(S)-N1,N3-Dibenzyl-1-cyclohexyl-N1,N3-bis((R)-1-phenylethyl)propane-1,3-diamine

Abstract

(S)-N¹,N³-dibenzyl-1-cyclohexyl-N¹,N³-bis((R)-1-phenylethyl)propane-1,3-diamine was prepared in good yield by the reduction of the corresponding amide, which was obtained by the addition of a chiral lithium amide to an α,β-unsaturated ester. The target compound was fully characterized by NMR (¹H and ¹³C), high-resolution mass spectrometry and polarimetry.

1. Introduction

1,3-Diamines represent a chemical space with attractive bioactivity, such as sparteine and its derivatives (Figure 1). These compounds showed diverse therapeutic effects [1,2], including antiarrhythmic [3], anticonvulsant [4], sodium channel blockers [5], and neuroprotective activity [6]. In addition to its clinical use, chiral 1,3-diamines present interesting applications in organic chemistry used as organocatalysts or chiral auxiliars [7,8,9,10]. The synthesis of 1,3-diamine scaffold has been reported using a wide variety of methodologies and starting materials [11,12,13], commonly using some types of catalyst. Therefore, a cheap and quick methodology for the asymmetric synthesis of this type of compounds would be interesting and useful.

In this study, we present the synthesis of a chiral 1,3-diamine using chiral lithium amides. Davies et al. had widely studied the asymmetric addition of this chiral lithium amides to different α,β-unsaturated esters, with a total control of the stereochemistry [15,16,17]. In our laboratory, this methodology has been used several times to afford the synthesis of a series of compounds with interesting biological activity [18,19,20], and recently using Ezetimibe analogs, through a domino protocol by the addition of the chiral lithium amide to Baylis–Hillman adducts.

The newly formed stereocenter is determined by the chirality of the amine which formed the lithium amide [21,22,23], giving us a quick method to the asymmetric synthesis of promising compounds obtaining the 1,3-diamine scaffold (Figure 2).

2. Results and Discussion

The addition of n-BuLi (1,6 M in hexane) to a THF solution of (R)-(+)-N-benzyl-N-methylbenzylamine at −78 °C furnished the corresponding lithium amide (5) [24]. Different (E)-3-cyclohexyl acrylates were used as substrates, particularly, methyl, ethyl, and tert-butyl acrylates. Table 1 shows the results obtained for each case.

When tert-butyl acrylate is used as a substrate, the only product obtained is the corresponding amino-ester as a result of the attack of the lithium amide in the β-position (98% yield) [Entry 1]. The product is obtained in high yield because of the high steric hindrance of the tert-butyl group, preventing the attack of another equivalent of lithium amide to the carbonyl moiety. If the ester’s protecting group is replaced with an ethyl group, the yield of the corresponding amino-ester 3 (spectroscopic information in the Supplementary Materials) drops to 37% and the main product is amide 4, resulting from the attack of two equivalents of lithium amide (5) (54% yield) [Entry 2]. Yield is increased to 72% if methyl acrylate is used [Entry 3], and when doubling the equivalents of lithium amide used, the yield increases up to 83% [Entry 4], due the low steric hindrance of this group.

The ¹³C NMR of amide 4 shows the duplicity of several signals, due the existence of rotamers. The C–N bond of the amide group has no free rotation; thus, the amide N-substituents show duplicated signals in both ¹C NMR and ¹H NMR. Thus, the spectra of compound 4 are presented, but the signals are not assigned. Spectra at different temperatures will be derived in order to fully characterize this compound. The results of the ¹H and ¹³C heteronuclear correlation experiments (HSQC and HMBC/Supplementary Materials) corroborate their structure and the full assignment of ¹H and ¹³C data of 1.

Chiral 1,3-diamine 1 is obtained in 73% yield by amide 4 treatment with strong reductive conditions. Amine substituents are suitable for modification by debenzylations and further functionalization.

3. Materials and Methods

All reagents were purchased from Sigma-Aldrich (Merck Group, Darmstadt, Germany) and used without purification, except for the solvents, purified by distillation. Specific rotation was measured with a digital polarimeter Perkin-Elmer 241 (PerkinElmer, Waltham, MA, USA) using chloroform as solvent and 1 dm optical pitch cuvettes. IR spectra were taken with a spectrometer Shimazdu FT IR-Affinity 1 (Shimadzu Europa GmbH, Duisburg, Germany) Mass spectra were referred to the Mass Spectrometry service of University of Salamanca. NMR spectra were recorded on a Bruker Avance Neo 400 MHz spectrometer (Bruker, Zagreb, Croatia) using the chloroform signal as a reference (7.26 ppm in ¹H and 77.00 ppm in ¹³C). TLC was run with Merck 60 F254 0.2 mm thickness TLC cards (Merck KGaA, Darmstadt, Germany).

Synthesis of N-benzyl-3-(benzyl((R)-1-phenylethyl)amino)-3-cyclohexyl-N-((R)-1-phenylethyl)propanamide (4): A solution of 780 mg (5.14 mmol; 2.4 Eq) of N-benzyl-N-(α)-(methyl)benzyl amine in dry THF (5 mL) and inert atmosphere was cooled at −78 °C, and 2.95 mL (4.73 mmol; 2.2 Eq) of n-BuLi 1.6 M in hexane was added dropwise while stirring in order to elaborate 5. After 15 min, the solution was immersed in an ice bath for a further 15 min. Subsequently, the solution of 5 was returned to −78 °C and transferred via cannula to the solution of 360 mg (2.15 mmol; 1 Eq) of methyl (E)-cyclohexylacrylate in dry THF (5 mL) at −78 °C and inert atmosphere. The mixture was gently stirred at −78 °C for 1.5 h. NH₄Cl sat. (10 mL) was added before heating to room temperature. THF was removed in vacuum and the aqueous phase was extracted with AcOEt (5 mL) 3 times. The organic phase was washed 3 times with 10% p/v citric acid, 3 times with H₂O, 3 times with brine, and the solvent was removed under vacuum. The concentrated extract was flash-chromatographed (hexane/ethyl ether 95/5 to 9/1) on silica gel obtaining 3 and 4 in 20% and 70% yields, respectively.

The same procedure was carried out but doubling lithium amide equivalents (N-benzyl-N-(α)-(methyl)benzyl amine: 1.54 g; 10.28 mmol; 4.8 Eq; n-BuLi: 5.9 mL; 9.45 mmol; 4.4 Eq) and only 4 was isolated, exhibited as a pale yellow oil in 83% yield. ¹H NMR (400 MHz, CDCl3) δ (ppm) 7.52–6.88 (m), 6.12 (q, J = 7.2 Hz), 4.92 (d, J = 15.5 Hz), 4.85 (q, J = 7.0 Hz), 4.03 (d, J = 17.8 Hz), 3.92 (d, J = 17.8 Hz), 3.89 (J = 17.8 Hz), 3.81 (m), 3.73 (m), 3.62 (J = 15.9, 7.0 Hz), 3.51 (d, J = 15.1 Hz), 3.48 (d, J = 15.0), 3.29 (d, J = 15.1 Hz), 2.29 (dd, J = 16.6, 9.4 Hz), 2.13 (d, J = 11.8 Hz), 1.98 (dd, J = 16.7, 9.7 Hz), 1.84 (d, J = 12.5 Hz). 1.43 (d, J = 7.2 Hz), 1.22 (d, J = 7.0 Hz), 1.80–0.85 (m). ¹³C NMR (101 MHz, CDCl₃) δ 172.80, 172.13, 141.66, 141.47, 141.38, 141.35, 141.30, 128.64, 128.46, 128.37, 128.32, 128.30, 128.27, 128.25, 128.18, 128.08, 128.03, 127.98, 127.88, 127.49, 127.38, 127.35, 127.22, 126.89, 126.77, 126.66, 126.61, 126.54, 126.51, 126.46, 125.87, 57.22, 56.93, 55.08, 54,79, 51.84, 51.75, 51.39, 47.04, 46.32, 33.71, 33.16, 31.16, 30.74, 30.45, 26.92, 26.73, 19.81, 19.75, 19.16, 17.06. HR-MS: calculated for [C₃₉H₄₆N₂O + H]⁺ = 559.3688, found = 559.3680 (Δ (ppm) = 1.43). IR: 3061.03 cm⁻¹, 3026.31 cm⁻¹, 2926.01 cm⁻¹, 2850.79 cm⁻¹, 1645.28 cm⁻¹, 1492.90 cm⁻¹, 1452.40 cm⁻¹, 1415.75 cm⁻¹, 1409.96 cm⁻¹, 1028.06 cm⁻¹, 748.38 cm⁻¹, 743.88 cm⁻¹, 698.23 cm⁻¹.

