Organic Chemistry InternationalVolume 2012 (2012), Article ID 647386, 10 pagesdoi:10.1155/2012/647386

Research Article

Environmentally Benign Mortar-Pestle-Induced Acylation and O-Alkylation of Aromatic and Heteroaromatic Compounds under Solvent-Free Micellar Conditions and Computation of Their Drug Likeliness Properties

Kancharla Rajendar Reddy, Kamatala Chinna Rajanna, Kusampally Uppalaiah, Mukka Satish Kumar, and Marri Venkateshwarlu

Department of Chemistry, Osmania University, Hyderabad 500 007, India

Received 12 September 2012; Accepted 10 November 2012

Academic Editor: Paul Watts

Copyright © 2012 Kancharla Rajendar Reddy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Environmentally benign mortar-pestle-induced practical methods have been developed for the acylation and O-alkylation of aromatic and heteroaromatic compounds under solventfree micellar conditions, which were found to efficiently afford moderate to excellent yields of products.

1. Introduction

The diverse nature of chemical universe requires various green strategic pathways in our quest towards attaining sustainability. The emerging area of green chemistry envisages minimum hazard as the performance criteria while designing new chemical processes. One of the thrust areas for achieving this target is to explore alternative reaction conditions and reaction media to accomplish the desired chemical transformations with minimized byproducts or waste as well as eliminating the use of conventional organic solvents, wherever possible. Consequently, several newer strategies have appeared such as solvent-free reactions (grinding), multicomponent reactions under solvent-free conditions could enhance their efficiency from an economic as well as an ecological point of view the solid-state organic reactions is gaining significance both from the mechanistic and synthetic point of view [1–3]. Number of articles are available reporting solid-state reactions by grinding such as, Grignard reaction [4], Reformatsky reaction [5], Aldol condensation [6], Dickhmann condensation [7], phenol coupling reaction [8], reduction reaction [9], Wittig reaction [10], Grignard and McMurry reaction [11], and Synthesis of Polyhydroquinolines [12]. In recent past, our research group is actively involved in the exploration of in the exploration of nonconventional methods for nitration, bromination, acetylation, and benzylation reactions in the direction of achieving greenery conditions [13–16]. Most of these griding reactions are carried out at room temperature, absolutely solvent-free and use only a mortar and pestle and also economical and green procedures. Therefore, we focus on developing the novel procedure involving a solid-state reaction performed by grinding.

Alkylated and acylated aromatic and heteroaromatic compounds are significant precursors in drug intermediates and industrial uses [17]. Specifically naphthalene derivatives such as naphthol ethers and acylated naphthol ethers have been identified as one of the best ranges of potent antimicrobials effective against wide range of human pathogens. A perusal of literature indicated that Williamson synthesis is probably one of the most common classical methods being used for the preparation of symmetrical and unsymmetrical ethers [18–24]. Recent publications of Swamy et al. [25], Debabrata and coworkers [26, 27], provide excellent bibliography and information on the synthesis of aryl, heteroaryl ethers derived from various roots.

The Friedel-Crafts reaction has a long history in organic synthesis for electrophilic aromatic substitution reactions such as alkylations and acylations. To date these reactions are of great importance for the synthesis of aromatic carbonyl compounds [28]. Aromatic ketones can also be prepared by the reaction of carboxylic acids with aromatic hydrocarbons catalyzed by Nafion-H [29]. A significant number of Lewis acid catalysts (AlCl₃, FeCl₃, SnCl₄, and BF₃•OEt₂) have been shown to be very successful for the acylation of aromatic substrates with acid chlorides or anhydrides, while the reaction is usually carried out using a stoichiometric amount of AlCl₃, reactive aromatic compounds are known to undergo acylation in the presence of a catalytic amount of Lewis acid. Recently, several effective catalyst systems for the acylation of anisole and its derivatives have also been developed [30–34]. A perusal of literature indicated that surfactants have been used to promote a variety of synthetic organic reactions [35–37]. Our preliminary studies in this direction ended up with fruitful results when we have performed the title reactions in presence of micelle forming anionic (SDS), cationic (CTAB, CTAC), and non-ionic (Tx-100) surfactants. This study is aimed at developing “greener synthetic protocols” for etherification and acylation reactions under solvent-free conditions, as encouraged by the “Green Chemistry strategies” of Paul Anastas and Warner [38]. We have used mortar-pestle grinding technique in this study because it is economically cheap and safer method and yet is known to good yields of products in the synthesis of several organic compounds [1–3]. These reactions underwent dramatic rate accelerations under these conditions. We were also successful to develop solvent-free synthetic methods in the above protocols by replacing acids with a variety of micelle forming surfactants such as sodium dodecyl sulphate (SDS), cetyl trimethyl ammonium bromide (CTAB), cetyl trimethyl ammonium chloride (CTAC), and Triton-X 100.

