α-Alkylidene-γ-butyrolactone Formation via Bi(OTf) - ACS Publications

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Cite This: J. Org. Chem. 2017, 82, 10883-10897

α‑Alkylidene-γ-butyrolactone Formation via Bi(OTf)3‑Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity Matthew J. Sandridge,† Brett D. McLarney,† Corey W. Williams,† and Stefan France*,†,‡ †

School of Chemistry and Biochemistry and ‡Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States S Supporting Information *

ABSTRACT: A Bi(OTf)3-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-alkylidene-γbutyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf)3 serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for E/Z selectivity was developed using DFT calculations.

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INTRODUCTION The α-alkylidene-γ-butyrolactone (ABL) framework represents an important structural motif to both organic and medicinal chemists (Figure 1). It is found in a vast collection of natural products and potential therapeutics with significant biological activities including anticancer, anti-inflammatory, antibacterial, antifungal, and antiviral.1 ABLs are also useful building blocks for chemical synthesis due to their facile derivatizations.2 It was estimated that by 2009 there were more than 5000 identified

ABL natural products along with another 9000 synthetic analogues.3 Synthesis of the ABL framework is an ongoing endeavor for the synthetic community. As such, several extensive reviews have been published highlighting the diverse approaches that can be taken toward the scaffold.1,3,4 The general synthetic approaches to the ABL core have been classified into the following types: alkylidenation of γbutyrolactones,5 various lactonization approaches,6 tandem (or sequential) intramolecular C−H insertion/olefination,7 the Dreiding−Schmidt organometallic approach,8 cross-methathesis between α-methylene-γ-butyrolactones and olefins,9 intramolecular enyne metathesis reactions,10 Pd-catalyzed cross-couplings,11 Diels−Alder and retro-Diels−Alder reactions,12 radical cyclizations,13 and Baeyer−Villiger reactions on cyclobutanones.14 Despite the abundant literature, the diversity within the ABLs has made the pursuit of strategic ABL targets and the development of methodologies to access them persistently meaningful endeavors in the synthetic community.15 Over the past 10 years, our laboratory has explored a variety of intra- and intermolecular ring-opening cyclizations of small,

Figure 1. Examples of ABL frameworks in target molecules.

Received: July 8, 2017 Published: September 6, 2017

© 2017 American Chemical Society

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The Journal of Organic Chemistry strained ring systems (e.g., cyclopropanes, cyclopropenes, alkylidene cyclopropanes, and cyclobutanes).16 In one pertinent example, we disclosed a calcium-catalyzed, dehydrative, ringopening cyclization of (hetero)aryl cyclopropyl carbinols to form (hetero)aryl-fused cyclohexa-1,3-dienes.17 Interestingly, we found that when cyclopropyl carbinol 4a was subjected to the reaction conditions, 14% yield of α-alkylidene-γ-butyrolactone 6a was obtained in addition to the expected dihydronaphthalenes 5a and 5a′ (Scheme 1). Product 6a was unexpected, as no mention of α-alkylidene-γ-butyrolactone formation had been reported in the previous literature for the transformation.18

Scheme 3. D−A Cyclopropane Approach to Cyclopropyl Carbinols 4a−v, 4x, and 4y

Scheme 1. Ca(II)-Catalyzed Ring-Opening Cyclization of Cyclopropyl Carbinols

While ABLs have been generated from the reactions of vinyl cyclopropanes with substituted benzaldehydes in the presence of DABCO, no examples of their synthesis from cyclopropyl carbinols have been reported.19 Intrigued by the formation of 6a, we were particularly interested in discerning the factors that govern the chemoselectivity of the reaction (formation of 5 and/or 6) and how they could be rationalized in terms of substituent effects. We envisioned that this knowledge would contribute to determining the conditions for selective ABL formation, establishing cyclopropyl carbinols 4 as a useful common precursor to multiple different, yet desirable, core structures. This type of approach represents one of the hallmarks of diversity-oriented synthesis.20 Toward that end, we disclose our studies on the Bi(OTf)3-calyzed, ring-opening cyclization of cyclopropyl carbinols 4 to form ABLs 6 and show how the dehydrative, ring-opening cyclization is dependent upon the electronic nature of the substituents on both the carbinol and the cyclopropane ring (Scheme 2).

Instead, 4w was synthesized using Nishii’s Reformatsky approach (Scheme 4).21 1,1-Dibromocyclopropane 10w Scheme 4. Reformatsky Approach to Carbinol 4w

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RESULTS AND DISCUSSION Synthesis of Carbinols 4. Carbinols 4a−v, 4x, and 4y were prepared using a three-step sequence from the corresponding β-ketoesters 1. Diazo transfer followed by Rh(II)-catalyzed cyclopropanation with various olefins gave donor−acceptor (D−A) cyclopropanes 3. LiEt3BH reduction generated secondary (2°) carbinols 4a−v. Tertiary (3°) carbinols 4x and 4y were obtained upon addition of methyl- or phenyllithium to the D−A cyclopropane, respectively (Scheme 3). For the preparation of trialkyl 3° carbinol 4w, the previously discussed sequence failed to provide the desired product.

(prepared from the reaction of styrene with CHBr3, aq NaOH, and catalytic BnEt3NBr) was treated with n-BuLi and quenched with dry ice (CO2). Following workup, the crude acid was converted to the ester 11w using K2CO3 and MeI in 46% yield over the two steps. Lastly, formation of the Reformatsky reagent and reaction with 3-pentanone gave carbinol 4w. In all cases, the carbinols are prepared and used as mixtures of diastereomers. Reaction Optimization. Given the benchmark formation of ABL 6a in the previous report17 (Scheme 1), carbinol 4a was

Scheme 2. Bi(OTf)3-Catalyzed Ring-Opening Cyclization of Cyclopropyl Carbinols

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6a was formed in 35% yield along with 49% of 5a (entry 4). A modest 27% yield of 6a was obtained with 5 mol % of Ga(OTf)3 along with 5a as an intractable mixture (entry 5). InCl3 (10 mol %) gave a 52% combined yield of 5a/5a′, and no ABL product (entry 6). GaCl3 (10 mol %) led to formation of 67% yield of 5 along with an intractable mixture containing a minor amount of 6a (entry 7). In searching for effective catalysts for carbinol activation, we were intrigued by Bi(III) salts. Due to their synthetic utility, low toxicity, and low cost, Bi(III) salts are attractive reagents for the practicing organic chemist.22 Over the past 15 years, a variety of Bi(III) compounds have been used in organic reactions as organobismuth reagents or as catalysts. They have been shown to be effective catalysts for etherification, allylation, cyanation, cycloaddition, and a host of protection/deprotection reactions.23 Given this versatilty, we screened three Bi(III) salts in the reaction: Bi(OTf)3, BiBr3, and Bi(NO2)3·5H2O. Bi(OTf)3 provided ABL 6a in 62% yield as a single diastereomer (entry 8). A small amount of 5a was also formed as an inseparable, complex mixture. In contrast, the reactions employing BiBr3 and Bi(NO2)3·5H2O did not to go to completion after 24 h and failed to provide any ABL product (entries 9 and 10). In the case of BiBr 3 , 18% of dihydronaphthalene 5a was formed, whereas 12% of hydroxylated product 7a was identified using Bi(NO2)3·5H2O.24,25 Due to the effectiveness of Bi(OTf)3 in catalyzing the transformation relative to the other Bi(III) salts, we hypothesized that Bi(OTf)3 is serving as a precursor to TfOH, which is generated in situ and behaves as the active catalytic species. This behavior of Bi(OTf)3 has precedent and is most commonly observed in esterification reactions.26 Moreover, the poor performances of all of the nontriflatecontaining Lewis acids seem to support the importance of TfOH. To probe this hypothesis, 4a was subjected to TfOH (15 mol %) at room temperature (entry 11). Product 6a was isolated in 61% yield along with an intractable mixture containing 5a, which is comparable to the outcome with Bi(OTf)3 (62% yield, entry 6). TfOH also outperformed other Bronsted acids (TsOH and TFA) that were examined (entries 12 and 13). When 15 mol % of preformed pyridinium triflate was used as the catalyst, only a trace product was generated (entry 14). Finally, when a reaction was run using Bi(OTf)3 (10 mol %) with 30 mol % of added 2,6-di-tert-butylpyridine, no reaction occurred (entry 15). Based on these controls, we are confident that Bi(OTf)3 is serving as a surrogate for TfOH. The Bi(OTf)3 presumably reacts with the carbinol stoichiometrically, as BiBr3 and Bi(NO2)3·5H2O did, but is immediately hydrolyzed to generate the TfOH, which proceeds to catalyze the reaction. Moreover, Bi(OTf)3 performed better than the other metal triflates studied due to both its ability to form TfOH more readily and its unique Lewis acidity.27 This is important, as the extent of Lewis acid coordination to the ester carbonyl seems to correlate with dihydronaphthalene formation (aryl trapping) versus ABL formation (ester trapping). Ultimately, due its superb ease of handling compared to TfOH, Bi(OTf)3 was chosen as the preferable catalyst for the remaining studies. In the previous report, 4 Å molecular sieves were included in the reaction mixture in order to sequester the generated water and prevent unwanted side reactions and Lewis acid deactivation. For ABL formation, the desired reaction pathway requires an equivalent of water in the hydrolysis step of the mechanism, releasing methanol. To determine if the 4 Å

logically chosen as the model system for reaction optimization (Table 1). In the previous work, similar to when no catalyst was Table 1. Reaction Optimization

entrya 1c 2

acid (mol %)

16h 17

none Ca(NTf2)2 (1), n-Bu4NPF6 (1) In(OTf)3 (15) Sc(OTf)3 (15) Ga(OTf)3 (5) InCl3 (10) GaCl3 (10) Bi(OTf)3 (5) BiBr3 (5) Bi(NO3)2·5H2O (5) TfOH (15) TsOH (20) TFA (20) [pyrH][OTf] (15) Bi(OTf)3 (10), 2,5-di-t-BuPyr (30) Bi(OTf)3 (5) Bi(OTf)3 (5)

18 19 20 21e

Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3

3 4 5 6e 7 8 9e 10e,g 11 12e 13c 14c 15c

(5) (5) (10) (2)

solvent (T, °C)

time (h)

% yield 5/6b

CH2Cl2 (23) 1,2-DCE (84) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23) CH2Cl2 (23)

24.0 0.5

0/0 85/14

2.5 1.0 2.5 24.0 24.0 1.0 24.0 24.0 0.5 24.0 24.0 24.0 24.0

45/39 49/35 −d/27 52/− 67/−f −d/62 18/0 0/0 −d/61 7/38 0/0 0/0 0/0

CH2Cl2 (23) 1,2-DCE (84) CH2Cl2 (40) CH2Cl2 (0) CH2Cl2 (23) CH2Cl2 (23)

1.0 0.5

−d/60i 39/55

1.0 3.0 1.0 24.0

49/36 −d/58 28/55 20/−

a

Reactions were performed with 1 equiv of cyclopropyl carbinol 4a, indicated mol % of Lewis acid in indicated solvent (0.1 M) at indicated temperature (T) in the presence of 4 Å molecular sieves. bRatios determined after product isolation. cNo reaction. Starting material 4a recovered. dComplex mixture containing 5. eReaction did not go to completion, and starting material 4a was recovered. fComplex, inseparable mixture containing 6a. g Isolated 12% of acyclic hydroxylated product 7a. hReaction performed without 4 Å molecular sieves. iComplex, inseparable mixture. Product yield based on 1H NMR using dimethyl terephthalate as an internal standard.

present (entry 1), no reaction was observed with Zn(OTf)2, Al(OTf)3, Cu(OTf)2, [Cu(OTf)]2·PhMe, Yb(OTf)3, Ni(ClO4)2·6H2O, La(OTf)3, Y(OTf)3, or Dy(OTf)3. Also, stoichiometric amounts of Lewis acid do not afford ABL products, and only dihydronaphthalenes 5 are generated.17,18 As discussed in Scheme 1, the calcium complex (Ca(NTf2)2, nBu4NPF6) (1 mol %) gave ABL 6a in 14% yield along with 85% of 5a/5a′ (entry 2). This result was obtained in 1,2-DCE at reflux since the Ca-catalyzed reaction did not occur at room temperature in CH2Cl2. In contrast, the reactions of 4a employing In(OTf)3, Sc(OTf)3, or Ga(OTf)3 as catalysts each proceeded at room temperature in CH2Cl2. In(OTf)3 at 15 mol % loading produced 39% yield of ABL 6a and 45% of 5a (entry 3). Sc(OTf)3 (15 mol %) provided a similar product profile as 10885

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Figure 2. Crystal structure of 6a drawn at the 50% probability level.

