Cycloaddition/aromatization sequence for the synthesis of 2,3-disubstituted benzenephosphonates

Article abstract of DOI:10.1055/s-0031-1289757

The [4+2] cycloaddition of diethyl 1-phosphonobuta-1,3-diene with tetracyanoethylene, (E)-1,4-diphenylbut-2-ene-1,4-dione, N-phenylmaleimide, and dialkyl acetylenedicarboxylates is described. For the last two cases, treatment of the cycloadducts with nitrobenzene and a palladium catalyst allows the aromatization. Selective deprotections lead to phthalimide/phthalate derivatives with an ortho-phosphonic acid function. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289757

PAPER
▌1923
paper
Cycloaddition/Aromatization Sequence for the Synthesis of 2,3-Disubstituted
Benzenephosphonates
Synthesis of 2,3-Disubstituted Benzenephosphonates
Elise Villemin, Jacqueline Marchand-Brynaert*
Université catholique de Louvain, Institute of Condensed Matter and Nanosciences (ICMN), Molecules, Solids and Reactivity (MOST),
Bâtiment Lavoisier, Place Louis Pasteur, L4.01.02, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)474168; E-mail: Jacqueline.marchand@uclouvain.be
Received: 13.02.2012; Accepted after revision: 18.03.2012
Our interest in phosphonated molecules13 led us to revisit
Abstract: The [4+2] cycloaddition of diethyl 1-phosphonobuta-
the cycloaddition reactions of diethyl 1- phosphonobuta-
1,3-diene with tetracyanoethylene, (E)-1,4-diphenylbut-2-ene-1,4-
1,3-diene (1) with various dienophiles and activation con-
ditions such as microwave (MW) heating. Using purpose-
dione, N-phenylmaleimide, and dialkyl acetylenedicarboxylates is
described. For the last two cases, treatment of the cycloadducts with
nitrobenzene and a palladium catalyst allows the aromatization. Se- ly functionalized alkenes (alkynes) the resulting
lective deprotections lead to phthalimide/phthalate derivatives with
an ortho-phosphonic acid function.
cyclohexenes (cyclohexadienes) may be precursors of
ortho-functionalized arylphosphonates by elimination or
Key words: cycloaddition, Diels–Alder reaction, phosphorus, bi-
cyclic compounds, carboxylic acids, hydrolysis
dehydrogenation reactions. We report here the scope and
limitation of the cycloaddition/aromatization cascade for
the synthesis of 2,3-substituted 1-phenylphosphonates
and related phosphonic acids.
Arylphosphonates are valuable building blocks in organic
synthesis for various applications in the fields of medici-
nal chemistry,1 polymers,2 and materials science.3 The
usual way to introduce phosphorus on organic skeletons
makes use of the Arbuzov-type chemistry well exempli-
fied in the aliphatic series.4 However, the poor reactivity
of aromatic halides has required the development of
palladium-catalyzed substitution reactions with the phos-
phorus-based nucleophiles.5 The reaction of dialkyl phos-
phites with arenes under oxidative conditions6 and free-
radical phosphonation methods7 have been also reported,
among others. Dedicated methods are applied for the syn-
thesis of ortho-substituted arylphosphonates,8 such as the
ortho-directed metallation followed by quenching with
chlorophosphates9 and the anionic phospho-Fries rear-
rangement.10
Among the traditional noncyclic C=C dienophiles tested
(acrylates, fumarates, nitroalkenes, cyanoalkenes, etc.),
tetracyanoethylene and (E)-1,4- diphenylbut-2-ene-1,4-
dione gave acceptable yields of cycloadducts 2 and 3, re-
spectively (Scheme 1). Compound 3 was a 53:47 mixture
of two diastereoisomers as revealed by the 31P NMR anal-
ysis (endo- and exo-relationships between the P-substitu-
ent and the ortho-benzoyl group; trans-relationship
between the two benzoyl groups). Thus, in this case, the
‘endo rule’ of Diels–Alder (DA) reaction (i.e. [4+2] cy-
cloaddition) is not observed. The ratio of diastereoisomers
does not change during the reaction course, as well as un-
der prolonged heating of the crude product 3.
All attempts to eliminate HCN from the cycloadduct 2
failed to furnish the corresponding aromatic compound or
partially eliminated compound (treatment with potassium
hexamethyldisilazide, or lithium diisobutylamide under
various conditions). Intractable mixtures were recovered.
The cycloadduct 3 was inert under dehydrogenation con-
ditions using palladium or platinum as catalysts; we hy-
pothesize that the good complexing properties11c of the
neighboring P=O and C=O motifs make the catalyst inac-
tive. For the same reason, the reduction of the C=C double
bond of the cycloadducts 2 and 3 by catalytic hydrogena-
tion did not work.
Beside the above strategies using aromatic compounds as
starting materials, the convergent assembly of unsaturated
reagents, one of them bearing a phosphonate substituent,
may be considered as an alternative approach for the syn-
thesis of arylphosphonates. Moreover, to reach the ortho
functionalization, the [4+2] cycloaddition of 1-phospho-
nobuta-1,3-dienes and activated dienophiles stands as the
method of choice for the regioselective construction of
six-membered cores.11
Since the pioneering work of Griffin and Daniewski,12 lit-
tle attention has been paid to the [4+2] cycloaddition of 1-
phosphonobuta-1,3-dienes with C=C dienophiles (i.e., al-
kenes and alkynes with electron-withdrawing substitu-
ents), most probably because the diene dimerization
occurs principally.
