Synthesis of phosphonate derivatives of 2,3-dihydroindene

Article abstract of DOI:10.1016/j.tetlet.2009.10.042

Simple and convenient procedures for the synthesis of derivatives of 2,3-dihydroinden-2-ylphosphonic acid are developed. The reaction strategies utilize both functionalization of the already existing 2,3-dihydroindene skeleton and an annulation reaction starting from readily available o-disubstituted benzene derivatives.

Full text of DOI:10.1016/j.tetlet.2009.10.042

Tetrahedron Letters 50 (2009) 7314–7317
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Tetrahedron Letters
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Synthesis of phosphonate derivatives of 2,3-dihydroindene
*
Monika Prokopowicz, Piotr Młynarz , Paweł Kafarski
_
´
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Revised 30 September 2009
Accepted 9 October 2009
Available online 14 October 2009
Simple and convenient procedures for the synthesis of derivatives of 2,3-dihydroinden-2-ylphosphonic
acid are developed. The reaction strategies utilize both functionalization of the already existing 2,3-dihy-
droindene skeleton and an annulation reaction starting from readily available o-disubstituted benzene
derivatives.
Ó 2009 Elsevier Ltd. All rights reserved.
Compounds based on the 2,3-dihydroindene skeleton are
important in medicine as agents for the treatment of anoxemic
and hypoxic symptoms and accompanying syndromes. They are
also used as cerebral activators and as drugs for treating amnesia
and presbyophrenia curvative therapy. Furthermore, indene deriv-
atives are potential medicaments for breathing arrest, agents for
hypoxia accompanied with KCN poisoning1 and anti-inflammato-
ries.2,3 Representatives of these compounds have been applied as
neuroactive dopamine b-hydroxylase inhibitors or calcium channel
modulators.4,5 Moreover, the antibacterial properties of this class
of compounds have also been reported.6 This wide variety of phys-
iological responses makes the synthesis of structurally related
compounds desirable.
The most common synthetic routes for the preparation of sim-
ple systems based on the dihydroindene skeleton involve function-
alization of commercially available 2,3-dihydroindene derivatives,
or by addition reactions to the double bond of indene proceeding
through ionic or radical mechanisms. However, when indene can-
not be used, the creation of a new five-membered ring is re-
quired.7–9 Several useful procedures have been published
including tandem SN2 Michael addition,10 intramolecular Friedel–
Crafts alkylation,11 Friedel–Crafts acylation,3 or dehydration–cycli-
zation of 3-phenylpropanol derivatives on heating in polyphospho-
ric acid.12 Furthermore, [2+2+2] addition reactions using acyclic
substrates in the presence of CpCo(CN)2 or Wilkinson’s catalyst
leading to 2,2-disubstitued derivatives of 2,3-dihydroindene have
been reported.13–15 Additionally, there is a possibility to obtain
analogues of natural products bearing a 2,3-dihydroindene moiety
via acid-catalyzed cyclodimerization of styrenes.16 Interestingly,
among various reports on the preparation of derivatives of 2,3-
dihydroindene, there are only a few papers describing the synthe-
ses of phosphonates based on this bicyclic system.17–19 Taking into
account the fact that these compounds, especially in free acidic
form, are expected to possess interesting complexing, biological,
and medicinal properties, we report herein our efforts to obtain a
series of phosphonic 2,3-dihydroindene derivatives of the general
formula:
X
R
P(O)(OH)2
X= CH2, C=O
R= H, CO2H, CO2Et
Initial attempts were focused on elaboration of the procedure for
the synthesis of 2,3-dihydro-1H-inden-2-ylphosphonic acid. This
compound was obtained by the reaction of indene with phosphorus
acid (H3PO3) via a free radical addition.9 However, this approach
had several limitations including the necessity of using an initiator,
elevated temperature, and long-term exposure to light.9
In order to avoid the above inconveniences, the Arbuzov reac-
tion was chosen as a simple method to create a new C–P bond.
The substrate, 2-bromo-2,3-dihydroindene 1, was obtained by
reaction of 2-indanol with bromine and triphenylphosphine at
low temperature20 (Scheme 1). Next, compound 1 was refluxed
with 20% molar excess of triethyl phosphite in dichloromethane.
