A Practical Synthesis of Indole-Based Heterocycles Using an Amidoaluminum-Mediated Strategy

Abstract

A large number of biologically active compounds consist of an indole scaffolding. Because of this, chemists are continually searching for more efficient means through which to successfully synthesize the required alkaloids. In our recent effort to synthesize indole-based p38 inhibitors and gramines, we found that a series of indole-based indole-3-carboxamides could be efficiently synthesized from various indole-3-carboxylates using an amidoaluminum-mediated strategy. The treatment of ethyl indole-3-carboxylates bearing a range of substitution patterns on the indole ring with various amidoaluminum complexes, led to the corresponding 1H-indole-3-carboxamides in yields up to 75%. Reduction by diisobutylaluminum hydride afforded the corresponding gramines in 63-85% yield. This is the first reported example of amidoaluminum complexes of type Al₂(CH₃)₄(NR₂)₂ promoting facile amidation of relatively inert indole esters. This particularly promising approach has resulted in the first strategy for generating medicinally important alkaloids of this type.

The diversity and significance of indole-based heterocycles as key biologically active alkaloids suggests that development of a versatile synthesis would have broad utility in medicinal research. Most challenges facing modern chemists in synthesizing indole-based alkaloids, such as those shown in Figure  [¹] and Figure  [²] , is the synthesis of the indole moiety itself. Although methods [¹] have been reported for the synthesis of various indole-based carboxamides, few methods have been reported for the synthesis of indole-based alkaloids with C-3 amide linkers (Scheme  [¹] ). Herein, we report a highly efficient synthetic strategy for generating indole-3-carboxamides and gramines from commercially available raw materials.

A common method for generating gramines from indoles is by Mannich reaction with dimethylamine and formaldehyde, [²] [³] however, complimentary extension to various substituted indoles either do not work as well or not take place at all. The lack of available methods for generating ring-A substituted gramines, in addition to indole-3-carboxamides, presented a novel synthetic challenge that attracted our attention. We recently reported a highly efficient fluoroboric acid (HBF₄) catalyzed synthesis of various substituted indole-3-carboxylates in excellent yields using readily available o-nitrobenzaldehydes and ethyl diazoacetate under moderate conditions. [4]

The two-step indole synthesis involves the synthesis of 2-aryl-3-hydroxypropenoic acid esters, followed by reduction over Pd/C. This method is simple and efficient, and provides access to functionalized indole esters as a possible substrate for carboxamides and gramine synthesis through an amidation-reduction sequence.

The diversity of synthetic tools available for amidating esters suggested amidation of indole-3-carboxylates would occur quite readily, however, our initial attempts at converting indole esters 1a-e into the corresponding amides 2a-e were unsuccessful using conventional methodology (Scheme  [²] ). This failure underlies our efforts in developing a method that efficiently transforms indole-3-carboxylates into indole-based carboxamides and gramines.

Trimethylaluminum reacts with ammonia and secondary amines in a 1:1 ratio at room temperature with evolution of methane, to give dimethylaluminum amides. [5a] [b] A quantitative procedure for converting esters into various carboxamides was reported by Weinreb [5a] and Ha [5b] using the amidoaluminum complex Al₂(CH₃)₄(NMe₂)₂. Insights from this transformation suggested that such aluminum complexes might be efficient at generating indole-based carboxamides from various indole esters, such as those shown in Scheme  [²] . Generating a range of amidoaluminum complexes 3 in toluene at 0 ˚C (Scheme  [³] ), and then heating at 100 ˚C in the presence of various N-protected indole-3-carboxylates 4a-d (Table  [¹] ), resulted in the formation of carboxamides 5a-k in 58-81% isolated yield. Table  [¹] shows that an assortment of amidoaluminum complexes are capable of efficiently amidating a variety of indole esters with varying substitution patterns. The direct formation of indole-based 3-carboxamides using amidoaluminum complexes is noteworthy, particularly since this type of transformation was reported to be ineffective for the reaction with pentafluorophenyl indole-3-carbox­ylates. [6]

It was previously reported [7] that lithium aluminum hydride (LAH) reduction of indole-3-carboxamide proceeded satisfactorily, however, initial attempts at reducing 5a-d with LAH failed, yielding instead 3-methylindoles as the major product. Substituting diisobutylaluminum hydride (DIBAL-H; 1 M in toluene) for LAH, resulted in facile amide reduction, generating 6a-k in 65-93% yield (Table  [²] ).

