Benzylic aroylation of toluenes with unactivated tertiary benzamides promoted by directed ortho-lithiation

Article abstract of DOI:10.1007/s11426-021-1035-5

The deprotonative functionalization of toluenes, for their weak acidity, generally needs strong bases, thus leading to the requirement of harsh conditions and the generation of by-products. Direct nucleophilic acyl substitution reaction of amides with organometallic reagents could provide an ideal solution for ketone synthesis. However, the inert amides and highly reactive organometallic reagents bring great challenges for an efficient and selective synthetic approach. Herein, we reported an lithium diisopropylamide (LDA)-promoted benzylic aroylation of toluenes with unactivated tertiary benzamides, providing a direct and efficient synthesis of various aryl benzyl ketones. This process features a kinetic deprotonative functionalization of toluenes with a readily available base LDA. Mechanism studies revealed that the directed ortho-lithiation of the tertiary benzamide with LDA promoted the benzylic kinetic deprotonation of toluene and triggered the nucleophilic acyl substitution reaction with the amide. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11426-021-1035-5

SCIENCE CHINA
Chemistry
•ARTICLES•
https://doi.org/10.1007/s11426-021-1035-5
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Benzylic aroylation of toluenes with unactivated tertiary
benzamides promoted by directed ortho-lithiation
Can-Can Bao1, Yan-Long Luo1, Hui-Zhen Du1 & Bing-Tao Guan2*
1College of Chemistry, Nankai University, Tianjin 300071, China;
2Department of Chemistry, Fudan University, Shanghai 200438, China
Received March 22, 2021; accepted May 28, 2021; published online June 29, 2021
The deprotonative functionalization of toluenes, for their weak acidity, generally needs strong bases, thus leading to the
requirement of harsh conditions and the generation of by-products. Direct nucleophilic acyl substitution reaction of amides with
organometallic reagents could provide an ideal solution for ketone synthesis. However, the inert amides and highly reactive
organometallic reagents bring great challenges for an efficient and selective synthetic approach. Herein, we reported an lithium
diisopropylamide (LDA)-promoted benzylic aroylation of toluenes with unactivated tertiary benzamides, providing a direct and
efficient synthesis of various aryl benzyl ketones. This process features a kinetic deprotonative functionalization of toluenes with
a readily available base LDA. Mechanism studies revealed that the directed ortho-lithiation of the tertiary benzamide with LDA
promoted the benzylic kinetic deprotonation of toluene and triggered the nucleophilic acyl substitution reaction with the amide.
toluene, aroylation, unactivated tertiary benzamides, directed ortho-lithiation, nucleophilic acyl substitution reaction
Citation:
Bao CC, Luo YL, Du HZ, Guan BT. Benzylic aroylation of toluenes with unactivated tertiary benzamides promoted by directed ortho-lithiation. Sci
China Chem, 2021, 64, https://doi.org/10.1007/s11426-021-1035-5
1 Introduction
gioselective benzylic metalation of toluene using a mixed-
metal amide composed of t-BuOK, n-BuLi, and 2,2,6,6,-
tetramethylpiperidine (Scheme 1a). With potassium amide or
potassium alkyl catalysts, Kobayashi and co-workers [15,16]
recently reported the catalytic addition of toluenes to imines
and alkenes (Scheme 1b). With the combined catalysts of
alkali amides and cesium salts, Walsh and co-workers [17–
19] realized the addition of toluenes to aldimines and nitriles
to synthesize amines and indoles (Scheme 1b). The co-
ordination of the phenyl ring with a metal could activate the
benzylic C–H bond, resulting in the deprotonation with re-
latively weak bases.
Takemoto, Matsuzaka and co-workers [20] reported the
first catalytic dehydrative condensation of the benzylic C−H
bonds of toluenes with aromatic aldehydes via the benzylic
deprotonation-functionalization of an η6-coordinated to-
luenes with a ruthenium complex. With the toluenes co-
ordinated with Cr(CO)3, Walsh and co-workers [21–23]
Toluene, a simple and readily available feedstock chemical,
has been widely used as a versatile building block in organic
synthesis. The homolytic cleavage of the benzylic C–H
bonds was extensively explored for diverse transformations
[1,2]. These reactions, however, always suffered from an
excessive amount of oxidants. The direct benzylic deproto-
nation of toluene could provide a benzyl carbanion, which
acts as a crucial intermediate for further various nucleophilic
reactions. However, for the weak acidity of toluene (pKa = 43
in tetrahydrofuran (THF)) [3,4], the benzylic deprotonation
needs bases even stronger than simple alkyl lithiums, usually
the combination of alkyl lithiums and activators such as N,N,
N',N'-tetramethylethane (TMEDA) and t-BuOK [5–14]. For
example, O’Shea and co-workers [12–14] reported the re-
*Corresponding author (email: bguan@fudan.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
chem.scichina.com link.springer.com

