molecules Communication
Convenient Synthesis of Functionalized Cyclopropa[c]coumarin-1a-carboxylates Olga A. Ivanova 1, * , Vladimir A. Andronov 1 , Irina I. Levina 2 , Alexey O. Chagarovskiy 3 , Leonid G. Voskressensky 4 and Igor V. Trushkov 3,4, * 1 2 3 4
*
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russia;
[email protected] N. M. Emanuel Institute of Biochemical Physics, Russia Academy of Sciences, Kosygina 4, Moscow 119334, Russia;
[email protected] Laboratory of Chemical Synthesis, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela 1, Moscow 117997, Russia;
[email protected] Faculty of Science, RUDN University, Miklukho-Maklaya 6, Moscow 117198, Russia;
[email protected] Correspondence:
[email protected] (O.A.I.);
[email protected] (I.V.T.); Tel.: +7-916-645-9951 (I.V.T.)
Received: 1 December 2018; Accepted: 22 December 2018; Published: 24 December 2018
Abstract: 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. Keywords: donor-acceptor cyclopropanes; coumarins; heterocycles
1. Introduction The longstanding interest to coumarin derivatives stems from their wide distribution in Nature and a broad spectrum of bioactivity, including anticoagulant, anticonvulsant, antidepressant, anti-HIV, antiinflammatory, antimicrobial, antioxidative, antituberculosis, antitumor activities, etc. [1–11]. Coumarin derivatives are used in medicinal practice for the treatment of dementia [12], varicose veins [13], hemorrhoids [13], etc. [14]; they are applied as rodenticides [15] and as fluorophores in cell biology [16]. The high value of these compounds has stimulated their intensive investigation, i.e. the synthesis of novel coumarin derivatives, the study of their transformations and screening of their bioactivity, 3- and 4-substituted coumarins as well as their 3,4-dihydro derivatives being the most interesting substrates for the medicinal applications. Cyclopropa[c]coumarins, being the members of the donor-acceptor cyclopropanes subclass, are highly potent substrates for the preparation of a large diversity of functionalized coumarin derivatives due to a rich reactivity of the three-membered ring. Even though the first cyclopropanation of 3-acylcoumarins and coumarin-3-carboxylates with α-haloketones was described by Widman exactly 100 years ago (Scheme 1a) [17,18], cyclopropacoumarins remain poorly investigated due to the absence of efficient methods for their synthesis. Since Widman’s study, a number of cyclopropa [c]coumarins bearing diverse acceptor substituents at both C(1) and C(1a) atoms have been obtained by the related cyclopropanations under phase transfer catalysis (Scheme 1a) [19] or using diazoketones (Scheme 1b) [20–22]. Nevertheless, the application of diazoketones usually resulted in the formation of complex mixtures and low yields of target products. Moreover, 1,1,1a-substituted cyclopropa[c]coumarins were synthesized in reasonable yields by the treatment of coumarin-3-
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propa[c]coumarins were obtained 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, product yields were not given [34,35]. Therefore, the development of efficient Molecules 2019,however, 24, 57 2 of 11 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 carboxylates -carboxamides with α,α-dibromoketones and zinc (Scheme 1c)1) [23–25], on the use ofand 2-(2-hydroxyphenyl)cyclopropane-1,1-dicarboxylates (Scheme whichtrichloroacetic can be easily acid [26], phenyliodonium (Scheme 1d) [27] and diphenylsulfonium ylides (Scheme 1e) [28]. obtained from the corresponding salicylic aldehydes [36,37].
Scheme 1. Syntheses of cyclopropa[c]coumarins.
Oppositely, the reaction of much more reactive dimethylsulfoxonium methylide [29,30] 2. Results and Discussion with 3-acylcoumarins, coumarin-3-carboxylates, the corresponding nitriles as well as sulfones We started our research with a search for the optimal conditions for the transesterification of 2under the typical conditions of Corey-Chaykovsky cyclopropanation was found to afford hydroxy- and 2-(methoxymethoxy)phenyl-substituted cyclopropane-1,1-dicarboxylates 1a,b as cyclopenta[b]-benzofuran derivatives as a result of the fast secondary reaction of the initially model substrates using their treatment with base (K2CO3 or N,N-diisopropylethylamine, DIPEA) or formed cyclopropa[c]coumarins with a second equivalent of the Corey ylide [31–33]. The target Brønsted acid (Table 1). We have found that the highest yield of the target methyl cyclopropa[c]coumarins were obtained in low-to-moderate yields when the reaction was performed at cyclopropa[c]coumarin-3-carboxylate 2a was obtained when toluene solution of cyclopropane 1a was 0 ◦ C (for 3-ethoxycarbonyl-, 3-pivaloyl- and 3-cyanocoumarins) or at −40 ◦ C (for 3-acetyl and 3-benzoyl heated under reflux with 2 equiv of acetic acid (Table 1, entry 8). The use of stronger acids such as derivatives) (Scheme 1f) [31]. Very recently it was proposed to perform this cyclopropanation using trifluoroacetic acid (TFA) or p-toluenesulfonic acid (TsOH) resulted in the formation of complex very slow addition of the Corey ylide solution (5 mL for 6 h) to the corresponding coumarin derivative, mixture of products; any attempts to isolate 2a were unsuccessful. Base-induced reaction produced however, product yields were not given [34,35]. Therefore, the development of efficient procedure the desired product 2a in low yield only. 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]. 2. 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 (K2 CO3 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, entry 8). The use of stronger acids such as trifluoroacetic acid (TFA) or p-toluenesulfonic acid (TsOH) resulted in the formation of complex
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Table 1. Optimization of reaction conditions forunsuccessful. the intramolecular transesterification of model mixture of products; any attempts to isolate 2a were Base-induced reaction produced the 3 of 11 cyclopropanes desired product 2a 1a,b. in low yield only.
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Table 1. Optimization of reaction conditions for the intramolecular transesterification of model of reaction conditions for the intramolecular transesterification of model Table 1. Optimization cyclopropanes 1a,b. cyclopropanes 1a,b.
Initiator R Solvent Temp (°C) t (h) Yield, % 1 (mol %) 1 К2СO3 (130) 2 H DMSO 20 ◦ 3 30 Entry Entry InitiatorInitiator (mol %) 2 RR Solvent Temp Temp ( C)t (h) t Yield, (h) Yield, % 1 Solvent (°C) 2 К2(mol СO3 (130) H DMSO 20 25 30% 1 %) 2 3 1 HH DMSO 3 45 30 (130) (120) 3K CODIPEA PhCl 10020 5 2 1 2 К32СO3 (130) H DMSO 20 3 30 2 3 2 HH DMSO 20 30 K CO (130) 3TFA (110) 2 4 2 PhCl reflux 7 25 - 4 2 DIPEA К2СO 3 (130) H DMSO 20100 25 30 3 3 H PhCl 5 45 (120) 3 4 5 TsOH (5) 3 H CHCl3 reflux 5 3 TFA DIPEA H PhCl 100 5 45 3(120) 4 4 H PhCl reflux 7 (110) 3 5 6 AcOH3 (200) H PhMe 110 8 30 3 4 4 TFA (110) H PhCl reflux 7 5 H CHCl3 reflux 5 TsOH (5) -4 3 7 AcOH (200) H PhMe reflux 5 6 46 3 4 3 5 TsOH (5) H CHCl 3 reflux 5 6 H PhMe 8 30 AcOH (200) 110 3 8 AcOH (200) H PhMe reflux 9 61 3 5 3 6 AcOH AcOH H PhMe 110 8 30 7 H PhMe reflux 6 46 (200)(200) 3 9 AcOH (100) H PhCl reflux 6.5 55 6 3 3 7 AcOH AcOH H PhMe reflux 6 46 8 H PhMe reflux 9 61 (200)(200) 3 10 AcOH (200) PhMe reflux 16 6.5 72 3 3 9 HHH PhCl reflux (100)(200) 55 6 8 AcOH AcOH PhMe reflux 9 61 3 11 AcOH (200) MOM PhMe reflux 16 16 -6 3 3 10 HH PhMe reflux 6.5 72 (200)(100) 9 AcOH AcOH PhCl reflux 55 1 Isolated yield. 2 0.1 M solution 3 4 5 3 1a.H 0.03 M solution of 1a,b. of products. 11 PhMe reflux Complex 16mixture (200)(200) 3of MOM 10 AcOH AcOH PhMe reflux 16 72 6 1Reaction 2 0.1 5 Reaction was was11 performed irradiation. Dimethyl (200) MOM PhMe reflux 16 (2,3-dihydrobenzofuran-2Isolated yield. M AcOH solutionunder of 1a.3 3 microwave 0.03 M solution of 1a,b. 4 Complex mixture of products. 6 Dimethyl (2,3-dihydrobenzofuran-2-yl)malonate was also formed as side under microwave irradiation. yl)malonate was also formed as side product. For details, see ref. [36]. 1performed 2 3 4 Isolated yield. 0.1 M solution of 1a. 0.03 M solution of 1a,b. Complex mixture of products. 5 Entry
product. For details, see ref. [36].
