Advances in the TBAF-induced aldol-type addition of α-trialkylsilyl-α-diazoacetones: TIPS versus TES

Article abstract of DOI:10.1016/j.crci.2016.12.005

α-Triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone) underwent high-yielding “diazo-side” Mukaiyama aldol-type addition with a range of aryl and alkyl aldehydes when subjected to stoichiometric amount of tetrabutylammonium fluoride at ?16 °C, in Et₂O. Robustness of the TIPS group makes TIPS-diazoacetone a stable surrogate for α-triethylsilyl-α-diazoacetone, on which generation of the corresponding carbanion can still be efficiently achieved under nucleophilic, weakly basic and practical conditions. These results highlight the synthetic potential that can be expected from TIPS-diazoacetone, promising building block for the convergent elaboration of highly functionalised versatile diazocarbonyl compounds.

Full text of DOI:10.1016/j.crci.2016.12.005

C. R. Chimie xxx (2017) 1e6
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ꢀ
Full paper/Memoire
Advances in the TBAF-induced aldol-type addition of
-trialkylsilyl- -diazoacetones: TIPS versus TES
a
a
,
b
a
a
a
Imen Abid a , Sigrid Gavelle , Anne-Caroline Chany , Frederic Legros ,
ꢀ ꢀ
Pascal Gosselin a, Souhir Abid b, Gilles Dujardin a, Catherine Gaulon-Nourry a
Universite du Maine, Institut des Molecules et Materiaux du Mans, UMR 6283 CNRS, Faculte des Sciences, 72085 Le Mans cedex 9,
,
*
a
ꢀ
ꢀ
ꢀ
ꢀ
France
b
ꢀ
ꢀ ꢀ
ꢁ
ꢀ
Laboratoire de Chimie Appliquee : Heterocycles, Corps Gras et Polymeres, Faculte des Sciences de Sfax, 3038 Sfax, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Triisopropylsilyl-
a
-diazoacetone (TIPS-diazoacetone) underwent high-yielding “diazo-
Received 23 September 2016
Accepted 13 December 2016
Available online xxxx
side” Mukaiyama aldol-type addition with a range of aryl and alkyl aldehydes when
subjected to stoichiometric amount of tetrabutylammonium fluoride at ꢀ16 ꢁC, in Et2O.
Robustness of the TIPS group makes TIPS-diazoacetone a stable surrogate for
a-trie-
thylsilyl-a-diazoacetone, on which generation of the corresponding carbanion can still be
Keywords:
efficiently achieved under nucleophilic, weakly basic and practical conditions. These re-
sults highlight the synthetic potential that can be expected from TIPS-diazoacetone,
promising building block for the convergent elaboration of highly functionalised versa-
tile diazocarbonyl compounds.
Diazo compounds
Aldol reactions
Fluorides
Carbanions
© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Aldehydes
1. Introduction
diazodicarbonyl scaffolds, which upon deacylation can
provide terminal diazoketones. Substitution at the diazo
The synthesis and transformation of
scaffolds have aroused a steady interest in organic syn-
thesis for many years [1]. These scaffolds are versatile in-
a
-diazocarbonyl
carbon of terminal diazoketones, commonly prepared via
route b or route c, while preserving the diazo moiety,
constitutes a convergent strategy to access diversely func-
tionalised diazocarbonyl scaffolds (route d).
