Convenient Synthesis of Functionalized Cyclopropa[c]coumarin-1a-carboxylates

A simple method has been developed for the synthesis of cyclopropa[c]coumarins, which belong to the donor-acceptor cyclopropane family and, therefore, are promising substrates for the preparation of chromene-based fine chemicals. The method, based on the acetic acid-induced intramolecular transesterification of 2-arylcyclopropane-1,1-dicarboxylates, was found to be efficient for substrates containing hydroxy group directly attached to the aromatic ring.


under reflux with 2 eq
iv of acetic acid (Table 1, entry 8).The use of stronger acids such as trifluoroacetic acid (TFA) or p-toluenesulfonic acid (TsOH) resulted in the formation of complex mixture of products; any attempts to isolate 2a were unsuccessful.Base-induced reaction produced the desired product 2a in low yield only. Oppositely, the reaction of much more reactive dimethylsulfoxonium methylide [29,30] with 3-acylcoumarins, coumarin-3-carboxylates, the corresponding nitriles as well as sulfones under the typical conditions of Corey-Chaykovsky cyclopropanation was found to afford cyclopenta[b]-benzofuran derivatives as a result of the fast secondary reaction of the initially formed cyclopropa[c]coumarins with a second equivalent of the Corey ylide [31][32][33].The target cyclopropa[c]coumarins were obtaine

in low-to-moderate yields when the reaction was
performed at 0 • C (for 3-ethoxycarbonyl-, 3-pivaloyl-and 3-cyanocoumarins) or at −40 • C (for 3-acetyl and 3-benzoyl derivatives) (Scheme 1f) [31].Very recently it was proposed to perform this cyclopropanation using very slow addition of the Corey ylide solution (5 mL for 6 h) to the corresponding coumarin derivative, however, product yields were not given [34,35].Therefore, the development of efficient procedure for the synthesis of 1-unsubstituted cyclopropa[c]coumarins remains a challenging task for organic chemists.Herein, we describe a new general approach to cyclopropa[c]coumarins based on the use of 2-(2-hydroxyphenyl)cyclopropane-1,1-dicarboxylates (Scheme 1) which can be easily obtained from the corresponding salicylic aldehydes [36,37].


Results and Discussion

We started our research with a search for the optimal conditions for the transesterification of 2-hydroxy-and 2-(methoxymethoxy)phenyl-substituted cyclopropane-1,1-dicarboxylates 1a,b as model substrates using their treatment with base (K 2 CO 3 or N,N-diisopropylethylamine, DIPEA) or Brønsted acid (Table 1).We have found that the highest yield of the target methyl cyclopropa[c]coumarin-3-carboxylate 2a was obtained when toluene solution of cyclopropane 1a was heated under reflux with 2 equiv of acetic acid (Table 1,

try 8).The use of stron
er acids such as trifluoroacetic acid (TFA) or p-toluenesulfonic acid (TsOH) resulted in the formation of complex mixture of products; any attempts to isolate 2a were unsuccessful.Base-induced reaction produced the desired product 2a in low yield only.   4 Complex mixture of products. 5eaction was performed under microwave irradiation. 6Dimethyl (2,3-dihydrobenzofuran-2yl)malonate was also formed as side product.For details, see ref. [36].

With the optimized reaction conditions in hand, we studied the scope of this transesterification and found that diverse substituents in the benzene ring (halogens, alkyl or nitro group) are tolerant to the reaction conditions (Scheme 2).Oppositely, the reaction of 2-hydroxy-3-methoxyphenylsubstituted cyclopropane 1g produced only trace amounts of the corresponding cyclopropa[c]coumarin 2g.Scheme 2. Synthesis of cyclopropa[c]coumarins 2a-h.a In chlorobenzene.

To extend the scope of the reaction, we have studied reactions of cyclopropane 3 with a 2-( ydroxymethyl)phenyl group as a donor and its analogue 8 bearing a 3-hydroxymethyl-4-indolyl substituent.However, in both cases we failed to obtain the corresponding products of intramolecular esterification.Thus, the heating of 3 with 2 equiv of acetic acid in both toluene and chlorobenzene did not produce the desired oxepanone 4 at all.When a large excess of acetic acid was applied, benzyl With the optimized reaction conditions in hand, we studied the scope of this transesterification and found that diverse substituents in the benzene ring (halogens, alkyl or nitro group) are tolerant to the reaction conditions (Scheme 2).Oppositely, the reaction of 2-hydroxy-3-methoxyphenyl-substituted cyclopropane 1g produced only trace amounts of the corresponding cyclopropa[c]coumarin 2g.   4 Complex mixture of products. 5 Reaction was performed under microwave irradiation. 6Dimethyl (2,3-dihydrobenzofuran-2yl)malonate was also formed as side product.For details, see ref. [36].

