α,α-Difluoro-α-(trimethylsilyl)acetamides as Versatile Reagents for the Preparation of Difluorinated Aldol and Mannich Adducts

Article abstract of DOI:10.1002/adsc.201700371

The very efficient addition of α,α-difluoro-α-(trimethylsilyl)acetamides to aldehydes, ketones and N-(tert-butanesulfinyl)imines is described. The reaction is promoted by a catalytic amount of tetra-n-butylammonium diphenyltrifluorosilicate (TBAT) and high yields, as well as very high stereoselectivities in the case of N-(tert-butanesulfinyl)imines, are achieved. The synthetic potential of this method is illustrated by the conversion of the resulting products to β-hydroxy ketones, diols and β-amino alcohols by addition of various Grignard reagents or reduction of the amide moiety. (Figure presented.).

Full text of DOI:10.1002/adsc.201700371

Title: α,α-Difluoro-α-(trimethylsilyl)acetamides as Versatile Reagents
for the Preparation of Difluorinated Aldol and Mannich Adducts
Authors: Aurelien Honraedt, Arie Van Der Lee, Jean-Marc Campagne,
and Eric Leclerc
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
,-Difluoro--(trimethylsilyl)acetamides as Versatile Reagents
for the Preparation of Difluorinated Aldol and Mannich
Adducts
Aurélien Honraedt,[a] Arie Van Der Lee,[b] Jean-Marc Campagne[a] and Eric Leclerc*[a]
a
Dr. A. Honraedt, Pr. J.-M. Campagne, E. Leclerc
Institut Charles Gerhardt UMR 5253 CNRS-UM2-UM1-ENSCM
Ecole Nationale Supérieure de Chimie de Montpellier
8, rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France.
E-mail: eric.leclerc@enscm.fr
b
Dr. A. Van Der Lee
Institut Européen des Membranes, ENSCM/UMII/UMR-CNRS 5635
Pl. Eugène Bataillon, CC 047, 34095 Montpellier, Cedex 5, France.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The very efficient addition of ,-difluoro-- The synthetic potential of this method is illustrated by the
(trimethylsilyl)acetamides to aldehydes, ketones and N-(tert- conversion of the resulting products to -hydroxyketones,
butanesulfinyl)imines is described. The reaction is promoted diols and -aminoalcohols by addition of various Grignard
by a catalytic amount of TBAT and high yields, as well as reagents or reduction of the amide moiety.
very high stereoselectivities in the case of N-(tert-
butanesulfinyl)imines, are achieved.
Keywords: fluorine; aldol reaction; Mannich reaction;
Grignard reagent; diastereoselectivity
heteroatom or carbon-centered functional groups can
also be introduced (Y = P(O)(OR)2, C(O)X, alkyl,
aryl, …), either for structural requirements or for
post-functionalization purposes.[7] For that matter, the
carbonyl function constitutes an interesting starting
point for further synthetic elaboration as well as a
stabilizing group for the addition of a nucleophilic
difluoromethylating agent. Consequently, the
preparation of difluorinated aldol and Mannich
products, either through direct aldol, Reformatsky-
type or Mukaiyama-type reactions, has known
considerable developments.[8,9] However, most of
these approaches either suffer from the use of strong
bases or overstoichiometric amounts of metallic salts,
or imply the sometimes delicate preparation of
difluorinated silyl enol ethers.[10] Alternatives to these
classical approaches have been recently devised, such
as the elegant trifluoroacetate release strategy
pioneered by Colby and Wolf, or a one-pot one-
Introduction
The tremendous interest that have generated
fluorinated molecules in the last few years finds its
origin in the peculiar properties that fluorine atoms
bestow to the bioactivity of drug-like molecules.
