Preparation and reactions of functionalized organocopper reagents

Article abstract of DOI:10.1055/s-2006-942496

Functionalized organocopper reagents have been prepared via an iodine-copper exchange by the reaction of aryl or alkenyl iodides with a sterically hindered cuprate reagent, lithium dineophylcuprate [(Me ₂PhCCH₂)₂CuLi]. The resulting copper reagents react readily with various electrophiles leading to polyfunctionalized molecules. This method represents a unique protocol for the preparation of aryl-, heteroaryl- and alkenylcopper reagents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942496

2618
PRACTICAL SYNTHETIC PROCEDURES
Preparation and Reactions of Functionalized Organocopper Reagents
P
reparationand Re
i
action
a
of Functio
o
nalizedOrga
y
nocopper
R
e
i
agentsn Yang, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München,
Butenandtstrasse 5-13 Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
PSP
Received 4 March 2006; revised 13 April 2006
No68
Abstract: Functionalized organocopper reagents have been prepared via an iodine–copper exchange by the reaction of aryl or alkenyl io-
dides with a sterically hindered cuprate reagent, lithium dineophylcuprate [(Me2PhCCH2)2CuLi]. The resulting copper reagents react readily
with various electrophiles leading to polyfunctionalized molecules. This method represents a unique protocol for the preparation of aryl-,
heteroaryl- and alkenylcopper reagents.
Key words: functionalized organocopper reagents, iodine–copper exchange reaction, sterically hindered cuprate, polyfunctionalized
molecules
EtO2C
O
EtO2C
O
I
EtO2C
1) (Nphyl)2CuLi
–78 °C, 1 h
1) (Nphyl)2CuLi
–78 °C, 1 h
Et
O
I
I
Et
Procedure 1
I
2) EtCOCl
r.t., 30 min
2) furoyl chloride
r.t., 1 h
I
I
O
1
2: 75%
EtO2C
3: 71%
O
1) (Nphyl)2CuLi
–78 °C, 1.5 h
Et
O
Nphyl = CH2CMe2Ph
2) c-pentCOCl, r.t., 1 h
O
O
4: 62%
EtO2C
I
O
O
1) (Nphyl)2CuLi
–78 °C, 1 h
O
I
1) (Nphyl)2CuLi
r.t., 30 min
N
Procedure 2
N
PhSO2
I
2) 6-chloronicotinoyl
chloride, r.t., 1 h
N
PhSO2
2) EtOCOCOCl
r.t., 30 min
N
N
PhSO2
Cl
Cl
5
6: 78%
7: 71%
O
CO2Et
Br
O
I
O
Pent
(Nphyl)2CuLi
Pent
Pent
Procedure 3
Ph
r.t., 1 h
THF, –100 °C, 5 min
Ph
Ph
Cu(Nphyl)Li
CO2Et
10: 82%
8
9
Scheme 1
have found that the iodine–magnesium exchange reaction
is an excellent method for the preparation of various func-
Introduction
The preparation of functionalized organometallics is an tionalized aryl-, heteroaryl-, and alkenylmagnesium re-
important synthetic task, since these reagents allow the agents.2 The resulting Grignard reagents display high
preparation of polyfunctional molecules.1 Recently, we reactivity and good functional group tolerance. We have
also developed an iodine–copper exchange reaction,3
which allows for the practical preparation of functional-
ized aryl-, heteroaryl-, and alkenylcopper reagents in the
presence of various functional groups, such as ketone, es-
SYNTHESIS 2006, No. 15, pp 2618–2623
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942496; Art ID: T03506SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

PRACTICAL SYNTHETIC PROCEDURES
Functionalized Organocopper Reagents
2619
ter, nitrile, and halide (Scheme 1).4 These unsaturated or-
ganocopper reagents combine good functional group
tolerance and excellent reactivity with various electro-
philes leading to polyfunctionalized products.4
O
Ph
Br
Cu(Nphyl)Li
(Nphyl)2CuLi
r.t., 30 min
PhCOCl
r.t., 30 min
CN
CN
CN
88%
Scope and Limitations
CO2Et
CO2Et
CO2Et
The use of sterically hindered of lithium cuprates such as
lithium dineopentylcuprate [(Me3CCH2)2CuLi, abbreviat-
ed as Np2CuLi] or lithium dineophylcuprate
[(Me2PhCCH2)2CuLi, abbreviated as (Nphyl)2CuLi] are
essential for the success of the reaction.4a,5 Thus, ester or
ketone groups are compatible with the generation of an
arylcopper reagent via an iodine–copper exchange reac-
tion. This exchange is completed at –30 °C within a few
hours. Under these mild conditions, no attack on the ester
or ketone occurs (Scheme 2).4a
Cu(Np)Li
Br
Np2CuLi
allyl bromide
r.t., 30 min
–40 °C, 30 min
CO2Et
CO2Et
CO2Et
76%
Scheme 3 Preparation of functionalized arylcopper reagents via a
bromine–copper exchange reaction.
