Regio- and chemoselective synthesis of fully substituted furans

Article abstract of DOI:10.1055/s-0030-1260035

Highly functionalized furyl-, indolyl-, and pyrrolylmagnesium reagents are efficiently prepared by direct C-H activation by using regio- and chemoselective magnesium amide bases, such as (tetramethylpiperidyl)magnesium chloride-lithium chloride (TMPMgClLiCl) or bis(tetramethylpiperidyl)magnesium-bis(lithium chloride) (TMPg2LiCl), tolerated by a range of sensitive functional groups. These organometallic reagents readily react with various electrophiles, leading to polyfunctional heterocycles. Furthermore, the full functionalization of the sensitive furan scaffold can be achieved. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260035

PAPER
1751
Regio- and Chemoselective Synthesis of Fully Substituted Furans
Synthesis of
F
a
ully Substit
b
uted Furansian M. Piller, Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, Haus F, 81377 Munich, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 22 January 2011; revised 17 March 2011
MgCl•LiCl
TMPMgCl•LiCl
(1; 1.1 equiv)
Abstract: Highly functionalized furyl-, indolyl-, and pyrrolylmag-
nesium reagents are efficiently prepared by direct C–H activation
EtO2C
CO2Et
THF
–78 °C, 10 min
by using regio- and chemoselective magnesium amide bases, such
as (tetramethylpiperidyl)magnesium chloride–lithium chloride
(TMPMgCl·LiCl) or bis(tetramethylpiperidyl)magnesium–bis(lith-
ium chloride) (TMP2Mg·2LiCl), tolerated by a range of sensitive
functional groups. These organometallic reagents readily react with
various electrophiles, leading to polyfunctional heterocycles. Fur-
thermore, the full functionalization of the sensitive furan scaffold
can be achieved.
EtO2C
CO2Et
O
2a
O
3a >90%
ClOC
F
O
4a
F
CuCN•2LiCl (20 mol%)
Key words: directed metalation, organometallic reagents, metal
amides, magnesium, furan
EtO2C
CO2Et
5a 85%
–20 °C, 1 h
O
Scheme 1 Magnesiation of the furan 2a and subsequent copper(I)-
catalyzed acylation
Polyfunctional furans are privileged structures in drug
discovery and are present in numerous natural products.1
Their direct synthesis or functionalization has proven to
be highly challenging due to poor tolerance of functional
groups and the necessity of activating substituents.2,3
However, we have recently reported the preparation of
highly chemoselective lithium chloride complexed
2,2,6,6-tetramethylpiperidyl (TMP) metal amide bases,
such as (tetramethylpiperidyl)magnesium chloride–lithi-
um chloride (TMPMgCl·LiCl; 1),4 (tetramethylpip-
eridyl)zinc chloride–lithium chloride (TMPZnCl·LiCl),5
bis(tetramethylpiperidyl)zinc–bis(magnesium chloride)–
bis(lithium chloride) (TMP2Zn·2MgCl2·2LiCl),6 and
Similarly, 3a also reacted smoothly with tosyl cyanide
(–78 °C, 30 min) to lead to the cyano-substituted furan 5c
in 66% yield (entry 2). In addition, transmetalation of 3a
with zinc chloride (1.1 equiv) gave the corresponding
hetarylzinc reagent, providing, after a Negishi cross-
coupling11 [Pd(PPh3)4 (1 mol%), 25 °C, 3 h] with 3-iodo-
1-(trifluoromethyl)benzene (4b), the 3-arylfuran 5d in
79% yield (entry 3). Remarkably, the trimethylsilyl-
substituted furan 2b was regioselectively metalated at the
position ortho to the carboxyl group when magnesium
complex 1 (1.1 equiv, –30 °C, 1 h) was used, generating
the hetarylmagnesium reagent 3b in ca. 90% yield. Chlo-
rination of 3b with hexachloroethane (–50 °C, 15 h) af-
forded the 2,3,5-trisubstituted furan 5e in 48% yield (entry
4). The 3-cyanofuran derivative 5f was obtained in 52%
yield after addition of tosyl cyanide to 3b (–30 °C, 15 min;
entry 5). Moreover, the electron-deficient 5-bromofuran-
2-carboxylate 2c was also regioselectively magnesiated
in position 3 with magnesium complex 1 (1.1 equiv) at
–78 °C for 30 minutes, generating the 3-furylmagnesium
reagent 3c. Its copper-catalyzed acylation [CuCN·2LiCl
(20 mol%), –40 °C, 15 h] with benzoyl chloride provided
the expected ketone 5g in 75% yield (entry 6). Chlorina-
tion of 3c (–78 °C, 30 min, then –78 to 25 °C) with ben-
zenesulfonyl chloride produced ethyl 5-bromo-3-
chlorofuran-2-carboxylate (5h) in 59% yield (entry 7).
Similarly, the reaction of 3c and tosyl cyanide (–78 °C, 30
min, then –78 to 25 °C) afforded the polyfunctional furan
5i in 63% yield (entry 8). After transmetalation of 3c with
zinc chloride (1.1 equiv), a palladium-catalyzed cross-
coupling11 [Pd(PPh3)4 (1 mol%), 25 °C, 6 h] with ethyl 4-
iodobenzoate (4c) provided the benzoate 5j in 86% yield
(entry 9). Interestingly, the furylzinc reagent obtained af-
ter transmetalation of 3c with zinc chloride (1.1 equiv)
tris(tetramethylpiperidyl)aluminum–tris(lithium
chlo-
ride) (TMP3Al·3LiCl),7 allowing the selective metalation
of polyfunctional aromatics and sensitive heterocycles.
Moreover, by using these tetramethylpiperidyl-derived
metal amides, the full functionalization of the thiophene
scaffold was achieved.8 Herein, we report concise routes
to the selective and full functionalization of the more sen-
sitive furan ring. Thus, the disubstituted furan derivative
2a was smoothly magnesiated by using magnesium com-
plex 1 (1.1 equiv, –78 °C, 10 min), producing the poly-
functional furylmagnesium derivative 3a (90% yield9). A
subsequent copper-catalyzed acylation10 [CuCN·2LiCl
(20 mol%), –20 °C, 1 h] with 3-fluorobenzoyl chloride
(4a) provided the 3-furyl ketone 5a in 85% yield
(Scheme 1).
