Copper-catalyzed cyanoisopropylation of beta-keto esters using azos: synthesis of beta-dicarbonyls bearing an alfa-tertiary nitrile moiety

Article abstract of DOI:10.1080/00397911.2019.1574350

A copper-catalyzed α-cyanoisopropylation reaction of β-keto esters using azo compounds as cyanoalkylating agents is presented, providing an easy access to β-dicarbonyls containing an α-tertiary nitrile moiety with adjacent tertiary and quaternary carbon centers. It is remarkable because a tremendous steric conflict is involved during reaction. Such nitriles were otherwise unavailable, and the reaction features simple and relatively mild conditions and good functional-group tolerance.

Full text of DOI:10.1080/00397911.2019.1574350

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Copper-catalyzed cyanoisopropylation of
beta-keto esters using azos: synthesis of beta-
dicarbonyls bearing an alfa-tertiary nitrile moiety
Yanni Li, Ruirong Yang, Xiaohui Zhao, Yongchao Yao, Siping Yang, Qiong Wu
& Deqiang Liang
To cite this article: Yanni Li, Ruirong Yang, Xiaohui Zhao, Yongchao Yao, Siping Yang, Qiong
Wu & Deqiang Liang (2019): Copper-catalyzed cyanoisopropylation of beta-keto esters using azos:
synthesis of beta-dicarbonyls bearing an alfa-tertiary nitrile moiety, Synthetic Communications, DOI:
10.1080/00397911.2019.1574350
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https://doi.org/10.1080/00397911.2019.1574350
Copper-catalyzed cyanoisopropylation of beta-keto
esters using azos: synthesis of beta-dicarbonyls bearing an
alfa-tertiary nitrile moiety
Yanni Lia, Ruirong Yanga, Xiaohui Zhaoa, Yongchao Yaoa, Siping Yanga,
Qiong Wub, and Deqiang Lianga,b,c
b
aDepartment of Chemistry, Kunming University, Kunming, China; Yunnan Engineering Technology
c
Research Center for Plastic Films, Kunming, China; College of Chemistry and Molecular Sciences,
Wuhan University, Wuhan, China
ABSTRACT
ARTICLE HISTORY
Received 30 November 2018
A copper-catalyzed a-cyanoisopropylation reaction of b-keto esters
using azo compounds as cyanoalkylating agents is presented, provid-
ing an easy access to b-dicarbonyls containing an a-tertiary nitrile
moiety with adjacent tertiary and quaternary carbon centers. It is
remarkable because a tremendous steric conflict is involved during
reaction. Such nitriles were otherwise unavailable, and the reaction
features simple and relatively mild conditions and good functional-
group tolerance.
KEYWORDS
Cyanoalkylation; C–C
coupling; Copper catalysis;
Azo compounds;
b-Dicarbonyls
GRAPHICAL ABSTRACT
Introduction
Nitriles are finding increasing applications in materials,[1] pharmaceuticals, agrochemi-
cals[2] and azacycle synthesis,[3,4] and the cyano group is among the most versatile
functionalities because it could be readily converted into other functional groups such
as formyl, amino, amido, or carboxyl group.[5] In this regard, 1,3-dicarbonyls bearing
an a-cyanoalkyl moiety are not only versatile synthons,[4,5] but also employed in
metal or host–guest complexation processes.[6] Thus, the development of new method-
ologies for the synthesis of a-cyanoalkyl-b-dicarbonyls is an attractive prospect and
highly valuable.
CONTACT Deqiang Liang
liangdq695@nenu.edu.cn
Department of Chemistry, Kunming University, 2 Puxin Road,
Kunming 650214, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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Y. LI ET AL.
Scheme 1. Cyanoalkylation of activated methylenes.
Traditionally, a-cyanoalkyl-b-dicarbonyl compounds could be prepared from 1,3-
dicarbonyls and 2-bromoacetonitrile by nucleophilic substitution reaction
(Scheme 1a).[7] This methodology requires excess strong base and prebrominated
reagent. In 2016, Kim and Wu reported a cross-dehydrogenative coupling reaction
between b-dicarbonyls and acetonitrile (Scheme 1b).[8] This protocol is rather appealing,
for the inexpensive solvent was used as the radical precursor,[9] although a high-tem-
perature, a long reaction time, and excess oxidant are required. Nevertheless, using nei-
ther method do the products obtained contain a tertiary nitrile moiety, since in both
cases nitrile sources are strictly restricted to primary ones, partly due to steric hin-
drance. Therefore, the synthesis of b-dicarbonyls bearing an a-tertiary nitrile moiety is
still highly desirable and challenging, and yet to be revealed.
In our research on radical chemistry[10] and coupling reaction,[11] it was found that
azobisisobutyronitrile (AIBN), a radical initiator traditionally used in polymer synthe-
sis[12] and organic chemistry,[13] might also function as a tertiary nitrile source,[14]
which was examined in the title reaction. In this communication, we wish to report a
copper-catalyzed C–C coupling of b-keto ester with azo compounds, affording b-dicar-
bonyls having an a-tertiary nitrile moiety and adjacent tertiary and quaternary carbon
centers (Scheme 1c). The construction of such centers is a formidable challenge, because
a tremendous steric conflict is involved. This protocol features simple and relatively
mild conditions and good functional-group tolerance, and eliminates the need for using
excess base or oxidant, and for prebromination of cyanoalkylating agent.
Results and discussion
Our preliminary reaction development was conducted with ethyl 3-oxo-3-phenylpropa-
noate 1a and 3 equiv of AIBN in 1,2-dichloroethane (DCE) at 80 ꢀC (Table 1). It was
found that the title C-C coupling reaction could occur under the catalysis of several

