Copper‐Catalyzed Borylative Cross‐Coupling of Allenes and Imines: Selective Three‐Component Assembly of Branched Homoallyl Amines

Abstract A copper‐catalyzed three‐component coupling of allenes, bis(pinacolato)diboron, and imines allows regio‐, chemo‐, and diastereoselective assembly of branched α,β‐substituted‐γ‐boryl homoallylic amines, that is, products bearing versatile amino, alkenyl, and borane functionality. Alternatively, convenient oxidative workup allows access to α‐substituted‐β‐amino ketones. A computational study has been used to probe the stereochemical course of the cross‐coupling.

Branched amines are common motifs in biologically active molecules.S ubstituted homoallylic amines are privileged synthetic precursors to such motifs in addition to being acommon substructure in bioactive synthetic targets in their own right (Scheme 1a). [1] While the allylation of imines provides the most direct access to important homoallylic amines, [2,3] theprocess is generally more challenging than the allylation of aldehydes because of the lower electrophilicity/ reactivity of imines and their increased steric bulk, difficulties in predicting the stereochemical outcome of additions,a nd imine/enamine E/Z isomerization. In particular,the additions of substituted allyl metals require sophisticated levels of regio-and stereocontrol, which, if unchecked, lead to complex mixtures. [4] Thus,n ew approaches to the selective generation and controlled addition of functionalized allyl metals,formed under catalytic conditions using inexpensive catalysts,t o imines,p romises to expand access to complex homoallylic amines while unlocking new avenues for their subsequent synthetic manipulation.
Theu se of allenes and imines in catalytic three-component coupling reactions which involve the in situ generation of allyl metals has emerged as an exciting strategy to afford valuable,substituted homoallylic amines (Scheme 1b). [5][6][7] For example,t he groups of Oshima, [5e] Grigg, [5a-d] and Malinakova [5f-i] have studied the catalytic generation of allyl metals from allenes,byorganometallic addition, and their addition to imines.I na ni mportant advance,M orken and co-workers described the asymmetric palladium-catalyzed diboration of allenes with subsequent addition of an imine to trap the functionalized allyl borane intermediates in as eparate operation. [5j] In the study from Morken et al.,linear adducts were obtained and products were typically isolated as ketones after in situ oxidation of the CÀBb ond. In the above studies, expensive and supply-risk platinum-group metals were used. [5] Herein we describe ar egio-, chemo-, and diastereoselective copper-catalyzed three-component coupling of allenes, [8] bis(pinacolato)diboron, and imines, [9,10] proceeding via allyl coppers to give readily isolable,branched homoallylic amines bearing versatile amino,a lkenyl, and borane functionalities (Scheme 1c). Faced with the challenge of controlling the regioselectivity of borylcopper addition to allenes,itwas clear that the use of awell-defined, bench-stable,and commercially available precatalyst would be highly desirable.O ptimization of the process commenced with using 5mol %I PrCuCl, the allene 1a,6mol %o fK O tBu, and 1.1 equivalents of B 2 pin 2 in the borylative cross-coupling with the N-phenyl imine 2a.T he corresponding homoallylic amine 3a was obtained with 27 % conversion ( Table 1, entry 1). Pleasingly,i ncreasing the amount of base to 1equivalent (entries 2-4) resulted in near complete conversion to give 3a.A lthough the base could be changed (entry 5; the use of Cs 2 CO 3 gave 41 %c onversion), the use of KOtBu appeared optimal. Pleasingly,the allene 1b, also underwent efficient borylative cross-coupling with 2a under these reaction conditions (entry 6) and temperature was found to influence the diastereoselectivity of threecomponent coupling (entries 7a nd 8). By initiating the borylative cross-coupling of 1b and 2a at À78 8 8C( entry 8), quantitative conversion into 3b was observed and the homoallylic amine was obtained in 85:15 d.r.
With optimized reaction conditions in hand, we evaluated the scope of the reaction. In general, the reaction proved to be high yielding,a nd aw ide range of allene (1)a nd imine (2) coupling partners were converted into the corresponding homoallylic amines 3 with complete regiocontrol and with up to greater than 98 %diastereocontrol (Scheme 2). Arange of allenes was tolerated, including substrates bearing linear alkyl (to give 3c, 3d,and 3u), aryl (to give 3a), and 1,1-dialkyl (to give 3p-t and 3v)s ubstituents.1 ,1-Disubstitution in the starting allene allowed assembly of homoallylic amines, bearing quaternary centers,i naselective three-component coupling.T he common para-methoxyphenyl (PMP) protecting group for the nitrogen atom was incorporated in arange of aryl-substituted imines and proved compatible with the cross-coupling process (to give 3e-q and 3s-u). Theb orylative cross-coupling showed good functional-group tolerance with OMe (3fand 3p), CF 3 (3g), Br (3h and 3q), thienyl (3j and 3t), and furanyl (3i and 3s)g roups proving compatible with the reaction conditions.W hen the steric bulk of the imine substituent R 1 was increased, higher diastereoselectivities were noted, with iPr-(3n), tBu-(3o), 1-naphthyl-(3k), and otolyl-substituted (3m)p roducts generated with excellent diastereoselectivity (between 94:6 and > 98:2 d.r.). The influence of the imine substituent R 1 is best illustrated by comparing the assembly of the products 3d and 3u:the use of an o-tolyl-substituted imine increases the diastereoselectivity of the process from 79:21 to 92:8 d.r. Interestingly,the use of a tert-butylimine and an isopropylimine (to give 3o and 3n, respectively) resulted in low yields of the isolated products, while the attempted use of am esityl imine resulted in no reaction. Thus,the reaction is significantly slowed by the use of bulky groups on the imine.T his slower reaction is likely ar esult of the large substituents diminishing the rate of the transmetallation event which closes the catalytic cycle and involves aCu ÀNs pecies and B 2 pin 2 (see below).
Pleasingly,t he use of N-aryl imines afforded threecomponent coupling products (3)w hich were stable to silica gel column chromatography,a nd showed no signs of protodeborylation, ac ommon issue for vinylboron-containing compounds. [11] In the case of adducts arising from the use of N-benzyl imines,p roducts decomposed on silica, and were best isolated as the analogous methyl ketones after oxidative

