BF3·OEt2-Mediated Tandem Annulation: A Strategy to Construct Functionalized Chromeno- and Pyrano-Fused Pyridines

Article abstract of DOI:10.1021/acs.joc.7b02463

A simple and efficient one-pot annulation of arylidenones, alkynes, and nitriles in the presence of BF₃·OEt₂ is described. A highly functionalized variety of N-substituted pyridine-fused chromeno and pyrano derivatives were obtained

Full text of DOI:10.1021/acs.joc.7b02463

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Article
BF3•OEt2 Mediated Tandem Annulation: A Strategy to Construct
Functionalized Chromeno-, and Pyrano- Fused Pyridines
Ashitha K. T., Praveen Kumar V, Fathimath Salfeena C T, and Balappa Somappa Sasidhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02463 • Publication Date (Web): 08 Dec 2017
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BF3•OEt2 Mediated Tandem Annulation: A Strategy to Construct Functionalized
Chromeno-, and Pyrano- Fused Pyridines
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Ashitha K. T, Praveen Kumar V, Fathimath Salfeena C. T, Sasidhar B. S*
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Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary
Science and Technology (NIIST), Thiruvananthapuram - 695 019, India.
Academy of Scientific and Innovative Research (AcSIR), CSIR-NIIST, Thiruvananthapuram 695
019, India.
*Corresponding author: Sasidhar B. S,
E-mail: drsasidharbs@niist.res.in
For Table of Contents Only
Abstract: A simple and efficient one-pot annulation of arylidenones, alkynes, and nitriles in the
presence of BF3.OEt2 is described. A highly functionalized variety of N-substituted pyridine
fused-, chromeno and pyrano derivatives obtained with satisfactory yields under mild reaction
conditions. The method was proven to be valid for the synthesis of the diverse library of
chromeno
[3,4-c]pyridines,
thiochromeno[3,4-c]pyridines,
pyrano[3,4-c]pyridines,
thiopyrano[3,4-c]pyridine derivatives from readily accessible substrates. This experimentally
simple protocol provides structurally complex, biologically relevant heterocycles in a one-pot
operation.
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Introduction
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Chromone is an essential class of oxygen-containing heterocyclic compounds. Chromones are
among the most exciting discoveries in the field of natural products which have successfully led
to the development of many approved drugs and clinical trial agents1 (Figure 1). In fact, these
class of compounds is known to have the broad spectrum of medicinal properties, including
antitumor,2 antibacterial,3 anti-HIV,4 acetyl-CoA carboxylase (ACC) inhibitor,5 etc. Many
pharmacologically relevant natural products such as hematoxylin, ripariochromene, clausenin
and calanolide A, have been synthesised from versatile intermediate chromanone.6 On the other
hand, pyridine as privileged N-heterocycle is associated with various natural products and
pharmaceuticals.7 Interestingly, more than a hundred currently marketed drugs contain this core.8
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Figure 1. Medicinally relevant chromane, thiochromane and pyridine derivatives
The medicinal properties of these compounds are associated with their bi- and tricyclic
molecular hybrids. Consequently, a variety of chimeric structures of chromones1d,9 and
pyridines8,10 have been prepared and evaluated for therapeutic applications. In 1997 Unangst et
al. synthesised chromeno[3,4-c]pyridin-5-ones by a cyclocondensation of an appropriate phenol
with a piperidone ester under strongly acidic conditions.11 Zhou et al. reported Microwave
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assisted, cobalt-catalysed intramolecular [2+2+2] cyclization of dialkynylnitriles to pyrano[3,4-
c][1,6]naphthyridines.12 Panda and coworkers demonstrated one-pot cyclization for the
preparation of cyclic ethers from their diols via a tandem oxidation-reduction protocol. The
protocol was also generalized for the synthesis of pyrano[3,4-c]pyridine derivative.13 In the total
synthesis of Camptothecin and SN-38, an important precursor (S)-4-ethyl-4-hydroxy-8-methoxy-
1H-pyrano[3,4-c]pyridin-3(4H)-one was achieved through the multi-step process starting from 2-
methoxypyridine-3-carboxylic acid.14 These highlighted methods mainly possess the drawbacks
such as unavailability of starting substrates and multi-step synthesis.
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The generation of hybrid pharmacophore through the fusion of medicinally active
chromenones / pyranones and pyridines will undoubtedly enrich the structural template.
Therefore, the development of these enriched structural templates through the multiple bond-
forming transformations involving multicomponent reactions (MCRs) in one-pot is the key to
generating molecular diversity. The significant applications of MCRs in the drug discovery
process,15 total synthesis,16 and in the development of various strategies for the construction of
new chemical entities is quite evident.17
Owing to the aforementioned biological importance of pyridines, related hybrids, and our
interest in the design and development18 of medicinally essential heterocycles, recently we have
unraveled a one-pot multicomponent cascade synthesis of pyridine appended heterocycles from
the readily accessible arylidenones, alkynes and nitriles.19 This simple protocol has led us now to
report the diverse library of chromeno[3,4-c]pyridines, thiochromeno[3,4-c]pyridines,
pyrano[3,4-c]pyridines and thiopyrano[3,4-c]pyridines.
Results and Discussion
In sharp contrast to the well-documented approaches to access either chromeno[4,3-
b]pyridines10b,20 or chromeno[3,2-c]pyridines,21 we report a one-pot, multicomponent cascade
annulation for the construction of chromeno[3,4-c]pyridines. To the extension of our recent
report,16 the feasibility of this annulation reaction was first tested using one equivalent of (E)-3-
benzylidene chroman-4-one (1a), phenylacetylene (2a) and acetonitrile in the presence of one
o
equivalent of BF3.OEt2 at 50 C, which presumably afforded 1-(2,4-diphenyl-4,5-dihydro-3H-
chromeno[3,4-c]pyridin-3-yl) ethanone (3a), in 22% of yield (Table 1, entry 2). The model
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reaction was also examined for various Lewis acids like Sc(OTf)3, Zn(OTf)2, Cu(OTf)2, La(OTf)3,
etc. However, the reaction did not afford the expected product. Bronsted acids TFA, benzoic
acid, and phenylboronic acid etc., failed to furnish the product even in trace amount. Addition of
two equivalent of acetonitrile in the presence of other solvents such as toluene, DCE, DCM,
afforded the product in meager yields, while THF and DMF did not show any positive result
(Table 1, entries 3−7). When we tried to optimize with carbophilic Lewis acids, such as AuCl3,
AuPPh3, AuCl3H2O, Cu(OAc)2 and I2 as additives, along with the BF3.OEt2, we could not find
any marked improvement in the reaction. Further, the reaction was observed at varying
temperature. Low yield of about 12% is obtained for the room temperature reaction. On
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o
increasing the temperature from 50 C, the reaction started to produce some byproducts which
apparently resulted in poor yields. From the optimization parameters listed in Table 1, an
addition of three equivalent of BF3.OEt2, with three equivalent of an alkyne, without any co-
o
solvent (Table 1, entry 26) at 50 C emerges as the optimized condition, furnishing the highest
yield (66%) of the targeted chromeno[3,4-c]pyridine.
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Table 1. Optimization of the Reaction Conditionsa
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Entry 1a
2a
Lewis acid
Solvent
Temp Yield
(oC)
(%)b
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2
3
4
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1equiv BF3.OEt2 (1 equiv)
CH3CN
CH3CN
rt
12
50
22
Toluene+ CH3CN (2 equiv) 50
Trace
Trace
DCE+ CH3CN (2 equiv)
50
5
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9
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1equiv BF3.OEt2 (1 equiv)
1 equiv 1 equiv AlCl3
DCM+ CH3CN (2 equiv)
THF + CH3CN (2 equiv)
DMF + CH3CN (2 equiv)
CH3CN
50
50
50
50
50
50
50
50
50
50
50
50
50
50
Trace
0
0
0
0
0
0
0
0
0
0
0
0
20
1 equiv 1 equiv GaBr3
CH3CN
10 1 equiv 1 equiv ZnCl2
11 1 equiv 1 equiv I2
CH3CN
CH3CN
12 1 equiv 1 equiv CF3COOH
13 1 equiv 1 equiv PTSA
14 1 equiv 1 equiv PhB(OH)2
15 1 equiv 1 equiv Sc(OTf)3
16 1 equiv 1 equiv Cu(OTf)2
17 1 equiv 1 equiv Zn(OTf)2
18 1 equiv 1 equiv BF3.OEt2 (1 equiv)+
AuPPh3 (20 mol%)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
19 1 equiv 1 equiv BF3.OEt2 + AuCl3
CH3CN
50
50
50
50
50
50
50
50
23
21
0
20 1 equiv 1 equiv BF3.OEt2 + AuCl3.H2O) CH3CN
21 1 equiv 1 equiv BF3.OEt2 + Cu(OAc)2
22 1 equiv 1 equiv BF3.OEt2 + I2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
23 1 equiv 2 equiv BF3.OEt2 (1 equiv)
24 1 equiv 3 equiv BF3. OEt2 (1 equiv)
25 1 equiv 3 equiv BF3.OEt2 (2 equiv)
30
42
56
66
26
BF3.OEt2 (3 equiv)
1 equiv 3 equiv
aUnless otherwise specified, all of the reactions were carried out at 50 C, 1a (0.12 mmol), H2O
o
(0.24 mmol) in 2 mL of CH3CN. bIsolated yield.
