ASIAN JOURNALOF ORGANIC CHEMISTRY

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Title: Synthesis of 2-cyclohexenone-2-carboxylate and 4-chloro-2-cyclohexenone-2-carboxylate derivatives via cyclization ofalkyne-tethered 1,3-ketoesters

Authors: Wilailak Kaewsri, Krissada Norseeda, SureepornRuengsangtongkul, Nattawadee Chaisan, CharnsakThongsornkleeb, Jumreang Tummatorn, and SomsakRuchirawat

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To be cited as: Asian J. Org. Chem 10.1002/ajoc.201700510

Link to VoR: http://dx.doi.org/10.1002/ajoc.201700510

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Synthesis of 2-cyclohexenone-2-carboxylate and 4-chloro-2-cyclohexenone-2-carboxylate derivatives via cyclization of alkyne-tethered 1,3-ketoesters Wilailak Kaewsri,[a] Krissada Norseeda,[a] Sureeporn Ruengsangtongkul,[c] Nattawadee Chaisan,[a] Charnsak Thongsornkleeb,*[a],[b] Jumreang Tummatorn,[a],[c] and Somsak Ruchirawat[a],[c] [a] W. Kaewsri, K. Norseeda, N. Chaisan, Dr. C. Thongsornkleeb,* Dr. J. Tummatorn and Prof. S. Ruchirawat

Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand. E-mail: charnsak@cri.or.th

[b] Dr. C. Thongsornkleeb* Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand. E-mail: charnsak@cri.or.th

[c] S. Ruengsangtongkul, Dr. J. Tummatorn and Prof. S. Ruchirawat Laboratory of Medicinal Chemistry, Chulabhorn Research Institute,

54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.

Supporting information for this article is given via a link at the end of the document.

Abstract: A procedure for TfOH-promoted cyclization of alkyne-tethered 1,3-ketoesters to afford 2-cyclohexenone-2-carboxylate derivatives is described. The method requires no transition metal reagent or catalyst and is practical to conduct under mild conditions. 2-Cyclohexenone-2-carboxylate products were obtained in moderate to good yields without any decarboxylation. In addition, the procedure can be conveniently extended to sequential cyclization-chlorination in one pot to selectively provide access to 4-chloro-2-cyclohexenone-2-carboxylate derivatives in moderate to good yields.

Introduction

Functionalized carbocyclic ketones are a versatile class of compounds which can serve as starting materials for transformations into other complex structures. For examples, functionalized 2-cyclohexenones can serve as important precursors to produce phenolic derivatives by various oxidative aromatization methods.1 The resulting phenolic systems, specifically 1-hydroxyaryl-2-carboxylate derivatives, are widely displayed in bioactive compounds,2 most notably in aspirin. In addition, 6-membered carbocyclic ketones themselves are ubiquitous core structures found in several natural products of biological or medicinal significance2 as exemplified in Figure 1.

One of the strategies used for the construction of carbocyclic ketones involves the direct C-annulation of the readily enolizable 1,3-dicarbonyl compounds onto the tethered alkenyl or alkynyl bonds. In this context, several preparations of 6-membered saturated carbocyclic ketones have been reported starting from alkene-tethered 1,3-dicarbonyl compounds employing catalysts such as Pd(OAc)2,3a PdCl2(MeCN)2,3b and AgOTf,3c to activate the double bond. In addition, Mn(OAc)33d or Mn(OAc)3/Cu(OAc)23e have also been employed to effect the cyclization of these substrates via a radical process. For the preparations of 6-membered 2-cycloalkenones, the C-annulation of both alkene- and alkyne-tethered 1,3-dicarbonyl substrates have been studied. The conversion from alkene-tethered 1,3-

Figure 1. Utilization of 2-cyclohexenones as precursors to phenols and examples of medicinal compounds with phenolic and 2-cyclohexenone skeletons.

dicarbonyl substrates to 2-cyclohexenones could be carried out using PdCl2(MeCN)2  alone (stoichiometric) or a combination of PdCl2(MeCN)2 (5 mol%) and CuCl2 (2.5 equiv).4a In comparison to the alkene-tethered compounds, the C-annulation of the alkyne-tethered 1,3-dicarbonyl substrates to give 2-cyclohexenones is much less studied in the literature with only a few methods reported. These methods, which required transition metal reagents as catalysts, or stoichiometric promoters, or both, include a combination of (CuOTf)2C6H6/AgSbF6,4b ZnCl2/Yb(OTf)3,4c and PPh3AuCl/AgNTf2.4d In addition to

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transition metal reagents required, these methods also required high temperature, lengthy reaction time, and the need for inert atmosphere to conduct the reactions. These are  especially problematic when alkyne-tethered 1,3-ketoesters were employed as substrates since high reaction temperature also led to decarboxylation side-products. These reaction conditions severely affected its practicality and limited its utilization. In this work, we wish to report a convenient and practical protocol for the preparation of 2-cyclohexenone-2-carboxylate derivatives via C-annulation of alkyne-tethered -ketoesters using Brønsted acid. We also applied this cyclization method to in situ chlorination to produce 4-chloro-2-cyclohexenone analogues using a combination of Brønsted acid and chlorinating agent (Scheme 1).

Scheme 1. 2-Cyclohexenone synthesis via C-annulation of alkyne-tethered 1,3-dicarbonyl compounds.

Results and Discussion

In starting our investigation, compound 1a5 was chosen to screen for optimal conditions. It was subjected to different Brønsted acids; the conditions and results are summarized in Table 1. When compound 1a was subjected to 1.2 equiv of TFA in DCM at room temperature both for 1 h and overnight (Entries 1-2), no reaction was observed. The result was identical when 1.2 equiv of p-TsOH in DCM was used at room temperature for 1 h (Entry 3). Next, concentrated H2SO4 (1.2 equiv) and HCl (1.2

Table 1. Optimization of the cyclization of alkyne 1a.

