The three-component ring transformation of 1-methyl-3,5-dinitro-2-pyridone with cycloalkanones of different ring sizes in the presence of ammonium acetate affords the corresponding nitrated cycloalka[b]pyridines in high yields. Furthermore, a double bond can be easily introduced into the product by changing the cycloalkanone into a cycloalkenone

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Asahara, Haruyasu

Le, Song Thi

Nishiwaki, Nagatoshi

Nagatoshi Nishiwaki

Thi Le

Haruyasu Asahara

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Synthesis

An Efficient Synthesis of Nitrated Cycloalka[b]pyridines

The three-component ring transformation of 1-methyl-3,5-dinitro-2-pyridone with cycloalkanones of different ring sizes in the presence of ammonium acetate affords the corresponding nitrated cycloalka[b]pyridines in high yields. Furthermore, a double bond can be easily introduced into the product by changing the cycloalkanone into a cycloalkenone.journal articl

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1	 SYNTHESIS:	PAPER		Template	for	SYNLETT	and	SYNTHESIS	©	Thieme		Stuttgart	·	New	York	 2017-03-14	 page	1	of	4	Abstract: The three-component ring transformation of 1-methyl-3,5-dinitro-2-pyridone with cycloalkanones of different ring sizes in the presence of ammonium acetate afforded the corresponding nitrated cycloalka[b]pyridines in high yields. Furthermore, a double bond could be easily introduced to the product by changing the cycloalkanone to a cycloalkenone. Keywords: pyridines, multicomponent reaction, ketones, heterocycles, bicyclic compounds, and ring transformation. Nitro compounds are important organic compounds that are widely used in organic syntheses because of diverse reactivities.1 We have reported a synthetic method for the arylated nitropyridines 3 by the three-component ring transformation (TCRT) of dinitropyridone 1 with aromatic ketones 2 in the presence of ammonia,2 in which dinitropyridone 1 serves as the synthetic equivalent of unstable nitromalonaldehyde (Scheme 1, method a).3 Recently, other research groups also reported the TCRT of 1 with ketones using ammonia as the nitrogen source.4 Although these methods easily provide nitropyridine derivatives via a single step, they suffer from low yields of the products because of the competitive ammonolysis of the substrate 1.5 Furthermore, methanolic ammonia should be prepared in advance, which is also troublesome.  These disadvantages were overcome by using less nucleophilic ammonium acetate (NH4OAc) instead of ammonia.6 The reaction of dinitropyridone 1 with aromatic ketones 2 in the presence of NH4OAc afforded the nitropyridines 3 in good to excellent yields (Scheme 1, method b).7 This TCRT is advantageous in terms of the use of solid NH4OAc compared to gaseous ammonia, and extra NH4OAc can be easily removed from the reaction mixture by thermal decomposition. The successful results of our study prompted us to extend the substrate scope of this method to a series of cyclic ketones 4. Thus, nitrated cycloalka[b]pyridines 5 could be successfully obtained and further used as useful intermediates for the synthesis of metacyclophanes,4 pharmacophores,8 and biologically active compounds.9   Scheme 1. Synthetic methods for 2-arylated-5-nitropyridines 3 by TCRT of dinitropyridone 1 with aromatic ketones 2 in the presence of a nitrogen source. The reaction of the dinitropyridone 1 with cyclohexanone 4a in the presence of 5 equiv. NH4OAc at 65 °C for 24 h afforded nitrated cyclohexa[b]pyridine 5a2b,4b,10 in a moderate yield, because of the shortage of the nitrogen source due to the competitive thermal decomposition of NH4OAc (Table 1, entry 1).7 This problem was easily solved by increasing the amount of NH4OAc, and the yield of 5a could be increased to 95% (entries 2 and 3). When microwave heating was used, nitropyridine 5a was afforded efficiently within 1 h (entry 4). Cyclopentanone 4b was less reactive than 4a, thus affording cyclopentapyridine 5b2b,10 in only 67% yield under the same reaction conditions used for 4a (entry 5). In such a case, microwave heating was effective, and the reaction was completed