Ruthenium-Catalyzed Three-Component Alkylation: A Tandem Approach to the Synthesis of Nonsymmetric N,N-Dialkyl Acyl Hydrazides with Alcohols

Article abstract of DOI:10.1002/adsc.202100554

The borrowing hydrogen strategy has been applied in the synthesis of nonsymmetric N,N-dialkylated acyl hydrazides via a tandem three-component reaction catalyzed by a phosphine free diaminocyclopentadienone ruthenium tricarbonyl complex. This strategy represents the first direct one-pot approach to nonsymmetric functionalized acyl hydrazides. Different aromatic acyl hydrazides underwent dialkylation with a variety of primary or secondary alcohols and methanol or ethanol as alkylating agents in mild reaction conditions and good yields. Deuterium labelling experiments suggested that the primary or secondary alcohol was the hydrogen source in this tandem process. DFT calculations show that the combination of the tandem mixed product cannot be perfectly explained neither structurally nor electronically, but might be dependent of the physical state of the aldehyde or ketone intermediate (gaz vs. liquid) at the reaction temperature. (Figure presented.).

Full text of DOI:10.1002/adsc.202100554

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100554
Ruthenium-Catalyzed Three-Component Alkylation: A Tandem
Approach to the Synthesis of Nonsymmetric N,N-Dialkyl Acyl
Hydrazides with Alcohols
Léo Bettoni,a Nicolas Joly,a, b Jean-François Lohier,a Sylvain Gaillard,a
Albert Poater,b,* and Jean-Luc Renauda,*
a
Normandie Univ., LCMT, ENSICAEN, UNICAEN, CNRS, 6 boulevard du Maréchal Juin, 14000 Caen, France
E-mail: jean-luc.renaud@ensicaen.fr
Departament de Química, Institut de Química Computacional i Catàlisi (IQCC), University of Girona, c/ Mª Aurèlia Capmany
b
69, 17003 Girona, Catalonia, Spain
E-mail: albert.poater@udg.edu
Manuscript received: May 9, 2021; Revised manuscript received: June 11, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100554
Abstract: The borrowing hydrogen strategy has been applied in the synthesis of nonsymmetric N,N-
dialkylated acyl hydrazides via a tandem three-component reaction catalyzed by a phosphine free
diaminocyclopentadienone ruthenium tricarbonyl complex. This strategy represents the first direct one-pot
approach to nonsymmetric functionalized acyl hydrazides. Different aromatic acyl hydrazides underwent
dialkylation with a variety of primary or secondary alcohols and methanol or ethanol as alkylating agents in
mild reaction conditions and good yields. Deuterium labelling experiments suggested that the primary or
secondary alcohol was the hydrogen source in this tandem process. DFT calculations show that the
combination of the tandem mixed product cannot be perfectly explained neither structurally nor electronically,
but might be dependent of the physical state of the aldehyde or ketone intermediate (gaz vs. liquid) at the
reaction temperature.
