Azulene Functionalization by Iron-Mediated Addition to a Cyclohexadiene Scaffold

The functionalization of azulenes via reaction with cationic η5-iron carbonyl diene complexes under mild reaction conditions is demonstrated. A range of azulenes, including derivatives of naturally occurring guaiazulene, were investigated in reactions with three electrophilic iron complexes of varying electronic properties, affording the desired coupling products in 43–98% yield. The products were examined with UV–vis/fluorescence spectroscopy and showed interesting halochromic properties. Decomplexation and further derivatization of the products provide access to several different classes of 1-substituted azulenes, including a conjugated ketone and a fused tetracycle.


■ INTRODUCTION
Azulene is a bicyclic nonalternant aromatic hydrocarbon, isomeric with naphthalene. The π-electrons of azulene are polarized toward the five-membered ring, resulting in a relatively large inherent dipole moment and a deep blue color. 1 Their unusual electronic properties make azulenes interesting as photocatalysts 2 and colorimetric indicators 3 and for optoelectronics such as solar cells, 4 photoswitches, 5 and organic electronics. 6 Azulene derivatives have also found use in medicine in the form of antiulcer, 7 antidiabetic, 8 and anticancer 9 agents. The ability to functionalize the azulene scaffold is thus of great interest.
Azulenes are potent nucleophiles for electrophilic aromatic substitution (S E Ar), with the 1-and 3-positions being the most reactive toward electrophiles. 10 Reported methods for derivatizing azulenes include (a) the Michael addition, 11 (b) Friedel−Crafts 11a, 12 and Vilsmeier−Haack reactions, 11a,13 (c) azulene addition to heteroaromatic triflates, 14 and (d) the formation of diazo compounds (Scheme 1). 15 Azulenes are also susceptible to (e) electrophilic halogenations. 10e,16 In addition, cross-coupling reactions have been reported. 17 While these latter reactions are attractive for coupling the azulene to sp 2 -and sp-carbons, they generally rely on the use of precious metal catalysts and require prefunctionalization of the azulene skeleton.
Another class of electrophile that could potentially react with nucleophilic azulenes are cationic η 5 -iron carbonyl dienyl complexes (Scheme 2). Such complexes are capable of reacting with a wide range of nucleophiles to form new carbon−carbon or carbon−heteroatom bonds. 18 Nucleophilic addition proceeds in a highly selective manner at the opposite face to the iron carbonyl moiety and at one of the ends of the conjugated system. 18b, 19 Substituents on the cation can act to direct the nucleophilic addition to either termini of the dienyl system; electron-withdrawing groups will generally favor addition in the meta position, while electron-donating groups will often favor the para or ipso addition. 20 The cationic complexes can be formed via hydride abstraction (Scheme 2, path a) or by acid treatment of a complex possessing a leaving group (Scheme 2,path b). Once formed, the complex can be isolated as a shelf-stable fine powder. 42 Aromatic nucleophiles that can react with cationic iron carbonyl dienyl complexes include furan, 21 indole, 21,22 aniline, 23 and oxygenated arenes. 24 The scope was recently increased by us to include the selective C-or O-addition of phenolic nucleophiles. 25 Although azulenes, with a nucleophilicity similar to that of indoles, 10d can be expected to be efficient nucleophiles, no previous report of their use in this context has been reported. Herein, we present a convenient iron-mediated electrophilic C−H functionalization of azulenes (Scheme 1). The products of this process are valuable in two contexts. First, they are stimuli-responsive substances with multimodal outputs (colorimetric, fluorescence, and infrared spectroscopic). Second, they are versatile substrates for further synthetic transformations such as cyclizations. The cyclohexadiene also constitutes a proaromatic substituent, which may be readily converted to a phenyl ring, giving a formal product of azulene electrophilic arylation, for which there is no direct S E Ar equivalent.

■ RESULTS AND DISCUSSION
To investigate if azulenes could react with cationic iron carbonyl dienyl complexes, we selected guaiazulene 1 as the nucleophile, due to its low cost and availability from natural sources. As the electrophile, we selected iron complex 2, which we have used in earlier studies. 25 Optimization of the reaction conditions for this addition was then performed (Table 1).
