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Trifluoroacetimidoyl lithium; generation and reaction with electrophiles
tWO4039,93
Temhedron Leum, Vol. 34. No. 12. pp. 1941-1944.1993 Ritcd in Great Britain
S6.00 + .OO
Pergamon Ross Ltd
Trifluoroacetimidoyl Lithium; Generation and Reaction with Electrophiles Hisayuki Watanahe, Fumio Yamashita, and Kenji Uneyama*
ofEngheering,
Department of Applied Chemistry, Faculty
Okayama University, Okayama 700, Japan
Generation and nucleophilic reactions of a-trifluoromethyl
carbanion would he a promising entry to the
syntheses of trifluoromethylated compounds of which unique proper&s play an important role in medicinal However, rapid elimination of fluoride anion
and agricultural chemistries and material sciences.l)s 2) from a-trifluoromethylated difficult.3)* 4)
sp3 carbanion makes its nucleophilic carbon-carbon
Whereas, a-trifluoromethylated
undergo smooth alkylation.5)
bond formation rather
~$2 carbanions such as trifluoropropenyl carbanion (la)
On this basis, it may he possible in principle to generate a stable a-
trifluoromethyl carbanion (lb and lc) bearing carbon-heteroatom double bond (C!=X, X = 0, NR) which can be trapped with elecuophiles.6 ) _
la; X I CR2 b;XrNR c;x=o
CF+X
Hem, we describe a generation of uifluoroacetimidoyl lithium 4.7) a synthetic quivalent
of tritluotoacetyl
lithium lc and its reaction with electrophiles which would extend a synthetic utility of tiuoroace
timidoyl
halides.8) X
n-BuLi NAr
CF3 2;Xtl
-1 1 LI@
CF&r
Electrophllo
E
-
5
4
Ar; Substituted Phenyl
3; x = Cl
The optimization of the reaction conditions was examined by the use of 2a (Ar = 2,6xylyl).
Iodine-
lithium exchange occurs smoothly at -78 “C in ether on reacting the iodide 2a with n-BuLi.
Jn contrast, butylation (substitution of chlorine with butyl group) pnnxeds exclusively on reacting the corresponding chloride 3a (Ar = 2,6_xylyl) in the same conditions. with N-lithium carhene species 6.9)
The quilibrium
The imidoyl lithium is not stable and is in quilibrium seems to be controlled by both suucture of N- aryl
group and reaction solvents. 1941
1942
Li@ 0 CF,bNAr
=
-Ar
CF+NAr
#
o@ 4
CFs
6
The lithium intermediate 6a underg~s
7
dimerization to give N, N’-~sryl-l,l.l,4P.4-hexafluoro-2-buten-
2.3-diamine 78, when there are no electrophile or less reactive ektrophiles
in the maction medimn.
Substituents on N-aryl ring of 2 and solvent msrkedly affected the reaction.
The results obtained by the
reaction of 2 with benxoyl chloride as an electtophile are summarized in Table-l. better solvent (entry 3).
Ether was found to be a
In nonpolar solvents such as hexane and tolueue the desired product 5a was
obtained in poor yields so far as examined (entries 1 and 2). obtained mainly in TH.F (entry 4).
Wheteas, the dimetixed product 70 was
Comparisolwofenay3withm~~6and7,andenoylOwithentry9
reveal the ortho substitution plays an important role in this alkylation.
Steric bulkiness of N-atyl group
would be favorable for shifting the equilibrium between 4 and 6 toward 4. Table-l
Effects of Aryl group and Solvent on the Reaction of 2 with.~Benxoyl Chkide.‘)
entry
2
Ar
solvent
yieldof5b) (96)
2,6-MezCsHj
Hexane
Sa
(trace
2a
2,6-Me&&
Toluene
St
(19)
3
2a
2,6-Me,CsH3
Ether
Sa
(62)
4
2a
2,6-Me&&Is
THF
5 a
(0)‘)
5
2P
2,6-Me&!&I3
DME
5a
(trace 1
6
2k
3,4-Me&H3
Ether
Sk
(33)
7
21
3,5-MeaCsHs
Ether
5 I
(36)
8
2m
p-MeCsHI
Ether
5 m
(-)d’
9
2n
p-MeOCsHJ
Ether
Sn
(32)
10
20
o-EtQH,
Ether
50
(43)
1
2a
2
a ) In a typical experimental procedure, to a solution of N -(2,6-xylyl)-2,2&trifluoroacetimidoy1
1
iodide (Zp)
(0.1 g, 0.31 mmol) in dry ether (1 ml) was added dxopwise n-butyllithium (0.15 ml of 2.5 M hexane solution, 0.37 mmol) under nitrogen at -78 “C and the solution was stirred for 3 min. Then, benxoyl chloride (0.067 g, 0.46 mmol) dissolved in dry ether (0.5 ml) was added dropwise.
