Synthesis of new polyhalogenoalkyl-containing phosphonates with an enaminone core and their use in the preparation of fluorinated heterocycles

Article abstract of DOI:10.1016/j.tetlet.2010.06.123

A number of polyhalogenoalkyl-containing phosphonates with an enaminone core were synthesized from readily available β-alkoxyvinyl polyhalogenoalkyl ketones by successive bromination, amination, and Arbuzov reaction. The new phosphonates were used for the syntheses of five- and six-membered heterocycles bearing both trifluoromethyl and methylenephosphonate groups.

Full text of DOI:10.1016/j.tetlet.2010.06.123

Tetrahedron Letters 51 (2010) 4623–4626
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new polyhalogenoalkyl-containing phosphonates with an
enaminone core and their use in the preparation of fluorinated heterocycles
a
b
a
c
a,*
Karen V. Tarasenko , Olga V. Manoylenko , Valery P. Kukhar , Gerd-Volker Röschenthaler , Igor I. Gerus
a
Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Murmanska Str. 1, Kiev 02094, Ukraine
Enamine Ltd, A. Matrosova Str. 23, Kiev 01103, Ukraine
Jacobs University Bremen gGmbH, School of Engineering and Science, Campus Ring 1, 28759 Bremen, Germany
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of polyhalogenoalkyl-containing phosphonates with an enaminone core were synthesized
from readily available b-alkoxyvinyl polyhalogenoalkyl ketones by successive bromination, amination,
and Arbuzov reaction. The new phosphonates were used for the syntheses of five- and six-membered het-
erocycles bearing both trifluoromethyl and methylenephosphonate groups.
Received 14 April 2010
Revised 14 June 2010
Accepted 25 June 2010
Available online 1 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Enaminones
Arbuzov reaction
Fluorinated phosphonates
Heterocycles
The chemistry of fluorinated organo phosphates and phospho-
nates has numerous attractive features. Phosphate esters are
important due to the participation of phosphate-containing mole-
cules in biological processes including signaling pathways, infor-
mation storage, and energy transfer.1 As a result, they have been
a topic of interest for many years, with applications mainly direc-
ted toward bioorganic and medicinal chemistry. The development
of new prodrugs among phosph(on)ates and bisphosph(on)ates is
of interest to many medicinal chemists.2 The interest in fluorine
substitution of organic groups attached to phosphorus stems from
the possible effect of such substitution on the physical, chemical,
As a part of our research program we have studied the reactions
of (b-alkoxy, amino)vinyl chloro(bromo)difluoromethyl ketones
6
d,7
and triethyl phosphite.
It was found that the reactivity of
chloro(bromo)difluoromethyl-containing b-alkoxy enones and
similar enaminones was very different in reactions with phos-
phites. b-Alkoxy enones reacted with triethyl phosphite at room
temperature via the Perkow reaction to yield difluoro-containing
6
d
dienyl phosphates. In contrast to b-alkoxy enones the reactivity
of enaminones in reactions with phosphites depends strongly on
the basicity of the nitrogen atom. Enaminones containing a nitro-
gen with high or medium basicity did not react with phosphites
under various conditions. At the same time, enaminones with a
nitrogen of low basicity reacted with triethyl phosphite under mild
3
and biological properties of the resulting phosphonates. In gen-
eral, incorporating fluorine as either a bioisosteric replacement
for hydrogen or an isoelectronic replacement for a hydroxy group
has profound consequences on metabolic degradation, lipophilic-
ity, hydrogen bonding, and the reactivity of organic molecules. Flu-
oro-containing phosphonates are important considering their
unique properties, whilst the development of useful methods for
the synthesis of fluoro-containing phosphonates is of interest for
the synthesis of potentially bioactive substances.4
conditions via Perkow rearrangement to give difluorodienyl phos-
7
phates. Also, the reactivity of
c-bromo-b-(alkoxy, amino)vinyl
polyhalogenomethyl ketones with phosphites depends strongly
on the nature of the b-substituent. -Bromo-substituted b-alk-
oxyenones afforded polyhalogenomethyl-containing dienyl phos-
c
6
d
phates
(Perkow route), while c-bromo-b-morpholinovinyl
trifluoromethyl ketone reacted with triethyl phosphite exclusively
b-Alkoxy- and b-aminovinyl polyfluoroalkyl ketones are readily
accessible building blocks for the preparation of fluorinated het-
erocycles, amino acids, etc. However, there are only a few commu-
via the Arbuzov protocol to yield a trifluoromethyl-containing
phosphonate (Scheme 1).