Considering a series of cyclic C=C dienophiles (1,4-ben-
zoquinone, naphthalene-1,4-dione, maleic anhydride, ma-
leimides, etc.), N-phenylmaleimide was retained as a good
partner, yielding the cycloadduct 4 in 75% yield (Scheme
2): a single diastereoisomer is formed, corresponding to
the all-cis stereochemistry in agreement with the usual
rules of DA cycloaddition.11c Under rhodium catalysis,
migration of the double bond occurred (several phospho-
rus signals in 31P NMR spectra). The major product 5,
with the double bond forming the cyclic junction, was iso-
lated by column chromatography in modest yield (see the
SYNTHESIS 2012, 44, 1923–1927
Advanced online publication: 26.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289757; Art ID: SS-2012-Z0147-OP
© Georg Thieme Verlag Stuttgart · New York

1924
E. Villemin, J. Marchand-Brynaert
PAPER
PO(OEt)2
CN
PO(OEt)2
CN
PO(OEt)2
PO(OEt)2
CN
CN
CN
NC
NC
CN
CN
1
DCE
6
5
2
3
+
and, or
//
CN
CN
4
140 °C
MW
CN
CN
2 47%
PO(OEt)2
1
PO(OEt)2
PO(OEt)2
PO(OEt)2
+
COPh
COPh
COPh
COPh
1
4
(neat)
6
2
3
and, or
//
5
140 °C
COPh
PhOC
COPh
COPh
1
3 70%
2 diastereoisomers
Scheme 1
Supporting Information). The conjugation of C=C double (Scheme 3). Aromatization as above (Pd/C, PhNO2) led
bond to the phosphonate ester by treatment of 4 with the ortho-phosphonated phthalic esters 10a and 10b (see
Pd(OAc)2, MnO2, and benzoquinone (MeCN, 65 °C)14 the Supporting Information). The phosphonate ester could
was not observed.
be selectively deprotected using the TMSBr–MeOH
method, while the reflux in aqueous HBr deprotected the
carboxylates as well. Thus 2,3-bis(alkoxycarbon-
yl)phenylphosphononic acids 11a, 11b (see the Support-
ing Information) and 3-phosphonophthalic acid (12) are
readily accessible (Scheme 3). Such derivatives 10–12 are
useful as resin modifiers,16 and monomers for the prepara-
tion of polyesters.17
EtO
EtO
O
O
P
P
O
O
EtO
O
EtO
1
Pd/C
(neat)
1
4
6
5
2
3
N
Ph
N
Ph
N
Ph
120 °C
PhNO2
toluene
Δ, 24 h
O
O
O
4 75%
6 ≥ 80%
1. TMSBr
2. MeOH
EtO
1. TMSBr, MW
2. MeOH
O
EtO
EtO
O
RhCl3
1
P
P
CO2R
EtO
(neat)
140 °C
1
CO2R
CO2R
CO2R
CO2R
Pd/C
1
4
2
6
5
2
3
HO
O
HO
O
O
EtO
EtO
O
P
P
(pressure
tube)
P
O
O
HO
PhNO2
toluene
Δ, 24 h
HO
3
CO2R
a R = Me
b R = Et
(excess)
9a 37%
9b 41%
10a 61%
10b 49%
N
Ph
N
Ph
N
Ph
O
O
O
1. TMSBr
2. MeOH
HBr (aq)
reflux
7 quant
5 17%
8 87%
HO
HO
O
O
P
P
Scheme 2
HO
HO
CO2R
CO2R
CO2H
Several methods of aromatization of 4 were tested. 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in re-
fluxing toluene and potassium permanganate supported
on alumina15 in refluxing acetonitrile led to low conver-
sion rates after 24 hours. Palladium on charcoal (0.12
equiv) and nitrobenzene (4.9 equiv) in refluxing toluene
gave the aromatic derivative 6 in high yield after column
chromatography (Scheme 2). Lastly, deprotection of the
diethyl phosphonate under usual conditions, namely sub-
stitution with trimethylsilyl bromide followed by metha-
nolysis,9b yielded the phosphonic acid derivatives 7 (see
the Supporting Information) and 8 (Scheme 2). Similar
phosphonate deprotection performed on the precursors 2
and 3 led to the desired acids along with several unidenti-
fied by-products.
CO2H
12 quant
11a quant
11b 76%
Scheme 3
In conclusion, we have shown that the DA/aromatization
cascade is efficient for the synthesis of ortho-phosphonat-
ed phthalimide and phthalate.
