Gem-difluoroolefination of diaryl ketones and enolizable aldehydes with difluoromethyl 2-pyridyl sulfone: New insights into the Julia-Kocienski reaction

Article abstract of DOI:10.1002/chem.201402183

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction. What a gem! The gem-difluoroolefination of diaryl ketones was realized by an acid-promoted Julia-Kocienski olefination reaction at elevated temperatures. The gem-difluoroolefination of aliphatic aldehydes and chemoselective gem-difluoroolefination of dicarbonyl compounds was achieved with the use of an amide base generated in situ (see scheme).

Full text of DOI:10.1002/chem.201402183

DOI: 10.1002/chem.201402183
Full Paper
&
Synthetic Methods
gem-Difluoroolefination of Diaryl Ketones and Enolizable
Aldehydes with Difluoromethyl 2-Pyridyl Sulfone: New Insights
into the Julia–Kocienski Reaction
Bing Gao, Yanchuan Zhao, Mingyou Hu, Chuanfa Ni, and Jinbo Hu*[a]
Abstract: The direct conversion of diaryl ketones and enoliz-
able aliphatic aldehydes into gem-difluoroalkenes has been
due to the retro-aldol type decomposition of the key inter-
mediate. Efficient gem-difluoroolefination of aliphatic alde-
hydes was achieved by the use of an amide base generated
in situ (from CsF and tris(trimethylsilyl)amine), which dimin-
ishes the undesired enolization of aliphatic aldehydes and
provides a powerful synthetic method for chemoselective
gem-difluoroolefination of multi-carbonyl compounds. Our
results provide new insights into the mechanistic under-
standing of the classical Julia–Kocienski reaction.
a
long-standing challenge in organofluorine chemistry.
Herein, we report efficient strategies to tackle this problem
by using difluoromethyl 2-pyridyl sulfone as a general gem-
difluoroolefination reagent. The gem-difluoroolefination of
diaryl ketones proceeds by acid-promoted Smiles rearrange-
ment of the carbinol intermediate; the gem-difluoroolefina-
tion is otherwise difficult to achieve through a conventional
Julia–Kocienski olefination protocol under basic conditions
Introduction
been extensively exploited; however, transformations that in-
volve reagent systems PPh3/ClCF2CO2Na,[7b–d] PPh3/CF2Br2,[7e]
PPh3/FSO2CF2CO2Me,[7f] and PPh3/TMSCF2Cl[7o] are limited to ar-
omatic aldehydes and activated ketones. Although examples
The synthesis of fluoroalkenes has attracted much attention
due to their unique chemical and biological properties, espe-
cially relative to their nonfluorinated counterparts.[1,2] gem-Di-
fluoroalkenes, for instance, are highly electrophilic toward
many nucleophiles at the terminal difluoromethylene group
(=CF2),[3] therefore, they can be employed as valuable inter-
mediates for the preparation of di- and tri-fluoromethylated
compounds, monofluoroalkenes, monofluorinated heterocy-
cles, carboxylic acids, and esters.[4] Moreover, the gem-difluoro-
vinyl functionality (C=CF2) is known to act as a bioisostere for
the carbonyl group and has been used in the design of mecha-
nism-based enzyme inhibitors.[2a,5] Synthetic methods for the
preparation of gem-difluoroalkenes can be mainly divided into
two categories: 1) the direct conversion of carbonyl com-
pounds into gem-difluoroalkenes[6,7] and 2) the incorporation
of gem-difluorovinyl-containing building blocks into the target
molecules.[8] In this context, the direct deoxygenative gem-di-
fluoroolefination of carbonyl compounds represents one of the
most straightforward methods because of the ready availability
of aldehydes and ketones. Among them, Wittig reactions that
involve difluoromethylene phosphorus ylides (R3P=CF2) have
of unactivated substrates have been illustrated for reactions
[7g,h]
with P(NMe2)3/CF2Br2
and PR3/(CF3)2Hg/NaI,[7i] they suffer
from the disadvantages of toxic reagents, moderate yields,
and/or production of undesired tetrafluorocyclopropanation
products. Recently, Xiao and co-workers have prepared di-
fluoromethylene phosphobetaines and applied them to the
conversion of carbonyl compounds into gem-difluoroalkenes
under base-free conditions.[7j] The Horner–Wadsworth–Emmons
reaction with difluoromethyl phosphonate anions and Horner–
Wittig reaction with difluoromethyl phosphine oxide anions
seemed to be more general than the classical Wittig reactions,
but the reactions with diaryl ketones were demonstrated with
only a few examples.[7l–n] Therefore, an easily accessible and
safe reagent for the direct and general gem-difluoroolefination
of both diaryl ketones and enolizable aldehydes is highly
desirable.
