green synthesis of some bioactive heterocyclic...

Green synthesis of some…… Chapter 3

187

Green synthesis of some bioactive heterocyclic compounds from natural

precursors

Chemistry without catalysis, would be a sword without a handle, a light without brilliance,a bell without sound………………………………………………………………Alwin Mittasch

3.1. Introduction

Heterocyclic compounds, particularly those possessing N- or S- containing moieties, have

attracted significant interest due to their useful biological and pharmaceutical properties.

Many natural and synthetic drugs [Remington (2005)], dyes, pesticides are heterocyclic in

nature. Also, biological processes such as provision of energy, transmission of nerve

impulses, sight, metabolism and transfer of hereditary information are all based on chemical

reaction involving the participation of heterocyclic compounds, such as vitamins, enzymes,

coenzymes, ATP, DNA, RNA and serotonin. Heterocycles display intrinsic reactivity which

enables rich, versatile and productive transformations. Taking into cognizance, the

ubiquitous presence of heterocycles in natural products and drugs, the development of new,

fast and efficient preparative protocols for these structures remain an urgent task in

medicinal chemistry.

3.2. Dihydropyrimidin-2(1H)-ones

Dihydropyrimidinones (DHPMs) are important class of heterocyclic compounds due to their

wide range of bioactivities and their applications in the field of drug research. Out of the

five major bases in found in DNA and RNA, three are pyrimidinone derivatives which

comprises of Cytosine (1), Uracil (2) and Thymine (3) (Figure 1) and thus, have become

very important in the world of synthetic organic chemistry.

NH

N

OH2N NH

NH

OO NH

NH

OO

H3C

Cytosine (1) Thymine (3)Uracil (2)

Figure 1

The scope of this pharmacophore further widened with the identification of monastrol (4;

Figure 2) – an aryl-substituted 3,4-dihydropyrimidin-2(1H)-one – as a novel cell-permeable

molecule for the development of new anticancer drugs [Mayer et al. (1999)]. Monastrol is

known to affect the cell-division (mitosis) by a new mechanism which does not involve


188

tubulin targeting and consists of the specific and reversible inhibition of the motility of the

mitotic kinesis, a motor protein required for spindle bipolarity [Mayer et al. (1999)].

NH

NH

S

OH

EtOOC

H3C NH

NH

S

OH

EtOOC

H3C

IC50 = 5 µM

vs

IC50 = 120 µM

Monastrol (mitotic kinase Eg5 inhibitor)

Figure 2

Over the years, several dihydropyrimidinone derivatives have been found as calcium

channel blocker (e.g. SQ 32926 (5) and SQ 32547 (6); Figure 3) [Atwal et al. (1991)],

alpha-1a-antagonist [Kappe et al. (1997)], neuropeptide Y antagonist [Sinder and Shi

(1993)], antiviral, antitumor, antibacterial, anti-inflammatory [Kappe (1993); (2000a);

(2000b)], antihypertensive [Jain et al. (2008)] and antimalarial [Chiang et al. (2009)]

agents.

NH

N

O2N

i-Pr OOC

H3C

CONH 2

O NH

NCOO

S

F3C

i-Pr OOC

H3C

SQ 32926 (5)(Antihypertensive agent)

N

FSQ 32547 (6)(Antihypertensive agent)

Figure 3

The most important examples of pharmaceutically active dihydropyrimidinone derivatives

are crambine (7) and batzelladine (8) alkaloids, which have been isolated from marine

sources and are potent HIV group-120-CD4 inhibitors (Figure 4) [Hojati et al. (2010)].

N

HNH2N

O

O

HN

(CH2)8CH3

NH2

NHNH2

H2NHN

O O

NHN

NH

O

O

NH

N

(CH2)6CH3H3C

HH

Batzelladine B (8) (Anti-HIV agent)Crambine (Anti HIV agent)

HO

3

6

7

3

Figure 4


189

For these reasons, dihydropyrimidinones have not only attracted the attention of chemists to

synthesize, but also represent an interesting research challenge. In consequence, numerous

methods have been reported for the synthesis of this heterocyclic nucleus, some of which

are discussed as below:

3.3. Synthetic methodologies for dihydropyrimidinones

3.3.1. Classical method

The conventional method for the synthesis of DHPMs is the one-pot three-component

reaction of benzaldehyde, ethyl acetoacetate and urea in the presence of an acid catalyst

(Scheme 1). The product of this novel one-pot, three components synthesis that precipitated

on cooling of the reaction mixture was identified as 3,4-dihydropyrimidin-2(1H)-one and

this reaction came to be known as “Biginelli reaction”, or “Biginelli condensation”, or

“Biginelli dihydropyrimidine synthesis” after the name of its inventor “Pietro Biginelli”

[Biginelli (1893)].

CHO

C2H5OO CH3

OO

H2N NH2

O HCl

N

NHEtOOC

MeH

O

++EtOH, reflux

Scheme 1

Mechanism

Forty years after Biginelli’s initial report, the first mechanism for the synthesis of DHPMs

was conducted by Folkers and Johnson based on the reaction yields and visual observation

where N,N''-benzylidene bisurea, i.e. the primary bimolecular condensation product of

benzaldehyde and urea was suggested as the first intermediate in this reaction [Folkers and

Johnson (1933)]. In 1973, a second mechanistic proposal was suggested by Sweet and

Fissekis, which involved an aldol condensation between benzaldeyde and ethyl acetoacetate

to form a stabilized carbenium ion as the primary step [Sweet and Fissekis (1973)].

Kappe re-investigated the mechanism [Kappe (1997)] using 1H and 13C NMR spectroscopy

and established that the first step in the reaction involves the acid-catalyzed condensation

between aldehyde and urea, generating iminium ion 1. Interception of this iminium ion by

ethyl acetoacetate, possibly through its enol tautomer, produces an open-chain ureide 2

which subsequently cyclizes to dihydropyrimidine 3 by the removal of H2O [Kappe (1998)]

(Scheme 2).


190

O

H2N NH 2

Ph-CHO

O

HN NH 2HO

Ph

H+

-H 2O O

HN NH 2HO

Ph

+

H3C

EtOOC

O

-H +

Ph

NHEtOOC

H3C O OH2N

-H2O

NH

NH

Ph

EtOOC

H3C O

1

23

Scheme 2

One major drawback of the classical Biginelli protocol is low to moderate yields of DHPMs

particularly, when substituted aromatic and aliphatic aldehydes are employed due to several

side reactions [Atwal et al. (1989); Barluenga et al. (1989)] besides harsh conditions and

high reaction times [Russowsky et al. (2004)]. This has led to the recent disclosure of

several improved reaction protocols for the synthesis of DHPMs, either by modification of

the classical one-pot Biginelli approach itself [Gupta et al. (1995); Dandia et al. (1998); Hu

et al. (1998); Lu and Ma (2000); Ma et al. (2000)] or by the development of novel, but more

complex multistep strategies [O’Reilly and Atwal (1987); Shutalev et al. (1998)].

3.3.2. Alternative multistep strategies

Apart from the traditional Biginelli condensation, there are only a few other synthetic

methods available that lead to DHPMs. One noticeable exception is the so-called “Atwal

modification” of the Biginelli reaction [Atwal et al. (1987); (1989); O’Reilly and Atwal

(1987)]. Here, an enone (a) is first condensed with a suitable protected urea or thiourea

derivative (b) under almost neutral conditions. Deprotection of the resulting 1,4-

dihydropyrimidine (c) with HCl or TFA leads to the desired DHPMs (Scheme 3).

NH 2

X NH

R

R1

O

O R2R3

+N

NH

R1

O

R2X

R

R3

HN

NH

R1

O

R2X

R

X= S, R3= 4-MeOC6H4CH2X= O, R3 = Me

NaHCO3, DMF

70oC

deprotection

a b cR1= CH3, C2H5R2 =CH3; R=CH3

Scheme 3

Another approach to DHPMs has been described by Shutalev et al. (1998). This synthesis is

based on the condensation of readily available R-tosyl-substituted (thio)ureas (a) with the


191

(in situ prepared) enolates of acetoacetates or 1,3-dicarbonyl compounds. The resulting

hexahydropyrimidines (b) need not to be isolated and can be converted directly into

DHPMs (Scheme 4). This method works particularly well for aliphatic aldehydes and

thiourea and produces high overall yields of the desired target compounds.

NH2

X NH2HN

NH

R1

O

R2X

R

HN

NH

R1

O

R2X

R

X= O, S; Ts= p-toluenesulfonyl

R-CHO,TsH

ab

R

Ts NH

H2N XH2O

O

R1

R2 O

NaH,MeCN HTs OH

R1= CH3, C2H5etc.R= R2 =CH3 etc.

Scheme 4

In addition, several combinatorial approaches towards DHPMs have been advanced using

solid phase [Wipf and Cunningham (1995); Kappe (2000c); Valverde et al. (2001); Perez et

al. (2002)] or fluorous phase reaction conditions [Studer et al. (1997a); (1997b)]. In both the

solid-phase (Scheme 5) and fluorous-phase modifications (Scheme 6) of the Biginelli

condensations, the urea component is linked to the solid (or fluorous) support via the amide

nitrogen, which invariably leads to the formation of N1-functionalized DHPMs.

NH2.H Cl

HN S

R1

O H

EtO OC

R2 O

NH

NEtO OC

R1

R2 SNMPCs2CO3

90oC, 16 h

NH

NHEtO OCR1

R2 O

NH

NHEtO OCR1

R2 S

NH

NHEtO OCR1

R2 NH

NH4OAcMeCN

TFAEtSH

AcOHH2O

R1 =C6H5, CF3C6H4, NO2C6H4R2 = CH3

Scheme 5: Solid-Phase Synthesis

Substrate SubstrateF F + byproductsF reaction

Product

F Product

extraction

F Product+detachment

Productextraction

Scheme 6: Fluorous-Phase Synthesis

Though these alternate strategies lead to somewhat higher yields, yet lack the experimental

and conceptual simplicity of the Biginelli one-pot, one-step procedure, hence could not

compete with the original Biginelli MCR approach. Therefore, Biginelli reaction was


192

reviewed and several modifications and improvements under classical reflux or solvent free

conditions, and microwave or ultrasound irradiation have been reported.

3.3.3. Modified Biginelli protocols

A number of improved variants employing Lewis acids or protic acids based new catalytic

systems, new solvents and new reagents have emerged allowing access to a large number of

multifunctionalized dihydropyrimidinone derivatives [Kappe and Roschger (1989); Kappe

(1993)].

For instance, with polyphosphate ester (PPE) as solvent in one-pot Biginelli's condensation,

a significant increase in the yields of DHPMs was observed, especially for systems that give

only moderate yields using traditional Biginelli conditions (Scheme 7) [Kappe and Falsone

(1998)].

H3C O

EtO OCNH 2

H2N O

O H

NH

NHEtOOC

H3C O

0.3 eq PPE

THF, reflux15 h

Scheme 7

In 2004, Tu and co-workers described an efficient synthesis of 3,4-dihydropryimidin-2(1H)-

one derivatives using potassium hydrogen sulfate as the promoter in glycol solution for the

Biginelli reaction (Scheme 8). The method was applicable not only to open-chained 1,3-

dicarbonyl compounds, but also to cyclic 1,3-dicarbonyl compounds. Bifunctional

compounds containing two dihydropyrimidinone units were also been synthesized using

isophthalaldehyde and terephthalaldehyde [Tu et al. (2004)].

O

R H

O

H3C R1

O O

H2N NH2 NH

NHR1

O

OH3C

R

KHSO 4+ +Ethylene glycol

R = C6H5, NO2C6H4, OCH3C6H4, ClC6H4 etc.; R1 = CH3, C2H5

Scheme 8

In another instance, catalytic behavior of a series of eleven transition metal

methanesulfonates [Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), La(III), Ce(III), Pr(III),

Nd(III), Yb(III)] in Biginelli condensation under reflux was investigated. The study

revealed that except for Mn(II), other ten methanesulfonates exhibited good catalytic effects

with Zn(II) methanesulfonate giving better results [Wang et al. (2005a); (2005b)].


193

Similarly, a one-pot method for the synthesis of Biginelli-type 3,4-dihydropyrimidin-2(1H)-

ones using a recyclable and eco friendly heterogeneous Keggin-type heteropolyacid catalyst

(H3PMo12O40) has been reported. It was proposed that the catalytic effect probably arises

due to the acidity of H3PMo12O40 (Scheme 9) [Heravi et al. (2006)].

