Flow microreactor synthesis of 2,2-disubstituted oxetanes via 2-phenyloxetan-2-yl lithium

Abstract A mild and sustainable synthesis of 2,2-disubstituted oxetanes has been achieved through the use of a flow microreactor system. By controlling the residence time a highly unstable intermediate such as 2-phenyloxetan-2-yl lithium can be generated and trapped with various electrophiles affording in moderate to good yields 2-substituted-2-phenyloxetanes at higher temperatures with respect to macrobatch-mode where –78 °C is required.


Introduction
Oxetane rings have an important role as the main core in naturally occurring compounds as well as versatile motifs both in the total synthesis of natural products [1] and in synthetic organic chemistry. [2] They have also received considerable attention as versatile elements in drug discovery [3,4] and their preparation has offered opportunities for the discovery of novel chemical transformations [5]. Moreover, oxetanes are also versatile starting materials for a wide variety of ring-expansion reactions [6].
Among the strategies for accessing oxetane rings, there are generally two synthetic approaches that have the widest application, although some interesting alternative synthetic approaches have been recently suggested by Bull's group [7][8][9][10][11]. The first approach entails a ring-closing etherification reaction [12,13], namely an intramolecular Williamson ether synthesis, and the second one involves the Paternò-Büchi reaction [14,15], namely a photochemical [2+2] cycloaddition of carbonyl compounds to alkenes. Following these approaches, the preparation of more elaborated oxetanes bearing a higher degree of functionalization can be sometimes a very laborious work. Therefore, the study on synthesis of oxetane containing molecules is yet an open issue showing the need for new synthetic methods for the rapid preparation of valuable functionalized oxetanes. In this context, a recent work by Capriati and co-workers [16] (scheme 1) demonstrated, for the first time, a direct method to obtain 2-substituted-2-phenyloxetanes (2) by electrophilic quenching of the 2-lithiated derivative 1-Li, although the latter was found to be thermally and configurationally unstable. In fact, at temperature higher than -78 °C, 1-Li was found to mainly undergo decomposition with the formation of a complex reaction mixture of unidentified products. However, it should be pointed out that in the reactivity of oxetanes towards alkyllithiums, it was already known that the nucleophilic substitution at C-2 can compete with α-lithiation [17] as well as oxetane moiety could undergo ring opening reactions [18,19].
More recently, Capriati's group [20], has shown that 2-substituted-2-phenyloxetanes, obtained as shown above, can be functionalized regioselectively on phenyl group via an ortho-lithiation reaction using s-BuLi as a base, opening new possibilities for the synthesis of oxetane derivatives. Next, Ley and co-workers [21], within this context, have successfully shown that oxetanes bearing a pyridine at C2 can be lithiated regioselectively on pyridine moiety using n-BuLi as a base affording new functionalized pyridine oxetane building blocks.
By taking in account the paucity of examples, employing 2-aryloxetanes as starting material for the synthesis of 2,2-disubstituted oxetanes, and continuing our research interests [22][23][24][25][26][27] in the fi eld of fl ow microreactor chemistry [28][29][30] and fl ash chemistry [31,32], we wondered if Capriati's protocol for the preparation of 2-substituted-2-phenyloxetanes (2) by electrophilic quenching of 1-Li, could be conducted under mild and sustainable conditions employing fl ow microreactor systems. We reasoned that within a microreactor system, we should have been able to control the thermal (and chemical) instability of 1-Li avoiding its decomposition. In fact, in the last decade microreactors and continuous fl ow technologies are emerging as a viable alternative to macrobatch processes both in academic research and in the industrial fi eld, off ering even more sustainable synthetic routes. Furthermore, organolithium compounds are generally very unstable and they have to be generated at very low temperatures and the reactions are sometimes diffi cult or impossible to control in batch-mode systems because they are oft en extremely fast and highly exothermic. In this context, fl ow chemistry could open new possibilities in organic synthesis involving organolithiums. Therefore, the use of a fl ow microreactor, by controlling residence time and temperature, allows the overcoming of these drawbacks [33,34]. The proper control of the residence time in microreactors can be fundamental to increase yields and selectivities in organic reactions compared to macrobatch-mode [35].

