A convenient palladium-catalyzed carbonylative synthesis of quinazolines from 2-aminobenzylamine and aryl bromides

Article abstract of DOI:10.1039/c4ra11303a

A novel and practical strategy towards quinazoline scaffolds synthesis has been achieved. Through palladium-catalyzed carbonylative coupling of 2-aminobenzylamine with aryl bromides, the desired quinazolines were produced in moderate to good yields for the first time. The reactions followed an aminocarbonylation-condensation-oxidation sequence in a one-pot one-step manner. Preliminary investigation showed DMSO serves both as solvent and oxidant in this procedure.

Full text of DOI:10.1039/c4ra11303a

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ARTICLE TYPE
A Convenient Palladium-Catalyzed Carbonylative Synthesis of
Quinazolines from 2-Aminobenzylamine and Aryl Bromides
Jianbin Chen+, Kishore Natte+, Helfried Neumann, and Xiao-Feng Wu*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
of zinc salt.21a,21b In 2013, Zhang’s group demonstrated a copper-
A novel and practical strategy towards quinazoline scaffolds
synthesis has been achieved. Through palladium-catalyzed
carbonylative coupling of 2-aminobenzylamine with aryl
bromides, the desired quinazolines were produced in
10 moderate to good yields for the first time. The reactions
followed by aminocarbonylation-condensation-oxidation
catalyzed annulation of amidines for the quinazoline synthesis through
C-H activation.21c However, to the best of our knowledge, no
carbonylative approach has been exploited for the preparation of
quinazolines until nowadays. In our continuing efforts to manifest
useful carbonylative reactivity profiles in this area,22 herein we wish
to report the first carbonylative protocol towards quinazoline
preparation with readily available aryl bromides and 2-
aminobenzylamine as starting materials.
sequence in
a one-pot one-step manner. Preliminary
investigation showed DMSO serves both as solvent and
oxidant in this procedure.
15 We initiated the optimization with 2-aminobenzylamine and
bromobenzene as the model substrates in the present of Pd(OAc)2
(2 mol%) and BuPAd2 (6 mol%) under 10 bar of CO with Et3N as
Palladium-catalyzed carbonylation reactions have been regarded as a
subject of great synthetic toolkit in modern organic synthetic
chemistry1 and numerous efforts have been made to apply
carbonylations in the synthesis of biological active compounds.2
Among the numerous heterocyclic compounds, nitrogen-containing
compounds frequently exist in natural products, agrochemicals and
pharmaceuticals.2c,3 Quinazolines and their derivatives, among these
heterocycle compounds, have been defined as the privileged scaffold
o
the base in DMAc at 120 C. Only few amounts of the desired
product were formed with 8% of the intermediate 4a and non-
20 cyclized compound 5a as the main by-product (Table 1, entry 1).
In order to accelerate the cyclization step, some Lewis acids were
tested such as FeCl3, MgSO4, MgCl2 and CuCl2, but no significant
improvement was got (Table 1, entries 2-5). Increasing the
temperature to 140 oC, 21% of the desired product 3a and 70% 5a
25 were observed (Table 1, entry 6). DBU as base shown better
selectivity compared with the other tested bases (Table 1, entry 7).
Some other aprotic polar solvents such as DMF, NMP and
DMSO were screened as well. Among them, DMSO gave the
best results (Table 1, entries 8-11). It is worthy to mention that no
30 non-cyclized intermediate 5a was observed when DMSO was
used as the solvent and DBU as the base. The inorganic bases,
taken an example of K2CO3 or K3PO4·H2O displayed
commonplace performance in this system (Table 1, entries 12 and
13). To our delight, 92% isolated yield of 2-phenylquinazoline
35 could be achieved by increasing the loading of palladium catalyst
and prolong the reaction time (Table 1, entry15).