Furthermore, the metalated diester 3a efficiently reacted
with S-methyl benzenethiosulfonate (MeSSO2Ph) to
afford the thioether 5b in 93% yield (Table 1, entry 1).
SYNTHESIS 2011, No. 11, pp 1751–1758
x
x.
x
x
.
2
0
1
1
Advanced online publication: 10.05.2011
DOI: 10.1055/s-0030-1260035; Art ID: T13811SS
© Georg Thieme Verlag Stuttgart · New York

1752
F. M. Piller, P. Knochel
PAPER
Table 1 Preparation of 2,3,5-Trisubstituted Furans of Type 5
Entry
1
Magnesium reagent
Metalation conditions Electrophile
Product
Yield (%)a
93
MgCl•LiCl
SMe
–78 °C, 10 min
–78 °C, 10 min
MeSSO2Ph
TsCN
EtO2C
CO2Et
EtO2C
CO2Et
O
O
O
3a
5b
CN
2
3
3a
3a
66
EtO2C
CO2Et
5c
CF3
–78 °C, 10 min
79b
I
CF3
EtO2C
CO2Et
CO2Et
O
O
O
4b
5d
Cl
MgCl•LiCl
4
5
–30 °C, 60 min
–30 °C, 60 min
C2Cl6
TsCN
48
52
Me3Si
Me3Si
CO2Et
O
3b
5e
CN
3b
Me3Si
CO2Et
5f
O
MgCl•LiCl
Ph
6
–78 °C, 30 min
PhCOCl
75
Br
CO2Et
O
Br
CO2Et
O
3c
5g
Cl
7
8
3c
3c
–78 °C, 30 min
–78 °C, 30 min
PhSO2Cl
TsCN
59
63
Br
CO2Et
O
O
5h
CN
Br
CO2Et
5i
CO2Et
CO2Et
9
3c
–78 °C, 30 min
86b
I
4c
Br
CO2Et
O
5j
Cl
O
EtO2C
Br
MgCl•LiCl
Cl
O
10
–78 °C, 30 min
80c
Br
CO2Et
O
Cl
O
Br
CO2Et
O
Cl
3c
5k
4d
a Isolated yield of analytically pure product.
b Obtained after transmetalation with ZnCl2 (1.1 equiv) and a palladium-catalyzed cross-coupling [Pd(PPh3)4 (1 mol%), 25 °C, 3 h].
c Obtained after transmetalation with ZnCl2 (1.1 equiv).
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

PAPER
Synthesis of Fully Substituted Furans
1753
was oxidatively dimerized by addition of chloranil12 (4d;
1.5 equiv, –40 °C, 2 h), leading to the polyfunctional furyl
dimer 5k in 80% yield (entry 10).
1. i-PrMgCl•LiCl (1.1 equiv)
Cl
Cl
THF, –50 °C
30 min
EtO2C
Br
EtO2C
CN
2. TsCN
–50 to 25 °C, 3 h
O
5e
O
8 73%
Remarkably, the 2,3,5-trisubstituted furan 5b was effi-
ciently magnesiated with magnesium complex 1 (1.1
equiv, –78 °C, 45 min), leading to the polyfunctional fu-
rylmagnesium reagent 6b (>90% yield9). Its addition to 4-
cyanobenzaldehyde (4e) afforded the fully functionalized
furan 7a in 67% yield (Scheme 2). Similarly, the electron-
deficient furan 5c could be metalated by magnesium com-
plex 1 (1.1 equiv, –78 °C, 45 min) in the presence of zinc
chloride (1.1 equiv) to generate the polysubstituted fu-
rylzinc chloride 6c (>90% yield). A Negishi cross-
coupling11 [Pd(PPh3)4 (1 mol%), 25 °C, 3 h] with 4-iodo-
benzonitrile (4f) provided the fully substituted furan 7b in
71% yield (Scheme 2).
1. TMPMgCl•LiCl (1; 1.1 equiv)
THF, –78 °C
Cl
25 min
2. CuCN•2LiCl (20 mol%)
–78 °C, 15 min
EtO2C
CN
O
9 74%
Br
Scheme 3 Preparation of the fully functionalized furan derivative 9
Furthermore, we could also apply this methodology to the
selective functionalization of more sensitive heterocycles
such as electron-deficient pyrrole and indole derivatives.
Thus, the 2-(ethoxycarbonyl)indole 10a was regioselec-
tively magnesiated by magnesium complex 1 (1.1 equiv,
–45 °C, 30 min), providing the functionalized hetaryl-
magnesium derivative 11a (Scheme 4). Its addition to
benzaldehyde (–45 °C, 30 min) or a copper-catalyzed al-
lylation [CuCN·2LiCl (20 mol%), –45 °C, 30 min] led to
the 2,3-disubstituted indole derivatives 12a and 12b in 91
and 95% yield, respectively (Scheme 4). Similarly, the
MeS
MeS
MgCl•LiCl
TMPMgCl•LiCl
(1; 1.1 equiv)
EtO2C
CO2Et
CHO
EtO2C
CO2Et
THF
O
O
5b
–78 °C, 45 min
6b >90%
HO
MeS
CN
NC
4e
–78 °C, 3 h
MgCl•LiCl
TMPMgCl•LiCl
(1; 1.1 equiv)
EtO2C
CO2Et
7a 67%
O
CO2Et
CO2Et
THF
–45 °C, 30 min
N
N
Ts
Ts
TMPMgCl•LiCl
(1; 1.1 equiv)
ZnCl2 (1.1 equiv)
NC
NC
ZnCl•LiCl
10a
11a >90%
HO
EtO2C
CO2Et
EtO2C
CN
CO2Et
THF, –78 °C
45 min
O
5c
O
Ph
6c >90%
PhCHO
–45 °C, 30 min
CN
CO2Et
N
Ts
12a 91%
I
NC
4f
Pd(PPh3)4 (1 mol%)
25 °C, 3 h
Br
EtO2C
O
CO2Et
CuCN•2LiCl (20 mol%)
7b 71%
–45 °C, 30 min
CO2Et
N
Scheme 2 Preparation of the fully functionalized furans 7a and 7b
Ts
12b 95%
Interestingly, attempted metalation of 5e with magnesium
complex 1 merely produced regioisomeric furylmagne-
sium reagents at positions 4 and 5 due to halogen-dance
side reactions.13 However, a chemoselective bromine–
magnesium exchange reaction of the furan-2-carboxylate
5e when using isopropylmagnesium chloride–lithium
chloride14 (1.1 equiv, –50 °C, 30 min) efficiently pro-
duced the expected 5-furylmagnesium derivative, which
reacted smoothly with tosyl cyanide (–50 to 25 °C, 3 h),
leading to the functionalized furan 8 in 73% yield
(Scheme 3). A subsequent metalation of 8 with magne-
sium complex 1 (1.1 equiv, –78 °C, 25 min) followed by
a copper-catalyzed allylation [CuCN·2LiCl (20 mol%),
–78 °C, 15 min] afforded the fully substituted furan-2-car-
boxylate 9 in 74% yield (Scheme 3).
