Rapid synthesis of alkylaminophenols via the Petasis borono-Mannich reaction using protonated trititanate nanotubes as robust solid-acid catalysts

Article abstract of DOI:10.1039/c5ra25064a

An effective and rapid synthesis of alkylaminophenols using the one-pot three-component Petasis borono-Mannich (PBM) reaction was carried out using protonated trititanate (H₂Ti₃O₇) nanotubes as a heterogeneous solid-acid c

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Peddiahgari, R. P. R. Bhoomireddy, D. Praveen Kumar, N. R. Bijivemula and M. V. Shankar, RSC Adv., 2016,
DOI: 10.1039/C5RA25064A.
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Rapid synthesis of alkylaminophenols via Petasis Borono-Mannich
reaction using protonated trititanate nanotubes as robust solid-
acid catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
DOI: 10.1039/x0xx00000x
Bhoomireddy Rajendra Prasad Reddy, Peddiahgari Vasu Govardhana Reddy,** Dharani Praveen
b
c
b
Kumar, Bijivemula N. Reddy and Muthukonda V. Shankar*
www.rsc.org/
An effective and rapid synthesis of alkylaminophenols using one-pot three-component Petasis Borono-Mannich (PBM)
reaction was carried out using protonated trititanate (H Ti ) nanotubes as a heterogeneous solid-acid catalyst.
2
3 7
O
Complimentary to earlier reports, Ti-O based materials with various morphologies, such as fine particles, nanospheres,
nanorods, and tubes were explored for their catalytic activity in PBM reaction. XRD pattern revealed the layered trititanate
structure of nanotubes and nanorods; anatase and biphasic anatase-rutile structure for fine particles and nanospheres,
respectively. Surface area analysis and NH
concentration of Brønsted and Lewis acid sites present in H
observed in the following order: H Ti nanotubes > H Ti
remarkable catalytic performance of H Ti
concentration of Brønsted and Lewis acid sites on the tubular surface, which is essential for adsorption and catalytic
reaction. The recyclability of H Ti catalyst is another emphasis for the proposed methodology. For the first time, we
reported novel alkylaminophenols bearing 2-(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane.
3
-TPD adsorption results confirmed the larger surface area and high
Ti
2 3
O
7
nanotubes. The catalytic efficiency for PBM reaction is
2
3
O
7
2
3
O
7
nanorods > TiO nanospheres > TiO fine particles. The
2
2
2
3 7
O nanotubes was ascribed to the plenty of hydroxy groups and high
2
3 7
O
general, the reaction tends to proceed exceptionally well when
1
. Introduction
there is a free hydroxyl group on the aldehyde fragment,
allowing the formation of an activated boronate complex. For
the first time, Petasis and co-workers reported that
organoboronic acids react with amines and salicylaldehydes to
The Petasis Borono-Mannich (PBM) reaction is a convenient
one-pot three component reaction due to broad substrate
scope, easy access to building blocks and amenability to
combinatorial synthesis strategies, besides structurally diverse
3
give alkylaminophenols. Many improved procedures with new
4
a,b
4c
2i
InBr3, Yb(OTf)
1
catalysts such as CuBr + bpy,
BF
3
.OEt
2
,
3
+
molecular libraries. This PBM reaction can be useful for the
2
4
d
4e
Pd(TFA)2, 4Å MS and CoFe
4f
nanoparticles for PBM
a,b
2
O
4
synthesis of Conduramines,
c
tetrahydroisoquinoline-1-
2d reaction have been reported. On the other hand for green
2
carboxylic
acids,
e
1,
4-benzodiazepine-3,5-diones,
5
a
5b
5c
)
2
2f-k
2l
approach, chitosan, glycerol, ionic liquids ([bmim]BF
4
and
microwave irradiation were employed to accelerate the PBM
2s reaction. The PBM reaction has also been developed in
quinoxalines,
2
chromenes,
α-amino
tertiary
acids,
amines,
1,2,3,4-tetrahydrocarbazoles,
allylamines,
2H-
5
d
m-o
2p,q
2-hydroxy-1,4-
2
r
dihydrobenzoxazines,
2
allenes,
6
a,b
6c
t
2u
water,
approach.
solvent free conditions
and in solid-phase
N-benzylPropargylamines,
oxadiazolones
&
6
d
2
oxazolidinones, 2,5-dihydrofurans, α-amino alcohols, 2-
v
2w
2x,y
2
z
amino morpholines, 2-hydroxymorpholines & amino diols,
2aa Nowadays, catalytic applications of metal and metal oxide
2
ab
2ac-ae
nanoparticles in various organic transformations have gained
α-hydrazinocarboxylic acids
and α-aryl glycines.
