Synthetic Strategy Studies for a Concise Access to Functionalized Pyrano[4,3-b]pyridin-7-ones: An Entry to Semi-Rigid Analogs of Antihistamines

Article abstract of DOI:10.1002/ejoc.202001016

We report short and efficient syntheses of polyfunctionalized 5,8-dihydro-7H-pyrano[4,3-b]pyridin-7-ones and 1,4-dihydro-3H-pyrano[4,3-c]pyridin-3-ones which can be considered as new aza analogs of 3-isochromanones and as promising scaffolds for medicinal chemistry. Depending on the nature of the substituent, three different and complementary synthetic methodologies were used allowing the introduction of significant diversity in the substituent on the lactone ring of the pyranopyridinones. The selective α-arylation of nitrile (S_NAr) and tert-butyl ester enolate (Pd catalyzed) followed by an acidic mediated lactonisation gives access to original C8-functionalized pyrano[4,3-b]pyridin-7-ones and a seleno-mediated cyclization to C1-functionalized pyrano[4,3-c]pyridin-3-ones. We have also applied the outlined synthetic methodologies to the preparation of potential semi-rigid analogs of antihistamines.

Full text of DOI:10.1002/ejoc.202001016

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthetic strategy studies for a concise access to functionalized
pyrano[4,3-b]pyridin-7-ones: An entry to semi-rigid analogs of
antihistamines
Authors: Anissa Beghennou, Kevin Passador, Anthony Passador,
Vincent Corcé, Serge Thorimbert, and Candice Botuha
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001016
Link to VoR: https://doi.org/10.1002/ejoc.202001016
01/2020

10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
Synthetic strategy studies for a concise access to functionalized
pyrano[4,3-b]pyridin-7-ones: An entry to semi-rigid analogs of
antihistamines
Anissa Beghennou,[a] Kevin Passador,[a] Anthony Passador,[a] Vincent Corcé,[a] Serge Thorimbert[a] and
Candice Botuha*[a]
[a]
Ms Anissa Beghennou, Dr Kevin Passador, Mr Anthony Passador, Dr Vincent Corcé, Pr Serge Thorimbert and Dr Candice Botuha, Institut Parisien de
Chimie Moléculaire, Sorbonne Université, CNRS, 4 place Jussieu, 75005 Paris, France
*Corresponding author Dr Candice Botuha (Email: candice.botuha@sorbonne-universite.fr) Web: http://www.ipcm.fr/article147.html
Abstract: We report short and efficient syntheses of
polyfunctionalized 5,8-dihydro-7H-pyrano[4,3-b]pyridin-7-ones and
1,4-dihydro-3H-pyrano[4,3-c]pyridin-3-ones which can be considered
as new aza analogs of 3-isochromanones and as promising scaffolds
for medicinal chemistry. Depending on the nature of the substituent,
three different and complementary synthetic methodologies were
used allowing the introduction of significant diversity in the substituent
on the lactone ring of the pyranopyridinones. The selective a-arylation
of nitrile (SNAr) and tert-butylester enolate (Pd catalyzed) followed by
an acidic mediated lactonisation gives access to original C8-
functionalized pyrano[4,3-b]pyridin-7-ones and a seleno-mediated
cyclization to C1-functionalized pyrano[4,3-c]pyridin-3-ones. We have
also applied the outlined synthetic methodologies to the preparation
of potential semi-rigid analogs of antihistamines.
Ph
N
O
HO
HO
O
O
O
OH
N
Ph
AKT2 enzyme inhibitor
antihistamines
F3C
O
A
N
C
B
N
N
O
D
N
O
E
O
N
O
OH O
Fungicide
DE Ring analogs of camptothecin
(anti-topoisomerase)
Figure 1. Example of molecules containing (aza) 3-isochromanone scaffold with
biological interest.
Among the four possible isomers of pyranopyridinones, three of
them, namely PP1 (N1)[4abc], PP3 (N3)[4de] and PP4 (N4)[4f], have been
described in the literature, albeit with a narrow range of substituent
(Scheme 1). However, the employed strategies narrow the
introduction of structural diversity on the lactone ring, a major
drawback for potential use in medicinal chemistry. Finally, the lack of
effective strategies to access these useful polyfunctionalized lactones
makes them still under-explored.
Introduction
3-isochromanones and derivatives belong to an important class
of heterocycle compounds found in several natural products or as
useful building blocks to access biological active compounds.[1]
Among them, aza analogs of 3-isochromanones or pyranopyridinones
derivatives containing a pyridine ring instead of a phenyl ring are less
known heterocycles despite some promising results obtained as
medicinal compounds (Figure 1).[2] Efforts have been dedicated to the
development of efficient syntheses of 3-isochromanones.[3] However,
limited synthetic procedures for the preparation of aza 3-
isochromanones analogs are reported.[4] The main synthetic
approaches to the construction of the delta lactone ring of 3-
isochromanones are based on sigmatropic rearrangement on
benzocyclobutenes, on ynamide or Baeyer Villiger oxidation on
benzocyclopentanones.[3bdk] These approaches arehardly appropriate
to the preparation of pyranopyridinones because pyridine based
starting material required in these strategies are not as accessible as
their benzo analogs.
Herein, we present a significant improvement in the synthesis
of pyranopyridinones using three different but complementary
synthetic methodologies allowing for the first time to easily access
polyfunctionalized 5,8-dihydro-7H-Pyrano[4,3-b]pyridin-7-ones PP1
and in particular 1,4-dihydro-3H-Pyrano[4,3-c]pyridin-3-ones PP2 for
which no synthesis has been reported yet. We report an optimized
synthetic procedure for selective monoarylation-nucleophilic
substitution of tert-butylester enolate and a-arylation of various
het(aryl)acetonitriles with ortho-substituted chloropyridine followed by
acidic mediated lactonisation. We described also an original seleno-
mediated cyclization on pyridyl substituted alkynol allowing to
construct substituted pyridine fused delta-lactones with efficiency. In
the second part of this article, we describe the preparation of original
potential semi-rigid analogs of antihistamines using the outlined
synthetic methodologies.
1
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10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
allyl, benzyl and propargyl substituent were thus obtained with yields
up to 89%.
Unsubstituted PP1 was first synthesized in 1957 by Bohlmann
and coll. from ethyl-2-methyl-pyridine-3-carboxylic acid in two steps
via a cyclocondensation of dilithiated intermediate.[4a] Then, in 1991,
OTBS
OH
CHO
Cl
NaBH4
TBSCl, imidazole
DMF, 20 °C, 20h,
87%
MeOH
0 °C to 20 °C, 4h
N
Cl
Alm and coll. reported the synthesis of
a polyhydroxylated
N
N
Cl
2
3
1
pyridolactone using a [2+2+2] cobalto-catalyzed cycloaddition in 9%
global yield with no functionalization of the lactone ring.[4b] Our first
approach to functionalized pyranopyridinone PP1 takes advantage of
a Buchwald type pallado-catalyzed a-arylation of tert-butyl acetate
ester with a TBS protected chloropyridine (method A, Scheme 1).[5a]
We prepared the required trimethylsilyl protected (2-chloropyridin-3-
yl)- methanol 3 from commercially available 2-chloropyridine-3-
carboxaldehyde 1 by reduction with sodium borohydride followed by
hydroxyl group protection with tert-butyltrimethylsilyl chloride
(Scheme 2).[6]
89%
O
Ot-Bu
tBuXPhos Pd G1
LiHMDS, toluene
0 °C 2h
61%
OTBS
OTBS
O
O
O
LiHMDS, R3X
PTSA. H2O
N
O
N
Ot-Bu
toluene,
20 °C, 20h
N
Ot-Bu
THF, 0 °C to 20 °C
20h
R2
R3
4
PP1 a-g
R3 = Me, 5b, 89%
R
R
R
R
R
3 = (Me)2, 5c, 89%
3 = i-Pr, 5d, 62%
3 = Allyl, 5e, 89%
3 = Bn, 5f, 61%
O
N
CO2Me
3 = Propargyl, 5g, 59%
reduction-lactonisation
sequence [4c]
R2
O
O
O
O
O
4
N
OH
3
O
N
N
O
N
Lithiation-carboxylation
hydrolysis sequence [4a]
Pinner reaction
rearrangement [4e]
N
O
O
N
2
O
R1
1
PP1a, 20%
PP1b, 55%
PP1c, 99%
CN
PP1d, 66%
N
N1, PP1, R1 = H or CH2OH, R2 = H
N3, PP3, R1 = H or CO2Me, R2 = Me
N4, PP4, R1 = R2 = H
O
O
O
O
O
N
O
N
N
Our work :
Ph
PP1e, 67%
PP1f, 68%
PP1g, 66%
A : (i) Pd-catalysed
R2
C : Seleno-mediated
cyclization
α-arylation. (ii) Substitution
(iii) Cyclization
O
O
OTBS
Cl
N
1
N
1
2
Scheme 2. Synthesis of alkyl substituted pyranopyridinones PP1a-g following
method A
2
O
B : (i) SNAr
(ii) Pinner reaction
N
R4
R3
Pyridopyridinones PP1&PP2
The pyranopyridinones PP1a-g are easily obtained from 5 by
an acidic deprotection followed by a lactonisation using 4 eq. of PTSA
monohydrate. The unsubstituted pyranopyridinone PP1a was
R2
R3
=
=
H, Alkyl, Aryl
H, Alkyl, Aryl, Heteroaryl
Allyl, Propargyl, Benzyl
R4 = H, Alkyl, NR2
obtained in 20
%
isolated yield whereas substituted
pyranopyridinones PP1b-g were isolated for the first time in yield from
55% to 99% for gem-dimethyl PP1c benefiting from Thorpe Ingold
effect for cyclization.[8]
Scheme 1. Main synthetic strategies for pyranopyridinones and our
approaches
We examined a strategy based on the Pinner reaction (method
B, Scheme 1) to introduce aromatic substituent on the methylene
group of the pyridine ester 4. It requires the preparation of nitrile
analogs of compounds 5 via nucleophilic aromatic substitution of a
chloropyridine (Scheme 2 and Scheme 3).[9]
The selective monoarylation reaction of tert-butyl acetate with 3
was achieved with tert-BuXphosPdCl (1 mol%) as a pre-catalyst and
LiHMDS as a base in toluene. The reaction was run at 0°C to prevent
the potential formation of bis-arylated by-product. The reaction
reached 86% conversion by adding 2 mol % of the pre-catalyst. In our
preliminary studies when ethyl acetate was employed instead of tert-
butyl acetate, less than 30% conversion was observed.
The aryl-substituted 2-pyridyl acetonitrile precursors 7a-e were
prepared from the protected 2-chloropyridine 3 and the corresponding
aryl or heteroaryl acetonitrile.
We first studied the substitution step by using phenylacetonitrile as a
model nucleophile (Table 1).[10] When treated with 3 equivalents of
LiHMDS in the presence of 2 equivalents of phenylacetonitrile in
toluene at room temperature, the chloropyridine 3 gave the expected
SNAr product 7a in a 62 % isolated yield (Table 1 entry 1). However,
these conditions were ineffective when using other substituted
arylacetonitriles.
