A new, mild one-pot synthesis of iodinated heterocycles as suitable precursors for N-heterocyclic carbene complexes

Article abstract of DOI:10.1016/j.tetlet.2010.07.178

The use of I₂/AgOAc in dichloromethane constitutes a cheap, mild, and efficient method for the selective iodination of a variety of heterocycles. In a number of cases, this method provides superior yields to other literature methods and affords iodo-functionalized heterocycles that are suitable precursors for carbene complexes.

Full text of DOI:10.1016/j.tetlet.2010.07.178

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Tetrahedron Letters 51 (2010) 5423–5425
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new, mild one-pot synthesis of iodinated heterocycles as suitable
precursors for N-heterocyclic carbene complexes
Manuel Iglesias a, Oliver Schuster b, , Martin Albrecht a,
*
a School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
b Department of Chemistry, University of Fribourg, Chemin du Musée 9, CH-1700 Fribourg, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of I2/AgOAc in dichloromethane constitutes a cheap, mild, and efficient method for the selective
iodination of a variety of heterocycles. In a number of cases, this method provides superior yields to other
literature methods and affords iodo-functionalized heterocycles that are suitable precursors for carbene
complexes.
Received 26 June 2010
Revised 22 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocycles
Iodination
Ligand precursors
Abnormal carbene complexes
Palladation
N-heterocyclic carbenes (NHCs) have been shown to be versa-
tile ligands for transition metal complexes.1 Most importantly,
these ligands have an outstanding impact on many homogeneous
catalysts, often outperforming more common phosphine ligands.2
Metal coordination to NHCs has been achieved by a variety of
methods. Among these, oxidative addition is particularly attractive
because of the typically mild reaction conditions and the high
product selectivity. Moreover, oxidative addition avoids the syn-
thesis of the corresponding free carbene or the silver carbene inter-
mediates, which may not be easily accessible or even unfeasible
due to their low stability.3 For the generation of N-heterocyclic car-
bene complexes via C–X bond oxidative addition, iodo-functional-
ized heterocycles serve particularly as convenient precursors.4 In
addition, the iodination of aromatic heterocycles is a matter of
continuing interest in medicinal chemistry5 and in modern organic
chemistry, which is making extensive use of iodinated derivatives
as building blocks for carbon–carbon bond-forming reactions.6
The synthesis of iodinated aromatic heterocycles can be
achieved by direct iodination of CHet–H bonds7 or by nucleophilic
substitution of CHet–X,8 where X is a good leaving group. The for-
mer method relies on the presence of Lewis acids or strong oxidiz-
ing agents to overcome the low electrophilicity of iodine. On the
other hand, the latter method requires the pre-installation of a
good leaving group. Even though the literature offers a variety of
synthetic protocols for the preparation of iodinated (hetero)aro-
matic compounds, harsh conditions and expensive or toxic chem-
icals are often required. In addition, one single methodology
typically does not perform well for different substrates, thus illus-
trating the need for the further development of efficient and reli-
able methodologies for the synthesis of iodinated heterocycles.
Herein we report convenient and inexpensive methods for the
synthesis of a range of iodinated N-heterocycles that are suitable
precursors for non-classical NHC transition metal complexes
(Scheme 1). We successfully applied the iodine–iodide (I2 and KI)
methodology4b for the preparation of compound 2a and its
N-methylated derivative 2b from the corresponding halide-free
imidazoles 1a and 1b, respectively (Table 1, entries 1 and 2). How-
ever, this method failed to iodinate 3,5-dimethylisoxazole (1c) for
which mainly the starting material was recovered (entry 3). In
contrast, the use of silver acetate and iodine afforded the desired
3,5-dimethyl-4-iodoisoxazole (2c) in almost quantitative yield
(98%). In addition, better yields were obtained for the iodination
H
I
Mn+2
I
N-alkylation
het
het
het
* Corresponding author. Tel.: +353 1716 2504; fax: +353 1716 2501.
E-mail addresses: oliver.schuster@unifr.ch (O. Schuster), martin.albrecht@ucd.ie
(M. Albrecht).
oxidative
addition of
Mn
iodination
Correspondence pertaining to crystallographic analyses should be addressed: fax:
+41 26300 9738.
