Synthesis of Amidine Derivatives by Intermolecular Radical ­Addition to Nitrile Groups of AIBN Derivatives

Dedicated to Professor Xue-Long Hou on the occasion of his 65^th birthday.

Abstract

A synthesis of amidine derivatives through intermolecular addition of nitrogen-centered radicals to nitriles is reported. Experimental studies and density functional theory calculations were conducted to probe the mechanism of this reaction. The results suggest that the alkyl nitriles are activated by attracting chlorine atoms and are subsequently attacked by nitrogen-centered radicals, resulting in the intermolecular radical addition of nitriles to amidines.

Amidine, a versatile group in organic synthesis, is often found in drug molecules and chemical intermediates,[1] including bottromycin A2,[2] pivmecillinam[3] and BB-Cl-amidine[4] (Scheme [1a]). Consequently, various methods have been developed for the synthesis of amidines from nitriles,[5] amides,[6] aldoximes,[7] or carbodiimides,[8] among others.[9] The strategy from nitriles is highly effective and economical, as numerous nitrile-containing compounds are commercially available. The nucleophilic addition reaction of nitriles to ammonium salts, amines, or their derivatives is a commonly used method for the synthesis of amidines[10] [Scheme [1b](i)]. However, direct syntheses of amidines through radical addition of nitriles to nitrogen-centered radicals are rare because of the high bond energy of the N≡C triple bond (179.3 ± 0.7 kcal/mol).[11] Therefore, the presence of a catalyst and/or activation of the nitrile are essential for this addition.

Because it easily decomposes into a radical initiator under light or on heating, azobis(isobutyronitrile) (AIBN) is often used in organic syntheses and polymerizations.[12] However, the nitrile group in azonitriles resists conversion due to the inertness of alkyl nitriles.[13] Huang et al. took advantage of the excellent ability of the nitrile group to bind metal ions, and achieved a radical addition to the nitrile group by coordination with a copper catalyst [Scheme [1b](ii)].[14] In this type of radical reaction, the cyanoisopropyl radical first attaches to other molecules, and then intramolecular radical addition of a nitrile group takes place.[15] With their higher activities, aryl nitrile groups can undergo radical addition reactions in the synthesis of imines.[16] For example, Sun[16a] [e] and Li[16b–d] and their respective co-workers reported that the nitrile group can act as a radical receptor to form an imine radical that can undergo homolytic aromatic substitution or hydrogen-abstraction reactions under metal-catalyzed conditions to produce various heterocycles [Scheme [1b](iii)]. Apart from these reactions, which are based on intramolecular radical addition of nitriles to form a five- or six-membered ring, few other studies of intermolecular radical addition to nitriles have appeared.

Here we report an effective method involving intermolecular radical addition of nitrogen-centered radicals that can transform inert nitriles into amidines without a catalyst (Scheme [1c]). In addition to their role as radical initiators, the AIBN derivatives also serve as sources of the alkyl nitriles. N-Chlorosuccinimide or N-chloroglutarimide derivatives activate the alkyl nitriles by substitution of a chlorine atom,[17] and also provide nitrogen-centered radicals to add to the alkyl nitrile through an intermolecular radical reaction. This strategy is an effective tool for synthesizing novel amidine-containing compounds.

In previous reports, N-chlorophthalimide (NCP; 1a) has frequently been used as an amination reagent in syntheses of nitrogen-containing compounds.[18] We therefore used NCP (1a) and AIBN (2a) as substrates to optimize the initial conditions for our reaction (Table [1]). The solvent and the molar ratio of reactants were found to have a significant influence on the yield of the reaction. o-Xylene and m-xylene were found to be the most efficient solvents at a given temperature and molar ratio of 1a to 2a (Table [1], entries 1–7). For economic reasons, o-xylene was chosen as the solvent for screening of the reaction temperature. We found that the reaction gave good results at 90 °C (entries 7–10). The molar ratio of 1a to 2a was then screened (entries 11–13), and the desired product (3aa) was obtained in 91% isolated yield when the molar ratio of 1a to 2a was 1:2.5 (entry 12). The reaction was almost complete after six hours at 90 °C, and 3aa was obtained in 91% isolated yield (entry 14).

