Facile synthesis of 1,1-difluoroallenes via the difluorovinylidenation of aldehydes and ketones

Article abstract of DOI:10.1021/ol9016673

2-Bromo-3,3-difluoroallylic acetates were readily prepared by the reaction of carbonyl compounds with 1-bromo-2,2-difluorovinyllithium, generated from 1,1 -dibromo-2,2-difluoroethylene, followed by acetylation. On treatment with butyllithium, the bromoace

Full text of DOI:10.1021/ol9016673

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3994-3997
Facile Synthesis of 1,1-Difluoroallenes
via the Difluorovinylidenation of
Aldehydes and Ketones
Misaki Yokota, Kohei Fuchibe, Mikiko Ueda, Yuka Mayumi, and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences, UniVersity
of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan
junji@chem.tsukuba.ac.jp
Received July 21, 2009
ABSTRACT
2-Bromo-3,3-difluoroallylic acetates were readily prepared by the reaction of carbonyl compounds with 1-bromo-2,2-difluorovinyllithium, generated
from 1,1-dibromo-2,2-difluoroethylene, followed by acetylation. On treatment with butyllithium, the bromoacetates underwent selective 1,2-
elimination of lithium acetate to afford mono- and disubstituted 1,1-difluoroallenes in high yields.
1,1-Difluoroallenes exhibit a wide range of reactivity. They
react with various unsaturated compounds to give cycload-
dition products: Diels-Alder1a and [3+2]1b-d cycloaddition
reactions with 1,3-dienes and 1,3-dipoles take place on the
internal, nonfluorinated alkene moiety to give the corre-
sponding products.1e,f The [2+2] cycloaddition reactions with
alkenes and alkynes occur on the terminal, fluorinated alkene
moiety to give cyclobutane2a and cyclobutene2b derivatives.
1,1-Difluoroallenes also serve as substrates for nucleophilic
reactions. Not only nucleophilic substitution on the terminal
alkene moiety3a but nucleophilic addition to the internal
alkene moiety3b has been reported in the literature. Further-
more, the palladium-catalyzed coupling reaction of difluo-
rohomoallenyl bromide with organoboronic acids takes place
to give substituted butadienes.4 Thus, 1,1-difluoroallenes are
potentially useful building blocks for the construction of
fluorinated molecules.
In addition, nonfluorinated allenes are found in the
structures of many natural and non-natural biologically active
compounds, and some of these have been used for therapeutic
purposes.5 The synthesis of their fluorinated analogues could
lead to the development of pharmaceuticals with improved
activity.
Despite their synthetic and practical importance, only
a limited number of synthetic methods for accessing 1,1-
(4) Shen, Q.; Hammond, G. B. Org. Lett. 2001, 3, 2213.
(5) Krause, N.; Hoffmnn-Ro¨der, A. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol.
2, pp 997-1039.
(6) For the synthesis of nonfluorinated allenes, see: Brummond, K. M.;
DeForrest, J. E. Synthesis 2007, 795.
(1) (a) Dolbier, W. R., Jr.; Burkholder, C. R.; Piedrahita, C. A. J.
Fluorine Chem. 1982, 20, 637. (b) Dolbier, W. R., Jr.; Burkholder, C. R.;
Winchester, W. R. J. Org. Chem. 1984, 49, 1518. (c) Dolbier, W. R., Jr.;
Burkholder, C. R. Isr. J. Chem. 1985, 26, 115. (d) Dolbier, W. R., Jr.;
Wicks, G. E.; Burkholder, C. R. J. Org. Chem. 1987, 52, 2196. (e) Dolbier,
W. R., Jr.; Burkholder, C. R.; Wicks, G. E.; Palenik, G. J.; Gawron, M.
J. Am. Chem. Soc. 1985, 107, 7183. (f) Dolbier, W. R., Jr. Acc. Chem. Res.
1991, 24, 63.
(7) Shi, G.; Xu, Y. J. Fluorine Chem. 1989, 44, 161.
(8) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547.
(9) For the synthesis of other fluorinated allenes, see: (a) Zens, A. P.;
Ellis, P. D.; Ditchfield, R. J. Am. Chem. Soc. 1974, 96, 1309. (b) Castelhano,
A. L.; Krantz, A. J. Am. Chem. Soc. 1987, 109, 3491. (c) Lu, H.; Friedrich,
H. B.; Burton, D. J. J. Fluorine Chem. 1995, 75, 83. (d) Xu, B.; Hammond,
G. B. Angew. Chem., Int. Ed. 2008, 47, 689.
(2) (a) Dolbier, W. R., Jr.; Wicks, G. E. J. Am. Chem. Soc. 1985, 107,
3626. (b) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534.
(3) (a) Mae, M.; Hong, J. A.; Xu, B.; Hammond, G. B. Org. Lett. 2006,
8, 479. (b) Xu, Y.-Y.; Jin, F.-Q.; Huang, W.-Y. J. Fluorine Chem. 1995,
70, 5.
(10) Thermal stability of allenes compared to the constitutionally
isomeric terminal acetylenes might contribute in part to selective elimination
of LiOE. For instance, 1,2-butadiene is more stable than 1-butyne by 2.9
kJ/mol: Pedley, J. B.; Naylor, R. D.; Kirby, S. P., Ed. Thermochemical
Data of Organic Compounds; Chapman and Hall: London, UK; 1977.
10.1021/ol9016673 CCC: $40.75
Published on Web 08/11/2009
 2009 American Chemical Society

