Iodine-magnesium exchange on unprotected imidazoles in the presence of LiCl

Article abstract of DOI:10.1055/s-2007-970784

The presence of LiCl allows the convenient preparation of magnesiated imidazoles starting from unprotected iodoimidazoles. They react with various electrophiles in satisfactory yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970784

980
LETTER
Iodine–Magnesium Exchange on Unprotected Imidazoles in the Presence
of LiCl
U
nprotected M
e
agnesiated
l
Imida
ioles x Kopp, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 28 December 2006
1) MeMgCl⋅LiCl
Abstract: The presence of LiCl allows the convenient preparation
(1.0 equiv)
MgCl
I
ClMg
X
of magnesiated imidazoles starting from unprotected iodoimid-
azoles. They react with various electrophiles in satisfactory yields.
N
N
–20 °C, THF, 30 min
⋅2 LiCl
2) i-PrMgCl⋅LiCl
(1.05 equiv)
–20 °C, THF, 45 min
N
H
N
X
Key words: magnesium, heterocycles, organometallic reagents,
imidazole, exchange reaction
1a: X = H
1b: X = I
2a: X = H
2b: X = I
The imidazole core is an important structural unit in the
field of natural products and bioactive compounds.1 The
functionalization of this basic structure using a halogen–
metal exchange reaction has been intensively
investigated2 as the halogenated starting materials are eas-
ily accessible.3,4 However, in almost all cases, the acidic
NH group should be protected and the protecting group
has to be removed after the reaction. A recent method
using the unprotected substrate requires large excess of all
reagents and gives only modest yields of the desired
products.4
1) E+
2) NH4Cl(aq)
I
N
N
H
X
3a–k; 42–98%
Scheme 1
yield (entry 5).7 However, using ethyl (2-bromometh-
yl)acrylate after transmetalation to copper, the yield drops
dramatically and the allylation product 3f is obtained in
42% (entry 6). The reaction of the magnesiated imidazole
2b with thiosulfonates proceeds cleanly providing the de-
sired thioethers 3g and 3h in 64% and 73% isolated yields
(entries 7, 8). The introduction of a benzyl group is often
accomplished by multistep processes in imidazole-de-
rived systems. Thus, the heterocyclic reagent 2b was
reacted directly with a benzylic bromide to afford the
expected product 3i in 54% yield (entry 9). The organo-
magnesium species can also be transmetalated to Zn
(ZnCl2, 1.1 equiv) and used in a Pd-catalyzed cross-cou-
pling reaction with 4-iodobenzonitrile. The expected
product 3j is obtained in 61% yield (entry 10). Further-
more, we subjected the thioether 3h to the usual condi-
tions and have found that the exchange was completed in
45 minutes at –20 °C giving the dimagnesiated species 4
(Scheme 2). A copper-catalyzed allylation affords the
desired product 5a in 63% yield. Reacting 4 with (2E)-
hex-2-enal gives the allylic alcohol 5b in 58% yield.
Recently, we have reported the double metalation of
unprotected phenol derivatives in the presence of LiCl.5
The role of LiCl is, to improve the solubility for all
organometallic reagents and, at the same time, to enhance
dramatically their reactivity.6 Herein, we have applied this
methodology to the imidazole core and have generated the
corresponding magnesiated heterocycles using stoichio-
metric amounts of the metalating reagents. We have react-
ed iodoimidazoles 1a,b with MeMgCl (1.0 equiv) in the
presence of LiCl (1.0 equiv) followed by the addition of
i-PrMgCl·LiCl affording the corresponding Grignard
reagents 2a,b which were quenched with different electro-
philes (Scheme 1).
Thus, trapping the organomagnesium reagent 2a with
pivaldehyde affords the expected alcohol 3a in 98% yield
(entry 1, Table 1). The installation of a thioether group is
realized by reacting 2a with MeSSO2Me, affording the
desired product 3b in 71% yield. The di-iodinated sub-
strate 1b can be transformed into the organomagnesium
species 2b using the same set of conditions. The reaction
with a sterically hindered aliphatic or an aromatic alde-
hyde proceeds smoothly and the products 3c and 3d were
isolated in 85% and 86% yield (entries 3 and 4). The reac-
tion of 2b with allyl bromide in the presence of a catalyt-
ical amount of CuCN·2LiCl affords the product 3e in 97%
In conclusion, we have shown that the use of LiCl as
additive allows to smoothly generate double magnesiated
imidazole derivatives employing stoichiometric amounts
of the respective organometallic reagents. These species
react with a broad variety of electrophiles, leading to
mono- or difunctionalized imidazole derivatives in good
yields.8
SYNLETT 2007, No. 6, pp 0980–0982
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-970784; Art ID: G37406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unprotected Magnesiated Imidazoles
981
Table 1 Preparation of Functionalized Imidazole Derivative
Entry
1
Starting halide of type 1
Electrophile
Product of type 3
Yield (%)a
OH
I
N
N
t-Bu
t-BuCHO
98
N
H
N
H
1a
1a
3a
MeS
N
2
MeSSO2Me
71
N
H
3b
OH
I
N
N
R
N
I
H
N
H
I
1b
3
4
t-BuCHO
3c: R = t-Bu
3d: R = Ph
85
86
PhCHO
N
5
6
1b
1b
AllBr
97b
N
I
H
3e
N
CO2Et
Br
42c
EtO2C
N
H
I
3f
R'S
N
N
H
I
7
8
1b
1b
PhSSO2Ph
3g: R¢ = Ph
64
73
MeSSO2Me
3h: R¢ = Me
N
p-BrC6H4
Br
9
54d
N
H
I
Br
3i
NC
I
N
10
1b
61e
N
NC
I
H
3j
a Isolated yields of analytically pure products.
b Conducted in the presence of 1 mol% CuCN·2LiCl.
c After transmetalation to copper using CuCN·2LiCl.
d The reaction was performed in the presence of 20 mol% CuCN·2LiCl.
e Pd-catalyzed cross-coupling after transmetalation using ZnCl2. Pd(dba)2 (5 mol%) and tfp (10 mol%) were used as catalyst system
[tfp = tri(2-furyl)phosphine].
Synlett 2007, No. 6, 980–982 © Thieme Stuttgart · New York

