Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

The synthesis of complex cyclic compounds is extremely challenging for organic chemists. Many transition-metal-salt-mediated cyclizations are reported in literature. Hg(II) salts have been successfully employed in cyclizations to form complex heterocyclic and carbocyclic structures that are impossible to synthesize with other transition metal salts. In this review, we have summarized cyclization reactions that are performed with Hg(II) salts. These salts are also successfully applied in stoichiometric or catalytic amounts to form complex cyclic structures and natural products.


Introduction
The use of transition metal reagents has found considerable applications in organic synthesis [1][2][3][4] and has radically changed the realm of chemical science. It also provides a powerful tool for the construction of complex molecular frameworks [5][6][7]. A plethora of reviews involving transition metals such as Pd(II) [8][9][10], Ru(II) [11][12][13], Rh(III) [14][15][16], Mn(II) [17][18][19], Au(II/I) [20][21][22], Ag(I) [23][24][25] etc. in both cascade and sequential reactions have been published. Electrophilic Hg(II) salts are important reagents in organic synthesis and there is published literature establishing this fact [26][27][28][29]. However, the main drawback of Hg(II) salts, as compared to other transition metal salts, is their increased toxicity [30,31]. Hg(II) salts on the other hand, are very cheap in comparison to other transition metal salts ( Table 1) and one of the soft Lewis acids of the periodic table [32]. Hg(II) salts have already manifested some unique reactivity and therefore attracted increasing interest from chemists [33]. Many examples involving Hg(II) salts with unsaturated bonds in presence of various nucleophiles giving rise to various types of products are abound in the literature. Utilization of Hg(II) salts in the intramolecular cationic cyclization of olefinic, acetylenic, and allenic substrates having aromatic rings, nucleophiles, and heteroatoms in the neighborhood were well documented. Hg(II) reagents were also often employed in the important cyclization step during total syntheses of many Scheme 2: First report of Hg(II)-mediated synthesis of 2,5-dioxane derivatives from allyl alcohol.

Scheme 3:
Stepwise synthesis of 2,6-distubstituted dioxane derivatives. natural products [34]. Despite its wide application in ring formation reactions, only a few review articles on Hg(II)-saltmediated cyclization reactions are available in the literature [35]. This review describes the intramolecular cyclization of unsaturated compounds in the presence of stoichiometric/catalytic amounts of Hg(II) salts. The classification of this review is based on the following topics.
• Cyclization reactions involving the stoichiometric amount of Hg(II) salts. • Cyclization reactions involving the catalytic amount of Hg(II) salts. • Total synthesis involving Hg(II)-salt-mediated cyclization reactions. The generalized mechanism for cyclization reactions are, alkenes/alkynes 1 initially react with Hg(II) salts (HgX 2 ) leading to the formation of a mercurial carbonium ion 2 followed by the attack of an intramolecular nucleophile giving rise to a cyclized mercuro-halide complex compound 3 (Scheme 1).
Scheme 1: Schematic representation of Hg(II)-mediated addition to an unsaturated bond.

Review
Cyclization reactions involving stoichiometric amounts of Hg(II) salts Cyclization involving alkenes (>C=C<) In 1900 and 1901, the Sand and Biilmann group had first reported the Hg(II)-mediated cyclization of allyl alcohol using Hg(II) nitrate (Hg(NO 3 ) 2 ) in two separate publications [36,37]. The cyclized product thus formed was further treated with iodine to get trans-2,5-bis(iodomethyl)-p-dioxane (4a). The formation of trans-isomer 4a as the major product and cis-isomer 4b as a minor product was later confirmed by Summerbell et al. by repeating the same experiments (Scheme 2) [38].
