Phosphine-free ruthenium complex-catalyzed synthesis of mono- Or dialkylated acyl hydrazides via the borrowing hydrogen strategy

Article abstract of DOI:10.1021/acs.joc.1c00654

Herein, we report a diaminocyclopentadienone ruthenium tricarbonyl complex-catalyzed synthesis of mono- or dialkylated acyl hydrazide compounds using the borrowing hydrogen strategy in the presence of various substituted primary and secondary alcohols as alkylating reagents. Deuterium labeling experiments confirm that the alcohols were the hydride source in this cascade process. Density functional theory (DFT) calculations unveil the origin and the threshold between the mono- and dialkylation.

Full text of DOI:10.1021/acs.joc.1c00654

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Phosphine-Free Ruthenium Complex-Catalyzed Synthesis of Mono-
or Dialkylated Acyl Hydrazides via the Borrowing Hydrogen
Strategy
Nicolas Joly, Léo Bettoni, Sylvain Gaillard, Albert Poater,* and Jean-Luc Renaud*
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ABSTRACT: Herein, we report a diaminocyclopentadienone ruthenium tricarbonyl complex-catalyzed synthesis of mono- or
dialkylated acyl hydrazide compounds using the borrowing hydrogen strategy in the presence of various substituted primary and
secondary alcohols as alkylating reagents. Deuterium labeling experiments confirm that the alcohols were the hydride source in this
cascade process. Density functional theory (DFT) calculations unveil the origin and the threshold between the mono- and
dialkylation.
(HFIP) and tert-amyl alcohol (Scheme 1).5 Enantiomeric
excesses, contained between 72 and 96%, were reached by
INTRODUCTION
■
The hydrogen autotransfer strategy is a blooming area of
combining Ni(II) and (S)-binapine.5 More recently, Gunana-
research.1 This methodology is a formal alkylation reaction of a
than described a Ru-Macho-catalyzed dialkylation of benzohy-
nucleophile with alcohols and allows the construction of new
drazides mainly with primary alcohols in toluene at 135 °C
C−C and/or C−N bonds.2 Such a strategy is a greener and
(Scheme 1).6
safer route than the traditional alkylation with halides or
In the last few years, the diaminocyclopentadienone iron
pseudohalides as water is the only side product and as it
tricarbonyl complexes demonstrated their efficiency not only as
shortens the synthesis. Since the pioneer work of Grigg,3 a
versatile precatalysts for the formation of C−C bonds in the
plethora of metal-based complexes, including both noble and
alkylation of ketones,7,8 indoles,9 oxidoles,10 and alcohols,11−13
earth-abundant ones, has been described in such bond-forming
but also as active complexes for the methylation and ethylation
reactions.1,2
of amines via the hydrogen autotransfer technology.8,14 Based
The N-alkylation of nitrogen-containing compounds via the
on these results and previous works by Zhou and Gunanathan,
borrowing hydrogen or hydrogen autotransfer methodology is
we initially envisioned the synthesis of substituted acyl
now a well-established area of research and an alternative to
hydrazides via the alkylation of an acyl hydrazide with a
the well-known alkylation chemistry with alkyl halides,
variety of primary and secondary alcohols in the presence of
hydrogenation of imines, or reductive amination.2a,3,4 How-
iron or ruthenium complexes (Scheme 2).
ever, while alkylation of amines or amides following this
concept has been well described in the literature, alkylation of
hydrazine derivatives is still underestimated. Zhou reported the
first alkylation of acyl hydrazides in acidic conditions in 2017.
Received: March 19, 2021
Published: April 20, 2021
A set of benzyl alcohols reacted with hydrazides in the
presence of a nickel/bis(dicyclohexylphosphine)propane
(dcpp) or nickel/(S)-binapine complex and molecular sieves
at 110 °C in a mixture of 1,1,1,3,3,3-hexafluoroisopropanol
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Scheme 1. Previous Syntheses of Alkylated Acyl Hydrazides via the Borrowing Hydrogen Strategy
Scheme 2. Outline of the Synthesis of Substituted Acyl Hydrazides
hydrazide 1a into the N,N-dialkylated hydrazide 2a in the
presence of 1 mol % of ruthenium complex Ru1 (entries 1−3,
Table 1). At lower temperatures, the N-alkylated derivative 3a
was selectively obtained albeit in low conversions. An excess of
hexanol (5 equiv) was required to reach a full conversion at
130 °C (entries 1−4, Table S1). When hexanol was introduced
as a proelectrophile in a lower amount (1.5 or 3 equiv), either
almost no reactivity or no selectivity was noticed at this
temperature (entries 1 and 2, Table S1). One of the key
parameters was the base. Inorganic bases, such as NaOH or
Na2CO3, led to low conversion when KOtBu provided the
dialkylated compound 2a with complete conversion and high
selectivity (entries 9−11, Table 1). Solvents other than
tBuOH, such as cyclopentyl methyl ether (CPME) or toluene,
led to lower selectivity and/or conversion (entries 10−11,
Table S1). Deviation of the base loading impeded both the
conversion and the selectivity (entries 4−8, Table 1). Low
conversion, but complete selectivity in favor of 3a, was
RESULTS AND DISCUSSION
■
Surprisingly, while cyclopentadienone iron complexes are
known to catalyze the amine alkylation reaction,8,14 the initial
alkylation of phenyl hydrazide with iron complexes (Fe1−Fe4)
1
failed and a mixture of compounds was observed by the H
NMR analysis. However, the introduction of ruthenium
analogues in this hydrogen-borrowing strategy opened the
way to the synthesis of alkylated hydrazide compounds. The
complex Ru1, bearing the electron-rich cyclopentadienone
ligand, has been initially developed and applied by Haak for
the activation of propargyl alcohol.15 The ruthenium
complexes Ru1−3 were activated either by addition of
Me3NO16 (Ru1 and Ru3) or thermally (Ru2), the Shvo’s
complex (Ru4) was used without any further activation. An
intensive screening of the reaction conditions is performed and
illustrated in Tables 1 and S1.
A screening of the temperature displayed that a minimum of
130 °C was necessary to obtain a full conversion of the benzoyl
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a
Table 1. Optimization of the Reaction Conditions
b
b
entry
Ru
base (equiv)
temp. (°C)
conv. (%)
2a/3a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru1
Ru2
Ru3
Ru4
NaOtBu (0.5)
NaOtBu (0.5)
NaOtBu (0.5)
NaOtBu (0.1)
NaOtBu (0.2)
NaOtBu (0.3)
NaOtBu (0.4)
NaOtBu (1)
NaOH (0.5)
Na2CO3 (0.5)
KOtBu (0.5)
NaOtBu (0.5)
NaOtBu (0.5)
NaOtBu (0.5)
90
110
130
130
130
130
130
130
130
130
130
130
130
130
23
52
100
39
64
87
100
100
23
59
100
97
−/100
−/100
98/2
−/100
34/66
59/41
71/29
98/2
−/100
83/17
91/9
95/5
60/40
63/37
38
51
a
General conditions: benzoyl hydrazide 1a (0.5 mmol), hexanol (2.5 mmol), Ru (1 mol %), Me3NO (2 mol %), base (equiv), and tBuOH (0.5 M)
b
1
for 24 h. Conversions and selectivity of 2a/3a were determined by H NMR analysis of the crude mixture.
obtained with 0.1 equiv of the base, when full conversion and
high selectivity in favor of 2a were reached with 0.5 equiv of
NaOtBu (Table 1). The ruthenium complex Ru2, a thermally
activated analogue of Ru1, also catalyzed the alkylation and
provided the N,N-dihexyl phenyl hydrazide but in a somewhat
lower conversion and selectivity (entries 3 and 12, Table 1).
The other cyclopentadienone ruthenium complexes Ru3 and
Ru4 (Shvo’s complex) were less efficient in this process
(entries 13 and 14, Table 1) and no conversion was observed
in the absence of the ruthenium complex (entry 20, Table S1).
These results, as noticed also in iron catalysis,7−14 shed light
on the importance of the diaminocyclopentadienone ligand,
which enhanced the reactivity and/or the selectivity of the
corresponding complex. Accordingly, the optimized conditions
were as follows: 0.5 mmol of benzoyl hydrazide 1a underwent
a double alkylation in the presence of 5 equiv of hexanol, 1 mol
% of complex Ru1 and 50 mol % of NaOtBu at 130 °C in
tBuOH (0.5 M) to yield 78% of the dialkylated compound 2a.
