Access to Multi-Substituted Furan-3-carbothioates via Cascade

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Access to Multi-Substituted Furan-3-carbothioates via Cascade Annulation of #-Oxo Ketene Dithioacetals with Isoindoline-1,3-dione-derived Propargyl Alcohols Li-Gang Bai, Ming-Tao Chen, Dong-Rong Xiao, Liu-Bin Zhao, and Qun-Li Luo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00401 • Publication Date (Web): 25 May 2018 Downloaded from http://pubs.acs.org on May 25, 2018

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The Journal of Organic Chemistry

Access to Multi-Substituted Furan-3-carbothioates via Cascade Annulation of α-Oxo Ketene Dithioacetals with Isoindoline-1,3-dione-derived Propargyl Alcohols Li-Gang Bai,†, a Ming-Tao Chen,†, a Dong-Rong Xiao,a Liu-Bin Zhao,*, a and Qun-Li Luo*, a, b a

College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China. [email protected]; [email protected]

b

Key Laboratory of Applied Chemistry of Chongqing Municipality, Southwest University, Chongqing

400715, China. †

These authors contributed equally.

Table of Contents: O

R5 O R2 R1S

X +

R4

SR1

R5

HO

R4

SR1

O 1,3-bis-nucleophiles 1,2-bis-electrophiles

R2

X

H+

NR3

O NR3

O f unctionalized f urans

R1S SR1

R5

via X R4

R2

C NR3

O

Nu + Nu

E

(3+2)

Nu

E

E

Annulation

Nu

E

HO

Abstract: A Brønsted acid promoted, unprecedented formal (3+2) annulation strategy for the synthesis of multi-substituted furan-3-carbothioates is reported. This transformation represents the first regioselective annulation of α-oxo ketene dithio-acetals as 1,3-bis-nucleophiles in a cascade manner. The choice of isoindoline-1,3-dione-derived propargyl alcohols is crucial to the uncommon annulation mode between an alkyne-type bis-electrophile and a 1,3-bis-nucleophile under metal-free conditions. The scale-up of the synthesis and several interesting transformations of an as-synthesized

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product were further investigated. A Nazarov-like cyclization is proposed for the ring-closure process according to the experimental observations.

Introduction Cascade annulations have enabled facile access to heterocycles of great complexity.1, 2 Since the first report in 1910, ketene dithioacetals and their derivatives have been confirmed to be versatile intermediates in cascade annulations.3 Owing to the ambident electrophilicity at carbon centers of the carbonyl and thioacetal groups, α-oxo ketene dithioacetals have been widely reported in the annulations as 1,3-bis-electrophilic three-carbon synthones.4 In recent years, these components have proven to be particularly useful as a two-carbon fragment equivalent to a polarized alkene.3c, 5 General interest in simple and efficient methodologies for constructing heterocycles and carbocycles from α-oxo ketene dithioacetals has rapidly grown.6 Cascade (2+x) annulation of dithioacetals as C2 synthons has emerged as a powerful synthetic tool. Through the use of this strategy, a large library of functionalized cyclic molecules have been prepared via nucleophilic attack at the electron-deficient site of ketene dithioacetals (Scheme 1a).5, 6

Scheme 1. α-Oxo ketene dithioacetals as two-carbon synthones in cascade annulations.


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Theoretically, α-oxo ketene dithioacetals can be used as ambident 1,3-bis-nucleophiles (denoted as Nu-Nu) in cascade (3+x) annulation owing to the electron-releasing conjugation of bisalkylthio groups, a strategy not yet been realized, presumably due to the lack of suitable bis-electrophiles (E-E).1f In traditional cascade annulations, cyclizations between polarized conjugated systems (Nu-E) are common (Scheme 1a); however, reaction of 1,3-bis-nucleophiles (Nu-Nu) with bis-electrophiles (E-E) are rare in the absence of metal catalysts (see below).1b Thus, achieving an annulation mode in the latter case, as shown in Scheme 1b, would be interesting. Alkynes, activated by π-acids,1, 2 can behave as formal 1,2-bis-electrophiles in various synthetically challenging transformations via α-oxo metal carbene species by oxidation, or imino metal carbenoids by the attack of nucleophiles containing labile N–O or N–N bonds (Scheme 2a). 2c, 2f, 7 Meanwhile, the 1,2- or 1,3-carbons of propargyl alcohols and their derivatives are usually

utilized for the

annulations as bis-electrophilic sites in the existent propargylation/cycloisomerization tandem processes (Scheme 2b),1b the 2,3-carbons are seldom

utilized. We envisioned that introduction of an

appropriate substituent into the α-position of propargyl alcohols could stabilize the subsequently formed allenic intermediate, allowing further control over the cyclization pattern (Scheme 2c). Herein, we report the first formal (3+2) annulation of α-oxo ketene dithioacetals with propargyl alcohol derivatives in which α-oxo ketene dithioacetals behave as the 1,3-bis-nucleophiles (Scheme 1b). This methodology realizes an uncommon cascade annulation utilizing 2,3-carbons of propargylic alcohol (Scheme 2c), and affords facile access to furans bearing many functionalities.1c



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Scheme 2. Alkynes as bis-electrophiles in cascade annulations.

Results and discussion Initially, the model reaction of the α-oxo ketene dithioacetal 1a with isoindoline-1,3-dione-derived propargylic alcohol 2a was explored to optimize the reaction conditions (Table 1).

8

A catalytic

amount of BF3·Et2O promoted the annulation, yielding 3a in 34%, whereas metal-based Lewis acids gave no reaction (Table 1, entries 1−3). To our delight, several Brønsted acids could be used (entries 4−7). Among them, triflic acid (TfOH) gave the best results, and was slightly superior to BF3·Et2O (entry 7 vs 1). An increase in the amounts of 1a and TfOH provided higher yields, while an increase in the amount of BF3·Et2O produced an inferior outcome (entries 8−11). Solvent and temperature screening experiments established the optimized conditions (entries 12−19). Thus, a yield of 80% of 3a was obtained by adding 1 equivalent of TfOH at 0 oC to the mixture in toluene containing 2 equivalents of 1a and 1 equivalent of 2a, and allowing the reaction to warm to room temperature with stirring for 4 h (entry 19).


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Table 1. Optimization of the reaction conditionsa

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17b 18c 19d a

1a:2a 1:1 1:1 1:1 1:1 1:1 1:1 1:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1 2:1

Acid (equiv.) BF3·Et2O (0.3) FeCl3·6H2O (0.3) ZnCl2 (0.3) TsOH (0.3) MsOH (0.3) TFA (0.3) TfOH (0.3) BF3·Et2O (0.3) TfOH (0.3) BF3·Et2O (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1) TfOH (1)

Solvent 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane THF CH3CN DMF CHCl3 toluene toluene toluene toluene

Yield 34% trace NR trace 14% 23% 35% 47% 43% 24% 64% 43% 41% trace 58% 66% NR trace 80%

Conditions: 1a, 2a (0.15 mmol), acid, solvent (0.5 mL) at r.t. unless otherwise noted. Isolated yields are given. NR

= no reaction. TsOH = 4-toluenesulfonic acid monohydrate. MsOH = methanesulfonic acid. TfOH = triflic acid. TFA = trifluoroacetic acid. THF = tetrahydrofuran. DMF = N,N- dimethylformamide. b −20 oC. c 0 oC. d 0 oC to r.t., 4 h.

We then applied the optimized conditions to the cascade annulations of α-oxo ketene dithioacetals 1 with a series of isoindoline-1,3-dione-derived propargyl alcohols 2,8 and successfully achieved a diverse array of functionalized furans. First, the use of α-oxoketene dithioacetals containing different



R1 and R2 substituents was investigated

in the reactions

Page 6 of 41

with 2a

(Table 2).

The

bis(methylthio)-substituted dithioacetal (1b) gave the product in lower yield than others (Table 2, 3b vs 3a,9, 10 3c & 3d) owing to the relatively low stability of α-oxoketene dithioacetals bearing small alkylthio groups in the presence of TfOH. Conversely, the α-oxoketene dithioacetals with small α-alkyl groups were superior to those with bulky groups (3a vs 3e−3g) owing to the effects of steric hindrance. Unfortunately, the reaction of α-oxoketene dithioacetal containing an α-aryl led to that the partial decomposition of dithioacetal (1h). Meanwhile, 2a was converted to the product of Meyer-Schuster rearrangement, but no desired product (3h) was isolated. This result implied that the nucleophilicity of an α-aryl α-oxoketene dithioacetal is inferior to that of an α-alkyl counterpart because the conjugation effect of aryl makes the polarization of carbon-carbon double bond in the α-oxoketene dithioacetal decrease. Table 2. Scope of α-oxo ketene dithioacetals.a


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S

S NBn

O

O

O

O

Ph

NBn

Ph O

O 3a 80% O

O

3b 54%

3a O

O

S NBn

Ph

NBn

O

O

O

S NBn

O 3c 79%

SEt

Ph

Ph

O 3e 69%

3d 83% O OEt O

O

O

O

SEt

SEt NBn

Ph

3f 62%

a

NBn

SEt

Ph

O

O

O

O

NBn

Ph

O 3g 52%

3h 0%

Conditions: 1 (0.3 mmol), 2a (0.15 mmol), TfOH (0.15 mmol), toluene (0.5 mL) at 0 oC to r.t. for 4 h. Isolated

yields are given.

Next, isoindoline-1,3-dione-derived propargyl alcohols (2) containing various substituents were systematically subjected to the reaction with 1a (Table 3). It was necessary to protect the N-H group in the pyrrolidin-2-one ring of 2. A NH-unprotected reactant (2b) failed to produce the corresponding furan, but gave the product of Meyer-Schuster rearrangement. This result suggested that the Meyer-Schuster rearrangement of NH-unprotected isoindoline-1,3-dione-derived propargyl alcohols was faster than the present cascade annulation. The reactivity of the N-ethyl substrate was similar to that of the N-benzyl substrate (3j vs 3a), which implied that the N-alkyl group of 2 had little effect on the annulation. Table 3. Scope of propargyl alcohols.a



O

O

O

O

O

N

Ph Bn 3a 80%

O O

O

O

N

H

O

3i 0%[b]

NBn

O2N

3k 74%

O

Et

5

O

O

SEt

SEt

Ph

O

Ph

3j 74%

O

6

Ph

NBn

SEt

Ph

O2N

SEt 7 O2N

O

O

SEt

SEt N

Page 8 of 41

NBn O

3l 72%

Ph

3m 59%

Ac Br

Br

O

6 NBn O

Ph

5

NBn

Ph

NBn

O

O

O

O

O SEt

SEt NBn

Ph

NBn O

3r 79%

3q 71%

3s 77%

O Br

O

6

O

Br 5 O SEt

NBn

SEt

Ph

O

O

O

O

3p 38%

3o 71%

SEt NBn

O

6

SEt O

O

O HN

O

SEt

3n 76% AcHN

5

O

O SEt

O

SEt

NBn NBn

O O 3u 57%

3t 61% O

O

O SEt

O

O SEt

O

Me

O 3v 58%

SEt

N R NBn

NBn

NBn OMe

O

O 3w 56%

a

3x 52%

O Br 3y 61% (R=Ph) 3z 65% (R=cyclopropyl)

Conditions: 1a (0.3 mmol), 2 (0.15 mmol), TfOH (0.15 mmol), toluene (0.5 mL) at 0 oC to r.t. for 4 h. Isolated

yields are given. b Thin-layer chromatography (TLC) results indicated that the reactants were fully converted, but no desired product was isolated.

