α-fluoro-benzylphosphonates as reagents for the preparation of 1-fluoro-1-aryl alkenes and α-fluorostilbenes

Article abstract of DOI:10.2533/000942904777678217

The preparation of several fluoro-benzylphosphonates Ar-CHF-PO(OEt) ₂ and their Wadsworth-Emmons type olefination with aldehydes and ketones are described affording fluorostyrenes and fluorostilbenes. Some of these compounds are incorporated in

Full text of DOI:10.2533/000942904777678217

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133
CHIMIA 2004, 58, No. 3
Chimia 58 (2004) 133–137
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
ꢀ-Fluoro-Benzylphosphonates as
Reagents for the Preparation of
1-Fluoro-1-Aryl Alkenes and
ꢀ-Fluorostilbenes
Thomas Allmendingera*, Roger Fujimotob, Fabrizio Gasparinic, Walter Schillingd,
and Yoshi Satohb
Abstract: The preparation of several fluoro-benzylphosphonates Ar-CHF-PO(OEt)2 and their Wadsworth-Emmons
type olefination with aldehydes and ketones are described affording fluorostyrenes and fluorostilbenes. Some of
these compounds are incorporated into target molecules tested as drug candidates.
Keywords: Fluoro-benzylphosphonates · Fluoroolefins · Horner-Wadsworth-Emmons olefination
the most widely applicable and also most
simple being the conversion of ꢀ-hydroxy-
benzylphosphonates (D) using DAST [8] or
similar fluorinating agents [2].
Introduction
Preparation of Fluoro-benzyl-
phosphonates
Ylide-type chemistry is well elaborated
in the field of fluorine-organic chemistry
and has been comprehensively reviewed re-
cently [1]. For example, the reaction of α-
fluoro-benzylphosphonate with benzalde-
hyde to form fluorostilbene (Scheme 1) was
reported as early as 1968 [2] but has
reached only limited attention until recent-
ly [3].
Several methods have been reported for
the preparation of ꢀ-fluoro-benzylphos-
phonates (Scheme 2, A [5], B [6], C [7]);
ꢀ-Hydroxy-benzylphosphonates 2 are
easily accessible by the base-catalyzed ad-
As part of our studies towards the prepa-
ration of fluoroolefins and their application
in medicinal chemistry [4], we have also in-
vestigated this reaction more closely, vary-
ing the structure of the carbonyl compound
as well as that of the fluoro benzylphospho-
nate; this paper summarizes the results.
Scheme 1. Initial report of Bergman
*Correspondence: Dr. T. Allmendingera
Tel.: + 41 61 3247700
E-Mail: thomas.allmendinger@pharma.novartis.com
aChemical and Analytical Development
Process Research and Development
Novartis Pharma AG
Lichtstrasse 35
CH-4002 Basel
bNovartis Institute for Biomedical Research
Arthritis and Bone Metabolism
One Health Plaza, East Hanover
New Jersey 07936, USA
cNovartis Institute for Biomedical Research
Neurosystem Research
CH-4002 Basel
dF. Hoffmann-La Roche Ltd.
Pharmaceuticals Division
Preclinical Research, PRBD-M
CH-4070 Basel
Scheme 2. Preparation of α-fluoro-benzylphosphonates

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CHIMIA 2004, 58, No. 3
Table 1. Preparation of α-hydroxy- and α-fluoro-benzylphosphonates 2 and 3
dition of diethylphosphite to aldehydes
[9]. Thus mixtures of the aromatic alde-
hyde, diethylphoshite and triethylamine
(molar ratio 1:1:0.1) are stirred without
solvent at elevated temperature (Table 1).
Upon completion of the reaction, most of
the mixtures solidify and may be used di-
rectly in the following step. Alternatively,
the solid compounds 2 may be isolated by
triturating with hexane and recrystallized.
For a representative example see [10].
The conversion to the corresponding ꢀ-
fluoro-benzylphosphonates 3 is simply
achieved by treating solutions of 2 in
dichloromethane with diethylamino sulfur
trifluoride at 0 °C.
