TBAF-Triggered Aldol-Type Addition of α-Triethylsilyl-α-diazoacetone

Article abstract of DOI:10.1021/acs.joc.5b01554

Aldol-type addition of α-triethylsilyl-α-diazoacetone was achieved under nucleophilic activation by tetrabutylammonium fluoride (TBAF). The use of a semistoichiometric amount of TBAF (protocol P1) provided the corresponding β-hydroxy-α-diazoacetone as the sole product. Alternatively, the use of a catalytic amount of TBAF led to a mixture of β-hydroxy- and β-silyloxy-α-diazoacetone products, which was cleanly desilylated with Et₃N·3HF (protocol P2). The weakly basic conditions employed tolerate a wide range of substrates and constitute a high-yielding, convenient complementary procedure to the low-temperature LDA-promoted aldol-type addition of diazoacetone.

Full text of DOI:10.1021/acs.joc.5b01554

Article
pubs.acs.org/joc
TBAF-Triggered Aldol-Type Addition of α‑Triethylsilyl-α-
diazoacetone
Imen Abid,†,‡ Pascal Gosselin,† Monique Mathe-Allainmat,§ Souhir Abid,‡ Gilles Dujardin,†
́
and Catherine Gaulon-Nourry*,†
†Institut des Molec
Cedex 9 Le Mans, France
‡Laboratoire de Chimie Appliquee
́ ́ ́ ́
ules et Materiaux du Mans, UMR 6283 CNRS, Faculte des Sciences et Techniques, Universite du Maine, 72085
́
, Het
́
er
́
ocycles, Corps Gras et Polymer
̀
es, Faculte
́
des Sciences de Sfax, 3038 Sfax, Tunisia
de Nantes, 44322 Cedex 3 Nantes,
§Laboratoire CEISAM, UMR 6230 CNRS, Faculte
France
́
des Sciences et des Techniques, Universite
́
S
* Supporting Information
ABSTRACT: Aldol-type addition of α-triethylsilyl-α-diazo-
acetone was achieved under nucleophilic activation by
tetrabutylammonium fluoride (TBAF). The use of a semi-
stoichiometric amount of TBAF (protocol P1) provided the
corresponding β-hydroxy-α-diazoacetone as the sole product.
Alternatively, the use of a catalytic amount of TBAF led to a
mixture of β-hydroxy- and β-silyloxy-α-diazoacetone products, which was cleanly desilylated with Et3N·3HF (protocol P2). The
weakly basic conditions employed tolerate a wide range of substrates and constitute a high-yielding, convenient complementary
procedure to the low-temperature LDA-promoted aldol-type addition of diazoacetone.
α-Diazocarbonyl compounds involved in such nucleophilic
additions are mainly diazoacetates (A1, Scheme 1). Intrinsically
less reactive α-diazoketones (A2, Scheme 1) have been much
less studied. Yet, high structural diversity can be expected for
the β-hydroxy-α-diazoketone products, leading recently to
important applications in multistep synthesis.8c,9 We have
recently reported a new methodology focused on the base-
promoted chemistry of α-triethylsilyl-α-diazoacetone (TES-
diazoacetone) (Scheme 2, eq 1).10 While α-trialkylsilyl-α-
diazoketones have been synthesized and used for a long time as
silylketene precursors,11 they had never been involved in aldol
processes. In order to elaborate diversely substituted 5-hydroxy-
1,3-diketones E in a convergent way, our strategy was based on
the insertion of the three-carbon building-block TES-
diazoacetone into a functionalized carbon chain via a base-
induced double cross-aldol addition sequence (Scheme 2, eq
1). Due to the sensitivity of diazoaldols B (Scheme 1),
particularly prone to retroaldolization, the TES group was
introduced on diazoacetone to protect the most reactive diazo-
side, allowing us to carry out the methyl-side aldolization first.
Indeed, TES-diazoacetone underwent an unprecedented LDA-
promoted methyl-side aldolization. Complete removal of the
TES protecting group by methanolysis provided diazoaldol C.
The latter was involved in a LDA-mediated diazo-side aldol-
type addition, leading to diversely substituted 2-diazo-3-oxo-
1,5-diols D. Clean 1,2-H migration induced by Rh2(OAc)4
provided the corresponding 5-hydroxy-1,3-diketones E, mainly
INTRODUCTION
■
α-Diazocarbonyl scaffolds play an important role in organic
synthesis. The CN2 function undergoes a large array of
transformations, including oxidations, reductions, cyclopropa-
nations, and C−C, C−H, or heteroatom−H insertions.1 This
remarkable reactivity profile makes α-diazocarbonyl com-
pounds valuable intermediates for organic synthesis, and
numerous strategies have been developed to elaborate them.2
The aldol-type addition of (diazomethyl)carbonyl moieties A
with various aldehydes provides a convergent route to β-
hydroxy-α-diazocarbonyl intermediates B (Scheme 1). This
Scheme 1. Base-Induced Aldol-Type Addition of
(Diazomethyl)carbonyl Compounds
reaction is usually achieved under strongly basic conditions
(KOH,3 NaOH,4 LDA,5 CH3MgBr,6 DBU7). This method-
ology takes advantage of the good stability displayed by the
diazo moiety of diazocarbonyl compounds in basic media. The
diazocarbonyl anions thus generated display unique properties,
with respect to their specific geometry and electronic structure.
They proved to be highly reactive toward imines and aldehydes,
tolerating hindered and sensitive substrates.8
Received: July 7, 2015
© XXXX American Chemical Society
A
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Article
Scheme 2. Aldol-Type Additions of TES-Diazoacetone
as their keto−enol tautomeric form. These results prompted us
to investigate further the synthetic interest of the triethylsilyl
moiety of TES-diazoacetone, particularly in the field of the
fluoride-induced aldol-type additions (Scheme 2, eq 2).
The fluoride-promoted generation of a nucleophilic inter-
mediate from an organotrimethylsilane precursor is well-
known.12 This nucleophilic activation has been successfully
applied to the addition of trimethylsilyl enol ethers13 and dienol
ethers,14 allyltrimethylsilane,15 benzyltrimethylsilane,16 and
trimethylsilylalkynes17 on carbonyl compounds and/or imines.
Aldol-type additions induced by an ammonium fluoride display
interesting features: (i) the mild generation of reactive and
“soft” ammonium enolates, (ii) the rapid trapping of silicon by
the aldol anion, allowing for the displacement of the
equilibrium and the use of a catalytic amount of the fluoride
source. The application of this methodology to α-trialkylsilyl-α-
diazocarbonyl compounds is restricted to a unique paper from
Kanemasa et al., reporting the TBAF-catalyzed aldol reaction
between ethyl trimethylsilyldiazoacetate (TMS-DZA) and
various aldehydes (40−99% yields).18 Although synthetically
promising, this approach has never been studied with α-
trialkylsilyl-α-diazoketones. We report here the development of
a mild and efficient TBAF-induced aldol-type addition of TES-
diazoacetone.
