A copper-catalyzed Ritter-type cascade via iminoketene for the synthesis of quinazolin-4(3H)-ones and diazocines

Article abstract of DOI:10.1039/c7cc01406f

We have developed a copper-catalyzed Ritter-type reaction/cyclization cascade of anthranilic acids and nitriles, affording the quinazolin-4(3H)-ones. The cascade proceeds through a Ritter-type reaction capturing the iminoketene intermediates by nitriles. Furthermore, we found a novel Ritter-type reaction/condensation/intramolecular anti-Markovnikov hydroamination cascade, providing access to functionalized diazocines in one-pot.

Full text of DOI:10.1039/c7cc01406f

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A copper-catalyzed Ritter-type cascade via
iminoketene for the synthesis of
Cite this:DOI: 10.1039/c7cc01406f
quinazolin-4(3H)-ones and diazocines†
Received 22nd February 2017,
Accepted 28th March 2017
Takumi Abe, * Koshiro Kida and Koji Yamada
DOI: 10.1039/c7cc01406f
rsc.li/chemcomm
We have developed a copper-catalyzed Ritter-type reaction/cyclization
cascade of anthranilic acids and nitriles, affording the quinazolin-4(3H)-
ones. The cascade proceeds through a Ritter-type reaction capturing the
iminoketene intermediates by nitriles. Furthermore, we found a novel
Ritter-type reaction/condensation/intramolecular anti-Markovnikov
hydroamination cascade, providing access to functionalized diazocines
in one-pot.
Quinazolinones, such as 2-methyl-4(3H)-quinazolinone,1 glyco-
sminine,2 bouchardatine,3 orirenierines A and B,4 tryptanthrin,5
and rutaecarpine,6 are not only prevalent in natural products but
are also known to possess a wide range of promising biological
activities (Fig. 1).7 Owing to their importance and potential
utility, significant progress has been made in the synthesis of
quinazolin-4(3H)-ones.7 It should be noted that the most common
synthesis route to quinazolin-4(3H)-ones involves the condensation
of 2-aminobenzamides and a carbonyl equivalent.8 The develop-
ment of an efficient synthesis of quinazolin-4(3H)-ones using
different substrates is highly desirable to increase the diversity of
quinazolin-4(3H)-ones.9 To the best of our knowledge, the synthesis
of quinazolin-4(3H)-ones from anthranilic acids and nitriles is
unprecedented.
Fig. 1 Selected quinazoline alkaloids.
copper-catalyzed Ritter-type reaction of unactivated alkenes with
nitriles (Scheme 1a).12
We next directed our interest toward the development of a
concise method for the construction of heterocycles by a copper-
catalyzed Ritter-type reaction. As a continuation of our effort in
the synthesis of quinazoline alkaloids,13 we herein describe a
concise approach for the synthesis of quinazolin-4(3H)-ones by
employing a copper-catalyzed Ritter-type reaction/cyclization
cascade via iminoketenes (Scheme 1b).
We began our experiment with the reaction of anthranilic
acid 1a with POCl3 (5 equiv.) in the presence of a catalyst in
The Ritter reaction, first reported in 1948,10a,b facilitates the
formation of amides from a nitrile and an alcohol or an olefin.
In a Ritter-type reaction, a carbocation generated in situ is trapped by
a nitrile.10 Recent efforts have been directed toward new applications
in the field of Ritter-type and multicomponent reactions.10c,d For
example, in 2016, Yao and Yang reported a one-pot synthesis of
benzo[c]phenanthridines via a new three-component reaction,
involving a [4+2]-cycloaddition/Ritter reaction, capture of a
bridged oxonium intermediate by acetonitrile.11 Previously, we
reported the one-pot synthesis of trans-chloroamidines by a
Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-tobetsu, Hokkaido 0610293, Japan. E-mail: abe-t@hoku-iryo-u.ac.jp
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectral data for all compounds, including scanned images of 1H
13
Scheme 1 Ritter-type cascade.
