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. 2021 Oct 27;12(46):15318-15328.
doi: 10.1039/d1sc04365j. eCollection 2021 Dec 1.

Intermolecular CDC amination of remote and proximal unactivated Csp3 -H bonds through intrinsic substrate reactivity - expanding towards a traceless directing group

Suresh Rajamanickam  1 , Mayank Saraswat  2 , Sugumar Venkataramani  2 , Bhisma K Patel  1
Affiliations

Intermolecular CDC amination of remote and proximal unactivated Csp3 -H bonds through intrinsic substrate reactivity - expanding towards a traceless directing group

Suresh Rajamanickam et al. Chem Sci. .

Abstract

An intermolecular radical based distal selectivity in appended alkyl chains has been developed. The selectivity is maximum when the distal carbon is γ to the appended group and decreases by moving from γ → δ → ε positions. In -COO- linked alkyl chains, the same distal γ-selectivity is observed irrespective of its origin, either from the alkyl carboxy acid or alkyl alcohol. The appended groups include esters, N-H protected amines, phthaloyl, sulfone, sulfinimide, nitrile, phosphite, phosphate and borate esters. In borate esters, boron serves as a traceless directing group, which is hitherto unprecedented for any remote Csp3 -H functionalization. The selectivity order follows the trend: 3° benzylic > 2° benzylic > 3° tertiary > α to keto > distal methylene (γ > δ > ε). Computations predicted the radical stability (thermodynamic factors) and the kinetic barriers as the factors responsible for such trends. Remarkably, this strategy eludes any designer catalysts, and the selectivity is due to the intrinsic substrate reactivity.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Substrate scope for the intermolecular amination of n-butyl acetate. a Reaction conditions: azole (0.5 mmol), n-butyl acetate (5 equiv. × 2), Bu4NI (10 mol% × 2) and aq TBHP (2 equiv. × 2) at 80 °C for 8 h in an inert atmosphere. b Isolated yields.
Scheme 2
Scheme 2. Substrate scope of amination at remote methylene, benzylic and tertiary-methine sites. a Reaction conditions: azole (0.5 mmol), ester (5 equiv. × 2), Bu4NI (10 mol% × 2) and aq TBHP (2 equiv. × 2) at 80 °C for 8 h. b Isolated yields.
Scheme 3
Scheme 3. Substrate scope for the amination of alkyl acetates. a Reaction conditions: 5-phenyl-2H-tetrazole (0.5 mmol), ester (5 equiv. × 2), Bu4NI (10 mol% × 2) and aq TBHP (2 equiv. × 2) at 80 °C for 8 h. b Isolated yields. c Products obtained as an inseparable regioisomeric mixture and the ratio determined by 1HMR analysis.
Scheme 4
Scheme 4. Substrate scope for intermolecular amination of esters.a Reaction conditions: aryl tetrazole (0.5 mmol), ester (5 equiv. × 2), Bu4NI (10 mol% × 2) and aq TBHP (2 equiv. × 2) at 80 °C for 8 h. a Isolated yield.
Scheme 5
Scheme 5. Substrate scope for the amination of various electron withdrawing groups. a Reaction conditions: (A–D), aryl tetrazole (0.5 mmol), substrates 12–22 (0.5 mmol), Bu4NI (10 mol% × 2), aq TBHP (2 equiv. × 2) and CH3CN (500 μl × 2) at 80 °C for 8 h. (E–H), azoles (0.5 mmol), substrates 23–27 (5 equiv. × 2), Bu4NI (10 mol% × 2) and aq TBHP (2 equiv. × 2) at 80 °C for 8 h. b Isolated yield. c Tributyl phosphite (26) used as the starting material. I, aryl tetrazole (0.5 mmol), substrates 28, 29 (0.5 mmol), Bu4NI (10 mol% × 2), aq TBHP (2 equiv. × 2) and CH3CN (500 μl × 2) at 80 °C for 8 h. d Isolated along with an inseparable mixture of uncharacterized impurities.
Scheme 6
Scheme 6. Substrate scope for alpha-site-selective amination. a Reaction conditions: 5-phenyl-2H-tetrazole (0.5 mmol), substrates 30–34 (0.5 mmol), Bu4NI (20 mol%), aq TBHP (4 equiv.) and CH3CN (1 mL) at 80 °C for 8 h. b Isolated yield.
Scheme 7
