English

• 1.   Introduction

  Aryl iodides represent widespread structural motifs distributed in a range of pharmaceuticals, agrochemicals and natural products.^[1] Over the past few decades, aryl iodides have been extensively used as aromatic synthons for constructing complex organic structures via nucleophilic substitution^[2] or a variety of cross-coupling reactions (such as Suzuki, ^[3] Heck^[4] and Ullmann reaction, ^[5] etc.). The traditional strategies to access aryl iodides are direct electrophilic substitution, Sandmeyer reaction and ortho-lithation/ halogenation, which were limited in application by poor regioselectivities, harsh reaction conditions and tedious long procedures.^[6]

  To overcome these above mentioned disadvantages, diverse C—I bond formation reactions promoted by rear- metal catalysts or more recently investigated base-metal catalysts^[7] have been developed. Ever since the first Pd-catalyzed C(sp²)—H bond iodination reaction disclosed by Sanford, ^[8] a series of protocols using Suárez reagent, ^[9] N-iodosuccinimide (NIS), ^[10] sole I₂^[11] or other iodine sour- ces^[12] have emerged to introduce iodine atom to different aryl substrates. A variety of directing groups have also been employed for ortho-C—H bond activation/iodine- tion.^[13] However, the thiazole based auxiliary-directed io- dination has rarely been reported. Recently, Petel et al.^[14] disclosed Pd-catalyzed benzothiazole-directed C(sp²)—H bond halogenation, in which only four disubstituted examples of iodination were included and the mono-selectivity was not obtained (Scheme 1A). Considering that highly functionalized thiazoles serve as important pharmacophores in drug discovery^[15], it is highly desirable to exploit the non-fused thiazole-directed C(sp²)—H bond mono- selective iodination reaction (Scheme 1B).

  Scheme 1

  

  Scheme 1.  Previous related works and present work

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  2.   Results and discussion

  Given our recent success in thiazole-directed C(sp²)—H bond activation/acyloxylation, ^[16] our research was initiated by briefly evaluating the substituted pattern of various thoizole directing groups. As indicated in Table 1, direct electrophilic iodination preferred to occurring on the thiazole bearing active site^[17] (DG₁), which restrained the aimed ortho-iodination. Introducing methyl group to C-5 site of thiazole drastically promoted the reaction both on reaction rate and yield (DG₂). Replacing methyl group with ethyl group (DG₃) performed similar efficiency. However the larger steric hinderance may potentially limit substrate scope, which means DG₂ is still the suitable directing group. To our surprise, changing carboxylate group on the C-2 site of thiazole to methyl (DG₄) notably inhibited the reaction, indicating that carboxylate is vital in this catalytic system. Furthermore, DG₅ resulted in inferior efficiencies and DG₆ was inefficient, both demonstrating that the appropriate electron density of DG₂ could promote the C—H bond activation. Thus, the fully substituted DG₂ was selected as the optimal directing group for further iodination investigations.

  Table 1

  

  Table 1.  Screening of directing groups^{a, b}

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  Upon the preferable directing group confirmed, the optimization of reaction conditions utilizing 1b as the model substrate was followed (Table 2). Firstly, a control experiment revealed that the C(sp²)—H bond activation/ iodination process does not occur in the absence of the catalyst (Entry 1). Compared to Pd(OAc)₂, other Pd salts led to lower efficiency (Entres 2 vs 3~6). Lowering the loading of Pd(OAc)₂ to 5 mol% distinctly depressed the reaction (Entry 7), howbeit further increasing the dosage of Pd(OAc)₂ did not result in significently better performance (Entry 8). Subsequently, screening of solvents, including DCE/HFIP (V:V＝4:1), DCE, HFIP, DMF, DCM and TCM uncovered that DCE exhibited the best result (Entries 9 vs 2, 10~13). Afterwards, adjusting the amount of NIS showed 2.5 equiv. is more favorable and economic loading (Entres 15 vs 14, 16). Finally, different scales of solvent were applied to this reaction, and 0.1 mol•L^－1 was the approprite concentration (Entries 15 vs 17~18). Hence, Entry 15 was selected as the standard reaction conditions for the subsequent functionalization.

  Table 2

  