Scheme 5. Proposed Mechanism for the Bi(OTf)3-Catalyzed Dehydrative, Ring-Opening Cyclization

reaction, Bi(OTf)3 is converted to OBi(OTf), and TfOH is generated. With Bi(OTf)3 consumed, TfOH catalyzes the transformation of remaining 4 to carbocation I. At this stage, the reaction can proceed through two different pathways to afford products 5 and/or 6. In the path toward product 6, cyclopropyl carbinyl carbocation I undergoes ring opening to form homoallylic carbinyl cation transition state TS1. Intramolecular trapping of the cation in TS1 by the pendant ester would then form oxonium intermediate II.29 Hydrolysis of II results in the loss of methanol, furnishing ABL 6 (pathway a). If R1 or R2 is a π-donating substituent (aryl or alkenyl group), Friedel−Crafts-type π-attack on an alternative ring-opened transition state (TS2) would generate the (hetero)aryl-fused cyclohexa-1,3-diene 5 (pathway b). It is also likely that if hydrolysis is slow, intermediate II could go back toward intermediate I and proceed toward product 5. To fully understand the nature of this chemodivergence, substituent effects on both the cyclopropane and carbinol were studied. Exploration of Substrate Scope and Substituents Effects. Toward exploring the scope of the reaction, the effects of changing the cyclopropane substituents were probed (Table 2). First, various aryl substituents were studied to identify any electronic effects. Interestingly, a clear trend emerged. Slightly electron-poor aryl rings favored ABL

molecular sieves were a hindrance or boon for ABL formation, the reaction was performed without the addition of 4 Å molecular sieves for comparison (entry 16). Although the reaction provided 60% NMR yield of ABL 6a, it resulted in a highly complex mixture, preventing the isolation of pure product. It is likely that the 4 Å molecular sieves help to control the amount of water in the flask, resulting in less side reactions.28 Further attempts to improve the yields by changing catalyst loading, solvent, or temperature were unsuccessful (entries 17−21). Thus, the optimized reaction conditions chosen for ABL formation were Bi(OTf)3 (5 mol %) with added 4 Å molecular sieves in CH2Cl2 at room temperature. E/Z Determination. With ABL 6a isolated as a single diastereomer, we sought to determine the absolute configuration. We predicted an E configuration based on the allylic coupling constants; however, initial attempts using NOE and 2D NMR techniques failed to conclusively elucidate the configuration. In order to conclusively determine the configuration of 6a, crystals were grown and the X-ray crystal structure was obtained (Figure 2). This confirmed our initial suspicion that 6a was indeed the E-isomer. Proposed Mechanism. Mechanistically, we propose that Bi(OTf)3 first reacts with cyclopropyl carbinol 4 to form cyclopropyl carbinyl carbocation I (Scheme 5). In this initial 10886

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(entries 5−7). To further probe this trend, cyclopropane 4h (bearing a 2-bromo-4-chlorophenyl substituent) was used. The reaction failed to reach completion under the standard conditions; however, at a higher loading (20 mol %) of Bi(OTf)3, ABL 6h was obtained in 78% yield as the Ediastereomer (entry 8). Other aryl (and heteroaryl) substituents were also studied. With the electron-rich 2-naphthyl-substituted derivative 4i, ABL 6i was obtained in 24% yield as the E-diastereomer in addition to 51% of dihydronaphthalene 5i (entry 9). Next, given its presence in various ABL natural products, a furyl substituent was employed. Unfortunately, an intractable mixture was formed from the 2-furyl substrate 4j (entry 10). This outcome is most likely due to acid-mediated furan degradation/polymerization pathways. The reaction proved amenable to certain geminally substituted cyclopropanes. The gem-methylphenyl cyclopropane 4k gave its ABL product 6k in 38% yield as the single Ediastereomer with dihydronaphthalene 5k also present in an inseparable mixture (entry 11). Conversely, no ABL product was formed from the gem-methyl 3-thienyl cyclopropane 4l, (entry 12); instead, acyclic elimination products 8l were obtained in 46% yield (Figure 3).10 These products presumably

Table 2. Probing the Effects of the Cyclopropane Donor Group(s)

Figure 3. Undesired elimination products 8.

arise from cyclic oxonium II as undesired E1-type elimination outpaces hydrolysis. Indanyl cyclopropane 4m gave 34% yield of the desired ABL 6m along with 43% of similar elimination products 8m (entry 13). Finally, the gem-dialkyl-substituted, spirocyclic cyclopropane 4n afforded ABL 6n in 43% NMR yield as a 12:1 mixture of ABL isomers to elimination product 8n (entry 14). The carbinol substituent was next changed from the 3,4dimethoxyphenyl group to other (hetero)aryl and alkyl groups to similarly probe electronic effects (Table 3). The 4methoxyphenyl carbinol 4o gave the desired ABL 6o in 73% yield as a 7:1 E/Z mixture (entry 1). Phenyl carbinol 4p afforded ABL product 6p in 65% yield as a 1:1 E/Z mixture (entry 2). 4-Chlorophenyl carbinol 4q generated a complex mixture that contained a 35% NMR yield of ABL 6q as a 1:1 mixture of diastereomers (entry 3). An intractable mixture was obtained with 3-chlorophenyl carbinol 4r (entry 4). Using the 3,5-dimethoxyphenyl substrate 4s also resulted in a complex mixture of products containing ABL product 6s in 26% yield as a 1:1 mixture of diastereomers by NMR (entry 5). ABL 6t was obtained as the single E-diastereomer in 48% yield from benzofuranyl carbinol 4t (entry 6). When 2° dialkyl carbinols (as in 4u and 4v) were employed, no reaction occurred, and starting materials were recovered (entries 7 and 8). In contrast, the trialkyl 3° carbinol 4w does react to give ABL 6w, albeit as a complex mixture with a low 27% yield by NMR (entry 9). As expected, tertiary benzylic carbinols similarly undergo the ring-opening cyclization to form ABL products. For instance, in the case of 4x (bearing methyl and aryl carbinol substituents), ABL 6x was formed in 54% yield as a single diastereomer (entry 10). For the diaryl-

a

Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf)3 (10 mol %) in CH2Cl2 (0.1 M) at 23 °C in the presence of 4 Å molecular sieves. bIsolated yield after column chromatography. cE/Z ratios determined by 1H NMR on the crude mixture. dReaction performed with 5 mol % of Bi(OTf)3. eE/Z ratio determined by combination of isolated yield of (E)-6b and 1H NMR yield of impure (Z)-6b using dimethyl terephthalate as an internal standard. fOnly dihydronaphthalene product 5c formed. gReaction performed with 20 mol % of Bi(OTf)3. hIntractable mixture. iNo desired product formed. j Isolated as a 5:1 mixture of unassigned diastereomers. kIsolated as a 12:1 mixture of 6n and an elimination product 8n. Product yield based on 1H NMR using dimethyl terephthalate as an internal standard.

formation, whereas electron-rich ones favored the formation of cyclohexa-1,3-diene products 5. For instance, changing from the phenyl in 4a to the more electron-rich tolyl or 4methoxyphenyl (as in 4b and 4c) afforded 23% yield of ABL 6b (as a 3:1 E/Z mixture of diastereomers) in the case of 4b, whereas no ABL was detected with 4c (entries 2 and 3). In each case, dihydronaphthalenes 5b and 5c were respectively isolated with 49% and 67% yield. In contrast, when the phenyl ring was substituted with a chlorine or bromine, the reaction proceeded efficiently to the ABL product. ABL 6d was isolated as the E-diastereomer in 81% yield from 4-chlorophenylsubstituted cyclopropane 4d (entry 4). Similarly, the 4bromophenyl-, 3-bromophenyl-, and 2-bromophenyl-substituted cyclopropanes (4e−g) each provided their respective ABL products (6e−g) in 87%, 89%, and 72% yield as single Ediastereomers, indicating minimal positional electronic effects 10887

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products while more electron-poor aryl donor substituents give preferential ABL formation. It is plausible that the extent of ester involvement in stabilizing the acyclic carbocationic transition state may facilitate cyclopropane ring opening and, ultimately, determine the chemoselectivity. Revisiting TfOH as the Catalyst. Despite the fact that Bi(OTf)3 was chosen as the optimum catalyst for the transformation in the optimization studies (due to ease of handling and overall performance), TfOH also presented itself as a viable option as a catalyst. To probe potential differences between TfOH and Bi(OTf)3 as catalysts, four moderately active substrates with varying E/Z selectivities were submitted to optimized catalytic TfOH conditions (Table 4). As

Table 3. Probing the Effects of the Carbinol Substituent(s)

Table 4. Comparison of Bi(OTf)3 vs TfOH Catalysis

a

Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf)3 (10 mol %) in CH2Cl2 (0.1 M) at 23 °C in the presence of 4 Å molecular sieves. bIsolated yield after column chromatography. cE/Z ratios determined by 1H NMR on the crude mixture. dE/Z ratios determined from yields of isolated E- and Z-isomers. eYield based on 1 H NMR using dimethyl terephthalate as an internal standard. f Intractable mixture. gNo reaction. Starting material recovered. h Reaction performed with 5 mol % of Bi(OTf)3. iIsolated as a 3:1 mixture of unassigned diastereomers.

a

Reactions were performed with cyclopropyl carbinol 4 (1 equiv) and Bi(OTf)3 (10 mol %) in CH2Cl2 (0.1 M) at 23 °C in the presence of 4 Å molecular sieves. bReactions were performed with cyclopropyl carbinol 4 (1 equiv) and TfOH (15 mol %) in CH2Cl2 (0.1 M) at 23 °C in the presence of 4 Å molecular sieves. cIsolated yield after column chromatography. dE/Z ratios determined by 1H NMR on the crude mixture. eNMR yield based on 1H NMR using dimethyl terephthalate as an internal standard.

substituted carbinol 4y, ABL 6y was obtained in 41% yield as a 3:1 diastereomeric mixture (entry 11). While it is assumed that the E-isomer is the major product in both cases, it was impossible to unambiguously assign the major and minor isomers using 1H NMR due to the absence of the allylic coupling. In both cases, dihydronaphthalene products were also observed (5% of 5x; 36% of 5y). The outcomes from the exploration of substrate scope aligned well with the proposed mechanism and also highlighted that substituent effects were critical in determining product outcomes through comparative stabilization of intermediates and/or transition states. For instance, since the carbinol substituents serve to stabilize cyclopropyl carbinyl cation I, the carbinols must be sufficiently activated to promote the reaction. While electron-rich aryl substituents are well-tolerated, electron-poor ones give substantially lowered yields, loss of E/Z selectivity, or increased unwanted side reactions. Similary, secondary (and by default, primary) carbinols are not amenable to the reaction as the cyclopropyl carbinyl cations do not form. For aryl cyclopropyl carbinols, the ABL formation pathway (ester trapping and hydrolysis) directly competes with the Friedel−Crafts pathway with substituent electronic effects determining product outcomes. Electron-rich aryl substituents on the cyclopropane result in predominantly Friedel−Crafts

previously mentioned, the reaction outcomes were almost identical for the formation of ABL 6a (entry 1). For spirocyclic ABL 6n, Bi(OTf)3 afforded a higher yield than TfOH (43% vs 30%, entry 2), whereas the reverse was observed for ABL 6p (60% vs 73% yield). In both cases, the same 1:1 E/Z selectivity was obtained. In contrast, a dramatic selectivity difference occurred with benzofuranyl ABL 6t (entry 4). While Bi(OTf)3 gave a >99:1 E/Z ratio with a modest 48% yield, TfOH provided a much higher yield (69%) but with a severely reduced 5:1 E/Z ratio. From this subset of reactions, it seems that there are some difference between the catalysts, which may arise from the amount of TfOH readily available to catalyze the reaction or the potential for interactions with the Lewis acidic Bi(OTf)3. Neither set of conditions was consistently better than the other in terms of product yields, but Bi(OTf)3 may provide more selectivity based on the outcomes of ABL 6t. This, along with the experimental precautions necessary for TfOH use, suggests Bi(OTf)3 as the catalyst of choice for this transformation; however, TfOH remains a strongly viable catalyst for the transformation should Bi(OTf)3 be unavailable for use. E/Z Selectivity. With a handle on trends for ABL vs cyclohexadiene chemodivergence, the origins of E/Z selectivity 10888

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Figure 4. Cyclopropane opening reaction coordinates for I-a (A) and I-p (B) given in both Gibbs free energy and enthalpy. Relevant geometries reflect a relatively late transition state from I-a to II-a.

