Modular allylation of C(sp3)–H bonds by combining decatungstate photocatalysis and HWE olefination in flow

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner–Wadsworth–Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules.

Especially, the decatungstate anion ([W 10 O 32 ] 4À ) has shown remarkable selectivity for specic C(sp 3 )-H bonds, governed by an intricate balance between steric and electronic interactions. 9,11,12 We envisioned that the regioselective introduction of an allyl moiety onto hydrocarbon frameworks would be particularly useful as it provides a convenient branching point for further late-stage synthetic exploitation. 13 To install such moieties, radical allylation has manifested itself as a valuable strategy. One approach relies on the use of transition metal complexes to activate a substrate containing an allylic leaving group to afford a p-allyl complex, which is then suited to trap a C-centered radical (Scheme 1B). 14 This strategy can engage a diverse set of allyl coupling partners but typically requires purposely designed radical precursors, which prevents the direct allylation of unactivated C(sp 3 )-H bonds.
Seeking to address these challenges, we sought to develop a robust and versatile synthetic platform for the allylation of strong aliphatic C(sp 3 )-H bonds. Hereto, a modular synthetic sequence is preferred in which the allylic moiety is assembled in a stepwise fashion, enabling the rapid generation of structurally diverse analogues. Specically, our sequence features the merger of two distinct synthetic steps to accomplish this goal (Scheme 1C). First, we planned to activate C(sp 3 )-H bonds via decatungstate-catalyzed Hydrogen Atom Transfer 29,30 and subsequently trap the resulting C-centered radical with a vinyl phosphonate. 31,32 The ensuing radical addition product serves as a suitable linchpin for the second step, in which a classical Horner-Wadsworth-Emmons (HWE) olenation 33,34 is able to deliver the targeted allylated compounds. In order to streamline these two steps, we reasoned that a telescoped ow protocol where the reactions are performed in tandem without the need for tedious purication of intermediates would be indispensable not only to accelerate access to these valuable building blocks but also to ensure facile scalability. [35][36][37] Herein, we report the successful realization of a ow platform enabling the allylation of a wide range of unactivated hydrocarbons.
Next, the obtained alkylphosphonates were subjected to the successive HWE olenation (Scheme 2). A telescoped ow approach was developed in which the two individual steps were connected in a single streamlined ow process without intermediate purication. We selected 1,3-benzodioxole (1a), a common moiety in many medicinally-relevant molecules, as the H-donor and exposed it to the photocatalytic reaction conditions. Upon exiting the photochemical reactor, the reaction mixture containing the alkylphosphonate is merged with a stream containing paraformaldehyde (3 equiv.) and lithium tert-butoxide (1.1 equiv.) in tetrahydrofuran. The combined reaction mixture is subsequently introduced into a second capillary microreactor (PFA, ID: 0.75 mm; V ¼ 7.1 mL; t r ¼ 5 min; T ¼ 40 C) and, aer only 5 minutes of residence time, the targeted C(sp 3 )-H allylated product 4 could be obtained in 80% overall NMR yield (70% aer isolation). Interestingly, the reaction performed decently also with 1 equivalent of 1a (65% NMR yield). Notably, the tactical combination of these two steps in ow results in a very efficient and operationally simple protocol, delivering these coveted scaffolds in only 10 minutes overall reaction time. As another benet, the ow process could be readily scaled to produce 10 mmol of the desired compound 4 (1.52 g, 65% isolated yield, Scheme 2) without the need for tedious reoptimization of the reaction conditions, which is typically associated with batch-type scale up procedures.
To further demonstrate the potential of this operationally facile approach to introduce allylic functional groups, we wondered whether paraformaldehyde-d 2 could be used in the HWE step. Such a straightforward, regioselective introduction of deuterium atoms in organic molecules would be of tremendous importance for mechanistic, 54,55 spectroscopic and tracer studies. 56 Using our two-step ow protocol, the analogous deutero-allylated compound 4-d 2 was isolated in 68% yield, perfectly matching the result obtained for the non-deuterated version 4. Similarly, N-Boc piperidinone and N-methyl-2pyrrolidone were competent substrates for this protocol affording the deuterated products 20 and 21 in 44% and 52% yield, respectively. Finally, in an effort to demonstrate the applicability of this method to the late-stage functionalization of medicinally relevant molecules, we subjected biologically active molecules to our two-step ow protocol: the terpenoid ambroxide (22, 40% yield) and the nootropic drug aniracetam (23, 21% yield) could be decorated with a deuterated allylic moiety.
