Metal-free catalytic cascade to chromones: Direct coupling of salicylaldehydes and activated alkynes triggered by aryloxyl radicals

Article abstract of DOI:10.1039/c5ra24634b

The first intermolecular addition reaction of aryloxyl radicals to CC bonds was disclosed, which can afford biologically important chromone scaffolds via a PhNMe₃I-catalyzed direct coupling of readily available salicylaldehydes and activated internal alkynes in only one step, and can tolerate a range of catalytically reactive functional groups.

Full text of DOI:10.1039/c5ra24634b

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ARTICLE TYPE
Metalꢀfree Catalytic Cascade to Chromones: Direct Coupling of
Salicylaldehydes and Activated Alkynes Triggered by Aryloxyl Radical†
Ping Wang,a,b,+ Zhongfeng Li,a,+ Shengli Cao,a and Honghua Rao*,a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The first intermolecular addition reaction of aryloxyl radicals
to C≡C bonds was disclosed, which can afford biologically
important chromone scaffolds via a PhNMe3Iꢀcatalyzed direct
coupling of readily available salicylaldehydes and activated
10 internal alkynes in only one step, and can tolerate a range of
catalytically reactive functional groups.
Chromones are ubiquitous structural scaffolds occurring in
numerous natural products, pharmaceutical agents, and drug
candidates that manifest high levels of various important
15 biological activities.1 For example, the 3ꢀcarboxylated chromone
analogues and their carboxamide derivatives can act as potent and
reversible monoamine oxidaseꢀB inhibitors,2 while 3ꢀ
carboxylated flavones as proteinꢀtyrosine kinase inhibitors3 and
antiinflamatories.4 Due to the significant biological activities of
20 these privileged structures, a variety of strategies have been
developed for the construction, functionalization, and
Figure 1. Chromones from various intermediates or starting materials via
50 conventional of catalyzed cyclization strategies.
C≡C πꢀsystem generating reactive vinyl radicals to perform
intramolecular cascade cyclizations have been well established
with carbonꢀ13b,14 sulphurꢀ,13b,15 and oxygenꢀcentered organic
radicals (typically TEMPO and its analogues, acyloxyl radicals,
55 or methoxyl radical).16 In this context, the synthetically attractive
strategy may also enable a rapid obtention of chromones if a
cascade cyclization could be initiated by the intermolecular
addition of a specific oxygenꢀcentered radical, namely the 2ꢀ
fomylaryloxyl radical, to C≡C bonds. We herein report a radical
60 cascade initiated by the intermolecular addition of 2ꢀ
formylaryloxyl radical to C≡C πꢀsystem for the first time, which
can afford chromones in moderate to good yields via a PhNMe3Iꢀ
catalyzed direct coupling of readily available salicylaldehydes
and activated alkynes (Scheme 1).
diversification of chromone scaffolds.
intramolecular cyclization of the previously synthesized
intermediates, such as orthoꢀhydroxyarylꢀ1,3ꢀdicarbonyl
Conventionally,
25 derivatives (or precursors) (Figure 1a),5 2′ꢀhydroxychalcones
(Figure 1b),6 2ꢀaryloxymaleates (Figure 1c),7 or vinyl ether
intermediates of salicylic acid derivatives (Figure 1d),8 can afford
functionalized chromones efficiently under strong acidic or basic
conditions.