difluoroallenes have been reported.6 1-Trifluoromethyl-
substituted alkenyllithium compounds, which are prepared
from 2-bromo-1,1,1-trifluoro-2-alkene1a or trifluoromethyl-
substituted hydrazones,7 afford 1,1-difluoroallenes via the
1,2-elimination of lithium fluoride. 1,1-Difluoropropar-
gylindium species, generated from the corresponding
propargyl bromides, react with formaldehyde to give 1,1-
difluoroallenes bearing a hydroxymethyl moiety.8 These
propargyl bromides also react with Grignard reagents in the
presence of a copper catalyst to give 1,1-difluoroallenes.3a
Notwithstanding these past contributions, general methods
that can provide a wide range of 1,1-difluoroallenes are
still needed.9
1 reacted with 3-phenylpropanal, and subsequent acetylation
with acetic anhydride gave 2-bromo-3,3-difluoroallylic ac-
etate 2a in a 93% yield. The corresponding pivalate 3,
benzoate 4, and pentafluorobenzoate 5 were also prepared
by using the same procedure.
The esters prepared above, 2a, 3, 4, and 5, were subjected
to the elimination reaction (Table 1). Treatment of the
Table 1. Optimization of the Reaction Conditions
In this Letter, we describe a new route to 1,1-
difluoroallenes starting from carbonyl compounds. Our
strategy to access 1,1-difluoroallenes is via the difluo-
rovinylidenation of carbonyl compounds, as shown in
Scheme 1. Aldehydes and ketones are treated with
alkyllithium
Scheme 1. Strategy for Accessing 1,1-Difluoroallenes
entry substrate
(equiv)
conditions
6a, %
pentane-Et2O (1:1),
-130 °C, 2 h
1
2
3
4
2a
3
t-BuLi (2)
t-BuLi (2)
t-BuLi (2)
t-BuLi (2)
56
48
49
56
pentane-Et2O (1:1),
-130 °C, 2 h
pentane-Et2O (1:1),
-130 °C, 2 h
4
pentane-Et2O (1:1),
-130 °C, 2 h
5
pentane-Et2O,
5
2a
2a
2a
2a
2a
2a
2a
t-BuLi (1)
t-BuLi (2)
t-BuLi (1)
s-BuLi (1)
n-BuLi (1)
MeLi (1)
-130 °C, 2 h
67
67
38
72
82
54
87
6
hexane, 0 °C, 0.5 h
hexane, 0 °C, 0.5 h
hexane, 0 °C, 0.5 h
hexane, 0 °C, 0.5 h
hexane, 0 °C, 0.5 h
hexane, 0 °C, 1 min
7
8
9
10
11
1-bromo-2,2-difluorovinyllithium 1, which is expected to
be prepared from 1,1-dibromo-2,2-difluoroethylene. The
resulting alkoxides are modified on their oxygen atom,
and 2-bromo-3,3-difluoroallylic precursors 2 are obtained.
Lithiation of 2 would cause the 1,2-elimination of LiOE,
affording the targeting 1,1-difluoroallenes. Although the
elimination of lithium fluoride can also take place, the
proper choice of the leaving group (OE) would promote
the selective 1,2-elimination of LiOE.10
n-BuLi (1)
precursors with tert-butyllithium (2 equiv) at -130 °C gave
the desired 1,1-difluoroallene 6a in 48-56% yields (entries
1-4). Acetate 2a was found to be the most suitable from
chemical and economical viewpoints.
Further optimization of the conditions revealed that the
elimination proceeded efficiently in hexane with butyl-
lithium (1 equiv, entry 9), whereas employing an equimo-
lar amount of tert-butyllithium gave a higher yield of 6a
(entry 5), suggesting a competitive decomposition of 6a.
The use of hexane as a solvent increased the yield of 6a
to 67% (entry 6). It is known that a nonpolar solvent brings
about a higher degree of aggregation of alkyllithium
reagents. The formation of higher aggregates with a low
reactivity could suppress undesired side reactions.12 sec-
Butyllithium and butyllithum increased the yield of 6a
further to 72% and 82%, respectively (entries 8 and 9),
whereas methyllithium was ineffective (entry 10). When
The lithiation of 1,1-dibromo-2,2-difluoroethylene was
successfully performed by treatment with 1 equiv of butyl-
lithium at -100 °C (Scheme 2).11 The generated vinyllithium
Scheme 2. Preparation of Precursors
(11) A trace amount of fluoroethyne was sometimes observed in the
reaction mixture (19F NMR analysis), which suggests that elimination of
lithium fluoride from vinyllithium 1 took place partially. However, this
elimination was negligible when the lithiation was carried out under -100
°C. For the report on fluoro(silyl)ethyne, see: Hanamoto, T.; Koga, Y.;
Kawanami, T.; Furuno, H.; Inanaga, J. Angew. Chem., Int. Ed. 2004, 43,
3582.
Org. Lett., Vol. 11, No. 17, 2009
3995

