Benzylic C-H addition of aromatic amines to alkenes using a scandium catalyst

Article abstract of DOI:10.1039/d1cc00306b

An efficient and selective benzylic C(sp³)-H addition ofo-CH₃-substituted tertiary aromatic amines to alkenes has been achieved using an anilido-oxazoline ligand supported scandium catalyst, which provides an atom-economic method for the synthesis of a new family of alkylated tertiary anilines. A wide range of amine and alkene substrates are compatible with the catalyst system.

Full text of DOI:10.1039/d1cc00306b

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Benzylic C–H addition of aromatic amines
to alkenes using a scandium catalyst†
Cite this: Chem. Commun., 2021,
57, 3688
Jianhong Su, Yuncong Luo and Xin Xu
*
Received 18th January 2021,
Accepted 8th March 2021
DOI: 10.1039/d1cc00306b
rsc.li/chemcomm
An efficient and selective benzylic C(sp3)–H addition of o-CH3- anilido-oxazoline ligand supported scandium alkyl complex as
substituted tertiary aromatic amines to alkenes has been achieved using the catalyst to achieve highly efficient and selective benzylic
an anilido-oxazoline ligand supported scandium catalyst, which provides C(sp3)–H alkylation of tertiary ortho-methyl anilines by employing
an atom-economic method for the synthesis of a new family of alkylated a wide range of alkenes (Scheme 1d). This represents the first
tertiary anilines. A wide range of amine and alkene substrates are example of the alkylation of benzylic methyl of the aniline sub-
compatible with the catalyst system.
strates with alkenes, which can afford the corresponding addition
products with substrate-dependent regioselectivity. In order to gain
Aromatic amines are ubiquitous structural motifs in biologically critical insights into the reaction mechanism, a series of control
active natural products, pharmaceuticals, and fine chemicals.1 experiments were also conducted.
There has been long standing interest in synthetic organic
We studied a series of non-metallocene rare-earth dialkyl com-
chemistry to develop efficient and selective methodologies for plexes together with one equivalent of [PhNHMe2][B(C6F5)4] for the
the preparation of aromatic amines.2 Among various synthetic reaction of tertiary aniline (5a) with allylbenzene (6a) (Table 1).10
approaches, one of the most direct methods to achieve aniline Scandium complex 111 supported with a bulky b-diketiminato ligand
derivatives having 100% atom economy is the intermolecular was found to be inert even when the reaction was carried out for
addition of either the N–H or C–H bond of anilines across CQC 12 h at 80 1C (Table 1, entry 1). Complex 2, which employed a less
double bonds of alkenes.3 Selective N-alkylation (Scheme 1a, sterically encumbered b-diketiminato ligand, and, in our previous
hydroamination4) and C-alkylation (Scheme 1b, hydroarylation;5,6 report,8b which was successfully applied for the para-alkylation of
Scheme 1c, hydroaminoalkylation7,8) products or their mixtures9
may be afforded by the transition-metal- or acid-mediated reac-
tions of anilines with alkenes. The introduction of an ortho-methyl
group into the anilines may not alter the chemo-selectivity of the
above reactions, but, in some cases, it may shut off the
reactions.5c,8b To the best of our knowledge, use of any catalytic
system for the benzylic C(sp3)–H alkylation of ortho-methyl
anilines has yet to be reported in the literature. This could be
due to the weak coordination of the N-alkyl group as a directing
group in transition-metal catalyzed C–H functionalization.
We have earlier reported selective synthesis of para-alkylated
products for primary/secondary anilines6d and a-C(sp3)–H alkylated
products for tertiary anilines8 by the reactions of aromatic amines
with alkenes via rare-earth complexes based on b-diketiminato
ligands. Herein, we report the use of a b-diketiminato-type
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, P. R. China. E-mail: xinxu@suda.edu.cn
Scheme 1 Selected examples for catalytic addition reactions of anilines
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
with alkenes.
d1cc00306b
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Table 1 Screening of reaction conditionsa
Table 2 Scandium-catalyzed benzylic C–H alkylation of tertiary aniline 5a
with alkenesa
Entry
[RE]
5a (mmol)
6a (mmol)
Yield of 7a
Yield of 7a0
1
2
3
4
5
6
7
1
2
3
4
3
3
3
0.45
0.45
0.45
0.45
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.45
1.2
0
0
0
0
0
5
7
65
97 (92)b
0
69
57
0
95 (90)b
a
Reaction conditions: RE dialkyl complex (0.03 mmol), [PhNMe2H]
[B(C6F5)4] (0.03 mmol), toluene (2 mL), 80 1C, 12 h, yields were
b
determined by LC–MS. Isolated yields in the parentheses.