Substituents on the benzene ring moiety of 2 markedly affected the outcome of the reaction (3k−3q) despite the distance from the reaction center. The electronic effects of substituents at the 6-position were particularly evident. An electron-withdrawing group (EWG) at the 6-position was more favorable than an electron-donating group (EDG) (3l & 3n vs 3p). Substrates containing either an EWG or an EDG at the 5-position gave similar yields (3o vs 3q). For EWGs, a location at the


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6-position was more favorable than that at the 5-position (3l vs 3m, 3n vs 3o, 3t vs 3u, respectively); however, the opposite tendency was found for EDGs (3p vs 3q). Notably, the distal alkyl-type substituent of the alkyne moiety in 2 had little effect on the yields of desired products (3a vs 3r, 3s), and cyclopropyl could tolerate the reaction conditions (3r, 3t, 3u). On the other hand, when R5 as a substituted aryl, such as 4-methylphenyl, 4-methoxyphenyl, or 4-bromophenyl, the yields of desired products decreased (3a vs 3v−3x), implying that the conjugation effect of R5 had a negative effect on the reaction. Finally, the reactivity of the aromatic heterocycle-fused pyrrolidin-2-one derivatives was tested in the annulations. The pyridine-derived products were successfully obtained (Table 3, 3y & 3z). However, the furan- or thiophene-derived substrates did not yield the expected products (4, 5) under the standard conditions, but decomposed (Equation 1). These results suggest that the aromatic 6-membered ring of propargyl alcohols (2) played a key role in the annulations. It offers an alternative path for electron flow and alters the course of the reaction, leading to the outcome different from that of Bi’s case (see below).6h By contrast, the aromatic 5-membered ring-fused reactants cannot offer such path for electron flow, and failed to give the desired products (4, 5).

The scale-up of the synthesis and further synthetic transformations of compound 3a were also explored (Scheme 3). Scaling the synthesis of 3a by as much as 30-fold had no obvious effect on the efficiency of this method, further attesting the robustness of the process. Unexpectedly, the thioester functionality of 3a could not be hydrolyzed through a common base-catalyzed method,11 likely



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because of steric hindrance. Oxidative hydrolysis was then realized with the use of alkaline hydrogen peroxide–urea (UHP), and furan-3-carboxylic acid 3aa was obtained in excellent yield. The thioester was converted into aldehyde 3ab in 71% yield via the Fukuyama reduction.12 In the presence of aqueous ceric ammonium nitrate (CAN), the thioester group of 3a was preserved, and 5-hydroperoxyfuran-3-carbothioate 3ac was obtained in excellent yield via oxidative cleavage of the Csp2-Csp3 bond at the 5-position of the furan moiety.13 Notably, a NaH-mediated autoxidation of 3a led to 3-hydroxyisoindolinone 3ad in high yield at room temperature.14 O (b)

1a (10 mmol) + 2a (5 mmol)

(a) 65% scale-up

O

NBn SEt

O HO

Ph NBn

(e) 83%

3ad O

O R

SEt Ph

O

OH

91%

O

H

(c)

O

71%

R

O 1.519 g 3a

Ph 3aa O

Ph 3ab O SEt

(d) 97%

O HO O

Ph 3ac

Scheme 3. Scale-up of the reaction and transformations of the product. Conditions: (a) TfOH, toluene, 0 o

C to r.t., 5 h. (b) LiOH, UHP, MeOH/H2O, r.t., 8 h. (c) Et3SiH, 5% Pd/C, acetone, r.t., 8 h. (d) CAN, MeCN/H2O, r.t.,

14 h. (e) NaH, air, THF, r.t., overnight.

To elucidate the reaction mechanism for the formation of 3, the deuterated α-oxo ketene dithioacetal D4-1a was used in the control experiments. Deuterium incorporated at the methyl position of product 3a was largely retained (84% D), whereas that at the benzylic position was approximately 20% D (Equation 2).9


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O

85% D CD3 SEt + D

2a

Standard conditions 4 h, 60% yield

SEt

84% D CD3 O

20% D O D

SEt

NBn

84% D D4-1a

O

(2)

Ph

D4-3a

Through the addition of 1 equivalent of D2O to the reaction mixture, the deuterium incorporation at the methyl position was unchanged; however, that at the benzylic position increased to 39% D (Equation 3).9 On the other hand, the annulation of 1a and propargylic alcohol 6 did not lead to a furan-3-carbothioate, but

cyclopentadiene 7, similar to the result of Bi et al (Equation 4).6h These

results suggest that: (1) the annulation includes an intermolecular proton transfer step; (2) keto-enol tautomerism of the acetyl, originating from 1a, does not occur during the annulation; and (3) introduction of an 3-oxoisoindolin-1-yl into the α-position of

propargyl alcohols causes the

annulation occur in a different mechanism from the existent ones. 1d, 6h

On the basis of experimental observations, we propose that the annulation of α-oxo ketene dithioacetals and isoindoline-1,3-dione-derived propargyl alcohols proceeds by the following mechanism

(Scheme

4).

In

the

presence

of

TfOH,

the

dehydrative

coupling

of

isoindoline-1,3-dione-derived propargyl alcohol 2 with α-oxo ketene dithioacetal 1a forms gem-bis(alkylthio)-substituted vinylallene B1 via cationic intermediates A1 and B.15 The protonation of B1 gives cation C. The cationic cyclization of C affords the furanoid intermediate D (path a). The



Page 12 of 41

tautomerization and hydrolysis of D eventually leads to the annulation product 3. If cation C is represented as the resonance contributor C1 via π-electron delocalization across the aromatic 6-membered ring moiety, the step from C to D can be a Nazarov-like cyclization, involving a cationic 4π ring-closure (path b).16 Compared with that on classic Nazarov cyclization, the studies on Nazarov-like cyclization are very limited. To our knowledge, the transition metal-free oxa-Nazarov cyclization is unprecedented, and there were only two cases of Au-mediated oxa-Nazarov cyclization reported.17

Scheme 4. Proposed mechanism.

Conclusion In conclusion, we report here a conceptually new strategy for synthesizing multi-substituted furan-3-carbothioates by Brønsted acid-promoted regioselective (3+2) annulation of α-oxo ketene dithioacetals and isoindoline-1,3-dione-derived propargyl alcohols in a cascade manner. In the


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absence of metallic reagents, α-oxo ketene dithioacetals and the carbon-carbon triple bond of propargylic alcohols showed uncommon behavior as a 1,3-bis-nucleophilic two-carbon synthone and 1,2-bis-electrophile, respectively. Control experiments suggest that a novel cationic cyclization takes place during the ring-closure process. A new class of fully substituted furans with a variety of useful functionalities were obtained. The scale-up synthesis and further synthetic transformations of one product were explored to show that our methodology offers expedient access to heterocycle scaffolds of potential biological interest.1g, 14a, 18

Experimental Section General methods Unless otherwise noted, commercially available reagents were used as received. All solvents for chromatographic separations were distilled before use. Solvents for the water-free reactions were dried with standard procedures and stored with Schlenk flasks over molecular sieves. Column chromatography was carried out with 200−300 mesh silica gel. Thin-layer chromatography (TLC) was performed on glass-backed silica plates. Melting points (uncorrected) were recorded on a microscope melting point detector. 1H and

13

C NMR spectra were recorded on a 600 MHz NMR

spectrometer at 293 K and the chemical shifts (δ) were internally referenced by the residual solvent signals relative to tetramethylsilane (CDCl3 at 7.26 ppm for 1H, and at 77.00 ppm for 13C; DMSO-d6 at 2.50 ppm for 1H, and at 39.50 ppm for 13C). All the known products were confirmed by comparison with spectroscopic analysis of the authentic samples. The yields in the text refer to isolated yields (average of two runs) of compounds. Syntheses of α-oxo ketene dithioacetals 1



Page 14 of 41

α-Oxo ketene dithioacetals 1a-1d were prepared according to literature procedures.19 1e-1g were prepared as follows. Typically, to a stirred mixture of compound 1a (381 mg, 2 mmol) in dry THF (4 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS, 1 M in THF, 2.2 mL, 2.2 mmol) via syringe at −78 oC under argon atmosphere. After stirring for 15 min, alkyl halide (2.2 mmol) was added via syringe, and the reaction temperature was raised to room temperature with continual stirring for 4 h. After quenching with saturated ammonium chloride solution carefully, the residue was extracted with EtOAc, and sequentially washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography. 4,4-Bis(hexylthio)but-3-en-2-one (1d) was prepared according to literature procedures.19 Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (18/1, v/v) gave 1d (1.475 g, 49%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 6.08 (s, 1H), 2.98 (t, J = 7.5 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 2.18 (s, 3H), 1.75 – 1.63 (m, 4H), 1.50 – 1.38 (m, 4H), 1.34 – 1.27 (m, 8H), 0.92 – 0.85 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 192.7, 161.7, 114.4, 34.1, 31.5, 31.3, 31.2, 30.4, 29.1, 28.6, 27.4, 22.5, 22.4, 14.0, 13.9. HRMS (ESI-TOF) calcd for C16H31OS2 [M+H]+: 303.1811; found: 303.1811. 1,1-Bis(ethylthio)pent-1-en-3-one (1e) was obtained from the reaction of 1a with methyl iodide. Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (15/1, v/v) gave 1e (180 mg, 44%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 6.09 (s, 1H), 3.02 (q, J = 7.4 Hz, 2H), 2.94 (q, J = 7.4 Hz, 2H), 2.45 (q, J = 7.4 Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H), 1.33 (t, J = 7.4 Hz, 3H), 1.11 (t, J = 7.4 Hz, 3H).

13

C NMR (151 MHz, CDCl3) δ 196.1, 160.7, 113.6, 36.3, 28.1, 25.6,

14.0, 12.5, 8.7. HRMS (ESI-TOF) calcd for C9H17OS2+ [M+H]+: 205.0715; found: 205.0722. 1,1-Bis(ethylthio)hepta-1,6-dien-3-one (1f) was obtained from the reaction of 1a (4 mmol) with allyl bromide (4.4 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl


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acetate (20/1, v/v) gave 1f (419 mg, 46%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 6.08 (s, 1H), 5.91 – 5.79 (m, 1H), 5.04 (d, J = 17.1 Hz, 1H), 4.97 (d, J = 10.1 Hz, 1H), 3.02 (q, J = 7.0 Hz, 2H), 2.94 (q, J = 7.0 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.42 – 2.34 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H).

13

C NMR (151 MHz, CDCl3) δ 194.5, 161.3, 137.7, 114.9, 113.6, 42.3, 28.7, 28.1,

25.6, 13.9, 12.5. HRMS (ESI-TOF) calcd for C11H19OS2+ [M+H]+: 231.0872; found: 231.0873. Ethyl 6,6-bis(ethylthio)-4-oxohex-5-enoate (1g) was obtained from the reaction of 1a (4 mmol) with ethyl 2-bromoacetate (4.4 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (8/1, v/v) gave 1g (528 mg, 48%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 6.10 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.02 (q, J = 7.4 Hz, 2H), 2.94 (q, J = 7.4 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 1.38 (t, J = 7.4 Hz, 3H), 1.33 (t, J = 7.4 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 192.8, 173.1, 161.8, 113.2, 60.5, 37.4, 28.6, 28.1, 25.6, 14.2, 13.9, 12.5. HRMS (ESI-TOF) calcd for C12H21O3S2 [M+H]+: 277.0927; found: 277.0931. Syntheses of propargylic alcohols 2 Propargylic alcohols 2 were prepared from the Grignard reactions of imides with the Grignard reagents of terminal alkynes. Typically, to a stirred mixture of N-alkyl imide (3 mmol) in dry THF (6 mL) was added dropwise a THF solution of (alkynyl)magnesium bromide (3.5 mmol, 1M in THF) via syringe under argon atmosphere at room temperature. The mixture was continually stirred at room temperature until the imide was completely consumed as monitored by TLC analysis (typically, for ten to decades minutes). The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, and sequentially washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. 3-Hydroxy-3-(phenylethynyl)isoindolin-1-one (2b) was obtained from the reaction of phthalimide



Page 16 of 41

(147 mg, 1 mmol) with (phenylethynyl)magnesium bromide (2.5 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) gave 2b (199 mg, 80%) as a white solid, m.p. 158−162 oC. 1H NMR (600 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.47 – 7.36 (m, 5H), 7.25(s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 168.0,148.8, 133.4, 131.9, 130.6, 130.2, 129.6, 129.2, 123.2, 123.1, 121.7, 88.9, 82.3, 79.9. HRMS (ESI-TOF) calcd for C16H11NNaO2 [M+Na]+: 272.0682; found: 272.0679. N-ethyl-3-hydroxy-3-(phenylethynyl)isoindolin-1-one (2c) was obtained from the reaction of N-ethylphthalimide (175 mg, 1 mmol) with (phenylethynyl)magnesium bromide (1.2 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2c (241 mg, 87%) as a light yellow solid, m.p. 132−134 oC. 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.37 – 7.34 (m, 2H), 7.30 – 7.27 (m, 1H), 7.25 – 7.21 (m, 2H), 3.95 – 3.86 (br.s, 1H), 3.68 – 3.60 (m, 1H), 3.53 – 3.43 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H).

