Cheng
Chen
a,
Pullaiah
Kattanguru
a,
Olesya A.
Tomashenko
ab,
Rafał
Karpowicz
ac,
Gabriela
Siemiaszko
a,
Ahanjit
Bhattacharya
a,
Vinícius
Calasans
a and
Yvan
Six
*a
aLaboratoire de Synthèse Organique (LSO), UMR 7652 CNRS/ENSTA/École Polytechnique, Université Paris-Saclay, 91128 Palaiseau Cedex, France. E-mail: yvan.six@polytechnique.edu
bSaint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St Petersburg, 199034 Russia
cDepartment of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland
First published on 6th June 2017
A series of 6,6-dihalo-2-azabicyclo[3.1.0]hexane and 7,7-dihalo-2-azabicyclo[4.1.0]heptane compounds were prepared by the reaction of dihalocarbene species with N-Boc-2,3-dihydro-1H-pyrroles or -1,2,3,4-tetrahydropyridines. Monochloro substrates were synthesised as well, using a chlorine-to-lithium exchange reaction. The behaviour of several aldehydes and ketones under reductive amination conditions with deprotected halogenated secondary cyclopropylamines was investigated, showing that this transformation typically triggers cyclopropane ring cleavage to give access to interesting nitrogen-containing ring-expanded products.
Nevertheless, reports involving nitrogen-substituted gem-dihalocyclopropane compounds are comparatively scarce.5e,6 Typically, the starting materials are stable amide, carbamate or urea derivatives, i.e. with the lone pair of the nitrogen atom being delocalised into a carbonyl group. These ring-opening reactions (Scheme 1) require heating and/or activation by silver salts (or a Pd catalyst as in the bottom example) and are often low-yielding. Interestingly, sporadic reports show that amines can be more reactive (Scheme 2),7 which can be rationalised by a much more efficient stabilisation of the developing positive charge during the ring-opening process leading to the allyl cation intermediate.
Scheme 1 Selected literature examples of cyclopropane ring-opening reactions of nitrogen-substituted gem-dihalocyclopropane derivatives, with departure of a halide ion. |
On the basis of these observations, we thought that a fairly general approach could be designed to prepare functionalised halogen-substituted 1,2,3,6-tetrahydropyridine and 2,3,4,7-tetrahydro-1H-azepine derivatives 5 (Scheme 3, n = 1 or 2). Starting from N-Boc-protected cyclic enamine derivatives 1, a dihalocyclopropanation reaction would produce stable N-Boc-bicyclic secondary cyclopropylamines 2. After the removal of the Boc group, reductive amination of aldehydes or ketones would generate thermally unstable dihalogenated aminocyclo-propanes 4. This transformation would thus not only introduce functionality but also trigger the ring-expansion process.
Scheme 3 Strategy for the production of functionalised ring-enlarged cyclic amines 5 from dihalogenated bicyclic aminocyclopropanes 2. |
Eventually, the corresponding allyl cation adducts would be reduced by the hydride reagent, affording the desired ring-enlarged products 5 (Scheme 3). It is worth noting that 1,2,3,6-tetrahydropyridines and 2,3,4,7-tetrahydro-1H-azepines are important heterocycles, which are present as substructures of many natural products: e.g. vinca alkaloids such as tabersonine, vindoline, vinblastine and vincristine;8 ergot alkaloids such as lysergol and ergotamine;9 pleurostylin,10 didehydrotuberostemonine A,11 huperserines A, B and C;12 and curindolizine.13 Moreover, 2-chlorohuperzine E is an interesting example of a 5-chloro-1,2,3,6-tetrahydropyridine isolated from a plant extract (Fig. 1).14
Fig. 1 Examples of natural product structures containing 1,2,3,6-tetrahydropyridine and 2,3,4,7-tetrahydro-1H-azepine subunits. |
Small amounts of the more complex cyclopropanes 2f and 2g were also isolated, resulting from cyclopropanation of the by-product 1f formed by oxidation of the N-Boc-enamine 1b. Application of the same method to N-Boc-pyrrolidine gave poor results in our hands. The stable N-Boc protected aminocyclopropane substrates 2a–f were then readily converted into secondary amine hydrochlorides by treatment with HCl (Scheme 6). In the process, the acetate group of 2f was hydrolysed into an alcohol function.
