General preparation of functionalized o-nitroarylmagnesium halides through an iodine-magnesium exchange

Article abstract of DOI:10.1002/1521-3773(20020503)41:9<1610::AID-ANIE1610>3.0.CO;2-T

Highly functionalized aryl Grignard reagents with an ortho-nitro substituent have been synthesized from 2-iodonitroaryl compounds through an I-Mg exchange reaction with PhMgCl or mesityl magnesium bromide (see scheme). These reagents are stable (T<-20°C f

Full text of DOI:10.1002/1521-3773(20020503)41:9<1610::AID-ANIE1610>3.0.CO;2-T

COMMUNICATIONS
Table 1. Products of the reaction of the functionalized nitro-substituted
arylmagnesium compounds 2 with electrophiles.
General Preparation of Functionalized
o-Nitroarylmagnesium Halides through an
Iodine Magnesium Exchange**
Entry Grignard reagent Electrophile
3
Yield
[%][a]
Ioannis Sapountzis and Paul Knochel*
1
2
PhCHO
87
Dedicated to Professor Lutz F. Tietze
on the occasion of his 60th birthday
The preparation of functionalized organometallic com-
pounds is an important research field since it allows the
2a
allyl bromide
75[b]
À
formation of new C C bonds between polyfunctional nucle-
ophiles and electrophiles, leading to multifunctional prod-
ucts.[1] Although organozinc compounds have proved to be
very useful, the recent use of the I Mg exchange allows the
straightforward synthesis of various highly functionalized
aryl-,[2] heteroaryl-,[3] and alkenylmagnesium[4] reagents. Nitro
groups are present in many important aromatic compounds,[5]
but have been regarded as being incompatible with organo-
metallic species.[6] Only scarce examples of nitro-substituted
aryl organometallic compounds have been reported.[7] Herein
we wish to report that the I Mg exchange allows an efficient
preparation of polyfunctional arylmagnesium reagents that
bear a nitro group ortho to the iodine atom. Furthermore, we
will show that this new class of organomagnesium compounds
is compatible with several transition metal catalyzed cross-
coupling reactions. In a preliminary experiment, we treated
2-iodonitrobenzene (1a) with phenylmagnesium chloride
(1.1 equiv) in THF at À408C. Within 5 min, a complete I
Mg exchange was observed, as indicated by GC analysis of
reaction aliquots. The resulting nitro-substituted Grignard
reagent (2a) reacted with benzaldehyde (1.2 equiv) within
0.5 h at À408C to give the expected benzhydryl alcohol (3a)
in 87% yield (Scheme 1 and Table 1, entry 1).
3
PhCHO
PhCHO
94
4
5
72
2c
72[b]
6
7
PhCHO
94
64
2d
cHexCHO
8
9
2d
2d
75[b]
76[b]
81
NO2
NO2
NO2
E+
PhMgCl
I
MgCl
E
–40 °C
5 min
FG
1a: FG = H;
b: FG = 5-CN;
c: FG = 4-OMe;
d: FG = 4-CO2Et;
e: FG = 4-NO2;
f: FG = 4-I
FG
FG
3a–m: 64–94 %
PhCOBr
PhCHO
2a–f
10
Scheme 1. Preparation of o-nitro substituted arylmagnesium reagents.
Interestingly, the use of other more reactive Grignard
reagents such as MeMgX or iPrMgCl for the I Mg exchange
led to complex reaction mixtures. These organometallic
reagents clearly react with the nitro functional group. The
11
2e
cHexCHO
PhCHO
74
[*] Prof. Dr. P. Knochel, Dipl.-Chem. I. Sapountzis
Department Chemie, Ludwig-Maximilians-Universit‰t M¸nchen
Butenandtstrasse 5 13, Haus F, 81377 M¸nchen (Germany)
Fax : (‡49)89-2180-76 80
12
13
89
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Deutsche Forschungsgemeinschaft (Leibniz program)
for financial support. I.S. thanks Aventis Pharma (Frankfurt a.M.) for
a fellowship. We also thank Chemetall GmbH (Frankfurt a.M.) and
BASF AG (Ludwigshafen) for generous gifts of chemicals.
2 f
74[b]
[a] Yield of isolated analytically pure product. [b] The Grignard reagent
was transmetalated with CuCN ¥ 2LiCl before reaction with the electro-
phile.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
1610
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1610 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9

