KF-Al2O3 Promoted Synthesis of Fully Substituted

Letters in Organic Chemistry, 2007, 4, ???-???

1

KF-Al2O3 Promoted Synthesis of Fully Substituted New Indeno- and Naphtho- Fused Thiophenes Under Solvent-Free Conditions by Controlled Microwave Heating Firouz Matloubi Moghaddam*, Hamdollah Saeidian, Zohreh Mirjafary and Azam sadeghi Sharif University of Technology, Department of Chemistry, P. O. Box 11155-9516 Tehran, Iran Received April 02, 2007: Revised July 21, 2007: Accepted September 13, 2007

Abstract: KF-Al2O3 catalyzes the reaction of arylthioacetamides with -bromo ketones to give fully substituted new indeno- and naphtho- fused thiophenes with good yields under solvent-free conditions by controlled microwave heating. A mechanism is proposed for the reaction course.

Keywords: 2-Aminothiophenes, KF-Al2O3, Controlled microwave heating, Interamolecular aldol condensation. 1. INTRODUCTION

thesis. Several recent articles have reviewed this field [2]. The strongly basic nature of KF-Al2O3, allows it to replace organic bases in a number of reactions such as N-alkylation of amides [3], epoxidations [4], Suzuki couplings [5] and

KF-Al2O3 was introduced by Clark [1] as solid base and has been applied as catalyst to a wide variety of organic syn-

O Br Ar 2 N

X

N

X

S

KF-Al2O3 MW

5a-5g

O Br X + S8 O

MW 10min X= CH2, O Ar= phenyl, 4-methylphenyl, 4-chlorophenyl, 4-biphenyl, 4- pyridyl,

3

N

Ar

Ar

Ar

X

N H

KF-Al2O3

S

S

MW

5h-51

1

O Br Br Br

Ar 4 N KF-Al2O3 MW

X

S 5m-5q

Scheme 1.

*Address correspondence to these authors at the Sharif University of Technology, Department of Chemistry, P. O. Box 11155-9516 Tehran, Iran; E-mail: [email protected]

1570-1786/07 $50.00+.00

Knoevenagel reactions [6]. Since 1986 microwave-assisted organic synthesis showed a significant impact on synthetic organic chemistry. The advantages of the microwave irradiation includes not only improving classical reactions, but also

© 2007 Bentham Science Publishers Ltd.

2

Letters in Organic Chemistry, 2007, Vol. 4, No. 8

Moghaddam et al.

shortening reaction times, improving the yields, and suppressing byproduct formation as compared with conventional thermal heating [7]. There are many reports in the literatures about the synthesis of heterocyclic compounds by solid supports under microwave heating [7f], Whereas the synthesis of substituted thiophenes have received less attention under these conditions. Thiophene derivatives are important chemical building blocks, and variety of molecules containing the thiophene ring display a wide range of biological activity, which have found pharmaceutical applications [8]. Highly substituted thiophenes have attracted a great deal of interest, due to their presence in natural products [9], as novel conducting polymers [10], isosteric replacements for phenyl group in medicinal chemistry [11], and as optical chromophores [12]. However, the synthesis of highly substituted thiophenes is restricted by the lack of enough available methods to construct the desired ring bearing functional groups in a controlled fashion. The most convenient method for the preparation of thiophene with a high degree of functionality is by the Gewald method, in which elemental sulfur is reacted with an activated acetonitrile and an aldehyde, ketone or 1, 3-dicarbonyl compound in the presence of a base [13]. A modification of the Gewald method has been reported in which an alkoxyacetone is reacted with ethyl cyanoacetate, sulfur and morpholine producing alkoxy thiophene derivatives in poor yields (19-39%) [14]. The synthesis of substituted thiophenes based on Pdcatalyzed cycloisomerization of Z-2-en-4-yne-1-thiols has been reported [15], but this procedure suffers from poor substituents tolerance and reaction needs an expensive catalyst. New and improved methodologies have also been developed [16]. Recently we have reported a versatile one-pot synthesis of trisubstituted thiophenes from thiomorpholides via SClaisen rearrangement [17]. Aryl thioacetamides are easily available starting materials by our methods [18]. The availability of such aryl thioacetamides provided a unique opportunity of examining further their synthetic utility. In continuation of our research in this area and to explore potential ability of microwave irradiation as an energy source for organic synthesis with the use of solid support reagents in solvent-free conditions and aiming to find new biologically active thiophene heterocyclic compounds, such as 2Table 1.

