Easy and stereoselective synthesis of cyclopropyl-substituted phosphonates via α-chlorophosphonates

Article abstract of DOI:10.1055/s-2007-966032

A facile stereoselective synthesis of cyclopropylphosphonates from the reaction of inexpensive α-chlorophosphonates with alkyl acrylates in the presence of sodium hydride is reported. Reaction with dimethyl maleate or fumarate also leads to cyclopropyl-su

Full text of DOI:10.1055/s-2007-966032

PAPER
1485
Easy and Stereoselective Synthesis of Cyclopropyl-Substituted Phosphonates
via a-Chlorophosphonates
Stereoselective
Sy
.
nthesis of Cy
C
clopropyl-Substi
.
tuted
P
hosph
K
onates via
a
-
Chlor
u
ophosphona
m
tes ara Swamy,* K. V. P. Pavan Kumar, R. Rama Suresh, N. Satish Kumar
School of Chemistry, University of Hyderabad, Hyderabad 500046, AP, India
Fax +91(40)23012460.; E-mail: kckssc@uohyd.ernet.in
Received 10 January 2007; revised 27 February 2007
useful phosphonates with, or without, a-substitution.2
Thus, while compounds 2 lead to the a-chloro- or a-bro-
mophosphonates 3 (X = Cl, Br) in high yields upon treat-
ment with thionyl chloride or bromide, the reaction of the
Abstract: A facile stereoselective synthesis of cyclopropylphos-
phonates from the reaction of inexpensive a-chlorophosphonates
with alkyl acrylates in the presence of sodium hydride is reported.
Reaction with dimethyl maleate or fumarate also leads to cyclopro-
pyl-substituted phosphonates. These reactions take place via phosphorus(III) precursor 1 with various acetals of alde-
Michael addition of acrylate, dimethyl maleate, or fumarate to the
phosphonate carbanion, followed by expulsion of the chloride ion.
hydes afforded the a-methoxyphosphonates 4 in excellent
yields. In a different approach, we have utilized the facile
Key words: phosphonates, Michael addition, acrylates, diastereo-
mers, cyclopropanes
Arbuzov rearrangement of 5, formed in situ using Baylis–
Hillman methodology, to lead to phosphonates of type 6.
In an analogous approach, the allenylphosphonates 7 are
also synthesized (Scheme 1). Considerable work has been
In view of the ease of synthesis, cost effectiveness, and performed in our laboratory using chloro-, methoxy-,
stability of the cyclic chlorophosphite 1,1 we have been in- allyl-, and allenyl-substituted phosphonates to synthesize
terested in utilizing this compound to obtain synthetically chlorostilbenes, dienes, unsymmetrically disubstituted
O
O
O
O
O
O
SOCl2 or SOBr2
a)
P
P
CHAr
OH
CHAr
X
(X = Cl or Br)
3
2
O
P
O
O
O
P
Cl
+ ArCH(OMe)2
b)
CHAr
OMe
O
1
4
OH
CN
O
O
.
.
ONC
P
O
O
O
O
O
P
Et3N
80 °C, 4 h
+
c)
P
Cl
Fe
toluene
0 °C
NC
Fe
Fe
H
1
5
6 [Ar = ferrocenyl]
O
P
O
O
O
O
base
H
P
Cl
+
d)
OH
1
7
Scheme 1
SYNTHESIS 2007, No. 10, pp 1485–1490
x
x.
x
x
.
2
0
0
7
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966032; Art ID: P00607SS
© Georg Thieme Verlag Stuttgart · New York

1486
K. C. Kumara Swamy et al.
nucleobase-substituted
PAPER
C(O)OR1
R2
H
acetylenes,
phosphonates,
O
O
R2
O
O
O
phosphono-benzofurans, phosphono-butadienes etc.3
Methods for the synthesis of functionalized cyclopro-
panes based on trans-N,N¢-dimethylcyclohexane-1,2-di-
amine derived phosphonamides4 and from the reaction of
bromomethylenebis(phosphonates) with electron-defi-
cient alkenes are known.5 If the latter reaction is conduct-
ed at low temperature, monophosphonates are the
products. Conformationally constrained rings like the cy-
clopropyl moiety, which is present in a number of natural
and unnatural compounds, have proven pharmacological
activity and biological properties.6 Since the a-chloro-
phosphonates 3 are more convenient (and inexpensive) to
prepare, we were interested in seeing whether they will
lead to cyclopropylphosphonates in the presence of an in-
expensive base like sodium hydride, which we have pre-
viously used effectively in Horner–Wadsworth–Emmons
reactions.3
C
C
O
NaH, THF
P
+
P
CH Ar
Cl
COOR1
reflux, 1 d
H
Ar
Cl
Ar = Ph (8)
= 4-MeC6H4 (9)
= 4-MeOC6H4 (10)
O
O
R2
P
O
COOR1
Ar
11–18
Scheme 2
Although a pure compound could not be isolated, the
peaks observed at d 1.68 and 2.24 in the H NMR spec-
1
trum are consistent with the presence of cyclopropyl
CHAHB along with CH(CN) protons in 19 rather than the
open-chain structure 20 (prior to HCl elimination; there
are examples of this type of compound in the literature7)
(Figure 1). We also tried to see if 2-[acetoxy(phenyl)-
methyl]-5,5-dimethyl-1,3,2-dioxaphosphinane 1-oxide
[prepared by treating 2 (Ar = Ph) with AcCl, Et3N,
DMAP] could lead to similar products. Although we did
not isolate pure products, the reaction mixture showed
two closely spaced peaks at d 21.2 and 22.1 (total intensi-
ty: ca 65%) in addition to starting material (d 11.4).