Having determined the optimized reaction conditions, the
scope of the dialkylation of acyl hydrazides 1 was delineated
(Scheme 3). A range of primary aliphatic alcohols were initially
applied in this dialkylation process (Scheme 3). N,N-
dialkylated benzoyl hydrazides 2a−h were isolated in good
yields (69−93%, Scheme 3). Methanol, whose dehydrogen-
ation is known to be more energetically demanding than this of
other alcohols,17 reacted even better than ethanol or longer
chain alcohols and the dimethylated benzoyl hydrazide 2f was
prepared in 93% yield (Scheme 3). In these reaction
conditions, primary alcohols bearing a strained small ring,
such as cyclopropyl methanol and cyclobutyl methanol, reacted
smoothly and the corresponding alkylated hydrazides 2h−i
were synthesized in 69 and 81% yield, respectively (Scheme 3).
Finally, pent-4-en-1-ol was introduced as the proelectrophile in
this process without any reduction of the alkene moiety and 2j
was obtained in 77% yield (Scheme 3). Electron-donating
(alkyl, methoxy) and electron-withdrawing groups (fluoride)
on the aryl ring were accepted in these conditions and did not
modify the reactivity. The corresponding alkylated acyl
hydrazides 2n−r were isolated in 56−90% yield (Scheme 3).
In contrast to the results reported by Gunanathan with the Ru-
Macho complex,6 alkylation of the furanoyl hydrazide
derivative furnished the dialkylated compound 2s in 77% yield.
To showcase the synthetic applicability of this approach, a
gram scale alkylation of the phenyl hydrazide with butanol was
performed and 2c was isolated in 78% yield.
When α-substituted primary alcohols were used as
proelectrophiles, whatever the reaction conditions, no N,N-
dialkylated hydrazide but only the monoalkylated product was
obtained. Owing to the opportunity to access the mono-
alkylated hydrazides 3, we extended this work to the alkylation
with secondary alcohols and sterically hindered primary
alcohols (Scheme 4).
Monoalkylated compounds 3b−e were isolated in 48−71%
yields from α- or β-substituted primary aliphatic alcohols
(Scheme 4). As observed previously, isolated alkene was
tolerated and not hydrogenated in these conditions. When
cyclopentanol was used as the proelectrophile, compound 3f
was obtained in 47% yield (Scheme 4). Benzylic secondary
alcohols can also be engaged in the monoalkylation of acyl
hydrazide. The N-alkylated derivatives 3g−n were prepared in
good yields (63−73%, Scheme 4). Electron-donating or
electron-withdrawing group on the aromatic ring have a
minimum impact on the yield and compounds 3i, 3k−n were
isolated in 63−73% yields (Scheme 4). Even a heteroaromatic
ring such as a thiophene ring can be introduced without any
depletion of the chemical yield (3j, 69%).
Under the optimized conditions, alkylation of benzoyl
hydrazide with deuterated methanol and benzylic alcohol
yielded 2f-d6 and 3g-d1 in 88 and 68% yield, respectively
(Scheme 5). The chemical yields were comparable to the
nondeuterated reaction (Schemes 3 and 4). The deuterium
incorporation, in the α-position relative to the hydrazide
function, suggested that the Ru−D complex reduced an acyl
hydrazone intermediate.
To gain more insights on the selectivity (mono- versus
dialkylation, Schemes 3 and 4), density functional theory
(DFT) calculations were performed (Figure 1). In a simplified
mechanism, the borrowing hydrogen strategy implies three
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a b
,
Scheme 3. Scope of the Ruthenium-Catalyzed Synthesis of Dialkylated Acyl Hydrazides
a
General conditions: benzoyl hydrazide 1 (0.5 mmol, 1 equiv), alcohol (2.5 mmol, 5 equiv), Ru1 (1 mol %), Me3NO (2 mol %), and NaOtBu
b
(0.25 mmol, 0.5 equiv) at 130 °C in tert-butanol (1 mL) for 24 h. Isolated yields.
steps: a metal-based complex catalyzed the dehydrogenation of
the alcohol into aldehyde or ketone and the reduction step
(steps 1 and 3), and a condensation step (in this work, the
formation of a hydrazone intermediate).17 The noncatalyzed
steps appeared to define the rate-limiting step (rds) in this
process. Figure 1 shows some mechanistic evidence for the
second alkylation of substituted benzoyl hydrazide with
methanol (providing 2f) or with the more sterically crowded
alcohols leading to the monoalkylated products 3b and 3d.18
Monoalkylation of the acyl hydrazide is always feasible,
whatever the starting alcohol, and, consequently, is not rate
determining. The second condensation of the ketone or
aldehyde on the substituted acyl hydrazide is a two-step
process (addition followed by the release of water) assisted by
the solvent (tBuOH). Finally, a facile reduction of the
unsaturated intermediate delivered the dialkylated product.
The rate-determining step of the reaction is the formation of
the iminium, the second unsaturated intermediate, with a
barrier of 31.9 kcal/mol, which leads to the achievement of 2f,
while the dialkylation giving 3b has an unbearable cost of 33.6
kcal/mol. This barrier was increased up to 37.6 kcal/mol when
the 2,2-dimethyl-1-propanol was used as the proelectrophile
for the dialkylation, thus concluding that the substitution of
hydrogens in the β-carbon of the alcohol blocks dialkylation.
On the other hand, the elongation of the alkyl chain does not
imply any impediment to this dialkylation with a maximum
kinetic cost of 31.6 and 31.8 kcal/mol for 2g and 2s,
respectively.
To avoid the study of the overall pathway for all alcohols,
calculations of the %VBur measurement index, introduced by
Cavallo and co-workers,19 allowed us to discern the threshold
between mono- and dialkylation. The results, reported in Table
S2, identify a %VBur of 47.7% for the alcohol above which the
dialkylation is unlikely. This value was obtained for cyclohexyl
methanol, an alcohol providing the monoalkylated compound
3c (Scheme 4). Even more clear is the 2,2-dimethyl propanol
that leads to the monoalkylated 3d since its sterical hindrance
is more pronounced with a %VBur of 53.1% and it shows a
more hindered steric map (see Figure 2d). In other words, the
substitution at the β-carbon of a primary alcohol is sufficient to
prevent dialkylation. The length of the alcohol alkyl chain is
also meaningless since it does not affect the environment
around the carbonyl group. Comparison of the %VBur of 2,2-
dimethyl propanol and 2-methylpentanol (%VBur of 47.9%,
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a b
,
Scheme 4. Scope of the Ruthenium-Catalyzed Synthesis of Monoalkylated Acyl Hydrazones
a
General conditions: benzoyl hydrazide 1a (0.5 mmol, 1 equiv), alcohol (2.5 mmol, 5 equiv), Ru1 (1 mol %), Me3NO (2 mol %), and NaOtBu
b
(0.25 mmol, 0.5 equiv) at 130 °C in tert-butanol (1 mL) for 24 h. Isolated yields.
Scheme 5. Deuterium Labeling Experiment
Figure 2c) also illustrated these calculations. However, it
should be noted that to perfectly reproduce the separation
between both families of substrates, it must be said that the
boundary is very subtle. As an example, 2-phenyl ethanol
furnished the dialkylated benzoyl hydrazide 2l, and the value of
its %VBur (45.2%, Figure 2b) is much higher than the value of
25.6% calculated for methanol (Figure 2a). Again, steric maps
in Figure 2 unveil such a huge difference.
CONCLUSIONS
■
In conclusion, we have disclosed the first phosphine-free
ruthenium complex-catalyzed alkylation of acyl hydrazides
using alcohols via the hydrogen autotransfer strategy. A variety
of primary as well as secondary alcohols were introduced in
this alkylation and afforded mono- and dialkylated acyl
hydrazides in moderate to good yields. These results again
highlighted that bifunctional diaminocyclopentadienone com-
plexes compete with phosphine-containing complexes in
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Figure 1. Energy profile for the dialkylation of the monoalkylated acyl hydrazides (relative Gibbs energies in kcal/mol). Alkylation of N-methyl
benzoyl hydrazide (leading to 2f, R = H in black) and alkylation of the monoalkylated compounds 3b (R = CH(CH3)C3H7 in violet) and 3d (R =
C(CH3)3, in red) using Ru1 as the catalyst.
Figure 2. Topographic steric maps (plane xy) of the alcohols that lead to the aldehyde/ketone to generate (a) 2f, (b) 2l, (c) 3b, and (d) 3d with a
radius of 3.5 Å.20
hydrogenation and dehydrogenation reactions and may open
new research areas with such complexes. Moreover, DFT
calculations and the buried volumes of the DFT-optimized
alcohols provided insight into the mechanism and allowed us
to explain the selectivity. The mono- versus dialkylation
selectivity can now be anticipated with this catalytic system as
it depends on the steric parameters of the alcohol.
Experimental Part. General considerations: All air- and
moisture-sensitive manipulations were carried out using
standard vacuum line Schlenk tube techniques. Dry toluene
was dried using a solvent purification system from Innovative
Technologies, by passage through towers containing activated
alumina. Xylene was purchased from Carlo Erba and was
distilled over sodium and stocked over 4 Å molecular sieves.
