Three-Component Coupling Reactions of Aryne, DMSO, and Activated

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Three-Component Coupling Reactions of Aryne, DMSO and Activated Alkyne: Stereoselective Synthesis of 2[(ortho-Methylthio)aryloxy] Substituted Dialkyl Maleates Hemanta Hazarika, Kashmiri Neog, Abhilash Sharma, Babulal Das, and Pranjal Gogoi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00090 • Publication Date (Web): 03 Apr 2019 Downloaded from http://pubs.acs.org on April 3, 2019

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The Journal of Organic Chemistry

Three-Component Coupling Reactions of Aryne, DMSO and Activated Alkyne: Stereoselective Synthesis of 2-[(ortho-Methylthio)aryloxy] Substituted Dialkyl Maleates Hemanta Hazarika,a,b Kashmiri Neog,a,b Abhilash Sharma,a,b Babulal Dasc and Pranjal Gogoia,b* aApplied

Organic Chemistry Group, Chemical Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India bAcademy

of Scientific and Innovative Research (AcSIR), CSIR-NEIST Campus, India

cDepartment

of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India

Email: [email protected]; [email protected] ABSTRACT

R1

TMS OTf

COOR

+

R1 KF, DMSO 50 oC

COOR 1

COOR COOR O SMe

Transition-metal-free Mild reaction Conditions Multiple bond cleavage and bond formation ortho-functionalization Stereoselective

R = Me, Et, iPr, nBu, tBu; R = H, Me, OMe

24 Examples

A transition-metal free coupling reaction of aryne, DMSO and activated alkyne for the synthesis of 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleates is reported. This cascade process is associated with several bond cleavage as well as bond formation reactions in one-pot. One of our synthesized maleates has been unambiguously established by single crystal XRD study. This methodology allows preparing trisubstituted vinyl ethers with excellent stereospecificity.

Arynes are one of the most important classes of transient species that have been emerged as powerful synthons and widely used in the synthesis of various functionalized arenes,1 heterocycles2 and complex natural products.3 This versatile reactive intermediate could be achieved in situ from their corresponding precursors using appropriate reagents and conditions. However, fluoride induced generation of aryne using readily available Kobayashi’s aryne precursor4 is broadly accepted and frequently used for aryne-based synthetic methodologies. In aryne chemistry, the synthesis of functionalized arenes particularly ortho-functionalized arenes, nucleophilic additions followed by trapping of electrophiles are the fundamental reactions mode.

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Additionally, multicomponent reactions5 and dipolar cycloaddition6 strategies have also been developed for difunctionalization of arenes with two important functional groups into adjacent positions of aromatic framework through the formation of carbon-carbon and carbon-heteroatom bonds. Insertion of aryne into σ-bond and π-bond has gained more preference over others for the synthesis of ortho-functionalized arenes. Aryne insertion into methylene-carbonyl σ-bond,7 C=C bond,8 C=O,9 various amides including DMF,9f, 9g,10 P−O11 and I-I12 bond for the synthesis of 1,2disubstituted arenes have been reported. This synthetic protocol offers a potent and valuable tool for the rapid construction of complex molecules in a high atom economic way. On the other hand, aryl sulphides are important structural unit present in pharmaceuticals and materials.13 They have been used as synthetic intermediates and also as chiral ligands in organic synthesis.14 Additionally, the oxidized form of aryl sulphide such as sulfoxide and sulfone are also important functional groups present in pharmaceuticals.13 Thus, the construction of Csp2-S bond is important and challenging task for chemist. Traditionally, this was relied on the transitionmetal catalyzed coupling reactions between organic halide and sulphur nucleophile, which are airsensitive and odourous.15 Therefore, development of transition-metal-free synthetic strategies for the synthesis of aryl sulphides are highly desirable. Synthesis of aryl sulphides via aryne has received tremendous attention as this strategy could be designed for the installation of other important functional groups along with sulphide moiety. Nucleophilic addition or insertion into aryne followed by electrophilic trapping cascade reactions made it feasible in a single operation. Therefore, several transition-metal catalyzed as well as transition-metal-free synthetic routes for the synthesis of functionalized aryl sulphides from aryne have been developed. Transition-metalfree synthesis of functionalized aryl sulphides from arynes proceeds via [2+2] or [3+2] cycloaddition of aryne with thioethers, sulfoxide or vinyl sulfoxides. The reaction of arynes with thioethers bearing α-CH protons16 or lacking α-CH protons17 were well studied and used for the synthesis of various sulphur containing valuable products. Surprisingly, the insertion of arynes into S-O bond of sulfoxides is rare, which proceeds via four membered cycloadduct product followed by cleavage of S-O bond which lead to the corresponding zwitterionic sulfonium salt. Xiao and Chen disclosed the synthesis of 1,2-O,S-disubstituted arenes via insertion of aryne into the “S=O” bond of sulfoxide followed by intermolecular trapping of zwitterionic sulfonium salt using α-bromo carbonyl compounds.18 Later, Wang and co-workers found that the reaction between arynes and sulfoxides could also take place in absence of external electrophile, where aryne itself associates to produce o-aryloxydiarylsulphides.19 Li and co-workers ingeniously merged the aryne insertion and Claisen rearrangement process for the synthesis of 1,2,3trifunctionalized arenes.20 Recently, Peng and co-workers synthesized o-aryloxytriaryl sulfonium


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salts instead of thioethers via aryne insertion into diaryl sulfoxides.21 Additionally, Studer22 and his group designed an interesting cascade reaction for o-arylsulfinyl aryl vinyl ethers using aryne and aryl vinyl sulfoxides which proceeds via insertion of aryne into the S-O σ–bond and concomitant stereospecific S-O-vinyl migration. As a part of our research work on development of aryne methodologies,23 we have developed a new synthetic protocol for the direct synthesis of functionalized aryl sulphide via three component reactions of aryne, DMSO and activated alkyne (Scheme 1).

