2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with Ketones

Abstract

We introduce a new strategy for synthesis of chiral amines: couplings of α-aminoalkyl nucleophiles generated by enantioselective migratory insertion of 2-azadienes to a Cu–H. In this report, we demonstrate its application in catalytic reductive coupling of 2-azadienes and ketones to furnish 1,2-amino tertiary alcohols with vicinal stereogenic centers.

Graphical abstract

New methods for the stereoselective synthesis of chiral amines are highly valuable as these units are found within numerous natural products, pharmaceuticals, ligands for metals, and fine chemicals. Classic C–C bond-forming approaches to chiral amines rely on nucleophilic addition to imines.¹ Yet several classes of chiral amines, including 1,2-amino alcohols,² are challenging to prepare by this normal polarity paradigm. A traditional reverse polarity strategy that addresses this issue utilizes nitroalkanes as a means of accessing N-substituted carbanions;³ however, this tactic requires subsequent nitro group reduction to form the amine, adversely affecting step/redox economy.⁴ A streamlined approach would enantioselectively assemble the desired amine building block via C–C bond formation with all atoms in the correct oxidation state.

Direct enantioselective α-lithiation of alkylamines for addition to electrophiles provides one path, but these methods rely on strong alkyllithium bases and often stoichiometric quantities of sparteine or its analogues.⁵ Catalytic formation of an α-aminoalkyl transition metal reagent (Scheme 1) is a powerful means of generating chiral amines with several established approaches. Deprotonation to form a 2-azaallyl anion and addition to a Pd catalyst⁶ or alternatively transmetalation of an α-amino zinc⁷ or α-amino borate⁸ to Ni or Pd has enabled aryl and alkyl cross-coupling reactions. Metal-catalyzed C–H functionalization at the N-α-position has also permitted aryl cross-coupling,⁹ allylic substitution reactions,¹⁰ or addition to olefins.¹¹ Finally, catalytic formation of an α-amino radical, followed by recombination with a Ni or Fe catalyst, has allowed a variety of aryl, alkyl, or acyl cross-couplings,¹² borylations,¹³ or conjugate additions to take place.¹⁴ In each approach, enantioselective reactions are uncommon.^{6b,7,10b,11b,c,12d}

Scheme 1.

Methods and Uses for Catalytically-Generated α-Aminoalkyl-Substituted Transition Metals

In this work, we introduce a new strategy for catalytically forming an α-aminoalkyl transition metal for the enantioselective synthesis of amines. 2-Azadienes, which have rarely been used in synthesis,¹⁵ undergo migratory insertion at their least-hindered π-bond with a Cu–H to generate a 2-azaallyl-Cu intermediate, which may participate in stereoselective addition to a carbon electrophile. This reaction modality thus constitutes umpolung reactivity of an enamine. We demonstrate the feasibility of this approach in reductive coupling^16–19 with ketones to furnish 1,2-amino tertiary alcohols in up to 87% yield, >20:1 dr, and >99:1 er.^20–23

1,2-Amino tertiary alcohols are important building blocks for synthesis, but enantioselective construction of this functionality is all but unknown. Enantioselective Henry reactions with ketone electrophiles are few.²⁴ The direct catalytic enantioselective synthesis of amino tertiary alcohols is limited.^25,26 Furthermore, there are few examples where this functionality bears vicinal stereogenic centers. Typically this moiety is prepared by stepwise stereoselective addition of organometallics to α-amino acid derivatives.²⁷

We envisioned that enantioselective Cu-catalyzed reductive coupling of 2-azadienes and ketones,^16a,d followed by hydrolytic workup, would directly form a 1,2-amino tertiary alcohol (Scheme 1). We therefore began by examining the reaction of terminal azadiene 1a, acetophenone 2a, and a silane reducing agent (Table 1) and quickly identified Ph-BPE (L1) as uniquely effective at delivering desired product 3a (entry 1).^16d Other ligands (entries 2–6) afford <2% 3a while generating significant amounts of ketone reduction product 4a and/or iminopyrrolidine 5, formed by reductive dimerization of 1a.²⁸ In contrast, within 1.5 h L1 gives >98% conv to 3a (entry 7), which is formed in 4:1 dr as the major product (<10% ketone hydrosilylation). After imine reduction and ether desilylation (for ease of handling/assay purposes), the major diastereomer 6a is solely isolated in 73% yield and 99:1 er.^29,30

Table 1.

