An efficient and green La(OTf)3 catalyzed Petasis borono–Mannich reaction for the synthesis of tertiary amines

Article abstract of DOI:10.1007/s11164-016-2551-6

Abstract: A variety of tertiary amine derivatives have been prepared by a one-pot three-component Petasis borono–Mannich reaction of two different salicylaldehydes and 2-formylpyridine, substituted morpholine/piperidines and aryl boronic acids. These reac

Full text of DOI:10.1007/s11164-016-2551-6

Res Chem Intermed
DOI 10.1007/s11164-016-2551-6
An efficient and green La(OTf)3 catalyzed Petasis
borono–Mannich reaction for the synthesis of tertiary
amines
Bijivemula N. Reddy1 Chinthaparthi Radha Rani2
•
•
S. M. Reddy1 Madhvesh Pathak1
•
Received: 7 February 2016 / Accepted: 18 April 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A variety of tertiary amine derivatives have been prepared by a one-pot three-
component Petasis borono–Mannich reaction of two different salicylaldehydes and
2-formylpyridine, substituted morpholine/piperidines and aryl boronic acids. These
reactions were carried out under microwave irradiation using a catalytic amount of
La(OTf)3 in a short reaction time. This procedure has the advantages of high conversions
with excellent chemoselectivity.
Graphical Abstract The attractive features of this methodology are simple procedure,
green reaction, reusability and high efficiency of the catalyst and easy workability.
&
Madhvesh Pathak
madhveshpathak@vit.ac.in
1
2
School of Advanced Science, Vellore Institute of Technology, Vellore, Tamil Nadu 632014,
India
Department of Chemistry, Sri Venkateswara Degree and PG College, Kadapa,
Andhra Pradesh 516003, India
123

B. N. Reddy et al.
Keywords 4-(5-methyl-2-phenyl-2H-1,2,4-triazol-3-yl) piperidine Á La(OTf)3 Á
2-hydroxybenzaldehyde Á PBM reaction
Introduction
Natural products, pharmaceutical agents and synthetic materials contain amine
functionality. They have a major role in the medicinal chemistry/pharmaceutical
industries. For this reason, the synthesis of amines is of prime importance for many
synthetic applications. Over the past decades, various methodologies have been
developed for the synthesis of a broad range of amines. Even so, in synthetic organic
chemistry, a rapid search for new compounds with preferred properties is still in
progress.
Nowadays, the generation of molecular diversity and complexity from simple
and readily available substrates is a major challenge. Therefore, the formation of
several bonds in a single operation is highly desirable to develop industrial
processes. In this way, a multi-component reaction (MCR) is one of the most
efficient ways to rapidly increase the molecular complexity of products with high
levels of atom efficiency [1, 2]. These reactions are convergent chemical processes
and involve well-defined condensation of more than two reactants to form a product
[3], while avoiding expensive starting materials, numbers of reaction steps, time-
consuming isolation and purification of synthetic intermediates [4–6]. Other
advantages of MCRs are numerous possible reagent combinations which usually
result in a high exploratory power, environmentally friendly procedures and high
product selectivity [7]. Therefore, MCRs exhibit the possibility of automatization
and allow systematic variations by their experimental simplicity [8–10]. With these
reasons, MCRs are especially suitable for diversity-oriented synthesis (DOS) [11–
14] and combinatorial synthesis [15].
Among the various MCRs, the Petasis reaction or borono–Mannich reaction
(BMR) [16–20] has been reported for the preparation of several small organic
molecules with distinct functional groups and has received much attention due to its
power to produce various amino compounds (e.g., substituted a-amino acids, a/b-
hydroxyl amines, alkylaminophenols, 2-hydroxyl morpholines, heterocyclic com-
pounds, carboxylic acids and 2H-chromenes) by a three-component coupling of an
aldehyde, an amine and aryl/vinyl boronic acid. However, it requires a period of
24 h or more (also, in some cases, refluxing) in various solvents. In recent years,
Petasis BMR has been reported in solvent-free conditions [21] and also with various
type of catalysts, such as BF3.OEt2 [22], (TFA)2 [23], and solid phase catalysts [24].
Candeias et al. [25] reported that water was a suitable medium for this reaction.
Chiral a-amino acids with various functionalities can also be conveniently prepared
using a chiral biphenol as a catalyst in toluene [26].
In this way, binaphthol catalyzed asymmetric Petasis reactions in the presence of
˚
4 A molecular sieves (MS) has been reported for products with up to 99 % ee [27].
Recently, we reported trititanate nanotubes as a robust solid–acid catalystst for this
reaction [28]. However, these procedures require a longer reaction time.
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An efficient and green La(OTf)3 catalyzed Petasis borono…
On the other hand, in recent years, the use of microwave irradiation (MWI) as a
thermal source to accelerate organic reactions has gained popularity [29]. The
advantages of this technique over conventional methods are shorter reaction times,
cleaner reactions, easy work-up and minimization of thermal decomposition of
products. To date, several three-component reactions have been reported using this
environmentally benign green protocol [30]. Tye and co-workers reported the
reaction between ortho hydroxy benzaldehyde with aryl boronic acids to generate
the products in moderate yields of amino acids under a microwave source [31].
Therefore, the development of a rapid and efficient method for the synthesis of
2-((4-(5-methyl-2-phenyl-2H-1,2,4-triazol-3-yl)piperidin-1-yl)(phenyl)methyl) phe-
nol derivatives is desirable, and we have sought to speed up the Petasis reaction
using focused La(OTf)3 as a catalyst and microwave sources.
