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Accessing the Ene–Imine Motif in 1H-Isoindole, Thienopyrrole, and Thienopyridine Building Blocks

A pathway to a range of diverse heterocycles was developed using a nucleophilic cyclization strategy. Lactams and ene-imines are accessed in a few steps from a common precursor, and these moieties are further elaborated to directly provide pyrroles or pyridines with extended conjugation. Reaction conditions are mild, and a broad range of structural types are available within a few steps.


■ INTRODUCTION
Molecular building blocks possessing discrete conjugated segments that can be combined with other conjugated molecular units in a facile manner are widely utilized in pharmaceuticals 1 and organic electronics. 2 Moieties such as diketopyrrolopyrrole 1 and isoindigo 2 are widely used in the latter field for the synthesis of conjugated small molecules and polymers. 3,4 Despite the many advances using these and similar building blocks, 5 the development of new heterocycles such as lactam 3 and thiophenium salts 4 is a critical factor in learning how to control the properties of organic materials. 6,7 Building blocks containing the ene−imine moiety, as highlighted in Figure 1, are rarely encountered in the literature despite the importance of this fragment in porphyrins 8 and other πextended structures such as BODIPY 5. 9 Our group has an interest in investigating and fine-tuning the electronic properties of conjugated oligomers and small molecules featuring ene−imine conjugation pathways. Accessing heteroaryl building blocks represented by compound 6 would greatly facilitate the incorporation of this fragment into larger, π-extended structures. Our goals therefore include the determination of a facile synthetic pathway to molecular units containing the ene−imine−triflate sequence illustrated in structure 6, use of this unit to make conjugated building blocks with a convenient synthetic handle for further elaboration, and the use of this technology to make rare or unknown heterocyclic structures containing the ene−imine fragment.

■ RESULTS AND DISCUSSION
Our strategy hinges on nucleophilic cyclization reactions between a nitrogen nucleophile and an alkynyl electrophile. For our initial target, isoindole 10a, o-alkynylamide 7a was used (Scheme 1). 10 Incorporation of the triflate handle required first a 5-exo-dig cyclization to lactam 8a, followed by deprotonation and then trapping of the oxygen with a triflating reagent. Although there are a number of interesting metal-catalyzed methods to make the isoindolinone moiety, 11 the cyclization can be carried out using our standard literature procedure, 11f with a mild base, to provide methyleneisoindolinone 8a in excellent yield. In a similar manner, phenyl-appended isoindolinone 8b could also be accessed using this procedure. The 5-exo ring closure is dominant when using benzamides such as 7a−b, with no competition from 6endo cyclization.
However, formation of the triflate synthetic handle in 9 did not proceed smoothly as it was realized that the appended functional group at the exocyclic alkene in isoindolinones 8a− b has a significant influence on the outcome with respect to 1H-isoindoles 10a−e. Attempts to form triflate 9a using NaH to deprotonate the amide and Comin's reagent or NPhTf 2 to trap the oxygen resulted in spot-to-spot conversion on thinlayer chromatography (TLC). 12 In contrast, a number of attempts were made to form triflate 9b from isoindolinone 8b using the same triflation conditions, with little to no conversion in any of the trials. It was found that the use of a 1 M solution of Tf 2 O in dichloromethane (DCM) successfully resulted in the formation of triflate 9b. However, the reaction does not go to completion using these conditions, and the lactam starting material was always present in the reaction mixture. Triflate 9b was found to be highly susceptible to nucleophilic attack by water to cause reversion to the lactam 8b. Instead of purifying and isolating triflate 9b, it was proposed that the most efficient method to access 1Hisoindoles 10 was to cross-couple triflate 9b immediately after its formation from lactam 8b. However, the presence of unreacted lactam resulted in low yields of 10. The triflation was found to be highly solvent dependent, and after testing various solvents, it was discovered that almost complete conversion (90−100%) to the triflate occurred in Et 2 O. This result allowed access to a range of building blocks containing electron-withdrawing and electron-donating groups via reaction at the C−OTf bond.
