Efficient preparation of polyfunctional indoles via a zinc organometallic variation of the Fischer indole synthesis

Article abstract of DOI:10.1055/s-0030-1258348

Functionalized organozinc reagents readily react with various aryldiazonium salts furnishing regioselectively polyfunctional indoles after heating with microwave irradiation. This new organometallic variation of the Fischer indole synthesis tolerates a wide range of functional groups and can be readily scaled up. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258348

PRACTICAL SYNTHETIC PROCEDURES
23
Efficient Preparation of Polyfunctional Indoles via a Zinc Organometallic
Variation of the Fischer Indole Synthesis
Zinc
O
rganome
h
tallic
V
ariati
i
on of th
-
e
Fische
G
r
Indole Synthesisuang Zhang,a,b Benjamin A. Haag,a Jin-Shan Li,b Paul Knochel*a
a
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
b
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P. R. of China
Received 28 October 2010; revised 11 November 2010
PSP
No198
Abstract: Functionalized organozinc reagents readily react with various aryldiazonium salts furnishing regioselectively polyfunctional in-
doles after heating with microwave irradiation. This new organometallic variation of the Fischer indole synthesis tolerates a wide range of
functional groups and can be readily scaled up.
Key words: organozinc reagents, indoles, regioselectivity, Fischer indole synthesis, N-heterocycles
MeO
procedure 1:
EtO2C
CO2Et
N2
BF4
MeO
Zn (2 equiv)
NO2
4a (1.25 equiv)
LiCl (1.1 equiv)
Br
EtO2C
ZnBr⋅LiCl
N
ZnBr2 (2 equiv)
–60 to 25 °C;
then Me3SiCl (1 equiv)
125 °C, 90 min
THF, 50 °C, 1 h
H
NO2
2a (10 mmol scale)
1a: 90%
3a
microwave irradiation
MeCO
procedure 2:
Li
O
N2
BF4
4b (1.25 equiv)
–60 to 25 °C;
ZnBr⋅LiCl
2b (10 mmol scale)
ZnBr⋅LiCl
ZnBr2 (3 equiv)
THF, 25 °C, 10 min
N
H
then Me3SiCl (1 equiv)
125 °C, 90 min
microwave irradiation
1b: 80%
3b
procedure 3:
Br
PivO
Mg (1.6 equiv)
LiCl (1.1 equiv)
ZnBr2 (1 equiv)
N2
BF4
4c (1.25 equiv)
ZnBr2 (2 equiv)
PivO
THF, 25 °C, 4 h
N
H
–60 to 25 °C;
then Me3SiCl (1 equiv)
125 °C, 90 min
1c: 72%
2c (10 mmol scale)
3c
microwave irradiation
Scheme 1
mixtures are often obtained.2 Recently, we have reported
a new strategy for the regioselective preparation of
Introduction
Polyfunctional indoles are privileged structures in drug polysubstituted indoles of type 1 from functionalized pri-
discovery and are present in numerous natural products.1 mary or secondary alkylzinc reagents of type 2. This orga-
The direct synthesis of polysubstituted indole derivatives nometallic variation of the Fischer indole synthesis
has proven to be highly challenging due to the need of tolerates
a broad spectrum of functional groups
harsh and acidic reaction conditions (Fischer indole syn- (Scheme 1, Procedures 1–3).5,6 Due to the good availabil-
thesis)2,3 or expensive transition metal catalysis.4 More- ity of functionalized organozincs,7,8 the efficiency, and
over, by means of classical approaches, regioisomeric practicability of the reaction, large-scale procedures
should be possible. We report herein our efforts to prepare
various polyfunctional indole derivatives in 10–20 mmol
SYNTHESIS 2011, No. 1, pp 0023–0029
Advanced online publication: 03.12.2010
DOI: 10.1055/s-0030-1258348; Art ID: T21110SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1
scale using this new method. Furthermore, we have ap-
plied the large-scale procedure to the preparation of the
antidepressant iprindole (6) (4 g scale).

24
Z.-G. Zhang et al.
PRACTICAL SYNTHETIC PROCEDURES
zinc reagent c-HexZnBr·LiCl (2e) added to readily avail-
able functionalized aryldiazonium tetrafluoroborates
Scope and Limitations
A variety of functionalized primary or secondary alkyl- (4a,b, 4d, 4f,g) and provided polyfunctional tetrahydro-
zinc bromides of type 2 are readily available via direct 1H-carbazoles 1k–o in 73–91% yields (Table 1, entries 9–
zinc insertion9 or direct magnesium insertion10 in the pres- 13). Besides microwave irradiation, conventional heating
ence of ZnBr2 from the corresponding alkyl bromides was also successfully used in the case of electron-rich
such as 3a or 3c or via transmetalation of s-BuLi with substrates; however, this required longer reaction time for
ZnBr2 such as 3b. Addition to aryldiazonium the cyclization step to form the corresponding indole de-
tetrafluoroborates11 of type 4 led to the polyfunctional in- rivatives.
doles of type 1 (Scheme 1).
