Synthesis of cyclohexylidenehydrazine-fused polycyclics via a photocatalytic radical cascade reaction of 2-ethynylaldehyde hydrazones

Article abstract of DOI:10.1039/c6cc09863k

A general and efficient visible-light photoredox-catalyzed cascade annulation of 2-ethynylaldehyde hydrazones with α-bromo-carbonyls for the synthesis of various cyclohexylidene-hydrazine-fused polycyclic compounds is described. This protocol is characterized by a broad substrate scope, mild conditions and amenability to gram-scale synthesis.

Full text of DOI:10.1039/c6cc09863k

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DOI: 10.1039/C6CC09863K
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Synthesis of cyclohexylidenehydrazines-fused polycyclics via
photocatalytic radical cascade reaction of 2-ethynylaldehyde
hydrazones
Received 00th January 20xx,
Accepted 00th January 20xx
Nengneng Zhou, a Jing Liu, a Zhongfei Yan, a Zhongkai Wu, a Honglin Zhang,a Weipeng Li a and
DOI: 10.1039/x0xx00000x
Chengjian Zhu*a,b
www.rsc.org/
A general and efficient visible-light photoredox-catalyzed cascade
annulation of 2-ethynylaldehyde hydrazones with α-bromo-
carbonyls for the synthesis of various cyclohexylidene-
hydrazines-fused polycyclic compounds is described. This
protocol is characterized by a broad substrate scope, mild
conditions and amenability to gram-scale synthesis.
Scheme 1 Selected examples of cyclopenta[α]naphthalene in natural products or
pharmacally interesting compounds
Cyclopenta[α]naphthalenes are an important structure unit
in agrochemicals and materials because of their unique
chemical properties and biological activities (Scheme 1).1
Therefore, a large number of methods for their construction
have been extensively researched in the past decades.2
However, many previous methods suffered from harsh
conditions and required the utilization of multi-step process,
which limit their applications. Very recently, some well-
designed one-pot procedures for building these skeletons have
been established.3 Although significant achievements have
organic chemistry.7 Recently, the others’ group and our group
has paid more attention on the C–H bond functionalization of
aldehyde hydrazones (scheme 2).8 As our follow-up work,
herein, we intend to establish a facile and efficient protocol for
the synthesis of cyclohexylidenehydrazines-fused polycyclic
compounds by visible-light photoredox catalysis (scheme 2). In
this reaction, three new C-C bonds can be formed, and
polycyclic rings can also be constructed in a one-pot manner.
Initially, the reaction was performed using N-(2-
been made,
a milder and more efficient method for
synthesizing complex organic compounds is still in demand.
Visible light photoredox catalysis has attracted widespread
attention in the field of synthetic organic chemistry as a
fascinating tool owing to its attractive features including mild
reaction conditions, natural abundance and environmental
friendliness.4 In the past few years, visible light induced
cascade reactions have proven to be highly valuable for the
synthesis of polycyclic compounds because of their highly
atom economic and simple operation.5 For instance, our group
successfully achieved important heterocyclic scaffolds via
radical cyclizations and annulations under visible-light
catalysis.6 Hydrazones are important and easily accessible
organic intermediates that are widely applied in the synthetic
ethynylbenzylidene)morpholin-4-amine (1a) and diethyl
α-
allyl- -bromomalonate 2a as model substrates in the
α
( )
presence of the photocatalyst fac-Ir(ppy)3 and inorganic base
K2CO3 at room temperature in CH3CN (Table 1). To our delight,
the desired product 3aa was obtained at a 41% isolated yield
a.State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China; E-mail:
cjzhu@nju.edu.cn
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
OrganicChemistry, Shanghai, 200032, P. R. China
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 2 Visible light promoted C–H bond functionalization of aldehyde
hydrazones.
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of aldehyde hydrazones a
View Article Online
DOI: 10.1039/C6CC09863K
Entry
1
photocatalyst
Base
solvent
CH3CN
Yield(%)b
41
fac-Ir(ppy)3
K2CO3
2
3
4
5
6
7
8
9
10
11
12
13c
14
Ru(bpy)3(PF6)2
Eosin Y
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
CH3CN
DCM
CH3OH
DMF
DMSO
DCM
DCM
DCM
DCM
DCM
DCM
trace
trace
68
19
51
39
85
89
84
26
25
NR
NR
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
-
K2CO3
NaHCO3
Na2HPO4
K2HPO4
NaOAc
KOAc
Na2HPO4
Na2HPO4
DCM
15
fac-Ir(ppy)3
DCM
15
-
a
reaction condition: 1a (0.1 mmol), 2a (0.2 mmol), base (0.2 mmol),
photocatalyst (2 mol%), solvent (1 mL), 33 W fluorescent light bulb under Ar
at room temperature for 16 h. b Isolated yield. c In the dark.
(Table 1, entry 1) under irradiation with 33 W fluorescent light
bulb for 16 hours. To improve the reaction efficiency, the
a
reaction condition: 1 (0.1 mmol), 2a (0.2 mmol), base (0.2 mmol),
photocatalyst (2 mol%), solvent (1 mL), 33 W fluorescent light bulb under Ar
reaction conditions of this cascade were further optimized. A at room temperature for 16 h. b Isolated yield.
serious of photoredox catalysts were evaluated, and fac-
yield (3ja). Substrates with multiple substituents on the aryl
ring provided the products in excellent yields (3ka, 3la). Even
thiophene derivative was found to be tolerated in this reaction
Ir(ppy)3 was the most effective catalyst (entries 1-3). Then,
different solvents were examined (entries 4-7). Among the
solvents, dichloromethane was determined to be the best
choice (entry 4). It was observed that the use of inorganic
bases such as NaHCO3, Na2HPO4, K2HPO4 promoted the
reaction and Na2HPO4 gave the best result. Other bases were