We chose Sonogashira−Hagihara cross-coupling reactions to test our ability to extend conjugation on triflates 9a−b. Unfortunately, conversion of lactam 8a to heterocycle 10a via triflate 9a was never successful and we cannot confirm that 9a is ever formed. On the other hand, coupling between triflate 9b and a range of arylacetylenes proceeded rapidly; the reactions were generally complete within 5 min. 13 The ene−imine− alkynyl monomers 10b−e were thus formed in yields ranging from 24 to 52% over two steps from 8b. Although the yields were typically moderate, it is worth emphasizing that this methodology is procedurally quite simple. Under the described conditions, the process, including purification by flash chromatography, can be completed in 4−5 h. Ene−imine− alkynyl derivatives 10b−e are very stable in ambient conditions, lasting for months at room temperature with no signs of decomposition. The successful reaction of building block 9b to produce a range of derivatives with varied substitution patterns leads us to believe that other crosscoupling reactions are likely to proceed in as facile a manner.
Our next goal involved determining the generality of our procedure by altering the aryl group appended to the exocyclic olefin, Scheme 2. Cyano-substituted o-alkynylbenzamide 11a was therefore synthesized and cleanly cyclized to isoindolinone 12a. However, formation of the triflate 13a did not proceed as expected and only the starting material was isolated in this case. We theorized that the electron-withdrawing cyanobenzene on the vinyl moiety of 12a negatively affected the nucleophilicity of the oxygen. To test this theory, isoindolinone 12b, with an electron-donating methoxy group, was then synthesized.
This time the triflation proceeded successfully to give methoxy-substituted 13b in 5 min using the same conditions as for cyano-substituted 12a. This result further underlines the sensitivity of this system to small changes in electronics and the difficulty of accessing ene−imine motifs in general.
As push−pull and push−push motifs are frequently targeted in organic electronics, 14 we decided to use methoxysubstituted 13b to make push−pull and electron-rich 1Hisoindoles. Cross-coupling of 13b with 4-ethynylbenzonitrile was successful, resulting in push−pull 1H-isoindole 14b in a 23% yield over 2 steps from 12b. Initial attempts to synthesize dimethoxy-substituted 14c using triflate 13b resulted in the formation of the desired product albeit in low yields. Another building block, tosylate 13c, was therefore targeted for this transformation. 15 This building block exhibited greater stability than triflate 13b and the electron-rich 1H-isoindole 14c was Once we determined a general procedure for obtaining the isoindole derivatives using o-alkynylbenzamides, we set our sights on various pyridine and pyrrole building blocks, Scheme 3, to determine if we could access a broader range of heterocyclic structures. We chose a thiophene backbone, as in 15−16, for this purpose as they are essential building blocks in organic electronics. In general, when switching from a benzene-annulated alkynylamide to a five-membered heterocyclic-annulated alkynylamide such as 15a−b and 16a−b, the 6-endo cyclization has been shown to be more favorable in radical as well as nucleophilic cyclizations. 16 However, our group has recently established that three structural features can be used to control the cyclization process. 17,18 For example, the phenyl substituent in alkynyl amides 16a−b can shift the favorability of the ring-closing reaction toward the 5-exo pathway via a stereoelectronic effect to provide thienopyrrolones 20a−b, which are unusual heterocyclic compounds that are difficult to access via available literature techniques. The amount of steric bulk on the N is the second important feature in controlling the cyclization pathway and could be used to promote formation of the 5-exo product. 18a We propose that when the N is unsubstituted, 6-endo cyclization becomes strongly favored; as the size of the group on the N is increased, so is the likelihood of a 5-exo cyclization. This effect is due to steric interactions between the alkynyl and amide substituents in the transition state, which are more significant in the case of the 6-endo pathway. Further indications of the importance of steric interactions are also noticeable in the E/Z ratio of the isoindolinone, where Z isomers are formed when the N substituent is small; the percentage of the E-isomer increases as the size is increased. 18b Figure S1 in the supporting information demonstrates these concepts. While our investigations of the stereoelectronic and steric effects on the reaction pathways of these cyclizations are ongoing, 19 we Scheme 3. Synthesis of Thiophene Building Blocks 18a−b, 21a−b decided to exploit this steric effect to try to access both 6-endo and 5-exo heterocyclic-annulated products in the present study.
We therefore synthesized t-butyl-substituted amides 15a−b and unsubstituted amides 16a−b using standard techniques. Base-induced cyclization of thiophenes 15a−b successfully resulted in the exclusive formation of the E-isomer of the 5-exo products 19 for both thiophenes a and b in excellent yields. Removal of the t-butyl group using trifluoroacetic acid to give lactams 20a−b proceeded smoothly in moderate to high yields and without the need for chromatography. The triflation/ Sonogashira−Hagihara sequence was then implemented to provide the bicyclic thienopyrroles 21a and 21b in 44 and 42% yields over 2 steps from 20a and 20b, respectively.
