On-Water Cp?Ir(III)-catalyzed C-H functionalization for the synthesis of chromones through annulation of salicylaldehydes with diazo-ketones

Article abstract of DOI:10.1021/acs.joc.9b00418

A high-valent Ir(III)-catalyzed C-H bond functionalization is carried out for the first time on water for the synthesis of a biologically relevant chromone moiety. The C-H activation and annulation of salicylaldehydes with diazo-compounds provided the desired chromones. The synthesis of C3-substitution-free chromones has also been demonstrated by a one-pot decarboxylation by employing tert-butyl diazoester. C3 and C5 C-H activations of the product chromone are also carried out under different conditions for further diversification.

Full text of DOI:10.1021/acs.joc.9b00418

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Article
On Water Cp*Ir(III)-Catalyzed C–H Functionalization for the Synthesis of
Chromones through Annulation of Salicylaldehydes with Diazo-Ketones
Suvankar Debbarma, Md Raja Sk, Biswabrata Modak, and Modhu Sudan Maji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00418 • Publication Date (Web): 19 Apr 2019
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On Water Cp*Ir(III)-Catalyzed C–H Functionalization for the Synthesis of Chromones
through Annulation of Salicylaldehydes with Diazo-Ketones
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Suvankar Debbarma, Md Raja Sk, Biswabrata Modak and Modhu Sudan Maji*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302,
India
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ABSTRACT: A high-valent Ir(III)-catalyzed C–H bond functionalization is carried out for
the first time on water for the synthesis of biologically relevant chromone moiety. The C–H
activation and annulation of salicylaldehydes with diazo-compounds provided the desired
chromones. The synthesis of C3-substitution free chromones has also been demonstrated by a
one-pot decarboxylation by employing tert.-butyl diazoester. C3 and C5 C–H activations of
the product chromone are also carried out under different conditions for the further
diversification.
INTRODUCTION
In the last few decades, transition-metal catalyzed C–H bond activation method has become
a powerful tool for step- and atom-economic1 synthesis of various target molecules.2 To reach
a ground in the sustainable synthesis through transition-metal catalyzed C–H bond activation,
the avoidance of toxic organic solvents and the use of more green-solvents are the key interest
for practical purpose.3 Water, the universal solvent owing to its non-toxic, environment friendly
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and easy availability became a central attraction to the chemists for its use as a solvent in the
various catalytic transformations related to the C–H bond activation.3 However, the C–H
functionalization are difficult to occur in water medium as the reactants are insoluble in water
and the water coordination to metal-catalyst can prevent the catalysis. In this line, although
Pd,4 Rh5 and Ru6 catalyzed C–H bond activation have been investigated using water as a
solvent, to the best of our knowledge Ir(III)-catalyzed C–H bond functionalizations on water
is still not encountered.
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Because of their wide range of biological activities and medicinal importance, chromones
have been an attractive target molecule.7 To minimize the number of reaction steps, bring
versatility, and overcome obstacles for the synthesis of this heterocycle moiety,8 aldehyde C–
H functionalization and annulation of salicylaldehydes with alkynes or diazo-compounds have
been employed mainly under Rh,9 Ru10 and Co-catalysis.11 In these cases, ortho-hydroxy group
of salicylaldehyde not only acts as a directing group for the aldehyde C–H bond activation,12
but also serves the heteroatom required for the construction of the heterocycle ring of
chromone. We found the synthesis of the chromone is possible in a more efficient route as
previous reports have drawbacks such as (1) organic solvents used which are toxic,9-11 (2) when
an α-diazo carbonyl is incorporated as an electrophile, the functionalization of C3 of chromones
are limited only to ester- or acyl-groups,9b and (3) catalyst-loading can only be minimized to
2.5 mol % for the electrophile α-diazo carbonyl to reach a practically useful yield of the
products.9b To find a fruitful and benign catalyst system for the synthesis of chromone, herein
we developed an Ir(III)-catalyzed C–H bond functionalization in water medium. To include
versatility in this annulation process we have incorporated differently substituted
salicylaldehydes and α-diazo carbonyls.13 Relatively low catalyst loading, short reaction time,
and the use of ubiquitous and inexpensive water as solvent for Ir(III)-catalyzed C–H bond
functionalization are main advantages of our present catalytic system. Additionally, a one-pot
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decarboxylation provided C3 free chromones, when a tert.-butyl diazoester was used as an
electrophile (Scheme 1).
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Scheme 1: Catalytic Approach for the Synthesis of Chromone Heterocycles
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RESULTS AND DISCUSSION
To recognize a benign, optimize catalyst system, we have commenced our proof-of-concept
study with the screening of the reaction parameters for the chromone synthesis (Table 1). Under
the iridium catalyst system, the coupling of salicylaldehyde 1a with ethyl diazoacetate 2a in
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the presence of acetic acid (1.0 equiv) as additive was carried out at 80 C, which results in
70% of coupling product 3a (Table 1, entry 1). Keeping these parameters constant while
screening various organic solvents (entries 2–4) the reaction profile did not improve much.
Table 1. Optimization of the Reaction Conditionsa
Entry
Solvent
Additive
Temp [oC]
Yield [%]b
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DCE
TCE
CHCl3
MeOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
AcOH
AcOH
AcOH
AcOH
AcOH
PivOH
NaOAc
KOAc
CsOAc
none
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90
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11c
12d
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14e
15f
16g
trace
n.d
65
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
66
n.d
n.d
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aReaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol
%), additive (1.0 equiv), solvent (1.5 mL), 80 oC, 2 h. bIsolated yield of 3a. cNo catalyst. d0.5
e
f
mol % of [Cp*IrCl2]2. [Ru(p-Cymene)Cl2]2 as catalyst. [Cp*Co(CO)I2] as catalyst.
g[Cp*RhCl2]2 as catalyst. n.d = not detected.
When methanol was employed, the output of the catalysis gave a positive hint towards the
effectiveness of polar protic solvent (entry 4). Based on this indication and to avoid organic
solvents we have introduced water as solvent for this reaction, and noticed a positive outcome
with respect to methanol (entry 5). Upon switching the additive from AcOH to pivalic acid, we
were delighted to isolate 3a in excellent yield (90%, entry 6). In the presence of acetate
additives, the reaction outcome did not improve (entries 7–9). In the absence of either catalyst
or additives the reaction did not proceed (entries 10–11), which indicates the necessity of
catalyst-additives combination. Moreover, the lowering of catalyst loading decreased the
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chemical yields dramatically (entry 12). On decreasing the reaction temperature to 50 C
outcome of 3a reduced to 66% (entry 13). Interestingly, the catalysis was not operative in
presence of other catalysts like Ru(II) or Co(III) (entries 14–15). A moderate result was
obtained in the presence of Cp*Rh(III)-catalyst instead of iridium catalyst (entry 16). To
mention, the optimization of the reaction conditions did not require any co-solvent, surfactant,
phase-transfer catalyst or silver salt.
