Facile Synthesis of Propranolol and Novel Derivatives

Article abstract of DOI:10.1155/2020/9597426

Propranolol is one of the first medications of the beta-blocker used for antihypertensive drugs. This study reports the facile route for the synthesis of propranolol and its novel derivatives. Herein, propranolol synthesis proceeded from 1-naphthol and isopropylamine under mild and less toxic conditions. Novel propranolol derivatives were designed by reactions of propranolol with benzoyl chloride, pyridinium chlorochromate, and n-butyl bromide through esterification, oxidation reduction, and alkylation, respectively. The isolation and purity of compounds were conducted using column chromatography and thin-layer chromatography. Mass spectrometry and 1H-NMR spectroscopy were applied to identify new compounds structure. Propranolol derivatives from 2-chlorobenzoyl chloride (compound 3), 2-fluorobenzoyl chloride (compound 5), and especially acetic anhydride (compound 6) manifested high yields and significantly increased water solubility. Six semisynthetic propranolol derivatives promise to improve antioxidative and biological activities.

Full text of DOI:10.1155/2020/9597426

Hindawi
Journal of Chemistry
Volume 2020, Article ID 9597426, 10 pages
https://doi.org/10.1155/2020/9597426
Research Article
Facile Synthesis of Propranolol and Novel Derivatives
,
Vy Anh Tran ,1 2 Nguyen Hai Tai Tran,3 Long Giang Bach ,4 Trinh Duy Nguyen,5
Thi Thuong Nguyen,5 Tan Tai Nguyen ,6 Thi Anh Nga Nguyen ,7 The Ky Vo,8
2,9
Thu-Thao Thi Vo ,2 and Van Thuan Le
1Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
2Faculty of Environmental and Chemical Engineering, Duy Tan University, Danang 550000, Vietnam
3Department of Chemical Engineering, Ho Chi Minh City University of Technology, Ho Chi Minh City, Vietnam
4NTT Hi-Tech Institute, Nguyen Tat )anh University, 300A Nguyen Tat )anh, Ward 13, District 4, Ho Chi Minh City, Vietnam
5Center of Excellence for Green Energy and Environmental Nanomaterials (CE GrEEN), Nguyen Tat )anh University,
300A Nguyen Tat )anh, District 4, Ho Chi Minh City 755414, Vietnam
6Department of Materials Science, School of Applied Chemistry, Tra Vinh University, Tra Vinh City 87000, Vietnam
7Biomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc )ang University,
Ho Chi Minh City, Vietnam
8Department of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Go Vap,
Ho Chi Minh City, Vietnam
9Center for Advanced Chemistry, Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam
CorrespondenceshouldbeaddressedtoVyAnhTran;trananhvy@duytan.edu.vn,ꢀu-ꢀaoꢀiVo;vothuthaobd@gmail.com,and
Van ꢀuan Le; levanthuan3@duytan.edu.vn
Received 2 May 2020; Revised 14 July 2020; Accepted 27 July 2020; Published 24 August 2020
Academic Editor: Matthias D’hooghe
Copyright © 2020 Vy Anh Tran et al. ꢀis 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.
Propranolol is one of the first medications of the beta-blocker used for antihypertensive drugs. ꢀis study reports the facile route
for the synthesis of propranolol and its novel derivatives. Herein, propranolol synthesis proceeded from 1-naphthol and iso-
propylamine under mild and less toxic conditions. Novel propranolol derivatives were designed by reactions of propranolol with
benzoyl chloride, pyridinium chlorochromate, and n-butyl bromide through esterification, oxidation reduction, and alkylation,
respectively. ꢀe isolation and purity of compounds were conducted using column chromatography and thin-layer chroma-
1
tography. Mass spectrometry and H-NMR spectroscopy were applied to identify new compounds structure. Propranolol de-
rivatives from 2-chlorobenzoyl chloride (compound 3), 2-fluorobenzoyl chloride (compound 5), and especially acetic anhydride
(compound 6) manifested high yields and significantly increased water solubility. Six semisynthetic propranolol derivatives
promise to improve antioxidative and biological activities.