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.178

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M. Iglesias et al. / Tetrahedron Letters 51 (2010) 5423–5425
Table 1
(1a), 2-methylimidazole (1e), and (1f). The iodinated imidazoles
2d and 2a and the diiodinated imidazole 3e were obtained in good
yields and high selectivity (88%, 58% and 93%, respectively). Con-
versely, iodination of 1-methylimidazole (1f) was not selective
and afforded a mixture containing several products. Analysis using
NMR spectroscopy and mass spectrometry, and comparison with
authentic products obtained via different routes indicated that
the product mixture includes 2,5-diiodo-1-methylimidazole and
1-methyl-2-iodoimidazole as the main products in an approximate
2:3 ratio. The desired mono-iodinated heterocycle 2f was easily
separated by column chromatography (SiO2, Et2O) to give the pure
product in 46% isolated yield (along with pure 3f, 30% isolated
yield). This method thus represents a more convenient alternative
to the synthesis of 1-methyl-2-iodoimidazole compared to other
literature methods,11 in particular because it does not require
strictly anhydrous conditions nor the handling of sensitive organo-
lithium reagents.
Attempts to iodinate 3-methylpyridine (1g) by either the I2/KI
or the I2/AgOAc route failed thus far. Successful formation of
2-iodo-3-methylpyridine (2g) was accomplished, however, by
reacting 2-bromo-3-methylpyridine (4) with sodium iodide and
trimethylsilyl chloride in MeCN (Scheme 2).8b Long reaction times
(>7 days) and high temperatures were required in order to obtain
the desired iodinated pyridine 2g in good yield (82%). The 1H and
13C NMR signals of the iodinated product barely differ from the
brominated starting material, and mass spectrometry was used
instead for monitoring the progress of the reaction.
The potential of iodinated N-heterocycles such as 2 can be illus-
trated by the straightforward synthesis of the new abnormal car-
bene complex 5 (Scheme 3). Thus, alkylation of 4-iodoisoxazole
(2c) with MeOTf followed by oxidative addition to Pd(dba)2 as a
palladium(0) source in the presence of pyridine afforded complex
5 in good overall yield.12 Complex 5 features a 4-isoxazolylidene li-
gand as a rare type of so-called abnormal carbenes, and has been
fully analyzed, including an X-ray structure analysis of single crys-
tals grown from CH2Cl2 and pentane.13 The Pd–C bond length is
1.974(4) Å and fits into the 1.95–2.03 Å range expected for abnor-
mal N-heterocyclic carbene palladium bonds.3d The two heterocy-
cles are almost coplanar (torsion angle less than 8°), and they are
nearly orthogonal to the palladium coordination plane (torsion an-
gle ca. 70°). In the 13C NMR spectrum, the palladium-bound car-
bene carbon appears at dC 155.5 (Fig. 1).
Iodination of heterocycles 1a–g
Entry Substrate
Product
Yield
using I2/
KIa
Yield using
I2/AgOAca
H
H
N
N
N
N
1
2
73%
78%
58%
n.d.
I
2a
1a
N
N
N
N
I
1b
2b
I
3
<5%
98%
N
O
N O
1c
2c
I
4
5
6
67%
n.d.
n.d.
88%
93%
N
N
N
N
1d
2d
H
H
N
N
N
N
I
I
1e
3e
I
I
N
N
N
N
76%
(3:2 ratio)
N
N
+
I
2f
I
3f
1f
N
N
7
<5%
<5%
1g
2g
n.d. = not determined.
a
Isolated yields of 1H NMR pure material obtained after extraction.
of 1d under milder conditions (88% at 45 °C as compared to 67% at
100 °C using I2/KI).
