University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Patrick Dussault Publications Published Research - Department of Chemistry 11-2011 A Mild One-Pot Conversion of Alkenes into Amines through Tandem Ozonolysis and Reductive Amination ShivaKumar Kyasa University of Nebraska–Lincoln Thomas J. Fisher University of Nebraska–Lincoln, Patrick Dussault University of Nebraska-Lincoln, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/chemistrydussault Part of the Chemistry Commons Kyasa, ShivaKumar; Fisher, Thomas J.; and Dussault, Patrick, "A Mild One-Pot Conversion of Alkenes into Amines through Tandem Ozonolysis and Reductive Amination" (2011). Patrick Dussault Publications. 13. https://digitalcommons.unl.edu/chemistrydussault/13 This Article is brought to you for free and open access by the Published Research - Department of Chemistry at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Patrick Dussault Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Published in Synthesis 21 (2011), pp. 3475–3481; doi: 10.1055/s-0030-1260244 Copyright © 2011 Georg Thieme Verlag, Stuttgart & New York. Used by permission. Submitted June 30, 2011; published online September 27, 2011; in print November 2, 2011. A Mild One-Pot Conversion of Alkenes into Amines through Tandem Ozonolysis and Reductive Amination ShivaKumar Kyasa,1 Thomas J. Fisher,1 and Patrick H. Dussault Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE 68588-0304, USA Corresponding author — P. Dussault, fax 402 472-9402, email [email protected] Abstract Table 1. Preparation of Hydroperoxyacetals The selective reduction of hydroperoxyacetals to aldehydes by sodium triacetoxyborohydride provides the basis for a mild one-pot synthesis of amines from alkenes. Keywords: ozonolysis, hydroperoxyacetal, reductive amina- tion, amine, sodium triacetoxyborohydride Reductive amination is a widely used transformation in or- ganic synthesis.2 The carbonyl precursors are often prepared from alkenes through ozonolysis followed by reduction of the ozonide or peroxide intermediates.3, 4 In the course of investi- gations into new transformations based upon fragmentation of ozonolysis intermediates,5 we became interested in the devel- opment of a mild method for a one-pot conversion of alkenes to amines. Reductive amination is frequently achieved through the reaction of carbonyls and amines in the presence of deac- 2b, 6, 7 tivated boron hydrides, and NaCNBH3-promoted reduc- tive amination has been applied in tandem with ozonolysis.8 However, NaCNBH3 reduces ozonides (1,2,4-trioxolanes) very slowly,9 and some of the reported transformations may actually involve amine-promoted E1cb fragmentation of terminal ozon- 10, 11 ides. We investigated the reaction of NaCNBH3 with more reactive hydroperoxyacetals, but observed significant formation of alcohols. Our attention was therefore turned to the less re- active triacetoxyborohydride, which has been investigated lit- tle in ozonolysis/amination sequences.12, 13 We now report that NaBH(OAc)3 allows rapid and efficient reduction of ozonoly- a Partial decomposition upon chromatography. sis-derived hydroperoxyacetals to aldehydes, enabling a mild and convenient one-pot synthesis of amines from alkenes based upon ozonolysis and reductive amination. The starting hydroperoxyacetals were readily available Reduction with NaBH(OAc) was next applied to a wider through ozonolysis of precursor alkenes or enol ethers in 3% 3 group of hydroperoxyacetals (Table 2). Hydroperoxyacetals MeOH-CH Cl (Table 1).14, 15 2 2 reacted faster (2 h) than hydroperoxyketals (5-8 h). In both Reduction conditions were initially screened on hydroperoxy- cases, a high yield of the carbonyl was obtained with little or acetal 1b using 1H NMR of crude reaction mixtures to monitor no overreduction. the ratio of starting hydroperoxyacetal, aldehyde (nonanal), Reductive amination was easily conducted through reduc- and the alcohol (nonanol) derived from overreduction. It was tion of the hydroperoxyacetal with NaBH(OAc) (1 equiv), found that NaBH(OAc) offered high selectivity for aldehyde 3 3 followed by addition of amine and additional hydride formation in several different solvent systems (CH Cl , DCE, 2 2 (Scheme 1). The reactions were found to give good yields THF) and under several sets of conditions. Performing the re- of monoalkylated amines. For the amination of aldehyde 2b duction with one equivalent of NaBH(OAc) proved opti- 3 with benzylamine, 8% of the tertiary amine derived from mal; and excess of reducing reagent (1.5-3 equiv) led to slow overalkylation was isolated, in addition to the expected sec- overreduction of the aldehyde. In contrast, the use of the more ondary amine 2f. reactive NaCNBH3 in stoichiometric amounts cleanly gener- ated alcohol, while a mixture of alcohol and starting material Finally, it was found that ozonolysis and reductive amina- was observed even with only 0.33 equivalent of reagent. tion could be easily combined into a one-pot transformation 3475 3476 