Preparation and Reactions of Polyfunctional Magnesium Arylcuprates Obtained by an Iodine-Copper Exchange

Article abstract of DOI:10.1055/s-2003-43358

The preparation of polyfunctional magnesium cuprates of type 1 can be achieved via an iodine-copper exchange reaction using the cyclic magnesium cuprate 3. A range of functional groups like an ester, halide (F, Br), nitrile or even a ketone can be tolerated. The new cuprates can be acylated and allylated in good yields leading to a range of polyfunctional products.

Full text of DOI:10.1055/s-2003-43358

LETTER
81
Preparation and Reactions of Polyfunctional Magnesium Arylcuprates
Obtained by an Iodine–Copper Exchange
P
reparationand Re
i
action
a
s
of Polyfu
o
M
ag
y
nesium
A
ryl
i
cuprate
n
s
Yang, Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: knoch@cup.uni-muenchen.de
Received 6 October 2003
magnesium cuprate reagents of type FG-ArCu(CN)MgBr
(1). To perform the exchange reaction, we have used 1,5-
bis(bromomagnesium)pentane,7 which was readily pre-
pared from 1,5-dibromopentane 2 and magnesium.7a Its
Abstract: The preparation of polyfunctional magnesium cuprates
of type 1 can be achieved via an iodine–copper exchange reaction
using the cyclic magnesium cuprate 3. A range of functional groups
like an ester, halide (F, Br), nitrile or even a ketone can be tolerated.
The new cuprates can be acylated and allylated in good yields lead- reaction with the THF-soluble copper salt CuCN·2LiCl8
ing to a range of polyfunctional products.
provided a magnesium cuprate reagent tentatively formu-
lated as 37c,d,9 (Scheme 1).
Key words: functionalized organometallics, cuprates, acylation,
magnesium, iodine–copper exchange
The ate-nature of the copper reagent 3 due to a possible
coordination of the cyanide anion makes it potentially
more reactive and useful for an iodine–copper ex-
change.10,11 Also the nature of the cation (MgBr instead of
the previously used Li) allows the exchange to be per-
formed very conveniently at room temperature. Especial-
ly interesting is that the cyclopentane should be the only
side-product formed if reagent 3 is used for a halogen-
copper exchange (see below).
The preparation of polyfunctional organometallics is an
important research field since these versatile nucleophiles
can react with a range of organic electrophiles with excel-
lent yields.1 The performance of an I/Mg- or a Br/Mg-ex-
change has been proved to be especially useful and
provided an efficient preparation of a broad range of aryl-
or heteroaryl- magnesium reagents,2 which displayed high
reactivity toward several important classes of electro-
philes.3 A keto group was found to be compatible with the
I/Mg-exchange reaction, but in some cases, low tempera-
ture and long reaction time had to be used for these ex-
changes due to the high reactivity of the Grignard reagent
toward the keto group present in the substrate.4 To over-
come these problems, we have developed a halide–copper
exchange reaction, which allows a practical preparation of
functionalized lithium cuprates compatible with the pres-
ence of a keto group.5,6 Herein we wish to report a related
iodine–copper exchange, which provides functionalized
We found that a wide range of aromatic iodides undergo
an I/Cu-exchange with reagent 3 (0.5 equiv) within 1–2
hours at 25 °C in THF providing the cyanocuprates of
type 1 (Scheme 1). Interestingly, this method allows the
copper compounds to be prepared free of organic iodide.
Thus, the cuprate resulting from the I/Cu-exchange was
anticipated to undergo a rapid elimination reaction pro-
viding cyclopentane, and the cyanocopper reagent 1. As
the detection of cyclopentane in the crude reaction mix-
ture was difficult, we have prepared the cuprate 5 of 3-
phenyl substituted 1,5-bis(bromomagnesium)pentane and
performed the reaction with ethyl 4-iodobenzoate under
1) Mg (2 equiv)
2) CuCN·2LiCl (2 equiv)
BrMg Cu
Cu MgBr
·2LiCN
2
THF, –78 °C, 0.5 h
Br
Br
2
3
Cu(CN)MgBr
I
3 (0.5 equiv)
+
r.t., 1–2 h
THF
FG
FG
1a–f
4a–f
FG = a: p-CO2Et; b: m-CO2Et; c: m-CN; d: p-COt-Bu; e: m-COC6H4m-OMe; f: m-F and p-Brm
Scheme 1
SYNLETT 2004, No. 1, pp 0081–0084
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43358; Art ID: G26503ST
© Georg Thieme Verlag Stuttgart · New York

