Synthesis of Chromeno[3,4-c]pyridines by Rhodium(III)-Catalyzed Annulation of Coumarinyl Ketoxime Esters and Alkynes

Article abstract of DOI:10.1016/j.tet.2019.07.002

An efficient, scalable synthetic method of chromeno[3,4-c]pyridine scaffolds through redox-neutral [4 + 2] annulation between coumarinyl ketoxime esters and internal alkynes has been developed using the rhodium(III) catalytic system. The present transform

Full text of DOI:10.1016/j.tet.2019.07.002

Accepted Manuscript
Synthesis of Chromeno[3,4-c]pyridines by Rhodium(III)-Catalyzed annulation of
coumarinyl ketoxime esters and alkynes
Jiang-Sheng Li, Xin-Yun Xie, Qian Yang, Pan-Pan Yang, Si Jiang, Zhi-Wei Li, Cui-
Hong Lu, Wei-Dong Liu
PII:
S0040-4020(19)30733-1
https://doi.org/10.1016/j.tet.2019.07.002
TET 30444
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 April 2019
Revised Date: 28 June 2019
Accepted Date: 2 July 2019
Please cite this article as: Li J-S, Xie X-Y, Yang Q, Yang P-P, Jiang S, Li Z-W, Lu C-H, Liu W-D,
Synthesis of Chromeno[3,4-c]pyridines by Rhodium(III)-Catalyzed annulation of coumarinyl ketoxime
esters and alkynes, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.07.002.
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Graphic Abstract
Title
Synthesis of Chromeno[3,4-c]pyridines by Rhodium(III)-Catalyzed Annulation of
Coumarinyl Ketoxime Esters and Alkynes
Authors
Jiang-Sheng Li,*a Xin-Yun Xie,†a Qian Yang,†a Pan-Pan Yang,a Si Jiang,a Zhi-Wei
Li,a Cui-Hong Lua and Wei-Dong Liub
* To whom correspondence should be addressed.
Email: jsli@csust.edu.cn (Dr. J.S. Li)
†X.Y. Xie & Q. Yang both contributed equally to this work.
Affiliations
a Hunan Provincial Key Laboratory of Materials Protection for Electric Power and
Transportation, School of Chemistry and Food Engineering, Changsha University of
Science & Technology, Changsha, 410114, China;
bNational Engineering Research Center for Agrochemicals, Hunan Research Institute
of Chemical Industry, Changsha 410007, China.
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Abstract
An efficient, scalable synthetic method of chromeno[3,4-c]pyridine scaffolds through
redox-neutral [4+2] annulation between coumarinyl ketoxime esters and internal
alkynes has been developed using the rhodium(III) catalytic system. The present
transformation proceeds under mild conditions, features good functional group
compatibility and obivates the use of external oxidants. Ready access to pyridine
derivatives bearing three carbon substituents is exemplified.
Keywords
Chromenopyridines; Coumarins; Oxime esters; Alkynes; Rhodium; C-H activation
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1. Introduction
The coumarin (2H-chromen-2-one) and pyridine cores constitute two families of
fundamental privileged heterocyclic scaffolds in a variety of naturally-occurring
products and bioactive compounds.1-4 As the fused derivatives from these two
fragments, chromeno[3,4-c]pyridin-5-ones have proven to be an emerging group of
tricyclic molecular hybrids found in the parent framework of several natural and
artificial bioactive molecules (Figure 1).5-14 These chromenopyridine derivatives have
exhibited a diverse array of biological activities (depressant, antiviral, antipsychotic,
antitumor and antimicrobial et al),5-9 photophysical properties,10,11 and the potential of
dopamine D4 receptor labeling agents.12,13 As such, elegant synthetic methods for the
preparation of this scaffold have been established, to date, to build up libraries of
chromenopyridines for the promising applicability in medicinal and material realms.
One traditional strategy lies upon the lactonization of 4-arylnicotinic acid derivatives
in the presence of polyphosphoric acid (PPA) or boron
Figure 1 Natural products and bioactive molecules incorporating chromeno[3,4-c]pyridine
nucleus
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tribromide.15-19 Another traditional one involves the multi-component condensation of
salicylaldehydes, cyanoacetates (or malononitrile), and ketones using ammonium
acetate as catalyst and nitrogen source, generally providing 4-amino chromeno[3,4-c]
pyridin-5-ones.20,21 Noteworthy, its variant can generate a chromenopyridinone
scaffold bearing three carbon-centered groups at the C1,2,4 positions of the pyridine
unit when salicylaldehydes and methyl 3-aminocrotonate were used instead.22 In
recent decade, the inverse electron demand Diels-Alder reaction has turned out to be a
powerful tool for the construction of the dihydro-derivatives, which readily undergo
further dehydrogenative aromatization to produce their saturated heterocycles.23-25 In
2014, Xiao’s group developed a tandem protocol for access to C4-functionalized
N-aryl chromeno[3,4-c]pyridine-5-ones using 4-alkynyl-3-formylcoumarins as a
novel building block.26 In 2016, Villemin and his co-workers disclosed an efficient
and practical procedure for the synthesis of 4-alkamino chromeno[3,4-c]pyridine-5
-ones through the reaction of 4-(2-dimethylamino)vinyl-3-cyanocoumarin with
primary alkylamines.27 In 2018, Chen et al. reported CuCl2-catalyzed tandem reaction
of the Blaise reaction intermediates and 3-cyanocoumarins to efficiently afford
4-amino-1,2-disubstituted chromeno[3,4-c]pyridine derivatives (Scheme 1, a).28 Later
on, Li et al. presented a redox-neutral rhodium(II)-catalyzed C-H carboxylation for
oxochromenopyridine derivatives from 2-pyridylphenols with CO2 in the presence of
phosphine ligand (Scheme 1, b).29 Despite the impressive achievements made to date,
the development of versatile and efficient methods for the assembly of the
chromeno[3,4-c]pyridine derivatives, especially bearing the carbon-centered
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functionalities at all three C-positions of a pyridine moiety, remains highly
challenging but desirable.
To date, aryl ketoxime derivatives serve as key precursors to enable versatile and
flexible access to isoquinoline/pyridine scaffolds through the directed aryl/vinyl sp2
C-H activation.30-38 As our continuing efforts to develop new methodologies to readily
access potentially bioactive heterocyclic compounds,39-45 herein, we present an
efficient synthetic method of highly substituted chromeno[3,4-c]pyridin-5-ones from
coumarinyl ketone O-acetyl oximes and internal alkynes utilizing the redox-neutral
rhodium(III) catalytic system without any external oxidants, wherein the oxime N-O
Scheme 1 Recent work and our contribution regarding the synthesis of the
chromeno[3,4-c]pyridin-5-one scaffold
Recent work
(a) Cu(II)-catalyzed tandem reaction of zinc reagent (Chen, 2018)
R1
R2O2C
N
1) Zn / BrCH2COOR2
R1CN
NH2
R3
2) 3-CN-coumarins, CuCl2
O
O
Excess zinc reagents in situ generated, and two steps required
(b) Rh(II)-catalyzed aryl C-H carboxylation with CO2 (Li, 2018)
N
[Rh(OAc)2]2 / MePhos
CO2 (1atm , closed)
N
O
R2
R2
R1
R1
t-BuOK, DMF, 100 oC
OH
O
Phosphine ligand and excess base required
This work
R4
OAc
N
R3
R4
N
R2
R2
R1
R3
R1
O
O
O
O
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section functions both as a directing group and as an internal oxidant to sustain the
catalytic rhodacycle (Scheme 1).