As an application of this method, the pharmaceutical
Similarly, the secondary alkylzinc bromide 2d obtained iprindole,12 a tricyclic antidepressant, was prepared in a
after direct zinc insertion9 with the reagent 3d [Zn one-pot procedure on a 20 mmol scale. Thus, cyclooctyl-
(2 equiv), LiCl (1.1 equiv), ZnBr2 (2 equiv), 50 °C, 12 h] zinc bromide (2f) added smoothly to phenyldiazonium
added smoothly to a substituted aryldiazonium salt11 such tetrafluoroborate (4h) (–60 to 25 °C) leading after micro-
as 4d (–60 °C to 25 °C) providing the azo compound 5a. wave irradiation (125 °C, 30 min) in the presence of
After isomerization to the unsaturated hydrazine 5b, in- Me3SiCl (1 equiv) to the indole derivative 1p. Subsequent
duced by addition of Me3SiCl (1 equiv), heating by micro- N-alkylation of the intermediate 1p [t-BuOK (1.2 equiv),
wave irradiation (125 °C, 30 min) furnished 0 °C, 20 min; then Cl(CH2)3NMe2 (1.2 equiv), 125 °C, 3
regioselectively the polyfunctional indole 1d in 67% yield h] provided iprindole (6) in 72% yield (Scheme 3).
(Scheme 2). No regioisomer like the indole 1e was detect-
In summary, we have demonstrated an efficient and regio-
ed. The presence of additional ZnBr2 (2.0 equiv) proved to
selective preparation of polyfunctional indoles using
be essential to ensure a selective reaction with the diazo-
readily available functionalized primary and secondary
nium salt in the next reaction step. In the absence of
ZnBr2, double addition products to diazonium salts were
detected. The primary alkylzinc bromide 2a reacted with
ZnBr⋅LiCl
PhN2BF4
(4h, 1.25 equiv)
the aryldiazonium salt 4a (–60 to 25 °C) providing after
microwave irradiation [Me3SiCl (1 equiv), 125 °C, 90
–60 to 25 °C;
then
N
H
1p
min], the indole 1a in 90% yield (Table 1, entry 1). Fur-
thermore, the ester-substituted secondary alkylzinc bro-
mide 2d added to the aryldiazonium tetrafluoroborate 4c
furnishing under our standard conditions the 3-substituted
indole 1f in 63% yield (Table 1, entry 2). Similarly, s-
BuZnBr·LiCl added to various polyfunctional aryldiazo-
nium salts (4a,b and 4e,f) affording regioselectively the
functionalized 2,3-dimethylindole derivatives 1b and 1g–
i in 68–80% yield (Table 1, entries 3–6). Under the same
reaction conditions, cyclopentylzinc bromide (2c) and
substituted aryldiazonium salts such as 4a and 4c led to
the corresponding indoles 1j and 1c in 68 and 72% yield,
respectively (Table 1, entries 7, 8). The secondary alkyl-
Me3SiCl (1 equiv)
125 °C, 30 min
microwave irradiation
2f (20 mmol)
KOt-Bu (1.2 equiv)
0 °C, 20 min;
then Cl(CH2)3NMe2 (1.2 equiv)
125 °C, 3 h, microwave irradiation
N
6: 72%
iprindole
NMe2
Scheme 3
MeO
OMe
Zn (2 equiv)
LiCl (1.1 equiv)
ZnBr2 (2 equiv)
N2
BF4
CO2Et
Br
ZnBr·LiCl
4d (1.25 equiv)
EtO2C
EtO2C
2d (20 mmol)
–60 to 25 °C
50 °C, 12 h
N
3d
N
5a
OMe
CO2Et
MeO
CO2Et
MeO
CO2Et
Me3SiCl (1 equiv)
N
125 °C, 30 min
microwave irradiation
N
H
H
HN
N
1e (not detected)
1d: 67%
H
5b
Scheme 2
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zinc Organometallic Variation of the Fischer Indole Synthesis
25
Table 1 Preparation of Polyfunctional Indole Derivatives of Type 1 on a 10 mmol Scale
Entry
1
Alkylzinc reagent
Aryldiazonium salt
Product
Yield (%)a
CO2Et
MeO
MeO
EtO2C
ZnBr⋅LiCl
90
N2
BF4
N
H
2a
NO2
NO2
4a
1a
CO2Et
PivO
ZnBr⋅LiCl
PivO
2
63
EtO2C
N2
BF4
N
H
2d
4c
1f
R1
R1
ZnBr⋅LiCl
N2
N
BF4
H
R2
R2
3
4
5
6
2b
2b
2b
2b
4b R1 = COMe, R2 = H
4a R1 = OMe, R2 = NO2
4e R1 = F, R2 = H
1b
1g
1h
1i
80
80
68
80
4f R1 = Br, R2 = H
R1
R1
ZnBr⋅LiCl
N
H
N2
BF4
R2
R2
7
8
2c
2c
4a R1 = OMe, R2 = NO2
1j
68
72
4c R1 = OPiv, R2 = H
1c
R1
R1
ZnBr⋅LiCl
N2
N
H
BF4
R2
R2
9
10
11
12
13
2e
2e
2e
2e
2e
4a R1 = OMe, R2 = NO2
4b R1 = COMe, R2 = H
4d R1 = OMe, R2 = H
4f R1 = Br, R2 = H
1k
1l
91
73
80
80
80
1m
1n
1o
4g R1 = CN, R2 = H
a Isolated yield of analytically pure product as determined by 1H NMR spectroscopy.
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 otherwise
stated. The functionalized aryldiazonium tetrafluoroborates 4a–h
were prepared according to literature procedures.11 THF was con-
tinuously refluxed and freshly distilled from sodium benzophenone
ketyl under N2. The cyclization reaction induced by microwave ir-
radiation was performed in a Biotage Initiator Unit (Biotage,
Uppsala, Sweden) in a closed-vessel system. Flash column chroma-
tography was performed using Al2O3 from Merck (Al2O3 90 active,
activity grade II–III, 70–230 mesh ASTM). Yields refer to isolated
compounds estimated to be >95% pure as determined by 1H NMR
spectroscopy and capillary GC analysis.
alkylzinc reagents and substituted aryldiazonium salts.
