Generation and reaction of metal free trifluoroacetimidoyl carbanion

Full text of DOI:10.1021/jo960259t

J . Org. Chem. 1996, 61, 6055-6057
6055
Sch em e 1
Gen er a tion a n d Rea ction of Meta l F r ee
Tr iflu or oa cetim id oyl Ca r ba n ion
Kenji Uneyama,* Chiemi Noritake, and Keiji Sadamune
Department of Applied Chemistry, Faculty of Engineering,
Okayama University, Okayama 700, J apan
Received February 7, 1996
Sch em e 2
One of the synthetic methods for trifluoromethylated
compounds involves the utilization of trifluoromethyl
building blocks.1 N-Aryl-2,2,2-trifluoroacetimidoyl ha-
lides 1-3 are among the promising building blocks for
trifluoromethylated heterocycles, which are potentially
bioactive.2 We have already demonstrated a one-pot
synthesis3 of 1 and 2 and their electrophilic,4 radical,5
and nucleophilic6-8 carbon-carbon bond formations at
the imino carbon. In particular, metalations of 3 such
as palladation,6 zincation,7 and lithiation8 are useful for
the generation of the carbanion equivalents (7) (Scheme
1).
Among them, lithium species (6) behave as the most
typical carbanions, but they are unstable at room tem-
perature and must be handled below -60 °C in the case
of the N-2,6-dimethylphenyl compound and -100 °C for
the N-4-methoxyphenyl compound.8 Lithium preferably
attaches on the nitrogen atom of the imine moiety; thus
the lithium species (6) behave as carbene type intermedi-
ates (8) and predominantly dimerize at temperatures
higher than -60 °C8,9 (Scheme 2).
Sch em e 3
stable than 6. It has been reported that the quaternary
ammonium species was more useful as a counter cation
than lithium for the R-carbanion of 2,2,2-trifluoroethyl
phenyl sulfone generated by the action of LDA in THF-
HMPA. The carbanion could be trapped with CH3I and
I2.11,12 Replacement of lithium with tetraalkylammonium
cation would stabilize the carbanion (7) and promote
preferential carbon-carbon bond formation at the imine
carbon. Here, we describe a synthesis of (trifluoroace-
timidoyl)trimethylsilanes (10), fluoride ion catalyzed
generation of carbanion (12), and its reaction with
various electrophiles.
The imine moiety (CdNR) of 1-3 is equivalent to an
acyl moiety so that the trifluoroacetimidoyl carbanion
(7)10 is a synthetic equivalent of a trifluoroacetyl car-
banion.
Therefore, it is challenging to generate the metal free
trifluoroacetimidoyl carbanion (12) as the corresponding
tetraalkylammonium species, which should be more
Resu lts a n d Discu ssion
P r ep a r a tion of (Tr iflu or oa cetim id oyl)tr im eth yl-
sila n es (10). (Trifluoroacetimidoyl)trimethylsilane (10a ,
Ar ) 2,6-Me2C6H3) was prepared in 84% yield by the
reaction of (trifluoroacetimidoyl)lithium (6) with TMSCl.
But, this method was usable only for the N-2,6-dimeth-
ylphenyl compound and useless for other substituted
phenyl compounds because of the instability of 6 under
the reaction conditions.8 Then, preparation of 10 by the
action of trimethylsilyl metals on chlorides (1) was
examined. The various types of silyl metals such as
silyllithium, silylsodium, and silylpotassium were unsuc-
cessful in this reaction. A successful reagent was silyl
cuprate which was prepared by the metal exchange
reaction of (trimethylsilyl)lithium with copper(I)13 (Scheme
3).
(1) (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine
Chemistry; Kodansha Ltd.: Tokyo, 1982. (b) Hudlicky, M. Chemistry
of Organic Fluorine Compounds; Ellis Horwood: New York, 1976. (c)
Ishikawa, N. Fussokagaku no Gousei to Kinou, in J apanese; CMC:
Tokyo, 1987.
(2) (a) Ishikawa, N. Biologically Active Organofluorine Compounds;
CMC: Tokyo, 1990. (b) Welch, J . T. Tetrahedron 1987, 43, 3123. (c)
Bravo, P.; Resnati, G. Tetrahedron Asymm. 1990, 1, 661. (d) Resnati,
G. Tetrahedron 1993, 49, 9385.
(3) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J . Org. Chem. 1993, 58, 32.