The Julia–Kocienski olefination reaction has been widely em-
ployed in synthetic chemistry for the direct construction of
C=C bonds from carbonyl groups because of its easy manipu-
lation, high efficiency, and excellent stereocontrol.[9] Recently,
we reported the first example of a Julia–Kocienski type gem-di-
fluoroolefination reaction of carbonyl compounds with difluor-
omethyl 2-pyridyl sulfone (2-PySO2CF2H, 1; Figure 1).[10a] Re-
agent 1 is a bench-stable, crystalline solid that is now commer-
cially available.[10d] Moreover, it is noteworthy that although 2-
pyridyl sulfones are not commonly used in classical Julia–Ko-
cienski olefination reactions,[9] reagent 1 unexpectedly shows
better reactivity in gem-difluoroolefination reactions than other
[a] B. Gao, Dr. Y. Zhao, Dr. M. Hu, Dr. C. Ni, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Ling-Ling Road
Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: jinbohu@sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402183.
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Table 1. Thermal stability of the carbanions of sulfones 1–6.
Sulfone
Recovery in DMF [%][a,b]
Recovery in THF [%][a,c]
1
2
3
4
5
6
41
73
90[d]
5
14
26
0
62
99[d]
0
0
<1
Figure 1. Heteroaryl sulfones for gem-difluoroolefination reactions
[a] Recovery was determined by 19F NMR spectroscopy with trifluoro-
methylbenzene as an internal standard. [b] Conditions: sulfone (1 equiv)
and LiHMDS (2.0 equiv) in DMF (0.5 mmol) at À508C for 1 h; then
CF3COOH (excess) quench. [c] Sulfone (1 equiv) and LiHMDS (2.0 equiv) in
THF (0.5 mmol) at À788C for 1 h; then CF3COOH (excess) quench. [d] Iso-
lated yield.
difluoromethyl heteroaryl sulfones, such as difluoromethyl 1,3-
benzothiazol-2-yl (BT, 4; Figure 1), difluoromethyl 1-phenyl-1H-
tetrazol-5-yl (PT, 5; Figure 1), and difluoromethyl 1-tert-butyl-
1H-tetrazol-5-yl (TBT) sulfone.[10a] We also realized that our
gem-difluoroolefination reaction with reagent 1 may provide
new insights into the classical Julia–Kocienski reaction. For in-
stance, we found that the gem-difluorinated sulfinate salt,
a key intermediate from the Smiles rearrangement in the Julia–
Kocienski reaction that has been overlooked in the past, was
indeed a stable species.[10a–c]
carried out thermal stability (lifetime) analysis of different aryl
sulfone carbanions.
Compounds 2–6 (Figure 1) were prepared by the procedure
reported for the synthesis of 1.[10a] As shown in Table 1, sul-
fones 1–6 were treated with strong base (lithium hexamethyl
disilazide (LiHMDS), 2.0 equiv) in both high-polarity solvent
DMF (À508C, 1 h) and low-polarity solvent THF (À788C, 1 h) in
the absence of electrophiles. Each reaction mixture was
quenched with excess CF3COOH after 1 h. For compounds 1, 2,
and 4–6, the amount of unreacted sulfone in the reaction mix-
ture was monitored by 19F NMR spectroscopy with trifluoro-
methylbenzene as an internal standard. In the case of sulfone
3, the isolated yield was obtained after flash chromatography.
