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Synthesis of (alkylaminomethyl)lactones and hydroxypiperidones using alkylaminomethylation methodology
Tetrahedron Letters 56 (2015) 6590–6592
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (alkylaminomethyl)lactones and hydroxypiperidones using alkylaminomethylation methodology Evgeny M. Buev, Vladimir S. Moshkin ⇑, Vyacheslav Y. Sosnovskikh Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation
a r t i c l e
i n f o
Article history: Received 3 August 2015 Revised 1 October 2015 Accepted 6 October 2015 Available online 8 October 2015 Keywords: Carbonyl compounds Nonstabilized azomethine ylides [3+2] Cycloaddition 5-Aryloxazolidines Lactones 2-Piperidones
a b s t r a c t We describe the reactions of carbonyl compounds bearing CO2R or CN groups with nonstabilized azomethine ylides. Oxazolidine–lactone rearrangement of the intermediate adducts was carried out for the first time to give (aminomethyl)lactones in good yields. The latter could be rearranged to give 5-hydroxy-2piperidones, which could also be directly obtained from the aromatic ketones thus avoiding isolation of the intermediate lactone. Ó 2015 Elsevier Ltd. All rights reserved.
The 1,3-dipolar cycloaddition reaction is known as an efficient tool for the construction of various five-membered heterocycles.1 In particular nonstabilized azomethine ylides are traditionally used for the synthesis of five-membered saturated azaheterocycles— pyrrolidines2 and more rarely—oxazolidines.3 Generally, these reactions utilize the [3+2] cycloaddition of electron-donating azomethine ylides with electron-withdrawing group containing C@C or C@O groups. Taking into account the accessibility and the reactivity of azomethine ylides, we decided to extend their application to the synthesis of other heterocycles, for example, c,d-lactones and piperidines, which can be obtained by the one-pot modification of primary cycloaddition adducts. To implement the proposed synthesis the starting substrate which initially undergoes reaction with the azomethine ylide should contain a fragment with high polarity, such as a keto group. The resulting oxazolidines, due to the presence of an aminoacetal methylene group, still possess synthetic potential, and in the second step can react with another functional group in the starting compound. Using this concept we earlier reported the convenient one-pot syntheses of (hetero)aryl annulated piperidines 1–3 and 1-benzopyrano[2,3-c:3,4-c0 ]dipyrrolidines 4 (Scheme 1).4 In this Letter we report a related approach for the synthesis of lactones 5 and piperidones 6. It should be pointed out that all previous syntheses of azaheterocycles did not require purification of the liquid ⇑ Corresponding author. Tel.: +7 3432616824; fax: +7 3432615978. E-mail address: [email protected] (V.S. Moshkin). http://dx.doi.org/10.1016/j.tetlet.2015.10.024 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
oxazolidine intermediates, and therefore are easily scalable and operationally simple. From another point of view the reactions resulting in the formation of heterocycles 4–6 are also the reaction of the alkylaminomethylation of carbonyl compounds using nonstabilized azomethine ylides.5 It is important to note that using nonstabilized azomethine ylides for the construction of heterocycles other than pyrrolidine is a rapidly developing field. Other routes include various 1,7-electrocyclizations for the formation of benzazepines;6 the work of Seidel and co-workers for the syntheses of functionalized carbolines, benzoxazines, benzothiazines, and tetrahydroquinazolines;7 as well as the work of Ryan and co-workers, who synthesized benzodiazepinones from isatoic anhydrides via a domino reaction.8 Taking into account the above mentioned publications we decided to examine aromatic aldehydes and ketones, bearing ester or nitrile groups in a 1,4- or 1,5-position relative to the carbonyl group. This decision was due to the fact