A cooperative catalytic system of platinum/iridium alloyed nanoclusters and a dimeric catechol derivative: An efficient synthesis of quinazolines through a sequential aerobic oxidative process

Article abstract of DOI:10.1002/adsc.201200880

A cooperative catalytic system of heterogeneous polymer-supported bi-metallic platinum/iridium (Pt/Ir) alloyed nanoclusters and 5,5′,6,6′-tetrahydroxy-3,3,3′,3′-tetramethyl-1, 1′-spiro-bisindane (TTSBI) enabled the facile preparation of quinazoline derivatives with low catalyst loadings and broad substrate scope under mild aerobic oxidative conditions. The ability to perform the reaction in gram-scale and under open-air conditions highlights the synthetic application of this cooperative catalytic system. Copyright

Full text of DOI:10.1002/adsc.201200880

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DOI: 10.1002/adsc.201200880
A Cooperative Catalytic System of Platinum/Iridium Alloyed
Nanoclusters and a Dimeric Catechol Derivative: An Efficient
Synthesis of Quinazolines Through a Sequential Aerobic
Oxidative Process
Hao Yuan,a Woo-Jin Yoo,a Hiroyuki Miyamura,a and Shu¯ Kobayashia,*
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81) 3-5684-0634; e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Received: September 30, 2012; Published online: October 30, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200880.
Abstract: A cooperative catalytic system of hetero-
geneous polymer-supported bi-metallic platinum/iri-
dium (Pt/Ir) alloyed nanoclusters and 5,5’,6,6’-tetra-
hydroxy-3,3,3’,3’-tetramethyl-1,1’-spiro-bisindane
(TTSBI) enabled the facile preparation of quinazo-
line derivatives with low catalyst loadings and
broad substrate scope under mild aerobic oxidative
conditions. The ability to perform the reaction in
gram-scale and under open-air conditions highlights
the synthetic application of this cooperative catalyt-
ic system.
polymers by a process known as the polymer incarcer-
ation (PI) method.[4] During our investigations for the
efficient synthesis of heterocyclic compounds with
metal NC catalysts,[5] we discovered a metalloenzyme-
like cooperative catalytic system of heterogeneous bi-
metallic Pt/Ir alloyed NCs and 4-tert-butylcatechol
(1a), which could act as an effective catalytic system
for the aerobic oxidation of amines to imines under
mild conditions.[6] Mechanistic studies suggested that
the Pt/Ir NCs and the catechol derivative work coop-
eratively to facilitate the oxidation of amines to
imines (Scheme 1).
Keywords: aerobic oxidation; cooperative catalysis;
nanoclusters; platinum/iridium alloy; quinazolines
The quinazoline core structure is found in many
natural and pharmaceutical compounds and they have
been utilized as a-adrenergic blockers for the treat-
ment of high blood pressure, anxiety and panic disor-
der (Prazosin)[7] and as an epidermal growth factor re-
ceptor inhibitor for the treatment of certain breast,
The ability of two or more discreet catalysts working lung and other cancers (Iressa)[8] (Figure 1).
cooperatively to facilitate chemical transformations
Substituted quinazolines have been synthesized by
represents one of the most effective strategies to a variety of methods. One strategy is through the oxi-
achieve high reactivity and selectivity in synthetic or- dative condensation of 2-aminobenzylamines with al-
ganic chemistry.[1] Such cooperative catalytic systems dehydes either mediated by stoichiometric amounts
are prevalent in Nature and are observed in metal- of strong oxidants such as DDQ,[9] MnO2,[10] and
loenzymes that utilize both a metal and an organic co- NaClO[11] or through copper-catalyzed aerobic oxida-
factor to facilitate biosynthetic processes essential for tion reactions using catalytic amounts of TEMPO and
life. For instance, amine oxidases are a family of DABCO.[12] However, due to the harsh conditions em-
redox-active enzymes that catalyze the oxidation of
primary amines to aldehydes through the cooperation
between a copper and quinone-based cofactor under
aerobic oxidative conditions.[2] Such enzymatic sys-
tems have inspired the development of biomimetic
multi-catalytic processes for aerobic oxidation reac-
tions.[3]
In our laboratory, we are interested in the develop-
ment of highly efficient heterogeneous catalysts
through an effective protocol for the immobilization
of metal nanoclusters (NCs) with styrene-based co- for the aerobic oxidation of amines to imines.
