Silver(I)-catalyzed iodination of arenes: Tuning the lewis acidity of N-iodosuccinimide activation

Article abstract of DOI:10.1021/acs.joc.5b02761

A mild and rapid method for the iodination of arenes that utilizes silver(I) triflimide as a catalyst for activation of N-iodosuccinimide has been developed. The transformation was found to be general for a wide range of anisole, aniline, acetanilide, and phenol derivatives and allowed the late-stage iodination of biologically active compounds such as PIMBA, a SPECT imaging agent of breast cancer, and (a?)-IBZM, a dopamine D₂ receptor antagonist. The method was also modified for the radioiodination of arenes using a one-pot procedure involving the in situ generation of [¹²⁵I]-N-iodosuccinimide followed by the silver(I)-catalyzed iodination.

Full text of DOI:10.1021/acs.joc.5b02761

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Featured Article
Silver(I)-Catalyzed Iodination of Arenes: Tuning
the Lewis Acidity of N-Iodosuccinimide Activation
Daugirdas T. Racys, Salaheddin A. I. Sharif, Sally L. Pimlott, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02761 • Publication Date (Web): 21 Jan 2016
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The Journal of Organic Chemistry
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Silver(I)ꢀCatalyzed Iodination of Arenes: Tuning the
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Lewis Acidity of NꢀIodosuccinimide Activation
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Daugirdas T. Racys,† Salaheddin A. I. Sharif,† Sally L. Pimlott‡ and Andrew Sutherland*†
†WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12
8QQ, United Kingdom.
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‡West of Scotland PET Centre, Greater Glasgow and Clyde NHS Trust, Glasgow G12 0YN, United
Kingdom.
Andrew.Sutherland@glasgow.ac.uk
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Abstract: A mild and rapid method for the iodination of arenes that utilizes silver(I) triflimide as a
catalyst for activation of Nꢀiodosuccinimide has been developed. The transformation was found to be
general for a wide range of anisole, aniline, acetanilide and phenol derivatives and allowed the lateꢀ
stage iodination of biologically active compounds such as PIMBA, a SPECT imaging agent of breast
cancer and (–)ꢀIBZM, a dopamine D2 receptor antagonist. The method was also modified for the
radioiodination of arenes using a oneꢀpot procedure involving the in situ generation of [125I]ꢀNꢀ
iodosuccinimide followed by the silver(I)ꢀcatalyzed iodination.
Keywords: Iodination, silver catalysis, Nꢀiodosuccinimide, SPECT imaging agents.
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The Journal of Organic Chemistry
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INTRODUCTION
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Aryl iodides are highly important building blocks widely used in total synthesis, medicinal chemistry
and material science. This general versatility is due to the higher reactivity of the CꢀI bond compared to
the corresponding aryl bromide or chloride, allowing their use in highly effective metalꢀcatalyzed crossꢀ
coupling reactions, nucleophilic aromatic substitution reactions and for the generation of freeꢀradical
intermediates.1–3 Aryl iodides are also found as components in a number of medicinally important
compounds such as 8ꢀiodoharmaline (1), a potent monoamine oxidase inhibitor,4 and 1ꢀ(2,5ꢀdimethoxyꢀ
4ꢀiodophenyl)ꢀ2ꢀaminopropane (DOI) (2), a 5ꢀHT2A receptor agonist and inhibitor of tumor necrosis
factorꢀαꢀinduced inflammation (Figure 1).5 When used in combination with single photon emission
computed tomography (SPECT) imaging, radioiodinated aryl compounds also have significant impact
on healthcare, finding application in clinical diagnosis, drug development and biomedical research.6 For
example, [123I]ꢀPIMBA (3)7 and (–)ꢀ[123I]ꢀIBZM (4)8 are SPECT imaging agents of human breast cancer
and the human D2 receptor, respectively, while the iodinated benzoxazole, [125I]ꢀIBOX (5) has been
used to image amyloid plaques in the brain (Figure 1).9
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Figure 1. Structures of aryl iodideꢀcontaining inhibitors and SPECT imaging agents.
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Due to the importance of aryl iodides, there has been much focus on the development of general
methods for their synthesis that overcome the harsh reagents and conditions associated with more
traditional approaches such as electrophilic aromatic substitution with iodine and the Sandmeyer
reaction.10,11 A recent advance has been the discovery of copper or nickel catalyzed Finkelstein reaction
of aryl bromides (Scheme 1a).12–14 Other iodide exchange reactions using leaving groups such as
triflates and boronic acids have also been reported.15,16 More direct methods that negate the need for
installation of a leaving group and which can be performed at lower temperatures have also been
developed.17,18 A common approach is the activation of electrophilic iodineꢀcontaining reagents such as
Nꢀiodosuccinimide (NIS).19 For example, Olah and coꢀworkers used a combination of boron trifluoride
and water for the Brønsted acid activation of NIS and the iodination of electronꢀdeficient arenes,20 while
the groups of Romo and Frontier used indium(III)ꢀ and gold(I)ꢀcomplexes, respectively, for the Lewis
acid activation of NIS and the iodination of electronꢀrich arenes (Scheme 1b).21
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We have a longstanding interest in rapid and efficient methods for the iodination and radioiodination
of arenes that can facilitate the development of novel SPECT imaging agents.22 To this end, we recently
reported an iron(III)ꢀcatalyzed method for NIS activation and the subsequent iodination of activated
arenes (Scheme 1b).23 While this method could be accelerated using a triflimide based ionic liquid,
leading to faster reactions at lower temperatures compared to other metalꢀcatalyzed methods, some
limitations were observed. In particular, we found that reaction of particularly active substrates such as
phenols with the highly charged, hard iron(III) Lewis acid led to the formation of bisꢀiodinated
products, thereby restricting the yield of the major monoꢀiodinated compounds. As SPECT imaging
agents often contain electron rich aryl moieties including phenols (see Figure 1), we decided to
investigate softer metals that would tune the activation of NIS leading to cleaner reactions of highly
activated aryl compounds. Herein, we report the development of a silver(I) triflimide catalyzed
iodination method that can be used for a wide range of substrates. As well as demonstrating the
application of this procedure for the iodination of medicinally important compounds, it is also shown
that this reaction can be modified for the radioiodination of activated arenes.
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The Journal of Organic Chemistry
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Scheme 1. Metal-Catalyzed Methods for Iodination of Arenes
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RESULTS AND DISCUSSION
Having previously shown that iron(III) was highly effective for activation of NIS (Table 1, entry 2),23
initial studies focused on screening softer, less charged Lewis acids that could result in cleaner
iodination reactions. Both copper(I) chloride and iron(II) chloride showed little activity for the
iodination of anisole (6a) (entries 3 and 4), and while a palladium(II) complex eventually gave good
conversion, the rate of the reaction was relatively slow (entry 5). A similarly slow reaction but good
overall conversion was observed when using silver(I) hexafluoroantimonate (entry 6). Interestingly, the
use of this silver(I) salt showed very clean conversion and so other more active silver(I) salts were
investigated. In our previous studies, we found that the Lewis acidic nature of a metal could be
enhanced by forming the triflimide salt.23 The combination of the highly delocalized nature of the
triflimide anion and its steric hindrance results in significant positive charge density on the metal cation
leading to powerful Lewis acidic character.24 Using this reasoning, silver(I) triflimide was next
attempted and this showed complete conversion after 1.5 h (entry 7). Further investigation revealed an
optimal catalyst loading of 7.5 mol % that gave after 1.5 h, an 86% isolated yield of iodoanisole as a
93:7 mixture of pꢀ and oꢀisomers, respectively.
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Table 1.
Activity Screen of Metal Catalysts for Iodination of Anisole (6a)a,b
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entry
catalyst
ꢀꢀꢀ
conversion at 1.5 h (%) conversion at 21 h (%)
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<2
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FeCl3
CuCl
FeCl2
Pd(MeCN)2Cl2
AgSbF6
AgNTf2
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100
aConversions were measured using H NMR spectroscopy. For all reactions, a ratio of >9:1 was
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observed in favor of the paraꢀisomer.