The mixture was stitred for 15 mitt,
while the temperanne was allowed to -55 OC. The reaction mixture was quenched with water. The ether The residue was phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. purified by silica gel column chromatography.
b ) Isolated yield based on trifluoroacetimidoyl iodide 2. d ) A complex mixture of products was
c ) Dimerized product 7a (50 96 yield) was mainly obtained. obtained and Sm could not be isolated.
1943
The maction of2a with various elcclrophilcs was cxamkd
(Table-2). ReStion with both ammatic and
alipbpticacidchloridesgnvetheiminohGtanesin~yie~(enaies1.2and3). alwnatic aldehydes plocc&d
Rcactkmof2rwith
cffickntly, afford@ the imino alcohol ill excellent yiclda@micr 4 and 5).
Ketones as less reactive elcctnqhiles matted mom slowly than al&hydu to give adducts in modante yields along with dimcr 711and some unidentified compounds.
Ethyl 3,3,3-t~ifl~~N-aryliminopropa~at~
(51)
was obtained in 69 96 yield by the reaction of 2a with ethyl chloroformate. Trimethylsilyl chloride xwctcd cleanly. affcxding the desired tSh~oroacctimidoyl uimethylsilane 91, which would be a good paeanar the metal-free imidoykarbanion least rcactlve elcclqhile
corresponding to 4n. 10)
Fom~ylation did axur aidumgh DMF w
of the
(entry 10).
Table - 2 The Reaction of 2 a (Ar = 2,6-xylyl) with Ekchophik? enw
Elccrrophile
EofproductS
yieldofsb) (%)
1
Pbcoci
Pbco-
Sa
(62)
2
m-tic
m-ClC (&CO-
Sb
(61)
3
n-C sH 11COCI
n-CSH,, CO-
SC
(61)“)
4
PhCHO
PhCH(OH)-
Sd
(89)
5
p-ClC (H&HO
P-C= rH,CH(OH)_
Se
(81)
6
PbCOMe
PhCMe(OH)-
Sf
(39)
7
0
5s
(40)
8
Me3 SKI
Me, Si-
Sh
(84)
9
CICOzEt
EtOCO-
51
(69)
10
MezNCHO
HCO-
Sj
(26)‘)
~H,c!OCl
=o
H co
a ) A typical experimental procedure is similar to that of the reaction with bcnzoyl chloride described in Table-l.
b ) Isolated yield based on N -(2.6-xylyl)-2.2,2-trifluoroacctimidoyl
iodide @a). c ) Yield as the derivatives & and Sj. Both SCand 5j are unstable under the conditions of pmilication through silica gel.
