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Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3-ethoxycyclobutanones
Accepted Manuscript Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3ethoxycyclobutanones Tatsuo Onnagawa, Yusuke Shima, Tomoyuki Yoshimura, Jun-ichi Matsuo PII: DOI: Reference:
S0040-4039(16)30671-2 http://dx.doi.org/10.1016/j.tetlet.2016.06.011 TETL 47738
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
22 April 2016 27 May 2016 2 June 2016
Please cite this article as: Onnagawa, T., Shima, Y., Yoshimura, T., Matsuo, J-i., Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3-ethoxycyclobutanones, Tetrahedron Letters (2016), doi: http:// dx.doi.org/10.1016/j.tetlet.2016.06.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3ethoxycyclobutanones
Leave this area blank for abstract info.
Tatsuo Onnagawa, Yusuke Shima, Tomoyuki Yoshimura, and Jun-ichi Matsuo*
1
Tetrahedron Letters
Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3ethoxycyclobutanones Tatsuo Onnagawa, Yusuke Shima, Tomoyuki Yoshimura, and Jun-ichi Matsuo* Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
3-Ethoxycyclobutanones reacted with pyridines, quinolines, and isoquinolines to give the corresponding formal [4+2] cycloadducts, 9a-hydro-2H-quinolizin-2-one derivatives, by using Me3SiOTf in acetonitrile. Cycloaddition of 3-ethoxy-2-monoalkylcyclobutanones to 5nitroquinoline or 4-cyanopyridine proceeded stereoselectively. 2009 Elsevier Ltd. All rights reserved .
Keywords: Cyclobutanone [4+2] Cycloaddition Quinoline Pyridine Isoquinoline
Cycloaddition to pyridines, quinolines, and isoquinolines is a promising method for construction of polycyclic heterocycles. However, their aromaticity retards cycloaddition reactions (e.g. the Diels-Alder reaction) to their aromatic rings. There have been two methods that enable cycloaddition to pyridines, quinolines, and isoquinolines. One is a [2+2+2] type cycloaddition to pyridines1 by using dimethyl acetylenedicarboxylate and alkenes,2 ketones,3 or imines.4,5 The other one is [3+2] type cycloaddition of pyridines and quinolines with a donor-acceptor cyclopropane.6,7 Therefore, the field of [4+2] cycloaddition to pyridines remains to be unexplored. The high electrophilicity and ring strain of cyclobutanones enable unique chemical reactions including four-membered ring cleavage and make them versatile synthetic blocks in organic synthesis.8 Our group developed various types of formal [4+2] cycloaddition and ring-cleaving carbon-carbon bond formation by using various cyclobutanones and a Lewis acid.9 3Ethoxycyclobutanones 1 were activated with a Lewis acid to form 1,4-zwitterionic intermediate 2, and it reacted with various C=C,10 C=N,11 C=O12 double bonds to form the corresponding six-membered cyclic compounds 5. It was thought that the 1,4zwitterionic intermediate 2 would react with N-heterocycles 3 to afford a formal [4+2] adduct 5 via an intermediate 4 (Scheme 1). In this paper, we would like to describe the first example of [4+2] type cycloaddition of pyridines, quinolines, and isoquinolines with 3-ethoxycyclobutanones.
Scheme 1. Formal [4+2] Cycloadditions to Pyridines 3 with Cyclobutanones 1
First, reaction conditions were optimized in a model reaction using 5-nitroquioline (8a) and 3-ethoxycyclobutanone 7a. Various Lewis acids including BF3 ‧ Et2O, SnCl4, AlCl3, EtAlCl2, TiCl4, and Me3SiOTf were screened in this reaction, and it was found that Me3SiOTf was the most suitable Lewis acid (Table 1, entries 1‒6). In all cases, the more substituted C2‒C3 bond of 7a was cleaved regioselectively, 12a and formal [4+2] cycloaddition with 8a proceeded to give 9a after elimination of ethanol in the presence of Lewis acid. After extensive experiments for optimization of reaction conditions, acetonitirile was found to be an appropriate solvent among the solvents that were tested including dichloromethane, acetonitrile, and propionitrile (entries 6‒8). Raising the reaction temperature from 5 °C to 24 °C improved the yield slightly, while raising the
2
Tetrahedron
reaction temperature to 40 °C lowered the yield of 9a. A longer reaction time decreased the yield of 9a (entry 9 and 11).