Entry Acid

(Equiv.) Solvent Temp. Time Yield[a]

1 TFA (1.2) DCM rt 1 h NR

2 TFA (1.2) DCM rt 24 h NR

3 p-TsOH (1.2) DCM rt 1 h NR

4 H2SO4 (1.2)[b] DCM rt 1 h NR

5 HCl (1.2)[b] DCM rt 1 h 55%

6 TfOH (1.2) DCM rt 1 h 79%

7 TfOH (1.2) DCM rt 22 h 78%

8 TfOH (1.2) DCM reflux 20 min 73%

9 TfOH (1.2) DCE rt 3 h 69%

10 TfOH (1.2) toluene rt 2 h 55%

11 TfOH (1.5) DCM rt 1 h 89% 12 TfOH (2.0) DCM rt 1 h 74%

13 TfOH (0.5) DCM rt 1 h 46%[c]

[a] Isolated yield. [b] Commercial concentrated acids were used. [c] The reaction was not complete (20% of SM was recovered).

equiv) were attempted (entries 4 and 5), both at room temperature for 1 h. For H2SO4, no reaction was observed and starting material 1a was recovered while with HCl, a full conversion was observed and 55% yield of the desired product (2a) was obtained. However, after switching to 1.2 equiv of TfOH in DCM, the reaction was complete within 1 h and the desired cyclic product (2a) was cleanly isolated in 79% yield (Entry 6). The reaction was next attempted with longer reaction time (22 h) with everything else identical. However, it was found that the yield of the desired product was almost unchanged (78%) compared to the reaction conducted at 1 h (Entries 6 and 7). We then attempted the reaction at higher temperature (refluxing DCM, Entry 8) and the starting material was fully consumed within 20 min but product 2a was obtained in lower yield (73%). To study the effect of solvents, the cyclization was conducted using 1.2 equiv of TfOH in DCE and toluene (Entries 9-10) to find that, in addition to requiring longer reaction times for a full conversion, product 2a was also obtained in lower yields (69% in DCE and 55% in toluene). To see the effect of concentrations of TfOH, the reaction was attempted with 1.5 equiv of TfOH in DCM for 1 h. Under these conditions, the reaction was complete and product 2a was obtained in higher yield (89%, Entry 11). And when the reaction was allowed to stir at ambient temperature with 2.0 equiv of TfOH for 1 h, although the reaction was complete, the desired product was obtained in lower yield (74%, Entry 12). Realizing that the transformation was an isomerization of the substrate to the product under acidic conditions with the release of acidic proton, a catalytic amount (0.5 equiv) of TfOH was employed. However, the reaction was not complete after stirring at room temperature for 1 h. In this case, the reaction afforded 46% of the desired product along with 20% of recovered starting material (Entry 13). From this optimization study, the most suitable conditions to affect the

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Scheme 2. Mechanism in Brønsted acid-mediated cyclization of substrate 1.

desired cyclization were 1.5 equiv of TfOH in DCM at room temperature for 1 h. To explain the formation of compound 2a, the mechanism of the reaction is proposed in Scheme 2. When substrate 1 is subjected to a Brønsted acid, the alkynyl group can be protonated at two different positions. When carbon a is

protonated, vinyl cation A intermediate is generated. Intermediate A could undergo C-annulation reaction by the enol carbon to form intermediate C which then isomerizes to give compound 2 (i.e. 2a) as the product (Pathway A). However, competitive protonation at carbon b is also plausible which will result in formation of vinyl cation B intermediate. From cation

intermediate B, two different annulation reactions could occur. As shown in Scheme 2, O-annulation reaction will result in the dihydrofuran intermediate D, which upon aromatization, 2,5-disubstituted furan 3 is afforded (Pathway B). However, C-annulation reaction of intermediate B is also plausible. In this case, the annulation will lead to cyclopentanone intermediate E which will eventually furnish cyclopentenone product 4 upon isomerization (Pathway C).

We next applied these conditions to other substrates to study the scope of the reaction (Table 2). After the successful result with 1a, substrate 1b, with the CN group as the electron-withdrawing group (EWG), was first tested on the applicability of the reaction. In this case, we observed a complex reaction mixture and the expected 2-nitrile-2-cyclohexenone product (2b) could be gratifyingly isolated, albeit in only 38% yield. The lower yield of product in this case may have been attributed to the interference of the basic nitrogen in the CN group under strongly acidic conditions. In reverting back to substrates with ethyl ester as EWG, our conditions were applied to substrate 1c with R = 4-tolyl, an electronically neutral group. In this case, the reaction proceeded smoothly and excellently to give the corresponding product 2c in 94% yield. Next, substrate 1d with R = 2-methoxyphenyl group was employed. As the mechanism in Scheme 2 suggested, the benzylic vinyl cation (intermediate A) of substrate 1d could be stabilized by the 2-methoxyphenyl group, the cyclization occurred smoothly to give product 2d in good yield (77%). The efficiency of the reaction was lower when 3-methoxyphenyl starting material 1e was attempted as the reaction afforded the desired compound 2e in 61% yield. In this case, the vinyl cation intermediate was somewhat destabilized via the inductive effect of the 3-methoxyphenyl group and the cyclization product was obtained in lower yield. When substrate 1f (R = 4-methoxyphenyl group) was employed, the reaction gave even lower yield of product 2f (42%). When comparing to compound 1d, the vinyl cation intermediate A generated from

substrate 1f was more reactive due to it being less steric and therefore was more prone to other side reactions, observed as complex reaction mixture by TLC, thus only product 2f was obtained in lower yield than product 2d. We next investigated the effect of halogen atoms by studying substrates 1g, 1h, and 1i (R = 4-fluoro-, 4-chloro-, and 4-bromophenyl groups, respectively). Under the optimal conditions, substrate 1g (R = 4-fluorophenyl group) smoothly afforded the desired product 2g in 78% yield. With substrate 1h (R = 4-chlorophenyl group), the yield of product 2h became slightly lower (76%) while substrate 1i (R = 4-bromophenyl group) provided the corresponding product 2i in lower yield (63%).