Materials and methods
All the chemicals, solvents and reagents procured from Sigma-Aldrich (Hyderabad,
India), Merck (Mumbai, India), Lancaster Chemical (Mumbai, India) and SD Fine
Chemicals were used as received without further purification. All the solvents for
the spectroscopic and other physical studies were reagent grade and were further
purified, employing the reported methods. All the reported melting points in the
experiment were determined in open capillary tubes on a Mel-Temp apparatus. All
the NMR spectra were recorded on a Bruker 400 MHz spectrometer operating at
400 MHz for 1H NMR and 100 MHz for13C NMR. The compounds were dissolved
in CDCl3 and DMSO and the chemical shifts were referenced to TMS. Coupling
constants were calculated in hertz (Hz). The elemental analysis was performed on a
Thermo Finnigan FLASH EA 1112 CHN analyzer, and the mass spectra were
recorded on Agilent LC/MSD SL 1100 instrument. All the microwave reactions
were carried out in a CEM Focused microwave reactor.
General procedure
Synthetic procedures for the model reaction: Synthesis of methyl 3-((2-
chlorophenyl)(morpholino)methyl)-4-hydroxybenzoate (4a)
MWI method A dry Pyrex tube fitted with an air-tight rubber cap was charged with
methyl 3-formyl-4-hydroxybenzoate (1a, 100 mg, 0.55 mmol), morpholine (2a,
48 mg, 0.55 mmol), and 2-chloro phenylboronic acid (3a, 86.0 mg, 0.55 mmol).
Under argon, La(OTf)3 (3.0 mg, 0.005 mmol) and argon-purged 1,4-dioxane
(2 mL) were added. The resulting mixture was placed in the CEM microwave
reactor and allowed to react at 39–110 °C for 2–22 min (Table 2). Then the reaction
mixture was cooled and filtered and the filtrate was transferred to a separating funnel
and diluted with ethyl acetate and water. The organic phase was separated and dried
over anhydrous sodium sulfate. The organic solution was filtered and the filtrate
concentrated prior to silica gel chromatography using hexane–ethyl acetate
(50:1).The fractions were concentrated and dried in vacuum to get 196 mg (yield,
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B. N. Reddy et al.
98 %) of methyl 3-((2-chlorophenyl)(morpholino)methyl)-4-hydroxybenzoate (4a)
as a white solid, m.p. 140–142 °C. The used catalyst from different experiments was
combined by filtration, washed with ether and dried overnight in a vacuum oven and
reused for further reactions.
Conventional/oil bath heating method In the second regular conventional method,
all the mentioned reactants in the MWI method were stirred at RT and 60 °C for
10–26 h in an oil bath, and the workup procedure and the purification of the
products were carried out in a similar way by following the MWI procedure.
The above MWI procedure was applied successfully for the preparation of all the
other titled compounds (4b–q) which were obtained (TLC) in 2 min at high yields
(Table 2). These compounds were characterized by 1H and 13C NMR and LC/MSD
spectral data.
Synthesis of tert-butyl 4-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-
carboxylate (6)
To a stirred solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid 5
(5.0 g, 21.83 mmol) in DMF (5.0 mL) was added N, N-isopropylehylamine
(5.5 mL, 32.74) followed by acetamidinehydrochloride (2.45 g, 26.2 mmol) and
HATU (9.9 g, 26.2 mmol) at RT, then stirred for 2 h. Next, phenylhydrazine
hydrochloride (3.4 g, 24 mmol) and acetic acid (4 mL, 65.5 mmol) were added
(Scheme 2). The resulting reaction mixture was stirred at 80 °C for 4 h. The
reaction mass was diluted with water and extracted by ethyl acetate, dried over
anhydrous sodium sulfate and concentrated under reduced pressure to get the crude
compound. The crude compound was triturated with diethyl etherto give compound
6 (7 g, quantitative yield) as an off-white solid. It was used for the next step without
further purification.
Synthesis of 4-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperidine (2b)
To a stirred solution of tert-butyl 4-(5-methyl-2-phenyl-2H-1, 2, 4-triazol-3-yl)
piperidine-1-carboxylate (2 g, 5.8 mmol) in dioxane HCl (10 mL) and stirred for 16 h
(Scheme 2). Then, the solvent was concentrated under reduced pressure to obtain a
residue, which was triturated with diethyl ether to give 2b (1.3 g, 78 %) as a salt.
1
IR (KBr, mmax (cm-1)): 3412, 3215, 2772, 2714, 1626, 1557, 1296; H NMR
(400 MHz, dmso-d6) d: 8.86 (s, 1H), 8.69 (br s, 1H), 7.60–7.50 (m, 5H), 3.28 (d,
J = 12.8 Hz, 2H), 3.17–3.09 (m, 1H), 2.92 (d, J = 10.0 Hz, 2H), 2.30 (s, 3H),
1.97–1.92 (m, 4H);13C NMR (100.57 MHz, dmso-d6) d: 156.5, 156.5, 136.0, 129.9,
129.9, 125.6, 42.0, 30.4, 26.6, 12.6.
Physical, analytical, and spectral data for the titled compounds, (4a–q)
Methyl 3-((2-chlorophenyl)(morpholino)methyl)-4-hydroxybenzoate (4a) Yield
97 %; white solid, m.p. 158–160 °C; IR (KBr, mmax (cm-1)): 3624 (Ar-OH), 3042
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An efficient and green La(OTf)3 catalyzed Petasis borono…
(C–HAr), 2964 (C–Hali), 1740 (C=O), 1575 (Ar–C=C), 1230 (C–N), 1102 (C–O); 1H
NMR (400 MHz, CDCl3) d: 12.6 (s, 1H), 7.84 (d d, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H),
7.73 (d, J = 2.0 Hz, 1H), 7.56 (m, 1 H), 7.40 (t, J = 3.6 Hz, 1H), 7.20 (m, 2H),
6.88 (d,J = 8.4 Hz, 1 H), 5.3 (s, 1 H), 3.82 (s, 3 H), 3.6 (m, 4 H), 2.7 (m, 2 H), 2.58
(m, 2 H); 13C NMR (100.57 MHz, CDCl3) d: 166.6, 160.2, 136.0, 134.1, 131.4,
130.9, 130.0, 129.4, 127.8, 124.0, 121.6, 117.2, 69.6, 66.8. 51.8. Anal. Calcd for
C19H20ClNO4: C, 63.07; H, 5.57; N, 3.87 %; Found: C, 63.04; H, 5.54; N, 3.83.
