Ethanol promoted titanocene Lewis acid catalyzed synthesis of quinazoline derivatives

Article abstract of DOI:10.1039/c6ra14583c

An efficient catalytic system involving in situ activation of kinetically inert titanocene dichloride with alcoholic solvent for the synthesis of quinazoline derivatives was developed. 1 mol% Cp₂TiCl₂ at 30 °C afforded 17 examples of quinazoline derivatives with yields of 95-98% in 7-12 minutes. Mechanistic experiments using in situ NMR and HRMS established that the coordination of ethanol to the titanocene moiety released the catalytic species [Cp₂Ti(OCH₂CH₃)₂].

Full text of DOI:10.1039/c6ra14583c

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Ethanol promoted titanocene Lewis acid catalyzed
synthesis of quinazoline derivatives†
Cite this: RSC Adv., 2016, 6, 66074
*
Yanlong Luo, Ya Wu, Yunyun Wang, Huaming Sun, Zunyuan Xie, Weiqiang Zhang
*
and Ziwei Gao
Received 5th June 2016
Accepted 27th June 2016
DOI: 10.1039/c6ra14583c
www.rsc.org/advances
An efficient catalytic system involving in situ activation of kinetically (Scheme 1a) can promote the condensation reaction with yields
inert titanocene dichloride with alcoholic solvent for the synthesis of of 83–96%.2–4 Lewis acids of simple metal salts are more
quinazoline derivatives was developed. 1 mol% Cp2TiCl2 at 30 ꢀC active,5–8 for example, Zn(PFO)2 gave yields of 80–91% with a 2.5
afforded 17 examples of quinazoline derivatives with yields of 95–98% mol% catalyst loading. Notably, group IVB transition metal
in 7–12 minutes. Mechanistic experiments using in situ NMR and HRMS Lewis acids are efficient for this transformation. 2 mol% ZrCl4
established that the coordination of ethanol to the titanocene moiety catalyzed the reaction of anthranilamide with aldehydes/
released the catalytic species [Cp2Ti(OCH2CH3)2].
ketones, giving yields of 80–97%.9 Dodecylsulfate radical was
employed to stabilize Zr4+ in aqueous solution, and 2.5 mol%
Zr(DS)4 successfully catalyzed the condensation reaction in
water with yields of 83–97% (Scheme 1b).10 Therefore, devel-
oping an efficient and robust Lewis acid catalyst is highly
desirable for the synthesis of quinazoline derivatives.
Group IVB metallocenes are promising Lewis acid catalyst
precursors11 due to their kinetic stability, electronically tunable
metal centres and intrinsic metallic Lewis acidity.12–15 Our
previous research found that O-donor ligands such as salicylic
acid, methanol and phenol derivatives enhanced the Lewis
acidity of the titanocene centre, which showed cooperative
catalytic activity in various organic condensation reactions,
such as the Mannich16–18 and Friedel–Cras reactions.19 Herein,
we report the direct activation of Cp2TiCl2 by alcoholic solvent
for the rapid synthesis of quinazoline derivatives.
Quinazoline derivatives are an important class of heterocycles
with a wide range of pharmacological and biological activities.1
The catalytic condensation of anthranilamide with aldehydes/
ketones provides a direct synthetic method for quinazolinone
derivatives. 10 mol% of 2-morpholinoethanesulfonic acid
In ethanol, as little as 1 mol% Cp2TiCl2 catalyzed the
condensation reaction of anthranilamide and aldehydes with
yields of up to 98% in 7 min. The catalytic system of Cp2TiCl2 in
ethanol showed a wide functional group tolerance with 17
examples with yields of 95–98%. Mechanistic experiments
unveiled Cp2Ti(OCH2CH3)2 as the catalytic species, and illumi-
nated the superior activity of Cp2TiCl2 in ethanol for the
condensation reaction.
