TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and Contribution to the Synthesis

Article abstract of DOI:10.1021/acs.joc.0c02725

Aldol addition of α-triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone), promoted by excess lithium diisopropylamide (LDA), was developed and applied to the synthesis of original C-TIPS diazoaldols, C-TIPS diazoketols, and a related Mannich-type product. An unprecedented mechanistic pathway has been proposed, involving a lithiated triazene intermediate resulting from the nucleophilic addition of LDA on the diazo moiety, supported by experimental results and DFT calculations.

Full text of DOI:10.1021/acs.joc.0c02725

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Article
TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and
Contribution to the Synthesis
̂
Sigrid Gavelle, Imen Abid, Bohdan Biletskyi, Sylvain Henrion, Annie Hémon-Ribaud, Jérome Lhoste,
Arnaud Martel, Gilles Dujardin, and Catherine Gaulon-Nourry*
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ABSTRACT: Aldol addition of α-triisopropylsilyl-α-diazoacetone
(TIPS-diazoacetone), promoted by excess lithium diisopropylamide
(LDA), was developed and applied to the synthesis of original C-TIPS
diazoaldols, C-TIPS diazoketols, and a related Mannich-type product.
An unprecedented mechanistic pathway has been proposed, involving a
lithiated triazene intermediate resulting from the nucleophilic addition
of LDA on the diazo moiety, supported by experimental results and
DFT calculations.
required to achieve lithium diisopropylamide (LDA)-induced
“methyl-side” aldol addition in a first step so that the stable
diazoaldol intermediate resulting from C-desilylation could
cleanly undergo LDA-induced “diazo-side” addition in a
second step. This methodology was successfully applied to
hindered and acid-sensitive aldehydes during the function-
oriented synthesis of peloruside A analogues.6
In the diazo strategy implemented on TES-diazoacetone E
(Scheme 1c), the triethylsilyl-protecting group on the diazo
carbon was sufficiently labile to be partially removed during
hydrolysis of the “methyl-side” aldol addition, and simple
methanolysis efficiently completed the deprotection before
“diazo-side” addition. Beyond this role of temporary
protection, trialkylsilyl groups attached to the diazo carbon
of diazocarbonyl scaffolds have proved useful to generate
original silyl-substituted scaffolds upon the transformation of
the diazo function via Wolff rearrangement7 or upon silicium
1,3-(C → O) migration, followed by either 1,3-dipolar
cycloadditions8 or diazo loss, inducing C−H insertion9 or
rearrangement to siloxyalkyne.10 On the other hand,
trialkylsilyl groups of TES-diazoacetone E and α-triisopropyl-
silyl-α-diazoacetone (TIPS-diazoacetone) 1 (Scheme 2)
behaved as efficient activating groups to allow mild TBAF-
triggered aldol additions.11
INTRODUCTION
■
The synthetic transformations that may be conceived on α-
diazocarbonyl compounds constitute a vast area of exploration
for organic chemists. Indeed, decomposition of the CN2
function into carbene is a gateway to chemical diversity via
numerous processes such as insertions, cyclopropanations,
Wolff, and sigmatropic rearrangements.1 α-Diazocarbonyl
compounds are thus high-value intermediates in organic
synthesis, and numerous efforts have been devoted to studying
how the generated carbene can evolve in order to create
original scaffolds.2 Conversely, the design of methods to
elaborate functionalized α-diazocarbonyl compounds while
keeping the diazo functionality intact has been less explored,
although constituting an important source of diversity
downstream. In this field, a widespread strategy to access
diversely substituted diazocarbonyl compounds B is the
electrophilic substitution at the diazo carbon atom of
(diazomethyl) carbonyl precursors A with various electro-
philes1,3 (Scheme 1a). The intrinsic nucleophilicity of the
diazotated carbon, which can be enhanced by deprotonation
with a large array of bases, accounts for the efficiency of this
“diazo-side” approach. A “methyl-side” carbon chain extension
has also been studied, however, to a lesser extent, mainly on
the methyl ketone moiety of diazodicarbonyl precursors C
(Scheme 1b). Aldol-type and Mannich-type additions,
involving boron,4a lithium,4b titanium enolates,4c−f or Lewis
acid-catalyzed Mukaiyama procedures from silyl enol
ethers,4g,h proved successful to provide scaffolds D. Besides,
the use of α-triethylsilyl-α-diazoacetone (TES-diazoacetone) E
was developed in our team as a three-carbon building block
allowing convergent access to functionalized carbon chains F5
(Scheme 1c). Protection of the more reactive diazo carbon was
Received: November 13, 2020
Published: March 16, 2021
https://doi.org/10.1021/acs.joc.0c02725
© 2021 American Chemical Society
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Scheme 1. Elaboration of Functionalized Diazocarbonyl Compounds by Aldol and Mannich-Type Methodologies
TIPS-diazoacetone 1 was easily prepared on a multigram scale
in three steps11a,b via a Regitz diazo transfer12 from 4-
acetamidobenzenesulfonyl azide (p-ABSA)13,14 as a safer
surrogate to TsN3 (Scheme 3). Pure TIPS-diazoacetone 1
could be stored in the freezer for several months without
noticeable decomposition.15
Scheme 2. This Work: “Methyl-Side” Aldol Addition on
TIPS-Diazoacetone 1
“Methyl-Side” Aldol Addition of TIPS-Diazoacetone.
While it has been well established that diazodicarbonyl
structures like C (Scheme 1b) are sufficiently stabilized to
generate diverse metal enolates,4 less stabilized simple
diazoacetyl substrates, although synthetically useful, have
been left aside. The only examples of “methyl-side” aldol
additions from α-alkyl-α-diazoacetones like G were reported
by Taber’s team (Scheme 4a), constituting a key step in their
elegant strategy dedicated to the synthesis of isoprostanes.16
Potassium enolate of the methylketone was generated using
KHMDS, and TESCl was necessary to activate the electro-
phile. Our group extended this methodology to the aldol
addition of α-triethylsilyl-α-diazoacetone (TES-diazoacetone,
E) (Scheme 4b), from which the lithium enolate was efficiently
formed using excess LDA and reacted with a range of
aldehydes.5
Based on these results, aldol addition between TIPS-
diazoacetone 1 and benzaldehyde was first investigated using
LDA as the base. The influence of the temperature and the
amount of LDA was first studied (Table 1).
The optimal conditions set up previously for the aldol
addition of TES-diazoacetone E consisted of reacting it with 2
equiv of LDA at −50 °C (T1), followed by the addition of the
electrophile at −100 °C (T2) (Scheme 4). These conditions,
applied to TIPS-diazoacetone 1, led to the expected diazoaldol
To date, only simple α-trialkylsilyl α-diazocarbonyl sub-
strates have been involved in the above-mentioned processes,
prepared by late C-silylation of the corresponding (diazo-
methyl) carbonyl scaffold using silyltrifate/iPr2NEt, just before
the diazo transformation.9,7d,e A methodology able to widen
the scope of the functional diversity that can be achieved on
these α-diazo-α-trialkylsilyl scaffolds would be valuable in this
field of research. For such purpose, the “methyl-side” aldol
addition of TIPS-diazoacetone 1 will be investigated here
(Scheme 2). Mechanistic aspects of this unexplored reaction,
providing stable original C-TIPS diazoaldols, will be unveiled
and discussed.
RESULTS AND DISCUSSION
■
TIPS-Diazoacetone Synthesis. The TIPS-protecting
group was selected in this work in order to avoid the
uncontrolled deprotection previously observed with TES-
diazoacetone E during “methyl-side” aldol addition,5 and
considering the propensity for hydrolysis of TBS-diazoace-
tone,9 which was observed by our group in preliminary assays.
Scheme 3. Preparation of TIPS-Diazoacetone 1
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Scheme 4. Methyl-Side Aldol Addition on α-Alkyl-α-diazoacetones and α-Triethylsilyl-α-diazoacetone
Table 1. Aldol Addition between TIPS-Diazoacetone 1 and Benzaldehyde using LDA
a
entry
LDA (x equiv)
T1 (°C)
T2 (°C)
isolated yield (%) 3a
b
1
2
3
4
5
6
7
8
2
2
2
2
−50
−25
−25
−25
−25
−25
−25
−25
−25
−100
−100
−78
−78
−78
−25
−100
−78
−78
−78
−78
−78
64
85
83
c
d
71−86
c
2.2
2.2
1.75
1.5
0.95−1.25
1 + HMPA (1 equiv)
1 + HMPA (2 equiv)
1 + LiBr (1 equiv)
84
70
73
77
c
b
c
c
b e
,
9
0−85
0−31
c
b
10
11
12
−25
−25
−25
c
b
0
c
b
0
a
b
Reactions performed on a 0.5−1 mmol scale. Conversion, based on the integration of the CH3 signal of 1 and the CH2 signals of 3a on the 1H
NMR spectrum of the crude product. T1 was maintained for 1 h. Range of yields obtained from 8 experiments. Highly unreproducible results,
c
d
e
based on 10 experiments.
3a as a unique product, albeit with a moderate 64% conversion
(Table 1, entry 1). When T1 was increased to −25 °C, the
nearly complete conversion was observed, and the aldol
addition product 3a was isolated in a high 85% yield (Table 1,
entry 2). Similar yields were obtained when T2 was increased
from −100 °C to −78 °C (Table 1, entry 3) or when the
contact time with LDA at −25 °C (T1) was extended from 30
min to 1 h (Table 1, entry 4). Performing the reaction with 2.2
equiv of LDA did not influence the yield (Table 1, entry 5).
However, increasing T2 from −78 °C to −25 °C was
detrimental to the reaction, resulting in a moderate 70%
conversion (Table 1, entry 6). An additional assay, carried out
under Barbier conditions at −78 °C, using 2 equiv of LDA, led
to a disappointing 23% yield. Attempts were then carried out
to decrease the amount of LDA used to generate the enolate.