2. Results and discussion
Initially, we screened 3-acylcoumarinyl oxime, its methyl ether and acetyl ester as
the potential directing group using the combination of [Cp*RhCl2]2-NaOAc as the
catalytic system without any external oxidants. Pleasingly, it was found that its acetyl
ester 1a worked well with 1,2-diphenylethyne (2a) in methanol at 60 oC to deliver the
tricyclic chromeno[3,4-c]pyridine 3a in 80% yield (Table S-1, entry 1, in the
Supporting Information). Then we chose the reaction of 1a with 2a as a model
reaction to identify the cyclization conditions. The replacement of [Cp*RhCl2]2 with
[Ru(p-cymene)Cl2]2 or Cp*Co(CO)I2 failed to generate the tricyclic product 3a, with
all the starting materials recovered (Table 1, entry 2). The other acetates such as
KOAc and CsOAc gave as comparable efficiency as NaOAc, while the carbonate and
phosphate tested could hardly work (Table 1, entry 3 vs 4). The solvent effects were
investigated and the reaction efficacy was found to show a considerable dependence
on the medium environment. The use of EtOH as a solvent delivered a good yield of
70%, whereas the utilization of HFIP, with a smaller pKa value, lowered the yield to
30% (Table 1, entry 5). The polar aprotic DMF and DMSO were ineffective solvents
for such a transformation (Table 1, entry 6). Besides, the silver additives, reaction
temperatures and time were identified to impose limited impact on the reaction yields
(Table 1, entries 7-9). Notably, the reaction at the lower temperature of 50 oC resulted
in the formation of 3a in a comparable yield of 81% (Table 1, entry 1).
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Table 1 Parameters Optimization for the annulationa
aReaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [Cp*RhCl2]2 (2.5 mol%), NaOAc (30
mol%), MeOH (1.5 mL), sealed with stirring at 50 oC for 8 hours under Ar. b The yields are for the
isolated products. cThe reactions were performed at 60 oC. N.R. means no reaction.
Having established the optimal conditions, we turned to the investigation of the
generality and substrate scopes of oxime ester-directed annulation of coumarins 1
with alkynes 2 catalyzed by the Cp*Rh (III) system. Firstly, in the case of
1,2-diphenylethyne (2a), an array of 3-acylcoumarinyl oxime esters 1a-o were
subjected to this rhodium(III)-catalyzed C-H functionalization of coumarins. As is
depicted in Table 2, the present protocol proved applicable to various coumarins with
Me, OMe, and Br on the benzene moiety of the coumarin scaffold. Noteworthily, the
C-Br bond could survive this catalytic condition, thus offering a potential opportunity
for late-stage functionalization.46,47 The electron donating groups are preferable to the
electron withdrawing ones in the reaction yields (3b vs 3e). Furthermore, it was found
that the OMe group in the 7-position (3d) was unfavorable to the catalytic annulation.
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The R2 tethered to the C=N portion of the oxime esters 1 varied from methyl to a
bulkier fragment including Et, n-Pr, and Ph, leading to the decrease in the reaction
efficiency (3a, 3f-h). Prolonging the reaction time up to 16-20 h could help improve
Table 2 Scope with respect to the coumarinyl oxime estersa
Ph
OAc
N
O
Ph
Cp*Rh (2.5 mol%)
NaOAc (30 mol%)
N
Ph
R2
R1
R2
Ph
CH3OH, 50 oC
R1
O
O
O
1a-o
2a
3a-o
Ph
Ph
Ph
Ph
N
Ph
Ph
Ph
Ph
N
N
N
O
O
MeO
O
O
O
O
O
O
OMe
3a, 81% (79%)b
3c, 73%
3b, 92%
3d, 61%
Ph
N
Ph
N
Ph
Ph
Ph
Ph
Ph
N
Ph
N
Br
Ph
O
O
O
O
O
O
O
O
3h, 49%
3g, 69% (20 h)
3f, 63%
3e, 70%
Ph
Ph
Ph
N
Ph
N
Ph
N
O
Ph
N
Ph
Ph
Br
O
MeO
O
O
O
O
O
O
N
OMe
3i, 68%
3j, 53%
3k, 70% (16 h)
3l, 64%
Ph
Ph
Ph
Ph
Ph
N
Ph
N
Ph
Ph
N
Pr-n
Pr-n
Pr-n
O
O
MeO
O
O
O
O
O
O
OMe
3o, 59% (18 h)
3p, 0%c
3n, 67% (20 h)
3m, 85% (20 h)
aReaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), [Cp*RhCl2]2 (2.5 mol%), NaOAc (30 mol%),
o
MeOH (1.5 mL), sealed with stirring at 50 C for 8 hours unless otherwise stated under Ar. The
yield are for the isolated products. bIn 5-mmol scale. cUse of Z-1p as substrate.
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the yields of the cyclized products 3g, 3k, 3m-o. To our surprise, chromenopyridine
3h was obtained in 49% yield from an E/Z-isomeric mixture of 1h (E/Z = 1:4.9), and
the potential 3-(isoquinolin-1-yl)coumarin product resulted from oxime ester-directed
activation of the phenyl C-H bond was not observed , suggesting that in the case of 1h
the Z-conformer may isomerize to the E-conformer under the reaction conditions.
When R2 was an iso-propyl, the predominant Z-conformer of 1p was isolated, and
found to be an inert substrate for such a transformation.
Next, we set out to examine the alkynes 2. Generally, the use of internal alkynes
successfully enabled the C-H functionalization of coumarins 1 (Table 3). The
presence of an aryl group in alkynes 1 exerted constructive influence on the reaction
efficiency. Just like diphenylethyne (2a), other phenylacetyne 2c-d performed well to
form chromeno[3,4-c]pyridines 3 in good (total) yields (65%-82%), whereas the
alkynes bearing no aryl groups 2b and 2e gave their annulated products in low yields
(29%-36%), and even dimethyl but-2-ynedioate was reacted to access no cyclized
product, solely providing an alkenylated coumarinyl ketoxime 4 in 31% yield.
Increasing the loading of 2b to 3 equiv could enhance the yield of 3ab to 42%. It is
worth noting that the unsymmetrical alkynes led to the formation of chromenopridines
3 in a regioisomeric ratio of more than 4 (3ac + (3ac)′, 3bc + (3bc)′), and in the case
of the substrates 2d-e, only the major isomers were isolated by means of the
preparative thin-layer chromatography, 3ad of which were identified by X-ray
diffraction48 (Section 6, in the Supporting Information). This may be ascribed to the
substituent steric effects of internal alkynes.
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Table 3 Scope with respect to the alkynesa
R4
OAc
N
O
R3
R3
N
O
[Cp*RhCl2]2 (2.5 mol%)
NaOAc (30 mol%)
R1
R1
CH3OH, 50 oC
R4
O
O
3 (3')
2b-e
1a-c
O
OEt
N
N
N
N
O
MeO
O
O
O
O
O
O
O
3cb, 33%
3ae, 29%
3bb, 36%
3ab, 34%
Ph
N
Ph
N
Ph
Ph
N
N
O
+
+
O
O
O
O
O
O
O
(3ac)', 12%
3ac, 64%
3bc, 67%
(3bc)', 15%
O
OMe
O
Ph
O
OH
EtO
N
MeO
N
O
O
O
O
3ad, 65%
4, 31%
aReaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), [Cp*RhCl2]2 (2.5 mol%), NaOAc (30 mol%),
o
MeOH (1.5 mL), sealed with stirring at 50 C for 8 hours under Ar. The yield are for the isolated
products.