Methyl 4-hydroxy-3-(morpholino (p-tolyl) methyl) benzoate (4b) Yield 98 %;
thick liquid, IR (KBr, mmax (cm-1)): 3624 (Ar-OH), 3046 (C–HAr), 2960 (C–Hali),
1742 (C=O), 1570 (Ar–C=C), 1236 (C–N), 1101 (C–O);1H NMR (400 MHz,
CDCl3) d: 12.58 (s, 1H), 7.81 (dd,J1 = 2 Hz, J2 = 8.4 Hz, 1H), 7.67 (d,
J = 2.0 Hz, 1H), 7.27 (t, J = 4.4 2H), 7.11 (d, J = 8.0 Hz, 2 H), 7.86 (d,
J = 8.4 Hz, 1H), 4.44 (s, 1 H), 3.8 (s, 3 H), 3.79 (m, 4 H), 2.45 (m, 4 H), 2.29 (s, 3
H). 13C NMR (100.57 MHz, CDCl3) d: 166.7, 160.8, 138.2, 135.6, 131.5, 130.6,
129.7, 128.3, 124.5, 121.5, 117.0, 76.2, 66.8, 53.4, 21.0. Anal. Calcd for
C20H23NO4: C, 70.36; H, 6.79; N, 4.10 % Found C, 70.34; H, 6.75; N, 4.7.
Methyl
4-hydroxy-3-(morpholino(4-morpholinophenyl)methyl)benzoate
(4c)
Yield 97 %; white solid, m.p. 160–162 °C; IR (KBr, mmax (cm-1)): 3620 (Ar-
OH), 3048 (C–HAr), 2962 (C–Hali), 1744 (C=O), 1576 (Ar–C=C), 1230 (C–N), 1103
(C–O);1H NMR (400 MHz, CDCl3) d: 12.65 (s, 1 H), 7.81 (m, 1H), 7.67 (d,
J = 2.0 Hz, 1H), 7.27 (t, J = 4.4 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.86 (d,
J = 8.4 Hz, 1H), 4.44 (s, 1H), 3.8 (s, 3H), 3.79 (m, 4 H), 2.45 (m, 4H), 2.29 (s, 3 H).
13C NMR (100.57 MHz, CDCl3) d: 166.7, 160.8, 138.2, 135.6, 131.5, 130.6, 129.7,
128.3, 124.5, 121.5, 117.01 76.2, 66.8, 53.4, 21.0. Anal. Calcd for C23H28N2O5: C,
66.97; H, 6.84; N, 6.79 % Found, 66.95; H, 6.80; N, 6.76.
Methyl 4-hydroxy-3-((3-(methylsulfonamido)phenyl)(morpholino)methyl)benzoate
(4d) Yield 96 %; thick liquid, IR (KBr, mmax (cm-1)): 3627 (Ar–OH), 3054 (C–
HAr), 2969 (C–Hali), 1749 (C=O), 1579 (Ar–C=C), 1233 (C–N), 1106 (C–O); H
1
NMR (400 MHz, CDCl3) d: 12.40 (s, 1 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.27 (t,
J = 8.8 Hz, 2 H), 7.13(m, 1 H), 7.40 (t, J = 3.6 Hz, 1 H), 7.20(m, 2 H), 6.88 (d,
J = 8.4 Hz, 1 H), 5.3 (s, 1 H), 3.82 (s, 3 H), 3.6(m, 4 H), 2.0.7 (m, 2 H), 2.58 (m, 2
H). 13C NMR (100.57 MHz, CDCl3) d: 166.6, 160.2, 136.0, 134.1, 131.4, 130.9,
130.0, 129.4, 127.8, 124.0, 121.6, 117.23 69.6, 66.8. 51.8. Anal. Calcd for
C20H24N2O6S: C, 57.13; H, 5.75; N, 6.66 % Found: C, 57.10; H, 5.71; N, 6.62.
Methyl
3-((3,5-dimethylisoxazol-4-yl)(morpholino)methyl)-4-hydroxybenzoate
(4e) Yield 95 %; white solid, m.p. 158–160 °C; IR (KBr, mmax (cm-1)): 3622
(Ar–OH), 3051 (C–HAr), 2963 (C–Hali), 1744 (C=O), 1567 (Ar–C=C), 1230 (C–N),
1101 (C–O) 1H NMR (400 MHz, CDCl3) d: 12.39 (s, 1 H), 7.83–7.80 (m, 1 H), 7.52
(d, J = 1.6 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 1 H), 4.65 (s, 1 H), 3.84 (s, 3 H), 3.7 (m,
4 H), 2.5 (m, 4 H), 2.3 (s, 3 H), 2.2 (s, 3 H), 13C NMR (100.57 MHz, CDCl3) d:
167.5, 166.5, 161.5, 131.1, 121.8, 120.6, 115.0, 66.5, 51.8. Anal. Calcd for
C18H22N2O4: C, 65.44; H, 6.71; N, 8.48 % Found: C, 65.40; H, 6.67; N, 8.45.
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B. N. Reddy et al.
