Article pubs.acs.org/joc
Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives Paul F. Thomson,† Damon Parrish,‡ Padmanava Pradhan,† and Mahesh K. Lakshman*,† †
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York 10031, United States ‡ Naval Research Laboratory, Code 6030, 4555 Overlook Avenue, Washington D.C. 20375, United States S Supporting Information *
ABSTRACT: Palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde with 4-methyl-1-naphthaleneboronic acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes. Corey−Fuchs olefination followed by reaction with n-BuLi led to various 1-(2-ethynylphenyl)naphthalenes. Cycloisomerization of individual 1-(2-ethynylphenyl)naphthalenes to various benzo[c]phenanthrene (BcPh) analogues was accomplished smoothly with catalytic PtCl2 in PhMe. In the case of 4,5-dihydrobenzo[l]acephenanthrylene, oxidation with DDQ gave benzo[l]acephenanthrylene. The dimethoxy-substituted benzo[c]phenanthrenes were demethylated with BBr3 and oxidized to the o-quinones with PDC. Reduction of these quinones with NaBH4 in THF/EtOH in an oxygen atmosphere gave the respective dihydrodiols. Exposure of the dihydrodiols to N-bromoacetamide in THF-H2O led to bromohydrins that were cyclized with Amberlite IRA 400 HO− to yield the series 1 diol epoxides. Epoxidation of the dihydrodiols with mCPBA gave the isomeric series 2 diol epoxides. All of the hydrocarbons as well as the methoxy-substituted ones were crystallized and analyzed by X-ray crystallography, and these data are compared to other previously studied BcPh derivatives. The methodology described is highly modular and can be utilized for the synthesis of a wide variety of angularly fused polycyclic aromatic hydrocarbons and their putative metabolites and/or other derivatives.
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INTRODUCTION One of the classical methods for the synthesis of compounds containing a phenanthrene moiety is oxidative photocyclization.1−8 In this approach, cis/trans stilbene-like molecules are subjected to photochemical ring closure to yield dihydroaromatic systems, which then undergo oxidation with catalytic I2 and air to yield the fully aromatized final products. The high value of this method has led to improvements in order to attain cleaner reactions and better product yields. The most notable of these improvements are the use of propylene oxide9 or THF10 as sponges for the liberated HI. More recently, C−H bond activation to yield substituted stilbenes, followed by oxidative-photochemical cyclization has been reported, wherein PhI(OAc)2 was used as the oxidant.11 The power of photocyclization chemistry is exemplified in the range of compounds that can be synthesized, and recent reviews provide relevant representative examples.12,13 Despite the broad applicability of the photocyclization approach, there are scenarios in which this method cannot be © XXXX American Chemical Society
readily applied. One case would be the unavailability of appropriate precursors for the photocyclization. Thus, alternative methods have been developed for the assembly of molecules containing a phenanthrene subunit. Some representative examples are cyclization reactions using electrophiles, such as ICl14 and IBF4,15 Pd-catalyzed annulation,16 intramolecular olefin metathesis,17 Friedel−Crafts type reactions of geminal difluoroalkenes in FSO3H·SbF5 (magic acid),18 Rh(II)catalyzed dimerization of carbenes formed from bis tosylhydrazones,19 t-BuOK-mediated intramolecular cyclization of 1(2-methylaryl)-3,4-dihydronaphthalene-2-carbaldehydes in the presence of light,20 intramolecular Diels−Alder reaction of allenyl alcohols obtained by AuCl3-catalyzed rearrangement of homopropargylic alcohols,21 Ru-catalyzed benzannulation processes,22 and Pd-mediated C−H bond-activation and arylation.23 PtCl2, AuCl3, GaCl3, InCl3, as well as designed Pt Received: April 24, 2015
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DOI: 10.1021/acs.joc.5b00931 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 1. Oxidative Metabolism of Polycyclic Aromatic Hydrocarbons and DNA Damage
Scheme 2. Retrosynthetic Analysis of the Proposed Approach
