Bromonium-catalyzed 1,2-diamination of various conjugated alkenes

Abstract

Alkene functionalization via cyclic halonium intermediates is highly effective for stereocontrol, and a catalytic approach further expands this strategy, offering access to more advanced functionalization. Although various studies have utilized halonium species, expanding their scope to electron-deficient or π-conjugated alkenes has remained challenging. In this report, using a bromonium catalytic system, we achieved the stereoselective intermolecular 1,2-diamination of various α,β-unsaturated carbonyl compounds and π-extended alkenes. The direct use of hazardous Br₂ was avoided by generating the active species, dibromamine-Ns (Br₂NNs), in situ from stable dichloramine-Ns (Cl₂NNs) and NaBr. The reaction proceeded with complete anti-selectivity, and mechanistic studies revealed a stereoselective pathway involving catalytic aziridination followed by ring opening. The resulting nosyl-protected diamines can be flexibly deprotected and derivatized, providing rapid access to useful scaffolds such as unnatural amino acids and nitrogen-containing functional molecules.

A diastereoselective 1,2-diamination applicable to a wide range of α,β-unsaturated carbonyls and π-conjugated alkenes is described. The bromonium catalytic system enables the reaction, affording products with complete anti-selectivity.

Introduction

Three-membered cyclic halonium ions (haliranium ions) are well-known classic intermediates, and these are well-established reactive intermediates for control of stereochemistry in organic synthesis. The existence of these species was postulated in 1937 and later confirmed through NMR and X-ray analysis.^1–4 Cyclic halonium species generally mediate stereoselective halofunctionalization, dihalogenation, and halocyclization of alkenes, in which the halogen substituents inevitably remain in the products (Fig. 1a). If the halogen substituent could be released and oxidized in the reaction process, a catalytic cyclic halonium system could be realized. Such catalysis would enable stereoselective alkene functionalizations beyond simple halogen incorporation (Fig. 1b). In 1998, Sharpless and our group independently and first developed bromine and iodine catalyzed stereoselective aziridination of alkenes using chloramine-T as a nitrogen source.^5,6 As the unique feature of both reactions, the combination of a catalytic amount of bromine or iodine and chloramine-T to be introduced could induce cyclic halonium-mediated catalytic cycles. An alternative reaction system was developed as well. When N-aminophthalimide (PhthNH₂) was treated with a catalytic amount of iodide, an excess oxidant and base, cyclic iodonium-mediated aziridination was revealed by Zhdankin in 2012.⁷ Using a similar reaction system employing catalytic halides and stoichiometric oxidants, various alkene difunctionalizations have been achieved, including intermolecular oxazoline synthesis^8,9 and intramolecular diamination.¹⁰ We have also recently succeeded in diastereodivergent diamination of unactivated alkenes enabled by iodonium catalysis.^11,12 Despite these developments, cyclic halonium-catalyzed alkene functionalization remains scarce, with the substrate scope restricted to simple alkenes and electron-deficient alkenes remaining challenging substrates. In 1999, Sudalai and co-workers reported an aziridination of alkenes, including a few electron-deficient olefins, using pyridinium hydrobromide perbromide as a catalyst.¹³ To date, no other types of stereoselective functionalization of electron-deficient alkenes using halonium catalysis have been reported.

Fig. 1. Overview. (a) Classical halonium-mediated alkene functionalization. (b) Catalytic halonium system. (c) Representative molecules containing 1,2-diamino acid motifs. (d) This work: catalytic and stereoselective diamination utilizing bromonium catalysis.

Diamination of α,β-unsaturated carbonyl compounds (carbonyl conjugated alkenes) would provide straightforward access to α,β-diamino carbonyl compounds, which are found in organic molecules with valuable biological properties and extraterrestrial organic compounds^14–17 (Fig. 1c). The diamination of α,β-unsaturated carbonyls reported so far has been restricted to non-catalytic systems and syn-diamination owing to the formation of (metalla)cyclic intermediates containing two nitrogen units.^18–28 Additionally, the nitrogen sources are typically excess acetonitrile (as solvent) and bis(imido)osmium(viii) complexes, making modification of the nitrogen moieties in the products difficult due to the limited availability of suitable nitrogen sources. In light of these challenges, we report the development of a method for the catalytic and stereoselective intermolecular 1,2-diamination of α,β-unsaturated carbonyl compounds utilizing bromonium catalysis (Fig. 1d(i)). Furthermore, the catalytic method developed herein was found to be applicable to π-conjugated alkenes as well (Fig. 1d(ii)). Despite their potential utility, direct diamination of π-conjugated alkenes, including phenanthrenes and related π-extended arenes, remains largely unexplored. Although diazidation of stilbene derivatives has been reported, stereocontrol has not been achieved.^29–31 Given that π-extended diamines serve as versatile building blocks for nitrogen-embedded functional materials, while chiral diamines constitute privileged scaffolds in organocatalysis and asymmetric metal catalysis,^32–36 direct access to these motifs would further highlight the broad synthetic potential of our bromonium catalysis.