During the new indole synthesis, a range of sensitive func-
tional groups such as nitro, ester, cyano, and keto groups
are well tolerated. As an application of this method, the
antidepressant iprindole was prepared on a four-gram
scale. We have extended the reaction scope and improved
the reaction conditions for the preparation of synthetically
interesting indoles. The reactions could be performed with
standard laboratory glassware and did not require the use
of expensive chemicals or catalysts.
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York

26
Z.-G. Zhang et al.
PRACTICAL SYNTHETIC PROCEDURES
Zinc Bromide Solution (1 M) in Tetrahydrofuran
MS (70 eV, EI): m/z (%) = 278 (M+, 29), 206 (11), 205 (100), 159
(17).
HRMS (EI): m/z [M]+ calcd for C13H14N2O5: 278.0903; found:
278.0895.
A dry, argon-flushed 1 L Schlenk flask, equipped with a magnetic
stirring bar and a septum was charged with ZnBr2 (113 g, 0.5 mol)
and heated to 150 °C for 5 h. After cooling to 25 °C under argon,
anhyd THF (500 mL) was added slowly and stirred continuously
until the salts had dissolved. The reagent ZnBr2 (1 M in THF) was
obtained as a colorless solution.
1-(2,3-Dimethyl-1H-indol-5-yl)ethanone (1b)
s-BuZnBr (2b; 10 mmol, 38.5 mL, 0.26 M in THF) was prepared via
addition of s-BuLi (3b, 10 mmol, 8.33 mL, 1.2 M in hexane) to a so-
lution of ZnBr2 (30 mmol, 30 mL, 1 M in THF) at 0 °C with contin-
uous stirring for 10 min. Following typical procedure 3, the
resulting alkylzinc reagent was reacted with 4-acetylbenzenediazo-
nium tetrafluoroborate (4b; 12.5 mmol, 2.92 g). The hydrazone in-
termediate was heated by microwave irradiation (125 °C, 30 min) in
the presence of Me3SiCl (1.08 g, 10 mmol). The crude product was
purified after the usual workup by flash column chromatography
(Al2O3; pentane–EtOAc–MeOH, 95:5:0.3) to give 1b as a pale yel-
low solid (1.49 g, 80%); mp 179.0–181.0 °C.
(4-Ethoxy-4-oxobutyl)zinc Bromide (2a); Typical Procedure 1
for Direct Zinc Insertion
A dry, argon-flushed Schlenk flask equipped with a magnetic stir-
ring bar and a septum was charged with Zn dust (2.54 g, 40 mmol)
and dry LiCl (dried in vacuo with a heat gun at 450 °C for 5 min;
933 mg, 22 mmol). After the addition of THF (10 mL), Zn dust was
activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%).
After stirring for 5 min, ethyl 4-bromobutanoate (3a; 3.9 g, 20
mmol) in THF (20 mL) was added at 25 °C to the suspension and
the reaction mixture was stirred for 1 h at 50 °C. The supernatant
solution was then cannulated into a new dry, argon-flushed Schlenk
flask and titrated against I2. The active alkylzinc reagent 2a was ob-
tained with a concentration of 0.74 M in THF.9
IR (ATR): 3286, 1654, 1612, 1578, 1458, 1356, 1264, 1232, 1142,
970, 898, 794, 692, 648 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.27 (br s, 1 H), 8.14 (s, 1 H), 7.77
(d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 2.67 (s, 3 H), 2.33 (s,
3 H), 2.25 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.7, 138.1, 132.4, 129.0, 129.0,
121.5, 119.9, 109.8, 108.7, 26.6, 11.5, 8.3.
MS (70 eV, EI): m/z (%) = 188 (16), 187 (M+, 87), 186 (20), 173
(14), 172 (100), 144 (51), 143 (20), 85 (13), 83 (12), 77 (14), 71
(27), 57 (36), 55 (23), 43 (32).
Cyclopentylzinc Bromide (2c); Typical Procedure 2 for Direct
Magnesium Insertion in the Presence of Zinc Bromide
A dry, argon-flushed Schlenk flask equipped with a magnetic stir-
ring bar and a septum was charged with Mg turnings (768 mg, 32
mmol) and LiCl (dried in vacuo with a heat gun at 450 °C for 5 min;
933 mg, 22 mmol). After the addition of THF (20 mL), the Mg was
activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%).
After stirring for 5 min, ZnBr2 (20 mmol, 20 mL, 1 M in THF) was
added to the mixture. Thereafter, the suspension was cooled to 0 °C,
cyclopentyl bromide (3c; 2.98 g, 20 mmol) in THF (20 mL) was
added, and the reaction mixture was stirred for 4 h at 25 °C. The su-
pernatant solution was then cannulated into a new dry, argon-
flushed Schlenk flask and titrated against I2. The active alkylzinc re-
agent 2c was obtained with a concentration of 0.36 M in THF.10
HRMS (EI): m/z [M]+ for C12H13NO: 187.0997; found: 187.0990.