1. TMP2Mg•2LiCl
ZnCl•LiCl
(13; 1.1 equiv)
THF, –30 °C, 1.5 h
EtO2C
CO2Et
EtO2C
CO2Et
N
2. ZnCl2 (1.1 equiv)
N
Boc
10b
Boc
11b >90%
Cl
Cl
I
4g
Pd(PPh3)4 (1 mol%)
25 °C, 1.5 h
EtO2C
CO2Et
N
Boc
12c 80%
Scheme 4 Preparation of the polyfunctional N-heterocycles of type
12
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

1754
F. M. Piller, P. Knochel
PAPER
CuCN·2LiCl in THF (0.2 mL, 20 mol%) at –78 °C and further stir-
ring for 15 min. At –20 °C, 3-fluorobenzoyl chloride (4a; 174 mg,
1.1 mmol) was added and the mixture was stirred for 1 h, and then
quenched with sat. aq NH4Cl (5 mL). The aqueous layer was ex-
tracted with Et2O (3 × 10 mL) and the combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel; pentane–
Et2O, 4:1); this afforded 5a as a colorless solid.
tert-butoxycarbonyl-protected ester-substituted pyrrole
10b smoothly reacted with a bis-amide base such as
bis(tetramethylpiperidyl)magnesium–bis(lithium chlo-
ride)15 (TMP2Mg·2LiCl; 13; 1.1 equiv, –30 °C, 1.5 h),
producing, after transmetalation with zinc chloride
(1.1 equiv), the polysubstituted pyrrol-3-ylzinc reagent
11b. A subsequent palladium-catalyzed cross-coupling11
[Pd(PPh3)4 (1 mol%), 25 °C, 1.5 h] with 1-chloro-4-iodo-
benzene (4g) provided the tetrasubstituted pyrrole 12c in
80% yield (Scheme 4).
Yield: 285 mg (85%); mp 73–75 °C.
IR (ATR): 2908, 2880, 1796, 1480, 1444, 1384, 1168, 1148, 968,
780 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.53 (m, 2 H), 7.48–7.41 (m,
1 H), 7.34–7.27 (m, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 4.18 (q, J = 7.1
Hz, 2 H), 1.40 (t, J = 7.1 Hz, 3 H), 1.07 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 188.3, 164.5, 161.2, 157.2 (d,
J = 36 Hz), 146.5, 143.9, 138.7 (d, J = 7 Hz), 130.8, 130.4 (d, J = 8
Hz), 125.4, 121.0 (d, J = 22 Hz), 118.2, 115.7 (d, J = 23 Hz), 62.1,
62.1, 14.2, 13.7.
MS (EI, 70 eV): m/z (%) = 334 (100) [M+], 289 (34), 262 (34), 239
(30), 210 (79), 187 (37), 122 (76).
HRMS (EI): m/z [M]+ calcd for C17H15O6F: 334.0853; found:
334.0857.
In summary, we presented regio- and chemoselective
magnesiations for the efficient functionalization of sensi-
tive heterocycles, such as electron-deficient furans,
pyrroles, or indoles. When selective (tetramethylpip-
eridyl)magnesium bases such as (tetramethylpiperidyl)mag-
nesium chloride–lithium chloride (TMPMgCl·LiCl) or
bis(tetramethylpiperidyl)magnesium–bis(lithium chlo-
ride) (TMP2Mg·2LiCl) are used, a range of functional
groups can be tolerated, such as esters or nitriles. More-
over, we showed the applicability of this method in the se-
lective functionalization of the furan scaffold at all
positions. Further extension of this methodology towards
the synthesis of furan-containing natural products is cur-
rently underway in our laboratories.
Diethyl 3-(Methylsulfanyl)furan-2,5-dicarboxylate (5b)
According to the general procedure, the metalation of diethyl furan-
2,5-dicarboxylate (2a; 2.0 mmol, 424 mg) in THF (2 mL) was com-
plete within 10 min at –78 °C when 1.1 M TMPMgCl·LiCl in THF
(1; 2 mL, 2.2 mmol) was used, followed by the addition of
PhSO2SMe (471 mg, 2.5 mmol). After warming to –50 °C, the re-
action mixture was continuously stirred for 3 h, and then quenched
with sat. aq NH4Cl (5 mL). The aqueous layer was extracted with
Et2O (3 × 10 mL) and the combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography (silica gel; CH2Cl2); this af-
forded 5b as a pale yellow solid.
All reactions were carried out under argon atmosphere in dried
glassware. All starting materials were purchased from commercial
suppliers and used without further purification, unless stated other-
wise. The reagents CuCN·2LiCl,4 TMPMgCl·LiCl (1),4 and
TMP2MgCl·2LiCl (13)15 were prepared according to literature pro-
cedures. Tetramethylpiperidine, liquid acid chlorides, aldehydes,
and allyl bromide were distilled prior to use. THF was continuously
refluxed and freshly distilled from sodium benzophenone ketyl un-
der N2. Purification by flash column chromatography was per-
formed on silica gel (0.040–0.063 mm, 230–400 mesh ASTM) from
Merck, unless indicated otherwise. Yields refer to isolated com-
Yield: 481 mg (93%); mp 69–70 °C.
IR (ATR): 2872, 1728, 1560, 1432, 1392, 1168, 1012, 972, 768
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (s, 1 H), 4.41 (q, J = 7.1 Hz,
2 H), 4.40 (q, J = 7.1 Hz, 2 H), 2.47 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3
H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.4, 157.8 145.9, 139.3, 133.6,
118.2, 116.5, 61.8, 61.4, 15.6, 14.3.