aminothiophene derivatives [19], herein we report a new and efficient KF-Al2O3 catalyzed solvent-free protocol for the synthesis of fully substituted new indeno- and naphtho-fused 2-aminothiophenes under controlled microwave heating (Scheme 1). 2. RESULTS AND DISCUSSIONS The reaction of biphenylthioacetomorpholide with 2bromoindanone was selected as model. First experiments focused on the optimized of the amount of KF-Al2O3. The results are summarized in the Table 1. The reaction of biphenylthioacetomorpholide with 2-bromoindanone was selected as model. First experiments focused on the optimized of the amount of KF-Al2O3. The results are summarized in the Table 1. We found that 0.25g of KF-Al2O3 could effectively catalyze the reaction for 1mmol of biphenylthioacetomorpholide and 1mmol 2-bromoindanone to produce the desired product (Table 1, entry 3). Using more KF-Al2O3 has less effect on the yield and time of the reaction (Table 1, entry 1, 2). As shown in Table 1, the use of KF- Al2O3, as a solidphase support for solventless reactions under controlled microwave heating, offers a convenient, environmentally friendly alternative to conventional reactions (Table 1, entry 1, 2, 3, 4,). Clearly, the reaction time by controlled microwave heating has been reduced 60 times with higher yield than conventional heating (64% versus 55%, Table 1 entry 3, 7). Since the product of interest is not covalently bound to the solid support, monitoring of the reactions and analysis can be accomplished by using standard methods (thin layer chromatography, column chromatography, 1H NMR, etc.). Finally, the products are isolated by column chromatography, eliminating the need for a cleavage step that is required in solid phase synthesis. To generalize this methodology, we subjected a series of arylthioacetamides with -bromo ketones to obtain the corresponding 2-aminothiophenes under the optimized reaction conditions (Table 2, 3, 4). As it is shown, 2-aminothiophens were obtained under microwave heating with high yields (63-90%) and very short time (57min), in comparison to conventional heating methods. The products were characterized by spectroscopic methods (1H-NMR, 13C-NMR, DEPT 90, DEPT 135, and GCMS). 5m-5o derivatives are well-known in the literature

The Reaction of Biphenylthioacetamide with 2-Bromoindanone Under Different Conditions

Entry

Catalyst(g)

Mode of heating

Solvent

Temperature(ºC)

Time(min)

Yield%

1

KF-Al2 O3(1)

MW

Solvent-free

80

7

71

2

KF-Al2 O3(0.5)

MW

Solvent-free

80

7

69

3

KF-Al2 O3(0.25)

MW

Solvent-free

80

7

64

4

KF-Al2 O3(0.25)

MW

Solvent-free

60

7

59

5

KF-Al2 O3(0.25)

MW

C6H5CH 3

80

7

56

6

KF-Al2 O3(0.25)

MW

CH2Cl2

50

7

45

7

KF-Al2 O3(0.25)

C6H5CH 3

80

420

55

8

KF-Al2 O3(0.25)

CH2Cl2

50

420

40

KF-Al2 O3 Promoted Synthesis of Fully Substituted

Table 2.


Synthesis of Fully Substituted New Indeno- Fused Thiophenes Under Controlled Microwave Heating and Conventional Heating O

Ar

X Br

+

N

Ar S

KF-Al2O3

N

X

S

microwave heating 5 min or conventional heating 7-8 h

5a-5g

Yield % (Time) Entry

5a

Ar

phenyl

X

Products

O

N

MW(min)

(h)

66(5)

54(8)

63(5)

50(8)

71(5)

57(8)

70(5)

60(7)

74(5)

63(7)

71(5)

64(7)

O

S

CH3

5b

4-methylphenyl

O

N

O

S Cl

5c

4-chlorophenyl

O

N

O

S

5d

4-biphenyl

O

N

O

S N

5e

4-pyridyl

O

N

O

S

5f

3

phenyl

CH2

N S

4


Moghaddam et al.

(Table 2). Contd…..


Ar

X

Products MW(min)

(h)

81(5)

69(7)

N

5g

4-pyridyl

CH2

N S

Table 3.

