# Solvent-Free Microwave Synthesis of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides

Authors: Rukhsana I. Kureshy; Irshad Ahmad; Kavita Pathak; N. H. Khan; Sayed H. R. Abdi; H. C. Bajaj; Eringathodi Suresh
Journal: Research Letters in Organic Chemistry
 (2009)

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## Abstract

The ring opening reaction of aryloxyepoxides with isopropylamine under solvent-free microwave irradiation produced therapeutically usefulβ-blockers-aryloxypropanolamines in excellent yield (up to 98%) in 10 minutes which is considerably less than the time taken in classical heating (∼16 hours).


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## Body

## 1. Introduction

Aryloxypropanolamines are important
class ofβ-adrenergic blocking agents (β-blockers) and extensively used in medicinal chemistry for
the treatment of hypertension, angina pectoris, glaucoma, anxiety, and obesity [1, 2]. The oxirane ring [3] due to its inherent
polarity and strain is susceptible to the attack of nucleophiles to give propan-2-ol
3 (Scheme 1), which is known for their β-adrenoceptor antagonist
activity. One
of the most straightforward synthetic approaches for the preparation of β–blockers involves
the heating of epoxides with an excess of amines at elevated temperature [4–7]. In
recent years, various metal salts as catalysts have been reported for epoxide
ring opening reaction with amine and amine derivatives giving good-to-poor regioselectivity
[8–12].Scheme 1
Solvent-free microwave-assisted ring opening of aryloxyepoxides with isopropylamine.Microwave-assisted organic
synthesis is currently gaining ground in synthetic chemistry largely due to the
dramatic reduction in reaction time (from days or hours to minutes or
even seconds) and advancement in the need-based
design of microwave reactors [13, 14]. As a part of our ongoing research in ring opening of epoxides with amines [15–19], herein
we report solvent-free microwave-assisted synthesis of
aryloxypropanolamines by ring
opening of aryloxyepoxides with isopropylamine. Excellent
yields (up to 98%) of aryloxypropanolamines were achieved in shorter
time (10 minutes)  with substantially reduced quantity of amine as compared to
method used under classical thermal conditions [20]. Quanitiative yields of 2-aminoalcohols have been reported earlier in the ring opening of epoxides with aliphatic and aromatic amines using montmorillonite K-10, metal salts and metal salts supported on montmorillonite K-10 as catalyst  [21–23].


## 2. Results and Discussion

The ring opening of 3-(1-naphthoxy)-1,2-epoxy
propane1a with isopropylamine 2 in solvent-free condition was used as a representative reaction to see
the effect of strength of microwave wattage and duration of its
exposure on % yield of aryloxypropanolamine. Data from Table 1 shows that with an increase in microwave output power as
well as reaction time, there is an increase in the formation of the product
(Table 1, entries 2–9). Best result
(yield, 98%) was achieved in 10 minutes at 400 W of microwave output (Table 1,
entry 9) at 50°C temperature hence these conditions were used for
our rest of experiments with different aryloxyepoxides 1a–f to
give excellent yield (up to 98%) in 10 minutes (Figure 1). Main advantage of the
present microwave-assisted epoxide ring opening protocol lies in substantial
decrease in the quantity of isopropylamine (1.5 equivalent) as compared to the
classical approach where the amine was used in large excess (10–15 equivalents
at rt to reflux temperature)with
longer duration of reaction time 4-5 hours.Table 1
Ring opening of 3-(1-naphthoxy)-1,2-epoxy
propane1a with isopropylamine 2 under different conditions
(3-(1-naphthoxy)-1,2-epoxypropane (1.0 g, 5 mmol) and
isopropylamine (0.59 g,
7.5 mmol) were heated at 50°C in
a Teflon reactor for the given time under specified MW power).
EntryConditionsYield(a) (%)1(b)Without MW9022 min/100 W4532 min/300 W5642 min/400 W6455 min/100 W6965 min/400 W75710 min/100 W67810 min/300 W85910 min/400 W98(a)Isolated yield after chromatographic separation.(b)Reaction carried out for 16 hours.Figure 1
Ring opening of
aryloxyepoxides1a–f with
isopropylamine 2 under MW
irradiation.The regioselectivity of the product aryloxypropanolamines
was confirmed by NMR analysis of the
crude product. Single crystals X-ray analysis of representative products3c, 3d, and 3f
(Figure 1, entries 3, 4, 6) further confirmed that the desired regioisomers
(Figure 2) were obtained under our microwave-assisted solvent-free epoxide ring
opening reaction procedure.Figure 2
ORTEP diagram (50% probability factor for the thermal
ellipsoids) of compounds with atom numbering scheme.