  Table 2.  Optimization of the reaction conditions^a

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  Entry	Catalyst	NIS (equiv.)	Solvent	Yieldb/%
  1	None	2.0	DCE/HFIP (V:V＝4:1)	0
  2	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	76
  3	Pd(CH3CN)2Cl2	2.0	DCE/HFIP (V:V＝4:1)	64
  4	Pd(TFA)2	2.0	DCE/HFIP (V:V＝4:1)	57
  5	PdCl2	2.0	DCE/HFIP (V:V＝4:1)	38
  6	Pd(PPh3)2Cl2	2.0	DCE/HFIP (V:V＝4:1)	27
  7c	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	58
  8d	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	75
  9	Pd(OAc)2	2.0	DCE	86
  10	Pd(OAc)2	2.0	HFIP	69
  11	Pd(OAc)2	2.0	DMF	85
  12	Pd(OAc)2	2.0	DCM	62
  13	Pd(OAc)2	2.0	TCM	21
  14	Pd(OAc)2	1.5	DCE	76
  15	Pd(OAc)2	2.5	DCE	93
  16	Pd(OAc)2	3.0	DCE	92
  17e	Pd(OAc)2	2.5	DCE	78
  18f	Pd(OAc)2	2.5	DCE	90
  a Reaction conditions: 1b (74.1 mg, 0.3 mmol), NIS, catalyst (10 mol%), solvent (3 mL, 0.1 mol·L－1), 100 ℃, 4 h; b NMR yield using CH2Br2 as the internal standard; c Pd(OAc)2 (5 mol%); d Pd(OAc)2 (15 mol%); e DCE (0.05 mol·L－1); f DCE (0.15 mol·L－1); NIS＝N-Iodosuccinimide; DCE＝1, 2-Dichloroethane; HFIP＝Hexafluoroisopropanol; DMF＝N, N-Dimethylfor- mamide; DCM＝Dichloromethane; TCM＝Trichloromethane; DMSO＝Dimethyl sulfoxide.

  With the optimized conditions for mono-selective C(sp²)—H bond activation/iodination established, we set about testing the generality of this methodology (Table 3). The iodination reaction with NIS catalyzed by Pd(OAc)₂ was found to be perfectly compatible with a wide range of functional groups, including OMe (4e, 4l, 4u), Me (4f, 4n, 4t), Et (4m), F (4c, 4g, 4o, 4v, 4w), Cl (4h, 4p), Br (4i, 4q, 4s) and CF₃ (4j, 4r).

  Table 3

  

  Table 3.  Scope of 4-phenylthiazols^{a, b}

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  However, most ortho-substituted 4-arylthiazoles failed to generate corresponding products, only with the exception of sterically less hindered F-substituted substrate (4b~4d). It is speculated that steric hinderance between the ortho-substituents and the C-5-methyl group on thiazole ring impedes the free rotation of benzene ring, thus preventing the formation of five-member cyclo- palladium intermediate. meta-Substituents were well tole- rated, and the desired products were obtained with up to 96% yield (4f). All iodination took place at the sterically less hindered ortho-positions (4e~4j). Notebly, substrate containing NO₂ group performed no react activity (4k). This can be attributed to the strong coordination of NO₂ to Pd center, which blocked the subsequent C—H bond activation^[18]. Not surprisingly, di-iodination was not observed when subjecting para-substituted substrates to this catalytic system, due to aforementioned steric-hinde- rance theory.

  Mono-iodinated thiohpene (4s), furan (4t) and naphthalene (4u) derivatives were sucessfully obtained in moderate to excellent yields. Furthermore, this protocol was also applicable in the cases of disubstituted masked 4-benzothiazoles (4v, 4w).

  To further expand the versatility of this newly developed C—H bond functionalization reaction, iodination product 4a was successfully converted to different functionalized 4-arylthiazoles through a series of reactions. As demon- strated in Scheme 2, compounds with various functional groups, including aryl, cyano and thiol were conveniently prepared in moderate to good yields.

  Scheme 2

  

  Scheme 2.  Diversification of the iodination products

  Reaction conditions: (a) 4a (111.9 mg, 0.30 mmol), 3-methoxylben-zoboric acid (59.3 mg, 0.39 mmol), I₂ (15.2 mg, 0.06 mmol), K₂CO₃ (82.9 mg, 0.60 mmol), PEG, 140 ℃, 24 h; (b) 4a (111.9 mg, 0.30 mmol), DDQ (68.1 mg, 0.30 mmol), Cu(OAc)₂ (60.0 mg, 0.30 mmol), Ag₂O (36.9 mg, 0.30 mmol), NMP, 120 ℃, 22 h; (c) 4a (111.9 mg, 0.30 mmol), 3-chlorothiophenol (56.2 mg, 0.39 mmol), CuI (1.4 mg, 2.5 mol%), K₂CO₃ (45.6 mg, 0.33 mmol), 100 ℃, 16 h; ^b Isolated yields

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  This mono-selective iodination reaction was also performed on gram scale in 88% yield (Scheme 3), illustra- ting that this protocol is still efficient on larger scale in the aspect of selectivity and productivity.

  Scheme 3

  

  Scheme 3.  Gram scale reaction

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  To gain insight into the mechanism of this catalytic system, a deuterium labeling isotope experiment was carried out to probe the kinetics of Pd-catalyzed C(sp²)—H iodination (Scheme 4). The intermolecular competition reactions between 3a and 3a' with NIS in one vessel performed the kinetic isotopic effect (KIE) value of 3.8, suggesting that the C(sp²)—H bond cleavage might be involved in the rate-limiting step.

