Activation of C-F bonds in preference to C-I bonds: Difluoromethylation of lithium enolates with trifluoromethyl iodide

Article abstract of DOI:10.1002/anie.201000435

(Figure Presented) The l's have it: A conceptually new C-F activation/C-C formation and its mechanism are described. Surprisingly, a reaction with Li-enolates and trifluoromethyl iodide gave (alpha)-difluoromethyl product via C-F bond cleavage in preference to the weaker C-I bond of trifluoromethyliodide. This reaction proceeds without the use of any late transitionmetal catalyst (see scheme; LHMDS = lithium hexamethyldlsilaxide).

Full text of DOI:10.1002/anie.201000435

Angewandte
Chemie
DOI: 10.1002/anie.201000435
Fluorine Chemistry
À
À
Activation of C F Bonds in Preference to C I Bonds:
Difluoromethylation of Lithium Enolates with Trifluoromethyl
Iodide**
Koichi Mikami,* Yuichi Tomita, and Yoshimitsu Itoh
Perfluorocarbons are among the most inert and, hence,
chemically stable functionalities, because of the large disso-
During the course of our research on a-trifluoromethy-
lation[18] of metal enolates catalyzed by late-transition-metal
complexes, a-difluoromethyl products were obtained using
lithium enolates (Figure 1), but without the need for any late-
transition-metal catalyst such as nickel complexes.[8,9] The
lithium enolate of 3-benzyldihydrofuran-2-one generated
with lithium hexamethyldisilazide (LHMDS) gave the
a-difluoromethyl product 1a (72% 19F NMR and 71% yield
of isolated product). The present synthetic method provides
difluoromethyl-attached all-carbon quaternary centers.
Carbon centers bearing four carbon atom ligands pose a
particular challenge because the creation of such all-carbon
quaternary centers is rather difficult as a result of the steric
repulsion between the four carbon ligands.[19]
[1–5]
À
ciation energy of a carbon–fluorine (C F) bond.
There-
À
fore, C F bond activation has attracted current interest,
[6]
À
because of the “challenge” in cleaving the inert C F bonds
and degradation of chlorofluorocarbons (CFC or freons),
which cause ozone depletion and global warming.[7] However,
only a limited number of examples have been reported so far
À
on C F bond cleavage even by “oxidative addition” of
2
transition metals in an aromatic sp -C F system.[8–11] Herein,
À
we report a conceptually different approach to the conversion
3
À
À
of sp -C F to C C bonds with lithium enolates, which are
widely employed in modern science and technology,[12,13] via
À
À
cleavage of a C F bond in preference to the weaker C I
bond[1–5] of trifluoromethyl iodide (Figure 1). The difluoro-
To shed light on the reaction mechanism, the metal
species in the enolate were scrutinized (Table S1 in the
Supporting Information). Among the alkaline metal enolates
(Na, K, Cs) employed, only the sodium enolate generated
with sodium hexamethyldisilazide (NaHMDS), except for the
lithium enolate (72% 19F NMR yield), gave the a-difluoro-
methyl product 1a, although in 12% yield. Potassium and
“naked” enolates prepared from the trimethylsilyl enol ether
and tetra-n-butylammonium fluoride (TBAF) did not give
any a-difluoromethyl product at all. It is highly likely that this
a-difluoromethylation takes place through the interaction of
the Lewis acidic lithium center with fluoride in preference to
iodide.[20] Indeed, the addition of [12]crown-4 to trap the Li
cation from the Li enolate and to generate a “naked” enolate
did not give the a-difluoromethyl product. In turn, the
addition of the lithium salt of weakly coordinating bis(tri-
fluoromethanesulfonyl)amide (LiNTf2) to the potassium
enolate led to the formation of the a-difluoromethyl product
1a.[21]
In sharp contrast to LHMDS, lithium diisopropylamide
(LDA) did not give the a-difluoromethyl product 1a (Table 1,
entries 7 and 8). Several lithium amides were then examined
(Table 1). In the case of bis(silylamide)s such as LHMDS and
lithium 1,1,3,3-tetramethyl-1,3-diphenyldisilazide (LTDDS),
the amount of lithium amide did not affect the yields of 1a
(entries 1–4). The use of 1 and 2 equivalents of LHMDS was
found to give approximately 70% yields constantly (entries 1
and 2). LTDDS gave relatively lower yield but in a similar
range of 63–68% (entries 3 and 4). The use of dialkylamides
such as lithium 2,2,6,6-tetramethylpiperidide (LTMP) gave
comparably good yields, when 2 equiv of the lithium amide
were used (entry 6 vs. entry 5). Amine-free lithium enolate
prepared from the trimethylsilyl enol ether and nBuLi[22] was
also investigated and found to give 1a in 68% yield (Table 1,
À
À
Figure 1. Conversion of a C F bond to a C C bond with lithium
enolate.
methyl compounds thus obtained are biologically and syn-
thetically important and, therefore, the introduction of the
difluoromethyl functionality into organic compounds is of
vital importance,[14,15] as typically shown in difluoromethyl
analogues of a-amino acids.[16,17] This conceptually new C F
À
À
activation/C C formation and the mechanism are the subjects
of this Communication.
