Mild Synthesis of Polyfunctional Benzimidazoles and Indoles by the Reduction of Functionalized Nitroarenes with Phenylmagnesium Chloride

Article abstract of DOI:10.1002/chem.200305090

Phenylmagnesium chloride has been used for the conversion of selected nitroarenes into nitrenes. Their insertion into a neighboring sp² C-H bond yielded functionalized heterocycles. A novel and mild synthesis of polyfunctional benzimidazoles and indoles is described.

Full text of DOI:10.1002/chem.200305090

FULL PAPER
Mild Synthesis of Polyfunctional Benzimidazoles and Indoles by the
Reduction of Functionalized Nitroarenes with Phenylmagnesium Chloride
[a]
Wolfgang Dohle,Anne Staubitz,and Paul Knochel*
Abstract: Phenylmagnesium chloride has been used for the conversion of selected
Keywords: Grignard reaction
heterocycles ¥ magnesium nitrenoids
¥ nitrenes
¥
2
À
nitroarenes into nitrenes. Their insertion into a neighboring sp C H bond yielded
functionalized heterocycles. A novel and mild synthesis of polyfunctional benzim-
idazoles and indoles is described.
nitroarene 6a (Scheme 2) was prepared and treated with
phenylmagnesium chloride. Neither an iodine magnesium
exchange reaction,nor the reduction of the nitro group to the
Introduction
The preparation of functionalized heterocycles is an impor-
tant synthetic objective,since many of these molecules have
interesting pharmaceutical properties.[1] Recently,we have
studied the reaction of functionalized nitroarenes 1 with
arylmagnesium reagents (Ar2MgX).[2,3] We have found that
nitroarenes react with arylmagnesium reagents,leading first
to an intermediate nitrosoarene of type 3,[4] which reacts with
a second equivalent of Ar2MgX to furnish the magnesiated
diarylhydroxylamine of type 4. Reduction of this gives
diarylamines of type 5 in good yields (Scheme 1).[2] This
method proved to be quite general and practical.
Scheme 2. Formation of benzimidazole 7a by treatment of nitroarene 6a
with phenylmagnesium chloride.
corresponding diarylamine was observed,but a clean reduc-
tive cyclization reaction occurred,leading to the correspond-
ing benzimidazole 7a,which was isolated in 75% yield
(Scheme 2).
This unexpected result led us to explore the scope of this
reaction. Thus,we have noticed that when nitroarenes of type
1 bear bulky substituents (Scheme 3),nitrosoarenes of type 3
Scheme 1. Reaction of arylmagnesium halides (Ar2MgX) with nitroarenes
(Ar1NO2): formation of diarylamines.
Scheme 3. Reaction of arylmagnesium halides (Ar2MgX) with nitroarenes
(Ar1NO2): formation of nitrenes.
However, ortho-iodo-substituted nitroarenes undergo io-
dine magnesium exchange reactions with phenylmagnesium
chloride and usually no reduction of the nitro group is
observed.[5] During our studies the question arose of whether
this iodine magnesium exchange reaction could also be
performed in the presence of a nitro group by use of protected
amines as directing groups.[6] Therefore,the iodo-substituted
are still formed,but due to steric hindrance the second
equivalent of the Grignard reagent does not add–as was
previously the case–at the nitrogen atom. Rather,it attacks
the more readily available oxygen atom of the nitroso
intermediate 3,leading to the magnesium nitrenoid
8
[a] Prof. Dr. P. Knochel,Dr. W. Dohle,Dipl. Biochem. A. Staubitz
Department Chemie,Ludwig-Maximilians-Universit‰t
Butenandtstrasse 5 13,Haus F,81377 M¸nchen (Germany)
Fax : (‡49)89-2180-77680
(Scheme 3). This behavior is further favored if the aromatic
system is electron poor.
Here we report the use of intermediates such as 8 (or
nitrenes of type 9 generated in situ) for the preparation of
E-mail: paul.knochel@cup.uni-muenchen.de
Chem. Eur. J. 2003, 9,5323 5331
DOI: 10.1002/chem.200305090
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
5323

P. Knochel et al.
FULL PAPER
Table 1. Preparation of nitro-substituted amidine and imine derivatives
6a m.
benzimidazoles of type 7 and indoles of type 10 under very
mild reaction conditions,starting from ortho-nitro-substituted
amidine and imine derivatives of type 6 and stilbenes of type
11,respectively (Scheme 4).
Entry Aniline type 12
Amidine and imine type 6
Yield [%][a]
1
2
3
4
12a: R1 ˆ CF3
12b: R1 ˆ CO2Et
12c: R1 ˆ CN
12d: R1 ˆ Cl
6a: R1 ˆ CF3
6b: R1 ˆ CO2Et
6c: R1 ˆ CN
6d: R1 ˆ Cl
95
91
83
78
Scheme 4. Preparation of functionalized benzimidazoles and indoles.
5
6
7
8
95
94
79
70
Results and Discussion
Preparation of the starting materials: The anilines 12a
e
were prepared by iodination of ortho-nitroanilines with silver
sulfate and iodine in ethanol at room temperature
(Scheme 5).[7]
9
68
[a] Isolated yield of analytically pure product.
Scheme 5. Preparation of iodinated nitroanilines 12a e.
The amidines 6a i and the imines 6j k were readily
prepared from the corresponding anilines of type 12 by
treatment either with (MeO)2CHNMe2 in toluene[8] at 1408C
for 18 h or with ArCHO in the presence of catalytic amounts
of conc. H2SO4 and MS (4 ä),respectively (Scheme 6 and
Table 1).
The ortho-nitro-substituted stilbenes 11a e were prepared
by condensation reactions from the corresponding ortho-
nitrotolyl derivatives 13a c with aromatic aldehydes in the
presence of piperidine at elevated temperatures (Scheme 8
and Table 3).[10]
Scheme 7. Preparation of aryl-substituted compounds 6g j.
Preparation of the functionalized benzimidazoles 7a l: The
protected ortho-nitro-substituted anilines 6a m were treated
with PhMgCl at À408C. (Scheme 9 and Table 4).
Scheme 6. Preparation of amidines 6a i and imines 6j k.
The functionalized benzimidazoles 7a l were obtained in
satisfactory to good yields (42 87%). Various substituents R1
and R2 can be attached to the aromatic ring. The iodo-
substituted compounds 6a d and 6l (entries 1 4 and en-
try 11 in Table 4) undergo the reductive cyclization reaction to
The aryl-substituted compounds 6g j were prepared by
palladium-catalyzed cross-coupling reactions between 6a
and 6k and the corresponding functionalized arylzinc halide
in THF at room temperature (Scheme 7 and Table 2).[9]
b
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Chem. Eur. J. 2003, 9,5323 5331

Functionalized Heterocycles
5323 5331
Table 2. Arylfunctionalized nitro-substituted amidines 6g j obtained by Table 3. Preparation of functionalized ortho-nitro stilbenes 11a e.
palladium-catalyzed cross-coupling reactions.
Entry Nitrotolyl
compound
type 13
Aldehyde
Nitrostilbene type 11
Yield
[%][a]
Entry Amidine type 6
Cross-coupling product
Yield [%][a]
1
1
82
73
21
67
59
2
3
4
2
80
3
4
6b: R1 ˆ CO2Et
6a: R1 ˆ CF3
6i: R1 ˆ CO2Et
6j: R1 ˆ CF3
85
80
[a] Isolated yield of analytically pure product.
5
20
give the functionalized benzimidazoles 7a d and 7k much
more rapidly than iodine magnesium exchange,which was
not observed under our reaction conditions. These mild
reaction conditions,allowing the performance of the ring
closures at À408C,assure broad functional group compati-
bility,so various functionalities (CN,CO 2Et,CF 3,Br,Cl,
OMe; entries 1 5 and entry 7 in Table 4) are tolerated. The
substituent R2 can also contain functionalized aryl substitu-
ents (entries 8 10 in Table 4) as well as a second nitro
functionality (entries 6 7 in Table 4).
[a] Isolated yield of analytically pure product.
the corresponding ortho-nitrostilbene (entries 1 5 in Ta-
ble 5).
As a tentative mechanism of this reaction we propose
nitrenes of type 9 as intermediates (Scheme 3). Closely
related reductive cyclization reactions with triethylphosphite
as deoxygenation agent proceed under much harsher reaction
conditions. This method,which has been described by
Cadogan[11] and others,[12] is also proposed to proceed through
nitrenes as intermediates. In order to check whether we could
compare our method to these known procedures,we also
treated 2-nitrobiphenyl with phenylmagnesium chloride at
À408C. As expected,carbazole was formed and could be
isolated in 24% yield (Scheme 11).
Scheme 8. Preparation of functionalized ortho-nitro stilbenes 11a e.
Preparation of functionalized indoles 10a e: This method
can also be used for the reductive cyclization of the nitro-
substituted stilbenes 11a e,furnishing the corresponding
indoles 10a e in good yields (56 76%; Scheme 10 and
Table 5).
This new indole synthesis shows the same functional group
tolerance as the new procedure described above for the
preparation of benzimidazoles. Ester,bromo,methoxy,het-
eroaryl,and also a second nitro functionality can be present in
Conclusion
Treatment of phenylmagnesium chloride with various 2-ami-
no-1-nitroaromatics or 2-nitrostilbenes under mild conditions
furnishes polyfunctional benzimidazoles of type 7 and indoles
of type 10,respectively,in satisfactory to good yields. The
reaction occurs very rapidly under mild conditions and is best
explained by the involvement of functionalized nitrenes as
intermediates.
Chem. Eur. J. 2003, 9,5323 5331
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P. Knochel et al.
FULL PAPER
Table 4. Functionalized benzimidazoles 7a l obtained by treatment of nitro-
substituted amidines and imines 6a m with phenylmagnesium chloride.
Entry Amidine and imine type 6
Benzimidazole type 7
Yield [%][a]
Scheme 10. Preparation of functionalized indoles 10a e by treatment of
nitro-substituted stilbenes 11a e with phenylmagnesium chloride.
