Organic Syntheses, CV 7, 34
INDOLES FROM
2-METHYLNITROBENZENES BY CONDENSATION WITH FORMAMIDE ACETALS FOLLOWED BY REDUCTION:
4-BENZYLOXYINDOLE
Submitted by Andrew D. Batcho
1 and Willy Leimgruber
2.
Checked by David J. Wustrow and Andrew S. Kende.
1. Procedure
C.
4-Benzyloxyindole. To a stirred solution of
162.2 g (0.50 mol) of (E)-6-benzyloxy-2-nitro-β-pyrrolidinostyrene (Note
9) in
1 L of THF and
1 L of methanol at 30°C under
nitrogen is added
10 mL of Raney nickel (Note
10) followed by
44 mL (0.75 mol) of 85% hydrazine hydrate. Vigorous gas evolution is observed. The red color turns to dark brown within 10 min, and the reaction temperature rises to 46°C. An additional
44 mL of 85% hydrazine hydrate is added after 30 min and again 1 hr later. The temperature is maintained between 45 and 50°C with a
water bath during the reaction and for 2 hr after the last addition. The mixture is cooled to room temperature and the catalyst is removed by filtration through a bed of Celite (Note
11) and is washed several times with
methylene chloride. The filtrate is evaporated and the residue dried by evaporating with
500 mL of toluene. The reddish residue (
118.5 g), dissolved in ca.
1 L of toluene-cyclohexane (1 : 1), is applied to a
column of 500 g of silica gel (70–230-mesh, Merck) prepared in the same solvent. Elution with
6.0 L of toluene–cyclohexane (1 : 1) followed by
3 L of toluene–cyclohexane (1 : 2) affords
108.3 g of white solid, which is crystallized from
150 mL of toluene and
480 mL of cyclohexane (Note
12). A total of
107.3 g (
96% yield) of
4-benzyloxyindole (Note
13) is obtained in three crops as white prisms, mp
60–62°C (Note
14).
2. Notes
2. The
1H NMR spectrum is as follows δ: 2.42 (s, 3 H), 5.10 (s, 2 H), 7.13 (m, 3 H), 7.35 (m, 5 H).
4. The reaction was followed by TLC on silica gel plates developed with
ether–petroleum ether (1 : 1).
5. Since it contained
nonvolatile
N-formylpyrrolidine, direct reduction of the crude material was not attempted.
8. The
1H NMR spectrum is as follows: δ: 1.8 (m, 4 H), 3.08 (m, 4 H), 5.03 (5, 2 H), 5.20 (d, 1 H,
J = 12.2), 6.91 (dd, 2 H,
J = 9), 7.25 (m, 6 H), 7.75 (d, 1 H,
J = 12.2).
10.
Raney nickel is commercially available as type #28 from the Davison Chemical Division of W. R. Grace and Co.
11. The catalyst is pyrophoric and should not be sucked dry.
12. The material tenaciously holds hydrocarbons, such as
pentane,
hexane, and
petroleum ether, which cannot be removed even under high vacuum. The solvated crystals show hydrocarbon protons in NMR and exhibit a broad melting point. However, we found that
cyclohexane is not retained in the crystals.
13. The
1H NMR spectrum is as follows: δ: 6.65 (m, 2 H), 6.95 (m, 3 H), 7.9 (br s, 1 H), 7.32 (m, 5 H).
14. We could not reproduce the reported
5 melting point of 72–74°C (
toluene). The material has the proper microanalysis and is pure by NMR and thin-layer chromatography (TLC).
3. Discussion
Through the years, widespread interest in the synthesis of natural products and their analogs bearing the oxygenated indole nucleus has led to the development of several routes to protected hydroxylated indoles. However,
4-benzyloxyindole was first prepared relatively recently in modest overall yield by the Reissert method, which involves condensation of
6-benzyloxy-2-nitrotoluene with
ethyl oxalate, reductive cyclization to the
indole-2-carboxylate, hydrolysis to the acid, and decarboxylation.