30
To avoid multistep procedure for the construction of
chromones, palladium catalysis (Figure 1e)9 and [RhCl(cod)]2
(Figure 1f)10 have been proposed, respectively. However, as trace
metals in products for human consumption are heavily regulated
by international bodies, the concerns associated with removing
65
Scheme 1. PhNMe3Iꢀcatalyzed intermolecular addition of 2ꢀ
formylaryloxyl radical to alkynes
At the outset of our study, an intermolecular radical addition of
phenol to dimethyl acetylenedicarboxylate (DMAD) was
70 successfully realized under nBu4NI/TBHP organocatalytic system
in our group. Following this initial discovery, salicylaldehyde 1a
(0.10 mmol) and DMAD 2a (0.15 mmol) were chosen as the
model substrates to test the possibility of chromone formation,
with TBAI (10 mol%) as the catalyst, TBHP (2.5 equiv.) as the
75 oxidant, and CH3CN (1.0 mL) as the solvent. As shown in Table
1, inspiringly, trace amount of chromone product 3a was detected
when using TBHP (70 wt. % in H2O) as the oxidant (Table 1,
entry 1), and the preliminary experiments identified TBHP (5ꢀ6
M in decane) as the oxidant of choice under an air atmosphere
80 (Table 1, entries 1ꢀ3). Notably, nearly no product 3a was detected
35 potentially toxic trace transitionꢀmetal catalysts from the end
biologically active products always exist in drug discoveries.11
For this reason, organocatalyzed reactions using Nꢀheterocyclic
carbenes (NHCs) are developed for the green syntheses of
chromones, although preꢀfunctionalizations of hydroxyl groups
40 on salicylaldehydes are still required.12 Thus, it remains desirable
to develop the organocatalyzed reactions that can realize the
chromone syntheses through direct couplings of readily available
starting materials in an atomꢀ and stepꢀeconomical way.
As is well recognized, radical cascade reactions, usually
45 initiated by simple organic molecules, can allow access to
complex and important molecular skeletons in only few synthetic
steps.13 During the last decades, intermolecular radical addition to
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Table 1. Reaction condition optimization for radical cascade to 30 Table 2. PhNMe3Iꢀcatalyzed radical cascade to chromonesa
chromonesa
EWG1
PhNMe3I (10 mol%)
TBHP (2.5 equiv.)
CH3CN, 120 oC, 24 h
O
O
EWG1
EWG2
+
H
H
Ar
Ar
EWG2
2
O
3
O
1
O
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Entry Cat.(mol %)
[Ox] (equiv.)
TBHPaq (2.5)
Solvent T (°C) Yieldb (%)
O
CO2Me
Me
1
2
TBAI (10)
TBAI (10)
TBAI (10)
ꢀ
CH3CN 120
<5
43
23
<5
0
3a, 71%; 68%b
3b, 63%
3c, 73%
Me
TBHPdec (2.5) CH3CN 120
TBHPdec (2.5) CH3CN 120
TBHPdec (2.5) CH3CN 120
3c
4
O
O
O
O
Me
CO2Me
CO2Me
CO2Me
CO2Me
MeO
CO2Me
CO2Me
5
6
7
TBAI (10)
THAI (10)
TEAI (10)
ꢀ
CH3CN 120
O
MeO
Cl
O
TBHPdec (2.5) CH3CN 120
TBHPdec (2.5) CH3CN 120
26
22
74d
30
11
12
12
18
23
17
59
45
54
63
59
3d, 75%
3e, 80%
3f, 78%
O
O
O
8
9
PhNMe3I (10) TBHPdec (2.5) CH3CN 120
BnNMe3I (10) TBHPdec (2.5) CH3CN 120
PhNMe3I (10) TBHPdec (2.5) Toluene 120
PhNMe3I (10) TBHPdec (2.5) Benzene 120
CO2Me
CO2Me
CO2Me
CO2Me
Br
CO2Me
CO2Me
BnO
Me
O
O
O
10
11
12
13
14
15
16
17
18
19
20
3g, 63%
3h, 52%
3i, 57%
PhNMe3I (10) TBHPdec (2.5) DCE
PhNMe3I (10) TBHPdec (2.5) TCE
PhNMe3I (10) TBHPdec (2.5) tBuOH
PhNMe3I (10) TBHPdec (2.5) EtOAc
120
120
120
120
O
O
O
CO2Et
CO2Et
CO2Et
MeO
CO2Et
CO2Et
O
O
CO2Et
O
3j, 69%
3k, 65%
3l, 69%
PhNMe3I (5)
TBHPdec (2.5) CH3CN 120
O
O
O
O
PhNMe3I (20) TBHPdec (2.5) CH3CN 120
PhNMe3I (10) TBHPdec (2.0) CH3CN 120
PhNMe3I (20) TBHPdec (2.5) CH3CN 110
PhNMe3I (20) TBHPdec (2.5) CH3CN 130
CO2Me
CO2Et
Ph
Ph
O
MeO
O
MeO
O
O
3m, 70%
3n, 47%
3o, 49%
O
O
O
O
aReaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), Solvent (1.0 mL),
CO2Me
CO2Me
CO2Me
b
under air for 24 h unless otherwise noted. Yield determined by 1H NMR
MeO
O
MeO
CN
O
MeO
Cl
spectroscopy with mesitylene as the internal standard. cUnder N2.