Keywords: borrowing hydrogen; ruthenium complex; catalysis; alkylation; multicomponent
Introduction
also applied in elegant synthesis of natural
compounds.[1j]
Modern organic synthesis relies on several pillars such
Regarding the environmental impact, the replace-
as the efficiency of the overall process (yield, number ment of toxic and/or non-renewable resources with
of steps, …), the control of the (chemo-, stereo- and/or sustainable feedstock, is currently a very active
regio-) selectivity, and the impact on the environment research area. In this context, the alkylation reactions
(atom economy, prevent waste, safer chemicals and are in the forefront. Traditionally, alkylation reactions
solvent…). Regarding the efficiency of a process, involve a base, electrophiles such as halide or pseudo-
tandem, cascade or domino reactions and multi- halide derivatives, and, consequently, generate number
component reactions are fascinating tools fulfilling of wastes. The borrowing hydrogen procedure is a
some of the objectives as they permit the rapid more recent, eco-friendly and secure alternative.[4] The
construction of functionalized and complex molecules advantages of the method are the employment of
from simple starting materials.[1–3] These processes alcohols, which can be produced from renewable raw
diminished the number of steps, the concomitant material,[5] as alkylating agents and the production of
purifications and are atom-economical by minimizing water as unique side product. The process is initiated
wastes. A plethora of metal-based catalytic processes by a metal-based complex catalyzed dehydrogenation
have been implemented to allow the formation of CÀ C of the alcohol to form a carbonyl derivative and a
and C-heteroatom bonds, the control of the chemo-, metal hydride species. After a condensation sequence,
regio- and stereoselectivity. Such strategies have been the complex reduces the in-situ generated activated
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alkene, or in other words “returns” the hydrogen atoms dialkylated benzoyl hydrazides and a consecutive two
to the unsaturated intermediate, enabling the synthesis step-one
pot
strategy
was
also
proposed
of functionalized building blocks. Whereas the hydro- (Scheme 1).[13a] We developed a phosphine-free ruthe-
gen auto-transfer strategy has been well explored for nium complex-catalyzed alkylation of acyl hydrazides
the formation of CÀ C and CÀ N bonds in the presence using alcohols via the hydrogen auto-transfer strategy.
of platinum or abundant metal-based complexes,[4] its A variety of primary as well as secondary alcohols
application in
a
tandem process is still were introduced in this alkylation and afforded mono-
underestimated.[6] As example, tandem reactions im- and dialkylated acyl hydrazides in moderate to good
plying an alcohol and a second partner bearing a yields (Scheme 1).[13b] But, to date, there is no tandem
reducible functionality, such as a nitrile, nitro or azide and/or multicomponent alkylation of hydrazine deriva-
group, have been reported,[6] and enabled a rapid tives with two different alcohols.
access to alkylated amines, amides, imines or to
Following our ongoing interest on the borrowing
heterocycles. A tandem arylation of alcohols or allylic hydrogen strategy catalyzed by diaminocyclopentadie-
alcohols involving a dual-catalytic transition metal none tricarbonyl metal-based complexes,[14–15a] we
system has also been recently reported.[7] However, report the first three-component alkylation catalyzed
multi-component hydrogen auto-transfer reaction with by a phosphine-free bifunctional complex, allowing the
two different alcohols is still rare. The challenge in synthesis of unsymmetric N,N-dialkylated hydrazide
tandem reaction involving a nucleophile and two from methanol, as C1 source, or ethanol, as C2 source,
different alcohols, as pro-electrophiles, relies on the and primary or secondary benzylic, aliphatic alcohols
possibility to form three dialkylated products (two in mild reaction conditions (Scheme 2).
symmetrically dialkylated compounds and the targeted
unsymmetrical dialkylated one) and also potentially
two monoalkylated compounds. One of the keys for
Results and Discussion
the success of such approach is the use of two alcohols The complex Ru1, initially synthesized and used by
having different reactivities. As example, dehydrogen- Haak in the activation of propargyl alcohols,[16] was
ation of methanol is the most energetic demanding prepared in 77% yield by heating one equivalent of
oxidation step compared to other alcohols, but the diaminocyclopentadienone with half equivalent of
generated formaldehyde is then one of the most Ru3(CO)12 in refluxing toluene overnight. The complex
reactive carbonyl intermediate. Kundu and our group Ru2 was prepared from Ru1 by exchanging one CO
have recently described a three-component alkylation ligand with PPh3 in refluxing xylenes overnight and
procedure, leading to the synthesis of α-methylated α- isolated in 65% yield (see in the E.S.I.).
