DOI: 10.1002/chem.201403637
Communication
& Heterocycles
Efficient Synthesis of Eight-Membered Nitrogen Heterocycles from O-Propargylic Oximes by Rhodium-Catalyzed Cascade Reactions Itaru Nakamura,*[a] Yoshinori Sato,[b] Keisuke Takeda,[b] and Masahiro Terada[a, b]
Chem. Eur. J. 2014, 20, 10214 – 10219
10214
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Abstract: Azocine derivatives were successfully synthesized from O-propargylic oximes by means of a Rh-catalyzed 2,3-rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines.
Eight-membered nitrogenous heterocycles (azocines) can be found in numerous naturally occurring products, such as manzamine alkaloids,[1] grandilodines,[2] and otonecines,[3] as well as biologically active compounds, such as XIAP antagonists[4] (Scheme 1). Moreover, azocine derivatives have been
Scheme 2. Rh-catalyzed cascade reactions of O-propargylic oximes in the syntheses of azepines (n = 0) and azocines (n = 1, present work).
Scheme 1. Selected examples of azocines as natural products or synthetic intermediates. Cbz = carbobenzyloxy.
a 2,3-rearrangement to form N-allenylnitrone intermediate A, then the formation of azarhodacycle B occurs, followed by ring expansion of the strained cyclopropyl group. Accordingly, we envisioned that our methods could be extended to the efficient construction of the elusive monocyclic azocine skeletons, without the use of high-dilution conditions, starting with a readily accessible cyclobutyl moiety as the ring-expanding functional group (Scheme 2, n = 1).[13] Herein, we report on the effective transformation of O-propargylic oximes 1 that possess a cyclobutyl group at the oxime moiety, in the presence of a Rh catalyst, into the corresponding azocine oxides 2 in good to excellent yields [Eq. (1)].
utilized as synthetic intermediates providing various alkaloids, such as loline[5] and FR-900482.[6] Accordingly, the efficient construction of nitrogen-containing eight-membered rings would contribute greatly toward organic synthetic methods.[7] In particular, the synthesis of eight-membered nitrogenous heteromonocyclic compounds has proven to be a challenge because the direct cyclization of a linear substrate into the corresponding eight-membered ring is entropically and enthalpically unfavorable.[8] Accordingly, such monocyclic skeletons are generally constructed in good to moderate yields by olefin metathesis reactions, which inevitably require high-dilution conditions (typically 0.002–0.005 m).[9, 10] We have recently reported the use of Rh-catalyzed cascade reactions for the efficient construction of seven-membered nitrogen heterocyclic azepine oxides from O-propargylic cyclopropanecarboaldoximes (Scheme 2, n = 0),[11, 12] in which the starting oxime undergoes [a] Prof. Dr. I. Nakamura, Prof. Dr. M. Terada Research and Analytical Center for Giant Molecules Graduate School of Science, Tohoku University 6-3 Aramaki Aza Aoba, Aoba-ku, Sendai, 980-8578 (Japan) Fax: (+ 81) 22-795-6602 E-mail: [email protected] [b] Y. Sato, K. Takeda, Prof. Dr. M. Terada Department of Chemistry, Graduate School of Science Tohoku University, 6-3 Aramaki Aza Aoba Aoba-ku, Sendai, 980-8578 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403637. Chem. Eur. J. 2014, 20, 10214 – 10219
www.chemeurj.org
Initially, the reaction conditions, as summarized in Table 1, were optimized by using (E)-1 a. In the presence of [RhCl(cod)]2 (2.5 mol %; cod = 1,5-cyclooctadiene) and PPh3 (10 mol %), the reaction was carried out in MeCN at 80 8C to afford desired product 2 a in 71 % yield (entry 1).[14] Among the solvents, the best results were obtained by using MeCN. Moreover, the mass balance was improved by lowering the reaction concentration from 0.2 to 0.1 m (entry 2). In contrast, the use of DMF and DMSO (entries 3 and 4, respectively) decreased the mass balance, whereas the use of 1,4-dioxane, THF, and toluene (entries 5–7, respectively) resulted in significant formation of the byproduct, four-membered cyclic nitrone 3 a.