Direct Use of Benzylic Alcohols for Multicomponent Synthesis of 2-Aryl Quinazolinones Utilizing the π-Benzylpalladium(II) System in Water

Article abstract of DOI:10.1002/adsc.202100535

We demonstrate the direct use of benzylic alcohols for a multicomponent reaction of readily available isatoic anhydrides with amines in water, which is a synthetic route for the direct construction of a series of 2-aryl quinazolinones. This one-pot synthetic method involves the dehydrative N-benzylation of in situ generated anthranilamides followed by an amide-directed benzylic C?H amination process utilizing the π-benzylPd(II) system. Comparison of independent rate measurements using benzyl alcohol and its deuterated form gave a kinetic isotope effect of 3.5. Therefore, the benzylic C?H bond is cleaved in the rate-determining step. We successfully carried out a gram-scale reaction in 85% yield with simplified product isolation. (Figure presented.).

Full text of DOI:10.1002/adsc.202100535

UPDATES
doi.org/10.1002/adsc.202100535
Direct Use of Benzylic Alcohols for Multicomponent Synthesis of
2-Aryl Quinazolinones Utilizing the π-Benzylpalladium(II) System
in Water
Hidemasa Hikawa,a,* Taku Nakayama,a Makiko Takahashi,a Shoko Kikkawa,a
and Isao Azumayaa,*
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Fax: (+81) 47-472-1595; phone: (+81) 47-472-1591
E-mail: hidemasa.hikawa@phar.toho-u.ac.jp; yokoyama@phar.toho-u.ac.jp
Manuscript received: May 5, 2021; Revised manuscript received: June 10, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100535
hydrogen cyanide and ammonia as substrates.[2] In
Abstract: We demonstrate the direct use of ben-
zylic alcohols for a multicomponent reaction of
1881, Hantzsch reported the three-component synthesis
of 1,4-dihydropyridines.[3] A calcium channel blocker,
readily available isatoic anhydrides with amines in
Nifedipine, was prepared by this method.[4] Further-
water, which is a synthetic route for the direct
more, the Ugi reaction is a four-component condensa-
construction of a series of 2-aryl quinazolinones.
tion, where the coupling between a ketone (or
This one-pot synthetic method involves the dehy-
aldehyde), amine, isocyanide and carboxylic acid
drative N-benzylation of in situ generated anthrani-
affords a bis-amide.[5] Therefore, performing MCRs
lamides followed by an amide-directed benzylic
enables the rapid construction of diverse molecular
CÀ H amination process utilizing the π-benzylPd(II)
skeletons through highly convergent one-pot processes,
which can be applied to the library synthesis of drug
candidates.
Quinazolinones are well represented in medicinally
relevant molecules, since the substrate scaffolds act as
key structural units in a wide range of relevant
system. Comparison of independent rate measure-
ments using benzyl alcohol and its deuterated form
gave a kinetic isotope effect of 3.5. Therefore, the
benzylic CÀ H bond is cleaved in the rate-determin-
ing step. We successfully carried out a gram-scale
reaction in 85% yield with simplified product
pharmacophores exhibiting a broad spectrum of bio-
isolation.
logical and pharmaceutical activities (Figure 1).[6]
Therefore, the development of efficient synthetic
protocols for accessing such motifs has attracted a
great deal of effort. Recently, multicomponent syn-
thesis of quinazolinones involving condensation be-
tween in situ generated anthranilamides and aldehydes
or orthoesters followed by dehydrogenation of the
Keywords: CÀ H activation; isatoic anhydride; palla-
dium; water; benzyl alcohol
aminal
has
been
successfully
developed
(Scheme 1A).[7] Despite these elegant protocols, stoi-
Introduction
Multicomponent reactions (MCRs) are recognized as
an atom-economic synthetic strategy allowing the
straightforward and efficient transformation of novel
fine chemicals directly from easily available starting
materials.[1] This system has many advantages such as
high atom economy and less waste generation com-
pared to stepwise reactions involving multistep and
hazardous processes. The first report of MCRs was in
1850 by Strecker, in the well-known Strecker reaction,
for the synthesis of α-amino acids using aldehydes,
Figure 1. Representative biologically active quinazolinones.