termediates that can undergo
a
large array of
transformations, especially on the reactive C]N2 site,
including oxidations, reductions, CeC, CeH, heteroatom-H
insertions and cyclopropanations. Numerous strategies
have been designed towards their formation [1,2]. Among
An important reaction in this field (route d) is the aldol-
type addition between terminal diazoketones 1 and various
aldehydes, in basic media, providing a convergent route to
b
-hydroxy-a-diazoketones 2 (Scheme 2a). Strong bases
them, oxidation of
a
-keto hydrazones has been successfully
such as lithium diisopropylamide (LDA) are commonly
used in stoichiometric amount, at low temperature, to
perform this reaction [3,4]. We recently reported an alter-
native procedure using nucleophilic and weakly basic
conditions, consisting of the tetrabutylammonium fluoride
developed (Scheme 1, route a), although limited by the
availability of the substrates. Acylation of diazomethane
(route b) is classically used to access terminal diazoketones
but suffers from safety hazards. Diazo-transfer, typically
from sulfonyl azides (route c), has been applied to a large
range of active methylene compounds to elaborate diverse
(TBAF)-triggered aldol-type addition between
thylsilyl- -diazoacetone (TES-diazoacetone, 3) and various
aldehydes (Scheme 2b) [5]. A large range of -hydroxy-a-
a-trie-
a
b
diazoketones 4 could thus be synthesised under convenient
experimental conditions.
* Corresponding author.
E-mail address: catherine.gaulon@univ-lemans.fr (C. Gaulon-Nourry).
http://dx.doi.org/10.1016/j.crci.2016.12.005
1631-0748/© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-

2
I. Abid et al. / C. R. Chimie xxx (2017) 1e6
triisopropylsilyl-a-diazoacetone (TIPS-diazoacetone, 7,
Scheme 4) towards fluoride-induced aldol-type addition.
2. Results and discussion
TIPS-diazoacetone 7 [7] was prepared in a good yield by
silylation of diazoacetone, using TIPS triflate/N,N-diiso-
propylethylamine as the silylating system, at 0 ꢁC (Scheme
4) [5,8]. Diazoacetone, stable yellow oil that can be stored
in freezer for months, was prepared beforehand on a
multigram scale by diazo-transfer from tosyl azide to ace-
tylacetone [5,9], followed by deacetylation [4] (Scheme 4).
We were pleased to observe that TIPS-diazoacetone was
stable, storable for months in the freezer, contrary to TES-
diazoacetone, which rapidly underwent desilylation/
degradation in a few weeks time, even in the freezer.
We investigated first the fluoride-induced aldol-type
reaction between TIPS-diazoacetone and benzaldehyde
(Table 1). TBAF, the optimal source of fluoride highlighted
for TES-diazoacetone [5], was initially selected and the best
catalytic conditions were applied: TBAF 5 mol %, 4 Å mo-
lecular sieves (MSs), anhydrous Et2O, ꢀ16 ꢁC, 2 h (Table 1,
entry 1). Unfortunately, very low conversion was achieved
and aldol 4a, contaminated by traces of bis-aldol 8a
(Scheme 5), was isolated in only 7% yield after column
chromatography [10]. No O-TIPSeprotected aldol was
detected. This first result seems to exclude that a fluoride-
triggered autocatalytic mechanism could proceed here.
This hypothesis was supported by the fact that no reactivity
was observed when TBAF was replaced by an equimolar
amount of the tetrabutylammonium alkoxide of benzylic
alcohol [11].
Scheme 1. Strategies towards the formation of diazoketone scaffolds.
Beside, TES-diazoacetone 3 revealed itself to be a useful
three-carbon building block, which could be introduced
into functionalised carbon chains via a LDA-induced double
cross-aldol addition sequence (Scheme 3) [4]. The presence
of the TES protecting group was crucial to carry out first the
LDA-induced “methyl-side” aldolisation, without any
competitive aldol-type addition on the more reactive
“diazo-side”. Methyl-side aldolisation resulted in a mixture
of the C-silylated and C-desilylated aldols 5. Methanolysis
on the crude mixture achieved complete desilylation
before the diazo-side aldol-type addition could be per-
formed classically with LDA, at low temperature, to pro-
duce diazodiols 6 (Scheme 3). This sequence allowed the
fragile b-hydroxy-a-diazoketone moiety of compounds 6 to
be successfully generated in the last step.
