Synthesis of 2-substituted quinazolines via iridium catalysis

Article abstract of DOI:10.1039/c2ra22278g

An iridium-catalyzed hydrogen transfer reaction was successfully applied in the synthesis of 2-substituted quinazolines in moderate yields starting from aldehydes or alcohols with 2-aminobenzylamines.

Full text of DOI:10.1039/c2ra22278g

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Synthesis of 2-substituted quinazolines via iridium
catalysis3
Cite this: RSC Advances, 2013, 3, 334
Jie Fang,a Jianguang Zhou*a and Zhijie Fangb
Received 25th September 2012,
Accepted 5th November 2012
DOI: 10.1039/c2ra22278g
www.rsc.org/advances
An iridium-catalyzed hydrogen transfer reaction was successfully
applied in the synthesis of 2-substituted quinazolines in moderate
yields starting from aldehydes or alcohols with 2-aminobenzyla-
mines.
Scheme 1 One-pot synthesis of quinazolines.
Quinazolines occur frequently in natural products and synthetic
pharmaceuticals which exhibit important biological properties,1
such as antidiabetic, antibacterial, anticonvulsant and anticancer
activities. For example, prazosin was an effective medicine as
a-adrenergic blockers for the treatment of high blood pressure,
panic disorder and anxiety,2 and lapatinib was used to treat solid
tumor and breast cancer.3
further transformed to the product quinazoline 4a under hydrogen
transfer catalysis, which accounted for the low yield of 4a in this
reaction. To improve the yields of 4a, we decided to add a
hydrogen acceptor to the reaction mixture. To our delight, the
Syntheses of substituted quinazolines have been widely
explored,4 and many efficient methods have been developed
recently. As shown in Scheme 1, one of the synthetic methods to
quinazolines utilizes condensations between aldehydes 2 and
2-aminobenzylamines 1 followed by oxidation of the aminal
intermediate 3. However, stoichiometric or large excess amounts
of toxic oxidants were required for this oxidation; e.g., DDQ,
Table 1 Optimization of conditions for the synthesis of quinazoline 4a between
1a and 2aa
4l
p-chloranil,4c NaClO4k and MnO2 were used. In continuation of
our work in the application of hydrogen transfer catalysis in the
syntheses of quinazolinones,5 we were interested to test if a
hydrogen transfer catalyst6 will catalyze the oxidation of aminal 3
to 2-substituted quinazoline 4 in one-pot as shown in Scheme 1.
Firstly, 2-aminobenzylamine 1a with benzaldehyde 2a was
selected as the model substrate to test the one-pot reaction and
the results are summarized in Table 1. We discovered that without
a hydrogen acceptor, only 10% product 4a was formed using
[Cp*IrCl2]2 (2.5 mol%) as the catalyst (Cp* = pentamethylcyclo-
pentadienyl, entry 1). The major byproduct isolated was the
N-benzylation product 57 as shown in Scheme 2.
Entry Catalyst
Additive Acceptor
Solvent Yieldb
1
2
3
4
[Cp*IrCl2]2
No
No
No
No
xylene 10%
xylene 66%c
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
styrene
E-crotonitrile xylene 50%c
AcOH
0.2 eq.
KOH
0.2 eq.
styrene
xylene 43%
xylene 54%
xylene 60%
xylene 46%
toluene 35%
5
6
7
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
styrene
t-BuONa styrene
0.2 eq.
K2CO3
0.2 eq.
No
No
No
KOH
0.2 eq.
styrene
8
9
10
11
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrI2]2
styrene
styrene
styrene
styrene
DMF
50%
This byproduct formation could have originated from hydrogen
transfer8 to the imine intermediate 6. Compound 5 could not be
xylene 57%
xylene 26%
RuCl2(PPh3)3
d
12
[Ru(p-cymene)Cl2]2 KOH
0.2 eq.
styrene
xylene 52%
aChemical and Analytical Development, Suzhou Novartis Pharma Technology Co.
Ltd, Changshu, Jiangsu, China 215537. E-mail: jianguang.zhou@novartis.com
bSchool of Chemical Engineering, Nanjing University of Science & Technology,
Nanjing, Jiangsu, China 210094
a
Conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (2.5 mol%),
styrene (4.0 eq.) in refluxing temperature of the solvent listed (1 mL)
under N2, 24 h. H-NMR yield. Isolated yield, 12% of byproduct 5
was also isolated in entry 2. 2.5 mol% dppf was added.
b
c