However, under these conditions the same a-arylation using
substituted esters was not productive. The presence of an a-
substituent on the enolate generally leads to the instability of alkali
ester enolates or the formation of bis-arylated products. [5b] The use of
substituted zinc enolate esters could be required. Besides, such
arylation reactions are subsequently substrate-dependent and limited
to a small range of substrate.[7] We introduce various substituent such
as alkyl/ benzylic/ allylic and propargyl groups on pyrido ester 4 by a
deprotonation/ nucleophilic substitution sequence. After optimization,
this transformation was achieved successfully by using LiHMDS as a
base and a slight excess of the corresponding halide compound as
the electrophile. The expected substituted pyridoesters 5 with alkyl,
Among the few modifications screened (solvent, base, temperature)
to improve the yield, the reaction time and the scope of the SNAr
reaction, the use of a large excess of NaH in THF at 70 °C was found
to be the best reaction conditions allowing us to isolate the expected
SNAr product with an optimized yield of 69% (Table 1, entry 5).
Interestingly, this protocol (2 equiv. of phenylacetonitrile in the
2
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10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
presence of 5 equiv. of NaH in THF at reflux 3h), was successively
extended to other (Het)arylacetonitrile compounds giving the
corresponding SNAr product with yields ranging from 56 to 74%
(Scheme 3). The nucleophilic substitution was also performed on the
more hindered phenyl substituted chloropyridine 6 giving the expected
product 7e as a 3/1 mixture of diastereoisomers (Scheme 3).
using pyridoalkynols (Scheme 4). We based our approach on the work
of Tiecco et al.[11] who described the conversion of hydroxyl alkynyl
phenyl selenides into delta-lactones through proton-induced ring-
closure reaction. However, there are limited examples of delta-
lactones synthesized using this methodology with only one example
of a benzofused lactone and no example containing a heteroaromatic
ring. We thus first investigated the possible conversion of
alkynylpyridyl derivatives into pyranopyridinones PP1 and PP2 using
this seleno mediated cyclization. The alkynyl pyridyl carboxaldehydes
8 and 9 were synthesized with good yields from the corresponding
bromopyridine derivatives via the Sonogashira reaction using an
improved procedure. The best conditions were using Pd(Cl)2(PPh3)2
and CuI as catalysts, DABCO as a base instead of Et3N (Scheme
4).[12] The alkynyl deprotection was carried out with potassium
carbonate in methanol in 5 min affording the expected alkynyl pyridyl
carboxaldehyde 10 and 11 in 95% and 89% yield respectively.
Table 1. Optimization table for nucleophilic substitution of 3
OTBS
OTBS
PhCH2CN
CN
N
Cl
Base, conditions
N
Ph
7a
3
Yield
(%)[a]
Entry
Base
Conditions
1
2
3
LiHMDS (3 equiv.) Toluene, 0 °C to rt, 24h
62
20
K2CO3
TMS
O
O
O
N
N
N
2
MeOH
20 °C 5 min
2
2
PdCl2(PPh3)2 cat.
Br
NaNH2 (4 equiv.)
Toluene, rt, 24h
NMP, 110 °C
1
1
1
CuI (cat.), DABCO
THF, 20 )C, 1h
TMS
[b]
N1, 8, 91%
N2, 9, 99%
N1, 10, 95%
N2, 11, 89%
tBuOK (3 equiv.)
-
OMe
NaBH4
THF/H2O
0 °C, 7 min
R1MgBr, THF
4
NaH (2 equiv.)
THF, reflux, 2h
59
O
N
or
-78 °C to 20 °C
1h
5
NaH (5 equiv.)
THF, reflux, 3h
69
12, 54%
R1
R1
R1
[a] Isolated yield. [b] The expected product was not observed only starting material was
recovered.
PhSeBr
CuI
PTSA.H2O
OH
OH
N
O
N
N
2
2
2
toluene, 120 °C
5h
O
DMF
20 °C, 2h
1
1
1
SePh
The intramolecular Pinner reaction (PTSA monohydrate at
reflux in toluene) was run on five aryl-substituted 2-pyridyl acetonitrile
compounds 7a-e, affording the desired lactones in 39 to 71% isolated
yields. Unfortunately, under these acidic conditions a competitive
decyanation of the dipyridyl substituted acetonitrile 7d was observed
during the reaction. It is proposed that, under acidic conditions, the
protonated electron withdrawing 2-pyridyl substituents activates the
benzylic position leading preferentially to decyanation over cyclization.
The high reactivity of the 2-position of the pyridine ring on protected
2-chloropyridylethanol 3 allowed an effective introduction of various
substituents on pyranopyridinone PP1 using SNAr approach.
N1, 13, R1 = H 73%
N2, 14, R1 = H 89%
N2, 15, R1 = Me 54%
N2, 16 R1= Ph 62%
N1, 17, R1 = H 74%
N2, 18, R1 = H 78%
N2, 19, R1 = Me 73%
N2, 20, R1 = Ph 53%
PP1a and PP2a-c
Me
Ph
O
O
O
O
N
N
N
O
N
O
O
O
PP1a, 65%
PP2a, 39%
PP2b, 63%
PP2c, 37%
Scheme 4. Synthesis of pyranopyridinones PP1a and PP2a-c via method C
Interestingly, when the TMS deprotection was run for longer
reaction time, the furo[3,4,c]pyridine 12 was isolated in 54% yield
resulting from an intramolecular 5-exo-dig cyclization (Scheme 4).
Reduction of the carbonyl function with NaBH4 in a mixture of THF/
H2O was performed on both regioisomers 10 and 11 giving the
corresponding alkynols 13 and 14 in good yields. In parallel, methyl
and phenyl substituted-alkynols 15 and 16 were obtained successfully
by the reaction of 10 or 11 with the corresponding Grignard reagent
(Scheme 4). The alkynyl pyridyl selenides 17-20 were prepared from
the corresponding alkynols 13-16 with phenylselenyl bromide and two
equivalent of copper iodide.[13] Finally, the reaction of selenides 17-20
with an excess of PTSA monohydrate proceeds smoothly in toluene
at 120 °C in 5 h to give selectively pyranopyridinones PP1a and
substituted PP2 a-c in moderate yield (Scheme 4).
R1
R1
R1
R2CH2CN
OTBS
OTBS
O
PTSA. H2O
CN
toluene, 120 °C, 4h
N
Cl
NaH, THF
70 °C
N
N
O
R3
R3
PP1h-l
R1 = H, 3
R1 = Ph, 6
R1 = H, R3 = Ph, 7a, 69%
R1 = H, R3 = 4-Br-Ph, 7b, 63%
R1 = H, R3 = 4-OMe-Ph, 7c, 74%
R1 = H, R3 = 2-Pyr, 7d, 56% (crude)
R1 = R3 = Ph, 7e, 30 % (dr : 3/1)
O
O
O
O
O
N
O
N
O
N
O
N
O
N
O
N
Br
PP1i, 71%
OMe
PP1j, 36%
PP1h, 55%
PP1k, 0%
PP1l, 76% (dr : 3/1)
Thus, we have developed a rapid access to diverse isomers
of functionalized pyranopyridinones using three complementary
strategies. To increase substituent diversity on pyranopyridinones, we
have investigated the synthesis of a new class of semi-rigid
compounds based on pyranopyridinones scaffolds with potentially
interesting properties as an antifungal, enzyme inhibitors or
antihistaminics. The latter are therapeutics targeting the histamine
receptors (H1R to H4R) involved in the regulation of many aspects of
Scheme 3. Synthesis of aryl substituted pyranopyridinones PP1h-l via method
B
Original functionalized pyranopyridinones PP2 possessing the
nitrogen atom at the 3 position of the pyridyl ring were prepared
following an unreported selenium-promoted ring closure reaction
3
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10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
diseases such as allergic rhinitis, autoimmune diseases and
infection.[14] Among these therapeutic agents, antihistamines H1 have
long been employed to treat allergy.
develop a new generation of anti-histamines with increased properties.
For a future structure-activity relationship studies, other substitution
and structural modifications of pyranopyridinones are highly needed
and could be easily envisioned based on our developed methodology.
The scope of the reaction as well as biological evaluation of these
compounds on H1 receptors are underway in the laboratory and will
be reported in due course.
R1
Ph
Ph
Ph
O
O
O
N
O
N
N
O
R3
N
N
N
N
N
R5
Diphenylhydramine
Phenbenzamine
Isochromanone
Pyranopyridinones
Experimental Section
General: NMR spectra were recorded on Bruker Avance III 300 MHz
or 400 MHz spectrometers at room temperature. Chemical shifts (δ)
are expressed in part per million (ppm), reported as s = singlet, d =
doublet, t = triplet, m = multiplet; and referenced to the solvent peak
of respectively CDCl3, CD2Cl2, (CD3)2SO (13C NMR: δ = 77.23; 53.84;
39.52 ppm; 1H NMR: δ = 7.26; 5.32; 2.50 ppm). IR spectra were
recorded on ThermoNicolet Avatar 330 FT IR on film. Exact mass
measurements were obtained on TQ R30-10 HRMS spectrometer by
ESI+ ionization and are reported in m/z for the major signal.
Commercially available flexible antihistamines
Semi-rigid antihistamines
Figure 2. New class of potential semi-rigid antihistamines based on
pyranopyridinones scaffold
First and second generations of H1-antihistamines are
commonly flexible molecules possessing a diarylmethane moiety i.e.
phenbenzamine, cetirizine, doxylamine (Figure 2).[15] However,
rotationally constrained molecules of these types are highly desired in
order to get more insight to identify the active conformation of
histamine itself and thus get more selective H1-receptor
antagonists.[16] Semi-rigid piperazine substituted 3-isochromones
have proved earlier to possess significant antihistaminic activity (H1)
in isolated guinea pig opening the way to develop other semi-rigid
molecules with increased antihistaminic properties through structure-
activity relationship studies. [1b]
Experimental procedures and characterization data for new
compounds or compounds made by a new method are listed below.
For the experimental procedure and characterization data of the
remaining compounds see references: Compounds 217, 36, 812, 912,
1018 ,1119 were reported in literature, PP1a4a was reported without full
characterization. Reagents were purchased as reagent-grade and
used without further purification. All anhydrous reactions were carried
out in oven dried glassware and under an inert atmosphere of argon.
THF and toluene were dried by purification through activated alumina
purification columns. Reactions were monitored by analytical TLC on
silica gel 60 F254 plates 0.25 mm, and visualized under UV light (λ =
254 and 354 nm). Silica gel (SDS 60 ACC 35–70 mm) was used for
In first instance, we have investigated the synthesis of piperazinyl
substituted pyranopyridinones, as starting point to develop other
original aza analogs of semi-rigid antihistamines described above.
PP1a and PP1h were converted into the corresponding
bromopyranopyridinones PP1m (R3 = H, R4 = Br) and PP1n (R3 = Ph,
R4 = Br) by reaction with 1 equivalent of N-bromosuccinimide. The title
compounds PP1o, PP1p and PP1q were then synthesized in yields
up to 71% by condensation of amines such as N-methyl- and N-
phenyl piperazine in the presence of trimethylamine or potassium
carbonate (Scheme 5).
column chromatography. Abbreviations: C̊ : degrees Celsius. DCM:
dichloromethane. ESI: electrospray ionization. Et2O: diethyl ether.