1
pounds that are estimated to be >95% pure as determined by H
NMR spectroscopy and capillary GC analysis. NMR spectra of
samples in CDCl3 (unless stated otherwise) were recorded on a
Bruker AC 300 spectrometer, and NMR chemical shifts are refer-
enced with respect to the residual solvent signal of CHCl3 (1H:
d = 7.25; 13C: d = 77.0). Melting points were determined on a Büchi
B-540 apparatus and are uncorrected. IR spectra were recorded on
a Perkin 281 infrared spectrophotometer. MS (EI) and HRMS mea-
surements were carried out on a Finnigan MAT 95Q or a Finnigan
MAT 90 mass spectrometer.
MS (EI, 70 eV): m/z (%) = 258 (100) [M+], 228 (7) 212 (17), 196
(20).
HRMS (EI): m/z calcd for C11H14N5S: 258.0562; found: 258.0555.
Magnesiation of Functionalized Furans by TMPMgCl·LiCl (1);
General Procedure
Diethyl 3-Cyanofuran-2,5-dicarboxylate (5c)
According to the general procedure, the metalation of diethyl furan-
2,5-dicarboxylate (2a; 5.0 mmol, 1.06 g) in THF (5 mL) was com-
plete within 10 min at –78 °C when 1.1 M TMPMgCl·LiCl in THF
(1; 5 mL, 5.5 mmol) was used, followed by the addition of tosyl cy-
anide (1.09 g, 6.0 mmol) and further stirring for 30 min, and then
the reaction mixture was quenched with sat. aq NH4Cl (15 mL). The
aqueous layer was extracted with Et2O (3 × 30 mL) and the com-
bined organic phases were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by flash column chromato-
graphy (silica gel; pentane–Et2O, 5:1); this afforded 5c as a color-
less solid.
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum was charged with the functionalized furan de-
rivative as a 1 M soln in THF and cooled to the given temperature.
Subsequently, 1.1 M TMPMgCl·LiCl in THF (1; 1.1 equiv) was
added dropwise and the reaction mixture was stirred for the indicat-
ed time. Complete conversion of the magnesiation was checked by
GC analysis of an iodolyzed reaction aliquot.
Diethyl 3-(3-Fluorobenzoyl)furan-2,5-dicarboxylate (5a)
According to the general procedure, the metalation of diethyl furan-
2,5-dicarboxylate (2a; 212 mg, 1.0 mmol) in THF (1 mL) was com-
plete within 10 min at –78 °C when 1.1 M TMPMgCl·LiCl in THF
(1; 1 mL, 1.1 mmol) was used, followed by the addition of 1 M
Yield: 781 mg (66%); mp 93–95 °C.
IR (ATR): 2948, 2248, 1724, 1584, 1524, 1496, 820, 780, 736 cm–1.
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

PAPER
Synthesis of Fully Substituted Furans
1755
1H NMR (300 MHz, CDCl3): d = 7.37 (s, 1 H), 4.48 (q, J = 7.3 Hz,
2 H), 4.41 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.3 Hz, 3 H), 1.38 (t,
J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.6, 155.6, 150.2, 147.0, 119.2,
110.8, 104.1, 63.0, 62.4, 14.1, 14.0.
MS (EI, 70 eV): m/z (%) = 237 (36) [M+], 209 (37), 192 (59), 181
(100), 164 (53), 137 (23).
Ethyl 3-Cyano-5-(trimethylsilyl)furan-2-carboxylate (5f)
According to the general procedure, the metalation of ethyl 5-(tri-
methylsilyl)furan-2-carboxylate (2b, 212 mg, 1.0 mmol) in THF
(1 mL) was complete within 1 h at –30 °C when 1.1 M TMP-
MgCl·LiCl in THF (1; 1 mL, 1.1 mmol) was used, followed by ad-
dition of TsCN (217 mg, 1.2 mmol) in THF (1 mL) and further
stirring for 15 min at –30 °C. The mixture was then quenched with
sat. aq NH4Cl (5 mL). The aqueous layer was extracted with Et2O
(3 × 10 mL) and the combined organic phases were dried (Na2SO4)
and concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; pentane–CH2Cl2, 1:1); this af-
forded 5f as a colorless solid.
HRMS (EI): m/z calcd for C11H11NO5: 237.0637; found: 237.0624.
Diethyl 3-[3-(Trifluoromethyl)phenyl]furan-2,5-dicarboxylate
(5d)
According to the general procedure, the metalation of diethyl furan-
2,5-dicarboxylate (2a; 1.0 mmol, 212 mg) in THF (1 mL) was com-
plete within 10 min at –78 °C when 1.1 M TMPMgCl·LiCl in THF
(1; 1 mL, 1.1 mmol) was used, followed by addition of 1 M ZnCl2
in THF (1.1 mL, 1.1 mmol) at –78 °C and further stirring for 15
min. Pd(PPh3)4 (12 mg, 1 mol%) and 4b (299 mg, 1.1 mmol) were
added and the reaction mixture was allowed to warm to 25 °C. After
stirring for 3 h, the mixture was quenched with sat. aq NH4Cl (5
mL). The aqueous layer was extracted with Et2O (3 × 10 mL) and
the combined organic phases were dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by flash column chroma-
tography (silica gel; CH2Cl2); this afforded 5d as a colorless solid.
Yield: 141 mg (52%); mp 100–102 °C.
IR (ATR): 3118, 2246, 1722, 1576, 1476, 1376, 1296, 1016, 838
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.84 (s, 1 H), 4.44 (q, J = 7.1 Hz,
2 H), 1.42 (t, J = 7.1 Hz, 3 H), 0.32 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 167.3, 156.7, 152.4, 122.3, 112.3,
103.0, 62.2, 14.1, –2.1.
MS (EI, 70 eV): m/z (%) = 237 (21) [M+], 222 (100), 194 (47), 43
(9).
HRMS (EI): m/z calcd for C11H15NO3Si: 237.0821; found:
237.0828.
Yield: 281 mg (79%); mp 78–79 °C.
IR (ATR): 1484, 1456, 1380, 1368, 1272, 1224, 972, 900, 872 cm–1.