dDimethyl 2ꢀ(2ꢀformylphenoxyl)ꢀ2ꢀbutenedioate detected as the major
byproduct in 10% yield. [Ox] = oxidant, TBAI = tetrabutylammonium
CF3
3p, 55%
3q, 47%
3r, 51%
aReaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), PhNMe3I (10 mol%,
0.02 mmol), TBHP (5ꢀ6 M in decane, 0.50 mmol), CH3CN (2.0 mL), 120
oC, 24 h, in air. Isolated yields were given. bReaction was carried out with
5.0 mmol of 1a (0.61 g), and 7.5 mmol of 2a (1.07g)
iodide, THAI
=
tetraꢀnꢀheptylammonium iodide, TEAI
=
tetraethylammonium iodide, TBHPaq = tertꢀbutyl hydroperoxide (70
wt. % in H2O), TBHPdec = tertꢀbutyl hydroperoxide (5ꢀ6 M in decane),
DCE = 1,2ꢀdichloroethane, TCE = 1,1,2ꢀtrichloroethane
well, such as chloro (3h) and bromo (3i) groups, albeit in slightly
lower yields of the desired chromone products. These useful
electrophilic halide groups promise further functionalizations of
the products, thus facilitating the diversification and postꢀ
35 modification of chromone scaffolds. It is worth noting that steric
hindrance effect is observed in this radical cascade reaction, for
example, 3ꢀmethyl group at salicylaldehyde gave 63% of the
desired product 3b, while 73% of 3c with 4ꢀmethyl and 75% of
3d with 5ꢀmethyl, respectively. To expand the substrate scope,
40 other internal alkynes were also tested, among which the
symmetrical alkynes, such as diethyl acetylenedicarboxylate (3jꢀl)
and dibenzoylacetylene (3m), could successfully provide the
desired chromone scaffolds in good yields. Moreover,
unsymmetrical alkyne substrates that would exhibit specific
45 selectivity challenges during intermolecular radical additions
were explored under the optimized conditions as well. Inspiringly,
all the examined methyl arylpropiolates (3nꢀr) underwent the
organoꢀmediated cascades smoothly and selectively to yield 3ꢀ
carboxylated flavones3,4 as the sole products,17 with the
50 catalytically reactive substituents (such as cyano and halide)
intact during the process. Unfortunately, the cascade reaction did
not occur when using less electronꢀdeficient alkynes (such as 1,2ꢀ
diphenylethyne, methyl propiolate, methyl 2ꢀbutynoate, 1ꢀphenylꢀ
1ꢀpropyne) or salicylaldehydes with strong electronꢀwithdrawing
55 groups (such as nitro and cyano groups)18 as the substrates.
Therefore, for successful formation of chromone derivatives,
in the absence of catalyst TBAI or oxidant TBHP (entries 4ꢀ5),
thus suggesting that it is crucial for this transformation to use
ammonium salt in combination with oxidant. And it is
noteworthy that PhNMe3I displayed the best catalytic reactivity
among a variety of quaternary ammonium salts, such as TBAI,
THAI, TEAI, and BnNMe3I, affording the desired product 3a in
74% yield (entries 2, and 6ꢀ9). Besides, the reaction efficiency
5
10 shows a strong dependency on solvent. For example, the use of
t
other solvents, such as toluene, benzene, DCE, TCE, BuOH, and
EtOAc, proved to be far less effective than acetonitrile (entries 8,
and 10ꢀ15). Other endeavours to improve the reaction efficiency
were attempted as well, such as loading 5% or 20% of the
15 catalyst (entries 16ꢀ17), changing the amount of TBHP (5ꢀ6 M in
decane) (entry 18), or carrying out the reaction at 110 oC or 130
oC (entries 19ꢀ20), but none of them afforded superior result.