However, when switching to 4-trifluoromethylphenyl substrate 1j, yield of the corresponding 2j became much lower under our standard conditions. In this case, furan 3j was also obtained as side-product of the reaction. From the reaction mechanism in Scheme 2, it is rationalized that with electron-withdrawing substituent para-CF3, intermediate A became less stable and the protonation at carbon b leading to vinyl cation intermediate B became competitive. However, only the O-annulation furan product 3j was obtained while the corresponding C-annulation product was not observed. In further optimizing the conditions, we noticed that 2.0 equiv of TfOH and refluxing the reaction could provide product 2j as the major product in higher yield while minimizing the formation of furan 3j. Thus, these conditions were applied to 1k (R = 4-CO2Me-phenyl group) to give product 2k in 34% as the major product while furan product 3k was still obtained as the minor product in 15%. Similarly, compound 1l, containing strongly electron-withdrawing 4-nitrophenyl group, was subjected to these conditions. In this case, Pathway B was even more strongly preferred than Pathway A when compared to compounds 1j and 1k to give furan 3l as the major product (50%) while product 2l was obtained in only 10% yield. The reaction was next conducted with substrate 1m (R = CH3). For this substrate, the reaction

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followed Pathways B and C (Scheme 2) to afford furan 3m and cyclopentenone 4m in 29% and 12% yield, respectively, while no corresponding cyclohexenone product was observed. This result seemed to suggest that for substrates 1 with R = alkyl group, the formation of vinyl cation intermediate B was preferred which further underwent transformations to products 3 and 4.

In addition to the investigation of the scope of the reaction, the amenability of the protocol to a large-scale preparation of the cyclohexenone product was also demonstrated with a large-scale synthesis of cyclohexenone 2a. In this experiment, we allowed substrate 1a (1.515 g, 6.2 mmol) to react with 1.5 equiv of TfOH in DCM at room temperature. The reaction proceeded uneventfully to afford the desired cyclic product 2a in 97% yield (1.465g, 6.0 mmol) as shown in Scheme 3.

Scheme 3. Gram-scale preparation of cyclohexenone 2a.

We next studied the possibility in adapting our reaction conditions to perform further functionalization of the initial 2-cyclohexenone products in the same reaction vessel. In light of our previous effort,6 we are particularly interested in assimilating the current protocol to electrophilic halogenation reaction since the presence of a halogen atom in 2-cyclohexenone nucleus may serve as a functionalization handle for further structural diversification. As proposed in Scheme 4,  2-cyclohexenone derivatives under the acidic conditions could generate either dienol intermediate F (thermodynamically  favored) or F (kinetically favored), which after reacting with an electrophilic halogen would lead to either compound 2-X or 2-X, respectively. Among published procedures, the method for electrophilic -functionalization of 2-cyclohexenones is sparser than -functionalization and may require specialized strategies, reagents, and/or specific structural constraints.7 It was hypothesized that the formation of thermodynamically favorable dienol F was more likely under our conditions. Furthermore, based on our previous experience with halogenation reaction,6 the proposed transformation could be plausible under acidic conditions; the reaction would lead to -halogenated product (2-X). To test this hypothesis, N-chlorosuccinimide (NCS) was employed as the electrophilic chlorinating agent to search for the optimal conditions for a one-pot protocol using alkyne 1a as the screening substrate with the results as shown in Table 3.

The reaction was optimized in DCM at room temperature as these were the best conditions from optimization of the first step (see Table 1). A solution of substrate 1a was first added with 1.2 equiv of TfOH and immediately followed by addition with a solution of 1.2 equiv of NCS in DCM (Entry 1). Substrate 1a was fully converted within 1 h and only the -chlorinated cyclized product (2a-Cl) was obtained in 54% yield. The regiochemistry of the chlorine atom in the product was identified to be on the -carbon as shown based on an HMBC NMR experiment and comparing its 1H NMR spectrum with those of similar

Table 2. Scope of TfOH-promoted cyclization of ketoalkynes.[a]

[a] Isolated yield. [b] 2.0 equiv of TfOH was employed at reflux for 1 h.

compounds in the literature, 4-chloro-3,4-dihydronaphthalen-1(2H)-one8a and 2-chloro-3,4-dihydronaphthalen-1(2H)-one.8b Thus, the result was consistent with the formation of the more thermodynamically favorable intermediate F under the conditions, lending a firm support for our hypothesis. The transformation also added as a valuable tool to the small repertoire of methods for -halogenation of 2-cyclohexenones. However, when substrate 1a was added to the mixture of TfOH and NCS in DCM (Entry 2) the desired reaction was completely shut down. As the chlorination was expected to occur after

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O O

OEt

R

2-X-halogenation)

X

OH O

OEt

RF[X+]

-H+

O O

OEt

R

[Dienolization]H+

O O

OEt

R2-X'

'-halogenation)

OH O

OEt

RF'[X+]

X

[Dienolization]H+ -H+2

'

'

'

Scheme 4. Proposed mechanism of in situ halogenation of 2-cyclohexenone-2-carboxylate 2.