## 3. Experimental

1H and 13C NMR spectra were
recorded on Bruker F113V. FTIR spectra were recorded on Perkin Elmer
Spectrum GX spectrophotometer in KBr window. Microanalysis was done on a Perkin Elmer model
2400 CHNS analyzer. High-resolution mass spectra were obtained with an
LC-MS (Q-TOF) LC (Waters), MS (Micromass) instruments. For the product purification, flash
chromatography was performed using silica gel 60–200 mesh. ETHOS 1600 Advanced
Microwave Lab station was used
to conduct experiment under microwave irradiation. CCDC-612074 to-612077 contains the supplementary crystallographic data in CIF
format for all the three compounds 3c, 3d, and 3f. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/datarequest/cif/.The aryloxyepoxides were synthesized
by the modified reported procedure [3d]  given as supplementary materials.


### 3.1. Procedure for The Preparation of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides under Solvent-Free Mw Irradiation

Aryloxyepoxides1a–f (5 mmol)
and isopropylamine 2 (7.5 mmol) were taken in a closed Teflon reactor.
The reactor was placed in a microwave oven at a selected power (400 W) for 10
minutes. After cooling the reactor to room temperature, excess amine was removed by distillation
under reduced pressure. The purification of the
reaction products was carried out by flash chromatography on silica gel using
CH2Cl2:MeOH (95:5), dried over anhydrous Na2SO4. All products 3a–f were
characterized by 1H and 13C NMR spectroscopy and data is given as follows.


#### 3.1.1. 1-[(1-Methylethyl) Amino]-3-(1-Naphthoxy)-2-Propanol (propranolol) (3a)

White Solid
Yield 1.27 g (98%); mp: 95–97°C; IR (KBr): ν  =  765 (CH wagging, NH bending), 1029 (CN
streching), 1582 (aromatic CC stretching), 2835 (CH stretch), 3271 (OH stretch) cm−1; 1H NMR (200 MHz, CDCl3): δ 8.22–8.27 (m, 1H, 8-CH),
7.75–7.80 (m, 1H, 11-CH),
7.29–7.48 (m, 4H, 7, 9,
10-, and 12-CH), 6.77 (d, 1H, J  =  7.4 Hz, 6-CH), 4.07–4.18 (m, 3H, OH, and
3-CH2), 2.75–3.0 (m, 5H, NH,
1-CH2, 2-CH, 2′-CH), 1.07 (d, 6H,
J  =  6.2 Hz, 3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 23.7 (2  ×  3′-CH3), 49.7 (2′-CH), 50.4 (1-CH2), 69.3
(2-CH), 71.6 (3-CH2), 105.8 (6-CH), 121.3 (12-CH), 122.6 (9-CH),
126.0 (11-CH), 126.4 (10-CH), 126.6 (8-CH), 127.1 (7a-c), 128.3(11a-c), 135.3
(7-CH), (155.2 5-C); LC-MS m/z 260 [M  +  H]; analytical calculation for C16H21NO2: C, 74.10; H, 8.16; N, 5.40 found C, 74.0; H,
8.10; N, 5.30.


