REACTIONS OF p-AMINOVINYL BROMODIFLUOROMETHYL KETONES WITH ALKYL PHOSPHITES: PERKOW VERSUS ARBUZOV

Article abstract of DOI:10.1135/cccc2008095

New bromodifluoromethyl enaminones la-lf and γ-bromo-β- morpholinopropenyl fluoro-methyl ketones 2a, 2b were synthesized. N-Substituted bromodifluoromethyl enaminones la-Id do not react with triethyl or diethyl phosphites, whereas N-acylated enaminones le

Full text of DOI:10.1135/cccc2008095

Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
335
REACTIONS OF β-AMINOVINYL BROMODIFLUOROMETHYL KETONES
WITH ALKYL PHOSPHITES: PERKOW VERSUS ARBUZOV
a3
Karen V. TARASENKOa1, Igor I. GERUSa2,*, Valery P. KUKHAR and
b
Vitaly V. POLOVINKO
a
Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry,
National Ukrainian Academy of Science, Murmanskaya Str. 1, Kiev, 02094, Ukraine;
2
3
e-mail:1 takaren@mail.ru, igerus@hotmail.com, kukhar@bpci.kiev.ua
b
Enamine Ltd., A. Matrosova Str. 23, Kiev, 01103, Ukraine; e-mail: nmr@enamine.net
Received April 30, 2008
Accepted Jan uary 8, 2009
Publish ed on lin e February 18, 2009
Dedicated to Professor Oldřich Paleta on the occasion of his 70th birthday in recognition of his
outstanding contributions to the area of organofluorine chemistry.
New brom odifluorom eth yl en am in on es 1a–1f an d γ-brom o-β-m orph olin opropen yl fluoro-
m eth yl keton es 2a, 2b were syn th esized. N-Substituted brom odifluorom eth yl en am in on es
1a–1d do n ot react with trieth yl or dieth yl ph osph ites, wh ereas N-acylated en am in on es 1e,
1f gave difluorodien yl ph osph ates 4a, 4b as Perkow rearran gem en t products. Fluoroketon e
2a reacts easily with trieth yl ph osph ite accordin g to th e Arbuzov protocol an d a perspective
buildin g block – trifluorom eth yl-con tain in g ph osph on ate 7a is form ed.
Keyw ord s: Fluorin e; En am in on es; Perkow reaction ; Ph osph ates; Arbuzov reaction ; Ph os-
ph on ates; Fluorin ated keton es; En ol ph osph ates.
It is well establish ed th at th e in troduction of fluorin e atom s or organ o-
fluorin e groups in to organ ic m olecules often ch an ges th eir ph ysical an d
ch em ical properties1. Man y n ew agroch em icals (n early 28% in 2002) an d
drugs (curren tly m ore th an 18%) con tain at least on e fluorin e atom 2. On
th e oth er h an d, th e in troduction of th e organ oph osph orus groups in to or-
gan ic m olecules often leads to th e appearan ce of biological activity3.
A com bin ation of th e two features (fluorin e an d ph osph orous atom s) in
on e m olecule is a useful m eth odology of search in g for n ew effective in h ibi-
tors of en zym e system s4. On e of con ven ien t m eth ods for syn th esis of
fluoroph osph orus com poun ds is th e ph osph orylation of fluo-
rin e-con tain in g buildin g blocks.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 2, pp. 335–346
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2008095

336
Tarasenko, Gerus, Kukhar, Polovinko:
β-Alkoxy-α,β-un saturated fluorin e-con tain in g keton es are readily accessi-
ble com poun ds, wh ich are widely used in th e fluoroorgan ic syn th esis5. At
th e sam e tim e, on ly a few exam ples of th e addition of ph osph ites to th e
β-eth oxyvin yl trifluorom eth yl keton es are kn own . Th us, [1+4] cyclo-
addition of trieth yl ph osph ite with (E)-4-eth oxy-1,1,1-trifluoro-3-buten -
2-on e resulted in an oxaph osph ole6; an addition of dieth yl ph osph ite to
th e en on e afforded a m ixture of E- an d Z-adducts7; an d th e reaction of
tris(trim eth ylsilyl) ph osph ite with en on es gave a m ixture of 1,2- an d 1,4-
adducts8.