In this paper, we report a very convenient procedure for
the conjugate addition of anions derived from inexpensive
and readily-synthesized a-chlorophosphonates to a,b-un-
saturated esters (alkyl acrylates and dimethyl maleate)
which takes place via Michael addition followed by in-
tramolecular expulsion of chloride to give the cyclopropyl-
phosphonates (Scheme 2). Thus, treatment of a-
chlorophosphonates 8–10 with sodium hydride in tetra-
hydrofuran followed by addition of excess of alkyl acry-
late under refluxing conditions resulted in the formation
of a Michael addition product that underwent intramolec-
ular cyclization with elimination of a chloride ion to give
the cyclopropylphosphonates 11–18 stereoselectively in
good yields (Table 1). The CH2 protons from the cyclo-
O
O
O
O
P
H
CN
O
P
O
CN
Ph
Ph
Cl
20
19
Figure 1
propyl ring appear as a multiplet with coupling to phos-
1
phorus [3J(PH) = 4.8 Hz] in the H NMR spectrum. The Since the reactions of 8–10 with alkyl acrylates took ~24
13C NMR spectra of these compounds show a characteris- hours to go to completion, we wanted to see if the analo-
tic peak at d 29.0 [2J(PC) ~190.0 Hz] for the a-carbon at- gous a-bromophosphonate 21 could reduce the reaction
tached to the phosphorus.
time; indeed the reaction was complete within 5–6 hours
and we obtained the cyclopropylphosphonate 17 in 60%
yield (Scheme 3). The stereochemistry of 17 was con-
firmed by X-ray crystallography (Figure 2). This result
When compound 8 was treated with acrylonitrile, the re-
action mixture showed a major peak at d 15.6 (95%) along
with a minor one at d 17.3 (5%) in the 31P NMR spectrum.
Table 1 Yield and 31P NMR Data for 11–18a,b
Compd
11
Ar
R1
R2
H
Yield (%)
31P NMR d
20.3
Ph
Me
Et
63
63
61
66
61
60
68
61
12
Ph
H
20.4, 25.0 (9:1)
20.6, 25.9 (9:1)
20.5
13
Ph
Me
Me
Et
Me
H
14
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
15
H
19.1
16
Me
Me
Me
Me
H
20.9, 26.3 (8:1)
19.1, 20.9 (20:1)
20.7
17
18
Me
a Obtained from a-chlorophosphonates 8–10.
b The predominant isomer in each case is assigned stereochemistry analogous to 17 based on the X-ray crystal structure of the latter.
Synthesis 2007, No. 10, 1485–1490 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Cyclopropyl-Substituted Phosphonates via a-Chlorophosphonates
1487
MeO
O
O
O
CO2Me
H
H
H
P
NaH, THF
Br
CH
C
C
CO2Me
H
+
O
O
reflux, 5–6 h
P
O
OMe
21
17
Scheme 3
may be used to assign the stereochemistry of the predom- An interesting observation that we have made as regards
inant isomer of 11–16 and 18 as analogous to 17. The a- 25 is that it exhibits polymorphism. From chloroform–
bromophosphonate precursor 21 can be conveniently syn- hexane solvent system, we obtained the polymorph that
thesized by reacting 2 (Ar = 4-MeOC6H4) with thionyl crystallized in the monoclinic space group P21/c while
bromide2a or inexpensive phosphorus tribromide.8,9
ethyl acetate–hexane afforded the polymorph that crystal-
lized in the orthorhombic space group P212121.10
O
O
O
MeO2C
MeO2C
O
O
O
NaH, THF
reflux, 1 d
P
Ar
P
Ar
+
Cl
MeO2C
CO2Me
Ar = Ph
[23; δ(P): 15.4]
[24; δ(P): 15.4]
[25; δ(P): 15.8]
[26; δ(P): 15.0]
Ar = Ph
(8)
4-MeC6H4
4-MeOC6H4
4-ClC6H4
= 4-MeC6H4 (9)
= 4-MeOC6H4 (10)
= 4-ClC6H4 (22)
Yield: 60–65%
CO2Me
NaH, THF
reflux, 1 d
25
10
+
MeO2C
Scheme 4
Figure 2 Molecular structure of 17 [P–C6 1.793(2), C6–C7
1.514(4), C6–C8 1.535(4), C7–C8 1.482(4) Å].
When dimethyl maleate was used as the Michael acceptor
in the reaction with a-chlorophosphonates 8–10 and 22, it
led to cyclopropyl-substituted phosphonates 23–26 as
shown in Scheme 4. These compounds are more conve-
nient to isolate than 11–18. The 31P NMR spectra of com-
pounds 23–26 showed a single peak at d ~15.0 while the
1H NMR spectra showed two characteristic multiplets
around d 3.00 and 3.30 corresponding to CHCO2Me pro-
tons of the cyclopropyl moiety. The 13C NMR spectra
1
showed a characteristic doublet at d 35.0 [d, J(PC)
~186.0 Hz] for the a-carbon attached to the phosphorus.
