Serendipitous formation of 3-tosyl-1,2,3,4-tetrahydroquinazoline

Article abstract of DOI:10.1039/c3nj00658a

Both experimental and computational studies were undertaken to elucidate the formation process of 3-tosyl-1,2,3,4-tetrahydroquinazoline from methanolic mother liquors of Pd(L_BS)·3H₂O, where L _BS is the dianionic form of th

Full text of DOI:10.1039/c3nj00658a

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Serendipitous formation of 3-tosyl-1,2,3,4-
tetrahydroquinazoline
Cite this: NewJ.Chem., 2013,
3
7, 3043
a
a
a
Jesus Sanmart ´ı n-Matalobos,* Ana M. Garc ´ı a-Deibe, Luc ´ı a Briones-Migu e´ ns,
b
b
a
Emilio Lence, Concepcion Gonz a´ lez-Bello,* Cristina Portela-Garc ´ı a and
a
Matilde Fondo
Both experimental and computational studies were undertaken to elucidate the formation process of
O, where LBS is the dianionic
3
-tosyl-1,2,3,4-tetrahydroquinazoline from methanolic mother liquors of Pd(LBS)ꢀ3H
2
Received (in Montpellier, France)
8th June 2013,
1
form of the imine ligand N-{2-[(8-hydroxyquinolin-2-yl)methyleneamino]benzyl}-4-methylbenzenesulfon-
Accepted 23rd July 2013
amide. Experimental studies have shown that the tetrahydroquinazoline is obtained by condensation of
2-tosylaminomethylaniline and formaldehyde, which come from the acid-catalyzed hydrolysis of the imine
DOI: 10.1039/c3nj00658a
ligand LBS and metal-mediated aerobic oxidation of methanol, respectively. Computational studies have
revealed relevant intermediates and key steps in the reaction pathway.
www.rsc.org/njc
Introduction
1
,2,3,4-Tetrahydroquinazoline derivatives possess a variety of
1
2
biological effects including antiinflammatory, antihypertensive,
antineurodegenerative, antioxidant, antimicrobial, antihepatitis
and anticancer activities among others. 1,2,3,4-Tetrahydro-
quinazolines substituted by aryl groups at the 2-position are
accessible in almost quantitative yield via reaction of 2-amino-
3
4
5
6
7
,8
9
1
0
benzylamine and benzaldehyde derivatives in a similar manner Fig. 2 Main and by-products (1 and 2 highlighted in red color) resulting from
2 TQ
the reaction of 2-(3-tosyl-1,2,3,4-tetrahydroquinazolin-2-yl)quinolin-8-ol (H L )
used for the synthesis of aromatic Schiff bases (Fig. 1). In fact,
it is known that 2-aryl-1,2,3,4-tetrahydroquinazolines are in
tautomeric equilibrium with the corresponding aromatic Schiff
with Pd(OAc)
2
ꢀ4H
2
O.
1
1
10
bases, which are most quickly formed.
was obtained by the above-mentioned convenient method. The
Recently, we have reported on the preparation of 2-(3-tosyl- reaction of H2LTQ with Pd(OAc) ꢀ4H O in a 1 : 1 molar ratio under
2
2
1
1
1
,2,3,4-tetrahydroquinazolin-2-yl)quinolin-8-ol (H2LTQ), which reflux or even at room temperature gave the main product
1
1
Pd(LSB)ꢀ3H
2
O, in which the ligand was in the Schiff base form.
During the course of those studies, we have spectroscopically
detected the presence of 3-tosyl-1,2,3,4-tetrahydroquinazoline (1)
and a palladium complex of 2-{hydroxy(methoxy)methyl}-8-
hydroxyquinoline (2) as by-products formed from the methanolic
mother liquors of the above-mentioned complex (Fig. 2). Intrigued
by the latter findings, we have undertaken an experimental and
Fig. 1 Synthetic approach to 2-aryl-1,2,3,4-tetrahydroquinazolines: imine condensa-
ꢁd
tion followed by intramolecular nucleophilic addition of the amino N atom to the
2
+d
electrophilic sp -hybridized imino C atom associated with hydrogen atom migration. computational study to elucidate the reaction pathway that
involves the formation of 1 and 2. Knowledge of the rate
limiting steps can be used for favoring or preventing the
mentioned process.
a
Dpto. de Qu ´ı mica Inorg a´ nica, Facultad de Qu ´ı mica, Universidad de Santiago de
Compostela, Avenida de las Ciencias s/n, 15782 Santiago de Compostela, Spain.