To demonstrate the applicability of this protocol in organic synthesis, we carried out
the rhodium(III)-catalyzed [4+2] annulation of coumarinyl ketoxime 1a with alkyne
2a in a 5 mmol scale, successfully affording the chromenopyridine 3a in 79% yield
(Table 2). Furthermore, the resulting products can be utilized for late-stage
functionalization via the conventional hydrolysis of the coumarin moiety, the
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reduction of the carbonyl group, and the directed C-H activation of the
2-phenylpyridine skeleton. Herein, fully substituted pyridines were derived simply
from chromenopyridine 3a in excellent yields through the hydrolysis under the solid
NaOH/DMSO system, followed by acidification or alkylation with alkyl bromide
(5a-c). Thus, this chemistry will provide a great potential for the synthesis of highly
substituted pyridine derivatives widely used in the pharmaceutical and material fields.
Scheme 2 Facile access to all-carbon substituted pyridines from chromenopyridines
To probe the mechanistic principles of this present transformation catalyzed by the
rhodium(III) catalytic system, a series of reactions were carried out including the
intermolecular competitive experiment and deuteration reactions (Section 4, in the
Supporting Information). When the oxime esters 1c (with a Me group) and 1d (with a
Br group) competed in the same reaction, the electron-rich substrate 1c was preferred
to the electron-deficient one 1d, affording their corresponding products 3c-d in the
yields of 54% and 6%, respectively. This difference can be rationalized by a concerted
base-assisted internal electrophilic substitution (IES)-type C-H activation
mechanism.49 When substrate 1a was reacted with or without alkyne in MeOD,
deuteration was observed at the C4 position of the deacetylated oxime 6a (18% D)
and the methyl group of the product 3a (n = 2.64, -CHnD3-n). These results could
imply that the ortho-C-H rhodation may occur in the initial reaction step, and an
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intermediate with a more acidic methyl group might exist in the catalytic annulation
process.
Based on our experimental observations and previous rhodium(III) catalytic
chemistry,50-54 a tentative mechanism was proposed for this 3,4-fused coumarin
formation (Scheme 3). First, ortho-C-H rhodation of coumarinyl oxime ester 1a takes
place with the chelating assistance of oxime ester sp2 nitrogen to generate
(2-oxo-2H-chromen-4-yl)rhodium intermediate A. Insertion of A to alkyne 2a
delivers rhodacyclic iminium cation species B, which then undergoes a concerted
redox process to generate chromenopyridine 3a, along with the regeneration of
rhodium(III) species.
Scheme 3 A proposed catalytic mechanism
OAc
OAc
[RhIII]
N
N
O
Ph
[RhIII]
- H+
Ph
2a
O
O
O
1a
A
Ph
Ph
[RhIII]
OAc
Ph
Ph
N
N
- [RhIII]OAc
O
3a
O
O
B
O
3. Conclusion
In summary, we have developed an efficient redox-neutral protocol for the
construction of chromeno[3,4-c]pyridine scaffolds through the [4+2] annulation of
coumarinyl ketoxime ester with internal alkynes catalyzed by the well-known Cp*Rh
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system. The present annulation proceeds under mild reaction conditions, featuring
good functional tolerance and easy scale-up. The late-stage functionalization of the
resulting chromeno[3,4-c]pyridines enables ready access to highly substituted
pyridine derivatives. This protocol will find its potential application in the synthesis
of fused azaheterocycles and polycarbon substutited pyridines with excellent
biological and physical properties.
4. Experimental section
4.1. General Information
All solvents and reagents were purchased from the suppliers and used without
further purification unless otherwise noted. The melting points (uncorrected) were
1
taken on an X4 Electrothermal Micromelting point meter. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded in solvents CDCl3 or DMSO-d6 at room
temperature on Bruker Avance III 400 spectrometer. The chemical-shift scale is based
on internal TMS. High-solution mass spectra were acquired on Waters UPLC/Xevo
G2 quadrupole time-of-flight tandem mass spectrometry (Xevo G2 Q-TOF).
4.2. Typical procedure for the synthesis of the oxime esters 1
Cyclization: A 50-mL round-bottom flask was charged with substituted
salicylaldehyde (5 mmol), 2-acyl acetate (7.5 mmol), piperidine (5 mol%) and ethanol
(20 mL), and then refluxed in an oil-bath for 5 hours (TLC monitoring). The reaction
mixture was poured into iced water, and filtered to afford 3-acyl coumarin as light
yellow solid.
Oximination: 3-Acyl coumarin (2 mmol), hydroxylamine hydrochloride (3 mmol),
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distilled water (0.26 mL), and ethanol (3.2 mL) were charged in a 25-mL
round-bottom flask, and stirred for 12 hours (TLC monitoring). After completion, the
resulting mixture was filtered and then washed with water to give its corresponding
oxime as white solid.
O-Acylation: Oxime (1.5 mmol) and acetic anhydride (1.65 mmol) were treated in
dichloromethane (5 mL) at room temperature for 12 hours (TLC monitoring). The
mixture was neutralized with aqueous saturated sodium carbonate till pH = 7, and
subjected to extraction, dryness, and concentration. Precursors 1 were obtained
through recrystallization of light yellow residues in a mixture of dichloromethane and
petroleum ether or flash chromatography.
4.2.1. (E)-3-(1-(acetoxyimino)ethyl)-2H-chromen-2-one (1a)
White solid, 298 mg, 81% yield, m.p. 132 – 133 oC. 1H NMR (400 MHz, CDCl3) δ
8.09 (s, 1H), 7.61 – 7.56 (m, 2H), 7.37 – 7.30 (m, 2H), 2.41 (s, 3H), 2.26 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 168.2, 161.8, 159.2, 154.3, 143.2, 132.0, 129.0, 124.9,
123.6, 118.5, 116.7, 19.6, 15.8. HRMS (ESI): Calcd for C13H12NO4 [M+H]+:
246.0766; Found: 246.0760.
4.2.2. (E)-3-(1-(acetoxyimino)ethyl)-6-methyl-2H-chromen-2-one (1b)
White solid, 354 mg, 91% yield, m.p. 160 – 163 oC. 1H NMR (400 MHz, CDCl3) δ
8.04 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 2.43 (s,
13
3H), 2.42 (s, 3H), 2.28 (s, 3H). C NMR (100 MHz, CDCl3) δ 168.2, 162.0, 159.4,
152.5, 143.2, 134.7, 134.0, 128.6, 123.4, 118.2, 116.4, 20.8, 19.6, 15.8. HRMS (ESI):
Calcd for C14H14NO4 [M+H]+: 260.0923; Found: 260.0922.
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4.2.3. (E)-3-(1-(acetoxyimino)ethyl)-7-methoxy-2H-chromen-2-one (1c)
White solid, 359 mg, yield 87%, m.p. 149 – 152 oC. 1H NMR (400 MHz, CDCl3) δ
8.05 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 3.90 (s,
13
3H), 2.40 (s, 3H), 2.25 (s, 3H). C NMR (100 MHz, CDCl3) δ 168.3, 163.9, 162.1,
159.5, 156.4, 143.4, 130.1, 119.7, 113.4, 112.2, 100.5, 55.9, 19.6, 15.8. HRMS (ESI):
Calcd for C14H14NO5 [M+H]+: 276.0872; Found: 276.0880.