To explore further the potential of the
a-trialkylsilyl-a-
diazoacetone scaffold as a three-carbon building block, it
appeared necessary to prevent unintentional diazo-side
desilylation, which readily occurs with the labile TES
group. Thus, we thought of replacing the TES protecting
group by the more robust triisopropylsilyl (TIPS) one [6]. To
assess the relevance of this scaffold, we needed to inves-
tigate if the diazo-side aldol-type addition could still be
conveniently performed under nucleophilic activation by a
The use of an equimolar amount of TBAF (Table 1, entry
2) led to the formation of aldol 4a and bis-aldol 8a in a 9:1
ratio, from the 1H NMR spectrum of the crude product
(Scheme 5). Pure aldol 4a was isolated in 67% yield after
column chromatography. Bis-aldol 8a, slightly more polar
than aldol 4a, could not be isolated and was recovered as a
fluoride. To this aim, we report here the behaviour of a-
Scheme 2. Base and fluoride-induced aldol-type additions on diazoketone scaffolds.
Scheme 3. TES-diazoacetone chain-extension by double cross-aldol addition sequence.
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-

I. Abid et al. / C. R. Chimie xxx (2017) 1e6
3
Scheme 4. Preparation of TIPS-diazoacetone.
Table 1
ꢀ78 ꢁC (entry 3), although bis-aldol 8a was no longer
detected. To prevent the methyl-side aldolisation to occur,
basicity of the TBAF was buffered by the use of a TBAF/AcOH
system as a ratio of 1:1 mixture [13] (Table 1, entries 4e7).
Fluoride-induced aldol-type addition between TIPS-diazoacetone and
benzaldehyde.
ꢁ
Although the reaction did not proceed at ꢀ16 C (entry 4),
increasing the temperature to room temperature resulted in
the convenient formation of the expected aldol 4a in 65%
yield (entry 5), which was not improved by the addition of
MSs (entry 6). Traces of the bis-aldol were still recovered
after chromatography in these two assays conducted at
room temperature (entries 5 and 6). When a TBAF/AcOH
ratio was changed from 1:1 to 1:2, reactivity was no longer
observed (entry 7). At that time, we thought about the in-
fluence of the MSs on the reaction. Its main role is to trap
some of the water present in various amounts in the com-
mercial tetrahydrofuran (THF) solutions of TBAF, thus
providing homogeneous quality of the reagent [5]. However,
TBAF becomes at the same time more reactive and above all
more basic [14]. We can suppose that the rate of desilylation
of TIPS-diazoacetone by nucleophilic attack from TBAF is
low, thus allowing degradation and side-reaction to proceed
in the basic medium generated, like retro-aldolisation pro-
cess and methyl-side aldolisation. To support our hypothe-
sis, the reaction was conducted in the presence of an
equimolar amount of TBAF without the addition of MSs
(entry 8). Pleasingly, a drastic increase in the yield was
achieved, from 67% (entry 2) to 95%, confirming that the
addition of MSs was detrimental to the reaction. On the
contrary, when the reaction was carried out using solid
TBAF$3H2O instead of the commercial THF solution of TBAF,
a moderate conversion of 42% was obtained (entry 9). The
less basic and non-hygroscopic tetrabutylammonium tri-
phenyldifluorosilicate [15] was also tested but led to the
expected aldol 4a with a disappointing 53% yield (entry 10).
The use of KF$18-crown-6 ether complex as an alternative
fluoride source, which had proven suitable for TES-
diazoacetone [5], resulted in a moderate 58% yield (entry
Entry Fꢀ source (mol %)
Additivea T (ꢁC) Isolated
yield of 4a (%)
1
2
TBAFb (0.05 equiv)
TBAF (1 equiv)
4 Å MSs
4 Å MSs
4 Å MSs
ꢀ16
ꢀ16
ꢀ78
ꢀ16
rt
rt
rt
¡16
ꢀ16
ꢀ16
ꢀ16
7
67
66
ec
65
62
ec
95
42d
53
58
3
TBAF (1 equiv)
4
5
TBAF/AcOH: 1:1 (1 equiv)
TBAF/AcOH: 1:1 (1 equiv)
6
7
8
TBAF/AcOH: 1:1 (1 equiv) 4 Å MSs
TBAF/AcOH: 1:2 (1 equiv)
TBAF (1 equiv)
9
10
11
TBAF$3H2O (1 equiv)
TBAT (1 equiv)e
KF$18-crown-6 ether
(1 equiv)e
12
CsF (5 equiv)/n-Bu4NCl
ꢀ16
67
(0.1 equiv)f
Abbreviations: rt, room temperature; TBAT, tetrabutylammonium tri-
phenyldifluorosilicate.