2. Results and Discussion

Synthesis of naphthol ethers under Williamson’s conditions (refluxing in sulfuric acid and organic solvent) required several hours (≥20 h) at relatively high temperature. Even though there are some reports to modify the drastic conditions of these reactions, many of them exhibited long reaction times, accumulation of unwanted byproducts, which ultimately involved tedious work-up procedures. Encouraged by this aspect, we have conducted O-alkylation of aromatic and heteroaromatic alcohol reaction (Scheme 1) in micellar media under acid-free conditions.

Scheme 1: O-alkylation of Aromatic/heteroaromatic compounds in micellar media.

However, for comparison, we have also conducted etherification of β-naphthol reactions under Williamson’s classical conditions in acidic media. Results obtained under acidic and acid-free micellar conditions are compiled in Table 1 and O-alkylation of hydroxy pyridines in Table 2, and the reaction time versus conversion of aromatic/heteroaromatic alcohols using micelles as a catalyst were reported in Table 3, which clearly indicate highly significant rate accelerations followed by very good yield of end products. Catalytic activity of different micelles is in the order: CTAB > SDS > Tx-100. It is believed that micelles themselves act as micro-reactors. By introducing a surfactant (CTAB), dehydration was successfully achieved. The catalytic effect of the micellar solution of CTAB may be attributed to the hydrophobic nature of organic substrates. Formation of emulsion droplets takes place in water in the presence of surfactant and substrate molecules. It is suggested that most of the organic substrates are concentrated in these spherical droplets, which act as a hydrophobic reaction sites and results in an increase in the effective concentration of the organic reactants, which might increase the reaction rate via a concentration effect. In micellar solution, organic substrates are pushed away from water molecules towards the hydrophobic core of micelle droplets thus inducing efficient collisions between organic substrates which eventually enhance the reaction rates. The hydrophobic interior of the micelles swiftly excludes the water molecules generated during the reaction, thus shifting the equilibrium towards the desired product that ultimately leads to an increase in the reaction yield [39, 40]. This explanation is schematically represented in Figures 1 and 2.

Table 1: Mortar-pestle-induced O-alkylation of β-naphthols under solvent-free conditions.

Reactants
H₂SO₄ (5 hr)
CTAB(2 hr)
SDS(2.5 hr)
TX-100(3.0 hr)
M.P/B.P(°C)

1
2
% yield
% yield
% yield
% yield

β-Naphthol
MeOH
89
93
90
90
70-71

EtOH
90
93
90
90
35–37

1-PrOH
88
91
91
91
37–39

2-PrOH
91
94
91
91
—

1-Bromonaphthalen-2-ol
MeOH
90
91
89
90
80-81

EtOH
88
92
90
90
64–66

1-PrOH
88
96
90
89
—

2-PrOH
91
94
89
89
37–39

1-Chloronaphthalen-2-ol
MeOH
90
90
93
89
64-65

EtOH
90
90
92
90
56–58

1-PrOH
91
91
91
88
—

2-PrOH
91
91
94
91
—

1-Iodonaphthalen-2-ol
MeOH
90
89
91
90
87–89

EtOH
90
90
92
88
35–37

1-PrOH
89
90
96
88
37–39

2-PrOH
89
89
94
91
—

Table 2: Mortar-pestle-induced micellar mediated O-alkylation of hydroxy pyridines under solvent-free conditions.