Both were deglazed prior to use by bubbling argon gas directly
in the solvent. Other solvents and chemicals were purchased
from different suppliers and used as received. Neutral alumina
was purchased from Alfa Aesar (Brockmann Grade I, 58 Å,
−60 mesh powder, S.A. 150 m2/g) and silica from Carlo Erba
(60 Å, 40−63 μm). Deuterated solvents for NMR spectros-
copy were purchased from Sigma-Aldrich and used as received.
NMR spectra were recorded on a 500 MHz Brucker
̈
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spectrometer. Proton (1H) NMR information is given in the
following format: multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; qui, quintet; sept, septet; and m, multiplet),
coupling constant(s) (J) in Hertz (Hz), and number of
protons. The prefix app is occasionally applied when the true
signal multiplicity was unresolved and br indicates the signal in
question broadened. Carbon 13C{1H} NMR spectra are
reported in ppm (δ) relative to CDCl3 unless noted otherwise.
Infrared spectra were recorded over a PerkinElmer Spectrum
100 FT-IR spectrometer using neat conditions. Melting points
were measured on noncrystalline solids using an Electro-
thermal IA 9100 apparatus. HRMS analyses were performed by
chromatography on silica gel (eluent: dichloromethane to
dichloromethane/methanol [98:2]) to afford the pure complex
Ru3 as a pale yellow powder (863 mg, 76%). 1H NMR
(CDCl3, 500 MHz): δ 7.48−7.47 (m, 4H), 7.25−7.22 (m,
6H), 7.20−7.17 (m, 2H), 7.13−7.10 (m, 4H), 7.07−7.05 (m,
4H). 13C{1H} NMR (CDCl3, 125 MHz): δ 194.5, 174.0,
132.1, 131.6, 130.9, 129.9, 128.7, 128.2, 128.1, 127.5, 107.9,
82.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C32H21RuO4 571.0483; found 571.0499.
Synthesis of Ruthenium Complex (Ru4). Ruthenium
complex Ru4 was prepared according to a procedure described
by Shvo.21 In a 50 mL dried Schlenk tube under an argon
atmosphere, ruthenium complex Ru3 (0.5 mmol, 285 mg) was
dissolved in acetone (20 mL) and a saturated solution of
sodium carbonate (10 mL) was added. The mixture was stirred
at room temperature for 0.5 h. The reaction was neutralized
with saturated ammonium chloride solution and acetone was
evaporated under vacuum. The residue was extracted with
dichloromethane, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
flash chromatography on silica gel using pentane−dichloro-
methane (1:1) as the eluent to afford the pure complex Ru4 as
́
Laboratoire de Chimie Moleculaire et Thioorganique analytical
Facilities.
Synthesis of Ruthenium Complexes. Synthesis of
Ruthenium Complex (Ru1). 15aIn a 50 mL dried Schlenk
tube under an argon atmosphere, the cyclopentadienone ligand
(2.53 mmol, 800 mg, 1 equiv) and Ru3CO12 (1.26 mmol, 806
mg, 0.5 equiv) were introduced in a dry and free-O2 toluene
solution (12 mL). The reaction mixture was stirred under
reflux in an oil bath overnight. After cooling down to room
temperature, the resulting mixture was purified on neutral
alumina oxide column chromatography (eluent: CH2Cl2 to
CH2Cl2/MeOH [98:2]). Precipitation in a mixture of
pentane/diethyl ether (1:1) followed by filtration under
vacuum gave the pure complex Ru1 as a yellow powder
1
an orange powder (195 mg, 72%). H NMR (CDCl3, 500
MHz): δ 7.12−7.06 (m, 15H), 7.01−6.99 (m, 25H), −18.37
(s, 1H). 13C{1H} NMR (CDCl3, 125 MHz): δ 200.9, 154.3,
132.2, 131.2, 130.7, 130.4, 128.0, 127.9, 127.7, 126.9, 103.6,
87.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C62H43Ru2O6 1087.1147; found 1087.1196.
1
(973 mg, 77%). H NMR (CDCl3, 500 MHz): δ 7.48−7.47
(m, 4H), 7.38−7.35 (m, 4H), 7.32−7.29 (m, 2H), 3.42−3.38
(m, 2H), 2.64−2.60 (m, 2H), 2.17 (s, 6H). 13C{1H} NMR
(CDCl3, 125 MHz): δ 199.1, 172.1, 132.9, 132.3, 128.5, 127.7,
116.7, 69.7, 50.1, 43.8. IR (neat) ν 2959, 2045, 2005, 1637,
1508, 1492, 1439, 1410, 1360, 1265, 1194, 1114, 1071, 1048,
1028, 1004, 946, 848, 785 cm−1. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C24H21RuN2O4 503.0545; found 503.0556.
Synthesis of Ruthenium Complex (Ru2). In a 50 mL dried
Schlenk tube under an argon atmosphere, tricarbonyl
ruthenium complex Ru1 (0.90 mmol, 1 equiv, 451 mg) and
triphenylphosphine (2.7 mmol, 3 equiv, 708 mg) were
solubilized in a O2-free xylene solution (24 mL) and then
refluxed in an oil bath at 140 °C overnight. Purification by flash
column chromatography on neutral aluminum oxide (eluent:
pentane/ethyl acetate [90:10] to [70:30]) afforded the pure
triphenylphosphine ruthenium complex Ru2 as a yellow
SYNTHESIS OF ACYL HYDRAZIDES
■
General Procedure A. In a round-bottomed flask, the
desired quantity of benzoic acid (10 mmol) was dissolved in
methanol (10 mL). Ten drops of sulfuric acid (96%) were
added to the solution. The mixture was refluxed for 12 h in an
oil bath. The reaction was then dissolved in water and
extracted three times with ethyl acetate. The combined organic
phases were dried over MgSO4 and concentrated under
reduced pressure. The crude product was directly engaged to
the next step. The ester was dissolved in methanol (5 mL);
hydrazine monohydrate (5 equiv) was then added and the
mixture was refluxed for 16 h. The solvent was then removed
under reduced pressure. The residue was dissolved in water
and extracted with dichloromethane. The organic layer was
washed with water and dried over sodium sulfate. The solvent
was then removed to afford the desired product 1 without
further purification.
1
powder (430 mg, 65%). H NMR (CDCl3, 500 MHz): δ
7.42−7.41 (m, 4H), 7.25−7.22 (m, 6H), 7.20−7.17 (m, 3H),
7.12−7.09 (m, 2H), 7.05−7.00 (m, 10H), 3.35−3.31 (m, 2H),
3.11−3.06 (m, 2H), 2.37 (s, 6H). 13C{1H} NMR (CDCl3, 125
MHz): δ 203.2, 166.9, 134.2, 133.9, 133.8, 133.3, 133.2, 132.0,
129.4, 128.0, 127.9, 127.6, 125.9, 111.5, 70.7, 48.7, 42.1. 31P
NMR (CDCl3, 162 MHz): δ 29.1. IR (neat): ν 3047, 2952,
2860, 2038, 1982, 1923, 1609, 1538, 1517, 1480, 1432, 1409,
1362, 1261, 1198, 1179, 1090, 1045, 944, 755, 735, 696, 586,
520, 496 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C41H36RuN2O3P 737.1507; found 737.1522.
Synthesis of Ruthenium Complex (Ru3). Ruthenium
complex Ru3 was prepared according to a procedure described
by Shvo.21 In a 50 mL dried Schlenk tube under an argon
atmosphere, 2,3,4,5-tetraphenylcyclopenta-2,4-dien-1-one (2
mmol, 768 mg, 1 equiv) and Ru3CO12 (1 mmol, 639 mg,
0.5 equiv) were introduced in a dry and free-O2 toluene
solution (12 mL). The reaction mixture was stirred under
reflux in an oil bath overnight. After cooling down to room
temperature, the resulting mixture was purified by column
4-Methoxybenzohydrazide (1b).22 According to the
general procedure A, 1b was obtained from 4-methoxybenzoic
acid (10 mmol, 1.66 g) as a white solid (1.49 g, 90%) without
1
further purification. H NMR (CDCl3, 500 MHz): δ 7.70 (d,
2H, J = 8.8 Hz), 7.43 (br. s, 1H), 6.92 (d, 2H, J = 8.8 Hz), 4.08
(br. s, 2H), 3.85 (s, 3H). 13C{1H} NMR (CDCl3, 125 MHz):
δ 168.5, 162.6, 128.8, 125.0, 114.1, 55.5.