Figure 5. (A) Substitution on either Ph1 or Ph2 can effect elongation of the Cβ-Cγ bond. (B) Spectrum of Cβ−Cγ bond lengths highlights the correlation between observed E/Z selectivities and cyclopropane lability.

state from I-a, prompting a later and more selective transition compared to that from I-p. Here, the difference in cyclopropane lability arises from the different electron donating potentials of the phenyl rings. Methoxy substitutions at the 3 and 4 positions increase stabilization of the benzylic cation at Cα. With less electrondonating potential on the unsubstituted phenyl ring, I-p compensates by elongating the Cβ−Cγ bond and delocalizing some of the positive charge onto the benzylic Cγ position. This phenomenon is reflected not only in the elongation of Cβ−Cγ but also in the shortening of the Ph−Cγ bond (1.47 Å in I-a vs 1.45 Å in I-p). Atomic partial charges (δ+) reflect these geometric changes by displaying a shift of positive charge accumulation from Cα to Cγ as the Cβ−Cγ length increases. Hypothetically, the cyclopropane could be polarized via substitution on the second phenyl ring as well. For example, comparing I-a and I-b we see that 4-methyl substitution is responsible for elongating Cβ−Cγ by 0.02 Å in the ground state (Figure 5A); a concomitant drop in E/Z selectivity from 99:1 to 3:1 is observed in the synthetic experiments. Holding sterics constant and examining this trend across structures I-a, I-b, I-d to I-h, I-o, I-p, I-q, and I-s suggests that, as a corollary to Hammond’s postulate, electron-donating groups at Ph1 and

were the next subject to be explored. While most substrates were completely E-selective, a handful offered either no selectivity or reduced diastereomeric ratios. In hopes of understanding these outliers, DFT calculations were employed to examine the cyclopropane opening transition states between intermediates I and II, derived from both the 3,4-dimethoxyphenyl-substituted carbinol 4a (high selectivity) and the phenyl carbinol 4p (low selectivity, Figure 4). The transformation generally agreed with our proposed mechanistic transformation between I and II, going through a homoallylic cation partially stabilized through an approaching ester. Consistent with the experimentally observed selectivities, the computations revealed a ΔΔG⧧ = 3.9 kcal/molin favor of E isomer formationfor the 3,4-dimethoxyphenyl carbinyl cation I-a. Meanwhile, ΔΔG⧧ = 1.3 kcal/mol for I-p, which displayed no E/Z selectivity under the optimized reaction conditions. The more exothermic ring opening for I-p suggests an earlier transition state and thus begs the application of Hammond’s postulate to rationalize observed selectivities. Indeed, not only is the transformation more exothermic for I-p, but the cyclopropane Cβ−Cγ bond in I-p is weakened compared to that in I-a, 1.73 Å vs 1.65 Å respectively. In this light, the Cβ− Cγ bond must undergo more elongation to reach the transition 10889

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry electron-withdrawing groups at Ph2 enhance E/Z selectivity by strengthening the Cβ−Cγ bond in the ground-state carbinyl cation I (Figure 5B). Through comparing the experimental results to DFT calculations, the selectivities can be reasonably rationalized by applying Hammond’s postulate to the transition from I to II through TS1. Moreover, the E/Z selectivity and the polarization (as measured by bond length) of the cyclopropyl Cβ−Cγ in the ground-state carbinyl cation I can then be correlated. This approach provides an easily accessible calculation (Cβ−Cγ bond length in intermediate I) as the basis for predicting the E/ Z selectivity in ABL formation. Conclusions. In summary, we have disclosed the Bi(OTf)3catalyzed ring-opening cyclizations of (hetero)aryl cyclopropyl carbinols to form functionalized α-alkylidene-γ-butyrolactones (ABLs). The overall transformation marks different chemoselectivity than observed in previous reports for the acidpromoted reactions of (hetero)aryl cyclopropyl carbinols. Bi(OTf)3 likely serves as a stable and user-friendly precursor to TfOH, which proceeds to catalyze the reaction. The resulting ABLs are formed in up to 89% yield, with generally high E-diastereoselectivity. Substituent effects play a major role in the determination of reaction chemoselectivity, with cyclopropyl carbinol substituents directly influencing cyclopropane ring-opening. The cyclopropane donor substituents directly influence the overall reaction chemoselectivity, with weakly stabilizing or electron-poor substituents providing better yields of the ABL products. In contrast, highly stabilizing cyclopropane donor substituents give copious amounts of competing products including, most importantly, (hetero)arylfused cyclohexa-1,3-diene products 5. Using DFT calculations, a predictive model was developed that correlates E/Z selectivity with the Cβ−Cγ bond length in the ground state cyclopropyl carbinyl cation. The ester plays an important role in stabilizing the transient acyclic homoallylic cation formed upon ring opening or, possibly, in facilitating cyclopropane ring opening by anchimeric assistance. Overall, we now have a better understanding of how different substituents can influence product outcomes through their interactions with intermediate I and ring-opening transition states in our proposed mechanism. Future efforts with enantiopure cyclopropyl carbinols will serve to better explore the hypothesis of ester involvement while enabling access to chiral ABLs. Future work will also focus on specific target synthesis and applying the trends we learned toward targets for both products 5 and 6.

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singlet, d = doublet, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet of doublet of doublets, t = triplet, m = multiplet, br = broad), coupling constants (Hz), and integration. High-resolution mass spectrometry (HRMS) measurements were obtained either through EI on a Micromass AutoSpec M [forward geometry (EBE) three sector tandem MS] or through ESI on a Thermo Orbitrap XL. The accurate mass analyses run in EI mode were at a mass resolution of 10000 and were calibrated using PFK (perfluorokerosene) as an internal standard. The accurate mass analyses run in ESI mode were at a mass resolution of 30000 using the calibration mixture supplied by Thermo. Uncorrected melting points were measured with a digital melting point apparatus (DigiMelt MPA 160). Computational Method. All calculations were performed using the Gaussian 09 package at the M06L/6-31g(d,p) level of theory.30,31 Gaussian’s default solvation model, the Polarizable Continuum Model implemented via integral equation formalism (IEF-PCM), was employed to simulate a dichloromethane solvent.32−34 Transitionstate calculations were verified to have only one imaginary vibrational frequency. Synthesis of β-Keto Esters 1. General Procedure. A dry roundbottom flask was charged with a stir bar, and sodium hydride (2.8 equiv) was added under nitrogen atmosphere. Dimethyl carbonate (2.0 equiv) was then added with toluene, and the reaction was stirred and heated to reflux. A solution of the aryl ketone (1.0 equiv) in toluene was added dropwise over 30 min using a syringe pump for an overall reaction concentration of 1.0 M. The reaction was monitored by TLC until complete conversion of the aryl ketone was observed. After the evolution of hydrogen gas, the reaction was allowed to cool to room temperature, and acetic acid (6 mL) was added dropwise to the reaction mixture. Ice-cold water was added to dissolve any solid that formed, and then the solution was diluted with EtOAc. The organic layer was extracted with EtOAc three times, dried over Na2SO4, and filtered through a Celite plug. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. Methyl 3-(4-Chlorophenyl)-3-oxopropanoate (1q). Prepared following the general procedure using sodium hydride (60% dispersion in mineral oil, 3.60 g, 90.6 mmol), dimethyl carbonate (99% pure, 5.5 mL, 64.7 mmol), and 1-(4-chlorophenyl)ethan-1-one (5.00 g; 32.3 mmol) in toluene (32.3 mL) over 30 min. After workup and purification (20% EtOAc/hexanes, Rf = 0.50), compound 1q was afforded as a thick orange oil (6.67 g, 97% yield). Characterizations were consistent with previously reported literature.35 Methyl 3-(3-Chlorophenyl)-3-oxopropanoate (1r). Prepared following the general procedure using sodium hydride (60% dispersion in mineral oil, 3.60 g, 90.6 mmol), dimethyl carbonate (99% pure, 5.5 mL, 64.7 mmol), and 1-(4-chlorophenyl)ethan-1-one (5.00 g; 32.3 mmol) in toluene (32.3 mL) over 30 min. After workup and purification (20% EtOAc/hexanes, Rf = 0.52), compound 1r was afforded as a orange oil (6.62 g, 96% yield). Characterizations were consistent with previously reported literature.35 Synthesis of Diazo Compounds 2. General Procedure. A 1 M solution in CH3CN of the starting β-keto ester (1.0 equiv) was added to a dry flask charged with a stir bar under nitrogen. Et3N (1.2 equiv) was added in one shot and was allowed to stir for 5 min. TsN3 (1.2 equiv) was then added in one shot and stirred at room temperature until completion. The reaction was monitored by TLC until complete conversion of the β-keto ester was observed. Upon completion, the reaction was concentrated under reduced pressure, and TsNH2 was recrystallized and filtered out using cold CH2Cl2. The filtrate was then concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. Methyl 2-Diazo-3-(3,4-dimethoxyphenyl)-3-oxopropanoate (2a). Compound 2a was synthesized as previously reported.17 Methyl 3-(4-Chlorophenyl)-2-diazo-3-oxopropanoate (2q). The general procedure was followed using compound 1q (4.35 g, 20.5 mmol) in acetonitrile (18.3 mL), Et3N (99% pure, 2.22 g, 21.9 mmol), and TsN3 (85% pure, 4.68 g, 23.7 mmol) over 18 h. After workup and

EXPERIMENTAL SECTION

General Information. Chromatographic purification was performed as flash chromatography with Silicycle SiliaFlash P60 silica gel (40−63 μm) or preparative thin-layer chromatography (prep-TLC) using silica gel F254 (1000 μm) plates and solvents indicated as eluent with 0.1−0.5 bar pressure. For quantitative flash chromatography, technical grade solvents were utilized. Analytical thin-layer chromatography (TLC) was performed on Silicycle SiliaPlate TLC silica gel F254 (250 μm) TLC glass plates. Visualization was accomplished with UV light. Infrared (IR) spectra were obtained using ATR on an IRAffinity-1S FTIR from Shimadzu. The IR bands are characterized as broad (br), weak (w), medium (m), and strong (s). Proton and carbon nuclear magnetic resonance spectra (1H NMR and 13C NMR) were recorded on a Varian Mercury Vx 300 MHz spectrometer or a Bruker 500 MHz spectrometer with solvent resonances as the internal standard (1H NMR: CDCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.0 ppm). 1H NMR data are reported as follows: chemical shift (ppm), multiplicity (s = 10890