Methods for the synthesis of propranolol were investi-
gated by using enzymes to resolve intermediate compounds
[8–10]. However, the enzyme strategy did not show effective
manufacturing because of several limitations, i.e., multistep,
low overall yields (lower than 30%), and use of hazardous
and costly reagents [10, 11]. Besides, the hydrogenation of
the chiral metal of the intermediate by polymer-supported
reagent was used [12]. Nevertheless, the methods used to
catalyze metal salts are often complex and costly. In addition,
the synthesis efficiency and the selectivity of propranolol are
1. Introduction
Propranolol is one of the original medicines of the beta-
blocker used to treat hypertension, tremors, angina, and
cardiovascular disorders [1, 2]. Besides, propranolol also is
an effective and safe drug for treating migraine headaches,
anxiety disorders, and infantile hemangiomas [3, 4].
Moreover, several studies have recently reported that pa-
tients receiving propranolol reduced the risk of neck and
head, colon, stomach, and prostate cancers [5–7].

2
Journal of Chemistry
not high [10, 13]. ꢀus, the development of propranolol
derivatives to improve biopharmaceutical and therapeutic
features, as well as to reduce the first level of metabolism, is
absolutely necessary. To minimize the extension of the first-
pass conjugation, many prodrugs of propranolol have been
synthesized in the investigation of new high-acting lipophilic
derivatives. Amongst them, homologous acyl ester prodrugs
of propranolol, e.g., O-acetyl and O-propionyl carboxylic
acid ester, were discovered with higher bioavailability and
lipophilicity than those of propranolol [14–16].
2.2.3. Mass Spectrometry (MS). ꢀe determination and
detection of fragments and molecular ions from propranolol
and its derivatives were carried out by MicroOTOF-Q 10187
mass spectrometer (Bruker, Germany).
2.2.4. Proton Nuclear Magnetic Resonance Spectroscopy (1H-
NMR). ꢀe structure of propranolol and its derivatives was
identified by 1H-NMR spectra recorded on a Bruker
Ultrashield 500 spectrometer (Germany).
In this study, the synthesis of propranolol was conducted
between 1-naphthol and isopropylamine under mild, less
toxic conditions and fast reaction time. Novel propranolol
derivatives were formed by reactions at the C-13 and N-15
position through esterification reactions between propran-
olol and 2-bromobenzoyl chloride, 2-chlorobenzoyl chlo-
ride, and 2-fluorobenzoyl chloride. ꢀe oxidation and
alkylation reactions between propranolol and pyridinium
chlorochromate and n-butyl bromide were also investigated.
Novel derivatives were achieved in high yields and signifi-
cantly enhanced water solubility.
2.3. Synthesis of Propranolol Derivatives. To enhance the
antioxidation and biological activity, target moieties at C-13
and N-15 of propranolol were investigated for further re-
actions. New derivatives were produced by reactions from
propranolol with benzoyl chloride (esterification), with
pyridinium chlorochromate (oxidation-reduction), and with
n-butyl bromide (alkylation) (Figure 1).
2.3.1. Synthesis of Propranolol from 1-Naphthol and
Isopropylamine. Propranolol was synthesized from reaction
between 1-naphthol and isopropylamine according to re-
actions described in Figure 2. Typically, 1.25 g of 1-naphthol
(8.67 mM) was dissolved in 10 mL of ethanol : water (9 :1),
followed by adding 0.5 g of KOH into the above mixture
under stirring for 30 min. Next step, 4 mL of epichlorohy-
drin (0.05 M) was drop-down until the color of the mixture
changed to orange-yellow. After every 30 min of the reac-
tion, the formation of propranolol and its derivatives was
determined by TLC. ꢀe solvent of the reaction mixture
was evaporated and the yellow-brown compound of oil
form was obtained. ꢀen, 50 mL of diethyl ether was added
to the resulting product under shake condition, and the
water was removed by Na2SO4 anhydrous. Next, the re-
action mixture were isolated by CC using the mobile phase
of hexane : ethyl acetate (H : E) 6 : 4, resulting in collecting
of 1.05 g (5.25 mM) of 2-((naphthalen-1-yloxy) methyl)
oxirane (1a). Besides, two compounds of 1b were also
obtained (Figure 2).