By using these optimized reaction conditions, we further explored the applicable range of substrates for the reaction (Scheme [2]). Azonitriles 2 with various alkyl chains were investigated, and the results indicated that this reaction is applicable to a range of common azonitriles. When the methyl groups on the isobutyronitrile moieties of AIBN were replaced by bulkier ethyl or isobutyl groups, the reaction delivered the desired products 3ab and 3ac in high yields of 86 and 96%, respectively. Cycloalkane-containing substrates such as 1,1′-azobis(cyanocyclohexane) could also be used in the system, and 3ad was obtained in 73% yield. These results imply that the reaction is less affected by steric hindrance by the alkyl groups on both sides of the azo group, and is suitable for common azonitrile derivatives. Next, we explored the scope of amination reagent, and found that the target products 3ba–bc were successfully obtained in yields of 76–94% when N-chlorosuccinimide, lacking an aromatic ring, was used. Meanwhile, good to excellent yields were realized from cycloalkane-fused N-chlorosuccinimide substrates (3cb, 3cc, 3da, 3dc, and 3dd). Furthermore, N-chloroglutarimide also gave the desired products 3ea–ed in the yields of 84, 95, 75, and 69%, respectively.

For mechanistic studies, radical scavengers were employed to examine the radical pathway of this reaction (Scheme [3]). When three equivalents of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) were used under the standard conditions, none of the expected product 3aa was obtained, and phthalimide (4a) was isolated in 86% yield. Upon addition of N-hydroxyphthalimide (NHPI), the yield of the target product 3aa was reduced to 47% and the NHPI adduct 5a was obtained as a byproduct in 33% yield. None of the hydrogenated product 6a was observed. These results are consistent with a radical process, and suggest the addition of a nitrogen-centered radical to the alkyl nitrile.

Accordingly, two pathways are proposed (Scheme [4]). Initially, AIBN (2a) decomposes thermally to the cyanoisopropyl radical A, which then abstracts a chlorine atom from NCP (1a) to deliver 2-chloro-2-methylpropanenitrile (B) and the nitrogen-centered radical C. Then, in proposed Path a, the addition of the nitrogen-centered radical C to nitrile B occurs sequentially to deliver the imino radical D, which couples with a second cyanoisopropyl radical A to produce the desired product 3aa or, alternatively, attacks another AIBN to produce 3aa and regenerate radical A. In the other plausible rout, Path b, a second cyanoisopropyl radical A adds to the nitrogen site in B to propagate an intermediate carbon-centered radical E, which then couples with radical C to generate product 3aa.

To further understand the mechanism at the molecular level, we performed density functional theory (DFT) calculations for these pathways (Figure [1]). Because the quantity of AIBN is 2.5 times more than that of NCP, a pathway in which an initial cyanoisopropyl radical (A, int1) adds to AIBN to generate a plausible precursor, 2-methyl-2-[(2-methylprop-1-en-1-ylidene)amino]propanenitrile was also considered and compared with chlorine abstraction from NCP. The free-energy barrier in the chlorine-abstraction pathway (TS1; 26.0 kcal/mol), is much lower than that for AIBN addition (TS3; 35 kcal/mol). The generated chloro nitrile (B, int2) with a nitrogen-centered radical (C, int3) is much more stable than the alternative (int5), indicating that the chlorine-abstraction pathway is both kinetically and thermodynamically favored. Accordingly, two possible pathways, the aforementioned Path a and Path b, were calculated starting from int2. The better path is Path a in which the energy barrier for int3 addition to int2 is 13.8 kcal/mol (TS2), 19.5 kcal/mol lower than the energy barrier in Path b (TS4). Moreover, the intermediate of the imino radical (int4) is a stable radical species, and can be regarded as a persistent radical that couples with the second transient cyanoisopropyl radical to deliver 3aa. On the other hand, the relative energy of int6 is only 0.4 kcal/mol lower than that of TS4, implying that int6 might not exist under the reaction conditions, due to the possibility of a reversible reaction. Path a, involving nitrogen-centered radical addition to the chloro nitrile, is therefore the more likely path, as judged from theoretical considerations.

In summary, a series of novel amidine derivatives have been synthesized by intermolecular addition of a nitrogen-centered radical to nitriles without a catalyst.[19] Azonitriles with linear alkyl or cycloalkyl groups act as radical initiators under the reaction conditions. The chlorosuccinimide derivatives activate the alkyl nitriles with a chlorine radical, providing a nitrogen-centered radical that successfully undergoes intermolecular radical addition of the alkyl nitrile. Mechanistic studies suggest a radical pathway involving the addition of radicals to the alkyl nitrile. According to the results of DFT calculations, chloro nitriles can be easily formed through chlorine abstraction by a cyanoisopropyl radical, and the addition of nitrogen-centered radical onto chloro nitrile is a favorable pathway with a lower energy barrier and a more stable imino radical.

Table 1 Optimization of Reaction Conditions^a

Entry	Solvent	Temp (°C)	Molar ratio 1a/2a	Yieldb (%)
1	MeCN (dry)	90	1:1.2	23
2	1,4-dioxane (dry)	90	1:1.2	3.5
3	DCE (dry)	90	1:1.2	42
4	PhCF3	90	1:1.2	46
5	toluene	90	1:1.2	40
6	m-xylene	90	1:1.2	49
7	o-xylene	90	1:1.2	49
8	o-xylene	70	1:1.2	40
9	o-xylene	110	1:1.2	45
10	o-xylene	130	1:1.2	42
11	o-xylene	90	1:2.0	84
12	o-xylene	90	1:2.5	91c
13	o-xylene	90	1:3.0	68
14	o-xylene	90	1:2.5	91c,d

^a Reaction conditions: 1a (0.5 mmol), solvent (2 mL), 16 h.

^b Determined by GC.

^c Isolated yield.

^d 6 h.

• References and Notes

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• 19 2-{[2-Chloro-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpropylidene]amino}-2-methylpropanenitrile (3aa); Typical ProcedureA Schlenk tube containing a stirrer bar was charged with N-chlorophthalimide (1a; 0.5 mmol, 1 equiv), AIBN (2a; 1.25 mmol, 2.5 equiv), and o-xylene (2 mL) under N₂, and the mixture was stirred at 90 °C in an oil bath for 6 h. The mixture was then cooled to rt and purified by flash column chromatography [silica gel, PE–EtOAc (20:1)] to give a white solid; yield: 144.5 mg (92%); mp 181.4–182.4 °C.IR (KBr): 2998, 2940, 2228, 1785, 1738, 1665 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.90 (m, 2 H), 7.82–7.75 (m, 2 H), 1.88 (s, 6 H), 1.68 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.77, 150.02, 134.94, 131.68, 124.63, 120.96, 71.28, 53.61, 32.00, 29.88. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₆ClN₃NaO₂: 340.0823; found: 340.0827.The structure of 3aa was confirmed by single-crystal x-ray analysis. CCDC 2022501 contains the supplementary crystallographic data for this compound. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

Corresponding Author

Publication History

Received: 21 October 2020

Accepted after revision: 02 January 2021

Accepted Manuscript online:
02 January 2021

Article published online:
22 January 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References and Notes