and NMR spectra. See DOI: 10.1039/c7cc01406f
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Table 1 Optimization of reaction conditionsa
Run
Cu-complexes
Mol%
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
100
30
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
16
16
16
16
16
16
6
16
16
16
16
16
16
16
16
6
42
85
73
72
3
24
90
61
85
18
86
40
90
0
88
89
92
86
87
84
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuOAc
CuCl
CuCl2
CuBr
9
CuBrÁMe2S
10
11
12
13
14
15
16
17
18
19
20
CuBr2
CuI
Cu(NO3)2
CuSO4
Cu(MeCN)4PF6
Cu(acac)2
Cu2O
CuO
CuCN
Cu(OTf)2
Cu(OTf)2Átoluene
6
16
16
16
a
1a (1 mmol), Cu-complexes (X mol%), and POCl3 (5 mmol) in MeCN
Scheme 2 Substrate scopea,b
:
a1 (3 mmol), CuO (0.3 mmol), and POCl3
b
(10 mL). Isolated yields.
(15 mmol) in R2CN (20 mL). bIsolated yields. c1 (3 mmol), CuO (0.3 mmol),
R2CN (5 mmol), and POCl3 (15 mmol) at 80 1C.
MeCN (Table 1). Gratifyingly, we found that Cu(OAc)2 (1 equiv.)
afforded the desired quinazolin-4(3H)-one 2a in 85% yield,
while the reaction in the absence of a catalyst led to 2a in nitrile solubility issue. When employing the neat reaction and
42% yield (entries 1 and 2). The catalytic reaction could be increasing the temperature to 80 1C, the desired quinazolines were
employed to obtain the desired product, albeit in relatively low obtained in 57% and 42% yields, respectively (2m and 2n). Nishida
yields (entries 3 and 4).
and co-workers reported the first synthesis of a revised structure
Our next step was to compare the performance of different of schizocommunin from isatin and commercially available
copper catalysts. Doping Cu(OAc)2 with CuOAc, CuCl, CuBr2, quinazoline 2a.16 Quinazoline 2n is the intermediate for Nagarajan’s
Cu(NO3)2, and Cu(MeCN)4PF6 resulted in lower yields (entries 5, bouchardatine synthesis17 and Pal’s 8-norrutaecarpine synthesis.18
6, 10, 12, and 14). Among the screened copper catalysts, CuO Although the yield of 2n was lower in comparison with those
gave the best yield (entries 5–20).14,15 Our results demonstrate reported by Nagarajan (81% yield) and Pal (80% yield), our
that CuO can be used in the catalytic formation of two C–N reaction needs neither the deep eutectic solvents with cumber-
bonds in one-pot, thus facilitating the Ritter-type reaction of some operations nor the expensive substrates.
anthranilic acids with nitriles.
To obtain mechanistic insights into this cascade sequence,
Encouraged by these results, we then investigated the substrate some control experiments were carried out (Scheme 3). Compound
scope of our new cascade reaction (Scheme 2). The presence of 4 was obtained in 71% yield instead of the expected product 5 when
electron-withdrawing groups on the benzene ring led to increased benzoic acid 3a was used as the substrate under reflux conditions
yields (2b–d). In contrast, the presence of electron-donating groups (Scheme 3a). This result suggested that the reaction proceeds via an
at the C3 (2e) and C4 (2f) positions of the anthranilic acids resulted iminoketene, and not via an acid chloride. Next, we investigated the
in decreased product yields. Chloroacetonitrile could also be used reaction with aniline 3b and MeCN (Scheme 3b). This reaction
in this reaction (2g). However, no product was obtained when resulted in the formation of a complex mixture. Thus, both an
bromine or iodine substituted acetonitriles were used (2h and 2i). amino group and a carboxylic acid are necessary in this transfor-
The combination of EtCN and anthranilic acid gave the desired mation to generate the important iminoketene intermediate. The
products but in decreased yields (2j). Benzylnitrile also favoured the reaction was re-examined in the absence of a catalyst in order to
cascade, affording glycosminine 2k2 in 60% yield. Cyanohydrin monitor the formation of side products (Scheme 3c). In the scale
could also be used in the cascade sequence (2l). To enhance the up experiment (10 mmol of 1a), 2a, as well as side products 7
efficiency of this cascade, several heterocyclic nitriles, not liquids, (12% yield) and 8 (7% yield), could be isolated. Dimer 7 was
were selected for use in the synthesis of indole alkaloids. 3-Cyano- formed by the dimerization of 6.19 Macrocycle 8 was produced
and 2-cyanoindole in various solvents could not be converted into via the dimerization of 6 accompanied by Ritter-type addition of
the corresponding quinazolines due to the steric hindrance and MeCN. These results suggest that the copper catalyst is necessary
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Scheme 4 Plausible reaction pathways.