X

H2N NH2

O

R1 H

O

H3C OR2

O

NH

NHR2OOC

HR1

XH3C

H3PMo12O40 (2 mol%)

AcOH, reflux

X= O, S; R1 = C6H5, NO2C6H4, OCH3C6H4, ClC6H4 etc.; R2 = CH3, C2H5

+ +

Scheme 9

Furthermore, chlorotrimethylsilane (TMSCl) has been used as a catalyst for the synthesis of

N1-alkyl-, N1-aryl- and N1,N3-dialkyl-3,4-dihydropyrimidin-2(1H)-(thi)ones using N-

substituted urea and thiourea in Biginelli reaction (Scheme 10) [Ryabukhin et al. (2007)].

NH

YNH

R

R' Ar

H O

COO Et

O

N

NY

R

COO Et

Ar

R'4 eq. TMSCl

+

1.1-1.3 eqY = O, S; R = alkyl, aryl; R' = alkyl, H

+DMF, rt, 48 h

Scheme 10

Alike, a simple methodology has been reported for the synthesis of 3,4-dihydropyrimidin-

2(1H)-ones and thione analogs in moderate to good yields by the reaction of aldehydes, β-

ketoesters and urea or thiourea using copper(II) sulfamate as catalyst (Scheme 11) [Liu and

Wang (2009)].

O

R1 H

O

H3C OR2

O X

H2N NH 2NH

NHR2O

O

XH3C

R1

1m ol% C u(NH2SO3)2+ +AcOH, reflux

R1 =OCH3C6H4, ClC6H4, NO2C6H4 etc.; R2= CH3, C2H5; X = O, S

Scheme 11

Recently, first Brønsted base catalyzed Biginelli type condensations using potassium-tert-

butoxide (t-BuOK) has been reported for three-component Biginelli-type condensation of

aldehyde, 2-phenylacetophenone, and urea/thiourea (Scheme 12). It was proposed that

enone and bis-urea were intermediates for reactions involving thiourea and urea as

substrates, respectively [Shen et al. (2010)].


194

O

R1 H

O

R2R3

O

H2N NH2

S

H2N NH2

+ t-BuOK (20 mol%)

EtOH, 70oC

NH

NHR3

R2

R1

O

NH

NHR3

R2

R1

S

via

via

R1HN

HN

O

NH2

O

NH2

O

R2R3

R1

Scheme 12

However, some of these catalyzed conditions still have certain drawbacks, including the

cost of the catalyst, harsh reaction conditions such as need of strong acidic conditions,

anhydrous conditions, requiring inert atmosphere, long reaction times, high temperatures,

incompatibility with other functional groups on the benzene ring and unsatisfactory yields.

Moreover, in Brønsted acid conditions, acid sensitive aldehydes provided low yields

[Ghassamipour and Sardarian (2010)]. Consequently, there is scope for further

improvement towards milder reaction conditions, variations of constituents in all three

components and better yields.

3.3.3.1 Green Chemistry context

For the increasing environmental and economical concerns, development of non-hazardous

synthetic methodologies for reactions is one of the latest challenges to the organic chemists.

The areas of opportunity being exploited to engage green chemistry are: (i) choice of

solvent, (ii) the catalytic agent employed, (iii) solvent free conditions, and (iv) energy

efficient techniques etc.

In one instance, 3,4-Dihydropyrimidin-2(1H)-ones were synthesized in high yields in the

presence of room temperature ionic liquids such as 1-butyl-3-methylimidazolium

tetrafluoroborate ([BMIm]BF4) or hexafluorophosphorate ([BMIm]PF6) as catalysts under

solvent-free and neutral conditions (Scheme 13) [Peng and Deng (2001)].

RCH O +O

H2N NH 2

O

H3C R1

O

NH

NHR1

O R

OH3C

+ Ionic Liquid100oC, 0.5 h

R = C6H5, 4-OCH3-C6H4,4-Cl-C6H4, 4-NO2-C6H4, C5H11R1= OEt, CH3

Scheme 13In another modification, synergic effect of ultrasound and ionic liquid 1-butylimidazolium

tetrafluoroborate ([Hbim]BF4) has been employed to synthesize DHPMs in excellent yields


195

within short reaction times and in the absence of any added catalyst (Scheme 14) [Gholap et

al. (2004)].

O

H3C OEt

O O

R H

Y

H2N NH2 NH

NHEtO

O R

H3C Y

+ + Ionic liquid,

30oC, 40-90minX = O, SR = alkyl, aryl

Scheme 14

A plausible mechanistic pathway was also postulated for illustrating the role of ionic liquid

in the above reaction (Scheme 15).

H

O H NN

BF4

Bu

O

O

O

H

H

H NN

Bu

BF4O

O

O

H NN

Bu

BF4

H

DHPM

d+

d +

Scheme 15

Furthermore, N-Bromosuccinimide (NBS) has also been reported as a neutral catalyst for

the synthesis of dihydropyrimidinones under microwave irradiation (Scheme 16)

[Hazarkhani and Karimi (2004)].

O

OEt

O O

R H

Y

H2N NH2 NH

NHEtO

O R

Y

+ + 0.2 eq. NBSEtOH, MW (600W)

3-6 minR = C6H5, 4-OCH3-C6H4,4-Cl-C6H4, 4-NO2-C6H4, C5H11; Y = O, S

Scheme 16

Similarly, benzyltriethylammonium chloride (TEBA) – a phase transfer catalyst has been

used as catalytic agent in Biginelli’s reaction under solvent-free conditions (Scheme 17).

The method presents an efficient route for the synthesis of important drug molecule

Monastrol [Bose et al. (2005)].


196

R2OOC

OR1

R

H O

NH2

H2N X

NH

NHR2OOC

R1

R

X

+

Benzyltriethylammoniumchloride (10 mol%)

100oC, 30-90 min

R= OCH3C6H4, N(CH3)2C6H4, NO2C6H4, OHC6H4 etc.; X = O, SR1= CH3, C2H5; R2= CH3, C2H5, C(CH3)3

Scheme 17

Yet another modification involving titanium dioxide (TiO2) nanopowder catalyzed and

microwave induced protocol was reported with an endeavor to develop a rapid and greener

preparation of dihydropyrimidinone fused benzoquinolines (Scheme 18) [Naik et al.

(2009)].

N

N

HN NH

XO

ZCOOR2

Z

R2OOCO

H2N

NH2

X

+

TiO2 Nanopowder

MW/ EtOH

Z =Cl/SH/SeH; X= O/S; R2= CH3/C2H5

Scheme 18

In 2010, a simple protocol for Biginelli like reaction was reported under solvent-free

grinding method using catalytic amount of hydrated ferric nitrate or clayfen (Scheme 19).

The advantage of this protocol lies in the avoidance of organic solvent, high yield, energy

efficiency, variation of substrates, and use of inexpensive catalyst along with the recycling

of catalyst for more than three times [Phukan et al. (2010)].

CHO

R

CH3

O

H2N NH2

O HN NH

O

R

++

Fe(NO3)3.9H2O

rt, grinding

R = OCH3, CH3, Br, Cl, OH etc.

Scheme 19

Similarly, a green and environmentally benign water assisted protocol has been reported for

the synthesis of 3,4 DHMPs in excellent yields without using additional solvent/acid

catalyst under conventional heating, microwave irradiation/ultrasound. The presence of

water was found to be vital and the reactions were found to be faster under microwave

irradiation/ultrasound in comparison to conventional heating and afforded products in high

yields [Singhal et al. (2010)].

Recently, lemon juice has been employed as natural catalyst as a suitable replacement to

conventional acids in Biginelli condensation reaction (Scheme 20) [Patil et al. (2011)].


197

RC 6H4CHO

H2N NH2

OR' NH

O R

ONH

+ + Lemon Juice

Stir, rt

R = H, Cl, NO2, OH etc; R' = OEt, Me

O

R'

O

Scheme 20

3.3.3.2. Organo- and biocatalytic protocols

In the past few years, several organocatalytic approaches have been developed for the

Biginelli reaction, mainly for the synthesis of asymmetric dihydropyrimidinones. The first

organocatalyst used in this multicomponent reaction was BINOL-derived phosphoric acid

developed by Gong and co-workers (Scheme 21) [Chen et al. (2006)].

CHO X

H2N NH2

O

R1O

O HN

HNX

COO R1

+ 10 mol% catalyst

CH2Cl2, 25oC,4 days

Catalyst =

+

R

R = H, Cl, NO2, CH3, OCH3, F, Br etc.; X = O, SR1 = Et, Me, i-Pr, t-Bu

R

OO

P OHO

Scheme 21

An enantioselective Biginelli reaction that proceeds by a dual-activation route has been

developed by using a combined catalyst of a readily available trans-4-hydroxyproline-

derived secondary amine and a Bronsted acid with an organic amino salt as additive

(Scheme 22). The corresponding dihydropyrimidinones were obtained in moderate-to-good

yields with up to 98% ee under mild conditions [Xin et al. (2008)]

CHO O

H2N NH2

O

EtO

OHN

HNO

COOEt

+5 mol% catalyst/5 mol%t-BuNH2.TFA5 mol% additive

1,4-dioxane/THF (2:8)rt, 36 h

HNCatalyst = Additive = t-BuNH2.HCl

+

R

R = H, Cl, NO2, CH3, OCH3 etc.

R

Scheme 22


198

Similarly, three chiral bicyclic diamines [(1S,4S)-2,5-diazadicyclo[2.2.1]heptane derivatives]

were utilized as organocatalysts in the enantioselective Biginelli reaction. It was found that

(1S,4S)-2,5-diazabicyclo[2.2.1]heptane·2HBr and its N-methylated derivative effectively

catalyze the reaction between ethyl acetoacetate, representative aromatic aldehydes, and

urea to afford the expected DHPMs in good yields and moderate enantioselectivities (18-

37% ee), favoring the (S) enantiomer [González-Olvera et al. (2008)].

Of late, several chiral primary amines, mainly those derived from the cinchona alkaloids,

were evaluated as the organocatalysts for the asymmetric Biginelli reaction. With the

quinine-derived amine catalyst, DHPMs were obtained in moderate to good yields and 51–

78% ee from a three-component reaction of aryl and aliphatic aldehydes, urea, and

acetoacetate [Ding and Zhao (2010)].

In addition, simple amino acids like L-proline (Scheme 23) and its derivatives (e.g. L-

Proline methyl ester hydrochloride) have been reported as effective catalysts for assembling

(±)-dihydropyrimidinones under mild conditions [Yadav et al. (2004); Mabry and Ganem

(2006); Sohn et al. (2009)].

O

H2N NH2

O

EtO

H3C O

+

rt, 18 h

+ NHHN

O

COO CH 3

PhH3C

OH3CPhCHO L-Proline

MeOH NHHN

O

COOCH 3

PhH3C

Scheme 23

In comparison to above, relatively little attention has been paid to the synthesis of

heterocyclic Biginelli compounds through biocatalysis. Till date, only one enzymatic

system involving Baker yeast as catalyst has been reported for the synthesis of DHPMs. It

was observed that Biginelli compounds could be synthesized in good yields under

fermenting yeast conditions (Scheme 24) [Kumar and Maurya (2007)].

OR1

O O

H2N NH2

XRCH O

NH

NHR1OOC

R

X

+

Baker's YeastD-glucose

Phosphate buffer (pH 7)rt, 24 h

Scheme 24

However, the attempts to synthesize DHPMs by organo- and biocatalytic reactions are met

with certain limitations such as prolonged reaction time, need of additives, complex

synthesis of organocatalyst etc. Consequently, from the green chemistry perspective, there

is scope for further renovation towards milder and practical routes towards the synthesis of


199

dihydropyrimidin-2(1H)-ones. Moreover, it would be doubly beneficial if such approaches

could be developed via utilization of abundantly available plant based feedstocks.

3.4. Results and discussion

In continuation of our recent forays into biocatalysis focusing on discovering new catalysts

for organic transformations [Kasana et al. (2007); Sharma et al. (2009); Sharma et al.

(2011a); (2011b)] and encouraged by the inspiring reports appearing on Brønsted base

[Shen et al. (2010)] and Baker’s yeast catalyzed Biginelli reaction [Kumar and Maurya

(2007)], we targeted the synthesis of chiral DHPMs using lipase as catalyst.