Scheme 1. Metalloenzyme-like cooperative catalytic system
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Hao Yuan et al.
Table 1. Optimization of reaction conditions.[a]
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Entry Metal Co-catalyst [mol%] Temp. [oC] Yield [%]b
1
2
3
4
5
6
7
8
9
Pt
Pt/Ir
–
–
30
30
30
35
35
35
35
35
35
0[c]
0[c]
Figure 1. Quinazolines as core structures in pharmaceuticals.
Pt/Ir 1a [10]
Pt/Ir 1a [10]
Pt/Ir 1a [5]
Pt/Ir 1b [2.5]
Pt/Ir 1b [3.5]
Pt/Ir 1b [3.5]
Pt/Ir 1b [3.5]
91
99
81
91
>99
99(95)[d]
93[e]
ployed in these protocols, the substrate scopes report-
ed thus far were limited. Therefore, the development
of more efficient and environmentally benign catalytic
systems is highly desirable. Herein, we report the ap-
plication of the cooperative catalytic system of metal
NCs and catechol derivatives as redox-active organo-
catalysts for the synthesis of quinazoline derivatives.
We initiated our studies by examining the reaction
between benzaldehyde and 2-aminobenzylamine 2a to
test the reactivity of cooperative catalytic systems for
the synthesis of quinazoline derivatives (Table 1).
We began by performing some control experiments,
and found that this reaction could not be catalyzed by
PI/CB-Pt or PI/CB-Pt/Ir in the absence of an organic
co-catalyst (entries 1 and 2). When the combination
of 0.5 mol% of PI/CB-Pt/Ir and 10 mol% of 1a in
a slightly more concentrated condition was employed,
the desired 2-phenylquinazoline 3a was obtained in
[a]
2-Aminobenzylamine 2a (0.5 mmol) and benzaldehyde
(0.5 mmol) were stirred in CDCl3 for 4 h then PI/CB-
metal and co-catalyst 1a or 1b were added. The mixture
was further stirred in CDCl3:H2O (9:1), C=0.5M for
16 h under O2 (1 atm).
[b]
Determined by 1H NMR analysis using 1,1,2,2-tetra-
chloroethane as an internal standard and the isolated
yield was shown in the parenthesis.
[c]
[d]
[e]
C=0.25M.
CHCl3 was used as solvent.
Using air (1 atm) as oxidant.
With the optimized conditions in hand, the sub-
91% yield (entry 3). The yield could be slightly im- strate scope of the oxidative quinazoline syntheses
proved when the reaction temperature was increased was examined (Table 2). Benzaldehyde derivatives
to 358C (entry 4). One of deficiencies of our previous bearing electron-withdrawing groups like chloro and
method for the general oxidation of amines to imines nitro on the aromatic ring are suitable with this cata-
was the relatively high loading of the catechol co-cat- lytic system, and the desired products 3b and 3c were
alyst. The search of a more robust cooperative cata- obtained in excellent yields with 4 mol% of 1b (en-
lyst was initiated and 5,5’,6,6’-tetrahydroxyl-3,3,3’,3’- tries 2 and 3). An aromatic aldehyde bearing a weak
tetramethyl-1,1’-spiro-bisindane (TTSBI, 1b)[13] was electron-donating group like a methyl group showed
shown to catalyze the oxidative quinazoline synthesis higher reactivity, and the desired quinazoline 3d could
with very low catalyst loadings (2.5 mol%) in 91% be isolated in 91% yield (entry 4). The reaction could
yield (entry 6). More importantly, a higher reactivity also proceed well to provide 92% yield of the 2-sub-
was observed with 2.5 mol% of 1b than with 5 mol% stituted quinazoline 3e when bulky 2-methylbenzalde-
of 1a (entries 5 and 6), which may be due to the for- hyde was employed (entry 5). The benzaldehyde bear-
mation of a more stable intermediate or be caused by ing a strong electron-donating methoxy group also
a stronger interaction with the surface of metal NCs. gave the desired product 3f in good yield when
When 3.5 mol% of 1b was used, a quantitative yield
a slight excess of 4-methoxylbenzaldehyde and
of the desired quinazoline 3a could be observed (en- 4 mol% of 1b was utilized (entry 6). Heteroatom-con-
tries 7 and 8). Finally, we found that the sequential taining substrates like 2-furalaldehyde and 3-pyridine-
oxidative process could be performed under an at- carboxaldehyde were examined and the correspond-
mospheric pressure of air to provide 3a in 93% yield ing quinazolines 3g and 3h were obtained in 88% and
(entry 9).
