Efficient Synthesis of Quinazolines from Aryl Imidates and N-Alkoxyamide by Ir(III)-Catalyzed C?H Amidation/Cyclization

Article abstract of DOI:10.1002/ejoc.202100726

An Ir(III) catalyst was used for the first time to realize the synthesis of quinazolines by C?H bond activation/cyclization with N-alkoxyamides as amidation reagents. This reaction has the advantages of wide substrate adaptability, good to excellent yield

Full text of DOI:10.1002/ejoc.202100726

Communications
doi.org/10.1002/ejoc.202100726
Efficient Synthesis of Quinazolines from Aryl Imidates and
N-Alkoxyamide by Ir(III)-Catalyzed CÀ H
Amidation/Cyclization
Wei-Tai Fan,[a] Zhibin Huang,[a] Xu Xu,[a] Guangliang Tu,[a] Jingyao Geng,[a] Shun-Jun Ji,*[a] and
Yingsheng Zhao*[a, b]
An Ir(III) catalyst was used for the first time to realize the
synthesis of quinazolines by CÀ H bond activation/cyclization
with N-alkoxyamides as amidation reagents. This reaction has
the advantages of wide substrate adaptability, good to
excellent yields under mild conditions, short reaction times, and
no need for an inert atmosphere. Importantly, several quinazo-
lines from bioactive compounds were obtained, which high-
lights the importance of this new method.
Introduction
As an important pharmacophore, quinazoline and its derivatives
have a wide range of pharmacological activities and always
attracted a great deal of medical research interest.[1] For
example, Prazosin[2] relaxes the smooth muscles of inner blood
vessel walls, widens (dilates) blood vessels and lowers blood
pressure. Lapatinib and Afatinib are well-known antitumor
drugs.[3] Rutaecarpine,[4] one of the main active alkaloids, has
long been used as a treatment for gastrointestinal diseases,
headaches and as an anti-inflammatory agent (Figure 1). There-
fore, organic chemists have been committed to finding new
and efficient methods to synthesize quinazoline and its
derivatives for many years.[5]
Recently, transition-metal-catalyzed ortho-CÀ H bond func-
tionalization reactions that result in CÀ C or CÀ N bonds have
been reported.[6] Among them, complex cyclic molecules have
been efficiently synthesized via activation of ortho-CÀ H bonds
and subsequent tandem reactions.[7] The strategy of using these
tandem reactions to synthesize the quinazoline skeleton is
worth exploring. Previous work reported that transition-metal-
catalyzed tandem annulation via CÀ H bond activation to
Figure 1. Selected bioactive quinazoline derivatives.
construct quinazoline compounds was limited to Rh and Co
catalysts.[8] Previously, our group has demonstrated that N-
alkoxyamides are a class of highly-efficient aminating reagents
that connect two different bioactive compounds via CÀ N
bonds.[9] As quinazolines are highly important in new drug
discovery, it would be of interest to develop new methods for
the synthesis of new quinazolines using just one bioactive
compound. Herein, we report an Ir(III)-catalyzed CÀ H activation/
amidation/annulation of imidate esters using N-methoxyamide
as the amidating reagent. Various quinazolines were obtained
in good to excellent yields under mild conditions with fifty
examples synthesized. Importantly, several quinazolines from
bioactive compounds were isolated and highlights the impor-
tance of this new method.
