Formal nitrogen-to-carbon replacement in isoindolines to form indenes via N-alkyl tetrahydroisoquinolines

Abstract

Herein, we report a Stevens rearrangement ring expansion of isoindolines to N-alkyl-2-aroyl-tetrahydroisoquinolines, followed by a photochemical nitrogen atom extruding ring contraction and elimination to give indene derivatives. By combining the ring expansion and ring contraction in a one-pot procedure, a net single-atom nitrogen-to-carbon replacement was realized. Factors that guide the stability of the immediate amino-indane products that are formed through photochemical ring contraction were studied. Reaction of the amino-indane intermediates with anhydrides yielded stable and isolable functionalized amino-indane derivatives in some cases.

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Introduction

Saturated nitrogen heterocycles are increasingly common motifs in natural products and FDA-approved pharmaceuticals.^1–4 Recently, there has been dedicated effort in the synthetic community to achieve single-atom “skeletal editing” of nitrogen-containing heterocycles to enable facile “scaffold hopping” in medicinal chemistry campaigns.^5–8 Skeletal editing methods that enable scaffold hopping may enable the exploration of novel chemical space and accelerate medicinal chemistry campaigns.⁹ Thus, many novel synthetic strategies have been developed to interconvert closely related core structures through ring expansion^10–14 or contraction.^15–20 Specifically, there has been recent interest in single-atom replacement strategies in cyclic scaffolds (atom transmutations) given that such transformations could modify, for example, a hydrogen-bonding vector without changing ring size. This type of change could facilitate interrogations of ligand–receptor interactions.^6,21 However, the majority of reports for atom transmutation use aromatic heterocycles as substrates.^22–40 Fewer examples exist for single-atom transmutation in saturated (hetero)cycles.^41–45

Recently, our laboratory reported a photochemical ring contraction of piperidines bearing an α-aryl ketone (aroyl group) to a corresponding amino-cyclopentane (Scheme 1a).^46–48 This reaction was previously explored with electron-withdrawing and aryl substituents on nitrogen. Our expansion of this photochemical ring contraction methodology to N-alkyl heterocycles has now set the stage of a formal N → C transmutation of isoindolines (Scheme 1b).

Scheme 1 Photochemical ring contraction of six-membered nitrogen heterocycles and strategies for the installation of an aryl ketone.

One challenge that has limited the applicability of the previously reported ring contraction chemistry is the direct installation of the requisite aryl ketone photochemical handle. While C–H functionalization strategies have been reported for the installation of α-aroyl groups for both N-Boc^49,50 and N-Aryl⁵¹ piperidines (Scheme 1a), no reports exist for the corresponding N-alkyl heterocycles. We recognized that α-aroyl bearing N-alkyl piperidines (and related derivatives, e.g., tetrahydroisoquinolines) could be accessed through a skeletal transformation. By using a Stevens rearrangement, ring expansion of cyclic tertiary amines to install an α-aroyl group could be achieved.^52,53 In general, because the Stevens rearrangement requires a radical-stabilized benzylic position (i.e., an aryl substituent or ring fusion), we chose to focus our initial studies on α-aryl pyrrolidines and isoindolines. Overall, the two-step ring expansion/ring contraction strategy that we have now achieved allows for a formal single-atom nitrogen-to-carbon replacement in isoindolines.

The photochemical ring contraction of N-alkyl heterocycles raises several mechanistic considerations (Scheme 1c).⁴⁷ First, the more electron-rich nitrogen atom in this case should enhance the efficiency of single-electron transfer (SET) from the tertiary amine to the excited state aryl ketone (see I → II). A potential issue is unproductive H-transfer from the exocyclic N-alkyl substituent (see II). This issue is partially circumvented with tetrahydroisoquinoline substrates, which feature increased reactivity at the desired benzylic methylene position (see II). Furthermore, we envisioned that the more electron-rich N-alkyl group would result in a stronger hydrogen bond in the imine intermediate (see IV) to facilitate the Mannich ring closure.