A much simpler version of the reaction involves the generation of secondary amines by deprotonation of the salts 3 with triethylamine. This was done on a few milligram scale in NMR tubes containing CDCl3 solutions of 3a and 3d. The rearrangement is fast under these conditions and the clean formation of the 5-chloro-2,3-dihydropyridines 6a and 6d is observed after 5 minutes at room temperature (Scheme 7).¶
Interestingly, starting from the methyl-substituted compound 3e and under the reductive amination conditions applied for substrates 3a–d, the reaction takes a different course. Indeed, 3-chloromethylenepiperidine derivatives 7ea and 7eb are isolated as single geometrical isomers (Scheme 8). A similar phenomenon is observed when 3b is reacted with cyclohexanone, with the formation of 7be as the major product.
Scheme 8 Formation of 3-chloromethylenepiperidine derivatives under reductive amination conditions performed with 3e. |
The formation of compounds 7 can be explained by a 2,2-dichloro-1-aminocyclopropane-ring opening proceeding at the C1–C2 bond (Scheme 8, bottom).18 Steric hindrance around the nitrogen atom appears to be a key factor for this process, as well as the size of the nitrogen-containing heterocycle. Indeed, starting from 3a and 3d, which are the lower homologues of 3b and 3e, selectivity is in favour of the ring-expanded molecules 5ae and 5da (Table 1). Nonetheless, careful analysis of the crude products of all the reductive amination experiments revealed, in several cases, the formation of minor amounts of compounds of type 7, as well as of other by-products.‡
Application of reductive amination conditions with benzaldehyde proceeds with high chemoselectivity: while the exo compound gives the tertiary cyclopropylamine exo-10, endo-9 is converted into the ring-expanded tetrahydroazepine 11 (Scheme 10), showing that the endo bicyclic aminocyclopropane endo-10 is not stable and readily undergoes rearrangement, like the dihalo derivatives 4. These divergent results are in agreement with the so-called Woodward–Hoffmann–DePuy rule.19,20 Briefly, the reaction is thought to proceed by a mechanism where the departure of the halide ion and the two-electron electrocyclic cyclopropane-cleavage take place in a concerted fashion. Moreover, the sense of the disrotatory ring-opening is dictated by the relative configurations of the cyclopropane carbon atoms, so that substituents that are trans to the leaving group move outward (Scheme 11, framed). While the substrates having a halogen substituent in the endo relative configuration, i.e. endo-10 and all the dihalo substrates, can be transformed into cyclic cation intermediates 13, exo-10 cannot participate in such a process because the unacceptably strained E cation 12 would be produced (Scheme 11).
Scheme 11 Stereochemical outcome of the transformation of halocyclopropanes into allyl cation species. |
Finally, the successful transformation of endo-9 into the amide endo-14 demonstrates that the reaction of the acyl chloride is fast enough to trap the free secondary amine before it undergoes cyclopropane cleavage. Like the N-Boc derivative endo-8, endo-14 is a stable compound that can be purified by flash chromatography. However, when heated under microwave conditions, it is transformed into the dihydroazepine derivative 15 (Scheme 12).** In contrast, exo-14, prepared in the same way as endo-14, does not react, even in the presence of AgBF4.‡
sec-Butyllithium (1.3–1.4 M solution in cyclohexane) was purchased from Sigma-Aldrich or Alfa Aesar and titrated according to a literature method.21 Diethyl ether, and dichloromethane were purified using a MB SPS-800 solvent purification system (MBRAUN). Other solvents and commercial reagents were used as received, without purification. Petroleum ether refers to the 40–60 °C fraction. The microwave-promoted experiments were run using a CEM Discover Microwave Synthesis System with the temperature and time parameters indicated; the reaction vessels were not flushed with an inert gas. All other reactions were carried out under nitrogen or argon. The temperatures mentioned are the temperatures of the cold baths or the oil baths used. Flash column chromatography was performed on VWR Chemicals or Merck silica gel 60 (40–63 μm). Concentration under reduced pressure was carried out using rotary evaporators at 40 °C. NMR spectra were recorded with AM 400 or AVANCE 400 Bruker spectrometers (1H at 400.2 MHz, 13C at 100.6 MHz). Chemical shifts δ are given in ppm, referenced to the peak of tetramethylsilane, defined at δ = 0.00 (1H NMR), or the solvent peak of CDCl3, defined at δ = 77.0 (13C NMR). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, sext = sextuplet, sept = septuplet, m = multiplet, and br = broad. Coupling constants J are given in Hz and are rounded to the closest multiple of 0.5. Infrared spectra were recorded with a PerkinElmer 2000 or a PerkinElmer Spectrum Two FT-IR spectrometer. Melting points were determined using a Büchi 535 apparatus and were not corrected. Low-resolution mass spectra were recorded on a Hewlett-Packard Quad GC-MS engine spectrometer via direct injection. High-resolution mass spectrometry was performed on a JEOL GC-mate II spectrometer. Underlined m/z values indicate the base peaks.