5
Although a variety of synthetic methods have been used to prepare indoles,
6,7 many of these lack generality and are somewhat restrictive since they employ conditions, such as acid or strongly basic cyclizations or thermal decarboxylations, which are too harsh for labile substituents. This efficient, two-step procedure
8,9 illustrates a general, simple, and convenient process for preparing a variety of indoles substituted in the carbocyclic ring, as can be seen in Table I. Since many of these examples served to determine the scope of this method, the yields in most cases have not been optimized. In many cases, the starting materials are readily available or can be easily prepared.
As can be seen in Table I, variation of the substituent has a profound effect on the rate of reaction of the
o-nitrotoluene derivative with
dimethylformamide acetals but has little effect on the yields, which are often almost quantitative. As can be predicted, electron-withdrawing groups accelerate the reaction. To shorten the somewhat lengthy reaction times that are often necessary when electron-donating substituents are present, more reactive aminomethylenating reagents such as pyrrolidine (or piperidine) acetals,
8 aminals,
10 or trisaminomethanes
11 can be employed. Alternatively, as described above, simply adding
pyrrolidine to the reaction mixture also generates in situ a very effective aminomethylenating reagent.
12,13 Thus, for example, in the case of
6-benzyloxy-2-nitrotoluene, the reaction with
N,N-dimethylformamide dimethyl acetal requires 51 hr versus 3 hr when
pyrrolidine is added.
Pyrrolidine undergoes exchange reactions with
N,N-dimethylformamide acetals to produce an equilibrium mixture of
formylpyrrolidine acetal and the mixed
pyrrolidine dimethylamine aminal (alkoxydimethylaminopyrrolidinomethane) as well as other
trisaminomethane species.
14 (In cases where
pyrrolidine reacts with the aromatic substrate, addition of the substrate can be delayed until
pyrrolidine exchange is complete.) This mixture of reagents gives rise to condensation products—
pyrrolidine enamines—that contain 5–10% of the corresponding
N,N-dimethylenamines.
TABLE I
INDOLES FROM 2-METHYLNITROBENZENES BY CONDENSATION WITH N,N-DIMETHYLFORMAMIDE ACETALS AND REDUCTION
|
|
Substituents |
|
|
|
|
|
|
R1 |
R2 |
R3 |
R4 |
Intermediates 2 (mp or bp/mm) |
Reaction Time |
Purified Yield (%) (Procedure)a |
Indoles 3 (mp or bp/mm) |
Yield (%) (Procedure)b |
Refs. |
|
— |
— |
— |
— |
125°/0.03 |
22 hr |
97(M,E) |
52.5–53.5° |
80(A) |
8, 9 |
OCH2Ph |
— |
— |
— |
67–68° |
51 hr |
90(M) |
60–62° |
70(B) |
12 |
— |
OCH2Ph |
— |
— |
98–99° |
29 hr |
78(E) |
103–105° |
45(B)[64]c |
8, 9, 12 |
— |
— |
OCH2Ph |
— |
108.5–110° |
41 hr |
97(M) |
118–120° |
75(B)i |
12 |
— |
OCH2Ph |
OCH2Ph |
— |
99.5–101° |
48 hr |
86(M) |
112–113° |
54(B)j |
8, 9 |
— |
OCH2Ph |
CH3 |
— |
113–134° |
31 hr |
87(M) |
82–83° |
84(B) |
12 |
— |
OCH3 |
— |
— |
68.5–70° |
16 hr |
92(M) |
56.5–57.5° |
83(A) |
8, 9 |
— |
— |
OCH3 |
— |
152°/0.06 |
70 hr |
64(E) |
88–90° |
63(A)[62]c |
8, 9, 12 |
— |
OCH3 |
OCH3 |
— |
125–126° |
48 hr |
68(M) |
154–155° |
28(A) |
8, 9 |
— |
OCH3 |
— |
CH3 |
100–101° |
8 hr |
54(M) |
100–110°/0.15 |
66(A) |
15