Indeed, the electronic and stereoelectronic features of
the fluorine atom and of the C–F bond has often
major consequences on the lipophilicity, the pKa, the
metabolic stability and, of course, the binding with a
receptor.[1] As a result, the pharmacodynamic or
pharmacokinetic properties of drugs featuring
fluorine atoms in judicious positions may be
considerably improved. This is illustrated by the
ever-increasing occurrence of fluorinated molecules
among the list of marketed drugs and
agrochemicals.[2] If most synthetic strategies
concentrate on fluorination and trifluoromethylation
reactions, the direct introduction of CF2Y (Y ≠ F)
group is also the subject of an increasing number of
studies.[3,4] This is of course a more widespread and
diffuse topic since the nature and the role of the Y
substituent may vary widely. Indeed, as far as
difluoromethylation is concerned, Y can be hydrogen
atom for the direct introduction of CF2H but also a
reducible, heteroatom-centered group for an indirect
reaction (Y = SR, SO2R, …).[5],[6] But various
catalyst
procedure
relying
on
a
Brook
rearrangement/fluoride elimination sequence recently
reported by us.[11,12] Both methods have indeed
allowed the mild in situ release of difluoroenolates
and their addition to carbonyl electrophiles and
imines. We wish to present herein a study
demonstrating
(trimethylsilyl)acetamides can act as stable
difluoroenoxysilane surrogates that can successfully
that
,-difluoro--
1
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
be added to aldehydes, ketones and N-(tert-
butanesulfinyl)aldimines in a high-yielding and
highly selective process. Moreover, it is shown that
the amide group of the resulting adducts can easily be
converted to useful functional groups such as a
primary alcohol and aliphatic or aromatic ketones.
,-Difluoro--(trimethylsilyl)acetamides 2a-c were
thus prepared from 1 according to the two-step
method reported by Hartwig.[17g] The addition of 2a
to 4-bromobenzaldehyde was first studied and
representative efforts in the optimization process are
depicted in table 1. The standard reaction conditions
used for the one-pot aldol and Mannich reactions
(TBAT 0.1 equiv., THF,
– 30°C, entry 1)
immediately allowed us to isolate the desired aldol-
type product in 83% yield. The reaction time was
however a bit long and could be reduced to 3h by
running the reaction at 0°C without erosion of the
yield (table 1, entry 2). However, these conditions
remained unsatisfactory for two reasons: (i) a mixture
of OH and OTMS products (3 and 4) was
systematically obtained when the reaction was
worked-up with a simple evaporation or a mild
hydrolysis with saturated NH4Cl; (ii) a residual
amount of unreacted aldehyde could be detected at
the end of these reactions while 2a was totally
consumed, leaving only its protodesilylated
derivative 2'a as a by-product. A short survey
allowed us to optimize our conditions (table 1, entry
3): the use of 1.2 equivalent of 2a allowed full
conversion of the aldehyde, performing the reaction
at rt and using a higher concentration shortened the
reaction time to 1h while an acidic work-up allowed
the isolation of only the free alcohol. Aldol 3 was
thus obtained in an excellent yield of 92%.
Interestingly, we were able to obtain only the OTMS
Results and Discussion
During the study of a one-pot three-component tetra-
n-butylammonium diphenyltrifluorosilicate (TBAT)-
catalyzed Mannich reaction starting from Ruppert-
Prakash reagent, acylsilanes and various activated
imines, we noticed that the ammonium
difluoroenolate, which is supposedly generated
during the one-pot process, was unreactive towards
N-(tert-butanesulfinyl)imines.[13]
A
careful
examination of the litterature indeed shows that the
addition to sulfinylimines has been mostly
accomplished either from difluoroenol ethers, under
Lewis or Brønsted acid activation,[8g,11d,14] or via
imino-Reformatsky reactions.[9a,9c,9k] The addition of
difluoroenoxysilanes to sulfinylimines promoted only
by a Lewis base, without any activation of the
electrophile, has never been reported. In contrast, the
Lewis base-promoted addition of TMSCH2CO2Et and
TMSCF2P(O)(OEt)2 to N-(tert-butanesulfinyl)imines
has been reported, suggesting a marked difference in
reactivity between these silyl carbon nucleophiles and
O-silyl enol ethers.[15] Reagents of the general type
TMSCF2COX thus appeared as interesting
alternatives to difluoroenolates and enoxysilanes.
