Synthesis of Isoquinoline Derivatives from β-Hydroxyarylethanamides

Article abstract of DOI:10.1080/00397911.2015.1042590

A simple and efficient protocol for the construction of medicinally important substituted isoquinolines through intramolecular cyclization of β-hydroxyarylethanamides using acetic anhydride and phosphorous pentoxide in dioxane has been described. The chem

Full text of DOI:10.1080/00397911.2015.1042590

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Synthesis of Isoquinoline Derivatives
from β-Hydroxyarylethanamides
Rajendran Sureshab & Shanmugam Muthusubramaniana
a Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai, India
b Syngene International Limited, Biocon, Bangalore, India
Published online: 26 May 2015.
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To cite this article: Rajendran Suresh & Shanmugam Muthusubramanian (2015) Synthesis of
Isoquinoline Derivatives from β-Hydroxyarylethanamides, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 45:14, 1696-1703, DOI:
10.1080/00397911.2015.1042590
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Synthetic Communications1, 45: 1696–1703, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1042590
SYNTHESIS OF ISOQUINOLINE DERIVATIVES FROM
b-HYDROXYARYLETHANAMIDES
Rajendran Suresh1,2 and Shanmugam Muthusubramanian1
1Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai, India
2Syngene International Limited, Biocon, Bangalore, India
GRAPHICAL ABSTRACT
Abstract A simple and efficient protocol for the construction of medicinally important
substituted isoquinolines through intramolecular cyclization of b-hydroxyarylethanamides
using acetic anhydride and phosphorous pentoxide in dioxane has been described. The
chemo- and regioselectivities due to the influence of different catalysts were investigated
and optimized for good to excellent yields. All the synthesized compounds have been
characterized by NMR and mass spectral analyses.
Keywords b-Hydroxyarylethanamide; intramolecular cyclization; isoquinolines;
phosphorous pentoxide; selectivity
INTRODUCTION
The isoquinoline nucleus is a common skeleton present in different classes of
alkaloids that exhibit important biological activities.[1] They also serve as building
blocks in pharmaceutical compounds[2] and find application in the preparation of
chiral ligands for transition-metal catalysts.[3] Many popular drugs such as emetine,
morphine, papaverine, and quinocarcin contain the isoquinoline nucleus. The avail-
able methods for the construction of isoquinoline ring include the Pomeranz–Fritsch
reaction,[4] Bischler–Napieralski reaction,[5] and Pictet–Splengler reaction.[6]
Homophthalaldehyde, which can readily be obtained by the ozonolysis of indene,
can be cyclized with ammonia to form the isoquinoline derivative in good yields.[7]
Palladium-catalyzed reaction of o-bromoarylaldehyde with an alkyne and subsequent
Received January 31, 2015.
Address correspondence to Shanmugam Muthusubramanian, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: muthumanian2001
@yahoo.com
1696

ISOQUINOLINE DERIVATIVES
1697
reaction with ammonia can also produce the isoquinoline derivative.[8] Recently, a
new method for the synthesis of isoquinoline derivative from 2-azido-3-arylacrylates
by treating them with an a-diazocarbonyl compound in the presence of triphenylpho-
sphine has been described. The reaction involves a Wolff rearrangement, an aza-
Wittig reaction, and an electrocyclic ring closure.[9] A mild and efficient one-step
synthesis of substituted dihydro- and tetrahydroisoquinoline has been developed by
the ferric chloride–catalyzed intramolecular cyclization of benzylamino-substituted
propargylic alcohols.[10] A method has been developed for the cyclization of N-
phenylethylbenzamide involving trifluoromethane sulfonic anhydride and 2-chloro-
pyridine, providing 3,4-dihydroisoquinoline in good yield.[11] 3-Arylisoquinoline
derivatives are potent antitumor agents. The structure–activity relationship (SAR)
studies of the 3-aryl isoquinolones and 3-arylisoquinolamine show potent in vitro
cytotoxicity.[12] These significant properties prompted us to synthesize novel isoqui-
noline derivatives through a simple route.
RESULTS AND DISCUSSION
A protocol for the generation of isoquinoline from b-acetoxyarylethanamide
employing acetic anhydride and phosphorous pentoxide is described in this article.
We have already described the synthetic utility of a-azido chalcones 1 in generating
heterocyclic compounds.[13] b-Hydroxyarylethanamide 2, derived from the chalcones
1, have also been exploited by us to construct new rings[14] and it has been shown that
the nature of the acid employed has emphatically dictated the course of cyclization.
Thus titatinum tetrachloride–catalyzed cyclization has led to isoxazolines 3 [Fig. 1;
Eq. (1)], whereas trifluoromethane sulfonic acid–catalysed cyclization has led to
indane derivatives 4 [Fig. 1; Eq. (2)].[14] The Lewis and Brønsted acidic characters
of the reagents employed have a telling effect on the course of the reactions in these
cases, providing hard and soft nature. In continuation of this work, we decided to
investigate the effect of attempting cyclization on the protected hydroxyl amide 5,
b-acetoxyarylethanamide. The acetyl derivatives 5 were obtained as a mixture of
Figure 1. Synthetic utility of b-hydroxylarylethanamides.