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Bao et al. Sci China Chem
of amides with less reactive organometallic reagents always
needed transition metal catalysts [46–50]. Despite that, the
major drawback of the nucleophilic acyl substitution reaction
of amides is the use of organometallic reagents, which was
always synthesized from organohalides or via deprotonation
under strong base conditions. Herein, we reported an lithium
diisopropylamide (LDA)-promoted benzylic aroylation of
toluenes with unactivated tertiary benzamides, providing an
ideal pathway for the synthesis of aryl benzyl ketones
(Scheme 1d).
2 Results and discussion
In our former work about base-catalyzed C–H bond alkyla-
tion reactions, we found that some relatively weak base
catalysts would not undergo the complete deprotonation of a
weakly acidic C–H bond to afford a stable carbanion inter-
mediate, but construct a deprotonative equilibration [51–54].
The reactive carbanion intermediate formed but in a low
concentration, which would help to avoid side reactions and
achieve the reaction selectively. The observation of the ki-
netic deprotonative functionalization reactions inspired us to
investigate the nucleophilic acyl substitution reaction of to-
luene under a relatively weak base condition. We firstly
examined several bases in the reaction between toluene and
N,N-diisopropyl benzamide at 60 °C in THF (Table 1).
Alkali bis(trimethylsilyl)amides failed to give the desired
ketone product (entries 1–3). LDA and LiTMP could
smoothly drive on the nucleophilic acyl substitution reaction
and give the benzyl phenyl ketone product 3aa in good yields
(entries 4 and 5). It is worthy of noting that neither LDA nor
LiTMP could deprotonate benzylic C–H bond of toluene for
their weak basicity. For the first time LDA or LiTMP, the
relatively weaker bases than alkyl lithiums, achieved the
deprotonation of benzylic C–H bond of toluene and the
following nucleophilic acyl substitution reaction with ben-
zamides. Even more basic TMSCH2Li and n-BuLi were also
subjected into the reaction. The amide was completely con-
sumed; however, the product was obtained in low yields of
18% and 14%, suggesting that some side reactions took place
possibly because of the strong reactivity of the alkyl lithium
reagents (entries 6 and 7). When 3 equiv. of toluene was
used, the reaction completed in 12 h and the product was
obtained in a high yield of 91% (entry 8). We tested the
reaction with different amount of LDA and found it to be a
stoichiometric reaction. To demonstrate the reliability, we
carried out a gram-scale reaction and obtained the product in
88% yield (1.04 g, for more condition screening, see Sup-
porting Information online).
Scheme 1 Deprotonative functionalization of benzylic C–H bond of to-
luenes (color online).
achieved the palladium-catalyzed allylation and arylation
reactions under weak base conditions (Scheme 1c). Recently,
they further reported the arylation of simple toluenes with
NIXANTPHOS-ligated palladium or nickel complex. The
key factor was proposed to be the η6-coordination with a
main group element, enabling toluene to be deprotonated
with the relatively weak bases such as KN(SiMe3)2 and NaN-
(SiMe3)2 [24,25]. Despite these developments, the deproto-
native functionalization of toluene generally needed strong
bases, or the relatively weak bases but with transition metal
catalysts. The direct deprotonative functionalization of to-
luene simply with relatively weak bases still leaves a great
challenge.
The transformation of the inert amide groups is a sig-
nificant challenge in synthetic chemistry for their decreased
electrophilicity and the enhanced C–N bond energy origi-
nating from the resonance stability. The reactions between
amides and strongly nucleophilic organolithium or organo-
magnesium reagents could take place but usually under harsh
conditions to prevent possible side reactions. To overcome
these challenges, various activated amides including che-
lating amides [26,27], electron-deficient amides [28–30] and
structurally distorted amides [31–34] were particularly de-
signed for the nucleophilic acyl substitution reactions [35].
With the in-situ amide activation strategies, the direct
transformations of secondary and tertiary amides with
Grignard reagents were recently achieved by Charette and
Huang [36–39], respectively. The highly electrophilic ni-
trilium intermediates generated from secondary amides and
Tf2O were reactive enough to readily undergo the reaction
with arenes and alkenes to afford ketone products [40–45].
The less reactive organozinc and organoboron compounds
are conducive to avoid side reactions. However, the reactions
Various substituted toluenes were then allowed to react
with amide 1a under present conditions, and the benzoyla-
tion products were obtained in good to high yields (Scheme

