Nitrile-assisted oxidation over oxidative-annulation: Pd-catalyzed α,β-dehydrogenation of α-cinnamyl β-keto nitriles

Article abstract of DOI:10.1039/c7ob00912g

A palladium-catalyzed oxidation reaction is disclosed where the nitrile functionality on the substrate simply changes the course of the reaction. Our previous finding showed that using the Pd(ii)-catalyst in the presence of benzoquinone as an oxidant, 2-cinnamyl-1,3-dicarbonyls provides functionalized furans via oxidative cyclization. When a nitrile group is replaced with one of the carbonyl functionalities of the same substrate, the oxidative cyclization was completely suppressed; instead, the oxidation at the α,β-position occurred to provide α,β,γ,δ-diene containing β-keto nitriles.

Full text of DOI:10.1039/c7ob00912g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00912G
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Nitrile‐Assisted Oxidation over Oxidative‐Annulation: Pd‐Catalyzed α,β‐
Dehydrogenation of α‐Cinnamyl β‐Keto Nitriles
Received 00th January 20xx,
Accepted 00th January 20xx
Rajender Nallagonda, Reddy Rajasekhar Reddy, and Prasanta Ghorai*
DOI: 10.1039/x0xx00000x
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carbonyl compounds, Saegusa oxidation is a convenient and well‐
established method where transformation of silyl enol ethers to the
corresponding α,β‐unsaturated carbonyl compounds occurs using
Pd(II)‐catalysts.6 Li and coworkers developed a novel amine‐Pd(OAc)2
co‐catalyzed direct saegusa oxidation of readily available β‐aryl
aldehyde to α,β‐unsaturated aldehydes.7 Huang and coworkers also
ABSTRACT: A palladium‐catalyzed oxidation reaction is disclosed
where the nitrile functionality on the substrate simply changes the
course of the reaction. Our previous finding showed that using Pd(II)‐
catalyst in the presence of benzoquinone as an oxidant, 2‐cinnamyl‐
1,3‐dicarbonyls provides functionalized furans via oxidative
cyclization. When a nitrile group replaces with one of the carbonyl
functionality of the same substrate, the oxidative cyclization was
completely suppressed; instead, the oxidation at α,β‐position
occurred to provide α,β,γ,δ‐diene containing β‐keto nitriles.
established
a
method for the palladium‐catalyzed aerobic
dehydrogenation of β‐aryl carbonyls to α,β‐unsaturated carbonyls.8
Very recently, Newhouse and coworkers made a report of palladium
catalyzed α,β‐dehydrogenation of esters, nitriles, and amides.9,10 In
addition to the above advancements, the dehydrogenation of 2‐
cinnamyl 1,3‐dicarbonyls has been developed by Han and co‐workers
using palladium(II)‐catalyst to α,β,γ,δ‐unsaturated‐1,3‐dicarbonyls.11
Here, in we report a direct oxidation of α‐cinnamyl β‐ketonitriles to
α,β,γ,δ‐unsaturated keto nitriles under mild reaction conditions.
α,β,γ,δ‐Unsaturated keto nitriles are important precursors in a broad
spectrum of chemical transformations. They are also the important
synthetic building blocks for the heterocycles such as dihydropyrans,
pyridines, pyrroles, etc.1a‐d Moreover, they are perhaps the most
versatile building blocks in organocatalysis.1d‐e During the past several
decades, only a few synthetic methods towards their synthesis have
been developed, among which the well‐known Knoevenagel
condensation of α,β‐unsaturated aldehydes with β‐ketonitriles is
remarkable.1e However, these reactions require the presence of
relatively strong acidic or basic conditions, producing a significant
amount of by‐products, suffers from several side reactions, and
displays the narrow substrate diversity. Driven by the ever‐growing
demand for α,β,γ,δ‐unsaturated ketonitrile in heterocycle synthesis,
new and more efficient approach is still demanding.
The first catalytic homogeneous dehydrogenation of cyclooctane to
cyclooctene was discovered by Crabtree and Felkin in 1982.2a
Tremendous progress has been made in the area of direct
dehydrogenation of alkanes to olefins using transition metal
catalysis.2 Recently, Stahl and co‐workers have developed oxidative
dehydrogenation of cyclohexanone to phenols.3,4 Similarly, Yoshikai
and co‐workers also developed the palladium‐catalyzed aerobic
dehydrogenative aromatization of cyclohexanone imines to
arylamines.5 In the direction of direct oxidation of β‐aryl substituted
Scheme 1: a) Oxidative Annulation of α‐Cinnamyl‐α,β‐diketones. b)
Oxidation of α‐Cinnamyl‐β‐Keto Nitriles
Recently, we have developed
a
novel palladium‐catalyzed
intramolecular oxidative cycloisomerization of α‐cinnamyl‐β‐
dicarbonyls for the creation of structurally diverse 2‐benzyl furans
(Scheme 1a).12 During this investigation, we noticed that the
replacement of one of the carbonyl group with nitrile functionality,
the course of the reaction is dramatically changed. The
intramolecular oxidative cycloisomerization is suppressed and only an
oxidation at α,β‐position occurred to provide α,β,γ,δ‐diene
containing β‐keto nitriles (Scheme 1b). Based on previous literature
Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhopal‐462066, India. Email: pghorai@iiserb.ac.in.
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization of products, 1H and 13C NMR spectra for products, and X‐ray
crystallographic analysis (CIF file for compound 3l) CCDC‐1444012. See
DOI: 10.1039/x0xx00000x
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reports,13a‐d we presumed that nitrile functional group has a strong oxidized to following products, with good yields. To our surprise, α‐
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coordination with transition metals and it could act as a successful cinnamyl nitriles having PO(OEt)2, and CO2EDtOwI: e10re.10i3n9e/fCfe7cOtBiv0e09u1n2dGer
directing group as well as ligand. Thus, the intramolecular oxidative these reaction conditions. Further, the oxidation product α,β,γ,δ‐
cycloisomerization phenomenon is suppressed.
We began our studies with
brief optimization of the crystallographic analysis (Figure 1).14
dehydrogenation of α‐cinnamyl‐β‐keto‐nitrile to α,β,γ,δ‐unsaturated
unsaturated ketonitrile 3l was confirmed by the X‐ray
a
keto nitrile. α‐Cinnamyl‐β‐ketonitrile (1a) was chosen as the model Scheme 2. Substrate Scope: variations of β‐carbonyls‐cyano
substrate, as shown in Table 1. The catalytic system consisting of counterpart a, b
PdCl2(CH3CN)2 (5 mol%), p‐toluenesulfonic acid (PTS, 1 equiv), and
benzoquinone (BQ, 1 equiv) in THF at 80 °C, which were employed
previously,12 afforded the α,β,γ,δ‐unsaturated keto nitrile 3a in 83%
conversion with 78% isolated yield and a small amount of
cycloisomerization product 4 (entry 1, Table 1). The requirement of
the acid was found to be crucial for the catalytic cycle13e (entry 2,
Table 1). To further improve the yield as well as the ratio of 3a:4,
various acids as additives as well as the solvents, such as CH3CN,
CH3NO2, and DMF were screened, however, no improvement was
observed (entry 3‐7, Table 1).
Table 1: Optimization study of direct oxidation of α‐cinnamyl‐β‐keto
nitrilea, c, d
Ent
ry
Catalyst Additive
(1 eq)
[O]
(1 eq)
Solvent
3a
3a:4
(%)b
1
2
3
4
5
6
7
PdCl2(ACN)2 PTS
BQ
THF
THF
THF
THF
ACN
CH3NO2
DMF
83 (78)b 94:6
PdCl2(ACN)2
‐
BQ
BQ
BQ
BQ
BQ
BQ
55
40
77
30
54
78
92:8
93:7
93:7
88:12
69:31
90:10
PdCl2(ACN)2 PivOH
PdCl2(ACN)2 AcOH
PdCl2(ACN)2 PTS
PdCl2(ACN)2 PTS
PdCl2(ACN)2 PTS
8
9
PdCl2(ACN)2 PTS
O2
‐
THF
THF
trace
‐
‐
‐
‐
PTS
aReaction conditions: α‐Cinnamyl‐β‐keto nitrile 1a (0.12 mmol), PdCl2(CH3CN)2
b
1
(5 mol %), solvent (1.0 mL), 12 h. The yields were determined based on H‐
NMR data of the reaction mixture using diphenyl acetonitrile as an internal
standard. c Isolated yield. d ACN is acetonitrile.
aReaction conditions: α‐cinnamyl‐β‐keto nitriles
1
(0.12 mmol),
PdCl2(CH3CN)2 (5 mol %), BQ (1.0 equiv), PTS (1.0 equiv), THF (1.0 mL). b
Isolated yields after column chromatography. c PdCl2(CH3CN)2 (10 mol %).
With the above optimization conditions, we explored the direct
dehydrogenation of a series of α‐cinnamyl‐β‐keto‐nitriles (Scheme 2).
