Expeditious construction of quinazolines via Bronsted acid-induced C-H activation: Further extension of "tert-amino effect"

Article abstract of DOI:10.1246/cl.2009.524

A simple method for the synthesis of quinazolines was developed by exploiting the "tert-amino effect." A catalytic amount of Br0nsted acid (TsOH·H₂O) worked as an effective activator for the concise construction of a quinazoline framework from o-formylaniline and amine. Copyright

Full text of DOI:10.1246/cl.2009.524

524
Chemistry Letters Vol.38, No.6 (2009)
Expeditious Construction of Quinazolines via Brønsted Acid-induced
C–H Activation: Further Extension of ‘‘tert-Amino Effect’’
Keiji Mori, Yoshitaka Ohshima, Kensuke Ehara, and Takahiko Akiyamaꢀ
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8558
(Received March 10, 2009; CL-090246; E-mail: takahiko.akiyama@gakushuin.ac.jp)
A simple method for the synthesis of quinazolines was
developed by exploiting the ‘‘tert-amino effect.’’ A catalytic
.
amount of Brønsted acid (TsOH H2O) worked as an effective
activator for the concise construction of a quinazoline frame-
Ph
H2N
O
N
N
1.05 equiv.
6
TsOH·H2O (10 mol%)
H
H
N
Benzene
reflux, 6 h
Ph
N
Ph
work from o-formylaniline and amine.
0%
Ph
Ph
Ph
5 1.0 equiv.
7
Ph
Ph
The term ‘‘tert-amino effect’’ is used to describe various
thermal ring-closure reactions of N,N-dialkyl-substituted ani-
lines with an unsaturated ortho substituent to afford fused aza-
ring systems.1,2 A representative example of this process is illus-
trated in eq 1. When 1 was heated in refluxing n-BuOH, [1,5] hy-
drogen shift from intermediate A and 6-endo-cyclization occur-
red simultaneously to give tetrahydroquinoline derivative 2 in
good yield.2a A notable step in this reaction is the replacement
of a C–H bond ꢀ to the tertiary amine nitrogen with a C–C bond,
which could be recognized as a kind of sp3 C–H activation with-
out transition metals.3 Although these internal redox processes
would be a viable method for the construction of various hetero-
cycles, conjugated substrates (such as 1) were mostly used as the
starting material and the use of imine analog 3 for the formation
of quinazoline 4 (eq 2) had been overlooked until quite recently
except for one report.4 These features encouraged us to investi-
gate imine analogs. Herein we report a catalytic approach to the
synthesis of quinazolines by exploiting the tert-amino effect.
N
X-ray structure of 8.
74%
8
Scheme 1. One-pot synthesis of quinazoline 8.
H+
H+
R3
H
H2NR3
O
N
R3
R2
H
N
imine
formation
R2
N
R1
N
R1
R2
N
R1
D
C
G
"H+"
6-endo-trig
cyclization
R3
H
R3
H
N
HN
H
[1,5] H-shift
N+ R2
N+ R2
R1
R1
E
F
Scheme 2. Supposed mechanism of this catalytic process.
NC
CN
NC
CN
NC
CN
–
–
H
CN
CN
and aniline (6) was heated in refluxing benzene without an acid
catalyst. Corresponding imine 7 was obtained as the sole product
and the formation of quinazoline 8 was not observed even after
24 h. The desired cyclization proceeded by the addition of
∆
H
H
H
ð1Þ
ð2Þ
[1,5] H-shift
n-BuOH
N+
N+
N
N
tert-Amino Effect
1
A
B
2
.
TsOH H2O (10 mol %) to imine 7, suggesting that an acid cata-
lyst was indispensable for this process.
This work
R3
N
R3
R2
H
∆
N
Ph
N
R2
O
N
N
N
N
R1
H2N
6
∆
10 mol%
TsOH•H2O
R1
Ph
Ph
N
H
H
ð3Þ
3
4
Benzene
reflux, 24 h
Benzene
reflux, 8 h
N
Ph
Ph
Firstly, to synthesize the imine 7 for the proposed reaction,
the reaction of o-formylaniline 5 (1.0 equiv) with aniline (6) was
Ph
Ph
Ph
quant.
70%
5
7
8
.
conducted in the presence of 10 mol % TsOH H2O (Scheme 1).
Scheme 2 illustrates the supposed mechanism of this reac-
tion. The acid catalyst plays two roles in this process: 1) promo-
tion of imine formation and 2) acceleration of the hydrogen shift
process. Activation of the corresponding imine nitrogen in D by
Brønsted acid facilitated the equilibrium between D and quinone
methide E, and consequently, the [1,5] hydrogen shift proceeded
rapidly.
Table 1 illustrates the results of investigation of the reaction
.
conditions. Gratifyingly, even in 5 mol % TsOH H2O, the de-
sired product was obtained in high yield (73%, Entry 2). In the