1,2,3,4-Tetrahydrocyclopenta[b]indol-7-yl Pivalate (1c)
Following typical procedure 3, cyclopentylzinc bromide (2c; 10
mmol, 27.7 mL, 0.36 M in THF), prepared from cyclopentyl bro-
mide (3c) via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20
mmol, 20 mL, 1 M in THF), was reacted with 4-[(2,2-dimethylpro-
panoyl)oxy]benzenediazonium tetrafluoroborate (4c; 12.5 mmol,
3.64 g). The hydrazone intermediate was heated by microwave irra-
diation (125 °C, 60 min) in the presence of Me3SiCl (1.08 g, 10
mmol). The crude product was purified after the usual workup by
flash column chromatography (Al2O3; pentane–EtOAc–MeOH,
96:4:0.2) to give 1c as a white powder (1.86 g, 72%); mp 141.5–
142.9 °C.
Ethyl (5-Methoxy-7-nitro-1H-indol-3yl)acetate (1a); Typical
Procedure 3
In a flame-dried and argon-flushed Schlenk flask, a solution of 2a
(10 mmol, 13.5 mL, 0.74 M in THF) prepared via typical procedure
1 from ethyl 4-bromobutanoate (3a) was added dropwise to a solu-
tion of ZnBr2 (20 mmol, 20 mL, 1 M in THF) at 25 °C. After stirring
at 25 °C for 10 min, the organozinc reagent was transferred slowly
to a solution of 4-methoxy-2-nitrobenzenediazonium tetrafluorobo-
rate (4a; 3.34 g, 12.5 mmol) in THF (50 mL) at –60 °C. The reac-
tion mixture was allowed to slowly warm to 25 °C. Subsequently,
the solvent volume was reduced by half, Me3SiCl (1.08 g, 10 mmol)
was added, and the mixture was heated by microwave irradiation for
90 min at 125 °C. After the reaction mixture had cooled to 25 °C,
the resulting solution was diluted with Et2O (20 mL), and quenched
with brine (50 mL). The aqueous layer was extracted with EtOAc
(3 × 50 mL). The combined organic phases were dried (Na2SO4)
and concentrated in vacuo. Purification by flash column chromatog-
raphy (Al2O3; pentane–EtOAc–MeOH, 95:5:0.3) afforded 1a as a
red solid (2.50 g, 90%); mp 121.6–122.6 °C.
IR (ATR): 3392, 2950, 2851, 1730, 1623, 1580, 1475, 1461, 1162,
1137, 1112, 786, 625 cm–1.
1H NMR (300 MHz): d = 7.89 (br s, 1 H), 7.15 (d, J = 8.7 Hz, 1 H),
7.08 (d, J = 2.4 Hz, 1 H), 6.73 (dd, J = 5.7 Hz, 2.4 Hz, 1 H), 2.84–
2.75 (m, 4 H), 2.55–2.46 (m, 2 H), 1.40 (s, 9 H).
13C NMR (75 MHz): d = 178.15, 145.27, 144.51, 138.75, 124.94,
119.87, 113.98, 111.46, 110.51, 39.03, 28.59, 27.29, 25.86, 24.35.
MS (70 eV, EI): m/z (%) = 257 (M+, 32), 174 (14), 173 (100), 172
(42).
HRMS (EI): m/z [M]+ calcd for C16H19NO2: 257.1416; found:
257.1412.
IR (ATR): 3390, 2940, 2854, 1708, 1584, 1562, 1512, 1476, 1440,
1410, 1362, 1308, 1266, 1208, 1192, 1130, 1090, 1040, 1022, 948,
932, 842 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.65 (br s, 1 H), 7.77 (d, J = 2.3
Hz, 1 H), 7.51 (d, J = 2.1 Hz, 1 H), 7.35 (d, J = 1.7 Hz, 1 H), 4.19
(q, J = 7.0 Hz, 2 H), 3.92 (s, 3 H), 3.76 (s, 2 H), 1.28 (t, J = 7.0 Hz,
3 H).
Ethyl (5-Methoxy-2-methyl-1H-indol-3-yl)acetate (1d)
Following typical procedure 3, the alkylzinc reagent 2d (20 mmol,
22.2 mL, 0.90 M in THF), prepared from ethyl 4-bromopentanoate
(3d) via typical procedure 1 (25 °C, 12 h) using ZnBr2 (40 mmol, 40
mL, 1 M in THF), was reacted with 4-methoxybenzenediazonium
tetrafluoroborate (4d; 25 mmol, 5.55 g). The hydrazone intermedi-
ate was heated by microwave irradiation (125 °C, 90 min) in the
presence of Me3SiCl (2.17 g, 20 mmol). The crude product was pu-
rified after the usual workup by flash column chromatography
13C NMR (75 MHz, CDCl3): d = 171.3, 153.0, 132.4, 131.5, 126.4,
125.3, 112.2, 109.5, 106.5, 61.0, 56.4, 31.1, 14.2.
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zinc Organometallic Variation of the Fischer Indole Synthesis
27
(Al2O3; isohexane–EtOAc–MeOH, 96:4:0.3) to give 1d as a pale
yellow solid (3.35 g, 67%); mp 69.0–70.9 °C.
5-Fluoro-2,3-dimethyl-1H-indole (1h)
s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via
addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a so-
lution of ZnBr2 (30 mmol, 30 mL, 1 M in THF) at 0 °C with contin-
uous stirring for 10 min. The resulting alkylzinc reagent was reacted
according to typical procedure 3 with 4-fluorobenzenediazonium
tetrafluoroborate (4e; 12.5 mmol, 2.62 g). The hydrazone interme-
diate was heated by microwave irradiation (125 °C, 90 min). The
crude product was purified after the usual workup by flash column
chromatography (Al2O3; pentane–EtOAc–MeOH, 96:4:0.2) to give
1h as a pale yellow solid (1.11 g, 68%); mp 98.2–99.0 °C.
