Access to Symmetrical and Unsymmetrical Cyclobutanes via Template-Directed [2+2]-Photodimerization Reactions of Cinnamic Acids

Abstract

In this work, we have developed a general and broadly applicable template-directed photochemical [2+2]-cycloaddition reaction which provides access to a wide range of symmetrical and unsymmetrical cyclobutane products. The use of 1,8-dihydroxynaphthalene as a covalent template paved the way for successful and highly selective photochemical homodimerization and heterodimerization reactions in the solid state between cinnamic acid derivatives. Notably, the method works equally well with aryl- and heteroaryl-containing substrates leading to the formation of β-truxinic acid analogues as single diastereomers and in high yields (up to 99%).

Key words

cinnamic acids - [2+2] cycloaddition - cyclobutanes - heterodimerization - photochemistry - template-directed synthesis - truxinic acids

Biographical Sketches

Bilge Banu Yagci received her B.Sc. in chemistry from Bilkent University in 2018. Subsequently, she completed her M.Sc. studies under the supervision of Dr. Yunus Türkmen in 2021. Her research is focused on template-directed photochemical [2+2]-cycloaddition reactions of cinnamic acid derivatives for the diastereocontrolled synthesis of cyclobutane products.

Badar Munir studied chemistry at the University of Sargodha (Pakistan) where he obtained his B.Sc. in Chemistry. Currently, he is doing his M.Sc. in Chemistry at Bilkent University (Türkiye) under the supervision of Dr. Yunus Emre Türkmen. His research is mainly focused on photochemical dimerization reactions to access carbocyclic compounds.

Yunus Zorlu was born in İstanbul in 1982. He carried out his Ph.D. on water soluble symmetrical and asymmetrical phthalocyanine-based photosensitizers for photodynamic therapy of cancer. After studying inorganic chemistry, he was then appointed research scientist position in the field of structural chemistry in 2008, then associate professor in 2015 at Gebze Technical University. Since 2020, he has been an inorganic chemistry professor at Gebze Technical University. His primary research interests include the development of functional porous materials (metal-organic frameworks, hydrogen-bonded organic frameworks, and porous organic polymers) and non-covalent interactions (halogen and tetrel bondings).

Yunus Emre Türkmen received his B.Sc. in 2005 at the Chemistry Department of Middle East Technical University (METU) with a minor study in biology. He finished his M.Sc. studies at the same institution under the supervision of Prof. Dr. Cihangir Tanyeli. He then moved to Chicago in 2006 and did his Ph.D. in the group of Prof. Dr. Viresh Rawal at the University of Chicago. Between 2013 and 2015, he worked as a postdoctoral fellow in the group of Prof. Dr. Varinder Aggarwal FRS at University of Bristol, UK. Since 2015, he has been working at the Chemistry Department of Bilkent University as a faculty member. His research interests include the development of new catalytic methods to access carbo- and heterocycles, and template-directed photochemical cycloaddition reactions. He has been a recipient of the BAGEP (Young Scientist Awards Program) award by the Science Academy, Türkiye, in 2019, and the GEBIP (Outstanding Young Scientists) award given by the Turkish Academy of Sciences in 2022.

Since early studies reported in the first half of the 20^th century,[1] regio- and stereoselective photodimerization reactions of cinnamic acids have continued to be of interest to the synthetic community.[2] As a consequence of the natural occurrence of many substituted cinnamic acid derivatives, it is not surprising that cinnamic acid dimers constitute a prevalent motif among cyclobutane-containing natural products. Examples of biologically active members of this class of natural products such as eucommicin A,[3] itoside N,[4] caracasandiamide,[5] and incarvillateine[6] are shown in Figure [1]. The early observation that solution phase irradiation of cinnamic acids gave primarily E to Z isomerization paved the way for the advancement of studies on their solid state photochemical [2+2] cycloadditions.[7] Extensive pioneering work of Schmidt and co-workers on the crystal structure-photochemical reactivity relationship for a large number of trans-cinnamic acid derivatives resulted in the formulation of a number of principles currently known as the Schmidt criteria.[8] Based on these findings, it was concluded that irradiation of the α- and β-crystal polymorphs of cinnamic acids, which have distances of 3.6–4.1 Å between their parallelly oriented olefin centroids, resulted in the selective formation of α-truxillic acids (syn-head-to-tail dimers) and β-truxinic acids (syn-head-to-head dimers), respectively (Scheme [1a] and 1b).[8] [9] However, cinnamic acids having the γ-polymorphic structure in solid state have a distance of >4.7 Å between their olefin centroids, and as a result, they are photo-resistant under UV irradiation conditions (Scheme [1c]).[9]

Figure 1 Examples of bioactive natural products having dimers of cinnamic acid derivatives in their structures

This is undoubtedly a powerful synthetic approach provided that the cinnamic acid derivative of interest has the aforementioned geometrical features in solid state, and thus is in agreement with the Schmidt criteria. Such photochemical cycloaddition reactions proceed generally with very high yields and diastereoselectivities.[7] [10] Moreover, this type of synthetic transformations is favored from a green chemistry perspective as they do not require the use of a solvent during the reaction.[11,12] Despite the advantages mentioned above, this approach does not provide a general solution to the selective photodimerization of any cinnamic acid derivative regardless of its solid-state structure. In this respect, several strategies were developed to achieve the selective photochemical [2+2] cycloadditions of a variety of olefin classes including cinnamic acids. One such strategy is the use of templates in solid state which involve the utilization of metal coordination[13] and salt formation[14] as well as a diverse range of non-covalent interactions such as hydrogen,[15] halogen,[16] and chalcogen bonding.[17] [18] Along these lines, a related second type of strategy is to utilize supramolecular host-guest complex formation[19] and non-covalent templates[20] for selective photochemical [2+2] cycloadditions in solution.[21] A particular advantage of these two approaches is that they operate in single synthetic reaction step as they do not involve the covalent binding of the reactants to the template. However, the first strategy requires the co-crystallization of the reactants with the template, which can be a limiting factor, whereas the second strategy requires a high binding constant between the reactants and the template in solution.

Scheme 1 Photochemical reactivity of different polymorphs of cinnamic acids

In addition to the strategies described above, a third approach is the use of covalent templates which can be used in solid state or in solution. The use of certain diols as templates in the early studies of this field resulted in the formation of diastereomeric mixtures in the investigated photodimerization reactions.[22] In 1996, König and co-workers demonstrated that 1,2-bis(hydroxymethyl)benzene was an effective diol-based covalent template for the photochemical homodimerization of trans-cinnamic acid in solution.[23] In the seminal studies of Hopf and co-workers, [2.2]paracyclophane core was shown to be an effective, rigid scaffold satisfying the distance criterion for a successful [2+2]-cycloaddition reaction as described by Schmidt.[8] [24] [25] In 2010, Wolf and co-workers developed bisaniline 1 as a covalent template for the homodimerization of two cinnamic acid derivatives to afford symmetrical β-truxinic acids in high yield (Scheme [2a]).[26]

Within the past decade, visible light photocatalysis has emerged as a highly efficient method for [2+2]-cycloaddition reactions.[27] In 2017, Reiser and co-workers reported anti-head-to-head photodimerization of cinnamate esters giving δ-truxinates catalyzed by an Ir-based photocatalyst (Scheme [2b]).[28] However, when heterodimerization reactions were tested in this study via reactions of two different cinnamates, no appreciable selectivity was observed for heterodimerization over homodimerization. Furthermore, the [2+2]-cycloaddition reactions of cinnamic acids, cinnamates, and chalcones were investigated using a variety of other visible light photocatalytic systems.[29] Despite this rich history, the photochemical dimerization reactions of cinnamic acid derivatives were mainly restricted to homodimerization,[30] and a general method for the selective heterodimerization of this compound class had yet to be discovered.[31]

Scheme 2 Selected examples of photochemical [2+2] cycloadditions of cinnamic acid derivatives

Table 1 Synthesis of the Symmetrical Diesters 6a–g

Entry	Ar	Product	Yield (%)
1	Ph	6a a	95
2		6b a	87
3		6c	74
4		6d	81
5		6e	73
6		6f	81
7		6g	72

^a The syntheses of these cycloadducts were reported previously.[32]

In 2021, we reported the use of 1,8-dihydroxynaphthalene (1,8-DHN, 5) as a highly effective covalent template for the selective photochemical homodimerization and heterodimerization reactions of cinnamic acids (Scheme [2c]).[32] It should be noted that, to the best of our knowledge, this method represents the first general solution for the selective heterodimerization reactions of this compound class. During our previous work on the hydrogen bonding properties of 1,8-DHN (5),[33] and its use in the synthesis of the fungal natural product daldiquinone,[34] we realized the potential of compound 5 to be utilized as an ideal covalent template for the photochemical [2+2]-cycloaddition reactions of cinnamic acids. Indeed, in addition to providing the right distance between the two reacting olefins (ca. 3.6 Å)[32] so as to ensure that Schmidt’s distance criterion (<4.2 Å) is satisfied, template 5 also enables the attachment of two different cinnamic acids selectively and sequentially (Scheme [2c]). We should note that, Beeler and co-workers recently described the use of catechol as a covalent tether in the photochemical heterodimerization reactions of cinnamic acids in solution, and showed the application of this method to the syntheses of the natural products piperarborenines C–E.[35] Herein, we report a full account of our studies on the selective and controlled homodimerization and heterodimerization reactions of cinnamic acids via the use of 1,8-DHN (5) as a covalent template, and extension of its scope to the selective photodimerization of heteroaromatic substrates (Scheme [2c]).

