.19%.
13b: Rf=0.46 (EtOAc–hexanes, 1:1); tR=19.9 min;
1
31P-NMR l: 14.0; H-NMR l: 7.85–7.80 (m, 2H); d
3.6. 2-Hydroxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphos-
phorin 2-oxide (17)
7.41–7.29 (m, 3H), 4.46–4.23 (m, 2H), 3.98–3.85 (m,
1H), 3.67–3.54 (m, 1H), 2.80–2.55 (m, 3H), 1.86–1.78
(m, 1H), 0.93 (dt, 3H, 3JHH=7.1, 4JHP=0.4); 13C-NMR
Compound 13b (0.33 g, 1.03 mmol) was treated with
LiCl in DMF for 3 h at 80 °C and worked up as in
method B. The compound 17 was characterized by
NMR methods without DMF removal and water-
workup in a DMF–CDCl3 solution. 31P-NMR (CDCl3–
DMF) l: 9.3. 1H-NMR (CDCl3–DMF) l: 7.67 (bs, 1H),
7.53–7.50 (m, 2H), 7.21–7.19 (m, 3H), 6.55 (dt, 1H,
3
l: 138.48 (bs), 128.53, 128.21, 127.55 (d, JCP=6.6),
70.24 (d, 2JCP=7.1), 63.84 (d, 2JCP=7.6), 58.18 (d,
1JCP=140.0), 35.91 (d, 2JCP=3.9), 23.84 (d, 3JCP=6.5),
3
15.75 (d, JCP=2.5); MS m/e (relative intensity) 320
([M+], 0.3), 318 ([M+], 0.3), 239 (100), 211 (18), 209 (21),
195 (24), 131 (58), 129 (72), 103 (25), 91 (43), 77 (33), 51
(18); Anal. Calc. for C12H16BrO3P: C, 45.16; H, 5.05.
Found: C, 45.12; H, 5.04%.
3
3
3
3JHP=40.7, JHH=4.0), 4.33 (dt, JHP=13.5, JHH
=
4.5, 2H), 2.45 (m, 2H); 13C-NMR (CDCl3–DMF) l:
139.3 (bs), 135.72 (d, 2JCP=9.6), 131.82 (d, JCP
=
1
3
3.5. 2-Ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphos-
phorin 2-oxide (14) ( from 13b)
165.8), 127.26, 126.51, 126.26 (d, JCP=6.4), 64.25 (d,
2JCP=5.1), 27.39 (d, JCP=9.6).
3
3.5.1. Method A (LiCl–Li2CO3)
3.7. Con6ersion of 13b to 14 by alkylation of 17
Bromide 13b (0.81 g, 2.54 mmol) was dissolved in dry
DMF (4 ml). To this solution (in a dry box) was added
LiCl (0.215 g, 5.08 mmol) and Li2CO3 (0.094 g, 1.27
mmol). The mixture was stirred at 80 °C for 2.0 h. The
DMF was evaporated under high vacuo at 40 °C, then
water (4 ml) was added, and the water phase was
extracted by ether (3×4 ml). The organic phase was
washed by brine (2 ml) and dried over Na2SO4. After
evaporation of the solvent, the crude product was
purified by flash chromatography on SiO2 (EtOAc–hex-
anes, 1:1, then EtOAc) to give 14 (0.17 g, 28%) as a
colorless oil: Rf=0.21 (EtOAc–hexanes, 1:1); tR=17.5
min; 31P-NMR l: 11.6; 1H-NMR l: 7.61–7.56 (m, 2H),
Compound 13b (0.33 g, 1.03 mmol) was treated with
LiCl in DMF for 3 h at 80 °C. The DMF was evapo-
rated in high vacuo at 40 °C and dry THF (3 ml) was
added. NaH (0.03 g, 12.5 mmol) was added in dry-box
at r.t. The mixture was stirred for 10 min and then
cooled to 0 °C. Ethyl iodide (0.195 g, 12.5 mmol) was
added and the mixture was allowed to warm up. The
THF was evaporated, then water (2 ml) was added and
water phase was extracted by ether (3×2 ml). The
organic phase was washed by brine (1 ml) and dried over
Na2SO4; yield 28%; spectral and chromatographic char-
acteristics identical with 14.