Finally, it was anticipated that the amino-indane ring contraction product would feature a weaker hydrogen bond, which could decrease product stability and promote an elimination of the amine to give an indene (see V → VI). Previously, Boswell et al. demonstrated that replacing an endocyclic nitrogen atom with a carbon atom bearing an exocyclic H-bonding carbonyl group can be used to extend hydrogen-bonding interactions.⁵⁴ Similarly, in this work, the introduction of an exocyclic carbonyl extends H-bonding interactions.

Results and discussion

We began our studies by testing the viability of the photochemical ring contraction of N-methyl piperidine 1 (Scheme 2a). The ring contraction of 1 at 400 nm proved to be low-yielding. The immediate amino-cyclopentane ring contraction product (2) spontaneously converted to cyclopentene 3, which was obtained in 17% yield upon purification on silica gel.

Scheme 2 Photochemical ring contraction of six-membered nitrogen heterocycles and strategies for the installation of an aryl ketone. Ring contraction conditions: 0.10 mmol starting material, 0.05 M toluene, 400 nm, 24 h.

Our proposed ring expansion/ring contraction strategy was then tested with N-methyl pyrrolidine 4 (Scheme 2b). The known ring expansion of 4 to a mixture of separable diastereomers of N-methyl piperidine (5a,b) set the stage for the nitrogen extrusion reaction.⁵³ The ring contraction of cis diastereomer 5a proceeded successfully to give cyclopentanone 6 in low yield. The ring contraction of trans diastereomer 5b proceeded sucessfully to give amino cyclopentane 7 as a single diastereomer, albeit in low yield, and benzoyl amide 8. We posit that 6 and 8 result from irradiation and photo-fragmentation of ring contraction product 7, and that the differing reactivity between diastereomers 5a,b arises from differences in the relative rates of the ring contraction arising from conformational differences in the starting materials (see the SI, Section S10, for a proposed mechanism and further discussion). Unlike amino cyclopentane 2, ring contraction product 7 was stable to purification on silica gel. The low yield of the products resulting from ring contraction of 5a and 5b, as well as photo-fragmentation leading to 6 and 8 suggests that ring contraction product 7 does not persist upon continued irradiation.

Given the low yields and challenges associated with 1 and 5a/b as substrates, N-methyl tetrahydroisoquinoline (9) was selected for further exploration (Table 1). Initial studies with this substrate proved more promising (entry 1). While the expected amino-indane product (10) was not observed in the crude reaction mixture or following purification, indene 11 and dimer 12 were observed in high combined yield. The presence of these products indicated that the photochemical ring contraction had occurred as expected and a subsequent elimination of the extruded nitrogen group led to indene 11. Dimer 12 presumably forms from continued irradiation of the indene, which forms spontaneously during the reaction rather than upon workup or purification. Further irradiation of a dilute solution of dimer 12 did not lead to reversion to the monomer, indicating that the photochemical dimerization is irreversible under the reaction conditions. The spontaneous elimination of the extruded nitrogen group appears to be unique to N-alkyl tetrahydroisoquinoline substrates on the basis of our studies.

Table 1 Optimization of photochemical ring contraction of N-methyl tetrahydroisoquinoline

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Decreasing the irradiation time to 7 h primarily gave the ring contracted monomer (i.e., indene 11) with full consumption of the starting material (entry 2). Additional screening of solvents identified THF and toluene as optimal, leading to the highest yields (entries 3,4).

With conditions that lead to good yields of the ring contraction product identified, we focused on accomplishing a one-pot, sequential, Stevens rearrangement ring expansion/photochemical ring contraction to effect the envisioned single-pot formal N → C replacement in isoindolines. Isoindoline ylides (see 14, Scheme 3) can be prepared directly from the parent isoindoline (see 13) in good yields by adding α-bromo acetophenones, followed by the addition of base. Purification of the resulting ylides, which are generally stable at ambient temperatures,⁵² is not required.

Scheme 3 General method for the preparation of isoindoline ylides.

We also investigated potential photochemical Stevens rearrangements of the ylides that would have enabled a single-step ring expansion/ring contraction cascade (Scheme 4). However, all attempts to effect a photochemical Stevens rearrangement of ylide 14 yielded only isoindoline 13 as the major product through a net heterolytic photochemical cleavage of the C–N bond.^55,56 While ammonium ylides did not undergo successful photochemical Stevens rearrangements, the analogous rearrangement of sulfonium ylide 15 is precedented.⁵⁷ Thus, we were able to accomplish a single-pot atom exchange of 1,3-dihydrobenzo[c]thiophene via photochemical Stevens rearrangement of the corresponding ylide (15), followed by ring contraction to thiol 16, using 365 nm light for both photochemical processes. However, the overall cascade in this case is low yielding. Unlike amino-indane 10, thiol 16 was stable to purification on silica.