Initially, cyclocondensation of 0.25 mmol of benzaldehyde (1), ethyl acetoacetate (2) (1

equiv.) and urea (3) (3 equiv.) was attempted using various lipases in EtOH at 28oC for 6

days (Table 1; entries 1-6). Among all, Candida antarctica lipase-B (CAL-B) and porcine

pancreas lipase (PPL) provided better yields (28%; entries 1 and 3) with about 5%

enantioselectivity (% ee). In order to improve the yield and % ee some other solvents

reported for chiral DHPMs synthesis (Table 1; entries 7-13) were screened with CAL-B as

catalyst but without any success. Thereafter, the effect of temperature was probed to stir the

reaction in desired direction. It was observed that though increase in temperature from 28o

to 60oC brought about a linear change on the yield (from 28% to 62%), yet could not

exerted any positive effect on % ee (Table 1; entry 1 vs 14, 15). Moreover, significant yield

was observed in case of both denatured lipase (52%, Table 1; entry 16) and protein bovine

serum albumin (BSA) (80%, Table 1; entry 17). With these results in hand (lack of

enantioselectivity together with considerable yield observed in case of both denatured lipase

and BSA), we assumed that instead of involvement of any catalytic sites of lipase, it might

be the amino acid distribution on enzyme surface responsible for Biginelli reaction.

To confirm our hypothesis, catalytic influence of two neutral amino acids (glycine and L-

proline) was assessed for the cyclocondensation of 0.25 mmol of benzaldehyde (1) with 1

equiv. ethyl acetoacetate (2) and 3 equiv. urea (3) at 60oC (Table 2, entries 1-8) in terms of

reaction time. From the results, it was inferred that 48 h is the optimum time for formation

of 1b at 60oC. Moreover, it was established that there is not much difference in the yield of

the product obtained with both amino acids catalysts (Table 2, entries 1-8).


200

Table 1: Screening of different enzymes and solvents for Biginelli reaction

CHO

EtO CH 3

O O

H2N NH2

O

NH

NHEtO

O

O

EtOH

CH 2Cl2

C6H5CH3

EtOH

EtOH

EtOH

EtOH

EtOH

EtOH

EtOH

EtOHBS A

H2O

EtOH

ACN

THF

DMSO

MeOH

S. No. Enzyme TemperatureSolvent % Conversiona ee

1 CAL-B 28oC 28% 5%

7 CAL-B 28oC 24% 5%

8 CAL-B 28oC 19% 6%

14 CAL-B 40oC 44% 5%

2 CCL 28oC 24% <5%

3 PPL 28oC 28% <5%

4 MJL 28oC 12% 7%

5 TLL 28oC 15% <5%6 CRL 28oC 15% 6%

16 denatured CAL-Bb60oC 52% <5%

17 60oC 80% <5%

9 CAL-B 28oC 15% <5%

15 CAL-B 60oC 62% <5%

+ +

1a 2 3 4a6 days

10 CAL-B 28oC 18% 5%

11 CAL-B 28oC 10% 6%12 CAL-B 28oC 23% <5%

13 CAL-B 28oC 26% <5%

catalyst (50 mg)

Experimental conditions: 0.25 mmol 1a, 1 equiv. ethyl acetoacetate, 3 equiv. urea, 3 mL solvent;aon the basis of HPLC; CAL-B=Candida antarctica lipase B, CCL= C. cylindracea lipase, PPL=Porcine pancreas lipase, MJL= Mucor javanicus lipase; TLL= Thermomyces lanuginosus lipase,CRL= C. rugosa lipase; bPre-treated with urea and thiourea (7:1) at 100oC for 2 h.

In order to improve the efficiency of the condensation, thermal effects (reflux and

microwave (MW)) on the reaction were considered (Table 2, entries 9-12). It was found that

under reflux, optimum conversion was achieved in 8 h while the reaction occurred very fast

under microwave irradiation and was completed within 10 min (Table 2, entry 11).

However, reduced yield was noticed in both cases which were much prominent in case of L-

proline (Table 2, entries 10, 12). Out of above two catalyst, L-proline and its derivatives

have been well established for the synthesis of DHPMs [Yadav et al. (2004); Mabry and

Ganem (2006); Sohn et al. (2009)]. Recently, glycine was reported for the synthesis of

polyhydroquinolines in Hantzsch condensation under MW irradiation [Singh and Singh

(2010)]. However, there is no report on use of glycine as catalyst for Biginelli reaction thus;


201

it was contemplated to exploit the potential of this organocatalyst for the synthesis of

DHPMs.

Table 2: Optimization of organo-catalyzed (glycine and L-proline) Biginelli reaction

CHO

EtO CH3

O O

H2N NH 2

OHN

NH

EtOO

O

MW b

MW b

EtOH

S. No. Catalyst TemperatureTime % Yielda

1 144 h 60oC 81%2 144 h 60oC 82%

3 96 h 60oC 80%

4 96 h 60oC 82 %

5 48 h 60oC 80%6 48 h 60oC 81%

9 reflux 71%10 reflux 61%

11 72%12 53%

1a 2 3 1b

7 24 h 60oC 64%8 24 h 60oC 68%

+

Catalyst

Temperature

+

8 h8 h10 min10 min

Experimental conditions: 0.25 mmol of benzaladehyde 1a, 1 equiv. ethylacetoacetate, 3 equiv urea, 3 equiv catalyst in 3 mL of solvent; aisolated yield ;bMW at P=100 W using CEM monomode microwave.

GlycineL-prolineGlycine

L-Proline

GlycineL-proline

GlycineL-proline

GlycineL-proline

GlycineL-proline

As indicated in Table 3, the

efficiency of glycine was

investigated by studying the

Biginelli condensation

reaction of 0.25 mmol of

benzaldehyde with different

amount of catalyst, ethyl

acetoacetate and urea under

focused MW irradiation at P

= 100 W for varying reaction

time. After several

permutations and

combinations (Table 3,

entries 1-8), the optimum

conditions selected for

conversion of benzaldehyde

CHO EtO CH3

O O

H2N NH2

O

NH

NHEtO

O

O

3 equiv.

EtOH, MW

2 equiv.4 equiv.4 equiv.3 equiv.

3 equiv.

S. No. Amount ofcatalyst

Time % Yielda

1 72%2 35%3 69%

1a

2

3 1b

+Glycine

10 min5 min

15 min

Experimental conditions: 0.25 mmol of benzaladehyde 1a, 1 equiv.dicarbonyl compound, 3 equiv urea, glycine in 3 mL of solvent underMW irradiation at P=100 W; aisolated yield ; b2 equiv. urea; c2 equiv.urea and 1.5 equiv. dicarbonyl compound

3 equiv.3 equiv.

4 63%10 min5 73%10 min6 71%15 min

7b 62%10 min8c 64%10 min

Table 3: Optimization of glycine catalyzed Biginelli

reaction


202

(1a; 0.25 mmol) were: 1 equiv. of dicarbonyl compound (ethyl acetoacetate in this case), 3

equiv. of urea and 3 equiv. of glycine as catalyst under 10 min of microwave irradiation.

Products were easily isolated after pouring the reaction mixture in ice-cold water, filtration

and recrystallization from water-alcohol mixture.

In view of environmental friendly procedure, the reuse of a catalyst is quite preferable.

However, in our study recovery of amino acid (glycine) catalyst from water posed a

problem for its reusability. In the past few years, amino acids have emerged as a powerful

class of starting materials for the construction of ionic liquids (AAILs) [Bao et al. (2003);

Fukumoto et al. (2005); Tao et al. (2005); Branco et al. (2006); Fukumoto and Ohno

(2006); Guillen et al. (2006); Luo et al. (2006)]. AAILs are considered as “natural ILs” or

“bio-ILs” or ‘‘fully green ILs’’ due to their environment friendly nature [Tao et al. (2006)],

biodegradability [Gathergood et al. (2004); Garcia et al. (2005); Fukumoto and Ohno

(2006)], and lesser toxicity [Jastorff et al. (2003); Rosłonkiewicz et al. (2005); Pretti et al.

(2006)]. Moreover, low cost, easy preparation and property of amino acids to act as both

anions and cations are added advantage of these AAILs [Ohno and Fukumoto (2007)].

Accordingly, AAILs consisting of glycine as cation in combination with suitable inorganic

anions of the general formula

[AA]X (glycine nitrate;

GlyNO3, glycine sulphate;

GlySO4, and glycine chloride;

GlyCl) were synthesized as per

the previous reports [Tao et al.

(2005); (2006)]. Regarding the

anions, NO32-, SO4

2- and Cl- are

non-toxic, pharmaceutically

acceptable inorganic anions

[Swatloski et al. (2003)] and

the synthesis involves

acidification of glycine with

acid (HNO3, H2SO4, HCl),

which is an atom-economic

reaction where water is the reaction medium; thus making these ionic liquids ideal fully

green ones [Tao et al. (2005)]. To evaluate the ability of above AAILs as catalyst in

Biginelli reaction, the three component condensation reaction of benzaldehyde, ethyl

Table 4: Optimization of amino acid ionic liquid

(AAIL) catalyzed Biginelli reaction

CHOEtO CH3

O O

H2N NH2

O

NH

NHEtO

O

O

EtOH

EtOH

EtOHWater

MW,10m in

S. No. Catalyst Solvent % Conversiona

1a

2

3 1b

1 92% [90%]

+

Catalyst

Solvent

2 85% [70%]3 88% [80%]4 22%

Experimental conditions: 0.25 mmol of 1a, 1 equiv. ethyl acetoacetate, 3 equiv.urea, catalyst in 3 mL of solvent under MW at P=100 W; a% conversion on thebasis of HPLC, isolated yield in parenthesis

GlySO4

GlyNO3

GlyClGlyNO3

EtOH5 95%GlyNO3

EtOH6 98% [90%]GlyNO3

Catalystamount

1 equiv.

1 equiv.1 equiv.1 equiv.

0.5 equiv.0.4 equiv.

EtOH7 79%GlyNO3 0.3 equiv.


203

acetoacetate and urea was performed at 1 equiv. of catalyst amount in EtOH (Table 4;

entries 1-3). From the results, it was noticed that all the three ionic liquids could promote

the reaction, with GlyNO3 (Table 4, entry 1) providing superior results. As a clean and

inexpensive solvent, water was also employed as reaction medium; however it failed to

produce any significant yield (Table 4; entry 4). Interestingly, in comparison with glycine,

the use of only 0.4 equiv. of GlyNO3 could make the yield reach 98% under the microwave

power (P) of 100 W and the irradiation time of 10 min (Table 4; entries 5-7).

Moreover, GlyNO3 was easily separated from the reaction medium by cooling the mixture

at 0oC and filtering the contents. The catalyst was regenerated by washing with water and

ethanol, followed by drying at room temperature. No appreciable loss of catalytic activity

was noticed for preparation of 1b up to ten cycles.

We next examined a variety of aromatic aldehydes obtained from abundantly available

phenylpropenes (Scheme 25) as per our previous reports [Sinha et al. (2003); Kasana et al.

(2007)] under the optimized reaction conditions to establish the catalytic importance of

GlyNO3 for this reaction.

R R

CHO

R= 2,4,5-OCH3 (3)beta-Asaronetrans-Anethole R= 4-OCH3 (2)

R

CH O

IsoeugenolR= 4-OH, 3-OCH3 (5)

Pseudomonas chlororaphisCDAE5

Isosafrole R= 3,4-(OCH2O)- (4)

NaIO4/OsO4

THF/H2OPTC, MW

Scheme 25

To expand the practical scope of developed method, some commercial benzaldehydes were

also subjected to Biginelli condensation. As shown in Table 5 (entries 1-19), yields of this

one-pot protocol reactions following recrystallization from ethanol were of the order 62-

90%, which is quite favorable. All the obtained products were characterized by NMR and

HRMS data. Another important aspect of the established protocol is the survival of a variety

of functional groups such as NO2, Cl, OH and OCH3 under the reaction conditions.

Thiourea was also used with similar success to provide the corresponding

dihydropyrimidine-(2H)-thiones, which are also of much interest with regard to the

biological activity (eg. monastrol 18, Table 5).


