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Synthesis of tetrasubstituted vicinal difluoroolefines
Tetrahedron Letters, Vol. 36, No. 28, pp. 5007-5010, 1995 Elsevier Science Lid Printed in Great Britain 004(g4039/95 $9.50+0.00
Pergamon 0040-4039(95)00934-5
Synthesis of Tetrasubstituted Vicinal Difluoroolefines Sylvia BHdstein, Jean-Bernard Oucep*, Detlef Jacobi and Pascale Zimmermann
Marion Men'ell Dow Research Institute, Strasbourg Research Center, 16 rue d'Ankara, 67080 Strasbourg, France
Abstract: Treatment of ot-arylthioacetoacetatewith DAST afforded a ot,f$,~-trifluoroesterwhich upon desulfurization followed by HF elimination gave access to tetrasubstituted vicinal difluoroolefines. The methods available to synthesize tetrasubstituted vicinal difluoroolefines are scarce. There are two general m e t h o d s : alkylation o f 1,2-difluorovinylzinc derivatives 1 and fluorination of [~-dicarbonyl derivatives 2 with diethylaminosulfur trifluoride (DAST). Since [~-ketoesters are readily available, the latter method seemed very attractive: treatment of ethyl acetoacetate l a with DAST in N-methyl-2-pyrrolidinone afforded ethyl 2,3-difluorobutenoate 2a as a 1:1 E:Z mixture along with the thio derivative 3a (Scheme 1).
0
F
.OS(O)N(C21-1,02
F 2a R: CH 3 50% 2b R : n-C3H7 trace
la R:CH 3 l b R : n-C3H7
F 3a R : C H 3 3b R : n-C3H7 52%
a) DAST (2.2 eq), 1-methyl-2-pyrrolidinone, 2 to 3 days, RT. Scheme I In our hands ethyl 3-0xohexanoate gave mainly 3 b and traces of difluoroolefine 2b. The mechanism proposed by W.J. Middleton 3 postulated reaction of the ethyl acetoacetate enol form, followed by an intramolecular fluorine transfer to give ethyl tx-fluomacetoacetate 4a. Further reaction with D A S T gave the difluoroolefine 2a (scheme 2). F
OH
./
(
cooc~.e~=. / ~ cooc~H,_--~" c~COOC~,
H3C ~
DAST
I / N(C2Hs)2 Q~'~F
H3C
L H3C" 4a
/COOC2HsDAST ~_FCOOC2H5 T HaG" T F F 2a
Scheme 2
5007
5008
The products of type 3 could arise from reaction of ethyl (x-fluoroacetoacetate enol form with DAST followed by hydrolysis during work up procedure (scheme 3). F
I / N(C2Hs)2 o~S~F QS(O)N(C21-1s)2 I DAST [ H20 4a ~ ~ ./COOC2H5~ ~/C00C2H5 -~COOC21.1S H3C/ " ~ -HF H3Cf T H3C F F F 3a OH
Scheme 3 One way to avoid the formation of product 3 could be to favorise the acetoacetate enolization and to restrict a-fluoroacetoacetate enolization. This goal could be achieved by introduction of a labile substituent at the tx position. Ethyl ~-arylthioacetoacetate fulfilled these goals: depending on the aryl group, the ratio of enolization is in the range of 85-100 %4 and a thioether ~ to a carbonyl group is easily cleaved using tri-nbutyltin hydride5. Thus, treatment of ethyl ct-arylthio-~-ketohexanoate 5 with DAST (1.25 eq) in methylene chloride afforded the trifluoroderivative 6. Subsequent desulfurization using tri-n-butyltin hydride in refluxing toluene with a catalytic amount of tx,~'-azoisobutyronitrile (AIBN) afforded ethyl 2,3,3-difluorobexanoate 7b. Finally HF elimination yielded ethyl 2,3-difluoro-2-hexenoate 2b as a 1:4 E:Z mixture (scheme 4).