Scheme 4 Ylide irradiation studies. 0.10 mmol scale, 0.2 M toluene, 7 h.

Given the limitation of a single-step photochemical cascade to sulfur-based substrates, we focused on optimizing the thermal Stevens rearrangement followed by photochemical ring contraction to accomplish a two-step, single-pot, protocol for isoindolines (Table 2). The Stevens rearrangement proceeds in quantitative yields in toluene at 90 °C — a higher yield and a significantly lower temperature than has been reported for the solid phase rearrangement, which occurs at 155 °C (entries 1,2).⁵² Interestingly, in THF, significant amounts of the parent isoindoline (13) were recovered upon heating ylide 14 (entry 3). Thus, the Stevens rearrangement was performed thermally at 90 °C in toluene, followed by irradiation at room temperature to effect the ring contraction without a need to change solvent.

Table 2 Optimization of Stevens rearrangement. 0.05 mmol scale

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The scope for the two-step, one-pot, transformation is illustrated in Scheme 5. Multiple isoindoline ylides with varying N-alkyl substituents (14a–c) underwent the two-step protocol to yield indene 11a. The two-step process is tolerant of electronically diverse aryl ketones (11d–g), heteroaryl ketones (11h,i), as well as various substituents on the arene portion (11j–l).

Scheme 5 Scope for single-pot isoindoline to indene conversion. Reaction conditions: 0.10 mmol starting material, 0.05 M toluene, 90 °C, 30 min, then 400 nm, 24 h.

Non-symmetric isoindoline ylides lead to two constitutional isomers of the indene product that differ with respect to the position of the double bond (11m–r). Poor position selectivity was observed for the alkene group in all cases except for 11m. Double-bond isomerization of indenes through sequential 1,5-hydrogen atom shifts is well precedented.⁵⁸ Therefore, the possibility that the observed product ratio reflects indene isomerization to a thermodynamic equilibrium (Table 3) was investigated. The ratios of two possible tetrahydroisoquinoline intermediates following Stevens rearrangement (9 I : 9 II; Table 3) should reflect the ratio of indene products (i.e., 11 I : 11 II) if double bond isomerization does not occur. For the case of methoxy substituted ylide 14m, a 50 : 50 ratio of tetrahydroisoquinoline isomers 9m I and 9m II was observed, which did not match the 70 : 30 mixture of indene isomers (i.e., 11m I : 11m II) in the crude reaction mixture. This observation is consistent with indenes 11m I and 11m II interconverting under the reaction conditions. In all other cases, the ratio of tetrahydroisoquinolines (determined by ¹H NMR) matched the ratio of indenes in the crude reaction mixture. This result indicates that the indene isomers do not interconvert under the reaction conditions, and that the Stevens rearrangement is the selectivity-determining step in these cases.

Table 3 Ratios of constitutional isomers of tetrahydroisoquinolines and indenes following Stevens rearrangement and ring contraction. Isomers were not assigned unambiguously unless otherwise stated. Crude ratio of 11r isomers could not be determined due to overlapping signals. ^*Isomers of 11m I : II were separated and assigned unambiguously

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Some indenes were observed to isomerize upon purification on silica, so this possibility was also investigated.⁵⁹ Upon purification, the ratio remained the same in all cases, providing no evidence that isomerization of the indene double bond occurs on silica.

A formal nitrogen-to-carbon exchange of C₁-substituted isoindolines was also explored (Scheme 5e). For this purpose, C₁ phenyl-substituted isoindoline 13s was used. Attempted formation of the corresponding isoindoline ylide led directly to the Stevens rearrangement product (tetrahydroisoquinoline 9s) at room temperature. The mixture of diastereomers of 9s was subjected to irradiation, which resulted in a crude mixture of diastereomers of the amino-indanes (see 10s), which cleanly converged to indene 11s II upon purification on silica with only trace amounts of isomer 11s I observed.

