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Synthesis Feature Article

Aryne-mediated arylation of Hantzsch esters: access to highly substituted aryl-dihydropyridines, aryl-tetrahydropyridines and spiro[benzocyclobutene-1,1’-(3’,4’-dihydropyridines)]

Weitao Suna

Piera Trincheraa

Nada Kurdia

David Palomasa

Rachel Crespo-Oteroa

Saeed Afshinjavidb

Farideh Javidb

Christopher R. Jones*a

a School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS .b Department of Pharmacy, University of Huddersfield, Queensgate, Huddersfield, HD1 [email protected]

Received: Accepted: Published online: DOI:

Abstract This is a full account of our studies into the generation of highly functionalized 2-aryl-1,2-dihydropyridines and 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via intermolecular aryne ene reactions of Hantzsch esters. Furthermore, exposure to excess aryne revealed unusual 3’-aryl-spiro[benzocyclobutene-1,1’-(3’,4’-dihydropyridines)]. Mechanistic insights were provided by deuterium-labeling studies and DFT calculations, whilst preliminary cytotoxicity investigations revealed the spirocycles were selective against colon carcinomas over ovarian cancer cell lines and that all compounds had high selectivity indices with regards to non-cancer cells.

Key words benzyne, arynes, Hantzsch ester, ene reaction, dihydropyridines, spirocyclobutenes

Dihydropyridines (DHPs) are an important class of N-heterocyclic compound.1 The first method to prepare DHPs was reported by Hantzsch, isolating 1,4-DHPs, such as 1 (Figure 1), as key intermediates in the generation of pyridines.2 Hantzsch esters (HEs) are easy to access and have found widespread application as reducing agents in a range of synthetic transformations.3 More broadly, 1,4-DHPs comprise the key redox-active core of the enzyme cofactors, NAD(P)H, with the reduction believed to operate via either (i) a single step hydride transfer (ionic or radical),4,5 or (ii) a two-step ene-fragmentation mechanism.6 In addition to synthetic value, 1,4-DHPs display a broad range of biological activities. For example, antihypertensive drug amlodipine 2 operates as a calcium channel modulator, whilst 1,4-DHPs have also been used as anticonvulsant and antimycobacterial agents.7

1,2-DHPs are less well-studied, compared to the 1,4-regioisomers, in part due to the relative lack of synthetic methods for their preparation.8,9 However, they are important scaffolds in the formation of the isoquinuclidine ring system

Figure 1 Hantzsch ester (1), amlodipine (2), ibogaine (3) and Tamiflu (4)

which is found in a number of alkaloid natural products that have wide-ranging biological properties, such as ibogaine 3.10

Scheme 1 Hantzsch ester-mediated reduction of arynes

The anti-influenza drug, oseltamivir phosphate 4 (Tamiflu), has also been synthesized from the isoquinuclidine nucleus.11

Template for SYNTHESIS © Thieme Stuttgart · New York 2023-05-19 page 1 of 15


Given the biological and synthetic potential of 1,2-DHPs, we decided to investigate a new approach to these partially saturated N-heterocycles, based on the functionalization of readily accessible HEs 5 (Scheme 1). Considering the mechanistic pathways by which 1,4-DHPs have been shown to reduce unsaturated substrates, we envisaged that the HE-mediated reduction of aryne 6 would furnish functionalized 1,2-DHPs 7, irrespective of whether the reaction operated via a hydride transfer or concerted mechanism (Scheme 1). Ene adducts have never been isolated from 1,4-DHP reductions,12

however, a reversal of the typical equilibrium between the adduct and ionic intermediates, such as 7, 8 and 9, was proposed due to the instability of aryl anion 9. Arynes are useful reactive intermediates that have undergone a recent renaissance, mainly due to the development of mild and convenient methods for their generation.13,14 As a result of these advancements, a number of exciting new modes of reactivity have been discovered.15 There is very little known about hydride transfer onto arynes; we recently developed the first examples of an intramolecular reaction,16 but there are no reports of an intermolecular variant. Conversely, the general propensity for arynes to participate in ene reactions is well-documented, with a number of intramolecular17 and intermolecular18-20 processes having been described.

We recently communicated our initial findings on the functionalization of HEs, showing that simple structural differences controlled the outcome of divergent C-2 and C-3 arylations.21 Evidence was also provided that the reactions proceeded via concerted aryne ene mechanisms. Herein we report our full investigations into this reaction manifold, including an increased substrate scope and the identification of a series of novel spiro(benzocyclobutene) derivatives. Preliminary cyctotoxicity studies are presented, wherein all compounds showed high selectivity over non-cancer cell lines.

We began our investigations with N-methyl HE derivatives 10, in order to prevent competitive aryne insertion into the N-H bond, and ortho-silylaryl triflates 11 as the aryne precursor.22

Selected optimization experiments, using HE 10a and benzyne precursor 11a as the test compounds, are presented in Table 1. A survey of common fluoride sources and solvents for ortho-silylaryl triflate activation pleasingly revealed that the C-2 ene adduct 12a was produced in all cases (entries 1-8). CsF and KF/18-crown-6 were found to be the most promising reagents; however, CsF was chosen for subsequent investigations as 18-crown-6 would not be required. Replacing fluoride with Cs2CO3

as the activator also afforded 12a (entries 9 and 10), albeit in lower yields than with the inorganic fluoride salts. Introducing toluene as a co-solvent enabled an increase in reaction temperature, however there was no effect on the yield at 90 ˚C rather than 70 ˚C (entry 6 vs. 5). As unreacted starting materials 10a and 11a were recovered from all of the previous entries, attempts were made to improve the conversion. The amount of CsF was raised from 3.0 to 5.0 equivalents and resulted in a marked increase in the yield (53% to 68%, entry 3 vs. entry 11), whilst 6.0 equivalents of fluoride led to complete consumption

Table 1 Selected optimization studies for the C-2 arylation of HE 10aa

Entry

Activator Equiv.

Additive Solvent Yield (%)b

1 TBAFc 3.0 – THF 102 CsF 3.0 – THF 243 CsF 3.0 – MeCN 534 KF 3.0 18-c-6 THF 555 KF 3.0 18-c-6 MeCN 426d KF 3.0 18-c-6 3:1

MeCN/PhMe40

7 TBAT 3.0 – THF 328 TBAT 3.0 – MeCN 279 Cs2CO3 3.0 18-c-6 THF 2610 Cs2CO3 3.0 18-c-6 MeCN 2611 CsF 5.0 – MeCN 6812 CsF 6.0 – MeCN 7213e CsF 6.0 – MeCN 3814f CsF 6.0 – MeCN 7715f,g CsF 6.0 – MeCN 67a Reaction conditions: 2-(trimethylsilyl)phenyl triflate 11a (2.0 equiv.), solvent [0.1 M], 70 ˚C, 15 h. b 1H NMR yield vs. dibromomethane internal standard. c 1M solution in THF. d 90 ˚C. e 1.0 equiv. aryne precursor 11a. f 2.5 equiv. aryne precursor 11a. g 40 ˚C. Equiv. = molar equivalents. TBAF = tetrabutylammonium fluoride. TBAT = tetrabutylammonium triphenyldifluorosilicateof aryne precursor 11a (72% yield, entry 12). Increasing the amount of aryne precursor from 2.0 to 2.5 equivalents improved the conversion of HE 10a, affording 12a in 77% yield (entry 14); however, higher loadings of 11a did not lead to any further consumption of HE. Finally, reducing the reaction temperature to 40 ˚C caused a reduction in yield (67%, entry 15). It is noteworthy that arylation occurred exclusively at the C-2 position of HE 10a, with no evidence of a C-4 adduct that might be expected from stepwise formation of intermediate pyridinium ion 8 and aryl anion 9 (see Scheme 1) and their subsequent combination at C-4 rather than C-2.

With optimized reaction conditions in hand (entry 14, Table 1), we began exploring the scope of the HEs 10a-f in this arylation process. Electron-rich (p-OMe, 10b) and electron-poor (p-F, 10c and p-Br, 10d) 2,6-diaryl HE derivatives were found to be equally amenable to the arylation conditions, affording the C-2 covalent ene adducts 12ba-da in similarly good yields (60-65%) (Scheme 2). Interestingly, the incorporation of halogen atoms in products 12ca and 12da should provide useful handles for subsequent synthetic manipulation. Elsewhere, 2,6-dimethyl HE 10e reacted smoothly to reveal the C-2 arylated 1,2-DHP 12ea. Substituted aryne precursors also proved to be viable reagents for the arylation of 10e. Methylenedioxy (11b) and 4-methyl (11c) precursors produced the corresponding 2-aryl-1,2-DHPs 12eb and 12ec in moderate yields, with 12ec isolated as a 1:1 mixture of regioisomers. A mixture of regioisomeric ene adducts was also generated when the unsymmetrical 2-methyl-6-phenyl HE 10f was treated with benzyne 11a, furnishing 12fa and 12fa’ in a combined 30% yield but with a slight preference (5:3) for arylation adjacent to



the phenyl substituent (12fa). Finally, no C-4 arylated 1,4-DHP products were detected in any reaction.



Scheme 2 C-2 Arylation of Hantzsch esters

Having established that 2,6-disubstituted HEs 10 afforded the desired C-2 covalent ene adducts upon exposure to different arynes, attention turned to HEs bearing additional substituents at C-4. It was postulated that appropriate substitution at C-4 could stabilize pyridinium ion 8 and therefore increase the propensity for HEs to undergo hydride transfer, which could potentially offer insight into whether a stepwise or concerted mechanism is in operation. To this end, a range of C-4 aryl HE derivatives 13a-d were exposed to the reaction conditions; however, despite undergoing arylation, surprisingly, none of the expected C-2 or C-4 adducts were observed (Scheme 3). Instead, bench-stable C-3 covalent ene adducts were exclusively generated; for example, 2,6-dimethyl-4-phenyl HE 13a afforded the highly substituted 2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine 14aa as a single diastereoisomer in 52% yield. It was found that the electronic nature of the aryl substituent had no influence on the

outcome of the reaction; electron-rich (p-OMe, 13b) and electron-poor (p-NO2, 13c) C-4 aryl groups were equally effective. Meanwhile, exposure of HE 13a to the substituted aryne precursors 11b and 11c resulted in the corresponding C-3 arylated THPs 14ab and 14ac in 51% and 56% yields respectively, with 14ac isolated as a 1:1 mixture of meta and para regioisomers. The use of 2-methyl-4,6-diphenyl HE 13d, a substrate with only one possible site for exocyclic alkene formation, led to the expected C-3 adduct 14da, albeit in slightly lower yield but with no trace of competing arylation at either C-2 or C-4. Finally, it was noted that unreacted HE was recovered in all examples of the C-3 arylation of HEs 13a-d, however, all attempts to increase the level of conversion were unsuccessful.