While a small decrease of the isolated yield was observed with
1.5 or 1.75 equiv of LDA (Table 1, entries 7 and 8),
surprisingly, unreproducible results were observed when the
amount of LDA used was in the range of 0.95−1.25 equiv
(Table 1, entry 9). Inconsistent conversions from 0% to 85%
were typically obtained with a given set of conditions. When
LiBr17 or HMPA,18 known to modify the aggregation state of
LDA and enolates complexes, were added to the THF solution
of LDA, no or low conversion was observed (Table 1, entries
10−12). Eventually, the use of 2 equiv of LDA and proper
control of the temperature after the addition of the electrophile
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Table 2. Influence of the Nature of the Base on the Aldol Addition of TIPS-Diazoacetone 1
a
entry
base (x equiv)
T1 (°C)
t1 (min)
additive (x equiv)
t2 (min)
products formed
3a
3a
3a
3a
isolated yield (%)
b
1
2
3
4
5
6
7
8
LTMP (1)
LTMP (2)
−25
−25
−25
−25
−25
−78
−78
−78
60
60
60
60
60
40
40
20
60
60
60
60
60
60
60
15
0
b
49
c
LiHMDS (1)
LiHMDS (2)
KHMDS (1)
KHMDS (1.1)
KHMDS (1.1)
37−81
d
76−83
e
3a/4a/1 = 6:55:39
f
g
e
3a/4a = 75:25
3a (38), 4a (12)
g
h
LiBr (1.3)
TESCl (1.2)
3a
58−79
i
j
KHMDS (1.05)
complex mixture
3a (22), 5a (36)
a
b
KHMDS and LiHMDS were used as a 0.5 M solution in toluene. Solvent: THF for entries 1−7; toluene for entry 8. Conversion based on the 1H
c
d
e
NMR of the crude product. Range of yields obtained from 4 experiments. Range of yields obtained from 3 experiments. Ratio based on the 1H
f
g
h
i
NMR spectrum of the crude product. Not purified. 0.9 equiv of benzaldehyde 2a was used. Based on 4 assays. 1.2 equiv of benzaldehyde 2a was
used. Diazoaldols 3a and 5a were formed, along with other silylated products.
j
Figure 1. Byproducts formed during the aldol addition between TIPS-diazoacetone 1 and benzaldehyde 2a.
(−78 °C) constituted the best conditions to ensure
reproducible and high yields of diazoaldol 3a.19 The stability
of this new C-TIPS diazoaldol is worth noticing.20 No
desilylated aldol was detected on the proton NMR spectrum
of the crude product, and purification by chromatography
using Et3N-neutralized silica gel induced the formation of a few
percent of the corresponding desilylated aldol.21 The structure
of diazoaldol 3a was confirmed by X-ray diffraction analysis.22
The unreproducible results obtained when the aldolisation
was conducted with 0.95−1.25 equiv of LDA suggested that a
pathway, competitive to deprotonation, could operate with this
lithium amide. In an attempt to rationalize these intriguing
results, the influence of the nature of the amide anion was
investigated (Table 2, entries 1−4).
At first, LDA was replaced by other lithium amides, more
hindered like lithium tetramethylpiperidide (LTMP), or less
basic like lithium bis(trimethylsilyl)amide (LiHMDS). With
LTMP, under the same reaction conditions as LDA, the same
trend was observed: no conversion was detected with 1 equiv
of LTMP while the reaction proceeded, although with a lower
conversion than with LDA, using 2 equiv (Table 2, entries 1
and 2). Contrary to LDA and LTMP, the use of 1 equiv of
LiHMDS consistently led to the expected aldol, although
fluctuating yields were obtained, from modest 37% to high
81% yield (Table 2, entry 3). On the other hand, good and
homogeneous yields, similar to those obtained with 2 equiv of
LDA, were achieved with 2 equiv of LiHMDS (Table 2, entry
4).
In order to assess the influence of the countercation, the
aldolisation of TIPS-diazoacetone 1 was next carried out with
potassium bis(trimethylsilyl)amide (KHMDS) (Table 2,
entries 5−8). Under the same conditions of temperature as
with LiHMDS, the use of a stoichiometric amount of KHMDS
led mainly to the formation of the bis-aldol 4a (Table 2, entry
5), the structure of which was confirmed by X-ray diffraction22
(Figure 1).
Decreasing the temperature of the enolate formation from
−25 °C to −78 °C favored the formation of the expected
diazoaldol 3a over the unwanted bis-aldol 4a but led to
diazoaldol 3a in a low 38% yield (Table 2, entry 6). The only
examples of aldol addition of diazoketones, described by
Taber’s team (Scheme 4a),16 systematically involved the
formation of the potassium enolate with KHMDS associated
with the activation of the aldehyde by adding either LiBr16a or
TESCl.16b Correlating these conditions and our previous
observations, it made clear that activation of the aldehyde was
necessary when using KHMDS, as a result of its lower pKa
compared with LDA, and its softer K+ countercation compared
to Li+.23 Thus, in order to prevent the double aldol addition to
proceed and to shift the equilibrium of the aldol addition
reaction, a mixture of benzaldehyde 2a and LiBr in THF was
added to the reaction mixture of TIPS-diazoacetone 1 and
KHMDS (1.1 equiv), following Taber’s procedure16a (Table 2,
entry 7). Indeed, these conditions inhibited the formation of
the bis-aldol 4a, and diazoaldol 3a was obtained in
homogeneous and reproducible yields (58−79%). In contrast,
when replacing LiBr by TESCl, as recommended by Taber’s
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Scheme 5. Proposed Mechanism for the LDA-Induced Aldol Addition of TIPS-Diazoacetone 1
team in order to overcome the lack of reproducibility noticed
with the former conditions,16b the expected diazoaldol 3a and
TES-protected diazoaldol 5a (Figure 1) were isolated in
moderate yields from a complex mixture (Table 2, entry 8).
The above study highlighted the influence of the nature of
the base on the outcome of the aldol addition between TIPS-
diazoacetone 1 and benzaldehyde 2a. A stoichiometric amount
of bis(trimethylsilyl) amides allowed the reaction to proceed.
With KHMDS, acceptable and reproducible yields were
obtained as soon as LiBr was added to the aldehyde, whereas
with LiHMDS, the reaction consistently occurred, albeit with
fluctuating isolated yields. In contrast, dialkylamides like LDA
and LTMP share the same trend: the stoichiometric amount of
base led to no conversion at all or highly unreproducible
conversions. However, high and reproducible yields of
diazoaldol 3a were achieved by using 2 equiv of LDA,
constituting the optimal aldol addition conditions for our
system.
Mechanistic Proposal. From the above results, two
hypotheses emerged, which could explain the highly
unreproducible results obtained with LDA. First, as LDA is
much more basic than bis(trimethylsilyl)amides, it could be
envisioned that LDA is able to competitively deprotonate
another position on the substrate. However, TIPS-diazoace-
tone 1 does not bear another acidic hydrogen, which precluded
this hypothesis. A second hypothesis was that LDA could,
competitively to its role of the base toward the methyl ketone,
play the role of a nucleophile toward the electrophilic terminal
nitrogen of the diazo function. Indeed, the dual mechanism
(deprotonation/nucleophilic addition) induced by LDA in
THF at a low temperature has been highlighted on α,β-
ethylenic esters and thoroughly investigated.24 Moreover, the
addition of PPh3,25 Ge[N(SiMe3)2]2,26 or a carbon nucleo-
phile27 on the diazo function of diazodicarbonyl moieties as
well as the addition of Et3N on the diazo function of
diazomalodinitrile28 have been well-documented. In the light
of these examples, an original mechanistic rationale was
proposed to explain the outcome of the aldolisation between
TIPS-diazoacetone 1 and benzaldehyde 2a in the presence of
LDA (Scheme 5).
In this mechanism, the reaction between LDA and TIPS-
diazoacetone 1 could follow two competitive pathways,
depending on whether LDA first acts as a base to deprotonate
the substrate (pathway 1, Scheme 5) or acts as a nucleophile,
which adds to the electrophilic diazo function (pathway 2,
Scheme 5). Deprotonation by LDA would generate, through
pathway 1, the expected lithium enolate 6, leading to aldol 3a
after aldol addition and hydrolysis. In a competitive way, TIPS-
diazoacetone 1, for which the diazonium enolate resonance
structure could be favored by complexation with the lithium
cation, could undergo, through pathway 2, the nucleophilic
addition of LDA. A lithiated triazene could thus be generated,
stabilized through the six-membered chelate 7 or through the
five-membered chelate 7′. Though inert toward benzaldehyde
2a, the lithiated triazene could undergo deprotonation by a
second molecule of LDA to produce lithiated carbanion 8,
stabilized by the silicon atom in the α-position. Lithiated
carbanion 8 would undergo aldol addition with benzaldehyde
2a to afford the triazene aldolate species 9. The latter should
decompose under NH4Cl hydrolysis to yield the expected aldol
3a and diisopropylamine. The proposed mechanism, involving
two competitive pathways and most probably reversible steps,
may explain the dramatic lack of reproducibility of the aldol
addition conducted with 1 equiv of LDA. The outcome of the
reaction (nucleophilic addition versus enolization) could
indeed be greatly affected by aggregation/deaggregation rates
of LDA in the medium, highly dependent on the salts
concentration like LiCl potentially present.24b The absence of
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Table 3. Aldol Addition of TIPS-Diazoacetone with t-BuLi
entry
t-BuLi (x equiv)
reaction time t (h)
isolated yield (%) 3a
isolated yield (%) 10
isolated yield (%) 11
1
2
3
1
2
2
1
1
5
13
a
a
42
46
23
13
23
53
a
Not observed.
Figure 2. ORTEP diagram of α-keto hydrazone 10 and structures of the postulated intermediates 12 and 13.
conversion surprisingly observed in several experiments
conducted with 1 equiv of LDA could be rationalized by the
quantitative formation of lithiated triazene 7 or 7′, inert to
benzaldehyde. On the contrary, the use of 2 equiv of LDA
would allow the aldol addition to proceed in a reproducible
way, via the formation of the lithiated carbanion 8 and/or the
lithium enolate 6. The fact that LTMP showed the same trend
than LDA suggested that, though hindered, this amide could
also add to the linear electrophilic diazo function, particularly
free from steric hindrance.29
Contrary to dialkylamides, bis(trimethylsilylamides) are
intrinsically not nucleophilic species due to electronic
delocalization on the d orbitals of the silicon atoms. Therefore,
the nucleophilic addition of KHMDS or LiHMDS to the diazo
function through pathway 2 is not conceivable, and only
deprotonation should proceed with these bases, resulting in
aldol 3a via the unique pathway 1. The requirement for an
excess of LiHMDS to obtain a good and homogeneous yield of
aldol 3a (Table 2, entry 4) could be rationalized by the fact
that bis(trimethylsilylamides) are much less basic than
dialkylamides, requiring the displacement of the aldol addition
equilibrium.
hydrazone 10 clearly resulted from the addition of t-BuLi on
the diazo moiety, generating lithium diazoenolate 12 (Figure
2), which was then hydrolyzed. Aldol hydrazone 11, obtained
as a 2:1 mixture of (E)/(Z) diastereoisomers, would be formed
via deprotonation of the lithium diazoenolate 12 by t-BuLi and
subsequent aldol addition of the generated stabilized carbanion
13 (Figure 2).
