Chapitre 3 : Agrandissements de pyrrolidines 2-iodométhylées
V. Résultats et discussion
V.3. Champ d’application
V.3.3. Cas particulier d’AgBF 4
Il a été constaté (Tableau 20, entrée 4) que l’utilisation de tétrafluoroborate d’argent à -15 °C pour réaliser l’agrandissement de cycle de 3.8, sous contrôle cinétique, en présence de méthanol conduisait à la pyrrolidine fluorée 3.9 en plus des composés 3.19 et 3.20 issus de l’ouverture de l’aziridinium par le méthanol (Schéma 152). Le produit 3.9 proviendrait a priori de l’ouverture de l’aziridinium formé à partir de 3.8 par un ion fluorure provenant de l’anion BF4 qui jouerait le rôle d’un nucléophile en compétition avec le méthanol.147 Cependant, il est intéressant de noter que la pipéridine 3.9 a été le seul produit fluoré formé lors de cette réaction et qu’aucune trace de la pyrrolidine 2-fluorométhylée 3.10 n’a été observée.
147 Le transfert d’un ion fluorure de l’anion BF4 à des espèces électrophiles a déjà été observé en présence de complexes métalliques très électrophiles. Voir : Reger, D. L.; Watson, R. P.; Gardinier, J. R.; Smith, M. D.; Pellechia, P. J. Inorg. Chem. 2006, 45, 10088–10097.
160
Schéma 152
La sélectivité de l’attaque de l’ion fluorure sur l’aziridinium semble nettement plus importante que celle des autres nucléophiles que nous avons utilisés jusqu’à présent. Pour tenter de tirer parti de cet avantage, nous avons souhaité optimiser les conditions pour augmenter le rendement en produit 3.9. Une réaction d’agrandissement de 3.8 a été réalisée en présence d’AgBF4 (1,5 équiv), dans le dichlorométhane sans ajout de nucléophile (Schéma 153). Dans ces conditions, après 1 h de réaction à -15 °C, la pipéridine 3.9 a été obtenue et isolée avec un rendement de 49% et, à nouveau, aucune trace de la pyrrolidine 3.10 n’a été détectée. Notons que cette réaction a fourni par ailleurs un mélange complexe de produits en plus du composé souhaité 3.9.
Schéma 153
L’obtention d’un mélange complexe de produits à l’issue du précédent essai pourrait expliquer le modeste rendement en produit 3.9 obtenu (49%). En effet, le transfert d’un ion fluorure de l’anion BF4à l’aziridinium 3.52 pourrait induire la formation de trifluoroborane. Ce composé ayant un caractère acide de Lewis très fort, il est possible qu’il soit responsable de la dégradation du produit 3.9 (Schéma 154).
161
Schéma 154
Nous nous sommes demandés si l’ajout d’un additif tel que l’éther diéthylique (Et2O), pouvant piéger le BF3 potentiellement libéré lors de la formation de 3.9, empêcherait la formation des produits secondaires. Pour tester cette hypothèse, un premier essai a été réalisé en utilisant l’Et2O en tant que solvant (Schéma 155). Cependant, à l’issue de cette réaction, aucune trace du produit fluoré 3.9 n’a été observée et les produits 3.53 et 3.54 issus de la réaction de l’éther diéthylique sur l’aziridinium ont été obtenus. Ces produits ont été isolés sous la forme d’un mélange inséparable, dans des proportions respectives de 85:15 et avec un excellent rendement global de 98%. Lorsque la quantité d’éther diéthylique a été réduite à 1,5 équivalent, les mêmes produits 3.53 et 3.54 ont été isolés, accompagnés cette fois-ci d’une faible quantité de la pipéridine souhaitée 3.9 (20%).
Schéma 155
Suite à ces observations, nous avons décidé de reprendre le premier essai réalisé sans additif (Schéma 153) en réduisant le temps de réaction, espérant ainsi obtenir la pipéridine fluorée 3.9 avec un bon rendement. C’est en réduisant le temps de contact entre la pyrrolidine
3.8 et le tétrafluoroborate d’argent à 0,25 h que la pipéridine 3-fluorée 3.9 a pu être obtenue
162
Schéma 156
Ces résultats montrent donc qu’il est possible d’obtenir la pipéridine 3-fluorée 3.9 par agrandissement de la pyrrolidine 2-iodométhylée 3.8 en présence de tétrafluoroborate d’argent avec une sélectivité totale et un bon rendement et que l’aziridinium formé à partir de 3.8 peut aisément réagir avec les éthers.
VI. Conclusion
L’agrandissement de cycle de pyrrolidines N-tosylées 2-iodométhylées en présence de sels d’argent permet d’accéder à des pipéridines fonctionnalisées en position C3 par formation d’une liaison carbone-oxygène, carbone-azote, carbone-fluor ou carbone-carbone avec de bonnes sélectivités en faveur du produit d’agrandissement de cycle (Schéma 157). Dans le cas particulier de l’utilisation du tétrafluoroborate d’argent, des pipéridines 3-fluorées ont été obtenues avec une sélectivité totale. A ce jour, 12 produits d’agrandissement de cycle ont été obtenus.
La conservation de l’excès énantiomérique du produit de départ au cours de la réaction nous a permis de montrer que l’agrandissement de cycle passait par un aziridinium intermédiaire. L’aziridinium obtenu à partir de la pyrrolidine N-tosylée 2-iodométhylée montre un caractère électrophile très fort qui lui permet de réagir avec des composés éthérés ainsi qu’avec l’anion BF4– par transfert d’un ion fluorure.
163 En termes de perspectives, le champ d’application de la méthode pourrait être étendu en réalisant des agrandissements de cycle à l’aide d’autres nucléophiles tels que des thiols, des cyanures ou encore des composés organométalliques (RMgX, R2CuLi).
Par ailleurs, nous avons déjà constaté que cette réaction fonctionnait à partir d’oxazinanes iodométhylées, Il serait intéressant de voir si la réaction est applicable à des hétérocycles de différentes tailles et de différentes natures tels que des pipéridines ou des isoxazolidines iodométhylées.
165
167 Au cours de nos travaux, nous avons développé une méthode de synthèse d’hétérocycles saturés oxygénés 2-aminométhylés par oxyamination cyclisante de N-tosylalcoxyamines O-alcénylées catalysée par des complexes de rhodium(III). Cette réaction permet d’accéder à des tétrahydrofuranes et tétrahydropyranes -aminométhylés ainsi qu’à des plateformes bicycliques intéressantes, présentes dans des composés d’intérêt biologique.
Nous avons également montré qu’il était possible d’accéder à des 3-iodo-1,2-oxazinanes par iodocyclisation des mêmes alcoxyamines insaturées.
Le traitement des oxazinanes ainsi obtenus par du fluorure d’argent nous a permis de mettre en évidence une réaction d’agrandissement de cycle stéréosélective. Suite à ce constat, nous avons développé des conditions réactionnelles permettant de réaliser l’agrandissement de cycle de N-tosyl-2-iodométhylpyrrolidines pour obtenir des pipéridines fonctionnalisées en position C3 par des groupements oxygénés, azotés, carbonés et fluorés avec de très bonnes sélectivités.