It was found that the carbanions of sulfones 1, 2, and 4–6 in
THF showed less thermal stability than in DMF, whereas the
carbanion of sulfone 3 exhibited excellent thermal stability in
both THF and DMF. The order of thermal stability of the di-
fluoromethyl aryl sulfone carbanions (1>6>5ꢀ4) was in
agreement with that of the corresponding nonfluorinated aryl
sulfones.[9] There is a clear tendency of the thermal stability of
the carbanions to decrease as the number of the fluorine sub-
stituents increases (3>2>1). This is also in agreement with
the “negative fluorine effect” that we found during our investi-
gation of fluoroalkylations of epoxides.[15] In general, the di-
fluoromethyl carbanions tend to decompose into difluorocar-
bene (DCF2) by a elimination and the difluorocarbene species
further degrades into fluoride ions or other products.[16]
On the other hand, although our reported procedure
showed good compatibility with aromatic aldehydes, prelimi-
nary exploration of the gem-difluoroolefination of diaryl ke-
tones and aliphatic aldehydes proved to be less efficient. In
view of the importance of 2,2-diaryl-1,1-difluoroethenes and
aliphatic gem-difluoroalkenes,[8i,j] we have carried out further
investigations and tried to solve these synthetic problems with
reagent 1. Herein, we report our recent success in the carbonyl
gem-difluoroolefination of diaryl ketones and aliphatic alde-
hydes with reagent 1 based on our new mechanistic insights
into the Julia–Kocienski reaction.
Results and Discussion
Thermal-stability evaluation of different aryl sulfones under
basic conditions
Since the initial exploration of the olefination reaction of car-
bonyl compounds with BT sulfones by Julia and co-workers,[11]
other heteroaryl sulfones (such as PT sulfones and TBT sul-
fones)[12] have been successively developed and applied in or-
ganic synthesis.[13] These sulfones are believed to increase the
stability of the corresponding metalated sulfone carbanions. In
a typical olefination reaction, the heteroaryl sulfone is first de-
protonated in solution by a strong non-nucleophilic base [lithi-
um diisopropylamide (LDA) or potassium hexamethyl disilazide
(KHMDS)], then the carbonyl compound is added to react with
the metalated sulfone carbanion. Finally Smiles rearrange-
ment[14] and SO2 extrusion give the alkene product. The fact
that the metalated nonfluorinated sulfone carbanions are suffi-
ciently stable in solution (even in the absence of electrophiles)
allows the scope of the Julia–Kocienski olefination to be ex-
tended to base-sensitive carbonyl substrates.[12] To explore the
potential impact of fluorine substitution on the chemical prop-
erties of heteroaryl sulfones in Julia–Kocienski reactions, we
The better performance of 1 in the gem-difluoroolefination
reaction relative to 4 and 5 can be partly attributed to the
À
higher thermal stability of its anion (2-PySO2CF2 ).[10] It should
be noted that the highly unstable nature of the difluoromethyl
carbanion makes conventional stepwise manipulation impossi-
ble and Barbier-type conditions[17] must be adopted. However,
the Barbier-type process intrinsically prevents the efficient ole-
fination of base-sensitive carbonyl compounds like aliphatic al-
dehydes.[11,12] With these considerations in mind, we next
sought to tackle the problems encountered in the gem-
difluoroolefination of diaryl ketones and aliphatic aldehydes.