In
much attention due to their stability under reaction
conditions, dual acid/base properties, reusability, low toxicity,
7
and non-hygroscopic properties. Owing to these attractive
a.
Department of Chemistry, Yogi Vemana University, Kadapa - 516 003, Andhra
Pradesh, INDIA. Tel.: +91-9985200965; fax: +91-8562-225419; e-mail:
pvgr@yogivemanauniversity.ac.in
features of nano-size metal oxide catalysts; we have focused
on titanium oxide (TiO2) based nanostructures, which
b.
Nano Catalysis and Solar Fuels Research Laboratory, Department of Materials
Science & Nanotechnology, Yogi Vemana University, Kadapa - 516 003, Andhra
Pradesh, INDIA. Tel.: +91-9966845899; fax: +91-8562-225419; e-mail:
shankar@yogivemanauniversity.ac.in
Department of Chemistry, Vellore Institute of Technology, Vellore, Tamil Nadu,
INDIA
8
efficiently catalyze diverse synthetically important reactions.
Among
TiO
2
nanomaterials,
one-dimensional
(1-D)
nanostructures such as tubes, rods, and wires attracted much
c.
attention due to their unique properties viz., large surface-to-
†
details, catalysts characterization, characterization data and copies of the NMR ( H
& C) spectra of all synthesized compounds, HRMS spectra of 4e, 4p, 9a and 9d;
and EI-Mass Spectra of 4a and 4b. See DOI: 10.1039/x0xx00000x
Electronic Supplementary Information (ESI) available: General experimental volume-ratio, better dispersibility, decreased inter-crystalline
1
8a-c, 9
1
3
contacts and increased accessibility of acid sites.
1-D TiO
2
nanostructures have been extensively investigated in areas
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such as organocatalysis, photocatalysis, electrocatalysis, combined filtrates were washed with 0.15 N HCl (5 mL, to
sensors, lithium batteries and treatment of autoimmune remove the excess secondary amine), 0.1 N NaOH (3 mL, to
1
0
diseases. In the field of catalysis, most of the studies for the remove the excess boronic acid) and brine, then dried over
material are directed towards the utilization of the material as anhydrous Na SO , filtered, and concentrated on a rotary
a support with a large surface area. evaporator to give pure product (not required column
In our recent studies, H Ti nanotubes (TNT) and nanorods purification) as an oil, which slowly turned into colourless
TNR) were used as efficient solid-acid catalysts for the solid. The products were structurally assigned by their IR, NMR
2
4
2
3 7
O
(
1
1
1
13
synthesis of tertiary α-aminophosphonates. In continuation ( H & C) and mass spectral (HRMS) analysis.
of our research interest on the introduction of nano-size TiO
2
catalysts in organic synthesis, for the first time we report our 3. Results and discussion
investigations towards the synthesis of alkylaminophenols by
one-pot
hydroxybenzaldehydes, secondary amines, and boronic acids Ti-O based catalysts
three-component
PBM
reaction
of
o- 3.1. Morphology, Crystal structure and Surface properties of
in the presence of three different Ti-O based nanostructures.
Further, we also extended this reaction for the synthesis of 2-
HR-TEM image of TNT catalyst (Fig. 1a) showed a bundle of
random aligned open ended nanotubes having length between
(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane
derived
2
00 to 500 nm. The TEM image of single nanotube displays
alkylaminophenols.
(
Fig.1b) cylindrical in shape hollow inside, have four layers on
R
2
R
3
N
the wall, the inner and outer diameters of the tubes have 3-5
nm and 8-12 nm, respecꢀvely. Fig. S1 (ESI†) shows the HR-TEM
images of TiO fine particles (TFP), TiO nanospheres (TNP),
CHO
TNT (15 mg)
Ar
R
1
+
R
2
R
3
R
1
+
Ar-B(OH)2
o
N
1,4-dioxane; 60 C
OH
OH
4a-q & 9a-h
2
2
H
1a-d
2 a-d & 8
3a-h
TNR, and cTNT. The catalysts TFP and TNP displayed spherical
particles with irregular shapes and dark spots observed due to
overlapping of particles with each other. The particle size of
TFP and TNP measures in the range of 60-160 nm and 23-28
nm, respectively. TNR catalyst showed the random alignment
Scheme 1. TNT catalyzed PBM reaction
2
. Experimental
of rods and varied in length of rod > 1 ꢀm. The image of single
nanotubes and nanorod confirms the clean surface completely filled inside.
