Amine-cation-driven heteroannulation of halomaleimides with C–N cleavage: metal-free access to heterobicyclic frameworks

Abstract

Maleimides and their derivatives are highly versatile scaffolds with broad applications in synthetic chemistry, medicinal chemistry, and materials science; however, methods to expand their structural diversity remain limited. Here, we present a so far undescribed, metal-free, and mild strategy for the rapid construction of functionalized maleimides from readily available dihalomaleimide derivatives. The reaction is initiated by tertiary amine-mediated formation of an ammonium cation, which directs heteroannulation to efficiently generate heterobicyclic scaffolds. This modular approach also enables the synthesis of 3,4-diamino-substituted maleimides, including challenging second halogen substitutions with weak nucleophiles. Mechanistic studies indicate that a quaternary enamine intermediate plays a central role in steering the transformation, providing broad functional group tolerance and synthetically useful yields. Overall, this strategy offers a versatile platform for accessing structurally diverse maleimides, unlocking new opportunities in bioconjugation, medicinal chemistry, and materials science.

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Introduction

Maleimides are an exceptional scaffold widely used in natural products and pharmaceuticals, serving as a versatile building block for synthesizing bioactive molecules and advanced materials.^1–5 Because of their efficiency, mild reaction conditions, and chemoselectivity, maleimides provide robust methods for protein conjugation and material modification.^6,7 Their widespread use is partly due to their ability to undergo two highly efficient reactions: Michael addition with nucleophiles and Diels–Alder cycloaddition with dienes.^8–12 Annulated^13,14 and spirocyclic¹⁵ maleimide products can be prepared by various methods, including metal-catalyzed reactions,^16–18 cycloadditions,^19–22 photochemical processes,^23–25 and oxidant-based approaches.^26–28 Compared to single substitution, double substitution offers improved functionalization, allowing both symmetric and asymmetric substitution patterns. A notable example is the addition–elimination reaction with halogenated maleimide derivatives.²⁹ Incorporating halogens into the maleimide scaffold creates predefined reactive sites.^30,31 This synthetic approach enables efficient halide anion loss, yielding substituted maleimides while retaining the synthetically valuable C=C bond. The singly substituted maleimide scaffold allows further manipulations for improved functionalization, enabling asymmetric disubstituted or (hetero)bicyclic structures, for example, by cross-coupling, Diels–Alder reaction, or reaction with nucleophiles such as alcohols, thiols, and amines. While substitution of the second halogen with thiols can be achieved under relatively mild conditions,³² reactions with alcohol or amino functionalities often require harsh conditions (Scheme 1A),^33–38 such as an excess of amine, high temperatures up to 140 °C, microwave irradiation or strong bases, as the initially incorporated amino group significantly reduces the electrophilicity of the maleimide.^39–43

Scheme 1 Diamination of halogenated maleimide derivatives.

During our studies on the functionalization of dihalogenated maleimides, we serendipitously discovered an addition–elimination reaction of halogenated maleimides with functionalized primary–tertiary diamines, which also enables double halogen substitution under mild conditions (Scheme 1B). Considering that this five-membered imide heterocycle has been identified in various families of natural products, synthetic pharmaceuticals, biochemistry,⁴⁴ and technological applications,⁴⁵ and represents a valuable building block, we wanted to explore the mechanism and develop a practical synthetic protocol for preparing heterobicyclic maleimide derivatives. As part of our design, we postulated that the tertiary amine functionality could initially generate a quaternary enammonium salt of maleimide, a potent electrophile, facilitating the second addition–elimination step and providing a promising route to construct structurally more diverse enaminone compounds.

Results and discussion

Dichloromaleimide 1a and N-(2-(dimethylamino)ethyl)benzenesulfonamide hydrochloride (2a) were selected as model substrates to test the feasibility of double amination of the electron-deficient substrate 1a (Table 1). After thoroughly optimizing the reaction conditions – including reaction temperature, choice of base, and amount of functionalized diamine to achieve maximum yield and optimal reaction time – the reaction was carried out using 1.5 equivalents of amine hydrochloride 2a, NMP as the solvent, and 2 equivalents of DIPEA as the optimal base at 25 °C, yielding the desired product 3a in a synthetically useful 93% yield (Table 1).

