Regioselective Synthesis of Highly Functionalized Arylphosphonates by Cyclocondensation of 1,3-Bis(trimethylsilyloxy)buta-1,3-dienes with 3-Ethoxy-2-phosphonylalk-2-en-1-ones

Article abstract of DOI:10.1055/s-0029-1219950

Highly functionalized arylphosphonates were prepared by TiCl ₄-mediated cyclocondensation of 3-ethoxy-2-phosphonylalk-2-en-1-ones with 1,3-bis(trimethylsilyloxy)buta-1,3-dienes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219950

LETTER
1525
Regioselective Synthesis of Highly Functionalized Arylphosphonates by
Cyclocondensation of 1,3-Bis(trimethylsilyloxy)buta-1,3-dienes with
3-Ethoxy-2-phosphonylalk-2-en-1-ones
S
ynthesis of
Highl
l
y Funct
u
ionalized
A
r
ylphosphonates ide Fatunsin,a Mohanad Shkoor,a Abdolmajid Riahi,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Received 12 February 2010
ly been studied so far.8a,9 Only one isolated example of a
cyclocondensation, that is, the reaction of 3-ethoxy-2-(di-
ethoxyphosphonyl)-1-phenylprop-2-en-1-one with hydra-
zine and hydroxylamine, has been reported.8a In recent
years, we have studied the synthesis of arenes by titani-
um(IV) chloride mediated [3+3] cyclizations10 of 1,3-
bis(trimethylsilyloxy)buta-1,3-dienes.11 Herein, we report
what is, to the best of our knowledge, the first application
of this methodology to the synthesis of arylphosphonates.
The cyclocondensation of aliphatic and aromatic 3-
ethoxy-2-phosphonylalk-2-en-1-ones with 1,3-bis(silyl-
oxy)buta-1,3-dienes provides a convenient approach to
highly functionalized arylphosphonates. These products,
which have not been prepared so far, are not readily avail-
able by other methods.
Abstract: Highly functionalized arylphosphonates were prepared
by TiCl4-mediated cyclocondensation of 3-ethoxy-2-phosphonyl-
alk-2-en-1-ones with 1,3-bis(trimethylsilyloxy)buta-1,3-dienes.
Key words: cyclizations, regioselectivity, phosphonic acid deriva-
tives, silyl enol ethers
Arylphosphonates are important core and lead structures
in medicinal chemistry,1 flame protection,2 and polymer
chemistry.3 In addition, arylphosphonic acid derivatives
play an important role as synthetic intermediates in organ-
ic chemistry.4 Classic syntheses of arylphosphonates in-
clude, for example, the Friedel–Crafts reaction of
phosphoric acid derivatives with aromatics,5a the copper-
catalyzed reaction of phosphorus trichloride with diazoni-
um salts,5b,c the nucleophilic aromatic substitution of sodi-
um dialkylphosphites with electron-poor aryl halides,5d
the nickel(II)- or copper(II)-mediated reaction of trialkyl
phosphates with aryl halides,5e–i and the reaction of tri-
alkyl phosphites with aromatic Grignard or organolithium
compounds.5j–l A more recent approach to arylphospho-
nates relies on the palladium-catalyzed reaction of dialkyl
phosphates with aryl halides.6,7 Despite the great useful-
ness of all these methods for the formation of carbon–
phosphorus bonds, they are generally limited by the fact
that more complex starting materials, highly functional-
ized and substituted aryl halides, are not readily available.
In fact, the halogenation and functionalization by aromat-
ic electrophilic substitution reactions is often limited by
their low ortho/para regioselectivity and other side reac-
tions. In fact, most of the C–P bond-forming reactions
outlined above have been carried out using simple, steri-
cally unhindered, and commercially available substrates.
Vinylphosphonates 2a12,9 and 2b13,8a are available by reac-
tion of b-ketophosphonates 1a,b with triethyl orthoformi-
ate (Scheme 1). 1,3-Bis(silyloxy)buta-1,3-dienes 3a–k
are prepared in two steps from the corresponding b-keto
esters.14–16
O
OEt
O
R
HC(OEt)3
i
R
P
O
OEt
OEt
P
O
OEt
OEt
1a,b
2a (R = Me, 86%)
2b (R = Ph, 74%)
Scheme 1 Synthesis of 2a,b. Reagents and conditions for com-
pound 2a: 1a (1.0 equiv), HC(OEt)3 (1.2 equiv), Ac2O, reflux, 4 h.
