Chemoselective Access to γ-Ketoesters with Stereogenic Quaternary α-Center or γ-Keto Nitriles by Aerobic Reaction of α-Cyanoesters and Styrenes

Article abstract of DOI:10.1021/acs.orglett.7b01264

Chemoselective access to either γ-ketoesters with a quaternary all-carbon α-stereogenic center or γ-keto nitriles is described by copper-catalyzed aerobic reaction of styrenes with α-cyanoesters. Formal oxo-enolation or oxo-cyanomethylation of styrenes is achieved via a sequence of addition of enolate (or cyanomethyl) radical to olefin and oxidation of the resulting radical adduct. This method starts from abundant and cheap feedstock under aerobic conditions, without any prefunctionalization or the production of stoichiometric metal salts waste, making it very attractive for practical use.

Full text of DOI:10.1021/acs.orglett.7b01264

Letter
pubs.acs.org/OrgLett
Chemoselective Access to γ‑Ketoesters with Stereogenic Quaternary
α‑Center or γ‑Keto Nitriles by Aerobic Reaction of α-Cyanoesters and
Styrenes
Song-Lin Zhang,* Xian-Jin Wang, and Ze-Long Yu
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi, Jiangsu 214122, China
S
* Supporting Information
ABSTRACT: Chemoselective access to either γ-ketoesters
with a quaternary all-carbon α-stereogenic center or γ-keto
nitriles is described by copper-catalyzed aerobic reaction of
styrenes with α-cyanoesters. Formal oxo-enolation or oxo-
cyanomethylation of styrenes is achieved via a sequence of
addition of enolate (or cyanomethyl) radical to olefin and
oxidation of the resulting radical adduct. This method starts
from abundant and cheap feedstock under aerobic conditions,
without any prefunctionalization or the production of
stoichiometric metal salts waste, making it very attractive for
practical use.
problems, and also environmental issues due to the production of
large quantities of metal salts waste. In the past decades, oxidative
C−H/C−H coupling reactions6 have attracted increasing
attentions for economical and environmental considerations
because abundant hydrocarbons, such as arenes and olefins, are
directly used without prefunctionalization. It is therefore of great
value to achieve oxidative 1,4-dicarbonyls synthesis from simple
and abundant hydrocarbons and related compounds via double
C−H activation.
1,4-Dicarbonyl compounds are versatile synthetic intermediates
and biologically active compounds. Typically, they are prepared
with the construction of C2−C3 bond by nucleophilic
substitution reaction of a ketone (or a preformed enolate, or
other activated enolate surrogates) with an α-halo carbonyl
compound under basic conditions1,2 or aldol-type addition of an
enolate to α-aldehyde carbonyls (Scheme 1a).3,4 Alternatively,
they can also be prepared through C1−C2 connection, such as
conjugate addition of an acyl to a Michael acceptor.5 In these
reactions, prefunctionalization of either one or both reaction
partners and the presence of stoichiometric amounts of base are
generally required. This gives rise to step- and atom-economy
Herein we describe an aerobic reaction7 between styrenes and
α-cyanoesters for the chemoselective synthesis of γ-ketoesters
with an all-carbon quaternary α-stereogenic center by formally
combining intermolecular oxidative enolate−olefin cross-cou-
pling8 and Wacker-type oxidation of olefins9 (Scheme 1b).
Interestingly, by slightly changing the solvent and reaction
temperature, the reaction produces selectively γ-keto nitriles
(Scheme 1b). Both products are versatile synthetic intermediates
toward a range of biologically active compounds. Considering
the direct use of abundant and cheap styrenes and α-cyanoesters
as substrates and abundant O2 as the terminal oxidant, this
method is an attractive straightforward and environmentally
benign method. During this study, Lan et al. reported a closely
related oxidative reaction of styrenes with alkyl nitriles to
produce γ-keto nitriles.10 The reaction occurred under neat
conditions promoted by DBU and excess TBHP, giving a range
of γ-keto nitriles in good yields. However, this reaction is limited
to alkyl nitriles, and α-cyanoesters are completely inactive under
their conditions. More, large quantities (4 equiv) of TBHP are
required as the terminal oxidant, which is less attractive than
Scheme 1. 1,4-Dicarbonyl Synthesis
Received: April 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01264
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Organic Letters
Letter
a
,b
using O2. Therefore, our method is still of great synthetic interest
using oxygen as the terminal oxidant and α-cyanoesters as the
substrates, giving γ-keto esters with the construction of
quaternary stereogenic α-center.