#### 3.1.2. 1-[4-(2-Methoxyethyl) Phenoxy]-3-[(1-Methylethyl) Amino]-2-Propanol (metoprolol) (3b)

White Solid
Yield 1.249 g (97%); mp: 96–98°C;
IR (KBr): ν  =  828(CH
wagging, NH bending), 1113(CN streching), 1512(aromatic CC stretching), 2869(CH
stretch), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.2 Hz, 7- and 9-CH), 6.79 (d, 2H, J  =  8.2 Hz, 6- and 10-CH), 4.14 (m, 2H,
3-CH2), 3.90 (m, 3H, OH, NH, and 2′-CH), 3.53 (t, 2H, J
=  7.0 Hz, 8a-CH2), 3.32 (s, 3H, 8d-CH3), 2.79 (t, 2H, J  =  7.0 Hz, 8b-CH2), 2.76 (m, 3H, 2-CH, 1-CH2), 1.05 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3);13
C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 35.6 (8a-CH2), 49.2 (2′-CH), 50.1(1-CH2),
58.9 (8d-CH3), 68.7 (2-CH), 71.3 (3-CH2), 74.2 (8b-CH2), 114.8
(6 and 10-CH), 130.1 (7- and 9-CH), 131.7 (8-C), 157.6 (5-C); LC-MS m/z 269;
analytical calculation for C15H25NO3: C,
67.38; H, 9.42.; N, 5.24 found C, 67.12; H, 9.23; N, 5.12.


#### 3.1.3. 1-[(1-Methylethyl) Amino]-3-(1-Phenoxy)-2-Propanol (3c)

White Solid
Yield 0.993 g (95%); mp: 75–78°C;
IR (KBr): ν  =  802(CH wagging, NH bending), 1177(CN streching), 1513(aromatic
CC stretching), 2875(CH stretch), 3308(OH stretching) cm−1;  1H NMR (200 MHz,
CDCl3): δ 7.25 (m, 2H, 7- and 9-CH), 6.91 (m, 3H, 6-, 8-, and 10-CH),
4.11 (m, 3H, 3-CH2, and 2-CH), 3.94 (m, 1H, 2′-CH), 3.56 (bs, 1H, OH),
2.64−2.90 (m, 3H, NH, 1-CH2), 1.07 (d, 6H, J  =  6.4 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 49.5 (2′-CH), 50.1 (1-CH2), 68.8 (2-CH), 71.2 (3-CH2),
115.1 (6- and 10-CH), 121.5 (8-CH), 130.0 (7- and 9-CH), 159.2 (5-C); LC-MS m/z 211; analytical calculation for C12H19NO2: C,
68.87; H, 9.15; N, 6.69 found C, 68.58;
H, 9.00; N, 6.59.


#### 3.1.4. 1-[(1-Methylethyl) Amino]-3-(4-Methylphenoxy)-2-Propanol (3d)

White Solid
Yield 1.048 g (94%); mp: 75–77°C; IR (KBr): ν  =  803(CH
wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH
stretching), 3308 (OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.4 Hz, 7- and
9-CH), 6.81 (d, 2H, J  =  8.4 Hz, 6- and 10-CH), 4.08 (m, 2H, 3-CH2),
3.92 (m, 2H, OH, and 2-CH), 3.28 (bs, 1H, NH), 2.63−2.89 (m, 3H, 1-CH2, 2-
and 2′-CH), 2.27 (s, 3H, 8a-CH3), 1.10 (d,
6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 21.0 (8a-CH3), 23.4 (2  ×  3′-CH3),
49.5 (2′-CH), 50.1(1-CH2), 69.0(2-CH), 71.4 (3-CH2),
115.0 (6- and 10-CH), 130.5 (8-C), 130.7 (7- and 9-CH),157.2 (5-C); LC-MS m/z 224; analytical calculation for C13H21NO2: C, 69.92; H, 9.48; N, 6.27 found C,
69.86; H, 9.38; N, 6.20.