Reaction was performed under microwave irradiation. 6 Dimethyl (2,3-dihydrobenzofuran-2With the optimized reaction conditions hand, wesee studied the scope of this transesterification yl)malonate was also formed as side product.in For details, ref. [36].
optimized reaction conditions in hand,ring we (halogens, studied thealkyl scope this group) transesterification and With foundthe that diverse substituents in the benzene orofnitro are tolerant and found that diverse substituents in the benzene ring (halogens, alkyl or nitro group) are tolerant to to the reaction conditions (Scheme 2). Oppositely, the reaction of 2-hydroxy-3-methoxyphenylWith the optimized reaction conditions in hand, we studied the scope of this transesterification the reaction conditions (Scheme 2). Oppositely, the reaction of 2-hydroxy-3-methoxyphenyl-substituted substituted 1g produced only amounts corresponding and found thatcyclopropane diverse substituents in the benzene ring trace (halogens, alkyl or of nitrothe group) are tolerant cyclopropane 1g produced only trace amounts of the corresponding cyclopropa[c]coumarin 2g. cyclopropa[c]coumarin 2g. to the reaction conditions (Scheme 2). Oppositely, the reaction of 2-hydroxy-3-methoxyphenyl-
substituted cyclopropane cyclopropa[c]coumarin 2g.
1g
produced
only
trace
amounts
of
the
corresponding
Scheme2.2.Synthesis Synthesisof ofcyclopropa[c]coumarins cyclopropa[c]coumarins2a–h. 2a–h.aa In In chlorobenzene. chlorobenzene. Scheme
To scope of the reaction, reaction, we have havestudied studied reactions cyclopropane3 3with with a To extend extend the the scope we reactions ofofcyclopropane a 2a In chlorobenzene. Scheme 2. Synthesis of cyclopropa[c]coumarins 2a–h. 2-(hydroxymethyl)phenyl group as a donor and its analogue 8 bearing a 3-hydroxymethyl-4-indolyl (hydroxymethyl)phenyl group as a donor and its bearing a 3-hydroxymethyl-4-indolyl substituent. However, in both cases we failed to obtain the corresponding of substituent. However, in both cases we failed to obtain the corresponding products of intramolecular intramolecular To extend the scope of the reaction, we have studied reactions of products cyclopropane 3 with a 2esterification. Thus, the heating of 3 with 2 equiv of acetic acid in both toluene and chlorobenzene (hydroxymethyl)phenyl group as a donor and its analogue 8 bearing a 3-hydroxymethyl-4-indolyl did not produce the desired 4 at all. large excess of acetic acid was applied, benzyl substituent. However, in bothoxepanone cases we failed to When obtainathe 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
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esterification. Thus, the heating of 3 with 2 equiv of acetic acid in both toluene and chlorobenzene did Molecules 2018, REVIEW 44of Molecules 2018,23, 23,xxxFOR FORPEER PEER REVIEW of11 11 Molecules 2018, 23, FOR PEER REVIEW 4 of 11 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 acetate acetate555was wasobtained obtainedas asaaasingle singlelow-molecular-weight low-molecular-weightproduct product(Scheme (Scheme3). 3).The Theuse useof ofaaastronger stronger acetate obtained as single low-molecular-weight product (Scheme of stronger led to the was formation of complex mixtures containing predominantly products3).ofThe the use three-membered acid led to the formation of complex mixtures containing predominantly products of acid led led to to the the formation formation of of complex complex mixtures mixtures containing containing predominantly predominantly products products of of the the threethreeacid the threering opening. membered ring opening. memberedring ringopening. opening. membered
aa Substrate concentration: Scheme 3. The attempt to synthesize benzoxepane 4. Scheme 0.04 M. Scheme3. Theattempt attemptto tosynthesize synthesizebenzoxepane benzoxepane4. Substrateconcentration: concentration:0.04 0.04M. M. Scheme 3.3.The The attempt to synthesize benzoxepane 4.4.a aSubstrate Substrate concentration: 0.04 M.
indolyl-substituted the Meanwhile, cyclopropane which Meanwhile, indolyl-substituted indolyl-substituted cyclopropane cyclopropane 8, which was was obtained obtained in in two two steps steps from from the the Meanwhile, indolyl-substituted cyclopropane 8,8, which which was obtained in two steps from the cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 reported cyclopropane 6 [38], under heating with acetic acid afforded bis(indolyl)methane 9 (Scheme 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 (Scheme 4). Similar AcOH-induced transformations of 3-indolylmethanols to bis(indolyl)methanes was 4). Similar Similar AcOH-induced AcOH-induced transformations transformations of of 3-indolylmethanols 3-indolylmethanols to to bis(indolyl)methanes bis(indolyl)methanes was was 4). previously described [39–41]. Meanwhile, the reactive previously [39–41]. Meanwhile, the presence of highly of reactive donor-acceptor cyclopropane previouslydescribed described [39–41]. Meanwhile, the presence presence of highly highly reactive donor-acceptor donor-acceptor previously described [39–41]. Meanwhile, the presence of highly reactive donor-acceptor cyclopropane functionality the 888and two moieties in product 999provides functionality the startingin alcohol 8 andalcohol two such moieties in the product 9the provides cyclopropanein functionality in thestarting starting alcohol and twosuch such moieties inthe productnon-trivial provides cyclopropane functionality in the starting alcohol and two such moieties in the product provides non-trivial nature this process. nature this process. non-trivialnature naturethis thisprocess. process. non-trivial
Scheme 4. Synthesis and acetic acid-induced dimerization of indolylmethanol 8. Scheme4. Synthesisand andacetic aceticacid-induced acid-induceddimerization dimerizationof ofindolylmethanol indolylmethanol8. Scheme 4.4.Synthesis dimerization of indolylmethanol 8.8.
