Cyclisation reactions of 2-substituted benzoylphosphonates with trialkyl phosphites via nucleophilic attack on a carbonyl-containing ortho substituent

Article abstract of DOI:10.1016/j.tet.2008.01.012

Dimethyl 2-acetoxy- and dimethyl 2-benzoyloxy-benzoylphosphonate undergo cyclisation and deoxygenation in the presence of excess trimethyl phosphite to give dimethyl (3-methyl-1-benzofuran-2-yl)phosphonate and dimethyl (3-phenyl-1-benzofuran-2-yl)phosphonate, respectively. The reaction pathway has been shown to involve phosphite attack on initially formed tricyclic dioxaphospholane intermediates with the subsequent loss of two molecules of trimethyl phosphate. In the absence of additional trimethyl phosphite the initially formed tricyclic dioxaphospholane intermediates lose one molecule of trimethyl phosphate and then undergo a novel rearrangement to give β-ketophosphonates. The mechanism for this reaction helps explain some previously reported epoxide rearrangements. In contrast, the initially formed anionic intermediate from the reaction of dimethyl 2-benzoyloxymethylbenzoylphosphonate with trimethyl phosphite undergoes decomposition to give a carbene intermediate which is trapped by the trimethyl phosphite to give an ylidic phosphonate.

Full text of DOI:10.1016/j.tet.2008.01.012

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2329e2338
www.elsevier.com/locate/tet
Cyclisation reactions of 2-substituted benzoylphosphonates
with trialkyl phosphites via nucleophilic attack on a
carbonyl-containing ortho substituent
*
Yuen-Ki Cheong, Philip Duncanson, D. Vaughan Griffiths
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
Received 15 October 2007; received in revised form 7 December 2007; accepted 3 January 2008
Available online 8 January 2008
Abstract
Dimethyl 2-acetoxy- and dimethyl 2-benzoyloxy-benzoylphosphonate undergo cyclisation and deoxygenation in the presence of excess
trimethyl phosphite to give dimethyl (3-methyl-1-benzofuran-2-yl)phosphonate and dimethyl (3-phenyl-1-benzofuran-2-yl)phosphonate, respec-
tively. The reaction pathway has been shown to involve phosphite attack on initially formed tricyclic dioxaphospholane intermediates with the
subsequent loss of two molecules of trimethyl phosphate. In the absence of additional trimethyl phosphite the initially formed tricyclic dioxa-
phospholane intermediates lose one molecule of trimethyl phosphate and then undergo a novel rearrangement to give b-ketophosphonates. The
mechanism for this reaction helps explain some previously reported epoxide rearrangements. In contrast, the initially formed anionic interme-
diate from the reaction of dimethyl 2-benzoyloxymethylbenzoylphosphonate with trimethyl phosphite undergoes decomposition to give a carbene
intermediate which is trapped by the trimethyl phosphite to give an ylidic phosphonate.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O O
P(OR)2
O
P(OR)3
P(OR)2
O
(RO)3P
We have previously shown that the reactions of dialkyl benz-
i
oylphosphonates 1 with trialkyl phosphites (R¼Me, Et, Pr)
R'
R'
R'
R'
1
2
usually proceed via the initial formation of anionic intermedi-
ates 2 which, in the absence of electrophiles, undergo aCeO
bond cleavage to give carbene intermediates 3 (Scheme 1).1
Moreover, if there is a substituent ‘R’ on the benzene ring
capable of reacting with this carbene centre, intramolecular
insertion reactions can occur leading to the formation of novel
cyclisation products via some interesting reaction pathways.2e5
Thus, for example, the 2-allyl-substituted system 1 (R¼Me,
R0¼CH2CH]CH2) reacts with trimethyl phosphite to give
the cyclopropane-containing system 7.2 Intermolecular trap-
ping of the carbene intermediates 3 by the trialkyl phosphite
present can also occur to give the ylidic phosphonate 4 which
can be used to prepare the analogous bisphosphonates 5 or 6.
– (RO)3PO
O
O
P(OR)2
(RO)3P
C
P(OR)2
P(OR)3
3
4
Insertion
into R'
Heat HX
(5) (6)
Cyclic products
R' = allyl
O
R' = C(O)Ph
P(OR)2
R"
Ph
P(OR)2
O
O
R'
P(OMe)2
P(OMe)2
O
O
5: R = R" = Me
6: R" = H
* Corresponding author. Tel.: þ44 (0)20 7882 5389; fax: þ44 (0)20 7882
7427.
E-mail address: d.v.griffiths@qmul.ac.uk (D.V. Griffiths).
7
8
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.012

2330
Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
(MeO)3P
More recently we have been investigating the reactions of
O
O
N
some dialkyl benzoylphosphonates where the substituent con-
tains an electrophilic centre such as a carbonyl-containing
functional group. In particular, we were interested to see if
such substituted benzoylphosphonates would preferentially un-
dergo cyclisation in the presence of trialkyl phosphites via the
initially formed anionic intermediates 2 rather than their im-
mediate decomposition products, the carbene intermediates 3.
It has been speculated that the cyclisation of diethyl
2-acetoxybenzoylphosphonate 9 in triethyl phosphite to give
diethyl 2-methyl-benzofuran-3-ylphosphonate 11 (Scheme
2)6 might involve such a mechanism although this has not
been established.
O
(MeO)3P
P(OMe)3
Δ
N
R
O
O
R
12a: R = Ph
12b: R = Me
13a,b
O
O
P(OMe)2
O
P(O)(OMe)2
(MeO)3P
NR '
R
R
N
R'
16a,b: R' = H
17a,b: R' = Me
14a,b: R' = H
15a,b: R' = Me
(MeO)3P
– (MeO)3PO
O
Me
P(OMe)2
O
O
O
Me
O
Δ
O
R
N
P(OEt)2
O
R'
18a,b: R' = H
O
P(OEt)2
O
(EtO)3P
19a,b: R' = Me
(EtO)3P
9
Scheme 3.
– (EtO)3PO
rationale could be applied to the formation of the proposed ep-
oxides 16a, 16b, 17a and 17b.
O
O
Me
(EtO)3P
Me
O
– (EtO)3PO
In the case of the 2-benzoyl-substituted system 1 [R¼Me,
R0¼C(O)Ph],4 the anionic centre in the intermediate 2
[R¼Me, R0¼C(O)Ph] was not appropriately positioned to be
able to attack the adjacent carbonyl group and the reaction
therefore had no option other than to proceed via a carbene
mechanism. We have therefore now investigated the reaction
of systems such as the 2-benzoyloxy- and 2-benzoyloxy-
methyl-substituted systems 1 [R¼Me, R0¼OC(O)Ph and
CH2OC(O)Ph] to see if a suitable spacer between the disubsti-
tuted benzene ring and the carbonyl group in the substituent
might facilitate the direct interaction of the carbanionic centre
with the carbonyl carbon.10 These studies have enabled us to
establish that the reaction pathway to diethyl 2-methyl-benzo-
furan-3-ylphosphonate 11 is not the one originally proposed.
P(OEt)2
P(OEt)2
O
O
11
10
Scheme 2.
An analogous pathway involving the epoxides 16a, 16b,
17a and 17b has also been proposed to explain the reported
formation of the indole systems 18a, 18b, 19a and 19b
when the benzoxazinones 12a and 12b were heated with tri-
alkyl phosphites such as trimethyl phosphite (Scheme 3).7
However, no evidence for the intermediates on this pathway
including the aroylphosphonates 14a, 14b, 15a and 15b could
be obtained and the formation of the aroylphosphonates 14a
and 14b clearly involves an additional source of protons.