In some other cases, we observed that the amino-indane product (10) was stable under the reaction conditions and only underwent elimination to 11 in the presence of silica gel (Table 4). In general, this was true for tetrahydroisoquinolines bearing strained rings or electron-withdrawing groups on nitrogen. As the ring strain of the cycloalkane increases (see 14v relative to 14t,u), more of amino-indane 10 relative to indene 11 is observed in the crude reaction mixture. This trend likely reflects the increasing electron-withdrawing nature of the attached carbon of the cyclopropane (i.e., greater s-character).

Table 4 Ratios of amino-indane to indene of crude reaction mixtures. *Isolated yield following purification. Compound 9 converts to 10a upon purification. 0.10 mmol, 0.05 M

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To further investigate this observed trend, an array of N-ethyl substrates was prepared with increasing fluorine substitution (see 14w → 14x → 14y). From these substrates, we again observed that as the electron-withdrawing nature of the substituent increases, more of amino-indane 10 can be observed in the crude reaction mixture.

The trends in elimination of the strained ring and fluorinated substituents are contrary to typical trends in elimination as one would expect an electron-withdrawing group to enhance the ability of the amine to act as a leaving group and more easily facilitate elimination. Instead, we observe that as the electron-withdrawing nature of the N-substituent is increased, the amino-indane (10) becomes more persistent.

On the basis of this observation, we hypothesized that by trapping the immediate amino-indane products with electrophilic reagents, stability could be achieved for a range of N-alkyl amino-indanes that would otherwise spontaneously eliminate to afford the corresponding indene (Scheme 6a). This strategy was effective using acetic anhydride to form N-acetyl indane 17 and Boc amino-indane 18. We were unable to further stabilize less nucleophilic amino-indanes (e.g., 10v, Table 4 entry 3) using this strategy.

Scheme 6 Anhydride trapping strategy. Ring contraction conditions: 0.10 mmol starting material, 0.05 M THF, 400 nm, 7 h. If listed, 1.5 equiv anhydride, 2.0 equiv triethylamine were used.

The persistence of 10v,x,y under continued irradiation could arise from the relatively strong intramolecular hydrogen bond in these cases due to the electron-withdrawing N-substituent, increasing the barrier to elimination. However, the persistence of compounds 17 and 18 cannot be rationalized by hydrogen-bonding interactions, suggesting the existence of another more significant stabilizing interaction.

The isolation of 17 and 18 from 9a supports high-selectivity for the cis diastereomer, consistent with our previous observations with N-phenyl and N-sulfonyl tetrahydroisoquinoline ring contractions.^46,47 N-Boc 18 is formed and isolated as a single diastereomer. However, we noted that over time and without additional irradiation, cis-configured 17 converts to the trans diastereomer (see Section S13.4 of the SI). Therefore, the exact diastereomeric ratio for the ring contraction of 9a to 17 cannot be unambiguously determined.

Similarly, N-acetyl cyclopentane 19 was isolated in good yield from piperidine 1 following addition of acetic anhydride to the reaction mixture (Scheme 6b). In this case as well, the cis diastereomer of 19 converts to the trans isomer over time, and upon purification. Nonetheless, the cis diastereomer was isolated as the major isomer.

In the absence of acetic anhydride, only low yields of cyclopentene 3 were obtained from 1 (Scheme 6b). The significantly higher yield of 19 relative to 3 suggests that the acetic anhydride additive leads to an increase in the yield of the ring contraction. Likely, N-acetyl 19 is more stable under the irradiation conditions than the corresponding secondary amine (i.e., 2). We had initially hypothesized that the low yield observed in the ring contraction of 1 → 3 could be due to unproductive reactivity of the exocyclic N-methyl group. However, the high-yield obtained for ring-contraction product 19 indicates that the exocyclic N-methyl substituent does not significantly compete as a H-atom source with the endocyclic methylene group that leads to productive reactivity (Scheme 1c). More likely is that ring contraction product 2 undergoes photo-fragmentation and decomposition under continued irradiation. In contrast, ring contraction of benzene-fused substrates (9) leads to indenes (11) that are presumably more persistent under continued irradiation, resulting in a significant increase in yield compared to the piperidine case (i.e., 1) where elimination of the amine (2 → 3) only occurs upon purification.