COOC2Hs C3H
F
a ~_~
/ ~
03H7~ SAr 5 E
C'aH7"
b .~
6 40-70% F
F
T F 7b 88-92%
/jCOOC2H5 T SAr
C.jH F 2b 65-75% (?8/22 Z/E)
a) DAST (l.25eq), CH2C12, -78°C to RT, 2 days; b) n-Bu3SnH (l.5eq), AIBN (cat.), Toluene, reflux, 6h; c) [(CH3)3Si]2N'Na+ (1. l eq), THF, RT, lh. Scheme 4 Aryl group substitution had little effect on fluorination of 5 by DAST, however a basic aromatic group (2- or 4-thiopyridine) gave no trifluoro derivative 6. Careful analysis of the reaction with DAST showed several side products. When 5e (At = 4-BrC6H4) was treated with methyl DAST, we were able to isolate three side products along with some starting material 5c (scheme 5).
5009
COOCH3
H3C
a ~
COOCH3 +
H3C
SC61-1,1Br-4
SCsH4Br-4
5c
6c 44%
. , ~ ?(O)N(CH3)2 H3C" 0 ~l COOCH3+ H3C SCd.-14Br-4 8c 24%
F COOCH3 ~ C O O C H 3 + SC6H4Br-4 H3C SCeH4Br-4 9c traces
10c 8%
a) MeDAST (l.25eq), CH2C12, -78°C to RT, 2 days. Scheme 5 The W. J. Middleton3 mechanism can only account for the formation of ct-fluoroacetoacetate 9e which was converted into trifluoro derivative 6c without possibility of elimination. But the following mechanism could explain all the products present in the mixture. The enol form of acetoacetate 5 reacts with the iminium form of DAST. The adduct 11 through iminium 12 would undergo simultaneously addition of fluorine ion and cyclization to give a four membered ring derivative 13. All the products formed in the fluorination of 5 could derive from 13. Fragmentation of the oxygen sulfur bond would give after hydrolysis product 8. Cyclo elimination of DAST moiety would yield monofluoroolefine 10. Finally the four membered ring would be opened by cleavage of the sulfur carbon bond assisted by the arylthio moiety to give a sulflnium derivative 14 which would then be converted into 15 by fluoride addition. Intermediate 15 would give either o~fluoroacetoacetate 16, or trifluoro derivative 6 after further fluorination (Scheme 6).
F ,,,.,,~ / COOR +
H30/ ~
E"
/
"
"
C2Hs
SAt I
_~ ~ N"'-C2H5 t.COOCH3~.,S/Va(" ~-"~F~,~C ~-"~" .,,c
,,,,,.1%~.,,. ij b
.
~c/"
o
10
T 11 ~
.C2Hs a
)
°"'
C2Hs I
a,.
~
~
oo.
14
I~p
~COOR H3C" I ~ "SAt F F
O /S(O)N(C~'Is)2
~ " ~ COOR
, coo. SAt
8
OH
~COOR I"~C" I ~ F +,%~r
" "
F" ' 12
F~ N+'~C2Hs / [ ~ ~ I"I20 H3C"
13 , ~ . J b
O"
!
H~ ~ 1 , , I " COOR ~C-
5
F\
/C H,
F
~, i..bC
,, SAt
15
16
Scheme 6
COOR
SAt 6
COOR
5010
In some cases trifluoro derivatives of type 6 were very difficult to separate from secondary products. Thus, we looked for alternative sequence. Treatment of acetoacetate type 5 with sodium hydride and selectfluor®6 afforded cleanly the 0t-fluoroacetoacetate 16a which treated with DAST yielded trifluoro derivative 6a 7 (Scheme 7). OH
O
~ ~COOC2H 5 a ~ , ~ H3C- ~" H3C /
b COOC2H5
6a 95%
SCeH5 SCeHs 5a 16a 95% a) Nail (leq), THF, RT, 30min; Selectfluor~ (1 .leq), DMF, RT, lh30;
b) DAST (1.5eq), CI-12C12,RT. Scheme 7 By introducing the o~-arylthio-~-ketoester moiety this method could be used to synthesize difluoro analogs of natural products containing difluoroolefine. 8 REFERENCES AND NOTES
2.