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With the optimized reaction conditions in hand (Table 1, entry 6), we surveyed the scope
of various salicylaldehydes (Scheme 2). Introduction of electron donating substituents such as
methyl, methoxy, tert.-butyl at the different positions of salicylaldehyde were well tolerated,
and the products 3a–3d were isolated in 77–90% yields. Moreover, highly electron-deficient
salicylaldehyde bearing ester substituent was well tolerated under the reaction conditions and
offered chromone 3e in 73% yield. Similarly, electron-deficient halide substituents namely
chlorine, and iodine at the different positions of 1 were also well tolerated, and the products
3f–3h were isolated in 68–84% yields. Irrespective of the electronic nature, when the
substituents are present at the ortho- position with respect to hydroxyl group, the chemical
yields were reduced significantly (3i–3k, 52–62%). On the other hand, 1-hydroxy-2-
naphthaldehyde 1l showed an excellent reactivity under this optimized conditions and formed
3l in 84% yield. To show the broad efficiency of our catalyst systems a late-stage modification
of a tyrosine derivative 1m was carried out through the optimized protocols. The substituted
tyrosine aldehyde 1m was smoothly coupled with 2a under our optimized conditions and
furnished chromone 3m in 50% yield. Salicylaldehyde bearing C4-methoxy groups provided
3n in 78% yield. When this annulation reaction was conducted in gram scale, 0.95 g of 3a was
isolated (82% yield).
Scheme 2. Scope of Salicylaldehydesa
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aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol
%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields.
After a successful investigation on salicylaldehydes, next the reactivity of diazoacetates
was studied which revealed that upon modification in the diazo-sources significantly switch
their reactivity (Scheme 3). Changing the ester moiety in diazoketone 2 from ethyl to methyl,
the chemical yield did not change much and we were pleased to isolate 4a in 88% yield. The
benzyl substituted α-ketodiazo ester 2c underwent a smooth coupling with salicylaldehyde 1a
to form a chromone 4b in 75% yield. In addition, the diacetyldiazomethane 2d also followed a
similar reaction pathway, which provided chromones 4c and 4d in excellent yields. Moreover,
we have investigated the reactivity of amide substituted diazo-acetates 2e–2g under the
optimized conditions. The amide containing –NEt2, –NiPr2, –morpholine were well tolerated
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and formed chromones 4e–4h in moderate to good yields. When a phenyl containing α-diazo
compound is used as an electrophile, only the trace amount of product formed as an inseparable
mixture with unknown side products.
Scheme 3. Scope of Substituted Diazo-Ketonesa
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aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol
%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields.
While negotiating on the reactivity of various diazo ketones, it was observed that on
treatment of tert-butyldiazo acetate 2h under the catalysis followed a decarboxylative pathway
to form chromone 5a in excellent yield of 86% (Scheme 4). After having a preliminary
successful result in hand, we further explored this approach with several salicylaldehydes.
Salicylaldehyde having electron-deficient substituents such as esters and halogens (F, Cl, Br)
at different positions are completely viable to provide chromones 5b–5g in moderate to
excellent yields (54–92%). Moreover, salicylaldehyde 1i bearing electron-donating methoxy
group underwent a smooth coupling with 2h to form chromone 5h in good yield. Most
importantly, the synthesized chromone 5h has an immense importance in medicinal chemistry
and functions as HBV inhibitor.14a Further we have explored this strategy for the late-stage
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modifications of tyrosine and received a promising outcome through the coupling of 2h with
tyrosine derived aldehyde (5i, 42% yield). 4-Methoxy salicylaldehyde furnished 5j in 81%
yield.
Scheme 4. Decarboxylation Approach of Chromones Synthesisa,b
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aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2h (0.3 mmol, 1.5 equiv), [Cp*IrCl2]2 (1.0 mol
%), PivOH (1.0 equiv), H2O (1.5 mL), 80 oC, 2 h. bIsolated yields.
Our studies with the tert.-butyl diazo compound 2h in DCE solvent provided no
decarboxylation signifying a vital role of water as solvent to switch the product selectivity
(Scheme 5). The possible reason could be a ready hydrolysis of the formed tert-butyl ester
containing chromone in the presence of water and then a facile decarboxylation. When the
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product is heated at 100 C in water, the hydrolysis followed by decarboxylation provided
chromone 5.
Scheme 5. Control Experiments for Decarboxylation Approach
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The literature represents several important features of chromones heterocycle in the various
field, as mentioned in the introduction. To show a broader impact in applications of our
synthesized chromones we have carried out several chemical transformations using chromone
5a as a key starting material (Table 2).14 The ketone directed C–H bond functionalizations at
C5 position are possible for the diversification of the synthesized chromones. Thus C(5)–H
allylation,14b amidation,14c oxidative alkenylation,14d and 1,4-addition14e are achieved for 5a.
Furthermore, a Pd-catalyzed electrophilic metallation and oxidative alkenylation provided C3
alkenylated chromone.14f
Table 2. Diversification of Chromone 5a
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To know the nature of the C–H-metallation we performed H/D-exchange experiments in
the presence of deuterium sources (Scheme 6).15 Around 17% deuterium exchange was
observed for the aldehyde C–H bond indicating a reversible C–H bond activation.
Scheme 6 H/D-Exchange Experiment
Based on our primary investigation and previous reports12,13 a plausible catalytic cycle can
be proposed (Scheme 7). In the presence of pivalic acid, the active catalyst A is formed. The
catalyst A forms the cyclometallated species B, after hydroxyl coordination and irreversible
aldehyde C–H activation. The formation of the intermediate B was supported by LC-MS
analysis.15 The intermediate B reacts with the diazo-compound 2a to give an iridium-carbenoid
species C. The migratory insertion to the carbenoid species produces the intermediate D, which
delivers the compound E and regenerates the catalyst A in the presence of pivalic acid. A
nucleophilic addition followed by dehydration in E, finally gives the desired product 3a.
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Scheme 7. Proposed Mechanism of Chromone Synthesis
CONCLUSION
Thus, we successfully developed Ir(III)-catalyzed C–H activation in water medium and
employed the concept for the chromone synthesis. The annulation between salicylaldehydes
and α-diazo carbonyl compounds were efficiently executed to achieve the target under the
reaction conditions. A one-pot annulation followed by decarboxylation of a tert-butyl
diazoester with salicylaldehydes provided C3-substitution free chromones in useful way. We
hope the method could be helpful in finding more reactions for Ir-catalyzed C–H activation in
water medium.
Experimental Section
General: All reactions were carried out in an oven dried reaction tube. Unless otherwise
stated, all solvents were dried by standard procedure: 1,2-dichloroethane was distilled over
calcium hydride. Analytical thin layer chromatography (TLC) was performed on Merck pre-
coated silica gel 60 F254 plates. Visualization on TLC was achieved by the use of UV light
(254 nm), exposure to iodine vapour or treatment with KMnO4 solution followed by heating.
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Column chromatography was performed through silica gel (100-200 mesh) using a proper
solvent system. Infrared (IR) spectra were recorded by FTIR spectrometer and reported in
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terms of wave number (cm-1). The H NMR spectroscopic data were recorded with a Bruker
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400, 500 or 600 MHz NMR instruments. C NMR spectra were similarly recorded by using
101, 126 or 151 MHz NMR instruments applying a broadband decoupled mode. Proton and
carbon NMR chemical shifts (δ) are reported in parts per million (ppm) relative to residual
proton signals in CDCl3 (δ = 7.26, 77.16) and DMSO-d6 (d = 2.50, 39.52). Coupling constants
(J) are reported in Hertz (Hz) and refer to apparent multiplicities. The following abbreviations
are used for the multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, dd:
doublet of doublets, dt: doublet of triplets, ddd: doublet of doublet of doublets, tt: triplet of
triplets, td: triplet of doublets, m: multiplet, br: broad. High resolution mass spectra (HRMS)
were recorded in ESI (+ Ve) method using TOF mass analyzer. Other chemicals were obtained
from commercial sources and used without further purification. All salicylaldehydes were
bought from the commercial sources and used without further purifications. The tyrosine
aldehyde 1m was synthesized according to the known literature procedure.9b All the known
compounds are characterized through NMR analysis and comparing the spectral data with the
reported value.