2a. Pale yellow solid. M.p. 54.3–55.9 °C. IR (neat) ν 2978 (m), 2934 (w), 2904 (w), 1707 (s, CO), 1478 (w), 1450 (w), 1393 (s), 1368 (m), 1356 (m), 1346 (m), 1288 (w), 1257 (m), 1173 (m), 1127 (m), 1052 (w), 877 (m), 860 (m) cm−1. 1H NMR (CDCl3, 400 MHz), :37 mixture of two rotamers. Major rotamer: δ 1.50 (9 H, s), 2.11–2.36 (3 H, m), 3.37–3.66 (2 H, m), 3.63 (1 H, d, J 7.0). Minor rotamer: δ 1.45 (9 H, s), 2.11–2.36 (3 H, m), 3.28 (1 H, td, J 10.5, 5.5), 3.37–3.66 (1 H, m), 3.82 (1 H, d, J 7.0). 13C NMR (CDCl3, 100.6 MHz), :37 mixture of two rotamers. Major rotamer: δ 24.4, 28.0, 35.9, 48.6, 48.8, 65.1, 80.2, 154.7. Minor rotamer: δ 25.2, 28.0, 34.6, 48.3, 49.0, 64.8, 80.1, 154.7. MS (EI): m/z 114, , 118, 132, 160, 162, 176, 178 ([M − tBuO]+ with two 35Cl), 180 ([M − tBuO]+ with one 35Cl and one 37Cl), 195, 200, 201, 226, 251 (M+˙ with two 35Cl). HRMS (EI): m/z 251.0474 (M+˙ C10H1535Cl2NO2+˙ requires 251.0475).
2b. Pale yellow oil. IR (neat) ν 2976 (m), 2935 (m), 2873 (w), 2361 (w), 2342 (w), 1710 (s, CO), 1476 (w), 1455 (m), 1403 (s), 1392 (m), 1368 (s), 1354 (m), 1308 (m), 1257 (m), 1168 (s), 1137 (m), 1093 (w), 1024 (w), 839 (w), 824 (w), 772 (w) cm−1. 1H NMR (CDCl3, 400 MHz), :15 mixture of two rotamers. Major rotamer: δ 1.39–1.51 (1 H, m), 1.53 (9 H, s), 1.61–1.75 (2 H, m), 1.93–2.06 (2 H, m), 2.82 (1 H, ddd, J 12.5, 8.5, 3.5), 3.24 (1 H, d, J 9.0), 3.51 (1 H, ddd, J 12.5, 7.0, 4.0). Minor rotamer, characteristic signals: δ 1.50 (9 H, s), 3.02 (1 H, ddd, J 12.0, 7.5, 4.0), 3.27 (1 H, ddd, J 12.0, 9.5, 4.5), 3.33 (1 H, d, J 9.0). 13C NMR (CDCl3, 100.6 MHz), :15 mixture of two rotamers. Major rotamer: δ 17.1, 21.2, 28.3, 28.4, 40.0, 40.2, 63.4, 80.4, 156.0. Minor rotamer, characteristic signals: δ 17.0, 21.4, 39.7, 41.6. MS (EI): m/z 128, , 132, 135, 174, 192 ([M − tBuO]+ with two 35Cl), 194 ([M − tBuO]+ with one 35Cl and one 37Cl), 209, 211, 232, 234. HRMS (EI): m/z 265.0627 (M+˙ C11H1735Cl2NO2+˙ requires 265.0631).
