Brook/Elimination/Aldol Reaction (BEAR) Sequence for the Direct Preparation of Fluorinated Aldols from β,β-Difluoro-α-(trimethylsilyl)alcohols

Article abstract of DOI:10.1002/adsc.201500481

A methodology allowing the preparation of aldols featuring a fluorinated stereogenic center is reported. The corresponding fluoroenolates are formed in situ from stable β,β-difluoro-α-(trimethylsilyl)alcohols, through a base-mediated process involving a Brook rearrangement followed by a fluoride elimination, and are directly added to aromatic aldehydes. Two different sets of conditions were disclosed. The first one involves the stoichiometric addition of potassium tert-butoxide (t-BuOK) while the second is based on the use of a catalytic amount of an ammonium phenoxide. The latter opens the way for a catalytic and asymmetric version of this Brook/elimination/aldol reaction (BEAR) sequence.

Full text of DOI:10.1002/adsc.201500481

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DOI: 10.1002/adsc.201500481
Brook/Elimination/Aldol Reaction (BEAR) Sequence for the
Direct Preparation of Fluorinated Aldols from b,b-Difluoro-a-
(trimethylsilyl)alcohols
MØlanie Decostanzi,a Arie Van Der Lee,b Jean-Marc Campagne,a
and Eric Leclerca,*
a
Institut Charles Gerhardt, UMR 5253 CNRS-UM2-UM1-ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier, Cedex 5,
France
Fax: (+33)-4-6714-4322; e-mail: eric.leclerc@enscm.fr
Institut EuropØen des Membranes, ENSCM/UMII/UMR-CNRS 5635, Pl. Eug›ne Bataillon, CC 047, 34095 Montpellier,
b
Cedex 5, France
Received: May 19, 2015; Revised: July 24, 2015; Published online: September 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500481.
Abstract: A methodology allowing the preparation
of aldols featuring a fluorinated stereogenic center
is reported. The corresponding fluoroenolates are
formed in situ from stable b,b-difluoro-a-(trimethyl-
silyl)alcohols, through a base-mediated process in-
volving a Brook rearrangement followed by a fluo-
ride elimination, and are directly added to aromatic
aldehydes. Two different sets of conditions were dis-
closed. The first one involves the stoichiometric ad-
dition of potassium tert-butoxide (t-BuOK) while
the second is based on the use of a catalytic amount
of an ammonium phenoxide. The latter opens the
way for a catalytic and asymmetric version of this
Brook/elimination/aldol reaction (BEAR) se-
quence.
become a major goal in modern organic chemistry.
The investigation of direct electrophilic or nucleophil-
ic fluorination as well as difluoromethylation and tri-
fluoromethylation reactions is still a privileged re-
search field.[5] However, the use of reactive, partially
fluorinated building blocks often offers interesting al-
ternatives with a higher flexibility and a greater mo-
lecular diversity. Fluorinated enol ethers and enolates
are representative of this strategy since they allow the
introduction of a fluorinated carbonyl moiety through
an aldol reaction.[6] The efficiency of aldol or Refor-
matsky reactions to provide monofluorinated aldols
has been demonstrated.[7] However, there are only
few examples of aldol reactions providing monofluori-
nated adducts featuring a tetrasubstituted stereogenic
center.[8,9] Moreover, among all these examples, direct
aldol reactions often require the use of strong bases
while Mukaiyama aldol reactions involve poorly
stable fluorinated silyl enol ethers. We wish to present
herein a new methodology allowing the preparation
of new aldols featuring a fluorinated tetrasubstituted
stereogenic center, and proceeding through the mild
Keywords: aldol reaction; Brook rearrangement;
fluorine; organocatalysis; stereogenic centers
Since the disclosure of fluorouracil and of fluorinated in situ generation of the enolate from a stable precur-
corticosteroids in the 1950s, the presence of fluorine sor.[10,11]
atoms in bioactive molecules has considerably in-
While studying for other purposes the addition of
creased, with a strong acceleration during the last difluoromethyllithium compounds onto electrophiles,
twenty years.[1,2] Up to 20% of the drugs and 30% of we were intrigued by the results obtained in the reac-
the agrochemicals launched every year since 2000 fea- tion between
1
and acetyltrimethylsilane 2a.[12]
ture a fluorinated group in their structure, and the Indeed, we expected that such an addition would lead
proportion is even higher for top-selling drugs.[3] The directly to the corresponding monofluorinated silyl
À
singular properties of the fluorine atom and of the C
enol ether 4a through the well known Brook rear-
F bond often allow interesting modulations of the be- rangement/elimination sequence (Scheme 1), even at
haviour of these molecules, which go from a higher the low temperatures required by the poor stability of
metabolic stability to an increased activity.[4] The de- the anion.[13] To our surprise, the addition of the
velopment of synthetic methodologies for the prepa- anion derived from 1 to acetyltrimethylsilane 2a yield-
ration of fluorinated organic molecules has thus ed a-(trimethylsilyl)alcohol 3a in 62% yield
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Scheme 3. Investigation of the BEAR sequence.
