Novel generation of 3,3,3-trifluoropropynyllithium and transformation of the carbonyl adducts to trifluoromethyl-substituted allenes

Article abstract of DOI:10.1055/s-2007-977422

A novel method for the generation of 3,3,3-trifluoropropynyllithium is reported, which involves treatment of trifluoromethyl-substituted enol tosylate, prepared from 1,1-dichloro-3,3,3-trifluoroacetone, with two equivalents of butyllithium. Palladium-cata

Full text of DOI:10.1055/s-2007-977422

CLUSTER
1163
Novel Generation of 3,3,3-Trifluoropropynyllithium and Transformation of
the Carbonyl Adducts to Trifluoromethyl-Substituted Allenes
G
eneration of 3, 3,3-Tr
i
fluoropropsynyllithiumaki Shimizu,* Masahiro Higashi, Youhei Takeda, Guofang Jiang, Masahito Murai, Tamejiro Hiyama
Department of Material Chemistry, Graduate School of Engineering, Kyoto University Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Fax +81(75)3832445; E-mail: shimizu@npc05.kuic.kyoto-u.ac.jp
Received 2 February 2007
At first, acetone 2 was converted into enol tosylate 3 in
Abstract: A novel method for the generation of 3,3,3-trifluoro-
97% yield by treatment with p-toluenesulfonyl chloride in
propynyllithium is reported, which involves treatment of trifluo-
romethyl-substituted enol tosylate, prepared from 1,1-dichloro-
3,3,3-trifluoroacetone, with two equivalents of butyllithium.
the presence of triethylamine (Equation 1).5 Tosylate 3
was easily isolated by distillation under reduced pressure
Palladium-catalyzed coupling reaction of sulfonates of the carbonyl (bp 122 °C/2 Torr) and the gram-scale preparation was
possible.5
adducts with organozinc reagents gave trifluoromethyl-containing
tri- and tetrasubstituted allenes.
Key words: alkynes, allenes, fluorine, lithium, palladium
TsCl (1.1 equiv)
Et3N (1.2 equiv)
Cl
Cl
CF3
CF3
OTs
Cl
Cl
CH2Cl2, r.t.
97%
O
Since trifluoromethyl-containing compounds have found
diverse applications in pharmaceutical, agrochemical, and
materials sciences, development of facile synthetic meth-
ods for the preparation of trifluoromethylated compounds
is one of the significant issues in organic synthesis.1 3,3,3-
Trifluoropropynylated compounds serve as versatile
building blocks for trifluoromethylated target molecules,
because diverse synthetic transformations of a carbon–
carbon triple bond are available.2 For example, trifluoro-
methylated benzofurans,2a sugars,2b isoquinolines,2d and
pyrazoles2g were synthesized starting from 3,3,3-tri-
fluoropropynylated compounds. To incorporate a 3,3,3-
trifluoropropynyl group into an organic compound, 3,3,3-
trifluoropropynyllithium (1) is widely used.3 Although 1
is efficiently generated by deprotonation of 3,3,3-tri-
fluoropropyne (bp –48 °C) with butyllithium, treatment of
2-bromo-3,3,3-trifluoropropene (bp 33 °C), or 1,1,1,3,3-
pentafluoropropane (bp 15 °C) with LDA, and by treat-
ment of (Z)-2,3,3,3-tetrafluoro-1-iodoprop-1-ene with
butyllithium, these protocols have to use volatile starting
materials or require multistep transformation from com-
mercially available 2,2,3,3,3-pentafluoropropan-1-ol in
the case of the last procedure. Thus, facile method of the
generation is desired in view of easy handling and con-
venience. In continuing our synthetic research on tri-
fluoromethylated molecules utilizing 1,1-dichloro-3,3,3-
trifluoroacetone (2) as a C3-building block,4 we turned
our attention to the generation of 1 from 2. We report
herein that novel generation and carbonyl addition of 1.
In addition, synthetic transformation of the carbonyl
adducts to trifluoromethyl-substituted allenes is also
demonstrated.