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With the optimized reaction condition in hand, all the subsequent reactions of (E)-3-
arylidene chroman-4-one (1 equiv) and aryl or heteroaryl alkynes (3 equiv) were performed in the
presence of BF3.OEt2 (3 equiv) at 50 oC in acetonitrile for 10 - 90 minutes. After completion of -
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R2
O
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N
O
X
R
R
BF3.Et2O (3 equiv)
H2O, 50 oC
R1
R1
+
R2
CH3CN
+
X
X= O, S
X= O, S
2
1
3a-3aq
R2
O
R2
O
3a; R2= Ph, 66%
3f; R2= Ph, 39%
3b; R2= 4-CH3-Ph, 56%
3c; R2= 4-Br-Ph, 52%
3d; R2= 4-F-Ph, 42%
3e; R2= 4-propyl-Ph, 43%
3g; R2= 4-CH3-Ph, 63%
3h; R2= 4-Br-Ph, 49%
3i; R2= 4-F-Ph, 48%
3j; R2= 4-propyl-Ph, 55%
3k; R2= 3-thiophen, 60%
N
N
O
Cl
O
3f-k
3a-e
R2
O
R2
O
3l; R2= Ph, 74%
3r; R2= Ph, 36%
3m; R2= 4-CH3-Ph, 77%
3n; R2= 4-Br-Ph, 61%
3o; R2= 4-F-Ph, 62%
3p; R2= 4-propyl-Ph, 74%
3q; R2= 3-thiophen, 77%
N
N
3s; R2= 4-CH3-Ph, 54%
3t; R2= 4-F-Ph, 32%
3u; R2= 4-propyl-Ph, 47%
O
O
CF3
3l-q
3r-u
R2
O
S
R2
O
3ab; R2= Ph, 63%
3v; R2= Ph, 50%
3ac; R2= 4-CH3-Ph, 67%
3ad; R2= 4-Br-Ph, 39%
3ae; R2= 4-F-Ph, 51%
3af; R2= 4-propyl-Ph, 50%
3ag; R2= 3-thiophen, 33%
3w; R2= 4-CH3-Ph, 74%
3x; R2= 4-Br-Ph, 38%
3y; R2= 4-F-Ph, 24%
3z; R2= 4-propyl-Ph, 47%
3aa; R2= 3-thiophen, trace
N
N
F
O
O
3v-aa
R2
3ab-ag
O
R2
O
N
N
3aj; R2= Ph, 64%
3ak; R2= 4-CH3-Ph, 41%
3ah; R2= Ph, trace
3ai; R2= 4-Br-Ph, 36%
F
F
S
O
O
3ah-ai
R2
3aj-ak
O
3al; R2= Ph, 46%
3am; R2= 4-CH3-Ph, 26%
3an; R2= 4-Br-Ph, 31%
3ao; R2= 4-F-Ph, 40%
3ap; R2= 4-propyl-Ph, 23%
3aq; R2= 3-thiophen, 39%
N
S
3al-aq
Scheme 1. Scope of the reaction for N-acetylated, chromeno and thiochromeno [3,4-c]pyridines
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- the reaction as evident from TLC, the product extracted with ethyl acetate and purified by
column chromatography to obtain pure chromeno[3,4-c]pyridine derivatives (3). The generality
of this three-component annulation was well explored for substituted (E)-3-arylidenechroman-4-
one, aromatic acetylenes, bearing a series of electron withdrawing and electron donating
substituents and heteroaryl ring thiophene. 6-Fluoro arylidene chromanones were also
generalized with the variety of arylidene and alkynes in the presence of acetonitrile. These
different, electronically substituted varied reagents reacted efficiently under the optimized
condition affording the corresponding chromeno[3,4-c] pyridines in acceptable yields (Scheme
1). We turned our attention to assessing the scope of this annulation reaction with arylidene
thiochromanone, alkynes, bearing a series of electron withdrawing and electron donating
substituents. In all the cases methodology worked well to synthesize the targeted
thiochromeno[3,4-c]pyridines (3al-aq) in moderate to good yields (Scheme 1). From our
observation, we found that the yields of the thiochromeno[3,4-c]pyridines are lower than that of
the chromeno[3,4-c]pyridines. It may be attributed to the basicity of heteroatom sulphur as
compared to that of oxygen.
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The successful annulation of chromeno[3,4-c]pyridines and thiochromeno[3,4-
c]pyridines led us to examine the reactivity of (3E,5E)-3,5-diarylidenedihydro-2H-pyran-4(3H)-
one and (3Z,5Z)-3,5-diarylidenedihydro-2H-thiopyran-4(3H)-one with various substituted
alkynes and acetonitrile under the same optimized condition. Pyranone and thiopyranone
diarylidenes (4) derived from phenyl and thiophenes were utilized for the three component
cascade annulation. To our delight, we were fortunate to get the new molecular templates of
pyrano[3,4-c]pyridines and thiopyrano[3,4-c]pyridines (5) in acceptable yields (Scheme 2).
Delighted with the success of broad diversity of arylidenones and alkynes, we further explored
the compatibility of other nitrile sources such as, benzonitrile and acrylonitrile. As targeted; we
successfully obtained N-substituted chromeno and thiochromeno-fused pyridines (7) under mild
and straightforward reaction conditions in acceptable yields (Scheme 3). Finally, under the DDQ
oxidation condition product 3 (3l & 3w) were successfully transformed in to the corresponding
5H-chromeno[3,4-c]pyridines of biological relevance (Scheme 4).
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Scheme 2. Generality of pyrano-, thiopyrano-, [3,4-c]pyridine synthesis.
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Scheme 3. Scope of nitriles for [3,4-c]pyridine synthesis.
Scheme 4. One-pot synthesis of 5H-chromeno[3,4-c]pyridines.
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Scheme 5. Plausible mechanism of chromeno[3,4-c]pyridine formation.
Based on the aforementioned experimental results, a plausible mechanistic pathway is
outlined in scheme 5. Being oxophilic in nature BF3.OEt2 coordinates to the carbonyl oxygen of
arylidene ketone 1, favouring the carbonyl group to undergo 1,2 addition by phenylacetylene.
This is followed by the attack of acetonitrile to phenyl acetylene leading to the formation of
intermediate A. Hydrolysis of nitrile group of intermediate A under acidic conditions leads to the
creation of intermediate B which on subsequent Intramolecular cyclisation of amide nitrogen
affords the product 3.
Conclusion
In conclusion, a simple and efficient BF3.OEt2 mediated cascade annulation of
arylidenones, alkynes and nitriles have been developed. This reaction affords a highly
generalized and straightforward way to construct N-substituted chromeno-, thiochromeno-,
pyrano- and thiopyrano-, [3,4-c]pyridines under mild conditions and tolerates a wide range of
functional groups. In addition, a one-pot synthesis of 5H-chromeno[3,4-c]pyridines was
successfully achieved. Notably, the reaction is process friendly, with easily accessible substrates
and without any inert conditions. A plausible mechanism of the reaction has proposed. Our
protocol will aid in the generation of a diverse library of fused pyridine hybrids with potential
biological significance. Further investigation for the construction of other heterocyclic appended
fused pyridines via this annulation reaction is in progress at our laboratory.
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Experimental Section
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General experimental methods: All the reactions are performed with commercially available
best grade chemicals without further purification. All the solvents used are reagent grade and
commercially available. Column chromatography was performed using 100 – 200 mesh silica gel
and mixtures of hexane – ethyl acetate were used for elution of the products. Proton nuclear
magnetic resonance spectra (1H NMR) were recorded on a Bruker AMX 500 spectrometer
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1
(CDCl3 as solvent). Chemical shifts for H NMR spectra are reported as δ in units of parts per
million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.25,
singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublet
of doublet); dt (doublet of triplet), m (multiplet). Coupling constants are reported as J value in
Hz. Carbon nuclear magnetic resonance spectra (13C NMR) are reported as δ in units of parts per
million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.03,
triplet). HRMS analysis was recorded on a Thermo Scientific Exactive-LCMS instrument by
electron spray ionization method with ions given in m/z using Orbitrap analyzer. IR spectra were
recorded on Bruker FT-IR spectrometer.
General procedure for the synthesis of arylidene chroman-4-ones, thiochroman-4-ones (1)22
To a solution of chroman-4-one/thiochroma-4-one (4.0 mmol) in ethanol added corresponding
o
aryl or hetero aryl aldehyde (4.40 mmol) at 0 C. An aqueous solution of NaOH (10%, 10 ml)
was added drop wise to this reaction mixture. The solid precipitate formed was collected by
filtration and washed with water and hexane. It was dried and used for further reaction.