|
— |
OCH2O |
— |
114–116° |
18 hr |
72(E) |
110–111° |
50(A)[52]c |
8, 9, 12 |
Cl |
— |
— |
— |
111°/0.03 |
6 hr |
89(E) |
90°/0.04 |
63(B) |
8, 9 |
— |
Cl |
— |
— |
81.5–82.5° |
7 hr |
88(E) |
71–72° |
78(B) |
8, 9 |
— |
— |
Cl |
— |
44–46° |
24 hr |
57(M) |
86.5–88° |
52(B)[75]c |
8, 9, 12 |
— |
— |
NH2d |
— |
173–174° |
2 hr |
82(E)f |
77.5–78.5° |
43(A) |
8, 9, 12 |
CN |
— |
— |
— |
66–68° |
3 hr |
93(M) |
116–117° |
67(C) |
22 |
— |
— |
CN |
— |
134–137.5° |
2.5 hr |
86(E) |
128–129° |
65(A) |
8, 9 |
— |
F |
— |
— |
57.5–59° |
3.5 hr |
92(E) |
46.5–47° |
51(B) |
8, 9 |
— |
— |
F |
— |
46–47° |
22 hr |
63(M) |
74–75° |
80(B)[80]c |
8, 12 |
CH3 |
— |
— |
— |
108°/0.05 |
24 hr |
70(E) |
82°/0.4 |
57(A) |
8, 9 |
— |
— |
CH3 |
— |
41.5–43.5° |
37 hr |
83(M) |
29–30.5° |
83(A) |
16 |
— |
— |
— |
CH3 |
76–76.5 |
46 hr |
40(E) |
83–84° |
48(A) |
8, 9 |
— |
— |
CH(CH3)2 |
— |
138–140°/0.06 |
42 hr |
84(E) |
40–41° |
51(A) |
8, 9 |
— |
— |
CH(OCH3)2 |
— |
67–68° |
8 hr |
55(E) |
62–63.5° |
31(A) |
8, 9 |
COOCH3 |
— |
— |
— |
120–130°/0.2 |
6 hr |
86(M) |
63° |
82(A)[63]c |
22, 17 |
COOC2H5 |
— |
— |
— |
(Oil) |
5 days |
93(E) |
67–69° |
38(D) |
22 |
— |
COOC2H5e |
— |
— |
55–56.5° |
4.5 hr |
70(E) |
95–96° |
39(A) |
8, 9 |
— |
— |
— |
COOCH3 |
132–134° |
9 hr |
88(M) |
46–48° |
72(A)g |
12 |
Cl |
OCH3 |
— |
— |
— |
Overnight |
—(M) |
109–111° |
(B)[59]c |
18 |
— |
OCH3 |
Cl |
— |
140–141° |
Overnight |
78(M) |
126–128° |
46(B)[45]c |
18 |
— |
OCH3 |
F |
— |
116–117° |
Overnight |
64(M) |
73–74° |
54(B) |
18 |
— |
— |
Br |
— |
— |
31 hr |
—(M) |
93° |
37(B)h |
19 |
|
|
|
cYield in brackets represents overall yield without purification of intermediate 2.
|
dR3 = NO2 in compounds 1 and 2.
|
eR2 = COOH in compound 1.
|
|
|
|
|
|
The enamine intermediates are usually crystalline, red compounds that can be stored at room temperature for reasonable periods. In cases where the enamines are noncrystalline, it is recommended that the crude product be used directly in the next step, since purification is, in such cases, not practical. Although the more volatile derivatives can be distilled under high vacuum, this entails some risk because of their thermal instability. Moreover, the enamines are not stable to silica gel (TLC or column) chromatography.
Conversion of the intermediate nitroenamine into the indole requires selective reduction of the nitro group. Catalytic hydrogenation results in spontaneous formation of the indole and is generally the mildest and most convenient method of reduction. Although selectivity does vary with the substituent on the aromatic ring, it is generally highly in favor of the nitro group. However, scale-up requires access to
large autoclaves or special equipment. To avoid hydrogenolysis of benzyl or chloro functions,
Raney nickel is the catalyst of choice. Excellent yields have been obtained using
hydrazine and the appropriate catalyst
20 as, in essence, a hydrogenation process which does not require an autoclave or special equipment and can be easily carried out in the laboratory.
This method has been applied to the preparation of polycyclic indoles
12,24 and azaindoles
24,25,26 as well.
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved