Photochemical Intermolecular [3σ+2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

Abstract

The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs and, bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ+2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines (CPAs). This transformation not only uses mild and operationally simple conditions, but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by some derivatization reactions.

Graphical Abstract

Bicyclic hydrocarbons have demonstrated the ability to replace aromatic rings in therapeutic molecules, providing greater solubility and metabolic stability, along with enhanced pharmacokinetic properties. Because of these enhanced properties, these bioisosteric scaffolds have received considerable attention in drug molecular design.¹ One of the most studied among small-ring cage hydrocarbons are bicyclo[1.1.1]pentanes (BCPs),² which serve as a bioisosteric replacement of ortho- and para-substituted phenyl rings as well as the tert-butyl group.³ Synthetic organic chemists have also made great progress in the development of new synthetic methods that provide geometrically complementary meta-substituted arene bioisosteres. However, these architectures have been explored using mainly bridge-substituted BCPs⁴ and bicyclo[2.1.1]hexanes,^4,5 although these motifs do not exactly mimic the bond vectors displayed in meta-substituted arenes. The preparation of bioisosteres that precisely reproduce the geometrics of meta-substituted arenes is a challenge from a synthetic point of view. Recently, the preparation of difunctionalized bicyclo[3.1.1]heptanes using [3.1.1]propellane as a feedstock demonstrates that these substructures can serve as meta-substituted arene analogues (Figure 1).⁶

Figure 1.

Comparison of para- and meta-substituted arene ioisosteres

Cyclopropylamines (CPAs) have shown their versatility as building blocks to access highly valuable nitrogenated organic motifs.⁷ They are extremely useful in [3+2] annulation reactions with alkenes for the construction of more complex cyclic amines.^7c Their use as synthetic scaffolds arises from an irreversible ring-opening upon an initial oxidation to the nitrogen radical cation.^7f In 1998 Cha⁸ and Iwata⁹ disclosed the use of N,N-dialkyl aminocyclopropanes bearing an alkene group for the construction of amino octahydropentalenes. In the development of photochemical [3+2] cycloadditions for the synthesis of bicycloaminoalkanes, bicyclic cyclopropylamines were used in an intermolecular approach using a ruthenium photocatalyst.^7a Later, intra-¹⁰ and intermolecular¹¹ cycloaddition reactions utilizing amino/iminocyclopropanes and alkenes (Figure 2) were reported.

Figure 2.

Photocatalytic [3+2] annulations of alkenes using aminocyclopropanes for the construction of bicyclic systems.

Bicyclo[1.1.0]butanes (BCBs) have received increasing attention¹² by the chemistry community for the synthesis of small ring systems because of their ability to engage in ring-opening reactions with different partners,¹³ including radical species. We envisioned that a photoredox [3σ+2σ] cyclization reaction could be applied using cyclopropylamines and bicyclo[1.1.0]butanes. This reaction design would provide unique functionalized bicyclo[3.1.1]heptanes, which expands chemical space because of the several diversifiable positions on the bicyclo[3.1.1]heptane ring. Additionally, this bicyclic motif can potentially act as a precise meta-substituted arene bioisostere.⁶ To the best of our knowledge, the photoinduced construction of bicyclo[3.1.1]heptanes has never been previously explored. This photocatalytic approach would overcome the challenge for the construction of multifunctionalized bicyclo[3.1.1]heptanes in a sustainable and straightforward manner.

BCB 1a and CPA 2a were chosen as representative substrates for optimization of reaction conditions. First, considering that the choice of photocatalyst significantly impacts the product formation, and that the oxidation potential of cyclopropylanilines is around 0.80 V vs SCE,^7a,f we initiated the studies utilizing Ir[dF(CF₃)ppy]₂(dtbpy)PF₆ (E_1/2 *Ir^III/Ir^II = 1.21 V vs SCE)¹⁴ in DMSO as solvent. Under these conditions the bicyclic compound 3 was obtained in 70% yield (Table 1 entry 1). The exploration of other photocatalysts (Table 1 entries 2–5) did not provide better efficiency toward the formation of the desired product. Next, other solvents were examined using the optimal photocatalyst, but no improvement was achieved (Table 1 entries 6–9). The photochemical nature of this transformation was confirmed when the reaction was performed either in the absence of photocatalyst (Table 1, entry 10) or light (Table 1, entry 11). Finally, the presence of the radical scavenger TEMPO in the reaction completely inhibited the formation of compound 3 (Table 1, entry 12) and unreacted 1a was observed by GCMS analysis (see Supporting Information). Of note, this transformation provides unprecedented access to functionalized, fully assembled bicyclo[3.1.1]heptane 3 in a single step from readily available BCB¹⁵ 1a and CPA 2a.