E-mail: jesus.sanmartin@usc.es; Fax: +34 981 528073; Tel: +34 981 563100
Centro Singular de Investigacion en Qu ´ı mica Biol o´ gica y Materiales Moleculares
b
Results and discussion
(
CIQUS), Universidad de Santiago de Compostela, Jenaro de la Fuente s/n,
5782 Santiago de Compostela, Spain. E-mail: concepcion.gonzalez.bello@usc.es;
Fax: +34 881 815704
1
The H NMR spectrum of the residual mixture obtained by
1
concentration of the methanolic mother liquors of Pd(LSB)ꢀ3H
2
O
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Experimental studies on the origin of 1 and 2
Convinced that the tetrahydroquinazoline 1 is not the result of
a C–C bond breaking in H2LTQ, we have undertaken an experi-
mental study to elucidate its origin. In this study the identifi-
cation of the palladium complex 2 played a key role, because
its formation is interpreted as a sign of an acid-catalyzed
hydrolysis of the Schiff base ligand (Fig. 5) due to the presence
1
2
of water in an acidic reaction medium. It must be noted that
the pH of the reaction medium is about 5.5 because of acetic
acid that is formed during the course of the reaction illustrated
in Fig. 2. Besides, it may be that the coordination of the imine
nitrogen to the palladium ion, which could act as a site for
1
Fig. 3 H NMR spectrum of 1 in dmso-d
6
. The most characteristic signals of the Lewis acid activity, and the use of a protic solvent like methanol
1
3
tetrahydroquinazoline were highlighted (using a color code).
enable the hydrolysis.
Under the described conditions, a proton catalyzed attack of
+
water on the C atom of the coordinated imino group can occur
revealed the formation of 3-tosyl-1,2,3,4-tetrahydroquinazoline (1) and thus a retro-Schiff base reaction would be initialized
and a palladium complex of 2-{hydroxy(methoxy)methyl}-8-hydro- (Fig. 5). The process would be more favorable when performed
xyquinoline (2) as by-products. The two constituents of the starting from the reactants that lead to Pd(LSB)ꢀ3H
2 2 TQ
O, i.e. H L
mixture were separated by flash chromatography by eluting with and Pd(OAc) O itself, because in
ꢀ4H
O, rather than Pd(LSB)ꢀ3H
2
2
2
diethyl ether : hexane (50 : 50) and subsequently characterized.
the latter case acetic acid is not generated. In order to verify the
imine hydrolysis of Pd(LSB)ꢀ3H O, we have performed an experi-
Organic molecule 1, which is represented in Fig. 3 with the
labeling scheme for H NMR, shows four non-aromatic proton
signals at about 2.3, 4.3, 4.5 and 6.0 ppm corresponding to
methyl, methylene at the 2-position, methylene at the 4-position
and amino groups, respectively. Two-dimensional proton–proton
2
1
ment by using an acidified methanol solution of Pd(LSB)ꢀ3H
2
O,
which was heated under reflux for 24 h (Experiment 1). After
4 h reaction time, there is clear evidence of the formation of 1.
O would lead to a palla-
2
The imine hydrolysis of Pd(LSB)ꢀ3H
2
dium complex of two different ligands, one of them carrying an
amine group and the other one an aldehyde group. In a
subsequent reaction step, which is also catalyzed by acid, the
Pd–hemiacetal complex 2 would be produced from addition of
methanol to the carbon atom of the aldehyde group that was
formed by imine hydrolysis.
(
COSY and NOESY experiments) and proton–carbon (HSQC and
HMBC experiments) NMR correlation spectra have been used
1
for the complete assignment of the one-dimensional H NMR
spectrum of 1.