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the three-component coupling reaction due to its
unusual chemical and physical properties such as
formation of an extensive hydrogen bonding network.
Results and Discussion
Reaction Optimization
We selected commercially available isatoic anhydride
(1a) and benzyl alcohol (2a) as model substrates to
optimize the MCR conditions. In the presence of
palladium(II) acetate (5 mol%) and sodium diphenyl-
phosphinobenzene-3-sulfonate (TPPMS, 10 mol%), the
reaction was performed employing MeNH2 (40% in
water) as an amine source to give the corresponding
quinazoline product 3a in only 3% yield along with
dihydroquinazolinone product 4a in 15% yield (Ta-
ble 1, entry 1). We speculated that the palladium
catalyst was poisoned by methylamine. To test our
hypothesis, addition of several acids was examined. As
expected, the use of MeNH2 ·AcOH was found to
significantly improve the yields of cyclized products
3a and 4a to 29% and 38%, respectively (entry 2).
Additionally, N-benzylated intermediate 5a was ob-
served in 22% yield. To our delight, the three-
component synthesis of the quinazolinone 3a could be
achieved by fine-tuning the mol ratio of MeNH2
(2.5 mmol) and AcOH (3 mmol) (entry 3). The yield of
Scheme 1. Multicomponent synthesis of quinazolinones.
chiometric amounts of toxic oxidants such as DDQ or 3a decreased from 90% to 60% when the temperature
°
°
I2 are generally needed for the oxidation step. was reduced from 100 C to 80 C (entry 4). Replacing
Furthermore, benzaldehydes are unstable and their AcOH with strong Brønsted acids such as HCl, TFA
preparation requires oxidation from readily available and TsOH·H2O was not effective (entries 5–7). When
alcohols. Therefore, a more efficient approach utilizing using Pd(TFA)2, PdCl2 PdBr2 or Pd2(dba)3 ·CHCl3,
non-activated coupling partners such as readily avail- almost the same or lower yields of desired product 3a
able alcohols is highly desirable.[8] In 2014, Habibi and were observed (entry 3 vs. entries 8–11). Furthermore,
Faramarzi et al. developed a MCR via the laccase- [Cp*IrCl2]2, which is often used for borrowing hydro-
mediated tandem oxidation of alcohols to aldehydes gen reactions, showed poor catalytic performance
followed by cyclocondensation under an O2 atmos- (entry 12). With regard to the phosphine ligand, the
phere in a citrate buffer solution (Scheme 1B).[8d] absence of TPPMS or replacing TPPMS with TPPTS
Despite this important advance, the direct use of significantly diminished the reactivity (entries 13–14).
simple benzylic alcohols for an efficient MCR remains The catalyst system was tested in several organic
a great challenge..
solvents such as toluene, 1,4-dioxane, dimethyl
We have been developing environmentally benign sulfoxide and ethanol, but all afforded inferior results
benzylic CÀ H functionalizations at sites adjacent to compared to the reaction in water (entries 15–18).
heteroatoms utilizing the π-benzylpalladium system in Furthermore, an aqueous biphasic system using cyclo-
water.[9] The catalytic amination of CÀ H bonds is pentyl methyl ether (CPME) resulted in lower yields
recognized as an atom-economic, straightforward and (entry 19). These results suggested that water plays an
efficient method that can incorporate nitrogen into important role in the Pd-catalyzed reaction.
molecular frameworks without pre-activation of start-
ing materials.[10] Herein, we present the first example
Reaction Scope
of the direct use of benzylic alcohols for MCR of
isatoic anhydrides with amines catalyzed by Pd(0)/ To expand the substrate scope, we examined the MCR
TPPMS in water, furnishing a series of 2-aryl of isatoic anhydrides 1 using various amines and
quinazolinone derivatives (Scheme 1C). Our π-benzyl- alcohols 2 under optimized conditions (Figure 2).
palladium(II) system shows water tolerance and
We first tested the scope of benzylic alcohols.
enables the key intramolecular CÀ N bond formation at Electron-donating groups (OMe and Me) at the meta
the benzylic position. Additionally, water accelerates or para positions were effective, furnishing the
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Table 1. Effects of catalysts and solvents.[a]
Entry Catalyst/Ligand
Amine
Acid
Solvent
NMR yield (%)[b]
(equiv.)