primary/secondary anilines, provided benzylic branched addition
product 7a in moderate yield under the same conditions (Table 1,
entry 2), with no other products observed. The ancillary ligand was
then modified into an anilido-imine containing an oxazoline
moiety,12 which was then used to prepare the corresponding dialkyl
complexes of Sc (3) and Y (4).13 Complex 3 showed considerably
a
Reaction conditions: amine 5a (0.45 mmol), alkene 6 (0.3 mmol),
Sc dialkyl complex 3 (0.03 mmol), [PhNMe2H][B(C6F5)4] (0.03 mmol),
toluene (2 mL), 80 1C, 12 h, isolated yield.
higher activity than complex 2, resulting in 97% yield for the alkylation of 5a with homoallylic substrates furnished the corres-
identical addition product 7a (Table 1, entry 3). Notably, no other ponding addition products 7m (83%) and 7n (93%). When using
regioisomer, e.g. hydroaminoalkylation or hydroarylation product, unactivated aliphatic alkenes, e.g. 1-hexene, allylcyclohexane, and
was detected in the reaction. In comparison, the Y complex 4 was vinylcyclohexane, as substrates, the reactions selectively afforded
found to be ineffective for this transformation (Table 1, entry 4), the corresponding branched products 7o–7q in marginally lower
presumably because the cationic active species of Y could not be isolated yields (75–88%). Selective C–H addition reactions
stabilized using such a ligand framework. The yield of 7a was found occurred across the mono-substituted CQC double bond, while
to decrease, with a small amount of dialkylation product 7a0 being retaining the other ones (in the case of generation of 7r and 7s).
observed when the alkene/amine molar ratio in the reaction was Internal alkenes such as norbornene was applicable in the reac-
increased (Table 1, entries 5 and 6). A high yield of compound 7a0 tion and produced 7t in moderate yield. However, other internal
was obtained when the alkene was used in large excess (Table 1, and disubstituted alkenes, e.g., cyclohexene, trans-3-hexene,
entry 7).
a-methylstyrene and methyl styryl ketone, were precluded from
After obtaining the optimal conditions, we evaluated the scope the current alkylation reaction presumably due to the steric
of the reaction. A variety of alkenes was studied for their reactivity, hindrance. Styrene and diphenylacetylene were also not tolerated
with 5a being promoted by the scandium complex 3 in combi- under this catalytic system. Allyltrimethylsilane was subjected to
nation with [PhNHMe2][B(C6F5)4], and the results are summarized the reaction and produced anticipated branched addition product
in Table 2. It is evident from the table that substituted allylben- 7u in 78% yield. Remarkably, vinylsilanes exclusively resulted in
zenes having methyl or phenyl substituents in ortho-, meta- or the formation of linear addition products 7v–7x with a com-
para-positions could serve as efficient alkylation reagents, selec- plete reversal of regioselectivity. A similar phenomenon was also
tively resulting in Markovnikov-type addition products 7b–7e with observed in Sc- and Zr-catalyzed hydroaminoalkylation
excellent yields (88–91%). It is worth noting that the allylbenzene reactions.14,15 This is because the insertion of vinylsilanes into
derivatives containing polar functional groups (OTIPS, F, Cl, Br, I) the metal–carbon bond is controlled by electronic factors rather
were also compatible with the current catalytic system, yielding than steric effects.16
benzylic C–H addition products 7f–7j in 79–93% yields. Allyl-
Subsequently, allylbenzene (6a) was used as the alkylation
naphthalenes were also transformed into the addition products reagent to explore the scope of aromatic amines under our
7k and 7l in 89% and 87% isolated yields, respectively. Benzylic typical reaction conditions (10 mol% catalyst loading, toluene
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as the solvent, 80 1C, 12 h), with the results presented in hindrance. No detectable products were formed for 2-ethyl-
Table 3. Regioselective benzylic C(sp3)–H alkylation facilely N,N-dimethylaniline under the given conditions, indicating
occurred for N,N-dimethyl-o-toluidine (5b) to form 8a in 89% non-applicability for benzylic methylene alkylation of the
yield. In contrast, the same substrate 5b was inert to present reaction. Primary and secondary anilines, such as
the 1-alkene in the presence of mono-Cp yttrium catalyst.5c o-toluidine and 2-methyl-N-methylaniline, were also not suitable
A computational study revealed that, although deprotonation of for the reaction, because in the presence of cationic rare-earth
the benzylic C(sp3)–H was favored by the Y catalyst, it was the alkyl species, N–H activation is preferred over the benzylic C–H
subsequent alkene insertion into the Y–C(sp3) bond which activation. When using vinyltrimethylsilane as an alkylation
was unfeasible and was responsible for the inertness of the reagent, linear addition product 8p was exclusively formed for
Y catalyst. Selective alkylation took place at the ortho-position 1,8-dimethyl-1,2,3,4-tetrahydroquinoline in 81% yield.