that, firstly, all of the resulting products would be derivatives of b-phenethylamine, which is a pharmacophore fragment of a large number of alkaloids and drugs;9 secondly, as a result of rearrangement, a stable five to six membered ring should be formed; thirdly, CN and CO2R groups would not compete with the aromatic carbonyl due to their low reactivity with the azomethine ylides. To test the feasibility of this idea the reaction of methyl 2formylbenzoate 7 with the nonstabilized azomethine ylide generated in situ from sarcosine and formaldehyde was first investigated. The aromatic CHO group underwent [3+2]
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E. M. Buev et al. / Tetrahedron Letters 56 (2015) 6590–6592
Alk N
OH R' O
N 1
N 3
Alk
N Alk
+
R
Ar
HO
Ar
Alk O
N
Ar
N R'' 2
Alk
HO Ar
NH N Alk O 4
R O
N H
N Alk Alk 6
O
this work
O
in the formation of an oxazolidine. Therefore, more drastic conditions (reflux, 5 h, DMF, 2.5 equiv 10, 3 equiv LiF) for cycloaddition of the nonstabilized azomethine ylide to the aromatic C@O were used. The corresponding oxazolidine 8c (NMR yield 74%) was obtained in a complicated mixture with various amines, formed by side reactions of N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine. To purify the oxazolidine intermediate, alkaline saponification of the ester group to form a water soluble salt was used. Subsequent acidic hydrolysis led to the formation of the crystalline hydrochloride salt of amine 9c in 35% yield (Table 1). With conditions in hand, we were able to obtain (aminomethyl) lactones 9a–f in 40–80% yields. All compounds 9a–f were isolated as hydrochlorides, which were easily purified by washing with hot acetone. To the best of our knowledge, phenethylamines 9c–f are previously unknown (Table 1). In the next step, the conditions for rearrangement of (aminomethyl)lactones 9 into amides were studied. Sugimoto et al. proposed heating the free base 9a at 80 °C in MeOH in a sealed tube Table 1 Yields of the hydrochlorides of 5-((alkylamino)methyl)butyrolactones 9 Starting substrate
Ylide formation method
5
Demethylenation method
Hydrochlorides of lactones 9, yield (%)
Me
Scheme 1. Synthetic equivalents for the alkylaminomethyl anion.
NH•HCl
CHO A
O
D
CO2Me
cycloaddition with the formation of 5-aryloxazolidine 8a (R = Me) in quantitative yield. Next, the latter was heated in 6 M hydrochloric acid to remove the aminoacetal methylene group, yielding the hydrochloride salt of 5-((methylamino)methyl)butyrolactone 9a (Scheme 2). After neutralization with NaHCO3 this salt formed the previously known free base, which was sufficiently stable and did not spontaneously recyclize to the amide.10,11 The reaction of aldehyde 7 with N-(methoxymethyl)-N(trimethylsilylmethyl)benzylamine (10) in the presence of TFA gave the corresponding oxazolidine 8b, which was successfully demethylenated using acidic conditions (H2O/HCl, 70 °C, 30 min) to form a hydrochloride salt of phthalide 9b in 63% yield. It should be noted that such oxazolidine–butyrolactone rearrangement was previously unknown, probably due to the low accessibility of the initial functionalized oxazolidines such as 8. This fact makes the 1,3-dipolar cycloaddition of nonstabilized azomethine ylides to carbonyl compounds an important step in the synthesis of lactones 9. The reaction of the methyl ester of o-acetylbenzoic acid with sarcosine and formaldehyde, as could be expected,5 did not result
O 9a (80)
Bn NH•HCl
CHO B
O
D
CO2Me
O 9b (63)
Bn
Me
O Me
C
NH•HCl O
E
O
CO2Me
9c (35)
Bn
Ph
O Ph
C
NH•HCl O
D
CO2Me
O 9d (57)
O
CHO
N R
N R
CO2 Me
i or ii
Ph
8a,b
7
C
NH•HCl O
D
CO2Et
CO 2Me
Bn
Ph
O
O 9d (55)
MeO
O
H2O/HCl
CHO A
O
O
O
O
NH•HCl Me
D
R OH
NH•HCl
R NH•HCl O
CO2 Me R = Me (a), Bn (b)
9e (58)
MeO
O
CHO B
D
NH•HCl Bn
O 9a,b
Scheme 2. Reaction sequence from methyl 2-formylbenzoate. Reagents and conditions: (i) sarcosine (1.2 equiv), CH2O, PhH, reflux 3 h with Dean–Stark trap; (ii) (MeOCH2)(Me3SiCH2)NBn (10) (2.5 equiv), LiF, DMF, reflux, 5 h.