R1

1

R

COOR

TMS

+

+

OTf

Me

O S

O

KF 50 oC

Me

COOR COOR

SMe

COOR 1

R = Me, Et, iPr, nBu, tBu; R = H, Me, OMe

Scheme 1. Synthesis of 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleates from aryne Herein, we report a synthetic methodology for 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleate derivatives via the reaction of arynes with activated alkynes under transition-metal free conditions. In our strategy, the zwitterionic sulfonium salt obtained from aryne and DMSO under mild reaction conditions was trapped by activated alkyne. This methodology for the introduction of sulphide and vinyl ether moiety into aromatic ring can be achieved under mild reaction conditions. Synthetic protocols reported by different groups along with our approach for the synthesis of sulphur containing ortho-disubstituted arenes via insertion of aryne into S=O bonds or ylide are shown in figure 1. SR2 OPh

O

Ph

S Ph

O R2 S

Ph

Ar

R Ar

R5

R3

Ph

Ref. 22

R4

COOR COOR

O

O

S

O S

4

R R4 & R5=EWG

OTf

Ref. 21

O

R5

R3

S

Br

ROOC O

O

COOR

DMSO

SMe Present work

R Me

Ref. 20

O

S Me

Me S O Ref. 19

Me Br

O

S

O

Me R1

O O S

R1 Me

Ref. 18

Figure 1. Sulphur containing ortho-disubstituted arenes from aryne



We

initiated

our

optimization

(methylthio)phenoxy]maleate

studies

(3aa)

by

for

using

the readily

Page 4 of 25

synthesis available

of

di-methyl

aryne

2-[2-

precursor

2-

(trimethylsilyl)phenyl trifluoromethanesulfonate 1a (0.5 mmol) and activated alkyne di-methyl acetylenedicarboxylate 2a (0.75 mmol). These two substrates were treated with CsF (2 mmol) as fluoride source in DMSO (2 mL) at room temperature for 12 h, which gave our desired product 3aa in 49% yield (Table 1, entry 1). Table 1. Optimization studiesa COOMe

TMS + OTf 1a

Entry 1 2 3 4 5 6 7 8 9 10 11 12

F- Source (equiv)

COOMe COOMe F - Source, Additive DMSO

COOMe

SMe 3aa

2a

Additive (1 equiv)

O

Solvent

CsF (4.0) -DMSO KF (4.0) -DMSO TBAF (4.0) -DMSO KF (4.0) 18-Crown-6 DMSO CsF (4.0) -DMSO KF (4.0) -DMSO KF (4.0) 18-Crown-6 DMSO KF (5.0) -DMSO KF (3.0) DMSO KF (4.0) DMSO/CH3CN (1:1) KF (4.0) -DMSO/THF (1:1) --DMSO

Time Temp Yield (h) (oC) (%)b 12 12 24 12 5 5 5 5 5 5 5 5

rt rt rt rt 50 50 50 50 50 50 50 50

49 43 Trace 47 83 81 75 73 65 63 69 ND

aConditions:

aryne precursor 1a (0.5 mmol), Dimethylacetylenedicarboxylate 2a (0.75 mmol), Additive (0.5 mmol), Fluoride source (1.5 to 2.5 mmol), DMSO (2 mL) stirred; bIsolated yield; ND: Not detected.

Several deviations have been made by changing fluoride source to increase the yield of 3aa (Table 1, entries 2-3). However, we didn’t get any significant improvement of yield. In addition, 18crown-6 was used as additive along with KF in our optimization studies. Under this reaction conditions, the product 3aa was isolated in 47% yield (Table 1, entry 4). However, when the reaction temperature was increased to 50 oC using CsF (4 equivalents) for 5 h, the product 3aa was obtained in 83% yield (Table 1, entry 5). Under the same reaction conditions, the fluoride source KF (4 equivalents) gave our desired product 3aa in 81% yield (Table 1, entry 6). Addition of 18-crown-6 (1 equiv) along with KF (4 equivalents) at 50 oC didn’t make any significant improvement of yield (Table 1, entry 7). Although, CsF works slightly better than KF as fluoride source, we considered KF during our generalization studies as it is cheaper and readily available.


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We also performed some other optimization experiments by varying the amount of KF as well as reaction media (Table 1, entries 8-11). However, no significant enhancement of yields was observed. A control experiment was also performed without any fluoride source during our optimization studies. However, the desired product 3aa was not obtained (Table 1, entry 12). Table 2. One-pot synthesis of substituted dialkyl maleates from aryne precursorsa R1

50 C

COOR

SMe 3aa-ce

2a-e

COOEt COOEt

O SMe

O O

SMe

SMe

3ab (76%)

OnBu OnBu

3ac (70%)

OtBu OtBu

O

O

O O

O

SMe

SMe

3ae (63%)

3ad (67%) OMe OMe

OEt

O

O

MeO

SMe

3ba (71%); E:Z=1:3

O

MeO

SMe

3bb (70%); E:Z=1:5.5

MeO

SMe

O

OiPr OiPr O O SMe

3cc (63%); E:Z=1:7.5 aConditions:

O

MeO

SMe

3bc (62%); E:Z=1:7.3 COOEt COOEt O

O

SMe

SMe

3bd (63%); E:Z=1:19

O MeO

COOMe COOMe

O O

OiPr OiPr

O MeO

OnBu OnBu

MeO

O

OEt

O MeO

O

OiPr OiPr

O

O

3aa (81%)

O

O

o

COOMe COOMe

O

COOR COOR

KF, DMSO

+ 1a-c

R

COOR

TMS OTf

1

3ca (77%); E:Z=1:9.7 O

OnBu OnBu

3cb (75%); E:Z=1:11 O

OtBu OtBu

O O SMe

3cd (62%); E:Z=1:13.5

O O SMe

3ce (59%); E:Z=1:17

aryne precursor 1 (0.5 mmol), Activated Alkyne 2 (0.75 mmol), KF (2 mmol), DMSO (2 mL) stirred at

50 oC for 5 hr.

