Mild and selective organocatalytic iodination of activated aromatic compounds

Article abstract of DOI:10.1055/s-0033-1338468

We describe an organocatalytic iodination of activated aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) as the iodine source with thiourea catalysts in acetonitrile. The protocol is applicable to a number of aromatic substrates with significantly different steric and electronic properties. The iodination is generally highly regioselective and provides high yields of isolated products. NMR kinetic investigations conducted in THF-d ₈indicate the role of sulfur in the thiourea motif as a nucleophile that is assisted by H-bonding in the key steps of the reaction. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1338468

SPECIAL TOPIC
▌1635
special topic
Mild and Selective Organocatalytic Iodination of Activated Aromatic
Compounds
Organocatalytic Aromatic Iodination
Gergely Jakab, Abolfazl Hosseini, Heike Hausmann, Peter R. Schreiner*
Institute of Organic Chemistry, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
Fax +49(641)9934309; E-mail: prs@uni-giessen.de
Received: 23.02.2013; Accepted: 17.03.2013
and computational tools.14 Husebye et al. proposed that
these adducts stemmed from a common [LS–X]+ type in-
termediate, where a halogen (X) is covalently bound to the
sulfur atom of an organic framework (L).15 Recently,
Abstract: We describe an organocatalytic iodination of activated
aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin
(DIH) as the iodine source with thiourea catalysts in acetonitrile.
The protocol is applicable to a number of aromatic substrates with
significantly different steric and electronic properties. The iodin- Barbas and co-workers observed that 1,3-dibromo-5,5-di-
ation is generally highly regioselective and provides high yields of
isolated products. NMR kinetic investigations conducted in THF-d8
indicate the role of sulfur in the thiourea motif as a nucleophile that
mechanism of the reaction has not been elucidated com-
is assisted by H-bonding in the key steps of the reaction.
methylhydantoin and a bifunctional thiourea organocata-
lyst promoted the bromination of anisole.16 Although the
pletely, partial evidence points to the sulfur atom of the
thiourea group as the essential catalytic moiety. However,
an H-bonding involvement cannot be unambiguously dis-
Key words: catalysis, electrophilic aromatic substitution, haloge-
nation, iodine, thiourea
missed. Intrigued by the potential value of an environ-
mentally benign organocatalytic iodination method, we
Iodinated aromatic compounds are versatile substrates for
decided to explore the feasibility of thiourea derivatives as
metal-catalyzed reactions,1 and isotopically labeled aryl
catalysts in the iodination of aromatics.
iodides find use in diagnostic medicine.2 As a conse-
We started our investigation by replacing the bifunctional
quence, several direct aromatic iodinations have been de-
thiourea derivative used by Barbas and co-workers16 with
T1 in a similar iodination reaction between 1,2-dimeth-
oxybenzene (1) and DIH in dichloromethane. To our de-
light, moderate conversion to the desired product was
veloped for their synthesis.3 Compared to other halogens,
iodine is scarce and shows poor reactivity in electrophilic
substitutions, and the use of elemental iodine alone is gen-
erally impractical. Activation often involves harsh reac-
observed (Table 1, entry 1), which was further improved
tion conditions, strong acids, and toxic heavy metal salts,
by adding an excess of iodinating reagent (entries 3, 4).
which limits functional group tolerance and raises envi-
However, overiodination became more prevalent as the
ronmental concerns.3a Instead, iodine transfer reagents
reagent load was increased. Note that NIS proved to be an
can be utilized, such as N-iodosuccinimide (NIS)4 or 1,3-
unsuitable iodine source under the applied reaction condi-
diiodo-5,5-dimethylhydantoin (DIH).5 In most cases
tions (entry 2). Dichloromethane gave satisfactory results
Brønsted or Lewis acids may be necessary to enhance
as solvent, but the reaction mixture was heterogeneous
their reactivity.6
owing to the low solubility of DIH. Although the precipi-
N,N′-Di[3,5-bis(trifluoromethyl)phenyl]thiourea
(T1)
tate had mostly dissolved by the end of the reaction, this
still denied the possibility for kinetic investigations. Tet-
rahydrofuran, on the other hand, turned out to be an excel-
lent solvent for all reaction components (Table 1, entry 6).