lows the bromine–copper exchange to take place under
milder conditions than usual.7 As expected, the iodine–
copper exchange reaction is considerably faster than the
corresponding bromine–copper exchange reaction
(Scheme 3).
I
Cu(Nphyl)Li
(Nphyl)2CuLi
–30 °C, 2 h
allyl bromide
r.t., 30 min
A selective mono-exchange reaction is observed with
polyhalogenated aryl and heteroaryl compounds. After
the first exchange, the electron density of the aromatic
ring increases to such an extent that no further exchange
reaction takes place (Scheme 4).4e,6
CO2Et
CO2Et
CO2Et
90%
O
Ph
I
The mixed lithium neophyl(phenyl)cuprate 11 reacts with
high SN2 selectivity with chiral cyclic allylic acetates,
such as 12 (98% ee), providing the chiral alkenyl iodide
13 (98% ee) in 77% yield. In the presence of zinc bromide,
a dramatic change of regioselectivity is observed and the
substitution reaction with the chiral acyclic pentafluo-
robenzoate 14 (97% ee) provides only the anti-SN2¢ prod-
uct 15 with 85% yield and 95% ee (Scheme 5).8
Cu(Nphyl)Li
COMe
(Nphyl)2CuLi
PhCOCl
r.t., 30 min
–30 °C to r.t., 1 h
COMe
COMe
77%
Scheme 2 Functionalized arylcopper reagents obtained via an
iodine–copper exchange reaction.
Interestingly, this method can also be extended to the
preparation of highly functionalized alkenylcopper spe-
cies (Scheme 6). Thus, the b-iodo unsaturated ester 16 can
be readily converted into the copper species 17. Carbocu-
pration of ethyl propiolate with 17 stereoselectively leads
to the diene 18 in 81% yield. The dibromide 19 undergoes
a selective bromine–copper exchange reaction with lithi-
um dineophylcuprate leading to the copper derivative 20
The rate of the halogen–copper exchange reaction greatly
depends on the electron density of the aromatic or het-
eroaromatic ring. The more electron-poor the aromatic
ring is, the faster the exchange reaction occurs.6 Also, the
presence of chelating groups ortho to the carbon–halogen
bond strongly accelerates the exchange reaction and al-
O
Cu(Nphyl)Li
CO2Et
I
I
I
(Nphyl)2CuLi
I
EtOCOCOCl
r.t., 30 min
N
N
N
THF–Et2O (3:1)
–10 °C, 1 h
N
N
N
Bn
Bn
Bn
82%
Br
Cu(Np)Li
Br
Br
Br
Np2CuLi
allyl bromide
r.t., 30 min
THF, 0 °C, 1 h
N
N
N
N
N
N
73%
Scheme 4 Selective halogen–copper exchange reaction for functionalization of dihalogenated aromatic compounds.
Synthesis 2006, No. 15, 2618–2623 © Thieme Stuttgart · New York

2620
X. Yang, P. Knochel
PRACTICAL SYNTHETIC PROCEDURES
n-Bu
CO2Et
OAc
Me
I
Cu(Nphyl)Li
12: 98% ee
1) ZnBr2, THF
2)
I
THF–Et2O (3:1)
–40 °C to –20 °C, 12 h
Me
OCOC6F5
CO2Et
CO2Et
14: 97% ee
n
-Bu
11
–40 °C to r.t., 12 h
13: 77%; 98% ee
15: 85%; 95% eem
SN2′ substitution
SN2 substitution
Scheme 5 Stereoselective substitutions of functionalized arylcopper reagents with chiral allylic electrophiles.
