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DOI: 10.1055/a-2593-6446
Nucleophilic Additions of Organolithium Reagents to Heterocyclic Aldimines
We gratefully acknowledge financial support from the South Carolina IDeA Networks of Biomedical Research Excellence (SC INBRE) for a Developmental Research Project grant (2022–2025) funded by grants from the National Center for Research Resources (5 P20 RR016461) and the National Institute of General Medical Sciences (8 P20 GM103499) from the National Institutes of Health. We additionally acknowledge financial support from the College of Charleston Department of Chemistry and Biochemistry, College of Charleston Faculty Research and Development fund, and the School of Natural and Environmental Sciences at the College of Charleston.
Abstract
The addition of alkyllithium reagents to heterocyclic aldimines is described. This method is a straightforward two-step procedure from the starting aldehyde and amine with one purification. The ability to use unprotected indole carboxaldehydes as substrates is a key feature of this method that makes it an attractive way to synthesize the corresponding amine products.
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The addition of an alkyl nucleophile to an imine is a very useful carbon–carbon bond-forming reaction.[1] [2] Due to the low difference in electronegativity between N and C, imines are less reactive than the precursor aldehydes from which they are often prepared. A common strategy to increase their reactivity is to attach an electron-withdrawing group to the nitrogen such as the use of N-tosyl,[3,4] N-tert-butylsulfinyl,[5] [6] and N-acyliminium.[7] [8] Many unstabilized organometallic alkyl nucleophiles have been used in additions to imines,[9] including alkyl reagents containing Li,[10] [11] [12] [13] Mg,[14] [15] Zn,[7] [16] [17] B,[18] and Si.[19] A Ni-catalyzed reductive coupling between alkyl halides and N-alkyl heteroaryl imines has also been reported.[20] Recently, new methods utilizing photocatalysts have been developed for alkyl additions to imines through a radical intermediate.[4] [18] [19] , [21] [22] [23]
We were interested in developing an addition reaction to N-aryl imines derived from heterocyclic aldehydes including indole carboxaldehydes. Indoles are an important heterocycle present in numerous pharmaceutical drugs that have been used in a variety of therapeutic applications including but not limited to the treatment of cancer, microbial infections, inflammation and depression.[24] [25] [26] There are no reported examples of nucleophilic alkyl addition to imines derived from indole carboxaldehydes to the best of our knowledge. For this method we sought to include a phenpropylamine moiety in the product as well by using a phenethyl nucleophile in the addition reaction. The phenpropylamine pharmacophore is present in a number of selective serotonin reuptake inhibitors (SSRIs) including fluoxetine and paroxetine (Figure [1]).[27,28]
The investigation began looking at the addition of phenethylmagnesium bromide to the N-phenyl imine 1 shown in Table [1]. Imines were prepared using pyrrolidine as a catalyst and were used unpurified in the addition reaction.[29] The reaction with the Grignard reagent afforded no desired product (entry 1). Previously employed strategies like using ZnCl2 [14] and TMSCl[7] as Lewis acid additives were also ineffective at promoting the desired reactivity (entries 2 and 3). Alkyllithium reagents were examined next and were found to provide the desired product 2 in a moderate yield.[30] Scaling down the amount of alkyllithium nucleophile resulted in an inefficient reaction, presumably due to the presence of an acidic unprotected N–H on the indole.
