Successive iodine-magnesium or -copper exchange reactions for the selective functionalization of polyhalogenated aromatics

Article abstract of DOI:10.1021/ol0341492

(Matrix presented) The presence of an electron-withdrawing group or chelating group was found to direct the halogen-copper and halogen-magnesium exchange with various di- or trihalogenated aromatics. Starting with a triiodobenzoate derivative, a range of

Full text of DOI:10.1021/ol0341492

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1229-1231
Successive Iodine−Magnesium or
−Copper Exchange Reactions for the
Selective Functionalization of
Polyhalogenated Aromatics
Xiaoyin Yang, Thomas Rotter, Claudia Piazza, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received January 27, 2003
ABSTRACT
The presence of an electron-withdrawing group or chelating group was found to direct the halogen−copper and halogen−magnesium exchange
with various di- or trihalogenated aromatics. Starting with a triiodobenzoate derivative, a range of tetraacylated benzenes could be prepared
and used for a short synthesis of benzodiazines.
The halogen-metal exchange is a general and chemoselec-
tive method for preparing functionalized magnesium1,2 and
copper3 reagents. It tolerates a wide range of functional
groups and allows the preparation of various polyfunctional
magnesium and copper organometallics. The rate of the
halogen-metal exchange greatly depends on the electron-
density of the aromatic or heterocyclic ring, so that an
aromatic or heterocyclic dibromide or diiodide undergoes
only a monoexchange.4 Herein, we wish to report that
polyhalogenated aromatics react with high regioselectivity
and that up to three consecutive I/Cu exchange reactions can
be performed with excellent regiocontrol leading to new
polyacylated aromatics that are difficult to prepare by
standard methods. Thus, readily available ethyl 2,3,5-
triiodobenzoate5 1 was treated in diethyl ether either with
i-PrMgCl (1.1 equiv, -78 °C, 1 h) leading to the Grignard
reagent 2 or with lithium bis-neopentylcuprate (Np2CuLi;
1.1 equiv, -78 °C, 20 min)3a furnishing the mixed lithium
cuprate 3 (Scheme 1).
Scheme 1. Regioselective Iodine/Metal Exchange Reactions
(1) (a) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 1701. (b) Jensen, A. E.; Dohle, W.; Sapountzis,
I.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 565. (c) Kneisel,
F. F.; Knochel, P. Synlett 2002, 1799.
Both organometallic species 2 and 3 reacted with various
electrophiles providing products of type 4 (Scheme 1 and
Table 1).
10.1021/ol0341492 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/19/2003