because they exhibit
a
wide spectrum of biological and
pharmacological activities including anticancer,4 antiviral,5
antitubercular6 and antimalarial7 properties. Recently, Yang and co-
workers reported that derivatives of quinazolines can serve as a novel
potent and selective FLT3 inhibitor and possess anti-acute myeloid
leukemia (AML) activities.8 As the accepted importance, many
attentions have been attracted for quinazolines preparation.9-21 Most
recent protocols toward quinazolines synthesis include the reaction
between 2-aminobenzophenones and benzylamines by using
supported copper oxide nanoparticles9 or 4-HO-TEMPO10 as the
catalyst; copper-catalyzed reactions between amidines and 2-
halophenyl carbonyl compounds,11 (2-bromophenyl)methylamine,12 or
ortho-halobenzyl halide.13 Copper-catalyzed Ullmann-type coupling
and aerobic oxidation of (2-bromophenyl)methylamine with
benzamides;14 copper-catalyzed tandem reaction of 2-bromobenzyl
bromides with aldehydes and aqueous ammonia;15 copper-catalyzed
condensation of ortho-bromoaryl carbonyl compounds, ammonia and
Table 1. Optimization of the reaction parameters.[a]
aldehydes;16
copper-catalyzed
cascade
reaction
of
(2-
aminophenyl)methanol, ammonium salts and aldehyde;17 and the
condensation of 2-aminobenzylamine with aldehyde followed by
subsequent oxidation by the strong oxidants such as 2,3- dichloro-5,6-
dicyanobenzoquinone (DDQ), tetrachloro-1,4-benzoquinone (TCQ),18
MnO2,19 or NaClO.20 Additionally, Walton and co-workers developed
microwave-promoted synthesis of quinazolines from 2-
(aminoaryl)alkanone O-phenyl oximes and aldehydes in the presence
Yield(%)[b]
Entry
1
Base
NEt3
Additive
-
Solvent
DMAc
T/oC
120
3a/4a/5a
10/8/50
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2
NEt3
NEt3
NEt3
NEt3
NEt3
DBU
NEt3
NEt3
NEt3
DBU
K2CO3
FeCl3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
120
120
120
120
140
140
140
140
140
140
140
14/2/45
1
2
92%
91%
3
MgSO4
2/1/3
4
MgCl2
11/3/44
4/0/0
5
CuCl2
6
-
-
-
-
-
-
-
21/7/70
22/25/4
17/8/46
27/5/22
18/3/58
50/31/0
41/21/22
7
8
3
87%
9
DMSO
NMP
10
11
12
DMSO
DMSO
4
5
6
61%
62%
78%
K3PO4
H2O
13
-
DMSO
140
28/8/34
140[c]
140[c]
62(54)/27/0
(92)[d]/0/0
14
15
DBU
DBU
-
-
DMSO
DMSO
Reaction conditions: [a] 1a (0.5 mmol, 1.0 equiv.), 2a (0.5 mmol,
1.0 equiv.), Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), base (3.0
equiv.), additive (2.0 equiv.), CO (10 bar), solvent (2 mL), 17 h,
indicated temperature. [b] GC yields with hexadecane as internal
standard, isolated yields in parentheses. [c] 36h. Pd(OAc)2 (5
mol%), BuPAd2 (10 mol%). [d] 36h.
7
8
9
81%
65%
93%
Having established the optimized system, we turned our attention
to the substrates scope of this approach. As shown in Table 2, a
wide range of substitutions could be tolerated under our reaction
conditions and delivering the corresponding products in good to
excellent yields. More specifically, aryl bromides with electron-
donating substitution such as methoxy (Table 2, entries 2 and 5),
dimethylamino (Table 2, entry 3), tert-butyl (Table 2, entry 4) all
reacted with 2-aminobenzylamine to give the corresponding
5
10 quinazolines in good to excellent yields. Trifluoromethyl (Table 2,
entry 7) and cyano (Table 2, entry 8) as representative examples
of electron-withdrawing groups worked as well in our conditions.
Notably, naphthyl (Table 2, entry 11), biphenyl (Table 2, entry 9)
and aryl ketone (Table 2, entry 10) bromides could be applied as
15 substrates and succeeded to provide the corresponding products
in high yields. Interestingly, heteroaryl bromides, taken the
quinoline (Table 2, entry 12), thiophene (Table 2, entry 13) and
indole (Table 2, entry 14) for examples, the target molecules were
successfully produced in 70%, 59% and 52% yields.
