Synthesis of Naphthoquinolizinones through Rh(III)-Catalyzed Double

Letter pubs.acs.org/OrgLett

Synthesis of Naphthoquinolizinones through Rh(III)-Catalyzed Double C(sp2)−H Bond Carbenoid Insertion and Annulation of 2‑Aryl-3-cyanopyridines with α‑Diazo Carbonyl Compounds Beibei Zhang, Bin Li, Xinying Zhang,* and Xuesen Fan* School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, China S Supporting Information *

ABSTRACT: An unprecedented Rh(III)-catalyzed double C(sp2)−H bond carbenoid insertion and annulation of 2aryl-3-cyanopyridines with α-diazo carbonyl compounds is presented. Through this cascade reaction, a series of naphthoquinolizinone derivatives with a large π-system were efficiently prepared. The reactions could selectively afford naphthoquinolizinones with either an amine or an amide unit attached on the 11-position depending on the nature of the solvent and the additive used. Compared with literature methods, this is a more efficient, convenient, and atom-economic way to provide polycyclic heteroaromatic compounds through direct π-extension of simple aromatics via inert C−H bond activation and functionalization.

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initiated by carbenoid insertion, N-cyclization vs C-cyclization, we were curious that 2-phenyl-3-cyanopyridine, bearing both the pyridinyl and the cyano moieties, would follow the reaction pattern as shown by 2-phenylpyridine to give benzoquinolizinone (A, Scheme 1-3) via N-cyclization or the reaction pattern as shown by 2-phenyl-3-cyanoindole to give benzo[h]quinoline (B, Scheme 1-3) through C-cyclization upon treatment with an αdiazo carbonyl compound. Herein, we report our detailed studies. Our study was initiated by treating 2-phenylnicotinonitrile (1a) with ethyl 2-diazo-3-oxo-3-phenylpropanoate (2a) using [RhCp*Cl2]2 as a catalyst and AgOAc as an additive in CH3CN at 80 °C for 6 h. From this reaction, neither the proposed Ncyclization product (A) nor the C-cyclization product (B, Scheme 1-3) was obtained. Instead, two naphthoquinolizinones, 3a and 4a, were obtained in yields of 6 and 15%, respectively (Table 1, entry 1). This unexpected finding is no less interesting and promising. First, formation of 3a/4a directly from 1a and 2a indicated that an unprecedented cascade process of double C(sp2)−H bond carbenoid insertion followed by C-cyclization and N-cyclization took place spontaneously. Second, naphthoquinolizine derivatives such as 3a and 4a belong to the biologically and optically significant azapyrene derivatives with a large π-system and thus hold the potential to find wide applications in the fields of material science and medicinal chemistry.9 Although the design and synthesis of novel polycyclic heteroaromatic compounds has already been intensively pursued, general and easy-to-run synthetic approaches toward azapyrene derivatives are still

ransition-metal-catalyzed C−H bond activation is rapidly prevailing as it can remarkably enhance the efficiency and atom-economy of the desired transformations by avoiding tedious preactivation of the starting materials and minimizing the production of unwanted byproducts.1 As one of the powerful strategies for C−H bond activation, carbenoid insertion into the challenging arene C(sp2)−H bonds is a well-established method for the construction and functionalization of aromatics.2−5 In this regard, Zhao et al. reported a Co(III)-catalyzed C−H bond coupling between 2-phenylpyridine and α-diazo malonate followed by a Lewis acid promoted intramolecular nucleophilic addition of the N-atom of the pyridinyl unit onto the ester moiety to give benzoquinolizinones (Scheme 1-1).6 Meanwhile, our recent study on carbene chemistry showed that 2-phenyl-3cyanoindole reacted with α-diazo carbonyl compounds under Rh(III) catalysis to give benzo[a]carbazoles via carbenoid insertion, intramolecular nucleophilic addition of an enolate onto the cyano unit followed by a deacylation (Scheme 1-2).7 As the above examples revealed two distinct annulation patterns Scheme 1. Carbenoid Insertions and Annulations

Received: March 20, 2017 Published: April 24, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b00839 Org. Lett. 2017, 19, 2294−2297

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Organic Letters Table 1. Optimization Studiesa

Scheme 2. Substrate Scope for the Synthesis of 3a,b

yieldb (%) entry

solvent

additive (equiv)

1c 2d 3 4e 5 6 7 8 9 10 11 12 13 14 15

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DCE acetone CH3OH CH3OH CH3OH CH3OH CH3OH CH3OH CH3OH

AgOAc (1) AgOAc (1) AgOAc (1) AgOAc (1) AgOAc (0.5) AgOAc (0.5) AgOAc (0.5) AgOAc (0.5) AgSbF6 (0.5) Cu(OAc)2 (0.5) HOAc (0.5) PivOH (0.5) HOAc (0.5) HOAc (0.5)

t (°C) 80 80 80 80 80 80 80 80 80 80 80 80 80 100 60

3a

4a

6 12 18

15 32 44

trace 17 8 25 62 50 55 82 61 63 72

trace 45 61 43 20 15 12 trace trace trace trace

a Conditions: 1a (0.3 mmol), 2a (0.9 mmol), [RhCp*Cl2]2 (0.015 mmol), additive, solvent (2 mL), 6 h. bIsolated yield. c2a (0.36 mmol). d 2a (0.6 mmol). eWithout [RhCp*Cl2]2.

