Eco-friendly methodology to prepare N-heterocycles related to dihydropyridines: Microwave-assisted synthesis of alkyl 4-arylsubstituted-6- chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(

Article abstract of DOI:10.3390/molecules16119620

Here we describe the efficient synthesis of alkyl 4-arylsubstituted-6- chloro-5- formyl-2-methyl-1,4-dihydropyridine-3-carboxylates and 4-arylsubstituted-4,7-dihydrofuro[ 3,4-b]pyridine-2,5(1H,3H)-diones via microwave-accelerated reaction of alkyl 4-aryls

Full text of DOI:10.3390/molecules16119620

Molecules 2011, 16, 9620-9635; doi:10.3390/molecules16119620
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Eco-Friendly Methodology to Prepare N-Heterocycles Related
to Dihydropyridines: Microwave-Assisted Synthesis of Alkyl
4-Arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-
dihydropyridine-3-carboxylate and 4-Arylsubstituted-4,7-
dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione
Hortensia Rodríguez 1,2,*, Osnieski Martin 1, Margarita Suarez 1, Nazario Martín 3 and
Fernando Albericio 2,4,5
*
1
Laboratory of Organic Chemistry, Department of Organic Chemistry, Chemistry Faculty,
University of Havana, 10400, Cuba; E-Mails: osniesky@gmail.com (O.M.); msuarez@fq.uh.cu (M.S.)
Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028 Barcelona,
Spain
2
3
4
5
Department of Organic Chemistry, Chemistry Faculty, Universidad Complutense, 28040 Madrid,
Spain; E-Mail: nazmar@quim.ucm.es (N.M.)
CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona
Science Park, Baldiri Reixac 10, 08028 Barcelona, Spain
Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11,
08028 Barcelona, Spain
* Authors to whom correspondence should be addressed; E-Mails: hrodriguez@pcb.ub.es (H.R.);
albericio@irbbarcelona.org (F.A.).
Received: 10 October 2011; in revised form: 26 October 2011 / Accepted: 15 November 2011 /
Published: 21 November 2011
Abstract: Here we describe the efficient synthesis of alkyl 4-arylsubstituted-6-chloro-5-
formyl-2-methyl-1,4-dihydropyridine-3-carboxylates and 4-arylsubstituted-4,7-dihydro-
furo[3,4-b]pyridine-2,5(1H,3H)-diones via microwave-accelerated reaction of alkyl
4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylates
with
the
appropriate reagents. This eco-friendly approach to these valuable dihydropyridine
derivatives does not involve the harsh or highly contaminating conditions common in
classical heating and offers a reduction or even elimination of solvent use and recovery,
simplification of the work-up procedures, facility of scale up, and low energy consumption,
in addition to moderate to higher yields.

Molecules 2011, 16
Keywords: microwave; dihydropyridines; green chemistry
9621
1. Introduction
Nitrogen heterocycles are frequently found in privileged (pharmacophore) structures [1,2], but their
incorporation is often hindered (multistep sequences, lack of generality, preparation from acyclic
precursors, etc.); thus, only a limited number of strategies have been successfully applied in the synthesis
of heterocyclic scaffolds [3-5]. The development of new, rapid, and clean synthetic routes toward
focused libraries of such compounds is of relevance to medicinal and synthetic chemists alike [6].
Undoubtedly, the most efficient strategies involve multicomponent reactions (MCRs), which are
powerful tools for the rapid introduction of molecular diversity [7,8]. Consequently, interest in the
design and development of MCRs for the generation of heterocycles is growing [9].
In recent years, increasing interest has been focused on the synthesis of 1,4-dihydropyridine
derivatives (1,4-DHPs) owing to their significant biological activity [10-12]. In particular,
dihydropyridine drugs, such as nifedipine, nicardipine, amlodipine, and others, are effective
cardiovascular agents for the treatment of hypertension [13]. However, in spite of the potential utility
of these drugs, their synthesis usually involves expensive reagents, organic solvents, long reaction
times, and affords unsatisfactory yields. Thus, the development of an efficient and versatile method for
the execution of of the Hantzsch reaction is an active ongoing field of research, and there is scope for
further improvements in the form of milder reaction conditions, shorter reaction times, and improved
yields [14-16].
The application of microwave irradiation (MW) as a non-conventional energy source for the
activation of reactions, in general and under solvent-free conditions in particular, has now gained
popularity compared to standard homogeneous and heterogeneous reactions because it provides
enhanced reaction rates and (usually) improved product yields. In addition, in the context of green
chemistry, MW irradiation has several eco-friendly advantages, which have been extended to modern
drug discovery processes. Generally, the rapid heating induced by MW avoids the harsh classical
conditions and decomposition of reagents, thus facilitating the formation of products under milder
reaction conditions with a consequent increase in yield [17-19].
In the context of our general interest in MCRs and as part of our ongoing research programs into
non-conventional synthesis as an eco-friendly approach to produce nitrogen heterocyclic compounds,
here we report the MW-assisted synthesis (MWAS) of alkyl 4-arylsubstituted-6-chloro-5-formyl-2-
methyl-1,4-dihydropyridine-3-carboxylates II and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-
2,5(1H,3H)-diones III from alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridine-
carboxylates I. The 1,4-DHPs bearing the chlorine and formyl group proved to be useful intermediates
for the synthesis of other pyridine-fused heterocycles (Figure 1).