7
5
Herein we report our results on the scope and limitations of the
nications on the reactions of fluorinated enones and enaminones
with phosphites.
Arbuzov reaction of various c-bromo-b-aminovinyl polyhaloge-
6
,7
nomethyl ketones with triethyl phosphite. We also demonstrate
the utility of polyfluoroalkyl-containing phosphonatesas precursors
for the synthesis of five- and six-membered heterocycles and a 1,3-
diketone bearing both trifluoromethyl and methylenephosphonate
*
Corresponding author. Tel.: +38 044 573 2598; fax: +38 044 573 2552.
E-mail address: igerus@hotmail.com (I.I. Gerus).
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.123

4
624
K. V. Tarasenko et al. / Tetrahedron Letters 51 (2010) 4623–4626
for the synthesis of enaminones containing both polyhalogenoalkyl
and methylenephosphonate groups is efficient and successful on
varying both the polyhalogenoalkyl and amino group. For instance,
bis-enaminone 5 was synthesized from piperazine and two equiv-
alents of enone 2a, and then converted successfully into the corre-
sponding bisphosphonate 6 (Scheme 3).
Compounds 2–6 were fully characterized by H, 13C, 19F, and 31
1
P
1
1
NMR spectroscopy and by elemental analysis. Exceptions were
1
3
the C NMR spectra of enaminones 5 and 6 because of poor solu-
bility and the presence of broad signals.
We and others have demonstrated the wide possibilities of
using fluorinated enones and enaminones in heterocyclization
5
,12
reactions.
The novel compounds 4 represent precursors for
Scheme 1. Reactions of
c-bromo-b-(alkoxy, amino)vinyl polyhalogenomethyl
ketones with triethylphosphite.
the synthesis of various heterocycles bearing both poly-
halogenoalkyl and methylenephosphonate groups. We used phos-
phonate 4a as a model compound for investigating the scope and
limitations of the utility of this type of phosphonate for the synthe-
sis of five- and six-membered heterocyclic systems (Scheme 4).
It was found that phosphonate 4a reacted with hydrazine hy-
drate under mild conditions to furnish pyrazole 7 in high yield
and purity without the need for any additional purification. In con-
trast, the reaction of enaminone 4a with hydroxylamine in water
afforded isoxazolinol 8 in a low isolated yield. The synthesis of
six-membered heterocycles from phosphonate 4a and (thio)urea
proceeded to give oxy- and thiopyrimidines 9 and 10 in low yields.
We examined various standard heterocyclization conditions, but
only in the case of aqueous methanol with HCl at rt did we obtain
pyrimidines 9 and 10 after preparative HPLC purification. The het-
groups. These products are potential precursors for Horner–Wads-
worth–Emmons reaction.8
Polyhalogenoalkyl-containing phosphonates were synthesized
using the strategy presented in Scheme 2. Compounds 2a–e were
obtained by bromination of the corresponding poly-
halogenoalkyl-containing enones 1a–e, as published previously.
This method is a general procedure for preparing -bromo-poly-
halogenoalkyl-containing enones 2 in high yields (80–93%). Enami-
6
d,9
c
nones 3a–e were synthesized by reaction of polyhalogenoalkyl
ketones 2a–e with morpholine at 25 °C for eight hours. It is worth
7
mentioning that various secondary aliphatic amines could be used
for the synthesis of enaminones such as 3, but morpholine pro-
vided better yields and led to easier isolation of the corresponding
enaminones.