2
3
Equation 1 Preparation of enol tosylate 3
A THF solution of 3 (1.0 equiv) was treated with 2.0
equivalents of butyllithium at –78 °C. To the solution was
added an aldehyde or ketone (1.1 equiv) at –78 °C and the
resulting solution was allowed to warm to room tempera-
ture before quenching with aqueous NH4Cl solution
(Equation 2).6 The results are shown in Table 1. Aromatic
and aliphatic aldehydes as well as ketones produced pro-
pargylic alcohols 4 in good to excellent yields. Thus, it is
apparent that the present protocol is a facile and efficient
method for the generation of 1.
BuLi
R1R2CO
R1
(2.0 equiv)
(1.1 equiv)
R2
3
Li
CF3
CF3
THF
–78 °C
–78 °C
to r.t.
HO
1
4
Equation 2 Generation and carbonyl addition of 1
In order to examine the synthetic utility of 4, we carried
out palladium-catalyzed coupling reaction of propargyl
sulfonates 5 derived from 4 with organozinc reagents to
synthesize trifluoromethyl-substituted allenes, prepara-
tion of which remains unexplored.7,8 Alcohols 4a,b,g
were converted into tosylates 5a,b,g (Table 2, entries 1, 2,
and 6), while sterically hindered tertiary alcohols 4e,h
were mesylated to afford 5e,h (Table 2, entries 5 and 7).9
Coupling reaction of 5a with PhZnCl prepared from Ph-
MgBr and ZnCl2·TMEDA in the presence of Pd(PPh3)4 (5
mol%) gave 6a in low yield due probably to the instability
of 5a (Table 2, entry 1). Meanwhile, phenylated allenes
6b,e,g,h were produced under the same conditions and
isolated by column chromatography on silica gel in mod-
erate to good yields (entries 2, 5–7).10 Trimethylsilyl-
methylzinc chloride also reacted with 5b and 5h in the
SYNLETT 2007, No. 7, pp 1163–1165
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-977422; Art ID: Y00307ST
© Georg Thieme Verlag Stuttgart · New York

1164
M. Shimizu et al.
CLUSTER
Table 1 Carbonyl Addition of 1a
In summary, we have developed a facile two-step method
for the generation of 3,3,3-trifluoropropynyllithium start-
ing from DCTFA, which is applicable to gram-scale
preparation of 3,3,3-trifluoropropynylated carbinols.
Sulfonates of the carbonyl adducts can be transformed
into trifluoromethyl-containing tri- and tetrasubstituted
allenes conveniently via palladium-catalyzed cross-cou-
pling reaction with organozinc reagents.
Entry
R1
R2
H
4
Yield (%)b
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
97
95
92
71
92
88
84
72
Ph(CH2)2
c-Hex
H
H
(E)-PhCH=CH
Ph
H
Ph
Me
CF3
Acknowledgment
Ph
This work was supported by Grant-in-Aid for Creative Scientific
Research, No 16GS0209, from Ministry of Education, Culture,
Sports, Science, and Technology, Japan. The authors thank Central
Glass Co Ltd. for the generous gift of 1,1-dichloro-3,3,3-trifluoro-
acetone.
Ph
4g
4h
–(CH2)5–
a Compound 3 (1.0 equiv), BuLi (1.6 M in hexane, 2.0 equiv),
R1R2CO (1.1 equiv), THF, –78 °C.
b Isolated yield.
References and Notes
(1) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Fluorine-
Containing Molecules: Structure, Reactivity, Synthesis, and
Applications; Liebman, J. F.; Greenberg, A.; Dolbier, W. R.
Jr., Eds.; VCH: Weinheim, 1988, 1. (c) Begue, J.-P.;
Bonnet-Delpon, D. Tetrahedron 1991, 47, 3207.
presence of a catalytic amount of Pd(PPh3)4 to give silyl-
methylated allenes 6b¢,h¢ (entries 3 and 8). When 4b was
treated with Et2Zn under the conditions, hydride incorpo-
ration took place giving rise to 6b¢¢ in good yield (entry 4),
which could be reasonable by assuming that b-elimination
of an ethyl group on a Pd complex, generated by oxidative
addition of a Pd catalyst into 4b followed by transmetalla-
tion with Et2Zn, and subsequent reductive elimination of
the hydride complex.