X
T
t
mp 2
Yield 3
a
b
c
d
e
f
H
p-F
p-Cl
m-Br
p-OMe
p-COOMe
3,5-Me2
60 °C
70 °C
70 °C
90 °C
40 °C
40 °C
25 °Ca
24 h
16 h
16 h
24 h
60 h
3 h
83 °C
–
67 °C
–
121 °C
108 °C
–
52%
59%
57%
51%
80%
66%
91%
g
1 h*
aNaOMe catalyzed reaction
The methoxy-substituted derivative 3e
was reported to be not accessible by this
route [1][8]. Following the procedures out-
lined in reference [11] the preparation of di-
ethyl 4-methoxy-α-fluoro-benzylphospho-
nate 3e proved to be reproducible.
Table 2. Preparation of α-fluoro-styrene derivatives by base-induced Wadsworth-Emmons
Wadsworth-Emmons Olefination
of Fluorophosphonates
reaction of diethyl α-fluoro-benzylphosphonate with aldehydes and ketones
entry 3, X= Carbonyl-compound 4 (only (Z)-isomer depicted)
yield (Z)/(E)
Having a simple way to access a wide
variety of ꢀ-fluoro-benzylphosphonates 3,
these compounds were used for the prepa-
ration of fluoroolefins. In a standard proce-
dure [12], compounds 3 were treated with
lithium diisopropylamide (LDA) as a base
at low temperature and subsequently react-
ed with carbonyl compounds (Table 2).
Aliphatic and aromatic aldehydes and ke-
tones are equally reactive forming ꢀ-fluo-
rostyrenes and ꢀ-fluorostilbenes 4 in mod-
erate to excellent yields.
1
p-F
a
82% 50:50
2
3
p-F
b
c
76%
72%
–
–
p-Cl
4
5
6
7
8
9
p-Cl
m-Br
d
e
f
98% 50:50
78% 50:50
33 % 50:50
In the case of aldehydes and unsymmet-
rical ketones, mixtures of (E)- and (Z)-iso-
mers are obtained in a ratio usually around
1:1. As Burton has already pointed out for
the simple unsubstituted 3a, this ratio is vir-
tually unaffected by the reaction conditions
and only slightly altered by solvent or salt
additives [3]. Some examples in Table 2
however indicate that the substituent in the
phosphonate has an influence on the ste-
reochemical outcome of the reaction. Re-
acting p-methoxy fluorophosphonate 3e
with methyl 4-formylbenzoate (entry 10)
affords the fluorostilbene 4j in a 1:1 ratio of
(E)- and (Z)-isomers. Exchanging the sub-
stituents in the starting materials (hence, re-
action 3f with p-anisaldehyde, entry 11) has
a substantial effect on the stereoselectivity;
the corresponding fluorostilbene 4k is ob-
tained predominantly as its (E)-isomer (cis-
stilbene).Another interesting observation is
the selectivity of the reaction of the
chlorophosphonate 5 [13] with ketone 6
(Scheme 3) to afford almost exclusively the
(E)-chloroolefine 7 in contrast to the cor-
responding fluoro-phosphonate 3a giving
raise to a 1:1 mixture of fluoroolefines 4l
(Table 2, entry 12).
m-Br
3,5-(CH3)2
p-OCH3
p-OCH3
g 30 % 32:68
h
i
52% 60:40
78%
–
10 p-OCH3
j
68% 50:50
73% 15:85
32% 50:50
11 p-COOCH3
k
l
12
H

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CHIMIA 2004, 58, No. 3
Applications
Some potential applications have ap-
peared in the literature (Fig.): Fluorostil-
bene A and related compound are claimed
to give nematic liquid crystal mixtures with
improved physical properties [14]; α-fluo-
ro-p-hydroxy-stilbene B is a potent in-
hibitor of LSD (ligninostilbene-α,β-dioxy-
genase) [15]; fluorinated retinoic acid ana-
logues C and D have been tested as
anticancer drugs [5a][6a]; a novel series of
antimicrobials E are described by Sciotti et
al. (Abbott Laboratories) [16]; substituted
isoxazole F and indole G are prepared and
tested as antidepressants [17]; stilbene de-
rivative H was tested as aromatase inhibitor
and antifungal agent [18]; a screening pro-
gram for antifungal agents in our company
included also fluoroolefine I [19], however
the final marketed drug Lamisil® contains
the alkyne derivative Terbinafine K.
(
)
(
)
Scheme 3. Reaction of chlorophosphonat 5 with ketone 6
The development of the dopamine an-
tagonist 8 as an antipsychotic agent was
discontinued due to its rapid metabolism to
the corresponding alcohol 9 (Scheme 4).
