Ruthenium-Catalyzed Oxidative Annulation and Hydroarylation of Chromene-3-carboxamides with Alkynes via Double C-H Functionalization

Article abstract of DOI:10.1021/acs.joc.7b00008

Ruthenium-catalyzed oxidative annulation of 2H-chromene-3-carboxamides with alkynes has been achieved by using the directing group nature of amide in the presence of Cu(OAc)₂·H₂O as an oxidant and AgNTf₂ as an additive. This reaction offers a broad substrate scope, and both symmetrical and unsymmetrical alkynes can be harnessed. High regioselectivity was achieved in the case of unsymmetrical alkynes. In addition, we have also accomplished double C-H activation by employing an excess of alkyne, where both annulation and hydroarylation took place regio- and stereoselectively in one pot, with the catalyst playing a dual role. While the first C-H functionalization could involve Ru-N covalent bond, the second C-H functionalization most likely involves Ru-O coordinate bond. The structures of key products are confirmed by X-ray crystallography.

Full text of DOI:10.1021/acs.joc.7b00008

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Article
Ruthenium-Catalyzed Oxidative Annulation and Hydroarylation of
Chromene-3-carboxamides with Alkynes via Double C-H Functionalization
R. N. Prasad Tulichala, Mallepalli Shankar, and K C Kumara Swamy
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 May 2017
Downloaded from http://pubs.acs.org on May 4, 2017
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Ruthenium-Catalyzed Oxidative Annulation and Hydroarylation of Chromene-3-
carboxamides with Alkynes via Double C-H Functionalization
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R. N. Prasad Tulichala, Mallepalli Shankar and K. C. Kumara Swamy*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, Telangana., India.
E-mail: kckssc@uohyd.ac.in; kckssc@yahoo.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Abstract
Ruthenium-catalyzed oxidative annulation of 2H-chromene-3-carboxamides with alkynes has
been achieved by using the directing group nature of amide in the presence of Cu(OAc)2.H2O as
an oxidant and AgNTf2 as an additive. This reaction offers a broad substrate scope, and both
symmetrical and unsymmetrical alkynes can be harnessed. High regioselectivity was achieved in
the case of unsymmetrical alkynes. In addition, we have also accomplished double C-H
activation by employing an excess of alkyne, where both annulation and hydroarylation took
place regio- and stereo-selectively in one pot, with the catalyst playing a dual role. While the first
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C-H functionalization could involve Ru-N covalent bond, the second C-H functionalization most
likely involves Ru-O coordinate bond. The structures of key products are confirmed by X-ray
crystallography.
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Introduction
Transition-metal-catalyzed organic reactions via C-H bond activation1 and
functionalization2 have been in the forefront of research in recent years. In particular, ruthenium-
catalyzed annulation reactions with alkynes via C(sp2)−H bond functionalization1d,2b,3 with
directing group assisted approach has emerged as an important tool for the construction of
heterocycles as synthetic targets. Functional groups that include imine, anilide, amide, ester,
heterocyclic, amine, carboxylic acid, ketone, and hydroxyl have been employed as directing
groups for transition metal-catalyzed direct C–H bond functionalization.4 The fundamental step
involved in these transformations is assumed to be the coordination of nitrogen and/or oxygen
atoms with the metal center that directs the metal to a specific proximal C-H bond thus
functionalizing the molecule. Among the myriad directing groups evaluated so far, amide has
shown distinct reactivity in transition metal-catalyzed C–H bond functionalizations and has
served as a crucial platform for the outcome of new transformations via C–H activation.5
Recently, the research groups of Satoh and Miura,5a Rovis,5b Guimond and Fagnou,5c,e and
Glorius5f established the Cp*Rh-catalyzed annulation of alkynes with various types of
benzamides. Later, the first use of less-expensive ruthenium catalysts6 for oxidative annulation
reaction of alkynes with benzamides was reported by Ackermann and coworkers3a,c followed by
the research groups of Li and Wang.3d,6a Huang and co-workers reported the palladium-ctalyzed7a
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while Chatani’s group reported the nickel-catalyzed7b annulation reactions of alkynes with
benzamides.
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C-H hydroarylation of alkynes is also a highly efficient route for the synthesis of alkenyl
arenes directly from simple arenes and alkynes.1,2a,e,8 However, such C-H functionalizations are
highly regioselective only when directed by amides, esters, ketones, pyridine and sulfoxide
groups. Subsequent to the pioneering work of Murai and co-workers,9 various transition-metal
catalysts such as Ru,10 Rh,11 Co12 and other metals13 have been developed for alkyne
hydroarylation via chelation-assisted C–H bond cleavage at the ortho position to a directing
group. The hydroarylation reactions of alkynes with a combination of ruthenium catalyst and
amide directing group has engrossed the recent interest in C-H functionalization reactions.10a-d,e
Benzopyran (chromene) ring system is an important structural component in natural
products with valuable and diverse biological properties.14-15 Naturally occurring benzopyran-
containing molecules (Figure 1; 1a-f) show antiproliferative activity against various carcinoma
cells,16 agonistic effect on the cannabinoid receptors, CB1 and CB2,17 inhibitory effect on cellular
glucose transport, phytotoxic properties and potent anti-HIV and anti-inflammatory
activities.18,19 The naturally occurring 5,7-dimethoxy-2-methyl-2H-chromene shows antifungal
activity and was isolated recently from Calyptranthes tricona. A large number of these
compounds have substituents at pyran-3,4-positions and hence developing methods, like that
using C-H functionalization, for substitution at these positions will be of tremendous synthetic
value.
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Figure 1. Examples for benzopyran (chromene) containing natural products (1a-f)
For achieving the above objective, we have chosen the benzopyran moiety with amide
directing group (DG, cf. structure 2a) at the 3-position. To our knowledge, C-H functionalization
at C(4)-H position on the benzopyran ring system has not been reported so far. Thus in
continuation of our studies on C-H activation/functionalization,3f,h,20 we report herein Ru-
catalyzed C-H functionalization followed by annulation of 2H-chromene-3-carboxamides with
unactivated alkynes that results in benzopyran fused 2-pyridones (pyrano[3,4-c]pyridones). It
should be noted that pyridones themselves are also pharmaceutically important.21-22 More
importantly, we have successfully achieved double C-H activation in the reaction of 2H-
chromene-3-carboxamides with an excess of alkyne, with the catalyst playing dual role. Here, in
an one-pot reaction, one alkyne moiety goes through oxidative annulation via C-H and N-H bond
cleavage, while the other alkyne undergoes regio- and stereo-selective hydroarylation at the
ortho position of aryl group attached to nitrogen atom involving amide-C=O directed C-H bond
cleavage. While the first C-H functionalization involves Ru-N covalent bond, the second one
requires Ru-O coordinate bond (cf. structures 2b-c).