The structure of compound 25 was proven by X-ray crys-
tallography (Figure 3); trans stereochemistry is found for
the CO2Me groups. This stereochemistry is consistent
with previous reports.4 The other isomer, wherein the two
CO2Me groups are cis oriented, is not observed, probably
because of unfavorable steric interactions in the interme-
diate (cf. Scheme 4). We also reacted 10 with dimethyl fu-
marate, but observed the same cyclopropylphosphonate
25. This is also consistent with the assumption that steric
factors in the intermediate control the formation of the fi-
nal product.
Figure 3 Molecular structure of 25 (monoclinic form). Only selec-
ted atoms are shown [P–C6 1.795(2), C6–C7 1.517(2), C6–C8
1.551(2), C7–C8 1.489(3) Å].
In summary, we have presented here a very convenient
and inexpensive route to cyclopropyl-substituted phos-
phonates, with the stereochemistry of two of the deriva-
tives established. The a-chlorophosphonates reported
Synthesis 2007, No. 10, 1485–1490 © Thieme Stuttgart · New York

1488
K. C. Kumara Swamy et al.
PAPER
Anal. Calcd for C17H23O5P: C, 60.35; H, 6.85. Found: C, 60.36; H,
6.87.
here are solids and readily purified; the simple base sodi-
um hydride works well for the reaction. Although the re-
actions in principle can give rise to several isomeric
products, only one isomer is formed stereoselectively.
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-1-methyl-2-phenylcyclopropanecarboxylate (13)
Yield: 0.21 g (61%); mp 99–101 °C.
IR (KBr): 1734, 1462, 1354, 1262 cm–1.
Chemicals were procured from Aldrich/Fluka or from local manu-
facturers; they were purified when required. Solvents were purified
according to standard procedures.11 All reactions, unless stated oth-
1H NMR: d = 0.41, 0.77 [2 s, 6 H, C(CH3)2], 1.06 [s, 3 H,
C(CH3)CO2Me], 1.24, 2.23 (2 dd, 2J(HH) ~8.5 Hz, 3J(PH) ~5.0 Hz,
2 H, CPhCHAHB), 3.32–3.69 (m, 2 H, OCHAHB), 3.74 (s, 3 H,
CO2CH3), 3.91–4.12 (m, 2 H, OCHAHB), 7.28 (br s, 5 H, Ar-H).
1
erwise, were performed in a dry N2 atmosphere. H, 13C{1H} and
31P{H} NMR spectra were recorded on a Bruker 200 MHz or 400
MHz spectrometer in CDCl3 (unless stated otherwise), with shifts
referenced to TMS (d = 0) or 85% H3PO4 (d = 0). IR spectra were
recorded on a JASCO FT/IR-5300 spectrophotometer. Elemental
analyses were carried out on a Perkin-Elmer 240C or Thermo Finni-
gan EA1112 analyzer. X-ray data were collected on a Bruker AXS
SMART diffractometer at 296 K using Mo-Ka (l = 0.71073 Å) ra-
diation. The structures were solved by direct methods;12 all non-
hydrogen atoms were refined anisotropically.
13C NMR: d = 19.7 (s, CMeCH2-), 20.8, 21.3 [2 s, C(CH3)2], 21.9
(d, 2J(PC) = 18.5 Hz, CMeCO2Me), 22.3 [s, C(CH3)CO2Me], 31.3
(d, 1J(PC) = 189.0 Hz, PC), 32.2 (d, 3J(PC) ~7.0 Hz, CMe2), 52.5 (s,
3
CO2CH3), 75.2, 75.9 (2 d, J(PC) = 6.3 Hz each, OCH2), 127.7,
128.3, 131.2, 132.1, 134.1, 172.5 (d, 3J(PC) ~5.0 Hz, CO2Me).
31P NMR: d = 20.6, 25.9 (9:1).
A pure product free of the component with d(P) 25.9 could not be
obtained.
Cyclopropyl-Substituted Phosphonates 11–18; General Proce-
dure
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-2-(p-tolyl)cyclopropanecarboxylate (14)
Yield: 0.22 g (66%); mp 134–135 °C.
To a stirred suspension of NaH (0.03 g, 1.2 mmol) in anhyd THF
(20 mL) at 0 °C was added the a-chlorophosphonate 8–10 (1.0
mmol) in anhyd THF (10 mL) over a period of 5 min. After 0.5 h,
the methyl acrylate, ethyl acrylate, or methyl methacrylate (1.5
mmol) was added dropwise via syringe. The mixture was allowed
to come up to r.t. and was heated under reflux for 1 d. After cooling
and quenching with cold H2O (20 mL), the mixture was extracted
with CH2Cl2 (3 × 15 mL). The CH2Cl2 layer was dried (Na2SO4),
the solvent removed and the crude product obtained was purified by
column chromatography (silica gel, hexane–EtOAc).
IR (KBr): 1732, 1518, 1441, 1381, 1258, 1053, 1003 cm–1.