In Scheme 6c, we illustrate a proposal for the role of the acetyl group in preventing photodegradation. Previously, we reported that the ring-closing Mannich step is reversible for N-sulfonyl substrates under continued irradiation (see VII → IX).⁴⁸ This reversibility could arise through a SET and PCET pathway (see VI → VII → VIII) or 1,5-HAT pathway (VI → VIII) followed by fragmentation to the Mannich precursor. Any aspect of the retro-Mannich pathway could ultimately lead to decomposition of the N-alkyl ring contraction products upon continued irradiation. The introduction of an electron-withdrawing group on the nitrogen group could prevent the retro-Mannich by either disfavoring electron transfer or by blocking the HAT process — stabilizing. 17 and 18 to continued irradiation.

The anhydride additive protocol now enables access to products bearing functionalized N-alkyl fragments. For example, isoindoline 13z, a pharmacologically active small molecule 5-HT₇ receptor antagonist, is converted to the corresponding N-acetyl indane derivative (20) in good yield (Scheme 6d)⁵⁹ via tetrahydroisoquinoline 9z, which is related to other biologically active tetrahydroisoquinolines.⁶⁰ N-Acetyl indane 20 is obtained as the cis diastereomer, and does not appear to epimerize over time unlike 17. Alternatively, irradiation of 9z in the absence of acetic anhydride yields indene 11a.

Conclusions

We have developed a photochemical ring contraction of N-alkyl tetrahydroisoquinolines, which expands the scope of this class of reactions. When combined with an initial thermal Stevens rearrangement ring expansion of isoindolines, a formal nitrogen-to-carbon replacement and scaffold hop to indenes from isoindolines proceeding through the intermediacy of isoindoline ylides is achieved.

Unique trends pertaining to the persistence of the immediate amino-indane products resulting from the ring contraction of N-alkyl tetrahydroisoquinolines were observed. From these trends, we concluded that increased electron-withdrawing character of the alkyl substituent on nitrogen increases the persistence of the amino-indane products. For substrates where elimination of the amino-indane nitrogen group occurs spontaneously, acylation with anhydrides stabilizes the molecule and reduces the propensity for elimination of the N-group.

Overall, this study highlights the power of combined ring-expansion and ring-contraction methodologies to convert between related core structures, providing a complementary approach to accessing novel chemical space that may facilitate interrogation of structure–activity relationships in medicinal chemistry campaigns.

Author contributions

R. T. S and R. S made the initial discovery and conceived the project. R. T. S optimized the reaction conditions. R. T. S. and J. D. performed the experiments. J. D. discovered the reaction of 15 to 16. R. T. S. wrote the original manuscript, with input from R. S. and J. D. R. S. directed the research.

Conflicts of interest

There are no conflicts to declare.

Data availability

All the primary data for this article is included in the supplementary information (SI). Ref. 61–77 are cited in the SI. Supplementary information is available. See DOI: https://doi.org/10.1039/d6sc03487j.

Acknowledgements

We are grateful to the National Institute of General Medical Sciences (NIGMS) (R35 GM130345) for funding this research. R.T.S. thanks the National Science Foundation for support through the NSF Graduate Research Fellowship Program (DGE 2146752). J.D. gratefully acknowledges generous fellowship support from the German National Academic Foundation (Studienstiftung des deutschen Volkes) and the Hans und Ria Messer Stiftung during a Master's program stay in the Sarpong Group at UC Berkeley. We thank Drs Hasan Celik, Raynald Giovine, and Pines Magnetic Resonance Center's Core NMR Facility (PMRC Core) for spectroscopic assistance. The 600 MHz instrument used in this work was in part supported by NIH S10OD024998. We thank Dr Z. Zhou from the QB3/Chemistry Mass Spectrometry Facility at UC Berkeley for high-resolution mass spectrometry analysis. We thank Dr J. Jurczyk (Gilead), Dr S. Kim (Caltech), Dr M. Fujiu (Shionogi), and Dr T. Fukuyama (UC Berkeley), for their mentorship. We are grateful to Prof. J. Rittle (UC Berkeley) for access to a UV–VIS spectrophotometer.

Notes and references

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