With the optimized reaction conditions in hand, we probed the
o
substrate scope at 120 C for 24 h under an air atmosphere by
20 using PhNMe3I (10 mol%) as the catalyst, TBHP (5ꢀ6 M in
decane, 2.5 equiv.) as the oxidant, and CH3CN as the solvent. As
summarized in Table 2, this PhNMe3Iꢀcatalyzed cascade reaction
was successfully performed with a variety of salicylaldehydes
and DMAD, affording useful chromones containing an ester
25 group at C3 position2 in moderated to good yields. Apparently,
the reaction proceeded well with electronꢀdonating groups at
salicylaldehydes, such as methyl (3bꢀd), methoxy (3eꢀf) and
benzyloxy (3g) groups. Electronꢀwithdrawing groups at
salicylaldehydes were well tolerated for this cascade reaction as
more electronꢀdeficient alkynes
salicylaldehydes are required.
and
electronꢀefficient
2
|
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To demonstrate the practicability of the developed strategy, we 45 Alternatively, 2ꢀfomylaryloxyl radicals can be generated upon
carried out a gramꢀscale synthesis of product 3a. The target
product was isolated in 68% yield without any significant
decrease in efficiency (versus 71% for the reaction on a 0.2 mmol
scale for 3a). Besides, 3ꢀcarboxylated flavones can undergo
reactions of peroxyl or alkyloxyl radicals with corresponding
phenols.18 As this aryloxyl radical might undergo a hydrogenꢀ
abstraction process to give 6ꢀoxomethylidenecyclohexaꢀ2,4ꢀ
dienone analogues (Structure G in Scheme 4), which can
5
efficient decarboxylative process to the desired biologically 50 facilitate a facile DielsꢀAlder reaction with DMAD, a reaction of
active flavones. For instance, reaction of product 3n with
hydrobromic acid (48% aqueous solution) gave 92% of 7ꢀ
hydroxyflavone 4 (Scheme 2).
salicylaldehyde with dimethyl maleate was thereby carried out.
However, none of the cyclization product 8 or 3a was detected
(Scheme 3ꢀiv), indicating that a DielsꢀAlder cyclization to
chromones is neither possible in our reaction. As such, we can
55 argue that this PhNMe3Iꢀcatalyzed cyclization reaction is initiated
by an intermolecular addition of aryloxyl radical to C≡C bond,
affording the reactive vinyl radical, which can undergo further
cyclization to the end product 3 or give vinyl ether byproducts.
Finally, when vinyl ether 5a or 5b was directly subjected to the
60 standard reaction conditions (an acyl radical generation system
directly from aldehyde group),19,20 only 16% or 15% of the
desired product 3a was detected, inferring that an intramolecular
acyl radical addition to C=C bond is possible in the process
(Scheme 3ꢀv). But considering their much lower reaction
65 efficiency, the acyl radical intermediate (structure C in Scheme 4)
may be relatively difficult to be generated directly from vinyl
ether 5a/5b in our catalytic system; instead it could form more
10
Scheme 2. Decarboxylation of 3ꢀcarboxylated flavones: 3n (0.2 mmol),
HBr (48% aqueous solution, 3 mL), 110ꢀ120 oC, under N2, 24 h.
i)
CO2Me
air or N2
K2CO3 (1.0 equiv.)
CH3CN, 120 oC, 24 h
O
CO2Me
OH
CHO
CO2Me
CO2Me
+
+
CHO CO2Me
Total Yield: 56%
OH
CO2Me
CO2Me
O
6,
10%
5a/5b 1:2.5
ii)
O
CHO
O
CO2Me
standard condition
CO2Me
+
+
BHT (2.5 equiv.)
or TEMPO (2.5 equiv.)
OH
CHO CO2Me
CO2Me
CO2Me
O
3a, 0%
5a + 5b: 0%
iii)
CHO
OMe
OMe
CO2Me
CO2Me
standard condition
+
MeO2C
CO2Me
O
O
7, 0%
iv)
v)
O
CHO
OH
CO2Me
standard condition
CO2Me
CO2Me
+
+
CO2Me
O
CO2Me
O
3a
, 0%
O
CO2Me
efficiently via
a direct intramolecular Hꢀabstraction from
8
, 0%
CHO
CO2Me
aldehyde group by vinyl radical.
