Synthesis ofN-alkoxyphthalimide derivativesviaPIDA-promoted cross dehydrogenative coupling reaction

Article abstract of DOI:10.1039/d1ra00375e

A PIDA-promoted cross-dehydrogenative coupling reaction betweenN-hydroxyphthalimide (NHPI) and aryl ketones for efficient synthesis ofN-alkoxyphthalimide products in moderate to good yields has been described. This methodology is distinguished by catalyst-free conditions, readily available starting materials, wide substrate scope and operational simplicity. In addition, a gram-scale reaction and synthetic transformation of the product into synthetically useful intermediates has been demonstrated.

Full text of DOI:10.1039/d1ra00375e

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Synthesis of N-alkoxyphthalimide derivatives via
PIDA-promoted cross dehydrogenative coupling
reaction†
Cite this: RSC Adv., 2021, 11, 8051
a
Rongxiang Chen,a Bing Liu,b Wenbo Li,b Kai-Kai Wang,
Changqing Miao,b
*
d
Zhizhuang Li,b Yingjie Lvc and Lantao Liu
*
A PIDA-promoted cross-dehydrogenative coupling reaction between N-hydroxyphthalimide (NHPI) and
aryl ketones for efficient synthesis of N-alkoxyphthalimide products in moderate to good yields has been
described. This methodology is distinguished by catalyst-free conditions, readily available starting
materials, wide substrate scope and operational simplicity. In addition, a gram-scale reaction and
synthetic transformation of the product into synthetically useful intermediates has been demonstrated.
Received 15th January 2021
Accepted 12th February 2021
DOI: 10.1039/d1ra00375e
rsc.li/rsc-advances
N-Alkoxyphthalimide derivatives are one of the privileged core H bond. Tetrabutylammonium iodide (TBAI)/tert-butyl hydro-
structural frameworks in the synthesis of pharmaceuticals and peroxide (TBHP) has been proved as an efficient transition-
functional materials.1 Consequently, the development of highly metal-free system to apply in C(sp3)–H bond functionaliza-
efficient methods for the synthesis of N-alkoxyphthalimides has tion,10 especially through cross dehydrogenative coupling
emerged as a research topic.2 Traditionally, the method to (CDC), which could assemble complicated molecules from the
generate N-alkoxyphthalimides mainly involved the modied widely available and simple materials.11 For example, Prabhu
Gabriel reaction of N-hydroxyphthalimide (NHPI) with alcohol.3 reported a TBAI-catalyzed a-aminoxylation of ketones using
Recently, the direct dioxygenation of alkenes with NHPI has been TBHP as oxidant to directly construct corresponding N-alkox-
developed to produce b-keto-N-alkoxyphthalimides, which was yphthalimide products (Scheme 1b).12 Although many notable
realized by copper,4 iron5 and manganese catalyst,6 separately. In advances toward the synthesis of N-alkoxyphthalimide deriva-
2016, the group of Adimurthy has developed an efficient method tives have been reported, the development of more simple,
for the synthesis of a-oxygenated ketones through PIDA (phe- concise and efficient synthetic routes remains highly attractive.
nyliodine diacetate)-mediated oxidative functionalization of As a continuation of our previous work focused on free radical
styrenes with NHPI and molecular oxygen (Scheme 1a).7
chemistry without transition metal catalyst,13 in this context,
In addition, due to its versatility and atom-economy poten- herein we disclose a novel and efficient method towards N-
tial, direct and selective C(sp3)–H bond functionalization has alkoxyphthalimides via direct cross dehydrogenative coupling
become one of the most powerful and efficient tool in organic of aryl ketones with NHPI without transition metal catalyst via
synthesis in recent years, which allow direct conversion of C–H a radical process (Scheme 1c).