Molecules 2011, 16
Figure 1. Chemical structures of alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-
9622
tetrahydro-3-pyridinecarboxylates I, alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-
1,4-dihydropyridine-3-carboxylates II and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-
2,5(1H,3H)-diones III.
Ar
O
Ar
O
O
Ar
O
OR
H
OR
O
N
H
O
N
H
CH3
O
Cl
N
H
CH3
I
II
III
2. Results and Discussion
To obtain the alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-
carboxylates IIa–j and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione DHP
derivatives III, we previously synthesized alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-
3-pyridinecarboxylates Ia–j. Briefly, compounds Ia–j were prepared under solvent-free conditions in a
one-pot condensation reaction assisted by MW irradiation using the methods previously reported by
our group [20,21]. When the irradiation was stopped, the solids were treated with appropriate solvents
and filtered to give the pure products Ia–j in moderate to good yields (44%–89%).
For the MWAS, the irradiation was provided by a CEM Discover LabMate Focused Single Mode
MW Synthesis System, which allows for continuous stirring and irradiation with temperature control [22].
All the reactions were followed by TLC and the experiments were replicated in order to ensure
reproducibility.
2.1. Microwave Assisted Synthesis (MWAS) of Methyl 4-Arylsubstituted-6-chloro-5-formyl-2-methyl-
1,4-dihydropyridine-3-carboxylates IIa–j
Some 6-chloro-5-formyl-1,4-dihydropyridine derivatives have been prepared by reaction of alkyl
2-methyl 6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylates I with Vilsmeier-Haack reagent (POCl3,
DMF) [12,23-25]; however, these reactions require long times (18 h) to obtain moderate or good
yields. We recently reported on the ultrasound-assisted synthesis of these derivatives and found
considerable improvements over conventional Vilsmeier-Haack chloroformylation [26]. In addition,
MW irradiation has been used to accelerate the Vilsmeier-Haack formylations of pyrrole substrates [27].
The MWAS of compounds IIa–j was performed in a one-step procedure by reaction in an open
vessel with previously prepared POCl3/DMF. The MW-accelerated Vilsmeier-Haack reaction is
typically carried out in a MW reactor at 180 Watts and a controlled temperature of 50 °C for 5 min.
Subsequent hydrolysis produces almost analytically pure compounds IIa–j, which requires minimal if
any purification (Scheme 1).

Molecules 2011, 16
9623
Scheme 1. Synthesis of compounds IIa–j.
Table 1 shows the results obtained for the MWAS of compounds IIa–j and the comparison with the
classic method previously reported by our group (Method B) [24,25].
Table 1. Results of MWAS (Method A) of alkyl 4-arylsubstituted-6-chloro-5-formyl-2-
methyl-1,4-dihydropyridine-3-carboxylate (IIa–j) and comparison with the conventional
method (Method B) [24,25].
Product
IIa
R
Ar
Method
T(°C)
50
t (min)
5
Yield (%)
69
CH3
2-NO2-C6H4
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
RT
50
1080
5
70
IIb
IIc
IId
IIe
IIf
CH3
CH3
3-NO2-C6H4
4-NO2-C6H4
68
RT
50
1080
5
73
65
RT
50
1080
5
69
CH3
4-COOCH3-C6H4
2,3-diOH-C6H4
4-N(CH3)2-C6H4
C6H5
63
RT
50
1080
5
73
CH3
70
RT
50
1080
5
63
CH3
60
RT
50
1080
5
68
IIg
IIh
IIi
CH2CH3
CH2CH3
CH2CH3
CH2CH3
62
RT
50
1080
5
75
2-NO2-C6H4
65
RT
50
1080
5
75
2,3-diOH-C6H4
4-N(CH3)2-C6H4
63
RT
70
1080
5
71
IIj
64
RT
1080
70
In all cases, the yields for these compounds by MWAS (Method A) were slightly lower than those
previously reported for conventional synthesis [24,25], although the reaction times were dramatically
reduced from 18 h under conventional synthesis to 5 min for MWAS. With MW irradiation as an
energy source, the partial decomposition of the Vilsmeier-Haack (VH) reagent was promoted by the
increase in reaction temperature, taking to account the presence of N,N-dimethylformamide in the
reaction mixtures. This polar molecule is highly sensitive to MW irradiation and allows higher
temperatures [28,29]. In fact, under our MW-assisted chloroformylation conditions, the presence of
DMF masked the specific effect of MWs, and the accelerations are attributed mainly to the
superheating effect of the solvent. However, in order to determine whether there is a specific MW

Molecules 2011, 16
9624
effect accelerating the reaction with respect to conventional heating, we carried out all the experiments
using classical heating (thermostated oil bath) in the same conditions as under MWAS (time, profiles
of rise in temperature, vessels, etc.). When the starting materials were heated at 50 °C for 5 min to 2 h
without solvent, only a complex mixture of by-products was detected (TLC and 1H-NMR).
The improvement achieved with MWAS (Method A) could be associated with the reaction
mechanism and the evolution of polarity during the MW-assisted reaction. This reaction was shown to
proceed through a mechanism involving several steps, beginning with the formation of the
electrophilic VH reagent from DMF and POCl3. Reaction of the electrophilic reagent with the enolic
form of the intermediate compound I proceeded through a pyridone intermediate, followed by reaction
with POCl3 to give the chloro derivative intermediate, which, via subsequent hydrolysis, provided the
desired 6-chloro-5-formyl-1,4-DHP II (Scheme 2).
Scheme 2. The proposed mechanism of the chloroformylation reaction.
On the basis of the previous result and the postulated mechanism, we propose that the specific MW
effect is attributable to the following: Improvements in the formation of the chloroiminium species
(VH reagent), and the enhancement of the subsequent reaction of the electrophilic reagent with the
enolic form of the intermediate compound I. In both cases, the polarity increased from the ground state
to the transition state (Scheme 3), thereby resulting in an enhancement of reactivity as a result of a
decrease in the corresponding activation energy [30].