General Procedure for the synthesis of diazo-compounds 2:
The substituted diazo-ketones were synthesized according to a known literature procedure
with slight modifications.13e In an oven dried 100 mL two-neck round bottom flask 1,3-
dicarbonyl compound (5.0 mmol, 1.0 equiv) and tosyl azide (6.0 mmol, 1.2 equiv) were
dissolved in 15 mL acetonitrile under nitrogen atmosphere. The reaction mixture was then
cooled down to 0 oC, and DBU (6.0 mmol, 1.2 equiv) in 10 mL of acetonitrile was added. The
reaction was then allowed to stir at room temperature for 3h. After completion of the reaction,
as indicated by TLC, the reaction mixture was extracted with ethyl acetate, the combined
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organic layers were washed with brine, dried over anhydrous sodium sulphate and solvent was
removed under vaccuo. The crude reaction mixture was purified by silica gel flash column
chromatography. The reported diazo-compounds [2a, 2c-d],13k 2b,16 [2e-g],13l 2h.13m are
analysed by comparing the known literature data. To show the purity of our synthesized diazo
compounds we have provided the proton NMR spectra of all the compound.15
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General Procedure for the annulation of salicylaldehydes with diazo-compounds: (GP I)
In a 10.0 mL screw capped sealed tube salicylaldehydes 1 (0.2 mmol, 1.0 equiv),
diazocopmpounds 2 (0.3 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (1.6 mg, 0.002 mmol, 1.0 mol
%) and pivalic acid (20.4 mg, 0.2 mmol, 1.0 equiv) were taken and 1.5 mL of water was
successively added. Then the reaction mixture was heated at 80 oC temperature for 2 h. After
completion of the reaction as indicated by TLC, the reaction mixture was extracted with ethyl
acetate and the collected organic layers were dried over anhydrous sodium sulfate. The solvent
was evaporated in rotary-evaporator and the crude residue was purified by silica gel column
chromatography by using petroleum ether/ ethylacetate eluent to obtain 3a–3m and 4a–4h.
General Procedure for the annulation of salicylaldehydes with tert.-butyl diazo-
compound 2h: (GP II)
In a 10.0 mL screw capped sealed tube salicylaldehydes 1 (0.2 mmol, 1.0 equiv), tert.-butyl
diazo-compound 2h (0.3 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (1.6 mg, 0.002 mmol, 1.0 mol
%) and pivalic acid (20.4 mg, 0.2 mmol, 1.0 equiv) were taken and 1.5 mL of water was
successively added. Then the reaction mixture was heated at 100 oC temperature for 8 h. After
completion of the reaction as indicated by TLC, the reaction mixture was extracted with ethyl
acetate and the collected organic layers were dried over anhydrous sodium sulfate. The solvent
was evaporated in rotary-evaporator and purified by silica gel column chromatography using
petroleum ether/ ethylacetate eluent to obtain 5a–5i.
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Ethyl 2-diazo-3-oxobutanoate (2a).13k The compound 2a was synthesized according to the
given procedure in 78% yield. 1H NMR (200 MHz, CDCl3) δ (ppm) 4.30 (q, J = 7.1 Hz, 2H),
2.48 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).
Methyl 2-diazo-3-oxobutanoate (2b).16 The compound 2b was synthesized according to the
given procedure in 75% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.83 (s, 3H), 2.47 (s, 3H).
Ethyl 2-diazo-3-oxo-5-phenylpentanoate (2c).13k The compound 2c was synthesized
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according to the given procedure in 72% yield. H NMR (400 MHz, CDCl3) δ (ppm) 7.31–
7.24 (m, 4H), 7.22–7.18(m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.20 (t, J = 7.7 Hz, 2H), 2.98 (t, J =
7.7 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
3-Diazopentane-2,4-dione (2d).13k The compound 2d was synthesized according to the
given procedure in 80% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.42 (s, 6H).
2-Diazo-N,N-diisopropyl-3-oxobutanamide (2e).13l The compound 2e was synthesized
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according to the given procedure in 55% yield. H NMR (200 MHz, CDCl3) δ (ppm) 3.77–
3.57 (m, 2H), 2.30 (s, 3H), 1.33 (d, J = 6.7 Hz, 12H).
2-Diazo-N,N-diethyl-3-oxobutanamide (2f).13l The compound 2f was synthesized according
to the same procedure as literature report in 66% yield. 1H NMR (200 MHz, CDCl3) δ (ppm)
3.38 (q, J = 7.1 Hz, 4H), 2.34 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H).
2-Diazo-1-morpholinobutane-1,3-dione (2g).13l The compound 2g was synthesized
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according to the given procedure in 50% yield. H NMR (400 MHz, CDCl3) δ (ppm) 3.72–
3.70 (m, 4H), 3.57–3.44 (m, 4H), 2.31 (s, 3H).
tert-Butyl 2-diazo-3-oxobutanoate (2h).13m The compound 2h was synthesized according
to the given procedure in 74% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.41 (s, 3H), 1.49
(s, 9H).
Ethyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (3a).9b The titled compound 3a was
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prepared according to the GP I and isolated as white solid (41.8 mg, 90%). H NMR (400
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MHz, CDCl3): δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 7.66–7.62 (m, 1H), 7.41–7.36 (m, 2H), 4.39
(q, 7.1 Hz, 2H), 2.49 (s, 3H), 1.38 (t, J = 7.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 174.5,
166.8, 165.2, 155.7, 134.1, 126.2, 125.6, 123.4, 118.3, 117.8, 61.8, 19.6, 14.3.
Gram scale synthesis of 3a: Salicylaldehyde 1a (0.61 g, 5.0 mmol, 1.0 equiv),
diazocopmpounds 2a (1.17 g, 7.5 mmol, 1.5 equiv), catalyst [Cp*IrCl2]2 (39.8 mg, 0.05 mmol,
1.0 mol %) and pivalic acid (0.51 g, 5.0 mmol, 1.0 equiv) were taken in a 60 mL pressure tube
and 37.0 mL of water was added. Then the reaction mixture was heated at 80 oC temperature
for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was
extracted with ethyl acetate and the collected organic layers were dried over anhydrous sodium
sulfate. The solvent was evaporated in rotary-evaporator and the crude residue was purified by
silica gel column chromatography by using petroleum ether/ ethylacetate eluent to obtain 0.95
g of pure 3a (82% yield).
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Ethyl 2,6,8-trimethyl-4-oxo-4H-chromene-3-carboxylate (3b). The titled compound 3b was
prepared according to the GP I and isolated as yellow solid (40 mg, 77 %). IR (KBr): 2924,
1641, 1719, 1475, 1268 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.81 (s, 1H), 7.31 (s, 1H),
4.41 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ (ppm) 175.0, 166.3, 165.5, 152.5, 136.4, 135.1, 126.9, 123.2,
117.9, 61.8, 29.8, 21.0, 19.6, 15.5, 14.3. HRMS (ESI) m/z: [M+H]+ calcd for C15H17O4
261.1121; found 261.1101.