Results and discussion

We have recently reported the I₂-catalyzed diastereoselective intermolecular 1,2-diamination of unactivated alkenes using N-chloro-N-sodio-2-nitrobenzenesulfonamide (chloramine-Ns) as the nitrogen source.^11,12 However, I₂ could not be applied as the catalyst for the diamination of α,β-unsaturated carbonyl compounds (Fig. 2a, entry 1). This striking contrast suggests that the formation and/or persistence of the corresponding iodonium intermediates is disfavored in electron-deficient systems. We therefore reasoned that a less polarized and more structurally defined bromonium intermediate might overcome this limitation. Accordingly, we examined the halogen congener Br₂ in the reaction of methyl cinnamate (1aa) with chloramine-Ns, affording the desired anti-diaminated product (4aa) in 58% yield (Fig. 2a, entry 2). This superior performance of bromine over iodine may reflect fundamental differences in halonium ion stability and reactivity. Although further mechanistic studies are required, these observations reveal the unique suitability of bromonium catalysis for electron-deficient substrates.

Fig. 2. Reaction development. (a) Selected optimization data. (b) In situ generation of dibromamine-Ns. (c) X-ray crystal analysis and synthesis of dichloramine-Ns.

For this bromine-mediated reaction, we envisioned the in situ generation of N,N-dibromonosylamide (dibromamine-Ns), as it is known that the reaction of Br₂ with chloramine-T yields N,N-dibrominated sulfonamide.³⁷ Upon verification using NMR analysis, it was observed that Br₂ and chloramine-Ns were quickly converted to dibromamine-Ns in MeCN-d₃ (Fig. 2b, scheme i). Moreover, the structure of dibromamine-Ns was confirmed via a single-crystal X-ray diffraction analysis (Fig. 2c(i)). Suspecting that dibromamine-Ns served as the active species, we separately prepared and employed it as a catalyst. The diamination proceeded more efficiently, providing the product in 71% yield (Fig. 2a, entry 3). Although this catalyst outperformed Br₂, it required the use of toxic and difficult-to-handle Br₂ for its preparation. In addition, dibromamine-Ns is difficult to store and particularly sensitive to light. As an alternative and environmentally more benign method to prepare the catalyst, we found that the reaction of N,N-dichloronosylamide (dichloramine-Ns) with two equivalents of NaBr instantly afforded dibromamine-Ns and NaCl (Fig. 2b, scheme ii). Dichloramine-Ns is highly stable and requires no special storage conditions and can also be readily prepared on the gram scale by treating simple nosylamide with two equivalents of NaOCl·5H₂O and acetic acid (Fig. 2c(ii)). Consequently, the in situ generation of dibromamine-Ns from dichloramine-Ns and NaBr in the dark efficiently promoted the anti-selective diamination of 1aa, without any detectable syn-diaminated product (Fig. 2a, entry 4). Control experiments confirmed that employing dichloramine-Ns or NaBr alone failed to induce any reaction (Fig. 2a, entries 5 and 6).

With the optimized conditions in hand, we investigated the substrate scope of this catalytic system using a broad range of α,β-unsaturated carbonyl compounds (Fig. 3). Esters that can be transformed into various functional groups were the first compounds employed in the diamination. α,β-Unsaturated esters substituted with aryl groups at the β-position, alkyl or phenyl cinnamates, were readily diaminated with complete anti-selectivity (4a–4c). Although both the amount of catalyst and reaction temperature had to be increased in the case of alkyl-substituted substrates, crotonate esters were efficiently converted to the corresponding diamines (4da–4dc). The presence of alkyl substituents, such as n-pentyl, benzyl, and isopropyl, at the β-position did not have a significant effect on the diamination, and complete anti-selectivity was still observed (4e–4g). Despite the oxidative conditions, hydroxy groups were tolerated, and cyano substituents were also compatible (4h and 4i). α,β-Unsaturated esters containing aryl and alkyl groups at the α-position could also be transformed into the corresponding diaminated products (4j–4n). Trisubstituted alkenes were also active under these reaction conditions (4o–4q). In particular, the reactions of 1p and 1q both afforded anti-diaminated adducts, indicating that the present reaction proceeds stereospecifically. Even for more electron-deficient alkenes, the desired diaminated compounds were obtained (4r–4t), albeit that a slight excess amount of reagent and catalyst was required.