Initially, we chose anthranilamide and benzaldehyde as the
model substrates to optimize the reaction conditions. As shown
in Table 1, ZrCl4 and TiCl4 catalyzed the reaction with yields of
56% and 63%, respectively (entries 1 and 2). Organometallic
Lewis acid precursors signicantly accelerated the condensa-
tion reaction, Cp2ZrCl2 afforded the desired quinazoline
product in 89% yield, and Cp2TiCl2 gave a 98% yield of quina-
zoline (entries 3 and 5). Half sandwich Cp*TiCl3 gave a 71%
Scheme 1 Approaches for the synthesis of quinazoline derivatives.
Key Laboratory of Applied Surface and Colloid Chemistry, MOE, School of Chemistry
and Chemical Engineering, Shaanxi Normal University, Xi’an 710062, China. E-mail:
zwq@snnu.edu.cn; zwgao@snnu.edu.cn; Fax: +86-29-81530727
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra14583c
66074 | RSC Adv., 2016, 6, 66074–66077
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
Table 1 Catalyst and concentration screening in the reaction of
anthranilamide with benzaldehydea
Entry
Catalyst
Catalyst (mol%)
Yieldb (%)
1
2
3
4
5
6
7
8
ZrCl4
TiCl4
5
5
5
5
5
4
3
2
1
0.5
5
5
5
5
56
63
89
71
98
98
98
97
97
83
30
20
42
55
30
Cp2ZrCl2
Cp*TiCl3
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
CuCl2
MgCl2
ZnCl2
SrCl2
HCl
Fig. 1 Alcohol-accelerated Cp2TiCl2 catalysis of the condensation
a
reaction of anthranilamide with benzaldehyde. Yields are of the
isolated product.
9
10
11
12
13
14
15
coordination mode for unleashing the Lewis acidity of titano-
cene dichloride. Owing to the fact that steric hindrance is
disadvantageous for the coordination of alcohols to organo-
metallic centres, the yield of the condensation reaction
5
a
Reaction conditions: anthranilamide (1 mmol), benzaldehyde (1 dramatically decreased with the use of polyethylene glycol,
mmol). b Yield of the isolated product.
affording only a 20% yield. These ndings led us to establish
a new protocol for the activation of inert Cp2TiCl2 using
a solvent strategy, thus accelerating the condensation reaction.
yield of the desired product (entry 4). Further experiments
showed that 1 mol% of Cp2TiCl2 still afforded a 97% yield, and
0.5 mol% of Cp2TiCl2 gave a yield of 83% (entries 5–10). This
solvent activation method was applied for other Lewis acids
such as CuCl2, MgCl2, ZnCl2 and SrCl2, giving yields of 30%,
20%, 42% and 55%, respectively (entries 11–14). The control
experiment using 5 mol% HCl afforded a 30% yield, which
eliminated the possibility that the alcoholysis of titanocene
chlorides released HCl as a catalytic species (entry 15). The
effects of solvent and temperature were also screened (see ESI†).
The activation effects of various alcohols were investigated to
demonstrate the pronounced accelerating effect on the titano-
cene dichloride catalyzed condensation reaction of anthranila-
mide with benzaldehyde (Fig. 1). It was found that ethanol was
the best solvent, in which the yield was 97%. Methanol, n-
propanol and n-butanol showed less of an accelerating effect
and gave yields from 77–87%. Based on the facile substitution
reactions of alkoxy groups with titanocene dichloride in alco-
hols,20 a probable explanation for this effect is that the coordi-
nation between alcohols and titanocene species results in
enhanced Lewis acidity of the Ti centre and thus improves the
catalytic efficiency. This hypothesis was further supported by
the condensation reaction catalyzed by titanocene dichloride in
sterically hindered t-butanol, as the yield of the condensation
reaction dramatically decreased to 50%. Furthermore, it was
also found that polyol suppressed the activity of titanocene
dichloride: the reaction in ethylene glycol afforded only a 30%
yield. This is because titanocene dichloride in polyol, which
readily formed a stable complex, was not an effective catalyst,
indicating that chelation might be an unfavourable
The scope and limitations of the new catalyst system were
evaluated with anthranilamide and a range of aldehydes/
ketones under the optimized conditions, as shown in Table 2.