ing to complete degradation (DMF). Similarly, other
alkoxide bases (i-PrOMgBr or t-BuOLi) failed to pro-
duce the desired compound. Finally, the optimized
conditions led, after desilylation with an aqueous so-
lution of HCl, to aldol 6a in 60% yield (Scheme 4).
Based on these conditions, the scope of the reaction
Scheme 1. Preparation of a-(trimethylsilyl)carbinol 3a.
(Scheme 1).[14] The product was stable and could be starting from 3a was examined with various aldehydes
purified by column chromatography over silica gel.
(Scheme 4). The yields are in the 45–65% range for
This result was seen as an opportunity to use b,b-di- most examples, with occasional drops below these
fluoro-a-(trimethylsilyl)alcohol 3a as a stable surro- values for three examples, and reflect an efficient
gate to the labile trimethylsilylenol ether 4a. Our goal three elementary step process (75–85% as average
was to release, under mild reaction conditions, the yield for each step). Indeed, one should keep in mind
corresponding enolate from 3a and make it readily that the reaction involves a Brook/elimination se-
react with aldehydes to afford the corresponding quence, a fluoride-promoted aldol reaction and a final
aldol products. We indeed envisioned a one-pot pro- deprotection. The method was on the other hand inef-
cess in which a moderately strong base M+BÀ would fective with aliphatic aldehydes, since pivalaldehyde
trigger the Brook/elimination sequence to deliver the and isobutyraldehyde only led to degradation prod-
corresponding enol ether, as well as a fluoride source ucts. Compounds 6–19 were isolated as unseparable
M+FÀ that could itself promote the aldol reaction mixtures of diastereomers. The diastereomeric ratios
(Scheme 2).
ranged from 62:38 to 88:12, with a majority of exam-
ples around 80:20. This diastereoselectivity should be
examined in light of the few reported reactions fur-
nishing tetrasubstituted fluorinated aldols. Our results
either favourably compare to or are in the same
range as the diastereoselectivity reported for most of
these reactions.[8] a-(Trimethylsilyl)carbinols 3b an 3c,
which were prepared similarly to 3a, were also used
as starting materials in this reaction with comparable
results. Finally, it should be mentioned that products
6–19 represent a novel class of polyfunctional fluo-
rine-containing compounds of pharmaceutical impor-
tance.