Cyclization of biallyl ether 5 in presence of mercuric acetate (Hg(OAc) 2 ) in an aqueous medium was reported to synthesize a diastereomeric mixture of 2,6-disubstituted-p-dioxane 6. The outcome of the reaction was much generalized with no detailed discussion about the ratio of diastereomeric products [39]. Later, Summerbell and co-workers modified the reaction conditions to synthesize 2,6-disubstituted dioxane derivatives 6 (cis/trans 16:1). Unlike 2,5-disubstituted dioxane derivatives, here the cis-isomer was the major product. A higher ratio of the cis-dioxane 6 was achieved by increasing the reaction time and acidity of the reaction medium, while elevated temperature showed no effect (Scheme 3) [40]. The mercuricyclization was also employed in the field of carbohydrate chemistry for the synthesis of α-ᴅ-C-glycopyranosyl derivatives. The reaction between carbohydrate alkene precursor 7 and Hg(OAc) 2 proceeds with high stereoselectivity to give the α-ᴅ-C-glycopyranosyl derivative (1,5-trans-isomer) 8 as a single isomer [41]. Treatment of compound 8 with sodium borohydride (NaBH 4 ) under phase transfer conditions (PTC) yields compound 9 as the only product. The selectivity of α-stereochemistry was primarily due to the strong directing effect of the neighboring benzyl ether group with the Hg(OAc) 2 . When cyclic mercuric halide 8 was treated with NaBH 4 and oxygen (O 2 ) in DMF oxidative demercuration takes place to give alcohol 10 in quantitative yield (Scheme 4).
In a similar manner, stereoselective cyclization of C-glycosyl amino acid derivative 13 using mercuric trifluoroacetate Hg(TFA) 2 at room temperature was performed. The reaction proceeds primarily through stereoselective cyclization to give α-ᴅ-C-glycopyranosyl amino acid derivative 14 as the major product [43]. Nevertheless, C-mannopyranosyl derivatives cannot be achieved in a similar manner as reductive elimination forms during the mercury removal process (Scheme 6). In contrast, when Reitz and co-workers carried out a ring formation of benzylated C-arabinofuranoside derivative 17 in presence of 1.4 equiv of Hg(OAc) 2 and sodium bromide (NaBr) at room temperature, then β-ᴅ-arabinose derivative 18 was formed as the major product (Scheme 8) [45]. The high stereoselectivity of β-derivative 18 at the anomeric position was predominantly due to the presence of the benzyl groups at the C-2 and C-3 positions of the starting material. It had been cited in many publications that the stereoselectivity of products formed due to Hg(II)-salt-mediated cyclization reactions of alkene-alcohol derivatives depends on several factors: the nature of the Hg(II) salts [46], the starting materials Scheme 10: Synthesis of Hg(TFA) 2 -mediated bicyclic nucleoside derivative. [47], and the effect of H 2 O (protic solvent) in the reaction media [48].
Pulido et al. had developed a conversion of allylsilyl alcohols 19 to diastereomeric mixtures of tetrahydrofuran derivatives 20A and 20B (Scheme 9) [47]. It was reported that more substituted alkyl groups present in allylsilyl alcohol 20b direct the selective formation of diastereomeric products. They also observed that changes in Hg(II) salts result in different ratios of the cis-and trans-isomer in the cyclized products [47]. The differences in cis and trans ratios were primarily due to the basicity of anions associated with Hg(II) salts [46].
For the synthesis of diastereomeric pyrrolidine derivatives, a Hg(II) salt had been used. When HgCl 2 was added to secondary methylamine derivatives 29 and 31 followed by reduction with NaBH 4 a mixture of diastereomers 30a,b and 32a,b was obtained, respectively. trans-Isomers were formed as major products over cis-isomers (Scheme 12) [52].
Mercury(II) salts had also been successfully utilized in the cyclization of ether derivatives 61 to form stereoselectively trans-4,5-disubstituted oxazolidine derivatives 62 (Scheme 22) [69]. Later it was reported, when homologous allyloxycarbamate derivative 63 was cyclized with Hg(TFA) 2 then five-and six-membered rings 64 and 65 were formed with a 1:4 ratio (Scheme 22) [70]. The greater yield of the six-membered prod-uct was primarily due to the electron-withdrawing effect of ethereal oxygen which in turn destabilizes the carbocation at the β-carbon and hence the nucleophilic attack at the γ-carbon took place.