We had concerns over the mechanism shown in Scheme 2
following our observation that the formation of the benzofu-
ran-3-ylphosphonate 11 from the aroylphosphonate 9 proceeds
even at room temperature. This would mean that the proposed
epoxide 10 would have to undergo deoxygenation at a much
lower temperature than has been reported for such deoxygen-
ations. For example, the deoxygenation of ethylene oxide by
triethyl phosphite8 is reported to require in excess of 1 h at
175 ꢀC while the more sterically hindered 2-butene oxide
could only be converted to butene in small yields even after
prolonged heating with triethyl phosphite at 200 ꢀC.9 It is
also worth noting that some time ago we showed that the
2-benzoyl-substituted system 1 [R¼Me, R0¼C(O)Ph] gave
the benzofuran 8 via the interaction of the carbene centre in
3 [R¼Me, R0¼C(O)Ph] with the carbonyl group,4 so that
even if an epoxide such as 10 is involved it could, in principle,
be produced by the interaction of the carbene centre in 3
(R¼Et, R0¼OAc) with the adjacent carbonyl group. A similar
2. Results and discussion
The reaction of the 2-benzoyloxy-substituted system 20a
with trimethyl phosphite proceeded to give the cyclic product,
dimethyl 2-phenylbenzofuran-3-ylphosphonate 25a, in good
yield in an analogous reaction to that observed for the corre-
sponding acetoxy-substituted system 9.
By using NMR spectroscopy to monitor the reaction of
2-benzoyloxybenzoylphosphonate 20a with trimethyl phos-
phite, we have been able to show that the initially formed
product is the dioxaphospholane 22a [dP ꢁ48 (d) and þ17
(d), JPP 33 Hz], which can be seen to result from attack by
the anionic centre in the intermediate 21a on the carbonyl
carbon in the ortho substituent (see Scheme 4).11,12
We have also established that the mode of decomposition of
this initial product depends on whether further trimethyl phos-
phite is present.

Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
2331
R
R
presence of a ketone carbonyl carbon [dC 194.6]. Interestingly,
oxidation of the benzofuran-3-ylphosphonate 25a with meta-
chloroperbenzoic acid gave this same carbonyl compound,
while reduction of this ketophosphonate oxidation product
with sodium borohydride gave 2-phenylbenzofuran 31.
O C
O
C
C
(MeO)3P
O
O
O
O
C
P(OMe)3
P(OMe)3
P(OMe)2
P(OMe)2
O
O
20a: R = Ph
20b: R = Me
21a,b
The solution to this problem was provided by a detailed
study of the reaction of the corresponding 2-acetoxybenzoyl-
phosphonate 20b with trimethyl phosphite. This system
proved to be a little more difficult to study than the corre-
sponding ‘benzoyloxy’ system since the intermediate dioxa-
phospholane 22b [dP ꢁ49.5 (d) and þ18.3 (d), JPP 32 Hz]
decomposed more quickly but our NMR studies clearly
showed that this system followed the same reaction pathway.
However, with the ‘acetoxy’ system the sodium borohydride
reduction of the ketophosphonate, from the decomposition of
the dioxaphospholane 22b in the absence of trimethyl phos-
phite, did not undergo elimination to give 2-methyl-benzofu-
ran but instead remained as a hydroxyphosphonate. This
hydroxyphosphonate was readily identified as the b-hydroxy-
phosphonate 32, which showed that its precursor was the b-
ketophosphonate 29b. The formation of the corresponding
b-ketophosphonate 29a in the phenyl-substituted system can
also account for the formation 2-phenylbenzofuran 31 on its
reduction with sodium borohydride (Scheme 5).13 This clearly
shows that the decomposition of the intermediates 28a and
28b in the absence of trimethyl phosphite proceeds with the
unexpected migration of the phosphonate groups from their
original positions on the carbon skeleton to an adjacent carbon
atom. We have therefore established that the decomposition of
the initially formed dioxaphospholane in these systems in the
absence of trimethyl phosphite proceeds as shown in Scheme 5
R
O
O
O
R
(MeO)3P
P(OMe)3
P(OMe)3
O
– (MeO)3PO
P(OMe)3
O
O
(MeO)2P
(MeO)2P
O
22a,b
23a,b
O
O
R
– (MeO)3PO
R
P(OMe)3
O
P(OMe)2
(MeO)2P
O
O
24a,b
25a,b
Scheme 4.
If additional phosphite is first removed from the reaction
mixture, either by evaporation in vacuo or by prior reaction
with sulfur, then thermal decomposition of 22a occurs over
several hours at room temperature with the loss of trimethyl
phosphate to give a compound of formula C16H15O5P
[MþHþ 319, dP 14.5] that is unreactive towards trimethyl
phosphite. In contrast, in the presence of trimethyl phosphite,
the dioxaphospholane 22a reacts more quickly to give two
molecules of trimethyl phosphate and the benzofuran-3-yl-
phosphonate 25a [dP 17.8] in an overall reaction analogous
to that observed by Chiusoli et al.6 for the related ‘acetoxy’
system 9.
R
O
O
R
– (MeO)3PO
O
R'
O
P(OMe)3
R
O
O
P(OMe)2
O
(MeO)2P
O
O
O
P(OMe)2
O
O
P(OMe)2
(MeO)2P
O
28a,b
22a: R = Ph
22b: R = Me
26a,b
27
R
O
P(OMe)2
O
To explain the more rapid decomposition of the dioxaphos-
pholane 22a in the presence of trimethyl phosphite we propose
that the phosphite attacks the dioxaphospholane 22a (as shown
in Scheme 4) leading to ring-opening and loss of trimethyl
phosphate. The subsequent loss of a second molecule of tri-
methyl phosphate from the intermediate 24a thus leads to
the formation of the benzofuran-3-ylphosphonate 25a without
passing through an epoxide of the type that was proposed by
Chiusoli et al.6 as a key intermediate on the reaction pathway
for the corresponding ‘acetoxy’ system.
O
29a,b
For 29b
For 29a
NaBH4
NaBH4
Ph
O Me
O
O
O
P(OMe)2
OH
P(OMe)2
O
H
H
30
32
– (MeO)2P(O)O
In contrast, the decomposition pathway for the dioxaphos-
pholane in the absence of trialkyl phosphite was initially much
less obvious due to difficulties identifying the final product. As
previously noted, this phosphonate product was resistant to
further reaction with trimethyl phosphite and was clearly not
the epoxide 26a since its 13C NMR spectrum showed the
O
Ph
H
31
Scheme 5.

2332
Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
O
N
O
N
and that this too does not involve the epoxide intermediate
proposed originally by Chiusoli et al.6
P(OMe)3
O
O
O
(MeO)3P
– MeCl
P(OMe)2
It is interesting to note that although considerable efforts
were made to prepare the epoxides 26a and 26b by the oxidation
of the analogous benzofuran-3-ylphosphonates 25a and 25b, us-
ing reagents such as dimethyldioxirane and meta-chloro-
perbenzoic acid, these were not successful. The latter reagent
with the benzofuran-3-ylphosphonate 25b did bring about
oxidation of the C2eC3 carbonecarbon double bond but
the product isolated was the b-ketophosphonate 29b. In this
context it is interesting to note that Adam et al.14 have
observed similar behaviour in some of the benzofurans they
have studied. Thus, for example, attempts to convert the
acetoxy-substituted system 33a and the silyloxy-substituted
system 33b into the corresponding epoxides led to the forma-
tion of the corresponding carbonyl systems 35a and 35b pos-
sibly via the initial formation of the epoxides 34a and 34b.
These rearrangements were rationalised as involving the migra-
tion of the R group to the epoxide oxygen, although such
a mechanism would not account for the formation of the b-ke-
tophosphonate 29b from the oxidation of the benzofuranyl-
phosphonate 25b. A more satisfactory mechanism might
therefore be that in Scheme 6, which involves the intermediates
36a and 36b that are analogous to the intermediates 28a and
28b used to explain the formation of the b-ketophosphonates
29a and 29b.
Ph
37
Ph
Cl
38
Scheme 7.
spacer between the carbonyl group in the substituent and the
phenyl ring of the dialkyl benzoylphosphonate could result
in the formation of a larger ring system via a non-carbenoid
pathway. However, this resulted in the formation of the ylidic
phosphonate 40 [dP 29.4 (d) and 50.5 (d), JPP 95 Hz] which
was isolated as its decomposition product, the bisphosphonate
6 [R¼Me, R0¼CH2OC(O)Ph], confirming that the initially
formed anionic intermediate 2 [R¼Me, R0¼CH2OC(O)Ph]
had undergone decomposition to the corresponding carbene
intermediate rather than directly undergoing reaction with
the carbonyl group. There were no signs of the formation of
a cyclisation product such as 41.