EtOAc: ethyl acetate. Eq: equivalent(s). Et: Ethyl g: gram. h: hour(s).
HRMS: High resolution-mass spectrometry. LiHMDS: Lithium
bis(trimethylsilyl)amide. IR: infra-red. M (moles per litre (mol L-1). Me:
methyl. MeCN: acetonitrile. mg: milligram. MgSO4: Magnesium sulfate.
min: minute(s). mL (milliliter). mm: millimeter. mmol: millimole. mol:
mole. m/z: mass-to-charge ratio. PTSA: paratoluenesulfonic acid.
N2: nitrogen (g). NBS. N-bromosuccinimide. Et3N: triethylamine. NMR:
Nuclear magnetic resonance. nm: nanometer. ppm: parts per millions.
r.t.: room temperature. tBu: tert-butyl. tBuXPhos Pd G1: tert-BuXPhos
palladium(II) phenethylamine chloride. THF: tetrahydrofuran. TFA:
trifluoroacetic acid. TIPS: triisopropylsilane. μL: microliter(s). μm:
micrometre(s). μM:micromolar. μmol: micromole(s). UV: ultraviolet.
5 N
N
H
R
O
O
O
1eq. NBS
DCM
N
N
O
N
O
Et3N, CH3CN
or K2CO3, DCM
R3
N
O
N
3 Br
R3
R
R3 = H, PP1m, 59%
R3 = Ph, PP1n, 80%
R3 = H, PP1a
R3 = Ph, PP1h
R5
R3 = H, R5 = Ph, PP1o, 22%
R3 = Ph, R5 = Ph, PP1p, 71%
R3 = Ph, R5 = Me, PP1q, 62%
Scheme 5. A new class of potential analogs of anti-histamines
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-
yl)acetate (4)
Compound 3 (2 g, 7.8 mmol, 1 eq.) and t-butyl acetate (1.95 mL, 11.7
mmol, 1.5 eq.) were dissolved in 20 mL of toluene. tBuXPhos Pd G1
(107 mg, 0.16 mmol, 2 mol%) was added under argon at 0 °C.
Solution was stirred for 5 min. Then, LiHMDS (1M in toluene, 23.4 mL,
3 eq.) was carefully added to the mixture which was allowed to warm
up to rt for 2 h. A saturated aqueous solution of NH4Clwas added and
the mixture was extracted with EtOAc (3 x 50 mL). Organic phase was
washed with brine, dried over MgSO4 and concentrated. The resulting
Conclusion
In
conclusion,
two
isomers
of
functionalized
pyranopyridinones were synthesized using three different and
complementary synthetic methodologies allowing the introduction of
various substituents on the lactone ring. We also applied the outlined
synthetic methodologies to prepare semi-rigid analogs of
antihistamines with potential biological importance opening the way to
residue
was
purified
by
silica
gel
chromatography
(Cyclohexane/EtOAc: 9:1 to 8:2). Yellow oil, Yield: 61%. 1H NMR (300
MHz, CDCl3): δ 8.47 (d, 1H, J = 4.2 Hz, H5), 7.89 (d, 1H, J = 7.3 Hz,
4
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10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
H3), 7.30 (m, 1H, H4), 4.75 (s, 2H, H6), 3.90 (s, 2H, H13), 1.45 (s, 9H,
H16,17,18), 0.95 (s, 9H, H9,10,11), 0.12 (s, 6H, H7,8) ppm; 13C {1H} NMR (75
MHz, CDCl3): δ 169.3 (C14), 151.8 (C1), 147.2 (C5), 135.1 (C2), 134.4
(C3), 122.0 (C4), 80.8 (C15), 61.7 (C6), 42.2 (C13), 27.8 (C16,17,18), 25.6
(C9,10,11), 18.1 (C12), -5.5 (C7,8) ppm; IR: 2930, 2857, 1731, 1577, 1391,
4.89 (d, 1H, J = 13.7 Hz, H15a), 4.81 (d, 1H, J = 13.7 Hz, H15b), 3.40 (d,
1H, J = 10.4 Hz, H6), 2.85-2.73 (m, 1H, H7), 1.36 (s, 9H, H12,13,14), 1.12
(d, 3H, J = 6.4 Hz, H8/9), 0.98 (s, 9H, H19,20,21), 0.68 (d, 3H, J = 6.7 Hz,
H8/9), 0.16 (s, 3H, H16/17), 0.14 (s, 3H, H16/17) ppm; 13C {1H} NMR (75
MHz, CDCl3): δ 170.9 (C10), 154.8 (C1), 147.6 (C5), 135.1 (C2), 134.0
(C3), 121.4 (C4), 80.3 (C11), 61.5 (C15), 57.1 (C6), 29.4 (C7), 27.8
1
1254, 1146, 1076, 837, 777 cm- ; HRMS (ESI): m/z calcd for
C18H31NNaO3Si: 360.1965, found: 360.1976 [M+Na]+
(C12,13,14), 25.8 (C19,20,21), 21.1 (C8/9), 20.1 (C8/9), 18.2 (C18), -5.4 (C16,17)
ppm; IR: 2957, 2858, 1739, 1574, 1434, 1367, 1255, 1113, 1073, 837,
1
General procedure A for the synthesis of compounds 5b and 5d-
g
777 cm- ; HRMS (ESI): m/z calcd for C21H37NNaO3Si: 402.2435,
found: 402.2447 [M+Na]+
Compound 4 (300 mg, 0.89 mmol, 1 eq.) was dissolved in 5 mL of
THF. LiHMDS (1M in toluene, 0.98 mL, 1.1 eq.) was added at 0 °C.
The mixture was stirred at this temperature for 20 min. The
appropriate halogenoalkane (1.1 eq.) was added dropwise and the
solution was allowed to warm up to rt for 20 h. A saturated aqueous
solution of NH4Clwas added and the mixture was extracted with DCM.
Organic phase was washed with brine, dried over MgSO4 and
concentrated. The resulting residue was purified by silica gel
chromatography (Cyclohexane/EtOAc: 9:1).
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-
yl)pent-4-enoate (5e)
From compound 4 according to general procedure A. Brown oil,
Yield: 89%. 1H NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J = 3.4 Hz, H5),
7.78 (d, 1H, J = 7.7 Hz, H3), 7.19 (dd, 1H, J1 = 7.7, J2 = 4.7 Hz, H4),
5.75 (m, 1H, H8), 5.05 (d, 1H, J = 17.0 Hz, H9a), 4.95 (d, 1H, J = 10
Hz, H9b), 4.84 (d, 1H, J = 13.7 Hz, H15a), 4.79 (d, 1H, J = 13.7 Hz, H15b),
3.86 (t, 1H, J = 7.3 Hz, H6), 2.92 (m, 1H, H7a), 2.72 (m, 1H, H7b), 1.36
(s, 9H, H12,13,14), 0.96 (s, 9H, H19,20,21), 0.14 (s, 3H, H16/17), 0.12 (s, 3H,
H16/17) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 171.0 (C10), 155.2 (C1),
147.5 (C5), 135.8 (C3), 134.7 (C2), 134.5 (C8), 121.8 (C4), 116.4 (C9),
80.8 (C11), 61.6 (C15), 49.2 (C6), 35.0 (C7), 27.9 (C12,13,14), 25.8
(C19,20,21), 18.3 (C18), -5.3 (C16,17) ppm; IR: 2930, 2857, 2362, 1737,
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-
yl)propanoate (5b)
From compound 4 according to general procedure A. Yellow oil,
Yield: 89%. 1H NMR (300 MHz, CDCl3): δ 8.47 (d, 1H, J = 3.8 Hz, H5),
7.75 (d, 1H, J = 7.7 Hz, H3), 7.16 (dd, 1H, J1 = 7.70, J2 = 4.9 Hz, H4),
4.82 (d, 1H, J = 13.3 Hz, H13a), 4.75 (d, 1H, J = 13.5 Hz, H13b), 3.93 (q,
1H, J = 6.9 Hz, H6), 1.49 (d, 3H, J = 7.15 Hz, H7), 1.36 (s, 9H, H10,11,12),
1
1576, 1436, 1367, 1255, 1148, 1076, 837, 777 cm- ; HRMS (ESI): m/z
calcd for C21H36NO3Si: 378.2459, found: 378.2468 [M+H]+
0.95 (s, 9H, H17,18,19), 0.13 (s, 3H, H14/15), 0.11 (s, 3H, H14/15) ppm; 13
C
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-
3-phenylpropanoate (5f)
{1H} NMR (75 MHz, CDCl3): δ 172.5 (C8), 157.4 (C1), 147.7 (C5), 134.6
(C3), 133.9 (C2), 121.6 (C4), 80.4 (C9), 61.8 (C13), 43.8 (C6), 27.9
From compound 4 according to general procedure A. Brown oil,
Yield: 61%. 1H NMR (300 MHz, CDCl3): δ 8.54 (d, 1H, J = 4.5 Hz, H5),
7.70 (d, 1H, J = 7.5 Hz, H3), 7.15 (m, 4H), 7.04 (m, 2H), 4.62 (d, 1H,
J = 13.7 Hz, H19a), 4.31 (d, 1H, J = 13.7 Hz, H19b), 4.02 (dd, 1H, J1 =
8.6 Hz, J2 = 6.6 Hz, H6), 3.49 (dd, 1H, J1 = 13.5 Hz, J2 = 6.4 Hz, H7a),
3.26 (dd, 1H, J1 = 13.5 Hz, J2 = 8.4 Hz, H7b), 1.33 (s, 9H, H16,17,18), 0.92
(s, 9H, H23,24,25), 0.03 (s, 6H, H20,21) ppm; 13C {1H} NMR (75 MHz,
CDCl3): δ 171.0 (C14), 155.1 (C1), 147.5 (C5), 139.5 (C8), 134.9 (C2),
134.0 (C3), 128.9 (C9,13), 128.0 (C10,12), 126.0 (C11), 121.7 (C4), 80.7
(C15), 61.2 (C19), 51.1 (C6), 37.1 (C7), 27.8 (C16,17,18), 25.8 (C23,24,25),
18.2 (C22), -5.4 (C20,21) ppm; IR: 2955, 2857, 1736, 1576, 1435, 1391,
(C10,11,12), 25.8 (C17,18,19), 18.2 (C16), 15.9 (C7), -5.3 (C14/15), -5.3 (C14/15
)
ppm; IR: 2931, 2857, 1736, 1576, 1458, 1367, 1254, 1150, 1063, 836,
1
777 cm- ; HRMS (ESI): m/z calcd for C19H33NNaO3Si: 374.2122,
found: 374.2129 [M+Na]+
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-
2-methylpropanoate (5c)
Compound 4 (300 mg, 0.89 mmol, 1 eq.) was dissolved in 5 mL of
THF. LiHMDS (1M in toluene, 1.96 mL, 2.2 eq.) was added at 0 °C.