Previously, alkyllithium reagents have been added to both N-arylimines and N-alkylimines.[9] In reactions of alkyllithium reagents with N-aryl imines, low yields were reported without the addition of Lewis base additives.[10] [11] [12] The addition of stochiometric and catalytic chiral Lewis base additives improved the reactivity, resulting in enantioselective additions of the alkyllithium reagents to the N-aryl imines.[10–12] In previously reported reactions of alkyllithium reagents to chiral N-alkylimines, Lewis acid and Lewis base additives were both found to improve the yields and diastereoselectivity of the addition reactions.[13] However, in other reports of alkyllithium additions to chiral N-alkylimines, no additives were employed.[31] [32] [33]
The substrate scope was then examined for this transformation (Scheme [1]). The procedure to form the imine substrate using pyrrolidine as a catalyst proved general for a variety of heteroaromatic aldehydes.[29] Acceptable yields were observed with N-phenyl imines derived from indole carboxaldehydes as shown in reactions to form products 2–5. Imines derived from N-alkylindole carboxaldehydes also were effective substrates providing amines 6 and 7. Expanding the heterocyclic imine scope to include a benzofuran provided amine 8 in 68% yield. The reaction of N-methylimines provided the amine products 9 and 10. Reactions with imines derived from indolecarboxaldehydes and larger alkylamines such as allyl amine or butyl amine were not successful under these conditions. Reactions with N-phenyl imines derived from pyridinecarboxaldehydes provided products 11–13. It has previously been reported that lithium reagents react with pyridine at the 2-position.[34] Notably, the imine derived from 3-pyridinecarboxaldehyde provided the amine product 12 in a much lower yield than the other regioisomers with two equivalents of nucleophile. With this substrate, the 2-position of the pyridine is more electrophilic than in the other regioisomers which may explain the lower isolated yield, although other addition byproducts were not isolated from this reaction. Using only 1.3 equivalents of the phenethyllithium reagent resulted in an improved 44% yield of product 12. With less nucleophile there was unreacted imine observed in the unpurified reaction mixture as well. N-Heteroaryl imines derived from aminopyridines provided the products 14–16. It was noted that the imine made using 2-aminopyridine was a less effective substrate than the imine derived from 3-aminopyridine under these reaction conditions. The amino group in 3-aminopyridine can donate electron density to the 2-. 4-, and 6-positions of the pyridine, making these sites less electrophilic than is the case with the 2-aminopyridine which could explain the observed difference in isolated yields in these substrates. For most imine substrates that did not have an acidic hydrogen, only two equivalents of the alkyllithium were added.
A brief evaluation of the nucleophile substrate scope was performed next (Scheme [2]). Commercially available methyllithium, n-butyllithium, and tert-butyllithium were examined in the reaction with imine 1. Notably, sterically hindered tert-butyllithium provided the desired product 19 in a similar yield to the other alkyllithium reagents.
In summary, an effective addition reaction of alkyllithium reagents to aldimines derived from indole carboxaldehydes and other heterocyclic aldehydes was developed.[35] This reaction is straightforward and was demonstrated to work on both protected and unprotected indole carboxaldimine substrates. The imines were used unpurified, making this method an attractive two-step, one purification synthesis of the amine products.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We acknowledge Dr. Jay Forsythe and Dr. Stephanie Boussert for their assistance collecting HRMS data.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2593-6446.