82
X. Yang, P. Knochel
LETTER
our standard reaction conditions to prove the formation of ketone 8b in 94% yield (entry 2). Similarly, aliphatic acid
a cyclopentane as reaction product. We have observed a chlorides like c-HexCOCl and t-BuCH2COCl provide the
rapid exchange and detected the formation of phenylcy- corresponding products in 92–93% yields (entries 3 and
clopentane 6 (94%) and the expected cuprate 1a as the 4). The acylation of 1a with an unsaturated acid chloride
sole reaction product. Cyclopentane derivative 6 was like cinnamyl chloride led to the (E)-ketoester 8e in 85%
formed via a fast intramolecular substitution of the inter- yield (entry 5). Ethyl 3-iodobenzoate 4b was treated with
mediate 7 generated during the iodine-copper exchange the cuprate 3 (0.5 equiv, 25 °C, 2 h) leading to the cyano-
reaction (Scheme 2).
cuprate 1b and reacted with typical acid chlorides in 84–
91% yields (entries 6–8). A cyano group is also well tol-
erated in the starting aryl iodide 4c and the I/Cu-exchange
is completed within 40 minutes at 25 °C furnishing the
magnesium cyanocuprate 1c. Its reaction with PhCOCl
and i-PrCOCl gave the cyanoketones 8i and 8j in 90–92%
yields (entries 9 and 10). Aromatic iodoketone was also
submitted with success to the I/Cu-exchange. Thus, 4-io-
dophenyl tert-butyl ketone (4d) and 2-iodophenyl 4-
methoxylphenyl ketone (4e) are converted to the corre-
sponding cuprates 1d and 1e by reaction with 3. In these
cases, the iodoketones were added at –78 °C and the reac-
tion mixtures were allowed to warm slowly to room tem-
perature over 2 hours. Quenching with acid chlorides like
PhCOCl and i-PrCOCl furnished the expected diketones
8k and 8l in 70–85% yields. The resulting ketone 8l can
be readily converted to the heterocycle 9 by treatment
with hydrazine monohydrate (EtOH, reflux, 30 min, 91%
yield; see Scheme 3).13
The newly prepared cyanocuprates of type 1 were
quenched with allyl bromide and various acid chlorides
providing the expected products of type 8 in 70–95%
yields (Table 1). Thus, ethyl 4-iodobenzoate (4a) reacts
with magnesium cuprate 3 (0.5 equiv) within 1 hour at
room temperature and provides the corresponding copper
reagent 1a (entries 1–5, Table 1).
This reagent was allylated with allyl bromide affording
the desired product (8a) in 91% yield (entry 1). This test
reaction indicated that the preparation of the cuprate was
complete and that the functionalized magnesium cyano-
cuprates had reacted as expected. Then, we focused our
attention on the preparation of polyfunctional ketones and
performed the acylation reaction of 1a with a range of acid
chlorides12 (Table 1). We found that the reaction of the
magnesium cuprate with benzoyl chloride was completed
within 15 minutes at room temperature leading to the
Ph
I
Ph
Cu
I
THF
MgBr
·LiCN
+
BrMg Cu
Cu MgBr·2LiCN
r.t., 1 h
COOEt
Ph
5 (0.5 equiv)
COOEt
4a
7
Cu(CN)MgBr
Ph
+
COOEt
6: 94%
1a: >95%
Scheme 2
N
N
O
O
I
O
NH2NH2·H2O
EtOH, reflux, 0.5 h
1) 3 (0.5 equiv.)
THF, –78 °C to r.t. 4 h
2) i-PrCOCl
MeO
MeO
8l: 85%
OMe
9: 91%
Scheme 3
Synlett 2004, No. 1, 81–84 © Thieme Stuttgart · New York

