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Cite This: J. Org. Chem. 2017, 82, 11865-11871

Hypervalent Iodine Mediated Chemoselective Iodination of Alkynes Yan Liu,*,† Daya Huang,† Ju Huang,† and Keiji Maruoka*,†,‡ †

School of Chemical Engineering and Light Industry, Guangdong University of Technology, No.100, West Waihuan Road, HEMC, Panyu District, Guangzhou 510006, China ‡ Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan S Supporting Information *

ABSTRACT: Reported herein are practical approaches for the chemoselective mono-, di-, and tri-iodination of alkynes based on efficient oxidative iodinations catalyzed by hypervalent iodine reagents. The reaction conditions were systematically optimized by altering the iodine source and/or the hypervalent iodine reagent system. The tetrabutylammonium iodide (TBAI)/ (diacetoxyiodo)benzene (PIDA) system is specific for monoiodination, while the KI/PIDA system results in di-iodination. Combining the TBAI/PIDA and KI/PIDA systems in one pot provided the corresponding tri-iodination products efficiently. These reaction conditions can be applied to the synthetically important iodination of aromatic and aliphatic alkynes, which was accomplished in good yield (up to 99%) and excellent chemoselectivity. These synthetic methods can also be applied to the efficient chemoselective synthesis of iodoalkyne derivatives, intermediates, and related biologically active compounds.

T

for the selective oxidative iodination of alkynes to afford 1iodoalkynes. Interestingly, the corresponding di-iodination products, i.e., the 1,2-diiodoalkenes, were observed when the potassium iodide (KI)/PIDA system was used. Both monoiodination and di-iodination products were obtained in high yields with high chemoselectivity when TBAI and KI were used as the iodine source, respectively. The tri-iodination of alkynes to furnish 1,1,2-triiodoalkenes also proceeded in good yield when the TBAI/PIDA and KI/PIDA systems were used sequentially in one pot. To investigate the oxidative iodination of alkynes mediated by PIDA, we initially studied the influence of the iodine source using p-tolylethyne as a model substrate. Under the reaction conditions specified in Table 1, 1-iodoalkyne 2a was obtained as the major product in 52% yield when TBAI was used as the iodine source. The molar ratio of 2a to 3a to 4a is 89.9:5.3:4.8 (Table 1, entry 1), indicating good selectivity toward 2a. However, when KI was used as the iodine source (entry 2), such a selectivity was not observed. Interestingly, using NH4I as

he oxidative iodination of alkynes offers an efficient and synthetically useful means of generating iodoalkyne derivatives, which exhibit desirable biological activities,1 and have hence found a variety of applications as synthetic key precursors and building blocks in organic synthesis.2 Although several methods have been reported for the iodination of alkynes using metal catalysts,3 anodic oxidation,4 hypervalent iodonium salts,5 ionic liquids,6 KI (or I2)/oxidant systems,7 phase-transfer catalysts (PTCs),8 ultrasound,9 an N-iodosuccinimide system,3b,8,10 Grignard reagents,11 a morpholinemediated system,7a,12 and n-BuLi,13 efficient and practical methods for the chemoselective mono-, di- or tri-iodination of alkynes remain scarce. In this context, we wish to report an efficient and practical approach for the mono-, di-, or triiodination of alkynes based on a highly chemoselective oxidative iodination method catalyzed by hypervalent iodine reagents. Hypervalent iodine compounds as oxidative functionalization reagents exhibit a variety of advantages relative to conventional oxidants such as heavy metals (Pb, Tl, or Hg)14 including low toxicity, ready availability, mild conditions, excellent selectivity, and a comparable reactivity. We have recently discovered that tetrabutylammonium iodide (TBAI) as a source of iodine in combination with (diacetoxyiodo)benzene (PIDA) works well © 2017 American Chemical Society

Special Issue: Hypervalent Iodine Reagents Received: June 23, 2017 Published: August 12, 2017 11865

DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

Note

The Journal of Organic Chemistry Table 1. Iodination of p-Tolylethyne with Hypervalent Iodine Reagents

entry

iodine source (equiv)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

TBAI (2.5) KI (2.5) NH4I (2.5) TBAI (1.2) TBAI (1.2) TBAI (1.2) TBAI (1.2) TBAI (1.2) TBAI (1.2) TBAI (1.2) TBAI (2.5) KI (2.5) NH4I (2.5) KI (2.5)

solvent MeOH MeOH MeOH MeOH CH3CN DCM Et2O THF toluene DMF CH3CN/H2O CH3CN/H2O CH3CN/H2O CH3CN/H2O

major product

% yield (2a:3a:4a) 52 25 34 64 99 82 99 99 93 96 34 72 76 99

2a 2a 3a 2a 2a 2a 2a 2a 2a 2a 2a 3a 3a 3a

(1:1) (1:1) (1:1) (1:3)

(89.9:5.3:4.8) (37.4:31.3:31.3) (10.5:52.6:36.9) (93.7:1.6:4.7) (100:0:0) (100:0:0) (100:0:0) (100:0:0) (93.1:4.1:2.8) (96.5:2.1:1.4) (69.8:23.2:7.0) (2.8:90.9:6.3) (1.7:87.0:11.3) (0.8:98.8:0.4)

ethynyltoluene (1.0 equiv), TBAI (1.2 equiv), and PIDA (1.0 equiv) were stirred at room temperature for 3 h, followed by adding an aqueous KI solution and PIDA. The results are summarized in Table 2.