2. Methods and Experiment
2.1. Chemical Materials. Sulphuric acid, iodine, chloroform,
dichloromethane, tetrahydrofuran (THF), potassium car-
bonate, 2-fluorobenzoyl chloride, 2-bromobenzoyl chloride,
2-chloromobenzoyl chloride, 1-naphthol, isopropylamine,
and epichlorohydrin were purchased from Sigma Aldrich.
ꢀin-layer chromatography (TLC) silica gel 60 F254 was
bought from Merck (Germany, 20.0 ×10.0 cm). Silica gel
230–400 mesh for column chromatography was purchased
from HiMedia (India). Water and ethanol (HPLC grade)
were used without additional purification. Other chemicals
were used as the highest possible quality as received.
Glassware was cleaned using an acidic solution of HNO3:
HCl (1 : 3 v/v) and then washed several times with deionized
water.
1.05 g of compound 1a dissolved in 10 mL of methanol
was added to 15 mL of isopropylamine (12 mM) and stirred
at 45°C until obtaining the yellow-brown solution (48 h) and
solution was cooled to 5°C. ꢀen, 1.5 ml of HCl (2 M) was
dropped slowly into the resulting mixture, followed by
adding NaOH (2 M) until white precipitate appeared. ꢀe
precipitate was washed by water, isolated by CC using a
mixture of H : E � 5 : 5. Finally, 0.738 g of 1-(iso-
propylamino)-3-(naphthalen-1-yloxy) propan-2-ol (com-
pound 2) or propranolol was collected (Figure 2).
2.2. Methods of Characterization
2.2.1. )in-Layer Chromatography (TLC). 5 μL of sample
and standard solutions was dropped on a TLC plate, which
was immersed in ethyl acetate : hexane system (mobile
phase) at different ratios. ꢀe moving of the mobile phase
was finished until it reached the highest limitation of the
TLC plate. ꢀe separated TLC plate was dried at room
temperature (RT) for 30 min and observed under visible
light or UV light.
2.3.2. Synthesis of Propranolol with 2-Chlorobenzoyl Chlo-
ride, 2-Bromobenzoyl Chloride, and 2-Flourobenzoyl Chlo-
ride (Compounds 3, 4, and 5). Briefly, 200 mg of propranolol
(0.77 mM) was dissolved in 10 mL CHCl3 at RT. ꢀen,
300 mg of 2-chlorobenzoyl chloride (1.71 mM) or 300 mg
(1.37 mM) of 2-bromobenzoyl chloride or 300 mg (1.89 mM)
of 2-flourobenzoyl chloride was added to the propranolol
mixture. Each reaction mixture was stirred and refluxed at
2.2.2. Column Chromatography (CC). ꢀe CC method was
applied for fractionation and purification of the synthesized
products by using columns filled with silica gel of 230–400
mesh and glass columns with different diameters of 1.5, 2,
and 5 cm and lengths of 30 and 40 cm. ꢀe mobile phase of
hexane : ethyl acetate at different ratios was used to separate
propranolol and its desired derivatives.

Journal of Chemistry
3
17
2.4. Aqueous Solubility Procedure. Aqueous solubility
was measured for each compound in phosphate buffered
saline (PBS, pH 7.4) [17]. Briefly, each equivalent
was incubated at a final concentration of 200 μM in
2% DMSO with the appropriate aqueous medium
under shaking for 24 h at RT. ꢀe compound identification
was done via HPLC with photodiode array detection.
CH3
12
14
16
13
CH3
18
11 O
N
H
15
6
3
10
OH
19
1
2
9
5
4
3. Results and Discussion
8
3.1. Other Propranolol Synthesis Methods. As shown in
Figure 7(a), (S)-propranolol was prepared by using
Zn(NO3)2/(+)-tartaric acid for the resolution of the terminal
epoxide. ꢀis method was conducted at 75°C in enantio-
selectivity through a kinetic resolution of intermediate
α-naphthyl glycidyl ether [10]. However, methods of using
metal salts as a catalyst for the synthesis of propranolol are
often complicated and costly. Besides, there was low se-
lectivity in isomer separation (S)-propranolol. ꢀe nucleo-
philic ring opening of epoxides was preceded by the
perchloric acid supported silica matrix (HClO4–SiO2). Be-
sides, microwave-assisted HClO4–SiO2 system was investi-
gated for efficient and cost-effective synthesis processing [18]
(Figure 7(b)).
