Synthetic protocols for the key functionalizations of the photochromic dihydroazulene scaffold

1,8a-Dihydroazulene-1,1-dicarbonitrile (DHA) is a photochromic molecule which upon irradiation undergoes ring-opening to a vinylheptafulvene (VHF). The system has many possible sites for functionalization and hence for tuning of its properties. In this account we summarize different synthetic protocols for attaching substituents at the ring carbon atoms of DHA as well as for replacing the cyano groups at position 1. In particular, positions 2 and 7 are most easily accessed, the latter from DHA by a regioselective bromination-elimination protocol.


Introduction
][3] Photo-and thermo-activated molecular switches are a family of compounds able to switch from one molecular structure to another upon light irradiation or changes in temperature, and whose characteristics depend on the nature of the functional groups that reside on the molecules. 4Thus, a molecule which upon excitation isomerizes to a more energetic metastable isomer, which in time will return to the more stable isomer by releasing energy as heat, may find use in lightharvesting energy storage devices. 3In this context, the dihydroazulene/vinylheptafulvene (DHA/VHF) system 1/2 (Scheme 1), reported for the first time by Daub and co-workers in 1984, 5,6 is particularly interesting.DHA 1 is a yellow photochromic compound, which undergoes a light-induced 10-electron retro-electrocyclization to the red VHF 2. The back-reaction to the parent DHA 1 can be realized by a thermally induced ring-closure and, as recently discovered, by treatment with mild Lewis acids that enhance the rate of the thermal conversion, 7 while it is not induced by light.The rate of the back reaction is strongly solvent dependent, increasing with solvent polarity. 8,9This is in line with a suggested mechanism that involves a zwitterionic transition state, with a positively charged seven-membered ring and a negatively charged malononitrile moiety. 10The longest-wavelength absorption maxima of DHA 1 and VHF 2 are at 353 and 470 nm, respectively, in acetonitrile (Figure 1). 9 In this solvent, the quantum yield of the ring-opening reaction from 1 to 2 is 0.55 8 , and the rate constant for the back-reaction is 5.36 x 10 -5 s -1 . 9It is worth noting that C-8a of DHA 1 is a stereocenter and the DHA hence exists as a pair of enantiomers.[14][15]  The switching event between the two isomers seems to be dependent on the presence of the two cyano groups in position 1; 16,17 besides, modulation of the optical and switching properties © ARKAT-USA, Inc.
of the system can be accomplished by introduction of diverse functional groups either on the five-membered or on the seven-membered ring of the skeleton or on both.Therefore, efficient synthetic protocols that allow easy access to new derivatives substituted at various positions of the original scaffold 1 have been explored and will be the focus of this account.
9][20][21] They are mainly 1-phenyl, 1,1-diphenyl or 1,1-dimethyl-3-phenyl derivatives, and in only one example there was evidence of a photo-switching event (Scheme 2). 20Compound 3 underwent a 1,3-sigmatropic arrangement upon irradiation, furnishing the isomer 4. Upon heating, the original isomer 3 was regenerated.The first procedure for the preparation of DHA skeletons like 1 consisted of a [8+2] cycloaddition reaction between 8-methoxyheptafulvene 5 and the 1,1-dicyanoethylene derivative, obtained by a Knoevenagel condensation between benzaldehyde (R 1 = Ph, R 2 = H) and malononitrile (Scheme 3).Thus, direct formation of DHA 1 (R 1 = Ph) was accomplished by elimination of methanol. 16This strategy suffered from the need of stoichiometric amounts of toxic mercury(II)acetate in the preparation of 8-methoxyheptafulvene 5.An alternative and more versatile route identifies I as a key intermediate in the synthetic pathway.As a matter of fact, I can be prepared either by nucleophilic addition of the enolate of acetophenones to tropylium, followed by a Knoevenagel condensation with malononitrile, 22 or, as later reported, 23 reversing the reaction order (which allows synthesis on a multigram scale), 9 by a Knoevenagel condensation of acetophenones and malononitrile, and then a base-catalyzed nucleophilic addition with tropylium salts.Next, intermediate I can be subjected to oxidation, or first to hydride abstraction and then proton abstraction, giving the VHF derivative, which in turn gives the corresponding DHA by thermal isomerization.
OMe Scheme 3. Possible routes to the DHA skeleton.