Ligand Identification for Reductive Coupling of Acetophenone and 2-Azadiene 1a^a

entry	ligand	conv of 2a (%)b	3a:4a:5c	dr of 3ac	er of 6ad
1	L1	82 (60)e	9:1:0	5:1	99:1
2	L2	<2	–	–	–
3	L3	<2	–	–	–
4	L4	60	0:6:1	–	–
5	L5	>98	0:1:0	–	–
6	L6	>96	0:1:0	–	–
7f	L1	>98 (73)e	11:1:0	4:1	99:1

^aReaction under N₂ with 0.1 mmol ketone 2a for 1 h.

^bDetermined by 400 MHz ¹H NMR spectroscopy according to remaining 2a in comparison to an internal standard.

^cDetermined by 400 MHz ¹H NMR spectroscopy of the unpurified mixture.

^dDetermined by HPLC analysis of purified 6a.

^eIsolated yield of amino alcohol 6a (>20:1 dr).

^fReaction with 0.2 mmol ketone 2a for 1.5 h. [Si] = Si(OMe)₂Me.

Several aryl/alkyl ketones undergo efficient reductive coupling with azadiene 1a under the optimized conditions (Table 2); the major diastereomer may be selectively isolated after the reductive/desilylative workup and chromatographic purification.²⁹ A variety of substituents on the aromatic ring are tolerated (6b–k),³¹ including N-heterocycles (6d) and free hydroxyl (6g) functionality (entries 1–10). For aromatic rings bearing ortho groups (6h–i), diastereoselectivity is significantly higher. For example, 6h is formed as a single stereoisomer and 6i is generated in13:1 dr. Enantioselectivity is high in all cases (96.5:3.5 to >99:1 er) and the major product stereoisomer is isolated in 45–87% yield. Ketones containing aromatic heterocycles deliver amino alcohols 6l–n in good diastereoselectivity and excellent enantioselectivity (5–9:1 dr and 95:5 to >99:1 er, entries 11–13). Longer alkyl chains within the ketone (2o–p) generate amino alcohols with improved diastereoselectivity (8–10:1 dr, entries 14–15) and with high enantioselectivity. Diaryl ketones undergo efficient azadiene coupling but with poor diastereoselectivity. For example, fenofibrate adduct 6q is formed in only 1:1 dr. The isomers may be separately isolated; each is generated in 99:1 er (entry 16). 2-Indanone undergoes reductive coupling to form 6r in 73% yield, 8:1 dr, and 97:3 er. Azadiene addition to the fragrance celestolide delivers 6s as a single stereoisomer in 72% yield.

Table 2.

Ketone Variation for Cu-Catalyzed Enantioselective Reductive Couplings with Azadiene 1a^a

entry	product, Ar, R	dr of 3b	yield (%)c	er of 6d
1e	6b, 4-MeOC6H4, Me	3.5:1	60	96.5:3.5
2	6c, 4-F3CC6H4, Me	4.0:1	50	>99:1
3	6d, 4-N-pyrazolylC6H4, Me	4.0:1	62	>99:1
4e	6e, 3-BrC6H4, Me	3.5:1	45	>99:1
5e	6f, 3-ClC6H4, Me	4.5:1	57	>99:1
6	6g, 3-HOC6H4, Me	7.5:1	62	>99:1
7e	6h, 2-BrC6H4, Me	>20:1	77	99:1
8	6i, 2-MeOC6H4, Me	13.0:1	87	97:3
9	6j, 2-napthyl, Me	3.5:1	65	99:1
10	6k, 3,4-dioxolatoC6H3, Me	5.5:1	61	98.5:1.5
11	6l, 2-furyl, Me	5.0:1	55	>99:1
12	6m, 3-thiophenyl, Me	9.0:1	83	99:1
13	6n, 3-pyrrolyl(NTs), Me	5.5:1	58	95:5
14	6o, Ph, Et	10.0:1	67	99:1
15	6p, Ph, CH2CH2Ph	8.0:1	63	98:2
16	6q, 4-ClC6H4, 4-(i-PrO2CCMe2O)C6H4	1.0:1	39, 37f	99:1, 99:1g

^aReaction with 0.2 mmol ketone 2.

^bDiastereomeric ratio of 3 determined by 400 MHz ¹H NMR spectroscopy of the unpurified mixture prior to workup.

^cIsolated yield of purified 6 (>20:1 dr).

^dEnantiomeric ratio determined by HPLC analysis of 6.

^eCu(OAc)₂· H₂O used.

^fIsolated yield of each diastereomer.