[*] Prof. K. Mikami, Dr. Y. Tomita, Dr. Y. Itoh[+]
Department of Applied Chemistry, Tokyo Institute of Technology
Tokyo 152–8552 (Japan)
E-mail: mikami.k.ab@m.titech.ac.jp
[+] Present address: Department of Chemistry and Biotechnology
School of Engineering, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
[**] We are grateful to Toray Pharmaceutical Research Laboratories for
the 0.6% acetic acid writhing test of a-difluoromethyl ibuprofen.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000435.
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Communications
Table 1: Amine base effect.[a]
Entry
n
Base
Yield [%]
1
2
3
4
5
6
7
8
9
1
2
1
2
1
2
1
2
1
LHMDS
72
68
68
63
32
68
0
LTDDS
LTMP
LDA
6[b]
68
nBuLi[c]
[a] To a solution of 3-benzyldihydrofuran-2-one in THF (0.5 mmol) was
added the base at room temperature over 5 min and gaseous CF3I at
À788C. The reaction mixture was stirred for 4 h at room temperature and
then quenched by acetic acid. The yield was determined by 19F NMR
spectroscopy using BTF (BTF=benzotrifluoride) as an internal stan-
dard. [b] 3% of trifluoromethyl product 2a was observed. [c] Butyllithium
was added to the reaction mixture of trimethylsilyl enol ether.
entry 9). The nature of the secondary amines derived from the
lithium amide sources thus affects the reactivity of the lithium
enolates in this a-difluoromethylation reaction.
The difference between the bis(silylamide) LHMDS and
dialkylamide LDA was further examined (Table S2 in the
Supporting Information). The corresponding secondary
amines were added to the amine-free lithium enolate
prepared from the trimethylsilyl enol ether and nBuLi (see
Table 1, entry 9: 68% yield of 1a). The addition of diisopro-
pylamine significantly retarded the a-difluoromethylation;
essentially, no difluoromethyl product was obtained. In
contrast, hexamethyldisilazane did not affect the yield in
this a-difluoromethylation at all (68% yield of 1a).
Further investigation on the diisopropylamine-free lith-
ium enolate, which was prepared by pumping off the amine
from the enolate prepared with LDA, provided an increased
yield of the a-difluoromethyl product 1a of up to 53% (vs.
0%) These experiments clearly indicate that
Figure 3. Plausible mechanism of the a-difluoromethylation.
nature.[25] Lithium amides in 2 equivalents, except for LDA,[26]
lead to the formation of the a-difluoromethyl product,
through mixed aggregates; upon addition of trifluoromethyl
iodide, open-chain dimers with the lithium enolate (b) are
involved to give the a-difluoromethyl product, wherein F in
CF3I interacts with the lithium cation. The positive charge as
formulated in the “CF2I+” carbocation is even partially
À
diisopropylamine inhibits the a-difluorome-
thylation reaction; relatively “less” bulky
and more-coordinating secondary diisopro-
pylamine, as compared with sterically more
demanding but less-coordinating hexame-
thyldisilazane, could interact with lithium
enolate to inhibit the difluoromethylation
developed in CF3I by the Li F interaction and stabilized by
the lone electron pairs of the a-F atoms (c)[15] to give the
a-difluoromethyl products. In sharp contrast, pentafluor-
oethyl iodide gave the pentafluoroethylation product (2a’)
(21% yield), and a defluoroethylation product was not
observed at all; perfluoroalkyl iodide cannot provide even
transiently the unstable carbocation (d), because of the strong
electron-withdrawing effect of the trifluoromethyl (CF3)
group.[1–5]
À
Figure 2. Li N
and NH–p
interactions.
À
through Li N and NH–p interactions
(Figure 2). In fact, the NH–p interaction
has been clarified by X-ray crystallographic analysis of the Li
enolate of pinacolone crystallized in the presence of N,N,N’-
trimethylethylenediamine (TriMEDA).[23]
A plausible reaction mechanism for this a-difluorome-
thylation can be exemplified as shown in Figure 3, depending
on the aggregation state of the lithium enolate.[24] Lithium
bis(silylamide)s, even in 1 equivalent, afford the a-difluoro-
methyl product by a six-electron pericyclic process (a), by
virtue of their sterically demanding and less-coordinating
Difluoromethylation of the Li enolates of several ketones,
esters, and amides was then executed using LHMDS and CF3I
under the optimized reaction conditions (Table 2). Both
acyclic and cyclic carbonyl substrates gave the a-difluoro-
methyl products 1 in good to moderate yields (entries 1–6).
