Letter pubs.acs.org/OrgLett
A C−H Activation-Based Strategy for N‑Amino Azaheterocycle Synthesis Pengfei Shi, Lili Wang, Shan Guo, Kehao Chen, Jie Wang, and Jin Zhu* Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing 210023, China S Supporting Information *
ABSTRACT: A C−H activation-based strategy has been developed for the synthesis of N-amino azaheterocycles. Rh(III)-catalyzed coupling of N-Boc hydrazones/N-Boc hydrazines with diazodiesters/diazoketoesters provides convenient access to synthetically and medicinally important compounds, N-amino isoquinolin-3-ones and N-amino indoles, by harnessing N-tert-butyloxycarbonyl (N-Boc) cleavage as an adaptable reactivity pattern in distinct synthetic scenarios.
aminating reagents has limited their synthetic practicality and utility. An innovative transition-metal-catalyzed C−H activation strategy (Scheme 1b)3 has recently been pursued for the synthesis of N-amino indoles.4 However, the N-acetyl protecting functional group associated with the original directing groups remains affixed as an unintended substituent to the respective products, an undesired synthetic feature as a result of the inopportune termination of reactivity relay cascades (for the definition of reactivity relay cascade, please see Supporting Information). We are interested in the exploration of C−H activation-based reactivity relay cascades as a synthetic tool for straightforward access to deprotected Namino azaheterocycles. In devising a viable transition-metalcatalyzed synthetic scheme (Scheme 1), one needs to fulfill three prerequisites: (1) an appropriate protecting functional group is required to ensure the ability of a N−N bond-based directing group to activate the C−H bond5 and initiate a subsequent reaction pathway; (2) no reaction pathway is available for driving the cleavage of the inherently labile N−N bond; (3) the reactivity of the protecting functional group should enable its cleavage under a reaction condition compatible with the formation of azaheterocycle. Although a myriad of protecting functional groups have been used in organic synthesis,6 the N-Boc group represents an ideal choice because of (1) demonstrated utility in the C−H activation arena (for prerequisite 1), (2) varied stabilities under different structural contexts (for prerequisite 3), and (3) clean transformation to carbon dioxide and isobutylene upon deprotection (for straightforward workup). The circumvention of the N−N bond cleavage issue (for prerequisite 2) mandates the termination of a transition-metal-associated reaction pathway prior to azaheterocycle ring closure. Otherwise, this
N-Amino azaheterocycles are an important class of compounds in synthetic and medicinal chemistry.1 Traditional approaches typically accomplish a synthesis via a two-step, initial azaheterocycle construction and subsequent electrophilic Namination procedures (Scheme 1a).2 Despite the effectiveness, the required use of strong bases and unsafe, even explosive NScheme 1. Synthetic Strategies for N-Amino Azaheterocycles
Received: July 7, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b02066 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters labile bond can readily react as an internal oxidant7 for catalyst turnover, resulting in its inevitable cleavage. We show herein that N-Boc hydrazones8 or N-Boc hydrazines9 as a C−H activation directing group, together with diazodiesters or diazoketoesters as coupling partners,10 allows first time delivery of target N-amino azaheterocycle products under Rh(III) catalysis (Scheme 1). In particular, N-Boc cleavage as an adaptable reactivity pattern can be integrated into diverse synthetic scenarios, leading to efficient synthesis of N-amino isoquinolin-3-ones and N-amino indoles. Initial reaction development was focused on the coupling of N-Boc hydrazones and diazodiesters. With acetophenone NBoc hydrazone (1a) and methyl diazomalonate (2a) as the model substrates, a comprehensive screening of reaction conditions was performed. The combination of [Cp*RhCl2]2 (2 mol %) and AgSbF6 (8 mol %) under acidic conditions (100 mol % HOAc) enables the catalytic synthesis of a N-amino azaheterocycle, N-amino isoquinolin-3-one derivative 3aa, in a variety of solvents at 50 °C. Trifluoroethanol (TFE) as a reaction medium gives the highest yield of 45% after 12 h. An increase of the yield to 82% can be achieved with elevation of the