In a similar vein, we turned our attention to introduce aromatic and aliphatic aldehydes in the second step, yielding trisubstituted allylic moieties, which are particularly challenging to synthesize via traditional photocatalyzed radical allylation approaches (Scheme 1B). By exploiting our modular protocol, a virtually limitless array of substituents can be systematically introduced (Scheme 3). In most cases, prolonged reaction times were required to obtain full conversion. In particular, electron-decient aldehydes were convenient substrates for a fully telescoped manifold, where the ow exiting the photoreactor was directly merged with a stream containing the aldehyde and the base (see e.g., [26][27][28][29][30][35][36][37][38][39][40]. The HWE step required 30 minutes residence time and the temperature was kept at 40 C. We found that a range of pyridine-derived nicotinaldehydes and heteroaromatic aldehydes (35)(36)(37)(38)(39)(40)(41) were ideal substrates for this approach as well. As for electron-neutral and -rich carbonyl compounds, the HWE step required considerably longer reaction times and thus a fedbatch approach was found to be more practical (e.g., 25,31). Here, the reaction stream exiting the photoreactor was directly dosed into a stirring solution of aldehyde and base. It is important to stress that a fully telescoped approach was still possible in these cases, however higher reaction temperature (60 C) and a back-pressure regulator (BPR, 2.8 bar) were needed to obtain full conversion within 1 hour (e.g., 24,33,45). Another general observation that could be made is that the presence of ortho-substituents resulted in higher E : Z ratios (e.g., 28-31, 33 and 40).
It is important to note that it would be extremely challenging to access either of these motifs with the current radical allylation methodologies (Scheme 1B). Unfortunately, all attempts to engage ketones in the HWE step did not afford the desired fullysubstituted olens.
Interestingly, our protocol was also amenable to aliphatic aldehydes containing enolizable positions (48-52, 57-71% yield). The use of protected piperidine-4-carboxaldehydes allowed to obtain the corresponding allylated products 51 and 52 in excellent yields (60-68%) and with good diastereomeric ratios. In addition, medicinal agents and natural products containing carbonyls, such as acetyl-protected helicin, citronellal and indomethacin aldehyde derivatives, were also reactive delivering the targeted olens in synthetically useful yields (53-55, 20-63%). This proves the potential of this strategy to rapidly diversify double bonds.
Next, the importance of the ester moiety as electronwithdrawing group (EWG) in the substrates to enable the targeted transformations was evaluated (Scheme 4A). Thus, we synthesized different vinyl phosphonates (2 0 -2 000 ) and found that all of them performed well (40-68% 1 H-NMR yield) in the photocatalytic radical hydroalkylation. We then tested our streamlined process with benzaldehyde (GP4) to study the effect of the EWG on the diastereomeric ratio in the nal allylated compound. The cyano group-bearing substrate furnished the targeted compound 56 with an excellent diasteroselectivity; however, a poor mass balance was observed (22% yield despite full conversion of 3 0 ). In contrast, products 57 and 58 (EWG : COR) were not formed, with a complete recovery of 3 00 and 3 000 . Interestingly, we found that compound 2 0000 could serve as a suitable radical trap as well (Scheme 4B). Using 1a as coupling partner, the targeted hydroalkylation product was obtained in excellent yield (3 0000 , 90% by 1 H-NMR). A solvent switch and a stronger base (nBuLi, n-butyl lithium) were however required to induce the subsequent HWE step yielding styrenes 59-61 in good yields aer isolation (see GP7 in the ESI †). 57,58 The regioselective and late-stage installation of allylic groups opens up innumerable possibilities for further diversication. 13 Scheme 3 Scope of the modular allylation of strong aliphatic C-H bonds with aromatic and aliphatic aldehydes. Yields are given over two steps. For the experimental details of the fed-batch procedure see GP4 in the ESI, † while for fully telescoped approach see GP5. a Reactions were carried out on a 0.5 mmol scale and yields refer to isolated products, E : Z ratios were measured by 1 H-NMR. b Reaction performed according to GP5, but the HWE step required 60 C, a BPR (2.8 bar) and 1 hour residence time. c Reaction time: 16 h. d Reaction performed via general procedure GP6 in the ESI. † As an illustration of this synthetic potential, we explored diverse conditions for the conversion of 4 into functionalized derivatives (Scheme 4C). The olen and the ester functionalities could be orthogonally reduced by exploiting different reduction conditions, yielding compounds 62 (70%) and 63 (62%), respectively. 59,60 Moreover, compound 4 was an ideal substrate for another Giese-type radical addition using decatungstatephotocatalyzed HAT (64, 62%). Finally, product 65 could be obtained via a classical Mizoroki-Heck-type coupling (60%). 61

Conclusions
In conclusion, we have developed a practical methodology which enables the modular and regioselective allylation of C(sp 3 )-H bonds. Our strategy involves a synergistic merger of a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons olenation in a scalable and telescoped ow protocol. In its present form, the synthetic platform offers rapid access to various di-and tri-substituted olens from commodity chemicals containing native functionalities such as C(sp 3 )-H bonds and aldehydes. The operational simplicity of our ow protocol, requiring no intermediate purication, should facilitate a rapid transition from academic to industrial settings.

Conflicts of interest
There are no conicts to declare.