Novel carbon-carbon bond formation between N-methyl-3-phenyl-3- hydroxypropylamine and cresols catalyzed by p-toluenesulphonic acid

Article abstract of DOI:10.1080/00397910600602776

The p-toluenesulphonic acid-catalyzed reaction between appropriate cresols and N-methyl-3-phenyl-3-hydroxypropylamine in refluxing toluene resulted in the formation of o -substituted phenol derivatives by an aromatic nucleophilic substitution reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600602776

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Novel Carbon–Carbon
Bond Formation between
N‐Methyl‐3‐phenyl‐3‐hydroxypropylamine and
Cresols Catalyzed by p‐Toluenesulphonic Acid
M. Gopalakrishnan a , P. Sureshkumar a , V. Kanagarajan a , J. Thanusu a ,
Shanmugam Govindan b & Mahesh Reddy Ghanta b
a Department of Chemistry , Annamalai University , Annamalainagar,
Tamilnadu, India
b Department of Research and Development , Dr. Reddy's Laboratories Ltd. ,
Jinnaram, Andhra Pradesh, India
Published online: 18 Aug 2006.
To cite this article: M. Gopalakrishnan , P. Sureshkumar , V. Kanagarajan , J. Thanusu , Shanmugam
Govindan & Mahesh Reddy Ghanta (2006) Novel Carbon–Carbon Bond Formation between
N‐Methyl‐3‐phenyl‐3‐hydroxypropylamine and Cresols Catalyzed by p‐Toluenesulphonic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:13,
1923-1926, DOI: 10.1080/00397910600602776
To link to this article: http://dx.doi.org/10.1080/00397910600602776
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Synthetic Communicationsw, 36: 1923–1926, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600602776
Novel Carbon–Carbon Bond Formation
between N-Methyl-3-phenyl-3-
hydroxypropylamine and Cresols Catalyzed
by p-Toluenesulphonic Acid
M. Gopalakrishnan, P. Sureshkumar, V. Kanagarajan,
and J. Thanusu
Department of Chemistry, Annamalai University,
Annamalainagar, Tamilnadu, India
Shanmugam Govindan and Mahesh Reddy Ghanta
Department of Research and Development,
Dr. Reddy’s Laboratories Ltd., Jinnaram, Andhra Pradesh, India
Abstract: The p-toluenesulphonic acid–catalyzed reaction between appropriate
cresols and N-methyl-3-phenyl-3-hydroxypropylamine in refluxing toluene resulted
in the formation of o-substituted phenol derivatives by an aromatic nucleophilic
substitution reaction.
Keywords: Anti-depressant drug, aromatic nucleophilic substitution, Atomoxetine,
carbon–carbon bond formation, cresol, N-methyl-3-phenyl-3-hydroxypropylamine,
p-toluenesulphonic acid
INTRODUCTION
Atomoxetine is one of the potent inhibitors of the presynaptic norepinephrine
transporter with minimal affinity for other monoamine transporters or
receptors.[1,2] Atomoxetine is used as a therapeutic agent for the treatment
Received in India December 26, 2005
Address correspondence to M. Gopalakrishnan, Department of Chemistry,
Annamalai University, Annamalainagar 608 002, Tamilnadu, India. Tel.: þ 91 4144
228 233; E-mail: emgeekk@yahoo.co.in
1923

1924
M. Gopalakrishnan et al.
of attention deficit hyperactivity disorder (ADHD) in children, adolescents,
and adults. Recently, Atomoxetine hydrochloride, a noradrenalin-reuptake
inhibitor,[3] was approved by the U.S. Food and Drug Administration (FDA)
for the treatment of ADHD, a neuropsychiatric disorder of childhood. In the
literature, several synthetic methods were reported for Atomoxetine.[4–6]
RESULTS AND DISCUSSION
During the course of our study aimed at synthesizing Atomoxetine, we
discovered a new synthetic rearrangement obtained during the condensation
of N-methyl-3-phenyl-3-hydroxypropylamine 3 with appropriate cresols 4–
6 catalyzed by p-toluenesulphonic acid (p-TSA) (Scheme 1). The synthesis
of N-methyl-3-phenyl-3-hydroxypropyl amine[7] 3 was carried out by a
conventional four-step procedure. Treatment of N-benzylmethylamine 1
with acetophenone, formaldehyde (excess) in the presence of methanol, and
hydrogen chloride under reflux yielded 2, whose reduction in the presence
of Pd-C afforded N-methyl-3-phenyl-3-hydroxypropylamine 3. Treatment of
3 with appropriate cresols 4–6 in the presence of p-TSA in toluene
furnished C-arylated products 10–12 and not the expected derivatives 7–9.
The compounds 10–12 were characterized by elemental analysis, IR, mass,
and NMR (1H and 13C) spectral data. The probable mechanism of the reaction is
depicted in Scheme 2. The mechanism of the reaction would have been the
result of the ability of the cresols 4–6 to exhibit keto-enol tautomerism.
Scheme 1. Possible synthetic pathway.