13

C NMR (151 MHz, CDCl3) δ 166.7, 146.1, 132.8,

131.9, 130.2, 130.0, 129.2, 128.4, 123.3, 122.5, 121.3, 85.1, 84.9, 83.8, 34.7, 14.3. HRMS (ESI-TOF) calcd for C18H15NNaO2 [M+Na]+: 300.0995; found: 300.0993. The reaction of N-benzyl-4-nitrophthalimide (3 mmol) with (phenylethynyl)magnesium bromide (3.5 mmol) gave 2e and 2f as a mixture of positional isomers (3.154 g, 83% total yield of two isomers). Each of them was isolated by silica gel column chromatography with petroleum ether/ethyl acetate (5/1, v/v). Major isomer: N-benzyl-3-hydroxy-6-nitro-3-(phenylethynyl)isoindolin-1-one (2e), light yellow solid, m.p. 154−158 oC. 1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.35 – 7.31 (m, 1H), 7.30 – 7.27 (m, 1H), 7.25 –


Page 17 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.13 (m, 6H), 4.89 (d, J = 15.4 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 4.54 (br.s, 1H).

13

C NMR (151

MHz, CDCl3) δ 164.8, 151.1, 149.6, 136.8, 131.9, 131.4, 129.6, 128.6, 128.4, 128.3, 128.1, 127.6, 124.0, 120.4, 119.1, 87.7, 83.4, 83.2, 43.6. HRMS (ESI-TOF) calcd for C23H16N2NaO4 [M+Na]+: 407.1002;

found:

407.1009.

Minor

isomer:

N-benzyl-3-hydroxy-5-nitro-3-(phenylethynyl)isoindolin-1-one (2f), gray solid, m.p. 180−184 oC. 1

H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.43 (d,

J = 7.0 Hz, 2H), 7.36 – 7.31 (m, 1H), 7.29 – 7.27 (m, 2H), 7.25 – 7.14 (m, 5H), 4.89 (d, J = 15.4 Hz, 1H), 4.82 (d, J = 15.5 Hz, 1H), 4.70 – 4.39 (br.s, 1H).

13

C NMR (151 MHz, CDCl3) δ 164.6, 151.2,

147.1, 136.9, 135.0, 132.0, 129.7, 128.6, 128.5, 128.4, 127.7, 125.7, 124.7, 120.4, 118.4, 87.7, 83.4, 83.2, 43.7. HRMS (ESI-TOF) calcd for C23H16N2NaO4 [M+Na]+: 407.1002; found: 407.1008. The reaction of N-benzyl-4-bromophthalimide (3 mmol) with (phenylethynyl)magnesium bromide (3.5 mmol) gave 2g and 2h as a mixture of positional isomers (712 mg, 85% total yield of two isomers). Each of them was isolated by column chromatography on silica gel with petroleum ether/ethyl

acetate

(5/1,

v/v)

gave

2g

and

2h.

Minor

isomer:

N-benzyl-6-bromo-3-hydroxy-3-(phenylethynyl)isoindolin-1-one (2g), white solid, m.p. 162−164 o

C. 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.43

(d, J = 7.2 Hz, 2H), 7.34 – 7.27 (m, 3H), 7.25 – 7.20 (m, 3H), 7.19 (d, J = 7.5 Hz, 2H), 4.84 (d, J = 15.5 Hz, 1H), 4.73 (d, J = 15.5 Hz, 1H), 3.96 (s, 1H);

13

C NMR (151 MHz, CDCl3) δ 165.7, 144.7,

137.3, 136.0, 131.9, 131.6, 129.3, 128.5, 128.4, 128.2, 127.4, 126.7, 124.4, 124.3, 120.9, 86.7, 83.9, 83.6, 43.4. HRMS (ESI-TOF) calcd for C23H16BrNNaO2 [M+Na]+: 440.0257; found: 440.0261. Major isomer: N-benzyl-5-bromo-3-hydroxy-3-(phenylethynyl)isoindolin-1-one (2h), white solid, m.p. 164−166 oC. 1H NMR (600 MHz, CDCl3) δ 7.88 (m, 1H), 7.62 (dd, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.32 (m, 1H), 7.27 (m, 2H), 7.23 (m, 5H), 4.85 (d, J = 15.5 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H), 3.94 (s, 1H);

13

C NMR (151 MHz, CDCl3) δ 166.2, 147.6, 137.3, 133.5,

132.0, 129.4, 128.6, 128.5, 128.4, 128.3, 127.6, 127.4, 126.2, 125.0, 120.8, 86.9, 83.8, 83.4, 43.3. HRMS (ESI-TOF) calcd for C23H16BrNNaO2 [M+Na]+: 440.0257; found: 440.0263. The reaction of N-benzyl-4-acetamidophthalimide (3 mmol) with (phenylethynyl)magnesium bromide



Page 18 of 41

(3.5 mmol) gave 2i and 2j as a mixture of positional isomers (341 mg, 86% total yield of two isomers). Each of them was isolated by column chromatography on silica gel with dichloromethane / ethyl acetate

(2/1,

v/v)

gave

and

2i

2j.

Minor

isomer:

N-(2-benzyl-1-hydroxy-3-oxo-1-(phenylethynyl)isoindolin-5-yl)acetamide (2i), yellow solid, m.p. 136−138 oC. 1H NMR (600 MHz, CDCl3) δ 9.37 – 9.06 (br.s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.35 (s, 1H), 7.30 – 7.27 (m, 1H), 7.25 – 7.17 (m, 5H), 7.14 (d, J = 7.4 Hz, 2H), 5.44 – 5.21 (br.s, 1H), 4.91 (d, J = 15.5 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 2.03 (s, 3H).

13

C NMR (151 MHz, CDCl3) δ 169.5, 167.1, 141.6, 140.0, 137.4, 131.9, 130.2, 129.0, 128.41,

128.36, 128.1, 127.3, 124.9, 123.6, 121.2, 113.7, 85.7, 84.7, 84.0, 43.3, 24.1. HRMS (ESI-TOF) calcd for

C25H21N2O3

[M+H]+:

397.1547;

found:

397.1556.

Major

isomer:

N-(2-benzyl-3-hydroxy-1-oxo-3-(phenylethynyl)isoindolin-5-yl)acetamide (2j), yellow solid, m.p. 134−136 oC. 1H NMR (600 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.17 (s, 1H), 7.67 (s, 2H), 7.61 (s, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.0 Hz, 1H), 7.33 – 7.25 (m, 4H), 7.21 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 4.83 (d, J = 16.0 Hz, 1H), 4.63 (d, J = 16.0 Hz, 1H), 2.11 (s, 3H).

13

C NMR (151

MHz, DMSO-d6) δ 169.4, 166.2, 148.5, 144.1, 138.8, 131.9, 129.7, 129.0, 128.5, 128.1, 127.1, 124.2, 124.0, 121.3, 120.5, 113.0, 87.3, 84.4, 82.8, 42.6, 24.6. HRMS (ESI-TOF) calcd for C25H21N2O3 [M+H]+: 397.1547; found: 397.1546. N-benzyl-3-hydroxy-3-(p-tolylethynyl)isoindolin-1-one (2k) was obtained from the reaction of Nbenzylphthalimide (237 mg, 1 mmol) with (p-tolylethynyl)magnesium bromide (1.2 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2k (307 mg, 87%) as a white solid, m.p. 158−160 oC. 1H NMR (600 MHz, CDCl3) δ 7.79 – 7.73 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.28−7.27 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 5.9 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 4.91−4.82 (m, 1H), 4.76−4.66 (m, 1H), 3.79−3.55 (m, 1H), 2.32 (s, 3H).

13

C NMR (151 MHz, CDCl3) δ 167.0, 146.1,

139.4, 137.7, 133.0, 131.8, 130.1, 129. 8, 129.0, 128.4, 127.3, 123.6, 122.6, 118.0, 86.5, 83.93, 83.88, 43.2, 21.5. HRMS (ESI-TOF) calcd forC24H19NNaO2 [M+Na]+: 392.1257; found: 392.1255. N-benzyl-3-hydroxy-3-((4-methoxyphenyl)ethynyl)isoindolin-1-one (2l) was obtained from the


Page 19 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


reaction of N-benzylphthalimide (237 mg, 1 mmol) with ((4-methoxyphenyl)ethynyl)magnesium bromide (1.2 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2l (302 mg, 82%) a white solid, m.p. 174−178 oC. 1H NMR (600 MHz, DMSO-d6) δ 7.80 (d, J = 7.4 Hz, 1H), 7.74 (t, J = 7.6 Hz, 2H), 7.77 − 7.72 (m, 1H), 7.60− 7.57 (br.s, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.87 (d, J = 16.0 Hz, 1H), 4.67 (d, J = 16.0 Hz, 1H), 3.75 (s, 3H). 13C NMR (151 MHz, DMSO−d6) δ 165.8, 159.7, 146.8, 138.1, , 132.9, 129.8, 129.5, 127.9, 127.5, 126.6, 122.7, 122.6, 114.1, 114.0, 112.6, 85.2, 84.0, 82.6, 55.2, 42.1. HRMS (ESI-TOF) calcd forC24H19NNaO3 [M+Na]+: 376.1308; found: 376.1307. N-benzyl-3-((4-bromophenyl)ethynyl)-3-hydroxyisoindolin-1-one (2m) was obtained from the reaction of N- benzylphthalimide (237 mg, 1 mmol) with ((4-bromophenyl)ethynyl)magnesium bromide (1.2 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2m (355 mg, 85%) as a white solid, m.p. 148−150 oC. 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.29 – 7.27(m, 2H), 7.24 – 7.19 (m, 1H), 7.01 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 15.5 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H), 3.73 − 3.43 (br.s, 1H). 13

C NMR (151 MHz, CDCl3) δ 166.9, 145.8, 137.7, 133.3, 133.1, 131.5, 130.3, 129.8, 128.5, 128.4,

127.3, 123.7, 123.6, 122.6, 120.0, 85.6, 85.1, 83.7, 43.1. HRMS (ESI-TOF) calcd for C23H15BrNO [M-OH]+: 400.0332; found: 400.0339. N-benzyl-3-(cyclopropylethynyl)-3-hydroxyisoindolin-1-one (2n) was obtained from the reaction of N-benzylphthalimide (1 mmol) with (cyclopropylethynyl)magnesium bromide (1.2 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2n (297 mg, 88%) as a white solid, m.p. 188−190 oC. 1H NMR (600 MHz, DMSO-d6) δ 7.73 – 7.64 (m, 3H), 7.57 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.3 Hz, 2H), 7.31 – 7.26 (m, 3H), 7.23 (t, J = 7.1 Hz, 1H), 4.74 (d, J = 16.0 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 1.21 – 1.12 (m, 1H), 0.68 – 0.57 (m, 2H), 0.30 – 0.21 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 166.7, 148.0, 139.0, 133.6, 130.5, 130.3, 128.7, 128.3, 127.4, 123.5, 123.3, 89.2, 83.1, 73.5, 42.8, 8.5, -0.5. HRMS (ESI-TOF) calcd



Page 20 of 41

forC20H17NNaO2 [M+Na]+: 326.1151; found: 326.1159. N-benzyl-3-(hex-1-yn-1-yl)-3-hydroxyisoindolin-1-one (2o) was obtained from the reaction of N-benzylphthalimide (3 mmol) with (n-butylethynyl)magnesium bromide (3.1 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 2o (917 mg, 95% yield) as a light yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.18 (, J = 7.6 Hz, 2H), 7.06 – 7.03 (m, 2H), 7.01−6.95 (m, 1H), 4.52 (d, J = 15.5 Hz, 1H), 4.37 (d, J = 15.5 Hz, 1H), 4.12−3.97 (br.s, 1H), 1.84 (t, J = 6.8 Hz, 2H), 1.14 – 1.07 (m, 2H), 1.06 – 1.07 (m, 2H), 0.63 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 167.1, 146.6, 137.8, 132.8, 129.8, 129.7, 128.7, 128.3, 128.2, 127.1, 123.4, 122.5, 87.7, 87.6, 83.6, 43.0, 30.0, 21.9, 18.2, 13.4.