Our studies commenced with the investigation of the homodimerization reactions of cinnamic acid derivatives. The synthesis of the symmetrical diesters 6a–g to be tested in the photochemical [2+2] cycloaddition was achieved via a DCC-mediated ester formation between 1,8-DHN (5) and the corresponding cinnamic acids 7 (Table [1]). We have previously shown that phenyl- and 4-methoxyphenyl-substituted diesters 6a and 6b could be prepared in high yields (95% and 87%, respectively) using this method (entries 1 and 2).[32] In the present work, diester 6c bearing the strongly electron-donating dioxolane moiety was synthesized in 74% yield (entry 3). In order to check the effect of an electron-withdrawing group on the aryl ring and assess the stability of an aryl halide group under photochemical reaction conditions, 4-chlorophenyl-substituted diester 6d was prepared in 81% yield (entry 4). Next, we turned our attention to the synthesis of diesters with heteroaromatic rings at the β-position of the acrylate moieties. To this end, diesters 6e–g possessing thiophene, furan and N-methylpyrrole rings were synthesized successfully in 73%, 81%, and 72% yields, respectively (entries 5–7).

With the successful preparation of symmetrical diesters 6a–g in hand, we next turned our attention to the construction of unsymmetrical diesters as photochemical cycloaddition precursors (Table [2]). Monoesters 8a and 8b were synthesized via deprotonation of 1,8-DHN (5) with NaH followed by treatment with one equivalent of the corresponding cinnamoyl chloride.[32] For the conversion of monoesters 8a and 8b to unsymmetrical diesters 6h–p two methods were employed. Method A involves reacting monoesters 8a or 8b with the second cinnamic acid partner under DCC coupling conditions. Following this method, diesters 6h, 6i, 6m, and 6o were synthesized in 66–90% yields (entries 1, 2, 6, and 8).[32]

Table 2 Synthesis of the Unsymmetrical Diesters 6h–p

Entry	Ar1	Ar2	Method, product, yield (%)
1	Ph		A, 6h a, 66
2	Ph		A, 6i a, 76
3	Ph		B, 6j, 86
4	Ph		B, 6k, 74
5	Ph		B, 6l, 72
6	Ph		A, 6m a, 90
7	Ph		B, 6n, 75
8			A, 6o a, 66
9			B, 6p, 77

^a The syntheses of these cycloadducts were reported previously.[32]

However, for some substrates method B, which involves the reaction of the monoester with an acyl chloride under basic conditions, was found to work better. During these experiments, we realized that deprotonation of monoester 8a with one equivalent of NaH followed by treatment with one equivalent of acyl chloride of a different cinnamic acid led to the formation of a mixture of the targeted unsymmetrical diester and the symmetrical diester 6a. In control experiments, when monoester 8a was treated with DBU (0.1 equiv) or NaH (1.0 equiv) in the absence of additional cinnamoyl chloride, monoester 8a was observed to undergo a non-redox disproportionation to form diester 6a and 1,8-DHN (5) (Scheme [3]). Pleasingly, we found that this pathway could be prevented by a simple change in the addition order of reagents. In this way, when one equivalent of NaH was added to a 1:1 mixture of monoester 8a and (E)-3-(4-nitrophenyl)acryloyl chloride in THF, unsymmetrical diester 6j was obtained in 86% yield without the formation of any symmetrical diester 6a (Table [2], entry 3). This new protocol was successfully applied to the synthesis of other unsymmetrical diesters (6k, 6l, 6n, and 6p) shown in Table [2], which were isolated in high yields (72–77%).

Scheme 3 Non-redox disproportionation of monoester 8a

The photochemical reactivity of the diesters 6 was examined using two different irradiation conditions (Table [3]). In method C, solid samples were irradiated for 8 h using a 400-W medium pressure mercury lamp, and samples were mixed thoroughly every two hours. Alternatively, in method D, a commercial nail dryer with four 9-W UV-A fluorescent lamps was used to irradiate diesters 6 in solid state for 16 h by mixing the samples every 4 h.[36] In general, both methods work comparably well with the majority of the tested cycloaddition precursors, albeit longer reaction times are required with method D. Please note that the substrates, which were investigated after our initial report,[32] were all tested with both irradiation methods. In this respect, the symmetrical template-bound β-truxinic acid esters 9a–d bearing electron-donating and -withdrawing substituents were isolated in high yields (78–96%) and as single diastereomers (Table [3], entries 1–4). Diesters 6e–g with heteroaromatic thiophene, furan, and N-methylpyrrole rings were also found to be excellent substrates under both irradiation conditions, and cycloadducts 9e–g were obtained in 80–98% yields (entries 5–7).

Table 3Photochemical [2+2] Cycloadditions of Diesters 6

Entry	Product	Ar1	Ar2	Yield (%)
				Method C	Method D
1	9a a	Ph	Ph	95	92
2	9b			78	–
3	9c			93	96
4	9d			89	90
5	9e			96	98
6	9f			86	98
7	9g			95	80
8	9h a	Ph		99	–
9	9i a	Ph		88	–
10	9j	Ph		77	61
11	9k	Ph		88	86
12	9l	Ph		44	49
13	9m a	Ph		88	–
14	9n	Ph		86	96
15	9o a			93	–
16	9p			57	84

^a The syntheses of these cycloadducts were reported previously.[32]

Previously, we had shown that unsymmetrical β-truxinates 9h and 9i, which have electron-rich 4-methoxyphenyl and electron-deficient 4-(trifluoromethyl)phenyl groups, could be obtained in 99% and 88% yields, respectively, using method C.[32] In the current work, we systematically examined the effect of the position of the NO₂ group on the photochemical [2+2] cycloaddition. Whereas diesters 6j and 6k with NO₂ groups at the para and meta positions were successful substrates providing cycloadducts 9j and 9k in 77% and 88% yields, respectively (entries 10 and 11), β-truxinate 9l with the NO₂ group at the ortho position was isolated in a lower yield (44% with method C, and 49% with method D; entry 12). We were pleased to confirm the structure and relative stereochemistry of cycloadduct 9j by single-crystal X-ray analysis (Figure [2], CCDC 2265841). Mixed aryl-heteroaryl-substituted diesters 6m and 6n were also competent substrates affording the unsymmetrical cyclobutane diester products 9m and 9n in 88% and 96% yields, respectively (entries 13 and 14). The effect of having one electron-rich and one electron-deficient aryl ring on the substrate was tested with diester 6o which gave cycloadduct 9o in 93% yield (entry 15).[32] Finally, the presence of having two electron-rich aromatic groups was checked with diester 6p having furyl and 4-methoxyphenyl groups. For this substrate, method D was found to be superior affording unsymmetrical cycloadduct 9p in 84% yield, while method C resulted in a moderate yield of 57% (entry 16). Cycloadducts 9a–p were observed to form as single diastereomers in all of the experiments shown in Table [3]. Finally, we checked the reversibility of the photochemical [2+2] cycloaddition under the irradiation conditions. To this end, we subjected a sample of pure cycloadduct 9a to irradiation using the Hg lamp (method C) for 4 h. At the end of this control experiment, cycloadduct 9a was found to be intact with no formation of diester 6a, which indicates that the photocycloaddition reaction is irreversible under these conditions.

Figure 2 X-ray crystal structure of cycloadduct 9j

In order to check the possibility of a single crystal-to-single crystal transformation[37] during the photochemical [2+2] reaction, crystals of 6d were irradiated with UVA light using the nail dryer. While cycloadduct 9d was found to form with full conversion upon irradiation for 16 h as determined by NMR spectroscopy, the crystals were observed to crumble during the irradiation process resulting in the formation of product 9d in powder form (Figure S1). Regarding the interaction of diesters 6 with UV light, we have previously shown that the λ_max values of diester 6a and 6o in their UV-vis spectra in CH₂Cl₂ are 279 and 283 nm (with a shoulder at 320 nm), respectively.[32] In order to acquire more relevant data related to their solid state photochemical reactivities, we recorded their diffuse reflectance UV-vis spectra in solid powder form, which exhibited absorption below 389 nm for 6a and 411 nm for 6o (Figure S2). This provides an explanation for the success of both irradiation sources (methods C and D) in the photochemical [2+2]-cycloaddition reactions of diesters 6 (Table [3]).

Scheme 4 Synthesis of β-truxinic acid products 10 via hydrolysis of cycloadducts 9 under basic conditions. ^a The syntheses of these β-truxinic acid products were reported previously.[32] ^b Product 11 was obtained by the reaction of 9g with NaOMe in MeOH at 23 °C.