The obtained cyclopropa[c]coumarins 222potent are substrates diverse The cyclopropa[c]coumarins 2 are substrates for the for synthesis of diverseof coumarin Theobtained obtained cyclopropa[c]coumarins are potent potent substrates for the the synthesis synthesis of diverse The obtained cyclopropa[c]coumarins are potent substrates for the synthesis of diverse coumarin derivatives (Scheme 5). Thus, it was recently shown that such cyclopropacoumarins derivatives (Scheme 5). Thus, it was recently shown that such cyclopropacoumarins undergo coumarin derivatives derivatives (Scheme (Scheme 5). 5). Thus, Thus, itit was was recently recently shown shown that that such such cyclopropacoumarins cyclopropacoumarins coumarin undergo nucleophilic ring opening under treatment with affording Ni(ClO -catalyzed nucleophilic ring opening under treatment with indole affording 4-(indolylmethyl) 4 )2Ni(ClO undergo Ni(ClO44)4))22-catalyzed 2-catalyzed -catalyzed nucleophilic ring opening under treatment with indole indole affording 44undergo Ni(ClO nucleophilic ring opening under treatment with indole affording 4(indolylmethyl)chroman-2-one-3-carboxylates [34]. chroman-2-one-3-carboxylates [34]. (indolylmethyl)chroman-2-one-3-carboxylates[34]. [34]. (indolylmethyl)chroman-2-one-3-carboxylates
Scheme 5. cyclopropa[c]coumarins. Scheme5. Nucleophilicring ringopening openingof ofcyclopropa[c]coumarins. cyclopropa[c]coumarins. Scheme 5.5.Nucleophilic Nucleophilic ring opening of cyclopropa[c]coumarins.
Nevertheless, attempts to transform compounds to the corresponding benzoxepan Nevertheless, our Nevertheless, our our attempts attempts to to transform transform compounds compounds 222 to to the the corresponding corresponding benzoxepan benzoxepan Nevertheless, to the corresponding benzoxepan derivatives via their reduction with Zn/AcOH system [42] or Lewis acid-induced isomerization [43] derivatives derivativesvia viatheir theirreduction reductionwith withZn/AcOH Zn/AcOHsystem system[42] [42]or orLewis Lewisacid-induced acid-inducedisomerization isomerization[43] [43] derivatives via their reduction with Zn/AcOH [43] were unsuccessful. Unexpectedly, the treatment of cyclopropacoumarin 2d with zinc and acetic acid were Unexpectedly,the thetreatment treatment cyclopropacoumarin 2d with acetic wereunsuccessful. unsuccessful.Unexpectedly, Unexpectedly, the treatment ofof cyclopropacoumarin 2dwith with zinczinc andand acetic acid were of cyclopropacoumarin 2d zinc and acetic acid in did the of ring reduction. Instead, it to acid in methanol did not afford the products of three-membered reduction. Instead, it led to in methanol methanol did not not afford afford the products products of three-membered three-membered ringring reduction. Instead, led to the the in methanol did not afford the products of three-membered ring reduction. Instead, itit led led to the methanolysis of the lactone moiety in 2d producing cyclopropane 1d and a small amount of acyclic the methanolysis methanolysis ofthe the of lactone the lactone lactone moiety moiety in2d 2din producing 2d producing cyclopropane cyclopropane 1dand and 1daaand small a amount small amount amount ofacyclic acyclic of methanolysis of moiety in producing cyclopropane 1d small of product 10 by of 6). this remains acyclic product 10 formed by the reduction of 1d (Scheme 6). Moreover, this cyclopropacoumarin product 10formed formed bythe thereduction reduction of1d 1d(Scheme (Scheme 6).Moreover, Moreover, thiscyclopropacoumarin cyclopropacoumarin remains product 10 formed by the reduction of 1d (Scheme 6). Moreover, this cyclopropacoumarin remains intact with triflate in and trimethylsilyl triflate in remains intactheating under heating withtin(II) both tin(II) triflate in dichloromethane trimethylsilyl triflate intact under under heating with both both tin(II) triflate in dichloromethane dichloromethane andand trimethylsilyl triflate in 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 chlorobenzene for for several several hours. hours. The The absence absence of of benzoxepane benzoxepane derivative derivative in in the the reaction reaction mixtures mixtures chlorobenzene together togetherwith withthe theaforementioned aforementionedliterature literaturedata dataon onthe thenucleophilic nucleophilicattack attackof ofcyclopa[c]coumarins cyclopa[c]coumarins 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 at the the CH CH22 atom atom [34] [34] demonstrate demonstrate the the decelerating decelerating effect effect of of annulation annulation on on the the reactivity reactivity of of the the C‐C C‐C at bond bondbetween betweenatoms atomsconnected connectedto todonor donorand andacceptor acceptorsubstituents. substituents.The Theeffect effectof ofthe theannulated annulatedring ring bond between atoms connected to donor and acceptor substituents. The effect of the annulated ring nature natureon onthe thereactivity reactivityof ofdonor-acceptor donor-acceptorcyclopropanes cyclopropanesdeserve, deserve,evidently, evidently,aaacareful carefulstudy. study. nature on the reactivity of donor-acceptor cyclopropanes deserve, evidently, careful study.
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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 Molecules 2018, 23, x FOR PEER REVIEW cyclopropanes deserve, evidently, a careful study. 5 of 11
Scheme 6. Attempts of a ring enlargement of cyclopropa[c]coumarin 2d.