HRMS (ESI-TOF) calcd for C21H21NNaO2 [M+Na]+: 342.1465; found:

342.1468. The reaction of N-benzyl-4-bromophthalimide (3 mmol) with (cyclopropylethynyl)magnesium bromide (3.5 mmol) gave 2p and 2r as a mixture of positional isomers (384 mg, 84% total yield of two isomers). Each of them was isolated by column chromatography on silica gel with dichloromethane/

ethyl

acetate

(45/1,

v/v).

Minor

isomer:

N-benzyl-6-bromo-3-(cyclopropylethynyl)-3-hydroxyisoindolin-1-one (2p), white solid, m.p. 146−148 oC. 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.71 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.25 – 7.21 (m, 1H), 4.77 (d, J = 15.5 Hz, 1H), 4.64 (d, J = 15.5 Hz, 1H), 3.35 (s, 1H), 1.16 – 1.08 (m, 1H), 0.69 (d, J = 8.4 Hz, 2H), 0.51 – 0.40 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 166.4, 145.8, 138.4, 136.7, 135.4, 132.5, 129.3, 129.1, 128.2, 127.5, 125.00, 124.96, 92.2, 84.1, 71.4, 44.0, 9.2, 0.8. HRMS (ESI-TOF) calcd for C20H16BrNNaO2 [M+Na]+:

404.0257;

found:

404.0252.

Major

isomer:

N-benzyl-5-bromo-3-(cyclopropylethynyl)-3-hydroxy isoindolin-1-one (2q), light yellow solid, m.p. 188−192 oC. 1H NMR (600 MHz, CDCl3) δ 7.78 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.25 – 7.21 (m, 1H), 4.76 (d, J = 15.5 Hz, 1H), 4.65 (d, J = 15.5 Hz, 1H), 3.42 (s, 1H), 1.17 – 1.12 (m, 1H), 0.73 – 0.69 (m, 2H), 0.51 – 0.46 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 166.9, 148.8, 138.4, 134.1, 129.4, 129.2, 129.1, 128.3, 128.2,


Page 21 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


126.9, 125.7, 92.4, 83.8, 71.3, 43.9, 9.2, 0.8. HRMS (ESI+) calcd for C20H16BrNNaO2 [M+Na]+: 404.0257; found: 404.0255. N-benzyl-7-hydroxy-7-(phenylethynyl)-6, 7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (2r) was obtained from the reaction of N-benzyl-3-azaphthalimide (10 mmol) with (phenylethynyl)magnesium bromide (10.5 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2r (1.1 g, 91%) as an yellow solid, m.p. 178−180 oC. 1H NMR (600 MHz, CDCl3) δ 8.78 – 8.72 (m, 1H), 8.16 – 8.10 (m, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.46 – 7.40 (m, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.25 – 7.21 (m, 2H), 7.17 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 7.5 Hz, 2H), 6.47 – 6.38 (br.s, 1H), 5.02 (d, J = 15.5 Hz, 1H), 4.92 (d, J = 15.5 Hz, 1H).

13

C NMR (151 MHz,

CDCl3) δ 165.1, 164.2, 152.9, 137.5, 132.6, 131.9, 129.2, 128.5, 128.4, 128.1, 127.3, 124.9, 124.2, 120.9, 87.8, 83.7, 83.1, 43.4. HRMS (ESI-TOF) calcd for C22H16N2NaO2 [M+Na]+: 363.1104; found: 363.1100. 7-(Cyclopropylethynyl)-7-hydroxy-6-methyl-6,

7-dihydro-5H-pyrrolo[3,4-b]pyridin-5one

(2s)

was obtained from the reaction of N-methyl-3-azaphthalimid (973 mg, 6 mmol) with (cyclopropylethynyl)magnesium bromide (6.5 mmol). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 2n (1.342 g, 98%) as a gray solid, m.p. 160−164 oC. 1H NMR (600 MHz, CDCl3) δ 8.77 – 8.71 (m, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.45 (dd, J = 7.4, 5.1 Hz, 1H), 6.16 – 5.95 (br.s, 1H), 3.16 (s, 3H), 1.23 – 1.15 (m, 1H), 0.76 – 0.67 (m, 2H), 0.63 – 0.56 (m, 1H), 0.55 – 0.48 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 164.5, 164.3, 152.5, 132.2, 124.6, 124.4, 91.8, 82.7, 69.6, 24.3, 8.4, -0.7. HRMS (ESI-FT-ICR) calcd for C13H12N2NaO2 [M+Na]+: 251.0791; found: 251.0789. General procedure for the annulation of 1 and 2 (Tables 2 and 3) To the mixture of α-oxo ketene dithioacetal 1 (0.3 mmol) and N-acyl ynone hemiaminal 2 (0.15 mmol) in toluene (0.5 mL) was added triflic acid (13 µL, 0.15 mmol) in one portion at 0 oC, then warmed to room temperature. The mixture was continually stirred until 2 was consumed as indicated by TLC (typically, for 4 h), and diluted with water (5 mL). Then a saturated aqueous solution of sodium carbonate (2 drops) was added, and the biphasic system was separated. The aqueous phase



Page 22 of 41

was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) to give the desired product 3. S-ethyl

5-(2-benzyl-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate

(3a):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (7/1, v/v) gave 3a (56 mg, 80%) as a yellow solid, m.p. 129−131 oC. 1H NMR (600 MHz, CDCl3) δ 7.90 – 7.88 (m, 1H), 7.52 – 7.46 (m, 2H), 7.36 – 7.31 (m, 3H), 7.25 (s, 1H), 7.23 – 7.20 (m, 2H), 7.16 – 7.14 (m, 3H), 7.06 – 7.04 (m, 2H), 5.36 (s, 1H), 4.99 (d, J = 15.1 Hz, 1H), 4.12 (d, J = 15.1 Hz, 1H), 2.89 (q, J = 7.4 Hz, 2H), 2.39 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H).

13

C NMR (151 MHz, CDCl3) δ 186.7, 168.1,

157.1, 143.4, 142.9, 136.8, 132.0, 131.8, 130.7, 130.0, 128.8, 128.4, 128.3, 128.2, 128.1, 127.3, 126.8, 123.9, 122.7, 122.2, 55.6, 44.6, 23.5, 14.6, 14.4. HRMS (ESI-TOF) calcd for C29H25NNaO3S [M+Na]+: 490.1447; found: 490.1455. S-methyl


(3b):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (8/1, v/v) gave 3b (37 mg, 54%) as a yellow solid, m.p. 160−162 oC. 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 6.4 Hz, 1H), 7.53 –7.47 (m, 2H), 7.34 (d, J = 7.3 Hz, 3H), 7.25 – 7.15 (m, 6H), 7.08 – 7.04 (m, 2H), 5.35 (s, 1H), 4.98 (d, J = 15.1 Hz, 1H), 4.15 (d, J = 15.1 Hz, 1H), 2.40 (s, 3H), 2.28 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 186.9, 168.2, 157.2, 143.5, 142.9, 136.8, 132.0, 131.8, 130.7, 130.1, 128.8, 128.4, 128.3, 128.2, 128.1, 127.3, 126.7, 124.0, 122.7, 122.0, 55.7, 44.7, 14.4, 11.8. HRMS (ESI-TOF) calcd for C28H24NO3S [M+H]+: 454.1471; found: 454.1475. S-butyl


(3c):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 3c (59 mg, 79%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 7.2 Hz, 1H), 7.54 – 7.45 (m, 3H), 7.35 – 7.31 (m, 3H), 7.21 (d, J = 6.4 Hz, 2H), 7.16 (d, J = 6.1 Hz, 3H), 7.04 (d, J = 6.4 Hz, 2H), 5.36 (s, 1H), 4.96 (d, J = 15.1 Hz, 1H), 4.12 (d, J = 15.1 Hz, 1H), 2.88 (t, J = 7.3 Hz, 2H), 2.38 (s, 3H), 1.55 – 1.47 (m, 2H), 1.36 – 1.29 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.2, 157.0, 143.3, 142.9, 136.8, 132.0, 131.8, 130.7, 130.0, 128.8, 128.4, 128.3,


Page 23 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


128.12, 128.10, 127.3, 126.8, 123.9, 122.7, 122.3, 55.7, 44.6, 31.5, 28.7, 21.9, 14.4, 13.5. HRMS (ESI-TOF) calcd for C31H30NO3S [M+H]+: 496.1941; found: 496.1947. S-hexyl


(3d):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (7/1, v/v) gave 3d (65 mg, 83%) as a light yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 6.8 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H), 7.34 – 7.30 (m, 3H), 7.25 – 7.19 (m, 3H), 7.16 (d, J = 6.4 Hz, 3H), 7.04 (d, J = 5.9 Hz, 2H), 5.36 (s, 1H), 4.97 (d, J = 15.1 Hz, 1H), 4.12 (d, J = 15.1 Hz, 1H), 2.88 (t, J = 7.3 Hz, 2H), 2.38 (s, 3H), 1.52 – 1.49 (m, 2H), 1.33 – 1.22 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.1, 156.9, 143.4, 142.9, 136.8, 132.1, 131.8, 130.7, 130.0, 128.8, 128.4, 128.3, 128.11, 128.10, , 127.3, 126.8, 123.9, 122.7, 122.3, 55.7, 44.6, 31.3, 29.4, 29.0, 28.5, 22.5, 14.4, 13.9. HRMS (ESI-TOF) calcd for C33H34NO3S [M+H]+: 524.2254; found: 524.2257. S-ethyl 5-(2-benzyl-3-oxoisoindolin-1-yl)-2-ethyl-4-phenylfuran-3-carbothioate (3e): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (12/1, v/v) gave 3e (50 mg, 69%) as a yellow solid, m.p. 117−120 oC. 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 6.6 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.35 – 7.28 (m, 3H), 7.23 (d, J = 7.4 Hz, 1H), 7.21– 7.13 (m, 5H), 7.08 – 7.01 (m, 2H), 5.37 (s, 1H), 5.05 (d, J = 15.0 Hz, 1H), 4.03 (d, J =15.1, 1H), 2.88 (q, J = 7.4 Hz, 2H), 2.83 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.2, 161.7, 143.4, 142.9, 136.8, 132.0, 131.7, 130.7, 130.0, 128.7, 128.5, 128.3, 128.11, 128.01, 127.4, 126.6, 123.9, 122.7, 121.5, 55.7, 44.6, 23.5, 21.6, 14.6, 12.1. HRMS (ESI-TOF) calcd for C30H28NO3S [M+H]+: 482.1784; found: 482.1788. S-ethyl