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Bao et al. Sci China Chem
Table 1 Base promoted benzylic benzoylation of toluene a)
b)
b)
entry
base
LiHMDS
NaHMDS
KHMDS
LDA
1a Conv. (%)
3aa yield (%)
1
2
3
4
5
6
7
16
5
< 5
< 5
< 5
83
7
99
100
100
99
97
LiTMP
78
TMSCH2Li
n-BuLi c)
LDA
18
14
d)
8
92 (91)
a) Reaction conditions: tertiary benzamide 1a (0.4 mmol), toluene 2a
(0.8 mmol), and base (0.48 mmol) in THF (1.0 mL) at 60 °C for 24 h.
HMDS: bis(trimethylsilyl)-amide; LiTMP: lithium 2,2,6,6-tetramethyl-
piperidide. b) gas mass (GC) yields with n-tridecane as an internal standard,
isolated yield in parenthesis. c) 2.5 M in hexane. d) Toluene (1.2 mmol),
12 h.
2). It is interesting to note that the benzoylation of ethyl
toluenes takes place selectively on the methyl group (3ag–
3ai). Ethylbenzene did undergo the benzoylation but gave
the product in a low yield of 19% under the same conditions
(see Supporting Information online). Ortho-substituted to-
luenes gave the benzoylation products in moderate to good
yields (3ai, 3ak and 3am) which was lower than that of para-
substituted toluenes (3ag, 3aj and 3al), suggesting that the
steric hindrance from toluenes would affect the benzoylation
reaction but not so significantly. Ortho- and meta-methoxy
toluenes smoothly underwent the benzoylation to give the
products in good yields (3an and 3ao). Para-methoxy to-
luene, however, under the same conditions gave a low yield
of 32% (3ar). N,N,2-trimethylaniline and N,N,3-trimethyla-
niline gave the products in 82% and 60% yields, respectively,
while N,N,4-trimethylaniline gave benzoylation product 3at
in 14% yield. The toluenes with sterically bulky tert-butoxyl
and diarylamino groups on the para-position, however,
smoothly afforded the product in good yields (3as 68% yield
and 3au 79% yield). These results hinted that the coordina-
tion groups near the methyl group of toluenes would be
helpful for the benzoylation reactions, while the coordination
groups on the para-position would inhibit the reactions. The
methoxyl and amino groups on the meta-position could
possibly work as an electron-withdrawing group to facilitate
the benzylic benzoylation reactions.
Scheme 2 Scope of toluenes. Conditions: tertiary benzamide 1a
(0.6 mmol), 2 (1.8 mmol), LDA (0.72 mmol), THF (1 mL), 60 °C, 12 h.
(color online).
zamides (Scheme 3). 4-Isopropyl benzamide 1b and 4-tert-
butyl benzamide 1c successfully gave the acyl substitution
products in good to high yields (3ba and 3ca). However, 4-
butyl benzamide 1d and 4-methyl benzamide 1e just yielded
the corresponding products in much lower yields (3da 47%
and 3ea 15%). The reason for their low yields could be the
side reactions of the alkyl groups on the benzamides. For an
example of 4-methyl benzamide 1e, the methyl groups of
amide and the substitution product (3ea) could further un-
dergo the aroylation reactions (see Supporting Information
online). Phenyl, phenoxyl and methoxyl benzamides were
also suitable substrates to give the substitution products in
good to high yields (3fa–3ka). 2-Methoxyl benzamide 1l did
not react with toluene but underwent the aroylation reaction
on its own methoxyl group to give benzofuran-3(2H)-one
(3l) in 45% yield. 2-Naphthamide 1m reacted with toluene
smoothly to afford the desired product in 80% yield (3ma).
1-Naphthamide, however, gave the product in a low yield of
8%. In addition, the tertiary benzamide bearing a phenyl
group on 2-position failed to react with toluene. These sig-
nificant reactivity difference revealed that the steric hin-
drance from benzamides would greatly inhibit the aroylation
reaction. Fluorobenzamides, 3-furanyl, and 3-thienyl amide
were also tested but failed to undergo the nucleophilic acyl
substitution reaction of toluene.
Several benzamides were examined in the reaction with
toluene. However, only the steric bulkier N,N-diisopropyl
and N,N-dicyclohexyl benzamides gave satisfactory yields.
N,N-dimethyl and N,N-diethyl benzamides did undergo the
benzylation reaction but the product was obtained in low
yields (see Supporting Information online). We then further
investigated the scope of substituted N,N-diisopropyl ben-
The deprotonation of toluene with LDA is the key step of