Ethyl 6-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3c).9b The titled compound
3c was prepared according to the GP I and isolated as yellow solid (41.9 mg, 81%). 1H NMR
(500 MHz, CDCl3): δ (ppm) 7.53 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.21 (dd, J =
9.1, 3.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.48 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3): δ (ppm) 174.4, 166.5, 165.4, 157.2, 150.5, 124.1, 123.9, 119.2,
117.5, 105.4, 61.8, 56.0, 19.5, 14.3.
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Ethyl 6-(tert-butyl)-2-methyl-4-oxo-4H-chromene-3-carboxylate (3d). The titled compound
3d was prepared according to the GP I and isolated as white solid (50.6 mg, 88%). IR (KBr):
2958, 1729, 1646, 1435, 1352 cm-1. 1H NMR (500 MHz, CDCl3): δ (ppm) 8.17 (d, J = 2.4 Hz,
1H), 7.70 (dd, J = 8.8, 2.5 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 1H), 2.49 (s,
3H), 1.39 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3): δ (ppm) 174.8, 166.6,
165.5, 153.9, 149.0, 131.9, 122.8, 122.1, 118.1, 117.4, 61.8, 35.0, 31.4, 19.6, 14.3. HRMS
(ESI) m/z: [M+H]+ calcd for C17H21O4 289.1434; found 289.1409.
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Ethyl 6-acetoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3e). The titled compound 3e
was prepared according to the GP I and isolated as yellow solid (42.34 mg, 73%). IR (KBr):
2922, 1715, 1615, 1437, 1273 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.84 (s, 1H), 8.30
(d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.51 (s,
3H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.8, 167.0, 165.7, 164.8,
158.0, 134.8, 128.6, 127.7, 123.2, 118.7, 118.3, 62.1, 52.6, 19.6, 14.3. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C15H15O6 291.0863; found 291.0837.
Ethyl 6-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3f).17 The titled compound 3f
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was prepared according to the GP I and isolated as yellow sticky solid (41.5 mg, 78%). H
NMR (400 MHz, CDCl3): δ (ppm) 8.14 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H),
7.38 (d, J = 8.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ (ppm) 173.3, 167.1, 164.9, 154.0, 134.3, 131.7, 125.6, 124.5,
119.6, 118.2, 62.0, 19.7, 14.3.
Ethyl 6-iodo-2-methyl-4-oxo-4H-chromene-3-carboxylate (3g).17 The titled compound 3g
was prepared according to the GP I and isolated as white solid (48.7 mg, 68%). 1H NMR (400
MHz, CDCl3): δ (ppm) 8.49 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 (d, J = 8.8
Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
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CDCl3): δ (ppm) 173.0, 167.1, 164.8, 155.1, 142.7, 135.1, 125.1, 119.9, 118.5, 89.5, 62.0, 19.7,
14.3.
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Ethyl 7-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3h). The titled compound 3h
was prepared according to the GP I and isolated as white solid (44.7 mg, 84%). IR (KBr):
2980, 1731, 1640, 1605, 1427 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (d, J = 8.5 Hz,
1H), 7.45 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 4.41 (q, J = 6.9 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.7, 167.0, 164.9, 155.8, 140.2, 127.7,
126.6, 122.1, 118.6, 118.0, 62.0, 19.6, 14.3. HRMS (ESI) m/z: [M +H]+ calcd for C13H12ClO4
267.0419; found 267.0395.
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Ethyl 8-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3i).9b The titled compound
3i was prepared according to the GP I and isolated as white solid (32.5 mg, 62%). 1H NMR
(500 MHz, CDCl3): δ (ppm) 7.73–7.72 (m, 1H), 7.30–7.26 (m, 1H), 7.15–7.13 (m, 1H), 4.40
(q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 2.54 (s, 3H), 1.38 (t, J = 7.7 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ (ppm) 174.4, 166.5, 165.2, 148.5, 146.1, 125.3, 124.6, 118.3, 117.0, 114.8, 61.9,
56.4, 19.6, 14.3.
Ethyl 8-chloro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3j). The titled compound 3j
was prepared according to the GP I and isolated as yellow solid (29.3 mg, 55%). IR (KBr):
2977, 1727, 1645, 1601, 1627, 1408 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.10 (d, J =
7.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.35–7.31 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.57 (s, 3H),
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1.39 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 173.9, 167.0, 164.8, 151.4,
136.3, 134.4, 125.7, 124.9, 122.9, 118.5, 62.1, 19.6, 14.3. HRMS (ESI) m/z: [M+H]+ calcd
for C13H12ClO4 267.0419; found 267.0412.
Ethyl 8-fluoro-2-methyl-4-oxo-4H-chromene-3-carboxylate (3k). The titled compound 3k
was prepared according to the GP I and isolated as white solid (26 mg, 52%). IR (KBr): 2971,
1726, 1645, 1488, 1404 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96–7.96 (m, 1H), 7.47–
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7.42 (m, 1H), 7.36 – 7.31 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J = 7.1 Hz,
3H). 13C NMR (151 MHz, CDCl3): δ (ppm) 173.6 (d, J = 2.9 Hz), 166.4, 164.8, 150.9 (d, J =
253.7 Hz), 144.5 (d, J = 11.5 Hz), 125.4, 125.3 (d, J = 6.5 Hz), 121.3 (d, J = 4.1 Hz), 119.9 (d,
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J = 16.6 Hz), 118.7, 62.1, 19.6, 14.3. F NMR (376 MHz, CDCl3) δ (ppm) -133.48 (s, 1F).
HRMS (ESI) m/z: [M+H]+ calcd. for C13H13FO4 251.0714; found 251.0700.
Ethyl 2-methyl-4-oxo-4H-benzo[h]chromene-3-carboxylate (3l).9b The titled compound 3l
was prepared according to the GP I and isolated as white solid (47.3 mg, 84%). 1H NMR (500
MHz, CDCl3): δ (ppm) 8.45 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.2 Hz,
1H), 7.76 (d, J = 8.7 Hz, 1H), 7.73–7.66 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H), 1.42
(t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ (ppm) 174.5, 165.9, 165.2, 153.2, 136.1,
129.6, 128.3, 127.4, 125.8, 123.6, 122.2, 121.0, 119.9, 119.4, 62.0, 19.5, 14.4.
Ethyl6-(2-(1,3-dioxoisoindolin-2-yl)-3-methoxy-3-oxopropyl)-2-methyl-4-oxo-4H-
chromene-3-carboxylate (3m).9b The titled compound 3m was prepared according to the GP I
and isolated as white solid (31.7 mg, 50%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96 (d, J =
2.0 Hz, 1H), 7.77 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.50 (dd, J = 8.6,
2.1 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 5.14 (dd, J = 11.1, 5.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H),
3.78 (s, 3H), 3.72–3.58 (m, 2H), 2.44 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ (ppm) 174.1, 169.1, 167.5, 166.6, 165.2, 154.7, 134.7, 134.4, 131.6, 126.3, 123.8,
123.4, 118.3, 61.9, 53.2, 34.4, 19.6, 14.3.