Table 1. Fluoride-Induced Aldol-Type Addition Using a
Stoichiometric Amount of Fluoride Source
2a/2b
isolated yield
(%)
a
entry
1
F− source
solvent
T (°C)
ratio
b
Et2O or
neat
rt
0
c
2
3
4
5
6
7
TBAF
Et2O
Et2O
Et2O
0
rt
100/0
98/2
79
32
98
17
53
35
TBAF
TBAF, 4 Å MS
TBAT
−16
rt
100/0
100/0
100/0
100/0
d
THF
TBAT
THF
−16
rt
d
KF·18-crown-6
THF
e
ether
8
KF·18-crown-6
THF
−16
100/0
84
e
ether
a
b
From the 1H NMR spectrum of the crude product. Reaction time: 3
c
d
days. 1 M/THF, commercial source. For solubility reasons, THF
was chosen as the solvent. Under the same reaction conditions, at
e
−16 °C and rt, CsF·18-crown-6 ether complex, prepared according to
ref 26, led to irreproducible yields (32−86%).
RESULTS AND DISCUSSION
■
Fluoride-Induced Aldol-Type Addition of TES-Diazo-
acetone with Benzaldehyde. TES-diazoacetone was pre-
pared by silylation of diazoacetone 1,19 readily synthesized in
two steps via diazo transfer from tosyl azide to acetylacetone,20
followed by rapid alkaline hydrolysis (Scheme 3).10 This route
was conveniently carried out on a multigram scale, affording
pure TES-diazoacetone in good yield.21
previously for TMS-DZA.18 The influence of the temperature
and the nature of the fluoride source was next studied.
Increasing the reaction temperature to rt resulted in a drastic
drop of the yield (32%), due to a retroaldolization process
(entry 3). To the contrary, we were delighted to observe that
decreasing the temperature to −16 °C while adding 4 Å
molecular sieves to the reaction mixture23 allowed us to reach a
98% yield of diazoaldol 2a (entry 4).24 Other sources of
fluoride were involved (entries 5−8), highlighting that TBAF
was the most effective one. Indeed, anhydrous tetrabutylam-
monium triphenyldifluorosilicate (TBAT)25 (entries 5 and 6)
and KF·18-crown-6 ether complex26 (entries 7 and 8) led to
moderate to good yields at −16 °C and low yields at rt.
We investigated next the influence of the amount of fluoride
on the course of the aldolization process (Table 2). Pleasingly,
we discovered that 5 mol % of TBAF was sufficient to induce
the addition in good to excellent yields (Table 2, entries 1−5).
A mixture of the diazoaldol 2a and the O-TES-protected
diazoaldol 2b was obtained and easily separated by column
chromatography. Decreasing the temperature from rt to −16
°C while adding 4 Å molecular sieves23 allowed for an increase
in the global yield of the isolated aldols 2a and 2b from 75 to
96% (entries 1−3). The influence of the reaction time was next
Scheme 3. Preparation of TES-Diazoacetone
The study of both the feasibility and optimization of the
aldolization process was carried out on the TES-diazoacetone/
benzaldehyde system (Table 1).22 While the reaction did not
proceed without fluoride activation (Table 1, entry 1), a
stoichiometric amount of commercial TBAF (1 M/THF) in
dry diethyl ether at 0 °C led to the expected diazoaldol 2a in
79% yield after 2 h (entry 2). These conditions were initially
chosen with regards to the optimal conditions developed
B
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Table 2. Influence of the amount of TBAF on the aldol-type
Table 3. O-Desilylation of Aldol 2b
addition of TES-diazoacetone
2a isolated yield
entry
F− source
T (°C)
time
(%)
global yield
a
1
2
3
4
TBAF (1.1 equiv)
TBAF (1.1 equiv)
TBAF (1.1 equiv)
rt
0
3.5 h
degradation
fluoride
(%) of isolated
2a + isolated
2b
30 min
10 min
5 h
67
79
77
amount
time
2a/2b
a
entry F− source (mol %) T (°C) (min)
ratio
−16
rt
b
TBAF/AcOH 1/1
(1.1 equiv)
1
2
3
TBAF
TBAF
TBAF,
5
5
5
rt
0
120
120
120
28/72
37/63
35/65
75
85
96
5
6
HF·pyridine (2.2 equiv)
Et3N·3HF (1.1 equiv)
rt
rt
22 h
3 h
degradation
100
−16
4 Å MS
TBAF,
4 Å MS
TBAF,
4 Å MS
a
4
5
5
5
−16
−16
60
10
27/73
35/65
92
90
1 M/THF, commercial source.
Degradation of the substrate was observed when treated with
the HF·pyridine complex at rt, certainly due to the acidity of
the medium (entry 5). To the contrary, 1.1 equiv of the mild
and neutral Et3N·3HF complex achieved quantitative O-
desilylation of aldol 2b in Et2O after 3 h at rt (entry 6).30 An
attempt was then made to perform the one-pot sequence: 5
mol % of TBAF-induced aldol-type addition followed by the
addition of Et3N·3HF to achieve O-desilylation. Unfortunately,
complete desilylation could not be achieved under these
conditions, even with 3 equiv of Et3N·3HF complex (2a/2b =
60:40). However, we were pleased to observe that O-
desilylation was complete when conducted on the crude
mixture of aldols (2a + 2b), in the more appropriate solvent
THF, at rt (Scheme 4). Aldol 2a was thus isolated as the unique
product in 88% global yield for the two-step sequence,
thereafter called protocol P2.
TBAF-Induced Aldol-Type Addition of TES-Diazoace-
tone: Scope of the Reaction. The methodology was next
extended to a range of aldehydes in order to obtain the
corresponding O-desilylated aldols in high yields (Table 4).
The one-step protocol P1, involving a semistoichiometric
amount of TBAF, was thus primarily carried out. When the
yields proved to be unsatisfactory, the milder two-step protocol
P2, involving 5 mol % of TBAF, was conducted.