within a short time under microwave heating (entries 6 and 7). In contrast, larger cycloalkanones 4c and 4d underwent the TCRT efficiently to afford the corresponding cyclohepta- and cyclooctapyridines 5c10 and 5d,4b,10 respectively (entries 8−11). When unsymmetrical 2-methylcyclohexanone 4e was employed, 8-methylated tetrahydroquinoline 5e was obtained efficiently (entries 12 and 13). This reaction was also applied to unsaturated cyclic ketone 4f, thus affording 7,8-dihydroquinoline 5f even though microwave heating was necessary for efficient TCRT (entries 14−16). On the other hand, cylopentenone 4g did not undergo the TCRT even though microwave heating was used (entry 17).    NH33NH4OAcArRO2EtOHN NO2NO2OMeNNO2RAr1 3ArRO2MeOHN NO2NO2OMeNNO2RAr(a)(b)1++An Efficient Synthesis of Nitrated Cycloalka[b]pyridines Thi Song Le, Haruyasu Asahara, and Nagatoshi Nishiwaki* School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan  Fax: +81-887-57-2520 E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp Received: The date will be inserted once the manuscript is accepted. 2	 SYNTHESIS:	PAPER		Template	for	SYNLETT	and	SYNTHESIS	©	Thieme		Stuttgart	·	New	York	 2017-03-14	 page	2	of	4	Table 1. Synthesis of cycloalka[b]pyridines 5 by TCRT.  Entry n Ketones  NH4OAc (equiv.) Time (h) Product   Yield (%) 1 2  4a 5 24  5a 56 2   10 24  88 3   15 24  95 4   15 1a  97 5 1  4b 15 24  5b 67 6   15 2a  87 7   15 1a  70 8 3  4c 15 24  5c 94 9   15 1a  91 10 4  4d 15 24  5d 85 11   15 1a  95 12 2  4e 15 24  5e 83 13   15 2a  86 14 2  4f 15 24  5f 59 15   15 3a  89 16   15 1a  40 17 1  4g 15 4a  5g 0 a: Microwave heating was used.  Scheme 2.  A plausible mechanism for the formation of the condensed nitropyridine 5a.On65 °CNNO25nNH4OAc4EtOHN NO2NO2OMe1+O NNO2ONO2NONNO2ONO2NO NNO2O NNO2ONO2NNNO2O2NO NNO2O2NMeONNO2O2NOH2NMeN NNO2NO2OMeHHNNO2NO2NHOMeHNNO2Me1 7a 8a9a 5aOHONH3H6a10a5a4aNNO2O2NOH2NMe3	 SYNTHESIS:	PAPER		Template	for	SYNLETT	and	SYNTHESIS	©	Thieme		Stuttgart	·	New	York	 2017-03-14	 page	3	of	4		Figure 1. Two plausible intermediates derived from 1-methylcyclohexanone 4e. 	Figure 2. The intermediate 7b and 7f. A plausible mechanism for this TCRT is shown in Scheme 2. After the addition of the enol form of 4a to the 4-position of 1, the resulting adduct 6a is transformed to enanine 7a by reacting with ammonium ion. The intramolecular attack of the amino group at the 6-position affords tricyclic intermediate 8a, from which nitroacetamide is eliminated to afford nitropyridine 5a after the aromatization of intermediate 9a. Although another reaction path via enamine 10a can be considered, the same product 5a is formed. In the case of unsymmetrical 2-methylcyclohexanone 4e, two kinds of intermediates 8e and 8e’ are possible (Figure 1), however, the latter intermediate cannot afford aromatized product. Therefore, only 5e is formed via the intermediate 8e. In the reactions using cyclopentanone 4b and cyclohexenone 4f, the loss of the flexibility of 7b and 7f makes the formation of tricyclic intermediates 8b and 8f more difficult (Figure 2). To the contrary, cyclopentenone 4g did not afford ring transformed product 5g because formation of a sterically restricted intermediate is necessary. In summary, nitrated cycloalka[b]pyridines 5 were efficiently synthesized by the TCRT of dinitropyridone 1 with saturated and unsaturated cyclic ketones 4 in the presence of NH4OAc. Because the method requires only simple manipulations and mild reaction conditions, it has great potential for the synthesis of [b]-condensed pyridine frameworks. Experimental Section The melting points were determined on a Yanaco micro-melting-points apparatus, and were uncorrected. The 1H NMR spectra were measured on a Bruker Ascend-400 at 400 MHz with TMS as an internal standard. The 13C NMR spectra were measured on a Bruker Ascend-400 at 100 MHz, and assignment was performed by DEPT experiments. The IR spectra were recorded on a JASCO FT/IR-4200 spectrometer. The high resolution mass spectrum was measured on a JEOL JMS-DX303HF. Microwave heating was performed using Anton-Paar Microwave 300. All the reagents and solvents were commercially available and