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gem-Difluoroolefination of diaryl ketones
The direct synthesis of 2,2-diaryl-1,1-difluoroethenes from
diaryl ketones possesses significant advantages in terms of
convenience and efficiency relative to multistep cross-coupling
reactions.[8e] In our previous report, the gem-difluoroolefination
of fluorenone (7) was demonstrated; alkene 8 was produced
in 87% yield (Scheme 1a).[10a] In sharp contrast, the reaction
Scheme 2. A stepwise mechanistic study of the gem-difluoroolefination of
9a. All reactions were monitored by 19F NMR spectroscopy with trifluoro-
methylbenzene as an internal standard.
warming of the reaction mixture to room temperature, directly
afforded product 10a in 19% yield (19F NMR spectroscopy)
without the observation of sulfinate salts. However, the regen-
eration of 1 (55%) was detected by 19F NMR spectroscopy
(Figure 2, spectrum B versus C).
On the basis of the generally accepted reaction mechanism
of the Julia–Kocienski reaction, we speculated that the differ-
ent performances of 7 and 9a might originate from decompo-
sition of the alcoholate intermediate 13 at elevated tempera-
tures (Scheme 3).[11,12] In the case of 9a, the two untied aryl
groups would cause strong steric hindrance around the qua-
ternary carbon center (O-substituted carbon atom) of inter-
mediate 13 due to their large size and free rotation and, as
a consequence, the competing decomposition process would
outstrip the rearrangement process. On the contrary, when the
two aryl groups are tied together, as in 7, free rotation is mini-
mized to some extent and the rigid geometry may even accel-
erate the rearrangement process by lowering the energy barri-
er. Overall, these results indicate that it is difficult to achieve ef-
ficient gem-difluoroolefination of normal diaryl ketones by the
typical Julia–Kocienski reaction under basic conditions.
Scheme 1. The gem-difluoroolefination of 7 and 9a.
with benzophenone (9a) under identical conditions gave
only 20% yield of the corresponding gem-difluoroalkene 10a
(Scheme 1b). The poor results seemed general for a broad
range of diaryl ketones (for example, under identical condi-
tions, 10b, 10 f, and 10l (see Table 3 below for structures)
were obtained in 19, 3, and 23% yield, respectively).
To gain a better understanding of this phenomenon, we per-
formed careful investigation of the reaction (Scheme 2). The re-
action between 1 and 9a was conducted in THF/HMPA (hexa-
methylphosphoramide) at À788C for 1 h. The mixture was
quenched with trifluoroacetic acid (TFA) and alcohol 11 a was
obtained in 98% yield (determined by 19F NMR spectroscopy)
with nearly quantitative conversion of 1 (Figure 2, spectrum A
versus B). Treatment of the crude product 11 a with excess 1,8-
diazabicycloundec-7-ene (DBU) at À608C, followed by gradual
Considering that intermediate 13 can be captured at low
temperatures by acid to afford the relatively stable alcohol 11,
Figure 2. 19F NMR spectroscopic study of the stepwise gem-difluoroolefination of 9a.
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the LiHMDS-mediated reaction
conditions proved more general
to a broad range of diaryl ke-
tones, especially those with poor
solubility in DMF at low temper-
atures (Table 2, entries 9–14).
With the optimized reaction
conditions in hand (Table 2,
entry 7), we next investigated
the generality of the gem-di-
fluoroolefination reaction with
various diaryl ketones. The re-
sults shown in Table 3 indicated
Scheme 3. Mechanistic consideration of the gem-difluoroolefination of 9a.
