chapter 2: multi-component synthesis of tetrahydrobenzo[b...
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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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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++
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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-
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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.
Chapter 2: 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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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].
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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.
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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,
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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.
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
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
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
69
SPECTRAS
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
70
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
71
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
72
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
73
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
74
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
75
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
76
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
77
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
78
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
79
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
80
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
81
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
82
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
83
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
84
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
85
References:
[1] a)
b)
c)
E. A. Couladourous, A. T. Strongilos, Angew. Chem. Int. Ed. 2002, 41,
3677.
Z. Gan, P. T. Reddy, S. Quevillon, S. Couve-Bonnaire, P. Arya, Angew.
Chem. Int. Ed. 2005, 44, 1366.
Comprehensive heterocyclic chemistry ; A. R. Katritzky, C. W. Rees, Eds.;
Pergamon; Oxford, 1984, 3, 737.
[2] Fang, X.; Liu, Y. C.; Li, C. J. Org. Chem. 2007, 72, 8608-8610.
[3] Green, G. R.; Evans, J. M.; Vong, A. K. Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.V., (Eds.);
Pergamon Press: Oxford, 1995, 5, 469.
[4] a)
b)
c)
d)
Foye, W. O. Prinicipi di Chemico Farmaceutica; Piccin: Italy. 1991, 416.
Andreani, L. L.; Lapi, E. Bull. Chim. Farm. 1960, 99, 583.
Zhang, Y. L.; Chen, B. Z.; Zheng, K. Q.; Xu, M. L.; Lei, X. H.; Bao, Y. X.
X. 1982, 17,17; Chem. Abstr. 1982, 96, 35383e.
Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med. Chem.1993,
28, 517;
Witte, E. C.; Neubert, P.; Roesch, A. Ger. Offen DE. 1986, 3427985; Chem.
Abstr. 1986, 104, 224915f.
[5] Konkoy, C. S.; Fick, D. B.; Cai, S. X.; Lan, N. C.; Keana, J. F. W. PCT Int.
Appl. 2000, WO 0075123; Chem. Abstr.2001, 134, 29313a.
[6] Arnesto, D.; Horspool, W. M.; Martin, N.; Ramos, A.; Seaone, C. J. Org.
Chem. 1989, 54, 3069.
[7] a)
b)
Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J. Chem. Soc., Chem.
Commun. 1988, 202.
Gonzalez, R.; Martin, N.; Seoane, C.; Soto, J. J. Chem. Soc., Perkin Trans.1
1985, 1202.
[8] a)
b)
Martin, N.; Martin, G.; Seoane, C.; Maco, J. L.; Albert, A.; Cano, F. H. Ann.
Chem. 1993, 7, 801.
Maco, J. L.; Martin, N.; Grau, A. M.; Seoane, C.; Albert, A. Cano, F. H.
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
86
Tetrahedron 1994, 50(11), 3509.
[9] Tu, S. J.; Liu, X. H.; Ma, H. J.; Shi, D. Q.; Liu, F. Chinese Chem. Lett. 2002,
13(5), 393.
[10] Muller, F. L.; Simon C.; Constantieux, T.; Rodriguez J. QSAR Comb. Sci.
2006, 25, 43.
[11] Xi, Z. L.; Huang, Y.; Li, Y. L.; Zheng W. J. Monatsh. fur. Chemie. 2008, 139,
129.
[12] Balalaie, S.; Abdolmohammadi S.; Bijanzadeh H. R.; Amani A. L. Mol.
Divers. 2008,12, 85.
[13] Jayashree, P.; Shanthi, G.; Perumal P. T. Synlett 2009, 6, 917.
[14] a)
b)
c)
d)
Litvinov, Y. M.; Shestopalov, A. A.; Rodinovskaya L. A.; Shestopalov A. M.
J. Comb. Chem. 2009, 11(5), 914.
Kumaravel K.; Vasuki G. Green Chem. 2009, 11, 1945.
Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov, A. A.; Rodinovskaya,
L. A.; Niazimbetova, Z. I.; Evans, D. H. Org. Lett. 2002, 4 (3), 423.
Gogoi, S.; Zhao, C. G. Tetrahedron Lett. 2009, 50(19), 2252.
[15] Luo, S. P.; Li, Z. B.; Wang, L. P.; Guo, Y.; Xia A. B.; Xu, D. Q. Org. Biomol.
Chem. 2009, 7, 4539.
[16] Rao, H. S.; Geetha, K. Tetrahedron Letters 2009, 50, 3836.
[17] Nagarajun P. S.; Thelagathoti H. B.; Perumal P. T. Tetrahedron 2009, 65(41),
8524.