2c. White solid. M.p. 46.8–48.0 °C. IR (neat) ν 2971 (m), 2933 (w), 2872 (w), 1704 (s, CO), 1451 (w), 1400 (m), 1392 (m), 1366 (m), 1348 (m), 1315 (w), 1255 (w), 1161 (m), 1135 (m), 1015 (w), 755 (m) cm−1. 1H NMR (CDCl3, 400 MHz), :12 mixture of two rotamers. Major rotamer: δ 1.44 (1 H, m), 1.55 (9 H, s), 1.52–1.62 (1 H, m), 1.74 (1 H, m), 2.02–2.13 (2 H, m), 2.90 (1 H, ddd, J 12.5, 8.0, 4.0), 3.29 (1 H, d, J 9.0), 3.43 (1 H, ddd, J 12.5, 8.0, 4.5). Minor rotamer, characteristic signals: δ 1.50 (9 H, s), 3.08 (1 H, ddd, J 12.5, 6.5, 4.0), 3.22 (1 H, ddd, J 12.5, 9.5, 4.0), 3.37 (1 H, d, J 9.0). 13C NMR (CDCl3, 100.6 MHz), :12 mixture of two rotamers. Major rotamer: δ 19.0, 21.1, 28.3, 29.4, 36.7, 40.2, 40.6, 80.4, 155.8. Minor rotamer, characteristic signals: δ 21.2, 28.3, 36.5, 40.1, 41.8, 80.3, 155.9. MS (EI): m/z 94, 95, 119, 146, , 175, 176, 199, 218, 220, 255, 280 ([M − tBuO]+ with two 79Br), 282 ([M − tBuO]+ with one 79Br and one 81Br), 284 ([M − tBuO]+ with two 81Br), 297, 299, 301, 353 (M+˙ with two 79Br), 355 (M+˙ with one 79Br and one 81Br), 357 (M+˙ with two 81Br). HRMS (EI): m/z 352.9629 (M+˙ C11H1779Br2NO2+˙ requires 352.9621).
exo-8. Colourless oil. IR (neat) ν 2977 (m), 2934 (m), 2868 (w), 1702 (s, CO), 1447 (w), 1418 (m), 1384 (m), 1366 (m), 1300 (w), 1269 (w), 1246 (w), 1164 (m), 1131 (m), 1035 (w), 1005 (w), 774 (w) cm−1. 1H NMR (CDCl3, 400 MHz), :21 mixture of two rotamers. Major rotamer: δ 1.12 (1 H, tddd, J 13.0, 12.0, 4.5, 3.5), 1.50 (9 H, s), 1.57 (1 H, br ddd, J 9.5, 6.0, 4.0), 1.61 (1 H, dddd, J 13.0, 6.0, 3.5, 2.0), 1.72 (1 H, ddt, J 13.5, 13.0, 6.0), 1.97 (1 H, br dd, J 13.5, 4.5), 2.43 (1 H, ddd, J 13.0, 12.0, 2.0), 2.65 (1 H, dd, J 4.0, 1.5), 3.03 (1 H, dd, J 9.5, 1.5), 3.76 (1 H, dt, J 13.0, 3.5). Minor rotamer: δ 1.45–1.77 (4 H, m, H2, H3a), 1.46 (9 H, s), 1.97 (1 H, br d, J 13.5), 2.56 (1 H, br t, J 12.5), 2.71 (1 H, br d, J 3.5), 3.15 (1 H, br d, J 9.5), 3.59 (1 H, br d, J 12.5). 13C NMR (CDCl3, 100.6 MHz), :21 mixture of two rotamers. Major rotamer: δ 19.2, 22.4, 23.1, 28.4, 35.8, 37.5, 39.7, 80.0, 156.0. Minor rotamer: δ 19.2, 22.3, 22.8, 28.4, 35.1, 37.3, 41.3, 80.1, 156.0. MS (EI) m/z , 110, 130, 140, 158 ([M − tBuO]+ with 35Cl), 160 ([M − tBuO]+ with 37Cl), 179, 196 ([M − Cl]+). HRMS m/z (EI) 158.0370 ([M − tBuO]+ C7H9ClNO+ requires 158.0368).
endo-8. Colourless crystals. M.p. 62–64 °C. IR (neat) ν 2975 (m), 2933 (m), 2869 (w), 1700 (s, CO), 1478 (w), 1454 (w), 1407 (m), 1391 (m), 1365 (m), 1309 (m), 1272 (w), 1256 (w), 1169 (m), 1137 (m), 1066 (w), 963 (w), 774 (m), 712 (w) cm−1. 1H NMR (CDCl3, 400 MHz), :28 mixture of two rotamers. Major rotamer: δ 1.40–1.73 (4 H, m), 1.48 (9 H, s), 1.94 (1 H, m), 2.86 (1 H, ddd, J 12.0, 8.5, 4.0), 2.89 (1 H, dd, J 9.0, 5.5), 3.14 (1 H, dd, J 8.0, 5.5), 3.53 (1 H, ddd, J 12.0, 7.0, 4.5). Minor rotamer: δ 1.40–1.73 (4 H, m), 1.48 (9 H, s), 1.98 (1 H, m), 2.96 (1 H, dd, J 9.0, 5.5), 3.06 (1 H, ddd, J 12.5, 7.0, 4.0), 3.24 (1 H, dd, J 8.0, 5.5), 3.26 (1 H, ddd, J 12.5, 8.5, 4.0). 13C NMR (CDCl3, 100.6 MHz), :28 mixture of two rotamers. Major rotamer: δ 15.1, 16.2, 22.3, 28.2, 29.5, 37.0, 40.7, 79.4, 156.3. Minor rotamer: δ 15.0, 15.9, 22.3, 28.2, 29.5, 36.7, 42.3, 79.6, 156.4. MS (EI) m/z 96, , 99, 140, 141, 158 ([M − tBuO]+ with 35Cl), 160 ([M − tBuO]+ with 37Cl), 175, 196 ([M − Cl]+). HRMS m/z (EI) 196.1335 ([M − Cl]+ C11H18NO2+ requires 196.1333).
3b. White solid. M.p. 136.5 °C (decomposition). 1H NMR (CDCl3, 400 MHz): δ 1.69 (1 H, m), 1.83 (1 H, br s), 1.97 (1 H, br ddd, J 13.5, 6.5, 5.5), 2.08–2.22 (2 H, m), 2.93 (1 H, br ddd, J 12.5, 9.5, 3.0), 3.35 (1 H, br ddd, J 12.5, 7.0, 3.0), 3.48 (1 H, br d, J 9.5), 9.14 (1 H, br s, NH), 11.60 (1 H, br s, NH). 13C NMR (CDCl3, 100.6 MHz): δ 15.0, 16.5, 25.2, 36.6, 40.5, 59.3. MS (EI): m/z 94, 102, 103, 104, , 131, 132, 164, 166 ([M − Cl]+ with two 35Cl), 167.
5aa. Pale yellow oil. IR (neat) ν 3063 (w), 3029 (m), 2919 (s), 2803 (s), 2761 (m), 2724 (w), 1664 (m), 1495 (m), 1455 (m), 1368 (m), 1347 (m), 1149 (m), 1126 (s), 1045 (m), 962 (m), 844 (s), 835 (s), 738 (s) cm−1. 1H NMR (CDCl3, 400 MHz): δ 2.22 (2 H, tdt, J 5.5, 4.0, 2.5), 2.58 (2 H, t, J 5.5), 3.10 (2 H, td, J 2.5, 1.5), 3.62 (2 H, s), 5.85 (1 H, tt, J 4.0, 1.5), 7.24–7.38 (5 H, m). 13C NMR (CDCl3, 100.6 MHz): δ 26.2, 48.4, 57.3, 61.7, 122.5, 127.2, 128.3, 128.8, 129.0, 137.8. MS (EI): m/z 116, 117, 118, 172, (M+˙ with 35Cl), 209 (M+˙ with 35Cl). HRMS (EI): m/z 207.0819 (M+˙ C12H1435ClN+˙ requires 207.0810).
5ae. Pale yellow oil. IR (neat) ν 2929 (s), 2855 (m), 2802 (w), 2361 (w), 2343 (w), 1665 (w), 1450 (m), 1379 (w), 1138 (w), 987 (w), 958 (w), 839 (w), 772 (w) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.18–1.30 (1 H, m), 1.24 (2 H, m), 1.25 (2 H, m), 1.64 (1 H, br d, J 12.0), 1.81 (2 H, m), 1.89 (2 H, m), 2.22 (2 H, tdt, J 5.5, 4.0, 2.5), 2.40 (1 H, m), 2.64 (2 H, t, J 5.5), 3.23 (2 H, td, J 2.5, 2.0), 5.84 (1 H, tt, J 4.0, 2.0). 13C NMR (CDCl3, 100.6 MHz): δ 25.8, 26.2, 26.7, 28.8, 44.9, 53.4, 62.7, 122.7, 129.2. MS (EI): m/z 130, 132, , 158, 170, 199 (M+˙ with 35Cl), 201 (M+˙ with 37Cl). HRMS (EI): m/z 199.1134 (M+˙ C11H1835ClN+˙ requires 199.1123).
5ba. Pale yellow oil. IR (neat) ν 3063 (w), 3029 (w), 2930 (s), 2839 (m), 2810 (m), 1642 (w), 1494 (m), 1453 (m), 1436 (m), 1361 (w), 1118 (m), 1028 (w), 1015 (w), 969 (w), 951 (w), 822 (w), 757 (m), 733 (s) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.70 (2 H, tt, J 6.0, 5.5), 2.24 (2 H, dtt, J 6.5, 5.5, 1.0), 2.94 (2 H, t, J 6.0), 3.56 (2 H, t, J 1.0), 3.75 (2 H, s), 6.08 (1 H, t, J 6.5), 7.26 (1 H, distorted tt, J 7.0, 1.5), 7.29–7.38 (4 H, m). 13C NMR (CDCl3, 100.6 MHz): δ 24.2, 26.9, 56.5, 58.2, 60.2, 127.1, 128.3, 128.9, 129.6, 132.6, 138.7. MS (EI): m/z (Bn+), 92, 120, 121, 130, 186 ([M − Cl]+), 220, 221 (M+˙ with 35Cl), 222, 223 (M+˙ with 37Cl). HRMS (EI): m/z 221.0977 (M+˙ C13H1635ClN+˙ requires 221.0966).
5be. Pale yellow oil. IR (neat) ν 2929 (s), 2855 (m), 2806 (w), 2361 (w), 2342 (w), 1698 (w), 1450 (w), 1260 (w), 1125 (w), 1018 (w), 963 (w), 772 (w) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.04–1.32 (3 H, m), 1.61 (1 H, dm, J 12.5), 1.67 (2 H, tt, J 6.0, 5.5), 1.77 (2 H, dm, J 12.0), 1.91 (2 H, br d, J 11.5), 2.20 (2 H, dt, J 6.0, 5.5), 2.56 (1 H, tt, J 10.5, 3.0), 2.95 (2 H, t, J 6.0), 3.57 (2 H, br s), 5.98 (1 H, br t, J 6.0). 13C NMR (CDCl3, 100.6 MHz): δ 25.2, 25.6, 26.2, 26.7, 29.7, 52.7, 58.0, 60.6, 129.2, 132.3. MS (EI): m/z 112, , 171, 172, 213 (M+˙ with 35Cl), 215 (M+˙ with 37Cl). HRMS (EI): m/z 213.1279 (M+˙ C12H2035ClN+˙ requires 213.1279).
5ca. Pale yellow oil. IR (neat) ν 3029 (w), 2928 (s), 2850 (m), 2811 (m), 2361 (w), 2342 (w), 1495 (w), 1454 (m), 1436 (w), 1362 (w), 1118 (m), 728 (m) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.69 (2 H, quint, J 5.5), 2.21 (2 H, dt, J 6.5, 5.5), 2.95 (2 H, t, J 5.5), 3.67 (2 H, s), 3.76 (2 H, s), 6.33 (1 H, t, J 6.5), 7.22–7.40 (5 H, m). 13C NMR (CDCl3, 100.6 MHz): δ 24.1, 28.5, 56.4, 57.9, 62.1, 123.0, 127.1, 128.3, 128.9, 134.0, 138.8. MS (EI): m/z , 121, 130, 186 ([M − Br]+), 265 (M+˙ with 79Br), 267 (M+˙ with 81Br). HRMS (EI): m/z 265.0468 (M+˙ C13H1679BrN+˙ requires 265.0461).
5da. Pale yellow oil. IR (neat) ν 3028 (w), 2976 (m), 2935 (m), 2836 (m), 2809 (m), 2361 (w), 2342 (w), 1495 (w), 1453 (m), 1368 (m), 1120 (m), 970 (m), 801 (m), 734 (s) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.31 (3 H, d, J 6.5), 1.99 (1 H, dddd, J 17.0, 5.5, 5.0, 3.0), 2.34 (1 H, dddd, J 17.0, 10.0, 3.0, 2.5), 2.62 (1 H, ddd, J 13.0, 5.5, 2.5), 2.94 (1 H, ddd, J 13.0, 10.0, 5.0), 3.17 (1 H, q, J 6.5), 3.72 (2 H, AB system, δA 3.68, δB 3.77, JAB 13.5), 5.87 (1 H, t, J 4.0), 7.22–7.39 (5 H, m). 13C NMR (CDCl3, 100.6 MHz): δ 16.6, 24.2, 42.1, 57.6, 58.3, 122.5, 127.0, 128.3, 128.7, 135.0, 139.0. MS (EI): m/z 120, ([M − Me]+ with 35Cl), 207, 208 ([M − Me]+ with 37Cl), 221 (M+˙ with 35Cl). HRMS (EI): m/z 221.0971 (M+˙ C13H1635ClN+˙ requires 221.0966).