Esters TMSCF2CO2R can be prepared by
product
4
in 75% yield by using N,O-
bis(trimethylsilyl)acetamide (BSA) as an additive
(table 1 entry 4). This very reactive silylating agent
had also an accelerating effect since the reaction
could be performed at –30°C in only 2h, even if
lowering the temperature to –78°C resulted in a
sluggish reaction. This point will be discussed below
but this accelerating effect highlight one of the few
drawbacks of using nucleophiles such as 2 instead of
difluoroenoxysilanes, meaning the catalyst turnover
and the initiation of a new catalytic cycle.
electroreduction
of
the
corresponding
chlorodifluoroacetate or trifluoroacetate and their
nucleophilic addition to aldehydes and imines has
been fragmentarily described in a handful of
reports.[16] On the other hand, ,-difluoro--
(trimethylsilyl)acetamides can be easily prepared in
large scale in a two-step sequence from ethyl
chlorodifluoroacetate. Such reagents have been used
in cross-coupling or radical addition reactions but, to
the best of our knowledge, their Lewis base-promoted
addition to carbonyl derivatives and imines is almost
ignored.[17,18] We thus embarked on an exhaustive
study of their reactivity towards carbonyl
electrophiles and imines.
Table 1. Optimization of the aldol-type reaction.[a]
Entry Temp.
[°C]
x
Time Work-up
[h]
3 + 4
[%][b]
1[c]
2[c]
3[d]
4[e,f]
–30
0
rt
–30
–78
1
1
1.2
1.2
1.2
20
3
1
evaporation
evaporation
aq. HCl/MeOH 92 + 0
sat. NH4Cl
sat. NH4Cl
83 + 6
80 + 7
2
0 + 75
0 + 34
5[e,f]
2
[a]
[b]
[c]
[d]
[e]
[f]
Ar = 4-BrC6H4.
Isolated yields of 3 and 4.
Scheme 1. ,-Difluoro--(trimethylsilyl)acetamides 2a-c. Concentration of the reaction medium was c = 0.2M.
Concentration of the reaction medium was c = 1M.
Concentration of the reaction medium was c = 0.1M.
BSA was used as an additive (1 equiv.).
2
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
Scheme 2. Scope of the aldol reaction. [a] Isolated yield on 4 mmol scale. [b] Hydrolysis was performed using aq. sat. NH4Cl.
The optimized conditions depicted in table 1, entry 3 this addition product as its TMS ether 18 (reaction
were applied to a wide range of carbonyl electrophiles, quenched with sat. NH4Cl) in 63 % yield. The use of
first using 2a as the nucleophile. Good to excellent enones as electrophiles was also investigated. The
yields were obtained in the addition to various reaction with pent-3-ene-2-one as the electrophile
aromatic aldehydes bearing electron-withdrawing or afforded a messy crude reaction mixture from which
electron-donating groups (compounds 3-8, 83 to 99% the 1,2-addition product appeared as the major
yield). Lower but still practical yields are obtained compound while only traces of the 1,4-adduct could be
with heteroaromatic aldehydes (compounds 9-11, 47 to detected. However, the addition onto chalcone
87% yield). To our delight, the reaction was also afforded exclusively the 1,2-addition product 24 in a
effective with non-aromatic aldehydes, which was not good 76% yield. The reaction is also quite insensitive
the case in our previous studies of one-pot aldol to the nature of the nitrogen substituents of 2. 2b and
reactions. Cinnamaldehyde but also linear or branched 2c indeed react with aldehydes and ketones with a
aliphatic aldehydes are efficiently converted to aldols similar efficiency (25-29, 67 to 95 %). Finally, this
12-16 in fair to good yields (48-74%). More methodology appears to be quite robust since a small
interestingly, ketones are also suitable electrophiles scale-up to 4 mmol resulted in a substantial increase of
that lead to compounds 17-23 in moderate to excellent the isolated yield (5, quantitative).