Synthesis of Fully Substituted New Naphtho- Fused Thiophenes Under Controlled Microwave Heating and Conventional Heating

O X

Br +

N

Ar

KF-Al2O3 N

microwave heating 5 min or conventional heating 7 h

S

O

S 5h-5l


5h

Ar

phenyl

X

Products

O

N

MW(min)

(h)

64(5)

53(7)

69(5)

54(7)

73(5)

59(7)

78(5)

63(7)

O

S Cl

5i

4-chlorophenyl

O

N

O

S

5j

4-biphenyl

O

N

O

S

5k

phenyl

CH2 N S



5



Ar

X

Products MW(min)

(h)

90(5)

67(7)

N

5l

4-pyridyl

CH2

N S

Table 4.

Synthesis of Tri Substituted Thiophenes Under Controlled Microwave Heating and Conventional Heating

O X

Br +

KF-Al2O3

N

Ar

N

microwave heating 7 min or conventional heating 7 h

S

O

S 5m-5q


Ar

X

Products MW(min)

(h)

66(7)

54(7)

64(7)

55(7)

76(7)

55(7)

77(7)

60(7)

Br 5m

phenyl

O

N

O

S

5n

4-biphenyl

O

Br

N

O

S Cl

Br 5o

4-chlorophenyl

O

N

O

S

Br 5p

phenyl

CH2

N S

6


Moghaddam et al.



Ar

X

Products MW(min)

(h)

87(7)

62(7)

N Br 5q

4-pyridyl

CH2

N S

[19a] and were identified by comparison of their physical and spectral data with those of authentic simples.

compound 7. Formation of 6 and 7 could confirm the proposed reaction mechanism.

Synthesis of tetra-substituted thiophenes proceeded more conveniently using thioamides with heteroaromatic substitutes such as 4-pyridyl (entries 5e, 5g, 5l and 5q Table 2) in high yields.

In conclusion, the alumina-supported potassium fluoride shows high catalytic activities for the synthesis 2aminothiophenes under solvent-free conditions by controlled microwave heating. This procedure offers several advantages including low loading of catalyst, high yields, clean reaction, and use of various arylthioacetamides, which make it a useful and attractive strategy for the synthesis of 2aminothiophenes. In addition, a very easy workup has been realized that does not require organic solvents. The generality of the method has been demonstrated by the successful conversion of seventeen substrates into fully substituted 2aminothiophenes in good yields. These materials have the potential to be used as new reagents for the synthesis of heterocyclic compounds.

A proposed mechanism for the reaction course is shown in Scheme 2. Arylthioacetamides undergoes an S-alkylation with -haloketone affording the iminium ions I, then subsequent treatment with KF-Al2O3 leading to cyclization and formation of thiophenes ring with elimination of water. It is seen that KF-Al2O3 is suitable not only for the abstraction of proton from 1-alkynes (pKa= 25), but also for the activation of carbonyl groups of aldehydes and ketones [2e]. This means that KF-Al2O3 can activate species II, therefore interamolecular aldol condensation is desirable. Final dehydration can be supported by the literature analogy [20]. To confirm the proposed mechanism, the reaction of the biphenylthioacetomorpholide with 2-bromo-(4- acetophenone) in the presence a trace amount of H2O was studied for trapping the iminium ion I (Scheme 3). Indeed, the Iminium ion I was hydrolyzed by the presence of water in the reaction medium to thioester 6, then thioester 6 was isolated and its structure was confirmed (see experimental section). Elimination of water from molecule 6 afforded the cyclized

3. EXPERIMENTAL The compounds gave all satisfactory spectroscopic data. A Bruker (DRX-500 Avanes) NMR was used to record the 1 H-NMR, 13C-NMR and DEPT 90 and DEPT 135 spectra. All NMR spectra were determined in CDCl3 at ambient temperature. Melting points were determined on a Buchi B540 apparatus. GC-MS (EI), 70ev, HP6890 Coulumn: HP-5 (30m H

O X

BrN

N

Br

Ar

O

X

S

Ar

KF-Al2O3 - HBr

S

I

Ar

Ar

H

Ar

HO

O N

N

X

X

S

S

HO KF-Al2O3

N S

H H

II Ar -H2O N S

Scheme 2.

X

X



7

Br O

O

S Br

N

O

S

MW

N+

+ Br

KF-Al2O3

Br

BrN

S

O O I

H2O

5n

KF-Al2O3

Br -H2O

O S O

Br 6

S

O

7

Scheme 3.

0.25mm 0.2uml MSD: HP5793) was used to record the mass spectra. The microwave-assisted reactions were performed in a microwave laboratory reactor (ETHOS. MR) producing controlled irradiation at 2450 MHz.

was added. The solvent was evaporated under vacuum and the reaction mixture was heated in a microwave cavity at 80ºC for 5-7 minute. After cooling, the residue was subjected to column chromatography (EtOAc/hexane; 1:10) on silica gel to obtain pure products.

