Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow‐Generated Diazo Compounds and Propargylated Amines

Abstract We report herein the asymmetric coupling of flow‐generated unstabilized diazo compounds and propargylated amine derivatives, using a new pyridinebis(imidazoline) ligand, a copper catalyst and base. The reaction proceeds rapidly, generating chiral allenes in 10–20 minutes with high enantioselectivity (89–98 % de/ee), moderate yields and a wide functional group tolerance.

Allenes continue to hold ag eneral interest due to their cumulated, orthogonal p bonds.S ince their initial discovery, they have been found in natural products and incorporated into various functional materials. [1,2] Perhaps most importantly,however,istheir utilization in awide range of chemical transformations,e specially cycloadditions [3] and cyclization reactions. [4] Thea symmetric synthesis of allenes remains an underdeveloped area, with most precedent literature proceeding via S N 2' type reactions with enantiopure propargyl derivatives. [5] Enantioselective coupling reactions of two simpler fragments using catalytic quantities of chiral ligand are even scarcer,due to the difficulty in controlling the stereochemistry of at hree-carbon axially chiral skeleton. Existing reports utilizing chiral ligands include the coupling of aldehydes and terminal alkynols in the presence of (R,R)-N-PINAP [6] and the coupling of stabilized a-diazoesters with terminal alkynes using chiral guanidinium salts (Scheme 1). [7] Very recently,an asymmetric process was described by Wang et al. to generate trisubstituted allenes using unstabilized ketone-derived diazo compounds (72-98 % ee). [8] We reported earlier the room-temperature racemic coupling of unstabilized flow-generated diazo compounds with terminal alkynes and found the process to be extremely general, tolerating al arge range of functional groups as ac onsequence of the mild conditions utilized for the diazo partner generation. [9] It would therefore be highly desirable to assess whether these same benefits [10,11] would allow an enantioselective variant of the process,i nt he presence of an appropriate chiral ligand. We report herein am ethod to access chiral disubstituted allenes via flow-generated aldehyde-derived diazo compounds and terminal alkynes,u sing an ew pyridinebis(imidazoline) ligand designed for this purpose.
With the knowledge that hydrazone 1a is able to generate the corresponding diazo compound 2a in the presence of activated MnO 2 under flow conditions,a ni nitial ligand screen was developed for the coupling with alkyne 3a (Table 1). We found that tridentate ligands were suitable for inducing enantioselectivity,w hereas mono-and bidentate ligands did not result in any selectivity (see the Supporting Information (SI) for further details). These results suggest that our tridentate ligand-mediated process for disubstituted allene synthesis is complementary to the bidentate ligand-mediated trisubstituted allene process described by Wang et al. [8] Interestingly,t he commercially available (S)-i Pr-PyBOX( L1)p rovided coupling products 4aand 4a' ',ina38:62 ratio with 68 % ee (entry 1). Attempts at Scheme 1. Asymmetric coupling reactions for allene synthesis using catalytic chiral ligand.
changing the structure of the PyBOXl igand offered some improvement in enantioselectivity (84 % ee,e ntry 3), though frustratingly,the desired allene remained aminor product of the reaction.
Fortunately,s witching the flanking oxazoline units to imidazolines (PyBIMs) proved fruitful, allowing an improvement in the enantioselectivity (96 % ee,entry 4). In particular, para-substituted electron-withdrawing groups on the N-aryl substituent proved essential to providing allene 4a as the major product, with the 4-SF 5 group providing the best result (entry 9). Further increases in the electron deficiency(4-nitro and 4-triflyl, entries 10 and 11) of the aromatic ring provided moderate enantioselectivities,p resumably due to poorer binding to the copper center.Webelieve that the ambidentate oxazoline units of the more commonly used PyBOX ligands are the origin of this differing efficiencyinenantioselectivity, as coordination to the oxygen atom could lead to poorer enantioselection (see SI for adetailed discussion). In contrast, PyBIM ligands were superior as they offer only as ingle binding site on the imidazoline units.F urthermore,m odulation of electronic effects was critical to achieve correct coupling selectivity.T ot he best of our knowledge,t his is the first rationalization of the performance of PyBOXv ersus PyBIM ligands, [12] which could be important for future development of new catalytic asymmetric reactions.