The crystallization of the major diastereomer of
14a made possible the determination of its relative
configuration. The X-ray diffraction study indicated
a syn relationship between the hydroxy group and the
fluorine atom.[15] The H NMR analysis of syn-14a re-
1
Scheme 2. Envisioned one-pot Brook/elimination/aldol reac-
tion (BEAR) sequence.
vealed that the chemical shift of the methyl group
was substantially higher than that for anti-14a
(2.25 ppm vs. 1.99 ppm). All 1H NMR spectra for
compounds 6a–19a followed the same pattern, with
The reaction was first investigated using t-BuOK as a chemical shift of the methyl group around 2.2–
a promoter and the crucial role of the solvent was im- 2.3 ppm for the major diastereomer and around 1.9–
mediately unveiled. Indeed, the reaction was com- 2.0 ppm for the minor one. The syn relative configura-
plete in 3 h at 08C in THF, leading to the expected tion was therefore assigned to all the major dia-
compound as a mixture of the free alcohol 6a and of steromers of compounds 6a and 8a–19a. By analogy,
the TMS ether 7a (Scheme 3). In contrast, the reac- and due to similar NMR data, the syn configuration
tion failed in all other solvents, either producing only was also assumed for the major diastereomer of com-
the fluoro ketone 5a (toluene, Et2O, MeCN) or lead- pounds 6b–c, 11b–c, 13b–c.
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Brook/Elimination/Aldol Reaction (BEAR) Sequence
Scheme 5. t-BuOK-mediated BEAR sequence with other
substrates.
mide,[17] led to an unexpected result. Although this
substrate was unreactive in THF, the reaction in DMF
provided lactol 23 in 51% yield (unoptimized) and as
a 1:1 mixture of diastereomers. Lactol 23 probably
arose from an additional base-promoted condensation
to DMF and a subsequent cyclization. This five ele-
mentary step sequence is an interesting result that
certainly deserves further investigation.
Our next step was to develop a catalytic process for
this reaction, which ideally could open the way for an
asymmetric version. Indeed, it should be possible to
introduce the base in a substoichiometric amount due
to the in situ generation during the process of the
fluoride catalyst required for the aldol reaction. How-
ever, this will be possible only if the alkoxide result-
ing from the aldol reaction is able to initiate the
Brook rearrangement or regenerate the base and thus
close the catalytic cycle. Regarding a future enantio-
selective version, and considering the mechanism of
the reaction, the chiral control element could only be
placed on the enolate counter-cation, which leaves
only two possibilities: the use of a metal complexed
by a chiral ligand or the use of a chiral organic cation
such as an ammonium.[18]
Scheme 4. Scope of the t-BuOK-mediated BEAR sequence.
We started this study by checking if our initial pro-
moter could be used as a catalyst. This was clearly not
the case since the use of 10 mol% of t-BuOK only led
Two other substrates, arising from bromides other to traces of the expected product (conversion <10%),
than 1, were also tested. a-(Trimethylsilyl)carbinols proving that the resulting alkoxide 6’a could not act
20 and 21 were indeed prepared in a similar manner as a base or regenerate one (Table 1, entry 1). One
from the corresponding bromides.[16] These two com- way to circumvent this problem would be the use an
pounds were chosen for their ability to generate an additive that could release a base upon reaction with
extended enolate that might lead to interesting aldoli- 6’a, strong enough to deprotonate 3a and thus reiniti-
zation regioselectivity outcomes. Unfortunately, the t- ate the cycle. We thus turned our attention to the
BuOK-mediated BEAR sequence applied to 20 and work of Levacher who designed a catalytic system for
21 only led to unidentified degradation products, de- the direct vinylogous aldol reaction of (5H)-furan-2-
spite a full conversion of the substrates (Scheme 5). ones.[19] This system is based on the use of an ammo-
On the other hand, benzoxazole-derived compound nium phenoxide as a catalyst and of N,O-bis(trime-
22, also prepared from the known corresponding bro- thylsilyl)acetamide (BSA) as a stoichiometric addi-
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Table 1. Development of a catalytic process for the BEAR
sequence.
Entry Cat.
Additive Temp.
Yield
[%]
[8C]
1
2
3
4
5
t-BuOK
t-BuOK
t-BuOK
(rac-BINAP)CuF
4-MeOC6H4OÀ (n-
Bu)4N+
–
0
0
À40
À40
À40
n.d.[a]
n.d[b]
n.d[b]
18[b]
BSA
BSA
BSA
BSA
63[b]
[a]
[b]
Conversion <10%.