982
F. Kopp, P. Knochel
LETTER
(3) Seley, K. L.; Salim, S.; Zhang, L.; O’Daniel, P. I. J. Org.
Chem. 2005, 70, 1612.
(4) Matsunaga, N.; Kaku, T.; Ojida, A.; Tasaka, A.
Tetrahedron: Asymmetry 2004, 15, 2021.
(5) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commun.
2004, 20, 2288.
(6) (a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 3333. (b) For the solubilization of lanthanide salts in the
presence of LiCl, see: Krasovskiy, A.; Kopp, F.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 497.
1) MeMgCl⋅LiCl
(1.0 equiv)
–20 °C, THF, 30 min
MgCl
PhS
I
PhS
N
N
⋅2 LiCl
2) i-PrMgCl⋅LiCl,
–20 °C, THF, 45 min
(1.05 equiv)
N
H
N
ClMg
3h
4
CHO
Br
Pr
(7) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390.
(8) Typical Procedure for the Synthesis of 4-Iodo-5-
(methylsulfanyl)-1H-imidazole (3i)
PhS
N
PhS
N
4,5-diiodo-1H-imidazole (1b, 640 mg, 2.00 mmol) was
placed in a dry and argon-flushed Schlenk tube equipped
with a magnetic stirring bar and a septum. A solution of LiCl
in THF (0.5 M, 4.0 mL, 2.0 mmol, 1.0 equiv) was added and
after stirring 5 min at r.t., the resulting slurry was cooled to
–20 °C and MeMgCl (3.0 M in THF, 0.7 mL, 2.0 mmol, 1.0
equiv) was added dropwise. After completion of the
addition, the mixture was stirred at –20 °C for further 20
min. Then, i-PrMgCl·LiCl (1.3 M in THF, 1.7 mL, 2.2
mmol, 1.1 equiv) was added slowly and the resulting mixture
was allowed to warm to r.t. The exchange reaction was
monitored by TLC (samples quenched with MeOH, silica
plates; CH2Cl2–MeOH, 19:1) versus the starting material
and was usually complete after 45 min. The resulting slurry
was cooled to –20 °C and (S)-methyl methanesulfonothioate
(610 mg, 2.40 mmol, 1.20 equiv) was added neat at this
temperature, then the mixture was allowed to warm to r.t.
After the completion of the reaction (TLC monitoring) the
reaction mixture was poured on H2O (20 mL) and sat. aq
NH4Cl (20 mL), and the aqueous layer was extracted with
CH2Cl2 (3 × 40 mL). The combined CH2Cl2 layers were
dried (Na2SO4) and evaporated in vacuo. Flash column
chromatography (silica gel, CH2Cl2–MeOH, 19:1) afforded
4-iodo-5-(methylsulfanyl)-1H-imidazole (3i) as colorless
solid (mp 126.1–128.4 °C).
N
H
Pr
N
H
OH
5b: 58%
5a: 63%
Scheme 2
Acknowledgment
We thank the Fonds der Chemischen Industrie and the G.I.F. (Ger-
man-Israeli Foundation for Scientific Research and Development;
grant: I-535-083.05/97) for financial support. We are grateful to
Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen) for
generous gifts of chemicals.
References and Notes
(1) Newkome, G. R.; Pandler, W. W. Contemporary
Heterocyclic Chemistry; Wiley: New York, 1982.
(2) For a recent example, see: Kitbunnadaj, R.; Zuiderveld, O.
P.; Christophe, B.; Hulscher, S.; Menge, W. M. P. B.;
Gelens, E.; Snip, E.; Bakker, R. A.; Celanire, S.; Gillard, M.;
Talaga, P.; Timmerman, H.; Leurs, R. J. Med. Chem. 2004,
47, 2414.
Synlett 2007, No. 6, 980–982 © Thieme Stuttgart · New York

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