Bold characters were used to highlight the best conditions resulting from
the study presented.
a
Activated powdered 4 Å MSs (250 mg) were added per 0.5 mmol of
substrate.
b
1 M/THF, commercial source.
No conversion.
c
d
e
f
Conversion estimated from 1H NMR of the crude product.
For solubility reason, THF was chosen as the solvent.
Reaction time: 24 h.
mixture with aldol 4a. When benzaldehyde was replaced by
p-chlorobenzaldehyde, a NMR-based 70:30 ratio of the
mixture aldol 4b/bis-aldol 8b was obtained (Scheme 5).
Aldol 4b was isolated in 50% yield, and the corresponding
bis-aldol 8b could be isolated as a single diastereoisomer in
20% yield [12] and fully characterised. Bis-aldols 8 are ex-
pected to result from methyl-side aldolisation, induced by
the basicity of the medium. No improvement of the yield in
aldol 4a was achieved when the reaction was conducted at
11). Finally,
a solideliquid phase-transfer system was
assessed, consisting of anhydrous CsF (5 equiv)/n-Bu4NCl
(0.1 equiv) in Et2O, at ꢀ16 ꢁC (entry 12). The expected aldol
was isolated in 67% yield after an extended reaction time of
24 h.
Scheme 5. Formation of bis-aldols 8a and 8b in the course of the aldolisation process. a4a/8a ¼ 9:1 from the 1H NMR spectrum of the crude product. b4b/8b ¼ 7:3
from the 1H NMR spectrum of the crude product.
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-

4
I. Abid et al. / C. R. Chimie xxx (2017) 1e6
With optimal conditions in hand (entry 8, Table 1), we
cinnamaldehyde (aldol 4m, 26%), low yields of the expected
investigated the scope of the TBAF-induced aldol-type re-
action of TIPS-diazoacetone (Scheme 6). The results were
systematically compared with those obtained from the
TBAF-triggered aldol-type reaction of TES-diazoacetone,
recently studied by our team [5]. Benzaldehyde and
electron-poor p-Cle, o-Cle and p-CF3 benzaldehyde led to
excellent yields of aldols (4aec, 4e), very similar to those
obtained from TES-diazoacetone. We were pleased to
isolate diazoaldol 4d in a high 88% yield from m-Cl-benz-
aldehyde. Indeed, this original diazoaldol had not been
isolated with the protocols previously developed from TES-
diazoacetone [5]. The less reactive, electron-rich anisalde-
hyde provided aldol 4f with a moderate 58% yield, sub-
stantially lower than previously obtained from TES-
substrate. Although some degradation was obvious, no
side product could be identified. Moreover, mixing together
TBAF and anisaldehyde under the reaction conditions (Et2O,
ꢀ16 ꢁC, and 2 h) resulted in clean recovery of the aldehyde.
In addition, we were delighted to observe that sensitive
heteroaromatic aldehydes like furfural and 2-thio-
phenecarboxaldehyde behaved as excellent substrates. Such
access to diazoaldols 4g (90%) and 4h (80%) is more rapid,
and thus more efficient, than the two-step procedure pre-
viously set up from TES-diazoacetone (Scheme 6, note c) [5].