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry

1732 (m), 1670 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C20H19BrO5 418.0416, found 418.0420. Methyl 2-(2-Bromophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3g). Prepared following the general procedure using compound 9b (1.10 g, 6.01 mmol), Rh2esp2 (96% pure, 5.9 mg, 0.076 mmol), and compound 2a (1.0 g, 3.78 mmol) in CH2Cl2 (38 mL) over 1 h. After workup and purification (30% EtOAc/hexane, Rf = 0.35), compound 3g was afforded as a colorless oil (309.2 mg, 20% yield): diastereomeric ratio (15:1); 1H NMR (300 MHz, CDCl3) δ = 7.58−7.51 (m, 3 H), 7.31−7.22 (m, 2 H), 7.16− 7.08 (m, 1 H), 6.90−6.84 (m, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.64 (t, J = 8.5 Hz, 1 H), 3.30 (s, 3 H), 2.46 (dd, J = 4.9, 8.1 Hz, 1 H), 1.67 (dd, J = 4.9, 8.9 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 192.0, 169.2, 153.1, 149.0, 134.9, 132.5, 130.3, 129.7, 128.8, 126.8, 126.2, 122.8, 110.6, 109.9, 56.0, 55.9, 52.3, 41.3, 31.3, 20.2; IR 2947 (w), 2839 (w), 1728 (m), 1670 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C20H19BrO5 418.0416, found 418.0411. Methyl 2-(2-Bromo-5-chlorophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3h). Prepared following the general procedure using compound 9c (0.935 g, 4.3 mmol), Rh2esp2 (96% pure, 5.9 mg, 0.0076 mmol), and compound 2a (1.0 g, 3.78 mmol) in CH2Cl2 (37.8 mL) over 18 h. After workup and purification (30% EtOAc/hexane, Rf = 0.37), compound 3h was afforded as a colorless oil (270.4 mg, 16% yield): diastereomeric ratio (15:1); 1H NMR (300 MHz, CDCl3) δ = 7.56−7.44 (m, 3 H), 7.24 (d, J = 2.5 Hz, 1 H), 7.11 (dd, J = 2.5, 8.5 Hz, 1 H), 6.91−6.85 (m, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.57 (t, J = 8.5 Hz, 1 H), 3.37−3.34 (m, 3 H), 2.41 (dd, J = 5.1, 8.1 Hz, 1 H), 1.68 (dd, J = 5.0, 8.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 191.6, 169.0, 153.3, 149.1, 136.9, 133.5, 132.9, 130.6, 129.4, 128.9, 124.0, 122.8, 110.5, 110.0, 56.1, 55.9, 52.4, 41.2, 30.9, 20.1; IR 2951 (w), 2841 (w), 1728 (m), 1673 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C20H18BrClO5 452.0026, found 452.0009. Methyl 1-(3,4-Dimethoxybenzoyl)-2-(furan-2-yl)cyclopropane-1carboxylate (3j). Prepared following the general procedure with modified equivalencies using vinyl furan (0.67 g, 7.512 mmol), Rh2esp2 (96% pure, 17.2 mg, 0.023 mmol), and compound 2a (2.02 g, 7.57 mmol) in CH2Cl2 (75 mL) over 16 h. After workup and purification (30% EtOAc/hexanes, Rf = 0.28), compound 3j was afforded as a white solid (593.8 mg, 31% yield): mp = 126−134 °C; diastereomeric ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.63 (dd, J = 2.1, 8.5 Hz, 1 H), 7.53 (d, J = 2.1 Hz, 1 H), 7.38−7.31 (m, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.33 (dd, J = 1.8, 3.3 Hz, 1 H), 6.21 (td, J = 0.9, 3.2 Hz, 1 H), 3.98−3.91 (m, 6 H), 3.43 (s, 3 H), 3.26 (t, J = 8.7 Hz, 1 H), 2.27 (dd, J = 4.9, 7.7 Hz, 1 H), 1.75 (dd, J = 4.9, 9.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 191.9, 169.0, 153.3, 150.0, 149.0, 142.1, 129.4, 123.2, 110.7, 110.4, 110.1, 108.1, 56.1, 56.0, 52.5, 40.7, 23.6, 19.2; IR 2951 (w), 2839 (w), 1728 (m), 1670 (m) cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C18H18O6Na 353.0996, found 353.0993. Methyl 1-(4-Chlorobenzoyl)-2-phenylcyclopropane-1-carboxylate (3q). Prepared following the general procedure using styrene (99% pure, 0.88 g, 8.38 mmol), Rh2esp2 (96% pure, 6.3 mg, 0.0084 mmol), and compound 2q (1.0 g, 4.19 mmol) in CH2Cl2 (42 mL) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.63, 0.55), compound 3q was afforded as a white solid (1.057 g, 80% yield): mp = 86−87 °C; diastereomeric ratio (20:1); 1H NMR (300 MHz, CDCl3) δ = 7.90−7.81 (m, 2 H), 7.47−7.39 (m, 2 H), 7.33− 7.21 (m, 5 H), 3.56 (t, J = 8.6 Hz, 1 H), 3.25 (s, 3 H), 2.45 (dd, J = 4.9, 8.1 Hz, 1 H), 1.69 (dd, J = 4.9, 9.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 193.3, 168.7, 139.4, 135.3, 134.5, 129.6, 129.0, 128.9, 128.1, 127.3, 52.3, 42.1, 30.8, 20.1; IR 3032 (w), 2951 (w), 1734 (s), 1676 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C18H15ClO3 314.0710, found 314.0703. Methyl 1-(3-Chlorobenzoyl)-2-phenylcyclopropane-1-carboxylate (3r). Prepared following the general procedure using styrene (99% pure, 0.89 g, 8.38 mmol), Rh2esp2 (96% pure, 6.6 mg, 0.0084 mmol), and compound 2r (1.0 g, 4.19 mmol) in CH2Cl2 (42 mL) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.55), compound 3r was afforded as a white solid (1.09 g, 75% yield): mp = 83−87 °C; diastereomeric ratio (15:1); 1H NMR (300 MHz, CDCl3) δ = 7.89 (t, J = 1.9 Hz, 1 H), 7.78 (qd, J = 0.9, 7.7 Hz, 1 H), 7.53 (ddd,

purification (20% EtOAc/hexanes, Rf = 0.40), compound 2q was afforded as a yellow solid (4.39 g, 90% yield). Characterizations were consistent with previously reported literature.36 Methyl 3-(3-Chlorophenyl)-2-diazo-3-oxopropanoate (2r). The general procedure was followed using compound 1r (3.07 g, 14.4 mmol) in acetonitrile (14.4 mL), Et3N (99% pure, 1.56 g, 15.4 mmol), and TsN3 (85% pure, 3.25 g, 16.7 mmol) over 18 h. After workup and purification (20% EtOAc/hexanes, Rf = 0.33), compound 2r was afforded as a yellow solid (3.33 g, 97% yield): mp = 53−54 °C; 1H NMR (300 MHz, CDCl3) δ = 7.61−7.58 (m, 1 H), 7.52−7.46 (m, 2 H), 7.39−7.32 (m, 1 H), 3.79 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 185.4, 161.0, 138.4, 134.0, 132.1, 129.1, 128.3, 126.4, 52.4; IR 2955 (w), 2852 (w), 2133 (s), 1722 (s), 1628 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C10H7ClN2O3 238.0145, found 238.0140. Synthesis of Styrene Derivatives. General Procedure. A general Wittig procedure was followed. Methyltriphenylphosphonium iodide (5.0 g, 12.4 mmol) was added to a clean, dry round-bottom flask under nitrogen charged with a stir bar. Dry THF (100 mL) was added, and the reaction was cooled to 0 °C with stirring. n-BuLi (4.8 mL of 2.5 M solution in hexanes, 12.0 mmol) was added dropwise and allowed to stir for 15 min. Aldehyde (10.7 mmol in 7 mL THF) was added over 1 min. After another 15 min of stirring at 0 °C, the reaction was allowed to warm to room temperature and stir for another 2 h. The reaction was quenched with water, extracted 3 times with EtOAc, dried using Na2SO4, passed through a Celite plug, concentrated under reduced pressure, and columned on silica gel using hexane as the mobile phase. 3-Bromostyrene (9a). Prepared using the general procedure using 3-bromobenzaldehyde (2.0 g, 10.7 mmol) as the aldehyde. After workup and purification, compound 9a was obtained as a colorless oil (1.51 g, 77%). Characterizations were consistent with previously reported literature.37 2-Bromostyrene (9b). Prepared using the general procedure using 2-bromobenzaldehyde (2.0 g, 10.7 mmol) as the aldehyde. After workup and purification, compound 9b was obtained as a colorless oil (1.47 g, 75%). Characterizations were consistent with previously reported literature.37 2-Bromo-5-chlorostyrene (9c). Prepared using the general procedure using 2-bromo-5-chlorobenzaldehyde (2.35 g, 10.7 mmol) as the aldehyde. After workup and purification, compound 9c was obtained as a colorless oil (1.59 g, 68%). Characterizations were consistent with previously reported literature.38 Synthesis of Cyclopropanes 3. General Procedure. A dry flask was charged with a stir bar, Rh2esp2 (0.2 mol %), and half the necessary dry CH2Cl2 for the reaction under nitrogen. The alkene (2.0 equiv) was then added in one portion, and the reaction was cooled to 0 °C. The diazo (1.0 equiv) was dissolved in the other portion of CH2Cl2 necessary to make a 0.1 M solution, cooled to 0 °C, and added to the reaction vessel over 1 min. The reaction stirred at 0 °C for 15 min and then was allowed to warm to room temperature and stir until completion. The reaction was monitored by TLC until complete conversion of the diazo was observed. Upon completion, the reaction was quenched with thiourea (aq), extracted with CH2Cl2 three times, dried using Na2SO4, and filtered through Celite. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. Methyl 2-(3-Bromophenyl)-1-(3,4-dimethoxybenzoyl)cyclopropane-1-carboxylate (3f). Prepared following the general procedure using compound 9a (180 mg, 1.0 mmol), Rh2esp2 (96% pure, 1.4 mg, 0.0018 mmol), and compound 2a (179 mg, 0.68 mmol) in CH2Cl2 (6.8 mL) over 4 h. After workup and purification (20% EtOAc/hexane, Rf = 0.35), compound 3f was afforded as an off-white oil (59.3 mg, 21% yield): diastereomeric ratio 25:1); 1H NMR (300 MHz, CDCl3) δ = 7.56 (dd, J = 2.1, 8.4 Hz, 1 H), 7.49 (d, J = 1.9 Hz, 1 H), 7.48−7.44 (m, 1 H), 7.39−7.33 (m, 1 H), 7.25−7.12 (m, 2 H), 6.88 (d, J = 8.5 Hz, 1 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.45 (t, J = 8.5 Hz, 1 H), 3.32 (s, 3 H), 2.37 (dd, J = 5.0, 8.1 Hz, 1 H), 1.63 (dd, J = 5.1, 9.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 192.1, 168.9, 153.3, 149.1, 137.4, 132.1, 130.3, 129.6, 129.4, 127.6, 123.0, 122.1, 110.5, 110.1, 56.0, 55.9, 52.4, 41.9, 29.4, 19.3; IR 2936 (w), 2839 (w), 10891