+
HPN H2N
10 36 HCI aq. MeOH 8a
5 a; R’ = Ph 5 c; R’ = n-CsHll bJ;R’rH
Ar; 2,~xylyl
1944
Teidoyl
group is a synthetic equivabnt oftriBuawx.tyl
m
so that a-keto (Sa SC) ti
formyl(5j) imidoyl compounds were bansformed to the 2-trifluoto1n&yl-3-substituted
a-
quinoxaliaes 80, c,
and j in quantitative (from Sa), 61% (from 2s). and 26 96 @om 2a) yields, m.specdvely by tsertment with orthephenylew
in MeOH in the presence of 10 % HCl aq.11)
References 1 ) R. Filler and Y. Kobayashi, “Biomedicinal Aspects of Fhmrine Chemistry”, Kodansha, Tokyo (1982); M. Hudlicky, “Chemistry of Organ0 Fluorine Compounds”, Ellis Hanvood New York&(1976). 2 ) N. Ishikawa Ed., “Synthesis and Speciality of Organofluorine Compounds”, CMC, Tokyo (1987); N. Ishikawa Ed., “Biologically Active organofluarine Compounds”, CMC, Tokyo (1990). 3 ) T. Nakai, K. Tanaka, and N. Ishikawa. C&m. Lcfr.. 1976 1263; T. Nakai, K. Tanaka, H. Setoi, and N. Ishikaw& Bull. Ckm. Sot. Jpn., SO,3069 (1977). 4 ) Examples of successful a-alkylation; N. Ishiiawa and T. Yokozawa, Bull. Chem. Sot. Jpn., 56,724 (1983); T. Fuchigami and Y. Nakagawa J. Org. Chem., 52.5276 (1987); K. Uneyama and M. Momota, Bull. Chem. Sot. Jpn.. 62,3378 (1989); A. K Beck and D. Seebach, Ckm. Ber., 124,2897 (1991). 5 ) F. G. Dmkesmith, 0. J. Stewart, and P. Tanant, J. Org. Ckm., 33.280 (1%7); P. A. Morken, H. Lu, A. Nakamura, and D. J. Burton, Terrahe&on Left., 32.4271(1991);
B. Jiang and Y. Xu, J. Org. Ckm.. 56,
7336 ( 1991). 6 ) Palladation of 2 has been reported; K. Uneyama and H. Watanabe, Tefrahedron L&t., 32,1459 (1991); H. Watanabe, Y. Hashizume, and K. Uneyama, Tezruhedron L&r., 33.4333 (1992). 7 ) Nonfluorinated acylimidoyl lithiums (R1-C(Li)=NR2) have b
prepared by the naction of ix&riles
with slkyl lithiums or tin-lithium exchange reaction of ((2,6-xylylimino)(bialkylsilyl)methyl)
stannanes;
G. E. Niznik, W. H. Morrison, III. and H. M. Walborsky, J. Org. Ckm., 39,600 (1974); Y. Ito, T. Matsuura, and M. Murakami, J. Am. Chem. Sot., 109,7888 (1987). 8 ) Nucleophilic carbon-carbon bond formations of trifluoroacetimidoyl
chlorides have been reported; F.
Clemence, R. Deraedt, A. Allais, and 0. LeMartmt, Eur. Par. Appl. 12,639 (Cl. cMD215 / 56)., Ckm. Absn., 94,1559Og (1981); K. Uneyama, 0. Morimoto, and F. Yamashita, Tetrahedron Lezr., 30,482l (1989); K. Uneyama, F. Yamashita, K. Sugimoto, and 0. Morimoto, Tetrahedron L&r., 31, 2717 (1990). 9 ) A similar type equilibrium,between benz.oyl lithium and its carbcne species is known; P. Jutzi and F. W. Schroder, J. Organomet. Ckm., 24.1 (1970); N. S. Nudelman and A. A. Vitale, J. Org. Ckm., 46. 4625 (1981); D. Seyferth and R. M. Weinstein, J. Am. Ckm. Sot., 104,5534 (1982). 10) Study on fluoride ion induced generation of the metal-free trifluoroacetimidoyl carbanion from uifluoroacetimidoyl uimethylsilane (Sh) is currently in progress. 11) R. Belcher, A. Sykes, and J. C. Tatlow, J. Ckm. Sot., 1957,2393; J. J. Baldwin, P. A. Kasinger, and F. C. Novello, J. M. Sprague, and D. E. Duggan, J. Med. Chem., 18, 895 (1975); J. J. Baldwin, M. E. Christy, G. H. Denny, C. N. Habecker, M. B. Freedman, P. A. Lyle, G. S. Ponticello, S. L. Varga, D. M. Gross, and C. S. Sweet, J. Med. Ckm.. 29,1065 (1986). 12) Acknowledgement; The authors are grateful to the Ministry of Education, Cultute and Science of Japan for a financial support (No. 04555204 and No. 04453101) and the SC-NMR Laboratory of Gkayama University for 19F4biR analysis.
(Received in Japan 27 November 1992)
Temhedron Leum, Vol. 34. No. 12. pp. 1941-1944.1993 Ritcd in Great Britain
S6.00 + .OO
Pergamon Ross Ltd
Trifluoroacetimidoyl Lithium; Generation and Reaction with Electrophiles Hisayuki Watanahe, Fumio Yamashita, and Kenji Uneyama*
ofEngheering,
Department of Applied Chemistry, Faculty
Okayama University, Okayama 700, Japan
Generation and nucleophilic reactions of a-trifluoromethyl
carbanion would he a promising entry to the
syntheses of trifluoromethylated compounds of which unique proper&s play an important role in medicinal However, rapid elimination of fluoride anion
and agricultural chemistries and material sciences.l)s 2) from a-trifluoromethylated difficult.3)* 4)
sp3 carbanion makes its nucleophilic carbon-carbon
Whereas, a-trifluoromethylated
undergo smooth alkylation.5)
bond formation rather
~$2 carbanions such as trifluoropropenyl carbanion (la)
On this basis, it may he possible in principle to generate a stable a-
trifluoromethyl carbanion (lb and lc) bearing carbon-heteroatom double bond (C!=X, X = 0, NR) which can be trapped with elecuophiles.6 ) _
la; X I CR2 b;XrNR c;x=o
CF+X
Hem, we describe a generation of uifluoroacetimidoyl lithium 4.7) a synthetic quivalent
of tritluotoacetyl
lithium lc and its reaction with electrophiles which would extend a synthetic utility of tiuoroace
timidoyl
halides.8) X
n-BuLi NAr
CF3 2;Xtl
-1 1 LI@
CF&r
Electrophllo
E
-
5
4
Ar; Substituted Phenyl
3; x = Cl
The optimization of the reaction conditions was examined by the use of 2a (Ar = 2,6xylyl).
Iodine-
lithium exchange occurs smoothly at -78 “C in ether on reacting the iodide 2a with n-BuLi.
Jn contrast, butylation (substitution of chlorine with butyl group) pnnxeds exclusively on reacting the corresponding chloride 3a (Ar = 2,6_xylyl) in the same conditions. with N-lithium carhene species 6.9)
The quilibrium
The imidoyl lithium is not stable and is in quilibrium seems to be controlled by both suucture of N- aryl
group and reaction solvents. 1941
1942
Li@ 0 CF,bNAr
=
-Ar
CF+NAr
#
o@ 4
CFs
6
The lithium intermediate 6a underg~s
7
dimerization to give N, N’-~sryl-l,l.l,4P.4-hexafluoro-2-buten-
2.3-diamine 78, when there are no electrophile or less reactive ektrophiles
in the maction medimn.
Substituents on N-aryl ring of 2 and solvent msrkedly affected the reaction.
The results obtained by the
reaction of 2 with benxoyl chloride as an electtophile are summarized in Table-l. better solvent (entry 3).
Ether was found to be a
In nonpolar solvents such as hexane and tolueue the desired product 5a was
obtained in poor yields so far as examined (entries 1 and 2). obtained mainly in TH.F (entry 4).
Wheteas, the dimetixed product 70 was
Comparisolwofenay3withm~~6and7,andenoylOwithentry9
reveal the ortho substitution plays an important role in this alkylation.
Steric bulkiness of N-atyl group
would be favorable for shifting the equilibrium between 4 and 6 toward 4. Table-l
Effects of Aryl group and Solvent on the Reaction of 2 with.~Benxoyl Chkide.‘)
entry
2
Ar
solvent
yieldof5b) (96)
2,6-MezCsHj
Hexane
Sa
(trace
2a
2,6-Me&&
Toluene
St
(19)
3
2a
2,6-Me,CsH3
Ether
Sa
(62)
4
2a
2,6-Me&&Is
THF
5 a
(0)‘)
5
2P
2,6-Me&!&I3
DME
5a
(trace 1
6
2k
3,4-Me&H3
Ether
Sk
(33)
7
21
3,5-MeaCsHs
Ether
5 I
(36)
8
2m
p-MeCsHI
Ether
5 m
(-)d’
9
2n
p-MeOCsHJ
Ether
Sn
(32)
10
20
o-EtQH,
Ether
50
(43)
1
2a
2
a ) In a typical experimental procedure, to a solution of N -(2,6-xylyl)-2,2&trifluoroacetimidoy1
1
iodide (Zp)
(0.1 g, 0.31 mmol) in dry ether (1 ml) was added dxopwise n-butyllithium (0.15 ml of 2.5 M hexane solution, 0.37 mmol) under nitrogen at -78 “C and the solution was stirred for 3 min. Then, benxoyl chloride (0.067 g, 0.46 mmol) dissolved in dry ether (0.5 ml) was added dropwise.