yields. If the reaction with cyclohexanone affords Having assessed the reactivity of 2 with a wide range
compound 20 in a disappointing 21% yield, other of carbonyl electrophiles, our next move was to
aromatic (17-18, 63 to 90%), aliphatic (19, 69%), and examine the addition to sulfinylimines. As mentioned
activated ketones (21-23, 83 to 98%) give satisfactory above, in situ-generated difluoroenoxysilanes failed to
results. Interestingly, if the addition to p- react with these electrophiles. Our first attempts in the
bromobenzophenone was efficient, the resulting TMS addition of 2a onto sulfinylimine 30 failed as long as
ether was surprisingly stable. The standard HCl the reactions were performed at temperatures below
hydrolysis was totally uneffective and so was an 0°C. However, a first attempt at room temperature
attempt of tetra-n-butylammonium fluoride (TBAF)- allowed us to observe a sluggish but workable reaction
mediated deprotection. It was thus decided to isolate (table 2, entry 1). A 54% conversion was indeed
3
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
observed for the sulfinamide after 18h of reaction and [a] The reaction was performed using 1.2 equiv. of 2a. [b]
addition product 31 could be detected in the crude Conversion of 30 assessed by 1H NMR analysis of the crude
mixture along with a substantial amount of the mixture. [c] 0.1 equiv. of TMAF was used instead of TBAT.
protodesilylation product 2'a. A short solvent survey [d] 31 was isolated in 78% yield
was therefore conducted in order to enhance the rate of
the reaction and limit the hydrolysis of 2a. However,
the use of less polar solvents such as CH2Cl2 or CHCl3 The scope and limitations of this Mannich reaction
(entries 2 and 3) totally inhibits the reaction while was afterwards examined on the basis of these
MeCN and DMF only led to complex mixtures that optimized conditions. A small range of aldimines were
were devoid of 31 (entries 4 and 5). As for our tested and, as for aldehydes, aromatic as well as
previous reports, THF appeared to be the sole aliphatic substrates were quite effective in this reaction.
operative solvent. If the use of tetramethylammonium The remarkable stereoselectivity observed for 31
fluoride (TMAF) as the promoter did not improve our appeared to be general, at least for aldimines, since
first result (entry 6), performing the reaction at higher only one diastereomer could be detected by 1H and 19F
concentration was eventually sufficient to fully convert NMR analysis of the crude mixture for compounds 31-
30 (entry 7). 31 was in that case obtained in 78% 37. As for the aldol reaction, a small scale-up resulted
isolated yield and, most remarkably, as only one in an increase of the yield from 78 to 91% for 31. The
1
diastereomer detectable by H and 19F NMR analysis reaction is also comparably efficient using substrates
of the crude mixture.
2b and 2c (products 39-43). The first limitation
appeared when the ketimine derived from
acetophenone was used as the electrophile. Compound
38 was obtained in low yield (30%) and with moderate
stereoselectivity (83:17 in the crude mixture).
Surprisingly, while the reaction was efficient on
aliphatic imines derived from pivalaldehyde and
cyclohexanecarboxaldehyde, no product could be
detected using linear imine 44. Finally, the use
"activated" imines derived from ethyl glyoxylate and
ethyl phenylglyoxylate was not as straightforward as
anticipated. Indeed, we were able to isolate -
aminoester 41 in 43% yield and as a single diasteromer
but complete conversion required the use of a
stoichiometric amount of TBAT. However, even under
these conditions, ketimine 45 remained totally
unreactive. Nonetheless, the preparation of product 41
paves the way for an efficient stereoselective access to
-amino-,-difluoroaminoacids.