Table 3. Optimization of the sequential cyclization-chlorination of alkyne 1a.

Entry TfOH NCS

Yield[a] Equiv. Time Equiv. Time

1 1.2 0 min 1.2 1 h 54% 2[b] 1.2 0 min 1.2 1 h 0% 3 1.2 1 h 1.2 15 min 73% 4 1.5 1 h 1.5 15 min 57%

[a] Isolated yields. [b] TfOH and NCS were pre-mixed in DCM prior to addition of the substrate.

product 2a was formed in the reaction, substrate 1a was allowed to react first with 1.2 equiv of TfOH at room temperature for 1 h before a solution of NCS (1.2 equiv) in DCM was added to the reaction and allowed to stir for additional 15 min (Entry 3). Under these conditions, the desired chlorinated product 2a-Cl could be uneventfully obtained in 73% yield. The amounts of TfOH and NCS were next increased to 1.5 equiv while keeping the same reaction time for each step to find that the yield dropped to 57% (Entry 4). Therefore, the most optimal conditions for the conversion of 1a to 2a-Cl were to submit the substrate to 1.2 equiv of TfOH in DCM at room temperature for 1 h, followed by addition of the solution of 1.2 equiv of NCS in DCM and stirred for additional 15 min. With these optimal conditions in hands, we next explored the scope of substrates (Table 4).

Starting with substrate 1c (R = 4-tolyl group), the reaction proceeded to give the desired product (2c-Cl) in only 54% isolated yield. The reaction underwent a better transformation with substrate 1d (R = 2-methoxyphenyl group) which provided the desired -chlorinated product 2d-Cl in 90%. Under these conditions, no electrophilic chlorination was observed on the 2-methoxyphenyl ring, which bolstered the chemoselectivity of the protocol. For R = 3-methoxyphenyl and 4-methoxyphenyl groups (substrates 1e and 1f), the reactions afforded the corresponding products in lower yields; 68% for 2e-Cl and 39% for 2f-Cl. Although yields were not as high, no electrophilic aromatic chlorination was observed in the products. The yields of products 2d-Cl, 2e-Cl,and 2f-Cl followed the same trend as the

Table 4. Scope of -chlorinative cyclization of alkyne 1.[a]

[a] Isolated yields.

yields of 2-cyclohexenone products 2d, 2e, and 2f, respectively (see Table 2). Next, reactions of substrates 1g, 1h, and 1i with R = 4-fluoro-, 4-chloro-, and 4-bromophenyl groups gave the corresponding products in moderate yields (2g-Cl; 69%, 2h-Cl; 62%, and 2i-Cl; 64%). In these cases, the trend of reaction efficiencies also correlated well with those of products 2g, 2h, and 2i in Table 2. Given that yields of chlorinative cyclization products 2g-Cl, 2h-Cl, and 2i-Cl (Table 4) were very close to yields of cyclization products 2g, 2h, and 2i (Table 2), it may be concluded that the second chlorination step in this series of compounds occurred with excellent efficiencies. The reactions of substrates 1j (R = 4-trifluoromethylphenyl group) and 1k (R = 4-CO2Me-phenyl group) were next tested to find the reactions less efficient than others as products 2j-Cl and 2k-Cl were afforded in 11% and 19% yields, respectively. In these cases, low yields of the final products most likely corresponded to the low efficiency of the initial cyclization step as shown in Table 2 that cyclization products 2j and 2k were also obtained in low yields. Next, we demonstrated the applicability of the current protocol in the construction of 4-bromo-2-cyclohexenone using N-bromosuccinimide (NBS). Thus, substrate 1a was subjected to our standard protocol using NBS, from which the desired product 2a-Br was obtained in 55% yield. Unfortunately, when the reaction was attempted using N-iodosuccinimide (NIS), no

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desired product was obtained. Instead, we observed decomposition possibly stemming from side reactions of the initial iodine-substituted product. From our proposed mechanism in Scheme 4, we believed that regioselective -halogenation occurred from 2-cyclohexenone 2 formed initially in the reaction via the thermodynamically more favorable dienol intermediate F. In addition to being generated directly from product 2, dienol intermediate F could also be generated from intermediate C (Scheme 2) under the conditions. However, the fact that product 2-Cl could be obtained in good yield by treating the reaction mixture with NCS solution only after product 2 was fully generated (from the first step of the sequence) seemed to indicate that dienol intermediate F should have emerged from compound 2. To verify this notion, cyclohexenone 2a was first subjected to 1.2 equiv of TfOH for 1 h followed by 1.2 equiv of NCS at room temperature for 15 min. Uneventfully, the desired product 2a-Cl was obtained in 81% yield, thus confirming the proposed mechanism that product 2-Cl (Scheme 4) was subsequently originated from product 2 under the optimal reaction conditions. For product 2a-Cl, the two-step yield (73%, Table 4) also corroborated well with yields of the individual steps (89% for cyclization and 81% for chlorination).

Scheme 5. -Chlorination of 2-cyclohexenone 2a under the standard optimal reaction conditions.