We continued our investigations into the scope of the DHP-aryne reactions by studying C-4 alkyl-substituted HEs 15a-i (Scheme 4). A range of cyclic (cyclohexyl, 15a; cyclopentyl,

Scheme 3 C-3 Arylation of C-4 aryl Hantzsch ester derivatives



Scheme 4 C-3 Arylation of C-4 alkyl Hantzsch ester derivatives

15b; cyclobutyl, 15c and cyclopropyl, 15d), branched (i-Pr, 15e) and linear (Me, 15g; Et, 15h and n-Pr, 15i) alkyl derivatives all afforded the corresponding C-3 arylated THPs 16, although the yields were found to be universally lower than the analogous C-4 aryl HEs 13. Interestingly, 4-t-Bu HE 15f did not yield any of the C-3 aryl THP 16fa, instead affording an unrelated compound that had lost the t-Bu group. The failure of 15f to engage in the same arylation reaction was postulated to be due to increased steric hindrance around the DHP ring and a more labile C-4 substituent. Finally, it was observed that the C-3 arylation of all HE derivatives 15 resulted in single product diastereoisomers 16, in agreement with adducts 14, generated from C-4 aryl HEs 13 (see Scheme 3). NOESY experiments were conducted on 4-methyl-3-phenyl THP 16ga and key correlations indicated an anti relationship between the C-3 phenyl and C-4 methyl groups.22 This is consistent with the aryne approaching the HE from the opposite face of the ring to the C-4 substituent. There are very few reports describing the preparation of highly functionalised 1,2,3,4-THPs related to adducts 14 and 16.23,24 As such, our findings represent the first method for the synthesis of 1,2,3,4-THPs bearing an aryl group at an all-carbon C-3 quaternary centre.

During our investigations into the C-3 arylation of C-4-substituted HEs 13 and 15, it was noted that the use of reaction conditions that had been optimized for the C-2 arylation process led to incomplete conversion of starting materials. As mentioned previously, attempts to increase the conversion of 4-aryl HE derivatives 13 were unsuccessful; however, a two-fold increase in the amount of aryne precursor did result in the complete consumption of 4-alkyl HEs 15. Intriguingly, the anticipated 4-alkyl THPs 16 were not detected; instead, when 4-cyclohexyl HE 15a was treated with 5.0 equivalents of aryne precursor 11a at 50˚C, the unusual spiro[benzocyclobutene-1,1’-(3’,4’-dihydropyridine)] 17aa was isolated as the major product in a combined 74% yield of a

1.7:1 mixture of C-2 epimers (Scheme 5). Indeed, upon closer examination of all the crude arylation reaction mixtures involving C-4-substituted HE derivatives 13 and 15, spirocyclic compounds were identified as minor products for a number of the 4-alkyl derivatives, which also explained the lower yields of THPs 16 in comparison to the 4-aryl counterparts 14. With a new mode of reactivity identified, the scope of the spirocyclization process was investigated.

Analogous spiro(benzocyclobutene-dihydropyridines) were produced when cyclic (cyclopentyl, 15b; cyclobutyl, 15c and cyclopropyl, 15d) and branched (i-Pr, 15e) C-4 alkyl HEs were exposed to the new reaction conditions, generally furnishing the corresponding spirocycles 17aa-ea in good yields (Scheme 5). However, the linear C-4 alkyl derivatives 15g-i afforded no trace of the expected spirocyclobutenes 17ga-ia, instead giving intractable mixtures. It was postulated that this change in reactivity was due to a reduction in the steric bulk at the C-4 position of the DHP, which was supported by the lower yield of 4-cyclopropyl spirocyclobutene 17da (30%), in comparison to the bulkier branched and cyclic alkyl derivatives 17ea and 17aa-ca respectively (58-74%). The spirocyclization process was also amenable to a range of substituted arynes: methylenedioxy (11b), 4,5-difluoro (11d), 4,5-dimethyl (11e) and cyclopentyl (11f) precursors all reacted smoothly with 4-cyclopentyl HE 15b to afford the corresponding spirocycles 17bb-bf Finally, all spirocyclic products 17 were obtained as epimeric mixtures at C-2. NOESY experiments on the major isomers of cyclohexyl and cyclopentyl derivatives 17aa and 17ba revealed contrasting selectivities, as key nOe correlations for 17aa suggested an anti relationship between the C-3 phenyl group and cyclobutene methylene, whereas 17ba indicated a syn isomer.25 The major isomers of 17ca, 17da and 17ea, 17bb, 17be and 17bf were all subsequently assigned as syn by analogy to the 1H NMR spectra of 17aa and 17ba.



Scheme 5 C-3 Arylation/C-2 spirocyclization of C-4 branched alkyl Hantzsch esters

Spirocyclic compounds have received increased attention in recent years, especially with respect to drug discovery.26 This is due to enhanced structural rigidity, which enables more precise control of the 3D fragment conformation and can result in improved recognition and physico-chemical properties. Despite these benefits, there are relatively few types of spirocyclic scaffolds in most drug discovery libraries,27 which reflects the need for more synthetic strategies that address their preparation.26 To this end, our studies have added to the diversity by revealing new complex benzo-fused spirocycles that are easily accessed from simple HEs in a single step.

Having investigated the contrasting reactivity of a range of substituted HEs 10, 13 and 15, attention turned to acquiring an understanding of the mechanisms of each process. Two main pathways were proposed for C-2 arylation, in line with the analogous NAD(P)H-mediated biological transformations: a two-step hydride transfer and subsequent combination (either radical or ionic), or a single-step concerted aryne ene reaction (see Scheme 1). Empirical evidence seemed to support a concerted reaction, as 1,4-DHP adducts were never detected in the reactions. Furthermore, a deuterium crossover experiment, involving an equimolar mixture of 2,6-dimethyl HE 10e and bisdeuterated isotopologue 10e-d2, afforded only the two “concerted products” 12ea and 12ea-d2 (Scheme 6a).21 While the absence of cross-products 12ea-dH and 12ea-Hd, as well as 1,4-DHP adducts, does not preclude the reaction operating

via a stepwise pathway, it would appear to suggest that an aryne ene mechanism is more likely. In order to provide more insight into the C-2 mechanism, the arylation reaction involving HE 10e was also studied using DFT analysis (B3LYP-D3/def2-TZVP in acetonitrile).21 No transition structure (TS) for either stepwise pathway (radical or ionic) could be located, whereas a low activation barrier for the concerted process was calculated at 7.5 kcal/mol, suggesting the reaction occurred in a single step and in agreement with experimental findings.

The different mechanistic hypotheses for C-3 arylation also invoked competing stepwise and concerted processes. It was proposed that the C-3 adducts 14 and 16 formed via either (i) enamine addition onto the aryne at C-3, followed by removal of an -proton from the intermediate iminium ion, or (ii) an alternative aryne ene reaction involving C-3 and a C-H from the exocyclic methyl group. With this in mind, no deuterium incorporation was observed when 2,6-dimethyl-4-phenyl HE 13a was exposed to precursor 11a in acetonitrile-d3. This tentatively suggested a concerted mechanism, as the postulated stepwise intermediate 18 (Scheme 6b) would be expected to deprotonate the solvent (acetonitrile) in at least trace amounts.16 Once again, DFT calculations (B3LYP-D3/def2-TZVP in acetonitrile)21 offered good support to the experimental evidence. Analysis of HE 13a revealed an energy barrier of



Scheme 6 Mechanistic studies. (a) Deuterium crossover experiments; (b) Deuterium incorporation experiments

9.7 kcal/mol for the ene reaction, whereas no TS for the stepwise process was found. Additional calculations showed that formation of the diasteroisomer of 14aa, wherein the C-3 and C-4 aryl groups are syn, was disfavoured by 14.7 kcal/mol, in agreement with the nOe assignment.

Considering the mechanism of the spirocyclization process, it was proposed that 17ba arose from initial C-3 arylation of 4-cyclopentyl HE 15b via the aryne ene reaction, followed by a formal [2+2]-cycloaddition between the exocyclic methylene of 16ba and a further equivalent of benzyne (Scheme 7). Whilst enamines have been shown to afford benzocyclobutenes upon treatment with arynes,28 their application to the formation of spirocyclic analogues has not been reported. To this end, when 4-cyclopentyl THP 16ba was submitted to the arylation reaction conditions, the corresponding spiro(benzocyclobutene) 17ba was isolated in 61% yield, which supported the intermediacy of the C-3 adduct (Scheme 8 top). DFT analysis (B3LYP-D3/def2-TZVP in acetonitrile)29 supported the feasibility of the formal [2+2]-cyclization, as the energy barriers for enamine addition of

Scheme 7 Proposed spirocyclization mechanism of 4-cyclopentyl HE 15b

16ba onto benzyne were calculated at 13.2 kcal/mol when benzyne approached syn to the C-3 aryl group and 13.4 kcal/mol for the anti trajectory. Furthermore, the subsequent cyclization of 19 proved extremely facile, as it was shown to proceed without a discernible energy barrier. Without a barrier, it seems likely that any diastereoselectivity in the spirocyclization reactions would arise due to small energy differences in the initial enamine step. In the case of spirocycle 17ba, the 1:1.1 diastereoisomeric product ratio reflects the very similar activation energies calculated for the aryne to approach either face of the enamine.