1698
R. SURESH AND S. MUTHUSUBRAMANIAN
Table 1. Screening impact of the reagents and solvents for the selective formation of isoquinolines
Entry
Reaction conditions
Yield 6a (%)a
Yield 3a (%)a
1
2
3
4
5
6
7
8
9
POCl3, 1,2-dichloroethane, 80 °C, 3 h
Eaton’s reagent, 90 °C, 5 h
—
—
—
—
—
—
—
35
38
30
42
78
88
74
92
71
—
—
—
28
37
41
27
5
TiCl4, 1,2-dichloroethane, 80 °C, 30 min
Polyphosphoric acid, 90 °C, 5 h
Ti(iOPr)4, 1,2-dichloroethane, 80 °C, 5 h
AlCl3, 1,2-dichloroethane, 80 °C, 5 h
ZnI, 1,2-dichloroethane, 80 °C, 5 h
P2O5, xylene, 140 °C, 6 h
P2O5, 1,2-dichloroethane, 90 °C, 5 h
P2O5, 1,2-dichlorobenzene, 120 °C, 6 h
P2O5, toluene, 110 °C, 6 h
10
11
12b
P2O5, 1,4-dioxan, 90 °C, 5 h
aIsolated yield.
bOptimized reaction condition: b-acetoxy amide (1 eq), P2O5 (4 eq) in 1,4-dioxan, 90 °C, 5 h.
the diastereomers from the respective hydroxyl compounds 2. Compound 5a was
reacted with various reagents, in anticipation of a different course of cyclization, as
the acetate is a relatively better leaving group than the hydroxyl group. The details
of the reagents treated with compound 5a are listed in Table 1. Use of polyphosphoric
acid, Eatons reagent, phosphorous oxychloride, and titanium chloride resulted in oxa-
zoline 3a as the major cyclization product. When compound 5a was treated with phos-
phorous pentoxide in xylene, 35% of isoquinoline 6a was obtained along with 28% of
oxazoline 3a (Table 1). Toluene, benzene, 1,2-dichloroethane, and o-dichlorobenzene
are not much effective for this conversion, whereas 1,4-dioxan is found to be effective
as a solvent for this conversion. Titanium isopropoxide, aluminum chloride, and zinc
iodide have also been tried but the reaction did not proceed in these cases. Finally, it
was found that the reaction of 5a with phosphorus pentoxide in 1,4-dioxane at 90 °C
delivered 78% of isoquinoline derivative, 6a. The procedure has been simplified by
allowing the hydroxyamide 2a to react with 1 equivalent of acetic anhydride in 1,4-
dioxan at 0 °C to rt and then adding phosphorous pentoxide to the reaction mixture
without isolating the intermediate. The resulting mixture was heated to 90 °C for 5 h
to furnish the isoquinoline 6a [Fig. 1; Eq. (3)]. The reaction has been carried out under
the optimized conditions (Ac2O, P2O5, 1,4-dioxane, 90 °C; Table 2) for various sub-
strates. Amides containing both the electron-releasing groups and electron-withdraw-
ing groups led to the corresponding isoquinoline derivatives with good to excellent
yield. Cyclohexyl carboxylamide also yielded the corresponding isoquinoline under

ISOQUINOLINE DERIVATIVES
1699
Table 2. Synthesis of 3-benzyl isoquinoline derivatives
Entry
R1
R2
Isoquinolines
Yield (%)
78
1
H
4-N,N-Dimethylaminophenyl
2
3
H
H
Cyclohexyl
67
79
4-Cyanophenyl
4
5
H
2-Chloro-5-trifluoromethylphenyl
60
H
4-Phenoxyphenyl
76
(Continued)