CO2Me
CO2Me
I
CO2Me
HC CCO2Et
r.t., 30 min
(Nphyl)2CuLi
TMS
–78 °C, 30 min
TMS
TMS
Cu(Nphyl)Li
CO2Et
18: 81%
16
17
O
O
O
O
O
Br
Cu(Nphyl)Li
(Nphyl)2CuLi
O
O
c-Hex
c-HexCOCl
r.t., 30 min
–78 °C, 30 min
Br
Br
21: 76%
Br
20
19
Scheme 6 Preparation of functionalized alkenylcopper reagents via a halogen–copper exchange reaction.
which can be readily acylated with cyclohexanecarbonyl neophylcuprate followed by acylation with 6-
chloride providing the ketone 21 in 76% yield.
chloronicotinoyl chloride provides the iodoindolyl ketone
6 in 78% yield. Treatment of 6 with a second equivalent
of lithium dineophylcuprate followed by further acylation
with ethyl oxaloyl chloride leads to the diketone 7 in 71%
yield. In the last procedure (Procedure 3), the b-iodo-a,b-
unsaturated ketone 811 can be readily converted into the
corresponding alkenylcopper compound 9 (–100 °C, 5
min). Its reaction with ethyl 2-(bromomethyl)acrylate fur-
nishes the allylated compound 10 in 82% yield.
In summary, the halogen–copper exchange reaction al-
lows the preparation of highly functionalized organocop-
per reagents bearing various functional groups. Many of
these copper reagents are versatile precursors for the prep-
aration of complex molecules.
Procedures
Unless otherwise indicated, all reactions were carried out
Herein, we describe three typical procedures demonstrat- with a magnetic stirring in flame-dried glassware under
ing the synthetic utility of functionalized organocopper argon. Melting points were measured on a Büchi B 540
reagents prepared by an iodine–copper exchange apparatus and were uncorrected. NMR spectra were re-
(Scheme 1). In Procedure 1, we report the successive io- corded in CDCl3 at 300 MHz for 1H NMR and 75 MHz for
dine–copper exchange for the selective functionalization 13C NMR (Varian XL 300). Chemical shifts were reported
of polyhalogenated aromatics. Thus, the triiodobenzoate in ppm relative to TMS. IR spectra were recorded on a
19 undergoes a selective mono-exchange reaction with Perkin Elmer FT-IR Spectrum 1000. Low-resolution MS
lithium dineophylcuprate providing the copper derivative, were recorded using a GC/MS combination of the type HP
which is readily acylated with propionyl chloride giving 6890 and MSD 5973 fitted with a HP-5 column (30
the ketone 2 in 75% yield. A second exchange can then be m × 0.25 mm × 0.25 mm). HRMS were recorded on a
realized with lithium dineophylcuprate followed by acyla- Finnigan-MAT 95Q spectrometer (EI, 70 eV). Flash col-
tion with 2-furoyl chloride to give the diketone 3 in 71% umn chromatographic purifications were carried out using
yield. Finally, a reaction with a further equivalent of lith- Merck Kieselgel 60 (230–400 mesh ASTM). Commer-
ium dineophylcuprate followed by acylation with cyclo- cially available starting materials with a purity >97% were
pentylcarbonyl chloride yields the triketone 4 in 62% used without further purification. Solvents were distilled
yield. In the second procedure (Procedure 2), the selective and dried before use.
functionalization of indoles in position 2 and 3 is achieved
Neophyllithium12
A dry, argon-flushed, 500-mL round-bottom flask was charged with
Li dust (3.0 g, 432 mmol) and 2-methyl-2-phenylethyl chloride
using an iodine–copper exchange reaction. Thus, the reac-
tion of the 2,3-diiodoindole derivative 510 with lithium di-
Synthesis 2006, No. 15, 2618–2623 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Functionalized Organocopper Reagents
2621
(14.0 mL, 86.9 mmol) in n-hexane (75 mL) and the mixture was re-
fluxed overnight. The mixture was cooled to r.t., n-hexane was re-
moved in vacuo and anhyd Et2O was added. The resulting mixture
was cannulated into a flame-dried Schlenk tube and centrifuged
(2000 rpm, 30 min). The clear soln of neophyllithium thus obtained
was titrated before use with menthol using o-phenanthroline as
indicator13 and can be stored at –30 °C for several days.