^gEnantiomeric ratio of each isomer.

A number of 4-alkyl-substituted 2-azadienes efficiently react with ketone 2i to afford α-alkyl chiral amines 7a–j as a single diastereomer in 43–59% yield (Table 3). The added steric hindrance imposed by the alkyl group necessitates a 12 h reaction time and leads to competitive ketone reduction, a pathway which is exacerbated with less-hindered ketones (e.g., acetophenone leads to >90% ketone reduction). A variety of functional groups are tolerated, such as thioether (entry 4), ether (entries 6–8), ester (entry 9), and halogen (entry 10).

Table 3.

Substituted 2-Azadienes for Enantioselective Additions to Ketones^a

entry	product, R	dr of 3b	yield (%)c	erd
1	7a, n-Bu	>20:1	43	96.5:3.5
2e	7b, (CH2)2Ph	>20:1	54	98.5:1.5
3	7c, (CH2)2(3-thiophenyl)	>20:1	52	>99:1
4f	7d, (CH2)2SMe	>20:1	52	98.5:1.5
5	7e, (CH2)3Ph	>20:1	45	98:2
6	7f, (CH2)3OBn	>20:1	47	98:2
7	7g, (CH2)3OPh	>20:1	59	99:1
8	7h, (CH2)3OTBS	>20:1	45	98.5:1.5
9	7i, (CH2)4OBz	>20:1	46	99:1
10	7j, (CH2)4C1	>20:1	48	98.5:1.5

^aReaction of (E)-azadiene 1 unless otherwise noted.

^bDetermined by 400 MHz ¹H NMR spectroscopy of the unpurified mixture prior to workup.

^cIsolated yield of purified 7.

^dEnantiomeric ratio determined by HPLC analysis of 7.

^e(E)- and (Z)-azadienes 1c deliver identical results.

^fFrom (Z)-1e.

Carbamates 8–9 (Scheme 2) may be obtained by the sequential reductive coupling of azadiene 1a and ketones 2h–i with desilylative workup, imine hydrolysis under mildly acidic conditions,²⁷ and Boc protection of the resulting primary amine (40–60% overall yield for the three-step sequence). The stereochemistry of the major isomer of 9 has been assigned as (R) at the amino center and (S) at the hydroxyl center. The free amine (10) may also be utilized for C–N cross-coupling reactions such as the Ullman coupling to generate aniline 11. The amine and hydroxyl group can instead both be engaged to form heterocycles such as oxazoline 12.

Scheme 2.

Derivatization of Coupled Products

Although we have been able in most cases to separate the two product diastereomers, we have not successfully isolated the minor stereoisomer of aryl/alkyl ketone addition in order to secure its stereochemical assignment. Experiments with symmetrical ketones (Scheme 3), however, suggest that the minor isomer differs in its stereochemistry at the hydroxyl-containing center. Both benzophenone and acetone³² undergo coupling with 1a with significantly higher enantioselectivity (6t–u formed in 95:5 to 97.5:2.5 er) than the diastereoselectivity observed in most other reactions (Tables 1–2). Additionally, unlike for 6q, where each diastereomer is formed in equal enantiopurity, in the case of 6v (Scheme 3), the major (2S,3R)-diastereomer is formed in >99:1 er but the minor, likely (2R,3R)-isomer, is furnished in only 95.5:4.5 er.

Scheme 3.

Implications for Stereochemistry of the Minor Diastereomer and Stereochemical Model

^aStandard catalysis conditions; see Table 2. ^b3.0 equiv acetone, 5.0 equiv silane, 5 mol % Cu(OAc)₂, 6 mol % L1, THF, 22 °C, 1 h.

Based on the available data, a working model that accounts for the stereochemical outcome of the azadiene/ketone couplings is proposed in Scheme 3. Coordination of azadienes to [(S,S)-Ph-BPE]Cu–H occurs to place the benzophenone imine portion in the least hindered quadrant, leading to insertion into the Re-face, consistent with previous models.^16d,e Stereorententive addition of the alkyl–Cu to the ketone’s Re-face delivers the major stereoisomer. The minor isomer arises from addition to the ketone’s Si-face, and all other stereoisomers are generated by stereoinvertive alkyl–Cu addition.

2-Azadienes are a promising class of reagents for preparation of chiral amines. Here, through reductive coupling with ketones, they have enabled catalytic enantioselective construction of 1,2-amino tertiary alcohols that have previously been inaccessible. Application of 2-azadienes for preparing other challenging amine scaffolds is underway.