The mixture was stirred at this temperature for 20 min. MeI (166 µL,
2.67 mmol, 3 eq.) was added dropwise and the solution was allowed
to warm at rt for 20 h. A saturated aqueous solution of NH4Cl was
added and the mixture was extracted with DCM. Organic phase was
washed with brine, dried over MgSO4 and concentrated. The resulting
1
1255, 1143, 837, 777, 700 cm- ; HRMS (ESI): m/z calcd for
C25H37NNaO3Si: 450.2435, found: 450.2434 [M+Na]+
residue
was
purified
by
silica
gel
chromatography
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-
yl)pent-4-ynoate (5g)
(Cyclohexane/EtOAc: 9:1). Yellow oil, Yield: 89%; 1H NMR (300 MHz,
CDCl3): δ 8.45 (d, 1H, J = 4.4 Hz, H5), 7.91 (d, 1H, J = 7.5 Hz, H3),
7.25-7.18 (m, 1H, H4), 4.65 (s, 2H, H14), 1.58 (s, 6H, H7,8), 1.42 (s, 9H,
H11,12,13), 0.96 (s, 9H, H18,19,20), 0.13 (s, 6H, H15/16) ppm; 13C {1H} NMR
(75 MHz, CDCl3): δ 176.0 (C9), 158.6 (C1), 146.3 (C5), 135.1 (C3),
134.4 (C2), 121.6 (C4), 80.4 (C10), 60.8 (C14), 49.9 (C6), 27.6 (C11,12,13),
25.8 (C7,8), 25.8 (C18,19,20), 18.1 (C17), -5.4 (C15/16) ppm; IR: 2930, 2858,
From compound 4 according to general procedure A. Brown oil,
Yield: 59%.1H NMR (300 MHz, CDCl3): δ 8.49 (d, 1H, J = 4.0 Hz, H5),
7.82 (d, 1H, J = 7.7 Hz, H3), 7.21 (dd, 1H, J1 = 7.7, J2 = 4.7 Hz, H4),
4.94 (d, 1H, J = 13.7 Hz, H15a), 4.88 (d, 1H, J = 13.7 Hz, H15b), 4.03 (t,
1H, J = 6.9 Hz, H6), 3.05 (ddd, 1H, J1 = 16.6 Hz, J2 = 6.4 Hz, J3 = 2.3
Hz, H7a), 2.86 (ddd, 1H, J1 = 16.6 Hz, J2 = 8.2 Hz, J3 = 2.3 Hz, H7b),
1.86 (t, 1H, J = 2.3 Hz, H9), 1.36 (s, 9H, H12,13,14), 0.97 (s, 9H, H19,20,21),
0.15 (s, 3H, H16/17), 0.14 (s, 3H, H16/17) ppm; 13C {1H} NMR (75 MHz,
CDCl3): δ 170.0 (C10), 154.2 (C1), 147.6 (C5), 134.9 (C2), 134.3 (C3),
122.0 (C4), 82.1 (C11), 81.1 (C8), 69.0 (C9), 61.6 (C15), 48.3 (C6), 27.8
(C12,13,14), 25.8 (C19,20,21), 20.4 (C7), 18.2 (C18), -5.4 (C16,17) ppm; IR:
3313, 2930, 2857, 1736, 1577, 1438, 1368, 1255, 1147, 1080, 838,
1
1723, 1569, 1470, 1367, 1255, 1145, 1117, 1068, 839, 776 cm- ;
HRMS (ESI): m/z calcd for C20H36NO3Si: 366.2459, found: 366.2453
[M+H]+
tert-butyl-2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-
3-methylbutanoate (5d)
1
From compound 4 according to general procedure A. Yellow oil,
Yield: 62%. 1H NMR (300 MHz, CDCl3): δ 8.54 (d, 1H, J = 3.6 Hz, H5),
7.80 (d, 1H, J = 7.5 Hz, H3), 7.17 (dd, 1H, J1 = 7.7, J2 = 4.7 Hz, H4),
777 cm- ; HRMS (ESI): m/z calcd for C21H33NNaO3Si: 398.2122,
found: 398.2113 [M+Na]+
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
General procedure B for the synthesis of compounds PP1a-g
The appropriate substrate (4 and 5bg) (1 eq.) was dissolved in 10 mL
of toluene. PTSA.H2O (2.5 eq.) was added to the mixture which was
stirred at rt for 20 h. 40 mL of a mixture of a saturated aqueous
solution of NaHCO3 and EtOAc (1:1) were added to the solution.
Organic phase was separated. Aqueous phase was extracted with
EtOAc (2 x 20 mL). The combined organic phases were washed with
brine, dried over MgSO4 and concentrated. The resulting residue was
purified by silica gel chromatography (Cyclohexane/EtOAc: 5/5).
126.0 (C2), 122.0 (C4), 117.9 (C9), 67.5 (C11), 48.0 (C6), 33.4 (C7) ppm;
1
IR: 3074, 2924, 1743, 1589, 1438, 1387, 1255, 1058, 919, 797 cm- ;
HRMS (ESI): m/z calcd for C11H11NNaO2: 212.0682, found: 212.0676
[M+Na]+
8-benzyl-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1f)
From compound 5f according to general procedure B; Brown solid,
Yield: 68%. 1H NMR (300 MHz, CDCl3): δ 8.63 (d, 1H, J = 4.2 Hz, H5),
7.34 (d, 1H, J = 7.5 Hz, H3), 7.25-7.11 (m, 4H, H4,10,11,12), 6.91 (dd, 2H,
J1 = 7.7 Hz, J2 = 1.6 Hz, H9,13), 4.92 (d, 1H, J = 14.6 Hz, H15a), 4.22-
4.13 (m, 2H, H6,15b), 3.63 (dd, 1H, J1 = 13.39 Hz, J2 = 4.9 Hz, H7a),
3.37 (dd, 1H, J1 = 13.3 Hz, J2 = 5.5 Hz, H7b) ppm; 13C {1H} NMR (75
MHz, CDCl3): δ 171.8 (C14), 152. (C1), 149.7 (C5), 136.9 (C8), 131.7
(C3), 129.25 (C9,13), 128.3 (C10,12), 127.0 (C11), 126.6 (C2), 122.1 (C4),
67.5 (C15), 49.5 (C6), 37.9 (C7) ppm; IR: 3028, 1742, 1590, 1496, 1452,
5H,7H,8H-pyrano[4,3-b]pyridin-7-one PP1a[4a]
From compound 4 according to general procedure B. Brown solid,
Yield: 20%. 1H NMR (300 MHz, CDCl3): δ 8.60 (d, 1H, J = 4.7 Hz, H5),
7.69 (d, 1H, J = 7.5 Hz, H3), 7.38 (dd, 1H, J1 = 7.5, J2 = 5.14 Hz, H4),
5.39 (s, 2H, H8), 4.07 (s, 2H, H6) ppm; 13C {1H} NMR (75 MHz, CDCl3):
δ 169.5 (C7), 151.0 (C1), 149.9 (C5), 132.3 (C3), 126.2 (C2), 122.3 (C4),
68.2 (C8), 38.9 (C6) ppm; IR: 2969, 1732, 1588, 1442, 1391, 1247,
1
1390, 1250, 1149, 1077, 798, 701 cm- ; HRMS (ESI): C15H13NNaO2:
262.0838, found: 262.0849 [M+Na]+
1
1213, 1151, 1057, 824 cm- ; HRMS (ESI): m/z calcd for C8H7NO2Li:
156.0632, found : 156.0629 [M+Li]+
8-(prop-2-yn-1-yl)-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1g)
From compound 5g according to general procedure B. Brown solid,
Yield: 66%.1H NMR (300 MHz, CDCl3): δ 8.65 (d, 1H, J = 4.40Hz, H5),
7.57 (d, 1H, J = 7.5 Hz, H3), 7.30 (m, 1H, H4), 5.47 (d, 1H, J = 14.4 Hz,
H11a), 5.35 (d, 1H, J = 14.4 Hz, H11b), 3.96 (t, 1H, J = 5.3 Hz, H6), 3.29
(ddd, 1H, J1 = 16.8 Hz, J2 = 5.1 Hz, J3 = 2.5 Hz, H7a), 3.15 (ddd, 1H,
J1 = 16.8 Hz, J2 = 5.50 Hz, J3 = 2.5 Hz, H7b), 1.97 (t, 1H, J = 2.5 Hz,
H9) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 170.5 (C10), 151.4 (C1),
149.6 (C5), 132.1 (C4), 126.4 (C2), 122.3 (C4), 81.1 (C8), 69.8 (C9),
67.6 (C11), 46.4 (C6), 18.06(C7) ppm; IR: 3282, 1746, 1586, 1440,
8-methyl-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1b)
From compound 5b according to general procedure B. Yellow oil,
Yield: 55%.1H NMR (300 MHz, CDCl3): δ 8.61 (d, 1H, J = 4.7 Hz, H5),
7.5 (d, 1H, J = 7.5 Hz, H3), 7.27 (m, 1H, H4), 5.3 (d, 1H, J = 14.4 Hz,
H9a), 5.30 (d, 1H, J = 14.3 Hz, H9b), 3.84 (q, 1H, J = 6.9 Hz, H6), 1.73
(d, 3H, J = 7.1 Hz, H7) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 172.7
(C8), 154.1 (C1), 149.5 (C5), 132.1 (C3), 126.3 (C2), 121.9 (C4), 67.2
(C9), 42.5 (C6), 11.9 (C7) ppm; IR: 2994, 2946, 1738, 1595, 1436, 1390,
1
1
1240, 1152, 1075, 1008, 804, 743 cm- ; HRMS (ESI): m/z calcd for
1386, 1262, 1145, 1063, 1031, 797, 733 cm- ; HRMS (ESI): m/z calcd
C9H9NNaO2: 186.0525, found: 186.0518 [M+Na]+
for C11H9NNaO2: 210.0525, found: 210.0523 [M+Na]+
8,8-dimethyl-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1c)
2-chloro-(3-{[(tert-
From compound 5c according to general procedure B. Beige solid,
Yield: 99%. 1H NMR (300 MHz, CDCl3): δ 8.62 (d, 1H, J = 4.4 Hz, H5),
7.51 (d, 1H, J = 7.5 Hz, H3), 7.25 (dd, 1H, J1 = 7.5 Hz, J2 = 4.7 Hz, H4),
5.40 (s, 2H, H10), 1.66 (s, 6H, H7,8) ppm; 13C {1H} NMR (75 MHz,
CDCl3): δ 175.0 (C9), 156.9 (C1), 149.4 (C5), 132.1 (C3), 124.6 (C2),
121.7 (C4), 66.9 (C10), 44.7 (C6), 23.7 (C7,8) ppm; IR: 3004, 1731, 1585,
butyldimethylsilyl)oxy](phenyl)methyl}pyridine (6)
2-Chloropyridin-3-yl)-phenylmethanol[20] (18,2 mmol, 1 eq.), tert-
butyldimethylchlorosilane (20,2 mmol, 1.1 eq.) and imidazole (36,4
mmol, 2 eq.) were added to 20 mL of dry DMF. The reaction mixture
was stirred at rt for 18 h. 200 mL of Et2O were added and the reaction
mixture was washed three time with water (3 x 100 mL). The
combined aqueous layers were extracted with Et2O (100 mL) and the
combined organic layers washed with an aqueous saturated solution
of LiCl and brine. The organic layer was dried over MgSO4 and
concentrated to afford the title compound. The residue was purified
by silica gel chromatography (DCM 100%). White solid, Yield: 79%.