General procedure for the synthesis of (3E, 5E)-3,5-diarylidenedihydro-2H-pyran-4(3H)-
one / (3Z, 5Z)-3,5-diarylidenedihydro-2H-thiopyran-4(3H)-one (4)22
To a solution of dihydro-2H-pyran-4(3H)-one / dihydro-2H-thiopyran-4(3H)-one (2.00 mmol) in
o
ethanol added corresponding aryl or hetero aryl aldehyde (2.20 mmol) at 0 C. An aqueous
solution of NaOH (10%, 10 ml) was added drop wise to this reaction mixture. The solid
precipitate formed was collected by filtration and washed with water and hexane. It was dried
and used for further reaction
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General procedure for BF3.OEt2 mediated one-pot synthesis of N-acetylated chromeno[3,4-
c]pyridines / thiochromeno[3,4-c]pyridines (3)
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To a mixture of 1 equiv of substituted arylidene chroman-4-one / thiochroman-4-one (0.12
mmol) and 3 equiv of aryl or hetero aryl alkyne (0.36 mmol) in acetonitrile (2 ml) with 2 equiv
o
of water at 50 C added 3 equiv of BF3.OEt2 (0.36 mmol). The reaction mixture was then
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allowed to stir for 10 - 90 minutes by monitoring the TLC. After the completion of reaction the
reaction mixture was extracted with ethyl acetate (3 X 10 ml), evaporated in vacuo and purified
by column chromatography using 100–200 mesh silica gel with ethyl acetate / hexane as the
eluent to afford the corresponding N-acetylated fused pyridines as the product.
1-(2,4-diphenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3a)
Yield: 30 mg, 66% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3062, 1661, 1601, 1036; 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 7.0 Hz, 2H),
7.40 (d, J = 6.5 Hz, 1H), 7.35 – 7.29 (m, 3H), 7.28 – 7.26 (m, 4H), 7.22 (td, J = 8.0, 1.5 Hz, 1H),
7.13 (s, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 6.44 (s, 1H), 4.90 (d,
J = 15.5 Hz, 1H), 4.77 (d, J = 15.0 Hz, 1H), 1.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 172.0,
153.9, 138.5, 138.3, 137.2, 129.5, 129.0, 128.8, 128.6, 128.5, 128.1, 125.8, 124.7, 123.0, 121.7,
120.9, 116.5, 112.0, 65.8, 53.5, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C26H21NO2Na 402.1470; Found 402.1461.
1-(4-phenyl-2-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3b)
Yield: 26 mg, 56% yield, as colorless foam; Rf = 0.21 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3061, 1666, 1604, 1116; 1H NMR (500 MHz, CDCl3): δ 7.52 – 7.49 (m, 2H), 7.39
(dd, J = 8.0, 1.5 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.07 (d, J = 8.0 Hz,
2H), 7.02 (td, J = 7.5, 1.0 Hz, 3H), 6.90 (dd, J = 8.0, 1.0 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.89
(d, J = 15.5 Hz, 1H), 4.76 (d, J = 15.0 Hz, 1H), 2.30 (s, 3H), 1.72 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 172.1, 153.9, 138.8, 138.3, 137.2, 135.7, 133.2, 129.7, 129.4, 128.8, 128.6, 128.4,
128.3, 128.1, 125.7, 125.5, 124.7, 123.1, 121.7, 121.0, 116.5, 111.3, 65.8, 53.5, 24.8, 21.2;
HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C27H23NO2Na 416.1626; Found 416.1620.
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1-(2-(4-bromophenyl)-4-phenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3c)
Yeild: 29 mg, 52% yield, as colorless foam; Rf = 0.19 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3062, 1669, 1586, 1072, 1040; H NMR (500 MHz, CDCl3): δ 7.50 – 7.46 (m,
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2H), 7.40 (d, J = 8.5 Hz, 2H), 7.37 (dd, J = 8.0, 1.5 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.22 (td, J =
8.0, 1.5 Hz, 1H), 7.02 (td, J = 7.5, 1.0 Hz, 1H), 6.99 (d, J = 7.0 Hz, 2H), 6.91 (dd, J = 8.0, 1.0
Hz, 1H), 6.50 (s, 1H), 6.44 (s, 1H), 4.88 (d, J = 15.5 Hz, 1H), 4.75 (d, J = 15.5 Hz, 1H), 1.72 (s,
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3H); C NMR (125 MHz, CDCl3) δ 171.7, 153.8, 137.5, 137.2, 137.0, 132.2, 129.6, 128.9,
128.6, 128.0, 127.2, 126.4, 124.7, 123.0, 122.7, 121.7, 120.7, 116.6, 112.6, 65.7, 53.5, 24.7;
HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C26H20BrNO2Na 480.0575; Found 480.0580.
1-(2-(4-fluorophenyl)-4-phenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3d)
Yeild: 20 mg, 42% yield, as colorless foam; Rf = 0.16 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3065, 1667, 1599,1098; 1H NMR (500 MHz, CDCl3): δ 7.50 – 7.49 (m, 2H), 7.38
(dd, J = 7.5, 1.5 Hz, 1H), 7.35 – 7.29 (m, 3H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.09 (s, 2H), 7.02
(td, J = 7.5, 1 Hz, 1H), 6.96 (t, J = 9.0 Hz, 2H), 6.91 (dd, J = 8.0, 0.5 Hz, 1H), 6.51 (s, 1H), 6.39
(s, 1H), 4.88 (d, J = 15.5 Hz, 1H), 4.76 (d, J = 15.0 Hz, 1H), 1.71 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 171.8, 153.8, 137.2, 137.1, 134.7, 134.7, 133.7, 131.6, 129.5, 128.9, 128.6, 128.1,
127.5, 127.4, 125.8, 124.7, 123.0, 121.7, 120.8, 116.6, 116.2, 116.0, 112.0, 65.7, 53.5, 24.7;
HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C26H20FNO2Na 420.1376; Found 420.1376.
1-(4-phenyl-2-(4-propylphenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3e)
Yeild:22 mg, 43% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3062, 1666, 1606, 1040; 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 7.0 Hz, 2H),
7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.34 – 7.28 (m, 3H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.08 – 7.00 (m,
5H), 6.91 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.76 (d, J =
15.5 Hz, 1H), 2.54 – 2.51 (m, 2H), 1.71 (s, 3H), 1.60 – 1.56 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ 172.2, 153.9, 143.5, 138.4, 137.3, 135.9, 129.4, 129.1, 128.8,
128.4, 128.1, 125.7, 125.4, 124.7, 123.1, 121.7, 121.0, 116.5, 111.2, 65.8, 53.5, 37.7, 24.7, 24.4,
13.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C29H27NO2Na 444.1939; Found
444.1943.
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1-(4-(4-chlorophenyl)-2-phenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3f)
Yield: 19 mg, 39% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3063, 1666, 1593, 1091; 1H NMR (500 MHz, CDCl3): δ 7.45 (d, J = 8.5 Hz, 2H),
7.40 (dd, J = 8.0, 1.5 Hz, 1H), 7.31 – 7.28 (m, 5H), 7.22 (td, J = 8.0, 1.5 Hz, 1H), 7.12 (s, 2H),
7.03 (td, J = 7.5, 1 Hz, 1H), 6.92 (dd, J = 8.5, 1.0 Hz, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 4.88 (d, J =
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15.5 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3) δ 172.1,
153.8, 138.3, 138.3, 135.8, 134.4, 129.6, 129.1, 129.1, 128.8, 125.7, 125.1, 125.0, 123.1, 121.8,
120.7, 116.6, 111.8, 65.6, 52.8, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C26H20ClNO2Na 436.1080; Found: 436.1089.
1-(4-(4-chlorophenyl)-2-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3g)
Yield: 32 mg, 63% yield, as colorless foam; Rf = 0.28 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3035, 1667, 1588, 1091; H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.5Hz, 2H),
7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (td, J = 8.0, 1.5 Hz, 1H), 7.10 (d, J
= 8.0 Hz, 2H), 7.02 (td, J = 7.5, 1.0 Hz, 3H), 6.91 (dd, J = 8.5, 1.0 Hz, 1H), 6.46 (s, 1H), 6.40 (s,
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1H), 4.87 (d, J = 15.5 Hz, 1H), 4.71 (d, J = 15.0 Hz, 1H), 2.31 (s, 3H), 1.71 (s, 3H); C NMR
(125 MHz, CDCl3) δ 172.2, 153.9, 139.0, 138.3, 135.8, 135.5, 134.3, 129.8, 129.6, 129.6, 129.0,
125.6, 125.0, 124.8, 123.1, 121.8, 120.8, 116.6, 111.2, 65.6, 52.8, 24.7, 21.2; HRMS (ESI –
Orbitrap) m/z: [M+Na]+ Calcd for C27H22ClNO2Na 450.1237; Found 450.1233.
1-(2-(4-bromophenyl)-4-(4-chlorophenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3h)
Yeild: 29 mg, 49% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR (neat,
cm-1): 2928, 1666, 1588, 1269, 1091; 1H NMR (500 MHz, CDCl3): δ 7.43 (dd, J = 8.5, 2.0 Hz,
4H), 7.37 (dd, J = 7.5, 1.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.23 (td, J = 8.0, 1.5 Hz, 1H), 7.03
(td, J = 7.5, 1.0 Hz, 1H), 6.99 (d,J = 7.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 6.44 (s,
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1H), 4.87 (d, J = 15.5 Hz, 1H), 4.70 (d, J = 15.0 Hz, 1H), 1.72 (s, 3H); C NMR (125 MHz,
CDCl3): δ 171.9, 153.8, 137.2, 137.1, 135.6, 134.5, 133.6, 132.3, 131.6, 129.8, 129.5, 129.2,
127.1, 125.6, 124.9, 123.1, 122.9, 121.8, 120.6, 116.6, 112.4, 65.5, 52.8, 24.7; HRMS (ESI –
Orbitrap) m/z: [M+Na]+ Calcd for C26H19BrClNO2Na 514.0185; Found 514.0177.
