Rearrangement Reactions for the Synthesis of Some Oxa- and Aza-tricyclic Rings Heterocyclic Compounds

This review article describes the main results of our research during the last 5-6 years. A series of new rearrangement reactions was discovered and used for the synthesis of novel heterocyclic compounds: furo[2,3-f]isoquinolines, furo[3,2 -f] quinolines, benzo[c]xanthene, benzo[h]chromene, benzo[a] xanthene, benzo[f]chromene, furo[2,3-f]isoquinoline, spirofuro[3,2-f]quinoline, cycloalkanoindoles, and benzotriazines.

Our interest in the preparation of new heterocyclic compounds which might be promising in the treatment of psychiatric disorders prompted us to elaborate a novel method for the preparation of new furo [2,3-f]isoquinolines and their cycloalkano derivatives [9].
The formation of this compound could be the following: the initial step a [3,3]-sigmatropic rearrangement of the ether (3b) afforded intermediate 4c which then underwent a homo [1,5]-H shift to yield compound 6 [Scheme 2]. A [1,5]-H shift on compound 6 led to the formation of compound 4b which by intermolecular cyclization furnished 5b in excellent yield.

Rearrangement of allyloxyquinolines. Preparation of furo[3,2 -f]quinolines
Furo [3,2-f]quinolines have not received much attention. So far only three papers have been published dealing with the preparation of this ring system [10][11][12]. Following our synthetic efforts toward the preparation of new heterocyclic compounds which might be useful intermediates for the developments of molecules of pharmaceutical or biological interest, we elaborated new synthesis generally applicable for the preparation of furo[3,2-f]quinolines [13].
Here, we used essentially the same synthetic strategy as was applied for the preparation of the isomeric furo-isoquinolines (Cf. 2.1). Namely, ethers of quinolin-6-ol (9, Scheme 3) were prepared by the reaction of the sodium salt of quinolin-6-ol (7) with the appropriate allyl bromide (8). The allyl ether (9a) was then subjected to thermal [3,3] rearrangement in a microwave oven to give compound 10a. Acid-catalyzed intramolecular cyclization of this rearrangement product afforded a furo [3,2- Starting with compound 9b, the microwave assisted rearrangement gave two products 10b and 10c in a ratio 3:1. Compound 10b was formed in the normal Claisen rearrangement and it afforded the wanted furo [3,2- Aryl geranyl ethers were isolated from the New Zealand liverwort (Trichocolea molissima) and showed cytotoxic effects against kidney cells and in AIDS-related lymphoma screens [14,15]. Several geranyl phenyl ethers were prepared and tested for inhibition of insect growth. The epoxide of these compounds showed significant insect juvenile hormone activity [16]. Furanone, coumarine and naphthol derivatives containing a geraniol-like fragment have been shown to process significant in vitro cytostatic activity [17]. These interesting biological effects of aryl geranyl ethers prompted us to prepare a series of these compounds and to elaborate short and efficient method for the conversion them into new heterocyclic compounds [18].
Geranyl naphth-1-yl ether (13, Scheme 5) was prepared from naphthalene-1-ol and geranyl bromide using the usual method. In the presence of PTSA, the thermal rearrangement of this ether afforded two unexpected products 17  Attempted thermal rearrangement in boiling chlorobenzene or under microwave irradiation resulted only the decomposition of ether 13, and naphthalene-2-ol was isolated.
Geranyl isoquinolinyl ether was prepared by the reaction between isoquinolin-5-ol (27) and geranyl bromide. The product 28 underwent rearrangement in a microwave oven to furnish furo[2,3-f]isoquinoline as a mixture of stereoisomers (32a and 32b, Scheme 7). A plausible mechanism for the formation of compound 32 was based on an abnormal Claisen rearrangement depicted in Scheme 7. Geranyl quinolin-8-yl ether (33, Scheme 8) was prepared from quinolin-8-ol and geranyl bromide according to the published procedure [19]. Thermal rearrangement of 33 in boiling toluene led to the formation of the Claisen product 34 in moderate yield (28%). The microwave assisted reaction gave better result and compound 34 was isolated in 61% yield.
Reaction of ether 33 with sulfuric acid at elevated temperature resulted only in the formation of compound 38 as the result of acid-catalyzed ring closure of the geranyl moiety.