204

Table 5: Substrate scope of GlyNO3 catalyzed Biginelli reaction

RCH O

R'O CH 3

O O

H2N NH2

X

R

NH

NHR'O

O

X

S. No. Time (min) Yield %a

10 98 [90]2 4-OMeC6H4 10 97 [72]3 2,4,5-(OMe)2C6H2 10 91 [64]4 10 90 [70]

6 4-OHC6H4

10 93 [83]

8 4-ClC6H4

910 96 [76]

103-BrC6H4 10 95 [78]

10 93 [85]

ab

7 3-OHC6H4

10 94 [65]10 91 [62]

GlyNO3 (0.4 equiv)

EtOH,

R

C6H5

3,4-(-OCH2O-)C6H3

R' X

4-NO2C6H4

13 4-MeC6H4

Et

EtEtEt

OOOO

O

O

O

OOO

Et

EtEt

EtEtEt

MW

16 20 96 [71]C6H5 Et S

1

Experimental conditions: 0.25 mmol of subsituted benzaladehyde a,1 equiv. dicarbonylcompound, 3 equiv. urea or thiourea, MW at P= 100 W in 5 mL of EtOH; a% Based onHPLC conversion, isolated yield (after recrystallization) in parenthesis

+ +X = O or S

11 10 97 [85]C10H7 OEt

17 20 91 [70]3-OMe, 4- OHC6H3 Et S

12 10 90 [74]4-N,N (CH3)2C6H4 OEt

15 10 93 [89]C6H5 t-Bu O

5 10 92 [70]3-OMe,4- OHC6H3 Et O

14 10 91 [84]C6H5 CH3 O

18 3-OHC6H4 20 85 [62]SEt19 4-ClC6H4 20 88 [73]SEt

Reaction of 2-hydroxy benzaldehyde, ethyl acetoacetate and urea provided a product (20c)

instead of the expected product (20b). The mass of both 20b and 20c was similar however;

the NMR spectral data was different from 20b (Scheme 26). Based on 1H NMR, 13C NMR

values and previous reports [Kumar and Maurya (2007); Abbas et al. (2008)], it was

confirmed that the structure of the compound 20c was oxygen-bridged instead of the

classical Biginelli structure (Scheme 26). The compound 20c was obtained in good yield

(75%) with high distereoselectivity as determined by 1H NMR.


205

CHO

OHOC2H5

OO

H2N NH 2

O+ +

NH

NH

OH3C

C2H5OOC

OH

NH

HN

OCH3C2H5OOC

O

H

Isolated in 75% yield

20b

20c

20a

Scheme 26

To increase the applicability of the developed method, the above conversion of 1a into 1b

with glycine nitrate as catalyst and the combination of benzaldehyde/ ethyl acetoacetate/

urea (1: 1: 3) was also performed under a multimode domestic microwave (due to its easy

access in almost every laboratory). The reaction was repeated thrice providing almost

similar yield each time (89%) which implied that our method worked efficiently in both

monomode and multimode microwave system.

Further, the applicability of the current method for the large scale synthesis was examined

by carrying out the reaction of 1 mol benzaldehyde with 1 mol ethyl acetoacetate, 3 mol

urea and 0.3 equiv GlyNO3. The product 1b was isolated in 85% yield after 10 minutes.

3.5. Conclusion

While exploring an enzymatic system for the synthesis of chiral DHPMs, it was found that

above reaction is protein catalyzed without any significant enantioselectivity. Further

exploration led to a novel amino acid ionic liquid (GlyNO3) based green approach for the

synthesis of bioactive 3,4-dihydropyrimidin-2(1H)-ones. The developed method not only

preserved the simplicity of Biginelli’s one-pot condensation but also provided good yields

of dihydropyrimidinones in shorter reaction times (10 min) besides good recyclability of the

catalyst.

3.6. Experimental

3.6.1. Materials and instrumentation

All reagents were obtained from commercial sources (Merck or Acros or HiMedia). The

phenylpropenes were purified from natural sources following the reported procedure [Sinha

et al. (2003)]. The solvents used for isolation/purification of compounds were obtained from

Merck and used without further purification. Melting points were obtained manually by


206

capillary methods and are uncorrected. 1H (300 MHz) and 13C (75.4 MHz) NMR spectra

were recorded on a Bruker Avance-300 spectrometer. TMS was used as internal reference

for NMR. HRMS-ESI spectra were determined using Micromass Q-TOF Ultima

spectrometer. Column chromatography was done on silica gel (60-100 mesh). Thin layer

chromatography (TLC) was performed on silica TLC plates and compounds visualized in

iodine or under UV lamp. CEM Discover© focused microwave (2450 MHz, 300W) was

used wherever mentioned. The temperature of reactions in microwave experiments was

measured by an inbuilt infrared temperature probe that determined the temperature on the

surface of reaction flask. The sensor is attached in a feedback loop with an on-board

microprocessor to control the temperature rise rate. In the case of conventional heating, the

temperature of reaction mixture was monitored by thermometer.

HPLC analysis was performed using a Shimadzu HPLC (Model LC-20AT pump, DGU-

20A5 degasser) equipped with auto sampler (SIL-20AC), photo diode array detector (CBM-

20A; Shimadzu, Kyoto, Japan) and interfaced with IBM Pentium 4 personal computer. The

separation was performed on a Purospher star RP-18e column (150 x 4.6 mm id, 5 µM;

Merck) at 30oC. The mobile phase consisted of (A) 0.05% TFA (Trifluoroacetic acid) in

H2O and (B) methanol/acetonitrile (in 70:30; v/v) with gradient elution (0-5 min, 40-70% B;

5-10 min, 70-100% B; 10-12 min, 100-40% B; 12-20 min, 40% B) with a flow rate of 1

mL/min. Analysis wavelength was set at 280 nm. The quantification was performed using

external standard method.

3.6.2. Optimization of reaction conditions

3.6.2.1. Condensation of benzaldehyde (1a) with ethyl acetoacetate and urea in ethanol

using various lipases [Candida antartica lipase (CAL-B), C. cylindracea lipase (CCL);

Porcine pancreas lipase (PPL), Mucor javanicus lipase (MJL), Thermomyces

lanuginosus lipase (TLL); C. rugosa lipase (CRL)] (Table 1, entries 1-6)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and lipase (50

mg) was taken in 3 mL ethanol in a round bottom flask and the reaction mixture was

incubated at 28oC for 6 days. Thereafter, ice cold water was added to the reaction mixture

resulting in formation of precipitates which were collected by filtration and air-drying. The

product was analyzed by HPLC (section 3.6.1) in comparison to a reference standard

showing a conversion yield of 12-28% (Table 1, entries 1-6).


207

3.6.2.2. Effect of various solvents on the condensation of benzaldehyde (1a) with ethyl

acetoacetate and urea using CAL-B (Table 1, entries 7-13)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and CAL-B

(50 mg) was taken in 3 mL dichloromethane or toluene or water or acetonitrile or

tetrahydrofuran or dimethyl sulfoxide or methanol in a round bottom flask and the reaction

mixture was incubated at 28oC for 6 days. After the completion of reaction, the reaction

mixture was worked up and analyzed with the HPLC as described above (section 3.6.1).

The conversion yield of 1b was in the range of 10-26% (Table 1, entries 7-13).

3.6.2.3. Effect of reaction temperature (40oC and 60oC) on the condensation of

benzaldehyde (1a) with ethyl acetoacetate and urea using CAL-B (Table 1, entries 14,

15)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and CAL-B

(50 mg) was taken in 3 mL ethanol in a round bottom flask and the reaction mixture was

incubated at 40oC or 60oC for 6 days. After the completion of reaction, the reaction mixture

was worked up and analyzed with the HPLC as described above (section 3.6.1). The

conversion yield of 1b was found to be 44% and 62%, respectively (Table 1, entries 14, 15).

3.6.2.4. Experiments with denatured CAL-B and bovine serum albumin at 60oC

(Table 1, entries 16, 17)

To study the exact role of enzyme in the above process, experiments with denatured lipase

(pretreated with urea and thiourea (7:1) at 100oC for 2 hours; Table 1, entry 16) or bovine

serum albumin (BSA) in place of lipase (Table 1, entry 17) were carried out. The

conversion yield of 1b was found to be 52% and 80%, respectively hinting at the role of

amino acid distribution on the enzyme surface for Biginelli condensation reaction.

3.6.2.5. Condensation of benzaldehyde (1a) with ethyl acetoacetate and urea in ethanol

using amino acid [glycine or L-proline] at different time intervals at 60oC (Table 2,

entries 1-8)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and amino acid

(glycine or L-proline; 3 equiv.) was taken in 3 mL ethanol in a round bottom flask and the

reaction mixture was incubated at 60oC for 24 h to 144 h. After the completion of reaction,

the reaction mixture was worked up and analyzed with the HPLC as described above

(section 3.6.1). From the results, 48 h of reaction time was found sufficient for conversion

of 1a to 1b with 81% yield in case of glycine and 82% yield in case of L-proline.


208

3.6.2.6. Effect of refluxing temperature on the condensation of benzaldehyde (1a)

with ethyl acetoacetate and urea in ethanol using amino acid [glycine or L-proline] as

catalyst (Table 2, entries 9, 10)



reaction mixture was refluxed for 8-10 h till completion of the reaction (indication by TLC).

Afterwards, the reaction mixture was worked up and analyzed with the HPLC as described

above (section 3.6.1). From the results, it was observed that 8 h of reaction time was

required for condensation reaction of 1a (Table 2, entries 9, 10).

3.6.2.7. Effect of microwave irradiation on the condensation of benzaldehyde (1a)

with ethyl acetoacetate and urea in ethanol using amino acid [glycine or L-proline] as

catalyst (Table 2, entries 11, 12)



reaction mixture was subjected to microwave irradiation using CEM monomode microwave

at Power = 100 W for 10 min. Afterwards, the reaction mixture was worked up and

analyzed with the HPLC as described above (section 3.6.1). From the results, it was

observed that, out of two catalyst, glycine provided better yield (72%; Table 2, entry 11) as

compared to L-Proline (53%; Table 2, entry 12).

3.6.2.8. Effect of microwave irradiation time on % yield of 1a in Biginelli condensation

with glycine as catalyst (Table 3, entries 1-3)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and glycine (3

equiv.) was taken in 3 mL ethanol in a round bottom flask and the reaction mixture was

subjected to microwave irradiation using CEM monomode microwave at Power = 100 W

for 5-15 min. Afterwards, the reaction mixture was worked up and analyzed with the HPLC

as described above (section 3.6.1). From the results, it was observed that 10 min of reaction

time was sufficient for condensation of 1a providing 72% yield (Table 3, entry 1).

3.6.2.9. Effect of increase or decrease in glycine amount on Biginelli condensation of 1a

(Table 3, entries 4-6)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and 2 equiv. or

4 equiv. glycine (instead of 3 equiv) was taken in 3 mL ethanol in a round bottom flask and

the reaction mixture was subjected to microwave irradiation using CEM monomode

microwave at Power = 100 W for 10-15 min. Afterwards, the reaction mixture was worked


209

up and analyzed with the HPLC as described above (section 3.6.1). The conversion yield of

1b was found to be 63% and 73%, respectively (Table 3, entries 4, 5).

3.6.2.10. Effect of decrease in urea amount on condensation of 1a (Table 3, entry 7)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), 2 equiv. urea (instead of 3

equiv.) and glycine (3 equiv.) was taken in 3 mL ethanol in a round bottom flask and the



analyzed with the HPLC as described above (section 3.6.1). Reduced yield of 1b (62%) was

observed (Table 3, entry 7).

3.6.2.11. Effect of change in ethyl acetoacetate and urea amount on condensation of 1a

(Table 3, entries 7, 8)

Benzaldehyde (1a, 0.25 mmol), 1.5 equiv. ethyl acetoacetate (instead of 1 equiv.), 2 equiv

urea (instead of 3 equiv.) and glycine (3 equiv.) was taken in 3 mL ethanol in a round

bottom flask and the reaction mixture was subjected to microwave irradiation using CEM

monomode microwave at Power = 100 W for 10 min. Afterwards, the reaction mixture was

worked up and analyzed with the HPLC as described above (section 3.6.1). Reduced yield

of 1b (64%) was observed (Table 3, entry 8).

3.6.3. Preparation of amino acid ionic liquids (glycine nitrate (GlyNO3), glycine

sulphate (GlySO4) and glycine chloride (GlyCl))

7.5 g (0.1 mol) of glycine was dissolved in 20 mL water. One mole equivalent of nitric acid

or hydrochloric acid or 0.5 mol equivalent of sulfuric acid was added drop wise. The

reaction mixture was then warmed to 60oC for 24 h. After evaporating in vacuo at 60oC and

lyophilization, the resulting white solid was collected and recrystallized from

methanol/ether. 1H and 13C NMR spectra were recorded and matched with reported values

[Tao et al. (2005)].COOH

H3N HH

X X = NO3-, Cl-, 1/2 SO4

2-

Glycine nitrate (GlyNO3)1H NMR (DMSO-d6, 300 MHz): δ 8.11 (3H, s), 3.68 (2H, s); 13C NMR (DMSO-d6, 75.4

MHz): δ 169.1, 39.7.


