Intermolecular 2+2 Imine-Olefin Photocycloadditions Enabled by Cu(I)-Alkene MLCT Daniel M. Flores, Michael L. Neville, and Valerie A. Schmidt* University of California San Diego, Department of Chemistry and Biochemistry, 9500 Gilman Drive, La Jolla, CA, 92093, USA *Correspondence to: [email protected] Abstract: 2+2 Photocycloadditions are idealized, convergent approaches to the construction of 4- membered heterocyclic rings, including azetidines. However, methods of direct excitation are limited by the unfavorable photophysical properties of imines and electronically unbiased alkenes. Here, we report copper-catalyzed photocycloadditions of non-conjugated imines and alkenes to produce a variety of substituted azetidines. Ligand design allows this base metal-catalyzed method to achieve 2+2 imine-olefin photocycloaddition via selective alkene activation through a coordination-MLCT pathway. Nitrogen heterocycles are prevalent motifs in small molecule pharmaceuticals and their rapid construction continues to drive new reaction development.1 While 3-, 5- and 6-membered N-heterocycles are exceptionally common, made possible by a variety of synthetically accessible routes for their construction, 4-membered heterocycles are scarce by comparison despite the promising biological activity displayed by many azetidine-containing compounds.2,3,4,5,6,7 The 2+2 photocycloaddition of two p-components is a prototypical approach to 4-membered ring construction. While limited in generality, the Paternò-Büchi reaction forms oxetanes through direct irradiation of a carbonyl C=O double bond followed by C=C double bond capture.8,9,10 Aza-Paternò-Büchi analogs using imines in place of aldehydes or ketones do not generally result in the formation of azetidines due to the low barrier E/Z isomerization available upon excitation of the imine C=N double bond.11 Maruoka reported a rare intermolecular azetidine-forming 2+2 photocycloaddition example using naphthyl derived N-sulfonyl aldimines and styrene or benzofuran (Figure 1A).12 However, this reactivity was exclusive to these substrate pairs and was enabled by a pi- stacking association of the substrates prior to excitation. Alternative strategies that overcome the challenge of imine isomerization have used cyclic imines which cannot undergo E/Z isomerization,13,14,15 via preferential excitation of a conjugated C=C double bond tethered to an imine,16,17 or both (Figure 1B). Despite these advances, catalyst-controlled approaches to 2+2 imine-olefin photocycloaddition (IOPC) remain limited as general strategies for azetidine construction. A. π-Stacking pre-organizationa TsN NTs 365 nm hv + 2-nap Ph 61% yield 2-nap Ph B. Intramolecular 2+2 photocycloadditionb R1 R1 O cat. xanthone N N O N N 350 nm hv 2 R2 R OR Ph RO Ph cat. [Ir] N N blue LEDs H H X X C. Cyclic glyoxylate iminec R1 N O Me R1 cat. [Ir] N O Me EtO Me + 427 nm hv 2 Me 2 3 R R R 3 O R CO2Et D. Intermolecular imine-olefin 2+2 (this work): H R3 R3 N cat. TpCu N + 100 W Hg lamp R1 R1 R2 R2 H R1 = H, alkyl, R2 = alkyl, R3 = alkyl, allyl, OMe Fig. 1. C=N Bond 2+2 photocycloadditions. aSee ref. 12. bSee refs. 13-14,16-17. cSee ref. 15. Transition metal compounds capable of photoexcitation via metal to ligand charge transfer (MLCT) to achieve intermolecular electron or energy transfer have recently gained significant recognition for their use in chemical synthesis.18,19,20,21 Meggers reported photochemical cyclobutane synthesis by in situ formation of the active chromophore as a chiral at metal, O-bound Rh-enone compound.22 Yoon achieved enantioselective 2+2 photocycloaddition of conjugated alkenes to form cyclobutanes via Dexter energy transfer through H-bonding and p-p interactions of substrate 3-alkoxyquinolones and Ir-based photocatalysts.23 We recently reported a Cu-catalyzed 2+2 carbonyl-olefin photocycloaddition approach for oxetane formation by inverting conventional Paternò-Büchi reactivity and achieved alkene activation via coordination followed by MLCT.24 We hypothesized that 2+2 imine-olefin photocycloadditions (IOPC) may be achieved to access azetidines by coordination and MLCT with either the alkene or imine p- component (Figure 1C). To assess this hypothesis, we irradiated a 1:3 mixture of N-butyl-2-methylpropan-1-imine (1) and norbornene with catalytic hydrotris(pyrazolyl)borate copper(I) (TpCu) in diethyl ether using a 100 W Hg lamp for 8 h which resulted in formation of the corresponding