7ea. Pale yellow oil. IR (neat) ν 3063 (w), 3028 (w), 2935 (s), 2854 (m), 2811 (m), 1731 (w), 1637 (w), 1494 (w), 1455 (m), 1366 (m), 1291 (m), 1125 (m), 1028 (m), 775 (m), 732 (m) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.21 (3 H, d, J 7.0), 1.55–1.74 (2 H, m), 2.19 (1 H, dddd, J 14.0, 12.0, 5.5, 1.5), 2.61 (1 H, dt, J 13.0, 3.5), 2.70 (1 H, dt, J 14.0, 4.0), 2.89 (1 H, ddd, J 13.0, 11.0, 3.5), 3.32 (1 H, qdd, J 7.0, 1.5, 1.0), 3.63 (2 H, AB system, δA 3.62, δB 3.64, JAB 14.0), 5.87 (1 H, d, J 1.0), 7.24 (1 H, br t, J 7.0), 7.31 (2 H, br dd, J 7.5, 7.0), 7.34 (2 H, br d, J 7.5). 13C NMR (CDCl3, 100.6 MHz): δ 14.3, 23.2, 23.5, 46.0, 57.4, 58.5, 110.9, 126.9, 128.3, 128.7, 139.0, 141.2. MS (EI): m/z 117, 149, ([M − Me]+ with 35Cl), 221, 222 ([M − Me]+ with 37Cl), 235 (M+˙ with 35Cl). HRMS (EI): m/z 235.1131 (M+˙ C14H1835ClN+˙ requires 235.1123).
exo-10. Colourless oil. IR (neat) ν 3029 (m), 2939 (s), 2859 (m), 2800 (m), 1494 (m), 1453 (s), 1349 (m), 1315 (m), 1247 (m), 1155 (m), 1061 (m), 1029 (m), 762 (s), 737 (s) cm−1. 1H NMR (CDCl3, 400 MHz) δ 1.28 (1 H, ddtd, J 13.0, 6.5, 5.5, 2.5), 1.35 (1 H, dddd, J 9.5, 9.0, 3.5, 2.5), 1.42 (1 H, ddddd, J 13.0, 9.5, 9.0, 5.5, 3.0), 1.51 (1 H, dddd, J 14.0, 9.0, 5.5, 2.5), 1.93 (1 H, ddt, J 14.0, 9.0, 5.5), 2.02 (1 H, ddd, J 11.5, 9.5, 2.5), 2.40 (1 H, dd, J 9.5, 2.5), 2.42 (1 H, ddd, J 11.5, 6.5, 3.0), 2.76 (1 H, dd, J 3.5, 2.5), 3.69 (2 H, AB system, δA 3.65, δB 3.73, JAB 13.0), 7.19 (1 H, br t, J 7.0), 7.23–7.32 (4 H, m). 13C NMR (CDCl3, 100.6 MHz) δ 20.6, 21.7, 22.3, 33.9, 44.4, 47.6, 61.4, 127.1, 128.2, 129.2, 138.0. MS (EI): m/z 91 (Bn+), 92, 94, 95, 102, ([M − Cl]+), 187, 220, 221 (M+˙ with 35Cl), 222. HRMS (EI): m/z 186.1273 ([M − Cl]+ C13H16N+ requires 186.1278), 221.0989 (M+˙ C13H1635ClN+˙ requires 221.0966).