Results obtained with 2 equiv of t-BuLi did corroborate this
hypothesis (Table 3, entries 2 and 3). When the reaction
mixture was stirred for 1 h after the addition of benzaldehyde
2a, diazoaldol 3a was not observed, and compounds 10 and 11
were isolated in 46% and 23% yields, respectively (Table 3,
entry 2). Extending the reaction time from 1 to 5 h led to a
similar global yield of compounds 10 and 11, but the ratio of
these two products was roughly exchanged with a 23% isolated
yield of α-keto hydrazone 10 and a 53% isolated yield of aldol
hydrazone 11 (Table 3, entry 3). These results confirm that
intermediate 13, the precursor of aldol 11, should result from
deprotonation of lithium diazoenolate 12 by excess t-BuLi.
Overall, the outcome of the assays carried out with t-BuLi
proved in accordance with the mechanistic proposal suggested
earlier for dialkylamide-induced aldol addition (Scheme 5),
involving a competition between pathways 1 and 2. However,
contrary to the N−N bond in the lithiated triazene
intermediates 7, 7′, and 9 (Scheme 5), the C−N bond
resulting from the addition of t-BuLi on the diazo function
could not be broken during hydrolysis. In that respect, the
identification of hydrazones 10 and 11 allowed to elucidate the
mechanism involved with t-BuLi, while providing support for
the proposed mechanism with dialkylamides.
Experimental results in favor of the above mechanistic
proposal were obtained when the aldol addition was carried
out with t-BuLi (Table 3).
Indeed, with 1 equiv of t-BuLi, under the same conditions of
temperature than used with LDA, using diethyl ether as the
solvent,30 the reaction led to the formation of three products
(Table 3, entry 1). Although deprotonation toward lithium
enolate 6 was expected to be favored with highly basic t-BuLi,
diazoaldol 3a was isolated as the minor product in only 13%
yield. Besides, α-keto hydrazone 10, whose structure was
confirmed by X-ray analysis (Figure 2), and aldol hydrazone 11
were isolated in 42% and 13% yields, respectively. α-Keto
In order to provide additional support to the mechanism
postulated with LDA, the intermediates were calculated by
DFT calculations at the M06-2X/6-311+G(d,p) SMD (THF)
level of theory,31 using TIPS-diazoacetone 1 and 2 molecules
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Table 4. Relative Electronic Energy (ΔΔE), Enthalpy (ΔΔH0248), and Free Energies (ΔΔG0248) of the Intermediates Involved
in the Postulated Mechanism with LDA at the M06-2X/6-311+G(d,p) SMD (THF) Level in kJ/mol
Table 5. Relative Electronic Energy (ΔΔE) and Enthalpy (ΔΔH0248) of the Postulated Intermediates with LDA as THF
Chelates at the M06-2X/6-311+G(d,p) SMD (THF) Level in kJ/mol
of LDA as the reference (Table 4). Enthalpy and Gibbs free
energies are calculated at 248 K (−25 °C). Intermediates 7 and
7′, resulting from the addition of LDA to the diazo function,
proved more stable than the lithium enolate intermediate 6
solvent is lithium enolate 6. The relatively low energy
differences between enolate 6 and lithiated triazenes 7 and
7′ bring support to the hypothesis of two competitive
pathways (deprotonation/nucleophilic addition), accounting
for the random reactivity observed with 1 equiv of LDA.
Furthermore, decomposition of the triazenes by breaking of
the N−N bond during hydrolysis proved consistent with the
high ΔΔG0248 values calculated between enol structures 14 and
14′ on the one hand (postulated through hydrolysis of
intermediates 7 and 7′, respectively) and TIPS-diazoacetone 1
+ i-Pr2NH on the other hand (Table 6). Indeed, a high
stabilization was gained through the decomposition of the
hydrolyzed triazenes 14 and 14′ to form diazoacetone 1, by
−111,7 kJ/mol and −75 kJ/mol, respectively. This result can
explain why no triazene could be observed or isolated
experimentally, whereas t-BuLi adduct 10 could be isolated
(Figure 2), since breaking of the C−N bond is not possible
due to the high basicity of t-BuLi and the stability of the C−N
bond formed.
Aldol Addition of TIPS-Diazoacetone: Scope of the
Reaction. With reproducible and high-yielding conditions in
our hands to perform the aldol addition between TIPS-
diazoacetone 1 and benzaldehyde 2a, we extended the method
to a range of aldehydes, ketones, and an imine. The conditions
implemented with 2 equiv of LDA were applied (Scheme 6).
Aromatic and heteroaromatic aldehydes behaved well in
those conditions, providing original C-TIPS-diazoaldols 3a−3f
resulting from deprotonation (ΔΔG0 = −13.9 and −20.8
248
kJ/mol, respectively). Noteworthy is the higher stability of the
five-membered chelate 7′ compared to the six-membered
chelate 7 (ΔΔG0 = −6.9 kJ/mol). As expected, stabilized
248
carbanion 8 was identified as the most stable intermediate by
far, stabilized by −36.1 kJ/mol as compared with triazene 7′
(Table 4).
Overall, the ΔΔG0
values between the different
248
intermediates are consistent with (i) the competitive formation
of intermediates 6, 7, and 7′ in favor of 7′ in the presence of 1
equiv of LDA and (ii) the formation of stabilized carbanion 8
from lithiated triazenes 7 and/or 7′ (Scheme 5) in the
presence of 2 equiv of LDA. With the purpose of evaluating the
real influence of the solvent on these intermediates, THF
molecules were introduced in order to position the lithium
cation in a tetrahedral coordinate sphere, and the
corresponding chelates were calculated at the same level as
previously. In order to focus on the electronic effect induced
by the presence of the THF on these molecules, the relative
electronic energy (ΔΔE) and the enthalpy (ΔΔH0248) are
given below (Table 5).
These results are very instructive as they show that the
intermediate that will most benefit from the stabilization by the
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synthesized here illustrates their value to access complex
silylated diazocarbonyl scaffolds, potential precursors to wide
molecular diversity through diazo transformation. Investigation
of the asymmetric extension of the “methyl-side” aldol addition
of α-trialkylsilyl-α-diazoacetones is underway, for which the
use of chiral lithium amides is naturally constituting a
privileged direction.
Table 6. Relative Electronic Energy (ΔΔE), Enthalpy
(ΔΔH0248), and Free Energies of the Corresponding Enols
14 and 14′ Compared to the Starting Materials at the M06-
2X/6-311+G(d,p) SMD(THF) Level in kJ/mol
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 fumehood. Aqueous layers containing azides traces should
undergo adequate treatment before discarding.33
General Information. All air- and moisture-sensitive reactions
were carried out under argon with anhydrous solvents using oven-
dried glassware (90 °C). Et2O and THF were dried through activated
alumina columns (Glass Technology GTS 100). DIPEA, 2,2,6,6-
tetramethylpiperidine, and CH3CN were distilled over CaH2. Et3N
was distilled over KOH. Commercial aldehydes and ketones were
distilled or recrystallized before use. Reactions at −25 °C and −78 °C
were performed using a bath cooled by the cryogenic flow.
Commercial LDA (2 M/THF) was titrated with menthol, and 1,10-
phenanthroline.34 n-BuLi,35 t-BuLi,36 LiHMDS,35 and KHMDS37
were titrated just before use. Melting points were measured with a
Kofler Heating Bench System Wagner & Munz.
Purifications by flash column chromatography were carried out
using Merck Kieselgel 60 silica gel (particle size: 32−63 μm). Column
chromatography was performed using 60 μm silica gel. Thin-layer
chromatography (TLC) was performed with SIL G/UV254 plates,
and products were detected by UV light or vanillin ethanolic solution.
High-performance thin-layer chromatography (HPTLC) was per-
formed with 1000 μm Silica Gel GF/UV254 20 cm × 20 cm plates.
1H NMR (200 or 400 MHz), 13C NMR (100.6 MHz), and 19F NMR
(188.3 MHz) spectra were recorded on a BRUKER DPX 200 or on a
BRUKER Advance AC 400 spectrometer. Chemical shifts, δ ,were
reported as parts per million (ppm) relative to Me4Si. Coupling
constants (J) were expressed in hertz (Hz), and splitting patterns were
expressed as follows: s (singlet), d (doublet), t (triplet), q (quartet),
quint (quintet), sep (septet), m (multiplet), bs (broad singlet), or
combinations of these. Proton and carbon assignments were
established using COSY, HSQC, HMBC, and DEPT-Q. Infrared
spectra (IR) were recorded on a PerkinElmer FT-IR Spectrum One
spectrometer equipped with an ATR unit. The wavenumbers of
representative absorption peaks were given in cm−1. High-resolution
mass spectra were recorded on a Bruker MicroTOF-QIII, ESI mode.
Preparation of TIPS-Diazoacetone (1). 1-Diazo-1-
(triisopropylsilyl)propan-2-one (TIPS-Diazoacetone)9 (1). To a
stirred solution of diazoacetone13,11a (1.8 g; 21 mmol) in a 1:1
mixture of anhydrous Et2O/hexane (260 mL) at 0 °C were added
diisopropylethylamine (4.9 mL; 28 mmol) and triisopropylsilyl
trifluoromethanesulfonate (63.5 mL; 24 mmol). After 90 min of
stirring at 0 °C under an argon atmosphere, the reaction mixture was
hydrolyzed by the addition of a saturated aqueous NaHCO3 solution
(100 mL). The organic layer 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 purified by flash column chromatography (silica gel,
petroleum ether/diethyl ether = 99:1) to afford TIPS-diazoacetone
(1) as an orange oil (4.6 g, 90% yield):15 Rf = 0.33 (petroleum ether/
ethyl acetate = 99:1); 1H NMR (200 MHz, CDCl3) δ (ppm) 2.30 (s,
3H), 1.45−1.21 (m, 3H), 1.10 (d, 18H, J = 6.9 Hz).