(d) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555. (e) Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Organofluorine Chemistry: Principles and Commercial
Applications; Plenum Press: New York, 1994.
(f) Chemistry of Organic Fluorine Compounds II: A Critical
Review; Hudlicky, M.; Pavlath, A. E., Eds.; ACS Mono-
graph 187, American Chemical Society: Washington/DC,
1995. (g) Hiyama, T. Organofluorine Compounds –
Chemistry and Applications; Springer: Berlin, 2000.
(h) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005,
44, 214.
R1
R1
R2
CF3
R3
R3ZnCl (3.0 equiv)
R2
CF3
•
Pd(PPh3)4 (5 mol%)
THF, 0 °C to r.t.
RO
(2) (a) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara, T.;
Suzuki, A. Bull. Chem. Soc. Jpn. 1990, 63, 2124.
(b) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org. Chem.
1995, 60, 6046. (c) Jeong, I. H.; Jeon, S. L.; Kim, B. T.
Tetrahedron Lett. 2003, 44, 7213. (d) Chae, J.; Konno, T.;
Ishihara, T.; Yamanaka, H. Chem. Lett. 2004, 33, 314.
(e) Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.; Ishihara, T.;
Yamanaka, H. Tetrahedron 2005, 61, 9391. (f) Konno, T.;
Chae, J. H.; Miyabe, T.; Ishihara, T. J. Org. Chem. 2005, 70,
10172. (g) Hanamoto, T.; Egashira, M.; Ishizuka, K.;
Furuno, H.; Inanaga, J. Tetrahedron 2006, 62, 6332.
(3) (a) Drakesmith, F. G.; Stewart, O. J.; Tarrant, P. J. Org.
Chem. 1968, 33, 280. (b) Ref. 2b. (c) Katritzky, A. R.; Qi,
M.; Wells, A. P. J. Fluorine Chem. 1996, 80, 145.
(d) Brisdon, A. K.; Crossley, I. R. Chem. Commun. 2002,
2420. (e) Konno, T.; Chae, J.; Kanda, M.; Nagai, G.;
Tamura, K.; Ishihara, T.; Yamanaka, H. Tetrahedron 2003,
59, 7571.
5
6
Equation 3 Pd-catalyzed coupling reaction of 5 with organozinc
reagents
Table 2 Preparation and Coupling Reaction of 5a
Entry
4
R
5
Yield R3
(%)b
6
Yield
(%)b
1
2
3
4
5
6
7
8
4a
4b
Ts
Ts
5a
5b
91
95
Ph
6a
21
69
31
86
94
42
69
61
Ph
6b
6b¢
6b¢¢
6e
CH2SiMe3
Hc
4e
4g
4h
Ms
Ts
5e
5g
5h
63
60
84
Ph
(4) (a) Shimizu, M.; Fujimoto, T.; Minezaki, H.; Hata, T.;
Hiyama, T. J. Am. Chem. Soc. 2001, 123, 6947.
Ph
6g
(b) Shimizu, M.; Fujimoto, T.; Liu, X.; Minezaki, H.; Hata,
T.; Hiyama, T. Tetrahedron 2003, 59, 9811. (c) Liu, X.;
Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2004, 43,
879. (d) Shimizu, M.; Fujimoto, T.; Liu, X.; Hiyama, T.
Chem. Lett. 2004, 33, 438. (e) Shimizu, M.; Jiang, G.;
Murai, M.; Takeda, Y.; Nakao, Y.; Hiyama, T.; Shirakawa,
E. Chem. Lett. 2005, 34, 1700.
Ms
Ph
6h
CH2SiMe3
6h¢
a Preparation of 5: 4 (1.0 equiv), TsCl (1.1 equiv), DMAP (5 mol%),
Et3N (1.2 equiv), CH2Cl2, 0 °C to r.t. Coupling reaction of 5: com-
pound 5 (1.0 equiv), R3ZnCl (3.0 equiv), Pd(PPh3)4 (5 mol%), THF,
r.t.
