Hypervalent Iodine Mediated Chemoselective Iodination of Alkynes

Article abstract of DOI:10.1021/acs.joc.7b01555

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

Full text of DOI:10.1021/acs.joc.7b01555

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Hypervalent Iodine Mediated Chemoselective Iodination of Alkynes
Yan Liu, Daya Huang, Ju Huang, and Keiji Maruoka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01555 • Publication Date (Web): 12 Aug 2017
Downloaded from http://pubs.acs.org on August 12, 2017
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Hypervalent Iodine Mediated Chemoselective Iodination of Alkynes
Yan Liu,*[a] Daya Huang,[a] Ju Huang,[a] Keiji Maruoka*[a,b]
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[a] School of Chemical Engineering and Light Industry, Guangdong University of Technology,
No.100, West Waihuan Road, HEMC, Panyu District, Guangzhou, 510006, China. E-mail:
yanliu@gdut.edu.cn
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[b] Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto
606-8502, Japan. E-mail: maruoka@kuchem.kyoto-u.ac.jp
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 mono-iodination, 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.
The 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 e.g. 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
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reagents,11 a morpholine-mediated 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 tri-iodination of alkynes based on a highly chemoselective oxidative iodination
method catalyzed by hypervalent iodine reagents.
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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 for the selective oxidative iodination of
alkynes to afford 1-iodoalkynes. Interestingly, the corresponding di-iodination
products, i.e. the 1,2-diiodoalkenes, were observed when the potassium iodide
(KI)/PIDA system was used. Both mono-iodination 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 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
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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).
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Table 1. Iodination of p-Tolylethyne with Hypervalent Iodine Reagents.
iodine source
(equiv)
major
product
% yield
(2a:3a:4a)
entry
solvent
1
2
TBAI (2.5)
KI (2.5)
MeOH
MeOH
MeOH
2a
2a
3a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
52 (89.9 : 5.3 : 4.8)
25 (37.4 : 31.3 : 31.3)
34 (10.5 : 52.6 : 36.9)
64 (93.7 : 1.6 : 4.7)
99 (100 : 0 : 0)
3
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)
4
MeOH
5
CH3CN
DCM
6
82 (100 : 0 : 0)
7
Et2O
99 (100 : 0 : 0)
8
THF
Toluene
99 (100 : 0 : 0)
9
93 (93.1 : 4.1: 2.8)
96 (96.5 : 2.1: 1.4)
34 (69.8 : 23.2 : 7.0)
72 ( 2.8 : 90.9 : 6.3)
76 (1.7 : 87.0 : 11.3)
99 (0.8 : 98.8 : 0.4)
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14
DMF
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:3)
NH4I (2.5)
KI (2.5)
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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 tri-iodination 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.
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Scheme 1. Synthesis of 4a using method B.
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-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.
Table 2. One-pot Iodination of p-Tolylethyne with Hypervalent Iodine Reagents.
% yield of 4a
(2a:3a:4a)
entry
t1 (h)
x
t2 (h)
t3 (h)
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2
3
4
3
3
3
3
1.0
1.0
2.0
2.0
24
48
3
0
0
42 (56 : 2 : 42)
43 (54 : 3 : 43)
88 (9.1 : 2.5 : 88.4)
93 (3.7 : 3.2 : 93.1)
0
12
3
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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 h 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 h 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.
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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).
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 electron-donating 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 and 8). The presence of ester and amide carbonyl
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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 mono-
and 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.
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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 electron-withdrawing 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).
Table 3. Selective Iodination of Terminal Alkynes with Hypervalent Iodine Reagents.
major
product
entry
Alkyne 1
methoda
% yield (2:3:4)
1
2
3
4
5
6
7
R = p-Tolyl
A
B
C
A
B
C
A
2a
3a
4a
2b
3b
4b
2c
99 (100 : 0 : 0 )
99 (0.8 : 98.8 : 0.4)
93 (3.7 : 3.2 : 93.1)
93 (100 : 0 : 0 )
R = Ph
97 (0.2 : 97.6 : 2.2)
91 (0.8 : 0.7 : 98.5)
98 (100 : 0 : 0 )
R = m-Tolyl
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B
A
B
C
A
B
A
B
C
A
3c
2d
3d
4d
2e
3e
2f
98 (0.9 : 98.1 : 1.0)
95 (100 : 0 : 0 )
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R = p-MeOC6H4
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98 (0.8 : 98.7 : 0.5)
87 (6.2 : 6.4 : 87.4 )
92 (100 : 0 : 0 )
R = p-F-C6H4
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86 (0.6 : 96.9 : 2.5)
94 (100 : 0 : 0 )
R = p-CF3-C6H4
3f
92 (0.3 : 98.3 : 1.4)
90 (8.1 : 1.6 : 90.3)
4f
2g
R =
17
94 (100 : 0 : 0 )
p-CH3OCOC6H4
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20
21
22
23
24
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28
B
C
A
B
C
A
B
C
A
B
C
3g
4g
2h
3h
4h
2i
94 (0 : 95.8 : 4.2)
91 (3.4 : 1.4 : 95.2)
99 (100 : 0 : 0 )
R = m-AcNHC6H4
R = CH2CH2OH
R = CH2OAc
96 (0.5 : 96.5 : 3.0)
94 (3.5 : 2.2 : 94.3)
79 (99.8 : 0 : 0.2)
77 (0 : 96.1 : 3.9)
81 (11.1 : 0.3 : 88.6)
86 ( 99.9 : 0.1 : 0 )
84 (0 : 98.8 : 1.2 )
97 ( 0 : 2.0 : 98.0 )
3i
4i
2j
3j
4j
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.
The iodination of 1-phenyl-1-butyne, an internal alkyne, by utilizing Method B
afforded di-iodination product 3k in 87% yield (Scheme 2).
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
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can be accomplished by a judicious choice of the iodine source. The TBAI/PIDA
system is specific toward the mono-iodination, 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.
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EXPERIMENTAL SECTION
1
13
General: H NMR and C{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
1
ppm) for the H 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.
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
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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
1
chromatography using hexane or hexane/ethyl acetate and analyzed by H and 13C
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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
13C 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
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using hexane or hexane/ethyl acetate and analyzed by H and CNMR 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,