1
2
3
4
6a: R1 ˆ CF3
6b: R1 ˆ CO2Et
6c: R1 ˆ CN
6d: R1 ˆ Cl
7a: R1 ˆ CF3
7b: R1 ˆ CO2Et
7c: R1 ˆ CN
7d: R1 ˆ Cl
75
79
48
61
Table 5. Functionalized indoles 10a e obtained by treatment of nitro-sub-
stituted stilbenes 11a e with phenylmagnesium chloride.
Entry Nitrostilbene of type 11
Indole of type 10
Yield
[%][a]
5
70
1
76
70
75
6
62
2
3
7
8
87
45
4
5
56
60
6i: R1 ˆ CO2Et
6j: R1 ˆ CF3
7i: R1 ˆ CO2Et
7j: R1 ˆ CF3
56
77
[a] Isolated yield of analytically pure product.
9
10
11
12
42
77
Scheme 11. Formation of carbazole by treatment of 2-nitrobiphenyl with
phenylmagnesium chloride.
[a] Isolated yield of analytically pure product.
Experimental Section
General methods: THF was distilled from sodium/benzophenone and
toluene from sodium. Reactions in solution were monitored by thin-layer
chromatography (TLC) and gas chromatography (GC) analysis of worked-
up reaction aliquots. Analytical TLC was performed on Merck silica gel
(60 F-254) plates (0.25 mm) precoated with a fluorescent indicator. Column
chromatography was carried out on silica gel 60 (70 230 mesh). NMR data
were recorded on 300 and 600 MHz NMR spectrometers from Bruker. IR
Scheme 9. Preparation of functionalized benzimidazoles 7a l by treat-
ment of nitro-substituted amidines and imines 6a m with phenylmagne-
sium chloride.
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Functionalized Heterocycles
5323 5331
spectra were performed with a Nicolet 510 FT-IR spectrometer. The
ionization method used for mass spectroscopy was electron impact
ionization (EI,70 eV). Melting points were measured on a B¸chi B 540
and are uncorrected.
4-Iodo-2,6-dinitroaniline (12e): 2,6-Dinitroaniline (1.83 g, 10.0 mmol) was
treated with iodine (3.61 g,14.2 mmol) and Ag 2SO4 (4.37 g,14.0 mmol) in
ethanol (30 mL) at room temperature for 18 h as described in procedure A.
After workup,the crude product was purified by flash column chromatog-
raphy (silica gel,CH 2Cl2). Compound 12e was isolated as a red/orange solid
Starting materials: The following starting materials were prepared by
literature procedures: ethyl 4-amino-3-nitrobenzoate[13] and ethyl 3-bromo-
4-methyl-5-nitrobenzoate.[14]
1
(2.33 g,7.54 mmol,75%). M.p. 173 174 8C; H NMR (CDCl3,300 MHz):
d ˆ 8.76 (s,2H),8.45 ppm (brs,2H);
13C NMR (CDCl3,75 MHz): d ˆ
141.9,140.9,135.8,71.4 ppm; IR (KBr):
nÄ ˆ 3451(m),3353(m),3078(w),
À1
Typical procedure A: 2-Iodo-6-nitro-4-(trifluoromethyl)aniline (12a):
4-Trifluoromethyl-2-nitroaniline (6.18 g,30.0 mmol) was treated with
iodine (10.64 g,42.0 mmol) and Ag 2SO4 (13.09 g,42.0 mmol) in ethanol
(300 mL) at room temperature for 36 h. The reaction mixture was filtered
and the solid was washed with ethyl acetate (3 Â 100 mL). The filtrate was
1632(s),1513(s),1388(m),1354(m),1259(s),898(m),769(m),539 cm
‡
(m); MS (EI): m/z (%): 309 [M] (100),263 (6),217 (5),90 (14),78 (9),63
‡
(9); HRMS (EI) calcd for C6H4IN3O4 [M] : 308.9247; found: 308.9261.
Typical procedure B: N'-[2-Iodo-6-nitro-4-(trifluoromethyl)phenyl]-N,N-
dimethylimidoformamide (6a): Compound 12a (6.65 g,20.0 mmol) was
treated with N,N-dimethylformamide dimethylacetal (DMF-DMA,4.79 g,
40.3 mmol) in toluene (100 mL) at 1408C for 36 h. After cooling down to
room temperature the reaction mixture was filtered. The filtrate was
concentrated in vacuo and the residue was purified by flash column
chromatography (silica gel,CH 2Cl2). Compound 6a was isolated as a
yellow/orange solid (7.37 g,19.0 mmol,95%). M.p. 85 86 8C; 1H NMR
(CDCl3,300 MHz): d ˆ 8.18 (s,1H),7.98 (s,1H),7.28 (s,1H),3.08 ppm (s,
concentrated in vacuo,and the residue was dissolved in CH Cl2 (250 mL).
2
The organic layer was then washed with aqueous NaOH (5%; 100 mL) and
water (100 mL),dried over Na 2SO4,filtered,and concentrated in vacuo.
The crude product was purified by flash column chromatography (silica gel,
CH2Cl2). Compound 12a was isolated as a yellow/orange solid (7.99 g,
24.1 mmol,80%). M.p. 101 102 8C; 1H NMR (CDCl3,300 MHz): d ˆ
8.41 8.39 (m,1H),8.06 (d,
J ˆ 2.1 Hz,1H),6.96 ppm (brs,2H);
13C NMR (CDCl3,75 MHz): d ˆ 145.9,141.5 (q, J ˆ 3.3 Hz),130.4,124.7
6H); 13C NMR (CDCl3,75 MHz): d ˆ 154.1,150.1,141.6,138.8 (q,
J ˆ
(q, J ˆ 4.3 Hz),124.2,120.6,87.2 ppm; IR (KBr):
nÄ ˆ 3463(s),3351(s),
2.5 Hz),124.8,124.3,122.3 (q, J ˆ 3.8 Hz),98.9,40.3,34.5 ppm; IR (KBr):
nÄ ˆ 3436(w),3087(w),1648(s),1604(s),1547(m),1521(m),1436(m),
3096(w),1633(s),1578(m),1519(m),1455(s),1342(s),1298(s),1252(s),
À1
1154(m),1123(s),906(m),765(w),720(w),658(m),467 cm
(w); MS
1378(m),1307(s),1272(m),1218(w),1157(m),1132(m),1104(s),
‡
(EI): m/z (%): 332 [M] (100),286 (14),274 (10),159 (84),140 (14);
À1
‡
906(w),772(w),718(w),682 cm
(w); MS (EI): m/z (%): 387 [M]
elemental analysis calcd (%) for C7H4F3IN2O2 (332.02): C 25.32,H 1.21,N
8.44; found: C 25.54,H 1.03,N 8.32.
(100),368 (15),341 (36),327 (15),314 (14),260 (17),214 (16),199 (9),
187 (13),173 (38),159 (13),143 (16),72 (24); elemental analysis calcd (%)
for C10H9F3IN3O2 (387.10): C 31.03,H 2.34,N 10.86,I 32.78; found: C 31.08,
H 2.32,N 10.84,I 32.75.
Ethyl 4-amino-3-iodo-5-nitrobenzoate (12b): Ethyl 4-amino-3-nitroben-
zoate (6.30 g,30.0 mmol) was treated with iodine (10.65 g,42.0 mmol) and
Ag2SO4 (13.10 g,42.0 mmol) in ethanol (150 mL) at room temperature for
36 h as described in procedure A. After workup,the crude product was
Ethyl
4-{[(E)-(dimethylamino)methylidene]amino}-3-iodo-5-nitroben-
zoate (6b): Compound 12b (6.72 g,20.0 mmol) was treated with DMF-
DMA (4.77 g,40.1 mmol) in toluene (100 mL) at 140 8C for 36 h as
described in procedure B. After workup,the crude product was purified by
flash column chromatography (silica gel,CH 2Cl2). Compound 6b was
isolated as a yellow/orange solid (7.14 g,18.3 mmol,91%). M.p. 80 8C;
1H NMR (CDCl3,300 MHz): d ˆ 8.58 (d, J ˆ 2.1 Hz,1H),8.34 (d, J ˆ
purified by flash column chromatography (silica gel,CH Cl2). Compound
2
12b was isolated as a yellow/orange solid (8.19 g,24.4 mmol,81%). M.p.
1
1368C; H NMR (CDCl3,300 MHz): d ˆ 8.83 (d, J ˆ 2.1 Hz,1H),8.53 (d,
J ˆ 2.1 Hz,1H),7.01 (brs,2H),4.36 (q,
J ˆ 7.2 Hz,2H),1.39 ppm (t, J ˆ
7.2 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 163.7,146.4,145.8,130.8,
129.1,120.1,86.5,61.5,14.3 ppm; IR (KBr): nÄ ˆ 3459(s),3346(s),3084(m),
2980(m),1715(s),1620(s),1510(s),1450(m),1398(m),1371(m),1334(s),
2.1 Hz,1H),7.28 (s,1H),4.35 (q,
J ˆ 7.2 Hz,2H),3.07 (s,6H),1.37 ppm
(t, J ˆ 7.2 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 163.6,153.9,150.5,
À1
1268(vs),1141(s),1026(m),867(m),756(s),717(m),677(m),478 cm
142.9,141.8,126.2,124.7,98.0,61.5,40.3,34.5,14.2 ppm; IR (KBr):
3435(m),2923(w),1708(s),1647(s),1588(s),1541(s),1516(m),1386(m),
1350(m),1270(s),1136(m),1104(m),1078(m),1024(m),759(m),716 cm
nÄ ˆ
‡
(m); MS (EI): m/z (%): 336 [M] (100),308 (53),291 (95),262 (12),245
(25),135 (10),118 (14),90 (21),63 (11); elemental analysis calcd (%) for
C9H9IN2O4 (336.08): C 32.16,H 2.70,N 8.34; found: C 32.42,H 2.51,N 8.29.
À1
‡
(m); MS (EI): m/z (%): 391 [M] (100),345 (25),317 (18),290 (15),264
(12),190 (9),145 (12),72 (16); elemental analysis calcd (%) for
C12H14IN3O4 (391.16): C 36.85,H 3.61,N 10.74,I 32.44; found: C 36.69,H
3.62,N 10.89,I 32.42.