5-(2-benzyl-3-oxoisoindolin-1-yl)-2-(but-3-en-1-yl)-4-phenylfuran-3-carbothioate (3f):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (12/1, v/v) gave 3f (47 mg, 62%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 5.5 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.36 – 7.28 (m, 3H), 7.23 (d, J = 6.1 Hz, 1H), 7.21 – 7.13 (m, 5H), 7.08 – 7.00 (m, 2H), 5.76 – 5.64 (m, 1H), 5.35 (s, 1H), 5.10 (d, J = 15.0 Hz, 1H), 4.92 – 4.86 (m, 2H), 3.99 (d, J = 15.1 Hz, 1H), 2.97 – 2.84 (m, 4H), 2.33 – 2.25 (m, 2H), 1.21 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.2, 159.8, 143.6, 142.9, 136.8, 136.6, 132.0, 131.7, 130.6, 130.0, 128.8, 128.5, 128.3,



Page 24 of 41

128.14, 128.01, 127.4, 123.9, 123.9, 122.6, 122.2, 115.7, 55.6, 44.5, 31.8, 27.5, 23.6, 14.6. HRMS (ESI-TOF) calcd for C32H30NO3S [M+H]+: 508.1941; found: 508.1943. Ethyl 3-{5-(2-benzyl-3-oxoisoindolin-1-yl)-3-[(ethylthio)carbonyl]-4-phenylfuran-2-yl}propionate (3g): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (5/1, v/v) gave 3g (43 mg, 52%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 6.4 Hz, 1H), 7.49 (dd, J = 8.9, 3.5 Hz, 2H), 7.36 – 7.28 (m, 3H), 7.23 (d, J = 6.9 Hz, 1H), 7.20 – 7.15 (m, 5H), 7.08 – 7.02 (m, 2H), 5.35 (s, 1H), 5.02 (d, J = 15.1 Hz, 1H), 4.06 (d, J = 15.1 Hz, 1H), 4.04 – 3.97 (m, 2H), 3.17 – 3.09 (m, 2H), 2.88 (q, J = 7.4 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.23 – 1.17 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 186.7, 171.7, 168.1, 158.2, 143.9, 142.8, 136.8, 132.0, 131.8, 130.4, 130.1, 128.8, 128.5, 128.3, 128.2, 128.1, 127.4, 126.6, 123.9, 122.6, 122.4, 60.6, 55.7, 44.6, 31.9, 23.7, 23.6, 14.6, 14.1. HRMS (ESI-TOF) calcd for C33H32NO5S [M+H]+: 554.1996; found: 554.1999. S-ethyl 5-(2-ethyl-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate (3j): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (8/1, v/v) gave 3j (46 mg, 74%) as a white solid, m.p. 121−123 oC. 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.45 – 7.39 (m, 3H), 7.37 (d, J = 6.4 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 5.42 (s, 1H), 3.83 – 3.74 (m, 1H), 3.08 – 3.01 (m, 1H), 2.88 (q, J = 7.4 Hz, 2H), 2.48 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.6, 167.7, 157.2, 143.9, 142.7, 132.6, 131.5, 131.0, 130.2, 128.7, 128.43, 128.37, 126.7, 123.7, 122.6, 122.3, 55.4, 35.3, 23.4, 14.64, 14.57, 13.4. HRMS (ESI-TOF) calcd for C24H24NO3S [M+H]+: 406.1471; found: 406.1478. S-ethyl 5-(2-benzyl-4-nitro-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate (3k): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 3k (57 mg, 74%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.23 – 7.18 (m, 5H), 7.15 (d, J = 6.1 Hz, 2H), 7.02 – 6.98 (m, 2H), 6.04 (s, 1H), 5.07 (d, J = 15.1 Hz, 1H), 4.09 (d, J = 15.1 Hz, 1H), 2.83 (q, J = 7.4 Hz, 2H), 2.49 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.6, 165.0, 156.4,


Page 25 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


143.6, 141.5, 136.8, 136.2, 136.0, 130.4, 130.3, 130.0, 129.6, 128.6, 128.1, 128.04, 128.01, 127.7, 127. 1, 125.7, 122.7, 57.0, 44.4, 23.4, 14.6, 14.5. HRMS (ESI-TOF) calcd for C29H25N2O5S [M+H]+: 513.1479; found: 513.1483. S-ethyl

5-(2-benzyl-5-nitro-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate

(3l):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) gave 3l (55 mg, 72%) as a light yellow solid, m.p. 160−162 oC. 1H NMR (600 MHz, CDCl3) δ 8.71 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.38 – 7.31 (m, 3H), 7.22 – 7.16 (m, 5H), 7.05 (d, J = 6.5 Hz, 2H), 5.46 (s, 1H), 5.01 (d, J = 15.1 Hz, 1H), 4.15 (d, J = 15.1 Hz, 1H), 2.89 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.5, 165.8, 157.47, 149.0, 148.4, 141.7, 136.1, 133.8, 130.2, 129.9, 128.6, 128.5, 128.1, 127.7, 127.6, 126.8, 123.9, 122.4, 119.6, 55.8, 44.9, 23.5, 14.6, 14.4. HRMS (ESI-TOF) calcd for: C29H24N2NaO5S [M+Na]+: 535.1298; found: 535.1303. S-ethyl 5-(2-benzyl-6-nitro-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate (3m): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) gave 3m (45 mg, 59%) as a yellow solid, m.p. 126−128 oC. 1H NMR (600 MHz, CDCl3) δ 8.36 (d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 7.0 Hz, 3H), 7.25 – 7.15 (m, 5H), 7.04 (d, J = 6.7 Hz, 2H), 5.47 (s, 1H), 5.00 (d, J = 15.0 Hz, 1H), 4.17 (d, J = 15.0 Hz, 1H), 2.89 (q, J = 7.4 Hz, 2H), 2.41 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.5, 165.8, 157.5, 150.4, 143.8, 141.6, 137.4, 136.0 130.2, 130.0, 128.6, 128.50, 128.47, 128.1, 127.8, 127.7, 125.0, 124.6, 122.5, 118.5, 55.8, 45.0, 23.5, 14.6, 14.4. HRMS (ESI-TOF) calcd for C29H24N2NaO5S [M+Na]+: 535.1298; found: 535.1300. S-ethyl 5-(2-benzyl-5-bromo-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate (3n): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 3n (62 mg, 76%) as a yellow solid, m.p. 151−153 oC. 1H NMR (600 MHz, CDCl3) δ 8.02 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.38 – 7.30 (m, 3H), 7.22 – 7.14 (m, 5H), 7.11 (d, J = 7.5 Hz, 1H), 7.03 (s, 2H), 5.31 (s, 1H), 4.96 (d, J = 15.0 Hz, 1H), 4.11 (d, J = 15.0 Hz, 1H), 2.93 – 2.84 (m, 2H), 2.39 (s, 3H), 1.24 – 1.15 (m, 3H).

13

C NMR (151 MHz, CDCl3) δ 186.6, 166.6, 157.2, 142.7, 141.5, 136.5,



Page 26 of 41

134.8, 134.1, 130.5, 130.0, 128.5, 128.4, 128.3, 128.1, 127.5, 127.2, 127.1, 124.3, 123.0, 122.3, 55.5, 44.8, 23.5, 14.6, 14.4. HRMS (ESI-TOF) calcd for C29H25BrNO3S [M+H]+: 546.0733; found: 546.0737. S-ethyl 5-(2-benzyl-6-bromo-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate (3o): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1, v/v) gave 3o (58 mg, 71%) a yellow solid, m.p. 157−159 oC. 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.36 – 7.31 (m, 3H), 7.22 – 7.14 (m, 5H), 7.02 (d, J = 6.7 Hz, 2H), 5.33 (s, 1H), 4.95 (d, J = 15.1 Hz, 1H), 4.10 (d, J = 15.1 Hz, 1H), 2.89 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.6, 167.2, 157.3, 144.6, 142.6, 136.5, 132.3, 131.0, 130.4, 130.0, 128.5, 128.4, 128.3, 128.0, 127.4, 127.2, 126.5, 126.1, 125.3, 122.3, 55.3, 44.7, 23.5, 14.6, 14.5. HRMS (ESI-TOF) calcd for C29H25BrNO3S [M+H]+: 546.0733; found: 546.0737. S-ethyl

5-(5-acetamido-2-benzyl-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate

(3p): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) gave 3p (30 mg, 38%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 7.32 (s, 3H), 7.24 – 7.14 (m, 6H), 7.03 (d, J = 5.3 Hz, 2H), 5.36 (s, 1H), 4.93 (d, J = 15.1 Hz, 1H), 4.15 (d, J = 15.1 Hz, 1H), 2.91 – 2.86 (m, 2H), 2.39 (s, 3H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.7, 168.9, 168.3, 157.1, 143.1, 139.7, 137.9, 136.5, 132.3, 130.6, 130.0, 128.5, 128.3, 128.2, 127.8, 127.5, 126.9, 123.9, 123.4, 122.2, 114.7, 55.8, 44.8, 24.5, 23.5, 14.6, 14.4. HRMS (ESI-TOF) calcd for C31H28N2NaO4S [M+Na]+: 547.1662; found: 547.1662. S-ethyl

5-(6-acetamido-2-benzyl-3-oxoisoindolin-1-yl)-2-methyl-4-phenylfuran-3-carbothioate

(3q): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) gave 3q (56 mg, 71%) as a yellow solid, m.p. 156−160 oC. 1H NMR (600 MHz, CDCl3) δ 7.85 – 7.71 (m, 3H), 7.39 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.3 Hz, 3H), 7.20 (d, J = 6.7 Hz, 2H), 7.18 – 7.11 (m, 3H), 7.01 (d, J = 6.5 Hz, 2H), 5.32 (s, 1H), 4.93 (d, J = 15.1 Hz, 1H), 4.10 (d, J = 15.1 Hz, 1H), 2.88 (q, J = 7.3 Hz, 2H), 2.38 (s, 3H), 2.17 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ


Page 27 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


186.9, 168.6, 167.9, 157.1, 144.4, 143.2, 141.7, 136.7, 130.6, 130.1, 128.4, 128.30, 128.27, 128.2, 128.0, 127.3, 127.0, 124.5, 122.2, 119.9, 113.6, 55.7, 44.7, 24.6, 23.5, 14.6, 14.5. HRMS (ESI-TOF) calcd for C31H28N2NaO4S [M+Na]+: 547.1662; found: 547.1667. S-ethyl

5-(2-benzyl-3-oxoisoindolin-1-yl)-2-methyl-4-(p-tolyl)furan-3-carbothioate

(3r) ：

Purification by flash column chromatography eluting with petroleum ether/ ethyl acetate (10/1, v/v) gave 3r (42 mg, 58%) as a yellow solid, m.p. 135−137 oC 1H NMR (600 MHz, CDCl3) δ 7.92 – 7.88 (m, 1H), 7.52 – 7.45 (m, 2H), 7.24 (d, J = 6.6 Hz, 1H), 7.19−7.09 (m, 7H), 7.04 (d, J = 6.5 Hz, 2H), 5.36 (s, 1H), 4.96 (d, J = 15.0 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H), 2.89 (q, J = 7.4 Hz, 2H), 2.37 (s, 6H), 1.22 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.2, 157.1, 143.3, 143.0, 138.0, 136.9, 132.1, 131.78, 129. 9, 129.1, 128.7, 128.4, 128.1, 127.6, 127.3, 126.8, 123.9, 122.7, 122.2, 55. 7, 44.6, 23.4, 21.3, 14.7, 14.5. HRMS (ESI-TOF) calcd forC30H28NO3S [M+H]+: 482.1784; found: 482.1782. S-ethyl