2-((2-Chlorophenyl)(morpholino)methyl)phenol (4f) Yield 98 %; white solid,
m.p. 84–86 °C; IR (KBr, mmax (cm-1)): 3639 (Ar–OH), 3023 (C–HAr), 2969 (C–
1
Hali), 1568 (Ar–C=C), 1215 (C–N), 1101 (C–O). H NMR (400 MHz, CDCl3) d:
11.5 (s, 1 H), 7.82 (m, 1 H), 7.70 (d, J = 2.0 Hz, 1H), 7.32–7.31 (m, 4 H), 6.87 (d,
J = 3.6 Hz, 1H), 6.86 (d, J = 4.8 Hz, 2 H), 4.47 (s, 1 H), 3.82 (s, 3 H), 3.77 (m, 4
H), 3.0 (s, 3 H), 2.49 (m, 4 H), 13C NMR (100.57 MHz, CDCl3) d: 166.8, 160.7,
140.4, 137.8, 137.7, 136.0, 131.4, 131.0.130.7, 130.5, 124.2, 121.6, 112.5, 107.5,
69.7, 66.8. 51.9, 39.6. Anal. Calcd for C17H18ClNO2 C, 67.21; H, 5.97; N, 4.61 %
Found: C, 67.17; H, 11.64; N, 4.58.
2-((3, 4-Dimethoxyphenyl)(morpholino)methyl)phenol (4g) Yield 97 %; white
solid, m.p. 47–50 °C; IR (KBr, mmax (cm-1)): 3615 (Ar–OH), 3029(C–HAr), 2960
(C–Hali), 1567 (Ar–C=C), 1220 (C–N), 1105 (C–O). 1H NMR (400 MHz, CDCl3) d:
11.65 (s, 1 H), 7.12 (t d, J1 = 1.6 Hz, J2 = 7.2 Hz, 1 H), 6.99 (s, 1H), 6.94 (d d,
J1 = 1.6 Hz, J2 = 6.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.79–6.71 (m, 2 H), 4.3
(s, 1 H), 3.86 (s, 6 H), 3.79–3.65 (m, 4 H), 2.5 (m, 2 H), 2.45(m, 2 H), 13C NMR
(100.57 MHz, CDCl3) d: 156.0, 149.2,131.9, 129.3, 128.6, 125.0, 121.0, 119.6,
117.0, 111.0, 156.0, 148.8, 131.9, 129.3, 128.6, 125.0, 121.0, 119.6, 117.0, 111.0,
66.9, 55.8, 52.2. Anal. Calcd for C19H23NO4 C, 69.28; H, 7.04; N, 4.25 % Found: C,
69.25; H, 7.01; N, 4.21.
2-((4-Methoxyphenyl)(morpholino)methyl) phenol (4h) Yield 94 %; white solid;
m.p. 46–48 °C; IR (KBr, mmax (cm-1)): 3630 (Ar–OH), 3035 (C–HAr), 2969 (C–
1
Hali), 1580 (Ar–C=C), 1225 (C–N), 1103 (C–O); H NMR (400 MHz, CDCl3) d:
11.65 (s, 1 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.11 (t d, J1 = 1.6 Hz, J2, 8.8 Hz, 1 H),
6.92 (d d, J1 = 1.2 Hz, J2 = 7.6 Hz, 2 H), 6.84 (t, J = 8.8 Hz, 2 H), 6.72 (t,
J = 7.2 Hz, 2 H), 4.37 (s, 1 H), 3.7 (s, 1 H), 3.76 (m, 4 H), 2.46–2.42 (m, 4 H), 13
C
NMR (100.57 MHz, CDCl3) d: 159.3, 156.1,131.3, 129.7,129.3, 128.5, 125.1,
119.5, 117.0, 114.2, 76.0, 67.0, 55.2, 52.1. Anal. Calcd for C18H21NO3 C, 72.22; H,
7.07; N, 4.68 % Found C, 72.17; H, 7.0; N, 4.60.
2-((2-(Cyclopropylmethoxy) phenyl) (morpholino) methyl) phenol (4i) Yield
94 %; white solid; m.p. 94–96 °C; IR (KBr, mmax (cm-1)): 3635 (Ar–OH), 3030
(C–HAr), 2957 (C–Hali), 1582 (Ar–C=C), 1229 (C–N), 1102 (C–O); 1H NMR
(400 MHz, CDCl3) d: 11.9 (s, 1 H), 7.4 (d, 7.2 Hz, 1 H), 7.26–7.09 (m, 2 H),
7.49–7.43 (m, 2 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.89–6.82 (m, 3 H), 6.71 (t,
J = 6.8 Hz, 1 H), 5.32 (s, 1 H), 3.91–3.82 (m, 2 H), 3.76–3.74 (m, 4 H), 2.69–2.54
(m, 4 H), 1.35- 1.32 (m, 1H), 0.68 (d, J = 7.6 Hz, 1H), 0.39 (s, 1 H), 13C NMR
(100.57 MHz, CDCl3) d: 157.0, 156.3, 129.5, 129.3, 128.8, 128.4, 127.0, 125.0,
119.2, 116.8, 111.8, 72.9, 67.1, 65.7, 10.3, 3.3 Anal. Calcd for C21H25NO3 C, 74.31;
H, 7.42; N, 4.13 % Found C, 72.27; H, 7.40; N, 4.11.