9f (40) Reagents and conditions. (A) sarcosine/CH2O; (B) 10 (1 equiv), TFA; (C) 10 (2.5 equiv), LiF, DMF, reflux, 5 h; (D) 6 M HCl, 70 °C, 30 min; (E) H2O, HCl, BuOH, 90 °C, 1.5 h.
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Table 2 Yields of 5-hydroxy-2-piperidones 11 Starting substrate
5-Hydroxy-2-piperidones 11, yield (%)
Me NH
OH N
O O
11a (74,a 77,b 52c)
9a
Acknowledgments
Ph OH
Bn
Ph
Me
O
NH O
N
This work was financially supported by the Russian Science Foundation (Grant 14-13-00388).
Bn
O
O
Supplementary data
11b (60)c
9d
Bn N
O CO2Me Me
O
OH d
12a
11c (44)
Bn N
O CN
O
OH EtO
12b
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10. 024. References and notes
Me
EtO
esters or nitriles proceeding via a 5-aryloxazolidine intermediate and its concomitant demethylenation. This one-pot synthesis can be considered as a formal C-nucleophilic addition of the methyl (benzyl)aminomethyl anion from sarcosine/formaldehyde or N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to the carbonyl group followed by two cyclizations. The proposed method allows easy access to complex phenethylamine derivatives, which are of interest due to their potential biological activity and the possibility of further synthetic modification.
11d (38)d
a
MeOH, 80 °C, 14 h. MW, 130 °C, 2 h. NaOH, then NH4Cl, reflux in n-BuOH. d 10 (2.5 equiv), LiF, DMF, reflux, 5 h; demethylenation using H2O, HCl, BuOH, 90 °C; then neutralization, D. b
c
for 14 h to promote recyclization into amide 11a (yield 74%).10 Clearly, such conditions were needed due to the inability of the nitrogen atom to intramolecularly attack the ester carbonyl group. We confirmed these data and found that heating in MeOH using a microwave reactor at 130 °C for 2 h transformed 9a into 11a in 77% conversion (1H NMR data), while reflux in n-BuOH for 1.5 h was inefficient (conversion 20%). On the other hand, we discovered that lactones 9a and 9d could rearrange into the corresponding dihydroisoquinolinone by opening with NaOH, followed by neutralization with NH4Cl and cyclization in boiling n-BuOH (52% (11a) and 60% (11b)). Exploring the breadth of application of this approach, we examined the reaction of b-toluoyl propionate 12a with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in the presence of LiF. As for the synthesis of amine 9c, we performed an alkaline saponification step with KOH for removal of amine side products. It is noteworthy that the intermediate oxazolidine was very stable and did not undergo demethylenation in HCl/H2O, or HCl/H2O/ MeOH at 70 °C. At the same time, we found that heating in n-butanol at 90 °C with concentrated HCl completely hydrolyzed the oxazolidine ring. The subsequent basification resulted in the formation of the expected piperidone 11c in 44% yield. A similar transformation was carried out using 4-(4-ethoxyphenyl)-4-oxobutanenitrile (12b) to give 5-(4-ethoxyphenyl)-5-hydroxypiperidin-2-one 11d in similar overall yield (Table 2). In summary we have developed a convenient route to ((alkylamino)methyl)lactones and hydroxypiperidones from carbonyl