[a] W.-T. Fan, Z. Huang, X. Xu, G. Tu, J. Geng, Prof. Dr. S.-J. Ji, Prof. Dr. Y. Zhao
Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical, Engineering and Materials Science,
Soochow University,
Results and Discussion
199 Renai Street, Suzhou,
Jiangsu 215123, China
E-mail: shunjun@suda.edu.cn
With this in mind, we initiated our investigation by reacting
ethyl benzimidate 1a with N-methoxyamide 2a in the presence
of [Cp*IrCl2]2 (5 mol%) as the catalyst and AgSbF6 (10 mol%) as
yszhao@suda.edu.cn
https://chemistry.suda.edu.cn/50/4b/c2131a20555/page.htm
https://chemistry.suda.edu.cn/51/00/c2144a20736/page.htm
[b] Prof. Dr. Y. Zhao
°
an additive at 140 C for 4 h (Table 1, entry 1). To our delight,
School of Chemistry and Chemical Engineering,
Henan Normal University,
Xinxiang 453000, China
the reaction afforded the expected annulated product 3aa in
66% yield (Table 1, entry 1). Encouraged by this, different
reaction temperatures were investigated. Lowering the reaction
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100726
°
temperature to 120 C improved the yield of 3aa significantly
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Table 1. Optimized reaction conditions.[a]
Table 2. Substrate scope of the aryl imidates.[a]
Entry[a]
Cat.
Additive
T [ C]
Yield [%][b]
°
1
2
3
4
5
6
7
8
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Ir(cod)Cl]2
[Cp*RhCl2]2
[Cp*IrCl2]2
–
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgTs
AgNTf2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
–
140
120
100
80
66
79
70
56
67
29
40
trace
36
92c
nr
120
120
120
120
120
120
120
120
9
10
11
12
[Cp*IrCl2]2
21
[a] Unless otherwise noted, reactions were carried out with 1a (0.2 mmol),
2a (0.2 mmol), Cat. (5 mol%) and AgSbF6 (10 mol%) in DCE (0.5 mL). [b]
Isolated yield. [c] 1a (0.24 mmol), 2a (0.2 mmol).
(to 79%, Table 1, entry 2). However, lowering reaction temper-
ature further resulted in the incomplete conversion of raw
materials, which indicated higher temperatures were necessary
for this reaction (Table 1, entries 3–4). Different silver salts were
tested; but none of them improved the reaction yield (Table 1,
entries 5–7). Other transition-metal complexes showed lower
catalytic activity (Table 1, entries 8–9). Increasing the dosage of
1a to 0.24 mmol improved the yield of 3aa to 92% (Table 1,
entry 10). Screening of different solvents showed that DCE was
the best solvent in the conversion process (Table S1). Control
experiments showed that [Cp*IrCl2]2 and AgSbF6 were essential
for the reaction to proceed (Table 1, entries 11–12).
[a] Unless otherwise noted, reactions were carried out with 1 (0.24 mmol),
2a (0.2 mmol), [Cp*IrCl2]2 (5 mol%) and AgSbF6 (10 mol%) in DCE (0.5 mL).
Table 3. Substrate scope of N-alkoxyamide derivatives.[a]
After optimizing the reaction conditions, myriad substituted
ethyl benzimidates 1 were tested with N-alkoxyamides 2a;
Table 2 summarizes those results. The substrates contained a
wide variety of functional groups, including halogens, CF3, Me,
and OMe on the para position. All of them efficiently afforded
the cyclization products (3ab–3af). To our surprise, strongly
electron-withdrawing nitro and ester groups were also tolerated
and gave the corresponding products in good yields (3ag–
3ah). When the effect of the meta-substituents on the benzene
ring was investigated, high-yield target products were obtained,
and formation of the CÀ N bond occurred selectively on the side
with less steric hindrance (3ai–3al). Changing an ethyl group to
a methyl group did not impact the reactivity (3am). Further-
more, heterocyclic substrates containing a thiophene moiety
were suitable for this system (3an).
[a] Unless otherwise noted, reactions were carried out with 1a
(0.24 mmol), 2 (0.2 mmol), [Cp*IrCl2]2 (5 mol%) and AgSbF6 (10 mol%) in
DCE (0.5 mL), R2 =Me. [b] R2 =Bn.
In order to investigate the universality of this method, the
scope of N-alkoxyamides 2 was carefully examined (see Table 3).
