Minisci-Type C–H Cyanoalkylation of Heteroarenes Through N–O/C–C Bonds Cleavage

Article abstract of DOI:10.1002/ejoc.201900406

A visible-light-induced C–H cyanoalkylation of heteroarenes was described, in which cycloketone oximes were readily transformed into carbon-centered radicals with a terminal cyano-group via N–O/C–C bonds cleavage in one phtochemical step. This reaction protocol displayed a broad substrate scope of heterocycle compounds, and it provided a promising strategy for the installation of cyanoalkyl groups onto heteroarenes.

Full text of DOI:10.1002/ejoc.201900406

A Journal of
Accepted Article
Title: Minisci-type C-H Cyanoalkylation of Heteroarenes via N-O/C-C
Bonds Cleavage
Authors: Yong Jian, Ming Chen, Chao Yang, and Wujiong Xia
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10.1002/ejoc.201900406
European Journal of Organic Chemistry
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Minisci-type C-H Cyanoalkylation of Heteroarenes via N-O/C-C
Bonds Cleavage
Yong Jian,[a] Ming Chen,[b] Chao Yang*[a] and Wu-jiong Xia*[a]
Dedication ((optional))
Abstract:
A
visible-light-induced C-H cyanoalkylation of
oxime esters have never been used in Minisci-type reaction
except the recent nickel-catalyzed cyanoalkylation discovered by
Guo and coworkers.[18] Inspired by the above-mentioned works,
we wonder if carbon centered radicals bearing a terminal-cyano
group could be formed from cycloketone oximes via N-O/C-C
bonds cleavage and then took a photomediated Minisci-type
reaction to unactivated hetroarenes. Herein we presented our
heteroarenes was described, in which cycloketone oximes were
readily transformed into carbon-centered radicals with a terminal
cyano-group via N-O/C-C bonds cleavage in one phtochemical step.
This reaction protocol displayed
a broad substrate scope of
heterocycle compounds, and it provided a promising strategy for the
installation of cyanoalkyl groups onto heteroarenes.
findings on
a visible-light-induced C-H cyanoalkylation of
heteroarenes by using cycloketone oximes as radical sources,
such developed protocol provided a convenient α-alkylation
mode to various nitrogen-bearing aromatics.
Introduction
The alkylation of nitrogen-bearing heterocyclic compounds is
always an essential research theme in catalysis and
pharmaceutical chemistry.[1] Among numerous synthetic
strategies, Minisci-type reaction, which was originally featured
with the oxidative coupling of carboxylic acids with heterocycles
via a radical process,[2] has evolved to be an applicable and
versatile method for this transformation.[3] Over the past decades,
with the development of photoredox catalysis,[4] great
achievements have been made in the visible-light-promoted
Minisci-type reactions by taking advantage of different alkylation
reagents (Scheme 1B). Since the first photocatalytic Minisci-type
alkylation with peroxides disclosed by Dirocco,[5] other types of
compounds, including alcohols,[6] aliphatic carboxylic acids[7] and
their
derivatives
(e.g.
N-(acyloxy)phthalimides),[8]
alkyltrifluoroborates[9] and alkyl boronic acids,[10] pyridinium
salts,[11] 1,4-dihydropyridine derivatives,[12] alkyl iodides,[13] even
alkanes,[14] have been successively reported to engage in
photomediated
Minisci-type
reactions
with
different
heteroaromatics.
On the other hand, oxime esters, which could be easily
accessed from corresponding ketones,[15] have proved to be an
elegant N- or C-radical precursor in visible-light catalysis.[16]
Mechanistic investigation indicated that radicals were easily
delivered from oxime esters through a photocatalyzed reductive
single-eletron-tranfer process. Recent works by Wu, Xiao and
Leonori et al have extensively demonstrated their high
reactivities with unsaturated double/triple C-C bond under the
irradiation of visible-light, providing a useful synthetic platform to
facilitate molecular diversity and complexity.[17] However, to date,
Scheme 1. The development of Minisci-type reactions.