1
The H NMR spectrum of 2 (Fig. 4) shows three characteristic
non-aromatic proton signals at about 3.5, 6.7 and 7.2 ppm
corresponding to methoxyl, hydroxyl and methanetriyl groups,
With the aim of establishing the critical role of the imine
hydrolysis in obtaining the tetrahydroquinazoline 1, we have
performed an experiment (Fig. 6) consisting of two reactions by
1
respectively. Complete assignments of H NMR data of 2 were
made by two-dimensional correlation spectroscopy (COSY, NOESY,
HSQC and HMBC).
using Pd(OAc)
addition of water and the other one in the absence of water
Experiment 2). The results showed that 1 was not formed after
4 h reaction time in the absence of water. In contrast, when we
2
as a starting metal salt, one of them with
(
2
added water to the reaction medium, the formation of 1 is
evident after 24 h. Thus, the experiment proves that the
hydrolysis of the imine is a necessary condition for obtaining 1.
In order to verify the latter deduction, we have performed an
experiment by using a methanol solution of 2-tosylamino-
methylaniline and Pd(OAc)
After 24 h under reflux, there is clear evidence of the formation of
. This fact supports the main role of 2-tosylaminomethylaniline
2
as starting reagents (Experiment 3).
1
in the process studied.
With the aim of clarifying the formation process of the
Pd–hemiacetal complex 2, we have performed an experiment
(Fig. 7) consisting of an attempt to reproduce its formation from
8-hydroxyquinoline-2-carboxaldehyde (ald), which would result
from the hydrolysis of the imine N-{2-[(8-hydroxyquinolin-2-yl)-
methyleneamino]benzyl}-4-methylbenzenesulfonamide.
The spectroscopic monitoring of the reaction between
1
Fig. 4 H NMR spectrum of 2. The signals corresponding to methoxyl, hydroxyl
and methanetriyl groups have been highlighted in green, blue and red colors,
respectively.
2
Pd(OAc) and 8-hydroxyquinoline-2-carboxaldehyde in methanol
3
044 New J. Chem., 2013, 37, 3043--3049
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Fig. 6 Reactions used to establish the influence of the imine hydrolysis upon the
1
formation of 1. Partial view of the H NMR spectrum of 1 was included. The yield
of 1 was determined by integration of the methylene signal at 4-position
(highlighted in blue color) against the internal standard 1,3,5-tri-tert-buthylbenzene
(ttbb). The integration value for the methyl signal of ttbb (at 1.35 ppm, highlighted
in brown color) was considered as 1.00 for ease of comparison.
Fig. 7 Reaction used to reproduce the formation process of Pd(hemi)
2
(2),
1
showing partial views of its H NMR monitoring. The signals corresponding to
Fig. 5 Acid-catalyzed hydrolysis of the coordinated Schiff base ligand in
the protons at 7-position of Pd(ald)(hemi) and Pd(hemi)
in red and blue colors, respectively.
2
have been highlighted
2
Pd(LSB)ꢀ3H O followed by Pd–hemiacetal complex formation.
clear from the observation of two sets of signals, which corre-
Fig. 7) shows that the reaction proceeds through the formation of spond to similar protons of aldehyde and hemiacetal ligands.
(
1
a palladium complex of aldehyde and hemiacetal Pd(ald)(hemi) Complete assignments of H NMR data of Pd(ald)(hemi) were
en route to Pd(hemi) (2). After ten minutes under reflux, there is made by two-dimensional correlation spectroscopy (COSY,
clear evidence of the formation of Pd(ald)(hemi) and Pd(hemi)
Then, Pd(ald)(hemi) gradually evolves into Pd(hemi) until it
2
2
.
NOESY, HSQC and HMBC).