The mixture was stitred for 15 mitt,
while the temperanne was allowed to -55 OC. The reaction mixture was quenched with water. The ether The residue was phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. purified by silica gel column chromatography.
b ) Isolated yield based on trifluoroacetimidoyl iodide 2. d ) A complex mixture of products was
c ) Dimerized product 7a (50 96 yield) was mainly obtained. obtained and Sm could not be isolated.
1943
The maction of2a with various elcclrophilcs was cxamkd
(Table-2). ReStion with both ammatic and
alipbpticacidchloridesgnvetheiminohGtanesin~yie~(enaies1.2and3). alwnatic aldehydes plocc&d
Rcactkmof2rwith
cffickntly, afford@ the imino alcohol ill excellent yiclda@micr 4 and 5).
Ketones as less reactive elcctnqhiles matted mom slowly than al&hydu to give adducts in modante yields along with dimcr 711and some unidentified compounds.
Ethyl 3,3,3-t~ifl~~N-aryliminopropa~at~
(51)
was obtained in 69 96 yield by the reaction of 2a with ethyl chloroformate. Trimethylsilyl chloride xwctcd cleanly. affcxding the desired tSh~oroacctimidoyl uimethylsilane 91, which would be a good paeanar the metal-free imidoykarbanion least rcactlve elcclqhile
corresponding to 4n. 10)
Fom~ylation did axur aidumgh DMF w
of the
(entry 10).
Table - 2 The Reaction of 2 a (Ar = 2,6-xylyl) with Ekchophik? enw
Elccrrophile
EofproductS
yieldofsb) (%)
1
Pbcoci
Pbco-
Sa
(62)
2
m-tic
m-ClC (&CO-
Sb
(61)
3
n-C sH 11COCI
n-CSH,, CO-
SC
(61)“)
4
PhCHO
PhCH(OH)-
Sd
(89)
5
p-ClC (H&HO
P-C= rH,CH(OH)_
Se
(81)
6
PbCOMe
PhCMe(OH)-
Sf
(39)
7
0
5s
(40)
8
Me3 SKI
Me, Si-
Sh
(84)
9
CICOzEt
EtOCO-
51
(69)
10
MezNCHO
HCO-
Sj
(26)‘)
~H,c!OCl
=o
H co
a ) A typical experimental procedure is similar to that of the reaction with bcnzoyl chloride described in Table-l.
b ) Isolated yield based on N -(2.6-xylyl)-2.2,2-trifluoroacctimidoyl
iodide @a). c ) Yield as the derivatives & and Sj. Both SCand 5j are unstable under the conditions of pmilication through silica gel.