#### 3.1.5. 1-[(1-Methylethyl) Amino]-3-(4-Cynophenoxy)-2-Propanol (3e)

Colorless Solid
Yield 1.123 g (96%); mp: 108–110°C; IR
(KBr): ν  =  839(CH wagging, NH bending),
1173(CN streching), 1508(aromatic CC stretching), 2932(CH stretching), 3504(OH
stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ
7.58 (d, 2H, J  =  8.2, 7- and 9-CH), 7.01 (d, 2H, J  =  8.2 Hz, 6- and
10-CH), 4.22 (m, 2H, 3-CH2), 4.02 (bs, 1H, OH), 3.30 (bs, 1H, NH),
2.66−2.89 (m, 4H, 1-CH2, 2- and 2′-CH), 1.08 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.3 (2  ×  3′-CH3), 49.4 (2′-CH), 49.7 (1-CH2), 68.6 (2-CH), 71.5 (3-CH2),
104.5 (8-C), 115.8 (6- and 10-CH), 118.0 (8a-CN), 134.4 (7- and 9-CH),
162.5(5-C); LC-MS m/z 235; analytical calculation for C13H18N2O2:
C, 66.64; H, 7.74; N, 11.96 found C, 66.51;
H, 7.60; N, 11.88.


#### 3.1.6. 1-[(1-Methylethyl) Amino]-3-(4-Methoxyphenoxy)-2-Propanol (3f)

Colorless Solid
Yield 1.123 g (94%); mp: 80–82°C;
IR (in KBr): ν  =  830(CH wagging, NH
bending), 1115(CN streching), 1525(aromatic CC stretching), 2928(CH
stretching), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 6.8 (s, 4H, 6, 7, 9-, and 10-CH),
4.08 (m, 2H, OH, 3-CH2), 3.80–4.0 (m, 1H, 2-CH), 3.73 (s, 3H,
8b-CH3), 2.95–3.20 (bs, 1H, NH), 2.62–2.87 (m, 4H, 1-CH2, 2- and 2′-CH),
1.06 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.4 (2  ×  3′-CH3), 49.4 (2′-CH), 50.2 (1-CH2), 56.1 (8b-CH3), 69.1(2-CH), 72.1(3-CH2), 115.2 (6- and 10-CH), 116.0 (7-
and 9-CH), 153.5 (5-C), 154.5 (8-C); LC-MS
m/z 240 [M  +  H]+; analytical calculation for C13H21NO3: C, 65.25; H, 8.84; N, 5.85 found C, 65.20; H, 8.69; N, 5.78.


## 3.1. Procedure for The Preparation of Aryloxypropanolamines by Ring Opening of Aryloxy Epoxides under Solvent-Free Mw Irradiation

Aryloxyepoxides1a–f (5 mmol)
and isopropylamine 2 (7.5 mmol) were taken in a closed Teflon reactor.
The reactor was placed in a microwave oven at a selected power (400 W) for 10
minutes. After cooling the reactor to room temperature, excess amine was removed by distillation
under reduced pressure. The purification of the
reaction products was carried out by flash chromatography on silica gel using
CH2Cl2:MeOH (95:5), dried over anhydrous Na2SO4. All products 3a–f were
characterized by 1H and 13C NMR spectroscopy and data is given as follows.