Interestingly, stepwise C-3 arylation/spirocyclization afforded spiro[benzocyclobutene-1,1’-(3’,4’-dihydropyridine)] 17ba in 21% yield over two steps from 4-cyclopentyl HE 15b (Scheme 8 top), whereas the one-pot process furnished 17ba in an improved 67% yield directly from 15b (see Scheme 5). The utility of the stepwise method was demonstrated when intermediate THP 16ba was treated with an alternative aryne precursor, methylenedioxy 11b, which enabled incorporation of two different aryl groups into the spirocyclic product 17bab and revealed the potential to generate a library of mixed-aryl spirocyclic DHPs (Scheme 8 bottom).

Scheme 8 Spirocyclization of THP 16ba with different arynes



Scheme 9 C-2 Arylation of C-4-substituted Hantzsch ester derivatives

With experimental and computational evidence to support the arylation and spirocyclization reaction mechanisms, attention turned to understanding the relationship between this divergent reactivity and the HE structure. In order to investigate whether C-4 substitution completely inhibited C-2 arylation, C-4 substituted derivatives incapable of forming the exocyclic methylene group in THPs 14 and 16 were exposed to the standard reaction conditions (Scheme 9). Interestingly, there was no reaction with the more sterically hindered 2,4,6- triphenyl HE 20a, however 2,6-diphenyl-4-methyl HE 20b did afford a small amount of the C-2 adduct 21ba (11 %); starting material remained in both cases. These observations suggested that C-4 substituents suppressed the rate of C-2 arylation and it was more pronounced with bulkier groups.

In order to investigate the cause of this steric effect, 2,6-dimethyl-4-phenyl HE 13a was chosen as a model substrate and DFT (B3LYP-D3/def2-TZVP in acetonitrile) was used to compare the theoretical reaction energy profiles for the competing C-2 and C-3 arylation pathways.21 The calculations revealed a lower activation barrier for the formation of C-3 adduct 14aa (9.7 kcal/mol) compared to the C-2 adduct (11.9 kcal/mol), in agreement with experimental observations. Analysis of the two transition structures showed that the C-4 phenyl substituent forced the ethyl ester groups at C-3 and C-5 to project onto the opposite face of the 1,4-DHP ring.30 This conformation caused the approach of aryne at C-2 of the DHP ring to be more hindered than at C-3, which resulted in a more asynchronous distribution of charge and a higher energy transition state for C-2 arylation. It was also noted that the large exothermic character and low activation energy barriers calculated for both transformations were consistent with previous reports on the aryne ene reaction, which invoked the aryne 1,2-pseudodiradical vinyl resonance structure.31

Steric effects at C-4 were also proposed as the controlling factor for spirocyclization, as derivatives bearing bulky branched alkyl substituents were the only substrates found to afford benzocyclobutenes 17 when exposed to excess aryne. Attempts were made to rationalize this narrow reactivity profile using DFT analysis, however we were unable to formulate a satisfactory understanding of these observations.

Finally, given the wide array of biological activities reported for DHP and THP-based compounds,1,8 the cyctotoxicities were assessed for a small sample of the three structurally distinct products obtained from our investigations. To this end, HCT +/+ (human colon carcinoma), A2780 (ovarian carcinoma), A2780-CP70 (cisplatin-resistant ovarian carcinoma) and ARPE19 (non-carcinoma) cell lines were treated with C-2 arylated DHPs 12ba

and 12ca, C-3 adducts 14ba and 14ab and the diastereoisomeric spirocycles 17ba and 17ba’ (Table 1).32

Table 1 Cytotoxicity studies

Entry

Compound & cell line, IC50 (µM)a

HCT +/+ A2780 A2780-CP70 ARPE19

1

0.12 ± 0.02 16.9 ± 10.7 58.3 ± 23.4 NAb

2

15.7 ± 2.3 8.9 ± 4.3 28.8 ± 4.0 NAb

3

0.72 ± 0.5 6.7 ± 0.8 11.3 ± 0.5 NAb

4

0.96 ± 0.2 5.8 ± 1.5 5.9 ±0.58 NAb

5

2.5 ± 0.33 NAb NAb NAb

6

61.0 ± 15.0 NAb NAb NAb

a Effect of compounds on HCT +/+ (human colon carcinoma), A2780 (ovarian carcinoma), A2780-CP70 (cisplatin-resistant ovarian carcinoma) and ARPE19 (non-carcinoma) cell lines; all experiments run in triplicate. b IC50 value not calculated as highest concentration (100 µM) did not induce 50% reduction in cell viability.Pleasingly, all six compounds displayed activity against HCT +/+ cells, with 12ba, 14ba and 14abaffording significant IC50 values in the nanomolar range. There were marked differences between the three compound classes with respect to their cyctotoxicities against ovarian carcinomas, A2780 and A2780-



CP70. The C-2 and C-3 aryl ene adducts 12ba, 12ca, 14ba and 14ab all displayed micromolar levels of efficacy towards both cell lines, whereas spiro(benzocyclobutenes) 17ba and 17ba’ did not even induce 50% reduction in cell viability, even at the highest concentration of compound used in the studies (100 µM), demonstrating a clear selectivity for colon over ovarian carcinomas by these unusual spirocycles. Finally, perhaps the most intriguing aspect of these studies, with regards to potential cancer therapeutic use, was that all of the compounds were inactive towards the non-carcinoma cell line, ARPE19, which indicated very high selectivity indices. This is particularly interesting as current cancer chemotherapeutic drugs, such as cisplatin, typically induce significant damage to normal cells which subsequently leads to serious side effects in patients.33 To this end, further experiments are underway in our laboratories to establish the pharmacological mechanism of action of these DHPs and THPs.

In conclusion, we have developed a divergent approach to the synthesis of highly functionalized 2-aryl-1,2-DHPs and 3-aryl-1,2,3,4-THPs, including the structurally diverse spiro(benzocyclobutene)dihydropyridines, via aryne-mediated arylation of readily available HEs. The N-heterocyclic scaffolds produced by this methodology contain all-carbon quaternary stereogenic centres and are the first examples of bench stable ene adducts formed between 1,4-DHPs and unsaturated substrates. DFT calculations and mechanistic experiments provide support for these adducts being formed by an intermolecular aryne ene reaction. This strategy is distinct from previous reports of intermolecular aryne alkene-ene processes, as the HE substrates are more complex and contain a greater number of heteroatoms,34 which points to the potential synthetic utility of this reactivity mode as a method to functionalize alternative heterocyclic scaffolds. Finally, preliminary cytotoxicity studies on a small sample of the DHP and THP compounds revealed that all were highly selective towards cancer cells over normal cells, whilst spirocyclic DHP 17ba displayed selectivity for colon carcinomas over ovarian cancer cell lines. Further investigations into the biological mode of action are currently underway.

The experimental section has no title; please leave this line here.

All chemicals were used directly as obtained from commercial sources without prior purification. Dry tetrahydrofuran (THF) was obtained from the MB SPS-80, dry acetonitrile (MeCN) was used as purchased from Alfa Aesar. Cesium fluoride was used directly as supplied and without additional drying. Reactions requiring anhydrous conditions were carried out in flame-dried apparatus under nitrogen. Flash column chromatography was carried out using 40-63 µm silica gel or the Biotage Isolera One flash purification system. Thin-layer cromatography (TLC) was performed on aluminium backed plates pre-coated with Silica Gel 60 F254 and visualized using a UV lamp (254 nm) or KMnO4 stain. 1H NMR and 19F NMR spectra were obtained from Bruker AVIII-400 and AV400 spectrometers. 13C NMR spectra were obtained from AVIII-400, AV400 and AV600 spectrometers. 1H NMR spectra chemical shifts ( ) areδ reported in parts per million (ppm) to the nearest 0.01 and referenced to residual protonated solvent peak (CDCl3, = 7.26 ppm; MeCN-δ d3, =δ 1.94 ppm). 13C NMR spectra chemical shifts ( ) are reported in parts perδ million (ppm) to the nearest 0.1 and referenced to the solvent peak (CDCl3, = 77.2 ppm). Spectral data are reported as follows: chemicalδ shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, ddt = doublet of doublet of triplets, dtd = doublet of triplet of doublets, m = multiplet, br = broad), coupling constant (J) in Hertz (Hz), and integration. IR spectra were recorded as solids or neat liquids on the PerkinElmer Spectrum 65 FT-IR

spectrometer fitted with a Universal ATR sampling accessory and are reported in wavenumbers (cm-1) to the nearest integer. High resolution mass spectra were acquired by electrospray ionisation (ESI) or nanospray ionisation (NSI) at the EPSRC UK National Mass Spectrometry Facility at Swansea University. All melting points were determined in open glass capillaries and are uncorrected.

See ESI for details of the synthesis and characterization of all starting materials.

Typical procedure for the aryne-mediated arylation of N-methyl-1,4-dihydropyridines

To an oven-dried microwave vial equipped with a magnetic stirrer bar was added N-methyl-1,4-dihydropyridine (0.25 mmol, 1.00 equiv.) and CsF (228 mg, 1.50 mmol, 6.00 equiv.). The vial was sealed and degassed by alternating vacuum evacuation and back filling with N2 (3 x 1 min). Acetonitrile (2.50 mL, 0.10 M) and the aryne precursor (0.625 mmol, 2.50 equiv.) were then added to the vial via syringe. The resulting mixture was heated at 50 or 70 °C and stirred for 16 hours. The reaction was allowed to cool to room temperature, the solvent removed in vacuo and the crude material dissolved in Et2O and passed through a silica gel plug. The Et2O was removed in vacuo and the resulting crude mixture was purified by flash column chromatography to afford the title compound.

The experimental data for 12aa-ea, 12eb, 12ec, 14aa-14ca, 14ab, 14ac, 16ga and 21ba have been reported previously.21

Diethyl 1,6-dimethyl-2,2-diphenyl-1,2-dihydropyridine-3,5-dicarboxylate (12fa) + Diethyl 1,2-dimethyl-2,6-diphenyl-1,2-dihydropyridine-3,5-dicarboxylate (12fa’): Combined yield: 30%. Data refer to an inseparable 3:2 mixture of 12fa and 12fa’. Rf: 0.31 (n-Hexane/EtOAc 8/2).