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and Au catalysts have been evaluated for the 6-endo-dig cyclization of o-ethynylbiaryl systems.24−26 The combination of PtCl2/PtCl4 has been reported for hydroarylation-cycloisomerization.27 For studies on the molecular mechanisms of chemical carcinogenesis by polycyclic aromatic hydrocarbons (PAHs), simple and facile routes to the hydrocarbons and their metabolites are necessary. PAHs are products of incomplete combustion of organic matter and are widely distributed in the environment. Because of their ubiquitous presence, they pose a significant health risk. Among this large family of compounds, alternant hydrocarbons possessing a bay or fjord region are particularly important. In mammalian systems, bay- and fjordregion-containing polycyclic aromatic hydrocarbons are metabolically converted to proximate carcinogens, dihydrodiols, by the combined actions of CYP450 and epoxide hydrolase.28 Further oxidation of the dihydrodiols by CYP450 produces four isomeric electrophilic diol epoxides, which then covalently modify DNA. 28,29 Dihydrodiols are also implicated in dihydrodiol dehydrogenase-mediated redox cycles, resulting in the formation of DNA damaging reactive oxygen species and oquinones (Scheme 1).30,31 Substituted chrysenes and benzo[c]phenanthrenes (BcPhs) have been of significant interest in chemical carcinogenesis and access to these ring systems is available by photocyclization of appropriate 1- and 2-styryl naphthalenes, respectively.32−34 Introduction of methoxy substituents into the angular ring then allows for the conversion of the hydrocarbons to their oxidized metabolites, the dihydrodiols and diol epoxides, via oquinones.33−36 Despite the convenience of the photochemical approach, availability of starting materials can be a limitation. Thus, we decided to explore the utility of PtCl2- and AuCl3mediated cycloisomerization of o-ethynylbiaryls as a method to access unusual polycyclic aromatic hydrocarbons and their putative metabolites.
RESULTS AND DISCUSSION
We chose to demonstrate the metal-mediated cycloisomerization approach via the modular synthesis of two remotely functionalized BcPh derivatives as well as their putative dihydrodiol and diol epoxide metabolites. The retrosynthetic analysis is shown in Scheme 2. In fact, this approach has been used for the synthesis of BcPh in a demonstration of the chemistry.24 In the present case, the key would be the identification of suitable building blocks that can be used to modularly assemble various polycyclic hydrocarbon derivatives, which can then be elaborated to the oxidized metabolites. In Scheme 2, either building block could serve as the electrophile in the cross coupling with the other serving as the nucleophile. Because various arylboronic acids and related derivatives are readily available, either commercially or by synthesis, these were selected as the nucleophiles for the cross-coupling step. Thus, 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde were chosen as the electrophilic cross-coupling partners. Whereas the former is commercially available, the latter (a known compound37) can be readily prepared on a multigram scale (Scheme 3). Bromination of 2,3-dimethoxybenzyl alcohol with NBS in THF gave the known 6-bromo-2,3-dimethoxybenzyl alcohol (2),38 which upon oxidation with PCC in CH2Cl2,39 then gave required aldehyde 3. Scheme 3. Synthesis of 6-Bromo-2,3dimethoxybenzaldehyde as a Key Building Block
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DOI: 10.1021/acs.joc.5b00931 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 4. Initial Tests on the in Situ Formation of a Boronate Ester and Cross Coupling
In earlier work,42 similar biaryl aldehydes were elaborated to either oxiranes (reaction with Me2SCH2) or methoxyethenes (reaction with MeOCHPPh3), which upon exposure to suitable Bronsted or Lewis acids underwent cyclization and aromatization to polycyclic hydrocarbons. In the present method, alkynylation was the next step in the sequence. Initially, the Bestmann−Ohira alkynylation was attempted on aldehyde 10. Use of dimethyl-2-oxopropylphosphonate (1.2 molar equiv), p-TsN3 (1.2 molar equiv), and K2CO3 (3 molar equiv), under literature conditions43 led to a 55% isolated yield of the alkyne. The use of NaH caused a drastic reduction in the yield (39%). By comparison, the Corey−Fuchs two-step alkynylation44 gave far superior results (97% yield for the gem-dibromide and 81% yield for the alkynylation, 78% overall). Thus, this became the preferred method to access the requisite