(4) (a) Uneyama, K.; Morimoto, O.; Yamashita, F. Tetrahedron Lett.
1989, 30, 4821. (b) Kobayashi, M.; Sadamune, K.; Mizukami, H.;
Uneyama, K. J . Org. Chem. 1994, 59, 1909. (c) Uneyama, K.;
Yamashita, F.; Sugimoto, K.; Morimoto, O. Tetrahedron Lett. 1990,
31, 2717.
(5) (a) Dan-oh, Y.; Matta, H.; Uemura, J .; Watanabe, H.; Uneyama,
K. Bull. Chem. Soc. J pn. 1995, 68, 1497. (b) Ueda, Y.; Watanabe, H.;
Uemura, J .; Uneyama, K. Tetrahedron Lett. 1993, 34, 7933.
(6) (a) Uneyama, K.; Watanabe, H. Tetrahedron Lett. 1991, 32, 1459.
(b) Watanabe, H.; Hashizume, Y.; Uneyama, K. Ibid. 1992, 33, 4333.
(7) Tamura, K.; Yan, F.-Y.; Sakai, T.; Uneyama, K. Bull. Chem. Soc.
J pn. 1994, 67, 300.
(8) (a) Watanabe, H.; Yamashita, F.; Uneyama, K. Tetrahedron Lett.
1993, 34, 1941. (b) Watanabe, H.; Yan, F.-Y.; Sakai, T.; Uneyama, K.
J . Org. Chem. 1994, 59, 758.
(Trifluoroacetimidoyl)trimethylsilane (10a ) was thus
prepared in 55% by the reaction of trifluoroacetimidoyl
chloride (1a ) and trimethylsilyl cuprate in HMPA-THF
at -55 °C for 10 min. However, in the cases of 10b (Ar
) 4-MeOC6H4) and 10c (Ar ) 4-ClC6H4), products were
a mixture of the desired 10 and the corresponding disilyl
(9) The carbene type intermediate has been proposed for benzoyl-
lithium. (a) Trzupek, L. S.; Newirth, T. L.; Kelly, E. G.; Nudelman,
N. S.; Whitesides, G. M. J . Am. Chem. Soc. 1973, 95, 8118. (b)
Nudelman, N. S.; Vitale, A. A. J . Org. Chem. 1981, 46, 4625. (c)
Seyferth, D.; Weinstein, R. M. J . Am. Chem. Soc. 1982, 104, 5534.
(10) Nonfluorinated alkyl and aryl imidoyl metals have been
reported. (a) Niznik, G. E.; Morrison, W. H., III; Walborsky, H. M. J .
Org. Chem. 1974, 39, 600. (b) Ito, Y.; Matsuura, T.; Murakami, M. J .
Am. Chem. Soc. 1987, 109, 7888. (c) Murakami, M.; Ito, H.; Bakar,
W. A. W. A.; Baba, A. B. Chem. Lett. 1989, 1603 and other literatures
cited in the references above.
(11) Methylation and iodination on methylene of 2,2,2-trifluoroethyl
phenyl sulfone. Uneyama, K.; Momota, M. Bull. Chem. Soc. J pn. 1989,
62, 3378.
(12) It has been also reported that the quaternary ammonium cation
was useful as counter cation for the generation of enolate from
R-trifluoromethyl malonates by electrogenerated base. Fuchigami, T.;
Nakagawa, Y. J . Org. Chem. 1987, 52, 5276.
(13) (a) Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Ricci, A. J . Org.
Chem. 1988, 53, 3612. (b) Bonini, B. F.; Busi, F.; de Laet, R. C.;
Mazzanti, G.; Thuring, J .-W. J . F.; Zani, P.; Zwanenburg, B. J . Chem.
Soc., Perkin Trans. 1 1993, 1011.
