Bicyclo[1.1.1]pentane Embedded in Porphyrinoids

We report a two-step approach to obtain synthetically versatile bicyclo[1.1.1]pentane (BCP) derivatives using Grignard reagents. This method allows the incorporation of BCP units in tetrapyrrolic macrocycles and the synthesis of a new class of calix[4]pyrrole analogues by replacing two bridging methylene groups with two BCP units. In addition, a doubly N-confused system was also formed in the presence of electron-withdrawing substituents at the BCP bridgeheads. The pyrrole rings in BCP containing macrocycles exist in 1,3-alternate or  conformation, as observed from singlecrystal X-ray diffraction analyses and 2D NMR spectroscopy. Bioisosteres are chemical moieties that can be substituted for common functional groups or linkages; for example, bicyclo[1.1.1]pentane offers a linear connection similar to paraphenylene, and this replacement can inhibit usual aggregation and metabolic inactivation in drugs.[1] BCP derivatives are also used as liquid crystals, molecular rotors, and as spacer unit in chromophoric arrays.[2] To meet the increased demand for BCPs in pharmaceutical and material sciences several research groups are developing synthetic protocols for novel BCP building blocks. Most BCP derivatives have been synthesized via ring opening of [1.1.1]propellane followed by multi-step chemical transformation to append functional groups at bridgehead positions.[3] Other popular approaches to derivatize BCP rely on converting the carboxylic acid group (1) into redox-active esters (2) followed by Fe or photoredox cross-coupling reactions (Figure 1a).[4] Despite the current development, practical access to useful BCP building blocks is limited due to lengthy and complex chemical transformation protocols. Since its discovery, Grignard reagents have been extensively used in industrial production.[5] Organomagnesium reagents show high reactivity and their chemoselectivity can be enhanced by transmetalation.[6] To this end, Knochel and coworkers reported a modified synthetic protocol to access 1,3bisaryl substituted BCPs. The authors used a conventional route, including the reaction of [1.1.1]propellane with ArMgX followed by transmetallation with zinc. The Zn derivative undergoes Negishi coupling reactions to access 1,3-bisaryl BCP derivatives.[7] Given the stability of the BCP scaffold towards Grignard reagents, we envisaged that a reaction between alkyl/arylmagnesium halide and dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate can introduce the BCP moiety into organic target molecules in a predictable way. To this end, we treated a variety of Grignard reagents with dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate to yield BCP-dimethanol derivatives. Furthermore, the diols were reacted with pyrrole followed by calix[4]pyrrole synthesis. Calix[4]pyrroles (5-8) are macrocycles containing four pyrrole rings linking via four sp3 carbons (Figure 1b).[8] The replacement of the methylene groups by other organic subunits can modulate the properties of the resulting compounds.[9] In this context, one insertion of BCP units within calix[4]pyrrole macrocycles is attractive with regard to potential 3D interactions in the core.

Bioisosteres are chemical moieties that can be substituted for common functional groups or linkages; for example, bicyclo [1.1.1]pentane offers a linear connection similar to paraphenylene, and this replacement can inhibit usual aggregation and metabolic inactivation in drugs. [1] BCP derivatives are also used as liquid crystals, molecular rotors, and as spacer unit in chromophoric arrays. [2] To meet the increased demand for BCPs in pharmaceutical and material sciences several research groups are developing synthetic protocols for novel BCP building blocks. Most BCP derivatives have been synthesized via ring opening of [1.1.1]propellane followed by multi-step chemical transformation to append functional groups at bridgehead positions. [3] Other popular approaches to derivatize BCP rely on converting the carboxylic acid group (1) into redox-active esters (2) followed by Fe or photoredox cross-coupling reactions (Figure 1a). [4] Despite the current development, practical access to useful BCP building blocks is limited due to lengthy and complex chemical transformation protocols.