To further evaluate the suitability of silver(I) triflimide as a catalyst for NISꢀmediated arene iodination
reactions, the relative rate of reaction of anisole (6a) was compared with other metalꢀbased Lewis acids
known to perform this transformation (Figure 2).21,23 At 36 °C and using a catalyst loading of 7.5 mol
%, silver(I) triflimide was found to be significantly faster than both indium(III) triflate and the gold(I)
triflimide complex. For comparison, data using iron(III) chloride under the optimized conditions of 5
mol % catalyst loading and a reaction temperature of 20 °C is also presented in figure 2. Although the
optimized conditions for the silver(I) triflimide procedure requires a slightly higher catalyst loading and
reaction temperature, the relative rate of reaction with the softer Lewis acid compares favorably to the
iron(III) chloride method.
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The Journal of Organic Chemistry
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Figure 2. Iodination of anisole (6a) with various Lewis acids.
The scope of iodination using silver(I) triflimide was then explored using a range of anisole, aniline,
and acetanilide derivatives (Scheme 2). For all substrates investigated, the silver(I)ꢀcatalyzed iodination
was found to be compatible with a wide range of functional groups, generating the products cleanly and
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efficiently.25 Analysis of crude reaction mixtures by H NMR spectroscopy showed the presence in all
cases of only a single monoiodinated regioisomer. Substrates such as 7h–7k with strongly deactivating
groups also showed high reactivity giving the products in nearly quantitative yields after only a few
hours reaction time. The ability to use this procedure for multiꢀgram synthesis of iodinated arenes was
investigated using 4ꢀnitroaniline 6j. It was found that on scaleꢀup, the catalyst loading of the silver(I)
triflimide could be lowered to 2 mol %. This lower catalyst loading in combination with the standard
reaction conditions (40 °C, 1.5 h) gave 7j on a gram scale, in 90% yield. Further exploration of the
scope of this procedure with other activated substrates such as methoxynaphthalenes 6n and 6o, 2,3ꢀ
dihydrobenzofuran (6p) and pyrrole 6q similarly gave iodinated products 7n–7q in high yields.
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Scheme 2. Scope of Silver(I) Triflimide Catalyzed Iodination
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aGram scale synthesis using a catalyst loading of 2 mol % gave 7j in 90% yield.
The ability of the silver(I) triflimide procedure for iodination of highly activated phenol substrates was
next investigated (Scheme 3). For the majority of compounds it was found that initial cooling of the
reaction mixture in combination with the soft silver(I) Lewis acid led to the suppression of overꢀ
iodination and the rapid and efficient formation of the monoiodinated compounds.26 Again, inspection
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of the reaction mixtures by H NMR spectroscopy revealed the presence of only a single iodinated
regioisomer. It should be noted that even highly active diol 9c gave only a single product, 3ꢀ
iodoacetophenone 10c, in 74% yield.
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The Journal of Organic Chemistry
Scheme 3. Silver(I) Triflimide Catalyzed Iodination of Phenols
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The silver(I)ꢀcatalyzed method was then extended for the synthesis of medicinally important iodineꢀ
containing compounds (Scheme 4). PIMBA (3),7 the SPECT imaging agent of human breast cancer was
prepared in two steps from amide 11. As NIS is known to react with nucleophilic groups,21a,23 the amine
functionality of 11 was initially protected as the tetrafluoroborate salt. Iodination with silver(I) triflimide
then gave 3 in 94% yield over the two steps. In a similar fashion, (–)ꢀIBZM (4),8 the SPECT imaging
agent of the dopamine D2 receptor was prepared in 71% yield from 12. When iron(III) was used to
activate NIS for the synthesis of (–)ꢀIBZM (4) in our previous study, the procedure was complicated by
the formation of the bisꢀiodinated product, resulting in a 47% yield of 4.23 Here, the use of the softer
silver(I) catalyst circumvented this issue with a cleaner iodination reaction and a higher yield of the
target compound. The selective iodination of a bisꢀarylated compound, 13 was also examined. Reaction
of 13 with NIS and silver(I) triflimide was complete after 1 h at 20 ºC and gave iodinated compound 14
as a single product in 94% yield. In this case, only the paraꢀposition of the more activated aryl ring was
iodinated. The carboxylic acid of compound 14 is a nanomolar inhibitor of the kinase, MEK1 and a
metabolite of PD0325901, a compound active against malignant tumours.27
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Scheme 4. Iodination of Medicinally Relevant Compounds
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Having achieved the main objective of this research programme, the identification of a soft metal
based Lewis acid for the rapid, general and selective iodination of a range of arenes, the final goal was
the modification of this procedure for radioiodination. Radiolabeled iodide is produced in the form of
the sodium salt and it was proposed that this could be used as part of a oneꢀpot radioiodination process
by reaction with Nꢀchlorosuccinimide (NCS) to produce radiolabeled NIS,28,29 followed by the silver(I)
triflimide catalyzed reaction with arenes. In a preliminary study, it has been shown that a oneꢀpot
procedure can be used from NCS to give radioiodinated compounds in good radiochemical yields
(RCY) (Scheme 5).30 Due to the high sensitivity of SPECT, [123I]ꢀ and [125I]ꢀimaging agents are
generally prepared in low micromole quantities and so during this part of the project, the scale of the
iodination procedure was adjusted to mimic these conditions (3 micromole of substrate). [125I]ꢀNIS was
initially prepared from NCS and 5.3 MBq of [125I]ꢀNaI and this was used for the radioiodination of 1ꢀ
methoxynaphthalene (6n). With [125I]ꢀNIS as the limiting reagent in these reactions, optimization
studies found that 0.6 equivalents of silver(I) triflimide gave the best conversion of 6n. Analysis using
radioꢀHPLC showed a 61% radiochemical yield of [125I]ꢀ7n after a reaction time of 1.1 hours. 2ꢀ
Hydroxyꢀ6ꢀmethoxybenzaldehyde (9d), a mimic of the aryl component of (–)ꢀIBZM (4) was next
investigated. Using [125I]ꢀNIS prepared from 2.7 MBq of [125I]ꢀNaI and then 0.3 equivalents of silver(I)
triflimide gave [125I]ꢀ10d after 0.3 hours in 64% radiochemical yield. Some sideꢀproducts were observed
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by radioꢀHPLC during the radioiodination of both compounds, but these were generally in small
amounts and easily separable from the major product. While these results are preliminary, they show
that this oneꢀpot approach can be used to access radioiodinated compounds.
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Scheme 5. One-Pot Radioiodination of 6n and 9d
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CONCLUSIONS
In summary, a method for the iodination of arenes via the activation of NIS using silver(I) triflimide
has been developed. The combination of using a soft, lowꢀcharged silver(I) Lewis acid which is still
relatively active due to the nonꢀcomplexing triflimide counterion led to the fast and efficient iodination
of a wide range of arenes. This tuning of NIS activation using silver(I) supresses overꢀiodination
resulting in monoꢀiodination of highly activated substrates such as phenols. The utility of this method
has been demonstrated with the high yielding regioselective synthesis of a range of medicinally
important imaging agents including phenol containing dopamine D2 SPECT tracer (–)ꢀIBZM (4). The
generality of this procedure was further exemplified by the oneꢀpot, twoꢀstep synthesis of [125I]ꢀlabelled
compounds from NCS and [125I]ꢀNaI. Further studies to extend the scope and application of this method
are underway.
EXPERIMENTAL SECTION
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All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed open to air
unless otherwise mentioned. Brine refers to a saturated solution of sodium chloride. Flash column
chromatography was performed using silica gel 60 (35–70 ꢀm). Aluminiumꢀbacked plates preꢀcoated
with silica gel 60F254 were used for thin layer chromatography and were visualized with a UV lamp or
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by staining with potassium permanganate. H NMR spectra were recorded on a NMR spectrometer at
either 400 or 500 MHz and data are reported as follows: chemical shift in ppm relative to
tetramethylsilane as the internal standard, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m
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= multiplet or overlap of nonequivalent resonances, integration). C NMR spectra were recorded on a
NMR spectrometer at either 101 or 126 MHz and data are reported as follows: chemical shift in ppm
relative to tetramethylsilane or the solvent as internal standard (CDCl3,
δ 77.0 ppm; CD3OD, δ 44.0
ppm; or DMSOꢀd6, 39.5 ppm), multiplicity with respect to hydrogen (deduced from DEPT
δ
experiments, C, CH, CH2 or CH3). Infrared spectra were recorded on a FTIR spectrometer;
wavenumbers are indicated in cm–1. Mass spectra were recorded using electron impact, chemical
ionization or electrospray techniques. HRMS spectra were recorded using a dualꢀfocusing magnetic
analyzer mass spectrometer. Melting points are uncorrected. A solution of 74 MBq of [125I]ꢀsodium
iodide in 3–4 µL of 0.01 M sodium hydroxide solution was azeotropically dried under argon at 110 °C
and reconstituted in anhydrous acetonitrile. Analytical HPLC was performed using a 80 Å column (150
× 4.6 mm) with 10 mm guard cartridge, UV 220 nm, radiodetection and flow of 1 mL/min. Analysis of
the reaction mixture (to assess radioiodide incorporation) used a gradient profile of 0.1% trifluoroacetic
acid in water and 0.1% trifluoroacetic acid in acetonitrile.