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry

(d, J = 1.8 Hz, 0.97 H), 6.98−6.90 (m, 2.16 H), 6.86−6.82 (m, 1.46 H), 5.44 (d, J = 3.1 Hz, 0.41 H), 4.51 (d, J = 9.5 Hz, 1.00 H), 3.91− 3.86 (m, 9.84 H), 3.40 (d, J = 3.1 Hz, 0.38 H), 3.30 (s, 1.16 H), 3.24 (s, 2.80 H), 2.62 (t, J = 8.1 Hz, 1.41 H), 2.15 (dd, J = 5.6, 7.5 Hz, 0.96 H), 1.89 (dd, J = 5.2, 7.6 Hz, 0.56 H), 1.43 (dd, J = 5.5, 8.9 Hz, 1.10 H), 1.13 (dd, J = 5.3, 9.0 Hz, 0.50 H); 13C NMR (126 MHz, CDCl3) δ = 172.5, 171.7, 148.8, 148.7, 148.6, 148.4, 139.3, 138.6, 134.2, 132.3, 132.0, 131.9, 130.0, 129.7, 129.5, 129.4, 127.7, 127.6, 122.0, 121.9, 119.4, 118.0, 110.8, 110.7, 110.2, 109.4, 77.2, 77.1, 72.0, 55.9, 55.9, 55.9, 51.5, 51.5, 38.2, 37.9, 30.4, 26.6, 15.7, 15.2; IR 3510 (br), 2949 (w), 2835 (w), 1721 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C20H21BrO5 420.0572, found 420.0558. Methyl 2-(2-Bromophenyl)-1-((3,4-dimethoxyphenyl)(hydroxy)methyl)cyclopropane-1-carboxylate (4g). The general procedure was followed using compound 3g (287 mg, 0.68 mmol) in THF (6.8 mL) and LiEt3BH (1 M in THF, 0.80 mL, 0.80 mmol) over 18 h. After workup and purification (30% EtOAc/hexane, Rf = 0.15, 0.26), compound 4g was afforded as a white oil (259.3 mg, 90% yield): diastereomeric ratio (1:1); 1H NMR (500 MHz, CDCl3) δ = 7.52 (ddd, J = 1.2, 2.7, 7.9 Hz, 1.95 H), 7.25−7.18 (m, 2.93 H), 7.16 (dt, J = 1.5, 7.0 Hz, 1.34 H), 7.12−7.02 (m, 5.29 H), 6.98 (dd, J = 2.1, 8.2 Hz, 0.97 H), 6.84 (dd, J = 6.1, 8.2 Hz, 2.00 H), 5.59 (d, J = 3.1 Hz, 0.98 H), 5.41 (d, J = 5.2 Hz, 1.00 H), 3.92−3.89 (m, 5.93 H), 3.87 (s, 5.93 H), 3.40 (d, J = 5.2 Hz, 1.03 H), 3.32 (s, 2.87 H), 3.26 (s, 2.82 H), 2.98 (d, J = 3.4 Hz, 0.95 H), 2.83 (t, J = 8.2 Hz, 1.03 H), 2.27 (t, J = 8.2 Hz, 1.01 H), 1.96 (td, J = 5.0, 7.5 Hz, 2.20 H), 1.38 (td, J = 5.3, 9.2 Hz, 2.10 H); 13C NMR (126 MHz, CDCl3) δ = 171.9, 171.7, 148.7, 148.7, 148.6, 148.5, 136.4, 136.2, 133.6, 132.3, 132.2, 132.2, 130.6, 130.5, 128.4, 128.2, 126.9, 126.7, 126.1, 126.0, 119.6, 119.3, 110.7, 110.6, 110.6, 110.4, 77.2, 74.5, 71.4, 55.9, 55.9, 51.6, 51.4, 37.9, 37.8, 31.5, 28.8, 14.2, 14.2; IR 3499 (br), 2951 (w), 2835 (w), 1721 (m) cm−1; HRMS (EI) m/z [M]+ calcd for C20H21BrO5 420.0572, found 420.0571. Methyl 2-(2-Bromo-5-chlorophenyl)-1-((3,4-dimethoxyphenyl)(hydroxy)methyl)cyclopropane-1-carboxylate (4h). The general procedure was followed using compound 3h (218 mg, 0.48 mmol) in THF (4.8 mL) and LiEt3BH (1 M in THF, 0.60 mL, 0.60 mmol) over 18 h. After workup and purification (30% EtOAc/hexane, Rf = 0.18, 0.30), compound 4h was afforded as a white oil (166 mg, 76% yield): diastereomeric ratio (2:1); 1H NMR (500 MHz, CDCl3) δ = 7.45−7.42 (m, 1.47 H), 7.17 (d, J = 2.4 Hz, 0.50 H), 7.14 (d, J = 2.7 Hz, 0.99 H), 7.08−7.04 (m, 3.13 H), 7.03−7.00 (m, 1.09 H), 6.97 (dd, J = 1.8, 8.5 Hz, 0.56 H), 6.86−6.82 (m, 1.56 H), 5.57 (d, J = 3.4 Hz, 0.49 H), 5.43 (d, J = 5.5 Hz, 1.00 H), 3.91−3.89 (m, 4.61 H), 3.87 (s, 4.68 H), 3.39−3.36 (m, 3.85 H), 3.31 (s, 1.41 H), 2.92 (d, J = 3.4 Hz, 0.48 H), 2.79 (t, J = 8.2 Hz, 0.53 H), 2.20 (t, J = 8.2 Hz, 1.01 H), 1.92 (ddd, J = 1.4, 5.4, 7.2 Hz, 1.58 H), 1.45−1.36 (m, 1.62 H); 13C NMR (126 MHz, CDCl3) δ = 171.7, 171.3, 148.7, 148.7, 148.6, 138.5, 138.3, 133.4, 133.2, 133.2, 132.9, 132.8, 132.0, 130.7, 130.6, 128.4, 128.2, 123.9, 123.8, 119.6, 119.3, 110.8, 110.6, 110.6, 110.3, 77.2, 74.2, 71.2, 55.9, 55.9, 51.8, 51.6, 37.9, 37.9, 31.2, 28.6, 14.3, 14.2; IR 3510 (br), 2953 (w), 2835 (w), 1724 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C20H20BrClO5 454.0183, found 454.0168. Methyl 1-((3,4-Dimethoxyphenyl)(hydroxy)methyl)-2-(furan-2yl)cyclopropane-1-carboxylate (4j). The general procedure was followed using compound 3j (656 mg, 1.99 mmol) in THF (20 mL) and LiEt3BH (1 M in THF, 2.40 mL, 2.40 mmol) over 18 h. After workup and purification (30% EtOAc/hexane, Rf = 0.19, 0.26), compound 4j was afforded as a light yellow oil (556.4 mg, 84% yield): diastereomeric ratio (1.3:1); 1H NMR (300 MHz, CDCl3) δ = 7.30− 7.23 (m, 2.21 H), 7.03 (d, J = 1.9 Hz, 1.07 H), 6.98−6.89 (m, 2.96 H), 6.86−6.78 (m, 2.04 H), 6.27 (dd, J = 1.8, 3.2 Hz, 1.91 H), 6.11−6.04 (m, 1.80 H), 5.32−5.27 (m, 0.97 H), 4.56 (d, J = 8.6 Hz, 1.00 H), 3.90−3.84 (m, 11.89 H), 3.75 (d, J = 8.8 Hz, 1.12 H), 3.42 (d, J = 0.6 Hz, 2.23 H), 3.40 (d, J = 0.6 Hz, 3.05 H), 3.22 (d, J = 4.0 Hz, 0.78 H), 2.60−2.52 (m, 0.84 H), 2.51−2.43 (m, 1.02 H), 2.09−2.02 (m, 1.09 H), 1.85 (dd, J = 5.1, 7.3 Hz, 0.81 H), 1.43 (dd, J = 5.4, 9.2 Hz, 0.99 H), 1.28 (dd, J = 5.1, 9.3 Hz, 0.91 H); 13C NMR (75 MHz, CDCl3) δ = 172.0, 171.6, 151.6, 151.1, 148.8, 148.6, 148.5, 148.4, 141.6, 141.4, 133.9, 132.8, 119.2, 118.1, 110.7, 110.3, 110.0, 109.4, 107.3, 107.2,

J = 1.0, 2.1, 8.0 Hz, 1 H), 7.43−7.36 (m, 1 H), 7.33−7.21 (m, 5 H), 3.57 (t, J = 8.6 Hz, 1 H), 3.25 (s, 3 H), 2.47 (dd, J = 4.8, 8.2 Hz, 1 H), 1.71 (dd, J = 4.8, 9.1 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 193.4, 168.5, 138.7, 134.9, 134.5, 132.9, 129.8, 129.0, 128.2, 128.1, 127.3, 126.2, 52.3, 42.2, 31.0, 20.3; IR 3032 (w), 2951 (w), 1734 (s), 1680 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C18H15ClO3 314.0710, found 314.0712. Methyl 2-Phenyl-1-propionylcyclopropane-1-carboxylate (3u). To dimethyl 2-phenylcyclopropane-1,1-dicarboxylate39 (501 mg, 2.13 mmol) in THF (8.1 mL) was added ethylmagnesium bromide (2.6 mL, 2.60 mmol, 1.0 M in THF) at −78 °C. The reaction was stirred for 2.5 h at −78 °C and quenched with satd aq NH4Cl. Water was added, and the mixture was extracted three times with EtOAc. The aqueous layer was acidified to pH 4 using 1 M HCl and extracted once more with EtOAc. The crude mixture was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (Rf = 0.58, 20% EtOAc/hexanes) to give 3u as a colorless oil (272 mg, 55% yield): diastereomeric ratio (6:1); 1H NMR (500 MHz, CDCl3) δ = 7.29− 7.15 (m, 4.35 H), 7.12−7.07 (m, 2.06 H), 3.85−3.75 (m, 3.00 H), 3.34 (s, 0.53 H), 3.24 (t, J = 8.7 Hz, 1.00 H), 3.05−2.95 (m, 0.18 H), 2.70 (qd, J = 7.3, 17.7 Hz, 1.12 H), 2.63−2.46 (m, 0.21 H), 2.31 (dd, J = 5.0, 8.1 Hz, 1.02 H), 2.24−2.18 (m, 0.28 H), 1.83 (qd, J = 7.2, 17.7 Hz, 1.07 H), 1.71−1.65 (m, 1.24 H), 1.59−1.48 (m, 0.19 H), 1.14− 1.07 (m, 0.80 H), 1.01−0.92 (m, 0.06 H), 0.86 (t, J = 7.5 Hz, 0.13 H), 0.62 (t, J = 7.3 Hz, 2.91 H); 13C NMR (126 MHz, CDCl3) δ = 204.9, 203.0, 171.1, 168.7, 134.9, 133.9, 130.2, 128.6, 128.4, 128.3, 128.2, 128.1, 127.4, 127.3, 127.3, 52.5, 51.9, 44.3, 44.1, 36.3, 36.0, 35.0, 34.8, 34.0, 32.4, 21.3, 17.6, 8.2, 8.1, 7.6, 7.5; IR 3026 (w), 2978 (w), 2951 (w), 1703 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C14H16O3 232.1099, found 232.1094. Methyl 1-Isobutyryl-2-phenylcyclopropane-1-carboxylate (3v). To dimethyl 2-phenylcyclopropane-1,1-dicarboxylate39 (498 mg, 2.13 mmol) in THF (8.1 mL) was added isopropylmagnesium bromide (2.6 mL, 2.6 mmol, 1.0 M in THF) at −78 °C. The reaction was stirred for 2.5 h at −78 °C and quenched with satd aq NH4Cl. Water was added, and the mixture was extracted three times with EtOAc. The aqueous layer was acidified to pH 4 using 1 M HCl and extracted once more with EtOAc. The crude mixture was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (Rf = 0.60, 20% EtOAc/hexanes) to give 3v as a colorless oil (370 mg, 71% yield): diastereomeric ratio (>99:1); 1H NMR (500 MHz, CDCl3) δ = 7.27− 7.17 (m, 3 H), 7.15−7.10 (m, 2 H), 3.79 (s, 3 H), 3.35 (t, J = 8.7 Hz, 1 H), 2.79 (spt, J = 6.9 Hz, 1 H), 2.38 (dd, J = 4.9, 8.2 Hz, 1 H), 1.65 (dd, J = 4.9, 9.2 Hz, 1 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.37 (d, J = 7.0 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ = 205.7, 171.2, 134.1, 128.6, 128.1, 127.4, 52.5, 44.3, 39.9, 34.9, 18.7, 18.5, 17.6; IR 2972 (w), 2872 (w), 1724 (s), 1695 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C15H18O3 246.1256, found 246.1253. Synthesis of Cyclopropyl Carbinols 4. Cyclopropyl carbinols 4a−e, 4i, 4k−p, 4s, 4t, 4x, and 4y were synthesized as previously reported.17 General Procedure. The starting cyclopropane (1.0 equiv) was added to a dry flask charged with a stir bar under nitrogen as a 0.1 M solution in THF. LiEt3BH (1 M in THF, 1.2 equiv) was then added in one shot and the reaction stirred at room temperature until completion. The reaction was monitored by TLC until complete conversion of the cyclopropane was observed. Upon completion, the reaction was quenched with NH4Cl (aq), extracted with EtOAc three times, dried using Na2SO4, and filtered through Celite. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. Methyl 2-(3-Bromophenyl)-1-((3,4-dimethoxyphenyl)(hydroxy)methyl)cyclopropane-1-carboxylate (4f). The general procedure was followed using compound 3f (125 mg, 0.30 mmol) in THF (3 mL) and LiEt3BH (1 M in THF, 0.35 mL, 0.35 mmol) over 18 h. After workup and purification (30% EtOAc/hexane, Rf = 0.17, 0.23), compound 4f was afforded as a white oil (93.6 mg, 75% yield): diastereomeric ratio (2.5:1); 1H NMR (500 MHz, CDCl3) δ = 7.42− 7.37 (m, 1.37 H), 7.36−7.30 (m, 1.44 H), 7.22−7.10 (m, 3.04 H), 7.05 10892

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry

Methyl 1-Bromo-2-phenylcyclopropane-1-carboxylate (11w). Prepared over two steps. Compound 10w (1.28 g, 4.64 mmol) was added to a dry flask charged with a stir bar under nitrogen as a 0.5 M solution in dry THF (9.3 mL). The solution was cooled to −78 °C with stirring, and n-BuLi (2.6 mL of 1.95 M solution in hexanes, 5.1 mmol) was added dropwise. After 30 min, CO2 gas was bubbled into the reaction using a cannula from a stoppered flask containing dry ice and a CO2 atmosphere over 3.5 h. The reaction was quenched at −78 °C with water and diluted with Et2O, and the organic phase was washed with NaHCO3. The aqueous layer was then acidified using concentrated HCl and extracted with Et2O three times. The organic layers were then combined, dried using Na2SO4, and filtered through Celite. The combined organic layers were concentrated under reduced pressure, and the resulting orange solid (760 mg) was carried forward to the next step without further purification. A new dry flask was charged with K2CO3 (828 mg, 6.0 mmol) and a stir bar under nitrogen. To it was added the crude product from the first step (730 mg orange solid) as a solution in DMF (30 mL) at room temperature with stirring. To the reaction vessel was added MeI (840 mg, 6.0 mmol) in one shot and the reaction stirred at room temperature for 12 h. The reaction was quenched at room temperature with water (15 mL) and extracted with CH2Cl2 three times. The combined organic layers were dried using MgSO4, filtered through Celite, concentrated under reduced pressure, and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. After purification (20% EtOAc/hexanes, Rf = 0.65), compound 11w was afforded as a yellow oil (545.7 mg, 46% yield over two steps). Characterizations were consistent with previously reported literature.41 Methyl 1-(3-Hydroxypentan-3-yl)-2-phenylcyclopropane-1-carboxylate (4w). Prepared using the procedure developed by Nishii.21 Zinc dust (343 mg, 5.25 mmol) was added to a clean, dry flask charged with a stir bar under nitrogen. THF (2 mL) was added to the flask and TMSCl (126 μmol) was added with stirring to activate the zinc dust. After 30 min, a solution of compound 11w (535 mg, 2.10 mmol) in THF (2.2 mL) was added. The reaction mixture was stirred at room temperature for another 30 min, followed by the addition of pentan-3one (172 mg, 2.0 mmol) as a solution in THF (2.3 mL). The reaction was then refluxed for 18 h with stirring. The reaction was quenched using 1 M HCl (16 mL) and extracted with Et2O three times. The organic layers were then combined, dried using Na2SO4, filtered through Celite, concentrated under reduced pressure, and purified by flash chromatography on silica gel using Et2O/hexanes as the mobile phase. After purification (20% EtOAc/hexanes, Rf = 0.54), compound 4w was afforded as a colorless oil (321 mg, 59%). Characterizations were consistent with previously reported literature.21 Synthesis of α-Alkylidene-γ-butyrolactones 6. General Procedure. To a dry flask charged with a stir bar and approximately 150 mg 4 Å molecular sieves under nitrogen was added Bi(OTf)3 (5 mol % or 10 mol %). The starting α-hydroxymethyl cyclopropane (0.1 M in CH2Cl2, 1.0 equiv) was then added in one shot and the reaction stirred at room temperature until completion. The reaction was monitored by TLC until complete conversion of the α-hydroxymethyl cyclopropane was observed. Upon completion, the reaction was concentrated under reduced pressure and purified by flash chromatography on silica gel using EtOAc/hexanes as the mobile phase. (E)-3-(3,4-Dimethoxybenzylidene)-5-phenyldihydrofuran-2(3H)one (6a). The general procedure was followed using compound 4a (100 mg, 0.29 mmol) in CH2Cl2 (2.9 mL) and 5 mol % Bi(OTf)3 (9.3 mg, 0.0145 mmol) over 1 h. After purification (20% EtOAc/hexanes, Rf = 0.09), compound 6a was afforded as a yellow solid (55.8 mg, 62%): mp = 110−112 °C; E/Z ratio (>99:1); 1H NMR (500 MHz, CDCl3) δ = 7.56 (t, J = 2.7 Hz, 1 H), 7.43−7.31 (m, 5 H), 7.10 (dd, J = 2.0, 8.4 Hz, 1 H), 6.98 (d, J = 1.8 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 5.59 (dd, J = 6.0, 8.4 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.67 (ddd, J = 2.6, 8.5, 17.3 Hz, 1 H), 3.12 (ddd, J = 3.1, 6.0, 17.2 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ = 172.2, 150.7, 149.0, 140.4, 137.0, 128.9, 128.5, 127.6, 125.4, 123.9, 121.4, 112.8, 111.2, 78.1, 56.0, 55.9, 36.5; IR 2935 (w), 2839 (w), 1740 (s) cm−1; HRMS (ESI) m/z [M + H]+ calcd for C19H19O4 311.1278, found 311.1275.

76.3, 72.0, 55.8, 55.8, 51.9, 37.3, 36.9, 23.1, 20.1, 15.6, 15.3; IR 3506 (br), 2951 (w), 2835 (w), 1718 (m) cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C18H20O6Na 355.1152, found 355.1151. Methyl 1-((4-Chlorophenyl)(hydroxy)methyl)-2-phenylcyclopropane-1-carboxylate (4q). The general procedure was followed using compound 3q (397 mg, 1.26 mmol) in THF (12.6 mL) and LiEt3BH (1 M in THF, 1.5 mL, 1.5 mmol) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.30, 0.40), compound 4q was afforded as a very thick off-white oil (335.3 mg, 84% yield): diastereomeric ratio (3:2); 1H NMR (500 MHz, CDCl3) δ = 7.45 (d, J = 8.2 Hz, 2.02 H), 7.41−7.32 (m, 4.74 H), 7.31−7.19 (m, 8.65 H), 5.47 (d, J = 3.4 Hz, 0.68 H), 4.42 (d, J = 10.1 Hz, 1.02 H), 4.19 (d, J = 10.1 Hz, 1.00 H), 3.61 (d, J = 3.4 Hz, 0.67 H), 3.24 (s, 1.98 H), 3.16 (s, 3.01 H), 2.81−2.75 (m, 1.03 H), 2.64 (t, J = 8.4 Hz, 0.69 H), 2.23 (dd, J = 5.5, 7.6 Hz, 1.05 H), 1.96 (dd, J = 5.3, 7.8 Hz, 0.70 H), 1.47 (dd, J = 5.6, 9.0 Hz, 1.05 H), 1.10 (dd, J = 5.2, 9.2 Hz, 0.71 H); 13 C NMR (126 MHz, CDCl3) δ = 172.7, 171.9, 140.7, 138.5, 136.4, 135.8, 133.6, 133.2, 128.9, 128.9, 128.6, 128.4, 128.3, 128.0, 127.9, 127.2, 126.9, 126.6, 77.3, 71.9, 51.4, 51.3, 37.9, 37.4, 31.3, 27.1, 16.0, 15.0; IR 3468 (br), 3028 (w), 2949 (w), 1697 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C18H17ClO3 316.0866, found 316.0865. Methyl 1-((3-Chlorophenyl)(hydroxy)methyl)-2-phenylcyclopropane-1-carboxylate (4r). The general procedure was followed using compound 3r (405 mg, 1.13 mmol) in THF (11 mL) and LiEt3BH (1 M in THF, 1.35 mL, 1.35 mmol) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.35, 0.42), compound 4r was afforded as a very thick white oil (337.5 mg, 86% yield): diastereomeric ratio (2:1); 1H NMR (500 MHz, CDCl3) δ = 7.51− 7.49 (m, 0.94 H), 7.46−7.43 (m, 0.54 H), 7.39−7.35 (m, 1.05 H), 7.31−7.17 (m, 11.44 H), 5.45 (d, J = 3.1 Hz, 0.53 H), 4.39 (d, J = 10.1 Hz, 0.99 H), 4.21 (d, J = 10.4 Hz, 0.97 H), 3.61 (d, J = 3.4 Hz, 0.52 H), 3.23 (s, 1.58 H), 3.14 (s, 2.91 H), 2.77 (dd, J = 7.6, 8.9 Hz, 0.98 H), 2.65 (t, J = 8.4 Hz, 0.53 H), 2.24 (dd, J = 5.6, 7.5 Hz, 1.00 H), 1.96 (dd, J = 5.3, 7.8 Hz, 0.55 H), 1.48 (dd, J = 5.5, 8.9 Hz, 1.02 H), 1.11 (dd, J = 5.3, 9.3 Hz, 0.58 H); 13C NMR (126 MHz, CDCl3) δ = 172.7, 171.8, 144.3, 142.1, 136.3, 135.7, 134.3, 134.2, 129.5, 129.4, 129.0, 128.9, 128.0, 127.9, 127.6, 127.3, 126.9, 126.6, 126.1, 125.4, 123.9, 77.3, 72.0, 51.4, 51.3, 37.8, 37.4, 31.3, 27.1, 16.1, 15.1; IR 3491 (br), 3028 (w), 2951 (w), 1699 (s) cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C18H17ClO3Na 339.0758, found 339.0752. Methyl 1-(1-Hydroxypropyl)-2-phenylcyclopropane-1-carboxylate (4u). The general procedure was followed using compound 3u (201 mg, 0.86 mmol) in THF (7.6 mL) and LiEt3BH (1 M in THF, 1.05 mL, 1.05 mmol) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.23, resolved using vanillin), compound 4u was afforded as a colorless oil (61 mg, 30% yield): diastereomeric ratio (>99:1); 1H NMR (500 MHz, CDCl3) δ = 7.31−7.26 (m, 2 H), 7.25− 7.19 (m, 3 H), 3.74 (s, 3 H), 3.07 (dd, J = 7.8, 8.7 Hz, 1 H), 2.72−2.61 (m, 2 H), 1.74−1.62 (m, 2 H), 1.59 (dd, J = 5.0, 9.0 Hz, 1 H), 1.24− 1.14 (m, 1 H), 0.56 (t, J = 7.5 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ = 174.1, 135.3, 128.9, 128.2, 126.9, 74.9, 51.9, 34.8, 30.1, 27.8, 18.9, 11.0; IR 3393 (br, w), 2961 (w), 2874 (w), 1707 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C14H18O3 234.1256, found 234.1257. Methyl 1-(1-Hydroxy-2-methylpropyl)-2-phenylcyclopropane-1carboxylate (4v). The general procedure was followed using compound 3v (200 mg, 0.81 mmol) in THF (7.2 mL) and LiEt3BH (1 M in THF, 0.97 mL, 0.97 mmol) over 18 h. After workup and purification (20% EtOAc/hexane, Rf = 0.42, resolved using vanillin), compound 4v was afforded as a colorless oil (91 mg, 45% yield): diastereomeric ratio (>99:1); 1H NMR (500 MHz, CDCl3) δ = 7.36− 7.29 (m, 4 H), 7.28−7.24 (m, 1 H), 3.76 (s, 3 H), 2.79 (d, J = 10.1 Hz, 1 H), 2.71 (dd, J = 7.5, 9.0 Hz, 1 H), 2.36 (t, J = 9.6 Hz, 1 H), 2.20− 2.09 (m, 1 H), 1.93 (dd, J = 5.3, 9.0 Hz, 1 H), 1.35 (dd, J = 5.2, 7.3 Hz, 1 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H); 13C NMR (126 MHz, CDCl3) δ = 174.5, 135.6, 129.5, 128.2, 127.2, 77.6, 51.9, 33.8, 33.2, 31.2, 20.2, 20.1, 17; IR 2955 (w), 2872 (w), 1697 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C15H20O3 248.1412, found 248.1401. Synthesis of Substrate 4w. (2,2-Dibromocyclopropyl)benzene (10w). Prepared using the procedure detailed by Hatakeyama; characterizations consistent with previously reported literature.40 10893