Reactants
CTAB(1.5 hr)
SDS(2.0 hr)
TX-100(2.5 hr)

1
2
% yield
% yield
% yield

2-Hydroxy pyridine
MeOH
89
85
86

EtOH
90
87
87

1-PrOH
90
86
82

2-PrOH
90
87
89

3-Hydrox pyridine
MeOH
91
85
82

EtOH
89
84
81

1-PrOH
85
83
80

2-PrOH
89
85
79

4-Hydroxy pyridine
MeOH
91
88
81

EtOH
88
85
83

1-PrOH
88
83
82

2-PrOH
89
84
81

5-Bromopyrimidin-2-ol
MeOH
91
87
89

EtOH
89
87
87

1-PrOH
89
86
86

2-PrOH
91
84
86

6-Hydroxypicolinaldehyde
MeOH
92
88
89

EtOH
88
86
89

1-PrOH
87
85
84

2-PrOH
88
87
86

Table 3: Reaction of aromatic/heteroaromatic alcohol (10 mmol) with methanol (20 mmol) using micelles as catalysts.

Aromatic/heteroaromatic alcohol (1)
CTAB
SDS
TX-100

Time(min)
Conversion of 1 (%)
Time(min)
Conversion of 1 (%)
Time(min)
Conversion of 1 (%)

β-Naphthol
60
50
60
50
60
45

80
63
90
65
100
60

100
75
120
75
140
78

120
93
150
90
180
90

2-Hydroxy pyridine
60
60
60
55
60
50

70
73
90
68
90
65

80
81
120
77
120
77

90
89
120
85
150
86

Figure 1: Schematic diagram representing the role of micelles in the reaction.

Figure 2: Schematic diagram representing the role of CTAB in the reaction.

The Friedel-Crafts acylation of 2-methoxy naphthalene in the presence of the electron-donating group (OMe) must be taken into account in order to figure out the reaction. Presence of the electron-donating group activates the 1, 6, and 8 positions of the naphthalene ring.

The 1-position is more active than the other two positions and the 6-position is more stable than the other two positions, so acylation of 2-methoxynaphthalene generally occurs at this kinetically favoured 1-position at low temperatures and at the thermodynamically favoured 6-position at high temperatures. At high temperatures, in the reaction mixture, migration of the acyl group from 1- to 6-position which is named as transacylation and protiodeacylation of the acyl group at the 1-position of 1-acyl-2-methoxy naphthalene are possible. These two reactions may result in the formation of the thermodynamically favoured product which is 6-acyl-2-methoxynaphthalene. Steric hindrance to acylation is reported in the order 1 > 8 > 6-position (Das, 2000). Therefore, the isomerisation of the sterically hindered ketone 1-acyl-2-methoxynaphthalene to sterically less hindered isomers like 6-acyl-2-methoxy naphthalene and 8-acyl-2-methoxynaphthalene will be favoured.

Catalytic reaction of 1-halo-2-methoxy naphthalene (2 mmol) was treated with acylchloride (2 mmol) in the presence of CTAB or CTAC, (0.1 mmol, 5 mol%) were grounded with pestle for 2 hr it gave 6-acyl-1-halo-2-methoxynaphthalene(3) as the major product along with 8-acyl-1-halo-2-methoxy naphthalene(4) selectivity (98 : 02) represented as in Scheme 2, Table 4 and the reaction time versus conversion of 1-halo-2-methoxy naphthalenes using CTAB/CTAC (various amounts) as a catalyst were reported in Table 5.

Table 4: Reaction of 1-halo-2-methoxy naphthalene (2 mmol) with acylchlorides (2 mmol) using CTAB/CTAC as a catalyst.

Naphthalene
Acylchloride
Total (%) Yield
Products ratio (3 : 4)

93
98 : 02

1a

90
98 : 02

1a

89
98 : 02

1a

92
98 : 02

1a

90
98 : 02

1a

93
98 : 02

1a

94
98 : 02

2a
93
97 : 03

1b
2b
90
98 : 02

1b
2c
89
98 : 02

1b
2d
92
98 : 02

1b
2e
90
98 : 02

1b
2f
93
98 : 02

1b
2g
94
98 : 02

Duration of all reactions was 2 hr.

Table 5: Reaction of 1-halo-2-methoxynaphthalene (2 mmol) With 2g (2 mmol) using CTAB/CTAC (various amounts) as a catalyst.

