Application of Hantzsch Ester and Meyer Nitrile in Radical Alkynylation Reactions

Article abstract of DOI:10.1021/acs.orglett.8b03050

The first example of constructing a C_sp3-C_sp bond with substituted Hantzsch ester and Meyer nitrile is reported. When benziodoxole-activated alkyne was applied as the alkynyl donor, products containing C_sp3-C_sp bonds involving primary, secondary, and tertiary carbon centers were achieved in up to 97% yields. K₂S₂O₈ was the optimum radical initiator in this reaction.

Full text of DOI:10.1021/acs.orglett.8b03050

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Application of Hantzsch Ester and Meyer Nitrile in Radical
Alkynylation Reactions
Xu Liu,† Ruoyu Liu,† Jie Dai,† Xu Cheng,*,†,‡ and Guigen Li†,§
†Institute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, National Demonstration
Center for Experimental Chemistry Education, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, China
‡State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023,
China
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States
S
* Supporting Information
ABSTRACT: The first example of constructing a Csp3−Csp
bond with substituted Hantzsch ester and Meyer nitrile is
reported. When benziodoxole-activated alkyne was applied as
the alkynyl donor, products containing Csp3−Csp bonds
involving primary, secondary, and tertiary carbon centers
were achieved in up to 97% yields. K2S2O8 was the optimum
radical initiator in this reaction.
Scheme 1. Application of Substituted Hantzsch Ester in C−
C Bond Formation Reactions
he alkynyl group is a highly reactive functionality that is
Tapplied as a precursor in a number of transformations.
Introductions of alkynyl groups into molecules have been
established via nucleophilic addition,1 electrophilic addition,2
and transition-metal-catalyzed coupling reactions.3 Recently,
alkynylation reactions via a radical pathway have been reported
with BI (benziodoxolone)-activated acetylenes in combination
with radicals from a variety of precursors such as carboxylic
acids,4 alkyl borates,5 aldehydes,6 alcohols,7 and ketones.8
These radical alkynylation reactions demonstrated comple-
mentary reactivity and selectivity to approaches involving ionic
species or transitional-metal catalysis.9
The synthetic potential of substituted Hantzsch ester (HE)
was first exhibited by Tang in Lewis acid catalyzed alkylation
reactions (Scheme 1).10 It was reported as a highly efficient
photoredox alkylation reagent in a visible-light-induced
reaction first by Nishibayashi.11 Our group reported an
intermolecular construction of a quaternary carbon center
fulfilled with substituted HE or Meyer nitrile12 as radical
donors.13 Substituted HE was successfully applied in the
coupling reaction with synergistic catalysis using nickel/
photocatalyst by Nishibayashi and Molander’s groups.14
Melchiorre and co-workers revealed the substituted HE
could fragment at its excited state in the absence of
photocatalyst and gave an alkyl radical that in turn participated
in nickel-catalyzed alkylation reactions.15 Recently, we have
disclosed that the substituted HE behaves as a radical reservoir
that is able to release a radical without an external electron
acceptor in photoredox catalysis.16 Yu and Zhang presented a
photoredox addition of an alkyl radical to imine with
substituted HE as radical donor.17 In addition to the reactivity
of substituted HE in the presence of transitional-metal
complex, the reaction reported by Molander and co-workers
showed HE also works with an organo-radical initiator such as
Na2S2O8 in the Csp2−H alkylation reaction.18 An asymmetric
radical 1,4-addition was achieved by Melchiorre with visible-
light-induced iminium catalysis employing substituted HE as
radical precursor.19 In spite of extensive applications of
substituted HE in various alkylation reactions, the alkylation
of alkyne giving the Csp−Csp3 bond remains elusive. Herein, we
report our study of the alkylation reaction with substituted HE
and Meyer nitrile and alkyne activated by a BI group to build a
Csp−Csp3 bond.