2.1. Hydrothermal synthesis of H
2
Ti
3
O
7
nanorods
The calcined material cTNT displayed fragmented tubes, rods
High purity chemicals were used for the synthesis of catalysts. and particles at nanoscale which are laying one over another.
Photocatalyst grade titanium dioxide (TiO P-25) composed of
anatase 80% and rutile 20% was procured from Degussa
Corporation, Germany. Titanium dioxide (anatase 99%, TiO
2
2
,
LAB) was purchased from Merck, India. Analytical reagent (A.R)
grade chemicals of sodium hydroxide pellets (97%),
hydrochloric acid (37%), and ethanol (99.9) were supplied by
Merck, India and used without any further purification. De-
ionized water used for synthesis and washing process. In a
typical synthesis process, TiO
2
fine particles (2.5 g) dispersed in
0 M NaOH aqueous solution (200 mL) and heated either at
30 C/20 h (for nanotubes) or 180 C/20 h (for nanorods) in
1
1
°
°
Teflon-lined autoclave (capacity 250 mL). The white precipitate Fig. 1 HR-TEM images of TNT catalyst
obtained was subjected to washing twice with distilled water
800 mL) followed by dil. HCl (0.1 N, 200 mL), finally with The XRD pattern of TNT and TNR catalysts (Fig. 2) showed four
(
1
0c-g
ethanol (200 mL) and dried at 80
°C for 12 h.
Thus obtained characteristic peaks at 2θ = 10.2⁰ (200), 24.1⁰ (202), 28.3⁰
catalysts were denoted as TNT and TNR respectively. A portion (112) and 48.2⁰ (303), which can be well indexed as the
of TNT was placed in a ceramic boat and calcined at 350
C for monoclinic structure of layered H Ti (JCPDS No. 47-0561). A
C min . The resulting catalyst is characteristic diffraction peak exhibited at 10.2⁰ illustrated the
°
2
3 7
O
-
1
5
h at a heating rate of 2
°
denoted as calcined TiO nanotubes (cTNT).
2
presence of typical layered crystal structure. The broad
diffraction pattern of TNT and TNR suggests the moderate
crystallinity of the catalysts. The XRD pattern of TFP, TNP and
2.2. General procedure for TNT catalyzed PBM reaction
To a magnetically stirred mixture of o-hydroxybenzaldehyde cTNT catalysts (Fig. S2, ESI†) showed characteristic diffraction
1.0 mmol), secondary amine (1.3 mmol) and boronic acid (1.2 peaks centred at 2 = 25.4 (101), 37.5 (004), 48.3 (200),
mmol) in 1,4-dioxane was added TNT (15 mg) and the mixture 53.9 (105) and 55.1 (211) can be well indexed as anatase
was stirred at 60
C for respective times (Table 2 and Table 3). phase with tetragonal structure (JCPDS No. 21-1272). In the
After completion of the reaction (TLC monitoring), the catalyst case of TNP and cTNT catalysts a minor peak at 2 = 27.5
(
θ
°
°
°
°
°
°
θ
°
was separated by centrifugation and subsequent washing with (110) appeared which confirms the presence of rutile-
EtOAc. The recovered catalyst was reused for next cycle. The
2
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Table 1. Physical properties of various Ti-O based catalysts
a
2
-1
b
-1
Acid concentration (mmol .g )
Catalyst
Morphology
Crystal Phase
S
BET (m .g )
c
d
BAS
LAS
TFP
TNP
TNR
TNT
cTNT
Spherical
Spherical
Rods
Anatase
Anatase/Rutile
Trititanate
5.1
51
n.d.
n.d.
0.006
0.445
1.510
2.162
n.d.
24
0.046
1.613
n.d.
Tubes
Trititanate
286
57
Rods, tubes and particles
Anatase/Rutile
a
b
surface area of titania nanostructures, acid sites concentrations of the titania nanostructures were estimated from the NH
c
-TPD, Brønsted
3
d
acid sites, Lewis acid sites and n.d. = not detected.
surface area that leads to a large volume of nitrogen
phase with tetragonal structure (JCPDS No. 21-1276) in adsorption both on the interior and exterior of the tubes. Fig.
addition to anatase phase.