Ethyl 3-Benzoyl-5-bromofuran-2-carboxylate (5g)
1H NMR (300 MHz, CDCl3): d = 7.82 (s, 1 H), 7.75 (d, J = 7.7 Hz,
1 H), 7.65 (d, J = 8.6 Hz, 1 H), 7.54 (t, J = 7.7 Hz, 1 H), 7.30 (s, 1
H), 4.42 (q, J = 7.3 Hz, 2 H), 4.34 (q, J = 7.3 Hz, 2 H), 1.41 (t,
J = 7.3 Hz, 3 H), 1.30 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.3, 157.9, 145.8, 141.4, 133.2,
132.6, 131.7, 128.7, 126.3, 125.4, 123.0, 119.8, 61.8, 61.7, 14.3,
14.0.
According to the general procedure, the metalation of ethyl 5-bro-
mofuran-2-carboxylate (2c; 219 mg, 1.0 mmol) in THF (1 mL) was
complete within 30 min at –78 °C when 1.1 M TMPMgCl·LiCl in
THF (1; 1 mL, 1.1 mmol) was used, followed by addition of 1 M
CuCN·2LiCl in THF (0.2 mL, 20 mol%) at –78 °C and further stir-
ring for 15 min. At –40 °C, BzCl (1.2 mmol, 169 mg) was added;
the mixture was stirred for 15 h, and then quenched with sat. aq
NH4Cl (5 mL). The aqueous layer was extracted with Et2O (3 × 10
mL) and the combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by flash col-
umn chromatography (silica gel; pentane–CH2Cl2, 5:4); this afford-
ed 5g as a colorless solid.
MS (EI, 70 eV): m/z (%) = 356 (100) [M+], 311 (32), 283 (34), 256
(17).
HRMS (EI): m/z calcd for C17H15O5F3: 356.0872; found: 356.0862.
Ethyl 3-Chloro-5-(trimethylsilyl)furan-2-carboxylate (5e)
According to the general procedure, the metalation of ethyl 5-(tri-
methylsilyl)furan-2-carboxylate (2b, 414 mg, 2.0 mmol) in THF
(2 mL) was complete within 1 h at –30 °C when 1.1 M TMP-
MgCl·LiCl in THF (1; 2 mL, 2.2 mmol) was used, followed by ad-
dition of hexachloroethane (710 mg, 3 mmol) in THF (3 mL) at
–50 °C and further stirring for 15 h. The mixture was then quenched
with sat. aq NH4Cl (5 mL). The aqueous layer was extracted with
Et2O (3 × 15 mL) and the combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography (silica gel; pentane–CH2Cl2,
2:1); this afforded 5e as a colorless oil.
Yield: 242 mg (75%); mp 95–96 °C.
IR (ATR): 3066, 2982, 1574, 1478, 1176, 1100, 934, 716, 686 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.85 (d, J = 7.0 Hz, 2 H), 7.60 (t,
J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 6.61 (s, 1 H), 4.09 (q,
J = 7.1 Hz, 2 H), 0.96 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 189.5, 156.7, 143.3, 136.7, 134.0,
132.8, 129.5, 128.6, 127.8, 114.4, 61.6, 13.5.
MS (EI, 70 eV): m/z (%) = 324 (98) [M+, 81Br], 322 (100) [M+,
79Br], 278 (25), 250 (45), 219 (37), 217 (36), 170 (18), 143 (15), 105
(46), 77 (36).
HRMS (EI): m/z calcd for C14H11BrO4: 321.9841; found: 321.9834.
Yield: 237 mg (48%).
IR (ATR): 2962, 1370, 1342, 1276, 1252, 1176, 1038, 932, 838
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.64 (s, 1 H), 4.38 (q, J = 7.1 Hz,
2 H), 1.38 (t, J = 7.1 Hz, 3 H), 0.29 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 165.3, 158.2, 143.0, 123.6, 123.1,
61.0, 14.3, –2.0.
Ethyl 5-Bromo-3-chlorofuran-2-carboxylate (5h)
According to the general procedure, the metalation of ethyl 5-bro-
mofuran-2-carboxylate (2c; 1.09 g, 5.0 mmol) in THF (5 mL) was
complete within 30 min at –78 °C when 1.1 M TMPMgCl·LiCl in
THF (1; 5 mL, 5.5 mmol) was used, followed by addition of
PhSO2Cl (7.5 mmol, 1.32 g). After 3 h at –78 °C, the reaction mix-
ture was allowed to warm to 25 °C, and then quenched with sat. aq
NH4Cl (15 mL). The aqueous layer was extracted with Et2O (3 × 30
mL) and the combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by flash col-
umn chromatography (silica gel; pentane–CH2Cl2, 8:1); this afford-
ed 5h as a colorless solid.
MS (EI, 70 eV): m/z (%) = 246 (53) [M+], 231 (100), 203 (33), 174
(6), 103 (28), 75 (41).
HRMS (EI): m/z calcd for C10H15ClO3Si: 246.0479; found
246.0454.
Yield: 748 mg (59%); mp 98–100 °C.
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

1756
F. M. Piller, P. Knochel
PAPER
IR (ATR): 2984, 2360, 1698, 1466, 1376, 1290, 1170, 1098, 932
cm–1.
HRMS (EI): m/z calcd for C16H15BrO5: 368.0082; found: 368.0062.
Diethyl 5,5¢-Dibromo-3,3¢-bifuran-2,2¢-dicarboxylate (5k)
According to the general procedure, the metalation of ethyl 5-bro-
mofuran-2-carboxylate (2c; 219 mg, 1.0 mmol) in THF (1 mL) was
complete within 30 min at –78 °C when 1.1 M TMPMgCl·LiCl in
THF (1; 1 mL, 1.1 mmol) was used, followed by addition of 1 M
ZnCl2 in THF (1.1 mL, 1.1 mmol) at –78 °C and further stirring for
15 min. Subsequently, chloranil (4d; 369 mg, 1.5 mmol) in THF (7
mL) was slowly added. After stirring for 15 min, the reaction mix-
ture was allowed to warm to –40 °C and stirred for 2 h. The reaction
mixture was quenched with sat. aq NH4Cl (5 mL). The aqueous lay-
er was extracted with Et2O (3 × 10 mL) and the combined organic
phases were dried (Na2SO4) and concentrated in vacuo. The crude
residue was purified by flash column chromatography (silica gel;
CH2Cl2); this afforded 5j as a pale brown solid.
1H NMR (300 MHz, CDCl3): d = 6.48 (s, 1 H), 4.38 (q, J = 7.1 Hz,
2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.8, 141.7, 127.2, 125.3, 116.1,
61.5, 14.3.
