Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b ...shodhganga.inflibnet.ac.in/bitstream/10603/4343/8/08_chapter 2.pdf · Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans

Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans

49

Introduction:

Chemistry of heterocycles has been of importance in understanding the formation

of bioactive molecules as well as having industrial applications especially in

pharmaceuticals1. The majority of pharmaceuticals and biologically active agrochemicals

contain heterocyclic moieties with addition of countless additives and modifiers. The

applications ranging from cosmetics, reprography, information storage and plastics

heavily depend upon the heterocyclic residues. One of the striking structural features

inherent to heterocycles, which is continued to be exploited to a great advantage by the

drug industry, lies in their ability to manifest substituent around a core scaffold in well

defined three-dimensional representations. Based upon these considerations in recent

years, a family of new heterocyclic scaffolds has come into existence having wide range

of applications such as switching on / off devices, photo catalysis, etc.2.

Tetrahydrobenzo[b]pyrans [Fig. 1], synthesized in this work are fused six membered

heterocyclic compounds which have attracted the attention of both synthetic chemists as

well as pharmacists due to plethora of applications possible for their derivatives.

Fig. 1

Applications of Tetrahydrobenzo[b]pyrans :

Tetrahydrobenzo[b]pyrans have recently attracted attention as an important class

of heterocyclic scaffolds in the field of drugs and pharmaceuticals3 due to their wide

applications [Fig. 2]. These compounds are widely used as anti-coagulant, diuretic,

spasmolytic, anticancer and anti-anaphylactin agents4. They can also be used as cognitive

O

O

NH2

CN

Structure of tetrahydrobenzo[b]pyran


50

enhancers for the treatment of neurodegenerative disease as Alzheimer’s disease,

amyoprophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, AIDS

associated dementia and Down’s syndrome as well as for the treatment of schizophrenia

and myoclonus 5. Other than their biological importance, some 2-amino-4H-pyrans have

been widely used as photoactive materials6. In addition, the tetrahydrobenzo[b]pyran

nucleus is an important structural scaffold of a series of natural products7 and can be

converted into pyridine systems which relate to pharmacologically important calcium

antagonists of the dihydropyridine [DHP] 8 types.

Synthetic Methods for Benzopyrans:

i) Tetrahydrobenzo[b]pyrans can be synthesized by two component condensation of

arylmethylene malononitrile or arylmethylene cyanoacetate with dimedone. Tu and co-

workers9 synthesized a series of tetrahydrobenzo[b]pyran derivatives by the reaction of

cyano-olefin and dimedone in ethylene glycol at 80 °C without catalyst in 61-96 % yield.

[Scheme1].

Scheme 1

O NH2

CNO R

diuretic

anticancer anti-anaphylactin agent

photoactive materials

natural products

calcium antagonists Fig. 2: Applications of Tetrahydrobenzo[b]pyrans

spasmolytic

anti-coagulant

ArCHX

CN

O

O

HOCH2CH2OH

O

O

X

NH2

Ar

+

X = COC2H5 or CN


51

Multi-component reactions (MCRs) have attracted considerable attention since

they are performed without need to isolate any intermediate during their processes which

reduces time as well as saves energy and raw materials10. These are superior to two-

component reactions in several aspects including the simplicity of a one-pot procedure,

possible structural variations and building up complex molecules. Taking into

consideration these advantages, an efficient and convenient synthesis of

tetrahydrobenzo[b]pyrans can generally be carried out via a one-pot, three component

condensation of an aromatic aldehyde, an active methylene compound and dimedone

under influence of acidic/basic/bi-functional or phase transfer catalysts11 [Scheme 2].

Scheme 2

ii) Balalaie et al.12 have used diammonium hydrogen phosphate to synthesize novel

4H-benzo[b]pyrans via one-pot, three-component tandem Knoevenagel

cyclocondensation reaction, consisting of aromatic aldehyde, malononitrile and

barbituric/thiobarbituric acid in aqueous ethanol at room temperature [Scheme 3].

Scheme 3

iii) Perumal and co-workers13 found InCl3-ethanol combination useful for the

synthesis of new type of benzopyrans via phosphorus-carbon bond formation by multi-

component reaction of salicylaldehyde, malononitrile with triethyl phosphate in good

yields [Scheme 4].

