No catalyst, radical initiator, and photochemical irradiation approach to direct α-trifluoromethylation of lithium enolates

Article abstract of DOI:10.3987/COM-13-S(S)95

Heterocyclic lactam lithium enolates exploit an access to the electrophilic radical α-trifluoromethylation without catalyst/radical initiator/photochemical irradiation.

Full text of DOI:10.3987/COM-13-S(S)95

HETEROCYCLES, Vol. 88, No. 2, 2014
961
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 961 - 968. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 25th July, 2013, Accepted, 19th September, 2013, Published online, 30th September, 2013
DOI: 10.3987/COM-13-S(S)95
NO CATALYST, RADICAL INITIATOR, AND PHOTOCHEMICAL
IRRADIATION
APPROACH
TO
DIRECT
-TRIFLUOROMETHYLATION OF LITHIUM ENOLATES
Yuichi Tomita, Toshiaki Iida, Ryota Hashimoto, Yoshimitsu Itoh, and Koichi
Mikami*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1-H113
Ookayama, Meguro-ku, Tokyo 152-8552, Japan
FAX: +81-3-5734-2776 E-mail: mikami.k.ab@m.titech.ac.jp
We are honored to dedicate to Prof. Victor Snieckus on the occasion of his 77th
birthday.
Abstract – Heterocyclic lactam lithium enolates exploit an access to the
electrophilic
radical
-trifluoromethylation
without
catalyst/radical
initiator/photochemical irradiation.
Organofluorine compounds have attracted current interest because of their important applications in
material1 and pharmaceutical2 sciences. Fluoromethyl compounds are employed as potent analogues
with remarkable physical properties and high physiological activity. Particularly, trifluoromethyl (CF3)
groups significantly influence the lipophilicity, membrane permeability, aqueous solubility, and metabolic
stability of hydrocarbon leads.3 Therefore, the development of synthetic methods to introduce the CF3
substituent at the -position of carbonyl compounds has emerged as a central issue in modern
organofluorine chemistry.4 However, only few methods have been reported for the trifluoromethylation
of metal enolates and enolate equivalents, which are widely employed in organic synthesis.5 Simple and
versatile alkylation methods of metal enolates with non-fluorinated alkyl halides are generally not
applicable to trifluoromethylation with trifluoromethyl halides, because of the negatively rather than
positively polarized trifluoromethyl carbon.6 Recently, a radical initiator (Et3B/O2),7 photochemical
irradiation,8-10 and Pd-,11 or Rh-catalyzed12 methods have been reported for the trifluoromethylation of
metal enolates and their equivalents. In order to solve the problem of -trifluoromethylation of enolates
with trifluoromethyl halides, we report here a direct and no catalyst/radical initiator/photochemical
irradiation approach to the -trifluoromethylation of carbonyl compounds through modification of our
recently reported -difluoroiodomethylation of lactam lithium enolates13 (Scheme 1).

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HETEROCYCLES, Vol. 88, No. 2, 2014
Scheme 1
The direct -trifluoromethylation of metal enolates derived from carbonyl compounds (1) was first
scrutinized on the alkaline metal involving Li+, Na+, and K+ as an enolate cation (Scheme 2). Lithium
enolates generated using lithium hexamethyldisilazide (LHMDS) could be employed as the metal enolate
source for the direct -trifluoromethylation (entry 1 and 2). However, LDA did not provide the
-trifluoromethylation product (2a) (entry 5).
Unfortunately, sodium and potassium
hexamethyldisilazide (NHMDS and KHMDS) gave only poor yields of the -trifluoromethylation
product (2a) (entry 3 and 4). Using LHMDS to generate the lithium enolate, the -trifluoromethylation
product (2a) was obtained in the highest (92%) yield (entry 1). Even when 12-crown-4 was added to the
lithium enolate, 51% yield of the -trifluoromethylation product was obtained (entry 2). In sharp
contrast to -difluoroiodomethylation of lithium enolates,13 the present -trifluoromethylation reaction
was not prohibited by the salt out operation of the lithium cation by the use of 12-crown-4.
Scheme 2