cyclization precursors. The overall methodology up to the cyclization step is shown in Scheme 5. Generally, good yields were obtained over two steps leading to alkynyl products 14−17 (56−78%). At this stage, both AuCl3 and PtCl2 were evaluated for the cyclization. Although 5 mol % AuCl3 in PhMe at 80 °C gave 84% yield of dimethoxy BcPh 18, the yield of analogue 19 with this catalyst was 59%. In contrast, 5 mol % PtCl2 in PhMe at 80 °C gave compounds 18 and 19 in comparable yields of 75 and 72%, respectively. Additional test reactions were conducted on the cyclization of 1-(2-ethynylphenyl)naphthalene. Here, in PhMe at 80 °C, PtCl2 gave a 69% yield of BcPh, which is comparable to the yield reported in the literature,24 whereas AuCl3 gave only 45% yield. On the basis of these results, as well as the hygroscopic nature of AuCl3, PtCl2 appears to be a suitable catalyst. Cyclization of alkynes 16 and 17 with PtCl2 led to BcPh derivatives 20 and 21 in yields of 81 and 69%, respectively. At this stage, we had completed the synthesis of the precursors to the putative oxidized metabolites of 5methylbenzo[c]phenanthrenene (5-MBcPh), 4,5-dihydrobenzo[l]acephenanthrylene (H2B[l]A), and the parent hydrocarbons. As shown in Scheme 6, demethylation of compounds 18 and 19 with BBr3 gave catechols, which were directly converted to o-quinones 22 and 23, respectively, by oxidation with PDC. Both quinones showed characteristic fjord-region quinonoid proton resonances (d, J = 10.5 Hz), which corresponded well with other quinones of BcPh and its derivatives.32e,33,34 Reduction of quinones 22 and 23 with NaBH4 in EtOH, under an oxygen atmosphere,33−35 led to dihydrodiols (±)-24
Because synthesis of biaryls via in situ formation of arylboronates has been reported,40 we initially considered the formation of pinacol boronate esters from aryl halides41 for cross coupling with bromo aldehyde 3. Along these lines, initial experiments were conducted on 1-bromonaphthalene as a representative example (Scheme 4). Reaction of 1-bromonaphthalene (4) with bis(pinacolato)diboron was performed using PdCl2(dppf)/KOAc in DMF at 80 °C, followed by cross coupling with aldehyde 3 as per the literature.41 Although product 6 could be obtained in respectable 79−86% yields, extensive and repeated column chromatography was necessary to obtain pure product. Thus, this approach was discontinued. The more traditional cross coupling of boronic acids was then considered. 4-Methyl-1-naphthaleneboronic acid (7) and acenaphthene-5-boronic acid (8) were selected for further elaboration to the respective hydrocarbons as well as the putative metabolites. Although both boronic acids are commercially available, they are relatively expensive. Hence, these were prepared by lithiation of commercially available 1bromo-4-methylnaphthalene as well as 5-bromoacenaphthene, followed by reaction with B(OMe)3, and hydrolysis (89% yield of compound 7 and 77% yield of compound 8). Each boronic acid was cross coupled with the bromo aldehydes 3 and 9 using Pd(PPh3)4 and CsF in DME at reflux. The product structures and yields are summarized in Table 1. Table 1. Products of the C−C Cross Coupling and Yields
Scheme 5. Synthesis of the Various Polycyclic Aromatic Hydrocarbons
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DOI: 10.1021/acs.joc.5b00931 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Scheme 6. Synthesis of the Dihydrodiols and Diol Epoxides of 5-MBcPh and H2B[l]A
in Figure 1). This was further supported by the additional weak interaction between H-1 and H-4. Similarly, and as compared to compound (±)-26, in diol epoxide (±)-27, interaction between H-9 (δ 4.83 ppm) and H-11 (δ 3.90 ppm) and a weak interaction between H-9 and H-12 (δ 4.45 ppm) were observed (see the Supporting Information for spectra). From a conformation standpoint, in the absence of unusual factors, bay-region series 1 diol epoxides of polycyclic aromatic hydrocarbons generally exhibit a quasidiaxial arrangement of the hydroxyl groups, and in the series 2 isomers, these are quasidiequatorial.28c Typically, series 2 diol epoxides, with quasiequatorial hydroxyl groups, are tumorigenic, whereas the series 1 isomers are not.28,29 In the case of BcPh, both series 1 and series 2 diol epoxides exhibit quasidiequatorial hydroxyl groups due to steric buttressing in the fjord region of the hydrocarbon.47 