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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Classical Example of Total Kinetic and Thermodynamic Control: The Diels−Alder Reaction between DMAD and Bis-furyl Dienes Kseniya K. Borisova,† Elizaveta A. Kvyatkovskaya,† Eugeniya V. Nikitina,† Rinat R. Aysin,‡ Roman A. Novikov,§ and Fedor I. Zubkov*,† †

Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russian Federation Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow, 119991, Russian Federation § V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow, 119991, Russian Federation ‡

S Supporting Information *

ABSTRACT: A rare example of chemospecificity in the tandem Diels−Alder reaction of activated alkynes and bis-dienes has been revealed. The reaction between bis-furyl dienes and DMAD occurs at 25−80 °C and leads to kinetically controlled “pincer” adducts, 4a,8a-disubstituted 1,4:5,8-diepoxynaphthalenes. On the contrary, only thermodynamically controlled “domino” adducts (2,3-disubstituted 1,4:5,8-diepoxynaphthalenes) are formed in the same reaction at 140 °C. The “pincer” adducts can be transformed to the “domino” adducts at heating. The rate constants for reactions of both types were calculated using dynamic 1H NMR spectroscopy.

T

view, tandem and domino reactions involving several consecutive [4+2] cycloaddition steps are the most attractive and widely used in the total synthesis of natural products, due to the possibility of a simultaneous creation of four or more new σ-bonds with the controlled stereochemistry.3 However, a limited number of examples of the intramolecular Diels−Alder (IMDA) reactions that can lead to either kinetically or thermodynamically controlled products, depending on temperature, are currently known.4 To the best of our knowledge, there are only two examples of full kinetic and thermodynamic control in the IMDA reaction.5 The impetus for the present study was given by the article by Lautens and Fillion published in 1997, which described the tandem [4+2] cycloaddition between dimethyl acetylenedicarboxylate (DMAD) and bis-furyl dienes (1a−c,e) at rt (Scheme 1), leading to the formation of compounds 3a−c,e only.6a Later, some useful transformations of the obtained pincer adducts 3 were demonstrated.6b

he phenomenon of thermodynamic and kinetic control is unique in organic chemistry, and it is the easiest method for the control of stereo-, regio-, or chemoselectivity, since it allows alteration the direction of the reaction pathway by varying only temperature and keeping the rest of the parameters unchanged. A very limited set of reactions illustrate this principle to a full extent. Among them, textbook examples of the sulfonation of phenol, aniline, and naphthalene are worth citing here. However, even in these simplest examples, no full kinetic (or vice versa thermodynamic) control is achieved since mixtures of regioisomeric arenesulfonic acids are formed both at high and especially low temperatures. In more complicated cases, the practical application of the kinetic/thermodynamic control is seriously hindered or rendered impossible by the formation of isomers. Woodward and Baer were first to report the formation of kinetically and thermodynamically controlled adducts in the Diels−Alder reaction as early as 1948.1 Since then, a significant amount of information about the reversibility of the [4+2] cycloaddition has been obtained.2 From a practical point of © XXXX American Chemical Society

Received: February 5, 2018

A

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Scheme 1. Temperature Control in the Course of the Tandem IMDA Reaction between 1 and DMAD

Scheme 2. Gibbs Free Energy Profile for the Reaction between 1f and DMADa

a

Computed potential energy surfaces (ΔG°) for pathways to 3f and 4f at the M06-2X/6-311++G(d,p) level are shown.

reliable and agree well with the thermodynamic/kinetic control notion and are presented in Table 2. The tandem reaction begins with the intermolecular [4+2] cycloaddition of DMAD at one of the furan ring of bis-diene 1, which occurs via TS1 (Scheme 2) and leads to the intermediate 2 (INTk and INTt). TS1 formation is the rate limiting step of the reaction; the activation barrier of which is ∼29 kcal/mol. Subsequently, the intermediate 2, undergoes the IMDA reaction via TS3 or TS2 to give corresponding cycloadducts 3 or 4. The calculated energetic parameters show that the domino adducts 4a−d,f are slightly (by 3.8−4.3 kcal/mol) more stable energetically, than the pincer adducts 3a−d,f for any X. However, activation energies for the pincer adducts 3 (energy values for “TS3 to 3” in Table 2) are smaller than those of the domino adducts 4 lying in the range 3.4−5.6 kcal/mol. Consequently, the theoretical calculation clearly established that adducts 3 are kinetically controlled and that adducts 4 are thermodynamically controlled products of the reaction. The geometrical parameters of the two target compounds 3f and 4f were refined based on X-ray diffraction data.7

A theoretical study concerning the mechanism of the reaction between acetylenedicarboxylic acid and 1,3-bis(2furyl)propane (1a) using DFT methods with the B3LYP functional and the 6-31G* basis set was carried out.6c These computations theoretically explained the exclusive formation of exo,exo-adduct similar to 3 (with the cis-oriented oxo-bridges) within the IMDA reaction6a and mentioned a high energy barrier for the retro Diels−Alder reaction of the pincer cycloadduct that prevents the domino-adduct formation. Comparing the data6 with earlier works5 and taking into account the possibility of an equilibrium between products of kinetic and thermodynamic control in the IMDA reactions, we were encouraged to study of this phenomenon in more detail. First of all, quantum-chemical calculations were needed to assign unambiguously the forms of adducts 3 and 4 to kinetically and thermodynamically controlled products. DFT calculations of reaction paths for five bis-dienes (1a−d,f) with a rather diverse X were performed by using the M06-2X functional and 6-311++G(d,p) basis set (Scheme 2, Table 2, and Supporting Information). The M06-2X results seems to be B

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 1. Yields of Adducts 3 and 4 and Conditions of Kinetic and Thermodynamic Control entry a b c d e f g h i j

X CH2 O S SO2 N-Bn N-Ac N-COCF3 N-COCCl3 N-Bz N-Boc

conditionsa

yield 3 (%) b

Et2O, 21 days Et2O, 21 days Et2O, 21 days

62, 71 67, 76b 64, 71b

Et2O, 21 days Et2O, 21 days Et2O, 21 days

64, 72b 54 57

conditionsc PhH, PhH, PhH, PhH, PhH, PhH, PhH, PhH, PhH, PhH,

20 20 20 20 20 30 30 30 25 24

ratio of 3/4d

yield 3 (%)e

94:6 89:11 97:3 86:14 95:5 94:6 95:5 85:15 98:2 91:9

56 58 60 54 67 61 62 56 77 52

h h h h h h h h h h

conditionsf Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4, Me2C6H4,

6 6 4 4 5 3 5 7 6 3

yield 4 (%)e h h h h h h h h h h

68 75 93 70 73 87 93 73 87 54

a

All reactions were carried out with 1.1 mol excess of DMAD in Et2O at rt for 3 weeks. bAccording to the published data.6a cCompounds 1 were heated at reflux in PhH with 1.5 mol excess of DMAD. dIsomer ratio was determined using 1H NMR analysis of the solids precipitating from reaction mixtures at cooling. (The mother liquors do not contain the target cycloadducts 3 and 4.) When adducts 3 did not precipitate from the reaction solutions, the volatiles were removed under reduced pressure and the obtained crude solids were analyzed by NMR. eIsolated yield after recrystallization. fCompounds 1 were heated at reflux in o-Me2C6H4 with 1.1 mol excess of DMAD.

Table 2. Apparent Gibbs Free Energy ΔG° Values (kcal/ mol) for Reactions of 1 with DMAD at M06-2X/6-311+ +G** Level of Theory (Gas Phase)a

After theoretical calculations, experiments were carried out. Initial bis-furyl dienes 1a−j were prepared according to standard procedures6a (Supporting Information). All preliminary experiments to optimize the reaction conditions were carried out using bis-furans 1b (X = O) and 1f (X = N-Ac) as model compounds. Bis-dienes 1b,f react slowly with DMAD under reflux in THF. Under these conditions, the completion of the reaction required from 4 days (when 1.5 equiv of DMAD was used) to 10 days (an equimolar quantity of DMAD). When the experiments were carried out in MeCN or toluene at reflux, the reactions proceeded faster (1−2 days), but the process chemoselectivity decreased: mixtures of 3/4 were formed in the ratio from 75:25 to 82:18. Benzene turned out to be the best solvent for the preparation of pincer adducts 3; in PhH, the tandem [4+2] cycloaddition was complete within 20−30 h in rather good yields and with a satisfactory chemoselectivity. The ratio of pincer 3/domino 4 adducts exceeded 85:15 in all cases. Kinetically controlled products 3 can be easily isolated by one-fold recrystallization (Table 1). In comparison with the conditions described earlier,6a our approach has an evident time advantage (1−2 days instead of 21 days) giving comparable yields of the target products 3. To confirm this conclusion we reproduced experiments in Et2O at rt (entries a−c and e−g, Table 1). All experiments at 80 °C also gave byproducts 4. Obviously, the raise of temperature would have to shift the equilibrium toward the thermodynamically controlled adducts 4. Therefore, when o-xylene was chosen as a solvent, only domino adducts 4 were isolated in excellent yields (Table 1). In these cases, an excess of DMAD (varied from 1.1 to 1.5 equiv) does not affect the reaction rate. As already mentioned, products of the thermodynamic control 4 were formed by the retro-DA/DA sequence from products of kinetic control 3 through the transition state 2. We were unable to detect open-chain intermediates 2 in reaction mixtures using 1H NMR analysis. This observation suggests that the first step of the tandem process, i.e., the intermolecular [4+2] cycloaddition (1 → 2), proceeds much slower than the second one, viz., the IMDA reaction (2 → 3 or 4), which is in a good correlation with the theoretical predictions (Scheme 2, Table 2). Dynamic 1H NMR experiments to monitor transformation of adducts 3b,c,g into 4b,c,g (X = O, S, NCOCF3) were carried

X

2

TS3 to 3 (Eact)

TS2 to 4 (Eact)

3

4

CH2 (a)

−1.9a −2.9b −1.1a −3.1b −1.9a −1.2b 0.7a 3.9b −2.1a −3.2b

13.0 (14.9) 13.9 (15.0) 15.4 (17.3) 20.6 (21.7) 15.3 (17.4)

18.3 (21.2) 19.5 (22.6) 20.5 (21.7) 25.4 (29.3) 18.7 (21.9)

−16.2

−20.0

−14.6

−18.7

−14.1

−18.2

−9.5

−13.8

−14.5

−18.8

O (b) S (c) SO2 (d) NAc (f)

ΔG° values of the reaction products are referenced to the sum of energies of reactants. TS stands for transition state. Eact is an ΔG° activation energy. Energy values for conformers formed via the pincerand domino-reaction pathways are labeled by superscript indices a and b, respectively (Scheme 2). a

out in an NMR tube in C2D2Cl4 at 140 °C that allowed us to determine the reaction rate constants (Supporting Information). The solvent selection was stipulated by its high boiling point (∼145 °C). The half-life (τ1/2) of the reactions varied within the range 11.5−22 min, which corresponds to the firstorder reaction rate constants of 0.031−0.060 min−1. The transformation of 3b to 4b (X = O) was the quickest one along the series. The analogical dynamic NMR experiments were also used to determine the reaction rates of the first step of the reaction, involving the interaction of alkynes with bis-dienes 1b,c,g. Dimethyl and diethyl acetylenedicarboxylates were chosen as dienophiles (Scheme 3). These reactions were carried out in C2D2Cl4 at 80 °C, and the half-lives for the cycloaddition of DMAD were 128, 228, and 564 min for X = S, O, and COCF3, respectively. For diethyl ester (E = CO2Et), τ1/2 were 270 and 390 min for 1c and 1b, respectively. The interaction of EtO2CCCCO2Et with amide 1g proceeded so slowly that it was impossible to measure the reaction half-life with a sufficient accuracy. The reaction rate with the more sterically demanding diethyl ether was roughly twice as slow than that with dimethyl ether. The formation of the impurity 4 complicated the calculation of the reaction rate constants for compounds 3b,c,g. C

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

■

Scheme 3. Interaction of Bis-dienes 1b,c,g with Dialkyl Acetylenedicarboxylates

Table 3. Yields and Conditions of the Synthesis of Esters 3 and 4 X

E

80 °C, (h)a

ratiob and yield 3/4 (%)