O
O
P(OMe)3
P(OMe)2
O
P(OMe)2
O
P(OMe)2
Ph
O
O
Ph
O
Ph
O
O
39
40
41
O
O
Me
R
Me
R
O
O
O
3. Conclusions
O
O
33a: R = CH3C(O)
33b: R = Bu Me2Si
34a,b
We have shown that the benzoylphosphonates 20a and 20b
react with trimethyl phosphite to give the benzofurans 25a and
25b by a reaction pathway that involves attack by the carba-
nionic centre in the initially formed anionic intermediates
21a and 21b on the adjacent carbonyl group rather than via
the corresponding carbene intermediates 3. This results in
the subsequent formation of the dioxaphospholanes 22a and
22b (Scheme 4), which then react further with trimethyl phos-
phite to give the observed products. However, if the dioxa-
phospholanes 22a and 22b are allowed to decompose in the
absence of trimethyl phosphite they undergo loss of trimethyl
phosphate and a subsequent rearrangement to give the b-keto-
phosphonates 29a and 29b, which are unreactive towards
trialkyl phosphites. The mechanism by which this rearrange-
ment occurs (Scheme 5) may also help explain the observed
rearrangements of some other related epoxides (Scheme 6).14
We also now know that this does not occur when a shorter
or longer spacer between the carbonyl group and the phenyl
ring of the benzoylphosphonate is used, as in the case of the
benzoyl-substituted system 1 [R¼Me, R0¼C(O)Ph]4 and the
benzoyloxymethyl-substituted system 39. In these circum-
stances the initially formed anionic intermediates undergoe
cleavage to give the corresponding carbene intermediates 3 be-
fore reacting further. In the case of the benzoyl-substituted
system 1 [R¼Me, R0¼C(O)Ph] the dominant pathway is an in-
tramolecular cyclisation of the carbene intermediate involving
t
O
O
Me
Me
O
R
O
O
R
O
36a,b
35a,b
Scheme 6.
We have also attempted to prepare the nitrogen-containing
aroylphosphonate 15a under mild conditions so that its subse-
quent reaction with trimethyl phosphite might be examined
under more controlled conditions. However, the reaction of
the N-methylated salt 37 with trimethyl phosphite at room
temperature resulted in attack at the iminium carbon to give
the monophosphonate 38 (Scheme 7) rather than attack at
the carbonyl group and ring-opening to give the benzoyl-
phosphonate 15a as proposed in Scheme 3.7 It would also ap-
pear that the conditions needed to bring about the conversion
of the benzoxazinones 12a and 12b to the indole systems 18a,
18b, 19a and 19b are rather critical since we have not yet been
able to successfully repeat these reactions under the conditions
reported, although work is continuing.
As noted earlier, we also studied the reaction of dimethyl
2-(benzoyloxymethyl)benzoylphosphonate 39 with trimethyl
phosphite to see whether the introduction of a slightly longer

Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
2333
the ortho substitutent to give the benzofuran 8. However, with
the 2-benzoyloxymethyl-substituted system 39 intermolecular
trapping of the carbene by the trimethyl phosphite present in
the reaction mixture occurs to give the corresponding ylidic
phosphonate 40.
We must therefore conclude that those reactions which
involve nucleophilic attack on an ortho substituent will be re-
stricted to those cases where the anionic centre in the initially
formed intermediate 2 can react quickly with the adjacent sub-
stituent. In other cases the anionic intermediates 2 will un-
dergo decomposition to give carbene intermediates 3 which
will react further by alternative pathways.
further purification. Found: C, 48.82; H, 4.93. C11H13O6P re-
quires C, 48.54; H, 4.81%; dH (270 MHz, CDCl3) 2.33 (3H,
s, CH3), 3.85 (6H, d, JPH 11, POCH3), 7.14 (1H, ddd, JHH
8
and 1, JPH 1.5, 3-H), 7.37 (1H, td, JHH 8 and 1, 5-H), 7.60
(1H, td, JHH 8 and 1.5, 4-H), 8.35 (1H, dd, JHH 8 and 1.5,
6-H); dC (67.9 MHz, CDCl3) 21.0 (CH3), 54.3 (ꢂ2) (d, JPC
7, POMe), 124.1 (d, JPC 3, C-3), 126.3 (C-5), 128.7 (d, JPC
65, C-1), 132.5 (C-6), 135.4 (C-4), 149.5 (d, JPC 6, C-2),
169.3 (MeC]O), 198.1 (d, JPC 181, PeC]O); dP
(109.3 MHz, CDCl3) 0.1; nmax (film)/cmꢁ1 3009, 2963,
2855, 1767, 1666, 1605, 1450, 1373, 1258, 1196, 1042, 910.
4.3. Dimethyl 2-benzoyloxybenzoylphosphonate 20a
4. Experimental
4.3.1. 2-Benzoyloxybenzoic acid
4.1. General details
To a cooled, stirred solution of 2-hydroxybenzoic acid
(10.0 g, 72 mmol) in a mixture of dry diethyl ether (50 mL)
and pyridine (15.0 g, 190 mmol) was added a solution of ben-
zoyl chloride (10.0 g, 71 mmol) in diethyl ether (50 mL) at
such a rate that the reaction temperature did not exceed 5 ꢀC.
The reaction mixture was then stirred at room temperature for
1 h and then poured onto water. The mixture was made acid to
litmus with hydrochloric acid (ca. 15 mL, 2 M) and the resulting
solution was then extracted with chloroform (3ꢂ25 mL). The
combined chloroform extracts were dried over magnesium sul-
fate and the solvent removed under reduced pressure to give
a colourless solid, which was recrystallised from hexane. 2-Ben-
zoyloxybenzoic acid (16.0 g, 93%) was obtained as colourless
needles, mp 131 ꢀC (lit.,15 132 ꢀC); dH (270 MHz, CDCl3)
7.23 (1H, dd, JHH 8 and 1, 3-H), 7.36 (1H, td, JHH 8 and 1,
5-H), 7.50 (2H, t, JHH 8, 30/50-H), 7.61 (2H, m, 40-H and 4-H),
8.06 (1H, dd, JHH 8 and 1, 6-H), 8.17 (2H, d, JHH 8, 20/60-H),
9.1 (1H, br s, OH); dC (CDCl3) 122.6 (C-1), 124.1 (C-3),
126.1 (C-5), 128.4 (C-30), 129.4 (C-10), 130.2 (C-20), 132.5
(C-6), 133.5 (C-40), 134.65 (C-4), 151.2 (C-2), 165.3 (C]O),
169.8 (C]O); nmax (KBr)/cmꢁ1 3500e2500 (br), 1740, 1685,
1684, 1650, 1609, 1489, 1452, 1420, 1312, 1263, 1204, 1180,
1088, 1078, 1065, 1022; m/z (EI) 242.0581 (Mþ, C14H10O4
requires 242.0579).
Melting points were obtained on a Buchi SMP-20 capillary
melting point apparatus and are uncorrected. NMR spectra
were recorded on JEOL EX-270, Bruker AMX400 and Bruker
¨
AV600 spectrometers. 31P NMR spectra are referenced to 85%
phosphoric acid, 1H NMR spectra to TMS and 13C NMR spec-
tra to CDCl3 at 77.23 ppm. J values are given in hertz, ‘J’ in-
dicates an apparent coupling in a second order spectrum. IR
spectra were taken on a Shimadzu FTIR-8300 instrument.
Low resolution mass spectra were recorded on a ES Bruker
Esquire 300 Plus Daltronics instrument with ES ionisation
whilst high resolution spectra were obtained from the mass
spectrometry facility at Kings College, London. TLC was
performed with aluminium backed silica gel 60 F254 plates
eluting with the solvent system used for the column chroma-
tography unless otherwise stated. The plates were visualised
under UV light or developed in an iodine tank. Column chro-
matography was carried out using silica gel with particle size
33e50 mm, purchased from BDH. All other materials were
purchased from SigmaeAldrich Ltd and used as received un-
less indicated otherwise.