were used as received. General procedure of TCRT. To a solution of the dinitropyridone 1 (50 mg, 0.25 mmol) in ethanol (5 mL), cyclohexanone 4a (26 µL, 0.25 mmol) and NH4OAc (289 mg, 3.75 mmol) were added, and the resultant mixture was heated at 65 °C on the oil bath for 24 h. After removal of the solvent, the residue was washed with benzene (3 × 10 mL) to afford 5,6,7,8-tetrahydro-3-nitroquinoline (5a) (42 mg, 0.24 mmol, 95%) as a yellow powder. The reactions of the dinitropyridone 1 with other ketones 4b-g were performed in a similar way. When the reaction was conducted using microwave heating, the experiment was conducted in a similar way. 6,7-Dihydro-3-nitro-5H-cyclopenta[b]pyridine (5b).2b,10 Yellow powder. Yield: 43 mg, 97%. 6,7,8,9-Tetrahydro-3-nitro-5H-cyclohepta[b]pyridine (5c).10 Yellow powder. Yield: 36 mg, 87%. 5,6,7,8,9,10-Hexahydro-3-nitro-cycloocta[b]pyridine (5d).4b,10 Yellow powder. Yield: 49 mg, 95%. 5,6,7,8-Tetrahydro-8-methyl-3-nitroquinoline (5e). 10 Yellow powder. Yield: 41 mg, 86%. 7,8-Dihydro-3-nitroquinoline 5f.  Yellow powder; mp 57-59 °C.  Yield: 40 mg, 89%. NNO2O2NOH2NMe7e'N NNO2NO2OMeHH8e'NNO2O2NOH2NMe7eN NNO2NO2OMeHH8eMeMeMe MeNNO2O2NOMe7bNNO2O2NOH2NMe7fH2NN NNO2NO2OMeHH8bN NNO2NO2OMeHH8f4	 SYNTHESIS:	PAPER		Template	for	SYNLETT	and	SYNTHESIS	©	Thieme		Stuttgart	·	New	York	 2017-03-14	 page	4	of	4	IR (KBr, cm-1) 1261, 1577, 1509. 1H NMR (CDCl3) δ = 2.49 (ddt, J = 2.8, 4.0. 8.4 Hz, 2H), 2.99 (t, J = 8.4 Hz, 2H), 6.57 (dt, J = 4.0, 8.0 Hz, 1H), 6.74 (ddt, J = 0.8, 2.8, 8.0 Hz, 1H), 8.16 (dd, J = 0.8, 2.8 Hz, 1H), 9.19 (d, J = 2.8 Hz, 1H). 13C NMR (CDCl3) δ = 22.6 (CH2), 26.5 (CH2), 128.9 (CH), 129.3 (CH), 131.3 (C), 139.1 (CH), 141.1 (C), 143.3 (CH), 158.8 (C). HRMS (EI, magnetic field) Calcd for C9H8N2O2: 176.0586. Found: 176.0586. Acknowledgment We sincerely thank Prof. Satoshi Minakata (Osaka University, Japan) for his kind assistance. References (1) (a) Nishiwaki, N. in Comprehensive Organic Synthesis, 2nd ed., Vol. 6, 100–130, Elsevier, Oxford, UK (2014); (b) Balini, R.; Gabrietti, S.; Palmieri, A.; Petrini, M. Curr. Org. Chem. 2011, 15, 1482–1506; (c) Ballini, R.; Barboni, L.; Fiorini, D.; Palmieri, A.; Petrini, M. ARKIVOC 2006, vi, 127–152; (d) Adams, J. P.; Peterson, J. R. J. Chem. Soc., Perkin Trans. 1 2000, 3695–3705. (2) Nishiwaki, N.; Ariga, M. in Topics in Heterocyclic Chemistry, Bioactive Heterocycles II, Vol. 8, Ed. by Eguchi, S., 43–72, Springer, Berlin (2007); (b) Tohda, Y.; Kawahara, T.; Eiraku, M.; Tani, K.; Nishiwaki, N.; Ariga, M. Bull. Chem. Soc. Jpn. 1994, 67, 2176–2186; (c) Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.; Ariga, M.; Kawashima, T.; Tani, K.; Wanatabe, H.; Mori.Y. Bull. Chem. Soc. Jpn. 1990, 63, 2820–2827. (3) Nishiwaki, N.; Hirao, S.; Sawayama, J.; Saigo, K. Heterocycles 2012, 84, 115–134.  (4) (a) Henry, C; Haupt, A.; Turner, S. C. J. Org. Chem. 2009, 74, 1932–1938; (b) Sagitullina, G. P.; Garkushenko, A. K.; Vinokurova, Y. O.; Nyrkova, V. A.; Atavin, E. G.; Sagitullin, R. S. Russ. J. Org. Chem. 2009, 45, 1045–1049. (5) Tohda, Y.; Ariga, M.; Kawashima, T.; Matsumura, E. Bull. Chem. Soc. Jpn. 1987, 60, 201–204. (6) The TCRT of 3-methyl-5-nitro-4-pyrimidinone with ketone in the presence of NH4OAc efficiently proceeds to afford pyrimidines, nitropyridones and aminopyridines. (a) Nishiwaki, N.; Sugimoto, R.; Saigo, K.; Kobiro, K. Tetrahedron Lett. 2013, 54, 956–959; (b) Nishiwaki, N.; Yamashita, K.; Azuma, M.; Adachi, T.; Tamura, M.; Ariga, M. Synthesis 2004, 1996–2000; (c) Nishiwaki, N.; Azuma, M.; Tamura, M.; Hori, K.; Tohda, Y.; Ariga, M. Chem. Commun. 2002, 2170–2171. (7) Le, T. S.; Asahara, H.; Kobiro, K.; Sugimoto, R.; Saigo, K.; Nishiwaki, N. Asian. J. Org. Chem. 2014, 3, 297–302.  (8) Yamada, S.; Goto, T.; Yamaguchi, T.; Aihara, K.; Kogi, K.; Narita, S. Chem. Pharm. Bull. 1995, 43 421–431. (9) Yamada, S.; Goto, T.; Shimanuki, E.; Narita, S. Chem. Pharm. Bull. 1994, 42, 718–720. (10) Marcelis, A. T. M.; van der Plas, H. C. Tetrahedron 1989, 45, 2693–2702. 

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An Efficient Synthesis of Nitrated Cycloalka[b]pyridines

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