Molecules 2011, 16
9625
Scheme 3. Postulated transition states (ET) for the formation of VH reagent and for the
reaction between the electrophilic reagent and the enolic form in the chloroformylation reaction.
The final products IIa–j were characterized by melting point, NMR and mass spectral data. Most
compounds synthetized in this study were known and their spectral characterization showed
1
satisfactory agreement with previous literature data [12,23-25]. The H-NMR spectra of the DHP
derivatives IIa–j showed two singlets at δ ~ 10.6 ppm and δ ~ 9.6 ppm, corresponding to the NH and
CHO protons, respectively. The singlet corresponding to the H4 proton appeared in the range of δ
4.9–5.3 ppm and the methyl group on C-2 as a singlet at δ ~ 2.3 ppm. The alkoxycarbonyl group on C3
appeared as a singlet (δ ~ 3.5 ppm) in the case of R = CH3 (compounds 5a–f) and as a quadruplet-
triplet when R = CH2CH3 (compounds 5g–j) at δ ~ 3.9 ppm and δ ~ 1.1 ppm, respectively. The
1H-NMR spectra also showed signals corresponding to the phenyl protons, depending upon the
substitution present on the aromatic ring. The 13C-NMR spectra of these compounds displayed signals
in the carbonyl, aromatic and aliphatic regions. For the nitrogen heterocyclic ring, the spectra showed
four quaternary carbon signals (C-2, C-3, C-5, and C-6), and one secondary carbon signal (C-4). The
formyl group (CHO) carbon in these systems appeared at 187–186 ppm. The alkoxycarbonyl group
appeared at 166.2–166.9 ppm.
MWAS of chloroformyl derivatives IIa–j offers considerable improvements over our previously
reported conventional Vilsmeier-Haack chloroformylation [12,23-25]. The reaction time was notably
reduced (conventional synthesis: 18 h, and MWAS: 5 min), and the final product was obtained with
excellent purity and hence could be used in further synthetic steps without any need for wasteful
purification.
2.2. Microwave Assisted Synthesis (MWAS) of 4-Arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-
2,5(1H,3H)-diones IIIa–i
Some substituents on the 1,4-DHP ring have a dramatic effect on its biological activities [31].
Specifically, cyclohexanone and -lactone rings fused to the 1,4-DHP moiety result in a striking effect

Molecules 2011, 16
9626
on the entry of calcium ions into the intracellular space (calcium antagonist effect) [32]. Our classical
method for the synthesis of 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-diones III in
moderate to good yields, comprised a one-pot reaction of the alkyl 2-methyl 6-oxo-1,4,5,6-
tetrahydropyridine-3-carboxylates I with N-bromosuccinimide (NBS) as the brominating reagent by
refluxing in chloroform in 12–14 h [33-35]. The microwave-accelerated lactonization to obtain the
furo[3,4-b]pyridines IIIa–i were performed in a one-step procedure by reaction of previously
synthesized I with NBS without solvent. This reaction was carried out at 240 Watts and under a
controlled temperature of 80 °C for 10 min (Scheme 4). When the irradiation was stopped, the mixture
was treated with the adequate solvents and filtered to give the pure products IIIa–i in excellent yields.
Scheme 4. Schematic representation for the synthesis of compounds IIIa–i.
Table 2 shows the results obtained for the MWAS of compounds IIIa–i, compared with the
classical method previously reported by our group (Method B) [33-35]. To check the possibility of
intervention of specific non-pure thermal effects of MWs, the reaction was performed by heating in
thermostated oil bath under the same experimental conditions used for MW irradiation (time, profiles
of rise in temperature, vessels). In no case was a reaction detected by TLC at 10 min of reaction, and
after 2 h of reaction the TLC showed a complex mixture of byproducts.
Table 2. Results of MWASwithout solvent (Method A) of 4-arylsubstituted-4,7-dihydro-
furo[3,4-b]pyridine-2,5(1H,3H)-diones IIIa–j and comparison with the conventional
method (Method B) [33-35].
Product
IIIa
R
Ar
Method
A
T(°C)
80
t (min)
10
Yield (%)
-CH3
2-NO2-C6H4
80
85
55
60
79
82
52
58
82
85
55
57
-CH2CH3
-CH3
80
10
B
A
B
A
B
62
720
720
10
-CH2CH3
-CH3
62
IIIb
IIIc
3-NO2-C6H4
4-NO2-C6H4
80
-CH2CH3
-CH3
80
10
62
720
720
10
-CH2CH3
-CH3
62
80
-CH2CH3
-CH3
80
10
62
720
720
-CH2CH3
62

