1,3-Dipolar cycloaddition of diazomethane to 1,1-difluoroallylphosphonates: Application to synthesis of cyclopropane derivatives having a diethoxyphosphoryldifluoromethylene unit

Article abstract of DOI:10.3987/COM-01-S(K)35

1,3-Dipolar cycloaddition of diazomethane to (1,1-difluoroallyl)phosphonates was examined to give pyrazolines functionalized by a diethoxyphosphoryldifluoromethylene unit. The pyrazolines were transformed to the cyclopropane derivatives possessing a dieth

Full text of DOI:10.3987/COM-01-S(K)35

HETEROCYCLES, Vol. 56, 2002, pp. 273-282, Received, 31st May, 2001
1,3-DIPOLAR CYCLOADDITION OF DIAZOMETHANE TO
,
1 1-DIFLUOROALLYLPHOSPHONATES:
APPLICATION
TO SYNTHESIS OF CYCLOPROPANE DERIVATIVES HAV-
ING A DIETHOXYPHOSPHORYLDIFLUOROMETHYLENE
UNIT¶
Tsutomu Yokomatsu,* Kenji Suemune, Tetsuo Murano, and Shiroshi
Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Abstract—1,3-Dipolar
cycloaddition
of
diazomethane
to
(1,1-
difluoroallyl)phosphonates was examined to give pyrazolines functionalized by
a diethoxyphosphoryldifluoromethylene unit. The pyrazolines were transformed
to the cyclopropane derivatives possessing
difluoromethylene functionality by photolysis.
a
diethoxyphosphoryl-
The ubiquitous presence of a phosphate group in a vast array of biologically active molecules has
stimulated intense research efforts in the search for structural analogues where different constitution and
chemical reactivity allow them to be used as either useful biochemical probes or potent inhibitors in
enzymatic reactions.1 Blackburn’s postulate2 that 1,1-difluoromethylenephosphonic acids (DFMPA) (2)
are a hydrolytically stable mimic of the corresponding phosphate esters (1) has gained wide experimental
support in recent years. As a result, many enzyme inhibitors with significant activity have been
identified.3 Despite the growing development of new and efficient methods for the synthesis of DFMPA-
functionalized molecules, few methods are available for stereoselective introduction of a DFMPA-
functionality to a secondary carbon within a cyclic array.4 We have been particularly interested in
introducing a DFMPA-functionality to cyclopropane rings; the resulting rigid molucules would be useful
as a probe for studying 3D-structural activity relationships of biologically active DFMPA-derivatives.3i
Recent reports from these laboratories described the sulfur-ylide-induced cyclopropanation of the
DFMPA-functionalized enoates.5 The reaction has been applied to stereoselective synthesis of novel
cyclopropane nucleotide analogue (3) with significant inhibitory activity aganist purine nucleoside
phosphorylase.3i,5b In this paper, we describe an alternative synthesis of DFMPA-functionalized
cyclopropane derivatives on the basis of photolysis of ∆1-pyrazoline derivatives readily available from
(1,1-difluoroallyl)phosphonates through 1,3-diploar cycloaddition with diazomethane.6
¶ This paper is dedicated to Professor James P. Kutney on the occasion of his 70th birthday.

O
N
N
N
NH
O
R O P OH
OH
O
R CF2 P OH
OH
CF2PO3H2
2 (DFMPA)
1
3
While 1,3-dipolar cycloaddition of electron-deficient olefins with diazomethane has been well
established,6 it was not clear how the DFMPA-ester functionality affects the 1,3-dipolar cycloaddition of
(1,1-difluoroallyl)phosphonates. We first examined 1,3-dipolar cycloaddition of diazomethane with (E)-
styryl-1,1-difluoromethylphosphonate ((E)-4a)7 and the analogous non-fluorinated phosphonate ((E)-5)8
to verify effects of the fluorine atom and phosphonate functionality on the reactivity of the 1,3-dipolar
cycloaddition (Eq. 1).
H
N
H
N
N
CH2N2 / ether
N
CX2PO3Et2
CF2PO3Et2
(Eq. 1)
CF2PO3Et2
Ph
H
Ph
H
(E)-4a X=F
X=H
6a
(E)-5
Figure 1. NOESY correlations of 6a
Treatment of (E)-4a with a large excess of an ethereal solution of diazomethane at room temperature for
15 h gave the corresponding ∆1-pyrazoline (6a) in 72% yield without detectable formation of the
regioisomer. The stereo- and regio-chemistry of 6a were confirmed on the basis of the diagnostic
NOESY-correlations (500 MHz, CDCl3) depicted in Figure 1. The non-fluorinated analogue ((E)-5) was
found to be inert to diazomethane under the same conditions, and
fr = 0.363
no adduct was obtained from the reaction. The results suggest the
HOMO
N
fluorine atoms of (E)-4a contribute toward lowering the LUMO-
energy to interact favorably with HOMO of diazomethane.6 The
direction of cycloaddition of diazomethane to (E)-4a is
consistent with the prediction from the calculated density of
LUMO and HOMO of (E)-4a and diazomethane, respectively
(Figure 2). The calculation (MOPAC 2000 / PM 3) reveals the
density of LUMO (fr) at the α- and β-carbon atoms of (E)-4a to
be 0.143 and 0.121; density of HOMO (fr) at the carbon and
nitrogen atoms of diazomethane to be 0.618 and 0.363,
respectively.