Preparation of Catalyst The KF-Al2O3 support was prepared according to previously reported procedure [21] by some modification. A mixture of potassium fluoride (45g) and basic alumina (55g, type T, Merck) in water (100ml) was stirred at room temperature for 10 minutes. The resulting suspension was concentrated in vacuum and dried in a vacuum oven at 120ºC for 15h. Use of basic alumina in the solid support gave better results relative to the neutral one. Procedures for Preparation 2-aminothiophenes (5a-q) Under Conventional Heating To a stirred solution of an arylthioacetamide (1 mmol) in toluene (5 ml), KF-Al2O3 (0.25 g) was added. Then a solution of -bromo ketones (1 mmol) in toluene (2 ml) was added dropwise over 10min. The reaction mixture was heated at 80C for about 7-8 hours. Then, the solvent was evaporated and the residue was subjected to column chromatography (EtOAc/Hexane; 1:10) on silica gel to obtain pure products.

Spectroscopic Data for Compounds (5a-5q) 4-(3-Phenyl-8H-indeno[2,1-b]thien-2-yl)morpholine (5a): light yellow solid. Mp: 156-158ºC. 1H-NMR (500 MHz, CDCl3): = 7.65(d, J=8.9Hz, 2H), 7.53-7.49(m, 3H), 7.43(t, J=5.7Hz, 1H), 7.21-7.15(m, 3H), 3.86(s, 2H), 3.72(t, J= 4.6Hz, 4H), 2.69(t, J= 4.6Hz, 4H). 13C-NMR (125 MHz, CDCl3): =156.1(C), 146.3(C), 143.9(C), 140.3(C), 135.6(C), 135.5(C), 130.2(CH), 128.8(CH), 127.6(CH), 126.7(CH), 125.4(C), 124.9(CH), 124.7(CH), 119.9(CH), 67.1(CH2), 54.2(CH2), 35.5(CH2). MS (EI) m/z: 333(M+, 100), 274(30), 202(7), 136(7).

Procedure for Preparation 2-aminothiophenes (5a-q) Under Controlled Microwave Heating

4-(3-p-tolyl-8H-indeno[2,1-b]thien-2-yl)morpholine (5b): light yellow solid. Mp: 159-161ºC. 1H-NMR (500 MHz, CDCl3): = 7.52(d, J=7.8Hz, 2H), 7.48(t, J=7.8Hz, 1H), 7.31(d, J= 7.8Hz, 2H), 7.23-7.14(m, 3H), 3.84(s, 2H), 3.71(t, J=4.5Hz, 4H), 2.94(t, J= 4.5Hz, 4H), 2.48(s, 3H). 13C-NMR (125 MHz, CDCl3): =156.8(C), 146.3(C), 144.0(C), 140.5(C), 137.0(C), 135.2(C), 132.6(C), 130.1(CH), 129.4(CH), 126.6(CH), 125.2(C), 124.7(CH), 124.5(CH), 119.9(CH), 67.3(CH2), 54.1(CH2), 35.5(CH2), 21.8(CH3). MS (EI) m/z: 347(M+, 100), 288(27), 256(12), 202(9), 136(11).

To solution of an arylthioacetamide (1 mmol) and KFAl2O3 (0.25 g) in CH2Cl2 (3 ml), -bromo ketone (1 mmol)

4-{3-(4-chloro Phenyl)-8H-indeno[2,1-b]thien-2yl}morpholine (5c): light yellow solid. Mp: 192-194ºC. 1H-