Fig. 3. Scope of diamination. See the SI for full experimental details. All yields are isolated yields. ^a35 °C. ^b30 °C. ^cChloramine-Ns (2.2 equiv.), dichloramine-Ns (20 mol%), NaBr (40 mol%). ^d40 °C, 28 h → 80 °C, 2 h. ^e48 h. ^fChloramine-Ns (3 equiv.), dichloramine-Ns (20 mol%), NaBr (40 mol%). ^grt, 3 h → 80 °C, 27 h. ^hDichloramine-Ns (100 mol%), NaBr (400 mol%). ⁱChloramine-Ns (2.3 equiv.), dichloramine-Ns (100 mol%), NaBr (430 mol%), rt, 18 h.

The catalytic system could be successfully extended to α,β-unsaturated amides and ketones. Pyrrolidine, morpholine, pyrazine and oxazolidinone-substituted amides were stereoselectively transformed into diamines in good yield (5a–5e). Aryl- and alkyl-substituted amides, the Weinreb amide, and the secondary amide were also compatible with these diamination conditions (5f–5j). Even though the reaction efficiency values were moderate, various α,β-unsaturated ketones were diaminated with complete anti-selectivity (6a–6e). Thus, the present catalytic system was found to be applicable for the diamination of a diverse array of α,β-unsaturated carbonyl compounds. Under the current diamination conditions, α,β-unsaturated aldehydes were not applicable.

The present nitrogen source, chloramine-Ns, can be readily obtained from the reaction of nosylamide with NaOCl·5H₂O in MeCN.¹¹ Furthermore, as mentioned above, treatment of nosylamide with NaOCl·5H₂O and AcOH in MeCN afforded the catalyst precursor dichloramine-Ns. These methods prompted us to investigate the direct diamination from commercially available nosylamide. Mixing prescribed amounts of nosylamide, NaOCl·5H₂O, and AcOH in MeCN generated the stoichiometric amounts of chloramine-Ns and catalytic amounts of dichloramine-Ns. The resulting mixture was treated with an α,β-unsaturated carbonyl compound and a catalytic amount of NaBr under appropriate conditions, leading to the corresponding diaminated compounds in acceptable yield (Fig. 4a). The nitrogen moieties of 4aa and 4da can subsequently be freely modified based on the Fukuyama method.³⁸ The two Ns groups can be readily detached by treatment with a thiolate to give 7a (Fig. 4b(i)). The diaminated product can also be efficiently converted into the precursor of a secondary amine 7b and directly transformed into a secondary amine 7cvia a one-pot process (Fig. 4b(ii) and (iii)). Moreover, it is also possible to synthesize anti-diamino acids 7d by sequential detachment of the Ns group and hydrolysis of the ester (Fig. 4b(iv)). As we have already reported the iodine-catalyzed syn-selective 1,2-diamination of unactivated alkenes using chloramine-BBS,¹¹ the present catalytic system was also applied to the syn-diamination of α,β-unsaturated esters. We found that the complete syn-diamination of methyl or benzyl crotonates (1da and 1db) afforded the corresponding compounds 8aa and 8ab in moderate yields. Furthermore, 8ab was converted into syn-diamino acid 9ab by treating with phenol and p-toluenesulfonic acid (Fig. 4c).^39,40 The diastereomers of α,β-diaminobutanoic acid (α,β-Dab) 7d and 9ab were identified in the root nodules of Lotus tenuis inoculated with the rhizobium strain, NZP2213.⁴¹ Moreover, α,β-Dab has been detected in a sample of the Murchison meteorite as a racemic mixture.^42,43 The present diamination method enables the diastereodivergent synthesis of these intriguing compounds from crotonates in two steps.

Fig. 4. Applications. (a) One-pot type diamination of α,β-unsaturated carbonyls. (b) Transformations of the diaminated product. (c) Syn-selective diamination of crotonates with chloramine-BBS.