2
With the aim of checking if the methylene group at the
finally disappears. This is a sign that the Pd–hemiacetal complex 2-position of the tetrahydroquinazoline 1 could come from the
would be produced from addition of methanol to the carbon metal mediated aerobic oxidation of methanol, which was used
2
atom of the aldehyde group that was formed by imine hydrolysis. as solvent, we have performed an experiment consisting of two
Both complexes Pd(ald)(hemi) and Pd(hemi) could be isolated reactions by using H2LTQ and Pd(OAc) ꢀ4H O as starting
2
2
2
1
and subsequently characterized. The H NMR spectrum of reagents, one of them was carried out in methanol and the
4
Pd(ald)(hemi) (Fig. 8) showed four characteristic signals at about other one in methanol-d (Experiment 4). Fig. 9 shows both
1
3
.6, 6.5, 7.3 and 10.5 ppm corresponding to methoxyl, hydroxyl, reaction processes and the H NMR spectra of 1 obtained from
methanetriyl and aldehyde groups, respectively. Besides, this is both methanol and methanol-d . After 15 h of refluxing,
4
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1
Fig. 8
H NMR spectrum of Pd(ald)(hemi). The signals corresponding to
methoxyl, hydroxyl, methanetriyl and aldehyde groups have been highlighted
in green, blue, red and magenta colors, respectively.
Fig. 10 Plausible pathway that would lead to both formaldehyde and
Pd–hemiacetal complex 2. The starting species is the palladium complex that
was obtained by imine hydrolysis of Pd(LSB)ꢀ3H
2
O.
Fig. 9 Reactions used to establish the influence of the reaction medium upon
the formation of 1. 2-Tosylaminomethylaniline comes from Pd(LSB)ꢀ3H
2
O by imine
1
hydrolysis. H NMR spectra (in dmso-d
6
) of 1 obtained from both methanol
2
finally to Pd(hemi) by addition of methanol to the carbon atom
(
4
bottom) and methanol-d (top). The signal of the methylene group at 2-position
of the aldehyde group. Fig. 10 shows a plausible pathway for the
formation of formaldehyde from methanol, which explains the
formation of the Pd–hemiacetal complex 2.
of non-deuterated 1 is highlighted in red color.
complete deuteration at 1- and 2-positions of the tetrahydro-
quinazoline 1 occurred, which prevents the observation of both
Computational study on the proposed reaction pathway
–
ND- and –CD
2
- signals. This reveals the oxidation of methanol Based on both experimental and theoretical studies, a proposed
reaction pathway for the formation of 1 and 2 is shown in
to formaldehyde.
In a subsequent reaction step, following a similar pathway to Fig. 11. Density functional theory (DFT) calculations have been
that reported for the synthesis of 1,2,3,4-tetrahydroquinazo- employed on optimized structural models to support a plausible
1
0
lines, 1 would be produced from nucleophilic addition of mechanism. Since the in vacuum computational approach implies
-tosylaminomethylaniline to the carbon atom of formaldehyde, quite crude approximations, the retrieved energy differences
which is favored under acidic conditions. It must be noted that should be considered as guides only.
-tosylaminomethylaniline comes from Pd(LSB)ꢀ3H O by imine First, the hydrolysis of the Pd–imino complex Pd(LSB)ꢀ3H
hydrolysis. would take place to afford the Pd–aldehyde complex B via
Based on mechanistic explanations for reported oxidation of the Pd–hydroxyamino complex A. Subsequent nucleophilic addi-
2
2
2
2
O
1
4–23
alcohols using molecular oxygen as the terminal oxidant,
tion of methanol would afford the Pd–hemiacetal complex C.
the oxidation of methanol to formaldehyde would involve the The next step would involve the access to the palladium
formation of a Pd–methanolate complex, which would lead to coordination sphere of a methanol molecule to give the
the formation of a Pd–hydride complex by b-hydride elimination. Pd–methanol complex D. This can occur with breaking of one
In a subsequent reaction step, in the presence of enough amounts of the current Pd–donor atom bonds in C. Among the two
of H
2
LTQ, the Pd–hydride complex would give Pd(HLSB)(hemi). evaluated possibilities, the replacement of the Pd–Namine bond
ꢁ1
This complex would lead to Pd(ald)(hemi) by imine hydrolysis and was 5.3 kcal mol more favorable (DG) than the replacement of
3
046 New J. Chem., 2013, 37, 3043--3049
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Fig. 12 DFT-optimized structures of palladium complexes D (left) and E (right)
showing hydrogen bonding (as dashed lines). All bond distances are in Å.