Scheme 7. Intermolecular selectivity between α-carbon to ketone and distal carbon. a Reaction conditions: 5-phenyl-2H-tetrazole (1 mmol), substrates 2 and 30 (1 mmol), Bu4NI (20 mol%), aq TBHP (4 equiv.) and CH3CN (1 mL) at 80 °C for 8 h. b Isolated yields.
Scheme 8
Scheme 8. Site-selective amination of tributyl borate. a Reaction conditions: 5-phenyl-2H-tetrazole (0.5 mmol), tributyl borate (5 equiv.), Bu4NI (20 mol%), aq TBHP (5 equiv.) and CH3CN (1 mL) at 80 °C for 8 h. b Isolated yield. Intermediate 35′a was not isolated.
Scheme 9
Scheme 9. Traceless directing group strategy for amination using borate esters. a Reaction conditions: 5-phenyl-2H-tetrazole (0.5 mmol), borate ester 35–38 (0.5 mmol), Bu4NI (20 mol%), tert-hexyl hydroperoxide (5 equiv.) and CH3CN (1 mL) at 80 °C for 8 h. b Isolated yield. c Trihexyl borate (38) was used.
Scheme 10
Scheme 10. Substrate scope of N-cycloalkylation of aryl tetrazoles. a Reaction conditions: aryl tetrazole (0.5 mmol), hydrocarbon 39, 40 (1.0 mmol), Bu4NI (20 mol%), aq TBHP (4 equiv.) and DMSO (1 mL) at 80 °C for 8 h. b Isolated yield. c Isomer ratio determined by 1H NMR.
Scheme 11
Scheme 11. Late stage amination of biologically active molecules. a Reaction conditions: 5-phenyl-2H-tetrazole (0.25 mmol), substrates 41 (0.25 mmol), 42 (1 mmol), Bu4NI (20 mol%), aq TBHP (4 equiv.) and CH3CN (1 mL) at 80 °C for 6 h.
Scheme 12
Scheme 12. The putative mechanism for an oxidative C–N bond formation.
Fig. 1
Fig. 1. Computed data on the distal selectivity in unactivated alkane (n-octane) 39. For each case, spin densities are represented in red and the BDEs (in kcal mol−1) are mentioned in blue; bold – (U)M06-2X/6-311G(d,p) and normal font – (U)wB97XD/6-311G(d,p) levels of theory.
Fig. 2
Fig. 2. Computed data on the distal selectivity in esters. (a) n-butyl acetate 1; (b) energy profile depicting the kinetic favourability of the γ-radical over α-radical formation in 1 through hydrogen abstraction by the tBuO radical (the corresponding transition states are indicated in Fig. S7 in the ESI‡); (c) n-pentyl acetate 6 and, (d)n-hexyl acetate 7; (for each case, spin densities are represented in red and the BDEs (in kcal mol−1) are mentioned in blue; the energies (in kcal mol−1) relative to the reactants, and the thermodynamic entropy changes (in cal K−1 mol−1) accompanying the reactions are indicated; bold – (U)M06-2X/6-311G(d,p) and normal font – (U)wB97XD/6-311G(d,p) levels of theory).
Fig. 3
Fig. 3. (a) Computed energy profiles depicting the kinetic and thermodynamic favorability of radical formation in 11; the energies relative to the 11 + tBuO radical are indicated (in kcal mol−1), the thermodynamic entropy changes accompanying the reactions are indicated (in cal K−1 mol−1); (the corresponding transition states are indicated in Fig. S8 in the ESI‡); (bold – (U)M06-2X/6-311G(d,p) and normal font – (U)wB97XD/6-311G(d,p) levels of theory). (b) Optimized geometries of possible isomeric radical intermediates in n-propyl acetate (11) at the (U)M06-2X/6-311G(d,p) level of theory; (c) The second-order perturbation energies (in kcal mol−1) from the natural bond orbital (NBO) analysis of the β-radical of n-propyl acetate (11) at the (U)M06-2X/6-311G(d,p) level of theory.
Fig. 4
Fig. 4. Computed data on the distal selectivity in ketones: (a) valerophenone 30; (b) energy profile depicting the formation of the radicals 32a and 32′a by hydrogen abstraction by the tBuO radical from 32 (the corresponding transition states are indicated in Fig. S9 in the ESI‡); (c), 33 (for each case, spin densities are represented in red and the BDEs (in kcal mol−1) are mentioned in blue; the energies (in kcal mol−1) relative to the reactants, and the thermodynamic entropy changes (in cal K−1 mol−1) accompanying the reactions are indicated; bold – (U)M06-2X/6-311G(d,p) and normal font – (U)wB97XD/6-311G(d,p) levels of theory).
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