IR (thin film) ν 2978, 2927, 1678, 1622, 1482, 1391, 1307, 1197, 1129, 1100, 1027, 752, 699 cm-1.

1H NMR (400 MHz, CDCl3) 7.96 (s, 1H), 7.91 (s, 1H), 7.66 – 7.25 (m, 20H), 4.17 (q, J = 7.1 Hz, 2H), 4.01 – 3.85 (m, 6H), 2.67 (s, 3H), 2.63 (s, 3H), 2.23 (s, 3H), 2.11 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.11 – 1.01 (m, 6H), 0.95 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 166.7, 165.7, 165.5, 165.4, 160.4, 160.3, 146.1, 142.0, 136.9, 135.1, 134.0, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.5, 127.3, 127.3, 127.1, 126.8, 116.6, 114.6, 96.3, 95.7, 74.2, 67.2, 59.7, 59.5, 59.1, 37.2, 35.8, 29.7, 22.1, 17.8, 14.5, 14.1, 14.0.

HRMS (NSI) [M+H]+ calcd. For C25H28NO4 406.2013, found 406.2012.

Diethyl 1-methyl-2-methylene-3,4,6-triphenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (14da): Yield: 34%; orange solid; mp: 153 – 156 °C (Et2O); Rf: 0.33 (n-Hexane/EtOAc 8.5/1.5).

IR (powder): 2983, 1728, 1663, 1630, 1575, 1492, 1362, 1205, 1148, 1051, 1033, 763, 715, 699 cm-1.

1H NMR (400 MHz, CDCl3) : 7.59 – 7.57 (m, 2H), 7.37 – 7.15 (m, 13H), 5.57 (d, J = 1.6 Hz, 1H), 5.28 (s, 1H), 4.97 (d, J = 1.6 Hz, 1H), 4.01 – 3.89 (m, 2H), 3.70 (q, J = 7.1 Hz, 2H), 2.81 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) 170.6, 166.9, 151.4, 144.4, 141.8, 140.1, 137.6, 130.2, 129.2, 128.4, 128.2, 127.9, 127.8, 127.7, 127.5, 126.9, 104.3, 98.9, 61.0, 59.2, 58.0, 44.9, 38.0, 13.9, 13.8.


Diethyl 4-cyclohexyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16aa): Yield: 31%; white solid; mp: 87-88 °C (Et2O); Rf: 0.58 (n-Hexane/EtOAc 2/1).

IR (powder): 2925, 2850, 1726, 1676, 1574, 1446, 1383, 1255, 1205, 1139, 1108, 1030, 771, 726, 695 cm-1.

1H NMR (400 MHz, CDCl3) 7.34 – 7.32 (m, 2H), 7.20 – 7.11 (m, 3H), 5.49 (d, J = 1.4 Hz, 1H), 4.73 (d, J = 1.3 Hz, 1H), 4.21– 3.97 (m, 4H), 3.92 (d, J = 2.8 Hz, 1H), 3.10 (s, 3H), 2.07 (s, 3H), 1.93 – 1.90 (m, 1H), 1.72 – 1.69 (m, 1H), 1.62 – 1.56 (m, 2H), 1.38 – 1.10 (m, 13H).



13C NMR (100 MHz, CDCl3) 171.8, 168.9, 149.4, 145.2, 140.5, 127.9, 127.4, 127.0, 103.0, 94.7, 60.9, 59.4, 57.8, 43.5, 42.9, 35.5, 34.2, 31.0, 27.8, 27.0, 26.6, 17.2, 14.8, 14.0.


Diethyl 4-cyclopentyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16ba): Yield: 35%; white solid; mp: 81-82 °C (Et2O); Rf: 0.68 (n-Hexane/EtOAc 2/1).

IR (powder): 2954, 2868, 1729, 1683, 1586, 1446, 1251, 1212, 1142, 1112, 752, 696 cm-1.

1H NMR (400 MHz, CDCl3) : δ 7.37-7.34 (m, 2H), 7.20-7.13 (m, 3H), 5.54 (d, J = 1.3 Hz, 1H), 4.72 (d, J = 1.2 Hz, 1H) 4.20-4.10 (m, 3H), 4.04 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 7.5 Hz, 1H), 3.11 (s, 3H), 2.07 (s, 3H), 1.85 – 1.82 (m, 1H), 1,73 – 1.66 (m, 1H), 1.55 – 1,50 (m, 2H), 1.46 – 1.36 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H), 1.03 – 0.97 (m, 1H).

13C NMR (101 MHz, CDCl3) : 171.6, 168.7, 149.3, 145.2, 140.2, 127.7,δ 127.4, 126.8, 103.7, 94.0, 60.7, 59.3, 57.6, 45.0, 40.9, 35.1, 31.8, 29.3, 24.3, 24.0, 17.2, 14.6, 13.7.

HRMS (ESI) [M+H]+ calcd. For C25H34NO4 412.2488; found 412.2481.

Diethyl 4-cyclobutyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16ca): Yield: 18%; orange oil; Rf: 0.59 (Pet/EtOAc 8.5/1.5).

IR (powder): 2974, 2869, 1727, 1681, 1583, 1445, 1257, 1206, 1143, 1109, 1025, 750, 695 cm-1.

1H NMR (400 MHz, CDCl3) : δ 7.32-7.29 (m, 2H), 7.20-7.13 (m, 3H), 5.46 (d, J = 1.5 Hz, 1H), 4.71 (d, J = 1.4 Hz, 1H) 4.22-4.14 (m, 2H), 4.06-4.01 (m, 3H), 3.09 (s, 3H), 2.12 (s, 3H), 1.93 – 1.81 (m, 2H), 1.69 – 1.55 (m, 5H), 1.32 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.4, 168.7, 149.5, 144.9, 140.1, 127.7,δ 127.2, 126.8, 102.4, 94.2, 60.6, 59.2, 56.6, 41.9, 39.3, 35.1, 27.9, 26.5, 19.0, 17.2, 14.6, 13.7.


Diethyl 4-cyclopropyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16da): Yield: 39%; yellow oil; Rf: 0.56 (n-Hexane/EtOAc 7.5/2.5).

IR (thin film): 2980, 2904, 1730, 1682, 1582, 1446, 1254, 1206, 1146, 1109, 752, 696 cm-1.

1H NMR (400 MHz, CDCl3) : 7.34-7.32 (m, 2H), 7.21-7.15 (m, 3H), 5.63δ (br s, 1H), 4.84 (br s, 1H), 4.21 – 4.12 (m, 2H), 4.09 – 4.03 (m, 2H), 3.67 (d, J = 7.5 Hz, 1H), 3.13 (s, 3H), 2.11 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H), 0.86 – 0.79 (m, 1H), 0.48 – 0.41 (m, 1H), 0.31 – 0.22 (m, 3H).

13C NMR (101 MHz, CDCl3) : 171.4, 168.5, 149.3, 145.2, 139.9, 127.7,δ 127.4, 126.9, 102.5, 95.5, 60.6, 59.3, 57.4, 41.0, 35.5, 17.3, 14.6, 13.9, 13.8, 4.1, 1.7.


Diethyl 4-isopropyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16ea): Yield: 29%; yellow oil; Rf: 0.39 (Pet/EtOAc 9/1).

IR (thin film): 2976, 2871, 1727, 1682, 1582, 1446, 1252, 1210, 1139, 1111, 753, 695 cm-1.

1H-NMR (400 MHz, CDCl3) : 7.35 – 7.33 (m, 2H), 7.20 – 7.13 (m, 3H),δ 5.52 (d, J = 1.5 Hz, 1H), 4.73 (d, J = 1.4 Hz, 1H), 4.19 – 4.13 (m, 2H), 4.09 – 4.01 (m, 2H), 3.98 (d, J = 3.2 Hz, 1H), 3.10 (s, 3H), 2.09 (s, 3H), 1.63 – 1.55 (m, 1H),1.32 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.6, 168.8, 149.4, 144.9, 140.3, 127.7,δ 127.2, 126.9, 102.7, 94.3, 60.7, 59.3, 57.6, 42.8, 35.2, 32.6, 23.8, 19.9, 17.1, 14.6, 13.7.


Diethyl 4-ethyl-1,6-dimethyl-2-methylene-3-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16ha): Yield: 39%; yellow oil; Rf: 0.56 (n-Hexane/EtOAc 7.5/2.5).

IR (thin film): 2974, 2873, 1726, 1682, 1583, 1448, 1247, 1213, 1132, 1111, 770, 695 cm-1.

1H NMR (400 MHz, CDCl3) :δ 7.31-7.28 (m, 2H), 7.21-7.14 (m, 3H), 5.23 (d, J = 1.6 Hz, 1H), 4.72 (d, J = 1.5 Hz, 1H), 4.17-4.02 (m, 4H), 3.89 (dd, J = 9.9, 2.8 Hz, 1H), 3.15 (s, 3H), 2.10 (s, 3H), 1.69 – 1.67 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.14 – 1.05 (m, 4H), 0.96 (t, J = 7.3 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.5, 168.5, 148.8, 144.7, 140.0, 127.8,δ 127.1, 126.9, 105.1, 93.8, 60.8, 59.2, 58.0, 39.0, 35.2, 27.6, 17.3, 14.6, 13.8, 12.1.


Diethyl 1,6-dimethyl-2-methylene-3-phenyl-4-propyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate (16ia): Yield: 31%; yellow oil; Rf: 0.40 (Pet/EtOAc = 9/1).

IR (thin film): 2956, 2873, 1726, 1682, 1582, 1446, 1264, 1207, 1132, 1107, 773, 695 cm-1.