Following protocol P1, electron-poor p-CF3-, p-Cl-, and o-Cl-
benzaldehyde afforded high yields of the corresponding aldols
3a−5a. For o-Cl-benzaldehyde, while a mixture of aldols 5a and
5b was formed in an 88:12 ratio after 2 h, extending the
reaction time to 6 h allowed complete O-desilylation to be
achieved. To the contrary, m-Cl-benzaldehyde led to
disappointing results. Protocol P1 led to a 6a/6b mixture,
even after an extended reaction time (6 h: 6a/6b = 88:12; 40 h:
6a/6b = 93:7), and Et3N·3HF treatment of the crude mixture
resulted in degradation. This limitation is probably due to the
propensity of electron-poor aromatic aldehydes to undergo
oxidation in the presence of fluoride sources.31,32 Protocol P2
proved to be appropriate for the electron-rich anisaldehyde (7a,
82%), furfural (8a, 97%), and thiophene carbaldehyde (9a,
83%). A significant 11−25% increase of the yield was observed
when compared to that of protocol P1. Hindered and/or
enolizable alkyl aldehydes (10a−12a) and octynal (13a) led to
excellent yields (92−100%) following protocol P1. For
citronellal, the milder protocol P2 was the most efficient,
affording the expected aldol 14a in 85% yield. The reactivity of
α,β-unsaturated aldehydes was also studied. Protocol P2 was
c
c
41/59
77/23
80
6
7
TBAF,
4 Å MS
25
−16
−16
120
95
d
e
TBAF,
4 Å MS
50
120
100/0
97
a
b
1
From the H NMR spectrum of the crude product. 1 M/THF,
c
d
commercial source. Without addition of molecular sieves. Condi-
e
tions of entry 7 constitute protocol P1. A mixture of 2a and 2b was
obtained when decreasing the reaction time (10 min: 2a/2b = 82:18;
30 min: 2a/2b = 94:6).
considered. The global yield of aldols (2a + 2b) slightly
decreased when the reaction time was shortened (60 min, entry
4; 10 min, entry 5). Under the latter experimental conditions,
the absence of molecular sieves resulted in a 10% drop of the
yield along with a higher amount of 2a in the product mixture.
Expectedly, increasing the amount of TBAF (entries 6 and 7)
favored the formation of the O-desilylated aldol 2a. Pleasingly,
we observed that a semistoichiometric amount of TBAF
allowed for the exclusive formation of 2a with an excellent 97%
yield (entry 7, thereafter called protocol P1).
O-Desilylation of Aldol 2b. O-TES-protected diazoaldols
are interesting substrates for further diazo transformation.27 It
was, however, important to design a clean and high-yielding O-
desilylation of aldol 2b, enabling one to obtain aldol 2a as the
unique product after TBAF-catalyzed aldol-type addition.
Various acidic conditions were first applied to aldol 2b
(AcOH/CH2Cl2,28a TFA/AcOH/H2O,28b PPTS/MeOH/
CH2Cl228c). These conditions resulted in degradation and/or
low conversions, preventing us from achieving a convenient O-
desilylating acidic workup of the aldolization reaction mixture.
Different sources of fluoride were thus considered (Table 3).
The TBAF-induced O-desilylation of aldol 2b could not be
carried out at rt (Table 3, entry 1). Extensive degradation of the
substrate was observed, due to retroaldolization. When the
reaction was carried out at 0 °C, aldol 2a could be isolated in a
moderate 67% yield (entry 2), while retroaldolization was still
evidenced by the NMR signal of the aldehydic proton.
Decreasing the temperature to −16 °C and the reaction time
to 10 min led to an optimal 79% yield of aldol 2a (entry 3).
Interestingly, when the basicity of the reaction mixture was
buffered by the addition of an equimolar amount of glacial
acetic acid to TBAF,29 the O-desilylation could be performed at
rt, affording aldol 2a in 77% yield (entry 4).
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Scheme 4. TBAF-Catalyzed Two-Step Access to Aldol 2a
Table 4. Extension of the TBAF-Induced Aldol-Type Addition of TES-Diazoacetone to a Range of Aldehydes
a
b
c
Literature yield: 79%.27b Ratio of a/b determined before Et3N·3HF treatment from the 1H NMR spectrum of the crude product. Reaction time: 6
d
e
h (5a/5b = 88:12 after 2 h). Reaction time: 40 h; Et3N·3HF treatment on the crude mixture (6a + 6b) resulted in degradation Literature yield:
92%.5c No conversion. 18c is the diol product resulting from desilylation of the TBDPS ether. Ratio of a/b/c determined before Et3N·3HF
f
g
h
1
treatment from the H NMR spectrum of the crude product.
more appropriate than protocol P1 for this class of compounds,
but the yields proved to be highly substrate-dependent. Indeed,
while a high yield of aldol 15a was obtained with
cinnamaldehyde, crotonaldehyde afforded a modest 44% yield
of the corresponding aldol 16a. It is noteworthy that no trace of
Michael addition product was observed in this case. A limitation
appeared with the less reactive 2-methyl-2-pentenal, for which
no conversion was observed, whatever the protocol used. We
finally investigated the behavior of the hindered aldehyde 17,33
displaying a TBDPS ether. Satisfyingly, the TBAF-catalyzed
protocol P2 proved to be efficient, affording the expected aldol
18c in 75% yield after treatment with Et3N·3HF (2 equiv),
resulting from concomitant removal of the TBDPS primary
alcohol protection.
a fluoride-triggered autocatalytic mechanism was involved
(Scheme 5). It parallels the mechanism widely accepted for
the fluoride-triggered Sakurai−Hosomi reaction and the related
reaction of allyltrimethylsilane with imines, thoroughly
investigated by Hou et al.15 Accordingly, we suggest that
TBAF behaves as an initiator, reacting with TES-diazoacetone
to generate triethylsilylfluoride and carbanion (I). This anionic
species undergoes reversible aldol-type addition with the
aldehyde, producing the ammonium alkoxy anion intermediate
(II). The latter is nucleophilic enough to trap the triethylsilyl
moiety from another TES-diazoacetone substrate. This non-
reversible step affords the O-silylated aldol 2b while generating
a new carbanion (I), which in turn undergoes reversible aldol-
type addition. We could notice that aldolate II induced the
desilylation of TES-diazoacetone more rapidly than TBAF.