KYASA, FISHER, & DUSSAULT IN SYNTHESIS 21 (2011) Table 2. Reduction of Hydroperoxyacetals with NaBH(OAc)3 Table 3. Stepwise versus One-Pot Reductive Amination a Based upon 15% recovered starting material. dergo a tandem oxidation/reduction amination sequence to Scheme 1. Stepwise reduction-reductive amination provide a variety of heterocyclic amines with an average yield of ~90% per reaction. In some cases, condensation of the prod- uct secondary amine with residual formaldehyde, a by-prod- uct of the ozonolysis of terminal olefins, gave rise to a tertiary (Table 3). Ozonolysis of an alkene substrate was conducted amine (e.g., 11b). in methanol-CH2Cl2 until the alkene could no longer be de- tected (TLC). The crude reaction mixture was then submit- A very similar protocol can be applied to the synthesis of hy- ted to one of two protocols. In the first (method A), addition drazones, hydrazines, and diazenes. Ozonolysis of 4a, fol- of acetoxyborohydride (1 equiv) was followed, after 45 min- lowed by treatment of the crude hydroperoxyacetal with utes to 1 hour, by addition of amine and additional acetoxy- phenylhydrazine and NaBH(OAc)3, cleanly furnished a phen- borohydride. More conveniently (method B), the crude ozon- ylhydrazone (TLC). Addition of NaCNBH3 resulted in the for- olysis product was treated with acetoxyborohydride (3 equiv) mation of the phenylhydrazide, which underwent rapid air and amine (1-2 equiv). Similar yields were obtained from the oxidation during isolation to furnish the diazene as the iso- two sequences. Under these conditions, cyclic alkenes un- lated material in 57% yield (Scheme 2). MILD ONE-POT CONVERSION of ALKENES INTO AMINES 3477 Carbonyl Compounds from Hydroperoxyacetals; General Procedure 2 (GP 2) To a r.t. solution of hydroperoxyacetal (~0.5 mmol) in DCE (10 mL) was added NaBH(OAc)3 (0.5 mmol). After product formation was complete (TLC, eluent: EtOAc-hexanes), the reaction was di- luted with CH2Cl2 (~40 mL) and washed sequentially with sat. aq NaHCO3 (~30 mL) and brine (~30 mL). The organic layer was dried (Na2SO4) and the residue obtained upon concentration in vacuo was purified by flash chromatography using EtOAc-hexanes. Amines from Hydroperoxyacetals; General Procedure 3 (GP 3) To a solution of hydroperoxyacetal (~0.5 mmol) in DCE (10 mL) was Scheme 2 added NaBH(OAc)3 (0.5 mmol). The reaction mixture was stirred for an hour at r.t., after which additional NaBH(OAc)3 (1 mmol) was added followed by amine (0.5 mmol). After the reaction appeared While there are many procedures for conversion of alkenes to complete (TLC, eluent: EtOAc-hexanes), the solution was diluted with CH Cl (40 mL), and washed sequentially with sat. aq NaHCO amines, most require separate oxidation and amination steps, 2 2 3 (30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) each involving isolation and purification. The procedure re- and the residue obtained upon concentration was purified by flash ported here, which allows a one-pot conversion of alkenes to chromatography with CH Cl -MeOH (1-2%) containing a few drops a variety of amines while avoiding any accumulation of per- 2 2 of Et3N. oxide intermediates, may be of particular use for preparation of an array of amines from a common precursor, or in proce- Direct Synthesis of Amines from Alkenes; General Procedure 4 (GP dures limited by concerns with isolation or handling of per- 4) oxide intermediates. Utilization of NaBH(OAc)3 in place of Stepwise (Method A): A solution of alkene (~1 mmol) and MeOH (0.3 NaCNBH provides a more economical, safe, and selective 3 mL) in CH2Cl2 (10 mL) in a round-bottomed flask was ozonized as protocol for the one-pot tandem ozonolysis/reductive ami- in GP 1. Following removal of free ozone, the cooling bath was re- nation sequence for the conversion of alkenes to amines. The moved and NaBH(OAc)3 (1 mmol) was added. The reaction mix- speed and selectivity of the reduction of the hydroperoxyace- ture was stirred at r.t. for 45 min, after which amine (~1 mmol) and tals suggests the formation and decomposition of a peroxybo- NaBH(OAc)3 (2 mmol) were sequentially added. The mixture was stirred at r.t. for 1-2 h and then filtered through Celite and the pad rate, ROOBH(OAc)2. washed with CH2Cl2 (20 mL). The filtrate was concentrated on a ro- All reagents were used as received from commercial vendors, with tary evaporator, and the residue was purified as in GP 3. the exception of CH2Cl2, which was distilled from CaH2, and THF, One Step (Method B): A solution of alkene (~1 mmol) and MeOH (0.3 which was distilled from Na/benzophenone. TLC was performed mL) in CH2Cl2 (10 mL) in a round-bottomed flask was ozonized as on 0.25 mm hard-layer silica G plates; developed plates were visu- in GP 1. Following removal of free ozone, the cooling bath was re- alized with a hand-held UV lamp or by staining: 1% Ce(SO ) and 4 2 moved and NaBH(OAc)3 (3 mmol) and the amine (1-2 mmol) were 10% (NH4)2MoO4 in 10% H2SO4 (general stain, after charring); 1% sequentially added.