3
3
7.39–7.31 (m, 3H), 6.78 (dt, 1H, JHP=42.3, JHH
=
4.2), 4.58–4.40 (m, 2H), 4.18–4.00 (m, 2H), 2.78–2.64
3.8. 5-Bromo-2-ethoxy-5,6-dihydro-3-phenyl-2H-
1,2-oxaphosphorin 2-oxide (15a,b) and 5,5-dibromo-2-
ethoxy-5,6-dihydro-3-phenyl-2H-1,2-oxaphosphorin
2-oxide (18) using 1.5 equi6alents NBS
3
(m, 1H), 2.59–2.46 (m, 1H), 1.23 (dt, 3H, JHH=7.1,
2
4JHP=1.4); 13C-NMR l: 141.73 (d, JCP=5.1), 135.68
(d, 2JCP=10.1), 131.29 (d, 1JCP=164.6), 128.32, 127.87,
3
2
126.86 (d, JCP=5.4), 65.36 (d, JCP=5.7), 62.13 (d,
2JCP=7.1), 27.92 (d, JCP=10.5), 16.02 (d, JCP=3.7);
MS m/e (relative intensity): 238 (M+, 50), 209 (100), 191
(25), 130 (18), 116 (38), 115 (77), 105 (11), 102 (19), 89
(14), 77 (23), 65 (14), 51 (19). Anal. Calc. for C12H15O3P:
C, 60.50; H, 6.35. Found: C, 59.91; H, 6.41%.
A solution of 14 (0.67 g, 2.81 mmol), NBS (0.75 g,
4.2 mmol), and AIBN (0.062 g, 0.42 mmol) in CCl4 (5
ml) was stirred and refluxed for 2.5 h. The residue was
cooled at 0 °C and the succinimide was removed by
filtration. The solvent was evaporated in vacuo and the
residue (15a:18, 1.7:1 by 31P-NMR) was chromato-
graphed on SiO2 (EtOAc–hexane, 1:3) to give 15a (0.09
g, 10%) and 15b (0.28 g, 31%) as colorless oils and
crystalline 18 (0.35 g, 32%).
3
3
3.5.2. Method B (LiCl)
Bromide 13b (4.50 g, 14.1 mmol) was dissolved in dry
DMF (20 ml) in a dry-box. To this solution was added

A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
159
15a: Rf=0.22 (EtOAc–hexanes, 1:3); tR=19.4 min;
31P-NMR l: 10.0; 1H-NMR l: 7.65–7.59 (m, 2H), 7.42–
(0.5 ml) was added triethylamine (134 mg, 0.19 ml, ten
equivalents) at r.t. After 0.5 h a 1:1.6 ratio of 15a:15b was
observed by 31P-NMR spectroscopy.