MS (EI, 70 eV): m/z (%) = 256 (14) [M+, 37Cl 81Br], 254 (53) [M+,
37Cl 79Br, 35Cl 81Br], 252 (43) [M+, 35Cl 79Br], 226 (93), 209 (100),
182 (64), 153 (24), 129 (23), 72 (21).
HRMS (EI): m/z calcd for C7H6BrClO3: 251.9189; found:
251.9185.
Ethyl 5-Bromo-3-cyanofuran-2-carboxylate (5i)
According to the general procedure, the metalation of ethyl 5-bro-
mofuran-2-carboxylate (2c; 1.09 g, 5.0 mmol) in THF (5 mL) was
complete within 30 min at –78 °C when 1.1 M TMPMgCl·LiCl in
THF (1; 5 mL, 5.5 mmol) was used, followed by addition of TsCN
(5.5 mmol, 997 mg) in THF (6 mL). After stirring for 30 min at
–78 °C, the reaction mixture was allowed to warm to 25 °C, and
then quenched with sat. aq NH4Cl (15 mL). The aqueous layer was
extracted with Et2O (3 × 30 mL) and the combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel; pentane–
CH2Cl2, 3:1); this afforded 5i as a colorless solid.
Yield: 174 mg (80%); mp 168–170 °C.
IR (ATR): 2904, 2112, 1628, 1596, 1448, 1148, 1088, 1020, 940,
684 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.61 (s, 2 H), 4.29 (q, J = 7.1 Hz,
4 H), 1.30 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 157.8, 142.8, 126.7, 125.6, 116.9,
61.6, 14.4.
MS (EI, 70 eV): m/z (%) = 438 (26) [M+, 81Br, 81Br], 436 (53) [M+,
79Br, 81Br], 434 ([M+, 79Br, 79Br], 357 (83), 327 (100), 299 (30), 227
(27).
Yield: 765 mg (63%); mp 103–105 °C.
IR (ATR): 2982, 1720, 1668, 1596, 1478, 1400, 1304, 1016, 934
cm–1.
HRMS (EI): m/z calcd for C14H12Br2O6: 435.8980; found:
435.8980.
1H NMR (300 MHz, CDCl3): d = 6.69 (s, 1 H), 4.45 (q, J = 7.1 Hz,
2 H), 1.42 (t, J = 7.1 Hz, 3 H).
Diethyl 3-[(4-Cyanophenyl)(hydroxy)methyl]-4-(methylsulfa-
nyl)furan-2,5-dicarboxylate (7a)
13C NMR (75 MHz, CDCl3): d = 155.3, 150.2, 128.7, 115.3, 110.6,
105.2, 62.7, 14.1.
According to the general procedure, the metalation of 5b (253 mg,
1.0 mmol) in THF (4 mL) was complete within 45 min at –78 °C
when 1.1 M TMPMgCl·LiCl in THF (1; 1 mL, 1.1 mmol) was used,
followed by addition of 4-cyanobenzaldehyde (197 mg, 1.5 mmol)
and further stirring for 3 h. Subsequently, the reaction mixture was
allowed to warm to 25 °C. The reaction mixture was quenched with
sat. aq NH4Cl (5 mL). The aqueous layer was extracted with Et2O
(3 × 10 mL) and the combined organic phases were dried (Na2SO4)
and concentrated in vacuo. The crude residue was purified by flash
column chromatography (silica gel; CH2Cl2); this afforded 7a as a
pale yellow oil.
MS (EI, 70 eV): m/z (%) = 245 (30), [M+, 81Br], 243 (34) [M+, 79Br],
217 (96), 215 (100), 200 (54), 198 (55), 173 (34), 171 (34), 144
(16), 142 (18), 108 (9), 63 (18).
HRMS (EI): m/z calcd for C8H6BrNO3: 242.9531; found: 242.9521.
Ethyl 5-Bromo-3-[4-(ethoxycarbonyl)phenyl]furan-2-carboxy-
late (5j)
According to the general procedure, the metalation of ethyl 5-bro-
mofuran-2-carboxylate (2c; 219 mg, 1.0 mmol) in THF (1 mL) was
complete within 30 min at –78 °C when 1.1 M TMPMgCl·LiCl in
THF (1; 1 mL, 1.1 mmol) was used, followed by addition of 1 M
ZnCl2 in THF (1.1 mL, 1.1 mmol) at –78 °C and further stirring for
15 min. Pd(PPh3)4 (12 mg, 1 mol%) and ethyl 4-iodobenzoate (4c;
1.1 mmol, 304 mg) were added and the reaction mixture was al-
lowed to warm to 25 °C. After stirring for 6 h, the reaction mixture
was quenched with sat. aq NH4Cl (5 mL). The aqueous layer was
extracted with Et2O (3 × 10 mL) and the combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel; pentane–
Et2O, 8:1); this afforded 5j as a colorless solid.
Yield: 262 mg (67%).
IR (ATR): 2908, 2872, 1780, 1608, 1368, 1284, 1180, 1016, 904,
696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (d, J = 8.6 Hz, 2 H), 7.47 (d,
J = 8.6 Hz, 2 H), 6.26 (d, J = 11.9 Hz, 1 H), 5.50 (d, J = 11.9 Hz, 1
H), 4.48–4.36 (m, 4 H), 2.39 (s, 3 H), 1.43 (t, J = 7.3 Hz, 3 H), 1.38
(t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.1, 157.5, 147.9, 146.2, 140.7,
140.5, 132.5, 128.0, 126.8, 118.9, 111.7, 67.7, 63.1, 62.3, 19.6,
14.5, 14.3.
Yield: 314 mg (86%); mp 71–72 °C.
MS (EI, 70 eV): m/z (%) = 389 (98) [M+], 360 (52), 341 (37), 313
(100), 297 (20), 131 (55).
IR (ATR): 2988, 2532, 1980, 1664, 1568, 1476, 1280, 1108, 1080,
1020 cm–1.
HRMS (EI): m/z calcd for C19H19NO6S: 389.0933; found:
389.0934.
1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 8.4 Hz, 2 H), 7.60 (d,
J = 8.4 Hz, 2 H), 6.57 (s, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 4.30 (q,
J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 157.8, 142.2, 135.5, 135.3,
130.6, 129.3, 129.2, 127.0, 115.9, 61.3, 61.1, 14.3, 14.1.