COMMUNICATIONS
use of meta- or para-substituted iodonitrobenzenes also gave
rise to mixtures of products. In these cases, the nitro
functionality also reacts with PhMgCl.[7] However, a variety
of functional groups including ester, cyano, and methoxy
groups, and other nitro or iodo functionalities are tolerated,
thus allowing the synthesis of a broad range of functionalized
ortho-nitro-substituted arylmagnesium species 2a–f, which
give aliphatic and aromatic alcohols in excellent yields
(Table 1, entries 1, 3, 4, 6, 7, 10 12). Remarkably, in the case
of 2,5-diiodonitrobenzene (1 f), only the ortho-iodine atom
undergoes I Mg exchange to give the alcohol 3l in 89% yield
after reaction with benzaldehyde (Table 1, entry 12). This
selectivity can be explained by a chelation effect of the nitro
functionality. Its inductive effect should also favor the ortho-
iodine magnesium exchange. Amazingly, a fast I Mg ex-
change was also observed for 2,5-dinitroiodobenzene (1e). In
this case, the I Mg exchange was complete within 30 s at
À408C. A smooth reaction is observed with aldehydes,
despite the presence of two nitro groups in the Grignard
reagent 2e, leading to the alcohols 3j and 3k in 81% and 74%
yields, respectively (Table 1, entries 10 and 11).
Experimental Section
Typical procedure (3 f): A dry argon-flushed 25-mL flask, equipped with a
magnetic stirrer and a septum, was charged with ethyl 4-iodo-3-nitro-
benzoate (642 mg, 2 mmol). Dry THF was added, the mixture was cooled
to À408C, and PhMgCl (1.1 mL, 2m in THF, 2.2 mmol) was then added
dropwise. The I Mg exchange was complete after 5 min (checked by GC
analysis of reaction aliquots). Benzaldehyde (254 mg, 2.4 mmol) was added
to the Grignard benzoate 2d. The reaction mixture was stirred for 0.5 h at
À408C, and then quenched with a saturated solution of NH4Cl (2 mL) and
poured into water (25 mL). The aqueous phase was extracted with ethyl
acetate (2 Â 40 mL), and the organic fractions were washed with brine
(30 mL), dried (Na2SO4), and concentrated in vacuo. The crude residue was
purified by flash chromatography (dichloromethane) to yield the benzylic
alcohol 3 f as a pale yellow oil (568 mg, 94%).
Received: January 30, 2002 [Z18611]
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¬
The reactivity and selectivity of the Grignard reagents of
type 2 is not always appropriate for reactions with all
electrophiles. In some cases, transmetalation with a transition
metal salt is required. Thus, for the reaction with allylic
halides or acid halides the intermediate o-nitroarylmagnesi-
um reagent is treated with CuCN ¥ 2LiCl[8] (1 equiv, À408C,
5 min), resulting in the formation in situ of an arylcopper
species, which can be smoothly allylated (Table 1, entries 2, 5,
8 and 13) and benzoylated with benzoyl bromide (Table 1,
entry 9). Similarly, a Pd0-catalyzed Negishi cross-coupling
reaction[9] is possible upon transmetalation of the Grignard
reagent with ZnBr2 to give the corresponding organozinc
reagent (Scheme 2).
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CO2Et
NO2
NO2
1. mesitylMgBr, –40 °C, 5 min
2. ZnBr2, –40 °C, 5 min
I
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3. [Pd(dba)2] (5 % mol)
tfp (10 % mol)
–40 °C - RT, 3 h
NC
NC
6: 73 %
4
I
5 (1.5 equiv)
EtO2C
¬
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In this case, it is advantageous to perform the I Mg
exchange of 4 with the sterically hindered mesitylmagnesium
bromide.[10] After transmetallation of the Grignard reagent
with ZnBr2, ethyl 4-iodobenzoate (5) is added in the presence
of [Pd(dba)2] (5 mol%; dba ˆ trans,trans-dibenzylideneace-
tone) and tri-o-furylphosphane (tfp, 10 mol%). The cross-
coupling reaction proceeds smoothly between À408C and
room temperature to afford the polyfunctional product 6 in
73% yield (Scheme 2).
[10] M. Poirier, F. Chen, C. Bernard, Y. S. Wong, G. G. Wu, Org. Lett. 2001,
3, 3795.
In summary, we have shown that the I Mg exchange
reaction allows the preparation of a variety of new function-
alized ortho-nitro arylmagnesium reagents, thus expanding
the scope of these organometallic compounds for applications
in organic synthesis.
Angew. Chem. Int. Ed. 2002, 41, No. 9
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1611 $ 20.00+.50/0
1611