Th e reaction s of β-alkoxyvin yl ch lorodifluorom eth yl keton es with tri-
eth yl ph osph ite were recen tly in vestigated an d various dien yl ph osph ates
were obtain ed as th e products of th e Perkow reaction 9. Th e β-alkoxyvin yl
trih alom eth yl keton es are th e vin ylogs of th e esters of trih aloacetic acid,
wh ich also react with ph osph ites yieldin g useful products of th e Perkow
reaction 10. At th e sam e tim e, trich loroacetam ides give trieth yl ph osph ate
an d (trich lorovin yl)am in es as th e m ajor products in th e reaction with tri-
eth yl ph osph ite10. Takin g in to accoun t th at β-am in ovin yl trih alom eth yl ke-
ton es are th e vin ylogs of th e am ides of trih aloacetic acid, it is very difficult
to predict th e results of th e reaction of th e en am in on es with ph osph ites
(Sch em e 1).
SCHEME 1
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Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
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In order to predict a poten tial reactivity of β-am in ovin yl trih alom eth yl
keton es, th e electron structure of th is class of com poun ds sh ould be con -
sidered. Th e presen ce of both electron -don or an d electron -with drawin g
groups an d th e occurren ce of six π-electron s m ake th e structure of
en am in on es sim ilar to h eteroarom atic substan ces11. Th e an alysis of litera-
ture data h as sh own th e absen ce of in form ation on reaction s of ph osph ites
an d h eteroarom atic com poun ds or en am in on es con tain in g th e brom o-
difluorom eth yl group. Con tin uin g our in vestigation s, we presen t in th is
work th e m ost recen t results of our research on th e reactivity of β-am in o-
vin yl brom odifluorom eth yl keton es in th e reaction with trieth yl ph osph ite
as well as direction of th e reaction (Perkow rearran gem en t an d/or Arbuzov
reaction ).
RESULTS AND DISCUSSION
Takin g in to accoun t th at brom ide is a better leavin g group th an ch loride,
we ch ose brom odifluorom eth yl-con tain in g en am in on es as objects in th is
research in stead of ch lorodifluorom eth yl-con tain in g on es. In order to study
scope an d lim itation s of th e reaction s between ph osph ites an d brom o-
difluorom eth yl en am in on es, two series of β-am in ovin yl keton es with gen -
eral form ulae 1 an d 2 were syn th esized (Fig. 1). In th e series of en am in on es
1 we m odified substituen ts on th e n itrogen atom in order to ch an ge gradu-
FIG. 1
Two syn th esized series of β-am in ovin yl keton es 1 an d 2
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338
Tarasenko, Gerus, Kukhar, Polovinko:
ally its basicity (h igh for 1a–1c, m edium for 1d an d low for 1e, 1f). We also
in cluded en am in on es 2 bearin g brom in e atom at γ-position to th e carbon yl
group.
Com poun ds 1a–1d were easily obtain ed by th e reaction of brom o-
difluorom eth yl β-eth oxyvin yl keton e12 (prepared by th e sam e m eth od as its
ch lorodifluorom eth yl an alog13) with th e correspon din g am in es14 in h igh
yields (Sch em e 2).
SCHEME 2
In con trast to com poun ds 1a–1d , en am in on e 1e can n ot be syn th esized
from th e correspon din g en on e because of very low n ucleoph ilicity of th e
n itrogen atom in pyrrolidon e. Th erefore, en am in on e 1e was obtain ed by an
altern ative m eth od based on brom odifluoroacetylation of N-vin ylpyrrolid-
on e, sim ilarly to th e previously publish ed trifluoroacetylation 15 (Sch em e 3).
SCHEME 3
Com poun d 1g was obtain ed by trifluoroacetylation of N-ben zyl-
en am in on e 1a un der sim ilar con dition s as was previously publish ed for
ch iral trifluorom eth yl en am in on e16 (Sch em e 4).
SCHEME 4
Th e structure of en am in on es 1a–1f was proved by NMR spectroscopy. It
is worth m en tion in g th at th e C=C double bon d of N,N-disubstituted
en am in on es 1b–1f h as exclusively th e E-con figuration , wh ereas N-m on o-
substituted en am in on e 1a sh ows an equilibrium between E- an d Z-isom ers
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Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
339
depen din g on th e polarity of solven ts, as is usual for polyfluoroalkylated
en am in on es17. We assum e th at en am in on es 1e, 1f h ave E-s-E-con form ation
on th e basis of X-ray data for N-trifluoroacetylated en am in on es publish ed
recen tly18
.
An alogously to (ch lorodifluorom eth yl)en on es9, brom odifluorom eth yl
β-eth oxyvin yl keton e reacts with trieth yl ph osph ite also un der very m ild
con dition s an d th e correspon din g dien yl ph osph ate 3 is form ed in good
yield by th e Perkow reaction (Sch em e 5). NMR spectral ch aracteristics of
dien yl ph osph ate 3 coin cide with th e data for th e sam e com poun d pub-
lish ed previously9.