Results and Discussion
To verify our hypothesis, initial investigation was conducted with
isoquinoline (1aa) and cyclobutanone oxime (2aa) in the
presence of trifluoroacetic acid (TFA) and photocatalyst under
the irradiation of blue LEDs (Table 1). It was delightful that
cyanoalkylated product (3aa) was obtained in 77% yield when
Ir[dF(CF3)ppy]2(dtbbpy)PF6 was used as photocatalyst after 20 h
at room temperature. Encouraged by this result, we evaluated
the performance of other photocatalysts (entries 2-5). Among
them, fac-Ir(ppy)3 was found to be the best catalyst giving 3aa in
94% yield. Control experiments indicated that blue LEDs
irradiation and photocatalyst were essential for the
cyanoalkylation (entries 7-8). It is worth noting that air
[a]
Y. Jian, Prof. Dr. C. Yang and Prof. Dr. W. Xia
State Key Lab of Urban Water Resource and Environment, Harbin
Institute of Technology (Shenzhen),
Shenzhen 518055, China.
E-mail: xyyang@hit.edu.cn
E-mail: xiawj@hit.edu.cn
http://www.hitsz.edu.cn/teacher/view/id-1360.html
Dr. M. Chen
[b]
School of Basic Medical Sciences, Xinxiang Medical University,
Xinxiang 453003, China.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900406
European Journal of Organic Chemistry
COMMUNICATION
atmosphere has a dramatically negative effect on reaction
results (94% vs 0%, entry 3 and 6).
Table 1. Optimization of reaction conditions[a]
Entry
Solvent
Photocatalyst
Yield[b]
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Ir[dF(CF3)ppy]2(dtbbpy)PF6
Ir(ppy)2(dtbbpy)PF6
fac-Ir(ppy)3
77%
71%
94%
n.d
Ru(bpy)3(Cl)2
Eosin Y
66%
n.d
fac-Ir(ppy)3, air
fac-Ir(ppy)3, in the dark
no photocatalyst
fac-Ir(ppy)3, no TFA
n.d
n.d
35%
[a] Reaction conditions: isoquinoline 1aa (0.1 mmol), oxime 2aa (0.2 mmol),
photocalyst (1.0 mol %), TFA (0.15 mmol), CH3CN (1.0 mL), N2, 15 W blue
LED, rt, 20 h. TFA= trifluoroacetic acid, ppy = 2-phenylpyridine, dtbbpy =
4,4’-di-tert-butyl-2,2’-bipyridine. [b] Isolated yield.
With the optimal reaction conditions in hand, we firstly
examined the scope of the hereroarenes. As listed in Scheme 2,
a wide range of heterocycle compounds were investigated,
among which isoquinolines with methyl or halogen on different
poisitions were discovered to afford desired products in good to
excellent yields (3ab-3aj). In addition, in which 4-substituted
quinolines effectively transformed into corresponding products in
41-57% yields, yet the electron-withdrawing groups had a slight
negative effect on yields (3ak-3am). When quinolines with a
substituent at C2 position, corresponding C4 cyanoalkylated
products were obtained in medium yield (3an, 3ao). Importantly,
this protocol was tolerant with muti-substituted quinolines,
providing target products 3ap and 3aq in 52%, 54% yields,
respectively. In respect to quinoline that possessed two reactive
sites for cyanoalkylation, two regioisomers, 3ar-1 and 3ar-2,
Scheme 2. Scope of cyanoalkylation of heteroarenes.[a,b] [a] Reaction
conditions: 1aa-1az (0.1 mmol), oxime 2aa (0.2 mmol), photocalyst (1.0
mol %), TFA (0.15 mmol), CH3CN (1.0 mL), 15 W blue LED, rt, 20 h. [b]
Isolated yield.
Encouraged by the successful cyanoalkylation of isoquinolines
and quinolines, other heteroarenes were also examined.
Gratifyingly, pyridine compounds were observed to smoothly
participated in the cyanoalkylation with 2aa. For examples, 3as
and 3at were respectively synthesized from 4-phenylpyridine
and 4-tert-butylpyridine in yields of 55% and 40%. Similar to the
behavior of quinoline 1ar, 2-phenylpyridine, whose derivatives
are commonly used as key ligands in photocatalyst,[19] could be
transformed to 3au-1 and 3au-2 in 23% and 29% yield,
respectively.
were isolated in
respectively).
a total yield of 57% (26% and 31%,
Besides, the current reaction conditions were also compatible
with quinoxaline, benzofuran and benzothiazole, affording
corresponding cyanoalkylated 3av, 3aw and 3ax in moderate
yields. Finally, other fused heterocycles, such as acridine and
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10.1002/ejoc.201900406
European Journal of Organic Chemistry
COMMUNICATION
phenanthridine, were exposed to the irraditions of blue LED to
deliver 3ay and 3az in yields of 80% and 57%, respectively.