  Scheme 4

  

  Scheme 4.  Kinetic isotope effect study

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  The radical inhibition experiment was then carried out to further understand the reaction path way. The use of 2, 2, 6, 6-tetramethylpiperidinooxy (TEMPO) or 2, 6-di-tert- butyl-4-methylphenol (BHT) as radical scavengers comp- letely restrained the formation of the desired product 4a (Scheme 5), implying radical may generated in this catalytic system. However, some control experiments showed that NIS reacted with TEMPO and BHT when no substrates were subjected into the reaction system. And for the difficulty of isolating, the products of radical inhibition experiments were failed to be obtained. Consequently, the oxidative addition/reductive elimination path still can not be excluded.

  Scheme 5

  

  Scheme 5.  Radical inhibition experiment

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  Based on these experimental investigations and the well-documented reports^{[10c, 10g, 14, 19]}, a plausible mechanism was proposed to account for this palladium-catalyzed mono-selective iodination reaction (Scheme 6). Firstly, Pd(OAc)₂ coordinates with nitrogen atom on thiazole ring to generate cyclopalladium intermediate A. Acetate then participates in aromatic proton abstraction to generate Pd^II intermediate B. There are two possible pathways for the reaction of intermediate B. The first pathway proceeds via oxidative addition of NIS to intermediate B to form Pd^IV intermediate C. The subsequent reductive elimination of C furnishes the ortho-iodinated product 4a and regenerates the Pd^II catalyst. The second pathway b involves the generating of iodine radical, radical attack to intermediate. B and the forming of Pd^IV intermediate D, which undergoes reductive elimination to produce 4a and the Pd^II catalyst.

  Scheme 6

  

  Scheme 6.  Plausible reaction mechanism

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  3.   Conclusions

  In summary, the first Pd-catalyzed non-fused thiazole- directed C(sp²)—H bond activation/ iodination reaction was realized. Various 4-(2-iodoaryl)thiazoles were obtained with excellent ortho- and mono-selectivities with up to 94% yield. The broad substrate scope and the subsequent diverse convenitent transformations of iodination products both increase the value of this metho- dology. A series of control experiments revealed a plausible Pd^II/Pd^IV mechanism.

  4.   Experimental section

  4.1   General methods

  All reactions were carried out in oven-dried glassware and monitored by thin layer chromatography (TLC, pre-coated silica gel plates containing HF254). NMR spectra were determined on a Bruker AV400 in CDCl₃ with TMS as internal standard for ¹H NMR (400 MHz) and ¹³C NMR (100 MHz), respectively. HRMS were measured on a QSTAR Pulsar I LC/TOF MS mass spectrometer or Micromass GCTTM gas chromatograph-mass spectrometer.

  4.2   Genreal procedure for screening of directing groups

  A mixture of substrate 1 (0.3 mmol), Pd(OAc)₂ (6.7 mg, 10 mol%), NIS (135.0 mg, 0.6 mmol) and DCE/HFIP (V:V＝4:1, 3 mL) was stirred at 100 ℃ for 12 h. Upon completion of the reaction (monitored by TLC), the mixture was transferred into saturated brine (20 mL), then extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous MgSO₄ and concentrated in vacuo to provide a crude product, which was purified via a column chromatography on silica gel (eluents: petroleum ether/ethyl acetate) to supply the desired product 2, which was identified by ¹H NMR, ¹³C NMR and HRMS.

  Ethyl 4-(2-iodophenyl)-5-methylthiazole-2-carboxylate (2b): 85 mg, 76% yield. Yellow solid, m.p. 71~72 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (dd, J＝8.0, 0.9 Hz, 1H), 7.38 (td, J＝7.5, 1.1 Hz, 1H), 7.30 (dd, J＝7.6, 1.7 Hz, 1H), 7.07 (td, J＝7.8, 1.8 Hz, 1H), 4.45 (q, J＝7.1 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 156.3, 154.1, 139.2, 139.1, 137.6, 131.1, 130.23, 128.1, 99.6, 62.5, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₂¹²⁷INO₂S: 372.9633, found 372.9635.

  Ethyl 5-ethyl-4-(2-iodophenyl)thiazole-2-carboxylate (2c): 86 mg, 74% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.92 (d, J＝7.8 Hz, 1H), 7.40 (t, J＝7.4 Hz, 1H), 7.31 (d, J＝7.4 Hz, 1H), 7.09 (t, J＝7.2 Hz, 1H), 4.48 (q, J＝6.9 Hz, 2H), 2.72 (q, J＝7.3 Hz, 2H), 1.43 (t, J＝7.0 Hz, 3H), 1.27 (t, J＝7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 155.2, 154.0, 145.4, 139.5, 139.0, 131.0, 130.2, 128.0, 99.9, 62.4, 21.0, 16.1, 14.4; HRMS (EI) calcd for C₁₄H₁₄¹²⁷INO₂S: 386.9790, found 386.9791.