The synthesis of the β-truxinic acid products was achieved via a saponification-type basic hydrolysis of the template-bound cycloadducts 9. In this respect, treatment of diesters 9 with KOH in a mixture of THF and H₂O at 23 °C followed by acidic workup afforded cyclobutanedicarboxylic acids 10 in high yields and as single diastereomers (Scheme [4]). The unsubstituted β-truxinic acid (10a) was isolated in quantitative yield along with complete recovery of the template (1,8-DHN, 5).[32] The method works successfully on diesters with electron-donating and withdrawing substituents affording β-truxinic acid analogues 10b–d in 84–95% yields (Scheme [4]). Thienyl- and furyl-substituted symmetrical cyclobutanedicarboxylic acids 10e and 10f were obtained in 90% and 71% yields, respectively. Unexpectedly, we faced problems during the isolation of N-methylpyrrole-substituted dicarboxylic acid. In order to circumvent this problem, cycloadduct 9g was subjected to a transesterification reaction with the use of NaOMe in MeOH leading to the formation of cyclobutane diester 11 in 65% yield. Not surprisingly, the basic hydrolysis method works equally well with the heterodimerization products giving unsymmetrical β-truxinic acid products 10h–p in 79–96% yields (Scheme [4]). Of particular note is the little variation of reaction yield depending on the position of the NO₂ group in substrates 9j–l. In these reactions, β-truxinic acid products 10j, 10k, and 10l were obtained in 91%, 91%, and 85% yields, respectively. Finally, mixed aryl-heteroaryl-substituted cycloadducts were also competent substrates, and hydrolysis products 10m, 10n, and 10p were isolated in 84–96% yields (Scheme [4]).

Scheme 5 Conversion of cycloadduct 9n to 12 and 13

Next, we wanted to show the synthetic utility of the photocycloaddition reaction developed in this work via other transformations (Scheme [5]). First, cycloadduct 9n was reacted with NaOMe in methanol giving dimethyl diester product 12 in 93% yield. In a second experiment, reduction of the two ester groups of 9n with LiAlH₄ afforded cyclobutanedimethanol 13 in 86% yield. In these reactions, both products were obtained as single diastereomers. Finally, we opted to check the [2+2] cycloaddition of diester 6a under visible light photocatalytic conditions.[29a] For this purpose, diester 6a was irradiated with blue LEDs (450 nm) in 1,4-dioxane in the presence of Ir(ppy)₃ photocatalyst, and the reaction was observed to be complete within one hour (Scheme [6]). Whereas this reaction also gave β-truxinate 9a as the major cycloadduct, the product was found to consist of a mixture of three diastereomers (dr = 1:0.32:0.16). The same reaction was further tested in the absence of a photocatalyst but via irradiation using the medium-pressure mercury lamp in solution phase. In this experiment, when a solution of 6a in acetone was irradiated, the reaction was complete in 2 h and afforded again a diastereomeric mixture (dr = 1:0.66:0.13) with cycloadduct 9a being the major diastereomer. These results underscore the advantage of our solid-state photochemical cycloaddition protocol for achieving high levels of diastereoselectivity when 1,8-DHN (5) is used as a template.

Scheme 6 Photocatalytic cycloaddition of diester 6a

In summary, we have developed a robust and selective method for the controlled photochemical homodimerization and heterodimerization reactions of cinnamic acids leading to the formation of symmetrical and unsymmetrical cyclobutanes. The method involves the use of 1,8-dihydroxynaphthalene (5) as a covalent template, that enables the positioning of the two reacting olefins within a distance of <4 Å which is in agreement with Schmidt’s distance criterion for a successful photochemical [2+2] cycloaddition in solid state. The photodimerization reactions work uniformly well with aryl- and heteroaryl-containing cinnamic acid derivatives affording cycloadducts in up to 99% yield and as single diastereomers. Cycloadducts were shown to be hydrolyzed easily under basic conditions at room temperature to yield symmetrical and unsymmetrical β-truxinic acids in excellent yields (71% to quant.). Research to render these photochemical [2+2] cycloadditions enantioselective is currently underway in our laboratory.

All air-sensitive solution phase reactions were run using oven-dried glassware under N₂. Reactions were monitored by TLC using aluminum-backed plates pre-coated with silica gel (Silicycle, indicator: F-254; thickness: 200 μm). UV light and/or KMnO₄ staining solution were used for the visualization of TLC plates. Flash column chromatographic separations were performed on Silicycle 40–63 μm (230–400 mesh) flash silica gel. ¹H NMR (400 MHz) and ¹³C{¹H} NMR (100 MHz) spectra were recorded using a Bruker Avance 400 spectrometer in CDCl₃ and DMSO-d ₆. Internal standard signal (TMS, δ = 0) or residual solvent signals (CDCl₃ δ = 7.26, and DMSO-d ₆ δ = 2.50 for ¹H NMR; CDCl₃­ δ = 77.16 and DMSO-d ₆ δ = 39.52 for ¹³C{¹H}-NMR spectra) were used for the calibration of ¹H and ¹³C{¹H} NMR spectra. Infrared (FTIR) spectra were recorded on a Bruker Alpha-Platinum-ATR spectrometer with only selected peaks reported. HRMS were performed using Agilent Technologies 6224 TOF LC/MS at UNAM-National Nanotechnology Research Center and Institute of Materials Science and Nanotechnology, Bilkent University. Single crystal X-ray diffraction analysis was performed at Gebze Technical University, Turkey. Photochemical experiments for method C were carried out using a reactor obtained from Photochemical Reactors Ltd., which consists of a 400-W medium-pressure mercury lamp (3040/PX0686) and a quartz double-walled immersion well with water cooling. Regular microscope slides made of soda-lime glass were used for the photochemical experiments in solid state. The slides were kept at ca. 4 cm away from the lamp during the experiments. Photochemical experiments for method D were carried out using a commercial UV gel nail dryer (Elle by Beurer, MPE58) fitted with four 9-W UVA (Philips PL-S, 365 nm) fluorescent lamps. Quartz microscope slides were used in method D, and were kept at ca. 4.5 cm away from the lamps during the experiments. All photochemical reactions in method C were performed inside a fully closed safety cabinet.[38] 1,8-Dihydroxynaphthalene (1,8-DHN, 5) was purchased from abcr Co. and used as received. Anhyd CH₂Cl₂ and THF were purchased from Acros Organics (AcroSeal®). All other commercially available reagents were used as received unless stated otherwise.

Synthesis of Symmetrical Diesters 6a–g; General Procedure I (Method A)

To a solution of 1,8-DHN (5; 1.0 equiv) in anhyd CH₂Cl₂ (10 mL) in a 100-mL round-bottomed flask were added sequentially trans-cinnamic acid derivative (2.0 equiv), DCC (2.0 equiv), and DMAP (20 mol%) at 23 °C under N₂. The resulting cloudy, heterogeneous mixture was stirred at 23 °C for 24 h. TLC analysis indicated full consumption of 1,8-DHN (5). The mixture was quenched with H₂O (10 mL), and the aqueous phase was extracted with CH₂Cl₂ (3 ×) The combined organic phases were dried (anhyd Na₂SO₄), filtered, and concentrated under vacuum. The crude reaction mixture was purified by flash column chromatography.

Naphthalene-1,8-diyl (2E,2′E)-Bis(3-(benzo[d][1,3]dioxol-5-yl)acrylate) (6c)

Diester 6c was synthesized using 1,8-DHN (5; 100 mg, 0.62 mmol), (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylic acid (240 mg, 1.25 mmol), DCC (258 mg, 1.25 mmol), DMAP (15.3 mg, 0.125 mmol), and anhyd CH₂Cl₂ (10 mL) following General Procedure I. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford pure 6c (234 mg, 74% yield) as a white solid; mp 253–254 °C; R_f = 0.56 (CH₂Cl₂).

IR (ATR, film): 2921, 1728, 1703, 1631, 1603, 1501, 1452, 1369 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 7.97 (d, J = 8.3 Hz, 2 H), 7.65 (d, J = 15.9 Hz, 2 H), 7.59 (t, J = 7.9 Hz, 2 H), 7.29 (d, J = 7.5 Hz, 2 H), 7.02–7.00 (m, 4 H), 6.74 (d, J = 7.8 Hz, 2 H), 6.56 (d, J = 15.9 Hz, 2 H), 6.02 (s, 4 H).

¹³C{¹H} NMR (DMSO-d ₆, 100 MHz): δ = 165.5, 149.5, 147.7, 146.4, 144.9, 136.2, 128.0, 126.6, 126.4, 125.5, 121.1, 120.9, 114.8, 108.0, 106.4, 101.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₂₀NaO₈: 531.1050; found: 531.1050.

Naphthalene-1,8-diyl (2E,2′E)-Bis(3-(4-chlorophenyl)acrylate) (6d)

Diester 6d was synthesized using 1,8-DHN (5; 100 mg, 0.62 mmol), (E)-3-(4-chlorophenyl)acrylic acid (228 mg, 1.25 mmol), DCC (258 mg, 1.25 mmol), DMAP (15.3 mg, 0.125 mmol), and anhyd CH₂Cl₂ (10 mL) following General Procedure I. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 6d (245 mg, 81% yield) as a white solid; mp 247–248 °C; R_f = 0.74 (CH₂Cl₂).