4.2.4. (E)-3-(1-(acetoxyimino)ethyl)-8-methoxy-2H-chromen-2-one (1d)
White solid, 293 mg, 71% yield, m.p. 199 – 202 oC. 1H NMR (400 MHz, CDCl3) δ
8.06 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 3.98 (s, 3H), 2.41 (s,
13
3H), 2.26 (s, 3H). C NMR (100 MHz, CDCl3) δ 168.2, 161.9, 158.7, 147.1, 144.0,
143.4, 124.8, 123.8, 120.3, 119.1, 114.6, 56.3, 19.6, 15.8. HRMS (ESI): Calcd for
C14H14NO5 [M+H]+: 276.0872; Found: 276.0880.
4.2.5. (E)-3-(1-(acetoxyimino)ethyl)-6-bromo-2H-chromen-2-one (1e)
White solid, 447 mg, 92% yield, m.p. 218 – 220 oC. 1H NMR (400 MHz, CDCl3) δ
8.01 (s, 1H), 7.70 – 7.68 (m, 2H), 7.26 (d, J = 8.5 Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 168.0, 161.4, 158.5, 153.1, 141.7, 135.7, 131.1, 124.7,
120.0, 118.4, 117.5, 19.6, 15.7. HRMS (ESI): Calcd for C13H11BrNO4 [M+H]+:
323.9871; Found: 323.9875.
4.2.6. (E)-3-(1-(acetoxyimino)propyl)-2H-chromen-2-one (1f)
White solid, 331 mg, 85% yield, m.p. 130 – 131 oC. 1H NMR (400 MHz, CDCl3) δ
8.03 (s, 1H), 7.61 – 7.55 (m, 2H), 7.37 – 7.30 (m, 2H), 2.93 (q, J = 7.6 Hz, 2H), 2.26
(s, 3H), 1.17 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.2, 166.8, 159.2,
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154.3, 144.0, 132.9, 128.9, 124.9, 122.8, 118.5, 116.7, 22.4, 19.6, 10.5. HRMS
(ESI): Calcd for C14H14NO4 [M+H]+: 260.0923; Found: 260.0922.
4.2.7. (E)-3-(1-(acetoxyimino)butyl)-2H-chromen-2-one (1g)
o
1
White solid, 365 mg, 89% yield, m.p. 99 – 101 C. H NMR (400 MHz, CDCl3) δ
8.05 (s, 1H), 7.64 – 7.58 (m, 2H), 7.40 (m, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.28 (s, 3H),
13
1.61 (sext, J = 7.6 Hz, 2H), 1.00 (t, J = 7.6 Hz, 3H). C NMR (100 MHz, CDCl3) δ
168.3, 165.8, 159.2, 154.3, 143.9, 132.9, 128.9, 124.9, 123.0, 118.5, 116.7, 30.5, 19.7,
19.6, 14.1. HRMS (ESI): Calcd for C15H16NO4 [M+H]+: 274.1079; Found: 274.1073.
4.2.8. 3-((Acetoxyimino)(phenyl)methyl)-2H-chromen-2-one (1h)
E-/Z-isomeric mixture = 1: 4.9 (based on the 4-C-H). White solid, 396 mg, 86%
o
1
yield, m.p. 138 – 140 C. H NMR (400 MHz, CDCl3) δ 8.16 (s, 0.16H), 7.75 – 7.34
(m, 9.83H), 2.18 and 2.16 (2s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.4, 168.3,
161.0, 158.2, 157.4, 154.6, 154.2, 144.7, 143.3, 133.1, 132.7, 131.5, 130.9, 130.6,
129.0, 128.8, 128.7, 128.6, 128.4, 128.1, 125.0, 124.9, 123.5, 121.7, 118.5, 118.0,
117.0, 116.8, 19.7, 19.6. HRMS (ESI): Calcd for C18H14NO4 [M+H]+: 308.0923;
Found: 308.0920.
4.2.9. (E)-3-(1-(acetoxyimino)propyl)-6-methyl-2H-chromen-2-one (1i)
White solid, 365 mg, 89% yield, m.p. 100 – 102 oC. 1H NMR (400 MHz, CDCl3) δ
7.96 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 2.91 (q, J
= 7.6 Hz, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 168.3, 166.9, 159.4, 152.5, 144.0, 134.7, 134.0, 128.5, 122.6, 118.2,
116.3, 22.4, 20.7, 19.6, 10.5. HRMS (ESI): Calcd for C15H16NO4 [M+H]+: 274.1079;
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Found: 274.1073.
4.2.10. (E)-3-(1-(acetoxyimino)propyl)-8-methoxy-2H-chromen-2-one (1j)
White solid, 390 mg, 90% yield, m.p. 126 – 128 oC. 1H NMR (400 MHz, CDCl3) δ
8.02 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 3.99 (s, 3H), 2.94 (q, J
= 7.5 Hz, 2H), 2.26 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
168.2, 166.8, 158.6, 147.1, 144.1, 144.0, 124.8, 123.0, 120.1, 119.2, 114.6, 56.3, 22.3,
19.6, 10.5. HRMS (ESI): Calcd for C15H16NO5 [M+H]+: 290.1028; Found: 290.1024.
4.2.11. (E)-3-(1-(acetoxyimino)propyl)-7-methoxy-2H-chromen-2-one (1k)
White solid, 360 mg, 83% yield, m.p. 118 – 120 oC. 1H NMR (400 MHz, CDCl3) δ
7.99 (s, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.83 (s, 1H), 3.90 (s,
13
3H), 2.92 (q, J = 7.5 Hz, 2H), 2.25 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H). C NMR (100
MHz, CDCl3) δ 168.3, 167.1, 163.8, 159.5, 156.4, 144.1, 129.9, 119.0, 113.3, 112.2,
100.5, 55.9, 22.4, 19.6, 10.6. HRMS (ESI): Calcd for C15H16NO5 [M+H]+: 290.1028;
Found: 290.1024.
4.2.12. (E)-3-(1-(acetoxyimino)propyl)-6-bromo-2H-chromen-2-one (1l)
White solid, 416 mg, 82% yield, m.p. 158 – 160 oC. 1H NMR (400 MHz, CDCl3) δ
7.94 (s, 1H), 7.68 – 7.66 (m, 2H), 7.25 (d, J = 8.6 Hz, 1H), 2.91 (q, J = 7.5 Hz, 2H),
2.26 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.1, 166.3,
158.5, 153.1, 142.5, 135.6, 131.0, 124.0, 120.0, 118.4, 117.5, 22.4, 19.6, 10.5. HRMS
(ESI): Calcd for C14H13BrNO4 [M+H]+: 338.0028; Found: 338.0034.
4.2.13. (E)-3-(1-(acetoxyimino)butyl)-6-methyl-2H-chromen-2-one (1m)
o
1
White solid, 401 mg, 93% yield, m.p. 92 – 94 C. H NMR (400 MHz, CDCl3) δ
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7.97 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 2.92 (t, J
= 7.6 Hz, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.58 (sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.3, 165.8, 159.3, 152.4, 143.8, 134.7,
134.0, 128.5, 122.8, 118.2, 116.3, 30.5, 20.7, 19.6, 19.5, 14.0. HRMS (ESI): Calcd for
C16H18NO4 [M+H]+: 288.1236; Found: 288.1230.