Scheme 4. Control experiments.
Scheme 3. Scope of cycloketone oximes.[a,b] [a] Reaction conditions: 1aa (0.1
mmol), oxime 2ba-2bg (0.2 mmol), photocalyst (1.0 mol %), TFA (0.15 mmol),
CH3CN (1.0 mL), 15 W blue LED, rt, 20 h. [b] Isolated yield.
Subsequently, the scope of cycloketone oximes was
investigated as shown in Scheme 3. The reactions of oxetan-3-
one oxime and substituted cyclobutanone oxime proceeded
smoothly with 1aa, affording corresponding products 3ba, 3bb
and 3bc in 46%, 56% and 62% yield, respectively. It’s
interesting to find that 3bd, which is difficult to be synthesized by
traditional methods, could be easily obtained from bicyclo[3.2.0]
oxime 2bd. The experiment results also proved ether, amide
and alkenyl were good tolerant groups. To increase the diversity
of oxime scope, reactions were conducted by using
cyclopentanone oxime and substituted cyclopentanone oximes
as reaction partners which were found to be amenable by this
protocol. More remarkably, cycloketone oximes with multi-
substituents could be successfully converted into corresponding
carbon radicals through selective C-C bonds cleavage, such as
the cases of 3be, 3bf and 3bg. In addition, we further
investigated the reactivity of six-, seven-, eight- and twelve-
membered ring ketoximes, disappointedly, no desired product
was detected under the optimal conditions.
To gain more insights into the mechanism of this protocol, a
series of control experiments were conducted as shown in
scheme 4. By employing isoquinoline 1aa and oxime 2bb as
model substrates, the standard conditions delivered 3bb in 56%
yield (scheme 4, eq (1)). The reaction system was almost
completely suppressed in the presence of 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) (4.0 equiv.), suggesting a
radical process might be involved (eqn (2)). Further investigation
showed that the alkyl radical with a terminal cyano- was trapped
by TEMPO, giving 4a in 48% yield (for details, see Supporting
information), implying a cascade N-O, C-C bonds cleavage
sequence might be involved in the process of radical formation.
Scheme 5. The proposed reaction mechanism.
In the previous reports, Xiao and other groups have already
described analogous mechanisms about alkyl radicals
generated from cyclobutanone oxime derivatives though
photocatalytic process. Based on the experimental results and
literatures, a possible mechanism was proposed as depicted in
Scheme 5. The Minisci reaction was initiated with the excitation
of photocatalyst fac-Ir(ppy)3 by visible light irradiation. Then the
*
* /
Ⅲ Ⅳ
excited Ir was oxidized to Ir (E1/2
= -1.73 V vs. SCE)[4a] by
Ⅲ
Ⅳ
oxime 2aa (Ered = -1.64 V vs. SCE)[17g]. Meanwhile, the obtained
radical intermediate I underwent a ring-opening event to deliver
radical Ⅱ which subsequently attacked protonated isoquinoline
Ⅳ
to afford radical cation Ⅲ. Through the reduction of III by Ir , the
final product 3aa was afforded in 94% yield via a SET process
and the catalyst was regenerated.
Conclusions
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10.1002/ejoc.201900406
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COMMUNICATION
Chem. Int. Ed. 2018, 57, 10034-10072; Angew. Chem. 2018, 130,
10188-10228.
In conclusion, in the report we developed a Minisci-type C-H
cyanoalkylation of heteroarenes via visible light photoredox
catalysis under mild conditions. This photochemical method
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substrate scope of heteroarenes. Finally, we clarified a possible
visible-light induced photoredox pathway by series of
mechanistic studies.
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Acknowledgments ((optional))
We are grateful for the financial support from the NSFC of China
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Keywords: Cyanoalkylation • Heteroarenes • Oximes •
Photocatalysis • C-C Bond
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Minisci Reactions
Yong Jian, Ming Chen, Chao Yang* and
Wujiong Xia*
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Minisci-type C-H Cyanoalkylation of
Heteroarenes via N-O/C-C Bonds
Cleavage
A visible-light-induced C-H cyanoalkylation of heteroarenes was described, in which
cycloketone oximes were readily transformed into carbon-centered radicals with a
terminal cyano-group via N-O/C-C bonds cleavage in one phtochemical step.
*one or two words that highlight the emphasis of the paper or the field of the study
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