We therefore were looking for metabolical-
ly stable compounds containing groups
mimicking the labile carbonyl group: 12,
13. Compound 4b was debenzylated and
the amine 10 thus obtained was reacted
with the N-aroyl-aziridine 11 affording flu-
oroolefine analogue 12. It shows only mod-
erate biological activity, similar to that of
the difluoromethylene analogue 13.
α-Fluorinated-β-pyridyl-substituted sty-
roles 4f and 4g (Table 2), were tested as an-
tagonists of subtype 5 of the metabotropic
glutamate receptor and are therefore of po-
tential interest for the treatment of a num-
ber of diseases [20].
The acids 14 and 15 prepared from the
esters 4l and 7 (Scheme 5) resemble the
structural requirements of thrombaxane A2
synthesis inhibitors (a basic nitrogen in dis-
tinct distance to a carboxylic acid) [21] and
are therefore strong inhibitors of human
platelet aggregation.
During a program to discover LTB4 an-
tagonists as new anti-inflammatory agents,
the Eli-Lilly antagonist LY223982 [22]
(Scheme 6) was modified. Part of this effort
was an attempt to understand the SAR of
the p-methoxystyrene olefin which seemed
to be important for antagonist activity. Un-
fortunately, introducing a fluorine sub-
stituent in α-position of the styrene moiety
(target compound 16) had the opposite ef-
fect: the building block 4h turned out to be
unstable; dissolved in CDCl3, 4h remained
unchanged for about 3 days but then de-
composed completely and rapidly to form a
product lacking the fluoroolefin moiety.
Closer examination revealed the formation
of the ketone 17 (the analogue 18 was inac-
tive in the biological assay). This phenom-
enon is easily explained by the presence of
Fig. Applications of fluorostyrenes and fluorostilbenes (references in the text)
Scheme 4. Analogues of dopamine antagonist 8

FLUORINE IN THE LIFE SCIENCE INDUSTRY
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CHIMIA 2004, 58, No. 3
Herold, L. Moesch, H.P. Schaer, R.O.
Duthaler, Helv. Chim. Acta 1992, 75,
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1991, 47, 4905–14; d) T. Allmendinger, E.
Felder, E. Hungerbuehler, ACS Symp. Ser.
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a p-MeO group which stabilizes a transient densed in a Wadsworth-Emmons reaction
carbocation formed by protonation of the with aldehydes and ketones (Scheme 8).
fluoroolefin moiety and by the formation of Aliphatic fluorophosphonates (similarly
HF inducing the autocatalytic effect. Simi- prepared by base-catalyzed addition of di-
lar observations have been made by Rolan- ethyl phosphite to aliphatic aldehydes
do in an attempt to cleave MOM-protected R1CHO followed by OH-F exchange us-
p-hydroxy-α-fluorostilbenes [23].
ing SF4) do not readily undergo the
Wadsworth-Emmons olefination reaction.
The initial report by Blackburn and Parat
Alternatives, Summary, and Outlook [25] was not verified [8]. Realization of this
goal however would lead to a general
Despite the utility of the Wadsworth- method for introducing fluorine sub-
Emmons method described here, modern stituents at sp2 and sp3-centers anywhere
Stille and Suzuki reactions have been com- into a carbon chain, as fluoroolefins can se-
monly used to generate the fluoroolefins lectively be hydrogenated [26].
(Scheme 7). These Pd-catalyzed reactions
[5] a) I. Dawson, R. Chan, P.D. Hobbes, W.
Chao, L.J. Schiff, J. Med. Chem. 1983, 26,
1282; b) M. Klaus, P. Loeliger, P. Mohr, E.
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Received: December 18, 2003
of arylboronic acids or stannanes with fluo-
rinated vinyl bromides or aryl iodides with
fluorinated vinylstannanes are stereoselec-
tive and have found some applications
[15][16][24]. However, the preparation of
bromo-fluoro olefins and fluorovinylstan-
nanes in pure (E) or (Z) form are laborious.
A general method is described to pre-
pare fluoroolefins Ar1-CF=CH-R2: aromat-
ic aldehydes Ar1CHO are converted to ꢀ-
fluoro-benzylphosphonates which are con-
[1] D.J. Burton, Z.-Y- Yang, W. Qiu, Chem.
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[7] X. Zhang, W. Qiu, D.J. Burton, Tetrahe-
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[2] E.D. Bergmann, I. Shahak, J. Appelbaum,
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[8] G.M. Blackburn, M.J. Parratt, J. Chem.