Ethyl 7-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxylate (3n). The titled compound
3n was prepared according to the GP I and isolated as gummy solid (40.8 mg, 78%). IR (KBr):
2982, 1728, 1630, 1438, 1398 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 8.9 Hz,
1H), 6.94 (dd, J = 8.9, 2.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.88 (s,
3H), 2.46 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 173.9, 166.2,
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165.4, 164.4, 157.4, 127.6, 118.1, 117.2, 114.7, 100.2, 61.8, 55.9, 19.4, 14.3. HRMS (ESI)
m/z: [M+H]+ calcd for C14H15O5 263.0914; found 263.0917.
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Methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate (4a).9b The titled compound 4a was
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prepared according to the GP I and isolated as white solid (38.4 mg, 88%). H NMR (400
MHz, CDCl3): δ (ppm) 8.17 (dd, J = 7.9, 1.6 Hz, 1H), 7.67–7.63 (m, 1H), 7.41–7.36 (m, 1H),
3.92 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.4, 167.4, 165.7, 155.6,
134.1, 126.2, 125.7, 123.4, 117.8, 52.7, 19.7.
Ethyl 4-oxo-2-phenethyl-4H-chromene-3-carboxylate (4b). The titled compound 4b was
prepared according to the GP I and isolated as white solid (48.3 mg, 75%). IR (KBr): 2981,
1724, 1646, 1616, 1465, 1383 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.20 (d, J = 6.9 Hz,
1H), 7.67 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 6.3 Hz, 2H), 7.30–7.26 (d, J = 6.6 Hz, 2H), 7.23–
7.21 (m, 3H), 4.38 (q, J = 7.1 Hz, 2H), 3.12–3.04 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ (ppm) 174.7, 168.6, 165.1, 155.7, 139.9, 134.1, 128.8, 128.6, 128.4,
126.7, 126.3, 125.7, 123.5, 118.4, 117.9, 61.9, 35.2, 33.7, 14.34. HRMS (ESI) m/z: [M+H]+
calcd for C20H19O4 323.1278; found 323.1276.
3-Acetyl-2-methyl-4H-chromen-4-one (4c).9b The titled compound 4c was prepared
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according to the GP I and isolated as yellow solid (36.4 mg, 90%). H NMR (500 MHz,
CDCl3): δ (ppm) 8.17 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.41–7.38(m, 2H), 2.62 (s,
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3H), 2.50 (s, 3H). C NMR (126 MHz, CDCl3) δ 200.6, 176.0, 168.7, 155.5, 134.2, 126.0,
125.7, 123.9, 123.8, 117.8, 32.3, 19.9.
3-Acetyl-6-bromo-2-methyl-4H-chromen-4-one (4d). The titled compound 4d was prepared
according to the GP I and isolated as white solid (42.6 mg, 76%). IR (KBr): 2924, 1696, 1644,
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1607, 1426 cm-1. H NMR (400 MHz, CDCl3): δ (ppm) δ 8.29 (s, 1H), 7.74 (d, J = 8.7 Hz,
1H), 7.32 (d, J = 8.9 Hz, 1H), 2.61 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm)
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200.2, 174.7, 169.0, 154.3, 137.2, 128.7, 125.3, 123.8, 119.8, 119.2, 32.3, 20.0. HRMS (ESI)
m/z: [M+H]+ calcd. for C12H10BrO3 280.9808; found 280.9793.
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N,N-Diisopropyl-2-methyl-4-oxo-4H-chromene-3-carboxamide (4e). The titled compound
4e was prepared according to the GP I and isolated as yellow solid (35.2 mg, 68%). IR (KBr):
2928, 1616, 1571, 1447, 1398 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 1H),
7.65 (t, J = 7.7 Hz, 1H), 7.42 – 7.36 (m, 2H), 3.85–3.79 (m, 1H), 3.55 – 3.48 (m, 1H), 2.41 (s,
3H), 1.60 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.5 Hz, 3H), 1.12 (d, J =
6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.9, 164.3, 163.1, 156.1, 133.8, 126.1,
125.2, 123.4, 122.6, 117.9, 51.7, 46.2, 21.5, 21.0, 20.6, 20.3, 18.8. HRMS (ESI) m/z: [M+H]+
calcd. for C17H22NO3 288.1594; found 288.1578.
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N,N-Diethyl-2-methyl-4-oxo-4H-chromene-3-carboxamide (4f).18 The titled compound 4f
1
was prepared according to the GP I and isolated as yellow solid (37.3 mg, 72%). H NMR
(400 MHz, CDCl3): δ (ppm) 8.17 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.43–7.37 (m,
2H), 3.58 (q, J = 7.1 Hz, 2H), 3.32–3.22 (m, 2H), 2.41 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 174.8, 164.7, 163.9, 156.1, 133.9,
126.1, 125.4, 123.3, 121.3, 117.9, 43.3, 39.5, 19.1, 14.6, 13.0.
N,N-Diethyl-6-methoxy-2-methyl-4-oxo-4H-chromene-3-carboxamide (4g).18 The titled
compound 4g was prepared according to the GP I and isolated as yellow solid (29.2 mg, 51%).
1H NMR (400 MHz, CDCl3): δ (ppm) 7.53 (d, J = 3.0 Hz, 1H), 7.35 (d, J = 9.1 Hz, 1H), 7.24
(dd, J = 9.1, 3.1 Hz, 1H), 3.86 (s, 3H), 3.58 (q, J = 7.1 Hz, 2H), 3.29–3.23 (m, 2H), 2.40 (s,
3H), 1.27 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm)
174.6, 164.9, 163.6, 157.1, 150.9, 123.9, 120.6, 119.3, 105.2, 56.0, 43.2, 39.5, 19.0, 14.6, 12.9.
2-Methyl-3-(morpholine-4-carbonyl)-4H-chromen-4-one (4h). The titled compound 4h
was prepared according to the GP I and isolated as yellow solid (30.6 mg, 56%). IR (KBr):
2922, 1715, 1621, 1462, 1270, 1250 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.17 (d, J =
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4H), 2.45 (s, 3H). C NMR (151 MHz, CDCl3): δ (ppm) 174.5, 164.9, 163.9, 155.9, 134.1,
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126.0, 125.5, 123.0, 119.8, 117.8, 67.2, 66.8, 47.3, 42.3, 19.1. HRMS (ESI) m/z: [M+H]+
calcd for C15H16NO4 274.1074; found 274.1080.
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2-Methyl-4H-chromen-4-one (5a).19 The titled compound 5a was prepared according to the
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GP II and isolated as yellow solid (27.52 mg, 86%). H NMR (400 MHz, CDCl3): δ (ppm)
8.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.65–7.61 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz,
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1H), 6.17 (s, 1H), 2.38 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 178.4, 166.3, 156.6,
133.6, 125.8, 125.1, 123.7, 117.9, 110.7, 20.7.
Methyl 2-methyl-4-oxo-4H-chromen-6-carboxylate (5b). The titled compound 5b was
prepared according to the GP II and isolated as white solid (40.1 mg, 92%). IR (KBr): 3058,
1721, 1670, 1609, 1421, 1261 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.82 (s, 1H), 8.26
(d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.18 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ (ppm) 177.6, 166.6, 165.9, 159.0, 134.2, 128.3, 127.1, 123.3, 118.4,
111.1, 52.5, 20.7. HRMS (ESI) m/z: [M +H]+ calcd for C12H11O4 219.0652; found 219.0654.