With the optimal conditions in hand, the substrates scope was then explored and the results are summarized in Table 2. As represented in Table 2, a variety of activated alkynes were treated with o-silyl aryl triflate 1a, leading to our desired 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleates in good yields (Table 2, 3aa-3ae). The results showed that bulky alkyl group substituted activated alkynes gave slightly lower yields. Interestingly, the symmetrical benzyne precursor 2-(trimethylsilyl) phenyltrifluoromethanesulfonate 1a gave predominantly our desired



Page 6 of 25

stereoisomers with various activated alkynes in good yields. One of the synthesized dialkyl maleate

derivative

di-tert-butyl

2-[2-(methylthio)phenoxy]maleate

3ae

was

confirmed

unambiguously by X-ray crystallography.24 In addition to 1a, symmetrical aryne precursors such as 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1b and 3-(trimethylsilyl)-2naphthyl trifluoromethanesulfonate 1c were also explored for our synthetic process and a series of maleate derivatives were obtained in 59-77% yield (Table 2, 3ba-3ce). However, these two symmetrical aryne precursors 1b and 1c gave small amount of fumarate derivatives under our optimized reaction conditions, which could be due to the steric hindrance. These stereoisomers are difficult to separate into individual isomers by column chromatography and are presented as mixtures (details are in SI). To investigate the substrate scope, unsymmetrical aryne precursors i.e. 2-methyl-6(trimethylsilyl)phenyl trifluoromethanesulfonate 1d and 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1e were also examined under our optimized conditions. Aryne precursors 1d & 1e gave substituted methyl and ethyl maleates 3da, 3db, 3ea and 3eb as single regioisomers with good yields (Table 3, entries 1-2). The structures of the single regioisomers were established by 1D and 2D (1H-1H NOESY experiment) NMR analysis (details are in SI). However,

when

the

unsymmetrical

trifluoromethanesulfonate 1f

aryne

precursor

4-methyl-2-(trimethylsilyl)phenyl

was treated with activated alkynes 2a and 2b, mixtures of

regioisomers were obtained in 69% and 63% yields respectively (Table 3, entry 3). It is noteworthy that both the mixtures 3fa & 3f'a and 3fb & 3f'b were not isolated into individual isomers and their ratios were calculated from 1H NMR analysis. To get insight the reaction mechanism, few deuterium-labelling experiments were carried out. In our initial investigation, DMSO-d6 was used instead of DMSO for the synthesis of 3aa under our optimized reaction conditions (Scheme 2). Here, the deuterium labelled product 3aa-D3 was isolated in 73% yield. 1H and

13C-NMR

analysis confirms the complete deuterium

incorporation at “CH3” moiety, which reveals that DMSO serves as “SMe” source. This result reveals that our reaction proceeds via [2+2] cycloaddition of aryne with DMSO solvent. To further investigate the reaction mechanism another independent experiment was performed, where D2O was used as fourth component along with 1a, 2a and DMSO in the presence of KF (Scheme 3). This experiment resulted in the formation of our expected product 3aa-D in 67% yield with 35% deuterium incorporation at the vinylic position. The percentage of deuterium incorporation was calculated from 1H NMR and confirmed by HRMS analysis (details are in experimental section and SI).


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Table 3. Synthesis of dialkyl maleates from unsymmetrical benzyne precursorsa TMS

R1

COOR

KF, DMSO

+

OTf

3da-3fb

Activated alkyne 2a

2b COOEt COOEt

COOMe COOMe

TMS OTf

Me

Me

O

Me

1d

O

SMe

SMe

3da (69%)

TMS OTf

2

SMe

2a-b

Benzyne precursor (1d-f)

1

O

R1

50 oC

COOR

1d-f

Entry

COOR COOR

3db (67%)

OMe OMe

O

OEt OEt

O

O

MeO

O

O

1e

O

SMe

MeO

3

TMS

O

OTf

OMe OMe

O

3eb (66%) OMe OMe O

O

1f

SMe

Me

O

OEt OEt O

O Me

O

O

SMe

Mixture of 3fa&3f'a (69%); ~1:1.3 ratio aConditions:

OEt OEt

O

O

O Me

Me

SMe

MeO

3ea (66%)

SMe

Me

SMe

Mixture of 3fb&3f'b (63%); ~1:1.3 ratio

aryne precursor 1 (0.5 mmol), Activated alkyne 2 (0.75mmol), KF (2 mmol), DMSO (2 mL) stirred at 50

°C for 5 hr.

Scheme 2. Deuterium labelling experiment using DMSO-d6 1

H-NMR: No "CH3" peak

CD3

13

C-NMR: 14.4 (m)

COOMe

TMS + OTf

1a

+

D3C

O S

S

F CD3

then work-up

COOMe

2a


O MeOOC COOMe

3aa-D3 (73%)


Page 8 of 25

Scheme 3. Deuterium labelling experiment using D2O CH3 S COOMe

TMS OTf

+

+

H3C

O S

KF, D2O

O

o CH3 50 C, 5 hr

H/D

MeOOC

COOMe

1a

35% D

COOMe

3aa-D (67%)