Table 2 Reactions with Various Quinolines 8b‒e and Cyclobutanone 7a‒ga
Table 1 Optimization of Reaction Cycloaddition of 7a with 8aa
Conditions
for Formal [4+2]
entry
X
7
9
yield (%)b
1
H (8b)
R1, R2 = Me (7a)
9b
29c
entry
Lewis acid
solvent
conditions
yield (%)b
2
6-NO2 (8c)
R1, R2 = Me (7a)
9c
64c
1
BF3‧ Et2O
MeCN
5 °C, 20 min
trace
3
8-NO2 (8d)
R1, R2 = Me (7a)
9d
trace
trace
4
5-F (8e)
R1, R2 = Me (7a)
9e
52
2
SnCl4
MeCN
5 °C, 20 min
3
AlCl3
MeCN
5 °C, 20 min
27
4
EtAlCl2
MeCN
5 °C, 20 min
27
5
TiCl4
MeCN
5 °C, 20 min
34
6
Me3SiOTf
MeCN
5 °C, 20 min
60
7
Me3SiOTf
EtNO2
5 °C, 20 min
56
8
5-NO2 (8a)
8
Me3SiOTf
CH2Cl2
5 °C, 20 min
49
9
5-NO2 (8a)
9
Me3SiOTf
MeCN
24 °C, 20 min
64
10
5-NO2 (8a)
10
Me3SiOTf
MeCN
40 °C, 20 min
44
a
11
Me3SiOTf
MeCN
24 °C, 1 h
51
5
5-NO2 (8a)
R, R (7b)
= –(CH2)4–
9f
51c
6
5-NO2 (8a)
R1, R2 = –(CH2)5– (7c)
9g
60c
7
5-NO2 (8a)
R1 = Me, R2 = H (7d)
9h
40
R = Bn, R = H (7e)
9i
45
R1 = H, R2 = tBu (7f)
9j
22c
R1, R2 = H (7g)
9k
16c
1
2
1
2
For reaction conditions, see Table 1. bIsolated yield unless otherwise noted. c Determined by 1H NMR analysis.
a
Quinoline 8a (1.0 equiv), cyclobutanone 7a (1.1 equiv), and Lewis acid (1.1 equiv) were used. bIsolated yield.
Cycloaddition reactions to various quinolines were performed under optimized reaction conditions by using Me3SiOTf in CH3CN at 24 °C for 20 min (Table 2, entries 1–4). Nonsubstituted quinoline reacted with 7a to give the corresponding adduct 9b in 29% yield (entry 1). Introduction of an electronwithdrawing group such as a 6-nitro or 5-fluoro group on the quinoline ring improved the yields of the cycloaddition products 9c,e (entry 2 and 4). On the other hand, quinoline with a nitro group at its 8-position 8d gave only a trace amount of the cycloadduct 9d (entry 3). A reaction of 8-fluoroquinoline and 7a also gave a trace amount of the corresponding cycloadduct. Most of the starting materials were recovered in these reactions. Various types of 3-ethoxycyclobutanones 7b–g reacted with 5-nitroquinoline (8a) giving fair to good yields. Spiro cyclobutanones 7b,c also reacted smoothly to give the corresponding adducts 9f,g (entry 5 and 6). The formal cycloaddition with 2-monoalkylcyclobutanones 7d,e gave the adducts 9h,i as single diastereomers, which had transrelationship between H4a and H4 (entries 7 and 8). The structure of 9h was determined unambiguously by X-ray crystallographic analysis. It should be noted that 9h had an almost sp2 hybridized C4a carbon (Figure 1). On the other hand, the reaction of 2-tbutylcyclobutanone 7f gave 9j as a single product, which had cisrelationship between H4a and H4 (entry 9).
Figure 1. ORTEP structure of 9h.
Next, formal [4+2] cycloaddition reactions with substituted pyridines 10a‒e and cyclobutanones 7a,c‒g were investigated (Table 3). It was found that an electron-withdrawing substituent on the pyridine ring was required for smooth cycloaddition reaction as in the case of reactions of quinolines (entry 1 vs entries 2‒5). The reaction of a spiro cyclobutanone 7c gave the desired product 11f in 17% yield, and 11f was particularly unstable in isolation procedures (entry 6). The formal [4+2] cycloaddition of 2-monoalkylcyclobutanones gave the corresponding cycloadducts 11g‒i in 11‒32% yields as single diastereomers (entries 7‒9), and the reaction of 3ethoxycyclobutanone (7g) gave a trace amount of 11j (entry 10).