Table 1.

Exploration of the reaction conditions^a for the photochemical synthesis of functionalized bicyclo[3.1.1]heptanes.

Entry	Solvent	PC	Yield of 3 (%)b
1	DMSO	Ir[dF(CF3)ppy]2(dtbpy)PF6	72 (70)e
2	DMSO	Ir(ppy)3	<10
3	DMSO	Ru(bpy)3(PF6)2	30
4	DMSO	MesAcr	traces
5	DMSO	4CzIPN	27
6	DMA	Ir[dF(CF3)ppy]2(dtbpy)PF6	46
7	MeCN	Ir[dF(CF3)ppy]2(dtbpy)PF6	40
8	1,4-dioxane	Ir[dF(CF3)ppy]2(dtbpy)PF6	0
9	MeNO2	Ir[dF(CF3)ppy]2(dtbpy)PF6	traces
10	DMSO	none	0
11c	DMSO	Ir[dF(CF3)ppy]2(dtbpy)PF6	0
12d	DMSO	Ir[dF(CF3)ppy]2(dtbpy)PF6	0

^aReaction conditions: 1a (0.1 mmol, 1 equiv), 2a (0.2 mmol, 2 equiv), photocatalyst (2 mol % metal-based PC or 5 mol % organic based PC), in dry and degassed solvent (0.2 M) under blue Kessil irradiation (λ_max = 427 nm) at rt.

^bYields determined by ¹H NMR using 1,3,5-trimethoxybenzene as internal standard.

^cReaction in the absence of light irradiation.

^dReaction as in entry 5 but in the presence of 5 equiv of TEMPO.

^eIsolated yield from 0.2 mmol scale.

Once the optimization reaction conditions were suitable for the development of this [3σ+2σ] cyclization reaction, the scope of the process using different CPAs was explored. This transformation works especially well with electron-withdrawing groups in the aryl ring of the N-cyclopropylaniline. The p-chlorophenyl-substituted CPA gave the desired compound 4 in 36% yield, but the presence of a fluorine atom in the meta position (5) as well as in the ortho- and para positions (6) provided the desired products in much higher yield. The presence of strongly deactivating groups such as trifluoromethyl (7) and difluoromethyl (8) gave the corresponding aminobicyclo[3.1.1]heptanes in 63 and 65%, respectively. Incorporation of the medicinally relevant trifluoromethoxy group afforded access to compound 9 in 62% yield. Of note, detailed NMR studies as well as the single crystal X-ray analysis of compound 9 (see Supporting Information) confirm the 3-dimensional structures of the 4-aminobicyclo[3.1.1]heptanes. Phenyl- and 1,3-dioxolanyl-substituted CPAs provided 10 and 11, respectively, in moderate yields. An electron-rich methoxy-substituted derivative group showed reactivity, although the desired product (12) was accessed in low yield. This result is not surprising given that the more electronically rich cyclopropylanilines are known to promote easier SET, while at the same time undergoing CPA ring-opening at a slower rate.¹⁶ Alkyl groups in the para- or ortho position showed good reactivity (13 and 14). Finally, some heteroarene-based amines were tested because of their outsized use in medicinal chemistry. Of note, benzothiophene (15) and benzofuran (16) motifs were well tolerated, providing the desired products in 51 and 47% yield, respectively. To explore further the use of heterocycles in this transformation, quinoline (17) and pyridine (18) derivatives were incorporated, although the desired products were isolated in lower yields.

Subsequently, the scope was further extended to the modification of the BCB ring. In general, we observed good reactivity toward the formation of the desired 4-aminobicyclo[3.1.1]heptanes when the BCB was tethered to an electron-poor arene. Thus, the presence of fluorine (20 and 21) and chlorine (22) substituents, as well as the p-trifluoromethylphenyl derivative (23), gave the corresponding products in good yields. Finally, m-CF₃ (24) and more electronically rich substituents (25-28) furnished the final compounds in moderate yields.