in yields ranging from 54 to 88%. Good yields of diazoaldols
3g−3k were also achieved from hindered and/or enolizable or
even functionalized alkyl aldehydes (54−99%). α,β-Unsatu-
rated aldehydes proved good substrates as well, leading to
diazoaldols 3l−3o in homogeneous yields (61−78%). Among
those, diazoaldol 3o was obtained as a mixture of
diastereoisomers from a highly functionalized enantiopure
aldehyde previously synthesized in our group as a key fragment
in total synthesis.6 Ketones like acetophenone and 1,1,1-
trifluoroacetone proceeded well in the reaction with TIPS-
diazoacetone 1, leading to the expected products in 77% and
80% yields, respectively. Finally, the Mannich-type reaction
proved feasible with N-benzylidene-p-toluene sulfonimine,32
affording the corresponding Mannich adduct in 71% isolated
yield. It should be noticed that while no desilylation occurred
during the aldol addition process, a few percent yields of
several C-desilylated diazoaldols 3′ were formed during
chromatography and isolated21 (Scheme 6). Pleasingly, X-ray
diffraction could be performed on diazoaldols 3b and 3e as
proofs of their structure.22
OUTLOOKS AND CONCLUSION
■
The “methyl-side” aldol addition of TIPS-diazoacetone 1 has
been developed as a convergent way to synthesize diversely
functionalized stable C-TIPS diazoaldols. Through the
investigation of different bases, the use of 2 equiv of LDA
turned up to constitute the appropriate conditions to achieve
the aldol addition in good and reproducible yields. These
conditions were successfully applied to 15 aldehydes, 2
ketones, and an imine. A novel mechanism was proposed to
rationalize the requirement of 2 equiv of the base in order to
achieve reproducible yields in the dialkylamide-promoted aldol
addition of TIPS-diazoacetone 1. Dialkylamides like LDA were
suggested to add to the terminal nitrogen atom of the diazo
function, made highly electrophilic due to very low bulkiness of
this group, competitively to their expected role of the base
toward the methyl ketone. The resulting lithiated triazene
could, in turn, undergo deprotonation by LDA and add to the
electrophile, eventually leading to the expected C-TIPS
diazoaldol after hydrolysis. Experimental results obtained
with t-Buli supported this hypothesis, as well as DFT
calculations of the postulated intermediates. The knowledge
of the specific reactivity of α-trialkylsilyl-α-diazoacetones
toward lithium amides, usually known for their non-
nucleophilic basic behavior, is crucial to explore further the
synthetic potential of these hardly explored versatile 3-carbon
building blocks. The library of stable C-TIPS diazoaldols
“Methyl-Side” Aldol Addition on TIPS-Diazoacetone (1)
with LDA. Protocol P1. To a stirred solution of freshly titrated
LDA34 (2 M/THF, 2.0 equiv) in anhydrous THF (4.8 mL/mmol of
TIPS-diazoacetone (1)), cooled at −25 °C, was added a solution of
TIPS-diazoacetone (1) (1.0 equiv) in anhydrous THF (4.8 mL/mmol
of (1)). After 1 h of stirring at −25 °C, the reaction mixture was
cooled to −78 °C, and a solution of aldehyde (2) (1 equiv) in
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Scheme 6. Extension of the LDA-Induced Aldol Addition of TIPS-Diazoacetone 1 to a Range of Electrophiles
a
b
c
On a 0.5−1 mmol scale; 67% yield on a 5 mmol scale. 2 equiv of ethyl glyoxylate was used. Diazoaldol 3m proved unstable in CDCl3, and
d
e
degradation was observed upon storage. T° = −100 °C instead of −78 °C. Traces of several desilylated diazoaldols 3′ were formed during
chromatographic purification and could be isolated, as detailed in the Experimental Section.
anhydrous THF (4.8 mL/mmol of aldehyde) was added dropwise.
After an additional 1 h of stirring at −78 °C, accurately maintained,19
the reaction mixture was hydrolyzed with saturated aqueous NH4Cl
and slowly warmed to rt. The aqueous layer was extracted with Et2O
(× 3). The combined organic layer was washed with brine, dried
(Na2SO4), and filtered, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed (silica gel
neutralized with 2% of NEt3; petroleum ether/ethyl acetate = 10:0 to
5:5) to afford the corresponding diazoaldol (3).
1-Diazo-4-hydroxy-4-phenyl-1-(triisopropylsilyl)butan-2-one
(3a). This compound was prepared from TIPS-diazoacetone (1)(232
mg, 1 mmol) and benzaldehyde (2a) (102 μL, 1 mmol) according to
protocol P1. Diazoaldol (3a) was obtained after column chromatog-
raphy as a yellow solid (288 mg, 86% yield), along with a small
amount of the corresponding C-deprotected aldol (3a′)5 (17 mg, 9%
yield) isolated as an orange oil. Diazoaldol (3a): mp = 86 °C; Rf =
0.65 (petroleum ether/ethyl acetate = 90:10); IR (neat) νmax (cm−1)
1
3419 (νOH), 2064 (νNN), 1627 (νCO); H NMR (400 MHz,
CDCl3) δ (ppm) 7.39−7.32 (m, 4H), 7.28−7.24 (m, 1H), 5.18−5.15
(m, 1H), 3.89 (d, 1H, J = 2.8 Hz), 2.99−2.87 (m, 2H), 1.33 (sep, 3H,
J = 7.4 Hz), 1.08 (d, 9H, J = 7.5 Hz), 1.07 (d, 9H, J = 7.5 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 198.3 (C), 142.9 (C),
128.6 (2 CH), 127.7 (CH), 125.8 (2 CH), 70.6 (CH), 53.7 (C), 47.0
(CH2), 18.4 (6 CH3), 11.5 (3 CH); HRMS (ESI/Q-TOF) m/z [M +
Na]+ calcd for C19H30N2O2SiNa 369.1969, found 369.1962. 1-Diazo-
4-hydroxy-4-phenylbutan-2-one (3a′):5 Rf = 0.10 (cyclohexane/ethyl
1
acetate = 70:30); H NMR (200 MHz, CDCl3) δ (ppm) 7.46−7.28
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(m, 5H), 5.28 (bs, 1H), 5.18 (dd, 1H, J = 8.1, 4.4 Hz), 2.88−2.52 (m,
2H).
When prepared from TIPS-diazoacetone (1) (1.20 g, 5 mmol) and
benzaldehyde (2a) (510 μL, 5 mmol) according to protocol P1,
diazoaldol (3a) was obtained in 67% yield (1.16 g) after column
chromatography.
7.5 Hz), 1.06 (d, 9H, J = 7.5 Hz); 13C{1H} NMR (100.6 MHz,
CDCl3) δ (ppm) 197.7 (C), 155.2 (C), 142.1 (CH), 110.4 (CH),
106.4 (CH), 64.7 (CH), 53.8 (C), 43.1 (CH2), 18.4 (6 CH3), 11.5 (3
CH); HRMS (ESI/Q-TOF) m/z [M
C17H28N2O3SiNa 359.1761, found 359.1752.
+
Na]+ calcd for
1-Diazo-4-hydroxy-4-(thiophen-2-yl)-1-(triisopropylsilyl)butan-
2-one (3f). This compound was prepared from TIPS-diazoacetone
(1) (240 mg, 1 mmol) and 2-thiophenecarboxaldehyde (2f) (93 μL, 1
mmol) according to protocol P1. Diazoaldol (3f) was obtained after
column chromatography as a brown solid (222 mg, 63% yield).
Diazoaldol (3f): mp = 84 °C; Rf = 0.23 (petroleum ether/ethyl
acetate = 95:5); IR (film) νmax (cm−1) 3395 (νOH), 2090 (νNN),
1602 (νCO); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.24 (dd, 1H, J
= 4.9, 1.5 Hz), 6.99−6.95 (m, 2H), 5.42 (dd, 1H, J = 8.0, 3.8 Hz),
4.10 (bs, 1H), 3.09 (dd, 1H, J = 16.3, 8.0 Hz), 3.02 (dd, 1H, J = 16.3,
3.8 Hz), 1.33 (sep, 3H, J = 7.5 Hz), 1.08 (d, 9H, J = 7.5 Hz), 1.07 (d,
9H, J = 7.5 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 197.8
(C), 146.7 (C), 126.8 (CH), 124.7 (CH), 123.5 (CH), 67.1 (CH),
53.9 (C), 46.7 (CH2), 18.4 (6 CH3), 11.5 (3 CH); HRMS (ESI/Q-
TOF) m/z [M + Na]+ calcd for C17H28N2O2SSiNa 375.1533, found
375.1529.
1-Diazo-4-hydroxy-4-(4-methoxyphenyl)-1-(triisopropylsilyl)-
butan-2-one (3b). This compound was prepared from TIPS-
diazoacetone (1) (144 mg, 0.6 mmol) and 4-methoxybenzaldehyde
(2b) (76 μL, 0.6 mmol) according to protocol P1. Diazoaldol (3b)
was obtained after column chromatography as an orange solid (198
mg, 88% yield), along with a small amount of the corresponding C-
deprotected aldol (3b′)5 (3 mg, 4% yield) isolated as an orange oil.
Diazoaldol (3b): mp = 80 °C; Rf = 0.31 (petroleum ether/ethyl
acetate = 90:10); IR (neat) νmax (cm−1) 3409 (νOH), 2064 (ν NN),
1620 (νCO); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.31 (d, 2H, J =
8.7 Hz), 6.89 (d, 2H, J = 8.7 Hz), 5.15−5.11 (m, 1H), 3.80 (s, 3H),
3.75 (d, 1H, J = 2.9 Hz), 2.98−2.86 (m, 2H), 1.33 (sep, 3H, J = 7.3
Hz), 1.09 (d, 9H, J = 7.5 Hz), 1.08 (d, 9H, J = 7.5 Hz); 13C{1H}
NMR (100.6 MHz, CDCl3) δ (ppm) 198.5 (C), 159.3 (C), 135.1
(C), 127.1 (2 CH), 114.1 (2 CH), 70.3 (CH), 55.4 (CH3), 53.7 (C),
47.0 (CH2), 18.5 (6 CH3), 11.6 (3 CH); HRMS (ESI/Q-TOF) m/z
[M + Na]+ calcd for C20H32N2O3SiNa 399.2074, found 399.2069. 1-
Diazo-4-hydroxy-4-(4-methoxyphenyl)butan-2-one (3b′):5 Rf = 0.11
(cyclohexane/ethyl acetate = 70:30); 1H NMR (200 MHz, CDCl3) δ
(ppm) 7.29 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 8.7 Hz), 5.28 (bs,
1H), 5.12 (dd, 1H, J = 8.3, 3.6 Hz), 3.80 (s, 3H), 3.49 (bs, 1H),
2.86−2.55 (m, 2H).
1-Diazo-4-hydroxy-5,5-dimethyl-1-(triisopropylsilyl)hexan-2-one
(3g). This compound was prepared from TIPS-diazoacetone (1) (224
mg, 0.9 mmol) and pivalaldehyde (2g) (109 μL, 0.9 mmol) according
to protocol P1. Diazoaldol 3g was obtained after column
chromatography as a yellow oil (236 mg, 78% yield). Diazoaldol
(3g): Rf = 0.56 (petroleum ether/ethyl acetate = 90:10); IR (film)
1
νmax (cm−1) 3461 (νOH), 2065 (νNN), 1620 (νCO); H NMR
(400 MHz, CDCl3) δ (ppm) 3.73 (ddd, 1H, J = 10.4, 3.0, 1.9 Hz),
3.21 (bs, 1H), 2.75 (dd, 1H, J = 15.8, 1.9 Hz), 2.55 (dd, 1H, J = 15.8,
10.4 Hz), 1.34 (sep, 3H, J = 7.5 Hz), 1.09 (d, 9H, J = 7.5 Hz), 1.08
(d, 9H, J = 7.5 Hz), 0.93 (s, 9H); 13C{1H} NMR (100.6 MHz,
CDCl3) δ (ppm) 199.7 (C), 75.7 (CH), 53.6 (C), 40.1 (CH2), 34.6
(C), 25.9 (3 CH3), 18.5 (3 CH3), 18.5 (3 CH3), 11.6 (3 CH); HRMS
(ESI/Q-TOF) m/z [M + Na]+ calcd for C17H34N2O2SiNa 349.2282,
found 349.2281.