Indeed, when the aldol-type addition with benzaldehyde was
carried out according to protocol P1 (50 mol % of TBAF),
Mechanistic Aspects. The observation that 5 mol % of
TBAF was sufficient to afford the expected aldols in good
yields, mainly in the O-silylated form b, strongly suggested that
D
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Scheme 5. Mechanistic Rationale for the Formation of Aldol
2b
CONCLUSION
■
We described here the TBAF-induced aldol-type addition
between α-triethylsilyl-α-diazoacetone and various aldehydes. A
large range of β-hydroxy-α-diazoacetone scaffolds could be
obtained in high yields. The nucleophilic, weakly basic
conditions employed allowed us to set up convenient
experimental protocols, which constitute complementary
procedures to the available low-temperature LDA-promoted
aldol-type addition of diazoacetone. A fluoride-triggered
autocatalytic mechanism has been shown to occur, allowing
for the use of a catalytic amount of TBAF, while producing the
O-TES-protected aldols. The latter underwent clean and
quantitative desilylation when treated with Et3N·3HF. This
study highlights the similar reactivity profile displayed by TES-
diazoacetone and TMS-enol ethers toward the fluoride ion. The
major prospect of this methodology is to carry out its
organocatalytic asymmetric extension using a chiral ammonium
cation, in a context where no enantioselective aldol-type
addition of either diazoketones or trialkylsilyldiazoketones is
available so far.
decreasing the reaction time resulted in the isolation of a 2a/2b
mixture (Table 2, entry 7). Similarly, the reaction with o-
chlorobenzaldehyde following protocol P1 required 6 h in
order for the TBAF, still present in the medium, to achieve
complete O-desilylation of aldol 5b (Table 4). Considering the
autocatalytic mechanism involved, we evaluated next if
hydroxide or alkoxide ions could be used with the same
efficiency as TBAF. Sodium methoxide and potassium
trimethylsilanolate led to low conversion (<15%) or degrada-
tion when a stoichiometric amount was used. The use of 5 mol
% of a commercial methanolic solution of tetrabutylammonium
hydroxide proved to be more efficient, affording a mixture of
aldols 2a and 2b (94:6 ratio), albeit with a modest 63% global
yield. These attempts showed the superiority of the less basic
and highly soluble TBAF to trigger the aldol-type addition of
TES-diazoacetone.
A surprising feature of the fluoride-induced aldol-type
addition described here is that a semistoichiometric amount
of TBAF was sufficient to afford the sole aldols a (protocol P1).
Additionally, a highly substrate-dependent a/b ratio was
obtained with protocol P2, varying from 4:96 to 37:63, where
a 5:95 ratio was expected. Having evidenced that (i) no
deprotection of O-TES-aldol 2b occurred during the aqueous
workup34 and (ii) intramolecular 1,5-(O→O) TES migration
did not take place on aldol 2b to provide 2a,35 the mechanism
leading to aldol a remains unclear. Among the parameters
influencing the a/b ratio, the ketone substituent of the TES-
diazoketone substrate proved to be important. Indeed, the
aldol-type addition with 5 mol % of TBAF between
benzaldehyde and TES-diazoacetophenone 19,19b prepared by
silylation of 2-diazo-1-phenyl-ethan-1-one,36 resulted in the
isolation of the unique O-silylated aldol 20b in 67% yield
(Scheme 6).
EXPERIMENTAL SECTION
■
Caution: Although we never had any trouble in handling the diazo
compounds described in this study, diazo compounds are potentially
explosive and should be handled with care in a well-ventilated
fumehood.
General Information. All reactions were performed under an
argon atmosphere. Et2O and THF were dried through activated
alumina columns. DIPEA and CH3CN were distilled over CaH2.
Commercial aldehydes were distilled or recrystallized before use.
TBAF (1 M/THF, 50 mL) was used as received. Molecular sieves 4 Å,
powder, were activated by heating under vacuum. Reactions at −16 °C
were performed using an ice/NaCl bath or using a bath cooled by
cryogenic flow. Melting points are uncorrected. Column chromatog-
raphy was performed using 60 μm silica gel. Thin-layer chromatog-
raphy was performed with silica gel 60F254 precoated TLC sheets, and
1
products were detected by UV light or vanillin ethanolic solution. H
NMR (200 or 400 MHz) and 13C NMR (100 MHz) spectra were
recorded in CDCl3. Chemical shifts were reported as parts per million
(ppm) relative to Me4Si, and coupling constants were expressed in
hertz (Hz). The splitting patterns were designated as follows: s,
singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. Proton and carbon assignments were established using
COSY, HSQC, and DEPT-Q experiments. IR spectra were recorded
on a FTIR spectrometer equipped with an ATR unit. The
wavenumbers of representative absorption peaks were given in cm−1.
High-resolution mass spectra were recorded on an ESI-QTOF
apparatus.
1. Preparation of α-Triethylsilyl-α-diazoacetone. Diazoace-
tone (1).10 To a solution of 3-diazopentane-2,4-dione20 (2.47 g, 19.6
mmol, 1.0 equiv) in diethyl ether (122 mL) was added an aqueous
NaOH solution (1 M, 94 mL), and the reaction mixture was stirred at
rt for 3.5 h. H2O (50 mL) was added, and the aqueous phase was
extracted with dichloromethane (4 × 80 mL). The combined organic
layer was dried over Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure (T = 20 °C, P ≥ 250 mbar) to
afford diazoacetone as a volatile yellow liquid (1.55 g, 94% yield): IR
(film) νmax (cm−1) 3089, 2095 (νCN2), 1640 (νCO), 1330, 1180,
970, 630; 1H NMR (200 MHz, CDCl3) δ (ppm) 2.10 (s, 3H), 5.28 (br
s, 1H).
Scheme 6. TBAF-Catalyzed Aldol-Type Addition of TES-
Diazoacetophenone 19
1-Diazo-1-(triethylsilyl)propan-2-one (TES-Diazoacetone).19a To
a stirred solution of diazoacetone (1) (1 g, 11.9 mmol) in a 1:1
mixture of anhydrous Et2O/hexane (90 mL) at 0 °C were added
DIPEA (2.7 mL, 15.5 mmol, 1.3 equiv) and TESOTf (2.8 mL, 13.1
mmol, 1.1 equiv). After being stirred for 90 min at 0 °C under an
argon atmosphere, the reaction mixture was quenched by the addition
of a saturated aqueous NaHCO3 solution (100 mL). The organic layer
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was washed with saturated aqueous NH4Cl (2 × 50 mL) and brine
(100 mL), dried over Na2SO4, and filtered, and the filtrate was
concentrated under reduced pressure. The oily residue was chromato-
graphed (silica gel, cyclohexane/ethyl acetate = 99:1) to afford TES-
diazoacetone as a yellow oil (1.74 g, 74% yield): Rf = 0.65 (petroleum
ether/ethyl acetate =80/20); IR (film) νmax (cm−1) 2954, 2876, 2060
(νCN2), 1637 (νCO), 1463, 1414, 1358, 1267, 1240, 1199, 1005,
964, 721; 1H NMR (200 MHz, CDCl3) δ (ppm) 2.26 (s, 3H), 0.98 (t,
9H, J = 7.7 Hz), 0.77 (q, 6H, J = 7.7 Hz).
2. General Procedures for the Fluoride-Induced Aldol-Type
Addition of TES-Diazoacetone. Protocol P1. To a stirred solution
of TES-diazoacetone (0.5 mmol, 1 equiv), aldehyde (0.55 mmol, 1.1
equiv), and 4 Å molecular sieves (250 mg, 500 mg/mmol) in
anhydrous Et2O (4 mL) at −16 °C was slowly added TBAF (1 M/
THF, 0.25 mmol, 50 mol %). After being stirred for 120 min 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 × 10 mL), and the combined organic
layer was dried over Na2SO4 and filtered, and the filtrate was
concentrated under reduced pressure. The oily residue was purified by
column chromatography (silica gel, cyclohexane/ethyl acetate = 95:5
to 60:40) to afford the expected O-desilylated aldol.