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Results and Discussion
The precursors for the present work are chromenes (2H-chromene-3-carboxamides) with
amide functionality on the ring containing the hetero atom. For this purpose, 2H-chromene-3-
carboxylic acid was prepared in a two-step sequence from salicylaldehyde using Corey’s
procedure (Scheme 1).23 The N-substituted 2H-chromene-3-carboxamides 3 were synthesized via
the acid chloride obtained by treating the carboxylic acid with oxalyl chloride using a catalytic
amount of DMF.24a,b,c In the alternative procedure, the 2H-chromene-3-carboxylic acids were
converted to the corresponding N-substituted 2H-chromene-3-carboxamides 3 in a single step by
using EDC.HCl/DMAP.24d,e Amides 3a and 3e were prepared by the method A, while 3b-d and
3f could be prepared by the method B. The dialkyl or diaryl acetylenes 4a-l were prepared by
following a literature procedure.25
Scheme 1. Synthesis of 2H-Chromene-3-carboxamide Precursors
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We shall first discuss the formation of benzopyran-fused 2-pyridones by Ru-catalyzed
oxidative annulation of alkynes by using 2H-chromene-3-carboxamides that involves C-H
activation. Following this, we shall deliberate on the formation of double C-H activation
products via Ru-catalyzed annulation followed by hydroarylation.
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(i)
Ruthenium-Catalyzed Synthesis of Benzopyran-fused 2-Pyridones via C-H Bond
Functionalization
Our investigation began with the reaction of equimolar N-(4-methoxyphenyl)-2H-
chromene-3-carboxamide 3a with diphenylacetylene 4a in the presence of [RuCl2(p-cymene)]2
o
and Cu(OAc)2·H2O in tAmOH at 100 C. This reaction afforded the desired cyclization product
5aa in 50% yield (Table 1, entry 1). Other oxidants like Ag2CO3, AgOAc and CuCl2 did not
improve the yield (entries 2-4). Gratifyingly, additives like NaOAc and KPF6 improved the yield
of 5aa (entries 5-6). Subsequently, a series of other additives that include AgSbF6, AgBF4,
AgOTf and AgNTf2 were examined. Among these, AgNTf2 was the most effective for the
annulation (entries 7–10). In this case, we isolated 5aa in 88% yield.
In the absence of Cu(OAc)2·H2O, the desired product 5aa (entry 11) was not formed. In
the presence of Cu(OAc)2·H2O but without the Ru-catalyst also, the desired product was not
observed (entry 12). Thus both Ru-catalyst and Cu(OAc)2·H2O are required for the reaction.
Changing the solvent to tBuOH decreased the yield of 5aa to 69% (entry 13). Other solvents like
nBuOH, DCE, DMF and H2O did not improve the yield (entries 14–17). It is noteworthy that
under the same catalytic conditions in open air also the reaction afforded the product in 65%
yield (entry 18). Other Ru-catalysts like [CpRuCl(PPh3)2], [Ru(OAc)2(p-cymene)] and
[RuCl2(benzene)]2 were less effective than [RuCl2(p-cymene)]2 (entries 19–21). Thus, the
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combination of 5.0 mol % of [RuCl2(p-cymene)]2 as the catalyst, 2 equiv of Cu(OAc)2·H2O as
the oxidant and 30 mol % of AgNTf2 as additive in tAmOH solvent at 100 °C for 14 h (88%
yield; Table 1, entry 10) was found to be the optimum condition.
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Table 1: Optimization Study for the Ru-Catalyzed Oxidative Annulationa
Entry
1
Oxidant
Cu(OAc)2.H2O
Ag2CO3
Additive
-
Solvent
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tBuOH
Yield of
5aa (%)b
50
2
-
trace
trace
36
3
AgOAc
-
4
CuCl2
-
5
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
-
NaOAc
KPF6
AgSbF6
AgBF4
AgOTf
AgNTf2
AgNTf2
AgNTf2
AgNTf2
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6
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88
n.d.
n.d.c
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Cu(OAc)2.H2O
Cu(OAc)2.H2O
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Cu(OAc)2.H2O
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
nBuOH
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52
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
DCE
DMF
48
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H2O
26
tAmOH
tAmOH
tAmOH
tAmOH
65d
tracee
75f
58g
aReaction conditions: 2H-chromene-3-carboxamide 3a (0.5 mmol), alkyne 4a (0.5 mmol),
[RuCl2(p-cymene)]2 (5.0 mol %), oxidant (1.0 mmol), additive (30 mol %), solvent (2 mL), 100
oC (oil bath temperature) for 14 h. bIsolated yields. cNo catalyst was added. dIn open air. e5.0 mol
f
% of [CpRuCl(PPh3)2] catalyst was used. 10.0 mol % of [Ru(OAc)2(p-cymene)] catalyst was
used. g5.0 mol % of [RuCl2(benzene)]2 catalyst was used.
With the optimal catalytic system in hand, we moved on to investigate the scope by
employing various 2H-chromene-3-carboxamides and alkynes (Table 2). Satisfyingly, the
present reaction proved broadly applicable and good to excellent yields of benzopyran fused 2-
pyridones were obtained. The scope of alkynes was investigated first using N-(4-
methoxyphenyl)-2H-chromene-3-carboxamide 3a as the partner. These results indicated that
symmetrical diarylacetylenes with electron-donating or electron-withdrawing groups proceeded
well and afforded the benzopyran derivatives in excellent yields. The reaction of 3a with
heteroarylalkyne (3g) under the same catalytic conditions produced 5ag in good yield. Moreover,
dialkylacetylenes such as 3-hexyne (4h) and 1,4-dimethoxybut-2-yne (4i) reacted smoothly and
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furnished the corresponding 2-pyridone derivatives 5ah-5ai in good yield. To understand the
regioselectivity of the present reaction, unsymmetrical alkyne was employed as the substrate for
the reaction with 3a. Thus, 1-phenyl-1-butyne 4j gave product 5aj in 75% yield. Only one
isomer in which C-aryl carbon occurred adjacent to amide nitrogen was obtained in a highly
regioselective manner. The regiochemistry of the product 5aj was confirmed by X-ray
crystallography (Figure S1, Supporting Information). Similarly, we also isolated the product 5ak
in 78% yield in a regioselective manner by using 3a and 1-phenyl-1-propyne (4k). In the reaction
using the unsymmetrical alkyne 1-methoxy-4-(phenylethynyl)benzene (4l), we observed 1:1 ratio
of isomeric mixture of 5al in 83% overall yield (Table 2). We also evaluated the effect of
substituents on the nitrogen atom of amide in the reaction with diphenylacetylene. Amides
bearing N-aryl or N-alkyl substituents were effectively converted to the corresponding
benzopyran fused 2-pyridones (5ba-5fa) in excellent yields (81-90%). The structure of the
product 5ba was further confirmed by single crystal X-ray analysis (Figure S2, Supporting
Information). The annulation reaction also worked well in gram scale, and we isolated the
compound 5aa in 80% yield starting with 1.0 g of the precursor 3a. Three possible intermediates
are I-III. A possible mechanistic pathway based on the literature reports3b,3d,3f,3h,3i,26 is presented
in Scheme S1 (Supporting Information).