To access thienopyridines, cyclization of unprotected 16b resulted in the almost exclusive formation of 6-endo product 17b, while for 16a, a 1:1 mixture of pyridinone 17a and lactam 20a was formed. This latter result reflects our previous study's conclusions that the composition of the heterocyclic backbone is the third important factor in controlling the 5-exo vs 6-endo cyclization pathway. Regardless, isomers 17a and 20a were easily separated by column chromatography, and 17a and 17b were carried onto the triflation/Sonogoshira−Hagihara sequence. Pyridines 18a−b were isolated in two steps in 58 and 53% yield, respectively.
Given the newfound availability of this isoindole building block, we decided to demonstrate its utility by employing it to access π-extended structures. Our initial experiments involved the isoindole 10b, Scheme 4. The silyl group was removed with tetrabutylammonium fluoride (TBAF) and the terminal alkyne carried on to either oxidative coupling or Sonogashira reactions. During these trials, it became clear that the alkynyl handle was not an effective way to incorporate the isoindole group into larger structures.
Decomposition of the deprotected alkyne 10b occurred in both of these preliminary experiments, with no evidence of the formation of extended structures. We found that using the triflate directly proved to be a much more efficient method and we targeted a few structural motifs using the isoindole building block 9b.
To access an ene−imine−ene system, a Sonogashira reaction between triflate 9b and 7c was carried out. Upon work-up and characterization, we were surprised to learn that cyclization to triene 22 had occurred under the conditions of the Sonogashira reaction. Interestingly, NMR spectroscopy shows that the N−H resonance appears at 12.4 ppm, indicating that a six-membered ring hydrogen bonding motif forms between the amide and the pyrrole nitrogen. 20 Compound 22, which features an extended conjugation pathway from vinyl moiety to a lactam carbonyl, is surprisingly stable to photochemical isomerization and thermal decomposition.
Alternatively, an excess of triflate 9b was subjected to Sonogashira conditions in the presence of a 1,4-dialkynylbenzene, Scheme 4. Dimer 23 was formed as an orange-red solid, primarily as the Z,Z isomer. Although dimer 23 could not be purified completely, its identity was confirmed by X-ray crystallography. Remarkably, both extended structures 22 and 23 are stable under ambient conditions and have not been observed to undergo decomposition via reaction with oxygen to form a dioxetane, the primary decomposition pathway of related structures. 21,22 Ultraviolet−visible (UV−vis) spectral analysis was performed for all monomers, Figures 2 and S2. Compounds 10b−10d absorb strongly in the 350−425 nm region. Although the push−pull derivative 14b does show the expected bathochromic shift with a λ max of 430 nm, the molar absorptivity is greatly reduced for both 14b (ε = 4824 L mol −1 cm −1 ) and cyano-substituted 10e (λ max = 399 nm, ε = 2869 L mol −1 cm −1 ). Interestingly, push−push 14c (λ max = 413 nm, ε = 27 840 L mol −1 cm −1 ) is also quite bathochromically shifted but has a large molar absorptivity. In comparison to TIPS-substituted 10b (λ max = 387 nm, ε = 31564 L mol −1 cm −1 ), absorption of thienopyridines 18a and 18b is markedly weaker and 18b is significantly hypsochromically shifted with a λ max of 337 nm (ε = 8796 L mol −1 cm −1 ). This blue-shift is likely due to the reduced conjugation in 18b between the alkyne and the thieno ring, due to the established aromaticity of the pyridine ring. In contrast, pyridine 18a is more highly conjugated due to the thiophene substitution pattern, resulting in a red-shift and a λ max of 386 nm (ε = 3176 L mol −1 cm −1 ). Dyes 21a and 21b possessing the thienopyrrole moiety exhibit similar levels of extended conjugation in comparison to 18a as well as 1H-isoindole monomers 10b−10e. With respect to the emissive properties, the majority of the new compounds made in this study are not fluorescent; notable exceptions include thienopyridines 18a−b and dimer 22, which are weakly emissive (see Figure S3). A full structure activity relationship investigation of the emissive properties of these compounds is ongoing.