In conclusion, we have synthesized a variety of iodinated N-het-
erocycles that are suitable precursors for abnormal carbenes by
using a novel protocol based on I2/AgOAc. This method is of consid-
erably broad scope and provides convenient access to a variety of
iodinated aromatic heterocycles under mild conditions. The
products were isolated in good yields and with satisfactory purity
after a simple extraction procedure. The procedure may prove use-
The I2/AgOAc route is a variation of a previously reported meth-
od9 and involves the substitution of the Lewis acidic silver trifluo-
roacetate, by less expensive silver acetate. Moreover, unlike the
literature procedure, I2/AgOAc-mediated iodination was performed
as a one-pot synthesis and does not require repetitive addition of
silver salt or iodine. To the best of our knowledge, this is the first
time that the system I2/AgOAc has been reported as a reagent for
the iodination of heterocycles.
The scope of this method is quite broad. A diverse range of het-
erocyclic iodides was prepared in good to excellent yields (Table 1).
In all cases, a small excess of iodine was sufficient to ensure high
conversions. In a typical procedure,10 solid iodine was added in
portions to a suspension containing the heterocyclic substrate
and AgOAc. After complete addition, the solution became dark
red and the desired product was isolated by an aqueous work-
up, and subsequently washed, and dried. Selective mono-
iodination was indicated specifically by the disappearance of the
pertinent 1H NMR resonance signal in the non-iodinated precursor
(e.g. dH 5.8 for the C4-bound hydrogen in 1) and was unambigu-
ously confirmed by mass spectrometry.
Br
I
NaI, Me3SiCl
MeCN
N
N
4
2g
(82%)
Scheme 2.
1. MeOTf, CH2Cl2
2. Pd(dba)2, CH2Cl2
3. pyridine, NaI, CH2Cl2
I
I
N
O
Pd
N
N
O
I
2c
5
The I2/AgOAc methodology also proved efficient for the iodination
of 1-ethyl-3,5-dimethyl-1H-pyrazole (1d), 2,4-dimethylimidazole
Scheme 3.

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5425
6. (a) Li, J. J.; Gribble, G. W.. In Tetrahedron Organic Chemistry Series; Pergamon:
Oxford, 2000; Vol. 20; (b) de Vries, J. G. Can. J. Chem. 2001, 79, 1086; (c) Cacchi,
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Synthesis 2004, 2419; (f) Guiry, P.; Kiely, D. Curr. Org. Chem. 2004, 8, 781; (g)
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H.; Warren, S. L. J. Am. Chem. Soc. 1943, 65, 1273; (c) Barnett, J. R.; Andrews, L. J.;
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1996, 61, 9621.
Figure 1. ORTEP representation of the molecular structure of 5 (50% probability,
H-atoms omitted). Selected bond lengths (Å): Pd1–C2 1.974(4), Pd1–N11 2.121(3),
Pd1–I1 2.6063(6), Pd1–I2 2.5936(7).
8. (a) Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181; (b) Maloney, K. M.;
Nwakpuda, E.; Kuethe, J. T.; Yin, J. J. Org. Chem. 2009, 74, 5111.
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M. P. WO Patent 2007/138048; Chem. Abstr. 2007, 148, 11078.
10. In a typical experiment, 3,5-dimethylisoxazole (1c) (500 mg, 5 mmol) was
added dropwise to a suspension of AgOAc (0.935 g, 5.5 mmol) in dry CH2Cl2
(20 mL). Subsequently, I2 (1.500 g, 6.4 mmol) was added in portions under N2
and the reaction mixture was stirred at 50 °C for 16 h. The resulting purple
solution was filtered and washed with a saturated solution of Na2S2O3 (30 mL).
The aqueous layer was basified to pH 9 with KOHaq and extracted with CH2Cl2
(3 Â 20 mL). The combined organic layers were then washed with saturated
NaHCO3 (40 mL) and brine (15 mL), dried over MgSO4, filtered, and dried under
reduced pressure to afford 3,5-dimethyl-4-iodoisoxazole (2c) (476 mg, 98%).
1H NMR (360 MHz, CDCl3): d 2.43 (s, 3H, CH3), 2.25 (s, 3H, CH3). 13C{1H} NMR
(90 MHz, CDCl3): d 169.0 (Cisox–Me), 160.5 (Cisox–Me), 59.1 (Cisox–I), 11.5 (CH3),
11.2 (CH3). HR-MS: 223.9578 (calcd for C5H7INO 223.9572).
ful for the synthesis of a wide variety of new NHC-type complexes,
and also for catalytic applications which rely on in situ generated
catalysts from low-valent metal precursors.