4-(4-Chlorophenyl)-1-diazo-4-hydroxy-1-(triisopropylsilyl)butan-
2-one (3c). This compound was prepared from TIPS-diazoacetone
(1) (149 mg, 0.6 mmol) and 4-chlorobenzaldehyde (2c) (88 mg, 0.6
mmol) according to protocol P1. Diazoaldol (3c) was obtained after
column chromatography as a yellow solid (142 mg, 60% yield).
Diazoaldol (3c): mp = 100 °C; Rf = 0.48 (petroleum ether/ethyl
acetate = 90:10); IR (neat) νmax (cm−1) 3411 (νOH), 2064 (νNN),
1
1622 (νCO); H NMR (400 MHz, CDCl3) δ (ppm) 7.31 (s, 4H),
5.14 (t, 1H, J = 6.0 Hz), 3.99 (bs, 1H), 2.94−2.86 (m, 2H), 1.32 (sep,
3H, J = 7.5 Hz), 1.08 (d, 9H, J = 7.5 Hz), 1.07 (d, 9H, J = 7.5 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 198.1 (C), 141.4 (C),
4-Cyclohexyl-1-diazo-4-hydroxy-1-(triisopropylsilyl)butan-2-one
(3h). This compound was prepared from TIPS-diazoacetone (1) (239
mg, 1 mmol) and cyclohexane carbaldehyde (2h) (121 μL, 1 mmol)
according to protocol P1. Diazoaldol (3h) was obtained after column
chromatography as an orange oil (283 mg, 81% yield), along with a
small amount of the C-deprotected aldol (3h′)5 (14 mg, 7% yield)
isolated as an orange oil. Diazoaldol (3h): Rf = 0.59 (petroleum
ether/ethyl acetate = 90:10); IR (neat) νmax (cm−1) 3446 (νOH),
133.4 (C), 128.7 (2 CH), 127.2 (2 CH), 70.0 (CH), 53.9 (C), 46.8
(CH2), 18.4 (6 CH3), 11.5 (3 CH); HRMS (ESI/Q-TOF) m/z [M +
Na]+ calcd for C19H29ClN2O2SiNa 403.1579, found 403.1563.
1-Diazo-4-hydroxy-4-(4-(trifluoromethyl)phenyl)-1-
(triisopropylsilyl)butan-2-one (3d). This compound was prepared
from TIPS-diazoacetone (1) (241 mg, 1 mmol) and 4-trifluorome-
thylbenzaldehyde (2d) (137 μL, 1 mmol) according to protocol P1.
Diazoaldol (3d) was obtained after column chromatography as an
orange solid (223 mg, 54% yield). Diazoaldol (3d): mp = 75 °C; Rf =
0.48 (petroleum ether/ethyl acetate = 90:10); IR (neat) νmax (cm−1)
1
2065 (νNN), 1623 (νCO); H NMR (400 MHz, CDCl3) δ (ppm)
3.85−3.79 (m, 1H), 3.28 (d, 1H, J = 3.2 Hz), 2.75 (dd, 1H, J = 16.2,
2.6 Hz), 2.64 (dd, 1H, J = 16.2, 9.3 Hz), 1.90−1.08 (m, 11H), 1.34
(sep, 3H,J = 7.5 Hz), 1.09 (d, 18H, J = 7.5 Hz); 13C{1H} NMR
(100.6 MHz, CDCl3) δ (ppm) 199.6 (C), 72.4 (CH), 53.5 (C), 43.2
(CH), 42.0 (CH2), 29.1 (CH2), 28.5 (CH2), 26.6 (CH2), 26.3
(CH2), 26.2 (CH2), 18.5 (6 CH3), 11.6 (3 CH); HRMS (ESI/Q-
TOF) m/z [M + Na]+ calcd for C19H36N2O2SiNa 375.2438, found
375.2428. 4-Cyclohexyl-1-diazo-4-hydroxybutan-2-one (3h′):5 Rf =
0.12 (cyclohexane/ethyl acetate = 70:30); 1H NMR (200 MHz,
CDCl3) δ (ppm) 5.31 (bs, 1H), 3.95−3.73 (m, 1H), 3.16 (bs, 1H),
2.54−2.38 (m, 2H), 1.91−1.46 and 1.44−0.76 (2 m, 11H).
1
3415 (νOH), 2067 (νNN), 1619 (νCO); H NMR (400 MHz,
CDCl3) δ (ppm) 7.62 (d, 2H, J = 8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz),
5.26−5.22 (m, 1H), 4.02 (bs, 1H), 2.97−2.89 (m, 2H), 1.33 (sep,
3H, J = 7.5 Hz), 1.08 (d, 9H, J = 7.5 Hz), 1.07 (d, 9H, J = 7.5 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 198.1 (C), 146.9 (C),
130.0 (q, J = 32.4 Hz, C), 126.1 (2 CH), 125.6 (q, J = 3.7 Hz, 2 CH),
124.2 (q, J = 272.5 Hz, C), 70.1 (CH), 54.0 (C), 46.6 (CH2), 18.4 (6
CH3), 11.5 (3 CH); 19F NMR (188.3 MHz, CDCl3) δ (ppm)
−62.47; HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for
C20H29F3N2O2SiNa 437.1843, found 437.1833.
1-Diazo-4-(furan-2-yl)-4-hydroxy-1-(triisopropylsilyl)butan-2-
one (3e). This compound was prepared from TIPS-diazoacetone (1)
(148 mg, 0.6 mmol) and furfural (2e) (51 μL, 0.6 mmol) according
to protocol P1. Diazoaldol (3e) was obtained after column
chromatography as an orange solid (155 mg, 75% yield). Diazoaldol
(3e): mp = 58 °C; Rf = 0.45 (petroleum ether/ethyl acetate = 90:10);
IR (neat) νmax (cm−1) 3434 (νOH), 2084 (νNN), 1599 (νCO); 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.34 (dd, 1H, J = 1.8, 0.8 Hz),
6.31 (dd, 1H, J = 3.2, 1.8 Hz), 6.26 (dt, 1H, J = 3.2, 0.8 Hz), 5.17−
5.15 (m, 1H), 3.88 (bs, 1H), 3.14 (dd, 1H, J = 16.2, 8.4 Hz), 3.00
(dd, 1H, J = 16.2, 3.7 Hz), 1.32 (sep, 3H, J = 7.5 Hz), 1.07 (d, 9H, J =
1-Diazo-4-hydroxy-6-methyl-1-(triisopropylsilyl)heptan-2-one
(3i). This compound was prepared from TIPS-diazoacetone (1) (141
mg, 0.6 mmol) and isovaleraldehyde (2i) (67 μL, 0.6 mmol)
according to protocol P1. Diazoaldol (3i) was obtained after column
chromatography as a yellow oil (122 mg, 64% yield), along with a
small amount of the C-deprotected aldol (3i′)5 (5 mg, 5% yield)
isolated as an orange oil. Diazoaldol (3i): Rf = 0.44 (petroleum ether/
ethyl acetate = 90:10); IR (film) νmax (cm−1) 3458 (νOH), 2068
(νNN), 1623 (νCO); 1H NMR (400 MHz, CDCl3) δ (ppm) 4.17−
4.11 (m, 1H), 3.32 (d, 1H, J = 2.8 Hz), 2.71 (dd, 1H, J = 16.3, 2.8
Hz), 2.61 (dd, 1H, J = 16.3, 8.8 Hz), 1.87−1.76 (m, 1H), 1.54−1.47
(m, 1H), 1.33 (sep, 3H, J = 7.5 Hz), 1.21−1.19 (m, 1H), 1.10 (d, 9H,
J = 7.5 Hz), 1.09 (d, 9H, J = 7.5 Hz), 0.93 (d, 6H, J = 6.6 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 199.3 (C), 66.4 (CH),
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53.4 (C), 45.7 (CH2), 45.4 (CH2), 24.6 (CH), 23.5 (CH3), 22.2
(CH3), 18.5 (6 CH3), 11.6 (3 CH); HRMS (ESI/Q-TOF) m/z [M +
Na]+ calcd for C17H34N2O2SiNa 349.2282, found 349.2274. 1-Diazo-
4-hydroxy-6-methylheptan-2-one (3i′):5 Rf = 0.10 (cyclohexane/ethyl
J = 16.0, 1.1 Hz), 6.24 (dd, 1H, J = 16.0, 6.0 Hz), 4.80−4.78 (m, 1H),
3.68 (d, 1H, J = 3.0 Hz), 2.96−2.76 (m, 2H), 1.42−1.27 (m, 3H),
1.09 (d, 18H, J = 7.0 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ
(ppm) 198.3 (C), 136.7 (C), 130.6 (CH), 130.2 (CH), 128.6 (2
CH), 127.8 (CH), 126.6 (2 CH), 69.2 (CH), 53.8 (C), 45.0 (CH2),
18.4 (6 CH3), 11.5 (3 CH); HRMS (ESI/Q-TOF) m/z [M + Na]+
calcd for C21H32N2O2SiNa 395.2125, found 359.2114. (E)-1-Diazo-4-
hydroxy-6-phenylhex-5-en-2-one (3m′):5 Rf = 0.13 (cyclohexane/
ethyl acetate = 70:30); 1H NMR (200 MHz, CDCl3) δ (ppm) 7.45−
7.22 (m, 5H), 6.66 (d, 1H, J = 16.0 Hz), 6.21 (dd, 1H, J = 16.0, 6.1
Hz), 5.33 (bs, 1H), 4.88−4.67 (m, 1H), 3.37 (bs, 1H), 2.73−2.54 (m,
2H).
1-Diazo-4-hydroxy-1-(triisopropylsilyl)undec-5-yn-2-one (3n).