For N-alkoxyamides 2 bearing either electron-donating (À Me, practicality of this method. The reaction proceeded even when
À OMe) or -withdrawing groups (À NO2, À CF3) at the meta
position of the phenyl ring, all reactions proceeded smoothly,
and target products obtained in excellent yields (3ar–3au). The
reaction tolerated many functional groups meaningful in
synthetic chemistry, such as chlorine, bromine, and iodine
(3ao–3aq). Such compatibility further enhances the synthetic
different functional groups occupied the para position (3av–
3ba). A comparison of meta- and para-substituted substrates
showed a slightly lower yield for substituents at the ortho
position, but the cyclized product was still obtained in
moderate to good yields (3bb–3bd). It is worth mentioning
that disubstituted substrates also showed good tolerance and
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gave the desired products 3be–3bf in moderate to good yields
(68–71%). In addition, substrates containing heterocycles,
naphthalene rings, and olefins participated in the reaction and
gave products 3bg–3bl in 47–92% yields. Furthermore, alkyl
substituent substrates also yielded the desired products with
yields of 62–77% (3bn–3br).
Different aminating reagents 2 transformed from several
drugs such as Aminalon, Pregabalin, Gabapentin, and Probene-
cid were further investigated.[9b] As shown in Table 4, they
coupled successfully with ethyl benzimidate 1a in the presence
of Ir(III) via intermolecular CÀ H amidation/cyclization (3bs–
3bv). Aminating reagents prepared by key intermediates of
Vismodegib and Fluxapyroxad participated in this reaction
smoothly and afforded target products in moderate to good
yields (3bw–3bx).[9b] It is worth mentioning that products 3bv
and 3bw have similar structures to Sildenafil[10] and Vardenafil[11]
that are known for treating erectile dysfunction; this further
emphasizes the importance of this method in promoting the
development of new pharmaceutical drugs (Figure 1).
Scheme 2. Possible reaction mechanism.
To demonstrate the practicicality of this synthetic method,
we investigated the reaction of N-alkoxyamides 2bu and ethyl
benzimidate 1a on a gram scale (Scheme 1a). To explore the
reaction mechanism, we carried out deuterium exchange
reactions in the presence of CD3OD. Those results showed that
29% of the hydrogen atoms were replaced by deuterium, which
indicated a reversible CÀ H activation process (Scheme 1b).
According to the mechanism proposed above and literature
precedent,[9,12] Scheme 2 depicts a reasonable catalytic cycle.
First, the anions from [Cp*IrCl2] dissociate and exchange with
AgSbF6 to produce catalyst A. Subsequently, 1a attaches to A
to produce an iridacyclic intermediate I via CÀ H activation.
Coordination of aminating reagent 2a to I produces complex II.
The protonic acid may activate the methoxy group, which
would produce an complex III, followed by reductive elimina-
tion to give complex IV. Subsequently, intermediate IV releases
intermediate V, which undergoes dehydrative cyclization to
provide the quinazoline product 3aa and simultaneously
regenerate the catalyst to complete the cycle.
Table 4. Substrate scope of N-alkoxyamide derivatives.[a]
Conclusion
In conclusion, we developed an unprecedented iridium-cata-
lyzed CÀ H activation/cyclization to synthesize quinazoline
compounds efficiently using ethyl benzimidate and N-alkoxya-
mides. This reaction has the advantages of wide substrate
adaptability, short reaction times and no need for an inert
atmosphere. In addition, some drug molecules smoothly
converted into aminating reagents, reacted efficiently and
afforded molecules with potential drug activity. Work to
determine the pharmacological activities of those products is
ongoing.
[a] Unless otherwise noted, reactions were carried out with 1a
(0.24 mmol), 2 (0.2 mmol), [Cp*IrCl2]2 (5 mol%) and AgSbF6 (10 mol%) in
DCE (0.5 mL).
Acknowledgements
This work was supported by Natural Science Foundation of China
(Nos. 21772139), the Major Basic Research Project of the natural
Scheme 1. Scale up synthesis of 3bu and deuteration experiment.
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[5] a) J. Fang, J. Zhou, Z. Fang, RSC Adv. 2013, 3, 334–336; b) Q. Liu, Y. Zhao,
Science Foundation of Jiangsu Higher Education Institutions
(17KJA150006), the Jiangsu Province Natural Science Found for
Distinguished Young Scholars (BK20180041), Project of Scientific
and Technologic Infrastructure of Suzhou (SZS201708), and the
PAPD Project. The project was also supported by the Open
Research Fund of the School of Chemistry and Chemical Engineer-
ing, Henan Normal University.