1H NMR (300 MHz, DMSO-d6): δ 8.30 (d, 1H, J = 4.2 Hz, H5), 8,03 (d,
1H, J1 = 7,7 Hz, J2 = 1.6Hz, H3), 7.40 (d, 1H, J = 7,7 Hz, H4), 7.27 (m,
5H, H8-12), 6,14 (s, 1H, H6), 0.91 (s, 9H, H15,16,17), 0.01 (d, 6H, J = 6,4
Hz, H13,14) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ = 148.5 (C1), 148.3
(C5), 142.7 (C2), 139.4 (C7), 137.2 (C3), 128.3 (C8,12), 127. 5 (C10),
126.4 (C9,11), 122.9 (C4), 72.3 (C6), 25.7 (C15,16,17), 18.1 (C18), -4.9
(C13,14); HRMS (ESI): m/z calcd for C18H25ClNOSi: 334.1388, found:
334.1389 [M+H]+
1
1469, 1442, 1396, 1256, 1146, 1108, 1058, 801 cm- ; HRMS (ESI):
m/z calcd for C10H11NNaO2: 200.682, found: 200.0675 [M+Na]+
8-(propan-2-yl)-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1d)
From compound 5d according to general procedure B. Yellow oil,
Yield: 66%. 1H NMR (300 MHz, CDCl3): δ 8.60 (d, 1H, J = 4.5 Hz, H5),
7.53 (d, 1H, J = 7.7 Hz, H3), 7.26 (m, 1H, H4), 5.53 (d, 1H, J = 14.8 Hz,
H11a), 5.23 (d, 1H, J = 14.8 Hz, H11b), 3.68 (d, 1H, J = 7.3 Hz, H6),
2.45-2.29 (m, 1H, H7), 1.13 (d, 3H, J = 6.7 Hz, H8/9), 1.07 (d, 3H, J =
6.7 Hz, H8/9) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 171.1 (C10), 153.8
(C1), 149.5 (C5), 132.2 (C3), 125.7 (C2), 122.0 (C4), 67.9 (C11), 55.5
(C6), 31.6 (C7), 20.7 (C8/9), 20.2 (C8/9) ppm; IR: 2966, 1741, 1587, 1444,
1
1389, 1242, 1183, 1039, 857 cm- ; HRMS (ESI): m/z calcd for
C11H13NNaO2: 214.0838, found: 214.0840 [M+Na]+
General procedure C for the synthesis of compounds 7a-7e
NaH (60% in oil, 17 mmol) was added portionwise to a solution of
compound 3 or 6 (3.4 mmol) in THF (10 mL) at room temperature.
The corresponding arylacetonitrile (4.12 mmol) was added to the
mixture and the reaction mixture was stirred à 70 °C for 12 h. Water
(20 mL) was added slowly to stop the reaction. EtOAc (20 mL) was
added and the two layers were separated. The aqueous layer was
extracted three times with EtOAc (20 mL). The combined organic
phases were washed with brine (20 mL), dried over MgSO4, filtered
8-(prop-2-en-1-yl)-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1e)
From compound 5e according to general procedure B. Brown oil,
Yield: 67%. 1H NMR (300 MHz, CDCl3): δ 8.61 (d, 1H, J = 4.5 Hz, H5),
7.55 (d, 1H, J = 7.5 Hz, H3), 7.27 (m, 1H, H4), 6.00-5.86 (m, 1H, H8),
5.41 (d, 1H, J = 14.4 Hz, H11a), 5.30 (d, 1H, J = 14.4 Hz, H11b), 5.13 (d,
1H, J = 18.5 Hz, H9a), 5.09 (d, 1H, J = 11.0 Hz, H9b), 3.92 (t, 1H, J =
6.2 Hz, H6), 3.03-2.84 (m, 2H, H7) ppm; 13C {1H} NMR (75 MHz,
CDCl3): δ 171.40 (C10), 153.0 (C1), 149.6 (C5), 134.0 (C3), 132.1 (C8),
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
and concentrated. The resulting residue was purified by silica gel
chromatography to afford the pure product.
3H, H8) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ = 154.5 (C1), 151.4
(C19), 149.5 (C5), 148.4 (C18), 137.3 (C3), 135.8 (C16), 135.3 (C2), 123.4
(C15), 123.0 (C17), 122.4 (C4), 118.2 (C14), 61.8 (C6), 44.9 (C13), 25.8
(C11,12,13), 18.3 (C9), -5.3 (C7,8) ppm; HRMS (ESI): m/z calcd for
C19H26N3OSi: 340.1840, found: 340.1842 [M+H]+
2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-2-
phenylacetonitrile (7a) From compound 3 and phenylacetonitrile
according to general procedure C. The residue was purified by silica
gel chromatography (Cyclohexane/Ether: 8/2, 7/3 to 5/5). Yellow oil,
69 % yield. 1H NMR (400 MHz, CDCl3): δ 8.60 (dd, 1H, J = 4.6 Hz, J
= 1.2 Hz, H5), 7.76 (d, 1H, J = 7.7 Hz, H3), 7.42-7.28 (m, 6H, H4, 8, 9, 10,
11, 12), 5.66 (s, 1H, H6), 4.68 (d, 1H, J = 13.7 Hz, H14a), 4.61 (d, 1H, J =
13.7 Hz, H14b), 0.91 (s, 9H, H18, 19, 20), 0.05 (s, 6H, H15,16), ppm; 13C {1H}
NMR (75 MHz, CDCl3): δ = 152.2 (C1), 148.5 (C5), 136.0 (C3), 134.2
(C2), 134.0 (C7), 129.0 (C8,12), 128.3 (C10), 127.8 (C9,11), 123.3 (C4),
118.6 (C13), 61.7 (C14), 42.3 (C6), 25.8 (C18,19,20), 18.2 (C17), -5.45
(C15,16) ppm; IR: 2954, 2857, 2250, 1576, 1435, 1257, 1117, 1076-837
cm-1; HRMS (ESI): m/z calcd for C20H26N2NaOSi: 361.1707, found:
361.1694 [M+Na]+
2-(3-{[(tert-butyldimethylsilyl)oxy](phenyl)methyl}pyridin-2-yl)-2-
phenylacetonitrile (7e)
From compound 6 and phenylacetonitrile according to general
procedure C. The resulting residue was purified by silica gel
chromatography (Cyclohexane/EtOAc: 9:1) and trituration with
petroleum ether. White solid, Yield: 30%.1H NMR (300 MHz, CDCl3):
δ 8.70 (d, 1H, J = 3,9 Hz, H1), 8,04 (d, 1H, J = 7.5 Hz, H3), 7.30 (m,
9H, H16, H17, H18, H19, H20, H24, H25, H26, H2), 7,03 (m, 2H, H22,23), 5,82 (s,
1H, H6), 5,55 (s, 1H, H13), 0,94 (s, 9H, H10,11,12), 0.00 (s, 3H, H7,8), -
0.09 (s, 3H, H7,8) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 152,3 (C5),
148,8 (C1), 142,0 (C4), 136,5 (C3), 134,4 (C21), 128,8-128,8-127,9-
126,5-123,0 (C16,17,18,19,20,22,23,24,25,26), 119, 1 (C14), 74,1 (C6), 41,4 (C13),
25,8 (C10,11,12), -4,8 (C7,8), -5,0 (C7,8) ppm; HRMS (ESI): m/z calcd for
C26H31N2OSi: 415.2200, found 415.2201 [M+H+]
2-(4-bromophenyl)-2-(3-{[(tert-
butyldimethylsilyl)oxy]methyl}pyridin-2- yl)acetonitrile (7b)
From compound
3 and 4-bromophenylacetonitrile according to
general procedure C. The residue was purified by silica gel
chromatography (Cyclohexane/Et2O: 8/2, 7/3 to 5/5). Yellow oil, 63 %
yield. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, 1H, J = 4.6 Hz, J = 1.8
Hz, H1), 7.73 (d, 1H J = 7.5 Hz, H3), 7.49 (d, 2H, J = 7.5 Hz, H18,19),
7.29-7.27 (m, 3H, H16,17,2), 5.64 (s, 1H, H13), 4.68 (d, 1H, J = 13.4 Hz,
H6a), 4.63 (d, 1H, J = 13.3 Hz, H6b), 0.90 (s, 9H, H10,11,12), 0.05 (s, 6H,
H7,8) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ = 152.1 (C5), 148.8 (C1),
136.4 (C3), 134.0 (C20), 133.2 (C4), 132.1 (C16,17), 129.6 (C18,19), 123.5
(C2), 122.5 (C15), 118.3 (C14), 62.0 (C6), 41.4 (C13), 25.8 (C10,11,12),
General procedure D for the synthesis of compounds PP1h to
PP1l
Compound 7a-7e (3.25 mmol, 1 eq.) was dissolved in 20 mL of
toluene. PTSA.H2O (19.5 mmol, 6 eq.) was added and the mixture
was vigorously stirred and refluxed at 120 °C for 4 h. The reaction
mixture was cooled to room temperature and poured into a mixture of
a saturated aqueous solution of NaHCO3 and EtOAc (1/1) (50 mL +
50 mL). Water was added and the layers were separated. The
aqueous layer was extracted with EtOAc (100 mL). The combined
organic layers were washed with water (100 mL), a saturated aqueous
solution of Na2CO3 (50 mL) and brine (50 mL). Finally, the organic
layer was dried over MgSO4 and concentrated to afford the title
compound. The residue was purified by silica gel chromatography.
18.28 (C9), -5.38 (C7,8
)
ppm; HRMS (ESI): m/z calcd for
C20H25N2NaOSi: 439.0811, found: 439.0813 [M+Na]+
2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-2-(4-
methoxyphenyl)acetonitrile (7c)
From compound 3 and 4-methoxyphenylacetonitrile according to
general procedure C. The residue was purified by silica gel
chromatography (Cyclohexane/ Et2O: 8/2, 7/3 to 5/5). Yellow oil, 74 %
yield.1H NMR (400 MHz, CDCl3): δ = 8.60 (d, 1H, J = 6.3 Hz, H1), 7.76
(d, 1H, J = 8.1 Hz, H3), 7.30-7.27 (m, 3H, H2,16,17), 6.88 (d, 2H, J = 8.1
Hz, H18, 19), 5.6 (s, 1H, H13), 4.64 (d, 1H, J = 13.5 Hz, H6a), 4.62 (d, 1H,
J = 13.8 Hz, H6b), 3.80 (s, 3H, H21), 0.92 (s, 9H, H10,11,12), 0.05 (s, 6H,
H7,8) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ = 159.7 (C20), 152.6 (C5),
148.6 (C1), 136.2 (C3), 134.27(C4), 129.2 (C16,17), 126.1 (C15), 123.4
(C2), 119.1 (C14), 114.6 (C18,19), 61.9 (C6), 55.5 (C21), 41.7 (C13), 25.9
(C10,11,12), 18.4 (C9), -5.1 (C7,8) ppm; HRMS (ESI): m/z calcd for
C21H28N2NaO2Si: 391.1812, found: 391.1814 [M+Na]+
8-phenyl-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1h)
From compound 7a according to general procedure D. The resulting
residue
was
purified
by
silica
gel
chromatography
(Cyclohexane/EtOAc: 5:5). Yellow oil, Yield: 60%. 1H NMR (300 MHz,
CDCl3) : δ 8.68 (d, 1H, J = 4.5 Hz, H5), 7.62 (d, 1H, J = 7.5 Hz, H3),
7.39-7.28 (m, 4H, H4,9,10,11), 7.19 (d, 2H, J = 6.7 Hz, H8,12), 5.32 (s, 1H,
H6), 5.29 (d, 1H, J = 14.4 Hz, H14a), 5.21 (d, 1H, J = 14.4 Hz, H14b
)
ppm. 13C {1H} NMR (75 MHz, CDCl3): δ 170.1 (C13), 153.5 (C1), 149.9
(C5), 133.2 (C2), 133.1 (C3), 129.08 (C8,12), 128.0 (C10), 127.5 (C9,11),
127.0 (C7), 122.7 (C4), 67.7 (C14), 54.3 (C6) ppm; IR: 3060, 2364, 1744,
1
1539, 1442, 1242, 1039, 761 cm- ; HRMS (ESI): m/z calcd for
C14H11NNaO2: 248.0677, found: 248.0682 [M+Na]+
2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)-2-
(pyridine-2-yl)acetonitrile (7d)
4-(4-bromophenyl)-3,4-dihydro-1H-2-benzopyran-3-one (PP1i)
From compound 7b according to general procedure D. The resulting
From compound 3 and 2-pyridylacetonitrile according to general
procedure C. The residue was purified by silica gel chromatography
(Cyclohexane/ Et2O: 8/2, 7/3 to 5/5). Purification of the compound led
to degradation. So, the crude was used directly in the next step.