2a

Based on the previous report9b,10a,19,25 and our experiments, a probable reaction mechanism for the one-pot synthesis of 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleate is proposed in scheme 4. As shown in scheme 4, the in situ generated benzyne undergoes insertion into the S=O 𝞹-bond of dimethyl sulfoxide to form a four-membered ring intermediate A. Due to the ring strain, it undergoes ring opening to afford an ortho-quinone intermediate B. The zwitterion C, a resonance form of B undergoes demethylation18 as well as nucleophilic attack to activated alkyne. This leads to anion D, which finally protonated in the presence of residual water to form our desired 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleate. Scheme 4. Probable reaction mechanism for the synthesis of 2-[(ortho-methylthio)aryloxy] substituted dialkyl maleate COOR ROOC TMS

1

ROOC

O

COOR

DMSO, KF

OTf

Me

S H2O

DMSO F

COOR

ROOC O

O S [A]

O

S [B]

O

2

S

S

[C]

[D] F

CONCLUSION In summary, we have developed an efficient, transition-metal-free approach for the synthesis of 2[(ortho-methylthio)aryloxy] substituted dialkyl maleate using readily available aryne precursors, activated alkynes and DMSO. A series of maleate derivatives were obtained by using our one-pot synthetic methodology in good yields with excellent stereospecificity. This multicomponent reaction proceeds via several bond cleavage as well as bond formation in one pot. In addition to that, our synthetic protocol will facilitate the direct installation of two important functionalities into adjacent positions of arene.


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EXPERIMENTAL SECTION: General Remarks: Oxygen- or moisture-sensitive reactions were carried out under inert atmosphere using super dried glasswares. All other solvents and reagents were purified using standard procedures or were used as received from reputed vendors. The progress of the reactions were monitored by thin-layer chromatography (TLC) using aluminium-backed silica gel plates (0.2 mm thickness) and

were visualized with ultraviolet light (254 nm). Flash column

chromatography was performed with silica gel 60 (230-400 mesh). HRMS data were recorded by electron spray ionization with a Q-TOF mass analyzer. Aryne precursors 1a-f are commercially available and purchased from TCI chemicals.

Experimental procedure for the synthesis of activated alkynes: Alkynes 2a, 2b and 2e are commercially available and purchased from sigma Aldrich. Alkynes 2c and 2d are prepared by using the following procedure. To a 100 mL RB flask was transferred acetylene dicarboxylic acid (2 g, 17.54 mmol), concentrated H2SO4 (0.5 mL), and respective alcohol (20 mL). The whole reaction mixture was stirred and heated to reflux (80 °C) for 5 h, after which it was cooled to room temperature and then concentrated under reduced pressure. The remaining clear-colorless liquid was taken up in Et2O (20 mL) and sequentially washed with NaOH (aq. 2N solution) until the aqueous layer was basic and with H2O (4 x 25 mL). The organic layer was dried over MgSO4, filtered, and washed with Et2O (3 x20 mL), and the solvent was removed under reduced pressure yielding the clear-colorless liquid product. Diisopropylacetylenedicarboxylate (2c):26 Applying the general experimental procedure on acetylene dicarboxylic acid (2 g, 17.54 mmol) and propan-2-ol (20 ml) compound 2c was obtained as colorless oil (2.8 g, 81%) after purification by flash column chromatography; 1H NMR (500 MHz, CDCl3): δ 5.07 (sept, J=6.02 Hz, 2H), 1.24 (d, J=6.3 Hz, 12H); 13C{1H} NMR (126 MHz, CDCl3): δ 151.4, 74.6, 71.3, 21.5. Dibutylacetylenedicarboxylate (2d):27 Applying the general experimental procedure on acetylene dicarboxylic acid (2g, 17.54 mmol) and 1-butanol (20 ml) compound 2d was obtained as colorless oil (2.9 g, 73%) after purification by flash column chromatography; 1H NMR (500 MHz, CDCl3): δ 4.22 (t, J=6.6 Hz, 4H), 1.28-1.78 (m, 8H), 0.93 (t, J=7.4 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3): δ 151.9, 74.6, 66.8, 30.2, 18.9, 13.5.



Page 10 of 25

General experimental procedure for the synthesis of di-alkyl maleates from aryne precursor, activated alkyne and DMSO: An oven-dried round bottomed flask (50 mL capacity) equipped with a magnetic stir bar was evacuated and backfilled with argon. Di-alkylacetylenedicarboxylate (0.75 mmol, 1.5 equiv), aryne precursor (0.5 mmol, 1 equiv), KF (2 mmol, 4 equiv), and DMSO (2 mL) were added at room temperature and stirred at 50 oC for 5 h. The reaction mixture was allowed to cool to room temperature. Water (10 mL) was poured into the reaction mixture and the organic layer was extracted with EtOAc (2 x 20 mL). The collected organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as an eluent. Characterization of dialkyl maleates: Di-methyl 2-[2-(methylthio)phenoxy]maleate (3aa) Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol, 1.5 equiv), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3aa was isolated as light brown gummy (0.114 g, 81% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.16-7.23 (m, 2H), 7.09-7.15 (m, 1H), 7.01 (dd, J1=1.1HZ, J2=7.9 Hz, 1H), 4.96 (s, 1H), 3.88 (s, 3H), 3.59 (s, 3H), 2.37 (s, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.8, 163.1, 159.7, 149.3, 131.8, 127.2, 127.1, 126.2, 121.4, 98.0, 53.1, 51.7, 14.8; IR (CHCl3): 2953, 1747, 1727, 1636, 1436, 1207cm-1; HRMS (+ESI)Calcd for C13H14O5NaS [M+Na]+: 305.0460 ; found: 305.0462. Di-ethyl 2-[2-(methylthio)phenoxy]maleate (3ab): Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11 mL; 0.75 mmol, 1.5 equiv), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ab was isolated as light brown gummy (0.118 g, 76% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.16-7.29 (m, 3H), 7.09 (dd, J1=1.2 Hz, J2=7.9 Hz, 1H), 5.04 (s, 1H), 4.41 (q, J=7.2 Hz, 2H), 4.13 (q, J= 7.1 Hz, 2H), 2.45 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.3, 162.7, 159.8, 149.4, 131.8, 127.2, 127.0, 126.2, 121.5, 98.3, 62.4, 60.6, 14.8, 14.1, 13.8; IR (CHCl3): 2982,