Table 2. Optimization of the Mannich-type reaction.[a]
Entry Solvent Concentration Conversion [%][b]
1
2
3
4
5
6
7
THF
CH2Cl2 0.1M
0.1M
54
<5
0
CHCl3
MeCN
DMF
0.1M
0.1M
0.1M
0.1M
1M
n.d.
n.d.
24
THF[c]
THF
100[d]
4
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
Scheme 3. Scope of the Mannich reaction. [a] Isolated yield on 1 mmol scale. [b] 1.2 equivalent of TBAT was used.
performed at –30°C. In contrast, the use of BSA as an
The relative configuration of the major diasteromer
was assigned on the basis of an X-Ray diffraction
study performed with compound 33.[19] As illustrated
in the ORTEP drawing (figure 1), the (RS,S)
configuration was assigned to 33 and, by analogy, to
the other products. This stereochemical outcome is
perfectly consistent with literature precedents.[15,20]
Indeed, in the absence on any chelating species, an
open transition state in which the imine adopts the
more stable s-cis conformation should be favored
(figure 1). This is of course in contrast with
Reformatsky reactions that affords the opposite
additive allows the reaction to work at –30°C. The
role of BSA in that case is dual: it allows a very fast
silylation of A, releasing at the same time a strong
Lewis base that can efficiently activate the
pronucleophile (scheme 4, pathway b). This results in
a global enhancement of the reaction rate. The
turnover issue in the absence of additive might also
explain the difference in reactivity between carbonyl
electrophiles and sulfinylimines. While reactions with
the first, including moderately reactive ketones, are
complete within 1h, the second require 18h for a full
conversion. The difference in electrophilicity
between these two classes of reagents can hardly
account for such a difference. On the other hand, the
poor Lewis basicity and the steric hindrance of the
resulting amide product A in the case of addition to
sulfinylimines might considerably slow down the
silyl transfer compared to the alkoxide intermediate
of the aldol reaction.
diastereomer through
a
chelated transition
state.[9a,9c,9k]
Figure 1. ORTEP drawing of 32 and transition state for the
addition.
The lack of reactivity with ketimines and electron-
poor imines may be another outward sign of the
problem of catalyst turnover when using 2 as the
pronucleophile. Indeed, in the absence of any additive,
a new catalytic cycle can begin only if the anion A
resulting from the TBAT-mediated addition to the
electrophile is able to activate another molecule of 2
(scheme 4, pathway a). The reaction product is thus
silylated to produce B and another addition can
proceed. This silyl transfer is probably much slower
in
the
case
of
,-difluoro--
(trimethylsilyl)acetamides 2 than in the case of
difluoroenoxysilanes. This hypothesis is illustrated by
the reaction temperature used for the aldol reaction: a
workable conversion can only be achieved at room
temperature with pronucleophiles 2 while the reaction
with in situ-generated difluoenoxysilane were
Scheme 4. Reaction intermediate and catalyst turnover.
5
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
Conclusion
Our next move was to explore the functionalization
of the amide residue and demonstrate that our aldol
and Mannich adducts could serve as versatile
intermediates for the synthesis of difluorinated
We have thus described the very efficient TBAT-
catalyzed addition of ,-difluoro--
(trimethylsilyl)acetamides to aldehydes, ketones and
N-(tert-butanesulfinyl)aldimines. The addition to
carbonyl electrophiles is fairly general as good to
excellent yields are obtained with a wide range of
aromatic and aliphatic aldehydes and ketones. The
addition to sulfinylaldimines allows the preparation
of -amino-,-difluoroamides with very high
diastereoselectivities while ketimines appeared to be
more reluctant substrates. Finally, these aldol and
Mannich products can be easily converted to ketones,
diols and aminoalcohols thanks to very efficient
addition of Grignard reagents or to the complete
reduction of the amide function. Overall, the
building-blocks.