With the optimized reaction conditions in hand, we studied the scope of this transesterification and found that diverse substituents in the benzene ring (halogens, alkyl or nitro group) are tolerant to the reaction conditions (Scheme 2).Oppositely, the reaction of 2-hydroxy-3-methoxyphenylsubstituted cyclopropane 1g produced only trace amounts of the corresponding cyclopropa[c]coumarin 2g.


Scheme 2. Synthesis of cyclopropa[c]coumarins 2a-h. a

In chlorobenzene.

To extend the scope of the reaction, we have studied reactions of cyclopropane 3 with a 2-(hydroxymethyl)phenyl group as a donor and its analogue 8 bearing a 3-hydroxymethyl-4-indolyl substituent.However, in both cases we failed to obtain the corresponding products of intramolecular esterification.Thus, the heating of 3 with 2 equiv of acetic acid in both toluene and chlorobenzene did not produce the desired oxepanone 4 at all.When a large excess of acetic acid was applied, benzyl To extend the scope of the reaction, we have studied reactions of cyclopropane 3 with a 2-(hydroxymethyl)phenyl group as a dono

and its analogue 8 bearing a 3-hydroxymethyl-4-indolyl substituent.Howev
r, in both cases we failed to obtain the corresponding products of intramolecular esterification.Thus, the heating of 3 with 2 equiv of acetic acid in both toluene and chlorobenzene did not produce the desired oxepanone 4 at all.When a large excess of acetic acid was applied, benzyl acetate 5 was obtained as a single low-molecular-weight product (Scheme 3).The use of a stronger acid led to the formation of complex mixtures containing predominantly products of the three-membered ring opening.

Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 acetate 5 was obtained as a single low-molecular-weight product (Scheme 3).The use of a stronger acid led to the formation of complex mixtures containing predominantly products of the threemembered ring opening.Meanwhile, indolyl-substituted cyclopropane 8, which was obtained in two steps from the reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme 4).Similar AcOH-induced transformations of 3-indolylmethanols to bis(indolyl)methanes was previously described [39][40][41].Meanwhile, the presence of highly reactive donor-acceptor cyclopropane functionality in the starting alcohol 8 and two such m ieties in the product 9 provides non-trivial nature this process.The obtained cyclopropa[c]coumarins 2 are potent substrates for the synthesis of diverse coumarin derivatives (Scheme 5).Thus, it was recently shown that such cyclopropacoumarins undergo Ni(ClO4)2-catalyzed nucleophilic ring opening under treatment with indole affording 4-(indolylmethyl)chroman-2-one-3-carboxylates [34].Nevertheless, our attempts to transform compounds 2 to the corresponding benzoxepan derivatives via their reduction with Zn/AcOH system [42] or Lewis acid-induced isomerization [43] were unsuccessful.Unexpectedly, the treatment of cyclopropacoumarin 2d with zinc and acetic acid in methanol did not afford the products of three-membered ring reduction.Instead, it led to the methanolysis of the lactone moiety in 2d producing cyclopropane 1d and a small amount of acyclic product 10 formed by the reduction of 1d (Scheme 6).Moreover, this cyclopropacoumarin remains intact under heating with both tin(II) triflate in dichloromethane and trimethylsilyl triflate in chlorobenzene for several hours.The absence of benzoxepane derivative in the reaction mixtures together with the aforementioned literature data on the nucleophilic attack of cyclopa[c]coumarins at the CH2 atom [34] demonstrate the decelerating effect of annulation on the reactivity of the C-C bond between atoms connected to donor and acceptor substituents.The effect of the annulated ring nature on the reactivity of donor-acceptor cyclopropanes deserve, evidently, a careful study.Meanwhile, indolyl-substituted cyclopropane 8, which was obtained in two steps from the reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme 4).Similar AcOH-induced transformations of 3-indolylmethanols to bis(indolyl)methanes was previously described [39][40][41].Meanwhile, the presence of highly reactive donor-acceptor cyclopropane functionality in the starting alcohol 8 and two such moieties in the product 9 provides non-trivial nature this process.

Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 acetate 5 was obtained as a single low-molecular-weight product (Scheme 3).The use of a stronger acid led to the formation of complex mixtures containing predominantly products of the threemembered ring opening.Meanwhile, indolyl-substituted cyclopropane 8, which was obtained in two steps from the reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme 4).Similar AcOH-induced transformations of 3-indolylmethanols to bis(indolyl)methanes was previously described [39][40][41].Meanwhile, the presence of highly reactive donor-acceptor cyclopropane functionality in the starting alcohol 8 and two such moieties in the roduct 9 provides non-trivial nature this process.The obtained cyclopropa[c]coumarins 2 are potent substrates for the synthesis of diverse coumarin derivatives (Scheme 5).Thus, it was recently shown that such cyclopropacoumarins undergo Ni(ClO4)2-catalyzed nucleophilic ring opening under treatment with indole affording 4-(indolylmethyl)chroman-2-one-3-carboxylates [34].Nevertheless, our attempts to transform compounds 2 to the corresponding benzoxepan derivatives via their reduction with Zn/AcOH system [42] or Lewis acid-induced isomerization [43] were unsuccessful.Unexpectedly, the treatment of cyclopropacoumarin 2d with zinc and acetic acid in methanol did not afford the products of three-membered ring reduction.Instead, it led to the methanolysis of the lactone moiety in 2d producing cyclopropane 1d and a small amount of acyclic product 10 formed by the reduction of 1d (Scheme 6).Moreover, this cyclopropacoumarin remains intact under heating with both tin(II) triflate in dichloromethane and trimethylsilyl triflate in chlorobenzene for several hours.The absence of benzoxepane derivative in the reaction mixtures together with the aforementioned literature data on the nucleophilic attack of cyclopa[c]coumarins at the CH2 atom [34] demonstrate the decelerating effect of annulation on the reactivity of the C-C bond between atoms connected to donor and acceptor substituents.The effect of the annulated ring nature on the reactivity of donor-acceptor cyclopropanes deserve, evidently, a careful study.The obtained cyclopropa[c]coumarins 2 are potent substrates for the synthesis of diverse coumarin derivatives (Scheme 5).Thus, it was recently shown that such cyclopropacoumarins undergo Ni(ClO 4 ) 2 -catalyzed nucleophilic ring opening under treatment with indole affording 4-(indolylmethyl) chroman-2-one-3-carboxylates [34].

Molecules 2018, 23, x FOR PEER REVIEW 4 of 11 acetate 5 was obtained as a single low-molecular-weight product (Scheme 3).The use of a stronger acid led to the formation of complex mixtures containing predominantly products of the threemembered ring opening.Meanwhile, indolyl-substituted cyclopropane 8, which was obtained in two steps from the reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme 4).Similar AcOH-induced transformations of 3-indolylmethanols to bis(indolyl)methanes was previously described [39][40][41].Meanwhile, the presence of highly reactive donor-acceptor cyclopropane functionality in the starting alcohol 8 and two such moieties in the product 9 provides non-trivial nature this process.The obtained cyclopropa[c]coumarins 2 are potent substrates for the synthesis of diverse coumarin derivatives (Scheme 5).Thus, it was recently shown that such cyclopropacoumarins undergo Ni(ClO4)2-catalyzed nucleophilic ring opening under treatment with indole affording 4-(indolylmethyl)chroman-2-one-3-carboxylates [34].Nevertheless, our attempts to transform compounds 2 to the corresponding benzoxepan derivatives via their reduction with Zn/AcOH system [42] or Lewis acid-induced isomerization [43] were unsuccessful.Unexpectedly, the treatment of cyclopropacoumarin 2d with zinc and acetic acid in methanol did not afford the products of three-membered ring reduction.Instead, it led to the methanolysis of the lactone moiety in 2d producing cyclopropane 1d and a small amount of acyclic product 10 formed by the reduction of 1d (Scheme 6).Moreover, this cyclopropacoumarin remains intact under heating with both tin(II) triflate in dichloromethane and trimethylsilyl triflate in chlorobenzene for several hours.The absence of benzoxepane derivative in the reaction mixtures together with the aforementioned literature data on the nucleophilic attack of cyclopa[c]coumarins at the CH2 atom [34] demonstrate the decelerating effect of annulation on the reactivity of the C-C bond between atoms connected to donor and acceptor substituents.The effect of the annulated ring nature on the reactivity of donor-acceptor cyclopropanes deserve, evidently, a careful study.Nevertheless, our attempts to transform compounds 2 to the corresponding benzoxepan derivatives via their reduction with Zn/AcOH system [42] or Lewis acid-induced isomerization [43] were unsuccessful.Unexpectedly, the treatment of cyclopropacoumarin 2d with zinc and acetic acid in methanol did not afford the products of three-membered ring reduction.Instead, it led to the methanolysis of the lactone moiety in 2d producing cyclopropane 1d and a small amount of acyclic product 10 formed by the reduction of 1d (Scheme 6).Moreover, this cyclopropacoumarin remains intact under heating with both tin(II) triflate in dichloromethane and trimethylsilyl triflate in chlorobenzene for several hours.The absence of benzoxepane derivative in the reaction mixtures together with the aforementioned literature data on the nucleophilic attack of cyclopa[c]coumarins at the CH 2 atom [34] demonstrate the decelerating effect of annulation on the reactivity of the C-C bond between atoms con

C NMR for synthesized compounds as well as 2D (HSQC and HMBC) N
R spectra for selected compounds are available in the Supplementary Material.


General Procedure for the Synthesis of Cyclopropa[c]coumarins.

A toluene solution of cyclopropane 1 (0.03 or 0.04 M, 1 equiv) and glacial acetic acid (2 equiv) was heated for the specified time under reflux or using backflow condenser without cooling with water providing slow removal of the formed methanol.When 1 was completely converted (TLC control), the reaction mixture was cooled, diluted with ether (10 mL), washed with saturated NaHCO3 solution (3 × 15 mL), dried with Na2SO4 and concentrated in vacuo.The resulting residue was purified b