1H NMR (400 MHz, CDCl3) : 7.31-7.29 (m, 2H), 7.20-7.14 (m, 3H), 5.25δ ( br s, 1H), 4.73 (br s, 1H), 4.18-4.02 (m, 4H), 3.98 (dd, J = 10.2, 2.4 Hz, 1H), 3.16 (s, 3H), 2.10 (s, 3H), 1.44 – 1.35 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.13 – 1.03 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.4, 168.4, 148.8, 144.6, 139.9, 127.8,δ 127.1, 126.9, 105.6, 93.8, 60.8, 59.2, 58.0, 37.1, 35.2, 20.6, 17.3, 14.5, 14.4, 13.8.


Typical procedure for the synthesis of spiro[benzocyclobutene-1,1’-(3’,4’-dihydropyridines)] (17)

To an oven-dried microwave vial equipped with a magnetic stirrer bar was added the N-methyl-1,4-dihydropyridine (0.25 mmol, 1.00 equiv.) and CsF (456 mg, 3.00 mmol, 12.00 equiv.). The vial was sealed and degassed by alternating vacuum evacuation and back filling with N2 (3 x 1 min). Acetonitrile (2.50 mL, 0.10 M) and the aryne precursor (1.25 mmol, 5.00 equiv.) were then added to the vial via syringe. The resulting mixture was heated at 50 °C and stirred for 16 hours. The reaction was allowed to cool to room temperature, the solvent removed in vacuo and the crude material dissolved in Et2O and passed through a silica gel plug. The Et2O was removed in vacuo and the resulting crude mixture was purified by flash column chromatography to afford the title compound.

Diethyl (3'R*,4'S*,7S*)-4'-cyclohexyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro [bicyclo [4.2.0] octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17aa): Yield: 25%; yellow solid; mp: 52-55 °C (Et2O); Rf: 0.50 (n-Hexane/EtOAc 7.5/2.5).

IR (powder): 2927, 2849, 1725, 1674, 1576, 1445, 1383, 1360, 1227, 1207, 1115, 1070, 1023, 747, 705 cm-1.

1H NMR (400 MHz, CDCl3) : δ 7.22 – 6.95 (m, 9H), 4.08 (d, J = 14.5 Hz, 1H), 3.81 – 3.71 (m, 2H), 3.68 – 3.57 (m, 2H), 3.52 (d, J = 14.6 Hz, 1H), 3.25 (d, J = 0.7 Hz, 1H), 2.78 (s, 3H), 2.36 (s, 3H), 2.26 – 2.21 (m, 1H), 2.09 – 2.06 (m, 1H), 1.69 – 1.57 (m, 4H), 1.37 – 1.27 (m, 3H), 1.06 – 1.02 (m, 2H), 0.95 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : δ 172.6, 168.7, 155.9, 146.9, 145.3, 143.6, 129.3, 127.5, 127.5, 126.9, 126.3, 124.7, 122.3, 98.7, 72.3, 61.8, 60.6, 58.5, 49.5, 43.4, 39.0, 36.3, 31.9, 30.5, 28.1, 27.4, 26.6, 17.6, 14.5, 13.5.


Diethyl (3'R*,4'S*,7R*)-4'-cyclohexyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro [bicyclo [4.2.0] octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17aa’): Yield: 39%; yellow solid; mp = 45-47 °C (Et2O); Rf: 0.56 (n-Hexane/EtOAc 7.5/2.5).

IR (powder): 2975, 2849, 1721, 1674, 1572, 1446, 1385, 1359, 1231, 1209, 1114, 1066, 1023, 755, 736, 704 cm-1.

1H NMR (400 MHz, CDCl3) : δ 7.31 – 7.29 (m, 2H), 7.23 – 7.14 (m, 4H), 7.07 – 7.01 (m, 2H), 6.88 – 6.86 (m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.89 – 3.74 (m, 3H), 3.42 (s, 1H), 3.25 (d, J = 14.4 Hz, 1H), 2.56 (s, 3H), 2.27 (s, 3H), 1.88 – 1.85 (m, 1H), 1.75 – 1.53 (m, 5H), 1.46 – 1.36 (m, 1H), 1.21 – 0.99 (m, 7H), 0.80 (t, J = 7.1 Hz, 2H).



13C NMR (101 MHz, CDCl3) : δ 172.9, 169.8, 153.7, 147.8, 144.1, 141.9, 129.2, 127.6, 127.5, 127.0, 126.8, 125.4, 122.1, 98.8, 71.8, 60.5, 60.3, 59.1, 47.7, 43.4, 42.2, 36.4, 33.8, 31.5, 28.2, 27.7, 26.7, 17.9, 14.7, 13.6.


Diethyl (3'R*,4'S*,7S*)-4'-cyclopentyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ba): Yield: 34%; yellow solid; mp = 45-47 °C (Et2O); Rf: 0.56 (n-Hexane/EtOAc 7.5/2.5).

IR (powder): 2951, 2867, 1721, 1674, 1573, 1496, 1445, 1384, 1365, 1227, 1114, 1067, 756, 733, 705 cm-1.

1H NMR (400 MHz, CDCl3) : 7.31 – 6.93 (m, 9H), 4.17 (d, δ J = 14.5 Hz, 1H), 3.87 – 3.78 (m, 2H), 3.74 – 3.58 (m, 4H), 2.88 (s, 3H), 2.44 (s, 3H), 1.71 – 1.56 (m, 7H), 1.32 – 1.19 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : δ 172.4, 168.3, 155.8, 146.9, 145.3, 143.0, 129.1, 127.4, 127.3, 126.9, 126.2, 124.8, 122.1, 99.6, 72.6, 61.8, 60.5, 58.3, 45.7, 43.0, 42.3, 33.9, 31.7, 30.1, 24.8, 23.2, 17.3, 14.4, 13.2.


Diethyl (3'R*,4'S*,7R*)-4'-cyclopentyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ba’): Yield: 30%; yellow solid; mp = 52-55 °C (Et2O); Rf: 0.50 (n-Hexane/EtOAc 7.5/2.5).

IR (powder): 2951, 2867, 1721, 1674, 1573, 1496, 1445, 1384, 1365, 1227, 1114, 1067, 756, 733, 705 cm-1.

1H NMR (400 MHz, CDCl3) : δ 7.41 – 7.37 (m, 2H), 7.30 – 7.01 (m, 7H), 3.98 – 3.76 (m, 6H), 3.45 (d, J = 14.6 Hz, 1H), 2.73 (s, 3H), 2.36 (s, 3H), 1.54 – 1.38 (m, 5H), 1.34 – 1.18 (m, 4H), 1.12 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : δ 172.7, 169.2, 153.9, 148.1, 143.7, 141.4, 129.0, 127.3, 127.1, 126.8, 126.8, 125.5, 121.9, 99.1, 71.7, 60.3, 60.2, 58.7, 45.8, 43.7, 43.2, 34.6, 33.3, 29.9, 25.3, 24.5, 17.6, 14.4, 13.3 cm-1


Diethyl (3'R*,4'S*,7S*)-4'-cyclobutyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ca) & Diethyl (3'R*,4'S*,7R*)-4'-cyclobutyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ca’): Combined yield: 58%. Data refer to an inseparable 1.7:1 mixture of 17ca and 17ca’. Rf: 0.22 (Pet/EtOAc = 9/1).

IR (thin film): 2976, 2938, 1725, 1670, 1573, 1445, 1382, 1361, 1228, 1210, 1118, 1068, 1023, 729, 703 cm-1.

1H NMR (400 MHz, CDCl3) : 7.39-7.37 (m, 1H), 7.31-7.04 (m, 17H), 4.14δ (d, J = 14.6 Hz, 1H), 4.00-3.93 (m, 2H), 3.88-3.83 (m, 3H), 3.77 (d, J = 15.3 Hz, 1H), 3.71-3.46 (m, 7H), 2.88 (s, 3H), 2.79 (s, 3H), 2.46 (s, 3H), 2.38 (s, 3H), 2.16-0.88 (m, 14H), 1.14 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.75-0.70 (m, 6H).

13C NMR (101 MHz, CDCl3) δC: 172.3, 172.2, 169.0, 168.2, 155.7, 153.7, 148.1, 147.0, 145.1, 143.5, 142.9, 141.3, 129.2, 129.0, 127.4, 127.3, 127.2, 126.9, 126.9, 126.7, 126.1, 125.6, 124.9, 122.1, 121.9, 100.0, 99.9, 98.8, 72.7, 71.6, 61.7, 60.4, 60.2, 59.0, 58.6, 58.3, 47.4, 47.3, 44.4, 42.7, 39.5, 38.3, 33.2, 31.8, 30.6, 30.1, 27.7, 27.7, 18.5, 18.4, 17.5, 17.4, 14.4, 14.4, 13.2, 13.1.


Diethyl (3'R*,4'S*,7S*)-4'-cyclopropyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17da) & Diethyl (3'R*,4'S*,7R*)-4'-cyclopropyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17da’): Combined yield: 30%. Data refer to an inseparable 1.7:1 mixture of 17da and 17da’. Rf: 0.4 (n-Hexane/EtOAc = 4/1).

IR (thin film): 2925, 2852, 11726, 1680, 1580, 1446, 1386, 1366, 1250, 1207, 1117, 1059, 1023, 755, 698 cm-1.

1H NMR (400 MHz, CDCl3) : 7.38-7.04 (m, 18H), 4.17 (d, δ J = 14.6 Hz, 1H), 3.99-3.59 (m, 12H), 3.49 (d, J = 15.1 Hz, 1H), 2.91 (s, 3H), 2.77 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.73-0.66 (m, 6H), 0.54-0.18 (m, 10H).

13C NMR (101 MHz, CDCl3) : 172.5, 172.2, 168.9, 168.0, 156.5,δ 148.0, 147.3, 144.9, 143.7, 142.8, 141.4, 129.2, 129.0, 127.5, 127.4, 127.2, 126.9, 126.8, 126.8, 126.2, 125.5, 125.2, 122.1, 122.0, 98.0, 72.5, 71.5, 61.6, 60.5, 60.3, 59.4, 58.6, 58.3, 445, 42.7, 33.3, 31.9, 17.4, 17.4, 14.5, 14.4, 13.2, 13.1, 12.5, 12.0, 4.8, 4.6, 4.1, 3.7.