• 1a Aly AA, Bräse S, Gomaa MA. M. ARKIVOC 2018; (vi): 85
  CrossrefPubMedSearch in Google Scholar
• 1b Greenhill JV, Lue P. Prog. Med. Chem. 1993; 30: 203
  CrossrefPubMedSearch in Google Scholar
• 1c Kaneda M. J. Antibiot. 2002; 55: 924
  CrossrefPubMedSearch in Google Scholar
• 1d Prevorsek D. J. Phys. Chem. 1962; 66: 769
  CrossrefSearch in Google Scholar
• 1e Soeiro MN. C, Werbovetz K, Boykin DW, Wilson WD, Wang MZ, Hemphill A. Parasitology 2013; 140: 929
  CrossrefPubMedSearch in Google Scholar
• 2a Crone WJ. K, Vior NM, Santos-Aberturas J, Schmitz LG, Leeper FJ, Truman AW. Angew. Chem. Int. Ed. 2016; 55: 9639
  CrossrefPubMedSearch in Google Scholar
• 2b Shimamura H, Gouda H, Nagai K, Hirose T, Ichioka M, Furuya Y, Kobayashi Y, Hirono S, Sunazuka T, Ōmura S. Angew. Chem. Int. Ed. 2009; 48: 914
  CrossrefPubMedSearch in Google Scholar
• 3 Roholt K, Nielsen B, Kristensen E. Chemotherapy 1975; 21: 146
  CrossrefPubMedSearch in Google Scholar
• 4 Ledet MM, Anderson R, Harman R, Muth A, Thompson PR, Coonrod SA, Van de Walle GR. BMC Cancer 2018; 18: 412
  CrossrefPubMedSearch in Google Scholar
• 5a Buckman BO, Chou Y.-L, McCarrick M, Liang A, Lentz D, Mohan R, Morrissey MM, Shaw KJ, Trinh L, Light DR. Bioorg. Med. Chem. Lett. 2005; 15: 2249
  CrossrefPubMedSearch in Google Scholar
• 5b Yin Z, Zhang Z, Zhu J, Wong H, Kadow JF, Meanwell NA, Wang T. Tetrahedron Lett. 2005; 46: 4919
  CrossrefSearch in Google Scholar
• 6a Charette AB, Grenon M. Tetrahedron Lett. 2000; 41: 1677
  CrossrefSearch in Google Scholar
• 6b Das VK, Thakur AJ. Tetrahedron Lett. 2013; 54: 4164
  CrossrefSearch in Google Scholar
• 7 Chavan NL, Naik NH, Nayak SK, Kusurkar RS. ARKIVOC 2010; (ii): 248
  CrossrefPubMedSearch in Google Scholar
• 8a Hagadorn JR, McNevin MJ. Organometallics 2003; 22: 609
  CrossrefSearch in Google Scholar
• 8b Obenauf J, Kretschmer WP, Bauer T, Kempe R. Eur. J. Inorg. Chem. 2013; 537
• 9a Meilahn MK, Augenstein LL, McManaman JL. J. Org. Chem. 1971; 36: 3627
  CrossrefSearch in Google Scholar
• 9b Wu Y, Chen X, Zhang M.-M. Synthesis 2020; 52: 1773
  Thieme ConnectSearch in Google Scholar
• 9c Youn SW, Lee EM. Org. Lett. 2016; 18: 5728
  CrossrefPubMedSearch in Google Scholar
• 9d Shriner RL, Neumann FW. Chem. Rev. 1944; 35: 351
  CrossrefSearch in Google Scholar
• 10a Duchamp E, Hanessian S. Org. Lett. 2020; 22: 8487
  CrossrefPubMedSearch in Google Scholar
• 10b Garigipati RS. Tetrahedron Lett. 1990; 31: 1969
  CrossrefSearch in Google Scholar
• 11 Luo Y.-R. Comprehensive Handbook of Chemical Bond Energies. CRC Press; Boca Raton: 2007: 403
  Search in Google Scholar
• 12 Androvič L, Bartáček J, Sedlák M. Res. Chem. Intermed. 2016; 42: 5133
  CrossrefSearch in Google Scholar
• 13 De Vleeschouwer F, Van Speybroeck V, Waroquier M, Geerlings P, De Proft F. Org. Lett. 2007; 9: 2721