4-Amino-3-iodo-5-nitrobenzonitrile (12c): 4-Amino-3-nitrobenzonitrile
(3.26 g,20.0 mmol) was treated with iodine (7.11 g,28.0 mmol) and Ag 2SO4
(8.74 g,28.0 mmol) in ethanol (150 mL) at room temperature as described
in procedure A. The reaction was stopped after 4 d (approximately 50%
conversion) and worked up. The crude product was purified by flash
column chromatography (silica gel,CH 2Cl2) to yield compound 12c as a
yellow/orange solid (2.43 g,8.41 mmol,42%). The starting material was
also reisolated (1.47 g,9.02 mmol,45%). M.p. 175 176 8C; 1H NMR
(CDCl3,300 MHz): d ˆ 8.42 (d, J ˆ 2.4 Hz,1H),8.04 (d, J ˆ 2.4 Hz,1H),
7.14 ppm (brs,2H); 13C NMR (CDCl3,75 MHz): d ˆ 146.5,145.6,131.6,
N'-(4-Cyano-2-iodo-6-nitrophenyl)-N,N-dimethylimidoformamide (6c):
Compound 12c (1.73 g,6.0 mmol) was treated with DMF-DMA (1.40 g,
11.8 mmol) in toluene (20 mL) at 1408C for 36 h as described in
procedure B. After workup,the crude product was purified by flash
column chromatography (silica gel,CH 2Cl2). Compound 6c was isolated as
1
an orange solid (1.72 g,5.00 mmol,83%). M.p. 123 8C; H NMR (CDCl3,
300 MHz): d ˆ 8.18 (d, J ˆ 1.8 Hz,1H),8.01 (d, J ˆ 1.8 Hz,1H),7.30 (s,
1H),3.10 (s,3H),3.09 ppm (s,3H); 13C NMR (CDCl3,75 MHz): d ˆ 153.8,
130.4,116.1,100.8,87.2 ppm; IR (KBr):
nÄ ˆ 3448(m),3329(m),3087(w),
2229(s),1614(vs) 1535(s),1508(s),1453 (m) 1402(w),1356(m),1280(s),
150.9,144.5,141.4,128.9,116.1,105.7,99.2,40.4,34.6 ppm; IR (KBr):
3437(m),3062(m),2921(m),2230(s),1643(vs),1585(vs),1540(s),
nÄ ˆ
À1
1204(w),1087(w),930(w),896(w),756(w),526 cm
(w); MS (EI): m/z
‡
(%): 289 [M] (100),243 (19),231 (8),163 (11),116 (36); HRMS (EI) calcd
1462(m),1388(s),1254(m),1220(m),1104(s),1085(s),982(m),894(w),
‡
‡
790(w),769(m),720(m),599 cm À1 (w); MS (EI): m/z (%): 344 [M] (100),
298 (28),284 (18),271 (14),217 (11),171 (16),144 (10),130 (31),116 811),
100 (16),72 (22); HRMS calcd for C 10H9IN4O2: 343.9770; found: 343.9766
for C7H4IN3O2 [M] : 288.9348; found: 288.9349.
4-Chloro-2-iodo-6-nitroaniline (12d): 4-Chloro-2-nitro-aniline (5.16 g,
30.0 mmol) was treated with iodine (10.66 g,42.0 mmol) and Ag 2SO4
(13.10 g,42.0 mmol) in ethanol (300 mL) at room temperature for 36 h as
described in procedure A. After workup,the crude product was purified by
flash column chromatography (silica gel,CH 2Cl2). Compound 12d was
isolated as an orange solid (6.26 g,21.0 mmol,70%). M.p. 132 133 8C;
1H NMR (CDCl3,300 MHz): d ˆ 8.04 (d, J ˆ 2.4 Hz,1H),7.80 (d, J ˆ
2.4 Hz,1H),6.70 ppm (brs,2H); 13C NMR (CDCl3,75 MHz): d ˆ 144.3,
‡
[M] .
N'-(4-Chloro-2-iodo-6-nitrophenyl)-N,N-dimethylimidoformamide (6d):
Compound 12d (2.38 g,8.0 mmol) was treated with DMF-DMA (1.94 g,
16.3 mmol) in toluene (30 mL) at 1408C for 36 h as described in
procedure B. After workup,the crude product was purified by flash
column chromatography (silica gel,CH 2Cl2). Compound 6d was isolated as
an orange solid (2.23 g,6.31 mmol,78%). M.p. 74 75 8C; 1H NMR
(CDCl3,300 MHz): d ˆ 7.95 (d, J ˆ 2.1 Hz,1H),7.72 (d, J ˆ 2.1 Hz,1H),
7.23 (s,1H),3.05 ppm (s,6H); 13C NMR (CDCl3,75 MHz): d ˆ 164.6,146.1,
142.4,130.3,125.3,120.7,87.1 ppm; IR (KBr):
nÄ ˆ 3462(s),3350(s),
3090(w),1622(s),1552(m),1498(s),1440(m),1386(m),1345(m),
1319(m),1246(s),1130(m),1078(w),896(w),880(m),762(m),726(m),
À1
‡
708(m),547(w),456 cm
(w); MS (EI): m/z (%): 300/298 [M] (32/100),
142.0,141.8,126.9,124.6,98.8,40.2,34.5 ppm; IR (KBr):
3075(w),2927(w),1639(vs),1590(s),1540(s),1514(s),1463(m),1416(m),
1399(s),1376(s),1342(s),1254(s),1212(m),1106(s),1082(m),885(m),
nÄ ˆ 3436(w),
‡
254/252 (10/32),127 (38),90 (10); HRMS (EI) calcd for C 6H4IClN2O2 [M] :
297.9006; found: 297.8988.
Chem. Eur. J. 2003, 9,5323 5331
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
5327

P. Knochel et al.
FULL PAPER
À1
‡
770(m),751(m),716 cm
(m); MS (EI): m/z (%): 355/353 [M] (32/100),
(100),368 (31),367 (25),352 (9),267 (10),72 (11); HRMS (EI) calcd for
C21H23N3O6: 413.1587; found: 413.1623 [M] .
‡
309/305 (11/33),293 (15),280 (12),226 (11),180 (14),153 (10),139 (21),124
(12),109 (10),72 (19); HRMS (EI) calcd for C 9H9IClN3O2: 352.9428;
Ethyl 2'-{[(E)-(dimethylamino)methylidene]amino}-3'-nitro-5'-(trifluoro-
methyl)[1,1'-biphenyl]-4-carboxylate (6j): Compound 6a (581 mg,
1.5 mmol) was treated with 4-ethoxycarbonylphenylzinc bromide
‡
found: 352.9421 [M] .
N'-(2,4-Dibromo-6-nitrophenyl)-N,N-dimethylimidoformamide (6e): 2,4-
Dibromo-6-nitroaniline (1.76 g,6.0 mmol) was treated with DMF-DMA
(1.45 g,12.2 mmol) in toluene (20 mL) at 140 8C for 36 h as described in
procedure B. After workup,the crude product was purified by flash column
chromatography (silica gel,CH 2Cl2). Compound 6e was isolated as a
yellow/orange solid (2.30 g,6.55 mmol,95%). M.p. 90 91 8C; 1H NMR
(CDCl3,300 MHz): d ˆ 7.83 (d, J ˆ 2.1 Hz,1H),7.78 (d, J ˆ 2.1 Hz,1H),
(4.0 mL,0.56
(21.3 mg,0.037 mmol) and TFP (17.1 mg,0.074 mmol) in THF (2 mL) at
room temperature for 2 h as described in procedure C. After workup,the
m
in THF,2.25 mmol) in the presence of [Pd(dba)
]
2
crude product was purified by flash column chromatography (silica gel,
pentane/ethyl acetate 90:10 and 2% NEt3). Compound 6j was isolated as a
yellow solid (493 mg,1.21 mmol,80%). M.p. 123 8C; 1H NMR (CDCl3,
300 MHz): d ˆ 8.03 (d, J ˆ 8.4 Hz,2H),7.97 7.96 (m,1H),7.66 7.65 (m,
1H),7.52 (d, J ˆ 8.4 Hz,2H),7.02 (s,1H),4.40 (q, J ˆ 7.1 Hz,2H),2.89 (s,
3H),2.81 (s,3H),1.42 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR (CDCl3,75 MHz):
d ˆ 166.3,153.9,146.2,147.2,142.5,137.3,130.0,129.8,129.6,129.4,123.8,
7.31 (s,1H),3.05 (s,3H),3.02 ppm (s,3H);
13C NMR (CDCl3,75 MHz):
d ˆ 154.6,144.4,144.3,138.4,126.3,121.2,112.8,40.2,34.3 ppm; IR (KBr):
nÄ ˆ 3436(m),2926(w),1643(s),1582(m),1542(m),1461(m),1397(m),
1248(m),1106(m),723 cm À1 (w); MS (EI): m/z (%): 353/351/349 [M] (50/
100/51),321 (5/9/4),307/305/303 (23/45/25),280/278/276 (12/21/13),264/262
(13/11),183 (27),170 (10),155 (12),88 (9),72 (21); HRMS (EI) calcd for
‡
123.3 (q, J ˆ 32.5 Hz),121.4,61.1,40.0,34.3,14.3 ppm; IR (KBr):
3431(m),3069(w),2977(m),1714(s),1646(s),1605(s),1525(s),1441(m),
1370(s),1331(s),1290(s),1258(s),1206(s),1181(s),1156(s),1124(s),
1071(s),1019(m),991(m),899(m),866(m),810(m),784(m),756(m),
nÄ ˆ
‡
C9H9Br2N3O2: 348.9061; found: 348.9070 [M] .
N'-(2,6-Dinitrophenyl)-N,N-dimethylimidoformamide (6 f): 2,6-Dinitro-
aniline (550 mg,3.0 mmol) was treated with DMF-DMA (723 mg,
6.1 mmol) in toluene (100 mL) at 1408C for 18 h as described in
procedure B. After workup,the crude product was purified by flash
column chromatography (silica gel,CH 2Cl2). Compound 6 f was isolated as
a yellow/orange solid (673 mg,2.83 mmol,94%). M.p. 69 8C; 1H NMR
À1
‡
707(m),692(m),666 cm
(w); MS (EI): m/z (%): 409 [M] (49),390 (9),
366 (20),365 (100),364 (20),363 (20),337 (24),319 (10),292 (11),291 (20),
275 (10),249 (11),246 (12),235 (10),72 (22); HRMS (EI) calcd for
‡
C19H18F3N3O4: 409.1249; found: 409.1258 [M] .