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Table 2. Substrate Scope for the Ruthenium-Catalyzed C-H Activation of 2H-Chromene-3-
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carboxamides (3a-f)a,b,c
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aReaction conditions: 2H-chromene-3-carboxamide 3a-f (0.5 mmol), alkyne 4a-l (0.5 mmol),
[RuCl2(p-cymene)]2 (5 mol %), Cu(OAc)2.H2O (1.0 mmol), AgNTf2 (30 mol %), t-AmOH (2
7
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9
o
b
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mL), 100 C (oil bath temperature) for 14 h. Isolated yield. Positional assignment (Me/Ph) in
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the case of 5ak is based on the structure of 5aj.
(ii)
Ruthenium-Catalyzed One-pot Double C-H Activation of 2H-Chromene-3-
carboxamides: Annulation Followed by Hydroarylation
In continuation of the above studies, when we treated the 2H-chromene-3-carboxamide
3a with 2.0 equiv of alkyne 4b, the double C-H activation product 6ab was isolated in 68% yield
(Scheme 2). This is important because here the activation must have come from the carbonyl
oxygen coordination to ruthenium rather than a Ru-N covalent bond formation observed in the
previous cyclization. Optimization studies revealed that best results could be obtained by using 8
mol % of [RuCl2(p-cymene)]2, Cu(OAc)2 H2O (2.0 equiv) and AgNTf2 (30 mol %), in t-AmOH
at 110 oC for 12 h (cf. Table 3).
Scheme 2. Ru-Catalyzed Double C-H Activation Reaction Using 2H-Chromene-3-
carboxamide 3a
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Table 3. Optimization Study for Ruthenium-Catalyzed Double C-H activationa
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6
7
8
Entry
Ru-
Alkyne 4b
(equiv)
T
Time
(h)
Yield of
catalyst
(oC)c
6ab (%)d
(mol %)b
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1
2
3
4
5
6
7
8
5
5
2.0
2.0
2.5
2.5
2.5
2.5
3.0
2.5
100
110
110
110
110
110
110
110
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12
10
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12
12
68
70
76
75
66
88
86
88
5
5
5
8
8
10
aReaction conditions: 2H-chromene-3-carboxamide 3a (0.5 mmol), alkyne 4b (1.0-1.5
mmol), [RuCl2(p-cymene)]2 (5.0-10 mol %), oxidant (1.0 mmol), additive (30 mol %),
solvent (2 mL) for 12-14 h. b[RuCl2(p-cymene)]2. cOil bath temperature. dIsolated yields.
Having the optimized reaction conditions in hand, the substrate scope was studied by
using differently substituted alkynes (Table 4). Diaryl alkynes bearing electron donating groups
as well as withdrawing groups reacted smoothly with chromene-3-carboxamide 3a and afforded
the double C-H activation products 6ab, 6ae and 6af (X-ray, Figure S3, Supporting Information)
in excellent yields (76-88%). This protocol was compatible with the presence of synthetically
important functional groups such as chloro and fluoro, producing the corresponding double C-H
activation products 6ac and 6ad in good yields. Moreover, dialkylacetylene such as 3-hexyne
(4h) was also converted to the corresponding double C-H activation product 6ah in good yield
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(78%). 3-Methyl substituted chromene-3-carboxamide (3c) underwent the C-H functionalization
with diphenyl acetylene (4a) exclusively at the less hindered position and produced the desired
product in good yields (6ba, 80%). The structure of compound 6ba was also confirmed by X-ray
crystallography (Figure S4, Supporting Information). Since there is a possibility of
regio/stereoisomerism in these hydroarylation products, we treated 5aa with the unsymmetrical
alkyne 4l, and 1-methyl-4-(phenylethynyl)benzene in separate experiments. As was the case with
symmetrical alkynes (vide infra), these reactions did not lead to the hydroarylation products.
Satisfyingly, though, the one pot reaction of 3a with two equivalents of unsymmetrical alkyne 4l
produced predominantly (>70%) hydroarylated product 6al, along with some of the cyclized
product 5al. Since the Rf values were too close, the separation was rather difficult. The NMR
data suggested the formation of at least three isomers in this case (see experimental and
Supporting Information).
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Table 4. Substrate Scope for the Ruthenium-Catalyzed Double C-H Activation of 2H-
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chromene-3-carboxamides (3a or 3c) with alkynes (4a-f and 4h)a,b
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aReaction conditions: 2H-chromene-3-carboxamide 3a or 3c (0.5 mmol), alkyne 4a-f and
4h (1.25 mmol), [RuCl2(p-cymene)]2 (8.0 mol %), Cu(OAc)2.H2O (1.0 mmol), AgNTf2
(30 mol %), t-AmOH (2 mL), 110 oC (oil bath temperature) for 12 h. bIsolated yields.
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Plausible pathway for the formation of double C-H activation products 6
Formation of double C-H activation products 6 involves annulation followed by
hydroarylation. To our knowledge, both of these in a single reaction sequence have not been
reported so far. On the basis of previous reports,3a,c,e,g,4b,6h,27b,28 a possible pathway for the
formation of double C-H activation products 6 via the annulated products of type 5 is shown in
Scheme 3. The active cationic ruthenium species I undergoes coordination to Ru via the C=O
oxygen atom followed by ortho metalation at phenyl ring of amide moiety with subsequent
elimination of AcOH providing the ruthenium complex IV. Migratory insertion of alkyne moiety
into the Ru-C bond furnishes ruthenium intermediate V. Finally, intermediate V undergoes
protonation in the presence of AcOH affording the regio- and stereo-selective formation of
double C-H activation products and regenerating the active ruthenium(II) catalyst. However, the
tandem annulation/hydroarylation reaction by taking the annulation product 5aa and alkyne 4a,
4j, 4k, or 4l) did not work under the conditions employed. Thus experimentally we did not
observe such a hydroarylation of 5aa in the tandem reaction. Hence it is possible that the
cyclization/hydroarylation products of type 6 are formed by a different pathway, without the
involvement of monocyclized products of type 5, like that from a doubly activated intermediate
like VI. The concomitant cyclization/hydroarylation reaction seems to be more facile in a one
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pot reaction than in the tandem reaction. Further studies on such hydroarylation in other systems
are needed to clarify these observations.
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Scheme 3. A Plausible Pathway for the Formation of Double C-H Activation Product (see
text also)
Conclusions
We have developed a new protocol of ruthenium-catalyzed oxidative annulation of chromene-3-
carboxamides with alkynes for the synthesis of a wide range of benzopyran fused 2-pyridones
via C-H activation. The reaction features high regioselectivity, good substrate scope, and large
functional group tolerance. High regioselectivity was achieved in the case of unsymmetrical
alkyne. More significantly, we have also discovered a one pot double C-H activation process,
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involving dual catalytic role for the Ru-complex, when an excess of alkyne is used. In these
reactions, one alkyne moiety undergoes annulation with chromene-3-carboxamides and the other
alkyne moiety is used up for hydroarylation regio- and stereo-selectively, involving amide- C=O
directed C-H bond functionalization.