11. Colourless oil. IR (neat) ν 3023 (m), 2928 (s), 2837 (m), 2803 (m), 2760 (m), 1652 (w), 1495 (m), 1453 (m), 1354 (m), 1153 (m), 1115 (m), 1028 (w), 741 (m) cm−1. 1H NMR (CDCl3, 400 MHz): δ 1.61 (2 H, distorted quint, J 5.5), 2.18 (2 H, br qd, J 5.5, 1.0), 2.80 (2 H, distorted t, J 5.5), 3.10 (2 H, dd, J 5.5, 1.0), 3.58 (2 H, s), 5.57 (1 H, dtt, J 11.0, 5.5, 1.0), 5.85 (1 H, dtt, J 11.0, 5.5, 1.0), 7.14–7.30 (5 H, m). 13C NMR (CDCl3, 100.6 MHz): δ 25.8, 28.2, 53.4, 58.1, 60.5, 126.8, 128.2, 128.9, 129.3, 133.5, 139.4. MS (EI): m/z (Bn+), 92, 96, 110, 120, 131, 172, 186, 187 (M+˙), 188. HRMS (EI): m/z 187.1354 (M+˙ C13H17N+˙ requires 187.1356).
endo-14. Thick pale yellow oil. IR (neat) ν 2996 (w), 2939 (m), 2871 (w), 2838 (w), 1651 (s, CO), 1590 (m), 1508 (m), 1457 (m), 1424 (m), 1334 (m), 1240 (m), 1125 (s), 1008 (m), 789 (w) cm−1. 1H NMR (CDCl3, 400 MHz), :16 mixture of two rotamers. Major rotamer: δ 1.50–1.75 (4H, m), 2.02 (1H, m), 2.83 (1H, ddd, J 13.0, 8.5, 3.5), 2.98 (1H, dd, J 9.5, 5.0), 3.34 (1H, dd, J 8.0, 5.0), 3.74 (2 H, AB system, δA 3.71, δB 3.77, JAB 15.0), 3.83 (3H, s), 3.85 (6H, s), 3.93 (1H, ddd, J 13.0, 6.5, 4.0), 6.51 (2H, s). Minor rotamer, characteristic signals: δ 3.15 (1H, ddd, J 12.0, 8.0, 4.0), 3.21 (1H, dd, J 9.0, 6.0), 3.35 (1 H, m), 6.51 (2H, s). 13C NMR (CDCl3, 100.6 MHz), :16 mixture of two rotamers. Major rotamer: δ 16.2, 16.3, 21.8, 30.5, 37.2, 39.9, 40.9, 56.0, 60.7, 106.3, 130.5, 136.6, 153.0, 172.8. Minor rotamer: δ 14.7, 16.0, 22.6, 29.9, 36.4, 41.3, 43.8, 56.0, 60.7, 105.6, 130.3, 136.5, 153.1, 172.3. MS (EI): m/z 96, 97, , 182, 208, 244, 246, 304 ([M − Cl]+), 339 (M+˙ with 35Cl), 341 (M+˙ with 37Cl). HRMS (EI): m/z 339.1228 (M+˙ C17H2235ClNO4+˙ requires 339.1232).
15. Pale yellow oil. IR (neat) ν 2996 (w), 2937 (w), 2838 (w), 1666 (m, CO), 1634 (m), 1599 (m), 1591 (m), 1508 (m), 1461 (m), 1425 (m), 1332 (m), 1240 (m), 1126 (s), 1007 (w), 715 (w) cm−1. 1H NMR (CDCl3, 400 MHz) δ 2.51 (2H, qd, J 5.0, 1.5), 3.75 (2H, s), 3.77 (2H, t, J 5.0), 3.83 (3H, s), 3.84 (6H, s), 5.30 (1H, dd, J 9.0, 7.5), 5.86 (1H, ddt, J 11.5, 7.5, 1.5), 5.98 (1H, dt, J 11.5, 5.0), 6.45 (2H, s), 6.62 (1H, d, J 9.0). 13C NMR (CDCl3, 100.6 MHz) δ 32.6, 41.7, 42.2, 56.1, 60.8, 105.9, 111.1, 122.7, 129.2, 129.9, 133.6, 136.9, 153.3, 169.1. MS (EI): m/z , 97, 109, 111, 121, 123, 125, 135, 147, 193, 208, 221, 303 (M+˙).
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ob01238a |
‡ See the ESI† for details. |
§ The quality of the hydride reagent proved important. See the ESI† for a short study in the case of the reaction of benzaldehyde with 3b. |
¶ Using K2CO3 as the base, no reaction was observed after several hours, most certainly because of the very low solubility of this reagent in chloroform. With NaOH, complex mixtures of products were generated after 5 minutes. |
|| Without TMEDA, yields are significantly lower. Using nBuLi/TMEDA instead of sBuLi/TMEDA, no Cl–Li exchange is observed. |
** The production of 15 can be explained by the loss of a proton from the iminium intermediate 13, which we were hoping would cyclise onto the electron-rich aromatic ring. |
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