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Bao et al. Sci China Chem
Scheme 3 Scope of amides. Conditions: tertiary benzamide 1 (0.6 mmol),
toluene 2a (1.8 mmol), LDA (0.72 mmol), THF (1 mL), 60 °C, 12 h (color
online).
Scheme 4 Control experiments (color online).
acyl substitution reaction with the tertiary benzamide, and it
is also of our greatest concern. The direct deprotonation of
toluene with LDA in THF, as expected, did not take place.
Thus, the amide should also play a very important role in the
deprotonation process. The acyl substitution reaction be-
tween the amide and benzyl lithium should generate benzyl
phenyl ketone (deoxybenzoin) and a new LDA. The α-H of
the ketone, for its acidity, would easily undergo the depro-
tonation reaction with LDA. This easy enolization could
provide the driving force for the entire reaction. To demon-
strate the formation of an enolate, we carried out the reaction
and quenched it with ethyl iodide or benzyl bromide rather
than water. As expected, further α-alkylation products were
obtained in high yields of 89% and 88%, respectively
(Scheme 4, Eqs. (1) and (2)). After getting the thermo-
dynamics validity, we further tried to find dynamics prob-
ability about the deprotonation of toluene with LDA. We
compared the reaction of the amide with toluene and toluene-
d8 exactly under the same conditions at 25 °C. We monitored
the reactions, measured the initiating reaction rates and
found out a remarkable primary kinetic isotope effects (KIE
= 4.0, Eqs. (3) and (4)), suggesting that the cleavage of the
benzylic C–H bond of toluene could be the rate-determining
step. More importantly, we found the reaction with toluene-
d8 gave the product with 0.72 deuterium incorporation on the
ortho-position of carbonyl group (3aa-d), which revealed
that the ortho-C–H bond of tertiary benzamide was involved
in the reaction. Early quench of this reaction recovered the
reactant amide 1a-d with deuterium incorporation (0.64 D).
The reaction with large excess of toluene-d8 (15 equiv.) gave
the product with even higher deuterium incorporation
(1.02 D, see the Supporting Information online). To find out
when the ortho-deuteration took place, we carried out the
reaction of the ketone product 3aa and toluene-d8 and found
no any deuterium scrambling product, which excluded the
deuteration of the ketone product. Thus, it is very possible
that the ortho-deprotonation of the tertiary benzamide took
place firstly to generate an aryl lithium intermediate, which
underwent the deuteration reaction with toluene-d8 before
the benzoylation reaction. The intermediate A was prepared
via the deprotonation of amide with t-BuLi and isolated as a
dimmer complex, which could undergo the reaction with
toluene to give the benzylation product 3aa. We further
measured the kinetic data through initial-rate methods. The
reaction was found to be first order in the amide, first order in
LDA, first order in toluene, and minus one order in HDA,
suggesting a deprotonation equilibrium of the amide and a
rate-determining deprotonation of toluene (see Supporting
Information online).
On the basis of the results described above, we proposed a
possible pathway for the benzoylation of toluene-d8 as shown
in Scheme 5. The deprotonation equilibrium between the
tertiary benzamide (pKa = 37.8 in THF) and LDA (HDA: pKa
= 35.7 in THF) provides ortho-lithiation intermediate A in
low concentration [55–62], which would undergo the σ-bond
metathesis reaction with toluene-d8 via a four-membered
ring transition state (TS). The σ-bond metathesis reaction
generates a benzyl lithium intermediate coordinating with
the deuterated tertiary benzamide (B), which would easily
undergo the nucleophilic acyl substitution reaction to give
the ketone intermediate (C) and LDA. The easy acid-base
reaction between the ketone and LDA could provide the
driving force of the reaction and give an enolate intermediate
D [63,64]. After quenched with water, the protonation of the
enolate D in the work-up process finally afforded the pro-
duct. The protonation of intermediate B with HDA could

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Bao et al. Sci China Chem
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In summary, we have developed a benzylic aroylation reac-
tion of toluenes with benzamides, which provides a direct
and efficient strategy for the synthesis of aryl benzyl ketones.
This reaction features a kinetic deprotonative functionaliza-
tion of toluenes with a relatively weak base LDA, which was
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