8


NMR (500 MHz, CDCl3): = 7.58(d, J=6.5Hz, 2H), 7.517.48(m, 3H), 7.20-7.16(m, 3H), 3.58(s, 2H), 3.72(t, J=4.6Hz, 4H), 2.93(t, J=4.6Hz, 4H). 13C-NMR (125 MHz, CDCl3): =157.4(C), 146.2(C), 143.5(C), 140.1(C), 135.7(C), 134.1(C), 133.2(C), 131.5(CH), 128.9(CH), 126.7(CH), 124.9(CH), 124.7(CH), 124.1(C), 119.7(CH), 67.2(CH2), 54.2(CH2), 35.5(CH2). MS (EI) m/z: 369(M+2, 35), 367(M+, 100), 308(25), 274(12), 256(12), 202(9). 4-{3-(1-biphenyl-4-yl)-8H-indeno[2,1-b]thien-2yl}morpholine (5d): light yellow solid. Mp: 168-170ºC. 1HNMR (500 MHz, CDCl3): = 7.78-7.72(m, 6H), 7.557.41(m, 4H), 7.32(t, J= 5.5Hz, 1H), 7.18-7.16(m, 2H), 3.87(s, 2H), 3.74(t, J= 4.6Hz, 4H), 2.98(t, J=4.6Hz, 4H). 13CNMR (125 MHz, CDCl3): = 157.3(C), 146.3(C), 143.8(C), 141.1(C), 140.4(C), 140.0(C), 135.5(C), 134.7(C), 130.6(CH), 129.3(CH), 127.7(CH), 127.4(CH), 127.2(CH), 126.7(CH), 124.9(C), 124.8(CH), 124.6(CH), 120.0(CH), 67.3(CH2), 54.2(CH2), 35.6(CH2). MS (EI) m/z: 409(M+, 100), 350(28), 323(11), 256(10). 4-{3-(4-pyridyl)-8H-indeno[2,1-b]thien-2-yl}morpholine (5e): light yellow solid. Mp: 183-185ºC. 1H-NMR (500 MHz, CDCl3): = 8.76(d, J=6Hz, 2H), 7.61(d, J=6Hz, 2H), 7.51(t, J=3Hz, 1H), 7.30-7.18(m, 3H), 3.85(s, 2H), 3.73(t, J=4.6Hz, 4H), 2.93(t, J=4.6Hz, 4H). 13C-NMR (125 MHz, CDCl3): = 158.9(C), 150.3(CH), 146.2(C), 144.0(C), 142.8(C), 139.7(C), 136.5(C), 126.8(CH), 125.1(CH), 125.0(CH), 124.8(CH), 122.7(C), 119.7(CH), 67.1(CH2), 54.4(CH2), 35.5(CH2). MS (EI) m/z: 334(M+, 100), 275(30), 248(20), 137(9). 4-(3-Phenyl-8H-indeno[2,1-b]thien-2-yl)piperidine (5f): light yellow solid. Mp: 125-127ºC. 1H-NMR (500 MHz, CDCl3): = 7.68(d, J=6.9Hz, 2H), 7.54-7.49(m, 3H), 7.41(t, J=6.2Hz, 1H), 7.28(t, J=4.1Hz, 1H), 7.18(d, J=4.2Hz, 1H), 7.15(d, J=4.1Hz, 1H), 3.85(s, 2H), 2.91(t, J=5.3Hz, 4H), 1.62-1.50(m, 6H). 13C-NMR (125 MHz, CDCl3): = 146.4(C), 143.6(C), 140.7(C), 136.1(C), 134.9(C), 130.4(C), 130.2(CH), 128.5(CH), 127.1(CH), 126.6(CH), 124.8(CH), 124.4(CH), 124.3(C), 119.9(CH), 55.5(CH2), 35.6(CH2), 26.4(CH2), 24.2(CH2). MS (EI) m/z: 331(M+, 100), 288(7), 274(27), 254(19), 221(20), 202(14).

Moghaddam et al.