MS (EI, 70 eV): m/z (%) = 426 (2) [M+], 397 (80), 381 (5), 301
(100), 229 (20), 174 (15), 95 (20), 75 (8).
HRMS (EI): m/z [M+] calcd for C17H15IO5: 425.9964; found:
425.9969.
Ethyl 5-(Cyclopentylcarbonyl)-3-(2-furoyl)-2-propionylben-
zoate (4)
To a suspension of CuCN (373 mg, 4.1 mmol) in anhyd Et2O (5 mL)
at –78 °C was added 1.35 M neophyllithium in Et2O (6.1 mL, 8.2
mmol) and the resulting mixture was stirred at r.t. for 15 min. The
resulting light yellow clear soln was cooled to –78 °C and added via
a cannula to a soln of the diketone 3 (1.0 g, 2.3 mmol) in anhyd THF
(10 mL). The resulting mixture was stirred at this temperature for
1.5 h. Then, anhyd NMP (0.5 mL) and cyclopentanecarbonyl chlo-
ride (1.1 g, 8 mmol) were added successively. The resulting mixture
was stirred at r.t. for 1 h. The mixture was quenched with sat. aq
NH4Cl (5 mL) and was poured into H2O (20 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL) and the combined or-
ganic fractions were washed with brine (20 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by flash chromatography
(n-pentane–Et2O, 2:1) gave the desired product 4 as a yellow oil;
yield: 0.57 g (62%).
Ethyl 3,5-Diiodo-2-propionylbenzoate (2)
To a suspension of CuCN (614 mg, 6.8 mmol) in anhyd THF (20
mL) at –78 °C was added 1.5 M neophyllithium in Et2O (9 mL, 13.6
mmol) and the resulting mixture was stirred at r.t. for 15 min. The
resulting light yellow clear soln was cooled to –78 °C and a soln of
ethyl 2,3,5-triiodobenzoate (3.0 g, 5.7 mmol) in anhyd THF (20
mL) was added via a cannula. The resulting mixture was stirred at
this temperature for 1 h. Then anhyd NMP (1 mL) and propionyl
chloride (15 mmol) were added successively. The resulting mixture
was stirred at r.t. for 30 min. The mixture was quenched with sat. aq
NH4Cl (10 mL) and the resulting mixture was poured into H2O (30
mL). The aqueous phase was extracted with CH2Cl2 (3 × 30 mL)
and the combined organic fractions were washed with brine (30
mL), dried (Na2SO4), and concentrated in vacuo. Purification by
flash chromatography (n-pentane–Et2O, 8:1) gave the desired prod-
uct 2 as white solid; yield: 2.0 g (75%); mp 75 °C.
IR (film): 3405 (w), 2942 (s), 1723 (vs), 1690 (vs), 1657 (vs), 1566
(s), 1463 (s), 1391 (m), 1299 (s), 1222 (s), 1018 (m), 950 (w), 795
(w), 769 (m), 593 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.63–8.62 (d, J = 1.7 Hz, 1 H),
8.42–8.41 (d, J = 1.7 Hz, 1 H), 7.64–7.63 (dd, J = 1.7 Hz, J = 0.8
Hz, 1 H), 7.11–7.10 (dd, J = 3.5 Hz, J = 0.8 Hz, 1 H), 6.55–6.54 (dd,
J = 3.5 Hz, J = 1.7 Hz, 1 H), 4.35–4.31 (q, J = 7.1 Hz, 2 H), 3.68–
3.63 (quint, J = 8.3 Hz, 1 H), 2.86–2.82 (q, J = 7.1 Hz, 2 H), 1.92–
1.85 (m, 4 H), 1.68–1.60 (m, 4 H), 1.34–1.31 (t, J = 7.0 Hz, 3 H),
1.17–1.15 (t, J = 7.0 Hz, 3 H).