Scheme 3 Mechanistic studies.
for accelerating the nucleophilic attack of the nitrile and inhibiting
the dimerization of iminoketenes. During the mechanistic studies,
we discovered a novel multicomponent reaction (Scheme 3d). The
reaction of 1a under reflux conditions afforded 6-substituted
quinazolino-quinazolinone 920 in 26% yield via 2a.
Based on the mechanistic studies and a literature survey,21,22
a
possible reaction pathway for this cascade is proposed in Scheme 4.
First, the dehydration of 1a by POCl3 affords iminoketene 6
through acid chloride 10.21 Then, the copper catalyst coordinates
to the iminoketene and MeCN, making it more electrophilic, and
MeCN attacks on 6 to generate a nitrilium intermediate 11.12,22
Upon interruption of the nitrilium ion by anthranilic nitrogen,22 11
is converted to quinazolinone 12, along with the regeneration of the
catalyst. Finally, tautomerization of 12 occurs to afford 2a. While
additional details are unavailable at present. 8 and 9 are thought to
have been produced through the reaction involving the capture of 6
by 11 and 12, respectively.
With the successful synthesis of quinazolinones 2, we sought to
expand the scope of the Ritter-type cascade. The reaction of 1a with
acrylonitrile furnished the quinazolinone-fused diazocine 13a in
76% yield through 14 (Scheme 5). The terminal alkene was
completely converted into a secondary amine via an intramolecular
anti-Markovnikov hydroamination of 15. Surprisingly, there is
no literature on the synthesis of quinazoline-fused diazocines in
contrast to the indole-fused diazocines.23 Quinazoline-fused
Scheme 5 Synthesis of quinazolinone-fused diazocinesa,b: a1 (3 mmol), CuO
(0.3 mmol), and POCl3 (15 mmol) in acrylonitrile (20 mL). bIsolated dimer yields.
diazocines are expected to find similar biological applications with acrylonitrile resulting in the isolation of diazocines 13b–m in
to indole-fused diazocines.24 27–80% yields. Compared with the reported methodologies,23,24
Finally, the scope of anthranilic acids was investigated in the our methodology provides a more concise route to the synthesis
new cascade. With the exception of nitroanthranilic acid (13f), of heterocycle-fused diazocines from commercially available
all the other anthranilic acids examined in this study reacted materials.
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X. Chen, Q. Li, Y. Zhou and S. F. Yin, J. Org. Chem., 2015, 80,
9392–9400.
9 For a recent report using other substrates, see: F.-C. Jia, Z.-W. Zhou,
C. Xu, Y.-D. Wu and A.-X. Wu, Org. Lett., 2016, 18, 2942–2945.
10 (a) J. J. Ritter and P. P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045–4048;
(b) J. J. Ritter and J. Kalish, J. Am. Chem. Soc., 1948, 70, 4048–4050. For
In summary, a novel copper-catalyzed Ritter-type reaction/
cyclization cascade of anthranilic acids with nitriles has been
developed, affording the quinazolin-4(3H)-ones. To the best of
our knowledge, this is the first example of the capture of an
iminoketene by a nitrile.10 Previous reports on the classical
Ritter reaction have been limited to carbocations;10 hence, the
cascade presented herein represents a significant improvement to
the Ritter reaction. Furthermore, a new class of quinazolinone-fused
diazocines could be synthesized through a Ritter-type reaction/
condensation/intramolecular anti-Markovnikov hydroamination
cascade. This cascade will be useful for a diversity-oriented
approach to explore the biological activities of these diazocines.
This work was financially supported by JSPS (KAKENHI
Grant Number 16K18849 for T. A.) as a Grant-in-Aid for Young
Scientists (B) and Hoyu Science Foundation (for T. A.).
