Letter pubs.acs.org/OrgLett
A Direct Cycloaminative Approach to Imidazole Derivatives via Dual C−H Functionalization Sagar Arepally,†,§ Venkata Nagarjuna Babu,†,§ Manickam Bakthadoss,‡ and Duddu S. Sharada*,† †
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi 502 285, Sangareddy, Telangana, India Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
‡
S Supporting Information *
ABSTRACT: Organoiodine(III)-promoted C(sp3)−H azidation was a key step for the cycloaminative process. An unprecedented method for metal-free dehydrogenative N-incorporation into C(sp3)−H and C(sp2)−H bonds for the synthesis of diverse imidazoles has been disclosed. The overall transformation involves the construction of four C−N bonds through hydroamination-azidation-cyclization sequence. The reaction can be easily handled and proceeds under mild conditions. Further, the potential of the present strategy is revealed by the practical synthesis of N-heterocyclic carbene (NHC) precursors.
C
Push−pull enamines are known to be versatile building blocks in organic synthesis.15 Recently, we have employed these enamines for N-incorporation strategy for the synthesis of quinoxalines via dual C(sp2)−H functionalization.13 In our continuing efforts to develop metal-free N-incorporation strategies, we envisioned employing these enamines for C(sp3)−H amination. A literature survey shows C−H amination on 2° enamines involving generation of iminyl radical B via β-C−H azidation is feasible. However, such a kind of iminyl radical B formation is less feasible in the case of 3° enamines C. It is well documented that functionalization at α-position to heteroatom is viable due to the stability of radical or cation by the heteroatom. On the basis of these literature reports,12 we hypothesized that the enamine A prepared from the amine 1 and electron deficient alkyne 2 can generate iminyl radical B which could lead to cycloamination resulting in N-heterocycle (Figure 1a). However, a push−pull nature of enamines makes functionalization or azidation at α to heteroatom a daunting challenge. On the other hand, hypervalent iodine reagents are well-known for facile ligand replacement and generation of reactive species.16 Herein, we are pleased to report an unprecedented metal-free tandem C(sp3)−H azidation/C(sp2)−H cycloamination sequence from in situ generated enamines for the synthesis of imidazoles (Figure 1b). Imidazoles and their fused derivatives are important Nheterocycles and are valuable building blocks for bioactive molecules and natural products.17
onstruction of C−N bonds has emerged as synthetically valuable transformations owing to the presence of nitrogen functionalities in a myriad of biologically active molecules.1 The well explored examples for C−N bond forming reactions are Buchwald−Hartwig2 amination and Ullmann-type coupling,3 which usually employ prefunctionalized substrates. In recent years, the demand for sustainable approaches led to significant advances in transition-metal-catalyzed direct conversion of C−H bonds to C−N bonds.4 The direct functionalization of multiple C−H bonds into C−N bonds leading to nitrogen heterocycles is a highly step economic and promising strategy. Accordingly, several research groups have made significant contributions through the direct installation of N atom into organic molecules using various N-sources, among which azides proved to be powerful amine sources due to structural diversity and environ mentally benignity.5 However, few research groups such as Glorius,6 Ellman,7 Driver,8 Jiao,9 Zhu,10 Zeng11 and Yu12 et al. employed only aromatic molecules as precursors under Ru, Rh, Pd, Fe and Cu catalysis. Recently the demand for metal-free approaches has led to some of the interesting and significant Nincorporation strategies. In this context, recently our group13 and Jiao’s9 group have developed a metal-free N-atom incorporation strategies using azide as N-source. Subsequently, metal-free approaches for dehydrogenative N-atom incorporation into C− H bonds have emerged as straightforward strategies for the synthesis of N-heterocycles, which also provides an opportunity for late-stage modification of complex biomolecules.14,5 However, there is a great scope for development of metal-free N-insertion strategies. © 2017 American Chemical Society
Received: June 16, 2017 Published: September 13, 2017 5014
DOI: 10.1021/acs.orglett.7b01840 Org. Lett. 2017, 19, 5014−5017
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Organic Letters
(entry 3). Upon conducting the reaction using TMSN3 instead of NaN3, the reaction yield improved to 36% (entry 4). To circumvent the formation of complex mixture of byproducts, lowering the temperature improved the yield at −5 °C (entry 5). We found the dilution of the reaction mixture has greatly influenced the outcome of the reaction (entries 7 and 8, also see Supporting Information (SI)). Next, we screened the reaction by varying the equivalents of TMSN3 and PIFA (see SI). Among various solvents tested, DCE found to be effective (entries 9− 13). Our attempts to further increase the yield with additives such as CuBr, BF3·Et2O, TFA and Na2CO3 were in vain (entries 14−17). Furthermore, our efforts to improve the yield by employing other N-sources and oxidants proved futile (entries 18−22). Gratifyingly, overall, we found TMSN3 and PIFA combination to be optimum in cycloaminative strategy (entry 8). Notably, PIFA (2 equiv), TMSN3 (2 equiv), in dry DCE (0.04 M), at −5 °C proved to be the optimum condition for the C(sp3)−H amination. With the optimized conditions, we next tested the scope and limitations of the dehydrogenative N-incorporation reaction. To our delight a wide array of amines including 2° cyclic amines with different ring sizes and 2° aliphatic amines were found to be compatible for hydroamination-azidation-cyclization reaction sequence. Diverse bicyclic imidazoles (Scheme 1, 3aa−3cb) and
Figure 1. Hypothesized plan and our present strategy.