In our previous studies involving phenolic nucleophiles, we performed the reaction in ethanol in the absence of base at an ambient temperature. 25 Similar conditions here afforded the desired addition product 3, albeit in a modest yield (Table 1, entry 1). Using water as the solvent afforded a heterogeneous reaction mixture where both guaiazulene and iron complex 2 were insoluble. Nevertheless, the yield was increased to 72% (entry 2). To investigate if solubility issues might play a role in limiting the yield, the reaction was performed in a 3:1 mixture of acetone and water, resulting in an enhanced yield of 85% (entry 3). Adding an amine base such as triethylamine (Et 3 N) was not beneficial, neither for methyl acetate as the solvent (entry 4) nor for acetone (entry 5). A near-quantitative yield could, however, be attained using acetone with sodium bicarbonate as the base (entry 6). This last protocol thus provides a set of green and benign reaction conditions for the addition reaction.
Azulene itself possesses two nucleophilic carbons, and a mixture of mono-and disubstituted products is thus to be expected. To see if azulene could be selectively functionalized to form either one of these products, the reaction was first performed using a slight excess of complex 2 relative to azulene. This afforded an equimolar mixture of the diastereomeric disubstituted azulenes 4 and 4′ in an 81% yield (Scheme 3). Using a large excess of azulene instead, a mixture of mono-and disubstituted products was formed, where the monosubstituted product 5 could be isolated in a yield of 48%.
The scope of the transformation was then explored further. In addition to the activated complex (2), electronically neutral 6 and deactivated complex 7 were also selected for evaluation as electrophiles in the reaction (Figure 1).
Azulenes with extended π-systems are of interest for optoelectronic applications, as the properties of azulene can be tuned by extension of the conjugated system. 4c Routes to  a Products are racemic with the relative stereochemistry shown. b Isolated yields. c Excess of 2 (2.2 equiv), 4 equiv NaHCO 3 . d Excess of azulene (5 equiv), 2 equiv NaHCO 3 . functionalizing these types of motifs could thus be valuable. A selection of 1-substituted azulene nucleophiles (8)(9)(10)(11)Figure 2), as well as a 6-substituted azulene (12), was prepared and explored in reactions with iron complexes 6 and 7.
Azulene is significantly more expensive than guaiazulene. As nucleophiles 8−11 were prepared from azulene itself, they were used as the limiting reagent in the ensuing reactions. The results of their reaction with electrophiles 6 or 7 are shown in Scheme 4. Treating 1-phenylazulene 8 with 1.1 equiv of iron complex 6 resulted in the formation of 13 in an excellent yield of 95%. The less activated iron complex 7 was equally effective with the same nucleophile, resulting in 94% of adduct 14. Azulene 9, with a thienyl functionality, reacted with 6 to form compound 15 in a 73% yield. No other coupling products were detected, indicating that the thiophene unit does not compete with azulene as a nucleophile in this case. Azulene 10, with a pendant alkyne group, and formylated azulene 11 afforded adducts 16 and 17 in 70 and 50% yields, respectively. These products contain functional handles, which can be utilized for further derivatization. As in the case of azulene, 6-phenylazulene 12 possesses two nucleophilic sites and could be doubly alkylated using an excess of the cationic iron complex 6, giving rise to an equimolar mixture of diastereomers 18 and 18′ in an 83% yield.
Naturally occurring guaiazulene (1) is an FDA-approved additive in cosmetics. 26 Being a large-scale commercial product, it is inexpensive and readily available and therefore of special interest for synthetic applications. In addition to guaiazulene itself, seven guaiazulene derivatives (19−25) with different substitution patterns on the five-membered ring were prepared to be used as nucleophiles in the addition reaction. Substituents included both electron-withdrawing and electrondonating groups, along with some potentially useful synthetic handles in the form of a boronic ester or a halogen ( Figure 3).
Addition of the guaiazulene nucleophiles 1 and 19−25 was performed using the optimized conditions shown in Table 1. The results are summarized in Scheme 5. Addition of guaiazulene itself to electrophilic iron complex 2 proceeded to give addition product 3 in an excellent yield of 97%. Complexes 6 and 7 were less reactive, but upon extending the reaction time from 4 to 16 h, alkylated azulenes 26 and 27 were obtained in yields of 98% and 93%, respectively. A deactivating effect was seen for the more electron-deficient 1formyl-substituted guaiazulene derivative 19, where compound 28 was produced in a 56% yield. The coupling reaction proved to be sensitive toward substituents in the 2-position of the guaiazulene scaffold. Guaiazulene derivative 20, with a boronic ester in the 2-position, reacted with iron complex 2 to produce 29 in a 43% yield. 2-Iodoguaiazulene (21) reacted sluggishly, but a 63% yield of 30 could be attained using a reaction time of 16 h and an excess of cation 2. The bromo-substituted guaiazulene 22 showed a higher reactivity, resulting in 79% of product 31 under the standard reaction conditions, with a 4 h reaction time. This suggests that steric factors may influence the reaction outcome in the case of 2-substituted azulenes. No reaction occurred with the tolyl-substituted derivative 23. For the coupling with 2-aminoguaiazulene (24), competing Naddition is a possibility. 23 The reaction was unsuccessful, however; while all starting material was consumed, neither Cor N-addition product could be isolated. To investigate if this reaction outcome was linked to instability introduced by the amino group, compound 24 was acetylated to amide 25 and the latter was subsequently used in a coupling reaction. While 1 H NMR analysis of the crude product looked promising, no product could be isolated in this case.