Synthesis of cycloalkanoindoles, the carba analogs of physostigmine
Alzheimer's disease is a progressive dementia associated with the chlorinerg system [19,20]. Acetylcholinesterase enzyme rapidly metabolizes the naturally released acetylcholine causing a lack in this neurotransmitter [21]. An alkaloid of the African Calabar bean (Physostigma venesonum), (-)-physostigmine, inhibits the acetylcholinesterase by transcarbamylation [22,23]. This inhibition reduces the rate of acetylcholine's hydrolysis in the brain and increases its cholinerg activity. Physostigmine (eserine) and its phenylcarbamoyl derivative have been used medically to improve memory and relief in Alzheimer's disease [24][25][26].
Nowdays, cholinesterase inhibitors -donepezil (aricept), rivastigmine (exelon, an aryl carbamate derivative), and galantamine (nivalin) are also used for the treatment in the mild to moderate stages of Alzheimer's disease.
The growing need for new acetylcholinesterase inhibitors in clinical trials and application had focused interest on the preparation of physostigmine congeners. For instance, the pyrrolo[2,3-b] indole skeleton was replaced by furo [2,3]indole. However, the carba analogs in which one of the nitrogen-containing ring had been substituted by cycloalkano skeleton, have not got attention.
Our general interest in the preparation of new heterocyclic compounds, which might be promising in the treatment of mental disease, prompted us to elaborate methods for the synthesis of the carba analogs of physostigmine [27][28][29][30].
In our synthesis the key step was an aza-Claisen rearrangement followed by an Alder-ene reaction of the intermediate. Aza-Claisen rearrangement is also a thermal [3,3]sigmatropic rearrangement which shows a suprafacial reaction pathway (Scheme 9) [3-6,31,32]. The aza-Claisen rearrangement can be efficiently catalyzed with acid and Lewis-acids.
In Alder-ene reaction a four electron system including an alkene π-bond and an allylic C-H bond react with an enophilic olefin in a [4+2]-addition reaction. In this pericyclic reaction a double bond is shifted and new C-H and C-C σ-bonds are formed (Scheme 9) [33,34]. Alder-ene reaction can also be catalyzed by Lewis-acid.
Synthesis of the carba analogs of physostigmine is depicted in Scheme 10. The reaction of aniline derivative (38) with 1-(chloromethyl)-cycloalkan-1-ene (39) gave the expected amine (40), which was subjected to thermal rearrangement using BF 3 . OEt 2 as a catalyst. The aza-Claisen rearrangement followed by a ring closure reaction afforded two products: compound 44 and side product 43. In case of cyclopent-1-ene (39a, n = 0), only the cis-isomer was formed. However, cyclohex-1ene and cyclohept-1-ene derivatives (39b, n =1 and 39c, n = 2, respectively) afforded a 3:1 mixture of cis-and trans-stereoisomers, which was separated by column chromatography. Side product 43 was formed by the migration of the carbon-carbon double bond. For the preparation of the carba analog of physostigmine the cis-44a-c was treated with BBr 3 and the hydroxy derivatives 45a-c formed were then reacted with phenyl isocyanate to afford the carba analog of physostigmine 46a and its congeners 46b,c.
Earlier we had considered the mechanism of the key step as aza-Claisen rearrangement followed by aromatic stabilization and nucleophilic attact of the nitrogen on the exo-double bond. But further investigation revealed another possible mechanism. Especially the ab initio DFT calculation on the transition states leading from 40c to 44c.
In the transition state of the first step (40c → 41c), there was a rather large difference between the energies of the chair and the boat geometry (∆∆E = -17.3 kJ mol -1 ), showing improbable boat conformation of the transition state in the aza-Claisen rearrangement. The cis-diastereoselectivity of the reaction can be rationalized on the above finding (Table 1 and Figs. 1 and 2). Surprisingly, the calculation for the transition state of the second step, aromatization, showed high energy (∆E = 358 kJ mol -1 ). For the closing step the transition state leading to the cisproduct (44c) had lower energy than the corresponding "trans" (∆∆E = -23.5 kJ mol -1 ), suggesting that the "trans" reaction pathway was unfavorable, in accordance with experiment. We got also lower energy for the cis-product (44c) than for the trans-isomer (∆∆E = -7.5 kJ mol -1 ).
Due to the calculated high activation energy of intermediate 42, we considered another possible mechanism for this reaction. We found that an intramolecular aza-Alder-ene reaction on the intermediate 41c might also take place. The calculated activation energy (41c → TS-41c→44) was significantly lower then that calculated for the TS-42 (∆∆E = 147 kJ mol -1 ). Therefore, this two-step pathway with its low activation barrier may be regarded as the mechanism of the formation of compounds 44c. We had further evidence for this mechanism. We treated the isolated side product 43c with BF 3 OEt 2 at 170 o C for longer time, but no ring closured product 44c could be isolated. We observed only some degradation.