CN

CNO NH2

Ar

CNN

N

O

X

H

H

Ar H

O

N

N

O

O

X

H

H

++DAHP (10mol%)

aq. EtOH, r.t.

X = O, S

O

O

CN

CNArCHO

Catalyst

SolventO NH2

ArO

CN++


52

Scheme 4

iv) Pyranopyrazoles are the new class of benzopyrans having important biological

properties which stimulated interest to develop new methods for their synthesis.

a) Litvinov et al.14a used triethyl amine as a catalyst for synthesis of

6-aminopyrano [2,3-c]pyrazol-5-carbonitriles by four-component reaction of aromatic

aldehydes, malononitrile, β-ketoesters and hydrazine hydrate in good to excellent yields

[Scheme 5].

Scheme 5

b) Kumaravel and his group14b synthesized a new pyrazolyl-4H-chromene

derivatives in water at ambient temperature by replacing aldehyde by

o-hydroxybenzaldehyde keeping other reactants same as in Scheme 5 [Scheme 6].

Scheme 6

c) Shestopalov and co-workers14c carried out three-component condensation of

4-piperidinone, 5-pyrazolone and malononitrile by electrochemical means, which yielded

6-amino- 5-cyano- spiro- 4- (piperidine-4¢)- 2H, 4H-dihydropyrazolo[3,4-b]pyran

[Scheme7].

NH2

NH2

O

O

O

CN

CN

R

H O

O NH2

R

CN

NH

N

+ + water, base

rt, 5-10 min

OH

CHO CN

CN

POEtEtO

EtO

InCl3

EtOHO

POO

O

NH2

CN

+ +

OH

CHO

NCCN

O

OO

NH2

NH2

O NH2

NH

N

OH

CN+water

30oC, 5-10 min


53

They claimed that the electrochemical reactions proceed under milder conditions

with the yields 12-15 % greater than those of the reactions catalyzed by chemical bases.

Scheme 7

d) The first enantioselective synthesis of biologically active 6-amino-5-

cyanodihydropyrano[2,3-c]pyrazoles was carried out by Gogoi and co-workers14d by a

tandem Michael addition and Thorpe-Ziegler type reaction between 2-pyrazolin-5-ones

and benzylidene malononitriles catalyzed by cinchona alkaloid catalyst [Scheme 8].

Scheme 8

v) Luo et al.15 reported asymmetric tandem oxa-Michael-aldol reaction of

salicylaldehyde derivatives with α,β-unsaturated aldehydes using a chiral amine/chiral

acid organocatalytic system as a catalyst. The organocatalytic system of (S)-

diphenylpyrrolinol trimethylsilyl ether with chiral shift reagent (S)-Mosher acid presented

a synergistic effect in the improvement of reaction performance and offered an efficient

steric effect in the transformation. The tandem oxa-Michael-aldol reaction proceeded

with high yields (up to 90%) and excellent enantioselectivities (ee up to 99%) to give the

corresponding chromene derivatives [Scheme 9].

Scheme 9

N

O

N

N

OH

CH2(CN)2

N

O NH2

CN

N

NH

R1

+

R2

+

R1

R2

NNH

O

R

R' CN

CN

NNH

O

R

NH2

R'

CN+

Cupreine

CH2Cl2, rt

O

O

NOTMS

N

Ph

-

R"

R'

H2

+

Chiral amine/chiral acidOrganocatalytic system

CHOPh

OH

CHO

O Ph

CHO+

Catalyst, 20mol%

toluene, rt


54

vi) A combinatorial library of the 2-alkylamino-3-nitro-4-alkylsulfanyl, 4H-

chromenes was synthesized by Rao and his group16 in excellent yields by base-catalyzed

reaction of the nitroketene N,S-acetals and the ring substituted o-hydroxybenzaldehydes.

Nucleophilic displacement of the C-4 alkylsulfanyl group with different thiols afforded

4H-chromenes with structural diversity [Scheme 10].

Scheme 10

vii) Selvam et al.17 achieved an efficient synthesis of pyrano[2,3-b]pyridines with the

help of SnCl2·2H2O (Lewis acid) mediated Friedlander reaction of 2-amino-3-cyano-4H-

pyrans with cyclopentanone / cyclohexanone under solvent-free condition [Scheme 11].