Reactivity and Functionalization of the Five-membered Ring of Dihydroazulene
Replacing one or both of the cyano groups on C-1 by esters or amides may have a significant impact on the switching ability.The synthesis of 1-R 1 ,1´-R 2 -DHA derivatives was accomplished by Daub and coworkers following the first strategy described for DHA 1. 17 A [8+2] cycloaddition reaction between 8-methoxyheptafulvene 5 and 6, obtained by Knoevenagel condensation, gave the intermediate 7, which furnished 8 by elimination with phosphorus pentoxide (Scheme 4).The switching properties of 8 and its analogs, however, were not described. 16,17The two different substituents on C-1 introduce a second stereocenter (C-1) in addition to C-8a, and in consequence diastereomeric mixtures of isomers can be formed.
© ARKAT-USA, Inc.Recently, we have shown that DHA 1 can be used as chemodosimeter for thiols, producing a visible color change from orange to yellow that allows detection of sulfhydryl groups in solution. 11Thus, DHA 1 reacts quantitatively with L-cysteine or its methyl ester furnishing DHA 9 (Scheme 5) as a mixture of two diastereomers, where one of the cyano groups at C-1 has reacted with the 1,2-aminothiol moiety of cysteine to give a 4,5-dihydro-1,3-thiazole ring.Albeit efforts to perform the reaction on a preparative scale were not successful in terms of the purification of the single diastereomers, a quantitative transformation seemed to occur, as did a switching event to VHF 10.A very slow conversion back to DHA 9 was observed.Apparently, the 4,5-dihydro-1,3-thiazole ring does not destroy completely the switching ability of the molecule.Functionalization of position 2 on the DHA skeleton has been most extensively explored. 5,6,9- 17,22-28Aromatic groups are the substituents most widely incorporated, but few examples with methyl group on C-2 or cyclopentyl between C-2/C-3 have also been reported. 22As described in the introduction (Scheme 3), the syntheses have followed either: (i) the [8+2] cycloaddition protocol, (ii) the route via nucleophilic addition of acetophenones to tropylium, followed by a Knoevenagel condensation with malononitrile, or (iii) an initial Knoevenagel condensation © ARKAT-USA, Inc.
followed by reaction with tropylium species.The last route was particularly convenient for a multigram synthesis of an iodophenyl-substituted DHA 11 (Figure 2). 23The same procedure was recently employed for synthesis of DHA 1 also in multigram scale. 9The different routes have in common that a substituent group on the phenyl ring at position 2 of the final DHA is present from the beginning in the starting materials.None direct functionalization in this position of the final DHA skeleton is reported.[26] NC CN DHA 11 DHA bearing a iodo substituent, prone to further functionalization.
Functionalization of position 3 has been little explored; a few derivatives are shown in Figure 3. 22,27,28 While the syntheses of 12 and 13 were straightforward, starting from malononitrile by Knoevenagel condensation, 27,28 the 3-methyl derivative 14 was never isolated, because it decomposed to the corresponding cyanoazulene under the reaction conditions. 22 CN Besides, a radical bromination of a VHF skeleton was previously reported by Kuroda and Asao, 29 but no thermal conversion to a DHA form was described.We have recently reported a direct functionalization at C-3 starting from the parent and readily available DHA/VHF system. 30onic and radical bromination were both considered and attempted, as shown in Scheme 6, but only the latter was successful.DHA 1 was treated with aluminum chloride and water to furnish quantitatively VHF 2 (i.e. via a Lewis acid induced ring-opening of DHA). 7When VHF 2 was reacted with bromine at low temperature, a complex mixture was detected, while radical bromination of 2 with N-bromosuccinimide (NBS) and a radical initiator in the presence of light © ARKAT-USA, Inc.
gave the 3-bromo derivative 15 in good yield.The procedure has been successfully applied also to a 2-tolyl DHA starting material to furnish 16 in 95% yield (estimated by NMR) over 3 steps.Interestingly, no evidence of benzylic bromination was registered on the tolyl substrate; the reaction hence shows complete regioselectivity.
Initial attempts of Sonogashira and Suzuki coupling reactions of compound 15 unfortunately failed and the bromide seems very unreactive.It was instead possible to introduce another bromine in position 7 to give a 3,7-dibromo-substituted DHA through a bromination/elimination protocol, which had already been established for DHA 1 itself (vide infra, Section 4). 31