Molecules 2011, 16
9627
Table 2. Cont.
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
-CH3
4-CH3-C6H4
A
80
80
62
62
80
80
62
62
80
80
62
62
80
80
62
62
80
80
62
62
80
80
62
62
10
10
89
85
61
56
72
79
52
55
84
85
59
53
84
85
59
61
88
85
51
58
83
81
63
59
-CH2CH3
-CH3
B
720
720
10
-CH2CH3
-CH3
2,3-diOH-C6H4
4-N(CH3)2-C6H4
C6H5
A
B
A
B
A
B
A
B
A
B
-CH2CH3
-CH3
10
720
720
10
-CH2CH3
-CH3
-CH2CH3
-CH3
10
720
720
10
-CH2CH3
-CH3
-CH2CH3
-CH3
10
720
720
10
-CH2CH3
-CH3
3-CH3O-C6H4
3,4,5-triCH3O-C6H4
-CH2CH3
-CH3
10
720
720
10
-CH2CH3
-CH3
-CH2CH3
-CH3
10
720
720
-CH2CH3
In all cases, the MWAS yields for these compounds (Method A) were higher than those achieved
previously with conventional synthesis conditions [33-35]. Moreover, the time of reaction was
dramatically reduced from 12 h (720 min) in the conventional synthesis (Method B) to 10 min for the
MWAS method. The presence of two distinct alkoxy groups in the three positions of the starting
dihydropyridine derivative I did not significantly alter the yields obtained.
Lactonization could be accounted for by the Wohl-Ziegler bromination (allylic bromination) [36] at
the methyl group to the 2nd position of the heterocycle I, yielding the non-isolable monobrominated
intermediate via a free radical process, followed by intramolecular cyclization to give the
corresponding -lactone (Scheme 5) in similar way to the pyridinium bromide perbromide procedure
reported for 1,4-DHPs [37]. Given the higher reactivity of the radical species, we propose that the
second stage is the determining step in the mechanism postulated for this reaction. The intramolecular
cyclization could take place through a polar mechanism. The non-isolable monobrominated
intermediate leads to a charged species as a result of an intramolecular nucleophilic attack through
SN2 mechanism. Subsequently, the bromide originated in this process could act as a nucleophile on the
methyl carbon, with the loss of a bromomethane molecule, to obtain the final product of reaction III
(Scheme 5). In both postulated steps for this second stage, the polarity is increased from the ground
states to the transition states (ET-1 and ET-2) (Scheme 5), thus resulting in an enhancement of
reactivity under MW irradiation by lowering the activation energy [30].

Molecules 2011, 16
9628
Scheme 5. The mechanism and the transition states postulated for the second step of the
lactonization reaction.
It is possible that the increase in the rate of the second stage of the lactonization reaction under MW
irradiation prevents the accumulation of the monobrominated intermediate, thus reducing the risk of
polybromation and consequently increasing yields.
The final products IIIa–i were characterized by melting point, NMR and mass spectral data. Most
compounds synthesized in this study were known and their spectral characterization showed
1
satisfactory agreement with the previous literature data [33-35]. The H-NMR spectra of DHP
derivatives IIIa–i showed one singlet corresponding to the NH at δ ~ 10.7–11.3 ppm. The signals
corresponding to the lactone ring methylene protons appeared as an AB system at δ 4.97 and δ 5.37
ppm, due to the germinal coupling between them, and confirmed the formation of lactone-fused DHP.
13
The C-NMR spectra of these compounds displayed signals in the carbonyl, aromatic, and aliphatic
regions. For the nitrogen heterocyclic ring, the spectra showed three quaternary carbon signals (C-2,
C-4a, and C-7a), one secondary carbon signal (C-4), and one primary carbon signal (C-3). The signals
of the quaternary carbons C-7a appeared at higher δ values than those expected for typical olefinic
carbon atoms. In contrast, the quaternary carbon C-4a was observed at unusually lower δ values. This
displacement of the signals is due to the strong push–pull effect of the groups linked to the olefinic
double bonds [33-35].
The MWAS without solvent of furopyridone derivatives IIIa–i (Method A) thus offers considerable
advantages over our previous reported conventional lactonization synthesis [33-35]. The reaction time
was notably reduced [conventional synthesis (Method B): 12 h, and MWAS (Method A): 10 min), and
the final product was obtained in excellent purity and yield and hence could be used in further
procedures without the need for any wasteful purification steps.
3. Experimental
3.1. General
Reagents and solvents were purchased from Fluka or Aldrich. The progress of the reaction and the
purity of compounds were monitored on TLC analytical silica gel plates (Merck 60F250) using
n-hexane-chloroform-ethyl acetate (3:2:1) and benzene-methanol (7:2) as eluents for the compounds
IIa–j and IIIa–I, respectively. The MW irradiation was provided by a CEM Discover LabMate
Focused Single Mode MW Synthesis Reactor, which produced continuous stirring and irradiation with
control of pressure and temperature. Melting points were determined in capillary tubes in an