1. Padwa, A.; Pearson, W. H. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley: New York, 2002; Vol. 59, pp 169–252. 2. (a) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231–344; (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484–4517; (c) Nájera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150; (d) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809; (e) Grigg, R.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 180–181; (f) Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 182–183; (g) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 49–51; (h) Grigg, R.; Idle, J.; McMeekin, P.; Surendrakumar, S.; Vipond, D. J. Chem. Soc., Perkin Trans. 1 1988, 2703–2713; (i) Grigg, R.; Vipond, D. Tetrahedron 1989, 45, 7587–7592; (k) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull. Chem. Soc. Jpn. 1987, 60, 4079–4089. 3. (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069–2072; (b) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235–244; (c) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988, 44, 519–541; (d) Nyerges, M.; Fejes, I.; Virányi, A.; Groundwater, P. W.; Töke, L. Synthesis 2001, 1479–1482; (e) Ryan, J. H.; Spiccia, N.; Wong, L. S.-M.; Holmes, A. B. Aust. J. Chem. 2007, 60, 898–904; (f) Lee, S.; Diab, S.; Queval, P.; Sebban, M.; Chataigner, I.; Piettre, S. R. Chem. Eur. J. 2013, 19, 7181–7192; (g) Nair, V.; Mathai, S.; Augustine, A.; Viji, S.; Radhakrishnan, K. V. Synthesis 2004, 2617–2619. 4. (a) Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 2455–2457; (b) Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 2699–2702; (c) Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2014, 55, 6121–6124; (d) Sosnovskikh, V. Y.; Kornev, M. Y.; Moshkin, V. S. Tetrahedron Lett. 2014, 55, 212–214; (e) Sosnovskikh, V. Y.; Kornev, M. Y.; Moshkin, V. S.; Buev, E. M. Tetrahedron 2014, 70, 9253–9261. 5. (a) Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 5869–5872; (b) Moshkin, V. S.; Buev, E. M.; Sosnovskikh, V. Y. Tetrahedron Lett. 2015, 56, 5278– 5281. }ke, L.; Groundwater, P. W.; Nyerges, M. 6. (a) Tóth, J.; Dancsó, A.; Blaskó, G.; To Tetrahedron 2006, 62, 5725–5735; (b) Nyerges, M.; Tóth, J.; Groundwater, P. W. Synlett 2008, 1269–1278. 7. (a) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011, 2, 233–236; (b) Dieckmann, A.; Richers, M. T.; Platonova, A. Yu.; Zhang, C.; Seidel, D.; Houk, K. N. J. Org. Chem. 2013, 78, 4132–4144; (c) Richers, M. T.; Deb, I.; Platonova, A. Yu.; Zhang, C.; Seidel, D. Synthesis 2013, 1730–1748; (d) Richers, M. T.; Breugst, M.; Platonova, A. Yu.; Ullrich, A.; Dieckmann, A.; Houk, K. N.; Seidel, D. J. Am. Chem. Soc. 2014, 136, 6123–6135; (e) Jarvis, C. L.; Richers, M. T.; Breugst, M.; Houk, K. N.; Seidel, D. Org. Lett. 2014, 16, 3556–3559. 8. D’Souza, A. M.; Spiccia, N.; Basutto, J.; Jokisz, P.; Wong, L. S.-M.; Meyer, A. G.; Holmes, A. B.; White, J. M.; Ryan, J. H. Org. Lett. 2011, 13, 486–489. 9. (a) Zvejniece, L.; Svalbe, B.; Veinberg, G.; Grinberga, S.; Vorona, M.; Kalvinsh, I.; Dambrova, M. Basic Clin. Pharmacol. Toxicol. 2011, 109, 407–412; (b) Kanes, S. J.; Tokarczyk, J.; Siegel, S. J.; Bilker, W.; Abel, T.; Kelly, M. P. Neuroscience 2007, 144, 239–246; (c) Ullyot, G. E.; Stehle, J. J.; Zirkle, C. L.; Shriner, R. L.; Wolf, F. J. J. Org. Chem. 1945, 10, 429–440. 10. Sugimoto, A.; Shinba-Tanaka, H.; Ishikawa, M. Synthesis 1995, 431–434. 11. Capriati, V.; Florio, S.; Luisi, R.; Musio, B. Org. Lett. 2005, 7, 3749–3752.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (alkylaminomethyl)lactones and hydroxypiperidones using alkylaminomethylation methodology Evgeny M. Buev, Vladimir S. Moshkin ⇑, Vyacheslav Y. Sosnovskikh Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation
a r t i c l e
i n f o
Article history: Received 3 August 2015 Revised 1 October 2015 Accepted 6 October 2015 Available online 8 October 2015 Keywords: Carbonyl compounds Nonstabilized azomethine ylides [3+2] Cycloaddition 5-Aryloxazolidines Lactones 2-Piperidones