All experiments were performed under argon atmosphere under
magnetic stirring. The chemicals purchased from Acros Organic,
Alfa Aesar, and Sigma-Aldrich were of reagent grade and used
without purification. TLC analyses were performed on aluminum
plates coated with silica gel Merck 60 F-254 and flash column chro-
matography over silica gel (230–400 mesh). Visualization of TLC
plates was performed under UV lamp (254 nm) or using p-anisalde-
hyde and KMnO4. Analytical grade solvents were used for reactions
and solvents for column chromatography were technical solvents
distilled before use. Reactions under microwave heating were con-
ducted in sealed tubes using a MicroSYNTH equipment (Milestone
Dialkyl acetylenedicarboxylates are less reactive than ma-
leimides towards the diene 1. The reaction required the
use of an excess of dienophiles, under pressure, to furnish
the cycloadducts 9a and 9b (see the Supporting Informa-
tion) in moderate yields after column chromatography
Synthesis 2012, 44, 1923–1927
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,3-Disubstituted Benzenephosphonates
1925
Srl). NMR spectra were recorded on a Bruker Avance II 300 spec-
trometer operating at 300 MHz for 1H, 75 MHz for 13C, 121 MHz
for 31P and 282 MHz for 19F, and on a Bruker Avance II 500 spec-
trometer operating at 500 MHz for 1H, 125 MHz for 13C, 202 MHz
for 31P. Chemical shifts are reported in ppm from TMS as the inter-
nal standard (δ = 0.0) for 1H spectra. The internal standard is CDCl3
for the 13C spectra (δ = 77.16). 31P downfield shifts (δ) are ex-
pressed with a positive sign, using 85% H3PO4 in H2O as external
standard. Spectra are reported as follows: chemical shift (δ ppm),
multiplicity (standard abbreviations were used to indicate multiplic-
ities), coupling constants (Hz), assignment, and integration. The
numbering of atoms considered for the assignment of the NMR sig-
nals is indicated on the schemes. Melting points were determined on
a Büchi B-540 apparatus calibrated with caffeine, vanillin and
phenacetin. IR spectra were recorded by transmittance on a Shimadzu
FTIR-8400S equipment and the absorption bands are reported in
cm–1. Products are analyzed as thin films deposited on a Se-Zn crys-
tal by evaporation from CHCl3 solutions. The intensity of peaks is
noted by (w), (m), and (s), respectively, for weak, medium and
strong. Mass spectra (MS) were recorded on a LCQ Finnigan MAT
spectrometer and the masses are reported in Dalton. High-resolution
mass spectrometry analyses (HRMS) were carried out at the
University College London (UK). The syntheses of diene 1 and cy-
cloadduct 4 are reported in references 13c and 11c, respectively.
CH(Ph), 2 H], 7.37 [t, J = 7.9 Hz, CH(Ph), 2 H], 7.06–7.05 [m,
CH(Ph), 2H], 6.07–6.00 (m, H-5 and H-6, 2 H), 4.91 (td,
3
3J2,3 = 3J3,4′ = 11.1 Hz and J3,4 = 6.1 Hz, H-3, 1 H), 4.37 (app q,
3J2,P = 3J2,3 = 3J1,2 = 10.7 Hz, H-2,
1
H), 4.05–3.02 [m,
2
3
PO(OCH2CH3)2, 4 H], 3.32 (dtt, J1,P = 25.8 Hz, J1,2 = 3J1,6 = 5.9
4
2
Hz, and J1,5 = 4J1,3 = 2.2 Hz, H-1, 1 H), 2.63 (dq, J4,4′ = 17.7 Hz,
3J3,4 = 3J4,5 = 5J4,P = 5.8 Hz, H-4, 1 H), 2.16 (dtq, J4,4′ = 18.4 Hz,
2
3J3,4′ = 3J4′,5 = 10.4 Hz, and 4J4′,P = 4J4′,6 = 4J2,4′ = 2.5 Hz, H′-4, 1 H),
3
3
1.18 [t, J = 7.1 Hz, PO(CH2CH3)2, 3 H], 1.18 [t, J = 7.1 Hz,
PO(CH2CH3)2, 3 H].
13 NMR (125 MHz, CDCl3): δ = 204.0 (s, C=O), 199.3 (d, 3J = 3.4
Hz, C=O), 137.5 [s, Cq(Ph)], 136.5 [s, Cq(Ph)], 133.2 [s, CH(Ph)],
133.1 [s, CH(Ph)], 128.7 [s, CH(Ph)], 129.9 (d, 3J5,P = 11.6 Hz, C-
5), 128.6 [s, CH(Ph)], 128.4 [s, CH(Ph)], 121.5 (d, 2J6,P = 9.9 Hz, C-
3
6), 62.3 [d, 2J = 7.3 Hz, PO(OCH2CH3)2], 46.3 (d, J3,P = 12.1 Hz,
2
1
C-3), 45.0 (d, J2,P = 3.0 Hz, C-2), 39.4 (d, J1,P = 140.8 Hz, C-1),
29.5 (d, 4J4,P = 2.5 Hz, C-4), 16.4 [d, 3J = 5.7Hz, PO(OCH2CH3)2],
16.3 [d, 3J = 6.0 Hz, PO(OCH2CH3)2].
31P NMR (121 MHz, CDCl3): δ = 25.69.
Diastereoisomer 2 (Minor)
1H NMR (500 MHz, CDCl3): δ = 8.01 [dd, J = 7.3, 1.2 Hz, CH(Ph),
2 H], 7.77 [dd, J = 7.3, 1.1 Hz, CH(Ph), 2 H], 7.05–7.43 [m,
CH(Ph), 6 H], 6.04–5.98 (m, J = 10.3, 1.9 Hz, H-5, 1 H), 5.89 (ddq,
3J5,6 = 9.8 Hz, 3J6,P = 5.0 Hz, and 3J1,6 = 4J4′,6 = 4J4,6 = 2.5 Hz, H-6, 1
H), 4.34 (m, H-2, 1 H), 4.04–3.92 (m, H-3, 1 H), 3.09–3.08 [m,
PO(OCH2CH3)2, 4 H], 3.30 (dt, 2J1,P = 25.7 Hz and 3J1,2 = 3J1,7 = 2.4
Hz, H-1, 1 H), 2.41 (ddtt, 2J4,4′ = 17.9 Hz, 3J3,4 = 3J4,5 = 4.7 Hz, and
Diethyl 5,5,6,6-Tetracyanocyclohex-2-enylphosphonate (2)
A solution of tetracyanoethylene (0.337 g, 2.63 mmol) and diene 1
(0.500 g, 2.63 mmol) in dichloroethane (5 mL) was stirred in a mi-
crowave oven under 600 W irradiation at 140 °C for 6 h. The reac-
tion mixture was concentrated under vacuum and directly purified
by column chromatography to afford 2 as a brown oil (0.392 g,
47%); Rf = 0.6 (silica gel, EtOAc).