Table 1. Reactions of Polyfunctional Magnesium and Copper
Organometallics of Type 2 or 3 with Various Electrophiles
Table 2. Selective Formation of Polyfunctional Monoiodoaryl
Copper 5a-c from Diiodobenzenes 4c-e and Reactions with
Electrophiles Leading to Products of Type 6
a Yield of Analytically Pure Product. b X ) Cl or Br. c Yield Obtained
with AcBr.
Thus, the reaction of the functionalized arylmagnesium
reagent 2 with aromatic or heterocyclic aldehydes gave the
corresponding lactones 4a,b in 77 and 83% yields, respec-
tively (entries 1 and 2 of Table 1). An iminium salt like
diallyl(methylene)ammonium trifluoroacetate6 readily reacted
with 2 providing the diallylamine 4c in 85% yield (entry 3
of Table 1). Also, the reaction with tosyl cyanide7 led to the
diiodobenzonitrile derivative (4d) in 90% yield. The mixed
lithium cuprate 3 reacted well with acyl halides and allyl
bromide.8 The acylation of cuprate 3 with acetyl chloride
led to the keto ester 4e in 60% yield. This result could be
improved by using acetyl bromide that gave 4e in 70% yield.9
The allylation of cuprate 3 led to the expected product 4f
(entry 6). The observed selectivity of the iodine-metal
exchange of the triiodobenzoate 1 was explained by a
precomplexation of i-PrMgCl or Np2CuLi to the ester
function that favors the iodine-metal exchange in the ortho-
position.
a Yield of analytically pure product.
more selective lithium dineophylcuprate ((Ph(Me)2C-CH2)2-
CuLi; Nphyl2CuLi) has been used.3a This reagent was able
to perform an I/Cu exchange in the presence of a methyl
ketone.3a It was also readily prepared from inexpensive 2,2-
dimethyl-2-phenylethyl chloride via the intermediate NphylLi
obtained by the direct reaction of NphylCl with lithium
powder.3a Thus, the reaction of the diiodobenzonitrile deriva-
tive 4d with Nphyl2CuLi (THF, -78 °C, 2 h) only led to
the formation of the mixed copper reagent 5b (entry 2 of
Table 2). Its reaction with ethyl cyanoformate (from -78 to
25 °C, 24 h) furnished the symmetrical product 6b in 70%
yield. The iodoaryl methyl ketone 4e was selectively
converted to the copper reagent 5c (ether, -78 °C, 2 h) and
Selected products of type 4 have again been submitted to
an iodine-copper exchange reaction. In the case of the
diiodide 4c (entry 3 of Table 1), which contained no sensitive
functionality, the second exchange was performed with Np2-
CuLi leading, after allylation, to iodoester 6a in 65% yield
(entry 1 of Table 2). In all other cases, where more sensitive
functional groups were present in the starting diiodide 4, the
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Org. Lett., Vol. 5, No. 8, 2003

Scheme 2. Preparation of Tetraacylated Arenes via an I/Cu
Scheme 3. Synthesis of Benzodiazines of Type 9
Exchange Reactiona
Finally, a third I/Cu exchange was performed on dike-
toesters 6f-h. Their reactions with Nphyl2CuLi (THF, -78
°C, 1.5 h) produced the corresponding copper reagents 7a-
c, which reacted with various aliphatic, heterocyclic, or
unsaturated acid chlorides leading to the tetraacylated
benzenes 8a-c in 60-65% yield (Scheme 2). Compounds
of type 8 are very difficult to prepare by standard methods.
Our synthesis offers a general approach to this new class of
functionalized aromatic molecules.
These polyacylated compounds are very useful for the
synthesis of heterocycles. This was demonstrated by treating
dicarbonylated iodoarenes 6g and 6h with hydrazine in
ethanol (reflux, 15 min) providing polyfunctional12 benzo-
diazines 9a and 9b in 90-93% yield (Scheme 3).
In summary, we have shown that functionalized di- or
triiodoarenes can undergo a selective I/Cu and I/Mg exchange
reaction. The I/Cu exchange was found to be superior to the
I/Mg exchange if sensitive functional groups such as acyl
groups were present in the starting aryl polyiodides. A range
of new polyacylated benzenes such as 8a-c became available
by this method.13 Further applications to the preparation of
polyfunctional heterocycles and molecules of biological
interest are currently underway.
a Reagents and conditions: (a) Nphyl2CuLi, THF, -78 °C, 1.5
h; (b) propionyl chloride, THF, from -78 to 0 °C, 3 h; (c) 2-furoyl
chloride, THF, from -78 to 0 °C, 3 h; (d) trans-crotonyl chloride,
THF, from -78 to 0 °C, 3 h.
treated with various allylic bromides10 (entries 3 and 4)
leading to the desired products 6c and 6d in 75 and 70%
yields, respectively. Also a range of aliphatic, aromatic, and
heterocyclic acid chlorides were treated with 5c providing
the corresponding ketones 6e-h in 64-70% yield (entries
5-8 of Table 2). In each case, a selective I/Cu exchange
has been observed. This selectivity was due to the presence
of an ortho-substituent,11 which by chelating or inductive
effect directed the I/Cu exchange reaction.
(2) (a) Lee, J.; Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.; Rieke, R.
D. J. Org. Chem. 2000, 65, 5428. (b) Kitagawa, K.; Inoue, A.; Shinokubo,
H.; Oshima, K. Angew. Chem., Int. Ed. 2000, 39, 2481. (c) Inoue, A.;
Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
(3) (a) Piazza, C.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 3263.
(b) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615. (c) Kondo,
Y.; Matsudaira, T.; Sato, J.; Muraka, N.; Sakamoto, T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 736.
(4) (a) Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez, G.;
Knochel, P. Synlett 2001, 4, 477. (b) Abarbri, M.; Dehmel, F.; Knochel, P.
Tetrahedron Lett. 1999, 40, 7449. (c) Vu, V. A.; Marek, I.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 351. (d) Tre´court, F.; Breton,
G.; Bonnet, V.; Mongin, F.; Marsais, F.; Que´guiner, G. Tetrahedron Lett.
1999, 40, 4339.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Chemetall GmbH,
Degussa AG, and BASF AG for the generous gifts of
chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(5) 2,3,5-Triiodobenzoic acid is commercially available from Aldrich.
(6) Millot, N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis 2000, 7,
941.
(7) Klement, I.; Lennick, K.; Tucker, C. E.; Knochel, P. Tetrahedron
Lett. 1993, 34, 4623.
(8) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(9) Typical Procedure: Preparation of 4e. A dry and argon-flushed
50 mL flask, equipped with a magnetic stirrer and a septum, was charged
with a solution of ethyl 2,3,5-triiodobenzoate (528 mg, 1.0 mmol) in dry
diethyl ether (30 mL). Np2CuLi (1.0 M/Et2O, 1.1 mmol, 1.1 equiv) was
added slowly at -78 °C, and the resulting mixture was stirred at this
temperature for 20 min to complete the iodine-copper exchange (checked
by GC-MS analysis of reaction aliquots). Then, acetyl bromide (369 mg,
3.0 mmol, 3.0 equiv) was added. The mixture was warmed to 0 °C, and
the reaction was quenched after 30 min with saturated aqueous NH4Cl
solution; the mixture was then poured into water (25 mL). The aqueous
phase was extracted with diethyl ether (3 × 80 mL). The organic fractions
were washed with brine (80 mL), dried over MgSO4, and concentrated in
vacuo. Purification by flash chromatography (n-pentane/diethyl ether ) 10:
1) yielded 310 mg (70% yield) of 4e as a white solid, mp 76 °C.
(10) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
OL0341492
(12) Haddadin, M. J.; Agha, B. J.; Tabri, R. F. J. Org. Chem. 1979, 44,
494.
(13) Typical Procedure: Preparation of 6g. A dry and argon-flushed
100 mL flask, equipped with a magnetic stirrer and a septum, was charged
with a solution of ethyl 2-acetyl-3,5-diiodobenzoate (444 mg, 1.0 mmol)
in dry diethyl ether (50 mL). (Nphyl)2CuLi (1.5 M/Et2O, 1.1 mmol, 1.1
equiv) was added slowly at -78 °C. After 1 h, the iodine-copper exchange
was complete (checked by GC-MS analysis of reaction aliquots). Then,
benzoyl chloride (422 mg, 3.0 mmol, 3.0 equiv) was added. The mixture
was warmed to 0 °C, and the reaction was quenched with saturated aqueous
NH4Cl solution after 3 h; the mixture was then poured into water (25 mL).
The aqueous phase was extracted with diethyl ether (3 × 80 mL). The
organic fractions were washed with brine (80 mL), dried over MgSO4, and
concentrated in vacuo. Purification by flash chromatography (n-pentane/
diethyl ether ) 2:1) yielded 295 mg (70%) of 6g as a colorless oil.
(11) This effect has been extensively used to perform ortho-directed
metalations: Snieckus, V. Chem. ReV. 1990, 90, 879.
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