IR (KBr): 3410 (w), 2925 (s), 1721 (vs), 1560 (w), 1535 (s), 1461
(w), 1271 (vs), 1204 (m), 1103 (w), 1017 (w), 878 (w), 738 (vs), 704
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.37–8.36 (d, J = 1.7 Hz, 1 H),
8.34–8.33 (d, J = 1.7 Hz, 1 H), 4.38–4.31 (q, J = 7.1 Hz, 2 H), 2.89–
2.82 (q, J = 7.1 Hz, 2 H), 1.39–1.36 (t, J = 7.1 Hz, 3 H), 1.31–1.28
(t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 206.7, 163.7, 151.1, 148.5, 139.2,
130.3, 94.5, 92.8, 62.7, 36.6, 14.5, 7.8.
MS (EI, 70 eV): m/z (%) = 458 (5) [M+], 429 (80), 401 (100), 373
(5), 356 (5), 274 (10), 201 (5), 74 (5).
13C NMR (75 MHz, CDCl3): d = 205.6, 199.8, 180.7, 164.1, 151.1,
147.8, 147.6, 136.2, 135.7, 132.1, 131.9, 128.9, 121.5, 112.2, 61.7,
46.0, 37.1, 29.1, 25.7, 13.4, 7.0.
HRMS (EI): m/z [M+] calcd for C12H12I2O3: 457.8876; found:
MS (EI, 70 eV): m/z (%) = 396 (5) [M+], 367 (70), 350 (10), 271
457.8851.
(100), 253 (10), 199 (35), 171 (15), 95 (20), 69 (15).
HRMS (EI): m/z [M+] calcd for C23H24O6: 396.1573; found:
396.1588.
Ethyl 3-(2-Furoyl)-5-iodo-2-propionylbenzoate (3)
To a suspension of CuCN (360 mg, 4 mmol) in anhyd THF (15 mL)
at –78 °C was added 1.5 M neophyllithium in Et2O (5.4 mL, 8
mmol) and the resulting mixture was stirred at r.t. for 15 min. The
resulting light yellow clear soln was cooled to –78 °C and a soln of
ethyl 3,5-diiodo-2-propionylbenzoate (1.5 g, 3.3 mmol) in anhyd
THF (10 mL) was added via a cannula. The resulting mixture was
stirred at this temperature for 1 h. Then anhyd NMP (1 mL) and 2-
furoyl chloride (8 mmol) were added successively. The resulting
mixture was stirred at r.t. for 1 h. The mixture was quenched with
sat. aq NH4Cl (10 mL) and the resulting mixture was poured into
H2O (30 mL). The aqueous phase was extracted with CH2Cl2
(3 × 25 mL) and the combined organic fractions were washed with
brine (30 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by flash chromatography (n-pentane–Et2O, 3:1) gave the de-
sired product 3 as a white solid; yield: 1.0 g (71%); mp 117 °C.
2-(6-Chloro-3-pyridinylcarbonyl)-3-iodo-1-(phenylsulfonyl)-
1H-indole (6)
To a suspension of CuCN (540 mg, 6.0 mmol) in anhyd THF (10
mL) at –78 °C was added 1.5 M neophyllithium in Et2O (8 mL, 12.0
mmol) and the resulting mixture was stirred at r.t. for 15 min. The
resulting light yellow clear soln was cooled to –78 °C and a soln of
the diiodoindole 5 (2.55 g, 5.0 mmol) in anhyd THF (15 mL) was
added via a cannula. The resulting mixture was stirred at r.t. for 0.5
h and cooled to –78 °C. Then, anhyd NMP (1.5 mL) and a soln of
6-chloronicotinoyl chloride (2.6 g, 15 mmol) in anhyd THF (6 mL)
were added successively. The resulting mixture was stirred at r.t. for
1 h. The reaction was quenched with sat. aq NH4Cl (10 mL) and the
resulting mixture was poured into H2O (30 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 30 mL) and the combined organic
fractions were washed with brine (30 mL), dried (Na2SO4), and con-
centrated in vacuo. Purification by flash chromatography (n-pen-
tane–Et2O, 5:1) gave the desired product 6 as a light yellow solid;
yield: 2.04 g (78%); mp 62 °C.