alkylated ketones, with various aliphatic and aromatic
ketones using benzylic alcohols and methanol as
alkylating reagent in the presence of a ruthenium and
an iron complex, respectively.[8]
In respect to the CÀ N bond formation, while
alkylation of amines or amides following the hydrogen
auto-transfer concept has been well-described,[9] no
general tandem process has been yet presented in the
literature.[10–11] Compared to other N-nucleophiles, little
is known on the use of hydrazine derivatives in
borrowing hydrogen methodology. We and others have
described recently the use of ruthenium and nickel in
alkylation of hydrazines with alcohols using the hydro-
gen autotransfer methodology.[12–13] Zhou reported the
first alkylation of acyl hydrazides with mainly secon-
dary benzylic alcohols in acidic conditions in the
presence of a combination of a nickel salt and an
electron rich diphosphine ligand, namely the bis
(dicyclohexyphosphine)propane dcpp.[12] Enantiomeric
excesses, contained between 72 and 96%, were
reached by combining Ni(II) and (S)-Binapine in the
°
presence of molecular sieves at 110 C in a mixture of
HFIP and tert-amyl alcohol. More recently, Gunana-
than described a more general procedure catalyzed by
the Ru-Macho complex.[13a] Various aliphatic and
Scheme 1. State of the art of the alkylation of acyl hydrazides.
benzylic alcohols were used furnishing the N,N-
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Table 1. Optimization of the reaction conditions.[a]
Entry Complex Temp. ( C) 1a (%)ç 2a (%)p 3a (%)[b]
°
1
Ru1
Ru2
Ru3
Ru4
Ru1
Ru1
Ru1
Ru1
Ru1
110
110
110
110
90
–
81
81
34
37
29
41
74
65
78
63
40
19
19
55
45
16
31
26
35
22
37
32
2[c]
3
4
5
6
–
11
18
55
28
–
–
–
–
28
100
120
130
110
110
110
7
8
9[d]
10[e] Ru1
11[f]
Ru1
[a] General conditions: Benzoyl hydrazide (0.5 mmol), benzyl
alcohol (2.5 mmol), Ru (1 mol%), Me3NO (2 mol%), t-
BuONa (1 equiv.), MeOH (0.5 mL) for 24 h;
1
[b] Conversions were determined by H-NMR analysis of the
Scheme 2. Outline of metal-based catalysed tandem three-
component alkylation of acyl hydrazides.
crude mixture;
[c] without Me3NO;
[d] t-BuOK was used as base;
[e] MeONa was used as base;
[f] Na2CO3 was used as base.
Single crystals were grown by slow diffusion of
pentane in a dichloromethane solution of Ru1 or Ru2.
X-ray diffraction unambiguously established the atom
connectivity, as showed in Figure 1. Both structures
present a distortion of the piperazine ring and a non-
coplanarity of the phenyl rings and the cyclopentadie- unfortunately, to complex mixtures of products. The
none, as also observed with the iron analog first breakthrough in this study came with the
complexes.[14a,17] As also noticed previously with the introduction of their ruthenium congeners Ru1À Ru4.
iron analogs,[14a] the phosphine ligand is located under- In the same reaction conditions, a mixture of the
neath the ketone function of the ancillary ligand to unsymmetrical N,N-dialkylated hydrazide 2a accom-
minimize the steric clash with the phenyl substituent panied by the dimethylated derivative 3a was observed
Preliminary attempts with complexes Fe1À Fe4 led,
and the piperazine ring.
(entries 1–4, Table 1). Neither the aldol condensation
To initiate the study, we chose the alkylation of nor the alkylation of the carbonyl derivative was
benzoyl hydrazide (1 equiv.) with benzyl alcohol and observed. In this tandem sequence, the reactivity and
methanol as a model reaction for the optimization of the selectivity depend on the nature of the cyclo-
the reaction conditions (Table 1 and S1) and applied pentadienone. As observed previously in iron
the conditions initially developed for the iron-catalyzed chemistry, the complex Ru1 and Ru2 bearing a
three-component alkylation of methyl ketones.8a
diaminocyclopentadienone ligand led to a higher
reactivity and a better selectivity in favor of the
unsymmetrical N,N-dialkylated hydrazide 2a. Thus,
complex Ru1, provided the N-methyl, N-benzyl
benzoyl hydrazide in 81% conversion, while the
dimethylated adduct 3a was the major compound with
the Shvo complexes Ru3 and Ru4 (entries 1, 3–4,
Table 1).[18] The complex Ru2, a thermally activated
complex, provided the unsymmetrical N,N-dialkylated
hydrazide with the same conversion and selectivity
than Ru1 (entries 1–2, Table 1). A rapid screening of
the temperature using complex Ru1 showed an
°
optimum at 110 C (entries 5–8, Table 1). At lower
Figure 1. Thermal ellipsoid representations (50% probability)
of complexes Ru1 and Ru2 (from left to right). Hydrogen
atoms have been omitted for clarity.