IR (ATR, film): 3082, 1729, 1658, 1640, 1512 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.84 (d, J = 8.3 Hz, 2 H), 7.76 (d, J = 16.1 Hz, 2 H), 7.51 (t, J = 7.9 Hz, 2 H), 7.21–7.18 (m, 6 H), 7.12 (d, J = 8.3 Hz, 4 H), 6.54 (d, J = 16.1 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.9, 146.8, 145.4, 141.9, 136.9, 135.7, 129.3, 128.8, 127.4, 126.9, 126.1, 126.0, 120.713.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₈ ³⁵Cl₂NaO₄: 511.0474; found: 511.0469; calcd for C₂₈H₁₈ ³⁵Cl³⁷ClNaO₄: 513.0445; found: 513.0438.

Naphthalene-1,8-diyl (2E,2′E)-Bis(3-(thiophen-2-yl)acrylate) (6e)

Diester 6e was synthesized using 1,8-DHN (5; 50 mg, 0.31 mmol), (E)-3-(thiophen-2-yl)acrylic acid (96 mg, 0.62 mmol), DCC (129 mg, 0.62 mmol), DMAP (7.7 mg, 0.062 mmol), and anhyd CH₂Cl₂ (5 mL) following General Procedure I. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 6e (98 mg, 73% yield) as an orange solid; mp 208–209 °C; R_f = 0.17 (CH₂Cl₂/ hexanes 1:1).

IR (ATR, film): 3060, 1726, 1623, 1603, 1422, 1363 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.95 (d, J = 15.7 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 2 H), 7.50 (t, J = 7.9 Hz, 2 H), 7.23 (d, J = 5.0 Hz, 2 H), 7.20 (d, J = 7.5 Hz, 2 H), 7.11 (d, J = 3.5 Hz, 2 H), 6.90 (app t, J = 4.6 Hz, 2 H), 6.42 (d, J = 15.7 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.9, 145.3, 139.44, 139.38, 136.9, 131.5, 129.3, 128.0, 127.0, 126.2, 121.6, 120.7, 116.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₁₇O₄S₂: 433.0563; found: 433.0562.

Naphthalene-1,8-diyl (2E,2′E)-Bis(3-(furan-2-yl)acrylate) (6f)

Diester 6f was synthesized using 1,8-DHN (5; 100 mg, 0.62 mmol), (E)-3-(furan-2-yl)acrylic acid (173 mg, 1.25 mmol), DCC (258 mg, 1.25 mmol), DMAP (15.3 mg, 0.125 mmol), and anhyd CH₂Cl₂ (10 mL) following General Procedure I. The crude product was purified by flash column chromatography (SiO₂, 1% MeOH in CH₂Cl₂/hexanes 1:1) to afford pure 6f (200 mg, 81% yield) as a brown solid; mp 179–180 °C; R_f = 0.23 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3144, 3053, 1722, 1633, 1603, 1549, 1471, 1370 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.81 (d, J = 8.3 Hz, 2 H), 7.58 (d, J = 15.7 Hz, 2 H), 7.49 (t, J = 7.9 Hz, 2 H), 7.27 (s, 2 H), 7.20 (d, J = 7.5 Hz, 2 H), 6.53–6.49 (m, 4 H), 6.36 (app s, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 166.0, 150.8, 145.34, 145.29, 136.9, 132.9, 126.9, 126.1, 121.5, 120.7, 115.5, 115.2, 112.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₁₇O₆: 401.1020; found: 401.1023.

Naphthalene-1,8-diyl (2E,2′E)-Bis(3-(1-methyl-1H-pyrrol-2-yl)acrylate) (6g)

Diester 6g was synthesized using 1,8-DHN (5; 85 mg, 0.53 mmol), (E)-3-(1-methyl-1H-pyrrol-2-yl)acrylic acid (200 mg, 1.32 mmol), DCC (252 mg, 1.22 mmol), DMAP (16 mg, 0.13 mmol), and anhyd CH₂Cl₂ (10 mL) following General Procedure I. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 6f (163 mg, 72% yield) as a red solid; mp 176–177 °C; R_f = 0.26 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2944, 1765, 1608, 1577, 1492 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.80 (dd, J = 8.3, 0.8 Hz, 2 H), 7.75 (d, J = 15.7 Hz, 2 H), 7.49 (t, J = 7.9 Hz, 2 H), 7.19 (dd, J = 7.5, 0.9 Hz, 2 H), 6.67 (t, J = 2.0 Hz, 2 H), 6.48 (dd, J = 3.9, 1.5 Hz, 2 H), 6.33 (d, J = 15.7 Hz, 2 H), 6.08 (dd, J = 3.8, 2.6 Hz, 2 H), 3.56 (s, 6 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 167.0, 145.7, 136.9, 134.4, 129.1, 128.0, 126.8, 126.1, 121.9, 120.7, 113.8, 111.4, 109.8, 34.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₂N₂NaO₄: 449.1472; found: 449.1471.

Synthesis of Unsymmetrical Diesters 6j–l, 6n, and 6p; General Procedure II (Method B)

In a 50-mL round-bottomed flask, monoester 8a or 8b (1 equiv) was dissolved in anhyd THF (10 mL) under N₂, and the resulting solution was cooled to 0 °C in an ice bath. Cinnamoyl chloride derivative (1.0 equiv) was added, and the mixture was stirred for 5 min. Then, NaH (1.1 equiv, 60% in mineral oil) was added carefully. The ice bath was removed, and the mixture was stirred at 23 °C for 1.5 h. It was then quenched with sat. aq NH₄Cl soln (10 mL), and the aqueous phase was extracted with CH₂Cl₂ (3 ×). The combined organic phases were dried (anhyd Na₂SO₄), filtered, and concentrated under vacuum. The crude reaction mixture was purified by flash column chromatography.

8-(Cinnamoyloxy)naphthalen-1-yl (E)-3-(4-Nitrophenyl)acrylate (6j)

Diester 6j was prepared using monoester 8a (90 mg, 0.31 mmol), NaH (13.7 mg, 0.34 mmol, 60% in mineral oil), (E)-3-(4-nitrophenyl)acryloyl chloride (66 mg, 0.31 mmol), and anhyd THF (15 mL) following General Procedure II. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 2:1) to afford pure 6j (125 mg, 86% yield) as a white solid; mp 222–223 °C; R_f = 0.33 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3058, 2930, 1731, 1634, 1600, 1512, 1344 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.89–7.81 (m, 6 H), 7.55–7.50 (m, 2 H), 7.35 (d, J = 8.7 Hz, 2 H), 7.30–7.28 (m, 3 H), 7.22 (d, J = 7.5 Hz, 2 H), 7.15 (t, J = 7.6 Hz, 2 H), 6.71 (d, J = 16.1 Hz, 1 H), 6.59 (d, J = 16.1 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.8, 165.0, 148.6, 147.0, 145.2, 145.0, 143.8, 139.8, 137.0, 133.8, 131.0, 129.0, 128.6, 128.2, 127.3, 127.2, 126.4, 126.2, 124.0, 121.8, 121.3, 120.9, 120.7, 117.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₉NNaO₆: 488.1105; found: 488.1101.

8-(Cinnamoyloxy)naphthalen-1-yl (E)-3-(3-Nitrophenyl)acrylate (6k)

Diester 6k was prepared using monoester 8a (72 mg, 0.25 mmol), NaH (11 mg, 0.27 mmol, 60% in mineral oil), (E)-3-(3-nitrophenyl)acryloyl chloride (55 mg, 0.26 mmol), and anhyd THF (12 mL) following General Procedure II. The crude product was purified by flash column chromatography (SiO₂, 3% MeOH in CH₂Cl₂/hexanes 1:1) to afford pure 6k (85 mg, 74% yield) as a white solid; mp 228–229 °C; R_f = 0.35 (3% MeOH in CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3085, 3055, 1746, 1723, 1629, 1601, 1575, 1523, 1375, 1346, 1305 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 8.04–8.03 (m, 2 H), 7.85–7.84 (m, 4 H), 7.57–7.50 (m, 3 H), 7.31–7.26 (m, 3 H), 7.22–7.17 (m, 3 H), 7.07 (t, J = 7.5 Hz, 2 H), 6.72 (d, J = 16.0 Hz, 1 H), 6.60 (d, J = 16.0 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.7, 165.1, 148.5, 146.9, 145.2, 145.1, 143.8, 137.0, 135.5, 133.7, 133.5, 130.8, 129.8, 128.9, 128.1, 127.3, 127.1, 126.4, 126.2, 124.8, 122.5, 121.4, 120.9, 120.7, 117.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₉NNaO₆: 488.1105; found: 488.1095.