As aromatic iodinations involve ionic transition states17
that are stabilized by polar media, other polar solvents
were also considered. In agreement with this argument,
NIS was reported to iodinate highly activated aromatics in
polar solvents (e.g., DMSO, acetonitrile) without addi-
tives.4b,j Therefore, we expected substantial background
reactivity in our reaction when carried out in such media.
Indeed, the uncatalyzed reaction in acetonitrile furnished
1-iodo-3,4-dimethoxybenzene in 69% yield after 20
hours. However, in the presence of 10 mol% T1 under
otherwise identical conditions the iodination was com-
pleted within only 30 minutes, and acetonitrile became
our solvent of choice. Note that acetonitrile failed to com-
pletely dissolve DIH in the reaction mixture, rendering it
unsuitable for kinetic studies. Acetone was discarded be-
was developed in our laboratory7 and has found many ap-
plications as H-bonding organocatalyst.8 The mode of ac-
tivation provided by such a catalyst resembles in many
aspects to that of Lewis acids,7,9 but under much milder re-
action conditions. Lately, the sulfur atom of T1 was also
recognized as a potential nucleophilic catalyst in the nu-
cleophilic activation of NBS for the oxidation of alco-
hols.10 Furthermore, sulfur-based nucleophilic catalysts
are very effective activators of bromine and iodine trans-
fer reagents.11 For instance, cinchona alkaloid-based thio-
carbamate catalysts are highly efficient in asymmetric
bromolactonizations.12 This is not surprising given the
well documented affinity between sulfur donors and halo-
gens;13 a myriad of different sulfur-halogen adducts have
been characterized via spectroscopic, crystallographic,
SYNTHESIS 2013, 45, 1635–1640
Advanced online publication: 25.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338468; Art ID: SS-2013-C0157-ST
© Georg Thieme Verlag Stuttgart · New York

1636
G. Jakab et al.
SPECIAL TOPIC
cause of the formation of iodoacetone in a side reaction at the same time. These two requirements often demand
(Table 1, entry 5).
contrasting catalytic features, since selectivity calls for the
recognition of subtle differences, while a generally appli-
cable system needs to transform a wide variety of sub-
strates. Since the substrate limitations of our method were
unknown, the reaction was first extended to a number of
different aromatic compounds without fine tuning reac-
tion conditions or altering the catalyst (Figure 1). A two-
fold scale-up was implemented to the standard procedure
of the optimization study to decrease the impact of prod-
uct loss on yields upon isolation. The selectivity of each
reaction was determined prior to purification via 1H NMR
spectroscopy by comparing integral values of characteris-
tic product signals and that of the major impurity. Reac-
tion times varied from 1.5 to 24 hours, largely depending
on the electronic properties of the substrates. The pres-
ence of electron-donating groups on the aromatic ring was
obviously decisive; the least electron-rich compound to
react was o-xylene. Aldehydes are generally prone to ox-
idation to the corresponding carboxylic acids, and they are
considered sensitive substrates. Note that no oxidation
side product was detected, when 3-methoxybenzaldehyde
was iodinated. However, the electron-withdrawing alde-
hyde group decreased the reactivity of the aromatic ring
leading to 4a in moderate yield. Compound 3a was previ-
ously synthesized via In(OTf)3-catalyzed iodination with
2:1 regioselectivity.4c In contrast, iodination of 3-chloro-
1-methoxybenzene with DIH in the presence of T1
showed a significantly higher preference for the desired
isomer (9:1). Recently, another iodination method was re-
ported for the same compound without discussing the se-
lectivity of the transformation.18 Electron-rich compounds
bearing multiple electron-donating groups on the same ar-
omatic ring proved to be potent substrates. However,
overiodination aptitude rose proportionally. In order to
prevent the introduction of a second iodine to 9a, only 0.5
Our goal was to develop a general method for the iodin-
ation of aromatics, which is broad in scope and selective
Table 1 Optimization of the Reaction Conditions in the T1-Cata-
lyzed Iodination of 1,2-Dimethoxybenzene with DIHa
MeO
MeO
MeO
MeO
MeO
MeO
I
I
T1 (10%)
+
I
1
1a
1b
Entry
DIH
Solvent
Conv.
(%)b
Yield (%)c
of 1b
(equiv)
1
0.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
acetone
THF
58
3
n.d.
n.d.
35
2
1.0d
1.0
3
100
100
84
4
0.75
0.75
0.75
0.75
0.75
0.75
19
5
45b,e
11
6
100
100 (86)f
7
7
MeCN
THF
4
8g
9g
n.d.
n.d.