Synthesis of new potential UV-filters
As the result of the decreasing of the protective ozone layer, the exposure to ultraviolet light (UV) is increasing worldwide. UVA light (320-400 nm), which is approximately 90% of the UV light, can pass through window glass, penetrates into the dermis, and may cause tanning, wrinkling, and skin cancer. Malignant melanoma is the most harmful of all skin cancers. Recently, it has been increasing faster than any other cancer and regarding the number of cases it has more than doubled in the last five years. Therefore, protection against the UV light has been growing and is of crucial significance [35][36][37][38][39][40][41].
A number of molecules are employed as UV light protecting agents. Among them compounds having intramolecular H-bond are strong UV absorbers and show proper photostability. Mexoryl XL, a benzotriazole derivative, is widely used as UV stabilizers. In this molecule the photoinduced excited state returns to the ground state by a proton transfer and rapid non-radiative dissipation of the harmful UV energy. The relaxation mechanism involves intramolecular proton transfer (ESIPT) from the S 1 state occurring in the femtosecond timescale, then radiative decay of the excited molecule (fluorescence emission with a large shift, λ em ≈ 640 nm) is followed by back proton transfer, causing a return to the ground state (back ESIPT) [42][43][44][45].
Recently we have elaborated new economical method for the preparation of 2-(2'-hydroxylphenyl)benzotriazoles (51, 52, Scheme 11) by the reduction of compounds 50 with benzyl alcohol [46]. These important building blocks were then used for the preparation of new potential UV-filters. The synthesis followed is shown in Scheme 11.
Treatment of the aniline derivatives (47) with NaNO 2 and HCl afforded compounds 48, which was coupled with phenols (49). The products (50) were treated with benzyl alcohol at 100 o C to yield N-oxide (51) and at higher temperature benzotriazole derivatives (52) were isolated in excellent yield. Compounds 52 were heated with methallyl chloride in the presence of K 2 CO 3 and KI to give ethers 53. Thermal rearrangement of the products in N,N-dimethylaniline afforded compounds 54,   which were then silylated using heptamethyltrisiloxane and Karlstedt catalyst [Pt 2 (divinyltetramethyldisiloxane) 3 ] to give the desired products 55 in good yield [47][48][49].
Compounds 55 were evaluated for their photochemical behavior as potential UV-filters. The results are shown by the example of compound 55a. The absorption spectra of compound 55a showed two maxima, λ 1 at ca. 300 nm and λ 2 at ca. 350 nm, in ethanol, and after excitation a new emission spectra was observed at λ 1 at 590 nm. Moreover, steady state photolysis showed that this compound exhibits a potential applicability as UV-filter due to its UVA-absorption capability and its photostability.

Concluding remarks
New methods have been elaborated for the economical preparation of novel heterocyclic compounds, the carba analogs of physostigmine, and potential UV-filters. The key step of these syntheses was a rearrangement reaction: Claisen rearrangement, "abnormal" Claisen rearrangement, and aza-Claisen rearrangement. These rearrangement reactions are excellent tools in the preparation of complex heterocyclic compounds.