6-Chloro-2-methyl-4H-chromen-4-one (5c).20 The titled compound 5c was prepared
1
according to the GP II and isolated as white solid (21.0 mg, 54%). H NMR (400 MHz,
CDCl3): δ (ppm) 8.13 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 6.17 (s, 1H),
2.39 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.1, 166.6, 154.9, 133.8, 131.0, 125.3,
124.7, 119.7, 110.7, 20.7.
7-Chloro-2-methyl-4H-chromen-4-one (5d).21 The titled compound 5d was prepared
1
according to the GP II and isolated as yellow solid (26.8 mg, 69%). H NMR (400 MHz,
CDCl3): δ (ppm) 8.09 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H),
2.37 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 177.5, 166.5, 156.7, 139.6, 127.2, 125.9,
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122.2, 118.0, 110.9, 20.7. HRMS (ESI) m/z: [M+Na]+ calcd for C10H7ClO2Na 217.0027;
found 217.0019.
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6-Bromo-2-methyl-4H-chromen-4-one (5e).17 The titled compound 5e was prepared
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according to the GP II and isolated as yellow solid (30.6 mg, 64%). H NMR (400 MHz,
CDCl3): δ (ppm) 8.29 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.31 (d, J = 8.9 Hz,
13
1H), 6.18 (s, 1H), 2.38 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 177.0, 166.7, 155.4,
136.6, 128.5, 125.1, 119.9, 118.5, 110.8, 20.7. HRMS (ESI) m/z: [M+Na]+ calcd for
C10H7BrO2Na 260.9522; found 260.9514.
8-Fluoro-2-methyl-4H-chromen-4-one (5f). The titled compound 5f was prepared
according to the GP II and isolated as white solid (23.5 mg, 66%). IR (KBr): 2924, 1716, 1644,
1
1362, 1264 cm-1. H NMR (400 MHz, CDCl3): δ (ppm) 7.92 (d, J = 8.0 Hz, 1H), 7.43–7.38
(m, 1H), 7.32 – 7.28 (m, 1H), 6.20 (s, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm)
177.3 (d, J = 2.8 Hz), 166.2, 151.1 (d, J = 253.0 Hz), 145.3 (d, J = 11.1 Hz), 125.6, 124.6 (d, J
19
= 6.6 Hz), 120.8 (d, J = 4.2 Hz), 119.4 (d, J = 16.7 Hz), 111.0, 20.6. F NMR (376 MHz,
CDCl3) δ (ppm) -133.67 (s, 1F). HRMS (ESI) m/z: [M+H]+ calcd. for C10H8FO2 179.0503;
found 179.0507.
8-Chloro-2-methyl-4H-chromen-4-one (5g). The titled compound 5g was prepared
according to the GP II and isolated as white solid (27.7 mg, 71%). IR (KBr): 2921, 1646, 1600,
1473, 1359 cm-1. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 8.0 Hz, 1H), 7.69 (d, J =
7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 6.20 (s, 1H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ (ppm) 177.6, 166.5, 152.3, 133.9, 125.1, 125.07, 124.4, 122.9, 110.9, 20.7. HRMS (ESI)
m/z: [M+H]+ calcd for C10H8ClO2 195.0207; found 195.0220.
8-Methoxy-2-methyl-4H-chromen-4-one (5h).17 The titled compound 5h was prepared
1
according to the GP II and isolated as white solid (26.6 mg, 70%). H NMR (400 MHz,
CDCl3): δ (ppm) 7.72 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H),
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6.18 (s, 1H), 3.98 (s, 3H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 178.3, 166.1,
148.7, 147.0, 124.7, 116.7, 114.3, 110.8, 56.4, 20.8.
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Methyl 2-(1,3-dioxoisoindolin-2-yl)-3-(2-methyl-4-oxo-4H-chromen-6-yl) propanoate (5i).
The titled compound 5i was prepared according to the GP II and isolated as white solid (33
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mg, 42%). IR (KBr): 2922, 1716, 1651, 1360, 1033 cm-1. H NMR (400 MHz, CDCl3): δ
(ppm) 7.95 (d, J = 2.0 Hz, 1H), 7.79–7.76 (m, 2H), 7.70–7.67 (m, 2H), 7.47 (dd, J = 8.6, 2.2
Hz, 1H), 7.28 (s, 1H), 6.08 (s, 1H), 5.14 (dd, J = 11.1, 5.0 Hz, 1H), 3.78 (s, 3H), 3.68–3.57 (m,
13
2H), 2.32 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 178.0, 169.1, 167.5, 166.2, 155.6,
134.4, 134.2, 134.0, 131.6, 125.9, 123.8, 123.6, 118.3, 110.7, 53.3, 53.2, 34.4, 20.7. HRMS
(ESI) m/z: [M+H]+ calcd. for C22H18NO6 392.1134; found 392.1129.
7-methoxy-2-methyl-4H-chromen-4-one (5j).22 The titled compound 5j was prepared
1
according to the GP II and isolated as gummy solid (30.7 mg, 81%). H NMR (400 MHz,
CDCl3): δ (ppm) 8.06 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.3 Hz, 1H), 6.79 (d, J = 2.3 Hz,
13
1H), 6.08 (s, 1H), 3.87 (s, 3H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 177.8,
165.7, 164.0, 158.3, 127.1, 117.5, 114.1, 110.5, 100.3, 55.9, 20.5.
5-Allyl-2-methyl-4H-chromen-4-one (6). The titled compound 6 was prepared according to
the literature known procedure14b using 0.2 mmol of 5a and isolated as white solid (18.8 mg,
47%). IR (KBr): 2923, 1649, 1603, 1471, 1388 cm-1. H NMR (400 MHz, CDCl3): δ (ppm)
1
7.50 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.13–6.05 (m, 2H),
13
5.04–4.99 (m, 2H), 4.10 (d, J = 6.3 Hz, 2H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3): δ
(ppm) 180.0, 164.3, 158.2, 142.8, 137.9, 132.7, 126.9, 121.4, 116.5, 115.5, 112.1, 38.8, 20.2.
HRMS (ESI) m/z: [M+Na]+ calcd for C13H12O2Na 223.0730; found 223.0721.
N-(2-Methyl-4-oxo-4H-chromen-5-yl)benzamide (7). The titled compound 7 was prepared
according to the literature known procedure14c using 0.2 mmol of 5a and isolated as yellow
solid (29.7 mg, 53%). IR (KBr): 2926, 1647, 1619, 1595, 1493, 1386 cm-1. H NMR (400
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MHz, CDCl3): δ (ppm) 13.58 (s, 1H), 8.85 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 7.6 Hz, 2H), 7.65
(t, J = 8.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H), 2.41 (s, 3H).
13C NMR (101 MHz, CDCl3): δ (ppm) 182.5, 166.4, 166.3, 157.5, 141.2, 135.0, 134.8, 132.1,
128.9, 127.7, 115.0, 111.7, 111.4, 110.9, 20.5. HRMS (ESI) m/z: [M+Na]+ calcd for
C17H13NO3Na 302.0788; found 302.0782.
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(E)-Methyl 3-(2-methyl-4-oxo-4H-chromen-5-yl) acrylate (8). The titled compound 8 was
prepared according to the literature known procedure14d using 0.2 mmol of 5a and isolated as
1
white solid (22.1 mg, 45%). IR (KBr): 2922, 1712, 1648, 1616, 1365 cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 8.98 (d, J = 16.0 Hz, 1H), 7.61–7.57 (m, 1H), 7.43 (d, J = 8.5 Hz, 1H),
7.40 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 6.14 (s, 1H), 3.81 (s, 3H), 2.35 (s, 3H) 13C
NMR (101 MHz, CDCl3): δ (ppm) 179.5, 167.1, 165.1, 157.6, 145.2, 137.0, 132.9, 124.6,
121.2, 121.1, 119.5, 112.0, 51.9, 20.3. HRMS (ESI) m/z: [M+Na]+ calcd for C14H12O4Na
267.0628; found 267.0604.