  4-(2-Iodophenyl)-2, 5-dimethylthiazole (2d): 9 mg, 9% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.92 (dd, J＝8.0, 1.0 Hz, 1H), 7.39 (td, J＝7.4, 1.0 Hz, 1H), 7.31 (dd, J＝7.6, 1.7 Hz, 1H), 7.06 (td, J＝7.7, 1.7 Hz, 1H), 2.69 (s, 3H), 2.25 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.9, 153.0, 140.3, 139.1, 131.0, 129.7, 129.3, 128.0, 99.8, 19.2, 12.2; HRMS (EI) calcd for C₁₁H₁₀¹²⁷INS: 314.9579, found 314.9581.

  4-(2-iodophenyl)-5-methylthiazole (2e'): 33 mg, 36% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.60 (s, 1H), 7.88 (dd, J＝8.0, 1.1 Hz, 1H), 7.34 (td, J＝7.5, 1.2 Hz, 1H), 7.24 (dd, J＝7.6, 1.7 Hz, 1H), 7.02 (ddd, J＝7.9, 7.5, 1.8 Hz, 1H), 2.26 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 154.4, 149.2, 139.9, 139.3, 131.0, 130.0, 129.9, 128.1, 99.6, 12.1; HRMS (EI) calcd for C₁₀H₈¹²⁷INO₂S: 300.9422, found 300.9424.

  4.3   General procedure for iodination reaction

  A mixture of substrate 3 (0.3 mmol), Pd(OAc)₂ (6.7 mg, 10 mol%), NIS (167.8 mg, 0.75 mmol) and DCE (3 mL) was stirred at 100 ℃ for 4 h. Upon completion of the reaction (monitored by TLC), the mixture was transferred into saturated brine (20 mL), then extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous MgSO₄ and concentrated in vacuo to provide a crude product, which was purified via a column chromatography on silica gel (eluents: petroleum ether/ethyl acetate, V:V＝75:1) to supply the desired product 4.

  Ethyl 4-(2-iodophenyl)-5-methylthiazole-2-carboxylate (4a): 97 mg, 87% yield. Yellow solid, m.p. 71~72 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (dd, J＝8.0, 0.9 Hz, 1H), 7.38 (td, J＝7.5, 1.1 Hz, 1H), 7.30 (dd, J＝7.6, 1.7 Hz, 1H), 7.07 (td, J＝7.8, 1.8 Hz, 1H), 4.45 (q, J＝7.1 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 156.3, 154.1, 139.2, 139.1, 137.6, 131.1, 130.23, 128.1, 99.6, 62.5, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₂¹²⁷INO₂S: 372.9633, found 372.9635.

  Ethyl 4-(2-fluoro-6-iodophenyl)-5-methylthiazole-2-car- boxylate (4c): 43 mg, 37% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (dd, J＝6.6, 2.4 Hz, 1H), 7.18~7.09 (m, 2H), 4.48 (q, J＝7.1 Hz, 2H), 2.37 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2 (t, ¹J_CF＝126.0 Hz), 154.8, 150.2, 139.3, 134.7 (d, ⁴J_CF＝3.6 Hz), 131.9 (d, ³J_CF＝8.7 Hz), 130.5 (d, ³J_CF＝8.2 Hz), 127.3 (d, ²J_CF＝18.4 Hz), 124.2 (d, ⁴J_CF＝3.6 Hz), 115.7 (d, ²J_CF＝22.5 Hz), 62.5, 14.3, 12.3; HRMS (EI) calcd for C₁₃H₁₁F¹²⁷INO₂S: 390.9539, found 390.9543.

  Ethyl 4-(2-iodo-5-methoxyphenyl)-5-methylthiazole-2- carboxylate (4e): 88 mg, 73% yield. Yellow solid, m.p. 101~103 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.76 (d, J＝8.8 Hz, 1H), 6.90 (d, J＝3.0 Hz, 1H), 6.71 (dd, J＝8.8, 3.0 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 3.79 (s, 3H), 2.39 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 159.7, 156.2, 154.1, 140.0, 139.6 (2C), 137.6, 117.0, 116.7, 88.0, 62.5, 55.5, 12.8; HRMS (EI) calcd for C₁₄H₁₄¹²⁷INO₃S: 402.9739, found 402.9740.

  Ethyl 4-(2-iodo-5-methylphenyl)-5-methylthiazole-2- carboxylate (4f): 111 mg, 96% yield. White solid, m.p. 81~82 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J＝8.1 Hz, 1H), 7.13 (d, J＝1.8 Hz, 1H), 6.88 (dd, J＝8.1, 1.8 Hz, 1H), 4.43 (q, J＝7.1 Hz, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 1.39 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.2, 155.4, 152.9, 137.8, 137.7, 137.1, 136.4, 131.0, 130.2, 94.3, 61.4, 19.8, 13.3, 11.8; HRMS (EI) calcd for C₁₄H₁₄¹²⁷INO₂S: 386.9790, found 386.9789.