(5) To a solution of 2 (13.6 g, 75 mmol) and p-toluenesulfonyl
chloride (15.7 g, 82 mmol) in CH2Cl2 (100 mL) was added
Et3N (13.0 mL, 90 mmol) at r.t. After stirring at r.t. for 1 h,
b Isolated yield.
c Et2Zn was used instead of R3ZnCl.
Synlett 2007, No. 7, 1163–1165 © Thieme Stuttgart · New York

CLUSTER
the reaction mixture was diluted with Et2O (50 mL). The
Generation of 3,3,3-Trifluoropropynyllithium
1165
(9) Representative Procedure for Preparation of
resulting solution was washed with H2O and then sat. NaCl
aq solution, and dried over anhyd MgSO4. Removal of
organic solvent in vacuo followed by distillation under
reduced pressure (122 °C/2 Torr) gave 3 (24.4 g, 97% yield)
as a colorless oil. Rf = 0.33 (hexane–EtOAc, 10:1). 1H NMR
(200 MHz, CDCl3): d = 2.49 (s, 3 H), 7.39 (d, J = 8.6 Hz, 2
H), 7.87 (d, J = 8.6 Hz, 2 H). 13C NMR (67.8 MHz, CDCl3):
d = 21.7, 119.1 (q, J = 275.5 Hz), 127.9, 128.3, 129.9, 132.4,
134.1 (q, J = 39.1 Hz). 19F NMR (188 Hz, CDCl3): d = –63.1.
IR (neat): 1618, 1394, 1196, 1153, 972 cm–1. MS (EI, 70
eV): m/z (%) = 180 (10) [M+ – Ts], 160 (12), 111 (33), 91
(23), 74 (100). Anal. Calcd for C10H7Cl2F3O3S: C, 35.84; H,
2.11. Found: C, 36.3, H, 2.22.
Compounds 5
To a solution of 4b (1.5 g, 6.6 mmol), p-toluenesulfonyl
chloride (1.4 g, 7.2 mmol), 4-dimethylaminopyridine (40
mg, 0.33 mmol) in CH2Cl2 (26 mL) was added Et3N (1.1 mL,
7.9 mmol) at 0 °C. The resulting solution was stirred at r.t.
for 2 h before quenching with sat. aq NH4Cl solution (20
mL) at 0 °C. The aqueous layer was extracted with CH2Cl2
(3 × 20 mL) and the combined organic solvent was washed
with sat. aq NaCl solution (60 mL), dried over anhyd MgSO4
and concentrated in vacuo. The crude product was purified
by silica gel column chromatography (hexane–EtOAc, 15:1)
to give 5b (2.4 g, 95% yield) as a colorless solid. Mp 48 °C.
Rf = 0.45 (hexane–EtOAc, 4:1). 1H NMR (400 MHz,
CDCl3): d = 2.13–2.28 (m, 2 H), 2.46 (s, 3 H), 2.74–2.82 (m,
2 H), 5.07–5.11 (m, 1 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.21–
7.37 (m, 3 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.80 (d, J = 8.4 Hz,
2 H). 13C NMR (101 MHz, CDCl3): d = 21.5, 30.5, 36.3,
68.3, 74.3 (q, J = 52.9 Hz), 81.9 (q, J = 6.4 Hz), 113.2 (q,
J = 257.9 Hz), 126.3, 127.9, 128.2, 128.4, 129.7, 132.7,
138.9, 145.5. 19F NMR (282 MHz, CDCl3): d = –51.8. IR
(KBr): 2361, 2341, 1364, 1271, 1159, 746, 677 cm–1. MS
(EI, 70 eV): m/z (%) = 382 (1) [M+], 210 (30), 141 (90), 91
(100). HRMS: m/z calcd for C19H17F3O3S [M+]: 382.0851;
found: 382.0839.
(6) Representative Procedure for Carbonyl Addition of 1
To a THF solution of 3 (10.0 g, 30 mmol) was added BuLi
(41 mL, 66 mmol, 1.6 M in hexane) at –78 °C. The solution
was stirred at –78 °C for 10 min before the addition of 3-
phenylpropanal (4.0 g, 30 mmol) in THF (20 mL) at –78 °C.
The resulting solution was stirred at –78 °C for 1 h and then
at r.t. for 1 h. The reaction mixture was quenched with sat.
aq NH4Cl solution (40 mL) at 0 °C and extracted with
EtOAc (3 × 40 mL). The combined organic layer was dried
over anhyd MgSO4 and concentrated by rotary evaporator.
The crude product was purified by column chromatography
on silica gel (hexane–EtOAc, 15:1) to give 4b (6.5 g, 95%
yield, CAS No. 94792-93-5) as colorless oil.
(10) Representative Procedure for the Preparation of
Compounds 6
(7) Review on transition-metal-catalyzed synthesis of allenes:
(a) Ogasawara, M.; Hayashi, T. In Modern Allene
To a solution of 5b (0.10 g, 0.26 mmol) and Pd(PPh3)4 (15
mg, 0.013 mmol) in THF (2.6 mL) was added PhZnCl (0.79
mL, 0.79 mmol, 1.0 M in THF) at 0 °C. The solution was
stirred at r.t for 2 h before quenching with sat. aq NH4Cl
solution (2 mL) at 0 °C. The aqueous layer was extracted
with EtOAc (3 × 2 mL). The combined organic solvent was
washed with sat. aq NaCl solution (6 mL), dried over anhyd
MgSO4, and concentrated by rotary evaporator. The crude
product was purified by column chromatography on silica
gel (hexane–EtOAc, 20:1) gave 6b (52 mg, 69% yield) as
colorless solid; mp 29 °C; Rf = 0.67 (hexane–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 2.54–2.67 (m, 2 H), 2.80–
Chemistry, Vol. 1; Krause, N.; Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004, 93. (b) Review on Pd-
catalyzed cross-coupling reactions of propargylic
compounds: Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2589.
(8) Yamazaki and coworkers reported three-step transformation
of alcohols 4 into trifluoromethyl-containing allenes CF3–
CHC=C=CR1R2. See: (a) Yamazaki, T.; Yamamoto, T.;
Ichihara, R. J. Org. Chem. 2006, 71, 6251. Examples of
trifluoromethyl-substituted allenes: (b) Bosbury, P. W. L.;
Fields, R.; Haszeldine, R. N.; Moran, D. J. Chem. Soc.,
Perkin Trans. 1 1976, 1173. (c) Bosbury, P. W. L.; Fields,
R.; Haszeldine, R. N. J. Chem. Soc., Perkin Trans. 1 1978,
422. (d) Hanzawa, Y.; Kawagoe, K.-i.; Yamada, A.;
Kobayashi, Y. Tetrahedron Lett. 1985, 26, 219. (e) Burton,
D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron Lett. 1990, 31,
3699. (f) Konno, T.; Tanikawa, M.; Ishihara, T.; Yamanaka,
H. Chem. Lett. 2000, 1360. (g) Han, H. Y.; Kim, M. S.; Son,
J. B.; Jeong, I. H. Tetrahedron Lett. 2006, 47, 209.
2.91 (m, 2 H), 5.96–6.01 (m, 1 H), 7.21–7.34 (m, 10 H). 13
C
NMR (101 MHz, CDCl3): d = 29.9, 34.9, 99.2, 102.1 (q,
J = 34.5 Hz), 123.3 (q, J = 273.2 Hz), 126.1, 126.8, 126.8,
127.8, 128.4, 128.5, 129.8, 140.5, 204.0. 19F NMR (282
MHz, CDCl3): d = –60.9. IR (neat): 3030, 2926, 1497, 1303,
1168, 1121, 934, 694 cm–1. MS (EI, 70 eV): m/z (%) = 288
(30) [M+], 219 (20) [M+ – CF3], 129 (45), 91 (100). HRMS:
m/z calcd for C18H15F3 [M+]: 288.1126; found: 288.1128.
Synlett 2007, No. 7, 1163–1165 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.