Diethyl (3'R*,4'S*,7S*)-4'-isopropyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ea) & Diethyl (3'R*,4'S*,7R*)-4'-isopropyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17ea’): Combined yield: 70%. Data refer to an inseparable 1.1:1 mixture of 17ea and 17ea’. Rf: 0.27 (Pet/EtOAc = 9/1).

IR (thin film): 2975, 2870, 1725, 1672, 1575, 1457, 1383, 1361, 1229, 1210, 1111, 1071, 1025, 735, 705 cm-1.

1H NMR (400 MHz, CDCl3) : 7.51 – 7.10 (m, 18H), 4.30 (d, δ J = 14.6 Hz, 1H), 4.20 – 4.15 (m, 2H), 4.07-3.96 (m, 5H), 3.86 – 3.81 (m, 2H), 3.75-3.70 (m, 2H), 3.59 (d, J = 1.5 Hz, 1H), 3.52 (d, J = 14.5 Hz, 1H), 3.01 (s, 3H), 2.81 (s, 3H), 2.58 (s, 3H), 2.50 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1.35-1.30 (m, 7H), 1.18 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.01-0.96 (m, 6H), 0.88 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 172.8, 172.4, 169.5, 168.5, 156.0, 153.7,δ 147.7, 146.7, 145.1, 143.8, 143.2, 141.7, 129.1, 129.0, 127.4, 127.4, 127.3, 127.2, 126.8, 126.7, 126.6, 126.2, 125.4, 125.2, 122.0, 121.9, 98.6, 98.2, 72.0, 71.5, 61.6, 60.5, 60.4, 60.3, 58.8, 58.3, 48.9, 47.9, 43.1, 43.0, 33.5, 31.6, 30.6, 29.1, 26.1, 25.9, 20.8, 20.3, 17.6, 17.3, 14.4, 14.3, 13.3, 13.2.


Diethyl (3'R*,4'S*,7S*)-3'-(benzo[d][1,3]dioxol-5-yl)-4'-cyclopentyl-1',6'-dimethyl-3',4'-dihydro-1'H,6H-spiro[cyclobuta[4,5]benzo[1,2-d][1,3]dioxole-5,2'-pyridine]-3',5'-dicarboxylate (17bb) & Diethyl (3'R*,4'S*,7R*)-3'-(benzo[d][1,3]dioxol-5-yl)-4'-cyclopentyl-1',6'-dimethyl-3',4'-dihydro-1'H,6H-spiro[cyclobuta[4,5]benzo[1,2-d][1,3]dioxole-5,2'-pyridine]-3',5'-dicarboxylate (17bb’): Combined yield: 74%. Data refer to an inseparable 2.8:1 mixture of 17bb and 17bb’. Rf: 0.4 (Pet/EtOAc 7/3).

IR (thin film): 2954, 2870, 1723, 1669, 1574, 1459, 1292, 1231, 1119, 1036, 730 cm-1.

1H NMR (400 MHz, CDCl3) : 7.35-7.06 (m, 10H), 6.58 (s, 1H), 6.56 (s,δ 1H), 6.54 (s, 1H), 6.47 (s, 1H), 5.91 (d, J = 1.3 Hz, 1H), 5.89 (d, J = 1.3 Hz, 1H), 5.88 (d, J = 1.3 Hz, 1H), 5.83 (d, J = 1.3 Hz, 1H), 3.99-3.95 (m, 3H), 3.82-3.77 (m, 7H), 3.67 (d, J = 14.2 Hz, 1H), 3.63 (d, J = 2.5 Hz, 1H), 3.39 (d, J = 14.1 Hz, 1H), 3.25 (d, J = 14.2 Hz, 1H), 2.88 (s, 3H), 2.74 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 1.63-1.15 (m, 18H), 1.12 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 172.7, 172.4, 169.2, 168.3, 155.9, 153.9,δ 148.5, 147.2, 146.8, 143.2, 141.3, 139.5, 138.3, 138.2, 136.4, 127.4, 127.3, 127.1, 126.9, 126.8, 126.2, 107.4, 106.9, 103.8, 103.7, 100.4, 100.3, 99.5, 99.0, 71.0, 69.9, 61.7, 60.5, 60.4, 60.0, 58.7, 58.3, 45.8, 45.7, 43.3, 42.3, 42.1, 41.5, 34.7, 34.0, 33.1, 31.4, 30.1, 29.8, 25.3, 24.8, 24.5, 23.2, 17.7, 17.4, 14.4, 14.4, 13.6, 13.5.


Diethyl (3'R*,4'S*,7S*)-4'-cyclopentyl-3'-(3,4-difluorophenyl)-3,4-difluoro-1',6'-dimethyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17bd): Yield: 27%; yellow oil; Rf: 0.21 (Pet/EtOAc 7/3).

IR (thin film): 2957, 2871, 1727, 1676, 1581, 1518, 1475, 1384, 1338, 1280, 1230, 1127, 1056, 1022 cm-1.

1H NMR (400 MHz, CDCl3) : 7.01-6.90 (m, 3H), 6.87-6.83 (m, 1H), 6.79 –δ 6.75 (m, 1H), 4.07 (d, J = 14.4 Hz, 1H), 3.91 – 3.81 (m, 4H), 3.62 (d, J = 3.5



Hz, 1H), 3.53 (d, J = 14.4 Hz, 1H), 2.85 (s, 3H), 2.39 (s, 3H), 2.35-1.50 (m, 9H), 1.07 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.3, 168.0, 154.9, 142. 7, 140.7, 140.7,δ 139.4, 122.9 (dd, JCF = 5.9, 3.6 Hz), 116.2 (dd, JCF = 18.0, 10.1 Hz), 115.0 (d, JCF = 19.1 Hz) 111.9 (d, JCF = 18.0 Hz), 100.2, 71.8, 61.1, 60.8, 58.8, 46.0, 42.5, 33.8, 31.7, 30.4, 24.5, 23.3, 17.4, 17.4, 14.3, 13.5.

HRMS (ESI) [M+H]+ calcd. For C31H34F4NO4 560.2424; found 560.2410.

Diethyl (3'R*,4'S*,7R*)-4'-cyclopentyl-3'-(3,4-difluorophenyl)-3,4-difluoro-1',6'-dimethyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17bd’): Yield: 19%; yellow oil; Rf: 0.3 (Pet/EtOAc 7/3).

IR (thin film): 2956, 2870, 1726, 1677, 1579, 1518, 1477, 1385, 1365, 1280, 1219, 1127 cm-1.

1H NMR (400 MHz, CDCl3) : 7.29-7.23 (m, 1H), 7.09-7.04 (m, 2H), 6.98-δ6.91 (m, 1H), 6.83-6.79 (m, 1H), 4.06-3.92 (m, 4H), 3.80 (d, J = 14.7 Hz, 1H), 3.70 (d, J = 3.6 Hz, 1H), 3.40 (d, J = 14.7 Hz, 1H), 2.73 (s, 3H), 2.33 (s, 3H), 1.46-1.35 (m, 4H), 1.30-1.20 (m, 5H), 1.16 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 171.8, 168.9, 152.8, 142.7 (m), 139.3,δ 138.0, 136.6, 123.2 (dd, JCF = 6.2, 3.5 Hz), 116.3 (dd, JCF = 23.8, 18.0 Hz), 115.0 (d, JCF = 18.4 Hz), 111.8 (d, JCF = 17.9 Hz), 99.7, 70.6, 61.0, 59.2, 59.1, 46.0, 43.4, 43.2, 34.6, 33.1, 29.9, 25.1, 24.6, 17.6, 14.4, 13.4.

HRMS (ESI) [M+H]+ calcd. For C31H34F4NO4 560.2424; found 560.2412.

Diethyl (3'R*,4'S*,7S*)-4'-cyclopentyl-3'-(3,4-dimethylphenyl)-1',3,4,6'-tetramethyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17be) & Diethyl (3'R*,4'S*,7R*)-4'-cyclopentyl-3'-(3,4-dimethylphenyl)-1',3,4,6'-tetramethyl-3',4'-dihydro-1'H-spiro[bicyclo[4.2.0]octane-7,2'-pyridine]-1(6),2,4-triene-3',5'-dicarboxylate (17be’): Combined yield: 38%. Data refer to an inseparable 2.3:1 mixture of 17be and 17be’. Rf: 0.21 (Pet/EtOAc 7/3).

IR (thin film): 2938, 2867, 1724, 1661, 1572, 1448, 1383, 1352, 1225, 1115, 1054, 1024, 730, 704 cm-1.

1H NMR (400 MHz, CDCl3) : 7.15-6.69 (m, 10H), 4.12 (d, δ J = 7.1 Hz, 1H), 4.01-3.94 (m, 2H), 3.86-3.65 (m, 8H), 3.64 (d, J = 2.8 Hz, 1H), 3.52 (d, J = 14.0 Hz, 1H), 3.33 (d, J = 14.3 Hz, 1H), 2.86 (s, 3H), 2.71 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.23-2.21 (m, 12H), 2.16-2.15 (m, 12H), 2.09-1.40 (m, 18H), 1.13 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 172.9, 172.6, 169.4, 168.4, 155.9,δ 153.9, 145.6, 144.4, 142.7, 141.2, 140.5, 138.8, 137.6, 137.5, 135.3, 135.1, 135.0, 134.9, 134.7, 134.1, 128.7, 128.6, 128.4, 128.1, 126.5, 125.8, 124.5, 124.3, 123.0, 122.8, 99.4, 98.9, 72.4, 71.6, 61.2, 60.3, 60.2, 59.5, 58.5, 58.1, 45.6, 43.4, 43.2, 42.6, 42.4, 34.6, 33.8, 33.4, 31.6, 30.3, 29.9, 25.2, 24.8, 24.6, 23.2, 20.7, 20.6, 20.4, 20.3, 20.0, 19.9, 19.3, 19.2, 17.6, 17.3, 17.3, 14.4, 14.3, 13.3, 13.2.