Reactivity and Functionalization of the Seven-membered Ring of Dihydroazulene
Recently, we reported the first direct and regioselective functionalization of the seven-membered ring of DHA 1. [31][32][33][34] It consists of a sequential bromination/elimination protocol, which furnished selectively the 7-bromo DHA 17 starting from DHA 1 (Scheme 7).Addition of up to three molar equivalents of elemental bromine was possible in the first step (Scheme 8).Bromination of 1 occurs selectively at the 7,8-positions in quantitative yield to provide the dibromide 18 as a pair of enantiomers when using only one molar equivalent of bromine. 31Treatment with two molar equivalents of bromine selectively furnished the tetrabromide 19, while treatment with three (or more) equivalents furnished the hexabromide 20. 32,34The elimination step to give the 7-bromo DHA 17 from 18 was accomplished in high yield but was successful only upon treatment with lithium hexamethyldisilazide (LiHMDS) at 0 °C; indeed, raising the temperature or using more common bases, such as KOtBu, pyridine, DBU, triethylamine or Hünig's base, gave azulene 21 and other azulene derivatives, and only in few cases, traces of 17.The straightforward access to the 7-bromo DHA 17 has opened the way via metal-catalyzed cross-couplings to a wide variety of 7-substituted DHA derivatives. 26,32,33Thus, while the 3bromo-derivative 15 described above was unreactive to such coupling conditions, the 7-bromosubstituted DHA is readily functionalized by aryl and alkynyl groups.
Another important step on DHA functionalization was taken while investigating light/heat cycles on 17.Indeed, light irradiation provoked opening of the five-membered ring of the DHA skeleton and formation of VHF E/Z-isomers.Thermal ring-closure hereof gave a mixture of the original 7-bromo DHA 17 and the 6-bromo DHA 22 (Scheme 9). 33The two DHA regioisomers can be easily distinguished by 1 H-NMR spectroscopy, and a COSY spectrum supported the assignment of the new DHA isomer as being the C-6 substituted.Regioselective methods for obtaining DHA regioisomers with functional groups at the remaining positions in the seven-membered ring are still unknown.Yet some of these derivatives have been isolated by a nonregioselective method.In this method, a phenyl substituent was incorporated on the seven-membered ring before building the DHA skeleton. 35Using the phenyltropylium species 23 in the key synthetic step shown in Scheme 10 resulted in a mixture of VHF precursors, from which a mixture of DHA isomers were ultimately obtained.By repeated chromatography it was possible to isolate the 5-phenyl DHA 24 in pure form as confirmed by X-ray crystallographic analysis.Light-induced ring-opening of this DHA to the corresponding VHF followed by thermal ring-closure gave both of the regioisomers 24 and 25.Yet, after four days in the dark at room temperature, 25 was almost fully converted to 24, possibly through a VHF intermediate.This result is in agreement with the absence of regioisomer 25 found in the crude mixture of the reaction and has been rationalized by calculations, which confirmed that 24 is more stable than the regioisomer 25 by 6.7 kcal/mol.The results show that 25 undergoes ring-opening without being subjected to light.

Double Functionalization of the Dihydroazulene Skeleton
Double functionalization of the DHA skeleton has been achieved applying the bromination/elimination protocol on 3-substituted DHA 15, 30 7-substituted DHA 17 30 and on a wide variety of 2-substituted DHAs bearing various functional groups on the phenyl ring on C-2. 13,36he bromination/elimination protocol described in Section 3 was successfully applied to 3bromo DHA 15 giving the 3,7-dibromo-functionalized DHA 26 in good yield (Scheme 11). 30owever, when applying the same bromination/elimination sequence to the 7-bromo-substituted DHA 17, the azulene 27 was obtained (Scheme 12); this product was even formed in the absence of base, showing the lability of the intermediate.When subjecting the iodophenyl-DHA 11 to the bromination/elimination protocol, the doubly-functionalized derivative 28 was obtained (Scheme 13), containing two reactive handles for metal-catalyzed cross-coupling reactions. 13Such reactions indicate that the iodine on 28 is more reactive than the bromine.

Conclusions
As functionalization of dihydroazulenes can strongly alter their optical and photochromic properties, development of efficient synthetic protocols for functionalizing the system is important.For example, we have found that the kinetics of the thermal ring-closure reaction of aryl-substituted VHFs follows Hammett correlations, with opposite effects of electronwithdrawing/donating aryl groups in the five-and seven-membered rings.Positions 2, 3, and 7 can today be regioselectively accessed by efficient protocols.In particular, the regioselective bromination-elimination protocol, which can be expanded to derivatized DHAs, has offered within the past six years a particularly convenient way of achieving functional DHA derivatives.
Ongoing research in our laboratory seeks to develop regioselective methods for functionalizing the other positions, with the prospect of being able to fine-tune the properties of the system.

1 . Introduction 2 .
Reactivity and Functionalization of the Five-membered Ring of Dihydroazulene 3. Reactivity and Functionalization of the Seven-membered Ring of Dihydroazulene 4. Double Functionalization of the Dihydroazulene Skeleton 5. Conclusions

24 Scheme 10 .
Scheme 10.Incorporation of substituent early in the synthesis of DHA.