The formation of dialkyl isobenzofuran-1-ylphosphonates by Lewis acid promoted reaction of o-phthalaldehyde with trialkyl phosphites

Article abstract of DOI:10.1055/s-2006-950371

The Lewis acid promoted reaction of o-phthalaldehyde with trialkyl phosphites results in the formation of dialkyl isobenzofuran-1-ylphosphonates, which reacted with various dienophiles, such as N-phenylmaleimide, to give Diels-Alder adducts. The factors i

Full text of DOI:10.1055/s-2006-950371

4124
PAPER
The Formation of Dialkyl Isobenzofuran-1-ylphosphonates by Lewis Acid
Promoted Reaction of o-Phthalaldehyde with Trialkyl Phosphites
Formation of
D
ialk
e
yl Isobenz
n
ofuran-1-ylph
j
ospho
i
nates Yamana,a Toshikazu Ibata,b Hirofumi Nakano*c
a
b
c
Division of General Science, Aichi Gakuin University, Nisshin, Aichi 470-0195, Japan
Department of Chemistry, Faculty of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Department of Chemistry, Aichi University of Education, Kariya, Aichi 448-8542, Japan
Fax +81(566)26 2310; E-mail: hnakano@auecc.aichi-edu.ac.jp
Received 27 June 2006; revised 8 August 2006
In this paper, we demonstrate the first Lewis acid promot-
ed reaction of o-phthalaldehyde with trialkyl phosphites
leading to the novel formation of dialkyl isobenzofuran-1-
ylphosphonates.9 Furthermore, we describe the substitu-
Abstract: The Lewis acid promoted reaction of o-phthalaldehyde
with trialkyl phosphites results in the formation of dialkyl isobenzo-
furan-1-ylphosphonates, which reacted with various dienophiles,
such as N-phenylmaleimide, to give Diels–Alder adducts. The fac-
tors influencing the reaction were the strength and amount of the ent effect of the trialkyl phosphite on the rate-determining
Lewis acid, the solvent, and the alkyl group of the phosphite. Fur-
step of the reaction.
thermore, the reaction mechanism and rate-determining step were
investigated.
Dialkyl isobenzofuran-1-ylphosphonates 4 were formed
by the reaction of o-phthalaldehyde (1) with trialkyl phos-
Key words: cycloaddition, Diels–Alder reaction, Lewis acids,
phites in the presence of a Lewis acid. The isobenzofurans
phosphites, isobenzofuran-1-yl phosphonate
4 were not isolated, due to the instability of 4 under the re-
action conditions, but we confirmed the formation of 4 by
trapping with dienophiles, such as N-phenylmaleimide, to
The chemistry of isobenzofuran1–5 is extremely interest-
give the Diels–Alder adducts 5a–d (Scheme 2). The ad-
ing both from a theoretical point of view and in the syn-
duct 3 was not detected in the reaction mixture by HPLC
thesis of natural products.6 Haddadin and co-workers7
analysis when its retention time was compared with that
showed that the reaction of o-phthalaldehyde with triethyl
of an authentic sample.10
phosphite in the presence of N-phenylmaleimide gave N-
phenylnaphthalenecarboximide 2 formed by initial attack
of triethyl phosphite onto N-phenylmaleimide
O
(Scheme 1). The naphthalene derivative 2 was not formed
N
Ph
O
O
by aromatization of isobenzofuran–N-phenylmaleimide
adduct 3, because the adduct 3 was not aromatized under
the reaction conditions as reported by Haddadin.
Lewis
acid
(RO)2P
O
H
H
O
O
P(OR)3
1
On the other hand, organic phosphonates are one of the
most important classes of organophosphorus compounds
for organic synthesis and biological activity.8
4a–d
4, 5
a R = Me
b R = Et
c R = Pr
d R = i-Pr
(RO)2P
O
N
O
O
O
O
Ph
N
Ph
5a–d
O
O
O
H
H
O
Scheme 2
N
Ph
P(OEt)3
2
1
O
In order to investigate the effects of the Lewis acid on the
reaction, we examined the effects of zinc(II) chloride,
zinc(II) bromide, tin(IV) chloride, titanium(IV) chloride,
and boron trifluoride–diethyl ether complex on the forma-
tion of isobenzofuran 4a, from o-phthalaldehyde (1) and
trimethyl phosphite, followed by trapping with N-phenyl-
maleimide to give 5a (Table 1). Using boron trifluoride–
diethyl ether complex as the Lewis acid led to the adducts
5a with the greatest yield (entry 7). On the other hand, the
adducts 5a were not obtained using zinc(II) chloride,
zinc(II) bromide, or tin(IV) chloride. It is likely that
strong Lewis acids promote the formation of the isoben-
zofuran 4a, but weak ones do not.
naphthalene derivative
O
N
Ph
O
O
3
O
isobenzofuran
Scheme 1
SYNTHESIS 2006, No. 24, pp 4124–4130
Advanced online publication: 21.11.2006
DOI: 10.1055/s-2006-950371; Art ID: F09906SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

PAPER
Formation of Dialkyl Isobenzofuran-1-ylphosphonates
4125
Table 1 Effect of the Lewis Acid on the Formation of Isobenzofu-
ran 4aa
Table 3 Effect of Solvent and Reaction Time on the Formation of
the Isobenzofuran 4aa
Entry
Lewis acid
Yieldb (%)
Entry Solvent
Timeb (h)
Yieldc (%)
endo-5a
exo-5a
endo-5a
exo-5a
–
1
2
3
4
5
6
7
none
0
0
0
1
2
3
4
5
6
7
THF
8
8
trace
17
ZnCl2
ZnBr2
SnCl4
AlCl3
TiCl4
0
toluene
benzene
CH2Cl2
MeCN
MeCN
MeCN
0.2
0.3
3.1
2.0
2.6
2.7
0
0
8
18
0
0
8
60
24
30
54
1.6
0.4
2.2
8
67
24
60
77
BF3·OEt2
87
a Reaction conditions: Lewis acid, o-phthalaldehyde, MeCN, 0 °C,
0.5 h then P(OMe)3 (1 equiv), N-phenylmaleimide, 25 °C, 6 h.
b Yield of the Diels–Alder adducts determined by HPLC analysis.
a Reaction conditions: BF3·OEt2, o-phthalaldehyde, solvent, 0 °C,
0.5 h then P(OMe)3, N-phenylmaleimide, 25 °C.
b From addition of P(OMe)3.
c Yield of the Diels–Alder adducts determined by HPLC analysis.
We investigated the influence of the amount of boron tri-
fluoride–diethyl ether complex on the formation of used acetonitrile as the solvent and increased the reaction
isobenzofuran 4a (Table 2). As a result, when we used one time, the yield increased and the best yield was obtained
equivalent of boron trifluoride–diethyl ether complex, after 60 hours (entries 5–7).
endo-5a was obtained with the greatest yield (entry 3) and
when we used a catalytic amount of boron trifluoride–di-
ethyl ether complex (entry 1), the yield was only 8%. On
the other hand, excess boron trifluoride–diethyl ether
Mechanistically, the formation of the isobenzofurans 4a
and 4b is explained as follows (Scheme 3). In the first
step, the Lewis acid coordinates to an oxygen atom in the
formyl group of dialdehyde 1 to give 6. In the next step,
complex decreased the yield of endo-5a (entries 4 and 5).
the other formyl oxygen atom of 6 nucleophilically at-
Thus boron trifluoride–diethyl ether complex is not a cat-
tacks the Lewis acid activated formyl carbon atom to give
alyst and if it is used in excess, then it reacts with trimethyl
the five-membered ring intermediate 7. Trialkyl phosphite
phosphite and hinders the reaction of trimethyl phosphite
and o-phthalaldehyde. We confirmed that dimethyl phos-
phonate was generated from the reaction of trimethyl
phosphite with boron trifluoride–diethyl ether complex
as nucleophile then undergoes addition to 7 to form 8,
which eliminates L– to give 9. The Arbuzov11,12 type reac-
tion of 9 gives 10, which forms 4a and 4b by the elimina-
tion of (HO)MLn–1. Several attempts to isolate 4a and 4b
were unsuccessful, because of their high reactivity. The
under the reaction conditions shown Table 2, entry 3.
formation of 4a and 4b was deduced from the isolation of
Diels–Alder adducts 5a and 5b.
Table 2 The Effect of the Amount of Boron Trifluoride–Diethyl
Ether Complex on the Formation of Isobenzofuran 4aa
Assuming that the rate-determining step for the formation
of the isobenzofurans 4a–d was the attack of halide anion
on the alkyl (methyl or ethyl) group of the phosphite, we
next tried adding a stronger nucleophile to the reaction
system. The reaction in the presence of potassium iodide
was accelerated, and the products were obtained in higher
yields (Table 4). For example, without potassium iodide
the Diels–Alder adduct endo-5a was generated in trace
amount only with a reaction time of two hours, but in the
presence of potassium iodide under the same conditions
endo-5a was obtained in 57% yield (entries 1, 2). These
results indicated that the rate-determining step was the at-
tack of halide anion on the methyl group of trimethyl
phosphite. Furthermore, when the same reaction was car-
ried out with acetonitrile-d3 as the solvent in an NMR
tube; a peak at the correct chemical shift for iodomethane
Entry
BF3·OEt2 (equiv)b
Yieldb (%) of endo-5a
1
2
3
4
5
0.1
0.5
1.0
1.2
2.0
8.0
40
67
57
47
a Reaction conditions: BF3·OEt2, o-phthalaldehyde (1 equiv), MeCN,
0 °C, 0.5 h then P(OMe)3 (1 equiv), N-phenylmaleimide, 25 °C, 8 h.
b Determined by HPLC analysis.
The reaction was almost complete in eight hours, as
shown in a preliminary communication, when we used
dichloromethane as the solvent.9 We examined the solvent
effects for the reaction (Table 3); acetonitrile was the best
solvent, whereas the yield was poor when toluene or ben-
zene was used (entries 2 and 3). Furthermore, when we
1
(d = 2.17) appeared in the H NMR spectra. This result
shows that iodide attacks on the methyl group of trimethyl
phosphite and an Arbuzov-type reaction proceeds as an
SN2-type reaction under these conditions.
Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York

4126
K. Yamana et al.
PAPER
O
O
O
Table 4 Effects of Potassium Iodide on the Formation of Novel
Isobenzofuransa
H
MLn
P(OR)3
H
H
H
+
O
Entry
R
Iodide
Time
Product Yieldb (%)
H
+
(1 equiv) (h)
O
-
O
1
7
6
MLn
MLn
endo
trace
57
exo
1
2
Me
Me
Et
–
2
2
5a
5a
5b
5b
5c
5c
5d
5d
5a
5a
5b
5b
5c
5c
5d
5d
5a
5b
5c
5d
–
(RO)2P+
O
H
R
(RO)2P+
O
H
R
(RO)2P
O
H
L–
KI
–
1.9
–
– MLn–1OH
– RL
O
O
O
3
2
trace
52
O
O
O
9
10
8
MLn–1
L
MLn–1
MLn–1
4
Et
KI
–
2
–
5
Pr
2
18
0.8
1.3
0.5
0.5
2.0
2.2
0.6
1.9
2.3
3.5
3.4
3.5
2.6
0.6
3.5
2.3
O
O
6
Pr
KI
–
2
32
N
Ph
(RO)2P
O
(RO)2P
O
O
O
7
i-Pr
i-Pr
Me
Me
Et
2
23
8
KI
–
2
24
O
O
N
Ph
9
8
67
4a R = Me
4c R = Et
5a R = Me
5b R = Et
10
11
12
13
14
15
16
17
18
19
20
KI
–
8
66
Scheme 3
8
15
Et
KI
–
8
76
The reaction of the other phosphites such as triethyl,
tripropyl, and triisopropyl phosphites gave the corre-
sponding adducts 5b–d, respectively, as shown in
Table 4. The effect of adding potassium iodide was differ-
ent depending on the alkyl substitution of the phosphite.