Phosphonates 4a–e were obtained via Arbuzov reaction of
enaminones 3 with triethyl phosphite by continuous heating in
1
13
19
31
erocycles were fully characterized by H, C, F, and P NMR
spectroscopy and by elemental analysis. We observed two tauto-
meric forms in the NMR spectra of compound 9. Similar behavior
of trifluoromethyl-containing 2-substituted pyrimidines was de-
1
,4-dioxane. We found that the presence of the longer chain per-
13
scribed earlier.
fluoroalkyl groups in enaminones 3b,c led to slightly higher yields
in shorter reaction times. It is interesting that in spite of the pres-
ence of two possible reaction centers in compounds 3d,e, we ob-
served exclusively nucleophilic substitution of bromine
furnishing trihalogenomethyl-containing phosphonates 4d,e in
high yields. Similar inactivity of chlorine in trichloromethyl and
chlorodifluoromethyl groups in reactions with phosphites was
noted previously. The ratio of reagents, reaction times, yields,
and conditions are summarized in Table 1.
To our knowledge, only one compound of similar structure was
previously prepared by trichloroacetylation of N-methylenamines
bearing a phosphonate group in 33% yield.10 Our methodology
Unfortunately, the corresponding substituted pyrimidines were
not obtained by the reaction of phosphonate 4a with guanidine or
amidines under standard conditions, although the disappearance
19
oftheenaminonesignalat À78 ppm wasevidentfrom F NMRspec-
troscopy. We observed an increase in the intensity of the singlet at
À85 ppm characteristic for hydrates of trifluoromethyl ketones.
The hydrolysis of enaminone 4a takes place in acidic aqueous med-
ium and the methylenephosphonate-containing trifluoromethyl
diketone 11 was formed, presumably according to the poor results
obtained during the pyrimidine synthesis.
7
We synthesized diketone 11 via hydrolysis of enaminone 4a in
the presence of hydrochloric acid to confirm our assumption
(Scheme 5). Diketone 11 did not react with (thio)urea, guanidine,
or amidines under various condensation conditions (in aqueous
methanol and ethanol, aqueous 1,4-dioxane, toluene, at 30–110 °C
and in the presence of hydrochloric or toluenesulfonic acids).
Compound 11 was isolated in hydrate form according to NMR
spectra and elemental analysis. As expected, diketone 11 formed
complex equilibria mixtures of various tautomers and hydrate
forms (Scheme 6) depending on the nature of the solvents. The
spectral data were complicated by the possible formation of intra-
molecular enol hydrogen bonds with keto- or phosphonate groups.
1
9
Thus, in the F NMR spectrum of diketone 11 we observed, in
CDCl
3
, the dominance of two signals at À77.0 and À87.5 ppm in
a 5:1 ratio, and in methanol, mainly two hydrate forms with sig-
nals at À83.9 and À87.9 ppm in a 3:1 ratio were observed. Only
6
in dry DMSO-d did compound 11 exists as nearly one isomer
which allowed us to prove its structure as 11d—the hydrate form
of diketophosphonate 11.
It should be noted that diketophosphonate 11 was reported pre-
viously but without any synthetic or characteristic data and was
used as the starting material for the synthesis of fluorinated hydro-
Scheme 2. Synthesis of polyhalogenoalkyl-containing phosphonates 4. Reagents
and conditions: (i) Br
morpholine, CH Cl , 0?25 °C, 8 h, 59–85%; (iii) P(OEt)
2–120 h, 70–85%.
2
,
CH
2
Cl ,
2
25 °C, 1 h; pyridine, 0 °C, 1 h, 80–93%; (ii)
2
2
3
, 1,4-dioxane, 50–100 °C,
1
4
7
xy phosphonic acid via reduction with Baker’s yeast.

K. V. Tarasenko et al. / Tetrahedron Letters 51 (2010) 4623–4626
4625
Table 1
Reaction conditions for the synthesis of phosphonates 4a–e, 6
Substrate
Ratio of 3 (5):P(OEt)
3
Temperature (°C)
Product
Time (h)
Yield (%)
3
3
3
3
3
5
a
b
c
d
e
1:1.2
1:1.2
1:1.2
1:0.8
1:0.8
1:2.2
100
100
100
50
50
100
4a
4b
4c
4d
4e
6
72
72
72
96
96
96
74
84
87
58
46
72
Scheme 5. Synthesis of diketone 11. Reagents and conditions: (i) MeOH, concd HCl,
rt, 15 h, 53%.