Fig. 13 Transition-states for two steps of the proposed reaction pathway: the
intramolecular deprotonation step (left) and the b-hydride elimination step
Fig. 11 Proposed pathway for the formation of 1 and 2. Solvated water
2
molecules of the initial palladium complex Pd(LSB)ꢀ3H O were not represented.
(
right). All bond distances are in Å.
ꢁ1
Calculated DG (kcal mol ) for each step is indicated.
meaning that the energy cost of this step is relatively low.
the Pd–Nquinoline. Consequently, we have ruled out the latter Among the two evaluated possibilities, coordination of form-
possibility in the proposed pathway for the formation of 1.
aldehyde through the oxygen atom or through the double bond,
ꢁ1
Next, the intramolecular deprotonation of methanol would the first was found to be 2.4 kcal mol
more favorable.
take place in D to give the Pd–methoxide complex E. Fig. 12 Consequently, we have ruled out the latter possibility in the
shows the optimized structures of D (left) and E (right), which proposed pathway for the formation of 1.
are stabilized by hydrogen bonding. In particular, the distance
The next step should be the dissociation of the Pd–Oformaldehyde
between the methanol hydrogen atom and the sulfonamide bond that would liberate formaldehyde to the reaction medium
nitrogen atom in D is about 2.5 Å. Based on the latter and on and afford the Pd–hydride complex H. Fig. 14 shows the optimized
the appropriate orientation of the sulfonamide nitrogen atom, structure of H, in which the hydroxyl group of the hemiacetal
the deprotonation process may have its origins in the existence occupies a position in the palladium coordination sphere. In a
of the mentioned hydrogen bond between coordinated methanol subsequent reaction step, the experimentally obtained tetrahydro-
and 2-tosylaminomethylaniline. The transition state of this rate- quinazoline 1 would be produced from nucleophilic addition of
limiting step is outlined in Fig. 13 (left), which has a calculated the previously evolved 2-tosylaminomethylaniline to the carbon
ꢁ1
activation energy of 10.1 kcal mol . The next step would be the atom of formaldehyde.
dissociation of the Pd–Nsulfonamide bond that would liberate
2-tosylaminomethylaniline to the reaction medium and afford
the Pd–alkoxide complex F. The Gibbs free energy involved in
ꢁ
1
this process is 14.3 kcal mol , meaning that, from a thermo-
dynamic point of view, this is the most unfavorable step.
A key step in the oxidation process of methanol is the
b-hydride elimination, which would take place in F to give
the Pd–formaldehyde complex G. The transition state of this
process is outlined in Fig. 13 (right), which shows that one of
the methyl hydrogen atoms is located closer to the metal center
(
1.575 Å) than to the carbon atom (2.068 Å). The activation
Fig. 14 DFT-predicted structure of the Pd–hydride complex H. All bond distances
ꢁ1
energy involved in the b-elimination process is 5.7 kcal mol
,
are in Å.
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Conclusions
the resulting suspension yielded a filtrate, which was then
concentrated under vacuum to remove methanol. The yield of
Based on both experimental results and DFT calculations we
propose a reaction pathway to explain the formation of 3-tosyl-
1
(2%) in obtained crude was determined by integration of the
methylene signal at the 4-position against the internal standard
1
,2,3,4-tetrahydroquinazoline (1) and the palladium complex of
-{hydroxy(methoxy)methyl}-8-hydroxyquinoline (2) from methanolic
mother liquors of Pd(LBS)ꢀ3H O, where LBS is the dianionic form of
ꢁ5
ꢁ5
1
,3,5-tri-tert-buthylbenzene (1 ꢂ 10 g, 4 ꢂ 10 mmol).