Hindered and/or enolizable alkyl aldehydes behaved
equally well, providing the expected diazoaldols (4iek) in
aldols were obtained [16].
3. Conclusions
This study highlighted that TIPS-diazoacetone consti-
tutes a stable, storable and thus convenient surrogate for
TES-diazoacetone in the fluoride-induced Mukaiyama-type
aldol addition towards alkyl and aryl aldehydes. TBAF
proved to be
a particularly suitable fluoride source,
required in stoichiometric amount, whereas MSs played a
detrimental role in the reaction. This aspect of the reac-
tivity of TIPS-diazoacetone, combined with the robustness
of the TIPS protecting group, makes this building block
valuable for further study towards the convergent elabo-
ration of highly functionalised a-diazocarbonyl chains. This
investigation is underway in our laboratory.
4. Experimental section
Caution: Although we never had any trouble with the
handling of the diazo compounds described in this study,
diazo compounds are potentially explosive and should be
handled with care in a well-ventilated fume hood.
4.1. General information
91e95% yields. With sensitive and less reactive
urated aldehydes like octynal (aldol 4l, 39%) and
a,b-unsat-
All reactions were performed under an argon atmo-
sphere. Et2O and THF were dried through activated alumina
Scheme 6. Scope of the TBAF-induced aldol-type addition of TIPS-diazoacetone. aYield resulting from TBAF-induced aldol-type addition to TES-diazoacetone
according to protocol P1: TBAF 50 mol %, Et2O, 4 Å MSs, ꢀ16 ꢁC, 2 h. See Ref. [5]. bTraces of the corresponding bis-aldol 8 were detected as a mixture with
aldol 4 in a minor discarded fraction of chromatography. cYield resulting from the two-step TBAF-induced aldol-type addition to TES-diazoacetone according to
protocol P2: (1) TBAF 5 mol %, Et2O, 4 Å MSs, ꢀ16 ꢁC, 2 h; (2) Et3N$3HF (2 equiv), THF, rt, 16 h. See Ref. [5].
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-

I. Abid et al. / C. R. Chimie xxx (2017) 1e6
5
columns. DIPEA and CH3CN were distilled over CaH2.
4.3. Formation of the bis-aldols 8
Commercial aldehydes were distilled or recrystallised
before use. TBAF (1 M/THF, 50 mL) was used as received.
MSs (4 Å, powder) were activated by hot gun heating under
vacuum. Reactions at ꢀ16 ꢁC were performed using an ice/
NaCl bath or using a bath cooled by cryogenic flow. Melting
points were measured with a Büchi B-540 apparatus and
are uncorrected. Column chromatography was performed
4.3.1. 1,5-Bis(4-chlorophenyl)-2-diazo-1,5-dihydroxypentan-3-
one (8b)
To a stirred solution of TIPS-diazoacetone (100 mg,
0.42 mmol,
1 equiv), p-chlorobenzaldehyde (65 mg,
0.46 mmol, 1.1 equiv) and 4 Å MSs (210 mg, 500 mg/mmol)
in anhydrous Et2O (4 mL) at ꢀ16 ꢁC was slowly added TBAF
(1 M/THF, 0.42 mL, 0.42 mmol, 1 equiv). After 120 min
stirring at ꢀ16 ꢁC under Ar, the reaction mixture was
quenched by the addition of a saturated aqueous NH4Cl
solution (8 mL). The aqueous layer was extracted with
diethyl ether (3 ꢂ 10 mL) and the combined organic layer
was dried over Na2SO4, filtered, and the filtrate was
concentrated under reduced pressure. The oily residue,
containing a 70:30 mixture of aldol 4b/bis-aldol 8b, eval-
uated from its 1H NMR spectrum, was purified by column
using 60
mm silica gel. Thin-layer chromatography was
performed with silica gel 60F254 precoated thin-layer
chromatography (TLC) sheets, and products were detected
by UV light or vanillin ethanolic solution. 1H NMR (200 or
400 MHz) and 13C NMR (100.6 MHz) spectra were recorded
in CDCl3. Chemical shifts are reported as parts per million
(ppm) relative to Me4Si and coupling constants are
expressed in hertz. The splitting patterns are designated as
follows: s, singlet; br s, broad singlet; d, doublet; t, triplet;
q, quartet; m, multiplet. Proton and carbon assignments
were established using correlation spectroscopy (COSY),
heteronuclear single quantum coherence (HSQC) and dis-
tortionless enhancement by polarization transfer with
retention of quaternaries (DEPT-Q) experiments. IR spectra
were recorded on a Fourier transform infrared (FTIR)
spectrometer equipped with an attenuated total reflec-
tance (ATR) unit. The wavenumbers of representative ab-
sorption peaks were given in cmꢀ1. High-resolution mass
spectra were recorded on an electrospray ionization-
quadrupole-time-of-flight (ESI-QTOF) apparatus.