4.2.14. (E)-3-(1-(acetoxyimino)butyl)-7-methoxy-2H-chromen-2-one (1n)
o
1
White solid, 368 mg, 81% yield, m.p. 83 – 85 C. H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.83 (s, 1H), 3.90 (s,
3H), 2.93 (t, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.59 (sext, J = 7.5 Hz, 2H), 0.97 (t, J = 7.6
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.4, 166.0, 163.8, 159.5, 156.4, 144.0,
129.9, 119.1, 113.3, 112.2, 100.5, 55.9, 30.5, 19.7, 19.6, 14.1. HRMS (ESI): Calcd for
C16H18NO5 [M+H]+: 304.1185; Found: 304.1191.
4.2.15. (E)-3-(1-(acetoxyimino)butyl)-8-methoxy-2H-chromen-2-one (1o)
White solid, 382 mg, 84% yield, m.p. 116 – 118 oC. 1H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.29 – 7.23 (m, 1H), 7.15 – 7.12 (m, 2H), 3.98 (s, 3H), 2.93 (t, J = 7.6
Hz, 2H), 2.25 (s, 3H), 1.57 (sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 168.3, 165.8, 158.6, 147.1, 144.04, 143.98, 124.8, 123.2, 120.1,
119.1, 114.6, 56.3, 30.4, 19.6, 19.5, 14.0. HRMS (ESI): Calcd for C16H18NO5 [M+H]+:
304.1185; Found: 304.1191.
4.3. Typical Procedure for the Synthesis of the Cyclization Products
To a 10-mL reaction tube was sequentially added 1a (0.3 mmol, 74 mg), 2a (0.36
mmol, 64 mg), [Cp*RhCl2]2 (2.5 mol%), NaOAc (30 mol%), and MeOH (1.5 mL).
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o
Then the tube was sealed and stirred at 50 C for 8 hours unless stated otherwise.
After the reaction completion, the reaction mixture was filtered over a short column of
silica, and purified by preparative thin-layer chromatography (petroleum ether/ethyl
acetate, 20/1, v/v) to give the tricyclic product 3a.
4.3.1. 4-Methyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3a)
1
White solid, 88 mg, 81% yield, m.p. 243 – 246 oC. H NMR (400 MHz, CDCl3) δ
7.37 – 7.28 (m, 5H), 7.19 (s, 5H), 7.12 (d, J = 6.4 Hz, 2H), 6.82 (d, J = 8 Hz, 1H),
13
6.75 (t, J = 7.4 Hz, 1H), 3.17 (s, 3H). C NMR (100 MHz, CDCl3) δ 162.8, 162.3,
160.1, 152.6, 141.8, 139.9, 138.3, 131.5, 130.8 (2C), 129.6 (2C), 129.4, 129.2 (2C),
128.8, 128.1, 127.9, 127.7 (2C), 123.3, 117.5, 117.3, 114.6, 27.5. HRMS (ESI): Calcd
for C25H18NO2 [M+H]+: 364.1338; Found: 364.1340.
4.3.2. 4,9-Dimethyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3b)
White solid, 104 mg, yield 92%, m.p. 233 – 236 oC. 1H NMR (400 MHz, CDCl3) δ
7.38 – 7.31 (m, 3H), 7.21 – 7.17 (m, 7H), 7.12 (d, J = 7.2 Hz, 2H), 6.48 (s, 1H), 3.17
(s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8, 162.0, 160.3, 150.7, 141.9,
139.9, 138.5, 132.5, 132.3, 130.8 (2C), 129.7 (2C), 129.4, 129.2, 129.1 (2C), 127.9,
127.9, 127.7 (2C), 117.0, 116.8, 114.7, 27.5, 20.9; HRMS (ESI): Calcd for
C26H20NO2 [M+H]+: 378.1494; Found: 378.1492.
4.3.3. 8-Methoxy-4-methyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one(3c)
1
White solid, 86 mg, 73% yield, m.p. 222 – 224 oC. H NMR (400 MHz, CDCl3) δ
7.32 – 7.31 (m, 3H), 7.18 (s, 5H), 7.12 (d, J = 4.8 Hz, 2H), 6.79 (s, 1H), 6.68 (d, J =
9.2 Hz, 1H), 6.33 (d, J = 9.2 Hz, 1H), 3.80 (s, 3H), 3.15 (s, 3H). 13C NMR (100 MHz,
19

ACCEPTED MANUSCRIPT
CDCl3) δ 162.8, 162.0, 160.3, 154.4, 142.1, 140.0, 138.5, 130.8 (2C), 129.9, 129.5
(2C), 129.2 (2C), 128.6, 128.0, 127. 8, 127.6 (2C), 113.5, 111.1, 110.2, 101.2, 55.6,
27.5. HRMS (ESI): Calcd for C26H20NO3 [M+H]+: 394.1443; Found: 394.1446.
4.3.4. 7-Methoxy-4-methyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one(3d)
1
White solid, 72 mg, 61% yield, m.p. 252 – 254 oC. H NMR (400 MHz, CDCl3) δ
7.35 – 7.28 (m, 3H), 7.19 (s, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H),
6.69 (t, J = 8.2 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.18 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 162.8, 162.3, 159.5, 147.6, 142.7, 142.0, 139.9, 138.4, 130.9
(2C), 129.6, 129.57 (2C), 129.1 (2C), 128.0, 127.8, 127.6 (2C), 122.6, 120.2, 118.1,
114.6, 113.1, 56.3, 27.5. HRMS (ESI): Calcd for C26H20NO3 [M+H]+: 394.1443;
Found: 394.1446.
4.3.5. 9-Bromo-4-methyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3e)
1
White solid, 93 mg, 70% yield, m.p. 239 – 241 oC. H NMR (400 MHz, CDCl3) δ
7.45 (d, J = 8.8 Hz, 1H), 7.42 – 7.36 (m, 3H), 7.22 – 7.11 (m, 8H), 6.81 (s, 1H), 3.18
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.0, 162.4, 159.5, 151.5, 140.6, 139.5,
137.6, 134.2, 131.8, 130.5 (2C), 129.6 (2C), 129.5 (2C), 128.5, 128.1, 127.7 (2C),
119.0, 119.0, 116.1, 114.4, 114.0, 27.5. HRMS (ESI): Calcd for C25H17BrNO2
[M+H]+: 422.0443; Found: 442.0448.
4.3.6. 4-Ethyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3f)
1
White solid, 71 mg, 63% yield, m.p. 236 – 238 oC. H NMR (400 MHz, CDCl3) δ
7.37 – 7.29 (m, 5H), 7.20 (s, 5H), 7.13 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.4 Hz, 1H),
6.75 (t, J = 7.6 Hz, 1H), 3.59 (q, J = 7.3 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR
20

ACCEPTED MANUSCRIPT
(100 MHz, CDCl3) δ 167.4, 162.2, 159.7, 152.6, 142.0, 140.0, 138.5, 131.4, 130.8
(2C), 129.7 (2C), 129.2 (2C), 129.16 (2C), 128.8, 128.1, 127.9, 127.8, 127.6 (2C),
123.2, 117.4, 114.0, 32.3, 13.5. HRMS (ESI): Calcd for C26H20NO2 [M+H]+:
378.1494; Found: 378.1496.