169
171
Annexe 1
Synthèse du composé 2.229 :
Le composé 2.229 a été synthétisé en appliquant la séquence alkylation/réduction suivie de la séquence Mitsunobu/déprotection de l’amine/N-tosylation à partie de l’isobutyrate de méthyle 2.11. L’alkylation de 2.11 à l’aide de 3-chloroprop-1-yn-1-ylbenzene en présence de LDA a conduit avec un rendement de 97% à l’ester A1.1 qui a ensuite été réduit par LiAlH4 ce qui a mené à l’alcool bis-homopropargylique A1.2 avec un rendement de 93%. La réaction de l’alcool
A1.2, dans les conditions de Mitsunobu avec le N-hydroxyphtalimide, a permis d’obtenir
l’alcoxyphtalimide A1.3 qui a été isolé avec un rendement de 25%. La coupure du phtalimide par l’hydrazine a ensuite conduit à l’alcoxyamine libre A1.4 (84%) qui a été N-tosylée pour fournir le produit 2.229, isolé avec un rendement de 72%.
173
175
General experimental methods
The nomenclature of organic compounds follows the rules recommended by IUPAC. The numbering of the atoms does not correspond to the nomenclature and is only used for the attribution of the signals in the NMR spectra.
Reactions run under anhydrous conditions were realized using flame-dried glassware and under an atmosphere of argon. CH2Cl2, Cl(CH2)2Cl, toluene and iPr2NH were dried over CaH2
and distilled and THF and Et2O were distilled from Na/benzophenone before to use. Other reagents were used as received from commercial supplier.
Analytical thin layer chromatography (TLC) was performed on Merk 60F254 silica gel plates with UV and p-anisaldehyde or KMnO4 stain visualization. Flash chromatography was performed on silica gel (230-400 mesh).
Melting points (Mp) were recorded using a Wagner & Munz Kofler bench or a Thomas-Hoover melting point apparatus in open capillaries. Optical rotations were measured with a Perkin Elmer model 343 polarimeter with a 1 dm path length. Infrared (IR) spectra were recorded on a Bruker TENSORTM 27 (IRFT) on an ATR plate, wave numbers are indicated in cm-1. NMR was performed on a Bruker Avance-1 400 instrument. 1H NMR spectra were recorded at 400 MHz in CDCl3 or deuterated benzene C6D6 and data are reported as follows: chemical shift in ppm from tetramethylsilane or residual solvent signals (CHCl3: 7.26 ppm, C6D5H: 7.16 ppm) as an internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, pent = pentuplet, sep = septet, m = multiplet or overlap of non-equivalent resonances, br = broad), coupling constant in Hz, integration, attribution. 13C NMR spectra were recorded at 100 MHz in CDCl3 or C6D6 and data are reported as follows: chemical shift in ppm with tetramethylsilane with the solvent as an internal indicator (CDCl3: 77.16 ppm, C6D6: 128.06 ppm), multiplicity, with respect to proton (deduced from DEPT experiment, s = quaternary, d = CH, t = CH2, q = CH3), attribution. Mass spectra (MS) were obtained with a Shimadzu (GCMS-QP2010S gas chromatograph-mass spectrometer. High resolution mass spectra (HRMS) were performed by the Groupe de Spectrométrie de Masse de l’Université Pierre et Marie Curie (Paris, France).
177
Rhodium(III)-catalysed intramolecular
oxyamination of unsaturated alcoxyamines
179
General procedures
General procedure for the alkylation of esters (A).
To a solution of iPrNH2 (1.1 equiv) in THF (0.4 M) at -78 °C was added dropwise n-BuLi (2.5 M in hexanes, 1.08 equiv). After 0.25 h at -78 °C, the ester (1 equiv) was slowly added and stirring was continued at the same temperature. After 0.2 h, the alkylating agent (1.2 equiv) was added and the reaction mixture was allowed to warm to rt. After 16 h, a saturated aqueous solution of NH4Cl was added. The two phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to obtain the desired alkylated ester.
General procedure for the reduction of esters (B)
To a suspension of LiAlH4 (1.5 equiv) in Et2O (0.4 M) at 0 °C was slowly added an Et2O solution of the previously obtained ester (1 M, 1 equiv). The reaction mixture was stirred at 0 °C until complete conversion of the starting material was observed by TLC analysis (usually 1 h). Water was added very slowly until no more gas evolution was observed. Then, more water was added and stirring was pursued at rt until the reaction mixture became white. The reaction mixture was filtered on a pad of Celite® and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel to obtain the desired alcohol.
General procedure for the Mitsunobu reaction with N-hydroxyphthalimide (C)
To a solution of the alcohol (1 equiv) in THF (0.2 M) at rt were added PPh3 (1.2-1.5 equiv) and N-hydroxyphthalimide (1.2-1.5 equiv). The reaction mixture was cooled down to 0 °C before DIAD (1.1-1.5 equiv) was added dropwise. The reaction mixture was stirred at rt for 16 h or less if total conversion was indicated by TLC. The solvent was evaporated under reduced pressure and the product was purified by silica gel flash chromatography on silica gel to obtain the alcoxyphthalimide.
180
General procedure for the Ing-Manske phthalimide cleavage (D)
To a solution of the phthalimide (1 equiv) in THF (0.4 M) was added hydrazine hydrate (67% in water, 5 equiv). The reaction mixture quickly became yellow before to fade and produce a white precipitate. The reaction mixture was stirred at rt until complete conversion of the starting material was observed by TLC analysis (usually 1 h). Et2O and water were added, the two formed phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on Et3N-neutralized silica gel to obtain the free alcoxyamine.
General procedure for the tosylation of the free alcoxyamine (E)
To a solution the free alcoxyamine (1 equiv) in CH2Cl2 at rt was added TsCl (1.2 equiv) followed by pyridine (3 equiv). The reaction mixture was stirred at rt until complete conversion of the starting material was observed by TLC analysis (typically 16 h). Water was added, the phases were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 10% aqueous HCl and with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel to obtain the sulfonamide.
General procedure for the rhodium(III)-catalyzed intramolecular oxyamination
of N-tosylalcoxyamines (F)
To a solution of the N-tosylalcoxyamine (1 equiv) in Cl(CH2)2Cl at rt in a microwave tube was added Cu(OAc)2 (2.1 equiv) followed by [Cp*Rh(MeCN)3](SbF6)2 (5 mol %). The tube was sealed and heated to 95 °C in a sand bath until complete conversion of the starting material was observed by TLC analysis. The reaction mixture was filtered on a pad of celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel to afford the cyclized product.