The reaction of trimethyl or triethyl phosphite in the pres-
ence of potassium iodide gave the adducts endo-5a and
endo-5b in higher yields (entries 2 and 4), but in the ab-
sence of potassium iodide endo-5a and endo-5b were
formed in trace amounts only (entries 1 and 3). However,
in the reaction of tripropyl or triisopropyl phosphite, the
effects of potassium iodide became weak (entries 5 and 6),
and its effects were almost lost completely in the reaction
of triisopropyl phosphite (entries 7 and 8). These results
indicate that for the phosphite containing smaller alkyl
groups, like methyl or ethyl group, the rate-determining
step was promoted by potassium iodide, but for the phos-
phite containing larger alkyl groups, like isopropyl, the
rate-determining step was not promoted. It is thought that
when alkyl groups are small, the Arbuzov-type reaction
progresses by attack of the nucleophile I– on the alkyl
group (SN2-type reaction), but when the alkyl groups are
large, the reaction progresses by the dissociation of the
alkyl group (SN1-type reaction), therefore the yields did
not improve even if the amount of nucleophile I– was in-
creased.
Pr
8
49
Pr
KI
–
8
61
i-Pr
i-Pr
Me
Et
8
46
KI
–
8
48
24
24
24
24
77
–
70
Pr
–
63
i-Pr
–
53
a Reaction conditions: BF3·OEt2, o-phthalaldehyde, MeCN, 0 °C,
0.5 h then P(OR)3, N-phenylmaleimide, KI, 25 °C.
b Yield of the adduct determined by HPLC analysis.
the reaction temperature fell from 25 °C to 5 °C, there was
a less dramatic change in the yields. In particular, for the
reaction of triisopropyl phosphite, the yields were almost
same at 25 °C and 5 °C (entries 7, 8). These results also
suggest that the reaction of triisopropyl phosphite pro-
ceeds by different mechanism from that of trimethyl or tri-
ethyl phosphite.
Other dienophiles have also been used to trap the isoben-
zofuran 4a to give the Diels–Alder adducts 11–13
(Figure 1, Table 6). When N-methylmaleimide and male-
ic anhydride were used as dienophiles, the Diels–Alder
adducts 11 or 12, respectively, were obtained in good
yields (Table 6, entries 2 and 3).
The temperature dependency of the reaction was exam-
ined for the formation of isobenzofuran 4 (Table 5). At
25 °C, the reaction of trimethyl phosphite and triethyl
phosphate gave the endo-adducts endo-5a (67%), and
endo-5b (15%) yield (entries 1, 3), but the both yields de-
creased considerably at 5 °C to give endo-5a (8%) and
endo-5c (2%) (entries 2, 4). However, for the reaction of
tripropyl and triisopropyl phosphite (entries 5–8), even if
When dimethyl acetylenedicarboxylate was used as the
dienophile, the adduct 13 was obtained in poor yield
(Table 6, entry 4). Dimethyl acetylenedicarboxylate was
polymerized under the reaction conditions, and the adduct
Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York

PAPER
Formation of Dialkyl Isobenzofuran-1-ylphosphonates
4127
O
Table 5 Effect of the Alkyl Substitution of Phosphite on the Forma-
(MeO)2P
O
BF3⋅OEt2 (1.0 equiv)
tion of Novel Isobenzofuransa
P(OMe)3 (1.0 equiv)
H
O
Yieldb (%)
Ph
Entry
R
Temp (°C) Product
MeCN, 25 °C
Ph
O
endo
67
exo
2.0
–
15
14
O
O
1
2
3
4
5
6
7
8
Me
Me
Et
25
5
5a
5a
5b
5b
5c
5c
5d
5d
N
Ph
8.3
15
(MeO)2P
O
O
O
25
5
0.6
–
O
N
Ph
Et
2.1
61
Ph
Pr
25
5
3.5
1.3
3.4
2.6
16
Scheme 4
Pr
32
i-Pr
i-Pr
25
5
46
duct 16 in 95% yield. The isobenzofuran 15 was stable in
solution (MeCN or EtOAc–hexane), but it decomposed
during the evaporation of the solvent.
45
a Reaction conditions: BF3·OEt2, o-phthalaldehyde, MeCN, 0 °C,
0.5 h then P(OR)3, N-phenylmaleimide, 8 h.
We have established a new method for the formation of
dialkyl isobenzofuran-1-ylphosphonates using a Lewis
acid; the dialkyl isobenzofuran-1-ylphosphonates under-
went a Diels–Alder reaction with various dienophiles to
give the corresponding adducts. Furthermore we con-
firmed the formation of the isobenzofuran by isolating the
novel 3-phenylisobenzofuran-1-ylphosphonate 15, and
showed that the rate-determining step of the isobenzofu-
ran forming reaction was an Arbuzov-type reaction.
b Yield of the Diels–Alder adducts determined by HPLC analysis.
(MeO)2P
O
(MeO)2P
O
O
O
O
O
O
O
N
Me
O
(MeO)2P
O
O
O
11
12
OMe
OMe
O
13
Melting points were obtained with a Yanako micro melting point
apparatus and are uncorrected. H and 13C NMR spectra were re-
1
Figure 1
corded on a JEOL EX-270 or an EX-400 in CDCl3, with TMS as an
internal standard. IR spectra were obtained with a JASCO FT/IR-
300E or a JASCO FT/IR-620. MS spectra were determined with a
JEOL JMS-DX300, by GC inlet, and measured by Finnigan MA+
mass spectrometer.