IR (ATR): 3314, 2976, 2924, 2832, 1708, 1588, 1486, 1454, 1370,
1320, 1264, 1216, 1172, 1124, 1102, 1030, 790, 686, 632 cm–1.
1H NMR (300 MHz): d = 7.81 (br s, 1 H), 7.10 (d, J = 8.6 Hz, 1 H),
7.00 (d, J = 2.2 Hz, 1 H), 6.76 (dd, J = 8.8, 2.4 Hz, 1 H), 4.12 (q,
J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 3.63 (s, 2 H), 2.35 (s, 3 H), 1.24 (t,
J = 7.1 Hz, 3 H).
13C NMR (75 MHz): d = 172.0, 154.1, 133.5, 130.1, 128.9, 110.9,
110.8, 104.5, 100.5, 60.6, 55.9, 30.6, 14.2, 11.7.
IR (ATR): 3408, 2916, 2862, 1628, 1586, 1482, 1442, 1386, 1288,
1228, 1184, 1130, 944, 792, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64 (br s, 1 H), 7.06–7.17 (m, 2
H), 6.83 (dd, J = 8.8, 2.6 Hz, 1 H), 2.35 (s, 3 H), 2.17 (s, 3 H).
MS (70 eV, EI): m/z (%) = 247 (27), 175 (10), 174 (100), 131 (7).
HRMS (EI): m/z [M]+ calcd for C14H17NO3: 247.1208; found:
247.1204.
13C NMR (75 MHz, CDCl3): d = 157.7 (d, J = 233.4 Hz), 132.7,
131.5, 129.9 (d, J = 9.5 Hz), 110.4 (d, J = 9.8 Hz), 108.8 (d,
J = 26.1 Hz), 107.5, 103.0 (d, J = 23.3 Hz), 11.6, 8.4.
MS (70 eV, EI): m/z (%) = 163 (M+, 18), 162 (24), 148 (15), 71 (54),
70 (18), 57 (75), 65 (38), 55 (26), 44 (32), 43 (100).
HRMS (EI): m/z [M]+ calcd for C10H10FN: 163.0797; found:
163.0796.
3-(2-Ethoxy-2-oxoethyl)-2-methyl-1H-indol-5-yl Pivalate (1f)
Following typical procedure 3, the zinc reagent 2d (10 mmol, 11.1
mL, 0.90 M in THF), prepared from ethyl 4-bromopentanoate (3d)
via typical procedure 1 (50 °C, 12 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4c (12.5 mmol, 3.65 g). The hydra-
zone intermediate was heated by microwave irradiation (125 °C, 1
h) in the presence of Me3SiCl (1.08 g, 10 mmol). The crude product
was purified after the usual workup by flash column chromatogra-
phy (Al2O3; pentane–EtOAc–MeOH, 90:10:0.5) to give 1f as a pale
yellow solid (2.00 g, 63%); >250 °C (dec.).
5-Bromo-2,3-dimethyl-1H-indole (1i)
s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via
addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a so-
lution of ZnBr2 (30 mmol, 30 mL, 1 M in THF) at 0 °C with contin-
uous stirring for 10 min. The resulting alkylzinc reagent reacted
according to typical procedure 3 with 4-bromobenzenediazonium
tetrafluoroborate (4f; 12.5 mmol, 3.38 g). The hydrazone interme-
diate was heated by microwave irradiation (125 °C, 90 min). The
crude product was purified after the usual workup by flash column
chromatography (Al2O3; isohexane–EtOAc–MeOH, 95:5:0.5) to
give 1i as a pale yellow solid (1.79 g, 80%); mp 152.6–154.1 °C.
IR (ATR): 3372, 2976, 2936, 1728, 1590, 1480, 1458, 1368, 1278,
1170, 1122, 1030, 900, 786 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.17 (br s, 1 H), 7.14 (s, 1 H), 6.92
(d, J = 8.6 Hz, 1 H), 6.68 (d, J = 8.6 Hz, 1 H), 4.11 (q, J = 7.1 Hz,
2 H), 3.59 (s, 2 H), 2.22 (s, 3 H), 1.39 (s, 9 H), 1.22 (t, J = 7.1 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 178.2, 172.0, 144.4, 134.3, 132.8,
128.6, 114.6, 110.6, 109.8, 104.3, 60.6, 38.9, 30.4, 27.2, 14.1, 11.4.
MS (70 eV, EI): m/z (%) = 317 (M+, 24), 244 (15), 233 (32), 161 (9),
160 (100), 159 (10), 131 (6), 57 (18).
IR (ATR): 3396, 2914, 1572, 1466, 1426, 1386, 1302, 1274, 1238,
1044, 1002, 966, 898, 864, 798, 744, 668 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62 (br s, 1 H), 7.59 (d, J = 1.7
Hz, 1 H), 7.19 (dd, J = 8.6, 1.7 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H),
2.33 (s, 3 H), 2.18 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 133.7, 132.2, 131.2, 123.4, 120.5,
112.2, 111.4, 106.9, 11.5, 8.3.