Novel Carbon–Carbon Bond Formation
1925
Scheme 2. Probable mechanistic route.
The present article describes a mild and efficient synthesis of o-sub-
stituted phenol derivatives 10–12 by the formation of novel carbon–carbon
bond formation between N-methyl-3-phenyl-3-hydroxypropylamine and
cresols catalyzed by p-TSA.
EXPERIMENTAL
General Remarks
TLC was performed to ascertain proof of the reactions and purity of products.
Melting points were recorded in open capillaries (uncorrected). IR spectra
were recorded with a Perkin-Elmer FT-IR spectrophotometer in KBr pellets,
and only noteworthy absorption levels are listed. 1H NMR spectra were
recorded on a Gemini-2000 spectrometer (200 MHz) in CDCl3 using TMS
as the internal standard. 13C NMR spectra were recorded on a Gemini-2000
spectrometer (50 MHz) in CDCl3 þ CD3CN. The Atmospheric Pressure
Chemical Ionization (APCI) þve mass spectra were recorded on a
Shimadzu LC MS-QP8000a spectrometer. Satisfactory microanalysis was
obtained with a Carlo Erba 1106 and a Perkin-Elmer 240 CHN analyzer.
Typical Procedure for the Synthesis of N-Methyl-3[3-(2-hydroxy-3-
methylphenyl)]phenylpropylamine 10
A suspension of N-methyl-3-phenyl-3-hydroxypropyl amine 3 (20.0 g,
0.12 mol), o-cresol 4 (16.0 g, 0.14 mol), and p-TSA (27.6 g, 0.15 mol), in
toluene (150 mL) was heated with continuous removal of water for 8 h. The
pH of the reaction mixture was adjusted between 7.5 and 8.5 by adding

1926
M. Gopalakrishnan et al.
water (150 mL) and 10% NaOH solution, and layers were separated. The
organic layer was washed with water (2 ꢀ 100 mL), dried over anhydrous
MgSO4, and concentrated to furnish the compound 10, crystallized from
petroleum ether (40 : 60), mp 998C. IR: cm21 (KBr) 3435, 3300, 2945,
1
2911, 2853, 1592, 744, 708. Mass: m/z 256 (Mþ). H NMR: CDCl3 d ppm
2.72–2.75 (m, 2H), 2.25 (s, 3H), 2.04–2.33 (m, 2H), 4.60 (d, 1H), 2.40
(s, 3H), 6.47–7.28 (m, Ar-H). 13C NMR: CDCl3 þ CD3CN d ppm 16.16,
47.12, 32.77, 38.23, 34.38, 126.3–129.3.
N-Methyl-3[3-(2-hydroxy-4-methylphenyl)]phenylpropylamine 11
Mp 96–978C. IR: cm21 (KBr) 3433, 3302, 2925, 2860, 2799, 1600, 744, 698.
1
Mass: m/z 256 (Mþ). H NMR: CDCl3 d ppm 2.58–2.65 (m, 2H), 2.38
(s, 3H), 2.02–2.35 (m, 2H), 4.49 (d, 1H), 2.47 (s, 3H), 6.25–7.15 (m, Ar-H).
13C NMR: CDCl3 þ CD3CN d ppm 17.16, 57.12, 30.29, 37.23, 36.38,
126.7–129.6.
N-Methyl-3[3-(2-hydroxy-5-methylphenyl)]phenylpropylamine 12
Mp 948C. IR: cm21 (KBr) 3436, 3310, 2924, 2854, 2799, 1603, 731, 700.
1
Mass: m/z 256 (Mþ). H NMR: CDCl3 d ppm 2.58–2.66 (m, 2H), 2.15
(s, 3H), 2.04–2.40 (m, 2H), 4.49 (d, 1H), 2.47 (s, 3H), 6.43–7.28 (m, Ar-
H). 13C NMR: CDCl3 þ CD3CN d ppm 18.16, 51.12, 30.29, 39.23, 36.08,
126.4–129.3.
ACKNOWLEDGMENT
We thank the management of Research and Development, Dr. Reddy’s Lab-
oratories Limited, Integrated Product Development, API, Unit-III, for
providing the necessary facilities.
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