3
4J4,6 = 5J4,P = 1.8 Hz, H-4, 1 H), 2.35 (ddd, J3,4′ = 11.9 Hz,
5
3
3J4′,5 = 7.8 Hz, and J4′,P = 4.2 Hz, H′-4, 1 H), 1.14 [t, J = 7.1 Hz,
PO(CH2CH3)2, 3 H], 0.96 [t, 3J = 7.1 Hz, PO(CH2CH3)2, 3 H].
13
NMR (125 MHz, CDCl3): δ = 203.4 (s, C=O), 202.2 (s, C=O),
IR (film): 2924 (m), 2870 (w), 2203 (w, CN), 1635 (w), 1445 (m),
1253 (m, P=O), 1163 (m), 1018 (s, P–O), 760 cm−1 (w).
136.4 [s, Cq(Ph)], 136.1 [s, Cq(Ph)], 133.4 [s, CH(Ph)], 133.1 [s,
CH(Ph)], 130.0 [s, CH(Ph)], 128.7 [s, CH(Ph)], 128.5 [s, CH(Ph)],
1H NMR (500 MHz, CDCl3): δ = 6.06–6.00 (m, H-5 and H-6, 2 H),
4.36–4.24 [m, PO(OCH2CH3)2, 4 H], 3.54 (dd, 1J1,P = 27.2 Hz and
3J1,6 = 2.4 Hz, H-1, 1 H), 3.20–3.19 (m, H-4, 2 H), 1.45 [t, 3J = 6.9
Hz, PO(OCH2CH3)2, 3 H], 1.42 [t, 3J = 6.9 Hz, PO(OCH2CH3)2, 3
H].
3
128.2 [s, CH(Ph)], 128.0 (d, J5,P = 11.9 Hz, H-5), 121.8 (d,
2J6,P = 8.8 Hz, H-6), 62.2 [d, 2J = 7.6 Hz, PO(OCH2CH3)2], 62.1 [d,
2J = 6.8 Hz, PO(OCH2CH3)2], 42.0 (s, C-2), 38.8 (s, C-3), 38.2 (d,
1J1,P = 139.1 Hz, C-1), 30.1 (d, 4J4,P = 3.1 Hz, C-4), 16.2 [d, 3J = 6.0
Hz, PO(OCH2CH3)2], 15.9 [d, 3J = 6.1 Hz, PO(OCH2CH3)2].
3
13C NMR (125 MHz, CDCl3): δ = 122.2 (d, J5,P = 10.4 Hz, C-5),
31P NMR (121 MHz, CDCl3): δ = 27.85.
120.2 (d, 2J6,P = 7.1 Hz, C-6), 110.8 (d, 3J = 5.7 Hz, CN), 110.1 (s,
CN), 108.6 (d, 3J = 4.9 Hz, CN) 64.9 [d, 2J = 6.9 Hz,
HRMS (ESI, positive mode): m/z (%) calcd for C24H28O5P [M + H]:
427.16689; found: 427.16696 (100); [M + H + H2O]: 445.12009
(72); [M + Na]: 449.14983 (12); [M – PO(OEt)2 – H – H2O]:
271.11179 (55).
2
PO(OCH2CH3)2], 64.7 [d, J = 7.0 Hz, PO(OCH2CH3)2], 40.7 (d,
3
1J1,P = 145.2 Hz, C-1), 39.8 (d, J3,P = 11.8 Hz, C-3), 39.1 (d,
2J2,P = 5.0 Hz, C-2), 32.0 (s, C-4), 16.3 [d, 3J = 5.7 Hz,
PO(OCH2CH3)2].
Diethyl 1,3-Dioxo-2-phenylisoindolin-4-yl-4-phosphonate (6)
A solution of 4 (83.7 mg, 0.230 mmol), nitrobenzene (116 μL, 139
mg, 1.128 mmol), and Pd/C (10 mol%, 54 mg, 0.028 mmol) in an-
hyd toluene (4.5 mL) was stirred under reflux for at least 24 h. The
reaction mixture was filtered through a Celite pad, rinsed with a so-
lution of CH2Cl2–MeOH (1:1, 6 mL) and concentrated under re-
duced pressure. The residue was purified by column
chromatography to give 6 as a brown oil (66.1 mg, 80%); Rf = 0.5
(silica gel, EtOAc–cyclohexane, 8:2) .
31P NMR (121 MHz, CDCl3): δ = 15.4.
MS (APCI): m/z (%) = 318.82 (42, [M + H]), 290.96 (36, [M –
CH2=CH2]), 264.13 (11, [M + H – 2 CH2=CH2]), 263.09 (100, [M
– 2 CH2=CH2]).
HRMS (EI): m/z calcd for C14H15N4O3P [M]: 318.08763; found:
318.08786 (100%).
Diethyl 5,6-(Dibenzoyl)cyclohex-2-en-1-ylphosphonate (3)
A neat mixture of diene 1 (0.300 g, 1.577 mmol) and (E)-1,4-diphe-
nylbut-2-ene-1,4-dione (0.372 g, 1.577 mmol) was stirred at 120 °C
for 7 h. The oily mixture was directly purified by column chroma-
tography to afford 3 as a brown oil (0.470 g, 70%).
IR (film): 1782 (s, C=O), 1722 (s, C=O), 1597 (m), 1502 (s), 1443
(w), 1383 (s), 1244 (s, P=O), 1169 (s), 1115 (s, P–O), 959 (s), 951
(s, P–O), 941 (w) 788 (s), 756 (s), 733 cm−1 (s).