140 °C, (h)c

yield 4 (%)d

b k l m c n o p

O O O O S S S S

CO2Me CO2Et CO2iPr CO2tBu CO2Me CO2Et CO2iPr CO2tBu

20 32 42 47 20 30 31 31

89:11 (67) 84:16 (61) 75:25 (54) 71:29 (72) 99:1 (73) 75:25 (81) 86:14 (83) 88:12 (57)

4 24 8 10 4 4 4 4

75 71 56 e 93 95 72 e

EXPERIMENTAL SECTION

General Methods. All commercially available reagents and solvents were used without further purification. Melting points were measured on a capillary point apparatus equipped with a digital thermometer and were uncorrected. Mass spectra were obtained using the Supporting Information method. 1H NMR, 13C NMR, and 19F NMR spectra were recorded on 400, 600 (for 1H), 100, 150 (for 13C), and 282 (for 19F) MHz spectrometers, with TMS (1H and 13C NMR) and CCl3F (19F NMR) as the internal standard, using CDCl3, DMSOd6, and C2D2Cl4 (for kinetic experiments) as solvents. Data for 1H NMR spectra are reported as follows: chemical shift δ (ppm), referenced to TMS; multiplicities are indicated as the following: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; coupling constants (Hz), and integration. Data for 13C NMR spectra are reported in terms of chemical shift δ (ppm) relative to residual solvent peak. Data for 19F NMR spectra are reported as follows: chemical shift δ (ppm), referenced to CCl3F; multiplicities are indicated as the following: s, singlet and coupling constants (Hz). Assignments of 1H and 13C signals were made with the aid of COSY, NOESY, and HSQC NMR spectra where necessary. IR spectra were recorded in thin films (for oils) or KBr pellets (for solids) using an FTIR Infralum FT-801 spectrometer in range 400−4000 cm−1. Mass spectra were taken either on Thermo Focus DSQ II (electron ionization, 70 eV, ion source temperature 200 °C, gas chromatographic inlet with Varian FactorFour VF-5 ms column) or Thermo Trace DSQ (electron ionization, 70 eV, ion source temperature was 200 °C, direct inlet probe) spectrometers. HRMS spectra were recorded on an LC TOF (ES). Analytical TLC was performed on silica plates, Sorbfil. General Procedure for the Synthesis of the Initial Bis-furyl Dienes (1). 1,3-Bis(2-furyl)propane 1a (X = CH2) and di-α-furfuryl ether 1b (X = O) were obtained as described previously.6a Difurfuryl sulfide 1c (X = S) is a commercially available product. Difurfuryl sulfone 1d (X = SO2) and N-benzyldifurfuryl amine 1e (X = NBn) are known compounds,6a,8 but they were synthesized by modified methods as described below. All other N-acyl derivatives 1f−j are new. 2-2′-(Sulfonyldimethanediyl)difuran (1d). A suspension of metachloroperoxybenzoic acid (m-CPBA, 70% in water) (15.86 g, 0.064 mol) was added in portions to a solution of difurfuryl sulfide (5.0 g, 0.026 mol) in CH2Cl2 (200 mL) at 0 °C within 15 min. The mixture was stirred for another 24 h at rt. (Precipitation of m-chlorbenzoic acid was observed.) The reaction mixture was poured into water (100 mL) and basified to pH 8−9 with a 25% solution of NH3 in H2O; the organic layer was separated, and the water layer was extracted with CH2Cl2 (4 × 100 mL). The combined organic layers were washed with a saturated solution of Na2CO3 (4 × 100 mL), dried over MgSO4, filtered, and concentrated. Recrystallization of the residue from hexane/EtOAc gave sulfone 1d as a colorless powder (3.02 g, 0.014 mol, 53%). Rf 0.56 (EtOAc/hexane, 1:6, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.51 (2H, d, J = 1.8 Hz, H-5 and H-5′-Furyl), 6.58 (2H, br d, J = 3.2 Hz, H-3 and H-3′-Furyl), 6.45 (2H, dd, J = 1.8 and J = 3.2 Hz, H-4 and H-4′-Furyl), 4.30 (4H, s, CH2−N−CH2). 13C NMR (150 MHz, CDCl3): δ 144.2 (C-5 and C-5′), 142.3 (C-2 and C-2′), 112.7 (C-4 and C-4′), 111.5 (C-3 and C-3′), 51.4 (CH2−S(O2)-CH2). IR νmax/cm−1 (KBr): 3142, 2974, 1274, 754, 491. HRMS (ESI-TOF): calcd for C10H10O4S [M + H]+, 226.0300; found, 226.0314. N-Benzyl-1-(furan-2-yl)-N-(furan-2-ylmethyl)methanamine (1e). Powdered LiAlH4 (3.80 g, 0.10 mol) was added in small portions to a stirred solution of amide 1i (9.40 g, 0.0335 mol) in absolute THF (100 mL) at +10 °C under an argon atmosphere. The reaction mixture was heated at reflux for 12 h. Then EtOAc (30 mL) was added to the mixture at reflux; the reaction was cooled to 0 °C, and H2O (20 mL) was carefully added. After additional stirring at constant reflux (∼10 min) and following cooling to rt, the resulting suspension was filtered through silica gel, concentrated, and purified by silica gel column chromatography (Et2O) to give tertiary amine 1e as a yellow oil (6.87 g, 0.0257 mol, 77%). Rf 0.56 (EtOAc/hexane, 1:3, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.40−7.32 (5H, m, H-Ph), 7.31−7.23 (2H, m, H-5-Furyl and H-5′-Furyl), 6.33 (2H, br dd, J = 3.2 and J = 1.8 Hz, H-

Effect of the steric volume of the ester group in the dienophilic part was investigated in the final part of the work (Scheme 3). In general, this influence is difficult to predict precisely; however, it is possible to derive some conclusions. On going from methyl to ethyl ester of acetylene dicarboxylic acid, the chemoselectivity of the kinetically controlled reactions decreases distinctly (entries b/k and c/n, Table 3). The pincer

entry

Note

a

Heating at reflux in PhH with 1.5 mol excess of alkyne. bAccording to H NMR analysis of reaction mixtures (solids obtained after solvent removing). cHeating at reflux in o-Me2C6H4 with 1.1 mol excess of alkyne. dYields are given for crude reaction mixtures before crystallization. eAdducts 4m,p were not isolated due to polymerization of the reaction mixtures. 1

adducts 3 predominated in the reaction mixtures even in the case of cycloaddition of bulky tert-butyl ester. The reaction of bis-dienes 1b,c with tert-butyl ester at 80 °C (entries m and p) demonstrated a rather good chemoselectivity; the ratio of 3m/ 4m and 3p/4p was 88:12 and 71:29. Under thermodynamic conditions, the steric volume of the ester groups does not play any crucial role. The domino adducts 4 form in good yields, except for the tert-butyl ethers 4m,p. At 140 °C, due to lability of the tert-butyl ester groups, both reactions were accompanied by a degradation of the starting materials. (We could not isolate adducts 4m,p.) In conclusion, this work is a logical extension of the preceding researches by Lautens and Fillion,6a,b and it demonstrates unique chemospecificity in the tandem IMDA reaction. The above-mentioned reactions can be considered as an illustrative example of the total kinetic and thermodynamic control and can be useful both for educational and theoretical purposes. D

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry 4-Furyl and H-4′-Furyl), 6.23 (2H, br d, J = 3.2 Hz, H-3-Furyl and H3′-Furyl), 3.66 (4H, s, CH2−N−CH2), 3.61 (2H, s, NCH2Ph). HRMS (ESI-TOF): calcd for C17H17NO2 [M + H]+, 267.1259; found, 267.1271. N,N-Bis(furan-2-ylmethyl)acetamide (1f). Acetic anhydride (Ac2O, 18.70 mL, 0.197 mol) was added dropwise under intensive stirring to a solution of difurfuryl amine (10.0 g, 0.056 mol) in PhH (30 mL) at 0 °C within 30 min. The mixture was heated at reflux for 1 h and then was poured into water (100 mL) and basified to pH 8−9 with a 25% solution of NH3 in H2O. The organic layer was separated, and the water layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (Et2O) to give amide 1f as a light-brown viscous oil (10.58 g, 0.048 mol, 86%). Rf 0.76 (EtOAc/hexane, 1:2, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.38 (1H, dd, J = 0.8 and J = 1.7 Hz, H-5-Furyl), 7.35 (1H, dd, J = 0.8 and J = 1.7 Hz, H-5′-Furyl), 6.33 (1H, dd, J = 1.7 and J = 3.2 Hz, H-4Furyl), 6.31 (1H, dd, J = 1.7 and J = 3.2 Hz, H-4′-Furyl), 6.25 (1H, br d, J = 3.2 Hz, H-3-Furyl), 6.20 (1H, br d, J = 3.2 Hz, H-3′-Furyl), 4.58 (2H, s, CH2−N), 4.42 (2H, s, N−CH2), 2.26 (3H, s, CH3). 13C NMR (150 MHz, CDCl3): δ 170.3 (COCH3), 150.6 and 149.7 (C-2′ and C2), 142.4 and 142.0 (C-5 and C-5′), 113.6 and 110.1 (C-4 and C-4′), 108.5 and 107.9 (C-3 and C-3′), 44.2 and 40.4 (CH2−N−CH2), 21.4 (CH3). IR νmax/cm−1 (thin film): 2920, 1645. HRMS (ESI-TOF): calcd for C12H13NO3 [M + H]+, 219.0895; found, 219.0879. 2,2,2-Trifluoro-N,N-bis(furan-2-ylmethyl)acetamide (1g). Trifluoroacetic anhydride (9.4 mL, 0.068 mol) was added dropwise under intensive stirring to a mixture of bis(furan-2-ylmethyl)amine (10.0 g, 0.056 mol) and NEt3 (17.1 mL, 0.12 mol) in CH2Cl2 (80 mL) at 0 °C within 20 min. The mixture was stirred for another 2 h at rt. The reaction mixture was poured into a 2% solution of HCl in H2O (150 mL). The organic layer was separated, and the water layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/Et2O) to give amide 1g as a brown viscous oil (13.72 g, 0.050 mol, 89%). Rf 0.80 (EtOAc/hexane, 1:2, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.42 (1H, br d, J = 2.1 Hz, H-5-Furyl), 7.39 (1H, br d, J = 2.1 Hz, H-5′Furyl), 6.38 (1H, dd, J = 2.1 and J = 3.4 Hz, H-4-Furyl), 6.35−6.32 (3H, m, H-3, H-3′and H-4′-Furyl), 4.60 (2H, s, N−CH2), 4.57 (2H, s, N−CH2). 13C NMR (150 MHz, CDCl3): δ 156.8 (q, J = 36.1 Hz, CO−CF3), 148.4 (2C, C-2 and C-2′), 143.3 (2C, C-5 and C-5′), 116.5 (q, J = 287.6 Hz, CF3), 110.6 (2C, C-3 and C-3′), 110.0 (2C, C-4 and C-4′), 43.2 (2C, CH2−N−CH2). 19F NMR (282 MHz, CDCl3): δ −68.1 (s, CF3). IR νmax/cm−1 (thin film): 1670, 2941, 1146. HRMS (ESI-TOF): calcd for C12H10F3NO3 [M + H]+, 273.0613; found, 273.0621. 2,2,2-Trichloro-N,N-bis(furan-2-ylmethyl)acetamide (1h). 2,2,2Trichloroacetyl chloride (6.2 mL, 0.055 mol) was added dropwise under intensive stirring to a solution of bis(furan-2-ylmethyl)amine (8.85 g, 0.05 mol) and NEt3 (8.3 mL, 0.06 mol) in CH3CN (100 mL) at 0 °C within 10 min. The mixture was stirred for another 30 min at rt. The reaction mixture was poured into a 2% solution of HCl in H2O (150 mL). The organic layer was separated, and the water layer was extracted with EtOAc (3 × 80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by aluminum oxide column chromatography (hexane/Et2O) to give amide 1h as a colorless oil (13.2 g, 0.041 mol, 82%). Rf 0.43 (EtOAc/ hexane, 1:2, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.39 (2H, br s, H-5 and H-5′-Furyl), 6.35−6.29 (4H, m, H-3, H-3′, H-4 and H-4′Furyl), 4.94 (2H, br s, N−CH2), 4.58 (2H, br s, N−CH2). 13C NMR (100 MHz, CDCl3): δ 160.4 (NCOCCl3), 149.2 and 148.6 (C-2 and C-2′), 143.1 and 143.0 (C-5 and C-5′), 110.7 and 110.6 (C-3 and C3′), 109.8 (C-4 and C-4′), 93.0 (NCOCCl3), 46.1 (NCH2), 43.7 (NCH2). IR νmax/cm−1 (thin film): 1686, 2930, 1149. HRMS (ESITOF): calcd for C12H10Cl3NO3 [M + H]+, 320.9726; found, 320.9738. N,N-Bis(furan-2-ylmethyl)benzamide (1i). NaOH (2.68 g, 0.067 mol) was added to a suspension of bis(furan-2-ylmethyl)amine (10.0 g, 0.056 mol) in water (40 mL). The mixture was cooled to 0 °C, and benzoyl chloride (7.2 mL, 0.062 mol) was added dropwise under