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[3] H.-J. Tsai, K.-W. Lin, T.-H. Ting, D.J.
Burton, Helv. Chim. Acta 1999, 82, 2231.
[4] a) T. Allmendinger, C. Angst, H. Kar-
funkel, J. Fluorine Chem. 1995, 72,
247–53; b) G. Bold, T. Allmendinger, P.
a) K. Sasse, in ‘Houben-Weyl, Methoden
der organischen Chemie’, Bd. XII/1, G.
ThiemeVerlag, Stuttgart 1963, p. 475ff; b)
E.K. Fields, US-patent 2,579,810, 1949;
Scheme 5. TxA2 synthesis inhibitors
Scheme 6. Hydrolysis of p-MeO-phenyl sub-
stituted fluoroolefin
Scheme 7. ‘Modern’ Stille and Suzuki reac-
tions to prepare fluorostilbenes

FLUORINE IN THE LIFE SCIENCE INDUSTRY
137
CHIMIA 2004, 58, No. 3
19920416, b) Imperial Chemical Indus-
tries, UK, EP 1998 306227 19880707
[19] A. Stuetz, P. Stuetz, DE 1986-3631297
19860913
[20] Novartis-patent
19980709.
WO
1998-EP4266
[21] a) H. Patscheke, Blut 1990, 60, 261; b) F.
Dorandeu, Lyon Pharmaceutique 1991,
42, 137; c) P.E. Cross, R.P. Dickinson,
Chemistry in Britain 1991, 27, 911; d)
A.T. Bach, J.A. Carlson, P.P. Giannousis,
Synthesis 1999, 769.
Scheme 8. Reaction of aromatic and aliphatic fluorophosphonates with aldehydes
[22] D.M. Gapinski, B.E. Mallett, L.L.
Froehlich, W.R. Jackson, J. Med. Chem.
1990, 33, 2807.
aldehyde was prepared by reduction of 5-
c) A.R. Sardarian, B. Kaboudin, Synthetic
Comm. 1997, 27, 543.
[23] S. Eddarir, Z. Abdelhadi, C. Rolando,
Tetrahedron Lett. 2001, 42, 9127.
bromovaleronitrile with diisobutylalu-
minum hydride followed by hydrolysis.)
The mixture is stirred for 45 min at –70 °C
and allowed to warm to r.t. over night. Af-
ter adding 20 ml of 2N HCl, the mixture is
extracted with a mixture of ethyl acetate
and hexane. The organic phase is washed
with 2N HCl and aq. sodium bicarbonate,
dried over sodium sulfate and evaporated
to dryness. The residue (10 g of crude
product) is purified by flash chromatogra-
phy on silica eluting with hexane/ethyl ac-
etate 3:2 affording 4.3 g (52%) of 4h as a
60:40 mixture of (Z)- and (E)-isomers. IR
(CH2Cl2, cm-1): 1679 cm-1 (C=CF); 1610
(ms), 1513 (s), 1179 (s, C-O-C), 1033 (s),
[10] Diethyl α-hydroxy-4-methoxy-benzyl-
phosphonate (2e), typical procedure: A
mixture of 13.6 g (0.1 mol) of freshly dis-
tilled p-anisaldehyde, 14.5 g (0.105 mol)
of diethylphosphite and 0.4 g (4 mmol) of
triethylamine is heated with stirring at 40
°C for 67 h to obtain 2e in quantitative
yield as a solid which can be used without
further purification. Mp. (from ethyl ac-
etate) 121–123 °C. IR (CH2Cl2, cm-1):
3373, 3279 (OH), 2985, 1612, 1513, 1239,
[24] a) C. Chen, K. Wilcoxen, Y.-F. Zhu, K.-I.
Kim, J.R. McCarthy, J. Org. Chem. 1999,
64, 3476; b) C. Chen, K. Wilcoxen, C.Q.
Huang, N. Strack, J.R. McCarthy, J. Fluo-
rine Chem. 2000, 101, 285.
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Soc. Chem. Comm. 1983, 886.
[26] T. Allmendinger, C. Dandois, B. Walliser,
Tetrahedron Lett. 1991, 32, 2735.
