Method for Direct Synthesis of α-Cyanomethyl-β-dicarbonyl Compounds with Acetonitrile and 1,3-Dicarbonyls

Article abstract of DOI:10.1021/acs.orglett.6b01871

A novel and efficient method for the synthesis of α-cyanomethyl-β-dicarbonyls in moderate to excellent yields is developed by using inactive CH₃CN and simple 1,3-dicarbonyls. A radical mechanism is proposed under the ESI-MS (electrospray ioniza

Full text of DOI:10.1021/acs.orglett.6b01871

Letter
pubs.acs.org/OrgLett
Method for Direct Synthesis of α‑Cyanomethyl-β-dicarbonyl
Compounds with Acetonitrile and 1,3-Dicarbonyls
Chenyang Wang, Yabo Li, Ming Gong, Qi Wu, Jianye Zhang, Jung Keun Kim,* Mengmeng Huang,
and Yangjie Wu*
College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key
Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P.R. China
S
* Supporting Information
ABSTRACT: A novel and efficient method for the synthesis
of α-cyanomethyl-β-dicarbonyls in moderate to excellent yields
is developed by using inactive CH3CN and simple 1,3-
dicarbonyls. A radical mechanism is proposed under the ESI-
MS (electrospray ionization mass spectrometry) analysis
results of control experiments.
ompounds, containing cyanoalkyl fragments, could be
peroxides, metal complexes, or visible light11 using inactive alkyl
1
Cwidely found in natural products and pharmaceuticals. nitriles. To date, a number of biologically active compounds
These derivatives are not only used as the target products but
also for the synthesis of heterocycles, amines, carbonyl acids,
etc.2 Besides the potential applications in medicine and organic
synthesis,3 1,3-diketones with a cyanoalkyl moiety (α-
cyanomethyl-β-dicarbonyls) might be employed in metal
complexation and “host−guest” chemistry. Despite these
attractive properties of cyanomethyl dicarbonyls, its synthetic
method is not well investigated. To the best of our knowledge,
only one method exists so far, alkylation of β-dicarbonyl
compounds with prefunctionalized cyanomethyl halogenides in
the presence of stoichiometric strong base,3a,4 which could be a
major obstacle to studying such substances (Scheme 1, a).
have been synthesized via the addition of these active α-cyano
carbon-centered radicals.11n,k,p Based on the inspiring results
reported herein, we report a convenient and efficient direct
cyanomethylation on the α-position of β-dicarbonyls using
unsubstituted acetonitrile via Fe-catalyzed radical CDC
reaction.
Initially, the model reaction of ethyl benzoylacetate (1a) with
acetonitrile (2) could be carried out in the presence of
Fe2(CO)9, PPh3, and di-tert-butyl peroxide (DTBP) to give the
desired product 3a in 76% yield (Table 1, entry 1). Other
tested iron salts such as Fe(OAc)2, Fe2(acac)3, and FeCl2 did
not improve the reaction yield excluding FeCl3 (Table 1, entries
2−5). No reaction occurred with TBHP, dicumyl peroxide, or
(NH4)2S2O8 (Table 1, entries 6−8). The results showed that
the PPh3 ligand was necessary to optimize the reaction
conditions (Table 1, entries 9−12). To our delight, the yield
was increased to 88% when the catalyst loading was reduced to
10 mol % (Table 1, entry 13). A higher yield (93%) was
obtained at 100 °C in 36 h (Table 1, entries 14 and 15).
Under the optimized reaction conditions, the scope and
limitation of various β-dicarbonyls were investigated (Scheme
2). Generally, all tested ethyl benzoylacetates were able to
tolerate this catalyzed system to afford the desired product 3a−
p in moderate to excellent yields. The product yields with meta-
substituted ethyl benzoylacetates (3a−i) were higher than
those with para-substituted ethyl benzoylacetates (3k−n),
except 3j. Because of the steric effect of ethyl o-
methylbenzoylacetates, a trace amount of 3q was formed.
Although this catalytic system was incompatible with ethyl 3-
(furan-2-yl)-3-oxopropanoate (1s), the ethyl 3-oxo-3-(thio-
phene-2-yl)propanoate could react with CH3CN to give 3r in
54% yield. When the substituent group of the ester fragment
Scheme 1. Synthetic Method of α-Cyanomethyl-β-dicarbonyl
Compounds
Recently, the radical-mediated cross-dehydrogenative-cou-
pling (CDC) reaction has been a useful tool for realizing the
direct allylation,5 carboxylation,6 and heteroarylation7 of β-
dicarbonyl compounds to construct the C−C bond via atom-
economic and environmentally friendly procedure. The studies
