Temperature-Controlled Thiation of Î±-Cyano-Î²-Alkynyl Carbonyl

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Temperature-Controlled Thiation of #-Cyano-#-Alkynyl Carbonyl Derivatives for De Novo Synthesis of 2-Aminothiophenes and Thieno[2,3-c]isothiazoles Tzu-Ting Kao, Bo-Kai Peng, Min-Chieh Liang, Chia-Jui Lee, I-Chia Chen, Kak-Shan Shia, and Yen-Ku Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01866 • Publication Date (Web): 02 Oct 2018 Downloaded from http://pubs.acs.org on October 2, 2018

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The Journal of Organic Chemistry

Temperature-Controlled Thiation of α-Cyano-β-Alkynyl Carbonyl Derivatives for De Novo Synthesis of 2-Aminothiophenes and Thieno[2,3-c]isothiazoles Tzu-Ting Kao†, Bo-Kai Peng‡, Min-Chieh Liang‡, Chia-Jui Lee†, I-Chia Chen§, Kak-Shan Shia*† and Yen-Ku Wu*‡ †

Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan § Department of Cosmetic Applications and Management, Cardinal Tien Junior College of Healthcare and Management, New Taipei City 23143, Taiwan ‡

Supporting Information Placeholder EWG R S

NH2

P4S10, EtOH

EWG

80 °C, air

14 examples up to 95% yield

P4S10, EtOH 80 °C; then

CN

Ar R S

LR, p-xylene 130 °C, air

R

EWG = COR, CO2R, CN, SO2R R = aryl, alkyl, H, TMS, CH2OBn

S

N

15 examples up to 73% yeild

ABSTRACT: Making use of temperature-controlled thiation as a key operation, a simple route to 2-aminothiophenes or thieno[2,3c]isothiazoles has been newly developed wherein the 2-aminothiophene nucleus was formed through an initial formation of thioamide followed by a 5-exo-dig addition to the tethered alkyne; however, under harsher thermal conditions, excess sulfur-transferring reagents enabled further oxidative thiation to generate the corresponding thieno[2,3-c]isothiazoles.

Heterocycles are common structural motifs in marketed pharmaceutical drugs.1 The search and identification of small heterocyclic molecules with desirable pharmacological properties are therefore essential for the progress in medicinal chemistry. Over the past decades, the practice of drug discovery has revealed that selected heterocycles seem to occupy biologically relevant regions of vast chemical space.2 Accordingly, those prominent structures have been collectively coined as the privileged scaffold.3 In the subset of sulfur-containing structures, the 2-aminothiophene core has received considerable attention because an increasing number of drug candidates, agrochemicals, and dyestuffs based on this modality has been widely developed (Figure 1).4 To expand the sulfur chemistry in this field, facile synthetic approaches to novel 2-aminothiophene analogs are evidently in high demand.

Scheme 1. Thiation Reactions of Activated Nitriles a) The Gewald reaction: CN

EWG

S8

O +

amine

R2

R1

O NH2 NH

S

F

Me N

TPCA-1 O

NH2

N

N

Me

CN

Ph

CF3

PD81723

O

O OMe

Bn N

NH2

NH2 S tinoridine

N S H olanzepine (Zyprexa®)

Cl S

NH2 T-62

Figure 1. Bioactive 2-Aminothiophene Derivatives

S

Lawesson's reagent (LR)

O

toluene, 110 °C

R2

NH2

S

O

P

Ar

Ph

LR =

NH S

Ar S

P

S S

P

S Ar

Ar = 4-MeOPh

c) This work: EWG

CN

R

Ar

EWG

thiation agent

Cl S

S

R1

EWG

b) Pedersen and Lawesson:

1

Me

R1

R2

solvent, temp. O

N

EWG

or

R S 3

NH2

R S S

N

4 (EWG = COAr)

Several methods have been documented for the de novo assembly of 2-aminothiophenes from acyclic precursors.5 A pioneering example was published by Gewald and co-workers in 1966 wherein the authors discovered that amine-mediated three-component coupling of ketones, activated nitriles, and sulfur resulted in the formation of functionalized 2aminothiophenes (Scheme 1a).6 Arguably, the Gewald reaction and its variants constitute the most widely used protocols for

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the preparation of 2-aminothiophenes.7,8 Alternative strategies for 2-aminothiophene syntheses mainly relied on various cyclization reactions of activated thioamides.9,10,11,12 As illustrated in Scheme 1b, Pedersen and Lawesson reported that α-cyano acetophenone could be efficiently converted into an oxazaphosphorine derivative under the treatment with Lawesson’s reagent (LR).13 This work together with Gewald’s thiophene synthesis inspired us to probe a potential new reaction via the treatment of alkyne-appended β-ketonitriles with various sulfur-transferring reagents (Scheme 1c). During the course of the investigation, we found that a complete control over creating either 2-aminothiophene 3 or thieno[2,3c]isothiazole 4 could be readily fulfilled by tuning the reaction parameters as detailed in the following. Scheme 2. Preparation of Alkyne-Appended Nitriles L-proline Hantzsch ester

O EWG

CN

+ R

EtOH, 70 °C

1a: EWG = C(O)Ph; R = Ph 1b: EWG = C(O)Ph; R = 4-MePh 1c: EWG = C(O)Ph; R = 4-ClPh 1d: EWG = C(O)2-MeOPh; R = Ph 1e: EWG = C(O)4-MeOPh; R = Ph 1f: EWG = C(O)2-furyl; R = Ph 1g: EWG = C(O)2-thienyl; R = Ph 1h: EWG = C(O)Ph; R = 2-thienyl S1: EWG = C(O)2-NO2Ph; R = TMS 1j: EWG = CO2Et; R = Ph 1k: EWG = C(O)t-Bu; R = Ph

EWG

1

CN

R

1l: EWG = SO2Tol; R = Ph 1m: EWG = CN; R = Ph 1n: EWG = C(O)2-thienyl; R = 4-MePh 1o: EWG = C(O)4-MeOPh; R = 4-ClPh 1p: EWG = C(O)4-ClPh; R = 4-ClPh 1q: EWG = C(O)4-MePh; R = Ph 1r: EWG = C(O)4-ClPh; R = Ph 1s: EWG = C(O)Ph; R = TMS 1t: EWG = C(O)Ph; R = Et 1u: EWG = C(O)Ph; R = CH2OBn 1v: EWG = C(O)Et; R = Ph

A series of alkyne-appended nitriles 1 were readily prepared in good yields by a reductive condensation reaction (Scheme 2). Compound 1a was chosen as a model substrate to study a series of thiation reactions under air (Table 1). At room temperature, reactions of 1a with either phosphorus decasulfide or Lawesson’s reagent could deliver thioamide 2a as the sole product (entries 1 and 2).14 Notably, the sulfur-transferring reagents were found to chemoselectively target the cyano group instead of the ketone moiety. When the reaction was conducted with P4S10 in refluxing ethanol,15 we observed that 2-aminothiophene 3a was formed in good yield (83%, entry 3). At elevated temperatures (130 °C), the LR-mediated reaction in p-xylene could furnish an unexpected product 4a in 58% yield (entry 6), the structure of which was unambiguously determined by X-ray crystallographic analysis as a substituted thieno[2,3-c]isothiazole.16 To our knowledge, only a few synthetic approaches were reported to synthesize thieno[2,3c]isothiazole scaffolds. 17 , 18 , 19 Among them, Gewald and coworkers had described the first synthesis of thieno[2,3c]isothiazoles involving a three-step sequence through an oxidative ring closure of 2-amino-3-thioamidethiophenes.17 Serendipitously, our method enables the one-pot conversion of various alkyne-appended β-ketonitriles into thieno[2,3-c]isothiazoles in the presence of LR (vide infra).

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Table 1. Screening of Reaction Conditions O Ph O Ph 1a

Ph S 3a

Ph

2a

solvent temp., air

Ph

NH2

[S]

CN

O

S

NH2

Ph Ph

Ph

S

≡

N

S 4a

entry

[S]

solvent/temp. (°C)

yield% of 2aa

yield% of 3aa

yield% of 4aa

1

P4S10

EtOH/rt

23

−

−

−

−

b

2

LR

THF/rt

46

3

P4S10

EtOH/80

−

83

−

4

LR

EtOH/80

−

36

−

5

P4S10

p-xylene/130

−

−

22

6

LR

p-xylene/130

−

−

58

7

c

LR

p-xylene/130

−

−

44

8

d

S8

toluene/100

−

−

−

NaSH

dioxane/100

−

−

−

9e a

b

Yield of the isolated product. A significant amount of starting material 1a could be recovered. cUnder N2 atmosphere. dNo reaction. eMixture of unidentifiable products. LR = Lawesson’s reagent.

From a mechanistic point of view (Scheme 3), the direct conversion of 1a into 4a calls for the action of an oxidant. Since the reactions were conducted under air, we wondered whether oxygen is an essential factor in this process. However, when we performed the reaction under nitrogen atmosphere, thieno[2,3-c]isothiazole 4a was still generated in only slightly lower yield (entry 7: 44% versus entry 6: 58%); hence, LR is supposed to be responsible for the oxidation event. The employment of other standard thiation reagents such as octasulfur and sodium sulfide failed to give the desired product 4a (entries 9 and 10). Taken together, a plausible mechanism is proposed in Scheme 3 to account for the formation of 3a and 4a.20 Scheme 3. Proposed Reaction Mechanism NH2

O LR 1a

Ph 2a

O Ph

NH2

Ph

S

80 °C

4a

±H

O

5-exodig

S Ph

Ph

LR

-H2O

±H S

H S N H S CH2Ph

O Ph -ArP=S

P

S

Ar S

NH2 S CH2Ph

Ar P S

3a

Ar = 4-OMe 130 °C

With the optimized reaction conditions, we first evaluated the scope of the thiation reactions transforming α-cyano ke-


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tones 1 to 2-aminothiophenes 3 (Table 2). In general, substrates with an electron-deficient and electron-rich aryl substituent afforded the cyclized products 3a-e in moderate to good yields. The presence of heteroaromatic group was also well tolerated (see 3f-h). 4-Alkyl-substituted thiophene 3i and 3j could be prepared from the substrate possessing a suitable alkyne (R = H or CH2CH2OBn). In addition to aryl ketone precursors, the method is applicable to other alkynyl carbonyl derivatives. Ester 3k was obtained in good yield, but those cases with the pivaloyl (see 3l) or sulfonyl (see 3m) functionality are less efficient due to a complex mixture formed in the reaction. Intriguingly, the reaction of malononitrile 1m resulted in the formation of thienyl thioamide 3n, clearly indicating that both nitrile groups could participate in the P4S10-mediated thiation reaction as illustrated in Scheme 4.