bonds to C–C and C–X bonds from simple precursors.8
As a cheap and readily available reagent, PIDA has been
Transition-metal-catalyzed C(sp3)–H functionalization has been widely used in organic synthesis.14 For example, Zhao and co-
extensively utilized for the construction of various chemical
bonds. Considering the fact that these strategies are not envi-
ronmentally friendly,9 therefore, great efforts have been devoted
to develop metal-free free oxidative functionalization of C(sp3)–
aSchool of Pharmacy, Xinxiang University, Xinxiang 453000, P. R. China. E-mail:
wangkaikaii@163.com
bSchool of Chemistry and Materials Engineering, Xinxiang University, Xinxiang
453000, P. R. China
cXinxiang Tuoxin Pharmaceutical Company Limited, Xinxiang 453000, P. R. China
dCollege of Chemistry and Chemical Engineering, Shangqiu Normal University,
Shangqiu, Henan, 476000, P. R. China. E-mail: liult05@iccas.ac.cn
† Electronic supplementary information (ESI) available: Data for new compounds
and experimental procedures. CCDC 2049393. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d1ra00375e
Scheme
products.
1
Strategies for the synthesis of N-alkoxyphthalimide
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Table 2 Scope of the linear-chain aryl ketonesa
workers described a PIDA-mediated oxygenation reaction of
N,N-diaryl tertiary amines.15 Recently, a PIDA-mediated radical
cyclization of o-(allyloxy)arylaldehydes with NHPI has been
realized by Wang's group.16 At the outset of this investigation,
we chose 1,2-diphenylethanone 1a and N-hydroxyphthalimide
2a as the model substrates to optimize the reaction conditions
(Table 1). The reaction went smoothly and the desired product
3a could be obtained in 92% yield by using PIDA as the oxidant
and dichloromethane as a solvent at room temperature under
air atmosphere (Table 1, entry 1). Encouraged by this result, we
next tested different solvents and the results indicated that
dichloromethane is the optimum solvent for this trans-
formation (entries 2–9). Meanwhile, the effect of different
oxidants was also investigated; however, they signicantly
hampered product formation (entries 10–15). When using high
valence iodine reagent 2-iodoisoindoline-1,3-dione (NIS) as an
oxidant, product 3a was afforded in 61% yield (entry 16).
Elevating reaction temperature to 60 ꢀC has no perceptible
effect on the reaction efficiency (entry 17). Shortening reaction
time to 4 h and 1 h delivered 93% and 64% yield of the desired
product, respectively (entries 18 and 19). Moreover, a control
experiment suggested that the oxidant was essential for this
transformation (entry 20).
a
Reaction conditions: 1a (0.3 mmol, 1 equiv.), 2a (1.2 equiv., 0.36
mmol), PhI(OAc)2 (1.2 equiv., 0.36 mmol) and CH2Cl2 (2 mL) at room
temperature for
phthalimide N-oxyl.
4
h
in
a
sealed tube. Isolated yield. NIPO
¼
Table 1 Optimization of the reaction conditionsa
With the optimized reaction conditions in hand, the gener-
ality and limitation of the protocol were examined in Table 2.
Firstly, the substrate scope of linear-chain aryl ketones was
explored and we found that various substituents on aryl rings of
aryl ketones were well tolerated under optimized reaction
Entry
Solvent
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
DCE
Toluene
THF
CH3CN
DMSO
Acetone
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
TBHP
DTBP
K2S2O8
BQ
H2O2
I2
NIS
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
92
74
77
<10
<5
77
13
53
52
n.d.
n.d.
n.d.
n.d.
n.d.
<5
61
93
93
64
Table 3 Scope of cyclic aryl ketonesa
9
10
11
12
13
14
15
16
17c
18d
19e
20e
n.d.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol, 1.2 equiv.), oxidant
(0.36 mmol, 1.2 equiv.), and solvent (2.0 mL) in a test tube at room
b
c
d
e
temperature for 10 h. Isolated yields. At 60 ꢀC. 1 h. 4 h. n.d. ¼
a
not detected. TBHP ¼ tert-butyl hydroperoxide (70% in water). DTBP
Reaction conditions: 4 (0.3 mmol, 1 equiv.), 2a (1.2 equiv., 0.36 mmol),
¼
di-tert-butyl peroxide. BQ
¼
1,4-benzoquinone. NIS
¼
N- PhI(OAc)2 (1.2 equiv., 0.36 mmol), and CH2Cl2 (2 mL) at room
iodosuccinimide.
temperature for 4 h in a sealed tube. Isolated yield.
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Scheme 4 Proposed reaction mechanism.