2-(Morpholino (naphthalen-2-yl) methyl) phenol (4j) Yield 96 %; white solid;
m.p. 74–76 °C; IR (KBr, mmax (cm-1)): 3630 (Ar–OH), 3035 (C–HAr), 2965 (C–
1
Hali), 1587 (Ar–C=C), 1237 (C–N), 1103 (C–O); H NMR (400 MHz, CDCl3) d:
11.8 (s, 1 H), 7.82–7.76 (m, 4 H), 7.62 (d, J = 7.6 Hz, 1H), 7.49–7.43 (m, 2 H),
7.12 (t d, J1 = 1.6 Hz, J2 = 7.6 Hz,1H), 7.99 (d, J = 7.2 Hz, 1 H), 6.88 (d,
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An efficient and green La(OTf)3 catalyzed Petasis borono…
J = 7.6 Hz, 1 H), 6.72 (t, J = 7.2 Hz, 1H), 4.58 (s, 1 H), 3.76 (m, 4 H), 2.66–2.47
(m, 4 H), 13C NMR (100.57 MHz, CDCl3) d: 156.0, 136.8, 133.3, 133.0, 129.5,
129.0, 128.7, 128.0, 127.6, 126.3, 125.7, 124.5, 119.6, 117.1, 66.9, 52.3, 29.7 Anal.
Calcd for C21H21NO2 C, 78.97; H, 6.63; N, 4.39 % Found C, 78.94; H, 6.60; N,
4.34.
2-(Morpholino(thiophen-2-yl)methyl)phenol (4k) Yield 92 %; white solid; m.p.
110–112 °C; IR (KBr, mmax (cm-1)): 3637 (Ar–OH), 3040 (C–HAr), 2967 (C–Hali),
1564 (Ar–C=C), 1230 (C–N), 1114 (C–O); 1H NMR (400 MHz, CDCl3) d: 11.85 (s,
1 H), 7.28 (m, 2 H), 7.19–7.12 (m, 2 H), 7.49–7.43 (m, 2 H), 7.01 (d, J = 7.6 Hz, 1
H), 6.89-6.82 (m, 3 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.85 (d, J = 7.6 Hz, 1 H), 6.74 (t,
J = 7.2 Hz, 1 H), 4.7 (s, 1H), 3.79–3.74 (m, 4 H), 2.58–2.43 (m, 4 H), 13C NMR
(100.57 MHz, CDCl3) d: 156.1, 139.5, 129.1, 128.8, 127.1, 126.7, 127.0,124.4,
123.7, 116.7, 119.5, 116.9, 71.1, 66.9, 51.8. Anal. Calcd for C15H17NO2S C, 65.43;
H, 6.22; N, 5.09 % Found C, 65.40; H, 6.20; N, 5.04.
2-((2-Chlorophenyl)(4-(5-methyl-2-phenyl-2H-1,2,4-triazol-3-yl)piperidin-1-
yl)methyl) phenol (4l) Yield 82 %; white solid;m.p. 180–182 °C; IR (KBr, mmax
(cm-1)): 3630 (Ar–OH), 3071 (C–HAr), 2939(C–Hali), 1594 (Ar–C=C), 1296 (C–N),
1H NMR (400 MHz, CDCl3) d: 10.36 (brs, 1 H), 7.66 (d, J = 6.8 Hz, 1 H),
7.56–7.42 (m, 5 H), 7.39–7.28 (m, 2 H), 7.26–7.21 (m, 1 H), 6.76–6.69 (m, 2 H),
5.21 (s, 1 H), 2.89–2.69 (m, 4 H), 2.29 (s, 3 H), 2.10–2.01(m, 2 H), 1.83–1.76 (m, 4
H). 13C NMR (100.57 MHz, CDCl3) d: 159.6, 159.1, 156.4, 137.5, 133.7, 129.7,
129.3, 129.2, 129.1, 129.0, 129.0, 128.5, 128.0, 126.4, 125.6, 119.5, 116.2, 65.0,
51.3, 50.8, 33.2, 31.2, 14.0. Anal. Calcd for C27H27ClN4O; C, 70.65; H, 5.93; N,
12.21 % Found C, 70.60; H, 5.90; N, 12.19.
2-((4-(5-Methyl-2-phenyl-2H-1, 2, 4-triazol-3-yl) piperidin-1-yl) (phenyl) methyl)
phenol (4m) Yield 80 %; white solid; m.p. 183–185 °C; IR (KBr, mmax (cm-1)):
3637 (Ar–OH), 3067 (C–HAr), 2940 (C–Hali), 1590 (Ar–C=C), 1286 (C–N), H
1
NMR (400 MHz, CDCl3) d: 11.71 (brs, 1 H), 748–7.26 (m, 10 H), 7.08 (d,
J = 7.16 Hz, 1 H), 6.86 (t, J = 7.96 Hz, 2 H), 6.68 (s 1 H), 4.47 (s, 1 H), 3.25 (d,
J = 8.6 Hz, 1 H), 2.89 (d, J = 8.2 Hz, 1 H), 2.78 (s, 1H), 2.42 (s, 3H), 2.19–2.02
(m, 4 H), 13C NMR (100.57 MHz, CDCl3) d: 156.46, 156.43, 136.07, 129.95,
129.88, 125.59, 41.95, 30.37, 26.56, 12.56. Anal. Calcd for C27H28N4O, C, 76.39;
H, 6.65; N, 13.20 % Found, 76.35; H, 6.61; N, 13.18.