Initially, we investigated the reaction using several benzalde-
hyes substituted with electron-donating and electron-
withdrawing groups (3a–3i) and anthranilamide under the
optimized conditions. The electronic effects had no signicant
impact on the reaction rate, with yields of 96–98%. Neverthe-
less, when o-methoxy substituted benzaldehyde was used as
a substrate for this reaction, the yield of the desired product was
95%, lower than p- and m- substituted benzaldehyde, which
directly reects the disadvantages of steric hindrance for this
reaction. Aliphatic aldehydes such as cyclohexanecarbaldehyde
(3j) was also readily introduced into this reaction, the desired
product being formed with a yield of 95%. The reaction of
anthranilamide and isovaleraldehyde (3k) proceeded slightly
slowly and afforded a 95% yield aer 12 min. Subsequently, the
optimized conditions were applied for the conversion of various
kinds of aliphatic ketones and anthranilamide into the corre-
sponding quinazoline derivatives. Among the three kinds of
cyclic ketones, the yield for cyclohexanone (3m) was 98%,
higher than that for cycloheptanone (3l) and cyclopentanone
(3n) which both gave yields of 96%. When the ketones were
chain ketones, such as acetone (3o), 3-pentanone (3p) and 3-
heptanone (3q), the reaction also proceeded smoothly and
resulted in yields of 96%, 95% and 97%, respectively.
To shed light on the delicate accelerating effect of alcohols,
the interaction between Cp2TiCl2 and CH3CH2OH was investi-
1
gated by H NMR and HRMS.21 1H NMR experiments were
conducted using Cp2TiCl2 in CD3CD2OD at intervals with
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 66074–66077 | 66075

View Article Online
RSC Advances
Communication
Table
2 Substrate scope for the synthesis of quinazolinone
derivativesa,b
Fig. 2 Partial 400 MHz 1H NMR spectra (CD3CD2OD) of a solution
containing Cp2TiCl2 with addition of aniline. 6.59 ppm I [Cp2TiCl2];
6.25 ppm III [Cp2TiCl(OCH2CH3)]; 6.34 ppm II [Cp2Ti(OCH2CH3)2].
performed in the positive ion mode (see ESI Fig. S2 and S3†).
The ion peak at m/z 270.9512 in the CH3CH2OH solution of
Cp2TiCl2 corresponds to [II + H+]. These observations clearly
demonstrate that the CH3CH2OH is not just a medium to
dissolve the sandwich complexes, but can also be another
reactant involved in the process of activating Cp2TiCl2 via
ethoxyl groups binding to the Cp2TiIV moiety. It can be
concluded that in the coordination reaction, the pre-catalyst
titanocene dichloride is readily converted into the detectable
titanocene species II, and presumably this is the organometallic
Lewis acid catalyst.23
A plausible mechanism for the formation of quinazoline
derivatives catalyzed by titanocene dichloride in ethanol solu-
tion is outlined in Scheme 2. Initially, the titanocene dichloride
I pre-catalyst is activated by ethanol and transformed into the
catalytically active titanocene diethoxy complex II in the pres-
ence of anthranilamide, with simultaneous release of HCl. The
newly formed complex II coordinates with the aldehyde as
shown in III, and the enolization is accelerated synergistically as
the carbonyl coordinates to the oxophilic Ti and the ethoxy
a
All the reactions were carried out in the presence of 1 mmol 1, 1.0
mmol 2. b Yields of the isolated product.
addition of aniline as a base (Fig. 2). The characteristic cyclo-
pentadienyl (Cp) protons can be regarded as a probe to measure
the formation of new titanocene complexes. No coordination
occurred and only one Cp singlet of Cp2TiCl2 at d 6.59 ppm ( )
was detected. When adding 1 equiv. aniline, the new titanocene
complex species Cp2TiCl(OCH2CH3) (III) formed with a reso-
nance at d 6.25 ppm ( ).22 The resonances of Cp2TiCl(OCH2CH3)
increased while the resonance of Cp2TiCl2 declined gradually.