7
Figure 1: Chemical structure of propranolol (1-(1-methyl-
ethylamino)-3-(1-naphthyloxy)propan-2-ol) and reactions at the
OH group at C-13 position and N-15 position.
50 C for 24 h. After every hour, the formation of a new
compound from each reaction was identified by TLC. Each
reaction mixture was isolated (3 times) by a CC system with
the mobile phase of water and ethyl acetate. Next step, 3 mL
of saturated NaHCO3 solution was added to the mixture
under stirring condition. ꢀe reaction mixture was filtered,
solvent was evaporated under vacuum, and the resulting
product was purified by CC using a solvent system of H : E 7 :
3. Finally, 136 mg/150 mg/115 mg of compound 3/4/5 were
obtained, respectively (Figure 3).
3.2. Results of Mass Spectrometry and 1H-NMR Spectra
3.2.1. 2-((Naphthalen-1-yloxy)methyl)oxirane (Compound
1a). Brownish-yellow oil form, 1H-NMR (500 MHz,
CDCl3), 2.86 (dd, J � 5.0, 2.7 Hz, 1H), 2.98 (dd, J � 5.0,
4.1 Hz, 1H), 3.51 (ddt, J � 5.7, 4.2, 2.8 Hz, 1H), 4.14 (dd,
J � 11.0, 5.6 Hz, 1H), 4.40 (dd, J � 11.0, 3.0 Hz, 1H), 6.84–8.41
(7H, m) of naphthalene.
2.3.3. Synthesis of Propranolol with Anhydride Acetic
(Compound 6). 100 mg of acetic anhydride (1.11 mM) was
added into 200 mg of the propranolol (0.77 mM) in 10 mL
CHCl3. ꢀe reaction mixture was refluxed at 45°C for 24
hours followed by examined TLC every hour. ꢀe reaction
mixture was isolated by CC three times. ꢀen, 5 mL of
saturated NaHCO3 solution was added into the reaction
mixture to isolate ethyl acetate and remove water by Na2SO4
anhydrous. ꢀe new compound of the reaction was isolated
by CC using solvent mixture of H : E 7 : 3. ꢀe result obtained
170 mg of compound 6 (Figure 4).
HRMS (ESI-MS, m/z), (M + Na)+, [C23H12O2 + Na]+,
theory: 223.0748, experiment: 200.0748.
3.2.2. Two Isomers of 1-Chloro-3-(naphthalen-1-yloxy)
propan-2-ol and 2-Chloro-3-(naphthalen-1-yloxy)propan-1-
1
ol (Compound 1b). H-NMR (500 MHz, CDCl3), 3.87 (dd,
J � 11.3, 5.7 Hz, 1H), 3.94 (dd, J � 11.3, 5.0 Hz, 1H), 4.35–4.26
(m, 2H), 4.41 (p, J � 5.3 Hz, 1H), 4.53–4.45 (m, 4H), 4.76 (p,
J � 5.3 Hz, 1H), 6.90–8.33 (7H, m) of naphthalene.
HRMS (ESI-MS, m/z), (M + Na)+, [C13H13ClO2 + Na]+,
theory: 260.1628, experiment: 236.69.
2.3.4. Synthesis of Propranolol with Pyridinium Chlor-
ochromate (PCC) (Compound 7). 40 mg of PCC was mixed
with 200 mg of propranolol (0.77 mM) in 15 mL of CH2Cl2.
ꢀen, reaction mixture was refluxed at 40°C for 20 h. After
ending the reaction, the mixture was filtered, solvent was
removed, and the resulting product was purified by CC using
a mobile system of dichloromethane : methanol (D : M) 8 : 2.
Finally, the result of reaction obtained 180 mg of 1-(iso-
propylamino)-3-(naphthalen-1-yloxy) propan-2-one com-
pound 7 (Figure 5).