chromatography
(silica
gel,
cyclohexane/ethyl
acetate ¼ 95:5 to 60:40). Aldol 4b was isolated as a yellow
solid (47 mg, 50% yield) [5], and bis-aldol 8b was isolated as
an orange oil (16 mg, 20% yield based on the limiting
reactant p-Cl-benzaldehyde): Rf ¼ 0.12 (petroleum ether/
ethyl acetate ¼ 80:20); IR (film) nmax (cmꢀ1) 3379 (nOH),
2924, 2088 (nC
]
N2), 1606 (
n
C]O), 1490, 1090, 1013, 780,
742; 1H NMR (400 MHz, CDCl3)
d
(ppm) 7.37e7.23 (m, 8H),
6.01 (s, 1H), 5.25 (dd, 1H, J ¼ 9.0, 3.2 Hz), 2.87 (dd, 1H,
J ¼ 15.6, 9.0 Hz), 2.75 (m, 1H); 13C NMR (100.6 MHz, CDCl3)
d
(ppm) 192.2, 141.2, 137.3, 134.5, 133.9, 129.2, 129.0, 127.3,
127.2, 75.6, 70.3, 67.3, 47.2. HRMS m/z calcd for
4.2. General procedure for the fluoride-induced aldol-type
addition of TIPS-diazoacetone
C
17H15Cl2N2O3 [M þ H]þ 365.0460; found, 365.0469.
Acknowledgements
To a stirred solution of TIPS-diazoacetone (0.42 mmol,
1 equiv) and aldehyde (0.46 mmol, 1.1 equiv) in anhydrous
Et2O (4 mL) at ꢀ16 ꢁC was slowly added TBAF (1 M/THF,
0.42 mmol, 1 equiv). After 120 min stirring at ꢀ16 ꢁC under
Ar, the reaction mixture was quenched by the addition of a
saturated aqueous NH4Cl solution (8 mL). The aqueous
layer was extracted with diethyl ether (3 ꢂ 10 mL) and the
combined organic layer was dried over Na2SO4, filtered, and
the filtrate was concentrated under reduced pressure. The
oily residue was purified by column chromatography (silica
gel, cyclohexane/ethyl acetate ¼ 95:5 to 60:40) to isolate
the expected aldol 4.
ꢀ
ꢀ
We gratefully acknowledge the “Office mediterraneen
ꢀ
de la jeunesse” (OMJ) and Erasmusþ Program e “Mobilites
ꢀ
ꢀ
internationales de credits de l'enseignement superieur”
(call for proposals 2015) for I. Abid's Ph.D. funding. We are
deeply grateful to Ligue contre le cancer”the “ for financial
ꢀ
support (CSIRGO 2013). We thank Amelie Durand and
Corentin Jacquemmoz for the NMR analyses and Patricia
Gangnery and Emmanuelle Mebold for the HRMS
analyses.