Scheme 11

viii) Xanthenes have been used as versatile synthons due to the inherent reactivity of the

inbuilt pyran ring. These benzopyran derivatives can be synthesized by the reaction of

substituted salicylaldehydes with dimedone / cyclohexane-1,3-dione under influence of

acidic catalysts such as KF/ Al2O318, triethylbenzylammonium chloride (TEBA)19, TCT20,

Cerium(III) chloride21, etc. [Scheme 12].

Scheme 12

O NH2

CN

O

O N

NH2

R R

+ SnCl2.2H2O

neat, 110oC

4-5h

OH

CHO

R

O

O

O

O

OOH

R

+ 2

R'

R'

Acid catalyst

R'

R'

R'R'

SMe

NHMeO2N

OH

CHO

O

CHO NO2

SMe

NHMe

-

O

NO2

SMe

NHMe

OH

O

NO2

NHMeO

NO2

NHMe

SMe

+

DBU

MeOH, rt

-H2O, -SMe

+

MeS-


55

ix) Coumarins are the important derivatives of benzopyrans which are generally

synthesized by Pechmann22 [Scheme 13], Knoevenagel23 [Scheme 14], Perkin24 [Scheme

15], Reformatsky25 [Scheme 16] and Wittig26 [Scheme 17] reactions under influence of

acidic or basic catalysts.

Scheme 13

Scheme 14

Scheme 15

Scheme 16

Scheme 17

OH

R

O O

OEt

O O

R+

H+

Pechmann Condensation

OH

CHO

RO

O

O

O O O

COOH

R+ Silica Sulfuric acid

1200C

Knoevenagel Condensation

O

OH

R

OH

H

O

O O

R

+DMSO, reflux

DCCPerkin reaction

OH

COMe

CH3CH(Br)COBrO

COMe

O

Me

Br O O

Me

Me

Base

M2Te, THF

Reformatsky Reaction

H

O

OHR

Cl CO2Me

O OR

+[bmim]+PF6

- , NaOMe

PPh3 , 200-2100C

Wittig Reaction


56

Catalysts for Tetrahydrobenzo[b]pyrans:

Tetrahydrobenzo[b]pyrans can be synthesized either using acidic or basic

catalysts under different experimental conditions. A detailed literature survey towards the

multi-component synthesis of tetrahydrobenzo[b]pyrans revealed that most of the

protocols employed for this reaction operate under high thermal activation27, microwave

activation28 and ultrasonic irradiation29. Recently, Fotouhi et al.30 reported

electrochemical synthesis of tetrahydrobenzo[b]pyrans. There are few protocols operable

at room temperature using N-methylimidazole31, (S)-proline32 and (D,L)-proline33. Each

of the above method has its own merit with at least one of the limitations of low yields,

commercially unavailable catalysts, long reaction times, harsh reaction conditions and

tedious work-up procedures. Hence, improved methods for multi-component synthesis of

tetrahydrobenzo[b]pyran using inexpensive and less toxic reagents coupled with simple

reaction conditions and easier work-up procedures are required.

Our earlier experience on potassium phosphate directed us that it would overcome

the above said drawbacks occurred during the synthesis of tetrahydrobenzo[b]pyrans.

Applications of K3PO4 in Our Laboratory:

We have studied alkylations of Meldrum’s acid34 [Scheme 18], Henry reaction

for synthesis of nitroaldols35 [Scheme 19], Claisen-Schmidt condensation for synthesis of

chalcones36 [Scheme 20] and Michael addition of thiols to α,β-unsaturated

ketones37[Scheme 21] using anhydrous K3PO4 as a base. As a continued research towards

K3PO4, we explored its efficacy in multi-component synthesis of

tetrahydrobenzo[b]pyrans.


57

Scheme 18

RO

H

K3PO4

CH3CN, rt R

OH

R'

NO2

R = alkyl, sub. aryl

+ R'-CH2-NO2

R' = H, CH3

Nitroaldol Condensation

Scheme 19

Scheme 20

Scheme 21

O

O

O

O

CH

OH

ArO

O

O

O

O

O

O

O

CH

Ar

O

O

O

O

CH2

Ar

O

O

O

O

R

Ar

Ar-CHO + K3PO4

EtOH, rt

NaBH4R-X

Alkylation Of Meldrums Acid

R"SH

R'

R

O

R

O

R' SR"

+ SSA/K3PO4

RT, neat

Michael Addition

CHO

RMe

O

R'

K3PO4

EtOH

O

R' R+

Synthesis Of Chalcones


58

Objectives:

Our aim for undertaking this work as outlined above was

i) To find out the ways to overcome the limitations and drawbacks of the reported

methods such as harsh reaction conditions, use of expensive catalysts.

ii) To develop a one-pot synthesis of tetrahydrobenzo[b]pyrans at room temperature

from aldehyde, malononitrile and dimedone using a commercially available reagent

and

iii) To find out the role of catalyst and to depict mechanistic pathway for the formation

of tetrahydrobenzo[b]pyrans.