1H NMR: d = 0.54, 0.88 [2 s, 6 H, C(CH3)2], 1.88, 2.75 (2 m, 3 H,
CHAHB CHCO2Me), 2.30, 2.31 (2 s, 3 H, ArCH3), 3.50 (m, 2 H,
OCHAHB), 3.52 (s, 3 H, CO2CH3), 4.07 (m, 2 H, OCHAHB), 7.28 (m,
4 H, Ar-H).
13C NMR: d = 16.4 (s, CH2CHCO2Me), 21.0, 21.4 [2 s, C(CH3)2],
1
21.2 (s, ArCH3), 24.7 (s, CH2CHCO2Me), 29.3 (d, J(PC) ~189.0
Hz, PC), 32.2 (d, 3J(PC) = 7.3 Hz, CMe2), 52.0 (s, CO2CH3), 75.8,
76.0 (2 d, 3J(PC) = 7.3 Hz each, OCH2), 129.0, 130.3, 131.1, 137.6,
169.5 (d, 3J(PC) ~5.0 Hz, CO2Me).
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-2-phenylcyclopropanecarboxylate (11)
Yield: 0.20 g (63%); mp 147–149 °C.
31P NMR: d = 20.5.
IR (KBr): 1732, 1447, 1381, 1258, 1053, 1005 cm–1.
1H NMR: d = 0.48, 0.85 [2 s, 6 H, C(CH3)2], 1.88 (m, 2 H,
Ethyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-yl)-
2-(p-tolyl)cyclopropanecarboxylate (15)
Yield: 0.21 g (61%); mp 128–129 °C.
CHAHBCHCO2Me,
CH2CHCO2Me),
2.72
(m,
1
H,
CHAHBCHCO2Me), 3.48 (s, 3 H, CO2CH3), 3.49 (m, 2 H,
OCHAHB), 4.07 (m, 2 H, OCHAHB), 7.28 (br s, 5 H, Ar-H).
IR (KBr): 1738, 1512, 1483, 1381, 1265, 1182, 1057, 1007 cm–1.
13C NMR: d = 16.3 (s, CH2CHCO2Me), 20.8, 21.3 [2 s, C(CH3)2],
24.7 (s, CH2CHCO2Me), 29.3 (d, 1J(PC) = 189.2 Hz, PC), 32.2 (d,
3J(PC) = 7.3 Hz, CMe2), 51.9 (s, CO2CH3), 75.7, 76.0 (2 d,
3J(PC) = 7.3 Hz each, OCH2), 127.9, 128.2, 131.2, 133.6, 169.5 (d,
3J(PC) = 4.9 Hz, CO2Me).
1H NMR: d = 0.55, 0.85 [2 s, 6 H, C(CH3)2], 1.28 (t, 3J(HH) = 7.1
Hz, 3 H, CO2CH2CH3), 1.78, 2.18 (2 m, 3 H, CHAHBCHCO2Et),
2.30 (s, 3 H, ArCH3), 3.49 (q→m, 2 H, OCHAHB), 4.07 (q,
3J(HH) = 6.9 Hz, 2 H, CO2CH2CH3), 4.17 (m, 2 H, OCHAHB), 7.09
(d, 3J(HH) = 7.8 Hz, 2 H, o-Ar-H), 7.32 (d, 3J(HH) = 7.8 Hz, 2 H,
m-Ar-H).
31P NMR: d = 20.3.
13C NMR: d = 14.1 (s, CO2CH2CH3), 16.7 (s, CH2CHCO2Et), 21.0,
Ethyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-yl)-
2-phenylcyclopropanecarboxylate (12)
Yield: 0.21 g (63%); mp 147–149 °C.
1
21.4 [2 s, C(CH3)2], 21.1 (s, ArCH3), 28.4 (d, J(PC) = 188.7 Hz,
PC), 29.1 (s, CH2CHCO2Et), 32.2 (d, 3J(PC) = 6.5 Hz, CMe2), 61.3
(s, CO2CH2CH3), 75.5, 75.6 (2 s, 2 OCH2), 129.0, 130.8, 130.9,
135.2, 137.6, 168.8 (d, 3J(PC) = 4.9 Hz, CO2Et).
31P NMR: d = 19.1.
IR (KBr): 1734, 1470, 1381, 1240, 1202, 1020 cm–1.
1H NMR: d = 0.43, 0.79 [2 s, 6 H, C(CH3)2], 0.95 (t, 3J(HH) = 6.9 Hz,
3 H, CO2CH2CH3), 1.78 (m, 2 H, CHAHBCHCO2Et, CH2CHCO2
Et), 2.65 (m, 1 H, CHAHBCHCO2Et), 3.46 (m, 2 H, OCHAHB), 3.85
(q, 3J(HH) = 6.9 Hz, 2 H, CO2CH2CH3), 4.04 (m, 2 H, OCHAHB),
7.23 (br, 5 H, Ar-H).
Anal. Calcd for C18H25O5P: C, 61.36; H, 7.15. Found: C, 61.30; H,
7.16.
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-1-methyl-2-(p-tolyl)cyclopropanecarboxylate (16)
Yield: 0.21 g (60%); mp 112–116 °C.
13C NMR: d = 13.8 (s, CO2CH2CH3), 16.0 (s, CH2CHCO2Et), 20.7,
21.2 [2 s, C(CH3)2], 24.8 (s, CH2CHCO2Et), 29.3 (d, 1J(PC) = 189.2
3
Hz, PC), 32.2 (d, J(PC) = 7.3 Hz, CMe2), 60.1 (s, CO2CH2CH3),
IR (KBr): 1736, 1514, 1460, 1352, 1265, 1155 cm–1.