Gillet, J.P.; SauvStre, R.; Normant, J.F. Tetrahedron Lett. 1985, 26, 3999-4002; Nguyen, T.; Wakselman, C. J. Org. Chem. 1989, 54, 5640-5642. Asato, A.E.; Liu, R.S.H. Tetrahedron Lett. 1986, 27, 3337-3340.
3. 4.
Hudlicky, M. Organic Reactions; John Wiley & Sons, inc : New York, 1985; 35; p. 526. Sasaki, T.; Hayakawa, K.; Ban, H. Tetrahedron 1982, 38, 85-91.
5. 6.
Gutierrez, C.G.; Summerhays, L.R.J. Org. Chem. 1984, 49, 5206-5213. Selectfluor® 1-chloromethyl-4-fluoro-l,4-diazoniabicyclo [2.2.2] octane ditetrafluoroborate. Banks, R.E.; Mohialdin-Khaffaf, S.N.; Lal, G.S.; Sharif, I.; Syvret, R.G.J. Chem. Soc., Chem. Commun. 1992, 595-596. All new compounds gave spectroscopic data in agreement with the assigned structure : 2b E/Z had 19F NMR ~ (188.38 MHz, CDC13, C6F6) -5.29 (1F, dt, J=129, 7 Hz, F2E) 7.19 (1F, s, F2Z), 37.21 (1F, dt, J = 129, 22.9 Hz, F3E), 54.94 (1F, t, J=25.5 Hz, F3Z). 6(: had IH NMR ~ (300 MHz, CDCI3, TMS) 1.88 (3H, dt, J= 2.1, 19.1 Hz, I-I4),3.61 (3H, s, OCH3), 7.30-7.55 (4H, m, HAt); 19F NMR 8 (282.4 MHz,
1.
7.
CDC13, C6F6) 19.36 (1F, t, J=12.4 Hz, F3), 64.63 (2F, m, J=256.2 Hz, F3). 7b had 1H NMR 6 (300 MHz, CDC13, TMS) 1.00 (3H, t, J=7.4 Hz, H6), 1.34 (3H, t, J=7.3 Hz; O-C-CH3), 1.58 (2H, m, H5), 1.85-2.15 (2H, m, H4), 4.34 (2H, q, J=7.3 Hz, OCH2), 4.92 (1H, ddd, J=47.1, 11.7, 8.8 Hz, H2); 19F NMR 8 (282.4 MHz, CDC13, C6F6) 39.47 (1F, dt, J=47.2, 20.7 Hz, F2), 54.00 (2F, m, J=259.3 Hz, F3). 8c had 1H NMR 6 (200 MHz, CDC13, TMS) 2.38 (3H, s, H4), 2.90 (6H, s, NCH3), 3.71 (3H, s, OCH3),
7.35-7.60 (4H, m, HAt). 10c had 1H NMR 8 (200 MHz, CDC13, TMS) 2.40 (3H, d, J=16.4 Hz, HI), 3.74 (3H, s, -OCH3), 7.05-7.50 (4H, m, HAr); 19FNMR 5 (188.3 MHz, CDC13, C6H6) 100.77 (1F, q, J=16.2 Hz, F2). 16a had IH NMR 8 (200 MHz, CDCI3, TMS) 1.21 (3H, t, J=7.2 I-Iz, O-C-CH3), 2.22 (3H, d, J=3.2 I-Iz, H4), 4.21 (2H, q, J=7.1 Hz, OCH2), 7.30-7.65 (5H, m, HAr); 191=NMR 6 (188.3 MHz, 8.