This compound was prepared from TIPS-diazoacetone (1) (220
mg, 0.9 mmol) and 2-octynal (2n) (130 μL, 0.9 mmol) according to
protocol P1. Diazoaldol (3n) was obtained after column chromatog-
raphy as an orange oil (261 mg, 78% yield). Diazoaldol (3n): Rf =
0.32 (petroleum ether/ethyl acetate = 90:10); IR (film) νm1ax (cm−1)
3402 (νOH), 2065 (νNN), 2104 (νCC), 1626 (νCO); H NMR
(400 MHz, CDCl3) δ (ppm) 4.81−4.77 (m, 1H), 3.51 (d, 1H, J = 5.3
Hz), 2.99 (dd, 1H, J = 16.0, 7.4 Hz), 2.88 (dd, 1H, J = 16.0, 4.0 Hz),
2.18 (td, 2H, J = 7.2, 2.0 Hz), 1.53−1.46 (m, 2H), 1.38−1.30 (m,
7H), 1.09 (d, 18H, J = 7.4 Hz), 0.89 (t, 3H, J = 7.2 Hz); 13C{1H}
NMR (100.6 MHz, CDCl3) δ (ppm) 197.3 (C), 85.6 (C), 79.6 (C),
59.3 (CH), 53.7 (C), 45.4 (CH2), 31.1 (CH2), 28.3 (CH2), 22.2
(CH2), 18.7 (CH2), 18.3 (6 CH3), 14.0 (CH3), 11.5 (3 CH); HRMS
(ESI/Q-TOF) m/z [M + Na]+ calcd for C20H36N2O2SiNa 387.2438,
found 387.2436.
1
acetate = 70:30); H NMR (400 MHz, CDCl3) δ (ppm) 5.29 (bs,
1H), 4.26−4.03 (m, 1H), 2.57−2.33 (m, 2H), 1.93−1.67 (m, 1H),
1.60−1.38 (m, 1H), 1.14−1.02 (m, 1H), 0.92 (d, 6H, J = 6.7 Hz).
Ethyl 5-Diazo-2-hydroxy-4-oxo-5-(triisopropylsilyl)pentanoate
(3j). This compound was prepared from TIPS-diazoacetone (1)
(150 mg, 0.6 mmol) and ethyl 2-oxoacetate (2j) (47 wt % in toluene,
264 μL, 1.2 mmol) according to protocol P1. Diazoaldol (3j) was
obtained after column chromatography as a yellow oil (115 mg, 54%
yield). Diazoaldol (3j): Rf = 0.30 (petroleum ether/ethyl acetate =
90:10); IR (film) νmax (cm−1) 3467 (νOH), 2065 (νNN), 1737
1
(νC=Oester), 1632 (νC=Oketone); H NMR (400 MHz, CDCl3) δ (ppm)
4.50 (dt, 1H, J = 6.1, 5.0 Hz), 4.24 (q, 2H, J = 7.1 Hz), 3.44 (d, 1H, J
= 6.1 Hz), 3.07 (d, 2H, J = 5.0 Hz), 1.33 (sep, 3H, J = 7.5 Hz), 1.29
(t, 3H, J = 7.1 Hz), 1.09 (d, 9H, J = 7.5 Hz), 1.08 (d, 9H, J = 7.5 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 195.7 (C), 173.6 (C),
67.8 (CH), 61.9 (CH2), 53.5 (C), 42.1 (CH2), 18.4 (3 CH3), 18.4 (3
CH3), 14.2 (CH3), 11.5 (3 CH); HRMS (ESI/Q-TOF) m/z [M +
Na]+ calcd for C16H30N2O4SiNa 365.1867, found 365.1872.
6-((tert-Butyldimethylsilyl)oxy)-1-diazo-4-hydroxy-5,5-dimethyl-
1-(triisopropylsilyl)hexan-2-one (3k). This compound was prepared
from TIPS-diazoacetone (1) (142 mg, 0.6 mmol) and 3-((tert-
butyldimethylsilyl)oxy)-2,2-dimethylpropanal (2k) (136 mg, 0.6
mmol) according to protocol P1. Diazoaldol (3k) was obtained
after column chromatography as a yellow oil (269 mg, 99% yield): Rf
= 0.68 (petroleum ether/ethyl acetate = 90:10); IR (film) νmax (cm−1)
(7R,Z)-1-Diazo-4-hydroxy-5,7-dimethyl-1-(triisopropylsilyl)-8-
((triisopropylsilyl)oxy)oct-5-en-2-one (3o). This compound was
prepared from TIPS-diazoacetone (1) (149 mg, 0.6 mmol) and
(R,Z)-2,4-dimethyl-5-((triisopropylsilyl)oxy)pent-2-enal (2o)6 (178
mg, 0.6 mmol) according to protocol P1. Diazoaldol (3o) was
obtained as a mixture of diastereoisomers after column chromatog-
raphy as an orange oil (196 mg, 61% yield). For analytical purpose,
diastereoisomers (3od1) and (3od2) were separated on HPTLC
neutralized with 2% of NEt3; petroleum ether/ethyl acetate = 98/2).
Diazoaldol (3od1): Rf = 0.70 (petroleum ether/ethyl acetate = 90:10);
IR (film) νmax (cm−1) 3449 (νOH), 2062 (νNN), 1630 (νCO); 1H
NMR (400 MHz, CDCl3) δ (ppm) 5.06−5.00 (m, 2H), 3.56−3.43
(m, 2H), 3.15 (bs, 1H), 2.94 (dd, 1H, J = 15.5, 9.4 Hz), 2.78−2.70
(m, 1H), 2.56 (dd, 1H, J = 15.5, 3.5 Hz), 1.74 (d, 3H, J = 1.4 Hz),
1.35 (sep, 3H, J = 7.5 Hz), 1.11−1.04 (m, 39H), 0.93 (d, 3H, J = 6.6
Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 198.2 (C), 136.5
(C), 131.8 (CH), 68.4 (CH2), 66.5 (CH), 53.5 (C), 43.4 (CH2), 35.0
(CH), 18.5 (6 CH3), 18.4 (CH3), 18.1 (6 CH3), 17.6 (CH3), 12.1 (3
CH), 11.6 (3 CH). Diazoaldol (3od2): Rf = 0.64 (petroleum ether/
ethyl acetate = 90:10); 1H NMR (400 MHz, CDCl3) δ (ppm) 5.05−
4.97 (m, 2H), 3.52−3.39 (m, 3H), 2.90 (dd, 1H, J = 16.2, 10.1 Hz),
2.82−2.74 (m, 1H), 2.63 (dd, 1H, J = 16.2, 2.5 Hz), 1.74 (d, 3H, J =
1.4 Hz), 1.35 (sep, 3H, J = 7.5 Hz), 1.11−1.04 (m, 39H), 0.94 (d, 3H,
J = 6.6 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 198.7 (C),
136.0 (C), 131.4 (CH), 68.7 (CH2), 67.4 (CH), 53.5 (C), 44.1
(CH2), 35.2 (CH), 19.0 (CH3), 18.5 (6 CH3), 18.1 (6 CH3), 17.8
(CH3), 12.1 (3 CH), 11.6 (3 CH). HRMS (ESI/Q-TOF) m/z [M +
Na]+ calcd for C28H56N2O3Si2Na 547.3722, found 547.3719.
1-Diazo-4-hydroxy-4-phenyl-1-(triisopropylsilyl)pentan-2-one
(3p). This compound was prepared from TIPS-diazoacetone (1) (239
mg, 1 mmol) and acetophenone (2p) (117 μL, 1 mmol) according to
protocol P1. Diazoketol (3p) was obtained after column chromatog-
raphy as a yellow solid (275 mg, 77% yield): mp = 66 °C; Rf = 0.53
(petroleum ether/ethyl acetate = 90:10); IR (neat) νmax (cm−1) 3276
(νOH), 2075 (νNN), 1600 (νCO); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.45−7.43 (m, 2H), 7.34−7.29 (m, 2H), 7.22−7.18 (m, 1H),
5.17 (s, 1H), 3.32 (d, 1H, J = 15.2 Hz), 2.78 (d, 1H, J = 15.2 Hz),
1.56 (s, 3H), 1.22 (sep, 3H, J = 7.5 Hz), 0.96 (d, 9H, J = 7.5 Hz), 0.92
(d, 9H, J = 7.5 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm)
199.5 (C), 147.2 (C), 128.4 (2 CH), 126.8 (CH), 124.5 (2 CH), 74.1
(C), 54.7 (C), 48.4 (CH2), 31.0 (CH3), 18.2 (3 CH3), 18.2 (3 CH3),
1
3495 (νOH), 2065 (νNN), 1626 (νCO); H NMR (400 MHz,
CDCl3) δ (ppm) 3.98 (ddd, 1H, J = 9.8, 3.5, 2.8 Hz), 3.63 (d, 1H, J =
3.5 Hz), 3.48 (d, 1H, J = 9.7 Hz), 3.45 (d, 1H, J = 9.7 Hz), 2.72 (dd,
1H, J = 15.0, 9.8 Hz), 2.64 (dd, 1H, J = 15.0, 2.8 Hz), 1.40−1.29 (m,
3H), 1.09 (d, 18H, J = 7.4 Hz), 0.90 (s, 3H), 0.89 (s, 9H), 0.87 (s,
3H), 0.05 (s, 6H); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm)
199.1 (C), 74.7 (CH), 71.5 (CH2), 53.4 (C), 41.1 (CH2), 38.8 (C),
26.0 (3 CH3), 21.9 (CH3), 19.9 (CH3), 18.5 (3 CH3), 18.5 (3 CH3),
18.4 (C), 11.6 (3 CH), −5.5 (2 CH3); HRMS (ESI/Q-TOF) m/z [M
+ Na]+ calcd for C23H48N2O3Si2Na 479.3096, found 479.3097.
(E)-1-Diazo-4-hydroxy-5-methyl-1-(triisopropylsilyl)oct-5-en-2-
one (3l). This compound was prepared from TIPS-diazoacetone (1)
(99 mg, 0.4 mmol) and (E)-2-methylpent-2-enal (2l) (48 μL, 0.4
mmol) according to protocol P1. Diazoaldol (3l) was obtained after
column chromatography as a yellow oil (107 mg, 77% yield), along
with a small amount of the C-deprotected aldol (3l′)5 (9 mg, 12%
yield) isolated as an orange oil. Diazoaldol (3l): Rf = 0.30 (petroleum
ether/ethyl acetate = 90:10); IR (film) νmax (cm−1) 3413 (νOH),
1
2063 (νNN), 1620 (νCO); H NMR (200 MHz, CDCl3) δ (ppm)
5−51−5.44 (m, 1H), 4.50−4.43 (m, 1H), 3.34 (d, 1H, J = 2.9 Hz),
2.87−2.69 (m, 2H), 2.11−1.96 (m, 2H), 1.65 (s, 3H), 1.38−1.24 (m,
3H), 1.09 (d, 18H, J = 7.0 Hz), 0.96 (t, 3H, J = 7.6 Hz); 13C{1H}
NMR (100.6 MHz, CDCl3) δ (ppm) 198.8 (C), 134.8 (C), 128.6
(CH), 73.6 (CH), 53.5 (C), 43.7 (CH2), 20.9 (CH2), 18.4 (6 CH3),
14.0 (CH3), 12.0 (CH3), 11.5 (3 CH); HRMS (ESI/Q-TOF) m/z
[M + Na]+ calcd for C18H34N2O2SiNa 361.2282, found 361.2271.
