A novel and efficient method to prepare 2-aryltetrahydrofuran-2- ylphosphonic acids

Article abstract of DOI:10.3762/bjoc.6.63

A novel one-pot method was developed for the synthesis of the title compounds starting from 4-chloro-1-aryl-1-butanones 1, phosphorus trichloride and acetic acid. The end products 2 were obtained in 20-94% yield. The cyclization step under acidic conditions probably occurs as a result of anchimeric assistance of the phosphonic acid group.

Full text of DOI:10.3762/bjoc.6.63

A novel and efficient method to prepare 2-aryl-
tetrahydrofuran-2-ylphosphonic acids
Vsevolod V. Komissarov1, Anatoly M. Kritzyn1 and Jouko J. Vepsäläinen*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 63. doi:10.3762/bjoc.6.63
1Engelhardt Institute of Molecular Biology, Russian Academy of
Sciences, Vavilov St., 32, Moscow 119991, Russia and 2Department
of Biosciences, Biocenter Kuopio, University of Eastern Finland, P.O.
Box 1627, FIN-70211, Kuopio, Finland
Received: 21 March 2010
Accepted: 18 May 2010
Published: 09 June 2010
Email:
Associate Editor: J. A. Porco Jr
Jouko J. Vepsäläinen* - Jouko.Vepsalainen@uef.fi
© 2010 Komissarov et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
4-chloro-1-aryl-1-butanones; cyclization; furan; heterocycle;
phosphonic acids
Abstract
A novel one-pot method was developed for the synthesis of the title compounds starting from 4-chloro-1-aryl-1-butanones 1, phos-
phorus trichloride and acetic acid. The end products 2 were obtained in 20–94% yield. The cyclization step under acidic conditions
probably occurs as a result of anchimeric assistance of the phosphonic acid group.
Introduction
Our laboratory has conducted systematic evaluation of poly- phosphonic acids 3 could be obtained from 1 after treatment
methylene derivatives of nucleic bases with various terminal with PCl3 and AcOH, followed by the elimination of water
functional groups [1-4]. As a part of our ongoing project, it (Figure 1). After the reduction of the double bond [11], these
seemed important to synthesize compounds with phosphonate compounds could then be used for nucleic bases alkylation as
and phenyl groups at one end of the hydrocarbon chain and a described earlier.
nucleic base residue at the other end. Previously, it was shown
that compounds with similar structures inhibit purine nucleo-
side phosphorylase and thymidine phosphorylase, enzymes
which have been targeted in a number of serious diseases [5-7].
Recently, we prepared nucleic base derivatives with a terminal
Ph-CO-group by alkylation methods starting from 4-chloro-1-
Figure 1: Treatment of 4-chloro-1-aryl-1-butanones 1 with PCl3/AcOH
lead to unexpected cyclic product 2 instead of the expected alkene 3.
aryl-1-butanones 1 [8]. According to the studies of Conant et al.
[9,10] conducted about 90 years ago, the target phenylvinyl-
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Beilstein J. Org. Chem. 2010, 6, No. 63.
Scheme 1: Preparation of cyclic furans 2a–e and ethyl esters 4a,c from chloroarylbutanones 1.
Results and Discussion
products were verified not only from molecular ion peaks in the
In this study, we employed the above noted reaction sequence mass spectra but also from 1H NMR data, in which three CH2-
with our model compound, 4-chloro-1-phenyl-1-butanone (1a) groups give rise to six chemical shifts. This phenomenon exists
[5]. However, the only product formed in good yield was if a chiral center (sometimes a prochiral center) is near a CH2-
2-phenyltetrahydrofuran-2-ylphosphonic acid (2a) instead of group or when a CH2 group is a part of a cyclic structure. In this
the expected acyclic product. Previously, to obtain phenylvinyl- case, the chemical shift difference between the furan ring CH2
phosphonic acids 3, Conant [9] heated the reaction mixture protons were 0.1–0.5 ppm, clear evidence for the existence of a
under atmospheric pressure at high temperature (~280 °C). cyclic structure. The complicated but characteristic 1H NMR
Initially, we also followed this procedure, but soon realized that spectra were analyzed by PERCH software [15]. In addition,
the yield of phosphonic acid 2a was significantly higher under 13C NMR spectra confirmed the presence of the tetrahydro-
the milder conditions shown in Scheme 1. The yields of the furan ring system since characteristic 1–3JCP coupling constants
prepared cyclic compounds 2b–e are summarized in Table 1. were found for all four CH2 carbons at ~84, ~69, ~36, and ~26
ppm. 31P NMR signals of the phosphonic acids 2 were at ca 23
ppm.
Table 1: Prepared compounds 2a–e with yields.