Diethyl (1S*,3'R*,4'S*)-4'-cyclopentyl-3'-(2,3-dihydro-1H-inden-5-yl)-1',6'-dimethyl-2,3',4,4',5,6-hexahydro-1'H-spiro[cyclobuta[f]indene-1,2'-pyridine]-3',5'-dicarboxylate (17bf) & Diethyl (1R*,3'R*,4'S*)-4'-cyclopentyl-3'-(2,3-dihydro-1H-inden-5-yl)-1',6'-dimethyl-2,3',4,4',5,6-hexahydro-1'H-spiro[cyclobuta[f]indene-1,2'-pyridine]-3',5'-dicarboxylate (17bf’): Combined yield: 75%. Data refer to an inseparable 2.4:1 mixture of 17bf and 17bf’. Rf: 0.32 (Pet/EtOAc 9/1).

IR (thin film): 2952, 2843, 1724, 1675, 1574, 1363, 1384, 1224, 1161, 1118, 1050, 1024, 911, 878, 783, 731 cm-1.

1H NMR (400 MHz, CDCl3) : 7.22-6.78 (m, 10H), 4.08 (d, δ J = 14.3 Hz, 1H), 3.98-3.92 (m, 2H), 3.84-3.65 (m, 8H)3.63 (d, J = 2.5 Hz, 1H), 3.48 (d, J = 14.3 Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H), 2.87-2.78 (m, 19H), 2.73 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 2.06-1.52 (m, 18H), 1.11 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.93-0.88 (m, 8H), 0.83 (t, J = 7.1 Hz, 3H), 0.70 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 173.2, 172.9, 169.3, 168.5, 156.3,δ 154.4, 145.7, 144.9, 144.8, 144.4, 143.1, 143.1, 142.9, 142.8, 142.4, 141.8, 141.2, 141.1, 139.3, 125.0, 124.9, 123.1, 123.0, 122.9, 122.8, 121.8, 121.0, 118.2, 118.0, 99.3, 98.8, 71.7, 70.8, 61.7, 60.3, 60.3, 60.0, 58.5, 58.1, 46.0, 45.9, 43.2, 42.3, 41.9, 40.9, 34.7, 33.9, 33.3, 33.1, 33.0, 32.5, 32.4, 31.7, 30.2, 29.9, 28.4, 25.4, 25.3, 25.3, 24.9, 24.6, 23.8, 23.2, 20.8, 17.6, 17.5, 17.4, 17.4, 17.3, 14.7, 14.4, 13.3, 13.2.


Diethyl (3'R*,4'S*,5S*)-4'-cyclopentyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H,6H-spiro[cyclobuta[4,5]benzo[1,2-d][1,3]dioxole-5,2'-pyridine]-3',5'-dicarboxylate (17bab) & Diethyl (3'R*,4'S*,5R*)-4'-cyclopentyl-1',6'-dimethyl-3'-phenyl-3',4'-dihydro-1'H,6H-spiro[cyclobuta[4,5]benzo[1,2-d][1,3]dioxole-5,2'-pyridine]-3',5'-dicarboxylate (17bab’): Combined yield: 48%. Data refer to an inseparable 2.9:1 mixture of 17bab and 17bab’.

IR (thin film): 2954, 2843, 1724, 1672, 1574, 1459, 1384, 1293, 1228, 1119, 1035, 731 cm-1.

1H NMR (400 MHz, CDCl3) : 7.28-6.99 (m, 10H), 6.52 (s, 1H), 6.49δ (s, 1H), 6.47 (s, 1H), 6.41 (s, 1H), 5.84-5.76 (m, 4H), 3.92-3.68 (m, 10H), 3.60 (d, J = 14.2 Hz, 1H), 3.57 (d, J = 2.5 Hz, 1H), 3.33 (d, J = 14.1 Hz, 1H), 3.18 (d, J = 14.1 Hz, 1H), 2.82 (s, 3H), 2.67 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.04-1.09 (m, 18H), 1.05 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H), 0.80 (t, J = 7.1 Hz, 3H).

13C NMR (101 MHz, CDCl3) : 172.7, 172.4, 169.2, 168.2, 155.9,δ 153.9, 148.4, 147.1, 146.7, 1431, 141.3, 139.5, 138.3, 138.2, 136.3, 127.4, 127.3, 127.1, 126.8, 126.8, 126.1, 108.5, 107.3, 106.9, 103.7, 103.7, 100.4, 100.2, 99.5, 99.0, 70.9, 69.9, 61.6, 60.5, 60.4, 59.9, 58.7, 58.3, 45.7, 45.7, 43.3, 42.2, 42.1, 41.4, 34.6, 33.9, 33.0, 31.4, 30.1, 29.8, 25.3, 24.8, 24.5, 23.1, 17.6, 17.4, 14.4, 14.3, 13.5.


Funding InformationWe are grateful to the EPSRC (EP/M02622/1, C.R.J. & P.T.; EP/K000128/1, R.C.-O.), Ramsay Memorial Trust (C.R.J.), China Scholarship Council (W.S.) and the RSC Research Fund for financial support.

AcknowledgmentWe thank the UK National Mass Spectrometry Facility at Swansea University.

Supporting InformationYes

Primary DataNo

References

(1) See selected reviews on DHPs and references therein: (a) Wan, J.-P.; Liu, Y. RSC Adv. 2012, 2, 9763. (b) Singh, S. K.; Sharma, V. K. Curr. Org. Chem. 2014, 18, 1159. (c) Sharma, V. K.; Singh, S. K. RSC Adv. 2017, 7, 2682.

(2) Hantzsch, A, Justus Liebigs Ann. Chem. 1882, 215, 1.(3) Selected reviews: (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C.

Acc. Chem. Res. 2007, 40, 1327. (b) Zheng, C.; You, S.-L. Chem. Soc. Rev. 2012, 41, 2498. (c) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621.

(4) Hydride transfer: (a) Abeles, R. H.; Hutton, R. F.; Westheimer, F. J. Am. Chem. Soc. 1957, 79, 712. (b) Wu, Y. D.; Houk, K. J. Am. Chem. Soc. 1987, 109, 2226.

(5) Single electron transfer: (a) Inagaki, S.; Hirabayashi, Y. Bull. Chem. Soc. Jpn. 1977, 50, 3360. (b) Gebicki, J.; Marcinek, A.; Zielonka, J. Acc. Chem. Res. 2004, 37, 379.



(6) Ene reaction: Hamilton, G. Prog. Bioorg. Chem. 1971, 1, 83.(7) Edraki, N.; Mehdipour, A. R.; Khoshneviszadeh, M.; Miri, R. Drug

Discovery Today 2009, 14, 1058.(8) Review of 1,2-DHPs: (a) Silva, E. M. P.; Varandas, P. A. M. M.; Silva,

A. M. S. Synthesis 2013, 45, 3053. Additions to pyridinium species: (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642.

(9) Selected synthetic examples using (a) pre-prepared building blocks: Tejedor, D.; Cotos, L.; Mendez-Abt, G.; García-Tellado, F. J. Org. Chem. 2014, 79, 10655. (b) 1,2-DHP functionalization: Zou, G.-F.; Zhang, S.-Q.; Wang, J.-X.; Liao, W.-W. J. Org. Chem. 2016, 81, 5717. (c) Reductive alkylation of pyridines: Donohoe, T. J.; McRiner, A. J.; Sheldrake, P. Org. Lett. 2000, 2, 3861.

(10) Faruk Khan, M. O.; Levi, M. S.; Clark, C. R.; Ablordeppey, S. Y.; Law, S.-L.; Wilson, N. H.; Borne, R. F. Stud. Nat. Prod. Chem. 2008, 34, 753.

(11) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem. Int. Ed. 2007, 46, 5734.

(12) In situ adduct detection: (a) Rosenthal, R. G.; Ebert, M. O.; Kiefer, P.; Peter, D. M.; Vorholt, J. A.; Erb, T. J. Nat. Chem. Biol. 2014, 10, 50. (b) Sulzbach, R. A.; Iqbal, A. F. M. Angew. Chem. Int. Ed. 1971, 10, 733. (c) Libby, R. D.; Mehl, R. A. Bioorg. Chem. 2012, 40, 57

(13) 2-(Trimethylsilyl)aryl triflate precursors: Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211.

(14) Hexadehydro-Diels-Alder reaction of polyalkynes: Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208.

(15) Recent reviews: (a) Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (b) Hoffmann, R. W.; Suzuki, K. Angew. Chem. Int. Ed. 2013, 52, 2655. (c) Holden, C.; Greaney, M. F. Angew. Chem. Int. Ed. 2014, 53, 5746. (d) Yoshida, S.; Hosoya, T. Chem. Lett. 2015, 44, 1450. (e) Bhojgude, S. S.; Bhunia, A.; Biju, A. T. Acc. Chem. Res. 2016, 49, 1658. (f) Karmakar, R.; Lee, D. Chem. Soc. Rev. 2016, 45, 4459. (g) García-Lo ez, J.-A.; Greaney, M. F. p Chem. Soc. Rev. 2016, 45, 6766. (h) Shi, J.; Li, Y.; Li, Y. Chem. Soc. Rev. 2017, 46, 1707. (i) Idiris, F. I. M.; Jones, C. R. Org. Biomol. Chem. 2017, 15, 9044.

(16) Idiris, F. I. M.; Majeste, C. E.; Craven, G. B.; Jones, C. R. Chem. Sci. 2018, 9, 2873.

(17) (a) Candito, D. A.; Panteleev, J.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14200. (b) Karmakar, R.; Mamidipalli, P.; Yun, S. Y.; Lee, D. Org. Lett. 2013, 15, 1938. (c) Niu, D.; Hoye, T. R. Nat. Chem. 2014, 6, 34. (d) Xu, H.; He, J.; Shi, J.; Tan, L.; Qiu, D.; Luo, X.; Li, Y. J. Am. Chem. Soc. 2018, 140, 3555.