MeCN
76 (69)f
a Reaction conditions: T1 (10 mol%), 1,2-dimethoxybenzene (0.3
mmol), solvent (1 mL), r.t., 20 h.
b Determined by GC-MS.
c Determined by 1H NMR analysis of the crude reaction mixture;
n.d. = not detected.
d NIS as iodine source.
e Iodoacetone.
f Isolated product yield in parentheses.
g In the absence of T1.
OMe
OMe
OMe
OMe
OMe
Cl
CHO
I
I
I
3a
I
4a
I
5a
1a
2a
76%
9:1
66%
6:1
85%
32:1
68%
49:1
65%
5:1
OMe
I
I
I
NHAc
OMe
MeO
OMe
I
OMe
I
7a
6a
8a
9a
10a
92%
>50:1
92%
49:1
89%
83%
>50:1
86%
>50:1
>50:1
Figure 1 Substrate scope of the organocatalytic iodination reaction of activated aromatic compounds catalyzed by T1 in acetonitrile. The stan-
dard reaction conditions were as follows: T1 (10 mol%), substrate (0.6 mmol), MeCN (2 mL), DIH (0.75 equiv), r.t., 1.5–24 h. Yields (%) were
determined after purification. Note that our attempts to isolate compound 2a from the isomeric by-product failed. The selectivity refers to the
ratio of the main product and the major by-product, which was determined by 1H NMR spectroscopy from the crude reaction mixture. For fur-
ther details, see Supporting Information.
Synthesis 2013, 45, 1635–1640
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Aromatic Iodination
1637
R1
R1
equivalent of DIH was added. No such measure was nec-
essary with acetanilide, probably due to the bulkier NHAc
substituent shielding the ortho-position of the ring from
iodination. The screening results were deemed satisfacto-
ry and no attempts were made to further improve them. In-
stead, we focused on kinetic investigations to shed some
light on the reaction mechanism.
X
R2
N
R3
N
R4
R2
T1: X = S, R1 = CF3, R2 = CF3, R3 = H, R4 = H
U1: X = O, R1 = CF3, R2 = CF3, R3 = H, R4 = H
T2: X = S, R1 = CF3, R2 = H, R3 = H, R4 = H
T3: X = S, R1 = H, R2 = H, R3 = H, R4 = H
Owing to insufficient solubility of DIH in acetonitrile, ki-
netic measurements were carried out in THF-d8. Assum-
ing that there is no fundamental difference between the
reaction mechanism in THF-d8 and that in acetonitrile, it
was considered that the conclusions of our kinetic investi-
gations obtained in THF-d8 to be generally applicable.
Apart from the better solubility of the reactants in THF, it
displayed negligible background activity producing 7% 1-
iodo-3,4-dimethoxybenzene after 20 hours (Table 1, entry
8). The reaction catalyzed by 10 mol% T1 under other-
wise identical conditions underwent full conversion after
6 hours, providing a convenient kinetic timescale. Recent-
ly, we demonstrated the beneficial role of the 3,5-bis(tri-
fluoromethyl)phenyl group in organocatalysis,19 and the
impact of CF3 groups on thiourea NH equilibrium acidi-
ties,20 which is directly connected to a catalyst’s H-bond
donor ability. Furthermore, the number of electron-with-
drawing groups attached to the aromatic rings of the bi-
phenyl thiourea derivatives is likely to influence the
nucleophilicity of the sulfur atom. Hence, a series of sim-
ilar (thio)urea derivatives were synthesized (Figure 2) to
demonstrate the effect of CF3 groups on catalytic activity
by comparing the performance of T1 (pKa = 8.5 in
DMSO),20 T2 (pKa = 10.9 in DMSO),20 and T3
(pKa = 13.4 in DMSO)21 in the iodination of 1,2-dimeth-
oxybenzene in THF-d8 (Figure 3). Although T1 accounted
for a much higher overall reaction rate, in the initial period
T2 exhibited higher activity, which was subsequently at-
tenuated. The reaction came to a complete stop after 41%
conversion. When additional DIH was added to this mix-
ture, the reaction resumed its original course displaying a
reaction progress similar to the initial one (Supporting
Information). One can conclude that the pause in reaction
was not caused by catalyst decomposition or inhibition,
but rather by a competing side reaction consuming the io-
dine source. We suspect that the side reaction displays
somewhat different dependence on catalyst structure than
the desired reaction. Consequently, different catalysts not