CH2
fr = 0.618
fr = 0.121
CF2PO3Et2
N
LUMO
fr = 0.143
Figure 2. Density HOMO and LUMO of
diazomethane and (E)-4a

To explore the scope and applicability of the reaction, we further examined 1,3-dipolar cycloaddition of
(1,1-difluoroallyl)phosphonates ((E)-4b-j) with varying electronic nature of the β-substituents. The
results of this exploratory study are summarized in Table 1. As expected, (1,1-difluoroallyl)phosphonates
((E)-4b) and ((E)-4c) having an electron-withdrawing substituent such as fluorine and carbomethoxy
functionality in the phenyl reacted with diazomethane to give ∆1-pyrazolines (6b) and (6c) in reasonable
yield, respectively (Entries 1 and 2). 3-Pyridinyl derivative ((E)-4d) was found to be a good substrate for
this reaction to give 6d in modest yield (Entry 3). However, 4-methoxyphenyl derivative ((E)-4e)7 and n-
butyl derivative ((E)-4f)7 were totally inert to diazomethane under the same conditions (Entries 4 and 5).
These results clearly demonstrated that the 1,3-dipolar cycloaddition was significantly affected by the
electronic nature of the substituents. The reaction of enoate ((E)-4g)5 and enones ((E)-4h)5 and ((E)-4i,j)
with diazomethane proceeded with concomitant tautomerization of the adducts to give ∆2-pyrazolines
(7g-j) in modest to good yield (Entries 6-9).
H
N
N
CH2N2 / ether
N
N
CF2PO3Et2
R
or
R
R
CF2PO3Et2
CF2PO3Et2
(E)-4b-j
7g-j
6b-d
Table 1. 1,3-dipolar cycloaddition of (E)-4b-j with diazomethanea
Yield (%)
Entry
Substrate R
6b-d
83
7g-i
—
—
—
—
—
79
59
80
81
1
2
3
4
5
6
7
8
9
(E)-4b
(E)-4c
(E)-4d
(E)-4e
(E)-4f
(E)-4g
(E)-4h
(E)-4i
(E)-4j
4-FC6H4
4-MeO2CC6H4
3-pyridinyl
4-MeOC6H4
n-Bu
64
60
n.r.b
n.r.b
—
EtO2C
MeCO
—
EtCO
—
i-PrCO
—
a All reactions were carried out at room temperature for 15 h. b Not reacted.
Photolysis of the ∆1-pyrazolidines (6a-c) was carried out by irradiation with a high-pressure mercury-
lamp (500 W) in acetone or chloroform to yield the corresponding cyclopropanes (8a-c) in nearly
quantitative yield9 (Eq. 2). The configuration of the stereogenic centers of the ∆1-pyrazolidines retains
through the photolysis; this was proved by NOE experiments (400 MHz, CDCl3) on the cyclopropane

derivative (8a) (Figure 3).
5.6%
H
H
CF2PO3Et2
hv / CHCl3 or acetone
H
6a-c
(Eq. 2)
R
CF2PO3Et2
8a-c
H
3.2%
a: R = C6H5; b: R = 4-FC6H4;
c: R = 4-MeO2CC6H4
Figure 3 Revalent % NOE values
for stereochemical assignment of 8a
Finally, the sequence was applied to stereoselective synthesis of novel spiro-cyclopropane derivative (8k)
(Eq. 3). (E)-2-Iodomethylenecyclohexanone (9)10 was transformed to the phosphonate (4k) in 63% yield
through cross-coupling reaction with BrZnCF2PO3Et2 in the presence of CuBr in DMF.7 Treatment of (E)-
4k with a large excess of diazomethane in ether gave the adduct (6k) in 65% yield. Photolysis of 6k in
acetone by irradiation with a high-pressure mercury-lamp (500 W) gave 8k in 91% yield. Transformation
of (E)-4k to 8k through cyclopropanation with dimethyloxosulfonium methylide in DMSO according to
the previous method5 results in very low yield (24%) due to unfavorable side reactions at the carbonyl.5a
Therefore, the present method complements our previous approach to DFMPA-functionalized
cyclopropanes based on sulfur-ylide-induced cyclopropanation of (1,1-difluoroallyl)phosphonates.5
O
O
O
H
N
N
X
hv
CF2PO3Et2 acetone
CF2PO3Et2
CH2N2 / ether
(Eq. 3)
9
X = I
6k
8k
(E)-4k X = CF2PO3Et2
EXPERIMENTAL
All reactions were carried out under nitrogen atmosphere. 1H NMR spectra were recorded at 400 MHz in
CDCl3 using TMS or residual CHCl3 (7.26 ppm) as internal references. 13C NMR(100 MHz) and 31P NMR
(162 MHz) were taken in CDCl3 using CDCl3 (77.0 ppm) as internal standard and 85% H3PO4 as an
1
external standard, respectively, with broad-band H decoupling. 19F NMR spectra (376 MHz) was
measured in CDCl3 using benzotrifluoride (BTF) as internal standard. The density of LUMO for (E)-4a
and density of HOMO for diazomethane were calculated by MOPAC 2000 (PM 3) implemented in
CAChe Worksystems (Fujitsu Corporation).