4-Fluorobenzohydrazide (1c).22 According to the general
procedure A, 1c was obtained from methyl 4-fluorobenzoic
acid (10 mmol, 1.54 g) as a white solid (1.42 g, 92%) without
1
further purification. H NMR (CDCl3, 500 MHz): δ 7.78−
7.75 (m, 2H), 7.42 (br. s, 1H), 7.14−7.11 (m, 2H), 3.02 (br. s,
2H). 19F NMR (500 MHz, CDCl3): −107.2. 13C{1H} NMR
(CDCl3, 125 MHz): δ 167.9, 165.1 (d, J = 250.9 Hz), 129.3
(d, J = 8.9 Hz), 128.9 (d, J = 3.2 Hz), 116.0 (d, J = 21.8 Hz).
4-Methylbenzohydrazide (1d).22 According to the general
procedure A, 1d was obtained from 4-methylbenzoic acid (10
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mmol, 1.36 g) as a white solid (1.35 g, 90%) without further
purification. H NMR (CDCl3, 500 MHz): δ 7.63 (d, 2H, J =
8.1 Hz), 7.37 (br. s, 1H), 7.24 (d, 2H, J = 8.0 Hz), 4.08 (br. s,
2H), 2.40 (s, 3H). 13C{1H} NMR (CDCl3, 125 MHz): δ
168.8, 142.6, 129.9, 129.5, 127.0, 21.6.
pure product 2b as a white solid (92 mg, 84%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 9:1). Mp 80.8−81.8 °C. 1H NMR (500
MHz, CDCl3): δ 7.73 (d, 2H, J = 7.0 Hz), 7.50 (t, 1H, J = 7.4
Hz), 7.43 (t, 2H, J = 7.5 Hz), 6.54 (br. s, 1H), 2.80 (t, 4H, J =
7.6 Hz), 1.65−1.55 (m, 4H), 0.94 (t, 6H, J = 7.4 Hz). 13C{1H}
NMR (125 MHz, CDCl3): δ 166.8, 134.2, 131.7, 128.8, 127.1,
60.4, 20.5, 11.8. IR (neat): ν 3228, 2960, 1648, 1539, 1290,
1067, 946, 913, 695, 668, 604, 523 cm−1. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C13H21N2O 221.1654; found
221.1658.
1
2-Phenylbenzohydrazide (1e). According to the general
procedure A, 1e was obtained from 2-phenylbenzoic acid (10
mmol, 2.12 g) as a white solid (1.73 g, 82%) without further
purification. Mp 102.3−102.7 °C. 1H NMR (CDCl3, 500
MHz): δ 7.65 (dd, 1H, J = 1.1; 7.6 Hz), 7.49 (td, 1H, J = 1.3;
7.6 Hz), 7.44−7.36 (m, 7H), 6.53 (br. s, 1H), 3.84 (br. s, 2H).
13C{1H} NMR (CDCl3, 125 MHz): δ 170.6, 140.0, 140.0,
133.6, 130.7, 130.5, 129.0, 128.9, 128.6, 128.1, 127.8. IR
(neat): ν 3248, 1649, 1541, 1446, 1292, 1162, 1072, 969, 909,
854, 749, 691, 664, 527 cm−1. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C13H13N2O 213.1028; found 213.1030.
N′,N′-Dibutylbenzohydrazide (2c).6 According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with butan-1-ol (5 equiv, 229 μL) afforded the
pure product 2c as a white solid (101 mg, 81%) after
purification by flash column chromatography on silica gel
1
2-Methylbenzohydrazide (1f).23 According to the general
procedure A, 1f was obtained from 2-methylbenzoic acid (10
mmol, 1.36 g) as a white solid (1.39 g, 93%) without further
(pentane/ethyl acetate 9:1). H NMR (500 MHz, CDCl3): δ
7.69 (d, 2H, J = 7.3 Hz), 7.42 (t, 1H, J = 7.4 Hz), 7.33 (t, 2H, J
= 7.5 Hz), 6.87 (br. s, 1H), 2.79−2.76 (m, 4H), 1.53−1.47 (m,
4H), 1.27 (sext, 4H, J = 7.3 Hz), 0.84 (t, 6H, J = 7.3 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ 166.7, 134.1, 131.4,
128.5, 127.0, 58.1, 29.2, 20.4, 14.0.
1
purification. H NMR (CDCl3, 500 MHz): δ 7.36−7.33 (m,
2H), 7.25−7.20 (m, 2H), 6.98 (br. s, 1H), 4.10 (br. s, 2H),
2.45 (s, 3H). 13C{1H} NMR (CDCl3, 125 MHz): δ 171.0,
136.8, 134.2, 131.3, 130.6, 127.1, 126.0, 19.9.
Scale up for 2c. In a 30 mL flame-dried Schlenk tube
equipped with a stirring bar, benzohydrazide 1a (5 mmol, 680
mg), butan-1-ol (5 equiv, 2.29 mL), ruthenium complex Ru1
(25.1 mg, 1 mol %), Me3NO (11.1 mg, 2 mol %), and NaOtBu
Furan-2-carbohydrazide (1g).22 According to the general
procedure A, product 1g was obtained from furan-2-carboxylic
acid (10 mmol, 1.12 g) as a white solid (1.12 g, 88%) without
t
1
(240 mg, 0.5 equiv) were added to a solution of BuOH (10
further purification. H NMR (CDCl3, 500 MHz): δ 7.56 (br.
mL, 0.5 M) under an argon atmosphere. The mixture was
rapidly stirred at room temperature for 2 min and then placed
into a preheated oil bath at 130 °C and stirred over 24 h. The
mixture was cooled down to room temperature, filtered over a
pad of Celite and eluted with diethyl ether. The conversion
was determined by 1H NMR spectroscopy and the residue was
purified by flash chromatography on silica gel using pentane−
ethyl acetate (9:1) as the eluent to afford the pure product 2c
as a white solid (968 mg, 78%). 1H NMR data were
comparable with the previous NMR data.
s, 1H), 7.45 (dd, 1H, J = 0.7; 1.7 Hz), 7.14 (dd, 1H, J = 0.7;
3.5 Hz), 6.51 (dd, 1H, J = 1.7; 3.5 Hz), 4.02 (br. s, 2H).
13C{1H} NMR (CDCl3, 125 MHz): δ 159.6, 146.8, 144.4,
115.0, 112.2.
ALKYLATION OF ACYL HYDRAZIDES
■
General Procedure B. In a 15 mL flame-dried Schlenk
tube equipped with a stirring bar, hydrazide 1 (0.5 mmol), the
alcohol (5 equiv), Me3NO (1.1 mg, 2 mol %), ruthenium
complex Ru1 (2,51 mg, 1 mol %), and NaOtBu (24 mg, 0.5
equiv) were added to a solution of tBuOH (1.0 mL) under an
argon atmosphere. The mixture was then placed into a
preheated oil bath and stirred at 130 °C for 24 h. The mixture
was cooled down to room temperature, filtered over a pad of
Celite and eluted with diethyl ether, and concentrated under
reduced pressure. The conversion was determined by 1H NMR
spectroscopy and the residue was purified by flash chromatog-
raphy on silica gel using pentane−ethyl acetate as the eluent to
afford the desired product. For some compounds, distillation
using a glass oven Kugelrohr was necessary to remove the
excess alcohol.
N′,N′-Dipentylbenzohydrazide (2d). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with pentan-1-ol (5 equiv, 271 μL) afforded the
pure product 2d as a white solid (114 mg, 83%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 9:1). Mp 80.8−82.1 °C. 1H NMR (500
MHz, CDCl3): δ 7.73 (d, 2H, J = 7.0 Hz), 7.50 (t, 1H, J = 7.4
Hz), 7.43 (t, 2H, J = 7.5 Hz), 6.53 (br. s, 1H), 2.84−2.79 (m,
4H), 1.61−1.54 (m, 4H), 1.33−1.29 (m, 8H), 0.88 (t, 6H, J =
7.1 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 166.8, 134.3,
131.6, 128.8, 127.1, 58.6, 29.6, 26.9, 22.7, 14.2. IR (neat): ν
3229, 2943, 2929, 1651, 1541, 1470, 1314, 1080, 937, 695,
680, 669, 604, 527, 506, 444 cm−1. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C17H29N2O 277.2280; found 277.2284.