1-Methyl-3-(2-methyl-4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione (9). The titled
compound 9 was prepared according to the literature knpwn procedure14f using 0.2 mmol of 5a
and isolated as white solid (37.9 mg, 57%). IR (KBr): 2925, 1697, 1647, 1361, 1278 cm-1. 1H
NMR (400 MHz, DMSO-D6): δ (ppm) 7.75–7.71 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J
= 6.0 Hz, 1H), 6.18 (s, 1H), 4.47–4.28 (m, 1H), 3.07–2.94 (m, 1H), 2.89 (s, 3H), 2.56–2.52 (m,
1H), 2.37 (s, 3H). 13C NMR (101 MHz, DMSO-D6): δ (ppm) 178.2, 177.5, 176.6, 166.0, 157.7,
133.6, 120.4, 118.9, 110.7, 37.1, 24.5, 19.6. HRMS (ESI) m/z: [M+Na]+ calcd for
C15H13NO4Na 294.0737; found 294.0731.
(E)-Butyl 3-(2-methyl-4-oxo-4H-chromen-3-yl)acrylate (10). The titled compound 10 was
prepared according to the literature known procedure14e using 0.2 mmol of 5a and isolated as
1
white solid (24.6 mg, 43%). IR (KBr): 2957, 1710, 1647, 1613, 1288 cm-1. H NMR (400
MHz, CDCl3): δ (ppm) 8.22 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 15.8 Hz,
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1H), 7.42–7.36 (m, 3H), 4.20 (t, J = 6.6 Hz, 2H), 2.62 (s, 3H), 1.69–1.66 (m, 2H), 1.46–1.40
(m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 176.4, 168.2, 167.8,
155.2, 134.9, 133.8, 126.4, 125.6, 123.6, 123.3, 117.8, 116.3, 64.5, 30.9, 19.3, 13.9. HRMS
(ESI) m/z: [M+Na]+ calcd for C17H18O4Na 309.1097; found 309.1074.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Mechanistic studies and NMR spectra (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: msm@chem.iitkgp.ac.in
ORCID
Modhu Sudan Maji: 0000-0001-9647-2683
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
M.S.M. gratefully acknowledge SERB, Department of Science and Technology, New Delhi,
India (Sanction No. CRG/2018/000317) for funding. S.D. and M.R.S. sincerely thanks IIT
Kharagpur for fellowships.
REFERENCES
(1) (a) Trost, B. M. The Atom Economy-a Search for Synthetic Efficiency. Science 1991, 254,
1471. (b) Wender, P. A.; Miller, B. L. Synthesis at the Molecular Frontier. Nature 2009, 460,
197.
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(2) (a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Recent Developments in Natural Product
Synthesis Using Metal-Catalysed C–H Bond Functionalisation. Chem. Soc. Rev. 2011, 40,
1885. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami. K. C-H Bond Functionalization: Emerging
Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51,
8960. (c) Chen, D. Y.-K.; Youn, S. W. C–H Activation: A Complementary Tool in the Total
Synthesis of Complex Natural Products. Chem. -Eur. J. 2012, 18, 9452. (d) Cernak, T.;
Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist's Toolbox for
Late Stage Functionalization of Drug-Like Molecules. Chem. Soc. Rev. 2016, 45, 546. (e)
Sinha, S. K.; Zanoni, G.; Maiti, D. Natural Product Synthesis by C−H Activation. Asian J. Org.
Chem. 2018, 7, 1178.
10
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12
13
14
15
16
17
18
19
20
21
22
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25
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54
55
56
57
58
59
60
(3) (a) Herrerías, C. I.; Yao, X.; Li, Z.; Li, C.-J. Reactions of C−H Bonds in Water. Chem. Rev.
2007, 107, 2546. (b) Zhang, J; Loh, T.-P. Ruthenium- and Rhodium-Catalyzed Cross-Coupling
Reaction of Acrylamides with Alkenes: Efficient Access to (Z,E)-Dienamides. Chem.
Commun. 2012, 48, 11232. (c) Li, B.; Dixneuf, P. H. sp2 C–H Bond Activation in Water and
Catalytic Cross-Coupling Reactions. Chem. Soc. Rev. 2013, 42, 5744. (d) Zhang, H.; Yang, Z.;
Ma, Q.; Liu, J.; Zheng, Y.; Guan, M.; Wu, Y. Controlled Mono-Olefination Versus
Diolefination of Arenes via C–H Activation in Water: A Key Role of Catalysts. Green Chem.
2018, 20, 3140. (e) Kitanosono, T.; Masuda, K.; Xu, P.; Kobayashi, S. Catalytic Organic
Reactions in Water Toward Sustainable Society. Chem. Rev. 2018, 118, 679.
(4) For selected examples: (a) Turner, G. L.; Morris, J. A.; Greaney, M. F. Direct Arylation of
Thiazoles on Water. Angew. Chem. Int. Ed. 2007, 46, 7996. (b) Ohnmacht, S. A.; Mamone, P.;
Culshaw, A. J.; Greaney, M. F. Direct Arylations on Water: Synthesis of 2,5-Disubstituted
Oxazoles Balsoxin and Texaline. Chem. Commun. 2008, 1241. (c) Joucla, L.; Batail, N.;
Djakovitch, L. “On Water” Direct and Site‐Selective Pd‐Catalysed C–H Arylation of (NH)‐
Indoles. Adv. Synth. Catal. 2010, 352, 2929. (d) Chen, F.; Min, Q.-Q.; Zhang, X. Pd-Catalyzed
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Direct Arylation of Polyfluoroarenes on Water under Mild Conditions Using PPh3 Ligand. J.
Org. Chem. 2012, 77, 2992. (e) Liu, W.; Wang, D.; Zhao, Y.; Yi, F.; Chen, J. Palladium‐
Catalyzed Mono‐Selective ortho C–H Arylation of Aryl Sulfonamides in Water: A Concise
Access to Biaryl Sulfoamide Derivatives. Adv. Synth. Catal. 2016, 358, 1968.
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(5) For selected examples: (a) Midya, S. P.; Sahoo, M. K.; Landge, V. G.; Rajamohanan, P. R.;
Balaraman, E. Reversed Reactivity of Anilines with Alkynes in the Rhodium-Catalysed C–H
Activation/Carbonylation Tandem. Nat. Commun. 2015, 6, 8591. (b) Shi, L.; Wang, B. Tandem
Rh(III)-Catalyzed C–H Amination/Annulation Reactions: Synthesis of Indoloquinoline
Derivatives in Water. Org. Lett. 2016, 18, 2820. (c) Kim, S.; Han, S.; Park, J.; Sharma, S.;
Mishra, N. K.; Oh, H.; Kwak, J. H.; Kim, I. S. Cp*Rh(III)-Catalyzed C(sp3)–H Alkylation of
8-Methylquinolines in Aqueous Media. Chem. Commun. 2017, 53, 3006. (d) Wu, S.; Wu, X.;
Fu, C.; Ma, S. Rhodium(III)-Catalyzed C–H Functionalization in Water for Isoindolin-1-one
Synthesis. Org. Lett. 2018, 20, 2831.