To probe the feasibility of multiple C−N bond formation using azides for N-incorporation leading to cycloamination, the required 3° enamine insituly generated from the piperidine 1a and diethylbut-2-ynedioate 2a. Initially, we tested the conditions developed in our previous work,13 which unfortunately resulted in only hydroamination product A (Table 1, entry 1). Using trimethylsilylazide (TMSN3) with iodosobenzene proved equally unsuccessful (Table 1, entry 2). We are pleased to find phenyliodine-bis(trifluoroacetate) (PIFA) as a suitable promoter to access the bicyclic imidazole compound 3a albeit in 21% yield
Scheme 1. Scope of Aliphatic Amines in N-Incorporation Strategya,b
Table 1. Optimization of Reaction Conditionsa
entry
oxidant
[N] source
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
PhI(OAc)2 PhIO PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 PhI(OCOCF3)2 − PhI(OH)(OTs) TBHP K2S2O8
NaN3 TMSN3 NaN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TsN3 IBA-N3 TMSN3 TMSN3 NaN3
DCE DCE DCE DCE DCE DCE DCE DCE DCM CH3CN EtOAc DMF DMSO DCE DCE DCE DCE DCE DCE DCE DCE DCE
ndc ndd 21d 36d 48 30e 63f 74g 57 45 25 0 0 64h 45i 48j 62k 0 17 nd nd nd
a Conditions: 1a (1.0 mmol), 2a (1.0 mmol), PIFA (2.0 equiv), TMSN3 (4.0 equiv) in dry DCE (0.04 M), at −5 °C, 8−16 h. bYields are reported for compounds isolated after silica gel column chromatography. cDetected by HRMS.
simple imidazoles (3db−3eb) were isolated in good yields under the standard conditions. In the case of unsymmetrical 2° amines, we have observed the formation of isolable mixture of compounds (3fa and 3fa′). However, terminal electron deficient alkynes resulted in trace amount of desired products (3ac and 3ed). Furthermore, 2° benzylamines with alkyl substituents on the N-center were also found to be efficient in imidazole synthesis (Scheme 2, 3ga−3ib), however requiring 2 equiv of Na2CO3 to reduce the formation of byproducts. Electrondonating groups on the aryl substrate were fair-yielding (3ja− 3ma). Notably, unsymmetrically substituted 2° dibenzyl amines provided isomers in almost equal ratio (3oa/3oa′ and 3pb/ 3pb′). We also investigated the transformation of the
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), oxidant (2.0 equiv), [N] source (4.0 equiv), dry solvent (0.04 M), −5 °C, 16 h. b Isolated yields. nd = Not detected. cHydroamination product isolated. dReaction performed at 25 °C. eReaction performed at −15 °C. fSolvent (0.02 M) used. gSolvent (0.04 M) used. hCuBr 10 mol % used. iBF3·Et2O 20 mol % used. jTFA 20 mol % used. kNa2CO3 (2 equiv) used. 5015
DOI: 10.1021/acs.orglett.7b01840 Org. Lett. 2017, 19, 5014−5017
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Organic Letters Scheme 2. Scope of Benzylic Amines and Alkynesa,b,c
reaction mixture, which did not show any radical species (see SI) suggesting a nonradical pathway.18 When we performed reaction with 2 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) it resulted in complex mixture with trace amount of product 3aa and TEMPO-adduct 4 was only detected in HRMS analysis which was not conclusive (eq 1). However, when we employed 0.3 equiv of TEMPO, it resulted in significant yield of the product with quantity recovery of TEMPO. Moreover, we could not detected any other radical trapped adduct 5 in HRMS, which only can form with methylene radical species. However, we detected TEMPO-adduct 4, which could have formed by other alternative pathway (eq 2). Similarly experiment with different radical scavenger such as 2,6-di-tert-butyl-4-methylphenol (BHT) was not conclusive (eq 3). To further rule out the radical pathway, we performed a radical clock experiment under standard conditions, which provided only the nitrogen incorporation product 3ua and no other ring-opened coupling products were observed (Scheme 4).18 Scheme 4. Radical Clock Experiment
On the basis of above results, we proposed a plausible mechanism as depicted in Scheme 5. An exchange of the a
Scheme 5. Plausible Reaction Mechanism
Conditions: 1a (1.0 mmol), 2a (1.0 mmol), PIFA (2.0 equiv), TMSN3 (4.0 equiv) in dry DCE (0.04 M), at −5 °C, 8−16 h. bYields are reported for compounds isolated after silica gel column chromatography. cNa2CO3 (2.0 equiv) used in all reactions to reduce the formation of byproducts.