N′,N′-Dioctylbenzohydrazide (2e). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with octan-1-ol (5 equiv, 392 μL) afforded the
pure product 2e as a white solid (142 mg, 79%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 9:1). The excess of octan-1-ol was then
removed by distillation (T = 120 °C, P = 110 mbar). Mp
82.1−84.5 °C. 1H NMR (500 MHz, CDCl3): δ 7.71 (d, 2H, J
= 7.0 Hz), 7.47 (t, 1H, J = 7.4 Hz), 7.40 (t, 2H, J = 7.5 Hz),
6.61 (br. s, 1H), 2.82−2.79 (m, 4H), 1.53 (app t, 4H, J = 7.3
Hz), 1.32−1.24 (m, 20H), 0.84 (t, 6H, J = 7.0 Hz). 13C{1H}
NMR (125 MHz, CDCl3): δ 166.8, 134.3, 131.6, 128.72,
N′,N′-Dihexylbenzohydrazide (2a).6 According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with hexan-1-ol (5 equiv, 309 μL) afforded the
pure product 2a as a white solid (119 mg, 78%) after
purification by flash column chromatography on silica gel
1
(pentane/ethyl acetate 9:1). H NMR (500 MHz, CDCl3): δ
7.74−7.72 (m, 2H), 7.52−7.49 (m, 1H), 7.45−7.42 (m, 2H),
6.52 (br. s, 1H), 2.83−2.80 (m, 4H), 1.58−1.54 (m, 4H),
1.34−1.24 (m, 12H), 0.85 (t, 6H, J = 6.9 Hz). 13C{1H} NMR
(125 MHz, CDCl3): δ 166.9, 134.4, 131.7, 128.9, 127.2, 58.8,
32.0, 27.3, 27.2, 22.8, 14.3.
N′,N′-Dipropylbenzohydrazide (2b). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with propan-1-ol (5 equiv, 187 μL) afforded the
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127.1, 58.6, 31.9, 29.6, 29.4, 27.4, 27.2, 22.8, 14.2. IR (neat): ν
32232, 2941, 1650, 1542, 1472, 1316, 1081, 932, 680, 672,
604, 527, 506, 482 cm−1. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H41N2O 361.3219; found 361.3219.
131.6, 128.5, 127.0, 114.9, 57.6, 31.3, 26.4. IR (neat): ν 3231,
3062, 2951, 2841, 1645, 1536, 1302, 1288, 1073, 991, 909,
801, 694, 669 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C17H25N2O 273.1967; found: 273.1968.
N′,N′-Dimethylbenzohydrazide (2f).6 According to a
modified general procedure B, alkylation of benzohydrazide
1a (0.5 mmol, 68 mg) with methanol, used as the solvent (0.5
M), afforded the pure product 2f as a white solid (76 mg, 93%)
after purification by flash column chromatography on silica gel
(pure ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.69 (d,
2H, J = 7.0 Hz), 7.42 (t, 1H, J = 7.4 Hz), 7.33 (t, 2H, J = 7.5
Hz), 7.24 (br. s, 1H), 2.64 (s, 6H). 13C{1H} NMR (125 MHz,
CDCl3): δ 165.8, 133.8, 131.6, 128.5, 127.1, 47.6.
N′,N′-Dibenzylbenzohydrazide (2k).24 According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with benzyl alcohol (5 equiv, 265 μL) afforded
the pure product 2k as a white solid (134 mg, 85%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 9:1). The excess of benzyl alcohol was
then removed by distillation (T = 105 °C, P = 110 mbar). 1H
NMR (500 MHz, CDCl3): δ 7.42 (t, 7H, J = 7.7 Hz), 7.36−
7.27 (m, 8H), 7.00 (br. s, 1H), 4.33 (s, 4H). 13C{1H} NMR
(125 MHz, CDCl3): δ 167.5, 137.5, 134.1, 131.5, 129.4, 128.6,
128.5, 127.6, 126.9, 59.4.
N′,N′-Diethylbenzohydrazide (2g).6 According to a
modified general procedure B, alkylation of benzohydrazide
1a (0.5 mmol, 68 mg) with ethanol (10 equiv, 292 μL)
afforded the pure product 2g as a white solid (81 mg, 84%)
after purification by flash column chromatography on silica gel
N′,N′-Diphenethylbenzohydrazide (2l). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with 2-phenylethan-1-ol (5 equiv, 299 μL)
afforded the pure product 2l as a white solid (145 mg, 84%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 3:1). The excess of 2-phenylethan-1-ol
was then removed by distillation (T = 120 °C, P = 110 mbar).
1
(pentane/ethyl acetate 2:8). H NMR (500 MHz, CDCl3): δ
7.74 (d, 2H, J = 7.2 Hz), 7.49 (t, 1H, J = 7.4 Hz), 7.32 (t, 2H, J
= 7.5 Hz), 6.41 (br. s, 1H), 2.86 (q, 4H, J = 7.1 Hz), 1.16 (t,
6H, J = 7.1 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 167.1,
134.2, 131.7, 128.8, 127.1, 52.5, 12.2.
1
Mp 87.3−88.4 °C. H NMR (500 MHz, CDCl3): δ 7.52 (d,
N′,N′-Bis(cyclopropylmethyl)benzohydrazide (2h). Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with cyclopropyl methanol (5
equiv, 202 μL) afforded the pure product 2h as a white solid
(84 mg, 69%) after purification by flash column chromatog-
raphy on silica gel (pentane/ethyl acetate 3:1). Mp 73.9−75.8
°C. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, 2H, J = 7.0 Hz),
7.51 (t, 1H, J = 7.4 Hz), 7.44 (t, 2H, J = 7.4 Hz), 6.98 (br. s,
1H), 2.86 (d, 4H, J = 6.7 Hz), 1.06−0.98 (m, 2H), 0.55−0.50
(m, 4H), 0.16 (q, 4H, J = 4.7 Hz). 13C{1H} NMR (125 MHz,
CDCl3): δ 166.7, 134.5, 131.6, 128.8, 127.0, 61.9, 8.4, 3.6. IR
(neat): ν 3232, 3070, 2995, 1649, 1543, 1313, 1177, 1017, 935,
892, 698, 670, 597, 520, 448, 409 cm−1. HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C15H21N2O 245.1654; found 245.1651.
N′,N′-Bis(cyclobutylmethyl)benzohydrazide (2i). Accord-
ing to the general procedure B, alkylation of benzohydrazide 1a
(0.5 mmol, 68 mg) with pent-4-en-1-ol (5 equiv, 256 μL)
afforded the pure product 2i as a white solid (105 mg, 77%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 3:1). Mp 75.6−77.7 °C. 1H NMR (500
MHz, CDCl3): δ 7.69 (d, 2H, J = 7.1 Hz), 7.43 (t, 1H, J = 7.4
Hz), 7.34 (t, 2H, J = 7.6 Hz), 7.00 (br. s, 1H), 5.74 (td, 2H, J =
6.7; 16.9 Hz), 4.98−4.95 (m, 2H), 4.92−4.88 (m, 2H), 2.83−
2.78 (m, 4H), 2.12−2.08 (m, 4H), 1.65−1.57 (m, 4H).
13C{1H} NMR (125 MHz, CDCl3): δ 166.8, 138.3, 134.0,
131.6, 128.5, 127.0, 114.9, 57.6, 31.3, 26.4. IR (neat): ν 3231,
3062, 2951, 2841, 1645, 1536, 1302, 1288, 1073, 991, 909,
801, 694, 669 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C17H25N2O 273.1967; found: 273.1968.
2H, J = 7.4 Hz), 7.40 (t, 1H, J = 7.4 Hz), 7.30 (t, 2H, J = 7.5
Hz), 7.20−7.17 (m, 5H), 7.12−7.09 (m, 5H), 6.75 (br. s, 1H),
3.15−3.12 (m, 4H), 2.85−2.81 (m, 4H). 13C{1H} NMR (125
MHz, CDCl3): δ 166.9, 139.9, 133.7, 131.8, 128.8, 128.7,
128.6, 127.1, 126.3, 59.4, 34.0. IR (neat): ν 3223, 3059, 3026,
2961, 2839, 1643, 1547, 1494, 1453, 1293, 1124, 1027, 934,
752, 727, 694, 671, 613, 498, 471 cm−1. HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C23H25N2O 345.1967; found 345.1967.
N′,N′-Bis(3-phenylpropyl)benzohydrazide (2m). Accord-
ing to the general procedure B, alkylation of benzohydrazide 1a
(0.5 mmol, 68 mg) with 3-phenylpropan-1-ol (5 equiv, 327
μL) afforded the pure product 2m as a white solid (141 mg,
76%) after purification by flash column chromatography on
silica gel (pentane/ethyl acetate 3:1). The excess of 3-
phenylpropan-1-ol was then removed by distillation (T =
1
130 °C, P = 110 mbar). Mp 85.5−88.9 °C. H NMR (500
MHz, CDCl3): δ 7.59 (d, 2H, J = 7.4 Hz), 7.38 (t, 1H, J = 7.5
Hz), 7.29 (t, 2H, J = 7.5 Hz), 7.18−7.15 (m, 5H), 7.10−7.07
(m, 5H), 6.52 (br. s, 1H), 2.74 (t, 4H, J = 7.2 Hz), 2.61 (t, 4H,
J = 7.3 Hz), 1.76 (quint, 4H, J = 7.3 Hz). 13C{1H} NMR (125
MHz, CDCl3): δ 166.8, 142.1, 134.0, 131.7, 128.7, 128.6,
128.4, 128.4, 127.0, 125.9, 57.7, 33.4, 28.9. IR (neat): ν 3245,
3026, 2946, 2851, 1650, 1533, 1312, 1286, 1107, 1028, 938,
800, 751, 694, 669, 607, 596, 503, 489, 460 cm−1. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C25H29N2O 373.2280; found
373.2284.