4.2. Dimethyl 2-acetoxybenzoylphosphonate 20b
A solution of oxalyl chloride (2.54 g, 22 mmol) and 2-ace-
toxybenzoic acid (1 g, 5.5 mmol) in dichloromethane (10 mL)
was stirred at room temperature overnight. Dry toluene
(20 mL) was added to the reaction mixture and the excess
oxalyl chloride and other volatile components were then re-
moved under reduced pressure (75 ꢀC at 10 mmHg). Ensuring
the exclusion of moisture from the reaction flask by means of
a rubber septum, the residue was cooled in an ice-bath (5 ꢀC)
and trimethyl phosphite (0.62 g, 5.5 mmol) was added drop-
wise, using a syringe. The reaction mixture was then allowed
to warm to room temperature and stirred for 30 min. Volatile
components were removed under reduced pressure (30 ꢀC at
0.005 mmHg) to give dimethyl 2-acetoxybenzoylphosphonate
20b as a pale yellow oil in essentially quantitative yield. If
necessary, this product can be purified for analytical purposes
by vacuum distillation (147 ꢀC at 0.4 mmHg), but in most
cases, the material is sufficiently pure to be used without
4.3.2. Dimethyl 2-benzoyloxybenzoylphosphonate 20a
This material was prepared in essentially quantitative yield
from 2-benzoyloxybenzoic acid using the same procedure as
that used for the preparation of dimethyl 2-acetoxybenzoyl-
phosphonate 20b. The benzoylphosphonate 20a was isolated
as a yellow oil; dH (270 MHz, CDCl3) 3.80 (6H, d, JPH 11,
POMe), 7.25 (1H, d, JHH 8, 3-H), 7.40 (1H, td, JHH 8 and 1,
5-H), 7.47 (2H, tm, JHH 8, 30/50-H), 7.60 (1H, tm, JHH 8,
4-H), 7.64 (1H, tm, JHH 8, 40-H), 8.17 (2H, dm, JHH 8, 20/
60-H), 8.45 (1H, dd, JHH 8 and 1.5, 6-H); dC (67.9 MHz,
CDCl3) 54.4 (ꢂ2) (d, JPC 8, POMe), 124.3 (d, JPC 3, C-3),
126.4 (C-5), 128.7 (C-30/50), 128.9 (d, JPC 64, C-1), 129.3
(C-10), 130.3 (C-20/60), 132.7 (C-6), 133.8 (C-40), 135.4
(C-4), 149.6 (d, JPC 7, C-2), 165.1 (CO2), 197.8 (d, JPC 179,
PC]O); dP (CDCl3) 0.0; nmax (film)/cmꢁ1 2959, 1740,
1659, 1601, 1450, 1261, 1204, 1192, 1075, 1026, 944; m/z
(ESI) 357.0470 (MþNaþ, C16H15NaO6P requires 357.0499).

2334
Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
4.4. Dimethyl 2-methylbenzofuran-3-ylphosphonate 25b
Neither of these compounds was stable under the reaction
conditions and both decomposed over a period of time to
give trimethyl phosphate and the corresponding 2-substituted
dimethyl benzofuran-3-ylphosphonates 25a and 25b.
Trimethyl phosphite (1.24 g, 11 mmol) was allowed to re-
act with dimethyl 2-acetoxybenzoylphosphonate 20b (1.50 g,
5.5 mmol) with the exclusion of moisture. After a period
of 2 h, volatile compounds were removed under reduced pres-
sure (65 ꢀC at 0.01 mmHg) and the residue was purified by
chromatotron chromatography on silica using mixtures of
ethyl acetate and petroleum ether (bp 40e60 ꢀC) as the
eluent. Dimethyl 2-methylbenzofuran-3-ylphosphonate 25b
(1.1 g, 85%) was obtained as a colourless oil; dH (270 MHz,
CDCl3) 2.74 (3H, d, JPH 2, CH3), 3.78 (6H, d, JPH 11.5,
POCH3), 7.23e7.33 (2H, m, 5-H and 7-H), 7.46 (1H, dt, J
8 and 2, 6-H), 7.67 (1H, m, 4-H); dC (67.9 MHz, CDCl3)
14.2 (Me), 52.7 (ꢂ2) (d, JPC 5, P(OMe)2), 101.6 (d, JPC
216, C-3), 111.1 (C-7), 121.0 (C-4), 123.9 (C-5), 124.8
(C-6), 128.0 (d, JPC 11, C-3a), 154.3 (d, JPC 15, C-7a),
165.4 (d, JPC 29, C-2); dP (109.3 MHz, CDCl3) 18.0; nmax
(film)/cmꢁ1 2950, 2850, 1600, 1576, 1475, 1455, 1320,
1281, 1249, 1176, 1026; m/z (EI) 240.0551 (Mþ, C11H13O4P
requires 240.0551).
4.6.1. Dimethyl 2,2,2-trimethoxy-3a-phenyl-2l5-[1,3,2]-
dioxaphos-pholo[4,5-b][1]benzofuran-8b(3aH)-
ylphosphonate 22a
dC (100.6 MHz, CDCl3) 52.4 (d, JPC 6, POCH3), 53.1 (d, JPC
6, POCH3), 54.7 (ꢂ3) (d, JPC 11, POCH3), 83.9 (d, JPC 192,
2
2
C-8b), 109.4 (dd, JPCþ JPC 16,16 C-3a), 109.4 (C-5), 121.1
(C-7), 126.7 (ꢂ2) (C-20/60), 126.8 (C-6), 127.5 (ꢂ2) (C-30/
50), 128.7 (d, JPC 3, C-8a), 129.7 (C-40), 131.5 (C-8), 136.7
(d, JPC 9, C-10), 158.7 (d, JPC 10, C-4a); dP (162 MHz,
CDCl3) ꢁ48.2 [d, JPP 33, O2P(OMe)3] and 17.1 [d, JPP 33,
P(O)(OMe)2].
4.6.2. Dimethyl 2,2,2-trimethoxy-3a-methyl-2l5-[1,3,2]-
dioxaphos-pholo[4,5-b][1]benzofuran-8b-(3aH)-
ylphosphonate 22b
dC (100.6 MHz, CDCl3) 22.0 (d, JPC 9, CH3), 53.3 (d, JPC 7,
POCH3), 54.1 (d, JPC 7, POCH3), 55.1 (ꢂ3) (d, JPC 10,
POCH3), 82.0 (d, JPC 189, C-8a), 109.2 (dd, JPC 11 and 3,
C-3a), 110.1 (C-5), 121.0 (C-7), 126.9 (C-6), 128.9 (d, JPC
4, C-8a), 131.7 (C-8), 158.2 (d, JPC 10, C-4a); dP (162 MHz,
CDCl3) ꢁ49.3 [d, JPP 30, O2P(OMe)3] and 18.1 [d, JPP 30,
P(O)(OMe)2].
4.5. Dimethyl 2-phenyl-1-benzofuran-3-ylphosphonate 25a
This material was prepared and purified using the procedure
previously described for the corresponding methyl-substituted
system 25b except that a 5 h reaction time was used in this
case. Dimethyl 2-phenyl-1-benzofuran-3-ylphosphonate 25a
(0.9 g, 75%) was obtained as a pale yellow oil; dH (270 MHz,
CDCl3) 3.70 (6H, d, JPH 11, P(OMe)2), 7.25e7.37 (2H, m,
5-H and 7-H), 7.42e7.47 (3H, m, 4-H and 30/50-H), 7.50
(1H, tm, JHH 7.5, 6-H), 7.94 (1H, dm, JHH 7, 4-H), 8.03 (1H,
dm, JHH 7, 20/60-H); dC (100.6 MHz, CDCl3) 52.5 (ꢂ2) (d,
JPC 6, P(OMe)2), 101.6 (d, JPC 213, C-3), 111.1 (C-7), 122.3
(C-4), 124.0 (C-5), 125.4 (C-6), 128.3 (ꢂ2) (C-20/60), 129.1
(ꢂ2) (C-30/50), 129.3 (C-10), 129.4 (d, JPC 12, C-3a), 130.3
(C-40), 154.1 (d, JPC 15, C-7a), 162.2 (d, JPC 26, C-2); dP
(109.3 MHz, CDCl3) 17.2; nmax (film)/cmꢁ1 2952, 2849,
1550, 1490, 1444, 1255, 1184, 1026; m/z (EI) 302.0708 (Mþ,
C16H15O4P requires 302.0708).
