Organic Syntheses, CV 9, 417
Submitted by Mercedes Amat, Sabine Hadida, Swargam Sathyanarayana, and Joan Bosch
1.
Checked by Ji Liu, Chris H. Senanayake, and Ichiro Shinkai.
1. Procedure
A.
3-Bromo-1-(tert-butyldimethylsilyl)indole. An oven-dried,
500-mL, three-necked, round-bottomed flask, equipped with a
magnetic stirring bar,
100-mL pressure-equalizing addition funnel, and an
argon inlet and outlet, is charged with
indole (8.0 g, 0.068 mol) (Note
1) and
tetrahydrofuran (200 mL) (Note
2). The solution is stirred and cooled to −78°C with a
dry ice/acetone bath, and a solution of
butyllithium in hexane (47 mL of a 1.6 M solution, 0.075 mol) (Note
3) is added dropwise via cannula. The mixture is warmed to −10°C, stirred for 15 min, and cooled to −50°C. A solution of
tert-butyldimethylsilyl chloride (11.6 g, 0.077 mol) (Note
3) in
tetrahydrofuran (60 mL) is added dropwise to this mixture. The temperature is raised to 0°C and after 3 hr the reaction mixture is cooled to −78°C. Freshly crystallized
N-bromosuccinimide (12.18 g, 0.0684 mol) (Note
4) is added via a
solid-addition funnel and the resulting mixture is stirred in the dark at −78°C for 2 hr and allowed to warm to room temperature.
Hexane (100 mL) and
pyridine (1 mL) are added and the resulting suspension is filtered through a Celite pad. The filtrate is evaporated under reduced pressure. The crude residue is purified (Note
5) by flash chromatography on
silica gel (Note 6) (350 g, 30 cm × 6 cm) (
100% hexane) to give
17.8 g (
84%) of
3-bromo-1-(tert-butyldimethylsilyl)indole as a colorless solid (Note
7).
B.
1-(tert-Butyldimethylsilyl)-3-ethylindole. An oven-dried, 500-mL, three-necked, round-bottomed flask, equipped with a magnetic stirring bar,
50-mL pressure-equalizing addition funnel, and an argon inlet and outlet, is charged with
3-bromo-1-(tert-butyldimethylsilyl)indole (10 g, 0.032 mol) and
tetrahydrofuran (100 mL). The mixture is stirred and cooled to −78°C with a dry ice/acetone bath. A solution of
tert-butyllithium (Note 8) (41.7 mL of a 1.7 M solution in pentane, 0.071 mol) is transferred slowly to the above mixture from a graduated tube via a stainless steel cannula under positive
argon pressure. The reaction mixture becomes yellow. Stirring is continued at −78°C for 10 min. A solution of
ethyl iodide (5.2 mL, 0.065 mol) (Note
9) in
tetrahydrofuran (20 mL) is added dropwise over 15 min to the resulting
1-(tert-butyldimethylsilyl)-3-lithioindole. The reaction mixture becomes colorless, and after 15 min it is allowed to reach room temperature, poured into a cold saturated
sodium carbonate solution (200 mL), and extracted with
methylene chloride (3 × 100 mL). The combined organic layers are washed with water (100 mL), dried over
sodium sulfate, and evaporated under reduced pressure to give
8.0 g (
96%) of
1-(tert-butyldimethylsilyl)-3-ethylindole as a light pink oil (Note
10).
C.
3-Ethylindole. An oven-dried,
250-mL, round-bottomed flask, equipped with a magnetic stirring bar,
rubber septum, and an argon inlet and outlet, is charged with
1-(tert-butyldimethylsilyl)-3-ethylindole (8 g, 0.031 mol) and
tetrahydrofuran (100 mL). The mixture is stirred and a
1 M solution of tetrabutylammonium fluoride (TBAF) in
tetrahydrofuran (31 mL, 0.031 mol) (Note
11) is added. After the solution is stirred for 10 min at room temperature, it is poured into a saturated solution of
sodium carbonate (200 mL) and extracted with
dichloromethane (3 × 100 mL). The combined organic layers are washed with water (100 mL), dried over
sodium sulfate, and evaporated under reduced pressure. The residue is subjected to flash chromatography on
silica gel (175 g, 32 cm × 4.5 cm) (
25% dichloromethane-hexane, v/v) to give
4.1 g (
92%) of
3-ethylindole as colorless plates (Note
12).
2. Notes
2.
Tetrahydrofuran was distilled from
sodium benzophenone ketyl immediately before use.
4.
N-Bromosuccinimide was obtained from Fluka Chemie AG, and crystallized from water and dried over
P2O5 before use.
5. Chromatographic purification of the reaction mixture must be effected as soon as possible after workup in order to separate traces of contaminating
3-bromoindole, which promotes rapid decomposition. Pure
3-bromo-1-(tert-butyldimethylsilyl)indole can be stored under
argon at 4°C without appreciable decomposition.
6.
Silica gel (35–70 mesh) was used as received.
7. The spectral properties for
3-bromo-1-(tert-butyldimethylsilyl)indole are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.60 (s, 6 H), 0.93 (s, 9 H), 7.17 (s, 1 H), 7.20 (m, 2 H), 7.48 (m, 1 H), 7.54 (m, 1 H);
13C NMR (75 MHz, CDCl
3) δ: −4.0 (CH
3Si), 19.3 [C(CH
3)
3], 26.2 [C(CH
3)
3], 93.6 (C-3), 114.0 (C-7), 119.1 (C-4), 120.5 (C-5), 122.5 (C-6), 129.6 (C-2), 129.8 (C-3a), 140.2 (C-7a). Anal Calcd for C
14H
20BrNSi: C, 54.18; H, 6.50; Br, 25.75; N, 4.51. Found: C, 54.21; H, 6.60; Br, 25.52; N, 4.62. Attempts to crystallize
3-bromo-1-(tert-butyldimethylsilyl)indole were unsuccessful.