Scheme 3. Synthesis of fluorinated bisphosphonate 6. Reagents and conditions: (i)
piperazine, CH Cl , 0?25 °C, 8 h, 86%; (ii) P(OEt) , 1,4-dioxane, 100 °C, 120 h, 68%.
2
2
3
Scheme 6. Tautomeric and hydrate forms of diketophosphonate 11.
reaction. Using diethyl (2E)-5,5,5-trifluoro-2-morpholin-4-yl-4-
oxopent-2-enylphosphonate (4a), we have demonstrated the util-
ity of this class of phosphonates for the synthesis of heterocycles
bearing both polyhalogenoalkyl and methylenephosphonate
groups.
Acknowledgments
Financial support was provided by grants from STCU 3558 and
DFG 436 UKR 113/101/0-1.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion and spectroscopic data for all obtained compounds) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.123.
Scheme 4. Synthesis of five- and six-membered heterocycles 7–10 bearing both
trifluoromethyl and methylene phosphonate groups. Reagents and conditions: (i)
N
3
2
H
4
ÁH
2
O, CH
2
Cl
2
, 0?25 °C 12 h, 73%; (ii) NH
2
OHÁHCl, NaHCO
3
, methanol–water, rt,
h, 27%; (iii, iv) (thio)urea, HCl, methanol–water, rt, 144 h, 21–23%.
References and notes
1
2
3
.
.
.
Westheimer, F. H. Science 1987, 235, 1173.
Hecker, S. J.; Erion, M. D. J. Med. Chem. 2008, 51, 2328.
In conclusion, we have investigated the scope and limitations of
the reactions of various c-bromo-b-aminovinyl polyhalogenoalkyl
ketones with triethyl phosphite. This reaction represents a method
to synthesize fluorinated phosphonates in moderate to high yields.
No side reactions/products were observed during the course of the
Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley, 2008.
Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868.
Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron 2007, 63, 7753.
(a) Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P.; Schmutzler, R. J. Fluorine Chem.
1998, 90, 1; (b) Zhu, S.; Jiang, H.; Jin, G. J. Fluorine Chem. 2005, 126, 931; (c)
4.
5.
6.

4
626
K. V. Tarasenko et al. / Tetrahedron Letters 51 (2010) 4623–4626
Chizhov, D. L.; Röschenthaler, G.-V. J. Fluorine Chem. 2006, 127, 235; (d)
General procedure for the preparation of compounds 4d,e: Triethyl phosphite
(1.14 mmol) was added to a solution of the corresponding enaminone 3
(1.42 mmol) in dry 1,4-dioxane (15 ml) under an argon atmosphere. The
reaction mixture was stirred at 50 °C for 120 h. The solvent was removed in
vacuum and the residue was purified by column chromatography [eluent
EtOAc–hexane (1:1), then MeOH].
Tarasenko, K. V.; Gerus, I. I.; Kukhar, V. P. J. Fluorine Chem. 2007, 128, 1264.
Tarasenko, K. V.; Gerus, I. I.; Kukhar, V. P.; Polovinko, V. V. Collect. Czech. Chem.
Commun. 2009, 74, 335.
Zhang, Y.; Xu, C.; Li, J.; Yuan, C. Tetrahedron: Asymmetry 2003, 14, 63.
Gerus, I. I.; Kacharova, L. M.; Vdovenko, S. I. Synthesis 2001, 431.
7
.
8
9
.
.
1
1
0. Sahibullina, V. G.; Polezhaeva, N. A.; Bagautdinova, D. A.; Arbuzov, B. A. Zh.
Obshch. Khim. 1991, 61, 2421.
1. General procedure for the preparation of compounds 1a–e: A solution of the
Preparation of compound 7: Hydrazine hydrate (151 mg, 2.78 mmol) was added
dropwise to a solution of phosphonate 4a (1 g, 2.78 mmol) in CH
with stirring at 0 °C. The mixture was stirred at rt for 12 h then washed with
O (2 Â 3 ml) and dried over Na SO . After evaporation of the solvent, pure
pyrazole 7 was obtained as a yellow oil.