Naphthalene
CTAB/CTAC(mmol)
Time(min)
Conversion of 1 (%)

1a
0.02
60
70

80
73

100
75

120
80

1a
0.04
60
72

80
78

100
82

120
85

1a
0.06
60
74

80
80

100
84

120
86

1a
0.08
60
76

80
83

100
86

120
90

1a
0.10
60
80

80
85

100
89

120
93

1b
0.02
60
70

80
75

100
78

120
83

1b
0.04
60
72

80
75

100
79

120
85

1b
0.06
60
74

80
79

100
80

120
87

1b
0.08
60
76

80
81

100
83

120
89

1b
0.10
60
80

80
85

100
88

120
93

Scheme 2: Acylation of 1-halo-2-methoxy naphthalenes in micellar media.

Mortar-pestle grinding synthetic methods were to avoid solvent. The reaction times fairly reduced from 24 h to about 2-3 h (under Williamson’s method to Mortar-pestle method) without many changes in the yield of products (Tables 1 and 2). Rate accelerations under grinding method could be attributed to bulk activation of molecules due to the conversion of mechanical energy (exerted due to grinding) into heat energy due to frictional forces operating between solid state reagents [1–3].

2.1. Calculation of Molecular Physicochemical Properties by Molinspiration

Drug likeness may be defined as a complex balance of various molecular properties and structure features which determine whether particular molecule is similar to the known drugs. These properties, mainly hydrophobicity, electronic distribution, hydrogen bonding characteristics, molecule size and flexibility, and various pharmacophoric features influence the behavior of molecule in a living organism, including bioavailability, transport properties, affinity to proteins, reactivity, toxicity, metabolic stability, and many others. Mol inspiration calculations are a set of simple molecular properties obtained by Lipinski Rule-5 of [41, 42], which are useful to explore drug likeliness nature of a molecule. Lipinski’s fifth rule states that a molecule possess “drug-likeliness” if the molecule has the properties: , molecular weight ≤500, number of hydrogen bond acceptors ≤10, and number of hydrogen bond donor’s ≤5. Molecules violating more than one of these rules may have problems with bioavailability. For the prediction of oral bioavailability of drug molecules [43], lipophilicity , and polar surface area (PSA) [44] values are the most important properties. The Calculated parameters from Mol inspiration methodology for each newly synthesized 6-acyl-1-halo-2-methoxynaphthalene derivative (entries 1 to 14) are compiled in Tables 6 and 7 and tested for specific activity with standard drugs Naproxen. For all the compounds, the calculated values were ≤5 (in comparison with the accepted the upper limit) indicating the ability of the drug to penetrate through biomembranes and also good water solubility (according to Lipinski’s rules). Further it is also interesting to note that all the synthesized molecules exhibit less than 140 PSA values indicating good intestinal absorption. Data presented in Table 7 are GPCR ligand activity, ion channel modulation, kinase inhibition activity, nuclear receptor ligand activity, Protease inhibitor, and Enzyme inhibitor are compared with Naproxen as standard drug indicate that most of the synthesized compounds depict by and large consistent negative values, which are in consonance with Lipinski’s Rule -5 and are also comparable with Naproxen drug.

Table 6: Molinspiration calculations of compounds.

S. number
6-Acyl-1-halo-2-methoxynaphthalene
M.Wt
miLog 
TPSA
OH–NH
-Vio
Volume

1
1-(1-Bromo-2-methoxynaphthalen-6-yl)ethanone
279.13
3.789
26.305
0
2
0

2
1-(1-Bromo-2-methoxynaphthalen-6-yl)pentan-1-one
321.21
5.356
26.305
0
2
1

3
1-(1-Bromo-2-methoxynaphthalen-6-yl)hexan-1-one
335.24
5.861
26.305
0
2
1

4
1-(1-Bromo-2-methoxynaphthalen-6-yl)-4-methylpentan-1-one
335.24
5.337
26.305
0
2
1

5
1-(1-Bromo-2-methoxynaphthalen-6-yl)-5-methylhexan-1-one
349.26
5.842
26.305
0
2
1

6
1-(1-Bromo-2-methoxynaphthalen-6-yl)-3,3-dimethylbutan-1-one
335.24
5.386
26.305
0
2
1