CDCI3, C6F6) 26.89 (1F, q, J=3.3 Hz). See forthcoming publication.
(Received in France 12 April 1995; accepted 19 May 1995)
Pergamon 0040-4039(95)00934-5
Synthesis of Tetrasubstituted Vicinal Difluoroolefines Sylvia BHdstein, Jean-Bernard Oucep*, Detlef Jacobi and Pascale Zimmermann
Marion Men'ell Dow Research Institute, Strasbourg Research Center, 16 rue d'Ankara, 67080 Strasbourg, France
Abstract: Treatment of ot-arylthioacetoacetatewith DAST afforded a ot,f$,~-trifluoroesterwhich upon desulfurization followed by HF elimination gave access to tetrasubstituted vicinal difluoroolefines. The methods available to synthesize tetrasubstituted vicinal difluoroolefines are scarce. There are two general m e t h o d s : alkylation o f 1,2-difluorovinylzinc derivatives 1 and fluorination of [~-dicarbonyl derivatives 2 with diethylaminosulfur trifluoride (DAST). Since [~-ketoesters are readily available, the latter method seemed very attractive: treatment of ethyl acetoacetate l a with DAST in N-methyl-2-pyrrolidinone afforded ethyl 2,3-difluorobutenoate 2a as a 1:1 E:Z mixture along with the thio derivative 3a (Scheme 1).
0
F
.OS(O)N(C21-1,02
F 2a R: CH 3 50% 2b R : n-C3H7 trace
la R:CH 3 l b R : n-C3H7
F 3a R : C H 3 3b R : n-C3H7 52%
a) DAST (2.2 eq), 1-methyl-2-pyrrolidinone, 2 to 3 days, RT. Scheme I In our hands ethyl 3-0xohexanoate gave mainly 3 b and traces of difluoroolefine 2b. The mechanism proposed by W.J. Middleton 3 postulated reaction of the ethyl acetoacetate enol form, followed by an intramolecular fluorine transfer to give ethyl tx-fluomacetoacetate 4a. Further reaction with D A S T gave the difluoroolefine 2a (scheme 2). F
OH
./
(
cooc~.e~=. / ~ cooc~H,_--~" c~COOC~,
H3C ~
DAST
I / N(C2Hs)2 Q~'~F
H3C
L H3C" 4a
/COOC2HsDAST ~_FCOOC2H5 T HaG" T F F 2a
Scheme 2
5007
5008
The products of type 3 could arise from reaction of ethyl (x-fluoroacetoacetate enol form with DAST followed by hydrolysis during work up procedure (scheme 3). F
I / N(C2Hs)2 o~S~F QS(O)N(C21-1s)2 I DAST [ H20 4a ~ ~ ./COOC2H5~ ~/C00C2H5 -~COOC21.1S H3C/ " ~ -HF H3Cf T H3C F F F 3a OH
Scheme 3 One way to avoid the formation of product 3 could be to favorise the acetoacetate enolization and to restrict a-fluoroacetoacetate enolization. This goal could be achieved by introduction of a labile substituent at the tx position. Ethyl ~-arylthioacetoacetate fulfilled these goals: depending on the aryl group, the ratio of enolization is in the range of 85-100 %4 and a thioether ~ to a carbonyl group is easily cleaved using tri-nbutyltin hydride5. Thus, treatment of ethyl ct-arylthio-~-ketohexanoate 5 with DAST (1.25 eq) in methylene chloride afforded the trifluoroderivative 6. Subsequent desulfurization using tri-n-butyltin hydride in refluxing toluene with a catalytic amount of tx,~'-azoisobutyronitrile (AIBN) afforded ethyl 2,3,3-difluorobexanoate 7b. Finally HF elimination yielded ethyl 2,3-difluoro-2-hexenoate 2b as a 1:4 E:Z mixture (scheme 4).