2-((4-(5-Methyl-2-phenyl-2H-1,2,4-triazol-3-yl)piperidin-1-yl)(4-morpholinophenyl)
methyl)phenol (4n) Yield 89 %;white solid; m.p. 184–186 °C; IR (KBr, mmax
(cm-1)): 3640 (Ar–OH), 3070 (C–HAr), 2950 (C–Hali), 1585 (Ar–C=C), 1270 (C–
N), 1115 (C–O)1H NMR (400 MHz, CDCl3) d: 11.9 (br s, 1 H), 7.47 (t,
J = 7.36 Hz, 3 H), 7.33(d, J = 7.12 Hz, 2 H), 7.26 (s, 2 H), 7.07 (d, J = 7.6 Hz, 2
H), 6.85 (d, J = 5.5 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 4 H), 6.66 (d, J = 7.3 Hz, 1 H),
4.40 (s, 1H), 3.82 (t, J = 8.3 Hz, 4 H), 3.21 (d, J = 10.3 Hz, 1 H), 3.12 (d,
J = 3.8 Hz, 4 H), 2.42 (s, 3 H), 2.14–2.07 (m, 4 H), 1.86–1.25 (m, 4 H) 13C NMR
(100.57 MHz, CDCl3) d: 160.1, 158.5, 156.7, 150.6, 137.2, 130.2, 129.4, 129.0,
123

B. N. Reddy et al.
128.2, 125.3, 125.3, 119.0, 117.0, 115.3, 75.3, 66.8, 52.5, 50.0, 48.8, 33.2, 31.0,
30.7, 29.6,13.7, 125.6, 42.0, 30.4, 26.6, 12.6 Anal. Calcd for C31H35N5O2.
2-((4-(5-Methyl-2-phenyl-2H-1, 2, 4-triazol-3-yl) piperidin-1-yl) (4-phe-
noxyphenyl) methyl) phenol (4o) Yield 89 %; white solid; m.p. 118–120 °C; IR
(KBr, mmax (cm-1)): 3645 (Ar–OH), 3067 (C–HAr), 2958 (C–Hali), 1590 (Ar–C=C),
1274 (C–N), 1H NMR (400 MHz, CDCl3) d: 11.73 (br s, 1 H), 7.48 (d, J = 7.12 Hz,
3 H), 7.36–7.26 (m, 6 H), 7.12 (d, J = 5.76 Hz, 2 H), 7.99 (d, J = 7.68 Hz, 2 H),
6.91–6.84 (m, 4 H), 6.71 (d, J = 7.12 Hz, 1 H), 4.43 (s, 1H), 3.23 (d, J = 8.56 Hz,
1 H), 2.99 (d, J = 9.04 Hz, 2 H), 2.79 (s, 1 H), 2.43 (s, 3 H),2.19–1.84 (m, 4 H),
1.84–1.26 (m, 4 H) 13C NMR (100.57 MHz, CDCl3) d: 160.1, 158.4, 157.0, 156.6,
156.5, 137.2, 133.9, 130.9, 129.7, 129.4, 129.0, 128.4, 125.3, 123.5, 119.2, 119.0,
118.5, 117.0, 75.41, 52.5, 50.0, 33.2, 30.7, 13.7; Anal. Calcd for C33H32N4 C, 76.72;
H, 6.24; N, 10.84 % Found C, 76.70; H, 6.20; N, 10.80.
2-((4-(3-Methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperidin-1-yl)(phenyl)methyl)pyri-
dine (4p) Yield 75 %; white solid; m.p. 118–120 °C; IR (KBr, mmax (cm-1)): 3067
(C–HAr), 2970 (C–Hali), 1580 (Ar–C=C), 1269 (C–N), 1H NMR (400 MHz, CDCl3)
d: 8.39 (s, 1 H), 8.05 (s, 1 H), 7.58 (d, J = 7.78 Hz, 2H), 7.52–7.46 (m, 3 H),
7.43(d, J = 7.28 Hz, 2 H), 7.37 (d, J = 7.39 Hz, 2 H), 7.25 (t, J = 7.43 Hz, 2 H),
7.15 (d, J = 5.16 Hz, 2 H), 4.42 (s, 1 H), 2.78–2.7 (m, 3 H), 1.86–1.69 (m, 6 H) 13
C
NMR (100.57 MHz, CDCl3) d: 159.4, 159.2, 149.1, 141.7, 137.4, 137.1, 134.8,
134.4, 130.9, 130.3, 129.8, 128.7, 128.5, 128.4, 128.3, 127.7, 127.3, 125.5, 122.4,
122.0, 77.1, 66.0, 63.1, 51.7, 51.3, 33.3, 30.0, 13.9. Anal. Calcd for C26H27N5 C,
76.25; H, 6.65; N, 17.10 % Found C, 76.20; H, 6.60; N, 17.08.
4-(4-((4-(3-Methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperidin-1-yl)(pyridin-2-
yl)methyl)phenyl)morpholine (4q) Yield 79 %; white solid; m.p. 118–120 °C;
IR (KBr, mmax (cm-1)): 3080 (C–HAr), 2967 (C–Hali), 1573 (Ar–C=C), 1275 (C–N),
1
1107 (C–O), H NMR (400 MHz, CDCl3) d: 8.37 (d, J = 3.6 Hz, 1 H), 7.71 (t,
J = 7.44 Hz, 1 H), 7.57–7.42 (m, 5 H), 7.21–7.14 (m, 3H), 6.82 (d, J = 8.08 Hz, 2
H), 4.30 (s, 1 H), 3.67 (s, 4 H), 3.0–2.92 (m, 4 H), 2.79-2.70 (m, 3H), 2.27 (s,3 H),
1.89-1.2(m, 6 H). 13C NMR (100.57 MHz, CDCl3) d: 162.9, 159.4, 159.2, 150.3,
149.0, 137.4, 137.02, 132.1, 129.9, 129.2, 129.0, 125.5, 122.2, 122.0, 121.7, 115.3,
76.6, 66.4, 51.9, 51.2, 48.7, 33.4, 31.0, 31.0, 14.10, 129.7, 129.3, 129.2, 129.1,
129.0, 128.7, 128.5, 127.9, 126.4, 125.6, 119.5, 116.2, 65.0, 51.3, 50.8, 33.2, 31.2,
14.0. Anal. Calcd for C26H27N5 C, 76.25; H, 6.65; N, 17.10 % Found C, 76.20; H,
6.60; N, 17.08.