Since its discovery, Grignard reagents have been extensively used in industrial production. [5] Organomagnesium reagents show high reactivity and their chemoselectivity can be enhanced by transmetalation. [6] To this end, Knochel and coworkers reported a modified synthetic protocol to access 1,3bisaryl substituted BCPs. The authors used a conventional route, including the reaction of [1.1.1]propellane with ArMgX followed by transmetallation with zinc. The Zn derivative undergoes Negishi coupling reactions to access 1,3-bisaryl BCP derivatives. [7] Given the stability of the BCP scaffold towards Grignard reagents, we envisaged that a reaction between alkyl/arylmagnesium halide and dimethyl bicyclo [1.1.1]pentane-1,3-dicarboxylate can introduce the BCP moiety into organic target molecules in a predictable way. To this end, we treated a variety of Grignard reagents with dimethyl bicyclo [1.1.1]pentane-1,3-dicarboxylate to yield BCP-dimethanol derivatives. Furthermore, the diols were reacted with pyrrole followed by calix [4]pyrrole synthesis.
Calix [4]pyrroles (5)(6)(7)(8) are macrocycles containing four pyrrole rings linking via four sp 3 carbons (Figure 1b). [8] The replacement of the methylene groups by other organic subunits can modulate the properties of the resulting compounds. [9] In this context, one insertion of BCP units within calix [4]pyrrole macrocycles is attractive with regard to potential 3D interactions in the core. HN (b) structures of calix [4]pyrrole derivatives; (c) schematic summary of current work.
We started this study with a reaction of dimethyl bicyclo [1.1.1]pentane-1,3-dicarboxylate (9) and four equiv. methylmagnesium bromide in THF under reflux conditions. The reaction worked well and the desired product 10 was obtained in 44% yield. A similar reaction of ethynylmagnesium bromide with 9 proved more difficult with large amounts of starting material evidenced in the 1 H NMR of the crude reaction mixture. Increasing the equivalents of Grignard reagent slightly improved the yield and 11 was obtained in 13% yield accompanied by traces of 12.
The overall yield of products (11 and 12) remained low in this case. Following, we attempted a reaction of vinylmagnesium bromide with 9, resulting in decomposition of the starting material. Due to the limited success with alkyl magnesium bromides, we employed aryl magnesium bromides for further reactions. Reaction of phenylmagnesium bromide with 9 afforded the quantitative formation of compound 13. To study the scope of the synthetic protocol we synthesized representative derivatives (14)(15)(16) bearing 4-fluorophenyl, 4-methoxyphenyl and 1-naphthyl substituents on the bridgehead position of the BCP moiety. In the case of the 1-naphthyl derivative, 17 was also obtained as a side product (Scheme 1).
Carbinols are suitable precursors for porphyrins [10] and thus reactions of the BCP-biscarbinols with pyrroles were the next target. Initially, treatment of compound 10 with excess pyrrole in the presence of BF3·OEt2 resulted only in degradation of the precursor. A similar result was observed for 11. In contrast, reaction of compounds 13-16 with excess pyrrole in the presence of BF3·OEt2 at RT afforded the compounds 18-26, respectively. Purification of the reaction mixture on column chromatography yielded monopyrroles (18,20,22,25) as major products while dipyrrole derivatives (19,21,23,24,26) were formed in minor quantities. The lower yields were attributed to the poor solubility of the diols 13-16 in pyrrole. Next, a mixture of pyrrole and BCP-diol 13 was dissolved in 1,2-DCE and heated at 90  C in the presence of BF3·OEt2 yielding the dipyrrole derivative (19) as major product (Scheme 2). Similar results were obtained for compounds 14 and 15. The reaction of 16 and pyrrole in the presence of DCE at higher temperature led to the decomposition of starting material and only polypyrroles were identified as products. Therefore, we performed the reaction at room temperature to obtain monopyrrole and dipyrrole derivatives in 45% and 21% yields, respectively.