75.7, 76.0 (2 d, 3J(PC) = 7.3 Hz each, OCH2), 127.8, 128.0, 131.2,
133.5, 168.7 (d, 3J(PC) = 4.9 Hz, CO2Me).
1H NMR: d = 0.44, 0.45, 0.80, 0.81 [s each, 6 H, C(CH3)2], 1.03,
1.04 [2 s, 3 H, C(CH3)CO2Me], 1.24, 2.21 [2 m, 2 H,
C(ArCH3)CHAHB], 2.30 (s, 3 H, ArCH3), 3.44 (m, 2 H, OCHAHB),
31P NMR: d = 20.4, 25.0 (20:1).
Synthesis 2007, No. 10, 1485–1490 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Cyclopropyl-Substituted Phosphonates via a-Chlorophosphonates
1489
3.72, 3.73 (2 s, 3 H, CO2CH3), 3.91–4.12 (m, 2 H, OCHAHB), 7.08,
7.11 (2 br, 4 H, Ar-H).
ringe. The mixture was allowed to come up to r.t. and was heated
under reflux for 1 d. After cooling and quenching with cold H2O (20
mL), the mixture was extracted with CH2Cl2 (3 × 15 mL). The
CH2Cl2 layer was dried (Na2SO4), the solvent removed, and the
crude product obtained was purified by column chromatography
(silica gel, hexane–EtOAc) to give compound 23. For compounds
24–26, 1.0 g of the phosphonate was used; all other amounts were
as given for the preparation of 23.
13C NMR: d = 19.6 (s, CMeCH2), 20.9, 21.1 [2 s, C(CH3)2], 21.9 [d,
3J(PC) = 18.5 Hz, C(CH3)CO2Me], 22.3 [s, C(CH3)CO2Me], 31.0
(d, 1J(PC) = 188.6 Hz, PC), 32.2 (d, 3J(PC) = 6.5 Hz, CMe2), 52.5
(s, CO2CH3), 75.3, 75.9 (2 d, 3J(PC) = 6.3 Hz each, OCH2), 128.9,
130.8, 131.2, 137.5, 172.5 (d, 3J(PC) = 7.6 Hz, CO2Me), 174.2.
31P NMR: d = 20.9, 26.3 (8:1).
Dimethyl 3-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-3-phenylcyclopropane-1,2-dicarboxylate (23)
Yield: 0.90 g (65%); mp 104–106 °C.
Anal. Calcd for C18H25O5P: C, 61.36; H, 7.15. Found: C, 61.37; H,
7.18.
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-2-(4-methoxyphenyl)cyclopropanecarboxylate (17)
Yield: 0.24 g (68%); mp 122–124 °C.
IR (KBr): 1732, 1607, 1437, 1341, 1271, 1219, 1169, 1057, 1005
cm–1.
1H NMR: d = 0.50 and 0.94 [2 s, 6 H, C(CH3)2], 3.03–3.09 and
3.27–3.28 (m each, 2 H, CHCO2Me), 3.46–3.57 (m, 2 H, OCHAHB),
3.59 and 3.82 (2 s, 6 H, CO2CH3), 4.00–4.08 (m, 2 H, OCHAHB),
7.28–7.38 (m, 5 H, Ar-H).
IR (KBr,): 1740, 1611, 1514, 1437, 1377, 1254, 1213 cm–1.
1H NMR: d = 0.56, 0.85 [2 s, 6 H, C(CH3)2], 1.46, 2.15 (2 m, 3 H,
CHAHBCHCO2Me), 3.52 (m, 2 H, OCHAHB), 3.75, 3.77 (2 s, 6 H,
CO2CH3, Ar-OCH3), 4.07 (dd, 2J(HH) = 11.0 Hz, 3J(PH) = 7.2 Hz,
2 H, OCHAHB), 6.81 (d, 3J(HH) = 8.6 Hz, 2 H, m-Ar-H), 7.36 (dd,
3J(HH) = 8.6 Hz, 4J(PH) = 3.8 Hz, 2 H, o-Ar-H).
13C NMR: d = 16.7 (s, CH2CHCO2Me), 20.9, 21.4 [2 s, C(CH3)2],
28.3 (d, 1J(PC) = 189.3 Hz, PC), 29.1 (s, CH2CHCO2Me), 32.2 (d,
3J(PC) = 7.3 Hz, CMe2), 52.3 (s, CO2CH3), 55.3 (s, ArOCH3), 75.6,
75.7 (2 s, OCH2), 113.7, 129.9, 132.0, 132.1, 158.2, 169.5 (d, 3J(PC)
~5.0 Hz, CO2Me).
13C NMR: d = 20.8 and 21.5 [2 s, C(CH3)2], 29.2 (s, CHCO2Me),
3
32.2 [d, J(PC) = 10 Hz, C(CH3)2], 33.0 (s, CHCO2Me), 35.8 (d,
1J(PC) = 184.4 Hz, PC), 52.3 and 52.7 (2 s, CO2CH3), 76.4 and 76.6
(2 s, OCH2), 128.4, 130.1, 133.6, 167.6, 168.0 (2 s, CO2Me).
31P NMR: d = 15.4.
Anal. Calcd for C18H23O7P: C, 56.54; H, 6.06. Found: C, 56.49; H,
6.06.