Results and Discussion
On the basis of previous experience of generating highly unstable oxiranyl [37][38][39] and aziridinyl lithium species [40,41] under fl ow chemistry, our study began by assembling a fl ow microreactor system that consisted of two T-shaped micromixers (M1 and M2) and two microtube reactors (R1 and R2) as shown in fi gure 1. A solution of 2-phenyloxetane 1 and a solution of s-BuLi were introduced to micromixer M1 by syringe pumps. The mixture passed through microtube reactor R1, with variable length; the resulting solution of generated 2-phenyloxetan-2-yllithium 1-Li and a solution of chlorotrimethylsilane were respectively introduced to micromixer M2. The resulting mixture was then passed through microtube reactor R2 with fi xed length (t R2 = 2.20 s) aff ording the desired product 2a.
In particular, the reaction was carried out by varying the residence time (t R1 ) from 0.38 to 25 s changing the length of microtube reactor R1, while maintaining a fi xed fl ow rate, and varying the temperature of cooling bath from -50 to -20 °C. Therefore, both deprotonation and quenching with chlorotrimethylsilane were conducted at the same temperature. The eff ects of an accurate control of both reaction temperature (T) and residence time (t R1 ) on the yield of 2a are highlighted in Figure 2.
By conducting the reaction using shorter residence times (i.e. between 0.38 and 2.5 s), we obtained low or moderate yields of 2a. On the other hand, employing higher residence times (i.e. between 2.5 and 25 s), at temperatures between -50 and -30 °C, 2a was obtained from moderate to high yield, but at temperatures higher than -30 °C the yields decreased signifi cantly. The assembled fl ow microreactor system has indeed provided an eff ective reactor for the generation and reactions of 2-phenyloxetan-2-yl lithium 1-Li without decomposition by using a residence time of 12.5 s and effi cient temperature control at -40 °C, which is an impracticable temperature in batch-mode. In particular, the systematic tuning of the residence time (t R1 ) has proved, as generally expected in fl ash chemistry, to be a key parameter for achieving a reaction with good yield and selectivity.
In order to increase the yield of 2a, we attempted a further tuning of the reaction conditions by changing the molarity of a solution of s-BuLi (from 0.5 M to 0.6 M). We found that the yield of 2a slightly depends on the amount of the base. However, with 3 equiv of s-BuLi, 2a was obtained in 85% yield.
Next, on the basis of the optimized conditions (1.0 equiv of 1, 3.0 equiv of s-BuLi, 3.0 equiv of electrophile, t R1 = 12.50 s, t R2 = 2.20 s at -40 °C), we examined the nucleophilicity of 1-Li towards various electrophiles in order to prepare diff erent 2,2-disubstituted-oxetane derivatives as reported in Table 1.
By using electrophiles such as chlorotrimethylsilane and MeI (entry 1 and 2), the corresponding 2-substituted-2-phenyloxetanes 2a and 2b were obtained in good yield. An aliphatic aldehyde such as pivalaldehyde (entry 3) also reacted aff ording the expected addition product 2c in good yield although, with diastereoselectivity poor (dr = 67:33) as observed in batch. [16] With an acetone (entry 4), the corresponding hydroxyalkylated products 2d was obtained in moderate yield suggesting that enolisation could in principle compete with the addition reaction. On the other hand, when enolisation is not possible as in the case of benzophenone (entry 5), the corresponding hydroxyarylated products 2e was even obtained in lower yield.

Conclusions
The use of a fl ow microreactor system, enabled the generation of 2-lithiated oxetane species such as 1-Li and its trapping with representative electrophiles. In particular, by controlling the residence time, the highly unstable intermediate 1-Li could be generated and trapped with electrophiles at higher temperatures with respect to batch-mode (i.e -40 °C instead of -78 °C) obtaining 2,2disubstituted oxetanes (2a-e) in moderate to good yields. Under fl ow conditions, it is worth noting that the accurate control of reaction parameters such as residence time and temperature proved to be fundamental for achieving a more sustainable reaction, that normally need to be carried out in bath-mode at much lower temperatures. This work could eventually open the possibility for a sustainable fl ow synthesis of substituted oxetanes in pharmaceutical fi eld.
Acknowledgements: This work has been realized under the framework of the National Project "FIRB -Futuro in Ricerca" (code: CINECA RBFR083M5N) coordinated by R.L.