temperature to 80 °C. Further tuning of the amount of HOAc to 50 mol % allows the delivery of 3aa in 97% yield. Remarkably, switching of HOAc to a basic condition (50 mol % LiOAc) provides an equally effective 97% yield catalytic system. With the optimized acidic and basic reaction conditions established, an extensive evaluation of the synthetic scope was undertaken (Scheme 2). By employing 2a as the coupling partner, the substrate scope of N-Boc hydrazones was first examined under acidic conditions. The reaction is tolerant of a change from a C-methyl group (1a) to either ethyl (1b), butyl (1c), or isopropyl (1d), with reactivity dictated by the bulkiness of the substituent. Benzaldehyde and benzophenone N-Boc hydrazones (1e, 1f) are also compatible with the transformation. Substrates bearing electronically diverse para substituents on the phenyl ring, including alkyl (1g, 1h), phenyl (1i), methoxy (1j), halogen (1k−1n), ester (1o), trifluoromethyl (1p), cyano (1q), and nitro (1r) groups, can participate in a high-yielding fashion, thus offering plentiful opportunities for further synthetic elaboration. The reaction also proceeds efficiently for meta-substituted substrates (1s− 1w), with C−H activation favored at the less hindered site. However, exclusive regiospecificity is observed only in the case of meta-methyl substitution (1s). The alteration of substituent location from para and meta to the ortho position results in lowered reactivity (1x−1z). The reactivity can be recovered by the cyclization of the ortho substituent into a six- or sevenmembered ring structure (1a′−1b′). The synthetic protocol is also suitable for the transformation of disubstituted substrates, whether in the open chain (1c′−1e′) or cyclic (1f′) form. Further, a heterocycle-bearing substrate, 2-acetylthiophene NBoc hydrazone (1g′), can react smoothly, allowing the generation of a fused biheterocyclic product. The substrate scope of diazo compounds was next investigated by reaction with 1a. The change of methyl group on 2a to a bulkier substituent (2b−2g) does not significantly hamper the reaction. Replacement of one ester group on 2b by a different electronwithdrawing moiety, a sulfonyl (2h) or phosphonate (2i) group, largely retains the reactivity. The reactions under basic conditions generally show similar or slightly inferior performance in comparison to those conducted under acidic conditions. Since the ketone group acts as the synthetic handle for installing the directing group and is ubiquitously present in
Scheme 2. Synthesis of N-Amino Isoquinolin-3-onesa,b,c,d,e
a
Conditions: N-Boc hydrazones (0.6 mmol), diazodiesters (0.4 mmol), TFE (2 mL). bYields of isolated products. cBlue: yields under HOAc. dRed: yields under LiOAc. eFor all diazo substrates except 2h and 2i: R3 = CO2R4. fFor 2h and 2i: R4 = Me.
natural products and medicinally relevant compounds, we conducted synthetic transformations for 4-chromanone (1h′)11 as a proof-of-concept demonstration of the synthetic utility of the reaction protocol developed herein (Scheme 3). Indeed, the N-Boc hydrazone directing group could be installed in a highyield fashion and furnished the target product efficiently. Scheme 3. Chemical Transformation for 4-Chromanone
The intriguing in situ N-Boc cleavage reactivity pattern prompts scrutiny of the reaction mechanism. A deuterium labeling experiment witnessed respectively 87% (3ea) and 40% (3ba) deuterium incorporation at the uncoupled ortho C−H site in the reaction of 1e and 1b with 2a (eqs 1, 2), consistent with the operation of a C−H activation mechanism. Kinetic isotope effect values obtained from competition experiments and two parallel runs are 2.0 and 2.2, respectively (eq 3), suggesting that C−H activation is the turnover-limiting step. A competition of 1h and 1o for the reaction with 2a favors electron-donating 1h (eq 4), supporting an electrophilic aromatic substitution C−H activation mechanism. Key mechanistic insight comes from the interception of an isolable B
DOI: 10.1021/acs.orglett.7b02066 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