General Iodination Procedure. To a dry flask (10 mL), fitted with a magnetic stirrer were added
substrate (1.0 equiv.), Nꢀiodosuccinimide (1.0–1.1 equiv.), silver triflimide (7.5 mol %) and
dichloromethane (5–6 mL) under an atmosphere of air. The reaction mixture was stirred in the dark at
the required temperature. The reaction progress was monitored by 1H NMR spectroscopy. The reactions
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were stopped once all substrate was consumed. The reaction mixture was diluted with dichloromethane
(15 mL) and washed with dilute aqueous solutions of sodium hydrogen carbonate (20 mL), sodium
thiosulfate (20 mL), and sodium chloride (20 mL). The organic layer was dried over magnesium sulfate
and filtered. The solvent was removed under reduced pressure and the product was purified by either
column chromatography or by recrystallization.
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Iodination of highly reactive / phenol substrates. To a dry flask fitted with a magnetic stirrer were
added substrate (1.0 equiv.), silver triflimide (7.5 mol %) and dichloromethane
(4 mL) under an atmosphere of air. The mixture was cooled to 0 °C and a solution of
Nꢀiodosuccinimide (1.03 equiv.) in dichloromethane (30 mL) was added dropwise over 10 min. The
reaction was then allowed to warm up to room temperature, and if necessary heated to 36 °C in the dark.
1
The reaction progress was monitored by H NMR spectroscopy. The reactions were stopped once all
substrate was consumed and worked up as described above.
Measurement of the rate of iodination of anisole (6a). Iodination of anisole (6a) was performed as
described in the general procedure above, using anisole (36 µL, 0.33 mmol), NIS (74 mg, 0.33 mmol)
and either InOTf3 (13.9 mg, 7.5 mol %), Ph3PAuNTf2 (38 mg, 7.5 mol %), FeCl3 (2.7 mg, 5.0 mol %) or
AgNTf2 (9.6 mg, 7.5 mol %) at the temperatures shown in Figure 2. At the various time points indicated
in Figure 2, an aliquot (0.5 mL) was removed from the reaction mixture. The sample was diluted with
dichloromethane (3 mL) and washed with dilute aqueous solutions of sodium hydrogen carbonate (5
mL), sodium thiosulfate (5 mL), and sodium chloride (5 mL). The dichloromethane layer was dried over
magnesium sulfate and filtered. The solvent was removed under reduced pressure. The resulting residue
was dissolved in CDCl3 and the conversion of the reaction was measured using 1H NMR spectroscopy.
The calculation was based on the integral values of iodoanisole (7a) signals at 7.52–7.58 ppm compared
to the starting material, anisole (6a) signals at 7.27–7.30 ppm.
4-Iodoanisole (7a).31 The reaction was performed as described in the general procedure using anisole
(6a) (53 µL, 0.49 mmol) and NIS (110 mg, 0.49 mmol). The reaction mixture was heated to 36 °C for
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1.5 h. Purification by column chromatography eluting with 10% ethyl acetate in petroleum ether gave
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2
3
the product as a white solid (98 mg, 86%; inseparable mixture of 4ꢀiodoanisole (7a) and 2ꢀiodoanisole
4
5
6
(8a), 93:7). Mp 40–43 °C. (lit.31 43–45 °C). The spectroscopic data are reported only for the major
7
8
1
isomer, 7a; H NMR (400 MHz, CDCl3)
δ
3.78 (s, 3H), 6.65–6.72 (m, 2H), 7.52–7.58 (m, 2H); 13C
9
10
11
12
13
14
15
16
17
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28
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (101 MHz, CDCl3)
δ 55.3 (CH3), 82.7 (C), 116.4 (2 × CH), 138.2 (2 × CH), 159.5 (C); MS (EI)
m/z 234 (M+, 96), 219 (55), 191 (12), 84 (100), 49 (66).
2-Iodo-4-bromoanisole (7b).32 The reaction was performed as described in the general procedure using
4ꢀbromoanisole (6b) (56 µL, 0.44 mmol) and NIS (115 mg, 0.51 mmol). The reaction mixture was
heated to 40 °C for 7.3 h. Purification by column chromatography eluting with 15% ethyl acetate in
petroleum ether gave 2ꢀiodoꢀ4ꢀbromoanisole (7b) (120 mg, 86%) as a light brown oil. The data were
consistent with the literature.32 1H NMR (500 MHz, CDCl3)
δ
3.86 (s, 3H), 6.69 (d, J 8.7 Hz, 1H), 7.41
56.6 (CH3), 86.7 (C),
13
(dd, J 8.7, 2.4 Hz, 1H), 7.88 (d, J 2.4 Hz, 1H); C NMR (126 MHz, CDCl3)
δ
112.0 (CH), 113.4 (C), 132.2 (CH), 141.2 (CH), 157.5 (C); MS (EI) m/z 312 (M+, 100), 297 (44), 269
(13), 170 (26), 127 (6), 63 (19).
2-Methoxy-5-iodobenzaldehyde (7c).33 The reaction was performed as described in the general
procedure using 2ꢀmethoxybenzaldehyde (6c) (60.5 mg, 0.44 mmol) and NIS (110 mg, 0.49 mmol). The
reaction mixture was heated to 36 °C for 4 h. Recrystallization from ethyl acetate and petroleum ether
gave 2ꢀmethoxyꢀ5ꢀiodobenzaldehyde (7c) (90 mg, 78%) as an offꢀwhite solid. Mp 141–142 °C (lit.33
140–141 °C); 1H NMR (500 MHz, CDCl3)
δ 3.91 (s, 3H), 6.78 (d, J 8.8 Hz, 1H), 7.81 (dd, J 8.8, 2.4 Hz,
13
1H), 8.09 (d, J 2.4 Hz, 1H), 10.34 (s, 1H); C NMR (126 MHz, CDCl3)
δ 55.9 (CH3), 83.0 (C), 114.1
(CH), 126.6 (C), 137.1 (CH), 144.1 (CH), 161.4 (C), 188.2 (CH); MS (ESI) m/z 284 (MNa+, 35), 236
(100), 218 (10).
2,4-Dimethoxy-5-iodobenzoic acid (7d).34 The reaction was performed as described in the general
procedure using 2,4ꢀdimethoxybenzoic acid (6d) (80 mg, 0.44 mmol) and NIS (114 mg, 0.51 mmol).
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The reaction mixture was heated to 36 °C for 2 h. Recrystallization from ethyl acetate and petroleum
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2
3
ether gave 2,4ꢀdimethoxyꢀ5ꢀiodobenzoic acid (7d) (91 mg, 67%) as a white solid. Mp 204–205 °C (lit.34
4
5
6
1
209.5–210.5 °C); H NMR (500 MHz, DMSOꢀd6)
δ
3.87 (s, 3H), 3.93 (s, 3H), 6.70 (s, 1H), 8.04 (s,
56.6 (CH3), 57.3 (CH3), 74.1 (C), 97.7 (CH),
7
8
13
1H), 12.45 (br s, 1H); C NMR (126 MHz, DMSOꢀd6)
δ
9
114.9 (C), 141.6 (CH), 161.7 (C), 162.2 (C), 165.7 (C); MS (EI) m/z 308 (M+, 100), 291 (16), 261 (14),
233 (10), 152 (11), 95 (7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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45
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47
48
49
50
51
52
53
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55
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58
59
60
2,4-Dimethoxy-5-iodobenzaldehyde (7e).35 The reaction was performed as described in the general
procedure using 2,4ꢀdimethoxybenzaldehyde (6e) (74 mg, 0.44 mmol) and NIS (115 mg, 0.51 mmol).