only alter the initial rate of the reaction, but cause distinct
curves (Figure 3). Instead of experimenting with thiourea
derivatives providing even weaker H-bonds, catalyst T4
was tested, which is completely deprived of this feature,
while maintaining an electronically very similar sulfur
moiety to that of T1. Significant acceleration was detect-
ed, which is in line with previous observations pointing to
the sulfur atom as the key ingredient for catalysis (Figure
4). Accordingly, urea derivative U1 showed poor perfor-
mance. Note that the oxygen–sulfur exchange also de-
creases acidic strength, which limits H-bonding
aptitude.20,21 These findings indicate that although the H-
bond donor ability is not a prerequisite for catalysis, the
presence of thiourea N–H bonds in T1 is clearly benefi-
T4: X = S, R1 = CF3, R2 = CF3, R3 = Me, R4 = Me
T5: X = S, R1 = CF3, R2 = CF3, R3 = Me, R4 = H
Figure 2 (Thio)urea derivatives used to perform kinetic investiga-
tion in the iodination reaction of 1,2-dimethoxybenzene and DIH in
THF-d8
Figure 3 Kinetic plot displaying the effect of CF3 groups on thiourea
catalytic activity in the iodination reaction of 1,2-dimethoxybenzene
in THF-d8
Figure 4 Kinetic plot displaying the effect of (thio)urea N–Hs on re-
action rates in the catalytic iodination reaction of 1,2-dimethoxyben-
zene in THF-d8
cial. Contrastingly, significant loss of activity was ob-
served when only one NH group is available in catalyst
T5.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1635–1640

1638
G. Jakab et al.
SPECIAL TOPIC
I
O
N
N
DIH
CF3
CF3
CF3
CF3
CF3
I
O
S
S
SH
H
F3C
N
N
CF3
F3C
N
N
F3C
N
N
CF3
H
H
H
H
IV
T1
I
F3C
CF3
1a
HDIH
CF3
CF3
F3C
F3C
MeO
MeO
O
O
N
N
H
H
N
N
H
H
I
I
S
N
N
S
I
N
N
I
H
O
O
1
F3C
F3C
III
II
CF3
CF3
Scheme 1 Proposed mechanism for the iodination of 1,2-dimethoxybenzene via catalytic iodine transfer reaction
Based on our experimental results we propose the follow- urea moiety. We suspect that H-bonding interactions are
ing mechanism for the model reaction of 1,2-dimethoxy- involved in the rate determining step. Since H-bonding
benzene and DIH catalyzed by T1 (Scheme 1). The first ability is the only cardinal difference between T1, T4, and
step is a complex formation between T1 and DIH that is T5 that differ significantly in their reaction rates. In order
held together by a mixture of hydrogen and halogen to determine the precise course of the reaction and to iden-
bonding13,22 (I). This weakens the N–I bond of DIH and tify the rate determining step further investigations are
eventually iodine transfer can occur to the sulfur atom of needed.
the catalyst to give, after C–N bond rotation, structure II.
In summary, a convenient and direct aromatic iodination
protocol was developed, offering a viable compromise be-
The formation of an [LS–I]+ like species is in line with the
aforementioned studies on chalcogen-halogen adducts.
tween general utility and selectivity. Variation in the cat-
Furthermore, 13C NMR measurements were conducted on
1
alyst motif and H NMR kinetic investigations provided
various thiourea derivatives prior to and following the ad-
the basis for a preliminary mechanistic proposal. Our
dition of an iodine source. The C=S carbon peak exhibited
findings underline the role of the nucleophilic sulfur atom
significant upfield shifts, which indicates a pronounced
of the thiourea motif as key structural element, and sug-
change in the electronic environment of the thiourea car-
gest H-bonding involvement in the transition state. Block-
bon atom (Supporting Information), consistent with the
ing one or two H-bonding sites of the thiourea moiety of
effects of the proposed iodine exchange between the cata-
T1 brought about significant reductions in reaction rates.
lyst and DIH. At the same time the electrophilic iodine is
Further investigations are currently underway in our labo-
more accessible in II, as the anion resides on the other side
ratory to explore the full potential of this reaction.