Table 6 Yields of the Diels–Alder Adducts from Isobenzofuran 4a
and a Dienophilea
Entry Dienophile
Product Config Yield
(%)
Dialkyl (1,3-Dioxo-2-phenyl-1,2,3,3a,9,9a-hexahydro-4H-4,9-
epoxybenzo[f]isoindol-4-yl)phosphonates 5a–d; General Proce-
dure
1
2
3
4
N-phenylmaleimide
5a
11
12
endo
endo
endo
–
67b
73b
46c,
13c
The Lewis acid was added to a soln of o-phthalaldehyde (1 mmol)
in MeCN (3 mL) at 0 °C. The mixture was stirred at this tempera-
ture for 0.5 h, and then trialkyl phosphite (1 mmol) and dienophile
(1 mmol) were added and the mixture was stirred at 25 °C. The re-
action was quenched by the addition of HCl soln, and the organic
layer was extracted with CH2Cl2, washed with NaHCO3, dried (an-
hyd Na2SO4), and concentrated in vacuo. The residue was chro-
matographed (silica gel, EtOAc–hexane, 1:1) to give 5a–d. The
reaction conditions are summarized in Table 5.
N-methylmaleimide
maleic anhydride
dimethyl acetylenedicarboxylate 13
a Reaction conditions: BF3·OEt2, o-phthalaldehyde, MeCN, 0 °C,
0.5 h then P(OMe)3, dienophile, 25 °C, 8 h.
b Determined by HPLC analysis.
c Isolated yield.
Dimethyl [(3aR*,4S*,9S*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (endo-5a)
13 decomposed to give a complex mixture on standing at
room temperature, because it was unstable presumably
due to a retro-Diels–Alder reaction.
Colorless crystals (EtOAc); mp 153.5–154.5 °C.
IR (KBr): 3000, 2970, 1718 (C=O), 1498, 1458, 1379, 1258 (P=O),
1190, 1180, 1055, 1025 (P-OCH3) cm–1.
Furthermore, we confirmed the presence of the isobenzo-
furan-1-ylphosphonate by using resonance stabilization 1H NMR (270.5 MHz, CDCl3): d = 3.89 (d, 3JP-O-C-H = 10.9 Hz, 3 H,
CH3), 4.06 (dd, J = 5.6 Hz, J = 8.6 Hz, 1 H, CH), 4.11 (d, 3JP-O-C-H
=
from the phenyl group in 15 (Scheme 4). The reaction of
2-benzoylbenzaldehyde (14) with trimethyl phosphite
gave the isobenzofuran 15 in 41% yield, in the presence of
N-phenylmaleimide this gave the endo-Diels–Alder ad-
10.9 Hz, 3 H, CH3), 4.26 (dd, 3JP-C-H = 8.9 Hz, J = 8.9 Hz, 1 H, CH),
5.91(dd, 4JP-C-O-C-H = 1.3 Hz, J = 5.6 Hz, 1 H, CH), 6.39–6.43 (m, 2
H, o-ArH), 7.26–7.39 (m, 6 H, ArH), 7.55–7.58 (m, 1 H, ArH).
Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York

4128
K. Yamana et al.
PAPER
2
13C NMR (67.80 MHz, CDCl3): d = 49.6 (d, JC-P = 4.9 Hz, CH),
50.7 (d, 3JC-P = 6.7 Hz, CH), 54.4 (d, 2JC-O-P = 6.1 Hz, POCH3), 54.5
(d, 2JC-O-P = 6.1 Hz, POCH3), 81.6 (d, 3JC-O-C-P = 15.3 Hz, CH), 86.0
(d, JC-P = 191.1 Hz, C-P), 121.3, 122.0, 126.3, 128.6, 128.78,
128.84, 129.0, 130.7, 139.55, 139.61, 140.6, 140.8 (ArC), 171.7
(C=O), 172.5 (C=O).
JC-P = 188.6 Hz, C-P), 120.0, 120.9, 126.5, 128.1, 128.2, 128.8,
129.1, 131.8, 142.7, 142.9, 143.6, 143.7 (ArC), 172.2 (d, 3JC-P = 3.1
Hz, C=O), 174.2 (C=O).
Anal. Calcd for C22H22NO6P: C, 61.83; H, 5.19; N, 3.28. Found: C,
61.72; H, 5.26; N, 3.26.
Anal. Calcd for C20H18NO6P: C, 60.16; H, 4.54; N, 3.51. Found: C,
59.93; H, 4.61; N, 3.47.
Dipropyl [(3aR*,4S*,9S*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (endo-5c)
Dimethyl [(3aR*,4R*,9R*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (exo-5a)
Colorless crystals (EtOAc); mp 146.8–147.0 °C.
IR (KBr): 2968, 1718 (C=O), 1502, 1387, 1254 (P=O), 1198, 1007
(P-OCH2), 948, 784 cm–1.
Colorless crystals (EtOAc); mp 197.8–198.5 °C.