The reaction mixture was heated to 40 °C for 1 h. Recrystallization from ethyl acetate and petroleum
ether gave 2,4ꢀdimethoxyꢀ5ꢀiodobenzaldehyde (7e) (127 mg, 98%) as a white solid. Mp 171–172 °C
(lit.35 170–172 °C); 1H NMR (400 MHz, CDCl3)
δ
3.95 (s, 3H), 3.97 (s, 3H), 6.40 (s, 1H), 8.22 (s, 1H),
13
10.20 (s, 1H); C NMR (126 MHz, CDCl3)
δ 55.9 (CH3), 56.6 (CH3), 75.6 (C), 94.8 (CH), 120.5 (C),
139.3 (CH), 163.8 (C), 164.1 (C), 186.9 (CH); MS (EI) m/z 292 (M+, 100), 246 (15), 148 (13), 84 (29),
49 (27).
N,N-Diethyl-2,3,4-trimethoxy-5-iodobenzamide (7f). The reaction was performed as described in the
general procedure using N,Nꢀdiethylꢀ2,3,4ꢀtrimethoxybenzamide (6f) (68 mg, 0.25 mmol) and NIS (63
mg, 0.28 mmol). The reaction mixture was heated to 45 °C for 6 h. Purification by column
chromatography eluting with 20% ethyl acetate in petroleum ether gave N,Nꢀdiethylꢀ2,3,4ꢀtrimethoxyꢀ5ꢀ
iodobenzamide (7f) (85 mg, 85%) as a colorless oil. IR (neat) 2973, 1626, 1580, 1455, 1394, 1292,
1220, 1070, 999 cm–1; 1H NMR (400 MHz, CDCl3)
δ 1.07 (t, J 7.2 Hz, 3H), 1.24 (t, J 7.2 Hz, 3H), 3.17
(q, J 7.2 Hz, 2H), 3.43 (br s, 1H), 3.66 (br s, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 7.33 (s, 1H);
13C NMR (101 MHz, CDCl3)
δ
12.8 (CH3), 14.0 (CH3), 39.0 (CH2), 43.1 (CH2), 60.9 (CH3), 61.1 (CH3),
61.7 (CH3), 85.6 (C), 129.8 (C), 130.3 (CH), 146.6 (C), 150.6 (C), 154.1 (C), 166.6 (C); MS (EI) m/z
393 (M+, 56), 321 (100), 266 (10), 195 (5), 105 (8), 73 (7); HRMS (EI) calcd for C14H20INO4 (M+),
393.0437, found 393.0435.
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4-Iodoaniline (7g).36 The reaction was performed as described in the general procedure using aniline
(6g) (45 µL, 0.49 mmol) and NIS (110 mg, 0.49 mmol). The reaction mixture was stirred at room
temperature for 1.5 h. Purification by column chromatography eluting with 10% ethyl acetate in
petroleum ether gave 4ꢀiodoaniline (7g) (88 mg, 82%) as a light brown solid. Mp 53–55 ºC (lit.36 55–
1
2
3
4
5
6
7
8
9
56.5 °C); 1H NMR (400 MHz, CDCl3)
δ
3.67 (s, 2H), 6.44–6.49 (m, 2H), 7.38–7.43 (m, 2H); 13C NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(101 MHz, CDCl3)
δ
79.4 (C), 117.3 (2 × CH), 137.9 (2 × CH), 146.0 (C); MS (EI) m/z 219 (M+, 100),
191 (3), 127 (12), 92 (43), 65 (31).
2-Amino-5-iodoacetophenone (7h).37 The reaction was performed as described in the general
procedure using 2ꢀaminoacetophenone (6h) (59 µL, 0.48 mmol) and NIS (110 mg, 0.49 mmol). The
reaction mixture was heated to 36 °C for 1.4 h. Recrystallization from dichloromethane gave 2ꢀaminoꢀ5ꢀ
iodoacetophenone (7h) (112 mg, 89%) as a light brown solid. Mp 95–97 °C (lit.37 98.5–99 °C); H
1
NMR (400 MHz, CDCl3)
δ
2.54 (s, 3H), 6.31 (br s, 2H), 6.45 (d, J 8.7 Hz, 1H), 7.46 (dd, J 8.7, 2.1 Hz,
13
1H), 7.96 (d, J 2.1 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 27.8 (CH3), 75.2 (C), 119.4 (CH), 120.4
(C), 140.3 (CH), 142.4 (CH), 149.6 (C), 199.6 (C); MS (EI) m/z 261 (M+, 100), 246 (52), 218 (20), 91
(18), 84 (18).
2-Amino-3-iodo-5-chlorobenzophenone (7i). The reaction was performed as described in the general
procedure using 2ꢀaminoꢀ5ꢀchlorobenzophenone (6i) (109 mg, 0.47 mmol) and NIS (115 mg, 0.51
mmol). The reaction mixture was heated to 40 °C for 3 h. Purification by column chromatography
eluting with 10% ethyl acetate in petroleum ether gave 2ꢀaminoꢀ3ꢀiodoꢀ5ꢀchlorobenzophenone (7i) (146
mg, 87%) as a bright yellow solid. Mp 88–90 °C; IR (neat) 3396, 3289, 1634, 1596, 1564, 1518, 1226,
1
952, 880 cm–1; H NMR (500 MHz, CDCl3)
δ
6.66 (br s, 2H), 7.44 (d, J 2.4 Hz, 1H), 7.46–7.51 (m,
86.7 (C), 118.4 (C),
2H), 7.55–7.64 (m, 3H), 7.81 (d, J 2.4 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ
120.2 (C), 128.4 (2 × CH), 129.2 (2 × CH), 131.9 (CH), 133.8 (CH), 138.7 (C), 143.0 (CH), 148.7 (C),
197.3 (C); MS (EI) m/z 357 (M+, 100), 280 (12), 229 (13), 125 (14), 105 (21), 77 (23); HRMS (EI)
35
calcd for C13H9 ClINO (M+), 356.9417, found 356.9419.
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2-Iodo-4-nitroaniline (7j).38 The reaction was performed as described in the general procedure using 4ꢀ
nitroaniline (6j) (71 mg, 0.51 mmol) and NIS (110 mg, 0.49 mmol). The reaction mixture was heated to
40 °C for 1.5 h. Recrystallization from ethyl acetate and petroleum ether gave 2ꢀiodoꢀ4ꢀnitroaniline (7j)
(124 mg, 99%) as a bright yellow solid. Mp 99–100 °C (lit.38 103–104 °C); 1H NMR (400 MHz, CDCl3)
1
2
3
4
5
6
7
8
9
δ
4.83 (br s, 2H), 6.70 (d, J 9.0 Hz, 1H), 8.06 (dd, J 9.0, 2.5 Hz, 1H), 8.57 (d, J 2.5 Hz, 1H); 13C NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
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47
48
49
50
51
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53
54
55
56
57
58
59
60
(126 MHz, CDCl3) 80.5 (C), 112.3 (CH), 125.7 (CH), 135.5 (CH), 139.3 (C), 152.3 (C); MS (EI) m/z
δ
264 (M+, 100), 234 (38), 218 (11), 127 (5), 91 (31).
3-Iodo-4-aminoacetophenone (7k).39 The reaction was performed as described in the general
procedure using 4ꢀaminoacetophenone (6k) (66 mg, 0.48 mmol) and NIS (110 mg, 0.49 mmol). The
reaction mixture was stirred at room temperature for 3 h. Purification by column chromatography
eluting with 20% ethyl acetate in petroleum ether gave 3ꢀiodoꢀ4ꢀaminoacetophenone (7k) (124 mg,
98%) as a yellow oil. The data were consistent with the literature.39 1H NMR (500 MHz, CDCl3)
(s, 3H), 4.62 (br s, 2H), 6.71 (d, J 8.4 Hz, 1H), 7.76 (dd, J 8.4, 2.0 Hz, 1H), 8.27 (d, J 2.0 Hz, 1H); 13C
δ 2.49
NMR (126 MHz, CDCl3)
δ 26.0 (CH3), 82.6 (C), 113.1 (CH), 129.3 (C), 130.3 (CH), 140.3 (CH), 150.9
(C), 195.1 (C); MS (CI) m/z 262 (MH+, 100), 136 (48), 85 (10), 69 (18).