Results and discussion
Our initial efforts focused on developing optimal reaction conditions for the
condensation of methyl 3-formyl-4-hydroxybenzoate (1a), morpholine (2a) and
2-chlorophenylboronic acid (3a) to generate methyl 3-((2-chlorophenyl)(mor-
pholino)methyl)-4-hydroxybenzoate (4a) as a model reaction (Scheme 1). This
123

An efficient and green La(OTf)3 catalyzed Petasis borono…
Scheme 1 Synthesis of methyl 3-((2-chlorophenyl) (morpholino) methyl)-4-hydroxybenzoate (4a)
Table 1 Optimization of reaction conditions for the synthesis of methyl 3-((2-chlorophenyl)(mor-
pholino)methyl)-4-hydroxybenzoate (4a)
Entry
Catalyst
(mol%)
Solvent
Conventional method
MWI methoda
Temp
(°C)
Time
(h)
Yield
(%)b
Temp
(°C)
Time
(min)
Yield (%)b
1
Free
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Ethanol
RT
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
26
12
15
11
16
12
12
12
10
10
10
10
10
10
12
10
10
10
10
10
10
10
10
10
10
40
54
58
60
61
63
62
65
64
65
66
68
73
80
50
65
88
90
90
84
82
78
81
83
82
100
80
80
80
80
80
80
80
80
80
80
80
80
80
60
80
80
80
80
78
66
110
101
39
76
22
7
8
6
7
6
6
6
4
4
4
4
4
2
2
2
2
2
2
2
2
2
2
2
2
68
2
CuI (5)
75
3
AgF (5)
72
4
InF3 (5)
75
5
FeCl3.SiO2 (5)
Pd(PPh3)4 (5)
PdCl2 (5)
80
6
84
7
82
8
Pd(OAc)2 (5)
Y(OAc)3.H2O (5)
Yb(OAc)2 (5)
Yb(OTf)3 (5)
AgOTf (5)
85
9
87
10
11
12
13
14c
15
16
17
18
19
20
21
22
23
24
25
86
85
85
Sc(OTf)3 (5)
La(OTf)3 (5)
La(OTf)3 (1)
La(OTf)3 (2)
La(OTf)3 (3)
La(OTf)3 (7)
La(OTf)3 (10)
La(OTf)3 (5)
La(OTf)3 (5)
La(OTf)3 (5)
La(OTf)3 (5)
La(OTf)3 (5)
La(OTf)3 (5)
86
97,94,91,87
62
75
90
98
98
95
92
94
94
94
93
THF
Toluene
MeOH
DCM
CCl4
Reaction of 3-formyl-4-hydroxy benzoate (1a, 0.55 mmol), morpholine (2a, 0.55 mmol), and 2-chloro
phenyl boronic acid (3a, 0.55 mmol)
a
All the reactants irradiated with 100 W microwaves
Isolated yields with [95 % purity as determined by 1H NMR and LC–MS analysis
b
c
Catalyst was reused five times
123

B. N. Reddy et al.
Fig. 1 Effect of solvent on catalytic activity of La(OTf)3 in Petasis reaction
Fig. 2 Reusability of the La(OTf)3 catalyst in Petasis reaction
Scheme 2 Synthesis of 4-(3-methyl-1-phenyl-1H-1,2,4-triazol-5-yl)piperidine (2b)
123

An efficient and green La(OTf)3 catalyzed Petasis borono…
Scheme 3 Synthesisofsubstituted phenyl/dimethylisoxazol/naphthalene/thiophen (morpholino/substituted
piperidin) phenyl/phenol/substituted benzoate/pyridine methyl derivatives (4a–q)
was investigated by utilizing different solvents and various catalysts under both
conventional and microwave conditions (Table 1).
We first investigated the model reaction without a catalyst in 1, 4-dioxane. The
desired product (4a) was obtained in lower yield even after a prolonged reaction
time under both conditions (Table 1, entry 1). When the reaction was performed
using various catalysts, it proceeded effectively to produce the desired product in
high yields (Table 1, entries 2–4). This indicates that the reaction is faster in the
presence of catalyst than that of the un-catalyzed pathway. Consequently, the
reaction was performed in the presence of La(OTf)3 to obtain 4a in high yields
under both conditions even at a lower catalytic amount (Table 1, entry 14).
In addition to this, we observed that the concentration of the catalyst played a
major role in this Petasis reaction as, when varying the concentration of La(OTf)3
from just 2 to 10 mol%, the product yield varied from 75 to 98 % (Table 1, entries
14–19). This shows that 5 mol% of La(OTf)3 is the suitable and sufficient choice for
the optimum reaction rate and yield (Table 1, entry 14). Considerable increases in
yields were not observed when an excess amount of the catalyst was used. These
results clearly indicate that 5 mol% La(OTf)3 is optimal for the synthesis of titled
compounds.
Next, we studied the influence of solvents in the model reaction using various
organic solvents at different reaction temperatures with 5 mol% of La(OTf)3
(Fig. 1). A slow rate of reaction was observed in CCl4, MeOH, DCM, THF, toluene,
and EtOH with low product yields (Table 1, entries 20–25). There was a better rate
of reaction with improved product yield in 1, 4-dioxane (Table 1, entry 14). High
yields were observed in 1,4-dioxane at 60 and 80 °C in conventional and MWI
conditions, respectively (Table 1, entry 14).