CHO
CO2Me
CO2Me
CO2Me
standard condition
or
O
O
O
CO2Me
CO2Me
5a
5b
3a:
from 5a, 16%
from 5b, 15%
Scheme 3. Control experiments for mechanism studies
15 When investigating the mechanism for this process, a reaction of
salicylaldehyde with DMAD was first carried out in the presence
of K2CO3 (a popular base for Michael addition reaction) in
CH3CN, and it gave only 10% of product 6, with vinyl ether
5a/5b as the major products, implying that a nucleophilic addition
20 of vinyl anion (obtained via a Michael addition of phenolate to
alkyne) to aldehyde group to form 4Hꢀchromenꢀ2,3ꢀdicarboxylate
(prone to be oxidized to chromone) is not a major pathway for the
formation of chromones (Scheme 3ꢀi). On the other hand, as it
has been disclosed by our group19 and others,20 when using
t
25 quarternary ammonium salts as the catalysts, tBuO• or BuOO•
can be generated efficiently from TBHP, and can abstract a
hydrogen to initiate radical reactions subsequently. Therefore, a
radical process is an alternative consideration, and the radical
trapping experiment was then carried out by introducing TEMPO
30 or BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) into the standard
reaction conditions. Indeed, none of the product 3a, vinyl ether
5a/5b, or direct hydroacylation product of C≡C bond was
observed (Scheme 3ꢀii), so that it may lead to two preliminary
conclusions: (1) the reaction most probably undergoes either 2ꢀ
35 fomylaryloxyl or 2ꢀhydroxybenzoyl radical initiated cascade
cyclizations to chromones; (2) no detection of vinyl ether
byproducts indicates that a polar addition of phenolate to alkynes
might be impossible under our standard conditions.
In order to explore that whether this cyclization is initiated by
40 the intermolecular addition of 2ꢀhydroxybenzoyl radical to C≡C
bond, reaction of oꢀanisaldehyde with DMAD was carried out
under the standard conditions, however, no hydroacylation
product 7 was detected (Scheme 3ꢀiii), thus suggesting that this
cyclization is probably not initiated by 2ꢀhydroxybenzoyl radical.
70
Scheme 4. Plausible mechanism for PhNMe3Iꢀcatalyzed intermolecular
addition of aryloxyl radicals to C≡C bond
Based on above results and previous work, a tentative mechanism
for this PhNMe3Iꢀcatalyzed radical cascade is depicted in Scheme
75 4. In the first step, tBuO• and tBuOO• radicals form
catalytically.19,20 After abstracting a hydrogen from hydroxy
group by these radicals,18 an intermolecular addition of the
resulting aryloxyl radical A to C≡C bond occurs, thereby
generating a reactive vinyl radical B, which prefers to abstract a
80 hydrogen from aldehyde group intramolecularly to produce acyl
radical C. The subsequent intramolecular addition of acyl radical
C to C=C bond forms a carbonꢀcentered radical D, which finally
produces product 3a via Hꢀabstraction by BuO• or BuOO•
radical. However, the pathway to form chromones via either
85 intramolecular addition of radical B to aldehyde (forming radical
E)21 or intramolecular coupling of acyl radical with vinyl radical
(intermediate F in Scheme 4) cannot be ruled out at this stage.22
t
t
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70
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Financial support from The National Natural Science Foundation of
China (21402128), Beijing Natural Science Foundation (2144045),
80
15 Beijing
Municipal
Education
Commission
Foundation
85
(KM201410028007), Scientific Research Base Development Program of
the Beijing Municipal Commission of Education, and Capital Normal
University are gratefully acknowledged.
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Notes and references
90
20 aDepartment of Chemistry, Capital Normal University, Beijing
100048, P. R. China; Eꢀmail: honghua.rao@gmail.com
bSchool of Chemical Engineering, Beijing Institute of Petrochemical
Technology, Beijing 102617, P. R. China
+These authors contributed equally to this work
95
25 †Electronic Supplementary Information (ESI) available: General
procedure for synthesis, characterization data, and 1H, 13C, and 19F NMR
spectra of compounds. See DOI: 10.1039/c000000x/
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