  Ethyl 4-(5-fluoro-2-iodophenyl)-5-methylthiazole-2- carboxylate (4g): 89 mg, 76% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (dd, J＝8.7, 5.5 Hz, 1H), 7.10 (dd, J＝8.8, 3.0 Hz, 1H), 6.88 (td, J＝8.5, 3.0 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.40 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.62 (d, ¹J_CF＝249.3 Hz), 160.1, 155.1, 154.5, 141.0 (d, ³J_CF＝7.9 Hz), 140.4 (d, ³J_CF＝7.9 Hz), 138.0, 118.6 (d, ²J_CF＝22.5 Hz), 117.8 (d, ²J_CF＝21.7 Hz), 92.6 (d, ⁴J_CF＝3.4 Hz), 62.6, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₁F¹²⁷INO₂S: 390.9539, found 390.9543.

  Ethyl 4-(5-chloro-2-iodophenyl)-5-methylthiazole-2- carboxylate (4h): 100 mg, 82% yield. Yellow solid, m.p. 69~71 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (d, J＝8.5 Hz, 1H), 7.35 (d, J＝2.5 Hz, 1H), 7.11 (dd, J＝8.5, 2.5 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.40 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 154.9, 154.5, 140.8, 140.1, 138.0, 134.4, 131.2, 130.5, 96.7, 62.6, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₁³⁷Cl¹²⁷INO₂S: 406.9244, found 406.9241.

  Ethyl 4-(5-bromo-2-iodophenyl)-5-methylthiazole-2- carboxylate (4i): 128 mg, 94% yield. Yellow solid, m.p. 87~89 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.77 (d, J＝8.5 Hz, 1H), 7.49 (d, J＝2.4 Hz, 1H), 7.24 (dd, J＝8.5, 2.4 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.40 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 154.8, 154.5, 141.1, 140.3, 138.1, 134.0, 133.4, 122.3, 97.6, 62.6, 14.3, 12.9; HRMS (EI) calcd for C₁₃H₁₁⁸¹Br¹²⁷INO₂S: 452.8718, found 452.8721.

  Ethyl 4-(2-iodo-5-(trifluoromethyl)phenyl)-5-methyl- thiazole-2-carboxylate (4j): 85 mg, 64% yield. Yellow solid, m.p. 70~72 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.1 (d, J＝8.3 Hz, 1H), 7.6 (s, 1H), 7.4 (d, J＝7.2 Hz, 1H), 4.5 (q, J＝7.1 Hz, 2H), 2.4 (s, 3H), 1.4 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 154.8, 154.7, 140.2, 139.8, 138.2, 130.8 (q, ²J_CF＝33.2 Hz), 127.8 (q, ³J_CF＝3.6 Hz), 126.7 (dd, ³J_CF＝7.4, 3.6 Hz), 126.4 (q, ¹J_CF＝270.6 Hz), 104.1 (d, ⁴J_CF＝1.3 Hz), 62.7, 14.3, 12.8; HRMS (EI) calcd for C₁₄H₁₁F₃¹²⁷INO₂S: 440.9507, found 440.9509.

  Ethyl 4-(2-iodo-4-methoxyphenyl)-5-methylthiazole-2- carboxylate (4l): 52 mg, 43% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.37 (d, J＝2.6 Hz, 1H), 7.15 (d, J＝8.5 Hz, 1H), 6.87 (dd, J＝8.5, 2.6 Hz, 1H), 4.40 (q, J＝7.1 Hz, 2H), 3.75 (s, 3H), 2.30 (s, 3H), 1.35 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.3, 158.9, 155.2, 152.7, 136.7, 130.4, 130.4, 123.1, 113.1, 98.7, 61.4, 54.6, 13.3, 11.8; HRMS (EI) calcd for C₁₄H₁₄¹²⁷INO₃S: 402.9739, found 402.9740.

  Ethyl 4-(4-ethyl-2-iodophenyl)-5-methylthiazole-2-car- boxylate (4m): 88 mg, 73% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.76 (s, 1H), 7.23 (d, J＝0.9 Hz, 2H), 4.47 (q, J＝7.1 Hz, 2H), 2.64 (q, J＝7.6 Hz, 2H), 2.38 (s, 3H), 1.42 (t, J＝7.1 Hz, 3H), 1.24 (t, J＝7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 156.4, 153.8, 146.7, 138.4, 137.5, 136.4, 130.8, 127.7, 99.6, 62.4, 28.1, 15.4, 14.3, 12.8; HRMS (EI) calcd for C₁₅H₁₆¹²⁷INO₂S: 400.9946, found 400.9950.

  Ethyl 4-(2-iodo-4-methylphenyl)-5-methylthiazole-2- carboxylate (4n): 93 mg, 79% yield. Yellow solid, m.p. 70~72 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.69 (s, 1H), 7.13 (s, 2H), 4.40 (q, J＝7.1 Hz, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 1.35 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.3, 156.4, 153.9, 140.4, 139.5, 137.5, 136.2, 130.7, 128.9, 99.5, 62.4, 20.7, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₁F¹²⁷INO₂S: 390.9539, found 390.9540.