a b s t r a c t We describe the reactions of carbonyl compounds bearing CO2R or CN groups with nonstabilized azomethine ylides. Oxazolidine–lactone rearrangement of the intermediate adducts was carried out for the first time to give (aminomethyl)lactones in good yields. The latter could be rearranged to give 5-hydroxy-2piperidones, which could also be directly obtained from the aromatic ketones thus avoiding isolation of the intermediate lactone. Ó 2015 Elsevier Ltd. All rights reserved.
The 1,3-dipolar cycloaddition reaction is known as an efficient tool for the construction of various five-membered heterocycles.1 In particular nonstabilized azomethine ylides are traditionally used for the synthesis of five-membered saturated azaheterocycles— pyrrolidines2 and more rarely—oxazolidines.3 Generally, these reactions utilize the [3+2] cycloaddition of electron-donating azomethine ylides with electron-withdrawing group containing C@C or C@O groups. Taking into account the accessibility and the reactivity of azomethine ylides, we decided to extend their application to the synthesis of other heterocycles, for example, c,d-lactones and piperidines, which can be obtained by the one-pot modification of primary cycloaddition adducts. To implement the proposed synthesis the starting substrate which initially undergoes reaction with the azomethine ylide should contain a fragment with high polarity, such as a keto group. The resulting oxazolidines, due to the presence of an aminoacetal methylene group, still possess synthetic potential, and in the second step can react with another functional group in the starting compound. Using this concept we earlier reported the convenient one-pot syntheses of (hetero)aryl annulated piperidines 1–3 and 1-benzopyrano[2,3-c:3,4-c0 ]dipyrrolidines 4 (Scheme 1).4 In this Letter we report a related approach for the synthesis of lactones 5 and piperidones 6. It should be pointed out that all previous syntheses of azaheterocycles did not require purification of the liquid ⇑ Corresponding author. Tel.: +7 3432616824; fax: +7 3432615978. E-mail address: [email protected] (V.S. Moshkin). http://dx.doi.org/10.1016/j.tetlet.2015.10.024 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
oxazolidine intermediates, and therefore are easily scalable and operationally simple. From another point of view the reactions resulting in the formation of heterocycles 4–6 are also the reaction of the alkylaminomethylation of carbonyl compounds using nonstabilized azomethine ylides.5 It is important to note that using nonstabilized azomethine ylides for the construction of heterocycles other than pyrrolidine is a rapidly developing field. Other routes include various 1,7-electrocyclizations for the formation of benzazepines;6 the work of Seidel and co-workers for the syntheses of functionalized carbolines, benzoxazines, benzothiazines, and tetrahydroquinazolines;7 as well as the work of Ryan and co-workers, who synthesized benzodiazepinones from isatoic anhydrides via a domino reaction.8 Taking into account the above mentioned publications we decided to examine aromatic aldehydes and ketones, bearing ester or nitrile groups in a 1,4- or 1,5-position relative to the carbonyl group. This decision was due to the fact that, firstly, all of the resulting products would be derivatives of b-phenethylamine, which is a pharmacophore fragment of a large number of alkaloids and drugs;9 secondly, as a result of rearrangement, a stable five to six membered ring should be formed; thirdly, CN and CO2R groups would not compete with the aromatic carbonyl due to their low reactivity with the azomethine ylides. To test the feasibility of this idea the reaction of methyl 2formylbenzoate 7 with the nonstabilized azomethine ylide generated in situ from sarcosine and formaldehyde was first investigated. The aromatic CHO group underwent [3+2]