Solid-state structural data for the lactam, pyrrole, isoindole, and pyridinyl building blocks was sought out in this phase of our studies to identify intermolecular interactions that could be used to control the organization of organic electronic materials incorporating these building blocks. Fortunately, we obtained single crystals of three of the compounds as shown in Figure 3, using vapor diffusion (EtOAc/hexanes) at room temperature. Yellow crystals of pyrrol-one E-20b were grown. There are two crystallographically independent molecules in the asymmetric unit, although they differ primarily by small differences in the degree to which the vinylic phenyl ring is twisted out of plane, 35 and 40°. The fused thiophene and lactam rings are planar as expected, and similarly to other lactam building blocks such as DPP, intermolecular hydrogen-bonded interactions (N···O distance = 2.846(5)/2.863(5) Å; N···O−C angle = 116.2(3)/ 115.8(3)) are observed between the carbonyl and the N−H to form a dimer. 23 Due to the thiophene ring, S···S contacts are also possible, and are observed in one of the molecules of 20b as shown in Figure 3a, with a S···S distance of 3.296(2) Å, conforming to a classic chalcogen···chalcogen interaction. 24 Crystals of pyrrole 10c were grown, confirming the Z assignment. 25 In contrast to the solid-state structure of pyrrolone 20b, the entire structure is planar, except for some minor twisting of the phenyl moiety appended to the vinyl group. Two intermolecular C−H···π interactions are observed, as labeled in Figure 3b. 26 The solid-state structure of dimer 23, grown as a red crystal, confirms the Z,Z assignment of the exocyclic double bonds. In addition, communication between the end-capping pyrrole units is uninterrupted due to the planarity of the primary conjugation pathway from the exocyclic double bond to the exocyclic double bond. The molecules of 23 are stacked in a herringbone arrangement, Figure 3d, although no π-stacking interactions are observed due to the large distance between the layers and slippage between the molecules in a stack.

■ CONCLUSIONS
In conclusion, we have developed an efficient two-step procedure for an ene−imine building block. This methodology provides access to a variety of heterocycles, including 1Hisoindoles, thienopyrroles, and thienopyridines, in good yields. Additionally, this strategy can also be used effectively and easily to make extended conjugated systems and can be used in a modular fashion to form repeat ene−imine units in large systems. Significantly, we have also shown that steric control of 5-exo vs 6-endo cyclization in thioalkynylamides can provide access to rare and unusual heterocyclic compounds.
Experimental Section. All commercially available reagents were purchased and used as received. All solvents were dried using a Grubbs apparatus prior to use. Tetrabutylammonium fluoride (TBAF) was used at a 1.0 mol L −1 concentration in tetrahydrofuran (THF). Sodium hydride (NaH) was used at a 60% dispersion in mineral oil (mass of dispersion used is reported, with moles of NaH). Trifluoromethanesulfonic anhydride (Tf 2 O) was used at a 1.0 mol L −1 concentration in dichloromethane (DCM). Sonogashira−Hagihara and triflation reactions were performed under N 2 . All other reactions were performed in air. TLC analysis was performed on glass-backed plates (60Å) and flash chromatography was performed on ultrapure flash silica (230−400 mesh size).  When appropriate, silica was deactivated by adding triethylamine (3% by volume) to the appropriate eluent and stirring with silica at rt for 30 min prior to being used for column chromatography. NMR spectra were recorded using a Varian Inova 300 MHz ( 1 H: 299.838 MHz, 13 C: 75.402 MHz) or Varian Unity 400 MHz spectrometer ( 1 H: 399.945 MHz, 13 C: 100.577 MHz) with CDCl 3 referenced at 7.26 ppm ( 1 H) or 77.16 ppm ( 13 C). X-ray diffraction data sets for compounds 10c, 20b, and 23 were collected on a Bruker AXS P4/SMART 1000 diffractometer. IR spectra were recorded using KBr discs on a Nicolet Nexus 470 FTIR spectrometer. UV−visible spectra were recorded on an Agilent 8453 spectrophotometer in CHCl 3 . Emission spectra were recorded at 298 K in CHCl 3 using an Agilent Cary Eclipse Fluorimeter. High-resolution mass spectra were recorded on a Bruker Daltonics spectrometer using electrospray ionization (ESI). Starting materials 2-iodobenzoic acid, 4-bromothiophene-3-carboxylic acid, 3-bromothiophene-2-carboxylic acid, and 4-bromothiophene-3-carboxamide were all purchased from Sigma-Aldrich.