(equiv.)
3a
4a
5a
1
2
3
4
5
6
7
8
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(TFA)2/TPPMS
PdCl2/TPPMS
MeNH2 (2.5)
MeNH2 ·AcOH (3)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
MeNH2 (2.5)
none
H2O
H2O
H2O
H2O (at 80 C)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
3
15
38
5
22
0
0
0
22
13
50
0
22
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
29
AcOH (3)
AcOH (3)
HCl (3)
90 (89)[d]
°
60
15
8
TFA (3)
TsOH·H2O (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
AcOH (3)
7
77
80
39
9
10
11
12
13
14
15
16
17
18
19
PdBr2/TPPMS
Pd2(dba)3 ·CHCl3[c]/TPPMS
[Cp*IrCl2]2[c]/TPPMS
Pd(OAc)2
84 (79)[d] 12
16
7
3
17
16
19
8
32
0
51
0
0
Pd(OAc)2/TPPTS[e]
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc) 2/TPPMS
Pd(OAc) 2/TPPMS
Pd(OAc)2/TPPMS
H2O
Toluene
1,4-dioxane
DMSO
°
EtOH (at 80 C) (7)[d]
CPME/H2O (1:1) 2
0
29
[a] Optimal conditions: isatoic anhydride 1a (1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohol 2a (5 equiv.), 40%
°
MeNH2aq. (2.5 mmol), AcOH (3 mmol), H2O (4 mL), 100 C, 16 h in a sealed tube under air;
[b] The conversion was determined by 1H NMR analysis of the crude product using 4-nitroanisole as an internal standard;
[c] 2.5 mol%;
[d] Yield of the isolated product in parenthesis;
[e] Trisodium 3,3’,3-phosphinetriyltribenzenesulfonate.
quinazoline products 3b–d in moderate to excellent quinazoline products 3h–j in excellent yields (79–
yields (60–92%). To our delight, 2-naphthalenemetha- 90%). Sterically demanding 3-methylisatoic anhydride
nol could be converted to the product 3e. The loss of (1k) and N-methylisatoic anhydride (1l) were tolerated
resonance energy for the formation of the η3- in the tandem coupling reaction (3l, 86%; 4m, 69%).
naphthalenemethylpalladium intermediate was less 4-Chloroisatoic anhydride 1n was converted into the
important than for the η3-benzylpalladium intermediate corresponding dehalogenated product 3a in 68% yield,
reported by Fiaud.[11] The reaction of 1-naphthaleneme- which suggested that the water-tolerant Pd(0)/TPPMS
thanol afforded the cyclized products (quinazolinone catalyst system could be formed in water.
3f, 14%; aminal 4f, 67%), and the dehydrogenation of
We next tested the alkylamine scope. Ethyl and n-
4f proceeded slowly, probably due to steric reasons. butylamines were capable coupling partners for the
The use of a benzyl alcohol with an electron-with- MCR, furnishing the quinazolinone products (3o,
drawing fluoro group resulted in excellent yield (3g, 71%; 3p, 48%). Aniline was converted to the
85%). In contrast, no reaction occurred when using 4- corresponding dihydroquinazolinone 3q in 47% yield.
nitrobenzyl alcohol or 2-phenylethyl alcohol, likely When utilizing the ammonia solution (28% in water),
because the corresponding π-benzyl Pd(II) cation the tandem reaction proceeded smoothly to give the
species was not generated.
desired quinazolinones 3r–v (65–77%).[12]
To further expand the substrate scope, various
substituted isatoic anhydrides were employed as
substrates to examine the catalytic tandem reactions in
Reaction Progress
water. Isatoic anhydrides with electron-donating To explore the full reaction profile for the MCR
groups (OMe and Me) were effective, affording the system, the reaction of isatoic anhydride with meth-
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Figure 2. Substrate scope of coupling reaction and isolated yields of 3 and 4.
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ylamine and benzyl alcohol was monitored over time.
