Direct C-H Cyanoalkylation of Heteroaromatic N-Oxides and Quinones via C-C Bond Cleavage of Cyclobutanone Oximes

Article abstract of DOI:10.1021/acs.orglett.7b02902

A direct C-H cyanoalkylation of heteroaromatic N-oxides and quinones with cyclobutanone oximes is reported. This redox-neutral, operationally simple cyanoalkylation reaction is successfully amenable to a wide range of heteroaromatic N-oxides, quinones, and cyclobutanone oximes. A novel catalytic system consisting of a nickel source proved crucial for cleavage of the C-C bond of cyclobutanone oximes and for selective C-C bond formation over β-hydride elimination. Mechanistic studies suggest that a radical intermediate might be involved in this transformation.

Full text of DOI:10.1021/acs.orglett.7b02902

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Direct C−H Cyanoalkylation of Heteroaromatic N‑Oxides and
Quinones via C−C Bond Cleavage of Cyclobutanone Oximes
Yu-Rui Gu, Xin-Hua Duan, Lin Yang, and Li-Na Guo*
Department of Chemistry, School of Science and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed
Matter, Xi’an Jiaotong University, Xi’an 710049, China
S
* Supporting Information
ABSTRACT: A direct C−H cyanoalkylation of heteroaromatic N-oxides and quinones with cyclobutanone oximes is reported.
This redox-neutral, operationally simple cyanoalkylation reaction is successfully amenable to a wide range of heteroaromatic N-
oxides, quinones, and cyclobutanone oximes. A novel catalytic system consisting of a nickel source proved crucial for cleavage of
the C−C bond of cyclobutanone oximes and for selective C−C bond formation over β-hydride elimination. Mechanistic studies
suggest that a radical intermediate might be involved in this transformation.
lkylnitriles represent a privileged class of structural motifs
Athat can be found in many natural products and
pharmaceutical compounds.1 Furthermore, cyanoalkyl moieties
are one of the most versatile building blocks in organic synthesis
owing to their easy conversions to other functional groups, such
as amines, amides, carboxylic acids, and heterocycles.2 As a result,
diverse methods for the synthesis of alkylnitriles have been
developed over the past few decades.3 One traditional method
for alkylnitrile synthesis is based on the addition of hydrogen
cyanide (HCN) or the related less volatile precursor, acetone
cyanohydrin (TMSCN), to alkenes.4a The use of toxic HCN is
associated with a somewhat troublesome gas handling procedure,
Figure 1. Carbon−carbon bond cleavage of cyclobutanone oximes.
which to some extent limits their further applications. In
addition, some different approaches to structurally diverse
alkylnitriles, including cyanation of alkyl halides,4b dehydration
Uemura and co-workers disclosed another alternative to nitriles
of amides or aldoximes,4c−e dehydrogenation of amines,4f,g direct
through the palladium-catalyzed ring opening of cyclobutanone
activation of nonactivated alkylnitriles2a,4h,l and others,5 have also
been developed. More recently, remarkable advances have been
made in the efficient and practical synthesis of alkylnitriles.5e,f
Despite this significant progress, new methods for incorporation
of cyanoalkyl groups, especially those bearing longer aliphatic
chains into organic skeletons, are still quite challenging and rare.3
Transition-metal-catalyzed carbon−carbon bond cleavage of
strained rings has emerged as a useful and powerful tool for
carbon−carbon and carbon−heteroatom bond formations.6 In
this field, strained cyclobutanone oximes and their derivatives are
efficient substrates to obtain alkylnitriles through the β-carbon
elimination pathway. In 1991, Zard and co-worker reported a
radical C−C bond cleavage of cyclobutanone sulfenylimines or
carboxymethyl oximes to alkylnitriles, wherein an iminyl radical
intermediate was involved (Figure 1, route a).7 Subsequently,
oximes. In this reaction, the cyanoalkylpalladium species was
formed first via β-carbon elimination, which underwent β-
hydride elimination to provide the alkenylnitriles (route b).8
Although active intermediates, such as γ-cyanoalkyl radical and γ-
cyanoalkyl metal complex, were formed in those processes,
further studies on their diverse transformations were less
exploited. Due to our continuous interest in C−C bond cleavage
reactions,9 we expect to develop novel catalytic systems, wherein
the β-hydrogen elimination of cyanoalkyl metal intermediate
could be inhibited, so that further transformations can be
performed.7 Herein, we report the first nickel-catalyzed direct
C−H cyanoalkylation of electron-deficient heteroaromatic N-
Received: September 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02902
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Letter
oxides and quinones with cyclobutanone oximes under redox-
neutral conditions (route c).