31P NMR: d = 19.1, 20.9 (20:1).
Dimethyl 3-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-3-(p-tolyl)cyclopropane-1,2-dicarboxylate (24)
Yield: 0.82 g (60%); mp 172–174 °C.
Anal. Calcd for C17H23O6P: C, 57.62; H, 6.54. Found: C, 57.57; H,
6.57.
IR (KBr): 1732, 1516, 1439, 1341, 1263, 1217, 1167, 1055, 1003
cm–1.
Methyl 2-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-2-(4-methoxyphenyl)-1-methylcyclopropanecarboxylate
(18)
Yield: 0.22 g (61%); mp 117–119 °C.
IR (KBr): 1736, 1613, 1514, 1458, 1244, 1161, 1003 cm–1.
1H NMR: d = 0.49, 0.82 [2 s, 6 H, C(CH3)2], 1.06 [s, 3 H,
C(CH3)CO2Me], 1.24, 2.23 (2 dd, 2J(HH) = 8.6 Hz each,
3J(PH) = 4.8 Hz each, 2 H, C(ArOCH3)CHAHB), 3.48 (m, 2 H,
OCHAHB), 3.74 (s, 3 H, CO2CH3), 3.77 (s, 3 H, ArOCH3), 4.05 (m,
2 H, OCHAHB), 6.89 (2 br s, 4 H, Ar-H).
1H NMR: d = 0.54 and 0.97 [2 s, 6 H, C(CH3)2], 2.34 (s, 3 H, Ar-
CH3), 3.00–3.06 and 3.25–3.29 (m each, 2 H, CHCO2Me), 3.44–
3.58 (m, 2 H, OCHAHB), 3.61, 3.82 (2 s, 6 H, CO2CH3), 3.99–4.05
(m, 2 H, OCHAHB), 7.14 and 7.27 (d each, 4 H, 3J (HH) = 8 Hz, Ar-
H).
13C NMR: d = 21.0 and 21.2 [2 s, C(CH3)2], 21.7 (s, Ar-CH3), 29.2
(s, CHCO2Me), 32.2 [d, 3J(PC) = 7.2 Hz, C(CH3)2], 33.0 (s,
1
CHCO2Me), 35.6 (d, J(PC) = 186.1 Hz, PC), 52.4 and 52.8 (2 s,
CO2CH3), 76.5 and 76.8 (2 s, OCH2), 129.2, 130.8, 138.1, 167.6,
168.1 (2 s, CO2Me).
31P NMR: d = 15.4.
13C NMR: d = 19.6 (s, CMeCH2), 21.0, 21.4 [2 s, C(CH3)2], 22.4 [s,
C(CH3)CO2Me, CH2CMeCO2Me], 30.8 (d, 1J(PC) = 189.6 Hz,
3
PC), 32.4 (d, J(PC) = 4.8 Hz, CMe2), 52.4 (s, CO2CH3), 55.3 (s,
Anal. Calcd for C19H25O7P: C, 57.66; H, 6.35. Found: C, 57.66; H,
6.34.
3
ArOCH3), 75.2, 75.9 (2 d, J(PC) = 6.3 Hz each, OCH2), 113.7,
126.1, 133.2 (br), 159.2, 172.4 (br, CO2Me).
31P NMR: d = 20.7.
Dimethyl 3-(5,5-Dimethyl-2-oxo-2l5-1,3,2-dioxaphosphinan-2-
yl)-3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate (25)
Yield: 0.89 g (66%); mp 118–120 °C.
Anal. Calcd for C18H25O6P: C, 58.69; H, 6.84. Found: C, 58.60; H,
6.81.
IR (KBr): 1734, 1615, 1514, 1437, 1339, 1262, 1215, 1163, 1057,
1003 cm–1.
2-[Bromo(4-methoxyphenyl)methyl]-5,5-dimethyl-1,3,2-dioxa-
phosphinane 2-Oxide (21)
1H NMR: d = 0.56 and 0.95 [2 s, 6 H, C(CH3)2], 3.00–3.04 and
3.23–3.29 (m each, 2 H, CHCO2Me), 3.47–3.57 (m, 2 H, OCHAHB),
3.60 (s, 3 H, CO2CH3), 3.81 (br s, 6 H, Ar-OCH3, CO2CH3), 4.00–
4.09 (m, 2 H, OCHAHB), 6.85 and 7.29 (d each, 3J (H–H) = 8 Hz, 4
H, Ar-H).
To a soln of a-hydroxyphosphonate (14.0 mmol) in CH2Cl2 (80 mL)
maintained at 0 °C was added PBr3 (35.1 mmol) dropwise under N2
atmosphere over a period of 30 min and the mixture was maintained
at 0 °C for another 0.5 h. After stirring at r.t. for 12 h, the mixture
was quenched with ice-cold H2O and the CH2Cl2 layer thoroughly
washed with H2O (3 × 20 mL), dried (anhyd Na2SO4), and the sol-
vent removed to give 21. The physical data are the same as those we
have previously reported.3a
13C NMR: d = 21.0 and 21.5 [2 s, C(CH3)2], 29.2 (s, CHCO2Me),
3
32.2 [d, J(PC) = 7.3 Hz, C(CH3)2], 33.1 (s, CHCO2Me), 35.1 (d,
1J(PC) = 187.1 Hz, PC), 52.4 and 52.7 (2 s, CO2CH3), 55.2 (s, Ar-
OCH3), 76.4 and 76.6 (2 s, OCH2), 114.0, 125.1, 132.0, 159.5,
167.6, 168.1 (2 s, CO2Me).