N'-(4-Iodo-2,6-dinitrophenyl)-N,N-dimethylimidoformamide (6k): Com-
pound 12e (1.85 g,6.0 mmol) was treated with DMF-DMA (1.45 g,
12.2 mmol) in toluene (30 mL) at 1408C for 18 h as described in
procedure B. After workup,the crude product was purified by flash
column chromatography (silica gel,CH 2Cl2). Compound 6k was isolated as
a yellow/orange solid (1.73 g,4.75 mmol,79%). M.p. 137 8C; 1H NMR
(CDCl3,300 MHz): d ˆ 8.12 (s,2H),7.38 (s,1H),3.06 (s,3H),2.97 ppm (s,
3H); 13C NMR (CDCl3,75 MHz): d ˆ 154.4,145.8,141.0,136.0,79.1,40.4,
34.3 ppm; IR (KBr): nÄ ˆ 3436(m),3088(m),2930(m),1639(vs),1596(s),
(CDCl3,300 MHz): d ˆ 7.85 (d, J ˆ 8.1 Hz,2H),7.39 (s,1H),7.04 (t,
J ˆ
8.1 Hz,1H),3.05 (s,3H),2.96 ppm (s,3H);
13C NMR (CDCl3,75 MHz):
d ˆ 154.6,145.4,141.3,127.7,120.2,40.3,34.2 ppm; IR (KBr):
nÄ ˆ 3436(w),
2922(w),1648(s),1600(s),1523(s),1404(m),1345(m),1258(m),1106(m),
1083(m),852(w),749(m),702 cm À1 (m); MS (EI): m/z (%): 238 [M] (100),
‡
192 (23),178 (19),165 (22),149 (11),146 (11),133 (10),119 (16),103 (16),
90 (23),75 (20),72(70),63 (15); elemental analysis calcd (%) for C 9H10N4O4
(238.20): C 45.38,H 4.23,N 23.52; found: C 45.58,H 3.96,N 23.72.
1535(s),1463(m),1428(m),1412(s),1400(s),1336(m),1250(m),1106(m),
Typical procedure C: N'-(4'-Methoxy-3,5-dinitro[1,1'-bi-phenyl]-4-yl)-
N,N-dimethylimidoformamide (6g): Compound 6k (364 mg,1.0 mmol)
was dissolved in a solution of the preformed catalyst {[Pd(dba)2] (14.4 mg,
0.025 mmol) and tris-2-furyl-phosphine (TFP,12.0 mg,0.050 mmol) in THF
(2 mL)} and treated with 4-methoxyphenylzinc bromide (3.0 mL,0.5 m in
THF,1.5 mmol) at room temperature for 2 h. The reaction mixture was
quenched by the addition of aqueous NH4Cl solution (5 mL),poured into
water (30 mL),and extracted with ethyl acetate (3 Â 30 mL). The combined
organics were washed with brine (30 mL),dried over MgSO 4,filtered,and
concentrated in vacuo. The crude product was purified by flash column
chromatography (silica gel,pentane/ethyl acetate 75:25). Compound 6g
was isolated as an orange solid (425 mg,1.23 mmol,82%). M.p. 123
À1
1000(m),920(m),888(m),774(m),718(m),554 cm
(w); MS (EI): m/z
‡
(%): 364 [M] (100),318 (28),304 (15),291 (26),245 (11),217 (12),189
(12),99 (19),88 (12),75 (22),72 (80); HRMS (EI) calcd for C 9H9IN4O4:
‡
363.9669; found: 363.9677 [M] .
2,4-Dibromo-6-nitro-N-[(E)-phenylmethylidene]aniline (6m): 2,4-Dibro-
mo-6-nitroaniline (1.77 g,6.0 mmol) was treated with benzaldehyde (1.91 g,
18.0 mmol) in the presence of molecular sieves (4 ä,400 mg) and 3 drops
of conc. H2SO4 in toluene (12 mL) at 1408C for 30 h. The reaction mixture
was allowed to cool to room temperature,filtered,and concentrated in
vacuo. The crude product was purified by flash column chromatography
(silica gel,pentane/ethyl acetate 85:15 and 2% NEt 3). Compound 6m was
obtained as a yellow solid (1.56 g,4.06 mmol,68%). M.p. 117 8C; 1H NMR
(C6D6,300 MHz): d ˆ 7.70 7.65 (m,3H),7.47 (d, J ˆ 2.1 Hz,1H),7.37 (d,
J ˆ 2.1 Hz,1H),7.12 7.00 ppm (m,3H); 13C NMR (C6D6,75 MHz): d ˆ
166.9,144.9,142.1,140.7,139.0,135.1,132.8,129.7,129.0,126.8,117.4,
1
1248C; H NMR (CDCl3,300 MHz): d ˆ 8.04 (s,2H),7.52 7.46 (m,2H),
7.43 (s,1H),7.02 6.96 (m,2H),3.85 (s,3H),3.07 (s,3H),2.99 ppm (s,3H);
13C NMR (CDCl3,75 MHz): d ˆ 160.1,154.7,145.7,19.4,133.7,129.2,127.7,
125.2,114.7,55.4,40.3,34.3 ppm; IR (KBr):
nÄ ˆ 3436(m),2929(m),
1652(vs),1516(vs),1472(s),1412(s),1376(s),1295(s),1249(vs),1184(s),
1102(s),1069(s),1032(m),985(m),924(m),899(m),831(s),802(m),
775(m),720(m),529 cm À1 (m); MS (EI): m/z (%): 344 [M] (100),312 (7),
298 (10),196 (17),135 (13),72 (24); elemental analysis calcd (%) for
C16H16N4O5 (344.32): C 55.81,H 4.68,N 16.27; found: C 55.96,H 4.57,N
16.48.
116.0 ppm; IR (KBr): nÄ ˆ 3466(s),3355(s),3075(w),1624(s),1581(m),
1545(s),1505(s),1446(m),1387(m),1346(s),1318(m),1260(s),1192(m),
‡
À1
1120(m),1099(m),876(m),762(m),726(m),692(m),544 cm
(w); MS
‡
(EI): m/z (%): 386/384/382 [M] (20/38/21),178 (13),177 (21),151 (19),150
(12),106 (11),105 (100),89 (17),77 (17); HRMS (EI) calcd for
‡
C13H8Br2N2O2: 381.8952; found: 381.8963 [M] .
Diethyl 6-{[(E)-(dimethylamino)methylidene]amino}-5-nitro-[1,1'-biphen-
yl]-3,4'-dicarboxylate (6i): Compound 6b (587 mg,1.5 mmol) was treated
Typical procedure D: Ethyl 3-bromo-4-[(E)-2-(4-methoxyphenyl)ethenyl]-
5-nitrobenzoate (11a): Compound 13a (864 mg,3.00 mmol) was placed in a
dry 50 mL round-bottomed flask,equipped with a magnetic stirrer and a
reflux condenser,and treated with 4-methoxybenzaldehyde (1.23 g,
9.0 mmol) and piperidine (383 mg,4.50 mmol) in the presence of molecular
sieves (4 ä,600 mg) in toluene (5 mL) at 100 8C for 4 d. After the mixture
had cooled to room temperature,THF (5 mL) was added,the reaction
mixture was filtered,and the remaining residue was washed with CH 2Cl2
(3 Â 5 mL). The solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography (silica gel,pentane/
diethyl ether 96:4). A yellow solid was obtained; this still contained some
aldehyde,which was mostly removed by Kugelrohr distillation. The
remaining residue was washed with diethyl ether,to afford compound
11a (630 mg,52%) as a yellow solid. The filtrate was concentrated in vacuo
and the residue was purified by Kugelrohr distillation to afford compound
with 4-ethoxycarbonylphenylzinc bromide (4.0 mL,0.56
m in THF,
2.25 mmol) in the presence of [Pd(dba)2] (21.6 mg,0.037 mmol) and TFP
(17.4 mg,0.075 mmol) in THF (2 mL) at room temperature for 2 h as
described in procedure C. After workup,the crude product was purified by
flash column chromatography (silica gel,pentane/ethyl acetate 90:10 and
2% NEt3). Compound 6i was isolated as a yellow oil (524 mg,1.27 mmol,
85%); 1H NMR (CDCl3/[D6]DMSO,300 MHz): d ˆ 8.35 (d, J ˆ 2.1 Hz,
1H),8.10 (d, J ˆ 2.1 Hz,1H),8.05 (d, J ˆ 8.4 Hz,2H),7.51 (d, J ˆ 8.4 Hz,
2H),7.01 (s,1H),4.33 (q, J ˆ 7.1 Hz,2H),4.32 (q, J ˆ 7.0 Hz,2H),2.88 (s,
3H),2.80 (s,3H),1.35 (t,
J ˆ 7.1 Hz,3H),1.33 ppm (t, J ˆ 7.0 Hz,3H);
13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 166.4,164.9,153.8,147.9,
144.5,143.0,136.2,134.3,129.8,129.3,125.3,123.6,61.4,60.1,40.0,34.3,
14.3 ppm; IR (KBr): nÄ ˆ 2982(s),1715(s),1651(s),1597(s),1532(s),
1369(s),1244(s),1183(s),1106(s),1073(s),1021(s),862(m),767(s),
11a (259 mg,21%; total yield 889 mg,2.19 mmol,73%). M.p. 129
8C;
À1
‡
739(m),716 cm
(s); MS (EI): m/z (%): 413 [M] (59),381 (11),369
1H NMR (CDCl3,300 MHz): d ˆ 8.43 (d, J ˆ 1.8 Hz,1H),8.26 (d, J ˆ
5328
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,5323 5331

Functionalized Heterocycles
5323 5331
pound 11d as a yellow solid (2.19 g,5.89 mmol,59%). M.p. 108 8C;
1H NMR (CDCl3,300 MHz): d ˆ 8.59 (s,2H),7.41 (dm, J ˆ 8.8 Hz,2H),
7.17 (d, J ˆ 16.8 Hz,1H),6.90 (d, J ˆ 8.8 Hz,2H),6.67 (d, J ˆ 16.8 Hz,1H),
4.47 (q, J ˆ 7.1 Hz,2H),3.83 (s,3H),1.44 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR
(CDCl3,75 MHz): d ˆ 162.5,160.9,150.2,137.6,131.7,130.7,128.9,128.1,
1.8 Hz,1H),7.44 (dm, J ˆ 8.8 Hz,2H),6.98 (d, J ˆ 16.6 Hz,1H),6.91 (dm,
J ˆ 8.8 Hz,2H),6.73 (d, J ˆ 16.6 Hz,1H),4.43 (q, J ˆ 7.1 Hz,2H),3.83 (s,
3H),1.42 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 163.3,
160.5,150.2,137.1,136.6,136.5,130.4,128.6,128.4,125.4,123.6,119.4,114.2,
62.2,55.3,14.2 ppm; IR (KBr): nÄ ˆ 3420(m),3076(m),2982(m),2937(m),
2842(w),1718(vs),1631(m),1600(s),1574(m),1532(s),1513(s),1462(m),
1422(m),1362(s),1250(vs),1178(s),1142(m),1034(m),970(m),907(w),
822(m),767(m),748(m),726(m),545 cm À1 (w); MS (EI): m/z (%): 407/405
127.7,114.7,114.3,62.7,55.34,14.2 ppm; IR (KBr):
nÄ ˆ 3431(w),2977(w),
1715(s),1604(s),1539(s)1,515(s),1460(m),1425(w),1353(m),1286(s),
1255(s),1179(s),1033(m),978(m),918(w),834(m),768(w),749(m),
‡
723(m),540 cm À1 (w); MS (EI): m/z (%): 372 [M] (9),163 (15),152 (10),
‡
[M] (6/7),390 (14),388 (14),362 (14),360 (15),271 (13),269 (13),243 (17),
137 (27),136 (75),135 (100),121 (17); HRMS (EI) calcd for C 18H16N2O7:
241 (11),216 (11),214 (10),164 (24),163 (41),152 (14),136 (64),135 (100),
134 (31),121 (48),77 (10); HRMS (EI) calcd for C 18H16BrNO5: 405.0212;
‡
372.0958; found: 372.0915 [M] ; elemental analysis calcd (%) for
C18H16N2O7 (372.34): C 58.06,H 4.33,N 7.52; found: C 58.05,H 4.54,N 7.56.