(i.e. formation of 8b and 8c) in the presence of additional
To gain further insights into this benzylic C–H functionali-
benzylic methyl substituents. Transformation of the para- zation reaction, a series of control experiments were conducted
phenyl substituted substrate into 8d was easily achieved with and are depicted in Scheme 2. Reaction of deuterium labeled
86% yield. The present reaction was suitable for halogen (F, Cl, N,N-dimethyl-o-toluidine (5b-d3) with allylbenzene (6a) catalyzed
Br, I) substituted anilines, giving rise to 8e–8h in high yields. by 3/[PhNHMe2][B(C6F5)4] afforded addition product 8a-d3
i
The presence of a polar electron-donating group [e.g., Pr3SiO (Scheme 2a), in which a deuterium atom was selectively trans-
(TIPSO), NMe2, or NEt2] at the para-position in N,N-dimethyl-o- ferred to the newly formed methyl group. This is distinct from
toluidine was also tolerated. The resulting benzylic alkylation our previous work of Sc-catalyzed C(sp3)–H alkylation reaction of
products 8i–8k were isolated in 85–92% yields. Varying the tertiary anilines with alkenes, which involved an ortho-C(sp2)–H
molar ratio of starting amines to alkenes could result in activation in the course of the reaction.8 Moreover, in the
selective production of the monoalkylation product 8l or di- reaction of 5n-d3 with allylbenzene (Scheme 2b), retention of
alkylation product 8m in satisfactory yield. In addition, when the deuterium atoms at N–Me indicated that the N–Me was not
increasing the steric hindrance at the nitrogen atom to some deprotonated during the course of the reaction. A competitive
fused rings, such benzylic alkylation reactions still occurred to deuterium labeling experiment under our typical conditions was
yield 8n and 8o, albeit in moderate yields (78% and 54%). performed using 5b, 5b-d3, and allylbenzene in a molar ratio of
However, the reaction did not occur when using N,N-diethyl-o- 1.5 : 1.5 : 1, which showed a significant kinetic isotope effect
toluidine as a substrate probably due to the severe steric (KIE) value of 4.0 (Scheme 2c). This observation implied involve-
ment of the C–H activation in the rate-determining step of this
reaction. Treatment of N,N-dimethyl-o-toluidine, N,N-dimethyl-
Table 3 Scandium-catalyzed benzylic C–H alkylation of tertiary anilines
aniline, and allylbenzene at a molar ratio of 1.5 : 1.5 : 1 resulted in
with allylbenzenea
the formation of benzylic alkylation product 8a in 86% yield,
whereas a trace amount of 9 was also observed to form through
activation of the ortho-C(sp2)–H bond (Scheme 2d). Apparently,
under the present catalytic system, benzylic sp3-C–H functionaliza-
tion is much preferred to the ortho-sp2-C–H alkylation.
a
Reaction conditions: amine 5 (0.45 mmol), alkene 6a (0.3 mmol), Sc
dialkyl complex 3 (0.03 mmol), [PhNMe2H][B(C6F5)4] (0.03 mmol),
b
toluene (2 mL), 80 1C, 12 h, isolated yield. 4-Allylbiphenyl (0.3 mmol)
c
Scheme 2 Control experiments for Sc-catalyzed benzylic alkylation
reaction.
was used instead of 6a. Amine (0.3 mmol) and alkene (1.2 mmol).
d
Vinyltrimethylsilane (0.3 mmol) was used instead of 6a.
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Based on the above experimental observations and previous
reports,6d,8,17 a plausible mechanistic framework for such
benzylic C–H alkylation reaction was proposed as shown in
Scheme 3. A cationic scandium monoalkyl species (10) is
formed by the reaction of complex 3 with [PhNHMe2][B(C6F5)4],
which then forms a five-membered cyclometalated intermedi-
ate 11 via selective deprotonation of the benzylic sp3-C–H of the
aniline substrate, with dimethylamino coordination to the
metal center working as a directing group. Subsequently, 1,
2-insertion of the alkene into the Sc–C(sp3) bond leads to the
formation of azametallacyclic species 12. Finally, 12 reacts with
another molecular amine substrate to form the branched
addition product 7 (or 8) along with the regeneration of 11
for the completion of the catalytic cycle.
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and X. Xu, Org. Chem. Front., 2018, 5, 59; (b) J. Su, Y. Zhou and X. Xu,
Org. Biomol. Chem., 2019, 17, 2013.
In summary, chemo- and regioselective ortho-benzylic C–H alky-
lation of tertiary anilines with a variety of alkenes has been achieved
by using an easily-accessible anilido-oxazoline ligand supported
scandium catalyst. This protocol offers high atom economy, a broad
scope of substrates, and good functional group tolerance, affording
a new family of alkylated anilines with substrate-dependent regios-
electivity. Mechanistic studies indicate that both the ortho-C(sp2)–H
and a-C(sp3)–H of the aniline substrates were not deprotonated
during the reaction. The work presented herein reveals a comple-
mentary result for the reaction of aromatic amines with alkenes.
Further work will focus on an asymmetric version of this transfor-
mation with chiral rare-earth catalysts.
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This work was supported by the National Natural Science
Foundation of China (21871204) and the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
10 Both rare-earth dialkyl complexes and the [PhNHMe2][B(C6F5)4]
reagent alone did not show any activity under our typical conditions.
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Conflicts of interest
There are no conflicts to declare.
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