that, by the one-pot protocol,
both symmetric and asymmetric
we speculated whether a Smiles rearrangement of 11 under
acidic conditions could generate alkene 10 (Scheme 3). Al-
though the base-promoted Smiles rearrangement of heteroaryl
sulfones is well known, neither the acid-promoted Smiles rear-
rangement,[18] nor its application in Julia–Kocienski olefination
reactions are widely reported. To test the feasibility of our hy-
pothesis, we first tested the transformation of alcohol 11 a by
using HCl as the promoter under different conditions
(Scheme 4). This strategy was successful; both the high reac-
diaryl ketones smoothly gave gem-difluoroalkenes in moder-
ate-to-good yields. The reaction conditions tolerate electron-
donating (phenyl (9e) and methoxy (9 f–h) groups) and elec-
tron-withdrawing substituents (halogen (9b–d, 9k–m) and tri-
fluoromethyl (9i) groups). It was reported that difluoroalkenes
10c and 10 f were prepared in 56 and 45% overall yield, re-
spectively, by a two-step palladium-catalyzed cross-coupling
reaction from 2,2-difluoro-1-tributylstannylethenyl p-toluene-
sulfonate;[8e] by our method, 10c and 10 f were obtained in 83
and 69% yield, respectively (Table 2, entries 3 and 9). gem-Di-
fluoroalkene 10m, which is difficult to prepare by palladium-
catalyzed transformation due to the inevitable CÀBr bond
cleavage by Pd0,[8f–h] was prepared in 77% yield from the readi-
ly available ketone 9m. The reaction conditions also worked
well with some heteroaryl ketones. For example, the reaction
of phenyl 2-thienyl ketone (9n) gave alkene 10n in 63% yield
Table 2. Optimization of the reaction conditions for one-pot synthesis of
10a.
Scheme 4. Acid-promoted transformations of 11 a into 10a.
tion temperatures and high acid concentration were beneficial
to the transformation. When the reaction was performed with
concentrated HCl (12m) at 1308C for 12 h, an excellent yield
(92%) of 10a was obtained, with full conversion of 11 a.
Entry
Base
Ratio [1/9a/base]
Acid[b]
Yield of 10a [%][a]
1
2
3
4
5
6
7[d]
8
9[e]
10[e]
11[g]
12[g]
13[i]
14[i]
KOtBu
1.0:2.0:1.8
1.0:2.0:1.8
1.0:2.0:1.8
2.0:1.0:3.0
1.0:1.2:2.0
1.0:2.0:2.0
1.0:2.0:2.0
2.0:1.0:3.0
1.0:2.0:1.8
1.0:2.0:2.0
1.0:2.0:1.8
1.0:2.0:2.0
1.0:2.0:1.8
1.0:2.0:2.0
HCl
HCl
CF3COOH
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
48[c]
75
65
60
25
56
61
59
48[f]
67[f]
51[h]
83[h]
15[j]
77[j]
Encouraged by these results, we next investigated the possi-
bility of a one-pot synthesis of 10a from 9a (Table 2). The ad-
dition reaction between 1 and 9a was conducted with our
previously developed KOtBu/DMF system[10a] at À608C for 1 h.
Thereafter, the reaction mixture was quenched with excess HCl
(12m) at À608C. The reaction mixture was warmed to ambient
temperature, then heated at reflux at 120–1308C for 10 h to
afford 10a in 48% yield (Table 2, entry 1). When NaOtBu was
used instead of KOtBu, difluoroalkene 10a was obtained in
a much higher yield (75%; Table 2, entry 2). CF3COOH was
found to be an inferior promoter for the olefination reaction
relative to HCl (12m) (Table 2, entry 3). LiHMDS was also
screened and the addition of HMPA (10%v/v) as co-solvent in
DMF with a 1:2 molar ratio of 1/9a gave an improved result.[19]
Although NaOtBu showed better performance in the reaction
than LiHMDS (Table 2, entries 2 and 7) on model substrate 9a,
NaOtBu
NaOtBu
NaOtBu
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaOtBu
LiHMDS
NaOtBu
LiHMDS
NaOtBu
LiHMDS
HCl
[a] Isolated yield. [b] c=12 m. [c] Yield determined by 19F NMR spectrosco-
py. [d] 10% v/v of HMPA was added as co-solvent. [e] 9b served as sub-
strate. [f] Yield of 10b. [g] 9c served as substrate. [h] Yield of 10c. [i] 9l
served as substrate. [j] Yield of 10l. See Table 3 (entries 2, 3, and 12)
below for structures other than 9a and 10a.
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Table 3. gem-Difluoroolefination of diaryl ketones 9 with reagent 1.
Table 4. Survey of the reaction conditions for gem-difluoroolefination of
aldehyde 17a with 1.
