Radical alkylation of C(sp3)-H bonds with diacyl peroxides under catalyst-free conditions

Article abstract of DOI:10.1039/c9cc08056b

Herein, we describe a protocol for alkylation reactions of C(sp³)-H bonds with diacyl peroxides by means of a process involving cross-coupling between an alkyl radical and an α-Aminoalkyl radical. The mild, catalyst-And additive-free conditions make this protocol superior to previously reported C(sp³)-H alkylation strategies. The protocol was applied to 1,2,3,4-Tetrahydroisoquinolines and a tetrahydro-β-carboline derivative and could be carried out on a gram scale, indicating its utility for the alkylation of late-stage synthetic intermediates.

Full text of DOI:10.1039/c9cc08056b

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Radical alkylation of C(sp3)–H bonds with diacyl
peroxides under catalyst-free conditions†
Cite this: Chem. Commun., 2019,
55, 14813
a
a
ab
Hao Tian,a Wentao Xu,
Yuxiu Liu
and Qingmin Wang
*
Received 14th October 2019,
Accepted 19th November 2019
DOI: 10.1039/c9cc08056b
rsc.li/chemcomm
Herein, we describe a protocol for alkylation reactions of C(sp3)–H
bonds with diacyl peroxides by means of a process involving cross-
coupling between an alkyl radical and an a-aminoalkyl radical. The mild,
catalyst- and additive-free conditions make this protocol superior to
previously reported C(sp3)–H alkylation strategies. The protocol was
applied to 1,2,3,4-tetrahydroisoquinolines and a tetrahydro-b-carboline
derivative and could be carried out on a gram scale, indicating its utility
for the alkylation of late-stage synthetic intermediates.
Alkyl groups in general, and alkyl groups bonded to sp3 carbons
in particular, play an important role in drug discovery because they
can affect both the biological activity and the physical properties of
a molecule.1 Therefore, the development of new and better alkyla-
tion methods would be valuable to the pharmaceutical industry.
Several methods for transition-metal-catalyzed C(sp3)–H
alkylation have been reported,2 but the need to use prefunctionalized
starting materials makes these methods inefficient and costly. In
recent years, photoredox catalysis has proved to be an efficient
Scheme 1 Alkylation with diacyl peroxides.
strategy to solve this problem, and a series of C(sp3)–H alkylation alkyl-etherification reactions),4a–e addition to electron-deficient
reactions have been reported.3 However, all of them require (hetero)arenes,4f–h addition to alkynes, and other reactions.4i–n
catalysts, and some require more than one catalyst or ligand. However, direct C(sp3)–H alkylation reactions involving diacyl
Thus there remains a need for economical, environmentally peroxides have not been reported.
friendly methods for C(sp3)–H alkylation.
In this study of the use of alkyl diacyl peroxides for C(sp3)–H
We speculated that diacyl peroxides might be useful for this alkylation, we began by carrying out reactions of N-phenyl-
purpose. Diacyl peroxides can be obtained easily from carboxylic 1,2,3,4-tetrahydroisoquinoline (1a) and dilauroyl peroxide (2a) as
acids and are inexpensive, nontoxic, and environmentally model substrates (Table 1). When CuI was used as the catalyst,
friendly. Bao et al. carried out a series of methodological studies reaction of 1a (0.2 M in MeCN) and 2a (1 equiv.) at room
on these compounds (Scheme 1)4 and found that when heated in temperature under argon afforded an 81% yield of alkylated
the presence of a photo-catalyst or a metal ion, they can be used product 3aa (entry 1). Interestingly, the yield was higher (84%) in
for C(sp)–H and C(sp2)–H alkylation reactions, such as addition to the absence of a catalyst (entry 6), which indicated that the acyloxy
alkenes (alkyl-esterification, alkyl-fluorination, alkyl-amination, and radicals generated by decomposition of the diacyl peroxide could
oxidize N-phenyl-1,2,3,4-tetrahydroisoquinoline directly. There-
a State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People’s Republic of China. E-mail: wangqm@nankai.edu.cn
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, People’s Republic of China
fore, we focused on optimizing catalyst-free reaction conditions.
Screening of several organic solvents revealed that MeCN gave the
best results (entries 3, 4 and 6). Increasing or decreasing the
amount of 2a slightly decreased the yield (compare entries 5 and
6 with entry 2). Neither increasing nor decreasing the concentration
of 1a improved the yield (entries 7–9).
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc08056b
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope with respect to the diacyl peroxidea
Entry
Variation from conditions shown above
Yieldb (%)
1c
2
CuI as catalyst
None
81
91
76
36
89
84
90
81
47
3c
4c
5
MeOH as solvent
EtOH as solvent
1.5 equiv. of 2a
1.0 equiv. of 2a
0.4 M 1a in MeCN
0.1 M 1a in MeCN
0.05 M 1a in MeCN
6
7
8
9
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol) and 2a
(0.22 mmol) in MeCN (1 mL) were stirred in an 8 mL bottle at rt under
b
c
Ar for 24 h. Isolated yields are given. 2a was used in 1 equiv.
Next we explored the substrate scope of the reaction with
respect to the diacyl peroxide by using the optimized conditions
to carry out reactions of N-phenyl-1,2,3,4-tetrahydroisoquinoline
(1a) with a variety of diacyl peroxides 2 (Table 2), which were
synthesized from the corresponding carboxylic acids. We
obtained good to moderate yields of products 3ab–3ad from
peroxides with unsubstituted linear alkyl chains. In addition,
diacyl peroxides with hexyl, cyclopentyl, tert-butyl, keto, and ester
groups in the chain also afforded good to excellent yields of the
desired products (3ae–3ai). Peroxides bearing aryl groups were
satisfactory, affording 3aj–3am, as were peroxides containing a
alkene or a thiophene moiety (3an–3ao).
The reaction conditions also appear to be general for a
variety of N-aryl tetrahydroisoquinolines 1 (Table 3). Substrates
with an N-phenyl ring bearing several kind of groups, such as
fluorine, bromine, methyl, tertiary butyl and methoxy group,
gave corresponding alkylation products 3ca–3ga in excellent
yields. Furthermore, substituent in different positions of the
N-phenyl do not affect the reaction (3ga–3ia). The substituent
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol) and 2
(0.22 mmol) in MeCN (1 mL) were stirred in an 8 mL bottle at rt under
Ar for 24 h.
on the benzene ring of the tetrahydroisoquinoline moiety could was not observed under these conditions confirmed that the
also be varied, as demonstrated by the selective alkylation of 1b reaction proceeded via cross-coupling of two different radicals.
in 88% yield (3ba). In addition, substrates with a naphthalene
On the basis of these experiments, we propose the mechanism
or biphenyl group on the nitrogen were also suitable, affording outlined in Scheme 3. Under argon, acyloxy radicals, alkyl radicals
3ja and 3ka, respectively. Meanwhile, we also use diphenyl- A, and CO2 are readily formed by means of thermal homolytic
benzylamine and isochroman as substrates. To our depressed, dissociation of oxygen–oxygen bonds in acylperoxides followed
none of them got desire products which mean that nitrogen by radical decarboxylation. A hydrogen abstraction between
atoms and cyclic substrate are necessary.
acyloxy radicals and N-phenyl-1,2,3,4-tetrahydroisoquinoline
To explore the reaction mechanism, we performed several control (1a) generates a-aminoalkyl radical cation C and corresponding
experiments. When a radical inhibitor (TEMPO, 1,1-diphenyl- carboxylic acid B.8 Finally, selective cross-coupling of radicals A
ethylene or BHT) was present in reaction mixture containing 1a and C generates product 3aa. It is worth noting that we cannot
and 2a,5 only a trace of alkylation product 3aa was observed, rule out the possibility of SET oxidation between 1a and acyloxy
and radical coupling products 3la and 3ma were detected by radicals.
high-resolution mass spectrometry (Scheme 2a). A radical clock
To demonstrate the utility of our protocol for late-stage
reaction of 1a and diacyl peroxide 2v produced cyclization functionalization, we carried out a gram-scale (5.0 mmol) reaction
product 3av in a 45% isolated yield (Scheme 2b).6 Taken between tetrahydroisoquinoline 1d and 2a (Scheme 4a), which
together, these results indicate that the reaction proceeded afforded target product 3da in 82% yield. In addition, tetrahydro-
via a radical mechanism. To rule out the possibility of free b-carboline derivative 1n could be used as a substrate (Scheme 4b);
radical addition, we synthesized substrate 1h and allowed it to its reaction with 2a afforded desired alkylation product 3na in an
react with 2a (Scheme 2c),7 the fact that alkylation product 3aa acceptable yield (63%).
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Table 3 Substrate scope with respect to the Michael acceptora
Scheme 3 Mechanistic experiments.
a
Reaction conditions, unless otherwise noted: 1 (0.2 mmol) and 2a
(0.22 mmol) in MeCN (1 mL) were stirred in an 8 mL bottle at rt under
b
Ar for 24 h. MeCN : DCM = 9 : 1 was used as the solvent.
Scheme 4 Demonstration of synthetic utility.
This work is supported by the National Key Research and
Development Program of China (2018YFD0200100), the National
Natural Science Foundation of China (21732002, 21672117).
Conflicts of interest
There are no conflicts to declare.
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of C(sp3)–H bonds with diacyl peroxides. The mild reaction pro-
ceeds at room temperature without the need for a catalyst or any
additives and is therefore atom-economical and environmentally
friendly. Various 1,2,3,4-tetrahydroisoquinolines and a tetrahydro-
b-carboline derivative were suitable substrates. Mechanistic studies
showed that the reaction proceeds via cross-coupling between an
alkyl radical and an a-aminoalkyl radical. The mild, catalyst- and
additive-free conditions make this protocol superior to previously
reported C(sp3)–H alkylation strategies.
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