Protocol P2. To a stirred solution of TES-diazoacetone (0.5 mmol,
1 equiv), aldehyde (0.55 mmol, 1.1 equiv), and 4 Å molecular sieves
(250 mg, 500 mg/mmol) in anhydrous Et2O (4 mL) at −16 °C was
slowly added TBAF (1 M/THF, 0.025 mmol, 5 mol %). After being
stirred for 120 min 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 × 10 mL),
and the combined organic layer was dried over Na2SO4 and filtered,
and the filtrate was concentrated under reduced pressure. The oily
residue was dissolved in anhydrous THF (5 mL/mmol), and
triethylamine trihydrofluoride complex (0.16 mL, 1.0 mmol, 2
equiv) was added dropwise. After being stirred for 16 h at room
temperature under Ar, the reaction mixture was quenched with
saturated aqueous NaHCO3 (8 mL). The aqueous layer was extracted
with diethyl ether (3 × 10 mL), and the combined organic layer was
dried over Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure. The oily residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate = 95:5 to
60:40) to afford the expected O-desilylated aldol.
TBAT Protocol. To a stirred solution of TES-diazoacetone (0.25
mmol, 1 equiv) and aldehyde (0.27 mmol, 1.1 equiv) in anhydrous
THF (2 mL) at −16 °C under argon was slowly added TBAT (0.25
mmol, 1 equiv). After being stirred for 120 min at −16 °C under Ar,
the reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (4 mL). The aqueous layer was extracted with diethyl
ether (3 × 5 mL), and the combined organic layer was dried over
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure. The oily residue was purified by column chromatography
(silica gel, cyclohexane/ethyl acetate = 95:5 to 60:40) to afford O-
desilylated aldol 2a (25.2 mg, 53% yield).
(νOH), 2922, 2086 (νCN2), 1618 (νCO), 1340, 1022, 733; 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.32−7.40 (m, 5H), 6.02 (br s, 1H), 3.72
(br s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
191.2, 138.5, 128.8, 128.5, 125.7, 74.0, 68.2, and 25.8; HRMS m/z
calcd for C10H10N2NaO2 [M + Na]+ 213,0634, found 213,0636.
3-Diazo-4-phenyl-4-(triethylsilyloxy)-butan-2-one (2b). A solu-
tion of TES-diazoacetone, benzaldehyde (0.55 mmol, 1.1 equiv), and 4
Å molecular sieves (250 mg, 500 mg/mmol) in anhydrous Et2O (4
mL) was cooled at −16 °C under Ar. TBAF (1 M/THF, 0.025 mmol,
5 mol %) was added slowly. After being stirred for 120 min −16 °C,
the reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (8 mL). The aqueous layer was extracted with diethyl
ether (3 × 10 mL), and the combined organic layer was dried over
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure. The crude mixture of aldols 2 (2a/2b = 35:65) was purified
by column chromatography (cyclohexane/ethyl acetate = 95:5),
affording aldol 2b (91 mg, 60% yield) as a yellow oil and aldol 2a
(34 mg, 36% yield) as a yellow solid. Aldol 2b: Rf = 0.82 (petroleum
ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 2956, 2079
(νCN2), 1644 (νCO), 1338, 1090, 734; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.26−7.39 (m, 5H), 5.98 (br s, 1H), 2.21 (s, 3H),
0.92 (t, 9H, J = 8.0 Hz), 0.63 (q, 6H, J = 8.0 Hz); 13C NMR (100
MHz, CDCl3) δ (ppm) 188.5, 141.6, 128.5, 127.8, 125.2, 75.4, 67.0,
25.8, 6.7, and 4.6; HRMS m/z calcd for C16H24N2NaO2Si [M + Na]+
327.1499, found 327.1498.
3-Diazo-4-hydroxy-4-(4-trifluoromethyl)phenyl)-butan-2-one
(3a). Prepared from TES-diazoacetone and 4-(trifluoromethyl)-
benzaldehyde according to general protocol P1. Aldol 3a was obtained
after column chromatography (cyclohexane/ethyl acetate = 95:5 to
60:40) as a yellow solid (112 mg, 87% yield): m p = 79 °C; Rf = 0.08
(petroleum ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 3371
1
(νOH), 2082 (νCN2), 1614 (νCO), 1320, 1110, 1015, 830, 787; H
NMR (400 MHz, CDCl3) δ (ppm) 7.64 (d, 2H, J = 8.2 Hz), 7.54 (d,
2H, J = 8.2 Hz), 6.07 (br s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 190.9, 143.2, 130.5 (q, 2JCF = 32.4 Hz), 126.1, 125.7
3
1
(q, JCF = 3.5 Hz), 123.9 (q, JCF = 272.4 Hz), 74.3, 67.0, and 25.7;
HRMS m/z calcd for C11H9F3N2NaO2 [M + Na]+ 281.0508, found
281.0513.
4-(4-Chlorophenyl)-3-diazo-4-hydroxybutan-2-one (4a). Pre-
pared from TES-diazoacetone and 4-chlorobenzaldehyde according
to general protocol P1. Aldol 4a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as a
yellow solid (103 mg, 92% yield): m p = 60−62 °C; Rf = 0.14
(petroleum ether/ethyl acetate = 80/20); IR (film) νmax (cm−1) 3379
(νOH), 2085 (νCN2), 1635 (νCO), 1265; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.36 (s, 4H), 5.99 (br s, 1H), 3.68 (br s, 1H, OH),
2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 191.0, 137.4,
134.2, 129.0, 127.2, 73.8, 67.4, and 25.8; HRMS m/z calcd for
C10H9ClN2NaO2 [M + Na]+ 247.0245, found 247.0237.
4-(2-Chlorophenyl)-3-diazo-4-hydroxybutan-2-one (5a). Pre-
pared from TES-diazoacetone and o-chlorobenzaldehyde according
to general protocol P1. Aldol 5a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as a
yellow solid (111 mg, 99% yield): m p = 89 °C; Rf = 0.23 (petroleum
ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 3369 (νOH), 2082
(νCN2), 1615 (νCO), 1025, 735, 703; 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.71 (dd, 1H, J = 7.6, 2.0 Hz), 7.33−7.39 (m, 2H), 7.28 (dd,
1H, J = 7.6, 1.8 Hz), 6.20 (br s, 1H), 2.28 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 191.3, 136.3, 131.6, 129.6, 129.4, 127.5, 127.2,
72.9, 65.8, and 25.7; HRMS m/z calcd for C10H9ClN2NaO2 [M +
Na]+ 247.0245, found 247.0236.