Present Work:

In continuation with our earlier experience with potassium phosphate in Michael

addition36, we envisaged that K3PO4 could be a suitable catalyst for the present

transformation, as potassium is oxophilic, the central K+ will make a strong co-ordinate

bond with ‘O’ of 1,3-diketone to form its enolate ion (6). The counteranion PO43- is

sufficiently basic for the formation of cyanoolefin (5) and subsequent Michael addition of

enolate of 1,3-diketone (6) on cyanoolefin (5), followed by cyclocondensation to form

corresponding tetrahydrobenzo[b]pyran (4). To remove the conflict that amongst two

active methylene compounds viz dimedone and malononitrile which competitively

undergo Knoevenagel condensation with aldehyde, we have carried out reaction of

dimedone and aldehyde (1:1) in ethanol using K3PO4 at room temperature for an hour.

However, we could obtain only reactants. Based on this a plausible mechanism for the

multi-component synthesis of tetrahydrobenzo[b]pyran using K3PO4 in ethanol is

suggested [Scheme 22].


59

Scheme 22: A plausible mechanism for formation of tetrahydrobenzo[b]pyran

Initially, the reaction of anisaldehyde (1), dimedone(2), malononitrile (3) and

potassium phosphate was carried out in ethanol medium at room temperature [Scheme

23]. The corresponding 2-amino-3-cyano-7,7-dimethyl-5-oxo-4-(4-methoxy phenyl)-

5,6,7,8-tetrahydro-4H-benzo[b]pyran was obtained in excellent yield within short

reaction time. Encouraged by this result, we then employed this reaction as a template to

optimize the reaction conditions.

O

O

CN

CN

O NH2

OCN

OMe

K3PO4

EtOH

RT

CHO

OMe

++,

1 2 3 4

Scheme 23: Potassium phosphate catalyzed multi-component synthesis of tetrahydro benzo[b]pyrans

O

R

NH2

CN

O

O

R

NH

CN

OH

PO4

3-

O

R

CN

OH

N

PO4

3-

K+

O

O

RH

CN

NC

H

O

R

CN

CNCN

CNH

H

O

O

H

K+

PO4

3-

K3PO4

K+

H+

H+

+

_

+

1

3

2

65

7

8

4


60

A brief screening of solvents showed that water, chloroform, methanol,

acetonitrile and ethanol were less effective than mixed solvent system H2O : C2H5OH

(80:20, v/v). We also found that the reaction carried out with other potassium sources

such as KH2PO4, K2HPO4, K2CO3 also gave inferior results. It is known that aqueous

ethanol solutions below 10 % concentration are characterized by hydrophobic hydration.

Many SN1 reactions as hydrolysis of t-BuCl exhibit extrema in thermodynamic as well as

in kinetic rate studies. Probably such mixtures stabilize the transition state involving

aductation. Upon examining the influence of the amount of anhydrous K3PO4 on the

reaction, it was found that 15 mol % of anhydrous K3PO4 was sufficient to promote the

reaction. In the presence of less than this amount, the yield dropped dramatically, even if

reaction performed for longer time (Table 1, entry 9). When the amount of anhydrous

K3PO4 was increased over 15 mol %, neither the yield nor the reaction time was found to

be improved (Table 1, entry 10).