Correspondingly, this has important implications on the biological activity, and the (+)-series 1 BcPh diol epoxide enantiomer showed high tumor-initiating ability in the mouse skin model.48 It would therefore be instructive to compare the conformational preferences of the various diol epoxides synthesized to date that contain the BcPh scaffold (Figure 2). We have not previously synthesized the series 1 diol epoxide from DMBcPh because of complications related to the P/M helicity elicited by its dihydrodiol.33 However, we have synthesized both series 1 and 2 diol epoxides of DFBcPh.34 In comparison to the series 1 diol epoxide of BcPh, the corresponding diol epoxide from DFBcPh shows a significantly smaller coupling constant between the carbinol protons (Figure 2), indicative of a predominantly diaxial orientation of the hydroxyl groups in the latter (the coupling constant between the carbinol protons for the BcPh series 1 diol epoxide in acetone-d6 is comparable to that in DMSO-d634). This difference between the two hydrocarbons is likely due to the extreme out-of-plane distortion of DFBcPh.34 The series 1 diol epoxide of benzo[ghi]fluoranthene (B[ghi]F), a compound that is expected to be more planar than both BcPh and DFBcPh, surprisingly, also shows a much smaller coupling constant between its carbinol protons (J = 2.1 Hz),49 identical to that observed with DFBcPh. By contrast, the hydroxyl group conformation in the series 1 diol epoxides of both 5-MBcPh [(±)-26)] and H2B[l]A [(±)-27)] are comparable to that in BcPh. Evaluation of the series 2 diol epoxides (Figure 2) shows a general uniformity in the hydroxyl group orientation, which are quasidiequatorial, with the carbinol coupling constants in the 8.0−8.7 Hz range. Remarkably, the more planar B[ghi]F as well as the highly nonplanar DFBcPh and DMBcPh diol epoxides have comparable conformations (diastereomeric P and M
and (±)-25, respectively. Diastereoselective conversion of the dihydrodiols to the diol epoxides, based upon literature procedures,45 depends upon the trans hydroxyl groups being predominantly diequatorial. Thus, the conformations of dihydrodiols 24 and 25 were evaluated by 1H NMR spectroscopy. In both cases, the hydroxyl groups were predominantly diequatorially disposed as indicated by the >11 Hz coupling constant between the carbinol protons in acetone-d6. This is comparable to the coupling constant observed for the carbinol protons in BcPh (J = 10.8 Hz in CD3OD)46 and the 1,4-difluoro derivative (DFBcPh, J = 11.0 Hz in acetone-d 6 ). 34 Unlike the dihydrodiol of 1,4dimethylbenzo[c]phenanthrene (DMBcPh),33 compounds 24 and 25 did not demonstrate P and M hydrocarbon helicity, and these were similar to dihydrodiols of BcPh and DFBcPh. Exposure of dihydrodiols 24 and 25 to N-bromoacetamide (NBA) in THF-H2O gave the respective bromotriols in 97 and 95% yield. Cyclization of the bromotriols to the series 1 diol epoxides (±)-26 and (±)-27 was accomplished with the hydroxide form of Amberlite IRA 400. Yields in the epoxidation step were 64% for 26 and 60% for 27. Synthesis of the series 2 diol epoxides was accomplished by exposure of the dihydrodiols to mCPBA in dry THF. Thus, (±)-24 gave (±)-28 in 69% yield and (±)-25 gave (±)-29 in 80% yield. NOESY spectra for the series 1 diol epoxides (±)-26 and (±)-27 were evaluated to support the relative stereochemistry (Figure 1). For compound (±)-26, NOESY cross peaks
Figure 1. NOESY correlations between protons leading to assignments (dashed blue lines) and relative stereochemical arrangement of substituents (green ovals).
between the resonance at δ 4.82 ppm and the upfield resonance of the ABq at δ 7.96 ppm led to the unequivocal assignment of the former resonance as H-4. The doublet at δ 4.36 ppm was assigned to H-1 on the basis of its NOESY cross peak with the doublet at δ 9.19 ppm (H-12), which was coupled to a proton that produced a triplet resonance. The rest of the tetrahydrobenzo protons were easily assigned on the basis of their coupling constants. In diol epoxide (±)-26, the relative stereochemistry of H-2 (δ 3.95 ppm) and H-4 (δ 4.82 ppm) was cis based on the NOESY interaction (shown in green ovals D
DOI: 10.1021/acs.joc.5b00931 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry
Figure 2. Various diol epoxides having the BcPh structure and the coupling constants of their carbinol protons.