3 Table 3 Reactions with Various Pyridines 10a‒e and Cyclobutanone 7a,c‒ga
entry
X
7
conditions
11
yield (%)b
1
H (10a)
R1, R2 = Me (7a)
rt, 20 min
11a
5
2
4-CN (10b)
R1, R2 = Me (7a)
rt, 20 min
11b
47
3
4-CF3 (10c)
R1, R2 = Me (7a)
rt, 20 min
11c
43
1
2
heteroaromatic ring accelerated the attack of silyl enol ether of 15.
Scheme 3．A Proposed Reaction Mechanism
4
4-COMe (10d)
R , R = Me (7a)
rt, 20 min
11d
28
5
4-CO2Et (10e)
R1, R2 = Me (7a)
rt, 40 min
11e
44
6
4-CN (10b)
R1, R2 = -(CH2)5-(7c)
5 °C, min
20
11f
17
7
4-CN (10b)
R1 = Me, R2 = H (7d)
5 °C, min
20
11g
11c
8
4-CN (10b)
R1 = Bn, R2 = H (7e)
5 °C, min
40
11h
32
9
4-CN (10b)
R1 = H, R2 = tBu (7f)
5 °C, min
40
11i
14
10
4-CN (10b)
R1, R2 = H (7g)
5 °C, min
80
11j
trace
In conclusion, we have developed the first example of a formal [4+2] cycloaddition of 3-ethoxycyclobutanones with quinolines, pyridines, and isoquinolines to give 9a-hydro-2Hquinolizin-2-one derivatives. This is a new method for construction of quinolizine and benzoquinolizine systems, which are essential frameworks of biologically active compounds such as potential anti-HCV drugs,13 p38 MAP kinase inhibitors,14 anti-DNA gyrase,15 and inhibitors of human 5-reductases.16 Easy preparation of 3-ethoxycyclobutanones17 and stereoselectivity of the present cycloaddition make this method useful for rapid construction of quinolizine and benzoquinolizine frameworks.
Acknowledgments
a
Pyridine 10 (1.0 equiv), cyclobutanone 7 (1.1 equiv), and Me3SiOTf (1.1 equiv) were used. bIsolated yield unless otherwise noted. c Determined by 1H NMR analysis.
Financial support from JSPS KAKENHI Grant Number 15K07855 is greatly appreciated. References and notes
Isoquinoline (12a) and 5-nitroisoquinoline (12b) also reacted with cyclobutanone 7a in the presence of Me3SiOTf in acetonitrile to afford cycloadducts 13a and 13b in 22% and 42% isolated yields, respectively (Scheme 2).
1. 2.
3. 4. 5.
6.
Scheme 2．Reactions of Isoquinolines 12a,b
A proposed reaction mechanism is shown in Scheme 3. Cyclobutanone 7a was activated with Me3SiOTf to form an intermediate 14 by cleaving the more substituted C2‒C3 bond. The nitrogen of quinoline, pyridine or isoquinoline attacks the part of the oxonium cation of 14 and the heteroaromatics are activated as in the form of 15. The part of silyl enol ether of 15 attacks the activated heteroaromatics to form a six-membered ring, and elimination of ethanol gives the product 16. It was assumed that the electron-withdrawing group on the
7.
8.
Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem. Ber. 1967, 100, 1094. (a) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Tetrahedron Lett. 2008, 49, 1469. (b) Alizadeh, A.; Sadeghi, V.; Bayat, F.; Zhu, L.-G. Helv. Chim. Acta 2014, 97, 1383. (c) Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron 2008, 64, 3567. Nair, V.; Sreekanth, A. R.; Biju, A. T.; Rath, N. P. Tetrahedron Lett. 2003, 44, 729. Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.; Gonnade, R. C. Org. Lett. 2002, 4, 3575. Related reactions: (a) Fan, X.; He, Y.; Zhang, X.; Wang, J. Green Chem. 2014, 16, 1393. (b) Acheson, R. M.; Wallis, J. D.; Woollard, J. J. Chem. Soc., Perkin Trans. 11979, 584. Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang, J.; Yu, M.; Pagenkopf, B. L. Adv. Synth. Catal. 2006, 348, 2385. [3+2] Cycloaddition reactions of pyridine N-oxides were reported: (a) Harano, K.; Kondo, R.; Murase, M.; Matsuoka, T.; Hisano, T. Chem. Pharm. Bull. 1986, 34, 966. (b) Hisano, T.; Harano, K.; Matsuoka, T.; Suzuki, T.; Murayama, Y. Chem. Pharm. Bull. 1990, 38, 605. (c) Hisano, T.; Matsuoka, T.; Tsutsumi, K.; Muraoka, K.; Ichikawa, M. Chem. Pharm. Bull. 1981, 29, 3706. (d) Hamana, M.; Funakoshi, K.; Shigyo, H.; Kuchino, Y. Chem. Pharm. Bull. 1975, 23, 346. (a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (b) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (c) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (d) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797. (e) Conia, J. M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975, 14, 473.