intensive stirring within 15 min. The mixture was stirred for another 30 min at rt, poured into water (150 mL), and extracted with CH2Cl2 (3 × 80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Flash chromatography purification of the residue on silica gel (Et2O) yielded amide 1i as a light-yellow viscous oil (13.89 g, 0.050 mol, 89%). Rf 0.68 (EtOAc/hexane, 1:2, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.57− 7.55 (2H, m, H-5 and H-5′-Furyl), 7.42−7.41 (5H, m, H-Ph), 6.35− 6.20 (4H, m, H-3, H-4, H-3′, H-4′-Furyl), 4.70 (2H, br s, CH2−N), 4.39 (2H, br s, CH2−N). 13C NMR (100 MHz, CDCl3): δ 171.8 (COPh), 150.7 and 149.9 (C-2 and C-2′), 142.9 and 142.5 (C-5 and C-5′), 135.9 (C-1-Ph), 129.8 (C-4-Ph), 128.5 (2C, C-3-Ph and C-5Ph), 127.3 (2C, C-2-Ph and C-6-Ph), 110.5 (C-3 and C-3′), 109.1 (C4 and C-4′), 45.4 (CH2−N), 40.4 (CH2−N). IR νmax/cm−1 (thin film): 1640, 1013, 739. HRMS (ESI-TOF): calcd for C17H15NO3 [M + H]+, 281.1052; found, 281.1066. tert-Butyl Bis(furan-2-ylmethyl)carbamate (1j). Di-tert-butyl dicarbonate ((Boc)2O, 40.6 mL, 0.19 mol) was added dropwise under intensive stirring to a solution of bis(furan-2-ylmethyl)amine (30 g, 0.17 mol) in CH2Cl2 (250 mL) at rt within 30 min. The mixture was stirred for another 2 h at rt. The reaction mixture was poured into water (100 mL) and basified to pH 8−9 with a 25% solution of NH3 in H2O. The organic layer was separated, and the water layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (Et2O) to give amide 1j as a bright-yellow viscous oil (41.1 g, 0.15 mol, 87%). Rf 0.72 (EtOAc/ hexane, 1:6, Sorbfil). 1H NMR (400 MHz, CDCl3): δ 7.34 (2H, d, J = 1.8 Hz, H-5 and H-5′-Furyl), 6.31−6.29 (2H, m, H-4 and H-4′-Furyl), 6.20−6.14 (2H, m, H-3 and H-3′-Furyl), 4.41−4.34 (4H, m, CH2−N− CH2), 1.47 (9H, s, C(CH3)3). 13C (150 MHz, CDCl3): δ 155.3 (COC(CH3)3), 151.9 and 151.6 (C-2′ and C-2), 142.3 and 142.1 (C-5 and C-5′), 110.4 (2C, C-4 and C-4′), 108.4 and 107.6 (C-3 and C-3′), 80.4 (COC(CH3)3), 42.9 (CH2−N), 42.4 (CH2−N), 28.5 (C(CH3)3). IR νmax/cm−1 (thin film): 1699, 1163, 1011, 735. HRMS (ESI-TOF): calcd for C15H19NO4 [M + H]+, 277.1314; found, 277.1329. General Procedure for the Synthesis of the Pincer Adducts 3 (Method A). Dimethyl acetylenedicarboxylate (DMAD, 1.84 mL, 0.015 mol) was added to a solution of the appropriate bis-diene 1 (0.01 mol) in PhH (30 mL). The mixture was heated at reflux for 15.5−40 h at 80 °C (GC−MS monitoring until disappearance of the starting material). The reaction mixture was cooled and left overnight at room temperature. Further treatment of the resulting mixtures is given below. The isomer ratio of 3/4 (Table 1) was determined using 1H NMR analysis of the solids precipitating from reaction mixtures at cooling. (The mother liquors do not contain the target cycloadducts.) When adducts 3 did not precipitate from the reaction solutions, the volatiles were removed under reduced pressure and the obtained crude solids were analyzed by NMR. Dimethyl (1RS,3aSR,6aRS,9SR)-5,6-Dihydro-1H,4H,9H-1,3a:6a,9diepoxyphenalene-9a,9b-dicarboxylate (3a). The precipitated crystals were filtered off and recrystallized from hexane/EtOAc to give compound 3a as a white powder (1.78 g, 5.6 mmol, 58%). Rf 0.62 (EtOAc/hexane, 1:3, Sorbfil). Mp: 151.8−153.4 °C (from hexane/ EtOAc). 1H NMR (600 MHz, CDCl3): δ 6.55 (2H, dd, J = 1.5 and J = 5.3 Hz, H-2 and H-8), 6.47 (2H, d, J = 5.3 Hz, H-3 and H-7), 5.05 (2H, d, J = 1.5 Hz, H-1 and H-9), 3.61 (3H, s, CO2Me), 3.60 (3H, s, CO2Me), 2.16 (4H, dd, J = 3.8 and J = 8.8 Hz, H-4 and H-6), 2.01− 1.93 (1H, m, H-5A), 1.72−1.68 (1H, m, H-5B). 13C NMR (150 MHz, CDCl3): δ 171.0 (CO2Me), 170.8 (CO2Me), 142.2 (2C, C-3 and C-7), 138.4 (2C, C-2 and C-8), 90.0 (2C, C-3a and C-6a), 83.5 (2C, C-1 and C-9), 73.4 and 68.6 (2C, C-9b and C-9a), 52.0 (CO2Me), 51.9 (CO2Me), 25.7 (2C, C-4 and C-6), 17.1 (C-5). Dimethyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9a-Diepoxybenzo[de]isochromene-6a,9b(1H,3H)-dicarboxylate (3b). The precipitated crystals were filtered off and recrystallized from EtOH (30 mL) to give the pure compound 3b as colorless prisms (1.86 g, 5.8 mmol, 58%). Rf 0.64 (EtOAc/hexane, 1:1, Sorbfil). Mp: 168.4−169.2 °C (from EtOH). 1H NMR (600 MHz, DMSO-d6): δ 6.63 (2H, dd, J = 2.1 and J E

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry = 5.5 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.14 (2H, d, J = 2.1 Hz, H-6 and H-7), 4.13 (2H, d, J = 13.1 Hz, H-1A and H-3A), 4.03 (2H, d, J = 13.1 Hz, H-1B and H-3B), 3.51 (6H, s, 2 × CO2Me). 13C NMR (150 MHz, DMSO-d6): δ 170.5 (CO2Me), 170.3 (CO2Me), 141.9 (2C, C-5 and C-8), 138.2 (2C, C-4 and C-9), 87.5 (2C, C-6 and C-7), 83.6 and 83.5 (2C, C-3a and C-9a), 71.0 and 64.3 (2C, C-6a and C-9b), 67.6 (2C, C-1 and C-3), 52.6 (CO2Me), 52.4 (CO2Me). IR νmax/cm−1 (KBr): 3055, 2956, 1736, 1715. HRMS (ESITOF): calcd for C16H16O7 [M + H]+, 320.0896; found, 320.0889. Dimethyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9a-Diepoxybenzo[de]isothiochromene-6a,9b(1H,3H)-dicarboxylate (3c). The precipitated crystals were filtered off and recrystallized from an EtOAc/EtOH mixture to give the pure compound 3c as colorless needles (2.01 g, 6.0 mmol, 60%). Rf 0.53 (EtOAc/hexane, 1:2, Sorbfil). Mp: 177.3−178.4 °C (with decomp from EtOAc/EtOH). 1H NMR (600 MHz, DMSOd6): δ 6.58 (2H, dd, J = 1.4 and J = 5.5 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.09 (2H, d, J = 1.4 Hz, H-6 and H-7), 3.52 (3H, s, CO2Me), 3.51 (3H, s, CO2Me), 3.48 (2H, d, J = 15.1 Hz, H-1A and H-3A), 2.84 (2H, d, J = 15.1 Hz, H-1B and H-3B). 13C NMR (150 MHz, DMSO-d6): δ 170.5 (CO2Me), 170.4 (CO2Me), 141.9 (C-4), 141.8 (C-9), 139.7 (2C, C-5 and C-8), 87.2 (2C, C-6 and C-7), 83.1 and 83.0 (2C, C-3a and C-9a), 73.4 and 67.4 (2C, C-9b and C-6a), 52.5 (CO2Me), 52.4 (CO2Me), 26.8 (2C, C-1 and C-3). IR νmax/cm−1 (KBr): 2983, 2948, 1740, 1706, 1091, 1010. HRMS (ESI-TOF): calcd for C16H16SO6 [M + H]+, 336.0668; found, 336.0679. Dimethyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9a-Diepoxybenzo[de]isothiochromene-6a,9b(1H,3H)-dicarboxylate 2,2-Dioxide (3d). The precipitated crystals were filtered off and recrystallized from EtOH (∼60 mL) to give the pure compound 3d as colorless needles (1.99 g, 5.4 mmol, 54%). Rf 0.47 (EtOAc/EtOH, 1:2, Sorbfil). Mp: 274.2−276 °C (with decomp from EtOH). 1H NMR (600 MHz, DMSO-d6): δ 6.65 (2H, dd, J = 1.6 and J = 5.5 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.19 (2H, d, J = 1.6 Hz, H-6 and H7), 4.10 (2H, d, J = 15.1 Hz, H-1A and H-3A), 3.80 (2H, d, J = 15.1 Hz, H-1B and H-3B), 3.57 (3H, s, CO2Me), 3.53 (3H, s, CO2Me). 13C NMR (150 MHz, DMSO-d6): δ 168.6 (CO2Me), 168.5 (CO2Me), 139.4 (C-4 and C-5), 138.9 (C-5 and C-8), 87.9 (C-3a and C-9a), 83.1 (C-6 and C-7), 72.8 and 67.0 (C-9b and C-6a), 51.5 (C-1 and C-3), 51.3 (2 × CO2Me). IR νmax/cm−1 (KBr): 2993, 2949, 1735, 1711, 1129. HRMS (ESI-TOF): calcd for C16H16SO8 [M + H]+, 368.0566; found, 368.0553. Dimethyl (3aRS,6SR,7RS,9aSR)-2-Benzyl-2,3-dihydro-1H,6H,7H3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3e). The precipitated crystals were filtered off and recrystallized from hexane/EtOAc to give the pure compound 3e as a light-brown powder (2.74 g, 6.7 mmol, 67%). Rf 0.56 (EtOAc/hexane, 2:1, Sorbfil). Mp: 161.7−162.0 °C (from hexane/EtOAc). 1H NMR (400 MHz, CDCl3): δ 7.37−7.22 (5H, m, H-Ph), 6.59 (2H, dd, J = 1.6 and J = 5.6 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.6 Hz, H-4 and H-9), 5.12 (2H, d, J = 1.6 Hz, H-6 and H-7), 3.81 (2H, br s, NCH2Ph), 3.60 (3H, s, CO2Me), 3.54 (3H, s, CO2Me), 3.32 (2H, d, J = 13.1 Hz, H-1A and H-3B), 3.00 (2H, br d, J = 13.1 Hz, H-1B and H-3B). 13C NMR (100 MHz, CDCl3): δ 170.5 (CO2Me), 170.4 (CO2Me), 139.8 (C-5 and C8), 139.1 (C-4 and C-9), 137.0 (C-1-Ph), 129.4 (C-2-Ph and C-6-Ph), 128.2 (C-3-Ph and C-5-Ph), 127.2 (C-1-Ph), 88.4 (C-3a and C-9a), 83.8 (C-6 and C-7), 72.0 and 67.8 (C-9b and C-6a), 62.5 (NCH2Ph), 52.0 (CO2Me), 51.9 (CO2Me), 50.7 (C-1 and C-3). IR νmax/cm−1 (KBr): 3447, 2951, 2782, 1734, 1708, 1237. HRMS (ESI-TOF): calcd for C23H23NO6 [M + H]+, 409.1525; found, 409.1517. Dimethyl (3aRS,6SR,7RS,9aSR)-2-Acetyl-2,3-dihydro-1H,6H,7H3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3f). The solvent was removed under reduced pressure. The residue (brown oil) was triturated with ether. The obtained crystals were filtered off and recrystallized from an EtOAc/EtOH mixture to give the pure compound 3f as light-brown rhombic crystals (2.20 g, 6.1 mmol, 61%). Rf 0.49 (EtOAc/EtOH, 8:1, Sorbfil). Mp: 144.7−145.3 °C (from EtOAc/EtOH). 1H NMR (600 MHz, CDCl3): δ 6.70 (1H, dd, J = 1.4 and J = 5.5 Hz, H-5), 6.67 (1H, dd, J = 1.4 and J = 5.5 Hz, H-8), 6.49 (1H, d, J = 5.5 Hz, H-4), 6.44 (1H, d, J = 5.5 Hz, H-9), 5.25 (1H, dd, J = 1.4 and J = 14.8 Hz, H-1A), 5.10 (2H, d, J = 1.4 Hz, H-6