Judging from the TLC results, aldehyde 5 was completely con-
sumed within 6 h in refluxing benzene and a new spot was ob-
served. Interestingly, the resulting product was not imine 7 but
quinazoline derivative 8 (74%). Thus, the imine formation and
the [1,5] hydrogen shift followed by 6-endo cyclization occurred
sequentially in a one-pot glass vessel. The structure of 8 was
unambiguously established by single-crystal X-ray analysis.5
In most cases, processes exploiting the tert-amino effect
have been triggered by thermal conditions.1,2 To confirm wheth-
er this reaction was promoted by heat or acid catalyst, we con-
ducted the following reaction (eq 3): a mixture of aldehyde 5
.
case of 2.5 mol % TsOH H2O, the yield of 8 was slightly low
(59%, Entry 3). Other acids (TfOH, Tf2NH, TFA, and AcOH)
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.6 (2009)
525
.
Table 1. Examination of the reaction conditions
cided that 5 mol % TsOH H2O in refluxing benzene provided the
optimal conditions.
O
X mol%
Ph
Next, the scope and limitations of this reaction were exam-
ined (Table 2). The electronic environment on the aniline-aro-
matic-ring group was of no concern in this reaction; both elec-
tron-deficient and electron-rich aniline gave desired products 9
and 10 in good yields (88 and 66%, respectively, Entries 2 and
3). On the other hand, the sterically encumbered anilines sup-
pressed the reaction dramatically; o-methylaniline gave 11 in
only 40% yield (Entry 4), and no product was obtained when
2,6-dimethylaniline was used as the starting material (Entry 5).
Polycyclic analogs 13 and 146 were also obtained, although an
elevated temperature was required (in refluxing toluene) possi-
bly owing to the decreased hydride donor capabilities of these
substrates.
H
catalyst
N
+
H2N Ph
Benzene
reflux
N
Ph
N
Ph
6
Ph
Ph
5
8
Entry
Catalyst
.
TsOH H2O
X/mol %
Time/h
Yield/%
1
2
3
4
5
6
7
8a
9b
10c
TsOH H2O
.
10
5
2.5
5
5
5
5
5
5
5
5.5
8
12
8
5
23
9
8
10
9
74
73
59
22
12
19
0
0
70
66
.
TsOH H2O
TfOH
Tf2NH
TFA
AcOH
.
TsOH H2O
Aliphatic amines also participated in this reaction but spe-
cial caution was needed (Entry 8). In contrast to aromatic
amines, not only an elevated temperature (in refluxing toluene)
but also the in situ generation of imine before the addition of
.
TsOH H2O
.
TsOH H2O
aThe reaction was conducted at 60 ꢁC. In the presence of
MS3A. In the presence of MS5A.
b
c
.
TsOH H2O and the use of a slight excess of aldehyde (1.1 equiv
vs. amine) were required; due to its strong basicity compared
with aromatic amine, TsOH was probably deprotonated by the
remnant amine that did not participate in the formation of the
corresponding imine, and consequently, the acid could not work
as a catalyst.7
In summary, we have developed a promising catalytic ap-
proach to the quinazoline skeleton by Brønsted acid-induced
C–H functionalization. This method is applicable to various o-
formyl N,N-dialkyl-substituted anilines and amines (aromatic
and aliphatic). Further work on related reactions is in progress
to synthesize various heterocycles.
Table 2. Scope and limitations
Entry
1
Time/h
Yield/%
73
Product
Ph
N
8
N
N
N
Ph
8
Ph
Ph
Ph
Cl
N
2
3
4.5
6.5
88
66
Ph
9
OMe
N
Ph
References and Notes
10
1
For reviews, see: a) O. Meth-Cohn, H. Suschitzky, Adv. Heterocycl.
Chem. 1972, 14, 211. b) J. M. Quintela, Recent Res. Dev. Org. Chem.
2003, 7, 259. c) P. Matyus, O. Elias, P. Tapolcsanyi, A. Polonka-
Balint, B. Halasz-Dajka, Synthesis 2006, 2625.
N
4
5
5.5
40
N
N
Ph
11
12
2
a) W. Verboom, D. N. Reinhoudt, R. Visser, S. Harkema, J. Org.
Chem. 1984, 49, 269. b) W. H. N. Nijhuis, W. Verboom, D. N.
Reinhoudt, Synthesis 1987, 641. c) W. H. N. Nijhuis, W. Verboom,
D. N. Reinhoudt, J. Am. Chem. Soc. 1987, 109, 3136. d) W. H. N.
Nijhuis, W. Verboom, A. A. El-Fadl, S. Harkema, D. N. Reinhoudt,
J. Org. Chem. 1989, 54, 199. e) W. H. N. Nijhuis, W. Verboom,
A. A. El-Fadl, G. J. van Hummel, D. N. Reinhoudt, J. Org. Chem.
1989, 54, 209. f) A. Polonka-Balint, C. Saraceno, K. Ludanyi, A.
Benyei, P. Matyus, Synlett 2008, 2846. g) C. Zhang, C. K. De, R.
Mal, D. Seidel, J. Am. Chem. Soc. 2008, 130, 416.
Ph
Ph
N

13
Ph
Ph
N
6a
11.5
11.5
6
92
34
92
N
N
N
13
14
Ph
N
7a
3
4
For reviews on C-H functionalization, see: a) V. Ritleng, C. Sirlin, M.
Pfeffer, Chem. Rev. 2002, 102, 1731. b) K. Godula, D. Sames, Science
2006, 312, 67. c) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013.
a) W. Verboom, M. R. J. Hamzink, D. N. Reinhoudt, R. Visser,
Tetrahedron Lett. 1984, 25, 4309. b) X. Che, L. Zheng, Q. Dang, X.
Bai, Synlett 2008, 2373. During the preparation of our manuscript,
Seidel reported similar redox process promoted by TfOH, see: c) C.
Zhang, S. Murarka, D. Seidel, J. Org. Chem. 2009, 74, 419.
Crystallographic data reported in this manuscript have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-717617.
N
Ph
8a,b
Ph
15
Ph
aIn toluene. bExcess amount of aldehyde (1.1 mol equiv vs.
amine) was used.
5
gave inferior results (Entries 4–7). At lower temperature (60 ꢁC),
the reaction was suppressed completely, giving only imine
(Entry 8). Some dehydrating agents (MS3A and MS5A) were in-
sufficient to improve the chemical yield (70 and 66%, respec-
tively, Entries 9 and 10). From the above investigations, we de-
6
7
The corresponding starting aldehydes were prepared as reported in
ref. 2d.
Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
Published on the web (Advance View) April 25, 2009; doi:10.1246/cl.2009.524