5-(2-benzyl-3-oxoisoindolin-1-yl)-4-(4-methoxyphenyl)-2-methylfuran-3-carbothioate

(3s)：Purification by flash column chromatography eluting with petroleum ether/ ethyl acetate (10/1, v/v) gave 3s (42 mg, 56%) as a yellow solid, m.p. 138−139 oC. 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 6.4 Hz, 1H), 7.53−7.46 (m, 2H), 7.24 (d, J = 6.9 Hz, 1H), 7.19 – 7.17 (m, 3H), 7.12 (d, J = 8.5 Hz, 2H), 7.07 – 7.04 (m, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.36 (s, 1H), 4.99 (d, J = 15.1 Hz, 1H), 4.12 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 2.89 (q, J = 7.4 Hz, 2H), 2.38 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.8, 168.2, 159.6, 157.1, 143.3, 143.0, 136.9, 132.0, 131.8, 131.2, 128.8, 128.4, 128.1, 127.3, 126.4, 123.9, 122.72, 122.67, 122.2, 113.8, 55.7, 55.2, 44.6, 23.4, 14.7, 14.5. HRMS (ESI-TOF) calcd for C30H28NO4S [M+H]+: 482.1784; found: 482.1782. S-ethyl 5-(2-benzyl-3-oxoisoindolin-1-yl)-4-(4-bromophenyl)-2-methylfuran-3-carbothioate (3t): Purification by flash column chromatography eluting with petroleum ether/ ethyl acetate (10/1, v/v) gave 3t (44 mg, 52%) as a yellow solid, m.p. 131−133 oC. 1H NMR (600 MHz, CDCl3) δ 7.93 – 7.89 (m, 1H), 7.52 – 7.48 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.23 – 7.17 (m, 4H), 7.04 (d, J = 6.5 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 5.32 (s, 1H), 5.06 (d, J = 15.2 Hz, 1H), 4.08 (d, J = 15.2 Hz, 1H), 2.90 (q, J = 7.4 Hz, 2H), 2.41 (s, 3H), 1.23 (t, J = 7.4 Hz, 3H).

13

C NMR (151 MHz, CDCl3) δ 186.4, 168.2,



Page 28 of 41

157.4, 143.7, 142.6, 136.7, 132.0, 131.8, 131.52, 131.50, 129.7, 128.9, 128.5, 127.9, 127.5, 125.6, 124.1, 122.6, 122.5, 122.0, 55.5, 44.6, 23.5, 14.6, 14.54. HRMS (ESI-TOF) calcd for C29H25BrNO3S [M+H]+: 546.0733; found: 546.0734. S-ethyl

5-(2-benzyl-3-oxoisoindolin-1-yl)-4-cyclopropyl-2-methylfuran-3-carbothioate

(3u):

Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (7/1, v/v) gave 3u (51 mg, 79%) as a light yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.96 – 7.91 (m, 1H), 7.53 – 7.47 (m, 2H), 7.29 – 7.27 (m, 1H), 7.25 – 7.21 (m, 2H), 7.19 (d, J = 7.2 Hz, 2H), 7.17 – 7.14 (m, 1H), 5.69 (s, 1H), 5.14 (d, J = 15.1 Hz, 1H), 4.07 (d, J = 15.1 Hz, 1H), 3.04 (q, J = 7.4 Hz, 2H), 2.31 (s, 3H), 1.61 (s, 1H), 1.34 (t, J = 7.4 Hz, 3H), 0.85 – 0.79 (m, 1H), 0.78 – 0.72 (m, 1H), 0.452 – 0.45 (m, 1H), 0.29 – 0.23 (m, 1H).

13

C NMR (151 MHz, CDCl3) δ 187.0, 168.3, 156.6, 143.6, 143.0, 137.0,

132.1, 131.7, 128.7, 128.5, 128.2, 127.5, 126.1, 124.0, 123.4, 122.6, 55.7, 44.6, 23.4, 14.7, 14.5, 7.7, 6.8, 5.7. HRMS (ESI-TOF) calcd for C26H26NO3S [M+H]+: 432.1628; found: 432.1632. S-ethyl 5-(2-benzyl-3-oxoisoindolin-1-yl)-4-butyl-2-methylfuran-3-carbothioate (3v): Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (8/1, v/v) gave 3v (52 mg, 77%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.97 – 7.91 (m, 1H), 7.53 – 7.43 (m, 2H), 7.30 – 7.27 (m,2H), 7.25 – 7.22 (m, 1H), 7.21 – 7.16 (m, 3H), 5.42 (s, 1H), 5.16 (d, J = 15.1 Hz, 1H), 4.01 (d, J = 15.1 Hz, 1H), 3.03 (q, J = 7.4 Hz, 2H), 2.61 – 2.51 (m, 1H), 2.39 (s, 3H), 2.28 – 2.18 (m, 1H), 1.42 – 1.35 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H), 1.28 – 1.20 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.7, 168.1, 157.4, 143.0, 142.0, 137.0, 132.1, 131.8, 128.7, 128.5, 128.1, 127.5, 125.7, 123.9, 122.7, 122.4, 55.5, 44.4, 33.3, 23.5, 23.3, 22.6, 15.0, 14.8, 13.7. HRMS (ESI-TOF) calcd for C27H30NO3S [M+H]+: 448.1941; found: 448.1944. S-ethyl 5-(2-benzyl-5-bromo-3-oxoisoindolin-1-yl)-4-cyclopropyl-2-methylfuran- 3-carbothioate (3w): Purification by flash column chromatography eluting with petroleum ether/actone (20/1, v/v) gave 3w (47 mg, 61%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.30 – 7.27 (m, 2H), 7.25 – 7.21 (m, 1H), 7.17 (d, J = 7.1 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 5.10 (d, J = 15.1 Hz, 1H), 4.07 (d, J = 15.1 Hz, 1H), 3.04 (q, J = 7.4 Hz, 2H), 2.31 (s, 3H), 1.78 – 1.66 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 0.86 – 0.79 (m, 1H), 0.78 – 0.70 (m, 1H), 0.48 – 0.41 (m,


Page 29 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1H), 0.31 – 0.21 (m, 1H).


13

C NMR (151 MHz, CDCl3) δ 186.9, 166.8, 156.7, 142.8, 141.6, 136.6,

134.7, 134.1, 128.6, 128.2, 127.6, 127.2, 126.4, 124.2, 123.4, 122.9, 55.5, 44.8, 23.5, 14.7, 14.5, 7.7, 6.8, 5.7. HRMS (ESI-TOF) calcd for C26H24BrNNaO3S [M+Na]+: 532.0552; found: 532.0555. S-ethyl 5-(2-benzyl-6-bromo-3-oxoisoindolin-1-yl)-4-cyclopropyl-2-methylfuran-3- carbothioate (3x): Purification by flash column chromatography eluting with petroleum ether/actone (20/1, v/v) gave 3x (44 mg, 57%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.25 – 7.22 (m, 2H), 7.17 (d, J = 7.4 Hz, 2H), 5.66 (s, 1H), 5.11 (d, J = 15.1 Hz, 1H), 4.05 (d, J = 15.1 Hz, 1H), 3.04 (q, J = 7.4 Hz, 2H), 2.33 (s, 3H), 1.66 – 1.60 (m, 1H), 1.35 (t, J = 7.4 Hz, 3H), 0.85 – 0.73 (m, 2H), 0.49 – 0.40 (m, 1H), 0.29 – 0.22 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 186.9, 167.3, 156.8, 144.7, 142.7, 136.6, 132.2, 131.1, 128.6, 128.1, 127.6, 126.55, 126.46, 126.0, 125.4, 123.5, 55.3, 44.7, 23.5, 14.7, 14.5, 7.8, 6.8, 5.7. HRMS (ESI-TOF) calcd for C26H24BrNNaO3S [M+Na]+: 532.0552; found: 532.0555. S-ethyl 5-(6-benzyl-5-oxo-6, 7-dihydro-5H-pyrrolo[3, 4-b]pyridin-7-yl)- 2-methyl-4-phenylfuran-3-carbothioate (3y): Purification by flash column chromatography eluting with petroleum ether/ ethyl acetate (5/1, v/v) gave 3y (43 mg, 61%) as a white solid, m.p. 136−138 oC. 1H NMR (600 MHz, CDCl3) δ 8.73 – 8.67 (m, 1H), 8.16 – 8.09 (m, 1H), 7.45 – 7.37 (m, 3H), 7.34 (d, J = 2.4 Hz, 3H), 7.19 – 7.10 (m, 3H), 7.00 (d, J = 6.8 Hz, 2H), 5.40 (s, 1H), 4.97 (d, J = 14.8 Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 2.88 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H).

13

C NMR (151 MHz,

CDCl3) δ 186.7, 166.2, 163.0, 157.0, 152.9, 142.1, 136.3, 131.9, 130.5, 130.3, 128.5, 128.3, 128.14, 128.13, 127.8, 127.5, 126.1, 123.7, 122.3, 57.1, 44.6, 23.4, 14.6, 14.4; HRMS (ESI-TOF) calcd for C28H24N2NaO3S [M+Na]+: 491.1400; found: 491.1398. S-ethyl 4-cyclopropyl-2-methyl-5-(6-methyl-5-oxo-6, 7-dihydro- 5H-pyrrolo[3, 4-b]-pyridin7-yl)-furan-3-carbothioate (3z): Purification by flash column chromatography eluting with petroleum ether/ ethyl acetate (2/1, v/v) gave 3z (35 mg, 65%) as a light yellow solid, m.p. 106−108 o

C. 1H NMR (600 MHz, CDCl3) δ 8.69 (d, J = 3.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.42 (dd, J = 7.1,

5.1 Hz, 1H), 5.82 (s, 1H), 3.08 – 3.02 (m, 2H), 3.01 (s, 3H), 2.38 (s, 3H), 1.89 – 1.81 (m, 1H), 1.34 (t, J = 7.4 Hz, 3H), 0.99 (d, J = 7.9 Hz, 2H), 0.92 – 0.82 (m, 1H), 0.61 – 0.52 (m, 1H). 13C NMR (151



Page 30 of 41

MHz, CDCl3) δ 186.9, 166.5, 162.7, 156.8, 152.7, 142.5, 131.7, 127.4, 126.2, 123.70, 123.65, 59.3, 27.4, 23.4, 14.8, 14.6, 7.7, 7.2, 5.6. HRMS (ESI-TOF) calcd for C19H21N2O3S [M+H]+: 357.1267; found: 357.1270. Scale-up synthesis and functional transformations of 3a (Scheme 3) A. Scale-up synthesis of 3a: To a 50 mL flask was added the suspension of 1a (1.90 g, 10 mmol) and 2a (5 mmol, 1.70 g) in toluene (16 mL). Then triflic acid (440 µL, 5 mmol) was added dropwise via syringe at 0 oC with continual stirring. The reaction mixture was warmed to room temperature, and stirred until 2a was consumed as indicated by TLC (for ca. 5 h). Then a saturated aqueous solution of sodium carbonate was added, and the biphasic system was separated. The aqueous phase was extracted with ethyl acetate. The organic phase was combined, and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 7/1, v/v) to provide compound 3a (1,519 mg, 65%). B. Hydrolysis of 3a: To a stirred mixture of compound 3a (140 mg, 0.3 mmol) in methanol (2 mL) was added aqueous solution (0.5 mL) of lithium hydroxide monohydrate (25 mg, 0.6 mmol) and urea hydrogen peroxide(55 mg, 0.6 mmol) at room temperature. The mixture was stirred at room temperature until 3a was completely consumed as indicated by TLC analysis (overnight), neutralized with 2 M aqueous HCl, stirred at room temperature for 30 min, extracted with CH2Cl2, and dried over anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude product was purified by silica gel chromatography with petroleum ether/ethyl acetate/acetic acid (5/1/, v/v, 0.2% AcOH) to provide compound 3aa (116 mg, 91% yield) as a white solid, m.p. 265−277 oC. 1H NMR


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(600 MHz, DMSO-d6) δ 12.36−12.13 (br.s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.64 – 7.60 (m, 1H), 7.58 – 7.54 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.35 – 7.31 (m, 3H), 7.30 – 7.26 (m, 2H), 7.19 – 7.13 (m, 3H), 6.99 – 6.93 (m, 2H), 5.34 (s, 1H), 4.71 (d, J = 15.3 Hz, 1H), 4.13 (d, J = 15.3 Hz, 1H), 2.31 (s, 3H). 13

C NMR (151 MHz, DMSO-d6) δ 167.6, 164.5, 159.6, 143.31, 143.27, 137.3, 132.7, 131.9, 131.6,

130.3, 129.5, 128.7, 128.33, 128.26, 128.0, 127.9, 127.6, 123.7, 123.7, 114.6, 55.7, 44.4, 14.2. HRMS (ESI-TOF) calcd for C27H22NO4 [M+H]+: 424.1543; found: 424.1547. C. Fukuyama reduction of 3a: The reaction is referred to the literature.