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Table 1. Screening of the reaction conditions.a
Entry
Catalyst (mol%)
x
Solvent
T (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
CuI (10)
CuBr (10)
CuCl (10)
Cu(OAc)2 (10)
CuSO4ꢁ5H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Fe(NO3)3ꢁ9H2O (10)
AgNO3 (10)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
2
3
3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
CH3CN
CH3NO2
THF
DMSO
EtOH
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
110
50
80
80
80
80
28
16
41
27
nr
52
trace
9
nr
trace
24
18
trace
trace
15
9
–
10
11
12
13
14
15
16
17
18
19
20
21
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (10)
Cu(NO3)2ꢁ3H2O (20)
Cu(NO3)2ꢁ3H2O (5)
38
8
48 (43)b
35
50
33
DCE
aReaction conditions: 1a (0.2 mmol), solvent (2.0 mL), in a sealed tube, 12 h.
bAIBN was added in two equal portions at 6 h intervals.
copper salts, including CuI (entry 1), CuBr (entry 2), CuCl (entry 3), Cu(OAc)2 (entry
4), and Cu(NO3)2ꢁ3H2O (entry 6), providing desired tertiary nitrile 2a in 16–52% yields.
While the use of 10 mol% Cu(NO3)2ꢁ3H2O gave a relatively better yield, CuSO4ꢁ5H2O
proved ineffective for this transformation (entry 5). When Fe(NO3)3ꢁ9H2O (entry 7) or
AgNO3 (entry 8) was used as the catalyst, great sluggishness was observed. A control
experiment confirmed that no reaction occurred in the absence of copper (entry 9). The
examination of other solvents demonstrated that the cyanoalkylation was significantly
retarded in toluene (entry 10), tetrahydrofuran (THF, entry 13) or dimethylsulfoxide
(DMSO, entry 14), whereas nitrile 2a was delivered in lower yields with CH3CN (entry
11), CH3NO2 (entry 12), or EtOH (entry 15) as the solvent. Raising (entry 16) or lower-
ing the reaction temperature (entry 17), or reducing the loading of AIBN (entry 19) or
the catalyst (entry 21), all led to diminished yields. Attempt to improve the yield by uti-
lizing a higher dosage of AIBN, added either in one portion or in two equal portions at
6-h intervals (entry 18), or by using a higher loading of the copper salt (entry 20), met
with no success. An array of oxidants, as well as various acids, bases, and salts, were
evaluated as additives. To our disappointment, beneficial effect was observed using none
of them (Table S1, see the Supporting Information), and tertiary nitrile 2a could be
obtained in only a moderate yield (entry 6, Table 1). Even this is remarkable, consider-
ing that a great steric hindrance is involved during reaction, and that a-cyanoisopropyl-
b-dicarbonyls were otherwise unavailable.

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Y. LI ET AL.
Table 2. Scope.a
aReaction conditions:
1
(0.2 mmol), azo compound (0.6 mmol), Cu(NO3)2ꢁ3H2O
(0.02 mmol), DCE (2.0 mL), in a sealed tube, 80 ꢀC, 12 h.
To evaluate the scope of this cyanoisopropylation reaction, a variety of tertiary nitriles
were synthesized from activated methylenes and azo compounds (Table 2). Ethyl ben-
zoylacetates bearing either an electron-donating or -withdrawing substituent at the para
or meta position of the benzoyl ring reacted with AIBN to provide corresponding