´
recent reviews on Ritter reaction, see: (c) A. Guerinot, S. Reymond and
J. Cossy, Eur. J. Org. Chem., 2012, 19–28; (d) D. Jiang, T. He, L. Ma and
Z. Wang, RSC Adv., 2014, 4, 64936–64946.
11 G.-G. Chen, J.-Q. Wei, X. Yang and Z.-J. Yao, Org. Lett., 2016, 18,
1502–1505.
12 T. Abe, H. Takeda, Y. Miwa, K. Yamada, R. Yanada and M. Ishikura,
Helv. Chim. Acta, 2010, 93, 233–241.
13 (a) T. Abe, T. Itoh, T. Choshi, S. Hibino and M. Ishikura, Tetrahedron
Lett., 2014, 55, 5268–5270; (b) T. Itoh, T. Abe, S. Nakamura and
M. Ishikura, Heterocycles, 2015, 91, 1423–1428; (c) T. Itoh, T. Abe,
T. Choshi, T. Nishiyama and M. Ishikura, Heterocycles, 2016, 92,
1132–1136; (d) T. Abe and K. Yamada, Org. Lett., 2016, 18, 6504–6507.
14 For selected examples, see: (a) J. B. Reitz and E. I. Solomon, J. Am.
Chem. Soc., 1998, 120, 11467–11478; (b) L. Rout, S. Jammi and
T. Punniyamurthy, Org. Lett., 2007, 9, 3397–3399; (c) S. Pande, A. Saha,
S. Jana, S. Sarkar, M. Basu, M. Pradhan, A. K. Sinha, S. Saha, A. Pal and
T. Pal, Org. Lett., 2008, 10, 5179–5181; (d) P. Maity, D. Kundu, R. Roy and
B. C. Ranu, Org. Lett., 2014, 16, 4122–4125.
Notes and references
1 (a) S. Yoshida, T. Aoyagi, S. Harada, N. Matsuda, T. Ikeda, H. Naganawa,
M. Hamada and T. Takeuchi, J. Antibiot., 1991, 44, 111–112; (b) R. P.
Maskey, M. Shaaban, I. Gru¨n-Wollny and H. Laatsch, J. Nat. Prod., 2004,
67, 1131–1134.
2 A. Chatterjee and S. G. Majumdar, J. Am. Chem. Soc., 1954, 76,
2459–2463.
3 C. Wattanapiromsakul, P. I. Forster and P. G. Waterman, Phyto-
chemistry, 2003, 64, 609–615.
˜
´
´
15 For selected examples, see: (a) D. Vina, E. del Olmo, J. L. Lopez-Perez
and A. S. Feliciano, Org. Lett., 2007, 9, 525–528; (b) S.-Y. Chen,
R.-S. Zeng, J.-P. Zou and O. T. Asekun, J. Org. Chem., 2014, 79,
1449–1453; (c) B. Niu, W. Zhao, Y. Ding, Z. Bian, C. U. Pittman Jr,
A. Zhou and H. Ge, J. Org. Chem., 2015, 80, 7251–7257; (d) Y. Yang,
R. Li, D. Zhao and Z. Shi, J. Am. Chem. Soc., 2016, 138, 8734–8737.
16 K. Uehara, N. Kimura, K. Hasegawa, S. Arai, M. Nishida, T. Hosoe,
K. Kawai and A. Nishida, J. Nat. Prod., 2013, 76, 2034–2039.
17 (a) M. Viji and R. Nagarajan, J. Chem. Sci., 2014, 126, 1075–1080;
(b) S. Ghosh and R. Nagarajan, RSC Adv., 2016, 6, 27378–27387.
18 K. R. Rao, R. Mekala, A. Raghunadh, S. B. Meruva, S. P. Kumar,
D. Kalita, E. Laxminarayana, B. Prasad and M. Pal, RSC Adv., 2015, 5,
61575–61579.