Preparation of compound 8: NaHCO (152 mg, 1.81 mmol) was added gradually
to solution of enaminone 4a (500 mg, 1.39 mmol) and hydroxylamine
hydrochloride (126 mg, 1.81 mmol) in H O (8 ml) and MeOH (3 ml) with
stirring at rt. The reaction mixture was stirred for 3 h at rt and extracted with
Et SO . After
2 2
Cl (15 ml)
corresponding acyl chloride (86 mmol) in dry CH
dropwise to a solution of 2-methoxypropene (7.13 g, 99 mmol) and pyridine
8.85 g, 112 mmol) in dry CH Cl (80 ml) at 0 °C. The mixture was stirred at
°C for 4 h until the reaction was complete. CH Cl (150 ml) was added and
the mixture was washed with 5% solution of HCl
(3 Â 50 ml),
SO ),
2
Cl
2
(40 ml) was added
H
2
2
4
(
2
2
3
0
2
2
a
H
2
O
a
2
(
3 Â 50 ml), and
H
2
O
(1 Â 50 ml). The organic layer was dried (Na
2
4
filtered, and concentrated. Distillation afforded compounds 1a–e as colorless
2
O (3 Â 10 ml). The combined organic layer was dried over Na
2
4
oils.
evaporation of the solvent, pure diethyl (5-hydroxy-5-trifluoromethyl-4,5-
dihydroisoxazol-3-yl)methylphosphonate (8) was obtained as a yellow oil.
General procedure for the preparation of compounds 9 and 10: Concentrated HCl
General procedure for the preparation of compounds 2a–e:
elemental Br (22.38 mmol) in dry CH Cl (10 ml) was added dropwise to a
solution of the corresponding enone (22.38 mmol) in dry CH Cl (80 ml) at 20–
5 °C. The mixture was stirred at rt for 1 h and pyridine (22.38 mmol) was
A solution of
2
2
2
2
2
(1 ml) was added to a solution of enaminone 4a (1.08 g, 3 mmol) and
(thio)urea (4 mmol) in 50% aqueous MeOH (30 ml). The reaction mixture
was stirred for 6 days and evaporated under reduced pressure. The residue was
2
added dropwise with stirring at 0 °C. The temperature was increased to rt and
the reaction mixture was stirred for 5 h. The solvent was removed in vacuum
and the residue was distilled to yield 2a–e.
chromatographed using
EtOAc–MeOH, gradient from 0% to 30% of MeOH in EtOAc, RediSep Normal-
phase Silica Flash Columns).
a Combiflash Companion chromatograph (eluent
Ò
General procedure for the preparation of compounds 3a–e:
morpholine (5 mmol) in CH Cl (10 ml) was added dropwise to a solution of
halogenoalkyl-containing enone 2 (5 mmol) in CH Cl (10 ml) at 0 °C. The
mixture was stirred at room temperature for 10 h. After evaporation of the
solvent, the residue was crystallized from a mixture of hexane–Et O to give
a–e.
General procedure for the preparation of compounds 4a–c: Triethyl phosphite
A solution of
2
2
Preparation of compound 11: Enaminone 4a (230 mg, 0.64 mmol) was dissolved
in MeOH (7 ml), concentrated HCl (0.3 ml) was added, and the reaction
mixture was stirred overnight. The MeOH was evaporated in vacuum, the
2
2
2
2 2
residue was dissolved in Et O (20 ml), and the solution was washed with H O
3
(4 ml). The organic layer was separated, dried over Na
evaporated under vacuum.
2 4
SO , and the solvent was
(
1.7 mmol) was added to
a
solution of the corresponding enaminone
3
12. Nenajdenko, V. G.; Sanin, A. V.; Balenkova, E. S. Russ. Chem. Rev. (Engl. Transl.)
1999, 68, 437.
(
1.3 mmol) in dry 1,4-dioxane (10 ml) under an argon atmosphere. The
reaction mixture was stirred at 100 °C for 72 h. The extent of reaction was
determined by 19F and P NMR spectroscopy. The solvent was removed in
vacuum and the residue was purified by column chromatography [eluent
EtOAc–hexane (1:1), then MeOH].
13. Gerus, I. I.; Vdovenko, S. I.; Gorbunova, M. G.; Kukhar, V. P. Khim. Geterotsikl.
Soed. 1991, 502.
14. Wang, K.; Li, J.-F.; Yuan, C.-Y. Chin. J. Chem. 2002, 20, 1379.
31