IR (KBr): 3055 (w), 2926 (s), 1722 (vs), 1656 (s), 1565 (m), 1463
(s), 1264 (vs), 1178 (m), 1017 (w), 738 cm–1 (vs).
1H NMR (300 MHz, CDCl3): d = 8.49 (d, J = 1.7 Hz, 1 H), 8.21 (d,
J = 1.7 Hz, 1 H), 7.73 (dd, J = 1.7 Hz, J = 0.8 Hz, 1 H), 7.19–7.18
(dd, J = 3.6 Hz, J = 0.8 Hz, 1 H), 6.64–6.62 (dd, J = 3.6 Hz, J = 1.7
Hz, 1 H), 4.42–4.36 (q, J = 7.1 Hz, 2 H), 2.91–2.84 (q, J = 7.1 Hz,
2 H), 1.42–1.37 (t, J = 7.1 Hz, 3 H), 1.24–1.19 (t, J = 7.1 Hz, 3 H).
IR (KBr): 3435 (vs), 2926 (w), 1673 (vs), 1581 (vs), 1447 (s), 1375
(s), 1364 (s), 1254 (m), 1176 (vs), 1089 (s), 1020 (w), 952 (m), 757
(m), 570 cm–1 (m).
13C NMR (75 MHz, CDCl3): d = 206.4, 180.8, 164.4, 151.9, 148.7,
144.8, 141.8, 141.6, 138.2, 130.8, 122.6, 113.2, 93.2, 62.8, 38.3,
14.5, 8.1.
1H NMR (300 MHz, CDCl3): d = 8.78–8.77 (d, J = 2.3 Hz, 1 H),
8.12–8.08 (dd, J = 8.4 Hz, J = 2.3 Hz, 1 H), 7.99–7.96 (d, J = 8.3
Hz, 1 H), 7.83–7.80 (m, 2 H), 7.52–7.29 (m, 7 H).
Synthesis 2006, No. 15, 2618–2623 © Thieme Stuttgart · New York

2622
X. Yang, P. Knochel
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (75 MHz, CDCl3): d = 186.9, 156.5, 151.8, 139.7, 136.8,
136.6, 136.1, 135.0, 132.2, 131.9, 129.7, 127.8, 125.7, 125.1, 123.7,
115.2, 75.0.
J = 7.19 Hz, 2 H), 4.10–4.09 (t, J = 1.55 Hz, 2 H), 2.59–2.54 (t,
J = 7.35 Hz, 2 H), 1.71–1.61 (m, 2 H), 1.38–1.28 (m, 4 H), 1.31–
1.27 (t, J = 7.08 Hz, 3 H), 0.94–0.89 (t, J = 6.90 Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 522 (20) [M+], 380 (41), 254 (55), 226
(17), 191 (23), 164 (20), 141 (32), 114 (30), 77 (100).
HRMS (EI): m/z [M+] calcd for C20H12ClIN2O3S: 521.9302; found:
521.9277.
13C NMR (75 MHz, CDCl3): d = 201.1, 167.2, 153.5, 141.1, 138.1,
129.6, 129.0, 127.2, 126.6, 125.4, 61.2, 45.3, 33.0, 31.8, 24.3, 22.9,
14.5, 14.3.
MS (EI, 70 eV): m/z (%) = 314 (13) [M+], 285 (10), 241 (100), 215
(30), 187 (18), 169 (11), 141 (13), 115 (10), 91 (4), 102 (2).
Ethyl [2-(6-Chloro-3-pyridinylcarbonyl)-1-(phenylsulfonyl)-
1H-indol-3-yl](oxo)acetate (7)
HRMS (EI): m/z [M+] calcd for C20H26O3: 314.1882; found:
314.1904.