Entry[a]
Ar1
Ar2
Yield [%][b]
1[c]
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph, 9a
10a, 75
10b, 67
10c, 83
10d, 75
10e, 70
10 f, 69
10g, 80
10h, 72
10i, 67
10j, 64
10k, 79
10l, 77
10m, 77
10n, 63
10o, 0
p-F-C6H4, 9b
p-Cl-C6H4, 9c
p-Br-C6H4, 9d
p-Ph-C6H4, 9e
p-MeO-C6H4, 9 f
m-MeO-C6H4, 9g
o-MeO-C6H4, 9h
p-CF3-C6H4, 9i
p-CF3-C6H4, 9j
p-F–C6H4, 9k
p-Cl-C6H4, 9l
p-Br-C6H4, 9m
2-thiophenyl, 9n
2-pyridyl, 9o
Entry
FÀ
Ratio [1/17a/FÀ/N(TMS)3]
Yield of 18a [%][a]
1
2
3
4
5
6
7
TMAF
TBAF
TBAT
CsF
CsF
CsF
1.0:1.5:2.0:2.0
1.0:1.5:2.0:2.0
1.0:1.5:2.0:2.0
1.0:1.5:2.0:2.0
1.0:2.0:2.5:2.5
1.0:1.2:2.0:2.0
1.0:1.5:0.05:2.0
78
88
63
95 (74)[b]
95
9
Ph
10
11
12
13
14
15
p-MeO-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
Ph
77
trace
CsF
[a] The yield of 18a was determined by 19F NMR spectroscopy. [b] The
yield of 19a determined by 19F NMR spectroscopy is given in parentheses.
Ph
[a] Reactions were conducted on 0.5 mmol scale with DMF (4 mL) and
HMPA (0.4 mL) as co-solvents. [b] Isolated yield. [c] NaOtBu was used
(Table 2, entry 2).
Inspired by Langlois’ seminal work on the trifluoromethyla-
tion of ketones and formamides with CF3H by using a substoi-
chiometric amount of base generated in situ from tris(trimeth-
ylsilyl)amine (N(TMS)3) and a FÀ source,[21] we thought a similar
strategy might be applicable to our reaction. The gem-difluoro-
olefination of aldehyde 17a with 1 was examined first and the
results are shown in Table 4. When Langlois’ method (CsF
(5 mol%); Table 4, entry 7) was used,[21a,b] only a trace amount
of sulfinate 18a was detected by 19F NMR spectroscopy, ac-
companied by nearly quantitative recovery of the starting ma-
terial 1. The failure of this reaction can probably be ascribed to
the weak nucleophilicity of sulfinate 18a, which is unreactive
toward N(TMS)3 (and the regeneration of the amide anion is
therefore stopped). When an excess of CsF was used, sulfinate
18a was obtained in excellent yield (95%; Table 4, entry 4) and
could be easily converted to difluoroalkene 19a in 74% yield
after acidic workup. Other fluoride sources, such as tetrameth-
ylammonium fluoride (TMAF), tetrabutylammonium fluoride
(TBAF), and tetrabutylammonium triphenyldifluorosilicate
(TBAT) were also examined, and it was found that CsF gave the
best result (Table 4, entries 1–4). A brief optimization of the re-
action conditions provided the appropriate molar ratio of 1/
17a/N(TMS)3/CsF to be 1.0:1.5:2.0:2.0 (Table 4, entry 4).
With the optimal reaction conditions obtained, we examined
the substrate scope of the gem-difluoroolefination of aliphatic
aldehydes 17 with 1. The results summarized in Table 5 show
that gem-difluoroalkenes 19a–f were obtained in moderate-to-
good yields. Aldehyde 17b, with a Br substituent, could be
converted to alkene 19b in 85% yield (Table 5, entry 2), which
is potentially useful for further functionalization by metal-cata-
lyzed cross-coupling.[22] For the long-chain alkyl aldehydes,
such as undecanal (17e) and palmitaldehyde (17 f), excess
(2.5 equiv) N(TMS)3 and CsF were required due to the poor sol-
ubility of these aldehydes in DMF (Table 5, entries 5 and 6).