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1-(4-(4-chlorophenyl)-2-(4-fluorophenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3i)
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Yield: 25 mg, 48% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3068, 1669, 1600, 1092; 1H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 8.5 Hz, 2H),
7.38 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.23 (td, J = 8.0, 1.5 Hz, 1H), 7.09 (s, 2H),
7.04 – 6.97 (m, 3H), 6.92 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 6.39 (s, 1H), 4.87 (d, J = 15.5 Hz,
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1H), 4.71 (d, J = 15.0 Hz, 1H), 1.71 (s, 3H); C NMR (125 MHz, CDCl3): δ 171.9, 163.9,
161.9, 153.8, 137.1, 135.7, 134.5, 129.7, 129.5, 129.1, 127.5, 127.4, 124.9, 123.1, 121.8, 120.6,
116.6, 116.3, 116.1, 111.8, 65.6, 52.9, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C26H19ClFNO2Na 454.0986; Found 454.0995.
1-(4-(4-chlorophenyl)-2-(4-propylphenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3j)
Yield: 30 mg, 55% yield, as colorless foam; Rf = 0.28 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3062, 1668, 1588, 1091; 1H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 7.5 Hz, 1H),
7.26 (d, J = 5.5 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.12 (s, 5H), 7.01 (t, J = 7.5 Hz, 1H), 6.93 –
6.89 (m, 2H), 6.65 (s, 1H), 6.41 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.84 (d, J = 15.5 Hz, 1H),
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2.57 – 2.54 (m, 2H), 1.70 (s, 3H), 1.63 – 1.58 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); C NMR (125
MHz, CDCl3): δ 171.7, 153.8, 143.6, 140.4, 138.2, 135.9, 129.5, 129.1, 126.8, 126.8, 126.5,
125.9, 125.2, 124.2, 123.2, 121.7, 120.8, 116.5, 110.7, 65.6, 49.7, 37.7, 24.8, 24.4, 13.8; HRMS
(ESI – Orbitrap) m/z: [M+Na]+ Calcd for C29H26ClNO2Na 478.1550; Found 478.1553.
1-(4-(4-chlorophenyl)-2-(thiophen-3-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3k)
Yield: 30 mg, 60% yield, as colorless foam; Rf = 0.21 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3106, 1666, 1596, 1090; 1H NMR (500 MHz, CDCl3): δ 7.43 (d, J = 8.5 Hz, 2H),
7.36 (dd, J = 8.0, 1.5 Hz, 1H), 7.29 – 7.27 (m, 3H), 7.22 (td, J = 8.0, 1.5 Hz, 1H), 7.03 – 7.00 (m,
2H), 6.92 – 6.90 (m, 2H), 6.42 (s, 2H), 4.87 (d, J = 15.5 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 1.81
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 172.2, 153.8, 140.1, 135.9, 134.3, 133.6, 130.9, 129.6,
129.5, 129.4, 129.0, 127.2, 125.3, 125.0, 125.0, 123.1, 122.0, 121.8, 120.7, 65.7, 52.7,
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24.1;HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C24H18ClNO2SNa 442.0644; Found
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442.0636.
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1-(2-phenyl-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3l)
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Yield: 35 mg, 74% yield, as colorless foam; Rf = 0.26 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3060, 1666, 1596, 1090; 1H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 8.0 Hz, 3H),
7.27 – 7.25 (m, 3H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 4H), 7.02 (td, J = 7.5, 1.0
Hz, 1H), 6.91 (dd, J = 8.0, 1.0 Hz, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 4.88 (d, J = 15.5 Hz, 1H), 4.75
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(d, J = 15.5 Hz, 1H), 2.30 (s, 3H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3): δ 172.0, 153.8,
138.6, 138.3, 138.2, 134.2, 129.5, 129.4, 129.0, 128.6, 128.1, 126.1, 125.8, 124.5, 123.0, 121.7,
121.0, 116.5, 111.9, 65.8, 53.3, 24.7, 21.2
C27H23NO2Na 416.1626; Found 416.1637.
.
; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
1-(2,4-di-p-tolyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3m)
Yield: 38 mg, 77% yield, as colorless foam; Rf = 0.28 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3031, 1666, 1606, 1041; 1H NMR (500 MHz, CDCl3): δ 7.39 – 7.37 (m, 3H), 7.20
(td, J = 7.5, 1.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.04 – 6.99 (m, 3H),
6.90 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 6.39 (s, 1H), 4.88 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 15.0
Hz, 1H), 2.30 (s, 6H), 1.71 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 172.1, 153.8, 138.7, 138.2,
138.1, 135.8, 134.1, 129.9, 129.7, 129.5, 129.4, 128.0, 125.7, 124.5, 123.0, 121.7, 121.0, 116.5,
111.2, 65.8, 53.2, 24.8, 21.2;HRMS (ESI – Orbitrap) m/z: [M+Na]+Calcdfor C28H25NO2Na
430.1783; Found 430.1761.
1-(2-(4-bromophenyl)-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3n)
Yield: 35 mg, 61% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3063, 1666, 1587, 1072; 1H NMR (500 MHz, CDCl3): δ 7.40 (d, J = 8.5 Hz, 2H),
7.37 – 7.34 (m, 3H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.02 (td, J = 7.5, 1.0
Hz, 3H), 6.91 (dd, J = 8.0, 1.0 Hz, 1H), 6.46 (s, 1H), 6.43 (s, 1H), 4.87 (d, J = 15.5 Hz, 1H), 4.74
(d, J = 15.5 Hz, 1H), 2.31 (s, 3H), 1.72 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 171.7, 153.8,
138.4, 137.5, 137.1, 133.9, 132.2, 129.6, 129.5, 128.0, 127.2, 126.7, 124.5, 123.0, 122.6, 121.7,
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120.7, 116.6, 112.5, 65.8, 53.3, 24.8, 21.2: HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
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C27H22BrNO2Na 494.0732; Found 494.0721.
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(3o)
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Yield: 31 mg, 62% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10);IR
(neat, cm-1): 3063, 1667, 1600, 1042; 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 7.5 Hz, 3H),
7.21 (td, J = 8.0, 2.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 4H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.97 (t, J =
9.0 Hz, 2H), 6. 91 (dd, J = 8.0, 1.0 Hz, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 4.87 (d, J = 15.5 Hz, 1H),
13
4.75 (d, J = 15.5 Hz, 1H), 2.31 (s, 3H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3): δ 171.8,
163.8, 161.8, 153.8, 138.3, 137.2, 134.8, 134.1, 129.6, 129.5, 128.0, 127.5, 127.5, 126.1, 124.5,
123.0, 121.7, 120.8, 116.5, 116.2, 116.0, 111.9, 65.8, 53.3, 24.7, 21.2; HRMS (ESI – Orbitrap)
m/z: [M+Na]+ Calcd for C27H22FNO2Na 434.1532; Found 434.1530.
1-(2-(4-propylphenyl)-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3p)
Yield: 39 mg, 74% yield, as colorless foam; Rf = 0.30 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 2958, 1666, 1588, 1228; 1H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 8.0 Hz, 3H),
7.20 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.08 – 7.07 (m, 4H), 7.01 (t, J = 7.5 Hz, 1H),
6.90 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 6.40 (s, 1H), 4.88 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 15.5
Hz, 1H), 2.55 – 2.52 (m, 2H), 2.30 (s, 3H), 1.70 (s, 3H), 1.61 – 1.56 (m, 2H), 0.90 (t, J = 7.5 Hz,
3H);13C NMR (125 MHz, CDCl3): δ 172.1, 153.9, 143.5, 138.4, 138.1, 136.0, 134.3, 129.5,
129.3, 129.0, 128.0, 125.7, 124.5, 123.0, 121.6, 121.0, 116.5, 111.1, 65.9, 53.3, 37.7, 24.7, 24.3,
21.2, 13.8;HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C30H29NO2Na 458.2096; Found
458.2086.
1-(2-(thiophen-3-yl)-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3q)
Yield: 37 mg, 77% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3103, 1663, 1587, 1041; 1H NMR (500 MHz, CDCl3): δ 7.37– 7.34 (m, 3H), 7.25
(dd, J = 5.0, 3.0 Hz, 1H), 7.20 (td, J = 8.0, 1.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.02 – 6.99 (m,
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= 15.0 Hz, 1H), 4.76 (d, J = 15.5 Hz, 1H), 2.29 (s, 3H), 1.80 (s, 3H); C NMR (125 MHz,
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CDCl3): δ 172.1, 153.8, 140.4, 138.1, 134.3, 133.6, 129.5, 129.4, 127.8, 127.0, 126.1, 125.5,
124.5, 123.0, 122.0, 121.7, 120.9, 116.5, 110.7, 65.9, 53.1, 24.2, 21.2; HRMS (ESI – Orbitrap)
m/z: [M+Na]+ Calcd for C25H21NO2SNa 422.1191; Found 422.1196.