2
2
Experiment 2. Compound 1 was obtained from a methanol–
the ligand N-{2-[(8-hydroxyquinolin-2-yl)methyleneamino]benzyl}-4- THF (1.82/1.28 mL) solution of H2LTQ (0.02 g, 0.05 mmol) and
methylbenzene-sulfonamide. Pd(OAc) (0.01 g, 0.05 mmol), which was heated under reflux for
2
We have demonstrated that the formation of the tetra- 24 h. Filtration of the resulting suspension yielded a filtrate, which
hydroquinazoline 1 would involve the acid-catalyzed hydrolysis was then concentrated under vacuum to remove methanol–
of the Schiff base ligand in Pd(LSB)ꢀ3H
2
O to give 2-tosylamino- THF. The yield of 1 (4%) in obtained crude was determined by
methylaniline. The latter species acts as a nucleophile in the integration of the methylene signal at the 4-position against
ꢁ5
palladium-mediated aerobic oxidation of methanol to formal- the internal standard 1,3,5-tri-tert-buthylbenzene (1 ꢂ 10 g,
ꢁ
5
dehyde. The formation of the Pd–hemiacetal complex 2 is a 4 ꢂ 10 mmol). The formation of 1 was prevented by addition
consequence of the addition of methanol to the carbon atom of of water (0.6 mL) to the reaction medium, i.e. a methanol–THF
the aldehyde group that was formed by hydrolysis of the Schiff (1.82/0.58 mL) solution.
base ligand due to the presence of water in an acidic reaction
medium.
Experiment 3. Compound 1 was obtained from a methanol
2 mL) solution of 2-tosylaminomethylaniline (0.06 g, 0.20 mmol)
(
and Pd(OAc) (0.02 g, 0.10 mmol), which was heated under reflux
2
Experimental
General
for 24 h. Filtration of the resulting suspension yielded a filtrate,
which was then concentrated under vacuum to remove methanol.
The yield of 1 (6%) in obtained crude was determined by integra-
tion of the methylene signal at the 4-position against the internal
standard 1,3,5-tri-tert-buthylbenzene (0.02 g, 0.07 mmol).
All starting materials and reagents were commercially available
and were used without further purification. H NMR spectra
1
1
3
(250, 300, 400 and 500 MHz) and C NMR spectra (63, 75, 100
and 125 MHz) were measured in deuterated solvents. J values
Experiment 4. Compound 1 was obtained from a methanol-d4
are given in Hertz. NMR assignments were carried out by a solution (2 mL) of H L (0.01 g, 0.03 mmol) and Pd(OAc) ꢀ
2
TQ
2
ꢁ3
combination of COSY, NOESY, HSQC, HMBC and DEPT-135 4H O (5.6 ꢂ 10 g, 0.02 mmol), which was heated under reflux
2
experiments. Infrared spectra were recorded as KBr pellets on a for 15 h. Filtration of the resulting suspension yielded a filtrate,
ꢁ
1
Jasco FT/IR-410 spectrophotometer in the range 4000–600 cm
.
which was then concentrated under vacuum to remove methanol.
1
0
Elemental analyses were performed using a Carlo Erba EA 1108
H NMR (250 MHz, dmso-d ): 7.63 (d, J = 8.3 Hz, 2H, 2xH-2 ),
analyzer. Electrospray mass spectra were recorded on a Bruker 7.24 (d, J = 8.3 Hz, 2H, 2xH-3 ), 6.84 (m, 2H, H-7 + H-5), 6.52
Microtof spectrometer. MALDI-TOF mass spectra were recorded (dt, J = 7.4 and 1.1 Hz, 1H, H-6), 6.35 (dd, J = 8.6 and 1.1 Hz,
6
0
on a Bruker Ultraflex III TOF/TOF using methanol as solvent and 1H, H-8), 6.06 (t, 1H, NH), 4.49 (d, J = 4.0 Hz, 2H, CH -2), 4.33
2
1
3
DCTB as a matrix.
(s, 2H, CH -4) and 2.29 (s, 3H, CH ) ppm. C NMR (125 MHz,
2 3
acetone-d ) d: 144.2 (C4 ), 143.2 (C8a), 136.9 (C1 ), 130.1 (2xC3 ),
28.5 (2xC2 ), 128.0 (C6), 127.6 (C5), 119.1 (C7), 118.7 (C4a),
0
0
0
6
Computational studies
0
1
1
2 2 3
16.9 (C8), 58.5 (CH -2), 47.9 (CH -4) and 21.6 (CH ) ppm. FT-IR
Geometry optimizations and energy calculations were performed
ꢁ
1
+
2
4
(KBr): 3361 (NH) cm . HRMS found, 311.0829 m/z [M + Na] ,
using the Gaussian 09W program package at the density
functional theory (DFT) level by means of the hybrid B3LYP
functional using the standard 6-31G(d) for C, H, O, S, and N and
the LANZL2DZ basis sets relativistic pseudopotential for Pd.
calcd for C15 NaO S: 311.0825; elemental analysis found:
C 62.7; H 5.5; N 9.5%; calcd for C15
N 9.7%.
H
16
N
2
2
16 2 2
H N O S: C 62.5; H 5.6;
1
1
Palladium complex of 2-{hydroxy(methoxy)methyl}-8-hydro-
The available crystal structure of Pd(LSB)ꢀCH
2
Cl
2
,
which
2
Cl ,
xyquinoline (2). This was obtained from a methanol solution
was obtained by recrystallization of Pd(LSB)ꢀ3H
2
O from CH
2
(60 mL) containing 8-hydroxyquinoline-2-carboxaldehyde (0.30 g,
was used for these studies. Harmonic frequencies were calculated
at the same level of theory to characterize the stationary points
and to determine the zero-point energies (ZPEs). The calculations
were performed in vacuum.
1.73 mmol) and Pd(OAc) O (0.19 g, 0.65 mmol) under reflux
ꢀ4H
2 2
for 1 hour. Filtration of the resulting suspension yielded a maroon
powder, which was washed with methanol followed by diethyl
ether and dried under vacuum. The crude, which is a mixture of
3-Tosyl-1,2,3,4-tetrahydroquinazoline (1). Since the prepara-
Pd(hemi) and Pd(ald)(hemi) in a 6 : 1 molar ratio, was purified
by flash chromatography by eluting with ethyl acetate : hexane
tion of this compound was the goal of four experiments, the
experimental details of each one of them are stated below.
2
(80 : 20). Vacuum concentration of the purified solution gave a
Experiment 1. Compound 1 was obtained from an acidified maroon powder. Yield = 39%.
1
methanol solution (3 mL, pH about 5.6) of Pd(LSB)ꢀ3H
2
O (0.03 g,
6
H NMR (500 MHz, dmso-d ): d = 8.57 (d, J = 8.7 Hz, 2H, H-4),
0
.05 mmol), which was heated under reflux for 24 h. Filtration of 7.82 (d, J = 8.7 Hz, 2H, H-3), 7.42 (t, J = 7.9 Hz, 2H, H-6), 7.22
3
048 New J. Chem., 2013, 37, 3043--3049
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(
7
d, J = 6,2 Hz, 2H, CH), 7.08 (d, J = 7.9 Hz, 2H, H-5), 6.93 (d, J =
7 C. Jiang, L. Yang, W.-T. Wu, Q.-L. Guo and Q.-D. You, Bioorg.
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8 N. M. Abdel Gawad, H. H. Georgey, R. M. Youssef and
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9 A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron,
1996, 52, 15031.
.9 Hz, 2H, H-7), 6.67 (d, J = 6.2 Hz, 2H, OH), 3.52 (s, 3H, OCH )
3
ꢁ1
ppm. IR (KBr): n(CQNquin) 1590(m) cm . MS (MALDI-TOF/
DCTB) 513.9 m/z (100%) [M + H] ; elemental analysis found:
C 51.7; H 3.5; N 5.5%; calcd for C H N O Pd: C 51.3; H 3.9;
N 5.4%.
+
2
2
20 2 6
Palladium complex of 8-hydroxyquinoline-2-carboxaldehyde 10 W. H. Correa, S. Papadopoulos, P. Radnidge, B. A. Roberts
and 2-{hydroxy(methoxy)methyl}-8-hydroxyquinoline. This was
and J. L. Scott, Green Chem., 2002, 4, 245.
obtained from a methanol solution (60 mL) containing 8-hydroxy- 11 A. M. Garcia-Deibe, J. Sanmartin-Matalobos, C. Gonzalez-
quinoline-2 carboxaldehyde (0.30 g, 1.73 mmol) and Pd(OAc)
2
ꢀ
Bello, E. Lence, C. Portela-Garcia, L. Martinez-Rodriguez
and M. Fondo, Inorg. Chem., 2012, 51, 1278.