Scheme 1. Scope of Direct C−H Cyanoalkylation of
Heteroaromatic N-Oxides with Cyclobutanone Oximes
We started our investigation by treatment of quinoline N-
oxide 1a and cyclobutanone pentafluorobenzoyloxime 2a with
nickel catalysts, which exhibited high reactivity toward alkyl
partners and favorable single-electron redox potentials.10
Satisfactorily, the reaction was proven uniquely effective in the
presence of 10 mol % of NiCl2·glyme and bipyridine in CH3CN
at 100 °C, leading to the desired product 3a in 46% yield (Table
1, entry 1; for details, see Supporting Information (SI)).
a
Table 1. Reaction Optimization
b
entry
deviation from above
yield (%)
1
2
3
4
5
6
7
8
10 mol % of L1 as ligand
10 mol % of L5 as ligand
10 mol % of L6 as ligand
10 mol % of L8 as ligand
10 mol % of FeCl2 as catalyst
10 mol % of CoCl2 as catalyst
10 mol % of [Ir(cod)Cl]2 as catalyst
without catalyst
46
66
71
62
51
60
11
c
nr
a
Reaction conditions: 10 or 15 mol % of catalyst and ligand, 1a (0.3
mmol 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), CH3CN (2 mL), 100 °C,
b
c
16 h. Yield of isolated product. No reaction.
Meanwhile, phenanthrolines L5 and L6 and oxazolin L8 were
also examined as ligand, and bathophenanthroline L6 gave the
best result (entries 2−4). Subsequently, a screening of catalysts
was performed carefully (entries 5−7). The iron and copper
catalysts also exhibited similar catalytic activity, but [Ir(cod)Cl]2
only led to the desired product 3a in 11% yield.7c Further
investigation revealed that 15 mol % of catalyst and ligand
loading improved the yield to 78%, whereas the 7.5 and 20 mol %
loading gave somewhat lower yields. Control experiments
disclosed that no desired product was detected in the absence
of catalyst (entry 8). It is noteworthy to mention that the
alkenylnitrile byproduct generated through β-hydride elimina-
tion was not observed in all those cases, which might be due to
the use of nickel catalyst as well as the radical pathway.10
With optimized conditions in hand, we sought to examine the
scope and generality of this reaction. As shown in Scheme 1, a
variety of quinoline N-oxides bearing electron-donating or
electron-withdrawing groups at the 6-position of the aromatic
ring reacted smoothly with 2a to give the corresponding products
3b−f in moderate to good yields. 8-Methyl- and 8-methoxy-
substituted quinoline N-oxides were also good substrates,
furnishing the desired products 3g and 3h in 50 and 46% yields,
respectively. Notably, 3-, 5-, or 6-bromo-substituted quinoline N-
oxides 1e, 1i, and 1k also survived this transformation and gave
the desired products in good yields (3e, 3i, and 3k), thereby
offering opportunities for further functionalization on the
product. To our delight, the reaction of sterically hindered 3-
methyl- or 3-bromoquinoline N-oxides also proceeded well
under the optimized conditions, leading to the corresponding 2-
cyanoalkyled products 3j or 3k in 76 or 72% yields, respectively.
Additionally, 4-methyl- and 4-chloroquinoline N-oxides were
also suitable substrates (3l and 3m). Subsequently, the scope of
cyclobutanone oximes was investigated. The simple substrate
derived from cyclobutanone also participated well in this
coupling process (3n). A wide range of cyclobutanone oximes
containing aryl, benzyl, or alkyl groups on the 3-position were
also efficiently converted to the corresponding products 3o−u in
moderate to good yields. The 3,3-disubstituted and tricyclic
cyclobutanone oximes were also applicable to the reaction, albeit
in somewhat low yields (3v and 3w). Notably, the C−C bond
cleavage of tricyclic cyclobutanone oximes occurred at the
sterically more hindered site regioselectively, which can be
attributed to the stability of the intermediate radical.7c
Unfortunately, the less-strained substrates such as camphor
oxime 2q and cyclopentanone oxime 2r failed to provide any
desired product. Besides quinoline N-oxides, other heteroar-
omatic N-oxides, including isoquinoline, pyridine, quinazoline,
quinoxaline, and benzoquinoline N-oxides, were also compatible
with the reaction conditions, providing the corresponding
products in acceptable yields (3x, 3y, 4a−f). Remarkably,
pharmaceuticals such as cinchonine N-oxide could also give the
desired cyanoalkylated product 4g in 71% yield.