7
1-(1-Bromo-2-methoxynaphthalen-6-yl)-2-phenylethanone
355.23
5.217
26.305
0
2
1

8
1-(1-Chloro-2-methoxynaphthalen-6-yl)ethanone
234.68
3.658
26.305
0
2
0

9
1-(1-Chloro-2-methoxynaphthalen-6-yl)pentan-1-one
276.76
5.225
26.305
0
2
1

10
1-(1-Chloro-2-methoxynaphthalen-6-yl)hexan-1-one
290.79
5.73
26.305
0
2
1

11
1-(1-Chloro-2-methoxynaphthalen-6-yl)-4-methylpentan-1-one
290.79
5.206
26.305
0
2
1

12
1-(1-Chloro-2-methoxynaphthalen-6-yl)-5-methylhexan-1-one
304.81
5.711
26.305
0
2
1

13
1-(1-Chloro-2-methoxynaphthalen-6-yl)-3,3-dimethylbutan-1-one
290.79
5.255
26.305
0
2
1

14
1-(1-Chloro-2-methoxynaphthalen-6-yl)-2-phenylethanone
310.78
5.086
26.305
0
2
1

STD
Naproxen
264.70
3.983
46.533
1
3
0

Table 7: Drug likeness of compounds.

S. number
6-Acyl-1-halo-2-methoxynaphthalene
GPCRL
ICM
KI
NRL

1
1-(1-Bromo-2-methoxynaphthalen-6-yl)ethanone
−0.56
−0.51
−0.71
−0.57

2
1-(1-Bromo-2-methoxynaphthalen-6-yl)pentan-1-one
−0.18
−0.36
−0.42
−0.20

3
1-(1-Bromo-2-methoxynaphthalen-6-yl)hexan-1-one
−0.13
−0.34
−0.35
−0.14

4
1-(1-Bromo-2-methoxynaphthalen-6-yl)-4-methylpentan-1-one
−0.14
−0.33
−0.39
−0.14

5
1-(1-Bromo-2-methoxynaphthalen-6-yl)-5-methylhexan-1-one
−0.09
−0.31
−0.34
−0.08

6
1-(1-Bromo-2-methoxynaphthalen-6-yl)-3,3-dimethylbutan-1-one
−0.19
−0.27
−0.46
−0.32

7
1-(1-Bromo-2-methoxynaphthalen-6-yl)-2-phenylethanone
−0.06
−0.30
−0.24
−0.05

8
1-(1-Chloro-2-methoxynaphthalen-6-yl)ethanone
−0.50
−0.22
−0.67
−0.49

9
1-(1-Chloro-2-methoxynaphthalen-6-yl)pentan-1-one
−0.13
−0.12
−0.39
−0.14

10
1-(1-Chloro-2-methoxynaphthalen-6-yl)hexan-1-one
−0.08
−0.11
−0.32
−0.08

11
1-(1-Chloro-2-methoxynaphthalen-6-yl)-4-methylpentan-1-one
−0.10
−0.10
−0.37
−0.08

12
1-(1-Chloro-2-methoxynaphthalen-6-yl)-5-methylhexan-1-one
−0.04
−0.09
−0.31
−0.02

13
1-(1-Chloro-2-methoxynaphthalen-6-yl)-3,3-dimethylbutan-1-one
−0.14
−0.04
−0.43
−0.26

14
1-(1-Chloro-2-methoxynaphthalen-6-yl)-2-phenylethanone
−0.02
−0.10
−0.21
0.00

STD
Naproxen
−0.06
0.00
−0.36
0.18

GPCR: ligand, ICM: Ion channel modulator, KI: Kinase inhibitor, NRL: Nuclear receptor ligand.

3. Conclusions

There are different shades of greener processes as we continue exploring several alternatives to conventional chemical transformations. That approach will require new environmentally benign syntheses of O-alkylation and acylation of naphthalene derivatives in aqueous micellar media. Thus, the present protocols show rate accelerations associated with high products yields, when compared with the similar reactions performed under classical conditions. Surfactants catalyze the reaction efficiently with short reaction times without using any harmful organic reagents and solvents. Molecular properties computed from Molinspiration methodology for all the synthesized 6-acyl-1-halo-2-methoxynaphthalene derivatives by and large indicate Drug likeliness behavior that is comparable to standard drugs. Thus, it is believed that the present work is a major breakthrough in the area of synthesis of 6-acyl, 1-halo-2-methoxy naphthalenes with potential biological activity.