Acknowledgments
This work has been financially supported by the Swiss National
Science Foundation, the European Research Council (ERC), a Marie-
Curie Intra-European Fellowship (to O.S.), and by UCD through a
start-up grant.
11. (a) Park, S. B.; Alper, H. Org. Lett. 2003, 5, 3209; (b) Traylor, T. G.; Hill, K. W.;
Tian, Z.-Q.; Rheingold, A. L.; Peisach, J.; McCracken, J. J. Am. Chem. Soc. 1988,
110, 5571.
Supplementary data
12. In a typical experiment, MeOTf (0.034 mL, 0.30 mmol) was added dropwise to a
solution of 3,5-dimethyl-4-iodoisoxazole (2c) (56 mg, 0.25 mmol) in CH2Cl2
(5 mL) and stirred at room temperature for 3 h. The volatiles were distilled
under reduced pressure and the residue was rinsed with Et2O (3 Â 5 mL). The
white solid thus obtained was dissolved in CH2Cl2 (10 mL) and stirred for
15 min at room temperature with Pd(dba)2 (75 mg, 0.25 mmol), subsequently,
an excess of NaI (75 mg, 0.50 mmol) and pyridine (0.025 mL, 0.25 mmol) were
added and the reaction mixture was stirred overnight at room temperature.
The resulting suspension was filtered through a short pad of Celite and the
solution was concentrated to ca. 2 mL. Addition of Et2O induced precipitation
Supplementary data (experimental details of all products from
Table 1) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.07.178.
References and notes
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of
(3 Â 10 mL), and dried under reduced pressure to afford 5 as a yellow solid
(98 mg, 72%). 1H NMR (360 MHz, CDCl3): d 9.05 (dt, 2H, o-CHPy 3JHH = 5.2,
a yellow solid which was collected by decantation, rinsed with Et2O
,
4JHH = 1.5), 7.68 (tt, 1H, p-CHPy 3JHH = 7.7, 4JHH = 1.5), 7.29 (m, 2H, m-CHPy), 3.98
,
(s, 3H, NCH3), 2.75 (s, 3H, CH3), 2.64 (s, 3H, CH3). 13C{1H} NMR (90 MHz, CDCl3):
d 170.1 (Cisox–Me), 162.6 (Cisox–Me), 155.5 (C–Pd), 154.0 (o-CPy), 137.1 (p-CPy),
124.2 (m-CPy), 37.0 (NCH3), 16.9 (CH3), 15.7 (CH3). Anal. Calcd for
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Raubenheimer, H. G.; Albrecht, M. Chem. Rev. 2009, 109, 3445; (c) Aldeco-Perez,
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2010, in press.
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V.; Tan, G. K. Organometallics 2007, 26, 6581; (c) Han, Y.; Huynh, H. V. Chem.
Commun. 2007, 1089.
C11H14I2N2OPd (550.47): C, 24.00; H, 2.56; N, 5.09. Found: C, 23.85; H, 2.70;
N, 4.85.
13. Crystal data for 5:
C11H14I2N2OPd, M = 550.46, monoclinic, a = 8.9614(18),
b = 14.124(3), c = 12.544(3) Å, V = 1559.4(6) Å, b = 100.83(3)°, T = 130(2) K,
space group Cc (No. 9), Z = 4,
calcd 2.345 g cm–3 (Mo-K ) = 5.137 cmÀ1, 9631
total reflections, 2891 unique (Rint = 0.031), R1 = 0.0150, wR2 = 0.0320, S = 1.13
for I > 2 (I). Crystallographic data (excluding structure factors) for this
q
, l
a
r
structure have been deposited with the Cambridge Crystallographic Data
Centre as Supplementary publication no. 781506. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
5. (a) Seevers, R. H.; Counsell, R. E. Chem. Rev. 1982, 82, 575; (b) Volkert, W. A.;
Hoffman, T. J. Chem. Rev. 1999, 99, 2269; (c) Yu, S.-B.; Watson, A. D. Chem. Rev.
1999, 99, 2353.