8-(Cinnamoyloxy)naphthalen-1-yl (E)-3-(2-Nitrophenyl)acrylate (6l)

Diester 6l was prepared using monoester 8a (65 mg, 0.22 mmol), NaH (9.9 mg, 0.25 mmol, 60% in mineral oil), (E)-3-(2-nitrophenyl)acryloyl chloride (50 mg, 0.24 mmol), and anhyd THF (5 mL) following General Procedure II. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 6l (75 mg, 72% yield) as a white solid; mp 198–199 °C; R_f = 0.21 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3064, 2961, 1918, 1717, 1635, 1603, 1570, 1517, 1335 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 8.27 (d, J = 15.8 Hz, 1 H), 7.91 (dd, J = 8.2, 1.0 Hz, 1 H), 7.86 (d, J = 15.7 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.54–7.50 (m, 2 H), 7.38–7.35 (m, 3 H), 7.30–7.11 (m, 7 H), 6.67 (d, J = 16.1 Hz, 1 H), 6.54 (d, J = 15.8 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.7, 164.8, 148.3, 146.9, 145.3, 145.1, 141.9, 137.0, 134.0, 133.3, 130.8, 130.5, 129.9, 129.0, 128.8, 128.3, 127.2, 127.1, 126.3, 126.2, 125.0, 122.5, 121.4, 120.8, 120.7, 117.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₉NNaO₆: 488.1105; found: 488.1092.

8-(Cinnamoyloxy)naphthalen-1-yl (E)-3-(Thiophen-2-yl)acrylate (6n)

Diester 6n was prepared using monoester 8a (88 mg, 0.30 mmol), NaH (13.3 mg, 0.33 mmol, 60% in mineral oil), (E)-3-(thiophen-2-yl)acryloyl chloride (55 mg, 0.32 mmol), and anhyd THF (5 mL) following General Procedure II. The crude product was purified by flash column chromatography (SiO₂, CHCl₃/hexanes 1:1) to afford pure 6n (96 mg, 75% yield) as a white solid; mp 208–209 °C; R_f = 0.16 (CH₂Cl₂/ hexanes 1:1).

IR (ATR, film): 3059, 1715, 1638, 1620, 1600, 1574, 1512 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.93 (d, J = 15.7 Hz, 1 H), 7.85 (d, J = 16.0 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 2 H), 7.47 (t, J = 7.7 Hz, 2 H), 7.31 (d, J = 7.5 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 7.21–7.13 (m, 5 H), 7.04 (d, J = 3.3 Hz, 1 H), 6.83 (t, J = 4.3 Hz, 1 H), 6.62 (d, J = 16.0 Hz, 1 H), 6.40 (d, J = 15.7 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 165.9, 165.8, 147.1, 145.28, 145.26, 139.3, 139.1, 136.9, 134.0, 131.5, 130.5, 129.3, 128.8, 128.3, 128.1, 126.9, 126.2, 121.5, 120.70, 120.67, 117.3, 115.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₁₈NaO₄S: 449.0818; found: 449.0832.

8-(((E)-3-(Furan-2-yl)acryloyl)oxy)naphthalen-1-yl (E)-3-(4-Meth­oxyphenyl)acrylate (6p)

Diester 6p was prepared using monoester 8b (75 mg, 0.23 mmol), NaH (9.4 mg, 0.24 mmol, 60% in mineral oil), (E)-3-(furan-2-yl)acryloyl chloride (40 mg, 0.26 mmol), and anhyd THF (15 mL) following General Procedure II. The crude product was purified by flash column chromatography (SiO₂, 1% MeOH in CH₂Cl₂/hexanes 1:1) to afford pure 6p (80 mg, 77% yield) as a pale brown solid; mp 138–140 °C; R_f = 0.30 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3059, 2932, 2839, 1729, 1635, 1601, 1512 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.82–7.79 (m, 3 H), 7.58 (d, J = 15.7 Hz, 1 H), 7.50 (t, J = 7.9 Hz, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 2 H), 7.22–7.18 (m, 3 H), 6.75 (d, J = 8.7 Hz, 2 H), 6.52 (d, J = 4.3 Hz, 1 H), 6.49–6.47 (m, 2 H), 6.33 (dd, J = 3.3, 1.8 Hz, 1 H), 3.82 (s, 3 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 166.3, 166.1, 161.6, 150.7, 146.7, 145.4, 145.2, 136.9, 132.8, 130.0, 127.0, 126.9, 126.8, 126.2, 126.1, 121.6, 120.8, 120.7, 115.8, 115.2, 115.0, 114.3, 112.3, 55.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₀NaO₆: 463.1152; found: 463.1166.

Photochemical Cycloaddition Reactions of 6; General Procedure III (Method C)

A solid powder sample of diester 6 was placed between two soda-lime glass microscope slides. The sample was irradiated with a 400-W broadband medium-pressure Hg lamp for 8 h inside a safety box. The solid powder was mixed with a spatula to ensure homogeneity every 2 h. At the end of 8 h, the sample was analyzed by ¹H NMR spectroscopy.

Photochemical Cycloaddition Reactions of 6; General Procedure IV (Method D)

A solid powder sample of diester 6 was placed between two quartz glass microscope slides. The sample was irradiated inside a UV gel nail dryer, equipped with four 9-W UVA fluorescent bulbs, for 16 h. The solid powder was mixed with a spatula to ensure homogeneity every 4 h. At the end of 16 h, the sample was analyzed by ¹H NMR spectroscopy.

(8aR,9S,10R,10aS)-9,10-Bis(benzo[d][1,3]dioxol-5-yl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (meso-9c)

Cycloadduct 9c was synthesized using diester 6c (24.9 mg, 0.049 mmol) following General Procedure III (irradiation time = 8 h) to give pure product (23.1 mg, 93% yield) as a brown solid.

Cycloadduct 9c was also synthesized using diester 6c (24.8 mg, 0.049 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9c (23.9 mg, 96% yield) as an orange solid; mp 209–213 °C; R_f = 0.27 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3060, 2957, 2900, 1764, 1608, 1504, 1492, 1444 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.50 (t, J = 7.9 Hz, 2 H), 7.26 (d, J = 7.9 Hz, 2 H), 6.66 (d, J = 7.9 Hz, 2 H), 6.54 (d, J = 8.0 Hz, 2 H), 6.50 (s, 2 H), 5.88 (s, 4 H), 4.61 (app d, J = 6.0 Hz, 2 H), 4.11 (app d, J = 6.1 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 170.0, 147.8, 146.4, 145.4, 137.1, 132.1, 127.1, 126.5, 121.09, 121.05, 119.6, 108.4, 108.2, 101.1, 45.2, 44.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₂₀NaO₈: 531.1050; found: 531.1035.

(8aR,9S,10R,10aS)-9,10-Bis(4-chlorophenyl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (meso-9d)

Cycloadduct 9d was synthesized using diester 6d (25.1 mg, 0.051 mmol) following General Procedure III (irradiation time = 8 h) to give pure product (22.3 mg, 89% yield) as a white solid.

Cycloadduct 9d was also synthesized using diester 6d (25.5 mg, 0.052 mmol) following General Procedure IV (irradiation time = 16 h) to give pure product (23.0 mg, 90% yield); mp 216–218 °C; R_f = 0.41 (CH₂Cl₂).

IR (ATR, film): 3060, 2925, 1765, 1607, 1577, 1366 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.83 (d, J = 8.3 Hz, 2 H), 7.52 (t, J = 7.9 Hz, 2 H), 7.28 (d, J = 7.4 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 4 H), 6.93 (d, J = 8.3 Hz, 4 H), 4.72 (app d, J = 5.9 Hz, 2 H), 4.17 (app d, J = 5.9 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.7, 145.4, 137.1, 136.4, 132.9, 129.2, 128.7, 127.2, 126.5, 121.1, 119.5, 44.8, 43.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₈ ³⁵Cl₂NaO₄: 511.0474; found: 511.0461.

(8aR,9S,10R,10aS)-9,10-Di(thiophen-2-yl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (meso-9e)

Cycloadduct 9e was synthesized using diester 6e (19.2 mg, 0.044 mmol) following General Procedure III (irradiation time = 8 h) to give pure product (18.5 mg, 96% yield).

Cycloadduct 9e was also synthesized using diester 6e (25.2 mg, 0.058 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9e (24.8 mg, 98% yield) as a pale-yellow solid; mp 193–195 °C; R_f = 0.45 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2926, 1763, 1608, 1577, 1365 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.83 (d, J = 8.3 Hz, 2 H), 7.52 (t, J = 7.8 Hz, 2 H), 7.29 (d, J = 7.4 Hz, 2 H), 7.15 (d, J = 5.1 Hz, 2 H), 6.91 (t, J = 4.0 Hz, 2 H), 6.84 (d, J = 3.1 Hz, 2 H), 4.90 (d, J = 5.5 Hz, 2 H), 4.23 (d, J = 5.5 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.2, 145.3, 141.0, 137.1, 127.1, 126.9, 126.5, 125.8, 125.2, 121.1, 119.5, 46.8, 41.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₁₆NaO₄S₂: 455.0382; found: 455.0385.

(8aR,9S,10R,10aS)-9,10-Di(furan-2-yl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (meso-9f)

Cycloadduct 9f was synthesized using diester 6f (21.6 mg, 0.054 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9f (18.6 mg, 86% yield).