‡
found: 405.0219 [M] .
1,3-Dinitro-2-[(E)-2-phenylethenyl]benzene (11e):[10a,10e] Compound 13c
(1.82 g,10.0 mmol) with benzaldehyde (3.18 g,30.0 mmol) and piperidine
(1.28 g,15.0 mmol) in the presence of molecular sieves (4 ä,2.00 g) at
1108C for 4 d was treated as described in procedure D. After the mixture
had cooled to room temperature,THF (25 mL) was added,the reaction
mixture was filtered,and the remaining residue was washed with CH 2Cl2
(3 Â 25 mL). The filtrate was concentrated in vacuo and the crude product
was purified by flash chromatography (silica gel,pentane/ethyl acetate
95:5) to afford compound 11e as a yellow solid (540 mg,2.0 mmol,20%).
1H NMR (CDCl3,300 MHz): d ˆ 7.99 (d, J ˆ 7.8 Hz,2H),7.54 (t, J ˆ 7.8 Hz,
1H),7.45 7.40 (m,2H),7.37 7.28 (m,4H),6.58 ppm (d, J ˆ 16.2 Hz,1H);
13C NMR (CDCl3,75 MHz): d ˆ 150.3,135.9,135.5,129.0,128.7,128.5,
128.1,127.3,127.0,118.3 ppm.
Ethyl 3-bromo-5-nitro-4-[(E)-2-(3-pyridinyl)ethenyl]benzoate (11b):
Compound 13a (864 mg,3.00 mmol) was treated with nicotinaldehyde
(964 mg,9.00 mmol) and piperidine (383 mg,4.50 mmol) in the presence of
molecular sieves (4 ä,600 mg) in toluene (5 mL) as described in
procedure D. The solution was heated at 1108C for 4 d. As the conversion,
as determined by GC,was still incomplete,the mixture was heated at 140 8C
for 1 d,after which the conversion remained still incomplete (43%). After
the mixture had cooled to room temperature,THF (5 mL) was added,the
reaction mixture was filtered,and the remaining residue was washed with
CH2Cl2 (3 Â 5 mL). The solvent was removed under reduced pressure and
the crude product was purified by flash column chromatography (silica gel,
pentane/ethyl acetate 65:35) and was subsequently recrystallized to afford
compound 11b as a light yellow solid (238 mg,0.63 mmol,21%). M.p.
1018C; 1H NMR (CDCl3,300 MHz): d ˆ 8.72 8.69 (m,1H),8.57 (dd, J ˆ
4.9,1.8 Hz,1H),8.48 (d, J ˆ 1.8 Hz,1H),8.35 (d, J ˆ 1.8 Hz,1H),7.87 7.82
(m,1H),7.33 (dd, J ˆ 8.0,4.9 Hz,1H),7.20 (d, J ˆ 16.8 Hz,1H),6.75 (d, J ˆ
Typical procedure E: N,N-Dimethyl-4-iodo-6-(trifluoromethyl)-1H-benz-
imidazole-2-amine (7a): Compound 6a (387 mg,1.0 mmol) in THF (2 mL)
was treated at À408C with PhMgCl (1.20 g,25% in THF,2.2 mmol). After
15 min the reaction was quenched by the addition of methanol (0.5 mL),
and the solvent was removed under reduced pressure. The crude product
was purified by flash column chromatography (silica gel,pentane/ethyl
acetate 50:50). Compound 7a was isolated as a white solid (266 mg,
0.75 mmol,75%). M.p. 226 8C; 1H NMR (CDCl3/[D6]DMSO,300 MHz):
16.8 Hz,1H),4.44 (q,
J ˆ 7.1 Hz,2H),1.43 ppm (t,
J ˆ 7.1 Hz,3H);
13C NMR (CDCl3,75 MHz): d ˆ 163.1,150.2,150.0,148.9,137.0,135.9,
133.6,133.3,131.4,125.5,124.2,123.8,123.7,62.3,14.2 ppm; IR (KBr):
3410(w),3080(m),2998(m),1729(s),1608(m),1533(vs),1480(m),
1465(m),1384(m),1364(s),1274(s),1206(m),1152(s),1023(m),906(m),
nÄ ˆ
870(m),854(m),770(m),748(m),729 cm À1 (m); MS (EI): m/z (%): 378/376
d ˆ 9.60 (brs,1H),7.54 (s,1H),7.28 (s,1H),3.10 ppm (s,6H);
(CDCl3/[D6]DMSO,75 MHz): d ˆ 157.6,146.2,134.5,126.1 (q, J ˆ 3.9 Hz),
125.8,122.5,122.1,106.9,38.1 ppm; IR (KBr):
13C NMR
‡
[M] (8/8),361/359 (67/68),333/331 (64/65),305/303 (28/27),271/269 (81/
81),260 (27),256/254 (26/23),243/241 (64/65),226/224 (41/38),216/214 (70/
73),199/197 (52/54),178 (70),177 (55),166 (35),151 (66),150 (78),139 (28),
125 (18),106 (74),92 (100),78 (53),75 (42),63 (19),51 (15); HRMS (EI)
nÄ ˆ 3435(w),2933(m),
1637(s),1606(s),1570(m),1433(s),1370(m),1317(vs),1269(m),1238(m),
1189(m),1153(s),1118(s),1074(m),963(w),924(m),863(m),758(w),
‡
‡
687(m),664(w),452 cm À1 (w); MS (EI): m/z (%): 355 [M] (100),340 (62),
calcd for C18H13BrN2O5: 376.0059; found: 376.0068 [M] .
326 (49),213 (22),186 (15); elemental analysis calcd (%) for C 10H9F3IN3
(355.10): C 33.82,H 2.55,N 35.74; found: C 33.85,H 2.61,N 35.81.
Ethyl 3-bromo-5-nitro-4-[(E)-2-phenylethenyl]benzoate (11c): Compound
13a (720 mg,2.50 mmol) was treated with benzaldehyde (795 mg,
7.50 mmol) and piperidine (319 mg,3.75 mmol) in the presence of
molecular sieves (4 ä,600 mg) in toluene (5 mL) at 80 8C for 4 d as
described in procedure D. After the mixture had cooled to room temper-
ature,THF (5 mL) was added,the reaction mixture was filtered,and the
remaining residue was washed with CH2Cl2 (3 Â 5 mL). The solvent was
removed under reduced pressure and the crude product was purified by
flash column chromatography (silica gel,pentane/ethyl acetate 96:4),which
afforded compound 11c as a yellow solid (629 mg,1.67 mmol,67%). M.p.
Ethyl 2-(dimethylamino)-4-iodo-1H-benzimidazole-6-carboxylate (7b):
Compound 6b (391 mg,1.0 mmol) in THF (2 mL) was treated at À408C
with PhMgCl (1.20 g,25% in THF,2.2 mmol) for 15 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (silica gel,pentane/ethyl acetate 50:50). Compound 7b
was isolated as a white solid (285 mg,0.79 mmol,79%). M.p. 250 251 8C;
1H NMR (CDCl3/[D6]DMSO,300 MHz): d ˆ 7.87 (d, J ˆ 1.5 Hz,1H),7.55
(d, J ˆ 1.5 Hz,1H),4.09 (q, J ˆ 7.2 Hz,2H),2.94 (s,6H),1.14 ppm (t,
J ˆ
1
7.2 Hz,3H); 13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 165.6,157.6,
1248C; H NMR (CDCl3,300 MHz): d ˆ 8.46 (d, J ˆ 1.8 Hz,1H),8.30 (d,
J ˆ 1.8 Hz,1H),7.54 7.48 (m,2H),7.43 7.31 (m,3H),7.13 (d,
J ˆ 16.4 Hz,
148.2,133.1,130.9,121.7,110.2,59.9,37.6,13.8 ppm; IR (KBr):
2930(w),1687(m),1636(s),1601(s),1558(m),1432(m),1368(m),1293(s),
nÄ ˆ 3429(m),
1H),6.78 (d, J ˆ 16.4 Hz,1H),4.44 (q, J ˆ 7.1 Hz,2H),1.43 ppm (t, J ˆ
7.1 Hz,3H); 13C NMR (CDCl3,75 MHz): d ˆ 163.3,150.3,137.4,136.7,
136.4,135.6,130.8,129.2,128.8,127.1,125.5,123.6,121.9,62.2,14.2 ppm; IR
À1
1228(m),1181(m),1096(w),1020(w),925(w),862(w),767 cm
(w); MS
‡
(EI): m/z (%): 359 [M] (100),344 (22),330 (29),316 (25),302 (17),286
(KBr): nÄ ˆ 3428(w),3080(w),1721(s),1539(m),1366(m),1279(m),
(11),144 (8); HRMS (EI) calcd for C 12H14IN3O2: 359.0131; found: 359.0138
[M] ; elemental analysis calcd (%) for C12H14IN3O2 (359.16): C 40.13,H
3.93,N 35.33; found: C 40.06,H 3.81,N 35.46.