Conclusions

In conclusion, we have demonstrated a convenient and metal-free protocol for the synthesis of 2-cyclohexenone-2-carboxylate via TfOH-promoted cyclization of alkyne-tethered 1,3-ketoesters. The conditions employ TfOH in DCM at room temperature for 1 h which is significantly milder and more convenient than the previously reported protocols, thus providing desired 2-cyclohexenone-2-carboxylate products without decarboxylation normally encountered under harsher conditions. The current method can be extended to conveniently prepare 4-chloro- and 4-bromo-2-cyclohexenone-2-carboxylate in a one-pot fashion via subsequent addition of NCS and NBS. Several 2-cyclohexenone-2-carboxylate and 4-halo-2-cyclohexenone-2-carboxylate derivatives could be prepared in moderate to good yields by the current protocol. The convenient and practical, as well as metal-free aspects of the current method will be useful for general practitioners of organic synthesis.

Experimental Section

General remarks: Commercial grade chemicals were used without further purification, unless otherwise specified. All solvents were used as received. Oven-dried glassware (110 °C at least for 2 h) was used for all reactions. Crude reaction mixtures were concentrated under reduced pressure on a rotary evaporator. Column chromatography was performed

using silica gel 60 (particle size 0.06−0.2 mm; 70−230 mesh ASTM). Analytical thin-layer chromatography (TLC) was performed with silica gel 60 F254 aluminum sheets. Nuclear magnetic resonance (NMR) spectra were recorded in deuteriochloroform (CDCl3) or dimethyl sulfoxide-d6 (DMSO-d6) with 300 and 400 MHz spectrometers. Chemical shifts for 1H NMR and 13C NMR spectra are reported in parts per million (ppm, δ), relative to tetramethylsilane (TMS) as the internal reference. Coupling constants (J) are reported in hertz (Hz). Infrared spectra were measured using an FT-IR spectrometer and are reported in cm-1. High resolution mass spectra (HRMS) were obtained using a time-of-flight (TOF) instrument.

General Procedure for the Synthesis of 2-Cyclohexenone-2-carboxylate (2): A solution of substrate 1a (113.8 mg, 0.47 mmol, 1.0 equiv) in DCM (5.0 mL, 0.094 mmol/mL) was added with TfOH (61 L, 0.70 mmol, 1.5 equiv) and the resulting solution was allowed to stir at room temperature for 1 h. After 1 h, the reaction mixture was quenched with sat. aq. NaHCO3 and the mixture was extracted with EtOAc. The combined organic phases were dried over anh. Na2SO4, concentrated on a rotary evaporator and the crude product was purified by silica gel column chromatography eluting 15% EtOAc-hexane to yield 2-cyclohexenone-2-carboxylate 2a (101.4 mg, 89%). (Note: For substrate 1m, the reaction yielded products 3m and 4m and for substrates 1j-1l, the reaction of each substrate was conducted under refluxing DCM to yield the corresponding products 2j-2l and 3j-3l, accordingly).

Ethyl 6-oxo-2-phenylcyclohex-1-enecarboxylate (2a). Yield 101.4 mg (89%, yellow solid); mp 74.9-75.3 °C; IR (neat): νmax 2977, 2953, 1728, 1670, 1222, 1044, 700 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 5H), 4.06 (q, J = 6.9 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.3 Hz, 2H), 2.17 (quint, J = 6.3 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.3, 166.5, 159.6, 138.9, 133.2, 129.4, 128.4, 126.5, 61.0, 36.9, 31.3, 22.0, 13.6; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C15H16NaO3 267.0992; Found 267.0988.

6-Oxo-2-phenylcyclohex-1-enecarbonitrile (2b). Yield 11.4 mg (38%, orange oil); IR (neat): νmax 2955, 2227, 1687, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.61-7.54 (m, 2H), 7.53-7.46 (m, 3H), 2.92 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 6.6 Hz, 2H), 2.20 (quint, J = 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 192.8, 173.1, 137.0, 131.5, 128.9, 127.3, 114.5, 113.2, 36.6, 32.1, 21.5; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C13H11NNaO 220.0733; Found 220.0738.

Ethyl 4'-methyl-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2c). Yield 81.4 mg (94%, yellow oil); IR (neat): νmax 2980, 2927, 2871, 1728, 1668, 1222, 1044, 817 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.28-7.25 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.3 Hz, 2H), 2.36 (s, 3H), 2.15 (quint, J = 6.3 Hz, 2H), 1.05 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.5, 167.0, 159.7, 139.9, 136.1, 133.0, 129.3, 126.7, 61.2, 37.1, 31.4, 22.2, 21.4, 13.9; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H18NaO3 281.1148; Found 281.1151.

Ethyl 2'-methoxy-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2d). Yield 69.1 mg (77%, yellow solid); mp 81.5-81.8 °C; IR (neat): νmax 2942, 2835, 1731, 1672, 1226, 756 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.29 (m, 1H), 7.13-7.10 (m, 1H), 6.95-6.90 (m, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.72 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 6.6 Hz, 2H), 2.14 (quint, J = 6.3 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.3, 166.0, 160.5, 155.8, 133.9, 130.3, 128.2, 127.9, 120.4, 111.0, 60.7, 55.6, 37.4, 31.0, 22.2, 13.6; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H18NaO4 297.1097; Found 297.1103.

Ethyl 2-(3-methoxyphenyl)-6-oxocyclohex-1-enecarboxylate (2e). Yield 30.6 mg (61%, yellow oil); IR (neat): νmax 2941, 1727, 1223, 786, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 1H), 6.95-6.90 (m, 3H), 4.08 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 2.75 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.6 Hz, 2H), 2.16 (quint, J = 6.0 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H); 13C

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NMR (75 MHz, CDCl3) δ 195.2, 166.5, 159.4, 140.1, 133.1, 129.6, 118.8, 115.0, 112.0, 61.0, 55.2, 36.9, 31.2, 21.9, 13.6; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H18NaO4 297.1097; Found 297.1103.