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Experimental Section
1
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General Comments. H (400 MHz or 500 MHz), C (100 MHz or 125 MHz) and F NMR
spectra (376 MHz) were recorded in CDCl3 with shifts referenced to SiMe4 (1H, C: δ = 0) or
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CFCl3 (δ = 0). IR spectra were recorded on an FTIR spectrophotometer. Melting points were
determined by using a local hot-stage melting point apparatus and are uncorrected. Elemental
analyses were carried out on a CHN analyzer. Mass spectra were recorded using LC-MS and
HRMS (ESI-TOF analyser) equipment. For column chromatography, silica gel of 100-200 mesh
size was used.
(i)
Synthesis of 2H-Chromene-3-carboxamides (3a-f): General Procedure
Method A: To a stirred solution of 2H-chromene-3-carboxylic acid (1.0 equiv) in DCM (50 mL
o
per 6.8 mmol of precursor carboxylic acid) at 0 C, oxalyl chloride (2.0 equiv, 13.6 mmol) was
added dropwise slowly over a period of 10 min and then catalytic amount (10 drops) of DMF
was added. The reaction mixture was kept at 0 oC for 30 min and then at rt (25 oC) overnight till
complete consumption of the starting material. The solvent was removed by using rotary
evaporator. The residue was dissolved in dry toluene (40 mL per 6.8 mmol of precursor
carboxylic acid) and DMAP (2.0 equiv) at rt (25 oC). Alkyl or aryl amine (1.2 equiv) was added
after 10 min to this solution and the mixture kept at rt (25 oC) for 2-3 h. After the completion of
the reaction (TLC), the solvent was removed using rotary evaporator and then water (2 x 10 mL
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per 6.8 mmol of precursor carboxylic acid) was added. The mixture was extracted with ethyl
acetate (2 x 30 mL per 6.8 mmol of precursor carboxylic acid), washed with brine (2 x 10 mL
per 6.8 mmol of precursor carboxylic acid), dried over Na2SO4, and filtered. The solvent was
removed and the crude product was purified by column chromatography by using silica gel with
ethyl acetate/hexane mixture (ratio ca 1:9) as the eluent to afford the corresponding 2H-
chromene-3-carboxamides. Amides 3a and 3e were prepared by this method. Amide 3e is known
but 3a is new.
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Method B: To a stirred solution of 2H-chromene-3-carboxylic acid (1.0 equiv) in DCM (50 mL
per 6.8 mmol of precursor carboxylic acid) at 0 oC, EDC.HCl (1.2 equiv) and DMAP (2.0 equiv)
were added. Alkyl or aryl amine (1.2 equiv) was added after 10 min to this solution and the
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mixture was kept at 0 C for 1 h and then at rt (25 C) for 2-3 h. After the completion of the
reaction (TLC), the solvent was removed using rotary evaporator and then water (2 x 10 mL per
6.8 mmol of precursor carboxylic acid) was added. The mixture was extracted with ethyl acetate
(2 x 30 mL per 6.8 mmol of precursor carboxylic acid), washed with brine (2 x 10 mL per 6.8
mmol of precursor carboxylic acid), dried over Na2SO4, and filtered. The solvent was removed
and the crude product was purified by column chromatography by using silica gel with ethyl
acetate/hexane mixture (ratio ca 1:9) as the eluent to afford the corresponding 2H-chromene-3-
carboxamides. Amides 3b-d and 3f were prepared by this method and they are new.
N-(4-methoxyphenyl)-2H-chromene-3-carboxamide (3a): Yield: 1.65 g (86 %) as pale yellow
o
solid; mp: 145–147 C; Rf = 0.52 (9:1 hexane/ethyl acetate); IR (KBr) 3370, 3215, 3035, 2957,
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2828, 1656, 1623, 1538, 1511, 1287, 1251, 1205, 1034, 827, 761 cm-1; H NMR (500 MHz,
CDCl3) δ 7.55 (s, 1H), 7.50-7.47 (m, 2H), 7.27-7.24 (m, 1H), 7.14 (dd, J = 7.5 Hz and J = 1.5
Hz, 1H), 7.09 (s, 1H), 6.97-6.94 (m, 1H), 6.92-6.89 (m, 3H), 5.09 (d, J = 1.0 Hz, 2H), 3.82 (s,
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3H); 13C NMR (125 MHz, CDCl3) δ 163.5, 156.7, 154.9, 131.5, 130.6, 128.4, 127.5, 127.2,
122.4, 121.8, 120.9, 116.2, 114.3, 64.9, 55.5. LC-MS: m/z 282 [M+1]+. Anal. Calcd. For
C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.43; H, 5.45; N, 4.89.
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N-(p-tolyl)-2H-chromene-3-carboxamide (3b): Yield: 1.50 g (83 %) as white solid; mp: 152–154
oC; Rf = 0.48 (9:1 hexane/ethyl acetate); IR (KBr) 3259, 2970, 2843, 1647, 1599, 1538, 1513,
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1407, 1252, 1211, 820, 746 cm-1; H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.46 (d, J = 8.5
Hz, 2H), 7.24-7.21 (m, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.06 (s, 1H), 7.02 (dd, J = 7.5 Hz and J =
2.0 Hz, 1H), 6.93-6.89 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.03 (d, J = 1.5 Hz, 2H), 2.32 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 163.6, 154.8, 134.9, 134.4, 131.4, 129.5, 128.4, 127.7, 127.0,
121.8, 120.9, 120.6, 116.1, 64.8, 20.9. LC-MS: m/z 266 [M+1]+. Anal. Calcd. For C17H15NO2: C,
76.96; H, 5.70; N, 5.28. Found: C, 76.85; H, 5.78; N, 5.23.
N-(m-tolyl)-2H-chromene-3-carboxamide (3c): Yield: 1.40 g (78 %) as brown solid; mp: 143–
o
145 C; Rf = 0.50 (9:1 hexane/ethyl acetate); IR (KBr) 3267, 3040, 2828, 1604, 1641, 1538,
1457, 1320, 1299, 1221, 1015 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.43 (s, 1H), 7.37
(d, J = 8.5 Hz, 1H), 7.28-7.19 (m, 2H), 7.07-7.04 (m, 2H), 6.96-6.86 (m, 3H), 5.04 (s, 2H), 2.32
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(s, 3H); C NMR (100 MHz, CDCl3) δ 163.6, 154.8, 139.0, 137.4, 131.5, 128.9, 128.5, 127.7,
127.1, 125.5 121.8, 121.1, 120.9, 117.5, 116.1, 64.8, 21.5. LC-MS: m/z 266 [M+1]+. Anal. Calcd.
For C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.85; H, 5.76; N, 5.23.