(Table 2, entry 14). Notably, even the ortho-methoxy-substitut-
ed diaryl ketone 9h could be converted to 10h in 72% isolat-
ed yield.
Compared to the reported methods for the synthesis of 2,2-
diaryl-1,1-difluoroethenes 10, this protocol possesses several
advantages, such as one-pot operation, good functional-group
tolerance, and high efficiency. Limitations mainly derive from
the reaction with nitrogen-containing ketones, such as phenyl
2-pyridyl ketone (9o). In this case, the difluoro[(2-pyridyl)sulfo-
nyl]methylated carbinol intermediate failed to undergo the
Smiles rearrangement, which probably results from the de-
creased nucleophilicity of the OH group caused by protonation
of the a-(hetero)aryl substituents.
gem-Difluoroolefination of enolizable aldehydes
The direct carbonyl gem-difluoroolefination of aliphatic alde-
hydes remains another challenge in fluorine chemistry. Meth-
ods reported in the literature seldom employ aldehydes with
long-chain alkyl groups as substrates because the a-hydrogen
atom of the corresponding carbonyl groups are quite acidic
and would easily result in self-condensation under strongly
basic conditions.[20] Preliminary efforts to expand the 1/KOtBu/
DMF reaction system to the enolizable aldehyde 17a proved
only moderately successful; product 19a was obtained in only
40% yield, even when LiHMDS was used as the base. We hy-
pothesized that the competing aldol condensation reaction
might have a direct relationship with the concentration of the
base; if the base concentration was controlled at a relatively
low level by a slow-release strategy, the side reaction might be
suppressed to some extent.
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ined, the aromatic aldehyde was
also exclusively transformed with
Table 5. gem-Difluoroolefination of aliphatic aldehydes with 1.
high
efficiency
(70%;
Scheme 5b). These two exam-
ples demonstrate that extra
steps to protect the keto-car-
bonyl group of keto-aldehydes
would be unnecessary if only
the gem-difluoroolefination of
the aldehyde is desired. In com-
parison, when a stoichiometric
amount of base was used, both
the ketone and aldehyde groups
of 22 were gem-difluoroolefinat-
ed to give 24 in a single step
(Scheme 5c). Protection of the
aldehyde was required for selec-
tive gem-difluoroolefination of
the ketone group. For example,
reaction of keto-acetal 25 with
1, followed by acid workup, af-
forded alkene 26 in 54% yield
(Scheme 5d).[24]
Entry
1[c]
Substrate
Product
Yield[b] [%]
60 (74)[d]
17a
17b
17c
19a
19b
19c
2
3
85
71
4
17d
17e
17 f
19d
19e
19 f
80
66
64
5[e]
6[e]
[a] Reactions were performed on 0.5 mmol scale in DMF (4 mL). [b] Isolated yield. [c] The low yield is partially
due to the volatility of the product. [d] The yield of 19a determined by 19F NMR spectroscopy is given in paren-
theses. [e] CsF (2.5 equiv) and N(TMS)3 (2.5 equiv) were used.
b,b-Difluoroacrylates are po-
tential precursors for com-
pounds used in coatings, poly-
Chemoselective transformations of dicarbonyl compounds
merization, special optical materials, etc.[25] We found that the
reaction between keto-ester 27 and 1 with KHMDS as the base
proceeded smoothly to give the difluorinated sulfinate inter-
mediate in high yield; subsequent workup with concentrated
HCl at À508C afforded the desired olefin 28 in 74% yield
(Scheme 5e).
