Letter pubs.acs.org/OrgLett
Metal-Free Sequential C(sp2)−H/OH and C(sp3)−H Aminations of Nitrosoarenes and N‑Heterocycles to Ring-Fused Imidazoles Anisha Purkait,‡ Subhra Kanti Roy,‡ Hemant Kumar Srivastava, and Chandan K. Jana* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, India 781039 S Supporting Information *
ABSTRACT: Hydrogen bond assisted ortho-selective C(sp2)−H amination of nitrosoarenes and subsequent α-C(sp3)-H functionalization of aliphatic amines is achieved under metal-free conditions. The annulation of nitrosoarenes and 2hydroxy-C-nitroso compounds with N-heterocycles provides a facile excess to a wide range of biologically relevant ring-fused benzimidazoles and structurally novel polycyclic imidazoles, respectively. Nucleophilic aromatic hydrogen substitution (SNArH) was found to be preferred over classical SNAr reaction during the C(sp2)−H amination of halogenated nitrosoarenes.
N
nitrosoarenes and alicyclic amines providing ring-fused imidazoles under metal-free conditions. Along the lines of our ongoing research for the development of novel C−H functionalization strategy that proceed through the classical reaction avoiding the use of metallic reagents and a hazardous oxidant,4f−i we were interested in investigating the possibility of direct C(sp2)−H functionalization of a nitrosoarene. SNArH reactions of nitroarenes, which involve nucleophilic addition to the arene as the key step using C, N, O, and P nucleophiles, were well studied.11,13 Therefore, we decided to compare the Fukui electrophilicity indices of nitrobenzene and nitrosobenzene to check the feasibility of SNArH reactions of nitrosoarenes. Electrophilicity indices revealed that nitrosobenzene, which has higher or analogous values of f+ as compared to nitrobenzene, could be a potential electrophile in the SNArH reaction (Scheme 1a). Therefore, we anticipated that C(sp2)−H functionalization of nitrosoarene can be achieved via SNArH reaction. Accordingly, to start our investigation, pyrrolidine was reacted with nitrosobenzene (1) in the presence of 2,4-dichclorobenzoic acid. To our surprise, ringfused benzimidazole 2 instead of a simple SNArH adduct was isolated in 7% yield (Table S1). Benzimidazoles are a privileged
itrosoarenes are frequently used in various synthetic applications for incorporating nitrogen and oxygen functionality in a molecule. Nitroso groups have acted extensively as dienophile, dipolarophile, and enophile in different pericyclic reactions.1 Except in pericyclic reactions, nitrosoarenes efficiently served as both oxy and amino electrophiles because of the high reactivity of the nitroso functionality.2 In addition, the nitroso group was reported recently to react well with the donor−acceptor cyclopropanes to provide the different heterocycles.3 In most of the cases, the arene moiety is sacrificed after the reaction. Amine functionalization4 and the reactivity of the nitroso functionality were well studied. However, only a few reports on the C−H functionalization of the arene moiety of a nitrosoarene to incorporate it into the product are known.5−9 Nitrosoarene reacted with Cl2, Br2, or copper halide via electrophilic halogenation reaction to provide halogenated nitroso compounds.5 Sundberg and co-workers reported a C(sp2)−H oxygenation reaction of nitrosoarene to provide corresponding α-oxygenated aniline derivatives.6 Srivastava, Penoni, and Nicholas et al. developed annulation reactions of nitrosoarenes and alkynes to indoles.7 A related annulation of arynes with nitrosoarenes to carbazoles was reported by Studer et al.8 Recently, the same group achieved arene functionalization through the reaction of a nitrosoarene and donor−acceptor cyclopropanes.9 Nitroso is isoelectronic with the carbonyl group, and thus the nucleophilic addition generally occurs at the nitrogen atom of the nitroso group. Accordingly, secondary amines react with nitrosoarenes to provide arylazoalkanes and azoxybenzene via a N-hydroxy-hydrazine derivative that is analogous to hemiaminal.10 In contrast, reactions of nitroarenes with the aliphatic amines provide corresponding functionalized arenes via nucleophilic aromatic hydrogen substitution (SNArH) reactions under various conditions.11 Although nitroso imparts a stronger electron-withdrawing effect to the ring as compared to the nitro group,12 the SNArH reaction of a nitrosoarene and an amine is difficult probably due to the high electrophilicity of the nitroso moiety. Herein, we report the first example of direct domino C(sp2)−H/OH and C(sp3)−H aminations reactions involving © 2017 American Chemical Society
Scheme 1. (a) Fukui Electrophilicity Indices of Nitrobenzene and Nitrosobenzene (b) Optimized Reaction Conditions for Metal-Free Sequential C(sp2)−H/OH and C(sp3)−H Amination
Received: March 20, 2017 Published: May 9, 2017 2540
DOI: 10.1021/acs.orglett.7b00832 Org. Lett. 2017, 19, 2540−2543
Letter
Organic Letters