Cyclization of amide derivative 66 induced by Hg(OAc) 2 followed by reduction with LiBH 4 afforded a mixture of compounds 67A/67B [71]. The formation of endo,trans-product as a major product over the exo,cis-isomer was primarily due to a stereoinduction effect (Scheme 23). The small amount of
A HgCl 2 -induced cyclization also takes place for acetylenic silyl enol ether derivative 79 forming carbocyclic compounds Thus, the chloride ion attacks from the frontside, producing synaddition molecules that, upon dehydration, formed furan rings.
Later they had reported similar mercuration of arylacetylenes to synthesize a broad spectrum of heterocycles, namely benzofurans, benzothiophenes, isocoumarins, chromones, benzopyrans, 1,2-dihydronaphthaIenes, coumarins, and coumestan including some physiologically active heterocyclic natural products like flavones [84]. In the presence of Hg(OAc) 2 in acetic acid, simple cyclization of ortho-substituted arylacetylenes 93, 95, and 97 yielded benzofurans 94, benzothiophenes 96, and indoles 98, respectively. When the carbonyl group was introduced between an aryl and a methoxy group (99) then six-membered isocoumarin ring 100 was formed, and when a carbonyl group was introduced in between an aryl and an alkyne group was preferred when substitutents were present at the alkyne terminus, whereas six-membered rings (111a,b) formed predominantly in case of unsubstituted alkyne dithioacetals (Scheme 33) [86]. They had reported the plausible mechanism for the formation of a six-membered pyranose ring follows 'path a,' while for the formation of five-membered pyrrolidine derivatives 'path b' was followed.

Cyclization involving allenes (>C=C=C<)
Apart Devan et al. had developed similar types of Hg(TFA) 2 -mediated cyclizations of allene 116 at low temperature followed by reduction with alkaline NaBH 4 to form cyclized product 117 in moderate yield [88]. The reaction was believed to proceed through Hg(II) ion-promoted electrophilic cyclization (Scheme 35).

Cyclization involving catalytic Hg(II) salts Cyclization involving alkenes (>C=C<)
Apart from the stoichiometric amount used in cyclization, there is abundant literature where a catalytic amount of Hg(II) salt was employed for cyclization reactions between nucleophiles and unsaturated bonds. Later, Namba et al. reported the synthesis of racemic vinylindoline derivatives 123 from N-tosylanilinoallylic alcohol derivative 122 by using 1-2 mol % of Hg(OTf) 2 in CH 2 Cl 2 at room temperature [90]. An asymmetric synthesis of vinylindoline derivatives 125 was achieved by utilizing chiral ligands like chiral binaphane (Scheme 37) [91]. They had observed that the formation of six-and seven-membered rings required elevated temperatures. Subsequently, the same group studied the cyclization of arylene 126 to furnish naphthalene derivative 127. The plausible mechanism for the formation of compound 127 proceeded consecutively with π-complex formation, Friedel-Crafts type addition, deprotonation, and finally protonation of alcohol for the elimination of water to get the final product [92].
A Hg(OTf) 2 -mediated cyclization was utilized for the synthesis of 1,4-dihydroquinoline 129 possessing a quaternary carbon center from 128 [93]. The reaction was reported via a sevenmembered bicyclic hemiaminal as mentioned in the mechanism. This catalytic rearrangement protocol was successfully applied for the construction of complex carbon frameworks from various tosylanilinoallyl acetals. 4H-Chromene derivatives were also synthesized starting from phenol derivatives (Scheme 38). Several unsaturated lactones had been synthesized from alkynoic acids via Hg(II)-salt-catalyzed cyclization reaction. For example, simple 4-pentynoic acid derivatives 137 afforded γ-methylene butyrolactones 139 in good yields via the formation of organomercural compounds 138 using catalytic mercuric oxide, mercuric acetate, or mercuric trifluoroacetate as shown in Scheme 41 [97].
Six-membered morpholine derivatives were also synthesized by catalytic Hg(II)-salt-induced cyclization. Yamamoto and co-workers published the intermolecular cyclization of alkynyl- carboxylic acid 153 to produce 6-membered morpholine type ring compound 154 and compound 155 [103]. The stereochemistry of the chiral amino acid was not conserved in the cyclized product hence it leads to the formation of racemic products with moderate yields (Scheme 44).