4. Experimental Details

All reactions were followed by TLC with detection by UV light. Melting points were recorded on BUCHI B-545 capillary melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded at a Varian VNMRS-400 and 100 MHz spectrometer. The Samples were analyzed in CDCl₃, DMSO-d₆ chemical shift values are reported in ppm relative to TMS as the internal reference. Mass spectra were recorded on a ZAB-HS mass spectrometer using ESI ionization. The isolation of pure products was carried out via preparative thin layer chromatography (silica gel 60 GF₂₅₄, Merck). Excess of solvent was evaporated under reduced pressure at a bath temperature of 50°C. All solvents, organic and inorganic compounds, were purchased from Aldrich, Merck, Fluka, and Sdfine and used without further purification.

4.1. General Procedure for Etherification of β-Naphthols under Mortar Pestle Conditions

A mixture of substrate (10 mmol), alcohol (20 mmol), and micelles (1.0 mmol, 25 mol %) were added to a mortar. The mixture was grounded by mortar and pestle at room temperature, after the indicated reaction time, the reaction mixture was purified by thin layer chromatography (silicagel, EtOAc-petroleum ether, 1 : 9) to obtain the desired product.

4.2. General Procedure for Acylation of β-Naphthols under Mortar Pestle Conditions

1-halo-2-methoxynaphthalene (2 mmol) and acylchloride (2 mmol) and CTAB (0.1 mmol, 5 mol %) were added to a mortar and grinded with pestle till the reaction is completed as ascertained by TLC. The final products were isolated by absorbing the reaction mixture into silica gel and purifying it by column chromatography using ethyl acetate/hexane gradient.

4.3. Spectroscopic Analysis of Representative Compounds

2-Methoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 3.91 (s, 3H), 7.15−7.17 (d, J = 8.8 Hz, 1 H), 7.29–7.36 (m, 2H), 7.43–7.47 (m, 1H), 7.72–7.77 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 55.6, 105.9, 113.7, 124.4, 126.2, 127.8, 128.2, 129.1, 129.9, 133.2, 153.8; IR (KBr, cm⁻¹) 3067, 3008, 2963, 1632, 1599, 1477, 1462, 1452, 1440, 1398, 1391, 1368, 1262, 1218, 1197, 1173, 1152, 1141, 1118, 1031, 1017, 963, 948, 874, 838, 818, 753, 743, 622, 481, 470; MS (EI) m/z 159.2 (M)⁺.

2-Ethoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 1.46 (t, J = 7.2 Hz, 3H), 4.127 (d, J = 6.8 Hz, 2H), 7.14–7.15 (d, J = 8.8 Hz, 1H), 7.28–7.39 (m, 2H), 7.39–7.43 (m, 1H), 7.69–7.75 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 14.8, 64.1, 106.5, 118.9, 123.4, 126.2, 126.7, 128.2, 129.1, 129.2, 133.6, 156.8; IR (KBr, cm⁻¹) 3067, 2984, 2940, 2876, 1829, 1601, 1579, 1511, 1457, 1440, 1395, 1390, 1367, 1358, 1350, 1269, 1259, 1185, 1166, 1144, 1122, 1046, 1020, 958, 928, 873, 823, 762, 719, 623, 477; MS (EI) m/z 173.2 (M)⁺.

2-Propoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 1.06 (t, J = 6.0 Hz, 3H), 1.83–1.86 (m, 2H), 4.01 (t, 2H), 7.10–7.14 (m, 2H), 7.30–7.41 (m, 2H), 7.69–7.74 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 10.5, 22.6, 69.4, 106.6, 119.1, 123.4, 126.2, 126.6, 127.6, 128.8, 129.3, 134.6, 156.7; IR (KBr, cm⁻¹) 3060, 2976, 2934, 2908, 2878, 1948, 1904, 1832, 1628, 1600, 1513, 1479, 1467, 1448, 1441, 1392, 1371, 1357, 1270, 1260, 1216, 1146, 1121, 1046, 1024, 1017, 1017, 986, 958, 916, 842, 819, 770, 746, 727, 727, 645, 623, 474; MS (EI) m/z 187.10 (M)⁺.