1H NMR (270.5 MHz, CDCl3): d = 0.88 (t, J = 7.3 Hz, 3 H, CH3),
1.03 (t, J = 7.3 Hz, 3 H, CH3), 1.67 (tq, J = 6.9 Hz, J = 7.3 Hz, 2 H,
CH2), 1.85 (tq, J = 6.9 Hz, J = 7.3 Hz, 2 H, CH2), 4.06 (dd, J = 5.6
Hz, J = 8.6 Hz, 1 H, CH), 4.20 (dt, 3JP-O-C-H = 7.6 Hz, J = 6.9 Hz, 2
H, CH2), 4.25 (dd, 3JP-C-H = 8.9 Hz, J = 8.6 Hz, 1 H, CH), 4.39 (dt,
3JP-O-C-H = 7.6 Hz, J = 6.9 Hz, 2 H, CH2), 5.90 (dd, 4JP-C-O-C-H = 1.3
Hz, J = 5.6 Hz, 1 H, CH), 6.39–6.42 (m, 2 H, o-ArH), 7.25–7.38 (m,
6 H, ArH), 7.56–7.59 (m, 1 H, ArH).
IR (KBr): 2975, 1718 (C=O), 1500, 1381, 1271 (P=O), 1190, 1030
(P-OCH3) cm–1.
1H NMR (270.5 MHz, CDCl3): d = 3.23 (dd, J = 6.9 Hz, J = 8.3 Hz,
3
2 H, 2 CH), 3.85 (d, JP-O-C-H = 10.9 Hz, 3 H, CH3), 3.94 (d,
3JP-O-C-H = 10.9 Hz, 3 H, CH3), 5.94 (s, 1 H, CH), 7.26–7.52 (m, 8 H,
ArH), 7.60–7.67 (m, 1 H, ArH).
2
13C NMR (67.80 MHz, CDCl3): d = 51.2 (d, JC-P = 3.8 Hz, CH),
53.8 (d, 3JC-P = 6.7 Hz, CH), 54.4 (d, 2JC-O-P = 6.7 Hz, CH3), 54.5 (d,
2JC-O-P = 6.1 Hz, CH3), 82.6 (d, 3JC-O-C-P = 14.7 Hz, CH), 87.1 (d,
JC-P = 189.2 Hz, C-P), 120.0, 120.8, 126.5, 128.3, 128.4, 128.8,
13C NMR (67.80 MHz, CDCl3): d = 9.9, 10.1 (CH3), 23.8 (d,
3
3JC-O-P = 5.5 Hz, CH2), 24.0 (d, JC-O-P = 5.5 Hz, CH2), 49.7 (d,
2JC-P = 4.9 Hz, CH), 50.7 (d, 3JC-P = 6.7 Hz, CH), 69.1 (d, 2JC-O-P
=
=
129.2, 131.8, 142.6, 142.7, 143.28, 143.34 (ArC), 172.3 (d, 3JC-P
=
6.1 Hz, CH2), 69.3 (d, JC-O-P = 6.1 Hz, CH2), 81.4 (d, JC-O-C-P
2
3
2.4 Hz, C=O), 174.1 (C=O).
15.7 Hz, CH), 86.2 (d, JC-P = 191.0 Hz, C-P), 121.2, 121.9, 126.4,
128.4, 128.5, 128.7, 128.9, 130.9, 139.9, 140.0, 140.7, 140.9 (ArC),
171.5 (C=O), 172.6 (C=O).
Anal. Calcd for C20H18NO6P: C, 60.16; H, 4.54; N, 3.51. Found: C,
60.36; H, 4.59; N, 3.50.
Anal. Calcd for C24H26NO6P: C, 63.29; H, 5.75; N, 3.08. Found: C,
63.03; H, 5.72; N, 3.11.
Diethyl [(3aR*,4S*,9S*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (endo-5b)
Dipropyl [(3aR*,4R*,9R*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (exo-5c)
Colorless crystals (EtOAc); mp 166.5–167.0 °C
IR (KBr): 2983, 1714 (C=O), 1496, 1459, 1387, 1269 (P=O), 1203,
1185, 1048, 1029 (P-OCH2), 943, 787 cm–1.
Colorless crystals (EtOAc); mp 166.5–167.0 °C.
IR (KBr): 2968, 1718 (C=O), 1502, 1387, 1254 (P=O), 1198, 1007
(P-OCH2), 948, 784 cm–1.
1H NMR (270.5 MHz, CDCl3): d = 1.31 (t, J = 6.9 Hz, 3 H, CH3),
1.47 (t, J = 6.9 Hz, 3 H, CH3), 4.05 (dd, J = 5.6 Hz, J = 8.6 Hz, 1 H,
CH), 4.20–4.36 (m, 3 H, CH, CH2), 4.50 (q, J = 6.9 Hz, 2 H, CH2),
5.90 (dd, 4JP-C-O-C-H = 1.3 Hz, J = 5.6 Hz, 1 H, CH), 6.39–6.44 (m, 2
H, o-ArH), 7.23–7.40 (m, 6 H, ArH), 7.57–7.60 (m, 1 H, ArH).
1H NMR (270.5 MHz, CDCl3): d = 0.83 (t, J = 7.3 Hz, 3 H, CH3),
0.92 (t, J = 7.3 Hz, 3 H, CH3), 1.59 (tq, J = 6.9 Hz, J = 7.3 Hz, 2 H,
CH2), 1.71 (tq, J = 6.9 Hz, J = 7.3 Hz, 2 H, CH2), 3.23 (dd, J = 6.9
Hz, J = 7.6 Hz, 2 H, 2 CH), 3.98–4.23 (m, 4 H, 2 CH2), 5.94 (s, 1 H,
CH), 7.27–7.51 (m, 8 H, ArH), 7.62–7.65 (m, 1 H, ArH).
13C NMR (67.80 MHz, CDCl3): d = 16.4 (d, 3JC-O-P = 6.1 Hz, CH3),
16.6 (d, 3JC-O-P = 6.1 Hz, CH3), 49.7 (d, 2JC-P = 4.3 Hz, CH), 50.7 (d,
3JC-P = 6.7 Hz, CH), 63.8 (d, JC-O-P = 6.1 Hz, CH2), 64.3 (d,
13C NMR (67.80 MHz, CDCl3): d = 9.9, 10.1 (CH3), 23.8 (d,
2
3
2JC-O-P = 6.1 Hz, CH2), 81.6 (d, 3JC-O-C-P = 15.3 Hz, CH), 86.0 (d,
JC-P = 191.0 Hz, C-P), 121.2, 122.1, 126.3, 128.5, 128.6, 128.8,
129.0, 130.8, 139.8, 139.9, 140.7, 140.8 (ArC), 171.5 (C=O), 172.6
(C=O).