General Sonogashira−Hagihara Procedure (A). One equivalent of aryl iodide was dissolved in a 3:1 mixture of anhydrous THF/Et 3 N. Pd(PPh 3 ) 2 Cl 2 (6−8 mol %) and CuI (6−8 mol %) were then added, and the solution was simultaneously degassed with nitrogen and heated to 55°C. The terminal acetylene (2.5 equiv) was then added to the solution, and the reaction was allowed to stir at 55°C until TLC or 1 H NMR analysis indicated reaction completion. Saturated NH 4 Cl (aq) was added to the solution, and the organic phase was extracted with EtOAc, dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography.
General Sonogashira−Hagihara Procedure (B). One equiv. of aryl bromide was dissolved in a 1:1 mixture of anhydrous DMF:diisopropylamine. Pd(PPh 3 ) 2 Cl 2 (8 mol %) and CuI (8 mol %) were then added, and the solution was degassed with nitrogen and heated to 90°C. The terminal acetylene (2.5 equiv) was then added to the solution, and the reaction was allowed to stir at 90°C until TLC or 1 H NMR analysis indicated reaction completion (5−12 h). Saturated NH 4 Cl (aq) was added to the solution, and the organic phase was extracted with EtOAc, dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography.
General Cyclization Procedure (C). One equivalent of alkynylamide was dissolved in anhydrous THF at rt. The solution was heated to the desired temperature. Tetrabutylammonium fluoride (1.1−3 equiv) was added and the reaction was allowed to stir at the corresponding temperature until TLC analysis indicated reaction completion (5 min−12 h). Saturated NH 4 Cl (aq) was added to the solution, and the organic phase was extracted with Et 2 O, dried over MgSO 4 , and filtered. The solvent was removed under reduced pressure. No further purification was necessary.
General tert-Butyl Removal Procedure (D). One equivalent of tert-butyl-protected thienopyrrolone was dissolved in neat TFA at rt. The solution was stirred until TLC analysis indicated the reaction completion. CHCl 3 was added to the solution, where saturated NaHCO 3 was added until the evolution of CO 2 gas subsided. The organic phase was dried over MgSO 4 , filtered, and solvent was removed under reduced pressure. No further purification was necessary.
General Triflation-Sonogashira−Hagihara Procedure (E). Anhydrous Et 2 O was brought to reflux, followed by addition of one equiv. of lactam. NaH (2 equiv) was added, followed by the immediate addition of Tf 2 O (1.5 equiv). The reaction was monitored by TLC until no further conversion to triflate was observed (about 3 min). The reaction mixture was then extracted with Et 2 O, washed with saturated NaCl (aq) , dried over MgSO 4 , and filtered directly into a two-neck flask containing Et 3 N, Pd(PPh 3 ) 2 Cl 2 (0.06 equiv), CuI (0.06 equiv), and LiCl (3 equiv) were then added. The solution was degassed with N 2 and heated to 55°C. The appropriate acetylene (2.5 equiv) was then added and the reaction was monitored by TLC analysis until all aryl triflate was consumed. Saturated NH 4 Cl (aq) was added to the solution, and the organic phase was extracted with EtOAc, dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography.
General Tosylation-Sonogashira−Hagihara Procedure (F). The lactam (1 equiv) and NaH (2 equiv) were added to a flame-dried and N 2 -backfilled RBF equipped with a magnetic stir bar. Anhydrous acetonitrile (ACN) was added via a syringe, and after 5 min, a solution of TsCl (1.5 equiv) dissolved in anhydrous ACN was added dropwise. The reaction was monitored by TLC analysis until no further conversion to the tosylate was observed (<5 min). The reaction was diluted with Et 2 O, transferred to a separatory funnel, and washed with saturated NaHCO 3(aq) (3×). The organic layer was isolated, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated to near dryness, diluted with a mixture of ACN/TEA (1:1 v/v), and transferred into a flamedried and N 2 -backfilled RBF equipped with a magnetic stir bar, Pd(PPh 3 ) 2 Cl 2 (0.08 equiv), CuI (0.08 equiv), and condenser. The reaction was brought to reflux and the appropriate acetylene (2.5 equiv) was added via syringe. The reaction was monitored via TLC analysis until all of the tosylate was consumed. After completion, the crude was diluted with Et 2 O, transferred into a separatory funnel, and washed with NH 4 Cl (3×). The organic layer was isolated, dried over MgSO 4 , and filtered and solvent was removed under reduced pressure. The crude product was purified by column chromatography.