210

Glycine sulphate (GlySO4)1H NMR (DMSO-d6, 300 MHz): δ 8.08 (3H, s), 3.64 (2H, s); 13C NMR (DMSO-d6, 75.4

MHz): δ 168.7, 38.8.

Glycine chloride (GlyCl)1H NMR (DMSO-d6, 300 MHz): δ 8.12 (3H, s), 3.67 (2H, s); 13C NMR (DMSO-d6, 75.4

MHz): δ 169.0, 39.6.

3.6.3.1. Biginelli condensation of benzaldehyde (1a) using amino acid ionic liquid

[glycine nitrate or glycine sulphate or glycine chloride] as catalyst in ethanol (Table 4,

entries 1-3)


ionic liquid glycine nitrate or glycine sulphate or glycine chloride (1 equiv.) was taken in 3

mL ethanol in a round bottom flask and the reaction mixture was subjected to microwave

irradiation using CEM monomode microwave at Power = 100 W for 10 min. Afterwards,

the reaction mixture was worked up and analyzed with the HPLC (section 3.6.1) showing a

conversion yield 85-92% Further, the crude product was purified by recrystallization from

water-ethanol mixture giving an isolated yield of 1b in the range of 70-90%. 1H and 13C

NMR spectra were recorded and matched with reported values and further confirmed by

HRMS/MS.

Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

(compound 1b, Table 4)

NHHN

O

CH3

COOC2H5 White solid (Yield 90%) m.p. 206-207°C, 1H NMR (DMSO-d6, 300

MHz): 9.21 (1H, s), 7.75 (1H, s), 7.35-7.23 (5H, m), 5.16 (1H, d, J = 3.08 Hz ), 4.02 (2H,

q, J = 7.07 Hz), 2.25 (3H, s), 1.12 (3H, t, J = 7.06 Hz ); 13C NMR (DMSO-d6, 75.4 MHz):

166.2, 153.0, 149.2, 145.7, 129.2, 128.1, 127.1, 100.1, 60.0, 54.8, 18.6 and 14.9. HRMS-

ESI: m/z [M+H]+ for C14H16N2O3, calculated 261.1370; observed 261.1374. The spectral

data matched well with the reported values [Karade et al. (2007)].

3.6.3.2. Biginelli condensation of benzaldehyde (1a) using glycine nitrate as catalyst in

water under microwave irradiation (Table 4, entry 4)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and glycine

nitrate (1 equiv.) was taken in 3 mL water (instead of ethanol) in a round bottom flask and


211

the reaction mixture was subjected to microwave irradiation using CEM monomode

microwave at Power = 100 W for 10 min. Afterwards, the reaction mixture was worked up

and analyzed with the HPLC (section 3.6.1) showing a conversion yield of 22%.

3.6.3.3. Effect of glycine nitrate amount on the Biginelli condensation of 1a (Table 4,

entries 5-7)

Benzaldehyde (1a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and glycine

nitrate (0.3 equiv. or 0.4 equiv. or 0.5 equiv.) was taken in 3 mL ethanol in a round bottom

flask and the reaction mixture was subjected to microwave irradiation using CEM

monomode microwave at Power = 100 W for 10 min. Afterwards, the reaction mixture was

worked up and analyzed with the HPLC as described above (section 3.6.1.). The conversion

yield of 1b was from 79-98% (Table 4, entries 5-7) with 0.4 equiv. glycine nitrate providing

better results (98%; Table 4, entry 6).

3.6.4. Synthesis of methoxylated benzaldehydes (2a-4a) from abundantly available

natural phenylpropenes (trans-anethole, β-asarone and isosafrole) (Table 5)

A mixture of phenylpropene derivative (1.5 mmol), OsO4 (1.5 mmol), NaIO4 (1.5 mmol)

and benzyltriethylammonium chloride (0.01 g) were dissolved in H2O-THF (3 mL, 4:1 v/v)

and irradiated under microwave. After completion of reaction, the mixture was filtered and

washed with dichloromethane. Evaporation of the solvent under reduced pressure gave a

crude product, which was purified on silica gel column with hexane: ethyl acetate to obtain

the corresponding benzaldehyde [Sinha et al. (2003)].

4-methoxybenzaldehyde (Compound 2a, Table 5) (obtained from trans-anethole)CHO

H3CO Colorless liquid (Yield 86%), 1H NMR (CDCl3, 300 MHz): 9.84 (1H,

s), 7.68 (2H, m), 6.94 (2H, m), 3.70 (3H, s); 13C-NMR (CDCl3, 75.4 MHz): 190.3, 164.4,

131.3, 129.2, 113.8 and 55.2. The spectral data matched well with the reported values

[Sinha et al. (2003)].

2,4,5-trimethoxybenzaldehyde (Compound 3a, Table 5) (obtained from β-asarone)OC H3

OC H3

H3CO

CHO

White needles (Yield 83%), 1H NMR (CDCl3, 300 MHz): δ 10.31 (1H,

s), 7.36 (1H, s), 6.52 (1H, s), 3.98 (3H, s), 3.92 (3H, s), 3.86 (3H, s); 13C NMR (CDCl3, 75.4


212

MHz): δ 187.7, 158.4, 155.8, 143.4, 117.1, 109.0, 98.3 and 56.2. The spectral data matched

well with the reported values [Sinha et al. (2003)].

3,4,-dioxymethylenebenzaldehyde (Compound 4a, Table 5) (obtained from isosafrole)CHOO

O Yellow oil (Yield 76%), 1H NMR (CDCl3, 300 MHz): δ 9.85 (1H, s),

7.25 (1H, d), 7.18 (1H, s), 6.84 (1H, d), 5.87 (2H, s); 13C NMR (CDCl3, 75.4 MHz): δ 190.2,

153.4, 147.9, 130.1, 123.4, 116.2, 115.5 and 91.2. The spectral data matched well with the

reported values [Sinha et al. (2003)].

3.6.4.1. Synthesis of vanillin (5a) from isoeugenol (Table 5)

To 2 g of isoeugenol taken in a round bottom flask, 100 mL of whole cell culture of

Pseudomonas chlororaphis CDAE5 was added and the reaction mixture incubated at 25oC

and 180 rpm for 24 h [Kasana et al. (2007)]. Thereafter, the mixture was extracted three

times with dichloromethane. Evaporation of the solvent under reduced pressure after drying

over anhydrous sodium sulphate gave a crude product, which was purified on silica gel

column with hexane: ethyl acetate to obtain the corresponding benzaldehyde 5a.

4-Hydroxy-3-methoxybenzaldehyde (Compound 5a, Table 5)CH O

OH

OC H3

Creamish white crystals. m.p. 81-83°C, 1H NMR (CDCl3, 300 MHz): 9.87

(1H, s), 7.41-7.43 (2H, m), 6.98 (1H, d, J = 8.15 Hz), 6.46 (1H, s), 3.94 (3H, s); 13C NMR

(CDCl3, 75.4 MHz): 190.5, 151.3, 147.2, 129.2, 127.1, 114.4, 108.3 and 56.1. HRMS-ESI:

m/z [M+H]+ for C8H8O3, calculated 153.0684; observed 153.0678.

3.6.4.2. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones (1b-13b) from substituted

benzaldehydes (Table 5, entries 1-13)

Substituted benzaldehyde (1a-13a, 0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.)

and glycine nitrate (0.4 equiv.) was taken in 3 mL ethanol in a round bottom flask and the



analyzed with the HPLC (see section 3.6.1.) with a conversion yield of 90-98%. Further, the

crude product was purified by recrystallization from water-ethanol mixture and subjected

for spectral analysis (NMR and mass spectrometry).


213

Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

(compound 1b, Table 5)

NHHN

O

CH3

COO C2H5 White solid (Yield 90%), The NMR spectra matched well with that

obtained in section 3.6.3.1.

Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-

carboxylate (Compound 2b Table 5)

NHHN

O

CH3

COOC2H5H3CO White solid (Yield 72%) m.p. 201-202oC, 1H NMR (DMSO-d6,

300 MHz): 9.17 (1H, s), 7.68 (1H, s), 7.17 (2H, d, J = 8.66 Hz), 6.89 (2H, d, J = 8.69 Hz),

5.10 (1H, d, J = 3.17 Hz), 4.01 (2H, q, J = 7.07 Hz), 3.72 (3H, s), 2.24 (3H, s), 1.13 (3H, t, J

= 7.07 Hz); 13C NMR (DMSO-d6, 75.4 MHz): 166.2, 159.3, 153.0, 148.9, 137.9, 128.3,

114.6, 100.4, 60.0, 55.9, 54.2, 18.6 and 14.9. HRMS-ESI: m/z [M+H]+ for C15H18N2O4,

calculated 291.1520; observed 291.1528. The spectral data matched well with the reported

values [Karade et al. (2007)].

Ethyl 6-methyl-2-oxo-4-(2,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-

carboxylate (Compound 3b, Table 5)

NHHN

O

CH3

COO C2H5

OCH 3

H3CO

OC H3

White solid (Yield 64%) m.p. 207-209°C, 1H NMR (DMSO-d6,

300 MHz): 8.66 (1H, s), 6.64 (1H, s), 6.52 (1H, s), 5.78 (1H, s), 5.68 (1H, s), 4.10 (2H, q,

J = 7.05 Hz), 3.88 (3H, s), 3.85 (3H, s), 3.76 (3H, s), 2.42 (3H, s), 1.14 (3H, t, J = 7.09 Hz);13C NMR (DMSO-d6, 75.4 MHz); 166.3, 154.2, 151.7, 149.9, 148.4, 143.2, 122.3, 112.1,

98.9, 97.8, 60.2, 57.3, 56.6, 50.3, 18.8 and 14.6. HRMS-ESI: m/z [M+H]+ for C17H22N2O6,


values [Beşoluk et al. (2010)].


214

Ethyl 4-(1,3-benzodioxol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

O

CH3

COOC2H5

O

O White solid (Yield 70%) m.p. 180-181°C, 1H NMR (DMSO-d6, 300

MHz): 9.18 (1H, s), 7.69 (1H, s), 6.86-6.69 (3H, m), 5.98 (2H, s), 5.08 (1H d, J = 2.85

Hz), 4.03 (2H, q, J = 7.01 Hz), 2.25 (3H, s), 1.13 (3H, t, J = 7.05 Hz); 13C NMR (DMSO-d6,

75.4 MHz): 166.2, 152.9, 149.1, 148.1, 147.2, 139.7, 120.2, 108.9, 107.5, 101.8, 100.2,

60.1, 54.5, 18.6 and 14.9. HRMS-ESI: m/z [M+H]+ for C15H16N2O5, calculated 305.1358;

observed 305.1361.

Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

O

CH3

COOC2H5

OCH3

HO

White solid (Yield 70%) m.p. 146-148°C, 1H NMR (DMSO-d6, 300

MHz): 9.11 (1H, s), 8.91 (1H, s), 7.64 (1H, d, J = 2.66 Hz), 6.80 (1H, d, J = 8.09 Hz ),

6.63-6.60 (2H, m), 5.07 (1H, d, J = 3.19 Hz), 4.03 (2H, q, J = 7.07 Hz ), 3.72 (3H, s), 2.23

(3H, s), 1.14 (3H, t, J = 7.21 Hz); 13C NMR (DMSO-d6, 75.4 MHz): 166.3, 153.1, 148.7,

148.1, 146.7, 136.8, 119.2, 116.1, 11.8, 100.4, 59.9, 56.9, 54.4, 18.6 and 15.0. HRMS-ESI:

m/z [M+H]+ for C15H18N2O5, calculated 307.1514; observed 307.1521.

Ethyl 4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

O

CH3

COOC2H5HO White solid (Yield 65%) m.p. 232-234°C, 1H NMR (DMSO-d6,

300 MHz): 9.34 (1H, s), 9.12 (1H, s), 7.63 (1H, s), 7.04 (2H, d, J = 7.99 Hz), 6.70 (2H, d,

J = 7.97 Hz), 5.05 (1H, s), 4.01 (2H, q, J = 6.71 Hz), 2.23 (3H, s), 1.12 (3H, t, J = 6.92 Hz );13C NMR (DMSO-d6, 75.4 MHz): 165.4, 156.5, 152.2, 147.7, 135.4, 127.4, 114.9, 99.8,


215

59.1, 53.4, 17.7 and 14.1. HRMS-ESI: m/z [M+H]+ for C14H16N2O4, calculated 277.1364;

observed 277.1374.

Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

O

CH3

COO C2H5

OH White solid (Yield 62%) m.p. 179-182°C, 1H NMR (DMSO-d6, 300

MHz): 8.46 (1H, s), 8.23 (1H, s), 6.76 (1H, s), 6.18 (1H, t, J = 8.12 Hz), 5.77-5.72 (3H,

m), 4.15 (1H, d, J = 3.17 Hz), 3.09 (2H, q, J = 7.10 Hz), 1.32 (3H, s), 0.22 (3H, t, J = 7.12

Hz); 13C NMR (DMSO-d6, 75.4 MHz): 166.3, 158.2, 153.1, 148.9, 147.1, 130.1, 117.8,



values [Xin et al. (2008)].

Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

(Compound 8b, Table 5)

NHHN

O

CH3

COOC2H5Cl White solid (Yield 76%) m.p. 213-214°C, 1H NMR (DMSO-d6,


5.15 (1H, s), 4.01 (2H, q, J = 7.05 Hz), 2.25 (3H, s), 1.12 (3H, t, J = 7.09 Hz); 13C NMR

(DMSO-d6, 75.4 MHz): 165.2, 151.9, 148.7, 143.8, 131.8, 128.4, 128.2, 98.8, 59.2, 53.4,

17.8 and 14.0. HRMS-ESI: m/z [M+H]+ for C14H15ClN2O3, calculated 295.5819; observed

295.58.23. The spectral data matched well with the reported values [Karade et al. (2007)].


216

Ethyl 4-(3-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOC2H5

Br White solid (Yield 78%) m.p. 187-189°C, 1H NMR (DMSO-d6, 300

MHz): 9.27 (1H, s), 7.80 (1H, s), 7.47-7.23 (4H, m), 5.15 (1H, d, J = 2.85 Hz), 4.02 (2H,

q, J = 7.07 Hz), 2.26 (3H, s), 1.13 (3H, t, J = 7.01 Hz); 13C NMR (DMSO-d6, 75.4 MHz):

166.0, 152.8, 149.8, 148.3, 131.7, 130.9, 130.0, 126.1, 122.4, 99.5, 60.2, 54.5, 18.7 and

14.9. HRMS-ESI: m/z [M+H]+ for C14H15N2O3Br, calculated 340.0332; observed 340.0338.

The spectral data matched well with the reported values [Karade et al. (2007)].

Ethyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOC2H5O2N Creamish solid (Yield 85%) m.p. 220-225°C, 1H NMR (DMSO-d6,

300 MHz): 9.38 (1H, s), 8.15 (2H, d, J = 8.31 Hz), 7.91 (1H, s), 7.72 (2H, d, J = 8.38 Hz),

5.31 (1H, d, J = 2.89 Hz), 4.05 (2H, q, J = 7.18 Hz), 2.28 (3H, s), 1.13 (3H, t, J = 7.13 Hz);13C NMR (DMSO-d6, 75.4 MHz): 165.9, 152.6, 150.3, 148.6, 147.9, 133.8, 131.1, 123.2,

121.9, 99.2, 60.2, 54.4, 18.7 and 14.9. HRMS-ESI: m/z [M+H]+ for C14H15N3O5, calculated

306.1411; observed 306.1417. The spectral data matched well with the reported values

[Karade et al. (2007)].

Ethyl 6-methyl-4-(naphthalen-2-yl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOC2H5 White solid (Yield 85%) m.p. 257-258°C, 1H NMR (DMSO-d6,

300 MHz): 9.24 (1H, s), 7.93 (1H, s), 7.86 (1H, d, J = 7.88 Hz), 7.79 (1H, s), 7.56-7.43

(5H, m), 6.07 (1H, d, J = 3.01 Hz), 3.83 (2H, q, J = 7.59 Hz), 2.37 (3H, s), 0.84 (3H, t, J =


217

7.07 Hz); 13C NMR (DMSO-d6, 75.4 MHz): 165.6, 151.9, 148.9, 140.7, 133.7, 130.3,

128.7, 126.3, 126.0., 125.9, 124.5, 123.9, 99.4, 59.3, 50.1, 18.0 and 14.1. HRMS-ESI: m/z

[M+H]+ for C18H18N2O3, calculated 311.1526; observed 311.1534. The spectral data

matched well with the reported values [Xin et al. (2008)].

Ethyl 4-[4-(dimethylamino)phenyl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

O

CH3

COOC2H5N

Creamish solid (Yield 74%) m.p. 252-255°C, 1H NMR (DMSO-d6,


5.04 (1H, d, J = 2.18 Hz), 4.01 (2H, q, J = 6.86 Hz), 2.85 (6H, s), 2.23 (3H, s), 1.14 (3H, t, J

= 7.02 Hz); 13C NMR (DMSO-d6, 75.4 MHz): 165.2, 151.9, 149.4, 147.2, 132.3, 126.6,

111.9, 99.6, 58.8, 53.0, 17.39 and 13.8. HRMS-ESI: m/z [M+H]+ for C16H21N3O3,


values [Yadav et al. (2001)].

Ethyl 6-methyl-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOC2H5H3C White solid (Yield 83%) m.p. 206-208oC, 1H NMR (DMSO-d6,

300 MHz): 9.12 (1H, s), 7.67 (1H, s), 7.11 (3H, s), 5.12 (1H, d, J = 2.67 Hz), 3.98 (2H, d,

J = 7.07 Hz), 2.25 (6H, s), 1.11 (3H, t, J = 7.07 Hz); 13C NMR (DMSO-d6, 75.4 MHz):

166.3, 153.2, 148.9, 142.7, 137.3, 129.8, 126.9, 100.4, 60.0, 54.5, 21.4, 18.6 and 14.9.

HRMS-ESI: m/z [M+H]+ for C15H18N2O3, calculated 275.1526; observed 275.1533. The

spectral data matched well with the reported values [Xin et al. (2008)].

3.6.4.3. Synthesis of 3,4-dihydropyrimidin-2(1H)-one (14b) from benzaldehyde with

methyl acetoacetate and urea (Table 5, entry 14)

Benzaldehyde (0.25 mmol), methyl acetoacetate (1 equiv.), urea (3 equiv.) and glycine

nitrate (0.4 equiv.) was taken in 3 mL ethanol in a round bottom flask and the reaction

mixture was subjected to microwave irradiation using CEM monomode microwave at

Power = 100 W for 10 min. Afterwards, the reaction mixture was worked up and analyzed


218

with the HPLC (see section 3.6.1.) with a conversion yield of 91%. Further, the crude

product was purified by recrystallization from water-ethanol mixture and isolated yield

calculated. Structure of the compound was confirmed through NMR and mass spectrometry.

Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOCH3 White solid (Yield 84%) m.p. 205-210°C, 1H NMR (DMSO-d6, 300

MHz): 9.22 (1H, s), 7.76 (1H, s), 7.35-7.30 (2H, m), 7.26-7.23 (3H, m), 5.16 (1H, d, J =

3.28 Hz), 3.53 (3H, s), 2.26 (3H, s); 13C NMR (DMSO-d6, 75.4 MHz): 166.7, 153.0,

149.5, 145.5, 129.3, 128.1, 127.0, 99.9, 54.7, 51.6 and 18.7. HRMS-ESI: m/z [M+H]+ for

C13H14N2O3, calculated 247.0714; observed 247.0725. The spectral data matched well with

the reported values [Karade et al. (2007)].

3.6.4.4. Synthesis of 3,4-dihydropyrimidin-2(1H)-one (15b) from benzaldehyde with

tert-butyl acetoacetate and urea (Table 5, entry 15)

Benzaldehyde (0.25 mmol), tert-butyl acetoacetate (1 equiv.), urea (3 equiv.) and glycine

nitrate (0.4 equiv.) was taken in 3 mL ethanol in a round bottom flask and the reaction






tert-Butyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

O

CH3

COOC(CH3)3 White solid (Yield 89%) m.p. 220-222°C, 1H NMR (DMSO-d6, 300


d, J = 2.67 Hz), 2.22 (3H, s), 1.28 (9H, s); 13C NMR (DMSO-d6, 75.4 MHz): 165.7, 153.0,

148.1, 145.8, 129.1, 128.1, 127.1, 101.5, 55.2, 49.4, 28.6 and 18.5. HRMS-ESI: m/z


219

[M+H]+ for C16H20N2O3, calculated 289.1682; observed 289.1694. The spectral data

matched well with the reported values [Falsone and Kappe (2001)].

3.6.4.5. Synthesis of 3,4-dihydropyrimidin-2(1H)-thiones (16b-19b) from substituted

benzaldehydes (Table 5, entries 16-19)

Substituted benzaldehyde (0.25 mmol), ethyl acetoacetate (1 equiv.), thiourea (3 equiv.) and

glycine nitrate (0.4 equiv.) was taken in 3 mL ethanol in a round bottom flask and the



analyzed with the HPLC (see section 3.6.1.) with a conversion yield of 85-96%. Further, the

crude product was purified by recrystallization from water-ethanol mixture and isolated

yield calculated. Structure of the compounds was confirmed through NMR and mass

spectrometry.

Ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate


NHHN

S

CH3

COOC2H5 White solid (Yield 71%) m.p. 202-206°C, 1H NMR (DMSO-d6, 300


q, J = 7.10 Hz), 1.60 (3H, s), 0.43 (3H, t, J = 7.03 Hz); 13C NMR (DMSO-d6, 75.4 MHz):

175.2, 165.9, 145.8, 144.3, 129.3, 128.5, 127.2, 101.6, 60.4, 54.9, 17.9 and 14.7. HRMS-

ESI: m/z [M+H]+ for C14H16N2O2S, calculated 277.2036; observed 277.2047. The spectral

data matched well with the reported values [Karade et al. (2007)].

Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4

tetrahydropyrimidine-5-carboxylate (Compound 17b, Table 5)

NHHN

S

CH3

COOC2H5

OC H3

HO

White solid (Yield 70%) m.p. 203°C, 1H NMR (DMSO-d6, 300

MHz): 10.25 (1H, s), 9.56 (1H, d, J = 1.74 Hz), 9.01 (1H, s), 6.63-6.60 (3H, m), 5.09 (1H,

d, J = 3.57 Hz), 4.04 (2H, q, J = 7.03 Hz ), 3.73 (3H, s), 2.28 (3H, s), 1.15 (3H, t, J = 7.08

Hz); 13C NMR (DMSO-d6, 75.4 MHz): 174.9, 166.1, 148.2, 147.8, 145.4, 153.4, 119.4,


220

116.3, 111.8, 101.9, 60.4, 56.4, 54.5, 17.9 and 14.9. HRMS-ESI: m/z [M+H]+ for

C15H18N2O4S, calculated 323.2180; observed 323.2194.

Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

S

C H 3

C OO C 2H 5

OH White solid (Yield 62%) m.p. 179-182°C, 1H NMR (DMSO-d6,

300 MHz): 9.37 (1H, s), 9.17 (1H, s), 7.70 (1H, s), 7.12 (1H, t, J = 7.92 Hz), 6.68-6.61

(3H, m), 5.06 (1H, s), 4.03 (2H, q, J = 6.97 Hz), 2.24 (3H, s), 1.19 (3H, t, J = 7.09 Hz ); 13C

NMR (DMSO-d6, 75.4 MHz): 165.4, 157.3, 152.2, 148.1, 146.3, 129.3, 116.9, 114.2,

113.1, 99.4, 59.2, 53.8, 17.8 and 14.1. HRMS-ESI: m/z [M+H]+ for C14H16N2O3S,


values [Dallinger and Kappe (2007)].

Ethyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-


NHHN

S

CH3

COOC2H5Cl White solid (Yield 71%) m.p. 172-178°C, 1H NMR (DMSO-d6,

300 MHz): 10.38 (1H, s), 9.66 (1H, s), 7.44 (2H, d, J = 8.43 Hz), 7.24 (2H, d, J = 8.43

Hz), 5.18 (1H, d, J = 3.60 Hz), 4.04 (2H, q, J = 7.02 Hz), 2.29 (3H, s), 1.12 (3H, t, J = 7.08

Hz); 13C NMR (DMSO-d6, 75.4 MHz); 175.1, 165.9, 146.2, 143.2, 133.1, 129.4, 129.2,

101.2, 60.5, 54.3, 18.0 and 14.9. HRMS-ESI: m/z [M+H]+ for C14H15N2O2SCl, calculated

311.6485; observed 311.6491. The spectral data matched well with the reported values

[Dallinger and Kappe (2007)].