tetrahydroisoquinolines (THIQ) under standard conditions as a potential substrate for a cascade comprising a hydroaminationazidation-cyclization sequence, which pleasingly resulted in Imidazo[2,1-a]dihydroisoquinolines (3sa−3tb). In an attempt to further expand the possibilities of this method, enol ether B was prepared and tested under standard conditions. Unfortunately, this failed to give the desired product (see SI). To probe the mechanism of this dehydrogenative nitrogen incorporation, some control experiments were conducted (Scheme 3). No nitrogen installation product 3aa was observed in the absence of PIFA (see SI), which indicates the key role played by PIFA in the dehydrogenative nitrogen insertion process. To investigate the possible radical pathway as hypothesized in Figure 1 (a) an electron paramagnetic resonance (EPR) experiment was carried out on a aliquot of incomplete
trifluoracetyl group in PIFA by azide ion would provide the reactive azidoiodinane, which undergoes a direct nucleophilic attack on the N center of hydroamination product A to generate ammonium ion B. The intermediate B would convert to iminium C in the presence of basic N3 anion, which undergoes nucleophilic addition by azido trimethylsilane to give intermediate D. Simultaneous cycloamination and denitrogenation of D would afford the compound E, which upon oxidation by azidoiodinane furnishes the desired product 3aa. Although HN3 is known for its explosive nature, it might readily get decomposed to H2 and N2 by stirring19 and any remnant HN3 would go into aqueous solution due to its high solubility (see SI). After having successfully synthesized trisubstituted imidazoles, owing to the vast applications of N-heterocyclic carbenes (NHCs) in organometallics and as organocatalysts,20 we envisioned our protocol could be applied for the synthesis of NHC precursors. In accordance, gratifyingly, we obtained NHC precursors in good yields via one-pot hydroamination-azidationcyclization sequence and methylation (Scheme 6, 3v and 3w). It is worth to mention that this present protocol offers a robust, step economic and cost-effective alternative to the existing methods for the synthesis of NHCs.21 In conclusion, we have developed a distinct metal-free cycloaminative strategy via C(sp3)−H and C(sp2)−H functionalization. Remarkably, the reaction endorsed a unique con-
Scheme 3. Control Experiments
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DOI: 10.1021/acs.orglett.7b01840 Org. Lett. 2017, 19, 5014−5017
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Blakey, S. B. Chem. Soc. Rev. 2015, 44, 5969. (g) Uttam, D.; Lupton, D. W.; Maiti, D. Org. Lett. 2016, 18, 860. (5) (a) Sun, K.; Sachwani, R.; Richert, K. J.; Driver, T. G. Org. Lett. 2009, 11, 3598. (b) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702. (c) Nguyen, Q.; Sun, K.; Driver, T. G. J. Am. Chem. Soc. 2012, 134, 7262. (d) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzi, S.; Piangiolino, C. Coord. Chem. Rev. 2006, 250, 1234. (e) Brase, S.; Gil, C.; K̈ nepper, K.; Zimmerman, V. Angew. Chem., Int. Ed. 2005, 44, 5188. (f) Alt, I. T.; Plietker, B. Angew. Chem., Int. Ed. 2016, 55, 1519. (g) Wang, X.; Jiao, N. Org. Lett. 2016, 18, 2150. (h) Li, Y.; Feng, Y.; Xu, L.; Wang, L.; Cui, X. Org. Lett. 2016, 18, 4924. (i) Liang, Y.; Liang, Y.-F.; Jiao, N. Org. Chem. Front. 2015, 2, 403. (j) Wang, T.; Jiao, N. Acc. Chem. Res. 2014, 47, 1137. (k) Ou, Y.; Jiao, N. Chem. Commun. 2013, 49, 3473. (6) Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802. (7) Lian, Y. J.; Hummel, R.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 12548. (8) (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pomphrey, A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500. (b) Dong, H.; Shen, M.; Redford, J. E.; Stokes, B. J.; Pomphrey, A. L.; Driver, T. G. Org. Lett. 2007, 9, 5191. (9) (a) Tang, C.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2206. (b) Zheng, Q.-Z.; Feng, P.; Liang, Y.-P.; Jiao, N. Org. Lett. 2013, 15, 4262. (10) (a) Xie, Z.; Peng, J.; Zhu, Q. Org. Chem. Front. 2016, 3, 82. (b) Xie, Z.; Deng, J.; Qiu, Z.; Li, J.; Zhu, Q. Chem. Commun. 2016, 52, 6467. (11) Chen, T.; Chen, X.; Wei, J.; Lin, D.; Xie, Y.; Zeng, W. Org. Lett. 2016, 18, 2078. (12) Ma, H.; Li, D.; Yu, W. Org. Lett. 2016, 18, 868. (13) Sagar, A.; Vidyacharan, S.; Shinde, A. H.; Sharada, D. S. Org. Biomol. Chem. 2016, 14, 4018. (14) (a) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010. (b) Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2014, 79, 4687. (c) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (15) (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277. (b) Elassar, A. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463. (c) Shawali, A. S. ARKIVOC 2012, 383. (d) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem. 1996, 67, 207. (e) Dar’in, D. V.; Lobanov, P. S. Russ. Chem. Rev. 2015, 84, 601− 633. (f) Yaghoub, S.; Marzieh, S.; Kamal, A.; Mahmood, T. Green Chem. 2011, 13, 2851. (16) (a) Zhdankin, V. V.; Stang, P. Chem. Rev. 2002, 102, 2523. (b) Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111. (c) Zhdankin, V. V.; Stang, P. Chem. Rev. 2008, 108, 5299. (d) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328. (e) Matcha, K.; Narayan, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 7985. (f) Narayan, R.; Antonchick, A. P. Chem. - Eur. J. 2014, 20, 4568. (17) (a) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931. (b) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (c) De Luca, L. Curr. Med. Chem. 2006, 13, 1. (18) We highly acknowledge the valuable comments/suggestions from reviewers (EPR and Radical Clock experiments), which gave greater insight into the mechanism. (19) Zhang, N.; Cheng, R.; Negrerie, D. Z.; Du, Y.; Zhao, K. J. Org. Chem. 2014, 79, 10581. (20) (a) Wang, M. H.; Scheidt, K. A. Angew. Chem., Int. Ed. 2016, 55, 14912. (b) Menon, R. S.; Biju, A. T.; Nair, V. Beilstein J. Org. Chem. 2016, 12, 444. (c) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44, 5040. (d) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (e) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307. (21) (a) Nakashima, T.; Goto, M.; Kawai, S.; Kawai, T. J. Am. Chem. Soc. 2008, 130, 14570. (b) Zhang, J.-Q.; Wang, Q.-C.; Zou, L.; Jia, C.-Y. Chin. Chem. Lett. 2014, 25, 762. (c) Wright, A. G.; Weissbach, T.; Holdcroft, S. Angew. Chem., Int. Ed. 2016, 55, 4818. (d) Hugar, K. M.; Kostalik, H. A.; Coates, G. W. J. Am. Chem. Soc. 2015, 137, 8730. (e) Hay, M. P.; Denny, W. A. Tetrahedron Lett. 1997, 38, 8425. (f) Hay, M. P.; Wilson, W. R.; Denny, W. A. Tetrahedron 2000, 56, 645.
Scheme 6. Synthetic Applications
struction of multiple C−N bonds in a one-pot fashion, affording a variety of synthetically and biologically important imidazole derivatives from readily available aliphatic amines. Furthermore, the mechanistic study revealed the formation of α-amine C(sp3)−H azidation as a key step in cycloamination strategy. The robustness of this strategy demonstrated by the synthesis of N-heterocyclic carbene precursors in one-pot fashion. Further investigations on more detailed mechanism, applications of our protocol and synthesis of chiral N-heterocyclic carbenes are currently underway in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01840. Experimental procedures, characterization data, and copies of NMR (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Phone: (040) 2301 7058. Fax: (040) 2301 6032. E-mail:
[email protected]. ORCID
Duddu S. Sharada: 0000-0001-5861-4126 Author Contributions §
A.S. and V.N.B. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the Department of Science and Technology − Science and Engineering Research Board (DSTSERB-EMR/2016/1000952) New Delhi, India and Indian Institute of Technology Hyderabad (IITH) for financial support. A.S. thanks CSIR and V.N.B. thanks UGC, New Delhi, India for the award of research fellowship.
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REFERENCES
(1) (a) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247. (b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (c) Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences, 1st ed.; WileyVCH: Weinheim, Germany, 2007. (d) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (e) Bariwalab, J.; Eycken, E. V. D. Chem. Soc. Rev. 2013, 42, 9283. (2) (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. (b) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. (c) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 3584. (3) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (4) (a) Cho, S. H.; Kim, J.; Kwak, Y. J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901. (c) Ackermann, L. Chem. Rev. 2011, 111, 1315. (d) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926. (e) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931. (f) Schafer, A. G.; 5017
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