Diethyl 3-Cyano-4-(4-cyanophenyl)furan-2,5-dicarboxylate
(7b)
Diethyl 3-cyanofuran-2,5-dicarboxylate (5c; 237 mg, 1 mmol) was
dissolved in THF (4 mL), and 1 M ZnCl2 in THF (1.1 mL, 1.1
mmol) was added. After the mixture had been cooled to –78 °C,
TMPMgCl·LiCl (1.2 mmol, 1.1 mL, 1.1 M in THF) was added and
MS (EI, 70 eV): m/z (%) = 368 (100), [M+, 81Br], 366 (99) [M+,
79Br], 233 (54), 295 (33).
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

PAPER
Synthesis of Fully Substituted Furans
1757
the mixture was continuously stirred for 20 min. Pd(PPh3)4 (12 mg,
1 mol%) and 4-iodobenzonitrile (4f; 275 mg, 1.2 mmol) were added
at –78 °C, and the reaction mixture was allowed to warm to 25 °C.
After stirring for 3 h, the mixture was quenched with sat. aq NH4Cl
(5 mL). The aqueous layer was extracted with Et2O (3 × 10 mL) and
the combined organic phases were dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by flash column chroma-
tography (silica gel; CH2Cl2); this afforded 7b as a pale brown solid.
13C NMR (75 MHz, CDCl3): d = 156.4, 142.8, 136.1, 131.3, 125.6,
124.4, 119.0, 109.9, 62.4, 27.9, 14.4.
MS (EI, 70 eV): m/z (%) = 239 (68) [M+], 211 (30), 194 (100), 167
(21), 136 (27), 102 (29).
HRMS (EI): m/z calcd for C11H10ClNO3: 239.0349; found:
239.0357.
Ethyl 3-[Hydroxy(phenyl)methyl]-1-tosylindole-2-carboxylate
(12a)
Yield: 239 mg (71%); mp 156–158 °C.
IR (ATR): 2988, 1504, 1452, 1324, 1180, 1080, 1012, 844, 776,
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.6 Hz, 2 H), 7.64 (d,
J = 8.6 Hz, 2 H), 4.52 (q, J = 7.1 Hz, 2 H), 4.35 (q, J = 7.1 Hz, 2 H),
1.46 (t, J = 7.1 Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.8, 155.5, 149.6, 142.1, 133.1,
132.1, 130.5, 118.0, 113.8, 110.2, 105.3, 63.3, 62.6, 14.1, 14.0.
According to the general procedure, the metalation of 10a (172 mg,
0.5 mol) in THF (2.5 mL) was complete within 30 min at –45 °C
when 1.1 M TMPMgCl·LiCl in THF (1; 0.5 mL, 0.55 mmol) was
used, followed by addition of benzaldehyde (0.6 mol, 64 mg) at
–45 °C. Stirring continued for 30 min, and then the mixture was
quenched with sat. aq NH4Cl (3 mL). The aqueous layer was ex-
tracted with Et2O (3 × 10 mL) and the combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel; CH2Cl2);
this afforded 12a as a colorless solid.
MS (EI, 70 eV): m/z (%) = 338 (100) [M+], 310 (34), 293 (24), 281
(34), 264 (33).
Yield: 205 mg (91%); mp 51–52 °C.
HRMS (EI): m/z calcd for C18H14N2O5: 338.0903; found: 338.0888.
IR (ATR): 3526, 1596, 1448, 1368, 1258, 1174, 1016, 748, 668
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 8.7 Hz, 1 H), 7.75 (d,
J = 8.4 Hz, 2 H), 7.44–7.12 (m, 10 H), 6.15 (d, J = 5.2 Hz, 1 H),
4.45 (q, J = 7.0 Hz, 2 H), 2.82 (d, J = 5.2 Hz, 1 H), 2.32 (s, 3 H) 1.37
(t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.2, 145.1, 141.5, 136.9, 134.2,
129.9, 129.6, 128.7, 128.3, 127.9, 127.6, 127.2, 126.7, 126.1, 124.3,
121.9, 115.4, 68.9, 62.7, 21.6, 13.9.
Ethyl 3-Chloro-5-cyanofuran-2-carboxylate (8)
After ethyl 5-bromo-3-chlorofuran-2-carboxylate (5e; 748 mg,
3.0 mmol) in THF (5 mL) had been cooled to –50 °C, 1.36 M i-
PrMgCl·LiCl in THF (2.4 mL, 3.3 mmol) was added dropwise. Af-
ter the mixture had stirred for 30 min, TsCN (181 mg, 1.1 mmol) in
THF (1.5 mL) was added and the reaction mixture was allowed to
warm to 25 °C. After further stirring for 3 h, the mixture was
quenched with sat. aq NH4Cl (5 mL). The aqueous layer was ex-
tracted with Et2O (3 × 10 mL) and the combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel; pentane–
CH2Cl2, 1:1); this afforded 8 as a colorless solid.
MS (EI, 70 eV): m/z (%) = 449 (4) [M+], 294 (54), 248 (100), 220
(14), 204 (9), 165 (6), 105 (12), 91 (13), 77 (6).
HRMS (EI): m/z calcd for C25H23NO5S: 449.1297; found:
449.1281.
Yield: 440 mg (73%); mp 80–81 °C.
IR (ATR): 2986, 2238, 1718, 1547, 1516, 1114, 1052, 1012, 856
cm–1.
Ethyl 3-Allyl-1-tosylindole-2-carboxylate (12b)
According to the general procedure, the metalation of 10a (172 mg,
0.5 mol) in THF (2.5 mL) was complete within 30 min at –45 °C
when 1.1 M TMPMgCl·LiCl in THF (1; 0.5 mL, 0.55 mmol) was
used, followed by addition of 1 M CuCN·2LiCl in THF (0.12 mL,
20 mol%) at –45 °C and further stirring for 15 min. Allyl bromide
(0.6 mmol, 73 mg) was added to the mixture at –45 °C, and stirring
continued for 30 min, after which the mixture was quenched with
sat. aq NH4Cl (3 mL). The aqueous layer was extracted with Et2O
(3 × 10 mL) and the combined organic phases were dried (Na2SO4)
and concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; pentane–CH2Cl2, 5:4); this af-
forded 12b as a colorless solid.
