Metal-Free Reductive Cleavage of C–N and S–N Bonds by Photoactivated Electron Transfer from a Neutral Organic Donor

A photoactivated neutral organic super electron donor cleaves challenging arenesulfonamides derived from dialkylamines at room temperature. It also cleaves a) ArC–NR and b) ArN–C bonds. This study also highlights the assistance given to these cleavage reactions by the groups attached to N in (a) and to C in (b), by lowering LUMO energies and by stabilizing the products of fragmentation.

but in the presence of photoactivation, and b) with 3, but in the absence of photoactivation. In all cases, no product was formed and the starting substrate was recovered in excellent yield (see the Supporting Information). This reinforced the message that photoactivation of the donor (or the donorsubstrate complex; see the Supporting Information), significantly enhances the driving force for electron transfer.
For completeness, the more reactive substrates, 6 and 8, were also treated with 3 under photoactivated conditions (Scheme 2). They underwent efficient cleavage, as expected, with the products 7 and 9, respectively, being isolated in excellent yield after shorter reaction times in the presence of three equivalents of 3.
For the radical anion 19, formed at the sulfonamide group in 10 after electron transfer (Scheme 2), we calculated whether fragmentation to either the dialkylamide anion 22 and a sulfonyl radical 23, or the dialkylaminyl radical 20 and a sulfinate anion 21 would be preferred. [4] Density functional theory [5,6] (DFT) calculations were employed to optimize all structures with the gradient corrected B97-D functional with a long-range dispersion correction. [7] All atoms were described with the 6-311 ++ G(d,p) basis set. [8,9] Subsequent single-point energy calculation of the optimized geometry was performed at the same level of theory within a polarizable continuum model (CPCM) [10] with the dielectric constant of N,N-dimethylformamide (DMF, e = 37.219; see the Supporting Information for details). These studies indicated that fragmentation of the radical anion 19 into 20 and 21 is thermodynamically preferred, both when 19 alone is considered as an entity, and also when a complex between the radical cation of the donor and 19 is considered. Experimental evidence in favor of the formation of an aminyl radical following fragmentation was also seen when substrate 24 was subjected to cleavage. Here fragmentation into the toluenesulfinyl radical 23 and dialkylamide anion 28 should lead to the isolation of the corresponding amine, N-cyclopropyl-Ntetradecylamine, upon work-up. In contrast, cleavage to 21 and the aminyl radical 29 should lead to rapid opening of the cyclopropane ring to afford the imine 30, which could undergo quenching of its radical in a number of ways [1k] to form the imine product 31, and thus undergo hydrolysis under mild work-up conditions to afford the tetradecylamine 26. In fact, the experiment afforded 26 (85 %) and 25 (78 %), thus supporting 29 as an intermediate.
The next task was to investigate whether N-benzyl groups could be cleaved. The outcome from the substrate 8 deserves comment because it shows no cleavage of the benzyl group. This is in accord with expectations in this case, as the LUMO is localized on the electron-poor p-toluenesulfonyl (tosyl) group, rather than on the benzyl group. When the S À N bond is cleaved, the aniline anion 18 results, and the arene ring is too electron-rich to receive another electron. Either during the reaction or upon work-up, 18 undergoes protonation to 9.
To modify the structure of 8 so that cleavage of an Nbenzyl bond might occur, we designed substrates such that the benzyl group was the site of the LUMO within the substrate. To this end, benzyl alkyl methanesulfonamide derivatives (33 a-i) were chosen (Table 1). DFT studies (B3LYP / 6-31G*), taking 33 c and 33 g as examples, in a DMF solvent Scheme 2. Reactions of sulfonamides with the photoactivated donor 3. continuum indicated that the LUMO of these compounds was located on the benzyl group. If electron transfer occurred to the benzyl group, then the leaving group would likely be the sulfonamide anion, and this would be protonated to form 34 upon work-up. Upon trying the reactions, very good yields of N-benzyl bond cleavage were seen in each case (Table 1). The substrate 33 e features a benzyl group and a dimethoxybenzyl group. The outcome shows competitive cleavage of these two benzyl groups, with marginal selectivity for the formation of 34 e*, which is consistent with a very slightly preferential electron transfer to the less electron-rich aryl ring, that is, the C 6 H 5 ring. To show that photoactivation was required for these reactions, 33 g was subjected to a parallel reaction in which photoactivation was omitted. This reaction afforded an excellent recovery of the unchanged 33 g (94 %).
Since benzyl methanesulfonamides had worked so well we next investigated the more challenging allyl methanesulfonamides. Because these compounds have less extensive p systems, their LUMO energies are expected to be higher than their benzyl counterparts. In support of this, the mixed allyl benzyl substrate 35 a showed selectivity for the benzyl cleavage to 37 (62 %; Table 2). This outcome was in line with expectations since the LUMO of this substrate (and the SOMO of its radical anion) were associated with the arene ring, rather than with the allyl group or with the sulfonyl group. However, the presence of some product resulting from allyl cleavage, that is, 36 a (10 %), encouraged us to think that substrates which did not feature an N-benzyl group might undergo cleavage of the allyl group. This selectivity in 35 a for benzyl cleavage over allyl cleavage contrasts with that seen in palladium-induced reduction of benzyl allylamines where the affinity of Pd 0 for olefins dominates the reactivity. [11] It also surprisingly contrasts with the selectivity in favor of deallylation seen in the reductive deprotection of sugars with SmI 2 reported by Hilmersson et al. [12] When the allyl alkyl methanesulfonamides 35 b-e were treated under photoactivation conditions with 3, cleavage of the allyl group was exclusively seen, with moderate to good yields of the products 36 being isolated. Taking the substrates 35 d and 35 e as examples, the LUMO of the substrates (and the SOMO of their radical anions) are sited on the allyl groups, thus allowing the selectivity of the observed reactions to be easily understood. In 35 b and 35 c, the LUMO lies on the aryl ring, however, the radical anion shows spontaneous cleavage of the allyl group. In this case, electron transfer to the arene should occur preferentially. There is no driving force for fragmentation of the arene radical anion in these two cases, since that would give an alkyl leaving group unstabilized by resonance, so intramolecular electron transfer to the allyl group can occur, thus leading to the observed fragmentation. To explore whether photoactivation was needed to trigger these reactions, the substrate 35 b was subjected to the same reaction conditions, except that no photoactivation was provided. In this case, no deprotection occurred and 35 b was recovered in quantitative yield.
