Chapter 2. Mechanistic insights on copper-catalyzed alkylations of amines: photoinduced
2.4. Experimental section
2.4.2. Procedures for photoinduced cross-couplings
Determination of photoinstability of 6-iodo-1-heptene
An equimolar mixture of 6-iodo-1-heptene (0.2 mmol) and LiO-tBu (0.2 mmol) in CH3CN (1 mL) was prepared in an 8 mL borosilicate vial equipped with a magnetic stir bar.
The mixture was capped and stirred for 5 minutes and the reaction vessel was fully submerged in an isopropanol bath kept at 0 °C with a cryostat. The mixture was irradiated with a 100-watt Hg lamp before it was diluted with a solution of dodecane in Et2O or EtOAc.
An aliquot was filtered through a short pad of silica gel (EtOAc eluent) and the sample was injected for GC analysis.
Alternatively, a 10 mL quartz tube was used to prepare the mixture of 6-iodo-1- heptene and LiO-tBu in CH3CN. A small, measured quantity of n-dodecane was added as the internal standard, followed by a magnetic stir bar. The quartz tube was capped with a rubber septum, stirred for 5 minutes and placed in a Luzchem photoreactor at room temperature for irradiation under 350 nm. After irradiation, the quartz tube was shaken vigorously and an aliquot was immediately taken via syringe. The sample was filtered through a short pad of silica gel (EtOAc eluent) and the sample was injected for GC analysis.
The data are summarized below for the irradiation under 350 nm.
45 Table 2.1. Conversion of 6-iodo-1-heptene at room temperature under 350 nm irradiation in CH3CN in the presence of an equivalent of LiOt-Bu.
General procedure for the coupling of alkyl bromides
[Li(CH3CN)n][Cu(carb)2] (0.007 mmol), Li(carb) (0.2 mmol), and alkyl bromide (0.13 mmol) were added to a 4 mL borosilicate vial in the glovebox under a nitrogen atmosphere. A magnetic stir bar and 4 mL CH3CN were added to the vial. The mixture was capped and stirred for 5 minutes and the reaction vessel was fully submerged in an isopropanol bath kept at 0 °C with a cryostat. The mixture was irradiated with a 100-watt Hg lamp while stirring for 8 hours, after which time it was diluted with a solution of dodecane in Et2O or EtOAc. An aliquot was filtered through a short pad of silica gel (EtOAc eluent) and the sample was injected for GC analysis. Products were isolated after removing the solvent in vacuo and loading the crude mixture on silica gel and eluting with hexanes.
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9-(hept-6-en-2-yl)-9H-carbazole (compound i). Following the general coupling procedure using 6-bromo-1-heptene, the title compound can be obtained after column chromatography (hexanes→1% EtOAc/hexanes) as colorless oil. A typical run produces 10% of the coupling product according to calibrated GC analysis.
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.0 Hz, 2H), 5.66 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 4.96–4.84 (m, 2H), 4.85–4.66 (m, 1H), 2.40–2.22 (m, 1H), 2.13–1.88 (m, 3H), 1.68 (d, J = 7.0 Hz, 3H), 1.47–1.28 (m, 1H), 1.24–1.09 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 139.9, 138.4, 125.5, 123.3, 120.4, 118.7, 115.0, 110.2, 51.3, 34.4, 33.5, 26.3, 19.5.
FT-IR (film): 2931, 1640, 1625, 1594, 1482, 1451, 1331, 1316, 1223, 1157, 746, 721 cm–1. MS (ESI) m/z (M)+ calcd for C19H21N: 263.2, found: 263.3.
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9-((2-methylcyclopentyl)methyl)-9H-carbazole (compound h). Following the general coupling procedure using 6-bromo-1-heptene, the title compound can be obtained as the mixture of diastereomers after column chromatography (hexanes→1% EtOAc/hexanes) as a colorless solid. A typical run produces 60% of the coupling product according to calibrated GC analysis. 1H NMR resonances were assigned for major and minor diastereomers based on COSY data. The stereochemistry of the major diastereomer was analyzed by NOESY.
NMR resonances of the major diastereomer are as follows.
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.48–7.41 (m, 4H), 7.24–7.20 (m, 2H), 4.37 (dd, J = 14.6, 4.6 Hz, 1H), 4.17 (dd, J = 14.6, 10.9 Hz, 1H), 2.69–2.44 (m, 1H), 2.26–2.19k (m, 1H), 1.96–1.75 (m, 2H), 1.53–1.38 (m, 4H), 1.13 (d, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 140.8, 125.6, 123.0, 120.4, 118.8, 109.0, 44.0, 43.1, 36.2, 33.3, 29.0, 22.7, 15.6.
FT-IR (film): 2954, 2870, 1597, 1484, 1461, 1452, 1326, 1218, 1153, 748, 722 cm–1. MS (ESI) m/z (M)+ calcd for C19H21N: 263.2, found: 263.3.
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Figure 2.13. 1H-1H COSY trace of the major diastereomer (CDCl3, rt, 600 MHz)
Figure 2.14. 1H-1H NOESY trace of the major (cis) diastereomer (CDCl3, rt, 600 MHz).
Couplings of the methyl resonances to the methine resonances are highlighted in yellow.
The difference in the magnitude of correlation is consistent with the cis configuration in a 5-membered ring.
49
Figure 2.15. 1H-1H COSY trace of the minor diastereomer (CDCl3, rt, 600 MHz).