3.2.3. Propranolol (Compound 2). White powder, yield:
70.3%, 1H-NMR (500 MHz, CDCl3), 1.16 (dd, J � 6.3, 1.5 Hz,
6H), 2.91 (ddd, J � 12.3, 8.3, 6.9 Hz, 2H), 3.06 (dd, J � 12.2,
3.5 Hz, 1H), 4.20–4.14 (m, 1H), 4.27–4.21 (m, 2H), 6.85–8.27
(7H) of naphthalene.
HRMS (ESI-MS, m/z), (M + Na)+, [C16H21NO2 + Na]+,
theory: 282.1469, experiment: 259.1666.
2.3.5. Synthesis of Propranolol with n-Butyl Bromide
(Compound 8). 1.06 g of K2CO3, 0.2 g of the propranolol
(0.77 mM), and 210 mg of n-butyl bromide (1.54 mM) were
put in 10 mL of acetonitrile under stirring for 30 min. ꢀe
reaction proceeded for 24 h at RT. ꢀe reaction mixture was
isolated using CC with mobile phase of D : M 8 : 2. 130 mg of
the compound 8 was collected (Figure 6).
3.2.4. Two Isomers of 2-Chloro-N-(2-hydroxy-3-(naphtha-
lene-1-yloxy)propyl)-N-isopropylbenzamide and 1-(Iso-
propylamino)-3-(naphthalene-1-yloxy)-propan-2-yl
2-
Chlorobenzoate (Compound 3). White amorphous powder,

4
Journal of Chemistry
O
OH
O
KOH
1a
+
ETOH : H2O
9 : 1
O
CI
CI
O
OH
1b
OH
O
CI
O
O
N
H
H2N
O
OH
MeOH, 40°C
2
1a
Figure 2: ꢀe scheme illustrates the synthesis reaction of propranolol from 1-naphthol and isopropylamine.
O
N
H
OH
(2)
O
Cl
C
CHCl3, NaHCO3
Cl
O
N
O
O
N
H
O
OH
C
O
Cl/Br/F
C
Cl/Br/F
CI
O
C
O
N
O
O
C
Cl/Br/F
(3)/(4)/(5)
Figure 3: ꢀe scheme describes the synthesis of propranolol with (i) 2-chlorobenzoyl chloride; (ii) 2-bromobenzoyl chloride; (iii)
2-flourobenzoyl chloride, at conditions of CHCl3 and NaHCO3 at 50°C for 24 h.

Journal of Chemistry
5
N
H
O
OH
(2)
CHCl3, NaHCO3 (CH3CO)2O
N
H
O
N
O
O
O
O
OH
C
C
CH3
CH3
CH3
O
C
C
N
O
O
O
(6)
CH3
Figure 4: ꢀe scheme describes the synthesis of propranolol with anhydride acetic at conditions of CHCl3 and NaHCO3 at 45°C for 24 h.
N
H
O
N
H
O
O
OH
(2)
PCC
(7)
CH2Cl2
1-(Isopropylamino)-3-(naphthalen-
1-yloxy)propan-2-one
Figure 5: ꢀe scheme describes the synthesis process between propranolol and pyridinium chlorochromate in presence of CH2Cl2, at 40°C
for 20 h.
N
H
O
O
N
OH
OH
C4H9
n-C4H9Br
(2)
CH3CN, K2CO3
(8)
1-(Butyl(isopropyl)amino)-3-(naphthalen-1-
yloxy)propan-2-ol
Figure 6: ꢀe scheme describes the synthesis of propranolol with n-butyl bromide (compound 8) at conditions of CH3CN for 24 h.
1
yield: 68.0%, H-NMR (500 MHz, CDCl3), 1.11–1.36 (dd,
J � 22.8, 6.6 Hz, 12H), 3.85–3.70 (m, 4H), 3.94 (ddd, J � 30.5,
14.6, 8.1 Hz, 2H), 4.18 (ddd, J � 24.2, 9.5, 7.7 Hz, 2H), 4.31
(dd, J � 9.4, 4.5 Hz, 2H), 4.49–4.40 (m, 1H), 6.91–8.25 (11H)
of naphthalene and 2-chlorobenzoyl.