2-Methyl-N′,N′-dipropylbenzohydrazide (2n). According
to the general procedure B, alkylation of 2-methylbenzohy-
drazide 1f (0.5 mmol, 75 mg) with propan-1-ol (5 equiv, 187
μL) afforded the pure product 2n as a white solid (92 mg,
79%) after purification by flash column chromatography on
N′,N′-Di(pent-4-en-1-yl)benzohydrazide (2j). According to
the general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with pent-4-en-1-ol (5 equiv, 256 μL) afforded
the pure product 2j as a white solid (105 mg, 77%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 3:1). Mp 70.7−71.3 °C. 1H NMR (500
MHz, CDCl3): δ 7.69 (d, 2H, J = 7.1 Hz), 7.43 (t, 1H, J = 7.4
Hz), 7.34 (t, 2H, J = 7.6 Hz), 7.00 (br. s, 1H), 5.74 (td, 2H, J =
6.7; 16.9 Hz), 4.98−4.95 (m, 2H), 4.92−4.88 (m, 2H), 2.83−
2.78 (m, 4H), 2.12−2.08 (m, 4H), 1.65−1.57 (m, 4H).
13C{1H} NMR (125 MHz, CDCl3): δ 166.8, 138.3, 134.0,
1
silica gel (pentane/ethyl acetate 9:1). Mp 74.0−78.9 °C. H
NMR (500 MHz, CDCl3): δ 7.32−7.29 (m, 2H), 7.23−7.17
(m, 2H), 6.15 (br. s, 1H), 2.76 (t, 4H, J = 7.7 Hz), 2.45 (s,
3H), 1.60 (sext, 4H, J = 7.6 Hz), 0.95 (t, 6H, J = 7.4 Hz).
13C{1H} NMR (125 MHz, CDCl3): δ 169.0, 136.5, 135.6,
131.1, 130.1, 126.7, 125.8, 60.4, 20.5, 19.8, 11.9. IR (neat): ν
3214, 3056, 2961, 2937, 2857, 2833, 1653, 1538, 1466, 1375,
1314, 1281, 1165, 1067, 948, 914, 867, 750, 723, 691, 660,
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466, 455 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H23N2O 221.1654; found 221.1658.
cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H31N2O2 307.2386; found 307.2383.
N′,N′-Dibutylfuran-2-carbohydrazide (2s). According to
the general procedure B, alkylation of furan-2-carbohydrazide
1g (0.5 mmol, 63 mg) with butan-1-ol (5 equiv, 229 μL)
afforded the pure product 2s as a white solid (92 mg, 77%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 3:1). Mp 68.9−71.1 °C. 1H NMR (500
MHz, CDCl3): 7.41 (dd, 1H, J = 0.7; 1.7 Hz), 7.14 (dd, 1H, J
= 0.7; 3.5 Hz), 6.78 (br. s, 1H), 6.49 (dd, 1H, J = 1.7; 3.5 Hz),
2.79−2.76 (m, 4H), 1.55−1.49 (m, 4H), 1.30 (sext, 4H, J = 7.4
Hz), 0.87 (t, 6H, J = 7.4 Hz). 13C{1H} NMR (125 MHz,
CDCl3): δ 157.5, 147.4, 143.9, 115.0, 112.2, 58.6, 29.1, 20.5,
14.1. IR (neat): ν 3238, 2956, 2865, 1655, 1591, 1470, 1293,
1082, 1008, 885, 748, 596 cm−1. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C13H23N2O2 239.1760; found 239.1763.
N′-(2-Methylpentyl)benzohydrazide (3b). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with 2-methylpentan-1-ol (5 equiv, 309 μL)
afforded the pure product 3b as a white solid (78 mg, 71%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 1:1). Mp 96.7−97.8 °C. 1H NMR (500
MHz, CDCl3): δ 8.03 (br. s, 1H), 7.76−7.73 (m, 2H), 7.51−
7.48 (m, 1H), 7.40 (t, 2H, J = 7.5 Hz), 4.93 (br. s, 1H), 2.84
(dd, 1H, J = 5.8; 11.2 Hz), 2.69 (dd, 1H, J = 7.5; 11.2 Hz),
1.69−1.63 (m, 1H), 1.42−1.33 (m, 2H), 1.31−1.24 (m, 1H),
1.17−1.11 (m, 1H), 0.96 (d, 3H, J = 6.7 Hz), 0.85 (t, 3H, J =
7.0 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 167.3, 133.1,
131.8, 128.7, 127.0, 58.8, 37.2, 31.9, 20.1, 18.1, 14.4. IR (neat):
ν 2988, 2901, 1648, 1493, 1392, 1232, 1067, 895, 694, 615,
432 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H21N2O 221.1654; found: 221.1658.
N′-(Cyclohexylmethyl)benzohydrazide (3c). According to
the general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with cyclohexyl methanol (5 equiv, 307 μL)
afforded the pure product 3c as a white solid (56 mg, 48%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 1:1). Mp 98.2−99.9 °C. 1H NMR (500
MHz, CDCl3): δ 7.73 (d, 2H, J = 7.3 Hz), 7.50 (t, 1H, J = 7.4
Hz), 7.43 (t, 2H, J = 7.5 Hz), 2.78 (d, 2H, J = 6.7), 1.83−1.81
(m, 2H), 1.74−1.67 (m, 2H), 1.54−1.49 (m, 1H), 1.29−1.14
(m, 4H), 1.02−0.95 (m, 2H). 13C{1H} NMR (125 MHz,
CDCl3): δ 167.3, 133.1, 131.9, 128.8, 126.9, 59.1, 36.8, 31.4,
26.7, 26.1. IR (neat): ν 3243, 2972, 2941, 1648, 1532, 1492,
1376, 1218, 1082, 896, 679, 652, 414 cm−1. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C14H21N2O 233.1654; found
233.1651.
N′,N′-Bis(cyclobutylmethyl)-4-fluorobenzohydrazide
(2o). According to the general procedure B, alkylation of 4-
fluorobenzohydrazide 1c (0.5 mmol, 77 mg) with cyclobutyl
methanol (5 equiv, 242 μL) afforded the pure product 2o as a
white solid (81 mg, 56%) after purification by flash column
chromatography on silica gel (pentane/ethyl acetate 3:1). Mp
77.9−79.2 °C. 1H NMR (500 MHz, CDCl3): δ 7.72−7.69 (m,
2H), 7.07 (t, 2H, J = 8.6 Hz), 6.59 (br. s, 1H), 2.87 (d, 4H, J =
6.9 Hz), 2.61−2.55 (m, 2H), 2.06−12.00 (m, 4H), 1.91−1.83
(m, 2H), 1.81−1.68 (m, 6H). 19F NMR (500 MHz, CDCl3):
−108.1. 13C{1H} NMR (125 MHz, CDCl3): δ 165.4, 132.4,
129.2 (d, J = 8.8 Hz), 115.7 (d, J = 22.5 Hz), 114.6, 64.0, 34.1,
27.6, 19.2. IR (neat): ν 3280, 3048, 2957, 2933, 2855, 1650,
1603, 1553, 1500, 1454, 1322, 1292, 1277, 1236, 1225, 1159,
1097, 930, 855, 765, 654, 625, 603 cm−1. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H24N2OF 291.1873; found
291.1879.
4-Methyl-N′,N′-di(pent-4-en-1-yl)benzohydrazide (2p).
According to the general procedure B, alkylation of 4-
methylbenzohydrazide 1d (0.5 mmol, 75 mg) with pent-4-
en-1-ol (5 equiv, 256 μL) afforded the pure product 2p as a
white solid (109 mg, 76%) after purification by flash column
chromatography on silica gel (pentane/ethyl acetate 3:1). Mp
71.2−72.4 °C. 1H NMR (500 MHz, CDCl3): δ 7.62 (d, 2H, J
= 8.1 Hz), 7.22 (d, 2H, J = 8.0 Hz), 6.59 (br. s, 1H), 5.75 (td,
2H, J = 6.7; 16.9 Hz), 5.03−4.98 (m, 2H), 4.95−4.93 (m, 2H),
2.86−2.83 (m, 4H), 2.39 (s, 3H), 2.14−2.10 (m, 4H), 1.69−
1.63 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3): δ 166.7,
142.2, 138.4, 131.2, 129.4, 127.1, 115.0, 57.8, 31.4, 26.5, 21.6.