Table 1 Optimization of the reaction conditions^a

Entry	Deviation from optimal conditions^a	Yield^b (%)
a Optimal reaction conditions unless specified otherwise: 1a (0.1 mmol), amine hydrochloride (0.11 mmol), DIPEA (0.22 mmol), NMP (1.0 mL), 25 °C, 16 h, reactions were performed using undried solvents under ambient atmosphere.b Isolated yields are reported.c A mixture of products was formed.d NMR conversion.e No conversion.
1	None	93
2	MeCN, Cs2CO3, 16 h	57
3	DMF, Cs2CO3, 16 h	65
4	DMSO, Cs2CO3, 24 h	72
5	NMP, Cs2CO3, 16 h	90
6	EtOAc, Cs2CO3, 96 h	34
7	MeOH, Cs2CO3, 16 h	—^c
8	DCM, Cs2CO3, 96 h	31
9	THF, Cs2CO3, 48 h	40
10	NMP, K2CO3, 16 h	90
11	NMP, KHCO3, 48 h	75
12	NMP, pyridine, 16 h	—^c
13	NMP, NaOH or KOH, 16 h	44
14	NMP, K3PO4, 48 h	65
15	NMP, without base, free amin, 24 h	48^d
16	NMP, without base, 96 h	0^e

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Different combinations of solvents and bases yielded the desired product 3a, but with inferior results compared to NMP/DIPEA (entries 2–14). Using protic methanol as a solvent or pyridine as a base (see entries 7 and 12) resulted in complex product mixtures. Using free amine 2a led to 48% conversion after 24 hours (entry 15), while no reaction occurred in the absence of base (entry 16).

Scope

To study the scope of our transformation, a series of 3,4-dihalomaleimide derivatives 1 was prepared from 3,4-dihalofuran-2,5-dione and the corresponding aliphatic and (hetero)aromatic amines, ammonia, and acetohydrazide in acetic acid at elevated temperature, with yields of 37–92% (Scheme 2A).⁴⁶ The iodo analogue 1c was prepared by transhalogenation of dichloromaleimide 1a with excess sodium iodide (see SI). Similarly, a library of twelve amino-sulfonamide hydrochlorides 2 was synthesized from the corresponding sulfonyl chlorides and tertiary-primary diamines, with yields of 43–99% (Scheme 2B). Compound 2l was prepared by HCl-catalyzed deprotection of the corresponding Boc-protected amino-sulfonamide (see SI).

Scheme 2 (A) Synthesis of 3,4-dihalomaleimide 1; (B) synthesis of amino-sulfonamide hydrochlorides 2. ^aKnown compound; see SI. ^bSynthesized from 3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione (1a) by chloride-iodide substitution with NaI. ^cSynthesized by acid deprotection of tert-butyl methyl(2-(phenylsulfonamido)ethyl)carbamate using 2 M HCl in ethyl acetate.

Next, the reactivity of the bromo analog 1b and the iodo analog 1c with diamine 2a was examined, yielding the corresponding bicyclic product 3a in 72% and 56% yield, respectively. The differences in reaction rates among the chloro analog 1a, bromo analog 1b, and iodo analog 1c are notable, with the iodo analog exhibiting the slowest rate. These trends correlate well with the isolated yields and reflect the reactivity of the carbon–halogen bond in nucleophilic aromatic substitution reactions⁴⁷ (see SI, Fig. S6).