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1740, 1714, 1634, 1442, 1203 cm-1; HRMS (+ESI)Calcd for C15H19O5S [M+H]+: 311.0953; found: 311.0963. Di-isopropyl-2-[2-(methylthio)phenoxy]maleate (3ac): Using the general experimental procedure on di-isopropylacetylenedicarboxylate (0.14 g; 0.75 mmol, 1.5 equiv), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ac was isolated as light brown gummy (0.118g, 70% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as eluent; 1H NMR (500 MHz, CDCl3): δ 7.20-7.29 (m, 2H), 7.15 (dt, J1=1.6 Hz, J2= 7.5 Hz, 1H), 7.08 (dd, J1=1.2 Hz, J2= 7.9Hz, 1H), 5.22 (m, 1H), 5.04 (s, 1H), 5.00 (m, 1H), 2.44 (s, 3H), 1.35 (d, J= 6.3 Hz, 6H), 1.20 (d, J=6.3 Hz, 6H);

13C{1H}

NMR (126 MHz, CDCl3): δ 164.7,

162.1, 159.7, 149.6, 131.8, 127.1, 126.7, 126.0, 121.4, 98.8, 70.2, 67.9, 21.7, 21.4, 14.7; IR (CHCl3): 2982, 1743, 1715, 1637, 1441, 1207 cm-1; HRMS (+ESI)Calcd for C17H23O5S [M+H]+: 339.1266; found: 339.1261. Di-nbutyl 2-[2-(methylthio)phenoxy]maleate (3ad): Using the general experimental procedure on di-nbutylacetylenedicarboxylate (0.169 g; 0.75 mmol, 1.5 equiv), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ad was isolated as light brown gummy (0.123g, 67% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.14-7.34 (m, 3H), 7.08 (dd, J1=1.3 Hz, J2= 7.9 Hz, 1H), 5.05 (s, 1H), 4.33 (t, J=6.8 Hz, 2H), 4.07 (t, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.28-1.77 (m, 8H), 0.95 (t, J=7.4 Hz, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.3, 162.7, 159.6, 149.5, 131.7, 127.2, 126.9, 126.1, 121.3, 98.4, 66.1, 64.5, 30.4, 30.2, 18.9, 14.7, 13.6, 13.5 (one peak is missing due to overlap); IR (CHCl3): 2960, 1748, 1717, 1637, 1440, 1203 cm-1; HRMS (+ESI)Calcd for C19H27O5S [M+H]+: 367.1579; found: 367.1576. Di-tert-butyl 2-[2-(methylthio)phenoxy]maleate (3ae): Using the general experimental procedure on di-tert-butylacetylenedicarboxylate (0.17 g; 0.75 mmol), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ae was isolated as colourless solid (0.115g, 63% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; mp 106-108 oC; 1H NMR (500 MHz, CDCl3): δ 7.05-7.21 (m, 3H), 6.98 (dd, J1=1.3 Hz, J2=7.8 Hz, 1H), 5.02 (s, 1H), 2.37 (s, 3H), 1.43 (s, 9H), 1.36 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3):



Page 12 of 25

δ 164.3, 161.3, 158.5, 150.2, 131.5, 127.1, 126.2, 125.9, 120.9, 101.5, 83.4, 80.7, 27.9, 27.7, 14.8; IR (CHCl3): 2978, 1741, 1714, 1637, 1444, 1218 cm-1; HRMS (+ESI)Calcd for C19H26O5NaS [M+Na]+: 389.1399; found: 389.1397. Di-methyl 2-[4,5-dimethoxy-2-(methylthio)phenoxy]maleate (3ba): Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol, 1.5 equiv), 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ba was isolated as yellow gummy (0.121 g, 71% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 6.89 (s, 1H), 6.65 (s, 1H), 4.99 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.8, 163.2, 160.4, 148.7 147.5, 144.4, 120.8, 113.1, 105.5, 97.6, 56.2, 56.1, 53.1, 51.7, 17.2; IR (CHCl3): 2924, 1746, 1719, 1635, 1436, 1210 cm-1; HRMS (+ESI)Calcd for C15H19O7S [M+H]+: 343.0851; found: 343.0852. Di-ethyl 2-[4,5-dimethoxy-2-(methylthio)phenoxy]maleate (3bb) Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11mL; 0.75 mmol, 1.5 equiv), 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3bb was isolated as yellow gummy (0.129g, 70% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ, 6.89 (s, 1H), 6.65 (s, 1H), 4.98 (s,1H), 4.41 (q, J= 7.2 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.42 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H), 1.22 (t, J= 7.2 Hz, 3H); 13C{1H}

NMR (126 MHz, CDCl3): δ 165.4, 162.9, 160.5, 148.7, 147.5, 144.6, 120.9, 113.3,

105.7, 97.9, 62.4, 60.6, 56.3, 56.2, 17.2, 14.1, 13.8; IR (CHCl3): 2982, 1746, 1716, 1637, 1440, 1213 cm-1; HRMS (+ESI)Calcd for C17H23O7S [M+H]+: 371.1164; found: 371.1166 .