and homopiperidine provided lower yields of the corresponding benzimidazoles (4o and 4p). Nevertheless, satisfactory yields of those were obtained when the reactions were carried out with 2fluoronitrosobenzene. Afterward, we investigated the scope of C(sp3)−H amination of N-heterocycles involving nitrosonaphthol. From the screening of various reaction conditions, the reaction of 1-nitroso-2naphthol with pyrrolidine in the presence of acetic acid in refluxing toluene was identified to provide the best yield (67%) of the desired imidazole 6a (Table S2). The best reaction conditions were then employed to investigate the scope of this successive C(sp2)−OH and C(sp3)−H amination reaction. Diversely substituted nitrosonaphthols (5a−5n) were reacted with pyrrolidine to obtain the novel class of ring fused imidazole derivatives 6a−6l, 6q, 6r with good to very good yields (Scheme 3).16 Hydroxy-, alkoxy-, and bromo-substituted nitrosonaphthols
moiety which are present in many bioactive molecules including natural products. Particularly, ring-fused benzimidazole derivatives were identified as important pharmacophores for anticancer activity.14 Syntheses of this valuable scaffold mainly relied on a multistep reaction sequence.15 The significant disadvantage of the known methods arises from the use of hazardous organic or metallic oxidants, reductants, and involvement of a multistep reaction sequence. In the context of the applicability, the syntheses of these important pharmacophores via direct annulation of nitrosoarenes with N-heterocycles under conditions free of metal and hazardous reagents would be advantageous as compared to the known protocols. Therefore, various reaction conditions were evaluated to obtain the best yield. The maximum yield of desired benzimidazole 2 was obtained from the reaction of nitrosobenzene and pyrrolidine in the presence of 2,4-dichlorobenzoic acid in refluxing toluene (Scheme 1b). The optimized conditions were then used to test the scope of the reaction. Various nitrosoarenes (3a−m) containing different substituents were reacted with pyrrolidine to obtain the corresponding benzimidazoles (4a−i) with good yields (Scheme 2).16 Both electron-donating and -withdrawing substituents in
Scheme 3. Scope of Successive C(sp2)−OH and C(sp3)−H Aminations
Scheme 2. Scope of Successive C(sp2)−H and C(sp3)−H Aminations
a
Ratio of regioisomeric products. See SI for the structure of the minor isomer 4ga. bYields of the imidazoles starting from corresponding ofluoronitrosobenzene.
reacted smoothly to provide the corresponding naphthoimidazole derivatives. However, a slightly lower yield of imidazole 6j (47%) as compared to 6d and 6h was obtained from sterically hindered 3-methoxy nitrosonaphthol relative to its 6-methoxy and 7-methoxy derivatives. Quinoline and phenanthroline derivatives 6k (60%) and 6l (64%) were also obtained from corresponding o-hydroxy-nitroso compounds. Other relatively bulky N-heterocycles also provided the desired imidazoles (6m−p), however, with lower yields. R-Prolinol provided the corresponding imidazole with excellent enantiopurity (>99%). We also examined the reactivity of a nonaromatic α-hydroxy-nitroso/keto-oxime (5m and 5n) in the presence of pyrrolidine under optimized conditions. Corresponding imidazole derivatives 6q and 6r were formed with satisfactory yields. Aliphatic primary amines with varying chain length were then reacted with the nitrosonaphthol under the standard reaction conditions (Table 1). The desired naphtho-imidazoles 7a−e were isolated along with corresponding N-alkylated derivatives 8a−e with very good to excellent combined yields. A plausible mechanism for unprecedented domino C(sp2)− H/OH and C(sp3)−H amination reaction is presented in Scheme 4. Nucleophilic addition of pyrrolidine to nitro-
the nitrosoarenes were tolerated in the reactions. The yield of imidazole derivative 4f significantly reduced due to the presence of strongly electron-donating dimethylamino substituents. Regioisomeric products were obtained from the reaction of mchloronitrosobenzene. C(sp2)−H aminations para to the chlorosubstituent were preferred over the ortho-position to provide psubstituted products 4g as the major isomers. In a reaction of ofuloronitrosobenzene with pyrrolidine, classical nucleophilic aromatic substitution (S NAr) followed by amine C−H functionalization occurred to provide 2 in 79% yield. To our surprise, in cases of other o-halo-nitrosobenzenes, halogenated imidazoles 4j−4l were obtained as the major products via domino C(sp2)−H and C(sp3)−H amination reactions. Interestingly, the yields of halogenated imidazoles 4j−4l, which were formed through C(sp2)−H functionalization, decrease with the increase in the electronegativity of halogens. Consequently, it was also found that the yield of imidazole 2 that is formed via SNAr reaction increases with the electronegativity. The reactions of nitrosobenzene with other N-heterocycles such as piperidine 2541
DOI: 10.1021/acs.orglett.7b00832 Org. Lett. 2017, 19, 2540−2543
Letter
Organic Letters Table 1. Reaction with Primary Aliphatic Amines
a
entry
n
% yield (7a−e and 8a−ea)
1 2 3 4 5
2 3 4 5 7
87 (38 and 49) 90 (42 and 48) 78 (36 and 42) 67 (33 and 34) 64 (32 and 32)
Figure 1. Optimized geometries of transition states and corresponding calculated activation barriers (in kcal/mol). Calculations were performed at the B3LYP/6-31G(d) level of theory in toluene medium using PCM method (see Supporting Information for further details).