  Ethyl 4-(4-fluoro-2-iodophenyl)-5-methylthiazole-2- carboxylate (4o): 99 mg, 84% yield. Yellow solid, m.p. 65~67 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.65 (dd, J＝8.1, 2.6 Hz, 1H), 7.31 (dd, J＝9.2, 5.2 Hz, 1H), 7.14 (td, J＝8.3, 2.6 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.38 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.0 (d, ¹J_CF＝253.4 Hz), 160.1, 155.3, 154.1, 137.9, 135.4 (d, ⁴J_CF＝3.6 Hz), 131.9 (d, ³J_CF＝8.4 Hz), 126.0 (d, ²J_CF＝23.8 Hz), 115.3 (d, ²J_CF＝21.2 Hz), 99.2 (d, ³J_CF＝8.2 Hz), 62.5, 14.3, 12.7; HRMS (EI) calcd for C₁₃H₁₁F¹²⁷INO₂S: 390.9539, found 390.9540.

  Ethyl 4-(4-chloro-2-iodophenyl)-5-methylthiazole-2-car- boxylate (4p): 79 mg, 65% yield. Yellow solid, m.p. 93~95 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.90 (d, J＝2.1 Hz, 1H), 7.37 (dd, J＝8.2, 2.1 Hz, 1H), 7.23 (d, J＝8.2 Hz, 1H), 4.45 (q, J＝7.1 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.1, 155.1, 154.3, 138.4, 137.4, 137.9, 135.1, 131.7, 128.4, 99.6, 62.5, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₁³⁷Cl¹²⁷INO₂S: 406.9244, found 406.9243.

  Ethyl 4-(4-bromo-2-iodophenyl)-5-methylthiazole-2- carboxylate (4q): 103 mg, 76% yield. Yellow solid, m.p. 103~104 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.08 (d, J＝1.9 Hz, 1H), 7.55 (dd, J＝8.2, 1.9 Hz, 1H), 7.20 (d, J＝8.2 Hz, 1H), 4.47 (d, J＝7.1 Hz, 2H), 2.38 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 155.1, 154.3, 141.1, 138.2, 137.9, 132.0, 131.3, 123.2, 100.1, 62.5, 14.3, 12.8; HRMS (EI) calcd for C₁₃H₁₁⁸¹Br¹²⁷INO₂S: 450.8739, found 452.8720.

  Ethyl 4-(2-iodo-4-(trifluoromethyl)phenyl)-5-methyl- thiazole-2-carboxylate (4r): 99 mg, 75% yield. Yellow solid, m.p. 80~82 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.18 (s, 1H), 7.68 (dd, J＝8.0, 1.0 Hz, 1H), 7.46 (d, J＝7.9 Hz, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.40 (s, 3H), 1.44 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 154.8 (d, ³J_CF＝14.9 Hz), 143.0, 138.0, 135.9 (q, ⁴J_CF＝3.8 Hz), 132.2 (q, ²J_CF＝33.0 Hz), 131.4, 129.1, 125.0 (q, ⁴J_CF＝3.6 Hz), 123.9(q, ¹J_CF＝271.3Hz), 99.4, 62.6, 14.3, 12.7; HRMS (EI) calcd for C₁₄H₁₁F₁₃¹²⁷INO₂S: 440.9507, found 440.9509.

  Ethyl 4-(5-bromo-3-iodothiophen-2-yl)-5-methylthia- zole-2-carboxylate (4s): 77 mg, 56% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.23 (s, 1H), 4.47 (q, J＝7.1 Hz, 2H), 2.51 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.8, 154.7, 146.4, 140.6, 137.2, 136.8, 115.3, 82.0, 62.7, 14.3, 13.5; HRMS (EI) calcd for C₁₁H₉⁸¹Br¹²⁷INO₂S₂: 458.8282, found 458.8285.

  Ethyl 4-(3-iodo-5-methylfuran-2-yl)-5-methylthiazole- 2-carboxylate (4t): 70 mg, 62% yield. White solid, m.p. 92~94 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.21 (s, 1H), 4.46 (q, J＝7.1 Hz, 2H), 2.63 (s, 3H), 2.35 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.0, 154.6, 154.1, 146.7, 143.9, 139.2, 115.2, 66.8, 62.5, 14.3, 13.6, 13.6; HRMS (EI) calcd for C₁₂H₁₂¹²⁷INO₃S: 376.9583, found 372.9584.

  Ethyl 4-(3, 5-diiodo-6-methoxynaphthalen-2-yl)-5-me- thylthiazole-2-carboxylate (4u): 154 mg, 89% yield. Yellow solid, m.p. 123~125 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.72 (s, 1H), 7.73 (d, J＝8.9 Hz, 1H), 7.70 (s, 1H), 7.19 (d, J＝8.8 Hz, 1H), 4.46 (q, J＝7.0 Hz, 2H), 4.00 (s, 3H), 2.37 (s, 3H), 1.41 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.2, 157.6, 155.8, 154.0, 141.6, 138.2, 136.9, 134.2, 130.6, 130.3, 128.7, 113.8, 99.8, 85.4, 62.5, 57.2, 14.4, 13.0; HRMS (EI) calcd for C₁₈H₁₅¹²⁷I₂NO₃S: 578.8862, found 578.8861.