3
1H NMR (500 MHz, CDCl3): δ = 8.35 (dd, J6,P = 13.0 Hz and
IR (film): 2978 (w), 1672 (s, C=O), 1597 (m, CH=CH), 1578 (m,
C=CPh), 1580 (m, C=CPh), 1447 (s, C=CPh), 1391 (m), 1248 (s,
P=O), 1207 (m), 1020 (s, P–O), 950 (s, P–O), 912 (s), 781 (s), 696
cm−1 (s).
3J5,6 = 7.7 Hz, H-6, 1 H), 8.13 (d, 3J4,5 = 7.5 Hz, H-4, 1 H), 7.87 (td,
4
3J4,5 = 3J5,6 = 7.6 Hz and J5,P = 2.7 Hz, H-5, 1 H), 7.51 [app t,
3
3
3J = 7.7 Hz and J = 7.6 Hz, CH(Ph), 2 H], 7.46 [d, J = 7.7 Hz,
3
CH(Ph), 2 H], 7.41 [t, J = 7.3 Hz, CH(Ph), 1 H], 4.38–4.27 [m,
PO(OCH2CH3)2, 4 H], 1.38 [(t, 3J = 7.1 Hz, PO(OCH2CH3)2, 6 H].
Diastereoisomer 1 (Major)
Rf = 0.4 (silica gel, EtOAc).
1H NMR (500 MHz, CDCl3): δ = 8.09 [dd, J = 7.2, 1.3 Hz, CH(Ph),
2 H], 7.97 [dd, J = 7.3, 1.2 Hz, CH(Ph), 2 H], 7.40 [t, J = 7.8 Hz,
13C NMR (125 MHz, CDCl3): δ = 166.5 (s, C=O), 165.1 (d, 3J = 4.2
Hz, C=O), 139.4 (d, 2J6,P = 9.0 Hz, C-6), 133.9 (d, 3J5,P = 12.6 Hz,
C-5), 133.2 (d, 2J2,P = 11.7 Hz, C-2), 133.1 (d, 3J3,P = 7.9 Hz, C-3),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1923–1927

1926
E. Villemin, J. Marchand-Brynaert
PAPER
131.5 [s, Cq(Ph)], 129.2 [s, CH(Ph)], 128.3 [s, CH(Ph)],127.4 (d,
Dimethyl 3-(Diethoxyphosphoryl)phthalate (10a)
4
1J1,P = 192.0 Hz, C-1), 127.1 (d, J4,P = 2.8 Hz, C-4), 126.7 [s,
A solution of 9a (102 mg, 0.31 mmol), nitrobenzene (154 μL, 184
mg, 1.50 mmol), Pd/C (73 mg, 0.04 mmol) in anhyd toluene (6.0
mL) was stirred under reflux at least for 24 h. The reaction mixture
was filtered through a Celite pad, rinsed with a solution of CH2Cl2–
MeOH (1:1, 8 mL) and concentrated under reduced pressure. The
reaction mixture was purified by column chromatography to give
10a as a yellow oil (62 mg, 61%); Rf = 0.6 (silica gel, EtOAc).
3
3
CH(Ph)], 63.4 [d, J = 6.2 Hz, PO(OCH2CH3)2], 16.5 [d, J = 6.3
Hz, PO(OCH2CH3)2].
31P NMR (202 MHz, CDCl3): δ = 12.14.
HRMS (MALDI TOF, positive mode): m/z (%) calcd for
C18H18NO5P + Na [M + Na]: 382.0820; found: 382.0819 (47); [M +
H]: 360.1006 (27); [M + H – CH2=CH2]: 332.0667 (34); [M + H –
2 CH2=CH2]: 304.0323 (100); [M + H – H2O – 2 CH2=CH2]:
286.0284 (34).
IR (film): 2988 (w), 1732 (s, C=O), 1580 (w, C=C), 1475 (w, C=C),
1447 (m, C=C), 1392 (m), 1278 (s, P=O), 1215 (w), 1140 (s), 1117
(s), 1018 (s, P–O), 964 (s, P–O), 752 (s), 655 cm−1 (s).
1H NMR (500 MHz, CDCl3): δ = 8.19 (d, 3J4,5 = 7.9 Hz, H-4, 1 H),
1,3-Dioxo-2-phenylisoindolin-4-yl-4-phosphonic Acid (8)
A solution of 6 (81.5 mg, 0.227 mmol), Me3SiBr (93 μL, 107.7 mg,
0.704 mmol), and anhyd MeCN (4 mL) was stirred in a microwave
oven under 500 W irradiation at 70 °C for 2 h. The by-product EtBr,
the excess of Me3SiBr, and the solvent were evaporated under re-
duced pressure. The reaction mixture was then hydrolyzed with an
excess of MeOH (7 mL) at r.t. during 1 h. The solvent was evapo-
rated to afford a brown oil (59.7 mg, 87%).
8.13 (ddd, 3J6,P = 13.3 Hz, 3J5,6 = 7.7 Hz, and 4J4,6 = 1.1 Hz, H-6, 1
3
4
H), 7.60 (td, J2,3 = 3J4,5 = 7.8 Hz and J5,P = 3.4 Hz, H-5, 1 H),
4.23–4.14 [m, PO(OCH2CH3)2,
2
H], 4.13–4.05 [m,
PO(OCH2CH3)2, 2 H], 3.98 (s, CO2CH3, 3 H), 3.91 (s, CO2CH3, 3
H), 1,34 [t, 3J = 7.1 Hz, PO(OCH2CH3)2, 6 H].
4
13C NMR (125 MHz, CDCl3): δ = 168.2 (d, J = 5.5 Hz, C=O),
166.9 (d, 3J = 2.4 Hz, C=O), 138.7 (d, 2J2,P = 11.1 Hz, C-2), 137.4
2
4
IR (film): 3672–3013 (large band, s, OH), 1778 (m, C=O), 1693 (s,
C=O), 1595 (m), 1502 (m), 1456 (w), 1385 (s), 1255 (m), 1175 (s),
1115 (s, P=O), 1011 (s, P–O), 947 (s, P–O), 869 (s) 825 (s), 756 (s),
739 (s), 710 cm−1 (s).
(d, J6,P = 8.0 Hz, C-6), 133.9 (d, J4,P = 2.3 Hz, C-4), 129.1 (d,
3J5,P = 13.8 Hz, C-5), 128.7 (d, J3,P = 13.5 Hz, C-3), 127.4 (d,
3
1J1,P = 184.6 Hz, C-1), 62.7 [d, 2J = 5.3 Hz, PO(OCH2CH3)2], 52.9
(s, CO2CH3), 52.8 (s, CO2CH3), 16.2 [d, 3J = 6.5 Hz,
PO(OCH2CH3)2].
3
1H NMR (500 MHz, MeOD): δ = 8.27 (dd, J6,P = 12.7 Hz and
3J5,6 = 7.7 Hz, H-6, 1 H), 8.10 (d, 3J4,5 = 7.5 Hz, H-4, 1 H), 7.94 (td,
3J5,6 = 3J4,5 = 7.6 Hz and 4J5,P = 2.2 Hz, H-5, 1 H), 7.50 [t, 3J = 7.7
31P NMR (202 MHz, CDCl3): δ = 15.06.
HRMS (MALDI-TOF, positive mode): m/z calcd for C14H19O7P +
Na [M + Na]: 353.0766; found: 353.0752 (100%).
3
Hz, CH(Ph), 2 H], 7.45 [d, J = 7.6 Hz, CH(Ph), 2 H], 7.41 [t,
3J = 7.3 Hz, CH(Ph), 1 H].
13C NMR (125 MHz, MeOD): δ = 167.9 (s, C=O), 167.6 (d, 3J = 3.4
Hz, C=O), 139.0 (d, 2J6,P = 8.1 Hz, C-6), 135.4 (d, 3J5,P = 11.9 Hz,
C-5), 134.1 (d, 3J3,P = 11.7 Hz, C-3), 133.7 (d, 2J2,P = 8.6 Hz, C-2),
133.1 [s, Cq(Ph)], 131.09 (d, J1,P = 184.5 Hz, C-1), 130.0 [s,
CH(Ph)], 129.3 [s, CH(Ph)], 128.2 [s, CH(Ph)], 127.3 (s, C-4).
2,3-Bis(methoxycarbonyl)phenylphosphonic Acid (11a)
A solution of 10a (61.5 mg, 0.19 mmol), Me3SiBr (76 μL, 88.4 mg,
0.58 mmol), and anhyd MeCN (1.8 mL) was stirred at reflux. The
by-product EtBr, the excess of Me3SiBr, and the solvent are evapo-
rated under reduced pressure. The reaction mixture was then hydro-
lyzed with an excess of MeOH (8 mL) at r.t. during 1 h. The solvent
was evaporated to afford 11a as an orange oil (50.4 mg, quant).
1
31P NMR (202 MHz, MeOD): δ = 10.00.
HRMS (MALDI-TOF, positive mode): m/z (%) calcd for
C14H11NO5P [M + H]: 304.0375; found: 304.0376 (100); [M + H +
H2O]: 286.0277 (69).
IR (film): 3600–3100 (large band, m, OH), 2923 (m), 1771 (m,
C=O), 1715 (s, C=O), 1580 (w, C=C), 1454 (m, C=C), 1286 (s),
1142 (m, P=O), 1119 (m), 1013 (s, P–O), 927 (m, P–O), 768 (m),
698 cm−1 (w).
Dimethyl 3-(Diethoxyphosphoryl)cyclohexa-1,4-diene-1,2-di-
carboxylate (9a)
3
1H NMR (500 MHz, MeOD): δ = 8.12 (app q, J4,5
=
3J5,6 = 3J5,P = 6.9 Hz, H-6 and H-4, 2 H), 7.65 (td, 3J5,6 = 3J4,5 = 7.7
Hz and J5,P = 2.8 Hz, H-5, 1 H), 3.90 (d, J = 0.4 Hz, CO2CH3, 3
A neat mixture of diene 1 (310 mg, 1.63 mmol) and dimethyl acet-
ylenedicarboxylate (601 μL, 695 mg, 4.89 mmol) was vigorously
stirred at 120 °C in a pressure tube overnight. The reaction mixture
was directly purified by column chromatography to afford 9a as a
yellow oil (198 mg, 37%); Rf = 0.3 (silica gel, EtOAc).
4
6
H), 3.88 (d, 5J = 0.4 Hz, CO2CH3, 3 H).
3
13C NMR (125 MHz, MeOD): δ = 170.4 (d, J = 5.3 Hz, C=O),
167.1 (s, C=O), 138.9 (d, 2J2,P = 10.7 Hz, C-2), 137.5 (d, 2J6,P = 8.3
Hz, C-6), 134.0 (d, 4J4,P = 2.0 Hz, C-4), 132.2 (d, 1J1,P = 183.2 Hz,
C-1), 130.4 (d, 3J5,P = 13.6 Hz, C-5), 130.0 (d, 3J3,P = 13.1 Hz, C-3),
53.4 (s, CO2CH3), 53.2 (s, CO2CH3).