Synthesis of1, reduction of4with LAH: 77 mg (1. Eq, 0.14 mmol) of 4 was dissolved in 10 mL of dry THF and immersed on an ice bath at 0 ºC while stirring. Then, 92 mg (5 Eq, 2.41 mmol) of LAH was slowly added. The solution was slowly heated up to 65 ºC while stirring under an inert atmosphere for 48 h. The crude was cooled to 0 ºC and 5 mL of saturated NH₄Cl was slowly added. The THF was removed under vacuum, and the crude was extracted 3 times with AcOEt. The organic phase was washed 3 times with 5 mL of water and 3 times more with 5 mL of saturated NaCl. The organic phase was concentrated under vacuum and the concentrated extract was flash-chromatographed (hexane/ethyl ether 95/5 to 9/1), obtaining 54 mg (72% yield) of 1,5 1 as a very pale yellow oil. ¹H NMR (400 MHz, CDCl3) δ (ppm) 7.36–7.09 (m, 20H), 3.73 (d, J = 15.4 Hz, 1H), 3.68 (q, J = 6.7 Hz, 1H), 3.63 (q, J = 7.0 Hz, 1H), 3.51 (d, J = 15.4 Hz, 1H), 3.42 (d, J = 14.0 Hz, 1H), 3.31 (d, J = 14.0 Hz, 1H),2.12 (m, 2H), 2,07 (td, J = 12.3, 4.9 Hz, 1H), 1.90 (d, J = 12.1 Hz, 1H), 1.63–1.46 (m, 4H), 1.25 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 7.0, 3H), 1.11 (m, 1H), 1.08 (m, 1H), 1.05–0.83 (m, 5H).¹³C NMR (101 MHz, CDCl₃) δ 144.29, 144.18, 142.70, 141.15, 128.56–126.23 (20C, CH Ar), 59.70, 58.97, 57.94, 54.33, 52.06, 49.05, 42.06, 31.58, 30.89, 30.59, 26.83, 26.81, 26.68, 26.46, 22.65, 15.28, 14.11. HR-MS: calculated for [C₃₉H₄₈N₂ + H]⁺ = 545.3896, found = 545.3881 (Δ (ppm) = 2.75). IR: 3085.25 cm⁻¹, 3061.03 cm⁻¹, 3026.31 cm⁻¹, 2968.45 cm⁻¹, 2916.01 cm⁻¹, 2850.79 cm⁻¹, 2804.50 cm⁻¹, 1492.90 cm⁻¹, 1450.47 cm⁻¹, 1371.39 cm⁻¹, 1265.30 cm⁻¹, 1201.65 cm⁻¹, 1147.65 cm⁻¹, 1111.00 cm⁻¹, 1083.99 cm⁻¹, 1074.35 cm⁻¹, 1028.06 cm⁻¹, 759.95 cm⁻¹, 742.59 cm⁻¹, 731.02 cm⁻¹, 451.34 cm⁻¹. [α]_D²⁰ = 27.9 (c = 4.16 M, CHCl₃).

4. Conclusions

The target chiral diamine (S)-N¹,N³-dibenzyl-1-cyclohexyl-N¹,N³-bis((R)-1-phenylethyl)propane-1,3-diamine has been synthetized in a 61% overall yield by the aza-Michael addition of lithium (R)-(+)-N-benzyl-α-methylbenzylamide excess (4.4 Eq) to an affordable α,β-unsaturated ester and further reduction with LAH. In the near future, we aim to synthesize a variety of chiral 1,3-diamines using this methodology in order to carry out QSAR studies.

Author Contributions

Conceptualization, N.M.G. and C.T.N.; investigation, L.B., Á.G.-G. and A.M.; writing—original draft preparation, L.B.; writing—review and editing, L.B., Á.G.-G., A.M., C.T.N. and N.M.G.; supervision, N.M.G. and C.T.N. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

The data of this study are available in this paper and its Supplementary Materials.

Acknowledgments

The authors are also grateful for the support from Servicios de la Universidad de Salamanca (Nucleus): A.M. Lthgow for the NMR and César Raposo for the mass spectra.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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Figures and Table

Figure 1. (a) 1,3-diamine-based compounds [14]. (b) Retrosynthetic analysis of 1.

Figure 2. Synthetic pathway of 1.

Table 1

Different R groups and their yields.

Entry	R	Eq (5)	Yield (3)(%)	Yield (4)(%)
1	Tert-butyl	2.2	98	-
2	Ethyl	2.2	37	54
3	Methyl	2.2	20	72
4	Methyl	4.4	-	83

Supplementary Materials

The following supporting information can be downloaded. Horner–Wadsworth–Emmons’ synthetic methodology. NMR spectra (¹H, ¹³C, HMBC, HSQC, and COSY), infrared spectrum, and HR-MS report of diamine 1 and amide 4 [23,25].