Scheme 2 Scaled-up version and synthetic transformations.
(Scheme 2a). The further conversion of the product 3a was also
conducted. Using m-chloroperbenzoic acid as the oxidant, 3a
could also be readily oxidized to afford the corresponding ester
6 in 85% yield. In addition, treatment of 3a and NEt3 led to the
formation of benzil 7 in 93% yield (Scheme 2b).
To shed light on the reaction mechanism for this trans-
formation, control experiments were performed, as shown in
Scheme 3. As expected, the addition of well-known radical-
trapping reagent BHT (3,5-di-tert-butyl-4-hydroxytoluene)
suppressed the reaction and the substrate was recovered,
which indicated that free radical intermediate may be involved
in this transformation (Scheme 3a). Furthermore, when
conditions, regardless of electron-donating and electron-
withdrawing functional groups (3a–3j). The structure of 3f was
conrmed by X-ray crystallographic analysis (see ESI†).17 1-
(Naphthalen-2-yl)-2-phenylethanone and 1-(2-methoxyphenyl)-
2-phenylethanone also exhibited excellent reactivity, in which
the corresponding products 3i and 3j were isolated in 92% and
95% yield, respectively. Meanwhile, 2-aryl substituted aceto-
phenones have also been shown to be suitable substrates to
furnish the corresponding products 3k–3l in moderate to good
yields. The efficiency of the reaction was not affected by the
substituents on both benzene rings (3m). To our delight, 1,2-
diphenylbutan-1-one and 2-phenoxy-1-phenylethanone were
compatible with reaction conditions, which reacted smoothly
with 2a to furnish the corresponding products in good yields
(3n–3o).
We next evaluated the scope of this C–H functionalization
reaction using cyclic aryl ketones as the substrates (Table 3).
Benzofuran-3(2H)-ones displayed no obvious detrimental effect
on the reaction efficiency and afford the desired products 5a–5d
in moderate to good yields. In addition, 1-acetylindolin-3-one
was proved to be a suitable substrate to deliver product 5e in
95% yield. Moreover, 2,3-dihydro-1H-inden-1-ones also
demonstrated satisfactory compatibility with the reaction (5f–
5h). To our delight, 3,4-dihydronaphthalen-1(2H)-ones were
shown to be slightly less efficient yet nonetheless suitable
substrates, affording the desired products 5i and 5j in 96% and
58% yield, respectively.
radical
scavenger
TEMPO
(2,2,6,6-tetramethyl-1-
piperidinyloxy) was subjected into the reaction system under
standard conditions, no product was detected and radical
adduct 8 was separated in 20% yield, which revealed a radical
process was involved in this PIDA-promoted C–H functionali-
zation reaction (Scheme 3b).
Based on the above experiments and previous studies from
the literatures,12,18 we propose a plausible mechanism for this
transformation, which is depicted in Scheme 4. Initially,
a ligand exchange between PhI(OAc)2 and NHPI would generate
intermediate I, which is converted into a PINO radical by
thermal homolytic cleavage. Radical intermediate II was formed
through H-abstraction of C(sp3)–H bonds by PINO radical and
regenerated NHPI (Scheme 4a), which undergoes second ligand
exchange and thermal homolytic cleavage with iodobenzene
acetate radical to yield PINO radical (Scheme 4b). Then, the
coupling reaction of radical intermediate II and PINO radical
gave nal product 3a (Scheme 4c).
We also inspected the scalability of this PIDA-promoted C–H
functionalization reaction and the current protocol could be
readily executed on a gram scale by successfully reacting
5 mmol of 1a with 2a in one pot to obtain 3a in 70% yield
Conclusions
In summary, we have implemented a novel metal-free dehy-
drogenation coupling of aryl ketones with N-hydroxyph-
thalimide through direct C(sp3)–H functionalization to furnish
a range of N-alkoxyphthalimide derivatives under mild condi-
tions. Our strategy features easily available starting materials,
operational simplicity, broad substrate scope and good func-
tionality tolerance. Moreover, we have conducted a gram-scale
reaction and further synthetic transformation of the product.
Further explorations on the synthetic utility of this trans-
formation are currently underway in our laboratory.
Scheme 3 Preliminary mechanism studies.
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