S3 (ESI†) shows the N
and TNR.
2
adsorption-desorption isotherms TNP
Fig. 2 XRD patterns of TNT and TNR catalysts
Fig. 3
2
N -Adsorption-desorption Isotherms of TNT and cTNT
catalysts
The N
) showed typical type IV isotherms with a hysteresis loop at
relative low-pressure P/P 0.8. According to the IUPAC
classification, it confirms the mesoporous nature of TNT and
2
-adsorption-desorption isotherms of TNT and cTNT (Fig.
3
The pore size distribution curve of TNT by (Fig. 4) the BJH
method consists of two portions with peak values of ca. 2.1-4.2
nm and 4.2-23 nm. Taking into the account of the morphology
of TNT, the smaller pores relates to the inner hollow spaces of
the nanotubes; while, the larger pores refers to the pores
0
≥
1
2
cTNT. Surface area of the catalysts were found to decrease in
the following order TNT > cTNT > TNP > TNR > TFP. The
2
-1
standard TiO
2
nanospheres showed surface area 51 m .g is
14
1
consistent with literature report. The surface area of TFP is
2
.1 m .g which can be used as a precursor for the preparation
3
between the nanotubes. The cTNT exhibits pore with a larger
size than TNT due to space between the deformed tubes, rods,
and particles (Fig. 4). The pore size distribution curves of TNP
and TNR (Fig. S4, ESI†) represents that there were no
significant distribution peaks were observed for pores hence
these catalysts are non-porous materials.
-1
5
of TNT and TNR. The BET surface area of as-synthesized TNT
2
-1
and TNR is 286 and 24 m .g respectively
,
which is ∼ 56 and 4
folds higher than that of TFP. The surface area of cTNT catalyst
2
-1
was declined to 57 m .g . The above results indicate that TNT
has porous and nanotubular morphology resulting in a high
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The Brønsted and Lewis acid sites on the catalysts were reaction was conducted in toluene at 60 °C. From Fig. 6 it is
examined by probing desorption spectra of adsorbed ammonia clearly evidenced that, the TFP and cTNT catalysts were
using temperature programmed desorption analysis (TPD) (Fig. displayed negligible catalytic activity whereas the catalytic
5
). The peak at high temperature region of TNT and TNR (302 activities of TNP and TNR were found to be moderate. In
1
C for TNR) and peak at 276.8
5
°C for TNT, 326.1
and 288
°
°C for TNP contrast to the catalytic activity of TFP, TNP, TNR and cTNT;
°C for TFP were observed (except cTNT), it is ascribed the TNT exhibited significant catalytic performance with 75%
4
+
to Lewis acid sites of coordinatively unsaturated Ti sites of yield in 60 min and with an increase in reaction time, no
present on the surface of the catalysts. Another peak noticed improvement in the product yield was observed. However, the
at the low-temperature region of TNT and TNR (160.9
6
°
C for reaction did not occur in the absence of the catalyst.
1
TNT and 148.8
°C for TNR) which is assigned to Brønsted acid
sites on TNT and TNR catalysts. This is attributed to linear Ti-
OH and bridged Ti-OH-Ti sites present in TNT and TNR. In the
case of cTNT, calcination at 400 °C for 5 h induced the
dehydration (loss of surface -OH groups) accompanied by
phase transformation to anatase-rutile biphasic material
besides partial collapse of nanotubes to particles leading to a
poor concentration of acid sites. The concentration of acid
sites of catalysts are depicted in Table 1
.
Fig. 6 Time courses of the alkylaminophenol (4a) formation
using various Ti-O based catalysts.
Reaction conditions: Catalyst (20 mg), salicyladehyde (1 mmol),
morpholine (1 mmol), phenylboronic acid (1 mmol), toluene (2 mL)
o
and at 60 C.
Catalytic performance of Ti-O based catalysts is explained in
terms of the concentration of acid sites, surface area and
density of –OH groups present in catalyst systems (Table 1).