99% yields respectively (entries 7 and 8). In order to
demonstrate the broad synthetic utility of our meth-
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A Cooperative Catalytic System of Platinum/Iridium Alloyed Nanoclusters
Table 2. Substrate scope for the synthesis of quinazoline derivatives.[a]
Entry
R1
R2
Product
1b [mol%]
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
6-F (2b)
5-Me(2c)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3.5
4
4
3.5
3.5
4
4
4
5
4
4
5
4.5
4
4
4
5
2.5
95
96
92
91
4-Cl-C6H4
4-NO2-C6H4
4-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
2-furyl
3-pyridyl
t-Bu
c-hexyl
92
77[c]
88
99
94
97
66
9
10
11
12
13
14
15
16
17
18
i-Bu
BnCH2
1-naphthyl
H
COOEt
CH
Ph
65
>99
74[c,d]
89
(OMe)2
94
70[e}
75
Ph
[a]
2-Aminobenzylamines (0.5 mmol) and aldehydes (0.5 mmol) were stirred in CHCl3 for 4 h then PI/CB-Pt/Ir and TTSBI
(1b) were added. The mixture was further stirred in CHCl3:H2O (9:1), C=0.5M for 16 h under O2 (1 atm) at 358C.
Yield based on 2a–c and was determined by weight of the isolated product 3a–r.
1.25 equiv. of aldehyde were used.
Paraformaldehyde was used as starting material.
1.5 equiv. of aldehyde were used.
[b]
[c]
[d]
[e]
odology, we investigated more challenging substrates hyde were directly employed under the cooperative
like aliphatic aldehydes. Possibly due to steric hin- catalytic system (entry 14). Ester and acetal groups
drance of the aldehyde, a higher catalyst loading of could be directly introduced in our cooperative cata-
1b was necessary when trimethylacetaldehyde was lytic system, and the corresponding 2-substituted qui-
employed as a substrate and the desired product 3i nazolines 3o and 3p could be obtained in excellent
was obtained in an excellent yield (entry 9). Cyclo- yields (Table 2, entries 15 and 16). Prior to this report,
hexanecarboxaldehyde was found to be a good sub- quinazolines bearing such functional groups have not
strate and 97% of the desired product 3j could be iso- been reported. Finally, the substrate scope of 2-substi-
lated under the optimized reaction conditions tuted aminobenzylamines was investigated. 2-Amino-
(entry 10). When linear aliphatic aldehydes such as 3- benzylamines bearing both electron-withdrawing 2b
methylbutanal and 3-phenylpropanal were employed and electron-donating substituents 2c could provide
as substrates, the desired quinazolines 3k and 3l were the products 3q and 3r in good yields. A higher cata-
obtained in good yields (entries 11–12). Next, a fused lyst loading of 1b was needed when 2-amino-6-fluoro-
aromatic aldehyde, 1-naphthaldehyde, was examined benzylamine 2b was used as substrate (entry 17),
and the desired quinazoline 3m could be obtained in while only 2.5 mol% catalyst loading was required
quantitative yield by slightly increasing the loading of when 2-amino-5-methylbenzylamine 2c was employed
1b to 4.5 mol% (entry 13). The parent quinazoline (entry 18).
without any substituent groups (3n) itself is a very im-
A gram-scale synthesis of quinazoline derivative 3p
portant natural product and also is a valuable precur- was conducted in order to demonstrate the synthetic
sor for many biologically active compounds. However, utility of our newly developed cooperative catalytic
to the best of our knowledge, there are no efficient system (Scheme 2). Under more concentrated condi-
methods to prepare this valuable intermediate. It was tions, the catalyst loading of PI/CB-Pt/Ir could be de-
found that the quinazoline 3n could be obtained in creased to 0.1 mol% and only 0.25 equiv. of K2CO3
77% isolated yield when 1.25 equiv. of paraformalde- was required to give 3p in 98% isolated yield.
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Hao Yuan et al.