position of nitrosobenzene remained unsuccessful. The presence of an intramolecular hydrogen bond (O···H = 1.925 Å) between the nitroso-oxygen and amine-hydrogen having a stable sixmembered cyclic structure is evident from the optimized transition state geometry (Figure 1, TS). The H-bond was found to be further strengthened (O···H = 1.005 Å) in the addition product (Figure S1). In addition, charges obtained from natural population analysis (NPA) revealed that para-attack is less probable due to the presence of an unfavorable repulsive interaction as compared to an ortho-attack (Figure S2). The higher stabilization of TS via synergistic charge transfer between the donor and acceptor also predicted the preference for the ortho-attack (Figure S3). Except for 2-fluoronitrosobenzene, SNArH was preferred over conventional SNAr in the reaction of o-halo-nitrosobenzene. This is probably due to the H-bond aided nucleophilic attack as shown in the preferred conformation20 20 (Scheme 4) where bulky halogens remain away from the nitroso to avoid unfavorable steric interaction. This is presumably the cause of the increase in the experimental yields of imidazoles (4j → 4k → 4l) with increasing sizes of the halogens (Cl → Br → I) in o-halonitrosobenzene. In contrast, fluorine that has comparable size with hydrogen and strong electron-withdrawing ability facilitates the nucleophilic addition at the carbon bearing a fluorine atom to exclusively provide imidazole 2. The calculated lower activation barrier for F-substitution (TS-F: 12.23 kcal/mol) as compared to H-substitution (TS-H: 16.37 kcal/mol) supported the experimental results on the exclusive formation of F-substituted products 2 (Figures 1 and S1). Strong attractive interaction involving opposite charges on the reacting atoms probably lowers the reaction barrier and thus drives the reaction to occur through TS-F (Figure S2). Benzimidazole 2 possesses analgesic activity.14c Gram scale synthesis of imidazole 2 proved the efficiency and practicability of our method (Scheme S2). Additionally, selected ring fused benzimidazoles were derivatized under different reaction conditions (Scheme 5). N-Methylation of imidazole 4m and 6a occurred readily to provide imidazolium iodide 21a and 21b, respectively. N-Acylation in the presence of di-tert-butyl
Reaction mechanism for 8 is proposed in Scheme S1.