- Supporting Information
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References and Notes
- 1 Paul J, Presset M, Le Gall E. Eur. J. Org. Chem. 2017; 2386
- 2 Bloch R. Chem. Rev. 1998; 98: 1407
- 3 Yamada K, Yamamoto Y, Maekawa M, Akindele T, Umeki H, Tomioka K. Org. Lett. 2006; 8: 87
- 4 Supranovich VI, Levin VV, Dilman AD. Org. Lett. 2019; 21: 4271
- 5 Liu G, Cogan DA, Ellman JA. J. Am. Chem. Soc. 1997; 119: 9913
- 6 Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600
- 7 Pinaud M, Plantiveau E, Huet E, Le Gall E, Presset M. Eur. J. Org. Chem. 2023; 26: e202300572
- 8 Le Gall E, Pignon A, Martens T. Beilstein J. Org. Chem. 2011; 7: 997
- 9 Enders D, Reinhold U. Tetrahedron Asymm. 1997; 8: 1895
- 10 Tomioka K, Inoue I, Shindo M, Koga K. Tetrahedron Lett. 1991; 32: 3095
- 11 Tomioka K, Inoue I, Shindo M, Koga K. Tetrahedron Lett. 1990; 31: 6681
- 12 Denmark SE, Nakajima N, Nicaise OJ.-C. J. Am. Chem. Soc. 1994; 116: 8797
- 13 Yamada H, Kawate T, Nishida A, Nakagawa M. J. Org. Chem. 1999; 64: 8821
- 14 Hatano M, Suzuki S, Ishihara K. J. Am. Chem. Soc. 2006; 128: 9998
- 15 Takahashi T, Liu Y, Xi C, Huo S. Chem. Commun. 2001; 31
- 16 Pinaud M, Le Gall E, Presset M. J. Org. Chem. 2022; 87: 4961
- 17 Knochel P, Singer RD. Chem. Rev. 1993; 93: 2117
- 18 Yi J, Badir SO, Alam R, Molander GA. Org. Lett. 2019; 21: 4853
- 19 Patel NR, Kelly CB, Siegenfeld AP, Molander GA. ACS Catal. 2017; 7: 1766
- 20 Turro RF, Brandstatter M, Reisman SE. Angew. Chem. Int. Ed. 2022; 61: e202207597
- 21 Gladkov AA, Levin VV, Dilman AD. J. Org. Chem. 2023; 88: 1260
- 22 Li Y, Zhou K, Wen Z, Cao S, Shen X, Lei M, Gong L. J. Am. Chem. Soc. 2018; 140: 15850
- 23 Kancherla R, Muralirajan K, Rueping M. Chem. Sci. 2022; 13: 8583
- 24 Zeng W, Han C, Mohammed S, Li S, Song Y, Sun F, Du Y. RSC Med. Chem. 2024; 15: 788
- 25 Sravanthi TV, Manju SL. Eur. J. Pharm. Sci. 2016; 91: 1
- 26 Chadha N, Silakari O. Eur. J. Med. Chem. 2017; 134: 159
- 27 Singh K, Pal R, Khan SA, Kumar B, Akhtar MJ. J. Mol. Struct. 2021; 1237: 130369
- 28 Coleman JA, Gouaux E. Nat. Struct. Mol. Biol. 2018; 25: 170
- 29 Morales S, Guijarro FG, García Ruano JL, Cid MB. J. Am. Chem. Soc. 2014; 136: 1082
- 30 Negishi E, Swanson DR, Rousset CJ. J. Org. Chem. 1990; 55: 5406
- 31 Hashimoto Y, Takaoki K, Sudo A, Ogasawara T, Saigo K. Chem. Lett. 1995; 24: 235
- 32 Alvaro G, Savoia D, Valentinetti MR. Tetrahedron 1996; 52: 12571
- 33 Hashimoto Y, Kobayashi N, Kai A, Saigo K. Synlett 1995; 1995: 961
- 34 Eisch JJ. Organometallics 2002; 21: 5439
- 35 General Procedure for Nucleophilic Addition to IminesTo a 25 mL round-bottomed flask containing 4 Å molecular sieves (0.5 g), heterocyclic aldehyde (0.50 mmol), and aniline (56 mg, 0.60 mmol), pyrrolidine (10 μL, 0.1 mmol) and dichloromethane (2 mL) were added.27 The solution was left to stir overnight at room temperature. The molecular sieves were removed by vacuum filtration, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was examined by 1H NMR spectroscopy to confirm conversion into the imine had occurred. In a separate 25 mL round-bottomed flask under argon, cooled to –78 ℃, phenethyl iodide (220 μL, 1.5 mmol) dissolved in 2 mL diethyl ether was added. To this