3. Experimental Experimental 3. 3.1. General Information 3.1. General Information The structures of synthesized compounds were elucidated with the aid of 1D NMR (1 H, 13 C) The structures of synthesized1compounds were elucidated with the aid of 1D NMR (1H, 13C) and 13 and 2D NMR (HSQC and HMBC H- C) spectroscopy. NMR spectra were acquired on Avance 500 2D NMR (HSQC and HMBC 1H-13C) spectroscopy. NMR spectra were acquired on Avance 500 (Bruker, Billerica, MA, USA) and 400-MR (Agilent, Santa Clara, CA, USA) spectrometers at room (Bruker, Billerica, MA, USA) and 400-MR (Agilent, Santa Clara, CA, USA) spectrometers at room temperature; the chemical shifts δ were measured in ppm with respect to solvent (11H: CDCl3 , δ = 7.27 temperature; the chemical shifts δ were measured in ppm with respect to solvent ( Н: CDCl 3, δ = 7.27 ppm; 13 C: CDCl , δ = 77.0). Splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, ppm; 13C: CDCl33, δ = 77.0). Splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, double doublet; br., broad. Coupling constants (J) are in Hertz. Infrared spectra were recorded on double doublet; br., broad. Coupling constants (J) are in Hertz. Infrared spectra were recorded on an an Infralum FT-801 spectrometer (Simex, Novosibirsk, Russia). High resolution and accurate mass Infralum FT-801 spectrometer (Simex, Novosibirsk, TM Russia). High resolution and accurate mass measurements were carried out using a micrOTOF-Q TM ESI-TOF (Electrospray Ionization/Time of measurements were carried out using a micrOTOF-Q ESI-TOF (Electrospray Ionization/Time of Flight, Bruker, Billerica, MA, USA), LTQ Orbitrap (Thermo Fischer Scientific, Waltham, MA, USA) mass Flight, Bruker, Billerica, MA, USA), LTQ Orbitrap (Thermo Fischer Scientific, Waltham, MA, USA) spectrometers and a Triple TOF 5600+ instrument (AB Sciex, Darmstadt, Germany) using ESI modes. mass spectrometers and a Triple TOF 5600+ instrument (AB Sciex, Darmstadt, Germany) using ESI Elemental analyses were performed with an EA-1108 CHNS elemental analyser instrument (Fisons, modes. Elemental analyses were performed with an EA-1108 CHNS elemental analyser instrument Ipswich, UK). Melting points (mp) are uncorrected and were measured on a 9100 capillary melting (Fisons, Ipswich, UK). Melting points (mp) are uncorrected and were measured on a 9100 capillary point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) was carried melting point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) out with silica gel plates (silica gel 60, F254 , supported on aluminium); visualization was done using a was carried out with silica gel plates (silica gel 60, F254, supported on aluminium); visualization was UV lamp (365 nm). Column chromatography was performed on silica gel 60 (230–400 mesh, Merck, done using a UV lamp (365 nm). Column chromatography was performed on silica gel 60 (230–400 Darmstadt, Germany). All reactions were carried out using freshly distilled and dry solvents. Dimethyl mesh, Merck, Darmstadt, Germany). All reactions were carried out using freshly distilled and dry 2-(2-hydroxyaryl)cyclopropane-1,1-dicarboxylate was synthesized by the published procedure [36,37]. solvents. Dimethyl 2-(2-hydroxyaryl)cyclopropane-1,1-dicarboxylate was synthesized by the Commercial reagents employed in the synthesis were analytical grade, obtained from Aldrich (St. Louis, published procedure [36,37]. Commercial reagents employed in the synthesis were analytical grade, MI, USA) or Alfa Aesar (Ward Hill, MO, USA). Cyclopropanes 3 and 6 were obtained by the reported obtained from Aldrich (St. Louis, MI, USA) or Alfa Aesar (Ward Hill, MO, USA). Cyclopropanes 3 procedures [36,38]. The 1 H NMR, 13 C NMR for synthesized compounds as well as 2D (HSQC and and 6 were obtained by the reported procedures [36,38]. The 1H NMR, 13C NMR for synthesized HMBC) NMR spectra for selected compounds are available in the Supplementary Material. compounds as well as 2D (HSQC and HMBC) NMR spectra for selected compounds are available in the Material. 3.2. Supplementary General Procedure for the Synthesis of Cyclopropa[c]coumarins A toluene solution cyclopropane 1 (0.03 or 0.04 M, 1 equiv) and glacial acetic acid (2 equiv) was 3.2. General Procedure forofthe Synthesis of Cyclopropa[c]coumarins. heated for the specified time under reflux or using backflow condenser without cooling with water A toluene solution of cyclopropane 1 (0.03 or 0.04 M, 1 equiv) and glacial acetic acid (2 equiv) providing slow removal of the formed methanol. When 1 was completely converted (TLC control), the was heated for the specified time under reflux or using backflow condenser without cooling with reaction mixture was cooled, diluted with ether (10 mL), washed with saturated NaHCO3 solution water providing slow removal of the formed methanol. When 1 was completely converted (TLC (3 × 15 mL), dried with Na2 SO4 and concentrated in vacuo. The resulting residue was purified by control), the reaction mixture was cooled, diluted with ether (10 mL), washed with saturated NaHCO3 flash chromatography on silica gel (eluent: 10–50% ethyl acetate in petroleum ether) to afford the target solution (3 × 15 mL), dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified cyclopropacoumarin 2 (Figure 1). by flash chromatography on silica gel (eluent: 10–50% ethyl acetate in petroleum ether) to afford the target cyclopropacoumarin 2 (Figure 1).