4.7. An investigation into the decomposition of the initially
formed tricyclic phosphorane 22a in the absence of trimethyl
phosphite: formation of dimethyl 3-oxo-2-phenyl-2,3-
dihydro-1-benzofuran-2-ylphosphonate 29a
A quantity of the tricyclic phosphorane intermediate 22a
was generated in toluene solution as described previously. Sul-
fur was then added to decompose any excess phosphite and the
subsequent decomposition of intermediate 22a was then mon-
itored by 31P NMR spectroscopy. This showed the formation
of dimethyl 3-oxo-2-phenyl-2,3-dihydro-1-benzofuran-2-yl-
phosphonate 29a, which was isolated as a colourless oil by
preparative reverse phase HPLC on a Dynamax C-18 column
using 80% aqueous methanol as the eluent; dH (600 MHz,
CDCl3) 3.71 (3H, d, JPH 10, POCH3), 3.73 (3H, d, JPH 10,
POCH3), 7.14 (1H, t, JHH 8, 40-H), 7.32 (1H, d, JHH 8, 4-H),
7.34 (1H, t, JHH 8, 5-H), 7.40 (2H, t, JHH 8, 30/50-H), 7.66
(1H, t, JHH 8, 6-H), 7.70 (1H, d, JHH 8, 7-H), 7.92 (2H, d,
JHH 8, 20/60-H); dC (150 MHz, CDCl3) 54.7 (d, JPC 6,
POCH3), 55.1 (d, JPC 6, POCH3), 89.2 (d, JPC 160, C-2),
113.6 (C-7), 120.4 (C-3a), 122.9 (C-5), 125.2 (C-4), 125.5
(ꢂ2) (d, C-20/60), 128.5 (ꢂ2) (d, C-30/50), 128.9 (d, JPC 3,
C-40), 131.4 (d, JPC 1.5, C-10), 138.2 (C-6), 171.3 (d, JPC
4.5, C-7a), 194.6 (C]O); dP (CDCl3) 14.5; nmax (film)/cmꢁ1
2958, 2854, 1718, 1625, 1608, 1475, 1464, 1448, 1325,
1297, 1264, 1240, 1182, 1147, 1030, 999, 943, 878, 839,
821, 748, 697, 668, 630; m/z (ESI) 341.0549 (MþNaþ,
C16H15NaO5P requires 341.0549).
4.6. NMR studies of the reaction of the 2-substituted dimethyl
benzoylphosphonates 20a and 20b with trimethyl phosphite in
the presence of excess trimethyl phosphite
The dimethyl benzoylphosphonates 20a and 20b (5.5 mmol)
were placed in a 50 mL round-bottomed Schlenk flask contain-
ing amagneticstirrer bar. The flask was evacuated and thenfilled
with dry nitrogen. Trimethyl phosphite (1.24 g, 11 mmol) was
then added slowly via a rubber septum while the contents of
the flask were stirred. When the addition was complete, a sample
of the reaction mixture was transferred to an NMR tube and the
progress of the reaction was monitored by NMR spectroscopy.
This showed the initial formation of the corresponding dioxa-
phospholanes 14a and 14b. At this point deuterochloroform
was added to the sample so that accurate NMR chemical shift
data could be obtained.

Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
2335
An alternative, equally successful, strategy for preventing
4.10. Reduction of 29a with sodium borohydride
the excess trimethyl phosphite from reacting with the tricyclic
phosphorane intermediate 22a involved removing the excess
trimethyl phosphite in vacuo as described for 22b.
A solution of dimethyl 3-oxo-2-phenyl-2,3-dihydro-1-ben-
zofuran-2-ylphosphonate 29a (0.1 g, 0.3 mmol) and sodium
borohydride (0.02 g, 0.6 mmol) in methanol (5 mL) was
stirred at room temperature overnight. Volatile components
were then removed under reduced pressure (60 ꢀC at
10 mmHg) and the organic residue was partitioned between
water (10 mL) and methylene chloride (20 mL). The methy-
lene chloride layer was separated and washed with water
(3ꢂ5 mL), dried (magnesium sulfate) and filtered. The solvent
was then removed under reduced pressure (40 ꢀC at 10 mmHg)
to give a colourless solid, subsequently identified as 2-phenyl-
benzofuran 31 (55 mg, 95%); dH (600 MHz, CDCl3) 7.03 (1H,
d, J 1, 3-H), 7.23 (1H, td, J 7.5 and 1, 5-H), 7.28 (1H, ddd, J 8,
7.5 and 1.5, 6-H), 7.35 (1H, tt, J 8 and 1, 40-H), 7.44 (2H, tm, J
8, 30/50-H), 7.52 (1H, dd, J 8 and 1, 7-H), 7.58 (1H, ddd, J 7.5,
1.5 and 1, 4-H), 7.87 (2H, dm, J 8, 20/60-H); dC (100.6 MHz,
CDCl3) 101.3 (C-3), 111.2 (C-7), 120.9 (C-4), 122.9 (C-5),
124.3 (C-6), 124.9 (ꢂ2) (C-20/60), 128.6 (C-40), 128.8 (ꢂ2)
(C-30/50), 129.2 (C-3a), 130.5 (C-10), 154.9 (C-7a), 155.9
(C-2) (lit.,17 101.3, 111.2, 120.9, 122.9, 124.2, 124.9, 128.5,
128.7, 129.2, 130.5, 154.9, 155.9); nmax (film)/cmꢁ1 2923,
2854, 1562, 1456, 1377, 1039, 1020; m/z (ESI) 195.0804
(MþHþ, C14H11O requires 195.0809).
4.8. Investigation of the decomposition of dimethyl (2,2,2-
trimethoxy-3a-methyl-2l5-[1,3,2]dioxaphos-pholo[4,5-b][1]-
benzofuran-8b(3aH)-yl)phosphonate 22b in the absence of
trimethyl phosphite: formation of dimethyl 2-methyl-3-oxo-
2,3-dihydro-1-benzofuran-2-ylphosphonate 29b
A quantity of the tricyclic phosphorane intermediate 22b
was generated in solution as previously described. Volatile
components were then removed from the reaction mixture at
room temperature in vacuo (0.005 mmHg) to ensure complete
removal of any unreacted trimethyl phosphite. The residue was
then taken up into deuterochloroform and the decomposition
of the tricyclic phosphorane 22b monitored by NMR. This
showed the formation of dimethyl 2-methyl-3-oxo-2,3-dihy-
dro-1-benzofuran-2-ylphosphonate 29b which was isolated in
a pure state as a pale yellow oil by preparative reverse phase
HPLC on a Dynamax C-18 column using 80% aqueous meth-
anol as the eluent; dH (270 MHz, CDCl3) 1.76 (3H, d, JPH 16,
CH3), 3.81 (3H, d, JPH 10, POCH3), 3.86 (3H, d, JPH 10,
POCH3), 7.15 (1H, tm, JHH 8, 5-H), 7.21 (1H, dm, JHH 8,
7-H), 7.67 (1H, t, JHH 8, 6-H), 7.71 (1H, d, JHH 8, 4-H); dC
(100.6 MHz, CDCl3) 18.7 (CH3), 54.3 (d, JPC 6, POCH3),
54.7 (d, JPC 6, POCH3), 87.4 (d, JPC 160, C-2), 113.7 (C-7),
120.3 (C-3a), 122.8 (C-5), 124.9 (C-4), 138.3 (C-6), 171.3
(d, JPC 5, C-7a), 197.8 (d, JPC 1, C]O); dP (162.0 MHz,
CDCl3) 16.8; nmax (film)/cmꢁ1 2958, 2854, 1717, 1612,
1470, 1462, 1300, 1261, 1030; m/z (ESI) 257.0573 (MþHþ,
C11H14O5P requires 257.0578).
