One-Step Synthesis of
Indole-3-Acetonitriles from Indole-3-Carboxaldehydes1

Fumio Yamada, Tomoko Hashizume, and Masanori Somei
Heterocycles 47(1), 509-516 (1998)

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Abstract

One step conversion method of indole-3-carboxaldehydes into indole-3-acetonitriles is developed. Applying the method, 4-nitro- (7a), 4-phenyl- (7b), 4-iodo- (7c), 4-methoxy- (7d), and 4-benzyloxyindole-3-acetonitrile (7e) are available in two steps from indole-3-carboxaldehyde (4).

Indole-3-acetonitriles (3) are known not only as plant growth regulators2 but also as important building blocks for tryptamines and natural products3-5. Probably the most common synthesis approach to them is the nucleophilic substitution with cyanide6 for the dimethylamino group of gramines (2) which are readily obtained by Mannich reaction of indoles (1), as shown in Scheme 1.

On the other hand, even at present, 4-substituted indole-3-acetonitriles (7, Scheme 2) are difficult to obtain due to the lack of simple preparation method for 4-substituted gramines (6). Our contribution in the indole chemistry has realized one pot syntheses7 of 4-substituted indole-3-carboxaldehydes (5) from indole-3-carboxaldehyde (4) and a direct conversion of 5 into 6.8 However, the need of one step method for transforming 5 into 7 is still remained, because the method would easily supply valuable building blocks (7a-e) and consequently provide a short cut for various natural products syntheses such as batzelline C (11),3 isobatzelline C (12),3 SF 2140,4 nephilatoxins (13),5 and so on. Now, we wish to report the discovery of the desired reaction.

Table 1

Entry
Solvent
Yield
7a
8
9a
1
MeOH
36%
53%
-
2
MeOH-MeNHCHO (1:1, v/v)
52%
27%
-
3
MeOH-DMF (1:1, v/v)
62%
31%
-
4
NH2CHO
61%
6%
3%
5
MeOH-NH2CHO (1:1, v/v)
88%
2%
9%
6
MeOH-NH2CHO (1:7, v/v)
69%
9%
5%

In order to accumulate basic knowledge, we chose 4-nitroindole-3-carboxaldehyde9 (5a) as a substrate and tested various trials employing cyanating reagents in the presence of reducing agents, such as Me3SiCl-NaI-KCN-Et3SiH, Me3SiCl-NaI-KCN-NaBH4, Me3SiCN-NaBH4, and so on. During these studies,8 we observed that simple treatment of 5a sequentially with NaBH4, and then with NaCN in MeOH, produced 4-nitroindole-3-acetonitrile9 (7a) and 4-nitroindole9,10 (8). Based on the finding, further examinations of the reaction conditions were carried out, and the combination of about 1.3 mol eq. of NaBH4 and about 10 mol eq. of NaCN was found to be suitable for our purposes as shown in Table 1 (Entry 1), affording 7a and 8, in 36 and 53% yields, respectively. Furthermore, when the solvent was changed to MeOH-MeNHCHO (1:1, v/v), the yield of 7a increased slightly (Entry 2). Change in solvent to MeOH-DMF (1:1, v/v) increased the yield of 7a to 62% (Entry 3). It is interesting to note that NH2CHO dramatically suppressed the formation of 8 and the yield of 7a was improved (Entry 4) in comparison with the results of Entries 1 and 2. Therefore, various mixed solvents using MeOH and NH2CHO were examined and finally 1:1 mixture of MeOH-NH2CHO was found to be a solvent of choice, producing 7a in 88% yield together with N-(4-nitroindol-3-yl)methylformamide (9a) as a by-product in 9% yield (Entry 5). When the same reaction was carried out without NaCN, 9a was exclusively produced in 75% yield together with 4% yield of 8. Under similar reaction conditions, 9b-f were prepared in 68, 72, 57, 62, and 64% yields, respectively.

Table 2

Entry
R
Yield
7
9
8
a
NO2
88%
9%
2%
b
Ph
89%
5%
-
c
I
88%
7%
-
d
OMe
86%
11%
-
e
OCH2Ph
89%
9%
-
f
H
95%
4%
-

Employing the above reaction conditions, various indole-3-acetonitriles (7b-f) having phenyl, halogen, oxygen functional groups, were obtained in excellent to good yields as shown in Table 2 in one step from the corresponding indole-3-carboxaldehydes (5b-f) together with a small amount of 9b-f, respectively.

Thus, we succeeded in developing a simple one step conversion method of indole-3-carboxaldehydes into indole-3-acetonitriles. Owing to the present method, 1,3,4,5-tetrahydropyrrolo- [4,3,2-de]quinoline3,8 (10) is obtained from 4 in three steps and our previous eight steps synthesis of marine alkaloids, batzelline C3 (11) and isobatzelline C (12),3 become shorter by one step (Scheme 2). The present two steps synthesis of 4-benzyloxyindole-3-acetonitrile (7e) from 4 could substitute for an expensive four steps synthesis5 of 7e from 4-hydroxyindole and would be utilized for the synthetic studies of nephillatoxins such as 135. 4-Methoxyindole-3-acetonitrile (7d), the aglycon of SF 2140,4 is now available in only two steps from 4 and could be applied for the syntheses of Mitragyna alkaloids such as 14.11 The present method is widely applicable for effective syntheses of indole natural products.