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry

white solid (65.6 mg, 72% yield): mp = 175−176 °C; E/Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.61−7.54 (m, 2 H), 7.47− 7.40 (m, 1 H), 7.34 (dt, J = 1.0, 7.5 Hz, 1 H), 7.24−7.15 (m, 1 H), 7.10 (dd, J = 1.9, 8.5 Hz, 1 H), 6.98 (d, J = 1.9 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 5.88 (dd, J = 5.4, 8.6 Hz, 1 H), 3.94−3.80 (m, 7 H), 3.05−2.93 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ = 172.2, 150.7, 149.0, 140.1, 137.6, 132.9, 129.6, 127.9, 127.4, 126.0, 123.8, 120.5, 120.5, 112.8, 111.1, 76.9, 55.9, 55.9, 35.5; IR 2932 (w), 2839 (w), 1749 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H17O4Br 388.0310, found 388.0310. (E)-5-(2-Bromo-5-chlorophenyl)-3-(3,4-dimethoxybenzylidene)dihydrofuran-2(3H)-one (6h). The general procedure was followed using compound 4h (60 mg, 0.132 mmol) in CH2Cl2 (1.3 mL) and 20 mol % of Bi(OTf)3 (17.3 mg, 0.132 mmol) over 24 h. After purification (30% EtOAc/hexanes, Rf = 0.33), compound 6h was afforded as a white solid (43.9 mg, 78% yield): mp = 179−181 °C; E/ Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.59 (t, J = 2.7 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.18 (dd, J = 2.5, 8.5 Hz, 1 H), 7.10 (dd, J = 2.0, 8.4 Hz, 1 H), 6.97 (d, J = 1.9 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 5.81 (dd, J = 5.5, 8.6 Hz, 1 H), 3.94− 3.81 (m, 7 H), 3.02−2.91 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ = 171.9, 150.9, 149.0, 141.9, 138.1, 134.3, 134.0, 129.7, 127.3, 126.3, 123.9, 119.8, 118.2, 112.9, 111.2, 76.3, 56.0, 55.9, 35.2; IR 2934 (w), 2837 (w), 1751 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H16O4BrCl 421.9920, found 421.9919. (E)-3-(3,4-Dimethoxybenzylidene)-5-(naphthalen-2-yl)dihydrofuran-2(3H)-one (6i). The general procedure was followed using compound 4i (100 mg, 0.25 mmol) in CH2Cl2 (2.5 mL) and 10 mol % of Bi(OTf)3 (16.6 mg, 0.025 mmol) over 20 min. After purification (30% EtOAc/hexanes, Rf = 0.24), compound 6i was afforded as a yellow paste (22 mg, 24%): E/Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.93−7.78 (m, 4 H), 7.61 (t, J = 2.7 Hz, 1 H), 7.55−7.46 (m, 2 H), 7.43 (dd, J = 1.6, 8.5 Hz, 1 H), 7.12 (dd, J = 1.8, 8.4 Hz, 1 H), 6.99 (d, J = 1.8 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 5.77 (dd, J = 5.9, 8.3 Hz, 1 H), 3.94−3.85 (m, 6 H), 3.74 (ddd, J = 2.6, 8.5, 17.2 Hz, 1 H), 3.20 (ddd, J = 2.9, 5.9, 17.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 172.3, 150.7, 149.0, 137.6, 137.2, 133.1, 133.0, 129.0, 128.0, 127.7, 127.5, 126.6, 126.5, 124.6, 123.9, 122.8, 121.2, 112.8, 111.1, 78.2, 55.9, 55.9, 36.4; IR 2936 (w), 2839 (w), 1740 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C23H20O4 360.1362, found 360.1353. Compound 5i was also isolated (51%) from this reaction; characterization matches that previously reported.17 (E)-3-(3,4-Dimethoxybenzylidene)-5-methyl-5-phenyldihydrofuran-2(3H)-one (6k). The general procedure was followed using compound 4k (100 mg, 0.28 mmol) in CH2Cl2 (2.8 mL) and 10 mol % of Bi(OTf)3 (18.6 mg, 0.028 mmol) over 15 min. After purification (30% EtOAc/hexanes, Rf = 0.36), compound 6k was afforded as a colorless oil (34.1 mg, 38%): E/Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 8.18 (d, J = 2.1 Hz, 1 H), 7.46−7.18 (m, 6 H), 6.87−6.78 (m, 2 H), 3.95 (s, 3 H), 3.90 (s, 3 H), 3.40−3.20 (m, 2 H), 1.76 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ = 168.4, 150.3, 148.3, 144.9, 140.0, 128.5, 127.5, 127.0, 125.6, 124.1, 122.2, 113.5, 110.1, 83.3, 55.9, 55.8, 46.5, 29.8; IR 2966 (w), 2835 (w), 1736 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C20H20O4 324.1362, found 324.1364. (E)-3-(3,4-Dimethoxybenzylidene)-3,3a,4,8b-tetrahydro-2Hindeno[1,2-b]furan-2-one (6m). The general procedure was followed using compound 4m (100 mg, 0.28 mmol) in CH2Cl2 (2.8 mL) and 10 mol % of Bi(OTf)3 (18.7 mg, 0.028 mmol) over 30 min. After purification (30% EtOAc/hexanes, Rf = 0.19, 0.25), compound 6m was afforded as an orange solid (31.1 mg, 34%): mp = 102−128 °C; E/Z ratio (4:1); 1H NMR (500 MHz, CDCl3) δ = 8.15 (d, J = 2.1 Hz, 0.95 H), 7.57−7.54 (m, 0.27 H), 7.52 (d, J = 7.3 Hz, 1.16 H), 7.37−7.19 (m, 5.35 H), 7.12 (d, J = 1.8 Hz, 0.23 H), 6.97 (d, J = 2.1 Hz, 1.10 H), 6.83 (d, J = 8.5 Hz, 1.05 H), 6.00 (d, J = 7.6 Hz, 0.22 H), 5.93 (d, J = 7.6 Hz, 0.96 H), 4.32−4.26 (m, 0.23 H), 4.03−3.97 (m, 1.13 H), 3.96−3.93 (m, 1.43 H), 3.93−3.89 (m, 6.00 H), 3.72−3.66 (m, 0.35 H), 3.57 (dd, J = 9.2, 16.5 Hz, 1.07 H), 3.15 (dd, J = 3.2, 16.6 Hz, 1.02 H), 3.12−3.07 (m, 0.23 H); 13C NMR (75 MHz, CDCl3) δ = 169.3, 150.5, 148.2, 142.2, 141.4, 139.5, 137.7, 130.1, 129.8, 127.5, 127.0,

(E)-3-(3,4-Dimethoxybenzylidene)-5-(p-tolyl)dihydrofuran-2(3H)one (6b). The general procedure was followed using compound 4b (100 mg, 0.281 mmol) in CH2Cl2 (2.8 mL) and 5 mol % of Bi(OTf)3 (9.2 mg, 0.014 mmol) over 15 min. After purification, compound 6b was afforded as a 3:1 E/Z mixture. The E isomer was isolated (20% EtOAc/hexanes, Rf = 0.13) as a yellow solid (15.7 mg, 17%) and characterized: mp = 110−114 °C; 1H NMR E (300 MHz, CDCl3 δ = 7.57 (t, J = 2.8 Hz, 1 H), 7.32−7.15 (m, 4 H [6b] + 0.75 H [CHCl3]), 7.11 (dd, J = 1.8, 8.4 Hz, 1 H), 6.99 (d, J = 1.9 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 5.57 (dd, J = 5.9, 8.3 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.66 (ddd, J = 2.6, 8.4, 17.3 Hz, 1 H), 3.13 (ddd, J = 2.9, 5.9, 17.3 Hz, 1 H), 2.36 (s, 3 H); 13C NMR E (75 MHz, CDCl3) δ = 172.3, 150.6, 149.0, 138.4, 137.4, 136.8, 129.5, 127.6, 125.5, 123.9, 121.6, 112.7, 111.1, 78.1, 55.9, 55.9, 36.5, 21.1; IR 2932 (w), 2839 (w), 1740 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C20H20O4 324.1362, found 324.1374. The reaction also afforded the Z isomer (20% EtOAc/ hexanes, Rf = 0.07) as an inseparable mixture (6% calculated NMR yield using dimethyl terephthalate (2.4 mg, 0.012 mmol) as an internal standard). Compounds 5b and 5b′ (12:1) were also isolated (53%) from this reaction; characterization matches previously reported.17 (E)-5-(4-Chlorophenyl)-3-(3,4-dimethoxybenzylidene)dihydrofuran-2(3H)-one (6d). The general procedure was followed using compound 4d (100 mg, 0.265 mmol) in CH2Cl2 (2.7 mL) and 10 mol % Bi(OTf)3 (17.6 mg, 0.0265 mmol) over 30 min. After purification (30% EtOAc/hexanes, Rf = 0.24), compound 6d was afforded as a yellow solid (73.9 mg, 81%): mp = 112−132 °C; E/Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.57 (t, J = 2.8 Hz, 1 H), 7.40−7.26 (m, 4 H), 7.10 (dd, J = 2.0, 8.4 Hz, 1 H), 6.97 (d, J = 1.9 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 5.57 (dd, J = 5.9, 8.4 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.68 (ddd, J = 2.6, 8.4, 17.2 Hz, 1 H), 3.13−3.01 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ = 171.9, 150.7, 149.0, 139.4, 137.3, 131.9, 127.3, 127.1, 123.8, 122.4, 120.7, 112.8, 111.1, 77.2, 55.9, 55.9, 36.3; IR 2936 (w), 2839 (w), 1744 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H17O4Cl 344.0815, found 344.0817. (E)-5-(4-Bromophenyl)-3-(3,4-dimethoxybenzylidene)dihydrofuran-2(3H)-one (6e). The general procedure was followed using compound 4e (100 mg, 0.237 mmol) in CH2Cl2 (2.4 mL) and 10 mol % of Bi(OTf)3 (15.6 mg, 0.024 mmol) over 30 min. After purification (30% EtOAc/hexanes, Rf = 0.24), compound 6e was afforded as a yellow solid (79.8 mg, 87%): mp = 102−127 °C; E/Z ratio (100:1); 1H NMR (300 MHz, CDCl3) δ = 7.53 (t, J = 2.7 Hz, 1 H), 7.39−7.23 (m, 4 H), 7.08 (dd, J = 1.8, 8.4 Hz, 1 H), 6.95 (d, J = 1.9 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 5.55 (dd, J = 6.0, 8.4 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.66 (ddd, J = 2.6, 8.4, 17.2 Hz, 1 H), 3.11−2.99 (m, 1 H); 13C NMR (75 MHz, CDCl3 δ = 171.9, 150.7, 148.9, 138.8, 137.2, 134.2, 128.9, 127.3, 126.8, 123.8, 120.7, 112.8, 111.1, 77.2, 55.9, 55.8, 36.2; IR 2936 (w), 2839 (w), 1744 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H17O4Br 388.0310, found 388.0324. (E)-5-(3-Bromophenyl)-3-(3,4-dimethoxybenzylidene)dihydrofuran-2(3H)-one (6f). The general procedure was followed using compound 4f (85 mg, 0.202 mmol) in CH2Cl2 (2.0 mL) and 10 mol % of Bi(OTf)3 (12.0 mg, 0.02 mmol) over 1.25 h. After purification (30% EtOAc/hexanes, Rf = 0.18), compound 6f was afforded as a white oil (69.6 mg, 89% yield): E/Z ratio (>99:1); 1H NMR (300 MHz, CDCl3) δ = 7.59 (t, J = 2.8 Hz, 1 H), 7.54−7.44 (m, 2 H), 7.33−7.26 (m, 2 H), 7.11 (dd, J = 2.1, 8.4 Hz, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 5.57 (dd, J = 5.9, 8.4 Hz, 1 H), 3.93 (s, 3 H), 3.90 (s, 3 H), 3.69 (ddd, J = 2.6, 8.5, 17.3 Hz, 1 H), 3.09 (ddd, J = 2.9, 6.0, 17.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ = 171.9, 150.8, 149.0, 142.7, 137.5, 131.6, 130.5, 128.4, 127.4, 123.9, 123.9, 122.9, 120.5, 112.9, 111.2, 56.0, 55.9, 36.3; IR 2934 (w), 2839 (w), 1746 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H17O4Br 388.0310, found 388.0306. (E)-5-(2-Bromophenyl)-3-(3,4-dimethoxybenzylidene)dihydrofuran-2(3H)-one (6g). The general procedure was followed using compound 4g (99 mg, 0.235 mmol) in CH2Cl2 (2.4 mL) and 10 mol % of Bi(OTf)3 (15.5 mg, 0.023 mmol) over 1 h. After purification (30% EtOAc/hexanes, Rf = 0.38), compound 6g was afforded as a 10894