4.11. Reduction of 29b with sodium borohydride
Dimethyl 2-methyl-3-oxo-2,3-dihydro-1-benzofuran-2-yl-
phosphonate 29b (0.1 g, 0.4 mmol) was reduced with sodium
borohydride using the procedure previously described for the
reduction of the analogous methyl system 29a. Dimethyl 3-hy-
droxy-2-methyl-2,3-dihydro-1-benzofuran-2-ylphosphonate
32 was isolated as a colourless oil in essentially quantitative
yield; dH (270 MHz, CDCl3) 1.60 (3H, d, JPH 15, CH3), 3.63
(1H, d, JHH 9.5, OH), 3.87 (3H, d, JPH 11, POCH3), 3.88
(3H, d, JPH 11, POCH3), 5.18 (1H, t, JPH 9.5, JHH 9.5, 3-H),
6.88 (1H, d, JHH 8, 7-H), 6.99 (1H, td, JHH 8 and 1, 5-H),
7.28 (1H, td, JHH 8 and 1, 6-H), 7.43 (1H, d, JHH 8, 4-
H); dC (100.6 MHz, CDCl3) 22.1 (d, JPC 2, CH3), 53.5 (d,
JPC 7, POCH3), 54.5 (d, JPC 7, POCH3), 80.7 (d, JPC 1,
C-3), 89.2 (d, JPC 170, PC-2), 111.2 (C-7), 122.0 (C-5),
126.3 (d, JPC 0.7, C-6), 127.3 (d, JPC 4, C-3a), 131.0 (C-4),
158.7 (d, JPC 8, C-7a); dP (109.3 MHz, CDCl3) 23.5; nmax
(film)/cmꢁ1 3330 (br), 2957, 2928, 2854, 1601, 1478, 1464,
1372, 1241, 1188, 1060, 1031; m/z (ESI) 281.0547 (MþNaþ,
C11H15NaO5P requires 281.0555).
An alternative, equally successful, strategy for preventing
the excess trimethyl phosphite from reacting with the
tricyclic phosphorane intermediate 22b involved adding ex-
cess sulfur to the solution, as described for 22a. This con-
verted the excess trimethyl phosphite to unreactive trimethyl
thiophosphate.
4.9. Oxidation of dimethyl 2-methylbenzofuran-3-
ylphosphonate 25b with m-CPBA
A solution of the phosphonate 25b (0.1 g, 0.4 mmol) and
meta-chloroperoxybenzoic acid (0.35 g, 2 mmol) in chloro-
form (10 mL) was heated at 35 ꢀC. After 24 h, NMR spectros-
copy showed that ca. 30% of the starting material had been
converted to dimethyl 2-methyl-3-oxo-2,3-dihydro-1-benzofu-
ran-2-ylphosphonate 29b. This component was isolated by
column chromatography on silica using mixtures of ethyl ac-
etate and hexane as the eluent and shown to have identical
spectroscopic properties to those of the sample of 29b
(R¼Me) prepared earlier from the decomposition of dimethyl
(2,2,2-trimethoxy-3a-methyl-2l5-[1,3,2]dioxaphos-pholo[4,5-
b][1]benzofuran-8b(3aH)-yl)phosphonate 22b in the absence
of trimethyl phosphite.
4.12. 2-(N-Benzoyl-N-methylamino)benzoic acid
2-Methylaminobenzoic acid (5 g, 33 mmol) was dissolved in
dry toluene (50 mL) containing triethylamine (4 g, 40 mmol)
under an atmosphere of dry nitrogen gas and the resulting so-
lution then cooled in an ice-bath (ꢁ5 ꢀC). This mixture was
then vigorously stirred under dry nitrogen and a solution of
benzoyl chloride (4.6 g, 33 mmol) in dry toluene (5 mL)
added dropwise over a period of 60 min. The temperature

2336
Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
of the reaction mixture was kept cool throughout the addi-
tion, but it was then allowed to warm to room temperature
and stirred for a further 3 h. The reaction mixture was then
filtered and the filtrate washed with hydrochloric acid
(4ꢂ15 mL, 2 M). The organic layer was then dried
(MgSO4), filtered and the volatile components removed un-
der reduced pressure (75 ꢀC at 10 mmHg). The residue was
purified by chromatography on silica using mixtures of chlo-
roform and methanol. The 2-(N-benzoyl-N-methylamino)ben-
zoic acid obtained in this way was recrystallised from
a mixture of methylene chloride and toluene to give the
product (2.36 g, 28%) as needle-like crystals, mp 166e
170 ꢀC (lit.,18 164e165.5 ꢀC); dH (400 MHz, CDCl3) 3.46
(1H, s, NCH3), 7.09 (2H, t, J 8, 30/50-H), 7.16 (1H, t, J 8,
40-H), 7.19 (1H, d, J 8, 3-H), 7.24 (1H, t, J 8, 5-H), 7.29
(2H, d, J 8, 20/60-H), 7.42 (1H, t, J 8, 4-H), 7.88 (1H, d, J
8, 6-H), 11.1 (1H, br s, CO2H); dC (100.6 MHz, CDCl3)
38.7 (NCH3), 127.7 (C-1), 127.8 (ꢂ2) (C-30/50), 127.9
(C-5), 128.5 (ꢂ2) (C-20/60), 129.8 (C-3), 130.2 (C-40),
132.4 (C-6), 133.7 (C-4), 135.7 (C-10), 145.0 (C-2), 168.9
(C]O), 171.5 (CO2H); nmax (KBr)/cmꢁ1 3500e2250 (br),
1925, 1717, 1589, 1566, 1497, 1435, 1389, 1254, 1188,
1142, 1076, 1030, 976, 930, 883, 795.
14.9; nmax (film)/cmꢁ1 3020, 2959, 2909, 2855, 2341, 2245,
1732, 1605, 1578, 1489, 1450, 1350, 1238, 1180, 1119, 1034,
918, 837; m/z (ESI) 348.1001 (MþHþ, C17H19NO5P requires
348.1001) and 370.0822 (MþNaþ, C17H18NO5PNa requires
370.0820).
4.14. Dimethyl 2-(benzoyloxymethyl)benzoylphosphonate 39
4.14.1. 2-(Benzoyloxymethyl)benzoic acid
This material was prepared using a modification of the
method of Cain.19
A mixture of phthalide (2.01 g, 15 mmol) and aqueous
NaOH (12 mL, 20%) was warmed at 35 ꢀC for ca. 30 min until
the phthalide had completely dissolved. The solution was then
cooled in an ice-bath (ꢁ5 ꢀC) and cold benzoyl chloride
(2.5 g, 18 mmol) added quickly with vigorous stirring. Sodium
2-(benzoyloxymethyl)benzoate precipitated from the aqueous
solution almost immediately. This sodium salt was filtered
off and washed with cold water, then ether and finally chloro-
form. Dilute hydrochloric acid (ca. 20 mL, 0.5 M) was then
added until the resulting solution was acidic (ca. pH 3). The
crude 2-(benzoyloxymethyl)benzoic acid was then filtered
off and recrystallised from a mixture of chloroform and hex-
ane to give the pure acid (1.2 g, 30%) as colourless crystals,
mp 132e136 ꢀC (lit.,19 128e129 ꢀC); dH (270 MHz, ace-
tone-d6) 5.80 (2H, s, CH2), 7.42e7.52 (3H, m, 30/50-H and
3-H), 7.60e7.69 (3H, m, 4-H, 40-H and 5-H), 8.07e8.10
(3H, m, 20/60-H and 6-H); dC (67.9 MHz, acetone-d6) 65.6
(CH2), 128.6 (C-5), 128.8 (C-4), 129.4 (ꢂ2) (C-30/50), 130.0
(C-10), 130.3 (ꢂ2) (C-20/60), 131.0 (C-1), 131.8 (C-3), 133.3
(C-40), 134.0 (C-6), 139.0 (C-2), 166.5 (C]O), 168.4
(CO2H); nmax (KBr, cmꢁ1) 3050e2525 (br), 1720, 1680,
1600, 1575, 1492, 1450, 1409, 1368, 1321, 1270, 1151, 1124,
1028, 998; m/z (ESI) 255 (MꢁHþ, C15H11O4ꢁ requires 255).