Table 1: Optimization of reaction conditions for the synthesis of Tetrahydro

benzo [b]pyrans

Entry Solvent* Catalyst Mol % Time (min)

Yield (%)a

1 H2O K3PO4 15 120 74

2 3

CHCl3

CH3CN

K3PO4

K3PO4 15 15

90 90

70 65

4 CH3OH K3PO4 15 65 81

5 C2H5OH K3PO4 15 60 87

6 H2O + C2H5OH(90:10) K3PO4 15 75 83

7 H2O + C2H5OH(80:20) K3PO4 15 50 94

8 H2O +C2H5OH(70:30) K3PO4 15 40 95

9 H2O +C2H5OH(80:20) K3PO4 10 80 81

10 H2O +C2H5OH(80:20) K3PO4 20 45 95

11 H2O +C2H5OH(80:20) K2CO3 15 75 77

12 H2O +C2H5OH(80:20) KH2PO4 15 90 70

13 H2O +C2H5OH(80:20) K2HPO4 15 80 81 * Reaction conditions: anisaldehyde (1 mmol), dimedone (1 mmol), malononitrile (1 mmol), H2O: ethanol [80:20, 5 mL], room temp; ayields refer to pure isolated products; b Entries in bracket indicate the ratio of H2O to C2H5OH on volume.


61

To check the generality of the present protocol under the optimized reaction

conditions, the reaction was then extended for a variety of aldehydes bearing electron

donating substituent in H2O : C2H5OH (80:20, v/v) as a medium using K3PO4 as a

catalyst at ambient temperature to yield different substituted tetrahydrobenzo[b]pyrans.

The reactions proceeded efficiently in all the cases yielding products in acceptable yields

and having high purity. The results are summarized in (Table 2). The structures of the

prepared compounds were established unambiguously using spectral methods.

IR spectrum (Fig. 3) of the product (entry 4c, table 2) obtained by reaction of

4-isopropylbenzaldehyde, dimedone and malononitrile showed the absence of carbonyl

from aldehyde. In IR spectrum stretching frequency of the starting carbonyl group

disappeared from the given 1710-1720 cm-1 and appeared at 1656 cm-1 because of

formation of α, β-unsaturated carbonyl compound. The 1H NMR spectrum (Fig. 4) of the

same compound showed a two different singlet at δ 1.05 and 1.11 for three protons each

of two methyl groups from dimedone moiety, another set of singlet was observed at

1.19, 1.21 due to three protons of two methyl groups from isopropyl moiety, methylene

protons of dimedone moiety appeared as singlet at 2.22 ‘α’ to carbonyl group, while

other methylene protons of same moiety appeared as singlet at 2.45, other signals

appeared as a multiplet at 2.83 for methine proton of isopropyl group, a singlet at 4.37

due to benzylic methine proton, singlet at 4.52 due to –NH2. The aromatic region

appeared as singlet at 7.12. CMR (Fig. 5) spectrum of the same compound shows signal

at 23.86, 27.75, 28.79, 29.64, 32.16, 33.63, 35.02, 40.66, 50.67, 63.59, 114.15, 118.81,

126.60, 127.29, signals at 140.50 and 147.42 due to olefinic carbons attached to –CN and

–NH2 group, respectively while other olefinic carbons at 157.50, 161.46 and at 195.93

due to carbonyl carbon. IR, NMR data is in agreement with the expected structures.

The IR spectrum (Fig. 6) of 2-amino-4-(2,5-dimethylphenyl)-7,7-dimethyl-5-oxo-

5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (entry 4d, table 2) obtained by multi-

component reaction of 2,5-dimethylbenzaldehyde, dimedone and malononitrile showed

the expected bands at 3409 and 3318 cm-1 due to primary amine, 2191 cm-1 due to nitrile

group and at 1659 cm-1 due to α, β-unsaturated carbonyl group. 1H-NMR of 4d (Fig. 7)

also supported the structure of the compound and exhibited peaks at δ 1.06, 1.11 as two

singlets corresponding to two methyl groups of dimedone, methylene protons of


62

dimedone appeared at 2.20, 2.47 as singlets, methyl group protons attached to aromatic

ring appeared at 2.22, 2.52 as singlets. Two singlets were observed at δ 4.49, 4.63 for

protons of primary amine group and benzylic methine proton, respectively. Aromatic

protons appeared at 6.73 as singlet for one proton, 6.87 as doublet for one proton and 7.0

as doublet for one proton. CMR (Fig. 8) spectrum of the same compound shows signals

at 19.07, 21.13, 27.58, 28.95, 30.95, 32.29, 40.63, 50.60, 114.67, 127.75, 128.04, 130.41,

132.65, 135.56, 141.66, 157.13, 161.56, 161.56 and carbonyl carbon signal at 195.95.