Both TFP and TNP mainly composed of anatase phase, the
larger surface area and a higher concentration of acid sites of
TNP beneficial for obtaining a higher yield than TFP. The higher
catalytic activity of TNR than TNP is ascribed to the presence of
Fig. 4 BJH pore size distributions of TNT and cTNT catalysts
–
OH groups on 1-D morphology, less agglomeration and more
acid sites even though the surface area of TNR is nearly 50%
lower. Although, TNT catalyst has similar crystalline structure
and morphology however due to the presence of hollow inner
space in TNT possess higher surface area than TNR itself.
Surface area, Brønsted and Lewis acid sites concentration of
TNT is about 11, 35 and 2 folds, respectively higher than TNR
and the presence of large amount of –OH groups in TNT
enhances the catalytic activity of TNT. The cTNT catalyst
showed lowest reaction yield due to the absence of acid sites
and surface –OH groups. It is explained that concentration of
acid sites and amount of –OH groups is extremely important
than the surface area of the same type of catalyst. Literature
reports also illustrate that acid catalysts promote the PBM
Fig. 5 NH -TPD of TFP, TNP, TNR, TNT and cTNT catalysts
3
2
i, 4c,d & 5a
reaction effectively.
On the basis of this encouraging results, efforts were made to
optimize the conditions (like the ratio of the substrates,
solvents, catalyst loading and temperatures) to attain the best
possible yield. Investigation on the ratio of reactants indicates-
3
.2. Catalytic activity
To develop an optimal catalyst for PBM reaction from Ti-O
based catalysts, the synthesis of 2-(morpholino(phenyl)methyl)
phenol (4a) via a three-component reaction of salicylaldehyde
(
1a), morpholine (2a) and phenylboronic acid (3a) and the
4
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Table 2. Optimization of reaction parameters
conditions, either delivered quite low yields (Table 2, Entries 8,
9 and 14) or gave no products (Table 2, Entries 10 and 11).
Further, reducing the amount of catalyst to 10 mg (Table 2,
Entry 18) down from 20 mg (Table 2, Entry 14), had a negative
effect on the yield of the reaction. A compromise of 15 mg
O
N
B(OH)
2
O
CHO
+
OH
TNT, 60 min
+
N
H
2a
solvent (2 mL)
OH
1a
3a
4a
(Table 2, Entry 15), however, seemed to be sufficient. Likewise,
reduction in temperature of the reaction also seemed to have
a deleterious effect on the yield (Table 2, Entries 19-20).
a
Entry
1a/2a/3a
ratio)
solvent
Catalyst
loading
T (°C) Yield
(
(%)
Further elevating the reaction temperature to 80 °C led to
(
mg)
decrease in yield (Table 2, Entry 21) (possibly because of the
volatility of the amine employed). As can be seen, from Table 2
the best conditions for the synthesis of 4a catalyzed by TNT is
Entry 16.
1
2
3
4
5
6
7
8
9
1.0/1.0/1.0
1.0/1.1/1.1
1.0/1.2/1.2
1.0/1.3/1.2
1.0/1.2/1.3
1.0/1.3/1.3
1.0/1.4/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
1.0/1.3/1.2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Water
20
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
RT
>80
75
20
20
20
20
20
20
20
20
20
20
20
20
20
20
15
12.5
10
15
15
15
78
81
89
Using the optimized reaction conditions, a variety of
83
structurally different salicylaldehydes, secondary amines, and
boronic acids were employed as reaction substrates, to
explore the scope and generality of the TNT promoted PBM
reaction. The results are outlined in Table 3. At the beginning
of the investigation to the salicylaldehydes substrate scope,
morpholine, and phenylboronic acid were used as model
89
89
<10
<10
n.d.
n.d.
63
Ethanol
DMF
1
1
1
1
1
1
1
1
1
1
2
2
0
3 2
substrates and salicylaldehyde; 5-OCH /5-NO /5-Br substituted
1
2
3
4
5
6
7
8
9
0
1
DMSO
salicylaldehydes were examined for the PBM reaction (Table 3,
entries 1-4). The results indicate that no significant changes in
the yields were observed with different substituents on
salicylaldehyde. In contrast, the reaction with benzaldehyde;
MeCN
THF
52
---
<10
96
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
3
3
-OH/2-OCH /2-Cl substituted benzaldehydes were failed to
96
participate in this reaction it indicates the importance of ortho
89
hydroxy group on the aldehyde fragment. To expand the scope
76
of secondary amine substrates,
a
combination of
83
salicylaldehyde-phenyboronic acid-secondary amine was
chosen and various amines were examined (Table 3, entries 1
51
79
&
5-7). The results indicate that cyclic (pyrrolidine/morpholine)
The bold values are the most effective conditions for the model reaction. and acyclic (diethyl/N-benzylmethyl) secondary amines gave
Reaction conditions: All reactions were performed on a 1 mmol scale with 2
excellent yields of products under the standard reaction
a
mL solvent for 60 min. n.d. = not detected. Isolated yield.