In a Hg(OTf) 2 -catalyzed process, 1,6-allenynes 158 were cycloisomerized to generate allenenes 159 in moderate to good yield (Scheme 46) [105]. However, depending on the substituents, allenene and/or unexpected triene were produced as a main product for disubstituted 1,6-allenynes. It was hypothesized based on experimental evidence that alkynes would first form a π-complex with Hg(OTf) 2 , followed by vinylmercuration, demercuration, and eventually isomerizes to allenene.  In 2003, a carbocyclization with a catalytic quantity of mercury salt was used to efficiently synthesize dihydronapthalene derivative 161 from exemplifying benzyl derivative 160 [106]. The reported methodology was an example of the Hg(OTf) 2 ·(TMU) 3 complex promoting a moderate and efficient procedure for arylalkyne cyclization to directly afford dihydronapthalene derivatives (Scheme 47). Later, Friedel-Crafts type reaction of alkynylfuran 162 and 164 were reported in presence of the Hg(OTf) 2 ·0.1 Sc(OTf) 3 complex (5 mol %) to form six-(163) and seven-membered rings (165) in good yield. For the cyclization at 2-position of the furan the Hg(OTf) 2 ·(TMU) 3 complex was used as catalyst [107].
Later it was reported that 1-alkyn-5-ones such as 166 also undergo an effective cyclization reaction to synthesize 2-methylfuran derivatives 167 with high yield in the presence of Hg(OTf) 2 as the catalyst under very mild reaction conditions (Scheme 48) [108]. method to synthesize indole derivatives had been developed [112]. Similarly, benzo[c]isoxazole was also formed in excellent yields with high selectivity using this strategy. In these transformations, two Hg-carbene intermediates were proposed to be involved (Scheme 52).
Mercury-catalyzed reactions were also well known for the formation of various complex scaffolds like tricyclic pyrazinones from the corresponding starting materials. For example, Zhang et al. showed that refluxing anilide 177 in presence of a catalytic amount of Hg(OAc) 2 and 90% formic acid gave the tricyclic heterocyclic scaffold 178 [113]. It involved a two-step process with the rearrangement of the primary cyclization products (Scheme 53).
In 2013, Lin et al. reported a Hg(II) chloride-mediated cyclization reaction of 2-alkynylphenyl alkyl sulfoxide 179 to synthesize benzothiophene derivatives 180 with good yields [114]. In this case, the reaction was believed to proceed via the initial formation of metal carbenoids followed by a sequential C-H insertion and then oxidation (Scheme 54). This methodology was later successfully utilized for the total synthesis of raloxifene and benzo[b]thiophene derivatives [115].

Cyclization involving allenes (>C=C=C<)
Hg(II) triflate salts had also been successfully employed for the arylallene 181 cyclization by Yamamoto et al [116]. The cata-lytic pathway was proved to involve the direct H-transfer to the vinylmercury complex from the aromatic ring. It involved Hg(OTf) 2 -catalyzed cyclization of aryl 1,1-disubstituted allenes with the formation of a quaternary carbon center followed by the formation of a cationic vinylmercury intermediate (Scheme 55).
For the synthesis of stereoselective tetrahydropyran derivatives 184, Hg(II)-catalyzed cyclization proved to be more effective than silver(I)-salt-mediated cyclization. It showed that methylsubstituted allenes undergo efficient cyclization to form polycyclic ethers under Hg(OTf) 2 -catalyzed conditions at lower temperature (Scheme 56) [117].
Following a similar strategy, mercury chlorate (Hg(ClO 4 ) 2 ) had been employed successfully as a cheap alternative to precious metals salts in the cyclization of α-allenol derivatives 185 to differently substituted 2,5-dihydrofurans 186 in an efficient and selective manner. It was also shown that from enantiopure allenyl derivatives, the desired pure cyclized product was generated by utilizing the above reaction conditions (Scheme 57) [118]. been successfully employed as one of the important steps during the total synthesis of natural products.
Later for the total synthesis of ventiloquinone J (194), a Hg(II)salt-catalyzed intramolecular cyclization reaction of the orthoallyl alcohol 192 was involved. The reaction went through the formation of a mixture of diastereoisomers 193a and 193b.