limited.6,8−10 Therefore, this new reaction deserves a detailed study to develop it into an efficient and practical synthetic approach toward azapyrenes and to enrich the chemistry of diazo compounds as carbene precursors. Reaction conditions for the formation of 3a and 4a were optimized. It was found that increasing the amount of 2a from 1.2 to 2 or 3 equiv could improve the yields of 3a and 4a to 12 and 32% or 18 and 44%, respectively (entries 2 and 3). Control experiments indicated that either the catalyst or the additive was indispensible (entries 4 and 5). In addition, reducing the amount of AgOAc from 1 to 0.5 equiv could give similar yields of 3a and 4a (entry 6). Next, study of the effect of different solvents including CH3CN, DCE, acetone, and CH3OH revealed that DCE is the most efficient for the formation of 4a whereas CH3OH is more effective than other solvents for the formation of 3a (entries 6−9). Next, with CH3OH as the solvent, AgSbF6, Cu(OAc)2, HOAc, and PivOH were tried as additives to replace AgOAc (entries 10−13). Using HOAc as an additive could remarkably enhance the efficiency and selectivity for the formation of 3a in that the yield of 3a increased to 82% while 4a was formed in trace amount (entry 12). Further study showed that temperature higher or lower than 80 °C resulted in diminished efficiency (entries 14 and 15). Thus, the following conditions for the formation of 3a were established for subsequent studies: [RhCp*Cl2]2 (5 mol %) and HOAc (0.5 equiv) in CH3OH at 80 °C under air for 6 h. With the optimized reaction conditions, the scope and generality for the synthesis of 3 were explored, and the results are listed in Scheme 2. First, using 1a as a model substrate, the reaction of different α-diazo carbonyl compounds (2) was studied. It was found that 2-diazo-3-oxo-3-phenylpropanoates with various functional groups attached on the phenyl ring underwent this reaction efficiently to give 3a−3g in 78−90% yields, and the electronic nature of the phenyl moiety rendered a slight effect on this reaction in that substrates bearing electronwithdrawing groups (EWGs) on the phenyl ring generally gave

a Conditions: 1 (0.3 mmol), 2 (0.9 mmol), [RhCp*Cl2]2 (0.015 mmol), HOAc (0.15 mmol), CH3OH (2 mL), 80 °C, 6 h. bIsolated yield.

higher yields than those bearing electron-donating groups (EDGs). 2-Diazo-3-oxo-3-(thiophen-2-yl)propanoate and 2diazo-3-(naphthalen-1-yl)-3-oxopropanoate were also suitable for this reaction, affording 3h and 3i in yields of 56 and 76%, respectively. When two alkyl-substituted α-diazo carbonyl compounds were used, the reactions proceeded successfully to give 3j and 3k in reasonably good yields. Just like ethyl 2-diazo-3oxo-3-phenylpropanoate, the reaction of methyl 2-diazo-3-oxo3-phenylpropanoate was equally successful to give 3l in 81% yield. Next, with 2a as a model substrate, different 2-aryl-3cyanopyridines (1) were tested. All of them took part in this reaction smoothly to give 3m−3u in good yields. Generally, yields of 3 were affected by the electronic nature of 1 in that 1 with EWGs attached on the 2-phenyl ring generally gave higher yields than those with EDGs. Dimethyl 2-diazo malonate was found to be suitable for this reaction to afford 3v in good yield. With the synthesis of 3 accomplished, we studied the preparation of 4. After some trials and errors, the following conditions were found to be optimal, giving 4a in 66% yield: [RhCp*Cl2]2 (5 mol %) and AgOAc (0.5 equiv) in DCE at 80 °C for 10 h. Under these conditions, the substrate scope for the synthesis of 4 was explored (Scheme 3). First, it was found that 2 bearing various R2 and R3 units reacted with 1a smoothly to give 4a−4j in moderate yields. Next, reactions of 1 bearing a different R1 group were also studied using 2a as a model substrate. They could undergo this reaction to give 4k−4r in moderate yields. 2295

DOI: 10.1021/acs.orglett.7b00839 Org. Lett. 2017, 19, 2294−2297

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Organic Letters Scheme 3. Substrate Scope for the Synthesis of 4a,b,c

densation to form VI, from which VII is formed through addition of methanol onto the imine moiety followed by aromatization via eliminating a methyl benzoate molecule.12 In the second stage of this cascade process, Rh(III)-catalyzed C(sp2)−H bond carbenoid insertion of VII with 2a followed by an intramolecular N-cyclization affords 3a via formation of intermediates VIII−XI. The mechanism shown in Scheme 4 is partly supported by the following experiments. First, the proposed rhodacycle I could be prepared separately by directly reacting 1a with [RhCp*Cl2]2 in the presence of NaOAc in CH2Cl2 at ambient temperature.11 Next, reacting 1a with 2a in the presence of 5 mol % of I and HOAc in methanol afforded 3a in 85% yield. When the reaction was carried out in the absence of HOAc, 3a was obtained in a decreased yield of 65%. Direct treatment of stoichiometric amount of I, instead of 1a, with 2a in the presence of HOAc in methanol afforded 3a in 83% yield (Scheme 5), indicating that in addition to being able to act as an active catalyst, I could also be used as the substrate for formation of 3a. Scheme 5. Preparation and Reaction of Rhodacycle I