Reagents and conditions for 2b: 1b (1.8 equiv) HC(OEt)3, (2.8 equiv)
Ac2O, reflux, 36 h, then column chromatography; products 2a,b were
isolated as mixtures of E/Z isomers
An alternative approach to more complex carba- and het-
erocyclic phosphonates relies on cyclocondensation reac-
tions of suitable phosphonate-containing building blocks.
Kouno and coworkers developed a versatile methodology
based on the reaction of lithiated vinylphosphonates with
electrophiles.8 3-Alkoxy-2-phosphonylalk-2-en-1-ones
represent interesting dielectrophilic building blocks.
However, reactions of these compounds have only scarce-
The TiCl4-mediated cyclization of vinylphosphonates
2a,b with dienes 3a–k afforded the novel arylphospho-
nates 4a–l (Scheme 2, Table 1).17,18 During the optimiza-
tion it proved to be important to carry out the reaction in a
highly concentrated solution (2 mL/1.0 mmol of 2a,b).
The cyclization can be explained by TiCl4-mediated con-
jugate addition of the terminal carbon atom of the diene to
the enone, cyclization by attack of the central carbon atom
of the diene to the carbonyl group, and subsequent arom-
atization (before or during the aqueous workup using 10%
HCl). The constitution of the products was proved by 2D
NMR studies (HMBC, NOESY, analysis of P–C and P–H
SYNLETT 2010, No. 10, pp 1525–1527
x
x
.x
x
.2
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1
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Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1219950; Art ID: D04210ST
© Georg Thieme Verlag Stuttgart · New York

1526
O. Fatunsin et al.
LETTER
coupling constants). All reactions proceeded with excel- methods. The scope and synthetic applications of this
lent regioselectivity. In all products the substituent R3 is methodology are currently studied in our laboratory.
located ortho to the ester group. The formation of the oth-
er regioisomer, containing the substituent R3 located para
Acknowledgment
to the ester group, was not observed. The moderate yields
Financial support by the State of Mecklenburg-Vorpommern (scho-
larship for M.S.) is gratefully acknowledged.
of the products can be explained by loss of material during
the chromatography. In addition, the yields are decreased
by some hydrolysis and TiCl4-mediated oxidative dimer-
ization of the diene and by decomposition. Similar yields
were obtained for reactions of methyl and phenyl substi-
tuted vinylphosphonates 2a and 2b.
References and Notes
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OSiMe3
OR1
Me3SiO
R2
O
OH
R2
OR1
3a–k
i
+
R3
OEt
OEt
O
P
O
R3
OEt
OEt
P
4a–l
O
OEt
2a,b
Scheme 2 Synthesis of 4a–l. Reagents and conditions: i, 1) 2a,b
(1.0 equiv), 3a–k (1.1 equiv), TiCl4 (1.1 equiv), CH2Cl2, –78 °C to
20 °C, 12 h; 2) HCl (H2O, 10%).
Table 1 Synthesis of 4a–l
2
a
a
a
a
b
b
b
b
b
b
b
b
3
a
b
c
d
e
b
f
4
a
b
c
d
e
f
R1
R2
R3
Yield of 4 (%)a
Me
Et
H
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
48
52
54
58
56
51
53
57
58
55
54
47
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n-Hex
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Et
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g
h
i
Me
Me
Et
n-Pr
n-Bu
n-Hex
n-Hept
n-Dec
i-Pr
g
h
i
j
Et
j
k
l
Et
k
Et
a Yield of isolated products.