Molecules 2011, 16
9629
Electrothermal C14500 apparatus and are uncorrected. The NMR spectra were recorded on a Mercury
400 spectrometer [400 MHz (1H) and 75.4 MHz (13C)]. Chemical shifts are given as δ values against
tetramethylsilane as the internal standard and J values are given in Hz. Mass spectra were obtained in a
LC/MSD-TOF(2006) Instrument (Agilent Technologies).
3.2. General Procedure for the MWAS of 4-Arylsubstituted alkyl 1,4,5,6-Tetrahydro-2-methyl-6-
oxopyridine-3-carboxylates I
4-Arylsubstituted alkyl 1,4,5,6-tetrahydro-2-methyl-6-oxopyridine-3-carboxylates I were prepared
following the previously reported procedure [20]. In this case the MW irradiation was provided by a
CEM Discover LabMate Focused Single Mode MW Synthesis Reactor, and the reaction mixtures were
irradiated for 10 min at 250 Watts. All the compounds were characterized by determination of physical
constants and by NMR spectroscopy, which coincided with those previously reported for these
compounds [20].
3.3. General Procedure for the MWAS of Methyl 4-Arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-
dihydropyridine-3-carboxylates IIa–j
4-Aryl-substituted alkyl 1,4,5,6-tetrahydro-2-methyl-6-oxopyridine-3-carboxylates (I, 7 mmol)
were added to the Vilsmeier-Haack reagent prepared from a mixture of POCl3 (1.1 mL, 12.2 mmol)
and DMF (1.4 mL, 18.2 mmol) at 5 °C. This mixture was then irradiated in the CEM Discover reactor
at 180 Watts for 5 min at the controlled temperature of 50 °C. After the completion of the reaction, an
aqueous sodium acetate solution was added (12 g in 21 mL of water). After 0.5 h, the mixture was
partitioned between water and chloroform, and the aqueous phase was extracted with ethyl acetate.
The organic phases were mixed and dried with anhydrous magnesium sulfate. The organic solvent was
removed in vacuo and the solid was precipitated from diethyl ether, filtered and washed with small
portions of cooled ethanol. The chracterization data of the compounds is given below.
Methyl
6-chloro-5-formy1-2-methyl-4-(2′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
(IIa).
1
Yellow solid; m.p. 178–180 °C; yield: 69%; H-NMR (DMSO-d6)  2.34 (s, 3H, CH3), 3.55 (s, 3H,
OCH3), 4.95 (s, 1H, H4), 7.64–7.53 (m, 3H, Ar), 8.04 (dt, J = 7.7 Hz, J = 2.1 Hz, 1H, Ar), 9.65 (s, 1H,
13
CHO), 10.56 (s, 1H, NH); C-NMR (DMSO-d6)  18.6 (CH3), 39.0 (C4), 60.6 (OCH3), 111.3 (C3),
104.8 (C5), 122.3 (C5′), 130.1 (C3′), 134.0 (C4′), 135.0 (C6′), 144.1 (C2), 147.1 (C6), 147.3 (C2′),
148.6 (C1′), 166.4 (COOCH3), 187.3 (CHO); ESI-MS: m/z 337 [M+H]+.
Methyl
6-chloro-5-formy1-2-methyl-4-(3′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
(IIb).
1
Yellow solid; m.p. 213–214 °C; yield: 68%; H-NMR (DMSO-d6)  2.36 (s, 3H, CH3), 3.54 (s, 3H,
OCH3), 5.05 (s, 1H, H4), 7.62–7.58 (m, 2H, Ar), 8.00 (t, J = 2.0 Hz, 1H, Ar), 8.05 (dt, J = 7.5 Hz,
13
J = 2.0 Hz, 1H, Ar), 9.67 (s, 1H, CHO), 10.53 (s, 1H, NH); C-NMR (DMSO-d6)  17.9 (CH3), 37.9
(C4), 51.2 (OCH3), 103.6 (C5), 110.4 (C3), 120.8 (C2′), 121.0 (C4), 129.6 (C6′), 133.6 (C5), 143.5
(C2), 147.6 (C3′), 147.7 (C6), 149.3 (C1′), 166.2 (COOCH3), 186.5 (CHO); ESI-MS: m/z 337 [M+H]+.
Methyl
6-chloro-5-formyl-2-methyl-4-(4′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate
(IIc).
1
Yellow solid; m.p. 190–192 °C; yield: 65%; H-NMR (DMSO-d6)  2.34 (s, 3H, CH3), 3,54 (s, 3H,