7.34 (m, 3H), 6.78 (ddd, 2JHP=40.0, 3JHH=4.6, 4JHH
=
3
4
0.7, 1H), 4.84 (d of parent qn, JHH=4.0, JHP=0.3,
1H), 4.74 (ddd, 2JHH=12.6, 3JHH=3.4, 3JHP=10.2,
3.11. 5-Chloro-2-ethoxy-5,6-dihydro-3-phenyl-
2H-1,2-oxaphosphorin 2-oxide (19a,b)
2
3
3
1H), 4.62 (dddd, JHH=12.6, JHH=4.1, JHP=16.7,
4JHH=0.7, 1H), 4.24–4.00 (m, 2H), 1.25 (t, JHH=7.1,
3
3H); 13C-NMR l: 139.94 (d, 2JCP=2.9), 134.43 (d,
In a dry-box, bromide 15a (30 mg, 0.09 mmol) was dis-
solved in dry DMF (0.5 ml) and to this solution was
added LiCl (15 mg, 0.36 mmol) and Li2CO3 (13 mg, 0.18
mmol). The mixture was stirred at 70 °C for 2.0 h to give
crude 19a,b. 31P-NMR l: 10.0; 9.8 (1:1) (DMF); 13C-
2JCP=10.5), 132.74 (d, 1JCP=163.7), 129.11, 128.77,
3
2
127.36 (d, JCP=6.4), 70.77 (d, JCP=6.7), 62.96 (d,
2JCP=6.2), 41.52 (d, JCP=9.3), 16.29 (d, JCP=2.3);
MS m/e (relative intensity) 318 ([M+], 0.5), 316 ([M+], 1),
314 ([M+], 0.5), 237 (65), 209 (100), 191 (13), 144 (14),
128 (29), 115 (41), 105 (20), 89 (70). Anal. Calc. for
C12H14BrO3P (mixture of isomers): C, 45.45; H 4.45.
Found: C, 45.20; H, 4.41%.
3
3
NMR (DMF) (mixture of isomers) l: 139.94 (d, 2JCP
=
8.6), 137.47 (d, 2JCP=8.8), 134.27 (d, 2JCP=11.1),
2
1
133.99 (d, JCP=10.0), 131.21 (d, JCP=163.8), 128.36
(d, 3JCP=2.0), 128.14 (d, JCP=7.9), 127.24, 126.77,
3
15b: Rf=0.18 (EtOAc–hexanes, 1:3); 31P-NMR l:
9.9; 1H-NMR l: 7.65–7.59 (m, 2H), 7.39–7.35 (m, 3H),
6.82 (ddd, 2JHP=39.9, 3JHH=5.0, 4JHH=0.9, 1H),
4.94–4.85 (m, 2H), 4.62–4.46 (m, 1H), 4.20–3.96 (m,
4
4
126.64 (d, JCP=6.2), 126.40 (d, JCP=5.9), 70.88 (d,
2JCP=7.8), 69.23 (d, JCP=5.4), 62.89 (d, JCP=6.1),
2
2
2
3
61.57 (d, JCP=7.5), 52.26 (d, JCP=12.1), 51.91 (d,
3
3
3JCP=9.2), 15.14 (d, JCP=6.0), 14.85 (d, JCP=4.7).
19a: tR=18.4; MS m/e (relative intensity) 274 ([M+], 6),
272 ([M+], 14), 237 (49), 209 (100), 191 (16), 128 (31), 115
(63), 77 (17), 51 (13). 19b: tR=18.6; MS m/e (relative in-
tensity) 274 ([M+], 6), 272 ([M+], 12), 237 (34), 209 (100),
154 (20), 128 (45), 115 (81), 77 (18), 51 (17).
2H), 1.20 (t, JHH=7.1, 3H); 13C-NMR l: 140.02 (d,
3
2JCP=3.6), 134.16 (d, 2JCP=9.0), 132.61 (d, JCP
=
1
3
159.5), 129.17, 128.84, 127.18 (d, JCP=6.3), 69.62 (d,
2JCP=5.5), 63.85 (d, JCP=6.4), 41.85 (d, JCP=9.7),
2
3
3
16.07 (d, JCP=4.1).