1700
R. SURESH AND S. MUTHUSUBRAMANIAN
Table 2. Continued
Entry
R1
R2
Isoquinolines
Yield (%)
6
H
2-Ethoxynaphth-1-yl
64
7
CH3
Methyl
75
Scheme 1. Proposed mechanism for the regioselective formation of isoquinoline derivative.
the optimized condition. The details are provided in Table 2. In both the single-step
reaction and the two-step reaction, the yields were almost the same.
Initially the mechanism of the reaction was considered to be simple: the
acid-catalyzed cyclization occurs at the aryl group geminal to the acetoxy followed
by the elimination of acetic acid. But we realized that the mechanism of this reaction
is not as simple as proposed. When 5 g, which has two different aryl groups at
geminal to acetoxy and at benzyl end, was subjected to the reaction, the isoquinoline
formed has been shown to be 1,7-dimethyl-3-benzylisoquinoline and not 1-methyl-3-
(4-methylbenzyl)isoquinoline (Table 2, entry 7). This is confirmed by the presence of
a singlet at 7.85 ppm accounting for one hydrogen, apart from the C4-H singlet at
1
7.17 ppm in the H NMR spectrum of 6 g. This clearly indicates that the cyclization
has not taken place in the ring geminal to the acetoxy as concluded earlier.
The cyclization has taken place on the other ring, followed by the elimination
of acetic acid, resulting in the formation of an exocyclic double bond. Then 1,3-
allylic shift could have taken place, the driving force being the aromaticity towards
isoquinoline.
It is clear that the cyclization takes place prior to the elimination–tautomeriza-
tion sequence. If the elimination–tautomerization takes place initially, the cyclization
could have occurred anywhere as the olefin is now symmetrical. The initial cycliza-
tion takes place preferentially at the aryl ring, which is not geminal to acetoxy, prob-
ably due to steric reason. The mechanism is shown in Scheme 1.

ISOQUINOLINE DERIVATIVES
1701
CONCLUSION
In summary, a regioselective formation of isoquinolines from b-hydroxyary-
lethanamides with phosphorous pentoxide in 1,4-dioxan has been described.
EXPERIMENTAL
All solvents were purchased from commercial sources and used without further
1
purification. H NMR spectra were recorded at 400 MHz and 13C NMR spectra
were recorded at 100 MHz in dimethylsulfoxide (DMSO-d6) or CDCl3 using a
300- or 400-MHz spectrometer. Chemical shifts are reported in d (ppm) relative to
tetramethylsilane (TMS). Elemental analyses were performed on a Perkin-Elmer
2400 series II Elemental CHNS analyzer. Silica-gel G plates (Merck) were used for
thin-layer chromatography (TLC).
Typical Procedure for the Synthesis of 1-Substituted-3-
benzylisoquinoline (6a–g)
Acetic anhydride (0.279 mmol, 1 eq) was added to a solution of b-hydroxy amide
2 (0.279 mmol, 1 eq.) in 1,4-dioxane (5 mL) at 0 °C. The resulting mixture was stirred
at room temperature for 1 h. Phosphorus pentoxide (1.11 mmol, 4 eq) was added to
the reaction mixture and it was stirred at 90 °C for 5 h. The reaction mixture was then
quenched with 10% sodium carbonate solution and extracted with ethyl acetate. The
organic layer was washed with water and brine, dried over sodium sulfate, and con-
centrated in vacuum. The crude product was purified by column chromatography
using 10% ethyl acetate in hexane as the solvent to give isoquinoline derivatives 6.
Selected Spectral Data for 4-(3-Benzylisoquinolin-1-yl)-N,N-
dimethylaniline (6a)
Pale yellow viscous solid; 1H NMR (400 MHz, CDCl3) d: 3.06 (s, 6H, -N(Me)2),
4.39 (s, 2H, -CH2), 6.89 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.26–7.44 (m, 7H, Ar-H), 7.59 (t,
J ¼ 8.0 Hz, 1H, Ar-H), 7.66 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.71 (d, J ¼ 8.0 Hz, 1H, Ar-H),
8.18 (d, J ¼ 8.4 Hz, 1H, Ar-H);13C NMR (100 MHz, CDCl3) d: 40.5, 44.4, 112.1,
117.0, 125.2, 126.1, 126.2 (2C), 126.6 (2C), 127.8, 128.5, 129.5, 129.7, 131.2, 137.8,
140.0, 150.8, 153.6, 160.5; UPLC (M þ 1) 339.4. Anal. calcd. for C24H22N2: C,
85.17; H, 6.55; N, 8.28%. Found C, 85.11; H, 6.50; N, 8.24%.
ACKNOWLEDGMENT
R. S. is grateful to Syngene International Limited, Bangalore, for providing the
necessary facilities.
FUNDING
S. M. thanks the Council of Scientific and Industrial Research (CSIR), New
Delhi, for the financial assistance under a major research project [Scheme No. 02
(0061)=12=EMR-II dated May 16, 2012].

1702
R. SURESH AND S. MUTHUSUBRAMANIAN
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
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