IR (film): 2986 (m), 1722 (s, C=O), 1715 (s, C=O), 1674 (s, C=C),
1637 (m, CH=CH), 1470 (m), 1445 (m), 1391 (m), 1367 (m), 1246
(s, P=O), 1022 (s, P–O), 957 (s, P–O), 747 cm−1 (s).
1H NMR (500 MHz, CDCl3): δ = 5.98–5.92 (m, H-5, 1 H), 5.92–
5.86 (m, H-6, 1 H), 4.15–4.05 [m, PO(OCH2CH3)2, 4 H], 4.05–3.92
(m, 1J1,P = 30.7 Hz, H-1, 1 H), 3.15 (dddt, J = 30.4 Hz, 2J4,4′ = 22.4
31P NMR (202 MHz, MeOD): δ = 12.07.
HRMS (CI, methane gas): m/z (%) calcd for C10H12O7P [M + H]:
275.03206; found: 275.03266 (16); [M – H2O]: 257 (11); [M –
MeOH]: 243 (100); [M – MeOH – H2O]: 225 (11); [M – 2 MeOH]:
211 (11).
3
4
Hz, J4,5 = 6.2 Hz, and J4,6 = 4J = 2.4 Hz, H′-4, 1 H), 2.93 (ddt,
2J4,4′ = 21.8 Hz, J4,5 = 16.4 Hz, and J4′,P = 2J4,6′ = 4.5 Hz, H′-4, 1
3
5
H), 1,29 [t, 3J = 7.0 Hz, PO(OCH2CH3)2, 6 H].
3
13C NMR (125 MHz, CDCl3): δ = 168.0 (d, J = 3.8 Hz, C=O),
3-Phosphonophthalic Acid (12)
166.7 (d, 4J = 2.5 Hz, C=O), 136.0 (d, 3J3,P = 10.8 Hz, C-3), 128.7
A solution of aromatic cycloadduct 10b (96.9 mg, 0.29 mmol) and
aq 48% HBr (6 mL, large excess) was stirred overnight at reflux.
The excess of HBr was evaporated under reduced pressure (bath
temp: 90 °C) to afford 12 as a brown oil (71.4 mg, quant).
2
3
(d, J2,P = 9.9 Hz, C-2), 125.5 (d, J5,P = 11.0 Hz, C-5), 120.5 (d,
2J6,P = 10.8 Hz, C-6), 62.9 [d, 2J = 7.3 Hz, PO(OCH2CH3)2], 62.7 [d,
2J = 6.9 Hz, PO(OCH2CH3)2], 52.2 (s, 2 × OCH3), 39.1 (d,
1J1,P = 138.6 Hz, C-1), 28.3 (d, 4J4,P = 6.7 Hz, C-4), 16.3 (d, 3J = 5.7
Hz, PO(OCH2CH3)2] 16.2 [d, 3J = 6.0 Hz, PO(OCH2CH3)2].
IR (film): 3686–2737 (large band, s, OH), 1697 (s, C=O), 1637 (s,
C=O), 1455 (w, C=C), 1400 (m), 1286 (m, P=O), 1155 (m, P–O),
1004 (m), 941 (w) 770 cm−1 (w).
31P NMR (202 MHz, CDCl3): δ = 22.14.
3
HRMS (MALDI-TOF, positive mode): m/z calcd for C14H21O7P +
Na [M + Na]: 355.0923; found: 355.0925 (100%).
1H NMR (500 MHz, D2O): δ = 8.07 (d, J4,5 = 7.8 Hz, H-4, 1 H),
3
3
8.01 (dd, J6,P = 13.5 Hz and J5,6 = 7.7 Hz, H-6, 1 H), 7.58 (td,
3J5,6 = 3J4,5 = 7.8 Hz and 4J5,P = 2.8 Hz, H-5, 1 H).
Synthesis 2012, 44, 1923–1927
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,3-Disubstituted Benzenephosphonates
1927
13C NMR (125 MHz, D2O): δ = 173.0 (d, 3J = 5.3 Hz, C=O), 168.8
(d) Zakeeruddin, S. M.; Nazeeruddin, M. K.; Pechy, P.;
Rotzinger, F. P.; Humphry-Baker, R.; Kalyanasundaram, K.;
Grätzel, M.; Shklover, V.; Haibach, T. Inorg. Chem. 1997,
36, 5937.
4
2
(d, J = 2.3 Hz, C=O), 136.9 (d, J2,P = 10.7 Hz, C-2), 136.6 (d,
4
2J6,P = 8.7 Hz, C-6), 133.5 (d, J4,P = 2.4 Hz, C-4), 129.9 (d,
1
3J5,P = 13.5 Hz, C-5), 130.0 (d, J1,P = 179.7 Hz, C-1), 128.0 (d,
3J3,P = 12.8 Hz, C-3).
(4) Bhattachary, A. K.; Thyarajan, G. Chem. Rev. 1981, 81, 415.
(5) (a) Prim, D.; Campagne, J.-M.; Joseph, D.; Andriolettti, B.
Tetrahedron 2002, 58, 2041. (b) Kohler, M. C.; Sokol, J. G.;
Stockland, R. A. Jr. Tetrahedron Lett. 2009, 50, 457.
(c) Goosen, L. J.; Dezfuli, M. K. Synlett 2005, 445.
(6) Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y. Org.
Lett. 2006, 8, 407.
31P NMR (202 MHz, D2O): δ = 11.64.