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Alk N
OH R' O
N 1
N 3
Alk
N Alk
+
R
Ar
HO
Ar
Alk O
N
Ar
N R'' 2
Alk
HO Ar
NH N Alk O 4
R O
N H
N Alk Alk 6
O
this work
O
in the formation of an oxazolidine. Therefore, more drastic conditions (reflux, 5 h, DMF, 2.5 equiv 10, 3 equiv LiF) for cycloaddition of the nonstabilized azomethine ylide to the aromatic C@O were used. The corresponding oxazolidine 8c (NMR yield 74%) was obtained in a complicated mixture with various amines, formed by side reactions of N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine. To purify the oxazolidine intermediate, alkaline saponification of the ester group to form a water soluble salt was used. Subsequent acidic hydrolysis led to the formation of the crystalline hydrochloride salt of amine 9c in 35% yield (Table 1). With conditions in hand, we were able to obtain (aminomethyl) lactones 9a–f in 40–80% yields. All compounds 9a–f were isolated as hydrochlorides, which were easily purified by washing with hot acetone. To the best of our knowledge, phenethylamines 9c–f are previously unknown (Table 1). In the next step, the conditions for rearrangement of (aminomethyl)lactones 9 into amides were studied. Sugimoto et al. proposed heating the free base 9a at 80 °C in MeOH in a sealed tube Table 1 Yields of the hydrochlorides of 5-((alkylamino)methyl)butyrolactones 9 Starting substrate
Ylide formation method
5
Demethylenation method
Hydrochlorides of lactones 9, yield (%)
Me
Scheme 1. Synthetic equivalents for the alkylaminomethyl anion.
NH•HCl
CHO A
O
D
CO2Me
cycloaddition with the formation of 5-aryloxazolidine 8a (R = Me) in quantitative yield. Next, the latter was heated in 6 M hydrochloric acid to remove the aminoacetal methylene group, yielding the hydrochloride salt of 5-((methylamino)methyl)butyrolactone 9a (Scheme 2). After neutralization with NaHCO3 this salt formed the previously known free base, which was sufficiently stable and did not spontaneously recyclize to the amide.10,11 The reaction of aldehyde 7 with N-(methoxymethyl)-N(trimethylsilylmethyl)benzylamine (10) in the presence of TFA gave the corresponding oxazolidine 8b, which was successfully demethylenated using acidic conditions (H2O/HCl, 70 °C, 30 min) to form a hydrochloride salt of phthalide 9b in 63% yield. It should be noted that such oxazolidine–butyrolactone rearrangement was previously unknown, probably due to the low accessibility of the initial functionalized oxazolidines such as 8. This fact makes the 1,3-dipolar cycloaddition of nonstabilized azomethine ylides to carbonyl compounds an important step in the synthesis of lactones 9. The reaction of the methyl ester of o-acetylbenzoic acid with sarcosine and formaldehyde, as could be expected,5 did not result
O 9a (80)
Bn NH•HCl
CHO B
O
D
CO2Me
O 9b (63)
Bn
Me
O Me
C
NH•HCl O
E
O
CO2Me
9c (35)
Bn
Ph
O Ph
C
NH•HCl O
D
CO2Me
O 9d (57)
O
CHO
N R
N R
CO2 Me
i or ii
Ph
8a,b
7
C
NH•HCl O
D
CO2Et
CO 2Me
Bn
Ph
O
O 9d (55)
MeO
O
H2O/HCl
CHO A
O
O
O
O
NH•HCl Me
D
R OH
NH•HCl
R NH•HCl O
CO2 Me R = Me (a), Bn (b)
9e (58)
MeO
O
CHO B
D
NH•HCl Bn
O 9a,b
Scheme 2. Reaction sequence from methyl 2-formylbenzoate. Reagents and conditions: (i) sarcosine (1.2 equiv), CH2O, PhH, reflux 3 h with Dean–Stark trap; (ii) (MeOCH2)(Me3SiCH2)NBn (10) (2.5 equiv), LiF, DMF, reflux, 5 h.