2-Isopropoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 1.45 (d, J = 6.0 Hz, 6H), 4.66–4.82 (m, 1H), 7.13–7.18 (m, 2H), 7.28–7.48 (m, 2H), 7.68–7.82 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 22.0, 69.8, 108.4, 119.7, 123.4, 126.2, 126.6, 127.6, 128.8, 129.3, 134.6, 155.7; IR (KBr, cm⁻¹) 3580, 2981, 2936, 2876, 1948, 1904, 1832, 1628, 1600, 1581, 1510, 1468, 1440, 1388, 1373, 1356, 1334, 1216, 1188, 1171, 1137, 1118, 1019, 974, 941, 900, 871, 842, 814, 675, 645, 623, 532; MS (EI) m/z 187.10 (M)⁺.

1-Chloro-2-methoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 3H), 7.25 (d, J = 8.6 Hz, 1H), 7.37–7.52 (m, 1H), 7.53–7.61 (m, 1H), 7.79–7.69 (m, 2H), 8.25 (d, J = 8.6 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 57, 105.9, 113.7, 124.4, 126.2, 127.8, 128.2, 129.1, 129.9, 133.2, 153.8; IR (KBr, cm⁻¹) 3430, 3049, 2972, 2948, 2846, 2541, 1948, 1763, 1625, 1590, 1505, 1469, 1355, 1337, 1273, 1246, 1187, 1148, 1068, 1018, 985, 894, 865, 804, 764, 740, 657, 588, 532; MS (EI) m/z 192 (M)⁺.

1-Bromo-2-methoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 4.04 (s, 3H), 7.28 (d, J = 8.6 Hz, 1H), 7.39–7.53 (m, 1H), 7.53–7.61 (m, 1H), 7.76–7.89 (m, 2H), 8.23 (d, J = 8.6 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 57.1, 105.9, 113.7, 124.4, 126.2, 127.8, 128.2, 129.1, 129.9, 133.2, 153.8; IR (KBr, cm⁻¹) 3430, 3045, 2970, 2941, 2841, 1620, 1594, 1500, 1466, 1454, 1351, 1334, 1270, 1245, 1185, 1153, 1134, 1061, 1021, 968, 890, 855, 803, 761, 743, 708, 644, 579, 516 cm⁻¹; MS (EI) m/z (M-H)⁺ 236.10.

1-Iodo-2-methoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 3H), 7.22 (d, J = 9.0 Hz, 1H), 7.34–7.42 (m, 1H), 7.50–7.56 (m, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 57.3, 87.8, 113.0, 124.4, 128.2, 128.3, 130.4, 131.3, 130.0, 135.7, 156.7; IR (KBr, cm⁻¹) 3042, 3006, 2969, 2937, 2838, 1617, 1587, 1551, 1497, 1451, 1423, 1346, 1328, 1263, 1242, 1181, 1153, 1132, 1058, 1021, 959, 887, 801, 761, 743; MS (EI) m/z 285.06 (M)⁺.

1-Bromo-2-ethoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 1.38–1.41 (t, J = 6.8 Hz, 3H), 4.13–4.14 (q, J = 6.8 Hz, 2H), 7.15–7.17 (d, J = 8.8 Hz, 1 H), 7.29–7.36 (m, 2H), 7.43–7.47 (m, 1H), 7.78–7.83 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 22.8, 64.6, 105.9, 113.7, 124.4, 126.2, 127.8, 128.2, 129.1, 129.9, 133.2, 153.8.

1-Bromo-2-propoxynaphthalene¹H NMR (400 MHz, CDCl₃) δ 1.03 (t, J = 7.5 Hz, 3H), 1.80–1.86 (m, 2H), 4.51 (t, 7.5 Hz, 2H), 7.10–7.14 (m, 2H), 7.30–7.41 (m, 2H), 7.69–7.74 (m, 3H); ¹³C NMR (50 MHz, CDCl₃) δ 10.5, 22.6, 78.4, 113.6, 123.4, 126.2, 126.6, 127.6, 128.8, 129.3, 131.3, 132.6, 154.7; MS (EI) m/z 266.04 (M)⁺.