Figure 2.16. 1H-1H NOESY trace of the minor (trans) diastereomer (CDCl3, rt, 600 MHz).
Couplings of the methyl resonances to the methine resonances are highlighted in yellow.
Approximately equal magnitude of correlation is consistent with the trans configuration in a 5-membered ring.
50
9-((2-methylcyclopentyl)methyl-d)-9H-carbazole. Following general coupling procedure with (E)-6-bromo-1-heptene-1-d, the title compound can be obtained as the mixture of diastereomers after column chromatography (hexanes→1% EtOAc/hexanes) as colorless solid. A typical run produces 60% of the coupling product according to calibrated GC analysis. NMR resonances of the major diastereomer are as follows.
1H NMR (400 MHz, C6D6) δ 8.22–8.02 (m, 2H), 7.50–7.38 (m, 2H), 7.30–7.21 (m, 4H), 3.96–3.79 (m, 0.5H), 3.80–3.65 (m, 0.5H), 2.41–2.16 (m, 1H), 1.89–1.79 (m, 1H), 1.59–1.50 (m, 2H), 1.27–1.21 (m, 2H), 1.20–1.13 (m, 2H), 0.81 (d, J = 7.1 Hz, 3H).
13C NMR (126 MHz, C6D6) δ 141.1, 125.8, 123.6, 120.8, 119.2, 109.3, 43.6 (t, J = 20.4 Hz), 43.0, 36.2, 33.3, 28.9, 22.7, 15.4.
2H NMR (61 MHz, C6D6) δ 3.86, 3.70.
MS (ESI) m/z (M)+ calcd for C19H20DN: 264.2, found: 264.1.
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Figure 2.17. 1H NMR spectrum of 9-((2-methylcyclopentyl)methyl-d)-9H-carbazole (C6D6, 400 MHz, rt).
52
Figure 2.18. 2H NMR spectrum of 9-((2-methylcyclopentyl)methyl-d)-9H-carbazole (C6H6, 61 MHz, rt).
Figure 2.19. 13C{1H} NMR spectrum of 9-((2-methylcyclopentyl)methyl-d)-9H-carbazole (C6D6, 126 MHz, rt).
53 Procedure for the coupling of alkyl bromides in the absence of [Cu(carb)2]–
Li(carb) (0.2 mmol) and alkyl bromide (0.13 mmol) were added to a 4 mL borosilicate vial in the glovebox under nitrogen atmosphere. A magnetic stir bar and 4 mL CH3CN were added to the vial. The mixture was capped and stirred for 5 minutes and the reaction vessel was fully submerged in an isopropanol bath kept at 0 °C with a cryostat. The mixture was irradiated with 100-watt Hg lamp while stirring for 8 hours, after which time it was diluted with a solution of dodecane in Et2O or EtOAc. An aliquot was filtered through a short pad of silica gel (EtOAc eluent) and the sample was analyzed by GC. 9,9′-bicarbazyl (1.2 mg, 3% yield) was quantified by preparative TLC with hexanes.
Procedure for standard photolytic reactions at varying reaction concentrations
Stock solutions of [Li(CH3CN)n][Cu(carb)2], Li(carb), and 6-bromo-1-heptene were prepared in CH3CN. Desired amounts of each were transferred to a 4 mL borosilicate vial,
54 and the mixture was diluted to a total volume of 4 mL with CH3CN. The vial was subjected to the standard photolytic conditions, and the products were analyzed by GC. Five reaction concentrations were tested: 0.011 M, 0.022 M, 0.033 M, 0.044 M, and 0.055 M in a total of 4 mL of CH3CN using 6-bromo-1-heptene as the limiting reagent. The data are summarized in Table 2.2; h/i values were calculated prior to rounding of yields of products h and i.
Table 2.2. Variation of yields of products h and i as a function of reaction concentrations.
Procedure for stoichiometric coupling of [Cu(carb)2]– with 2-bromo-4-phenylbutane
Stock solutions (0.0067 mmol mL–1) of [Li(CH3CN)n][Cu(carb)2] and 2-bromo-4- phenylbutane were prepared in CH3CN. Then, 0.0067 mmol of each reactant was added to a 4 mL vial containing a magnetic stir bar. The mixture was diluted to a total of 4 mL with CH3CN. The mixture was capped and stirred for 5 minutes and the reaction vessel was fully submerged in an isopropanol bath kept at 0 °C with a cryostat. The mixture was irradiated with 100-watt Hg lamp while stirring for 8 hours, after which time it was diluted with a solution of dodecane in Et2O or EtOAc. An aliquot was filtered through a short pad of silica
55 gel (EtOAc eluent) and the sample was analyzed by GC. Run 1: 95% yield. Run 2: 96%
yield.
Procedure for the time-course analysis of reactions with and without [Cu(carb)2]Li
Stock solutions of [Li(CH3CN)n][Cu(carb)2], Li(carb), and 2-bromo-4- phenylbutane were prepared in CH3CN. Desired amounts of each were transferred to a 4 mL borosilicate vial as outlined in the general procedure, and the vial was diluted to a total of 4 mL with CH3CN. The vial was subjected to the standard photolytic conditions for the specified amount of time, and the products were analyzed by GC. The data are summarized in Table 2.3 and Table 2.4.
Table 2.3. Yields of debromination, homocoupling, and C–N cross-coupled product over time under catalysis conditions.
56 Table 2.4. Yields of debromination, homocoupling, and C–N cross-coupled product over time in the absence of copper.