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Beckmann Rearrangement of 3-Carboxybicyclo[3.3.1]Nonane and [3.2.1]Octane Oximes Andriy S

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Beckmann Rearrangement of 3-Carboxybicyclo[3.3.1]Nonane and [3.2.1]Octane Oximes Andriy S FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2017, VOLUME 05, ISSUE 02) Beckmann Rearrangement of 3-carboxybicyclo[3.3.1]nonane and [3.2.1]octane Oximes Andriy S. Bulochnikov, Olga O. Ryzhenko, Marian V. Gorichko* Department of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Street, 64/13, Kyiv 01601, Ukraine [email protected] Keywords: Beckmann rearrangement, oxime, bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, lactam Regiospecific Beckmann rearrangement of substituted 2-hydroximinonorbornanone carboxylic acids has been investigated. Selective formation of new functionalized 10-oxo-9- azabicyclo[3.3.2]decanes and 7-oxo-6-azabicyclo[3.2.2]nonanes in good yield has been demonstrated. Presence of neighboring carboxylic group allows conducting of Beckmann rearrangement of strained bicyclic compounds. ________________________________________________________________________________ Introduction been reported to form a mixture of Beckmann rearrangement, discovered fragmentation products under various acidic, 130 years ago, has been widely used for the basic and photochemical conditions. Bicyclic purposes of modern organic synthesis of large lactames were detected as minor byproducts variety of natural products, pharmaceuticals and only in a few cases [12-15]. products of bulk industrial processes [1-3]. Nevertheless strained cyclic systems undergo Results and discussion abnormal rearrangement (Beckmann We have chosen two pairs of model fragmentation) which is often accomplished substrates in order to examine the assumption, with different carbocation rearrangements that carboxyl group in proper position can be resulting in complex mixture of products [4-10]. involved in Beckmann rearrangement by Thus norbornanone oximes, among them the influencing on its products or on the kinetics of most available and as a consequence the most the rearrangement. In our studies we investigated are terpenoid derivatives, showed investigated anti- and syn-8- very poor ability to form classic rearrangement oximinobicyclo[3.2.1]octane- and 9- products. Camphor oxime can give up to 12 oximinobicyclo[3.3.1]nonane-3-carboxylic products under different reaction conditions, but acids (1.1, 1.2, 2.1, 2.2) (Figure 1). no formation of desired lactame was observed [11]. Substituted norbornanone oximes have 121 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2017, VOLUME 05, ISSUE 02) O OH H All the oximino acids were prepared HO H from corresponding keto acids and O hydroxylamine hydrochloride in presence of HON n HON n pyridine. Ketoacids 3, 4, 5 and 6 were 1.1 (n = 1) 1.2 (n = 1) synthesized by alkylation of 1-pyrrolidino-1- 2.1 (n = 2) 2.2 (n = 2) cyclopentene (7) or 1-pyrrolidino-1- Figure 1. Bicyclic oximinocarboxylic acids. cyclohexene (8) with ethyl 3-bromo-2- Compounds 1.1 and 2.1 contain bromometylpropionate (9) [16-18]. As a result significantly distant carboxyl group, which we obtained bicyclic esters of anti-configuration probably does not affect the reaction behavior. (10, 11) due to steric factors. These esters was In turn, compounds 1.2 and 2.2 have close subjected to hydrolysis in aqueous LiOH carboxyl group, which is probably able to resulting anti-keto acids 3 and 4, another part of stabilize the transition state of the Beckman the esters 10 and 11 was isomerized in MeONa rearrangement by overlapping of vacant orbitals to syn-keto esters 12, 13 and then also of intermediate carbocations with the lone pairs hydrolyzed to syn-keto acids 5 and 6 of oxygen atoms of carboxyl groups and (Scheme 1). O O O OH contribute to obtaining products of normal O O N TEA 1. LiOH, r t, 20 h + H H reflux 3 h 2. HCl rearrangement or influence the reaction, Br Br n O n O n resulting in recyclization or fragmentation 7 (n = 1) 9 10 (n = 1) 3 (n = 1) 8 (n = 2) 11 (n = 2) 4 (n = 2) products. In addition, it should be noted that MeONa both types of bicyclic oximes have features that r t H H H HO O allow using them as convenient model O 1. LiOH, r t, 20 h 1. LiOH, r t, 20 h O O O compounds. Firstly, these oximes are not able to 2. HCl 2. HCl O O n HO 5 12 (n = 1) 6 deuterium exchange of the bridgehead α-protons 13 (n = 2) according to the Bredt`s rule. This greatly Scheme 1. Synthesis of syn- and anti-keto acids. facilitates rearrangement monitoring in a Spectral measurements showed solution of deuterated trifluoroacetic acid. differences between these acids. Syn-keto acid 6 Secondly, in the