Scheme 4. Proposed Mechanism for Annulation Reaction
sobenzene occurred in the first step. The oxidation of resulting intermediate 9 and/or 10 could lead to corresponding 2-amino nitrosoarene 11.17 On the other hand, nitroso naphthalene derivative 11 could be formed from the nucleophilic ipsosubstitution reaction of nitrosonaphthol 5 or its keto-oxime tautomer 12 with pyrrolidine through intermediate 13.18 Amino nitroso derivative 11 then readily undertook a 1,5-hydride shift to provide the iminium ion 14.4,19 A similar 1,5-H shift was reported for a related reaction involving an amino aldehyde corresponding to 11.4o Alternatively, the iminium ion 14 could also be produced through deprotonation and consequent mesomerization of the corresponding isomeric iminium ion 15 and 16, which resulted from 11 and 13, respectively. Annulation of 14 followed by acid mediated dehydration of resulting N-hydroxy derivative 17 provided the desired imidazole 18. Amino phenylhydroxylamine 10 and corresponding nitroso derivative 11 were detected through mass spectrometry. Further, the thermal/areal oxidation of arylhydroxylamine to the corresponding nitroso compound is known to be facile.17 These support the intermediacy of 10 and 11 in the reaction. The preference of the SNArH reaction at the para-carbon of nitrosobenzene would be expected because it has the highest Fukui electrophilicity coefficient value at that carbon (Scheme 1a). However, the substitution reaction occurred selectively at the ortho-position probably due to the hydrogen bond assisted directing effect of the nitroso group as shown in 19. This hypothesis was supported by DFT studies. The transition state for ortho-substitution (TS in Figures 1 and S1) in the SNArH reaction between nitrosobenzene and pyrrolidine is obtained with an activation barrier of 18.23 kcal/mol. However, all attempts to obtain transition states for substitution at the para-
Scheme 5. Synthetic Elaboration of Imidazole Derivatives
2542
DOI: 10.1021/acs.orglett.7b00832 Org. Lett. 2017, 19, 2540−2543
Letter
Organic Letters
Maulide, N. Chem. - Eur. J. 2013, 19, 13274. (d) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. (e) Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351. For selected reports from our group, see: (f) Haldar, S.; Mahato, S.; Jana, C. K. Asian J. Org. Chem. 2014, 3, 44. (g) Mahato, S.; Haque, M. A.; Dwari, S.; Jana, C. K. RSC Adv. 2014, 4, 46214. (h) Haldar, S.; Roy, S. K.; Maity, B.; Koley, D.; Jana, C. K. Chem. - Eur. J. 2015, 21, 15290. (i) Mandal, S.; Mahato, S.; Jana, C. K. Org. Lett. 2015, 17, 3762. For selected reports from others, see: (j) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416. (k) Richers, M. T.; Breugst, M.; Platonova, A. Y.; Ullrich, A.; Dieckmann, A.; Houk, K. N.; Seidel, D. J. Am. Chem. Soc. 2014, 136, 6123. (l) Manjappa, K. B.; Jhang, W.-F.; Huang, S.-Y.; Yang, D.-Y. Org. Lett. 2014, 16, 5690. (m) Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.; Lou, H. Angew. Chem., Int. Ed. 2014, 53, 3904. (n) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127, 12180. (o) Jurberg, I. D.; Peng, B.; Wöstefeld, E.; Wasserloos, M.; Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 1950. (p) Mori, K.; Kurihara, K.; Yabe, S.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2014, 136, 3744. (5) (a) van der Werf, A.; Selander, N. Org. Lett. 2015, 17, 6210. (b) Ingold, C. K. J. Chem. Soc., Trans. 1925, 127, 513. (c) Robertson, P. W.; Hitchings, T. R.; Will, G. M. J. Chem. Soc. 1950, 808. (6) (a) Sundberg, R. J.; Smith, R. H.; Bloor, J. E. J. Am. Chem. Soc. 1969, 91, 3392. (7) (a) Penoni, A.; Volkmann, J.; Nicholas, K. M. Org. Lett. 2002, 4, 699. (b) Penoni, A.; Palmisano, G.; Zhao, Y.-L.; Houk, K. N.; Volkman, J.; Nicholas, K. M. J. Am. Chem. Soc. 2009, 131, 653. (c) Murru, S.; Gallo, A. A.; Srivastava, R. S. ACS Catal. 