4.3.7. 1,2-Diphenyl-4-propyl-5H-chromeno[3,4-c]pyridin-5-one (3g)
1
White solid, 81 mg, 69% yield, m.p. 168 – 170 oC. H NMR (400 MHz, CDCl3) δ
7.36 – 7.28 (m, 5H), 7.19 (s, 5H), 7.12 (d, J = 6.4 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H),
6.74 (t, J = 7.6 Hz, 1H), 3.54 (t, J = 7.6 Hz, 2H), 1.90 (sext, J = 7.4 Hz, 2H), 1.11 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.4, 162.1, 159.7, 152. 6, 141.9,
140.0, 138.5, 131.4, 130.8 (2C), 129.7 (2C), 129.2 (2C), 129.2, 128.8, 128.1, 127.9,
127.6 (2C), 123.2, 117.4, 117.4, 114.1, 40.8, 22.8, 14.5. HRMS (ESI): Calcd for
C27H22NO2[M+H]+: 392.1651; Found: 392.1656.
4.3.8. 1,2,4-Triphenyl-5H-chromeno[3,4-c]pyridin-5-one (3h)55
o
o
1
White solid, 63 mg, 49% yield, m.p. 292 – 294 C (lit.20: 280 – 282 C). H NMR
(400 MHz, CDCl3) δ 7.68 (app s, 2H), 7.47 (app s, 3H), 7.40 – 7.31 (m, 5H), 7.27 (d,
J = 6.8 Hz, 2H), 7.21 – 7.16 (m, 5H), 6.86 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 162.4, 162.0, 159.3, 152.7, 142.5, 141.1, 139.6, 138.2,
131.6, 130.9 (2C), 130.0 (2C), 129.7, 129.4 (2C), 129.2 (2C), 128.9, 128.8, 128.3,
128.1, 128.0 (2C), 127.6 (2C), 123.3, 117.6, 117.4, 113.4. HRMS (ESI): Calcd for
C30H20NO2 [M+H]+: 426.1494; Found: 426.1494.
4.3.9. 4-Ethyl-9-methyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3i)
21

ACCEPTED MANUSCRIPT
1
White solid, 80 mg, 68% yield, m.p. 218 – 220 oC. H NMR (400 MHz, CDCl3) δ
7.38 – 7.31 (m, 3H), 7.26 – 7.12 (m, 9H), 6.48 (s, 1H), 3.58 (q, J = 7.3 Hz, 2H), 1.89
(s, 3H), 1.44 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.4, 161.9, 159.8,
150.6, 142.1, 140.0, 138.7, 132.4, 132.2, 130.8 (2C), 129.8 (2C), 129.3, 129.1 (2C),
127.9, 127.8, 127.6 (2C), 116.9, 116.8, 114.1, 32.3, 20.9, 13.5. HRMS (ESI): Calcd
for C27H22NO2 [M+H]+: 392.1651; Found: 392.1651.
4.3.10. 4-Ethyl-7-methoxy-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3j)
1
White solid, 65 mg, 53% yield, m.p. 263 – 265 oC. H NMR (400 MHz, CDCl3) δ
7.35 – 7.28 (m, 3H), 7.19 (s, 5H), 7.11 (d, J = 7.2 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H),
6.68 (t, J = 8.2 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.59 (q, J = 7.3 Hz,
2H), 1.44 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.4, 162.2, 159.1,
147.6, 142.6, 142.2, 140.0, 138.5, 130.9 (2C), 129.7 (2C), 129.4, 129.1 (2C), 128.0,
127.8, 127.6 (2C), 122.5, 120.2, 118.1, 114.0, 113.0, 56.3, 32.2, 13.5. HRMS (ESI):
Calcd for C27H22NO3 [M+H]+: 408.1600; Found: 408.1604.
4.3.11. 4-Ethyl-8-methoxy-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3k)
o
1
White solid, 86 mg, 70% yield, m.p. 246 – 249 C. H NMR (400 MHz, CDCl3) δ
7.32 – 7.31 (m, 3H), 7.19 (s, 5H), 7.12 (d, J = 6.8 Hz, 2H), 6.77 (s, 1H), 6.67 (d, J =
9.6 Hz, 1H), 6.31 (d, J = 9.2 Hz, 1H), 3.79 (s, 3H), 3.56 (q, J = 7.3 Hz, 2H), 1.43 (t, J
= 9.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.4, 161.9, 161.9, 159.9, 154.3,
142.3, 140.2, 138.7, 130.9 (2C), 129.89, 129.7 (2C), 129.2 (2C), 128.4, 128.0, 127.8,
127.6 (2C), 112.9, 111.0, 110.3, 101.1, 55.6, 32.3, 13.6. HRMS (ESI): Calcd for
C27H22NO3 [M+H]+: 408.1600; Found:408.1604.
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ACCEPTED MANUSCRIPT
4.3.12. 9-Bromo-4-ethyl-1,2-diphenyl-5H-chromeno[3,4-c]pyridin-5-one (3l)
White solid, 101 mg, 74% yield, m.p. 248 – 250 oC. 1H NMR (400 MHz, CDCl3) δ
7.45 – 7.37 (m, 4H), 7.26 – 7.16 (m, 6H), 7.12 (d, J = 7.2 Hz, 2H), 6.80 (s, 1H), 3.58
13
(q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.4 Hz, 3H). C NMR (100 MHz, CDCl3) δ 167.6,
162.3, 159.1, 151.4, 140.7, 139.7, 137.8, 134.1, 131.8, 130.5 (2C), 129.8 (2C), 129.5
(2C), 129.2, 128.5, 128.1, 127.7 (2C), 118.9, 118.9, 115.9, 113.8, 32.2, 13.4. HRMS
(ESI): Calcd for C26H19BrNO2 [M+H]+: 456.0599; Found: 456.0601.
4.3.13. 9-Methyl-1,2-diphenyl-4-propyl-5H-chromeno[3,4-c]pyridin-5-one (3m)
White solid, 103 mg, 85% yield, m.p. 189 – 192 oC. 1H NMR (400 MHz, CDCl3) δ
7.38 – 7.31 (m, 3H), 7.24 – 7.20 (m, 5H), 7.15 – 7.11 (m, 4H), 6.47 (s, 1H), 3.53 (t, J
13
= 7.8 Hz, 2H), 1.96 – 1.86 (m, 5H), 1.10 (t, J = 7.4 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 166.4, 161.8, 159.9, 150. 6, 142.1, 140.0, 138.7, 132.4, 132.2, 130.8 (2C),
129.8 (2C), 129.3, 129.2 (2C), 127.9, 127.9, 127.6 (2C), 116.9, 116.8, 114.2, 40.9,
22.8, 21.0, 14.5. HRMS (ESI): Calcd for C28H24NO2 [M+H]+: 406.1807; Found:
406.1810.
4.3.14. 8-Methoxy-1,2-diphenyl-4-propyl-5H-chromeno[3,4-c]pyridin-5-one (3n)
1
White solid, 85 mg, 67% yield, m.p. 196 – 198 oC. H NMR (400 MHz, CDCl3) δ
7.32 – 7.30 (m, 3H), 7.18 (s, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.76 (s, 1H), 6.67 (d, J =
9.2 Hz, 1H), 6.31 (d, J = 9.2 Hz, 1H), 3.78 (s, 3H), 3.51 (t, J = 7.6 Hz, 2H), 1.99 (sext,
J = 7.3 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.4, 161.9,
161.8, 159.9, 154.3, 142.3, 140.1, 138.6, 130.9 (2C), 129.9, 129.7 (2C), 129.2 (2C),
23

ACCEPTED MANUSCRIPT
128.4, 128.0, 127.8, 127.6 (2C), 113.0, 111.0, 110.3, 101.1, 55.6, 40.8, 22.9, 14.5.