of the thiourea group. It is likely that the inefficiency of
T5 bearing only one N–H bond is due to this conforma-
tional change not being favorable. The next step is the
Melting points were recorded on a Krüss KSP1N melting-point
Meter and are uncorrected. IR spectra were obtained using a Bruker
classical formation of the σ-complex of a typical electro-
philic aromatic substitution, where the positively polar-
ized iodine attacks the aromatic ring of the 1,2-
dimethoxybenzene (1) to form ternary complex III. Sub-
sequent re-aromatization of the phenyl ring occurs, when
a proton eliminates from the σ-complex intermediate. The
catalyst thus acts as a proton shuttle, providing a basic (S)
and an acidic (NH) site in an apparent transfer of the elim-
inating proton to the DIH anion, thereby completing the
substitution reaction (IV). As a final step the catalyst un-
dergoes a tautomeric transformation that restores the thio-
Alpha FT-IR Spectrometer. 1H and 13C NMR spectra were recorded
on a Bruker AV400, or a Bruker AV600 Spectrometer, using TMS
as the internal standard with chemical shifts given in ppm relative
to TMS, or the respective solvent residual peaks. HRMS spectra
were recorded on a Thermo Finnigan MAT 95 Mass Spectrometer
or on an AP MALDI23 Q Exactive Mass Spectrometer (Thermo
Fisher Scientific). C, H, N analyses were performed on a Thermo
Flash EA 1112 device. Column chromatography was conducted us-
ing Merck silica gel 60 (0.040–0.063 mm). Starting materials, sol-
vents, and reagents were purchased from commercial sources,
unless otherwise noted and were used without purification. For fur-
ther details see Supporting Information.
Synthesis 2013, 45, 1635–1640
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Organocatalytic Aromatic Iodination
1639
1
N,N′-Dimethyl-N,N′-di[3,5-bis(trifluoromethyl)phenyl]thio-
urea (T4)
rity profile was determined prior to purification using H NMR
spectroscopy; the major by-product was 1-iodo-2,3-dimethoxyben-
zene (2%). The crude product was purified by column chromatog-
raphy on silica gel (hexanes–EtOAc, 10:1) to furnish 1a (137 mg,
86%) as a white solid; mp 31–32 °C.
A dry 100 mL two-necked flask was equipped with an argon inlet.
Under protective atmosphere the flask was charged with N-methyl-
3,5-bis(trifluoromethyl)aniline (0.600 g, 2.5 mmol) and anhyd THF
(10 mL). The solution was cooled to –78 °C in a dry ice/acetone
bath and n-BuLi (1.6 M in hexanes, 1.6 mL, 2.6 mmol) was added
dropwise via syringe. The yellow reaction mixture was stirred for
15 min followed by the addition of thiophosgene (100 μL, 1.3
mmol). The solution was stirred at –78 °C for 1 h, and then it was
allowed to warm to r.t. and stirred overnight. Sat. aq NH4Cl (6 mL)
was added to quench the reaction and the crude product was extract-
ed with EtOAc (2 × 40 mL). The combined organic phases were
washed with H2O (2 × 20 mL), dried (Na2SO4), and concentrated.
Purification by column chromatography (hexanes–EtOAc, 20:1) on
silica gel furnished 59 mg of a yellow oil. MeOH (1 mL) was added
and the precipitated white solid was collected by filtration and dried
in vacuo to yield pure T4 (43 mg, 3%) as a white solid; mp 173–
174 °C.
IR (KBr): 2955, 2927, 2835, 1580, 1501, 1250, 1227, 1176, 1135,
1020, 836, 797 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.23 (dd, J1 = 8.6 Hz, J2 = 2.1 Hz,
1 Harom, H-6), 7.12 (d, J = 2.1 Hz, 1 Harom, H-2), 6.62 (d, J = 8.6 Hz,
1 Harom, H-5), 3.86 (s, 3 H, CH3), 3.85 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 149.8, 149.1, 129.8, 120.3, 113.1,
82.4, 56.1, 55.9.
HRMS (EI): m/z calcd for C8H9IO2: 263.965; found: 263.968.
Acknowledgment
We thank Erwin Röcker for HRMS measurements on Thermo Fin-
nigan MAT 95 Mass Spectrometer and Dhaka Ram Bhandari and
Bernhard Spengler for HRMS measurements on AP MALDI Q
Exactive Mass Spectrometer.