3.2.5. Two Isomers of 2-Bromo-N-(2-hydroxy-3-(naphtha-
lene-1-yloxy)propyl)-N-isopropylbenzamide and 1-(Iso-
propylamino)-3-(naphthalene-1-yloxy)-propan-2-yl
2-
Bromobenzoate (Compound 4). White amorphous powder,
yield: 73.1%, 1H-NMR (500 MHz, CDCl3), 1.10–1.39 (d,
J � 6.6 Hz, 312H), 3.69–3.85 (m, 4H), 3.94 (ddd, J � 39.7,
14.6, 8.0 Hz, 2H), 4.19 (ddd, J � 33.1, 9.5, 7.7 Hz, 2H), 4.32
HRMS (ESI-MS, m/z), (M + Na)+, [C23H24ClNO3 + Na]+,
theory: 420.1329, experiment: 397.14.

6
Journal of Chemistry
OH
O
OH
O
O
O
CI
(
K2CO3
MeCN
+
+CI
K2CO3, 3h
2-butanone
O
O
1-Naphthol
O
)-Epichlohydrin
( )-Naphthyl glycidic
(CH3)2CH-NH2
H2O, 1h, 75°C
N
H
O
O
O
NH
OH
Microwave, 300W
HClO4-SiO2
OH
O
NH
H
NH2
Propranolol
OH
(S)-(–)propranolol
(a)
(b)
Figure 7: (a) Synthesis of propranolol used a catalyst of tartaric acid and metal salts; (b) ring opening of epoxides employing thiophenol
under microwave conditions and synthesis of propranolol using silica perchloric acid catalyst.
(dd, J � 9.4, 4.5 Hz, 2H), 4.39–4.51 (m, 2H), 6.91–8.25 (11H,
1.15 (d, J � 6.7 Hz, 2H), 1.06 (d, J � 6.6 Hz, 2H), 1.27 (t,
J � 6.2 Hz, 2H), 1.44–1.33 (m, 2H), 1.58–1.50 (m, 1H), 2.57
(dt, J � 8.1, 6.0 Hz, 1H), 2.79–2.66 (m, 1H), 3.17–3.07 (m,
1H), 4.21–4.12 (m, 2H), 4.25 (p, J � 4.1 Hz, 1H).
m) of naphthalene and 2-chlorobenzoyl.
HRMS
(ESI-MS,
m/z),
(M + Na)+(79/81Br),
[C23H24BrNO3+Na]+(79/81Br), theory: 464.0834/466.0813.
HRMS (ESI-MS, m/z), (M + H)+, [C22H29NO2 + H]+,
theory: 340.4787, experiment: 339.4764.
3.2.6. Two Isomers of 2-Fluoro-N-(2-hydroxy-3-(naphtha-
lene-1-yloxy)propyl)-N-isopropylbenzamide and 1-(Iso-
propylamino)-3-(naphthalene-1-yloxy)-propan-2-yl
2-
3.3.ReactionMechanisms. Propranolol has been synthesized
according to the drug manufacturing process from 1-
naphthol and isopropylamine. Besides the formation of
propranolol, two intermediate compounds 1a and 1b also
were found. From the pristine propranolol, seven new de-
rivatives have been synthesized from the compound (2) to
(8), in which every compound of 3, 4, 5, and 6 produced only
two isomers, different from the theory of 3 isomers (as
shown in Table 1). ꢀe new compounds structures were
confirmed by MS and 1H-NMR spectra, indicating that these
compounds were entirely suitable. ꢀe propranolol deriv-
atives were obtained in high yields from 57.4% to 90.2%.
ꢀe mechanism of the esterification reactions for for-
mation compounds 3, 4, and 5 is very close. ꢀe OH group of
propranolol is reacted with the activating group (Cl/Br/F)
replaced by the alcohol moiety. ꢀe reaction continues by
either an addition–elimination through attack of the in-
coming nucleophile at the sp2 carbon atom or an elimi-
nation–addition chain. Cl/Br/F is a good leaving group to
maximize the efficiency of the esterification protocol by
minimizing electron donation to the carbonyl functional
group. Besides, when anhydrides are employed in the es-
terification reaction, 50% of the acid component is lost
because only one of the acid moieties is transformed to the
desired ester. ꢀerefore, this approach was used for simple,
inexpensive carboxylic acids with a low degree of func-
tionalization, including acetic anhydride (compound 6)
[19, 20].