and H-7), 4.25 (1H, dd, J = 1.4 and J = 14.8 Hz, H-3A), 4.00 (1H, d, J = 14.8 Hz, H-3B), 3.62 (6H, s, 2 × CO2Me), 3.34 (1H, d, J = 14.8 Hz, H-1B), 2.17 (3H, s, N−Ac). 13C NMR (100 MHz, CDCl3): δ 170.9 (2 × CO2Me), 170.3 (N-COMe), 140.9 (C-5 and C-8), 137.9 (C-4 and C-9), 87.7 (C-3a and C-9a), 83.6 (C-6 and C-7), 71.3 and 68.8 (C-6a and C-9b), 52.3 (2 × CO2Me), 45.7 and 40.6 (C-1 and C-3), 22.0 (NCOMe). IR νmax/cm−1 (KBr): 3096, 3009, 3010, 1711, 1640. HRMS (ESI-TOF): calcd for C18H19NO7 [M + H]+, 361.1162; found, 361.1179. Dimethyl (3aRS,6SR,7RS,9aSR)-2-(Trifluoroacetyl)-2,3-dihydro1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3g). The solvent was removed under reduced pressure. The residue (brown oil) was triturated with ether. Obtained crystals were filtered off and recrystallized from hexane/EtOAc to give the pure compound 3g as a white powder (2.57 g, 6.2 mmol, 62%). Rf 0.56 (EtOAc/hexane, 2:1, Sorbfil). Mp: 194.2−194.9 °C (from hexane/ EtOAc). 1H NMR (400 MHz, CDCl3): δ 6.74−6.71 (2H, m, H-4 and H-9), 6.46 (2H, dd, J = 2.3 and J = 5.5 Hz, H-5 and H-8), 5.14 (2H, br s, H-6 and H-7), 5.10 (1H, d, J = 14.9 Hz, H-1A), 4.43 (1H, br d, J = 14.9 Hz, H-3A), 4.08 (1H, d, J = 14.9 Hz, H-3B), 3.64 (6H, s, 2 × CO2Me), 3.59 (1H, d, J = 14.9, H-1B). 13C NMR (100 MHz, CDCl3): δ 170.1 (2 × CO2Me), 157.2 (q, J = 35.5 Hz, F3C-C), 141.2 (C-5 and C-8), 137.5 (C-4 and C-9), 116.4 (q, J = 288.1 Hz, CF3), 87.1 (C-3a and C-9a), 83.8 (C-6 and C-7), 71.4 and 68.8 (C-9 and C-6a), 52.4 (2 × CO2Me), 44.8 (q, J = 3.8 Hz, C-1), 42.4 (C-3). 19F NMR (282 MHz, CDCl3): δ −67.7 (s, CF3). IR νmax/cm−1 (KBr): 3109, 3055, 2956, 1713, 1688, 1197. HRMS (ESI-TOF): calcd for C18H16F3NO7 [M + H]+, 415.0879; found, 415.0889. Dimethyl (3aRS,6SR,7RS,9aSR)-2-(Trichloroacetyl)-2,3-dihydro1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3h). The solvent was removed under reduced pressure. Obtained crystals were recrystallized from an EtOAc/DMF mixture to give the pure compound 3h as coarse colorless prisms (2.59 g, 5.6 mmol, 56%). Rf 0.55 (from EtOAc/hexane, 1:2, Sorbfil). Mp: 194.8− 195.2 °C (with decomp, EtOAc/DMF). 1H NMR (400 MHz, CDCl3): δ 6.72 (2H, dd, J = 1.4 and J = 5.6 Hz, H-5 and H-8), 6.47 (2H, d, J = 5.6 Hz, H-4 and H-9), 5.14 (2H, br d, J = 1.4 Hz, H-6 and H-7), 5.11 (2H, d, J = 14.5 Hz, H-1 and H-3), 3.85 (2H, br d, J ∼ 14.5 Hz, H-1 and H-3), 3.63 (6H, s, 2 × CO2Me). 13C NMR (100 MHz, DMSO-d6): δ 170.1 (CO2Me), 170.0 (CO2Me), 160.9 (NCOCCl3), 141.0 (C-5 and C-8), 137.8 (C-4 and C-9), 92.9 (NCOCCl3), 87.2 (C-3a and C-9a), 83.9 (C-6 and C-7), 71.3 and 68.4 (C-6a and C-9b), 52.4 (CO2Me), 52.3 (CO2Me), 46.6 and 44.4 (C-1 and C-3). IR νmax/cm−1 (KBr): 2997, 2951, 1741, 1686, 1288. HRMS (ESI-TOF): calcd for C18H16Cl3NO7 [M + H]+, 462.9992; found, 462.9977. Dimethyl (3aRS,6SR,7RS,9aSR)-2-Benzoyl-2,3-dihydro-1H,6H,7H3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3i). The precipitated crystals were filtered off and recrystallized from an EtOH/DMF mixture to give the pure compound 3i as a colorless powder (3.25 g, 7.7 mmol, 77%). Rf 0.71 (EtOAc, Sorbfil). Mp: 174.3−175.1 °C (from EtOH/DMF). 1H NMR (400 MHz, CDCl3): δ 7.53−7.52 (2H, m, H-2′ and 6′-Ph), 7.38−7.36 (3H, m, H-3′, H-4′, H5′-Ph), 6.70 (1H, br s, H-5), 6.67 (1H, br s, H-8), 6.51 (1H, br s, H-4), 6.35 (1H, br s, H-9), 5.33 (1H, d, J = 14.0 Hz, H-1A), 5.16−5.13 (2H, m, H-6 and H-7), 4.31 (1H, d, J = 14.0 Hz, H-3A), 3.90 (1H, d, J = 14.0 Hz, H-3B), 3.62 (6H, s, 2 × CO2Me), 3.63 (1H, br d, J = 14.0 Hz, H-1B). 13C NMR (150 MHz, CDCl3): δ 172.1 (CO-Ph), 170.2 (2 × CO2Me), 140.8 (C-4), 140.6 (C-9), 138.4 (C-5), 138.0 (C-8), 135.7 (C-1′-Ph), 129.7 (C-4′-Ph), 128.4 (C-3′-Ph and C-5′-Ph), 127.8 (C2′-Ph and C-6′-Ph), 87.6 (C-3a and C-9a), 83.8 (C-6 and C-7), 70.3 (C-6a and C-9b), 52.3 (2 × CO2Me), 46.7 and 41.2 (C-1 and C-3). IR νmax/cm−1 (KBr): 2954, 1736, 1749, 1631, 1077, 1055. HRMS (ESITOF): calcd for C23H21NO7 [M + H]+, 423.1318; found, 423.1326. 2-tert-Butyl 6a,9b-Dimethyl (3aRS,6SR,7RS,9aSR)-1H,6H,7H3a,6:7,9a-Diepoxybenzo[de]isoquinoline-2,6a,9b(3H)-tricarboxylate (3j). The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (hexane/EtOAc = 9:1) to give compound 3j as a colorless powder (2.09 g, 5.2 mmol, 52%). Rf 0.72 (EtOAc/hexane, 1:6, Sorbfil). Mp: 117.7−118.3 °C (from F