Encouraged by the above results, we turned our efforts toward
extending this direct C−H cyanoalkylation protocol to other
attractive targets. Quinones were considered to be quite
important structural motifs in many biologically active natural
products, pharmaceuticals, and functional materials. Recently,
great efforts have been devoted to direct C−H functionalization
of quinones, but it is still deficient due to relatively few coupling
partners and requirement of excessive oxidants and noble
B
DOI: 10.1021/acs.orglett.7b02902
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Letter
metals.11 Therefore, we aim to develop an efficient and practical
synthesis of cyanoalkylated quinone derivatives. To our delight,
the reaction of benzoquinone with cyclobutanone oxime 2a
proceeded very well under the above reaction conditions,
affording the desired product 6a in 88% yields (Scheme 2).
Scheme 3. Mechanistic Studies
Scheme 2. Scope of Direct C−H Cyanoalkylation of Quinones
with Cyclobutanone Oximes
conditions gave the corresponding annulated products 8b or 9b
in 30 or 58% yields, respectively, as sole product (eq 2).
Unexpectedly, treatment 1a and 5g with 7c resulted in the
products 8c and 9c in moderate yields, respectively (eq 3).
Furthermore, the intermolecular competitive and parallel
experiments using 1a and deuterated 1a with 2a were also
conducted. The kinetic isotope effect values of 1.84 and 1.67
were observed (eqs 4 and 5). On the other hand, heat-induced
activation of cyclobutanone oximes to generate iminyl radicals
was ruled out by a contrast experiment.12
Dichloro- or dimethyl-substituted benzoquinones were success-
fully converted into the corresponding products 6b−d in
moderate yields. Naphthoquinone was also found to be a
suitable substrate for this reaction and gave the desired product
6e in 62% yield. Notably, an unprotected hydroxyl group was
well tolerated in this reaction, providing good opportunities for
further modifications (6f). The 2-methyl- or 2-chloronaphtho-
quinone also resulted in the desired products 6g and 6h in
excellent yields. More importantly, a variety of substituted
cyclobutanone oximes bearing aryl, benzyl, or alkyl substituents
underwent direct C−H cyanoalkylation efficiently to afford the
cyanoalkylated naphthoquinones 6i−q in good to excellent
yields. When tricyclic cyclobutanone oxime was subjected to the
reaction, the cyanoalkylated product 6r was isolated in 67% yield.
Significantly, the apoptosis inducer coenzyme Q0 also furnished
the target product 6s in 88% yield.
Based upon the preliminary results, a possible mechanism is
proposed (Scheme 4). First, single-electron transfer from the Ni
Scheme 4. Proposed Mechanism
Interestingly, cyclobutanone oxime 7a containing an o-
substituted styryl group at the 3-position also worked well with
1a or 5g under the nickel catalytic system, affording the
anticipated product 8a or 9a in moderate yields, respectively. In
this transformation, a tandem ring-opening/cyclization/coupling
process is involved (eq 1a).
complex to cyclobutanone oxime 2a leads to the iminyl radical I,
which gives the radical II via a β-carbon elimination process.
Second, addition of radical II to quinoline N-oxide 1a affords
radical cation III, which undergoes single-electron oxidation by
Ni catalyst followed by the loss of H+ to produce the product 3a.
More studies are underway to elucidate the detailed mechanism
of this transformation.