Molecules 2011, 16
9630
OCH3), 5.03 (s, 1H, H4), 7.44 (d, J = 7.9 Hz, 2H, Ar), 8,12 (d, J = 7.9 Hz, 2H, Ar), 9,67 (s, 1H, CHO),
10.48 (s, 1H, NH); 13C-NMR (DMSO-d6)  ppm 18.7 (CH3), 39.2 (C4), 51.2 (OCH3), 104.6 (C5),
111.1 (C3), 124.4 (C3′,C5′), 129.6 (C2′,C6′), 141.1 (C2), 147.1 (C4′), 146.9 (C6), 153.7 (C1′), 166.6
(COOCH3), 187.4 (CHO); ESI-MS: m/z 337 [M+H]+.
Methyl
6-chloro-5-formyl-4-(4-methoxycarbonylphenyl)-2-methyl-l,4dihydropyridine-3-carboxylate
(IId). White solid; mp 202–204 °C; yield: 63%; 1H-NMR (DMSO-d6)  2.34 (s, 3H, CH3), 3.53 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 5.00 (s, 1H, CH), 7.29 (d, J = 7.9 Hz, 2H, Ar), 7.84 (d, J = 7.9 Hz, 2H,
Ar), 9.67 (s, 1H, HCO), 10.46 (s, 1H, NH); 13C-NMR (DMSO-d6)  17.8 (CH3), 38.0 (C4), 51.1
(OCH3), 103.8 (C3), 110.5 (C5), 127.6 (C3′,C5′), 129.3 (C2′,C6′), 143.1 (C2),146.1 (C6), 150.7 (C1′),
166.4 (COOCH3), 186.5 (CHO); ESI-MS: m/z 350 [M+H]+.
Methyl 4-(2′,3′-dihidroxyphenyl)-6-chloro-5-formyl-2-methyl-l,4dihydropyridine-3-carboxylate (IIe).
1
White solid; mp 239–241 °C; yield: 70%; H-NMR (DMSO-d6)  2.24 (s, 3H, CH3), 3,77 (s, 3H,
OCH3), 4.98 (s, 1H, H4), 5.40 (brs, 2H, OH), 6.62(m, 3H, Ar) 9.71 (s, 1H, HCO), 10.38 (s, 1H, NH);
13C-NMR (DMSO-d6)  17.8 (CH3), 38.2 (C4), 51.3 (OCH3), 103.7 (C3), 110.3 (C5), 114.3 (C4′),
122.2 (C5′), 123.2 (C6′), 124.1 (C1′), 145.2 (C3′), 147 (C2′), 143.1 (C2), 146.5 (C6), 150.3 (C1′),
166.6 (COOCH3), 186.8 (CHO); ESI-MS: m/z 324 [M+H]+.
Methyl
6-chloro-4-(4′-dimethylaminophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate
1
(IIf). Yellow solid; m.p. 290–292 °C; yield: 60%; H-NMR (DMSO-d6)  2.34 (s, 3H, CH3), 3.10 (s,
6H, CH3), 3,52 (s, 3H, OCH3), 5.00 (s, 1H, H4), 7.39 (d, J = 7.9 Hz, 2H, Ar), 8,08 (d, J = 7.9 Hz, 2H,
Ar), 9,77 (s, 1H, CHO), 10.48 (s, 1H, NH); 13C-NMR (DMSO-d6)  18.7 (CH3), 39.2 (C4), 41.7
(2CH3), 51.2 (OCH3), 104.4 (C5), 110.9 (C3), 124.2 (C3′,C5′), 129.8 (C2′,C6′), 141.1 (C2), 147.2
(C4′), 146.7 (C6), 153.5 (C1′), 166.8 (COOCH3), 187.2 (CHO). ESI-MS: m/z 335 [M+H]+.
Ethyl 6-chloro-5-formyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (IIg). White solid; m.p.
201–202 °C; yield: 62%; 1H-NMR (DMSO-d6)  1.10 (t, J = 7.1 Hz, 3H, CH3), 2.33 (s, 3H, CH3), 4.02
(q, J = 7.1 Hz, 2H, OCH2), 4.93 (s, 1H, H4), 7.09 (d, J = 7.8 Hz, 2H, Ar), 7.31–7.11 (m, 3H, Ar), 9.72
13
(s, 1H, CHO), 10.35 (s, 1H, NH); C-NMR (DMSO-d6)  14.6 (CH3), 18.3 (CH3), 38.1 (C4), 59.8
(OCH2), 103.9 (C5), 109.3 (C3), 126.1 (C4′), 126.6 (C2′,C6′), 128.2 (C3′,C5′), 144.3 (C2), 146.9 (C1′),
147.9 (C6), 166.2 (COOCH2CH3), 187.4 (CHO); ESI-MS: m/z 306 [M+H]+.
Ethyl 6-chloro-5-formyl-2-methyl-4-(2′-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (IIh). Yelow
solid; m.p. 198–200 °C; yield: 65%; 1H-NMR (DMSO-d6)  1.10 (t, J =7.1 Hz, 3H, CH3), 2.35 (s, 3H,
CH3), 3.99 (q, J =7.1 Hz, 2H, OCH2), 5.03 (s, 1H, H4), 7.64–7.53 (s, 2H, Ar), 7.96 (t, J = 2.0 Hz, 1H,
Ar), 8.02 (dt, J = 7.7 Hz, J = 2.0 Hz, 1H, Ar), 9.68 (s, 1H, CHO), 10.52 (1H, s, NH); 13C-NMR
(DMSO-d6)  14.8 (CH3), 18.6 (CH3), 39.0 (C4), 60.6 (OCH2), 104.8 (C5), 111.3 (C3), 122.4 (C3′),
122.7 (C5′), 130.7 (C4′), 135.0 (C6′), 144.1 (C2), 147.1 (C6), 148.4 (C2′), 148,6 (C1′), 166.5
(COOCH2CH3), 187.4 (CHO); ESI-MS: m/z 351 [M+H]+.
Ethyl 4-(2′,3′-dihidroxyphenyl)-6-chloro-5-formyl-2-methyl-l,4dihydropyridine-3-carboxylate (IIi).
1
White solid; mp 248–250 °C; yield: 63%; H-NMR (DMSO-d6)  1.28 (t, 3H, CH3), 4,17 (q, 2H,