Cycloadduct 9f was also synthesized using diester 6f (25.7 mg, 0.064 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9f (25.2 mg, 98% yield) as a brown-orange solid; mp 164–165 °C; R_f = 0.49 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2922, 1765, 1608, 1504, 1363 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.50 (t, J = 7.9 Hz, 2 H), 7.28–7.25 (m, 4 H), 6.25 (dd, J = 3.0, 1.8 Hz, 2 H), 6.04 (d, J = 3.1 Hz, 2 H), 4.61 (d, J = 5.8 Hz, 2 H), 4.28 (d, J = 5.7 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.5, 152.0, 145.3, 142.2, 137.1, 127.1, 126.5, 121.1, 119.5, 110.5, 107.6, 44.3, 38.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₁₆NaO₆: 423.0839; found: 423.0839.

(8aR,9S,10R,10aS)-9,10-Bis(1-methyl-1H-pyrrol-2-yl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (meso-9g)

Cycloadduct 9g was synthesized using diester 6g (25.3 mg, 0.059 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9g (24.0 mg, 95% yield) as a pale purple solid.

Cycloadduct 9g was also synthesized using diester 6g (18.7 mg, 0.044 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9g (15.0 mg, 80% yield) as a purple solid; mp 224–227 °C; R_f = 0.68 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3061, 2916, 1732, 1633, 1605, 1576 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.81 (d, J = 8.3 Hz, 2 H), 7.51 (t, J = 7.8 Hz, 2 H), 7.26 (d, J = 8.1 Hz, 2 H), 6.53 (br s, 2 H), 6.04 (t, J = 2.7 Hz, 2 H), 5.79–5.74 (m, 2 H), 4.56 (app d, J = 5.3 Hz, 2 H), 4.08 (app d, J = 5.3 Hz, 2 H), 3.35 (s, 6 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.9, 145.5, 137.1, 129.8, 127.1, 126.5, 122.5, 121.1, 119.7, 107.4, 107.1, 46.2, 36.2, 33.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₂N₂NaO₄: 449.1472; found: 449.1462.

(8aR,9S,10R,10aS)-9-(4-Nitrophenyl)-10-phenyl-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (rac-9j)

Cycloadduct 9j was synthesized using diester 6j (24.3 mg, 0.052 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9j (18.8 mg, 77% yield) as a gray solid.

Cycloadduct 9j was also synthesized using diester 6j (23.8 mg, 0.051 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9j (14.4 mg, 61% yield); mp 219–220 °C; R_f = 0.24 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2924, 2853, 1760, 1606, 1515, 1343 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 8.00 (d, J = 8.5 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H), 7.533 (t, J = 7.9 Hz, 1 H), 7.528 (t, J = 7.9 Hz, 1 H), 7.30 (d, J = 7.4 Hz, 2 H), 7.21–7.12 (m, 5 H), 7.02 (d, J = 7.1 Hz, 2 H), 4.88 (dd, J = 10.5, 5.5 Hz, 1 H), 4.82 (dd, J = 10.5, 4.9 Hz, 1 H), 4.31–4.24 (m, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.62, 169.58, 146.7, 145.9, 145.3, 137.3, 137.1, 128.8, 128.7, 127.8, 127.5, 127.3, 127.2, 127.0, 126.5, 123.5, 121.1, 121.0, 119.4, 44.8, 44.5, 44.3, 44.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₁₉NNaO₆: 488.1105; found: 488.1115.

(8aR,9S,10R,10aS)-9-(3-Nitrophenyl)-10-phenyl-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (rac-9k)

Cycloadduct 9k was synthesized using diester 6k (17.0 mg, 0.037 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9k (14.9 mg, 88% yield) as a white solid.

Cycloadduct 9k was also synthesized using diester 6k (26.7 mg, 0.057 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9k (23.0 mg, 86% yield); mp 185–187 °C; R_f = 0.24 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2954, 2921, 2852, 1761, 1746, 1606, 1526, 1347 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.98–7.95 (m, 1 H), 7.91 (s, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.53 (t, J = 7.9 Hz, 2 H), 7.33–7.30 (m, 4 H), 7.19 (t, J = 7.3 Hz, 2 H), 7.11 (t, J = 7.3 Hz, 1 H), 7.03 (d, J = 7.2 Hz, 2 H), 4.88 (dd, J = 9.9, 4.6 Hz, 1 H), 4.82 (dd, J = 9.6, 3.4 Hz, 1 H), 4.33–4.27 (m, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.7, 169.6, 148.2, 145.3, 140.4, 137.1, 134.1, 129.2, 128.8, 127.9, 127.4, 127.23, 127.19, 126.6, 126.5, 122.7, 121.9, 121.12, 121.06, 119.4, 44.48, 44.46, 44.2, 44.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₉NNaO₆: 488.1105; found: 488.1103.

(8aR,9S,10R,10aS)-9-(2-Nitrophenyl)-10-phenyl-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (rac-9l)

Cycloadduct 9l was synthesized using diester 6l (24.7 mg, 0.053 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9l (10.8 mg, 44% yield) as a pale-yellow solid.

Cycloadduct 9l was also synthesized using diester 6l (24.3 mg, 0.052 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9l (11.8 mg, 49% yield); mp 191–193 °C; R_f = 0.53 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2922, 1761, 1606, 1574, 1525, 1359 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.83 (d, J = 8.3 Hz, 3 H), 7.59–7.50 (m, 3 H), 7.46 (d, J = 7.7 Hz, 1 H), 7.34–7.28 (m, 3 H), 7.15–7.08 (m, 3 H), 7.02 (d, J = 7.7 Hz, 2 H), 5.48 (t, J = 9.6 Hz, 1 H), 4.84 (dd, J = 10.2, 4.8 Hz, 1 H), 4.52 (t, J = 10.0 Hz, 1 H), 4.01 (dd, J = 10.8, 4.9 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 170.0, 169.8, 148.2, 145.37, 145.35, 137.9, 137.1, 134.3, 133.4, 128.8, 128.6, 128.4, 127.9, 127.3, 127.2, 127.1, 126.6, 126.5, 125.4, 121.2, 121.1, 119.4, 45.2, 44.6, 44.1, 43.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₀NO₆: 466.1285; found: 466.1277.

(8aS,9S,10S,10aS)-9-Phenyl-10-(thiophen-2-yl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (rac-9n)

Cycloadduct 9n was synthesized using diester 6n (25.3 mg, 0.059 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9n (21.8 mg, 86% yield) as a white solid.

Cycloadduct 9n was also synthesized using diester 6n (25.7 mg, 0.060 mmol) following General Procedure IV (irradiation time = 16 h) to give pure product (24.8 mg, 96% yield); mp 202–203 °C; R_f = 0.30 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 3057, 2925, 1752, 1606, 1576, 1497, 1365 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.81 (d, J = 8.3 Hz, 2 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.29–7.21 (m, 4 H), 7.19–7.16 (m, 1 H), 7.11 (d, J = 7.3 Hz, 2 H), 7.05 (d, J = 5.0 Hz, 1 H), 6.82 (t, J = 4.2 Hz, 1 H), 6.73 (d, J = 3.0 Hz, 1 H), 4.91 (dd, J = 9.9, 5.9 Hz, 1 H), 4.76 (t, J = 8.8 Hz, 1 H), 4.33 (dd, J = 10.4, 7.8 Hz, 1 H), 4.14 (dd, J = 10.5, 5.9 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 169.7, 169.6, 145.39, 145.37, 141.6, 137.6, 137.1, 128.4, 127.8, 127.14, 127.11, 126.5, 125.6, 124.9, 121.11, 121.05, 119.6, 47.0, 44.8, 44.4, 40.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₁₈NaO₄S: 449.0818; found: 449.0832.

(8aR,9S,10R,10aS)-9-(Furan-2-yl)-10-(4-methoxyphenyl)-8a,9,10,10a-tetrahydrocyclobuta[g]naphtho[1,8-bc][1,5]dioxonine-8,11-dione (rac-9p)

Cycloadduct 9p was synthesized using diester 6p (25.8 mg, 0.059 mmol) following General Procedure III (irradiation time = 8 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9p (14.7 mg, 57% yield).

Cycloadduct 9p was also synthesized using diester 6p (15.5 mg, 0.035 mmol) following General Procedure IV (irradiation time = 16 h). The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/hexanes 1:1) to afford pure 9p (13.0 mg, 84% yield) as a white solid; mp 154.8–155.3 °C; R_f = 0.32 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2929, 2838, 1765, 1609, 1515, 1364 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.81 (d, J = 7.8 Hz, 2 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 1 H), 7.29–7.25 (m, 2 H), 7.22 (m, 1 H), 7.03 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 8.5 Hz, 2 H), 6.19 (t, J = 2.2 Hz, 1 H), 6.03 (d, J = 3.1 Hz, 1 H), 4.66 (t, J = 9.2 Hz, 1 H), 4.57 (dd, J = 10.1, 4.8 Hz, 1 H), 4.33 (dd, J = 10.5, 8.5 Hz, 1 H), 4.19 (dd, J = 10.6, 4.8 Hz, 1 H), 3.76 (s, 3 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 170.2, 169.6, 158.6, 152.2, 145.4, 142.2, 137.1, 130.2, 128.5, 127.08, 127.05, 126.5, 121.1, 121.0, 119.6, 113.7, 110.4, 108.2, 55.3, 45.7, 43.8, 43.6, 38.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₀NaO₆: 463.1152; found: 463.1160.