Yellow oil (impure product, 56 % estimated yield). 1H NMR (400 MHz,
CDCl3): 8.47 (d, 1H, 5Hz, H5), 8.46 (d, 1H, 4Hz, H18), 7.72 (m, 1H, H3),
7.65 (m, 1H, H16), 7.52 (d, 1H, J = 8 Hz, H15), 7.20 (m, 1H, H17), 7.15
(m, 1H, H4), 5.69 (s, 1H, H13), 4.83 (d, 1H, J = 13 Hz, H6a), 4.76 (d,
1H, J = 13 Hz, H6b), 0.85 (s, 1H, H10,11,12), 0. 02 (s, 3H, H7), 0.00 (s,
residue
was
purified
by
silica
gel
chromatography
(Cyclohexane/EtOAc: 5:5). Yellow oil, 71 % yield. 1H NMR (400 MHz,
CDCl3): δ 8.49 (d, 1H, J = 4.1 Hz, H1), 7.87 (d, 1H, J = 7.5 Hz, H3),
7.56 (d, 2H, J = 8.7 Hz, H10/11), 7.42 (dd, 1H, J1 = 7.6 Hz, J2 = 4.9 Hz,
H2), 7.13 (d, 2H, J = 8.7 Hz, H12/13), 5.52 (d, 1H, J = 14.6 Hz, H6a), 5.42
(d, 1H, J = 14.3 Hz, H6b), 5.41 (s, 1H, H8) ppm; 13C {1H} NMR (75 MHz,
CDCl3) : δ = 169.5 (C7), 153.0 (C5), 150.4 (C1), 132.8 (C3), 132.6 (C4),
132.1 (C10/11), 129.5 (C12/13), 126.7 (C9), 122.8 (C2), 122.2 (C14), 67.7
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
(C6), 53.9 (C8) ppm; HRMS (ESI): m/z calcd for C14H11BrNO2:
303.9894, found: 303.9969 [M+H]+
H6), 4.54 (s, 1H, H8) ppm; 13C {1H} NMR (75 MHz, DMSO-d6): δ 148.0
(C5), 140.4 (C1), 139.0 (C2), 134.1 (C3), 123.7 (C4), 84.5 (C8), 80.6 (C7),
1
59.7 (C6) ppm; IR: 3207, 2915, 2104, 1585, 1432, 1048, 695 cm- ;
HRMS (ESI): m/z calcd for C8H8NO: 134.0600, found: 134.0599
8-(4-methoxyphenyl)-5H,7H,8H-pyrano[4,3-b]pyridin-7-one
(PP1j)
[M+H]+
From compound 7c according to general procedure D. The resulting
(3-ethynylpyridin-4-yl)methanol (14)
residue
was
purified
by
silica
gel
chromatography
From compound 11 using the same experimental procedure as for the
preparation of 13. Brown solid, Yield: 90%. 1H NMR (300 MHz,
CDCl3): δ 8.66 (s, 1H, H1), 8.58 (d, 1H, J = 4.9 Hz, H5), 7.52 (d, 1H, J
= 5.1 Hz, H4), 4.89 (d, 1H, J = 2.5 Hz, H6), 3.47 (s, 1H, H8), 2.87 (bt,
1H, J = 5.3 Hz, OH) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 153.5 (C3),
151.8 (C1), 148.6 (C5), 120.3 (C4), 116.5 (C2), 85.5 (C8), 77.5 (C7),
61.2 (C6) ppm; IR: 3286, 3166, 2834, 1597, 1404, 1062, 836, 670, 615
(Cyclohexane/EtOAc: 5:5). Yellow oil, 36 % yield. 1H NMR (400 MHz,
CDCl3) : δ = 8.65 (dd, 1H, J1 = 4.9 Hz, J2 = 1.7 Hz, H1), 7.60 (dd, 1H,
J1 = 8.1, J2 = 1.2 Hz, H3), 7.33 (dd, 1H, J1 = 8.4 Hz, J2 = 1.6 Hz, H2),
7.06 (d, 2H, J = 8.4 Hz, H10,11), 6.86 (d, 2H, J = 8.2 Hz, H12,13), 5.28 (d,
1H, J = 14.2 Hz, H6a), 5.21 (s, 1H, H8), 5.18 (d, 1H, J = 14.2 Hz, H6b),
3.77 (s, 3H, H15) ppm; 13C {1H} NMR (75 MHz, CDCl3): 171.0 (C7),
159.7 (C5), 154.5 (C14), 150.7 (C1), 133.1 (C3), 129.2 (C10/11), 127.2
(C9), 125.7 (C4), 123.0 (C2), 114.9 (C12/13), 68.2 (C6), 55.7 (C15), 54.3
(C8) ppm; HRMS (ESI): m/z calcd for C15H13NNaO3: 278.0789, found:
278.0788 [M+Na]+
1
cm- ; HRMS (ESI): m/z calcd for C8H8NO: 134.0600, found: 134.0597
[M+H]+
1-(3-ethynylpyridin-4-yl)ethan-1-ol (15)
Compound 11 was dissolved in 5 mL of dry THF. At -78 °C, a
methylmagnesium chloride solution (3 M in THF, 330 µL, 0.99 mmol,
1.3 eq.) was carefully added. The reaction mixture was allowed to
warm at room temperature for 1 h. A saturated aqueous solution of
NH4Cl was added, followed by a saturated aqueous solution of
NaHCO3. EtOAC was added to the mixture and the two layers
decanted. The aqueous layer was extracted with EtOAc (2 x 20 mL).
The combined organic layers were dried over MgSO4 and
concentrated. The resulting residue was purified by silica gel
chromatography (Cyclohexane/EtOAc: 1:1) to afford the title
5,8-diphenyl-5H, 7H, 8H-pyrano[4,3-b]pyridin-7-one. (PP1l)
From compound 7e according to general procedure D.
The resulting residue was purified by silica gel chromatography
(Cyclohexane/EtOAc: 7:3) and trituration with petroleum ether. Yellow
solid, 76% yield. Mixture of 2 inseparable diasteroisomers 3/1; 1H
NMR (400 MHz, CDCl3) of the major diasteroisomer: δ = 8.69 (d, 1H,
J = 4,8 Hz, H1), 7,49-7,27 (m, 11H, H3, H8,9,10,11,12,16,17,18,19,20), 7,08 (d,
1H, J = 7,5 Hz, H2), 6,23 (s,1H, H6), 5.50 (s, 1H, H14); 13C {1H} NMR
(75 MHz, CDCl3): 170,1 (C13), 154,0 (C5), 150,3 (C1), 135,5 (C4), 134,0
(C3), 133,4 (C7 or C15), 131,1 (C15 or C7), 129,4-129,1-128,9-128,1-
128,0-127,5 (C8,9,10,11,12, 6,17,18,19,20), 122,6 (C2), 79,9 (C4), 54.9 (C13)
ppm; HRMS (ESI): m/z calcd for C20H16NO2: 302.1176, found:
302.1176 [M+H]+
1
compound as a white solid. White solid, Yield: 54%. H NMR (300
MHz, CDCl3): δ 8.67 (s, 1H, H1), 8.58 (d, 1H, J = 5.1 Hz, H5), 7.6 (d,
1H, J = 5.1 Hz, H4), 5.30 (q, 1H, J = 6.4 Hz, H6), 3.51 (s, 1H, H9), 1.54
(d, 3H, J = 6.6 Hz, H7) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 157.7
(C3), 152.5 (C1), 149.0 (C5), 119.3 (C4), 116.2 (C2), 85.2 (C9), 78.0 (C8),
66.8 (C6), 23.7 (C7) ppm; IR: 3210, 3100, 2961, 2103, 1595, 1326,
1-methoxy-3-methylidene-1H,3H-furo[3,4-c]pyridine (12)
1
Compound 9 (300 mg, 1.48 mmol, 1 eq.) was dissolved in 5 mL of
MeOH. K2CO3 (409 mg, 2.96 mmol, 2 eq.) was added to the mixture,
which was stirred at room temperature for 4 h. Water (12 mL) was
added and the mixture was extracted with DCM (3 x 15 mL). Organic
phase was washed brine, dried over MgSO4 and concentrated. The
resulting residue was purified by silica gel chromatography
(Cyclohexane/EtOAc: 7:3 to 6:4) to afford the title compound as a
white solid. White solid, Yield: 54%. 1H NMR (300 MHz, CDCl3): δ 8.88
(s, 1H, H1), 8.65 (d, 1H, J = 4.9 Hz, H5), 7.38 (d, 1H, J = 4.9 Hz, H4),
6.36 (s, 1H, H6), 4.78 (d, 1H, J = 2.5 Hz, H9a), 4.76 (d, 1H, J = 2.5 Hz,
H9b), 3.51 (s, 3H, H7) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 156.3
(C8), 149.3 (C5), 145.5 (C3), 142.9 (C1), 129.9 (C2), 117.5 (C4), 105.5
(C6), 82.8 (C9), 55.0 (C7) ppm; IR: 3008, 2941, 1675, 1426, 1373, 1340,
1230, 1103, 1059, 845, 691, 627 cm- ; HRMS (ESI): m/z calcd for
C9H10NO: 148.0757, found: 148.0755 [M+H]+
1-(3-phenylpyridin-4-yl)ethan-1-ol (16)
Compound 11 (314 mg, 2.39 mmol) was dissolved in 15 mL of dry
THF. At -78°C, a solution of phenylmagnesium chloride (3M in THF,
1,14mL, 5,26 mmol) was carefully added. The reaction mixture was
allowed to warm at room temperature for 1 h. An aqueous saturated
solution of NH4Cl was added, followed by an aqueous saturated
solution NaHCO3. EtOAc was added (20 mL) and the two layers
decanted. The aqueous layer was extracted with EtOAc (2 x 20 mL).