4
Tetrahedron 9. Review: Matsuo, J. Tetrahedron Lett. 2014, 55, 2589. 10. (a) Matsuo, J.; Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50, 5831. (b) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett. 2009, 11, 3822. (c) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Chem. Comm. 2010, 46, 934. 11. Matsuo, J.; Okado, R.; Ishibashi, H. Org. Lett. 2010, 12, 3266. 12. (a) Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc. 2008, 130, 11600. (b) Harada, K.; Nowaki, A.; Matsuo, J. Asian J. Org. Chem. 2013, 2, 923. 13. Wang, G.; Zhang, L.; Wu, X.; Das, D.; Ruhrmund, D.; Hooi, L.; Misialek, S.; Ravi Rajagopalan, P. T.; Buckman, B. O.; Kossen, K.; Seiwert, S. D.; Beigelman, L. Bioorg. Med. Chem. Lett. 2009, 19, 4484. 14. Tynebor, R. M.; Chen, M.-H.; Natarajan, S. R.; O'Neill, E. A.; Thompson, J. E.; Fitzgerald, C. E.; O'Keefe, S. J.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2010, 20, 2765. 15. Guarna, A.; Occhiato, E. G.; Scarpi, D.; Tsai, R.; Danza, G.; Comerci, A.; Mancina, R.; Serio, M. Bioorg. Med. Chem. Lett. 1998, 8, 2871. 16. Fecik, R. A.; Devasthale, P.; Pillai, S.; Keschavarz-Shokri, A.; Shen, L.; Mitscher, L. A. J. Med. Chem. 2005, 48, 1229. 17. Matsuo, J.; Okuno, R.; Takeuchi, K.; Kawano, M.; Ishibashi, H. Tetrahedron Lett. 2010, 51, 3736 and references are cited threin.
Supplementary Material Supplementary data associated with this article can be found in the online version, at __.
5 Formal [4+2] cycloaddition of 3ethoxycyclobutanones to pyridines, quinolines, and isoquinolines was developed. High stereoselectivity for the cycloadditon was observed in the case of 3-ethoxy-2monoalkylcyclobutanones. A characteristic feature of the structure of 9ahydro-2H-quinolizin-2-ones was found by X-ray crystallography.
S0040-4039(16)30671-2 http://dx.doi.org/10.1016/j.tetlet.2016.06.011 TETL 47738
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
22 April 2016 27 May 2016 2 June 2016
Please cite this article as: Onnagawa, T., Shima, Y., Yoshimura, T., Matsuo, J-i., Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3-ethoxycyclobutanones, Tetrahedron Letters (2016), doi: http:// dx.doi.org/10.1016/j.tetlet.2016.06.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3ethoxycyclobutanones
Leave this area blank for abstract info.
Tatsuo Onnagawa, Yusuke Shima, Tomoyuki Yoshimura, and Jun-ichi Matsuo*
1
Tetrahedron Letters
Formal [4+2] cycloaddition of quinolines, pyridines, and isoquinolines with 3ethoxycyclobutanones Tatsuo Onnagawa, Yusuke Shima, Tomoyuki Yoshimura, and Jun-ichi Matsuo* Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
3-Ethoxycyclobutanones reacted with pyridines, quinolines, and isoquinolines to give the corresponding formal [4+2] cycloadducts, 9a-hydro-2H-quinolizin-2-one derivatives, by using Me3SiOTf in acetonitrile. Cycloaddition of 3-ethoxy-2-monoalkylcyclobutanones to 5nitroquinoline or 4-cyanopyridine proceeded stereoselectively. 2009 Elsevier Ltd. All rights reserved .