(E)-1-Diazo-4-hydroxy-5-methyloct-5-en-2-one (3l′):5 Rf = 0.12
1
(cyclohexane/ethyl acetate = 70:30); H NMR (200 MHz, CDCl3)
δ (ppm) 5.47 (t, 1H, J = 7.2 Hz), 5.32 (bs, 1H), 4.45 (dd, 1H, J = 8.9,
3.6 Hz), 2.68−2.40 (m, 2H), 2.03 (quint, 1H, J = 7.2 Hz), 1.62 (s,
3H), 0.96 (t, 3H, J = 7.5 Hz).
(E)-1-Diazo-4-hydroxy-6-phenyl-1-(triisopropylsilyl)hex-5-en-2-
one (3m). This compound was prepared from TIPS-diazoacetone (1)
(240 mg, 1 mmol) and cinnamaldehyde (2m) (126 μL, 1 mmol)
according to protocol P1. Diazoaldol (3m) was obtained after column
chromatography as an orange oil (236 mg, 63% yield), which proved
unstable in CDCl3 and upon storage, along with a small amount of the
C-deprotected aldol (3m′)5 (5 mg, 2% yield) isolated as an orange oil.
Diazoaldol (3m): Rf = 0.44 (petroleum ether/ethyl acetate = 90:10);
IR (film) νmax (cm−1) 3413 (νOH), 2065 (νNN), 1629 (νCO); 1H
NMR (200 MHz, CDCl3) δ (ppm) 7.41−7.23 (m, 5H), 6.67 (dd, 1H,
4927
https://doi.org/10.1021/acs.joc.0c02725
J. Org. Chem. 2021, 86, 4917−4931

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
11.4 (3 CH); HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for
C20H32N2O2SiNa 383.2125, found 383.2115.
KHMDS (freshly titrated,37 0.5 M/toluene, 0.92 mL, 0.45 mmol, 1.1
equiv) in anhydrous THF (4.2 mL) at −78 °C under argon was
added a solution of TIPS-diazoacetone (1) (99 mg, 0.41 mmol, 1.0
equiv) in anhydrous THF (2.1 mL) over 10 min. The mixture was
stirred for 40 min at −78 °C, after which a solution of benzaldehyde
(2a) (38 μL, 0.37 mmol, 0.9 equiv) in anhydrous THF (2.1 mL) was
added over 5 min. This mixture was stirred for 60 min at −78 °C,
after which 10 mL of saturated NH4Cl solution was added, and the
mixture was warmed to rt. The mixture was then partitioned between
ethyl acetate and, sequentially, water (20 mL) and brine (20 mL).
The combined organic layer was dried (Na2SO4) and filtered, and the
filtrate was concentrated under reduced pressure. The residue was
chromatographed (silica gel neutralized with 2% of NEt3; petroleum
ether/ethyl acetate = 10:0 to 5:5) to afford the corresponding
diazoaldol (3a) (50 mg, 38% yield) and bis-aldol (4a) (21 mg, 12%
yield) as an orange solid.
1-Diazo-5,5,5-trifluoro-4-hydroxy-4-methyl-1-(triisopropylsilyl)-
pentan-2-one (3q). This compound was prepared from TIPS-
diazoacetone (1) (238 mg, 1 mmol) and 1,1,1-trifluoroacetone (2q)
(89 μL, 1 mmol) according to protocol P1. Diazoketol (3q) was
obtained after column chromatography as a white solid (279 mg, 80%
yield): mp = 60 °C; Rf = 0.36 (petroleum ether/ethyl acetate = 95:5);
IR (neat) νmax (cm−1) 3362 (νOH), 2070 (νNN), 1606 (νCO); 1H
NMR (400 MHz, CDCl3) δ (ppm) 5.63 (bs, 1H), 3.03 (d, 1H, J =
15.5 Hz), 2.64 (d, 1H, J = 15.5 Hz), 1.43 (s, 3H), 1.35 (sep, 3H, J =
7.5 Hz), 1.09 (d, 18H, J = 7.5 Hz); 13C{1H} NMR (100.6 MHz,
CDCl3) δ (ppm) 197.6 (C), 125.9 (q, J = 286.0 Hz, C), 73.5 (q, J =
29.2 Hz, C), 55.6 (C), 40.1 (CH2), 22.2 (m, CH3), 18.3 (3 CH3),
18.3 (3 CH3), 11.5 (3 CH); 19F NMR (188.3 MHz, CDCl3) δ (ppm)
−82.32; HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for
C15H27F3N2O2SiNa 375.1686, found 375.1682.
N-(4-Diazo-3-oxo-1-phenyl-4-(triisopropylsilyl)butyl)-4-methyl-
benzenesulfonamide (3r). This compound was prepared from TIPS-
diazoacetone (1) (149 mg, 0.6 mmol) and (E)-N-benzylidene-4-
methylbenzenesulfonamide (2r)32 (162 mg, 0.6 mmol) according to
protocol P1. Mannich adduct (3r) was obtained after column
chromatography as a yellow solid (222 mg, 71% yield). Compound
3r: mp = 121 °C; Rf = 0.24 (petroleum ether/ethyl acetate = 90:10);
IR (neat) νmax (cm−1) 3272 (νNH), 2067 (νNN), 1629 (νCO); 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.62 (d, 2H, J = 8.3 Hz), 7.18−
7.15 (m, 5H), 7.14−7.11 (m, 2H), 6.20−6.17 (m, 1H), 4.77−4.72
(m, 1H), 3.09 (dd, 1H, J = 15.5, 5.2 Hz), 2.86 (dd, 1H, J = 15.5, 5.9
Hz), 2.37 (s, 3H), 1.21 (sep, 3H, J = 7.5 Hz), 0.96 (d, 9H, J = 7.5
Hz), 0.95 (d, 9H, J = 7.5 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ
(ppm) 196.1 (C), 143.1 (C), 139.6 (C), 137.7 (C), 129.5 (2 CH),
128.5 (2 CH), 127.6 (CH), 127.2 (2 CH), 126.6 (2 CH), 55.0 (CH),
53.9 (C), 43.9 (CH2), 21.5 (CH3), 18.2 (6 CH3), 11.4 (3 CH);
HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for C26H37N3O3SSiNa
522.2217, found 522.2213.
1-Diazo-4-hydroxy-3-(hydroxy(phenyl)methyl)-4-phenyl-1-
(triisopropylsilyl)butan-2-one (4a): mp = 145 °C; Rf = 0.67
(petroleum ether/ethyl acetate = 70:30); IR (neat) νmax (cm−1)
1
3382 (νOH), 3351 (νOH), 2077 (νNN), 1593 (νCO); H NMR
(400 MHz, CDCl3) δ (ppm) 7.44−7.42 (m, 2H), 7.38−7.27 (m, 7H),
7.22−7.18 (m, 1H), 5.47−5.46 (m, 1H), 5.25 (d, 1H, J = 9.2 Hz),
4.74 (d, 1H, J = 9.2 Hz), 3.64 (dd, 1H, J = 9.2, 2.7 Hz), 3.24 (bs, 1H),
0.99 (sep, 3H, J = 7.5 Hz), 0.70 (d, 9H, J = 7.5 Hz), 0.70 (d, 9H, J =
7.5 Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 200.5 (C),
142.7 (C), 141.7 (C), 128.9 (2 CH), 128.6 (2 CH), 128.5 (CH),
127.2 (CH), 126.9 (2 CH), 125.0 (2 CH), 73.4 (CH), 71.8 (CH),
59.6 (CH), 56.7 (C), 17.9 (6 CH3), 11.2 (3 CH);HRMS (ESI/Q-
TOF) m/z [M + Na]+ calcd for C26H36N2O3SiNa 475.2387, found
475.2375.
Procedure with LiBr as an Additive. To a solution of KHMDS
(freshly titrated,37 0.5 M/toluene, 0.92 mL, 0.46 mmol, 1.1 equiv) in
anhydrous THF (4.2 mL) at −78 °C under argon was added a
solution of TIPS-diazoacetone (1) (100 mg, 0.42 mmol, 1.0 equiv) in
anhydrous THF (2.1 mL) over 10 min. The mixture was stirred for 40
min at −78 °C, after which a solution of dry LiBr (47 mg, 0.54 mmol,
1.3 equiv) and benzaldehyde (2a) (38 μL, 0.38 mmol, 0.9 equiv) in
anhydrous THF (2.1 mL) was added over 5 min. This mixture was
stirred for 60 min at −78 °C, after which 10 mL of saturated NH4Cl
solution was added, and the mixture was warmed to rt. The mixture
was then partitioned between ethyl acetate and, sequentially, water
(20 mL) and brine (20 mL). The combined organic layer was dried
(Na2SO4) and filtered, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed (silica gel
neutralized with 2% of NEt3, petroleum ether/ethyl acetate = 10:0 to
5:5) to afford the corresponding diazoaldol (3a) in yields ranging
from 58 to 79% on 4 assays.
Procedure with TESCl as an Additive. To a stirred solution of
TIPS-diazoacetone (1) (100 mg, 0.42 mmol, 1 equiv) in anhydrous
toluene (8.5 mL) at −78 °C was added dropwise KHMDS (freshly
titrated,37 0.5 M/toluene, 0.87 mL, 0.44 mmol, 1.05 equiv) over 15
min. After 5 min of stirring, a solution of benzaldehyde (2a) (51 μL,
0.5 mmol, 1.2 equiv) and TESCl (83 μL, 0.5 mmol, 1.2 equiv) in
anhydrous toluene (1.8 mL) was added. After 15 min of stirring at
−78 °C, the reaction mixture was partitioned between EtOAc and,
sequentially, saturated aqueous NH4Cl (20 mL) and brine (20 mL).
The combined organic extract was dried (Na2SO4) and concentrated.
The residue was chromatographed (silica gel neutralized with 2% of
NEt3, petroleum ether/ethyl acetate = 10:0 to 5:5), and two products
were isolated from a complex mixture: (3a) as a yellow solid (30 mg,
22% yield) and (5a) as an orange oil (66 mg, 36% yield).