CN

EtOH, 80 °C, 3 h air

R

O

R

R = H: 3a, 83% yield R = Me: 3b, 95% yield R = Cl: 3c, 46% yield

Ph S

S

3h, 76% yield

O

S

Ph S

NH2

2-OMe: 4d, 60% yield 4-OMe: 4e, 55% yield

4f, 74% yield

R

NO2

Ph S N

R = Cl: 4g, 55% yield R = OMe: 4h, 43% yield

NH2

S

3j, 68% yield

Ph R S N

S EWG

S N

S

Me

S S

S N

S

N

R = Me: 4i, 50% yield R = Cl: 4j, 56% yield

4k, 41% yield Me

BnO

3i, 89% yield

S N

S

R

X = O: 3f, 89% yield X = S: 3g, 65% yield

O2N

NH2

S

NH2

Ph Me

Me

Cl

Ph NH2

4

Ph

N

S O

N

S

MeO

X

S

2-OMe: 3d, 60% yield 4-OMe: 3e, 76% yield

O S

R2

S

O

Ph

NH2

S

LR (1.2 equiv), p-xylene 130 °C, 1 h, air

R = H: 4a, 62% yield R = Me: 4b, 52% yield R = Cl: 4c, 40% yield

OMe

R2

Ph

NH2

S 3

O

NH2

1

R1

P4S10 (2 equiv) EtOH, 80 °C, 3 h; then

CN

S

R

Ph S

O R1

EWG

P4S10 (2 equiv)

1

Table 3. Scope of Thieno[2,3-c]isothiazole Synthesis via the One-Pot Procedurea

R

Table 2. Scope of 2-Aminothiophene Synthesisa EWG

alkynes also furnished the cyclized products 4k-n in 40~61% yields. The modest yield of 4o was due to the labile characteristic of alkyl ketone 1v. Although the yields are generally in a moderate range, this protocol offers a rapid access to thieno[2,3-c]isothiazole scaffold that would be otherwise difficult to synthesize by any existing methods.

EWG = CO2Et: 3k, 60% yield EWG = COt-Bu: 3l, 19% yield EWG = SO2Tol: 3m, 9% yield

a

Reactions were conducted following the optimized procedure (Table 1, entry 3). Yields refer to isolated products.

Ph

R = CH2OBn: 4l, 61% yield R = SiMe3: 4m, 40% yieldb R = Et: 4n, 43% yield

S S

N

4o, 15% yield

a Unless otherwise noted, all reactions were conducted following the one-pot, two-step procedure. Yields refer to isolated products. b Only LR was used at 110 °C.

Scheme 5. Strategic Transformation of Compound 4k

Scheme 4. Reaction of Alkynyl Malononitrile 1m NC

S

CN

P4S10 (2 equiv)

Ph 1m

EtOH, 80 °C, 3 h air

NH2 Ph S

NO2 Me

S

80 °C, 3 h

N

S

NH2

I

NIS, DMF

NO2

Me

S S

4k

N

5, 73% yield

3n, 46% yield Pd(PPh3)4 (2 mol %) K2CO3, 4-BrPhB(OH)2

For the synthesis of thieno[2,3-c]isothiazoles from 1, we later found that a one-pot, two-step procedure gave better and more consistent results than those solely employing Lawesson’s reagent in p-xylene at 130 °C (See the Experimental Section). The reaction conditions as shown in Table 3 were applied to examine the scope of the process. Substrates with various substitution patterns on the aryl units (R1 and R2) were successfully converted to the desired products 4a-j (40~74%). The thiation reaction of terminal and alkyl- or silyl-capped

Br

PhMe/EtOH/H2O 80 °C, 16 h

Br Fe, 2 N HCl NH2

Me

S S

N

7, 86% yield


CHCl3/EtOH/H2O Me reflux, 1.5 h

NO2 S S

N

6, 88% yield


To showcase the utility of the method, a few advanced derivatives of 4k were prepared (Scheme 5). An iodo substituent was introduced to the thieno[2,3-c]isothiazole framework by the treatment of 4k with N-iodosuccinimide (NIS). The resulting heteroaryl iodide 5 could efficiently undergo the Suzuki coupling reaction in a co-solvent system (PhMe/EtOH/H2O) to give an extended polyaromatic product 6 (88%). The chemoselective reduction of the nitro group afforded 7 in good yield (86%). Conceivably, these sample transformations might open new opportunities for further exploring the structureactivity relationship of a library of structurally diverse thiophene-derived compounds.21 In conclusion, we have developed a new method to synthesize 2-aminothiophenes and thieno[2,3-c]isothiazoles from the common linear alkynyl nitriles using phosphorus decasulfide and/or Lawesson’s reagent as a sulfur-transferring reagent. The reaction course was governed by the setting of solvent and temperature. The thiation processes could be carried out with ease under air and required no sophisticated experimental techniques. Studies directed toward the design and synthesis of bioactive 2-aminothiophene-based compounds are underway, and results will be reported in due course.

EXPERIMENTAL SECTION General Information. All reactions were performed under air unless otherwise stated. All solvents (ACS grade) were used as received. Commercially available reagents were used as received without further purification. Thin layer chromatography (TLC) analysis was conducted on glass plates precoated with 0.25 mm silica gel, visualized with 254 nm UV lamp and stained with potassium permanganate followed by heating until development of color. Flash chromatography was performed on 230-400 mesh silica gel with the indicated eluents. Nuclear magnetic resonance (NMR) spectra were recorded in indicated deuterated solvents and are reported in ppm with residual protiated solvent used as a reference. Coupling constants (J) are reported in Hertz (Hz). Infrared (IR) spectra were recorded neat and reported in cm-1. Mass spectra were recorded on a TOF mass spectrometer by using FD, ESI or FI as specified in each case. Procedure for the Synthesis of 2-Benzoyl-5-phenylpent-4ynenitrile (1a). Benzoylacetonitrile (1.03 g, 7.10 mmol), Lproline (159 mg, 1.38 mmol) and Hantzsch ester (1.74 g, 6.87 mmol) were added to a round-bottom flask charged with a magnetic bar, and then the flask was sealed with a rubber septum and purged with nitrogen (N2). Ethanol (70 mL) and 3phenylpropiolaldehyde (1.34 g, 10.30 mmol) were sequentially added to the mixture. The resulting mixture was stirred for 10 min at room temperature. Next, the reaction was stirred at 70 °C (oil bath) until completion as indicated by TLC (typically for 4 h). After cooling to room temperature, the crude reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (15% EtOAc/hexanes) to give the desired compound 1a (1.51 g, 82% yield) as a yellow oil. 1a: IR (neat) 3063, 2923, 1608, 1571, 1527, 1485, 1345, 1270, 1250, 1070, 1008, 954, 808 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.058.03 (m, 2H), 7.68 (td, J = 7.2, 1.6 Hz, 1H), 7.57-7.53 (m, 2H), 7.38-7.36 (m, 2H), 7.31-7.26 (m, 3H), 4.60 (t, J = 7.6 Hz, 1H), 3.16 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.8, 134.8, 133.9, 131.7, 129.2, 128.9, 128.4, 128.2, 122.4, 116.3, 84.4, 83.4, 39.0, 20.5; HRMS (ESI, [M+Na]+) calcd. for C18H13NNaO: 282.0889, found: 282.0888; Rf = 0.2 (9% EtOAc/hexanes). 2-Benzoyl-5-p-tolylpent-4-ynenitrile (1b). According to the procedure for the preparation of 1a, compound 1b was synthesized from benzoylacetonitrile (227 mg, 1.56 mmol), 3-(p-

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tolyl)propiolaldehyde (302 mg, 2.09 mmol), L-proline (32 mg, 0.28 mmol) and Hantzsch ester (350 mg, 1.38 mmol) in 44% yield (190 mg) as a brown solid. 1b: IR (neat) 3029, 2923, 2244, 1698, 1596, 1510 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.4, 1.2 Hz, 2H), 7.67 (tt, J = 7.4, 1.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.09 (dd, J = 8.0, 0.4 Hz, 2H), 4.59 (t, J = 7.2 Hz, 1H), 3.14 (d, J = 7.8 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.9, 138.5, 134.7, 133.9, 131.6, 129.1, 129.0, 128.9, 119.9, 116.4, 84.5, 82.7, 39.1, 21.4, 20.6; HRMS (ESI, [M+Na]+) calcd. for C19H15NNaO: 296.1046, found: 296.1044; Rf = 0.2 (9% EtOAc/hexanes); mp 59-60 oC. 2-Benzoyl-5-(4-chlorophenyl)pent-4-ynenitrile (1c). According to the procedure for the preparation of 1a, compound 1c was synthesized from benzoylacetonitrile (92 mg, 0.63 mmol), 3-(4chlorophenyl)propiolaldehyde (150 mg, 0.91 mmol), L-proline (14 mg, 0.12 mmol) and Hantzsch ester (154 mg, 0.61 mmol) in 68% yield (137 mg) as a brown solid. 1c: IR (neat) 3062, 2943, 2357, 2241, 1703, 1487 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H), 7.30-7.24 (m, 4H), 7.09-7.02 (m, 2H), 4.59 (t, J = 7.2 Hz, 1H), 3.14 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.7, 134.8, 134.5, 133.8, 132.9, 129.2, 128.9, 128.6, 120.9, 116.2, 84.5, 83.3, 38.9, 20.4; HRMS (EI, [M]+) calcd. for C18H12NClO: 293.0602, found: 293.0600; Rf = 0.39 (25% EtOAc/hexanes); mp 85-86 oC. 2-(2-Methoxybenzoyl)-5-phenylpent-4-ynenitrile (1d). According to the procedure for the preparation of 1a, compound 1d was synthesized from 2-methoxybenzoylacetonitrile (311 mg, 1.78 mmol), 3-phenylpropiolaldehyde (341 mg, 2.62 mmol), L-proline (41 mg, 0.36 mmol) and Hantzsch ester (443 mg, 1.75 mmol) in 58% yield (298 mg) as a brown oil. 1d: IR (neat) 2945, 2360, 2341, 1682, 1597, 1486, 1291 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 7.6, 2.0 Hz, 1H), 7.57 (td, J = 7.6, 2.0 Hz, 1H), 7.41-7.39 (m, 2H), 7.30-7.26 (m, 3H), 7.09-7.02 (m, 2H), 4.73(dd, J = 8.0, 5.6 Hz, 1H), 4.01 (s, 3H), 3.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 190.4, 158.8, 135.5, 131.7, 131.6, 128.2, 128.2, 124.6, 122.8, 121.4, 117.0, 111.8, 84.1, 83.7, 55.9, 44.1, 20.2; HRMS (ESI, [M+Na]+) calcd. for C19H15NO2Na: 312.0995, found: 312.0991; Rf = 0.38 (25% EtOAc/hexanes). 2-(4-Methoxybenzoyl)-5-phenylpent-4-ynenitrile (1e). According to the procedure for the preparation of 1a, compound 1e was synthesized from 4-methoxybenzoylacetonitrile (306 mg, 1.75 mmol), 3-phenylpropiolaldehyde (341 mg, 2.62 mmol), L-proline (40 mg, 0.35 mmol) and Hantzsch ester (442 mg, 1.74 mmol) in 99% yield (504 mg) as a brown solid. 1e: IR (neat) 3057, 2935, 2243, 2340, 1686, 1599, 1512 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 2H), 7.39-7.36 (m, 2H), 7.30-7.27 (m, 3H), 7.38-7.36 (m, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.54 (t, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.13 (dd, J = 7.2, 2.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.0, 164.8, 131.7, 131.4, 128.3, 128.2, 126.8, 122.5, 116.6, 114.4, 84.2, 83.7, 55.7, 38.6, 20.5; HRMS (ESI, [M+Na]+) calcd. for C19H15NNaO2: 312.0995, found: 312.0997; Rf = 0.38 (25% EtOAc/hexanes); mp 72-73 oC. 2-(Furan-2-carbonyl)-5-phenylpent-4-ynenitrile (1f). According to the procedure for the preparation of 1a, compound 1f was synthesized from 3-(furan-2-yl)-3-oxopropanenitrile (243 mg, 1.80 mmol), 3-phenylpropiolaldehyde (326 mg, 2.50 mmol), Lproline (38 mg, 0.33 mmol) and Hantzsch ester (423 mg, 1.67 mmol) in 74% yield (330 mg) as a brown oil. 1f: IR (neat) 3134, 2958, 2925, 2247, 1795, 1723, 1598, 1567, 1462, 1288 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 1.6, 0.8 Hz, 1H), 7.48 (dd, J = 3.6, 0.8 Hz, 1H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 3H), 6.66 (dd, J = 3.6, 1.6 Hz, 1H), 4.45 (t, J = 0.8 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 177.3, 150.2, 148.1, 131.7, 128.4, 128.2, 122.4, 120.3, 115.9, 113.4, 84.4, 83.0,