Keywords: Cyclobutanone [4+2] Cycloaddition Quinoline Pyridine Isoquinoline
Cycloaddition to pyridines, quinolines, and isoquinolines is a promising method for construction of polycyclic heterocycles. However, their aromaticity retards cycloaddition reactions (e.g. the Diels-Alder reaction) to their aromatic rings. There have been two methods that enable cycloaddition to pyridines, quinolines, and isoquinolines. One is a [2+2+2] type cycloaddition to pyridines1 by using dimethyl acetylenedicarboxylate and alkenes,2 ketones,3 or imines.4,5 The other one is [3+2] type cycloaddition of pyridines and quinolines with a donor-acceptor cyclopropane.6,7 Therefore, the field of [4+2] cycloaddition to pyridines remains to be unexplored. The high electrophilicity and ring strain of cyclobutanones enable unique chemical reactions including four-membered ring cleavage and make them versatile synthetic blocks in organic synthesis.8 Our group developed various types of formal [4+2] cycloaddition and ring-cleaving carbon-carbon bond formation by using various cyclobutanones and a Lewis acid.9 3Ethoxycyclobutanones 1 were activated with a Lewis acid to form 1,4-zwitterionic intermediate 2, and it reacted with various C=C,10 C=N,11 C=O12 double bonds to form the corresponding six-membered cyclic compounds 5. It was thought that the 1,4zwitterionic intermediate 2 would react with N-heterocycles 3 to afford a formal [4+2] adduct 5 via an intermediate 4 (Scheme 1). In this paper, we would like to describe the first example of [4+2] type cycloaddition of pyridines, quinolines, and isoquinolines with 3-ethoxycyclobutanones.
Scheme 1. Formal [4+2] Cycloadditions to Pyridines 3 with Cyclobutanones 1
First, reaction conditions were optimized in a model reaction using 5-nitroquioline (8a) and 3-ethoxycyclobutanone 7a. Various Lewis acids including BF3 ‧ Et2O, SnCl4, AlCl3, EtAlCl2, TiCl4, and Me3SiOTf were screened in this reaction, and it was found that Me3SiOTf was the most suitable Lewis acid (Table 1, entries 1‒6). In all cases, the more substituted C2‒C3 bond of 7a was cleaved regioselectively, 12a and formal [4+2] cycloaddition with 8a proceeded to give 9a after elimination of ethanol in the presence of Lewis acid. After extensive experiments for optimization of reaction conditions, acetonitirile was found to be an appropriate solvent among the solvents that were tested including dichloromethane, acetonitrile, and propionitrile (entries 6‒8). Raising the reaction temperature from 5 °C to 24 °C improved the yield slightly, while raising the
2
Tetrahedron
reaction temperature to 40 °C lowered the yield of 9a. A longer reaction time decreased the yield of 9a (entry 9 and 11).
Table 2 Reactions with Various Quinolines 8b‒e and Cyclobutanone 7a‒ga
Table 1 Optimization of Reaction Cycloaddition of 7a with 8aa
Conditions
for Formal [4+2]
entry
X
7
9
yield (%)b
1
H (8b)
R1, R2 = Me (7a)
9b
29c
entry
Lewis acid
solvent
conditions
yield (%)b
2
6-NO2 (8c)
R1, R2 = Me (7a)
9c
64c
1
BF3‧ Et2O
MeCN
5 °C, 20 min
trace
3
8-NO2 (8d)
R1, R2 = Me (7a)
9d
trace
trace
4
5-F (8e)
R1, R2 = Me (7a)
9e
52
2
SnCl4
MeCN
5 °C, 20 min
3
AlCl3
MeCN
5 °C, 20 min
27
4
EtAlCl2
MeCN
5 °C, 20 min
27
5
TiCl4
MeCN
5 °C, 20 min
34
6
Me3SiOTf
MeCN
5 °C, 20 min
60
7
Me3SiOTf
EtNO2
5 °C, 20 min
56
8
5-NO2 (8a)
8
Me3SiOTf
CH2Cl2
5 °C, 20 min
49
9
5-NO2 (8a)
9
Me3SiOTf
MeCN
24 °C, 20 min
64
10
5-NO2 (8a)
10
Me3SiOTf
MeCN
40 °C, 20 min
44
a
11
Me3SiOTf
MeCN
24 °C, 1 h
51
5
5-NO2 (8a)
R, R (7b)
= –(CH2)4–
9f
51c
6
5-NO2 (8a)
R1, R2 = –(CH2)5– (7c)
9g
60c
7
5-NO2 (8a)
R1 = Me, R2 = H (7d)
9h
40
R = Bn, R = H (7e)
9i
45
R1 = H, R2 = tBu (7f)
9j
22c
R1, R2 = H (7g)
9k
16c
1
2
1
2
For reaction conditions, see Table 1. bIsolated yield unless otherwise noted. c Determined by 1H NMR analysis.