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(k) Edmundson, R. S.; Wrigley, J. O. L. Tetrahedron 1967,
In conclusion, we have reported an efficient synthesis of
highly functionalized arylphosphonates by cycloconden-
sation of 3-ethoxy-2-phosphonylalk-2-en-1-ones with
1,3-bis(trimethylsilyloxy)buta-1,3-dienes. These trans-
formations represent a rare example for the synthesis of
arylphosphonates based on the application of a building
block approach. Reactions of 3-alkoxy-2-phosphonylalk-
2-en-1-ones have only scarcely been reported to date. The
products reported herein are not readily available by other
Synlett 2010, No. 10, 1525–1527 © Thieme Stuttgart · New York

LETTER
23, 283. (l) Freeman, S.; Harger, M. J. J. Chem. Soc., Perkin
Synthesis of Highly Functionalized Arylphosphonates
1527
7.48 (m, 5 H, CHAr), 7.80–7.82 (m, 1 H, CH). 31P NMR (250
MHz, CDCl3): d = 16.25 Hz. 13C NMR (75 MHz, CDCl3):
d = 15.1, 16.1, 16.2 (CH3), 62.3, 62.4, 71.4 (OCH2), 106.4
(d, JP,C = 189.3 Hz), 128.2 (2 × CHAr), 129.3 (2 × CHAr),
133.0 (CHAr), 137.6 (d, JP,C = 4.3 Hz), 163.5 (d, JP,C = 21.0
Hz, CH), 192.2 (d, JP,C = 4.8 Hz, CO). IR (neat): 3060 (w),
2982 (w), 2932 (w), 2905 (w), 1716 (w), 1660 (m), 1597
(m), 1448 (m), 1391 (m), 1305 (w), 1244 (s), 1204 (m), 1145
(m), 1050 (m), 1016 (s), 959 (s), 853 (m), 790 (s), 723 (m),
690 (m), 659 (m), 564 (m), 534 (m) cm–1. GC-MS (EI, 70
eV): m/z (%) = 312 (4) [M+], 297 (3), 283 (11), 267 (53),
239 (25), 211 (17), 183 (21), 159 (14), 151 (34), 129 (45),
105 (100), 77 (54). ESI–HRMS: m/z calcd for C15H22O5P [M
+ H]+: 313.1199; found: 313.1198.
Trans. 1 1987, 1399.
(6) (a) Hirao, T.; Masunga, T.; Ohshiro, Y.; Agawa, T. Synthesis
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Chem. 1998, 34, 93. (f) Gooßen, L. J.; Dezfuli, M. K. Synlett
2005, 445.
(7) For reviews of catalytic carbon–heteroatom bond
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Amination of Aryl Halides and Related Reactions, In
Handbook of Organopalladium Chemistry for Organic
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Wiley-Interscience: New York, 2002, 1051.
(14) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
(15) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
(8) (a) Kouno, R.; Okauchi, T.; Nakamura, M.; Ichikawa, J.;
Minami, T. J. Org. Chem. 1998, 63, 6239. (b) Kouno, R.;
Tsubota, T.; Okauchi, T.; Minami, T. J. Org. Chem. 2000,
65, 4326. (c) Arimori, S.; Kouno, R.; Okauchi, T.; Minami,
T. J. Org. Chem. 2002, 67, 7303.
(9) Yoffe, S. T.; Petrovsky, P. V.; Goryunov, Y. I.; Yershova,
T. V.; Kabachnik, M. I. Tetrahedron 1972, 28, 2783.
(10) For a review of [3+3] cyclizations of 1,3-bis(silyl enol
ethers), see: Feist, H.; Langer, P. Synthesis 2007, 327.
(11) For a review of the chemistry of 1,3-bis(silyl enol ethers),
see: Langer, P. Synthesis 2002, 441.
(12) Diethyl (1-Ethoxy-3-oxobut-1-en-2-yl)phosphonate (2a)
A mixture of 1a (1.10 g, 1.0 mL, 5.55 mmol), triethyl
orthoformiate (1.1 mL, 6.62 mmol) and Ac2O (1.5 mL, 16.0
mol) was stirred for 2 h at 120 °C and subsequently for 2 h
at 140 °C. The resulting mixture was distilled to give 2a as a
brownish oil (1.20 g, 86%). 1H NMR (300 MHz, CDCl3):
d = 1.21–1.24 (m, 6 H, 2 × OCH2CH3), 1.36 (t, 3J = 6.9 Hz,
3 H, OCH2CH3), 2.25 (s, 3 H, CH3), 4.04–4.08 (m, 4 H,
2 × OCH2CH3), 4.23 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.70
(d, 3JP,H = 11.4 Hz, 1 H, CH). 13C NMR (CDCl3, 75 MHz):
d = 15.0, 15.9, 16.0, 20.6 (CH3), 62.2, 62.4, 73.0 (OCH2),
107.3 (d, JC,P = 191 Hz,Cq), 169.9 (d, JCH,P = 25.5 Hz, CH),
195.0 (CO). 31P NMR (250 MHz, CDCl3): d = 19.64. GC-
MS (EI, 70 eV): m/z (%) = 250 (5) [M+], 235 (47), 221 (12),
207 (43), 205 (13), 179 (42), 177 (11), 151 (100), 123 (23),
121 (15), 105 (11), 81 (11), 53 (13), 43 (13), 29 (10). HRMS
(EI): m/z calcd for C10H19O5P [M]+: 250.09646; found:
250.09666.