References

1. Hidalgo, M.; Asmat Marrufo, P.; Lezama Asencio, P.; Ramos, C.; Chimoy Tuñoque, C.A.; Zolla, G. Evaluation of in vitro susceptibility to sparteine in four strains of Mycobacterium tuberculosis. Rev. Peru. Med. Exp. Salud Pública; 2022; 39, pp. 77-82. [DOI: https://dx.doi.org/10.17843/rpmesp.2022.391.10136] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35766744]

2. Chen, J.; Kassenbrock, A.; Li, B.X.; Xiao, X. Discovery of a potent anti-tumor agent through regioselective mono-N-acylation of 7 H-pyrrolo [3, 2-f] quinazoline-1, 3-diamine. MedChemComm; 2013; 4, pp. 1275-1282. [DOI: https://dx.doi.org/10.1039/c3md00134b] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24163729]

3. Pugsley, M.K.; Saint, D.A.; Hayes, E.; Berlin, K.D.; Walker, M.J. The cardiac electrophysiological effects of sparteine and its analogue BRB-I-28 in the rat. Eur. J. Pharmacol.; 1995; 294, pp. 319-327. [DOI: https://dx.doi.org/10.1016/0014-2999(95)00551-X]

4. Zhou, J.; Yang, Q.; Lee, C.S.; Wang, J. Enantio-and Regioselective Construction of 1, 4-Diamines via Cascade Hydroamination of Methylene Cyclopropanes. Angew. Chem. Int. Ed.; 2022; 61, e202202160. [DOI: https://dx.doi.org/10.1002/anie.202202160]

5. Gawali, V.S.; Simeonov, S.; Drescher, M.; Knott, T.; Scheel, O.; Kudolo, J.; Kählig, H.; Hochenegg, U.; Roller, A.; Todt, H. C2-Modified Sparteine Derivatives Are a New Class of Potentially Long-Acting Sodium Channel Blockers. ChemMedChem; 2017; 12, pp. 1819-1822. [DOI: https://dx.doi.org/10.1002/cmdc.201700568] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29045055]

6. Gavilan, J.; Mennickent, D.; Ramirez-Molina, O.; Trivino, S.; Perez, C.; Silva-Grecchi, T.; Godoy, P.A.; Becerra, J.; Aguayo, L.G.; Moraga-Cid, G. 17 Oxo Sparteine and Lupanine, Obtained from Cytisus scoparius, Exert a Neuroprotection against Soluble Oligomers of Amyloid-β Toxicity by Nicotinic Acetylcholine Receptors. J. Alzheimer’s Dis.; 2019; 67, pp. 343-356. [DOI: https://dx.doi.org/10.3233/JAD-180945]

7. Kodama, K.; Sugawara, K.; Hirose, T. Synthesis of Chiral 1, 3-Diamines Derived from cis-2-Benzamidocyclohexanecarboxylic Acid and Their Application in the Cu-Catalyzed Enantioselective Henry Reaction. Chem. Eur. J.; 2011; 17, pp. 13584-13592. [DOI: https://dx.doi.org/10.1002/chem.201102136]

8. Kizirian, J. Chiral tertiary diamines in asymmetric synthesis. Chem. Rev.; 2008; 108, pp. 140-205. [DOI: https://dx.doi.org/10.1021/cr040107v]

9. Mayans, E.; Gargallo, A.; Álvarez-Larena, Á.; Illa, O.; Ortuño, R.M. Diastereodivergent Synthesis of Chiral vic-Disubstituted-Cyclobutane Scaffolds: 1, 3-Amino Alcohol and 1, 3-Diamine Derivatives–Preliminary Use in Organocatalysis. Eur. J. Org. Chem.; 2013; 2013, pp. 1425-1433. [DOI: https://dx.doi.org/10.1002/ejoc.201201307]

10. Csillag, K.; Szakonyi, Z.; Fülöp, F. Stereoselective syntheses of pinane-based 1, 3-diamines and their application as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde. Tetrahedron Asymmetry; 2013; 24, pp. 553-561. [DOI: https://dx.doi.org/10.1016/j.tetasy.2013.04.003]

11. Ji, X.; Huang, H. Synthetic methods for 1, 3-diamines. Org. Biomol. Chem.; 2016; 14, pp. 10557-10566. [DOI: https://dx.doi.org/10.1039/C6OB01976E]

12. Li, K.; Weber, A.E.; Tseng, L.; Malcolmson, S.J. Diastereoselective and enantiospecific synthesis of 1, 3-diamines via 2-azaallyl anion benzylic ring-opening of aziridines. Org. Lett.; 2017; 19, pp. 4239-4242. [DOI: https://dx.doi.org/10.1021/acs.orglett.7b01886] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28771013]