3JC-O-P = 5.5 Hz, CH2), 24.0 (d, JC-O-P = 5.5 Hz, CH2), 49.7 (d,
2JC-P = 4.9 Hz, CH), 50.7 (d, 3JC-P = 6.7 Hz, CH), 69.1 (d, 2JC-O-P
6.1 Hz, CH2), 69.3 (d, JC-O-P = 6.1 Hz, CH2), 81.4 (d, JC-O-C-P
=
=
2
3
15.7 Hz, CH), 86.2 (d, JC-P = 191.0 Hz, C-P), 121.2, 121.9, 126.4,
128.4, 128.5, 128.7, 128.9, 130.9, 139.9, 140.0, 140.7, 140.9 (ArC),
171.5 (C=O), 172.6 (C=O).
Anal. Calcd for C22H22NO6P: C, 61.83; H, 5.19; N, 3.28. Found: C,
61.57; H, 5.18; N, 3.31.
Anal. Calcd for C24H26NO6P: C, 63.29; H, 5.75; N, 3.08. Found: C,
63.07; H, 5.72; N, 3.02.
Diethyl [(3aR*,4R*,9R*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (exo-5b)
Diisopropyl [(3aR*,4S*,9S*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (endo-5d)
Colorless crystals (EtOAc); mp 138.8–139.6 °C.
IR (KBr): 3000, 1719 (C=O), 1499, 1387, 1269 (P=O), 1200, 1020
(P-OCH2) cm–1.
Colorless crystals (EtOAc); mp 151.5–152.0 °C.
IR (KBr): 2988, 1718 (C=O), 1497, 1389, 1256 (P=O), 1192, 1103,
983 (P-OCH), 941, 784 cm–1.
1H NMR (270.5 MHz, CDCl3): d = 1.23 (t, J = 7.1 Hz, 3 H, CH3),
1.32 (t, J = 7.1 Hz, 3 H, CH3), 3.22 (dd, J = 6.9 Hz, J = 7.3 Hz, 2 H,
2 CH), 4.11–4.40 (m, 4 H, 2 CH2), 5.94 (s, 1 H, CH), 7.27–7.51 (m,
8 H, ArH), 7.63–7.66 (m, 1 H, ArH).
1H NMR (400 MHz, CDCl3): d = 1.15 (d, J = 6.2 Hz, 3 H, CH3),
1.31 (d, J = 6.2 Hz, 3 H, CH3), 1.40 (d, J = 6.2 Hz, 3 H, CH3), 1.43
(d, J = 6.2 Hz, 3 H, CH3), 3.96 (dd, J = 5.8 Hz, J = 8.4 Hz, 1 H, CH),
3
13C NMR (67.80 Hz, CDCl3): d = 16.3 (d, JC-O-P = 6.1 Hz, CH3),
3
4.15 (dd, JP-C-H = 8.8 Hz, J = 8.8 Hz, 1 H, CH), 4.82 (sept,
16.5 (d, 3JC-O-P = 6.1 Hz, CH3), 51.1 (d, 2JC-P = 4.3 Hz, CH), 51.2 (d,
3
3JP-O-C-H = 6.3 Hz, J = 6.3 Hz, 1 H, CH), 4.99 (sept, JP-O-C-H = 6.3
2
3JC-P = 6.7 Hz, CH), 63.4 (d, JC-O-P = 6.7 Hz, CH2), 64.0 (d,
Hz, J = 6.3 Hz, 1 H, CH), 5.81 (dd, 4JP-C-O-C-H = 1.4 Hz, J = 5.8 Hz,
2JC-O-P = 6.7 Hz, CH2), 82.5 (d, 3JC-O-C-P = 14.0 Hz, CH), 86.9 (d,
Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York

PAPER
Formation of Dialkyl Isobenzofuran-1-ylphosphonates
4129
3
1 H, CH), 6.32–6.35 (m, 2 H, o-ArH), 7.17–7.18 (m, 3 H, ArH),
7.25–7.29 (m, 3 H, ArH), 7.57–7.60 (m, 1 H, ArH).
J = 8.8 Hz, 1 H, CH), 4.32 (dd, JP-C-H = 8.8 Hz, J = 8.8 Hz, 1 H,
CH), 5.84 (dd, 4JP-C-O-C-H = 1.7 Hz, J = 5.8 Hz, 1 H, CH), 7.24–7.35
(m, 3 H, ArH), 7.51–7.54 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 22.7, 22.8, 23.00, 23.03 (CH3),
2
2
48.6 (CH), 49.7 (CH), 68.1 (d, JC-O-P = 6.5 Hz, CH), 68.5 (d,
13C NMR (67.80 MHz, CDCl3): d = 50.7 (d, JC-P = 4.1 Hz, CH),
3
3
2
2JC-O-P = 6.5 Hz, CH), 80.4 (d, JC-O-C-P = 15.7 Hz, CH), 85.3 (d,
51.9 (d, JC-P = 6.6 Hz, CH), 54.2 (d, JC-O-P = 5.8 Hz, P-OCH3),
54.5 (d, 2JC-O-P = 5.8 Hz, P-OCH3), 81.7 (d, 3JC-O-C-P = 15.7 Hz, CH),
86.3 (d, JC-P = 191.9 Hz, C-P), 121.3, 122.0, 129.2, 129.4, 138.7,
138.7, 139.7, 139.8 (ArC), 165.9 (C=O), 166.9 (C=O).