Preparation of (1,1-difluoroallyl)phosphonates ((E)-4a-k). All (1,1-difluoroallyl)phosphonates used in
this study were synthesized through cross-coupling reaction between the corresponding iodoalkenes and
BrZnCF2PO3Et2 according to the general procedure described previously.7 The required iodoalkenes were

prepared by the literature procedure.11 Yield and physical data of new (1,1-difluoroallyl)phosphonates
((E)-4b-d) and ((E)-4i-k) are as follows:
Diethyl (2E)-1,1-difluoro-3-(4-fluorophenyl)prop-2-enylphosphonate ((E)-4b). Yield: 45%; an oil; 1H
NMR δ 7.49-7.40 (2H, m), 7.11-6.98 (3H, m) 6.23 (1H, ddt, JHH=16.0 Hz, JHF = 12.8 Hz, JHP=2.9 Hz),
4.37-4.18 (4H, m), 1.38 (6H, t, J = 7.0 Hz); 13C NMR δ 163.4 (d, JCF = 250.0 Hz), 135.8 (dt, JCP = 6.1 Hz,
JCF = 10.7 Hz), 130.5, 128.2 (d, JHF = 8.4 Hz), 118.5 (dt, JCP = 13.3 Hz, JCF = 22.0 Hz), 117.3 (dt, JCP =
19
221.1 Hz, JCF = 259.5 Hz), 115.8 (d, JCF = 21.9 Hz), 64.7 (d, JCP = 6.7 Hz), 16.3 (d, JCP = 5.2 Hz); F
31
NMR δ –45.7 (2F, dd, JHF = 12.8 Hz, JPF = –48.4 (1F, m); P NMR δ 6.89 (t, JPF = 114.4 Hz); 171
(M+–P(O)(OEt)2); IR (neat) 2987, 1653, 1603, 1511, 1269, 1038 cm-1; MS (EI) m/z 308 (M+); Anal. Calcd
for C13H16O3F3P: C, 50.66; H, 5.23. Found: C, 50.49; H, 5.17.
Methyl 4-[(1E)-3-diethoxyphosphoryl]-3,3-difluoroprop-1-enyl]benzoate ((E)-4c). Yield: 42%; an oil;
1H NMR δ 8.04 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.3 Hz), 7.11 (1H, ddt, JHH = 16.2 Hz, JHP = 2.8 Hz,
JHF = 2.3 Hz), 6.40 (1H, ddt, JHH = 16.2 Hz, JHP = 2.7 Hz, JHF = 12.6 Hz), 4.40-4.21 (4H, m), 3.92 (3H, s),
13
1.38 (6H, t, J = 7.1 Hz); C NMR δ 166.3, 138.4, 135.8 (dt, JCP = 6.2 Hz, JCF = 10.5 Hz), 130.7, 129.9,
127.2, 121.2 (dt, JCP = 12.9 Hz, JCF = 21.3 Hz), 52.0, 16.3 (d, JCP = 5.2 Hz); 19F NMR δ –46.2 (2F, ddd, JHF
31
= 2.3, 12.6 Hz, JPF = 113.3 Hz); P NMR δ 6.56 (t, JPF = 113.3 Hz); IR (neat) 2986, 1723, 1282, 1181,
1110, 1037 cm-1; MS (EI) m/z 348 (M+), 211 (M+–P(O)(OEt)2); HREIMS calcd for C15H19O5F2P (M+):
348.0938. Found: 348.0944.
1
Diethyl (2E)-1,1-difluoro-3-(pyridin-2-yl)prop-2-enylphosphonate ((E)-4d). Yied: 35%; an oil; H
NMR δ 8.61 (1H, d, J = 4.7 Hz), 7.69 (1H, dt, J = 1.8, 7.8 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.24 (1H, dd, J =
4.7, 7.7 Hz), 7.13 (1H, ddt, JHH = 15.6 Hz, JHP = 2.8 Hz, JHF = 2.8 Hz), 6.87 (1H, ddt, JHH = 15.6 Hz, JHP =
2.7 Hz, JHF = 13.1 Hz), 4.41-4.20 (4H, m), 1.38 (6H, t, J = 7.1 Hz); 13C NMR δ 152.6, 149.8, 136.8, 136.2
(dt, JCP = 6.2 Hz, JCF = 10.2 Hz), 123.7, 123.4, 123.1 (dt, JCP = 13.0 Hz, JCF = 21.3 Hz), 117.4 (dt, JCP =
19
226.0 Hz, JCF = 259.4 Hz), 64.8 (d, JCP = 6.7 Hz), 16.3 (d, JCP = 5.3 Hz); F NMR δ –46.2 (1F, dd, JPF =
31
113.4 Hz, JHF = 13.1 Hz); P NMR δ 6.67 (t, JPF = 113.4 Hz); IR (neat) 2986, 1585, 1472, 1435, 1270,
1037 cm–1; MS (EI) m/z 292 (M++1), 154 (M+–P(O)(OEt)2); HREIMS calcd for C12H16NO3F2P (M+):