181
Methyl cyclopentanecarboxylate (2.7)
C7H12O2
M = 128,17 g/mol
To a solution of cyclopentanecarboxylic acid 2.6 (1.05 g, 9.3 mmol, 1 equiv) and MeOH (380 mg, 11.2 mmol, 1,2 equiv) in CH2Cl2 at 0 °C was added EDCI (1.73 g, 11.2 mmol, 1.2 equiv) followed by DMAP (1.14 g, 9.3 mmol, 1 equiv). The reaction mixture was stirred at rt until complete conversion of the starting material was observed by TLC analysis (3 h). A saturated aqueous solution of NH4Cl was added, the two formed phases were separated and the aqueous phase was extracted with CH2Cl2. After the combined organic layers were washed with brine and dried over MgSO4, filtration on silica gel and evaporation of the solvents afforded pure 2.7 (977.3 mg, 7.63 mmol, 82%) as a colorless liquid. The spectral data match those reported in the literature.148
IR: 2953, 2872, 1732, 1435, 1362, 1311, 1265, 1196, 1158, 1041, 1008 cm-1. 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H, H5), 2.72 (pentapp, J = 8.0 Hz, 1H, H1), 1.92 – 1.51 (m, 8H, H2, H3). 13C NMR (100 MHz, CDCl3):δ 177.4 (s, C4), 51.7 (q, C5), 43.8 (d, C1), 30.1 (t, 2C2), 25.9 (t, 2C3). MS (EI) m/z: 128 (M+●,9), 100 (17), 97 (19), 87 (100), 69 (51), 68 (19), 67 (13), 55 (19). tert-Butyl cyclopropanecarboxylate (2.9) C8H14O2 M = 142.20 g/mol
To a suspension of t-BuOK (6.70 g, 57.73 mmol, 1 equiv) in t-BuOMe (70 mL) at 0 °C was added dropwise cyclopropanecarbonyl chloride 2.8 (6.24 g, 59.73 mmol, 1 equiv). The reaction thick mixture was stirred at 0 °C until no more starting material was observed by IR analysis (3 h). A saturated aqueous solution of NaHCO3 was added, the two formed phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with
182 brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product were distillated under vacuum (T = 35 °C/P = 9 Torr) to afford 2.9 (3.14 g, 22.10 mmol, 37%) as a colorless liquid. The spectral data match those reported in the literature.149
IR: 2976, 2935, 2864, 1725, 1448, 1388, 1367, 1284, 1257, 1211, 1154, 1120, 1085, 1028 cm-1. 1H NMR (400 MHz, CDCl3): δ 1.50 (m, 1H, H2), 1.44 (s, 9H, H5), 0.92 – 0.88 (m, 2H, H1), 0.79 – 0.74 (m, 2H, H1). 13C NMR (100 MHz, CDCl3):δ 174.3 (s, C=O), 80.2 (s, Ct-Bu), 28.3 (q, 3C5), 14.0 (d, C2), 8.1 (t, 2C1). MS (EI) m/z: 87 (39), 69 [(M-Ot-Bu)+ , 73], 57 [(t-Bu)+, 100], 56 (37). Ethyl 2-isopropylpent-4-enoate (2.14) C10H18O2 M = 170.23 g/mol
Prepared from methyl isovalerate 2.10 (878.8 mg, 6.76 mmol) and allyl bromide 2.13 (981.3 mg, 8.11 mmol) following general alkylation procedure A. Purification by flash chromatography on silica gel (PE/AcOEt = 95:5) yielded 2.14 (1.07 g, 6.29 mmol, 93%) as a colorless liquid. The spectral data match those reported in the literature.150
1H NMR (400 MHz, CDCl3): δ 5.78 – 5.68 (m, 1H, H2), 5.07 – 5.01 (m, 1H, H1), 4.97 (ddq, J = 10.2, 2.1, 1.1 Hz, 1H, H1), 4.17 – 4.06 (m, 2H, H8), 2.34 – 2.15 (m, 3H, H3 and H4), 1.87 (dsep, J = 6.8, 6.9 Hz, 1H, H5), 1.24 (t, J = 7.2 Hz, 3H, H9), 0.94 (d, J = 6.7 Hz, 3H, H6), 0.91 (d, J = 6.7 Hz, 3H, H6).
13C NMR (100 MHz, CDCl3):δ 175.1 (s, C7), 136.1 (d, C2), 116.4 (t, C1), 60.0 (t, C8), 52.5 (d, C4), 34.1 (t, C3), 30.4 (d, C5), 20.4 (q, C6), 20.3 (q, C6), 14.5 (q, C9).
MS (EI) m/z: 155 [(M-Me)+, 6], 129 [(M-allyl)+, 6], 128 (46), 127 ( 67), 125 [(M-OEt)+, 17], 101 (12), 100 (34), 99 (75), 97 [(M-CO2Et)+, 31], 83 (12), 82 (13), 81 (28), 69 (20), 56 (13), 55 (100), 54 (11), 53 (13).
149 Yang, D.; Cwynar, V.; Donahue, M. G.; Hart, D. J.; Mbogo, G. J. Org. Chem. 2009, 74, 8726–8732.
150 Ayala, L.; Lucero, C. G.; Antoinette, J.; Romero, C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528.
183
Methyl 2,2-dimethylpent-4-enoate (2.15)
C8H14O2
M = 142.20 g/mol
Prepared from methyl isobutyrate 2.11 (3.00 g, 29.4 mmol) and allyl bromide 2.13 (4.27 g, 35.3 mmol) following general alkylation procedure A. Purification by flash chromatography on silica gel (PE/Et2O = 95:5) yielded 2.15 (3.02 g, 21.2 mmol, 72%) as a colorless liquid. The spectral data match those reported in the literature.151
IR: 3080, 2977, 1732, 1641, 1471, 1435, 1388, 1367, 1304, 1253, 1206, 1147, 1089 cm-1.
1H NMR (400 MHz, CDCl3): δ 5.72 (m, 1H, H2), 5.05 – 5.01 (m, 2H, H1), 3.66 (s, 3H, H7), 2.27 (dt, J = 7.5, 1.2 Hz, 2H, H3), 1.17 (s, 6H, H5).
13C NMR (100 MHz, CDCl3):δ 178.0 (s, C6), 134.2 (d, C2), 117.8 (t, C1), 51.7 (q, C7), 44.7 (t, C3), 42.3 (s, C4), 24.8 (q, C5).
MS (EI) m/z: 142 (M+•,2), 127 [(M-Me)+,15], 111 [(M-OMe)+, 7], 110 (9), 101 [(M-allyl)+, 8], 95 (9), 84 (7), 83 [(M-CO2Me)+, 100], 82 (20), 73 (35), 70 (6), 69 (16), 67 (22), 59 (20), 56 (6), 55 (76), 53 (6).
Methyl 1-allylcyclohexane-1-carboxylate (2.16)
C11H18O2
M = 182.26 g/mol
Prepared from methyl cyclohexanecarboxylate 2.12 (500 mg, 3.5 mmol) and allyl bromide 2.13 (510.5 mg, 4.2 mmol) following general alkylation procedure A. Purification by flash chromatography on silica gel (PE/Et2O = 95:5) yielded 2.16 (612.0 mg, 3.36 mmol, 80%) as a colorless liquid. The spectral data match those reported in the literature.152
151 Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.; Covel, J. A. J. Am. Chem. Soc. 2011, 133, 744–747. 152 Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988–2995.
184
IR: 3078, 2934, 2856, 1731, 1640, 1453, 1434, 1357, 1328, 1384, 1211, 1157, 1135, 1039
cm-1.
1H NMR (400 MHz, CDCl3): δ 5.68 (ddt, J = 16.4, 10.6, 7.4 Hz, 1H, H2), 5.03 – 4.97 (m, 2H, H1), 3.66 (s, 3H, H9), 2.22 (dtapp, J = 7.5, 1.2 Hz, 2H, H3), 2.06 – 2.02 (m, 2H, H5 or H6 or H7), 1.61 – 1.50 (m, 3H, H5 and/or H6 and/or H7), 1.38 – 1.17 (m, 5H, H5 and/or H6 and/or H7).
13C NMR (100 MHz, CDCl3):δ 176.9 (s, C=O), 133.8 (d, C2), 117.7 (t, C1), 51.5 (q, C9), 47.5 (s, C4), 44.8 (t, C3), 33.9 (t, 2C5 or 2C6), 25.9 (t, C7), 23.3 (t, 2C5 or 2C6).
MS (EI) m/z: 182 (M+●, 3), 167 [(M-Me)+, 1], 140 (8), 123 [(M-CO2Me)+, 26], 122 (13), 109 (12), 81 (100), 79 (17), 67 (27), 59 (10), 55 (17), 53 (12).
HRMS (ESI): Calculated for C11H18O2Na [M+Na]+ : 205.1199, Found : 205.1199.
Methyl 1-allylcyclopentane-1-carboxylate (2.17)
C10H16O2
M = 168,24 g/mol
Prepared from 2.7 (956.3 g, 7.47 mmol) and allyl bromide 2.13 (3.2 g, 26.47 mmol) following general alkylation procedure A. Purification by flash chromatography on silica gel (PE/Et2O = 40:1) yielded 2.17 (766.6 mg, 4.56 mmol, 61%) as a colorless liquid.
IR: 3078, 2952, 2873, 1730, 1641, 1435, 1336, 1275, 1196, 1162 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.70 (ddt, J = 16.8, 10.4, 7.2 Hz, 1H, H2), 5.05 – 4.99 (m, 2H, H1), 3.66 (s, 3H, H8), 2.35 (dt, J = 7.2, 1.2 Hz, 2H, H3), 2.10 – 2.04 (m, 2H, H5), 1.66 – 1.50 (m, 6H, H5 and H6). 13C NMR (100 MHz, CDCl3):δ 178.1 (s, C7), 135.1 (d, C2), 117.4 (t, C1), 53.9 (s, C4), 51.9 (q, C8), 43.1 (t, C3), 35.7 (t, 2C5), 25.1 (t, 2C6).
MS (EI) m/z: 153 [(M-Me)+, 2], 137 [(M-OMe)+, 3], 136 (8), 127 (7), 126 (6), 110 (6), 109 (69), 108 (19), 95 (16), 93 (10), 79 (11), 67 (100), 59 (11), 55 (13).
185
tert-Butyl 1-allylcyclopropane-1-carboxylate (2.18)
C11H18O2
M = 182.26 g/mol
Prepared from 2.9 (3.13 g, 22.06 mmol) and allyl bromide 2.13 (3.2 g, 26.47 mmol) following general alkylation procedure A. Purification by flash chromatography on silica gel (PE/Et2O = 40:1) yielded 2.18 (2.17 g, 11.91 mmol, 54%) as a colorless liquid. The spectral data match those reported in the literature.153
IR: 3078, 3006, 2978, 2931, 1718, 1640, 1420, 1392, 1367, 1353, 1227, 1151, 1027 cm-1.
1H NMR (400 MHz, CDCl3): δ 5.85 (ddt, 1H, H2), 5.05 – 4.98 (m, 2H, H1), 2.27 (dd, J = 6.7, 1.4 Hz, 2H, H3), 1.42 (s, 9H, H8), 1.12 (dd, J = 6.8, 4.0 Hz, 2H, H5), 0.66 – 0.63 (m, 2H, H5).
13C NMR (100 MHz, CDCl3):δ 174.3 (s, C=O), 136.2 (d, C2), 116.1 (t, C1), 80.2 (s, C7), 37.7 (t, C3), 28.2 (q, 3C8), 23.6 (s, C4), 14.8 (t, 2C5).
MS (EI) m/z: 126 (37), 111 (13), 109 [(M-Ot-Bu)+, 17], 83 (12), 81 [(M-CO2t-Bu)+, 51], 80 (18), 79 (21), 67 (10), 57 (t-Bu+, 100), 56 (16), 53 (14).
2-Isopropylpent-4-en-1-ol (2.19)
C8H16O M = 128.22 g/mol
Prepared from 2.14 (1.05 g, 6.17 mmol) following general reduction procedure B. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1) yielded 2.19 (703.3 g, 5.49 mmol, 89%) as a colorless liquid. The spectral data match those reported in the literature.154
IR: 3333, 3077, 2958, 2929, 2874, 1640, 1467, 1440, 1416, 1387, 1368, 1211, 1178, 1130, 1041 cm-1.
153 Häner, R.; Maetzke, T.; Seebach, D. Helv. Chim. Acta 1986, 69, 1655–1665. 154 Kraft, P.; Denizot, N. Eur. J. Org. Chem. 2013, 2013, 49–58.
186 1H NMR (400 MHz, CDCl3): δ 5.84 (m, 1H, H2), 5.04 – 5.09 (m, 1H, H1), 5.02 – 4.99 (m, 1H, H1), 3.64 – 3.56 (m, 2H, H7), 2.21 – 2.14 (m, 1H, H3), 2.08 – 2.00 (m, 1H, H3), 1.86 – 1.76 (m, 1H, H5), 1.50 – 1.40 (m, 2H, OH and H4), 0.92 (d, J = 3.6 Hz, 3H, H6), 0.90 (d, J = 3.6 Hz, 3H, H6). 13C NMR (100 MHz, CDCl3):δ 138.3 (d, C2), 116.0 (t, C1), 63.9 (t, C7), 46.6 (d, C4), 33.1 (t, C3), 28.1 (d, C5), 20.1 (q, C6), 19.5 (q, C6). MS (EI) m/z: 110 [(M-H2O)+● 6], 97 (14), 96 (8), 95 (81), 86 (20), 82 (18), 81 (25), 71 (51), 69 (74), 68 (42), 67 (55), 57 (30), 56 (43), 55 (100), 54 (38), 53 (17). 2,2-Dimethylpent-4-en-1-ol (2.20) C7H14O M = 114.19 g/mol
Prepared from 2.15 (2.98 g, 21.0 mmol) following general alkylation procedure B. Purification by flash chromatography on silica gel (PE/AcOEt = 8:2) yielded 2.20 (2.20 g, 19.3 mmol, 92%) as a colorless liquid. The spectral data match those reported in the literature.155
IR: 3347, 3076, 2958, 2930, 2871, 1831, 1640, 1605, 1472, 1439, 1415, 1388, 1365, 1293, 1260, 1165, 1039 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.85 (m, 1H, H2), 5.08 – 5.02 (m, 2H, H1), 3.33 (s, 2H, H6), 2.02 (dt, J = 7.5, 1.2 Hz, 2H, H3), 1.44 (br s, 1H, OH), 0.89 (s, 6H, H5). 13C NMR (100 MHz, CDCl3):δ 135.3 (d, C2), 117.1 (t, C1), 71.7 (t, C6), 43.4 (t, C3), 35.5 (s, C4), 23.8 (q, 2C5). MS (EI) m/z: 95 (9), 83 (14), 81 (13), 73 [(M-allyl)+, 66], 72 (13), 55 (100). (1-Allylcyclohexyl)methanol (2.21) C10H18O M = 154.25 g/mol
187 Prepared from 2.16 (500 mg, 2.75 mmol) following reduction procedure B. Purification by flash chromatography on silica gel (PE/AcOEt = 8:2) yielded 2.21 (423.9 mg, 2.75 mmol, quant) as a colorless liquid. The spectral data match those reported in the literature.156