When adding another 1 equiv. aniline, as the singlet at 6.25
ppm increased, one new Cp singlet for Cp2Ti(OCH2CH3)2
appeared at d 6.34 ppm ( ) (II). Cp2TiCl(OCH2CH3) was
consumed gradually in CD3CD2OD in the presence of base and
formed the new titanocene species Cp2Ti(OCH2CH3)2 (II). The
putative species II was further supported by HRMS experiments
Scheme 2 Proposed mechanism for the synthesis of quinazoline
derivatives catalyzed by Cp2TiCl2 in ethanol.
66076 | RSC Adv., 2016, 6, 66074–66077
This journal is © The Royal Society of Chemistry 2016

View Article Online
Communication
RSC Advances
ligand abstracts the proton. Then, the condensation of the
activated aldehyde with the amino group of anthranilamide
produces an imine intermediate with the H+ in solution. In the
meantime, the imine part could be activated by the cation as
shown in V. Thus, the nal product could be formed by intra-
molecular nucleophilic attack of the amide nitrogen on the
activated imine carbon, followed by a proton transfer. Once the
product is released, the catalytically active species II is regen-
erated by the coordination of CH3CH2OH and releases H+ for
the next cycle.
5 L. M. Wang, L. Hu, J. H. Shao, J. J. Yu and L. Zhang, J. Fluorine
Chem., 2008, 129, 1139.
6 M. Wang, T. T. Zhang, Y. Liang and J. J. Gao, Chin. Chem.
Lett., 2011, 22, 1423.
7 J. X. Chen, D. Z. Wu, F. He, M. C. Liu and H. Y. Wua,
Tetrahedron Lett., 2008, 49, 3814.
8 J. Safari and S. G. Ravandi, RSC Adv., 2014, 4, 11654.
9 M. Abdollahi-Alibeik and E. Shabani, Chin. Chem. Lett., 2011,
22, 1163.
10 H. R. Safaei, M. Shekouhy, S. Khademi, V. Rahmanian and
M. Safaei, J. Ind. Eng. Chem., 2014, 20, 3019.
11 (a) A. Gansauer, D. Franke, T. Lauterbach and M. Nieger, J.
Am. Chem. Soc., 2005, 127, 11622; (b) G. Erker, G. Kehr and
R. Froehlich, Coord. Chem. Rev., 2006, 250, 36; (c)
P. J. Chirik, Organometallics, 2010, 29, 1500; (d) T. Saito,
H. Nishiyama, H. Tanahashi, K. Kawakita, H. Tsurugi and
K. Mashima, J. Am. Chem. Soc., 2014, 136, 5161; (e)
D. F. Chen, Z. Y. Han, X. L. Zhou and L. Z. Gong, Acc.
Chem. Res., 2014, 47, 2365; (f) M. E. Sloan, A. Staubitz,
T. J. Clark, C. A. Russell, G. C. L. Jones and I. Manners, J.
Am. Chem. Soc., 2010, 132, 3831; (g) A. Zydor, V. G. Kessler
and S. D. Elliott, Phys. Chem. Chem. Phys., 2012, 14, 7954;
(h) A. M. Chapman and D. F. Wass, Dalton Trans., 2012, 41,
9067.
Conclusions
In summary, a robust Lewis acid catalytic system was developed
through the activation of inert Cp2TiCl2 by ethanol for the
efficient synthesis of quinazoline derivatives. As little as 1 mol%
of Cp2TiCl2 efficiently catalyzed the condensation reaction, with
17 examples giving 95–98% yields. The mechanistic studies
including 1H NMR and HRMS analyses suggested that the
coordination of CH3CH2OH to titanocene dichloride formed the
catalytically active species Cp2Ti(OCH2CH3)2, which led to
superior activity for the condensation reaction. These results
illuminated a new catalytic system, which allows for a more
concise, efficient and mild protocol for the synthesis of quina-
zoline derivatives. Furthermore, the moderate reaction condi-
tions, air-stable organometallic Lewis acid catalyst, and absence
of any cocatalyst or ligand make this an environmentally
friendly methodology amenable to scale-up.
12 A. Gansaeuer, I. Winkler, D. Worgull, D. Franke,
T. Lauterbach, A. Okkel and M. Nieger, Organometallics,
2008, 27, 5699.
13 R. Qiu, X. Xu, L. Peng, Y. Zhao, N. Li and S. Yin, Chem.–Eur.
J., 2012, 18, 6172.