Scheme 7. Synthesis of Benzo[l]acephenanthrylene and the Structures of the Related Hydrocarbons Cholanthrene and Cyclopenta[c,d]pyerene
Figure 3. Crystal structures of several of the synthesized BcPh derivatives.
helical dihydrodiols from DMBcPh have very similar carbinol coupling constants33). From this evaluation it appears that, among the BcPh analogues, conformations of the series 1 diol epoxides have a greater dependence on subtle differences in molecular structure, whereas the series 2 diol epoxides appear generally independent of it. Because we have synthesized H2B[l]AP (21 in Scheme 5), an isomer of the carcinogen cholanthrene,50 we decided to dehydrogenate compound 21 to benzo[l]acephenanthrylene (B[l]AP, 30). Compound 30 is related to cyclopenta[c,d]pyrene, a powerful mutagen and carcinogen.51 Exposure of BcPh derivative 21 to DDQ in PhMe at 80 °C gave B[l]AP (30) in 72% yield (Scheme 7). Compound 21 has previously been synthesized in 24−42% yields via a Wittig reaction/ photocyclization approach starting from 1-indanone.52 By comparison, the three-step yield of 21 obtained herein was 36%. A marginally better yield (by 12%) was obtained for the conversion of H2B[l]AP (21) to B[l]AP 30 as compared to the literature.52
To gain greater insight into the new hydrocarbons synthesized, we undertook X-ray crystallographic analysis. Figure 3 shows the structures of 5-MBcPh (20), H2B[l]AP (21), B[l]AP (30), as well as the two dimethoxy compounds 18 and 19. From these structures, the molecular distortion in BcPh derivatives 18−21 is clearly evident, but compound 30 is significantly more planar. Table 2 provides quantitative data on the plane angles between the four aromatic rings of BcPh, 1,4-DFBcPh, 1,4DMBcPh, 5-MBcPh, H2B[l]AP, B[l]AP, as well as the two methoxy derivatives 18 and 19. As can be seen from the A−D plane angles of the unsubstituted hydrocarbons in this table, nonplanarity decreases in the order 1,4-DMBcPh > 1,4-DFBcPh > BcPh > 5-MBcPh > H2B[l]AP > B[l]AP. What is perhaps surprising is that a remote substitution, namely a methyl group at the C-5 position of BcPh, actually produces a decrease in overall nonplanarity of the BcPh structure by ∼3°. The ethylene bridge in H2B[l]AP causes a further flattening of the molecule, and finally, B[l]AP is only distorted by ∼2°. The A−B plane E
DOI: 10.1021/acs.joc.5b00931 J. Org. Chem. XXXX, XXX, XXX−XXX
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The Journal of Organic Chemistry Table 2. Crystallographically Determined Plane Angles in BcPh and its Analoguesa
a
Data for BcPh, DFBcPh, and DMBcPh were obtained from refs 33 and 34.
quinone, trans dihydrodiol, as well as the series 1 and series 2 diol epoxides, which are of biological interest. In the context of the potential biological properties of these new compounds, the conformational preferences of the newly synthesized series 1 and series 2 diol epoxides have been compared to known data from other related BcPh derivatives. In addition, we have comparatively assessed the crystallographically derived molecular structures of the new compounds, as well as those previously reported. We anticipate the utilization of these new compounds for metabolism and DNA binding studies, and on the chemical side, we expect that the methodology will draw broad interest in organic synthesis approaches.
angles in BcPh, 1,4-DFBcPh, and 1,4-DMBcPh are in the 10− 12° range. Remote functionalization reduces this angle to