The combined organic layers were dried over MgSO4 and
concentrated. The resulting residue was purified by silica gel
chromatography (Cyclohexane/EtOAc: 7/3 à 5/5) to afford the title
compound as a white solid. White solid, 62% yield. 1H NMR (400 MHz,
CDCl3): δ 8.66 (s, 1H, H1), 8.59 (d, J = 4 Hz, 1H, H5), 7.74 (d, J = 4
Hz, 1H, H4), 7.43 – 7.27 (m, 5H, H8-12), 6.24 (s, 1H, H6), 3.50 (s, 1H,
H15); 13C {1H} NMR (75 MHz, CDCl3): δ 155.3 (C3), 152.5 (C1), 148.8
(C5), 141,7 (C7), 128.4 (C9,11),127.9 (C10), 126.7 (C8,12), 120.4 (C4), 117.
0 (C2), 85.5 (C14), 78, 5 (C13), 72, 3(C6). ppm; HRMS (ESI): m/z calcd
for C14H12NO: 210.0913, found: 210.0914 [M+H]+
1
1204, 1101, 972, 914, 811 cm- ; HRMS (ESI): m/z calcd for C9H10NO2:
164.0706, found: 164.0709 [M+H]+
(2-ethynylpyridin-3-yl)methanol (13)
Compound 10 (200 mg, 1.53 mmol, 1 eq.) was dissolved in a mixture
of 10 mL of THF and 1 mL of water. At 0 °C, NaBH4 (58 mg, 1.53
mmol, 1 eq.) was added. Mixture was stirred at 0 °C for 7 min. Water
(10 mL) was added and mixture was extracted with DCM (3 x 20 mL).
Organic phase was dried over MgSO4 and concentrated. The title
compound was obtained in pure form without any further purification.
Brown solid, Yield: 73%. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, 1H,
J = 4.7 Hz, H5), 7.88 (d, 1H, J = 7.7 Hz, H3), 7.4 (dd, 1H, J1 = 7.8 Hz,
J2 = 4.77 Hz, H4), 5.45 (t, 1H, J = 5.6 Hz, H), 4.63 (d, 2H, J = 5.5 Hz,
{2-[2-(phenylselanyl)ethynyl]pyridin-3-yl}methanol (17)
General procedure E: Compound 13 (18.8 mmol, 1 eq.) was
dissolved in 30 mL of DMF. PhSeBr (18.8 mmol, 1 eq.) and CuI (37.6
mmol, 2 eq.) were then added to the mixture. The reaction mixture
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
was stirred at room temperature for 2 h. Et2O(200 mL) was added and
the mixture was washed with ammonia solution (20% wt.) (4 x 100
mL). The layers were decanted and the aqueous layer extracted with
Et2O (1 x 100 mL). Combined organic layers were washed with water,
brine (1 x 100 mL) and then dried over MgSO4. After evaporation, the
resulting residue was purified by silica gel chromatography
(DCM/MeOH: 100/0 to 95/5) to afford the title compound as a brown
reaction mixture was cooled to room temperature and basified with a
saturated aqueous solution of NaHCO3. EtOAc was added and the
two layers decanted. The aqueous layer was extracted with EtOAc (2
x 100 mL). The combined organic layers were dried over MgSO4 and
concentrated. The resulting residue was purified by silica gel
chromatography (DCM/MeOH: 95:5) to afford the title compound.
Beige solid, Yield: 65%. 1H NMR (300 MHz, CDCl3): δ 8.60 (d, 1H, J
= 4.7 Hz, H5), 7.69 (d, 1H, J = 7.5 Hz, H3), 7.38 (dd, 1H, J1 = 7.5, J2 =
5.1 Hz, H4), 5.39 (s, 2H, H8), 4.07 (s, 2H, H6) ppm; 13C {1H} NMR (75
MHz, CDCl3): δ 169.5 (C7), 151.0 (C1), 149.9 (C5), 132.3 (C3), 126.2
(C2), 122.3 (C4), 68.2 (C8), 38.9 (C6) ppm; IR: 2969, 1732, 1588, 1442,
1
solid, Yield: 74%. H NMR (300 MHz, DMSO-d6): δ 8.46 (d, 1H, J =
4.5 Hz, H5), 7.89 (d, 1H, J = 7.7 Hz, H3), 7.73-7.67 (m, 2H, H10,14),
7.48-7.32 (m, 4H, H4,11,12,13), 5.46 (t, 1H, J = 5.5 Hz, OH), 4.65 (d, 2H,
J = 5.5 Hz) ppm; 13C {1H} NMR (75 MHz, DMSO-d6): δ 148.1 (C5),
139.6, 139.5, 134.3, 129.8, 129.1, 127.8 (C9), 127.5, 123.3, 100.4 (C8),
75.3 (C7), 59.9 (C6) ppm; IR: 3224, 3872, 2159, 1577, 1424, 1045,
1
1391, 1247, 1213, 1151, 1057, 824 cm- ; HRMS (ESI): m/z calcd for
C8H7NO2Li: 156.0632, found : 156.0629 [M+Li]+
1
734, 666 cm- ; HRMS (ESI): m/z calcd for C14H12NOSe: 290.0074,
found: 290.0079 [M+H]+
1,4-dihydro-3H-pyrano[4,3-c]pyridin-3-one (PP2a)
From compound 18 according to general procedure F.
{3-[2-(phenylselanyl)ethynyl]pyridin-4-yl}methanol (18)
Beige solid, Yield: 39%. 1H NMR (300 MHz, CDCl3): δ 8.58 (d, 1H, J
= 4.7 Hz, H5), 8.50 (s, 1H, H1), 7.19 (d, 1H, J = 4.9 Hz, H4), 5.33 (s,
2H, H6), 3.75 (s, 2H, H8) ppm;13C {1H} NMR (75 MHz, CDCl3): δ 168.8
(C7), 148.8 (C5), 148.0 (C1), 139.7 (C3), 126.4 (C2), 119.0 (C4), 68.8
(C6), 32.8 (C8) ppm; IR: 2969, 1731, 1392, 1256, 1146, 1032, 829,
From compound 14 according to general procedure E.
1
Brown solid, Yield: 78%. H NMR (300 MHz, CDCl3): δ 8.66 (s, 1H,
H1), 8.56 (d, 1H, J = 5.1 Hz, H5), 7.60 (d, 2H, J = 6.7 Hz, H10,14), 7.49
(d, 1H, J = 5.1 Hz, H4), 7.35 (m, 3H, H11,12,13), 4.88 (d, 2H, J = 4.5 Hz,
H6), 2.26 (bt, 1H, J = 5.1 Hz, OH) ppm; 13C {1H} NMR (75 MHz, DMSO-
d6): δ 152.8 (C5), 151.2 (C3), 149.0 (C1), 129.8 (C10,14), 128.9 (C11,13),
127.4 (C9), 120.3 (C4), 116.5 (C2), 97.1 (C7), 78.1 (C8), 60.3 (C6) ppm;
IR : 3197, 2161, 1578, 1475, 1439, 1398, 1335, 1233, 1064, 843, 730,
1
707 cm- ; HRMS (ESI): m/z calcd for C8H8NO2: 150.0550, found:
150.0553 [M+H]+
1
688 cm- ; HRMS (ESI): m/z calcd for C14H12NOSe: 290.0079, found:
1-methyl-1H,3H,4H-pyrano[4,3-c]pyridin-3-one (PP2b)
290.0089 [M+H]+
From compound 19 according to general procedure F. The reaction
mixture was refluxed at 120°C for 5 h. The resulting residue was
purified by silica gel chromatography (100% EtOAc) to afford the title
compound. Beige solid, Yield: 63%.1H NMR (300 MHz, DMSO-d6): δ
8.54 (d, 1H, J = 4.9 Hz, H5), 8.50 (s, 1H, H1), 7.38 (d, 1H, J = 4.9 Hz,
H4), 5.64 (q, 1H, J = 6.7 Hz, H6), 3.92 (d, 1H, J = 18.5 Hz, H8a), 3.85
(d, 1H, J = 18.5 Hz, H8b), 1.65 (d, 3H, J = 6.6 Hz, H7) ppm; 13C {1H}
NMR (75 MHz, CDCl3): δ 168.9 (C9), 148.9 (C1), 147.8 (C5), 143.9 (C3),
126.1 (C2), 118.0 (C4), 75.2 (C6), 32.7 (C8), 18.7 (C7) ppm; IR: 2950,
1-{3-[2-(phenylselanyl)ethynyl]pyridin-4-yl}ethan-1-ol (19)
From compound 15 according to general procedure E. The reaction
mixture was stirred at room temperature for 20 h. The resulting
residue was purified by silica gel chromatography (DCM/MeOH: 1:0
to 97:3) to afford the title compound. Yellow oil, Yield: 73%. 1H NMR
(300 MHz, CDCl3): δ 8.64 (s, 1H, H1), 8.53 (d, 1H, J = 4.4 Hz, H5),
7.63-7.56 (m, 3H), 7.41-7.31 (m, 3H), 5.26 (q, 1H, J = 6.4 Hz, H6),
1.51 (d, 3H, J = 6.6 Hz, H7) ppm. 13C {1H} NMR (75 MHz, DMSO-d6):
δ 157.4 (C3), 151.5 (C1), 149.1 (C5), 129.8 (C11,15), 129.1 (C12,14), 128.0
(C10), 127.5 (C13), 119.5 (C4), 116.4 (C2), 97.3 (C9), 78.0 (C8), 65.6
1
1740, 1410, 1340, 1250, 1165, 1077, 651 cm- ; HRMS (ESI): m/z
calcd for C9H10NO2: 164.0706, found: 164.0706 [M+H]+
1
(C6), 24.1 (C7) ppm; IR: 3166, 2972, 2162, 1477, 1099, 731, 687 cm- ;
1-phenyl-1H,3H,4H-pyrano[4,3-c]pyridin-3-one (PP2c)
HRMS (ESI): m/z calcd for C15H14NOSe: 304.0236, found: 304.0227
From compound 20 according to general procedure F. The reaction
mixture was refluxed at 120°C for 6 h. The resulting residue was
purified by silica gel chromatography (Cyclohexane/Et2O 1/9) to afford
the title compound. Beige solid, 37% yield. 1H NMR (400 MHz, CDCl3):
δ 8.49 (m, 2H, H1,5), 7.35 (m, 3H, H4, H9,11), 7.23 – 7.19 (m, 2H, H8,12),
6.98 (m, 1H, H10), 6.33 (s, 1H, H6), 3.72 (dd, J = 16 Hz, 1H, H14a), 3.64
(dd, J = 16 Hz, 1H, H14b). 13C {1H} NMR (101 MHz, CDCl3): δ 168.7
(C13), 148.6 (C1), 147.8 (C5), 143.4 (C3), 135.3 (C2), 129.5 (C10), 129.1
(C8,12), 127.3 (C9,11), 126.7 (C7), 120.3 (C4), 81.0 (C6), 33.2 (C14). IR:
[M+H]+
1-{3-[2-(phenylselanyl)phenyl]pyridin-4-yl}ethan-1-ol (20)
From 16 according to the general procedure E: The reaction mixture
was stirred at room temperature for 20h. The resulting residue was
purified by silica gel chromatography (DCM/EtOAc 9/1 à 7/3) to afford
the title compound as a yellow oil, Yield: 55%.
