Umpolung of fluoroform by C-F bond activation: Direct difluoromethylation of lithium enolates

Article abstract of DOI:10.1002/anie.201203588

Double agent: The direct α-difluoromethylation of lithium enolates using an umpolung form of fluoroform as a difluoromethyl carbocation equivalent leads to an all-carbon quaternary center. Late transition metals are not necessary and the reaction involves activation of inert C-F bonds with subsequent C-C bond formation. Copyright

Full text of DOI:10.1002/anie.201203588

Angewandte
Chemie
DOI: 10.1002/anie.201203588
À
C F Bond Activation
À
Umpolung of Fluoroform by C F Bond Activation: Direct
Difluoromethylation of Lithium Enolates
Toshiaki Iida, Ryota Hashimoto, Kohsuke Aikawa, Shigekazu Ito, and Koichi Mikami*
À
The synthesis of organofluorine compounds has flourished
because of the wide scope of their applications in biological
and material sciences in recent years.[1] Difluoromethyl
fuctionalized compounds in particular are employed because
of their significantly increased lipophilicity, membrane per-
meability, aqueous solubility, and metabolic stability, as
exemplified by the anesthetic Desflurane, anticancer Gem-
citabine, respiratory Roflumilast derivatives, antiulcer
(À)-Pantoprazole, and antiviral difluoromethoxyquinolone
Garenoxacin.[2] Generally, synthetic methods for the fluoro-
methylation reactions involve radical, electrophilic, or nucle-
ophilic reactions.[1,3,4] In particular, the treatment of fluoro-
form with sodium or potassium alkoxide in DMF affords its
trifluoromethyl adduct.[5] Fluoroform can thus be employed
as the nucleophilic trifluoromethyl carbanion equivalent for
non-enolizable carbonyl compounds. Herein we wish to
report our polarity-inversion approach, namely the umpo-
lung[6] of fluoroform by activation of an inert carbon–fluorine
of lithium enolates with fluoroform by using a C F bond
À
activation is described. A direct Csp2 F bond activation and
À
C C bond formation sequence can be attained with lithium
enolates, which take a central role in modern synthetic
organic chemistry.[13] The difluoromethyl products are bio-
logically and synthetically important, and therefore the
introduction of the difluoromethyl group into organic com-
pounds is of vital importance,[14] as shown for difluoromethyl
ethers[2] or a-difluoromethyl a-amino acids.[15]
The direct and simple a-difluoromethylation was found to
proceed with lithium enolates using fluoroform as the
difluoromethylating reagent (Scheme 2). The a-difluoro-
À
(C F) bond to formally generate a difluoromethyl carbocat-
ion equivalent (Scheme 1).
Scheme 2. Direct difluoromethylation of the lithium enolate with
fluoroform. Bn=benzyl, Ts=4-toluenesulfonyl.
Scheme 1. Umpolung of fluoroform with a lithium enolate.
methyl products were obtained with lithium enolates in
particular, even in the absence of late-transition-metal com-
plexes used to catalyze the Tamao–Kumada-type coupling of
[7]
À
C F bond activation has posed a challenge in trans-
À1
forming the inert C F bond (490 kJmol ; C C bond:
C
sp2-aromatic and -vinylic fluorides.[8,9] Among the alkaline
À
À
350 kJmolÀ1; C H bond: 420 kJmol ). Actually, only limited
metal enolates (Li, Na, K) generated with the metal
hexamethyldisilazide (MHMDS), only the lithium enolate
(from LHMDS) gave the a-difluoromethyl product because
of the strong Li–F interaction.[1] In contrast to LHMDS,
lithium diisopropylamide (LDA) did not give the a-difluoro-
methyl product, presumably because of the less bulky and
more coordinating secondary dialkylamine generated. The
present synthetic method provides difluoromethyl-substi-
tuted all-carbon quaternary centers,[16] the congested struc-
ture of which was confirmed by the X-ray analysis of 2a
(Scheme 2).[17] The a-difluoromethyl product 2a was thus
obtained even at low temperature (À788C). The formation of
difluorocyclopropane and the a-deuteriodifluoromethyl
product was not observed from the generation of difluoro-
methylene (difluorocarbene)[18–20] in the presence of electron-
rich olefins and upon quench with D2O, respectively.