Scheme 2. Bis-α-Enolation of α-C−H Bonds of Cyanoester
This study was initially inspired by our recent study on
developing cyanation reactions using α-cyanoesters as the
nontoxic and readily available cyanating reagent via C−CN
bond cleavage under aerobic conditions.11 Given the well-known
Wacker-type reaction, we consider that reaction of olefins with α-
cyanoesters under aerobic conditions may achieve the oxy-
cyanation of olefins to produce α-cyano ketones. As our test
reaction, reaction of para-fluoride styrene (1a) and ethyl α-
cyanoacetate (2a) was studied in the presence of catalytic Cu2O/
PPh3 in DMSO under O2 atmosphere with catalytic AgF as co-
oxidant. To our surprise, the expected oxy-cyanation product was
not observed, but a minor amount of another product was
produced in about 10% yield. Further screening of other copper
sources indicated that CuI performed better, improving the yield
to 25% (Table 1, entries 1−4). This product was able to be fully
characterized to be α-cyanoacetate bis-α-enolation product 3a
with an all-carbon quaternary α-center.
Table 1. Optimization Study for the Synthesis of γ-Ketoesters
a
from α-Cyanoesters and Styrene
a
Reaction conditions: 1 (0.5 mmol), 2a (2.0 mmol), CuI (0.1 mmol),
PPh3 (0.1 mmol), AgF (0.2 mmol), and DCE (2 mL) stirred at 80 °C
b
(oil bath) under O2 balloon. Isolated yields after column
b
entry
catalyst
Cu2O
ligand
PPh3
solvent
yield (%)
chromatography.
1
DMSO
DMSO
DMSO
DMSO
NMP
10
12
8
2
Cu(OAc)2
CuBr
CuI
PPh3
two equivalents of styrenes. Either para- or meta-substituent on
the aromatic ring can be tolerated. A β-naphthyl olefin 1g was
also a good substrate under the conditions, giving 3g in 65%
isolated yield.
Furthermore, α-cyanoesters with an additional α-substituent
were also compatible with the optimized reaction conditions.
Thus, mono-α-enolation of the tertiary α-C−H bond of
cyanoesters by styrenes and naphthyl olefin can be achieved,
giving rise to highly functionalized γ-ketoesters 4 with an all-
carbon quaternary stereogenic α-center (Scheme 3). This
stereogenic α-center distinguishes the two protons on β-C
atom and also protons of methylene of ethoxy group, as reflected
3
PPh3
4
PPh3
25
NR
25
35
37
5
CuI
PPh3
6
CuI
PPh3
CH3CN
DMA
DMF
7
CuI
PPh3
8
CuI
PPh3
c
9
CuI
PPh3
Xantphos
bpy
DCE
66
c
10
11
12
CuI
DCE
25
c
CuI
DCE
28
c
CuI
BINAP
DCE
34
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), copper catalyst
(0.1 mmol), ligand (0.1 mmol), AgF (0.2 mmol), and solvent (2 mL)
stirred at 120 °C (oil bath) under O2 balloon. Isolated yield after
1
by two sets of separated resonances for both positions in H
b
NMR spectroscopy (please refer to Supporting Information).
This is in contrast to the situation in products 3 with a prochiral
α-carbon where protons on both carbons are indistinguishable.
Interestingly, when ortho-vinylpyridine (1j) was subjected to
react with 2b under the reaction conditions, an unexpected
product 7 was obtained in good isolated yield of 79% (eq 1).
Compound 7 should be the product of formal hydroenolation of
double bond of 1j.
c
column chromatography. At 80 °C.
It was later found that the solvent plays a crucial role for this
reaction. After evaluating a series of common organic solvents
including NMP, CH3CN, DMA, DMF, and 1,2-dicholoroethane
(DCE) (entries 4−9), it was pleasing to see that the reaction gave
a good yield of 66% in DCE at 80 °C (entry 9). Further attempts
to improve the reaction yield were unsuccessful, including
examining other ancillary ligands, such as Xantphos, bpy, and
BINAP (entries 10−12), and additives other than AgF.12
Various styrenes were then studied under the optimized
reaction conditions and γ-ketoesters with an all-carbon
quaternary prochiral α-carbon were obtained in moderate to
good yields (Scheme 2). The products come formally from
consecutive double oxidative cross-coupling of α-cyanoester with
B
DOI: 10.1021/acs.orglett.7b01264
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Scheme 3. Mono-α-Enolation of Tertiary α-C−H of
Scheme 5. Control Reaction and Radical Trapping
Experiments
a,b
Cyanoesters
a
Reaction conditions: 1 (0.5 mmol), 2b (2.0 mmol), CuI (0.1 mmol),
PPh3 (0.1 mmol), AgF (0.2 mmol), and DCE (2 mL) stirred at 80 °C
b
(oil bath) under O2 balloon. Isolated yields after column
chromatography.
tetramethylpiperidinyloxy), a radical scavenger, was added to the
reaction solution, the reaction yield of 3b decreased dramatically
to only 18% (43% without TEMPO) (Scheme 5b). Similarly, in
the presence of TEMPO, reaction of 1a with 2b gave trace
amounts of the desired 4a (Scheme 2c). These results indicate
that radical species should be involved during the reaction
course. Furthermore, a 1:1 mixture of two TEMPO adducts
(adduct1 and adduct2 in Scheme 5c) were generated from
trapping experiment, indicating the involvement of radicals A
and B (please refer to Figure 1) during the reaction course. The
formation of 7 in eq 1 is also evidence suggesting the involvement
of radical B.