Experimental

Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. Preparative thin-layer chromatography was performed on Merck Kiesel-gel GF254 (Type 60)(SiO2). Column chromatography was performed on silica gel (SiO2, 100-200 mesh).

General procedure

NaBH4 (1.3 mol eq.) was added to a solution of indole-3-carboxaldehyde in MeOH and NH2CHO. After stirring at rt for 1 h, NaCN (10 mol eq.) was added to the reaction mixture and the whole was refluxed on oil bath at 100C for 5 h with stirring. After cooling, brine was added and the whole was extracted with MeOH-CHCl3 (5:95, v/v). The organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave the residue, which was column chromatographed on SiO2 with an appropriate solvent as an eluent.

4-Nitroindole-3-acetonitrile (7a), 4-nitroindole (8), and N-(4-nitroindol-3-yl)methylformamide (9a) from 4-nitroindole-3-carboxaldehyde (5a): Table 1, Entry 5

In the general procedure, 23.4 mg (0.619 mmol) of NaBH4, 86.0 mg (0.453 mmol) of 5a,7g 4 mL of MeOH and 4 mL of N H2CHO, 230.5 mg (4.70 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with CHCl3 and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 8 (1.8 mg, 2%) as the early part of the fractions. From the middle part, 7a (80.0 mg, 88%) was obtained. From the later part, 9a (8.5 mg, 9%) was obtained. 7a and 8 are identical with the authentic samples prepared according to our procedures.9,109a: mp 224.0-225.0C (yellow needles, recrystallized from MeOH).

4-phenylindole-3-acetonitrile (7b) and N-(4-phenylindol-3-yl)methylformamide (9b) from 4-phenylindole-3-carboxaldehyde (5b)

In the general procedure, 22.6 mg (0.597 mmol) of NaBH4, 102.8 mg (0.465 mmol) of 5b7b,d, 4 mL of MeOH and 4 mL of NH2CHO, 230.8 mg (4.71 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with CHCl3 and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 7b (96.1 mg, 89%) as the early part of the fractions. From the later part, 9b (5.6 mg, 5%) was obtained. 7b: colorless oil. 9b: mp 197.0-198.0C (colorless leaves, recrystallized from MeOH).

4-Iodoindole-3-acetonitrile (7c) and N-(4-iodoindol-3-yl)methylformamide (9c) from 4-iodoindole-3-carboxaldehyde (5c)

In the general procedure, 21.0 mg (0.555 mmol) of NaBH4, 121.0 mg (0.447 mmol) of 5c7a,c, 4 mL of MeOH and 4 mL of NH2CHO, 226.0 mg (4.61 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with MeOH-CHCl3 (1:99, v/v) and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 7c (111.3 mg, 88%) as the early part of the fractions. From the later part, 9c (9.9 mg, 7%) was obtained. 7c is identical with the authentic samples prepared according to our procedures.9 9c: mp 207.0-209.0C (colorless needles, recrystallized from MeOH).

4-Methoxyindole-3-acetonitrile (7d) and N-(4-methoxyindol-3-yl)methylformamide (9d) from 4-methoxyindole-3-carboxaldehyde (5d)

In the general procedure, 23.0 mg (0.608 mmol) of NaBH4, 80.4 mg (0.459 mmol) of 5d7a, 4 mL of MeOH and 4 mL of NH2CHO, 223.8 mg (4.57 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with CHCl3 as an eluent to give 7d (73.5 mg, 86%) as the early part of the fractions. From the later part, 9d (10.2 mg 11%) was obtained. 7d: mp 145.0-146.0C (colorless prisms, recrystallized from CHCl3-hexane). 9d: mp 190.0-192.0C (colorless prisms, recrystallized from MeOH).

4-Benzyloxyindole-3-acetonitrile (7e) and N-(4-methoxyindol-3-yl)methylformamide (9e) from 4-benzyloxyindole-3-carboxaldehyde (5e)

In the general procedure, 26.2 mg (0.693 mmol) of NaBH4, 111.0 mg (0.442 mmol) of 5e,7a 4 mL of MeOH and 4 mL of NH2CHO, 222.7 mg (4.54 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with CHCl3 and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 7e (102.8 mg, 89%) as the early part of the fractions. From the later part, 9e (11.2 mg, 9%) was obtained. 7e: mp 84.0-86.0C (colorless needles, recrystallized from benzene). 9e: colorless oil.