JC-P = 190.7 Hz, C-P), 120.1, 121.0, 125.3, 127.4, 127.5, 127.7,
127.9, 129.9, 138.3, 139.0, 139.7, 139.8 (ArC), 170.3 (C=O), 171.5
(C=O).
Anal. Calcd for C24H26NO6P: C, 63.29; H, 5.75; N, 3.08. Found: C,
63.27; H, 5.84; N, 3.13.
Anal. Calcd for C14H13O7P: C, 51.86; H, 4.04. Found: C, 51.52; H,
4.14.
Diisopropyl [(3aR*,4R*,9R*,9aR*)-1,3-Dioxo-2-phenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (exo-5d)
Dimethyl 1-(Dimethoxyphosphoryl)-1,4-dihydro-1,4-epoxy-
naphthalene-2,3-dicarboxylate (13)
Colorless oil.
Colorless crystals (EtOAc); mp 162.0–162.8 °C.
IR (KBr): 2959, 1742 (C=O), 1723 (C=O), 1634, 1437, 1318, 1271
(P=O), 1120, 1038 (P-OCH3), 830, 759 cm–1.
IR (KBr): 2999, 1719 (C=O), 1500, 1385, 1261 (P=O), 1196, 990
(P-OCH), 758 cm–1.
1H NMR (270.5 MHz, CDCl3): d = 3.76 (s, 3 H, COOCH3), 3.85 (s,
3 H, COOCH3), 3.87 (d, 3JP-O-H = 10.9 Hz, 3 H, CH3), 3.93 (d,
3JP-O-H = 10.9 Hz, 3 H, CH3), 6.06 (d, 4JP-C-O-C-H = 2.0 Hz, 1 H, CH),
7.11–7.14 (m, 2 H, ArH), 7.41–7.44 (m, 1 H, ArH), 7.71–7.76 (m,
1 H, ArH).
13C NMR (67.80 MHz, CDCl3): d = 52.5 (COOCH3), 52.7
(COOCH3), 54.1 (d, 2JC-O-P = 6.7 Hz, POCH3), 54.3 (d, 2JC-O-P = 6.7
Hz, POCH3), 84.3 (d, 3JC-O-C-P = 12.8 Hz, CH), 90.9 (d, JC-P = 189.8
Hz, C-P), 121.37, 121.43, 122.7, 126.40, 126.42, 126.7 (ArC),
144.9 (C=C), 145.7 (C=C), 161.8 (C=O), 163.6 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 6.2 Hz, 3 H, CH3),
1.35 (t, J = 6.2 Hz, 6 H, 2 CH3), 1.41 (d, J = 6.2 Hz, 3 H, CH3), 3.19
(dd, J = 6.6 Hz, J = 16.5 Hz, 2 H, 2 CH), 4.85 (sept, 3JP-O-C-H = 6.3
Hz, J = 6.3 Hz, 1 H, CH), 5.12 (sept, 3JP-O-C-H = 6.3 Hz, J = 6.3 Hz,
1 H, CH), 5.93 (s, 1 H, CH), 7.27–7.59 (m, 8 H, ArH), 7.60–7.61
(m, 1 H, ArH).
3
13C NMR (100 MHz, CDCl3): d = 23.4 (d, JC-O-P = 6.1 Hz, CH3),
23.8 (d, 3JC-O-P = 6.1 Hz, CH3), 24.3 (d, 3JC-O-P = 6.1 Hz, CH3), 24.4
3
2
(d, JC-O-P = 6.1 Hz, CH3), 51.1 (d, JC-P = 6.1 Hz, CH), 51.3 (d,
3JC-P = 4.3 Hz, CH), 72.4 (d, 2JC-O-P = 6.7 Hz, CH), 72.7 (d, 2JC-O-P
=
HRMS (EI): m/z [M+] calcd for C16H17O8P: 368.0661; found:
368.0641.
6.7 Hz, CH), 82.6 (d, 3JC-O-C-P = 14.7 Hz, CH), 87.1 (d, JC-P = 189.8
Hz, C-P), 119.9, 121.0, 126.6, 127.98, 128.04, 128.6, 129.1, 131.9,
142.5, 143.0, 144.09, 144.14 (ArC), 172.1 (d, 3JC-P = 2.4 Hz, C=O),
174.3 (C=O).
Dimethyl (3-Phenylisobenzofuran-1-yl)phosphonate (15)
Yellow oil.
Anal. Calcd for C24H26NO6P: C, 63.29; H, 5.75; N, 3.08. Found: C,
63.27; H, 5.82; N, 3.12.
1H NMR (270.5 MHz, CDCl3): d = 3.82 (d, 3JP-O-C-H = 11.5 Hz, 6 H,
2 CH3), 7.06–7.95 (m, 9 H, ArH).
2
13C NMR (100 MHz, CDCl3): d = 53.2 (d, JC-O-P = 5.8 Hz,
Dimethyl [(3aR*,4S*,9S*,9aR*)-2-Methyl-1,3-dioxo-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (11)
POCH3), 119.4, 120.1, 120.2, 125.4, 126.0, 127.6, 128.5, 128.7,
129.0, 129.6, 129.9 (d, JC-P = 129.8 Hz, ArC-P), 130.5, 135.5, 135.8
(ArC).
HRMS (EI): m/z [M+] calcd for C16H15O4P: 302.0709; found:
Colorless crystals (EtOAc); mp 165.4–167.1 °C.
IR (KBr): 2966, 1704 (C=O), 1458, 1437, 1381, 1280, 1257 (P=O),
1127, 1074, 1053 (P-OCH3), 980, 835 cm–1.
302.0703.