Aryl group
Product
2a
Yield [%]
In order to understand the mechanism of the reaction, we
conducted the reactions of 1a and PCl3 in the absence of AcOH
and with phosphorous acid in AcOH solution. In the first case,
there was no evidence of that any reaction had occurred,
whereas in the second case cyclization was observed only under
reflux conditions; however, the yield of 2a was extremely low.
Accordingly, in the initial step either PCl3 reacts with ketone 1
to form the adduct 5, as proposed by Conant [9], which is then
converted to intermediate 6 via 5a by the addition of AcOH, or
alternatively, HOPCl2 (and/or (HO)2PCl), formed after acetic
acid addition to the mixture, reacts directly with the ketone 1 to
produce intermediate 6 as shown in Scheme 2.
94
59
83
57
2b
2c
2d
2e
20a
The intermediate 6 rapidly forms ring 8 possibly via intermedi-
ate 7. However, the cyclization reaction in which hydroxyl
group and chlorine atom are sterically near to each other are
aIsolated via the ammonium salt.
The synthesized phosphonic acids 2 can be easily converted normally conducted under basic conditions [16] or at elevated
into diethyl esters 4 by refluxing in triethyl orthoformate in the temperatures [17]. A plausible explanation for the cyclization
presence of p-TSA [12]. Previously, these esters 4 were occurring at room temperature without an alkoxide intermedi-
prepared directly from 1a–d by refluxing in an excess of ate would be to invoke anchimeric assistance of the P=O group,
P(OEt)3. However, this procedure provides high yields of which could serve as a general base to facilitate cyclization
2-aryltetrahydrofuran-2-ylphosphonic acid esters 4 only if the leading to the formation of 7 [18].
starting ketones have electron donating substituents at the para-
position of the aromatic ring [13,14].
The length of hydrocarbon chain is also of major importance,
since cyclic tetrahydropyran derivatives are not formed in the
The structures of phosphonic acids 2 were established from MS case of arylpentanones 9a,b under the same conditions as those
and NMR spectral data. The cyclic structures of the end used for the synthesis of furans 2 (Scheme 3). According to the
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Beilstein J. Org. Chem. 2010, 6, No. 63.
Scheme 2: Proposed reaction mechanism for the cyclization reaction.
NMR spectra, the only phosphorus containing products in the [15]. Mass spectra were obtained on an Applied Biosystems/
reaction mixtures were the corresponding α-hydroxyphos- MDS Sciex QSTAR XL spectrometer using ESI technique.
phonic acids 10. Similarly, acid 10c is formed from phenyl-
butanone 4c in 41% yield.
General procedure for the synthesis of compounds 2a–e:
PCl3 (1.2 mL, 13.75 mmol) was added dropwise to 4-chloro-1-
aryl-1-butanone (10 mmol) with stirring at 0 °C. Cooling was
removed and the reaction mixture stirred at room temperature
for 30 min followed by dropwise addition of glacial acetic acid
(1.72 mL, 30 mmol) with stirring at 0 °C. Stirring was then
continued without cooling for 20 h, ice (50 g) was added and
the reaction mixture heated slowly over a water bath to 90 °C.
After 40 min at this temperature, the solvents were evaporated
in vacuo and the resulting oil was re-evaporated with water (3 ×
20 mL). The crystalline residue was washed with cold water (20
mL) and benzene (40 mL). The residue was dried under vacuum
(P2O5 and paraffin) to yield the target acids 2a–d in 57–94%
Scheme 3: Acyclic products are obtained from pentanones 9a,b and
butanone 9c.
In summary, a direct and efficient route was developed for the yield.
synthesis of 2-aryltetrahydrofuran-2-ylphosphonic acids – com-
pounds containing a relatively exotic motif – via a one-pot 2-Phenyltetrahydrofuran-2-ylphosphonic acid (2a):
experimental procedure from 4-chloro-1-aryl-1-butanones. The 1H NMR (DMSO-d6): δH 7.5 (2H, bs), 7.450 (2H, d, 3JHH =
cyclic structure of the synthesized compounds was reliably 7.80 Hz), 7.288 (2H, dd, 3JHH = 7.80, 7.39 Hz), 7.203 (1H, dd),
established by means of various NMR experiments. A mech- 3.923 (1H, ddd, 2JHH = −7.84 Hz, 3JHH = 7.11, 6.90), 3.847
anism for the cyclization is proposed and it is suggested, that (1H, ddd, 2JHH = −7.84 Hz, 3JHH = 7.37, 5.42 Hz), 2.599 (1H,
the crucial feature of the reaction is the anchimeric assistance of dddd, 3JHP = 15.58 Hz, 2JHH = −12.54 Hz, 3JHH = 8.13, 7.82
the P=O group. We have also demonstrated that the tetrahydro- Hz), 2.137 (1H, dddd, 3JHP = 10.97 Hz, 2JHH = −12.54 Hz,
pyran analogs of the title phosphonic acids were not formed 3JHH = 7.77, 5.12 Hz), 1.980 (ddddd, 2JHH = −11.74 Hz, 3JHH =
under similar conditions.