Fluorobenzoate (Compound 5). Dark blue liquid, yield:
1
57.4%, H-NMR (500 MHz, CDCl3), 0.86–1.40 (m, 12H),
3.36–3.51 (m, 4H), 3.65 (d, J � 5.8 Hz, 2H), 4.11 (dd, J � 9.6,
6.1 Hz, 2H), 4.29–4.18 (m, 2H), 4.52 (d, J � 3.8 Hz, 2H),
6.69–8.28 (m, 20H) of naphthalene and 2-chlorobenzoyl.
HRMS (ESI-MS, m/z), (M + H)+, [C23H25FNO3 + H]+,
theory: 382.1820, experiment: 381.4488.
3.2.7. Two Isomers of N-(2-Hydroxy-3-(naphthalene-1-yloxy)
propyl)-N-isopropylacetamide and 1-(Isopropylamino)-3-
(naphthalen-1-yloxy)propan-2-yl Acetate (Compound 6).
White amorphous powder, yield: 85.0%, 1H-NMR
(500 MHz, CDCl3), 1.24 (dd, J � 8.8, 6.2 Hz, 6H), 1.33 (dd,
J � 17.3, 6.7 Hz, 6H), 2.14–2.25 (6H, m), 3.43 (1H, dd,
J � 14.3, 6.9 Hz), 3.83 (1H, dd, J � 14.4, 5.3 Hz), 4.06 (1H, p,
J � 6.5 Hz), 4.19–4.36 (2H, m), 6.81–8.21 (1H, m, H-9).
HRMS (ESI-MS, m/z), (M + H)+, [C23H18NO3+H]+,
theory: 302.1748, experiment: 301.1700.
3.2.8. 1-(Isopropylamino)-3-(naphthalene-1-yloxy)propan-2-
one (Compound 7). White amorphous powder, yield: 90.2%,
1H-NMR (500 MHz, CDCl3), 1.50 (dd, J � 9.5, 6.4 Hz, 6H),
3.33–3.25 (m, 1H), 3.41 (d, J � 13.1 Hz, 1H), 3.53–3.46 (m,
1H), 4.12 (dd, J � 9.6, 5.6 Hz, 1H), 4.22 (dd, J � 9.5, 3.9 Hz,
1H), 6.81–8.21 (1H, m, H-9).
HRMS (ESI-MS, m/z), (M + H)+, [C16H19NO2 + H]+,
theory: 258.3349, experiment: 257.3326.
In the oxidation reaction of propranolol using pyr-
idinium chlorochromate, the first step is the attack of oxygen
on the chromium to form the Cr-O bond. Secondly, a proton
on the OH is transferred to one of the oxygen atoms of the
chromium, possibly through the intermediacy of the
3.2.9.
1-(Butyl(isopropyl)amino)-3-(naphthalene-1-yloxy)
propan-2-ol (Compound 8). Brownish-yellow liquid, yield:
65.5%, 1H-NMR (500 MHz, CDCl3), 0.98 (t, J � 7.3 Hz, 2H),

Journal of Chemistry
7
Table 1: Summary of propranolol derivatives.
O
N
H
O
O
OH
1a
2
2-((Naphthalen-1-yloxy)methyl)oxirane
Propranolol
CH2Cl
CH2OH
O
O
Cl
OH
1b
1b
2-Chloro-3-(naphthalen-1-yloxy)propan-1-ol
1-Chloro-3-(naphthalen-1-yloxy)propan-2-ol
N
H
O
N
O
O
O
OH
O
C
C
Cl
Cl
3
3
2-Chloro-N-(2-hydroxy-3-(naphthalen-1-yloxy)propyl)-N-
isopropylbenzamide
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-yl 2-
chlorobenzoate
N
H
O
O
N
O
O
O
OH
C
C
Br
Br
4
4
2-Bromo-N-(2-hydroxy-3-(naphthalen-1-yloxy)propyl)-N-
isopropylbenzamide
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-yl 2-
bromobenzoate
O
N
H
N
O
O
O
OH
O
C
C
F
F
5
5
2-Flouro-N-(2-hydroxy-3-(naphthalen-1-yloxy)propyl)-N-
isopropylbenzamide
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-yl 2-
fluorobenzoate

8
Journal of Chemistry
Table 1: Continued.