After which the inseparable mixture of products underwent further oxidative demethylation and yielded the final products (Scheme 59) [120].
Kraus and co-workers had reported the synthesis of the racemic naphthohydroquinone hongconin (197) starting from the orthoallyl alcohol derivative 195. The starting material was cyclized using a Hg(II) salts to get an inseparable mixture of products 196a and 196b in the ratio of 1:5 [121]. The synthetic route proceeded by benzylic alcohol ortho-metalation followed by a regioselective mercuri-cyclization reaction (Scheme 60). N,N-dimethylaniline (DMA) (1.2 equiv) was initially used for olefin cyclization to produce a regio-and a stereoisomeric mixture of acetate 205 after reduction and acetylation of the crude product. The Hg(OTf) 2 -catalyzed isomerization of the double bond in compound 205 yielded thermodynamically favorable isomer 206 as a major product [123].
In 2010, Ravindar et al. developed the total synthesis of the steroidal natural product hippuristanol (211) starting from 11-ketotigogenin 208 (Scheme 63). They had utilized a Hg(OTf) 2 -catalyzed spiroketalization reaction in their key step to form the desired ketal intermediate 210 [124]. Subsequently, in 2011, the same group reported another synthesis of hippuristanol (211) and its analog from easily available starting materials [125]. In this work, hippuristanol and some analogs were successfully synthesized utilizing a Hg(OTf) 2 -catalyzed cascade spiroketalization step of the 3-alkyne-1,7-diol motif. The Hg(OTf) 2 -catalyzed cascade spiroketalization step was proved to be more convenient than Suárez cyclization.
A Hg(TFA) 2 -mediated cyclization was efficiently utilized for the synthesis of highly strained tricyclo[5.2.1.0 1,6 ]decene intermediate 214 containing a cyclobutane ring (Scheme 64). Compound 213 is an important precursor for the asymmetric total synthesis of solanoeclepin A. The formation of β-hydroxyketone 213 was achieved by Hg(TFA) 2 -mediated cyclization of compound 212 using TFA/H 2 O (1.7: 1) as the solvent. In presence of other mercury compounds like HgO and Hg(OAc) 2 no product or starting material was recovered [126].
Spiro-skeleton structures are found in many natural products and synthesizing stereoselective spiro-skeletons has always been difficult for organic chemists. Morimoto and co-workers were the first to disclose the Hg(OTf) 2 -catalyzed cycloisomerization of amino ynone to produce the azaspiro skeleton. Later, this methodology was successfully used for the synthesis of several spiroskeleton structures. Natural products such as histrionicotoxin alkaloids 218 (Scheme 65) [127,128] and lepadoformine [129,130] were being successfully synthesized using this methodology for spirocyclic ring structure synthesis. The proposed mechanism proceeded initially with aminoketal formation by 6-exo-dig intramolecular oxymercuration, followed by Petasis-Ferrier-type cyclization, and finally nucleophilic addition of mercuric enolate to iminium results in the formation of azaspiro structure.

Conclusion
In conclusion, this review summarizes Hg(II)-salt-mediated cyclization reactions either for direct synthesis of cyclized products or as a part of the total synthesis of important natural products. Different Hg(II) salts were used stoichiometrically or catalytically depending upon the nature of functional groups and reactants. However, the reactivity of different unsaturated bonds involved in the cyclization primarily depends on the nucleophile as well as nature of functional groups attached to unsaturated bonds. When alkenes are linked to activating groups like methoxy or hydroxy, a catalytic quantity of Hg(II) ions is re-quired for cyclization. Nothing can be predicted in case of alkynes; however, the presence of a strong nucleophile promotes the Hg(II)-salt-catalyzed cyclization of allenes in most circumstances. In cyclization reactions, Hg(OTf) 2 showed to be the most effective and versatile of all Hg(II) salts. Mercury(II) salts can also be used to cyclize unsaturated bonds in a regio-and diastereoselective manner. Apart from toxicity concerns, Hg(II) salts are cheap, stable, and versatile in terms of reactivity, making them a viable option to similar transition metal catalysts.