HRMS (ESI): Calcd for C27H22NO2 [M+H]+: 392.1656; Found: 392.1651.
4.3.15. 7-Methoxy-1,2-diphenyl-4-propyl-5H-chromeno[3,4-c]pyridin-5-one (3o)
1
White solid, 76 mg, 60% yield, m.p. 208 – 210 oC. H NMR (400 MHz, CDCl3) δ
7.31 – 7.29 (m, 3H), 7.19 (s, 5H), 7.11 (d, J = 6.8 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H),
6.68 (t, J = 8.2 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.55 (t, J = 7.4, 2H),
13
1.95 – 1.86 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3) δ 166.4,
162.1, 159.1, 147.6, 142.6, 142.2, 140.1, 138.5, 130.9 (2C), 129.7 (2C), 129.3, 129.1
(2C), 128.0, 127.8, 127.6 (2C), 122.5, 120.2, 118.2, 114.1, 113.0, 56.3, 40.7, 22.8,
14.4. HRMS (ESI): Calcd for C28H24NO3 [M+H]+: 422.1756; Found: 422.1753.
4.3.16. 1,2-Diethyl-4-methyl-5H-chromeno[3,4-c]pyridin-5-one (3ab)
1
White solid, 27 mg, 34% yield, m.p. 138 – 140 oC. H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.30 – 7.23 (m, 2H), 3.07 (q, J = 7.3
13
Hz, 2H), 2.98 – 2.92 (m, 5H), 1.43 (t, J = 7.4 Hz, 3H), 1.29 (t, J = 7.6 Hz, 3H). C
NMR (100 MHz, CDCl3) δ 167.2, 160.9, 160.4, 152.2, 141.7, 131.3, 129.1, 127.8,
123.9, 117.9, 114.3, 28.9, 27.2, 23.1, 14.4, 14.1. HRMS (ESI): Calcd for C17H18NO2
[M+H]+: 268.1338; Found: 268.1335.
4.3.17. 1,2-Diethyl-4,9-dimethyl-5H-chromeno[3,4-c]pyridin-5-one (3bb)
1
White solid, 30 mg, 36% yield, m.p. 104 – 107 oC. H NMR (400 MHz, CDCl3) δ
7.95 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.14 (q, J = 7.2 Hz,
2H), 3.04 – 2.99 (m, 5H), 2.46 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 167.0, 160.9, 160. 6, 150.2, 141.8, 133.2, 132.1,
24

ACCEPTED MANUSCRIPT
129.0, 127.9, 117.5, 114.3, 28.9, 27.2, 23.1, 21.5, 14.4, 14.1. HRMS (ESI): Calcd for
C18H20NO2 [M+H]+: 282.1494; Found: 282.1496.
4.3.18. 1,2-Diethyl-8-methoxy-4-methyl-5H-chromeno[3,4-c]pyridin-5-one (3cb)
1
White solid, 29 mg, 33% yield, m.p. 155 – 157 oC. H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 9.2 Hz, 1H), 6.91 – 6.88 (m, 1H), 6.85 (t, J = 2.6 Hz, 1H), 3.92 (d, J = 1.6
Hz, 3H), 3.13 (q, J = 7.5 Hz, 2H), 3.04 – 2.99 (m, 5H), 1.49 (t, J = 7.4 Hz, 3H), 1.38
(t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.8, 161.7, 160.9, 160.5, 153.9,
142.0, 128.9, 128.2, 113.2, 111.7, 110.7, 101.5, 55.7, 28.9, 27.2, 23.0, 14.3, 14.1.
HRMS (ESI): Calcd for C18H20NO3 [M+H]+: 298.1443; Found: 298.1445.
4.3.19. 1-Ethyl-4-methyl-2-phenyl-5H-chromeno[3,4-c]pyridin-5-one (3ac)
o
1
White solid, 61 mg, 64% yield, m.p. 182 – 184 C. H NMR (400 MHz, CDCl3) δ
7.55 – 7.54 (m, 3H), 7.33 (t, J = 7.0 Hz, 1H), 7.27 – 7.26 (m, 3H), 6.78 – 6.73 (m, 2H),
3.12 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.4, 163.0, 160.2, 152.6, 140.8, 138.9, 131.3, 129.8 (2C), 129.5 (2C),
129.2, 128.6, 128.4, 123.3, 117.5, 117.3, 113.6, 29.9, 27.5, 13.8. HRMS (ESI): Calcd
for C21H18NO2 [M+H]+: 316.1338; Found: 316.1342.
4.3.20. 2-Ethyl-4-methyl-1-phenyl-5H-chromeno[3,4-c]pyridin-5-one ((3ac)′)
1
White solid, 11 mg, 12% yield, m.p. 167 – 169 oC. H NMR (400 MHz, CDCl3) δ
8.28 (d, J = 8.0 Hz, 1H), 7.58 – 7.49 (m, 6H), 7.41 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.8
13
Hz, 1H), 3.20 (q, J = 7.2 Hz, 2H), 3.08 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). C NMR
(100 MHz, CDCl3) δ 164.5, 160.7, 160.2, 152.3, 142.5, 140.9, 131.6, 130.1, 128.53
25

ACCEPTED MANUSCRIPT
(2C), 128.47 (2C), 128.4, 127.9, 124.1, 117.9, 117.8, 115.3, 27.3, 24.5, 14.1. HRMS
(ESI): Calcd for C21H18NO2 [M+H]+: 316.1338; Found: 316.1342.
4.3.21. 1-Ethyl-4,9-dimethyl-2-phenyl-5H-chromeno[3,4-c]pyridin-5-one (3bc)
1
White solid, 66 mg, 67% yield, m.p. 138 – 140 oC. H NMR (400 MHz, CDCl3) δ
7.55 (s, 3H), 7.26 (s, 2H), 7.14 (s, 2H), 6.43 (s, 1H), 3.12 (s, 3H), 2.66 (q, J = 7.5 Hz,
2H), 1.91 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1,
163.0, 160.4, 150.6, 140.9, 139.0, 132.5, 132.1, 129.7 (2C), 129. 6 (2C), 129.2, 129.1,
128.3, 117.0, 116.8, 113.7, 29.9, 27.6, 21.0, 13.8. HRMS (ESI): Calcd for C22H20NO2
[M+H]+: 330.1494; Found: 330.1494.
4.3.22. 2-Ethyl-4,9-dimethyl-1-phenyl-5H-chromeno[3,4-c]pyridin-5-one ((3bc)′)
1
White solid, 15 mg, 15% yield, m.p. 164 – 167 oC. H NMR (400 MHz, CDCl3) δ
8.11 (s, 1H), 7.55 – 7.52 (m, 5H), 7.40 (dd, J = 8.4, 1.2 Hz, 1H), 7.33 (d, J = 8.4 Hz,
1H), 3.25 (q, J = 7.3 Hz, 2H), 3.11 (s, 3H), 2.50 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 164.4, 160. 7, 160.4, 150.3, 142.7, 141.0, 133.4, 132.5,
130.0, 128.6, 128.5, 128.4, 128.0, 117.6, 117.4, 115.4, 27.3, 24.5, 21.4, 14.1. HRMS
(ESI): Calcd for C22H20NO2 [M+H]+: 330.1494; Found: 330.1494.