IR (KBr): 3038, 2935, 1615, 1473, 1380, 1278, 1181, 1147, 1035,
892, 846, 702, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.48 (s, 2 Harom, p-H), 7.06 (s, 4
Harom, o-H), 3.62 (s, 6 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 189.9, 148.0, 132.9 (q, J = 34.2
Hz), 125.2, 122.4 (q, J = 276.4 Hz), 119.3, 44.8.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (AP MALDI): m/z [M + H]+ calcd for C19H13F12N2S:
529.05968; found: 529.07468.
References
N-Methyl-N,N′-di[3,5-bis(trifluoromethyl)phenyl]thiourea
(T5)
(1) (a) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
(b) Tsuji, J. Transition Metal Reagents and Catalysts;
Wiley: New York, 2003. (c) Hassan, J.; Sévignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359. (d) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 58, 9633. (e) Diederich, F.; Stang, P. J. Metal-
Catalyzed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 1998. (f) Fanta, P. E. Synthesis 1974, 9.
(2) (a) Koehler, L.; Gagnon, K.; McQuarrie, S.; Wuest, F.
Molecules 2010, 15, 2686. (b) Welch, M. J.; Redvanly, C. S.
Handbook of Radiopharmaceuticals: Radiochemistry and
Applications 2005. (c) Seevers, R. H.; Counsell, R. E. Chem.
Rev. 1982, 82, 575.
A dry 10 mL two-necked flask was equipped with argon inlet. The
flask was charged with N-methyl-3,5-bis(trifluoromethyl)aniline
(0.5 g, 2.1 mmol) and anhyd CH2Cl2 (2 mL). Under argon atmo-
sphere i-Pr2NEt (0.35 mL, 2.1 mmol) and 3,5-bis(trifluorometh-
yl)phenyl isothiocyanate (0.613 g, 413 μL, 2.3 mmol) were added
and the reaction mixture was stirred overnight at r.t. The solution
was diluted with CH2Cl2 (30 mL), and the organic layer was washed
with aq HCl (2 × 10 mL, 5% v/v) and H2O (10 mL). The organic
layer was dried (Na2SO4) and concentrated to furnish a yellow oil.
The crude product was purified by column chromatography (hex-
anes–CH2Cl2, 1:1) on silica gel to give T5 (0.55 g, 52%) as an off-
white solid; mp 105–106 °C.
(3) (a) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487.
(b) Merkushev, E. B. Synthesis 1988, 923.
IR (KBr): 3378, 3085, 2948, 1620, 1526, 1475, 1430, 1377, 1279,
1179, 1135, 884, 703, 683 cm–1.
(4) (a) Mortensen, M. A.; Guo, C.; Reynolds, N. T.; Wang, L.;
Helle, M. A.; Keefe, D. K.; Haney, B. P.; Paul, B. J.;
Bruzinski, P. R.; Wolf, M. A.; Malinowski, N. L.; Yang, Q.
Org. Process Res. Dev. 2012, 16, 1811. (b) Shen, H.;
Vollhardt, K. P. C. Synlett 2012, 23, 208. (c) Zhou, C.-Y.;
Li, J.; Peddibhotla, S.; Romo, D. Org. Lett. 2010, 12, 2104.
(d) Bovonsombat, P.; Leykajarakul, J.; Khan, C.; Pla-on, K.;
Krause, M. M.; Khanthapura, P.; Ali, R.; Doowa, N.
Tetrahedron Lett. 2009, 50, 2664. (e) Bovonsombat, P.;
Khanthapura, P.; Krause, M. M.; Leykajarakul, J.
1H NMR (400 MHz, CDCl3): δ = 7.91 (s, 1 Harom, p-H), 7.80 (s, 2
Harom, o-H), 7.75 (s, 2 Harom, ortho-H), 7.67 (s, 1 Harom, p-H), 7.05
(br s, 1 H, NH), 3.77 (s, 3 H, NCH3).
13C NMR (100 MHz, CDCl3): δ = 182.2, 144.9, 140.0, 134.3 (q,
J = 35.6 Hz), 132.1 (q, J = 35.6 Hz), 127.4, 125.4, 122.8 (q,
J = 273.4 Hz), 122.4 (q, J = 273.4 Hz), 122.4, 119.7, 43.9.