N-(4-Iodophenyl)acetamide (7l).13c The reaction was performed as described in the general procedure
using Nꢀphenylacetamide (6l) (59 mg, 0.44 mmol) and NIS (110 mg, 0.49 mmol). The reaction mixture
was heated to 40 °C for 2 h. Recrystallization from ethyl acetate and petroleum ether gave Nꢀ(4ꢀ
1
iodophenyl)acetamide (7l) (104 mg, 89%) as a white solid. Mp 174–176 °C (lit.13c 178–180 °C); H
NMR (400 MHz, CDCl3)
δ
2.17 (s, 3H), 7.12 (br s, 1H), 7.29 (d, J 8.7 Hz, 2H), 7.62 (d, J 8.7 Hz, 2H);
24.7 (CH3), 87.4 (C), 121.6 (2 × CH), 137.6 (C), 137.9 (2 × CH), 168.2
13C NMR (101 MHz, CDCl3)
δ
(C); MS (EI) m/z 261 (M+, 100), 219 (93), 92 (26).
N-(2-Chloro-4-iodophenyl)acetamide (7m).40 The reaction was performed as described in the general
procedure using Nꢀ(2ꢀchlorophenyl)acetamide (6m) (73 mg, 0.43 mmol) and NIS (110 mg, 0.49 mmol).
The reaction mixture was heated to 40 °C for 7 h. Recrystallization from ethyl acetate and petroleum
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ether gave Nꢀ(2ꢀchloroꢀ4ꢀiodophenyl)acetamide (7m) (110 mg, 87%) as a white powder. Mp 138–139
1
2
3
4
5
1
°C (lit.40 144 °C); H NMR (500 MHz, CDCl3)
δ
2.24 (s, 3H), 7.52–7.59 (m, 2H), 7.69 (d, J 2.0 Hz,
24.9 (CH3), 86.2 (C), 122.8 (CH), 123.1
13
1H), 8.17 (d, J 8.7 Hz, 1H); C NMR (126 MHz, CDCl3)
δ
6
7
8
9
(C), 134.5 (C), 136.8 (CH), 137.0 (CH), 168.2 (C); MS (EI) m/z 295 (M+, 48), 253 (100), 224 (6), 126
(15), 90 (15).
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11
12
13
14
15
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17
18
19
20
21
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23
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26
27
28
29
30
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32
33
34
35
36
37
38
39
40
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42
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44
45
46
47
48
49
50
51
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53
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55
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59
60
4-Iodo-1-methoxynaphthalene (7n).41 The reaction was performed as described in the general
procedure using 1ꢀmethoxynaphthalene (6n) (69 µL, 0.48 mmol) and NIS (110 mg, 0.49 mmol). The
reaction mixture was heated to 36 °C for 1 h. Purification by column chromatography eluting with 2.5%
ethyl acetate in petroleum ether gave 4ꢀiodoꢀ1ꢀmethoxynaphthalene (7n) (114 mg, 83%) as a colorless
oil. The data were consistent with the literature.41 1H NMR (500 MHz, CDCl3)
δ 3.99 (s, 3H), 6.60 (d, J
8.1 Hz, 1H), 7.51 (ddd, J 8.3, 6.8, 1.1 Hz, 1H), 7.58 (ddd, J 8.4, 6.8, 1.3 Hz, 1H), 7.95 (d, J 8.1 Hz, 1H),
13
8.02 (ddd, J 8.4, 1.1, 0.6, 1H), 8.23 (ddd, J 8.3, 1.3, 0.6 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 55.7
(CH3), 88.2 (C), 105.6 (CH), 122.5 (CH), 126.0 (CH), 126.7 (C), 128.2 (CH), 131.8 (CH), 134.7 (C),
136.9 (CH), 156.3 (C); MS (EI) m/z 284 (M+, 100), 269 (35), 241 (31), 114 (30).
1-Iodo-2-methoxynaphthalene (7o).19 The reaction was performed as described in the general
procedure using 2ꢀmethoxynaphthalene (6o) (76 mg, 0.48 mmol) and NIS (110 mg, 0.49 mmol). The
reaction mixture was heated to 36 °C for 1 h. Purification by column chromatography eluting with 5%
ethyl acetate in petroleum ether gave 1ꢀiodoꢀ2ꢀmethoxynaphthalene (7o) (132 mg, 97%) as an offꢀwhite
1
solid. Mp 84–86 °C (lit.19 86–87 °C); H NMR (400 MHz, CDCl3)
δ 4.03 (s, 3H), 7.22 (d, J 8.9 Hz,
1H), 7.38 (ddd, J 8.1, 6.9, 1.2 Hz, 1H), 7.54 (ddd, J 8.6, 6.9, 1.2 Hz, 1H), 7.74 (ddd, J 8.1, 1.2, 0.6 Hz,
13
1H), 7.83 (d, J 8.9 Hz, 1H), 8.14 (ddd, J 8.6, 1.2, 0.6 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 57.3
(CH3), 87.7 (C), 112.9 (CH), 124.4 (CH), 128.1 (CH), 128.2 (CH), 129.9 (C), 130.4 (CH), 131.2 (CH),
135.6 (C), 156.6 (C); MS (EI) m/z 284 (M+, 52), 241 (21), 142 (20), 114 (23), 84 (24), 44 (100).
5-Iodo-2,3-dihydrobenzofuran (7p).42 The reaction was performed as described in the general
procedure using 2,3ꢀdihydrobenzofuran (6p) (54 µL, 0.48 mmol) and NIS (110 mg, 0.49 mmol). The
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reaction mixture was heated to 36 °C for 1 h. Purification by column chromatography eluting with 2.5%
1
2
3
ethyl acetate in petroleum ether gave 5ꢀiodoꢀ2,3ꢀdihydrobenzofuran (7p) (117 mg, 99%) as a white
4
5
6
solid. Mp 61–63 °C (lit.42 64–65 °C); 1H NMR (400 MHz, CDCl3)
δ
3.20 (br t, J 8.7 Hz, 2H), 4.56 (t, J
7
8
13
8.7 Hz, 2H), 6.57 (d, J 8.4 Hz, 1H), 7.38 (ddt, J 8.4, 1.9, 0.7 Hz, 1H), 7.47 (dt, J 1.9, 1.1 Hz, 1H); C
9
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (126 MHz, CDCl3)
δ 29.5 (CH2), 71.4 (CH2), 81.6 (C), 111.7 (CH), 130.1 (C), 133.7 (CH), 136.7
(CH), 160.0 (C); MS (EI) m/z 246 (M+, 89), 232 (10), 117 (20), 91 (41), 84 (39), 44 (100).
Methyl 4-iodo-1H-pyrrole-2-carboxylate (7q).43 The reaction was performed as described in the
general procedure using methyl 1Hꢀpyrroleꢀ2ꢀcarboxylate (6q) (61 mg, 0.48 mmol) and NIS (110 mg,
0.49 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Purification by column
chromatography eluting with 15% ethyl acetate in petroleum ether gave methyl 4ꢀiodoꢀ1Hꢀpyrroleꢀ2ꢀ
carboxylate (7q) (87 mg, 72%) as a white solid. Mp 87–90 °C (lit.43 87–89 °C); H NMR (400 MHz,
1
13
CDCl3)
δ
3.86 (s, 3H), 6.98 (dd, J 2.7, 1.5 Hz, 1H), 7.00 (dd, J 2.7, 1.5 Hz, 1H), 9.10 (br s, 1H); C
NMR (126 MHz, CDCl3)
δ
51.8 (CH3), 61.7 (C), 121.7 (CH), 124.4 (C), 127.6 (CH), 160.5 (C); MS
(EI) m/z 251 (M+, 100), 219 (70), 192 (11), 124 (5), 93 (6), 65 (8), 44 (10).
4-Iodophenol (10a).44 The reaction was performed as described in the highly reactive substrate
procedure using phenol (9a) (46 mg, 0.49 mmol) and NIS (113 mg, 0.50 mmol) at 0 °C. After 15 min,
the reaction mixture was slowly heated to 36 °C for 4 h. Purification by column chromatography,
eluting with 10% ethyl acetate in petroleum ether gave 4ꢀiodophenol (10a) (93 mg, 86%) as waxy solid.
The data were consistent with the literature.44 1H NMR (400 MHz, CDCl3)
δ 4.68 (s, 1H), 6.63 (d, J 8.8
13
Hz, 2H), 7.52 (d, J 8.8 Hz, 2H); C NMR (126 MHz, CDCl3)
δ 82.7 (C), 117.8 (2 × CH), 138.5 (2 ×
CH), 155.3 (C); MS (EI) m/z 220 (M+, 100), 191 (3), 127 (6), 93 (37), 65 (20).