¨
14 A. Gansauer, M. Behlendorf, A. Cangonul, C. Kube,
Acknowledgements
J. M. Cuerva, J. Friedrich and M. V. Gastel, Angew. Chem.,
Int. Ed., 2012, 51, 3266.
This work was supported by the 111 Project (B14041), grants
from the National Natural Science Foundation of China
(21271124, 21272186, 21371112), the Fundamental Funds
Research for the Central Universities (GK201501005,
GK201302015, GK201503029), the Project Supported by Natural
Science Basic Research Plan in Shaanxi Province of China
(Program No. 2015JQ2056), the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT_14R33).
¨
15 A. Gansauer, S. Hildebrandt, A. Michelmann, T. Dahmen,
D. v. Laufenberg, C. Kube, G. D. Fianu and R. A. Flowers II,
Angew. Chem., Int. Ed., 2015, 54, 7003.
16 Y. Wu, C. Chen, G. Jia, X. Y. Zhu, H. M. Sun, G. F. Zhang,
W. Q. Zhang and Z. W. Gao, Chem.–Eur. J., 2014, 20, 1.
17 X. Y. Zhu, C. Chen, B. X. Yu, G. F. Zhang, W. Q. Zhang and
Z. W. Gao, Chem. Lett., 2014, 43, 1832.
18 Y. Wu, X. Wang, Y. L. Luo, J. Wang, Y. J. Jian, H. M. Sun, G. F
Zhang, W. Q. Zhang and Z. W Gao, RSC Adv., 2016, 6, 15298.
19 X. Wang, Z. H. Wang, G. F. Zhang, W. Q. Zhang, Y. Wu and
Z. W. Gao, Eur. J. Org. Chem., 2016, 3, 502.
Notes and references
1 (a) M. J. Hour, L. J. Huang, S. C. Kuo, Y. Xia, K. Bastow,
Y. Nakanishi, E. Hamel and K. H. Lee, J. Med. Chem., 2000,
43, 4479; (b) H. L. Birch, G. M. Buckley, N. Davies,
H. J. Dyke, E. J. Frost, P. J. Gilbert, D. R. Hannah,
A. F. Haughan, M. J. Madigan, T. Morgan, W. R. Pitt,
A. J. Ratcliffe, N. C. Ray, M. D. Richard, A. Sharpe,
A. J. Taylor, J. M. Whitworth and S. C. Williams, Bioorg.
Med. Chem. Lett., 2005, 15, 5335; (c) E. Cohen, B. Klarberg
and J. R. Vaughan, J. Am. Chem. Soc., 1959, 81, 5508.
2 Z. Karimi-Jaberi and L. Zarei, S. Afr. J. Chem., 2012, 65, 36.
3 B. L. Vilas, V. S. Pravin and S. S. Murlidhar, Tetrahedron Lett.,
2013, 54, 5778.
20 (a) J. H. Toney and T. J. Marks, J. Am. Chem. Soc., 1985, 107,
947; (b) R. Fandos, B. Gallego, A. Otero, A. Rodriguez,
M. J. Ruiz, P. Terreros and C. Pastor, Organometallics, 2007,
26, 2896.
´
21 (a) A. F. A. Peacock, A. Habtemariam, R. Fernandez,
V. Walland, F. P. A. Fabbiani, S. Parsons, R. E. Aird,
D. I. Jodrell and P. J. Sadler, J. Am. Chem. Soc., 2006, 128,
1739; (b) D. Schroder, Acc. Chem. Res., 2012, 45, 1521.
22 J. C. Huffman, K. G. Moloy, J. A. Marsella and K. G. Caulton,
J. Am. Chem. Soc., 1980, 80, 3009.
23 J. L. Li, Z. W. Gao, P. Sun, L. X. Gao and W. Tikkanen, Inorg.
Chim. Acta, 2011, 368, 231.
4 S. Nagarajan, T. M. Shaikh and E. Kandasamy, New J. Chem.,
2015, 39, 9693.
This journal is © The Royal Society of Chemistry 2016
RSC Adv., 2016, 6, 66074–66077 | 66077