Mild and Efficient Winterfeldt Oxidation of 1,2,3,4-Tetrahydro-γ-carbolines for the Synthesis of Dihydropyrrolo[3,2-b]-quinolones and Pyrrolo[3,2-b]quinolones

The Winterfeldt oxidation (NaOH, DMF, air, rt) of substituted 1,2,3,4-tetrahydro-γ-carbolines has been developed, which provides a convenient and efficient method for the synthesis of the corresponding dihydropyrrolo[3,2-b]quinolones in moderate to excellent yields (38–94%). The generality and substrate scope of this reaction are explored and a possible mechanism is proposed. The results imply that electron-withdrawing groups on N2 of tetrahydro-γ-carbolines and N5-H are necessary. The synthesis of 5 or 7-substituted pyrrolo[3,2-b]quinolones in near quantitative yields was also achieved through deprotection and aromatization of N1-boc-dihydropyrrolo[3,2-b]quinolones.


Introduction
Fused tricyclic and tetracyclic quinolone scaffolds have been reported to possess many biological properties. For example, pyrroloquinolone 1 is a highly potent and selective PDE5 inhibitor [1], 2,3-dihydro-1H-cyclopenta[b]quinolin-9(4H)-one derivative 2 shows antimalarial activity [2], and cryptolepine analogue 3 displays antiplasmodial activity [3]. Among all the reported synthetic methods for the construction of fused quinolone scaffolds, the biomimetic Winterfeldt oxidation has attracted much interest because of its simple procedure and widely available substrates [4]. Particularly, the Winterfeldt oxidation of 1,2,3,4-tetrahydro-β-carbolines with different reagent systems including OPEN ACCESS the past few years, which has not only provided an efficient method for the preparation of pyrroloquinolone derivatives such as 1 and 4, but also for crucial indole-quinolone transformations in the total synthesis of potent antitumor agent (±)-camptothecin 5 [9] and TNF production inhibitor (S)-(−)-quinolactacin B 6 [10,11].
Encouraged by this initial finding, we turned our attention towards the development of a convenient and efficient method on the synthesis of dihydropyrrolo [3,2-b]quinolones and pyrrolo[3,2-b]-quinolones via Winterfeldt oxidation.
As shown in Table 1, by using 2-Boc-1,2,3,4-tetrahydro-γ-carboline (8a) as a model compound, a survey of reaction conditions was carried out. We first examined the effect of different bases on the yields of product. The results demonstrated that t-BuOK, NaOCH 3 , and NaOH were all capable of promoting the Winterfeldt oxidation with almost the same yields of product as NaH, while the reaction using K 2 CO 3 as base failed, probably due to its weak basicity (Table 1, entries 3-6). Because of its simple handling and wide availability, NaOH was chosen as the suitable base for the following optimization. Subsequently, the molar ratio of NaOH to substrate 8a was examined, the results suggested that 2.0 equiv. of base was sufficient for this reaction (Table 1, entries 7, 8). A screen of solvents revealed that DMF provided the best yield, MeOH completely inhibited the oxidation, and the yield in THF was poor because of the incomplete conversion of substrate, even under reflux conditions (Table 1, entries 9-11). Usually the Winterfeldt oxidation is carried out with a base in DMF in the presence of oxygen [4][5][6], therefore, a similar reaction with a balloon containing oxygen was performed, and the reaction was complete in 2 h with the same yield as seen in the air. These results suggest that the air performs the same role as the oxygen. (Table 1, entry 12). Considering the convenience of operation and wide availability of reagents, the Winterfeldt oxidation of 2-Boc-1,2,3,4tetrahydro-γ-carbolines was thus best run in DMF with 2.0 equiv. of NaOH at room temperature for 5 h in the presence of air (Table 1, entry 5). With the optimized reaction conditions, we next examined the generality and substrate scope of this Winterfeldt oxidation reaction. A series of 6-or 8-substituted 2-Boc-1,2,3,4-tetrahydro-γ-carbolines were employed and the diversity of substituents in the 2-position of 1,2,3,4-tetrahydro-γ-carbolines was investigated (Scheme 2).

As shown in
All these results imply that electron-withdrawing groups on the 2-position of 1,2,3,4-tetrahydro-γcarbolines are necessary for this variant of the Winterfeldt oxidation, which may favor the formation of ketolactam intermediates. It also shows that 2-Boc-5-methyl-1,2,3,4-tetrahydro-γ-carboline could not be converted to corresponding quinolone under the optimized conditions, which clearly indicates that prior formation of the N-anion is necessary in this reaction. On the basis of these results and previous studies by Mentel and others [4,13], a plausible mechanism for this improved Winterfeldt oxidation is proposed in Scheme 3.

Scheme 3.
Proposed mechanism for the formation of substituted dihydropyrrolo After a careful survey of reaction conditions, the substituted 2-Boc-dihydropyrrolo[3,2-b]quinolones 10a-e were refluxed in HCl-EtOAc/CH 3 OH under nitrogen to afford dihydropyrrolo-[3,2b]quinolones 11a-e in excellent yields as the corresponding hydrochloride salts. We found that the free amines of 11a-e were unstable in air and part of them transferred to the corresponding pyrrolo[3,2-b]quinolones 12a-e. Therefore, the conversation of 11a-e to 12a-e in near quantitative yields was accomplished through refluxing in ethanol with K 2 CO 3 (Scheme 4, Table 3).  Table 3. Synthesis of 11a-e and 12a-e. Entry 10

General
All melting points were measured on a Büchi apparatus and were not corrected. IR spectra (KBr pellets, 400-4,000 cm −1 ) were recorded on a Bruker VECTOR 22 FTIR spectrophotometer. 1 H-and 13 C-NMR spectra were recorded on a Brucker Avance DMX500 NMR spectrometer (500 and 125 MHz, respectively) using CDCl 3 , CD 3 OD, D 2 O, or DMSO-d 6 as solvents with TMS as an internal standard. Elemental analyses were determined with a Thermo-Finnigan Flash EA 1112 elemental analyzer. ESI-HRMS spectra were measured with a Bruker Daltonics Apex β 7.0 FT-ICR MS instrument. Mass spectra (MS, ESI positive) were recorded on an Esquire-LC-00075 spectrometer.