+
HPN H2N
10 36 HCI aq. MeOH 8a
5 a; R’ = Ph 5 c; R’ = n-CsHll bJ;R’rH
Ar; 2,~xylyl
1944
Teidoyl
group is a synthetic equivabnt oftriBuawx.tyl
m
so that a-keto (Sa SC) ti
formyl(5j) imidoyl compounds were bansformed to the 2-trifluoto1n&yl-3-substituted
a-
quinoxaliaes 80, c,
and j in quantitative (from Sa), 61% (from 2s). and 26 96 @om 2a) yields, m.specdvely by tsertment with orthephenylew
in MeOH in the presence of 10 % HCl aq.11)
References 1 ) R. Filler and Y. Kobayashi, “Biomedicinal Aspects of Fhmrine Chemistry”, Kodansha, Tokyo (1982); M. Hudlicky, “Chemistry of Organ0 Fluorine Compounds”, Ellis Hanvood New York&(1976). 2 ) N. Ishikawa Ed., “Synthesis and Speciality of Organofluorine Compounds”, CMC, Tokyo (1987); N. Ishikawa Ed., “Biologically Active organofluarine Compounds”, CMC, Tokyo (1990). 3 ) T. Nakai, K. Tanaka, and N. Ishikawa. C&m. Lcfr.. 1976 1263; T. Nakai, K. Tanaka, H. Setoi, and N. Ishikaw& Bull. Ckm. Sot. Jpn., SO,3069 (1977). 4 ) Examples of successful a-alkylation; N. Ishiiawa and T. Yokozawa, Bull. Chem. Sot. Jpn., 56,724 (1983); T. Fuchigami and Y. Nakagawa J. Org. Chem., 52.5276 (1987); K. Uneyama and M. Momota, Bull. Chem. Sot. Jpn.. 62,3378 (1989); A. K Beck and D. Seebach, Ckm. Ber., 124,2897 (1991). 5 ) F. G. Dmkesmith, 0. J. Stewart, and P. Tanant, J. Org. Ckm., 33.280 (1%7); P. A. Morken, H. Lu, A. Nakamura, and D. J. Burton, Terrahe&on Left., 32.4271(1991);
B. Jiang and Y. Xu, J. Org. Ckm.. 56,
7336 ( 1991). 6 ) Palladation of 2 has been reported; K. Uneyama and H. Watanabe, Tefrahedron L&t., 32,1459 (1991); H. Watanabe, Y. Hashizume, and K. Uneyama, Tezruhedron L&r., 33.4333 (1992). 7 ) Nonfluorinated acylimidoyl lithiums (R1-C(Li)=NR2) have b
prepared by the naction of ix&riles
with slkyl lithiums or tin-lithium exchange reaction of ((2,6-xylylimino)(bialkylsilyl)methyl)
stannanes;
G. E. Niznik, W. H. Morrison, III. and H. M. Walborsky, J. Org. Ckm., 39,600 (1974); Y. Ito, T. Matsuura, and M. Murakami, J. Am. Chem. Sot., 109,7888 (1987). 8 ) Nucleophilic carbon-carbon bond formations of trifluoroacetimidoyl
chlorides have been reported; F.
Clemence, R. Deraedt, A. Allais, and 0. LeMartmt, Eur. Par. Appl. 12,639 (Cl. cMD215 / 56)., Ckm. Absn., 94,1559Og (1981); K. Uneyama, 0. Morimoto, and F. Yamashita, Tetrahedron Lezr., 30,482l (1989); K. Uneyama, F. Yamashita, K. Sugimoto, and 0. Morimoto, Tetrahedron L&r., 31, 2717 (1990). 9 ) A similar type equilibrium,between benz.oyl lithium and its carbcne species is known; P. Jutzi and F. W. Schroder, J. Organomet. Ckm., 24.1 (1970); N. S. Nudelman and A. A. Vitale, J. Org. Ckm., 46. 4625 (1981); D. Seyferth and R. M. Weinstein, J. Am. Ckm. Sot., 104,5534 (1982). 10) Study on fluoride ion induced generation of the metal-free trifluoroacetimidoyl carbanion from uifluoroacetimidoyl uimethylsilane (Sh) is currently in progress. 11) R. Belcher, A. Sykes, and J. C. Tatlow, J. Ckm. Sot., 1957,2393; J. J. Baldwin, P. A. Kasinger, and F. C. Novello, J. M. Sprague, and D. E. Duggan, J. Med. Chem., 18, 895 (1975); J. J. Baldwin, M. E. Christy, G. H. Denny, C. N. Habecker, M. B. Freedman, P. A. Lyle, G. S. Ponticello, S. L. Varga, D. M. Gross, and C. S. Sweet, J. Med. Ckm.. 29,1065 (1986). 12) Acknowledgement; The authors are grateful to the Ministry of Education, Cultute and Science of Japan for a financial support (No. 04555204 and No. 04453101) and the SC-NMR Laboratory of Gkayama University for 19F4biR analysis.
(Received in Japan 27 November 1992)