1
1174, 1032, 971. H-NMR (CDCl3, 200
MHz, J [Hz]): 1.20, 1.27 (2t, J = 7 each,
3H, 3H, diastereotopic P-O-C-CH3); 3.80
(s, OCH3); 3.9–4.1 (m, 4H, OCH2); 4.32*
1
3
3
836 (s, p-subst. aromatic C–C). H-NMR
(dd, JHP = 9, JHH = 5, OH); 4.94 (dd,
2JHP = 10, 3JHH = 5, O-CH-P); 6.88 (d, J =
8, aryl-H-C(3), H-C(5)); 7.41 (dd, J = 8,
4JHP = 2, aryl-H-C-(2), H-C(6)). *OH-sig-
nal does not appear always split; if not, the
signal at 4.94 is a doublet (J = 10) only.
[11] Diethyl α-fluoro-4-methoxy-benzylphos-
phonate (3e), typical procedure: To the
soln. of 2e (22 g, 80 mmol) in 120 ml of
dichloromethane is added (at –5 to 0 °C,
during 50 min) a soln. of diethylamino sul-
furtrifluoride (DAST, 14.5 g, 90 mmol) in
15 ml of dichloromethane. The organic so-
lution is stirred for 20 min and then
washed with water, aq. sodium bicarbon-
ate, and brine. The organic phase is dried
over magnesium sulfate and evaporated,
the residue is chromatographed on silica
(200 g, ethyl acetate) affording 17.7 g
(80%) of 3e. IR (CH2Cl2, cm-1): 2984,
1619, 1515, 1240, 1030. 1H-NMR
(CDCl3, 300 MHz, J [Hz]): 1.22, 1.28 (2t,
J = 7 each, 3H, 3H, diastereotopic P-O-C-
CH3); 3.79 (s, OCH3); 3.9–4.1 (m, 4H,
(CDCl3, 250 MHz, J [Hz]); (Z)-4h:
1.5–1.7 and 1.8–2.0 (2m, H-C(4), H-
3
4
C(5)); 2.30 (qd, JHH = 6.5, JHF = 1.5,
CH2–C=CF); 3.45 (t, J = 6.5, Br-CH2);
3.83 (s, OCH3); 5.22 (dt, 3JHF = 31, 3JHH
= 6.3, CH=CF); 6.88 and 7.43 (each d, 6.8
Hz, each 2H, C6H4); (E)-4h: 1.5-1.7 and
1.8-2.0 [each m, each 2H, C(4,5)-H]; 2.22
(q, 6.3 Hz, CH-C=CF); 3.38 (t, 6.3 Hz,
CH2-Br); 3.85 (s, 3H, OCH3); 5.28 (dt,
3
3JHF = 18 Hz, JHH = 6, J = 3, CH=CF);
6.92 and 7.38 (2d, J = 6.8 each, 2 aryl-H
each.
[13] Chlorobenzylphosphonates for the prepa-
ration of vinyl chlorides and acetylenes:
H. Zimmer, K.R. Hickey, R.J. Schumach-
er, Chimia 1974, 28, 656; H. Zimmer, P.J.
Berez, O.J. Maltenieks, M.W. Moore, J.
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20011122; b) Y. Fujimoto, Y. Miyamoto,
M. Minamii (Sumitomo Chemical Co.) JP
1997-51771 19970306; c) E. Bartmann, R.
Hittich, U. Finkenzeller, R. Eidneschink,
DE 1992-4205970 19920227.
2
2
OCH2); 5.57 (dd, JHF = 44, JHP = 7.5,
P-CH-F); 6.90 (d, J = 8, aryl-H-C(3),
H-C(5)); 7.40 (d, J = 8, aryl-H-C-(2),
H-C(6)).
[15] S.-Y. Han, H. Inoue, T. Tereda, S. Kamo-
da, Y. Saburi, K. Sekimata, T. Saito, M.
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[12] Preparation of 6-bromo-1-fluoro-1-(p-
methoxyphenyl)-1-hexene (4h), typical
procedure: a soln. of 3.54 g (35 mmol) of
diisopropylamine in 25 ml of anhydrous
THF is treated with 15 ml of a 2.5 M soln.
of n-butyllithium in hexane at –50 to –60
°C and allowed to warm to 0 °C for 10
min. After cooling again, a soln. of diethyl
α-fluoro-p-methoxybenzylphosphonate
(3e) (9.12 g) in THF (25 ml) is added dur-
ing 20 min at –70 °C, followed by the ad-
dition of a solution of 5-bromovaleral-
dehyde in 10 ml of THF. (5-Bromovaler-
[16] R.J. Sciotti, M. Pliushchev, P.E. Wiede-
mann, D. Balli, R. Flamm, A.M. Nilius, K.
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