Morpholinoamides
generally
exhibits a reactivity similar to Weinreb amides thanks
to a stabilization of the tetrahedral intermediate
resulting from an organometallic addition by an
internal chelation. In the case of difluorinated amide,
this stabilization is reinforced by the electron-
withdrawing effect of the CF2 moiety that slows
down the collapse of the tetrahedral intermediate.
Consequently, the addition of an excess of Grignard
reagents to aldol 5 and sulfinamide 31 cleanly affords
the corresponding ketones 46 and 47 (scheme 5).[17g]
An important feature is the facile access to aliphatic
ketone derivatives that cannot be directly prepared
through Mukaiyama-type reaction, as mentioned
earlier, and that have never been reported through
imino-Reformatsky approach.[9a] Our two-step
process is an efficient route to such compounds that
therefore still competes with our former one-pot
procedure or with direct Reformatsky reactions.
Complete reduction of the amide group is also
possible and affords 1,3-diols or 1,3-aminoalcohols
48 and 49 in good yields (scheme 5). Other
transformations were described by Hartwig for -
efficiency
of
,-difluoro--
(trimethylsilyl)acetamides as stable and easily
accessible surrogates to difluoroenoxysilanes was
clearly demonstrated, as well as their versatility in
terms of reactivity and synthetic potential. A catalytic
asymmetric addition of 2 to carbonyl electrophiles is
currently under investigation in our group and results
will be reported in due course.
aryl-,-difluoroacetamides and should be applicable Experimental Section
to our aldol and Mannich products.[17g] Finally, and as
widely described in the literature, the sulfinamide
group of 34 could be converted to the free amine (50,
General procedure for the aldol reaction.
52%) using HCl in methanol (scheme 5).
To a solution of the aldehyde/ketone (0.5 mmol) and
trimethyl silyl α,α-difluoroacetamide 2a-c (0.6 mmol, 1.2
eq) in dry THF (0.5 mL, C=1) at room temperature was
added TBAT (27.0 mg, 10 mol%). The mixture was stirred
for one hour and then diluted with methanol (1.0 mL,
EtOH was used in presence of ethyl ester derivatives). A
2M HCl aqueous solution (1.0 mL) was added and the
stirring continued for 1h. The mixture was carefully
quenched with a saturated aqueous solution of NaHCO3
(10 mL). The mixture was extracted with EtOAc (3 x 10
mL). The combined organic layers were successively
washed with brine (10 mL), dried on Na2SO4, filtered and
concentrated in vacuo. The crude reaction mixture was
purified by Biotage Isolera (25 g SNAP Ultra cartridge,
EtOAc/pentane mixture) to afford the title compound.
General procedure for the Mannich reaction.
To
a
solution
of
the
(RS)-tert-
butanesulfinylaldimine/ketimine (0.5 mmol) and trimethyl
silyl α,α-difluoroacetamide 2a-c (0.6 mmol, 1.2 eq) in dry
THF (0.5 mL, C=1) at room temperature was added TBAT
(27.0 mg, 10 mol%). The mixture was stirred for 18 hours
at room temperature and then quenched with a saturated
aqueous solution of NH4Cl (10 mL). The mixture was
extracted with EtOAc (3 x 10 mL). The combined organic
layers were successively washed with brine (10 mL), dried
on Na2SO4, filtered and concentrated in vacuo.
Diastereomeric ratios were determined by NMR 1H. The
crude reaction mixture was purified by Biotage Isolera (25
g SNAP Ultra cartridge, EtOAc/pentane mixture) to afford
the title compound.
General procedure for the Grignard addition to 5 and
30.
Scheme 5. Derivatization of aldol and Mannich adducts.