### 3.1.1. 1-[(1-Methylethyl) Amino]-3-(1-Naphthoxy)-2-Propanol (propranolol) (3a)

White Solid
Yield 1.27 g (98%); mp: 95–97°C; IR (KBr): ν  =  765 (CH wagging, NH bending), 1029 (CN
streching), 1582 (aromatic CC stretching), 2835 (CH stretch), 3271 (OH stretch) cm−1; 1H NMR (200 MHz, CDCl3): δ 8.22–8.27 (m, 1H, 8-CH),
7.75–7.80 (m, 1H, 11-CH),
7.29–7.48 (m, 4H, 7, 9,
10-, and 12-CH), 6.77 (d, 1H, J  =  7.4 Hz, 6-CH), 4.07–4.18 (m, 3H, OH, and
3-CH2), 2.75–3.0 (m, 5H, NH,
1-CH2, 2-CH, 2′-CH), 1.07 (d, 6H,
J  =  6.2 Hz, 3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 23.7 (2  ×  3′-CH3), 49.7 (2′-CH), 50.4 (1-CH2), 69.3
(2-CH), 71.6 (3-CH2), 105.8 (6-CH), 121.3 (12-CH), 122.6 (9-CH),
126.0 (11-CH), 126.4 (10-CH), 126.6 (8-CH), 127.1 (7a-c), 128.3(11a-c), 135.3
(7-CH), (155.2 5-C); LC-MS m/z 260 [M  +  H]; analytical calculation for C16H21NO2: C, 74.10; H, 8.16; N, 5.40 found C, 74.0; H,
8.10; N, 5.30.


### 3.1.2. 1-[4-(2-Methoxyethyl) Phenoxy]-3-[(1-Methylethyl) Amino]-2-Propanol (metoprolol) (3b)

White Solid
Yield 1.249 g (97%); mp: 96–98°C;
IR (KBr): ν  =  828(CH
wagging, NH bending), 1113(CN streching), 1512(aromatic CC stretching), 2869(CH
stretch), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.2 Hz, 7- and 9-CH), 6.79 (d, 2H, J  =  8.2 Hz, 6- and 10-CH), 4.14 (m, 2H,
3-CH2), 3.90 (m, 3H, OH, NH, and 2′-CH), 3.53 (t, 2H, J
=  7.0 Hz, 8a-CH2), 3.32 (s, 3H, 8d-CH3), 2.79 (t, 2H, J  =  7.0 Hz, 8b-CH2), 2.76 (m, 3H, 2-CH, 1-CH2), 1.05 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3);13
C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 35.6 (8a-CH2), 49.2 (2′-CH), 50.1(1-CH2),
58.9 (8d-CH3), 68.7 (2-CH), 71.3 (3-CH2), 74.2 (8b-CH2), 114.8
(6 and 10-CH), 130.1 (7- and 9-CH), 131.7 (8-C), 157.6 (5-C); LC-MS m/z 269;
analytical calculation for C15H25NO3: C,
67.38; H, 9.42.; N, 5.24 found C, 67.12; H, 9.23; N, 5.12.


### 3.1.3. 1-[(1-Methylethyl) Amino]-3-(1-Phenoxy)-2-Propanol (3c)

White Solid
Yield 0.993 g (95%); mp: 75–78°C;
IR (KBr): ν  =  802(CH wagging, NH bending), 1177(CN streching), 1513(aromatic
CC stretching), 2875(CH stretch), 3308(OH stretching) cm−1;  1H NMR (200 MHz,
CDCl3): δ 7.25 (m, 2H, 7- and 9-CH), 6.91 (m, 3H, 6-, 8-, and 10-CH),
4.11 (m, 3H, 3-CH2, and 2-CH), 3.94 (m, 1H, 2′-CH), 3.56 (bs, 1H, OH),
2.64−2.90 (m, 3H, NH, 1-CH2), 1.07 (d, 6H, J  =  6.4 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 49.5 (2′-CH), 50.1 (1-CH2), 68.8 (2-CH), 71.2 (3-CH2),
115.1 (6- and 10-CH), 121.5 (8-CH), 130.0 (7- and 9-CH), 159.2 (5-C); LC-MS m/z 211; analytical calculation for C12H19NO2: C,
68.87; H, 9.15; N, 6.69 found C, 68.58;
H, 9.00; N, 6.59.