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39.3, 20.4; HRMS (EI, [M]+) calcd. for C16H11NO2: 249.0784, found: 249.0788; Rf = 0.26 (20% EtOAc/hexanes). 5-Phenyl-2-(thiophene-2-carbonyl)pent-4-ynenitrile (1g). According to the procedure for the preparation of 1a, compound 1g was synthesized from 2-thenoylacetonitrile (150 mg, 0.99 mmol), 3-phenylpropiolaldehyde (185 mg, 1.42 mmol), L-proline (23 mg, 0.20 mmol) and Hantzsch ester (251 mg, 0.99 mmol) in 83% yield (218 mg) as a brown oil. 1g: IR (neat) 3094, 2957, 2923, 2247, 1717, 1597, 1571, 1490, 1442 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 4 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.38-7.34 (m, 2H), 7.33-7.25 (m, 3H), 7.21 (t, J = 4.8 Hz, 1H), 4.44 (t, J = 7.2 Hz, 1H), 3.16 (d, J = 7.6 Hz, 2H)；13C NMR (100 MHz, CDCl3) δ 181.5, 140.6, 136.8, 134.4, 131.7, 128.9, 128.5, 128.3, 122.4, 116.4, 84.6, 83.4, 39.9, 21.0; HRMS (EI, [M]+) calcd. for C16H11NOS: 265.0556, found: 265.0560; Rf = 0.34 (20% EtOAc/hexanes). 2-Benzoyl-5-(thiophen-2-yl)pent-4-ynenitrile (1h). According to the procedure for the preparation of 1a, compound 1h was synthesized from benzoylacetonitrile (127 mg, 0.88 mmol), 3(thiophen-2-yl)propiolaldehyde (170 mg, 1.25 mmol), L-proline (20 mg, 0.17 mmol) and Hantzsch ester (222 mg, 0.88 mmol) in 59% yield (137 mg) as a brown oil. 1h: IR (neat) 3106, 2957, 2923, 2244, 1697, 1596, 1492, 1448 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 2H), 7.68 (tt, J = 7.4, 1.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.23 (dd, J = 5.2, 1.2 Hz, 1H), 7.15 (dd, J = 3.6, 1.2 Hz, 1H), 6.94 (dd, J = 5.2, 3.6 Hz, 1H), 4.59 (t, J = 7.2 Hz, 1H), 3.17 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.8, 134.9, 133.8, 132.3, 129.2, 129.0, 127.2, 126.9, 122.4, 116.3, 87.5, 77.6, 38.8, 20.7; HRMS (EI, [M]+) calcd. for C16H11NOS: 265.0556, found: 265.0555; Rf = 0.4 (20% EtOAc/hexanes). Procedure for the Synthesis of Compound S1. According to the procedure for the preparation of 1a, compound S1 was synthesized from 3-(2-nitrophenyl)-3-oxopropanenitrile (6.80 g, 35.76 mol), 3-(Trimethylsilyl)propiolaldehyde (8.70 mL, 58.86 mmol) L-proline (0.82 g, 7.12 mol) and Hantzsch ester (9.00 g, 35.53 mol) in 58% yield (6.28 g) as a yellow oil. S1: IR (neat) 2958, 2924, 2182, 1724, 1532, 1347 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 8.0, 0.8 Hz, 1H), 7.83 (td, J = 7.6, 1.2 Hz, 1H), 7.76-7.71 (m, 1H), 7.52 (dd, 1H, J = 7.6, 1.2 Hz, 1H), 4.12 (dd, J = 7.2, 5.6 Hz, 1H), 3.11-2.99 (m, 2H), 0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 192.4, 145.1, 135.0, 134.6, 131.8, 128.1, 124.5, 115.8, 99.5, 89.8, 43.8, 21.0, -0.2; HRMS (ESI, [M+Na]+) calcd. for C15H16N2NaO3Si 323.0822, found: 323.0821; Rf = 0.36 (25% EtOAc/hexanes). Procedure for the Synthesis of Compound 1i. To a roundbottom flask charged with a magnetic bar, S1 (1.61 g, 5.36 mmol) and methanol (53 mL) was sequentially added at room temperature. The flask was sealed with a rubber septum and purged with nitrogen (N2). The solution was cooled down to 0 °C (ice/water). K2CO3 (1.50 g, 10.85 mmol) was added, and then the reaction was allowed to warm to room temperature. After 16 h, the flask was placed in an ice/water bath, and then the reaction was neutralized with 2N aqueous HCl. The reaction mixture was then transferred to a separatory funnel and extracted with EtOAc (15 mL×3), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated in vacuo to give a black crude oil. The residue was purified by flash column chromatography over silica gel (10% EtOAc/hexanes) to afford 1i (1.15 g, 94% yield) as a yellow oil. 1i: IR (neat)：3293, 3106, 2926, 2251, 1722, 1530, 1347 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 8.4, 0.8 Hz, 1H), 7.85 (td, J = 8.4, 1.2 Hz, 1H), 7.74 (td, J = 7.6, 1.2 Hz, 1H), 7.52 (dd, J = 7.6, 1.2 Hz, 1H), 4.14 (dd, J = 7.2, 6.0 Hz, 1H), 3.05 (t, J = 2.8 Hz, 1H), 3.03 (dd, J = 2.8, 1.2 Hz, 1H), 2.22 (t, J = 2.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 192.1,

145.0, 135.2, 134.3, 131.9, 128.0, 124.6, 115.7, 77.7, 72.8, 43.6, 19.5; HRMS (ESI, [M+Na]+) calcd. for C12H8N2O3Na: 251.0427, found: 251.0425; Rf = 0.17 (25% EtOAc/hexanes). Ethyl 2-cyano-5-phenylpent-4-ynoate (1j). According to the procedure for the preparation of 1a, compound 1j was synthesized from ethyl cyanoacetate (526 mg, 4.65 mmol), 3phenylpropiolaldehyde (897 mg, 6.89 mmol), L-proline (108 mg, 0.94 mmol) and Hantzsch ester (1.18 g, 4.66 mmol) in 53% yield (557 mg) as a brown oil. 1j: IR (neat) 2957, 2925, 2252, 1745, 1599, 1464, 1377, 1211 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.437.41(m, 2H), 7.32-7.28 (m, 3H), 4.31 (q, J = 7.2 Hz, 2H), 3.76 (t, J = 6.8 Hz, 1H), 3.07 (d, J = 6.8 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 165.4, 132.5, 129.0, 129.2, 123.2, 116.3, 85.2, 83.4, 64.0, 38.1, 21.8, 14.8; HRMS (EI, [M]+) calcd. for C14H13NO2: 227.0941, found: 227.0944; Rf = 0.25 (30% EtOAc/hexanes). 5-Phenyl-2-pivaloylpent-4-ynenitrile (1k). According to the procedure for the preparation of 1a, compound 1k was synthesized from pivaloylacetonitrile (500 mg, 3.99 mmol), 3phenylpropiolaldehyde (743 mg, 5.71 mmol), L-proline (92 mg, 0.80 mmol) and Hantzsch ester (1.01 g, 3.99 mmol) in 87% yield (831 mg) as a light yellow solid. 1k: IR (neat) 3035, 2972, 2873, 2243, 1723, 1598, 1477, 1442, 1370 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39-7.37 (m, 2H), 7.30-7.28 (m, 3H), 4.11 (t, J = 7.6 Hz, 1H), 3.04-2.93 (m, 2H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ/ppm: 203.9, 131.6, 128.5, 128.4, 122.5, 116.3, 84.0, 83.8, 45.5, 36.3, 25.9, 20.8; HRMS (EI, [M]+) calcd. for C16H17NO: 239.1305, found: 239.1307; Rf = 0.59 (30% EtOAc/hexanes); mp 57-58 oC. 5-Phenyl-2-tosylpent-4-ynenitrile (1l). According to the procedure for the preparation of 1a, compound 1l was synthesized from 4-(methylphenyl)sulfonylacetonitrile (200 mg, 1.02 mmol), 3phenylpropiolaldehyde (191 mg, 1.47 mmol), L-proline (24 mg, 0.21 mmol) and Hantzsch ester (260 mg, 1.02 mmol) in 94% yield (297 mg) as a brown oil. 1l: IR (neat) 3055, 2925, 2248, 1722, 1596, 1442, 1337, 1154 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.30-7.24 (m, 3H), 4.28 (dd, J = 9.0, 5.2 Hz, 1H), 3.26 (dd, J = 17.0, 5.2 Hz, 1H), 3.10 (dd, J = 16.8, 9.2 Hz, 1H), 2.38 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 147.2, 132.1, 131.8, 130.4, 129.9, 128.7, 128.3, 122.1, 113.4, 85.2, 80.9, 56.4, 21.8, 19.2.; HRMS (EI, [M]+) calcd. for C18H15NO2S: 309.0818, found: 309.0817; Rf = 0.46 (30% EtOAc/hexanes). 2-(3-Phenylprop-2-yn-1-yl)malononitrile (1m). According to the procedure for the preparation of 1a, compound 1m was synthesized from malononitrile (300 mg, 4.54 mmol), 3phenylpropiolaldehyde (844 mg, 6.49 mmol), L-proline (105 mg, 0.91 mmol) and Hantzsch ester (1.15 g, 4.54 mmol) in 89% yield (724 mg) as a brown solid. 1m: IR (neat) 3058, 2958, 2918, 2259, 2242, 1719, 1598, 1490 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.507.47 (m, 2H), 7.37-7..31 (m, 3H), 3.98 (t, J = 6.4 Hz, 1H), 3.14 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 131.9, 129.1, 128.5, 121.6, 111.8, 86.4, 80.3, 23.3, 22.8; HRMS (EI, [M]+) calcd. for C12H8N2: 180.0682, found: 180.0681; Rf = 0.44 (30% EtOAc/hexanes); mp 59-60 oC. 2-(Thiophene-2-carbonyl)-5-(p-tolyl)pent-4-ynenitrile (1n). According to the procedure for the preparation of 1a, compound 1n was synthesized from 3-oxo-3-(thiophen-2-yl)propanenitrile (300 mg, 1.98 mmol), 3-(p-tolyl)propiolaldehyde (435 mg, 3.02 mmol), L-proline (46 mg, 0.40 mmol) and Hantzsch ester (503 mg, 1.99 mmol) in 57% yield (314 mg) as a brown oil. 1n: IR (neat) 2923, 2359, 2340, 1673, 1510, 1412 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.26-7.20 (m, 3H), 7.08 (d, J = 8.0 Hz, 2H), 4.42 (t, J = 7.2 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz,



