Letter Cite This: Org. Lett. 2018, 20, 6943−6947
pubs.acs.org/OrgLett
Construction of Substituted 2‑Aminophenols via Formal [3 + 3] Cycloaddition of Alkyl 2‑Aroyl-1-chlorocyclopropanecarboxylate with in Situ Generated Enamines Sen Yang, Dengfu Lu, Hengrui Huo, Fan Luo,* and Yuefa Gong* School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, Hubei 430074, China
Org. Lett. 2018.20:6943-6947. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 11/02/18. For personal use only.
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ABSTRACT: A one-pot, three-component reaction between alkyl 1-chlorocyclopropanecarboxylate, alkyne diester, and amine is developed. This cascade reaction proceeds smoothly to afford substituted 2-aminophenols in high yields. The process proceeds through a formal [3 + 3] cycloaddition between an enamine and a cyclopropene intermediate formed in situ. The substituted 2-aminophenols can be transformed into phenoxazines and benzoxazole derivatives with the treatment of PIDA.
C
Scheme 1. Direct Synthesis of Substituted Aminophenols
onstruction of the benzene skeleton has been a subject of current interest for synthetic chemists since substituted benzenes are the core structural units of many bioactive compounds, natural products, and functional materials.1 Traditional access to substituted benzene involves a sequence process starting from the Diels−Alder reactions of common dienophiles with dienes involving furan.2 The well-explored method is relevant to the transition-metal-catalyzed classic [2 + 2 + 2] cyclotrimerization of alkynes,3 and this methodology has successfully extended to [2 + 2 + 2] cyclotrimerization of other unsaturated substrates from alkynes to alkenes,4a ketone or β-keto esters,4b enol ethers,4c,d and oxime esters.4e In recent years, increasing interest has been paid to the development of transition-metal-free multicomponent benzannulation from simple acyclic precursors such as active methylene compounds,5a electron-deficient olefins,5b and diester acetylenedicarboxylates.5c Chi’s group reported that the benzene core can be also constructed through base-mediated formal [4 + 2] cycloaddition reaction6a or through a N-heterocyclic carbenecatalyzed formal [3 + 3] reaction between crotonaldehydes and enones.6b On the other hand, cyclopropenes as a kind of versatile building block have found wide application in organic synthesis,7 mainly owing to their unique reactivities8 which cannot be found in normal olefins, allenes, and alkynes. Recently, we have developed an efficient one-step procedure to produce highly reactive cyclopropene I (Scheme 1), which is a valuable intermediate in organic synthesis and can be used as a new type of three-carbon synthon via the cleavage of its CC bond.9 When a dipole reagent is employed in the reaction with I, a formal [3 + 2] cycloaddition product was achieved via a nucleophilic addition, ring opening, and ring closure sequence.10 As is known, enamines II could be conveniently © 2018 American Chemical Society
generated in situ from commercially available amines and alkyne esters,11 and β-imine ester III, the tautomer of enamine II, can be considered a dipole reagent (Scheme 1). We envisaged that the intermediates I and III would undergo a formal [3 + 3] cycloaddition12 and subsequent aromatization to produce substituted benzenes. This idea encourages us to perform the reaction between methyl 2-aroyl-1-chlorocyclopropanecarboxylates, amines, and dialkyl acetylenedicarboxylates. As a consequence, substituted 2-aminophenols are found to be the main products of the above one-pot, threecomponent reactions. In fact, 2-aminophenol derivatives are an important class of redox-active ligands13 and useful organic intermediates in pharmaceutical chemistry.14 They are commonly prepared by direct reduction of 2-nitrophenols, though a few synthetic methods of 2-aminophenol derivatives were reported previously involving cationic cobalt-catalyzed 1,3-rearrangement of N-arylhydroxylamine esters and organocatalytic reaction Received: September 27, 2018 Published: October 18, 2018 6943
DOI: 10.1021/acs.orglett.8b03090 Org. Lett. 2018, 20, 6943−6947
Letter
Organic Letters
Scheme 2. Reactions for Arylamines 1 and Substrate 3a,b
between cyclohexenone and nitrosoarenes.15 Therefore, it is still important to develop efficient strategies for the straightforward synthesis of substituted aminophenols. The cycloaddition reaction between aniline (1a), dimethyl acetylenedicarboxylate (2a), and methyl 2-benzoyl-1-chlorocyclopropanecarboxylate (3a) was chosen as a model for the optimization of reaction conditions. At the beginning of our study, 1a was mixed with 2a in a solvent and stirred for 1 h to form enamine. Then the substrate 3a and a base were added to the reaction mixture successively at room temperature. In view of our previous work, 1,2-elimination of alkyl 2-aroyl-1chlorocyclopropanecarboxylate proceeded easily and gave the cyclopropene I in the presence of Cs2CO3. Therefore, we first chose Cs2CO3 as the base and CH3CN as the solvent. The reaction proceeded smoothly and afforded product 4aaa in 51% yield (Table 1, entry 1). The structure of the product Table 1. Condition Optimizationa
entry
base
solvent
time (h)
yieldb (%)
1 2 3 4 5 6 7
Cs2CO3 Cs2CO3 t-BuOK NaOH DBU TEA Cs2CO3
CH3CN DMF DMF DMF DMF DMF DMSO
12 6 3 6 10 10 2
51 83 36 78 21