a

Conditions: 1 (0.3 mmol), 2 (0.9 mmol), [RhCp*Cl2]2 (0.015 mmol), AgOAc (0.15 mmol), DCE (2 mL), 80 °C, 10 h. bIsolated yield. cYields in parentheses refer to those of compound 3. d24 h.

Second, 2-(2-fluorophenyl)nicotinonitrile (5), in which one of the two C(2)−H bonds of the 2-phenyl unit is replaced by a C−F bond, and therefore only one C(sp2)−H bond carbenoid insertion would be possible, was treated with 2a under standard conditions. From this reaction, 6, the C-cyclization product, was obtained in a yield of 58%. Formation of the plausible Ncyclization product (7) was not observed (Scheme 6). This result indicated that after the initial C(sp2)−H bond carbenoid insertion, C-cyclization occurred preferentially to N-cyclization.

Substrates bearing EDGs on the 2-phenyl moiety of 1 generally resulted in yields higher than those bearing EWGs, and this is in contrast to what had been observed in the synthesis of 3. Note that the functional groups attached on different sites of the newly formed naphthoquinolizinone skeleton might be used as synthetic handles for azodination, alkylation, reduction, etc. to tune their photophysical or other properties. Based on reports,6,11 a plausible mechanism for the formation of 3a is proposed in Scheme 4. First, a C−H bond cleavage of 1a assisted by [RhCp*Cl2]2 takes place to form five-membered rhodacycle I or II. Next, I or II reacts with 2a to afford a rhodium−carbene III by dediazonization. Migratory insertion of carbene into the Rh−C bond affords IV. Next, protonolysis of IV leads to formation of V and allows the Rh complex to start a new catalytic cycle. Then, V undergoes an intramolecular con-

Scheme 6. Reaction of 5 with 2a

Third, a kinetic isotopic effect value of 2.03 was observed in the competitive reactions of an equimolar mixture of 1a and 1a-d5 with 2a (Scheme 7). This result showed that an arene C(sp2)−H bond cleavage might involve the rate-limiting step of this cascade process. For the pathway leading to formation of 4a, it is postulated that when the reaction of 1a and 2a is carried out in the non-

Scheme 4. Proposed Mechanism for the Formation of 3a

Scheme 7. Competitive Reactions of 1a and 1a-d5 with 2a

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (NSFC) (Grant No. 21572047), Program for Innovative Research Team in Science and Technology in Universities of Henan Province (15IRTSTHN003), and Program for Science and Technology Innovation Talents in Universities of Henan Province (15HASTIT005) for financial support.

nucleophilic DCE, an intramolecular version of nucleophilic addition occurs with intermediate VI to give XII featured with the formation of a four-membered ring. XII undergoes an aromatization-driven ring opening to give XIII. C(sp2)−H bond carbenoid insertion of XIII with 2a gives XIV. Finally, Ncyclization of XIV, a process similar that described in Scheme 4 (from intermediate IX to 3a), occurs to afford 4a (Scheme 8).

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Scheme 8. Proposed Mechanism for the Formation of 4a

Scheme 9. Control Experiments

In summary, we developed a novel and efficient synthesis of naphthoquinolizinone derivatives through Rh(III)-catalyzed double C(sp2)−H bond carbenoid insertion and annulation of 2-aryl-3-cyanopyridines with α-diazo carbonyl compounds. This should be the first example in which two distinct aromatic systems are efficiently constructed in one pot via double C(sp2)− H bond carbenoid insertion and annulation of simple substrates. Compared with previous reports, this new protocol provides an alternative approach toward naphthoquinolizinones with advantages such as easily obtainable substrates, good functional group tolerance, tunable chemoselectivity, and high efficiency.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00839. Experimental procedure, characterization data and NMR spectra of all products, X-ray crystal structures and data of 4a and I (PDF)

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REFERENCES

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The proposal that formation of 4a should proceed via an intramolecular rather than an intermolecular version of acyl transfer is supported by the following control experiments. First, treating 2-(4-methoxyphenyl)nicotinonitrile with 2a and 3a under standard conditions afforded 4l in 72% yield. Meanwhile, 3a was recovered in 88% yield, and formation of 4a was not observed. Second, treating the mixture of 3a and benzoic acid under standard conditions afforded 4a only in a trace amount. Meanwhile, 3a was recovered in 86% yield (Scheme 9).

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Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xuesen Fan: 0000-0002-2040-6919 Notes

The authors declare no competing financial interest. 2297

DOI: 10.1021/acs.orglett.7b00839 Org. Lett. 2017, 19, 2294−2297