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry hexane/EtOAc). 1H NMR (400 MHz, CDCl3): δ 6.67 (2H, dd, J = 1.4 and J = 5.5 Hz, H-5 and H-8), 6.46 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.10 (2H, br s, H-6 and H-7), 4.73 (1H, br d, J = 14.0 Hz, H-1A), 4.57 (1H, br d, J = 14.0 Hz, H-3A), 3.66 (1H, br d, J = 14.0 Hz, H-3B), 3.61 (6H, s, 2 × CO2Me), 3.51−3.47 (1H, d, J = 14.0 Hz, H-1B), 1.46 (9H, s, CO2C(CH3)3). 13C NMR (150 MHz, CDCl3): δ 170.5 (CO2Me), 170.3 (CO2Me), 155.6 (NCO2tBu), 140.4 (C-4), 140.3 (C-9), 138.7 (C-5 and C-8), 87.5 (NCO2C(CH3)3), 83.8 (C-6 and C-7), 80.5 (C-3a and C-9a), 71.7 and 68.4 (C-9b and C-6a), 52.3 (CO2Me), 52.2 (CO2Me), 43.4 and 42.2 (C-1 and C-3), 28.3 (NCO2C(CH3)3). IR νmax/cm−1 (KBr): 2971, 1710, 1694, 1284. HRMS (ESI-TOF): calcd for C21H25NO8 [M + H]+, 419.1580; found, 419.1591. General Procedure for the Synthesis of the Pincer Adducts 3a−c and 3e−g (Method B). Cycloadducts 3a−c and 3e−g were also obtained according to the procedure described previously.6a A solution of DMAD (1.47 mL, 0.012 mol) and 3 (0.010 mol) in Et2O (10.0 mL) was left at rt for 3 weeks. The precipitated crystals were filtered off and washed with Et2O. According to the 1H NMR data, the obtained powders did not need additional purification. Yields of compounds 3f and 3g are given below as an example. The yields of the remaining adducts 3a−c and 3e are given in Table 1. Dimethyl (3aRS,6SR,7RS,9aSR)-2-Acetyl-2,3-dihydro-1H,6H,7H3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3f). The precipitate from Et2O crystals were filtered off and recrystallized from an EtOAc/EtOH mixture to give compound 3f as light-yellow crystals (1.95 g, 5.4 mmol, 54%). Dimethyl (3aRS,6SR,7RS,9aSR)-2-(Trifluoroacetyl)-2,3-dihydro1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-6a,9b-dicarboxylate (3g). The precipitate from Et2O crystals were filtered off and recrystallized from hexane/EtOAc to give compound 3g as a white powder (2.37 g, 5.7 mmol, 57%). General Procedure for the Synthesis of the Domino Adducts 4. Dimethyl acetylenedicarboxylate (DMAD, 1.35 mL, 0.011 mol) was added to a solution of the appropriate diene 1 (0.010 mol) in oMe2C6H4 (30 mL). The mixture was heated at reflux for 3−7 h at 140 °C (TLC monitoring). The reaction mixture was cooled and left overnight at room temperature. Further treatment of the resulting mixtures is given below. Dimethyl (1RS,3aSR,6aSR,9RS,9aSR,9bRS)-5,6,9a,9b-Tetrahydro1H,4H,9H-1,3a:6a,9-diepoxyphenalene-2,3-dicarboxylate (4a). The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to give compound 4a as colorless prisms (2.16 g, 6.8 mmol, 68%). Rf 0.62 (EtOAc/hexane, 2:5, Sorbfil). Mp: 138.1−139.3 °C (hexane/EtOAc). 1 H NMR (400 MHz, CDCl3): δ 6.43 (1H, dd, J = 1.8 and J = 5.6 Hz, H-8), 6.27 (1H, d, J = 5.6 Hz, H-9), 5.09 (1H, s, H-1), 4.88 (1H, d, J = 1.8 Hz, H-9), 3.78 (3H, s, CO2Me), 3.73 (3H, s, CO2Me), 2.23−2.17 (3H, m, H-4A, H-6A and H-9a), 2.00−1.88 (4H, m, H-4B, H-6B, H5A and H-9b), 1.71−1.68 (1H, m, H-5B). 13C NMR (100 MHz, CDCl3): δ 164.7 (CO2Me), 162.6 (CO2Me), 150.6 (C-3), 143.8 (C2), 140.8 (C-7), 138.5 (C-8), 89.3 (C-3a), 85.8 (C-6a), 81.3 (C-1), 80.5 (C-9), 52.2 (C-9a), 52.0 (2 × CO2Me), 49.8 (C-9b), 26.7 (C-9), 25.0 (C-6), 17.2 (C-5). IR νmax/cm−1 (KBr): 1709, 1628, 1284, 1261. HRMS (ESI-TOF): calcd for C17H18O6 [M + H]+, 318.1103; found, 318.1125. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro-6H,7H3a,6:7,9a-diepoxybenzo[de]isochromene-4,5(1H,3H)-dicarboxylate (4b). The precipitated crystals were filtered off and recrystallized from EtOH (30 mL) to give the pure compound 4b as bright-yellow needles (2.40 g, 7.5 mmol, 75%). Rf 0.66 (EtOAc, Sorbfil). Mp: 167.9−169.1 °C (from EtOH). 1H NMR (600 MHz, DMSO-d6): δ 6.53 (1H, dd, J = 2.0 and J = 5.8 Hz, H-8), 6.41 (1H, d, J = 5.8 Hz, H9), 5.19 (1H, s, H-6), 4.97 (1H, d, J = 2.0 Hz, H-7), 4.15 (1H, d, J = 13.1 Hz, H-3A), 4.11 (1H, d, J = 12.4 Hz, H-1B), 4.03 (1H, d, J = 12.4 Hz, H-1B), 3.98 (1H, d, J = 13.1 Hz, H-3B), 3.73 (6H, s, 2 × CO2Me), 2.15 and 2.01 (2H, d, J = 6.2 Hz, H-6a and H-9b). 13C NMR (150 MHz, CDCl3): δ 163.5 (CO2Me), 162.8 (CO2Me), 146.9 (C-4), 146.5 (C-5), 139.4 (C-8), 137.7 (C-9), 86.5 and 83.8 (C-3a and C-9a), 82.3 (C-6), 81.1 (C-7), 66.2 and 64.6 (C-1 and C-3), 52.6 (CO2Me), 52.4 (CO2Me), 50.4 and 48.8 (C-6a and C-9b). IR νmax/cm−1 (KBr): 1731,

1712, 1272, 975. HRMS (ESI-TOF): calcd for C16H16O7 [M + H]+, 320.0896; found, 320.0883. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro-6H,7H3a,6:7,9a-diepoxybenzo[de]isothiochromene-4,5-(1H,3H)-dicarboxylate (4c). The precipitated crystals were filtered off and recrystallized from DMF (∼25 mL) to give the pure compound 4c as small colorless needles (3.12 g, 9.3 mmol, 93%). Rf 0.75 (EtOAc, Sorbfil). Mp: 216.3217.8 °C (with decomp from DMF). 1H NMR (600 MHz, DMSO): δ 6.53 (1H, br d, J = 4.8 Hz, H-8), 6.31 (1H, d, J = 4.8 Hz, H-9), 5.13 (1H, s, H-6), 4.90 (1H, s, H-7), 3.70 (6H, s, 2 × CO2Me), 3.41 (1H, d, J = 15.1 Hz, H-1A), 3.38 (1H, d, J = 15.1 Hz, H-3A), 2.83 (2H, m, H-1B and H-3B), 2.15 and 1.83 (2H, d, J = 5.5 Hz, H-6a and H-9b). 13 C NMR (100 MHz, CDCl3): δ 164.2 (CO2Me), 162.5 (CO2Me), 148.7 (C-5), 145.8 (C-4), 139.9 (C-8), 140.0 (C-9), 86.5 and 83.3 (C9a and C-3a), 81.6 (C-6), 80.7 (C-7), 52.9 (CO2Me), 52.7 (CO2Me), 52.6 and 48.8 (C-9b and C-6a), 28.8 and 27.0 (C-3 and C-1). IR νmax/ cm−1 (KBr): 1732, 1715, 1277, 984. HRMS (ESI-TOF): calcd for C16H16O6S [M + H]+, 336.0668; found, 336.0684. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro-6H,7H3a,6:7,9a-diepoxybenzo[de]isothiochromene-4,5-(1H,3H)-dicarboxylate 2,2-Dioxide (4d). The precipitated crystals were filtered off and recrystallized from DMF (∼20 mL) to give adduct 4d as a white powder (2.58 g, 7.0 mmol, 70%). Rf 0.42 (EtOAc/EtOH, 2:1, Sorbfil). Mp: 268.4−269.6 °C (with decomp from DMF). 1H NMR (600 MHz, DMSO-d6): δ 6.61 (1H, dd, J = 1.4 and J = 5.7 Hz, H-8), 6.37 (1H, d, J = 5.7 Hz, H-9), 5.20 (1H, s, H-6), 4.99 (1H, d, J = 1.4 Hz, H-7), 4.18 (1H, d, J = 14.6 Hz, H-1A), 4.08 (1H, d, J = 14.6 Hz, H-3A), 3.78 (3H, s, CO2CH3), 3.76 (3H, s, CO2CH3), 3.70 (1H, dd, J = 2.5 and J = 14.6 Hz, H-1B), 3.63 (1H, dd, J = 2.5 and J = 14.6 Hz, H-3B), 2.38 and 2.32 (2H, d, J = 6.4 Hz, H-9b and H-6a). 13C NMR (100 MHz, CDCl3): δ 161.7 (2 × CO2Me), 152.5 (C-4), 146.1 (C-5), 138.8 (C8), 138.5 (C-9), 86.3 (C-6), 83.9 (C-7), 81.0 and 79.8 (C-3a and C9a), 52.2 (2 × CO2CH3), 51.6 (C-1), 51.5 and 50.2 (C-6a and C-9b), 47.4 (C-3). IR νmax/cm−1 (KBr): 1734, 1717, 1278, 1133. HRMS (ESI-TOF): calcd for C16H16O8S [M + H]+, 368.0566; found, 368.0538. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-2-Benzyl-2,3,6a,9b-tetrahydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-4,5-dicarboxylate (4e). The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 3/1) to give compound 4e as light-yellow crystals (2.99 g, 7.3 mmol, 73%). Rf 0.51 (EtOAc/hexane, 1:1, Sorbfil). 1H NMR (600 MHz, CDCl3): δ 7.36 (2H, br d, J = 7.4 Hz, H-2-Ph and H-6-Ph), 7.32 (2H, t, J = 7.4 Hz, H-3-Ph and H-5-Ph), 7.25 (1H, br t, J = 7.4 Hz, H-4-Ph), 6.48 (1H, dd, J = 1.4 and J = 6.2 Hz, H-8), 6.31 (1H, d, J = 6.2 Hz, H-9), 5.22 (1H, s, H-6), 5.01 (1H, d, J = 1.4 Hz, H7), 3.84 (1H, d, J = 13.4 Hz, N-CH2A−Ph), 3.82 (1H, d, J = 13.4 Hz, N-CH2B−Ph), 3.80 (3H, s, CO2Me), 3.76 (3H, s, CO2Me), 3.44 (1H, d, J = 13.1 Hz, H-1A), 3.42 (1H, d, J = 13.1 Hz, H-3A), 2.85 (1H, d, J = 13.1 Hz, H-1B), 2.73 (1H, d, J = 13.1 Hz, H-3B), 2.25 and 1.96 (1H and 1H, d and d, J = 6.2 Hz, H-6a and H-9b). 13C NMR (100 MHz, CDCl3): δ 164.1 (CO2Me), 162.6 (CO2Me), 149.0 (C-4), 144.7 (C5), 139.2 (C-9), 138.8 (C-8), 136.6 (C-1-Ph), 129.4 (C-2-Ph and C-6Ph), 128.3 (C-3-Ph and C-5-Ph), 127.4 (C-4-Ph), 87.6 and 84.5 (C-3a and C-9a), 81.7 (C-6), 80.8 (C-7), 62.4 (N-CH2−Ph), 52.3 (CO2Me), 52.2 (CO2Me), 51.9 (C-1), 50.8 and 49.3 (C-6a and c-9b), 50.2 (C-3). IR νmax/cm−1 (KBr): 1726, 1627, 1316, 1142. HRMS (ESI-TOF): calcd for C23H23NO6 [M + H]+, 409.1525; found, 409.1539. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-2-Acetyl-2,3,6a,9b-tetrahydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-4,5-dicarboxylate (4f). The precipitated crystals were filtered off and recrystallized from DMF to give the pure compound 4f as a brightyellow powder (3.14 g, 8.7 mmol, 87%). Rf 0.44 (EtOAc/EtOH, 8:1, Sorbfil). Mp: 126.9−127.6 °C (from DMF). 1H NMR (600 MHz, CDCl3), the mixture of amide rotamers in the ratio 1:1.1: δ 6.57 and 6.51 (1H, dd, J = 0.6 and J = 6.2 Hz, H-8), 6.39 and 6.38 (1H, d, J = 6.2 Hz, H-9), 5.34 (1H, d, J = 14.4 Hz, H-1A), 5.18 and 5.17 (1H, s, H-6), 5.01 (1H, br d, J = 0.6 Hz, H-7), 4.37 and 4.34 (1H, d, J = 14.4 Hz, H-3A), 3.92 and 3.72 (1H, d, J = 14.4 Hz, H-1B), 3.84 and 3.82 (3H, s, CO2Me), 3.81 and 3.79 (3H, s, CO2Me), 3.33 and 3.15 (1H, d, J = 14.4 Hz, H-3B), 2.30, 2.27, 2.15, and 2.13 (2H, d, J = 6.2 Hz, H-6a G