Unfortunately, the reaction failed even after prolonged reaction
times and the use of elevated temperature (up to 180 °C), which
presumably results from the very low reactivity of the secondary
cycloalkyl bromide in the Arbuzov reaction. The above failure re-
quired the introduction of a nucleophilic center at C-2 to enable
electrophilic attack of a suitable phosphorus reagent.
Indeed, conversionof thebromide1 into organomagnesiumcom-
pound 2 provided a straightforward access to the desired ester 3 via
reaction with diethyl chlorophosphite followed by oxidation with
dilute aqueous hydrogen peroxide. The resulting product 3 was
hydrolyzed using an aqueous solution of hydrochloric acid to yield
the desired 2,3-dihydro-1H-inden-2-ylphosphonic acid 4.21
The phosphonates 3 and 4 proved to be inconvenient substrates
in further reactions. Thus, a strategy exploiting a CH-acid with sub-
sequent five-membered ring-closure seemed to be more appropri-
ate for the introduction of a carboxylic moiety at position 2 of the
* Corresponding author.
E-mail address: piotr.mlynarz@pwr.wroc.pl (P. Młynarz).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.042

M. Prokopowicz et al. / Tetrahedron Letters 50 (2009) 7314–7317
7315
Br2, Ph3P
0 oC
HClaq
P(OEt)3
P(O)(OEt)2
OH
Br
P(O)(OH)2
Δ
3 46%
1 94%
4 60%
1. ClP(OEt)2
2. H2O2
Mg
Et2O
MgBr
2
Scheme 1. Synthesis of compound 4.
phosphonic acid 4. Therefore, treatment of 1,2-bis(bromo-
methyl)benzene with triethyl phosphonoacetate in the presence
of a base resulted in the generation of an anion which reacted with
the dibromide to yield annulated product 5 (Scheme 2). The best
yield was obtained on heating an equimolar amount of substrates
with potassium carbonate at 140 °C without solvent. The desired
triethyl ester 5 of 2-phosphono-2,3-dihydro-1H-indene-2-carbox-
ylic acid was thus formed in a satisfactory yield.
for phosphonate deprotection giving derivative 7 while the ethoxy-
carbonyl group remained intact.22 On the other hand, refluxing
compound 5 in dilute hydrochloric acid afforded compound 6. This
indicated that the ethyl carboxylate group was highly resistant to
decarboxylation, but not to hydrolysis under such conditions.
A similarsynthetic strategywas employedin an attempt toobtain
bisphosphonate analogs utilizing tetraethyl methylenebisphosphonate
as an active methylene compound. However, in this case the reac-
tion failed, most likely because the substrate is a weaker CH-acid
than phosphonoacetate. The product was not formed irrespective
of the reaction conditions and despite the application of strong
Hydrolysis of 5 was carried out under mild conditions using
bromotrimethylsilane (TMSBr) in order to avoid decarboxylation.
However, it soon became clear that this approach was only suitable
COOH
HClaq
P(O)(OH)2
Br
6 80%
COOEt
COOEt
K2CO3
140 o
C
P(O)(OEt)2
5 70%
PO3Et2
COOEt
Br
TMSBr
P(O)(OH)2
7 96%
Scheme 2. The synthesis of compounds 5, 6 and 7.
O
O
n
O
n
O
n
P(OEt)3
Br2
HClaq
Br
P(O)(OEt)2
P(O)(OH)2
n
10a n=1 22%
10b n=2 16%
9a n=1 99%
9b n=2 99%
8a n=1
8b n=2
11a n=1 54%
11b n=2 49%
Scheme 3. A general synthetic route to compounds 11a and 11b.
(EtO)2(O)PO
O
O
10c 76%
Br
P(OEt)3
Br2
O
P(O)(OEt)2
9c 99%
8c
Scheme 4. The synthesis of side-product 10c.