To a suspension of CuCN (207 mg, 2.3 mmol) in anhyd THF (8 mL)
at –78 °C was added 1.5 M neophyllithium in Et2O (3.1 mL, 4.6
mmol) and the resulting mixture was stirred at r.t. for 15 min. The
resulting light yellow clear soln was cooled to –78 °C and a soln of
the iodoindole 6 (1.0 g, 1.92 mmol) in anhyd THF (6 mL) was added
via a cannula. The resulting mixture was stirred at –78 °C for 1 h.
Then, anhyd NMP (1 mL) and ethyl oxalyl chloride (685 mg, 5
mmol) in anhyd THF (6 mL) were added successively. The result-
ing mixture was stirred at r.t. for 1 h. The reaction was quenched
with sat. aq NH4Cl (10 mL) and the resulting mixture was poured
into H2O (30 mL). The aqueous phase was extracted with CH2Cl2
(3 × 20 mL) and the combined organic fractions were washed with
brine (30 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by flash chromatography (n-pentane–Et2O, 2:1) gave 7 as white
solid; yield: 0.7 g (71%); mp 53 °C.
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 Cheme-
tall GmbH (Frankfurt) for the generous gift of chemicals.
References
(1) (a) Knochel, P. Handbook of Functionalized
Organometallics; Wiley-VCH: Weinheim, 2005.
(b) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E.
Org. React. 2001, 58, 417. (c) Knochel, P.; Dohle, W.;
Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;
Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42,
4302.
IR (KBr): 3436 (vs), 1735 (s), 1677 (vs), 1582 (m), 1448 (w), 1380
(vs), 1365 (s), 1291 (m), 1152 (s), 1107 (s), 1040 (s), 952 (w) 753
(w), 684 (w), 569 cm–1 (m).
(2) (a) Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 897. (b) Staubitz, A.; Dohle, W.; Knochel, P. Synthesis
2003, 233. (c) Thibonnet, J.; Knochel, P. Tetrahedron Lett.
2000, 41, 3319. (d) Rottländer, M.; Boymond, L.; Cahiez,
G.; Knochel, P. J. Org. Chem. 1999, 64, 1080. (e) Ren, H.;
Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
(f) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun.
2005, 543.
(3) For previous preparation of functionalized copper reagents,
see: (a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968,
90, 5615. (b) Kondo, Y.; Matsudaira, T.; Sato, J.; Muraka,
N.; Sakamoto, T. Angew. Chem. Int. Ed. 1996, 35, 736;
Angew. Chem., 1996, 108, 818. (c) Ebert, G. W.; Rieke, R.
D. J. Org. Chem. 1984, 49, 5281. (d) Rieke, R. D.;
Wehmeyer, R. H.; Wu, T. C.; Ebert, G. W. Tetrahedron
1989, 45, 443. (e) Ebert, G. W.; Cheasty, J. W.; Tehrani, S.
S.; Aouad, E. Organometallics 1992, 11, 1560. (f) Ebert, G.
W.; Pfennig, D. R.; Suchan, S. D.; Donovan, T. A.
Tetrahedron Lett. 1993, 34, 2279.
(4) (a) Piazza, C.; Knochel, P. Angew. Chem. Int. Ed. 2002, 41,
3263. (b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org.
Lett. 2003, 5, 1229. (c) Yang, X.; Knochel, P. Synlett 2004,
81. (d) Yang, X.; Althammer, A.; Knochel, P. Org. Lett.
2004, 6, 1665. (e) Yang, X.; Knochel, P. Synlett 2004, 2303.
(5) For a chemoselective halogen–lithium exchange, see:
Kondo, Y.; Asai, M.; Uchiyama, T.; Sakamoto, T. Org. Lett.
2001, 3, 13.
(6) (a) Varchi, G.; Jensen, A. E.; Dohle, W.; Ricci, A.; Cahiez,
G.; Knochel, P. Synlett 2001, 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) Trécourt, F.; Breton, G.; Bonnet, V.;
Mongin, F.; Marsais, F.; Quéguiner, G. Tetrahedron Lett.
1999, 40, 4339.