The IR spectrum (Fig. 9) of 2-amino-4-cyclohexyl-7,7-dimethyl-5-oxo-5,6,7,8-

tetrahydro-4H-chromene-3-carbonitrile (entry 4 i, table 2) showed two prominent bands

at 3414 and 3249 cm-1 corresponding to primary amine and –CN appeared at 2193 cm-1.

Band at 1654 cm-1 marked the presence of α, β-unsaturated carbonyl group. The 1H–NMR spectrum of the compound 4 i (Fig. 10) has two singlets at δ 1.11, 1.16 for

protons of two methyl groups of dimedone and a multiplet of eleven protons of

cyclohexyl group observed at δ 1.24-1.71. Four protons of the two methylene groups of

dimedone moiety appeared at 2.28 and 2.37 ppm. Benzylic methine proton and primary

amine protons showed doublet at 3.30 and a singlet at 4.53, respectively. 13C-NMR

spectrum (Fig. 11) of the same compound showed peaks at δ 26.19, 26.31, 26.56, 27.41,

27.84, 29.27, 30.52, 32.05, 34.74, 40.67, 43.79, 50.84, 58.91, 114.18, 120.23, 159.87,

163.12, 196.46 corresponding to 18 carbons of the 4 i molecule. Peak at 196.46 is the

indication of carbonyl carbon.

We then diverted our attention towards aldehydes bearing electron withdrawing

substituents viz –Cl, -NO2, -CN and found that there is no noticeable effect of substituent

on the rate of reaction.

To check efficacy of potassium phosphate, we decided to replace dimedone by

cyclohexane-1,3-dione. We observed that present protocol works equally well with

dimedone as well as with cyclohexane-1,3-dione.

IR spectrum (Fig.12) of compound 2-amino-4-(4-cyanophenyl)-5-oxo-5,6,7,8-

tetrahydro-4H-chromene-3-carbonitrile (entry 4 m, table 2) showed bands at 3423, 3334

cm-1 indicating the presence of primary amine group in moiety. Presence of nitrile group

is confirmed by prominent peak at 2199 cm-1. α, β-unsaturated carbonyl group from the

structure appeared at 1653 cm-1. 1H-NMR (Fig. 13) of the same compound executed three


63

multiplets at up-field region of the spectra having values δ 1.94-2.13, 2.35-2.39, and

2.58-2.64 corresponding to three methylene group protons of cyclohexane-1,3-dione ring

moiety. Benzylic methine proton appeared as singlet at 4.47 while protons from primary

amine group also exhibited singlet at 4.66 ppm. Four aromatic protons from

4-cyanophenyl ring appeared in characteristic “doublet of the doublet” (dd) manner with

7.37 and 7.59 (J = 8 Hz). 13C-NMR spectra (Fig. 14) of 4 m furnished carbon signals at

20.09, 27.04, 35.73, 36.61, 100, 110, 114.31, 118.41, 119.81, 128.82, 132.64, 148.61,

158, 163.89 and 195.84.

After a careful literature survey, it is essential to state that, synthesis of

tetrahydrobenzo[b]pyrans involving organometallic moiety remained ignored and hence

we have focussed our attention towards ferrocene carboxylaldehyde. Gratifyingly, we

achieved tetrahydrobenzo[b]pyran of ferrocene carboxylaldehyde in good yield. [Scheme

24] (entry 4n, Table 2).

O

O

NH2R

R

CN

Fe

Fe

CHOO

OR

R

CN

CNC2H5OH

RT

+ +K3PO4

Scheme 24: Potassium phosphate catalyzed synthesis of tetrahydrobenzo[b]pyran of

ferrocene carboxylaldehyde

The IR spectrum (Fig. 15) of 2-amino-4-(2,5-dimethylphenyl)-7,7-dimethyl-5-

oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (entry 4n, table 2) obtained by

multi-component reaction of ferrocene carboxylaldehyde , dimedone and malononitrile

showed the expected bands at 3378 cm-1 due to primary amine, 2185 cm-1 due to nitrile

group and at 1645 cm-1 due to α, β-unsaturated carbonyl group. 1H-NMR of 4n (Fig. 16)

also supported the structure of the compound and exhibited peaks at δ 0.96, 1.08 as two

singlets corresponding to protons of two methyl groups of dimedone, protons of two

methylene groups of dimedone appeared at 2.26 and 2.32 as singlets. The protons of

ferrocene ring appeared in the region of 3.87-4.22 ppm. Two singlets were observed at