12

To a stirred mixture of

compound 3a (46 mg, 0.1 mmol) and 5% Pd/C (22 mg, 0.01 mmol, 10 mol% loading) in dry acetone was added Et3SiH (48 µL, 0.3 mmol) at room temperature under argon atmosphere. Stirring was continued at room temperature until the reduction was completed as indicated by TLC analysis. The catalyst was filtered off through Celite, and washed with acetone. After the solvent was removed under reduced pressure, the crude product was purified by silica gel chromatography with petroleum ether/ethyl acetate (5/1, v/v) to provide compound 3ab (29 mg, 71%) as a white solid, m.p. 140−142 o

C. 1H NMR (600 MHz, CDCl3) δ 9.80 (s, 1H), 7.97 – 7.90 (m, 1H), 7.55 – 7.48 (m, 2H), 7.42 – 7.34

(m, 3H), 7.25 – 7.23 (m, 3H), 7.19 – 7.10 (m, 3H), 7.02 (d, J = 6.9 Hz, 2H), 5.48 (s, 1H), 4.98 (d, J = 15.0 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H), 2.42 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 185.9, 168.1, 161.6, 143.5, 142.7, 136.7, 132.1, 131.9, 129.7, 129.4, 128.9, 128.8, 128.43, 128.38, 128.1, 127.5, 127.4, 124.1, 122.6, 120.6, 55.5, 44.7, 13.5. HRMS (ESI-TOF) calcd for C27H22NO3 [M+H]+: 408.1594; found: 408.1595. D. Oxidation of 3a with cerium(IV) ammonium nitrate: Cerium(IV) ammonium nitrate (CAN, 548 mg, 1.0 mmol) was added to a solution of compound 3a (46 mg, 0.1mmol) in acetonitrile (5 mL)



Page 32 of 41

and water (1 mL). The reaction was left to stir at room temperature overnight. The aqueous layer was diluted with brine. The aqueous and organic layers separated. The aqueous layer was then extracted with EtOAc. The combined organic layer was dried (Na2SO4), and concentrated in vacuo. Column chromatography (silica; petroleum ether/ethyl acetate, 10/1, v/v) afforded product 3ac (27 mg, 97%) as a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.3 Hz, 2H), 7.46 – 7.38 (m, 3H), 4.28 – 3.96 (br.s, 1H), 3.06 – 2.94 (m, 2H), 1.89 (s, 3H), 1.25 (t, J = 7.4 Hz, 3H).

13

C NMR (151 MHz,

CDCl3) δ 189.8, 168.1, 154.0, 131.7, 130.4, 129.4, 128.5, 127.5, 103.7, 24.6, 24.0, 14.0. HRMS (ESI-FT-ICR) calcd for C14H14NaO4S [M+Na]+: 301.0505; found: 301.0504; calcd for C14H13O4S [M-H]−: 277.0540; found: 227.0540.

E. Aerobic oxidation of 3a: To the solution of compound 3a (46 mg, 0.1 mmol) in dry THF (2 mL) was added NaH (60% suspended in mineral oil, 6 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred (overnight) at room temperature until 3a was consumed as indicated by TLC analysis. The mixture was diluted with water, and extracted 3 times with EtOAc. The combined organic layer was dried with anhydrous Na2SO4. After the solvent was removed under reduced pressure, the crude product was purified by silica gel chromatography with petroleum ether/ ethyl acetate (5/1, v/v) to provide compound 3ad (40 mg, 83%) as a yellow solid, m.p. 172−176 oC. 1H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 6.9 Hz, 1H), 7.41 (t, J = 7.1 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.30 – 7.27 (m, 3H), 7.25 – 7.21 (m, 4H), 7.20 – 7.16 (m, 1H), 7.03 (d, J = 6.9 Hz, 2H), 4.50 (s, 2H), 3.08 – 3.02 (br.s, 1H), 2.78 (q, J = 7.4 Hz, 2H), 2.36 (s, 3H), 1.13 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 186.7, 167.0, 155.7, 145.8, 143.6, 137.5, 132.4, 130.9, 130.6,


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130.1, 130.0, 128.4, 128.2, 128.0, 127.8, 127.2, 123.9, 123.5, 123.3, 122.6, 88.5, 42.9, 23.4, 14.5, 14.3. HRMS (ESI-TOF) calcd for C29H25NNaO4S [M+Na]+: 506.1397; found: 506.1397. Synthesis of deuterated compound D4-1a The synthesis was referred to the literature procedure.6d To a well-stirred suspension of t-BuOK (2,693 mg, 24 mmol) in deuterated acetone (772 mg, 12 mmol) and dry THF (30 mL) was added CS2 (725 µL, 24 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 0.5 h, EtBr (1.8 mL, 24 mmol) was added dropwise within 15 min. The mixture was allowed to warm to room temperature and stirred for 12 h, then poured into ice-water (100 mL) with stirring, and extracted with CH2Cl2 (3 × 30 mL). The combined organic phase was washed with water (3 × 25 mL), dried over MgSO4, and concentrated in vacuum. The crude product was purified by silica gel chromatography petroleum ether/ ethyl acetate (10/1, v/v) to provide compound D4-1a (1.28 g, 55%) as a yellow solid, m.p. 66–68 oC.6d 1H NMR (600 MHz, CDCl3) δ 6.09 (s, 0.16 H, 84% D), 3.02 (q, J = 7.4 Hz, 2H), 2.94 (q, J = 7.4 Hz, 2H), 2.19 – 2.12 (m, 0.46H, 85% D), 1.38 (t, J = 7.4 Hz, 3H), 1.34 (t, J = 7.4 Hz, 3H).

Supporting Information The crystal data for 3a, 1H NMR and

13

C NMR spectra for new compounds, 1H NMR spectra for

D4-1a and D4-3a. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected] Notes



Page 34 of 41

The authors declare no competing financial interest. Acknowledgement The authors thank the financial support from NSFC of China (20971105), the Science Foundation of Chongqing Science & Technology Commission (cstc2017jcyjAX0423), and the Fundamental Research Funds for the Central Universities (XDJK2012B011). References and Footnotes (1) For reviews, see: (a) Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity. Chem. Rev. 2015, 115, 9028−9072, and literatures cited therein. (b) Wen, J.-J.; Zhu, Y.; Zhan, Z.-P. The Synthesis of Aromatic Heterocycles from Propargylic Compounds. Asian J. Org. Chem. 2012, 1, 108−129. For selected examples of cascade annulation, see: (c) Albrecht, Ł.; Ransborg, L. K.; Gschwend, B.; Jørgensen, K. A. An Organocatalytic Approach to 2-Hydroxyalkyl- and 2-Aminoalkyl Furanes. J. Am. Chem. Soc. 2010, 132, 17886−17893. (d) Lou, J.; Wang, Q.; Wu, K.; Wu, P.; Yu, Z. Iron-Catalyzed Oxidative C−H Functionalization of Internal Olefins for the Synthesis of Tetrasubstituted Furans. Org. Lett. 2017, 19, 3287−3290. (e) He, Y.; Zhang, X.; Fan, X. Synthesis of Diversely Substituted 2-(Furan-3-yl)acetates from Allenols through Cascade Carbonylations. Chem. Commun. 2015, 51, 16263−16266. (f) Goudedranche, S.; Bugaut, X.; Constantieux, T.; Bonne, D.; Rodriguez, J. α,β-Unsaturated Acyl Cyanides as New Bis‐Electrophiles for Enantioselective Organocatalyzed Formal [3+3]Spiroannulation. Chem. Eur. J. 2014, 20, 410−415. (2) For reviews, see: (a) Johansson, J. R.; Beke-Somfai, T.; Stålsmeden, A. S.; Kann, N. Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications.


Page 35 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Chem. Rev. 2016, 116, 14726−14768. (b) Singh, M. S.; Chowdhury, S.; Koley, S. Progress in 1,3-Dipolar Cycloadditions in the Recent Decade: an Update to Strategic Development towards the Arsenal of Organic Synthesis. Tetrahedron 2016, 72, 1603−1644. For selected examples, see: (c) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W. Atom-economic Generation of Gold Carbenes: Gold-Catalyzed Formal [3+2] Cycloaddition between Ynamides and Isoxazoles. Chem. Sci. 2015, 6, 1265−1271. (d) Glinkerman, C. M.; Boger, D. L. Catalysis of Heterocyclic Azadiene Cycloaddition Reactions by Solvent Hydrogen Bonding: Concise Total Synthesis of Methoxatin. J. Am. Chem. Soc. 2016, 138, 12408−12413. (e) Bartlett, S. L.; Sohtome, Y.; Hashizume, D.; White, P. S.; Sawamura, M.; Johnson, J. S.; Sodeoka, M. Catalytic Enantioselective [3 + 2] Cycloaddition of α-Keto Ester Enolates and Nitrile Oxides. J. Am. Chem. Soc. 2017, 139, 8661−8666. (f) Xu, W.; Wang, G.; Sun, N.; Liu, Y. Gold-Catalyzed Formal [3 + 2] Cycloaddition of Ynamides with 4,5-Dihydro-1,2,4-oxadiazoles: Synthesis of Functionalized 4-Aminoimidazoles. Org. Lett. 2017, 19, 3307−3310. (3) (a) Kelber, C. Effect of Carbon Disulfide and Potassium Hydroxide on Acetophenone (in German). Ber. Dtsch. Chem. Ges. 1910, 43, 1252−1259. (b) Kolb, M. Ketene Dithioacetals in Organic Synthesis: Recent Developments. Synthesis 1990, 171−190. (c) Zhang, L.; Dong, J.; Xu, X.; Liu, Q. Chemistry of Ketene N,S-Acetals: An Overview. Chem. Rev. 2016, 116, 287−322. (d) Zhao, Y.-L.; Yang,

S.-C.;

Di,

C.-H.;

Han,

X.-D.;

Liu,

Q.

Highly

Efficient

Synthesis

of

3-Amino-/alkylthio-cyclobut-2-en-1-ones Based on the Cyclization of Acyl Ketene Dithioacetals. Chem. Commun. 2010, 46, 7614−7616. (e) Fang, Z.; Liu, Y.; Barry, B.-D.; Liao, P.; Bi, X.