KF·18-Crown-6 Ether Protocol. To a stirred solution of TES-
diazoacetone (0.5 mmol, 1 equiv) and aldehyde (0.55 mmol, 1.1
equiv) in anhydrous THF (4 mL) at −16 °C under argon was slowly
added KF·18-crown-6 ether complex, prepared according to ref 26 (0.5
mmol, 1 equiv). After being stirred for 120 min at −16 °C under Ar,
the reaction mixture was quenched by the addition of saturated
aqueous NH4Cl (8 mL). The aqueous layer was extracted with diethyl
ether (3 × 10 mL), and the combined organic layer was dried over
Na2SO4 and filtered, and the filtrate was concentrated under reduced
pressure. The oily residue was purified by column chromatography
(silica gel, cyclohexane/ethyl acetate = 95:5 to 60:40) to afford O-
desilylated aldol 2a (80 mg, 84% yield).
3-Diazo-4-hydroxy-4-(4-methoxyphenyl)-butan-2-one (7a). Pre-
pared from TES-diazoacetone and 4-methoxybenzaldehyde according
to general protocol P2. Aldol 7a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as a
yellow solid (90 mg, 82% yield): m p = 97−100 °C; Rf = 0.07
(petroleum ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 3414
(νOH), 2086 (νCN2), 1613 (νCO), 1370; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.33 (d, 2H, J = 8.6 Hz), 6.91 (d, 2H, J = 8.6 Hz),
5.96 (br s, 1H), 3.81 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz,
3-Diazo-4-hydroxy-4-phenyl-butan-2-one (2a).27b Prepared from
TES-diazoacetone and benzaldehyde according to the general protocol
P1. The O-desilylated aldol 2a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as a
yellow solid (92 mg, 97% yield): m p = 69−72 °C; Rf = 0.14
(petroleum ether/ethyl acetate = 80/20); IR (film) νmax (cm−1) 3312
F
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The Journal of Organic Chemistry
Article
CDCl3) δ (ppm) 191.3, 159.6, 130.7, 127.1, 114.1, 74.0, 67.8, 55.3,
and 25.8; HRMS m/z calcd for C11H12N2NaO3 [M + Na]+ 243.0740,
found 243.0739.
75.0, 73.4, 58.0, 31.0, 28.1, 25.7, 22.1, 18.5, and 13.9; HRMS m/z calcd
for C11H16N2NaO2 [M + Na]+ 231.1104, found 231.1106.
3-Diazo-4-hydroxy-6,10-dimethylundec-9-en-2-one (14a). Pre-
pared from TES-diazoacetone and citronellal according to general
protocol P1. After column chromatography (cyclohexane/ethyl acetate
= 95:5 to 60:40), aldol 14a was obtained as a mixture of
diastereosisomers, 14ad1 and 14ad2, as a yellow oil (101 mg, 85%
yield): Rf = 0.08 (petroleum ether/ethyl acetate = 80:20); IR (film)
νmax (cm−1) 3398 (νOH), 2962, 2915, 2082 (νCN2), 1614 (νCO),
3-Diazo-4-(furan-2-yl)-4-hydroxybutan-2-one (8a). Prepared
from TES-diazoacetone and furfural according to general protocol
P2. Aldol 8a was obtained after column chromatography (cyclo-
hexane/ethyl acetate = 95:5 to 60:40) as a yellow oil (87 mg, 97%
yield): Rf = 0.15 (petroleum ether/ethyl acetate = 80:20); IR (film)
νmax (cm−1) 3347 (νOH), 2085 (νCN2), 1614 (νCO), 1336, 1005,
737; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.40 (d, 1H, J = 1.2 Hz),
6.36−6.40 (m, 2H), 5.93 (br s, 1H), 2.28 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 190.6, 151.8, 142.8, 110.4, 107.6, 72.5, 62.5,
and 25.6; HRMS m/z calcd for C8H8N2NaO3 [M + Na]+ 203.0427,
found 203.0421.
1
1371, 1292, 617; H NMR (400 MHz, CDCl3) δ (ppm) 5.10−5.06
(m, 1Hd1+d2), 4.93−4.87 (m, 1Hd1+d2), 2.88 (br s, 1H, OHd1+d2), 2.26
(s, 3Hd1), 2.25 (s, 3Hd2), 2.08−1.91 (m, 2Hd1+d2), 1.68 (s, 3Hd1+d2),
1.77−1.68 (m, 1Hd1+d2), 1.60 (s, 3Hd1+d2), 1.58−1.52 (m, 1Hd1+d2),
1.45−1.15 (m, 3Hd1+d2), 0.95 (d, 3Hd1, J = 6.3 Hz), 0.94 (d, 3Hd2, J =
6.3 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 191.6, 191.4, 131.5,
131.4, 124.5, 124.4, 72.5, 72.1, 64.2, 63.7, 40.8, 40.7, 37.4, 36.7, 29.2,
28.8, 25.8, 25.7, 25.4, 25.3, 19.9, 18.9, 17.7, and 17.6; HRMS m/z calcd
for C13H22N2NaO2 [M + Na]+ 261.1573, found 261.1572.
3-Diazo-4-hydroxy-4-(thiophen-2-yl)-butan-2-one (9a). Prepared
from TES-diazoacetone and 2-thiophenecarboxaldehyde according to
general protocol P2. Aldol 9a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as an
orange oil (81 mg, 83% yield): Rf = 0.13 (petroleum ether/ethyl
acetate = 80:20); IR (film) νmax (cm−1) 3343 (νOH), 2081 (νCN2),
3-Diazo-(E)-4-hydroxy-6-phenylhex-5-en-2-one (15a).5c Prepared
from TES-diazoacetone and (E)-cinnamaldehyde according to general
protocol P2. Aldol 15a was obtained after column chromatography
(cyclohexane/ethyl acetate = 95:5 to 60:40) as an orange solid (96 mg,
89% yield): m p = 74 °C; Rf = 0.15 (petroleum ether/ethyl acetate =
80/20); IR (film) νmax (cm−1) 3377 (νOH), 2087 (νCN2), 1631
1
1607 (νCO), 1335, 1285, 1014, 945, 853, 780; H NMR (400 MHz,
CDCl3) δ (ppm) 7.29 (dd, 1H, J = 5.0, 1.2 Hz), 7.00−7.05 (m, 2H),
6.21 (br s, 1H), 3.69 (br s, 1H, OH), 2.28 (s, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) 190.7, 142.8, 127.1, 125.4, 124.4, 74.4, 64.9,
and 25.8; HRMS m/z calcd for C8H8N2NaO2S [M + Na]+ 219.0199,
found 219.0201.