4.36, 4.68 for the protons of benzylic methine proton and primary amine group,

respectively. CMR (Fig. 17) spectrum of the same compound shows signals at δ 27.21,


64

28.45, 29.03, 32.13, 40.61, 50.76, 61.11, 65.73, 66.70, 66.99, 68.09, 69.14, 93.41, 100.00,

160.07, 161.46, and carbonyl carbon signal at 196.18.

Table 2: Potassium phosphate catalyzed multi-component synthesis of tetrahydrobenzo[b]pyrans at room temperature

Entry Product (4) Time

(min) Yield (%)a,b

MP Obs.(lit.0 C)

a

45

94

228-230 (228-230)12

b

50

94

200 (201)10

c

50

91

198-200

d

50

90

240-242

e

60

93

211-212 (209-211)12

f

45

89

212-214 (212-214)12

g

60

91

224-226 (227-230)7f

O

O

NH2

CN

O

O

NH2

CN

OMe

O

O

NH2

CN

O

O

NH2

CN

O

O

NH2

CN

Cl

O

O

NH2

CN

NO2

O

O

NH2

CN

CN


65

h

60

87

210-212 (209-211)8b

i

30

91

209-210

j

60

92

232-234 (236-237) 7f

k

60

91

193-195 (190-192)7d

l

60

89

228-230 (225-227)7d

m

60

87

234-236

n

90

80

193-195

a All products showed satisfactory spectroscopic data. (IR, 1H and 13C NMR, MS). b Yields refer to pure, isolated products

O

O

NH2

CN

S

O

O

NH2

CN

O

O

NH2

CN

Cl

O NH2

CNO

OMe

O NH2

CNO

Cl

O

O

NH2

CN

CN

O

O

NH2R

R

CN

Fe


66

Conclusion:

We are successful in developing efficient method for multi-component synthesis

of tetrahydrobenzo[b]pyran at ambient temperature using anhydrous K3PO4 as an

inexpensive catalyst. This procedure offers several advantages including mild condition,

high yields, inexpensive catalyst, wide scope of substrates and operational simplicity,

simple work-up, and purification of products by non-chromatographic methods, i.e. by

simple recrystallization from ethanol.

Experimental:

Various aldehydes (Lancaster and Alfa-Aesar), 1,3-diketones viz cyclohexane-

1,3-dione (Alfa-Aesar) and dimedone(Thomas Baker) were used as received.

IR spectra were recorded on Perkin-Elmer [FT-IR-783] spectrophotometer. NMR

spectra were recorded on Bruker AC or MSL (300 MHz for 1H NMR and 75 MHz for 13C

NMR) spectrometer in CDCl3 using TMS as an internal standard and δ values are

expressed in ppm. Melting points recorded are uncorrected.

Typical Procedure:

A mixture of aldehyde (1 mmol), malononitrile (1 mmol), 1,3-diketone (1 mmol)

and K3PO4 (21 mg, 15 mol %) in 20 % ethanol (5 mL) was stirred at r.t. for the time

indicated in Table 2. The reaction mixture was poured into ice water and just filtered to

yield corresponding tetrahydrobenzo[b]pyran. The residue was purified by

recrystalization in ethanol to provide the desired product.


67

O

O NH2

CN

Spectroscopic Data:

2-amino-4-(4-isopropylphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-

carbonitrile (entry 4c, table 2) :

Mp.198-200 oC IR (KBr): 3369, 3181, 2984, 2185, 1656,

1509, 1469, 1408, 1363, 1249, 778, 696 cm-1; 1H NMR (300

MHz, CDC13): 1.05 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.19 (s,

3H, CH3), 1.21 (s, 3H, CH3), 2.22 (s, 2H, -CH2 ), 2.45 (s, 2H,

-CH2), 2.83 (m, 1H, CH3-CH-CH3), 4.37 (s, 1H), 4.52 (s, 2H,

NH2), 7.12(s, 4H, Ar-H); 13C NMR (75 MHz, CDCl3): δ

23.86, 27.75, 28.79, 29.64, 32.16, 33.63, 35.02, 40.66, 50.67,

63.59, 114.15, 118.81, 126.60, 127.29, 140.50, 147.42,

157.50, 161.46, 195.93.