Electronic supplementary information (ESI) available: Experimental procedures
3
d
and compound characterization data. See DOI: 10.1039/c2ra22278g
334 | RSC Adv., 2013, 3, 334–336
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Scheme 3 One-pot synthesis of 2-phenylquinazoline starting with benzyl alcohol.
Scheme 2 Possible pathway to 5 from hydrogenation of imine 6 and reaction of
5 under hydrogen transfer conditions.
Subsequently, a variety of substituted quinazolines were
synthesized using our optimized conditions. As shown in
Table 2, both aliphatic and aromatic aldehydes reacted with
2-aminobenzylamines to give the corresponding quinazolines 4 in
moderate yields. Reactions between 1a and aromatic aldehydes
with either electron-withdrawing or electron-donating groups
(entries 2 to 10) showed that the yields were not affected
significantly in the range of 48% to 58%. Furthermore, the
reactions also performed well when 2-furyl aldehyde (55% yield,
entry 11), 2-phenylacetaldehyde (49% yield, entry 12) and hexanal
(57% yield, entry 13) were involed. Investigations of 2-(amino-
methyl)-3-fluoroaniline 1b with several aldehydes again gave
substituted quinazolines 4n to 4q in moderate yields (56% to
65%, entries 14 to 17).
yields of 4a were improved to 66% with addition of styrene (entry
2) and 50% with E-crotonitrile (entry 3). Further optimizations of
the reaction by using acid or base additives were also tried (entries
4 to 7), but the best yield of 60% obtained by addition of NaOtBu
(entry 6) was inferior to the results of 66% without such additives
in entry 2. The effects of solvents (entries 8 and 9) and catalysts
(entries 10 to 12) were also examined briefly with no increase of
the yield of 4a. After examining the reaction profiles, we decided to
select the conditions of entry 2 (2.5 mol% [Cp*IrCl2]2 in refluxing
xylene with addition of 4.0 eq. styrene) for our investigations of the
substrate scope of the reaction.
It was our next interest to test the employment of benzyl
alcohol 7 instead of benzaldehyde 2a in the synthesis of
quinazoline 4a. The above described conditions using benzalde-
hyde did not give a satisfactory yield of 4a (only 10%) when
benzylalcohol 7 was used. Some optimizations (see supporting
Table 2 One-pot synthesis of quinazolines via Ir-catalyzed hydrogen transfersa
information, ESI ) identified that the addition of base additives,
3
such as KOH (0.2 eq.) was necessary to increase the yield of 4a to
61% (Scheme 3).
When 2-aminobenzyl alcohol 8 was used, the condensation
with benzaldehydes 2a gave 2-phenyl-4H-benzo[d][1,3]oxazine 9 in
45% yield as shown in Scheme 4.9 The optimized conditions also
involved the use of KOH (2 eq.) to give a better yield (see
supporting information, ESI ).
3
Entry
R1
R2
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
H
H
H
H
H
F
C6H5
4a 66%
4b 54%
4c 48%
4d 58%
4e 54%
4f 51%
4g 51%
4h 55%
4i 57%
4j 50%
4k 55%
4l 49%
4m 57%
4n 56%
4o 60%
4p 62%
4q 65%
3–Cl–C6H4
3–Br–C6H4
3–NO2–C6H4
3–Me–C6H4
3–OMe–C6H4
4–F–C6H4
4–Br–C6H4
4–NO2–C6H4
4–Me–C6H4
Furyl
Benzyl
n-Pentanyl
C6H5
4–Br–C6H4
4–Me–C6H4
n-Pentanyl
F
F
F
a
Conditions: Entries 1–13: 1a (1.0 mmol), 2 (1.0 mmol), catalyst (2.5
mol%), styrene (4.0 eq.) in refluxing xylene (2 mL) under N2, 24 h.
Entries 14–17: 1b (1.0 mmol), 2 (1.0 mmol), catalyst (2.5 mol%),
styrene (4.0 eq.) in refluxing xylene (2 mL) under N2, 24 h. Isolated
yield.
b
Scheme 4 One-pot synthesis of 2-phenyl-4H-benzo[d][1,3] oxazine between 8
and 2a.
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Conclusion
We have demonstrated a one-pot synthesis of 2-substituted
quinazolines between 2-aminobenzylamines 1 and aldehydes 2
via iridium-catalyzed hydrogen transfers using styrene as a
hydrogen acceptor. The use of benzyl alcohol 7 instead of
benzyaldehyde also successfully gave a quinazoline product in
moderate yield. Further extension for the synthesis of 4H-3,1-
benzoxazine was also demonstrated by the example using
2-aminobenzyl alcohol 8.
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336 | RSC Adv., 2013, 3, 334–336
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