18: m.p. 81–82 °C (EtOAc–hexanes, 1:3); Rf=0.30
(EtOAc–hexanes, 1:3); tR=19.0 min; 31P-NMR l: 8.2;
1H-NMR l: 7.67–7.59 (m, 2H), 7.46–7.35 (m, 3H), 7.08
3.12. 2-Ethoxy-3-phenyl-2H-1,2-oxaphosphorin 2-oxide
(3)
(d, 3JHP=38.7, 1H), 4.99 (parent t, 3JHP=12.6, 2JHH
=
3
2
4
12.6, 1H), 4.81 (ddd, JHP=14.6, JHH 12.6, JHH 0.9,
1H), 4.23–4.04 (m, 2H), 1.24 (t, 3H, 3JHH 6.6); 13C-NMR
A solution of 15a (0.42 g, 1.3 mmol) and triethylamine
(1.34 g, 1.85 ml, ten equivalents) in toluene (5 ml) was
stirred at 95 °C for 1.5 h. Then it was filtrated, washed
with toluene, and the solvent and excess of triethylamine
were removed in vacuo. The residue was chro-
matographed on silica gel (EtOAc–hexanes, 1:3) to give
3 (0.24 g, 71%). Rf=0.21 (EtOAc–hexanes, 1:3); tR=
2
l: 143.26, 132.31 (d, JCP=8.6), 129.35 (bs), 128.62,
127.78 (d, 1JCP=162.8), 127.12 (d, 3JCP=6.4), 75.62 (d,
2
3
2JCP=7.0), 63.61 (d, JCP=6.1), 52.61 (d, JCP=9.8),
3
15.76 (d, JCP=6.3); MS m/e (relative intensity): 316
([M+−HBr], 84), 314 ([M+−HBr], 82), 288 (98), 286
(100), 224 (17), 222 (16), 143 (16), 115 (86), 77 (16), 63
(19). Anal. Calc. for C12H13Br2O3P: C, 36.40; H 3.31.
Found: C, 36.02; H, 3.23%.
1
16.5 min; 31P-NMR l: 10.9; H-NMR l: 7.65–7.62 (m,
3
4
2H), 7.42–7.31 (m, 3H), 7.98 (ddd, JHH=6.9, JHH
=
3
3
4
1.8, JHP=39.5, 1H), 6.89 (ddd, JHH=5.4, JHH=1.8,
3JHP=19.5, 1H), 5.80 (ddd, 3JHH=6.9, 3JHH=5.4,
3.9. Treatment of 14 with 1.05 equi6alents of NBS
4JHP=2.4, 1H), 4.13 (dq, JHH=7.1, JHP=0.8, 1H),
3
3
3
3
3
A solution of 14 (0.83 g, 3.48 mmol), NBS (0.65 g, 3.66
mmol), and AIBN (0.057g, 0.35 mmol) in CCl4 (6 ml) was
stirred and refluxed for 2.5 h. The residue was cooled at
0 °C and the succinimide was removed by filtration. The
solvent was evaporated in vacuo and the residual mixture
of 15a:15b (2.3:1) and 18 (the ratio of 15a,b:18 was 2.2:1
by 31P-NMR) was chromatographed on SiO2 (EtOAc–
hexane, 1:3) to give a mixture of 15a,b (0.31 g, 28%) as a
colorless oil and crystalline 18 (0.27 g, 20%).
4.10 (dq, JHH=7.1, JHP=1.4, 1H), 1.24 (dt, JHH
=
7.1, 4JHP=0.5, 3H); 13C-NMR l: 144.49 (d, 2JCP=13.4),
2
2
135.25 (d, JCP=3.6), 134.30 (d, JCP=11.3), 128.43,
128.13, 126.56 (d, JCP=7.6), 125.91 (d, JCP=166.1),
3
1
3
2
105.56 (d, JCP=20.6), 63.13 (d, JCP=7.2), 15.67 (d,
3JCP=6.8); MS m/e (relative intensity) 236 ([M+], 70),
208 (73), 144 (43), 115 (100), 89 (20), 77 (11), 63 (16), 51
(11). HREI MS Anal. Calc. for C12H13O3P 236.0613.
Found: 236.0602.