Received: September 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
On the outset of our study, we chose phenylacetylene BI
derivative 1a and benzyl-substituted Hantzsch ester 2a as
starting materials in the presence of different catalysts or
reagents (Table 1). At room temperature, 1 mol % of fac-
Scheme 2. Reaction of Substituted HEs and BI-alkynes
a
Table 1. Optimization of Alkylation of BI-Activated Alkyne
b
c
d
entry
photocatalyst (1 mol %)
oxidant (equiv)
yield (%)
1
2
3
4
5
6
fac-Ir(ppy)3
Ru(bpy)3Cl2
Safranine
12
8
42
88 (84)
trace
84
e
K2S2O8 (1.5)
K2S2O8 (1.5)
Na2S2O8 (1.5)
TBHP (1.5)
f
7
48
8
BPO (1.5)
15
9
30% H2O2 (1.5)
PhI(OAc)2 (1.5)
m-CPBA (1.5)
K2S2O8 (1)
19
10
23
71
10
11
12
a
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Ar atmosphere,
b
18 h. Cs2CO3 (0.1 mmol), DCE (1 mL), 24 W blue LEDs, rt.
c
d
MeCN/H2O (v/v = 1:1, 1 mL), 50 °C. NMR yield using
e
diphenylmethane as the internal standard. Isolated yield in
f
parentheses. Room temperature.
Ir(ppy)3 was used as the photoredox catalyst, and phenyl
benzyl acetylene 3a was generated with only 12% NMR yield
(entry 1). Another widely applied complex, Ru(bpy)3Cl2, gave
an even poorer result (entry 2). Further evaluation of other
photocatalysts showed safranine gave a moderate yield of 42%
(entry 3). We then turned to thermal radical initiators and
found that with 1.5 equiv of K2S2O8 3a could be obtained in
84% isolated yield at 50 °C (entry 4, 75% yield at 1 mmol
scale). It was also confirmed that heating was necessary to
achieve the conversion as the reaction run at room temperature
could not offer the desired product (entry 5). If Na2S2O8 was
applied, a marginal loss of yield of 3a was observed (entry 6).
Other oxidative reagents did not give competitive results in
comparison to K2S2O8 (entries 7−11). In a reaction employing
1.0 equiv of K2S2O8, an inferior yield of 71% was obtained.
Subsequently, we explored the substrate scope of this
formation process of the Csp−Csp3 bond (Scheme 2). At first, a
variety of BI-derived aryl acetylenes 1 were used as alkynyl
donors in reactions with 2a. Compound 3b with a methyl
group at the para position was produced in 95% yield.
Biphenyl benzyl acetylene 3c was achieved in 73% yield.
Compounds 3d, 3e, and 3f bearing halogen atoms were
obtained in good yields. Further increasing the electron-
withdrawing ability in substrate 1g did not decrease the yield
of 3g. On the other hand, a conjugative electron-withdrawing
group such as an ester, aldehyde, or nitrile group, impacted the
transformation. Corresponding products 3h, 3i, and 3j were
prepared in only moderate yields. Next, BI-activated acetylene
1k substituted with a silyl group was evaluated, and 3k was
isolated in 35% yield. Consequently, Hantzsch esters 2 bearing
varied substituents were screened. 4-Methoxybenzyl and 4-
a
Conditions: (a) 1 (0.2 mmol), 2 (0.4 mmol), K2S2O8 (0.3 mmol),
MeCN/H2O = 1:1 (v/v), 2 mL, 50 °C, 18 h, isolated yields; (b) 1
(0.1 mmol), 2 (0.2 mmol), Ar atmosphere, 18 h. Safranine (1 mol
%), Cs2CO3 (0.1 mmol), DCE (2 mL), 24 W blue LEDs, rt.
b
chlorobenzyl groups could be introduced into molecules 3l and
3m in moderate yields. Alkyne 3n with a thiophene moiety was
generated in 58% yield. Hantzsch esters with secondary alkyl
side chains were also reactive, and desired molecules 3o, 3p
and 3q were isolated in moderate to good yields. Two
compounds 3r and 3s were prepared using photoredox (Table
1, entry 3) instead of persulfate to avoid acidic decomposition.