Given previous literature precedents,^10,11,17 a mechanism for the presented photoinduced aminobicyclo[3.1.1]heptane synthesis is postulated in Scheme 1. After photoexcitation of the Ir^III photocatalyst by blue light irradiation, the photoexcited state (Ir^III*) (E_1/2 *Ir^III/Ir^II = 1.21 V vs SCE) is accessed.¹⁴ Single-electron transfer to the cyclopropylaniline (2) (E_1/2 = 0.80 V vs SCE)^7a,f induces the formation of the radical cation species (I) followed by ring opening via β-scission to the distonic radical cation (II). Subsequent addition of this reactive intermediate to BCB 1 furnishes another relatively stabilized distonic radical cation where the radical is localized in a secondary benzylic position (III). Subsequently, this species (III) undergoes cyclization, providing access to the radical cation (IV). At this stage, (IV) could be reduced by the Ir^II species generated in the reductive quenching photoredox cycle or it can be reduced by the presence of the cyclopropylaniline 2a. Given these two mechanistic scenarios, we explored the photochemical quantum yield of this transformation. We observed a quantum yield (ϕ) value of 0.47. Although the quantum yield is lower than 1, it does not guarantee a closed catalytic cycle.¹⁸ Given that single-electron transfer processes with amines are highly influenced by post-oxidation reactivity, a propagative mechanistic pathway is a more likely process because the reduction of IV by 2a is an enthalpically-driven step.¹⁹ This artificially low quantum yield value was also observed in other photochemical [3+2] cycloadditions reactions based on the use of CPA.^10a

Scheme 1.

Proposed reaction mechanism for the photoinduced synthesis of 4-aminobicyclo[3.1.1]heptanes.

To showcase the applicability of the preparation of bicyclo[3.1.1]heptanes toward further functionalization, we prepared four different 4-anilinyl bicyclo[3.1.1]heptane derivatives (Scheme 2, 29-32), forming new C-C, C-O and C-N bonds. First, compound 25 was functionalized to the corresponding 3-oxobutanenitrile 29 in 73% yield using a combination of acetonitrile and LDA. This functional unit, containing α-methylene active protons, offers further opportunities for postfunctionalization. Subsequently, 25 was hydrolyzed to the corresponding carboxylic acid (30) in excellent yield, which was further coupled with estrone to provide 31 in 80% yield. Additionally, 30 was transformed to amide 32 in 85% yield. This Weinreb-type²⁰ amide 32 serves as a carbonyl precursor for the formation of ketones, aldehydes, or alcohols.

Scheme 2.

Derivatization reactions of 25. Reaction conditions: a) LiOH in MeOH, then HCl 1 M. b) LDA (2.2 equiv) and MeCN (2 equiv). c) Estrone (1 equiv), DMAP (0.05 equiv), DIC (1.2 equiv) in CH₂Cl₂. d) N,O-dimethylhydroxylamine (1 equiv), DMAP (0.05 equiv), DIC (1.2 equiv) in CH₂Cl₂. See Supporting Information for more details.

In summary, a general and highly practical method for the construction of 4-aminobicyclo[3.1.1]heptanes under mild conditions has been developed. The well-orchestrated and serialized mechanism steps furnished new bicyclo[3.1.1]heptanes containing a wide range of functional groups. Derivatization to other functional groups has also been achieved. Overall, the photochemical [3σ+2σ] annulation reaction presented herein enables access to unprecedented 4-aminobicyclo[3.1.1]heptanes assembled from BCBs and CPAs. These structures appear likely to serve as useful meta-disubstituted arene bioisosteres in the drug discovery field.

Table 2.

Substrate Scope Exploration for the Synthesis of Bicyclo[3.1.1]heptanes^a

^aReaction conditions: BCB 1 (0.2 mmol, 1 equiv), CPA 2a (0.4 mmol, 2 equiv), Ir[dF(CF₃)ppy]₂(dtbpy)PF₆ (2 mol %), in dry and degassed DMSO (0.2 M) under blue Kessil irradiation (λ_max = 427 nm) at room temperature.