6
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
To a solution of 5 or 31 (0.5 mmol) in dry THF (5.0 mL,
C=0.1) at –40°C was added the Grignard reagent solution
(2.0 mmol). The mixture was allowed to warm up to r.t. for
one hour (4h at 0°C for the addition of PhMgCl). The
solution was cooled to 0°C and then quenched with a 1M
HCl aqueous solution (10 mL). The mixture was extracted
with EtOAc (3 x 10 mL). The combined organic layers
were successively washed with brine (10 mL), dried on
Na2SO4, filtered and concentrated in vacuo. The crude
reaction mixture was purified by Biotage Isolera (25 g
SNAP Ultra cartridge, EtOAc/pentane mixture) to afford
the title compound.
7949-7976; e) Charpentier, J.; Früh, N.; Togni, A.
Chem. Rev. 2015, 115, 650-682; f) Liu, X.; Xu, C.;
Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683-730; g)
Egami, H.; Sodeoka, M. Angew. Chem. Int. Ed.. 2014,
53, 8294-8308; h) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem. Int. Ed. 2013, 52, 8214-8264; i) Studer,
A. Angew. Chem. Int. Ed. 2012, 51, 8950-8958.
[4] For reviews including difluoromethylation methods,
see references 3f, 3h and the following ones : a)
Chatterjee, T.; Iqbal, N.; You, Y.; Cho, E. J. Acc. Chem.
Res. 2016, 49, 2284; b) Ni, C.; Zhu, L.; Hu, J. Acta
Chim. Sinica 2015, 73, 90; c) Ni, C.; Hu, J. Synthesis
2014, 46, 842; d) Hu, J.; Zhang, W.; Wang, F. Chem.
Commun. 2009, 7465.
General procedure for the reduction of 5 and 31.
To a solution of of 5 or 30 (0.5 mmol) in EtOH (C= 0.025)
was added NaBH4 (7.5 mmol). The mixture was heated at
reflux for four hours. The mixture was cooled down to 0°C
then quenched with a 1M HCl aqueous solution (10 mL).
The mixture was extracted with EtOAc (3 x 10 mL). The
combined organic layers were successively dried on
Na2SO4, filtered and concentrated in vacuo. The crude
reaction mixture was purified by Biotage Isolera (25 g
SNAP Ultra cartridge, EtOAc/pentane mixture) to afford
the title compound.
[5] For recent and representative examples of direct
introduction of CF2H, see : For some recent and
representative examples, see : a) D. Chen, C. Ni, Y.
Zhao, X. Cai, X. Li, P. Xiao, J. Hu, Angew. Chem. Int.
Ed. 2016, 55, 12632-12636; b) Q.-Y. Lin, X.-H. Xu, K.
Zhang, F.-L. Qing, Angew. Chem. Int. Ed. 2016, 55 (4),
1479-1483; c) D. Chang, Y. Gu, Q. Shen, Chem. Eur. J.
2015, 21, 6074-6078; d) P. S. Fier, J. F. Hartwig,
Angew. Chem. Int. Ed. 2013, 52, 2092-2095; e) T. Iida,
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references cited therein.
Supporting Information Available.
Detailed experimental procedures, analytical data of
1
compounds 3 and 5-50 as well as copies of their H, 13C
and 19F NMR spectra are presented in the Supporting
Information. Crystallographic data and the CIF file relative
to 32 are also included.
Acknowledgements
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This work was supported by the Ecole Nationale Supérieure de
Chimie de Montpellier and by the Centre National de la
Recherche Scientifique, which we gratefully acknowledge.
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8
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9
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10.1002/adsc.201700371
Advanced Synthesis & Catalysis
FULL PAPER
,-Difluoro--(trimethylsilyl)acetamides as
Versatile Reagents for the Preparation of
Difluorinated Aldol and Mannich Adducts
Adv. Synth. Catal. Year, Volume, Page – Page
Aurélien Honraedt,[a] Arie Van Der Lee,[b] Jean-
Marc Campagne[a] and Eric Leclerc*[a]
10
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