CDCl3) δ 181.4, 138.6, 136.6, 134.2, 131.6, 129.1, 129.0, 128.8, 119.3, 116.3, 84.7, 82.4, 40.0, 21.4, 20.9; HRMS (ESI, [M+Na]+) calcd. for C17H13NNaOS: 302.0616, found: 302.0610; Rf = 0.34 (20% EtOAc/hexanes). 5-(4-Chlorophenyl)-2-(4-methoxybenzoyl)pent-4-ynenitrile (1o). According to the procedure for the preparation of 1a, compound 1o was synthesized from 4-methoxybenzoylacetonitrile (110 mg, 0.63 mmol), 3-(4-chlorophenyl)propiolaldehyde (150 mg, 0.91 mmol), L-proline (15 mg, 0.13 mmol) and Hantzsch ester (160 mg, 0.63 mmol) in 95% yield (193 mg) as a brown solid. 1o: IR (neat) 2958, 2926, 2241, 1722, 1599, 1173, 827 cm-1; 1 H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.8, 1.6 Hz, 2H), 7.30 (dd, J = 8.4, 1.6 Hz, 2H), 7.25 (dd, J = 8.4, 1.6 Hz, 2H), 7.00 (dd, J = 7.2, 1.6 Hz, 2H), 4.55-4.51 (m, 1H), 3.90 (dd, J = 8.4, 1.6 Hz, 2H), 3.14-3.11 (dd, J = 8.4, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 165.4, 135.0, 133.5, 132.0, 129.2, 127.3, 121.6, 117.2, 115.0, 85.4, 83.7, 56.3, 39.1, 21.0; HRMS (EI, [M]+) calcd. for C19H14ClNO2: 323.0708, found: 323.0703; Rf = 0.35 (30% EtOAc/hexanes); mp 119-120 oC. 2-(4-Chlorobenzoyl)-5-(4-chlorophenyl)pent-4-ynenitrile (1p). According to the procedure for the preparation of 1a, compound 1p was synthesized from 4-chlorobenzoylacetonitrile (350 mg, 1.95 mmol), 3-(4-chlorophenyl)propiolaldehyde (480 mg, 2.92 mmol), L-proline (50 mg, 0.43 mmol) and Hantzsch ester (490 mg, 1.93 mmol) in 79% yield (504 mg) as a brown solid. 1p: IR (neat) 2923, 2357, 2244, 1697, 1589, 1489 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.30-7.25 (m, 4H), 4.52 (t, J = 7.2 Hz, 1H), 3.13 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.5, 141.6, 134.6, 132.9, 132.1, 130.3, 129.6, 128.6, 120.8, 115.9, 84.2, 83.4, 38.9, 20.3; HRMS (EI, [M]+) calcd. for C18H11NOCl2: 327.0212, found: 327.0210; Rf = 0.46 (20% EtOAc/hexanes); mp 149-150 oC. 2-(4-Methylbenzoyl)-5-phenylpent-4-ynenitrile (1q). According to the procedure for the preparation of 1a, compound 1q was synthesized from 4-methylbenzoylacetonitrile (368 mg, 2.31 mmol), 3-phenylpropiolaldehyde (300 mg, 2.31 mmol), L-proline (43 mg, 0.37 mmol) and Hantzsch ester (477 mg, 1.88 mmol) in 99% yield (511 mg) as a brown . 1q: IR (neat) 3060, 2923, 2243, 2190, 1606, 1489 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.40-7.36 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.31-7.28 (m, 3H), 4.57 (t, J = 7.2 Hz, 1H), 3.14 (d, J = 7.2 Hz, 2H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.3, 146.1, 133.3, 131.7, 129.9, 129.1, 128.4, 128.2, 122.5, 116.5, 84.3, 83.6, 38.9, 21.8, 20.5; HRMS (ESI, [M+H]+) calcd. for C19H16NO: 274.1226, found: 274.1227; Rf = 0.33 (25% EtOAc/hexanes). 2-(4-Chlorobenzoyl)-5-phenylpent-4-ynenitrile (1r). According to the procedure for the preparation of 1a, compound 1r was synthesized from 4-chlorobenzoylacetonitrile (500 mg, 2.78 mmol), 3-phenylpropiolaldehyde (515 mg, 3.96 mmol), L-proline (64 mg, 0.56 mmol) and Hantzsch ester (705 mg, 2.78 mmol) in 47% yield (381 mg) as a brown solid. 1r: IR (neat) 2924, 2245, 1697, 1589, 1490 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.37-7.35 (m, 2H), 7.31-7.26 (m, 3H), 4.54 (t, J = 7.2 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.7, 141.5, 132.2, 131.7, 130.3, 129.5, 128.5, 128.3, 122.3, 116.0, 84.5, 83.2, 39.0, 20.4; HRMS (ESI, [M+H]+) calcd. for C18H13NClO: 294.0680, found: 294.0680; Rf = 0.45 (25% EtOAc/hexanes); mp 85-86 oC. 2-Benzoyl-5-(trimethylsilyl)pent-4-ynenitrile (1s). According to the procedure for the preparation of 1a, compound 1s was synthesized from benzoylacetonitrile (330 mg, 2.27 mmol), 3-(4(trimethylsilyl)phenyl)propiolaldehyde (410 mg, 3.25 mmol), Lproline (52 mg, 0.45 mmol) and Hantzsch ester (575 mg, 2.27 mmol) in 95% yield (554 mg) as a yellow oil. 1s: IR (neat) 3063, 2958, 2245, 2181, 1700, 1596, 1448, 1250, 843 cm-1; 1H NMR

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(400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H), 4.50 (t, J = 7.4 Hz, 1H), 2.95 (d, J = 7.2 Hz, 2H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 188.9, 134.8, 133.9, 129.1, 128.9, 116.2, 99.9, 89.6, 38.8, 20.9, -0.2; HRMS (EI, [M]+) calcd. for C15H17NOSi: 255.1074, found: 255.1069; Rf = 0.55 (30% EtOAc/hexanes). 2-Benzoylhept-4-ynenitrile (1t). According to the procedure for the preparation of 1a, compound 1t was synthesized from benzoylacetonitrile (397 mg, 2.73 mmol), 2-pentynal (321 mg, 3.91 mmol), L-proline (63 mg, 0.55 mmol) and Hantzsch ester (693 mg, 2.74 mmol) in 62% yield (359 mg) as a yellow oil. 1t: IR (neat) 3086, 2976, 2935, 2242, 1694, 1595, 1448 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 4.47 (t, J = 7.2 Hz, 1H), 2.88 (d, J = 7.2 Hz, 2H), 2.17-2.10 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 189.3, 134.7, 133.9, 129.1, 128.9, 116.6, 86.2, 73.2, 39.4, 20.1, 13.8, 12.3; HRMS (EI, [M]+) calcd. for C14H13NO: 211.0992, found: 211.0998; Rf = 0.38 (20% EtOAc/hexanes). 2-Benzoyl-6-(benzyloxy)hex-4-ynenitrile (1u). According to the procedure for the preparation of 1a, compound 1u was synthesized from benzoylacetonitrile (233 mg, 1.61 mmol), 4(benzyloxy)but-2-ynal (400 mg, 2.30 mmol), L-proline (37 mg, 0.32 mmol) and Hantzsch ester (407 mg, 1.61 mmol) in 71% yield (344 mg) as a brown oil. 1u: IR (neat) 3086, 3062, 2952, 2923, 2243, 1696, 1595, 1450, 1263, 1071 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.02-8.00 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.38-7.32 (m, 4H), 7.31-7.27 (m, 1H), 4.57 (s, 2H), 4.50 (t, J = 7.2 Hz, 1H), 4.15 (t, J = 2.0 Hz, 2H), 2.99 (dt, J = 7.2, 1.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.7, 137.3, 134.8, 133.7, 129.2, 128.9, 128.4, 128.2, 127.9, 116.3, 80.8, 80.2, 71.6, 57.3, 38.9, 19.8; HRMS (EI, [M]+) calcd. for C20H17NO2: 303.1254, found: 303.1253; Rf = 0.37 (30% EtOAc/hexanes). 5-Phenyl-2-propionylpent-4-ynenitrile (1v). According to the procedure for the preparation of 1a, compound 1v was synthesized from 3-oxopentanenitrile (2.60 g, 26.77 mmol), 3phenylpropiolaldehyde (4.98 g, 38.26 mmol), L-proline (616 mg, 5.35 mmol) and Hantzsch ester (6.73 g, 26.57 mmol) in 64% yield (3.63 g) as a brown oil. 1v: IR (neat) 3057, 2981, 2941, 2245, 1729, 1490, 1287 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.42-7.40 (m, 2H), 7.31-7.27 (m, 3H), 3.67 (t, J = 6.6 Hz, 1H), 3.07-2.96 (m, 2H), 2.90 (dq, J = 18.8, 7.2 Hz, 1H), 2.78 (dq, J = 18.8, 7.2 Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 158.1, 149.7, 138.8, 138.3, 128.8, 128.7, 126.9, 111.4, 38.5, 21.0, 15.2.; HRMS (FD, [M]+) calcd. for C14H13NO: 211.0992, found: 211.0997; Rf = 0.55 (30% EtOAc/hexanes). Procedure for the Synthesis of Compound 2a. To a roundbottom flask, 1a (99 mg, 0.38 mmol), Lawesson’s reagent (251mg, 0.62 mmol) and THF (7.7 mL) were sequentially added. The resulting solution was stirred under air at room temperature for 72 h. The reaction was concentrated in vacuo, and the crude residue was purified by flash column chromatography over silica gel (10% EtOAc/hexanes) to give the desired substrate 2a (52 g, 46% yield) as an orange solid. 2a: IR (neat) 3373, 3173, 2958, 2925, 1721, 1664, 1615, 1443, 1276 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.24-7.21 (m, 3H), 5.29 (t, J = 6.8 Hz, 1H), 3.17 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 202.2, 198.4, 136.1, 134.4, 131.5, 129.0, 128.9, 128.2, 128.1, 122.7, 84.7, 84.4, 59.9, 25.4; HRMS (EI, [M]+) calcd. for C18H15NOS: 293.0869, found: 293.0870; Rf = 0.28 (30% EtOAc/hexanes); mp 127-128 oC. Procedure for the Synthesis of (2-Amino-5-benzylthiophen-3yl)(phenyl)methanone (3a). To a flask charged with a magnetic bar, 1a (70 mg, 0.27 mmol), phosphorus decasulfide (360 mg,