the iodine source afforded 3a as the major product (entry 3). Encouraged by these promising results, we further investigated the selectivity in order to develop methods for the mono-, di-, or tri-iodination of alkynes by using hypervalent iodine reagents. Lowering the loading of TBAI from 2.5 equiv to 1.2 equiv resulted in an increased selectivity toward 2a (entry 4). The use of different solvents strongly influenced both the selectivity and the yield of 2a. CH3CN, DCM, Et2O, or THF afforded 2a in good to excellent yield with absolute selectivity (entries 5−8), toluene or DMF afforded similar yields albeit with slightly lower selectivity (entries 9 and 10). Interestingly, changing the solvent to a CH3CN/H2O mixture (1:1, v/v) enhanced the selectivity toward 3a (entries 11−13), and increasing the amount of water provided 3a almost exclusively (entry 14). Therefore, the optimal conditions for the synthesis of 2a or 3a were established as follows: (i) reaction of the alkyne (1.0 equiv) with TBAI (1.2 equiv) and PIDA (1.0 equiv) in CH3CN, Et2O, or THF at room temperature for 2−24 h affords 2a (method A); (ii) reaction of the alkyne (1.0 equiv) with KI (2.5 equiv) and PIDA (1.0 equiv) in MeCN/H2O (1:3, v/v) at room temperature for 2−24 h provides 3a (method B). Having established efficient and practical methods for the chemoselective mono- and di-iodination of alkynes, we became interested in developing a chemoselective method for the triiodination of alkynes. Tri-iodination product 4a can be regarded as a derivative of the corresponding di-iodination product if 2a would be used as a starting material. Therefore, we initially investigated the potential di-iodination of 2a using method B (Scheme 1). Indeed, the reaction proceeded smoothly within 24 h to afford 4a in 90% yield. Inspired by this result, we further studied the feasibility of a direct transformation of 1a into tri-iodination product 4a by combing methods A and B in a one-pot system. Typically, 4-

Table 2. One-Pot Iodination of p-Tolylethyne with Hypervalent Iodine Reagents

entry

t1 (h)

x

t2 (h)

t3 (h)

1 2 3 4

3 3 3 3

1.0 1.0 2.0 2.0

24 48 3 3

0 0 0 12

% yield of 4a (2a:3a:4a) 42 43 88 93

(56:2:42) (54:3:43) (9.1:2.5:88.4) (3.7:3.2:93.1)

Even though 1a was fully consumed under the applied reaction conditions, 4a was obtained in only 42% yield when 1.0 equiv of PIDA was added during the second step (method B), leaving 56% of 2a untransformed (Table 2, entry 1). Extending the reaction time from 24 to 48 h, however, did not increase the transformation (entry 2). In order to accelerate this transformation, we added 2.0 equiv of PIDA during the second step, which lead to the formation of 4a as the major product in 88% yield (entry 3). Prolonging the reaction time from 3 to 24 h under otherwise identical reaction conditions did not enhance the conversion. To our delight, 4a was obtained in 93% yield (entry 4) upon delivering an additional portion of KI/PIDA to the reaction system. The optimal conditions for the synthesis of 4a were thus established as method C: (i) the alkyne (1.0 equiv) was stirred for 3 h at room temperature in MeCN in the presence of TBAI (1.2 equiv) and PIDA (2.0 equiv); (ii) H2O, KI (2.5 equiv), and PIDA (2.0 equiv) were added and the mixture was stirred for 3 h; (iii) H2O, KI (2.5equiv), and PIDA (2.0 equiv) were added and the mixture was stirred for additional 12 h.

Scheme 1. Synthesis of 4a Using Method B

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DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

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and 8). The presence of ester and amide carbonyl moieties smoothly afforded the corresponding products (2 and 3) in good yield with high chemoselectivity (entries 17, 18, 20, and 21). In contrast, the yields of aliphatic alkynes with hydroxy groups were decreased. For example, the yields of the monoand di-iodination products of 3-butyn-1-ol were 79% and 77%, respectively (entries 23 and 24). Slightly decreased yields for both mono- and di-iodination products (86% and 84%, respectively) were observed when an aliphatic ester was used as a substrate. To our delight, however, the chemoselectivities for the mono- and di-iodination products of all substrates are very high. Inspired by these results, we became interested in the development of tri-iodination of the aforementioned various alkynes by utilizing one pot system as described in Table 2. Aromatic alkynes bearing electron-donating and electronwithdrawing groups smoothly furnished the corresponding tri-iodination products in good yield (90−97%) with high chemoselectivity (entries 3, 6, 11, and 16). Aromatic alkynes containing ester and amide moieties were also tolerated, and afforded the corresponding products in high yield and high selectivity (entries 19 and 22). An aliphatic alkyne with a hydroxy group furnished the tri-iodination product in 81% yield with good selectivity (entry 25), and an aliphatic alkyne with ester moieties was also very favorable (entry 28).15,16 The iodination of 1-phenyl-1-butyne, an internal alkyne, by utilizing method B afforded di-iodination product 3k in 87% yield (Scheme 2).