conditions (Table 3, entries 1 and 5-7). However, no product
was observed when diphenyl/benzyl amine as substrates and
that a 1.0:1.3:1.2 ratio of 1a/2a/3a gave the best result with trace amount of product was obtained with a diisopropyl
an isolated yield 89% (Table 2, Entry 4). In the present study, amine. Subsequently, a variety of boronic acids were also
useof 1.3 eq of amines and 1.2 eq boronic acids has specific examined for the PBM reaction using salicylaldehyde and
advantage i.e o-hydroxy aldehyde conversion was increased. morpholine as model substrates (Table 3, entries 1 & 8-11).
These excess amines and boronic acids were conveniently The reaction proceeded smoothly with phenylboronic acid and
removed by simple acid-base work up to avoid the usage of 2-Me/3-Br/3, 5-di-F substituted phenyl boronic acids and gave
4
f
column separation. Subsequently, solvent screening showed the corresponding alkylamino phenol in good yield (Table 3,
that 1,4-dioxane provided an improved yield of 96% (Table 2, entries 1 & 8-10). In the case of 2, 3-dihydrobenzofuran-5-
Entry 15), while MeCN, THF were less effective and afforded ylboronic acid (Table 1, entry 11), 93% product yield was
the product in 63% and 59% yields, respectively (Table 2, obtained. No desired product was observed when employed
1
7
Entries 12 and 13). Replacement of toluene with other furan-3-ylboronic acid and pyridin-3-ylboronic acid.
solvents, such as water, ethanol, DMF, DMSO and solvent free
Table 3. Coupling of o-hydroxybenzaldehydes, secondary amines and aryl/heteroaryl boronic acid catalyzed by TNT (15 mg) in
1
, 4-dioxane.
a
Entry
Aldehyde (1a-d)
Amine (2a-e)
Boronic acid (3a-d)
Product (4a-r)
Time (min)
60
Yield (%)
HO
O
O
B(OH)
2
HO
N
1
2a
96
1
a
N
H
3a
OHC
4
a
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HO
O
B(OH)
2
HO
O
N
OCH
3
2
1b
2a
2a
50
65
60
45
50
60
55
60
50
93
88
90
98
97
90
87
96
85
OHC
OCH
3
N
H
3a
4
b
HO
O
O
B(OH)
2
HO
N
NO
2
3
4
5
6
7
8
9
1c
OHC
NO
2
N
H
3a
4
c
HO
O
O
B(OH)
2
HO
N
Br
1d
2a
2b
N
H
3a
OHC
Br
4
d
HO
B(OH)2
HO
N
1
1
1
1
1
1
a
a
a
a
a
a
N
H
OHC
3a
4e
HO
B(OH)
2
HO
N
2
c
N
H
OHC
3a
4
f
HO
B(OH)
2
HO
Ph
Ph
N
2
d
N
H
OHC
3a
4
g
h
HO
O
O
B(OH)
2
HO
N
2a
2a
2a
N
H
3b
OHC
4
HO
O
B(OH)
2
O
HO
N
N
H
3c
OHC
Br
4i
Br
HO
O
O
B(OH)2
HO
N
1
1
0
1
N
H
3d
OHC
F
F
4j
F
F
HO
O
B(OH)
2
N
O
HO
2a
50
93
1
a
3e
N
H
OHC
4
k
O
O
HO
B(OH)
2
HO
N
1
1
1
2
3
4
2b
2b
2b
60
60
65
89
97
89
1
1
1
a
a
a
N
H
OHC
3b
4
l
HO
B(OH)
2
HO
N
N
H
3
c
OHC
4m
Br
Br
HO
N
B(OH)
2
HO
N
H
3
d
4n
OHC
F
F
F
F
6
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HO
O
B(OH)
2
HO
O
N
OCH
3
1
1
1
5
6
7
1b
2a
2a
2a
90
55
60
87
OHC
OCH
3
N
H
3b
4
o
HO
O
B(OH)
2
HO
O
N
OCH
3
1b
OCH
3
94
87
N
H
3c
OHC
Br
4p
Br
HO
O
O
B(OH)2
HO
N
OCH
3
1b
N
H
3d
OHC
OCH3
F
F
4
q
F
F
Reaction conditions: O-hydroxybenzaldehyde (1 mmol), secondary amine (1.3 mmol), boronic acid (1.2 mmol), TNT (15 mg), 1,4-dioxane (2 mL)
a
and at 60 °C. Isolated yield.