3.6.4.5. Synthesis of 3,4-dihydropyrimidin-2(1H)-thiones (20c) from 2-hydroxy

benzaldehyde (Scheme 26)

2-hydroxy benzaldehyde (0.25 mmol), ethyl acetoacetate (1 equiv.), urea (3 equiv.) and

glycine nitrate (1 equiv.) was taken in 3 mL ethanol in a round bottom flask and the reaction



221





Ethyl 9-methyl-11-oxo-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-

carboxylate (Compound 20c, Scheme 26)

NH

HN

OCH3C2H5OOC

O

H

White solid (Yield 75%) m.p. 202-205°C, 1H NMR (DMSO-d6,

300 MHz): 7.60 (1H, s), 7.24-7.17 (3H, m), 6.96-6.88 (1H, m), 6.80 (1H, d, J = 8.35 Hz),

4.49 (1H, m), 4.19 (2H, q, J = 7.31 Hz ), 3.26 (1H, s), 1.74 (3H, s), 1.26 (3H, t, J = 7.11 Hz

); 13C NMR (DMSO-d6, 75.4 MHz): 168.7, 154.8, 150.9, 129.6, 128.9, 125.7, 120.7,



values [Kumar and Maurya (2007)].

3.7. References

Abbas, E.M.H, Abdallah, S.M., Abdoh, M.H., Tawfik, H.A. and El-Hamouly, W.S. (2008).

Behaviour of salicylaldehyde and some of its derivatives in the Biginelli reaction for the

preparation of aryl tetrahydropyrimidines. Turkish Journal of Chemistry 32: 297-304.

Atwal, K.S., O'Reilly, B.C., Gougoutas, J.Z. and Malley, M.F. (1987). Synthesis of

substituted 1,2,3,4-tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic acid esters.

Heterocycles 26: 1189-92.

Atwal, K.S., Rovnyak, G.C., O’Reilly, B.C. and Schwartz, J. (1989). Synthesis of

selectivity functionalized 2-hetero-1,4-dihydropyrimidines. The Journal of Organic

Chemistry 54: 5898-907.

Atwal, K.S., Swanson, B.N., Unger, S.E., Floyd, D.M., Moreland, S., Hedberg, A. and

O’Reilly, B.C. (1991). 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-

pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. Journal of

Medicinal Chemistry 34: 806-11.


222

Bao, W., Wang, Z. and Li, Y. (2003). Synthesis of chiral ionic liquids from natural amino

acids. The Journal of Organic Chemistry 68: 591-93.

Barluenga, J., Tomas, M., Ballesteros, A. and Lopez, L.A. (1989). 1,4-Cycloaddition of 1,3-

diazabutadienes with enamines: An efficient route to the pyrimidine ring. Tetrahedron

Letters 30: 4573-76.

Beşoluk, Ş., Küçükislamoğlu, M., Zengin M., Arslan, M. and Nebioğlu, M. (2010). An

efficient one-pot synthesis of dihydropyrimidinones catalyzed by zirconium hydrogen

phosphate under solvent-free conditions. Turkish Journal of Chemistry 34: 411-16.

Biginelli, P. (1893). Aldehyde-urea derivatives of aceto- and oxaloacetic acids. Gazzetta

Chimica Italiana 23: 360-413.

Bose, D.S., Sudharshan, M. and Chavhan, S.W. (2005). New protocol for Biginelli reaction-

a practical synthesis of Monastrol. Arkivoc (iii): 228-36.

Branco, L.C., Gois, P.M.P., Lourenço, N.M.T., Kurteva, V.B. and Afonso, C.A.M. (2006).

Simple transformation of crystalline chiral natural anions to liquid medium and their use

to induce chirality. Chemical Communications 2006: 2371-72.

Chen, X.H., Xu, X.Y., Liu, H., Cun, L.F. and Gong, L.Z. (2006). Highly enantioselective

organocatalytic Biginelli reaction. Journal of the American Chemical Society 128:

14802-03.

Chiang, A.N., Valderramos, J.C., Balachandran, R., Chovatiya, R.J., Mead, B.P., Schneider,

C., Bell, S.L., Klein, M.G., Huryn, D.M., Chen, X.S., Day, B.W., Fidock, D.A., Wipf, P.

and Brodsky, J.L. (2009). Select pyrimidinones inhibit the propagation of the malarial

parasite, Plasmodium falciparum. Bioorganic and Medicinal Chemistry 17: 1527-33.

Dallinger, D. and Kappe, C.O. (2007). Rapid preparation of the mitotic kinesin Eg5

inhibitor Monastrol using controlled microwave-assisted synthesis. Nature Protocols 2:

317-21.

Dandia, A., Saha, M. and Taneja, H. (1998). Synthesis of fluorinated ethyl 4-aryl-6-methyl-

1,2,3,4-tetrahydropyrimidin-2-one/thione-5-carboxylates under microwave irradiation.

Journal of Fluorine Chemistry 90: 17-21.

Ding, D. and Zhao, C.G. (2010). Primary amine-catalyzed Biginelli reaction for the

enantioselective synthesis of 3,4-dihydropyrimidin-2(1H)-ones. European Journal of

Organic Chemistry 20: 3802-05.

Falsone, S.F. and Kappe, C.O. (2001). The Biginelli dihydropyrimidone synthesis using

polyphosphate ester as a mild and efficient cyclocondensation/dehydration reagent.

Arkivoc (ii): 122-34.


223

Folkers, K. and Johnson, T.B. (1933). Researches on pyrimidines. CXXXVI. The

mechanism of formation of tetrahydropyrimidines by the Biginelli reaction. Journal of

the American Chemical Society 55: 3784-91.

Fukumoto, K. and Ohno, H. (2006). Design and synthesis of hydrophobic and chiral anions

from amino acids as precursor for functional ionic liquids. Chemical Communications

2006: 3081-83.

Fukumoto, K., Yoshizawa, M. and Ohno, H. (2005). Room temperature ionic liquids from

20 natural amino acids. Journal of the American Chemical Society 127: 2398-99.

Garcia, M.T., Gathergood, N. and Scammells, P.J. (2005). Biodegradable ionic liquids Part

II. Effect of the anion and toxicology. Green Chemistry 7: 9-14.

Gathergood, N., Garcia, M.T. and Scammells, P.J. (2004). Biodegradable ionic liquids: Part

I. Concept, preliminary targets and evaluation. Green Chemistry 6: 166-75.

Ghassamipour, S. and Sardarian, A.R. (2010). One-pot synthesis of dihydropyrimidinones

by dodecylphosphonic acid as solid Brønsted acid catalyst under solvent-free conditions

via Biginelli condensation. Journal of Iranian Chemical Society 7: 237-42.

Gholap, A.R., Venkatesan, K., Daniel, T., Lahoti, R.J. and Srinivasan, K.V. (2004). Ionic

liquid promoted novel and efficient one pot synthesis of 3,4-dihydropyrimidin-2(1H)-

ones at ambient temperature under ultrasound irradiation. Green Chemistry 6: 147-50.

González-Olvera, R., Demare, P., Regla, I. and Juaristi, E. (2008). Application of (1S,4S)-

2,5-diazabicyclo[2.2.1]heptane derivatives in asymmetric organocatalysis: the Biginelli

reaction. Arkivoc (vi): 61-72.

Guillen, F., Brégeon, D. and Plaquevent, J.C. (2006). (S)-Histidine: the ideal precursor for a

novel family of chiral aminoacid and peptidic ionic liquids. Tetrahedron Letters 47:

1245-48.

Hazarkhani, H. and Karimi, B. (2004). N-Bromosuccinimide as an almost neutral catalyst

for efficient synthesis of dihydropyrimidinones under microwave irradiation. Synthesis

2004: 1239-42.

Heravi, M.M., Bakhtiari, K. and Bamoharram, F.F. (2006). 12-Molybdophosphoric acid: A

recyclable catalyst for the synthesis of Biginelli-type 3,4-dihydropyrimidine-2(1H)-

ones. Catalysis Communications 7: 373-76.

Hojati, S.F., Gholizadeh, M., Haghdoust, M. and Shafiezadeh, F. (2010). 1,3-Dichloro-5,5-

dimethylhydantoin as a novel and efficient homogeneous catalyst in Biginelli reaction.

Bulletin of Korean Chemical Society 31: 3238-40.


224

Hu, E.H., Sidler, D.R. and Dolling, U.H. (1998). Unprecedented catalytic three component

one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-

dihydropyrimidin-2(1H)-ones. The Journal of Organic Chemistry 63: 3454-57.

Jain, K.S., Bariwal, J.B., Kathiravan, M.K., Phoujdar, M.S., Sahne, R.S., Chauhan, B.S.,

Shah, A.K. and Yadav, M.R. (2008). Recent advances in selective α1-adrenoreceptor

antagonists as antihypertensive agents. Bioorganic and Medicinal Chemistry 16: 4759-

800.

Jastorff, B., Störmann, R., Ranke, J., Mölter, K., Stock, F., Oberheitmann, B., Hoffmann,

W., Hoffmann, J., Nüchter, M., Ondrushka, B. and Filser, J. (2003). How hazardous are

ionic liquids? Structure–activity relationships and biological testing as important

elements for sustainability evaluation. Green Chemistry 5: 136-42.

Kappe, C.O. (1993). 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron

49: 6937-63.

Kappe, C.O. (1997). A re-examination of the mechanism of the Biginelli dihydropyrimidine

synthesis. Support for an N-acyliminium ion intermediate. The Journal of Organic

Chemistry 62: 7201-04.

Kappe, C.O. (1998). 4-Aryldihydropyrimidines via the Biginelli condensation: Aza-analogs

of nifedipine-type calcium channel modulators. Molecules 3: 1-9.

Kappe, C.O. (2000a). Recent advances in the Biginelli dihydropyrimidine synthesis. New

tricks from an old dog. Accounts of Chemical Research 33: 879-88.

Kappe, C.O. (2000b). Biologically active dihydropyrimidines of the Biginelli type-a

literature survey. European Journal of Medicinal Chemistry 35: 1043-52.

Kappe, C.O. (2000c). Highly versatile solid-phase synthesis of biofunctional 4-aryl-3,4-

dihyropyrimidines using resin-bound isothiourea building blocks and multidirectional

resin cleavage. Bioorganic and Medicinal Chemistry Letters 10: 49-51.

Kappe, C.O., Fabian, W.M.F. and Semones, M.A. (1997). Conformational analysis of 4-

aryl-dihydropyrimidine calcium channel modulators. A comparison of ab-initio,

semiempirical and X-ray crystallographic studies. Tetrahedron 53: 2803-16.

Kappe, C.O. and Falsone, S.F. (1998). Polyphosphate ester-mediated synthesis of

dihydropyrimidines. Improved conditions for the Biginelli reaction. Synlett 7: 718-20.

Kappe, C.O. and Roschger, P. (1989). Synthesis and reactions of Biginelli-compounds.

Journal of Heterocyclic Chemistry 26: 55-64.


225

Karade, H.N., Sathe, M. and Kaushik, M.P. (2007). Synthesis of 4-aryl substituted 3,4-

dihydropyrimidinones using silica-chloride under solvent free conditions. Molecules 12:

1341-51.

Kasana, R.C., Sharma, U.K., Sharma, N. and Sinha, A.K. (2007). Isolation and

identification of a novel strain of Pseudomonas chlororaphis capable of transforming

isoeugenol to vanillin. Current Microbiology 54: 457-61.

Kumar, A. and Maurya, R.A. (2007). An efficient bakers’ yeast catalyzed synthesis of 3,4-

dihydropyrimidin-2-(1H)-ones. Tetrahedron Letters 48: 4569-71.

Liu, C.J. and Wang, J.D. (2009). Copper (II) sulfamate: An efficient catalyst for the one-pot

synthesis of 3,4-dihydropyrimidine-2(1H)-ones and thiones. Molecules 14: 763-70.

Lu, J. and Ma, H. (2000). Iron(III)-catalyzed synthesis of dihydropyrimidinones. Improved

conditions for the Biginelli reaction. Synlett 2000: 63-64.

Luo, S., Zu, D., Yue, H., Wang, L.,Yang, W. and Xu, Z. (2006). Synthesis and properties of

novel chiral-amine-functionalized ionic liquids. Tetrahedron: Asymmetry 17: 2028-33.