128.7(CH), 128.3(CH), 127.2(CH), 126.4(CH), 126.1(CH), 125.2(CH), 67.3(CH2), 54.2(CH2), 30.7(CH2), 24.9(CH2). MS (EI) m/z: 347(M+, 100), 345(10), 288(16), 260(5), 215(3). 4-{1-(4-chlorophenyl)-4,5-dihydronaphtho[2,1-b]thien2-y1)morpholine (5i): light yellow solid. Mp: 131-133ºC. 1HNMR (500 MHz, CDCl3): = 7.45-7.35(m, 4H), 7.23(d, J=7.3Hz, 1H), 7.08(t, J=7.4Hz, 1H), 6.94(t, J=7.5Hz, 1H), 6.95(d, J=7.8Hz, 1H), 3.67(t, J=4.5Hz, 4H), 3.02(t, J=6.8Hz, 2H), 2.88(t, J=6.8Hz, 2H), 2.83(t, J=4.5Hz, 4H). 13C-NMR (125 MHz, CDCl3): = 171.7(C), 152.3(C), 136.2(C), 135.4(C), 133.0(C), 132.5(C), 132.4(C), 131.9(CH), 130.0(C), 128.9(CH), 128.4(CH), 126.5(CH), 126.3(CH), 125.1(CH), 67.3(CH2), 54.3(CH2), 30.6(CH2), 24.8(CH2). MS (EI) m/z: 383(M+2, 33), 381(M+, 100), 379(9), 322(9), 288(14), 258(10). 4-(1-Biphenyl-4-yl-4,5-dihydronaphtho[2,1-b]thien-2y1)morpholine (5j): light yellow solid. Mp: 191-193ºC. 1HNMR (500 MHz, CDCl3): = 7.75(d, J=7.8Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.59-7.47(m, 4H), 7.41(t, J=7.4Hz, 1H), 7.25(d, J=7.4Hz, 1H), 7.07(t, J= 7.4, 1H), 6.92(t, J=7.6, 1H), 6.77(d, J=7.8, 1H), 3.68(t, J=4.4Hz, 4H), 3.05(t, J=6.8Hz, 2H), 2.90-2.87(m,6H). 13C-NMR (125 MHz, CDCl3): = 152.1(C), 144.9(C), 141.1(C), 139.6(C), 136.2(C), 136.0(C), 132.7(C), 132.0(C), 130.9(CH), 129.2(CH), 129.1(C), 128.3(CH), 127.7(CH), 127.3(CH), 127.2(CH), 126.5(CH), 126.1(CH), 125.3(CH), 67.3(CH2), 54.2(CH2), 30.6(CH2), 24.9(CH2). MS (EI) m/z: 423(M+, 100), 421(14), 364(14). 4-(1-phenyl-4,5-dihydronaphtho[2,1-b]thien-2-y1) piperidine (5k): light yellow solid. Mp: 110-112ºC. 1H-NMR (500 MHz, CDCl3): = 7.43-7.33(m, 5H), 7.23(d, J=7.3Hz, 1H), 7.05(t, J=7.4Hz, 1H), 6.90(t, J=7.7Hz, 1H), 6.67(d, J=7.8Hz, 1H), 3.03(t, J=6.8Hz, 2H), 2.86(t, J=6.8Hz, 2H), 2.80(t, J=4.6Hz, 4H), 1.56-1.46(m, 6H). 13C-NMR (125 MHz, CDCl3): = 153.9(C), 137.4(C), 136.2(C), 133.0(C), 132.5(C), 131.5(C), 130.6(CH), 128.9(C), 128.5(CH), 128.3(CH), 127.0(CH), 126.5(CH), 125.9(CH), 125.2(CH), 55.6(CH2), 30.8(CH2), 26.4(CH2), 25.0(CH2), 24.3(CH2). MS (EI) m/z: 345(M+, 100), 343(17), 288(4), 215(5).

4-{3-(4-pyridyl)-8H-indeno[2,1-b]thien-2-yl}piperidine (5g): light yellow solid. Mp: 193-195ºC. 1H-NMR (500 MHz, CDCl3): = 8.76(m, 2H), 7.65(d, J=4.0Hz, 2H), 7.50(t, J=3.5Hz, 1H), 7.29(t, J=4.9Hz, 1H), 7.19(m, 2H), 3.84(s, 2H), 2.88(t, J=5.2Hz, 4H), 1.59(d, J=4.8Hz, 4H), 1.52(d, J=4.8Hz, 2H). 13C-NMR (125 MHz, CDCl3): =161.0(C), 150.1(CH), 146.3(C), 144.3(C), 142.6(C), 140.0(C), 135.9(C), 126.8(CH), 125.1(CH), 124.9(CH), 124.8(CH), 121.7(C), 119.7(CH), 55.7(CH2), 35.5(CH2), 26.3(CH2), 24.1(CH2). MS (EI) m/z: 332(M+, 100), 275(23), 254(17), 221(15).

4-(1-(4-pyridyl)-4,5-dihydronaphtho[2,1-b]thien-2y1)piperidine (5l): light yellow solid. Mp: 187-189ºC. 1HNMR (500 MHz, CDCl3): = 8.65(d, J=6.0Hz, 2H), 7.40(d, J=6.0Hz, 2H), 7.24(d, J=7.4Hz, 1H), 7.08(t, J=7.4Hz, 1H), 6.93(t, J= 7.6, 1H), 6.66(d, J=7.8Hz, 1H), 3.01(t, J=6.8Hz, 2H), 2.84(t, J=6.8Hz, 2H), 2.78(t, J=4.6Hz, 4H), 1.551.48(m, 6H). 13C-NMR (125 MHz, CDCl3): = 155.6(C), 150.1(CH), 145.5(C), 136.2(C), 132.8(C), 132.2(C), 131.8(C), 128.5(CH), 126.5(CH), 126.3(CH), 126.2(CH), 125.6(C), 125.2(CH), 55.9(CH2), 30.6(CH2), 26.3(CH2), 24.9(CH2), 24.1(CH2). MS (EI) m/z: 346(M+, 100), 345(22), 289(4), 230(6).