1
The conversion yield was determined by H NMR
analysis. After 1 h, N-benzylated product 5a and
cyclized product 4a as key intermediates were
generated, which were smoothly transformed into
quinazolinone 3a (Figure 3A). Furthermore, a decrease
of alcohol 2a was observed as the catalytic reaction
progressed (Figure 3B).
Control Experiments
To gain preliminary mechanistic insights into this
catalytic system, we performed several control experi-
ments. First, starting from 2-amino-N-meth-
ylbenzamide (6a), the corresponding quinazolinone 3a
was formed (Scheme 2A). Next, N-benzyl substrate 5a
was prepared by benzylation of 6a with benzyl
bromide, and subjected to the standard reaction
conditions, furnishing the cyclized product 3a in
quantitative yield (Scheme 2B).[13] In contrast, a lower
yield of 3a was observed in the absence of alcohol 2a
(Pd(OAc)2-catalyzed oxidation of 5a occurred to give
product 3a in 36% yield). The reaction of N-
benzylisatoic anhydride (1w) also gave 3a (Sche-
me 2C), suggesting that the oxidative cyclization of N-
benzylated 5a proceeds smoothly in the benzylic CÀ H
amination step, which is consistent with the observa-
tion of 5a over the time course of the reaction (see
Figure 3). The NMR determined yield of 94% for a
reaction conducted under an Ar atmosphere was almost
the same as that for a reaction conducted under air (see
Scheme 2. Control experiments.
entry 3 in Table 1), suggesting that oxygen is not of N-benzylated anthranilamide 5a followed by a
essential for either oxidative cyclization of N-benzy- subsequent cascade of dehydrogenation occurs,
lated 5a or dehydrogenation of aminal 4a 2 equiv. of toluene would be generated through the π-
(Scheme 2D).
benzylpalladium system along with desired product
3a.
First, the yield of 3a was found to be dependent on
the concentration of benzyl alcohol (2a) in the
Deuterium-Labeling Studies
We next performed deuterium-labeling studies using examined range (0.5–2.5 mmol) (Scheme 3A). We
D2O, while monitoring the reaction by 1H NMR were delighted to observe deuterium-labeled toluene
spectroscopy. If Pd-catalyzed intramolecular amination (79% D incorporation of one H on the methyl group)
Figure 3. Monitoring of reaction progress. Conditions: isatoic anhydride 1a (1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%),
°
MeNH2 (2.5 mmol), AcOH (3 mmol), alcohol 2a (5 mmol), H2O (4 mL), 100 C.
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Scheme 4. Catalytic reaction of benzamide and benzenesulfona-
mide in D2O.
trends suggest that the anthranilamide complexes A-1
would be stable compared with electron deficient
sulfonamide complex A-2, and therefore the CÀ H
amination can proceed preferentially at electron-rich
benzylic CÀ H bonds.
Kinetic Isotope Effect
Scheme 3. Deuterium-labeling experiments.
Next, we performed kinetic isotope effect (KIE)
experiments to study the reaction mechanism by
identifying the rate-determining step. Comparison of
and no formation of benzaldehyde in the reaction independent rate measurements using alcohol 2a and
mixture, when the reaction between 1 mmol of sub- benzyl-d7 alcohol 2a–d showed a KIE of 3.5,[14]
strate 1a and 1 mmol of alcohol 2a was conducted suggesting that the benzylic CÀ H bond in the TS is
(Scheme 3B). This observation revealed that benzylic cleaved in the rate-determining step (Figure 4).
CÀ H amination product 3a is formed from N-benzy-
When the reaction rates in H2O and in D2O were
lated intermediate 5a with π-benzylPd complex I via compared, the conversion to cyclized products 3a and
C-palladated species A-1. In contrast, Pd-catalyzed 4a was clearly faster in H2O than in D2O (Figure 5A).
disproportionation of 2a leads to the corresponding Furthermore, the pseudo first-order plot for the
non-deuterated toluene via dehydrogenation (Sche- reaction of alcohol 2a gave a KSIE (kinetic solvent
me 3C), suggesting that the minor pathway for the isotope effect) of 1.6 (Figure 5B). These results
construction of quinazolinone 3a involves the con- suggest that hydrogen bonding between water mole-
densation of in situ generated amine with benzaldehyde cules plays an important role in our catalytic system.
to form the imine intermediate B.