  CrossrefPubMedSearch in Google Scholar
• 14 Xie Y, Guo S, Wu L, Xia C, Huang H. Angew. Chem. Int. Ed. 2015; 54: 5900
  CrossrefPubMedSearch in Google Scholar
• 15a Barolli JP, Maia PI. S, Colina-Vegas L, Moreira J, Plutin AM, Mocelo R, Deflon VM, Cominetti MR, Camargo-Mathias MI, Batista AA. Polyhedron 2017; 126: 33
  CrossrefSearch in Google Scholar
• 15b Kang Q.-Q, Liu Y, Huang X.-J, Li Q, Wei W.-T. Eur. J. Org. Chem. 2019; 7673
• 15c Yu J, Sheng H.-X, Wang S.-W, Xu Z.-H, Tang S, Chen S.-L. Chem. Commun. 2019; 55: 4578
  CrossrefPubMedSearch in Google Scholar
• 15d Liu Y, Meng Y.-N, Huang X.-J, Qin F.-H, Wu D, Shao Q, Guo Z, Li Q, Wei W.-T. Green Chem. 2020; 22: 4593
  CrossrefSearch in Google Scholar
• 16a Zhang C, Pi J, Chen S, Liu P, Sun P. Org. Chem. Front. 2018; 5: 793
  CrossrefSearch in Google Scholar
• 16b Yang T, Xia W.-J, Shang J.-Q, Li Y, Wang X.-X, Sun M, Li Y.-M. Org. Lett. 2019; 21: 444
  CrossrefPubMedSearch in Google Scholar
• 16c Li Y.-M, Wang S.-S, Yu F, Shen Y, Chang K.-J. Org. Biomol. Chem. 2015; 13: 5376
  CrossrefPubMedSearch in Google Scholar
• 16d Wang S.-S, Fu H, Shen Y, Sun M, Li Y.-M. J. Org. Chem. 2016; 81: 2920
  CrossrefPubMedSearch in Google Scholar
• 16e Ji L, Gu W, Liu P, Sun P. Org. Biomol. Chem. 2020; 18: 6126
  CrossrefPubMedSearch in Google Scholar
• 17a Grivas JC, Taurins A. Can J. Chem. 1961; 39: 761
  CrossrefSearch in Google Scholar
• 17b Rousselet G, Capdevielle P, Maumy M. Tetrahedron Lett. 1993; 34: 6395
  CrossrefSearch in Google Scholar
• 18 Zhu N, Li Y, Bao H. Org. Chem. Front. 2018; 5: 1303
  CrossrefSearch in Google Scholar
• 19 2-{[2-Chloro-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpropylidene]amino}-2-methylpropanenitrile (3aa); Typical ProcedureA Schlenk tube containing a stirrer bar was charged with N-chlorophthalimide (1a; 0.5 mmol, 1 equiv), AIBN (2a; 1.25 mmol, 2.5 equiv), and o-xylene (2 mL) under N₂, and the mixture was stirred at 90 °C in an oil bath for 6 h. The mixture was then cooled to rt and purified by flash column chromatography [silica gel, PE–EtOAc (20:1)] to give a white solid; yield: 144.5 mg (92%); mp 181.4–182.4 °C.IR (KBr): 2998, 2940, 2228, 1785, 1738, 1665 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.90 (m, 2 H), 7.82–7.75 (m, 2 H), 1.88 (s, 6 H), 1.68 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.77, 150.02, 134.94, 131.68, 124.63, 120.96, 71.28, 53.61, 32.00, 29.88. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₆ClN₃NaO₂: 340.0823; found: 340.0827.The structure of 3aa was confirmed by single-crystal x-ray analysis. CCDC 2022501 contains the supplementary crystallographic data for this compound. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures

• Supplementary Material