(6) For selected examples: (a) Li, C.-J.; Wei, C. Highly Efficient Grignard-Type Imine
Additions via C–H Activation in Water and under Solvent-Free Conditions. Chem. Commun.
2002, 268. (b) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. C–H Bond
Functionalization in Water Catalyzed by Carboxylato Ruthenium(II) Systems. Angew. Chem.
Int. Ed. 2010, 49, 6629. (c) Ackermann, L.; Pospech, J. Ruthenium-Catalyzed Oxidative C–H
Bond Alkenylations in Water: Expedient Synthesis of Annulated Lactones. Org. Lett. 2011,
13, 4153. (d) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Ruthenium-Catalyzed
Oxidative C–H Alkenylations of Anilides and Benzamides in Water. Org. Lett. 2012, 14, 728.
(e) Han, W.-J.; Pu, F.; Li, C.-J.; Liu, Z.-W.; Fan, J.; Shi, X.-Y. Carboxyl‐Directed Conjugate
Addition of C−H Bonds to α,β‐Unsaturated Ketones in Air and Water. Adv. Synth. Catal. 2018,
360, 1358.
27
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The Journal of Organic Chemistry
Page 28 of 32
1
2
3
4
5
6
7
8
9
(7) (a) Borges, F.; Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E. Chromone: A Valid
Scaffold in Medicinal Chemistry. Chem. Rev. 2014, 114, 4960. (b) Keri, R. S.; Budagumpi, S.;
Pai, R. K.; Balakrishna, R. G. Chromones as a Privileged Scaffold in Drug Discovery: A
Review. Eur. J. Med. Chem. 2014, 78, 340. (c) Emami, S.; Ghanbarimasir, Z. Recent Advances
of Chroman-4-one Derivatives: Synthetic Approaches and Bioactivities. Eur. J. Med. Chem.
2015, 93, 539. (d) Simonetti, S. O.; Larghi, E. L.; Bracca A. B. J.; Kaufman, T. S. Angular
Tricyclic Benzofurans and Related Natural Products of Fungal Origin. Isolation, Biological
Activity and Synthesis. Nat. Prod. Rep. 2013, 30, 941. (e) Jagadeesh, S. G.; David
Krupadanam, G. L.; Srimannarayana, G. Synthesis of 2-Methyl chromone-8-acetic Acids and
2-Methyl chromone-8-carboxylic Acids. Synth. Commun. 2001, 31, 1547. (f) Kornev , M. Y.;
Sosnovskikh, V. Y. Synthesis and Chemical Properties of Chromone-3-carboxylic Acid. Chem.
Heterocycl. Compd. 2016, 52, 71.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) (a) Li, N.-G.; Shi, Z.-H.; Tang, Y. P.; Ma, H.-Y.; Yang, J.-P.; Li, B.-Q.; Wang, Z.-J.; Song,
S.-L.; Duan, J.-A. Synthetic Strategies in the Construction of Chromones. J. Heterocyclic
Chem. 2010, 47, 785. (b) Kumar, P.; Bodas, M. S. A Novel Synthesis of 4H-Chromen-4-ones
via Intramolecular Wittig Reaction. Org. Lett. 2000, 2, 3821. (c) Yang, Q.; Alper, H. Synthesis
of Chromones via Palladium-Catalyzed Ligand-Free Cyclocarbonylation of o-Iodophenols
with Terminal Acetylenes in Phosphonium Salt Ionic Liquids. J. Org. Chem. 2010, 75, 948.
(d) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Efficient Assembly of Chromone Skeleton from 2,3-
Allenoic Acids and Benzynes. Org. Lett. 2011, 13, 5196. (e) Vedachalam, S.; Wong, Q.-L.;
Maji, B.; Zeng, J.; Ma, J.; Liu, X.-W. N‐Heterocyclic Carbene Catalyzed Intramolecular
Hydroacylation of Activated Alkynes: Synthesis of Chromones. Adv. Synth. Catal. 2011, 353,
219. (f) Zhao, J.; Zhao, Y.; Fu, H. K2CO3-Catalyzed Synthesis of Chromones and 4-Quinolones
through the Cleavage of Aromatic C–O Bonds. Org. Lett. 2012, 14, 2710.
28
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(9) (a) Shimizu, M.; Tsurugi, H.; Satoh, T.; Miura, M. Rhodium‐Catalyzed Oxidative Coupling
between Salicylaldehydes and Internal Alkynes with C–H Bond Cleavage to Produce 2,3‐
Disubstituted Chromones. Chem. Asian J. 2008, 3, 881. (b) Sun, P.; Gao, S.; Yang, C.; Guo,
S.; Lin, A.; Yao, H. Controllable Rh(III)-Catalyzed Annulation between Salicylaldehydes and
Diazo Compounds: Divergent Synthesis of Chromones and Benzofurans. Org. Lett. 2016, 18,
6464.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) (a) Baruah, S.; Kaishap, P. P.; Gogoi, S. Ru(II)-Catalyzed C–H Activation and Annulation
of Salicylaldehydes with Monosubstituted and Disubstituted Alkynes. Chem. Commun. 2016,
52, 13004. (b) Raja, G. C. E.; Ryu, J. Y.; Lee, J.; Lee, S. Ruthenium-Catalyzed C–H Activation
of Salicylaldehyde and Decarboxylative Coupling of Alkynoic Acids for the Selective
Synthesis of Homoisoflavonoids and Flavones. Org. Lett. 2017, 19, 6606.
(11) Yang, J.; Yoshikai, N. Cobalt-Catalyzed Annulation of Salicylaldehydes and Alkynes to
Form Chromones and 4-Chromanones. Angew. Chem. Int. Ed. 2016, 55, 2870.
(12) For selected examples, see: (a) Willis, M. C. Transition Metal Catalyzed Alkene and
Alkyne Hydroacylation. Chem. Rev. 2010, 110, 725. (b) von Delius, M.; Le, C. M.; Dong, V.
M. Rhodium-Phosphoramidite Catalyzed Alkene Hydroacylation: Mechanism and Octaketide
Natural Product Synthesis. J. Am. Chem. Soc. 2012, 134, 15022. (c) Shi, Z.; Schröder, N.;
Glorius, F. Rhodium(III)‐Catalyzed Dehydrogenative Heck Reaction of Salicylaldehydes.
Angew. Chem. Int. Ed. 2012, 51, 8092. (d) Wang, H.; Xie, F.; Qi, Z.; Li, X. Iridium- and
Rhodium-Catalyzed C–H Activation and Formyl Alkynylation of Benzaldehydes under
Chelation-Assistance. Org. Lett. 2015, 17, 920. (e) Kuppusamy, R.; Gandeepan, P.; Cheng, C.-
H. Rh(III)-Catalyzed [4 + 1] Annulations of 2-Hydroxy- and 2-Aminobenzaldehydes with
Allenes: A Simple Method toward 3-Coumaranones and 3-Indolinones. Org. Lett. 2015, 17,
3846. (f) Nagamoto M.; Nishimura, T. Stereoselective Hydroacylation of Bicyclic Alkenes
with 2-Hydroxybenzaldehydes Catalyzed by Hydroxoiridium/Diene Complexes. Chem.
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