HRMS (MALDI-TOF, positive mode): m/z (%) calcd for C8H7O7P
+ Na: [M + Na]: 268.9827; found: 268.9840 (100); [M + H]:
246.0730 (15).
(7) Jiao, X.-Y.; Bentrude, W. G. J. Org. Chem. 2003, 68, 3303.
(8) Defacqz, N.; de Bueger, B.; Touillaux, R.; Cordi, A.;
Marchand-Brynaert, J. Synthesis 1999, 1368.
(9) (a) Bruyneel, F.; D’Auria, L.; Payen, O.; Courtoy, P. J.;
Marchand-Brynaert, J. ChemBioChem 2010, 11, 1451.
(b) Lagadic, E.; Garcia, Y.; Marchand-Brynaert, J. Synthesis
2012, 44, 93.
Acknowledgment
This work was supported by the Fonds de la Recherche Scientifique
(F.R.S. – FNRS, Belgium), and the Université catholique de Lou-
vain through the ARC program (Action de Recherche Concertée)
number 08/13-009.
(10) (a) Jayasundera, K. P.; Watson, A. J.; Taylor, C. M.
Tetrahedron Lett. 2005, 46, 4311. (b) Taylor, C. M.;
Watson, A. J. Curr. Org. Chem. 2004, 8, 623.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental protocols and spectroscopic analyses of com-
(11) (a) Monbaliu, J.-C.; Villemin, E.; Elias, B.; Marchand-
Brynaert, J. In Targets in Heterocyclic Systems, Vol. 14;
Attanasi, O. A.; Spinelli, D., Eds.; Springer: Berlin, 2010,
49. (b) Monbaliu, J.-C.; Tinant, B.; Marchand-Brynaert, J.
J. Org. Chem. 2010, 75, 5478. (c) Villemin, E.; Elias, B.;
Robiette, R.; Robeyns, K.; Herent, M.-F.; Habib-Jiwan,
J.-L.; Marchand-Brynaert, J. Tetrahedron Lett. 2011, 52,
5140.
pounds 1, 5, 7, 9b, 10b, 11b.onmionfrtIangiomnSiounrpfotIan
riSutpor
g
References
(1) (a) Nagarajan, R.; Pratt, R. F. Biochemistry 2004, 43, 9664.
(b) Stankovic, C. J.; Surendran, N.; Lunney, E. A.; Plummer,
M. S.; Para, K. S.; Shahripour, A. S.; Fergus, J. H.; Marks, J.
S.; Herrera, R.; Hubbell, S. E.; Humblet, C.; Saltiel, A. R.;
Stewart, B. H.; Sawyer, T. K. Bioorg. Med. Chem. Lett.
1997, 14, 1909. (c) Ma, D.; Zhu, W. J. Org. Chem. 2001, 66,
348. (d) Thurieau, C.; Simonet, S.; Paladino, J.; Prost, J.-F.;
Verbeuren, T.; Fauchère, J.-L. J. Med. Chem. 1994, 37, 625.
(2) (a) Bock, T.; Moehwald, H.; Muelhaupt, R. Macromol.
Chem. Phys. 2007, 208, 1324. (b) Consiglio, G. A.; Failla,
S.; Finocchiaro, P.; Siracusa, V. Phosphorus, Sulfur Silicon
Relat. Elem. 2002, 177, 2561. (c) Onouchi, H.; Miyagawa,
T.; Furuko, A.; Maeda, K.; Yashima, E. J. Am. Chem. Soc.
2005, 127, 2960. (d) Allcock, H. R.; Hofmann, M. A.;
Ambler, C. M.; Morford, R. V. Macromolecules 2002, 35,
3484.
(12) Griffin, C. E.; Daniewski, W. M. J. Org. Chem. 1970, 35,
1691.
(13) (a) Monbaliu, J.-C.; Cukalovic, A.; Marchand-Brynaert, J.;
Stevens, C. V. Tetrahedron Lett. 2010, 51, 5830.
(b) Monbaliu, J.-C.; Tinant, B.; Peeters, D.; Marchand-
Brynaert, J. Tetrahedron Lett. 2010, 51, 1052. (c) Monbaliu,
J.-C.; Marchand-Brynaert, J. Synthesis 2009, 1876.
(14) Principato, B.; Maffei, M.; Siv, C.; Buono, G.; Peiffer, G.
Tetrahedron 1996, 52, 2087.
(15) Vanden, Eyden. J.-J.; D’Orazio, R.; Van Haverbeke, Y.
Tetrahedron 1994, 50, 2479.
(16) Suzuki, H.; Nomura, M.; Tokunaga, K.; Hashiba, I. (Nissan
Chem. Ind. Ltd.) US Patent 5880309A1, 1999; Chem. Abstr.
1998, 129, 149095.
(3) (a) Chandrasekhar, V.; Sasikumar, P.; Senapati, T.; Dey, A.
Inorg. Chim. Acta 2010, 363, 2920. (b) Ouellett, W.; Wang,
G.; Liu, X.; Yee, G. T.; O’Connor, C. J.; Zubieta, J. Inorg.
Chem. 2009, 48, 953. (c) Latham, K.; Coyle, A. M.; Rix, C.
J.; Fowless, A.; White, J. M. Polyhedron 2007, 26, 222.
(17) Odorisio, P.; Andrews, S.; Thompson, T. F.; Wu, S.; Thanki,
P.; Rane, D. M.; Joseph, D.; Wang, J. (Ciba Corp.) WO
2009121796 A1, 2009; Chem. Abstr. 2009, 151, 426211.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1923–1927