SCHEME 5
It is foun d th at th e reactivity of brom odifluorom eth yl en am in on es 1a–1d
(with th e n itrogen atom of stron g or m edium basicity for 1a–1c an d 1d , re-
spectively) in th e reaction with trieth yl ph osph ite is very differen t from
difluoroh alom eth yl-con tain in g β-eth oxyvin yl keton es. All our attem pts to
react en am in on es 1a–1d with ph osph ites failed alth ough various reaction
con dition s were used (th e process was m on itored by 31P an d 19F NMR spec-
troscopy of th e reaction m ixtures). En am in on es 1a–1d did n ot react with
trieth yl ph osph ite in various solven ts (eth er, dioxan e) an d at varied tem -
peratures (20–100 °C) for several days. Also th e Mich aelis–Becker reaction
between en am in on e 1c an d dieth yl ph osph ite in th e presen ce of NEt3
in THF or dioxan e un der reflux failed. In 19F NMR spectra of th e above-
m en tion ed reaction m ixtures, ch aracteristic sign als of n eith er th e Perkow
n or Arbuzov products were observed: two doublets in th e region from
–90 to –110 ppm (difluorodien yl ph osph ate)9 or doublet at –110 ppm
(RCOCF2P(O)(OEt)2 group)19.
In th e case of en am in on es 1e, 1f (with n itrogen atom of low basicity), th e
reaction with trieth yl ph osph ite occurs an d difluorodien yl ph osph ates 4a,
4b (products of th e Perkow rearran gem en t) are form ed un der m ild con di-
tion s (20 °C/12 h ) in h igh yields, as sh own by th e 19F an d 31P NMR spectra
of th e reaction m ixtures (Sch em e 6). Th e spectral an d ph ysicoch em ical
properties of ph osph ates 4a, 4b are very close to th ose of th eir alkoxy
an alogs syn th esized previously9. Th eir in stability un der th e con dition s of
colum n ch rom atograph y led to low yields of th e products. However, in
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340
Tarasenko, Gerus, Kukhar, Polovinko:
con trast to th e alkoxy an alogs9, we observed in 1H an d 19F NMR spectra of
th e products 4a, 4b addition al set of sign als of olefin ic h ydrogen an d fluo-
rin e atom s with th e in tegration in ten sity about 20–25% close to m ajor
products. Th is can be explain ed by eith er asym m etric substitution on th e
n itrogen atom or restricted rotation aroun d th e C–N bon d between th e
dien yl an d am ide fun ction s14,17,20. In Experim en tal we h ave listed th e spec-
tral data on ly for m ajor isom ers of com poun ds 4a, 4b.
SCHEME 6
Th e recen tly publish ed results9 dem on strate th at fluorin ated γ-brom o-
β-alkoxy-a,β-un saturated keton es 5a, 5b react with trieth yl ph osph ite form -
in g th e correspon din g dien yl ph osph ates 6a, 6b. Th e direction of th e reac-
tion stron gly depen ds on th e n ature of en on es 5 (Sch em e7).
SCHEME 7
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Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
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We believe9 th at th e dien yl ph osph ates 3 an d 6 are form ed via cyclic in -
term ediate oxaph osph ole, th e form ation of wh ich does n ot take place in
th e reaction of en am in on es 1a–1d with trieth yl ph osph ite. Takin g th is in to
accoun t th e study of th e reactivity of en am in on es 2 (am in o an alogs of
en on es 5) is of in terest. Th e startin g en am in on es 2a, 2b were syn th esized
from th e correspon din g en on es 5a an d 5c in h igh yields (Sch em e 8). Th e
21
latter was obtain ed by th e sam e m eth od as en on es 5a, 5b
.
SCHEME 8
It was foun d th at en am in on e 2a reacts with trieth yl ph osph ite in eth er
at 20 °C for 21 days affordin g trifluorom eth yl-con tain in g ph osph on ate 7a
in h igh yield as th e product of th e Arbuzov reaction . Th e use of dioxan e
as a solven t an d th e in crease in th e reaction tem perature up to 100 °C
decrease th e reaction tim e with out an y ch an ge of th e yield an d quality
of product 7a (Sch em e 9). In con trast to 2a en am in on e 2b reacts with
trieth yl ph osph ite very slowly in eth er at 20 °C (a con version after 2 weeks
by 19F NMR spectroscopy was on ly about 5%) an d th e form ation of ph os-
ph on ate 7b was also observed by 31P NMR spectroscopy of th e reaction
m ixture (a weak ch aracteristic sign al of ph osph on ate group at 26 ppm ap-
peared, th at com plied with correspon din g data of 7a). Un fortun ately, our
attem pts to decrease th e reaction tim e an d to im prove th e yield of ph os-
ph on ate 7b by an in crease in reaction tem perature failed an d a com plex
m ixture of products was obtain ed.