À1
‡
1257(m),1149(m),1024(w),974(w),758(m),727(w),694 cm
(w); MS
‡
(EI): m/z (%): 377/375 [M] (5/5),360/358 (43/43),332/330 (51/51),304/302
(28/28),271/269 (42/42),243/241 (39/39),226 (20),224 (27),216/214 (38/41),
199/197 (27/28),177 (40),176 (100),165 (38),163 (21),151 (33),134 (10),
105 (33),91 (69),88 (38),77 (31); HRMS (EI) calcd for C 17H14BrNO4:
2-(Dimethylamino)-4-iodo-1H-benzimidazole-6-carbonitrile (7c): Com-
pound 6c (344 mg,1.0 mmol) in THF (2 mL) was treated at À408C with
PhMgCl (1.20 g,25% in THF,2.2 mmol) for 15 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (silica gel,pentane/ethyl acetate 50:50). Compound 7c
was isolated as a white solid (151 mg,0.48 mmol,48%). M.p. 261 8C;
1H NMR ([D6]DMSO,300 MHz): d ˆ 7.91 (d, J ˆ 1.5 Hz,1H),7.61 (d, J ˆ
1.5 Hz,1H),3.13 ppm (s,6H); 13C NMR ([D6]DMSO,300 MHz): d ˆ 156.9,
‡
375.0106; found: 375.0092 [M] .
Ethyl 4-[(E)-2-(4-methoxyphenyl)ethenyl]-3,5-dinitrobenzoate (11d):
Compound 13b (2.54 g,10.0 mmol) was treated with 4-methoxybenzalde-
hyde (4.08 g,30.0 mmol) and piperidine (1.28 g,15.0 mmol) in the presence
of molecular sieves (4 ä,2.00 g) in toluene (25 mL) at 80 8C for 1 d as
described in procedure D. After the mixture had cooled to room temper-
ature,THF (25 mL) was added,the reaction mixture was filtered,and the
remaining residue was washed with CH2Cl2 (3 Â 25 mL). The filtrate was
concentrated in vacuo and the crude product was purified by flash
chromatography (silica gel,pentane/ethyl acetate 95:5) to afford com-
146.1,134.7,130.7,120.3,118.6,104.0,95.7,37.6 ppm; IR (KBr):
3435(m),2924(w),2229(m),1642(s),1592(vs),1544(s),1481(w),
nÄ ˆ
À1
1423(m),1376(s),1197(w),1114(m),832(w),781 cm
(w); MS (EI):
‡
m/z (%): 312 [M] (100),297 (63),283 (54),170 (20),143 (14); HRMS (EI)
calcd C10H9IN4 311.9872; found: 311.9881 [M] ; elemental analysis calcd
‡
Chem. Eur. J. 2003, 9,5323 5331
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
5329

P. Knochel et al.
FULL PAPER
(%) for C10H9IN4 (312.11): C 38.48,H 2.91,N 17.95; found: C 38.30,H 2.75,
N 18.10.
7.75 (d, J ˆ 1.3 Hz,1H),4.34 (q, J ˆ 7.2 Hz,2H),4.32 (q, J ˆ 7.2 Hz,2H),
3.14 (s,6H),1.35 (t, J ˆ 7.2 Hz,3H),1.34 ppm (t, J ˆ 7.2 Hz,3H); 13C NMR
([D6]DMSO,75 MHz): d ˆ 166.3,165.6,158.9,142.8,136.6,129.0,128.2,
N-(6-Chloro-4-iodo-1H-benzimidazol-2-yl)-N,N-dimethylamine
(7d):
127.8,123.5,121.1,109.3,60.6,60.2,37.6,14.2,14.1 ppm; IR (KBr):
3432(m),1840(w),1709(m),1663(w),1608(s),1505(w),1394(m),
1378(m),1367(m),1352(w),1322(m),1306(w),1248(m),1162(w),
nÄ ˆ
Compound 6d (354 mg,1.0 mmol) in THF (2 mL) was treated at À408C
with PhMgCl (1.20 g,25% in THF,2.2 mmol) for 15 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (silica gel,pentane/ethyl acetate 50:50). Compound 7d
was isolated as a light brownish solid (197 mg,0.61 mmol,61%). M.p. 228
2298C; 1H NMR ([D6]DMSO,600 MHz): d ˆ 7.29 (d, J ˆ 1.8 Hz,1H),7.13
(d, J ˆ 1.8 Hz,1H),3.07 ppm (s,6H); 13C NMR ([D6]DMSO,150 MHz):
À1
1104(m),1053(w),1022(w),957(w),926(w),910(w),765 cm
(w); MS
‡
(EI): m/z (%): 381 [M] (100),367 (20),352 (28),336 (14),324 (11),308 (7),
265 (5),192 (4); HRMS (EI) calcd for C 21H23N3O4: 381.1689; found:
‡
381.1657 [M] .
Ethyl 4-[2-(dimethylamino)-6-(trifluoromethyl)-1H-benzimidazol-4-yl]-
benzoate (7j): Compound 6j (205 mg,0.5 mmol) in THF (2 mL) was
treated at À408C with PhMgCl (602 mg,25% in THF,1.1 mmol). After
30 min the reaction mixture was quenched by the addition of methanol
(0.5 mL),poured into water,and extracted with ethyl acetate (4 Â 20 mL).
The combined organics were washed with brine (20 mL),dried over
Na2SO4,filtered,and concentrated in vacuo. The crude product was
purified by flash column chromatography (silica gel,pentane/ethyl acetate
85:15). Compound 7j was isolated as a white solid (145 mg,0.38 mmol,
77%). M.p. 1918C; 1H NMR (CDCl3,300 MHz): d ˆ 8.03 (d, J ˆ 8.4 Hz,
d ˆ 157.0,144.8,133.3,127.6,122.5,108.3,80.7,37.7 ppm; IR (KBr):
nÄ ˆ
3435(m),1630(s),1593(s),1565(m),1430(s),1315(m),1266(m),1180(w),
À1
‡
923(m),838(w),744 cm
(w); MS (EI): m/z (%): 323/321 [M] (32/100),
308/306 (17/53),294/292 (19/58),179 (13),152 (12); HRMS (EI) calcd for
‡
C9H9IClN3: 320.9530; found: 320.9507 [M] ; elemental analysis calcd (%)
for C9H9IClN3 (321.55): C 33.62,H 2.82,N 13.07; found: C 33.54,H 2.70,N
13.21.
4,6-Dibromo-N,N-dimethyl-1H-benzimidazole-2-amine (7e): Compound
6e (349 mg,1.0 mmol) in THF (2 mL) was treated at À408C with PhMgCl
(1.20 g,25% in THF,2.2 mmol) for 15 min as described in procedure E.
After workup,the crude product was purified by flash column chromatog-
raphy (silica gel,pentane/ethyl acetate 50:50). Compound 7e was isolated
as a light brownish solid (223 mg,0.70 mmol,70%). M.p. 214 8C; 1H NMR
(CDCl3/[D6]DMSO,300 MHz): d ˆ 10.40 (brs,1H),7.16 (s,2H),3.07 ppm
(s,6H); 13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 157.1,143.5,134.4,
2H),7.84 (d, J ˆ 8.4 Hz,2H),7.47 (s,1H),7.40 (s,1H),4.37 (q,
J ˆ 7.1 Hz,
2H),3.17 (s,6H),1.41 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR (CDCl3,75 MHz):
d ˆ 166.5,157.6,142.5,129.9,129.2,128.3,126.8,124.5,123.2,117.3,(q,
J ˆ
32.5 Hz),108.9,61.1,38.3,14.3 ppm; IR (KBr):
1698(s),1638(s),1609(s),1581(s),1421(s),1395(s),1368(m),1335(s),
nÄ ˆ 3350(m),2983(m),
1263(s),1237(s),1165(s),1109(s),1022(m),969(w),926(m),857(m),
127.6,124.3,120.7,110.9,38.0 ppm; IR (KBr):
nÄ ˆ 3434(m),1630(m),
‡
783(m),707(m),620 cm À1 (w); MS (EI): m/z (%): 377 [M] (100),362 (28),
À1
1597(m),1434(m),1317(w),1267(w),922 cm
(w); MS (EI): m/z (%):
348 (33),334 (15),332 (13),320 (13),158 (10); HRMS (EI) calcd for
‡
321/319/317 [M] (50/100/52),306/304/302 (39/80/41),292/290/280 (41/85/
‡
C19H18F3N3O2: 377.1351; found: 377.1359 [M] .