À1
À
À
types of reactions have thus far been reported for C F bond
activation in the transition metal catalyzed cross-coupling of
C
sp2-hybridized systems.[8,9] Amii and Uneyama have
À
reviewed precedent reports on C F bond activation including
À
their own reductive C F bond cleavage of trifluoromethyl
ketones using a reducing metal.[10] In view of the environ-
mental issues,[11] hydrodefluorination of perfluoroalkanes was
recently developed by Douvris and Ozerov as an efficient
strategy for chlorofluorocarbon (CFC) degradation through
À
Si F bond formation using silylium carborane catalysts and
hydride sources.[12] Herein electrophilic difluoromethylation
[*] T. Iida, R. Hashimoto, Dr. K. Aikawa, Dr. S. Ito, Prof. Dr. K. Mikami
Department of Applied Chemistry, Tokyo Institute of Technology
Tokyo 152-8552 (Japan)
The effect of the amount of the lithium amide base
(LHMDS) on the difluoromethylation of the lithium enolate
are shown in Table 1. An additional amount of LHMDS gave
E-mail: mikami.k.ab@m.titech.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203588.
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Table 1: The effects of the amount of the lithium amide.[a]
Entry
Equiv
of base
T [8C]
t [h]
Yield
[%][b]
1
2
3
4
5
1
2
3
2
3
À78
À78
À78
RT
14
14
14
6
17
45
25
64
24
RT
6
[a] The a-Benzyl-d-lactam 1b (0.1 mmol) was added to a solution of
LHMDS at À788C under an argon atmosphere. The reaction mixture was
then stirred at 08C for 30 min. CF3H (ca. 5 equiv) was then added to the
reaction mixture at À958C, warmed to the indicated temperature, and
reacted for the specified time. [b] The yields were determined by 19F NMR
spectroscopy using BTF (benzotrifluoride) as an internal standard.
a higher yield by almost three times than obtained with only
one equivalent of LHMDS (entries 1 versus 2). These results
clearly show the critical dependence of the reaction rate on
the amount of the base used. The lithium enolate with
a second equivalent of LHMDS reacted with fluoroform to
give 2b in the highest (64%) yield at room temperature
(entry 4). A further increase in the amount of LHMDS (up to
3 equiv) led to a decrease in the yield (entries 3 and 5).
Two equivalents of LHMDS could lead to a stable mixed
À
aggregate (see below), which should be reactive for C F
À
activation but not for C H deprotonation, thus affording the
Scheme 3. Plausible mechanism of a-difluoromethylation.
higher product yield relative to that obtained with one
equivalent of LHMDS (Table 1, entries 1 versus 2). However,
one more equivalent of free LHMDS (3 equiv) might
deprotonate fluoroform and therefore give the lower yield
of 2b as actually observed (entries 3 and 5).
2.280 ꢀ), elongation of the F1–C3 bond (1.362 ꢀ; F2-C3
1.338 ꢀ, F3-C3 1.337 ꢀ), the C1···C3 contact (3.510 ꢀ), and
the obtuse C1-C3-F1 angle indicate desirable geometries for
À
The possible reaction mechanisms can be viewed for the
a difluoromethylation (Scheme 3). Lithium enolates could
the SN2-type C F activation. The F in HCF3 could directly
interact with the lithium cation, and the difluormethyl
cation[25] could be formed only partially in HCF3. Indeed,
silyl enol ethers did not provide the captured difluoromethyl
cation product under the reaction conditions.
À
directly afford the a-difluoromethyl products by C F bond
activation through a Li–F interaction[21] upon addition of
fluoroform, as pictured in the mixed aggregate and the open
dimer of a lithium enolate with the lithium amide.[22,23] To
obtain more information on the proposed reaction mecha-
nism, DFT calculations on both complexes (homodimer and
mixed aggregate) with fluoroform were performed at the
wB97XD/6-31 + G(d) level of theory (Scheme 3). According
to the predicted structures of the lithium enolates,[24] one
solvent (Me2O) molecule coordinates to each lithium atom. In
the homodimer, one of the lithium ions (Li’1) interacts with
the F’1 atom with distance of 2.281 ꢀ, and the C’3–F’1 bond is
slightly elongated (1.357 ꢀ). Indeed, the characteristic Li–F
Both cyclic and acyclic substrates led to the a-difluoro-
methyl products 2 under the optimized reaction conditions
(Table 2). Difluoromethylation of the lithium enolates of not
only protected lactams 1a–c,e,f with five- and six-membered
rings but also the lactones 1g–i and ketone 1j was established
to give the corresponding products (entries 1, 2, and 4–9).
Unfortunately, the reaction of the a-nonsubstituted lactam 1d
did not provide any a-fluoromethyl(ene) product under the
same reaction conditions as it proceeded with a greater than
99% substrate recovery (entry 3). In the case of acyclic
substrates, the difluoromethylation also proceeded with the 2-
phenylpropanate 1k and a-methylmalonate (1m) to give the
a-difluoromethyl products 2k and 2m, respectively, in yields
of up to 80% upon isolation (82% yield as determined by
NMR spectroscopy; entries 11 and 13). The difluoromethy-
lated mandelate derivative (2l) was also obtained (entry 12).