1H NMR (300 MHz, CDCl3): d = 8.76 (d, J = 2.1 Hz, 1 H), 8.04–
8.02 (dd, J = 8.35 Hz, J = 2.1 Hz, 1 H), 7.99–7.97 (d, J = 8.58 Hz,
1 H), 7.95–7.94 (d, J = 7.94 Hz, 1 H), 7.78–7.76 (d, J = 8.58 Hz, 2
H), 7.50–7.47 (t, J = 7.40 Hz, 1 H), 7.40–7.35 (m, 4 H), 7.32–7.30
(t, J = 7.15 Hz, 1 H), 4.12–4.08 (q, J = 6.91 Hz, 2 H), 1.18–1.15 (t,
J = 6.91 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 186.6, 181.3, 163.0, 156.4, 151.1,
141.6, 139.1, 136.5, 135.6, 135.6, 132.8, 130.0, 128.0, 126.8, 126.6,
125.0, 123.1, 119.3, 114.8, 63.3, 14.2.
MS (EI, 70 eV): m/z (%) = 356 (8) [M – C6H3ClNO]+, 283 (100),
170 (11), 140 (15), 112 (9), 76 (4).
HRMS (FAB): m/z [M + H]+ calcd for C24H18ClN2O6S: 497.0574;
found: 497.0528.
Ethyl (E)-2-Methylene-6-oxo-4-phenyl-4-undecenoate (10)
To a suspension of CuCN (323 mg, 3.6 mmol) in anhyd THF (10
mL) at –78 °C was added 1.5 M neophyllithium in Et2O (4.8 mL,
7.2 mmol) and the resulting mixture was stirred at r.t. for 15 min.
The resulting light yellow clear soln was recooled to –100 °C and
was added via a cannula to a soln of the iodoenone 8 (1.0 g, 3.0
mmol) in anhyd THF (10 mL) at –100 °C. The resulting mixture
was stirred at this temperature for 5 min. Ethyl (bromomethyl)acry-
late (1.5 g, 8 mmol) was added successively and resulting mixture
was stirred at r.t. for 1 h. The mixture was quenched with sat. aq
NH4Cl (8 mL) and was poured into H2O (20 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL) and the combined or-
ganic fractions were washed with brine (30 mL), dried (Na2SO4),
and concentrated in vacuo. Purification by flash chromatography
(n-pentane–Et2O, 8:1) gave the desired product 10 as a colorless oil;
yield: 0.77 g (82%).
IR (film): 3415 (w), 2957 (s), 2931 (s), 1714 (vs), 1686 (vs), 1601
(m), 1572 (m), 1446 (m), 1367 (m), 1247 (s), 1130 (s), 1075 (m),
951 (w), 761 (w), 697 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.49–7.46 (m, 2 H), 7.38–7.35 (m,
3 H), 6.67 (s, 1 H), 6.17–6.15 (dd, J = 2.65 Hz, J = 1.32 Hz, 1 H),
5.42–5.40 (dd, J = 3.00 Hz, J = 1.75 Hz, 1 H), 4.24–4.17 (q,
(7) This effect has been extensively used to perform ortho-
directed metalations: Snieckus, V. Chem. Rev. 1990, 90,
879.
Synthesis 2006, No. 15, 2618–2623 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Functionalized Organocopper Reagents
2623
(8) Calaza, M. I.; Yang, X.; Soorukram, D.; Knochel, P. Org.
Lett. 2004, 6, 529.
(9) 2,3,5-Triiodobenzoic acid is commercially available from
Aldrich.
(11) (a) Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.
Tetrahedron Lett. 1986, 27, 4763. (b) Verkruijsse, H. D.;
Heus-Kloos, Y. A.; Brandsma, L. J. Organomet. Chem.
1988, 338, 289.
(10) (a) Witulski, B.; Buschmann, N.; Bergsträßer, U.
Tetrahedron 2000, 56, 8473. (b) Saulnier, M. G.; Gribble,
G. W. J. Org. Chem. 1982, 47, 757.
(12) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem.
1990, 55, 5406.
(13) Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.
Synthesis 2006, No. 15, 2618–2623 © Thieme Stuttgart · New York