4-(1-phenyl-4,5-dihydronaphtho[2,1-b]thien-2y1)morpholine (5h): light yellow solid. Mp: 165-167ºC. 1HNMR (500 MHz, CDCl3): = 7.43-7.36(m, 5H), 7.23(d, J=7.4Hz, 1H), 7.07(t, J=7.4Hz, 1H), 6.90(t, J=7.7Hz, 1H), 6.66(d, J=7.8Hz, 1H), 3.66(t, J=4.5Hz, 4H), 3.04(t, J=6.8Hz, 2H), 2.90(t, J=6.8Hz, 2H), 2.85(t, J=4.5Hz, 4H). 13C-NMR (125 MHz, CDCl3): =151.9(C), 137.1(C), 136.1(C), 132.7(C), 132.6(C), 131.8(C), 130.5(CH), 129.6(C),

1-{4-(4-Bromo-phenyl)-3-phenyl-thiophen-2-ylpiperidine (5p): light yellow solid. Mp: 149-151ºC. 1H-NMR (500 MHz, CDCl3): = 7.33(d, J=8.4Hz, 2H), 7.30-7.20(m, 5H), 6.96(d, J=8.4Hz, 2H), 6.79(s, 1H), 2.85(t, J=4.6Hz, 4H), 1.58-1.50(m, 6H). 13C-NMR (125 MHz, CDCl3): = 157.3(C), 140.8(C), 136.9(C), 136.1(C), 131.4(CH), 130.9(CH), 130.6(CH), 128.4(CH), 127.7(C), 126.8(CH), 121.2(C), 114.1(CH), 55.0(CH2), 26.3(CH2), 24.3(CH2).


4-{4-(4-Bromo-phenyl)-2-piperidin-1-yl-thiophen-3-ylpyridine (5q): light yellow solid. Mp: 195-197ºC. 1H-NMR (500 MHz, CDCl3): = 8.50(d, J=4.9Hz, 2H), 7.39(d, J=8.2Hz, 2H), 7.20(d, J=4.9Hz, 2H), 6.96(d, J=8.2Hz, 2H), 6.82(s, 1H), 2.85(t, J=4.6Hz, 4H), 1.61-1.31(m, 6H). 13CNMR (125 MHz, CDCl3): = 159.4, 149.9, 144.3, 140.4, 136.2, 131.8, 130.9, 125.3, 124.8, 121.7, 115.2, 55.3, 26.2, 24.1. Biphenyl-4-yl-thioacetic acid S-[2-(4-bromo-phenyl)-2oxo-ethyl] ester (6): light yellow solid. Mp: 138-140 ºC. 1HNMR (500 MHz, CDCl3): = 7.86(d, J=8.4Hz, 2H), 7.63(d, J=8.4Hz, 2H), 7.60(m, 4H), 7.47-7.36(m, 5H), 4.33(s, 2H), 3.95(s, 2H). 13C-NMR (125 MHz, CDCl3): = 195.6(CO), 192.1(CO), 141.1, 141.0, 134.7, 132.7, 132.2, 130.4, 131.5, 129.3, 129.1, 127.9, 127.8, 127.5, 50.1, 36.7. 3-Biphenyl-4-yl-4-(4-bromo-phenyl)-5H-thiophen-2-one (7): light yellow oil. 1H-NMR (500 MHz, CDCl3): = 7.86(d, J=8.4Hz, 2H), 7.63(d, J=8.4Hz, 2H), 7.60(m, 4H), 7.477.36(m, 5H), 4.33(s, 2H), 3.95(s, 2H). 7.09-7.88(m, 5H), 7.73-7.61(m, 8H), 3.45(s, 2H).