1
(νCO), 1369; H NMR (400 MHz, CDCl3) δ (ppm) 7.24−7.40 (m,
5H), 6.80 (dd, 1H, J = 16.0, 1.2 Hz), 6.23 (dd, 1H, J = 16.0, 5.5 Hz),
5.54 (d, 1H, J = 5.5 Hz), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 191.0, 135.9, 132.5, 128.7, 128.3, 126.7, 125.4, 72.2, 66.5, and
25.8; HRMS m/z calcd for C12H12N2NaO2 [M + Na]+ 239.0791,
found 239.0781.
3-Diazo-4-hydroxy-5,5-dimethylhexan-2-one (10a). Prepared
from TES-diazoacetone and pivalaldehyde according to general
protocol P1. Aldol 10a was obtained after column chromatography
(cyclohexane/ethyl acetate = 95:5 to 60:40) as a yellow solid (79 mg,
93% yield): m p = 86.5 °C; Rf = 0.21 (petroleum ether/ethyl acetate =
80:20); IR (film) νmax (cm−1) 3406 (νOH), 2086 (ν CN2), 1627
(νCO), 1266, 739; 1H NMR (400 MHz, CDCl3) δ (ppm) 4.36 (br s,
1H), 3.04 (br s, 1H, OH), 2.26 (s, 3H), 0.97 (s, 9H); 13C NMR (100
MHz, CDCl3) δ (ppm) 191.3, 73.4, 69.8, 38.4, 25.7, and 25.6; HRMS
m/z calcd for C8H14N2NaO2 [M + Na]+ 193.0947, found 193.0947.
4-Cyclohexyl-3-diazo-4-hydroxybutan-2-one (11a). Prepared
from TES-diazoacetone and cyclohexanecarboxaldehyde according to
general protocol P1. Aldol 11a was obtained after column
chromatography (cyclohexane/ethyl acetate = 95:5 to 60:40) as a
yellow solid (90 mg, 92% yield): m p = 38 °C; Rf = 0.24 (petroleum
ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 3397 (νOH), 2927,
3-Diazo-(E)-4-hydroxyhept-5-en-2-one (16a). Prepared from TES-
diazoacetone and (E)-crotonaldehyde according to general protocol
P2. Aldol 16a was obtained after column chromatography (cyclo-
hexane/ethyl acetate = 95:5 to 60:40) as an orange oil (34 mg, 44%
yield): Rf = 0.11 (petroleum ether/ethyl acetate = 80:20); IR (film)
νmax (cm−1) 3406 (νOH), 2090 (νCN2), 1621 (νCO), 1371; 1H NMR
(400 MHz, CDCl3) δ (ppm) 5.91 (m, 1H), 5.53 (dd, 1H, J = 15.5, 5.2
Hz), 5.30 (d, 1H, J = 5.2 Hz), 3.12 (br s, 1H, OH), 2.26 (s, 3H), 1.75
(d, 3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 191.3,
129.8, 127.2, 72.0, 66.6, 25.7, and 17.7; HRMS m/z calcd for
C7H10N2NaO2 [M + Na]+ 177.0634, found 177.0635.
3-Diazo-4,6-dihydroxy-5,5-dimethylhexan-2-one (18c). Prepared
from TES-diazoacetone and 3-(tert-butyldiphenylsilyloxy)-2,2-dime-
thylpropanal according to general protocol P2. Aldol 18c was obtained
after column chromatography (cyclohexane/ethyl acetate = 95:5 to
50:50) as a yellow oil (70 mg, 75% yield): Rf = 0.04 (petroleum ether/
ethyl acetate = 80:20); IR (film) νmax (cm−1) 3362 (νOH), 2963, 2876,
1
2082 (νCN2), 1620 (νCO), 1371; H NMR (400 MHz, CDCl3) δ
(ppm) 4.40 (d, 1H, J = 6.1 Hz), 2.79 (br s, 1H, OH), 2.25 (s, 3H),
2.01 (d, 1H, J = 12.6 Hz), 1.52−1.80 (m, 5H), 1.00−1.29 (m, 5H);
13C NMR (100 MHz, CDCl3) δ (ppm) 191.5, 71.0, 70.8, 42.0, 29.3,
29.1, 26.4, 26.0, 25.9, and 25.8; HRMS m/z calcd for C10H16N2NaO2
[M + Na]+ 219.1104, found 219.1110.
1
2085 (νCN2), 1607 (νCO), 1367, 1077, 1037, 730, 624; H NMR
(400 MHz, CDCl3) δ (ppm) 4.67 (br s, 1H), 3.48 (d, 1H, J = 11.4
Hz), 3.39 (d, 1H, J = 11.4 Hz), 2.29 (s, 3H), 1.06 (s, 3H), 0.86 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 191.7, 72.1, 71.0, 70.0,
41.8, 25.6, 20.2, and 20.1; HRMS m/z calcd for C8H15N2O3 [M + H]+
187.1083, found 187.1075.
3-Diazo-4-hydroxy-6-methylheptan-2-one (12a). Prepared from
TES-diazoacetone and isovaleraldehyde according to general protocol
P1. Aldol 12a was obtained after column chromatography (cyclo-
hexane/ethyl acetate = 95:5 to 60:40) as a yellow oil (85 mg, 100%
yield): Rf = 0.14 (petroleum ether/ethyl acetate = 80:20); IR (film)
νmax (cm−1) 3417 (νOH), 3054, 2082 (νCN2), 1633 (νCO), 1265,
739; 1H NMR (400 MHz, CDCl3) δ (ppm) 4.88 (dd, 1H, J = 8.2, 5.7
Hz), 2.88 (br s, 1H, OH), 2.26 (s, 3H), 1.80 (m, 1H), 1.63−1.68 (m,
1H), 1.34−1.43 (m, 1H), 0.95 (d, 6H, J = 6.6 Hz); 13C NMR (100
MHz, CDCl3) δ (ppm) 191.6, 72.1, 64.2, 42.3, 25.8, 24.6, 23.0, and
22.0; HRMS m/z calcd for C8H14N2NaO2 [M + Na]+ 193.0947, found
193.0935.