solution, tert-butyllithium (1.9 mL, 3.3 mmol, 1.7 M in pentane) was added. The solution was stirred and allowed to warm to room temperature over 1 h, so following lithium–halogen exchange, the excess tert-butyllithium would react with the diethyl ether.28 The phenethyl lithium solution was then chilled back to –78 ℃, and the unpurified imine product was added as a solution in 3 mL of THF. The solution was slowly allowed to warm to room temperature over 1 h, then quenched with water (10 mL). The product was extracted with ethyl acetate (3 × 10 mL), dried with Na2SO4, and concentrated under reduced pressure. The product was then purified either with a manual flash column or with an automated flash chromatography system.[1-(5-Indolyl)-3-phenylpropyl]aniline (2)The product was prepared according to the general procedure and purified with a silica column with a gradient of 5–15% ethyl acetate in hexanes providing 2 as a light brown oil in 53% yield (87 mg, 0.27 mmol). 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.51 (s, 1 H), 7.31–6.82 (m, 10 H), 6.52 (t, J = 7.3 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 2 H), 6.40 (s, 1 H), 4.34 (t, J = 6.8 Hz, 1 H), 4.03 (br s, 1 H), 2.69–2.48 (m, 2 H), 2.23–1.93 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 147.65, 141.91, 135.24, 135.18, 129.18, 128.59, 128.52, 128.11, 126.01, 124.65, 120.91, 118.59, 117.19, 113.55, 111.37, 102.65, 58.30, 40.54, 32.87. HRMS (ESI): m/z [M + H]+ calcd for C23H23N2: 327.1855; found: 327.1852.
Corresponding Author
Publication History
Received: 07 March 2025
Accepted after revision: 23 April 2025
Accepted Manuscript online:
23 April 2025
Article published online:
20 June 2025
© 2025. Thieme. All rights reserved
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References and Notes
- 1 Paul J, Presset M, Le Gall E. Eur. J. Org. Chem. 2017; 2386
- 2 Bloch R. Chem. Rev. 1998; 98: 1407
- 3 Yamada K, Yamamoto Y, Maekawa M, Akindele T, Umeki H, Tomioka K. Org. Lett. 2006; 8: 87
- 4 Supranovich VI, Levin VV, Dilman AD. Org. Lett. 2019; 21: 4271
- 5 Liu G, Cogan DA, Ellman JA. J. Am. Chem. Soc. 1997; 119: 9913
- 6 Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600
- 7 Pinaud M, Plantiveau E, Huet E, Le Gall E, Presset M. Eur. J. Org. Chem. 2023; 26: e202300572
- 8 Le Gall E, Pignon A, Martens T. Beilstein J. Org. Chem. 2011; 7: 997
- 9 Enders D, Reinhold U. Tetrahedron Asymm. 1997; 8: 1895
- 10 Tomioka K, Inoue I, Shindo M, Koga K. Tetrahedron Lett. 1991; 32: 3095
- 11 Tomioka K, Inoue I, Shindo M, Koga K. Tetrahedron Lett. 1990; 31: 6681
- 12 Denmark SE, Nakajima N, Nicaise OJ.-C. J. Am. Chem. Soc. 1994; 116: 8797
- 13 Yamada H, Kawate T, Nishida A, Nakagawa M. J. Org. Chem. 1999; 64: 8821
- 14 Hatano M, Suzuki S, Ishihara K. J. Am. Chem. Soc. 2006; 128: 9998
- 15 Takahashi T, Liu Y, Xi C, Huo S. Chem. Commun. 2001; 31
- 16 Pinaud M, Le Gall E, Presset M. J. Org. Chem. 2022; 87: 4961
- 17 Knochel P, Singer RD. Chem. Rev. 1993; 93: 2117
- 18 Yi J, Badir SO, Alam R, Molander GA. Org. Lett. 2019; 21: 4853
- 19 Patel NR, Kelly CB, Siegenfeld AP, Molander GA. ACS Catal. 2017; 7: 1766
- 20 Turro RF, Brandstatter M, Reisman SE. Angew. Chem. Int. Ed. 2022; 61: e202207597