IR (neat): ν 3230, 2949, 1646, 1492, 1312, 1288, 1071, 909,
774, 694, 669 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H27N2O 287.2123; found 287.2127.
N′,N′-Dibutyl-[1,1′-biphenyl]-2-carbohydrazide (2q). Ac-
cording to the general procedure B, alkylation of [1,1′-
biphenyl]-2-carbohydrazide 1e (0.5 mmol, 106 mg) with
butan-1-ol (5 equiv, 229 μL) afforded the pure product 2q as a
white solid (88 mg, 54%) by silica flash column chromatog-
raphy (pentane/ethyl acetate 9:1). Mp 77.5−80.9 °C. 1H
NMR (500 MHz, CDCl3): δ 7.65 (dd, 1H, J = 1.3; 7.6 Hz),
7.49−7.45 (m, 3H), 7.43−7.37 (m, 5H), 5.76 (br. s, 1H), 2.43
(t, 4H, J = 7.3 Hz), 1.20−1.18 (m, 8H), 0.82 (t, 6H, J = 7.1
Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 168.3, 140.4,
139.6, 135.1, 130.3, 130.1, 129.0, 128.9, 128.8, 128.0, 127.7,
57.5, 28.4, 20.5, 14.0. IR (neat): ν 3215, 3058, 2955, 2861,
1651, 1543, 1466, 1317, 1304, 1073, 919, 760, 741, 696, 660,
565, 521 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C21H29N2O 325.2280; found 325.2286.
N′-Neopentylbenzohydrazide (3d). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with 2,2-dimethylpropan-1-ol (5 equiv, 220 mg)
afforded the pure product 3d as a white solid (71 mg, 69%)
after purification by flash column chromatography on silica gel
(pentane/ethyl acetate 1:1). Mp 95.8−96.9 °C. 1H NMR (500
MHz, CDCl3): δ 7.97 (br. s, 1H), 7.73 (d, 2H, J = 7.3 Hz),
7.47 (t, 1H, J = 7.4 Hz), 7.39 (t, 2H, J = 7.5 Hz), 4.88 (br. s,
1H), 2.72 (s, 2H), 0.98 (s, 9H). 13C{1H} NMR (125 MHz,
CDCl3): δ 167.3, 133.1, 131.8, 128.8, 126.9, 64.4, 31.3, 27.8.
IR (neat): ν 3231, 2954, 2843, 1628, 1460, 1364, 1328, 1160,
888, 695, 550 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C12H19N2O 207.1497; found 207.1499.
4-Methoxy-N′,N′-dipentylbenzohydrazide (2r). According
to the general procedure B, alkylation of 4-methoxybenzohy-
drazide 1b (0.5 mmol, 83 mg) with pentan-1-ol (5 equiv, 271
μL) afforded the pure product 2r as a white solid (138 mg,
90%) after purification by flash column chromatography on
1
silica gel (pentane/ethyl acetate 9:1). Mp 77.2−78.8 °C. H
NMR (500 MHz, CDCl3): δ 7.70 (d, 2H, J = 8.8 Hz), 6.91 (d,
2H, J = 8.8 Hz), 6.46 (br. s, 1H), 3.85 (s, 3H), 2.82−2.79 (m,
4H), 1.57−1.53 (m, 4H), 1.31−1.29 (m, 8H), 0.86 (t, 6H, J =
7.0 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 166.3, 162.3,
128.9, 126.5, 114.0, 58.7, 55.6, 29.6, 26.9, 22.7, 14.2. IR (neat):
ν 3243, 2932, 2858, 1647, 1607, 1537, 1508, 1459, 1289, 1253,
1182, 1082, 1026, 942, 929, 848, 771, 668, 631, 609, 534, 515
N′-(3,7-Dimethyloct-6-en-1-yl)benzohydrazide (3e). Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with 3,7-dimethyloct-6-en-1-ol
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(5 equiv, 456 μL) afforded the pure product 3e as a light
yellow solid (77 mg, 56%) after purification by flash column
chromatography on silica gel (pentane/ethyl acetate 1:1). Mp
Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 167.5, 148.0,
147.0, 137.2, 133.0, 131.9, 128.8, 127.0, 120.8, 108.3, 107.4,
101.1, 59.9, 21.4. IR (neat): ν 3061, 2970, 2888, 1634, 1485,
1438, 1239, 1037, 934, 806, 692, 638, 442 cm−1. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H17N2O3 285.1239; found
285.1245.
1
98.7−99.4 °C. H NMR (500 MHz, CDCl3): δ 7.87 (br. s,
1H), 7.74 (d, 2H, J = 7.3 Hz), 7.50 (t, 1H, J = 7.4 Hz), 7.42 (t,
2H, J = 7.6 Hz), 5.09−5.06 (m, 1H), 3.00−2.90 (m, 2H),
2.02−1.91 (m, 2H), 1.73−1.62 (m, 5H), 1.59−1.49 (m, 5H),
1.83−1.81 (m, 2H), 0.89 (d, 3H, J = 6.6 Hz). 13C{1H} NMR
(125 MHz, CDCl3): δ 167.4, 133.0, 131.9, 131.4, 128.8, 127.0,
124.8, 50.5, 37.3, 35.2, 30.6, 25.8, 25.6, 19.7, 17.8. IR (neat): ν
3243, 2985, 2905, 1649, 1497, 1421, 1364, 1292, 1068, 982,
926, 692, 617, 418 cm−1. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H27N2O 275.2123; found 275.2119.
N′-(1-(Thiophen-2-yl)ethyl)benzohydrazide (3j).5 Accord-
ing to the general procedure B, alkylation of benzohydrazide 1a
(0.5 mmol, 68 mg) with (thiophen-2-yl)ethan-1-ol (5 equiv,
320 mg) afforded the pure product 3j as a light yellow solid
(85 mg, 69%) after purification by flash column chromatog-
raphy on silica gel (pentane/ethyl acetate 3:1). 1H NMR (500
MHz, CDCl3): δ 7.71 (br. s, 1H), 7.67 (d, 2H, J = 7.2 Hz),
7.48 (t, 1H, J = 7.3 Hz), 7.39 (t, 2H, J = 7.5 Hz), 7.26−7.24
(m, 1H), 6.98−6.95 (m, 2H), 5.13 (br. s, 1H), 4.54 (q, 1H, J =
6.5 Hz), 1.50 (d, 3H, J = 6.5 Hz). 13C{1H} NMR (125 MHz,
CDCl3): δ 167.6, 147.1, 132.9, 132.0, 128.8, 127.0, 126.8,
124.9, 124.7, 55.8, 22.0.
N′-Cyclopentylbenzohydrazide (3f). According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with cyclopentanol (5 equiv, 218 μL) afforded
the pure product 3f as a white solid (48 mg, 47%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 1:1). Mp 94.5−96.8 °C. 1H NMR (500
MHz, CDCl3): δ 7.76−7.74 (m, 2H), 7.68 (br. s, 1H), 7.53−
7.50 (m, 1H), 7.46−7.43 (m, 2H), 4.87 (br. s, 1H), 3.59−3.58
(m, 1H), 1.79−1.70 (m, 4H), 1.61−1.51 (m, 4H). 13C{1H}
NMR (125 MHz, CDCl3): δ 167.4, 133.2, 131.9, 128.9, 127.0,
61.9, 31.4, 24.3. IR (neat): ν 3062, 2956, 1634, 1578, 1536,
1455, 1075, 989, 798, 693 cm−1. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C12H17N2O 205.1341; found 205.1342.
N′-(1-Phenylethyl)benzohydrazide (3g).5 According to the
general procedure B, alkylation of benzohydrazide 1a (0.5
mmol, 68 mg) with 1-phenylethan-1-ol (5 equiv, 299 μL)
afforded the pure product 3g as a white solid (86 mg, 72%)
after purification by flash column chromatography on silica gel
N′-(1-(4-Methoxyphenyl)ethyl)benzohydrazide (3k).5 Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with 1-(4-methoxyphenyl)-
ethan-1-ol (5 equiv, 380 mg) afforded the pure product 3k as a
white solid (93 mg, 69%) after purification by flash column
1
chromatography on silica gel (pentane/ethyl acetate 3:1). H
NMR (500 MHz, CDCl3): δ 7.56−7.55 (m, 2H), 7.43−7.40
(m, 1H), 7.34−7.31 (m, 3H), 7.25 (d, 2H, J = 8.5 Hz), 6.81
(d, 2H, J = 8.5 Hz), 4.12 (q, 1H, J = 6.6 Hz), 3.73 (s, 3H), 1.34
(d, 3H, J = 6.6 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ
167.4, 159.2, 135.2, 133.1, 131.9, 128.8, 128.5, 127.0, 114.1,
59.5, 55.4, 21.3.
