The Synthetic Versatility of Acyloxyborohydrides

Abstract

Acyloxyborohydrides are unsurpassed in their versatility as reagents in organic synthesis. In addition to their superior ability in effecting reductive amination of aldehydes and ketones, acyloxyborohydrides can reduce nitrogen heterocycles (indoles, quinolines, isoquinolines), imines, enamines, oximes, amides, nitriles, benzylic alcohols, aryl ketones, aldehydes (but not ketones), acetals, -hydroxy ketones, and other substrates. The ability to control chemoselectivity, regioselectivity, and stereoselectivity by adjusting the carboxylic acid, borohydride reagent, stoichiometry, and temperature has no parallel in the repertoire of the organic chemist.

Novel Enamine Derivatives of 5,6-Dihydro-2′-Deoxyuridine Formed in Reductive Amination of 5-Formyl-2′-Deoxyuridine

“…In particular, the 1,4-reductive amination products are not observed for various aromatic aldehydes under similar reductive amination conditions with NaBH(OAc) 3 . [4][5][6] In the case of 5-formyl-2 -deoxyuridine 1, the formation of 1,4-conjugated product is probably possible due to the stabilization of dihydrouridine derivative by intramolecular hydrogen bonding. Similar effect of the intramolecular H-bonding was observed for many compounds with analogous enaminone functionality, for example, in the products derived from reactions of 3-formylchromones with amino compounds [16] and for 6-aminomethylene derivatives of 5-oxo-2-phenyl-5,6,7,8-tetrahydroquinazoline.…”

“…In all the reported reactions of the reductive amination of f 5 dU, employing various amine components and NaBH 4 or NaBH 3 CN, the secondary amine derivatives of 2 -deoxyuridines were the only isolated amino-modified products. [6][7][8][9][10]14] The scope of f 5 dU reductive amination carried out with NaBH(OAc) 3 was investigated with a series of primary amines of different nucleophilicity (aliphatic and aromatic amines), steric hindrance (t-butylamine) and with additional functionality present (histamine; Table 1). …”

“…In general, the reductive amination is a two-step transformation which proceeds via imine intermediate, further reduced to the corresponding amine by a variety of reducing agents, including NaBH 4 , [2] NaBH 3 CN, [3] and NaBH(OAc) 3 . [4][5][6] Recently, reductive amination has found wide application in the synthesis of various modified nucleosides and nucleic acid conjugates. [7] In particular, reductive amination of 5-formyl-2 -deoxyuridine (f 5 dU) has been used in the synthesis of 5-alkylamino derivatives of pyrimidine nucleosides.…”

“…of Z ),3.82 (s, 3H, OCH 3 of E), 3.68-3.98 (m, 4H, CH 2 -6 of Z and E), 3.99-4.39 (m, 6H, H4 , H5 , H5 of Z and E), 5.06-5.19 (m, 3H, H3 of Z and E, CH 2 NH CH of E),6.30 (dd, J H1 ,H2 = 5.9 Hz, J H1 ,H2 = 8.9 Hz, 1H, H1 of Z ),6.41 (dd, J H1 ,H2 = 5.9 Hz, J H1 ,H2 = 8.8 Hz, 1H, H1 of E),6.60 (d,4 J H5,H2 = 1.0 Hz, 1H, Im-CH -5 of Z ),6.61 (d,4 J H5,H2 = 1.0 Hz, 1H, Im-CH -5 of E), 6.70 (d, J H7,NH = 13.1 Hz, 1H, H7 of Z ), 6.79-7.41 (m, 31H, MMTr, NH -3 of Z and E, Im-CH -2 of E), 7.43 (d, 4 J H2,H5 = 1.3 Hz, 1H, Im-CH -2 of Z ), 7.46 (m, 1H, H7 of E), 8.43 (m, 1H, CH 2 NH CH of Z ); 13 C NMR (63 MHz, CDCl 3 ) δ 21.00 (CH 3 COO of E and Z ), 21.06 (CH 3 COO of E and Z ), 28.90 (ImCH 2 of E), 30.09 (ImCH 2 of Z ), 32.69 (C2 of E), 33.30 (C2 of Z ), 36.84 (C6 of E), 40.32 (C6 of Z ), 48.75 (CH 2 NH of Z ), 49.34 (CH 2 NH of E), 55.42 (OCH 3 of Z and E), 63.94 (C5 of E), 64.16 (C5 of Z ), 74.34 (C3 of E), 74.46 (C3 of Z ), 75.10 (MMTr-CPh 3 of Z ), 75.22 (MMTr-CPh 3 of E), 80.44 (C4 of Z ), 80.66 (C4 of E), 84.20 (C1 of Z ), 84.59 (C1 of E), 85.00 (C5 of Z ), 87.43 (C5 of Z ), 113.44 (MMtr-o of Z and E), 118.91 (Im-CH-5 of E), 119.60 (Im-CH-5 of Z ), 128.17 (MMTr-o of Z and E, MMTr-p of Z ), 128.44 (MMTr-p of E), 129.74 (MMTr-m of Z and E), 131.23 131.30 (MMTr-m of Z and E), 134.31 (Im-CH-4 of E), 134.43 (Im-CH-4 of Z ), 137.18 (MMTr-i of Z ), 137.75 (MMTr-i of E), 138.57 (Im-CH-2 of E), 138.83 (Im-CH-2 of Z ), 142.61 (MMTr-i of E), 142.70 (MMTr-i of Z ), 146.72 (C7 of E), 150.15 (C7 of Z ), 153.09 (C2 of E), 153.81 (C2 of Z ), 159.25 (MMTr-p of Z and E), 164.91 (C4 of E), 166.71 (C4 of Z ), 170.63 (CH 3 COO of Z and E), 171.09 (CH 3 COO of Z and E); UV (CHCl 3 ) λ max = 305 nm (ε = 12600). Direct Reductive Amination with Benzylamine Isolated products: 3d, 250 mg, yield 58%; 4d, 168 mg, yield 39%.…”

Sodium Triacetoxyborohydride

“…In addition to its superior ability in effecting reductive amination of aldehydes and ketones, it can reduce N-heterocycles (indoles, quinolines, and isoquinolines), imines, enamines, oximes, amides, aryl ketones, acetals, and other substrates. 1 STAB-H is a milder and more selective reducing agent than NaBH 4 . The mild nature of STAB-H may be attributed both to the bulky nature of the reagent and to the inductive electron-withdrawing ability of the three acetoxy groups which stabilize the boron-hydrogen bond.…”