The a-difluoromethylation reaction was used in the
synthesis of the a-difluoromethyl analogue (3) of the anti-
À
interaction and possible C C bond formation pathway were
optimized (C’1···C’3 3.530 ꢀ), but the acute C’1-C’3-F’1 angle
of 86.208 implies a slow SN2-type removal of the fluoride in
the homodimer of lithium enolates.[24] In contrast, in the
mixed aggregate,[24] the obtuse C1-C3-F1 angle of 105.948
À
suggests facile C C bond formation via the putative open
dimer (for DFT calculations, see the Supporting Informa-
tion). Substantial interaction between Li1 and F1 (Li1···F1
2
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Table 2: a-Difluoromethylation of various carbonyl compounds.
the racemic ibuprofen analogue
reserves the analgesic activity even
with the non-epimerizable quater-
nary center.[22]
This report is the first on the
direct a-difluoromethylation of lith-
ium enolates for construction of the
difluoromethyl-functionalized all-
carbon quaternary centers using
fluoroform as a simple difluorome-
thylating reagent. Lithium enolates
lead to the a-difluoromethyl car-
Entry
Substrate
1a (R=Bn)
Conditions
Product
Yield [%][a]
1
2
3
RT, 30 min
RT, 2 h
RT, 2 h
2a 69 (68[b])
2c 45
1c (R=allyl)
1d (R=H)
2d 0[c]
4
5
6
1b
1e
RT, 6 h
2b 64
2e 57
2 f 37
À
bonyl compounds by C F bond
À
activation/C C bond formation
through the umpolung form of flu-
oroform.
08C, 2 d
1 f
08C, 2 d
08C, 2 d
Experimental Section
General procedure of a-difluoromethy-
lation of lithium enolate (Scheme 2): 3-
Benzyl-1-tosylpyrrolidin-2-one
(1a;
7
8
1g (R=Bn)
1h (R=CO2Et) 08C, 20 h
2g 47
2h 47
50 mg, 0.15 mmol, 1.0 equiv) in THF
(0.3 mL) was added to a solution of
lithium hexamethyldisilazide (LHMDS;
1.0m in THF, 0.3 mL, 0.3 mmol,
2.0 equiv) at À788C under an argon
atmosphere. The reaction mixture was
then stirred at 08C for 30 min. CF3H (ca.
5 equiv) was then added to the reaction
mixture at À958C. After 30 min at room
temperature, the reaction mixture was
poured into a mixture of H2O and ethyl
acetate. The aqueous layer was
extracted with ethyl acetate. The com-
bined layers were washed with H2O and
brine, dried over MgSO4, and concen-
trated in vacuo. The yield (69%) was
determined by 19F NMR spectroscopy of
the crude reaction mixture using BTF as
an internal standard. The residue was
purified by column chromatography on
silica gel (5% ethyl acetate in n-hexane)
to afford the difluoromethylated prod-
uct in 68% yield.
9
1i
1j
08C, 6 h
2i 33
10
08C, 10 h
2j 36
11
12
13
1k
1l
RT, 6 h
2k 78
RT, 12 h
08C, 20 h
2l 35
1m
2m 82 (80[b])
[a] Yields were determined by 19F NMR spectroscopy using BTF as an internal standard. [b] Yield of
isolated product. [c] A greater than 99% substrate recovery. Boc=tert-butoxycarbonyl.
Received: May 9, 2012
Revised: July 4, 2012
Published online: && &&, &&&&
inflammatory and analgesic drug ibuprofen (Scheme 4).[26]
Ibuprofen methyl ester was a-difluoromethylated with fluo-
roform in 73% yield upon isolation. It should be noted that
À
Keywords: C F bond activation · fluorine · lithium ·
synthetic methods · umpolung
.
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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À
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4
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À
C F Bond Activation
T. Iida, R. Hashimoto, K. Aikawa, S. Ito,
K. Mikami*
&&&& — &&&&
À
Umpolung of Fluoroform by C F Bond
Activation: Direct Difluoromethylation of
Lithium Enolates
Double agent: The direct a-difluoro-
methylation of lithium enolates using an
umpolung form of fluoroform as
a difluoromethyl carbocation equivalent
leads to an all-carbon quaternary center.
Late transition metals are not necessary
and the reaction involves activation of
À
À
inert C F bonds with subsequent C C
bond formation.
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