Ethyl 2-(4-methoxyphenyl)-6-oxocyclohex-1-enecarboxylate (2f).4b Yield 29.3 mg (42%, red oil); IR (neat): νmax 2939, 2840, 1726, 1604, 1030, 831 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.75 (t, J = 5.7 Hz, 2H), 2.54 (t, J = 6.6 Hz, 2H), 2.15 (quint, J = 6.3 Hz, 2H), 1.08 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.4, 167.2, 160.7, 159.1, 132.4, 131.0, 128.3, 113.8, 61.0, 55.3, 36.9, 31.1, 21.9, 13.8; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H18NaO4 297.1097; Found 297.1104.

Ethyl 2-(4-fluorophenyl)-6-oxocyclohex-1-enecarboxylate (2g). Yield 53.6 mg (78%, yellow oil); IR (neat): νmax 2979, 2940, 1734, 1046, 689 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.10-7.05 (m, 2H), 4.09 (q, J = 6.9 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.3 Hz, 2H), 2.17 (quint, J = 6.0 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.2, 166.6, 163.2 (d, JC-F = 248 Hz), 158.2, 134.9 (d, JC-F = 4 Hz), 133.5, 128.7 (d, JC-F = 9 Hz), 115.6 (d, JC-F = 21 Hz), 61.2, 36.9, 31.3, 22.0, 13.8; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C15H15FNaO3 285.0897; Found 285.0901.

Ethyl 2-(4-chlorophenyl)-6-oxocyclohex-1-enecarboxylate (2h). Yield 58.9 mg (76%, yellow oil); IR (neat): νmax 2977, 2937, 1729, 1672, 1225, 1014, 827 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 4.09 (q, J = 7.2 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.6 Hz, 2H), 2.17 (quint, J = 6.0 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.1, 166.4, 157.9, 137.2, 135.5, 133.5, 128.8, 128.0, 61.2, 36.8, 31.1, 21.9, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C15H15ClNaO3 301.0602; Found 301.0603.

Ethyl 2-(4-bromophenyl)-6-oxocyclohex-1-enecarboxylate (2i). Yield 49.8 mg (63%, orange oil); IR (neat): νmax 2938, 1728, 1671, 1224, 1043, 822, 734 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 4.09 (q, J = 7.5 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.56 (t, J = 6.6 Hz, 2H), 2.17 (quint, J = 6.0 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.0, 166.3, 157.9, 137.7, 133.5, 131.7, 128.2, 123.7, 61.2, 36.8, 31.1, 21.9, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Br-79) Calcd for C15H15BrNaO3 345.0097; Found 345.0109.

Ethyl 3-oxo-4'-(trifluoromethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2j). Yield 44.1 mg (37%, yellow oil); IR (neat): νmax 2922, 2853, 1733, 1677, 1324, 1126, 837 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 2.21 (quint, J = 6.0 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 194.7, 165.9, 157.4, 142.5, 134.2, 131.4 (q, JC-F = 36 Hz), 127.0, 125.5 (q, JC-F = 4 Hz), 123.7 (q, JC-F = 271 Hz), 61.3, 36.9, 31.3, 22.1, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H15F3NaO3 335.0866; Found 335.0873.

Ethyl 2-(5-(4-(trifluoromethyl)benzyl)furan-2-yl)acetate (3j). Yield 23.4 mg (19%, yellow oil); IR (neat): νmax 2923, 2853, 1740, 1324, 1123, 1067, 789 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.13 (d, J = 3.0 Hz, 1H), 5.97 (d, J = 3.3 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.99 (s, 2H), 3.63 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 152.7, 147.1, 142.2, 131.8, 129.0, 127.8 (q, JC-F = 270 Hz), 125.4 (d, JC-F = 3 Hz), 108.7, 107.7, 61.1, 34.3, 34.2, 14.1; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C16H15F3NaO3 335.0866; Found 335.0866.

Methyl 4-(2-(ethoxycarbonyl)-3-oxocyclohex-1-enyl)benzoate (2k). Yield 31.6 mg (34%, yellow oil); IR (neat): νmax 2954, 1721, 1277, 772 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 6.3 Hz, 2H), 2.19 (quint, J = 6.3 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 195.0, 166.3, 166.1, 158.1, 143.3,

133.8, 130.8, 129.7, 126.6, 61.3, 52.3, 36.9, 31.1, 22.0, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C17H18NaO5 325.1046; Found 325.1059.

Methyl 4-((5-(2-ethoxy-2-oxoethyl)furan-2-yl)methyl)benzoate (3k). Yield 14.2 mg (15%, yellow oil); IR (neat): νmax 2923, 2853, 1721, 1276, 1106, 731 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.13 (d, J = 3.0 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.99 (s, 2H), 3.90 (s, 3H), 3.62 (s, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 167.0, 152.9, 147.0, 143.5, 129.8, 128.7, 128.4, 108.7, 107.7, 61.1, 52.0, 34.4, 34.2, 14.1; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C17H18NaO5 325.1046; Found 325.1059.

Ethyl 4'-nitro-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2l). Yield 13.6 mg (10%, orange oil); IR (neat): νmax 2929, 2851, 1731, 1346, 859, 701 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.27-8.23 (m, 2H), 7.55-7.50 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.3 Hz, 2H), 2.22 (quint, J = 6.3 Hz, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.6, 165.7, 156.3, 148.1, 145.2, 134.5, 127.7, 123.8, 61.5, 36.9, 31.1, 22.0, 13.8; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C15H15NNaO5 312.0842; Found 312.0838.