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry and 6−9b), 2.19 and 2.18 (3H, s, CO2Me). 13C NMR (150 MHz, CDCl3), the mixture of amide rotamers: δ 171.0 and 170.8 (NCOCH3), 163.7 and 163.3 (CO2Me), 162.7 and 162.6 (CO2Me), 147.1 and 147.2 (C-5), 146.2 and 146.1 (C-4), 139.9 and 139.8 (C-9), 138.2 and 137.9 (C-8), 86.8, 86.7, and 83.9 (C-3a and C-9a), 82.1 and 81.8 (C-6), 80.9 and 80.7 (C-7), 52.6 and 52.5 (CO2Me), 52.5 and 52.4 (CO2Me), 50.7 and 50.1 (C-9b and C-6a), 46.7, 45.5, 41.8, and 40.3 (C-1 and C-3), 21.9 (N-COMe). IR νmax/cm−1 (KBr): 2956, 1714, 1736, 1640, 1302, 1248. HRMS (ESI-TOF): calcd for C18H19NO7 [M + H]+, 361.1162; found, 361.1140. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-2-(Trifluoroacetyl)2,3,6a,9b-tetrahydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-4,5-dicarboxylate (4g). The solvent was removed under reduced pressure. The residue (viscous brown oil) was triturated with Et2O. Obtained crystals were filtered off and recrystallized from hexane/EtOAc to give the pure compound 4g as a bright-yellow powder (3.86 g, 9.3 mmol, 93%). Rf 0.57 (EtOAc/hexane, 2:1, Sorbfil). Mp: 146.7−147.9 °C (from EtOAc). 1H NMR (400 MHz, CDCl3), the mixture of amide rotamers in the ratio 1:1: δ 6.60 and 6.66 (1H, br dd, J = 1.6 and J = 5.5 Hz, H-8), 6.41 and 6.39 (1H, d, J = 5.5 Hz, H9), 5.23 and 5.17 (1H, d, J = 14.7 Hz, H-1A), 5.20 and 5.19 (1H, s, H6), 5.03 (1H, br s, H-7), 4.54 and 4.50 (1H, d, J = 14.7 Hz, H-3A), 4.06 and 3.79 (1H, d, J = 14.7 Hz, H-1B), 3.84 and 3.83 (3H, s, CO2Me), 3.82 and 3.81 (3H, s, CO2Me), 3.64 and 3.39 (1H, d, J = 14.7 Hz, H-3B), 2.36, 2.34, 2.20, and 2.19 (2H, d, J = 6.4 Hz, H-6a and H-9b). 13C NMR (100 MHz, CDCl3), the mixture of amide rotamers: δ 163.2 and 163.0 (CO2Me), 162.6 and 162.5 (CO2Me), 157.2 and 157.1 (q, J = 36.4 Hz, N-COCF3), 147.9 and 147.1 (C-5), 145.7 and 145.0 (C-4), 140.1 and 139.7 (C-9), 137.6 and 137.3 (C-8), 116.3 (q, J = 288.5 Hz, N-COCF3), 85.9, 85.6, 83.3, and 83.2 (C-3a and C-9a), 82.1 and 82.0 (C-6), 80.9 and 80.8 (C-7), 52.6 and 52.5 (CO2Me), 52.4 and 52.3 (CO2Me), 51.0, 50.9, and 50.1 (C-3 and C-1), 45.8, 44.5, 43.7, and 42.3 (C-9b and C-6a). 19F NMR (282 MHz, CDCl3), mixture of amide rotamers: δ −68.4 (s, CF3), −68.5 (s, CF3). IR νmax/ cm−1 (KBr): 2955, 1739, 1690, 1333, 1245. HRMS (ESI-TOF): calcd for C18H16F3NO7 [M + H]+, 415.0879; found, 415.0855. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-2-(Trichloroacetyl)2,3,6a,9b-tetrahydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-4,5-dicarboxylate (4h). The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 2:1) to give the title compound as a brown solid. The obtained crystals were recrystallized from EtOAc to give adduct 4h as small colorless needles (3.38 g, 7.31 mmol, 73%). Rf 0.41 (EtOAc/hexane, 1:2, Sorbfil). Mp: 179.8−181.0 °C (from hexane/EtOAc). 1H NMR (600 MHz, DMSO-d6): δ 6.57 (1H, dd, J = 1.4 and J = 5.3 Hz, H-8), 6.51 (1H, d, J = 5.3 Hz, H-9), 5.20 (1H, s, H6), 4.96 (1H, d, J = 1.4 Hz, H-7), 4.93 (1H, br d, J = 14.4 Hz, H-3A), 4.87 (1H, br d, J = 14.4 Hz, H-1A), 4.13 (1H, br d, J = 14.4 Hz, H-3B), 3.77 (1H, br d, J = 14.4 Hz, H-1B), 3.75 (3H, br s, CO2Me), 3.73 (3H, br s, CO2Me), 2.22 and 2.13 (1H and 1H, d and d, J = 6.2 Hz, H-6a and H-9b). 13C NMR (100 MHz, CDCl3): δ 163.2 (CO2Me), 162.6 (CO2Me), 160.9 (N-COCCl3), 146.9 (C-4), 145.9 (C-5), 139.7 (C-8), 137.9 (C-9), 92.9 (N-COCCl3), 86.0 and 83.5 (C-3a and C-9a), 81.1 (C-6), 80.9 (C-7), 52.6 (CO2Me), 52.5 (CO2Me), 50.8 and 49.9 (C-6a and C-9b), 46.7 and 45.1 (C-1 and C-3). IR νmax/cm−1 (KBr): 2954, 1741, 1711, 1676, 1238. HRMS (ESI-TOF): calcd for C18H16Cl3NO7 [M + H]+, 462.9992; found, 462.9976. Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-2-Benzoyl-2,3,6a,9btetrahydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline-4,5dicarboxylate (4i). The solvent was removed under reduced pressure. The residue (viscous brown oil) was triturated with Et2O. The precipitated crystals were filtered off and recrystallized from an EtOH/ DMF mixture to give the pure compound 4i as a bright-yellow powder (3.68 g, 8.7 mmol, 87%). Rf 0.36 (EtOAc/hexane, 4:1, Sorbfil). Mp: 193.0−194.1 °C (from EtOH/DMF). 1H NMR (600 MHz, CDCl3), all signals broaden due to restricted C−N amide bond rotation: δ 7.56−7.54 (2H, m, H-2-Ph and H-6-Ph), 7.38−7.37 (3H, m, H-3-Ph, H-4-Ph and H-5-Ph), 6.54 (1H, br d, J = 5.5 Hz, H-8), 6.44−6.27 (1H, m, H-9), 5.41 (1H, d, J = 13.5 Hz, H-1A), 5.22 (1H, s, H-6), 5.04 (1H, s, H-7), 4.42 (1H, br d, J = 13.5 Hz, H-3A), 3.85 (3H, br s, CO2Me),

3.80 (3H, s, CO2Me), 3.76 (1H, br d, J = 13.5 Hz, H-1B), 3.57−3.35 (1H, m, H-3B), 2.31 and 2.18 (1H and 1H, d and d, J = 6.2 Hz, H-6a and H-9b). 13C NMR (150 MHz, CDCl3), the mixture of amide rotamers: δ 172.1 (CO-Ph), 163.8 and 163.4 (2 × CO2Me), 162.7 and 162.6 (2 × CO2Me), 147.5 and 147.3 (C-4), 146.2 and 146.1 (C-5), 139.8 and 139.5 (C-8), 138.4 and 137.9 (C-9), 135.6 and 135.5 (C-1Ph), 129.8 (C-4-Ph), 128.4 (C-3-Ph and C-5-Ph), 127.9 (C-2-Ph and C-6-Ph), 86.7, 86.5, 82.1, and 81.0 (C-3a and C-9a), 83.8 (C-6), 80.9 (C-7), 52.6 and 52.5 (C-6a and C-9b), 50.9 (CO2Me), 50.5 (CO2Me), 47.8, 46.3, 42.5, and 41.0 (C-1 and C-3). IR νmax/cm−1 (KBr): 2954, 1714, 1628, 1272, 1076. HRMS (ESI-TOF): calcd for C23H21NO7 [M + H]+, 423.1318; found, 423.13135. 2-tert-Butyl 4,5-Dimethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9bdihydro-1H,6H,7H-3a,6:7,9a-diepoxybenzo[de]isoquinoline2,4,5(3H)-tricarboxylate (4j). The solvent was removed under reduced pressure. The residue (viscous light-brown oil) was triturated with hexane/Et2O, and the obtained solid was recrystallized from hexane/ EtOAc to give adduct 4j as a colorless powder (2.18 g, 5.4 mmol, 54%). Rf 0.35 (EtOAc/hexane, 1:1, Sorbfil). Mp: 148.7−149.2 °C (from hexane/EtOAc). 1H NMR (600 MHz, CDCl3): δ 6.53 (1H, d, J = 5.5 Hz, H-8), 6.37 (1H, d, J = 5.5 Hz, H-9), 5.18 (1H, s, H-7), 4.99 (1H, s, H-6), 4.82 (1H, br d, J = 12.9 Hz, H-1A), 4.66 (1H, br d, J = 12.9 Hz, H-3A), 3.83 (3H, s, CO2Me), 3.79 (3H, s, CO2Me), 3.57− 3.42 (1H, m, H-1B), 3.41−3.26 (1H, m, H-3B), 2.28 and 2.08 (1H and 1H, d and d, J = 6.0 Hz, H-9b and H-6a), 1.46 (9H, s, C(CH3)3). 13 C NMR (150 MHz, CDCl3), the mixture of amide rotamers: δ 163.9 and 162.7 (CO2Me), 155.5 (C-5), 147.9 and 147.5 (C-4), 146.3 and 145.6 (N-CO2tBu), 139.5 and 139.4 (C-9), 138.4 (C-8), 85.6 (C-2), 83.7 and 80.5 (C-3a and C-9a), 81.9 (C-6), 80.9 (C-7), 52.5 (CO2Me), 52.4 (CO2Me), 50.9 and 49.7 (C-9b and C-6a), 44.5, 43.3, 42.0, and 41.8 (C-1 and C-3), 28.4 (NCO2C(CH3)3). IR νmax/cm−1 (KBr): 2960, 1697, 1623, 1273, 1152. HRMS (ESI-TOF): calcd for C21H25NO8 [M + H]+, 419.1580; found, 419.1565. General Procedure for the Synthesis of the Pincer Adducts 3k− m. The appropriate alkyne (7.50 mmol) was added to a solution of difurfuryl ether 1b (0.89 g, 5.00 mmol) in PhH (15 mL). The mixture was heated at reflux for 32−47 h (Table 3). The solvent was removed under reduced pressure. The residue (viscous yellow oil) was dissolved in Et2O (15 mL) and left for 48 h at −14 °C. Further treatment of the resulting mixtures is given below. Diethyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9a-Diepoxybenzo[de]isochromene-6a,9b-(1H,3H)-dicarboxylate (3k). After cooling, the solid was filtered off and recrystallized from hexane/EtOAc to give compound 3k as a white powder (0.85 g, 2.45 mmol, 49%). Rf 0.59 (EtOAc, Sorbfil). Mp: 113.7−114.9 °C (from hexane/EtOAc). 1H NMR (600 MHz, CDCl3): δ 6.69 (2H, dd, J = 1.5 and J = 5.5 Hz, H-5 and H-8), 6.41 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.16 (2H, d, J = 1.5 Hz, H-6 and H-7), 4.28 (2H, d, J = 12.3 Hz, H-1A and H-3A), 4.25 (2H, d, J = 12.3 Hz, H-1B and H-3B), 4.09 (4H, q, J = 7.4 Hz, 2 × OCH2Me), 1.25 (3H, t, J = 7.4 Hz, OCH2Me), 1.22 (3H, t, J = 7.4 Hz, OCH2Me). 13C NMR (150 MHz, CDCl3): δ 169.9 and 169.7 (2 × CO2Et), 140.5 (C-4 and C-9), 137.6 (C-5 and C-8), 87.7 (C-3a and C9a), 84.1 (C-6 and C-7), 71.4 and 67.6 (C-9b and C-6a), 64.8 (C-1 and C-3), 61.4 and 61.3 (2 × OCH2CH3), 14.1 and 14.0 (2 × OCH2CH3). IR νmax/cm−1 (KBr): 2840, 1742, 1731, 1075, 1003. HRMS (ESI-TOF): calcd for C18H20O7 [M + H]+, 348.1209; found, 348.1234. Dipropan-2-yl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9aDiepoxybenzo[de]isochromene-6a,9b(1H,3H)-dicarboxylate (3l). After cooling, the white powder of byproduct 4l (0.17 g, 0.45 mmol, 9%) was filtered off. The mother liquid was concentrated and purified by silica gel column chromatography (petroleum ether/Et2O) to give compound 3l as colorless prisms (0.50 g, 1.33 mmol, 27%). Rf 0.61 (hexane/EtOAc, 8:1, Sorbfil). Mp: 114.4−115.7 °C (from hexane/ Et2O). 1H NMR (600 MHz, CDCl3): δ 6.68 (2H, dd, J = 1.4 and J = 5.5 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.14 (2H, d, J = 1.4 Hz, H-6 and H-7), 4.98−4.91 (2H, m, 2 × OCHMe2), 4.28 (2H, d, J = 12.4 Hz, H-1A and H-3A), 4.23 (2H, d, J = 12.4 Hz, H-1B and H-3B), 1.24 and 1.22 (12H, d, J = 6.2 Hz, 2 × OCHMe2). 13 C NMR (100 MHz, CDCl3): δ 168.8 and 168.7 (2 × CO2CHMe2), H

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

(3p). According to 1H NMR analysis, the resulting solid was the mixture of 3p/4p (1.20 g, 2.86 mmol, 57%) in the ratio 88:12. Recrystallization of this solid from hexane/EtOAc gave the mixture of 3p/4p in the ratio 82:18 as colorless needles (0.61 g, 1.45 mmol, 29%). Rf 0.64 (hexane, Sorbfil). 1H NMR for 3p (600 MHz, CDCl3): δ 6.60 (2H, dd, J = 1.7 and J = 5.0 Hz, H-5 and H-8), 6.45 (2H, d, J = 5.0 Hz, H-4 and H-9), 5.05 (2H, d, J = 1.7 Hz, H-6 and H-7), 3.57 (2H, d, J = 14.9 Hz, H-1A and H-3A), 2.90 (2H, d, J = 14.9 Hz, H-1B and H-3B), 1.44 (9H, s, CO2tBu), 1.42 (9H, s, CO2tBu). 13C NMR for 3p (100 MHz, CDCl3): δ 168.6 and 168.5 (2 × CO2tBu), 141.4 (C-4 and C-9), 138.7 (C-5 and C-8), 87.2 (C-3a and C-9a), 83.5 (C-6 and C-7), 74.3 and 67.9 (C-9b and C-6a), 28.1 (2 × CO2tBu), 27.4 (C-1 and C-3). IR νmax/cm−1 (KBr): 2981, 1728, 1709, 1008, 969. HRMS (ESI-TOF): calcd for C22H28SO6 [M + H]+, 420.1607; found, 420.1622. General Procedure for the Synthesis of the Domino Adducts 4k− m. The appropriate alkyne (5.50 mmol) was added to a solution of difurfuryl ether 1b (0.89 g, 5.00 mmol) in o-Me2C6H4 (15 mL). The mixture was heated at reflux for 4−7 h (Table 3), then was cooled to rt, and was left for 24 h at −14 °C. The obtained solids were filtered off and washed with Et2O to give compounds 4k−m. Diethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro-6H,7H3a,6:7,9a-diepoxybenzo[de]isochromene-4,5(1H,3H)-dicarboxylate (4k). White prisms (1.23 g, 3.54 mmol, 71%). Rf 0.52 (EtOAc/hexane, 1:4, Sorbfil). Mp: 158.6−159.2 °C (from EtOH). 1H NMR (600 MHz, CDCl3): δ 6.54 (1H, dd, J = 1.7 and J = 5.8 Hz, H-8), 6.35 (1H, d, J = 5.8 Hz, H-9), 5.23 (1H, s, H-6), 5.04 (1H, d, J = 1.7 Hz, H-7), 4.41 (1H, d, J = 12.4 Hz, H-1A), 4.39 (1H, d, J = 13.2 Hz, H-3A), 4.28− 4.24 (4H, m, 2 × OCH2Me), 4.15 (1H, d, J = 12.4 Hz, H-1B), 3.99 (1H, d, J = 13.2 Hz, H-3B), 2.30 and 2.13 (1H and 1H, d and d, J = 6.6 Hz, H-6a and H-9b), 1.32 (3H, t, J = 7.4 Hz, OCH2Me), 1.31 (3H, t, J = 7.4 Hz, OCH2Me). 13C NMR (150 MHz, CDCl3): δ 163.2 and 162.6 (2 × CO2CHMe2), 146.6 (C-5), 146.4 (C-4), 139.5 (C-8), 137.7 (C-9), 86.5 and 83.9 (C-9a and C-3a), 82.3 and 81.2 (C-6 and C-7), 66.3 and 64.7 (2 × CH2Me), 61.7 and 61.5 (C-3 and C-1), 50.5 and 48.9 (C-6a and C-9b), 14.2 and 14.1 (2 × CHMe2). IR νmax/cm−1 (KBr): 2824, 1716, 1702, 1102, 1027. HRMS (ESI-TOF): calcd for C18H20O7 [M + H]+, 348.1209; found, 348.1232. Dipropan-2-yl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro6H,7H-3a,6:7,9a-diepoxybenzo[de]isochromene-4,5(1H,3H)-dicarboxylate (4l). Light-brown powder (1.05 g, 2.79 mmol, 56%). Rf 0.47 (hexane, Sorbfil). Mp: 138.1−139.4 °C (from EtOH). 1H NMR (600 MHz, CDCl3): δ 6.55 (1H, dd, J = 2.0 and J = 6.2 Hz, H-8), 6.35 (1H, d, J = 6.2 Hz, H-9), 5.20 (1H, s, H-6), 5.11 (2H, heptet, J = 6.5 Hz, 2 × OCHMe2), 5.04 (1H, d, J = 2.0 Hz, H-7), 4.41 (1H, d, J = 13.1 Hz, H-1A), 4.39 (1H, d, J = 13.1 Hz, H-3A), 4.11 (1H, d, J = 13.1 Hz, H1B), 3.98 (1H, d, J = 13.1 Hz, H-3B), 2.30 and 2.12 (1H and 1H, d and d, J = 6.2 Hz, H-6a and H-9b), 1.32−1.28 (12H, m, 2 × OCHMe2). 13C NMR (100 MHz, CDCl3): δ 162.8 and 162.1 (2 × CO2iPr), 146.8 (C-5), 145.9 (C-4), 139.4 (C-8), 137.6 (C-9), 86.4 and 83.8 (C-9a and C-3a), 82.2 and 81.2 (C-6 and C-7), 69.7 and 69.3 (2 × CO2CHMe2), 66.3 and 64.7 (C-3 and C-1), 50.5 and 28.8 (C-6a and C-9b), 21.8 and 21.7 (2 × CO2CHMe2). IR νmax/cm−1 (KBr): 2981, 1726, 1709, 1260, 1107, 1075. HRMS (ESI-TOF): calcd for C20H24O7 [M + H]+, 376.1522; found, 376.1501. Di-tert-butyl (3aRS,6SR,6aS,7SR,9aRS,9bSR)-6a,9b-Dihydro6H,7H-3a,6:7,9a-diepoxybenzo[de]isochromene-4,5(1H,3H)-dicarboxylate (4m). Light-brown prisms 4m (0.40 g, 1.0 mmol, 20%). Rf 0.41 (hexane/EtOAc, 1:4, Sorbfil). Mp: 142.1−143.6 °C (from hexane/EtOAc). 1H NMR (600 MHz, CDCl3): δ 6.54 (1H, dd, J = 1.4 and J = 6.2 Hz, H-8), 6.33 (1H, d, J = 6.2 Hz, H-9), 5.14 (1H, s, H-6), 5.02 (1H, d, J = 1.4 Hz, H-7), 4.40 (1H, d, J = 13.0 Hz, H-1A), 4.38 (1H, d, J = 13.0 Hz, H-3A), 4.08 (1H, d, J = 13.0 Hz, H-1B), 3.97 (1H, d, J = 13.0 Hz, H-3B), 2.29 and 2.10 (1H and 1H, d and d, J = 6.2 Hz, H-6a and H-9b), 1.51 and 1.49 (18H, s, 2 × CO2tBu). 13C NMR (100 MHz, CDCl3): δ 162.1 and 161.6 (2 × CO2tBu), 146.7 (C-5), 145.9 (C-4), 139.3 (C-8), 137.4 (C-9), 86.1 and 83.7 (C-9a and C-3a), 83.0 and 82.4 (2 × CO2CMe3), 82.2 and 81.0 (C-6 and C-7), 66.2 and 64.7 (C-1 and C-3), 50.3 and 48.7 (C-6a and C-9b), 28.1 and 28.0 (2 × CO2CMe3). IR νmax/cm−1 (KBr): 2973, 1732, 1700, 1258, 1160, 1132.

140.0 (C-4 and C-9), 137.3 (C-5 and C-8), 87.4 (C-3a and C-9a), 83.8 (C-6 and C-7), 71.5 and 67.4 (C-9b and C-6a), 69.1 and 68.8 (2 × CHMe2), 64.7 (C-1 and C-3), 21.6 and 21.5 (2 × CHMe2). IR νmax/ cm−1 (KBr): 2981, 1744, 1727, 1101, 1073. HRMS (ESI-TOF): calcd for C20H24O7 [M + H]+, 376.1522; found, 376.1501. Di-tert-butyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9aDiepoxybenzo[de]isochromene-6a,9b(1H,3H)-dicarboxylate (3m). After cooling, light-brown prisms of byproduct 4m (0.40 g, 1.0 mmol, 20%) were filtered off. The mother liquid was concentrated and purified by silica gel column chromatography (petroleum ether/Et2O) to give compound 3m as colorless needles (0.94 g, 2.32 mmol, 46%). Rf 0.52 (hexane/EtOAc, 2:1, Sorbfil). Mp: 132.8−139.4 °C (from hexane). 1H NMR (600 MHz, CDCl3): δ 6.66 (2H, dd, J = 1.5 and J = 5.5 Hz, H-5 and H-8), 6.42 (2H, d, J = 5.5 Hz, H-4 and H-9), 5.09 (2H, d, J = 1.5 Hz, H-6 and H-7), 4.27 (2H, d, J = 12.7 Hz, H-1A and H-3A), 4.22 (2H, d, J = 12.7 Hz, H-1B and H-3B), 1.44 (9H, s, CO2tBu), 1.43 (9H, s, CO2tBu). 13C NMR (100 MHz, CDCl3): δ 168.4 and 168.3 (2 × CO2tBu), 139.6 (C-4 and C-9), 137.6 (C-5 and C-8), 87.4 (C-3a and C-9a), 83.9 (C-6 and C-7), 82.1 and 81.7 (2 × CO2CMe3), 72.2 and 67.5 (C-9b and C-6a), 64.8 (C-1 and C-3), 28.1 (2 × CO2CMe3). IR νmax/cm−1 (KBr): 2980, 1724, 1707, 1172, 1092. HRMS (ESI-TOF): calcd for C22H28O7 [M + H]+, 404.1835; found, 404.1858. General Procedure for the Synthesis of the Pincer Adducts 3n−p. The corresponding alkyne (7.50 mmol) was added to a solution of bis(furan-2-ylmethyl)sulfane 1c (1.0 g, 5.0 mmol) in PhH (20 mL). The mixture was heated at reflux for 30−31 h (GC−MS monitoring until disappearance of the starting material). The solvent was removed under reduced pressure. The residue (viscous light-brown oil) was triturated with hexane, and the obtained solid was filtered off and recrystallized to give compounds 3n−p as colorless needles. Diethyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9a-Diepoxybenzo[de]isothiochromene-6a,9b-(1H,3H)-dicarboxylate (3n). According to 1 H NMR analysis, the resulting solid was the mixture of 3n/4n (1.44 g, 4.00 mmol, 81%) in the ratio 75:25. Recrystallization from a DMF/ EtOH mixture gave the mixture of 3n/4n = 20:80 as colorless needles (1.08 g, 2.96 mmol, 60%, partial isomerization observed at recrystallization). Rf 0.59 (hexane/EtOAc, 4:1, Sorbfil). 1H NMR for 3n (600 MHz, CDCl3): δ 6.62 (2H, dd, J = 1.7 and J = 5.0 Hz, H-5 and H-8), 6.46 (2H, d, J = 5.0 Hz, H-4 and H-9), 5.13 (2H, d, J = 1.7 Hz, H-6 and H-7), 4.11−4.05 (4H, m, 2 × OCH2Me), 3.58 (2H, d, J = 14.9 Hz, H-1A and H-3A), 2.93 (2H, d, J = 14.9 Hz, H-1B and H-3B), 1.23 (6H, dt, J = 2.5 and J = 7.4 Hz, 2 × OCH2Me). 13C NMR for 3n (150 MHz, CDCl3): δ 168.9 and 168.7 (2 × CO2Et), 141.4 (C-4 and C-9), 138.1 (C-5 and C-8), 87.3 (C-3a and C-9a), 83.6 (C-6 and C-7), 73.8 and 67.5 (C-9b and C-6a), 61.4 and 61.3 (2 × OCH2CH3), 27.4 (C-1 and C-3), 14.2 and 14.1 (2 × OCH2CH3). IR νmax/cm−1 (KBr): 2870, 1737, 1720, 1098, 1022. HRMS (ESI-TOF): calcd for C18H20SO6 [M + H]+, 364.0981; found, 364.0993. Dipropan-2-yl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9aDiepoxybenzo[de]isothiochromene-6a,9b(1H,3H)-dicarboxylate (3o). According to 1H NMR analysis, the resulting solid was the mixture of 3o/4o (1.60 g, 4.15 mmol, 83%) in the ratio 86:14. Recrystallization of this solid from hexane/EtOAc gave the mixture 3o/4o in the ratio 91:9 as colorless needles (0.88 g, 2.25 mmol, 45%). Rf 0.53 (hexane, Sorbfil). 1H NMR for 3o (600 MHz, CDCl3): δ 6.62 (2H, dd, J = 1.7 and J = 5.8 Hz, H-5 and H-8), 6.46 (2H, d, J = 5.8 Hz, H-4 and H-9), 5.10 (2H, d, J = 1.7 Hz, H-6 and H-7), 4.96 (1H, heptet, J = 6.4 Hz, OCHMe2), 4.91 (1H, heptet, J = 6.4 Hz, OCHMe2), 3.57 (2H, d, J = 14.9 Hz, H-1A and H-3A), 2.93 (2H, d, J = 14.9 Hz, H-1B and H-3B), 1.25 and 1.23 (6H and 6H, d and d, J = 6.4 Hz, 2 × OCHMe2). 13C NMR for 3o (150 MHz, CDCl3): δ 168.9 and 168.7 (2 × CO2CHMe2), 141.3 (C-4 and C-9), 138.9 (C-5 and C8), 87.2 (C-3a and C-9a), 83.5 (C-6 and C-7), 73.9 and 69.2 (C-9b and C-6a), 68.9 and 67.5 (2 × CHMe2), 27.4 (C-1 and C-3), 21.7 (2 × CHMe2). IR νmax/cm−1 (KBr): 2936, 1727, 1709, 1085, 1051. HRMS (ESI-TOF): calcd for C20H24SO6 [M + H]+, 392.1294; found, 392.1275. Di-tert-butyl (3aRS,6SR,7RS,9aSR)-6H,7H-3a,6:7,9aDiepoxybenzo[de]isothiochromene-6a,9b(1H,3H)-dicarboxylate I