MS (70 eV, EI): m/z (%) = 226 (24), 225 (M+, 65), 224 (95), 223
(M+, 81), 222 (69), 210 (42), 208 (45), 143 (62), 115 (26), 89 (17),
75 (22), 71 (56), 57 (42), 44 (32), 43 (100).
HRMS (EI): m/z [M]+ calcd for C10H1079BrN: 222.9997; found:
222.9974.
HRMS (EI): m/z [M]+ calcd for C18H23NO4: 317.1627; found:
317.1622.
5-Methoxy-2,3-dimethyl-7-nitro-1H-indole (1g)
s-BuZnBr (2b; 10 mmol, 38.6 mL, 0.26 M in THF) was prepared via
the addition of s-BuLi (3b, 10 mmol, 8.3 mL, 1.2 M in hexane) to a
solution of ZnBr2 (30 mmol, 30 mL, 1 M in THF) at 0 °C with con-
tinuous stirring for 10 min. The resulting alkylzinc reagent was re-
acted, according to typical procedure 3, with 4a (12.5 mmol, 3.33
g). The hydrazone intermediate was heated by microwave irradia-
tion (125 °C, 2 h). The crude product was purified after the usual
workup by flash column chromatography (Al2O3; pentane–EtOAc–
MeOH, 96:4:0.5) to give 1g as a red solid (1.77 g, 80%); mp 153.0–
154.0 °C.
7-Methoxy-5-nitro-1,2,3,4-tetrahydrocyclopenta[b]indole (1j)
Following typical procedure 3, cyclopentylzinc bromide (2c; 10
mmol, 27.7 mL, 0.36 M in THF), prepared from cyclopentyl bro-
mide (3c) via typical procedure 1 (25 °C, 4 h) using ZnBr2 (20
mmol, 20 mL, 1 M in THF), was reacted with 4a (12.5 mmol,
3.33 g). The hydrazone intermediate was heated by microwave irra-
diation (125 °C, 90 min) in the presence of Me3SiCl (1.08 g, 10
mmol). The crude product was purified after the usual workup by
flash column chromatography (Al2O3; pentane–EtOAc–MeOH,
96:4:0.2) to give 1j as a red solid (1.56 g, 68%); mp 138.0–
139.0 °C.
IR (ATR): 3420, 3370, 3110, 3024, 2914, 2836, 1604, 1576, 1502,
1474, 1458, 1388, 1364, 1330, 1288, 1192, 1178, 1140, 1082, 1044,
966, 878, 834, 756, 700, 606 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.25 (br s, 1 H), 7.61 (d, J = 2.2
Hz, 1 H), 7.30 (d, J = 2.2 Hz, 1 H), 3.89 (s, 3 H), 2.39 (s, 3 H), 2.19
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 152.6, 134.8, 133.8, 131.3, 124.8,
111.8, 107.9, 103.9, 56.4, 11.6, 8.3.
MS (70 eV, EI): m/z (%) = 221 (13), 220 (M+, 100), 219 (20), 205
(24), 174 (17), 159 (39), 131 (14), 130 (10).
IR (ATR): 3472, 2960, 2932, 2856, 1570, 1510, 1464, 1372, 1326,
1274, 1194, 1178, 1154, 1088, 1032, 836, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.45 (br s, 1 H), 7.61 (d, J = 2.2
Hz, 1 H), 7.27 (d, J = 2.1 Hz, 1 H), 3.88 (s, 3 H), 2.85–2.99 (m, 2
H), 2.72–2.85 (m, 2 H), 2.46–2.69 (m, 2 H).
HRMS (EI): m/z [M]+ calcd for C11H12N2O3: 220.0848; found:
220.0834.
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York

28
Z.-G. Zhang et al.
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (75 MHz, CDCl3): d = 152.8, 147.8, 132.0, 130.0, 128.6,
1H NMR (200 MHz, CDCl3): d = 7.56 (br s, 1 H), 7.15 (d, J = 8.6
Hz, 1 H), 6.95 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.6 Hz, 2.4 Hz, 1
H), 3.87 (s, 3 H), 2.73–2.69 (m, 4 H), 2.67–1.89 (m, 4 H).
120.4, 112.1, 103.7, 56.4, 28.7, 25.9, 24.1.
MS (70 eV, EI): m/z (%) = 233 (14), 232 (M+, 100), 231 (38), 186
(14), 185 (11), 171 (18), 143 (9).
HRMS (EI): m/z [M]+ calcd for C12H12N2O3: 232.0848; found:
232.0864.
6-Bromo-2,3,4,9-tetrahydro-1H-carbazole (1n)
Following typical procedure 3, cyclohexylzinc bromide (2e; 10
mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4f (12.5 mmol, 3.38 g). The hydra-
zone intermediate was heated by microwave irradiation (125 °C, 30
min) in the presence of Me3SiCl (1.08 g, 10 mmol). The crude prod-
uct was purified after the usual workup by flash column chromatog-
raphy (Al2O3; isohexane–EtOAc–MeOH, 95:5:0.5) to give 1n as a
pale yellow solid (2.00 g, 80%); mp 152.6–154.1 °C.
6-Methoxy-8-nitro-2,3,4,9-tetrahydro-1H-carbazole (1k)
Following typical procedure 3, cyclohexylzinc bromide (2e; 10
mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4a (12.5 mmol, 3.33 g). The hydra-
zone intermediate was heated by microwave irradiation (125 °C, 30
min) in the presence of Me3SiCl (1.08 g, 10 mmol). The crude prod-
uct was purified after the usual workup by flash column chromatog-
raphy (Al2O3; pentane–EtOAc–MeOH, 95:4:0.5) to give 1k as a red
solid (2.25 g, 91%); mp 137.1–138.6 °C.