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1-(2-phenyl-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3r)
Yield: 19 mg, 36% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3064, 1665, 1609, 1067; 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 2H),
7.60 (d, J = 8.5 Hz, 2H), 7.41 (dd, J = 7.5, 1.0 Hz, 1H), 7.31 – 7.29 (m, 3H), 7.23 (dd, J = 7.5,
1.5 Hz, 1H), 7.13 (s, 2H), 7.04 ( t , J = 7.5 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.45
(s, 1H), 4.90 (d, J = 15.5 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 1.72 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 172.2, 153.9, 141.4, 138.4, 138.1, 129.8, 129.1, 128.9, 128.6, 125.9, 125.8, 125.7,
125.3, 124.5, 123.2, 121.9, 120.7, 116.6, 111.8, 65.6, 53.0, 24.7; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C27H20F3NO2Na 470.1344; Found 470.1335.
1-(2-(p-tolyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3s)
Yield: 30 mg, 54% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3066, 1663, 1166, 1067; 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.5 Hz, 2H),
7.59 (d, J = 8.5 Hz, 2H), 7.41 (dd, J = 7.5, 1.5 Hz, 1H), 7.23 (td, J = 8.0, 1.5 Hz, 1H), 7.10 (d, J
= 8.0 Hz, 2H), 7.05 – 7.02 (m, 3H), 6.92 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 4.89 (d, J
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= 15.5 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 2.31 (s, 3H), 1.73 (s, 3H); C NMR (125 MHz,
CDCl3): δ 172.3, 153.9, 141.4, 139.1, 138.4, 135.3, 129.8, 129.7, 128.6, 125.8, 125.8, 125.6,
125.3, 124.2, 123.2, 121.8, 120.7, 116.6, 111.0, 65.6, 53.0, 24.7, 21.2; HRMS (ESI – Orbitrap)
m/z: [M+Na]+ Calcd for C28H22F3NO2Na 484.1500; Found 484.1487.
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1-(2-(4-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-chromeno[3,4-
c]pyridin-3-yl)ethanone (3t)
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Yield: 18 mg, 32% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3073, 1666, 1601, 1067; 1H NMR (500 MHz, CDCl3): δ 7.62 (q, J = 8.5 Hz, 4H),
7.39 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.10 (s, 2H), 7.05 (d, J = 7.5 Hz, 1H), 7.02 –
6.98 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.41 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.72
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(d, J = 15.5 Hz, 1H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3): δ 172.1, 164.0, 162.0, 153.9,
141.3, 137.3, 134.3, 129.8, 128.5, 127.5, 127.4, 125.9, 125.9, 125.3, 124.6, 123.1, 121.9, 120.6,
116.7, 116.4, 116.2, 111.7, 65.5, 53.0, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C27H19F4NO2Na 488.1250; Found 488.1256.
1-(2-(4-propylphenyl)-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-chromeno[3,4-
c]pyridin-3-yl)ethanone (3u)
Yield: 28 mg, 47% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3056, 1666, 1606, 1065; 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.0 Hz, 2H),
7.59 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 8.0, 1.5 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.10 (d, J = 8.5 Hz,
2H), 7.04 (td, J = 7.5, 1.5 Hz, 3H), 6.92 (dd, J = 8.0, 1.0 Hz, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 4.89
(d, J = 15.0 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 2.56 – 2.53 (m, 2H), 1.73 (s, 3H), 1.62 – 1.57 (m,
2H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 172.4, 153.9, 143.9, 141.5, 138.5,
135.5, 129.7, 129.2, 128.6, 125.8, 125.8, 125.7, 125.3, 124.2, 123.2, 121.8, 120.8, 116.6, 111.0,
65.6, 53.0, 37.7, 24.7, 24.3, 13.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C30H26F3NO2Na 512.1813; Found 512.1823.
1-(2-phenyl-4-(thiophen-2-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3v)
Yield: 23 mg, 50% yield, as colorless foam; Rf = 0.23 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 2922, 1648, 1605, 1033; 1H NMR (500 MHz, CDCl3): δ 7.39 (dd, J = 7.5, 1.5 Hz,
1H), 7.31 – 7.28 (m, 3H), 7.27 (dd, J = 5.5, 1.5 Hz, 1H), 7.22 – 7.18 (m, 3H), 7.13 (d, J = 3.5 Hz,
1H), 7.01 (td, J = 7.5, 1.5 Hz, 1H), 6.93 (dd, J = 5.5, 4.0 Hz 1H), 6.90 (dd, J = 8.0, 1.0 Hz, 1H),
6.66 (s, 1H), 6.45 (s, 1H), 4.89 (d, J = 15.0 Hz, 1H), 4.83 (d, J = 15.0 Hz, 1H), 1.69 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 171.5, 153.9, 140.3, 138.5, 138.1, 129.6, 129.0, 128.8, 128.7,
126.8, 126.8, 126.6, 126.0, 125.6, 124.2, 123.2, 121.7, 120.7, 116.6, 111.5, 65.6, 49.7, 33.6,
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24.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C24H19NO2SNa 408.1034; Found
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408.1028.
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1-(4-(thiophen-2-yl)-2-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3w)
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Yield: 35 mg, 74% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3069, 1665, 1606, 1040; 1H NMR (500 MHz, CDCl3): δ 7.38 (dd, J = 7.5, 1.5 Hz,
1H), 7.25 (dd, J = 5.0, 1.0 Hz, 1H), 7.20 (td, J = 8.0, 1.5 Hz, 1H), 7.16 (s, 5H), 7.01 (td, J = 7.5,
1.5 Hz, 1H), 6.92 (dd,J = 5.5, 1.5 Hz, 1H), 6.89 (dd, J = 8.0, 1.0 Hz, 1H),6.65 (s, 1H), 6.41 (s,
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1H), 4.88 (d, J = 15.5 Hz, 1H), 4.83 (d, J = 15.5 Hz, 1H), 2.32 (s, 3H), 1.71 (s, 3H); C NMR
(125 MHz, CDCl3): δ 171.7, 153.8, 140.3, 138.9, 138.1, 135.7, 129.7, 129.5, 126.8, 126.7,
126.5, 125.9, 125.3, 124.2, 123.2, 121.7, 120.8, 116.5, 110.8, 65.6, 49.7, 24.8, 21.2; HRMS
(ESI – Orbitrap) m/z: [M+Na]+ Calcd for C25H21NO2SNa 422.1191; Found 422.1188.
1-(2-(4-bromophenyl)-4-(thiophen-2-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3x)
Yield: 21 mg, 38% yield, as colorless foam; Rf = 0.23 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3063, 1670, 1586, 1072; H NMR (500 MHz, CDCl3): 7.45 (d, J = 8.5 Hz, 2H),
7.37 (dd, J = 7.5, 1.3 Hz, 1H), 7.27 (dd, J = 5.0, 1.0 Hz, 1H), 7.21 (td, J =8.0, 1.5 Hz, 1H), 7.12
(d, J = 3.5 Hz, 1H), 7.09 (d, J = 6.0 Hz, 2H), 7.01 (td, J = 7.5, 1.1 Hz, 1H), 6.93 (dd, J = 5.10,
3.5 Hz, 1H), 6.90 (dd, J = 8.0, 1.0 Hz, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 4.88 (d, J = 15.0 Hz, 1H),
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4.83 (d, J = 15.5 Hz, 1H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3): δ 171.3, 153.8, 140.0,
137.4, 137.0, 132.3, 129.7, 127.4, 126.9, 126.7, 126.1, 124.1, 123.2, 122.8, 121.8, 120.6, 116.6,
112.1, 65.5, 49.6, 24.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C24H18BrNO2SNa
486.0139; Found 486.0132.
1-(2-(4-fluorophenyl)-4-(thiophen-2-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3y)
Yield: 12 mg, 24% yield, as colorless foam; Rf = 0.37 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3072, 1670, 1599, 1229; 1H NMR (500 MHz, CDCl3): δ7.37 (dd, J = 7.5, 1.5 Hz,
1H), 7.28 (dd, J = 5.5, 1.5 Hz, 1H), 7.23 – 7.19 (m, 3H), 7.13 (d, J = 3.5, Hz, 1H), 7.06 – 6.99
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(m, 3H), 6.94 (dd, J = 5.0, 3.5 Hz, 1H), 6.90 (dd, J = 8.0, 1.0 Hz, 1H), 6.65 (s, 1H), 6.40 (s, 1H),
4.89 (d, J = 15.5Hz, 1H), 4.83 (d, J = 15.0 Hz, 1H), 1.70 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 171.4, 163.9, 161.9, 153.8, 140.2, 137.0, 134.7, 129.6, 127.8, 127.7, 126.9, 126.6, 125.6, 124.2,
123.1, 121.7, 120.6, 116.6, 116.2, 116.1, 111.5, 65.5, 49.7, 24.8; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C24H18FNO2SNa 426.0940; Found 426.0930.
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1-(2-(4-propylphenyl)-4-(thiophen-2-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3z)
Yield: 24 mg, 47% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3070, 1667, 1606, 1040; H NMR (500 MHz, CDCl3): δ 7.39 (d, J = 8.5Hz, 1H),
7.26 – 7.25 (m, 1H), 7.20 (td, J = 8.0, 1.5 Hz, 1H), 7.12 (s, 5H), 7.01 (t, J = 7.5Hz, 1H), 6.92 (
dd, J = 5.0, 3.5 Hz1H), 6.90 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 4.89 (d, J = 15.0 Hz,
1H), 4.84 (d, J = 15.0 Hz, 1H), 2.55 (t, J = 7.5 Hz, 2H), 1.70 (s, 3H), 1.63 – 1.57 (m, 2H), 0.92
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(t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl3): δ 171.7, 153.8, 143.6, 140.4, 138.2, 135.9,
129.5, 129.1, 126.8, 126.8, 126.5, 125.9, 125.2, 124.2, 123.2, 121.7, 120.8, 116.5, 110.7, 65.6,
49.7, 37.7, 26.9, 24.8, 24.4, 13.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C27H25NO2SNa 450.1504; Found 450.1512.