SCHEME 9
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Tarasenko, Gerus, Kukhar, Polovinko:
Th e structure of ph osph on ate 7a was elucidated by NMR spectroscopy.
Th us in 31P NMR spectrum of com poun d 7a a ch aracteristic ph osph on ate
sign al appeared at about 26 ppm in 13C NMR spectra th e ch aracteristic dou-
blet of m eth ylen e group lin ked to ph osph orus atom is observed at 48 ppm
1
with JCP = 132 Hz; at th e sam e tim e th e sign al of th e trifluorom eth yl group
alm ost does n ot ch an ge. We believe th at th e trifluorom eth yl con tain in g
ph osph on ate 7a is a perspective buildin g block for organ ic ch em istry, espe-
cially for h eterocyclization s an d olefin syn th esis.
CONCLUSION
New brom odifluorom eth yl en am in on es 1a–1f an d γ-brom o-β-m orph olin o-
propen yl fluorom eth yl keton es 2a, 2b were syn th esized. First exam ples of
th e reaction s of fluorin ated en am in on es with alkyl ph osph ites are pre-
sen ted. Th e scope an d lim itation s of th e reaction of ph osph ites with differ-
en t fluorin e-con tain in g en am in on es h ave been in vestigated. Ph osph oryl-
ation of N-substituted brom odifluorom eth yl-con tain in g en am in on es 1a–1d
did n ot take place, wh ereas N-acylated en am in on es 1e, 1f gave fluorin e-
con tain in g dien yl ph osph ates 4a, 4b as a result of th e Perkow rearran ge-
m en t. γ-Brom o-β-m orph olin o-α,β-un saturated trifluorom eth yl keton e 2a
reacts with trieth yl ph osph ite form in g fluorin e-con tain in g ph osph on ate 7a
as a result of th e Arbuzov reaction . Th e syn th esized fluorin e-con tain in g
com poun ds are of in terest for syn th esis due to th e form ation of h igh ly
fun ction alized organ oph osph orus com poun ds such as 1,3-dien yl ph os-
ph ates 3, 4a, 4b, an d ph osph on ate 7a.
EXPERIMENTAL
1H, 13C, 19F an d 31P NMR spectra were recorded on a Bruker DRX-500 in strum en t. Ch em ical
sh ifts (δ) are given in ppm relative to TMS (1H, 13C), CFCl3 19F), or 85% ph osph oric acid
(
(
31P); couplin g con stan ts (J) are given in Hz. Colum n ch rom atograph y was perform ed on sil-
ica gel 60 (Merck). Merck Silica Gel F254 plates were used for TLC an d visualization was ef-
fected with UV ligh t (254 n m ). Meltin g poin ts were m easured in th e open capillary; th e
values are un corrected. Dieth yl eth er an d dioxan e were dried with sodium an d ben zoph e-
n on e. Dich lorom eth an e was dried with P2O5. Th e reaction s with ph osph ites were perform ed
un der argon usin g th e Sch len k tech n ique. P(OEt)3 was com m ercially available from Aldrich .
Com poun ds 1-brom o-4-eth oxy-1,1-difluorobut-3-en -2-on e9 an d 5-brom o-1,1,1-trifluoro-
4-m eth oxypen t-3-en -2-on e21 (5a) were prepared accordin g to th e publish ed procedures.
En am in on es 1a–1d an d 2a, 2b. Gen eral Procedure
A solution of th e correspon din g am in e (5 m m ol) in dich lorom eth an e (10 m l) was added
dropwise to a solution of brom odifluorom eth yl-con tain in g en on e (5 m m ol) in dich loro-
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Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
343
m eth an e (10 m l) un der stirrin g at 0 °C. Th e m ixture was stirred at room tem perature for
10 h to com plete th e reaction . After evaporation of solven t, th e residue was crystallized
from h exan e.
4-(Benzylamino)-1-bromo-1,1-difluorobut-3-en-2-one (1a ). From brom odifluorom eth yl-
con tain in g en on e (1.15 g, 5 m m ol), product 1a (1.32 g, 91%) was obtain ed as yellow oil.
1H NMR (CDCl3, 500 MHz): 10.35 br s, 1 H (NH); 7.10–7.55 m , 6 H (ArH; =CH-N); 5.40 d,
1 H, 3J = 6.1 (=CH-C); 4.50 d, 2 H, 3J = 5.1 (CH2). 19F NMR (CDCl3, 470 MHz): –60.2 s.
2
13C NMR (CDCl3, 125 MHz): 180.7 t, JCF = 24.5; 158.1; 136.2; 129.1; 128.4; 127.6; 115.5 t,
1JCF = 319.6; 85.6; 53.3. For C11H10BrF2NO calculated: 45.54% C, 3.47% H, 4.83% N; foun d:
45.63% C, 3.48% H, 4.82% N.