[8] [9] [10] [11] [12] [13] [14] [15] [16]

REFERENCE [1] [2]

[3] [4] [5] [6] [7]

Clark, J. H. Chem. Rev., 1980, 80, 429. Clark, J. H.; Macquarrie, D.J. Org. Proc. Res. Dev., 1997, 1, 149; (b) Blass, E. B. Tetrahedron, 2002, 58, 9301; (c) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. J. Org. Chem., 2005, 70, 5320; (d) Kabashima, H.; Tsuji, H.; Nakata, S.; Tanaka, Y.; Hattori, H. Appl. Catal. A., 2000, 227, 194; (e) Kawanami, Y.; Yuasa, H.; Toriyama, F.; Yoshida, I. S.; Baba, T. Catal. Commun., 2003, 4, 455. Yamawaki, J.; Ando, T.; Hanafusa, T. Chem. Lett., 1981, 1143. Yadav, V. K.; Kapoor, K. K. Tetrahedron, 1996, 52, 3659. Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org. Lett., 1999, 1, 1423. Nakano, Y.; Shi, W.; Nishii, Y.; Igarashi, M. J. Hetrocycl. Chem., 1999, 36, 33. Loupy, A. Microwaves in organic synthesis, John Wiley-VCH: New York, 2002 ; (b) Xu, L. W.; Xia, C. G.; Li, J. W.; Li, F. W.;

[17] [18] [19]

[20] [21]

9

Zhou, S. L. Catal. Commun., 2004, 5, 121; (c) Perreux, L.; Loupy, A. Tetrahedron, 2001, 57, 9199; (d) Radoiu, M. T.; Hájek, M. J. Mol. Catal. A., 2002, 186, 121; (e) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett., 2002, 4, 1231; (f) Bougrin, K.; Loupy, A.; Soufiaoui, M. J. Photochem. Photobio. C., 2005, 6, 139; (g) Gold, H.; Ax, A.; Vrang, L.; Samuelsson, B.; Karlen, A.; Hallberg, A.; Larhed, K. M.; Anders, H.; Mats, L. Tetrahedron, 2006, 62, 4671. Gronowitz, S. The chemistry of Heterocyclic Compounds: Thiophenes and Its Derivatives; Ed.; Wiley: New York, 1991, 44. Koike, K.; Jia, Z.; Nikaib, T.; Liu Y.; Guo, D. Org. Lett., 1999, 1, 197. Roncali, J. Chem. Rev., 1992, 92, 711; (b) Press, J. B.; Pelkey, E. T. Progress in Heterocyclic chemistry; Gribble, G. W., Gilchrist, T. W., Eds.; Pergamon: New York, 1997, 9, 77. Jarvest, R. L.; Pinto, I. L.; Ashamn, S. M.; Dabrowsky, C. E.; Fernandez, A.V.; Jennings, L. J.; Bioorg. Med. Chem. Lett., 1999, 9, 443. Cheng, Z.; Harper, A. W.; Spells, D. S.; Dalton, L. R. Synth. Commun., 2000, 30, 1359. Gewald, K.; Schinke, E.; Bottcher H. Chem. Ber., 1966, 99, 94. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett., 2000, 41,1597. Gabriele, B.; Salerno, G.; Fazio, A. Organic Lett., 2000, 2, 351. Russell, R. K.; Press, J. B. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Padwa, A. Eds.; Pergamon: New York, 1996, 2, 679; (b) Kasano, Y.; Okada, A.; Hiratsuka D.; Oderaotoshi, Y.; Minakata, S.; Komatsu, M. Tetraedron, 2006, 62, 537. Matloubi Moghadam. F.; Zali- Boinee. H. Tetrahedron Lett., 2003, 44, 6253. Matloubi Moghadam. F.; Dekamin. M, G.; Ghafarzadeh, M. J. Chem. Res., 2000, 228; (b) Matloubi Moghadam. F.; Ghafarzadeh, M. Synth. Commun., 2001, 31, 317. Matloubi Moghadam. F.; Zali- Boinee. H. Tetrahedron, 2004, 60, 6085; (b) Matloubi Moghadam. F.; Zali- Boinee. H. Synlett, 2005, 1612; (c) Matloubi Moghadam. F.; Dekamin. M, G. Tetrahedron Lett., 2000, 41, 3479; (d) Matloubi Moghadam. F.; Porkaleh, H.; Zali- Boinee. H. Lett. Org. Chem., 2006, 3, 123; (e) Matloubi Moghadam. F.; Ismaili, H.; Rezanezad, G. Hetroatom Chem., 2006, 17, 136. Gal, J.; Weinkam, J. R.; Castagnoli, J. N. J. Org. Chem., 1974, 39, 418. Schmittiling, A. E.; Sawyer, J. S. Tetrahedron Lett., 1991, 32, 7207.