1H NMR (300 MHz, CDCl3): d = 7.12 (s, 1 H), 4.42 (q, J = 7.0 Hz,
2 H), 1.40 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.2, 142.9, 127.3, 124.0, 123.4,
109.5, 62.3, 14.1.
MS (EI, 70 eV): m/z (%) = 199 (25) [M+], 171 (82), 154 (100), 127
(20), 98 (15).
HRMS (EI): m/z calcd for C8H6ClNO3: 199.0036; found: 199.0020.
Ethyl 4-Allyl-3-chloro-5-cyanofuran-2-carboxylate (9)
According to the general procedure, the metalation of 8 (136 mg,
0.68 mmol) in THF (1.4 mL) was complete within 25 min at –78 °C
when 1.1 M TMPMgCl·LiCl in THF (1; 0.7 mL, 0.75 mmol) was
used, followed by addition of 1 M CuCN·2LiCl in THF (0.14 mL,
20 mol%) at –78 °C and further stirring for 15 min. Allyl bromide
(121 mg, 1.0 mmol) was added to the mixture at –78 °C and the
mixture was continuously stirred for 15 min, and then quenched
with sat. aq NH4Cl (3 mL). The aqueous layer was extracted with
Et2O (3 × 10 mL) and the combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by flash column chromatography (silica gel; pentane–CH2Cl2,
1:1); this afforded 9 as a colorless oil.
Yield: 182 mg (95%); mp 66–68 °C.
IR (ATR): 1640, 1598, 1440, 1308, 1260, 1180, 1146, 810, 750
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.02 (d, J = 8.3 Hz, 1 H), 7.76 (d,
J = 6.6 Hz, 2 H), 7.47 (d, J = 7.9 Hz, 1 H), 7.37 (t, J = 5.9 Hz, 1 H),
7.23 (t, J = 7.0 Hz, 1 H), 7.17 (d, J = 6.8 Hz, 2 H), 5.93–5.80 (m, 1
H), 5.03–4.93 (m, 2 H), 4.45 (q, J = 7.1 Hz, 2 H), 3.51 (td, J = 6.2,
1.7 Hz, 2 H), 2.31 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 162.4, 144.8, 137.1, 134.6, 134.5,
129.8, 129.4, 128.8, 127.2, 126.7, 126.5, 124.0, 120.7, 116.3, 115.6,
62.1, 28.7, 21.6, 14.1.
Yield: 120 mg (74%).
IR (ATR): 2986, 1532, 1406, 1286, 1184, 1032, 992, 768 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.93–5.80 (m, 1 H), 5.22–5.13 (m,
2 H), 4.42 (q, J = 7.1 Hz, 2 H), 3.37–3.34 (m, 2 H), 1.40 (t, J = 7.1
Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 383 (33) [M+], 338 (8), 228 (100), 200
(16), 183 (27), 154 (77), 128 (28), 91 (34).
HRMS (EI): m/z calcd for C21H21NO4S: 383.1191; found:
383.1186.
Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York

1758
F. M. Piller, P. Knochel
PAPER
1-tert-Butyl 2,5-Diethyl 3-(4-Chlorophenyl)pyrrole-1,2,5-tricar-
boxylate (12c)
(2) (a) Carpenter, A. J.; Chadwick, D. J. J. Org. Chem. 1985, 50,
4362. (b) Doat, E. G.; Snieckus, V. Tetrahedron Lett. 1985,
26, 1149.
According to the general procedure, the metalation of 10b (311 mg,
1.0 mmol) in THF (1 mL) by 0.58 M TMP2Mg·2LiCl in THF (13;
1.9 mL, 1.1 mmol) was complete within 1.5 h at –30 °C; 1 M ZnCl2
in THF (1.1 mL, 1.1 mmol) was added to the mixture at –30 °C and
stirring continued for 15 min. Pd(PPh3)4 (12 mg, 1 mol%) and 1-
chloro-4-iodobenzene (4g; 358 mg, 1.5 mmol) were added and the
reaction mixture was allowed to warm to 25 °C. After stirring for
1.5 h, the reaction mixture was quenched with sat. aq NH4Cl (5 mL).
The aqueous layer was extracted with Et2O (3 × 10 mL) and the
combined organic phases were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (silica gel; CH2Cl2); this afforded 12c as a colorless solid.
(3) (a) Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc.,
Perkin Trans. 1 2001, 442. (b) Bayh, O.; Awad, H.;
Mongin, F.; Hoarau, C.; Trécourt, F.; Quéguiner, G.;
Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R.
Tetrahedron 2005, 61, 4779. (c) L’Helgoual’ch, J.-M.;
Seggio, A.; Chevallier, F.; Yonehara, M.; Jeanneau, E.;
Ushiyama, M.; Mongin, F. J. Org. Chem. 1998, 73, 177.
(d) Mongin, F.; Bucher, A.; Bazureau, J. P.; Bayh, O.; Awad,
H.; Trécourt, F. Tetrahedron Lett. 2005, 46, 7989.
(4) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958.
(5) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837.
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3406. (c) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P.
Chem. Commun. 2009, 5615.
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(9) Determined by GC analysis of an iodolyzed reaction aliquot
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Yield: 339 mg (80%); mp 80–81 °C.
IR (ATR): 2984, 1724, 1548, 1440, 1384, 1296, 1152, 1124, 928,
784 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.31 (m, 4 H), 6.82 (s, 1 H),
4.34 (q, J = 7.1 Hz, 2 H), 4.21 (q, J = 7.1 Hz, 2 H), 1.65 (s, 9 H),
1.35 (t, J = 7.1 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 160.1, 159.5, 148.5, 133.5, 132.6,
130.9, 129.9, 127.9, 125.9, 123.2, 117.3, 86.3, 61.2, 61.2, 27.4,
14.3, 13.9.
MS (EI, 70 eV): m/z (%) = 421 (4) [M+], 321 (100), 274 (14), 202
(13).
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HRMS (EI): m/z calcd for C21H24ClNO6: 421.1292; found:
421.1270.
Acknowledgment
We thank the European Research Council (ERC) under the Euro-
pean Community’s Seventh Framework Programme (FP7/2007-
2013) ERC grant agreement No. 227763 for financial support. We
also thank the BASF AG (Ludwigshafen), W. C. Heraeus GmbH
(Hanau), and Chemetall (Frankfurt) for the generous gifts of chemi-
cals.
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Synthesis 2011, No. 11, 1751–1758 © Thieme Stuttgart · New York