[15] With regards to the ligands, the use of electron-poor phosphines (entry 9) afforded 2 a in excellent yield, whereas that of electron-rich ligands (entry 8) resulted in the formation of undesired byproduct 3 a. The use of a phosphite ligand (triphenylphosphite, entry 10) gave intermediate results. Bidentate ligands such as dppp (dppp = 1,3-bis(diphenylphosphino)propane; entry 11) resulted in the preferential formation of byproduct 3 a. Notably, product 2 a was readily separated from triarylphosphine oxides by using silica gel chromatography. In contrast, the previous
10215
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication aromatic ring. Alkyl groups, such as propyl (entry 4) and cyclohexyl (entry 5), were effective as the alkyne substituent R1, whereas the reaction of terminal alkyne 1 g afforded unidentified byproducts (entry 6). Alkyl substituents were also acceptable at the propargylic position (entries 9–11). In terms of the electronic effects at the propargylic position, the reaction of 1 h (entry 7), which involves an electron-deficient aryl group, proceeded much faster than the substrate with an electronrich substituent (entry 8). Using the same reaction conditions as for the E oximes (Table 1, entry 9), the reaction for the corresponding Z oxime [(Z)-1 a, Eq. (2)] led to complete consumption of the starting material within a shorter time (12 h), affording the product, 2 a, in an excellent isolated yield.[17] In contrast, the reaction of dicyclobutyl ketoxime 1 m did not give the azocine; instead, the four-membered cyclic nitrone 3 m was obtained [Eq. (3)].
Table 1. Optimization of reaction conditions.
Entry
Ligand
Solvent [0.2 m]
Time [h]
2a [%][a]
3a [%][a]
1a [%][a]
1 2 3 4 5 6 7 8 9 10 11
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 (p-MeOC6H4)3P (p-F3CC6H4)3P (PhO)3P dppp[d]
MeCN MeCN[b] DMF DMSO dioxane THF toluene MeCN[b] MeCN[b] MeCN[b] MeCN[b]
24 36 60 48 72 72 72 36 24 24 24
71 88 28 32 17 19 30 57 (93)[c] 76 27
trace 7 46 41 35 52 30 23 3 20 56
Communication
& Heterocycles
Efficient Synthesis of Eight-Membered Nitrogen Heterocycles from O-Propargylic Oximes by Rhodium-Catalyzed Cascade Reactions Itaru Nakamura,*[a] Yoshinori Sato,[b] Keisuke Takeda,[b] and Masahiro Terada[a, b]
Chem. Eur. J. 2014, 20, 10214 – 10219
10214
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication Abstract: Azocine derivatives were successfully synthesized from O-propargylic oximes by means of a Rh-catalyzed 2,3-rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines.
Eight-membered nitrogenous heterocycles (azocines) can be found in numerous naturally occurring products, such as manzamine alkaloids,[1] grandilodines,[2] and otonecines,[3] as well as biologically active compounds, such as XIAP antagonists[4] (Scheme 1). Moreover, azocine derivatives have been
Scheme 2. Rh-catalyzed cascade reactions of O-propargylic oximes in the syntheses of azepines (n = 0) and azocines (n = 1, present work).
Scheme 1. Selected examples of azocines as natural products or synthetic intermediates. Cbz = carbobenzyloxy.
a 2,3-rearrangement to form N-allenylnitrone intermediate A, then the formation of azarhodacycle B occurs, followed by ring expansion of the strained cyclopropyl group. Accordingly, we envisioned that our methods could be extended to the efficient construction of the elusive monocyclic azocine skeletons, without the use of high-dilution conditions, starting with a readily accessible cyclobutyl moiety as the ring-expanding functional group (Scheme 2, n = 1).[13] Herein, we report on the effective transformation of O-propargylic oximes 1 that possess a cyclobutyl group at the oxime moiety, in the presence of a Rh catalyst, into the corresponding azocine oxides 2 in good to excellent yields [Eq. (1)].