azetidine 1A in 31% yield with exclusive exo selectivity (Table 1, entry 1). Removing either TpCu or any light source both resulted in no appreciable formation of 1A (entries 2 and 3). Using a small excess of imine relative to norbornene (1.1:1) improved reaction efficiency (entry 4), while using a 3-fold excess of 1, produced 1A in 79% yield (entry 5). Application of a 300 nm cut-on filter resulted in a significant decrease in the yield of 1A to 39% even after a prolonged 36 h reaction time suggesting that product forming irradiation occurred at wavelengths shorter than 300 nm (entry 6). Using CuCl or CuOTf in place of TpCu did not result in any detectable quantities of 1A (entries 7 and 8), underscoring the importance of the coordination environment of the Cu(I) source used. Reaction optimization: H nBu nBu N TpCu (20 mol %) + N 100 W Hg lamp C2 H iPr Et2O (0.15 M), 24 h H 1 iPr H 1 equiv 3 equiv standard conditions 1A Entry deviation from standard conditions Yield of 1Aa 1 none 31%b 2 no TpCu <5% 3 no light n.d. 4 1.1 equiv 1, 1 equiv norbornene 55% 5 3 equiv 1, 1 equiv norbornene 79% 6 entry 5 with 300 nm cut-on filter 39%c 7 CuCl (20 mol %) in place of TpCu n.d. 8 CuOTf (20 mol %) in place of TpCu n.d. Table 1. Summary of reaction optimization studies. a1A was detected as a >95:5 exo:endo mixture and 62:48 diastereomer mixture at C2 in all experiments; yields determined by 1H NMR analysis of crude reactions using durene as an internal standard. bReaction time 8 h due to consumption of 1. cReaction time 36 h. In exploration of imines that similarly undergo Cu-catalyzed 2+2 IOPC with norbornene, we found that aldimines from N-allyl amine and isobutyraldehyde, 3-(methylthio)propanal, and melonal all successfully were converted to their corresponding azetidines, 2, 3, and 4, respectively, in good to excellent yields (Figure 2). Imines bearing cyclopropyl groups participated in this 2+2 IOPC to produce azetidines exclusively without the detection of cyclopropyl ring-opened products (5 and 6).25,26 While imines derived from acetophenone, benzaldehyde, or aniline did not participate in this 2+2 IOPC, a phenethylamine derived isobutyraldimine, produced azetidine 7, suggesting that arene groups are tolerated when not conjugated to the imine. Heterocycles including tetrahydrofuran (8), thiophene (9), and morpholine (10) as well as an acyclic 3° amine (12) were all well tolerated in this process. Productive 2+2 IOPC was particularly notable in the presence of a g-lactam (11), showcasing the chemoselectivity of olefin activation even in the presence of other p-components capable of absorbing UV light. Imines derived from ketones also reacted efficiently to produce the corresponding azetidines even when the imine also contained Lewis-basic 3° amine (13), acetal (14), or ether (15) functionalities. H R3 R TpCu (20 mol %) R3 N 100 W Hg lamp N R + 1 R1 R2 R Et2O, 24-48 h R R R2 H Imine variation (R=norbornane): H H H H allyl R H nBu allyl allyl R N N R N R N N R Me R R R H R i R MeS i H Pr H H Pr H 2 92% yield 3 62% yield 4 71% yield 5 95% yielda 6 94% yielda 55:45 C2 dr 55:45 C2 dr 55:45 C2 dr 55:45 C2 dr 55:45 C2 dr H O H H O H Ph O R S R H N R N N N N N R N R R R R i i R i Pr Pr H R i Pr H H i Pr H Pr H 7 51% yield 8 71% yield 9 59% yield 10 51% yield 11 60% yield 51:49 C2 dr 58:42 C2 dr 67:32 C2 dr 64:34 C2 dr 59:41 C2 dr H H H H H H Et N R N R R N R MeO R 2 N R N N N R R R R R R H H iPr H O H H H MeN O n 12 37% yield O 14 n = 1, 16 95% yielda 54:46 C2 dr 13 91% yield 52% yield 15 66% yield n = 2, 17 78% yield 19 91% yield n = 3, 18 58% yielda Alkene variation: O H H H 23-HI salt H allyl allyl CN allyl N allyl N Me N N H H H H 20 95% yield 21 85% yield 22 47% yield 23 82% yield 65:35 rr 56:44 rr, 75:25 dr 50:50 rr, 60:40 dr 53:47 dr H O O allyl OTBS H O H H O H N allyl allyl allyl allyl N N N N O O O NMe H H iPr H H O MeN O H O O 24 91% yield 50:50 rr, 90:10 dr 25 98% yield (51%)b 26 68% yield (13%)b 27 96% yield (47%)b 28 49% yield (25%)b Fig. 2. 2+2 Imine-Olefin photocycloaddition reaction scope. All reactions carried out with 1 equiv norbornene, 1.1 equiv imine, 20 mol % TpCu, in diethyl ether (0.15 M) and irradiated with a 100 W Hg lamp; all yields are of isolated material following purification via basic alumina chromatography and diastereomeric ratios were determined via gas chromatography of crude reaction mixtures; all products detected as >95:5 exo:endo diastereomers.