tested including NaOAc, KOAc, which gave poor yields of 3aa
(Table 1, entries 8−12). The control experiment disclosed that
no reaction occurred in the absence of a photoredox catalyst
or visible light (Table 1, entries 13 and 14), and only 15% yield
of 3aa was obtained without a base (Table 1, entry 15).
Consequently, the reaction proceeded efficiently in the
presence of Ir(ppy)3 (2 mol%) and Na2HPO4 (2 equiv.) in DCM
at room temperature.
(3ma). Meanwhile, the alkynyl hydrazine on the aliphatic ring
was also suitable for this protocol in 76% yield (3na).
Then, the scope of the reaction was explored by studying
the reactions of various
compounds with N-(2-ethynylbenzylidene)morpholin-4-
amine 1a. As shown in Table 3, it was found that a methyl
group at the C5 position of produced 3ab in 79% yield (dr =
5:1). In contrast, substitution of the C–C double bond of by
α-bromo γ,δ-unsaturated carbonyl
2
2
2
phenyl group was obtained the corresponding product in 35%
yield (3ac). Introduction of two methyl groups at the C5
position of
2
produced 3ad in an excellent yield. Installation of
were also
a methyl group at the C3 or C4 position of
2
With the optimized conditions in hand, we investigated the
scope of this photocatalytic domino annulations by varying
tolerated well in this process and smoothly converted into
products 3ae and 3af in 83% and 75% yields, respectively.
Under the standard reaction conditions, 2g proved to be viable
substrate to provide 3ag in 86% yield. Unfortunately,
secondary bromide 2h failed to give the desired product. It is
hydrazones and diethyl
α-allyl-α-bromomalonate (2a). The
results are summarized in Table 2. When the nitrogen atom
was connected two alkyl groups, the corresponding products
were obtained in excellent yields (3ba, 3ca). Moreover,
replacement of one alkyl group with a phenyl group did not
affect the reaction efficiency, and the desired product was also
obtained in 85% yield (3da). The hydrazone connected with
two phenyl groups was also suitable for this protocol in 85%
yield (3ea). The N-morpholine hydrazones bearing either
electron-rich groups (Me or MeO) or electron-poor groups (F,
Br) on the benzene ring could react smoothly to furnish the
desired products in good yields (3fa-3ia). In addition, the
position of the substituent on the aryl ring has no effect on this
reaction and the corresponding product was obtained in 86%
noteworthy that an
2i could also successfully got the desired product in 75% yield
3ai).
To further show the practical application of this method, a
α-bromo δ, ε-unsaturated carbonyl such as
(
gram-scale reation was carried out under standard reaction
conditions. We were delighted to find that the synthesis of 3aa
with a good yield of 81% on a 5 mmol scale (Scheme 3a).
Hydrozones are important organic intermediates for a series of
transformations in organic chemistry. 3aa can be easily
converted to ketone 4 in 85% when treated with simple acid
2 | J. Name., 2012, 00, 1-3
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Table 3 Scope of α-bromocarbonyl compounds a
Based on the above-mentioned experiments and literature
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precedents,3b,8a a possible reaction mecDhOaIn: i1s0m.10w39a/Cs6pCrCo0p9o8s6e3dK
(Scheme 4). Under visible-light irridation, the photocatalyst
Ir(ppy)3 undergoes a metal-to-ligand charge transfer (MLCT)
process to produce the excited state IrIII*. A SET process then
occurs between IrIII* and 2a with the generation of IrIV and
radical precursor
with 1a to generate intermediate
alkyl radical species via a 5-exo-trig cyclization. Then,
anintramolecular addition of carbon radical to the C=N bond
leads to the aminyl radical intermediate , which should be
4
. Subsequently, active radical
4 will react
5
, which is converted to the
6
7
stabilized by the adjacent nitrogen through possible three-
electron π bonding interaction. At this stage, a key aminyl
radical/polar crossover step between
thus regenerating the photocatalyst and either the diazenium
cation or . Further tautomerization and deprotonation of
diazenium cation would give the product . Finally, the
diazenium cation can be easily tautomerized and
7
and IrIV can take place,
8
9
3
deprotonated, generating the desired product 3.
a
reaction condition: 1a (0.1 mmol), 2 (0.2 mmol), base (0.2 mmol),
photocatalyst (2 mol%), solvent (1 mL), 33 W fluorescent light bulb under Ar
at room temperature for 16 h. b Isolated yield.
(Scheme 3b). Moreover, 3aa could react with
diphenylacetylene toward isoquinoline
5 in 76% by using the
[(RhCp*Cl2)2]/AgNO3/Cu(OAc)2 catalytic system (Scheme 3b).9
The product isoquinoline is ubiquitous structural component
of multitudinous natural products and biomolecules.10 To gain
further understanding of this mechanism, a preliminary
mechanistic experiment was performed. When the reaction
was conducted with a radical scavenger TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy), the reaction was substantially
inhibited and 1a was almost completely recovered, suggesting
that the reaction involves a single electron transfer (SET)
process (Scheme 3c).
Scheme 4 Proposed mechanism.
Conclusions
In summary, we have successfully developed a visible-light
photocatalyzed cacased annulation of hydrazones with alkenyl
α
-bromocarbonyls, providing a direct access to various
cyclohexylidenehydrazines-fused polycyclic compounds. This
reaction accommodates a broad substrate scopes and is
distinguished by its mild conditions and excellent functional
group compatibility (fluorides chlorides, and methyl as well as
methoxy included).
We gratefully acknowledge the National Natural Science
Foundation of China (21474048, 21372114 and 21672099).
Notes and references
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