IR: 3344, 3074, 3003, 2923, 2852, 1825, 1638, 1453, 1414, 1291, 1269, 1234, 1173, 1129, 1028 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.86 (ddt, J = 17.0, 10.1, 7.6 Hz, 1H, H2), 5.10 – 5.03 (m, 2H, H1), 3.42 (s, 2H, H8), 2.12 (dtapp, J = 7.6, 1.2 Hz, 2H, H3), 1.46 – 1.30 (m, 11H, H5, H6, H7, OH). 13C NMR (100 MHz, CDCl3):δ 135.5 (d, C2), 117.2 (t, C1), 68.9 (t, C8), 40.1 (t, C3), 37.9 (s, C4), 32.4 (t, 2C5 or 2C6), 26.5 (t, C7), 21.6 (t, 2C5 or 2C6). MS (EI) m/z: 136 [(M-H2O) +●,2], 113 [(M-allyl)+, 15], 112 (8), 96 (9), 95 (100), 81 (34), 79 (16), 69 (17), 67 (49), 55 (31), 53 (13). (1-Allylcyclopentyl)methanol (2.22) C9H16O M = 140,23 g/mol
Prepared from 2.17 (752.9 mg, 4.48 mmol) following general reduction procedure B. Purification by flash chromatography on silica gel (PE/Et2O = 8:2) yielded 2.22 (626.3 mg, 4.47 mmol, 59%) as a colorless liquid. The spectral data match those reported in the literature.157
IR: 3347, 3075, 2948, 2866, 1829, 1638, 1439, 1415, 1327, 1231, 1036 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.85 (ddt, J = 17.0, 10.1, 7.4 Hz, 1H, H2), 5.11 – 5.02 (m, 2H, H1), 3.39 (s, 2H, H7), 2.15 (dtapp, J = 7.4, 1.2 Hz, 2H, H3), 1.62 – 1.37 (m, 9H, H5, H6, OH). 13C NMR (100 MHz, CDCl3):δ 136.3 (d, C2), 117.1 (t, C1), 69.1 (t, C7), 47.3 (s, C4), 42.1 (t, C3), 34.2 (t, 2C5), 25.3 (t, 2C6). MS (EI) m/z: 140 (M+●, 1), 122 [(M-H20) +●, 3)] 109 (9), 99 (15), 98 (14), 81 (100), 79 (26), 67 (52), 57 (10), 55 (27), 53 (12).
HRMS (ESI): Calculated for C9H16ONa [M+Na]+ : 163.1093, Found : 163.1094.
156 Fujita, S.; Abe, M.; Shibuya, M.; Yamamoto, Y. Org. Lett. 2015, 17, 3822–3825.
157 Bovino, M. T.; Liwosz, T. W.; Kendel, N. E.; Miller, Y.; Tyminska, N.; Zurek, E.; Chemler, S. R. Angew. Chem. Int. Ed. 2014, 53, 6383–6387.
188
(1-Allylcyclopropyl)methanol (2.23)
C7H12O M = 112.17 g/mol
Prepared from 2.18 (2.16 g, 11.88 mmol) following general reduction procedure B. Purification by flash chromatography on silica gel (PE/Et2O = 8:2) yielded 2.23 (785.3 g, 7.01 mmol, 59%) as a colorless liquid. The spectral data match those reported in the literature.153
IR: 3330, 3076, 3002, 2977, 2911, 2872, 1834, 1640, 1429, 1383, 1365, 1319, 1279, 1239, 1205, 1110, 1029 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.84 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H, H2), 5.10 (ddt, J = 17.1, 2.1, 1.4, Hz, 1H, H1), 5.04 (ddt, J = 10.1, 2.1, 1.0 Hz, 1H, H1), 3.42 (s, 2H, H6), 2.17 (dtapp, J = 7.1, 1.2 Hz, 2H, H3), 1.51 (br s, 1H, OH), 0.41 (s, 4H, H5). 13C NMR (100 MHz, CDCl3):δ 136.3 (d, C2), 116.7 (t, C1), 69.0 (t, C6), 38.6 (t, C3), 22.2 (s, C4), 9.5 (t, 2C5). MS (EI) m/z: 94 [(M-H2O)+●, 6], 91 (5), 84 (34), 83 (54), 81 (23), 79 (75), 77 (18), 71 [(M-allyl)+, 11], 70 (12), 69 (20), 68 (13), 67 (32), 66 (20), 65 (14), 57 (19), 56 (44), 55 (100), 54 (16), 53 (38), 51 (14). 3,3-Dimethylpent-4-en-1-ol (2.26) C7H14O M = 114,19 g/mol
To a solution of 3-methylbut-2-en-1-ol 2.24 (5 g, 58.1 mmol, 1 equiv) in MeC(OEt)3 (67.5 g, 406.4 mmol, 7 equiv) at rt was added propionic acid (257.8 mg, 3.48 mmol, 6 mol %). The reaction mixture was stirred at 150 °C for 21 h before to be cooled down to rt and poured onto a mixture of ice (100 g) and sulfuric acid (5 mL). The resulting opaque mixture was stirred at rt for 20 h after what it became clear. Et2O was added, the two formed phases were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with a saturated aqueous solution of NaHCO3 and with brine, dried over MgSO4, filtered and
189 concentrated under reduced pressure. The crude product was distillated under vacuum (42.3 °C, 9 Torr) to afford impure ethyl 3,3-dimethylpent-4-enoate 2.25 (2.38 g) as colorless liquid which was immediately used in the next step. Compound 2.25 was treated following general reduction procedure B. Purification by flash chromatography on silica gel (PE/Et2O = 7:3) yielded 2.26 [596.7 g, 5.23 mmol, 9% (2 steps)] as a colorless liquid. The spectral data match those reported in the literature.158
IR: 3322, 3083, 2961, 2931, 2361, 1641, 1461, 1212, 1380, 1363, 1264, 1158, 1052, 1002 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.83 (dd, J = 17.3, 10.8 Hz, 1H, H2), 4.97 – 4.92 (m, 2H, H1), 3.64 (t, J = 7.2 Hz 2H, H6), 1.61 (t, J = 7.2 Hz, 2H, H5), 1.52 (m, 1H, OH), 1.02 (s, 6H, H4). 13C NMR (100 MHz, CDCl3):δ 148.3 (d, C2), 110.9 (t, C1), 60.2 (t, C6), 45.2 (t, C5), 35.9 (s, C3), 27.2 (q, 2C4). MS (EI) m/z: 96 [(M-H2O) +●,17), 83 (15), 82 (7), 81 (100), 79 (16), 71 (12), 70 (47), 69 (99), 68 (11), 67 (22), 56 (11), 55 (79), 53 (25). 2-[(2-Isopropylpent-4-en-1-yl)oxy]isoindoline-1,3-dione (2.27) C16H19NO3 M = 273.34 g/mol
Prepared from 2.19 (624.2 mg, 4.95 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 95:5) yielded 2.27 (1.05 g, 3.84 mmol, 78%) as a colorless oil.