3.10. Equilibration of 5-Bromo-2-ethoxy-5,6-dihydro-
3-phenyl-2H-1,2-oxaphosphorin 2-oxide (15a,b) by
triethylamine
3.13. 5-Bromo-2-ethoxy-3-phenyl-2H-1,2-oxaphos-
phorin 2-oxide (4)
A solution of 18 (0.30 g, 0.76 mmol) and triethylamine
(0.77 g, 7.6 mmol) in toluene (3 ml) was heated
To a solution of pure 15a (42 mg, 0.13 mmol) in CDCl3

160
A.M. Polozo6, S.E. Cremer / Journal of Organometallic Chemistry 646 (2002) 153–160
at 80 °C for 2.5 h. The work-up and chromatography
was similar to that described for 3. Compound 4 (0.13
g, 54%) was isolated as a yellowish oil. Rf=0.37
(EtOAc–hexanes, 1:3); tR=19.0 min; 31P-NMR l: 7.6;
1H-NMR (benzene-d6) l: 7.54–7.00 (m, 2H), d 7.07–
of LiClO4 (25%) and TCE in CH2Cl2 (0.5 ml) at r.t. It
was subjected with ultrasonic radiation for 1 h. Only
starting material was found by 31P-NMR, GC-MS and
TLC.
4
3
6.98 (m, 3H), 6.56 (dd, JHH=2.3, JHP=37.3, 1H),
4
3
6.33 (dd, JHH=2.3, JHP=18.2, 1H), 3.88–3.69 (m,
Acknowledgements
2H), 0.78 (t, JHH=7.1, 3H); 13C-NMR l: 141.77 (d,
3
2JCP=15.1), 138.56 (d, JCP=3.4), 133.41 (d, JCP
=
We thank the S.C. Johnson and Son for financial
support. High resolution mass spectra were provided by
the Washington University Mass Spectrometry Re-
source, an NIH Research Resource (Grant no.
P41RR0954). We also acknowledge the assistance of Dr
Pat Giles of the Chemical Abstract Service for providing
CA Index names for many of the structures in this
paper.
2
2
11.3), 129.14, 128.88, 127.80 (d, 1JCP=168.1), 127.55 (d,
3JCP=7.6), 101.74 (d, 3JCP=22.8), 64.08 (d, 2JCP=8.2),
3
16.00 (d, JCP=6.9); MS m/e (relative intensity) 316
([M+], 74), 314 ([M+], 72), 288 (79), 286 (79), 224 (14),
222 (14), 143 (16), 115 (100), 77 (19), 63 (23), 47 (15).
HREI MS Anal. Calc. for C12H12BrO3P 313.9707.
Found. 313.9711.
3.14. 5-Bromo-2-hydroxy-3-phenyl-2H-1,2-oxaphos-
phorin 2-oxide (20)
References
[1] S. Thaisrivongs, D.L. Romero, R.A. Tommasi, M.N. Janakira-
man, J.W. Strohbach, J. Med. Chem. 39 (1996) 4630.
[2] H.W. Hamilton, B.D. Tait, C. Gajda, S.E. Hagen, D. Ferguson,
Bioorg. Med. Chem. Lett. 6 (1996) 719.
[3] L. Cook, B. Ternai, P. Ghosh, J. Med. Chem. 30 (1987) 1017.
[4] W.C. Groutas, T.L. Huang, M.A. Stanga, M.J. Brubaker, M.K.
Moi, J. Heterocycl. Chem. 22 (1985) 433.
[5] G.H. Posner, J.K. Lee, M.C. White, R.H. Hutchings, H. Dai, J.
Org. Chem. 62 (1997) 3299.
[6] G.H. Posner, J. Ishihara Tetrahedron Lett. 35 (1994) 7545.
[7] D. Perez, G. Bures, E. Guitian, L. Castedo, J. Org. Chem. 61
(1996) 1650.
[8] D. Vedaldi, S. Caffieri, S. Frank, F. Dall’Acqua, A. Jakobs, J.
Piette, Farmaco 50 (1995) 527.