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0.81 mmol) and ethanol (3 mL) were sequentially added at room temperature, and then the flask was sealed with a rubber septum. After 10 min, the reaction was stirred at 80 °C (oil bath) until completion as indicated by TLC (typically for 5 h). After cooling to room temperature, the crude reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (15% EtOAc/hexanes) to give the desired substrate 3a (66 g, 83% yield) as an orange solid. 3a: IR (neat) 3382, 3273, 2961, 2926, 1720, 1566, 1451, 1366, 1276 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69-7.66 (m, 2H), 7.51-7.42 (m, 3H), 7.32-7.28 (m, 2H), 7.24-7.20(m, 3H), 6.90 (br, 2H), 6.64 (t, J = 1.0 Hz, 1H), 3.90 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.8, 166.2, 166.1, 141.0, 139.7, 130.6, 128.6, 128.4, 128.1, 128.1, 126.7, 124.5, 124.3, 114.4, 36.1; HRMS (ESI, [M+H]+) calcd. for C18H16NOS 294.0947, found: 294.0950; Rf = 0.28 (20% EtOAc/hexanes); mp 113-114 oC. (2-Amino-5-(4-methylbenzyl)thiophen-3-yl)(phenyl)methanone (3b). According to the procedure for the preparation of 3a, compound 3b was synthesized from 1b (31 mg, 0.11 mmol) and phosphorus decasulfide (100 mg, 0.22 mmol) in 95% yield (33 mg) as an orange solid. 3b: IR (neat) 3376, 3272, 2956, 2924, 1725, 1567, 1451, 1274 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.51-7.42 (m, 3H), 7.11 (s, 4H), 6.90 (br, 2H), 6.63 (s, 1H), 3.86 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.8, 166.0, 141.0, 136.7, 136.2, 130.6, 129.3, 128.2, 128.1, 128.1, 124.7, 124.3, 114.4, 35.7, 21.0; HRMS (EI, [M]+) calcd. for C19H17NOS: 307.1025, found: 307.1021; Rf = 0.47 (25% EtOAc/hexanes); mp 129-130 oC. (2-Amino-5-(4-chlorobenzyl)thiophen-3-yl)(phenyl)methanone (3c). According to the procedure for the preparation of 3a, compound 3c was synthesized from 1c (100 mg, 0.34 mmol) and phosphorus decasulfide (303 mg, 0.68 mmol) in 46% yield (51 mg) as an orange oil. 3c: IR (neat) 3378, 3276, 3146, 2957, 2924, 1719, 1567, 1451, 1367, 1275, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 2H), 7.50-7.42 (m, 3H), 7.28-7.25 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.05 (br, 2H), 6.63 (s, 1H), 3.85 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.8, 166.3, 140.9, 138.2, 132.4, 130.7, 129.7, 128.7, 128.2, 128.1, 124.8, 123.5, 114.3, 35.4; HRMS (EI, [M]+) calcd. for C18H14ClNOS: 327.0479, found: 327.0472; Rf = 0.35 (20% EtOAc/hexanes). (2-Amino-5-benzylthiophen-3-yl)(2-methoxyphenyl)methanone (3d). According to the procedure for the preparation of 3a, compound 3d was synthesized from 1d (30 mg, 0.10 mmol) and phosphorus decasulfide (89 mg, 0.20 mmol) in 60% yield (20 mg) as an orange oil. 3d: IR (neat) 3439, 3380, 2960, 2929, 1599, 1457, 1246, 1025 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-7.36 (m, 1H), 7.33-7.28 (m, 3H), 7.23-7.17 (m, 3H), 7.02-6.98 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.90 (br, 1H), 6.29 (s, 1H), 3.84 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.2, 165.2, 156.2, 139.8, 130.9, 130.7, 128.6, 128.5, 128.3, 126.6, 124.7, 123.9, 120.3, 116.0, 111.3, 55.6, 36.0; HRMS (EI, [M]+) calcd. for C19H17NO2S: 323.0975, found: 323.0980; Rf = 0.33 (25% EtOAc/hexanes). (2-Amino-5-benzylthiophen-3-yl)(4-methoxyphenyl)methanone (3e). According to the procedure for the preparation of 3a, compound 3e was synthesized from 1e (58 mg, 0.20 mmol) and phosphorus decasulfide (178 mg, 0.40 mmol) in 76% yield (49 mg) as an orange oil. 3e: IR (neat) 3442, 3394, 3284, 2959, 2931, 1565, 1452, 1253, 1168 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.71-7.67 (m, 2H), 7.33-7.28 (m, 2H), 7.25-7.21 (m, 3H), 6.96-6.93 (m, 2H), 6.84 (br, 1H), 6.68 (t, J = 1.2 Hz, 1H), 3.91 (s, 2H), 3.86 (s, 3H)； 13C NMR (100 MHz, CDCl3) δ 189.9, 165.6, 161.7, 139.8, 133.5, 130.3, 128.6, 128.4, 126.6, 124.6, 124.2, 114.5, 113.4, 55.4, 36.1; HRMS (EI, [M]+) calcd. for C19H17NO2S: 323.0975, found: 323.0974; Rf = 0.34 (25% EtOAc/hexanes).

(2-Amino-5-benzylthiophen-3-yl)(furan-2-yl)methanone (3f). According to the procedure for the preparation of 3a, compound 3f was synthesized from 1f (200 mg, 0.80 mmol) and phosphorus decasulfide (670 mg, 1.51 mmol) in 89% yield (202 mg) as an orange solid. 3f: IR (neat) 3439, 3370, 2956, 2923, 1578, 1557, 1468, 1307 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 1.6, 0.8 Hz, 1H), 7.35-7.31 (m, 3H), 7.21 (dd, J = 3.2, 0.8 Hz, 1H), 7.08 (br, 2H), 6.54 (dd, J = 3.6, 1.6 Hz, 1H), 3.98 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 175.7, 167.8, 153.9, 144.9, 139.8, 128.6, 128.5, 126.7, 124.8, 123.1, 116.5, 112.8, 111.9, 36.23; HRMS (EI, [M]+) calcd. for C16H13NO2S: 283.0662, found: 283.0654; Rf = 0.34 (25% EtOAc/hexanes); mp 98-99 oC. (2-Amino-5-benzylthiophen-3-yl)(thiophen-2-yl)methanone (3g). According to the procedure for the preparation of 3a, compound 3g was synthesized from 1g (70 mg, 0.26 mmol) and phosphorus decasulfide (235 mg, 0.53 mmol) in 65% yield (51 mg) as a brown oil. 3g: IR (neat) 3437, 3385, 2956, 2924, 1565, 1453 cm1 1 ; H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 3H),7.12 (dd, J = 4.8, 3.6 Hz, 1H), 6.99 (s, 1H), 6.87 (br, 2H), 3.96 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 181.0, 166.2, 145.3, 139.6, 131.0, 130.6, 128.6, 128.4, 127.4, 126.7, 125.0, 123.3, 113.8, 36.1; HRMS (EI, [M]+) calcd. for C16H13NOS2: 299.0433, found: 299.0429; Rf = 0.42 (25% EtOAc/hexanes). (2-Amino-5-(thiophen-2-ylmethyl)thiophen-3yl)(phenyl)methanone (3h). According to the procedure for the preparation of 3a, compound 3h was synthesized from 1h (140 mg, 0.53 mmol) and phosphorus decasulfide (500 mg, 1.12 mmol) in 76% yield (120 mg) as a brown oil. 3h: IR (neat) 3387, 3283, 2956, 2922, 1728, 1585, 1435, 1307 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.51-7.42 (m, 3H), 7.17 (dd, J = 5.2, 1.2 Hz, 2H), 6.98 (br, 2H), 6.93 (dd, J = 3.4, 1.5 Hz, 1H), 6.876.85 (m, 1H), 6.69 (t, J = 1.0 Hz, 1H), 4.09 (t, J = 1.0 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 190.9, 166.1, 142.7, 140.9, 130.7, 128.1, 128.1, 126.9, 125.2, 124.7, 124.4, 123.4, 114.4, 30.3; HRMS (EI, [M]+) calcd. for C16H13NOS2: 299.0433, found: 299.0428; Rf = 0.4 (25% EtOAc/hexanes). (2-Amino-5-methylthiophen-3-yl)(2-nitrophenyl)methanone(3i). According to the procedure for the preparation of 3a, compound 3i was synthesized from 1i (0.91 g, 3.99 mmol) and phosphorus decasulfide (3.50 g, 7.87 mmol) in 89% yield (933 mg) as an orange solid. 3i: IR (neat) 3444, 1585, 1526, 1456 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.86 (br, 2H), 5.96 (s, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.7, 165.7, 146.2, 137.1 133.7, 129.7, 128.6, 124.3, 122.2, 121.0, 114.5, 14.8; HRMS (ESI, [M+Na]+) calcd. for C12H10N2O3SNa 285.0304, found: 285.0309; Rf = 0.24 (25% EtOAc/hexanes); mp 114-115 oC. (2-amino-5-(2-(benzyloxy)ethyl)thiophen-3yl)(phenyl)methanone (3j). According to the procedure for the preparation of 3a, compound 3j was synthesized from 1u (200 mg, 0.66 mmol) and phosphorus decasulfide (600 mg, 1.35 mmol) in 68% yield (158 mg) as an yellow oil. 3j: IR (neat) 3399, 3283, 2924, 2855, 1724, 1584, 1452, 1278 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.49-7.40 (m, 3H), 7.36-7.27 (m, 5H), 6.91 (br, 2H), 6.60 (s, 1H), 4.53 (s, 2H), 3.62 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 190.9, 165.8, 141.1, 138.1, 130.6, 128.4, 128.1, 128.1, 127.7, 124.6, 121.8, 114.6, 73.2, 70.4, 30.6.; HRMS (EI, [M]+) calcd. for C20H19NO2S: 337.1131, found: 337.1118; Rf = 0.27 (20% EtOAc/hexanes). Ethyl 2-amino-5-benzylthiophene-3-carboxylate (3k). According to the procedure for the preparation of 3a, compound 3k was synthesized from 1j (367 mg, 1.61 mmol) and phosphorus deca-