291.0836. Found: 291.0849.
1
Diethyl (2E)-1,1-difluoro-4-oxohex-2-enylphosphonate ((E)-4i). Yield: 42%; an oil; H NMR δ 6.78-
6.58 (2H, m), 4.36-4.19 (4H, m), 2.65 (2H, t, J = 7.2 Hz), 1.38 (6H, t, J = 7.1 Hz), 1.13 (3H, t, J = 7.2
13
Hz); C NMR δ 198.8, 133.6 (dt, JCP = 5.6 Hz, JCF = 8.3 Hz), 132.2 (dt, JCP = 13.1 Hz, JCF = 21.8 Hz),
19
116.4 (dt, JCP = 217.1 Hz, JCF = 259.8 Hz), 65.0 (d, JCP = 6.8 Hz), 34.7, 16.2 (d, JCP = 4.8 Hz), 7.4; F
NMR δ –48.6 (2F, dd, JHF = 10.9 Hz, JPF = 108.6 Hz); 31P NMR δ 5.54 (t, JPF = 108.6 Hz); IR (neat) 2985,
1710, 1269, 1171, 1038 cm-1; MS (EI) m/z 271 (M++1); HREIMS calcd for C10H17O4F2P (M+): 270.0833.
Found: 270.0856.
1
Diethyl (2E)-1,1-difluoro-5-methyl-4-oxohex-2-enylphosphonate ((E)-4j). Yield: 67%; an oil; H
NMR δ 6.83-6.68 (2H, m), 4.36-4.20 (4H, m), 2.82 (1H, septet, J = 6.9 Hz), 1.38 (6H, t, J = 7.1 Hz), 1.15
(6H, d, J = 6.9 Hz); 13C NMR δ ; 201.4, 132.5 (dt, JCP = 12.9 Hz, JCF = 21.8 Hz), 132.2 (dt, JCP = 5.8 Hz,
JCF = 8.0 Hz), 116.4 (dt, JCP = 217.1 Hz, JCF = 259.8 Hz), 64.9 (d, JCP = 6.7 Hz), 39.7, 17.5, 16.1 (d, JCP =
5.3 Hz); 19F NMR δ –48.4 (2F, dd, JHF = 9.0 Hz, JPF = 108.8 Hz); 31P NMR δ 5.59 (t, JPF = 108.8 Hz); IR

(neat) 2978, 1705, 1273, 1019 cm-1; MS (EI) m/z 569 (2M++1), 285 (M++1); HREIMS calcd for
C11H19O4F2P (M+): 284.0959. Found: 284.0996.
1
Diethyl (2E)-1,1-difluoro-2-(2-oxocyclohexylidene)ethylphosphonate ((E)-4k). Yield: 63%; an oil; H
NMR δ 6.39-6.26 (1H, m), 4.36-4.18 (4H, m), 2.89-2.78 (2H, m), 2.52 (2H, t, J = 6.7 Hz), 1.95-1.85 (2H,
m), 1.83-1.73 (2H, m), 1.38 (6H, t, J = 7.1 Hz); 13C NMR δ 200.1, 146.3 (dt, JCP = 6.2 Hz, JCF = 6.2 Hz),
124.0 (dt, JCP = 12.2 Hz, JCF = 22.2 Hz), 118.0 (dt, JCP = 217.5 Hz, JCF = 259.1 Hz), 64.7 (d, JCP = 6.3 Hz),
40.6, 28.1, 23.2, 16.2; 19F NMR δ –43.4 (2F, ddt, JHF = 3.0, 16.3 Hz, JPF = 111.2 Hz); 31P NMR δ 6.50 (t,
JFP = 111.2 Hz); IR (neat) 2942, 1700, 1272, 1033 cm-1; MS (EI) m/z 297 (M++1); HREIMS calcd for
C12H19O4F2P (M+): 296.0989. Found: 296.1004.
General procedure for the cycloaddition of diazomethane to (1,1-difluoroallyl)phosphonates ((E)-
4a-k). A typical experiment is described for the synthesis of pyrazoline (6a). An ethereal solution (15
mL) of diazomethane was prepared from N-nitroso-N-methylurea (3.1 g, 30 mmol) and 50% KOH (15
mL) at 0 °C as usual. The solution was added to an ethereal solution (15 mL) of (E)-4a (870 mg, 3.0
mmol) at 0 °C. The light-protected solution was stirred at 25 °C for 15 h, then, excess diazomethane was
eliminated by addition of acetic acid (3 drops) and the solvent was evaporated. The residue was
chromatographed on silica gel (n-hexane: EtOAc = 3:1) to afford 6a (717 mg, 72%) as an oil. The new
pyrazolines (6b-d, 6k, and 7g-j) were prepared in a similar manner.
Diethyl difluoro[(3S*,4S*)-3-phenyl-4,5-dihydro-3H-pyrazol-4-yl]methylphosphonate (6a). Yield:
72%; an oil; 1H NMR δ 7.48-7.24 (3H, m), 7.21-7.09 (2H, m), 6.10-5.97 (1H, m), 4.93 (1H, dd, J = 5.5,
18.6 Hz), 4.79 (1H, ddd, J = 2.5, 9.7, 18.6 Hz), 4.36-4.11 (4H, m), 2.82-2.63 (1H, m), 1.35 (3H, t, J = 7.0
Hz), 1.33 (3H, t, J = 7.0 Hz); 13C NMR δ 137.1, 128.9, 128.2, 127.2, 127.1, 119.2 (dt, JCP = 216.1 Hz, JCF
= 263.3 Hz), 90.9, 76.6, 64.9 (d, JCP = 6.9 Hz), 64.7 (d, JCP = 6.9 Hz), 44.3 (dt, JCP = 15.4 Hz, JCF = 20.7
Hz). 16.2 (d, JCP = 4.8 Hz), 16.1 (d, JCP = 4.9 Hz); 19F NMR δ –51.0 (1F, ddd, JFF = 300.8 Hz, JHF = 13.1
Hz, JFP = 108.9 Hz), –53.7 (1F, ddd, JFF = 300.8 Hz, JHF = 17.9 Hz, JFP = 105.0 Hz); IR (neat) 1274, 1039,
MS (EI) m/z 333 (M++1). Anal. Calcd for C14H19N2O3F2P: C, 50.59; H, 5.77; N, 8.43. Found: C, 50.29; H,
5.64; N, 8.40.
Diethyl difluoro[(3S*,4S*)-3-(4-fluorophenyl)-4,5-dihydro-3H-pyrazol-4-yl]methylphophonate (6b).
Yield: 83%; an oil; 1H NMR δ 7.18-7.00 (4H, m), 6.03-5.96 (1H, m), 4.91 (1H, dd, J = 5.6, 18.6 Hz), 4.80
(1H, ddd, J = 2.6, 9.7, 18.6 Hz), 4.35-4.15 (4H, m), 2.77-2.58 (1H, m), 1.36 (3H, t, J = 7.2 Hz), 1.33 (3H,
t, J = 7.2 Hz); 13C NMR δ 162.4 (d, JCF = 247.2 Hz), 133.1 (d, JCF = 3.2 Hz), 128.9 (d, JCF = 8.3 Hz), 119.2
(dt, JCP = 216.1 Hz, JCF = 263.4 Hz), 115.8 (d, JCF = 21.7 Hz), 90.2, 76.7, 64.9 (d, JCP = 7.0 Hz), 64.6 (d,
19
JCP = 6.0 Hz), 44.4 (dt, JCP = 15.6 Hz, JCF = 20.6 Hz), 16.2 (d, JCP = 4.8 Hz), 16.1 (d, JCP = 5.0 Hz); F
NMR δ –50.9 (1F, m), -51.2 (1F, ddd, JHF = 14.5 Hz, JFF = 300.7 Hz, JPF = 106.1 Hz), –53.5 (1F, ddd, JHF
31
= 19.3 Hz, JFF = 300.7 Hz, JPF = 106.1 Hz); P NMR δ 6.04 (t, JPF = 106.1 Hz), IR (neat) 1512, 1271,
1162, 1035 cm-1; MS (EI) m/z 351 (M++1); HREIMS calcd for C14H18N2O3F3P (M+): 350.1007. Found:
350.0996.
Methyl
4-{(3S*,4S*)-4-[(diethoxyphosphoryl)(difluoro)methyl]-4,5-dihydro-3H-pyrazol-3-
yl}benzoate (6c). Yield: 64%; an oil; 1H NMR δ 8.05 (2H, d, J =8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 6.09-
6.02 (1H, m), 4.94 (1H, dd, J = 5.7, 18.7 Hz), 4.82 (1H, ddd, J = 2.5, 9.7, 18.7 Hz), 4.36-4.15 (4H, m),

13
3.92 (3H, s), 2.82-2.62 (1H, m), 1.35 (3H, t, J = 7.1 Hz), 1.33 (3H, t, J = 7.1 Hz); C NMR δ 166.4,
142.0, 130.2, 130.0, 127.2, 119.0 (dt, JCP = 215.9 Hz, JCF = 263.5 Hz), 76.9, 65.0 (d, JCP = 6.8 Hz), 64.8 (d,
JCP = 4.3 Hz), 16.2 (d, JCP = 4.4 Hz); 19F NMR δ –51.0 (1F, ddd, JHF = 14.2 Hz, JFF = 300.9 Hz, JPF = 107.2
Hz), –53.8 (1F, ddd, JHF = 19.6 Hz, JFF = 300.9 Hz, JPF = 104.6 Hz), 31P NMR δ 5.93 (dd, JPF = 104.6 Hz,
107.2 Hz); IR (neat) 2987, 1723, 1281, 1020 cm-1; MS (EI) m/z 391 (M++1). Anal. Calcd for
C16H21N2O5F2P: C, 49.24; H, 5.42; N, 7.18. Found: C, 48.77; H, 5.43; N, 6.85.
Diethyl difluoro[(3S*,4S*)-3-pyridin-2-yl-4,5-dihydro-3H-pyrazol-4-yl]methylphosphonate (6d).