IR: 2959, 1789, 1728, 1640, 1610, 1467, 1392, 1370, 1291, 1187, 1159, 1128, 1082, 1065, 1017 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.84 – 7.80 (m, 2H, HAr), 7.76 – 7.71 (m, 2H, HAr), 5.86 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H, H2), 5.11 (dddapp, J = 17.1, 3.5, 1.5 Hz, 1H, H1), 5.04 (ddt, J = 10.1, 2.1, 1.1 Hz, 1H, H1), 4.17 (ddABsyst, J = 8.4, 5.9 Hz, 1H, H7), 4.12 (ddABsyst, J = 8.5, 5.8 Hz, 1H, H7), 2.31 – 2.18 (m, 2H, H3), 1.98 (m, 1H, H5), 1.76 (m, 1H, H4), 0.99 (d, J = 6.9 Hz, 6H, H6).
190
13C NMR (100 MHz, CDCl3):δ 163.6 (s, 2C=O), 137.0 (d, C2), 134.5 (d, 2CHAr), 129.2 (s, 2CqAr), 123.5 (d, 2CHAr), 116.7 (t, C1), 79.2 (t, C7), 43.3 (d, C4), 32.6 (t, C3), 28.0 (d, C5), 19.7 (q, C6), 19.5 (q, C6).
MS (EI) m/z: 164 (5), 163 [(HONPhth)+●, 8], 111 [(M-ONPhth)+, 21], 110 (24), 104 (10), 95 (14), 69 (100), 67 (10), 57 (12), 55 (51).
HRMS (ESI): Calculated for C16H19NO3Na [M+Na]+ : 296.1257, Found : 296.1253.
2-[(2,2-Dimethylpent-4-en-1-yl)oxy]isoindoline-1,3-dione (2.28)
C15H17NO3
M = 259.31 g/mol
Prepared from 2.20 (2.11 g, 18.5 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1) yielded 2.28 (2.54 g, 9.8 mmol, 53%) as a colorless oil. IR: 3507, 3075, 2962, 2877, 1789, 1729, 1639, 1609, 1468, 1397, 1381, 1367, 1291, 1265, 1188, 1172, 1160, 1131, 1082, 1065, 1018 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 5.4, 3.1 Hz, 2H, 2HAr), 7.73 (dd, J = 5.4, 3.1 Hz, 2H, 2HAr), 5.92 (ddt, J = 16.9, 10.2, 7.5 Hz, 1H, H2), 5.14 – 5.08 (m, 2H, H1), 3.90 (s, 2H, H6), 2.19 (dtapp, J = 7.5, 1.1 Hz, 2H, H3), 1.06 (s, 6H, H5). 13C NMR (100 MHz, CDCl3):δ 163.4 (s, 2CO), 134.40 (d, C2 or 2CHAr), 134.37 (d, C2 or 2CHAr), 129.0 (s, 2CqAr), 123.4 (d, 2CHAr), 118.0 (t, C1), 85.8 (t, C6), 43.3 (t, C3), 34.7 (s, C4), 24.1 (q, 2C5).
MS (EI) m/z: 218 [(M-allyl)+, 1], 148 (6), 130 (11), 104 (10), 97 [(M-ONPhth)+, 33], 96 (39), 90 (7), 81 (24), 76 (12), 69 (7), 67 (6), 56 (6), 55 (100).
HRMS (ESI): Calculated for C15H18NO3Na [M+Na]+ : 260.1281, Found : 260.1285.
191 C18H21NO3
M = 299,38 g/mol
Prepared from 2.21 (415.7 mg, 2.7 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 95:5) yielded 2.29 (363.5 mg, 1.22 mmol, 45%) as a white solid. Mp: 59 °C. IR: 3074, 2926, 2854, 1789, 1729, 1638, 1609, 1466, 1454, 1303, 1368, 1293, 1188, 1127, 1082, 1017 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.84 – 7.79 (m, 2H, HAr), 7.75 – 7.70 (m, 2H, HAr), 5.98 (ddt, J = 17.1, 10.1, 7.6 Hz, 1H, H2), 5.20 – 5.10 (m, 2H, H1), 4.00 (s, 2H, H8), 2.28 (dtapp, J = 7.5, 1.1 Hz, 2H, H3), 1.59 – 1.37 (m, 10H, H5, H6, H7). 13C NMR (100 MHz, CDCl3):δ 163.6 (s, 2C=O), 134.5 (d, 2CHAr), 134.4 (d, C2), 129.2 (s, 2CqAr), 123.5 (d, 2CHAr), 118.2 (t, C1), 82.7 (t, C8), 40.0 (s, C4), 37.4 (t, C3), 32.5 (t, 2C5 or 2C6), 26.2 (t, C7), 21.5 (t, 2C5 or 2C6). MS (EI) m/z: 164 (18), 137 [(M-ONPhth)+, 21], 136 (32), 95 (100), 81 (70), 79 (11), 69 (14), 67 (34), 55 (28).
HRMS (ESI): Calcld for C18H21NO3Na [M+Na]+ : 322.1414, Found : 322.1417.
2-[(1-Allylcyclopentyl)methoxy]isoindoline-1,3-dione (2.30)
C17H19NO3
M = 285,35 g/mol
Prepared from 2.22 (601.4 mg, 4.29 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1 to 8:2) yielded 2.30 (905.2 mg, 3.17 mmol, 74%) as a white solid.
192 IR: 3074, 2950, 2868, 1789, 1728, 1639, 1609, 1467, 1390, 1367, 1291, 1187, 1129, 1082, 1017 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.85 – 7.80 (m, 2H, HAr), 7.76 – 7.71 (m, 2H, HAr), 5.96 (ddt, J = 17.5, 10.1, 7.5 Hz, 1H, H2), 5.20 – 5.10 (m, 2H, H1), 3.99 (s, 2H, H7), 2.30 (d, J = 7.5, 2H, H3), 1.74 – 1.50 (m, 8H, H5, H6). 13C NMR (100 MHz, CDCl3):δ 163.6 (s, 2C=O), 135.2 (d, C2), 134.5 (d, 2CHAr), 129.2 (s, 2CqAr), 123.5 (d, 2CHAr), 118.0 (t, C1), 83.7 (t, C7), 45.9 (s, C4), 41.6 (t, C3), 34.6 (t, 2C5), 25.4 (t, 2C6). MS (EI) m/z: 164 (8), 123 [(M-ONPhth)+, 25], 122 (31), 81 (100), 79 (16), 69 (10), 67 (42), 55 (14).
HRMS (ESI): Calculated for C17H19NO3Na [M+Na]+ : 308.1257, Found : 308.1259.
2-[(1-Allylcyclopropyl)methoxy]isoindoline-1,3-dione (2.31)
C15H15NO3
M = 257.30 g/mol
Prepared from 2.23 (778.4 mg, 6.94 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1 to 8:2) yielded 2.31 (1.55 g, 6.03 mmol, 87%) as a yellowish oil.