Table 2. Synthesis of 1,1-Difluoroallenes
a
19F NMR yield based on PhCF3. b Acetylation was performed with isopropenyl acetate/TsOH. See the Supporting Information for details.
butyllithium was used, the reaction reached completion
within 1 min, yielding 6a in an 87% yield (entry 11).13
A variety of 1,1-difluoroallenes were synthesized under
optimized conditions (Table 2).14 Not only less hindered
1,1-difluoroallenes, but also sterically hindered 1,1-
difluoroallenes were obtained from aldehyde-derived al-
lylic acetates 2a-i (entries 1-9). It is noteworthy that
the lithium-bromine exchange of acetate 2i occurred
selectively on the bromoalkene moiety to afford the
bromophenyl-substituted allene 6i in an 84% yield (entry
9). Acetates, prepared from ketones also underwent
elimination, and 3,3-disubstituted allenes were obtained
in high yields (entries 10 and 11).15
(12) Yokoo, T.; Shinokubo, H.; Oshima, K.; Utimoto, K. Synlett 1994,
645.
(13) 19F NMR analysis revealed that 3-fluoropropargylic acetate was
not generated.
3996
Org. Lett., Vol. 11, No. 17, 2009

In summary, we have developed a new method for the
synthesis of 1,1-difluoroallenes. Difluorovinylidenation of
aldehydes and ketones realized a general, expedient synthesis
of 1,1-difluoroallenes.
(14) Typical procedure: To a solution of 1,1-dibromo-2,2-difluoroet-
hylene (444 mg, 2.0 mmol) in Et2O (16 mL) was added an Et2O solution
(2.0 mL) of butyllithium (1.28 mL, 1.60 M in hexane, 2.0 mmol) at -100
°C under argon. After the solution was stirred for 15 min at the same
temperature, 3-phenylpropanal (0.28 mL, 2.0 mmol) was added. The mixture
was then stirred for an additional 15 min. After acetic anhydride (0.19 mL,
2.0 mmol) was added, the mixture was allowed to warm to 0 °C over 2 h.
The reaction was quenched with saturated NH4Cl aq, and the products were
extracted with Et2O. The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. After removal of the solvents under
reduced pressure, the residue was purified by column chromatography (SiO2,
hexane-AcOEt, 20:1) to give 2a as a colorless liquid (593 mg, 93%).
Butyllithium (2.6 mL, 1.60 M in hexane, 0.23 mmol) was added to a solution
of 2a (60 mg, 0.19 mmol) in hexane (2.6 mL) at 0 °C under argon. After
the mixture was stirred for 1 min at the same temperature, the reaction was
quenched with NH4Cl aq, and the products were extracted with Et2O. The
combined organic layer was washed with brine and dried over anhydrous
Na2SO4. After removal of the solvent under reduced pressure, the residue
was purified by column chromatography (SiO2, pentane) to give 6a (29
mg, 87%) as a colorless liquid.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Japan Society for
the Promotion of Science. This work was also supported by
the Uehara Memorial Foundation and the Asahi Glass
Foundation.
Supporting Information Available: Experimental details
1
and characterization data of 2-6 and H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9016673
(15) On attempted reactions of 2-naphthaldehyde and 4-phenylbenzal-
dehyde, the 19F NMR analysis of the reaction mixtures suggested the
generation of the corresponding aromatic difluoroallenes. We, however,
failed to isolate the products, probably due to their instability.
Org. Lett., Vol. 11, No. 17, 2009
3997