### 3.1.4. 1-[(1-Methylethyl) Amino]-3-(4-Methylphenoxy)-2-Propanol (3d)

White Solid
Yield 1.048 g (94%); mp: 75–77°C; IR (KBr): ν  =  803(CH
wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH
stretching), 3308 (OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.4 Hz, 7- and
9-CH), 6.81 (d, 2H, J  =  8.4 Hz, 6- and 10-CH), 4.08 (m, 2H, 3-CH2),
3.92 (m, 2H, OH, and 2-CH), 3.28 (bs, 1H, NH), 2.63−2.89 (m, 3H, 1-CH2, 2-
and 2′-CH), 2.27 (s, 3H, 8a-CH3), 1.10 (d,
6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 21.0 (8a-CH3), 23.4 (2  ×  3′-CH3),
49.5 (2′-CH), 50.1(1-CH2), 69.0(2-CH), 71.4 (3-CH2),
115.0 (6- and 10-CH), 130.5 (8-C), 130.7 (7- and 9-CH),157.2 (5-C); LC-MS m/z 224; analytical calculation for C13H21NO2: C, 69.92; H, 9.48; N, 6.27 found C,
69.86; H, 9.38; N, 6.20.


### 3.1.5. 1-[(1-Methylethyl) Amino]-3-(4-Cynophenoxy)-2-Propanol (3e)

Colorless Solid
Yield 1.123 g (96%); mp: 108–110°C; IR
(KBr): ν  =  839(CH wagging, NH bending),
1173(CN streching), 1508(aromatic CC stretching), 2932(CH stretching), 3504(OH
stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ
7.58 (d, 2H, J  =  8.2, 7- and 9-CH), 7.01 (d, 2H, J  =  8.2 Hz, 6- and
10-CH), 4.22 (m, 2H, 3-CH2), 4.02 (bs, 1H, OH), 3.30 (bs, 1H, NH),
2.66−2.89 (m, 4H, 1-CH2, 2- and 2′-CH), 1.08 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.3 (2  ×  3′-CH3), 49.4 (2′-CH), 49.7 (1-CH2), 68.6 (2-CH), 71.5 (3-CH2),
104.5 (8-C), 115.8 (6- and 10-CH), 118.0 (8a-CN), 134.4 (7- and 9-CH),
162.5(5-C); LC-MS m/z 235; analytical calculation for C13H18N2O2:
C, 66.64; H, 7.74; N, 11.96 found C, 66.51;
H, 7.60; N, 11.88.


### 3.1.6. 1-[(1-Methylethyl) Amino]-3-(4-Methoxyphenoxy)-2-Propanol (3f)

Colorless Solid
Yield 1.123 g (94%); mp: 80–82°C;
IR (in KBr): ν  =  830(CH wagging, NH
bending), 1115(CN streching), 1525(aromatic CC stretching), 2928(CH
stretching), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 6.8 (s, 4H, 6, 7, 9-, and 10-CH),
4.08 (m, 2H, OH, 3-CH2), 3.80–4.0 (m, 1H, 2-CH), 3.73 (s, 3H,
8b-CH3), 2.95–3.20 (bs, 1H, NH), 2.62–2.87 (m, 4H, 1-CH2, 2- and 2′-CH),
1.06 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.4 (2  ×  3′-CH3), 49.4 (2′-CH), 50.2 (1-CH2), 56.1 (8b-CH3), 69.1(2-CH), 72.1(3-CH2), 115.2 (6- and 10-CH), 116.0 (7-
and 9-CH), 153.5 (5-C), 154.5 (8-C); LC-MS
m/z 240 [M  +  H]+; analytical calculation for C13H21NO3: C, 65.25; H, 8.84; N, 5.85 found C, 65.20; H, 8.69; N, 5.78.