Boc-protected lactam was also investigated. It gave, in
contrast, the a-trifluoromethyl product 2 (entries 7 and 8),
even in the presence of [12]crown-4 (entry 8). Relatively
electron-rich lactams lead to the a-trifluoromethyl prod-
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Table 2: a-Difluoromethylation of carbonyl compounds.[a]
The a-difluoromethyl products
can be used, through the iodide
À
functionality, for further C C bond
forming reactions, such as radical
and late-transition-metal-catalyzed
alkylation, or geminal difluorocy-
clopropane cyclization and hydro-
deiodination. In addition to the
difluoromethyl analogues of a-
amino acids,[16,17] the a-difluorome-
thylated analogue 3 of the anti-
inflammatory and analgesic drug
ibuprofen, which is known to exert
its activity by inhibiting cyclooxy-
genase,[29] could be synthesized by
hydrodeiodination under the opti-
mized conditions (Figure 4). This
racemic ibuprofen analogue with
Entry
Substrate
Product
Yield [%][b]
1
2
1
2
1a
72 (71)
54
-
1b
1c
1d
2b
7
3
4
52 (51)
41 (43)
–
–
non-epimerizable
quaternary
center retains the analgesic activity
in the 0.6% acetic acid writhing
test,[30] which is intriguing on the
basis of the results that (S)-ibupro-
fen is the active form both in vitro
and in vivo and that in vivo 2-
arylpropionyl-CoA epimerase con-
verts (R)-ibuprofen into (S)-ibupro-
fen.[31]
This is an unprecedented route
to construct difluoromethyl-at-
tached all-carbon quaternary cen-
ters using lithium enolates and
CF3I, without any metal catalyst,
5
6
1e
1 f
56 (60)
32
–
–
7
–
–
62 (63)
51
8[c]
1g
1h
2g
9
43 (41)
–
[a] A solution of the substrate in THF (0.5 mmol) was treated with LHMDS at room temperature
(addition over 5 min) and gaseous CF3I at À788C. The reaction mixture was stirred for 4 h at room
temperature and then quenched by acetic acid. The yield was determined by 19F NMR spectroscopy.
[b] Yield of isolated product in brackets. [c] In the presence of [12]crown-4 (1 equiv).
À
through activation of a C F bond in
À
preference to the weaker C I bond.
The highlight of the present report
ucts[27] without any radical initiator, presumably through
single electron transfer from the lactam enolate.[28] Indeed, an
electron-withdrawing tosyl-protected lactam led to the a-CF2I
product (entry 9). Five-membered lactams behaved similarily
to the six-membered lactams.
is the synthesis of the a-difluoromethylated analogue of
ibuprofen with retention of the analgesic activity even with
non-epimerizable all-carbon quaternary centers.
Received: January 25, 2010
Published online: April 15, 2010
Keywords: cleavage reactions · enolates · fluorine · lithium
.
[1] T. Hiyama, K. Kanie, T. Kusumoto, Y. Morizawa, M. Shimizu,
Organofluorine Compounds: Chemistry and Applications,
Springer, Berlin, 2000.
[2] R. D. Chambers, Fluorine in Organic Chemistry, Wiley-Black-
well, Oxford, 2004.
[3] P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Wein-
heim, 2004.
[4] K. Uneyama, Organofluorine Chemistry, Wiley-Blackwell,
Oxford, 2006.
[5] J.-P. Begue, D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, Wiley, Hoboken, 2008.
[6] T. G. Richmond in Activation of Unreactive Bonds and Organic
Synthesis (Ed.: S. Murai), Springer, Berlin, 1999. Also see
Ref. [10].
Figure 4. Synthesis of the a-difluoromethyl analogue of ibuprofen from
À
À
ibuprofen through C F bond activation, C C bond formation, and
hydrodeiodination in a total yield of 53%.
[7] K. P. Shine, W. T. Sturges, Science 2007, 315, 1804 – 1805.
Angew. Chem. Int. Ed. 2010, 49, 3819 –3822
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www.angewandte.org
3821

Communications
[8] K. Tamao, K. Sumitani, Y. Kiso, M. Zembayashi, A. Fujioka, S.
Chem. Rev. 1993, 93, 2037 – 2066; c) J. Christoffers, A. Baro, Adv.