Conversion=100%
tive, which simultaneously acts as a silylation agent
and as a Brønsted pro-base. In our hands, BSA was
equally efficient as, in the presence of 1 equivalent of
this reagent and using t-BuOK as the catalyst, silylat-
ed aldol 7 was obtained with full conversion (Table 1,
entry 2). Not surprisingly, the reaction using only
BSA failed, proving that the introduction of a base is
necessary to initiate the reaction. The temperature
could be lowered to À408C without reducing the con-
version or slowing down too much the reaction
(Table 1, entry 3). The next step was to identify an
ion pair or a metal salt able to initiate the reaction
and ultimately deliver a chiral enolate. A tetrabuty-
lammonium phenoxide was of course tested, as well
as a racemic copper(I) fluoride-BINAP complex pre-
viously used in Mukaiyama vinylogous aldol reactions
(Table 1, entry 4).[20] Although the latter led to a low
18% yield, the catalytic system reported by Levacher
provided 7 in 63% yield, a result similar to the reac-
tion mediated by stoichiometric t-BuOK (Table 1,
entry 5). The postulated catalytic cycle, similar to the
one proposed by Levacher, is displayed in
Scheme 6.[19]
Scheme 6. Catalytic cycle.
These catalytic conditions were next tested on
other aromatic aldehydes in order to assess their gen-
erality (Scheme 7). The products were isolated as
their TMS ethers and yields were in most cases com-
parable to the stoichiometric reaction. The diastereo-
selectivity was, however, lower and reversed, ranging
from 45:55 to 36:64 in favour of the anti diasteromer.
The configuration of the major diastereomer was as-
Scheme 7. Scope of the catalytic BEAR sequence.
1
signed on the basis of the H NMR spectrum after
conversion of the TMS ether to the free alcohol and
comparison with the former products.
might allow a closed, Zimmerman–Traxler-type transi-
The diastereoselectivity of both t-BuOK-mediated tion state that should reflect the geometry of the in-
and ammonium aryloxide-catalyzed reactions raises termediate silyl enol ether. In contrast, the ammoni-
questions about their respective mechanisms. In the um counter-cation is not likely to allow any coordina-
first case, the coordinating potassium counter-cation tion with the aldehyde and the catalyzed reaction
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Brook/Elimination/Aldol Reaction (BEAR) Sequence
generation of the TBS enol ether 32 are consistent
with a closed transtion state. In contrast, the weak
anti-selectivity of the catalyzed reaction probably
arises from a poorly selective open transition state,
a model that is more credible in this situation, and
should not depend on the configuration of the enoxy-
silane. The results obtained in the reaction of Z-33
with benzaldehyde in the presence of TBAT supports
this hypothesis since aldol 6a was this time obtained
with almost no selectivity (Scheme 9). As expected,
Figure 1. Transition states for the aldol reactions.
should proceed through an open transition state the ammonium aryloxide-catalyzed BEAR sequence
(Figure 1). starting from 32 produced aldol 7a in a 40:60 syn:anti
Our first task was thus to assess the E/Z ratio of ratio, almost the same as from 3a (Scheme 9). Finally,
the intermediate silyl enol ethers for both reactions. it should be mentioned that the reaction 32 with t-
Unfortunately, the reaction of 3a with t-BuOK in the BuOK in the presence benzaldehyde afforded only
absence of aldehyde did not allow us to isolate 4a. enol ether 33, with no traces of 6a.
Only ketone 5a could be observed, even by direct
NMR analysis of the reaction medium when the reac-
tion was performed in THF-d8 (Scheme 8). We thus
Scheme 8. Investigations on the intermediate silyl enol
ethers.