N-isopropyl-2H-chromene-3-carboxamide (3d): Yield: 1.27 g (86 %) as white solid; mp: 108–
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110 C; Rf = 0.69 (9:1 hexane/ethyl acetate); IR (KBr) 3264, 3070, 2968, 2828, 1650, 1602,
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1547, 1460, 1352, 1292, 1208, 1020, 755 cm-1; H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.6
Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.89 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H),
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6.04 (s, 1H), 5.0 (s, 2H), 4.20-4.16 (m, 1H), 1.22 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 164.5, 154.7, 131.1, 128.2, 127.2, 126.6, 121.7, 121.1, 116.0, 64.9, 41.6, 22.7. LC-MS:
m/z 218 [M+1]+. Anal. Calcd. For C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.69; H,
6.91; N, 6.54.
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N-cyclohexyl-2H-chromene-3-carboxamide (3f): Yield: 1.31 g (75 %) as white solid; mp: 136–
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138 C; Rf = 0.67 (9:1 hexane/ethyl acetate); IR (KBr) 3320, 2936, 2853, 1652, 1614, 1529,
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1486, 1452, 1325, 1201, 896, 757 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.19 (m, 1H), 7.10
(dd, J = 7.6 Hz and J = 1.6 Hz, 1H), 6.95-6.91 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 5.70 (d, J = 7.2
Hz, 1H), 5.01 (d, J = 1.6 Hz, 2H), 3.93-3.84 (m, 1H), 2.02-1.98 (m, 2H), 1.79-1.65 (m, 3H),
1.48-1.37 (m, 2H), 1.26-1.15 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3, 159.1, 154.8, 131.2,
128.2, 126.4, 121.8, 121.1, 116.1, 65.1, 48.4, 33.3, 25.6, 25.4, 25.0, 24.8. LC-MS: m/z 258
[M+1]+. Anal. Calcd. For C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.52; H, 7.38; N,
5.49.
(ii)
Procedure
Into a 10 mL round-bottomed flask, 2H-chromene-3-carboxamide (one of 3a-f, 0.5
Synthesis of Benzopyran fused 2-Pyridone Derivatives 5aa-5al and 5ba-5fa: General
mmol), diaryl or dialkyl acetylene (one of 4a-l, 0.5 mmol), [RuCl2(p-cymene)]2 (5 mol %),
Cu(OAc)2.H2O (1.0 mmol) and AgNTf2 (30 mol %) were added under N2 atmosphere. To this,
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tAmOH (2 mL) was added and the mixture stirred at 100 C (oil bath temperature) for 14 h.
After cooling to rt, saturated NH4Cl solution (50 mL) was added and the contents extracted with
EtOAc (3 x 30 mL). The combined organic phase was washed with brine solution (2 x 25 mL),
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dried over anhy. Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using n-hexane-EtOAc (4:1) mixture as the eluent.
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3-(4-methoxyphenyl)-1,2-diphenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5aa): This compound
was prepared by using precursors 3a and 4a. Yield: 0.201 g (88%) as pale yellow solid; mp:
228–230 oC; Rf = 0.28 (4:1 hexane/ethyl acetate); IR (KBr) 3055, 2828, 1650, 1511, 1490, 1438,
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1242, 1025, 839, 798, 762, 694 cm-1; H NMR (400 MHz, CDCl3) δ 7.15 (~t, J = 7.0 Hz, 2H),
7.10-7.09 (m, 2H), 7.03-6.92 (m, 8H), 6.83-6.82 (m, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.52 (t, J =
7.6 Hz, 1H), 6.45 (~d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
160.1, 158.7, 157.5, 147.4, 139.7, 137.4, 134.4, 131.5, 130.8, 130.7, 129.9, 128.9, 128.1, 127.5,
127.3, 126.9, 122.4, 121.4, 120.9, 117.7, 117.5, 114.0, 64.1, 55.3; HRMS (ESI) m/z: [M+H]+
Calcd. for C31H24NO3 458.1756; Found 458.1756.
1,2,3-tris(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one (5ab): Precursors 3a and 4b
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were used. Yield: 0.238 g (92%) as pale yellow solid; mp: 215–217 C; Rf = 0.20 (4:1
hexane/ethyl acetate); IR (KBr) 3008, 2838, 1644, 1605, 1501, 1293, 1244, 1184, 1041, 838, 756
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cm-1; H NMR (400 MHz, CDCl3) δ 7.18-7.14 (m, 1H), 7.03-7.01 (m, 1H), 6.97 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 8.8 Hz, 2H), 6.76-6.71 (m, 4H), 6.66 (d, J = 8.8 Hz, 2H), 6.59-6.55 (m, 1H),
6.52-6.50 (m, 1H), 6.47 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.64 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.1, 158.6, 158.3, 157.5, 147.5, 139.9, 132.5, 131.9, 131.8,
130.6, 129.9, 129.8, 128.8, 126.9, 122.3, 121.7, 120.9, 117.6, 117.5, 114.1, 113.6, 112.7, 64.2,
55.3, 55.1, 55.0; HRMS (ESI) m/z: [M+H]+ Calcd. for C33H28NO5 518.1967; Found 518.1965.
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1,2-bis(4-chlorophenyl)-3-(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ac):
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= 0.36 (4:1 hexane/ethyl acetate); IR (KBr) 2932, 2833, 2362, 1644, 1595, 1512, 1485, 1392,
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Hz, 2H), 7.04 (dd, J = 1.2 Hz and J = 8.0 Hz, 1H), 6.98-6.94 (m, 4H), 6.89 (d, J = 8.4 Hz, 2H),
6.78-6.75 (m, 4H), 6.62-6.58 (m, 1H), 6.44 (dd, J = 1.6 Hz and J = 8.0 Hz, 1H), 5.17 (s, 2H),
3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 157.5, 146.3, 139.5, 135.8, 133.9, 133.3,
132.8, 132.7, 131.9, 131.2, 131.1, 129.9, 128.6, 127.9, 123.1, 121.10, 121.08, 117.8, 116.6, 114.3,
64.1, 55.4; HRMS (ESI) m/z: [M+H]+ Calcd. for C32H22Cl2NO3 526.0976; Found 526.0973.
1,2-bis(4-fluorophenyl)-3-(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ad):
Precursors 3a and 4d were used. Yield: 0.205g (83%) as pale brown solid; mp: 276–278 oC; Rf =
0.31 (4:1 hexane/ethyl acetate); IR (KBr) 3052, 2997, 2959, 2833, 1644, 1595, 1496, 1299, 1238,
1211, 1156, 1008, 767 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.21-7.16 (m, 1H), 7.04 (dd, J = 8.2
Hz and J = 0.6 Hz, 1H), 6.97-6.91 (m, 4H), 6.85-6.75 (m, 6H), 6.67 (t, J = 8.6 Hz, 2H), 6.61-
6.56 (m, 1H), 6.45 (dd, J = 8.0 Hz and J = 1.2 Hz, 1H), 5.18 (s, 2H), 3.74 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.7 (d, J = 246.0 Hz), 161.6 (d, J = 247.0 Hz), 160.0, 158.9, 157.5, 146.7,
139.6, 133.3 (d, J = 3.0 Hz), 133.1 (d, J = 8.0 Hz), 131.4, 131.0, 132.5 (d, J = 8.0 Hz), 130.4 (d,
J = 3.0 Hz), 129.9, 128.6, 122.9, 121.2, 121.0, 117.7, 116.9, 115.4 (d, J = 21.0 Hz), 114.7 (d, J =
22.0 Hz), 114.2, 64.1, 55.4; 19F NMR (376 MHz; proton coupled; CDCl3): δ -112.5, -114.4;
HRMS (ESI) m/z: [M+H]+ Calcd. for C31H22F2NO3 494.1567; Found 494.1563.