2-amino-4-(2,5-dimethylphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-

carbonitrile (entry 4d, table 2) :

Mp.240-242 oC IR (KBr): 3409, 3315, 3045, 2963, 2927,

2191, 1659, 1692, 1500, 1461, 1404, 1367, 814, 769 cm-1; 1H

NMR (300 MHz, CDC13): 1.06 (s, 3H, CH3), 1.11 (s, 3H,

CH3), 2.21 (s, 2H, -CH2), 2.22 (s, 3H, CH3), 2.47 (s, 2H, -

CH2 ), 2.52 (s, 3H, -CH3), 4.49 (s, 2H, NH2), 4.63 (s, 1H, -

CH), 6.73(s, 1H, Ar-H), 6.87(d, J = 8 Hz,1H, Ar-H), 7.0(d, J

= 8 Hz,1H, Ar-H), ; 13C NMR (75 MHz, CDCl3): δ 19.07,

21.13, 27.58, 28.95, 30.95, 32.29, 40.63, 50.60, 114.67,

127.75, 128.04, 130.41, 132.65, 135.56, 141.66, 157.13,

161.56, 161.56,195.95.

2-amino-4-cyclohexyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-

carbonitrile (entry 4i, table 2) :

Mp.209-210 oC IR (KBr): 3414, 3327, 3249, 2923, 2193,

1675, 1654, 1594, 1380, 1251, 693 cm-1; 1H NMR (300 MHz,

CDC13): δ = 1.11 (s, 3H,CH3), 1.16 (s, 3H, CH3), 1.24-1.71

(m, 11H), 2.9 (s, 2H, -CH2), 2.37 (s, 2H, -CH2), 3.09 (d, J=

2.7Hz, 1H, -CH), 4.53 (s, 2H, NH2); 13C NMR (75 MHz,

O

O NH2

CN

O

O NH2

CN


68

CDCl3): δ 26.19, 26.31, 26.56, 27.41, 27.84, 29.27, 30.52,

32.05 34.74, 40.67, 43.79, 50.84, 58.91, 114.18, 120.23,

159.87, 163.12, 196.46.

2-amino-4-(4-cyanophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile

(entry 4m, table 2):

Mp. 234-236 oC; IR (KBr): 3423, 3334, 3190, 2918, 2228,

2199, 1679, 1653, 1602, 1498, 1456, 1416, 1332, 762 cm-1;

1H NMR (300 MHz, CDCl3): δ = 2.05 (m, 2H, -CH2-CH2-

CH2), 2.37(t, 2H, -CH2), 2.61 (t, 2H, CO-CH2), 4.47 (s, 1H),

4.66 (s, 2H, NH2), 7.37(d, J=8 Hz, 2H, Ar-H), 7.59(d, J=8

Hz, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): δ 20.09,

27.04, 35.73, 36.61, 100, 110, 114.31, 118.41, 119.81,

128.82, 132.64, 148.61, 158, 163.89, 195.84.

2-amino-4-(ferrocenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile

(entry 4n, table 2):

Mp. 200-202 oC; IR (KBr): 3378, 3177, 2959, 2185,1678,

1645, 1602, 1332, 1216, 1030, 808, 699 cm-1; 1H NMR

(300 MHz, CDC13): δ = 0.96 (s, 3H,CH3), 1.08 (s, 3H,

CH3), 2.26 (s, 2H, -CH2), 2.32 (s, 2H, -CH2), 3.87 (s, 1H, -

C5H5), 4.02(s, 1H, -C5H5), 4.08 (s, 1H, -C5H5), 4.22 (s, 5H,

-C5H5), 4.36 (s,1H, -CH), 4.68 (s, 2H, NH2); 13C NMR (75

MHz, CDCl3): δ 27.21, 28.45, 29.03, 32.13, 40.61, 50.76,

61.11, 65.73, 66.70, 66.99, 68.09, 69.14, 93.41, 100.00,

160.07, 161.46, 196.18.

O

O NH2

CN

CN

Fe

O

O

NH2

CN


69

SPECTRAS


70


71


72


73


74


75


76


77


78


79


80


81


82


83


84


85

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