Scheme 3 illustrates the reaction scope of functionalized diamines 2 with dichloromaleimide derivatives 1 under optimized conditions. Varying the benzensulfonamide moiety from neutral to electron-poor and electron-rich analogs yielded the corresponding bicyclic products 3b–3d in 63–74% yields. N-(2-(dimethylamino)ethyl)methanesulfonamide (2e) reacted equally well, affording the corresponding bicyclic maleimide 3e in 62% yield. The impact of the diamine structure on the cyclization reaction showed that, in general, the reaction was compatible with a range of structurally diverse diamine derivatives, including 1,3-diamine 2f, N-(2-(pyrrolidin-1-yl)ethyl)benzenesulfonamide hydrochloride (2g), and 1,2-tertiary diamine (Scheme 3, examples 3f–3i). Attempts to position the diamine functionality beyond the 1,3-position, such as by reacting N-(4-(dimethylamino)butyl)benzenesulfonamide (2h) with 1a, were unsuccessful and did not produce the corresponding eight-membered bicyclic structure. Instead, the monosubstituted maleimide analog 3h was isolated in 44% yield. Notably, when N¹,N¹,N²,N²-tetramethylethane-1,2-diamine was reacted with 1a under optimized conditions, the corresponding bicyclic ammonium chloride 3i was isolated in 80% yield. The reaction of the N-(2-(benzyl(methyl)amino)ethyl)benzenesulfonamide (2i) with dichloromaleimide 1a was not regioselective and produced an inseparable mixture of dealkylated products. The transformation was not compatible with the electron-deficient morpholine scaffold exemplified by N-(2-morpholinoethyl)benzenesulfonamide (2j) and the α-branched pyrrolidine-based diamine derivative N-((1-ethylpyrrolidin-2-yl)methyl)benzenesulfonamide (2k), as these did not produce the desired products. Various amine protecting groups, such as Boc, Cbz, and Ac, were introduced to expand the synthetic utility of the transformation. Diamines with Boc and Cbz protecting groups on the vicinal amine afforded the desired bicyclic products 3j and 3k in 32% and 38% yield, respectively, while the acetamido group was unreactive toward cyclization, resulting in the isolation of the corresponding substituted maleimide 3l in 53% yield. The follow-up three-component reaction of dichloromaleimide 1a, N-benzylbenzenesulfonamide, and DABCO yielded the doubly substituted maleimide 3m in 78% yield. Finally, the N-substituent at the maleimide core was varied. As shown in Scheme 3, various dichloromaleimides 1 successfully undergo a double addition–elimination reaction under mild, optimized conditions to afford the corresponding bicyclic products 3n–3u in synthetically useful yields (52–93%), including the N-acetylamino-substituted maleimide product 3t in 41% yield. To test the influence of scalability on the yield, a gram-scale reaction of 1a (1.980 g, 11.0 mmol) with 2b was performed under optimized conditions, yielding pure compound 3a in an excellent 93% yield (3.280 g).

Scheme 3 Scope and limitations of the reaction of diamine derivatives with 3,4-dichloromaleimide.

The structures of several products 3 were unambiguously confirmed by X-ray diffraction analysis, and the corresponding ORTEP structures are shown in Scheme 3. Diaminated products 3 exhibit characteristic yellow fluorescence under UV-A light (see SI for optical data for 3a, 3e, 3f, 3h, and 3k).

The mild conditions developed for this double or single substitution process suggest that it can serve as a precise tool for late-stage modification of more complex, biologically relevant substrates. As shown in Scheme 4, the maleimide scaffold was successfully incorporated into olanzapine, yielding derivative 4a in 20%. The corresponding three-component reaction with N-benzylbenzenesulfonamide did not produce the desired product, presumably due to steric reasons.

Scheme 4 Reaction of Olanzapine with N-methyl-3,4-dichloromaleimide.