sulfide (1.44 g, 3.23 mmol) in 60% yield (251 mg) as an orange oil. 3k: IR (neat) 3441, 3335, 2957, 2922, 1721, 1565, 1499, 1263 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 2H), 7.26-7.23 (m, 3H), 6.72 (s, 1H), 5.84 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.92 (s, 2H), 1.34 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 162.2, 139.9, 128.6, 128.5, 126.6, 125.2, 122.8, 106.2, 59.7, 36.0, 14.6; HRMS (EI, [M]+) calcd. for C14H15NO2S 261.0818, found: 261.0816; Rf = 0.57 (30% EtOAc/hexanes). 1-(2-Amino-5-benzylthiophen-3-yl)-2,2-dimethylpropan-1-one (3l). According to the procedure for the preparation of 3a, compound 3l was synthesized from 1k (625 mg, 2.61 mmol) and phosphorus decasulfide (2.32 g, 5.22 mmol) in 19% yield (133 mg) as an orange solid. 3l: IR (neat) 3399, 3284, 2966, 2924, 1725, 1563, 1439 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.26-7.24 (m, 3H), 6.92 (br, 2H), 6.91 (s, 1H), 3.94 (s, 2H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.9, 166.3, 139.8, 128.6, 128.4, 126.7, 123.3, 123.2, 112.1, 43.5, 36.2, 27.9; HRMS (EI, [M]+) calcd. for C16H19NOS: 273.1182, found: 273.1184; Rf = 0.58 (30% EtOAc/hexanes); mp 99-100 oC. 5-Benzyl-3-tosylthiophen-2-amine (3m). According to the procedure for the preparation of 3a, compound 3m was synthesized from 1l (169 mg, 0.55 mmol) and phosphorus decasulfide (485 mg, 1.09 mmol) in 9% yield (16 mg) as an orange solid. 3m: IR (neat) 3450, 3346, 2958, 2925, 1721, 1598, 1515, 1286, 1138, 1087 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 7.16 (d, J = 7.2 Hz, 2H), 6.51 (s, 1H), 5.43 (s, 2H), 3.84(s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 143.6, 140.3, 139.1, 129.7, 128.6, 128.5, 127.6, 126.8, 126.3, 121.5, 112.5, 35.8, 21.6; HRMS (EI, [M]+) calcd. for C18H17NO2S2: 343.0695, found: 343.0695; Rf = 0.38 (30% EtOAc/hexanes); mp 110-111 oC. 2-Amino-5-benzylthiophene-3-carbothioamide (3n). According to the procedure for the preparation of 3a, compound 3n was synthesized from 1m (300 mg, 1.66 mmol) and phosphorus decasulfide (1.48 mg, 3.33 mmol) in 46% yield (190 mg) as an orange solid. 3n: IR (neat) 3439, 2997, 2912, 1654, 1437 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (br, 2H), 8.36 (d, J = 26.4 Hz, 2H), 7.32-7.29 (m, 2H), 7.23-7.20 (m, 3H), 6.95 (s, 1H), 3.84 (s, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 189.1, 164.8, 140.5, 128.9, 128.7, 126.8, 121.8, 121.2, 110.9, 35.6; HRMS (EI, [M]+) calcd. for C12H12N2S2: 248.0436, found: 248.0441; Rf = 0.28 (30% EtOAc/hexanes); mp 59-60 oC. Procedure for the Synthesis of 5-Benzyl-3-phenylthieno[2,3c]isothiazole (4a). To an oven-dried flask charged with a magnetic bar, 1a (143 mg, 0.55 mmol), phosphorus decasulfide (490 mg, 1.10 mmol) and ethanol (10 mL) were sequentially added at room temperature, and then the flask was sealed with a rubber septum. After 10 min, the reaction was stirred at 80 °C until completion as indicated by TLC (typically for 3 h). After cooling to room temperature, the volatiles were removed in vacuo [NOTE: the removal of ethanol at this stage is essential for the use of Lawesson’s reagent in the next step]. To the flask containing the residue, pxylene (10 mL) and Lawesson’s reagent (334 mg, 0.83 mmol) were sequentially introduced. The reaction flask was then placed in a 130 °C oil bath. After the completion of reaction that was indicated by TLC, typically 1 h, the reaction was quenched by water (10 mL). The resulting biphasic mixture was stirred vigorously at 60 °C for 15 min, and then concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (15% EtOAc/hexanes) to afford compound 4a (105 mg, 62% yield) as a yellow solid. 4a: IR (neat) 3060, 3027, 2338, 1601, 1492, 1336, 1270 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.40-7.28 (m, 5H), 4.16 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 169.6, 154.1, 152.0, 138.2, 137.3, 131.1, 129.4, 129.2, 128.8, 128.7, 127.2, 127.0, 112.4, 38.7; HRMS (ESI, [M+H]+)

Page 8 of 11

calcd. for C18H14NS2: 308.0562, found: 308.0566; Rf = 0.48 (9% EtOAc/hexanes); mp 91-92 oC. 5-(4-Methylbenzyl)-3-phenylthieno[2,3-c]isothiazole (4b). According to the procedure for the preparation of 4a, compound 4b was synthesized from 1b (100 mg, 0.37 mmol), phosphorus decasulfide (374 mg, 0.84 mmol) and Lawesson’s reagent (178 mg, 0.44 mmol) in 52% yield (61 mg) as a yellow solid. 4b: IR (neat) 2923, 2854, 1513, 1445, 1337, 1268 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H),7.19 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 4.12 (s, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6, 154.0, 152.4, 137.3, 136.6, 135.2, 131.1, 129.4, 129.4, 129.2, 128.6, 127.2, 112.2, 38.3, 21.1; HRMS (ESI, [M+H]+) calcd. for C19H16NS2: 322.0719, found: 322.0712; Rf = 0.68 (25% EtOAc/hexanes); mp 88-89 oC. 5-(4-Chlorobenzyl)-3-phenylthieno[2,3-c]isothiazole (4c). According to the procedure for the preparation of 4a, compound 4c was synthesized from 1c (68 mg, 0.23 mmol), phosphorus decasulfide (205 mg, 0.46 mmol) and Lawesson’s reagent (94 mg, 0.23 mmol) in 40% yield (32 mg) as a yellow solid. 4c: IR (neat) 3062, 2924, 1595, 1487, 1093 cm-1; 1H NMR (400 MHz, DMSOd6) δ 7.80 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.35-7.32 (m, 5H), 7.26 (br, 1H), 4.23 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 169.7, 152.6, 152.6, 138.1, 137.5, 135.2, 129.6, 128.8, 128.8, 128.3, 127.1, 112.1, 38.7; HRMS (EI, [M]+) calcd. for C18H12NS2Cl: 341.0094, found: 341.0099; Rf = 0.64 (25% EtOAc/hexanes); mp 87-88 oC. 5-Benzyl-3-(2-methoxyphenyl)thieno[2,3-c]isothiazole (4d). According to the procedure for the preparation of 4a, compound 4d was synthesized from 1d (112 mg, 0.39 mmol), phosphorus decasulfide (470 mg, 1.06 mmol) and Lawesson’s reagent (188 mg, 0.47 mmol) in 60% yield (78 mg) as a yellow solid. 4d: IR (neat) 3025, 2926, 2362, 1597, 1504, 1462, 1252 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.6, 1.2 Hz, 1H), 7.40-7.27 (m, 5H), 7.10 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 4.18 (s, 2H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 155.7, 150.4, 149.1, 138.5, 137.1, 129.9, 128.7, 128.7, 127.7, 126.9, 121.1, 120.9, 113.6, 111.4, 55.6, 38.7; HRMS (ESI, [M+H]+) calcd. for C19H16NOS2 338.0668, found: 338.0673; Rf = 0.66 (25% EtOAc/hexanes); mp 124-125 oC. 5-Benzyl-3-(4-methoxyphenyl)thieno[2,3-c]isothiazole (4e). According to the procedure for the preparation of 4a, compound 4e was synthesized from 1e (198 mg, 0.68 mmol), phosphorus decasulfide (553 mg, 1.24 mmol) and Lawesson’s reagent (332 mg, 0.82 mmol) in 55% yield (127 mg) as a yellow solid. 4e: IR (neat) 3027, 2925, 2836, 1605, 1504, 1453, 1252 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.36-7.26 (m, 5H), 6.99 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 0.8 Hz, 1H), 4.14 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 160.4, 154.2, 151.2, 138.3, 136.6, 128.8, 128.7, 128.6, 128.5, 127.0, 123.7, 114.8, 112.4, 55.4, 38.7; HRMS (ESI, [M+H]+) calcd. for C19H16NOS2 338.0668, found: 338.0673; Rf = 0.5 (25% EtOAc/hexanes); mp 110-111 oC. 5-(4-Methylbenzyl)-3-(thiophen-2-yl)thieno[2,3-c]isothiazole (4f). According to the procedure for the preparation of 4a, compound 4f was synthesized from 1n (74 mg, 0.26 mmol), phosphorus decasulfide (250 mg, 0.56 mmol) and Lawesson’s reagent (113 mg, 0.28 mmol)) in 74% yield (64 mg) as a yellow solid. 4f: IR (neat) 2921, 2853, 2219, 1539, 1213, 1427, 1330, 1218 cm-1; 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 5.2 Hz, 1H), 7.60 (dd, J = 1.4, 1.2 Hz, 1H), 7.25-7.23 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.6, 152.9, 146.5, 136.4, 136.0, 135.6, 131.0, 129.3, 129.0, 128.9, 128.6, 127.5, 112.6, 37.4, 20.7; HRMS (EI, [M]+) calcd. for C17H13NS3:


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327.0205, found: 327.0204; Rf = 0.67 (25% EtOAc/hexanes); mp 79-80 oC. 5-(4-Chlorobenzyl)-3-(4-chlorophenyl)thieno[2,3-c]isothiazole (4g). According to the procedure for the preparation of 4a, compound 4g was synthesized from 1p (70 mg, 0.21 mmol), phosphorus decasulfide (189 mg, 0.43 mmol) and Lawesson’s reagent (86 mg, 0.21 mmol) in 55% yield (44 mg) as a yellow solid. 4g: IR (neat) 3029, 2924, 2853, 1896, 1594, 1488, 1403 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55-7.51 (m, 2H), 7.45-7.41 (m, 2H), 7.327.29 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 4.11 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 169.5, 152.9, 151.8, 137.3, 136.5, 135.3, 133.0, 130.1, 129.6, 129.4, 128.9, 128.3, 112.3, 38.0; HRMS (ESI, [M+H]+) calcd. for C18H12Cl2NS2: 375.9783, found: 375.9788; Rf = 0.77 (25% EtOAc/hexanes); mp 113-114 oC. 5-(4-Chlorobenzyl)-3-(4-methoxyphenyl)thieno[2,3c]isothiazole (4h). According to the procedure for the preparation of 4a, compound 4h was synthesized from 1o (150 mg, 0.46 mmol), phosphorus decasulfide (412 mg, 0.93 mmol) and Lawesson’s reagent (225 mg, 0.56 mmol) in 43% yield (74 mg) as a yellow solid. 4h: IR (neat) 2957, 2925, 1725, 1505, 1285, 1253 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 4.10 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 160.5, 154.5, 150.4, 136.7, 136.5, 132.9, 130.1, 128.9, 128.5, 123.6, 114.8, 112.6, 55.4, 38.0; HRMS (EI, [M]+) calcd. for C19H14NOS2Cl 371.0200, found: 371.0191; Rf = 0.61 (25% EtOAc/hexanes); mp 131-132 oC. 5-Benzyl-3-p-tolylthieno[2,3-c]isothiazole (4i). According to the procedure for the preparation of 4a, compound 4i was synthesized from 1q (100 mg, 0.42 mmol), phosphorus decasulfide (374 mg, 0.84 mmol) and Lawesson’s reagent (178 mg, 0.44 mmol) in 50% yield (59 mg) as a yellow solid. 4i: IR (neat) 2995, 2911, 1659, 1437, 1407, 1310 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.0 Hz, 2H), 7.37-7.32 (m, 7H), 7.26 (s, 1H), 4.21 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 169.4, 154.3, 152.3, 140.1, 139.2, 136.8, 130.7, 129.1, 127.7, 127.3, 127.2, 113.6, 38.2, 21.4 ; HRMS (EI, [M]+) calcd. for C19H15NS2: 321.0640, found: 321.0647; Rf = 0.69 (25% EtOAc/hexanes); mp 112-113 oC. 5-Benzyl-3-(4-chlorophenyl)thieno[2,3-c]isothiazole (4j). According to the procedure for the preparation of 4a, compound 4j was synthesized from 1r (32 mg, 0.11 mmol), phosphorus decasulfide (97 mg, 0.22 mmol) and Lawesson’s reagent (44 mg, 0.11 mmol) in 56% yield (21 mg) as a yellow solid. 4j: IR (neat) 3061, 3028, 2923, 2853, 1600, 1488, 1453, cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.78 (m, 2H), 7.64-7.60 (m, 2H), 7.37-7.32 (m, 5H), 7.28-7.24 (m, 1H), 4.23 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 169.6, 152.6, 152.5, 138.1, 137.4, 135.2, 129.6, 129.5, 128.8, 128.7, 128.3, 127.1, 112.0, 38.7; HRMS (ESI, [M+H]+) calcd. for C18H13ClNS2: 342.0172, found: 342.0172; Rf = 0.70 (25% EtOAc/hexanes); mp 117-118 oC. 5-Methyl-3-(2-nitrophenyl)thieno[2,3-c]isothiazole (4k). According to the procedure for the preparation of 4a, compound 4k was synthesized from 1i (400 mg, 1.75 mmol), phosphorus decasulfide (1.56 g, 3.51 mmol) and Lawesson’s reagent (1.06 g, 2.62 mmol) in 41% yield (197 mg) as a yellow solid. 4k: IR (neat) 3065, 2919, 2855, 2357, 1605, 1569, 1526, 1437, 1350 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.69 (td, J = 7.4, 1.2 Hz, 1H), 7.63-7.57 (m, 2H), 6.37 (d, J = 1.2 Hz, 1H), 2.49 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 149.2, 148.5, 146.6, 140.6, 132.8, 132.7, 130.0, 125.4, 124.9, 111.5, 18.1; HRMS (ESI, [M+H]+) calcd. for C12H9N2O2S2: 277.0100, found: 277.0101; Rf = 0.48 (25% EtOAc/hexanes); mp 81-82 oC.

5-(2-(Benzyloxy)ethyl)-3-phenylthieno[2,3-c]isothiazole (4l). According to the procedure for the preparation of 4a, compound 4l was synthesized from 1u (100 mg, 0.33 mmol), phosphorus decasulfide (293 mg, 0.66 mmol) and Lawesson’s reagent (133 mg, 0.33 mmol) in 61% yield (37 mg) as a yellow oil. 4l: IR (neat) 2954, 2918, 1727, 1455, 1285, 1097 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.43-7.25 (m, 6H), 6.92 (s, 1H), 4.57 (s, 2H), 3.79 (t, J = 6.2 Hz, 2H), 3.13 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.7, 153.8, 149.7, 137.9, 137.3, 131.2, 129.3, 129.2, 128.4, 127.8, 127.7, 127.2, 112.7, 69.5, 33.2; HRMS (EI, [M]+) calcd. for C20H17NOS2: 351.0712, found: 351.0726; Rf = 0.53 (20% EtOAc/hexanes). Procedure for the Synthesis of 3-Phenyl-5((trimethylsilyl)methyl)thieno[2,3-c]isothiazole (4m). To an ovendried flask charged with a magnetic bar, 1s (107 mg, 0.42 mmol) and Lawesson’s reagent (508 mg, 1.26 mmol) and toluene (5 mL) were added sequentially and the flask was sealed with a rubber septum. The reaction flask was stirred in a 110 °C oil bath until the reaction was complete as indicated by TLC (typically for 12 h). After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (15% toluene/hexanes) to give the desired compound 4m (37 mg, 40% yield) as a yellow solid. 4m: IR (neat) 2953, 2922, 1727, 1529, 1490, 851 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.50-7.46 (m, 2H), 7.42-7.38 (m, 1H), 6.63 (t, J = 1.2 Hz, 1H), 2.31 (d, J = 0.8 Hz, 2H), 0.12 (t, J = 3.4 Hz, 9H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 151.4, 151.4, 138.1, 131.5, 129.3, 128.9, 127.1, 109.7, 24.0, -1.6; HRMS (EI, [M]+) calcd. for C15H17NS2Si 303.0566, found: 303.0564; Rf = 0.59 (10% EtOAc/hexanes). 3-Phenyl-5-propylthieno[2,3-c]isothiazole (4n). According to the procedure for the preparation of 4a, compound 4n was synthesized from 1t (100 mg, 0.47 mmol), phosphorus decasulfide (420 mg, 0.95 mmol) and Lawesson’s reagent (230 mg, 0.57 mmol) in 43% yield (53 mg) as a yellow oil. 4n: IR (neat) 2955, 2921, 1727, 1460, 1284 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (m, 2H), 7.51-7.46 (m, 2H), 7.43-7.39 (m, 1H), 6.84 (s, 1H), 2.82 (t, J = 7.8 Hz, 2H), 1.77 (qt, J = 7.4, 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 153.6, 153.3, 137.5, 131.3, 129.3, 129.1, 127.2, 111.4 34.6, 23.6, 13.6; HRMS (EI, [M]+) calcd. for C14H13NS2: 259.0484, found: 259.0484; Rf = 0.61 (25% EtOAc/hexanes). 5-Benzyl-3-ethylthieno[2,3-c]isothiazole (4o). According to the procedure for the preparation of 4a, compound 4o was synthesized from 1v (250 mg, 1.18 mmol), phosphorus decasulfide (1.05 g, 2.37 mmol) and Lawesson’s reagent (480 mg, 1.19 mmol) in 15% yield (45 mg) as a yellow oil. 4o: IR (neat) 2956, 2924, 1728, 1454, 1378, 1284 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.367.32 (m, 2H), 7.30-7.25 (m, 3H), 6.55 (t, J = 1.2 Hz, 1H), 4.10 (s, 2H), 3.05 (q, J = 7.6 Hz, 2H), 1.40 (q, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 158.1, 149.7, 138.8, 138.3, 128.8, 128.7, 126.9, 111.4, 38.5, 21.0, 15.2; HRMS (FD, [M]+) calcd. for C14H13NS2: 259.0484, found: 259.0483; Rf = 0.68 (30% EtOAc/hexanes). Procedure for the Synthesis of Compound 5. To an oven-dried flask charged with a magnetic bar, 4k (97 mg, 0.35 mmol), DMF (1.1 mL) and N-iodosuccinimide (158 mg, 0.70 mmol) was sequentially added. The flask was sealed with a rubber septum, purged with nitrogen (N2) and wrapped with aluminium foil. The reaction mixture was stirred at room temperature for 30 min, and then heated to 80 °C (oil bath) for 3 h. The reaction was quenched with sodium thiosulfate at 0 °C (water/ice bath), and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash



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chromatography (15% EtOAc/hexanes) to afford 5 (103 mg, 73% yield) as a yellow solid. 5: IR (neat): 3065, 2920, 2855, 2359, 1609, 1571, 1525, 1343, 1323, 1264, 1247, 1158, 1068, 953 cm-1; 1 H NMR (400 MHz, CDCl3) δ 8.25-8.23 (m, 1H), 7.75-7.68 (m, 2H), 7.53-7.51 (m, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 150.4, 149.1, 146.0, 139.9, 134.0, 132.6, 130.8, 125.0, 124.1, 66.7, 20.4; HRMS (ESI, [M+H]+) calcd. for C12H8N2O2S2I: 402.9066, found: 402.9074; Rf = 0.59 (25% EtOAc/hexanes); mp 109-110 oC.

Corresponding Author

Procedure for the Synthesis of Compound 6. To an oven-dried flask charged with a magnetic bar, 5 (242 mg, 0.60 mmol), 4bromophenylboronic acid (181 mg, 0.90 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and K2CO3 (208 mg, 1.50 mmol) were sequentially added. The flask was sealed with a rubber septum and purged with argon (Ar). A co-solvent (PhMe/EtOH/H2O = 20/5/1; 2 mL) was introduced to the flask at room temperature. After 10 min, the reaction was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (10% EtOAc/hexanes) to afford 6 (229 mg, 88% yield) as a yellow solid. 6: IR (neat): 3063, 2923, 1608, 1571, 1527, 1485, 1345, 1270, 1250, 1070, 1008, 954, 808 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84-7.81 (m, 1H), 7.48-7.45 (m, 2H), 7.23-7.21 (m, 1H), 7.15 (d, J = 4.0 Hz, 2H), 6.77 (d, J = 4.0 Hz, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 148.6, 148.0, 143.2, 139.7, 132.8, 132.4, 131.6, 131.0, 130.8, 129.9, 124.9, 124.5, 121.3, 15.8; HRMS (ESI, [M+H]+) calcd. for C18H12N2O2S2Br 430.9518, found: 430.9516; Rf = 0.65 (25% EtOAc/hexanes); mp 181-182 oC.

We thank the National Health Research Institutes and the Ministry of Science and Technology, Taiwan for financial support.