Di-isopropyl 2-[4,5-dimethoxy-2-(methylthio)phenoxy]maleate (3bc): Using the general experimental procedure on di-isopropylacetylenedicarboxylate (0.14 g; 0.75 mmol, 1.5 equiv), 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3bc was isolated as yellow


Page 13 of 25 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


gummy (0.123 g, 62% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 6.88 (s, 1H), 6.65 (s, 1H), 5.24 (m, 1H), 4.99 (m, 1H), 4.96 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.42 (s, 3H), 1.37 (d, J=6.3 Hz, 6H), 1.20 (d, J=6.3 Hz, 6H);

13C{1H}

NMR (126

MHz, CDCl3): δ 164.9, 162.4, 160.6, 148.7, 147.4, 144.9, 120.9, 113.5, 105.9, 98.3, 70.4, 67.9, 56.3, 56.2, 21.8, 21.5, 17.3; IR (CHCl3): 2929, 1742, 1714, 1636, 1439, 1199 cm-1; HRMS (+ESI)Calcd for C19H27O7S [M+H]+: 399.1477; found: 399.1476. Di-nbutyl 2-[4,5-dimethoxy-2-(methylthio)phenoxy]maleate (3bd): Using the general experimental procedure on di-nbutylacetylenedicarboxylate (0.169 g; 0.75 mmol, 1.5 equiv), 4,5-dimethoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3bd was isolated as yellow gummy (0.134 g 63% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 6.88 (s, 1H), 6.64 (s, 1H), 4.98 (s, 1H), 4.33 (t, J=6.8 Hz, 2H), 4.05 (t, J=6.7 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.41 (s, 3H), 1.30-1.75 (m, 8H), 0.95 (t, J=7.4 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.4, 162.9, 160.4, 148.7, 147.4, 144.6,

120.8, 113.3, 105.7, 97.8, 66.2, 64.4, 56.2, 56.1, 30.4, 30.2, 19.0, 18.9, 17.2, 13.6, 13.5; IR (CHCl3): 2959, 1746, 1716, 1636, 1439, 1213 cm-1; HRMS (+ESI)Calcd for C21H31O7S [M+H]+ : 427.1790; found: 427.1794. Di-methyl 2-[(3-(methylthio)naphthalen-2-yl)oxy]maleate (3ca): Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol, 1.5 equiv), 3-(trimethylsilyl)-2-napthyl-trifluoromethanesulfonate (0.14 mL; 0.5mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ca was isolated as yellow gummy (0.128 g, 77% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.43-7.51 (m, 2H), 5.14 (s, 1H), 3.96 (s, 3H), 3.66 (s, 3H), 2.55 (s, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.7,

163.1, 159.8, 147.7, 132.2, 131.3, 131.2, 127.4, 126.7, 126.6, 126.1, 125.2, 118.5, 99.0, 53.2, 51.7, 14.9; IR (CHCl3): 2923, 1751, 1719, 1638, 1435, 1214 cm-1; HRMS (+ESI)Calcd for C17H16O5NaS [M+Na]+: 355.0616; found:355.0617. Di-ethyl 2-[(3-(methylthio)naphthalen-2-yl)oxy]maleate (3cb):



Page 14 of 25

Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11mL; 0.75mmol, 1.5 equiv), 3-(trimethylsilyl)-2-napthyl-trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3cb was isolated as yellow gummy (0.135 g, 75% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J=8.2 Hz, 1H), 7.74 (d, J= 7.9 Hz, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.42-7.50 (m, 2H), 5.14 (s, 1H), 4.41 (q, J=7.2 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H) ;

13C{1H}

NMR (126 MHz, CDCl3): δ 165.2, 162.6, 159.8, 147.8, 132.1, 131.3, 127.4,

126.6x2, 126.5, 126.0, 125.1, 118.5, 99.3, 62.4, 60.6, 14.9, 14.0, 13.9; IR (CHCl3): 2981, 1744, 1718, 1638, 1446, 1213 cm-1; HRMS (+ESI)Calcd for C19H21O5S [M+H]+: 361.1110; found: 361.1114. Di-isopropyl 2-[(3-(methylthio)naphthalen-2-yl)oxy]maleate (3cc): Using the general experimental procedure on di-isopropylacetylenedicarboxylate (0.14 g; 0.75 mmol, 1.5 equiv), 3-(trimethylsilyl)-2-napthyl-trifluoromethanesulfonate (0.14 mL; 0.5mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3cc was isolated as yellow gummy (0.122 g, 63% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.41-7.50 (m, 2H), 5.22 (m, 1H), 5.15 (s, 1H), 5.00 (m, 1H), 2.55 (s, 3H), 1.34 (d, J=6.3 Hz, 6H), 1.19 (d, J= 6.3 Hz, 6H); 13C{1H}

NMR (126 MHz, CDCl3): δ 164.7, 162.1, 159.8, 148.0, 132.0, 131.4, 131.3, 127.3,

126.6, 126.5, 125.9, 124.9, 118.4, 99.8, 70.4, 68.0, 21.7, 21.5, 14.8; IR (CHCl3): 2981, 1741, 1715, 1638, 1448, 1214 cm-1; HRMS (+ESI)Calcd for C21H25O5S [M+H]+: 389.1423; found: 389.1421. Di-nbutyl 2-[(3-(methylthio)naphthalen-2-yl)oxy]maleate (3cd) Using the general experimental procedure on di-nbutylacetylenedicarboxylate (0.169 g; 0.75 mmol, 1.5 equiv), 3-(trimethylsilyl)-2-napthyl-trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3cd was isolated as yellow gummy (0.129 g, 62% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ 7.78 (d, J=8.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.42-7.51 (m,2H), 5.16 (s, 1H), 4.33 (t, J=6.7 Hz, 2H), 4.06 (t, J=6.7 Hz, 2H), 2.55 (s, 3H), 1.17-1.82 (m, 8H), 0.93 (t, J= 7.4 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.3, 162.6, 159.6,