Mechanistic studies

We performed key control experiments (Scheme 5) and DFT calculations to elucidate the sequential reaction pathway of cyclization. First, we monitored the reaction progress of 1a with N-(2-(dimethylamino)ethyl)benzenesulfonamide (2a) over time by ¹H NMR in DMSO-d₆ under standard reaction conditions for 14 hours. The proton NMR analysis revealed rapid consumption of the starting material within the first hour, with significant formation of the intermediate INT2 before the demethylation step. The identity of intermediate INT2 was confirmed by ESI-HRMS. Intermediate INT2 reached its maximum concentration after approximately 2 hours and was then consumed to form the neutral end product 3a. These results indicate that the demethylation step is rate-determining for the formation of product 3a (Scheme 5a and h).

Scheme 5 Mechanistic studies. (a) Time-course monitoring of the reaction 1a + 2a → 3a. (b–e) Key control experiments for the heteroannulation reaction cascade of diamine derivatives 2 with dichloromaleimide 1a. (f) and (g) Computational DFT study (M06-2X/Def2-TZVPP//wB97X-D/Def2-TZVP, SMD(DMF) at 298 K, free energies in kcal mol⁻¹) for the reactions 1a + 2e → 3e and 1a + 2e′ → 3e′, respectively. (h) Proposed reaction pathway for the cation-driven heteroannulation of diamine 2a with dichloromaleimide 1a.

Key control experiments were performed to elucidate the relative reactivity of sulfonamide (RSO₂NH−) and tertiary amine (Me₂RN) groups in N-(2-(dimethylamino)ethyl)sulfonamide reagents and to provide insight into the role of the quaternary ammonium functionality formed during the cyclization reaction. When benzenesulfonamide and N-benzylbenzenesulfonamide were used as reagents under standard reaction conditions with 1a, only the starting material was recovered. The corresponding substitution products 5a and 5b (Scheme 5b) were obtained only when the reaction mixture was heated at 110 °C for 24 hours, indicating low reactivity of the sulfonamide nucleophile toward substitution with 1a. In contrast, treatment of maleimide 1a with N-benzylbenzenesulfonamide and DABCO as the tertiary amine under optimized reaction conditions gave the monocyclic, doubly substituted product 3m in 78% yield (Scheme 5c). When 1a was dissolved in ethanol in the presence of a base, no substitution occurred under standard reaction conditions, whereas reaction of 1a with 2-(dimethylamino)ethan-1-ol led to the formation of a bicyclic product 5c, albeit in a modest yield of 33% (Scheme 5d). When the secondary amine N-(2-(methylamino)ethyl)benzenesulfonamide was used, the corresponding substituted maleimide 5d was isolated in 61% yield, with no detection of bicyclic product 3a. Repeating the reaction in the presence of DIPEA at 90 °C gave product 5d in 65% yield (Scheme 5e). Heating substituted maleimide 5d above 90 °C resulted in thermal decomposition of 5d (see SI, Table S3), with no detection of bicyclic product 3a. This result confirms that the heteroannulation leading to the bicyclic maleimide products 3 proceeds via a crucial ammonium intermediate INT2 that facilitates the second vinylic substitution under milder reaction conditions.

Density functional theory (DFT) calculations were performed to provide deeper insight into the underlying reaction mechanism. The calculated Gibbs free energy profile in DMF for the proposed reaction pathway is shown in Scheme 5 (see SI for computational details). The reaction pathway was examined starting from substrate 1a and the functionalized diamine 2e, as illustrated in Scheme 5f. Initially, 1a undergoes nucleophilic substitution with the tertiary amine moiety (R–NMe₂) via transition state TS1, with an activation free energy of 25.1 kcal mol⁻¹, to afford the cationic intermediate INT1. This step is endergonic and reversible. The resulting quaternary ammonium group in INT1 facilitates the subsequent base-catalyzed addition–elimination–cyclization sequence involving the relatively weak sulfonamide nucleophile (–SO₂NH–), which proceeds through TS2 with an activation barrier of 24.7 kcal mol⁻¹ and is overall exergonic, yielding intermediate INT2. In the final step, energetically favorable demethylation of the quaternary ammonium moiety in INT2 by chloride anion occurs via TS3, with an activation barrier of 25.3 kcal mol⁻¹, furnishing the bicyclic product 3e.