8.13, 6.90, 5.42, 5.12), 1.660 (ddddd, 3JHH = 7.82, 7.77, 7.37,
7.11); 13C NMR (DMSO-d6): δC 142.4 s, 127.3 s, 126.4 s,
126.3 s, 83.6 (d, JCP = 167.0 Hz), 68.4 (d, JCP = 6.4 Hz), 35.7 s,
Experimental
General remarks. 1H, 13C and 31P NMR spectra were recorded 25.5 (d, JCP = 4.8 Hz); 31P NMR (DMSO-d6): δP 23.11; MS
on a Bruker Avance 500 DRX instrument at 500 MHz, 125 (ESI): m/z 227 [M+−H].
MHz and 162 MHz, respectively. Chemical shifts (δ) are
reported in ppm relative to tetramethylsilane as internal 2-(4-Methylphenyl)tetrahydrofuran-2-ylphosphonic acid
standard for protons and carbon atoms, and to H3PO4 (85%) for (2b): 1H NMR (DMSO-d6): δH 8.6 (2H, bs), 7.326 (2H, d, 3JHH
phosphorus chemical shifts. Exact chemical shifts and coupling = 7.87 Hz), 7.089 (2H, d), 3.906 (1H, ddd, 2JHH = −7.81 Hz,
constants for protons were calculated using PERCH software 3JHH = 7.13, 6.94), 3.831 (1H, ddd, 2JHH = −7.81 Hz, 3JHH =
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Beilstein J. Org. Chem. 2010, 6, No. 63.
7.40, 5.36 Hz), 2.270 (3H, s), 2.567 (1H, dddd, 3JHP = 15.51 d, J = 7.2 Hz), 7.85 (2H, m), 7.70 (1H, d, J = 8.7 Hz), 7.46 (2H,
Hz, 2JHH = −12.51 Hz, 3JHH = 8.09, 7.96 Hz), 2.110 (1H, dddd, m), 4.01 (1H, m), 3.92 (1H, m), 2.73 (1H, m), 2.26 (1H, m),
3JHP = 10.78 Hz, 2JHH = −12.51 Hz, 3JHH = 7.71, 4.98 Hz), 2.00 (1H, m), 1.67 (1H, m); 13C NMR (DMSO-d6): δC 140.4 (d,
1.964 (ddddd, 2JHH = −11.73 Hz, 3JHH = 8.09, 6.94, 5.36, 4.98), JCP = 5.6 Hz), 132.7 (d, JCP = 2.4 Hz), 132.3 (d, JCP = 1.6 Hz),
1.648 (ddddd, 3JHH = 7.96, 7.70, 7.40, 7.13); 13C NMR 128.1 s, 127.5 s, 127.0 s, 126.1 s, 125.8 s, 125.5 (d, JCP = 2.4
(DMSO-d6): δC 139.7 (d, JCP = 5.6 Hz), 135.9 (d, JCP = 2.4 Hz), 124.9 (d, JCP = 5.6 Hz), 84.1 (d, JCP = 167.0 Hz), 68.8 (d,
Hz), 128.4 s, 126.6 (d, JCP = 3.2 Hz), 83.9 (d, JCP = 169.0 Hz), JCP = 6.4 Hz), 35.8 (d, JCP = 3.2 Hz), 25.8 (d, JCP = 4.8 Hz);
68.8 (d, JCP = 6.4 Hz), 36.0 (d, JCP = 2.4 Hz), 25.9 (d, JCP = 4.8 31P NMR (DMSO-d6): δP 22.98; MS (ESI): m/z 277 [M+−H].
Hz), 20.9 s; 31P NMR (DMSO-d6): δP 23.56; MS (ESI): m/z
241 [M+−H].
Acknowledgements
The authors would like to thank Ewen McDonald for language
2-(4-Fluorophenyl)tetrahydrofuran-2-ylphosphonic acid editing, Dr. Alex Khomutov, Engelhardt Institute of Molecular
(2c): 1H NMR (DMSO-d6): δH 8.3 (2H, bs), 7.463 (2H, dd, Biology, RAS, Russia, for critical remarks and helpful discus-
3JHH = 8.71 Hz, 4JHF = 5.58 Hz), 7.111 (2H, dd, 3JHF = 8.01 sions, and PhoSciNet COST action (CM0802). This work was
Hz), 3.919 (1H, ddd, 2JHH = −7.87 Hz, 3JHH = 7.16, 6.90 Hz), supported by Grants of the Russian Foundation for Basic
3.854 (1H, ddd, 2JHH = −7.87 Hz, 3JHH = 7.39, 5.36 Hz), 2.588 Research (06-04-48716) and the Academy of Finland.
(1H, dddd, 3JHP = 15.41 Hz, 2JHH = −12.58 Hz, 3JHH = 8.11,
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