1-(4-(thiophen-2-yl)-2-(thiophen-3-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3aa)
Yield: Trace, HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C22H17NO2S2Na 414.0598;
Found 414.0599.
1-(9-fluoro-2,4-diphenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone (3ab)
Yield: 30 mg, 63% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3063, 1665, 1591, 1074; 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 7.0 Hz, 2H),
7.36 – 7.30 (m, 3H), 7.28 – 7.27 (m, 3H), 7.13 (s, 2H), 7.09 (dd, J = 9.0, 3.0 Hz, 1H), 6.92 – 6.88
(m, 1H), 6.86 (dd, J = 9.0, 5.5 Hz, 1H), 6.53 (s, 1H), 6.34 (s, 1H), 4.86 (d, J = 15.5 Hz, 1H), 4.74
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(d, J = 15.5 Hz, 1H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3): δ 172.0, 158.8, 156.9, 149.7,
138.7, 138.3, 137.0, 129.0, 128.9, 128.8, 128.6, 128.1, 127.0, 125.8, 124.2, 122.1, 117.4, 117.3,
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115.5, 115.3, 111.4, 109.8, 109.6, 65.8, 53.4, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+
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Calcd for C26H20FNO2Na 420.1376; Found 420.1368.
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1-(9-fluoro-4-phenyl-2-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3ac)
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Yield: 33 mg, 67% yield, as colorless foam; Rf = 0.22 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3060,1667, 1589, 1025; H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 7.0 Hz, 2H),
7.34 – 7.27 (m, 3H), 7.10 – 7.07 (m, 3H), 7.02 (s, 2H), 6.89 (td, J = 8.5, 3.0 Hz, 1H), 6.85 (dd, J
= 9.0, 5.0 Hz, 1H), 6.52 (s, 1H), 6.30 (s, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.73 (d, J = 15.5 Hz,
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1H), 2.30 (s, 3H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3): δ 172.1, 158.8, 156.9, 149.7,
139.0, 138.8, 137.0, 135.5, 129.7, 128.9, 128.5, 128.1, 125.7, 124.4, 122.2, 122.1, 117.4, 117.3,
115.4, 115.3, 110.7, 109.8, 109.6, 65.9, 53.4, 24.8, 21.2; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C27H22FNO2Na 434.1532; Found 434.1522.
1-(2-(4-bromophenyl)-9-fluoro-4-phenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3ad)
Yield: 22 mg, 39% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3062, 1669, 1489, 1073, 1032; 1H NMR (500 MHz, CDCl3): δ 7.46 (d, J = 7.0 Hz,
2H), 7.41 (d, J = 8.5 Hz, 2H), 7.35 – 7.30 (m, 3H), 7.07 (dd, J = 9.0, 3.0 Hz, 1H), 6.99 (d, J = 7.0
Hz, 2H), 6.91 (td, J = 8.5, 3.0 Hz, 1H), 6.86 (dd, J = 9.0, 5.5 Hz, 1H), 6.52 (s, 1H), 6.35 (s, 1H),
4.85 (d, J = 15.5 Hz, 1H), 4.73 (d, J = 15.5 Hz, 1H), 1.72 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 171.7, 158.8, 156.9, 149.7, 137.6, 137.2, 136.8, 132.3, 129.0, 128.7, 128.0, 127.2, 124.3, 122.9,
117.4, 117.4, 115.6, 115.5, 112.0, 109.8, 109.6, 65.8, 53.4, 24.7; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C26H19BrFNO2Na 498.0481; Found 498.0472.
1-(9-fluoro-2-(4-fluorophenyl)-4-phenyl-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3ae)
Yield: 25 mg, 51% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3064, 1669, 1597, 1099, 1024; 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 7.0 Hz,
2H), 7.36 – 7.29 (m, 3H), 7.09 – 7.06 (m, 3H), 6.98 (t, J = 9.0 Hz, 2H), 6.90 (td, J = 9.0, 3.0 Hz,
1H), 6.86 (dd, J = 9.0, 5.0 Hz, 1H), 6.52 (s, 1H), 6.29 (s, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.73 (d,
13
J = 15.5 Hz, 1H), 1.71 (s, 3H); C NMR (125 MHz, CDCl3): δ 171.8, 163.9, 161.9, 158.8,
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156.9, 149.7, 137.6, 136.9, 129.0, 128.7, 128.0, 127.5, 127.4, 127.1, 117.4, 117.3, 116.3, 116.1,
115.6, 115.4, 111.4, 109.8, 109.6, 65.8, 53.4, 24.7; HRMS (ESI – Orbitrap) m/z: [M+Na]+
Calcd for C26H19F2NO2Na 438.1282; Found 438.1265.
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1-(9-fluoro-4-phenyl-2-(4-propylphenyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3af)
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Yeild: 26 mg, 50% yield, as colorless foam; Rf = 0.25 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3063, 1669, 1591, 1549, 1041; 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 7.0 Hz,
2H), 7.35 – 7.29 (m, 3H), 7.08 (d, J= 6.5 Hz, 3H), 7.04 (s, 2H), 6.90 (t, J = 8.5 Hz, 1H), 6.87 –
6.83 (m, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H),
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2.54 (t, J = 8.0 Hz, 2H), 1.71 (s, 3H), 1.61 – 1.56 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); C NMR
(125 MHz, CDCl3): δ 172.1, 158.8, 156.9, 149.7, 143.7, 138.8, 137.1, 135.7, 129.1, 128.9,
128.5, 128.1, 126.7, 125.7, 124.4, 122.1, 117.4, 117.3, 115.4, 115.2, 110.6, 109.8, 109.6, 65.9,
53.4, 37.7, 24.8, 24.4, 13.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C29H26FNO2Na
462.1845; Found 462.1848.
1-(9-fluoro-4-phenyl-2-(thiophen-3-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3ag)
Yield: 16 mg, 33% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3066, 1664, 1490, 1079; 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J = 7.0 Hz, 2H),
7.34 – 7.26 (m, 4H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.93 (d, J = 5.5 Hz,
1H), 6.89 (dd, J = 8.5, 3.0 Hz, 1H), 6.86 (dd, J = 8.5, 5.0 Hz, 1H), 6.48 (s, 1H), 6.32 (s, 1H), 4.85
13
(d, J = 15.5 Hz, 1H), 4.75 (d, J = 15.5 Hz, 1H), 1.81 (s, 3H); C NMR (125 MHz, CDCl3): δ
172.1, 158.8, 156.9, 149.7, 140.1, 137.2, 134.1, 128.9, 128.5, 127.8, 127.1, 125.4, 124.3, 122.2,
117.4, 117.3, 115.5, 115. 3, 110.2, 109.8, 109.6, 65.9, 53.3, 24.2; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C24H18FNO2SNa 426.0940; Found 426.0929.
1-(9-fluoro-2-phenyl-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-yl)ethanone
(3ah)
Yield: Trace, HRMS (ESI – Orbitrap) m/z: [M-1]+ Calcd for C27H22FNO2 410.1556; Found
410.1546.
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1-(2-(4-bromophenyl)-9-fluoro-4-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3ai)
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Yield: 21 mg, 36% yield, as colorless foam; Rf = 0.23 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3058, 1666, 1589, 1073; H NMR (500 MHz, CDCl3): 7.42 (d, J = 8.0 Hz, 2H),
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7.34 (d, J = 7.0 Hz, 2H), 7.26 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 7.5 Hz, 2H), 7.06 (d, J = 8.5 Hz,
1H), 7.01 (d, J = 5.0 Hz, 1H), 6.91 – 6.83 (m, 2H), 6.48 (s, 1H), 6.34 (s, 1H), 4.84 (d, J = 15.0
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Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 2.32 (s, 3H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3): δ
171.7, 158.8, 156.8, 149.7, 138.5, 137.5, 137.3, 133.7, 132.3, 129.7, 127.9, 127.2, 124.1, 122.8,
121.9, 121.9, 117.4, 117.3, 115.6, 115.4, 112.0, 109.8, 109.6, 65.8, 53.2, 24.7, 21.2; HRMS (ESI
– Orbitrap) m/z: [M+Na]+ Calcd for C27H21BrFNO2Na 512.0637; Found 512.0627.