Yield: 60%; an oil; 1H NMR δ 8.55-8.48 (1H, m), 7.75 (1H, dt, J = 1.8, 7.6 Hz), 7.64 (1H, d, J = 7.8 Hz),
7.24 (1H, ddd, J = 1.1, 4.8, 7.6 Hz), 6.15-6.06 (1H, m), 4.99 (1H, ddd, J = 0.9, 5.6, 18.4 Hz), 4.90 (1H,
ddd, J = 2.5, 9.5, 18.4 Hz), 4.40-4.06 (4H, m), 3.48-3.28 (1H, m), 1.35 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J =
13
7.1 Hz); C NMR δ 154.8, 149.8, 136.9, 124.2, 123.2, 119.4 (dt, JCP = 216.1 Hz, JCF = 262.9 Hz), 92.9,
77.5, 64.8 (d, JCP = 6.8 Hz), 64.6 (d, JCP = 6.9 Hz), 41.2 (dt, JCP = 15.9 Hz, JCF = 20.6 Hz), 16.2 (d, JCP =
6.0 Hz), 16.1 (d, JCP = 6.5 Hz); 19F NMR δ –51.5 (1F, ddd, JHF = 17.8 Hz, JFF = 300.7 Hz, JPF = 106.9 Hz),
31
–52.5 (1F, ddd, JHF = 17.8 Hz, JFF = 300.7 Hz, JPF = 106.9 Hz). P NMR δ 6.30 (t, JPF = 106.9 Hz), MS
(EI) m/z 334 (M++1); HREIMS calcd for C13H18N3O3F2P (M+): 333.1054. Found: 333.1051.
Diethyl difluoro[(4R*,5R*)-6-oxo-1,2-diazaspiro[4,5]dec-1-en-4-yl]methylphosphonate (6k). Yield:
1
63%; an oil; H NMR δ 4.85 (1H, dd, J = 9.7, 18.5 Hz), 4.66 (1H, dd, J = 9.1, 18.5 Hz), 4.38-4.21 (4H,
m), 3.66-3.47 (4H, m), 3.66-3.47 (1H, m), 3.17 (1H, dt, J = 6.2, 14.0 Hz), 2.76-2.66 (1H, m), 2.54-2.22
(3H, m), 2.14-2.03 (1H, m), 2.02-1.83 (2H, m), 1.40 (6H, t, J = 7.1 Hz); 13C NMR δ 202.8, 120.5 (dt, JCP
= 217.4 Hz, JCF = 264.8 Hz), 104.3 (dd, J = 2.1, 6.9 Hz), 76.4, 64.9 (d, JCP = 6.7 Hz), 40.8, 37.0 (dt, JCP =
19
16.5 Hz, JCF = 19.8 Hz), 34.8 (t, JCF = 3.8 Hz), 27.3, 22.1, 16.3 (d, JCP = 5.2 Hz); F NMR δ –46.9 (1F,
ddd, JHF = 7.6 Hz, JFF = 301.9 Hz, JPF = 106.9 Hz), –50.8 (1F, ddd, JHF = 28.6 Hz, JFF = 301.9 Hz, JPF =
106.9 Hz); 31P NMR δ 5.70 (t, JCP = 106.9 Hz); IR (neat) 2943, 1719, 1270, 1025 cm-1; MS (EI) m/z 339
(M++1), 311 (MH+-N2). Anal. Calcd for C13H21N2O4F2P: C, 46.16; H, 6.26; N, 8.28. Found: C, 45,91; H,
6.21; N, 8.31.
Ethyl 4-[(diethoxyphosphoryl)(difluoro)methyl]-4,5-dihydro-1H-pyrazole-3-carboxylate (7g). Yield:
79%; an oil; 1H NMR δ 4.42-4.18 (6H, m), 4.14-3.94 (1H, m), 3.82 (1H, t, J = 11.9 Hz), 1.39 (3H, t, J =
7.0 Hz), 1.38 (3H, t, J = 7.0 Hz), 1.35 (3H, t, J = 7.1 Hz); 13C NMR δ 162.5, 136.7, 119.4 (dt, JCP = 211.9
Hz, JCF = 265.7 Hz), 65.4 (d, JCP = 6.2 Hz), 65.4 (d, JCP = 6.1 Hz), 61.4, 51.2 (t, JCF = 4.7 Hz), 47.8 (dt, JCP
= 16.6 Hz, JCF = 22.0 Hz), 16.6 (d, JCP = 5.1 Hz), 16.6 (d, JCP = 5.0 Hz), 14.5; 19F NMR δ –47.2 (1F, ddd,
JHF = 7.2 Hz, JPF = 104.7 Hz, JFF = 304.2 Hz), -53.3 (1F, ddd, JHF = 24.3 Hz, JPF = 104.7 Hz, JFF = 304.2
Hz); 31P NMR δ (t, JPF = 104.7 Hz), IR (neat) 2986, 1726, 1266, 1229 cm-1; MS (EI) m/z 329 (M++1), 297
(M+-OEt), 141 (M+–CF2P(O(OEt)2); HREIMS calcd for C11H19N2O5F2P (M+): 328.1000. Found: 328.1007.
Diethyl (3-acetyl-4,5-dihydro-1H-pyrazol-4-yl)difluoromethylphosphonate (7h). Yield: 59%; an oil;
1H NMR δ 6.36 (1H, br s), 4.39-4.19 (5H, m), 4.15-3.94 (1H, m), 3.77 (1H, t, J = 12.0 Hz), 2.44 (3H, s),
1.39 (3H, t, J = 6.9 Hz), 1.38 (3H, t, J = 7.0 Hz); 13C NMR δ 192.8, 144.7, 119.0 (dt, JCP = 211.4 Hz, JCF
= 266.1 Hz), 65.0 (d, JCP = 5.9 Hz), 51.1 (t, JCF = 5.1 Hz), 45.7 (dt, JCP = 16.6 Hz, JCF = 22.1 Hz), 25.9,
16.3 (d, JCP = 4.5 Hz), 16.2 (d, JCP = 4.3 Hz); 19F NMR δ –46.6 (1F, ddd, JHF = 6.9 Hz, JFF = 303.2 Hz, JPF
31
= 105.3 Hz), -53.4 (1F, ddd, JHF = 25.2 Hz, JFF = 303.2 Hz, JPF = 105.3 Hz) ; P NMR δ 5.81 (t, JPF =

105.3 Hz); IR (neat) 3293, 2986, 1667, 1264, 1025 cm–1; MS (EI) m/z 298 (M+); HREIMS calcd for
C10H17N2O4F2P (M+): 298.0894. Found: 298.0890.