4.13. Dimethyl 1-methyl-4-oxo-2-phenyl-1,4-dihydro-2H-3,1-
benzoxazin-2-ylphosphonate 38
2-(N-Benzoyl-N-methylamino)benzoicacid(1 g, 3.91 mmol)
was dissolvedin boiling thionyl chloride (10 mL, 0.14 mol) and
the mixture stirred for 1 h at room temperature. NMR anal-
ysis of the reaction mixture indicated that cyclisation had oc-
curred to give 1-methyl-4-oxo-2-phenyl-4H-3,1-benzoxazin-
1-ium chloride 37 [dC (67.9 MHz, SOCl2) 42.6 (NCH3),
115.4 (C-2), 120.6 (C-8), 125.3 (C-10), 130.3 (ꢂ2) (C-20/
60), 131.1 (C-40), 132.0 (ꢂ2) (C-30/50), 132.7 (C-4), 136.8
(C-6), 139.2 (C-8a), 139.8 (C-5), 162.8 (C-4a), 170.1
(C]O)]. Dry toluene (10 mL) was added and then removed
under reduced pressure (75 ꢀC at 10 mmHg), to ensure the
complete removal of unreacted thionyl chloride, and a solu-
tion of trimethyl phosphite (2 mL, 17 mmol) in dry toluene
was then slowly added. The reaction mixture was then stirred
at room temperature overnight. Volatile components were re-
moved under reduced pressure (65e70 ꢀC at 0.005 mmHg)
and the product purified by chromatography on silica using
acetonitrile as the eluent. Dimethyl 1-methyl-4-oxo-2-phenyl-
1,4-dihydro-2H-3,1-benzoxazin-2-ylphosphonate 38 (0.98 g,
72%) was isolated as a pale yellow oil; dH (400 MHz,
CDCl3) 2.99 (3H, s, NeCH3), 3.40 (3H, d, J 10, POCH3),
3.45 (3H, d, J 10, POCH3), 6.67 (1H, t, J 8, 6-H), 6.73
(1H, d, J 8, 8-H), 7.14 (3H, m, 30/50-H and 40-H), 7.27
(1H, t, J 8, 7-H), 7.54 (2H, d, J 7, 20/60-H), 7.66 (1H, d, J
8, 5-H); dC (100 MHz, CDCl3) 52.6 (d, JPC 7, POCH3),
52.8 (d, JPC 7, POCH3), 93.7 (d, JPC 186, PC-2), 114.2
(C-4a), 114.8 (C-8), 119.7 (C-6), 127.6 (C-20), 127.7
(C-60), 127.9 (C-30 and C-50), 129.1 (C-40), 129.4
(C-5), 135.5 (C-7), 136.4 (d, JPC 7, C-10), 147.4 (d, JPC 6,
C-8a), 161.4 (d, JPC 6, C]O); dP (109.3 MHz, CDCl3)
4.14.2. Dimethyl2-(benzoyloxymethyl)benzoylphosphonate39
A mixture of 2-(benzoyloxymethyl)benzoic acid (1 g,
3.9 mmol) and oxalyl chloride (2.0 g, 15.6 mmol) in dichloro-
methane (10 mL) was stirred overnight under an atmosphere
of dry nitrogen. Dry toluene (15 mL) was added to the mixture
and then removed under reduced pressure (70 ꢀC at 10 mmHg)
to ensure removal of all the excess oxalyl chloride. While ex-
cluding moisture, the resulting 2-(benzoyloxymethyl)benzoyl
chloride was cooled in an ice-bath (ca. 5 ꢀC) and trimethyl
phosphite (0.5 g, 4 mmol) was then added dropwise, with stir-
ring. The reaction mixture was then allowed to warm to room
temperature and stirred for 30 min. Volatile components were
removed under reduced pressure (30 ꢀC at 0.005 mmHg) to
yield the benzoylphosphonate 39 in essentially quantitative
yield and in a good state of purity; dH (270 MHz, CDCl3)
3.75 (6H, d, JPH 11, POCH3), 5.52 (2H, s, CH2), 7.27 (2H,
t, JHH 7, 30/50-H), 7.37 (1H, t, JHH 7, 40-H), 8.39 (1H, d, JHH
8, 6-H), 7.49e7.53 (2H, m, 4-H and 5-H), 7.93 (2H, d, JHH
7, 20/60-H), 8.43 (1H, d, JHH 8, 3-H); dC (67.9 MHz, CDCl3)
54.0 (2C, d, JPC 7, POCH3), 64.2 (CH2), 127.7 (C-5), 128.0
(d, JPC 3, C-3), 128.2 (ꢂ2) (C-30/50), 129.4 (ꢂ2) (C-20/60),
129.6 (C-10), 132.8 (d, JPC 2, C-6), 132.9 (C-40), 133.3 (d,

Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
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J
PC 64, C-1), 133.9 (C-4), 137.8 (d, JPC 9, C-2), 165.6 (C]O),
10, a-CH), 7.38e7.46 (4H, m, 30/50-H, 4-H and 5-H), 7.54e
7.58 (2H, m, 5-H and 6-H), 7.79 (1H, td, JHH 2 and 8, 3-H),
8.12 (2H, dd, JHH 1 and 8, 20/60-H); dC (100.6 MHz, CDCl3)
54.1 (d, JPC 7, POCH3), 54.3 (d, JPC 7, POCH3), 54.5
(d, JPC 6, POCH3), 54.7 (d, JPC 6, POCH3), 64.4 (CH2),
70.8 (dd, JPC 6, 145 Hz, a-C), 128.5 (ꢂ2) (C-30/50), 129.07
(C-40), 129.1 (C-6), 129.6 (d, JPC 2, C-5), 130.04 (ꢂ2)
(C-20/60), 130.12 (C-10), 130.5 (d, JPC 2, C-3), 132.7 (C-1),
133.3 (C-40), 134.5 (d, JPC 7, C-2), 166.4 (C]O); dP
(109.3 MHz, CDCl3) 2.0 [d, JPP 35, OP(O)(OMe)2] and 19.7
[d, JPP 35, P(O)(OMe)2]; nmax (film)/cmꢁ1 2958, 2855, 1719,
1492, 1452, 1377, 1315, 1270, 1182, 1110, 1029, 950; m/z
(ESI) 481.0785 (MþNaþ, C19H24NaO9P2 requires 481.0793).
200.3 (d, JPC 174, C]O); dP (109.3 MHz, CDCl3) 0.8; nmax
(film)/cmꢁ1 2958, 2854, 1721, 1653, 1601, 1573, 1489,
1452, 1375, 1315, 1271, 1226, 1179, 1110, 1029, 945; m/z
(ESI) 371.0650 (MþNaþ, C17H17NaO6P requires 371.0660).
To minimise side reactions, the benzoylphosphonate 39 was
used immediately in its subsequent reaction with trimethyl
phosphite without further purification.
4.15. The reaction of dimethyl 2-(benzoyloxymethyl)-
benzoylphosphonate 39 with trimethyl phosphite
Taking steps to exclude moisture, trimethyl phosphite
(0.96 mL, 8 mmol) was added to the dimethyl 2-(benzoyloxy-
methyl)benzoylphosphonate 39, prepared as described above,
and the mixture heated at 100 ꢀC. After ca. 6 h NMR analysis
of the reaction mixture showed that the major product was the
ylidic phosphonate 40; dP (109.3 MHz, CDCl3) 29.4 [d, JPP 95,
P(O)(OMe)2] and 50.5 [d, JPP 95, P(OMe)3]; dC (100.6 MHz,
CDCl3) 25.2 (dd, JPC 226 and 214, P]CeP). Heating was
continued untilthereaction was complete(ca. 12 h). Atthispoint
NMRshowed that, in addition totrimethyl phosphate, three other
components were present in the molar ratio of ca. 2:3:1. These
were the phosphate-phosphonate 27 [R0¼CH2OC(O)Ph], the
ylidic phosphonate 40, its decomposition product the bisphosph-
onate 6 [R¼Me, R0¼CH2OC(O)Ph]. Volatile components were
then removed under reduced pressure (70 ꢀC at 0.005 mmHg)
and the components isolated by chromatography on silica using
ethyl acetate as the eluent.