2-Hydroxy-5-iodoacetophenone (10b).45 The reaction was performed as described in the general
procedure using 2ꢀhydroxyacetophenone (9b) (56 µL, 0.46 mmol) and NIS (109 mg, 0.49 mmol). The
reaction mixture was heated to 40 °C for 6.7 h. Recrystallization from ethyl acetate and petroleum ether
gave 2ꢀhydroxyꢀ5ꢀiodoacetophenone (10b) (112 mg, 93%) as a light yellow solid. Mp 84–86 °C (lit.45
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90 °C); δH (400 MHz, CDCl3)
δ 2.62 (s, 3H), 6.78 (d, J 8.8 Hz, 1H), 7.71 (dd, J 8.8, 2.2 Hz, 1H), 8.01
1
2
3
4
(d, J 2.2 Hz, 1H), 12.19 (s, 1H); 13C NMR (126 MHz, CDCl3)
δ
26.8 (CH3), 79.7 (C), 120.9 (CH), 121.8
(C), 139.1 (CH), 144.8 (CH), 162.0 (C), 203.5 (C); MS (EI) m/z 262 (M+, 100), 247 (72), 219 (19), 120
(10), 92 (14), 63 (9).
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2,6-Dihydroxy-3-iodoacetophenone (10c). The reaction was performed as described in the highly
reactive substrate procedure using 2,6ꢀdihydroxyacetophenone (9c) (75 mg, 0.49 mmol) and NIS (115
mg, 0.51 mmol) at 0 °C for 10 min. The reaction mixture was warmed to room temperature and stirred
for 1 h. Recrystallization from ethyl acetate and petroleum ether gave 2,6ꢀdihydroxyꢀ3ꢀ
iodoacetophenone (10c) (100 mg, 74%) as a yellow solid. Mp 143–146 °C (decomp.); IR (neat) 3254,
1
2922, 1607, 1575, 1419, 1409, 1362, 1339, 1263, 1206, 1132, 1046, 803 cm–1; H NMR (400 MHz,
CDCl3)
δ 2.76 (s, 3H), 6.38 (d, J 8.8 Hz, 1H), 7.48 (br s, 1H), 7.64 (d, J 8.8 Hz, 1H), 11.82 (br s, 1H);
13C NMR (126 MHz, CDCl3)
δ
33.4 (CH3), 74.1 (C), 110.3 (C), 112.1 (CH), 143.7 (CH), 157.2 (C),
163.8 (C), 204.8 (C); MS (EI) m/z 278 (M+, 54), 263 (56), 247 (11), 137 (22), 108 (10), 44 (100);
HRMS (EI) calcd for C8H7IO3 (M+), 277.9440, found 277.9439.
2-Hydroxy-3-iodo-6-methoxybenzaldehyde (10d). The reaction was prepared as described in the
highly reactive substrate procedure using 2ꢀhydroxyꢀ6ꢀmethoxybenzaldehyde (9d) (72 mg, 0.47 mmol)
and NIS (109 mg, 0.49 mmol) at 0 °C. After 10 min, the reaction mixture was warmed to room
temperature and stirred for 1 h. Recrystallization from ethyl acetate and petroleum ether gave 2ꢀ
hydroxyꢀ3ꢀiodoꢀ6ꢀmethoxybenzaldehyde (10d) (127 mg, 97%) as a yellow solid. Mp 123–125 °C; IR
1
(neat) 2942, 2900, 1634, 1597, 1384, 1283, 1246, 1089, 780 cmꢀ1; H NMR (500 MHz, CDCl3)
δ 3.91
(s, 3H), 6.29 (d, J 8.8 Hz, 1H), 7.85 (d, J 8.8 Hz, 1H), 10.21 (s, 1H), 12.83 (s, 1H); 13C NMR (126 MHz,
CDCl3) 56.1 (CH3), 74.2 (C), 103.7 (CH), 111.0 (C), 146.9 (CH), 162.1 (C), 162.9 (C), 193.7 (C); MS
δ
(EI) m/z 278 (M+, 71), 260 (10), 218 (7), 133 (9), 105 (8), 84 (96), 49 (100); HRMS (EI) calcd for
C8H7IO3 (M+), 277.9440, found 277.9438.
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2,4-Dimethoxy-5-iodo-6-hydroxybenzaldehyde (10e). The reaction was performed as described in the
general procedure using 2,4ꢀdimethoxyꢀ6ꢀhydroxybenzaldehyde (9e) (84 mg, 0.46 mmol) and NIS (110
mg, 0.49 mmol). The reaction mixture was heated to 36 °C for 2 h. Recrystallization from ethyl acetate
and petroleum ether gave 2,4ꢀdimethoxyꢀ5ꢀiodoꢀ6ꢀhydroxybenzaldehyde (10e) (128 mg, 90%) as an offꢀ
white solid. Mp 205–208 °C (decomp.); IR (neat) 3022, 2943, 1635, 1603, 1462, 1449, 1293, 1233,
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2
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1210, 1177, 1127, 1080, 977, 783 cm–1; 1H NMR (400 MHz, CDCl3)
δ
3.94 (s, 3H), 3.98 (s, 3H), 6.00
13
(s, 1H), 10.00 (s, 1H), 13.22 (s, 1H); C NMR (101 MHz, CDCl3)
δ 56.0 (CH3), 56.7 (CH3), 65.7 (C),
86.7 (CH), 106.4 (C), 164.0 (C), 164.8 (C), 166.0 (C), 191.5 (C); MS (EI) 308 (M+, 100), 277 (13), 246
(11), 163 (20), 91 (8), 69 (7); HRMS (EI) calcd for C9H9IO4 (M+), 307.9546, found 307.9547.
N-[2’-(1”-Piperidinyl)ethyl]-4-methoxybenzamide
(11).7a
1ꢀEthylꢀ3ꢀ(3ꢀ
dimethylaminopropyl)carbodiimide hydrochloride (1.44 g, 7.5 mmol), hydroxybenzotriazole (1.08 g,
8.0 mmol) and 4ꢀmethoxybenzoic acid (761 mg, 5.0 mmol) were dissolved in dichloromethane (20 mL).
N,NꢀDiisopropylethylamine (2.8 mL, 16 mmol) was added and the mixture was stirred at room
temperature for 1 h. 2ꢀ(1’ꢀPiperidyl)ethylamine (1.00 mL, 5.0 mmol) was added and the reaction
mixture was stirred at room temperature for 24 h. The mixture was diluted with dichloromethane (100
mL) and extracted with 1 M hydrochloric acid (100 mL). The aqueous layer was neutralized with 1 M
sodium hydroxide (~120 mL) and extracted with dichloromethane (3 × 100 mL). The organic layer was
dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. Purification by
column chromatography eluting with 5% to 10% methanol in dichloromethane gave Nꢀ[2’ꢀ(1”ꢀ
piperidinyl)ethyl]ꢀ4ꢀmethoxybenzamide (11) (916 mg, 70%) as a colorless solid. The data were
consistent with the literature.7a Mp 71–73 °C; 1H NMR (500 MHz, CDCl3)
δ 1.42–1.51 (m, 2H), 1.57–
1.66 (m, 4H), 2.39–2.49 (br m, 4H), 2.55 (t, J 6.1 Hz, 2H), 3.51 (td, J 6.1, 4.7 Hz, 2H), 3.85 (s, 3H),
6.86 (br s, 1H), 6.91–6.97 (m, 2H), 7.73–7.78 (m, 2H); 13C NMR (126 MHz, CDCl3)
δ
24.4 (CH2), 26.1
(2 × CH2), 36.4 (CH2), 54.2 (2 × CH2), 55.4 (CH3), 57.0 (CH2), 113.7 (2 × CH), 127.1 (C), 128.7 (2 ×
CH), 162.0 (C), 166.8 (C); MS (ESI) m/z 263 (MH+, 75), 178 (100).