## 3.1.1. 1-[(1-Methylethyl) Amino]-3-(1-Naphthoxy)-2-Propanol (propranolol) (3a)

White Solid
Yield 1.27 g (98%); mp: 95–97°C; IR (KBr): ν  =  765 (CH wagging, NH bending), 1029 (CN
streching), 1582 (aromatic CC stretching), 2835 (CH stretch), 3271 (OH stretch) cm−1; 1H NMR (200 MHz, CDCl3): δ 8.22–8.27 (m, 1H, 8-CH),
7.75–7.80 (m, 1H, 11-CH),
7.29–7.48 (m, 4H, 7, 9,
10-, and 12-CH), 6.77 (d, 1H, J  =  7.4 Hz, 6-CH), 4.07–4.18 (m, 3H, OH, and
3-CH2), 2.75–3.0 (m, 5H, NH,
1-CH2, 2-CH, 2′-CH), 1.07 (d, 6H,
J  =  6.2 Hz, 3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 23.7 (2  ×  3′-CH3), 49.7 (2′-CH), 50.4 (1-CH2), 69.3
(2-CH), 71.6 (3-CH2), 105.8 (6-CH), 121.3 (12-CH), 122.6 (9-CH),
126.0 (11-CH), 126.4 (10-CH), 126.6 (8-CH), 127.1 (7a-c), 128.3(11a-c), 135.3
(7-CH), (155.2 5-C); LC-MS m/z 260 [M  +  H]; analytical calculation for C16H21NO2: C, 74.10; H, 8.16; N, 5.40 found C, 74.0; H,
8.10; N, 5.30.


## 3.1.2. 1-[4-(2-Methoxyethyl) Phenoxy]-3-[(1-Methylethyl) Amino]-2-Propanol (metoprolol) (3b)

White Solid
Yield 1.249 g (97%); mp: 96–98°C;
IR (KBr): ν  =  828(CH
wagging, NH bending), 1113(CN streching), 1512(aromatic CC stretching), 2869(CH
stretch), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.2 Hz, 7- and 9-CH), 6.79 (d, 2H, J  =  8.2 Hz, 6- and 10-CH), 4.14 (m, 2H,
3-CH2), 3.90 (m, 3H, OH, NH, and 2′-CH), 3.53 (t, 2H, J
=  7.0 Hz, 8a-CH2), 3.32 (s, 3H, 8d-CH3), 2.79 (t, 2H, J  =  7.0 Hz, 8b-CH2), 2.76 (m, 3H, 2-CH, 1-CH2), 1.05 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3);13
C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 35.6 (8a-CH2), 49.2 (2′-CH), 50.1(1-CH2),
58.9 (8d-CH3), 68.7 (2-CH), 71.3 (3-CH2), 74.2 (8b-CH2), 114.8
(6 and 10-CH), 130.1 (7- and 9-CH), 131.7 (8-C), 157.6 (5-C); LC-MS m/z 269;
analytical calculation for C15H25NO3: C,
67.38; H, 9.42.; N, 5.24 found C, 67.12; H, 9.23; N, 5.12.


## 3.1.3. 1-[(1-Methylethyl) Amino]-3-(1-Phenoxy)-2-Propanol (3c)

White Solid
Yield 0.993 g (95%); mp: 75–78°C;
IR (KBr): ν  =  802(CH wagging, NH bending), 1177(CN streching), 1513(aromatic
CC stretching), 2875(CH stretch), 3308(OH stretching) cm−1;  1H NMR (200 MHz,
CDCl3): δ 7.25 (m, 2H, 7- and 9-CH), 6.91 (m, 3H, 6-, 8-, and 10-CH),
4.11 (m, 3H, 3-CH2, and 2-CH), 3.94 (m, 1H, 2′-CH), 3.56 (bs, 1H, OH),
2.64−2.90 (m, 3H, NH, 1-CH2), 1.07 (d, 6H, J  =  6.4 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.2 (2  ×  3′-CH3), 49.5 (2′-CH), 50.1 (1-CH2), 68.8 (2-CH), 71.2 (3-CH2),
115.1 (6- and 10-CH), 121.5 (8-CH), 130.0 (7- and 9-CH), 159.2 (5-C); LC-MS m/z 211; analytical calculation for C12H19NO2: C,
68.87; H, 9.15; N, 6.69 found C, 68.58;
H, 9.00; N, 6.59.


## 3.1.4. 1-[(1-Methylethyl) Amino]-3-(4-Methylphenoxy)-2-Propanol (3d)

White Solid
Yield 1.048 g (94%); mp: 75–77°C; IR (KBr): ν  =  803(CH
wagging, NH bending), 1177(CN streching), 1513(aromatic CC stretching), 2875(CH
stretching), 3308 (OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 7.07 (d, 2H, J  =  8.4 Hz, 7- and
9-CH), 6.81 (d, 2H, J  =  8.4 Hz, 6- and 10-CH), 4.08 (m, 2H, 3-CH2),
3.92 (m, 2H, OH, and 2-CH), 3.28 (bs, 1H, NH), 2.63−2.89 (m, 3H, 1-CH2, 2-
and 2′-CH), 2.27 (s, 3H, 8a-CH3), 1.10 (d,
6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz,
CDCl3): δ 21.0 (8a-CH3), 23.4 (2  ×  3′-CH3),
49.5 (2′-CH), 50.1(1-CH2), 69.0(2-CH), 71.4 (3-CH2),
115.0 (6- and 10-CH), 130.5 (8-C), 130.7 (7- and 9-CH),157.2 (5-C); LC-MS m/z 224; analytical calculation for C13H21NO2: C, 69.92; H, 9.48; N, 6.27 found C,
69.86; H, 9.38; N, 6.20.


## 3.1.5. 1-[(1-Methylethyl) Amino]-3-(4-Cynophenoxy)-2-Propanol (3e)

Colorless Solid
Yield 1.123 g (96%); mp: 108–110°C; IR
(KBr): ν  =  839(CH wagging, NH bending),
1173(CN streching), 1508(aromatic CC stretching), 2932(CH stretching), 3504(OH
stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ
7.58 (d, 2H, J  =  8.2, 7- and 9-CH), 7.01 (d, 2H, J  =  8.2 Hz, 6- and
10-CH), 4.22 (m, 2H, 3-CH2), 4.02 (bs, 1H, OH), 3.30 (bs, 1H, NH),
2.66−2.89 (m, 4H, 1-CH2, 2- and 2′-CH), 1.08 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.3 (2  ×  3′-CH3), 49.4 (2′-CH), 49.7 (1-CH2), 68.6 (2-CH), 71.5 (3-CH2),
104.5 (8-C), 115.8 (6- and 10-CH), 118.0 (8a-CN), 134.4 (7- and 9-CH),
162.5(5-C); LC-MS m/z 235; analytical calculation for C13H18N2O2:
C, 66.64; H, 7.74; N, 11.96 found C, 66.51;
H, 7.60; N, 11.88.


## 3.1.6. 1-[(1-Methylethyl) Amino]-3-(4-Methoxyphenoxy)-2-Propanol (3f)

Colorless Solid
Yield 1.123 g (94%); mp: 80–82°C;
IR (in KBr): ν  =  830(CH wagging, NH
bending), 1115(CN streching), 1525(aromatic CC stretching), 2928(CH
stretching), 3301(OH stretching) cm−1; 1H NMR (200 MHz, CDCl3): δ 6.8 (s, 4H, 6, 7, 9-, and 10-CH),
4.08 (m, 2H, OH, 3-CH2), 3.80–4.0 (m, 1H, 2-CH), 3.73 (s, 3H,
8b-CH3), 2.95–3.20 (bs, 1H, NH), 2.62–2.87 (m, 4H, 1-CH2, 2- and 2′-CH),
1.06 (d, 6H, J  =  6.2 Hz, 2  ×  3′-CH3); 13C NMR (50 MHz, CDCl3): δ 23.4 (2  ×  3′-CH3), 49.4 (2′-CH), 50.2 (1-CH2), 56.1 (8b-CH3), 69.1(2-CH), 72.1(3-CH2), 115.2 (6- and 10-CH), 116.0 (7-
and 9-CH), 153.5 (5-C), 154.5 (8-C); LC-MS
m/z 240 [M  +  H]+; analytical calculation for C13H21NO3: C, 65.25; H, 8.84; N, 5.85 found C, 65.20; H, 8.69; N, 5.78.



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*Source: 109717-2009-03-04.xml*