O
N
H
N
O
O
OH
6
O
CH3
O
6
CH3
N-(2-Hydroxy-3-(naphthalen-1-yloxy)propyl)-N-isopropylacetamide
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-yl acetate
N
O
O
N
H
OH
O
C4H9
7
(8)
1-(Butyl(isopropyl)amino)-3-(naphthalen-1-yloxy)propan-2-ol
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-one hydrate
Pyridiniumchlorochromate
Propranolol
R1
H
R2
R1
R2
O
CI
Cr
+
+
O
+
–
N
–
OH
N
CI
Cr
O
O
O
O
H
–
H
O
H+ transfer
Propranolol
derivative
R1
O
R1
R2
CI
R2
Cr
H
R1
R2
–Cl
O
+
+
OH
N
OH
Cr
O
N
O
O
–
H
O
O
H
(a)
Figure 8: Continued.

Journal of Chemistry
9
C4H9
N
H
O
O
+N
H
OH
OH
Br
C4H9
–CN
Propranolol
C4H9
O
N
OH
(b)
Figure 8: (a) Oxidation reaction mechanism of propranolol using pyridinium chlorochromate; (b) amine alkylation reaction mechanism
between propranolol and n-butyl bromide.
Table 2: ꢀe solubility of propranolol derivatives.
Compound Water solubility (μg/mL)
hydrophilic functional supplement groups. Propranolol
derivatives from 2-chlorobenzoyl chloride (3), 2-fluo-
robenzoyl chloride (5), and especially acetic anhydride (6)
showed a significant increase toward water solubility
compared to propranolol. ꢀe water solubility of other
compounds was not much changed compared to that of
propranolol.
2
3
4
5
6
7
8
61.7
92.4
74.7
112.5
243.6
55.4
51.3
4. Conclusions
Polypharmacology remains one of the significant difficulties
in drug improvement, and it initiates novel avenues to create
the next generation of drugs. A route for the synthesis of
propranolol has been developed under simple, inexpensive,
and mild reaction conditions. Remarkably, we successfully
synthesized seven novel propranolol derivatives at the C-13
and N-15 of propranolol, obtained in high yields. ꢀe water
solubility of compounds 3, 5, and 6, corresponding to
products of propranolol with 2-chlorobenzoyl chloride, 2-
fluorobenzoyl chloride, and acetic anhydride, was improved
significantly. ꢀe present study shows that the synthesized
propranolol derivatives represent promising new com-
pounds to enhance antioxidative, biological activities and
the need for investigation in the near future.
pyridinium salt. A chloride ion is then displaced to form
what is known as a chromate ester. ꢀe C-O double bond is
formed when a base removes the proton on the carbon
adjacent to the oxygen. It is also necessary for pyridine to be
used as the base here, but only very small amounts of the
deprotonated component would be found under such acidic
conditions. ꢀe electrons from the C-H bond move to form
the C=O bond of compound 7, and in the process, the Cr-O
bond is broken, and Cr(VI) becomes Cr(IV) as shown in
Figure 8(a) [21].
N of propranolol functions as the nucleophile and at-
tacks the electrophilic C of n-butyl bromide, displacing the
bromide and creating the new C-N bond. ꢀen the base
(excess amine) deprotonates the positive N (ammonium)
center, creating the alkylation product [22], so-called
compound 8 (Figure 8(b)).
Data Availability
ꢀe data used to support the findings of this study are in-
cluded in the article.
3.4. Solubilityof PropranololDerivatives. ꢀe water solubility
of these propranolol derivatives was investigated (as shown in
Table 2). ꢀe water solubility of propranolol was 61.7 μg/mL.
In contrast, new derivatives from acetone and n-butyl
groups were slightly less soluble due to the involvement of
Conflicts of Interest
ꢀe authors declare that there are no conflicts of interest
regarding the publication of this article.

10
Journal of Chemistry
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Acknowledgments
ꢀis research was funded by Duy Tan University, Da Nang
city, Vietnam, and Vietnam National Foundation for Sci-
ence and Technology Development (NAFOSTED) under
grant no. 104.05-2019.03.
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