Methyl (1aRS,7bRS)-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2a). Dimethyl 2- (2hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1a, 120 mg, 0.48 mmol), AcOH (58 mg, 55 µ L, 0.96 mmol), toluene (12 mL), reflux, 16 h. Rf = 0.55 (ethyl acetate:petroleum ether 1:2). Yield 75 mg (72%);
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Figure Figure 1. 1. Atom Atom numbering numbering in in compounds compounds 2. 2.
Methyl (1aRS,7bRS)-6-chloro-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2b). Dimethyl Methyl (1aRS,7bRS)-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2a). Dimethyl 22-(5-chloro-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1b) (120 mg, 0.42 mmol), AcOH (51 (2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1a, 120 mg, 0.48 mmol), AcOH (58 mg, 55 µL, mg, 48 µ L, 0.84 mmol), toluene (12 mL), reflux, 10 h. Rf = 0.31 (ethyl acetate:petroleum ether 1:4). Yield 0.96 mmol), toluene (12 mL), reflux, 16 h. Rf = 0.55 (ethyl acetate:petroleum ether 1:2). Yield 75 mg 71 mg (67%); colorless solid; mp = 111–112 °C (lit. 119–121 °C [34]). 1Н-NMR (CDCl3, 500 MHz) δ = ◦ C (lit. 100–102 ◦ C [34,35]; oil [37]). Spectral data are consistent (72%); colorless solid; mp = 98–100 1.41 (dd, 2J = 5.2 Hz, 3J = 6.4 Hz, 1H, CH2), 2.50 (dd, 2J = 5.2 Hz, 3J =9.2 Hz, 1H, CH2), 2.89 (dd, 3J = 9.2 with reported ones [34,35]. Hz, 3the J = 6.4 Hz, 1H, CH), 3.86 (s, 3H, CH3O), 7.00 (d, 3J = 8.7 Hz, 1H, Ar), 7.24 (dd, 3J = 8.7 Hz, 4J = 2.3 Hz, 1H, Ar), 7.37 (d, 4J = 2.3 Hz, 1H, Ar). 13С-NMR (CDCl3, 125 MHz) δ = 21.1 (CH2), 28.7 (CH), 29.7 Methyl (1aRS,7bRS)-6-chloro-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2b). Dimethyl (C), 53.4 (CH3O), 118.6 (CH, Ar), 121.7 (C, Ar), 127.6 (CH, Ar), 128.6 (CH, Ar), 129.8 (С, Ar), 148.0 (C, 2-(5-chloro-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1b) (120 mg, 0.421763, mmol), AcOH (511435, mg, Ar), 161.7 (CO), 167.7 (CO2Me). IR (сm−1) 3110, 3066, 2950, 2955, 2922, 2853, 1723, 1484, 48 µL,1319, 0.84 mmol), toluene mL),1052, reflux, 10HRMS h. Rf =ESI-TOF: 0.31 (ethyl acetate:petroleum ether 1:4). Yield 71 + (253.0262 1369, 1283, 1259, 1107,(12 1085, 946. m/z = 253.0265 [M + H] сalcd ◦ C (lit. 119–121 ◦ C [34]). 1 H-NMR (CDCl , 500 MHz) δ = 1.41 mg (67%); colorless solid; mp = 111–112 3 for C12H10ClO4). (dd, 2 J = 5.2 Hz, 3 J = 6.4 Hz, 1H, CH2 ), 2.50 (dd, 2 J = 5.2 Hz, 3 J =9.2 Hz, 1H, CH2 ), 2.89 (dd, 3 J = 9.2 Hz, (2c).4 JDimethyl 3Methyl J = 6.4 (1aRS,7bRS)-6-bromo-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate Hz, 1H, CH), 3.86 (s, 3H, CH3 O), 7.00 (d, 3 J = 8.7 Hz, 1H, Ar), 7.24 (dd, 3 J = 8.7 Hz, = 2.3 Hz, 2-(5-bromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1c, 200 mg, 0.61 mmol), AcOH (73 mg, 4 13 1H, Ar), 7.37 (d, J = 2.3 Hz, 1H, Ar). C-NMR (CDCl3 , 125 MHz) δ = 21.1 (CH2 ), 28.7 (CH), 29.7 (C), 70 µ L, 1.2 mmol), toluene (15 mL), reflux, 18 h. Rf = 0.70 (ethyl acetate:petroleum ether 1:4). Yield 126 53.4 (CH3 O), 118.6 (CH, Ar), 121.7 (C, Ar), 127.6 (CH, Ar), 128.6 (CH, Ar), 129.8 (C, Ar), 148.0 (C, Ar), mg (71%); colorless solid; mp = 114–115 °C (lit. 105–107 °C [34]). 1Н-NMR (CDCl3, 500 MHz) δ = 1.40 161.72(CO), 167.73 (CO2 Me). IR (cm−1 ) 3110, 3066, 2950, 2955, 2922, 2853, 1763, 1723, 1484, 1435, 1369, (dd, J = 5.1 Hz, J = 6.4 Hz, 1H, CH2), 2.21 (dd, 2J = 5.1 Hz, 3J = 9.2 Hz, 1H, CH2),+2.89 (dd, 3J = 9.2 Hz, 1319, 1283, 1259, 1107, 1085, 1052, 946. HRMS ESI-TOF: m/z = 253.0265 [M + H] (253.0262 calcd for 3J = 6.4 Hz, 1H, CH), 3.85 (s, 3H, CH3O), 6.92 (d, 3J = 8.7 Hz, 1H, Ar), 7.38 (dd, 3J = 8.7 Hz, 4J = 2.3 Hz, C12 H10 ClO4 ). 1H, Ar), 7.50 (d, 4J = 2.3 Hz, 1H, Ar). 13С-NMR (CDCl3, 125 MHz) δ = 21.1 (CH2), 28.3 (C), 28.5 (CH), 53.3 (CH3O), 117.0 (C, Ar), 118.8 (CH, Ar), 122.1 (C, Ar), 130.4 (CH, Ar), 131.5 (CH, Ar), 148.5 (С, Ar), Methyl (1aRS,7bRS)-6-bromo-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2c). Dimethyl 161.5 (CO), 167.6 (CO2Me). IR (сm−1) 3256, 2956, 1762, 1673, 1498, 1440, 1415, 1352, 1276, 1196, 1154, 2-(5-bromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1c, 200 mg, 0.61 mmol), AcOH (73 mg, 1108, 1074. HRMS ESI-TOF: m/z = 296.9757 [M + H]+ (296.9757 сalcd for C12H10BrO4). 70 µL, 1.2 mmol), toluene (15 mL), reflux, 18 h. Rf = 0.70 (ethyl acetate:petroleum ether 1:4). Yield Methyl Dimethyl 126 mg (1aRS,7bRS)-6-fluoro-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (71%); colorless solid; mp = 114–115 ◦ C (lit. 105–107 ◦ C [34]). 1 H-NMR (CDCl3 ,(2d). 500 MHz) δ= 2 3 2 3 3 2-(5-fluoro-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1d, 200 mg, 0.75 mmol), AcOH (90 mg, 1.40 (dd, J = 5.1 Hz, J = 6.4 Hz, 1H, CH2 ), 2.21 (dd, J = 5.1 Hz, J = 9.2 Hz, 1H, CH2 ), 2.89 (dd, J = 3 J = 6.4 3 J = 8.7 85 µHz, L, 1.49 mmol), toluene boiling with backflow condenser, 8 h; 7.38 then(dd, an extra portion 9.2 Hz, 1H, CH), (11 3.85mL), (s, 3H, CH3 O), 6.92 (d, 3 J = 8.7 Hz, 1H, Ar), Hz, 4 J of = 4 13 AcOH (90 mg, 85 µ L, 1.49 mmol), reflux, 7 h. R f = 0.69 (ethyl acetate:petroleum ether 1:2). Yield 150 2.3 Hz, 1H, Ar), 7.50 (d, J = 2.3 Hz, 1H, Ar). C-NMR (CDCl3 , 125 MHz) δ = 21.1 (CH2 ), 28.3 (C), 28.5 mg (75%); colorless solid; mp = 90–91 °C (lit. 93–95 °C [34]). 