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N-[2’-(1”-Piperidinyl)ethyl]-3-iodo-4-methoxybenzamide
(3).7a
Nꢀ[2’ꢀ(1”ꢀPiperidinyl)ethyl]ꢀ4ꢀ
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4
5
6
7
8
9
methoxybenzamide (11) (50 mg, 0.19 mmol) was suspended in acetonitrile (3 mL) and then
tetrafluoroboric acid (25 µL, 0.19 mmol, 48% wt in water) was added at room temperature. The
resulting solution was concentrated to a yellowish gum under reduced pressure. The reaction was then
performed as described in the general procedure using the HBF4 salt and NIS (56 mg, 0.25 mmol). The
reaction mixture was heated to 40 °C for 2.3 h. Purification by column chromatography eluting with 5%
to 10% methanol in dichloromethane gave Nꢀ[2’ꢀ(1”ꢀpiperidinyl)ethyl]ꢀ3ꢀiodoꢀ4ꢀmethoxybenzamide (3)
(70 mg, 94%) as a viscous colorless oil. The data were consistent with the literature.7a 1H NMR (500
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MHz, CDCl3)
δ 1.42–1.51 (m, 2H), 1.56–1.64 (m, 4H), 2.35–2.48 (br m, 4H), 2.54 (t, J 6.1 Hz, 2H),
3.49 (td, J 6.1, 4.7 Hz, 2H), 3.93 (s, 3H), 6.80 (br s, 1H), 6.84 (d, J 8.6 Hz, 1H), 7.77 (dd, J 8.6, 2.2 Hz,
13
1H), 8.21 (d, J 2.2 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 24.4 (CH2), 26.1 (2 × CH2), 36.5 (CH2),
54.3 (2 × CH2), 56.5 (CH3), 57.0 (CH2), 85.7 (C), 110.1 (CH), 128.7 (CH), 128.9 (C), 138.5 (CH), 160.3
(C), 165.5 (C); MS (ESI) m/z 389 (MH+, 100), 304 (43).
(2’S)-2-Hydroxy-6-methoxy-N-[(1’-ethyl-2’-pyrrolidinyl)methyl]benzamide (12).8a 1ꢀEthylꢀ3ꢀ(3ꢀ
dimethylaminopropyl)carbodiimide hydrochloride (494 mg, 2.57 mmol), hydroxybenzotriazole (371
mg, 2.75 mmol) and 2ꢀhydroxyꢀ6ꢀmethoxybenzoic acid (289 mg, 1.72 mmol) were dissolved in
dichloromethane (5 mL). N,NꢀDiisopropylethylamine (747 µL, 4.29 mmol) was added and the mixture
was stirred at room temperature for 0.1 h. (S)ꢀ(–)ꢀ1ꢀEthylꢀ2ꢀaminomethylpyrrolidine (239 µL, 1.72
mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The mixture was
diluted with dichloromethane (50 mL) and washed with 1 M sodium hydroxide (50 mL), dried
(MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography
eluting with 0% to 3.5% methanol in dichloromethane gave (2’S)ꢀ2ꢀhydroxyꢀ6ꢀmethoxyꢀNꢀ[(1’ꢀethylꢀ
2’ꢀpyrrolidinyl)methyl]benzamide (12) (363 mg, 76%) as a colorless oil. The data were consistent with
the literature.8a [α]D23 –78.0 (c 2.0, acetone); 1H NMR (500 MHz, CDCl3)
δ 1.13 (t, J 7.2 Hz, 3H), 1.63
(dt, J 12.6, 5.9 Hz, 1H), 1.67–1.76 (m, 2H), 1.91 (dq, J 12.6, 8.5 Hz, 1H), 2.17–2.29 (m, 2H), 2.65 (m,
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1H), 2.85 (dq, J 13.5, 7.2 Hz, 1H), 3.17–3.33 (m, 2H), 3.70 (ddd, J 13.8, 7.2, 2.5 Hz, 1H), 3.92 (s, 3H),
6.39 (dd, J 8.3, 1.0 Hz, 1H), 6.62 (dd, J 8.4, 1.0 Hz, 1H), 7.26 (dd, J 8.4, 8.3 Hz, 1H), 8.92 (br s, 1H),
1
2
3
4
5
6
14.14 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ 14.2 (CH3), 23.0 (CH2), 28.5 (CH2), 40.7 (CH2), 47.9
7
8
9
(CH2), 53.6 (CH2), 55.9 (CH3), 61.9 (CH), 100.8 (CH), 104.2 (C), 111.6 (CH), 133.0 (CH), 158.8 (C),
164.5 (C), 170.3 (C); MS (EI) m/z 278 (M+, 4), 151 (41), 136 (10), 98 (100), 70 (22).
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(2’S)-2-Hydroxy-3-iodo-6-methoxy-N-[(1’-ethyl-2’-pyrrolidinyl)methyl]benzamide (4).8a (2’S)ꢀ2ꢀ
Hydroxyꢀ6ꢀmethoxyꢀNꢀ[(1’ꢀethylꢀ2’ꢀpyrrolidinyl)methyl]benzamide (12) (69 mg, 0.25 mmol) was
suspended in ethanol (3 mL) and then tetrafluoroboric acid (32.4 µL, 0.25 mmol, 48% wt in water) was
added at room temperature. After 0.5 h, the resulting solution was concentrated to a yellowish gum
under reduced pressure. The reaction was then performed as described in the general procedure using
the prepared salt and NIS (57 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for
0.8 h. Purification by column chromatography eluting with 2% to 5% methanol in dichloromethane gave
(2’S)ꢀ2ꢀhydroxyꢀ3ꢀiodoꢀ6ꢀmethoxyꢀNꢀ[(1’ꢀethylꢀ2’ꢀpyrrolidinyl)methyl]benzamide (4) (71 mg, 71%) as
a colorless viscous oil. The data were consistent with the literature.8a [α]D24 –47.3 (c 1.0 in acetone); 1H
NMR (500 MHz, CD3OD)
δ 1.19 (t, J 7.3 Hz, 3H), 1.62–1.72 (m, 1H), 1.74–1.88 (m, 2H), 2.01 (dq, J
12.7, 8.3 Hz, 1H), 2.35–2.50 (m, 2H), 2.83–2.91 (m, 1H), 3.01 (dq, J 12.2, 7.3 Hz, 1H), 3.26–3.33 (m,
1H), 3.41 (dd, J 13.8, 5.6 Hz, 1H), 3.63 (dd, J 13.8, 4.0 Hz, 1H), 3.95 (s, 3H), 6.43 (d, J 8.8 Hz, 1H),
7.74 (d, J 8.8 Hz, 1H); 13C NMR (126 MHz, CD3OD)
δ 12.3 (CH3), 22.2 (CH2), 28.0 (CH2), 40.9 (CH2),
48.5 (CH2), 53.4 (CH2), 55.8 (CH3), 63.2 (CH), 75.7 (C), 103.5 (CH), 103.9 (C), 142.2 (CH), 159.4 (C),
162.1 (C), 169.8 (C); MS (EI) m/z 404 (M+, 3), 277 (22), 261 (9), 234 (5), 149 (8), 98 (100), 70 (14).
3,4-Difluoro-2-(2’-fluorophenylamino)benzoic acid.46 2,3,4ꢀTrifluorobenzoic acid (250 mg, 1.42
mmol) was dissolved in THF (10 mL) under an atmosphere of argon. 2ꢀFluoroaniline (0.28 mL, 2.84
mmol) was added and the mixture was cooled to –78 °C. Lithium bis(trimethylsilyl)amide (1 M in THF,
4.4 mL, 4.26 mmol) was slowly added over 0.1 h. The reaction mixture was warmed to room
temperature and stirred for 72 h. The reaction was quenched with water (10 mL) and acidified to pH 2
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with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 80 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure. The resulting brown residue was
recrystallized from ethyl acetate and hexane to give 3,4ꢀdifluoroꢀ2ꢀ(2’ꢀfluorophenylamino)benzoic acid
1
2
3
4
5
6
7
8
(232 mg, 61%) as white solid. Mp 174–175 °C (lit.46 170–172 °C); 1H NMR (400 MHz, CDCl3)
δ 6.76
9
13
(td, J 9.2, 6.8 Hz, 1H), 6.98–7.16 (m, 4H), 7.89 (ddd, J 9.2, 5.8, 2.1 Hz, 1H), 8.91 (s, 1H); C NMR
10
11
12
13
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(126 MHz, CD3OD) δ 108.6 (d, J 18.4 Hz, CH), 115.9 (C), 116.1 (d, J 19.4 Hz, CH), 121.9 (d, J 5.8 Hz,
CH), 124.5 (d, J 7.5 Hz, CH), 125.1 (d, J 3.7 Hz, CH), 129.1 (dd, J 9.6, 4.0 Hz, CH), 131.2 (d, J 10.0
Hz, C), 138.0 (d, J 7.6 Hz, C), 142.1 (dd, J 247.9, 14.9 Hz, C), 155.4 (dd, J 252.3, 11.2 Hz, C), 156.1 (d,
19
J 243.3 Hz, C), 170.3 (C); F NMR (377 MHz, CDCl3)
δ –144.2 (d, J 18.6 Hz, 1F), –127.4 (s, 1F), –
126.3 (d, J 18.6 Hz, 1F); MS (EI) m/z 267 (M+, 51), 249 (100), 221 (23), 201 (16), 84 (64), 49 (44).