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ing the aerobic oxidized product in a higher yield
than when 5 mol% of 1a was used. In order to reveal
the nature of this phenomenon, the model reaction
1
was monitored by in situ H NMR analysis with the
two catechol-based co-catalysts (Figure 2).
From our studies, we determined that TTSBI (1b)
was a superior catalyst than catechol 1a since the rate
of the reaction was faster.
Finally, we performed recovery and reuse studies
with the PI/CB-Pt/Ir NC catalyst for the synthesis of
quinazoline 3p, and found that the NC catalyst could
be reused at least five times without noticeable loss of
catalytic activity and leaching of the metals
Scheme 2. Gram-scale synthesis.
Since 2-(dimethoxymethyl)quinazoline 3p could be (Scheme 4).
obtained in a relatively large quantity, we attempted
to prepare the synthetically useful quinazoline-2-car-
baldehyde 3s via deprotection under acidic conditions
(Scheme 3). This aldehyde was found to serve as
a useful precursor for the synthesis of symmetric 2,2’-
bis-quinazoline 5a under our cooperative catalytic
system. Applying our previously reported method for
the synthesis of heterocycles with PI/CB-Pt catalysts
under aerobic oxidative conditions,[5a] we were also
able to obtain mixed bis-heterocyclic compounds 5b
and 5c in excellent yields. These examples demon-
strate the synthetic applications of the cooperative
catalytic system to deliver these bis-heterocyclic spe-
cies that may serve as potentially interesting ligands
or materials with unique properties.
Next, we examined the reactivity of the newly dis-
covered TTSBI (1b) co-catalyst by comparing it with
4-tert-butyl catechol (1a). We have shown that only
2.5 mol% of 1b was found to be sufficient in provid- Figure 2. Comparison of the reactivities between 1a and 1b.
Scheme 3. Synthesis of bis-heterocycles.
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A Cooperative Catalytic System of Platinum/Iridium Alloyed Nanoclusters
(EtOAc:hexane=1:9) to provide 3a as a white solid; yield:
0.0976 g (0.475 mmol, 95%).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from the Japan Society for the Promotion of
Science (JSPS), Global COE Program, The University of
Tokyo, MEXT (Japan), and NEDO.
Scheme 4. Recovery and reuse of PI/CB-Pt/Ir.
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In summary, a metalloenzyme-like cooperative cat-
alytic system of heterogeneous bimetallic NCs and
TTSBI (1b) was developed and was successfully ap-
plied for the preparation of quinazoline derivatives
from 2-aminobenzylamines and aldehydes under mild
aerobic oxidative conditions with wide substrate
scope. Compared to the simple 4-tert-butylcatechol
(1a), TTSBI (1b) was discovered to be a robust and
highly reactive cooperative catalyst that facilitated the
formation of quinazolines in excellent yields with
broad substrate scope. Kinetic studies revealed that
the reactivity of TTSBI (1b) was higher than that of
catechol 1a and this cooperative catalytic system was
found to be amenable for the gram-scale synthesis of
2-substituted quinazoline 3p. This product was then
applied as a precursor for the preparation of a variety
of bis-heterocyclic compounds using our PI/CB-M
nanocluster catalysts. Finally, we demonstrated that
the heterogeneous metal NCs could be recovered and
reused at least for 5 times without loss of reactivity
and the leaching of the metals. We anticipate that this
cooperative catalytic system could be applied for
other aerobic oxidation reactions and the preparation
of heterocyclic compounds under mild aerobic condi-
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Typical Procedure
In a screw-cap glass test tube were added 2-aminobenzyla-
mine (2a) (0.0610 g, 0.5 mmol), benzaldehyde (0.0508 mL,
0.5 mmol) and CHCl3 (0.45 mL). The mixture was stirred for
4 h at 358C. Then PI/CB-Pt/Ir (0.0140 g, 0.0025 mmol,
0.5 mol%), TTSBI (1b) (0.0060 g, 0.00175 mmol), K2CO3
(0.0350 g, 0.25 mmol), CHCl3 (0.45 mL) and H2O (0.1 mL)
were added. The resultant reaction mixture was allowed to
stir for another 16 h at 358C under an O2 balloon. Then the
reaction mixture was filtered, washed with DCM, and 20 mg
MgSO4 were added. The filtrate was concentrated under re-
duced pressure. The crude product was purified by PTLC
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