but this would also perturb the electronics and sterics of the
substituted arene due to the large electronegative iodine atom
enabling focused SAR studies (Scheme 1). Coupling reactions
of the iodinated natural products would allow access to probes
through attachment of various tags useful for biological studies.
ment of such a process and describe its utility for derivatization
of arene-containing NPs and subsequent metal-mediated cou-
plings.
To identify a mild catalyst for iodination, we chose 4-me-
thylanisole as a test substrate and screened various Lewis acids
(10 mol %) with NIS in MeCN at ambient temperature (23
°C). An initial control experiment showed no reaction in the
absence of catalyst after 18 h (Table 1, entry 1). We identified
AgOTf, Yb(OTf)3, InBr3, In(OTf)3, and TMSOTf as effective
catalysts (Table 1, entries 2- 6). We focused further studies
on In(OTf)3 due to its mildness and lack of moisture sensitiv-
ity.10 A brief survey of solvents indicated that CH3CN was
optimal; however, THF and CH2Cl2 gave lower but comparable
yields (Table 1, entries 7 and 8), providing some flexibility for
solvent choice based on NP solubility.11
Scheme 1
.
Methods and Possible Outcomes for Derivatizing and
Tagging Arene-Containing Natural Products
Table 1. Screening of Catalysts and Solvents for Mild
Iodination of 4-Methylanisole
The direct arene iodination with molecular iodine is difficult
to accomplish compared to the chlorination or bromination due
to the low electrophilicity of iodine. Rather, iodide coupled with
a strong oxidizing reagent is typically employed to generate an
electrophilic I+ species.7 However, this reaction suffers from
lack of generality due to the required strong oxidants which
may react with sensitive functional groups in complex NPs.
Recently, N-iodosuccinimide (NIS) was reported to be an
efficient iodinating agent either at elevated temperature8 or in
conjunction with trifuoroacetic acid, triflic acid, ZrCl4, or
BF3·H2O as catalysts.9 However, elevated temperatures or strong
Bronsted/Lewis acids are likely incompatible with sensitive
natural products. Thus, the paucity of mild methods for arene
iodination led us to explore a mild Lewis acid-mediated
iodination employing NIS. Herein, we demonstrate the develop-
entry
catalyst
solvent
% yielda
1
2
3
4
5
6
7
8
no catalyst
AgOTf
Yb(OTf)3
In(OTf)3
InBr3
TMSOTf
In(OTf)3
In(OTf)3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
NRb
48
80
97
97
98
>90c
92
CH2Cl2
a Refers to isolated yields. b NR ) no reaction. c Estimated conversion
1
by H NMR (300 MHz).
The iodination of various simple arenes was explored to
determine generality and also to provide a profile for site
selectivity when applying this method to NPs (Table 2). As
expected, highest yields were obtained with electron-rich
arenes12 (Table 2, entries 1- 3, 6, 7, and 9-12). Although
moderately electron-rich arenes required longer reaction time
(up to 3 days), high yields were obtained under otherwise
identical standard conditions (Table 2, entries 4 and 5). The
regioselectivities observed with these substrates were as ex-
pected.
To study the applicability of the developed conditions in more
complex settings, the iodination of several commercially avail-
able arene-containing NPs and derivatives was investigated
(Scheme 2). Iodination of ꢀ-estradiol (15) under standard
conditions gave monoiodination product 15a in 80% yield along
with 7% of diiodination product 15b and 9% of recovered
starting material. Compared with previously reported ꢀ-estradiol
iodinations with NaClO2/NaI/HCl,13 chloramine-T/NaI,14 and
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(11) Use of benzene as solvent gave <50% conversion.
(12) Low conversions (<10%) were observed for electron poor arenes,
such as chlorobenzene and methyl benzoate under standard conditions.
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