4.15.3. Dimethyl 2-(benzoyloxymethyl)benzylphosphonate
When aqueous methanol (70%) was added to the reaction
mixture prior to the chromatographic separation a further com-
pound, dimethyl 2-(benzoyloxymethyl)benzylphosphonate,
was formed from the hydrolysis20 of the ylidic phosphonate
4 [R¼Me, R0¼CH2OC(O)Ph]. Dimethyl 2-(benzoyloxyme-
thyl)benzylphosphonate was purified by chromatography on
silica using a mixture of ethyl acetate and methanol (90:10)
as the eluent and isolated as pale yellow oil; dH (CDCl3,
400 MHz) 3.38 (2H, d, JPH 22, PCH2), 3.66 (6H, d, JPH 11,
POCH3), 5.49 (2H, s, CH2), 7.29e7.35 (2H, m, 4-H and
5-H), 7.37 (1H, dt, JHH 7 and 1, 6-H), 7.44 (2H, t, JHH 8, 30/
50-H), 7.49 (1H, d, JHH 7, 3-H), 7.56 (1H, tt, JHH 8 and 1,
40-H), 8.06 (2H, dd, JHH 8 and 1, 20/60-H); dC (CDCl3,
100.6 MHz) 30.0 (d, JPC 139, PCH2), 53.2 (ꢂ2) (d, JPC 6,
POCH3), 64.9 (CH2), 127.7 (d, JPC 4, C-4), 128.6 (ꢂ2)
(C-30/50), 128.9 (d, JPC 3, C-3), 129.9 (ꢂ2) (C-20/60), 130.2
(C-10), 130.5 (d, JPC 3, C-5), 130.6 (d, JPC 9, C-1), 131.4 (d,
JPC 5, C-6), 133.3 (C-40), 135.0 (d, JPC 7, C-2), 166.5
(C]O); dP (CDCl3, 109.3 MHz) 29.3; nmax (film)/cmꢁ1
2955, 1720, 1450, 1273, 1180, 1111, 1035, 1026; m/z (ESI)
357.0862 (MþNaþ, C17H19NaO5P requires 357.0862).
4.15.1. Tetramethyl [2-(benzoyloxymethyl)phenyl]methane-
1,1-bisphosphonate 6 [R¼Me, R0¼CH2OC(O)Ph]
The ylidic phosphonate 40 was isolated as its hydrolysis
product the bisphosphonate 6 [R¼Me, R0¼CH2OC(O)Ph] as
a colourless oil; dH (400 MHz, CDCl3) 3.57 (6H, d, JPH 11,
POCH3), 3.74 (6H, d, JPH 11, POCH3), 4.39 (1H, t, JPH 26,
1-H), 5.41 (2H, s, CH2), 7.34 (1H, t, JHH 8, 4-H), 7.40 (1H,
d, JHH 8, 5-H), 7.42 (2H, t, JHH 8, 30/50-H), 7.52 (1H, d, JHH
8, 3-H), 7.55 (1H, m, 40-H), 7.94 (1H, dd, JHH 8 and 1,
6-H), 8.08 (2H, dd, JHH 8 and 1, 20/60-H); dC (100.6 MHz,
CDCl3) 40.3 (t, JPC 133, a-C), 53.7 (m, POCH3), 54.3 (m,
POCH3), 65.3 (CH2), 128.3 (t, JPC 3, C-5), 128.5 (C-30/50),
129.2 (t, JPC 3, C-3), 129.4 (t, JPC 8, C-1), 123.0 (C-20/60),
130.05 (C-10), 131.1 (t, JPC 4.5, C-6), 131.5 (t, JPC 1.6,
C-4), 133.3 (C-40), 134.9 (t, JPC 8, C-2), 166.5 (C]O); dP
(109.3 MHz, CDCl3) 21.7; nmax (film)/cmꢁ1 2955, 1717,
1450, 1269, 1180, 1107, 1026, 860, 833; m/z (ESI) 465.0831
(MþNaþ, C19H24NaO8P2 requires 465.0844).
Acknowledgements
The authors would like to thank Mr. G.S. Coumbarides for
his help with the NMR studies and to acknowledge the use of
the EPSRC’s Chemical Database Service at Daresbury.
References and notes
1. Griffiths, D. V.; Griffiths, P. A.; Whitehead, B. J.; Tebby, J. C. J. Chem.
Soc., Perkin Trans. 1 1992, 479.
2. Griffiths, D. V.; Harris, J. E.; Karim, K.; Whitehead, B. J. Arkivoc 2000, 1,
304.
4.15.2. Dimethyl [1-(dimethoxyphosphoryloxy)-1-
[2-(benzoyloxymethyl)phenyl]methylphosphonate
3. Griffiths, D. V.; Griffiths, P. A.; Karim, K.; Whitehead, B. J. J. Chem. Soc.,
Perkin Trans. 1 1996, 555.
27 [R¼CH2OC(O)Ph]
4. Griffiths, D. V.; Karim, K.; Whitehead, B. J. Zh. Obshch. Khim. 1993, 63,
2245.
This component was isolated as a pale yellow viscous oil
using ethyl acetate as the eluent; dH (400 MHz, CDCl3) 3.5
(3H, d, JPH 11.3, POCH3), 3.59 (3H, d, JPH 10.6, POCH3),
3.68 (3H, d, JPH 11.3, POCH3), 3.76 (3H, d, JPH 10.6,
POCH3), 5.58 (2H, d, JPH 3, CH2), 6.05 (1H, dd, JPH 14 and
5. Griffiths, D. V.; Griffiths, P. A.; Karim, K.; Whitehead, B. J. J. Chem. Res.,
Synop. 1996, 176; J. Chem. Res., Miniprint 1996, 901.
6. Chiusoli, G. P.; Corrietti, G.; Bellotti, V. J. Chem. Soc., Chem. Commun.
1977, 216.

2338
Y.-K. Cheong et al. / Tetrahedron 64 (2008) 2329e2338
7. Abdou, W. M.; Kamel, A. A.; Khidre, M. D. Heteroat. Chem. 2004, 15, 77.
8. Scott, C. B. J. Org. Chem. 1957, 22, 1118.
12. Although the overall conversion of 20a into 21a can be represented by the
mechanistic arrows shown, these are ‘dashed’ to indicate that this is likely
to be an oversimplification of the process involved.
9. Neureiter, N. P.; Bordwell, F. G. J. Am. Chem. Soc. 1959, 81, 578.
10. Attempts to prepare the benzoylphosphonates 1 [R¼Me, R0¼CH2C(O)Ph]
were unsuccessful, efforts to prepare its precursor, 2-(2-oxo-2-phenyl-
ethyl)benzoyl choride, from the corresponding carboxylic acid led to
the formation of 3-phenyl-4a,8a-dihydroisochromen-1-one which is un-
reactive towards trimethyl phosphite.
13. The observed elimination of phosphonate from 30 is likely to be facili-
tated by the formation of a fully conjugated system.
14. Adam, W.; Kab, G.; Sauter, M. Chem. Ber. 1994, 127, 433.
¨
15. Einhorn, A.; Rothlauf, L.; Seuffert, R. Chem. Ber. 1911, 4, 3309.
16. Central portion of resonance partially obscured.
17. Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017.
18. Ninomiya, I.; Kiguchi, T.; Yamauchi, S.; Naito, T. J. Chem. Soc., Perkin
Trans. 1 1980, 197.
11. The anionic intermediate 21a can also become protonated if a proton do-
nor, e.g., moisture, is present, leading to the formation of the phosphate-
phosphonate 27 [R0¼OC(O)Ph]; dP (CDCl3) 1.9 [d, JPP 32, OP(O)(OMe)2]
and 19.1 [d, JPP 32, P(O)(OMe)2]. Small quantities of this type of compo-
nent are therefore invariably present following the reaction of the benzoyl-
phosphonates 1 with trimethyl phosphite.
19. Cain, B. F. J. Org. Chem. 1976, 41, 2029.
20. Griffiths, D. V.; Karim, K.; Harris, J. E. J. Chem. Soc., Perkin Trans. 1
1997, 2539.