Hydrolysis of Cycloadducts 9; General Procedure V

To a solution of cycloadduct 9 (1.0 equiv) in THF (2.0 mL) in a 20-mL scintillation vial was added distilled water (1.0 mL) and KOH (19 equiv). The resulting mixture was stirred at 23 °C for 2 h and then quenched with 1.0 M HCl solution until pH 1–2. The aqueous phase was extracted with EtOAc (3 ×). The combined organic phases were dried (anhyd Na₂SO₄), filtered, and concentrated under vacuum. The crude mixture was purified by flash column chromatography.

(1R,2S,3R,4S)-3,4-Bis(benzo[d][1,3]dioxol-5-yl)cyclobutane-1,2-dicarboxylic Acid (meso-10c)

Dicarboxylic acid 10c was synthesized using cycloadduct 9c (24.2 mg, 0.048 mmol), KOH (51.2 mg, 0.91 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, EtOAc/hexanes 1:1 → 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10c (17.5 mg, 95% yield) as a dark brown solid; mp 151–152 °C; R_f = 0.11 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3012, 2891, 1745, 1697, 1503, 1491, 1442 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.43 (br s, 2 H), 6.66 (d, J = 8.0 Hz, 2 H), 6.65 (d, J = 1.2 Hz, 2 H), 6.54 (d, J = 8.0, 1.2 Hz, 2 H), 5.88 (s, 4 H), 4.07 (d, J = 6.2 Hz, 2 H), 3.71 (d, J = 6.2 Hz, 2 H).

HRMS (ESI): m/z [M – H]^– calcd for C₂₀H₁₅O₈: 383.0772; found: 383.0780.

(1R,2S,3R,4S)-3,4-Bis(4-chlorophenyl)cyclobutane-1,2-dicarboxylic Acid (meso-10d)

Dicarboxylic acid 10d was synthesized using cycloadduct 9d (22.3 mg, 0.046 mmol), KOH (48.5 mg, 0.86 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10d (14.2 mg, 84% yield) as a pale brown solid; mp 178–180 °C; R_f = 0.15 (0.5% AcOH in EtOAc/hexanes 1:1). The ¹H and ¹³C NMR spectroscopic data are in agreement with those reported in the literature.[30a]

IR (ATR, film): 3123 (br), 1710, 1493, 1425 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.45 (br s, 2 H), 7.16 (d, J = 8.2 Hz, 4 H), 7.07 (d, J = 8.0 Hz, 4 H), 4.22 (app d, J = 5.4 Hz, 2 H), 3.80 (app d, J = 5.5 Hz, 2 H).

¹³C{¹H} NMR (DMSO-d ₆, 100 MHz): δ = 173.8, 138.2, 130.7, 129.8, 127.7, 43.8, 42.4.

HRMS (ESI): m/z [M – H]^– calcd for C₁₈H₁₃ ³⁵Cl₂O₄: 363.0196; found: 363.0196; calcd for C₁₈H₁₃ ³⁵Cl³⁷ClO₄: 365.0167; found: 365.0166.

(1R,2S,3R,4S)-3,4-Di(thiophen-2-yl)cyclobutane-1,2-dicarboxylic Acid (meso-10e)

Dicarboxylic acid 10e was synthesized using cycloadduct 9e (24.8 mg, 0.057 mmol), KOH (48.5 mg, 0.86 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, EtOAc/hexanes 1:1 → 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10e (16.0 mg, 90% yield) as a pale brown solid; mp 173–175 °C; R_f = 0.13 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 2925, 1708, 1419, 1239 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.60 (br s, 2 H), 7.24 (d, J = 4.8 Hz, 2 H), 6.86–6.83 (m, 4 H), 4.31 (app d, J = 6.1 Hz, 2 H), 3.70 (app d, J = 6.1 Hz, 2 H).

¹³C{¹H} NMR (DMSO-d ₆, 100 MHz): δ = 173.1, 142.0, 126.6, 125.4, 124.9, 45.1, 40.7.

HRMS (ESI): m/z [M – H]^– calcd for C₁₄H₁₁O₄S₂: 307.0104; found: 307.0119.

(1R,2S,3R,4S)-3,4-Di(furan-2-yl)cyclobutane-1,2-dicarboxylic Acid (meso-10f)

Dicarboxylic acid 10f was synthesized using cycloadduct 9f (24.0 mg, 0.060 mmol), KOH (62.8 mg, 1.12 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10f (11.8 mg, 71% yield) as a pale-yellow solid; mp 175–177 °C; R_f = 0.24 (0.5% AcOH in EtOAc/hexanes 1:1). The ¹H NMR spectrum in DMSO-d ₆ is in agreement with the spectrum reported in the literature.[30c]

IR (ATR, film): 2924, 1710, 1505, 1427 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 9.16 (br s, 2 H), 7.24 (app s, 2 H), 6.21 (app t, J = 1.4 Hz, 2 H), 5.96 (d, J = 2.8 Hz, 2 H), 4.29 (app d, J = 5.6 Hz, 2 H), 3.97 (app d, J = 5.4 Hz, 2 H).

¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.61 (br s, 2 H), 7.41–7.40 (m, 2 H), 6.25 (dd, J = 3.0, 1.9 Hz, 2 H), 6.10 (d, J = 3.2 Hz, 2 H), 4.05 (app d, J = 6.1 Hz, 2 H), 3.66 (app d, J = 6.1 Hz, 2 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 179.2, 152.2, 142.1, 110.5, 107.4, 43.6, 38.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₂NaO₆: 299.0526; found: 299.0535.

Dimethyl (1R,2S,3R,4S)-3,4-Bis(1-methyl-1H-pyrrol-2-yl)cyclobutane-1,2-dicarboxylate (meso-11)

NaOMe (3.0 mg, 0.056 mmol) was added to a solution of cycloadduct 9g (11.8 mg, 0.028 mmol) in MeOH (4 mL) at 23 °C. The resulting mixture was stirred at 23 °C for 3.5 h at which time TLC analysis indicated complete consumption of the reactant. MeOH was then evaporated under reduced pressure and the crude mixture was mixed with CDCl₃­. Ionic components including the sodium salt of 5 did not dissolve in CDCl₃. The supernatant liquid was transferred to another flask, and all volatiles were removed under reduced pressure to afford pure 11 (6.0 mg, 65% yield) as a blackish amorphous solid; R_f = 0.43 (CH₂Cl₂/hexanes 1:1).

IR (ATR, film): 2950, 2928, 1735, 1435, 1354, 1208 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 6.48–6.47 (m, 2 H), 5.98 (dd, J = 3.5, 2.8 Hz, 2 H), 5.61 (dd, J = 3.6, 1.7 Hz, 2 H), 4.20 (app d, J = 6.0 Hz, 2 H), 3.72 (s, 6 H), 3.69 (app d, J = 5.9 Hz, 2 H), 3.28 (s, 6 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 173.1, 130.5, 122.2, 107.1, 106.7, 52.3, 45.2, 36.8, 33.6.

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O₄: 331.1652; found: 331.1666.

(1S,2R,3S,4R)-3-(4-Nitrophenyl)-4-phenylcyclobutane-1,2-dicarboxylic Acid (rac-10j)

Dicarboxylic acid 10j was synthesized using cycloadduct 9j (14.4 mg, 0.031 mmol), KOH (32.9 mg, 0.59 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, EtOAc/hexanes 1:1 → 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10j (9.6 mg, 91% yield) as a brownish amorphous solid.; R_f = 0.18 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3030, 2925, 2854, 1707, 1601, 1517, 1425, 1345 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 10.13 (br s, 2 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.17–7.11 (m, 3 H), 7.06 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 7.0 Hz, 2 H), 4.64 (t, J = 8.8 Hz, 1 H), 4.40 (dd, J = 9.6, 5.5 Hz, 1 H), 4.02 (t, J = 8.8 Hz, 1 H), 3.91 (dd, J = 9.2, 5.4 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 179.5, 178.9, 146.7, 146.0, 137.2, 128.8, 128.5, 127.8, 127.5, 123.5, 45.0, 44.6, 44.1, 43.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₅NNaO₆: 364.0792; found: 364.0791.

(1S,2R,3S,4R)-3-(3-Nitrophenyl)-4-phenylcyclobutane-1,2-dicarboxylic Acid (rac-10k)

Dicarboxylic acid 10k was synthesized using cycloadduct 9k (20.0 mg, 0.043 mmol), KOH (46 mg, 0.82 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10k (13.4 mg, 91% yield) as a yellow amorphous solid; R_f = 0.17 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3030, 2925, 2855, 1706, 1527, 1422, 1346 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 8.25 (br s, 2 H), 7.93 (d, J = 7.9 Hz, 1 H), 7.80 (s, 1 H), 7.29–7.25 (m, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.17–7.14 (m, 2 H), 7.11–7.07 (m, 1 H), 6.96 (d, J = 7.2 Hz, 2 H), 4.66 (t, J = 9.0 Hz, 1 H), 4.41 (dd, J = 10.0, 5.4 Hz, 1 H), 4.04 (t, J = 9.1 Hz, 1 H), 3.95 (dd, J = 10.0, 5.7 Hz, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 179.5, 178.8, 148.1, 140.5, 137.2, 134.0, 129.1, 128.8, 127.8, 127.4, 122.6, 121.9, 44.9, 44.4, 43.9, 43.5.