HETEROCYCLES, Vol. 88, No. 2, 2014
963
Several solvents such as THF, DME, MTBE (methyl tert-butyl ether), Et2O and less polar toluene were
examined at -78 ˚C for 4 h (Scheme 3). MTBE, DME, and Et2O gave moderate yields (entry 2, 3, 5).
Less polar solvent such as toluene gave only low yiled of the -trifluoromethylation product (2a) along
with the -difluoroiodomethylation product (3a). Amongst the ethereal solvents thus examined, THF
gave the best (92%) yield of the -trifluoromethylation product (2a) (enrty 2).
OLi
O
LHMDS (1 eq.)
Boc
Boc
Bn
Boc
Bn
N
N
solvent, rt, 5 min.
1a
O
O
CF3
Bn
CF2I
Bn
CF3I (ca 10 eq.)
-78 °C, 4 h
Boc
N
N
+
2a
3a
Yield (%)a)
Entry
Solvent
3a
9
-
2a
23
92
51
30
53
1
2
3
4
5
toluene
THF
DME
-
MTBE
Et2O
-
-
a) Yield was determined by 19F-NMR using
BTF as an internal standard.
Scheme 3
The effect of lithium amide source was the key in the present -trifluoromethylation (Scheme 4).
Furthermore, the molarity of lithium amides affects the ratio of the -trifluoromethylation product (2)/the
-difluoroiodomethylation product (3). One equivalent of the lithium amide selectively leads to the
formation of the -trifluoromethylation product (2) except for the case of LDA (entry 1 and 3 vs. 5).
Intriguingly, two equivalents of LTMP provided only -difluoroiodomethylation product (3) in 70%
isolated yield without formation of the -trifluoromethylation product (2) (entry 4). The result suggests
that more electron donating and less sterically demanding dialkyl amides such as LTMP provide tight
mixed aggregate with the lithium enolates14 than the less electron donating and more sterically demanding
bis(silyl) amides such as LHMDS.

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HETEROCYCLES, Vol. 88, No. 2, 2014
Scheme 4
In view of the asymmetric photocatalytic perfluoroalkylation of aldehydes reported by MacMillan,9 the
effect of photochemical irradiation was further investigated on the present no catalyst/radical initiator
trifluoromethylation of lithium enolates (Scheme 5). However with or without photochemical
irradiation, Boc-protected lactam substrates afforded a similar level of good yields for the
-trifluoromethylation products (2) up to 92% yields.
Scheme 5

HETEROCYCLES, Vol. 88, No. 2, 2014
965
The following reaction mechanism could involve in the present trifluoromethylation of lithium enolates
with trifluoromethyl iodide that should be different from our previous mechanistic rationale for the
-difluoromethylation of lithium enolates with the same trifluoromethyl iodide via Li–F interaction.13
Single electron transfer (SET) to trifluoromethyl iodide8-10,16 from the lithium enolates would be operative
to generate the electrophilic trifluoromethyl radical via abstraction of iodide with Lewis acidic lithium
cation (Scheme 6).8e Through addition of the trifluoromethyl radical to the lithium enolates, a ketyl
radical intermediate would be generated and then react with another trifluoromethyl iodide molecule to
produce the trifluoromethyl radical along with the formation of the -trifluoromethyl product (2) and
lithium iodide.8e
Scheme 6
The reaction conditions were optimized to construct even sterically congested quaternary17 carbon centers
(Table 1). The electrophilic radical trifluoromethylation shows a substrate applicability that exhibits
electronic and steric scope. In Boc-protected six-membered lactam (1a) gave the -trifluoromethylation
product (2a) in 92% yield. In five-membered lactam, the -trifluoromethylation product (2b) was
specifically obtained along with high (92%) chemical yield in a similar manner to the six-membered
lactam. A relatively electron-donating Boc protecting group thus leads to the high yields for the
-trifluoromethylation product (2), because of the facile SET from the electron rich Boc-protected
enolates. Cbz-protected lactams (1c and d) also gave a similar but slightly lower level of chemical
yields for the -trifluoromethylation products (2c and d) up to 61% yield. In contrast, a relatively
electron-withdrawing benzoyl-protecting group (1e) provides low yield for the -trifluoromethylation
product (2e) in 18% yield.

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HETEROCYCLES, Vol. 88, No. 2, 2014
1) LHMDS (1 eq.)
O
O
2) CF3I (ca 10 eq.)
PG
CF3
R
n
PG
N
N
R
n
THF
-78 °C, 4 h
1
2
O
O
CF3
Bn
CF3
Boc
Boc
N
N
Bn
92%a
2b
92%a
2a
O
N
CF3
Bn
Cbz
O
N
CF3
Cbz
Bn
46%a
2d
61%a (60%)b
2c
O
N
CF3
Bn
Bz
18%a
2e
a) Yield was determined by 19F-NMR using BTF as an internal standard.
b) Isolated yield.
Scheme 7
In conclusion, this novel methodology exploits an access to electrophilic radical trifluoromethylation
without catalyst/radical initiator/photochemical irradiation to devise a direct approach to the
trifluoromethylation of heterocyclic lactam lithium enolates.
Fortunately, high levels of
trifluoromethylation efficiency could be established for these substrates to afford the desired products
with good overall efficiency. This novel methodology is a compliment to MacMillan’s photocatalytic
perfluoroalkyl radical approach to aldehydes. Further investigation on our asymmetric version is now
under way for wide substrate scope.
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