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OCH2), 4.98 (s, 1H, H4), 5.40 (brs, 2H, OH), 6.62(m, 3H, Ar) 9.71 (s, 1H, HCO), 10.38 (s, 1H, NH);
13C-NMR (DMSO-d6)  14.8 (CH3), 18.5 (CH3), 38.2 (C4), 61.3 (OCH2), 103.7 (C3), 110.3 (C5),
114.3 (C4′), 122.2 (C5′), 123.2 (C6′), 124.1 (C1′), 145.2 (C3′), 147 (C2′), 143.1 (C2),146.5 (C6), 150.3
(C1′), 166.6 (COOCH3), 186.8 (CHO); ESI-MS: m/z 338 [M+H]+.
Ethyl
6-chloro-4-(4′-dimethylaminophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate
1
(IIj). Yellow solid; m.p. 300–302 °C; yield: 64%; H-NMR (DMSO-d6)  1.25 (t, 3H, CH3), 3.10 (s,
6H, CH3), 4,17 (q, 2H, OCH2), 4.89 (s, 1H, H4), 7.35 (d, J = 7.9 Hz, 2H, Ar), 8,02 (d, J = 7.9 Hz, 2H,
Ar), 9,87 (s, 1H, CHO), 10.48 (s, 1H, NH); 13C-NMR (DMSO-d6)  14.5 (CH3), 18.3 (CH3), 39.2 (C4),
41.7 (2CH3), 61.5 (OCH2), 104.4 (C5), 110.9 (C3), 124.2 (C3′,C5′), 129.8 (C2′,C6′), 141.1 (C2), 147.2
(C4′), 146.7 (C6), 153.5 (C1′), 166.8 (COOCH3), 187.2 (CHO). ESI-MS: m/z 349 [M+H]+.
3.4. General Procedure for the MWAS of 4-Arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-
2,5(1H,3H)-diones IIIa–i
A mixture of 4-aryl-substituted alkyl 1,4,5,6-tetrahydro-2-methyl-6-oxopyridine-3-carboxylate (I,
5 mmol) and N-bromosuccinimide (0.89 g, 5 mmol) was irradiated without solvent in the CEM
Discover reactor at 240 Watts for 10 min, and at the controlled temperature of 80 °C. When the
irradiation was stopped, the mixture was treated with chloroform, and the solid obtained was filtered
and washed with small portion of cool chloroform and diethyl ether to give the pure products.
Compound data is given below.
4-(3′-Nitrophenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIa). Pale yellow solid; m.p.
218–219 °C; yield: 80% from I (R = Me), and 85% from I (R = Et); 1H-NMR (DMSO-d6)  3.03 (dd,
1H, H3b, J = 16.7 Hz, J = 3.8 Hz B part of ABX), 3.64 (dd, 1H, H3a, J = 16.7 Hz, J = 8.9 Hz A part of
ABX), 4.85 (dd, 1H, H4, J = 8.9 Hz, J = 3.8 Hz, X part of ABX), 5.34 (dd, 2H, OCH2),
13
8.38–7.82 (m, 4H, Ar), 11.27 (s, 1H, NH); C-NMR (DMSO-d6)  29.6 (C4), 38.1 (C3), 65.5 (C7),
99.8 (C4a), 124.7 (C5′), 128.7 (C4′), 129.1 (C6′), 133.8 (C3′), 135.1 (C1′), 148.6 (C2′), 162.0 (C7a),
168.0 (C5), 170.4 (C2); ESI-MS: m/z 275 [M+H]+.
4-(3′-Nitrophenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIb). Pale yellow solid; m.p.
1
234–235 °C; yield: 79% from I (R = Me), and 82% from I (R = Et); H-NMR (DMSO-d6)  2.67 (d,
1H, H3b, J = 16.9 Hz, J = 8.9 Hz B part of ABX) 3.15 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part of
ABX), 4 .25 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz X part of ABX); 4.97 (dd, 2H, OCH2), 8.12–7.64 (m,
13
4H, Ar), 10.86 (s, 1H, NH); C-NMR (75 MHz, DMSO-d6)  33.1 (C4), 38.0 (C3), 65.5 (C7), 100.5
(C4a), 148.0; 143.9; 133.6; 130.3; 122.1; 121.6 (C aromatics), 161.4 (C7a), 169.3 (C5), 170.8 (C2);
ESI-MS: m/z 275 [M+H]+.
4-(4′-Nitrophenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIc). Pale yellow solid; m.p.
241–243 °C; yield: 82% from I (R = Me), and 85% from I (R = Et); 1H-NMR (DMSO-d6)  2.67 (dd,
1H, H3b, J = 16.6 Hz, J = 3.6 Hz B part of ABX), 3.15 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part of
ABX), 4.25 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz, X part of ABX), 4.97 (dd, 2H, OCH2), 8.15–7.42 (m;
13
4H; Ar), 10.81 (s, 1H, NH); C-NMR (DMSO-d6)  33.1 (C4), 38.0 (C3), 65.5 (C7), 100.5 (C4a),