S0022-3263(96)00259-9 CCC: $12.00 © 1996 American Chemical Society

6056 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
Ta ble 1. Rea ction of 1 w ith Tr im eth ylsilyl Cu p r a tea
entry
Ar
product (yield,b %)
1
2
3
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
10a (55)
10b (65)c
10c (75)c
a
1 (0.4 mmol), CuCN (0.4 mmol), and TMSLi (0.8 mmol) in dry
THF (1.5 mL), -55 °C. Isolated yield based on 1. c Yield of a
mixture of 10 and 11.
b
SiMe2SiMe3
NAr
CF3
11
10b: 11b = 89:11
10c: 11c = 92:8
Ta ble 2. Rea ction of 6 a n d 12 w ith Ben za ld eh yd e
yield of 13 (%)c
F igu r e 1. Effect of the reaction temperature.
entry
Ar
Bu4N (0 °C)a Li (0 °C)b Li (-100 °C)b
Sch em e 4
1
2
3
2,6-Me2C6H3
4-MeOC6H4
4-ClC6H4
86
0
0
0
90
70d
65d
60d
trace
a
10 (0.18 mmol), TBAF (0.18 mmol), and benzaldehyde (0.36
b
mmol) in dry THF (0.2 mL), 0 °C. 3 (0.31 mmol), n-BuLi (0.37
mmol), and benzaldehyde (0.47 mmol) in dry ether (1.5 mL), 0 or
d
-100 °C. c Isolated yield based on 10 and 3. Yields of the
compound 11.14 The best results were obtained in ratios
of 10b:11b (89:11) and 10c:11c (92:8).15 Separation of
the mixture by medium pressure column chromatography
afforded pure 10b and 10c (Table 1).
corresponding acetates.
Ta ble 3. Rea ction of 10a (N ) 2,6-Dim eth ylp h en yl) w ith
Electr op h ilesa
yield (%)b
Rea ction s of Tr iflu or oa cetim id oyl Ca r ba n ion (12)
w ith Electr op h iles. The reaction of 10a with benzal-
dehyde by the action of tetrabutylammonium fluoride
(TBAF) was conducted in the presence of 4 Å molecular
sieves in THF at room temperature. It was completed
within 3 min. The desired aldol type adduct 13a was
obtained in 88% yield (Scheme 4). This result was in
sharp contrast to the complete failure in the same
reaction of the lithium species (6) at room temperature.8
In this reaction, trifluoroacetimidoyl carbanion (12) must
be generated as an intermediate. We envisaged that the
carbanion (12) with the tetrabutylammonium counter ion
was more stable at the higher temperature than the
lithiated (6). Therefore, the stabilities of the two species
6 and 12 were compared by analyzing the yield of 13a at
each reaction temperature.
The stability of the imidoyl carbanions was dramati-
cally increased when the counter cation was changed
from lithium to tetrabutylammonium as shown in Figure
1. The reaction of the lithium species was markedly
affected by the reaction temperature, and the desired
products could not be obtained above -40 °C (circle
point). At higher temperature, the dimers 9 from 6 were
the major products. On the other hand, the metal free
carbanion 12 was stable even at 40 °C to react with
benzaldehyde without decomposition (filled circle), af-
fording 13.
entry
electrophiles
PhCHO
4-ClC6H4CHO
4-MeOC6H4CHO
n-C5H11CHO
PhCHdCHCHO
PhCOCH3
product
Bu4N (rt) Li (-78 °C)
1
2
3
4
5
6
7
8
13
14
15
16
17
18
19
20
88
80
81
67
56
71
40
46c
89
81
81
74
48
39
40
69
cyclohexanone
ClCO2Et
a
10a (0.18 mmol), TBAF (0.18 mmol), and electrophile (0.36
b
mmol) in dry THF (0.2 mL), room temperature. Isolated yield
based on 10a . c TBAF (2.5 equiv) and ClCO2Et (1.5 equiv) were
employed.
2 and 3). As shown in Table 2, the lithium species 6 gave
no 13 at 0 °C and formed the carbon-carbon bond with
benzaldehyde only at -100 °C for 6a and 6b. 4-Chlo-
rophenyl species (6c) failed even at -100 °C. In contrast
to these, the carbanions 12b and 12c were stable at 0 °C
to react with benzaldehyde, affording the adduct 13.