Procedure for the Synthesis of Compound 7. To a round-bottom flask charged with a magnetic bar, 6 (61 mg, 0.14 mmol), a cosolvent (CHCl3/EtOH/H2O = 1/4/1; 3 mL) and iron powder (50 mg, 0.89 mmol) were sequentially added. The flask was sealed with a rubber septum and purged with nitrogen (N2). The reaction mixture was stirred at 0 °C (ice/water) bath for 10 min, and then 2N aqueous HCl (0.132 mL) was added to the flask. The resulting mixture was stirred at 80 °C for 1.5 h. After cooling to room temperature, the suspension was filtered through a pad of celite. The filtrate was neutralized with saturated aqueous NaHCO3, and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (10% EtOAc/hexanes) to afford 7 (49 mg, 86% yield) as a white solid. 7: IR (neat): 3443, 3355, 2923, 1615, 1487 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19-7.16 (m, 2H, ArH), 7.07 (td, J = 7.6, 1.2 Hz, 1H, ArH), 6.89-6.86 (m, 3H, ArH), 6.59 (td, J = 7.6, 1.2 Hz, 1H, ArH), 6.43 (d, J = 8.0 Hz, 1H, ArH), 3.44 (s, 2H, NH2), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 151.6, 144.4, 142.1, 138.3, 131.7, 130.8, 130.5, 130.4, 125.4, 121.1, 117.9, 115.1, 113.9, 16.0; HRMS (ESI, [M+H]+) calcd. for C18H14N2S2Br 400.9776, found: 400.9781; Rf = 0.47 (25% EtOAc/hexanes); mp 141-142 oC.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1

H and 13C NMR spectra and an ORTEP diagram of 4a (PDF) Crystallographic data for 4a (CIF)

AUTHOR INFORMATION

*E-mail: [email protected] (K.-S.S.). *E-mail: [email protected] (Y.-K.W.).

ORCID Kak-Shan Shia: 0000-0001-9560-2466 Yen-Ku Wu: 0000-0002-9269-7444

ACKNOWLEDGMENT

REFERENCE

1 (a) Gomtsyan, A. Heterocycles in drugs and drug discovery. Chem. Heterocycl. Compd. 2012, 48, 7-10. (b) Heterocyclic Chemistry in Drug Discovery; Li, J., Ed.; Wiley: Hoboken, 2013. 2 Rabal, O.; Oyarzabal, J. Biologically Relevant Chemical Space Navigator: From Patent and Structure–Activity Relationship Analysis to Library Acquisition and Design. J. Chem. Inf. Model. 2012, 52, 3123-3137. 3 Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol. 2010, 14, 347-361. 4 For reviews, see: (a) Sabnis, R. W. The Gewald reaction in dye chemistry. Colora. Technol. 2016 132, 49-82. (b) Bozorov, K.; Nie, L. F.; Zhao, J.; Aisa, H. A. 2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry. Eur. J. Med. Chem. 2017, 140, 465-493. 5 Gewald, K. Methods for the synthesis of 2-aminothiophenes and their reactions (review). Chem. Heterocycl. Compd. 1976, 12, 10771090. 6 Gewald, K.; Schinke, E.; Böttcher, H. Heterocyclen aus CH‐aciden Nitrilen, VIII. 2‐Amino‐thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Schwefel. Chem. Ber. 1966, 99, 94-100. 7 For reviews, see: (a) Forero, J. S. B.; Jones, J.; da Silva, F. M. The Synthetic Potential and Chemical Aspects of the Gewald Reaction: Application in the Preparation of 2-Aminothiophenes and Related Heterocycles. Curr. Org. Synth. 2013, 10, 347-365. (b) Huang, Y.; Dömling, A. The

Gewald multicomponent reaction. Mol. Diversity 2011, 15, 3-33. (c) Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. 2‐ aminothiophenes by the gewald reaction. J. Heterocycl. Chem. 1999, 36, 333-345. 8 For selected recent examples, see: (a) Han, Y.; Tang, W.-Q.; Yan, C.-G. Gewald-type reaction of double activated 2,3diarylcyclopropanes with elemental sulfur for synthesis of polysubstituted 2-aminothiophenes. Tetrahedron Lett. 2014, 55, 1441-1443. (b) Abaee, M. S.; Hadizadeh, A.; Mojtahedi, M. M.; Halvagar, M. R. Exploring the scope of the Gewald reaction: Expansion to a fourcomponent process. Tetrahedron Lett. 2017, 58, 1408-1412. (c) Thomas, J.; Jana, S.; Sonawane, M.; Fiey, B.; Balzarini, J.; Liekens, S.; Dehaen, W. A new four-component reaction involving the Michael addition and the Gewald reaction, leading to diverse biologically active 2-aminothiophenes. Org. Biomol. Chem. 2017, 15, 38923900. 9 For miscellaneous examples, see: (a) Lugovik, K. I.; Eltyshev, A. K.; Benassi, E.; Belskaya, N. P. Synthesis of 5‐Acyl‐2‐Amino‐3‐ Cyanothiophenes: Chemistry and Fluorescent Properties. Chem. Asian J. 2017, 12, 2410-2425. (b) Zali-Boeini, H.; Fadaei, N. Novel Route to Thiophene-2,4-diamines. Synlett 2015, 26, 1819-1822. (c) Moghaddam, F. M.; Boinee, H. Z. A versatile one-pot synthesis of 2,3,5-tri-substituted thiophenes from thiomorpholides. Tetrahedron Letters 2003, 44, 6253-6255. 10 For selected examples of the base-mediated coupling of βketothioamides and carbonyl compounds bearing a α-leaving group,


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see: (a) Jalani, H. B.; Pandya, A. N.; Pandya, D. H.; Sharma, J. A.; Sudarsanam, V.; Vasu, K. K. A concise, greener, solvent-free novel one-pot synthesis of trisubstituted thiophenes. Tetrahedron Lett. 2012, 53, 6927-6930. (b) Samuel, R.; Chandran, P.; Retnamma, S.; Sasikala, K. A.; Sreedevi, N. K.; Anabha, E. R.; Asokan, C. V. Alkylation of aryl 3-oxopropanedithioate and 3-amino-1-aryl-3-thioxo-1propanones as an effective tool for the construction of differently substituted thiophenes and annulated thiophenes. Tetrahedron 2008, 64, 5944-5948. (c) Ransborg, L. K.; Albrecht, L.; Weise, C. F.; Bak, J. R.; Jørgensen, K. A. Optically Active Thiophenes via an Organocatalytic One-Pot Methodology. Org. Lett. 2012, 14, 724-727. 11 For formal (3+2) cycloadditions of thioamides with various reaction partners, see: (a) Ge, L.-S.; Wang, Z.-L.; An, X.-L.; Luo, X.; Deng, W.-P. Direct synthesis of polysubstituted 2-aminothiophenes by Cu(II)-catalyzed addition/oxidative cyclization of alkynoates with thioamides. Org. Biomol. Chem. 2014, 12, 8473-8479. (b) Wang, Z.L.; Li, H.-L.; Ge, L.-S.; An, X.-L.; Zhang, Z.-G.; Luo, X.; Fossey, J. S.; Deng, W.-P. DDQ-Mediated Oxidative Coupling: An Approach to 2,3-Dicyanofuran (Thiophene). J. Org. Chem. 2014, 79, 1156-1165. (c) Zhang, X.; Wu, M.; Zhang, J.; Cao, S. Synthesis of N,Ndisubstituted 2-aminothiophenes by the cyclization of gemdifluoroalkenes with β-keto thioamides. Org. Biomol. Chem. 2017, 15, 2436-2442. 12 For an intermolecular coupling reaction of thioamides and 2-ynals in alcohols, see: (a) Luo, X.; Ge, L.-S.; An, X.-L.; Jin, J.-H.; Wang, Y.; Sun, P.-P.; Deng, W.-P. Regioselective Metal-Free One-Pot Synthesis of Functionalized 2-Aminothiophene Derivatives. J. Org. Chem. 2015, 80, 4611-4617. For an intramolecular addition of thioamides to alkynes, see: (b) Nandi, G. C.; Singh, M. S. p-TSA/Base-Promoted Propargylation/Cyclization of β-Ketothioamides for the Regioselective Synthesis of Highly Substituted (Hydro)thiophenes. J. Org. Chem. 2016, 81, 5824-5836. 13 (a) Pedersen, B. S.; Lawesson, S.-O. Studies on organophosphorus compounds—XXVIII1: Syntheses of 3H-1,2-dithiole-3-thiones and 4H-1,3,2,-oxazaphosphorine derivatives from the dimer of pmethoxyphenyl-thionophosphine sulfide and der. Tetrahedron 1979, 35, 2433-2437. For a review on the synthetic applications of LR, see:

(b) Ozturk, T.; Ertas, E.; Mert, O. Use of Lawesson's Reagent in Organic Syntheses. Chem. Rev. 2007, 107, 5210-5278. 14 (a) Lecher, H. Z.; Greenwood, R. A.; Whitehouse, K. C.; Chao, T. H. The Phosphonation of Aromatic Compounds with Phosphorus Decasulfide. J. Am. Chem. Soc. 1956, 78, 5018-5022. (b) Scheibye, S.; Kristensen, J.; Lawesson, S.-O. Studies on organophosphorus compounds—XXVII1: Synthesis of thiono-, thiolo- and dithiolactones. Tetrahedron 1979, 35, 1339-1343. 15 (a) Kaboudin, B.; Elhamifar, D. Phosphorus Decasulfide: A Mild and Versatile Reagent for the Preparation of Thioamides from Nitriles. Synthesis 2006, 224-226. For a review on the synthetic applications of P4S10, see: (b) Ozturk, T.; Ertas, E.; Mert, O. A Berzelius Reagent, Phosphorus Decasulfide (P4S10), in Organic Syntheses. Chem. Rev. 2010, 110, 3419-3478. 16 CCDC 1532241 (4a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. 17 Gewald, K.; Hentschel, M.; Heikel, R. 2‐Amino‐thieno [2,3‐d] thiazole und 3‐Amino‐thieno [2,3‐c]‐isothiazole. J. Prakt. Chem. 1973, 315, 539-548. 18 James, F. C.; Krebs, H. D. Thienoisothiazoles. I. The synthesis of Thieno[2,3-c]isothiazole and some of its derivatives. Aus. J. Chem. 1982, 35, 385-391. 19 Shestopalov, A. M.; Larionova, N. A.; Fedorov, A. E.; Rodinovskaya, L. A.; Mortikov, V. Y.; Zubarev, A. Z.; Bushmarinov, I. S. Synthesis of Isomeric Isothiazolo[4′,3′:4,5]- and Isothiazolo[4′,5′:4,5]thieno[3,2-b]pyrano[2,3-d]pyridines by Combination of Domino Reactions. ACS Comb. Sci. 2013, 15, 541-545. 20 To further support the proposed mechanism, we showed that 2aminothiophene 3i could be converted to thieno[2,3-c]isothiazole 4k in 49% isolated yield with LR in p-xylene at 130 °C. 21 Cinar, E. M.; Ozturk, T. Thienothiophenes, Dithienothiophenes, and Thienoacenes: Syntheses, Oligomers, Polymers, and Properties. Chem. Rev. 2015, 115, 3036-3140.


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