N′-(1-(4-(Trifluoromethyl)phenyl)ethyl)benzohydrazide
(3l).5 According to the general procedure B, alkylation of
benzohydrazide 1a (0.5 mmol, 68 mg) with 1-(4-
(trifluoromethyl)phenyl)ethan-1-ol (5 equiv, 475 mg) afforded
the pure product 3l as a white solid (97 mg, 63%) after
purification by flash column chromatography on silica gel
1
(pentane/ethyl acetate 3:1). H NMR (500 MHz, CDCl3): δ
7.76 (br. s, 1H), 7.64−7.63 (m, 2H), 7.49−7.46 (m, 2H),
7.40−7.33 (m, 5H), 7.30−7.27 (m, 1H), 5.12 (br. s, 1H), 4.23
(q,1H, J = 6.6 Hz), 1.42 (d, 3H, J = 6.6 Hz). 13C{1H} NMR
(125 MHz, CDCl3): δ 167.4, 143.1, 132.9, 131.9, 128.7, 128.7,
127.7, 127.3, 127.0, 60.1, 21.2.
1
(pentane/ethyl acetate 3:1). H NMR (500 MHz, CDCl3): δ
N′-(1-(Naphthalen-2-yl)ethyl)benzohydrazide (3h). Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with 1-(naphthalen-2-yl)ethan-
1-ol (5 equiv, 430 mg) afforded the pure product 3h as a white
solid (97 mg, 67%) after purification by flash column
chromatography on silica gel (pentane/ethyl acetate 3:1).
7.63−7.61 (m, 4H), 7.53 (d, 2H, J = 8.1 Hz), 7.52−7.49 (m,
1H), 7.42−7.37 (m, 3H), 5.07 (br. s, 1H), 4.33 (q, 1H, J = 6.6
Hz), 1.43 (d, 3H, J = 6.6 Hz). 19F NMR (500 MHz, CDCl3):
−62.4. 13C{1H} NMR (125 MHz, CDCl3): δ 167.8, 147.6,
132.8, 132.2, 128.9, 128.7 (d, J = 139 Hz), 127.7, 127.0, 125.7
(q, J = 3.7 Hz), 59.9, 21.6.
1
Mp 100.1−100.6 °C. H NMR (500 MHz, CDCl3): δ 7.87−
N′-(1-(4-Chlorophenyl)ethyl)benzohydrazide (3m). Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with 1-(4-chlorophenyl)ethan-
1-ol (5 equiv, 390 mg) afforded the pure product 3m as a
white solid (96 mg, 70%) after purification by flash column
chromatography on silica gel (pentane/ethyl acetate 3:1). Mp
98.3−99.9 °C. 1H NMR (500 MHz, CDCl3): δ 7.63−7.61 (m,
2H), 7.51−7.48 (m, 1H), 7.45 (br. s, 1H), 7.41−7.38 (m, 2H),
7.35−7.31 (m, 4H), 5.05 (br. s, 1H), 4.22 (q, 1H, J = 6.6 Hz),
1.39 (d, 3H, J = 6.6 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ
167.6, 141.9, 133.4, 132.9, 132.1, 128.9, 128.8, 128.7, 127.0,
59.6, 21.4. IR (neat): ν 2968, 1636, 1462, 1312, 1129, 1075,
1017, 867, 805, 716, 692, 483, 413 cm−1. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H16N2OCl 275.1602; found
275.1608.
7.81 (m, 4H), 7.61−7.57 (m, 3H), 7.51−7.44 (m, 4H), 7.37−
7.34 (m, 2H), 5.19 (br. s, 1H), 4.41 (q, 1H, J = 6.6 Hz), 1.51
(d, 3H, J = 6.6 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ
167.5, 140.8, 133.6, 133.2, 133.0, 132.0, 128.8, 128.6, 128.0,
127.8, 127.0, 126.3, 126.0, 125.3, 60.4, 21.5. IR (neat): ν 3266,
2962, 1648, 1519, 1392, 1285, 912, 893, 751, 693, 486 cm−1.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O
291.1422; found 291.1426.
N′-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)benzohydrazide (3i).
According to the general procedure B, alkylation of
benzohydrazide (0.5 mmol, 68 mg) with 1-(benzo[d][1,3]-
dioxol-5-yl)ethan-1-ol (5 equiv, 415 mg) afforded the pure
product 3i as a light yellow solid (94 mg, 66%) after
purification by flash column chromatography on silica gel
(pentane/ethyl acetate 3:1). Mp 99.2−99.8 °C. 1H NMR (500
MHz, CDCl3): δ 7.65−7.63 (m, 3H), 7.47 (t, 1H, J = 7.5 Hz),
7.37 (t, 2H, J = 7.5 Hz), 6.93 (d, 1H, J = 1.4 Hz), 6.80 (dd,
1H, J = 1.4; 7.9 Hz), 6.74 (d, 1H, J = 7.9 Hz), 5.93 (s, 2H),
5.04 (br. s, 1H), 4.15 (q, 1H, J = 6.5 Hz), 1.36 (d, 3H, J = 6.6
N′-(1-(4-Fluorophenyl)ethyl)benzohydrazide (3n).5 Ac-
cording to the general procedure B, alkylation of benzohy-
drazide 1a (0.5 mmol, 68 mg) with 1-(4-fluorophenyl)ethan-1-
ol (5 equiv, 350 mg) afforded the pure product 3n as a white
solid (94 mg, 73%) after purification by flash column
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1
Author Contributions
chromatography on silica gel (pentane/ethyl acetate 3:1). H
NMR (500 MHz, CDCl3): δ 7.71 (br. s, 1H), 7.63 (d, 2H, J =
7.2 Hz), 7.50−7.47 (m, 1H), 7.40−7.34 (m, 4H), 7.06−6.99
(m, 2H), 5.00 (br. s, 1H), 4.24 (q, 1H, J = 6.6 Hz), 1.38 (d,
3H, J = 6.6 Hz). 19F NMR (500 MHz, CDCl3): −115.1.
13C{1H} NMR (125 MHz, CDCl3): δ 167.5, 161.3 (d, J =
243.8 Hz), 138.9 (d, J = 3.1 Hz), 132.9, 132.0, 128.9 (d, J = 7.9
Hz), 128.8, 127.0, 115.4 (d, J = 21.1 Hz), 59.4, 21.3.
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the
■
Deuterium Labeling. N′,N′-Dimethylbenzohydrazide
(2f-d6). According to a modified general procedure B,
alkylation of benzohydrazide 1a (0.5 mmol, 68 mg) with
methanol-d4 used as the solvent (0.5 M) afforded the pure
product 2f-d6 as a white solid (75 mg, 88%) after purification
by flash column chromatography on silica gel (pure ethyl
̀
“Ministere de la Recherche et des Nouvelles Technologies”,
Normandie Université, University of Caen Normandie, CNRS,
“Région Normandie”, and the LABEX SynOrg (ANR-11-
́
LABEX-0029). A.P. is a Serra Hunter Fellow and wishes to
thank ICREA Academia prize 2019 and the Spanish MICINN
for project PGC2018-097722-B-I00.
1
acetate). H NMR (500 MHz, CDCl3): δ 8.05 (br. s, 1H),
7.76−7.74 (m, 2H), 7.52−7.49 (m, 1H), 7.41 (t, 2H, J = 7.5
REFERENCES
■
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1
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00654.
Spectroscopic details of the catalytic reactions and DFT
calculations; optimization of benzohydrazide dialkyla-
tion; mechanistic studies; NMR spectra of ruthenium
complexes; NMR spectra of starting materials; NMR
spectra of products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Albert Poater − Departament de Química, Institut de Química
̀
Computacional i Catalisi (IQCC), University of Girona,
17003 Girona, Catalonia, Spain; orcid.org/0000-0002-
8997-2599; Email: albert.poater@udg.edu
Jean-Luc Renaud − LCMT, ENSICAEN, UNICAEN, CNRS,
Normandie Université, 14000 Caen, France; orcid.org/
0000-0001-8757-9622; Email: jean-luc.renaud@
ensicaen.fr
Authors
Nicolas Joly − LCMT, ENSICAEN, UNICAEN, CNRS,
Normandie Université, 14000 Caen, France; Departament de
Química, Institut de Química Computacional i Catalisi
(IQCC), University of Girona, 17003 Girona, Catalonia,
Spain
Léo Bettoni − LCMT, ENSICAEN, UNICAEN, CNRS,
Normandie Université, 14000 Caen, France
Sylvain Gaillard − LCMT, ENSICAEN, UNICAEN, CNRS,
Normandie Université, 14000 Caen, France; orcid.org/
0000-0003-3402-2518
̀
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00654
6824
https://doi.org/10.1021/acs.joc.1c00654
J. Org. Chem. 2021, 86, 6813−6825

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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