3-(4-methoxyphenyl)-1,2-bis(4-(trifluoromethyl)phenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ae): Precursors 3a and 4e were used. Yield: 0.232 g (78%) as brown solid; mp: 241–243 oC; Rf
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= 0.27 (4:1 hexane/ethyl acetate); IR (KBr) 3008, 2953, 2844, 2367, 1644, 1512, 1321, 1249,
1162, 1134, 1068, 1014, 855, 773 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 2H),
7.25 (d, J = 8.4 Hz, 2H), 7.22-7.17 (m, 1H), 7.11-7.04 (m, 3H), 6.97 (d, J = 8.8 Hz, 4H), 6.76 (d,
J = 9.2 Hz, 2H), 6.58-6.54 (m, 1H), 6.34 (dd, J = 1.6 Hz and J = 8.0 Hz, 1H), 5.19 (s, 2H), 3.73
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(s, 3H); C NMR (100 MHz, CDCl3) δ 159.9, 159.2, 157.6, 146.1, 141.0, 139.4, 137.7, 131.9,
131.3, 131.1, 130.9, 129.9, 129.4, 128.5, 125.2 (qrt, J = 3.7 Hz), 124.6 (qrt, J = 3.7 Hz), 123.6,
123.7 and 123.3 (two qrt, J ~ 272.0 Hz), 121.1, 120.8, 117.9, 116.4, 114.4, 64.0, 55.4; 19F NMR
(376 MHz; proton coupled; CDCl3): δ -62.7, -63.0; HRMS (ESI) m/z: [M+H]+ Calcd. for
C34H22F6NO3 594.1504; Found 594.1508.
1,2-bis(3,5-dimethylphenyl)-3-(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one (5af):
Precursors 3a and 4f were used. Yield: 0.232g (90%) as pale yellow solid; mp: 216–218 oC; Rf =
0.30 (4:1 hexane/ethyl acetate); IR (KBr) 3057, 2997, 2915, 2838, 1649, 1605, 1512, 1463, 1249,
1030, 822, 844, 750 cm-1; H NMR (400 MHz, CDCl3) δ 7.18-7.14 (m, 1H), 7.03-6.97 (m, 3H),
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6.75-6.71 (m, 3H), 6.60-6.53 (m, 5H), 6.44 (s, 2H), 5.19 (s, 2H), 3.72 (s, 3H), 2.10 (s, 6H), 2.01
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 160.1, 158.7, 157.4, 147.7, 139.7, 137.12, 137.09, 136.3,
134.1, 131.8, 130.7, 129.9, 129.3, 129.1, 128.8, 128.6, 128.3, 121.7, 121.6, 120.8, 117.9, 117.4,
113.8, 64.1, 55.4, 21.1, 21.0; HRMS (ESI) m/z: [M+H]+ Calcd. for C36H32NO3 514.2382; Found
514.2385.
3-(4-methoxyphenyl)-1,2-di(thiophen-2-yl)-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ag):
Precursors 3a and 4g were used. Yield: 0.195 g (83%) as pale yellow solid; mp: 256–258 oC; Rf
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= 0.36 (4:1 hexane/ethyl acetate); IR (KBr) 3074, 2833, 1496, 1436, 1249, 1162, 1123, 1019,
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838, 756, 701 cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.20 (m, 2H), 7.12 (d, J = 4.5 Hz, 1H),
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7.05 (t, J = 9.5 Hz, 3H), 6.86-6.85 (m, 1H), 6.81 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 3.0 Hz, 1H),
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6.70-6.64 (m, 3H), 6.61 (d, J = 3.0 Hz, 1H), 5.17 (s, 2H), 3.77 (s, 3H); C NMR (125 MHz,
CDCl3): δ 160.0, 159.1, 157.4, 142.4, 140.0, 138.6, 134.3, 131.4, 131.2, 131.1, 129.9, 129.7,
128.1, 128.0, 127.0, 126.8, 125.8, 123.4, 121.2, 121.1, 117.5, 114.1, 112.4, 64.0, 55.4; HRMS
(ESI) m/z: [M+H]+ Calcd. for C28H20NO3S2 470.0884; Found 470.0887.
1,2-diethyl-3-(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one (5ah): Precursors 3a
o
and 4h were used. Yield: 0.138g (76%) as pale yellow solid; mp: 198–200 C; Rf = 0.32 (4:1
hexane/ethyl acetate); IR (KBr) 2975, 2844, 2362, 1879, 1638, 1501, 1457, 1293, 1249, 1025,
767 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 1.3 Hz and J = 9.8 Hz, 1H), 7.37-7.33 (m,
1H), 7.18 (d, J = 11.0 Hz, 2H), 7.12-7.08 (m, 2H), 7.04 (d, J = 11.0 Hz, 2H), 5.00 (s, 2H), 3.88
(s, 3H), 2.79 (qrt, J = 9.3 Hz, 2H), 2.54 (qrt, J = 9.3 Hz, 2H), 1.34 (t, J = 9.3 Hz, 3H), 1.00 (t, J =
9.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 160.4, 159.5, 157.9, 148.7, 141.1, 131.5, 130.8,
129.4, 127.4, 122.5, 121.8, 121.6, 118.1, 115.6, 114.8, 55.6, 23.3, 21.6, 15.9, 13.7; HRMS (ESI)
m/z: [M+H]+ Calcd. for C24H24NO3 362.1756; Found 362.1759.
1,2-bis(methoxymethyl)-3-(4-methoxyphenyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ai):
Precursors 3a and 4i were used. Yield: 0.153 g (78%) as gummy liquid; Rf = 0.29 (4:1
hexane/ethyl acetate); IR (neat) 2921, 2833, 1721, 1644, 1605, 1518, 1463, 1397, 1299, 1244,
1085, 942, 762 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz,
1H), 7.22 (d, J = 8.4 Hz, 2H), 7.16-7.10 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 4.36 (s,
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2H), 4.12 (s, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 3.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3,
159.8, 157.5, 146.1, 141.6, 131.4, 129.6, 127.6, 123.7, 122.2, 121.8, 121.6, 117.9, 114.5, 112.4,
68.2, 67.2, 64.1, 58.7, 58.2, 55.6; HRMS (ESI) m/z: [M+H]+ Calcd. for C24H24NO5 394.1654;
Found 394.1652.