During the investigation of the gem-difluoroolefination of eno-
lizable aldehydes, we found that generation of the base in situ
also worked well with aromatic aldehydes, however, ketones
failed to undergo the transformation under identical reaction
conditions. Taking into account that various ketones can be
successfully gem-difluoroolefinat-
ed by using
a stoichiometric
amount of base, we decided to
make a comparison of the che-
moselectivity of the gem-
difluoroolefination of dicarbonyl
compounds by using different
base systems (Scheme 5).[23]
The gem-difluoroolefination of
substrates that contained both
aldehyde and ketone functional
groups were investigated; such
substrates have not been dem-
onstrated in previously reported
deoxygenative gem-difluoroolefi-
nation reactions. When com-
pound 20 was treated with
1 under the N(TMS)3/CsF/DMF
reaction conditions, the alde-
hyde group was selectively con-
verted to the corresponding
alkene 21 in 72% yield, and the
ketone was left untouched
(Scheme 5a). When an analo-
gous substrate 22 was exam- Scheme 5. Chemoselective transformations of dicarbonyl compounds.
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aqueous HCl (2m, 1.5 mL, 3.0 mmol) were added sequentially, and
the reaction mixture was stirred for another 30 min at 508C until
complete consumption of the sulfinate intermediate was deter-
mined by 19F NMR spectroscopy. The mixture was poured into
water (50 mL) and extracted with diethyl ether (3ꢁ20 mL). The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. Difluoro-
alkene 19 was obtained after purification by column chromatogra-
phy on silica gel (eluent=hexane).
Conclusion
We have described an efficient carbonyl gem-difluoroolefina-
tion of diaryl ketones, enolizable aldehydes, and dicarbonyl
compounds by using difluoromethyl 2-pyridyl sulfone as
a robust deoxygenative gem-difluoroolefination reagent. We
have demonstrated that the substitution of fluorine atoms re-
duces the thermal stability of corresponding carbanion and, as
a consequence, all reactions need to be conducted under
Barbier-type reaction conditions. Our investigation reveals that
the gem-difluoroolefination of diaryl ketones under conven-
tional basic Julia–Kocienski reaction conditions is difficult due
to retro-aldol type decomposition of the key intermediate.
However, a modified acid-promoted one-pot procedure can be
used to successfully tackle this problem. So far as we know,
these findings represent the first example of a Julia–Kocienski
olefination performed under acidic conditions. Moreover, this
reaction is also potentially applicable to the nonfluorinated
olefination of sterically hindered carbonyl compounds.[26] The
gem-difluoroolefination of aldehydes with a substoichiometric
amount of base generated in situ not only tackles the problem
of enolization of the aliphatic aldehydes, but also provides
a synthetically useful method for the selective functionalization
of multi-carbonyl compounds. The results reported in this arti-
cle provide an intriguing example of fluorine chemistry re-
search as a powerful tool to probe reaction mechanism, which
can provide inspiration to solve existing synthetic problems.[27]
Acknowledgements
Support of our work by the National Basic Research Program
of China (2012CB215500 and 2012CB821600), the National Nat-
ural Science Foundation of China (21372246 and 21202189),
Shanghai QMX program (13QH1402400), and Chinese Academy
of Sciences is gratefully acknowledged.
Keywords: chemoselectivity
·
difluoromethyl
2-pyridyl
sulfone · Julia–Kocienski reaction · olefination · rearrangements
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Received: February 14, 2014
Revised: March 10, 2014
Published online on && &&, 0000
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FULL PAPER
&
Synthetic Methods
B. Gao, Y. Zhao, M. Hu, C. Ni, J. Hu*
&& – &&
gem-Difluoroolefination of Diaryl
Ketones and Enolizable Aldehydes
with Difluoromethyl 2-Pyridyl Sulfone:
New Insights into the Julia–Kocienski
Reaction
What a gem! The gem-difluoroolefina-
tion of diaryl ketones was realized by an
acid-promoted Julia–Kocienski olefina-
tion reaction at elevated temperatures.
The gem-difluoroolefination of aliphatic
aldehydes and chemoselective gem-di-
fluoroolefination of dicarbonyl com-
pounds was achieved with the use of
an amide base generated in situ (see
scheme).
Chem. Eur. J. 2014, 20, 1 – 9
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These are not the final page numbers! ÞÞ