H. Fu, C. Cheng, Synlett 2013, 24, 2089–2094; c) Y. Ohta, Y. Tokimizu, S.
Oishi, N. Fujii, H. Ohno, Org. Lett. 2010, 12, 3963–3965.
[6] a) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2011, 45, 788–
802; b) B. Su, Z.-C. Cao, Z. J. Shi, Acc. Chem. Res. 2015, 48, 886–896; c) L.
McMurray, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885–1898;
d) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369–375; e) C. Liu, J.
Yuan, M. Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115, 12138–
12204; f) S. Rej, Y. Ano, N. Chatani, Chem. Rev. 2020, 120, 1788–1788;
g) Q. Shao, K. Wu, Z. Zhuang, S. Qian, J.-Q. Yu, Acc. Chem. Res. 2020, 53,
833–851; h) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L.
Ackermann, Chem. Rev. 2019, 119, 2192–2452.
[7] a) R. Mei, U. Dhawa, R. C. Samanta, W. Ma, J. Wencel-Delord, L.
Ackermann, ChemSusChem. 2020, 13, 3306–3356; b) S. Das, A. Dutta,
New J. Chem. 2021, 45, 4545–4568; c) X. Tan, X. Hou, T. Rogge, L.
Ackermann, Angew. Chem. Int. Ed. 2021, 60, 4619–4624; Angew. Chem.
2021, 133, 4669–4674; d) L. Ackermann, L. Wang, A. V. Lygin, Chem. Sci.
2012, 3, 177–180; e) Z. Yang, Z. Song, L. Jie, L. Wang, X. Cui, Chem.
Commun. 2019, 55, 6094–6097; f) Z. Yu, Y. Zhang, J. Tang, L. Zhang, Q.
Liu, Q. Li, G. Gao, J. You, ACS Catal. 2020, 10, 203–209; g) S. D. Sarkar, W.
Liu, S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356, 1461–
1479; h) J. R. Hummel, J. A. Boerth, J. A. Ellman, Chem. Rev. 2017, 117,
9163–9227.
[8] a) H. Wang, M. M. Lorion, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
10386–10390; Angew. Chem. 2016, 128, 10542–10546; b) J. Wang, S.
Zha, K. Chen, F. Zhang, C. Song, J. Zhu, Org. Lett. 2016, 18, 2062–2065;
c) X. Wang, A. Lerchen, F. Glorius, Org. Lett. 2016, 18, 2090–2093; d) F.
Wang, H. Wang, Q. Wang, S. Yu, X. Li, Org. Lett. 2016, 18, 1306–1309;
e) X. Y. Wang, N. Jiao, Org. Lett. 2016, 18, 2150–2153; f) H.-B. Xu, Y.-Y.
Zhu, J.-H. Yang, X.-Y. Chai, L. Dong, Org. Chem. Front. 2020, 7, 1230–
1234.
[9] a) G. Ju, G. Li, G. Qian, J. Zhang, Y. Zhao, Org. Lett. 2019, 21, 7333–7336;
b) G. Ju, C. Yuan, D. Wang, J. Zhang, Y. Zhao, Org. Lett. 2019, 21, 9852–
9855.
[10] a) D. J. Dale, P. J. Dunn, C. Golightly, M. L. Hughes, P. C. Levett, A. K.
Pearce, P. M. Searle, G. Ward, A. S. Wood, Org. Process Res. Dev. 2000, 4,
17–22; b) P. J. Dunn, S. Galvin, K. Hettenbach, Green Chem. 2004, 6, 43–
48.