  Ethyl 4-(2, 4-difluoro-6-iodophenyl)-5-methylthiazole- 2-carboxylate (4v): 48 mg, 39% yield. White solid, m.p. 62~64 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.23 (q, 1H), 7.17~7.09 (m, 1H), 4.48 (q, J＝7.1 Hz, 2H), 2.37 (s, 3H), 1.43 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.1, 154.5, 154.3 (d, ³J_CF＝1.9 Hz), 151.4 (dd, ^{1, 3}J_CF＝245.0, 13.7 Hz), 149.7 (dd, ^{1, 3}J_CF＝253.4, 15.1 Hz), 138.1, 136.3 (d, ³J_CF＝4.0 Hz), 126.6 (dd, ^{2, 2}J_CF＝6.5, 3.7 Hz), 117.1 (d, ²J_CF＝18.0 Hz), 88.9 (d, ²J_CF＝21.7 Hz), 62.6, 14.3, 12.7; HRMS (EI) calcd for C₁₃H₁₀F₂¹²⁷INO₂S: 408.9445, found 408.9446.

  Ethyl 4-(3, 5-difluoro-2-iodophenyl)-5-methylthiazole- 2-carboxylate (4w): 90 mg, 73% yield. White solid, m.p. 71~73 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.96 (d, J＝8.4 Hz, 1H), 6.90 (td, J＝8.3, 2.6 Hz, 1H), 4.47 (q, J＝7.1 Hz, 2H), 2.38 (s, 3H), 1.42 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.9 (dd, ^{1, 3}J_CF＝249.6, 12.2 Hz), 162.1 (dd, ^{1, 3}J_CF＝246.2, 12.6 Hz), 160.0, 154.7, 153.8, 142.1 (dd, ^{3, 3}J_CF＝9.4, 3.1 Hz), 138.1, 114.4 (dd, ^{2, 4}J_CF＝22.3, 3.4 Hz), 104.3 (dd, ^{2, 2}J_CF＝28.5, 25.8 Hz), 81.2 (dd, ^{2, 4}J_CF＝25.9, 4.3 Hz), 62.6, 14.3, 12.7; HRMS (EI) calcd for C₁₃H₁₀F₂¹²⁷INO₂S: 408.9445, found 408.9448.

  4.4   Porcedures for derivatizations of iodinated products

  A mixture of 4a (111.9 mg, 0.3 mmol), 3-boronoanisole (59.3 mg, 0.39 mmol), I₂ (82.9 mg, 0.06 mmol), K₂CO₃ (82.9 mg, 0.06 mmol) and PEG (3 mL) was stirred in a sealed tube at 140 ℃ for 24 h. Upon completion of the reaction (as monitored by TLC), the mixture was transferred into saturated brine (20 mL) then extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous MgSO₄ and concentrated in vacuo to provide a crude product, which was purified via a column chromatography on silica gel (eluents: petroleum ether/ethyl acetate, V:V＝100:1) to supply the desired product 4-(3'-methoxy-[1, 1'-biphenyl]-2-yl)-5-methylthia- zole (5a), 62 mg, 73% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.61 (s, 1H), 7.54~7.39 (m, 4H), 7.16 (t, J＝7.9 Hz, 1H), 6.83~6.74 (m, 2H), 6.63 (dd, J＝2.4, 1.7 Hz, 1H), 3.64 (s, 3H), 1.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.1, 152.0, 149.1, 142.7, 141.7, 133.2, 131.1, 130.0, 129.3, 129.1, 128.7, 127.4, 121.5, 114.1, 113.0, 55.1, 11.6; HRMS (EI) calcd for C₁₇H₁₅NOS 281.0874, found 281.0872.

  A mixture of 4a (111.9 mg, 0.3 mmol), DDQ (68.1 mg, 0.3 mmol), Cu(OAc)₂ (60 mg, 0.3 mmol), AgO (36.9 mg, 0.3 mmol) and NMP (3 mL) was stirred in a sealed tube at 120 ℃ for 22 h. Upon completion of the reaction (as monitored by TLC), the mixture was transferred into saturated brine (20 mL), then extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous MgSO₄ and concentrated in vacuo to provide a crude product, which was purified via a column chromatography on silica gel (eluents: petroleum ether/ethyl acetate, V:V＝30:1) to supply the desired product ethyl 4-(2-cyanophenyl)-5-methylthiazole-2-carboxylate (5b), 63 mg, 77% yield. White solid, m.p. 100~101 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (dd, J＝7.8, 0.9 Hz, 1H), 7.64 (td, J＝7.7, 1.3 Hz, 1H), 7.57 (dd, J＝7.8, 0.9 Hz, 1H), 7.48 (td, J＝7.6, 1.3 Hz, 1H), 4.44 (q, J＝7.1 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J＝7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 159.9, 155.1, 150.7, 138.9, 137.6, 133.1, 132.8, 131.3, 129.0, 117.8, 113.0, 62.6, 14.3, 12.9; HRMS (EI) calcd for C₁₄H₁₂N₂O₂S: 272.0619, found 272.0620.