7316
M. Prokopowicz et al. / Tetrahedron Letters 50 (2009) 7314–7317
2-Indanol (3.0 g, 22.0 mmol) and 6.15 g (23.0 mmol) of PPh3 were dissolved in
dry CH2Cl2 (20 ml) and cooled in an ice bath. To this solution, 1.2 ml (3.7 g,
23.0 mmol) of Br2 was added dropwise over a period of 0.5 h and then stirring
was continued for 2 h at rt. Next, the mixture was poured onto 100 ml of
cooled Et2O. The solid triphenylphosphine oxide was filtered off and the
resulting solution was concentrated. The crude bromo derivative was purified
by column chromatography (silica/hexane) (4.08 g, yield 94%, colorless oil).
In a two-neck round-bottomed flask equipped with a condenser and dropping
funnel, Mg shavings (0.32 g, 13.0 mmol), dry Et2O (50 ml), and a crystal of I2
were placed. After 10 min as needed to start the reaction, 2.50 g (13.0 mmol) of
2-bromo-2,3-dihydroindene dissolved in dry Et2O (5.0 ml) was added
dropwise while simultaneously heating the flask. When all the substrate had
been added the reaction was continued until the Mg had dissolved. Next, the
flask was cooled in an ice bath and a solution of ClP(OEt)2 (2.03 g, 13.0 mmol)
in Et2O (5.0 ml) was added dropwise. The mixture was then stirred for an
additional 24 h. A 30% solution of H2O2 (5.0 ml) was added to the flask and the
mixture was poured onto water (100 ml) and acidified with HCl (2 ml). The
crude product was extracted with CH2Cl2 and purified by column
chromatography (silica/Et2O) yielding the desired ester as a pale yellow oil
(1.5 g, yield 46%). The resulting ester was hydrolyzed by refluxing in HCl (20%,
20 ml) for 4 h. After completion of the reaction the volatile components were
evaporated and the crude phosphonic acid 4 was crystallized from hot H2O
(0.55 g, yield 60%, mp 194–195 °C, lit. 196 °C,28 195–196 °C9).
bases such as sodium t-butoxylate, sodium ethoxylate, or sodium
hydride.
Finally, we undertook studies on the synthesis of 1-oxo-2,3-
dihydro-1H-inden-2-ylphosphonic acid 11a (Scheme 3).23 Since
the preparation of b-ketophosphonates relying on electrophilic
phosphorus reagents via Arbuzov reaction is still an attractive ap-
proach we intended to prepare the desired compound utilizing this
strategy. Thus, 2-bromo-1-indanone 9a was obtained almost quan-
titatively by bromination of 1-indanone 8a. Treatment of 9a with
triethyl phosphite and subsequent hydrolysis gave phosphonic
acid 11a. Extension of this reaction to the preparation of higher
homologues of 11a was also studied. When
a-tetralone 8b was
used as substrate the same sequence of reactions gave the desired
product 11b, but in a decreased overall yield. This was due to the
formation of vinyl phosphate as a side-product of the Perkov reac-
tion, which is competitive with the Arbuzov reaction. This was
even more apparent when 1-benzosuberone 8c was used as the
starting compound. The process resulted in the undesired vinyl
phosphate 10c as the sole product (Scheme 4).
Various modifications in order to counteract side-product for-
mation were thus applied. Attempts involving either protection
of the carbonyl group (ketal, hydrazone or oxime) or replacement
of bromine with iodine24,25 were unsuccessful. This is presumably
due to stabilization of the intermediate of the phosphate–phospho-
nate rearrangement by conjugation with the benzene ring. This
assumption is based on the literature data, which indicates that vi-
nyl phosphates rearrange smoothly to b-ketophosphonates on
reaction with LDA as a result of intramolecular 1,3-migration of
phosphorus from oxygen to a carbon atom.26 This is the reverse
reaction to that observed in the case of the benzosuberone
derivative.
1H NMR (300 MHz, D2O): d 2.57–2.80 (m, 1H), 3.10–3.22 (m, 4H), 7.08–7.14
(m, 2H), 7.14–7.21 (m, 2H). 13C NMR (75 MHz, D2O): 34.26, 35.82 (d, JP–C
=
143.8 Hz), 124.69, 126.75, 142.67 (d, JP–C = 11.8 Hz). 31P NMR (121 MHz, D2O):
d 31.5. ESI MS m/z: 197 [MÀH+]À, 395 [M2ÀH+]À.