Indole-3-acetonitrile (7f) and N-(indol-3-yl)methylformamide (9f) from indole-3-carboxaldehyde (5f)

In the general procedure, 23.4 mg (0.619 mmol) of NaBH4, 68.4 mg (0.472 mmol) of 5, 4 mL of MeOH and 4 mL of NH2CHO, 237.0 mg (4.84 mmol) of NaCN were used. The residue was column chromatographed on SiO2 with CHCl3 and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 7f (70.1 mg, 95%) as the early part of the fractions. From the later part, 9f (3.6 mg, 4%) was obtained. 7f was identical with the commercially available sample. 9f: colorless oil.

N-(4-Nitroindol-3-yl)methylformamide (9a) from 4-nitroindole-3-carboxaldehyde (5a)

In the general procedure, 25.0 mg (0.661 mmol) of NaBH4, 86.0 mg (0.453 mmol) of 5a, 4 mL of MeOH, and 4 mL of NH2CHO were used. After stirring at room temperature for 1 h, the whole was refluxed on oil bath at 100C for an additional 12 h with stirring. The residue was recrystallized from MeOH to afford 9a as yellow needles (50.3 mg). Mother liquor was purified by column chromatography on SiO2 with CHCl3 and then MeOH-CHCl3 (5:95, v/v) as an eluent to give 8 (3.2 mg, 4%) as the early part of the fractions. From the later part, 9a (24.2 mg) was obtained. Total yield of 9a was 74.5 mg (75%).

Similar experiments starting from 5b-f afforded 9b-f in 68, 72, 57, 62, and 64% yields, respectively.

References and Notes

  1. This is Part 83 of a series entitled "The Chemistry of Indoles". Part 82: M. Somei and K. Nakagawa, Heterocycles, 1997, 45, submitted.
  2. E. R. H. Jones and W. C. Taylor, Nature, 1957, 179, 1138; T. Okamoto, Y. Isogai, T. Koizumi, H. Fujishiro, and Y. Sato, Chem. Pharm. Bull., 1967, 15, 163; M. Nomoto and S. Tamura, Agr. Biol. Chem., 1970, 3 4, 1590; D. Edgerton, A. Tropsha, and A. M. Jones, Phytochemistry, 1994, 35, 1111 and references cited therein.
  3. F. Yamada, S. Hamabuchi, A. Shimizu, and M. Somei, Heterocycles, 1995, 41, 1905 and references cited therein.
  4. T. Ito, K. Ohba, M. Koyama, M. Sezaki, H. Tohyama, T. Shomura, H. Fukuyasu, Y. Kazuno, T. Niwa, M. Kojima, and T. Niida, J. Antibiotics, 1984, 37, 931; J. G. Buchanan, J. Stoddart, and R. H. Wightman, J. Chem. Soc., Chem. Commun., 1989, 823. Synthetic work of the sugar part of SF2140: D. Fattori and P. Vogel, Tetrahedron, 1992, 4 8, 10587.
  5. T. Shinada, M. Miyachi, Y. Itagaki, H. Naoki, K. Yoshihara, and T. Nakajima, Tetrahedron Lett., 1996, 37, 7099 and references cited therein.
  6. R. J. Sundberg, "The Chemistry of Indoles", Academic Press, New York, 1970; R. T. Brown, J. A. Joule, and P. G. Sammes, "Comprehensive Organic Chemistry", Vol. 4, ed. by P. G. Sammes, Pergamon Press, Oxford, 1979, pp. 411-492; R. J. Sundberg, "Indoles", Academic Press, New York, 1996.
  7.  
    1. M. Somei, F. Yamada, M. Kunimoto, and C. Kaneko, Heterocycles, 1984, 22, 797;
    2. M. Somei, H. Amari, and Y. Makita, Chem. Pharm. Bull., 1986, 34, 3971;
    3. F. Yamada and M. Somei, Heterocycles, 1987, 26, 1173;
    4. M. Somei, F. Yamada, and K. Naka, Chem. Pharm. Bull., 1987, 35, 1322;
    5. M. Somei, M. Wakida, and T. Ohta, Chem. Pharm. Bull., 1988, 36, 1162;
    6. M. Somei, T. Ohta, J. Shinoda, and Y. Somada, Heterocycles, 1989, 29, 653;
    7. M. Somei, F. Yamada, H. Hamada, and T. Kawasaki, Heterocycles, 1989, 29, 643;
    8. Review: M. Somei, Yakugaku Zasshi, 1988, 108, 361 and references cited therein.
  8. F. Yamada, K. Kobayashi, A. Shimizu, N. Aoki, and M. Somei, Heterocycles, 1993, 36, 2783 and references cited therein.
  9. M. Somei, K. Kizu, M. Kunimoto, and F. Yamada, Chem. Pharm. Bull., 1985, 33, 3696.
  10. M. Somei and M. Tsuchiya, Chem. Pharm. Bull., 1981, 29, 3145.
    Other literatures for the preparation of 4-nitroindole are summarized in Ref 8.
  11. C. M. Lee, W. F. Trager, and A. H. Beckett, Tetrahedron, 1967, 23, 375; H. M-Manga, J. Q-Leclerco, G. Llabres, M-L. B-Pinheiro, A. F. I. Da Rocha, and L. Angenot, Phytochemistry, 1996, 43, 1125.