20 Unfortunately, multi fluoro substituted bromobenzene (Table 2,
entries 15 and 16) did not work under our conditions. And more
steric substrate such as the 2,4,6-trimethylbromobenzene failed in
this process (Table 2, entry 17).
10
11
72%
83%
12
13
14
70%
59%
52%
Table 2. Substrates scope for the quinazolines synthesis.[a]
15
<5%
Entry
Product
Yield[b]
2
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Conclusions
16
17
<5%
<5%
In summary, a novel and practical protocol for the synthesis of
quinazolines has been developed. Through palladium-catalyzed
carbonylative coupling of 2-aminobenzylamine with aryl
35 bromides, the desired quinazolines were produced in moderate to
good yields. The reactions followed by aminocarbonylation-
condensation-oxidation sequence in a one-pot one-step manner.
Preliminary investigation shown DMSO serves both as solvent
and oxidant in this procedure.
Reaction conditions: [a] 1a (0.5 mmol, 1.0 equiv.), 2 (0.5 mmol, 1.0
equiv.), Pd(OAc)2 (5 mol%), BuPAd2 (10 mol%), DBU (3.0 equiv.), CO (10
bar), DMSO (2 mL), 36 h, 140 oC. [b] Isolated yield.
40
General reaction procedure: An oven-dried 12 mL vial with stir
bar was charged with 2-aminobenzylamine (0.5 mmol, 1 equiv.),
Pd(OAc)2 (5 mol%), and BuPAd2 (10 mol%). Then, aryl bromide
(0.5 mmol, 1.0 equiv.), DMSO (2 mL), DBU (1.5 mmol, 3 equiv)
45 were injected into the vial under argon flow sequentially. The vial
(or several vials) was placed in an alloy plate, which was
transferred into a 300 mL autoclave of the 4560 series from Parr
Instruments under an argon atmosphere. After flushing the
autoclave three times with CO, a pressure of 10 bar CO was
50 adjusted at ambient temperature. The reaction mixture was heated
at 140 °C for 36 h. After the reaction finished, the autoclave was
cooled down to room temperature and the pressure was released
carefully. The product was extracted with ethyl acetate (5 × 3
mL). The organic layers were washed with brine, dried over
55 Na2SO4, and evaporated to yield the crude reaction mixture. The
purification was done by combi flash machine flash
chromatography on silica gel (eluent: heptanes:EtOAc = 60:40).
In order to gain some details about the mechanism, control
experiment was conducted. The reaction was run in the present of
4,4’-dimethyldiphenylsulfoxide 6 with DMF as the solvent
instead of DMSO (Scheme 1). The desired product 3a and di-p-
tolylthio ether 7 were observed with full conversion of starting
materials which proven that DMSO played as oxidant in our
system.
5
10
Scheme 1. Preliminary investigation.
a
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-
Taken the above observations together, we proposed a most
60
Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: xiao-feng.wu@catalysis.de
15 plausible reaction mechanism in Scheme 2. The reduction of
Pd(II) to Pd(0) started the catalyst cycle, then was followed by
the oxidative addition of aryl bromides to Pd(0) delivering the
corresponding organopalladium species A. After the coordination
and insertion of CO, the key intermediate acylpalladium complex
20 B was formed. Then nucleophilic attack of 1a to intermediate B
took place giving the compound 5a and Pd(0) under the assistant
of base which ready for next cycle. The produced compound 5a
underwent intramolecular cyclization and produced the
intermediate 4a. Then intermediate 4a was subsequently oxidized
25 into the terminal quinazoline product under the assistant of
palladium and DMSO.
+ These authors contributed equally to this work.
65 Acknowledgments: The authors thank the state of Mecklenburg-
Vorpommern and the Bundesministerium für Bildung und Forschung
(BMBF) for financial support. Dr. C. Fischer, S. Schareina and Dr. W.
Baumann in LIKAT are acknowledged for their excellent technical and
analytical support. We also appreciate the general support from Prof.
70
Matthias Beller in LIKAT.
† Electronic Supplementary Information (ESI) available: [Analytic datas
and NMR spectrums]. See DOI: 10.1039/b000000x/
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Scheme 2. Proposed reaction mechanism.
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