  A mixture of 4a (111.9 mg, 0.3 mmol), 3-chlorothio- phenol (56.2 mg, 0.39 mmol), CuI (1.4 mg, 0.0075 mmol), K₂CO₃ (45.6 mg, 0.33 mmol) and NMP (3 mL) was stirred in a sealed tube at 100 ℃ for 16 h. Upon completion of the reaction (as monitored by TLC), the mixture was transferred into saturated brine (20 mL), then extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous MgSO₄ and concentrated in vacuo to provide a crude product, which was purified via a column chromatography on silica gel (eluents: petroleum ether/ethyl acetate, V:V＝100:1) to supply the desired product 5-methyl-4-(2-(phenylthio)phenyl)thiazole (5c), 52 mg, 55% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 8.65 (s, 1H), 7.34 (dd, J＝5.9, 3.3 Hz, 1H), 7.29 (dd, J＝6.4, 2.9 Hz, 3H), 7.25~7.17 (m, 4H), 2.34 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.1, 149.3, 136.9, 135.4, 133.7, 133.5, 133.4 (2C), 131.3, 131.0, 130.4, 129.3 (2C), 129.1, 126.9, 12.1; HRMS (EI) calcd for C₁₆H₁₂³⁷ClNS₃: 319.0070, found 319.0072.

  
  
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• 

  Scheme 1  Previous related works and present work

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  Scheme 2  Diversification of the iodination products

  Reaction conditions: (a) 4a (111.9 mg, 0.30 mmol), 3-methoxylben-zoboric acid (59.3 mg, 0.39 mmol), I₂ (15.2 mg, 0.06 mmol), K₂CO₃ (82.9 mg, 0.60 mmol), PEG, 140 ℃, 24 h; (b) 4a (111.9 mg, 0.30 mmol), DDQ (68.1 mg, 0.30 mmol), Cu(OAc)₂ (60.0 mg, 0.30 mmol), Ag₂O (36.9 mg, 0.30 mmol), NMP, 120 ℃, 22 h; (c) 4a (111.9 mg, 0.30 mmol), 3-chlorothiophenol (56.2 mg, 0.39 mmol), CuI (1.4 mg, 2.5 mol%), K₂CO₃ (45.6 mg, 0.33 mmol), 100 ℃, 16 h; ^b Isolated yields

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  Scheme 3  Gram scale reaction

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  Scheme 4  Kinetic isotope effect study

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  Scheme 5  Radical inhibition experiment

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  Scheme 6  Plausible reaction mechanism

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  Table 1.  Screening of directing groups^{a, b}

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  Table 2.  Optimization of the reaction conditions^a

  Entry	Catalyst	NIS (equiv.)	Solvent	Yieldb/%
  1	None	2.0	DCE/HFIP (V:V＝4:1)	0
  2	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	76
  3	Pd(CH3CN)2Cl2	2.0	DCE/HFIP (V:V＝4:1)	64
  4	Pd(TFA)2	2.0	DCE/HFIP (V:V＝4:1)	57
  5	PdCl2	2.0	DCE/HFIP (V:V＝4:1)	38
  6	Pd(PPh3)2Cl2	2.0	DCE/HFIP (V:V＝4:1)	27
  7c	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	58
  8d	Pd(OAc)2	2.0	DCE/HFIP (V:V＝4:1)	75
  9	Pd(OAc)2	2.0	DCE	86
  10	Pd(OAc)2	2.0	HFIP	69
  11	Pd(OAc)2	2.0	DMF	85
  12	Pd(OAc)2	2.0	DCM	62
  13	Pd(OAc)2	2.0	TCM	21
  14	Pd(OAc)2	1.5	DCE	76
  15	Pd(OAc)2	2.5	DCE	93
  16	Pd(OAc)2	3.0	DCE	92
  17e	Pd(OAc)2	2.5	DCE	78
  18f	Pd(OAc)2	2.5	DCE	90
  a Reaction conditions: 1b (74.1 mg, 0.3 mmol), NIS, catalyst (10 mol%), solvent (3 mL, 0.1 mol·L－1), 100 ℃, 4 h; b NMR yield using CH2Br2 as the internal standard; c Pd(OAc)2 (5 mol%); d Pd(OAc)2 (15 mol%); e DCE (0.05 mol·L－1); f DCE (0.15 mol·L－1); NIS＝N-Iodosuccinimide; DCE＝1, 2-Dichloroethane; HFIP＝Hexafluoroisopropanol; DMF＝N, N-Dimethylfor- mamide; DCM＝Dichloromethane; TCM＝Trichloromethane; DMSO＝Dimethyl sulfoxide.

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  Table 3.  Scope of 4-phenylthiazols^{a, b}

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