HRMS (AP MALDI): m/z [M + H]+ calcd for C18H11F12N2S:
515.04404; found: 515.04464.
Anal. Calcd for C18H10F12N2S: C, 42.03; H, 1.96; N, 5.45. Found: C,
41.75; H, 2.02; N, 5.16.
Tetrahedron Lett. 2008, 49, 7008. (f) Chaikovskii, V.;
Filimonov, V.; Skorokhodov, V.; Ogorodnikov, V. Russ. J.
Org. Chem. 2007, 43, 1278. (g) Yadav, J. S.; Reddy, B. V.
S.; Reddy, P. S. R.; Basak, A. K.; Narsaiah, A. V. Adv. Synth.
Catal. 2004, 346, 77. (h) Pu, Y.-M.; Grieme, T.; Gupta, A.;
Plata, D.; Bhatia, A. V.; Cowart, M.; Ku, Y.-Y. Org. Process
Res. Dev. 2004, 9, 45. (i) Castanet, A.-S.; Colobert, F.;
Broutin, P.-E. Tetrahedron Lett. 2002, 43, 5047. (j) Carreño,
M. C.; García Ruano, J. L.; Sanz, G.; Toledo, M. A.; Urbano,
A. Tetrahedron Lett. 1996, 37, 4081. (k) Olah, G. A.; Wang,
Q.; Sandford, G.; Surya Prakash, G. K. J. Org. Chem. 1993,
58, 3194. (l) Bovonsombat, P.; Angara, G. J.; McNelis, E.
Synlett 1992, 131.
Iodination of Aromatic Compounds; 1-Iodo-3,4-dimethoxyben-
zene (1a); Typical Procedure
A dry Schlenk tube was equipped with a stirring bar and was purged
with argon. T1 (30 mg, 0.06 mmol, 10%) was placed in the reaction
vessel followed by anhyd MeCN (2 mL) and 1,2-dimethoxybenzene
(82 mg, 76 μL, 0.60 mmol). DIH (171 mg, 0.45 mmol, 0.75 equiv)
was added in one portion, and the mixture was stirred at r.t. The pro-
gression of the reaction was followed by GC-MS. After 90 min, aq
Na2S2O3 (20 mL, 10 m/m%) was added to quench the reaction. The
resulting mixture was extracted with CH2Cl2 (3 × 20 mL), the com-
bined organic phases were dried (Na2SO4), and concentrated. Impu-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1635–1640

1640
G. Jakab et al.
SPECIAL TOPIC
(5) (a) Kamei, T.; Shibaguchi, H.; Sako, M.; Toribatake, K.;
Shimada, T. Tetrahedron Lett. 2012, 53, 3894.
Grimaldi, P.; Isaia, F.; Lelj, F.; Lippolis, V. Eur. J. Inorg.
Chem. 2006, 2166. (c) Aragoni, M. C.; Arca, M.; Demartin,
F.; Devillanova, F. A.; Garau, A.; Isaia, F.; Lippolis, V.;
Verani, G. J. Chem. Soc., Dalton Trans. 2005, 2252.
(d) Corban, G. J.; Hadjikakou, S. K.; Hadjiliadis, N.;
Kubicki, M.; Tiekink, E. R. T.; Butler, I. S.; Drougas, E.;
Kosmas, A. M. Inorg. Chem. 2005, 44, 8617. (e) Antoniadis,
C.. D.; Hadjikakou, S.. K.; Hadjiliadis, N.; Kubicki, M.;
Butler, I.. S. Eur. J. Inorg. Chem. 2004, 4324. (f) Antoniadis,
C.. D.; Corban, G.. J.; Hadjikakou, S.. K.; Hadjiliadis, N.;
Kubicki, M.; Warner, S.; Butler, I. S. Eur. J. Inorg. Chem.
2003, 1635. (g) Daga, V.; Hadjikakou, S. K.; Hadjiliadis, N.;
Kubicki, M.; dos Santos, J. H. Z.; Butler, I.. S. Eur. J. Inorg.
Chem. 2002, 1718. (h) Aragoni, M. C.; Arca, M.; Demartin,
F.; Devillanova, F. A.; Garau, A.; Isaia, F.; Lelj, F.; Lippolis,
V.; Verani, G. Chem. Eur. J. 2001, 7, 3122. (i) Boyle, P. D.;
Godfrey, S. M. Coord. Chem. Rev. 2001, 223, 265.