1H NMR (270.5 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.87 (dd,
J = 5.6 Hz, J = 8.6 Hz, 1 H, CH), 3.88 (d, 3JP-O-C-H = 10.9 Hz, 3 H,
P-OCH3), 4.07 (dd, 3JP-C-H = 8.6 Hz, J = 8.6 Hz, 1 H, CH), 4.11 (d,
Dimethyl [(3aR*,4S*,9R*,9aR*)-1,3-Dioxo-2,4-diphenyl-
1,2,3,3a,9,9a-hexahydro-4H-4,9-epoxybenzo[f]isoindol-4-
yl]phosphonate (16)
4
3JP-O-C-H = 10.9 Hz, 3 H, P-OCH3), 5.82 (dd, JP-C-O-C-H = 1.3 Hz,
Colorless crystals (EtOAc); mp 222.8–224.9 °C.
J = 5.6 Hz, 1 H, CH), 7.25–7.28 (m, 3 H, ArH), 7.47–7.50 (m, 1 H,
ArH).
IR (KBr): 2961, 1709 (C=O), 1502, 1458, 1387, 1265 (P=O), 1197,
1046 (P-OCH3) cm–1.
13C NMR (67.80 MHz, CDCl3): d = 23.9 (N-CH3), 50.1 (CH), 50.6
(d, 3JC-P = 6.1 Hz, CH), 54.1 (d, 2JC-O-P = 6.1 Hz, P-OCH3), 54.5 (d,
2JC-O-P = 6.1 Hz, P-OCH3), 81.3 (d, 3JC-O-C-P = 15.9 Hz, CH), 85.7 (d,
JC-P = 191.0 Hz, C-P), 121.0, 121.7, 128.4, 139.0, 140.2 (ArC),
172.6 (C=O), 173.5 (C=O).
1H NMR (270.5 MHz, CDCl3): d = 3.79 (d, 3JP-O-C-H = 10.9 Hz, 3 H,
CH3), 4.14 (d, 3JP-O-C-H = 10.9 Hz, 3 H, CH3), 4.16 (d, J = 8.6 Hz, 1
H, CH), 4.48 (dd, 3JP-C-H = 8.9 Hz, J = 8.9 Hz, 1 H, CH), 6.45–6.49
(m, 2 H, o-ArH), 7.02 (m, 1 H, ArH), 7.25–7.62 (m, 9 H, ArH),
7.92–7.95 (m, 2 H, ArH).
Anal. Calcd for C15H16NO6P: C, 53.42; H, 4.78; N, 4.15. Found: C,
53.42; H, 4.71; N, 4.17.
2
13C NMR (67.80 MHz, CDCl3): d = 52.6 (d, JC-P = 6.1 Hz, CH),
3
2
52.9 (d, JC-P = 4.3 Hz, CH), 54.1 (d, JC-O-P = 6.1 Hz, P-OCH3),
54.5 (d, 2JC-O-P = 6.1 Hz, P-OCH3), 86.0 (d, JC-P = 189.8 Hz, C-P),
93.5 (d, 3JC-O-C-P = 15.3 Hz, CH), 121.0, 121.8, 126.2, 127.0, 128.4,
128.5, 128.7, 128.7, 128.78, 128.82, 130.8, 135.1, 139.3, 143.8,
143.9 (ArC), 171.3 (C=O), 172.6 (C=O).
Dimethyl [(3aR*,4S*,9S*,9aR*)-3,3a,9,9a-Tetrahydro-4,9-ep-
oxynaphtho[2,3-c]furan-4(1H)-yl]phosphonate (12)
Colorless crystals (EtOAc); mp 150.1–151.9 °C.
IR (KBr): 2968, 1789 (C=O), 1260 (P=O), 1227, 1080, 1056, 1037
(P-OCH3) cm–1.
Anal. Calcd for C26H22NO6P: C, 65.68; H, 4.66; N, 2.95. Found: C,
65.55; H, 4.74; N, 2.94.
1H NMR (270.5 MHz, CDCl3): d = 3.84 (d, 3JP-O-C-H = 10.7 Hz, 3 H,
CH3), 4.04 (d, 3JP-O-C-H = 10.9 Hz, 3 H, CH3), 4.14 (dd, J = 5.6 Hz,
Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York

4130
K. Yamana et al.
PAPER
(6) (a) Cochran, J. E.; Padwa, A. Tetrahedron Lett. 1995, 36,
3495. (b) Cochran, J. E.; Padwa, A. J. Org. Chem. 1995, 60,
3938.
(7) Haddadin, M. J.; Agha, B. J.; Tabri, R. F. J. Org. Chem.
1979, 44, 494.
Acknowledgment
We thank Dr Horiuchi for IR measurements at National Institute of
Advanced Industrial Science and Technology.
(8) (a) Ruzziconi, R.; Gourves, H. C.; Grouves, J. P.; Corbel, B.
Synlett 2001, 703. (b) Erker, T.; Handler, N. Synthesis 2004,
668.
(9) Yamana, K.; Nakano, H. Tetrahedron Lett. 1996, 37, 5963.
(10) Naito, K.; Rickborn, B. J. Org. Chem. 1980, 45, 4061.
(11) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
415.
References
(1) Haddadin, M. J. Heterocycles 1978, 9, 865.
(2) Smith, J. G.; Dibble, P. W. J. Org. Chem. 1983, 48, 5361.
(3) Thibault, M. E.; Closson, T. L. L.; Manning, S. C.; Dibble,
P. W. J. Org. Chem. 2003, 68, 8373.
(4) Luo, Y.; Herndon, J. W.; Cervantes-Lee, F. J. Am. Chem.
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(5) Ohmura, H.; Mikami, K. Synlett 2002, 1868.
(12) Waszkuc, W.; Janecki, T. Org. Biomol. Chem. 2003, 1,
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Synthesis 2006, No. 24, 4124–4130 © Thieme Stuttgart · New York