Reaction of 8–11 or 22 with Dimethyl Maleate; Typical
Procedure
To a stirred suspension of NaH (9.1 mmol) in anhyd THF (30 mL)
at 0 °C was added the a-chlorophosphonate 8 (1.0 g, 3.6 mmol). Af-
ter 0.5 h, dimethyl maleate (3.6 mmol) was added dropwise via sy-
31P NMR: d = 15.8.
Anal. Calcd for C19H25O8P: C, 55.34; H, 6.11. Found: C, 55.32; H,
6.10.
Synthesis 2007, No. 10, 1485–1490 © Thieme Stuttgart · New York

1490
K. C. Kumara Swamy et al.
PAPER
Dimethyl 3-(4-Chlorophenyl)-3-(5,5-dimethyl-2-oxo-2l5-1,3,2-
dioxaphosphinan-2-yl)cyclopropane-1,2-dicarboxylate (26)
Yield: 0.80 g (60%); mp 174–176 °C.
Srinivas, B.; Muthiah, C.; Kumara Swamy, K. C. Synthesis
2003, 2368. (f) Kumara Swamy, K. C.; Kumaraswamy, S.;
Senthil Kumar, K.; Muthiah, C. Tetrahedron Lett. 2005, 46,
3347.
IR (KBr): 1730, 1516, 1439, 1341, 1263, 1217, 1167, 1055, 1003
cm–1.
1H NMR: d = 0.57 and 0.92 [2 s, 6 H, C(CH3)2], 3.00–3.05 and
3.27–3.33 (m each, 2 H, CHCO2Me), 3.50–3.57 (m, 2 H, OCHAHB),
3.62 and 3.83 (2 s, 6 H, CO2CH3), 4.09–4.16 (m, 2 H, OCHAHB),
7.29–7.33 (m, 4 H, Ar-H).
(3) (a) Muthiah, C.; Praveen Kumar, K.; Kumaraswamy, S.;
Kumara Swamy, K. C. Tetrahedron 1998, 54, 14315.
(b) Muthiah, C.; Praveen Kumar, K.; Aruna Mani, C.;
Kumara Swamy, K. C. J. Org. Chem. 2000, 65, 3733.
(c) Senthil Kumar, K.; Kumara Swamy, K. C. J. Organomet.
Chem. 2001, 637-639, 616. (d) Chakravarty, M.; Kumara
Swamy, K. C. J. Org. Chem. 2006, 71, 9128. (e) Kumara
Swamy, K. C.; Balaraman, E.; Kumar, N. S. Tetrahedron
2006, 62, 10152.
13C NMR: d = 21.0 and 21.4 [2 s, C(CH3)2], 29.1 (s, CHCO2Me),
3
32.3 [d, J(PC) = 7.1 Hz, C(CH3)2], 33.0 (s, CHCO2Me), 34.8 (d,
1J(PC) = 186.7 Hz, PC), 52.5 and 52.8 (2 s, CO2CH3), 76.1 and 76.2
(2 s, OCH2), 128.6, 132.1, 134.4, 167.2, 167.9 (2 s, CO2Me).
(4) Hanessian, S.; Cantin, L.-D.; Roy, S.; Andreotti, D.;
Gomtsyan, A. Tetrahedron Lett. 1997, 38, 1103.
31P NMR: d = 15.0.
(5) Yuan, C.; Li, C.; Ding, Y. Synthesis 1991, 854.
(6) (a) Sitachitta, N.; Gerwick, W. H. J. Nat. Prod. 1998, 61,
681. (b) Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1,
1799. (c) Esposito, A.; Piras, P. P.; Ramazzotti, D.; Taddei,
M. Org. Lett. 2001, 3, 3273. (d) Ono, S.; Ogawa, K.;
Yamashita, K.; Yamamoto, T.; Kazuta, Y.; Matsuda, A.;
Shuto, S. Chem. Pharm. Bull. 2002, 50, 966. (e)Kazuta,Y.;
Matsuda, A.; Shuto, S. J. Org. Chem. 2002, 67, 1669.
(f) Frydman, B.; Blokhin, A. V.; Brummel, S.; Wilding, G.;
Maxuitenko, Y.; Sarkar, A.; Bhattacharya, S.; Church, D.;
Reddy, V. K.; Kink, J. A.; Marton, L. J.; Valasinas, A.; Basu,
H. S. J. Med. Chem. 2003, 46, 4586. (g) Janjic, J. M.; Mu,
Y.; Kendall, C.; Stephenson, C. R. J.; Balachandran, R.;
Raccor, B. S.; Lu, Y.; Zhu, G.; Xie, W.; Wipf, P.; Day, B. W.
Bioorg. Med. Chem. 2005, 13, 157. (h)Reichelt, A.;Martin,
S. F. Acc. Chem. Res. 2006, 39, 433.
Anal. Calcd for C18H22ClO7P: C, 51.86; H, 5.32. Found: C, 51.88;
H, 5.36.