41),278/276/274 (10/20/10),223 (10),196 (19),144 (9); HRMS (EI) calcd
4,6-Dibromo-2-phenyl-1H-benzimidazole (7l): Compound 6m (384 mg,
1.0 mmol) in THF (2 mL) was treated at À408C with PhMgCl (1.22 g,25%
in THF,2.2 mmol). After 30 min the reaction mixture was quenched by the
addition of methanol (0.5 mL) and poured into water (15 mL),and
saturated NH4Cl solution (15 mL) was added. The mixture was extracted
with ethyl acetate (4 Â 30 mL). The combined organics were washed with
brine (30 mL),dried over MgSO 4,filtered,and concentrated in vacuo. The
crude product was transferred onto silica gel and purified by flash column
chromatography (silica gel,pentane/ethyl acetate 90:10). Compound 7l
was isolated as a light brownish solid (271 mg,0.77 mmol,77%). M.p. 177
1788C; 1H NMR (CDCl3/[D6]DMSO,300 MHz): d ˆ 8.19 8.15 (m,2H),
7.51 (d, J ˆ 1.9 Hz,1H),7.42 (d, J ˆ 1.3 Hz,1H),7.37 7.35 ppm (m,3H);
13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 149.0,134.6,130.2,128.7,
‡
for C9H9Br2N3: 316.9163; found: 316.9166 [M] ; elemental analysis calcd
(%) for C9H9Br2N3 (319.00): C 33.89,H 2.84,N 13.17; found: C 33.63,H
2.70,N 13.28.
N,N-Dimethyl-N-(4-nitro-1H-benzimidazole-2-yl)amine (7 f): Compound
6 f (239 mg,1.0 mmol) in THF (2 mL) was treated at À408C with PhMgCl
(1.20 g,25% in THF,2.2 mmol) for 15 min. After workup,the crude
product was purified by flash column chromatography (silica gel,ethyl
acetate/methanol 90:10). Compound 7 f was isolated as a red/orange solid
(129 mg,0.62 mmol,62%). M.p. 168 170 8C; 1H NMR (CDCl3,300 MHz):
d ˆ 10.13 (brs,1H),7.68 (d, J ˆ 8.4 Hz,1H),7.55 7.48 (m,1H),7.06 6.98
(m,1H),3.16 ppm (s,6H); 13C NMR (CDCl3,75 MHz): d ˆ 157.1,146.3,
128.9,121.1,120.2,113.7,37.9 ppm; IR (KBr):
nÄ ˆ 3398(m),1648(s),
1610(s),1583(m),1512(m),1433(m),1334(m),1297(m),1247(m),
128.2,127.6,127.5,115.3,113.4,111.4 ppm; IR (KBr):
nÄ ˆ 3432(m),
À1
‡
924(m),809(w),738(m),560 cm
(w); MS (EI): m/z (%): 206 [M]
1618(m),1570(m),1447(m),1397(m),1286(m),946(m),842(m),
(100),191 (39),189 (30),177 (33),159 (71),144 (24),130 (14),119 (12);
À1
‡
751(m),691(m),583 cm
(m); MS (EI): m/z (%): 354/352/350 [M] (50/
‡
HRMS (EI) calcd for C9H10N4O2: 206.0804; found: 206.0811 [M] .
100/51),192 (19); HRMS (EI) calcd for C 13H8Br2N2: 349.9054; found:
‡
349.8982 [M] .
6-(4-Methoxyphenyl)-N,N-dimethyl-4-nitro-1H-benzimidazol-2-ylamine
(7g): Compound 6g (172 mg,0.5 mmol) in THF (1 mL) was treated at
À408C with PhMgCl (0.60 g,25% in THF,1.1 mmol) for 15 min. After
workup,the crude product was purified by flash column chromatography
(silica gel,ethyl acetate). Compound 7g was isolated as a red/orange solid
(137 mg,0.44 mmol,87%). M.p. 179 180 8C; 1H NMR (CDCl3,300 MHz):
Ethyl 4-bromo-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (10a):
Compound 11a (406 mg,1.0 mmol) in THF (1 mL) was treated at À408C
with PhMgCl (1.9m in THF,1.1 mL,2.1 mmol) for 30 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (pentane/ethyl acetate 80:20 to 50:50). Compound 10a
was isolated as a yellow solid (285 mg,0.76 mmol,76%). M.p. 230 8C;
1H NMR ([D5]pyridine,300 MHz),: d ˆ 8.30 (s,2H),8.01 (d, J ˆ 8.8 Hz,
2H),7.18 7.16 (m,1H),7.10 (d, J ˆ 8.8 Hz,2H),4.33 (q, J ˆ 7.1 Hz,2H),
d ˆ 7.99 (s,1H),7.75 (s,1H),7.60 (d,
J ˆ 8.7 Hz,2H),7.04 (d, J ˆ 8.7 Hz,
2H),3.87 (s,3H),3.27 ppm (s,6H); 13C NMR (CDCl3,75 MHz): d ˆ 161.1,
156.1,146.3,141.0,139.9,139.0,136.1,129.8,120.2,112.4,110.8,55.3,
3.70 (s,3H),1.22 ppm (t,
J ˆ 7.1 Hz,3H); 13C NMR ([D5]pyridine,
37.8 ppm; IR (KBr): nÄ ˆ 3400(m),2934(m),1651(m),1610(s),1513(s),
1430(m),1304(m),1246(s),1179(m),1037(m),922(m),830(m),762(w),
75 MHz): d ˆ 166.5,160.6,143.7,137.4,134.1,127.9,124.8,124.7,123.7,
‡
558 cmÀ1 (m); MS (EI): m/z (%): 312 [M] (100),297 (29),283 (20),265
115.0,113.6,113.0,99.3,61.0,55.3,14.4 ppm; IR (KBr):
nÄ ˆ 3346(s),
(19),250 (25),207 (81); HRMS (EI) calcd for C 16H16N4O3: 312.1222; found:
2985(w),2837(w),1690(s),1610(s),1566(m),1543(m),1495(s),1440(m),
1368(m),1311(s),1254(s),1228(s),1180(s),1096(w),1026(m),980(w),
878(w),832(m),794(m),766(m),598 cm À1 (m); MS (EI): m/z (%): 375/373
(100/97),347/345 (37/35),330 (42),302 (17),221(8),206 (12); HRMS (EI)
‡
312.1235 [M] .
Ethyl 2-(dimethylamino)-4-[4-(ethoxycarbonyl)phenyl]-1H-benzimidaz-
ole-6-carboxylate (7i): Compound 6i (207 mg,0.5 mmol) in THF (2 mL)
was treated at À408C with PhMgCl (617 mg,25% in THF,1.1 mmol).
After 30 min the reaction mixture was quenched by the addition of
methanol (0.5 mL),poured into water,and extracted with ethyl acetate
(4 Â 20 mL). The combined organics were washed with brine (20 mL),
dried over Na2SO4,filtered,and concentrated in vacuo. The crude product
was purified by flash column chromatography (silica gel,pentane/ethyl
acetate 75:25). Compound 7i was isolated as a white solid (107 mg,
0.28 mmol,56%). M.p. 223 224 8C; 1H NMR ([D6]DMSO,300 MHz): d ˆ
8.27 (d, J ˆ 8.1 Hz,2H),8.04 (d, J ˆ 8.1 Hz,2H),7.96 (d, J ˆ 1.3 Hz,1H),
‡
calcd for C18H16BrNO3: 373.0314; found: 373.0292 [M] ; elemental analysis
calcd (%) for C18H16BrNO3 (374.23): C 57.77,H 4.31,N 3.74; found: C:
57.74,H 4.28,N 3.72.
Ethyl 4-bromo-2-(3-pyridinyl)-1H-indole-6-carboxylate (10b): Compound
11b (195 mg,0.52 mmol) in THF (1 mL) was treated at À408C with
PhMgCl (1.9m in THF,0.77 mL,1.47 mmol) for 30 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (pentane/ethyl acetate 80:20 to 50:50). Compound 10b
was isolated as a yellow solid (124 mg,0.36 mmol,70%). M.p. 264 8C;
5330
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9,5323 5331

Functionalized Heterocycles
5323 5331
1H NMR ([D5]pyridine,300 MHz): d ˆ 13.03 (brs,1H),9.35 (s,1H),8.68
8.62 (m,1H),8.27 8.21 (m,2H),8.20 8.14 (m,1H),7.34 7.26 (m,1H),
7.15 (s,1H),4.34 (q, J ˆ 7.1 Hz,2H),1.24 ppm (t, J ˆ 7.1 Hz,3H); 13C NMR
([D5]pyridine,75 MHz): d ˆ 166.4,148.1,140.4,138.0,133.8,133.4,128.4,
Acknowledgements
We thank the DFG (Leibniz program) and the Fonds der Chemischen
Industrie for financial support. We thank Chemetall GmbH (Frankfurt),
Degussa AG (Hanau),and BASF AG for the generous gifts of chemicals.
W.D. was supported by the BMBF program (03 D00562) and BASF AG.
126.3,124.1,114.4,113.5,101.7,89.2,61.2,14.5 ppm; IR (KBr):
nÄ ˆ 3350(w),
2984(w),1701(m),1567(w),1366(w),1315(m),1279(w),1230(m),
À1
1094(w),1024(w),790(w),764 cm
(w); MS (EI): m/z (%): 346/344 (99/
100),318/316 (30/32),301/299 (46/44),273/271 (14/15),192 (31),164 (8);
‡
HRMS (EI) calcd for C16H13BrN2O3: 344.0160; found: 344.0151 [M] .
Ethyl 4-bromo-2-phenyl-1H-indole-6-carboxylate (10c): Compound 11c
(282 mg,0.75 mmol) in THF (1 mL) was treated at À408C with PhMgCl
(1.9m in THF,1.21 mL,1.58 mmol) for 30 min as described in procedure E.
After workup,the crude product was purified by flash column chromatog-
raphy (pentane/ethyl acetate 90:10 to 75:25). Compound 10c was isolated
as a yellow solid (194 mg,0.57 mmol,75%). M.p. 216 8C; 1H NMR (CDCl3/
[D6]DMSO,300 MHz): d ˆ 11.39 (brs,1H),7.76 7.73 (m,1H),7.52 7.45
(m,3H),7.09 (tm, J ˆ 7.4 Hz,2H),6.99 (tm, J ˆ 7.4 Hz,1H),6.48 6.45 (m,
[1] For an overview see: M. Balasubramanian,J. G. Keay, Comp.
Heterocycl. Chem. II, 1996, 5,245 300.
[2] I. Sapountzis,P. Knochel, J. Am. Chem. Soc. 2002, 124,9390 9391.