COOC2Hs C3H
F
a ~_~
/ ~
03H7~ SAr 5 E
C'aH7"
b .~
6 40-70% F
F
T F 7b 88-92%
/jCOOC2H5 T SAr
C.jH F 2b 65-75% (?8/22 Z/E)
a) DAST (l.25eq), CH2C12, -78°C to RT, 2 days; b) n-Bu3SnH (l.5eq), AIBN (cat.), Toluene, reflux, 6h; c) [(CH3)3Si]2N'Na+ (1. l eq), THF, RT, lh. Scheme 4 Aryl group substitution had little effect on fluorination of 5 by DAST, however a basic aromatic group (2- or 4-thiopyridine) gave no trifluoro derivative 6. Careful analysis of the reaction with DAST showed several side products. When 5e (At = 4-BrC6H4) was treated with methyl DAST, we were able to isolate three side products along with some starting material 5c (scheme 5).
5009
COOCH3
H3C
a ~
COOCH3 +
H3C
SC61-1,1Br-4
SCsH4Br-4
5c
6c 44%
. , ~ ?(O)N(CH3)2 H3C" 0 ~l COOCH3+ H3C SCd.-14Br-4 8c 24%
F COOCH3 ~ C O O C H 3 + SC6H4Br-4 H3C SCeH4Br-4 9c traces
10c 8%
a) MeDAST (l.25eq), CH2C12, -78°C to RT, 2 days. Scheme 5 The W. J. Middleton3 mechanism can only account for the formation of ct-fluoroacetoacetate 9e which was converted into trifluoro derivative 6c without possibility of elimination. But the following mechanism could explain all the products present in the mixture. The enol form of acetoacetate 5 reacts with the iminium form of DAST. The adduct 11 through iminium 12 would undergo simultaneously addition of fluorine ion and cyclization to give a four membered ring derivative 13. All the products formed in the fluorination of 5 could derive from 13. Fragmentation of the oxygen sulfur bond would give after hydrolysis product 8. Cyclo elimination of DAST moiety would yield monofluoroolefine 10. Finally the four membered ring would be opened by cleavage of the sulfur carbon bond assisted by the arylthio moiety to give a sulflnium derivative 14 which would then be converted into 15 by fluoride addition. Intermediate 15 would give either o~fluoroacetoacetate 16, or trifluoro derivative 6 after further fluorination (Scheme 6).
F ,,,.,,~ / COOR +
H30/ ~
E"
/
"
"
C2Hs
SAt I
_~ ~ N"'-C2H5 t.COOCH3~.,S/Va(" ~-"~F~,~C ~-"~" .,,c
,,,,,.1%~.,,. ij b
.
~c/"
o
10
T 11 ~
.C2Hs a
)
°"'
C2Hs I
a,.
~
~
oo.
14
I~p
~COOR H3C" I ~ "SAt F F
O /S(O)N(C~'Is)2
~ " ~ COOR
, coo. SAt
8
OH
~COOR I"~C" I ~ F +,%~r
" "
F" ' 12
F~ N+'~C2Hs / [ ~ ~ I"I20 H3C"
13 , ~ . J b
O"
!
H~ ~ 1 , , I " COOR ~C-
5
F\
/C H,
F
~, i..bC
,, SAt
15
16
Scheme 6
COOR
SAt 6
COOR
5010
In some cases trifluoro derivatives of type 6 were very difficult to separate from secondary products. Thus, we looked for alternative sequence. Treatment of acetoacetate type 5 with sodium hydride and selectfluor®6 afforded cleanly the 0t-fluoroacetoacetate 16a which treated with DAST yielded trifluoro derivative 6a 7 (Scheme 7). OH
O
~ ~COOC2H 5 a ~ , ~ H3C- ~" H3C /
b COOC2H5
6a 95%
SCeH5 SCeHs 5a 16a 95% a) Nail (leq), THF, RT, 30min; Selectfluor~ (1 .leq), DMF, RT, lh30;
b) DAST (1.5eq), CI-12C12,RT. Scheme 7 By introducing the o~-arylthio-~-ketoester moiety this method could be used to synthesize difluoro analogs of natural products containing difluoroolefine. 8 REFERENCES AND NOTES
2.