Scheme 9. Control experiments.
moved to the more stable TBDMS derivative and 33
In conclusion, we have reported a methodology al-
was eventually detected after the reaction of 32 with lowing the preparation of unprecedented aldols fea-
t-BuOK, and isolated as a 95:5 mixture of isomers turing fluorinated tetrasubstituted stereogenic
a
(Scheme 8).[21] NOESY and HOESY experiments center. The corresponding fluoroenolates are formed
showed that the Z isomer (19F NMR, d=À137.6 ppm) in situ from stable b,b-difluoro-a-(trimethylsilyl)alco-
was the major one (19F NMR, d=À151.8 ppm for the hols, through a base-mediated Brook rearrangement/
E isomer).[22] Regarding the ammonium aryloxide-cat- elimination sequence and then added to aromatic al-
alyzed reaction, the presence of highly reactive trime- dehydes via a fluoride-mediated aldol reaction. Two
thylsilylating agent BSA allows the observation of 4a sets of conditions were disclosed for this original one-
in the reaction mixture, as the sole product and as pot BEAR sequence that avoids the isolation of
a 35:65 mixture of isomers (Scheme 8). Although 4a poorly stable fluorinated enoxysilanes. The first one
was still too labile to perform conclusive NOESY ex- involves the stoichiometric addition of t-BuOK at
periments, the 19F NMR chemical shifts of the two 08C, which yielded aldols in fair yield and diasterose-
isomers of 4a were almost identical to that of 33 lectivity. A catalytic process was next devised using
(À138.6 ppm and À152.1 ppm for 4a). Based on this an ammonium phenoxide as catalyst and BSA as a si-
analogy, the E configuration was assigned to the lylating agent and relay base. Although the latter con-
major isomer of 4a.
ditions open the way for an asymmetric version, some
Drawing conclusions on the diastereoselectivity of improvement must be brought to the reaction, espe-
each reaction from these results is, at best, specula- cially to its diastereoselectivity, to obtain a synthetical-
tive. The syn selectivity of the t-BuOK-mediated ly useful enantioselective methodology. Results in this
BEAR sequence and the Z-selectivity observed in the area will be reported in due course.
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[6] For a review on fluorinated enol ethers, see: M. Deco-
stanzi, J.-M. Campagne, E. Leclerc, Org. Biomol.
Chem. 2015, 13, 7351-7380.
Experimental Section
General Procedure for the t-BuOK-Mediated BEAR
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[9] For Reformatsky or aldol-type reactions from perfluor-
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Sequence
Under an argon atmosphere, t-BuOK (0.36 mmol, 1.2 equiv.)
was added to
a solution of a-trimethylsilylcarbinol 3
(0.3 mmol, 1 equiv.) and aldehyde (0.33 mmol, 1.1 equiv.) in
dry THF (2 mL) at 08C. The solution was stirred at this tem-
perature for 3 h and a saturated solution of NH4Cl was then
added. The aqueous layer was extracted with Et2O and the
combined organic layers were washed with brine, dried over
MgSO4, filtered and concentrated under vacuum. The crude
product was then diluted in THF (2 mL) and a 10% aqueous
HCl solution (5 mL) was added. The solution was stirred for
1 h and neutralized with a saturated aqueous NaHCO3 solu-
tion. The layers were separated and the aqueous layer was
extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4, filtered and concen-
trated under vacuum. The crude product was purified by
flash column chromatography (80:20 petroleum ether/dieth-
yl ether) to afford the expected fluorinated aldol as an in-
separable mixture of syn and anti diasteromers.
Acknowledgements
Dr. Vincent Levacher and Dr. Sylvain Oudeyer are gratefully
acknowledged for fruitful discussions. This work was sup-
ported by the Ecole Nationale SupØrieure de Chimie de
Montpellier (PhD grant for M.D.) and by the Centre Nation-
al de la Recherche Scientifique, which we gratefully acknowl-
edge.
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[21] Compound 28 was prepared similarly as 3a. See the
Supporting Information for details.
[22] A correlation between the CH3 and CH2OBn groups
was indeed observed for the major isomer (NOESY),
as well as a correlation between the fluorine atom and
the silicon substituents (HOESY). See the Supporting
Information for details.
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Adv. Synth. Catal. 2015, 357, 3091 – 3097
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