Next, the same technique was used to determine the
influence of the amide groups on the key benzylic
Mechanistic Considerations
CÀ H amination step (Scheme 4). The reaction of Following our previous proposals on Pd-catalyzed
anthranilamide (6r) afforded the quinazolinone 3r benzylic CÀ H amination and considering the results of
with
deuterium-labeled
toluene
(86%
D
several mechanistic studies, we propose a plausible
incorporation).[9b] In contrast, the reaction of sulfona- catalytic cycle for the direct use of benzyl alcohol in
mide substrate 7 showed significant diminishment of the multicomponent synthesis of quinazolinones
deuterium incorporation (46% D incorporation in (Scheme 5).
toluene) and benzaldehyde was detected by 1H
Step 1: Initially, the reaction of Pd(OAc)2/TPPMS
NMR.[9a] These observed intramolecular reactivity with alcohol 2a generates an active Pd(0) species with
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Figure 4. KIE determined from two parallel reactions using alcohol 2a and benzyl-d7 alcohol 2a–d. Reaction conditions: 1a
(1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), MeNH2 (2.5 equiv.), AcOH (3 equiv.), 2a or 2a–d (5 equiv.), H2O (4 mL),
°
100 C. (A) Reaction time course for conversion to product 3a, and (B) cyclized products 3a and 4a.
Figure 5. (A) Reaction time course for conversion to cyclized products 3a and 4a in H2O and D2O. (B) Pseudo-first-order kinetic
plot in H2O and D2O. kH2O/kD2O=1.6. Reaction conditions: isatoic anhydride 1a (1 mmol), Pd(OAc)2 (5 mol%), TPPMS
°
(10 mol%), MeNH2 (2.5 equiv.), AcOH (3 equiv.), benzyl alcohol (2a, 5 equiv.), H2O or D2O (4 mL), 100 C.
an aldehyde via Uemura type oxidation in water.[15] amine and amide ligands (Scheme 5C). Consequently,
Subsequently, oxidative addition of 2a to the Pd(0)Ln CÀ H cleavage of complex II occurs to generate the
complex generates the π-benzylPd(II) cation intermedi- bis-π-benzyl species III since the positive charge of
ate I (Scheme 5A).[16] The water dangling hydroxy cationic palladium(II) increases the acidity of the
groups activate the carbon-oxygen bond of 2a by a benzylic proton in the transition state TS. Additionally,
hydrogen bonding network, generating an active Pd(II) the resulting acetoxy anion (conjugate base) acts as a
complex I having a positive charge stabilized by base for the deprotonation of the amine and amide
water.[17] This proposed mechanism is consistent with nucleophiles. Indeed, the use of a strong acid such as
the observed KSIE (kH2O/kD2O=1.6). Furthermore, TFA is not effective for the Pd-catalyzed tandem
the use of acetic acid is the key to the success of the reaction. The observed KIE of 3.5 supports the notion
catalyst system, since it accelerates the formation of that the rate-determining step is CÀ H activation in the
the π-benzylPd(II) species.[18–19]
TS. The bis-π-benzyl species III is in equilibrium with
Steps 2–3: Decarboxylative amide formation of η3-π-benzyl-η1-σ-benzyl Pd(II) A-1, whose δ+ charge
isatoic anhydride (1a) with methyl amine generates 2- is stabilized due to proximity to the nitrogen atom.
amino-N-methylbenzamide (6a), which attacks the Consequently, an intramolecular nucleophilic substitu-
cationic π-benzylpalladium(II) intermediate I via dehy- tion reaction to the π-benzyl ligand of A-1 generates a
drative Tsuji-Trost type N-benzylation to form the N- CÀ N bond, since the complex A-1 involves a
benzylated anthranilamide 5a and regenerate Pd(0)Ln nucleophilic σ-benzyl ligand with an electrophilic π-
(Scheme 5B).[20]
benzyl ligand (path A). Indeed, dehydrative tandem
Step 4: Anthranilamide 5a coordinates to the benzylation of 2-amino-N,N-dimethylbenzamide 9 af-
cationic Pd(II) complex I to form an activated complex fords the corresponding dibenzylated product 10,
II, whose positive charge is stabilized by the chelating suggesting that the η1-σ-benzyl ligand attacks the η3-π-
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Scheme 5. (A)-(C) Proposed mechanism. (D) Control experiment for benzylic CÀ H activation.
benzyl ligand of intermediate A-3 (Scheme 5D).