Molecules 2011, 16
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148.0, 143.9, 133.6, 130.3, 122.1,121.6 (C aromatics), 161.4 (C7a), 169.3 (C5), 170.8 (C2); ESI-MS:
m/z 275 [M+H]+.
4-(4′-Tolyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIId). White solid; m.p. 200–202 °C;
1
yield: 89% from I (R = Me), and 85% from I (R = Et); H-NMR (DMSO-d6)  2.65 (dd, 1H, H3b,
J = 16.6 Hz, J = 3.6 Hz B part of ABX), 3.15 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part of ABX),
4.26 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz, X part of ABX), 4.95 (dd, 2H, OCH2), 7.32–8.12 (m; 4H;
Ar), 10.78 (s, 1H, NH); 13C-NMR (DMSO-d6)  33.3 (C4), 38.2 (C3), 65.3 (C7), 100.4 (C4a), 121.5,
122.5, 130.1, 133.6, 144.0, 148.1 (C aromatics), 161.4 (C7a), 169.3 (C5), 170.8 (C2); ESI-MS: m/z
244 [M+H]+.
4-(2′,3′-Dihydroxyphenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIe). White solid; m.p.
1
291–293 °C; yield: 72% from I (R = Me), and 79% from I (R = Et); H-NMR (DMSO-d6)  2.65 (d,
1H, H3b, J = 16.9 Hz, J = 8.9 Hz B part of ABX) 3.10 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part of
ABX), 4.18 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz X part of ABX); 4.92 (dd, 2H, OCH2), 7.54–8.08 (m,
3H, Ar), 10.88 (s, 1H, NH); 13C-NMR (DMSO-d6)  30.9 (C4), 38.5 (C3), 65.3 (C7), 99.8 (C4a),
145.2; 145.9; 130.6; 123.7; 122.8; 119.9 (C aromatics), 162.1 (C7a), 169.3 (C5), 170.5 (C2); ESI-MS:
m/z 262 [M+H]+.
4-(4′-(Dimethylamino)phenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIf). Yellow solid;
m.p. 243–245 °C; yield: 84% from I (R = Me), and 85% from I (R = Et); 1H-NMR (DMSO-d6)  2.63
(d, 1H, H3b, J = 16.9 Hz, J = 8.9 Hz B part of ABX), 2.99 (s, 6H, 2CH3), 3.05 (dd, 1H, H3a,
J = 16.6 Hz, J = 8.9 Hz A part of ABX), 4.09 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz X part of ABX);
13
4.85 (dd, 2H, OCH2), 7.14–7.78 (m, 4H, Ar), 10.88 (s, 1H, NH); C-NMR (DMSO-d6)  32.8 (C4),
38.5 (C3), 40.9 (NCH3), 65.2 (C7), 99.9 (C4a), 119.9, 120.2; 128.9; 129.6, 132.7; 148.2, (C aromatics),
162.0 (C7a), 169.0 (C5), 170.1 (C2); ESI-MS: m/z 273 [M+H]+.
4-Phenyl-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIg). White solid; m.p. 239–240 °C;
1
yield: 84% from I (R = Me), and 85% from I (R = Et); H-NMR (DMSO-d6)  2.57 (d, 1H, H3b,
J = 16.6 Hz, J = 3.6 Hz B part of ABX), 3.12 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part of ABX),
4.01 (d, 1H, H4, J = 9.0 Hz, J = 3.6 Hz, X part of ABX), 4.91 (dd, 2H, OCH2), 7.18–7.35 (m; 4H; Ar),
10.74 (s, 1H, NH); 13C-NMR (DMSO-d6)  33.3 (C4), 38.4 (C3), 65.3 (C7), 101.7 (C4a), 126.5, 126.9,
128.7, 144.8 (C aromatics), 160.7 (C7a), 169.0 (C5), 170.9 (C2); ESI-MS: m/z 230 [M+H]+.
4-(3′-Methoxyphenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIh). Pale yellow solid;
m.p. 268–270 °C; yield: 88% from I (R = Me), and 85% from I (R = Et); 1H-NMR (DMSO-d6)  2.61
(d, 1H, H3b, J=16.9 Hz, J= 8.9 Hz B part of ABX) 3.14 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part
of ABX), 3.75 (s, 3H, OCH3), 4.20 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz X part of ABX); 4.82 (dd, 2H,
OCH2), 7.43–8.12 (m, 4H, Ar), 10.70 (s, 1H, NH); 13C-NMR (DMSO-d6)  33.5 (C4), 38.3 (C3), 53.2
(OCH3), 65.3 (C7), 101.0 (C4a), 120.9, 121.9, 130.3, 133.4, 141.9, 158.2 (C aromatics), 161.8 (C7a),
169.0 (C5), 170.1 (C2), ESI-MS: m/z 260 [M+H]+.

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4-(3′,4′,5′-Trimethoxyphenyl)-3,4-dihydrofuro[3,4-b]pyridine-2,5-(1H,7H)-dione (IIIi). Yellow solid;
m.p. 288–290 °C; yield: 83% from I (R = Me), and 81% from I (R = Et); 1H-NMR (DMSO-d6)  2.63
(d, 1H, H3b, J = 16.9 Hz, J = 8.9 Hz B part of ABX) 3.10 (dd, 1H, H3a, J = 16.6 Hz, J = 8.9 Hz A part
of ABX), 3.83 (s, 9H, 3OCH3), 4.18 (dd, 1H, H4, J = 9.0 Hz, J = 3.6 Hz X part of ABX); 4.82 (dd, 2H,
OCH2), 7.53 (s, 2H, Ar), 10.70 (s, 1H, NH); 13C-NMR (DMSO-d6)  33.5 (C4), 38.3 (C3), 56.2
(2OCH3), 60.8 (OCH3), 65.3 (C7), 101.0 (C4a), 109.9, 134.9, 136.5, 153.4 (C aromatics), 161.9 (C7a),
169.2 (C5), 170.3 (C2), ESI-MS: m/z 320 [M+H]+.
4. Conclusions
The MW-assisted methods presented here for the synthesis of alkyl 4-arylsubstituted-6-chloro-5-
formyl-2-methyl-1,4-dihydropyridine-3-carboxylates IIa–j and 4-arylsubstituted-4,7-dihydrofuro[3,4-
b]pyridine-2,5-(1H,3H)-diones IIIa–i are straightforward, mild, and efficient. In both cases, the overall
process was more energy-efficient than classical heating, since direct “in-core” heating of the medium
occurred. These protocols have advantages over other techniques as they offer a shorter reaction times,
cleaner reaction profiles, solvent-free reactions (for compounds IIIa–i), higher yields and an easy
eco-friendly work-up.
Acknowledgements
The work at Barcelona was partially supported by CICYT (CTQ2009-07758), the Generalitat de
Catalunya (2009SGR 1024), the Institute for Research in Biomedicine, and the Barcelona Science Park.
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