LETTER
Preparation and Reactions of Polyfunctional Magnesium Arylcuprates
83
Table 1 Reactions of Cyanocuprates of Type 1 Generated from the Corresponding Functionalized Aryl Iodides of Type 4 with Allyl Bromide
and Acid Chlorides to Form 8
Entry
Functionalized cuprate
Cu(CN)MgBr
Electrophile
Product of type 8
Yield (%)a
R
EtOOC
EtOOC
1
2
3
4
5
1a
Allyl bromide
PhCOCl
8a: R = Allyl
91
94
93
92
85
8b: R = COPh
c-HexCOCl
8c: R = COc-Hex
8d: R = COCH2t-Bu
8e: R = COCH=CHPh
t-BuCH2COCl
(E)-ClCOCH=CHPh
O
EtOOC
Cu(CN)MgBr
EtOOC
R
6
7
8
1b
c-PentCOCl
4-FC6H4COCl
2-FurylCOCl
8f: R = c-Pent
91
84
85
8g: R = 4-FC6H4
8h: R = 2-Furyl
NC
R
NC
Cu(CN)MgBr
9
10
11
1c
PhCOCl
i-PrCOCl
PhCOCl
8i: R = Ph
90
8h: R = i-Pr
92
70b
COPh
Cu(CN)MgBr
Cu(CN)MgBr
t-Bu
t-Bu
O
O
1d
8k
12
i-PrCOCl
85b
O
O
i-Pr
O
MeO
MeO
8l
1e
F
F
Br
COR
Br
Cu(CN)MgBr
13
14
1f
PhCOCl
8m : R = Ph
95
92
c-HexCOCl
8n : R = c-Hex
a Yield of analytically pure products.
b In this case, the aryl iodide was added at –78 °C and the resulting mixture was then warmed slowly to r.t. over 2 h.
Finally, we have examined the reaction of a polyhaloge- In summary, we have shown that the magnesium cuprate
nated aromatic substrate like 1-iodo-2-fluoro-4-bro- 3 is an excellent reagent for performing an iodine–copper
mobenzene (4f). Only the I/Cu-exchange was observed exchange reaction, providing for the first time a range of
and no Br/Cu-exchange could be detected. After the reac- new polyfunctional cyanocuprates, which react with acid
tion with acid chlorides like PhCOCl and c-HexCOCl, the chlorides leading to highly functionalized ketones in high
expected halogenated ketones 8m and 8n were obtained in yields.14
92–95% yields (entries 13, 14).
Synlett 2004, No. 1, 81–84 © Thieme Stuttgart · New York

84
X. Yang, P. Knochel
LETTER
(9) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(b) Krause, N. Modern Organocopper Chemistry; Wiley-
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Acknowledgment
We thank the Fonds der Chemischen Industrie and the Ludwig-
Maximilians-University (Munich) for the financial support. We
thank the BASF AG (Ludwigshafen), Degussa (Hanau) and
Chemetall GmbH (Frankfurt) for the generous gift of chemicals.
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References
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(14) Typical Procedure: A dry and argon filled 25 mL flask,
equipped with a magnetic stirrer and a septum, was charged
with a solution of 1,5-bis(bromomagnesium)pentane (0.46
M/THF, 4.4 mL, 2.0 mmol) in THF (8 mL). The solution of
CuCN·2LiCl in THF (1.0 M/THF, 2.0 mL, 2.0 mmol) was
added dropwise at –78 °C. The resulting mixture was stirred
for 30 min and ethyl 4-iodobenzoate 4a (552 mg, 2.0 mmol)
was added at –78 °C. The resulting mixture was warmed to
r.t. for 1 h and then benzoyl chloride (421 mg, 3.0 mmol) was
added. After 30 min, the solution was quenched with sat. aq
NH4Cl solution and poured into H2O (20 mL). The organic
layer was separated and the aqueous phase was extracted
with Et2O (3 × 50 mL). The organic fractions were washed
with brine (30 mL), dried over MgSO4 and concentrated in
vacuo. Purification by chromatography (SiO2, n-pentane/
Et2O = 50:1) yielded 478 mg (94% yield) of 8b as a colorless
oil. IR (film): 3402 (m, br), 2982 (m), 1720(vs), 1661 (vs),
1597 (m), 1579 (w), 1448 (m), 1405 (s), 1356 (s), 1369 (s),
1317 (s), 1275(vs), 1105(vs), 1020 (m), 939 (m), 927 (m),
851 (w), 769 (w), 715 (s), 698 (m), 657 (m)cm–1. 1H NMR
(300 MHz, CDCl3): d = 8.07 (dd, J = 8.4 and 1.8 Hz, 2 H),
7.73 (m, 4 H), 7.53 (m, 1 H), 7.40 (t, J = 8.0 Hz, 2 H), 4.34
(q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 195.0, 164.8, 140.2, 136.0, 132.6, 131.9,
129.1, 128.7, 128.4, 127.4, 126.2, 60.4, 13.3. MS (EI, 70
eV): m/z (%) = 254 (48) [M+], 226 (14), 209 (45), 181 (18),
177 (57), 152 (10), 149 (14), 130 (20), 118 (17), 104 (100).
HRMS (EI): calcd for C16H14O3 [M+]: 527.7580. Found:
527.7579.
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Synlett 2004, No. 1, 81–84 © Thieme Stuttgart · New York