Diethyl difluoro(3-propionyl-4,5-dihydro-1H-pyrazol-4-yl)methylphosphonate (7i). Yield: 80%; an
oil; 1H NMR δ 6.32 (1H, br s), 4.37-4.17 (5H, m), 4.12-3.93 (1H, m), 3.75 (1H, t, J = 11.9 Hz), 3.00-2.72
(2H, m), 1.39 (3H, t, J = 6.9 Hz), 1.37 (3H, t, J = 7.4 Hz); 13C NMR δ 196.0, 144.2, 119.1 (dt, JCP = 211.1
Hz, JCF = 266.1 Hz), 65.0 (d, JCP = 5.5 Hz), 50.8 (t, JCF = 5.0 Hz), 45.7 (dt, JCP = 16.7 Hz, JCF = 22.0 Hz),
31.4, 16.3, 8.3. 19F NMR δ –46.6 (1F, ddd, JHF = 6.4 Hz, JFF = 302.6 Hz, JPF = 105.4 Hz), –54.1 (1F, ddd,
JHF = 25.7 Hz, JFF = 302.6 Hz, JPF = 105.4 Hz); 31P NMR δ 5.80 (t, JPF = 105.4 Hz); IR (neat) 3301, 2983,
1665, 1446, 1266, 1031 cm-1; MS (EI) m/z 313 (M++1). Anal. Calcd for C11H19N2O4F2P: C, 42.31; H,
6.13; N, 8.97. Found: C, 42.24; H, 6.10; N, 9.44.
Diethyl difluoro(3-isobutyryl-4,5-dihydro-1H-pyrazol-4-yl)methylphosphonate (7j). Yield: 81%; an
oil; 1H NMR δ 6.33 (1H, br s), 4.37-4.18 (5H, m), 4.15-3.93 (1H, m), 3.74 (1H, t, J = 11.8 Hz), 3.54 (1H,
septet, J = 6.9 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 6.9 Hz), 1.16 (3H, d, J = 6.9 Hz), 1.12 (3H,
d, J = 6.9 Hz); 13C NMR δ 199.4, 143.4, 119.2 (dt, JCP = 210.9 Hz, JCF = 266.2 Hz), 65.0 (d, JCP = 5.7 Hz),
65.0 (d, JCP = 6.0 Hz), 50.8 (t, JCF = 5.0 Hz), 45.5 (dt, JCP = 16.5 Hz, JCF = 21.9 Hz), 35.7, 19.2, 18.2, 16.3
(d, JCP = 4.7 Hz); 19F NMR δ –46.4 (1F, ddd, JHF = 4.9 Hz, JFF = 302.3 Hz, JPF = 103.4 Hz), –55.9 (1F, ddd,
JHF = 27.9 Hz, JFF = 302.6 Hz, JPF = 107.4 Hz); 31P NMR δ 5.84 (dd, JPF = 107.0 Hz); IR (neat) 3303, 2977,
1663, 1533, 1445, 1267, 1031 cm-1; MS (EI) m/z 327 (M++1). Anal. Calcd for C12H21N2O4F2P: C, 44.17;
H, 6.49; N, 8.59. Found: C, 44.09; H, 6.30; N, 8.82.
1
∆
General procedure for the photolysis of -pyrazolines (6a-c and 6k). In a typical experiment, an
acetone solution (1.5 mL) of 6c (270 mg; 0.7 mmol) in a Pyrex reactor under nitrogen atmosphere was
irradiated at 25 °C for 3 h with a 500 W high-pressure mercury lamp. The solvent was evaporated and the
residue was chromatographed on silica gel. Elution with n-hexane:EtOAc=5:1 gave 8c (230 mg, 91%) as
an oil. In case of photolysis of 6a, chloroform was used as a solvent. Physical data of 8a-c and 8k are
given below:
Diethyl difluoro[(1S*,2S*)-2-phenylcyclopropyl]methylphosphonate (8a). Yield: 95%; an oil;1H
NMR δ 7.34-7.12 (6H, m), 4.34-4.20 (4H, m), 2.38 (1H, ddd, J = 9.2, 5.1, 5.1 Hz), 1.87-1.68 (1H, m),
1.45-1.34 (7H, m), 1.21 –1.12 (1H, m); 13C NMR δ 139.8, 128.3, 126.4, 126.3, 118.5 (dt, JCP = 220.5 Hz,
JCF = 258.1 Hz), 64.3 (d, JCP = 6.6 Hz), 23.2 (dt, JCP = 18.9 Hz, JCF = 24.1 Hz), 19.2, 16.3 (d, JCP = 5.3 Hz),
19
31
10.4; F NMR δ –51.6 (2F, dd, JHF = 13.7 Hz, JFP = 117.0 Hz), P NMR δ 6.83 (t, JPF = 117.0 Hz); IR
(neat) 1273, 1039, 1029 cm-1; MS (EI) m/z 304 (M+). Anal. Calcd for C14H19O3F2P: C, 55.24; H, 6.30.