Equipped with these efficient methods for the chemoselective mono-, di-, and tri-iodination of p-tolylethyne catalyzed by hypervalent iodine reagents, we examined the generality and selectivity of the iodination of terminal alkynes (Table 3). Table 3. Selective Iodination of Terminal Alkynes with Hypervalent Iodine Reagents

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

alkyne 1 R = p-tolyl

R = Ph

R = m-tolyl R = p-MeOC6H4

R = p−F-C6H4 R = p-CF3−C6H4

R = pCH3OCOC6H4

R = m-AcNHC6H4

R = CH2CH2OH

R = CH2OAc

methoda

major product

A B C A B C A B A B C A B A B C A

2a 3a 4a 2b 3b 4b 2c 3c 2d 3d 4d 2e 3e 2f 3f 4f 2g

99 99 93 93 97 91 98 98 95 98 87 92 86 94 92 90 94

(100:0:0) (0.8:98.8:0.4) (3.7:3.2:93.1) (100:0:0) (0.2:97.6:2.2) (0.8:0.7:98.5) (100:0:0) (0.9:98.1:1.0) (100:0:0) (0.8:98.7:0.5) (6.2:6.4:87.4) (100:0:0) (0.6:96.9:2.5) (100:0:0) (0.3:98.3:1.4) (8.1:1.6:90.3) (100:0:0)

B C A B C A B C A B C

3g 4g 2h 3h 4h 2i 3i 4i 2j 3j 4j

94 91 99 96 94 79 77 81 86 84 97

(0:95.8:4.2) (3.4:1.4:95.2) (100:0:0) (0.5:96.5:3.0) (3.5:2.2:94.3) (99.8:0:0.2) (0:96.1:3.9) (11.1:0.3:88.6) (99.9:0.1:0) (0:98.8:1.2) (0:2.0:98.0)

% yield (2:3:4)

Scheme 2. Synthesis of 3k Using Method B

In conclusion, we have demonstrated a practical chemoselective approach for the mono-, di-, or tri-iodination of alkynes based on the efficient oxidative iodination catalyzed by hypervalent iodine reagents. Practically, the chemoselective iodination can be accomplished by a judicious choice of the iodine source. The TBAI/PIDA system is specific toward the monoiodination, while the KI/PIDA system is selective toward the di-iodination. Combining the TBAI/PIDA and KI/PIDA systems in one pot furnishes an efficient tri-iodination protocol. Our process is broad in scope, and both aromatic and aliphatic alkynes can be used. This synthetically important iodination affords good yields (up to 99%) and proceeds highly selective (up to 100%). These synthetic methods can thus be applied to the efficient chemoselective synthesis of iodoalkyne derivatives, intermediates, and related biologically active compounds.

a

Method A: Alkyne (1.0 equiv), TBAI (1.2 equiv), and PIDA (1.0 equiv) in MeCN, rt, 2−24 h. Method B: Alkyne (1.0 equiv), KI (2.5 equiv), and PIDA (1.0 equiv) in MeCN/H2O (1:3, v/v), rt, 2−24 h. Method C: (i) alkyne (1.0 equiv), TBAI (1.2 equiv), and PIDA(1.0 equiv) in MeCN, rt, 3 h; (ii) H2O, KI (2.5 equiv), and PIDA (2.0 equiv), 3h; (iii) H2O, KI (2.5 equiv), and PIDA (2.0 equiv), 12 h.

We initially focused on the mono- and di-iodination of various types of terminal alkynes that contain both aromatic and aliphatic groups. Various types of terminal alkynes are suitable for the highly chemoselective mono- and di-iodination using methods A and B, respectively. The iodination of aromatic alkynes, affording mono- or di-iodination products in good to high yield (86−99%), was not significantly affected by the substituents on the aromatic ring of the alkynes (entries 1, 2, 4, 5, 7−10, 12−15, 17, 18, 20, and 21). Both electrondonating and electron-withdrawing groups were tolerated under the applied reaction conditions (methods A or B). The reaction is moreover not noticeably affected by the position of the substituents on the aromatic ring of the alkyne (entries 7

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EXPERIMENTAL SECTION

General. 1H NMR and 13C{1H} NMR spectra were recorded on a Bruker AVANCE III 400 MHz spectrometer (400 MHz for 1H NMR, 100 MHz for 13C{1H} NMR, and 376 MHz for 19F NMR). Tetramethylsilane (TMS) was used as an internal standard (0 ppm) for the 1H NMR spectra, and CDCl3 or DMSO-d6 was used as the internal standard (77.0 and 39.5 ppm, respectively) for the 13C{1H} NMR spectra. High-performance liquid chromatography (HPLC) was performed on a Shimadzu 20A instrument using a GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm× 150 mm) column. High-resolution mass spectra (HRMS) were recorded on a Thermo MAT95XP, or on an Agilent 6540 UHD Accurate-Mass Q-TOF LC-MS spectrometer. 11867

DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

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The Journal of Organic Chemistry

mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.7 min. 2b: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (64 mg, 93%). 1H NMR (400 MHz, CDCl3): δ = 7.43−7.41 (m, 2H), 7.31−7.28 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 132.4, 128.8, 128.3, 123.4, 94.2, 6.2; the NMR data are consistent with previously reported values.17 HPLC analysis (2b): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 5.2 min. 3b: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (104 mg, 97%). 1H NMR (400 MHz, CDCl3): δ = 7.36−7.25 (m, 5H), 7.24 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 143.1, 129.0, 128.5, 128.4, 96.2, 80.8; the NMR data are consistent with previously reported values.7c HPLC analysis (3b): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 8.1 min. 4b: The crude product was purified via flash chromatography, eluting with hexanes to give a white powder (132 mg, 91%). 1H NMR (400 MHz, CDCl3): δ = 7.38−7.32 (m, 3H), 7.27−7.25 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3): δ = 147.7, 128.7, 128.6, 127.4, 112.4, 22.3; IR (KBr): 2922, 1481, 1438, 1193, 1154, 1069, 1026, 917, 859, 768, 723.5, 692, 606, 551 cm−1; HRMS (EI) calcd for C8H5I3: 481.7525 ([M]+); found: 481.7516; HPLC analysis (4b): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 8.8 min. 2c: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (71 mg, 98%). 1H NMR (400 MHz, CDCl3): δ = 7.25−7.11 (m, 4H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 138.0, 132.9, 129.8, 129.4, 128.2, 123.2, 94.4, 21.1, 5.6; the NMR data are consistent with previously reported values.10a HPLC analysis (2c): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/ min, λ = 254 nm, retention time: 6.8 min. 3c: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (109 mg, 98%). 1H NMR (400 MHz, CDCl3): δ = 7.26−7.22 (m, 2H), 7.16−7.12 (m, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 143.0, 138.2, 129.8, 129.1, 128.3, 125.6, 96.6, 80.6, 21.5; the NMR data are consistent with previously reported values.7b HPLC analysis (3c): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min−1, λ = 254 nm, retention time: 10.8 min. 2d: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (74 mg, 95%). 1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 159.9, 133.8, 115.6, 113.8, 93.9, 55.3, 3.7; the NMR data are consistent with previously reported values.18 HPLC analysis (2d): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 70/30, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 6.0 min. 3d: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (113 mg, 98%). 1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.8 Hz, 2H), 7.24 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 159.8, 135.3, 130.3, 113.7, 96.7, 79.9, 55.4; the NMR data are consistent with previously reported values.7b HPLC analysis (3d): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/ H2O = 70/30, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 10.3 min. 4d: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (134 mg, 87%). 1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 159.6, 140.2, 129.0, 113.9, 112.9, 55.4, 22.6; IR (KBr): 2963, 2926, 2833, 1599, 1571, 1545, 1500, 1459, 1435, 1407, 1293, 1255, 1171, 1106, 1028, 830, 782, 697, 645, 601, 537 cm−1; HRMS (EI) calcd for C9H7I3O: 511.7631 ([M]+); found: 511.7621; HPLC analysis (4d): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm),

Infrared (IR) spectra were obtained on a Thermo scientific Nicolet FT/IR-6700 spectrometer. Reactions were monitored by thin-layer chromatography (TLC). Reaction products were purified by column chromatography on silica gel. Chemical reagents were purchased from common commercial suppliers and used as received. General Procedures for the Iodination of Alkynes. Method A. PIDA (96.6 mg, 0.3 mmol) was added in portions over a period of 20 min to a mixture of the alkyne (0.3 mmol) and TBAI (133.0 mg, 0.36 mmol) in CH3CN (3 mL), and the reaction mixture was stirred at room temperature for 2−24 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated aqueous Na2S2O3, washed with brine, extracted with ethyl acetate, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure to afford the crude product, which was purified by column chromatography using hexane or hexane/ethyl acetate and analyzed by 1H and 13C NMR spectroscopy as well as HPLC. Method B. PIDA (96.6 mg, 0.3 mmol) was added in portions over a period of 20 min to a mixture of the alkyne (0.3 mmol) and KI (124.5 mg, 0.75 mmol) in CH3CN (1 mL) and H2O (3 mL), and the reaction mixture was stirred at room temperature for 2−24 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated aqueous Na2S2O3, washed with brine, extracted with ethyl acetate, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure to afford the crude product, which was purified by column chromatography using hexane or hexane/ethyl acetate and analyzed by 1H and 13 C NMR spectroscopy as well as HPLC. Method C. PIDA (96.6 mg, 0.3 mmol)was added in portions over a period of 20 min to a mixture of the alkyne (0.3 mmol) and TBAI (133.0 mg, 0.36 mmol) in CH3CN (1 mL). After stirring at room temperature for 3 h, H2O (3 mL) and KI (124.5 mg, 0.75 mmol) were added. More PIDA (193.2 mg, 0.6 mmol) was added in portions over a period of 20 min. After stirring for 3 h, H2O (3 mL), KI (124.5 mg, 0.75 mmol), CH3CN (1 mL), and PIDA (193.2 mg, 0.6 mmol) were added. The reaction mixture was stirred for another 12 h at room temperature. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated aqueous Na2S2O3, washed with brine, extracted with ethyl acetate, and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure to afford the crude product, which was purified by column chromatography using hexane or hexane/ethyl acetate and analyzed by 1H and 13C NMR spectroscopy as well as HPLC. 2a: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (73 mg, 99%). 1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 139.1, 132.2, 129.0, 120.4, 94.3, 21.6, 5.1; the NMR data are consistent with previously reported values.17 HPLC analysis (2a): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min−1, λ = 254 nm, retention time: 6.5 min. 3a: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (111 mg, 99%). 1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 140.2, 139.0, 129.0, 128.4, 96.6, 80.1, 21.4, the NMR data are consistent with previously reported values.7b HPLC analysis (3a): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/ H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 10.6 min. 4a: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (138 mg, 93%). 1H NMR (400 MHz, CDCl3): δ = 7.16 (s, 4H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 144.9, 138.9, 129.3, 127.4, 112.9, 22.2, 21.5. IR (KBr): 3019, 2916, 2853, 1906, 1604, 1544, 1498, 1401, 1173, 1111, 1019, 868, 817, 779, 725, 698, 597, 597, 509, 474 cm−1; HRMS (EI) calcd for C9H7I3: 495.7682 ([M]+); found: 495.7672; HPLC analysis (4a): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 11868

DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

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The Journal of Organic Chemistry

μm, 4.6 mm × 150 mm), CH3CN/H2O = 70/30, flow rate = 1.0 mL/ min, λ = 254 nm, retention time: 9.1 min. 4g: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a yellow powder (147 mg, 91%). Mp: 129−131 °C; 1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 166.3, 151.8, 130.2, 130.0, 127.5, 110.7, 52.3, 23.1; IR (KBr): 2950, 1708, 1605, 1563, 1496, 1435, 1401, 1303, 1278, 1191, 1175, 1116, 1018, 956, 853, 804, 771, 737, 697, 642, 585, 478 cm−1; HRMS (EI) calcd for C10H7I3O2: 539.7580 ([M]+); found: 539.7571; HPLC analysis (4g): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 70/30, flow rate = 1.0 mL/ min, λ = 254 nm, retention time: 10.3 min. 2h: The crude product was purified via flash chromatography, eluting with 10:1 hexanes/EtOAc to give a white powder (86 mg, 99%). Mp: 130−132 °C; 1H NMR (400 MHz, CDCl3): δ = 7.73, (s, 1H), 7.58 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 2.16 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.8, 137.9, 128.9, 128.2, 124.0, 123.6, 120.5, 93.7, 24.5, 7.0; IR (KBr): 3288, 3063, 1664, 1603, 1542, 1480, 1403, 1369, 1308, 1255, 1164, 1088, 985, 878, 802, 793, 711, 688, 612, 531 cm−1; HRMS (ESI-TOF) calcd for C10H8INO: 285.9729 ([M + H]+); found: 285.9726; HPLC analysis (2h): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 50/50, flow rate = 1.0 mL/ min, λ = 254 nm, retention time: 5.3 min. 3h: The crude product was purified via flash chromatography, eluting with 10:1 hexanes/EtOAc to give a light yellow powder (119 mg, 96%). Mp: 139−141 °C; 1H NMR (400 MHz, CDCl3): δ = 7.75, (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 2.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 168.7, 143.8, 138.0, 129.2, 124.3, 120.4, 119.6, 95.4, 81.3, 24.7; IR (KBr): 3261, 3189, 3061, 2919, 2848, 1664, 1582, 1547, 1471, 1421, 1365, 1307, 1288, 1257, 1205, 1167,1129, 1019, 945, 885, 773, 701, 682, 619, 538, 467 cm−1; HRMS (ESI-TOF) calcd for C10H9I2NO: 413.8852 ([M + H]+); found: 413.8842; HPLC analysis (3h): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 50/50, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 9.3 min. 4h: The crude product was purified via flash chromatography, eluting with 10:1 hexanes/EtOAc to give a yellow powder (152 mg, 94%). Decompose at ∼189 °C; 1H NMR (400 MHz, DMSO-d6): δ = 10.04 (s, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 2.05 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6): δ = 169.0, 148.9, 139.8, 129.4, 122.1, 119.0, 117.6, 113.3, 33.3, 24.6; IR (KBr): 3287, 2921, 1655, 1606, 1584, 1554, 1478, 1422, 1400, 1365, 1316, 1291, 1256, 1160, 1023, 884, 784, 743, 690, 636, 532, 514 cm−1; HRMS (ESI-TOF) calcd for C10H8I3NO: 539.7818 ([M + H]+); found: 539.7808; HPLC analysis (4h): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/ H2O = 50/50, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 12.7 min. 2i: The crude product was purified via flash chromatography, eluting with 20:1 hexanes/EtOAc to give a yellow oil (46 mg, 79%). 1 H NMR (400 MHz, CDCl3): δ = 3.73 (t, J = 6.4 Hz, 1H), 2.63 (t, J = 6.4 Hz, 1H), 2.38 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 91.3, 61.0, 25.0, 4.3; the NMR data are consistent with previously reported values.21 HPLC analysis (2i): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 40/60, flow rate = 1.0 mL/min, λ = 200 nm, retention time: 3.5 min. 3i: The crude product was purified via flash chromatography, eluting with 20:1 hexanes/EtOAc to give a light yellow oil (75 mg, 77%). 1H NMR (400 MHz, CDCl3): δ = 7.02 (s, 1H), 3.84 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H), 2.02 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 99.0, 82.2, 60.7, 47.5; the NMR data are consistent with previously reported values.7b HPLC analysis (3i): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 40/60, flow rate = 1.0 mL/min, λ = 200 nm, retention time: 8.2 min. 4i: The crude product was purified via flash chromatography, eluting with 20:1 hexanes/EtOAc to give a light yellow powder (109 mg, 81%). 1H NMR (400 MHz, DMSO-d6): δ = 4.8 (brs, 1H), 3.54 (t,