Page 36 of 41

Formation of Benzo[f]-1-indanone Frameworks by Regulable Intramolecular Annulations of gem-Dialkylthio Trienynes. Org. Lett. 2015, 17, 782−785. (f). Nandi. S. K. G. C. Catalyst-Controlled Straightforward Synthesis of Highly Substituted Pyrroles/Furans via Propargylation/Cycloisomerization of α-Oxoketene-N,S-acetals. J. Org. Chem. 2016, 81, 11909−11915. (4) (a) Dieter, R. K. α-Oxo Ketene Dithioacetals and Related Compounds: Versatile Three-Carbon Synthons. Tetrahedron 1986, 42, 3029−3096. (b) Junjappa, H.; Ila, H.; Asokan. C. V. α-Oxoketene -S,S-, N,S- and N,N-acetals: Versatile Intermediates in Organic Synthesis. Tetrahedron 1990, 46, 5423−5506. (c) Ila, H.; Junjappa, H.; Barun, O. Studies on Regioselective Addition of Benzylic Organometallics to α-Oxoketene Dithioacetals in Our Aromatic Annelation Protocol. J. Organometal. Chem. 2001, 624, 34−40. (5) (a) Ila. H.; Junjappa, H. Molecular Diversity through Novel Organosulfur Synthons: Versatile Templates for Heterocycle Synthesis. Chimia, 2013, 67, 17−22; (b) Pan, Bi, X.; Liu, Q. Recent Developments of Ketene Dithioacetal Chemistry. Chem. Soc. Rev. 2013, 42, 1251−1286. (6) For selected examples, see: (a) Rao, H. S. P.; Sivakumar, S. Condensation of α-Aroylketene Dithioacetals and 2-Hydroxyarylaldehydes Results in Facile Synthesis of a Combinatorial Library of 3-Aroylcoumarins. J. Org. Chem. 2006, 71, 8715−8723. (b) Misra, N. C.; Panda, K.; Ila, H.; Junjappa. H. An Efficient Highly Regioselective Synthesis of 2,3,4-Trisubstituted Pyrroles by Cycloaddition of Polarized Ketene S,S- and N,S-Acetals with Activated Methylene Isocyanides. J. Org. Chem. 2007, 72, 1246−1251. (c) Yuan, H.-J.; Wang, M.; Liu, Y.-J.; Liu, Q. Copper(II)‐


Page 37 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Catalyzed C−C Bond‐Forming Reactions of α-Electron‐Withdrawing Group‐Substituted Ketene S,S‐Acetals with Carbonyl Compounds and a Facile Synthesis of Coumarins. Adv. Synth. Catal. 2009, 351, 112−116. (d) Yuan, H.; Wang, M.; Liu, Y.; Wang, L.; Liu, J.; Liu, Q. Unexpected Hydrobromic Acid‐Catalyzed C−C Bond‐Forming Reactions and Facile Synthesis of Coumarins and Benzofurans Based on Ketene Dithioacetals. Chem. Eur. J. 2010, 16, 13450−13457. (e) Liang, D.; Wang, M.; Bekturhun, B.; Xiong, B.; Liu, Q. One‐Pot Synthesis of Polyfunctionalized 4H‐Chromenes and Dihydrocoumarins Based on Copper(II) Bromide‐ Catalyzed C−C Coupling of Benzylic Alcohols with Ketene Dithioacetals. Adv. Synth. Catal. 2010, 352, 1593−1599. (f) Verma, G. K.; Verma, R. K.; Shukla, G.; Anugula, N.; Srivastava, A.; Singh, M. S. One-pot Straightforward Approach to 2,3-Disubstituted Benzo/naphtho[b]furans via Domino Annulation of α-Oxoketene Dithioacetals and 1,4-Benzo/naphthoquinone Mediated by AlCl3 at Room Temperature. Tetrahedron 2013, 69, 6612−6619. (g) Dong, J.; Pan, L.; Xu, X.; Liu, Q. α-Trifluoromethyl-(indol-3-yl)methanols

as

Trifluoromethylated

C3

1,3-Dipoles:

[3+2]

Cycloaddition for the Synthesis of 1-(Trifluoromethyl)-cyclopenta[b]indole Alkaloids. Chem. Commun. 2014, 50, 14797−14800. (h) Fang, Z.; Liu, J.; Liu, Q.; Bi, X. [3+2] Cycloaddition of Propargylic

Alcohols

and

α-Oxo

Ketene

Dithioacetals:

Synthesis

of

Functionalized

Cyclopentadienes and Further Application in a Diels–Alder Reaction. Angew. Chem., Int. Ed. 2014, 53, 7209−7213. (7) For reviews, see: (a) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Ynamides in Ring Forming Transformations. Acc. Chem. Res. 2014, 47, 560−578. (b)



Page 38 of 41

Zhang, L. A Non-Diazo Approach to α-Oxo Gold Carbenes via Gold-Catalyzed Alkyne Oxidation. Acc. Chem. Res. 2014, 47, 877−888. (c) Yeom, H.-S.; Shin, S. Catalytic Access to α-Oxo Gold Carbenes by N–O Bond Oxidants. Acc. Chem. Res. 2014, 47, 966−977. For selected examples, see: (d) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. Copper- or Phosphine-Catalyzed Reaction of Alkynes with Isocyanides. Regioselective Synthesis of Substituted Pyrroles Controlled by the Catalyst. J. Am. Chem. Soc. 2005, 127, 9260−9266. (e) Shapiro, N. D.; Toste, F. D. Rearrangement of Alkynyl Sulfoxides Catalyzed by Gold(I) Complexes. J. Am. Chem. Soc. 2007, 129, 4160−4161. (f) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. Tempering the Reactivities of Postulated α-Oxo Gold Carbenes Using Bidentate Ligands: Implication of Tricoordinated Gold Intermediates and the Development of an Expedient Bimolecular Assembly of 2,4-Disubstituted Oxazoles. J. Am. Chem. Soc. 2012, 134, 17412−17415. (g) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Gold‐Catalyzed C−H Annulation of Anthranils with Alkynes: A Facile, Flexible, and Atom‐Economical Synthesis of Unprotected 7-Acylindoles. Angew., Chem, Int. Ed. 2016, 55, 794−797. (8) An isoindoline-1,3-dione-derived propargyl alcohol is a N-acyl ynone hemiaminal. Simple N-acyl ynone hemiaminals are inclined to decompose into ynones or ynone imines. Isoindolinone-derived ynone hemiaminals are stable and isolable. (9) For details, see the Supporting Information. (10) The crystal data and experimental details of the structural refinement for 3a are provided in the Supporting Information (Ref. 9). CCDC 1574695 (3a) contains the supplementary crystallographic


Page 39 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


data for this publication. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (11) Cashman, J. R.; Berkman, C. E.; Underiner, G.; Kolly, C. A.; Hunter, A. D. Cocaine Benzoyl Thioester: Synthesis, Kinetics of Base Hydrolysis, and Application to the Assay of Cocaine Esterases. Chem. Res. Toxicol. 1998, 11, 895−901. (12) Fukuyama, T.; Lin, S. C.; Li, L. Facile Reduction of Ethyl Thiol Esters to Aldehydes: Application to a Total Synthesis of (+)-Neothramycin A Methyl Ether. J. Am. Chem. Soc. 1990, 112, 7050−7051. (13) The cleavage mechanism was unknown at the present stage. For the mechanism of CAN-mediated oxidation, see: Torii, S.; Tanaka, H.; Inokuchi, T.; Nakane, S.; Akada, M.; Saito, N.; Sirakawa, T. Indirect Electrooxidation (an Ex-cell Method) of Alkylbenzenes by Recycle Use of Diammonium Hexanitratocerate in Various Solvent Systems. J. Org. Chem. 1982, 47, 1647−1652. (14) (a) 3-Hydroxyisoindolinones and related structures appear in abundant bioactive molecules. For example

of

3-aryl-3-hydroxyisoindolinone

derivatives

as

small-molecule

protein−protein interaction, see: Hardcastle, I. R.; Ahmed, S. U.; Atkins, H.;

inhibitors

of

Farnie, G.; Golding,

B. T.; Griffin, R. J.; Guyenne, S.; Hutton, C.; Kallblad, P.; Kemp, S. J.; Kitching, M. S.; Newell, D. R.; Norbedo, S.; Northen, J. S.; Reid, R. J.; Saravanan, K.; Willems, H. M. G.; Lunec, J. Small-Molecule Inhibitors of the MDM2-p53 Protein−Protein Interaction Based on an Isoindolinone Scaffold. J. Med. Chem. 2006, 49, 6209−6221. (b) For examples of base-mediated



Page 40 of 41

autoxidation of 3-arylisoindolinones, see: Castro-Castillo, V.; Rebolledo-Fuentes M.; Cassels, B. K. Synthesis of A-ring-substituted 5,6,8,12b-Tetrahydroisoindolo[1,2-a]isoquinolin-8-ones. J. Chil. Chem. Soc. 2009, 54, 417−423. (15) Li, Q.; Wang, Y.; Fang, Z.; Liao, P.; Barry, B.-D.; Che, G.; Bi, X. Iron(III)-Catalyzed Dehydration C(sp2)–C(sp2) Coupling of Tertiary Propargyl Alcohols and α-Oxo Ketene Dithioacetals: A New Route to gem-Bis(alkylthio)-Substituted Vinylallenes. Synthesis 2013, 45, 609−614. (16) (a) Di Grandi, M. J. Nazarov-like cyclization reactions. Org. Biomol. Chem. 2014, 12, 5331−5345. (b) Wang, Z.; Xu, X.; Gu, Z.; Feng, W.; Qian, H.; Li, Z.; Sun, X. Kwon, O. Nazarov Cyclization of 1,4-Pentadien-3-ols: Preparation of Cyclopenta[b]indoles and Spiro[indene-1,4′ -quinoline]s. Chem. Commun. 2016, 52, 2811−2814. (c) Vinogradov, M. G.; Turova, O. V.; Zlotin, S. G. Nazarov reaction: current trends and recent advances in the synthesis of natural compounds and their analogs. Org. Biomol. Chem. 2017, 15, 8245− 8269. (17) (a) Kramer, S.; Skrydstrup, T. Gold-Catalyzed Carbene Transfer to Alkynes: Access to 2,4-Disubstituted Furans. Angew. Chem., Int. Ed. 2012, 51, 4681− 4684. (b) Dateer, R. B.; Pati, K.; Liu, R.-S. Gold-catalyzed synthesis of substituted 2-aminofurans via formal [4+1]-cycloadditions on 3-en-1-ynamides. Chem. Commun. 2012, 48, 7200−7202. (18) For recent example of biological study of furanoid compounds, see: Nagy, E.; Liu, Y.; Prentice, K. J.; Sloop, K. W.; Sanders, P. E.; Batchuluun, B.; Hammond, C. D.; Wheeler, M. B.; Durham, T. B. Synthesis

and

Characterization

of

Urofuranoic

Acids:


In

Vivo

Metabolism

of

Page 41 of 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2-(2-Carboxyethyl)-4-methyl-5-propylfuran-3carboxylic Acid (CMPF) and Effects on in Vitro Insulin Secretion. J. Med. Chem. 2017, 60, 1860−1875. (19) (a) Chang, J.; Liu, B.; Yang, Y.; Wang, M. Pd-Catalyzed C–S Activation/Isocyanide Insertion/Hydrogenation Enables a Selective Aerobic Oxidation/Cyclization. Org. Lett. 2016, 18, 3984−3987. (b) Lubbe, M.; Bendrath, F.; Trabhardt, T.; Villinger, A.; Fischer, C.; Langer, P. Regioselective Synthesis of 3-(Methylthio)phenols by Formal [3+3]-Cyclocondensations of 3-Oxo-bis(methylthio)ketenacetals

with

1,3-Bis(trimethylsilyloxy)-1,3-butadienes

1,3-Dicarbonyl Dianions. Tetrahedron. 2013, 69, 5998−6007.


and

Access to Multi-Substituted Furan-3-carbothioates via Cascade

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