4 J. D. Wansi, E. N. Happi, J. L. D. Bavoua, K. P. Devkota and
N. Sewald, Planta Med., 2012, 78, 71–75.
5 G. Honda and M. Tabata, Planta Med., 1979, 36, 85–86.
6 A. L. Chen and K. K. Chen, J. Am. Pharm. Assoc., 1933, 22, 716–719.
7 (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62, 9787–9826;
(b) L. He, H. Li, J. Chen and X.-F. Wu, RSC Adv., 2014, 4, 12065–12077.
8 (a) Y. Kabri, A. Gellis and P. Vanelle, Green Chem., 2009, 11, 201–208;
(b) X. Zhang, D. Ye, H. Sun, D. Guo, J. Wang, H. Huang, X. Zhang,
H. Jiang and H. Liu, Green Chem., 2009, 11, 1881–1888; (c) X. Liu,
H. Fu, Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348–351;
(d) J. Zhou and J. Fang, J. Org. Chem., 2011, 76, 7730–7736; (e) B. Ma,
Y. Wang, J. Peng and Q. Zhu, J. Org. Chem., 2011, 76, 6362–6366;
( f ) W. Xu, Y. Jin, H. Liu, Y. Jiang and H. Fu, Org. Lett., 2011, 13,
1274–1277; (g) B. V. S. Reddy, G. Narasimhulu, N. Umadevi and
J. Yadav, Synlett, 2012, 1364–1370; (h) M. Adib, E. Sheikhi and
H. R. Bijanzadeh, Synlett, 2012, 85–88; (i) H. Hikawa, Y. Ino,
H. Suzuki and Y. Yokoyama, J. Org. Chem., 2012, 77, 7046–7051;
( j) X. F. Wu, L. He, H. Neumann and M. Beller, Chem. – Eur. J., 2013,
19, 12635–12638; (k) X. Jiang, T. Tang, J. M. Wang, Z. Chen, Y. M. Zhu
and S. J. Ji, J. Org. Chem., 2014, 79, 5082–5087; (l) L. X. Wang,
J. F. Xiang and Y. L. Tang, Eur. J. Org. Chem., 2014, 2682–2685;
(m) H. Chai, J. Li, L. Yang, H. Lu, Z. Qi and D. Shi, RSC Adv., 2014, 4,
44811–44814; (n) W. He, H. Zhao, R. Yao and M. Cai, RSC Adv., 2014,
4, 50285–50294; (o) S. Mohammed, R. V. Vishwakarma and
S. B. Bharate, J. Org. Chem., 2015, 80, 6915–6921; (p) Z. Li, J. Dong,
19 (a) A. N. Grinyov and S. Y. Ryabova, Khim. Geterotsikl. Soedin., 1982,
199–200; (b) E. D. Jacob and L. Mathew, Curr. Sci., 2004, 86,
1368–1369.
20 (a) J. Azizian, A. A. Mohammadi, A. R. Karimi and M. R.
Mohammadizadeh, J. Chem. Res., 2004, 435–437; (b) K. Butler, M. W.
Partrldge and J. A. Waite, J. Chem. Soc., 1960, 4970–4976.
21 (a) T. Kametani, T. Higa, M. Koizumi, M. Ihara and K. Fukumoto,
J. Am. Chem. Soc., 1977, 99, 2306–2309; (b) T. Kametani, T. Higa,
V. L. Chu, M. Ihara, M. Koizumi and K. Fukumoto, J. Am. Chem. Soc.,
1976, 98, 6186–6188.
22 For a literature of the copper-catalyzed Ritter-type reaction, see:
Q. Michaudel, D. Thevenet and P. S. Baran, J. Am. Chem. Soc., 2012,
134, 2547–2550.
23 (a) T. U. Thikekar, M. Selvaraju and C.-M. Sun, Org. Lett., 2016, 18,
316–319; (b) A. M. Jones, S. Patterson, M. M. Lorion, A. M. Z. Slawin
and N. J. Westwood, Org. Biomol. Chem., 2016, 14, 8998–9011.
24 I. Stansfield, C. Ercolani, A. Mackay, I. Conte, M. Pompei, U. Koch,
N. Gennari, C. Giuliano, M. Rowley and F. Narjes, Bioorg. Med.
Chem. Lett., 2009, 19, 627–632.
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