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a-cyanoalkyl-b-keto esters 2b,c in 36–65% yields. Aryl C–Br and C–Cl bonds were well-
tolerated, facilitating further elaboration to more complex molecules. The reaction was
found to be sensitive to steric effect, and use of ortho-substituted substrates, as well as
ethyl 2,4,5-trifluorobenzoylacetate and ethyl (2,3,4,5-tetrafluorobenzoyl)acetate, gave
relatively modest yields of tertiary nitriles 2d–f. Notably, c-heteroaroyl nitriles 2g,h
were prepared from related 2-thenoyl and picolinoyl substrates, respectively. Methyl,
isopropyl and tert-butyl benzoylacetates also worked well in this C–C coupling reaction,
furnishing expected nitriles 2i,j in 31–55% yields. The combination of an aroyl group
and an ester moiety is essential. Whereas we failed to isolate any pure product from the
complex reaction mixture of N-methyl-3-oxo-N,3-diphenylpropanamide and AIBN,
dimerization reaction was dominant when 1,3-diphenylpropane-1,3-dione was used as
the substrate, delivering tetrabenzoyl product 3 in 64% yield. No reaction occurred with
a-methylated b-keto ester due to steric hindrance. A wide range of other b-dicarbonyls/
activated methylenes were tested as substrates, and they failed to undergo a-cyanoiso-
propylation with AIBN (Table S2, see the Supporting Information), probably owing to
steric hindrance and/or polarity mismatching.[15,16] 2,20-Azobis(2-methylbutyronitrile)
(AMBN) and 2,20-azobis(2,4-dimethyl)valeronitrile (AMVN) are usable cyanoalkylating
agents as well, and their reactions with ethyl benzoylacetate 1a gave tertiary nitriles 2k1,
2 in moderate yields. The reaction of dimethyl 2,20-azobis(isobutyrate) (MAIB) with 1a
also gave a complex mixture, from which we failed to isolate the desired C–C cou-
pling product.
Radical trapping experiments were performed to confirm the radical nature of this
cyanoisopropylation (Scheme 2a). As might be expected, upon adding either 1.2 equiv
of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or 2 equiv of 2,6-di-tert-butyl-4-
methylphenol (BHT) as the radical scavenger, the model reaction under standard condi-
tions was almost completely suppressed. Furthermore, cyanoisopropyl-TEMPO and
-BHT adducts 4 and 5 were isolated in 29% and 45% yields, respectively.
Scheme 2. Proposed reaction mechanism.

6
Y. LI ET AL.
On the basis of the above observations and previous works,[10,14] a tentative mechan-
ism for the copper-catalyzed cyanoisopropylation is proposed (Scheme 2b). To start
with, isobutyronitrile radical A is produced through thermal decomposition of AIBN,
while ligand metathesis of Cu(NO3)2 with ethyl benzoylacetate 1a affords the copper
enolate B. Addition of radical A to the enolate double bond gives radical intermediate
C, the breakup of which releases cyanoalkylated product 2a and CuNO3. The reaction
of CuNO3 with cyanoisopropyl radical A and HNO3 regenerates CuNO3 for fur-
ther reactions.
Conclusions
To conclude, we have developed a copper-catalyzed a-cyanoisopropylation of b-keto
esters using azo compounds as cyanoalkylating agents. This protocol permits direct syn-
thesis of b-dicarbonyls containing an a-tertiary nitrile moiety and adjacent tertiary and
quaternary carbon centers, under simple and relatively mild conditions and with good
functional-group tolerance.
Experimental
Chemicals were all purchased from commercial sources and used without treatment.
Reactions were monitored by Thin Layer Chromatography (TLC) using silica gel F254
plates. Products were purified by column chromatography over 300–400 mesh silica gel
1
under a positive pressure of air. H NMR, 13C NMR, DEPT and 19F NMR spectra were
recorded at 25 ꢀC on a Bruker AscendTM 400 spectrometer using tetramethyl silane
1
(TMS) as an internal standard. Data for H NMR are reported as follows: chemical shift
(d ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet),
coupling constant (Hz), integration. High-resolution mass spectra (HRMS) were
obtained using a Bruker microTOF II Focus spectrometer (ESI).
General procedure (1a as an example)
A 35 mL Schlenk tube, equipped with a magnetic stirring bar, was charged with ethyl 3-
oxo-3-phenylpropanoate 1a (38 mg, 0.2 mmol), AIBN (99 mg, 0.6 mmol), and
Cu(NO3)2ꢁ3H2O (4.8 mg, 0.02 mmol), followed by the addition of DCE (2.0 mL). The
mixture was stirred at 80 ꢀC for 12 h; then it was quenched with saturated aqueous
Na2S2O3 (1.0 mL) and water (10.0 mL) and extracted with CH2Cl2 (10.0 mL) three times.
The residue obtained after evaporation of the solvent was purified by column chroma-
tography on silica gel (petroleum ether:ethyl acetate = 8:1, v/v) to afford ethyl 2-ben-
1
zoyl-3-cyano-3-methylbutanoate 2a as a pale yellow oil (27 mg, 52% yield): H NMR
(400 MHz, CDCl3) d ¼ 1.17 (t, J ¼ 7.1 Hz, 3H), 1.55 (s, 3H), 1.58 (s, 3H), 4.13–4.25 (m,
2H), 4.35 (s, 1H), 7.50 (dd, J ¼ 7.6, 7.9 Hz, 2H), 7.62 (dd, J ¼ 7.4, 7.4 Hz, 1H), 7.98–8.00
(m, 2H); 13C NMR (100 MHz, CDCl3) d ¼ 191.37, 166.38, 136.18, 134.09, 128.94, 128.53,
123.09, 62.32, 60.37, 32.87, 26.05, 26.03, 13.86; HRMS (ESI-TOF) Calcd for
þ
C15H18NO3 ([M þ H]þ) 260.1281. Found 260.1286.

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Funding
We gratefully acknowledge the financial support from the National Natural Science Foundation
of China [21702083], the General Projects of Yunnan Education Department [2017ZZX093], the
Program for Innovative Research Team (in Science and Technology) in Universities of Yunnan
Province, and the Yunnan Ten Thousand Talent Program for Young Top-Notch Talents.
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