Yamamoto et al. proposed nucleophilic reactivity of
bis-π-allylpalladium complexes, whereas mono-(π-
allyl)PdCl complexes with an electron-withdrawing
chloro group exhibited electrophilic reactivity.[19]
As a route to generate the dihydroquinazolinone
Scheme 6. Gram-scale synthesis of 3a.
intermediate 4a, the control experiments (see
Scheme 4) revealed that there was a minor route
through nucleophilic addition to imine intermediate B
(path B in Scheme 5C).
zation of the resulting crude product from n-hexane/
Step 5: Finally, Pd-catalyzed dehydrogenation of EtOAc provided the desired product 3a in 85%
aminal intermediate 4a generates the quinazoline isolated yield. Notably, this method is operationally
product 3a along with toluene and regenerated Pd(0).
facile and can be applied to gram-scale synthesis
without purification by column chromatography. Fur-
thermore, a key advantage for the direct utilization of
alcohols rather than the corresponding aldehydes is
Scale-Up Experiment
Finally, to demonstrate the applicability of the multi- that the use of toxic and unstable reagents can be
component synthesis of quinazolinones, a gram scale avoided.
reaction of isatoic anhydride (1a) with benzyl alcohol
(2a) was performed in water (Scheme 6). Recrystalli-
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Conclusion
In summary, we have developed a palladium-catalyzed
three-component reaction of isatoic anhydrides in
water. This method enables the synthesis of a wide
range of 2-aryl quinazolinone derivatives from readily
available benzylic alcohols while avoiding the use of
unstable aldehydes. Several control experiments and
kinetic investigations revealed that CÀ H bond cleavage
is the rate-determining step. Notably, the water-tolerant
π-benzylpalladium(II) system that enables the selective
functionalization of benzylic CÀ H bonds provides a
powerful means of rapid conversion to such motifs,
and has the potential to achieve various other chemical
transformations in water. This multicomponent syn-
thesis provides ample opportunities to construct a
quinazolinone library.
Experimental Section
General procedure: A mixture of isatoic anhydrides 1
(1 mmol), palladium(II) acetate (5–10 mol%), TPPMS (10–
20 mol%), benzylic alcohols 2 (5 mmol), amines (2.5 mmol)
[9] a) H. Hikawa, N. Matsuda, H. Suzuki, Y. Yokoyama, I.
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°
and AcOH (3 mmol) in water (4 mL) was heated at 100–140 C
for 16–20 h in a sealed tube under air. After cooling, the
reaction mixture was poured into water and extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, hexane/EtOAc) to
give the desired product 3.
[11] J. Y. Legros, J. C. Fiaud, Tetrahedron Lett. 1992, 33,
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Acknowledgements
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Baumler, C. Bauer, R. Kempe, ChemSusChem 2020, 13,
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[13] Pd-catalyzed benzylic CÀ H amination of 2-(benzylami-
no)benzamide did not proceed without benzyl alcohol
(2a), see ref. 9b.
[14] BnOH (0–0.5 h): 0.08 M/0.5 h=0.16 M/h; BnOH-d7
(0.5–1 h): 0.023 M/0.5 h=0.046 M/h. Therefore, com-
parison of slopes at low conversion reveals a KIE=3.5
(see, Figure 4B).
This work was supported by JSPS KAKENHI Grant Number
19 K07003.
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Direct Use of Benzylic Alcohols for Multicomponent
Synthesis of 2-Aryl Quinazolinones Utilizing the π-Benzyl-
palladium(II) System in Water
Adv. Synth. Catal. 2021, 363, 1–11
H. Hikawa*, T. Nakayama, M. Takahashi, S. Kikkawa, I.
Azumaya*