2011, 1, 29. (8) Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A. Angew. Chem., Int. Ed. 2013, 52, 2968. (9) (a) Das, S.; Chakrabarty, S.; Daniliuc, C. G.; Studer, A. Org. Lett. 2016, 18, 2784. (b) Das, S.; Daniliuc, C. G.; Studer, A. Org. Lett. 2016, 18, 5576. (10) (a) Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621. Direct C−H amination was achieved using either bulky tert-butyl or adamentyl amines. See (b) Lipilin, D. L.; Churakov, A. M.; Ioffe, S. L.; Strelenko, Y. A.; Tartakovsky, V. A. Eur. J. Org. Chem. 1999, 1999, 29. (11) For review, see: (a) Ma̧kosza, M.; Wojciechowski, K. Top. Heterocycl. Chem. 2013, 37, 51. (12) Patai, S. The Chemistry of functional groups, Supplement F2: The chemistry of amino, nitroso, nitro and related group Part 1, 2; John Wiley & Sons Ltd.: Munchen, Germany, 1996. (13) (a) Makosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20, 282. (b) Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631. (c) Makosza, M. Chem. Soc. Rev. 2010, 39, 2855. (14) (a) Zhou, R.; Skibo, E. B. J. Med. Chem. 1996, 39, 4321. (b) Fahey, K.; O’Donovan, L.; Carr, M.; Carty, M. P.; Aldabbagh, F. Eur. J. Med. Chem. 2010, 45, 1873. (c) Charlson, A. J.; Harington, J. S. Carbohydr. Res. 1975, 43, 383. (15) (a) Nair, M. D.; Adams, R. J. Am. Chem. Soc. 1961, 83, 3518. (b) Suleman, A.; Skibo, E. B. J. Med. Chem. 2002, 45, 1211. (c) Baars, H.; Beyer, A.; Kohlhepp, S. V.; Bolm, C. Org. Lett. 2014, 16, 536. (d) Xue, D.; Long, Y.-Q. J. Org. Chem. 2014, 79, 4727. (e) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Green Chem. 2016, 18, 2966. (f) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Chem. Commun. 2016, 52, 4914. (16) A side reaction of reactive nitrosoarene and lower reactivity of sterically demanding N-heterocycles resulted in relatively lower yields for some cases. (17) Ogata, Y.; Sawaki, Y.; Mibae, J.; Morimoto, T. J. Am. Chem. Soc. 1964, 86, 3854. (18) For related substitution reaction of nitrosophenol, see Hays, J. T.; De Butts, E. H.; Young, H. L. J. Org. Chem. 1967, 32, 153. (19) For an other mechanistic possibility, see Scheme S3, and for a review on the tert-amino effect, see: (a) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-Dajka, B. Synthesis 2006, 2006, 2625. (20) (a) Okazaki, R.; Inamoto, N. J. Chem. Soc. B 1970, 1583. (b) Sundberg, R. J. Tetrahedron 1967, 23, 1583.
dicarbonate followed by hydrolysis of the resulting imidazolium salt led to the cleavage of imidazole ring to provide corresponding o-diamino arenes 22a and 22b with very good yields. Nitro imidazole derivative 23 was obtained from the reaction of 2 in the nitrating mixture. The bromo functionality of 6g was utilized for Suzuki coupling with phenylboronic acid to obtain corresponding phenyl substituted imidazole 24 with an excellent yield. In summary, we have developed a novel annulation reaction of a nitrosoarene and an aliphatic amine via an unprecedented ortho-selective C(sp2)−H amination of a nitrosoarene and followed by α-C(sp3)−H amination of aliphatic amines without aid of a metallic reagent/catalyst and an external oxidant. A wide variety of bioactive ring-fused benzimidazoles were easily prepared from readily available nitrosoarenes and N-heterocycles in a mild and simple operation. Similarly, novel polycyclic imidazoles were prepared readily from the reaction of 2-hydroxyC-nitroso compounds. C(sp2)−H amination via SNArH reaction of o-halo-nitrosoarene was favored over conventional SNAr to provide halogen (Cl, Br, I) containing products which are otherwise difficult to prepare. DFT studies revealed the involvement of H-bonding in controlling the ortho-selectivity of C(sp2)−H amination.
■
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00832. Crystallographic data (CIF, CIF, CIF, CIF) Additional schemes, tables, and figures; experimental details; copies of NMR spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chandan K. Jana: 0000-0002-6296-1240 Author Contributions ‡
These authors contributed equally.
Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS We acknowledge financial support from SERB. H.K.S. is recipient of Ramanujan fellowship (SB/S2/RJN-004/2015). REFERENCES
(1) (a) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131. (b) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50, 5630. (2) For a review, see: (a) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514. Selected recent reports: (b) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 953. (c) Fisher, D. J.; Burnett, G. L.; Velasco, R.; de Alaniz, J. R. J. Am. Chem. Soc. 2015, 137, 11614. (3) (a) Chakrabarty, S.; Chatterjee, I.; Wibbeling, B.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed. 2014, 53, 5964. (b) Vemula, N.; Stevens, A. C.; Schon, T. B.; Pagenkopf, B. L. Chem. Commun. 2014, 50, 1668. (c) Chidley, T.; Vemula, N.; Carson, C. A.; Kerr, M. A.; Pagenkopf, B. L. Org. Lett. 2016, 18, 2922. (4) For selected reviews, see: (a) Mahato, S.; Jana, C. K. Chem. Rec. 2016, 16, 1477. (b) Seidel, D. Acc. Chem. Res. 2015, 48, 317. (c) Peng, B.; 2543
DOI: 10.1021/acs.orglett.7b00832 Org. Lett. 2017, 19, 2540−2543