Next, the reaction of 12a with various electrophiles was
examined and the yields of the adducts were compared
with those obtained from 6a (Table 3). Reactions of 10a
with aromatic aldehydes proceeded readily, affording the
imino alcohols in reasonable yields (entries 1, 2, and 3)
regardless of the electronic nature of the substituent on
the benzene ring. The carbanion 12a also reacted with
hexanal to give the desired product in 67% (entry 4) and
smoothly with the less reactive R,â-unsaturated aldehyde
(entry 5) which, in contrast, gave a lower yield of 17 on
reacting with the lithium imidoyl 6 at -78 °C.8 In
particular, reaction of 12a with a less reactive ketone
gave the corresponding adduct in much higher yield
(entry 6). When ethyl chloroformate was used as an
electrophile, almost all of the starting material 10a was
recovered under the usual conditions. But, the treatment
with 2.5 molar equiv of TBAF yielded ethyl 3,3,3-
trifluoro-2-(N-arylimino)propanoate (20) up to 46% (entry
8). This suggests that the reaction proceeds via the
The effect of solvents revealed that THF and diethyl
ether were favorable, but toluene, DMF, and acetonitrile
were less useful. Therefore, THF was employed as the
solvent for the reaction of 10 with various electrophiles.
At first, reactions of 10a -c with benzaldehyde were
carried out (Table 2). The products 13b and 13c were
so unstable toward the column chromatography that they
were transformed into the corresponding acetates (entries
(14) The cleavage of the carbon-silicon bond in the reaction of Me3-
SiSiMe3 with MeLi has been proposed. Hudrlik, P. F.; Waugh, M. A.;
Hudrlik, A. M. J . Organomet. Chem. 1984, 271, 69.
(15) Determined by GC analysis.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6057
(M+, 8), 210 (66), 73 (100). Anal. Calcd for C11H31ClF3NSi
(279.76): C, 47.23; H, 4.68; N, 5.01. Found: C, 47.36; H, 4.82;
N, 4.98.
replacement of chlorine atom of ethyl chloroformate with
fluorine atom followed by the reaction of the fluorofor-
mate with 12a to give the product 20.16
11b: IR (neat) 1504, 1278, 1246, 1130, 834 cm-1; 1H NMR (200
MHz, CDCl3) δ -0.03 (s, 6 H), δ 0.13 (s, 9 H), 3.81 (s, 3 H), 6.70
(d, 2 H, J ) 8.9 Hz), 6.86 (d, 2 H, J ) 8.9 Hz); 19F NMR (188
MHz, CDCl3) δ 93.58 (CF3); 13C NMR (50 MHz, CDCl3) δ -3.45,
-1.91, 55.44, 114.00, 119.07, 121.01 (q, J C-F ) 284 Hz, CF3),
144.12, 157.52, 175.69 (q, J C-C-F ) 41 Hz, C-CF3); EI MS m/ z
(relative intensity) 333 (M+, 1), 264 (10), 131 (63), 73 (100);
HRMS calcd for C14H22F3NOSi2 (M+) 333.1190, found 333.1141
and calcd for C13H22NOSi2 (M+ - CF3) 264.1239, found 264.1240.
Exp er im en ta l Section
Gen er a l Meth od s. THF was freshly distilled from Na and
benzophenone, and HMPA was distilled from CaH2 and stored
under nitrogen over molecular sieves. A commercially available
THF solution of TBAF was also dried with 4 Å molecular sieves
prior to use. Column chromatography was carried out with E.
Merck silica gel (kieselgel 60, 230-400 mesh). The 19F NMR
1
11c: IR (neat) 1484, 1280, 1276, 1132, 834 cm-1; 1H NMR (200
MHz, CDCl3) δ -0.03 (s, 6 H), δ 0.13 (s, 9 H), 6.69 (d, 2 H, J )
8.7 Hz), 7.29 (d, 2 H, J ) 8.7 Hz); 19F NMR (188 MHz, CDCl3)
δ 93.17 (CF3); 13C NMR (50 MHz, CDCl3) δ -3.44, -1.95, 118.90,
120.80 (q, J C-F ) 280 Hz, CF3), 128.89, 130.51, 149.03, 176.98
(q, J C-C-F ) 34 Hz, C-CF3); EI MS m/ z (relative intensity) 337
(M+, 1), 268 (7), 131 (60), 73 (100); HRMS calcd for C13H19F3-
were recorded using C6F6 as an internal standard. The IR, H
NMR, and 19F NMR spectral data of compounds 14-20 were
consistent with those reported.8
Silyla tion of Tr iflu or oa cetim id oyl Ch lor id e (1). MeLi
(0.6 mL, 0.8 mmol, 1.4 M solution in hexane) was added dropwise
into a solution of hexamethyldisilane (0.2 mL, 1.2 mmol) in 0.5
mL of anhydrous HMPA under an argon atmosphere. After 15
min, 1.5 mL of THF was added to the mixture which was cooled
at 0 °C. Then, the solution of Me3SiLi was added to 38 mg (0.4
mmol) of CuCN in one portion. After being stirred for 30 min,
the mixture was added to an equimolar amount of trifluoro-
acetimidoyl chloride (1a ) (0.1 g, 0.4 mmol) in 1.5 mL of
anhydrous THF cooled at -55 °C. The mixture was stirred for
10 min and then quenched with aqueous NH4Cl and extracted
with ether. The organic layer was washed with brine, dried over
Na2SO4, filtered, and condensed. Column chromatography of
the residue gave 10a in 55% yield. The spectral data of 10a
were compared with those reported.8
NClSi2 (M+) 337.0695, found 337.0677 and calcd for C12H19
-
NClSi2 (M+ - CF3) 268.0743, found 268.0744.