Synth. Catal. 2005, 347, 1473 – 1482.
[20] Li–F interaction plays an important role in regioselective
deprotonation: M. Schlosser in Organometallics in Synthesis-A
Manual (Ed.: M. Schlosser), Wiley, Chichester, 1994, pp. 1 – 166,
and references therein.
[21] The high lattice energy of LiF relative to other alkali metal
fluorides is also a possible reason for the high yield when using Li
enolate.
[22] G. Stork, P. F. Hudrlik, J. Am. Chem. Soc. 1968, 90, 4462 – 4465.
[23] The NH–p interaction was observed for the Li enolate of
pinacolone crystallized in the presence of TriMEDA: T. Laube,
J. D. Dunitz, D. Seebach, Helv. Chim. Acta 1985, 68, 1373 – 1393.
[24] D. Seebach, Angew. Chem. 1988, 100, 1685 – 1715; Angew. Chem.
Int. Ed. Engl. 1988, 27, 1624 – 1654, and references therein.
[25] B. L. Lucht, D. B. Collum, Acc. Chem. Res. 1999, 32, 1035 – 1042,
and references therein.
Kodama, I. Nakajima, A. Minato, M. Kumada, Bull. Chem. Soc.
Jpn. 1976, 49, 1958 – 1969, and references therein.
[9] N. Yoshikai, H. Mashima, E. Nakamura, J. Am. Chem. Soc. 2005,
127, 17978 – 17979.
[10] H. Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119 – 2183, and
references therein.
[11] C. Douvris, O. V. Ozerov, Science 2008, 321, 1188 – 1190.
[12] C. H. Heathcock in Asymmetric Synthesis, Vol. 3 (Ed.: J. D.
Morrison), Academic Press, New York, 1984, chap. 2.
[13] T. Mukaiyama, S. Kobayashi, Organic Reactions (Ed.: L. A.
Paquette), Wiley, New York, 1994.
[14] S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320 – 330.
[15] D. OꢀHagan, Chem. Soc. Rev. 2008, 37, 645 – 652.
[16] Fluorine in Medicinal Chemistry and Chemical Biology (Ed. I.
Ojima), Blackwell, Oxford, 2009.
[17] “Current Fluoroorganic Chemistry”: V. A. Soloshonok, K.
Mikami, T. Yamazaki, J. T. Welch, J. F. Honek, ACS Symp. Ser.
2006, 949.
[26] D. B. Collum, A. J. McNeil. A. Ramirez, Angew. Chem. 2007,
119, 3060 – 3077; Angew. Chem. Int. Ed. 2007, 46, 3002 – 3017.
[27] The a-trifluoromethylation of lactams will be reported sepa-
rately. The a-trifluoromethylation of lithium enolates is gener-
ally difficult, but can be attained by using a radical initiator
(Refs. [1–5]).
[28] Trifluoromethylation of enamine has been reported to proceed
by single electron transfer: D. Cantacuzꢁne, C. Wakselman, R.
Dorme, J. Chem. Soc. Perkin Trans. 1 1977, 1365 – 1371.
[29] P. Rao, E. E. Knaus, J. Pharm. Pharm. Sci. 2008, 11, 81 – 110.
[30] The biological activity of a-CF2H-ibuprofen (3) will be reported
separately.
[18] a) Y. Itoh, K. Mikami, Org. Lett. 2005, 7, 649 – 651; b) Y. Itoh, K.
Mikami, J. Fluorine Chem. 2006, 127, 539 – 544; c) Y. Itoh, K.
Mikami, Org. Lett. 2005, 7, 4883 – 4885; d) Y. Itoh, K. Mikami,
Tetrahedron 2006, 62, 7199 – 7203; e) Y. Itoh, K. N. Houk, K.
Mikami, J. Org. Chem. 2006, 71, 8918 – 8925; f) K. Mikami, Y.
Tomita, Y. Ichikawa, K. Amikura, Y. Itoh, Org. Lett. 2006, 8,
4671 – 4673; g) Y. Tomita, Y. Ichikawa, Y. Itoh, K. Kawada, K.
Mikami, Tetrahedron Lett. 2007, 48, 8922 – 8925; h) Y. Tomita, Y.
Itoh, K. Mikami, Chem. Lett. 2008, 37, 1080 – 1081.
[19] Review on the construction of quaternary carbon centers:
a) S. F. Martin, Tetrahedron 1980, 36, 419 – 460; b) K. Fuji,
[31] C. Reichel, R. Brugger, H. Bang, G. Geisslinger, K. Brune, Mol.
Pharmacol. 1997, 51, 576 – 582.
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