IR: 3077, 3002, 1789, 1727, 1640, 1611, 1467, 1429, 1397, 1372, 1290, 1187, 1132, 1083, 1019 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.84 – 7.79 (m, 2H, HAr), 7.76 – 7.71 (m, 2H, HAr), 5.86 (ddt, J = 17.2, 10.1, 7.2 Hz, 1H, H2), 5.20 (ddt, J = 17.1, 2.1, 1.4 Hz, 1H, H1), 5.09 (ddt, J = 10.1, 2.1, 1.0 Hz, 1H, H1), 4.00 (s, 2H, H6), 2.36 (d, J = 7.2, Hz, 2H, H3), 0.57 – 0.50 (m, 4H, H5). 13C NMR (100 MHz, CDCl3):δ 163.6 (s, 2C=O), 135.4 (d, C2), 134.5 (d, 2CHAr), 129.1 (s, 2CqAr), 123.5 (d, 2CHAr), 117.5 (t, C1), 83.9 (t, C6), 38.0 (t, C3), 19.1 (s, C4), 9.7 (t, 2C5).
MS (EI) m/z: 163 [(HONPhth)+●, 7], 105 (8), 104 (24), 95 [(M-ONPhth)+, 95], 94 (39), 93 (16), 90 (10), 79 (54), 77 (22), 76 (31), 67 (100), 66 (14), 65 (14), 55 (38), 53 (23), 50 (17).
193
2-[(3,3-Dimethylpent-4-en-1-yl)oxy]isoindoline-1,3-dione (2.32)
C15H17NO3
M = 259,31 g/mol
Prepared from 2.26 (588.7 mg, 5.16 mmol) following general Mitsunobu procedure C. Purification by flash chromatography on silica gel (PE/AcOEt = 95:5 to 9:1) yielded 2.32 (1.28 g, 4.95 mmol, 96%) as a colorless oil.
IR: 2962, 2360, 1789, 1731, 1641, 1467, 1396, 1367, 1187, 1128, 1082, 1016 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.84 – 7.82 (m, 2H, HAr), 7.75 – 7.73 (m, 2H, HAr), 5.79 (m, 1H, H2), 4.98 – 4.94 (m, 2H, H1), 4.21 – 4.17 (m, 2H, H6), 1.87 – 1.83 (m, 2H, H5), 1.08 (s, 6H, H4). 13C NMR (100 MHz, CDCl3):δ 163.8 (s, 2C=O), 147.2 (d, C2), 134.6 (d, 2CHAr), 129.1 (s, 2CqAr), 123.6 (d, 2CHAr), 111.5 (t, C1), 76.3 (t, C6), 39.8 (t, C5), 35.7 (s, C3), 27.2 (q, 2C4). MS (EI) m/z: 147 (6), 104 (16), 97 (34), 96 (32), 90 (8), 872 (6), 81 (28), 79 (6), 77 (5), 76 (22), 70 (13), 69 (72), 68 (5), 67 (13), 56 (8), 55 (100), 53 (12), 50 (12).
HRMS (ESI): Calculated for C15H17NO3Na [M+Na]+ : 282.1101, Found : 282.1104.
O-(2-Isopropylpent-4-en-1-yl)hydroxylamine (2.33)
C8H17NO M = 143.23 g/mol
Prepared from 2.27 (1.02 g, 3.75 mmol) following general phthalimide cleavage procedure D. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1) yielded 2.33 (451.8 mg, 3.16 mmol, 84%) as a colorless liquid.
IR: 3315, 3076, 2958, 2926, 2873, 1726, 1639, 1587, 1466, 1441, 1387, 1369, 1187, 1025 cm-1.
1H NMR (400 MHz, C6D6): δ 5.79 (ddt, J = 17.1, 10.1, 7.1 Hz, 1H, H2), 5.08 – 4.99 (m, 2H, H1), 4.74 (s, 2H, NH2), 3.63 (ddABsyst, J = 9.9, 6.0 Hz, 1H, H7), 3.57 (ddABsyst, J = 9.8, 6.0 Hz, 1H, H7), 2.12 –
194 2.00 (m, 2H, H3), 1.78 (heptd, J = 6.8, 4.8 Hz, 1H, H5), 1.62 (m, 1H, H4), 0.86 (d, J = 6.8 Hz, 3H, H6), 0.85 (d, J = 5.8 Hz, 3H, H6). 13C NMR (100 MHz, C6D6):δ 138.3 (d, C2), 115.7 (t, C1), 76.7 (t, C7), 43.3 (d, C4), 33.5 (t, C3), 28.5 (d, C5), 19.8 (q, C6), 19.6 (q, C6). MS (EI) m/z: 96 (5), 95 (6), 81 (10), 70 (14), 69 (100), 67 (11), 57 (19), 55 (81). O-(2,2-Dimethylpent-4-en-1-yl)hydroxylamine (2.34) C7H15NO M = 129,20 g/mol
Prepared from 2.28 (2.51 g, 9.68 mmol) following general phthalimide cleavage procedure D. Purification by flash chromatography on silica gel (PE/AcOEt = 8:2) yielded 2.34 (963.2 g, 7.46, 77%) as a colorless liquid. IR: 3314, 3076, 2959, 2905, 2871, 1719, 1639, 1588, 1474, 1389, 1365, 1190, 1020 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.80 (ddt, J = 16.6, 10.5, 7.5 Hz, 1H, H2), 5.37 (s, 2H, NH2), 5.05 – 4.98 (m, 2H, H1), 3.40 (s, 2H, H6), 2.00 (dtapp, J = 7.5, 1.2 Hz, 2H, H3), 0.88 (s, 6H, H5). 13C NMR (100 MHz, C6D6):δ 135.6 (d, C2), 117.2 (t, C1), 84.8 t, C6), 44.2 (t, C3), 34.7 (s, C4), 24.8 (q, 2C5).
MS (EI) m/z: 114 [(M-Me)+, 3], 97 [(M-ONH2)+, 20], 69 (7), 67 (6), 56 (9), 55 (100).
HRMS (ESI): Calculated for C7H16NOH [M+H]+ : 130.1226, Found : 130.1226.
O-[(1-allylcyclohexyl)methyl]hydroxylamine (2.35)
C10H19NO M = 169,27 g/mol
Prepared from 2.29 (351.1 mg, 1.17 mmol) following general phthalimide cleavage procedure
D. Purification by flash chromatography on silica gel (PE/Et2O = 7:3) yielded 2.35 as a colorless liquid (165.8 mg, 0.98 mmol, 84%).
195 IR: 3313, 3240, 3074, 3003, 2975, 2925, 2852, 2665, 1827, 1728, 1638, 1586, 1453, 1414, 1375, 1296, 1271, 1187, 1001 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.80 (m, 1H, H2), 5.34 (br s, 2H, NH2), 5.0048 – 4.99 (m, 2H, H1), 3.48 (s, 2H, H8), 2.08 (dtapp, J = 7.5, 1.2 Hz, 2H, H3), 1.47 – 1.24 (m, 10H, H5, H6, H7). 13C NMR (100 MHz, CDCl3):δ 135.2 (d, C2), 117.1 (t, C1), 82.2 (t, C8), 40.3 (t, C3), 37.1 (s, C4), 32.9 (t, 2C5 or 2C6), 26.4 (t, C7), 21.6 (t, 2C5 or 2C6).