1Н-NMR (CDCl3, 400 MHz) δ = 1.40 (dd, (CH), 53.3 (CH 3 O), 117.0 (C, Ar), 118.8 (CH, Ar), 122.1 (C, Ar), 130.4 (CH, Ar), 131.5 (CH, Ar), 148.5 (C, 2J = 5.1 Hz, 3J = 6.3 Hz, 1H, CH2), 2.59 (dd, 2J = 5.1 Hz, 3J =9.0 Hz, 1H, CH2), 2.88 (dd, 3J = 9.0 Hz, 3J = 6.3 Ar), 161.5 (CO), 167.6 (CO2 Me). IR (cm−1 ) 3256, 2956, 1762, 1673, 1498, 1440, 1415, 1352, 1276, 1196, Hz, 1H, CH), 3.84 (s, 3H, CH3O), 6.93–7.02 (m, 2H, Ar), 7.07 (dd, 3J = 8.2 Hz, 4JHF = 3.0 Hz, 1H, Ar). 13С1154, 1108, 1074. HRMS ESI-TOF: m/z = 296.9757 [M + H]+ (296.9757 calcd for C12 H10 BrO4 ). NMR (CDCl3, 100 MHz) δ = 21.2 (CH2), 28.3 (C), 29.0 (CH), 53.5 (CH3O), 114.5 (d, 2JCF = 24 Hz, CH, Ar), 115.5 (d, 2JCF = 24 Hz, CH, Ar), 118.7 (d, 3JCF = 9 Hz, CH, Ar), 121.7 (d, 3JCF = 8 Hz, C, Ar),Dimethyl 145.6 (C, Methyl (1aRS,7bRS)-6-fluoro-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2d). Ar), 158.5 (d, 1JCF = 243 Hz, C, Ar), 162.1 (CO), 167.9 (CO2Me). IR (сm−1) 1759, 1724, 1579, 1496, 1441, 2-(5-fluoro-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1d, 200 mg, 0.75 mmol), AcOH (90 mg, 1375, 1325, 1288, 1250, 1197, 1149, 1107, 1057, 987, 966, 931. HRMS ESI-TOF: m/z = 237.0555 [M + H]+ 85 µL, 1.49 mmol), toluene (11 mL), boiling with backflow condenser, 8 h; then an extra portion of (237.0558 сalcd for C12H10 FO4). AcOH (90 mg, 85 µL, 1.49 mmol), reflux, 7 h. Rf = 0.69 (ethyl acetate:petroleum ether 1:2). Yield 150 mg 2J = Methylcolorless (1aRS,7bRS)-4-methyl-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (75%); solid; mp = 90–91 ◦ C (lit. 93–95 ◦ C [34]). 1 H-NMR (CDCl3 , 400 MHz) δ = 1.40 (dd, (2e). Dimethyl (1e,(dd, 1803 J mg, 5.1 Hz, 3 J =2-(3-methyl-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate 6.3 Hz, 1H, CH2 ), 2.59 (dd, 2 J = 5.1 Hz, 3 J =9.0 Hz, 1H, CH2 ), 2.88 = 9.00.64 Hz, 3mmol), J = 6.3 3 4 AcOH L, 2.6 toluene (12 mL), reflux, 10 h. R f =8.2 0.75 (ethyl acetate:petroleum Hz, 1H,(158 CH),mg, 3.84160 (s, µ3H, CHmmol), O), 6.93–7.02 (m, 2H, Ar), 7.07 (dd, J = Hz, J = 3.0 Hz, 1H, Ar). 3 HF 1Н-NMR (CDCl3, 500 MHz) 13 2 ether 1:2). Yield 113 mg (76%); colorless solid; mp = 82–83 °C. δ = 1.37 (dd, C- NMR (CDCl3 , 100 MHz) δ = 21.2 (CH2 ), 28.3 (C), 29.0 (CH), 53.5 (CH3 O), 114.5 (d, JCF = 24 Hz, 2J = 4.9 Hz, 3J = 6.7 2Hz, 1H, CH2), 2.30 (s, 3H, CH3), 32.46 (dd, 2J = 4.9 Hz, 3J =9.2 Hz, 31H, CH2), 2.90 (dd, CH, Ar), 115.5 (d, JCF = 24 Hz, CH, Ar), 118.7 (d, JCF = 9 Hz, CH, Ar), 121.7 (d, JCF = 8 Hz, C, Ar), 3J = 9.2 Hz, 3J = 6.7 Hz, 1H, 3O), 7.03 (dd, 3J = 7.6 Hz, 3J = 7.4 Hz, 7.111579, (br. 145.6 (C, Ar), 158.5 (d, 1 JCF CH), = 2433.84 Hz,(s, C,3H, Ar),CH 162.1 (CO), 167.9 (CO2 Me). IR (cm−1 ) 1H, 1759,Ar), 1724, 3 3 13 d, J =1441, 7.6 Hz, 1H,1325, Ar), 1288, 7.18 (br. d, 1197, J = 7.41149, Hz, 1107, 1H, Ar). 3, 125 MHz) δ = 15.6 (CH3), 20.9 1496, 1375, 1250, 1057,С-NMR 987, 966,(CDCl 931. HRMS ESI-TOF: m/z = 237.0555 (CH 2), 28.6 (C), 29.3 (CH), 53.1 (CH 3O), 119.6 (C, Ar), 124.0 (CH, Ar), 125.2 (CH, Ar), 126.5 (C, Ar), + [M + H] (237.0558 calcd for C12 H10 FO4 ). 130.0 (CH, Ar), 147.7 (C, Ar), 162.4 (CO), 168.1 (CO2Me). IR (сm−1) 3106, 3040, 2957, 2924, 2853, 1746, 1730, 1471, 1434, 1395, 1327, 1292, 1230, 1192, 1116, 1098, 1057, 1039, 946, 925. HRMS ESI-TOF: m/z = 233.0810 [M + H]+ (233.0808 сalcd for C13H13O4). Methyl (1aRS,7bRS)-4,6-dibromo-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2f). Dimethyl 2-(3,5-dibromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1f, 200 mg, 0.49 mmol),
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Methyl (1aRS,7bRS)-4-methyl-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2e). Dimethyl 2-(3-methyl-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1e, 180 mg, 0.64 mmol), AcOH (158 mg, 160 µL, 2.6 mmol), toluene (12 mL), reflux, 10 h. Rf = 0.75 (ethyl acetate:petroleum ether 1:2). Yield 113 mg (76%); colorless solid; mp = 82–83 ◦ C. 1 H-NMR (CDCl3 , 500 MHz) δ = 1.37 (dd, 2 J = 4.9 Hz, 3 J = 6.7 Hz, 1H, CH2 ), 2.30 (s, 3H, CH3 ), 2.46 (dd, 2 J = 4.9 Hz, 3 J =9.2 Hz, 1H, CH2 ), 2.90 (dd, 3 J = 9.2 Hz, 3 J = 6.7 Hz, 1H, CH), 3.84 (s, 3H, CH3 O), 7.03 (dd, 3 J = 7.6 Hz, 3 J = 7.4 Hz, 1H, Ar), 7.11 (br. d, 3 J = 7.6 Hz, 1H, Ar), 7.18 (br. d, 3 J = 7.4 Hz, 1H, Ar). 13 C-NMR (CDCl3 , 125 MHz) δ = 15.6 (CH3 ), 20.9 (CH2 ), 28.6 (C), 29.3 (CH), 53.1 (CH3 O), 119.6 (C, Ar), 124.0 (CH, Ar), 125.2 (CH, Ar), 126.5 (C, Ar), 130.0 (CH, Ar), 147.7 (C, Ar), 162.4 (CO), 168.1 (CO2 Me). IR (cm−1 ) 3106, 3040, 2957, 2924, 2853, 1746, 1730, 1471, 1434, 1395, 1327, 1292, 1230, 1192, 1116, 1098, 1057, 1039, 946, 925. HRMS ESI-TOF: m/z = 233.0810 [M + H]+ (233.0808 calcd for C13 H13 O4 ). Methyl (1aRS,7bRS)-4,6-dibromo-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2f). Dimethyl 2-(3,5-dibromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1f, 200 mg, 0.49 mmol), AcOH (30 mg, 28 µL, 0.49 mmol), toluene (11 mL), boiling with backflow condenser, 5 h, then an extra portion of AcOH (60 mg, 56 µL, 0.98 mmol), reflux, 4 h. Rf = 0.52 (ethyl acetate:petroleum ether 1:4). Yield 90 mg (49%); colorless solid; mp = 77–78 ◦ C. 1 H-NMR (CDCl3 , 500 MHz) δ = 1.45 (dd, 2 J = 5.2 Hz, 3 J = 6.4 Hz, 1H, CH ), 2.51 (dd, 2 J = 5.2 Hz, 3 J =9.2 Hz, 1H, CH ), 2.90 (dd, 3 J = 9.2 Hz, 3 J = 6.4 Hz, 2 2 1H, CH), 3.86 (s, 3H, CH3 O), 7.47 (d, 4 J = 2.3 Hz, 1H, Ar), 7.67 (d, 4 J = 2.3 Hz, 1H, Ar). 