2-Diazo-1,3-diphenyl-3-(triethylsilyloxy)propan-1-one (20b). A
solution of TES-diazoacetophenone 19, benzaldehyde (0.47 mmol,
1.1 equiv), and 4 Å molecular sieves (215 mg, 500 mg/mmol) in
anhydrous Et2O (4 mL) was cooled at −16 °C under Ar. TBAF (1 M/
THF, 0.021 mmol, 5 mol %) was added slowly. After being stirred for
120 min at −16 °C, the reaction mixture was quenched by the addition
of saturated aqueous NH4Cl (8 mL). The aqueous layer was extracted
with diethyl ether (3 × 10 mL), and the combined organic layer was
dried over Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure. Aldol 20b was obtained after column chromatog-
raphy (cyclohexane/ethyl acetate = 95:5) as an orange oil (105 mg,
67% yield): Rf = 0.73 (petroleum ether/ethyl acetate = 80:20); IR
(film) νmax (cm−1) 2953, 2875, 2079 (νCN2), 1621 (νCO), 1342,
3-Diazo-4-hydroxyundec-5-yn-2-one (13a). Prepared from TES-
diazoacetone and 2-octynal according to general protocol P1. Aldol
13a was obtained after column chromatography (cyclohexane/ethyl
acetate = 95:5 to 60:40) as an orange oil (98 mg, 94% yield): Rf = 0.23
(petroleum ether/ethyl acetate = 80:20); IR (film) νmax (cm−1) 3368
1
(νOH), 2090 (νCN2), 1636 (νCO), 1339, 733; H NMR (400 MHz,
1
CDCl3) δ (ppm) 5.64 (br s, 1H), 3.77 (br s, 1H, OH), 2.27 (s, 3H),
2.22−2.25 (m, 2H), 1.48−1.55 (m, 2H), 1.27−1.40 (m, 4H), 0.90 (t,
3H, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ (ppm) 190.2, 88.9,
1237, 1060, 1002, 840, 729; H NMR (400 MHz, CDCl3) δ (ppm)
7.58−7.30 (m, 10H), 6.21 (s, 1H), 0.95 (m, 9H), 0.68 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 186.8, 141.5, 131.6, 128.7, 128.5,
G
DOI: 10.1021/acs.joc.5b01554
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The Journal of Organic Chemistry
Article
128.5, 128.2, 127.9, 127.6, 127.1, 125.4, 74.9, 67.9, 6.7, and 4.6; HRMS
Wang, J.; Stewart, J. E.; Bentley, W. E.; Sintim, H. O. J. Am. Chem. Soc.
2010, 132, 11141−11150.
(10) Lancou, A.; Haroun, H.; Kundu, U. K.; Legros, F.;
m/z calcd for C21H26N2NaO2Si [M + Na]+ 389.1656, found 389.1652.
́
Zimmermann, N.; Mathe-Allainmat, M.; Lebreton, J.; Dujardin, G.;
ASSOCIATED CONTENT
■
Gaulon-Nourry, C.; Gosselin, P. Tetrahedron 2012, 68, 9652−9657.
(11) (a) Marsden, S. P.; Steer, J. T.; Orlek, B. S. Tetrahedron 2009,
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01554.
65, 5503−5512. (b) Bruckmann, R.; Schneider, K.; Maas, G.
̈
Tetrahedron 1989, 45, 5517−5530.
1H and 13C NMR spectra for all aldols (PDF)
(12) Furin, G. G. Tetrahedron 1988, 44, 2675−2749.
(13) (a) Noyori, R.; Yokoyama, K.; Sakata, J.; Kuwajima, I.;
Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99, 1265−1267.
(b) Nakamura, E.; Shimizu, M.; Kuwajima, I.; Sakata, J.; Yokoyama, K.;
Noyori, R. J. Org. Chem. 1983, 48, 932−945. (c) Kuwajima, I.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: catherine.gaulon@univ-lemans.fr.
Notes
The authors declare no competing financial interest.
(14) Bluet, G.; Campagne, J. M. J. Org. Chem. 2001, 66, 4293−4298.
(15) Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J.
Org. Chem. 1999, 64, 4233−4237.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Office Mediterranee
́
n de la
(16) Zhang, W.-X.; Ding, C.-H.; Luo, Z.-B.; Hou, X.-L.; Dai, L.-X.
Tetrahedron Lett. 2006, 47, 8391−8393.
Jeunesse (OMJ) for I.A.’s PhD funding, and La Ligue contre le
Cancer for financial support (CSIRGO 2013). We are grateful
to Dr. Dominique Cahard (COBRA/UMR CNRS 6014,
(17) Chintareddy, V. R.; Wadhwa, K.; Verkade, J. G. J. Org. Chem.
2011, 76, 4482−4488.
Universite
́
de Rouen) for fruitful discussions. We also thank
(18) Kanemasa, S.; Araki, T.; Kanai, T.; Wada, E. Tetrahedron Lett.
1999, 40, 5059−5062.
Frederic Legros for the synthesis of diazoacetone and technical
́
́
support, Dr. Anne-Caroline Chany for the synthesis of aldehyde
(19) (a) Brueckmann, R.; Maas, G. Chem. Ber. 1987, 120, 635−641.
(b) Marsden, S. P.; Ducept, P. C. Beilstein J. Org. Chem. 2005, 1, 1−6.
(c) Bucher, S. M.; Brueckmann, R.; Maas, G. Eur. J. Org. Chem. 2008,
4426−4433.
17 and fruitful discussions, Bohdan Biletskyi for the synthesis of
́
citronellal, Amelie Durand and Corentin Jacquemmoz for the
NMR analyses, and Patricia Gangnery and Emmanuelle Mebold
for the HRMS analyses.
(20) Presset, M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. Synthesis
2011, 2549−2552.
(21) TES-diazoacetone should not be contaminated with silylated
residues in order to get optimal and reproducible yields in the
following fluoride-induced aldol-type addition study.
(22) TMS-diazoacetone is known to be highly sensitive to
protodesilylation and could not be isolated or handled; see ref 19c.
(23) Addition of activated powdered 4 Å molecular sieves to the
reaction medium (250 mg/0.5 mmol of substrate) allowed
reproducible yields of product to be obtained, whatever the quality
of the commercial TBAF solution employed.
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H
DOI: 10.1021/acs.joc.5b01554
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(32) Accordingly, some degradation was observed when TBAF was
added to a mixture of TES-diazoacetone and p-NO2-benzaldehyde,
leading to poor and irreproducible yields.
(33) Raghavan, S.; Kumar, V. V. Org. Biomol. Chem. 2013, 11, 2847−
2858.
(34) Formation of aldol 2a was not observed when O-silylated aldol
2b was stirred during several hours at room temperature in a biphasic
Et2O/saturated aqueous NH4Cl medium.
(35) O-TES-aldol 2b remained unchanged when stirred in Et2O at
−16 °C or at rt during several hours. Besides, the addition of 5 mol%
of TBAF to a solution of aldol 2b in Et2O, followed by 2 h stirring at
−16 °C, provided the formation of aldol 2a with 5% conversion.
(36) Kitamura, M.; Tashiro, N.; Okauchi, T. Synlett 2009, 2943−
2944.
I
DOI: 10.1021/acs.joc.5b01554
J. Org. Chem. XXXX, XXX, XXX−XXX