a
Quinoline 8a (1.0 equiv), cyclobutanone 7a (1.1 equiv), and Lewis acid (1.1 equiv) were used. bIsolated yield.
Cycloaddition reactions to various quinolines were performed under optimized reaction conditions by using Me3SiOTf in CH3CN at 24 °C for 20 min (Table 2, entries 1–4). Nonsubstituted quinoline reacted with 7a to give the corresponding adduct 9b in 29% yield (entry 1). Introduction of an electronwithdrawing group such as a 6-nitro or 5-fluoro group on the quinoline ring improved the yields of the cycloaddition products 9c,e (entry 2 and 4). On the other hand, quinoline with a nitro group at its 8-position 8d gave only a trace amount of the cycloadduct 9d (entry 3). A reaction of 8-fluoroquinoline and 7a also gave a trace amount of the corresponding cycloadduct. Most of the starting materials were recovered in these reactions. Various types of 3-ethoxycyclobutanones 7b–g reacted with 5-nitroquinoline (8a) giving fair to good yields. Spiro cyclobutanones 7b,c also reacted smoothly to give the corresponding adducts 9f,g (entry 5 and 6). The formal cycloaddition with 2-monoalkylcyclobutanones 7d,e gave the adducts 9h,i as single diastereomers, which had transrelationship between H4a and H4 (entries 7 and 8). The structure of 9h was determined unambiguously by X-ray crystallographic analysis. It should be noted that 9h had an almost sp2 hybridized C4a carbon (Figure 1). On the other hand, the reaction of 2-tbutylcyclobutanone 7f gave 9j as a single product, which had cisrelationship between H4a and H4 (entry 9).
Figure 1. ORTEP structure of 9h.
Next, formal [4+2] cycloaddition reactions with substituted pyridines 10a‒e and cyclobutanones 7a,c‒g were investigated (Table 3). It was found that an electron-withdrawing substituent on the pyridine ring was required for smooth cycloaddition reaction as in the case of reactions of quinolines (entry 1 vs entries 2‒5). The reaction of a spiro cyclobutanone 7c gave the desired product 11f in 17% yield, and 11f was particularly unstable in isolation procedures (entry 6). The formal [4+2] cycloaddition of 2-monoalkylcyclobutanones gave the corresponding cycloadducts 11g‒i in 11‒32% yields as single diastereomers (entries 7‒9), and the reaction of 3ethoxycyclobutanone (7g) gave a trace amount of 11j (entry 10).
3 Table 3 Reactions with Various Pyridines 10a‒e and Cyclobutanone 7a,c‒ga
entry
X
7
conditions
11
yield (%)b
1
H (10a)
R1, R2 = Me (7a)
rt, 20 min
11a
5
2
4-CN (10b)
R1, R2 = Me (7a)
rt, 20 min
11b
47
3
4-CF3 (10c)
R1, R2 = Me (7a)
rt, 20 min
11c
43
1
2
heteroaromatic ring accelerated the attack of silyl enol ether of 15.
Scheme 3．A Proposed Reaction Mechanism
4
4-COMe (10d)
R , R = Me (7a)
rt, 20 min
11d
28
5
4-CO2Et (10e)
R1, R2 = Me (7a)
rt, 40 min
11e
44
6
4-CN (10b)
R1, R2 = -(CH2)5-(7c)
5 °C, min
20
11f
17
7
4-CN (10b)
R1 = Me, R2 = H (7d)
5 °C, min
20
11g
11c
8
4-CN (10b)
R1 = Bn, R2 = H (7e)
5 °C, min
40
11h
32
9
4-CN (10b)
R1 = H, R2 = tBu (7f)
5 °C, min
40
11i
14
10
4-CN (10b)
R1, R2 = H (7g)
5 °C, min
80
11j
trace
In conclusion, we have developed the first example of a formal [4+2] cycloaddition of 3-ethoxycyclobutanones with quinolines, pyridines, and isoquinolines to give 9a-hydro-2Hquinolizin-2-one derivatives. This is a new method for construction of quinolizine and benzoquinolizine systems, which are essential frameworks of biologically active compounds such as potential anti-HCV drugs,13 p38 MAP kinase inhibitors,14 anti-DNA gyrase,15 and inhibitors of human 5-reductases.16 Easy preparation of 3-ethoxycyclobutanones17 and stereoselectivity of the present cycloaddition make this method useful for rapid construction of quinolizine and benzoquinolizine frameworks.