13. Rossolini, T.; Leitch, J.A.; Grainger, R.; Dixon, D.J. Photocatalytic three-component umpolung synthesis of 1, 3-diamines. Org. Lett.; 2018; 20, pp. 6794-6798. [DOI: https://dx.doi.org/10.1021/acs.orglett.8b02923] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30350662]

14. Ričko, S.; Svete, J.; Štefane, B.; Perdih, A.; Golobič, A.; Meden, A.; Grošelj, U. 1, 3-Diamine-Derived Bifunctional Organocatalyst Prepared from Camphor. Adv. Synth. Catal.; 2016; 358, pp. 3786-3796. [DOI: https://dx.doi.org/10.1002/adsc.201600498]

15. Davies, S.G.; Smith, A.D.; Price, P.D. The conjugate addition of enantiomerically pure lithium amides as homochiral ammonia equivalents: Scope, limitations and synthetic applications. Tetrahedron Asymmetry; 2005; 16, pp. 2833-2891. [DOI: https://dx.doi.org/10.1016/j.tetasy.2005.08.006]

16. Davies, S.G.; Fletcher, A.M.; Roberts, P.M.; Thomson, J.E. The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part II: 2005–2011. Tetrahedron Asymmetry; 2012; 23, pp. 1111-1153. [DOI: https://dx.doi.org/10.1016/j.tetasy.2012.08.009]

17. Davies, S.G.; Fletcher, A.M.; Roberts, P.M.; Thomson, J.E. The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part III: 2012–2017. Tetrahedron Asymmetry; 2017; 28, pp. 1842-1868. [DOI: https://dx.doi.org/10.1016/j.tetasy.2017.10.031]

18. Garrido, N.M.; Nieto, C.T.; Diez, D. Enantioselective synthesis of a (1R, 5R, 9R)-2-azabicyclo [3.3.1] nonane-9-carboxylic acid with an embedded morphan motif: A multipurpose product. Synlett; 2013; 24, pp. 169-172. [DOI: https://dx.doi.org/10.1055/s-0032-1317950]

19. Nieto, C.T.; Gonzalez-Nunez, V.; Rodríguez, R.E.; Diez, D.; Garrido, N.M. Design, synthesis, pharmacological evaluation and molecular dynamics of β-amino acids morphan-derivatives as novel ligands for opioid receptors. Eur. J. Med. Chem.; 2015; 101, pp. 150-162. [DOI: https://dx.doi.org/10.1016/j.ejmech.2015.06.025]

20. Salgado, M.M.; Manchado, A.; Nieto, C.T.; Díez, D.; Garrido, N.M. Synthesis and Modeling of Ezetimibe Analogues. Molecules; 2021; 26, 3107. [DOI: https://dx.doi.org/10.3390/molecules26113107]

21. Urones, J.G.; Garrido, N.M.; Díez, D.; Dominguez, S.H.; Davies, S.G. Asymmetric synthesis of (R)-and (S)-methyl (2-methoxy-carbonylcyclopent-2-enyl) acetate and (R)-and (S)-2-(2-hydroxy-methyl-cyclopent-2-enyl) ethanol. Tetrahedron Asymmetry; 1997; 8, pp. 2683-2685. [DOI: https://dx.doi.org/10.1016/S0957-4166(97)00340-6]

22. Davies, S.G.; Walters, I.A. Asymmetric synthesis of anti-α-alkyl-β-amino Acids. J. Chem. Soc. Perkin Trans. 1; 1994; pp. 1129-1139. [DOI: https://dx.doi.org/10.1039/P19940001129]

23. Davies, S.G.; Ichihara, O. Asymmetric synthesis of R-β-amino butanoic acid and S-β-tyrosine: Homochiral lithium amide equivalents for Michael additions to α, β-unsaturated esters. Tetrahedron Asymmetry; 1991; 2, pp. 183-186. [DOI: https://dx.doi.org/10.1016/S0957-4166(00)82354-X]

24. Koperniku, A.; Schafer, L.L. Zirconium catalyzed hydroaminoalkylation for the synthesis of α-Arylated amines and N-Heterocycles. Chem. Eur. J.; 2021; 27, pp. 6334-6339. [DOI: https://dx.doi.org/10.1002/chem.202100014]

25. Das, M.; Manvar, A.; Fox, I.; Roberts, D.J.; O’Shea, D.F. Bu4N-controlled addition and olefination with ethyl 2-(trimethylsilyl) acetate via silicon activation. Synlett; 2017; 28, pp. 2401-2406.