(E)-1-Bromo-1,1-difluoro-4-(piperidin-1-yl)but-3-en-2-one (1b). From brom odifluorom eth yl-
con tain in g en on e (1.15 g, 5 m m ol), product 1b (1.18 g, 88%) was obtain ed as ligh t yellow
n eedle. M.p. 57–59 °C. 1H NMR (CDCl3, 500 MHz): 7.80 d, 1 H, 3J = 12.1 (=CH-N); 5.32 d,
1 H, 3J = 12.1 (=CH-C); 3.46 m , 2 H (CH2-N); 3.35 m , 2 H (CH2-N); 1.69 m , 6 H (CH2).
2
19F NMR (CDCl3, 470 MHz): –60.9 s. 13C NMR (CDCl3, 125 MHz): 180.0 t, JCF = 23.6; 135.4;
1
116.3 t, JCF = 320.8; 84.5; 55.9; 47.0; 26.5; 25.0; 23.7. For C9H12BrF2NO calculated:
40.32% C, 4.51% H, 5.22% N; foun d: 40.40% C, 4.52% H, 5.22% N.
(E)-1-Bromo-1,1-difluoro-4-(morpholin-4-yl)but-3-en-2-one (1c). From brom odifluorom eth yl-
con tain in g en on e (1.15 g, 5 m m ol), product 1c (1.19 g, 88%) was obtain ed as yellow pow-
der. M.p. 72 °C. 1H NMR (CDCl3, 500 MHz): 7.81 d, 1 H, 3J = 12.7 (=CH-N); 5.36 d, 1 H, 3J =
12.7 (=CH-C); 3.73–3.80 m , 4 H (OCH2); 3.49–3.55 m , 2 H (NCH2); 3.37–3.43 m , 2 H
2
(NCH2). 19F NMR (CDCl3, 470 MHz): –61.7 s. 13C NMR (CDCl3, 125 MHz): 180.3 t, JCF
=
1
24.3; 155.4; 115.8 t, JCF = 320.8; 85.3; 66.8; 65.6; 53.8; 46.2. For C7H10BrF2NO2 calculated:
35.58% C, 3.73% H, 5.19% N; foun d: 35.65% C, 3.73% H, 5.19% N.
(E)-1-Bromo-1,1-difluoro-4-(N-methylanilino)but-3-en-2-one (1d ). From brom odifluorom eth yl-
con tain in g en on e (1.15 g, 5 m m ol), product 1d (1.29 g, 89%) was obtain ed as yellow pow-
der. M.p. 54 °C. 1H NMR (CDCl3, 500 MHz): 8.20 d, 1 H, 3J = 12.7 (=CH-N); 7.40 m , 2 H
(ArH); 7.26 t, 1 H, 3J = 7.1 (ArH); 7.20 d, 2 H, 3J = 7.6 (ArH); 5.60 d, 1 H, 3J = 12.7 (=CH-C);
3.41 s, 3 H (CH3). 19F NMR (CDCl3, 470 MHz): –61.7 s. 13C NMR (CDCl3, 125 MHz): 180.5 t,
1
2JCF = 24.6; 153.3; 145.9; 129.8; 126.3; 121.0; 115.7 t, JCF = 319.3; 89.9; 37.7. For
C
11H10BrF2NO2 calculated: 45.54% C, 3.47% H, 4.83% N; foun d: 45.58% C, 3.48% H,
4.82% N.
(E)-5-Bromo-1,1,1-trifluoro-4-(morpholin-4-yl)pent-3-en-2-one (2a). From trifluorom eth yl-
con tain in g en on e (1.48 g, 6 m m ol), product 2a (1.63 g, 90%) was obtain ed as yellow pow-
der. M.p. 74–76 °C. 1H NMR (CDCl3, 500 MHz): 5.38 s, 1 H (=CH-C); 4.86 br s, 2 H (CH2Br);
3.84 m , 4 H (OCH2); 3.57 br m , 4 H (NCH2). 19F NMR (CDCl3, 470 MHz): –77.6 s. 13C NMR
2
1
(CDCl3, 125 MHz): 176.3 q, JCF = 31.4; 163.5; 117.4 q, JCF = 292.3; 87.6; 66.1; 47.3; 22.6.