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry HRMS (ESI-TOF): calcd for C22H28O7 [M + H]+, 404.1835; found, 404.1807. General Procedure for the Synthesis of the Domino Adducts 4n,o. The appropriate alkyne (5.50 mmol) was added to a solution of bis(furan-2-ylmethyl)sulfane 1c (1.00 g, 5.00 mmol) in o-Me2C6H4 (20 mL). The mixture was heated at reflux for 4 h (∼140 °C), and then the reaction mixture was cooled to +4 °C. The solvent was decanted, and the obtained solids were washed with hexane and dried in air to give compounds 4n,o. Diethyl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro-6H,7H3a,6:7,9a-diepoxybenzo[de]isothiochromene-4,5(1H,3H)-dicarboxylate (4n). White powder (1.72 g, 4.75 mmol, 95%). Rf 0.53 (hexane/ EtOAc, 4:1, Sorbfil). Mp: 192.8−193.7 °C (with decomp from DMF). 1 H NMR (600 MHz, CDCl3): δ 6.56 (1H, dd, J = 1.7 and J = 5.8 Hz, H-8), 6.29 (1H, d, J = 5.8 Hz, H-9), 5.22 (1H, s, H-6), 5.02 (1H, d, J = 1.7 Hz, H-7), 4.31−4.22 (4H, m, 2 × OCH2Me), 3.48 (1H, d, J = 14.0 Hz, H-1A), 3.35 (1H, d, J = 14.0 Hz, H-3A), 3.02 (2H, dd, J = 1.6 and 14.0 Hz, H-1B and H-3B), 2.34 and 2.03 (1H and 1H, d and d, J = 6.3 Hz, H-6a and H-9b), 1.32 (3H, t, J = 7.4 Hz, OCH2Me), 1.30 (3H, t, J = 7.4 Hz, OCH2Me). 13C NMR (150 MHz, CDCl3): δ 163.8 and 162.2 (2 × CO2CHMe2), 148.5 (C-5), 145.4 (C-4), 139.9 (C-8), 139.7 (C-9), 86.4 and 83.1 (C-9a and C-3a), 81.5 and 80.6 (C-6 and C-7), 61.7, 61.4, 52.9, and 48.8 (2 × CH2Me, C-9b and C-6a), 28.7 and 26.8 (C-3 and C-1), 14.1 and 14.0 (2 × CHMe2). IR νmax/cm−1 (KBr): 2833, 1727, 1709, 1091, 984. HRMS (ESI-TOF): calcd for C18H20SO6 [M + H]+, 364.0981; found, 364.0969. Dipropan-2-yl (3aRS,6SR,6aRS,7SR,9aRS,9bSR)-6a,9b-Dihydro6H,7H-3a,6:7,9a-diepoxybenzo[de]isothiochromene-4,5(1H,3H)-dicarboxylate (4o). White powder (1.39 g, 3.60 mmol, 72%). Rf 0.44 (hexane/EtOAc, 4:1, Sorbfil). Mp: 145.0−147.6 °C (with decomp from DMF). 1H NMR (600 MHz, CDCl3): δ 6.56 (1H, dd, J = 1.7 and J = 5.6 Hz, H-8), 6.28 (1H, d, J = 5.6 Hz, H-9), 5.19 (1H, s, H-6), 5.12 (2H, heptet, J = 6.6 Hz, 2 × OCHMe2), 5.02 (1H, d, J = 1.7 Hz, H-7), 3.43 (1H, d, J = 14.0 Hz, H-1A), 3.34 (1H, d, J = 14.0 Hz, H-3A), 3.05 (1H, d, J = 14.0 Hz, H-1B), 3.03 (1H, d, J = 14.0 Hz, H-3B), 2.32 and 2.02 (1H and 1H, d and d, J = 6.4 Hz, H-6a and H-9b), 1.32 (6H, d, J = 6.6 Hz, OCHMe2), 1.30 (6H, d, J = 6.6 Hz, OCHMe2). 13C NMR (150 MHz, CDCl3): δ 163.5 and 161.7 (2 × CO2iPr), 148.7 (C-5), 139.8 (C-4), 129.6 (C-8), 125.8 (C-9), 86.3 (C-9a), 83.1 (C-3a), 81.4 and 80.6 (C-6 and C-7), 69.7, 69.3, and 52.8 (2 × CO2CHMe2 and C9b), 48.8 (C-6a), 28.7 and 26.9 (C-3 and C-1). IR νmax/cm−1 (KBr): 2878, 1729, 1706, 1036, 984. HRMS (ESI-TOF): calcd for C20H24SO6 [M + H]+, 392.1294; found, 392.1311.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Dr. Victor N. Khrustalev (RUDN University) for the X-ray diffraction study. (This part of the research was prepared with the support of the “RUDN University Program 5-100”.) Funding for this research was provided by the Ministry of Education and Science of the Russian Federation (award no. 4.1154.2017/4.6). R.A.N. thanks the Program of Fundamental Research for state academies for years 2013−2020 (no. 01201363817) for support of NMR studies (Engelhardt Institute of Molecular Biology, Russian Academy of Sciences).

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(1) Woodward, R. B.; Baer, R. The reaction of furan with maleic anhydride. J. Am. Chem. Soc. 1948, 70, 1161−1166. (2) For selected references regarding the kinetic and thermodynamic control in the Diels−Alder reaction, see: (a) Boutelle, R. C.; Northrop, B. H. Substituent effects on the reversibility of furan-maleimide cycloadditions. J. Org. Chem. 2011, 76, 7994−8002. (b) Taffin, C.; Kreutler, G.; Bourgeois, D.; Clot, E.; Périgaud, C. Diels−Alder reaction of vinylene carbonate and 2,5-dimethylfuran: kinetic vs. thermodynamic control. New J. Chem. 2010, 34, 517−525. (c) White, J. D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.; Snyder, J. P. Conformational study of the intramolecular Diels−Alder reaction of a pentadienyl acrylate. Theoretical evaluation of kinetic and thermodynamic control. Org. Lett. 2000, 2, 3313−3316. (d) Marchand, A. P.; Ganguly, B.; Watson, W. H.; Bodige, S. G. Thermodynamic vs. kinetic control in the Diels−Alder cycloaddition of cyclopentadiene to 2,3dicyano-p-benzoquinone: kinetic control revisited. Tetrahedron 1998, 54, 10967−10972. (e) Manoharan, M.; Venuvanalingam, P. The role of cumulenic strain on the kinetic and thermodynamic control ofthe Diels−Alder reactions involving allenes as dienes. J. Chem. Soc., Perkin Trans. 2 1997, 1799−1804. (f) Bott, S. G.; Marchand, A. P.; Kumar, K. A. Thermodynamic vs. kinetic control in the Diels−Alder cycloaddition of cyclopentadiene to 2,3-dicyano-p-benzoquinone. J. Chem. Crystallogr. 1996, 26, 281−286. (g) Suarez, D.; Sordo, T. L.; Sordo, J. A. A comparative analysis of the mechanisms of cheletropic and Diels− Alder reactions of 1,3-dienes with sulfur dioxide: kinetic and thermodynamic controls. J. Org. Chem. 1995, 60, 2848−2852. (h) Bartlett, P. D.; Wu, C. Reactions of maleic anhydride and dimethyl acetylenedicarboxylate (DMAD) with the three isodicyclopentadiene isomers. Kinetic vs. thermodynamic control in cycloadditions. J. Org. Chem. 1985, 50, 4087−4092. (3) For reviews concerning the tandem intramolecular Diels−Alder reaction, see: (a) Sears, J. E.; Boger, D. L. Tandem intramolecular Diels−Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles: initial scope and applications. Acc. Chem. Res. 2016, 49, 241−251. (b) Parvatkar, P. T.; Kadam, H. K.; Tilve, S. G. Intramolecular Diels− Alder reaction as a key step in tandem or sequential processes: a versatile tool for the synthesis of fused and bridged bicyclic or polycyclic compounds. Tetrahedron 2014, 70, 2857−2888. (c) Padwa, A.; Bur, S. K. The domino way to heterocycles. Tetrahedron 2007, 63, 5341−5378. (d) Wu, J.; Sun, L.; Dai, W.-M. Microwave-assisted tandem Wittig−intramolecular Diels−Alder cycloaddition. Product distribution and stereochemical assignment. Tetrahedron 2006, 62, 8360−8372. (e) Takao, K.-I.; Munakata, R.; Tadano, K.-I. Recent advances in natural product synthesis by using intramolecular Diels− Alder reactions. Chem. Rev. 2005, 105, 4779−4807. (f) Winkler, J. D. Tandem Diels−Alder cycloadditions in organic synthesis. Chem. Rev. 1996, 96, 167−176. (4) (a) Cram, D. J.; Knox, G. R. A cross-breeding reaction, a bent benzene ring, and a multiple Diels−Alder reaction. J. Am. Chem. Soc. 1961, 83, 2204−2205. (b) Cram, D. J.; Montgomery, C. S.; Knox, G. R. Macro rings. XXXIII. A 1,6 to 1,6 cycloaddition reaction, a Diels−

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00336. Copies of NMR spectra, details of kinetic and quantumchemical calculations, and X-ray crystallography data for compounds 3f and 4f (PDF) Crystal data of 3f (CIF) Crystal data of 4f (CIF)

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Corresponding Author

*E-mail: [email protected]. Fax: +7 495-952-2644. Tel: +7 495-955-0779. ORCID

Rinat R. Aysin: 0000-0003-1402-9878 Roman A. Novikov: 0000-0002-3740-7424 Fedor I. Zubkov: 0000-0002-0289-0831 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. J

DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.8b00336 J. Org. Chem. XXXX, XXX, XXX−XXX