temperature, no complete conversion was observed and
at higher temperatures, the dimethylation became more
competitive and the selectivity decreased (entries 7–8,
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Table 1). Decreasing the amount of benzyl alcohol synthesized in 47–81% yield Scheme 4). Benzyl
(below 5 equiv.) or increasing the amount of methanol alcohols having an ortho-substituted aromatic ring
(above 25 equiv.) modified more or less the selectivity furnished the dialkylated acyl hydrazide compounds in
in favor of the dimethylated benzoyl hydrazide 3a lower yields (47–55%, Scheme 4). This decrease might
(entries 1–8, Table S1). Any other deviation from the be due to an enhanced steric hindrance around the
best reaction conditions, such as variation of the nature reducible C=N bond, disfavoring its approach to the
or the amount of the base, hampered the conversion metal-hydride center. The use of more reluctant
and the selectivity (entries 4–5, Table S1 and entries 9– alcohols to oxidation was then considered. Admittedly,
11, Table 1). Control experiments in the absence of a oxidation of primary aliphatic alcohols is less energetic
ruthenium complex did not furnish any alkylated demanding compared to methanol, but it is also more
product.
difficult than the dehydrogenation of benzyl alcohols.
The scope of this unprecedented ruthenium-cata- The tandem three-component alkylation is then more
lyzed multi-component alkylation via the hydrogen challenging. To our delight, the N,N-unsymmetrically
auto-transfer strategy was explored first starting with substituted acyl hydrazides were isolated in moderate
acyl hydrazide derivatives, methanol and benzyl to good yields (35–65%, Scheme 4). Cyclopropyl
alcohol (Scheme 3). Both electron-donating and elec- methanol and cyclobutyl methanol led to compounds
tron-withdrawing groups were tolerated on the aro- 2ab and 2ac in 64 and 61% yield, respectively,
matic ring and the unsymmetrical N,N-dialkylated acyl without any ring opening, excluding any radical path-
hydrazides 2a–f were isolated in 49–77% yield way. The N,N-unsymmetrically substituted acyl hydra-
(Scheme 3). Heteroaryl acyl hydrazides (2- and 3- zides were synthesized in lower yields (35–39%,
furanyl) underwent also this tandem multicomponent Scheme 4) due to a competitive dimethylation reaction
alkylation and the corresponding dialkylated products when sterically hindered primary alcohols, such as 2-
2g and 2h were isolated in 57 and 69%, respectively methyl pentanol, 2-ethyl hexanol or citronellol, were
(Scheme 3). Alkyl acyl hydrazides were also intro- engaged in this process.
duced in the same reaction conditions, but no alkylated
The same trend was also noticed when secondary
product was observed. The tandem reactions with alcohols were introduced as alkylating agents. The
bromo- and amino-substituted phenyl hydrazide were development of tandem three-component alkylation
also evaluated, however, unexpectedly, no reaction was with methanol and a secondary alcohol, as alkylating
observed.