For C9H11BrF3NO2 calculated: 35.78% C, 3.67% H, 4.64% N; foun d: 35.81% C, 3.60% H,
4.64% N.
(E)-1,5-Dibromo-1,1-difluoro-4-(morpholin-4-yl)pent-3-en-2-one (2b). From brom odifluorom eth yl-
con tain in g en on e (1.85 g, 6 m m ol), product 2b (1.9 g, 89%) was obtain ed as yellow powder.
M.p. 37–39 °C. 1H NMR (CDCl3, 500 MHz): 5.36 s, 1 H (=CH-C); 4.84 br s, 2 H (CH2Br);
3.82 m , 4 H (OCH2); 3.55 br m , 4 H (NCH2). 19F NMR (CDCl3, 470 MHz): –60.84 s. 13C NMR
2
1
(CDCl3, 125 MHz): 178.7 t, JCF = 25.8; 163.6; 115.9 t, JCF = 321.6; 86.3; 66.1; 47.3; 22.6.
For C9H11Br2F2NO2 calculated: 29.78% C, 3.05% H, 3.86% N; foun d: 29.83% C, 3.05% H,
3.86% N.
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Tarasenko, Gerus, Kukhar, Polovinko:
1-[(E)-4-Brom o-4,4-difluoro-3-oxobut-1-en -1-yl]pyrrolidin -2-on e (1e)
A solution of brom odifluoroacetyl ch loride acid (2 g, 10.34 m m ol) in dich lorom eth an e
(10 m l) was added dropwise to a m ixture of N-vin ylpyrrolidon e (1.26 g, 11.38 m m ol) an d
pyridin e (1.06 g, 13.45 m m ol) in dich lorom eth an e (15 m l) un der stirrin g at 0–4 °C. Th e
m ixture was stirred at 0 °C for 10 h to com plete th e reaction . Th en dich lorom eth an e
(20 m l) was added, th e reaction m ixture was wash ed with water (5 × 30 m l), organ ic layer
was separated an d dried with an h ydrous MgSO4. After evaporation of solven t th e product
was crystallized from h exan e to afford product 1e (2.13 g, 77%) as ligh t yellow powder. M.p.
73 °C. 1H NMR (CDCl3, 500 MHz): 8.35 d, 1 H, 3J = 14.1 (=CH-N); 5.77 d, 1 H, 3J = 14.1
(=CH-C); 3.64–3.70 m , 2 H (CH2); 2.56–3.62 m , 2 H (CH2); 2.19–2.27 m , 2 H (CH2). 19F NMR
2
(CDCl3, 470 MHz): –64.0 s. 13C NMR (CDCl3, 125 MHz): 181.0 t, JCF = 26.2; 174.6; 141.9;
1
114.4 t, JCF = 320.0; 97.9; 45.1; 30.8; 17.4. For C8H8BrF2NO2 calculated: 35.85% C,
3.01% H, 5.23% N; foun d: 35.81% C, 3.01% H, 5.24% N.
N-Ben zyl-N-[(E)-4-brom o-4,4-difluoro-3-oxobut-1-en -1-yl]-2,2,2-trifluoroacetam ide (1f)
Trifluoroacetic an h ydride (1.74 g, 8.27 m m ol) was added dropwise to a cooled (ice bath ) so-
lution of 1a (2 g, 6.89 m m ol) an d pyridin e (0.66 g, 8.27 m m ol) in dich lorom eth an e (15 m l)
un der stirrin g an d in th e argon atm osph ere. Th e coolin g bath was rem oved an d th e reaction
m ixture was stirred for 4 h . Th en th e reaction m ixture was wash ed with water (2 × 10 m l),
organ ic layer was separated an d dried with an h ydrous MgSO4. Evaporation an on ly th e sol-
ven t gave th e product 1f (2.4 g, 90%) as oil wh ich was used with out furth er purification .
1H NMR (CDCl3, 500 MHz): 8.33 d, 1 H, 3J = 13.6 (=CH-N); 7.32–7.42 m , 3 H (ArH); 7.20 d,
2 H, 3J = 6.5 (ArH); 6.15 d, 1 H, 3J = 13.6 (=CH-C); 5.07 s, 2 H (CH2). 19F NMR (CDCl32, 470 MHz):
–65.3 s, 2 F (CF2Br); –68.17 br s, 3 F (CF3). 13C NMR (CDCl3, 125 MHz): 180.1 t, JCF = 27.3;
2
1
1
158.5; 157.2 q, JCF = 37.6; 143.2; 129.3; 128.54; 126.55; 115.7 q, JCF = 288.1; 113.7 t, JCF
=
320.1; 103.0; 48.9. For C13H9BrF5NO2 calculated: 40.44% C, 2.35% H, 3.63% N; foun d:
40.52% C, 2.35% H, 3.62% N.