13 C-NMR (CDCl3 , 125 MHz) δ = 21.1 (CH2 ), 28.8 (C), 29.0 (CH), 53.7 (CH3 O), 112.0 (C, Ar), 117.2 (C, Ar), 123.5 (C, Ar), 129.8 (CH, Ar), 134.9 (CH, Ar), 146.0 (C, Ar), 160.6 (CO), 167.5 (CO2 Me). IR (film, cm−1 ) 3447, 3078, 3005, 2954, 2924, 2851, 1777, 1725, 1453, 1439, 1368, 1324, 1239, 1207, 1071, 1045, 991, 985. HRMS ESI-TOF: m/z = 374.8856 [M + H]+ (374.8862 calcd for C12 H9 Br2 O4 ). Methyl (1aRS,7bRS)-6-nitro-2-oxo-1,7b-dihydrocyclopropa[c]chromene-1a(2H)-carboxylate (2h). Dimethyl 2-(5-nitro-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1h, 200 mg, 0.68 mmol), AcOH (81 mg, 78 µL, 1.35 mmol), toluene (17 mL), boiling with backflow condenser, 7 h, then an extra portion of AcOH (81 mg, 78 µL, 1.35 mmol), reflux, 10 h. Rf = 0.63 (ethyl acetate:petroleum ether 1:4). Yield 97 mg (55%); colorless solid; mp = 146–147 ◦ C. 1 H-NMR (CDCl3 , 500 MHz) δ = 1.49 (dd, 2 J = 5.3 Hz, 3 J = 6.4 Hz, 1H, CH2 ), 2.59 (dd, 2 J = 5.3 Hz, 3 J =9.2 Hz, 1H, CH2 ), 3.06 (dd, 3 J = 9.2 Hz, 3 J = 6.4 Hz, 1H, CH), 3.88 (s, 3H, CH3 O), 7.19 (d, 3 J = 9.0 Hz, 1H, Ar), 8.18 (dd, 3 J = 9.0 Hz, 4 J = 2.8 Hz, 1H, Ar), 8.33 (br. d, 4 J = 2.8 Hz, 1H, Ar). 13 C-NMR (CDCl3 , 125 MHz) δ = 21.2 (CH2 ), 28.3 (C), 28.4 (CH), 53.5 (CH3 O), 118.2 (CH, Ar), 121.3 (C, Ar), 123.8 (CH, Ar), 124.3 (CH, Ar), 144.2 (C, Ar), 153.7 (C, Ar), 160.6 (CO), 167.2 (CO2 Me). IR (film, cm−1 ) 3117, 2957, 2923, 2854, 1778, 1730, 1591, 1527, 1492, 1443, 1337, 1316, 1252, 1128, 1107, 1048, 979. HRMS ESI-TOF: m/z = 264.0502 [M + H]+ (264.0503 calcd for C12 H10 NO6 ). Dimethyl 2-[2-(acetoxymethyl)phenyl]cyclopropane-1,1-dicarboxylate (5). A solution of cyclopropane 3 (190 mg, 0.72 mmol) and glacial acetic acid (1.6 mL, 28 mmol, 40 equiv.) in chlorobenzene (14 mL) was refluxed for 16 h, cooled, diluted with CH2 Cl2 (10 mL), washed with saturated NaHCO3 solution (3 × 15 mL), dried with Na2 SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent: 10–30% ethyl acetate in petroleum ether) to afford acetate 4 as colorless oil. Rf = 0.57 (ethyl acetate:petroleum ether 1:3). Yield 148 mg (67%). 1 H-NMR (CDCl3 , 400 MHz) δ = 1.74 (dd, 2 J = 5.2 Hz, 3 J = 9.2 Hz, 1H, CH2 ), 2.07 (s, 3H, CH3 CO), 2.28 (dd, 2 J = 5.2 Hz, 3 J = 8.2 Hz, 1H, CH2 ), 3.28 (s, 3H, CH3 O), 3.30 (dd, 3 J = 9.2 Hz, 3 J = 8.2 Hz, 1H, CH), 3.78 (s, 3H, CH3 O), 5.12 (AB system, 2 J = 12.7 Hz, 1H, CH2 O), 5.27 (AB system, 2 J = 12.7 Hz, 1H, CH2 O), 7.07–7.10 (m, 1H, Ar), 7.23–7.27 (m, 2H, Ar), 7.30–7.33 (m, 1H, Ar). 13 C-NMR (CDCl3 , 100 MHz) δ = 18.2 (CH2 ), 20.8 (CH3 ), 29.9 (CH), 36.6 (C), 52.1 (CH3 O), 52.8 (CH3 O), 64.2 (CH2 O), 127.5 (CH, Ar), 127.7 (CH, Ar), 128.1 (CH, Ar), 129.3 (CH, Ar), 133.1 (C, Ar), 136.2 (C, Ar), 166.7 (MeCO2 ), 169.8 (CO2 Me), 170.7 (CO2 Me). IR (cm−1 ) 3066, 3027, 3005, 2954, 2904, 2848, 2256, 1741, 1735, 1496, 1438, 1378, 1332, 1282, 1230, 1207, 1134, 1026, 968, 920. HRMS ESI-TOF: m/z = 307.1176 [M + Na]+ (307.1176 calcd for C16 H19 O6 ).
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Dimethyl 2-(3-formyl-1-methyl-1H-indol-4-yl)cyclopropane-1,1-dicarboxylate (7). DMF (1 mL) and POCl3 (0.3 mL, 3.2 mmol) were mixed at 10 ◦ C under argon atmosphere. After 20 min to the resulting mixture cyclopropane 6 (840 mg, 2.9 mmol) in DMF (1 mL) was added. The obtained mixture was stirred at room temperature for 2 h and poured into ice-cold water (15 mL). The formed clear solution was treated with aq. NaOH (620 mg in 3 mL). Product was extracted with ethyl acetate. Combined organic fractions were washed with brine (4 × 10 mL) and dried with Na2 SO4 . Solvent was evaporated. Product was obtained as brown crystals (850 mg, 92%). Analytical sample was obtained by column chromatography on silica gel as yellow crystals. Rf = 0.54 (ethyl acetate); mp 192–193 ◦ C. 1 H-NMR (CDCl3 , 500 MHz) δ = 1.95 (dd, 2 J = 5.0 Hz, 3 J = 9.0 Hz, 1H, CH2 ), 2.40 (dd, 2 J = 5.0 Hz, 3 J = 8.1 Hz, 1H, CH2 ), 3.18 (s, 3H, CH3 O), 3.87 (s, 6H, CH3 N, CH3 O), 4.01 (dd, 3 J = 9.0 Hz, 3 J = 8.1 Hz, 1H, CH), 7.07 (br.d, 3 J = 7.3 Hz, 1H, Ind), 7.24 (dd, 3 J = 8.2 Hz, 3 J = 7.3 Hz, 1H, Ind), 7.31 (br.d, 3 J = 8.2 Hz, 1H, Ind), 7.83 (s, 1H, Ind), 10.13 (s, 1H, CHO). 13 C-NMR (CDCl3 , 125 MHz) δ = 19.2 (CH2 ), 33.2 (CH), 33.8 (CH3 N), 37.5 (C), 51.8 (CH3 O), 52.7 (CH3 O), 109.8 (CH, Ind), 119.1 (C, Ind), 122.1 (CH, Ind), 123.1 (CH, Ind), 125.9 (C, Ind), 128.3 (C, Ind), 138.1 (C, Ind), 138.5 (CH, Ind), 167.2 (CO2 Me), 170.1 (CO2 Me), 184.3 (CHO). IR (Nujol, cm−1 ): 2938, 2873, 1726, 1657, 1530, 1462, 1447, 1356, 1296, 1214, 1081, 1042. Anal. calcd for C17 H17 NO5 : C, 64.75; H, 5.43; N, 4.44. Found: C, 64.59; H, 5.21; N, 4.35. Dimethyl 2-(3-hydroxymethyl-1-methyl-1H-indol-4-yl)cyclopropane-1,1-dicarboxylate (8). To a stirred solution of cyclopropane 7 (381 mg, 1.2 mmol) in MeOH (1.2 mL) and CHCl3 (5 mL), NaBH4 (51 mg, 1.3 mmol) was added at 0 ◦ C and stirred for 10 min. Then the mixture was allowed to warm to room temperature and stirred for 5 h until full conversion (TLC control). The solvent was removed in vacuo and the slurry was transferred to a separatory funnel with water and CH2 Cl2 . The product solution was extracted with CH2 Cl2 (3 × 5 mL), the organic fractions were washed with water (3 × 5 mL) and dried with Na2 SO4 affording the title compound. Yield 314 mg (82%). 1 H-NMR (CDCl3 , 500 MHz) δ = 1.84 (dd, 2 J = 5.0 Hz, 3 J = 8.9 Hz, 1H, CH2 ), 2.32 (dd, 2 J = 5.0 Hz, 3 J = 7.9 Hz, 1H, CH2 ), 3.05 (br. s, 1H, OH), 3.20 (s, 3H, CH3 ), 3.76 (s, 3H, CH3 ), 3.87 (s, 3H, CH3 ), 3.92 (dd, 3 J = 8.9 Hz, 3 J = 7.9 Hz, 1H, CH), 4.73 (d, 2 J = 12.5 Hz, 1H, CH2 ), 4.97 (d, 2 J = 12.5 Hz, 1H, CH2 ), 6.85 (br. d, 3 J = 7.3 Hz, 1H, Ar), 7.13 (s, 1H, Ar), 7.14 (dd, 3 J = 8.2 Hz, 3 J = 7.3 Hz, 1H, Ar), 7.22 (br. d, 3 J = 8.2 Hz, 1H, Ar). 