9f (40) Reagents and conditions. (A) sarcosine/CH2O; (B) 10 (1 equiv), TFA; (C) 10 (2.5 equiv), LiF, DMF, reflux, 5 h; (D) 6 M HCl, 70 °C, 30 min; (E) H2O, HCl, BuOH, 90 °C, 1.5 h.
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E. M. Buev et al. / Tetrahedron Letters 56 (2015) 6590–6592
Table 2 Yields of 5-hydroxy-2-piperidones 11 Starting substrate
5-Hydroxy-2-piperidones 11, yield (%)
Me NH
OH N
O O
11a (74,a 77,b 52c)
9a
Acknowledgments
Ph OH
Bn
Ph
Me
O
NH O
N
This work was financially supported by the Russian Science Foundation (Grant 14-13-00388).
Bn
O
O
Supplementary data
11b (60)c
9d
Bn N
O CO2Me Me
O
OH d
12a
11c (44)
Bn N
O CN
O
OH EtO
12b
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10. 024. References and notes
Me
EtO
esters or nitriles proceeding via a 5-aryloxazolidine intermediate and its concomitant demethylenation. This one-pot synthesis can be considered as a formal C-nucleophilic addition of the methyl (benzyl)aminomethyl anion from sarcosine/formaldehyde or N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to the carbonyl group followed by two cyclizations. The proposed method allows easy access to complex phenethylamine derivatives, which are of interest due to their potential biological activity and the possibility of further synthetic modification.
11d (38)d
a
MeOH, 80 °C, 14 h. MW, 130 °C, 2 h. NaOH, then NH4Cl, reflux in n-BuOH. d 10 (2.5 equiv), LiF, DMF, reflux, 5 h; demethylenation using H2O, HCl, BuOH, 90 °C; then neutralization, D. b
c
for 14 h to promote recyclization into amide 11a (yield 74%).10 Clearly, such conditions were needed due to the inability of the nitrogen atom to intramolecularly attack the ester carbonyl group. We confirmed these data and found that heating in MeOH using a microwave reactor at 130 °C for 2 h transformed 9a into 11a in 77% conversion (1H NMR data), while reflux in n-BuOH for 1.5 h was inefficient (conversion 20%). On the other hand, we discovered that lactones 9a and 9d could rearrange into the corresponding dihydroisoquinolinone by opening with NaOH, followed by neutralization with NH4Cl and cyclization in boiling n-BuOH (52% (11a) and 60% (11b)). Exploring the breadth of application of this approach, we examined the reaction of b-toluoyl propionate 12a with N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in the presence of LiF. As for the synthesis of amine 9c, we performed an alkaline saponification step with KOH for removal of amine side products. It is noteworthy that the intermediate oxazolidine was very stable and did not undergo demethylenation in HCl/H2O, or HCl/H2O/ MeOH at 70 °C. At the same time, we found that heating in n-butanol at 90 °C with concentrated HCl completely hydrolyzed the oxazolidine ring. The subsequent basification resulted in the formation of the expected piperidone 11c in 44% yield. A similar transformation was carried out using 4-(4-ethoxyphenyl)-4-oxobutanenitrile (12b) to give 5-(4-ethoxyphenyl)-5-hydroxypiperidin-2-one 11d in similar overall yield (Table 2). In summary we have developed a convenient route to ((alkylamino)methyl)lactones and hydroxypiperidones from carbonyl
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