(E)-4-Eth oxy-1,1-difluorobuta-1,3-dien -2-yl Dieth yl Ph osph ate (3)
A solution of trieth yl ph osph ite (0.95 m l, 5.5 m m ol) in dieth yl eth er (10 m l) was added
dropwise to a solution of en on e (1.15 g, 5 m m ol) in dieth yl eth er (10 m l) at –30 °C un der
stirrin g in th e argon atm osph ere. After th e addition h ad been fin ish ed, th e tem perature of
th e reaction m ixture was arisen to room tem perature. Th e en d of th e reaction was deter-
m in ed by 31P an d 19F NMR spectra. Reaction m ixture was wash ed with 5% solution NaHCO3
(2 × 3 m l) an d dried with an h ydrous MgSO4. Th e solven t was rem oved in vacuum an d ph os-
ph ate 3 of 90% purity (1.15 g, 73%) was obtain ed as yellow oil. 1H NMR (CDCl3, 500 MHz):
6.78 d, 1 H, 3J = 12.7 (=CH-O); 5.29 dd, 1 H, 3J = 12.7, 4J = 3.3 (=CH-C); 4.07–4.26 m , 6 H
2
(3 OCH2); 1.27–1.40 m , 9 H (3 CH3). 19F NMR (CDCl3, 470 MHz): –101.11 d, 1 F, JFF = 61.2;
2
–113.46 d, 1 F, JFF = 61.2. 31P NMR (CDCl3, 202 MHz): 0.46 m .
Ph osph ates 4. Gen eral Procedure
A solution of trieth yl ph osph ite (0.95 m l, 5.5 m m ol) in dieth yl eth er (10 m l) was added
dropwise to a solution of correspon din g en am in on e (5 m m ol) in dieth yl eth er (30 m l) un der
stirrin g at 0 °C in argon . Th en th e tem perature of th e reaction m ixture was raised to room
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 2, pp. 335–346

Reactions of β-Aminovinyl Bromodifluoromethyl Ketones
345
tem perature. Th e en d of th e reaction was determ in ed by TLC, 31P an d/or 19F NMR spectra.
Th e reaction m ixture was wash ed with 5% solution of NaHCO3 (2 × 3 m l) an d dried with
an h ydrous MgSO4. Th e solven t was rem oved in vacuum an d th e product was obtain ed as
sligh tly im pure brown oil in alm ost quan titative yield. Th e product was purified by colum n
ch rom atograph y (eluen t eth yl acetate).
[(E)-1,1-Difluoro-4-(2-oxopyrrolidin-1-yl)buta-1,3-dien-2-yl] diethyl phosphate (4a) (m ajor iso-
m er). By colum n ch rom atograph y, product 4a (0.6 g, 37%) was obtain ed as yellow oil.
1H NMR (CDCl3, 500 MHz): 7.05 d, 1 H, 3J = 14.2 (=CH-O); 5.13 d, 1 H, 3J = 14.2 (=CH-C);
3.75–3.85 m , 4 H (OCH2CH3); 3.27–3.33 m , 2 H (CH2); 2.18–2.25 m , 2 H (CH2); 1.84–1.91 m ,
2
2 H (CH2); 0.99–1.07 m , 6 H (OCH2CH3). 19F NMR (CDCl3, 470 MHz): –98.5 dm , 1 F, JFF
=
2
53.6; –111.12 dm , 1 F, JFF = 53.6. 31P NMR (CDCl3, 202 MHz): 0.22 m . 13C NMR (CDCl3,
1
1
3
2
125 MHz): 173.1; 153.3 ddd, JCF = 288.7, JCF = 286.9, JCP = 6.5; 124.2; 112.4 ddd, JCF
=
2
2
2
3
43.7, JCF = 19.6, JCP = 8.5; 98.1; 64.7 d, JCP = 6.1; 44.8; 30.7; 17.1; 15.7 d, JCP = 6.1. For
C
13H20F2NO4P calculated: 48.30% C, 6.24% H, 4.33% N; foun d: 48.30% C, 6.24% H, 4.34% N.