The applicability of optimized reaction conditions was further deprotection of tert-butyl carboxylate group of
extended to the synthesis of novel 2-(pyrimidin-2-yl)-2,5- HCl in dichloromethane (Scheme 2).
7
with dioxane-
diazabicyclo[2.2.1]heptane bearing alkylaminophenols (9a-h
using as synthesized 2-(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]-
heptane ( ), o-hydroxybenzaldehydes and boronic acids. 2-
Pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane can be
synthesized from tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-
carboxylate hydrochloride ( ) and 2-chloropyrimidine ( ) in the
)
HHCl
N
8
1. 4N HCl in dioxane,
o
Et
3
N, Toluene
N
N
O
O
N
0
C-RT, 30 min
+
N
N
N
N
N
NH
(
(
8)
N
Reflux, 5h
2
.
Neutralizition with
NaHCO
N
Cl
O
O
3
5
6
7
8
5
6
yield (90%)
yield (95%)
presence of triethylamine in toluene at reflux temperatures for Scheme 2. Synthesis of 2-(pyrimidin-2-yl)-2,5-diazabicyclo
five hours to form tert-butyl-5-(pyrimidin-2-yl)-2,5-diaza- [2.2.1]heptane
bicyclo[2.2.1]heptane-2-carboxylate
(7) and subsequently
Table 4. Coupling of o-hydroxybenzaldehydes, 2-(pyrimidin-2-yl)-2,5-diazabicyclo [2.2.1]- heptane and aryl/heteroaryl boronic
acid catalyzed by TNT (15 mg) in 1,4-dioxane.
a
Entry
Aldehyde (1a, b)
Boronic acid (3a, b & 3f-h)
Product (9a-h)
Time (min)
Yield (%)
OH
B(OH)
2
HO
N
N
1
90
81
1
1
1
a
a
a
9a
9b
9c
N
N
N
3
a
OHC
N
OH
B(OH)
2
HO
N
2
3
4
120
90
79
82
79
3
b
N
OHC
N
OH
HO
B(OH)
2
N
S
3f
N
N
OHC
S
3
H CO
OH
B(OH)
2
HO
1b
N
120
9
d
OHC
OCH
3
3a
N
N
N
H
3
CO
OH
B(OH)
2
HO
N
5
1b
180
75
9
e
OHC
OCH
3
3b
N
N
N
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3
H CO
OH
HO
B(OH)
2
6
1b
N
S
120
75
9
g
f
3
f
OHC
OCH
3
N
N
S
N
3
H CO
B(OH)
2
OH
HO
7
8
1b
3g
N
150
180
80
70
9
OHC
OCH
3
N
N
OCH
3
OCH
3
N
3
H CO
OH
B(OH)2
HO
N
1b
9
h
OHC
OCH
3
3h
N
N
N
Reaction conditions:
O-hydroxybenzaldehyde (1 mmol), 2-(pyrimidin-2-yl)-2,5-diazabicyclo [2.2.1] heptane (1.3 mmol), boronic acid (1.2 mmol),
a
C. Isolated yield.
TNT (15 mg), 1,4-dioxane (2 mL) and at 60
°
From these results, a plausible mechanism is proposed for the concentration of acid sites on the catalyst surface. Which is
process of TNT catalyzed PBM reaction. Initially, a nucleophilic confirmed by NH -TPD experiment, the concentration of
addition of the amine to o-hydroxy aldehyde produced the key Brønsted and Lewis acid sites of TNT after the 5 cycle was
3
th
-1
iminium intermediate (
anion of phenolate and the boron atom of boronic acid lead to
the formation of a tetracoordinate borate ( ) intermediate. Table 5. TNT Catalyst recycling studies in the coupling of
Subsequently, the aryl carbanion moiety of boronic acid salicylaldehyde, morpholine, and phenylboronic acid.
4). Co-ordination between the oxygen found to be 0. 826 and 1.721 mmol .g , respectively (Fig. 8).
5
favorably attacked the iminium ion. Finally, hydrolysis took Run
1
2
3
4
5
a
Yield (%)
place to form the desired product (
Fig.7).
6) by the loss of a boric acid
96
96
96
93
86
(
Reaction conditions: Salicylaldehyde (1 mmol), morpholine (1.3
mmol), phenylboronic acid (1.2 mmol), TNT (15 mg), 1,4-dioxane (2
o
mL), at 60 C and for 60 min. Isolated yield.
a
3
Fig. 8 NH -TPD profile of (a) Fresh TNT and (b) Reused TNT
Fig. 7 Plausible mechanism for TNT catalyzed PBM reaction
after the fifth cycle.
For practical applications of heterogeneous catalysts, the level
of reusability is a very important factor. The recyclability of
TNT catalyst was investigated in the coupling reaction of
salicylaldehyde, morpholine, and phenylboronic acid. After
each run, the TNT catalyst was separated by centrifugation,
3. Conclusion
We demonstrated here that PBM reaction can run in the
presence of Ti-O based solid-acid catalysts. Among them,
H
2
Ti
3
O
7
nanotubes showed the remarkable catalytic
performance due to the presence of sufficient Brønsted and
Lewis acid sites and –OH groups on the large surface area of
nanotubes. This method offers several advantages including:
1) good to excellent yields for a variety of substrates in short
washed twice with EtOAc and dried in an oven at 100 °C for 6
h. The recovered TNT catalyst was reused for five times in this
PBM reaction and smooth loss of activity was observed from
th
the 4 cycle (Table 5). It may be due to the decrease in
8
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reaction times, 2) simple work-up procedure (not required
column purification), 3) catalyst is readily prepared from
available low cost starting materials, 4) catalyst has very good
stability in air, moisture and elevated temperatures and 5) high
recoverability and the reusability of the catalyst. Further, it is
worthy to mention that first time we have shown the synthesis
of alkylaminophenols from 2-(pyrimidin-2-yl)-2,5-diazabicyclo-
2012, 134, 5782-5785; (u) H. Feng, H. Jia, and Z. Sun, J. Org.
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Lett. 2000,
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aa) F. Berree, A. Debache, Y. Marsac, B. Collet, P. G. L. Bleiz
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Acknowledgements
(
Financial support from Department of Atomic Energy, Board of
Research in Nuclear Sciences (2012/37C/33/BRNS), Mumbai,
India and Department of science and technology (SR/FT/CS-
and B. Carboni, Tetrahedron, 2006, 62, 4027-4037; (ab) D.
E. Portlock, D. Naskar, L. West and M. Li, Tetrahedron Lett.
2
002, 43, 6845-6847; (ac) N. A. Petasis, A. Goodman and I.
0
13/2010/DST), New Delhi, India is gratefully acknowledged.
A. Zavialov, Tetrahedron, 1997, 53, 16463-16470; (ad) D.
Font, M. Heras and J. M. Villalgordo, Tetrahedron, 2008,
B.R.P Reddy thanks to the CSIR-UGC, New Delhi, India for the
award of Junior Research Fellowship. Authors thankful to co-
ordinator, DST-FIST, Department of Physics, YV University for
providing XRD facility. Authors are thankful to Dr. M. Karthik
and Dr. V. Roddatis of CIC ENERGIGUNE, Spain for their
support in the characterization of catalysts.
64, 5226-5235; (ae) N. J. McLean, H. Tye and M. Whittaker,
Tetrahedron Lett. 2004, 45, 993-995.
3
4
N. A. Petasis and S. Boral, Tetrahedron Lett. 2001, 42, 539-
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42.
(a) R. Frauenlob, C. Garcia, G. A. Bradshaw, H. M. Burke
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DOI: 10.1039/C5RA25064A
Graphical Abstract
Rapid synthesis of alkylaminophenols via Petasis Borono-Mannich reaction using
protonated trititanate nanotubes as robust solid-acid catalyst
a
a
Bhoomireddy Rajendra Prasad Reddy , Peddiahgari Vasu Govardhana Reddy ** , Dharani
b
c
b
Praveen Kumar , Bijivemula N. Reddy and Muthukonda V. Shankar*
Petasis Borono-Mannich reaction was applied to synthesis of alkylaminophenols from o-
hydroxybenzaldehydes, secoundary amines and boronic acids in presence of H
2 3 7
Ti O nanotubes as
reusable solid-acid catalyst.