To investigate the reaction pathway, the diamination of methyl crotonate was stopped after 5 hours, and the reaction mixture was found to contain aziridine 4da-Az as well as the diaminated product 4da (see SI data for details). When the diamination was carried out with a stoichiometric amount of the catalyst for 2 h, it was found that in addition to the two compounds 4da and 4da-Az, bromoamidated product 4da-BA was also produced (Fig. 5a). Time-course monitoring of the reaction by ¹H NMR revealed that, as the starting material was consumed, 4da-BA was formed first, followed by 4da-Az, and finally 4da (Fig. 5b). This sequence clearly indicates that 4da-BA and 4da-Az are reaction intermediates. Additionally, these intermediates were obtained as single diastereomers, suggesting that the diamination proceeds through a stereospecific mechanism. Based on these results, we would like to propose the reaction pathway, which consists of two processes: a catalytic aziridination cycle and a diamination step, shown in Fig. 5c. First, the active catalyst species, dibromamine-Ns, is smoothly generated by halogen exchange from dichloramine-Ns, before dibromamine-Ns transfers a bromonium ion to the α,β-unsaturated carbonyl compound to generate a cyclic bromonium species I. The counter nitrogen anion II present in the vicinity of the bromonium would attack from the rear of the bromonium species to form anti-bromoamidated intermediate III. The bromo substituent on the nitrogen of bromoamidated intermediate III would then be abstracted by chloramine-Ns to give aziridine IV, N-chloro-N-bromonosylamide V and NaBr. The catalytic cycle is completed by halogen exchange between N-chloro-N-bromonosylamide V and NaBr to regenerate dibromamine-Ns. The resulting aziridine IV would then undergo ring opening via backside attack by chloramine-Ns, followed by quenching to afford the diaminated products. Subjecting the isolated aziridine 4da-Az to the reaction conditions resulted in efficient conversion to the diamine 4da, supporting our proposed diamination step (see SI data for details).

Fig. 5. Mechanism investigations. (a) Intermediate trapping by early quenching. (b) Monitoring the reaction. (c) Proposed reaction pathway.

The unique bromonium catalysis led us to investigate whether other conjugated alkenes could be accommodated in this system. 1,2-Ethylenediamine motifs represent valuable structural units^36,44,45 motivating us to explore the reactivity of its catalysis with phenanthrene (10aa). Preliminary adjustments enabled the efficient anti-diamination of phenanthrene, providing the desired diaminated product 11aa in 69% yield (Fig. 6a). The diamination conditions are applicable to different substituted π-conjugated alkenes. Substituents on the phenanthrene were compatible with halogens, alkyl groups and electron-withdrawing groups, as well as those with multiple substituents (11ab–11dc). During these investigations, we also considered the possibility of side reactions such as aromatic bromination. Indeed, in the reaction with substrate 10b, we isolated a byproduct retaining the phenanthrene skeleton that gave a positive Beilstein test, indicating the presence of a halogen-containing species. Electronically and sterically diverse π-expanded alkenes can also be transformed into diamines in synthetically useful yields (11e–11i). Furthermore, dibenzosuberenone (11j), dibenzooxepine (11k), and N-acetyl dibenzoazepine (11l) were applicable to the catalytic system. Although the above π-conjugated alkenes were transformed into anti-diaminated compounds completely, the reaction of cis-stilbenes gave a diastereomer mixture (11ma–11mb), owing to catalyst-induced isomerization of cis- to trans-stilbene (see SI data for details). As expected, the diamines derived from phenanthrene could also be transformed into corresponding free diamine 12aa, and this was converted into π-extended pyrazine derivatives through condensation with 1,2-diketones (Fig. 6b(i)). In addition, enantiomers of 1,2-diamines 14mb were obtained from 11mbvia denosylation and tartaric acid-mediated optical resolution (Fig. 6b(ii)). We also attempted to investigate the reaction mechanism for these π-conjugated alkenes using phenanthrene (10aa) through intermediate trapping and ¹H NMR monitoring. In contrast to α,β-unsaturated carbonyls, attempts to trap the intermediate were unsuccessful. ¹H NMR monitoring showed the immediate formation of the diamination product as the starting material was consumed, without any detectable intermediates.

Fig. 6. Diamination of π-conjugated alkenes. (a) Scope of diamination of 1,2-diarylethylenes. (b) Synthetic applications.

Conclusions

In summary, we report a unique catalytic system, which involves a bromonium species, that can realize a high-utility diamination. This reaction proceeds with complete diastereoselectivity, and the amino moieties of the products can be freely modified thereafter. With these advantages, the present diamination offers a practical and direct approach to producing a diverse range of functionalized α,β-diamino carbonyls and diaryl ethylenediamines, which serve as valuable precursors to unnatural amino acids, various chiral diamine ligands, and π-conjugated molecules with embedded nitrogen atoms. In conjunction with our prior investigations into efficient alkene diamination processes,^11,12 this study significantly augments the diamine synthesis platform, thereby enhancing the preparation of these essential structures, which are anticipated to be suitable for diverse applications, particularly within medicinal chemistry.

Author contributions

S. M. conceived and directed this project. T. S., R. N., Y. K., and Y. Y. performed experiments and analysis.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2323575–2323581, 2413043 and 2419782 (4aa, 4da, 8aa, 4da-Az, 4da-BA, 11aa, and 11m) contain the supplementary crystallographic data for this paper.^46a–i

All experimental data supporting the findings of this study are available within the article and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d6sc06084f.