13 C-NMR (CDCl3 , 125 MHz) δ = 18.3 (CH2 ), 31.4 (CH3 N), 32.8 (CH), 37.4 (C), 52.1 (CH3 O), 53.0 (CH3 O), 57.1 (CH2 O), 109.3 (CH, Ar), 115.0 (C, Ar), 118.6 (CH, Ar), 121.2 (CH, Ar), 126.1 (C, Ar), 126.9 (C, Ar), 129.9 (CH, Ar), 137.5 (C, Ar), 167.8 (CO2 Me), 170.6 (CO2 Me). IR (cm−1 ) 3476, 3022, 3003, 2951, 2925, 2855, 1726, 1674, 1455, 1437, 1334, 1281, 1210, 1132. HRMS ESI-TOF: m/z = 340.1159 [M + Na]+ (340.1155 calcd for C17 H19 NNaO5 ). Dimethyl 2-[3-({4-[2,2-bis(methoxycarbonyl)cyclopropyl]-1-methyl-1H-indol-3-yl}methyl)-1-methyl-1H-indol4-yl]cyclopropane-1,1-dicarboxylate (9). Cyclopropane 8 (170 mg, 0.53 mmol), AcOH (32 mg, 30 L, 0.53 mmol), toluene (13 mL), boiling with backflow condenser, 6 h. Rf = 0.63 (ethyl acetate:petroleum ether 1:2). Yield 75 mg (48%); colorless solid; mp = 79–80 ◦ C. Mixture of diastereoisomers in the A:B ratio of 62:38; 1 H-NMR (CDCl3 , 500 MHz) for mixture of isomers: δ = 1.74 (dd, 2 J = 5.0 Hz, 3 J = 9.0 Hz, 2H, CH2 , A), 1.83 (dd, 2 J = 5.2 Hz, 3 J = 9.4 Hz, 2H, CH2 , B), 2.40 (dd, 2 J = 5.2 Hz, 3 J = 8.2 Hz, 2H, CH2 , B), 2.45 (dd, 2 J = 5.0 Hz, 3 J = 8.4 Hz, 2H, CH2 , A), 3.23 (s, 6H, CH3 O, B), 3.29 (s, 6H, CH3 O, A), 3.37 (s, 6H, CH3 O, B), 3.56 3.29 (s, 6H, CH3 O, A), 3.68 (s, 6H+6H, CH3 N, A, B), 3.82 (dd, 3 J = 9.0 Hz, 3 J = 8.4 Hz, 2H, CH, A), 3.85 (dd, 3 J = 9.4 Hz, 3 J = 8.2 Hz, 2H, CH, B), 6.66 (broad signal, ν1/2 = 34 Hz, 2H, Ind, A), 6.69 (br. d, 3 J = 7.3 Hz, 2H, Ind, B), 6.76 (br. s, 2H, Ind, B), 6.79 (br. d, 3 J = 7.3 Hz, 2H, Ar, A), 7.07–7.13 (m, 2H + 2H, Ind, A, B), 7.18–7.21 (m, 2H + 2H, Ind, A, B). 13 C-NMR (CDCl3 , 125 MHz) for mixture of isomers: δ = 18.3 (2 × CH2 , A), 19.7 (2 × CH2 , B), 24.6 (CH2 , A), 25.7 (CH2 , B), 31.2 (2 × CH, A), 31.5 (2 × CH, B), 32.7 (2 × CH3 N, B), 32.8 (2 × CH3 N, A), 38.4 (2 × C, A), 38.7 (2 × C, B), 52.1 (2 × CH3 O + 2 × CH3 O, A, B), 52.2 (CH3 O + CH3 O, A, B), 52.4 (CH3 O + CH3 O, A, B), 108.9 (2 × CH, Ind, B), 109.0 (2 × CH, Ind, A), 114.9 (2 × C + 2 × C, Ind, A, B), 116.4 (2 × CH, Ind, A), 117.7 (2 × CH, A, B), 120.87 (2 × CH, Ar, B), 120.94 (2 × CH, Ind, A), 127.0 (2 × C, Ind, A), 127.4 (2 × C, Ind, B),
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127.6 (2 × C, Ind, B), 127.7 (2 × C, Ind, A), 128.5 (2 × CH, Ind, A), 129.2 (2 × CH, Ind, B), 137.9 (2 × C + 2 × C, Ind, A, B), 167.27 (2 × CO2 Me, B), 167.33 (2 × CO2 Me, A), 169.8 (2 × CO2 Me, B), 170.0 (2 × CO2 Me, A). IR (cm−1 ) 3618, 3442, 3055, 3022, 2950, 2924, 2852, 2254, 1728, 1608, 1570, 1550, 1456, 1437, 1371, 1330, 1281, 1209, 1128, 1103, 910. HRMS ESI-TOF: m/z = 587.2390 [M + H]+ (587.2388 calcd for C33 H35 N2 O8 ). Dimethyl 2-[2-(5-fluoro-2-hydroxyphenyl)ethyl]malonate (10). To a solution of cyclopropane 1d (236 mg, 1 mmol) in MeOH (10 mL) Zn dust (0.69 g, 0.01 mol) and glacial acetic acid (0.29 mL, 5 mmol) were added. The reaction mixture was refluxed for 1 h, cooled, remaining Zn was filtered off and washed with ethyl acetate (5 mL). Filtrates were combined and diluted with water (8 mL), MeOH was evaporated under reduced pressure and aqueous phase was extracted with ethyl acetate (3 × 10 mL). Combined organic fractions were washed with saturated NaHCO3 solution (2 × 5 mL), dried with Na2 SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent: 10–50% ethyl acetate in petroleum ether) to afford product 10 as a colorless liquid; Rf = 0.63 (ethyl acetate:petroleum ether 1:2). 1 H-NMR (CDCl3 , 400 MHz) δ = 2.11–2.17 (m, 2H, CH2 ), 2.61–2.65 (m, 2H, CH2 ), 3.44 (dd, 3 J = 7.6 Hz, 3 J = 6.5 Hz, 1H, CH), 3.77 (s, 6H, 2 × CH3 O), 6.10 (br. s, 1H, OH), 6.76–6.81 (m, 3H, Ar). 13 C-NMR (CDCl3 , 100 MHz) δ = 28.0 (CH2 ), 28.8 (CH2 ), 50.6 (CH), 53.0 (2 × CH3 O), 114.1 (d, 2 JCF = 23 Hz, CH, Ar), 116.5 (d, 2 JCF = 23 Hz, CH, Ar), 116.9 (d, 3 JCF = 8 Hz, CH, Ar), 127.9 (d, 3 JCF = 7 Hz, C, Ar), 150.4 (C, Ar), 157.4 (d, 1 JCF = 238 Hz, C, Ar), 170.3 (2 × CO2 Me). IR (cm−1 ) 3442, 3394, 2954, 1730, 1620, 1510, 1437, 1342, 1273, 1230, 1186, 1101, 1079, 1045. HRMS ESI-TOF: m/z = 271.0968 [M + H]+ (271.0976 calcd for C13 H16 FO5 ). 4. Conclusions The simple method for the synthesis of cyclopropa[c]coumarins based on the acid-induced intramolecular transesterification of 2-(2-hydroxyaryl)cyclopropane-1,1-dicarboxylates has been developed. Various functional groups in the aromatic ring including alkyl, halogen and nitro functionalities were shown to be tolerant to the optimized reaction conditions. The proposed method was, however, found to be inefficient for the preparation of the corresponding lactones with a larger ring size. The investigation of the reactivity of the synthesized compounds is in progress. Supplementary Materials: Copies of 1 H NMR and 13 C NMR spectra for synthesized compounds as well as 2D (HSQC and HMBC) NMR spectra for selected compounds are available online. Author Contributions: Conceptualization, O.A.I. and I.V.T.; methodology, O.A.I.; investigation, O.A.I., V.A.A., A.O.C., and I.I.L.; resources, I.V.T. and L.G.V.; writing, O.A.I., A.O.C., and I.V.T.; supervision, O.A.I. and I.V.T.; project administration, O.A.I.; funding acquisition, A.O.C., I.V.T., and L.G.V. Funding: This research was funded by the Russia Foundation for Basic Research (grant 18-03-00954) and the Ministry of Education and Science of the Russia Federation (Project 4.5386.2017/8.9 and grant MK-1567.2018.3). Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors. © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