Notably, treatment of compound 14 with pyrrole in the presence of BF3·OEt2 yielded four compounds: two isomers for each monopyrrole (20 and 22) and dipyrrole derivatives (21 and 23). This is akin to the situation found in N-confused porphyrins. [11] These isomers have distinct Rf values and were separated via routine column chromatography. NMR spectroscopic analysis revealed that the first fraction has two pyrrole rings, and both were attached at the -position, whereas in the second fraction one pyrrole unit has an -linkage and another pyrrole unit is connected via the -position. The third fraction has one pyrrole unit connected via the -position while the fourth fraction contained the pyrrole unit attached via the -position. Compounds 21 and 23 have distinct NMR spectra but the same molecular ion peak in ESI-MS (m/z 601.2263 and 601.2269). The 1 H NMR spectrum of 21 showed one singlet at 7.41 ppm corresponding to both pyrrolic NHs and three sets of pyrrolic CH signals between 5.97-6.79 ppm. Owing to the asymmetric conformation, compound 23 showed five signals corresponding to the six pyrrolic CHs and two singlets for two pyrrolic NHs. A similar NMR profile was reported for Nconfused 5,5-dimethyldipyrromethane. [12] Further, we tested different Lewis acids such as TFA, InCl3, and MgBr2 to catalyze the pyrrole-BCP-diol condensation, leading to a significant decrease in the product yield along with the disintegration of BCP moiety. The first synthesis of calix [4]pyrrole was reported by Baeyer in 1887. [13] Sessler and coworkers discovered the anion detection properties of calix [4]pyrrole in 1996. [14] Since then, calix [4]pyrrole derivatives have been explored as sensors, catalysts, and drug carriers. [8] Taking inspiration from this, we envisioned incorporating the BCP unit into a calixpyrrole-type framework to access a system that was expanded compared to 5-7 and where, akin to their use as bioisosteres the "3D" BCP units could give rise to new binding motifs. [15] A reaction of compound 19 with excess acetone in the presence of TFA gave calix [4]pyrrole[2]BCP 27 in a 65% yield. Compounds 21 and 24 were subjected to similar reaction conditions, yielding calix [4]pyrrole[2]BCP 28 and 29 in 65% and 71% yield, respectively. Despite the progress in nonaromatic porphyrinoid chemistry, N-confused analogues are rarely explored; possibly due to their low yields and tedious purification. To this end, we subjected compound 23 to the reaction conditions given in Scheme 3. This reaction gave two isomers, namely 30 and 31 in 31% and 35% yield, respectively. Compound 30 exhibits two resonances at 1.64 ppm and 1.57 ppm corresponding to meso-CH3 groups while HMBC analysis showed a correlation between two CH3 signals, indicating that both CH3 groups are connected via a three-bond connection ( Figure S43). Furthermore, two methyl groups are connected to two different pyrroles, indicating that this fraction is most likely corresponds to compound 30. As shown in the NOESY NMR ( Figure S44), both NH signals show different types of H-H correlation. The NH resonance at 7.77 ppm shows a correlation with the CH3 group at 1.63 ppm, whereas NH peak at 7.48 shows a correlation with the CH3 group at 1.55 ppm and BCP-CH2 at 1.85 ppm. These correlations indicate that the 1,3-alternate or  conformation of pyrrole units is prominent in solution. Compounds 10-14, 16, 18, 19, 21, and 27 were found to yield diffraction quality single crystals when solutions in CDCl3, CH3Cl, or CH2Cl2 were subjected to slow evaporation. Structural parameter tables and refinement details (Tables S1, S2, and S3) are given in the supporting information. The OH group(s) in compounds 10-14 participate ubiquitously in H-bonding as the dominant intermolecular motif. The relative orientation of the bridgehead-appended groups seems to dictate the pattern of non-covalent interactions, with minimal influence of the BCP unit. [15] In compound 10, the two hydroxyl groups on the BCP scaffold project to the same side of the molecule, forming opposite-facing H-bonding arrangements ( Figure S47). Each hydroxyl group in this structure participates in a four-fold hydrogen bonding arrangement as shown in Figure 2 (D⋯A 2.81-2.87 Å; ∠DHA 160.8°-167.9°); one-dimensional quadruply hydrogenbonded fibers are formed which propagate on the crystallographic b-axis ( Figure 2). The presence of four near-identical molecules in the asymmetric unit is indicative of the unusual packing between these fibers, with an offset of ¼ between adjacent stacks preventing additional translational symmetry from being