8.
tert-Butyllithium (1.7 M solution in pentane) was obtained from Aldrich Chemical Company, Inc., and used as received.
9.
Ethyl iodide was obtained from Fluka Chemie AG and distilled prior to use.
10. NMR spectrum shows the presence of less than
3% of 1-(tert-butyldimethylsilyl)indole. Crude
1-(tert-butyldimethylsilyl)-3-ethylindole can be purified by flash column chromatography on
silica gel (35-70 mesh) (350 g, 30 cm × 6 cm) (
100% hexane) to give pure
1-(tert-butyldimethylsilyl)-3-ethylindole as a colorless oil in about
90% yield. The spectral properties are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.57 (s, 6 H), 0.92 (s, 9 H), 1.32 (t, 3 H, J = 7.5), 2.76 (g, 2 H, J = 7.5), 6.92 (s, 1 H), 7.12 (m, 2 H), 7.47 (m, 1 H), 7.58 (m, 1 H);
13C NMR (75 MHz, CDCl
3) δ: −3.9 (CH
3Si), 14.5 (CH
3CH
2), 18.4 (CH
2CH
3), 19.5 [C(CH
3)
3], 26.3 [C(CH
3)
3], 113.8 (C-7), 118.8 (C-4), 119.2 (C-5), 119.8 (C-3), 121.3 (C-6), 126.9 (C-2), 130.9 (C-3a), 141.6 (C-7a). Anal. Calcd for C
16H
25NSi: C, 74.06; H, 9.71; N, 5.40. Found: C, 74.18; H, 9.73; N, 5.46.
12. The spectral properties for
3-ethylindole are as follows:
1H NMR (200 MHz, CDCl
3) δ: 1.37 (t, 3 H, J = 7.5), 2.82 (q, 2 H, J = 7.5), 6.98 (br s, 1 H), 7.18 (m, 2 H), 7.37 (d, 1 H, J = 7.5), 7.66 (d, 1 H, J = 7.8), 7.85 (br s, 1 H);
13C NMR (50 MHz, CDCl
3) δ: 15.0 (CH
3CH
2), 18.9 (CH
2CH
3), 111.6 (C-7), 119.3 (C-3), 119.5 (C-4), 119.6 (C-5), 121.1 (C-6), 122.4 (C-2), 128.0 (C-3a), 136.9 (C-7a).
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Although there are many studies about the preparation and synthetic applications of N-protected 2-lithioindoles,
2 their isomers, the 3-lithioindoles, have received little attention. Thus, the only indole protecting group used for the preparation of simple 3-lithioindoles is the benzenesulfonyl group.
1-(Benzenesulfonyl)-3-lithioindole is prepared at −100°C by halogen-metal exchange with
tert-butyllithium from the corresponding 3-iodo-
3 or
3-bromoindole.
4 At higher temperatures it rearranges to the thermodynamically more stable 2-lithio isomer. On the other hand, some 2-substituted 1-(benzenesulfonyl)-3-lithioindoles undergo ring fragmentation to give 2-aminophenylacetylene derivatives.
5 The change of the benzenesulfonyl protecting group for a trialkylsilyl group allows the preparation of 3-lithioindoles that are relatively stable species even at room temperature.
TABLE
SYNTHESIS OF 3-SUBSTITUTED INDOLES
|
Entry |
Electrophile |
R |
2 Yield(%) |
3Yield(%)a |
|
a |
MeI |
Me |
90 |
85 |
b |
BuBr |
Bu |
64 |
61 |
c |
(CH2CH2)O |
CH2CH2OH |
63 |
62 |
d |
Me2C=CHCH2Brb |
CH2CH=CMe2 |
|
69c |
e |
HCONMe2d |
CHO |
e |
94 |
f |
C6H5COCld |
COC6H5 |
e |
84 |
g |
C6H5CO2CH3d |
COC6H5 |
69 |
58 |
h |
ClCO2CH3d |
CO2CH3 |
84 |
80 |
i |
CO2 |
CO2H |
94 |
70f |
j |
C6H5CHO |
CHOHC6H5 |
67 |
g |
k |
4-CHO-C5H4N |
4-CHOH-C5H4N |
55 |
g |
l |
ClSnMe3 |
SnMe3 |
94 |
h |
|
aOverall yield after purification by column chromatography. bThe 3-lithioindole 1 was converted into a cuprate by addition of 1 equiv of CuBr·SMe2. cAn 85:15 mixture of 3d and the isomer in which R is CMe2CH=CH2, respectively, is obtained. dThe best yields were obtained by reverse addition of the lithium derivative 1 to a THF solution of the electrophile at −78°C. eThe corresponding 3-acyl derivatives undergo partial desilylation during the work-up. fThis desilylation was best effected by using CsF instead of TBAF. gThese carbinols were obtained as pink oils, which partially decomposed during purification by column chromatography. hAttempts to deprotect the tin derivative 2l afforded only indole.
|
The triisopropylsilyl group gave comparable satisfactory results.
7
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