(E)-4-(N-Benzyl-2,2,2-trifluoroacetamido)-1,1-difluorobuta-1,3-dien-2-yl diethyl phosphate (4b)
(m ajor isom er). By colum n ch rom atograph y, product 4b (0.89 g, 40%) was obtain ed as yel-
low oil. 1H NMR (CDCl3, 500 MHz): 7.09–7.35 m , 6 H (=CH-N, Ar-H); 5.68 d, 1 H, 3J = 13.4
(=CH-C); 4.96 s,
2
H
(-CH2-Ar); 4.10–4.20 m ,
4
H
(OCH2CH3); 1.25–1.35 m ,
6
H
=
2
4
(OCH2-CH3). 19F NMR (CDCl3, 470 MHz): –68.9 s, 3 F (CF3); –94.8 dd, 1 F, JFF = 45.1, JFP
6.2 (F-C=C); –108.41 dd, 1 F, JFF = 45.1, JFP = 9.1 (F-C=C). 31P NMR (CDCl3, 202 MHz):
0.58 m . 13C NMR (CDCl3, 125 MHz): 156.1 q, JCF = 37.7; 153.8 br dd, JCF = ~290; 134.4;
129.0; 127.9; 126.6; 125.5; 116.2 q, JCF = 288.3; 111.6 ddd, JCF = 43.3, JCF = 20.1, JCP
8.7; 103.9; 65.2 d, JCP = 5.5; 48.5; 15.8 d, 2J = 5.5. For C18H21F5NO4P calculated: 48.99% C,
2
4
2
1
1
2
2
2
=
2
4.80% H, 3.17% N; foun d: 49.08% C, 4.79% H, 3.18% N.
(E)-1,5-Dibrom o-1,1-difluoro-4-m eth oxypen t-3-en -2-on e (5c)
Brom in e (2.24 m l, 43.66 m m ol) was added dropwise to
a solution of en on e (10 g,
43.66 m m ol) in dich lorom eth an e (50 m l) at 0 °C with stirrin g. After 1 h , pyridin e (3.45 m l,
43.66 m m ol) was added. Th e coolin g bath was rem oved an d th e reaction m ixture was stirred
for 2 h . Th en th e reaction m ixture was wash ed with water (2 × 10 m l), organ ic layer was
separated an d dried with an h ydrous MgSO4 an d th e solven t was evaporated. Th e residue was
distilled in vacuum . Th e product (10.3 g, 76.5%) was obtain ed as yellow oil. 1H NMR
(CDCl3, 500 MHz): 5.75 s, 1 H (=CH-C); 4.47 s, 2 H (CH2Br); 3.88 s, 3 H (OCH3) 19F NMR
(CDCl3, 470 MHz): –64.0 s. For C6H6Br2F2O2 calculated: 23.40% C, 1.96% H; foun d: 23.39% C,
1.96% H.
Dieth yl [(E)-5,5,5-Trifluoro-2-m orph olin -4-yl-4-oxopen t-2-en -1-yl] Ph osph on ate (7a)
Method A. Trieth yl ph osph ite (0.66 m l, 3.81 m m ol) was added to a solution of en am in on e
2a (1 g, 3.31 m m ol) in dry eth er (10 m l) un der stirrin g in argon . Th e reaction m ixture was
stirred at room tem perature for 21 days. Th e en d of th e reaction was determ in ed by 19F an d
31P NMR spectra. Th e solven t was rem oved in vacuum . Th e product was purified by colum n
ch rom atograph y (eluen t eth yl acetate, th en m eth an ol).
Method B. Th e sam e as m eth od A but with dioxan e as th e solven t an d th e reaction m ix-
ture was stirred at 100 °C for 72 h .
By procedure A, from 1 g of en am in on e 2a, ph osph on ate 7a was obtain ed as brown oil
(0.88 g, 74%). By procedure B, from 1 g en am in on e 2a, ph osph on ate 7a was obtain ed as
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 2, pp. 335–346

346
Tarasenko, Gerus, Kukhar, Polovinko:
brown oil (0.85 g, 72%). 1H NMR (CDCl3, 500 MHz): 5.42 s, 1 H (=CH-C); 4.00–4.28 m , 6 H
(OCH2CH3); 3.79 m , 4 H (OCH2); 3.61 br m , 4 H (NCH2); 1.20–1.41 m , 6 H (C-CH2-P,
OCH2CH3). 19F NMR (CDCl3, 470 MHz): –77.7 s. 31P NMR (CDCl3, 202 MHz): 26.05 m .
2
2
1
13C NMR (CDCl3, 125 MHz): 176.12 q, JCF = 31.6; 161.15 d, JCP = 7.6; 117.15 q, JCF
=
292.1; 88.11; 66.25; 63.0 d, 2J = 6.5; 47.94 d, JCP = 132.4; 16.2 d, JCP = 6.5. For
1
3
C
13H21F3NO5P calculated: 43.46% C, 5.89% H, 3.90% N; foun d: 43.54% C, 5.89% H, 3.89% N.
This research work was supported by STCU 3558 grant.
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