Acknowledgments
a
Pyridine 10 (1.0 equiv), cyclobutanone 7 (1.1 equiv), and Me3SiOTf (1.1 equiv) were used. bIsolated yield unless otherwise noted. c Determined by 1H NMR analysis.
Financial support from JSPS KAKENHI Grant Number 15K07855 is greatly appreciated. References and notes
Isoquinoline (12a) and 5-nitroisoquinoline (12b) also reacted with cyclobutanone 7a in the presence of Me3SiOTf in acetonitrile to afford cycloadducts 13a and 13b in 22% and 42% isolated yields, respectively (Scheme 2).
1. 2.
3. 4. 5.
6.
Scheme 2．Reactions of Isoquinolines 12a,b
A proposed reaction mechanism is shown in Scheme 3. Cyclobutanone 7a was activated with Me3SiOTf to form an intermediate 14 by cleaving the more substituted C2‒C3 bond. The nitrogen of quinoline, pyridine or isoquinoline attacks the part of the oxonium cation of 14 and the heteroaromatics are activated as in the form of 15. The part of silyl enol ether of 15 attacks the activated heteroaromatics to form a six-membered ring, and elimination of ethanol gives the product 16. It was assumed that the electron-withdrawing group on the
7.
8.
Huisgen, R.; Morikawa, M.; Herbig, K.; Brunn, E. Chem. Ber. 1967, 100, 1094. (a) Shaabani, A.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Tetrahedron Lett. 2008, 49, 1469. (b) Alizadeh, A.; Sadeghi, V.; Bayat, F.; Zhu, L.-G. Helv. Chim. Acta 2014, 97, 1383. (c) Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron 2008, 64, 3567. Nair, V.; Sreekanth, A. R.; Biju, A. T.; Rath, N. P. Tetrahedron Lett. 2003, 44, 729. Nair, V.; Sreekanth, A. R.; Abhilash, N.; Bhadbhade, M. M.; Gonnade, R. C. Org. Lett. 2002, 4, 3575. Related reactions: (a) Fan, X.; He, Y.; Zhang, X.; Wang, J. Green Chem. 2014, 16, 1393. (b) Acheson, R. M.; Wallis, J. D.; Woollard, J. J. Chem. Soc., Perkin Trans. 11979, 584. Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang, J.; Yu, M.; Pagenkopf, B. L. Adv. Synth. Catal. 2006, 348, 2385. [3+2] Cycloaddition reactions of pyridine N-oxides were reported: (a) Harano, K.; Kondo, R.; Murase, M.; Matsuoka, T.; Hisano, T. Chem. Pharm. Bull. 1986, 34, 966. (b) Hisano, T.; Harano, K.; Matsuoka, T.; Suzuki, T.; Murayama, Y. Chem. Pharm. Bull. 1990, 38, 605. (c) Hisano, T.; Matsuoka, T.; Tsutsumi, K.; Muraoka, K.; Ichikawa, M. Chem. Pharm. Bull. 1981, 29, 3706. (d) Hamana, M.; Funakoshi, K.; Shigyo, H.; Kuchino, Y. Chem. Pharm. Bull. 1975, 23, 346. (a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (b) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (c) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (d) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27, 797. (e) Conia, J. M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975, 14, 473.
4
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Supplementary Material Supplementary data associated with this article can be found in the online version, at __.
5 Formal [4+2] cycloaddition of 3ethoxycyclobutanones to pyridines, quinolines, and isoquinolines was developed. High stereoselectivity for the cycloadditon was observed in the case of 3-ethoxy-2monoalkylcyclobutanones. A characteristic feature of the structure of 9ahydro-2H-quinolizin-2-ones was found by X-ray crystallography.