1-(9-fluoro-2-phenyl-4-(thiophen-2-yl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3aj)
Yield: 31 mg, 64% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3070, 1666, 1590, 1177; 1H NMR (500 MHz, CDCl3): δ 7.33– 7.30 (m, 3H), 7.28
(dd, J = 5.0, 1.5 Hz, 1H), 7.22 (s, 2H), 7.12 (d, J = 3.5 Hz, 1H), 7.09 (dd, J = 9.0, 3.0 Hz, 1H),
6.94 (dd, J = 5.0, 3.5 Hz, 1H), 6.90 (td, J = 9.0, 3.0 Hz, 1H), 6.85 (dd, J = 9.0, 5.0 Hz, 1H), 6.68
13
(s, 1H), 6.35 (s, 1H), 4.86 (d, J = 15.5 Hz, 1H), 4.81 (d, J = 15.0 Hz, 1H) 1.70 (s, 3H); C
NMR (125 MHz, CDCl3): δ 171.6, 158.8, 156.9, 149.71, 140.0, 138.5, 138.3, 129.1, 126.9,
126.7, 126.0, 123.8, 121.9, 121.9, 117.4, 117.4, 115.7, 115.5, 110.9, 109.9, 109.8, 65.6, 49.6,
24.8; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C24H18FNO2SNa 426.0940; Found
426.0940.
1-(9-fluoro-4-(thiophen-2-yl)-2-(p-tolyl)-4,5-dihydro-3H-chromeno[3,4-c]pyridin-3-
yl)ethanone (3ak)
Yield: 21 mg, 41% yield, as colorless foam; Rf = 0.22 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3071, 1670, 1492, 1031; 1H NMR (500 MHz, CDCl3): δ 7.26 – 7.25 (m, 1H), 7.12
– 7.11 (m, 5H), 7.08 (dd, J = 9.0, 3.0 Hz, 1H), 6.93 (dd, J = 5.0, 3.5 Hz, 1H), 6.90 – 6.86 (m,
1H), 6.84 (dd, J = 9.0, 5.0 Hz,1H) 6.67 (s, 1H), 6.32 (s, 1H), 4.85 (d, J = 15.5 Hz, 1H), 4.80 (d,
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J = 15.0 Hz, 1H), 2.33 (s, 3H), 1.71 (s, 3H); C NMR (125MHz, CDCl3): δ 171.6, 158.8,
156.9, 149.7, 149.7, 140.0, 139.1, 138.6, 135.5, 129.8, 126.8, 126.6, 126.5, 125.9, 117.4, 117.3,
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115.6, 115.4, 110.2, 110.0, 109.8, 65.7, 49.6, 24.8, 21.2; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C25H20FNO2SNa 440.1096; Found 440.1087.
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1-(2,4-diphenyl-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone (3al)
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Yield: 22 mg, 46% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3059, 1667, 1596, 1032; 1H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 7.5 Hz, 2H),
7.51 (dd, J = 7.5, 1.5 Hz, 1H), 7.36 – 7.33 (m, 3H), 7.31 (d, J = 7.5 Hz, 1H), 7.26 – 7.24 (m, 4H),
7.22 (dd, J = 3.0, 2.0 Hz, 1H), 7.20 (dd, J = 7.5, 1.5 Hz, 1H), 7.13 (s, 1H), 6.62 (s, 1H), 6.40 (s,
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1H), 3.83 (d, J = 16.0 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 1.72 (s, 3H); C NMR (125 MHz,
CDCl3): δ 171.9, 138.4, 137.7, 137.3, 133.6, 132.6, 132.2, 131.6, 129.2, 128.9, 128.7, 128.5,
128.4, 128.1, 127.8, 127.5, 126.1, 125.8, 125.1, 115.1, 57.0, 27.3, 24.6; HRMS (ESI –
Orbitrap) m/z: [M+Na]+ Calcd for C26H21NOSNa 418.1242; Found 418.1232.
1-(4-phenyl-2-(p-tolyl)-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone (3am)
Yield: 13 mg, 26% yield, as colorless foam; Rf = 0.21 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 2925, 1663, 1371, 1039; 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 7.0 Hz, 2H),
7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 – 7.32 (m, 3H), 7.29 (d, J = 7 Hz, 1H), 7.23 – 7.21 (m, 1H),
7.19 (dd, J = 7.5, 1.5 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 7.0 Hz, 2H), 6.61 (s, 1H),
6.36 (s, 1H), 3.83 (d, J = 16.0 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 2.29 (s, 3H), 1.73 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 172.0, 138.6, 137.7, 137.3, 135.5, 133.6, 132.6, 132.3, 131.6,
129.6, 129.2, 128.7, 128.4, 128.4, 128.0, 127.8, 127.2, 126.1, 125.7, 125.1, 114.4, 57.0, 27.3,
24.6, 21.1; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C27H23NOSNa 432.1398; Found
432.1406.
1-(2-(4-bromophenyl)-4-phenyl-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone
(3an)
Yield: 18 mg, 31% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3059, 1668, 1584, 1072, 1035; 1H NMR (500 MHz, CDCl3): δ 7.62 (d, J = 7.0 Hz,
2H), 7.48 (dd, J = 8.0, 2.0 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.37 – 7.34 (m, 2H), 7.33 – 7.30 (m,
2H), 7.23 (dd, J = 7.5, 2.0 Hz 1H), 7.20 (dd, J = 7.5, 1.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 2H), 6.61
(s, 1H), 6.40 (s, 1H), 3.82 (d, J = 15.5 Hz, 1H), 3.14 (d, J = 15.5 Hz, 1H), 1.74 (s, 3H); 13CNMR
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(125 MHz, CDCl3): δ 171.7, 137.3, 137.1, 136.6, 132.6, 132.2, 132.1, 129.1, 128.8, 128.6,
128.3, 128.2, 128.1, 127.9, 127.1, 126.1, 125.1, 122.6, 115.7, 56.9, 27.3, 24.6; HRMS (ESI –
Orbitrap) m/z: [M+Na]+ Calcd for C26H20BrNOSNa 496.0347; Found 496.0346.
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1-(2-(4-fluorophenyl)-4-phenyl-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone
(3ao)
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Yield: 20 mg, 40% yield, as colorless foam; Rf = 0.22 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3061, 1668, 1598, 1077, 1034; 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 7.0 Hz,
2H), 7.49 (dd, J = 8.0, 2.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 3H), 7.32 (d, J = 7.0 Hz, 1H), 7.23 (td, J
= 8.0, 2.0 Hz, 2H), 7.09 (s, 2H), 6.96 (t, J = 8.5 Hz, 2H), 6.61 (s, 1H), 6.35 (s, 1H), 3.83 (d, J =
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16.0 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3): 171.8,
163.8, 161.8, 137.2, 132.6, 132.2, 129.1, 128.8, 128.5, 128.3, 128.1, 127.9, 127.5, 127.4, 126.1,
125.1, 116.1, 116.0, 115.1, 57.0, 27.3, 24.6; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C26H20FNOSNa 436.1147; Found 436.1149.
1-(4-phenyl-2-(4-propylphenyl)-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone
(3ap)
Yield: 12 mg, 23% yield, as colorless foam; Rf = 0.20 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3058, 1668,1605, 1035; H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 7.5 Hz, 2H),
7.51 (dd, J = 7.5, 1.5 Hz, 1H), 7.36 – 7.33 (m, 3H), 7.30 (d, J = 7.5 Hz, 1H), 7.23 – 7.18 (m, 2H),
7.07 – 7.03 (m, 4H), 6.61 (s, 1H), 6.36 (s, 1H), 3.83 (d, J = 15.5 Hz, 1H), 3.15 (d, J = 16.0 Hz,
13
1H), 2.54 – 2.51 (m, 2H), 1.72 (s, 3H), 1.60 – 1.56 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); C NMR
(125 MHz, CDCl3): δ 172.1, 143.4, 137.8, 137.4, 135.8, 132.6, 132.3, 129.0, 128.7, 128.4,
128.3, 128.0, 127.8, 127.1, 126.1, 125.7, 125.1, 114.3, 57.0, 37.7, 27.4, 24.6, 24.4, 13.8; HRMS
(ESI – Orbitrap) m/z: [M-1]+Calcd for C29H27NOS 436.1735; Found 437.1741.
1-(4-phenyl-2-(thiophen-3-yl)-4,5-dihydro-3H-thiochromeno[3,4-c]pyridin-3-yl)ethanone
(3aq)
Yield: 18, 39% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3103, 1670, 1588, 1230; 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 7.0 Hz, 2H),
7.47 – 7.45 (m, 1H), 7.36 (dd, J = 7.5, 2.0 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H), 7.25 – 7.24 (m, 1H),
7.23 – 7.20 (m, 2H), 7.02 (d, J = 1.5 Hz, 1H), 6.92 (dd, J = 5.0, 1.0 Hz, 1H), 6.56 (s, 1H), 6.37
(s, 1H), 3.83 (d, J = 15.5 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 1.83 (s, 3H); 13C NMR (125 MHz,
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CDCl3): δ 172.0, 140.2, 137.5, 132.6, 132.2, 129.1, 128.7, 128.3, 128.1, 128.1, 127.8, 127.4,
126.9, 126.1, 125.5, 125.1, 121.8, 113.9, 56.9, 27.5, 24.0; HRMS (ESI – Orbitrap) m/z:
[M+Na]+ Calcd for C24H19NOS2Na 424.0806; Found: 424.0803.