accessed, as observed previously for bicyclo[3.3.1]nonane-diols. [16] Hydroxyl groups in compound 11 are oriented in an antiarrangement that exhibits intermolecular O-H⋯O (2.8299(12) Å; 175.0(17)°) and alkynyl C-H⋯O (3.2322 (14) Å; 164°) interactions to give a two-dimensional network ( Figure S48). In compound 12, the C=O group of COOCH3 moiety and OH group adopt an anticonformation, resulting in the O-H⋯O interaction at the distance of 2.991(3) Å with an angle of 163(4)° ( Figure 3a). Compound 13, as shown in Figure 3b, displays a synarrangement of hydroxy groups. Due to the bulk of the benzhydryl backbone, this hydroxyl group can only access one available hydrogen bond and exhibits disorder of the proton across this bond. This is best described as a 1:1 disorder, with a second orientation of the H atom (H32B and H33B) not participating in Hbonding. The O-H⋯O distances of 2.994(2) Å (O32) and 2.765(2) Å (O33) indicate that these are on the stronger side of normal O-H⋯O interactions, not the shorter 'symmetrical' interactions observed for the triethylammonium salt of BCP diacid.   Compound 19 has two pyrrole units in place of the hydroxyl groups of compound 13. Pyrrolyl and phenyl groups are disordered about the pseudo-threefold axis of the molecule, which is the threefold axis of the trigonal crystal system. This structure is similar to those observed studying symmetry interplay in bis(trityl)alkynes, with this structure resembling the interactions and packing of the Ph3-C≡C-C≡C-Ph3 compound. [17] Further Xray analysis of compound 21 displayed similar packing and disorder characteristics to 19. Compound 18, with one hydroxyl and one pyrrole substituent, displays hydrogen bonding similar to 13 and pyrrole/phenyl disorder similar to compound 19. The pyrrole and phenyl moieties are disordered around the BCP principal threefold axis; the OH group interacts with an equivalent O-H moiety at the distance of 2.991(3) Å with an angle of 163(4)  . The crystallographically determined structure of macrocycle 27 is shown in Figure 4; this is one of three solvate polymorphs investigated (DCM, chloroform, EtOAc). The macrocycle contains two 1,3-bis(diphenyl(1H-pyrrol-2-yl)methyl)bicyclo[1.1.1]pentane units connected via two dimethylmethylene bridges. In the chloroform-solvated compound, BCP units are arranged at approx. 90° to each other and the angle between pyrrole A and B is 87.50° (Figure 4). Only two of the four pyrrolic NH units point inside the macrocycle. Discounting the BCP linkages, the calix [4]pyrrole exhibits the 1,3-alternate orientation (or  conformation) of pyrrole rings. The conformation of pyrrole and BCP units remained the same under different solvent conditions (Tables S2 and S3); the use of ethyl acetate induced a C-H⋯O interaction (3.268 (14) Å; 147°) between the BCP-CH2 and C=O subunit of ethyl acetate.
In summary, we present a facile and cost-efficient pathway to incorporate BCP building blocks into functional organic materials. BCP derivatives can be rapidly generated with quaternary carbons at the -position by this protocol, essential for pushing medicinal chemistry beyond the aryl plateau. Crystallographic studies of BCP structures indicate superficial similarity to structures with alkynyl linkers and show characteristic interactions arising from the strained CH2 units. Furthermore, for the first time, the incorporation of a rigid scaffold in a porphyrin analogue was achieved, a crucial milestone in understanding the interactions of these carbon motifs with partners localized into the macrocycle core. We are currently exploring the use of these calix [4]pyrrole-type and other BCP-infused systems as molecular receptors with orthogonal selectivity, where supramolecular interaction can lead to further understanding of these cryptic moieties.

General Information
Most reactants were dried under a high vacuum before use. All reactions were performed under an inert atmosphere and carried out in flame or oven-dried glassware using standard Schlenk line techniques. All commercial reagents and anhydrous solvents (THF and acetone) were used as received from suppliers (Acros Organics, Fischer Scientific, Merck and SpiroChem AG). CH2Cl2 and CHCl3 were dried over phosphorous pentaoxide (P2O5). Progress of reactions was monitored by thin-layer chromatography (TLC) carried out on silica gel plates using UV light as a visualizing agent or p-anisaldehyde or KMnO4 with heat as a staining/developing agent. Unless otherwise stated, solutions of inorganic salts are saturated aqueous solutions. Room temperature refers to 20-25 °C.