CH3CN/H2O = 70/30, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.6 min. 2e: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow oil (68 mg, 92%). 1H NMR (400 MHz, CDCl3): δ = 7.42−7.40 (m, 2H), 7.01 (t, J = 8.8 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3): δ = 162.7(d, J = 249 Hz), 134.3 (d, J = 8.4 Hz), 119.5 (d, J = 3.5 Hz), 115.7 (d, J = 22.1 Hz), 93.0, 5.9; the NMR data are consistent with previously reported values.19 HPLC analysis (2e): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/5, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 5.2 min. 3e: The crude product was purified via flash chromatography, eluting with hexanes to give a light yellow powder (97 mg, 86%). 1H NMR (400 MHz, CDCl3): δ = 7.36−7.33 (m, 2H), 7.26 (s, 1H), 7.06 (t, J = 8.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ = 162.5 (d, J = 248 Hz), 139.1 (d, J = 3.4 Hz), 130.6 (d, J = 8.5 Hz), 115.6 (d, J = 21.9 Hz), 94.9, 81.5; the NMR data are consistent with previously reported values.7b HPLC analysis (3e): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 8.1 min. 2f: The crude product was purified via flash chromatography, eluting with hexanes to give a white powder (84 mg, 94%). 1H NMR (400 MHz, CDCl3): δ = 7.58−7.52 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ = 132.6, 130.5 (q, J = 32.6 Hz), 127.1, 125.2 (q, J = 3.8 Hz), 123.8 (q, J = 270.6 Hz), 92.9, 10.2; 19F NMR (376 MHz, CDCl3): δ = 62.91; the NMR data are consistent with previously reported values.18 HPLC analysis (2f): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 7.3 min. 3f: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (117 mg, 92%). 1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ = 146.6, 130.8 (q, J = 32.6 Hz), 129.0, 125.6 (q, J = 3.7 Hz), 125.3 (q, J = 270.7 Hz), 93.7, 82.4; 19F NMR (376 MHz, CDCl3): δ = 62.76; the NMR data are consistent with previously reported values.7c HPLC analysis (3f): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 10.5 min. 4f: The crude product was purified via flash chromatography, eluting with hexanes to give a yellow powder (148 mg, 90%). Mp: 50− 52 °C; 1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 2H), 7.38(d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ = 151.0, 130.6 (q, J = 32.5 Hz), 127.9, 125.7 (q, J = 3.7 Hz), 123.8 (q, J = 270.7 Hz), 110.1, 23.6; 19F NMR (376 MHz, CDCl3): δ = 62.74; IR (KBr): 2923, 1613, 1403, 1325, 1183, 1170, 1134, 1106, 1068, 1018, 956, 872, 836, 777, 744, 717, 633, 607 cm−1; HRMS (EI) calcd for C9H4F3I3: 549.7399 ([M]+); found: 549.7399; HPLC analysis (4f): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 11.5 min. 2g: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a white powder (81 mg, 94%). 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 166.4, 132.2, 130.0, 129.4, 127.9, 93.4, 52.3, 10.6; the NMR data are consistent with previously reported values.20 HPLC analysis (2g): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 70/30, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 6.0 min. 3g: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a light yellow oil (117 mg, 94%). 1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 166.3, 147.4, 130.4, 129.8, 128.6, 94.4, 82.1, 52.3; IR (KBr): 3061, 2947, 1720, 1606, 1546, 1495, 1433, 1402, 1309, 1275, 1191, 1178, 1151, 1102, 1018, 964, 866, 844, 812, 768, 709, 597, 561 cm−1; HRMS (EI) calcd for C10H8I2O2: 413.8614 ([M]+); found: 413.8605; HPLC analysis (3g): GL Sciences Inc. InertSustain C18 (5 11869

DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

Note

The Journal of Organic Chemistry J = 6.8 Hz, 1H), 2.72 (t, J = 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6): δ = 115.5, 59.6, 53.3, 30.2; IR (KBr): 3202, 2945, 2919, 2867, 1548, 1454, 1427, 1409, 1365, 1240, 1185, 1057, 1010, 904, 847, 730, 587, 545, 426 cm−1; HRMS (EI) calcd for C4H5I3O: 449.7474 ([M]+); found: 449.7465; HPLC analysis (4i): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 40/60, flow rate = 1.0 mL/min, λ = 200 nm, retention time: 13.9 min. 2j: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a light yellow powder (58 mg, 86%). 1H NMR (400 MHz, CDCl3): δ = 4.81 (s, 2H), 2.1(s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ = 170.0, 88.0, 53.4, 20.7, 4.3; the NMR data are consistent with previously reported values.21 HPLC analysis (2j): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 50/50, flow rate = 1.0 mL/min, λ = 210 nm, retention time: 3.7 min. 3j: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a light yellow oil (89 mg, 84%). 1H NMR (400 MHz, CDCl3): δ = 7.20 (s, 1H), 4.78 (s, 2H), 2.16 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ = 170.0, 96.0, 83.2, 71.1, 20.9; the NMR data are consistent with previously reported values.22 HPLC analysis (3j): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 50/50, flow rate = 1.0 mL/ min, λ = 210 nm, retention time: 6.8 min. 4j: The crude product was purified via flash chromatography, eluting with 50:1 hexanes/EtOAc to give a light yellow oil (139 mg, 97%). 1H NMR (400 MHz, CDCl3): δ = 4.76 (s, 2H), 2.16 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ = 169.9, 112.6, 74.7, 35.7, 21.3; IR (KBr): 2933, 1738, 1424, 1373, 1214, 1063, 1031, 964, 908, 745, 603 cm−1; HRMS (EI) calcd for C5H5I3O2: 350.8379 ([M-I]+); found: 350.8376; HPLC analysis (4j): GL Sciences Inc. InertSustain C18 (5 μm, 4.6 mm × 150 mm), CH3CN/H2O = 50/50, flow rate = 1.0 mL/ min, λ = 210 nm, retention time: 8.6 min. 3k: The crude product was purified via flash chromatography, eluting with hexanes to give a light yellow oil (100 mg, 87%). 1H NMR (400 MHz, CDCl3): δ = 7.35−7.31 (m, 2H), 7.28−7.25 (m, 1H), 7.20 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 2.87 (q, J = 7.2 Hz, 2 H), 1.17 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3): δ = 148.1, 128.5, 128.4, 128.2, 106.6, 93.8, 44.9, 13.0; the NMR data are consistent with previously reported values.7b

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(c) Butini, S.; Gemma, S.; Brindisi, M.; Borrelli, G.; Lossani, A.; Ponte, A. M.; Torti, A.; Maga, G.; Marinelli, L.; La Pietra, V.; Fiorini, I.; Lamponi, S.; Campiani, G.; Zisterer, D. M.; Nathwani, S. M.; Sartini, S.; La Motta, C.; Da Settimo, F.; Novellino, E.; Focher, F. J. Med. Chem. 2011, 54, 1401−1420. (d) Kabalka, G. W.; Shoup, T. M.; Daniel, G. B.; Goodman, M. M. Nucl. Med. Biol. 2000, 27, 279−287. (2) For selected examples, see: (a) Sun, G. D.; Wei, M. J.; Luo, Z. H.; Liu, Y. J.; Chen, Z. J.; Wang, Z. Q. Org. Process Res. Dev. 2016, 20, 2074−2079. (b) Wang, D.; Chen, S.; Chen, B. H. Tetrahedron Lett. 2014, 55, 7026−7028. (c) Chen, Z. W.; Zeng, W.; Jiang, H. F.; Liu, L. X. Org. Lett. 2012, 14, 5385−5387. (d) Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320−5327. (3) For selected examples, see: (a) Lei, C. H.; Jin, X. J.; Zhou, J. R. ACS Catal. 2016, 6, 1635−1639. (b) Chen, W. W.; Zhang, J. L.; Wang, B.; Zhao, Z. X.; Wang, X. Y.; Hu, Y. F. J. Org. Chem. 2015, 80, 2413− 2417. (c) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77, 6443−6455. (d) Abe, H.; Suzuki, H. Bull. Chem. Soc. Jpn. 1999, 72, 787−798. (4) Nishiguchi, I.; Kanbe, O.; Itoh, K.; Maekawa, H. Synlett 2000, 89−91. (5) For selected examples, see: (a) Yan, J.; Li, J.; Cheng, D. Synlett 2007, 2007, 2442−2444. (b) Ochiai, M.; Uemura, K.; Masaki, Y. J. Am. Chem. Soc. 1993, 115, 2528−2529. (6) Nouzarian, M.; Hosseinzadeh, R.; Golchoubian, H. Synth. Commun. 2013, 43, 2913−2925. (7) For selected examples, see: (a) Mader, S.; Molinari, L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Chem. - Eur. J. 2015, 21, 3910− 3913. (b) Jiang, Q.; Wang, J. Y.; Guo, C. C. Synthesis 2015, 47, 2081− 2087. (c) Madabhushi, S.; Jillella, R.; Mallu, K. K. R.; Godala, K. R.; Vangipuram, V. S. Tetrahedron Lett. 2013, 54, 3993−3996. (d) Reddy, K. R.; Venkateshwar, M.; Maheswari, C. U.; Kumar, P. S. Tetrahedron Lett. 2010, 51, 2170−2173. (8) Naskar, D.; Roy, S. J. Org. Chem. 1999, 64, 6896−6897. (9) Stefani, H. A.; Cella, R.; Dorr, F. A.; de Pereira, C. M. P.; Gomes, F. P.; Zeni, G. Tetrahedron Lett. 2005, 46, 2001−2003. (10) For selected examples, see: (a) Gómez-Herrera, A.; Nahra, F.; Brill, M.; Nolan, S. P.; Cazin, C. S. J. ChemCatChem 2016, 8, 3381− 3388. (b) Wang, B.; Zhang, J. L.; Wang, X. Y.; Liu, N.; Chen, W. W.; Hu, Y. F. J. Org. Chem. 2013, 78, 10519−10523. (c) Li, M.; Li, Y.; Zhao, B.; Liang, F.; Jin, L. RSC Adv. 2014, 4, 30046−30049. (11) Rao, M. L. N.; Periasamy, M. Synth. Commun. 1995, 25, 2295− 2299. (12) For selected examples, see: (a) Zeiler, A.; Ziegler, M. J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Adv. Synth. Catal. 2015, 357, 1507−1514. (b) Dumele, O.; Wu, D. N.; Trapp, N.; Goroff, N.; Diederich, F. Org. Lett. 2014, 16, 4722−4725. (c) Hashmi, A. S. K.; Dopp, R.; Lothschutz, C.; Rudolph, M.; Riedel, D.; Rominger, F. Adv. Synth. Catal. 2010, 352, 1307−1314. (13) For selected examples, see: (a) Pérez, J. M.; Crosbie, P.; Lal, S.; Díez-González, S. ChemCatChem 2016, 8, 2222−2226. (b) Wilkins, L. C.; Lawson, J. R.; Wieneke, P.; Rominger, F.; Hashmi, A. S. K.; Hansmann, M. M.; Melen, R. L. Chem. - Eur. J. 2016, 22, 14618− 14624. (c) Usanov, D. L.; Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 1286−1289. (d) Luithle, J. E. A.; Pietruszka, J. Eur. J. Org. Chem. 2000, 2000, 2557−2562. (e) Blackmore, I. J.; Boa, A. N.; Murray, E. J.; Dennis, M.; Woodward, S. Tetrahedron Lett. 1999, 40, 6671−6672. (f) Lee, G. C. M.; Tobias, B.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E. J. Am. Chem. Soc. 1990, 112, 9330−9336. (14) For selected examples, see: (a) Wang, X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712−1724. (b) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328−3435. (d) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650−682. (e) Zhdankin, V. V.; Protasiewicz, J. D. Coord. Chem. Rev. 2014, 275, 54−62. (f) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123−1178. (c) Kohlhepp, S. V.; Gulder, T. Chem. Soc. Rev. 2016, 45 (22), 6270−6288. (15) In method A, the reaction of alkynes with PhI(OAc)2 forms an intermediate A, which can transform into an intermediate B. Intermediate B undergoes a rapid elimination of iodobenzene, affording monoiodination products. In method B, oxidation of the