agents, faces several problems. First, the dehydrogen-
Next, the alkylation of benzoyl hydrazide with a ation of secondary alcohols is faster than the methanol
variety of primary and secondary alcohols was inves- dehydrogenation, but formaldehyde is more electro-
tigated (Scheme 4). Under the optimized reaction philic than a ketone. Reduction of the imine intermedi-
conditions, we started with substituted benzyl alcohols. ate is also faster than ketimine’s one. Consequently,
Both electron-donating and electron-withdrawing sub- both monoalkylated acyl hydrazide intermediate might
stituent were tolerated on the aromatic ring and do not be produced in similar rate and the non-desired
influence the chemical yields. Compounds 2i–r were dimethylated adduct produced in higher yields. After a
rapid optimization, the amount of methanol was
evaluated in this tandem three component alkylation
with 1-phenylethanol. The best conditions for the
synthesis of nonsymmetric N,N-dialkylated acyl hydra-
°
zides were a 1 M solution of methanol at 130 C (see
Table S2). Compounds 2ah–am were thus isolated in
moderate but still reasonable yields (34–49%,
Scheme 4). Both secondary aliphatic and (hetero-)
benzylic alcohols can be used without any significant
variation of the chemical yield (Scheme 4).
To demonstrate the synthetic applicability of this
methodology, a gram scale synthesis of 2a and 2v was
planned and the nonsymmetric N,N-dialkyl acyl
hydrazides were isolated in 78 and 57% yield,
respectively.
Following up on this multicomponent reaction
based on a hydrogen auto-transfer strategy with acyl
hydrazides and two different alcohols, we thought up
to replace methanol by the more reactive ethanol. Such
tandem process would be more challenging as the
Scheme 3. Variation on the acyl substituent.
energetic demanding dehydrogenation step of ethanol
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Scheme 4. Scope of the ruthenium-catalyzed tandem three-component alkylation of phenyl hydrazide with methanol and primary or
secondary alcohols.
is appreciably lower (enthalpy of dehydrogenation: experimental results. First, DFT calculations were
ΔH= +84 kJmolÀ 1 for methanol vs. ΔH= + envisaged in Figure 2 to unveil the kinetics and to
68 kJmolÀ 1 for ethanol). After optimization of the determine the reactivity of methanol as pro-electro-
amount of ethanol, the three-component alkylation phile, compared to the n-butanol and the benzyl
furnished the benzoyl hydrazides in moderate to good alcohol, in this competitive alkylation of hydrazides.
yields (48–71%, Scheme 5). Benzylic and aliphatic The role of complex Ru1 is not only dual but also
primary alcohols (including the more sterically hin- synergistic in this process. First, Ru1 dehydrogenated
dered 2-methyl pentanol) can be use without any the alcohols to generate the carbonyl intermediate,[14a]
detrimental effect on the reactivity.
then reduced the mono or dialkylated product by
Having delineated the scope of the tandem three- returning the hydrogen atoms (Figure 2). Contained
component alkylation of hydrazides with alcohols, between the oxidation and reduction steps, two non-
DFT calculations and deuterium labelling studies were metal-catalyzed steps, consisting of the addition of the
underwent to propose a mechanism consistent with the benzoyl hydrazide to aldehyde followed by the
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energy, whatever the initial alkylated acyl hydrazide, is
very similar. In detail, the highest energy barriers to
overcome for the methylation of the N-methyl, N-
benzyl and N-butyl intermediate are 31.2, 32.3 and
31.9 kcal/mol, respectively. In sharp contrast, benzyla-
tion of the N-methyl acyl hydrazide requires an energy
of 36.5 kcal/mol, and, as a result, should not be a
feasible pathway in this tandem multicomponent
reaction. The synthesis of the nonsymmetric function-
alized acyl hydrazides depend on the formation of the
first alkylated intermediate. Accordingly, based on
these calculations and the use of a large excess of
methanol (leading to a large amount of in-situ
generated formaldehyde), the dimethylated acyl
hydrazide 3a should be theoretically the main product
in this reaction. At this stage, the reaction conditions
have to be taken into account. Formaldehyde and
Scheme 5. Scope of the ruthenium-catalyzed tandem three-
component alkylation of phenyl hydrazide with ethanol and
primary alcohols.