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1-ethyl-3-(4-methoxyphenyl)-2-phenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5aj): Precursors
o
3a and 2j were used. Yield: 0.153 g (75%) as yellow solid; mp: 216–218 C; Rf = 0.28 (4:1
hexane/ethyl acetate); IR (KBr) 2964, 2838, 1638, 1551, 1512, 1299, 1244, 1030, 827, 762, 707
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 8.0 Hz and J = 1.5 Hz, 1H), 7.39-7.35 (m, 1H),
7.25-7.20 (m, 3H), 7.15 (dd, J = 8.3 Hz and J = 1.3 Hz, 1H), 7.11-7.08 (m, 3H), 6.92 (d, J = 9.0
Hz, 2H), 6.72 (d, J = 9.0 Hz, 2H), 5.11 (s, 2H), 3.72 (s, 3H), 2.57 (qrt, J = 7.3 Hz, 2H), 0.97 (t, J
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= 7.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ 159.8, 158.6, 157.8, 147.3, 140.7, 134.8, 131.9,
131.2, 131.0, 130.2, 130.0, 128.2, 128.0, 127.4, 123.4, 122.5, 121.7, 118.1, 116.9, 114.0, 64.2,
55.3, 22.8, 15.3; HRMS (ESI) m/z: [M+H]+ Calcd. for C28H24NO3 410.1756; Found 410.1758.
3-(4-methoxyphenyl)-1-methyl-2-phenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one
(5ak):
o
Precursors 3a and 4k were used. Yield: 0.155 g (78%) as yellow solid; mp: 186–188 C; Rf =
0.30 (4:1 hexane/ethyl acetate); IR (KBr) 2929, 2838, 1643, 1509, 1297, 1248, 1026, 834, 756,
704 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.77 (dd, J = 7.8 Hz and J = 1.3 Hz, 1H), 7.38-7.34 (m,
1H), 7.24-7.22 (m, 3H), 7.14 (dd, J = 8.3 Hz and J = 1.0 Hz, 1H), 7.09-7.07 (m, 3H), 6.97-6.94
(m, 2H), 6.75-6.72 (m, 2H), 5.13 (s, 2H), 3.73 (s, 3H), 2.11 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.8, 158.6, 157.8, 147.3, 140.7, 134.8, 131.9, 131.2, 131.0, 130.2, 130.0, 128.2,
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128.0, 127.4, 123.4, 122.5, 121.7, 118.1, 116.9, 114.0, 64.2, 55.3, 19.1; HRMS (ESI) m/z:
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[M+H]+ Calcd. for C26H22NO3 396.1599; Found 396.1598.
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2,3-bis(4-methoxyphenyl)-1-phenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5al): Precursors 3a
and 4l were used. Yield: 0.202 g (83%, 1:1 isomeric mixture) as yellow solid; mp: 204–206 oC;
Rf = 0.32 (4:1 hexane/ethyl acetate); IR (KBr) 2926, 2838, 1645, 1605, 1508, 1294, 1248, 1180,
1029, 761, 701 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.19-7.11 (m, 5H), 7.04-7.02 (m, 2H), 6.99-
6.95 (m, 9H), 6.87-6.86 (m, 2H), 6.84-6.82 (m, 2H), 6.77-6.72 (m, 6H), 6.64 (d, J = 8.5 Hz, 2H),
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6.60-6.51 (m, 3H), 6.47-6.42 (m, 3H), 5.19 (s, 4H), 3.75-3.73 (3 s, 9H), 3.64 (s, 3H); C NMR
(125 MHz, CDCl3) δ 160.2, 160.1, 158.8, 158.7, 158.41, 158.38, 157.5, 147.6, 147.4, 140.0,
139.7, 137.7, 134.6, 132.6, 132.0, 131.8, 131.7, 131.6, 130.7, 130.0, 129.9, 129.7, 128.9, 128.2,
127.42, 127.35, 126.9, 126.8, 122.4, 121.7, 121.6, 121.0, 120.9, 118.0, 117.6, 117.3, 114.13,
114.06, 113.6, 112.8, 64.2, 55.39, 55.38, 55.2, 55.0; HRMS (ESI) m/z: [M+H]+ Calcd. for
C32H26NO4 488.1862; Found 488.1863.
1,2-diphenyl-3-(p-tolyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one (5ba): Precursors 3b and 4a
o
were used. Yield: 0.190 g (86%) as pale yellow solid: mp: 234–236 C; Rf = 0.30 (4:1
hexane/ethyl acetate); IR (KBr) 2992, 2838, 2236, 1649, 1485, 1441, 1348, 1271, 1238, 1123,
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1014, 762 cm-1; H NMR (400MHz, CDCl3) δ 7.19-7.14 (m, 1H), 7.11-7.08 (m, 3H), 7.05-7.02
(m, 3H), 6.99-6.97 (m, 3H), 6.96-6.92 (m, 4H), 6.85-6.82 (m, 2H), 6.56-6.51 (m, 1H), 6.46 (dd, J
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= 8.0 Hz and J = 1.6 Hz, 1H), 5.20 (s, 2H), 2.25 (s, 3H); C NMR (400MHz, CDCl3) δ 159.9,
157.5, 147.2, 139.7, 137.7, 137.4, 136.2, 134.3, 131.6, 130.8, 129.4, 128.8, 128.7, 128.1, 127.4,
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127.2, 126.9, 122.5, 121.5, 120.9, 117.6, 117.5, 64.1, 21.1; HRMS (ESI) m/z: [M+H]+ Calcd. for
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C31H24NO2 442.1807; Found 442.1805.
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1,2-diphenyl-3-(m-tolyl)-3H-chromeno[3,4-c]pyridin-4(5H)-one (5ca): Precursors 3c and 4a
o
were used. Yield: 0.179 g (81%) as yellow solid;. Mp: 246–248 C; Rf = 0.30 (4:1 hexane/ethyl
acetate); IR (KBr) 3052, 3025, 2921, 2849, 1638, 1485, 1342, 1244, 1205, 1129, 1019, 762 cm-1;
1H NMR (400MHz, CDCl3) δ 7.19-7.15 (m, 1H), 7.13-7.09 (m, 4H), 7.04 (dd, J = 8.0 Hz and J =
1.2 Hz, 1H), 6.99-6.96 (m, 3H), 6.94-6.87 (m, 5H), 6.85-6.84 (m, 2H), 6.56-6.52 (m, 1H), 6.46
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(dd, J = 8.0 Hz and J = 1.6 Hz, 1H), 5.21 (s, 2H), 2.23 (s, 3H); C NMR (100MHz, CDCl3) δ
159.8, 157.5, 147.1, 139.7, 138.7, 138.6, 137.4, 134.3, 130.81, 130.76, 129.6, 128.9, 128.7, 128.5,
128.1, 127.5, 127.2, 127.1, 126.9, 126.0, 122.5, 121.5, 120.9, 117.7, 117.6, 64.1, 21.1; HRMS
(ESI) m/z: [M+H]+ Calcd. for C31H24NO2 442.1807; Found 442.1801.