To test the practicability of this protocol, the reaction was
performed on a gram scale (3 mmol). Satisfyingly, the desired
product 3a was obtained in 70% yield (for details, see SI). To
further demonstrate the synthetic utility of this reaction,
derivatization reactions of the cyanoalkylated quinoline N-
oxide 3a were carried out. 3a could be easily reduced by
treatment with PhB(OH)2 to furnish the corresponding
quinoline 11a in 90% yield. The CN group of the 11a could
be efficiently transformed into carboxylic acid 12a through basic
To probe the mechanism of this reaction, some control
experiments were conducted (for details, see SI). When
TEMPO, a typical radical scavenger, was added to the standard
system, the reaction was suppressed completely, and only
cyanoalkyl-TEMPO adduct 10a was isolated in 78% yield
(Scheme 3, eq 1). As expected, the butylated hydroxytoluene also
inhibited the reaction remarkably. These results suggest that a
free radical process would be involved. Subsequently, some
radical clock experiments were performed with substituted
cyclobutanone oximes 7b and 7c. The reaction of quinoline N-
oxide 1a or 2-methylnaphthoquinone 5g with 7b under standard
C
DOI: 10.1021/acs.orglett.7b02902
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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by H2O2 oxidation in moderate yield. Reduction of 11a with
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with acetic anhydride, 3a was easily converted to 15a in 73%
yield.13
In summary, we have developed a nickel-catalyzed direct C−H
cyanoalkylation of heteroaromatic N-oxides and quinones with
cyclobutanone oximes. This novel nickel catalytic system was
first applied to the ring-opening reaction of cyclobutanone
oximes, which allows for direct installation of structurally diverse
cyanoalkyl groups into the electron-deficient molecules. This
protocol exhibits good compatibility with a broad range of
heteroaromatic N-oxides, quinones, as well as cyclobutanone
oximes. This work represents one of the examples of C−C bond
formation via catalytic C−C cleavage of cyclobutanone oximes.
(6) For selected reviews, see: (a) Gansauer, A.; Lauterbach, T.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02902.
(7) (a) Boivin, J.; Fouquet, E.; Zard, S. Z. J. Am. Chem. Soc. 1991, 113,
1055. (b) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32,
4299. (c) Nishimura, T.; Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.;
Uemura, S. Org. Lett. 2005, 7, 2425. (d) Yang, H.-B.; Selander, N. Chem.
- Eur. J. 2017, 23, 1779. During the completion of our work on this
chemistry, a copper-catalyzed Heck-type coupling of cyclobutanone
oximes with alkenes was reported by Shi et al.: (e) Zhao, B.; Shi, Z.
Angew. Chem., Int. Ed. 2017, 56, 12727.
Experimental procedures and spectroscopic data of new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: guoln81@xjtu.edu.cn.
ORCID
(8) (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049.
(b) Nishimura, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org. Chem.
2004, 69, 5342.
Li-Na Guo: 0000-0002-9789-6952
Notes
(9) (a) Wang, S.; Guo, L.-N.; Wang, H.; Duan, X.-H. Org. Lett. 2015,
17, 4798. (b) Guo, L.-N.; Deng, Z.-Q.; Wu, Y.; Hu, J. RSC Adv. 2016, 6,
27000.
The authors declare no competing financial interest.
(10) For recent reviews, see: (a) Frisch, A. C.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 674. (b) Rudolph, A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 2656. (c) Tasker, S. Z.; Standley, E. A.; Jamison, T. F.
Nature 2014, 509, 299. (d) Ananikov, V. P. ACS Catal. 2015, 5, 1964.
(11) For selected examples, see: (a) Fujiwara, Y.; Domingo, V.; Seiple,
I. B.; Gianatassio, R.; Del Bel, M.; Baran, P. S. J. Am. Chem. Soc. 2011,
133, 3292. (b) Zhang, S.; Song, F.; Zhao, D.; You, J. Chem. Commun.
2013, 49, 4558. (c) Walker, S. E.; Jordan-Hore, J. A.; Johnson, D. G.;
Macgregor, S. A.; Lee, A. L. Angew. Chem., Int. Ed. 2014, 53, 13876.
(d) Xu, X.-L.; Li, Z. Angew. Chem., Int. Ed. 2017, 56, 8196.
(12) After heating cyclobutanone pentafluorobenzoyloxime 2a in 1 mL
of CD3CN at 100 °C for 16 h, 2a was recovered in 95% yield. This result
implies that nickel catalyst plays an important role in the activation of
oxime ester process. Heat-induced activation of oxime esters to generate
iminyl radicals usually requires harsh reaction conditions. For selected
examples, see: (a) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org.
Chem. 2008, 73, 5558. (b) Cai, Y.; Jalan, A.; Kubosumi, A. R.; Castle, S.
L. Org. Lett. 2015, 17, 488.
ACKNOWLEDGMENTS
■
Financial support from Natural Science Basic Research Plan in
Shaanxi Province of China (No. 2016JZ002) and the
Fundamental Research Funds of the Central Universities (Nos.
zrzd2017001, xjj2016056, and 2015qngz17) is greatly appre-
ciated.
DEDICATION
■
This paper is dedicated to Professor Herbert Mayr on the
occasion of his 70th birthday.
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DOI: 10.1021/acs.orglett.7b02902
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