In order to investigate the recyclability and reusability of the catalyst, it was
recovered by simple filtration, washing twice with dry ether (10 mL) and dried in
vacuum at 60 °C. Under similar reaction conditions, the dried catalyst was reused
for subsequent experiments in at least five consecutive cycles without much
appreciable loss in its catalytic activity (Table 1, entry 14). These data demonstrate
the high stability of the catalyst under the reaction conditions (Fig. 2) under
microwave irradiation conditions.
A novel amine, 4-(5-methyl-2-phenyl-2H-1, 2,4-triazol-3-yl) piperidine (2b), was
prepared in two steps (Scheme 2). First, a commercially available 1-(tert-
butoxycarbonyl)piperidine-4-carboxylic acid (5) was treated with phenylhydrazine
hydrochloride in the presence of HATU, DIPEA and acetamidine.HCl to obtain the
123

B. N. Reddy et al.
Table 2 Synthesis of substituted phenyl/dimethylisoxazol/naphthalene/thiophen (morpholino/substituted
piperidin) phenyl/phenol/substituted benzoate/pyridine methyl derivatives (4a–q)
Amine
(2a-f)
Time
(min)
Yield
(%)a
Entry
Aldehyde (R)
R3
Product
O
N
O
Cl
1
2
97
O
OH
(4a)
O
N
O
2
3
1a
1a
2a
2a
2
2
98
97
O
OH
(4b)
O
N
O
O
OH
N
O
(4c)
O
N
O
O
NH
O
S
4
5
1a
1a
2a
2a
2
2
96
95
O
OH
(4d)
6
7
2a
2a
3a
2
2
98
97
1b
123

An efficient and green La(OTf)3 catalyzed Petasis borono…
Table 2 continued
Amine
Time
(min)
Yield
(%)a
Entry
8
Aldehyde (R)
R3
Product
(2a-f)
1b
2a
2
2
2
2
94
94
96
92
9
1b
1b
1b
2a
2a
2a
10
11
N
N
N
12
1b
3a
2
82
N
Cl
OH
(4l)
N
N
N
13
1b
2b
2
80
N
OH
(4m)
123

B. N. Reddy et al.
Table 2 continued
Amine
(2a-f)
Time
(min)
Yield
(%)a
Entry
Aldehyde (R)
R3
3c
Product
N
N
N
14
1b
2b
2
89
N
OH
(4n)
N
O
N
OH
N
N
HO
B
15
1b
2b
2
86
N
O
(3l)
OH
(4o)
O
N
N
N
16
2b
3k
2
75
N
N
(4p)
N
N
N
17
1c
2b
3c
2
78
N
N
N
O
(4q)
18
19
1b
1b
3k
3k
15
15
---
---
123

An efficient and green La(OTf)3 catalyzed Petasis borono…
Table 2 continued
Amine
Time
(min)
Yield
(%)a
Entry
20
Aldehyde (R)
1b
R3
3k
Product
(2a-f)
12
13
21
1b
3k
12
19
Reaction conditions: various aldehydes (1a–c), various amines (2a–f) and aryl boronic acids (3a–l) on
5 mol% La(OTf)3 catalyst at 100 W power MWI in 1,4-dioxane
a
Isolated yields
Scheme 4 Schematic illustration of formation of the titled compounds (4a–u)
tert-butyl 4-(5-methyl-2-phenyl-2H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (6).
In the next step, Boc group was de-protected using dioxane.HCl to obtain the
desired amine 2b.
123

B. N. Reddy et al.
The condensation of various aldehydes (1a–c) and amines (2a–b) with a range of
aryl boronic acids (3a–l) using 5 mol% La(OTf)3 gave the desired compounds (4a–
q) in good to excellent yields without the formation of side products under MWI
with 100 W power at 80 °C in 1,4-dioxane (Scheme 3), and the results are
presented in Table 2. Notably, all ortho-hydroxy aldehydes participated effectively
in this reaction and the corresponding products were obtained in excellent product
yields (Table 2, entries 1–15). But aldehydes without a hydroxyl group at the ortho-
position did not result in good yields (Table 2, entries 16 and 17). Other than this
effect, none of the factors (e,g., electron donor) influenced the rate of reaction to
obtain the product yields. In addition to these cyclic secondary amines, to further
establish the scope and ultimate utility of the chemistry we were tested the reaction
with few general secondary amines (2c–f). In this study, most of the simple amines
are not proceed the reaction at all, even at higher temperatures and longer reaction
times (Table 2, entries 18 and 19). Even the phenyl substituted amines did not
shown significant product yields (Table 2, entries 20 and 21).
Reaction mechanism of formation of titled compounds
At the beginning of this one-pot three-component Petasis BMR, the La(OTf)3
catalyst should connect with the two components of aldehyde followed by the amine
to form the exiplex complex (B) under MWI. Then, this complex can also interact
with boronic acid derivatives by one of the OTf ligands and form the complex
C. All these are together at one place on the catalyst surface and interact with each
other in the Mannich condensation followed by elimination of the OH group and the
formation of the desired titled products (4a–u) selectively in higher yields
(Scheme 4). Finally, the catalyst complex with boronic acid derivative residues
undergoes cleavage as the pure catalyst with boronic acid as a byproduct.
Conclusion
In summary, a series of tertiary amine derivatives were synthesized by one-step
Petasis reaction under microwave irradiation using La(OTf)3 as an efficient catalyst.
The procedure exhibits several advantages such as mild reaction conditions, shorter
reaction times, high efficiency, a wide range of functional group tolerance and
1
excellent product yields. Their structures were characterized H NMR, 13C NMR,
HRMS and elemental analysis.
Acknowledgments The authors express their grateful thanks to the Department of Chemistry, Vellore
Institute of Technology, Vellore-632014, Tamil Nadu, India for providing financial assistance and
infrastructure facilities for this work.
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