1H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H, H1), 8.58 (d,1H, J = 4
Hz, H5), 7.68 (d, 1H, J = 4 Hz, H4), 7.58 (m, 2H, H8,12), 7.40 – 7.22 (m,
8H, H9,10, 11, 16, 17, 18, 19, 20), 6.24 (d, 1H, J = 4 Hz, H6).13C {1H} NMR (75
MHz, CDCl3): δ 155.2 (C3), 152.0 (C1), 149.3 (C5), 142.8 (C7), 129.8,
129.4, 128.1, 127.5, 127.3, 126.6, 120.4 (C4), 117. 1 (C2), 97.5 (C14),
1
1737, 1421, 1308, 1237, 1182, 1008, 760, 699 cm- , HRMS (ESI+):
+
calcd for C14H11NO2: 225,08; found m/z 226,08 [M+H]
78,
5
(C13), 71,4 (C6).
ppm; HRMS (ESI): m/z calcd for
8-bromo-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1m)
C20H15NNaOSe: 388.0212, found: 388.0204 [M+Na]+
Compound PP1a (100 mg, 0.67 mmol, 1 eq.) was dissolved in 10 mL
of DCM. NBS (119 mg, 0.67 mmol, 1 eq.) was then added and the
reaction mixture was stirred at room temperature for 10 min. DCM was
added and the resulting organic layer was washed twice with an
aqueous saturated solution of NaHCO3. The organic layer was dried
over MgSO4 and concentrated to afford the title compound in pure
5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1a)
Procedure F: Compound 17 (2.76 mmol, 1 eq) was dissolved in 40
mL of toluene. PTSA. monohydrate (11.04 mmol, 4 eq.) was then
added and the reaction mixture was refluxed at 120 °C for 20 h. The
9
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10.1002/ejoc.202001016
European Journal of Organic Chemistry
FULL PAPER
form. Brown solid, Yield: 59%. 1H NMR (300 MHz, CDCl3): δ 8.65 (d,
1H, J = 6 Hz, H5), 7.65 (d, 1H, J = 9 Hz, H3), 7.38 (dd, 1H, J1 = 9 Hz,
J2 = 6 Hz, H4), 5.63 (d, 1H, J = 12 Hz, H6a), 5.51 (s, 1H, H7), 5.30 (d,
1H, J = 12 Hz, H6b) ppm; 13C {1H} NMR (100 MHz, CD3OD): δ 167.4
(C8), 151.6 (C1), 151.3 (C5), 135.7 (C3), 130.6 (C2), 126.0 (C4), 69.4
(C6), 49.3 (C7) ppm; IR: 2935, 1755, 1432, 1207, 1182, 1023, 779
J = 7 Hz, H18), 5.09 (d, 1H, J = 12 Hz, H6a), 4.89 (d, 1H, J = 12 Hz,
H6b), 3.35-3.18 (m, 6H, H9/10/11/12), 3.00-2.91 (m, 2H, H9/10/11/12) ppm;
13C {1H} NMR (75 MHz, CDCl3): δ 170.5 (C7), 155.4 (C1), 149.8 (C5),
134.8 (C13), 132.5 (C3), 128.8 (C14,15), 128.7 (C16,17, 20, 21), 128.6 (C22,
23, 24), 127.7 (C19), 122.2 (C4), 116.1 (C18), 75.2 (C8), 66.5 (C6), 47.4
(C9,10, 11, 12) ppm; HRMS (ESI): m/z calcd for C24H24N3O2: 386.1863,
found: 386.1865 [M+H]+
1
cm- ; HRMS (ESI): m/ z calcd for C8H6BrNNaO2: 249.9474, found:
249.9480 [M+Na]+
8-phenyl-8-(4-methylpiperazin-1-yl)-5H,7H,8H-pyrano[4,3-
b]pyridin-7-one (PP1q)
8-bromo-8-phenyl-5H,7H,8H-pyrano[4,3-b]pyridin-7-one (PP1n)
Compound PP1h (100 mg, 0.44 mmol, 1 eq.) was dissolved in 10 mL
of DCM. NBS (79 mg, 0.44 mmol, 1 eq.) was then added and the
reaction mixture was stirred at room temperature for 5 minutes. DCM
was added and the resulting organic layer was washed twice with an
aqueous saturated solution of NaHCO3. The organic layer was dried
over MgSO4 and concentrated to afford the title compound in pure
form. Orange solid, Yield: 80%. 1H NMR (300 MHz, CDCl3): δ 8.72 (d,
1H, J = 3 Hz, H5), 7.62 (d, 1H, J = 6Hz, H3), 7.41-7.33 (m, 6H,
H4,10,11,12,13,14), 5.46 (d, 1H, J = 15 Hz, H6a), 5.16 (d, 1H, J = 15 Hz, H6b)
ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 166.9 (C8), 152.7 (C1), 150.0
(C5), 135.7 (C2), 132.7 (C3), 128.7 (C12), 128.3 (C10,14), 128.3 (C11,13),
126.5 (C9), 123.5 (C4), 67.2 (C6), 63.4 (C7) ppm; IR : 3092, 1732, 1439,
Compound PP1n (300 mg, 0.99 mmol, 1 eq.) was dissolved in 5 mL
of DCM. K2CO3 (274 mg, 1.98 mmol, 2 eq.) and N-methylpiperazine
(121µL, 1.09 mmol, 1.1 eq.) were successively added. The solution
was stirred at room temperature for 6 h. Water (10 mL) was added,
followed by an aqueous saturated solution of Na2CO3 (10 mL) and
DCM (30 mL). The two layers were decanted and the aqueous layer
extracted with DCM (2 x 30 mL). The combined organic layers were
washed with an aqueous saturated solution of Na2CO3, dried over
MgSO4 and concentrated. The resulting residue was purified by silica
gel chromatography (DCM/ NEt3: 99/1 to DCM/MeOH/NEt3 97/2/1) to
afford the title compound. Yellow oil: 62%.1H NMR (300 MHz, CDCl3):
δ 8.80 (d, 1H, J = 6 Hz, H5), 7.45 (d, 1H, J = 6 Hz, H3), 7.41-7.18 (m,
6H, H4,15,16,17,18, 19), 5,05 (d, 1H, J = 12 Hz, H6a), 4.84 (d, 1H, J = 12 Hz,
H6b), 3.03 (m, 2H, H9), 2,81 (m, 2H, H12), 2,50 (m, 4H, H10,11), 2,31 (s,
3H, H13) ppm; 13C {1H} NMR (75 MHz, CDCl3): δ 170.4 (C8), 155.7 (C1),
149.9 (C5), 135.1(C2),132.4 (C3), 128.7 (C15,19), 128.6 (C16,18), 127.8
(C14), 122.1 (C4), 75.2 (C7), 66.5 (C6), 55.9 (C9/12), 47.3 (C10/11), 46.0
(C13) ppm; HRMS (ESI): calcd for C19H22N3O2: 324.1707, found: m/z
324.1707 [M+H]+
1
1388, 1240, 1176, 1049, 754 cm- ; HRMS (ESI): m/z calcd for
C14H10BrNNaO2: 325.9787, found: 325.9797 [M+Na]+
8-(4-phenylpiperazin-1-yl)-5H,7H,8H-pyrano[4,3-b]pyridin-7-one
(PP1o)
Compound PP1m (130 mg, 0.6 mmol, 1 eq.) was dissolved in 5 mL of
acetonitrile. N-phenylpiperazine (229 µL, 1.5 mmol, 2.5 eq.) was then
added. The reaction mixture was stirred at room temperature for 20
hours. An aqueous saturated solution of Na2CO3 was added to the
mixture, followed by DCM (20 mL) The two layers were decanted and
the aqueous layer extracted with DCM (2 x 20 mL). The organic layer
was dried over MgSO4 and concentrated. The resulting residue was
purified by silica gel chromatography (Cyclohexane/EtOAc: 1:1) to
Keywords: pyridopyridinones • antihistamines • delta-lactone •
Pinner reaction • seleno-mediated cyclization
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afford the title compound in pure form. White solid, Yield: 22%. H
NMR (300 MHz, CDCl3): δ 8.64 (d, 1H, J = 6 Hz, H5), 7.63 (d, 1H, J =
6 Hz, H3), 7.35 (d, 1H, J = 6 Hz, H4), 7.30-7.20 (m, 2H, H15,17), 6.94-
6.82 (m, 3H, H14,16,18), 5.92 (d, 1H, J = 15 Hz, H6a), 5.14 (d, 1H, J = 15
Hz, H6b), 4.27 (s, 1H, H7), 3.23-3.07 (m, 4H,H9/10/11/12), 2.94-2.83 (m,
2H, H9/10/11/12), 2.70-2.57 (m, 2H, H9/10/11/12) ppm. 13C {1H} NMR (75
MHz, CDCl3): δ 168.8 (C8), 152.3 (C1), 150.9 (C13), 149.6 (C5), 133.1
(C3), 129.1 (C15,17), 128.8 (C2), 123.4 (C4), 119.8 (C16) 116.0 (C14,18),
70.8 (C6), 68.1 (C7), 51.2 (C9/10/11/12), 49.0 (C9/10/11/12) ppm; HRMS
(ESI): m/z calcd for C18H20N3O2: 310.1550, found: 310.1557 [M+H]+
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8-phenyl-8-(4-phenylpiperazin-1-yl)-5H,7H,8H-pyrano[4,3-
b]pyridin-7-one (PP1p)
Compound PP1n (100 mg, 0.33 mmol, 1 eq.) was dissolved in 5 mL
of acetonitrile. Et3N (92 µL, 0.66 mmol, 2 eq.) and N-phenylpiperazine
(75 µL, 0.49 mmol, 1.5 eq.) were successively added. The solution
was stirred at room temperature for 20 h. Water (10 mL) was added,
followed by DCM (30 mL). The two layers were decanted and the
aqueous layer extracted with DCM (2 x 20 mL). The combined organic
layers were washed with an aqueous saturated solution of Na2CO3,
dried over MgSO4 and concentrated. The resulting residue was
purified by silica gel chromatography (Cyclohexane/EtOAc: 8:2 to 6:4)
to afford the title compound. Brown oil, Yield: 71%. 1H NMR (400 MHz,
CDCl3): δ 8.75 (d, 1H, J = 4 Hz, H5), 7.41 (d, 1H, J = 7 Hz, H3), 7.40-
7.16 (m, 8H, H4,16,17, 20, 21, 22, 23, 24), 7.00-6.94 (m, 2H, H14,15), 6.86 (t, 1H,
10
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10.1002/ejoc.202001016
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Entry for the Table of Contents
Original pyranopyridinones containing polyfunctionalized delta-lactones ring have been synthesized using three concise and efficient synthetic
methodologies. Potential semi-rigid analogs of antihistamines containing a pyranopyridinone scaffold have also been prepared using the
outlined synthetic methodologies.
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12
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