Gillet, J.P.; SauvStre, R.; Normant, J.F. Tetrahedron Lett. 1985, 26, 3999-4002; Nguyen, T.; Wakselman, C. J. Org. Chem. 1989, 54, 5640-5642. Asato, A.E.; Liu, R.S.H. Tetrahedron Lett. 1986, 27, 3337-3340.
3. 4.
Hudlicky, M. Organic Reactions; John Wiley & Sons, inc : New York, 1985; 35; p. 526. Sasaki, T.; Hayakawa, K.; Ban, H. Tetrahedron 1982, 38, 85-91.
5. 6.
Gutierrez, C.G.; Summerhays, L.R.J. Org. Chem. 1984, 49, 5206-5213. Selectfluor® 1-chloromethyl-4-fluoro-l,4-diazoniabicyclo [2.2.2] octane ditetrafluoroborate. Banks, R.E.; Mohialdin-Khaffaf, S.N.; Lal, G.S.; Sharif, I.; Syvret, R.G.J. Chem. Soc., Chem. Commun. 1992, 595-596. All new compounds gave spectroscopic data in agreement with the assigned structure : 2b E/Z had 19F NMR ~ (188.38 MHz, CDC13, C6F6) -5.29 (1F, dt, J=129, 7 Hz, F2E) 7.19 (1F, s, F2Z), 37.21 (1F, dt, J = 129, 22.9 Hz, F3E), 54.94 (1F, t, J=25.5 Hz, F3Z). 6(: had IH NMR ~ (300 MHz, CDCI3, TMS) 1.88 (3H, dt, J= 2.1, 19.1 Hz, I-I4),3.61 (3H, s, OCH3), 7.30-7.55 (4H, m, HAt); 19F NMR 8 (282.4 MHz,
1.
7.
CDC13, C6F6) 19.36 (1F, t, J=12.4 Hz, F3), 64.63 (2F, m, J=256.2 Hz, F3). 7b had 1H NMR 6 (300 MHz, CDC13, TMS) 1.00 (3H, t, J=7.4 Hz, H6), 1.34 (3H, t, J=7.3 Hz; O-C-CH3), 1.58 (2H, m, H5), 1.85-2.15 (2H, m, H4), 4.34 (2H, q, J=7.3 Hz, OCH2), 4.92 (1H, ddd, J=47.1, 11.7, 8.8 Hz, H2); 19F NMR 8 (282.4 MHz, CDC13, C6F6) 39.47 (1F, dt, J=47.2, 20.7 Hz, F2), 54.00 (2F, m, J=259.3 Hz, F3). 8c had 1H NMR 6 (200 MHz, CDC13, TMS) 2.38 (3H, s, H4), 2.90 (6H, s, NCH3), 3.71 (3H, s, OCH3),
7.35-7.60 (4H, m, HAt). 10c had 1H NMR 8 (200 MHz, CDC13, TMS) 2.40 (3H, d, J=16.4 Hz, HI), 3.74 (3H, s, -OCH3), 7.05-7.50 (4H, m, HAr); 19FNMR 5 (188.3 MHz, CDC13, C6H6) 100.77 (1F, q, J=16.2 Hz, F2). 16a had IH NMR 8 (200 MHz, CDCI3, TMS) 1.21 (3H, t, J=7.2 I-Iz, O-C-CH3), 2.22 (3H, d, J=3.2 I-Iz, H4), 4.21 (2H, q, J=7.1 Hz, OCH2), 7.30-7.65 (5H, m, HAr); 191=NMR 6 (188.3 MHz, 8.
CDCI3, C6F6) 26.89 (1F, q, J=3.3 Hz). See forthcoming publication.
(Received in France 12 April 1995; accepted 19 May 1995)