utilized as synthetic intermediates providing various alkaloids, such as loline[5] and FR-900482.[6] Accordingly, the efficient construction of nitrogen-containing eight-membered rings would contribute greatly toward organic synthetic methods.[7] In particular, the synthesis of eight-membered nitrogenous heteromonocyclic compounds has proven to be a challenge because the direct cyclization of a linear substrate into the corresponding eight-membered ring is entropically and enthalpically unfavorable.[8] Accordingly, such monocyclic skeletons are generally constructed in good to moderate yields by olefin metathesis reactions, which inevitably require high-dilution conditions (typically 0.002–0.005 m).[9, 10] We have recently reported the use of Rh-catalyzed cascade reactions for the efficient construction of seven-membered nitrogen heterocyclic azepine oxides from O-propargylic cyclopropanecarboaldoximes (Scheme 2, n = 0),[11, 12] in which the starting oxime undergoes [a] Prof. Dr. I. Nakamura, Prof. Dr. M. Terada Research and Analytical Center for Giant Molecules Graduate School of Science, Tohoku University 6-3 Aramaki Aza Aoba, Aoba-ku, Sendai, 980-8578 (Japan) Fax: (+ 81) 22-795-6602 E-mail: [email protected] [b] Y. Sato, K. Takeda, Prof. Dr. M. Terada Department of Chemistry, Graduate School of Science Tohoku University, 6-3 Aramaki Aza Aoba Aoba-ku, Sendai, 980-8578 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201403637. Chem. Eur. J. 2014, 20, 10214 – 10219
www.chemeurj.org
Initially, the reaction conditions, as summarized in Table 1, were optimized by using (E)-1 a. In the presence of [RhCl(cod)]2 (2.5 mol %; cod = 1,5-cyclooctadiene) and PPh3 (10 mol %), the reaction was carried out in MeCN at 80 8C to afford desired product 2 a in 71 % yield (entry 1).[14] Among the solvents, the best results were obtained by using MeCN. Moreover, the mass balance was improved by lowering the reaction concentration from 0.2 to 0.1 m (entry 2). In contrast, the use of DMF and DMSO (entries 3 and 4, respectively) decreased the mass balance, whereas the use of 1,4-dioxane, THF, and toluene (entries 5–7, respectively) resulted in significant formation of the byproduct, four-membered cyclic nitrone 3 a.[15] With regards to the ligands, the use of electron-poor phosphines (entry 9) afforded 2 a in excellent yield, whereas that of electron-rich ligands (entry 8) resulted in the formation of undesired byproduct 3 a. The use of a phosphite ligand (triphenylphosphite, entry 10) gave intermediate results. Bidentate ligands such as dppp (dppp = 1,3-bis(diphenylphosphino)propane; entry 11) resulted in the preferential formation of byproduct 3 a. Notably, product 2 a was readily separated from triarylphosphine oxides by using silica gel chromatography. In contrast, the previous
10215
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication aromatic ring. Alkyl groups, such as propyl (entry 4) and cyclohexyl (entry 5), were effective as the alkyne substituent R1, whereas the reaction of terminal alkyne 1 g afforded unidentified byproducts (entry 6). Alkyl substituents were also acceptable at the propargylic position (entries 9–11). In terms of the electronic effects at the propargylic position, the reaction of 1 h (entry 7), which involves an electron-deficient aryl group, proceeded much faster than the substrate with an electronrich substituent (entry 8). Using the same reaction conditions as for the E oximes (Table 1, entry 9), the reaction for the corresponding Z oxime [(Z)-1 a, Eq. (2)] led to complete consumption of the starting material within a shorter time (12 h), affording the product, 2 a, in an excellent isolated yield.[17] In contrast, the reaction of dicyclobutyl ketoxime 1 m did not give the azocine; instead, the four-membered cyclic nitrone 3 m was obtained [Eq. (3)].
Table 1. Optimization of reaction conditions.
Entry
Ligand
Solvent [0.2 m]
Time [h]
2a [%][a]
3a [%][a]
1a [%][a]
1 2 3 4 5 6 7 8 9 10 11
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 (p-MeOC6H4)3P (p-F3CC6H4)3P (PhO)3P dppp[d]
MeCN MeCN[b] DMF DMSO dioxane THF toluene MeCN[b] MeCN[b] MeCN[b] MeCN[b]
24 36 60 48 72 72 72 36 24 24 24
71 88 28 32 17 19 30 57 (93)[c] 76 27
trace 7 46 41 35 52 30 23 3 20 56