Found: C, 55.02; H, 6.22.
Diethy difluoro[(1S*,2S*)-2-(4-fluorophenyl)cyclopropyl]methylphosphonate (8b). Yield: 91%; an
oil; 1H NMR δ 7.13 (2H, dd, JHH=8.7 Hz, JHF = 5.3 Hz), 6.97 (2H, dd, JHH = 8.7 Hz, JHF = 8.7 Hz), 4.35-
13
4.16 (4H, m), 2.39-2.29 (1H, m), 1.77-1.61 (1H, m), 1.37 (6H, t, J = 7.0 Hz), 1.13-1.05 (1H, m); C
NMR δ 161.6 (d, JCF = 244.6 Hz), 135.5 (d, JCF = 2.9 Hz), 128.2 (d, JCF = 7.9 Hz), 118.5 (dt, JCP = 222.2
Hz, JCF = 259.8 Hz), 115.2 (d, JCF = 21.5 Hz), 64.4 (d, JCP = 6.7 Hz), 23.2 (dt, JCP = 19.0 Hz, JCF = 24.3
Hz), 18.7, 16.4 (d, JCP = 5.3 Hz), 10.3; 19F NMR δ –51.3 (1F, ddd, JHF = 13.6 Hz, JFF = 295.2 Hz, JPF = 2.9
Hz), –52.3 (1F, ddd, JHF = 14.1 Hz, JHF = 13.6 Hz, JFF = 295.2 Hz, JPF = 2.9 Hz), –53.7 ~ –53.8 (1F, m);

31P NMR δ 7.47 (t, JPF = 115.9 Hz), IR (neat) 2987, 1514, 1271, 1037 cm-1; MS (EI) m/z 322 (M+);
HREIMS calcd for C14H18O3F3P(M+): 322.0946. Found: 322.0954.
Methyl 4-{(1S*,2S*)-2-[(diethoxyphosphoryl)(difluoro)methyl]cyclopropyl}benzoate (8c). Yield:
96%; an oil; 1H NMR δ 7.95 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J = 8.3 Hz), 4.34-4.15 (4H, m), 3.90 (3H, s),
2.44-2.36 (1H, m), 1.88-1.74 (1H, m), 1.49-1.41 (1H, m), 1.36 (6H, t, J = 7.1 Hz), 1.25-1.15 (1H, m); 13C
NMR δ 166.8, 145.4, 129.7, 128.3, 126.3, 118.2 (dt, JCP = 222.0 Hz, JCF = 260.2 Hz), 64.4 (d, JCP = 6.7
Hz), 51.9, 24.0 (dt, JCP = 19.1 Hz, JCF = 24.4 Hz), 19.4, 16.3 (d, JCP = 5.4 Hz), 11.0; 19F NMR δ –52.0 (1F,
dd, JHF = 13.4 Hz, JPF = 115.0 Hz), –51.9 (1F, dd, JHF = 13.4 Hz, JPF = 115.0 Hz); 31P NMR δ 7.38 (t, JPF
= 115.0 Hz); IR (neat) 2987, 1721, 1280, 1113, 1036 cm–1; MS (EI) m/z 362 (M+). Anal. Calcd for
C16H21O5F2P: C, 53.04; H, 5.84. Found: C, 52.50; H, 5.84.
1
Diethyl difluoro(1S*,3R*)-4-oxospiro[2,5]oct-1-yl]methylphosphonate (8k). Yield: 91%; an oil; H
NMR δ 4.38-4.20 (4H, m), 2.57-2.13 (4H, m), 2.02-1.84 (4H, m), 1.83-1.69 (1H, m), 1.38 (6H, t, J = 7.0
Hz), 1.11-1.02 (1H, m); 13C NMR δ 208.3, 119.5 (dt, JCP = 221.0 Hz, JCF = 260.7 Hz), 64.4 (d, JCP = 6.5
Hz), 39.6, 33.7 (d, JCP = 5.0 Hz), 28.1, 25.6 (dt, JCP = 23.7 Hz, JCF = 21.1 Hz), 24.0, 23.4, 19.2, 16.3 (d,
JCP = 3.1 Hz); 19F NMR δ –45.1 (1F, ddd, JHF = 8.8 Hz, JFF = 298.0 Hz, JPF = 115.5 Hz), –48.1 (1F, ddd,
31
JHF = 23.3 Hz, JFF = 298.0 Hz, JPF = 110.5 Hz); P NMR δ 6.77 (dd, JFP = 110.5, 115.5 Hz); IR (neat)
2940, 1701, 1271, 1031 cm-1; MS (EI) m/z 311 (M++1). Anal. Calcd for C13H21O4F2P: C, 50.32; H, 6.82.
Found: C, 49.92; H, 6.76.
ACKNOWLEDGMENT
This work was supported in part by Grant-in-Aid for Scientific Research (C) from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
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