The overall process was shown to be effective in the presence of
variously substituted carbonyls (3a‐p). Various aliphatic moieties,
i
such as Pr‐ (3a), Et‐ (3b), benzyl‐ (3c), cyclobutyl‐ (3d), cyclohexyl‐
methyl‐ (3e), and 9‐dacenyl (3f) ketones of α‐cinnamyl nitriles were
tolerated to give the corresponding α,β,γ,δ‐unsaturated ketonitrile
products, with consistently good yields. Further, aryl‐ketones with
electron‐donating (3h) as well as electron‐deficient (3i) substitutions
on the aryl ring were successful. On the other hand, other aryls such
as 1‐naphthyl‐(3j) moiety as well as heteroaryls such as 2‐thiophenyl‐
(3k) and 2‐furyl‐ (3l) groups provided the desired α,β,γ,δ‐unsaturated
ketonitriles in good yields.
Figure 1: ORTEP diagram of compound 3l (Ellipsoids: 30% probability) Color
code: Carbon (gray), Nitrogen (blue), Oxygen (red) and hydrogens (yellow).14
To further expand the substrate scope, we next turned our
attention towards testing the feasibility of the substitution on the
cinnamyl counterpart (Scheme 3). Different aryls such as phenyl‐
Interestingly, cinnamyl ketone (3m), phenyl 1,3‐diketone (3n), ethyl
oxalate (3o) and cyano group (3p) of α‐cinnamyl nitriles could be
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(3a), p‐methoxyphenyl‐ (5a), p‐methylphenyl‐(5b), and α‐naphthyl‐ On the basis of the above results, a possible mechanism was
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(5c) cinnamyl moiety were well tolerated and provided the proposed in Scheme 4. We envisioned thaDt OthI:e10s.t1r0o3n9g/Cc7oOoBr0d0in91a2tGing
corresponding products in 80−92% yields. In addiꢀon to the aryl ability of nitrile functionality with the transition metals13 has changed
substitution at γ‐position on α,β,γ,δ‐unsaturated ketonitrile, the the course of the reaction. Instead of annulation (Scheme 4, path
aryl substitution at β‐position is also well tolerated (5d‐e). a),12 probably, the coordination of nitrile functionality with PdII
Interestingly, starting with an appropriately designed substrate, complex (intermediate I, path b) occurs, followed by formal
α,β,γ,δ‐unsaturated ketonitrile with different aryl groups at γ‐, δ‐, elimination of HX to form ketenimine (or keteniminate)
and β‐positions could be synthesized as shown in the case of 5d‐5f.
intermediates II and III. Presumably, the presence of acid facilitates
such tautomerization. Further, the intermediate III undergoes an
oxidative β‐deprotonation/de‐palladation, as shown through the
arrow pushing, to produce the α,β,γ,δ‐unsaturated ketonitrile.
Notably, the conformational stability of III over II (steric crowding)
could be the probable reason for the observed diastereoselectivity.
Further, the Pd(0) was reoxidized to Pd(II) with the aid of
benzoquinone. The control experiments (see, Supporting
Information) also indicate that the nitrile functional group is assisting
the direct oxidation of α‐cinnamyl‐β‐ketonitrile to give α,β,γ,δ‐
unsaturated ketonitriles.
Scheme 3. Substrate Scope: Variations of Cinnamyl Counterparta,b
In summary, we have developed a process for the nitrile assisted
direct oxidation of readily available α‐cinnamyl‐β‐keto‐nitriles into
valuable α,β,γ,δ‐unsaturated ketonitrile. The disclosed synthetic
strategy involves a chemoselective oxidation over the oxidative
annulation of α‐cinnamyl‐β‐keto‐nitriles, which furnishes α,β,γ,δ‐
unsaturated ketonitrile in good yield and with broad substrate scope.
Acknowledgement
This work has been financially supported by IISER Bhopal. R.N. is
grateful to CSIR, New Delhi and R.R.R. is thankful to IISER Bhopal for
their research fellowship. We thank Mr. Lalit Mohan Jha, IISER
Bhopal, for single crystal XRD analysis.
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aReaction conditions: α‐cinnamyl‐β‐keto‐nitriles 1 (0.12 mmol),
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Scheme 4. Proposed Mechanism for Current Oxidation
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Table of contents entry:
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DOI: 10.1039/C7OB00912G
A palladium‐catalyzed oxidation reaction is disclosed where the
nitrile functionality on the substrate simply changes the course of
the reaction. α‐Cinnamyl β‐keto nitriles provide α,β,γ,δ‐diene
containing β‐keto nitriles using PdCl2(CH3CN)2 as a catalyst and
benzoquinone with a great diastereoselectivity and good substrate
scope.
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