Page 15 of 25 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


147.8, 132.0, 131.2, 127.3, 126.5, 125.9, 124.9, 118.3, 99.4, 66.2, 64.5, 30.4, 30.2, 18.9, 14.8, 13.6; IR (CHCl3): 2958, 1746, 1719, 1638, 1447, 1213 cm-1; HRMS (+ESI)Calcd for C23H29O5S [M+H]+ : 417.1736; found: 417.1735. Di-tert-butyl 2-[(3-(methylthio)naphthalen-2-yl)oxy]maleate (3ce): Using the general experimental procedure on di-tert-butylacetylenedicarboxylate (0.17 g; 0.75 equiv, 1.5 equiv), 3-(trimethylsilyl)-2-napthyl-trifluoromethanesulfonate (0.14 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ce was isolated as yellow gummy (0.122g, 59% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; Characterization data for major isomer; 1H NMR (500 MHz, CDCl3): δ7.76 (d, J=7.9 Hz, 1H), 7.73 (d, J= 7.9 Hz, 1H), 7.59 (s, 1H), 7.38-7.51 (m, 3H), 5.24 (s, 1H), 2.55 (s, 3H), 1.47 (s, 9H), 1.44 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3): δ 164.2, 161.3, 158.2, 148.6, 131.7, 131.3, 131.2, 127.1, 126.5, 126.2, 125.7, 124.7, 117.3, 102.9, 83.5, 80.8, 27.9, 27.7, 14.8; IR (CHCl3): 2978, 1740, 1714, 1638, 1449, 1216 cm-1; HRMS (+ESI)Calcd for C23H28O5NaS [M+Na]+ : 439.1555; found: 439.1553. Di-methyl 2-[2-methyl-6-(methylthio)phenoxy]maleate (3da): Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol, 1.5 equiv), 2-methyl-6-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3da was isolated as light brown gummy (0.102 g, 69% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.15 (t, J=7.7 Hz, 1H), 7.08 (d, J= 6.8 Hz, 1H), 7.01-7.06 (m, 1H), 4.87 (s, 1H), 3.97 (s, 3H), 3.65 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.8, 163.1, 158.9, 146.9, 131.9, 130.8, 127.9,

126.9, 124.3, 96.0, 53.1, 51.6, 15.6, 14.7; IR (CHCl3): 2952, 1752, 1718, 1637, 1436, 1210 cm-1; HRMS (+ESI)Calcd for C14H17O5S [M+H]+ : 297.0797; found:297.0796. Di-ethyl 2-[2-methyl-6-(methylthio)phenoxy]maleate (3db): Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11mL; 0.75 mmol, 1.5 equiv), 2-methyl-6-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3db was isolated as light brown gummy (0.108 g, 67% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.14 (d, J=7.6 Hz, 1H), 7.007.11 (m, 2H), 4.85 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.11 (q, J= 7.1 Hz, 2H), 2.42 (s, 3H), 2.25 ( s, 3H), 1.41 (t, J=7.2 HZ, 3H), 1.21 (t, J=7.2 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.4, 162.8, 159.1, 147.1, 132.1, 130.9, 127.9, 126.8, 124.3, 96.1, 62.3, 60.5, 15.7, 14.8, 14.0, 13.9; IR



Page 16 of 25

(CHCl3): 2925, 1747, 1717, 1636, 1460, 1209 cm-1; HRMS (+ESI) Calcd for C16H21O5S [M+H]+ : 325.1110; found: 325.1116. Di-methyl 2-[4-methoxy-2-(methylthio)phenoxy]maleate (3ea): Using the general experimental procedure on dimethylacetylene carboxylate (0.09 mL; 0.75 mmol), 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.13 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3ea was isolated as light brown gummy (0.103 g, 66% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 6.98 (d, J=8.8 Hz, 1H), 6.77 (d, J=2.9 Hz, 1H), 6.67 (dd, J1= 2.9 Hz, J2= 8.8 Hz, 1H), 5.01 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.64 (s, 3H), 2.42 (s, 3H);

13C{1H}

NMR (126 MHz, CDCl3): δ 165.8, 163.2, 160.4, 158.1, 142.7, 132.9,

122.1, 112.8, 110.3, 97.4, 55.6, 53.0, 51.6, 14.7; IR (CHCl3): 2953, 1751, 1719, 1637, 1437, 1203 cm-1; HRMS (+ESI)Calcd for C14H17O6S [M+H]+: 313.0746; found: 313.0740. Diethyl 2-[4-methoxy-2-(methylthio)phenoxy]maleate (3eb): Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11mL; 0.75 mmol, 1.5 equiv), 4-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.13 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3eb isolated as light brown gummy (0.112 g, 66% yield) after purification by flash column chromatography using hexane/EtOAc (4:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 6.99 (d, J=8.8 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 6.67 (dd, J1=2.9 Hz, J2=8.8 Hz, 1H), 5.01(s, 1H), 4.39 (q, J=7.2 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.81 (s, 3H), 2.42 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C{1H}

NMR (126 MHz, CDCl3): δ 165.3, 162.8, 160.5, 158.0, 142.9, 132.9, 122.1, 112.8,

110.3, 97.5, 62.3, 60.4, 55.6, 14.7, 13.9, 13.8; IR (CHCl3): 2982, 1747, 1716, 1637, 1440, 1197 cm-1; HRMS (+ESI)Calcd for C16H21O6S [M+H]+: 341.1059; found: 341.1063 Di-methyl

2-[5-methyl-2-(methylthio)phenoxy]maleate

and

di-methyl

2-[4-methyl-2-

(methylthio)phenoxy)maleate] (3fa) and (3f'a): Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol), 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.13 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3fa and 3f'a were isolated as light brown gummy (0.102 g, 69% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.20 (d, J=8.0 Hz, 1H), 7.047.09 (m, 2H), 6.89-7.00 (m, 3H), 5.03 (s, 1H), 5.02 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.67, (s,