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General procedure for BF3.OEt2 mediatedsynthesis of N-acetylated pyrano /
thiopyranopyridines (5)
To a mixture of 1 equiv of (3E,5E)-3,5-diarylidenedihydro-2H-pyran-4(3H)-one / (3Z,5Z)-3,5-
diarylidene dihydro-2H-thiopyran-4(3H)-one (0.12 mmol) and 3 equiv of aryl or hetero aryl
o
alkyne (0.36 mmol) in acetonitrile (2 ml) with 2 equiv of water at 50 C added 3 equiv of
BF3.OEt2 (0.36 mmol). The reaction mixture was then allowed to stir for 10 - 90 minutes by
monitoring the TLC. After the completion of reaction the reaction mixture was extracted with
ethyl acetate (3 X 10 ml), evaporated in vacuo and purified by column chromatography using
100 – 200 mesh silica gel with ethyl acetate/ hexane as the eluent to afford the corresponding N-
acetylated pyridine as the product.
(Z)-1-(6-phenyl-8-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)-3,4-dihydro-1H-pyrano[3,4-
c]pyridin-7(8H)-yl)ethanone (5a)
Yield: 40 mg, 77% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
1
(neat, cm-1): 3063, 1668, 1587, 1097, 1040; H NMR (500 MHz, CDCl3): δ 7.36 (d, J = 5.0,
Hz, 1H), 7.31 (d, J = 6.5 Hz, 3H), 7.26 – 7.25 (m, 1H), 7.20 (d, J = 4.0 Hz, 2H), 7.09 – 7.06 (m,
2H), 7.04 (d, J = 3.5 Hz, 1H), 6.93 (dd, J = 5.0, 3.5 Hz, 1H), 6.89 (s,1H), 6.61 (s,1H), 6.43
(s,1H), 4.95 (dd, J = 14.5, 1.5 Hz, 1H), 4.71 (dd, J = 14.5, 1.5 Hz, 1H), 4.36 (s, 2H), 1.68 (s,
13
3H); C NMR (125 MHz, CDCl3): δ 171.3, 140.3, 139.4, 138.5, 137.2, 133.1, 132.9, 129.0,
128.7, 128.6, 128.4, 127.6, 126.8, 126.6, 126.4, 126.1, 115.6, 111.9, 66.1, 65.9, 50.0, 24.7;
HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C25H21NO2S2Na 454.0911; Found 454.0911.
(Z)-1-(8-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)-6-(p-tolyl)-3,4-dihydro-1H-pyrano[3,4-
c]pyridin-7(8H)-yl)ethanone (5b)
Yield: 21 mg, 40% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
1
(neat, cm-1): 3063, 1669, 1587, 1183; H NMR (500 MHz, CDCl3): δ 7.35 (dd, J = 5.5, 1.0
Hz, 1H), 7.24 (dd, J = 5.0 Hz, 1.0 Hz, 1H), 7.10 (s, 3H), 7.08 (dd, J = 5.0, 4.0 Hz, 2H), 7.06 –
7.02 (m, 2H), 6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.88 (s, 1H), 6.60 (s, 1H), 6.39 (s, 1H), 4.94 (dd, J
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= 14.5, 1.5 Hz, 1H), 4.71 (dd, J = 14.5, 2.0 Hz, 1H), 4.36 (s, 2H), 2.32 (s, 3H), 1.69 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 171.4, 140.3, 139.4, 138.8, 137.2, 135.7, 132.7, 129.7, 129.1,
128.4, 127.6, 126.7, 126.7, 126.6, 126.3, 125.9, 125.8, 115.5, 112.4, 111.1, 66.13, 65.9, 50.0,
24.7, 21.2; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C26H23NO2S2Na 468.1068; Found
468.1074.
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(Z)-1-(4-benzylidene-6,8-diphenyl-3,4-dihydro-1H-thiopyrano[3,4-c]pyridin-7(8H)-
yl)ethanone (5c)
Yield: 17 mg, 33% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3058, 1665, 1599, 1054, 1030; 1H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.5 Hz,
2H), 7.41 (t, J = 8.0 Hz, 2H), 7.34 – 7.28 (m, 7H), 7.24 – 7.23 (m, 2H), 7.08 (s, 2H), 6.96 (s,
1H), 6.48 (s, 1H), 6.41 (s, 1H), 3.74 (d, J = 14.5 Hz, 1H), 3.69 (d, J = 14.5 Hz, 1H) 3.50 (d, J =
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18.5 Hz, 1H), 3.36 (d, J = 18.5 Hz, 1H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3): δ171.7,
138.4, 137.3, 136.8, 136.5, 131.5, 131.4, 129.6, 129.3, 128.9, 128.8, 128.5, 128.3, 128.2, 127.3,
125.8, 125.6, 115.0, 57.7, 29.2, 27.1,24.5; HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for
C29H25NOSNa 458.1555; Found 458.1560.
(Z)-1-(4-benzylidene-8-phenyl-6-(p-tolyl)-3,4-dihydro-1H-thiopyrano[3,4-c]pyridin-7(8H)-
yl)ethanone (5d)
Yield: 9 mg, 17% yield, as colorless foam; Rf = 0.18 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3028, 1665, 1607, 1033; H NMR (500 MHz, CDCl3): δ7.44 (d, J = 7.5 Hz, 3H),
7.40 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 5H), 7.05 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 7.0 Hz,
2H), 6.95 (s, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 3.73 (d, J = 14.5 Hz, 1H), 3.69 (d, J = 14.5 Hz, 1H),
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3.49 (d, J = 18.0 Hz, 1H), 3.37 (d, J = 18.5 Hz, 1H), 2.29 (s, 3H), 1.71 (s, 3H); C NMR (125
MHz, CDCl3): δ171.8, 138.6, 137.3, 136.8, 136.5, 135.5, 131.4, 131.2, 129.7, 129.6, 129.3,
128.7, 128.5, 128.2, 127.2, 125.7, 125.5, 114.3, 57.6, 29.2, 27.1, 24.6, 21.2; HRMS (ESI –
Orbitrap) m/z: [M+Na]+ Calcd for C30H27NOSNa 472.1711; Found 472.1710.
(Z)-1-(6-phenyl-8-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)-3,4-dihydro-1H-
thiopyrano[3,4-c]pyridin-7(8H)-yl)ethanone (5e)
Yield: 33 mg, 61% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
(neat, cm-1): 3069, 1666, 1592, 1036; 1H NMR (500 MHz, CDCl3): δ 7.37 (dd, J = 5.5, 1.5 Hz,
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1H), 7.30 – 7.29 (m, 3H), 7.26 (dd, J = 5.0, 1.5 Hz, 1H), 7.20 (d, J = 6.0 Hz, 2H), 7.14 (d, J =
3.5 Hz, 1H), 7.10 – 7.07 (m, 2H), 7.00 (s, 1H), 6.93 (dd, J = 5.0, 3.5 Hz, 1H), 6.62 (s, 1H), 6.38
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(s, 1H), 3.86 (s, 2H), 3.49 (d, J = 18.0 Hz, 1H), 3.41 (d, J = 18.0 Hz, 1H), 1.68 (s, 3H); C
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NMR (126 MHz, CDCl3): δ 171.2, 140.2, 139.5, 138.3, 136.6, 132.2, 129.5, 129.1, 129.0,
129.0, 128.6, 127.4, 126.9, 126.7, 126.6, 126.4, 126.1, 118.7, 114.5, 53.9, 28.6, 27.6, 24.6;
HRMS (ESI – Orbitrap) m/z: [M+Na]+ Calcd for C25H21NOS3Na 470.0683; Found 470.0683.
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(Z)-1-(8-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)-6-(p-tolyl)-3,4-dihydro-1H-
thiopyrano[3,4-c]pyridin-7(8H)-yl)ethanone (5f)
Yield: 24 mg, 43% yield, as colorless foam; Rf = 0.15 (hexane/ethyl acetate = 90/10); IR
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(neat, cm-1): 3026, 1667, 1510, 1038; H NMR (500 MHz, CDCl3): δ 7.37 (dd, J = 5.0, 1 Hz,
1H), 7.24 (dd, J = 5.5, 1.5 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 7.10 – 7.06 (m, 6H), 6.99 (s, 1H),
6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 3.86 (s, 2H), 3.48 (d, J = 18.5 Hz, 1H),
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3.41(d, J = 18.0 Hz, 1H), 2.32 (s, 3H), 1.69 (s, 3H); C NMR (125 MHz, CDCl3): δ 171.3,
140.3, 139.6, 138.7, 136.6, 135.5, 132.0, 129.6, 129.2, 128.9, 127.4, 126.9, 126.7, 126.5, 126.3,
126.0, 118.7, 113.8, 53.9, 31.6, 28.6, 27.6, 24.6, 21.2; HRMS (ESI – Orbitrap) m/z: [M+Na]+
Calcd for C26H23NOS3Na 484.0839; Found: 484.0834.
General procedure for BF3.OEt2 mediated synthesis of N-substituted chromeno /
thiochromeno pyridines (7)
To a mixture of 1 equiv of substituted arylidene chroman-4-one/thiochroman-4-one (0.12 mmol)
and 3 equiv of aryl or hetero aryl alkyne (0.36 mmol) in respective nitrile (2 ml) with 2 equiv of
water at 50 oC added 3 equiv of BF3.OEt2 (0.36 mmol). The reaction mixture was then allowed to
stir for 10 - 90 minutes by monitoring the TLC. After the completion of reaction the reaction
mixture was extracted with ethyl acetate (3 X 10 ml), evaporated in vacuo and purified by
column chromatography using 100 – 200 mesh silica gel with ethyl acetate/ hexane as the eluent
to afford the product.
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