Ethyl 2-(5-(4-nitrobenzyl)furan-2-yl)acetate (3l). Yield 66.5 mg (50%, orange oil). IR (neat): νmax 2983, 2932, 1736, 1517, 1345, 1016, 788 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.16 (d, J = 3.0 Hz, 1H), 6.02 (d, J = 2.7 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 3.63 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.3, 151.7, 147.3, 146.7, 145.8, 129.4, 123.6, 108.8, 108.1, 61.1, 34.2, 34.1, 14.0; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C15H15NNaO5 312.0842; Found 312.0849.

Ethyl 2-(5-ethylfuran-2-yl)acetate (3m).9 Yield 22.0 mg (29%, colorless oil); IR (neat): νmax 3080, 2984, 2938, 1736, 1517, 1345, 1016, 723 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.10 (d, J = 3.0 Hz, 1H), 5.91 (d, J = 3.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.62 (s, 2H), 2.61 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.6, 157.3, 145.7, 108.3, 104.7, 61.0, 34.2, 21.3, 14.1, 12.0; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C10H14NaO3 205.0835; Found 205.0844.

Ethyl 2-ethyl-5-oxocyclopent-1-enecarboxylate (4m). Yield 8.9 mg (12%, yellow oil); IR (neat): νmax 2980, 2940, 1708, 1212, 1029, 827 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.32 (q, J = 6.9 Hz, 2H), 2.77 (q, J = 7.5 Hz, 2H), 2.70-2.66 (m, 2H), 2.50-2.47 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.8, 188.5, 163.4, 132.3, 60.8, 34.9, 29.8, 25.8, 14.2, 11.9; HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for C10H14NaO3 205.0835; Found 205.0834.

General Procedure for the Synthesis of 4-Chloro-2-cyclohexenone-2-carboxylate (2-Cl):  A solution of substrate 1a (64.1 mg, 0.26 mmol, 1.0 equiv) in DCM (4.0 mL, 0.065 mmol/mL) was added with TfOH (28 L, 0.31 mmol, 1.2 equiv). The resulting solution was allowed to stir at room temperature for 1 h before it was added with a solution of NCS (42.5 mg, 0.31 mmol, 1.2 equiv) in DCM (2.0 mL, 0.16 mmol/mL). The resulting reaction mixture was stirred for another 15 min at room temperature and then quenched with sat. aq. NaHCO3 and the mixture was extracted with EtOAc. The combined organic phases were dried over anh. Na2SO4, concentrated on a rotary evaporator and the crude product was purified by silica gel column chromatography eluting 30% EtOAc-hexane to yield 4-chloro-2-cyclohexenone-2-carboxylate 2a-Cl (52.6 mg, 73%). (Note: For product 2a-Br, NBS was employed with substrate 1a following the same procedure).

Ethyl 3-chloro-6-oxo-2-phenylcyclohex-1-enecarboxylate (2a-Cl). Yield 52.6 mg (73%, white solid); mp 112.3-112.7 °C; IR (neat): νmax 2982, 2932, 1732, 1679, 1230, 1052, 699 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42 (s, 5H), 5.02 (t, J = 3.0 Hz, 1H), 4.06 (q, J = 6.9 Hz, 2H),

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3.10-2.98 (m, 1H), 2.72-2.46 (m, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.9, 165.4, 154.7, 136.0, 133.6, 130.0, 128.6, 127.2, 61.4, 56.2, 32.0, 30.9, 13.7; HRMS (ESI-TOF) m/z: (M+H)+ (Cl-35) Calcd for C15H16ClO3 279.0783; Found 279.0782.

Ethyl 6-chloro-4'-methyl-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2c-Cl). Yield 30.7 mg (54%, yellow oil); IR (neat): νmax 2980, 2927, 2871, 1713, 1676, 1227, 1050, 820 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.03 (t, J = 3.0 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.08-2.96 (m, 1H), 2.69-2.46 (m, 3H), 2.38 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.9, 165.7, 154.7, 140.4, 133.2, 133.1, 129.3, 127.2, 61.4, 56.2, 32.0, 30.8, 21.3, 13.7.

Ethyl 6-chloro-2'-methoxy-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2d-Cl). Yield 49.9 mg (90%, yellow solid); mp 82.6-83.1 °C; IR (neat): νmax 2983, 2932, 2835, 1736, 1662, 1215, 947 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.37 (td, J = 8.4, 1.8 Hz, 1H), 7.20 (dd, J = 7.2, 1.5 Hz, 1H), 6.98-6.92 (m, 2H), 5.17 (t, J = 1.8 Hz, 1H), 4.07-3.94 (m, 2H), 3.85 (s, 3H), 3.07-2.90 (m, 1H), 2.74-2.42 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.9, 164.9, 155.9, 155.1, 134.3, 131.1, 130.1, 124.6, 120.5, 110.8, 61.0, 55.7, 55.4, 32.5, 30.6, 13.6; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C16H17ClNaO4 331.0708; Found 331.0706.

Ethyl 3-chloro-2-(3-methoxyphenyl)-6-oxocyclohex-1-enecarboxylate (2e-Cl). Yield 48.3 mg (68%, yellow gum); IR (neat): νmax 2964, 2937, 2835, 1732, 1228, 1054, 696 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 1H), 7.01-6.94 (m, 3H), 5.01 (t, J = 3.3 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.09-2.98 (m, 1H), 2.71-2.45 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.9, 165.4, 159.6, 154.5, 137.2, 133.5, 129.8, 119.5, 115.7, 112.8, 61.5, 56.1, 55.3, 32.0, 30.8, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C16H17ClNaO4 331.0708; Found 331.0712.