4
H O (0.19 g, 0.65 mmol) under reflux for 30 min. Filtration
2
of the resulting suspension yielded a maroon powder, which 12 A. S. Kirdanta, B. K. Magarb and T. K. Chondhekar, J. Chem.,
was washed with methanol followed by diethyl ether and dried
Biol. Phys. Sci., 2012, 2, 147.
under vacuum. The crude, which is a mixture of Pd(ald)(hemi) 13 H. Adams, D. E. Fenton, S. R. Haque, S. L. Heath, M. Ohba,
and Pd(hemi)
chromatography by eluting with ethyl acetate : hexane (80 : 20).
2
in a 1 : 1 molar ratio, was purified by flash
H. Okawa and S. E. Spey, J. Chem. Soc., Dalton Trans., 2000,
1849.
Vacuum concentration of the purified solution gave a maroon 14 D. R. Jensen, M. J. Schultz, J. A. Mueller and M. S. Sigman,
powder. Yield = 25%.
Angew. Chem., Int. Ed., 2003, 42, 3810.
1
H NMR (500 MHz, dmso-d ): d = 10.52 (s, 1H; HCO) 8.74 15 M. J. Schultz, C. C. Park and M. S. Sigman, Chem. Commun.,
6
0
(
d, 1H, J = 8.5 Hz; H-4), 8.60 (d, 1H, J = 8.7 Hz; H-4 ), 7.94 (d, 1H,
J = 8.5 Hz; H-3), 7.84 (d, 1H, J = 8.7 Hz; H-3 ), 7.60 (t, 1H, J = 16 J. A. Mueller and M. S. Sigman, J. Am. Chem. Soc., 2003,
.9 Hz; H-6), 7.41 (t, 1H, J = 7.8 Hz; H-6 ), 7.29 (d, 1H, J = 6.3 Hz;
CH), 7.20 (d, 1H, J = 7.8 Hz; H-5), 7.11 (d, 1H, J = 7.3 Hz; H-5 ), 17 J. A. Mueller, D. R. Jensen and M. S. Sigman, J. Am. Chem.
.01 (d, 1H, J = 7.9 Hz; H-7), 6.87 (d, 1H, J = 7.8 Hz; H-7 ), 6.64
d, 1H, J = 6.3 Hz; OH), 3.55 (s, 3H; OCH
2002, 3034.
0
0
7
125, 7005.
0
0
7
(
Soc., 2002, 124, 8202.
ꢁ
1
); IR (KBr, cm ): 18 B. A. Steinhoff and S. S. Stahl, Org. Lett., 2002, 4, 4179.
3
n(CQO) 1692(s), n(CQNquin) 1589(m); MS (MALDI-TOF/DCTB): 19 B. A. Steinhoff, S. R. Fix and S. S. Stahl, J. Am. Chem. Soc.,
+
4
81.9 m/z (20%) [M + H] ; elemental analysis found: C 52.0;
2002, 124, 766.
H 2.9; N 6.0%; calcd for C H N O Pd: C 52.2; H 3.3; N 5.8%. 20 G. ten Brink, I. W. C. E. Arends and R. A. Sheldon, Adv.
2
1
16 2 5
Synth. Catal., 2002, 344, 355.
2
1 S. S. Stahl, J. L. Thorman, R. C. Nelson and M. A. Kozee,
J. Am. Chem. Soc., 2001, 123, 7188.
Acknowledgements
Financial support from the Ministerio de Ciencia e Innovaci o´ n 22 M. J. Schultz, R. S. Adler, W. Zierkiewicz, T. Privalov and
CTQ2010-19191 to JSM and SAF2010-15076 to CGB) and the
M. S. Sigman, J. Am. Chem. Soc., 2005, 127, 8499.
Xunta de Galicia (10PXIB2200122PR and GRC2010/12 to CGB) 23 T. Privalov, C. Linde, Z. Zetterberg and C. Moberg, Organo-
is gratefully acknowledged. We are also grateful to the Centro
metallics, 2004, 24, 885.
de Supercomputaci o´ n de Galicia (CESGA) for the use of the 24 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
(
Finis Terrae computer.
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin,
V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
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