X-ray Crystallography: The structures were solved by direct meth-
ods;12 all nonhydrogen atoms were refined anisotropically. Crystal-
lographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC 632867–
632869. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
Crystal data for 17: C17H23O6P, M = 354.32, monoclinic, space
group C2/c, a = 38.155(2), b = 5.8878(3), c = 17.5994(9),
b = 112.9260(10), V = 3641.3(3) Å3, Z = 8, m = 0.179 mm–1,
S = 1.091. Data/restraints/parameters: 3187/0/221. R indices [I >
2s(I)]: R1 = 0.0568, wR2 (all data) = 0.1378. max/min residual
electron density [eÅ–3]: 0.311/–0.420.
(7) (a) Yamaguchi, M.; Tsukamoto, Y.; Hayashi, A.; Minami, T.
Tetrahedron Lett. 1990, 31, 2423. (b) Haynes, R. K.;
Stokes, J. P.; Hambley, T. W. J. Chem. Soc., Chem.
Commun. 1991, 58. (c) Haynea, R. K.; Vonwiller, S. C.;
Hambley, T. W. J. Org. Chem. 1989, 54, 5162.
Crystal data for 25: C19H25O8P, M = 412.36. Form 1: monoclinic,
space group P21/c, a = 11.5535(7), b = 8.7141(6), c = 21.4828(14),
b = 92.3740(10), V = 2161.0(2) Å3, Z = 4, m = 0.167 mm–1,
S = 1.028. Data/restraints/parameters: 3807/0/258. R indices [I >
2s(I)]: R1 = 0.0437, wR2 (all data) = 0.1210. max/min residual
electron density [eÅ–3]: 0.224/ –0.294. Form 2: orthorhombic, space
group P212121, a = 9.6173(6), b = 12.2141(8), c = 17.4002(11),
V = 2043.9(2) Å3, Z = 4, m = 0.177 mm–1, S = 1.06. Data/restraints/
parameters: 4023/0/275. Flack parameter: 0.03 (11). R indices [I >
2s(I)]: R1 = 0.0453, wR2 (all data) = 0.1102. max/min residual
electron density [eÅ–3]: 0.184/–0.253. In Form 2, the nonhydrogen
atoms of OCH3 group occupy two equivalent positions each with
half occupancy.
(d) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.;
Beaudoin, S. J. Org. Chem. 1993, 58, 5032.
(8) We have utilized the reaction of inexpensive PBr3 with a-
hydroxyphosphonates also to prepare a series of 2-
[aryl(bromo)methyl]-5,5-dimethyl-1,3,2-dioxaphosphinane
1-oxides (aryl = phenyl, 4-methylphenyl, 4-chlorophenyl,
4-bromophenyl); some of these compound have been
previously reported.2a Note that 2-(1-hydroxy-3-phenyl-
prop-2-enyl)-5,5-dimethyl-1,3,2-dioxaphosphinane 1-oxide
affords two types of cinnamyl-substituted bromophos-
phonates 2-(1-bromo-3-phenylprop-2-enyl)-5,5-dimethyl-
1,3,2-dioxaphosphinane 1-oxide and 2-(3-bromo-3-phenyl-
prop-1-enyl)-5,5-dimethyl-1,3,2-dioxaphosphinane1-oxide,
while the using 2-[hydroxy(2-furyl)methyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane 1-oxide affords 2-(5-bromo-2-
furyl)-5,5-dimethyl-1,3,2-dioxaphosphinane 1-oxide. More
details are available from the authors or in ref. 9.
(9) Pavan Kumar, K. V. P. PhD Thesis; University of
Hyderabad: India, 2006.
(10) All data has been deposited at the Cambridge database. We
believe that such information will be useful, in case these
compounds are pharmacologically active.
(11) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification
of Laboratory Chemicals; Pergamon: Oxford, 1986.
(12) (a) Sheldrick G. M., SHELX-97, University of Göttingen,
Germany, 1997. (b) Sheldrick G. M., SADABS, Siemens
Area Detector Absorption Correction, University of
Göttingen, Germany, 1996. (c) Sheldrick G. M., SHELXTL
NT, version 5.10; Bruker AXS, Analytical X-ray System,
WI, 1999.
Acknowledgment
We thank the Council of Scientific and Industrial Research for fi-
nancial support and the Department of Science and Technology for
the setting up of the National Single Crystal Diffractometer Facility
at the University of Hyderabad. K.V.P.P.K. and R.S. thank CSIR
(New Delhi) for fellowships. We also thank UGC-UPE program for
equipment.
References
(1) Zwierzak, A. Can. J. Chem. 1967, 45, 2501.
(2) (a) Kumaraswamy, S.; Selvi, R. S.; Kumara Swamy, K. C.
Synthesis 1997, 207. (b) Kumaraswamy, S.; Kumara
Swamy, K. C. Tetrahedron Lett. 1997, 38, 2183.
(c) Praveen Kumar, K.; Muthiah, C.; Kumaraswamy, S.;
Kumara Swamy, K. C. Tetrahedron Lett. 2001, 42, 3219.
(d) Muthiah, C.; Senthil Kumar, K.; Vittal, J. J.; Kumara
Swamy, K. C. Synlett 2002, 1787. (e) Chakravarty, M.;
Synthesis 2007, No. 10, 1485–1490 © Thieme Stuttgart · New York