Ethyl 3-chloro-2-(4-methoxyphenyl)-6-oxocyclohex-1-enecarboxylate (2f-Cl). Yield 38.2 mg (39%, orange oil); IR (neat): νmax 2982, 2838, 1733, 1217, 810 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.44-7.39 (m, 2H), 6.95-6.90 (m, 2H), 5.05 (t, J = 3.3 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.07-2.95 (m, 1H), 2.68-2.45 (m, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.0, 166.0, 161.1, 154.2, 132.7, 129.0, 128.1, 114.1, 61.4, 56.2, 55.3, 31.9, 30.6, 13.8; HRMS (ESI-TOF) m/z: (M+H)+ (Cl-35) Calcd for C16H18ClO4 309.0888; Found 309.0886.

Ethyl 3-chloro-2-(4-fluorophenyl)-6-oxocyclohex-1-enecarboxylate (2g-Cl). Yield 59.6 mg (69% as a yellow oil); IR (neat): νmax 2979, 2940, 1734, 1046, 689 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.15-7.07 (m, 2H), 4.98 (t, J = 3.3 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.08-2.96 (m, 1H), 2.71-2.46 (m, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.7, 165.2, 163.6 (d, JC-F = 259 Hz), 153.4, 133.8, 132.0 (d, JC-F = 3 Hz), 129.4 (d, JC-F = 8 Hz), 115.8 (d, JC-F = 22 Hz), 61.5, 56.1, 31.9, 30.7, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C15H14ClFNaO3 319.0508; Found 319.0514.

Ethyl 3-chloro-2-(4-chlorophenyl)-6-oxocyclohex-1-enecarboxylate (2h-Cl). Yield 65.6 mg (62%, yellow oil); IR (neat): νmax 2982, 1732, 1680, 1226, 1051, 830 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.35 (m, 4H), 4.97 (t, J = 3.3 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.08-2.96 (m, 1H), 2.71-2.45 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.7, 165.2, 153.2, 136.2, 134.3, 133.8, 128.9, 128.7, 61.6, 55.9, 31.9, 30.7, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C15H14Cl2NaO3 335.0212; Found 335.0221.

Ethyl 2-(4-bromophenyl)-3-chloro-6-oxocyclohex-1-enecarboxylate (2i-Cl). Yield 47.9 mg (64%, orange oil); IR (neat): νmax 2981, 1732, 1680, 1229, 1051, 827 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.96 (t, J = 3.0 Hz, 1H), 4.09 (q, J = 7.2 Hz,

2H), 3.08-2.96 (m, 1H), 2.71-2.45 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.6, 165.1, 153.2, 134.8, 133.8, 131.9, 128.9, 124.4, 61.6, 55.9, 31.9, 30.8, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) (Br-79) Calcd for C15H14BrClNaO3 378.9707; Found 378.9707.

Ethyl 6-chloro-3-oxo-4'-(trifluoromethyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2j-Cl). Yield 11.3 mg (11%, brown oil); IR (neat): νmax 2984, 2932, 2132, 1735, 1684, 1325, 1128 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 4.97 (t, J = 3.2 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.09-3.00 (m, 1H), 2.74-2.50 (m, 3H), 1.00 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 193.4, 164.8, 152.9, 139.5, 134.4, 131.8 (q, JC-F = 32 Hz), 127.7, 125.6 (q, JC-F = 3.5 Hz), 123.6 (q, JC-F = 271 Hz), 61.7, 55.8, 32.0, 30.9, 13.6; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C16H14ClF3NaO3 369.0476; Found 369.0476.

Methyl 4-(6-chloro-2-(ethoxycarbonyl)-3-oxocyclohex-1-enyl)benzoate (2k-Cl). Yield 10.0 mg (19%, yellow oil); IR (neat): νmax 2952, 2925, 2851, 1722, 1276, 1112, 703 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.10-8.07 (m, 2H), 7.51-7.48 (m, 2H), 4.99 (t, J = 3 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.11-2.99 (m, 1H), 2.75-2.48 (m, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.6, 166.2, 165.0, 153.5, 140.3, 134.1, 131.4, 129.8, 127.4, 61.7, 55.8, 52.4, 32.1, 30.9, 13.7; HRMS (ESI-TOF) m/z: (M+Na)+ (Cl-35) Calcd for C17H17ClNaO5 359.0657; Found 359.0651.

Ethyl 6-bromo-3-oxo-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (2a-Br). Yield 51.7 mg (55%, orange oil); IR (neat): νmax 2983, 1661, 1269, 1217, 759 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.42-7.38 (m, 5H), 5.14 (t, J = 3.0 Hz, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.04-2.91 (m, 1H), 2.72-2.50 (m, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.8, 165.3, 155.8, 136.0, 132.9, 130.0, 128.6, 127.2, 61.3, 48.2, 33.0, 31.4, 13.6; HRMS (ESI-TOF) m/z: (M+H)+ (Br-79) Calcd for C15H16BrO3 323.0277; Found 323.0269.

Acknowledgements

This research work was supported in part by grants from Chulabhorn Research Institute, Chulabhorn Graduate Institute, Mahidol University, the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education.

Keywords: 1,3-ketoesters • annulation • chlorinative cyclization • cyclohexenone • chlorination

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Entry for the Table of Contents

Access to 2-cyclohexenone and 4-chloro-2-cyclohexenone: Alkyne-tethered 1,3-ketoesters are employed for a rapid construction of 2-cyclohexenone-2-carboxylate derivatives via TfOH-promoted cyclization at room temperature. With the subsequent addition of NCS, the reactions conveniently led to the regioselective formation of 4-chloro-2-cyclohexenone-2-carboxylate derivatives in one pot.

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