4.3.23. Ethyl 4-methyl-5-oxo-2-phenyl-5H-chromeno[3,4-c]pyridine-1-carboxylate
(3ad)
White solid, 70 mg, 65% yield, m.p. 120 – 122 oC. 1H NMR (400 MHz, DMSO-d6)
δ 7.77 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.54 (s, 5H), 7.48 (d, J = 8.4 Hz,
1H), 7.41 (t, J = 7.6 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.03 (t, J = 7.0 Hz,
3H). 13C NMR (100 MHz, DMSO-d6) δ 168.7, 163.7, 159.4, 158.9, 152.5, 140.0,
26

ACCEPTED MANUSCRIPT
138.8, 133.7, 129.8, 128.8 (2C), 128.76 (2C), 125.9, 125.1, 121.8, 118.2, 115.3, 114.5,
62.8, 27.6, 13.6. HRMS (ESI): Calcd for C22H18NO4 [M+H]+: 360.1236; Found:
360.1235.
4.3.24. Ethyl 1,4-dimethyl-5-oxo-5H-chromeno[3,4-c]pyridine-2-carboxylate (3ae)
o
1
White solid, 26 mg, 29% yield, m.p. 128 – 131 C. H NMR (400 MHz, CDCl3) δ
7.82 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.27 (d, J =
5.6 Hz, 1H), 4.52 (q, J = 6.9 Hz, 2H), 3.07 (s, 3H), 2.67 (s, 3H), 1.41 (t, J = 7.0 Hz,
13
3H). C NMR (100 MHz, CDCl3) δ 169.4, 164.6, 159.4, 159.2, 152.5, 139.8, 132.7,
125.7, 124.3, 121.9, 118.0, 115.5, 113.2, 62.6, 27.3, 23.3, 13.9. HRMS (ESI): Calcd
for C17H16NO4 [M+H]+: 298.1079; Found: 298.1084.
4.3.25. Dimethyl 2-(3-((E)-1-(hydroxyimino)ethyl)-2-oxo-2H-chromen-4-yl)maleate
(4)
The same procedure for compounds 3 was used. White solid, 32 mg, yield 31%. 1H
NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.69 (t, J = 7.8
Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 6.11 (s, 1H), 3.83 (s, 3H),
3.68 (s, 3H), 2.35 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.4, 162.7, 159.8,
158.9, 154.1, 153.2, 143.3, 133.6, 129.9, 125.4, 123.0, 118.7, 116.6, 107.2, 53.5, 52.2,
40.6, 40.4, 40.2, 40.0, 39.8, 39. 6, 39.4, 15.4. HRMS (ESI): Calcd for C17H16NO7
[M+H]+: 346.0927; Found: 346.0930.
4.4. Synthesis of Fully Substituted Pyridines 5 through Hydrolysis and
Subsequent Alkylation
4.4.1. 4-(2-Hydroxyphenyl)-2-methyl-5,6-diphenylnicotinic acid (5a)
27

ACCEPTED MANUSCRIPT
To a 10-mL vial was added 3a (0.1 mmol, 36 mg), solid sodium hydroxide (0.2
mmol, 8 mg) and DMSO (0.3 mL). The reaction system was stirred at room
temperature for 2 hours. And then hydrochloric acid (1 M) was added dropwise until
no more precipitate formed. The precipitate was collected and the filtrate was
extracted with ethyl acetate (20 mL × 3) followed by washing with saturated brine.
The combined crude product was subjected to purification to furnish 5a. White solid,
o
1
35 mg, 93% yield, m.p. 209 – 211 C. H NMR (400 MHz, DMSO-d6) δ 7.21 – 7.19
(m, 5H), 7.00 – 6.96 (m, 5H), 6.89 (d, J = 7.2 Hz, 2H), 6.61 (t, J = 7.2 Hz, 2H), 2.61
13
(s, 3H). C NMR (100 MHz, DMSO-d6) δ 169.6, 156.7, 154.7, 152.0, 145.4, 140.8,
138.0, 133.7, 130.9, 130.6, 130.1 (2C), 129.4, 127.9 (2C), 127.8, 126.9, 124.5, 118.3,
115.2, 23.0. HRMS (ESI): Calcd for C25H20NO3 [M+H]+: 382.1443; Found: 382.1444.
4.4.2. Ethyl 4-(2-ethoxyphenyl)-2-methyl-5,6-diphenylnicotinate (5b)
To a 10-mL vial was added 3a (0.1 mmol, 36 mg), solid sodium hydroxide (0.24
mmol, 10 mg) and DMSO (0.3 mL). The reaction system was stirred at room
temperature for 0.5 hour. And then to the reaction system was added bromoethane
(0.24 mmol, 26 mg), and stirred for additional 3 hours. Standard work-up furnished
5b. White solid, 36 mg, 82% yield, m.p. 154 – 156 oC. 1H NMR (400 MHz, CDCl3) δ
7.29 – 7.27 (m, 2H), 7.17 – 7.10 (m, 4H), 7.00 – 6.76 (m, 7H), 6.61 (d, J = 8.4 Hz,
1H), 4.00 (q, J = 6.9 Hz, 2H), 3.83 (quint, J = 7.5 Hz, 1H), 3.61 (quint, J = 7.5 Hz,
13
1H), 2.72 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H). C NMR (100
MHz, CDCl3) δ 168.5, 157.6, 155.5, 153.6, 145.9, 140.5, 137.6, 133.3, 130.7, 130.0
(2C), 129.2, 128.7, 127.6 (2C), 127.5, 127.0 (2C overlapped), 126.5, 126.4, 119.5,
28

ACCEPTED MANUSCRIPT
110.9, 63.3, 61.0, 23.2, 14.6, 13.6. HRMS (ESI): Calcd for C29H28NO3 [M+H]+:
438.2069; Found: 438.2065.
4.4.3. n-Butyl 4-(2-butoxyphenyl)-2-methyl-5,6-diphenylnicotinate (5c)
The procedure for 5b was applied except with 1-bromo-n-butane (0.24 mmol, 0.033
o
1
g) instead. White solid, 42 mg, 85% yield, m.p. 101 – 103 C. H NMR (400 MHz,
CDCl3) δ 7.27 (s, 2H), 7.16 – 7.09 (m, 4H), 7.00 – 6.74 (m, 7H), 6.61 (d, J = 8.4 Hz,
1H), 3.94 (t, J = 6.2 Hz, 2H), 3.73 (q, J = 7.6 Hz, 1H), 3.56 (q, J = 7.5 Hz, 1H), 2.71
(s, 3H), 1.62 – 1.55 (m, 2H), 1.30 – 1.26 (m, 4H), 1.20 – 1.11 (m, 2H), 0.86 (t, J = 7.2
Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 168.6, 157.5, 155.7,
153.5, 145.8, 140.5, 137.6, 133.3, 130.8 (2C overlapped), 130.5, 129.9 (2C), 129.2,
128.9, 127.6 (2C), 127.5, 127.0 (2C overlapped), 126.5, 126.4, 119.5, 111.0, 67.6,
64.9, 31.1, 30.3, 23.2, 19.2, 19.0, 13.8, 13.7. HRMS (ESI): Calcd for C33H36NO3
[M+H]+: 494.2695; Found: 494.2691.
Acknowledements
We would thank the Financial support from National Key R&D Program of China
(No. 2017YFB0307200), Hunan Provincial Natural Science Foundation of China (No.
2017JJ2275), the Scientific Research Fund of Hunan Provincial Education
Department (No. 16B003), Changsha Municipal Science and Technology Project
(kq1801053).
Supplemental data
Crystalographic data for 3ad (1902110) has been deposited at the Cambridge
Crystallographic Database Centre and can be found at http://www.ccdc.ac.uk.
29