- 21 Gladkov AA, Levin VV, Dilman AD. J. Org. Chem. 2023; 88: 1260
- 22 Li Y, Zhou K, Wen Z, Cao S, Shen X, Lei M, Gong L. J. Am. Chem. Soc. 2018; 140: 15850
- 23 Kancherla R, Muralirajan K, Rueping M. Chem. Sci. 2022; 13: 8583
- 24 Zeng W, Han C, Mohammed S, Li S, Song Y, Sun F, Du Y. RSC Med. Chem. 2024; 15: 788
- 25 Sravanthi TV, Manju SL. Eur. J. Pharm. Sci. 2016; 91: 1
- 26 Chadha N, Silakari O. Eur. J. Med. Chem. 2017; 134: 159
- 27 Singh K, Pal R, Khan SA, Kumar B, Akhtar MJ. J. Mol. Struct. 2021; 1237: 130369
- 28 Coleman JA, Gouaux E. Nat. Struct. Mol. Biol. 2018; 25: 170
- 29 Morales S, Guijarro FG, García Ruano JL, Cid MB. J. Am. Chem. Soc. 2014; 136: 1082
- 30 Negishi E, Swanson DR, Rousset CJ. J. Org. Chem. 1990; 55: 5406
- 31 Hashimoto Y, Takaoki K, Sudo A, Ogasawara T, Saigo K. Chem. Lett. 1995; 24: 235
- 32 Alvaro G, Savoia D, Valentinetti MR. Tetrahedron 1996; 52: 12571
- 33 Hashimoto Y, Kobayashi N, Kai A, Saigo K. Synlett 1995; 1995: 961
- 34 Eisch JJ. Organometallics 2002; 21: 5439
- 35 General Procedure for Nucleophilic Addition to IminesTo a 25 mL round-bottomed flask containing 4 Å molecular sieves (0.5 g), heterocyclic aldehyde (0.50 mmol), and aniline (56 mg, 0.60 mmol), pyrrolidine (10 μL, 0.1 mmol) and dichloromethane (2 mL) were added.27 The solution was left to stir overnight at room temperature. The molecular sieves were removed by vacuum filtration, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was examined by 1H NMR spectroscopy to confirm conversion into the imine had occurred. In a separate 25 mL round-bottomed flask under argon, cooled to –78 ℃, phenethyl iodide (220 μL, 1.5 mmol) dissolved in 2 mL diethyl ether was added. To this solution, tert-butyllithium (1.9 mL, 3.3 mmol, 1.7 M in pentane) was added. The solution was stirred and allowed to warm to room temperature over 1 h, so following lithium–halogen exchange, the excess tert-butyllithium would react with the diethyl ether.28 The phenethyl lithium solution was then chilled back to –78 ℃, and the unpurified imine product was added as a solution in 3 mL of THF. The solution was slowly allowed to warm to room temperature over 1 h, then quenched with water (10 mL). The product was extracted with ethyl acetate (3 × 10 mL), dried with Na2SO4, and concentrated under reduced pressure. The product was then purified either with a manual flash column or with an automated flash chromatography system.[1-(5-Indolyl)-3-phenylpropyl]aniline (2)The product was prepared according to the general procedure and purified with a silica column with a gradient of 5–15% ethyl acetate in hexanes providing 2 as a light brown oil in 53% yield (87 mg, 0.27 mmol). 1H NMR (400 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.51 (s, 1 H), 7.31–6.82 (m, 10 H), 6.52 (t, J = 7.3 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 2 H), 6.40 (s, 1 H), 4.34 (t, J = 6.8 Hz, 1 H), 4.03 (br s, 1 H), 2.69–2.48 (m, 2 H), 2.23–1.93 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 147.65, 141.91, 135.24, 135.18, 129.18, 128.59, 128.52, 128.11, 126.01, 124.65, 120.91, 118.59, 117.19, 113.55, 111.37, 102.65, 58.30, 40.54, 32.87. HRMS (ESI): m/z [M + H]+ calcd for C23H23N2: 327.1855; found: 327.1852.