“Methyl-Side” Aldol Addition on TIPS-Diazoacetone (1)
with 2 Equiv of LTMP. To a stirred solution of LTMP (1.35 M, 1.48
mL, 2.0 mmol, 2 equiv) prepared from 2,2,6,6-tetramethylpiperidine,
freshly distilled over CaH2, and n-BuLi (freshly titrated,35 1.35 M/
hexane) in anhydrous THF (4.8 mL) at −25 °C was added a solution
of α-triisopropylsilyl-α-diazoacetone (1) (0.240 g, 1.0 mmol, 1.0
equiv) in anhydrous THF (4.8 mL). After 1 h of stirring at the same
temperature, the reaction mixture was cooled to −78 °C, and a
solution of benzaldehyde (2a) (0.102 mL, 1.0 mmol, 1 equiv) in
anhydrous THF (4.8 mL) was added dropwise. After an additional 1
h of stirring at −78 °C, the reaction mixture was quenched with
saturated aqueous NH4Cl and slowly warmed to rt. The aqueous layer
was extracted with Et2O (3 × 10 mL). The combined organic layer
was washed with brine (20 mL), dried (Na2SO4), and filtered, and the
filtrate was concentrated under reduced pressure. A conversion of
1
49% into diazoaldol (3a) was observed on the H NMR spectrum of
this crude product.
“Methyl-Side” Aldol Addition on TIPS-Diazoacetone (1)
with LiHMDS. To a stirred solution of LiHMDS (freshly titrated,35 1
M/THF, 2.0 equiv) in anhydrous THF (2 mL) at −25 °C was added
a solution of α-triisopropylsilyl-α-diazoacetone (1) (100 mg, 0.42
mmol, 1 equiv) in anhydrous THF (2 mL). After 1 h of stirring at the
same temperature, the reaction mixture was cooled to −78 °C, and a
solution of aldehyde (42 μL, 0.42 mmol, 1.0 equiv) in anhydrous
THF (2 mL) was added dropwise. After an additional 1 h of stirring at
−78 °C, the reaction mixture was quenched with saturated aqueous
NH4Cl and slowly warmed to rt. The aqueous layer was extracted
with Et2O (3 × 10 mL). The combined organic layer was washed with
brine (20 mL), dried (Na2SO4), and filtered, and the filtrate was
concentrated under reduced pressure. The residue was chromato-
graphed (silica gel neutralized with 2% of NEt3; petroleum ether/
ethyl acetate = 10:0 to 5:5) to afford the corresponding diazoaldol
(3a) in yields ranging from 76 to 83% on 3 assays.
1-Diazo-4-phenyl-4-((triethylsilyl)oxy)-1-(triisopropylsilyl)butan-
2-one (5a): Rf = 0.90 (petroleum ether/diethyl ether = 90:10,
phosphomolybdic acid stain); IR (film) νmax (cm−1) 2068 (νNN),
1622 (νCO); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36−7.28 (m,
4H), 7.25−7.21 (m, 1H), 5.20 (dd, 1H, J = 7.7, 5.3 Hz), 3.04 (dd,
1H, J = 14.3, 7.7 Hz), 2.74 (dd, 1H, J = 14.3, 5.3 Hz), 1.35−1.27 (m,
3H), 1.05 (d, 18H, J = 7.4 Hz), 0.85 (t, 9H, J = 8.0 Hz), 0.53−0.46
(m, 6H); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 196.1 (C),
144.6 (C), 128.4 (2 CH), 127.6 (CH), 126.1 (2 CH), 72.3 (CH),
“Methyl-Side” Aldol Addition on TIPS-Diazoacetone (1)
with KHMDS. Procedure without an Additive. To a solution of
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53.6 (C), 50.0 (CH2), 18.5 (6 CH3), 11.6 (3 CH), 6.9 (3 CH3), 4.9
(3 CH2); HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for
C25H44N2O2Si2Na 483.2834, found 483.2823.
AUTHOR INFORMATION
Corresponding Author
■
Catherine Gaulon-Nourry − Institut des Molécules et
Matériaux du Mans, IMMM UMR 6283 CNRS − Le Mans
Université, 72085 CEDEX 9 Le Mans, France; orcid.org/
0000-0002-3601-8216; Email: catherine.gaulon@univ-
lemans.fr
“Methyl-Side” Aldol Addition on TIPS-Diazoacetone (1)
with t-BuLi. To a stirred solution of t-BuLi (freshly titrated,36 1.5 M/
pentane, 0.84 mL, 1.26 mmol, 2.0 equiv) in anhydrous Et2O (3 mL)
at −25 °C was added a solution of α-triisopropylsilyl-α-diazoacetone
(1) (151 mg, 0.63 mmol, 1.0 equiv) in anhydrous Et2O (3 mL). After
1 h of stirring at the same temperature, the reaction mixture was
cooled to −78 °C, and a solution of benzaldehyde (2a) (64 μL, 0.63
mmol, 1 equiv) in anhydrous Et2O (3 mL) was added dropwise. After
an additional 5 h of stirring at −78 °C, the reaction mixture was
quenched with saturated aqueous NH4Cl and slowly warmed to rt.
The aqueous layer was extracted with Et2O (3 × 4 mL). The
combined organic layer was washed with brine (20 mL), dried
(Na2SO4), and filtered, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed (silica gel
neutralized with 2% of NEt3, petroleum ether/ethyl acetate = 10:0 to
5:5) to afford α-ketohydrazone (E)-(10) as a yellow solid (43 mg,
23% yield) and α-ketohydrazone (11) as a mixture of diaster-
eoisomers ((E)-11/(Z)-11 = 2:1) as a yellow liquid (135 mg, 53%
yield).
Authors
Sigrid Gavelle − Institut des Molécules et Matériaux du Mans,
IMMM UMR 6283 CNRS − Le Mans Université, 72085
CEDEX 9 Le Mans, France
Imen Abid − Institut des Molécules et Matériaux du Mans,
IMMM UMR 6283 CNRS − Le Mans Université, 72085
CEDEX 9 Le Mans, France
Bohdan Biletskyi − Institut des Molécules et Matériaux du
Mans, IMMM UMR 6283 CNRS − Le Mans Université,
72085 CEDEX 9 Le Mans, France
Sylvain Henrion − Institut des Molécules et Matériaux du
Mans, IMMM UMR 6283 CNRS − Le Mans Université,
72085 CEDEX 9 Le Mans, France
(E)-1-(2-(tert-Butyl)hydrazono)-1-(triisopropylsilyl)propan-2-one
(10): mp = 76 °C; Rf = 0.80 (petroleum ether/ethyl acetate = 90:10);
1H NMR (400 MHz, CDCl3) δ (ppm) 13.55 (bs, 1H), 2.19 (s, 3H),
Annie Hémon-Ribaud − Institut des Molécules et Matériaux
du Mans, IMMM UMR 6283 CNRS − Le Mans Université,
72085 CEDEX 9 Le Mans, France; orcid.org/0000-
0003-4845-5971
1.36 (sep, 3H, J = 7.5 Hz), 1.30 (s, 9H), 1.09 (d, 18H, J = 7.5 Hz);
13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 197.5 (C), 131.0 (C),
55.8 (C), 29.5 (CH3), 28.9 (3 CH3), 19.1 (6 CH3), 12.6 (3 CH);
HRMS (ESI/Q-TOF) m/z [M + Na]+ calcd for C16H34N2OSiNa
321.2333, found 321.2322.
̂
Jérome Lhoste − Institut des Molécules et Matériaux du Mans,
IMMM UMR 6283 CNRS − Le Mans Université, 72085
CEDEX 9 Le Mans, France; orcid.org/0000-0002-4570-
6459
1-(2-(tert-Butyl)hydrazono)-4-hydroxy-4-phenyl-1-
(triisopropylsilyl)butan-2-one (11): IR (neat) νmax (cm−1) 3449,
2943, 2864, 1643, 1582, 1463, 1389, 1364, 1182, 1118, 1057, 1017,
917, 881. Major diastereoisomer (E)-11: Rf = 0.50 (petroleum ether/
Arnaud Martel − Institut des Molécules et Matériaux du Mans,
IMMM UMR 6283 CNRS − Le Mans Université, 72085
CEDEX 9 Le Mans, France
Gilles Dujardin − Institut des Molécules et Matériaux du
Mans, IMMM UMR 6283 CNRS − Le Mans Université,
72085 CEDEX 9 Le Mans, France; orcid.org/0000-
0003-0734-8109
1
ethyl acetate = 90:10); H NMR (400 MHz, CDCl3) δ (ppm) 13.61
(bs, 1H), 7.42−7.35 (m, 5H), 5.16 (dd, 1H, J = 9.5, 2.6 Hz), 4.27 (bs,
1H), 2.88 (dd, 1H, J = 16.7, 2.6 Hz), 2.78 (dd, 1H, J = 16.7, 9.5 Hz),
1.33 (s, 9H), 1.31−1.25 (m, 3H), 1.06 (d, 18H, J = 7.4 Hz); 13C{1H}
NMR (100.6 MHz, CDCl3) δ (ppm) 199.0 (C), 143.5 (C), 130.9
(C), 128.7 (2 CH), 127.6 (CH), 125.8 (2 CH), 71.1 (CH), 56.4 (C),
48.6 (CH2), 28.9 (3 CH3), 19.1 (6 CH3), 12.6 (3 CH). Minor
diastereoisomer (Z)-11: Rf = 0.44 (petroleum ether/ethyl acetate =
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02725
1
90:10); H NMR (400 MHz, CDCl3) δ (ppm) 7.33−7.22 (m, 5H),
7.20 (bs, 1H), 5.11 (dd, 1H, J = 9.6, 2.8 Hz), 4.15 (bs, 1H), 3.33 (dd,
1H, J = 16.6, 2.8 Hz), 3.08 (dd, 1H, J = 16.6, 9.6 Hz), 1.43 (sep, 3H, J
= 7.5 Hz), 1.26 (s, 9H), 1.07 (d, 9H, J = 7.5 Hz), 1.07 (d, 9H, J = 7.5
Hz); 13C{1H} NMR (100.6 MHz, CDCl3) δ (ppm) 205.1 (C), 144.2
(C), 130.9 (C), 128.4 (2 CH), 127.2 (CH), 126.0 (2 CH), 71.3
(CH), 55.8 (C), 45.8 (CH2), 28.9 (3 CH3), 19.1 (6 CH3), 12.9 (3
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CH); HRMS (ESI/Q-TOF) m/z [M
C23H40N2O2SiNa 427.2751, found 427.2751.
+
Na]+ calcd for
We gratefully acknowledge Le Mans Université for Sigrid
Gavelle’s Ph.D. funding and the Office Mediterranéen de la
Jeunesse (OMJ) for Imen Abid’s Ph.D. funding. We want to
express our sincere gratitude to “La Ligue Contre le Cancer du
Grand-Ouest”, departmental committee 72, for financial
support. We also thank Frédéric Legros for the synthesis of
diazoacetone and technical support, Corentin Jacquemmoz
and Sullivan Bricaud for the NMR analyses, Patricia Gangnery,
Emmanuelle Mebold, and Alexandre Benard for the HRMS
analyses.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02725.
1H and 13C NMR spectra for all new products; single-
crystal X-ray diffraction data for structures 3a, 3b, 3e, 4a,
and 10; computational methods and data (PDF)
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