subsequent dehydration, completed the alkylation. It methanol are gas at the reaction temperatures and are
should be noted that these non-metal-catalyzed steps more volatile with respect to other alcohols and
required the catalytic role of methanol molecules as generated aldehydes. In the optimized conditions, the
hydrogen shuttles, and more specifically one in the amount of formaldehyde and methanol might be lower
addition step and two explicit molecules for the than those of the other alcohols/aldehydes. Then, all
dehydration (Figure 2).
the possible pathway might be not driven by energetics
First, none of the hydrogenation or dehydrogenation but by the concentration of formaldehyde and methanol
steps with Ru1 is either thermodynamically or kineti- in both liquid and gas phases.
cally demanding. Then, regarding the non-catalyzed
The deuterated adducts 2a–d4, 2v–d4 and 2am–d4
steps, namely the dehydration and to a lesser extent the were prepared in comparable yields to that of the
condensation, are the most kinetically demanding, nondeuterated versions (Schemes 2–3). Deuterium la-
whatever the combination of alcohols. Surprisingly, the belling studies highlight that the primary aliphatic or
first dehydration is in these reaction conditions more benzylic alcohols are mainly the hydride donor in the
energetically demanding than the second one. In detail, tandem reaction (Scheme 6), while both the secondary
the kinetic cost is higher with benzyl alcohol than with alcohol and methanol competed and both acted as
butanol and methanol by 4.0 and 3.4 kcal/mol, hydride donors when they are engaged in the tandem
respectively. For the second alkylation, considering the three-component alkylation (Scheme 6). HMRS analy-
formaldehyde as the main electrophile, the cost of sis were carried out also to try to determine the ratio of
Figure 2. Energy profile for the Ru1-catalyzed tandem three-component alkylation of phenyl hydrazide with methanol and butanol
or benzyl alcohol (relative Gibbs energies in kcal/mol; in black R1 =R2 =H; in red R1 =C6H5 and R2 =H; in pink R2 =C6H5; in blue
R1 =(CH2)3CH3 and R2 =H and assisting methanol molecules in green).
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been developed. The diaminocyclopentadienone ruthe-
nium carbonyl complex displayed a unique reactivity
in this hydrogen auto-transfer reaction among all the
different other cyclopentadienone iron- or ruthenium
complexes evaluated in this work. The reaction showed
a broad applicability in terms of alcohols. Not only the
still challenging methanol but also ethanol can be used
as pro-electrophilic partners, opening a route to a
diverse family of unsymmetrical N,N-dialkylated
benzoyl hydrazides. Moreover, DFT calculations as-
sume that, under competitive conditions between two
alcohols, methanol will be the most active pro-electro-
phile for the alkylation of acyl hydrazides. While this
result may seem contrary to experiments, it is the
ultimate expression that the experimentally achieved
multicomponent tandem alkylation represents the
perfect compromise between methanol and any other
alcohol tested, at the right temperature, and right
combination of alcohols.
Experimental Section
General Procedure for the Tandem Three Compo-
nent Alkylation of Acyl Hydrazides with a Primary
Alcohol and Methanol
In a 15 mL flame-dried Schlenk tube equipped with a stirring
bar, the acyl hydrazide 1 (0.5 mmol, 1 equiv.), the desired
primary alcohol (5 equiv.), Me3NO (1.11 mg, 2 mol%), meth-
anol (25 equiv., 0.5 mL), ruthenium complex Ru1 (2.51 mg,
1 mol%) and t-BuONa (48 mg, 1 equiv.) were poured in under
an argon atmosphere. The mixture was then placed into a pre-
Scheme 6. Deuterium labelling and consecutive addition.
deuterated compounds. While the precise ratio re-
mained unsuccessful, this study confirmed that com-
pound 2a bearing a CD2H fragment was the main
compound (see Scheme S135). Deuterium incorpora-
tion was more important with 2v and 2am, as the
major products contained 3 and 4 deuterium atoms for
2v, and 5 and 6 deuterium atoms for 2am (see
Schemes S135–136).