Ma, Y., Qian, C., Wang, L. and Yang, M. (2000). Lanthanide triflate catalyzed Biginelli

reaction. One-pot synthesis of dihydropyrimidinones under solvent-free conditions. The

Journal of Organic Chemistry 65: 3864-68.

Mabry, J. and Ganem, B. (2006). Studies on the Biginelli reaction: a mild and selective

route to 3,4-dihydropyrimidin-2(1H)-ones via enamine intermediates. Tetrahedron

Letters 47: 55-56.

Mayer, T.U., Kapoor, T.M., Haggarty, S.J., King, R.W., Schreiber, S.L. and Mitchison, T.J.

(1999). Small-molecule inhibitor of mitotic spindle bipolarity indentified in a

phenotype-based screen. Science 286: 971-74.

Naik, H.R.P., Naik, H.S.B. and Aravinda, T. (2009). Nano-Titanium dioxide (TiO2)

mediated simple and efficient modification to Biginelli reaction. African Journal of

Pure and Applied Chemistry 3: 202-07.

O’Reilly, B.C. and Atwal, K.S. (1987). Synthesis of substituted 1,2,3,4-tetrahydro-6-

methyl-2-oxo-5-pyrimidinecarboxylic acid esters: The Biginelli condensation revisited.

Heterocycles 26: 1185-88.

Ohno, H. and Fukumoto, K. (2007). Amino acid ionic liquids. Accounts of Chemical

Research 40: 1122-29.

Patil, S., Jadhav, S.D. and Deshmukh, M.B. (2011). Natural acid catalyzed multi-component

reactions as a green approach. Archives of Applied Science Research 3: 203-08.


226

Peng, J. and Deng, Y. (2001). Ionic liquids catalyzed Biginelli reaction under solvent-free

conditions. Tetrahedron Letters 42: 5917-19.

Perez, R.; Beryozkina, T., Zbruyev, O.I., Haas, W. and Kappe, C.O. (2002). Traceless solid-

phase synthesis of bicyclic dihydropyrimidones using multidirectional cyclization

cleavage. Journal of Combitorial Chemistry 4: 501-10.

Phukan, M., Kalita M.K., and Borah, R. (2010). A new protocol for Biginelli (or like)

reaction under solvent-free grinding method using Fe (NO3)3.9H2O as catalyst. Green

Chemistry Letters and Reviews 3: 329-334.

Pretti, C., Chiappe, C., Pieraccini, D., Gregori, M., Abramo, F., Monni, G. and Intorre, L.

(2006). Acute toxicity of ionic liquids to the zebrafish. Green Chemistry 8: 238-40.

Remington. (2005). The science and practice of pharmacy. Troy, D.B. (ed). 21st edn. Vol 2.

Lippincott Williams and Wilkens, Philadelphia.

Rosłonkiewicz, A.C., Pernak, J., Feder, J.K., Ramani, A., Robertson, A.J. and Seddon, K.R.

(2005). Synthesis, anti-microbial activities and anti-electrostatic properties of

phosphonium-based ionic liquids. Green Chemistry 7: 855-62.

Roy, D.K. and Bordoloi, M. (2006). Synthesis of some substituted 2-oxo-1,2,3,4-

tetrahydropyrimidines(3,4-dihydropyrimidin-2(1)-ones) and 2-thioxo-1,2,3,4-

tetrahydropyrimidines catalyzed by tin(II) chloride dihydrate and tin(II) iodide under

microwave irradiation. Indian Journal of Chemistry B 45: 1067-71.

Russowsky, D., Lopesa, F.A., da Silvaa, V.S.S., Cantoa, K.F.S., Montes D’Ocab, M.G. and

Godoi, M.N. (2004). Multicomponent Biginelli’s synthesis of 3,4-dihydropyrimidin-

2(1H)-ones promoted by SnCl2.2H2O. Journal of Brazilian Chemical Society 15: 165-

69.

Ryabukhin, S.V., Plaskon, A.S., Ostapchuk, E.N., Volochnyuk, D.M. and Tolmachev, A.A.

(2007). N-Substituted ureas and thioureas in Biginelli reaction promoted by

chlorotrimethylsilane: Convenient synthesis of N1-alkyl-, N1-aryl-, and N1, N3-dialkyl-

3,4-dihydropyrimidin-2(1H)-(thi)ones. Synthesis 2007: 417-27.

Sharma, N., Sharma, U.K., Kumar, R., Katoch, N., Kumar, R. and Sinha, A.K. (2011a).

First bovine serum albumin promoted synthesis of enones, cinnamic acids and

coumarins in ionic liquid: An insight into the role of protein impurities in porcine

pancreas lipase for olefinic bond formations. Advanced Synthesis and Catalysis 353:

871-78.

Sharma, N., Sharma, U.K., Salwan, R., Kasana, R.C. and Sinha, A.K. (2011b). A synergic

blend of newly isolated Pseudomonas mandelii KJLPB5 and [hmim]Br for


227

chemoselective 2o aryl alcohol oxidation in H2O2: Synthesis of aryl ketone or aldehydes

via sequential dehydration-oxidative C=C cleavage. Catalysis Letters 141: 616-22.

Sharma, U.K., Sharma, N., Kumar, R., Kumar, R. and Sinha, A.K. (2009). Biocatalytic

promiscuity of lipase in chemoselective oxidation of aryl alcohols/acetates: A unique

synergism of CAL-B and [hmim]Br for the metal-free H2O2 activation. Organic Letters

11: 4846-48.

Shen, Z.L., Xu, X.P. and Ji, S.J. (2010). Brønsted base-catalyzed one-pot three-component

Biginelli-type reaction: An efficient synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-

2(1H)-one and mechanistic study. 75: 1162-67.

Shutalev, A.D., Kishko, E.A., Sivova, N. and Kuznetsov, A.Y. (1998). A new convenient

synthesis of 5-acyl-1,2,3,4-tetrahydropyrimidine-2-thiones/ones. Molecules 3: 100-06.

Sinder, B.B. and Shi, Z. (1993). Biomimetic synthesis of (+-)-crambines A, B, C1, and C2.

Revision of the structure of crambines B and C1. The Journal of Organic Chemistry 58:

3828-39.

Singh, S.K. and Singh, K.N. (2010). Glycine-catalyzed easy and efficient one-pot synthesis

of polyhydroquinolines through Hantzsch multicomponent condensation under

controlled microwave. Journal of Heterocyclic Chemistry 47: 194-98.

Singhal, S., Joseph, J.K., Jain, S.L. and Sain, B. (2010). Synthesis of 3,4-

dihydropyrimidinones in the presence of water under solvent free conditions using

conventional heating, microwave irradiation/ultrasound. Green Chemistry Letters and

Reviews 3: 23-26.

Sinha, A.K., Acharya, R. and Joshi, B.P. (2002). A mild and convenient procedure for the

conversion of toxic beta-asarone into rare phenylpropanoids: 2,4,5-

trimethoxycinnamaldehyde and gamma-asarone. Journal of Natural Products 65: 764-

65.

Sinha, A.K., Joshi, B.P. and Acharya, R. (2003). Microwave-promoted synthesis of

methoxylated benzaldehydes from natural cis-phenylpropenes using NaIO4/OsO4 (cat.).

Chemistry Letters 32: 780-81.

Sohn, J.H., Choi, H.M., Lee, S., Joung, S. and Lee, H.Y. (2009). Probing the mode of

asymmetric induction of Biginelli reaction using proline ester salts. European Journal of

Organic Chemistry 2009: 3858-62.

Studer, A., Hadida, S., Ferritto, R., Kim, S.Y., Jeger, P., Wipf, P. and Curran, D.P. (1997a).

Fluorous synthesis: A fluorous-phase strategy for improving separation efficiency in

organic synthesis. Science 275: 823-26.


228

Studer, A., Jeger, P., Wipf, P., Curran, D.P. (1997b). Fluorous synthesis: Fluorous protocols

for the Ugi and Biginelli multicomponent condensations. The Journal of Organic


Swatloski, R.P., Holbrey, J.D. and Rogers, R.D. (2003). Ionic liquids are not always green:

hydrolysis of 1-butyl-3-methylimidazolium hexafluorophosphate. Green Chemistry 5:

361-63.

Sweet, F. and Fissekis, J.D. (1973). On the synthesis of 3,4-dihydro-2(1H)-pyrimidones and

the mechanism of the Biginelli reaction. Journal of the American Chemical Society 95:

8741-49.

Tao, G.H., He, L., Sun, N. and Kou, Y. (2005). New generation ionic liquids: cations

derived from amino acids. Chemical Communications 2005: 3562-64.

Tao, G.H., He, L., Liu, W.S., Xu, L., Xiong, W., Wang, T. and Kou, Y. (2006). Preparation,

characterization and application of amino acid-based green ionic liquids. Green


Tu, S., Fang, F., Zhu, S., Li, T., Zhang, X. and Zhuang, Q. (2004). A new Biginelli reaction

procedure using potassium hydrogen sulfate as the promoter for an efficient synthesis of

3,4-dihydropyrimidin-2(1H)-one. Synlett 2004: 537-39.

Valverde, M.G., Dallinger, D. and Kappe, C.O. (2001). Solid-phase synthesis of

dihydropyrimidones via N-acyliminium ion-based α-ureidoalkylations. Synlett 2001:

741-44.

Wang, M., Wang, Z.C., Sun, Z.L. and Jiang, H. (2005a). Synthesis and characterization of

transition metal methanesulfonates and their catalytic behavior in Biginelli reactions.

Transition Metal Chemistry 30: 792-96.

Wang, M., Jiang, H. and Wang, Z. (2005b). Biginelli condensation of aliphatic aldehydes

catalysed by zinc methanesulfonate. Journal of Chemical Research 2005: 691-93.

Wipf, P. and Cunningham, A. (1995). A solid-phase protocol of the Biginelli

dihydropyrimidine synthesis suitable for combinatorial chemistry. Tetrahedron Letters

36: 7819-22.

Xin, J., Chang, L., Hou, Z., Shang, D., Liu, X. and Feng, X. (2008). An enantioselective

Biginelli reaction catalyzed by a simple chiral secondary amine and achiral Brønsted

acid by a dual-activation route. Chemistry- A European Journal 14: 3177-81.

Yadav, J.S., Kumar, S.P., Kondaji, G., Rao, R.S. and Nagaiah, K. (2004). A novel L-Proline

catalyzed Biginelli reaction: One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

under solvent-free conditions. Chemistry Letters 33: 1168-69.


229

Yadav, J.S., Reddy, B.V.S., Reddy, K.B., Raj, K.S. and Prasad, A.R. (2001). Ultrasound-

accelerated synthesis of 3,4-dihydropyrimidin-2(1H)-ones with ceric ammonium nitrate.

Journal of Chemical Society, Perkin Transactions 1: 1939-41.


i

NMR spectra of some compounds

NHHN

O

CH3

COOCH3

9 8 7 6 5 4 3 2 1 ppm1H NMR (in DMSO-d6) spectrum of Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-

5-carboxylate (14b, Table 5)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

13C NMR (in DMSO-d6) spectrum of Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-

tetrahydropyrimidine-5-carboxylate (14b, Table 5)


ii

NHHN

S

CH3

COOC2H5

OCH3

HO

10 9 8 7 6 5 4 3 2 1 ppm1HNMR (in DMSO-d6) spectrum of Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-

1,2,3,4 tetrahydropyrimidine-5-carboxylate (17b, Table 5)

180 160 140 120 100 80 60 40 20 ppm

13CNMR (in DMSO-d6) spectrum of Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-

1,2,3,4 tetrahydropyrimidine-5-carboxylate (17b, Table 5)


iii

NHHN

S

C H 3

C OO C 2H 5

OH

10 9 8 7 6 5 4 3 2 1 ppm

1HNMR (in DMSO-d6) spectrum of Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

13CNMR (in DMSO-d6) spectrum of Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-



iv

NH

HN

OCH3C2H5OOC

O

H

9 8 7 6 5 4 3 2 1 ppm

1HNMR (in DMSO-d6) spectrum of Ethyl 9-methyl-11-oxo-8-oxa-10,12-

diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (20c, Scheme 26)

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

13CNMR (in DMSO-d6) spectrum of Ethyl 9-methyl-11-oxo-8-oxa-10,12-

diazatricyclo[7.3.1.02,7]trideca-2,4,6-triene-13-carboxylate (20c, Scheme 26)

green synthesis of some bioactive heterocyclic...

Documents