Three-Component Betti Condensation for Synthesis of Aminomethylnaphthols Incorporating Deoxy-isoequilenine Scaffold-Absolute Configuration and Application

Zagranyarska, Irena; Kostova, Kalina; Dikova, Krasimira; Shivachev, Boris; Dimitrov, Vladimir

doi:10.21577/0103-5053.20220124

Brasil

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Article • J. Braz. Chem. Soc. 34 (4) • 2023 • https://doi.org/10.21577/0103-5053.20220124 linkcopy

Three-Component Betti Condensation for Synthesis of Aminomethylnaphthols Incorporating Deoxy-isoequilenine Scaffold-Absolute Configuration and Application

Authorship SCIMAGO INSTITUTIONS RANKINGS

Chiral aminomethylnaphthols have been prepared highly diastereoselective by means of three-component “Betti condensation”, using steroidal 2-naphthol analogue, synthesized from estrone. The use of 2-methoxybenzaldehyde or 2-pyridinecarboxaldehyde as aldehyde component and (S)-(–)-1-phenylethan-1-amine or (S)-(–)-1-(naphthalen-2-yl)ethan-1-amine, as chiral non-racemic amine component providing the diastereoselectivity, allowed the synthesis of structurally diverse aminomethylnaphthols. The latter easily form 1,3-dihydronaphthoxazines through reaction with formaldehyde. The absolute configurations of the new aminomethylnaphthols synthesized have been determined through advanced nuclear magnetic resonance (NMR) experiments and confirmed by X-ray crystallography. The chiral steroidal aminomethylnaphthols obtained as pure diastereoisomers have been evaluated as pre-catalysts in the enantioselective addition of diethylzinc to aldehydes with enantioselectivities of up to 97% enantiomeric excess (ee).

Keywords: Betti condensation; chiral ligands; NOESY spectra; absolute configuration; enantioselectivity


entry	Aldehyde	Ligand	Yield^a / %	ee (config.)^b / %
1	benzaldehyde	5a	34	33 (R)^c
2	2-methoxybenzaldehyde	5a	99	90 (R)^c
3	2,4,6-trimethylbenzaldehyde	5a	65	73 (unknown)^d
4	cinnamaldehyde	5a	90	56 (R)^d
5	2-naphthaldehyde	5a	88	97 (R)^c
6	4-chlorobenzaldehyde	5a	39	33 (R)^c
7	2,6-dichlorobenzaldehyde	5a	88	81 (unknown)^d
8	benzaldehyde	6a	25	20 (S)^c
9	2-methoxybenzaldehyde	6a	93	3 (S)^c
10	cinnamaldehyde	6a	52	1 (S)^d
11	2-naphthaldehyde	6a	63	26 (S)^c
12	benzaldehyde	8a	45	22 (R)^c
13	2-methoxybenzaldehyde	8a	50	77 (R)^c
14	cinnamaldehyde	8a	57	64 (R)^d
15	2-naphthaldehyde	8a	59	76 (R)^c
16	4-chlorobenzaldehyde	8a	38	27 (R)^c
17	2,6-dichlorobenzaldehyde	8a	90	72 (unknown)^d
18	benzaldehyde	9a	69	24 (S)^c
19	2-methoxybenzaldehyde	9a	47	7 (S)^c
20	2-naphthaldehyde	9a	51	26 (S)^c

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[TFN1] ^aYield of isolated pure products after column chromatography; ^bthe configuration was determined by comparison of the measured specific rotation with literature data; ^cenantiomeric excess (ee) was determined by GC (see SI section); ^denantiomeric excess was determined by HPLC (see SI section); unknown configuration, since no literature data about the specific rotation available.