[11] a) S. Singh, B. Prasad, A. A. Savaliya, R. P. Shah, V. M. Gohil, A. Kaur, TrAC
Trends Anal. Chem. 2009, 28, 13–28; b) D. P. Rotella, Nat. Rev. Drug
Discovery 2002, 1, 674–682; c) D. Pissarnitski, Med. Res. Rev. 2006, 26,
369–395.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Bioactive compounds · CÀ H activation · Cyclization ·
Ir(III)-catalyzed · Quinazolines
[1] a) K. S. Van Horn, W. N. Burda, R. Fleeman, L. N. Shaw, R. Manetsch, J.
Med. Chem. 2014, 57, 3075–3093; b) T.-C. Chien, C.-S. Chen, F.-H. Yu, J.-
W. Chern, Chem. Pharm. Bull. 2004, 52, 1422–1426; c) T. Herget, M.
Freitag, M. Morbitzer, R. Kupfer, T. Stamminger, M. Marschall, Antimicrob.
Agents Chemother. 2004, 48, 4154–4162; d) S. E. Abbas, F. M. Awadallah,
N. A. Ibrahim, E. G. Said, G. Kamel, Chem. Pharm. Bull. 2013, 61, 679–687;
e) E. A. Henderson, V. Bavetsias, D. S. Theti, S. C. Wilson, R. Clauss, A. L.
Jackman, Bioorg. Med. Chem. 2006, 14, 5020–5042; f) X.-F. Shang, S. L.
Morris-Natschke, Y.-Q. Liu, X. Guo, X.-S. Xu, M. Goto, J.-C. Li, G.-Z. Yang,
K.-H. Lee, Med. Res. Rev. 2018, 38, 775–828; g) R. E. Beveridge, H. A.
Wallweber, A. Ashkenazi, M. Beresini, K. R. Clark, P. Gibbons, E. Ghiro, S.
Kaufman, A. Larivée, M. Leblanc, J.-P. Leclerc, A. Lemire, C. Ly, J.
Rudolph, J. B. Schwarz, S. Srivastava, W. Wang, L. Zhao, M.-G. Braun, ACS
Med. Chem. Lett. 2020, 11, 2389–2396; h) A. A. K. Al-Ashmawy, K. M.
Elokely, O. Perez-Leal, M. Rico, J. Gordon, G. Mateo, A. M. Omar, M.
Abou-Gharbia, W. E. Childers Jr, ACS Med. Chem. Lett. 2020, 11, 2156–
2164.
[2] a) M. Rosini, A. Antonello, A. Cavalli, M. L. Bolognesi, A. Minarini, G.
Marucci, E. Poggesi, A. Leonardi, C. Melchiorre, J. Med. Chem. 2003, 46,
4895–4903; b) A. Antonello, P. Hrelia, A. Leonardi, G. Marucci, M. Rosini,
A. Tarozzi, V. Tumiatti, C. Melchiorre, J. Med. Chem. 2005, 48, 28–31.
[3] a) A. Malhotra, R. Bansal, C. E. Halim, C. T. Yap, G. Sethi, A. P. Kumar, M.
Bishnoi, K. Yadav, Med. Chem. Res. 2020, 29, 2112–2122; b) W. Shagufta,
I. Ahmad, Chem. Commun. 2017, 8, 871–885.
[12] H.-B. Xu, J.-H. Yang, X.-Y. Chai, Y.-Y. Zhu, L. Dong, Org. Lett. 2020, 22,
2060–2063.
[4] a) L.-C. Lin, Li, S.-H. Y.-T. Wu, K.-L. Kuo, T. H. J. Tsai, Agric. Food Chem.
2012, 60, 1595–1604; b) Y.-C. Chen, X.-Y. Zeng, Y. He, H. Liu, B. Wang, H.
Zhou, J.-W. Chen, P.-Q. Liu, L.-Q. Gu, J.-M. Ye, Z.-S. Huang, ACS Chem.
Biol. 2013, 8, 2301–2311; c) Y. Li, T. Feng, P. Liu, C. Liu, X. Wang, D. Li, N.
Li, M. Chen, Y. Xu, S. Si, ACS Med. Chem. Lett. 2014, 5, 884–888.
Manuscript received: June 21, 2021
Revised manuscript received: July 16, 2021
Accepted manuscript online: July 19, 2021
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