In our previous research on phenolic nucleophiles, we developed a shorter route for the coupling reaction starting from neutral iron cyclohexadiene complexes. 25 This method foregoes the formation and isolation of the cationic iron carbonyl complex by forming the electrophile in situ from a neutral precursor using a catalytic amount of acid. We applied this strategy here and found that guaiazulene could be alkylated directly from the neutral iron complex 32 (precursor to cationic complex 2) in the presence of tetrafluoroboric acid (Scheme 6). When a catalytic amount of acid was used, only a small amount of product was formed. Upon increasing the amount of tetrafluoroboric acid to 1.1 equiv, however, the desired addition product 3 was obtained in an 86% yield. Using an excess of acid (2 equiv) lowered the yield to 45%, which may be due to protonation of guaiazulene, reducing its nucleophilicity. The 86% yield obtained under the optimal conditions is higher than the combined 76% yield obtained when preforming the complex, 25 followed by the addition of guaiazulene, opening up for a shorter synthetic path. As the isolation of the cationic complex includes precipitation using large amounts of solvent, this variant of the reaction can significantly reduce the amount of waste created in the synthesis of products such as 3.
Iron carbonyl complexes are of interest as bioprobes, 27 indicating that the azulenes formed in this study could be useful in their own right. In addition to a strong and distinctive absorption in the IR region from the iron carbonyl moiety, the azulene fragment introduces both a fluorophore and a clearly visible colorimetric indicator, thus potentially allowing multimodal chemical sensing. Accordingly, we investigated the UV− vis, fluorescence, and IR spectroscopic properties of a representative selection of the novel compounds reported here.
Azulene derivatives are known sometimes to exhibit halochromism, i.e., to undergo changes in color upon protonation (at the azulene-1-or 3-position). 28,29 Compounds 4/4′, 14, 26, 33, and 34 were assessed for their colorimetric responses to trifluoroacetic acid (TFA). Exposure to excess TFA (1000 equiv) resulted in each case in a color change discernible to the naked eye ( Figure S67, see the Supporting Information (SI)), which became more pronounced when TFA was used as cosolvent ( Figure 4). UV−vis absorption spectra of the neutral and protonated azulenes were also acquired ( Figure S68). The relationship between azulene substitution pattern and halochromism has been studied and a trend can be determined. It has been shown that for some strongly halochromic azulenes with a particular substituent at the 2-or 6-position, moving the substituent to the 1-or 3position may significantly attenuate the halochromic response. 28b−g This may be due to the change in connectivity resulting in a different preferred site of protonation. The tricarbonyliron(diene)-substituted azulenes 4/4′, 14, and 26 exhibit pronounced halochromism regardless of the fact the substituents are at 1-and 3-positions of the azulene core. This suggests that in 4/4′, 14, and 26, the azulene core remains the preferred site of protonation, as opposed to the tricarbonyliron(diene) motif.