°
heated oil bath at 110 C and stirred for 24 hours. The mixture
was cooled-down to room temperature, filtrated over celite with
diethyl ether and concentrated under reduced pressure. The
1
conversion was determined by H-NMR spectroscopy and the
residue was purified by flash chromatography on silica gel
using pentane-ethyl acetate as eluent to afford the desired
product.
Consecutive additions were conducted to gain more
insights on this tandem alkylation reaction. Reaction
between benzoyl hydrazide and 2-thiophenyl-ethan-2-
General Procedure for the Tandem Three Compo-
nent Alkylation of Acyl Hydrazides with a Secon-
dary Alcohol and Methanol
°
ol at 130 C in the presence of 1 mol% of Ru1
furnished the monoalkylated product in 69% yield. A
second alkylation in methanol in the same reaction
conditions delivered the compound 2ar in 86% yield
(route (b), Scheme 6). When the order of alkylation
was reversed (route (a), Scheme 6), no alkylation of
the N-methylated intermediate 1h was observed by 1H-
NMR-analysis of the crude mixture. These results
In a 15 mL flame-dried Schlenk tube equipped with a stirring
bar, the acyl hydrazide 1 (0.5 mmol, 1 equiv.), the desired
secondary alcohol (5 equiv.), Me3NO (1.11 mg, 2 mol%),
methanol (25 equiv., 0.5 mL), ruthenium complex Ru1
(2.51 mg, 1 mol%) and t-BuONa (48 mg, 1 equiv.) were poured
in under an argon atmosphere. The mixture was then placed
°
into a pre-heated oil bath at 130 C and stirred for 24 hours. The
demonstrate that the order of reaction of the two pro- mixture was cooled-down to room temperature, filtrated over
electrophiles is crucial to reach the tandem product,
and also validate our DFT calculations.
celite with diethyl ether and concentrated under reduced
1
pressure. The conversion was determined by H-NMR spectro-
scopy and the residue was purified by flash chromatography on
silica gel using pentane-ethyl acetate as eluent to afford the
desired product.
Conclusion
In conclusion, a tandem multicomponent alkylation of
acyl hydrazides involving two different alcohols has
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Int. Ed. 2016, 55, 862–875; Angew. Chem. 2016, 128,
General Procedure for the Tandem Three Compo-
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Alcohol and Ethanol
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In a 15 mL flame-dried Schlenk tube equipped with a stirring
bar, the acyl hydrazide 1 (0.5 mmol, 1 equiv.), the desired
primary alcohol (5 equiv.), Me3NO (1.11 mg, 2 mol%), ethanol
(2,5 equiv., 73 μL), ruthenium complex Ru1 (2.51 mg, 1 mol%)
and t-BuONa (48 mg, 1 equiv.) were poured in under an argon
atmosphere. The mixture was then placed into a pre-heated oil
°
bath at 110 C and stirred for 24 hours. The mixture was cooled-
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ether and concentrated under reduced pressure. The conversion
1
was determined by H-NMR spectroscopy and the residue was
purified by flash chromatography on silica gel using pentane-
ethyl acetate as eluent to afford the desired product.
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Acknowledgements
We gratefully acknowledge financial support from the “Minis-
tère de la Recherche et des Nouvelles Technologies”, Norman-
die Université, University of Caen Normandie, CNRS, “Région
Normandie”, and the LABEX SynOrg (ANR-11-LABEX-0029).
A.P. is a Serra Húnter Fellow and thanks ICREA Academia
prize 2019 and the Spanish MICINN for project PGC2018-
097722-B-I00.
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Ruthenium-Catalyzed Three-Component Alkylation: A
Tandem Approach to the Synthesis of Nonsymmetric N,N-
Dialkyl Acyl Hydrazides with Alcohols
Adv. Synth. Catal. 2021, 363, 1–10
L. Bettoni, N. Joly, J.-F. Lohier, S. Gaillard, A. Poater*, J.-L.
Renaud*