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2H), 7.11 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H); C{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.15 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.
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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,
13
2H), 7.21 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H); C{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
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give a yellow powder (138 mg, 93%). H 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 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.15 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
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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,
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3H), 7.27-7.25 (m, 2H); 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.16 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.
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3d: The crude product was purified via flash chromatography, eluting with hexanes to
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give a yellow powder (113 mg, 98%). H NMR (400 MHz, CDCl3): δ = 7.34 (d, J =
7
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.
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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), 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); 13C{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.17 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),
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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
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give a white powder (84 mg, 94%). H 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.16
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
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give a yellow powder (117 mg, 92%). H 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 =
19
270.7 Hz), 93.7, 82.4; F 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 ºC; 1H NMR (400 MHz, CDCl3):
13
δ = 7.63 (d, J = 8.0 Hz, 2H), 7.38(d, J = 8.0 Hz, 2H); C{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 =
19
270.7 Hz), 110.1, 23.6; F 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.18 HPLC analysis (2g): GL Sciences Inc.
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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.
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3g: The crude product was purified via flash chromatography, eluting with 50:1
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hexanes/EtOAc to give a light yellow oil (117 mg, 94%). H NMR (400 MHz,
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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 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
1
hexanes/EtOAc to give a yellow powder (147 mg, 91%). Mp: 129–131 ºC; H 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
1
hexanes/EtOAc to give a white powder (86 mg, 99%). Mp: 130–132 ºC; H 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
13
= 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 2.16 (s, 3H); C{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.
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3h: The crude product was purified via flash chromatography, eluting with 10:1
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hexanes/EtOAc to give a light yellow powder (119 mg, 96%). Mp: 139–141 ºC; H
7
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.
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4h: The crude product was purified via flash chromatography, eluting with 10:1
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hexanes/EtOAc to give a yellow powder (152 mg, 94%). Decompose at ~189 ºC; H
NMR (400 MHz, DMSO-d6): δ = 10.04 (s, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H),
13
7.30 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 2.05 (s, 3H); C{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
1
hexanes/EtOAc to give a yellow oil (46 mg, 79%). 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.19 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):
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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.
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4i: The crude product was purified via flash chromatography, eluting with 20:1
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hexanes/EtOAc to give a light yellow powder (109 mg, 81%). H NMR (400 MHz,
DMSO-d6): δ = 4.8 (brs, 1H), 3.54 (t, 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
1
hexanes/EtOAc to give a light yellow powder (58 mg, 86%). H NMR (400 MHz,
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CDCl3): δ = 4.81 (s, 2H), 2.1(s, 3H); 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.19
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):
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δ = 7.20 (s, 1H), 4.78 (s, 2H), 2.16 (s, 3H); C{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.20 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
1
hexanes/EtOAc to give a light yellow oil (139 mg, 97%). H NMR (400 MHz,
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CDCl3): δ = 4.76 (s, 2H), 2.16 (s, 3H); 13C{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, 603cm-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.
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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
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website
Copies of NMR and HPLC spectra for all compounds, and HRMS spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: yanliu@gdut.edu.cn
*E-mail: maruoka@kuchem.kyoto-u.ac.jp
ORCID
Yan Liu: 0000-0003-1626-1363
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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Part of this work was supported by the NSFC (21502023).
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(21) 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 mono-iodination products. In Method B,
oxidation of the 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 anti-addition onto the alkyne to
give the corresponding (E)-1,2-diiodoakene. The transformation of terminal
alkynes into tri-iodination 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 mono-iodination products, which react with
KI/PIDA system affording tri-iodination products. The plausible reaction
pathways are proposed in the Supporting Information.
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(22)
We conducted the iodination on a gram-scale by using p-tolylethyne as a
model substrate. When 1.2 g (10.3 mmol) p-tolylethyne was conducted for
iodination, mono-iodination 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)
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TOC
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