It is known that for many azulenes, protonation can induce a significant fluorescence turn-on response, 30 whereas fluorescence properties of tricarbonyliron(diene) complexes have been studied only rarely. 27a Exposure to UV irradiation is an established method of cleaving Fe−C bonds in tricarbonyliron-(diene) complexes (see below), but the reaction time required for this process is >3 orders of magnitude greater than the acquisition time for a fluorescence spectrum (days vs seconds). On the basis of this semiquantitative consideration, we reasoned that fluorescence spectra could nevertheless be acquired. Compounds 4/4′, 14,26,33, and 34 were all found to exhibit significant fluorescence enhancement upon addition of TFA, with 4/4′ showing the greatest turn-on response (λ ex = 266 nm, λ em = 336 nm; Figure 5), and our current findings show that the tricarbonyliron(diene) motif does not quench the fluorescence of the pendent azulenium fluorophore. A titration of azulene 4/4′ with TFA was also performed, monitored by UV−vis and fluorescence spectroscopy ( Figures S69 and S70). A weak second emission maximum was observed at higher acid concentrations, implying a possible further reaction under these conditions. Iron carbonyl diene complexes exhibit strong vibrational absorption bands in the 2100−1800 cm −1 region, a window where most biological media are transparent. 27a,31 This makes them interesting in applications such as bioimaging using mid-IR and Raman spectroscopy. 31b Iron carbonyl diene complexes substituted with fluorescent coumarin moieties have been suggested as IR-fluorescent probes, 27a and we therefore envision that the azulene-functionalized iron carbonyl complexes could be useful for similar applications. The IRabsorption spectra of the azulene addition products were measured using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) in the neat state. As expected, characteristic strong peaks in the 2100−1900 cm −1 region were observed for all products possessing the iron carbonyl moiety.
To increase the synthetic utility of the formed products, we investigated the oxidative removal of the iron carbonyl moiety. Several methods have been developed for this transformation, where strong oxidative conditions are generally used, including the use of hydrogen peroxide in aqueous sodium hydroxide, 32 cerium ammonium nitrate, 33 trimethylamine N-oxide, 34 or cupric chloride. 35 Initial application of these methods, however, showed that these conditions were too harsh for these compounds, resulting in poor yields, partial degradation of the oxidatively sensitive azulenes, and in some cases partial aromatization of the formed cyclohexadiene. Successful demetallation of the addition products could, however, be achieved by applying mild, photolytic decomplexation conditions, using a modification of a procedure reported by Knolker. 36 Irradiation of an acetonitrile solution of 13 with a low-energy UV light (370 nm, 15 W) for 72 h, in the presence of air, yielded the free diene 33 in a 78% yield (Scheme 7, entry 1). An advantage of the current procedure is that the demetallation can be carried out without the need for specialized equipment. However, it is likely that the reaction time can be significantly shortened with a more powerful light source. Notably, this photolytic decomplexation is more tolerant toward oxidatively labile groups than traditional   The Journal of Organic Chemistry pubs.acs.org/joc Article methods. The free diene could also be liberated without concomitant aromatization. This has previously proved to be difficult for iron complexes possessing an aromatic substituent, which is not conjugated to the diene. 25,37 Photolytic demetallation of the methoxy-substituted adduct 14 instead resulted in the formation of unsaturated ketone 34 in a 74% yield (Scheme 7, entry 2). This type of reactivity is known upon decomplexation of 2-methoxy-substituted iron carbonyl cyclohexadiene complexes 38 and provides access to a different compound class in terms of substituted azulenes. Guaiazulenederived adduct 27 could also be demetallated (Scheme 7, entry 3), affording the unsaturated ketone 35 in a 42% yield. Another product class could be accessed by oxidative aromatization of diene 33 using 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ), producing 1, 3-diphenylazulene (36) in an 82% yield (Scheme 8).
The C-4 methyl group of guaiazulene is acidic. Upon deprotonation, the formed anion is stabilized via conjugation with the electron-poor seven-membered ring. This has been utilized for condensation reactions with aldehydes under basic conditions. 28a, 39 Limited examples of conjugate additions have also been reported in this context. 40 Demetallated guaiazulene derivative 35 possesses an unsaturated ketone moiety in close proximity to the C-4 methyl group, which could allow for an intramolecular conjugate addition. We were pleased to see that the treatment of 35 with t-BuOK in tetrahydrofuran (THF) at 0°C yielded a tetracyclic product 37 in a 39% yield (Scheme 9). A strong nuclear Overhauser effect (NOE) interaction between the two ring-junction protons indicates a cis-fused ring system. The formed tetracyclic compound possesses an unusual 6/6/5/7 ring system, similar to the carbon skeleton of swinhoeisterols, isolated from the marine sponge Theonella swinhoei. 41 Swinhoeisterols have been reported to have cytotoxic properties 41 and have recently been the target of a total synthesis. 42 We therefore envision that tetracyclic structures of this type could be of interest in the synthesis of natural products and bioactive compounds. A photoswitch incorporating guaiazulene and cyclohexene was recently reported by Hecht and co-workers, and compounds such as 35 and 37 may find additional applications in this area. 5