To elucidate the role of the ammonium moiety in INT1 during the cyclization step, a comparative reaction profile was calculated for an analogous system with an amino nucleophile containing a secondary amine functionality (R–NHMe, 2e′; see Scheme 5g). Under the investigated conditions, reaction with the secondary amine N-(2-(methylamino)ethyl)benzenesulfonamide does not produce the cyclized product; instead, the monosubstituted product 5d is observed experimentally (see Scheme 5e). As shown in Scheme 5g, substrate 1a undergoes a favorable, exergonic base-catalyzed substitution with the secondary amine of 2e′ to form the neutral intermediate INT1′. In contrast to the ammonium containing system, the subsequent cyclization step via TS2′ has a much higher activation barrier (42.9 kcal mol⁻¹) leading to the bicyclic product 3e, making this pathway kinetically inaccessible at ambient temperature. Overall, these results indicate that cyclization to bicyclic products 3 is significantly facilitated by the involvement of ammonium cationic intermediates, which, due to their limited thermodynamic stabilization, readily undergo a second substitution at the vinylic position under relatively mild reaction conditions.

Based on experimental observations and DFT analysis, a plausible reaction mechanism for the heteroannulation cascade between diamine derivatives 2 and dihalogenated maleimides 1 is proposed, as shown in Scheme 5h. The transformation is initiated by an elementary addition–elimination step involving the tertiary amine nucleophile, leading to the formation of the key quaternary ammonium intermediate INT1. Under mild reaction conditions, this intermediate undergoes a second addition–elimination event with the intrinsically electron-deficient sulfonamide nucleophile; this transformation proceeds via a general base-catalyzed pathway to yield the cyclized cationic intermediate INT2. In the final stage, INT2 undergoes demethylation by a chloride anion, producing the heteroannulated product 3.

Conclusions

In summary, we have developed a novel and synthetically feasible strategy for the rapid construction of functionalized maleimides under metal-free, mild conditions, starting from inexpensive bulk dihalomaleimide derivatives. This modular approach enables efficient access to heterobicyclic and 3,4-diamino-substituted maleimides in synthetically useful yields. The protocol demonstrates broad functional group tolerance and uniquely allows a second halogen substitution with relatively weak nucleophiles – an otherwise challenging transformation with 3-amino-4-halomaleimide substrates. Both experimental and theoretical studies indicate that the formation of a quaternary enamine intermediate plays a central role in directing the reaction toward 3,4-diaminomaleimide derivatives. Taken together, these results provide a new and versatile platform for accessing structurally diverse maleimides with potential applications in bioconjugation, medicinal chemistry, and materials science.

Author contributions

Conceptualization, B. Š., L.C. and U. G.; methodology, H. B., L. C., and N. P.; software, B. Š.; validation, B. Š., N. P., and J. S.; formal analysis, B. Š. and L. C.; investigation, H. B., N. P., and L. C.; data curation, B. Š., N. P., L. C., and U. G.; writing – original draft preparation, B. Š.; writing – review and editing, J. S., U. G., L. C., and N. P.; visualization, B. Š.; supervision, B. Š. and U. G.; funding acquisition, J. S. All authors have read and agreed to the published version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data that support the findings of this study are available in the supplementary information (SI). Supplementary information: all experimental data, characterization data (¹H NMR, ¹³C NMR, HRMS spectra), and computational details. See DOI: https://doi.org/10.1039/d6qo00010j.

The authors have cited additional references within the SI.^46–68

Raw data files are available from the corresponding author upon reasonable request.

CCDC 2483901 (3a), 2479097 (3c), 2479096 (3f), 2479092 (3g), 2479093 (3n) and 2479094 (3o) contain the supplementary crystallographic data for this paper.^69a–f

Acknowledgements

Financial support from the Slovenian Research and Innovation Agency (ARIS) through grant P1-0179 and infrastructure programme I0-0022 is gratefully acknowledged.

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