Angewandte
Chemie workup ( Figure 1). Thus, a,b-substituted Mannich adducts were also available from the copper-catalyzed three-component coupling in good to excellent yields and with high diastereocontrol. [12] Thes uitability of the copper-catalyzed three-component coupling for preparative scale synthesis was next investigated. Pleasingly,upon cross-coupling with B 2 pin 2 and 1b,0.5 grams (2.2 mmol) of 2b gave 1.0 gram of the functionalized homoallylic amine 3m in 97 %y ield and it was essentially isolated as asingle diastereoisomer (Scheme 3). 11 BNMR analysis of functionalized homoallylic amine products 3 ( 11 B: d = À2.9 to 11 ppm; 11 B d = 35 ppm for atypical Bpin group) indicates an sp 3 -hybridized boron center resulting from dative coordination of the N n !B p in solution. [13] However,X -ray crystallographic analysis of 3v suggested that the B-N interaction is disrupted in the solid state ( Figure 2a). TheB -N interaction could also be broken by protonation of the nitrogen atom, that is,treatment of 3m with 1equivalent of trifluoromethane sulfonic acid afforded the salt 5a (Figure 2b).
Interestingly,N -sulfinyl and N-sulfonyl imines were unreactive under the reaction conditions of the coppercatalyzed three-component coupling.I namechanistic study designed to explore this observation, no conversion was observed in an experiment involving both 2a and the N-tosyl imine 2c (Scheme 4a). Both imines were detected unchanged in the 1 HNMR spectra of the crude reaction mixture.A n unproductive coordination of 2cto copper appears to prevent reaction of the boryl copper intermediate with the allene.T o probe this further, as toichiometric amount of the IPrCl was used to generate the allylcopper intermediate 6.A ddition of 2c to the preformed 6 generated the expected adduct 3w in 56 %y ield (Scheme 4b). This control experiment shows that allylcopper intermediates are efficiently trapped by N-sulfonyl imines and suggests that catalyst inhibition by the imine, possibly by formation of the coordination adduct 7,i nw hich the N-tosyl imine chelates to the copper catalyst through both the nitrogen and oxygen atoms,l ies behind the lack of reactivity observed with these imines. [14] Ap roposed mechanism for the copper-catalyzed threecomponent coupling is shown in Scheme 5. After initial formation of the ligated copper alkoxide I,t ransmetallation with B 2 pin 2 yields II.R egioselective insertion of the allene into the CuÀBbond then gives the allylcopper III,which can undergo diastereoselective addition to the imine to afford the homoallylic amine IV.B ase-assisted transmetallation then   11 BNMR data and X-ray crystallographic [21] analysis of 3v. b) Formation of asalt of 3m by disrupting the the N n !B p interaction. Ar = o-tolyl, Tf = trifluoromethanesulfonyl.

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Communications 1104 www.angewandte.org regenerates II and yields V,w hich upon workup gives the homoallylic amines 3 after protonation.
Theo bserved anti diastereoselectivity of the cross-coupling may arise from the addition of Z-allyl copper III through either the six-membered chair transition structure (TS) 8a,i nw hich copper interacts with the imine nitrogen atom, or through the half-chair-like transition structure 8b,in which the imine nitrogen atom interacts with boron (Scheme 6).
To explore the origin of the diastereoselectivity further, we have carried out computational studies on the coupling of the model imine A and allylcopper B (Scheme 7). Geometries were fully optimized in the gas phase and also in THF solvent. [15,16] As A and B approach each other, the potential energy decreases until the minimum energy structure (C)i s formed through interaction of copper with the nitrogen atom. In the gas phase this structure lies 29.6 kJ mol À1 in energy lower than the separated reactants.F rom the intermediate C, as ix-membered transition-state structure is formed (D;s ee 8a in Scheme 6). Theenergy barrier to the formation of D is only 10.0 kJ mol À1 (THF). After the formation of D,t he anti product E,w ith the Cu atom coordinated centrally over the C=Cb ond, is formed with an exothermicity of about 113 kJ mol À1 .
Thec omputational studies clearly suggest that the anti selectivity of the copper-catalyzed three-component coupling arises from the interaction of copper with the imine nitrogen atom and the formation of 8a (see transition structure D in Scheme 7), despite several substituents occupying pseudoaxial orientations. [17] Initial interaction of the imine nitrogen atom with boron is calculated to be less favorable and there is al arge barrier to carbon-carbon bond formation via the alternative half-chair-like transition structure 8b (see the Supporting Information).
In summary,t he first copper-catalyzed three-component coupling of allenes,i mines,a nd bis(pinacolato)diboron furnishes stable borylated homoallylic amines,orM annich-type products after oxidative work-up,w ith high control. The process utilizes ac ommercially available copper catalyst, tolerates ar ange of allene and imine building blocks,a nd affords complex homoallylic amine products in high yield with excellent regiocontrol and high diastereocontrol. [20] Computational studies suggest the diastereoselectivity of the

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Chemie coupling arises from imine complexation to the copper of the allylcopper intermediate and addition through as ix-membered chair transition structure.