Rea ction of (Tr iflu or oa cetim id oyl)tr im eth ylsila n e 10a
w ith Ben za ld eh yd e. To a mixture of (N-(2,6-dimethylphenyl)-
2,2,2-trifluoroacetimidoyl)trimethylsilane (10a ) (0.05 g, 0.18
mmol), benzaldehyde (0.04 mL, 0.36 mmol), and 4 Å molecular
sieves in dry THF (0.2 mL) was added dropwise tetrabutylam-
monium fluoride (0.18 mL, 0.18 mmol, 1.0 M solution in THF)
under nitrogen at room temperature. The mixture was stirred
for 3 min, and the usual workup gave 13a in 88% yield. The
spectral data of 13a were also compared with those reported.8
10b: IR (neat) 1506, 1282, 1246, 1124, 850 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.06 (s, 9 H), 3.81 (s, 3 H), 6.71 (d, 2 H, J ) 8.8
Hz), 6.87 (d, 2 H, J ) 8.8 Hz); 19F NMR (188 MHz, CDCl3) δ
93.06 (CF3); EI MS m/ z (relative intensity) 275 (M+, 23), 206
(98), 73 (100). Anal. Calcd for C12H16F3NOSi (275.35): C, 52.35;
H, 5.86; N, 5.09. Found: C, 52.38; H, 5.83; N, 4.85.
10c: yellow crystal, mp 48-49 °C; IR (CH2Cl2) 1482, 1192,
1130, 846 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.06 (s, 9 H), 6.70
(d, 2 H, J ) 8.7 Hz), 7.31 (d, 2 H, J ) 8.7 Hz); 19F NMR (188
MHz, CDCl3) δ 92.59 (CF3); EI MS m/ z (relative intensity) 279
13b: IR (neat) 1758, 1506, 1292, 1248, 1216, 836 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 2.15 (s, 3 H), 3.80 (s, 3 H), 6.77 (s, 1
H), 6.88 (s, 4 H), 7.16-7.36 (m, 5 H); 19F NMR (188 MHz, CDCl3)
δ 94.67 (CF3); EI MS m/ z (relative intensity) 351 (M+, 2), 202
(8), 107 (34), 43 (100). Anal. Calcd for C18H16F3O3N (351.33):
C, 61.54; H, 4.59; N, 3.99. Found: C, 61.42; H, 4.45; N, 3.76.
13c: IR (neat) 1756, 1486, 1216, 1186, 1148, 840 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 2.14 (s, 3 H), 6.62 (s, 1 H), 6.81 (d, 2
H, J ) 8.6 Hz), 7.13-7.36 (m, 7 H); 19F NMR (188 MHz, CDCl3)
δ 94.25 (CF3); EI MS m/ z (relative intensity) 355 (M+, 8), 206
(12), 107 (100), 43 (76). Anal. Calcd for C17H13ClF3O2N (355.74):
C, 57.40; H, 3.68; N, 3.94. Found: C, 57.21; H, 3.75; N, 4.18.
(16) 19F NMR analysis of crude reaction mixture after 5 min showed
peak of 145.2 ppm which was also detected in the absence of
a
imidoyltrimethylsilane 10a and almost consistent with that (145.5
ppm) of 2-ethylhexyl fluoroformate.
J O960259T