(j) Bricklebank, N. J.; Skabara, P. E.; Hibbs, D. B.;
Hursthouse, M. M.; Abdul Malik, K. J. Chem. Soc., Dalton
Trans. 1999, 3007.
(b) Chaikovskii, V.; Filimonov, V. D.; Funk, A. A.;
Skorokhodov, V. I.; Ogorodnikov, V. D. Russ. J. Org. Chem.
2007, 43, 1291. (c) Raab, C. E.; Dean, D. C.; Melillo, D. G.
J. Labelled Compd. Radiopharm. 2001, 44, 815. (d) Orazi,
O. O.; Corral, A.; Bertorello, H. E. J. Org. Chem. 1965, 30,
1101.
(6) Selected example: Prakash, G. K. S.; Mathew, T.; Hoole, D.;
Esteves, P. M.; Wang, Q.; Rasul, G.; Olah, G. A. J. Am.
Chem. Soc. 2004, 126, 15770.
(7) (a) Wittkopp, A.; Schreiner, P. R. Diels–Alder Reactions in
Water and in Hydrogen-Bonding Environments, In The
Chemistry of Dienes and Polyenes; Vol. 2; Rappoport, Z.,
Ed.; John Wiley & Sons Inc.: Chichester, 2000, 1029.
(b) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
(8) (a) Hof, K.; Lippert, K. M.; Schreiner, P. R. In Science of
Synthesis. Asymmetric Organocatalysis 2. Bønsted Base and
Acid Catalysis and Additional Topics; Maruoka, K., Ed.;
Thieme: Stuttgart, 2012. (b) Zhang, Z.; Schreiner, P. R.
Chem. Soc. Rev. 2009, 38, 1187. (c) Kotke, M.; Schreiner, P.
R. In Hydrogen Bonding in Organic Synthesis; Wiley-VCH:
Weinheim, 2009, 141. (d) Schreiner, P. R. Chem. Soc. Rev.
2003, 32, 289.
(15) Rudd, M. D.; Lindeman, S. V.; Husebye, S. Acta Chem.
Scand. 1997, 51, 689.
(16) Hernández-Torres, G.; Tan, B.; Barbas, C. F. Org. Lett.
2012, 14, 1858.
(9) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259.
(10) Tripathi, C. B.; Mukherjee, S. J. Org. Chem. 2012, 77, 1592.
(11) (a) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew.
Chem. Int. Ed. 2012, 51, 10938. (b) Zhou, L.; Chen, J.; Tan,
C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164.
(c) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A.
2010, 107, 20655.
(12) (a) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012,
48, 5793. (b) Chen, J.; Zhou, L.; Yeung, Y.-Y. Org. Biomol.
Chem. 2012, 10, 3808. (c) Chen, J.; Zhou, L.; Tan, C. K.;
Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999. (d) Tan, C. K.;
Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738. (e) Zhou,
L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 15474.
(17) Galli, C. J. Org. Chem. 1991, 56, 3238.
(18) Albadi, J.; Abedini, M.; Iravani, N. Chin. Chem. Lett. 2012,
23, 261.
(19) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.;
Guenther, S.; Schreiner, P. R. Eur. J. Org. Chem. 2012,
5919.
(20) Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K. M.; Schreiner,
P. R. Org. Lett. 2012, 14, 1724.
(21) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(22) (a) Arman, H. D.; Gieseking, R. L.; Hanks, T. W.;
Pennington, W. T. Chem. Commun. 2010, 46, 1854. (b) Jay,
J. I.; Padgett, C. W.; Walsh, R. D. B.; Hanks, T. W.;
Pennington, W. T. Cryst. Growth Des. 2001, 1, 501.
(23) Koestler, M.; Kirsch, D.; Hester, A.; Leisner, A.; Guenther,
S.; Spengler, B. Rapid Commun. Mass Spectrom. 2008, 22,
3275.
(13) Aragoni, M. C.; Arca, M.; Devillanova, F. A.; Isaia, F.;
Lippolis, V. Cryst. Growth Des. 2012, 12, 2769.
(14) (a) Papayannis, D. K.; Kosmas, A. M. THEOCHEM 2008,
851, 175. (b) Aragoni, M. C.; Arca, M.; Devillanova, F. A.;
Synthesis 2013, 45, 1635–1640
© Georg Thieme Verlag Stuttgart · New York