of alkylation on the α-position were only limited to the
coupling with cycloalkanes,8 (cyclo)ethers,9 and benzylic
compounds.10 On the other hand, some reports demonstrated
that α-cyano carbon-centered radicals could be generated by
Received: June 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01871
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Fe-Catalyzed Radical CDC Reaction of
Acetonitrile with 1,3-Dicarbonyls
b
yield
entry
catalyst
oxidant
DTBP
DTBP
additive
(%)
1
2
3
4
5
6
7
Fe2(CO)9
Fe(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
76
71
Fe2(acac)2 DTBP
58
FeCl2
FeCl3
FeCl3
FeCl3
DTBP
DTBP
TBHP
60
81
trace
trace
dicumyl
peroxide
8
FeCl3
FeCl3
FeCl3
FeCl3
(NH4)2S2O8
DTBP
PPh3
trace
65
9
10
11
DTBP
4,4′-bipyridine
bis(diphenyl-phosphno)
methane
34
DTBP
42
12
FeCl3
DTBP
1,10-phenanthroline
hydrate
34
c
13
14
15
FeCl3
FeCl3
FeCl3
DTBP
DTBP
DTBP
PPh3
PPh3
PPh3
88
d
89
e
93
a
Reaction conditions: 1a (0.25 mmol), catalyst (20 mol %), additive
(20 mol %), oxidant (3 equiv), CH3CN (2 mL) in a sealed tube under
b
c
N2 at 100 °C (oil bath) for 24 h. Isolated yield. 10 mol % of FeCl3.
120 °C. 36 h.
d
e
a
was changed to tert-butyl or benzyl, the corresponding products
3t and 3u could be also prepared in good yields. In addition,
the reaction with diketones 1v−z were carried out only at 120
°C to afford products 3v−z in moderate yields.
Reaction conditions: 1a (0.25 mmol), catalyst (10 mol %), additive
(20 mol %), oxidant (3 equiv), CH3CN (2 mL) in a sealed tube under
N2 at 100 °C (oil bath) for 36 h. 120 °C.
b
Subsequently, several controlled experiments were inves-
tigated to gain insights on this transformation (Scheme 3). The
result of the intermolecular competing kinetic isotope effect
(KIE) study (KH/KD = 8.9 for acetonitrile and KH/KD = 9.0 for
dicarbonyl 1a) suggested that the rate-determining step was the
Csp3−H bond cleavage of acetonitrile and dicarbonyls (Scheme
3, eq I). The reaction was completely quenched with the radical
scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) or
butylated hydroxytoluene (BHT). Under the standard con-
ditions in the presence of BHT for 1 h, two strong molecular
ion peaks (m/z = 260.2011 and 433.2351) were detected by
ESI-MS (electrospray ionization mass spectrometry) and
attributed to [BHT-2 + H]+ (exact mass: 260.2009) and
[BHT-1a + H]+ (exact mass 433.2349). In addition, we found
another one (m/z = 131.9297) from the reaction with
TEMPO, which could be attributed to [ClFeCH2CN + H]+
(exact mass 131.9298) (Scheme 3, eq II). Although no product
3a was isolated in the absence of DTBP, a small amount of α-
cyanomethyl dicarbonyl 3a (37%) was obtained under standard
condition without FeCl3. These results indicated the following:
(i) the free radicals might be involved in this process, and the
premier (t-BuO•) radical could be obtained from the
decomposition of DTBP; (ii) the complex Cl−FeII−CH2CN
might be the active catalytic species for this conversion; (iii)
only a small amount of 3a generated via the coupling of radicals
A and B, and this way was not the main synthesis path of
product 3a.
Scheme 3. Mechanistic Studies
thylation of β-dicarbonyls is proposed in Scheme 4. Initially, the
radical initiator DTBP produced the premier radical (t-BuO•).
Subsequently, t-BuO• could be used to generate the Fe(II)
species E and radicals A and B. Then, the cyanomethylation
proceeded as follows: (a) radicals A and B might direct react
with each other to afford 3a; (b) radical B attacked Fe(III)
enolate C to afford the radical D which released Fe(II) species
to give 3a; (c) after homolytic cleavage of Fe(II)−C bond (E),
the obtained cyanomethyl radical B might be involved in path
On the basis of the above results and literature
precedent,5−11 a tentative mechanism for the novel cyanome-
B
DOI: 10.1021/acs.orglett.6b01871
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 4. Proposed Reaction Mechanism
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01871.
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Detailed experimental procedures and characterization
data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kim@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation (NSF) of China (21172200 and 21302172).
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DOI: 10.1021/acs.orglett.6b01871
Org. Lett. XXXX, XXX, XXX−XXX