(18) Hetera-ene: (a) Aly, A. A.; Mohamed, N. K.; Hassan, A. A.; Mourad, A.-F. E. Tetrahedron 1999, 55, 1111. (b) Aly, A. A.; Shaker, R. M. Tetrahedron Lett. 2005, 46, 2679. (c) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.; Greaney, M. F. Angew. Chem. Int. Ed. 2012, 51, 1006.

(19) Propargylic ene: Jayanth, T. T.; Jeganmohan, M.; Cheng, M.-J.; Chu, S.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2006, 128, 2232.

(20) Alkene ene: (a) Arnett, E. M. J. Org. Chem. 1960, 25, 324. (b) Simmons, H. E. J. Am. Chem. Soc. 1961, 83, 1657. (c) Friedman, L.; Osiewicz, R. J.; Rabideau, P. W. Tetrahedron Lett. 1968, 9, 5735. (d) Wasserman, H. H.; Solodar, A. J.; Keller, L. S. Tetrahedron Lett. 1968, 9, 5597. (e) Crews, P.; Beard, J. J. Org. Chem. 1973, 38, 522. (f) Garsky, V.; Koster, D. F.; Arnold, R. T. J. Am. Chem. Soc. 1974, 96,

4207. (g) Wasserman, H. H.; Keller, L. S. Tetrahedron Lett. 1974, 15, 4355. (h) Nakayama, J.; Yoshimura, K. Tetrahedron Lett. 1994, 35, 2709. (i) Chen, Z.; Liang, J.; Yin, J.; Yu, G.-A.; Liu, S. H. Tetrahedron Lett. 2013, 54, 5785. (j) Bhojgude, S. S.; Bhunia, A.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2014, 16, 676. (k) Gupta, S.; Xie, P.; Xia, Y.; Lee, D. Org. Chem. Front. 2018, 5, 2208.

(21) Trinchera, P.; Sun, W.; Smith, J. E.; Palomas, D.; Crespo-Otero, R.; Jones, C. R. Org. Lett. 2017, 19, 4644.

(22) See ESI for the preparation of starting materials. (23) Intramolecular cyclization: (a) Aritomi, J.; Nishimura, H. Chem.

Pharm. Bull. 1981, 29, 1193. (b) Hartman, G. D.; Phillips, B. T.; Halczenko, W. J. Org. Chem. 1985, 50, 2423. (c) Hartman, G. D.; Halczenko, W.; Cochran, D. W. Can. J. Chem. 1986, 64, 556.

(24) Intermolecular alkylation: (a) Patterson, J. W. J. Heterocycl. Chem. 1986, 23, 1689. (b) Rimoli, M. G.; Avallone, L.; Zanarone, S.; Abignente, E.; Mangoni, A. J. Heterocycl. Chem. 2002, 39, 1117.

(25) See ESI for more details of nOe correlations.(26) For synthetic approaches to spirocyclic compounds, see selected

reviews and references therein: (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (b) Roche, S. P.; Tendoung, J.-J. Y.; Treguier, B. Tetrahedron 2015, 71, 3549. (c) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Chem. – Eur. J. 2016, 22, 2856. (d)Xie, X.; Huang, W.; Peng, C.; Han, B. Adv. Synth. Catal. 2018, 360, 194. (e) Ding, A.; Meazza, M.; Guo, H.; Yang, J. W.; Rios, R. Chem. Soc. Rev. 2018, 47, 5946.

(27) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett. 2014, 24, 3673.

(28) (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Hayasaka, T.; Kusama, O. J. Chem. Soc. C 1971, 1051. (b) Crews, P.; Beard, J. Org. Chem. 1973, 38, 522. (c) Heaney, H.; Ley, S. V. J. Chem Soc. Perkin Trans. 1 1974, 2693. (d) J. Gingrich, H. L.; Huang, Q.; Morales, A. L.; Jones, M. J. Org. Chem. 1992, 57, 3803.

(29) See Supporting Information for full details; calculations were performed using Queen Mary MidPlus computational facilities supported by QMUL Research-IT.

(30) See Figure S1 in ESI for more details.(31) Perez, P.; Domingo, L. R. Eur. J. Org. Chem. 2015, 2826.(32) See ESI for full details of biological testing.(33) Selected examples of adverse effects: (a) Pabla, N.; Dong, Z. Kidney

Int. 2008, 73, 994. (b) Coletti, D. Eur. J. Transl. Myol. 2018, 28, 7587. (c) Lui, G.; Bouazza, N.; Denoyelle, F.; Moine, M.; Brugières, L.; Chastagner, P.; Corradini, N.; Entz-Werle, N.; Verite, C.; Landmanparker, J.; Sudour-Bonnange, H.; Pasquet, M.; Verschuur, A.; Faure-Conter, C.; Doz, F.; Treluyer, J. M. Oncotarget. 2018, 9, 30883. (d) Helmy, M. W.; Helmy, M. M.; Abd Allah, D. M.; Abo Zaid, A. M.; Mohy El-Din, M. M. J. Physiol. Pharmacol. 2014, 65, 393. (e) Zhang, Y.; Wu, J.; Ye, M.; Wang, B.; Sheng, J.; Shi, B.; Chen, H. Cancer Cell Int. 2018, (f) Kandula, T.; Farrar, M. A.; Cohn, R. J.; Mizrahi, D.; Carey, K.; Johnston, K.; Kiernan, M. C.; Krishnan, A. V.; Park, S. B. JAMA Neurol. 2018, 75, 980. (g) Tsuji, D.; Suzuki, K.; Kawasaki, Y.; Goto, K.; Matsui, R.; Seki, N.; Hashimoto, H.; Hama, T.; Yamanaka, T.; Yamamoto, N.; Itoh, K. Support Care Cancer 2018, doi.org/10.1007/s00520-018-4403-y.

(34) Example with imidazole derivative: Watson, L. J.; Harrington, R. W.; Clegg, W.; Hall, M. J. Org. Biomol. Chem. 2012, 10, 6649.

Biosketches



Weitao Sun graduated in Applied Chemistry from Anhui University in 2013, then moved to University of Birmingham to study Drug Discovery and Medical Chemistry. Weitao joined the group of Dr Chris Jones at Queen Mary University of London in 2015. His PhD research is focused on the reaction of arynes with readily available N-heterocycles.

Piera Trinchera received her Master’s in Biotechnological Sciences from the University of Salento in 2009 and completed her Ph.D. in synthetic organic chemistry under the supervision of Prof. Renzo Luisi at the University of Bari in 2012. She then took up a postdoctoral position in the group of Prof. Andrei K. Yudin at the University of Toronto before moving to London (UK) where she joined the Chris Jones group as a postdoctoral researcher in autumn 2015. Her current research interests include exploiting the reactivity of arynes for the development of new synthetic methodologies.

Nada Kurdi graduated from Queen Mary University of London in 2015, where she conducted her undergraduate research project in the group of Dr Chris Jones. She then joined the Centre for Doctoral Training in Synthesis for Biology and Medicine at the University of Oxford and is currently pursuing a DPhil in the group of Professor Jonathan Burton. Her DPhil research looks at the use of oxidative radical cyclisation reactions and their use in total synthesis

David Palomas graduated in chemistry at the University of Zaragoza (Spain) and obtained his PhD in 2009 at the University of Oviedo (Spain) under the supervision of Professors Jose Barluenga and Jose Manuel Gonzalez. He then moved to Germany to join the group of Professor Manuel Alcarazo at the Max Planck Institute for Coal Research. In 2012 David spent a year as a researcher at the CAT Catalytic Center, a joint research centre of Covestro and the University of Aachen (Germany). In 2013 David joined the group of Dr Mark Crimmin at Imperial College of London. Since 2015 David is a lab manager at Queen Mary University of London where he is in charge of running the teaching laboratories at The School of Biological and Chemical Sciences. His research interests include C-H activation and molecular modelling.

Rachel Crespo-Otero earned her PhD at the University of Havana and the Autonomous University of Madrid supervised by Prof. Luis Alberto Montero (UH) and Prof. Jose Manuel García de la Vega (UAM). In 2010, she joined the group of Prof. Mario Barbatti at the Max Planck Institut for Coal Research (Mülheim an der Ruhr, Germany), where she worked on the application and development of methods to investigate nonadiabatic processes. In 2013, she moved to the University of Bath (UK) for postdoctoral research on metastable materials and water splitting with Prof. Aron Walsh. Since January 2015, she is a Lecturer at Queen Mary University of London. Her research interests include the investigation of excited states and nonadiabatic phenomena at the frontier of Molecular and Materials Sciences.

Saeed Afshinjavid obtained his PhD from the University of Bradford in Medical Engineering in 2010. Since then he has had various positions in the UK as a Lecturer, Course Leader, researcher and Laboratory Manager. As a postdoc researcher at the University of Huddersfield, under the supervision of Dr Farideh Javid, Saeed was involved in cancer research through screening novel compounds on a variety of tumour cell lines. In January 2018, Saeed moved to his current role as a Senior Engineer in the College of Architecture, Technology & Innovation at the University of East London.



Farideh Javid completed her first degree in Chemistry (1st Class Hons) at the University of Tehran, followed by an MSc in Pharmacology from the University of Bradford. She completed a PhD from the University of Bradford in 1999 on the neuropharmacological investigation of drugs- and motion-induced emesis and changes in the gastrointestinal motility. She moved to her current position of Senior Lecturer in Pharmacology at the University of Huddersfield in 2008. Her research interests focus on identifying and investigating the mechanism of actions of novel drugs in cancer pharmacology.

Christopher R. Jones read Natural Sciences at the University of Cambridge (MSci Hons, 2005), where he later joined the group of Dr Martin D. Smith and received his PhD in 2009. He then moved to the University of Oxford as a Junior Research Fellow to work with Professor Timothy J. Donohoe. In 2013 Chris joined Queen Mary University of London where he is currently a Senior Lecturer in Chemistry. In 2015 he was awarded an EPSRC Early Career Fellowship. His research interests are based on the development of new synthetic methodologies, with a particular focus on aryne chemistry.


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