IR (ATR): 3400, 2938, 2906, 2848, 1578, 1434, 1310, 1232, 1046,
974, 862, 796 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.63 (br s, 1 H), 7.58 (d, J = 1.8
Hz, 1 H), 7.19 (dd, J = 8.4 Hz, 1.8 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1
H), 2.73–2.64 (m, 4 H), 1.95–1.84 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 135.60, 134.26, 129.68, 123.59,
120.42, 112.32, 111.71, 110.01, 23.22, 23.14, 23.06, 20.76.
MS (70 eV, EI): m/z (%) = 252 (10), 251 (M+, 76), 250 (26), 249
(M+, 81), 248 (16), 224 (12), 223 (98), 221 (100), 168 (19), 167
(15), 142 (11), 115 (12).
IR (ATR): 3424, 2934, 2844, 1734, 1604, 1574, 1508, 1466, 1440,
1382, 1278, 1194, 1134, 1036, 834, 758, 648, 606 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.27 (br s, 1 H), 7.62 (d, J = 2.1
Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 3.89 (s, 3 H), 2.77 (t, J = 5.9 Hz,
2 H), 2.65 (t, J = 5.9 Hz, 2 H), 1.89–2.00 (m, 2 H), 1.80–1.89 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 152.7, 138.1, 132.3, 131.5, 125.3,
111.7, 110.9, 103.9, 56.4, 23.2, 22.9, 22.8, 20.6.
HRMS (EI): m/z [M]+ calcd for C12H1279BrN: 249.0153; found:
249.0137.
MS (70 eV, EI): m/z (%) = 246 (10), 247 (M+, 78), 245 (11), 219
(11), 218 (100), 203 (8).
HRMS (EI): m/z [M]+ calcd for C13H14N2O3: 246.1004; found:
246.0997.
2,3,4,9-Tetrahydro-1H-carbazole-6-carbonitrile (1o)
Following typical procedure 3, cyclohexylzinc bromide (2e; 10
mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4-cyanobenzenediazonium tetrafluo-
roborate (4g; 12.5 mmol, 2.71 g). The hydrazone intermediate was
heated by microwave irradiation (125 °C, 30 min) in the presence of
Me3SiCl (1.08 g, 10 mmol). The crude product was purified after
the usual workup by flash column chromatography (Al2O3; isohex-
ane–EtOAc–MeOH, 95:6:1) to give 1o as a pale yellow solid (1.56
g, 80%); mp 124.0–125.0 °C.
1-(2,3,4,9-Tetrahydro-1H-carbazol-6-yl)ethanone (1l)
Following typical procedure 3, cyclohexylzinc bromide (2e; 10
mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4b (12.5 mmol, 3.33 g). The hydra-
zone intermediate was heated by microwave irradiation (125 °C, 30
min) in the presence of Me3SiCl (1.08 g, 10 mmol). The crude prod-
uct was purified after the usual workup by flash column chromatog-
raphy (Al2O3; pentane–EtOAc–MeOH, 90:10:0.5) to give 1l as a
pale yellow solid (1.56 g, 73%); mp 122.5–124.0 °C.
IR (ATR): 3314, 2926, 2846, 2216, 1686, 1622, 1478, 1318, 1236,
1180, 872, 806, 798, 626 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.13 (br s, 1 H), 7.76 (s, 1 H),
7.19–7.49 (m, 2 H), 2.74 (t, J = 5.7 Hz, 2 H), 2.67 (t, J = 5.8 Hz, 2
H), 1.75–2.03 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 137.4, 136.6, 127.7, 124.1, 123.1,
121.2, 111.0, 111.0, 101.7, 23.1, 22.9, 22.8, 20.6.
MS (70 eV, EI): m/z (%) = 197 (11), 196 (M+, 79), 195 (17), 169
(12), 168 (100).
HRMS (EI): m/z [M]+ calcd for C13H12N2: 196.1000; found:
196.0997.
IR (ATR): 3286, 2926, 2854, 1652, 1614, 1578, 1460, 1354, 1232,
1122, 812, 798, 686, 648 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (s, 1 H), 8.09 (br s, 1 H), 7.78
(d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1 H), 2.73 (t, J = 5.9 Hz, 4
H), 2.65 (s, 3 H), 1.78–2.01 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 198.5, 138.5, 135.8, 129.2, 127.5,
121.7, 119.7, 111.8, 110.0, 62.7, 26.6, 23.2, 23.0, 20.8.
MS (70 eV, EI): m/z (%) = 214 (19), 213 (M+, 100), 212 (11), 198
(51), 185 (42), 170 (18), 142 (8).
HRMS (EI): m/z [M]+ calcd for C14H15NO: 213.1154; found:
213.1151.