Page 17 of 25 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


3H), 3.66 (s, 3H), 2.44 (s, 3H), 2.43 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.8, 163.2, 163.1, 160.1, 159.9, 149.5, 147.1, 137.1, 136.9, 131.1, 127.9, 127.8, 127.7, 127.6, 126.8, 122.0, 121.1, 97.8, 97.5, 53.1, 51.6, 20.9, 20.7, 15.3, 14.8; IR (CHCl3): 2952, 1753, 1719, 1637, 1436, 1204 cm-1; HRMS (+ESI)Calcd for C14H17O5S [M+H]+: 297.0797; found: 297.0797. Di-ethyl

2-[5-methyl-2-(methylthio)phenoxy]maleate

and

di-ethyl

2-[4-methyl-2-

(methylthio)phenoxy]maleate; (3fb) and (3f'b) Using the general experimental procedure on di-ethylacetylenedicarboxylate (0.11 g; 0.75 mmol), 4-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.13 mL; 0.5mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO (2 mL), 3fb and 3f'b were isolated as brown gummy (0.102 g, 63% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.13 (d, J=8.0 Hz, 1H), 6.95-7.01 (m, 2H), 6.83-6.91 (m, 3H), 4.95 (s, 1H), 4.94 (s, 1H), 4.33 (q, J= 7.2Hz, 4H), 4.02-4.08 (m, 4H), 2.37 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.23-2.30 (m, 6H), 1.10-1.19 (m, 6H);

13C{1H}

NMR (126

MHz, CDCl3): δ 165.4, 165.3, 162.8, 162.7, 160.2, 160.0, 149.7, 147.3, 137.1, 136.9, 131.2, 128.0, 127.8, 127.7, 126.9, 122.1, 121.2, 98.2, 97.8, 62.4, 60.6, 60.5, 21.0, 20.7, 15.4, 14.9, 14.1, 13.9; IR (CHCl3): 2982, 1748, 1717, 1637, 1439, 1225 cm-1; HRMS (+ESI)Calcd for C16H21O5S [M+H]+: 325.1110; found:325.1110. Di-methyl 2-[2-{(methyl-d3)thio}phenoxy]maleate (3aa-D3) Using the general experimental procedure on di-methylacetylenedicarboxylate (0.09 mL; 0.75 mmol, 1.5 equiv), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.12 mL; 0.5 mmol, 1 equiv), KF (0.116 g; 2 mmol, 4 equiv) in DMSO-d6 (2 mL), 3aa-D3 was isolated as light brown gummy (0.104 g, 73% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.22-7.31 (m, 2H), 7.19 (m, 1H), 7.07 (dd, J1= 1.1 Hz, J2= 7.9 Hz, 1H), 5.04 (s, 1H), 3.95 (s, 3H), 3.67 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.7, 163.1, 159.7, 149.4, 131.7, 127.3, 127.1, 126.2, 121.4, 98.1, 53.1, 51.7, 14.4 (m);IR (CHCl3): 2993, 1749, 1716, 1635, 1435, 1206 cm-1; HRMS (+ESI)Calcd for C13H11D3O5S [M-OMe]+: 254.0566; found: 254.0566. Di-methyl 2-{2-(methylthio)phenoxy}maleate-d (3aa-D): An oven-dried round bottomed flask (25 mL capacity) equipped with a magnetic stir bar was evacuated and backfilled with argon. Di-methylacetylenedicarboxylate (0.09 mL, 0.75 mmol, 1.5 equiv), aryne precursor (0.12 mL, 0.5 mmol, 1 equiv), KF (0.116g, 2 mmol, 4 equiv), DMSO (2



Page 18 of 25

mL) and D2O (9.0 µL, 0.5 mmol) were added in presence of argon at room temperature. The reaction mixture was evacuated and backfilled with argon for three times. The reaction mixture was stirred at 50 oC for 5 h and then allowed to cool to room temperature. Water (10 mL) was added to the reaction mixture and the organic layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The compound 3aa-D was isolated as colorless gummy (0.095 g, 67% yield) after purification by flash column chromatography using hexane/EtOAc (9:1) as the eluent; 1H NMR (500 MHz, CDCl3): δ 7.227.30 (m, 2H), 7.16-7.22 (m, 1H), 7.07 (dd, J1= 1.1 Hz, J2= 7.9 Hz, 1H), 5.03 (s, 0.65H), 3.95 (s, 3H), 3.66 (s, 3H), 2.45 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.8, 163.1, 159.7, 149.3, 131.8, 127.2, 127.1, 126.2, 121.4, 98.0, 53.1, 51.7, 14.8; IR (CHCl3): 2923, 1750, 1717, 1634, 1436, 1218 cm-1; HRMS (+ESI)Calcd for C13H13DNaO5S [M+Na]+: 306.0522; found: 306.0540. Conflicts of interest There is no conflict to declare. Acknowledgments We are thankful to the Director, CSIR-NEIST, Jorhat, India for the interest in this work and facilities. HH and AS acknowledge the DST, New Delhi, India for DST-Inspire fellowship grants. KN acknowledges the UGC, New Delhi for a fellowship.

Supporting Information Copies of 1H NMR, 13C NMR and HRMS spectra of all the synthesized compounds along with crystallographic data of compound 3ae are available free of charge via the internet at http://pubs.acs.org.

Notes and references 1. For recent reviews on aryne chemistry, see: (a) Shi, J.; Li, Y.; Li, Y. Aryne Multifunctionalization with Benzdiyne and Benztriyne Equivalents. Chem. Soc. Rev. 2017, 46, 1707-1719. (b) Diamond, O. J.; Marder, T. B. Methodology and Applications of the Hexadehydro-Diels-Alder (HDDA) Reaction. Org. Chem. Front. 2017, 4, 891-910. (c) Idiris, F. I. M.; Jones, C. R. Recent Advances in Fluoride-Free Aryne Generation from


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