HRMS (ESI): m/z [M – H]^– calcd for C₁₈H₁₄NO₆: 340.0827; found: 340.0812.

(1S,2R,3S,4R)-3-(2-Nitrophenyl)-4-phenylcyclobutane-1,2-dicarboxylic Acid (rac-10l)

Dicarboxylic acid 10l was synthesized using cycloadduct 9l (20.5 mg, 0.044 mmol), KOH (46.9 mg, 0.84 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, 0.5% AcOH in EtOAc/hexanes 1:1 → 5% MeOH in EtOAc) to afford pure 10l (12.7 mg, 85% yield) as a white solid; mp 182–185 °C; R_f = 0.25 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3055, 3032, 2924, 1709, 1524, 1423, 1346 cm^–1.

¹H NMR (CD₃OD, 400 MHz): δ = 7.76 (d, J = 8.1 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.08–7.00 (m, 5 H), 5.09 (t, J = 10.1 Hz, 1 H), 4.33 (t, J = 10.2 Hz, 1 H), 4.18 (dd, J = 10.0, 3.7 Hz, 1 H), 3.59 (dd, J = 10.0, 3.7 Hz, 1 H).

¹³C{¹H} NMR (CD₃OD, 100 MHz): δ = 176.6, 175.8, 149.8, 140.1, 136.1, 134.1, 130.5, 129.3, 129.2, 128.4, 127.8, 125.6, 47.0, 46.0, 44.2, 42.6.

HRMS (ESI): m/z [M – H]^– calcd for C₁₈H₁₄NO₆: 340.0827; found: 340.0825.

(1S,2S,3S,4S)-3-Phenyl-4-(thiophen-2-yl)cyclobutane-1,2-dicarboxylic Acid (rac-10n)

Dicarboxylic acid 10n was synthesized using cycloadduct 9n (19.8 mg, 0.046 mmol), KOH (49.5 mg, 0.88 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, 0.1% AcOH in EtOAc/hexanes 1:1) to afford pure 10n (13.5 mg, 96% yield) as a pale brown solid; mp 181–182 °C; R_f = 0.30 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3031, 2922, 1698, 1413, 1255 cm^–1.

¹H NMR (CD₃OD, 400 MHz): δ = 7.16–7.12 (m, 2 H), 7.09–7.06 (m, 3 H), 7.03 (dd, J = 5.1, 1.0 Hz, 1 H), 6.75 (dd, J = 5.0, 3.5 Hz, 1 H), 6.68 (d, J = 3.4 Hz, 1 H), 4.46 (dd, J = 9.8, 6.3 Hz, 1 H), 4.32 (t, J = 8.7 Hz, 1 H), 3.94 (dd, J = 9.7, 7.8 Hz, 1 H), 3.74 (dd, J = 9.9, 6.3 Hz, 1 H).

¹³C{¹H} NMR (CD₃OD, 100 MHz): δ = 176.1, 175.8, 143.9, 139.9, 129.0, 128.9, 127.5, 127.4, 126.2, 125.0, 47.3, 46.8, 44.3, 42.2.

HRMS (APCI): m/z [M – H]^– calcd for C₁₆H₁₃O₄S: 301.0540; found: 301.0521.

(1S,2R,3S,4R)-3-(Furan-2-yl)-4-(4-methoxyphenyl)cyclobutane-1,2-dicarboxylic Acid (rac-10p)

Dicarboxylic acid 10p was synthesized using cycloadduct 9p (8.2 mg, 0.019 mmol), KOH (19.8 mg, 0.35 mmol), THF (2 mL), and H₂O (1 mL) following General Procedure V. The crude product was purified by flash column chromatography (SiO₂, EtOAc/hexanes 1:1 → 0.5% AcOH in EtOAc/hexanes 1:1) to afford pure 10p (5.5 mg, 93% yield) as a pale brown amorphous solid; R_f = 0.21 (0.5% AcOH in EtOAc/hexanes 1:1).

IR (ATR, film): 3418 (br), 2917, 2849, 1720, 1514, 1463, 1249 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 9.53 (br s, 2 H), 7.18 (s, 1 H), 6.94 (d, J = 8.4 Hz, 2 H), 6.72 (d, J = 8.4 Hz, 2 H), 6.16 (br app s, 1 H), 5.95 (d, J = 2.9 Hz, 1 H), 4.41 (t, J = 9.4 Hz, 1 H), 4.18 (dd, J = 9.5, 4.7 Hz, 1 H), 4.05 (t, J = 9.6 Hz, 1 H), 3.82 (dd, J = 9.9, 4.8 Hz, 1 H), 3.73 (s, 3 H).

¹³C{¹H} NMR (DMSO-d ₆, 100 MHz): δ = 173.46, 173.43, 157.7, 153.3, 141.9, 131.1, 128.4, 113.1, 110.2, 107.2, 54.9, 43.4, 43.2, 42.3, 38.4.

HRMS (ESI): m/z [M – H]^– calcd for C₁₇H₁₅O₆: 315.0874; found: 315.0871.

Dimethyl (1S,2S,3S,4S)-3-Phenyl-4-(thiophen-2-yl)cyclobutane-1,2-dicarboxylate (rac-12)

NaOMe (7.9 mg, 0.15 mmol) was added to a solution of cycloadduct 9n (31.2 mg, 0.073 mmol) in MeOH (2 mL) at 23 °C. The resulting mixture was stirred at 23 °C for 2 h at which time TLC analysis indicated complete consumption of the reactant. MeOH was then evaporated under reduced pressure. The remaining crude oil was dissolved in EtOAc (10 mL), and to this solution water (10 mL) and brine (5 mL) were added. The two phases were partitioned in a separatory funnel. The aqueous phase was further extracted with EtOAc (3 × 15 mL). The combined organic phases were dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, EtOAc/hexanes 1:1) to afford pure 12 (22.5 mg, 93% yield) as yellow oil; R_f = 0.72 (EtOAc/hexanes 1:1).

IR (ATR, film): 2951, 1736, 1435, 1264, 1207 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.20–7.13 (m, 3 H), 7.02 (d, J = 7.0 Hz, 2 H), 7.00 (d, J = 5.1 Hz, 1 H), 6.77 (dd, J = 5.0, 3.6 Hz, 1 H), 6.61 (d, J = 3.5 Hz, 1 H), 4.55 (dd, J = 9.8, 6.2 Hz, 1 H), 4.41 (t, J = 8.8 Hz, 1 H), 3.95 (dd, J = 10.0, 7.7 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.78–3.71 (m, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 172.8, 172.6, 142.3, 138.1, 128.2, 127.8, 126.9, 126.6, 125.3, 124.5, 52.4, 52.3, 46.1, 45.6, 42.9, 41.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₈NaO₄S: 353.0818; found: 353.0830.

((1S,2S,3S,4S)-3-Phenyl-4-(thiophen-2-yl)cyclobutane-1,2-diyl)dimethanol (rac-13)

LiAlH₄ (25.8 mg, 0.68 mmol) was added to a solution of cycloadduct 9n (29.1 mg, 0.068 mmol) in anhyd THF (2 mL) at 0 °C under N₂. The resulting gray-colored mixture was stirred at 23 °C for 3 h at which time TLC analysis indicated complete consumption of the reactant. The mixture was then quenched carefully with water, and gas formation was observed. The aqueous phase was extracted with EtOAc (3 ×). The combined organic phases were dried (anhyd Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, 5% MeOH in CH₂Cl₂) to afford pure 13 (16.0 mg, 86% yield) as a brown oil; R_f = 0.23 (5% MeOH in CH₂Cl₂).

IR (ATR, film): 3317 (br), 2926, 2872, 1496, 1451, 1264 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.18–7.08 (m, 3 H), 7.04 (d, J = 7.0 Hz, 2 H), 6.96 (d, J = 5.1 Hz, 1 H), 6.75 (dd, J = 5.0, 3.5 Hz, 1 H), 6.57 (d, J = 3.3 Hz, 1 H), 4.08–3.99 (m, 2 H), 3.93–3.82 (m, 3 H), 3.63 (t, J = 8.5 Hz, 1 H), 3.41 (br s, 2 H), 3.29–3.22 (m, 1 H), 3.14–3.07 (m, 1 H).

¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 144.0, 139.4, 128.2, 128.1, 126.6, 126.4, 124.7, 123.8, 62.4, 62.2, 44.8, 43.6, 40.2, 40.1.

HRMS (ESI): m/z [M – H]^– calcd for C₁₆H₁₇O₂S: 273.0955; found: 273.0972.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank Eylül Çalıkyılmaz for providing assistance in the diffuse reflectance UV-vis spectroscopic measurements.

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Publikationsverlauf

Eingereicht: 31. Mai 2023

Angenommen nach Revision: 10. Juli 2023

Accepted Manuscript online:
10. Juli 2023

Artikel online veröffentlicht:
16. August 2023