22. Triethyl ester of 2-phosphono-2,3-dihydro-1H-indene-2-carboxylic acid 5:
1,2-Bis(bromomethyl)benzene (2.64 g, 10.0 mmol), 4.14 g (30 mmol) of
anhydrous K2CO3, and 2.24 g (10.0 mmol) of triethyl phosphonoacetate were
placed in a round-bottomed flask and heated at 140 °C for 6 h. The crude ester
was then extracted with CH2Cl2 and purified by column chromatography
(silica/Et2O) yielding 2.28 g (70%) of pure product 5.
1H NMR (300 MHz, CDCl3): d 1.26 (t, 3H, J = 7.1 Hz), 1.28 (t, 6H, J = 7.1 Hz), 3.57
(dd, 2H, J = 16.4 Hz, J = 18.3 Hz), 3.71 (dd, 2H, J = 9.6 Hz, J = 16.9 Hz), 4.05–4.24
(m, 6H), 7.11–7.23 (m, 4H). 13C NMR (75 MHz, CDCl3): 14.04, 16.32 (d, J =
3.9 Hz), 54.60 (d, J = 138.1 Hz), 61.92, 63.00 (d, JP–C = 6.2 Hz), 124.11, 126.81,
140.00 (d, JP–C = 9.3 Hz), 171.40. 31P NMR (121 MHz, CDCl3): d 25.76
ESI MS m/z: 675 [2M+Na+]+, 349 [M+Na+]+, 253 [MÀCOOC2H5]+, 225
[MÀCOOC2H5–C2H5+H+]+.
Ethyl ester of 2-phosphono-2,3-dihydro-1H-indene-2-carboxylic acid 7:
Ester 5 (0.67 g, 2.0 mmol) was dissolved in dry CH2Cl2 (15 ml) and 1.05 ml
(1.22 g, 8.0 mmol) of TMSBr was added dropwise. The solution was stirred at
room temperature for 24 h. The solvent was removed on a rotary evaporator,
MeOH (10 ml) was added and the mixture was stirred for 1 h followed by
evaporation of the solvent under reduced pressure. The residue was washed
with MeOH, then with Et2O and dried. Pure product 7 was obtained as an
amorphous solid (0.52 g, 96%, 61–62 °C).
Summing up, we have presented simple procedures for the
preparation of various derivatives of 2,3-dihydro-1H-inden-2-
ylphosphonic acid. These procedures might be easily modified
and applied to the preparation of a wider range of structurally sim-
ilar compounds.
1H NMR (300 MHz, DMSO-d6):
d 1.13 (t, 3H, J = 7.2 Hz), 3.38 (dd, 2H,
References and notes
J = 16.5 Hz, J = 18.8 Hz), 3.56 (dd, 2H, J = 7.6 Hz, J = 16.5 Hz), 4.04 (q, 2H,
J = 7.2 Hz), 7.08–7.14 (m, 2H), 7.15–7.22 (m, 2H). 13C NMR (75 MHz, DMSO-d6):
14.89, 55.21, 61.96 (d, JP–C = 132.0 Hz), 125.00, 127.45, 141.68 (d, JP–C = 8.3 Hz),
173.12. 31P NMR (121 MHz, DMSO-d6): d 20.75. ESI MS m/z: 241 [MÀC2H5+]À,
269 [MÀH+]À, 539 [M2ÀH+]À.
1. Oshiro, Y.; Ueda, H.; EP 173331, 1986; Chem. Abstr. 1986, 105, 42509q.
2. Noda, K.; Nakagawa, A.; Yamagata, K.; Nakashima, Y.; Tsuji, M.; Aoki, T.; Ide, H.
U.S. Patent 4443626, 1984; Chem. Abstr. 1984, 100, 138786a.
3. Fülöp, F.; Lázár, L.; Szakonyi, Z.; Philavisto, M.; Alaranta, S.; Vainio, P. J.;
Juhakoski, J.; Marjamäki, A.; Smith, D. J. Pure Appl. Chem. 2004, 76, 965–972.
4. Yang, L.-M.; Shwu-Jiuan, L.; Tsang-Hsiung, Y.; Kuo-Hsiung, L. Bioorg. Med. Chem.
Lett. 1995, 5, 941–944.