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

Article

The Journal of Organic Chemistry

(ddd, J = 2.6, 8.4, 19.1 Hz, 1 H), 3.43−3.29 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ = 171.4, 155.8, 152.5, 140.2, 128.8, 128.5, 128.0, 126.5, 125.4, 124.8, 123.5, 123.3, 121.9, 112.5, 111.4, 78.5, 36.6; IR 3028 (w), 2936 (w), 1732 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C19H14O3 290.0943, found 290.0943. 3-(Pentan-3-ylidene)-5-phenyldihydrofuran-2(3H)-one (6w). The general procedure was followed using compound 4w (70 mg, 0.27 mmol) in CH2Cl2 (2.7 mL) and 10 mol % of Bi(OTf)3 (17.5 mg, 0.027 mmol) over 24 h. After purification (15% EtOAc/hexanes, Rf = 0.40), compound 6w was afforded in a complex mixture as a colorless oil (30.6 mg, 27% calculated yield using dimethyl terephthalate (5.9 mg, 0.03 mmol) as an internal standard). A small amount (approximately 3 mg) of pure product was isolated for characterization purposes: 1H NMR (300 MHz, CDCl3) δ = 7.42−7.28 (m, 5 H), 5.44 (dd, J = 7.0, 8.1 Hz, 1 H), 3.32 (dd, J = 8.4, 16.1 Hz, 1 H), 2.86−2.72 (m, 3 H), 2.17 (q, J = 7.5 Hz, 2 H), 1.07 (td, J = 7.6, 10.2 Hz, 6 H); IR 2968 (w), 2874 (w), 1740 (s) cm−1; HRMS (ESI) m/z [M]+ Calcd for C15H18O2 230.1307, found 230.1302. (E)-3-(1-(3,4-Dimethoxyphenyl)ethylidene)-5-phenyldihydrofuran-2(3H)-one (6x). The general procedure was followed using compound 4x (108 mg, 0.303 mmol) in CH2Cl2 (3 mL) and 6 mol % of Bi(OTf)3 (12.1 mg, 0.018 mmol) over 45 min. After purification (20% EtOAc/hexanes, Rf = 0.10), compound 6x was afforded as an offwhite solid (53.1 mg, 54%): mp = 115−118 °C; E/Z ratio (100:1); 1H NMR (300 MHz, CDCl3) δ = 7.45−7.29 (m, 5 H), 6.89−6.85 (m, 2 H), 6.84 (d, J = 0.9 Hz, 1 H), 5.52 (dd, J = 6.8, 8.1 Hz, 1 H), 3.91− 3.85 (m, 6 H), 3.48 (ddd, J = 1.5, 8.2, 16.6 Hz, 1 H), 2.96 (ddd, J = 1.8, 6.8, 16.6 Hz, 1 H), 2.17 (t, J = 1.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ = 168.2, 150.6, 149.1, 148.1, 140.6, 131.9, 128.7, 128.3, 125.3, 120.4, 119.9, 111.4, 110.4, 104.9, 76.3, 55.9, 55.7, 37.7, 25.1; IR 2936 (w), 2835 (w), 1748 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C20H20O4 324.1362, found 324.1369. Compound 5x was also isolated (8%) from this reaction; characterization matches previously reported.17 (E)-3-((3,4-Dimethoxyphenyl)(phenyl)methylene)-5-phenyldihydrofuran-2(3H)-one (6y). The general procedure was followed using compound 4y (100 mg, 0.24 mmol) in CH2Cl2 (2.4 mL) and 10 mol % of Bi(OTf)3 (15.9 mg, 0.024 mmol) over 20 min. After purification (20% EtOAc/hexanes, Rf = 0.17), compound 6y was afforded as a thick yellow oil (37.9 mg, 41%): E:Z ratio (3:1); 1H NMR (300 MHz, CDCl3) δ = 7.44−7.29 (m, 10.84 H), 7.25−7.15 (m, 2.70 H), 6.90− 6.71 (m, 3.70 H), 6.64 (d, J = 1.5 Hz, 0.35 H), 5.52−5.40 (m, 1.30 H), 3.92−3.86 (m, 4.02 H), 3.81 (s, 3.00 H), 3.74 (s, 1.06 H), 3.58−3.47 (m, 0.46 H), 3.41 (dd, J = 7.1, 16.3 Hz, 1.02 H), 3.22−3.06 (m, 1.38 H); 13C NMR (75 MHz, CDCl3) δ = 169.3, 152.5, 152.4, 149.5, 148.4, 148.1, 141.1, 139.9, 139.8, 138.8, 133.4, 130.9, 129.5, 129.3, 128.9, 128.7, 128.7, 128.5, 128.3, 128.2, 127.9, 125.4, 123.0, 122.8, 121.4, 121.1, 113.2, 112.5, 110.4, 110.3, 77.2, 55.9, 55.9, 55.7, 40.4, 40.4; IR 3059 (w), 2936 (w), 2835 (w), 1751 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C25H22O4 386.1518, found 386.1526. Compound 5y was also isolated (36%) from this reaction; characterization matches previously reported.17

126.7, 126.2, 125.8, 125.1, 125.0, 113.7, 110.1, 85.2, 84.4, 56.0, 55.9, 55.8, 44.8, 40.7, 40.2; IR 2935 (w), 2839 (w), 1732 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C20H18O4 322.1205, found 322.1207. 3-(3,4-Dimethoxybenzylidene)-1-oxaspiro[4.4]nonan-2-one (6n). The general procedure was followed using compound 4n (150 mg, 0.47 mmol) in CH2Cl2 (4.7 mL) and 10 mol % of Bi(OTf)3 (31.3 mg, 0.047 mmol) over 10 min. After purification (20% EtOAc/hexanes, Rf = 0.17, 0.25), compound 6n was afforded as a thick yellow oil with elimination product 8n (63.2 mg total, 43% calculated yield of 6n): E/ Z/8n ratio (6:6:1); 1H NMR (300 MHz, CDCl3) δ = 8.14 (d, J = 1.9 Hz, 0.98 H), 7.45 (t, J = 2.7 Hz, 0.83 H), 7.21 (dd, J = 1.9, 8.4 Hz, 1.02 H), 7.07 (dd, J = 1.8, 8.4 Hz, 0.86 H), 6.96 (d, J = 1.8 Hz, 0.88 H), 6.90 (d, J = 8.4 Hz, 0.88 H), 6.85−6.77 (m, 2.51 H), 3.93−3.85 (m, 11.33 H), 3.85−3.83 (m, 1.12 H), 3.64 (s, 0.53 H), 3.16 (d, J = 2.8 Hz, 1.94 H), 3.04 (d, J = 2.2 Hz, 2.00 H), 2.34−2.22 (m, 0.86 H), 2.12− 1.96 (m, 4.20 H), 1.96−1.62 (m, 12.31 H); 13C NMR (75 MHz, CDCl3) δ = 171.7, 168.7, 150.3, 150.1, 148.9, 148.2, 138.8, 135.9, 127.7, 127.1, 125.3, 123.5, 123.5, 123.4, 113.4, 112.7, 111.0, 110.1, 91.7, 91.1, 55.9, 55.8, 55.8, 55.7, 42.6, 39.6, 38.9, 38.1, 23.5; IR 2955 (w), 2839 (w), 1732 (s) cm−1; HRMS (EI) 6n m/z [M]+ calcd for C17H20O4 288.1362, found 288.1361; HRMS (EI) 8n m/z [M]+ calcd for C18H22O4 302.1518, found 302.1515. (E)-3-(4-Methoxybenzylidene)-5-phenyldihydrofuran-2(3H)-one (6o). The general procedure was followed using compound 4o (100 mg, 0.32 mmol) in CH2Cl2 (3.2 mL) and 10 mol % of Bi(OTf)3 (21.2 mg, 0.032 mmol) over 1.5 h. After purification (20% EtOAc/hexanes, Rf = 0.21, 0.35), compound 6o was afforded as a yellow solid (65.5 mg, 73%): mp = 92−94 °C; E/Z ratio (7:1); 1H NMR E (300 MHz, CDCl3) δ = 7.58 (t, J = 2.8 Hz, 1 H), 7.47−7.41 (m, 2 H), 7.40−7.32 (m, 5 H), 6.97−6.91 (m, 2 H), 5.59 (dd, J = 5.9, 8.4 Hz, 1 H), 3.83 (s, 3 H), 3.66 (ddd, J = 2.7, 8.4, 17.3 Hz, 1 H), 3.11 (ddd, J = 2.9, 6.0, 17.3 Hz, 1 H); 13C NMR E (75 MHz, CDCl3) δ = 172.3, 160.9, 140.4, 136.6, 131.8, 128.8, 128.4, 127.2, 125.3, 121.0, 114.3, 77.9, 55.3, 36.4; IR 3036 (w), 2936 (w), 2839 (w), 1744 (s) cm−1; HRMS (EI) m/z [M]+ calcd for C18H16O3 280.1099, found 280.1094; 1H NMR Z (300 MHz, CDCl3) δ = 8.01−7.91 (m, 2 H), 7.44−7.32 (m, 5 H), 6.97− 6.88 (m, 3 H), 5.55 (t, J = 7.4 Hz, 1 H), 3.85 (s, 3 H), 3.49 (ddd, J = 1.9, 7.8, 16.1 Hz, 1 H), 3.09 (ddd, J = 2.5, 7.0, 16.1 Hz, 1 H). (E/Z)-3-Benzylidene-5-phenyldihydrofuran-2(3H)-one (6p). The general procedure was followed using compound 4p (100 mg, 0.35 mmol) in CH2Cl2 (3.5 mL) and 10 mol % of Bi(OTf)3 (23.5 mg, 0.035 mmol) over 10 min. After purification (20% EtOAc/hexanes, Rf = 0.50), compound 6p was afforded as a white solid (52.2 mg, 60%). E/Z ratio: (1:1). Characterizations were consistent with previously reported literature.6d (E/Z)-3-(4-Chlorobenzylidene)-5-phenyldihydrofuran-2(3H)-one (6q). The general procedure was followed using compound 4q (75 mg, 0.24 mmol) in CH2Cl2 (2.4 mL) and 10 mol % of Bi(OTf)3 (15.5 mg, 0.024 mmol) over 3.5 h. After purification (20% EtOAc/hexanes, Rf = 0.29), compound 6q was afforded in a complex mixture as a white solid (33.9 mg, 35% calculated NMR yield using dimethyl terephthalate (4.8 mg, 0.025 mmol) as an internal standard). E/Z ratio (1:1); HRMS (EI) m/z [M]+ calcd for C17H13ClO2 284.0604, found 284.0598. (E/Z)-3-(3,5-Dimethoxybenzylidene)-5-phenyldihydrofuran2(3H)-one (6s). The general procedure was followed using compound 4s (95 mg, 0.28 mmol) in CH2Cl2 (2.8 mL) and 10 mol % of Bi(OTf)3 (18.2 mg, 0.028 mmol) over 1 h. Dimethyl terephthalate (23.2 mg, 0.12 mmol) was added to the crude mixture, and a crude NMR was obtained. Compound 6s was identified, and a 26% yield was calculated from the mixture. E/Z ratio (1:1). HRMS (ESI) m/z [M]+ calcd for C19H18O4 310.1205, found 310.1198. (E)-3-(Benzofuran-2-ylmethylene)-5-phenyldihydrofuran-2(3H)one (6t). The general procedure was followed using compound 4t (100 mg, 0.31 mmol) in CH2Cl2 (3.1 mL) and 10 mol % of Bi(OTf)3 (20.6 mg, 0.031 mmol) over 10 min. After purification (20% EtOAc/ hexanes, Rf = 0.48), compound 6t was afforded as a white solid (43.4 mg, 48%): mp = 144−146 °C; E/Z ratio (100:1); 1H NMR (300 MHz, CDCl3) δ = 7.61 (td, J = 0.6, 7.7 Hz, 1 H), 7.52−7.31 (m, 8 H), 7.31−7.22 (m, 1 H), 7.01 (s, 1 H), 5.66 (dd, J = 6.1, 8.3 Hz, 1 H), 3.94

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01706. Optimization tables for the reaction of cyclopropane 4a, control reactions, 1H and 13C NMR spectra for all new compounds, structure energies, and structure geometries (PDF) X-ray crystallographic data (CIF)

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*E-mail: [email protected]. 10895

DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

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The Journal of Organic Chemistry ORCID

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Stefan France: 0000-0001-5998-6167 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.F. gratefully acknowledges financial support from the National Science Foundation (CAREER Award CHE1056687). M.S. thanks Georgia Tech for a GAANN graduate fellowship. B.D.M. thanks the NSF for a graduate research fellowship (DGE-1148903). Single-crystal diffraction experiments were performed at the Georgia Tech SCXRD facility directed by Dr. John Basca. The authors gratefully acknowledge Dr. Djamaladdin G. Musaev, NSF-MRI-R2 grant (CHE0958205), and the use of the resources of the Cherry Emerson Center for Scientific Computation at Emory University.

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DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897

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DOI: 10.1021/acs.joc.7b01706 J. Org. Chem. 2017, 82, 10883−10897