[9] K. Afarinkia, V. Vinader, T.D. Nelson, G.H. Posner, Tetrahe-
dron 48 (1992) 9111.
[10] T. Shimo, K. Kataoka, A. Maeda, K. Somekawa, J. Heterocycl.
Chem. 29 (1992) 811.
A solution of 18 (70 mg, 0.22 mmol), LiCl (19 mg,
0.45 mmol), Li2CO3 (8 mg, 11 mmol) in DMF (0.5 ml)
was heated at 70 °C for 2 h. The DMF was removed
and isolated, crude compound was characterized: 31P-
1
NMR l: 3.8; H-NMR l: 7.86–7.75 (m, 2H), d 7.43–
4
3
7.41 (m, 3H), 7.01 (dd, JHH=1.7, JHP=16.6, 1H),
6.82 (dd, 4JHH=1.7, 3JHP=34.1, 1H); 13C-NMR l:
142.15 (d, 2JCP=9.5), 134.89 (d, 2JCP=8.8), 133.51,
131.86 (d, 1JCP=169.9), 128.08, 127.53, 126.54 (d,
3
3JCP=6.7), 101.74 (d, JCP=22.7).
3.15. Attempted reaction of 3-phenyl-2-ethoxy-2-oxo-
1,2-oxaphosphorinane-3,5-diene (3) with tetracyano-
ethylene (thermal and (or) BF3·OEt2 acti6ation)
[11] I.E. Marko, G.R. Evans, J.-P. Declercq, Tetrahedron 50 (1994)
4557.
To a solution of diene 3 (30 mg, 0.13 mmol) in THF
(0.25 ml) was added a solution of tetracyanoethylene (17
mg, 0.13 mmol) in THF (0.25 ml) at r.t. The solution
immediately turned to brown–orange. It was kept for 2
h at r.t. The solution was heated at 75 °C over 1 h.
After it was cooled, BF3·OEt2 (18 mg, 0.13 mmol) was
added at r.t. and kept for 2 h at r.t. The solution was
refluxed for 1 h. Only starting material was found by
31P-NMR, GC-MS and TLC after each attempt.
[12] C. Tanyeli, O. Tarhan, Synth. Commun. 19 (1989) 2453.
[13] K. Afarinkia, G.H. Posner, Tetrahedron 33 (1992) 7839.
[14] L. Sigal, L. Loew, J. Am. Chem. Soc. 100 (1978) 6394.
[15] A.I. Razumov, B.G. Liorber, M.P. Sokolov, T.V. Zykova, R.A.
Salakhutdinov, J. Obshch. Khim. 48 (1978) 51.
[16] T.M. Lane, O.P. Rodriguez, S.E. Cremer, D.W. Bennett, Phos-
phorus, Sulfur, Silicon Relat. Elem. 103 (1995) 63.
[17] S.E. Cremer, A.G. Sommese, O.P. Rodriguez, Phosphorus, Sul-
fur, Silicon Relat. Elem. 75 (1993) 107.
[18] A.M. Polozov, S.E. Cremer, J. Can. Chem. 77 (1999) 1274.
[19] L. Forti, F. Ghelfi, U.M. Pagnoni, Tetrahedron Lett. 36 (1995)
3023.
[20] A. Weisz, A. Mandelbaum, J. Org. Chem. 49 (1984) 2648.
[21] H.-J. Liu, W.M. Feng, J.B. Kim, E.N.C. Browne, Can. J. Chem.
72 (1994) 2163.
3.16. Attempted reaction of 3-phenyl-2-ethoxy-2-
oxo-1,2-oxaphosphorinane-3,5-diene (3) with
tetracyanoethylene (LiClO4 acti6ation)
To diene 3 (30 mg, 0.13 mmol) was added a solution
[22] T. Calogeropoulou, D.F. Wiemer, J. Org. Chem. 53 (1988) 2295.