■ CONCLUSIONS
Azulenes are here shown to be competent nucleophiles in the addition to cationic iron carbonyl dienyl complexes with different electronic properties. The reaction proceeds smoothly at room temperature with acetone as the solvent, using an inexpensive base (NaHCO 3 ) as the only additive. Apart from azulene itself, functionalized azulenes with extended conjugated systems, as well as derivatives of naturally occurring guaiazulene, were evaluated as nucleophiles affording the targeted products in a 43−98% yield. Photolytic decomplexation allowed the oxidative removal of iron under mild conditions. The synthetic utility of the formed azulenes was demonstrated via further transformations, including the formation of a tetracyclic product. UV−vis and fluorescence properties of selected products were also explored, displaying some unusual halochromic properties. In conclusion, we believe that the reported methodology provides a valuable new method for azulene derivatization and could find applications in areas such as optoelectronics, sensors, pharmaceuticals, and natural product synthesis.   25 6, 43 and 7 44 (starting from commercial 1-methoxy-1,3-cyclohexadiene, technical grade 65%), and guaiazulene derivatives 11, 45 12, 46 19, 12 20−22, 47 and 23 48 were synthesized according to literature procedures. All other solvents and reagents were purchased from commercial suppliers and used without purification or drying, unless otherwise stated. Photocatalytic decomplexation was performed using a low-energy black light lamp (Velleman lighting, 15 W, 850 lm). Structural assignments were made with additional information from gradient correlation spectroscopy (gCOSY), gradient heteronuclear single-quantum coherence (gHSQC), nuclear Overhauser enhancement spectroscopy (NOESY), and gradient heteronuclear multiple-bond correlation (gHMBC) experiments.
Analytical Methods. Column chromatography was performed on a Biotage Isolera Spektra One with Biotage SNAP KP-sil (silica gel) or KP-C18-HS (C18, reverse phase) columns. NMR spectra, 1 H NMR and 13 C NMR, were recorded on an Agilent 400 MHz (101 MHz for 13 C NMR). The chemical shifts for 1 H and 13 C NMR spectra are reported in parts per million (ppm) using the residual solvent peak for reference. The following abbreviations are used for reporting NMR peaks: singlet (s), doublet (d), triplet (t), quartet (q), heptet (hept), multiplet (m), broad (br), and apparent (app). All coupling constants (J) are reported in hertz (Hz). For diastereomeric mixtures, peaks that can be attributed to single diastereomers are labeled d 1 /d 2 . ATR-FTIR spectra were recorded on a PerkinElmer Spectrum Frontier infrared spectrometer with a pike-GladiATR module and reported in wavenumber (cm −1 ). Melting points were recorded on a Buchi Melting Point B-545. High-resolution mass spectrometry (HRMS) was performed on an Agilent 1290 infinity LC system equipped with an autosampler tandem to an Agilent 6520 Accurate Mass Q-TOF LC/MS. 29a Fluorescence spectra were acquired on an Agilent Technologies Cary Eclipse fluorescence spectrophotometer. UV−vis spectra were acquired on a PerkinElmer Lambda20 Spectrophotometer, using a Starna Silica (quartz) cuvette with 10 mm path length, two faces polished.
General Procedure A: Addition of Guaiazulene-Derived Nucleophiles to Cationic Iron Carbonyl Complexes. Cationic iron carbonyl complex (1.0 equiv), guaiazulene derivative (1.1 equiv), NaHCO 3 (1.5 equiv), and acetone (2.0 mL) were added to a 5 mL microwave vial equipped with a stir bar. The vial was capped and stirred at room temperature for 4 or 16 h. The crude reaction mixture was diluted with diethyl ether (5.0 mL), filtered through a pad of basic aluminum oxide, concentrated under a stream of N 2 gas, and purified by reversed-phase flash column chromatography (MeOH/ H 2 O).
General Procedure B: Addition of Azulene-Derived Nucleophiles to Cationic Iron Carbonyl Complexes. Azulene derivative (1.0 equiv), cationic iron carbonyl complex (1.1 equiv), NaHCO 3 (2.0 equiv), and acetone (1.0 mL) were added to a 5 mL microwave vial equipped with a stir bar. The vial was capped and stirred at room temperature for 5 h. The crude reaction mixture was diluted with diethyl ether (3.0 mL), filtered through a pad of silica, concentrated under a stream of N 2 gas, and purified by flash column chromatography.
Spectroscopic data for all products; NMR assignments and stereochemical elucidation of 37; colorimetric response to TFA and UV−vis/fluorescence spectra for The Journal of Organic Chemistry pubs.acs.org/joc Article selected compounds; and emission spectrum of lamp used for photolytic decomplexations (PDF)