[3] a) H. Wieland, Chem. Ber. 1903, 36,2315 2319; b) H. Gilman,R.
McCracken, J. Am. Chem. Soc. 1927, 49,1052 1061; c) T. Severin,R.
Schmitz, Chem. Ber. 1963, 96,3081 3084; d) T. Severin,M. Adam,
Chem. Ber. 1964, 97,186 189; for an excellent review,see: e) G.
Bartoli, Acc. Chem. Res. 1984, 17,109 115; f) G. Bartoli,M. Bosco,G.
Cantagalli,R. Dalpozzo,F. Ciminale, J. Chem. Soc. Perkin Trans. 2
1985,773 779.
[4] G. Koebrich,P. Buck, Chem. Ber. 1970, 103,1412 1419.
[5] a) I. Sapountzis,P. Knochel, Angew. Chem. 2002,114,1680 1681;
Angew. Chem. Int. Ed. 2002, 41,1610 1611; b) C. E. Tucker,T. N.
Majid,P. Knochel, J. Am. Chem. Soc. 1992, 114,3983 3985; c) J. F.
1H),4.00 (q, J ˆ 7.4 Hz,2H),1.05 ppm (t,
J ˆ 7.4 Hz,3H); 13C NMR
(CDCl3/[D6]DMSO,75 MHz): d ˆ 165.4,141.3,135.7,132.0,130.5,128.0,
127.6,124.9,123.3,122.1,112.2,112.1,98.3,59.9,13.5 ppm; IR (KBr):
3328(m),2977(w),1692(m),1618(w),1566(w),1487(w),1367(m),
1316(m),1276(m),1231(s),1177(w),1027(w),877(w),762(m),734(w),
nÄ ˆ
691 cmÀ1 (w); MS (EI): m/z (%): 345/343 (97/100),317/315 (38/40),300/298
(44/46),272/270 (16/14),207 (25),192 (10),191 (41),190 (38),177 (36),163
(16),96 (10); HRMS (EI) calcd for C 17H14NO2: 343.0208; found: 343.0180
√
Cameron,J. M. J. Fre chet, J. Am. Chem. Soc. 1991, 113,4303 4313.
[6] a) D. M. Lindsay,W. Dohle,A. E. Jensen,F. Kopp,P. Knochel, Org.
‡
[M] ; elemental analysis calcd (%) for C17H14NO2 (264.31): C 59.32,H 4.10,
Lett. 2002, 4,1819 1822; b) G. Varchi,A. E. Jensen,P. Knochel,
Synlett 2001,477 480.
N 4.07; found: C 59.61,H 4.21,N 4.05.
[7] W.-W. Sy, Synth. Commun. 1992, 22,3215 3219.
[8] D. Toste,J. McNulty,I. W. J. Still, Synth. Commun. 1994, 24,1617
1624.
Ethyl 2-(4-methoxyphenyl)-4-nitro-1H-indole-6-carboxylate (10d): Com-
pound 11d (372 mg,1.0 mmol) in THF (2 mL) was treated at À408C with
PhMgCl (1.9m in THF,1.11 mL,2.1 mmol) for 30 min as described in
procedure E. After workup,the crude product was purified by flash column
chromatography (pentane/ethyl acetate 75:25). Compound 10d was
isolated as a yellow solid (190 mg,0.56 mmol,56%). M.p. 245 246 8C;
1H NMR (CDCl3/[D6]DMSO,300 MHz): d ˆ 11.73 (brs,1H),8.65 (s,1H),
8.28 8.22 (m,1H),7.77 7.71 (m,2H),7.40 7.34 (m,1H),6.94 6.86 (m,
[9] a) J. Tsuji, Palladium Reagents and Catalysts,Wiley,New York, 1995;
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Pure Appl. Chem. 1980, 52,669 679.
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Synthesis 1999,2065 2070; b) B. G. Tiemann,S. R. Marder,J. W.
Perry,L.-T. Cheng, Chem. Mater. 1990, 2,690 695; c) J. S. Splitter,M.
Calvin, J. Org. Chem. 1955, 20,1086 1115; d) H. B. Nisbet, J. Chem.
Soc. 1927,2081 2086; e) P. Pfeiffer, Chem. Ber. 1915, 48,1777 1809;
f) F. Ullmann,M. Gschwind, Chem. Ber. 1908, 41,2291 2297; g) P.
Pfeiffer,J. Monath, Chem. Ber. 1906, 39,1304 1306.
[11] a) J. I. G. Cadogan,M. J. Todd, J. Chem. Soc. Chem. Commun. 1967,
178 179; b) J. I. G. Cadogan,M. J. Todd, J. Chem. Soc. C 1969,2808
2813; c) J. I. G. Cadogan,A. Cooper, J. Chem. Soc. B 1969,883 885;
d) J. I. G. Cadogan,S. Kulik, J. Chem. Soc. Chem. Commun. 1970,233;
e) J. I. G. Cadogan,S. Kulik, J. Chem. Soc. C 1971,2612 2632.
[12] a) T. Kametani,K. Ogasawara,T. Yamanaka, J. Chem. Soc. C 1969,
138 140; b) S. Togashi,J. G. Fulcher,B. R. Cho,M. Hasegawa,J. A.
Gladysz, J. Org. Chem. 1980, 45,3044 3053; c) G. Smolinsky,B. I.
Feuer, J. Org. Chem. 1966, 31,3882 3884; d) R. Garner,G. V. Garner,
H. Suschitzky, J. Chem. Soc. C 1970,825 829; e) H. Suschitzky,K. E.
Chippendale,B. Iddon, J. Chem. Soc. Chem. Commun. 1971,203 204;
f) Y. Maki,T. Hosokami,M. Suzuki, Tetrahedron Lett. 1971, 38,3509;
g) T. Kametani,K. Nyu,T. Yamanaka,S. Takano, J. Heterocycl. Chem.
1971, 8,1071 1073; h) F. R. Atherton,R. W. Lambert, J. Chem. Soc.
Perkin Trans. 1 1973,1079 1084; i) T. Kametani,F. F. Ebetino,K.
Fukumoto, J. Chem. Soc. Perkin Trans. 1 1974,861 863; j) Y.
Tsunashima,M. Kuroki, J. Heterocycl. Chem. 1981, 18,315 318.
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162 179; b) S. S. Naim,S. K. Singh,S. Sharma,S. Grupta,N. Fatma,
R. K. Chatterjee,J. C. Katiyar, Indian J. Chem. Sect. B 1988, 27,1106
1109.
2H),4.34 (q, J ˆ 7.1 Hz,2H),3.84 (s,3H),1.24 ppm (t,
J ˆ 7.1 Hz,3H);
13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 165.6,160.5,146.2,138.8,
138.2,131.5,127.5,126.1,123.0,121.5,118.4,114.1,98.6,60.8,55.0,14.0 ppm;
IR (KBr): nÄ ˆ 3351(m),2982(w),1712(m),1688(s),1630(m),1609(s),
1501(s),1484(s),1369(m),1332(s),1256(vs),1182(s),1028(m),835(w),
798 cmÀ1 (w); MS (EI): m/z (%): 340 (3),322 (100),250 (18),236 (8);
‡
HRMS (EI) calcd for C18H16N2O5: 340.1059; found: 340.1072 [M] ;
elemental analysis calcd (%) for C18H16N2O5 (340.33): C 63.52,H 4.74,N
8.23; found: C 63.41,H 4.64,N 8.31.
4-Nitro-2-phenyl-1H-indole (10e):[10a] Compound 11e (242 mg,0.9 mmol)
in THF (2 mL) was treated at À408C with PhMgCl (1.9m in THF,1.0 mL,
1.9 mmol) for 30 min as described in procedure E. After workup,the crude
product was purified by flash column chromatography (pentane/ethyl
acetate 80:20). Compound 10e was isolated as an orange solid (129 mg,
0.54 mmol,60%); 1H NMR (CDCl3/[D6]DMSO,300 MHz): d ˆ 11.59 (brs,
1H),8.00 (d, J ˆ 8.1 Hz,1H),7.84 7.80 (m,2H),7.69 (d,
J ˆ 8.4 Hz,1H),
J ˆ 8.1 Hz,1H);
7.48 7.37 (m,3H),7.34 7.27 (m,1H),7.12 ppm (t,
13C NMR (CDCl3/[D6]DMSO,75 MHz): d ˆ 142.4,139.1,138.9,130.8,
128.3,128.0,125.3,122.6,119.5,117.6,116.7,98.6 ppm.
9H-Carbazole (15):[15] 2-Nitrobiphenyl 14 (199 mg,1.0 mmol) was treated
with phenylmagnesium chloride (0.67m in THF,3.15 mL,2.1 mmol) as
described in procedure E. The reaction mixture was quenched by the
addition of methanol (0.5 mL). The solvent was removed,and the residue
was dissolved in ethyl acetate and poured into saturated NH4Cl solution
(25 mL). Water (25 mL) was added,and the aqueous layer was extracted
with ethyl acetate (2 Â 50 mL). The combined organics were washed with
brine,dried over MgSO 4,filtered,and concentrated in vacuo. The crude
product was purified by flash column chromatography (pentane/diethyl
etherˆ 85:15). Compound 15 was isolated as a white,crystalline solid
(41 mg,0.24 mmol,24%). 1H NMR (CDCl3,300 MHz): d ˆ 8.12 (d, J ˆ
7.7 Hz,2H),7.51 (d, J ˆ 8.0 Hz,2H),7.39 (dd, J ˆ 8.0,7.2 Hz,2H),7.20 ppm
[14] a) M. S. Gin,T. Yokozawa,R. B. Prince,J. S. Moore,
J. Am. Chem.
Soc. 1999, 121,2643 2644; b) A. R. Leed,S. D. Boettger,B. Ganem, J.
Org. Chem. 1980, 45,1098 1106.
[15] R. B. Miller,S. C. Farmer, Molecules 2001, 6,668 672.
(dd, J ˆ 7.7,7.2 Hz,2 H) ;
13C NMR (CDCl3,75 MHz): d ˆ 139.6,125.2,
122.8,120.1,118.6,110.9 ppm.
Received: April 30,2003 [F5090]
Chem. Eur. J. 2003, 9,5323 5331
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
5331