5. Neubert, T.; Kawatkar, A. S.; Martinborough, E.; Termin, A. WO/2006/133459
Patent, 2006; Chem. Abstr. 2007, 146, 62703y.
6. Sharaf El Din, N. Acta Pharm. 1999, 49, 119–125.
7. Arp, O. F.; Fu, C. G. J. Am. Chem. Soc. 2005, 127, 10482–10483.
8. Kazemizadeh, A. R.; Ramazani, A. J. Braz. Chem. Soc. 2009, 20, 309–312.
9. Griffin, C. E.; Wells, H. J. J. Org. Chem. 1959, 24, 2049–2051.
10. Gharpure, S. J.; Raja Bhushan Reddy, S.; Sanyal, U. Synlett 2007, 1889–1892.
11. Basavaiah, D.; Bakthadoss, M.; Reddy, G. J. Synthesis 2001, 6, 919–924.
12. Roy, A.; Paul, T.; Mukherjee, D. ARKIVOC 2005, xi, 218–225.
13. Kotha, S.; Brahmachary, E. Tetrahedron Lett. 1997, 38, 3561–3564.
14. Kotha, S.; Mohanraja, K.; Durani, S. Chem. Commun. 2000, 1909–1910.
15. Kotha, S.; Brahmachary, E. Bioorg. Med. Chem. 2002, 10, 2291–2295.
16. Alesso, E.; Torviso, R.; Lantaño, B.; Erlich, M.; Finkielsztein, L. M.; Moltrasio, G.;
Aguirre, J. M.; Brunet, E. ARKIVOC 2003, x, 283–297.
2-Phosphono-2,3-dihydro-1H-indene-2-carboxylic acid 6:
Ester 5 (2.28 g, 7.0 mmol) was refluxed in HCl (20%, 15 ml) for 5 h. The excess
HCl was evaporated under reduced pressure and the phosphonic acid was
crystallized from a mixture of PhMe and MeOH (1.35 g, yield 80%, 79–81 °C).
1H NMR (300 MHz, D2O): d 3.40 (dd, 2H, J = 18.5 Hz, J = 16.6 Hz), 3.55 (dd, 2H,
J = 16.6 Hz, J = 8.3 Hz), 7.15 (m, 2H), 7.22 (m, 2H). 13C NMR (75 MHz, D2O):
38.77 (d, JP–C = 2.2 Hz), 54.73 (d, JP–C = 130.4 Hz), 124.28, 126.86, 140.82
(d, JP–C = 7.7 Hz), 177.11. 31P NMR (121 MHz, D2O): d 21.25.
ESI MS m/z: 197 [MÀCOOH]À, 241 [MÀH+]À, 483 [2MÀH+]À.
23. General procedure for the synthesis of b-ketophosphonates:
To a solution of the appropriate ketone (68.4 mmol) in Et2O (40 ml), Br2
(68.4 mmol, 10.8 g, 3.5 ml) was added dropwise whilst cooling in an ice bath.
To complete the reaction, the mixture was stirred for an additional 15 min,
then poured onto distilled H2O (100 ml) and the organic phase was separated,
washed with 5% Na2S2O3, and once more with distilled H2O. After drying over
MgSO4 and evaporation of the solvent, the corresponding bromoketone was
obtained almost quantitatively. The resulting products were used in the next
step without further purification.
17. Laber, B.; Kilitz, H.-H.; Amrhein, N. Z. Naturforsch. 1986, 41c, 49–55.
18. Zon´ , J.; Amrhein, N. Liebigs Ann. Chem. 1992, 625–628.
2-Bromoketone (68.0 mmol) was mixed with P(OEt)3 (11.6 g, 12.0 ml,
70 mmol) and heated at 100 °C for 3–7 h (monitoring by TLC). The resulting
b-ketophosphonate was isolated by column chromatography (silica/AcOEt).
Diethyl 1-oxo-2,3-dihydro-1H-inden-2-ylphosphonate 10a was obtained in
22% yield (4.0 g) and diethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-
ylphosphonate 10b in 16% yield (3.0 g).