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01555. Copies of NMR and HPLC spectra for all compounds, and HRMS spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Yan Liu: 0000-0002-3864-1992 Keiji Maruoka: 0000-0002-0044-6411 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Part of this work was supported by the NSFC (21502023). REFERENCES

(1) For selected examples, see: (a) Heravi, M. M.; Asadi, S.; Nazari, N.; Lashkariani, B. M. Curr. Org. Chem. 2015, 19, 2196−2219. (b) Vaidyanathan, G.; McDougald, D.; Koumarianou, E.; Choi, J.; Hens, M.; Zalutsky, M. R. Nucl. Med. Biol. 2015, 42, 673−684. 11870

DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871

Note

The Journal of Organic Chemistry iodide ion (KI) by PhI(OAc)2 generates molecular iodine. The formation of I2 has been confirmed by observation of a color change from dark purple to deep-blue when starch was added into the reaction solution. Finally, the molecular iodine undergoes electrophilic antiaddition onto the alkyne to give the corresponding (E)-1,2diiodoakene. The transformation of terminal alkynes into triiodination products were obtained by combing methods A and B in a one-pot system (method C). In brief, the reaction of alkynes with TBAI/PIDA system forms monoiodination products, which react with KI/PIDA system affording tri-iodination products. The plausible reaction pathways are proposed in the Supporting Information. (16) We conducted the iodination on a gram-scale by using ptolylethyne as a model substrate. When 1.2 g (10.3 mmol) ptolylethyne was conducted for iodination, monoiodination product 2a was obtained in 94% yield (2a:3a:4a = 100:0:0). Di-iodination product 3a was obtained in 92% yield (2a:3a:4a = 0.3:97.3:2.4) (17) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018−8021. (18) Starkov, P.; Rota, F.; D’Oyley, J. M.; Sheppard, T. D. Adv. Synth. Catal. 2012, 354, 3217−3224. (19) Lal, S.; Rzepa, H. S.; Díez-González, S. ACS Catal. 2014, 4, 2274−2287. (20) Lehnherr, D.; Alzola, J. M.; Lobkovsky, E. B.; Dichtel, W. R. Chem. - Eur. J. 2015, 21, 18122−18127. (21) Chen, S. N.; Hung, T. T.; Lin, T. C.; Tsai, F. Y. J. Chin. Chem. Soc. 2009, 56, 1078−1081. (22) Hollins, R. A.; Campos, M. P. A. J. Org. Chem. 1979, 44, 3931− 3934.

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DOI: 10.1021/acs.joc.7b01555 J. Org. Chem. 2017, 82, 11865−11871