With the new ligand in hand, we then tested av ariety of propargylated amine derivatives and flow-generated diazo compounds for the asymmetric allenylation reaction ( Table 2). Overall although yields in general are moderate (30-57 %), the enantioselectivity of the reaction is excellent (89-98 % de/ee)a nd proceeds rapidly under mild conditions. Ther emaining mass balance was mainly due to the alkyne cross-coupled product, which could generally be removed by careful column chromatography.Amyriad of sensitive functional groups were found to be compatible with the reaction conditions,i ncluding ketones (4c), aldehydes (4d), epoxides (4e), unprotected alcohols (4i), esters (4l, 4u)a nd terminal/ internal olefins (4s, 4t and 4v), all with excellent enantioselectivities.N otably,s everal heterocyclic examples including thiophenes (4f), furans (4j), indoles (4ac)and pyrroles (4ad) were also tolerated despite their potential to interfere with the catalytic cycle,a ll with good enantioselectivity.V ariation in the electronic properties of the diazo compound had as mall effect on the yield and enantioselectivity,w ith more electron-withdrawing substituents such as 4-fluoro (4o)a nd 3-cyano (4q)leading to slightly lower ee values (91 % ee and 89 % ee,respectively,compared to 94-96 % ee for 4m, 4n, 4p and 4r). It was also easy to scale up the asymmetric allenylation to 5mmol of propargylamide for allene 4w in our flow system without the need to store excessive quantities of diazo compound, which provided 0.89 go fc hiral material in similar yield and ee to the smaller scale run.
To further probe the functional group tolerance of this procedure,wewere able to conduct the late-stage asymmetric allenylation of various propargylated amine derivatives of seven drug molecules/natural products (4x-4ad), including (S)-ibuprofen, aspirin, penicillin G, topiramate,p regabalin, indomethacin and atorvastatin, again all proceeding with high de/ee values.S urprisingly,t he presence of the thioether functionality on penicillin Gw as not detrimental to the stereoselectivity.
We were able to demonstrate the utility of the chiral allenes generated in am edicinal chemistry context by conducting the silver-mediated cyclization [13] of allene 4a to its corresponding 3-pyrroline 5 (Scheme 2), with good chirality transfer and excellent yield (97 % ee to 95 % ee). The process can therefore overall be regarded as af ormal enantioselective sp 2 -sp 3 coupling,w ith af unctional handle (internal olefin) for potential further derivatization.
We anticipate that the reaction mechanism proceeds as depicted below (Scheme 3). In the presence of base and the copper catalyst, the initially generated ligand-copper acety- [a] Using 0.2 mmol of alkyne 3a,0.02 mmol of CuI, 0.03 mmol of ligand and 0.4 mmol of Et 3 NatRTin2mL 1,4-dioxane, with 0.4 mmol of hydrazone 1a (with DIPEA as buffer) flowed through activated MnO 2 then ab ack pressure regulator (BPR). All reactions proceeded in > 95 %c onversion.
[b] Allene/alkyner atio determined by 1 HNMR analysis of the crude reaction mixture.
[c] ee determined by chiral HPLC. lide complex 7 undergoes an enantioselective concerted CuÀ Cbond insertion with the diazo compound 2.The approach of this species is controlled by the bulky t Bu arms of the PyBIM ligand, with the hydrogen substituent of the diazo compound on the same side as the ligand t Bu groups.S elective 1,3protonation (most likely via the N À Hgroup from the amide/ sulfonyl group) of the transient copper species 8 from the front face of the catalyst then generates the desired allene 4 and regenerating the ligand-copper complex 6.Itappears that the copper species 8 is fairly labile and can dissociate leading to the anionic species 9,w hich subsequently protonates to give the undesired alkyne cross-coupled product 4' '. [14] In summary,w eh ave reported an ew flow-enabled catalytic asymmetric coupling reaction of aldehyde-derived unstabilized diazo compounds with propargylamine derivatives,p roceeding rapidly in moderate yields and high enantioselectivities.G iven the underdeveloped methods for enantioselective allene synthesis,o ur results represent an important achievement in this field, particularly due to the high level of functional group tolerance and potential for latestage functionalization. Further investigations into generalizing the scope and the development of new bifunctional ligands are currently ongoing in our laboratories. [a] Standard reaction conditions:0.2 mmol of alkyne, 0.02 mmol of CuI, 0.03 mmol of ligand L9 and 0.4 mmol of Et 3 NatRTin2mL 1,4-dioxane, with 0.4 mmol of hydrazone (with DIPEA as buffer) flowed through activated MnO 2 then aback pressure regulator (BPR), see SI for more detail;yields stated are of isolated product; de/ee determined by chiral HPLC;a bsolute configuration of allene 4w determined by X-ray crystallography,others assigned by analogy.

Conflict of interest
Theauthors declare no conflict of interest.