[3-(6,7,8,9,10,11-Hexahydro-5H-cycloocta[b]indol-5-yl)pro-
pyl]dimethylamine (6, Iprindole)
Following typical procedure 3, cyclooctylzinc bromide (2f; 20
mmol, 57 mL, 0.35 M in THF), prepared from cyclooctyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (40 mmol, 40 mL,
1 M in THF), was reacted with phenyldiazonium tetrafluoroborate
(4h; 25 mmol, 4.80 g). The hydrazone intermediate was heated by
microwave irradiation (125 °C, 30 min) in the presence of Me3SiCl
(2.17 g, 20 mmol). After cooling to 0 °C, t-BuOK (24 mmol, 2.29
g) was slowly added. The reaction mixture was stirred for 20 min at
0 °C followed by the addition of (3-chloropropyl)dimethylamine
(24 mmol, 2.92 g). The resulting solution was heated by microwave
irradiation (125 °C, 3 h) and quenched with brine (50 mL). The
6-Methoxy-2,3,4,9-tetrahydro-1H-carbazole (1m)
Following typical procedure 3, cyclohexylzinc bromide (2e; 10
mmol, 27 mL, 0.37 M in THF), prepared from cyclohexyl bromide
via typical procedure 2 (25 °C, 4 h) using ZnBr2 (20 mmol, 20 mL,
1 M in THF), was reacted with 4d (12.5 mmol, 2.77 g). The hydra-
zone intermediate was heated by microwave irradiation (125 °C, 30
min) in the presence of Me3SiCl (1.08 g, 10 mmol). The crude prod-
uct was purified after the usual workup by flash column chromatog-
raphy (Al2O3; pentane–EtOAc–MeOH, 95:4:0.5) to give 1m13 as a
pale yellow solid (2.25 g, 80%); mp 107.9–109.8 °C.
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zinc Organometallic Variation of the Fischer Indole Synthesis
29
aqueous phase was extracted with EtOAc (3 × 50 mL). The com-
bined organic phases were dried (Na2SO4) and the solvent was re-
moved in vacuo. The crude product was purified by flash column
chromatography (Al2O3; pentane–EtOAc–MeOH, 97:3:0.3) to give
iprindole (6) as a yellow oil (4.09 g, 72%).
Katritzky, A. R.; Ress, C. W.; Scriven, E. F. V.; Bird, C. W.,
Eds.; Pergamon Press: Oxford, 1996. (d) Joule, A. In
Science of Synthesis, Vol. 10; Thomas, E. J., Ed.; Thieme:
Stuttgart, 2000, Chap. 10.13.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285.
(3) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(4) (a) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16,
2241. (b) Robinson, B. The Fischer Indole Synthesis; Wiley-
Interscience: New York, 1982.
IR (ATR): 3050, 2920, 2848, 2814, 2764, 1464, 1370, 1338, 1316,
1180, 1040, 734, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.50 (d, J = 7.3 Hz, 1 H), 7.29 (d,
J = 7.8 Hz, 1 H), 7.10 (t, J = 7.9 Hz, 1 H), 7.01–7.08 (m, 1 H), 4.12
(t, J = 7.6 Hz, 2 H), 2.79–2.95 (m, 4 H), 2.30 (t, J = 6.9 Hz, 2 H),
2.23 (s, 6 H), 1.83–1.97 (m, 2 H), 1.64–1.78 (m, 4 H), 1.35–1.47 (m,
4 H).
(5) Handbook of Functionalized Organometallics; Knochel, P.,
Ed.; Wiley-VCH: Weinheim, 2005.
13C NMR (75 MHz, CDCl3): d = 136.6, 136.0, 127.5, 120.1, 118.4,
117.6, 111.8, 108.9, 56.8, 45.4, 40.9, 30.4, 29.3, 28.7, 26.1, 25.9,
23.0, 22.9.
MS (70 eV, EI): m/z (%) = 284 (M+, 57), 213 (33), 212 (20), 198
(20), 185 (21), 184 (20), 171 (21), 170 (73), 157 (21), 156 (26), 145
(22), 144 (24), 71 (15), 58 (100), 43 (58), 41 (48).
(6) Haag, B. A.; Zhang, Z.-G.; Li, J.-S.; Knochel, P. Angew.
Chem. Int. Ed. 2010, 49, in press; DOI: anie.201005319.
(7) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC-
Press: Boca Raton, 1996.
(8) (a) Dong, Z.; Manolikakes, G.; Li, J.; Knochel, P. Synthesis
2009, 681. (b) Despotopoulou, C.; Gignoux, C.; McConnell,
D.; Knochel, P. Synthesis 2009, 3661. (c) Monzon, G.;
Knochel, P. Synlett 2010, 304. (d) Metzger, A.; Argyo, C.;
Knochel, P. Synthesis 2010, 882.
HRMS (EI): m/z [M]+ calcd for C19H28N2: 284.2252; found:
284.2246.
(9) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 6040.
Acknowledgment
(10) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(b) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
(11) (a) Haag, B. A.; Peng, Z.; Knochel, P. Org. Lett. 2009, 11,
4270. (b) Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed.
2004, 43, 897.
(12) (a) Rice, L. M.; Hertz, E.; Freed, M. E. J. Med. Chem. 1964,
7, 313. (b) Baxter, B. L.; Gluckman, M. I. Nature 1969, 223,
750.
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. Z.-
G. Zhang thanks especially the Chinese Scholarship for financial
support. We also thank BASF AG (Ludwigshafen), W. C. Heraeus
GmbH (Hanau) and Chemetall GmbH (Frankfurt) for the generous
gift of chemicals.
(13) Chen, J.; Hu, Y. Synth. Commun. 2006, 36, 1485.
References
(1) (a) Sundberg, R. T. Indoles; Academic Press: London,
1996. (b) Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 207–257. (c) Sundberg, R.
J. In Comprehensive Heterocyclic Chemistry II, Vol. 2;
Synthesis 2011, No. 1, 23–29 © Thieme Stuttgart · New York