1-Bromo-2-isopropoxy Naphthalene¹H NMR (400 MHz, CDCl₃) δ 1.45 (d, J = 6.0 Hz, 6H), 4.61–4.87 (m, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.39–7.53 (m, 1H), 7.53–7.61 (m, 1H), 7.76–7.85 (m, 2H), 8.23 (d, J = 8.6 Hz, 1H); ¹³C NMR (50 MHz, ) δ 22.0, 69.8, 108.4, 119.7, 123.4, 126.2, 126.6, 127.6, 128.8, 129.3, 134.6, 155.7; IR (KBr, cm⁻¹) 3580, 2981, 2936, 2876, 1948, 1904, 1832, 1628, 1600, 1581, 1510, 1468, 1440, 1388, 1373, 1356, 1334, 1216, 1188, 1171, 1137, 1118, 1019, 974, 941, 900, 871, 842, 814, 675, 645, 623, 532; MS (EI) m/z 266.10 (M)⁺.

4-Methoxy Pyridine¹H NMR (400 MHz, CDCl₃) δ 3.84 (s, 3H), 6.81 (d, J = 8.6 Hz, 2H), 8.43 (d, J = 8.6 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 55.1, 109.9, 151.4, 165.4, MS (EI) m/z 110.3(M)⁺, (B.P.168.2°C).

3-Methoxy Pyridine¹H NMR (400 MHz, CDCl₃) δ 3.84 (s, 3H), 7.34 (t, J = 8.65, J = 4.75 Hz, 1H), 7.38 (d, J = 8.65 Hz, 1H); 8.19 (d, J = 4.75 Hz, 1H); 8.32 (s, 1H); MS (EI) m/z 110.3(M)⁺, (B.P.168.4°C).

2-Methoxy Pyridine¹H NMR (400 MHz, CDCl₃) δ 3.94 (s, 3H), 6.72 (d, J = 8.65 Hz, 1H); 6.82 (t, J = 8.65, J = 4.75 Hz, 1H), 7.59 (t, J = 8.65, J = 4.75 Hz 1H); 8.18 (d, J = 4.75 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃) δ 53.1, 110.9, 116.4, 138, 147, 165.4, MS (EI) m/z 110.3 (M)⁺, (B.P.142.5°C).

4-Ethoxy Pyridine¹H NMR (400 MHz, CDCl₃) δ 1.34 (q, 2H), 3.94 (t, 3H), 6.81 (d, J = 8.4 Hz, 2H), 8.43 (d, J = 8.4 Hz, 2H); MS (EI) m/z 123.8(M)⁺, (B.P.165°C).

6-Methoxypicolinaldehyde¹H NMR (400 MHz, DMSO) δ 3.971 (s, 3H), 6.986 (d, J = 8.3 Hz, 1H), 8.108–8.136 (m, 1H), 8.770 (d, J = 2.5 Hz, 1H); 9.968 (s, 1H); MS (EI) m/z 137.9(M)⁺.

5-Bromo-2-methoxypyrimidine¹H NMR (400 MHz, DMSO) δ 3.915 (s, 3H), 8.765 (s, 2H); MS (EI) m/z 188.9(M)⁺.

1-(5-Bromo-6-methoxynaphthalen-2-yl)hexan-1-one¹H NMR (400 MHz, CDCl₃) δ 0.95 (t, J = 6.6 Hz, 3H), 1.38−1.42 (m, 4H), 1.93 (d, J = 7.7 Hz, 2H), 3.03 (t, J = 7.7 Hz, 2H), 4.02 (s, 3H), 7.28 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 8.04 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.41 (d, J = 8.7 Hz, 1H); IR (KBr) 3430, 3057, 3016, 2957, 2922, 2882, 2126, 1943, 1716, 1672, 1621, 1559, 1492, 1472, 1440, 1408, 1357, 1328, 1272, 1252, 1219, 1177, 1065, 965, 908, 863, 822, 801, 768, 732, 663, 596, 520, 467 cm⁻¹; MS (ES) m/z (337.0 M)⁺².

Acknowledgments

The authors are thankful to Professor P. K. Saiprakash for constant encouragement and Heads of the Chemistry Department at Osmania University and Nizam College, Hyderabad for providing facilities.

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