[18] Li, Y.L.; Chen, H.; Zeng, Z. S.; Wang, X. S.; Shi, D. Q.; Tu, S. J. Chinese
Jour. Org. Chem. 2005, 25 (7), 846.
[19] Wang, X. S.; Shi, D. Q.; Li, Y. L.; Chen, H.; Wei, X.Y.; Zong, Z. M. Synth.
Commun. 2005, 35 (1), 97.
[20] Zhang, P.; Yu, Y. D.; Zhang, Z. H. Synth. Commun. 2008, 38(24), 4474.
[21] Gowravaram, S.; Arundhathi, K.; Sudhakar, K.; Sastry, B. S.; Yadav, J. S.
Synth. Commun. 2008, 38(20), 3439.
[22] Maheswara, M.; Siddaiah, V.; Damu, G. L. V.; Rao, Y. K.; Rao, C. V. J.
Mol. Catal. A: Chem. 2006, 255, 49.
[23] Hekmatshoar, R.; Rezaei, A.; Shirazi-Beheshtiha, S. Y Phosphorus Sulfur
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
87
Silicon Relate. Element. 2009,184, 2491.
[24] Quezada, E.; Delogu, G.; Picciau, C.; Santana, L.; Podda, G.; Borges, F.;
García-Morales, V.; Orallo, F. Molecules 2010, 15 (1), 270.
[25] Dittmer, D. C.; Li, Q.; Avilov, D. V. J. Org. Chem. 2005, 70(12), 4682. [26] Valizadeh, H.; Vaghefi, S. Synth. Commun.2009, 1(39), 1666. [27] a)
b)
c)
d)
e)
f)
Bandgar, S. B.; Bandgar, B. P.; Korbad, B. L.; Totre, J. V.; Patil, S. Aust.
Jour. Chem. 2007, 60(4), 30.
Saini, A.; Kumar, S.; Sandhu, J. S. Synlett 2006, 1928.
Bhosale, R. S.; Magar, C. V.; Solanke, K. S.; Mane, S. B.; Choudhary, S. S.;
Pawar, R. P. Synth. Commun. 2007, 37, 4353.
Seifi, M.; Sheibani, H. Catal. Lett. 2008, 126, 275.
Wang, L. M.; Shao, J. H.; Tian, H.; Wang, Y. H.; Liu, B. J. Fluorine Chem.
2006, 127, 97.
Balalie, S.; Bararjanian, M.; Sheikh-Ahmadi, M.; Hekmat, S.; Salehi, P.
Synth. Commun. 2007, 37, 1097. [28] a)
b)
c)
Tu, S. J.; Gao, Y.; Guo, C.; Shi, D.; Lu, Z. Synth. Commun.2002, 32, 2137.
El-Rahaman, N. M. A.; El- Kateb, A. A.; Mady, M. F. Synth. Commun. 2007,
37(22), 3961.
Saini, A.; Kumar, S.; Sandhu, J. S. Synlett 2006, 1928. [29] a)
b)
Tu, S. J.; Jiang, H.; Zhuang, Q. Y.; Miao, C. B.; Shi, D. Q.; Wang, X. S.;
Gao, Y. Chin. J. Org. Chem. 2003, 23, 488.
Li, J. T.; Xu, W. Z.; Yang, L. C.; Li, T. S. Synth.Commun. 2004, 34, 4565. [30] Fotouhi, L.; Heravi, M. M.; Fatehi, A.; Bakhtiari, K. Tetrahedron Lett. 2007,
48, 5379. [31] Lian, X. Z.; Huang, Y.; Li, Y. Q.; Zheng, W. J. Monatsh. Fur. Chimie 2008,
139, 129. [32] Balalaie, S.; Bararjanian, M.; Amani, A. M.; Movassagh B. Synlett 2006, 2,
263. [33] Guo, S. B.; Wang, S. X.; Li, J. T. Synth. Commun. 2007, 37, 2111. [34] Desai, U. V.; Pore, D. M.; Mane, R. B.; Solabannavar, S. B.; Wadgaonkar, P.
P. Synth. Commun. 2004, 34, 25. [35] Desai, U. V.; Pore, D. M.; Mane, R. B.; Solabannavar, S. B.; Wadgaonkar, P.
P. Synth. Commun. 2004, 34, 19.
Chapter 2: Multi-Component Synthesis of Tetrahydrobenzo[b]pyrans
88
[36] Pore, D. M.; Desai, U. V.; Thopate, T. S.; Wadgaonkar P. P. Rus. J. Org.
Chem. 2007, 7( 43),1088. [37] Pore, D. M.; Soudagar, M. S.; Desai, U. V.; Thopate, T. S.; Wadagaonkar, P.
P. Tetrahedron Lett. 2006, 47, 9325.