CDCl3 or DMSO-d6 was used as a deuterated solvent for the NMR spectroscopy. Chemical shifts () are referenced to the residual solvent peak (CDCl3 or DMSO-d6) and given in ppm. The signals in proton NMR were assigned using 2D NMR spectroscopy (NOSEY, HMBC, HSQC). The signal range was used for the multiplets and the median value was reported for the centrosymmetric signals. The following abbreviations were used to describe couplings: d = doublet, t = triplet, m = multiplet, dd = doublet of doublet. The values of coupling constants (J) were given in Hertz [Hz]. The characteristic peaks corresponding to BCP in the 13 C spectrum were assigned with the help of DEPT135 and/or HSQC. As required, ESI mass spectra were acquired in positive or negative modes using a Bruker mircoOTOF-Q II spectrometer interfaced to a Dionex UltiMate 3000 LC. The characteristic fragment and/or molecular ion peaks are indicated with their mass-to-charge ratio (m/z  (9) This compound was synthesized according to the procedure reported by Pellicciari and co-workers. 1 1.00 g (6.405 mmol, 1.0 eq.) of bicyclo[1.

General procedure 1: Synthesis of Grignard's reagent
In a 50 mL Schlenk tube, 1.0 equiv. of magnesium was heated (using a heat gun) and dried under vacuum for 1h.
The vacuum was released followed by argon and anhydrous THF was added to the Schlenk tube. 1.0 equiv. of haloalkanes or haloarenes was dropwise added to the above solution. In a few minutes, a vigorous reaction was initiated, and the reaction mixture was left to stir at rt for 2 h. The obtained grey colored Grignard solution was used without further purification.
The reaction mixture was heated to reflux for 1.5 h. The reaction mixture was poured into ice-cold water. The pH of the mixture was adjusted to 3 using 1 M hydrochloric acid. The organic compound was extracted with DCM (×3). The combined organic layers were washed with saturated NaHCO3 and H2O. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as a light brown oil which solidified over time.
General procedure 3: Synthesis of BCP-dipyrrole derivatives (18-26) A mixture of pyrrole (20 equiv.) and bicyclo[1.  BF3·Et2O (0.048 mL, 0.396 mmol, 1.0 equiv.) was slowly added to the above reaction mixture and left to stir at 90  C for 2 h. The reaction mixture was quenched by the addition of 0.1 N aqueous NaOH (ca. 20-30 mL), and the organic layer was washed with water three times until the pH of the washings was about 7. The organic layer was collected and dried over Na2SO4. After filtration and removal of the solvent on the rotary evaporator, brown viscous oil was subjected to column chromatography. The desired compound was eluted via DCM/hexane.
Single-crystal X-ray diffraction data for all compounds were collected on a Bruker APEX 2 DUO CCD diffractometer by using graphite-monochromated MoKα (λ = 0.71073 Å) radiation (10, 12 and 27) and Incoatec IμS CuKα (λ = 1.54178 Å) (11, 13, 16, 18, 19, 21, and 27) radiation. Crystals were mounted on a MiTeGen MicroMount and collected at 100(2) K, 215(2) K or 296(2) K. Data were collected by using omega and phi scans and were corrected for Lorentz and polarization effects by using the APEX software suite. 2 Using Olex2, the structure was solved with the XT structure solution program, using the intrinsic phasing solution method, and refined against │F│ 2 with XL using least-squares minimization. 3 Hydrogen atoms were generally placed in geometrically calculated positions and refined using a riding model. Details of data refinements can be found in Table S1, S2, and S3. All images were prepared by using Mercury3.7 4 Olex2 3a and CrystalMaker® 5 .

Refinement details for the compound 10
The appearance of four essentially identical molecules in the asymmetric unit was unexpected, however, no solution with additional symmetry converged. A TWIN model (0 0 1 0 1 0 1 0 0 2) was used to account for a-and c-axis confusion, and refined to 6.7%.

Refinement details for the compound 11
Donor hydrogens are located on the difference map and refined using restraints (DFIX).

Refinement details for the compound 13
No special restraints were used on any atoms except the OH protons, which were held to DFIX restraints. The hydrogen atom positions indicated hydrogen bonding to symmetry-related atoms, with refined protons pointing at one another; these were constrained to 0.5 occupancies, with a second proton orientation (0.5 occ.) allowed to refine positionally; this proton could not be observed to form any hydrogen bonding interactions. PART -1 was used to account for disorder over a symmetry element.