MS (EI) m/z: 154 [(M-Me)+, 7), 137 [(M-ONH2)+, 7], 110 (7), 96 (10), 95 (93), 83 (15), 81 (100), 79 (20), 69 (26), 67 (49), 55 (69), 53 (11).
HRMS (ESI): Calculated for C10H19NOH [M+H]+ : 170.1539, Found : 170.1538.
O-[(1-Allylcyclopentyl)methyl]hydroxylamine (2.36)
C9H17NO M = 155,24 g/mol
Prepared from 2.30 (880.5 g, 3.09 mmol) following general phthalimide cleavage procedure D. Purification by flash chromatography on silica gel (PE/Et2O = 7:3) yielded 2.36 (316.5 mg, 2.04 mmol, 66%) as a colorless liquid.
IR: 3312, 3074, 2950, 2865, 1638, 1586, 1470, 1439, 1369, 1188, 1023 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.80 (m, 1H, H2), 5.36 (s, 2H, NH2), 5.05 – 4.99 (m, 2H, H1), 3.46 (s, 2H, H7), 2.10 (dtapp, J = 7.4, 1.2 Hz, 2H, H3), 1.58 – 1.52 (m, 4H, H5 and/or H6), 1.47 – 1.34 (m, 4H, H5 and/or H6). 13C NMR (100 MHz, CDCl3):δ 136.0 (d, C2), 117.0 (t, C1), 82.8 (t, C7), 45.8 (s, C4), 42.1 (t, C3), 34.7 (t, 2C5), 25.3 (t, 2C6).
MS (EI) m/z: 140 [(M-Me)+, 1], 123 [(M-ONH2)+, 7], 93 (5), 82 (9), 81 (100), 79 (24), 69 (18), 67 (63), 55 (33), 53 (15).
196
O-[(1-Allylcyclopropyl)methyl]hydroxylamine (2.37)
C7H13NO M = 127.19 g/mol
Prepared from 2.31 (1.12 g, 4.35 mmol) following general phthalimide cleavage procedure D. Purification by flash chromatography on silica gel (PE/Et2O = 7:3) yielded 2.37 (404.18 mg, 3.18 mmol, 73%) as a colorless liquid.
IR: 3314, 3244, 3155, 3076, 3002, 2978, 2904, 2860, 2068, 1835, 1639, 1586, 1472, 1438, 1427, 1376, 1280, 1189, 1017 cm-1. 1H NMR (400 MHz, CDCl3): δ 5.79 (ddt, J = 17.2, 10.1, 7.1 Hz, 1H, H2), 5.37 (br s, 2H, NH2), 5.07 – 4.99 (m, 2H, H1), 3.47 (s, 2H, H6), 2.11 (dtapp, J = 7.1, 1.3 Hz, 2H, H3), 0.44 – 0.37 (m, 4H, H5). 13C NMR (100 MHz, CDCl3):δ 136.1 (d, C2), 116.5 (t, C1), 81.8 (t, C6), 38.7 (t, C3), 19.1 (s, C4), 9.5 (t, 2C5). MS (EI) m/z: 96 (6), 95 [(M-ONH2)+, 71], 94 (5), 93 (14), 91 (6), 79 (17), 77 (14), 67 (100), 65 (17), 55 (51), 53 (33).
HRMS (ESI): Calculated for C7H13NONa [M+Na]+ : 150.0889, Found : 150.0887.
O-(3,3-Dimethylpent-4-en-1-yl)hydroxylamine (2.38)
C7H15NO M = 129,20 g/mol
Prepared from 2.32 (1.25 g, 4.82 mmol) following general phthalimide cleavage procedure D. Purification by flash chromatography on silica gel (PE/Et2O = 7:3) yielded 2.38 (386.1 mg, 2.99 mmol, 62%) as a colorless liquid.
IR: 3315, 3083, 2960, 2929, 2870, 1640, 1587, 1473, 1415, 1379, 1364, 1186 cm-1.
1H NMR (400 MHz, CDCl3): δ 5.78 (dd, J = 17.9, 10.5 Hz, 1H, H2), 5.06 (s, 2H, NH2), 4.94 – 4.89 (m, 2H, H1), 3.65 (t, J = 7.4 Hz, 2H, H6), 1.58 (t, J = 7.4 Hz 2H, H5), 1.01 (s, 6H, H4).
197
13C NMR (100 MHz, CDCl3):δ 147.9 (d, H2), 110.7 (t, C1), 73.5 (t, C6), 40.3 (t, C5), 35.7 (s, C3), 27.2 (q, 2C4).
HRMS (ESI): Calculated for C7H15NOH [M+H]+ : 130.1226, Found : 130.1225.
N-[(2-Isopropylpent-4-en-1-yl)oxy]-4-methylbenzenesulfonamide (2.39)
C15H23NO3S M = 297.41 g/mol
Prepared from 2.33 (447.3 mg, 3.13 mmol) following general tosylation procedure E. Purification by flash chromatography on silica gel (PE/AcOEt = 9:1) yielded 2.39 (668.6 mg, 2.25 mmol, 72%) as a colorless yellowish oil.
IR: 3221, 3074, 2959, 2929, 2874, 1640, 1598, 1494, 1466, 1443, 1388, 1370, 1334, 1307, 1292, 1213, 1186, 1164, 1120, 1092, 1037, 1019 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.81 – 7.78 (m, 2H, HAr), 7.34 – 7.32 (m, 2H, HAr), 7.09 (s, 1H, NH), 5.72 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H, H2), 5.02 – 4.96 (m, 2H, H1), 3.97 (ddABsyst, J = 9.7, 5.9 Hz, 1H, H7), 3.89 (ddABsyst, J = 9.7, 6.3 Hz, 1H, H7), 2.44 (s, 3H, ArCH3), 2.07 (m, 1H, H3), 1.94 (m, 1H, H3), 1.70 (m, 1H, H5), 1.56 (m, 1H, H4), 0.86 (d, 6.9 Hz, 3H, H6), 0.84 (d, 6.9 Hz, 3H, H6). 13C NMR (100 MHz, CDCl3):δ 144.9 (s, CqArSO2), 137.3 (d, C2), 133.9 (s, CqArMe), 129.8 (d, 2CHAr), 128.7 (d, 2CHAr), 116.2 (t, C1), 78.4 (t, C7), 42.9 (d, C4), 32.8 (t, C3), 27.9 (d, C5), 21.8 (q, ArCH3), 19.5 (q, C6), 19.4 (q, C6). MS (EI) m/z: 155 [(Ts)+, 6], 111 [(M-ONHTs)+, 15], 91 [(PhCH2)+, 31], 69 (100), 65 (17), 57 (20), 55 (66).
HRMS (ESI): Calculated for C15H23NO3SNa [M+Na]+ : 320.1291, Found : 320.1287.
N-[(2,2-Dimethylpent-4-en-1-yl)oxy]-4-methylbenzenesulfonamide (2.3)
C14H21NO3S M = 283,39 g/mol