In comparison to the Hantzsch ester, the backbone of the
Meyer nitrile was less bulky and able to accommodate more
hindering side chains such as tertiary alkyl groups. Next, we
investigated the transformation involving substituted Meyer
nitriles 4 and BI-derived alkynes 1 (Scheme 3). We were glad
to find that the target product 3t bearing a quaternary carbon
center was produced in 75% yield. Compound 3u was achieved
in almost quantitative yield with the same approach. When
halogen atoms or CF3 groups were present on the side chains
in the Meyer nitrile, corresponding alkynes 3v−x were
obtained in moderate to acceptable yields. Meyer nitrile
bearing thiophene was examined, and 3y was prepared in 61%
yield. Consequently, more combinations of BI-derived aryl
acetylene 1 and Meyer nitrile 4 were subjected to this coupling
protocol. Compound 3z was isolated in good yield. Products
3aa and 3ab containing four-membered ring moieties were
acquired in 85% and 97% yields, respectively. In addition,
B
DOI: 10.1021/acs.orglett.8b03050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
concentration 0.15 mol/L, a peak at −0.6 V (vs SCE) was
present. This species was not detected in the same experiment
carried out with a 0.01 mol/L solution of K2S2O8 (Scheme 5a).
Scheme 3. Reaction of Substituted Meyer Nitrile and BI-
alkyne
a
Scheme 5. Plausible Reaction Pathway
a
Conditions: 1 (0.2 mmol), 2 (0.4 mmol), K2S2O8 (0.3 mmol),
MeCN/H2O = 1:1 (v/v), 2 mL, 50 °C, 18 h, isolated yield.
compound 3ac incorporating a five-membered ring was also
available in 97% yield. A tert-butyl group was also introduced
into product 3ad in 80% yield. Product 3ae bearing an
admantyl group was synthesized in 78% yield. Abietyl phenyl
acetylene 3af was also prepared in good yield.
To explore the applications of this transformation, we
subjected compound 3a to further derivations (Scheme 4). At
Recently, we found that the substituted HE can cleave to
dihydropyridine radical A and alkyl radical B.15 The excess
persulfate might provide a species that could undergo faster
electron transfer from highly reductive dihydropridine radical
A;22 this process might lead to accelerated generation of alkyl
radical B (Scheme 5b). Then, species B would add to the BI
derived aryl acetylene 1, giving intermediate D. Then the BI
group could leave as an iodo radical E that could react with HE
2 or radical A in a chain manner. Meanwhile, the desired
molecule 3 is furnished as a terminal product.
Scheme 4. Transformations of Compound 3a
In summary, we report the first application of substituted
Hantzsch ester and Meyer nitrile in the formation of Csp−Csp3
bonds. With K2S2O8 as initiator, substituted dihydropyridine
released an alkyl radical to react with BI-activated alkyne. The
corresponding 1,2-disubsituted acetylene was obtained in up to
97% yield. By applying Meyer nitrile as an alkyl radical donor,
intermolecular construction of a quaternary carbon center was
fulfilled.
first, with stoichiometric DDQ as oxidant, the propargylic C−
H was converted to phenol ether 6 in 76% yield.20 Mediated
with 2.5 equiv of copper(II) triflate, alkyne 3a reacted with
benzyl azide, forming quinoline 7 substituted with benzyl and
phenyl groups.21
Next, we turned our attention to the role of excess K2S2O8 in
this reaction. As reported by Molander and co-workers, the
oxidation potential of persulfate was not in direct relation with
the reactivity with HE.17 We carried out a cyclic voltammetry
experiment of K2S2O8 in MeCN/H2O and found that a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03050.
Detailed procedures of this Csp−Csp3 bond formation
reaction and derivatization of product 3a; character-
C
DOI: 10.1021/acs.orglett.8b03050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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AUTHOR INFORMATION
■
2481.
Corresponding Author
*e-mail: chengxu@nju.edu.cn.
ORCID
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Xu Cheng: 0000-0001-6218-611X
Guigen Li: 0000-0002-9312-412X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
of China (Nos. 21572099 and 21332005) and the Natural
Science Foundation of Jiangsu Province (No. BK20151379).
This study was supported by the Open Project of State Key
Laboratory Cultivation Base for TCM Quality and Efficacy,
Nanjing University of Chinese Medicine (Nos. TCMQ and E
201702). R.L. and J.D. appreciate the open training program of
the undergraduate organic experiment course (0205145031-6)
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