References
4.2.1. 4-(3-Chlorophenyl)-3-diazo-4-hydroxybutan-2-one (4d)
Prepared from TIPS-diazoacetone and m-chlor-
obenzaldehyde according to the general procedure. Aldol
(4d) was obtained after column chromatography (cyclo-
hexane/ethyl acetate ¼ 95:5 to 60:40) as a yellow solid
(83 mg, 88% yield): mp ¼ 98 ꢁC; Rf ¼ 0.12 (petroleum ether/
ethyl acetate ¼ 80:20); IR (film) nmax (cmꢀ1) 3363 (nOH),
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2079 (nC
(400 MHz, CDCl3)
5.98 (br s, 1H), 3.72 (br s, 1H, OH), 2.27 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) (ppm) 191.0, 140.9, 134.8, 130.1, 128.6,
]
N2), 1613 (
n
C]O), 1336, 1025, 766, 736; 1H NMR
d
(ppm) 7.43 (s, 1H), 7.27e7.34 (m, 3H),
[4] A. Lancou, H. Haroun, U.K. Kundu, F. Legros, N. Zimmermann,
ꢀ
M. Mathe-Allainmat, J. Lebreton, G. Dujardin, C. Gaulon-Nourry,
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P. Gosselin, Tetrahedron 68 (2012) 9652e9657.
126.0, 123.9, 73.9, 67.3 and 25.8; HRMS m/z calcd for
ꢀ
[5] I. Abid, P. Gosselin, M. Mathe-Allainmat, S. Abid, G. Dujardin,
10H9ClN2NaO2 [M þ Na]þ 247.0245; found, 247.0238.
C. Gaulon-Nourry, J. Org. Chem. 80 (2015) 9980e9988.
[6] Preliminary assays showed that tert-butyldimethylsilyl (TBS) was
C
The spectroscopic data for aldols (4a), (4b), (4c), (4e),
not
a suitable “diazo-side” protecting group for diazoacetone.
(4f), (4g), (4h), (4i), (4j), (4k), (4l) and (4m) proved
consistent with the literature [5].
Indeed, TBS-diazoacetone is known to be rather unstable, easily
desilylated by hydrolysis. See Ref. [7].
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-

6
I. Abid et al. / C. R. Chimie xxx (2017) 1e6
[7] R. Brückmann, G. Maas, Chem. Ber. 120 (1987) 635e641.
[12] Yield based on the limiting reactant of the bis-aldol addition reac-
tion: p-Cl-benzaldehyde.
[13] A.B. Smith III, S.S.-Y. Chen, F.C. Nelson, J.M. Reichert, B.A. Salvatore, J.
Am. Chem. Soc. 117 (1995) 12013e12014.
[8] TIPS-diazoacetone should not be contaminated with silylated resi-
dues to get optimal and reproducible yields in the following
fluoride-induced aldol-type addition study.
[9] M. Presset, D. Mailhol, Y. Coquerel, J. Rodriguez, Synthesis (2011)
2549e2552.
[14] A. Hameed, R.D. Alharthy, J. Iqbal, P. Langer, Tetrahedron 72 (2016)
2763e2812.
[10] Bis-aldol 8a was unambiguously identified: this original product
was already obtained by our team in the course of a previous study
(unpublished results).
[11] D.-K. Wang, Y.-G. Zhou, Y. Tang, X.-L. Hou, L.-X. Dai, J. Org. Chem. 64
(1999) 4233e4237.
[15] (a) A.S. Pilcher, H.L. Ammon, P. DeShong, J. Am. Chem. Soc. 117
(1995) 5166e5167;
(b) A.S. Pilcher, P. DeShong, J. Org. Chem. 61 (1996) 6901e6905.
[16] No aldol product could be isolated from crotonaldehyde and 2-
methyl-2-pentenal.
Please cite this article in press as: I. Abid, et al., Advances in the TBAF-induced aldol-type addition of
acetones: TIPS versus TES, Comptes Rendus Chimie (2017), http://dx.doi.org/10.1016/j.crci.2016.12.005
a-trialkylsilyl-a-diazo-