With N-Boc cleavage identified as a handy reactivity paradigm in the reactivity relay cascade synthesis of N-amino isoquinolin-3-ones, we next examined the synthetic versatility of this reactivity pattern. An appealing candidate transformation is the coupling of N-Boc hydrazines with diazoketoesters for synthetic access to N-amino indoles. Reaction development using N-Boc phenylhydrazine (4a) and ethyl diazoacetoacetate (5a) indeed leads to the identification of [Cp*RhCl2]2 (2 mol %) and CsOAc (50 mol %) in TFE at 80 °C as the optimized conditions, which allows the synthesis of target N-amino indole derivative 6aa in 90% yield after 12 h. Gratifyingly, under this synthetic conditions, a broad substrate scope for both N-Boc hydrazines and diazoketoesters is observed (Scheme 5). Both Scheme 5. Synthesis of N-Amino Indolesa,b
N-Boc-retained intermediate 3aa−im from a reaction between 1a and 2a at a lower reaction temperature (under 50 mol % HOAc, 50 °C) that can be efficiently converted to the target product 3aa (92% yield under HOAc, 76% under LiOAc) at 80 °C (eq 5). The reactivity relay cascade is therefore proposed to encompass three reactivity paradigms (for the definition of reactivity paradigm, please see Supporting Information), although reversal of the reaction sequence for the second and third reactivity paradigms cannot be excluded (Scheme 4): Scheme 4. Proposed Reaction Pathway
a
Conditions: N-Boc hydrazines (0.4 mmol), diazoketoesters (0.6 mmol), TFE (2 mL). bYields of isolated products.
electron-donating (4b−4d, 4j, 4k) and electron-withdrawing (4e−4i, 4l−4o) groups on the phenyl ring of N-Boc hydrazines can be tolerated. Compared to the N-Boc hydrazone circumstance, regiospecific C−H coupling is achieved for more meta-substituted substrates (4j, 4l, 4o). The reactions involving disubstituted substrates (4p−4r) also proceed with high yields. For diazoketoesters, a high degree of structural diversity in compatible substituents is observed, including alkyl (5b, 5c), cycloalkyl (5d), aryl (5e−5j), and heteroaryl (5k, 5l) groups. An effort to elucidate the reaction mechanism identifies an intermediate 6aa−im under HOAc at 50 °C (eq 6). 6aa−im Rh(III)-catalyzed C−C coupling, intramolecular C−Nα cyclization (enolization might occur before C−N bond formation), and N-Boc cleavage. The reactivity paradigm relay from Rh(III)-catalyzed C−C coupling to intramolecular C−Nα cyclization can be immediately rationalized by the transition from an intermolecular to an intramolecular reaction. The unique reactivity paradigm relay from C−Nα cyclization to NBoc cleavage is a more subtle event and cannot be readily anticipated. Most likely, C−Nα cyclization destabilizes the Nβ− C bond through an inductive effect. A noteworthy example of an inductive effect previously observed is the iodoform reaction with aldehydes and ketones.12
can be readily converted to 6aa in high yield (94%) under CsOAc at 80 °C (eq 6). With this key mechanistic evidence, the N-amino indole synthesis is proposed to proceed likewise via three reactivity paradigms (reversal of the second and third reactivity paradigms is possible): Rh(III)-catalyzed C−C coupling, intramolecular C−Nα cyclization (enolization might occur before C−N bond formation), and N-Boc cleavage. C
DOI: 10.1021/acs.orglett.7b02066 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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In conclusion, a versatile C−H activation strategy has been developed for straightforward access to N-amino azaheterocycles. N-Boc cleavage as a versatile reactivity paradigm has been orchestrated into diverse reactivity relay cascades for Rh(III)-catalyzed coupling of N-Boc hydrazones/N-Boc hydrazines and diazodiesters/diazoketoesters. The intriguing synthetic reactivity identified herein promises vast exciting synthetic opportunities offered thorough exploration of the ability to integrate seemingly only remotely relevant reactivity paradigms into feasible reactivity relay cascades.
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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.7b02066. Experimental procedure, characterization of the products (PDF) Copies of the 1H and 13C NMR spectra of selected products (PDF) Crystallographic data for complex 3fa (CIF) Crystallographic data for complex 6ha (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jin Zhu: 0000-0003-4681-7895 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS J.Z. gratefully acknowledge support from the National Natural Science Foundation of China (21425415, 21274058) and the National Basic Research Program of China (2015CB856303).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02066 Org. Lett. XXXX, XXX, XXX−XXX