Methyl 3,4-difluoro-2-(2’-fluorophenylamino)benzoate (13). 3,4ꢀDifluoroꢀ2ꢀ(2’ꢀ
fluorophenylamino)benzoic acid (160 mg, 0.60 mmol) was dissolved in toluene (6 mL) under an
atmosphere of argon. Thionyl chloride (2.6 mL) was added and the reaction mixture was heated to 80
°C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced
pressure. The residue was dissolved in toluene (4 mL) and a mixture of methanol (6 mL) and
triethylamine (1.5 mL) was added. The mixture was stirred overnight at room temperature. The volatiles
were removed under reduced pressure. The resulting residue was dissolved in dichloromethane (40 mL)
and washed with a saturated solution of sodium hydrogencarbonate (40 mL). The aqueous layer was
extracted with dichloromethane (2 × 50 mL). The organic phases were combined, dried (MgSO4),
filtered and concentrated under reduced pressure. The residue was purified by filtration through a plug
of silica eluting with 4% ethyl acetate in hexane to give methyl 3,4ꢀdifluoroꢀ2ꢀ(2’ꢀ
fluorophenylamino)benzoate (13) (150 mg, 89%) as white solid. Mp 65–67 °C; IR (neat) 3281, 2955,
1692, 1611, 1501, 1437, 1258, 1192, 1134, 1103, 1053, 1003, 746 cm–1; 1H NMR (400 MHz, CDCl3)
δ
3.91 (s, 3H), 6.73 (td, J 9.1, 6.9 Hz, 1H), 6.93–7.14 (m, 4H), 7.79 (ddd, J 9.1, 5.9, 2.2 Hz, 1H), 9.08 (s,
1H); 13C NMR (101 MHz, CDCl3)
δ
52.4 (CH3), 107.6 (d, J 18.3 Hz, CH), 113.7 (t, J 2.7 Hz, C), 115.4
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(d, J 19.3 Hz, CH), 120.9 (dd, J 6.0, 1.8 Hz, CH), 123.5 (d, J 7.4 Hz, CH), 123.8 (d, J 3.8 Hz, CH),
127.3 (dd, J 9.5, 4.2 Hz, CH), 129.7 (dd, J 11.2, 2.5 Hz, C), 136.8 (dd, J 7.7, 3.4 Hz, C), 141.9 (dd, J
249.7, 14.7 Hz, C), 154.3 (dd, J 254.6, 11.4 Hz, C), 154.8 (d, J 244.8 Hz, C), 167.5 (d, J 2.7 Hz, C); 19F
1
2
3
4
5
6
7
8
NMR (377 MHz, CDCl3)
δ –143.7 (d, J 18.7 Hz, 1F), –128.3 (d, J 18.7 Hz, 1F), –128.1 (s, 1F); HRMS
9
(ESI) calcd for C14H10F3NNaO2 (MNa+), 304.0556, found 304.0552.
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Methyl 3,4-difluoro-2-(2’-fluoro-4’-iodophenylamino)benzoate (14).46 The reaction was performed
as described in the general procedure using methyl 3,4ꢀdifluoroꢀ2ꢀ(2’ꢀfluorophenylamino)benzoate (13)
(47 mg, 0.17 mmol) and NIS (38 mg, 0.17 mmol). The reaction mixture was stirred at room temperature
for 1 h. The residue was purified by filtration through a plug of silica eluting with 4% ethyl acetate in
hexane to give methyl 3,4ꢀdifluoroꢀ2ꢀ(2’ꢀfluoroꢀ4’ꢀiodophenylamino)benzoate (14) (64 mg, 94%) as an
1
offꢀwhite solid. The data were consistent with the literature.46 Mp 109–111 °C; H NMR (400 MHz,
CDCl3)
δ
3.91 (s, 3H), 6.68 (td, J 8.5, 5.8 Hz, 1H), 6.77 (td, J 9.1, 7.0 Hz, 1H), 7.35 (dt, J 8.5, 1.5 Hz,
13
1H), 7.42 (dd, J 10.2, 2.0 Hz, 1H), 7.80 (ddd, J 9.1, 5.8, 2.0 Hz, 1H), 9.05 (br s, 1H); C NMR (101
MHz, CDCl3)
δ 52.5 (s, CH3), 83.6 (d, J 7.6 Hz, C), 108.3 (d, J 18.3 Hz, CH), 114.1 (t, J 2.6 Hz, C),
121.8 (dd, J 6.5, 2.1 Hz, CH), 124.4 (d, J 21.7 Hz, CH), 127.4 (dd, J 9.4, 4.1 Hz, CH), 130.0 (dd, J 10.1,
2.5 Hz, C), 132.9 (d, J 3.9 Hz, CH), 135.9 (dd, J 7.9, 3.7 Hz, C), 142.0 (dd, J 250.2, 14.8 Hz, C), 154.1
(d, J 250.4 Hz, C), 154.2 (dd, J 255.3, 11.4 Hz, C), 167.4 (d, J 2.7 Hz, C); 19F NMR (377 MHz,
CDCl3) δ
–142.9 (d, J 18.7 Hz, 1F), –127.8 (d, J 18.7 Hz, 1F), –125.8 (s, 1F); MS (ESI) m/z 430 (MNa+,
100), 381 (54), 353 (19), 317 (99), 257 (22), 117 (53).
[125I]-4-Iodo-1-methoxynaphthalene ([125I]-7n). To a vial was added Nꢀchlorosuccinimide (0.44 mg,
3.3 µmol) in acetonitrile (0.1 mL) and [125I]ꢀsodium iodide in acetonitrile (5 µL, 5.3 MBq). The mixture
was stirred at ambient temperature for 0.75 h. Silver triflimide (0.72 mg, 1.86 µmol) in dichloromethane
(0.3 mL) and 1ꢀmethoxynaphthalene (6n) (0.45 µL, 3.1 µmol) in dichloromethane (0.3 mL) were then
added via syringe and the reaction mixture was stirred at 36 °C for 1.1 h. A 50% aqueous acetonitrile
solution (0.8 mL) was added and the reaction volume was concentrated by blowing argon over the
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solution. The mixture was diluted with aqueous acetonitrile solution and passed through a 0.22 µm
filter. The filtrate was analyzed by analytical radioꢀHPLC which showed incorporation of radioiodide to
obtain [125I]ꢀ4ꢀiodoꢀ1ꢀmethoxynaphthalene ([125I]-7n) in 61% radiochemical yield.
1
2
3
4
5
6
7
8
9
[125I]-2-Hydroxy-3-iodo-6-methoxybenzaldehyde ([125I]-10d). To
a
vial was added Nꢀ
10
11
12
13
14
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18
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chlorosuccinimide (0.43 mg, 3.2 µmol) in acetonitrile (0.1 mL) and [125I]ꢀsodium iodide in acetonitrile
(4 µL, 2.7 MBq). The mixture was stirred at ambient temperature for 0.75 h. Silver triflimide (0.36 mg,
0.93 µmol) in dichloromethane (0.3 mL) and 2ꢀhydroxyꢀ6ꢀmethoxybenzaldehyde (9d) (0.45 mg, 3.0
µmol) in dichloromethane (0.3 mL) were then added via syringe and the reaction mixture was stirred at
36 °C for 0.3 h. The reaction volume was concentrated by blowing argon over the solution. A 50%
aqueous acetonitrile solution (0.7 mL) was added and the mixture was passed through a 0.22 µm filter.
The filtrate was analyzed by analytical radioꢀHPLC which showed incorporation of radioiodide to
obtain [125I]ꢀ2ꢀhydroxyꢀ3ꢀiodoꢀ6ꢀmethoxybenzaldehyde ([125I]-10d) in 64% radiochemical yield.
SUPPORTING INFORMATION AVAILABLE. RadioꢀHPLC chromatograms of [125I]ꢀ7n and
[125I]ꢀ10d and NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
ACKNOWLEDGEMENT. Financial support from the EPSRC (EP/K503903/1), the Ministry of
Higher Education and Scientific Research and the University of Benghazi, Libya (studentship to
S.A.I.S.) is gratefully acknowledged.
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