case of Beckmann exists in the lactole form, which shows the rearrangement regioisomeric products should spatial proximity of carbonyl and carboxylic not be expected due to the symmetry of the groups. In turn, anti-keto acid 4 does not have molecules, which contributes to easier such proximity of functional groups and lactole identification of the reaction products. is not formed. Despite the more electrophilic character of carbonyl group in keto acid 5 than in 6, bicyclo[3.2.1]octane-carboxylic acid 5 122 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2017, VOLUME 05, ISSUE 02) does not form lactole. This obviously indicates a ratio of 3: 2. The appearance of the lactone 16 greater spatial distance between carboxyl and could be explained by fragmentation process of carbonyl groups. oxyme 1.1 and recovering of cation by Beckman rearrangement was carried out neighboring carboxyl group (Scheme 3). COOH COOH by heating of oximino acids in trifluoroacetic H H O H + H COOH + acid (Scheme 2). + H - H O -H O + 2 N N N + O OH O OH HON H H H 1.1 O 16 TFA H H o + O 75 C, 6 h HN NC Scheme 3. Plausible mechanism of formation of lactone H HON n n n O 1.1 (n = 1) 14 (n = 1) 56% 16 (n = 1) 38% 16. 2.1 (n = 2) 15 (n = 2) 85% 17 (n = 2) 0% H H Conclusions HO HO TFA We can conclude that O o O no fragmentation 75 C, 6 h HN HON n n bicyclo[3.3.1]nonane skeleton is large enough to O 1.2 (n = 1) 18 (n = 1) 84% stabilize the 9-azabicyclo[3.3.2]decene 2.2 (n = 2) 19 (n = 2) 86% Scheme 2. Beckmann rearrangement of bicyclic oximes. carbocation transition state of normal Beckmann rearrangement, unlike the above mentioned The obtained data indicate that oximes bicyclo[2.2.1]heptanes. Therefore, several 2.1 and 2.2 in solution of trifluoroacetic acid at cationic transition states may exist, which a temperature of 73-75 °C after 6 hours promotes Beckmann rearrangement similar to completely converted to the corresponding oxime of cyclohexanone. Carboxyl group in lactams 15 and 19. Intermediate probes in compounds 2.1 and 2.2 does not participate deuterated trifluoroacetic acid show that the significantly in the reaction, although likely syn-oxime 2.2 reacts slightly faster than anti- contributes to more rapid progress in syn-oxime oxime 2.1. Conversion ratio for syn-/anti- 2.2. Considering that there is no fragmentation oximes was 31.5/23 after 1 h heating and 79/68 of syn-oxime 1.2 it is arguable that spatially after 3 h heating. contiguous carboxyl group stabilizes the Bicyclo[3.2.1]octane oximes 1.1 and 1.2 transition state, showing anchimeric assistance, react with the same speed, but in different promotes the formation of lactam. directions. syn-Oxime 1.2 underwent classical Experimental part Beckmann rearrangement forming lactam 18. All starting materials were purchased However, anti-oxime 1.1 gave a mixture of from Acros, Merck, Aldrich and Fluka products - lactam 14 (rearrangement product) chemicals. All solvents were distilled before use and lactone 16 (recyclization product) in the [19]. All experiments, unless otherwise stated, 123 FRENCH-UKRAINIAN JOURNAL OF CHEMISTRY (2017, VOLUME 05, ISSUE 02) 1 were carried under Argon atmosphere. The H Anal. calсd. for C9H13NO3: C, 59.00; H, 7.15; and 13C NMR spectra were recorded on a N, 7.65. Found: C, 58.89; H, 7.24; N, 7.59. “Mercury 400” Varian and Bruker AM 400 (400 MHz) spectrometers. Tetramethylsilane was syn-8-oximinobicyclo[3.2.1]octane-3-carboxylic used as an internal standard. Mass spectra ware acid (1.2). Yield of 93 %, a white solid, m.p. 1 recorded on Agilent 1100 LSMS SL instrument 135–138 °C; H NMR (400 МHz, DMSO-d6): with chemical ionization. Melting points are δ = 12.15 (br s, 1H, COOH), 10.07 (br s, 1H, N- uncorrected. OH), 3.18 (br s, 1Н), 2.74 (pent, 1Н, J = 7.4 Hz), 2.52 (s, 1Н), 1.96–1.92 (m, 1Н), 1.85–1.82 General method of preparation. anti- (m, 1H), 1.67–1.59 (m, 6H). 13C NMR (125 and syn-8-oximinobicyclo[3.2.1]octane- and 9- МHz, DMSO-d6): δ = 176.17, 166.86, 38.13, oximinobicyclo[3.3.1]nonane-3-carboxylic 37.46, 35.42, 34.14, 31.61, 25.27, 25.12. Anal. acids (1.1, 1.2, 2.1, 2.2). Hydroxylamine calсd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. hydrochloride (6 mmol) and pyridine (6 mmol) Found: C, 58.86; H, 7.25; N, 7.57. was added to a stirred solution of 5 mmol of keto acid (compounds 3-6) in 2-propanol. The anti-9-oximinobicyclo[3.3.1]nonane-3- reaction mixture was heated under reflux for 5 carboxylic acid (2.1). Yield of 89 %, a white h. After that, the reaction was evaporated under solid, m.p. 185–187 °C; 1H NMR (400 МHz, reduced pressure and 100 ml of distilled water DMSO-d6): δ = 11.87 (br s, 1H, COOH), 9.95 was added to the residue.
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