In some of the reactions for the synthesis of γ-ketoesters,
minor amounts of byproducts were observed and identified to be
γ-keto nitriles 5 from oxo-cyanomethylation of olefins. This kind
of product can be produced in higher yields in more polar DMSO
at higher temperature of 120 °C. Scheme 4 shows several
examples of such products from reactions between styrenes and
α-cyanoester (2a).
a,b
Scheme 4. Synthesis of γ-Keto Nitriles
a
Reaction conditions: 1 (0.5 mmol), 2a (2.0 mmol), CuI (0.1 mmol),
PPh3 (0.1 mmol), AgF (0.2 mmol),and DMSO (2 mL) stirred at 120
°C (oil bath) under O2 balloon. Isolated yields after column
chromatography.
Figure 1. Plausible mechanism.
b
Based on the above information, a plausible mechanism is
suggested for this chemoselective aerobic cross-coupling
between styrenes and α-cyanoesters (Figure 1). Enolate radical
species A should be initially formed from α-cyanoester and adds
to olefins to get an enolate−olefin coupling radical B. Oxidation
of radical B by O2 and dehydration would deliver the desired
product 4. When α-H is present in intermediate C or 4 (i.e., R =
H), C or 4 can further generate a new radical E that couples with
a second styrene to give the bis-enolation product 3.
To shed light on the reaction mechanism, control experiment
using acetophenone as substrate in place of styrene showed that
no reaction occurred and that acetophenone was recovered
under the optimized reaction conditions in Scheme 2 or 4
(Scheme 5a). This implies a late-stage oxidation of the alkene
double bond for the synthesis of γ-ketoesters. In addition, radical
trapping experiment indicates that when TEMPO (2,2,6,6-
C
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Organic Letters
Letter
(6) For selected reviews on oxidative C−H/C−H cross-coupling, see:
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cleavage13,14 may be enabled for α-cyanoester or radical
intermediate A to generate cyanomethyl radical that couples
with olefins followed by oxidation to give the γ-keto nitrile 5.
In conclusion, an aerobic oxidative coupling between olefins
and α-cyanoesters is described to produce 1,4-dicarbonyl
compounds with the construction of C2−C3 bond. By slightly
changing the solvent and temperature, the reaction produces
selective γ-keto nitriles instead. A radical mechanism is suggested
to involve a key step of addition of enolate radical to olefins,
followed by aerobic oxidation. This method enables novel access
to two important classes of biologically active compounds and
synthetic intermediates from abundant and cheap starting
materials in a straightforward and environmentally benign way.
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̈
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ASSOCIATED CONTENT
* Supporting Information
■
S
(9) Wacker reaction: (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.;
Sieber, R.; Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. (b)
Applied Homogeneous Catalysis with Organometallic Compounds, 2nd ed.;
Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002; Vol.
1, pp 386−412.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01264.
Experimental details, spectroscopic characterization data,
and NMR spectra for all the products (PDF)
(10) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Lan, C.-L.; Zhang, T.; Chen,
S.-L.; Xing, Y. Org. Lett. 2016, 18, 5986.
(11) Zhang, S.-L.; Huang, L. Org. Biomol. Chem. 2015, 13, 9963.
(12) Other additives, e.g., peroxides, were also examined but gave
lower yields than under the optimized conditions in entry 9 of Table 1.
(13) For C−C activation reviews, see: (a) Jun, C.-H. Chem. Soc. Rev.
2004, 33, 610. (b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114,
8613. (c) Dong, G., Ed.; C−C Bond Activation. Topics in Current
Chemistry, Vol. 346; Springer: Berlin, 2014. (d) Souillart, L.; Cramer, N.
Chem. Rev. 2015, 115, 9410. (e) Marek, I.; Masarwa, A.; Delaye, P.-O.;
Leibeling, M. Angew. Chem., Int. Ed. 2015, 54, 414.
(14) For selected examples of C(carbonyl)−C activation, see:
(a) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (b) Jun,
C.-H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880. (c) Jun, C.-H. J. Am.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slzhang@jiangnan.edu.cn.
ORCID
Song-Lin Zhang: 0000-0002-5337-8600
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the National Natural Science
Foundation of China (Nos. 21472068 & 21202062). Financial
support from MOE & SAFEA for the 111 Project (B13025), is
gratefully acknowledged.
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D
DOI: 10.1021/acs.orglett.7b01264
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