(16) Nguyen, V. T. H.; Bellur, E.; Appel, B. Synthesis 2006,
2865.
(17) General Procedure for the Synthesis of
Arylphosphonates 4a–l
To a CH2Cl2 solution (2 mL/1.0 mmol of 2a,b) of 2a,b was
added 3a–k (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol)
at –78 °C. The temperature of the solution was allowed to
warm to 20 °C over 12 h with stirring. To the solution was
added HCl (10%, 20 mL), and the organic and the aqueous
layer were separated. The latter was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in
vacuo. The residue was purified by chromatography (silica
gel, n-heptane–EtOAc) to give 4a–l.
(18) Methyl 3-(Diethoxyphosphoryl)-6-hydroxy-2-methyl-
benzoate (4a)
Starting with 2a (0.375 g, 1.5 mmol) and 3a (0.429 g, 1.65
mmol), 4a was isolated after chromatography (silica gel,
heptanes–EtOAc) as a yellowish oil (0.217 g, 48%). 1H
NMR (300 MHz, CDCl3): d = 1.24 (m, 6 H, 2 × OCH2CH3),
2.65 (s, 3 H, CH3), 3.91 (s, 3 H, OCH3), 3.99–4.07 (m, 4 H,
2 × OCH2CH3), 6.83 (dd, 3JH,H = 8.6 Hz, 4JP,H = 3.3 Hz, 1 H,
CHAr), 7.90 (dd, 3JH,H = 9.0 Hz, 3JP,H = 14.0 Hz, 1 H, CHAr),
11.0 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): d = 16.2,
16.2, 20.6 (CH3), 52.5 (OCH3), 62.0, 62.0 (OCH2), 114.9 (d,
JP,CH = 15.2 Hz, CHAr), 115.9 (d, JP,C = 16.1 Hz), 119.0 (d,
JP,C = 193.0 Hz), 139.3 (d, JP,CH = 11.0 Hz, CHAr), 145.8 (d,
JP,C = 13.5 Hz), 164.0 (d, JP,C = 3.4 Hz, COH), 171.2 (d,
JP,C = 2.4 Hz, CO). 31P NMR (250 MHz, CDCl3): d = 19.56.
IR (neat): 2920 (m), 2851 (m), 1733 (m), 1660 (w), 1636
(w), 1580 (m), 1456 (m), 1437 (m), 1376 (w), 1308 (m),
1285 (m), 1199 (m), 1161 (m), 1158 (m), 1016 (s), 961 (m),
906 (m), 844 (m), 793 (m), 741 (m), 678 (w), 614 (w), 535
(m) cm–1. GC-MS (EI, 70 eV): m/z (%) = 302 (65) [M]+, 287
(50), 274 (20), 270 (48), 259 (17), 242 (100), 229 (18), 227
(13), 214 (84), 197 (43), 186 (21), 167 (17), 161 (31), 158
(23), 134 (15), 105 (19), 77 (27), 65 (10), 51 (12), 29 (14).
HRMS (EI): m/z calcd for C13H19O6P [M]+: 302.09138;
found: 302.09139.
(13) Diethyl (1-Ethoxy-3-oxo-3-phenylprop-1-en-2-
yl)phosphonate (2b)
A mixture of 1b (1.50 g, 1.27 mL, 5.85 mmol), triethyl
orthoformiate (1.70 mL, 10.24 mmol), and Ac2O (1.56 mL,
16.61 mmol) was stirred for 36 h at 140 °C. The mixture was
cooled to 20 °C and purified by column chromatography to
give 2b as a brownish oil (1.350 g, 74%). 1H NMR (300
MHz, CDCl3): d = 1.08 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 1.21
(t, 3J = 7.0 Hz, 6 H, 2 × OCH2CH3), 3.94 (q, 3J = 7.1 Hz, 2
H, OCH2CH3), 4.01–4.10 (m, 4 H, 2 × OCH2CH3), 7.34–
Synlett 2010, No. 10, 1525–1527 © Thieme Stuttgart · New York

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