To the resulting phosphonic diester (10.0 mmol) a 10% aqueous solution of HCl
(30 ml) was added and the mixture was refluxed for 10 h. After cooling, the
crude phosphonic acid precipitated and was recrystallized from hot H2O to
yield the pure product as the monohydrate.
´
19. (a) Rychlewski, T.; Zon, J. Phosphorus, Sulfur Silicon 1999, 147, 463; (b) Deron,
A.; Gancarz, R.; Gancarz, I.; Halama, A.; Kuz´ma, Ł.; Rychlewski, T.; Zon´ , J.
Phosphorus, Sulfur Silicon 1999, 144–146, 437–440.
20. Gavina, F.; Costero, A. M.; Gonzales, A. M. J. Org. Chem. 1990, 55, 2060–2063.
21. 2,3-Dihydro-1H-inden-2-ylphosphonic acid 4:
To 5.0 g (37.6 mmol) of 2-indanone dissolved in 20 ml of MeOH, 0.54 g
(14.3 mmol) of NaBH4 in 20 ml of MeOH was added dropwise. The reaction was
stirred vigorously for 2 h at rt. The solvent was evaporated under reduced
pressure, the residue was mixed with distilled H2O and the product was
extracted with CHCl3. After drying over anhydrous Na2SO4 and removal of the
solvent, the crude indanol was crystallized from hexane (3.16 g, yield 63%, mp
67–68 °C, lit. 68–69 °C27).
1-Oxo-2,3-dihydro-1H-inden-2-ylphosphonic acid monohydrate 11a:
(1.4 g, 54%, 8.8% overall, mp 184–186 °C).
1H NMR (300 MHz, DMSO-d6): d 3.10–3.37 (m, 3H(CH)+(CH2)), 7.39 (t, 1H,
J = 7.0 Hz), 7.56–7.66 (m, 3H). 13C NMR (75 MHz, DMSO-d6): 29.33 (d, JP–C
=

M. Prokopowicz et al. / Tetrahedron Letters 50 (2009) 7314–7317
7317
2.4 Hz), 47.97 (d, JP–C = 129.4 Hz), 123.76, 127.21, 127.91, 135.19, 137.14 (d,
JP–C = 2.9 Hz), 154.13 (d, JP–C = 5.1 Hz), 200.99 (d, JP–C = 5.5 Hz). 31P NMR
(121 MHz, DMSO-d6): d 18.45.
48.70 (d, JP–C = 123.6 Hz), 126.87, 127.10, 129.38, 132.61 (br s), 133.88, 144.80,
193.86 (d, JP–C = 4.93 Hz). 31P NMR (121 MHz, DMSO-d6): d 18.18.
ESI MS m/z: 225 [MÀH+]À, 451 [M2ÀH+]À, 207 [MÀH+–H2O]À.
24. Calogeropoulou, T.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem. 1987, 52,
4185–4190.
25. Jacobsen, H. I.; Griffin, M. J.; Preis, S.; Jensen, E. V. J. Am. Chem. Soc. 1957, 79,
2608–2612.
26. Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67, 5709–5717.
27. Hursey, B. J. Tetrahedron 1982, 38, 3769–3774.
28. Bergmann, E. Ber. 1930, 63B, 1158–1173.
ESI MS m/z: 193 [MÀH+–H2O]À, 211 [MÀH+]À, 423 [M2ÀH+]À.
1-Oxo-1,2,3,4-tetrahydronaphthalen-2-ylphosphonic acid monohydrate 11b:
(1.1 g, 49%, 6.6% overall, mp: 188–189 °C).
1H NMR (300 MHz, DMSO-d6): d 2.14–2.36 (m, 3H(CH2)+(CHP)), 2.80 (dt, 1H,
J = 16.7 Hz, J = 4.4 Hz), 3.01 (dt, 1H, J = 25.8 Hz, J = 5.1 Hz), 7.28 (d, 1H,
J = 7.5 Hz), 7.29 (t, 1H, J = 8.0), 7.5 (t, 1H, J = 7.6 Hz), 7.82 (d, 1H, J = 7.8 Hz).
13C NMR (75 MHz, DMSO-d6): 24.86 (d, JP–C = 3.8 Hz), 26.79 (d, JP–C = 5.3 Hz),