3-isopropyl-1,2-diphenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5da): Precursors 3d and 4a
o
were used. Yield: 0.177 g (90%) as yellow solid; mp: 262–264 C; Rf = 0.44 (4:1 hexane/ethyl
acetate); IR (KBr) 2995, 2843, 1619, 1531, 1469, 1443, 1386, 1237, 1240, 1113, 1012, 890, 760
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.24-7.20 (m, 3H), 7.10-7.04 (m, 6H), 6.97 (dd, J = 8.0 Hz
and J = 1.0 Hz, 1H), 6.91-6.89 (m, 2H), 6.48-6.44 (m, 1H), 6.38 (dd, J = 8.0 Hz and J = 1.5 Hz,
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1H), 5.17 (s, 2H), 4.14-4.09 (m, 1H), 1.56 (d, J = 6.5 Hz, 6H); C NMR (125 MHz, CDCl3) δ
159.9, 157.2, 147.4, 138.1, 138.0, 135.2, 131.5, 130.4, 129.4, 128.5, 128.3, 128.1, 127.9, 126.7,
122.8, 121.3, 120.8, 117.9, 117.3, 63.9, 54.5, 19.3; HRMS (ESI) m/z: [M+H]+ Calcd. for
C27H24NO2 394.1807; Found 394.1805.
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3-butyl-1,2-diphenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5ea): Precursors 3e and 4a were
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used. Yield: 0.180 g (88%) as pale yellow solid; mp: 196–198 C; Rf = 0.38 (4:1 hexane/ethyl
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acetate); IR (KBr) 2994, 2843, 2235, 1655, 1489, 1445, 1344, 1276, 1243, 1129, 1015, 761 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.26-7.23 (m, 3H), 7.15-7.07 (m, 6H), 7.00 (dd, J = 8.0 Hz and J
= 1.0 Hz, 1H), 6.93-6.91 (m, 2H), 6.51-6.48 (m, 1H), 6.41 (dd, J = 8.5 Hz and J = 1.5 Hz, 1H),
5.20 (s, 2H), 3.82-3.79 (m, 2H), 1.64-1.61 (m, 2H), 1.20-1.12 (m, 2H), 0.75 (t, J = 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 159.3, 157.3, 147.2, 138.6, 137.7, 134.3, 131.5, 130.6, 129.9,
128.7, 128.4, 128.0, 127.9, 126.8, 121.5, 121.4, 120.8, 117.9, 117.4, 64.1, 46.6, 30.7, 20.1, 13.4;
HRMS (ESI) m/z: [M+H]+ Calcd. for C28H26NO2 408.1963; Found 408.1966.
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3-cyclohexyl-1,2-diphenyl-3H-chromeno[3,4-c]pyridin-4(5H)-one (5fa): Precursors 3f and 4a
o
were used; Yield: 0.202 g (93%) as white solid; mp: 218–220 C; Rf = 0.60 (4:1 hexane/ethyl
acetate); IR (KBr) 2931, 2848, 1634, 1521, 1485, 1443, 1402, 1247, 1113, 1056, 751, 710 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.25-7.23 (m, 3H), 7.14-7.06 (m, 6H), 6.99 (d, J = 8.0 Hz, 1H),
6.93-6.91 (m, 2H), 6.51-6.47 (m, 1H), 6.38 (dd, J = 8.0 Hz and J = 1.2 Hz, 1H), 5.17 (s, 2H),
3.62-3.59 (m, 1H), 2.90-2.82 (m, 2H), 1.76-1.63 (m, 4H), 1.53-1.21 (m, 2H), 0.91-0.79 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 160.1, 159.1, 157.2, 147.6, 138.1, 135.3, 131.5, 130.5, 129.3,
128.5, 128.3, 128.1, 127.9, 126.7, 122.9, 121.4, 120.8, 117.9, 117.4, 64.0, 48.8, 32.6, 26.2, 25.4,
25.0, 24.7; HRMS (ESI) m/z: [M+H]+ Calcd. for C30H28NO2 434.2120; Found 434.2123.
(iii) Synthesis of Annulation cum Hydroarylation Products by the Ru-Catalyzed Double
C-H Activation: General Procedure
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In a 10 mL round-bottomed flask, a mixture of 2H-chromene-3-carboxamide (3a or 3c,
0.5 mmol), diaryl or dialkyl acetylene (one of 4a-f or 4h 1.25 mmol), [RuCl2(p-cymene)]2 (8 mol
%), Cu(OAc)2.H2O (1.0 mmol) and AgNTf2 (30 mol %) was taken under N2 atmosphere. To this,
tAmOH (2 mL) was added and the mixture was stirred at 110 oC (oil bath temperature) for 12 h.
After cooling to rt, saturated NH4Cl solution (50 mL) was added and the contents extracted with
EtOAc (3 x 30 mL). The combined organic phase was washed with brine solution (2 x 15 mL),
dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using n-hexane-EtOAc (4:1) mixture as the eluent.
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(E)-3-(2-(1,2-bis(4-methoxyphenyl)vinyl)-4-methoxyphenyl)-1,2-bis(4-methoxyphenyl)-3H-
chromeno[3,4-c]pyridin-4(5H)-one (6ab): Precursors 3a and 4b were used. Yield: 0.332 g (88
%) as brown solid; mp: 166–168 oC; Rf = 0.28 (4:1 hexane/ethyl acetate); IR (KBr) 2932, 2827,
1
2044, 1715, 1638, 1611, 1496, 1348, 1293, 1249, 1030, 833, 745 cm-1; H NMR (500 MHz,
CDCl3) δ 7.17 (d, J = 8.5 Hz, 1H), 7.11-7.08 (m, 1H), 6.98-6.93 (m, 5H), 6.86 (d, J = 8.5 Hz,
2H), 6.81-6.78 (m, 3H), 6.71-6.66 (m, 5H), 6.56-6.46 (m, 5H), 6.33 (dd, J = 8.0 Hz and J = 1.5
Hz, 1H), 6.00 (s, 1H), 4.75-4.66 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 3.73 (s, 3H),
3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 159.0, 158.5, 158.4, 158.2, 157.3, 146.8,
142.7, 139.0, 138.3, 132.8, 132.4, 132.3, 131.9, 130.6, 130.2, 130.0, 129.9, 129.83, 129.80, 128.7,
126.3, 121.6, 120.6, 117.4, 117.3, 116.8, 113.5, 113.2, 113.0, 111.9, 111.7, 63.9, 55.4, 55.2, 55.1,
55.0, 54.9; HRMS (ESI) m/z: [M+H]+ Calcd. for C49H42NO7 756.2961; Found 756.2966.
(E)-3-(2-(1,2-bis(4-chlorophenyl)vinyl)-4-methoxyphenyl)-1,2-bis(4-chlorophenyl)-3H-
chromeno[3,4-c]pyridin-4(5H)-one (6ac): Precursors 3a and 4c were used. Yield: 0.317 g (82 %)
29
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