This ability to transfer an electron to an N-allylsulfonamide takes the photoactivated electron donors into new territory, as no previous deallylation reaction has been reported. To check if the allyl group was really needed, or if N,N-dialkyl methanesulfonamides would undergo reaction by electron transfer to the sulfonyl group, the N,N-dioctyl methanesulfonamide 38 was subjected to reaction with the photoactivated 3. In this case, no new product was detected and the starting material 38 (92 %) was recovered unchanged.
The ability to transfer an electron to an ArCÀN ring group is evident in the above results with the substrates 33 a-i, and this led us to investigate what happens in the transposed case, that is, ArN À C. An amine nitrogen atom directly attached to the arene should make electron transfer to the arene more difficult, but the accessibility of the LUMO for electron transfer should depend upon the third group attached to the nitrogen atom. With the simple N-methyl-N-allylaniline 39 a, very little cleavage occurred, but the product that was isolated, 40 a (6 %), showed cleavage of the N-allyl bond ( Table 3). To better facilitate the cleavage reaction, the N-Me group was replaced by an N-acyl group. The electron-withdrawing acyl group can lower the LUMO energy and hence make electron transfer to the LUMO easier. In the event, protection of the nitrogen atom as an acetamide (39 c), a pivalamide (39 d), and a urethane (39 e), all enhanced the cleavage of the allyl group. [13] A blank experiment was also conducted on 39 c (in the absence of photoactivation) and this  showed no conversion into the product, but rather quantitative recovery of 39 c, thus illustrating the essential role of the photoactivation of the donor. The pivalamide was most successful, thus affording the product 40 d in 83 % yield. The significant difference in efficiency between 39 c and 39 d led us to investigate whether deprotonation of the acetyl group by the basic donors might be occurring. When a repeat of the experiment with 39 c was subjected to addition to D 2 O, as opposed to H 2 O, prior to acidification and extraction, both the product 40 c and the recovered starting material 39 c showed incorporation of a single deuterium atom by mass spectrometry. For further thoughts on the role of deprotonation, see discussion of reactivity of substrate 44.
Since the ease of bond cleavage in the radical anion seems to correlate with the stabilization given to the radical and anion products, then replacing the alkene of the allyl group in 39 by a carbonyl group, as in 41, (Table 4) might additionally facilitate the cleavage reactions, since the anionic leaving group would be an enolate, in place of an allyl anion. Accordingly, the substrates 41 a-c were prepared. Encouragingly, the N-methyl substrate 41 a showed a higher yield of cleavage product [here 40 a (34 %)] than had been seen for the corresponding allyl case, 39 a (6 %). The N-acetyl and the Ncarbethoxy cases, 41 b and 41 c, respectively, underwent very efficient reaction (74 % and 92 % yield of products respectively) with loss of the CH 2 CO 2 Et side chain. This outcome shows that ArNÀC bonds are also subject to reductive cleavage, and that the efficiency of cleavage correlates with stabilization of the radical and anion produced. A repeat reaction was carried out for 41 b, but in the absence of photoactivation. This reaction gave no 40 c, but gave recovered starting material (41 b, 91 %). A final example of this series, 41 d, was reacted to give a comparison with other sulfonamide substrates reported herein, and this afforded 42 (89 %), the expected product of fragmentation of the arenesulfonamide radical anion.
To verify the importance of the aryl group, the substrate 43 was next prepared (Scheme 3). If electron transfer to the ester group occurred, then cleavage of the N À CH 2 CO 2 Et bond might have been expected, but none was seen. Accordingly, the N-aryl group is crucial for the NÀC cleavage to occur.
Finally, we prepared the modified ArNÀC substrate 44 where cleavage of the ArNÀC bond at the radical anion stage (46) would leave the radical and anion tethered together in 47 (Scheme 3). In this case, an intriguing rearrangement of the pyrrolidine into a piperidone product 45 (30 %) occurred. Efforts to improve the conversion by adding more equivalents of 3 were not successful, and this is consistent with the representation in Scheme 3. The initial radical anion 46 undergoes fragmentation to 47. In the presence of excess 3, further reduction to the amidyl anion 48 should occur rapidly. The dianion 48 is unlikely to cyclize, but cyclization could occur after proton transfer from another molecule of 44, thereby forming the enolate 49 which will not undergo any reduction. Finally, cyclization of the anion 50 would afford the piperidone 45. If this proposal is correct, it would also be relevant for the closest analogue of 44, that is, 41 a. The lower yield in these two substrates could therefore be explained both by this proton transfer from substrate and by the inherent difficulty of electron transfer to an N,N-dialkylaniline.
To conclude, electron transfer from the photoactivated neutral electron donor 3 delivers high yields of SÀN and CÀN cleavage products for a range of nitrogen-containing species including anilines, sulfonamides, and amides. These reactions proceed at room temperature and under mild reaction conditions in the absence of any metal reagents, thus illustrating challenging reactions which can be achieved by photoactivated neutral organic electron donors.