Facile formation of 3-methylindoles in the LAH reduction of amides prompted our investigation into the possibility of generating these indole amides directly from unprotected 1H-indole-3-carboxylates via indolene-type intermediates. Although direct amidation of N-protected indole-3-carboxylates using amidoaluminum complexes proceeded in good yield (Scheme  [³] , Table  [¹] ), eliminating unwanted protection and deprotection steps would be valuable. Despite­ the potential utility of this transformation, no synthetically­ useful examples of direct indole carboaluminations have been reported in the literature.

Table 1 Synthesis of N-(Phenylsulfonylamide)-indole-3-carbox­amides 5a-k Using Amidoaluminum Complexes 3

Entry	Indole	R¹	Z	Product	Yield (%)
1	4a	H	NMe2	5a	77
2		H	N(n-Pr)2	5b	65
3		H		5c	63
4		H		5d	69
5		H		5e	58
6		H		5f	81
7		H		5g	71
8		H		5h	64
9	4b	5-MeO	NMe2	5i	73
10	4c	6-MeO	NMe2	5j	64
11	4d	5-Br	NMe2	5k	61

Table 2 Synthesis of N-(Phenylsulfonylamide)gramines 6a-k Using­ DIBAL-H

Entry	R¹	Z	Product	Yield (%)
1	H	NMe2	6a	91
2	H	N(n-Pr)2	6b	87
3	H		6c	88
4	H		6d	93
5	H		6e	79
6	H		6f	82
7	H		6g	85
8	H		6h	80
9	5-MeO	NMe2	6i	87
10	6-MeO	NMe2	6j	90
11	5-Br	NMe2	6k	65

Addition of amidoaluminum complexes 3a-h to various 1H-indole-3-carboxylates 1a-d in toluene (Table  [³] ), resulted in substantial gas evolution. Acidic aqueous workup resulted in the formation of amides 2a-k in 41-65% yield. Subsequent reduction with DIBAL-H resulted in the formation of gramines 7a-k in 63-85% yield.

Carbometalation is well accepted as a mechanistic step in reactions such as Heck coupling and olefin polymerization. [8] We believe that direct amidoalumination of N-protected indole-3-carboxylates 4 (Table  [¹] ) proceeds by a similar route (Scheme  [4] ). Indirect amidoalumination of unprotected 1H-indole-3-carboxylates 1 (Scheme  [5] ) is unknown, and presumably proceeds via a 1,4-shift, with the initial metalation occurring at the indolic nitrogen, resulting in the liberation of methane.

In summary, we have developed a novel approach to the construction of various indole-based alkaloids without the need for protecting groups, using easily accessible amidoaluminum complexes [Al₂(CH₃)₄(NR₂)₂] and indole-3-carboxylates in toluene. A study on the scope of this process, as well as its application to natural product synthesis, is currently underway in our laboratories.

Table 3 Synthesis of Gramines from Unprotected 1H-Indole-3-carboxylates 1a-d Using DIBAL-H

Entry	Indole	R¹	Z	Yield of 2 (%)	Yield of 7 (%)
1	1a	H	NMe2	2a (59)	7a (85)
2		H	N(n-Pr)2	2b (42)	7b (79)
3		H		2c (55)	7c (73)
4		H		2d (58)	7d (81)
5		H		2e (41)	7e (65)
6		H		2f (62)	7f (75)
7		H		2g (61)	7g (79)
8		H		2h (75)	7h (74)
9	1b	5-MeO	NMe2	2i (65)	7i (77)
10	1c	6-MeO	NMe2	2j (63)	7j (81)
11	1d	5-Br	NMe2	2k (57)	7k (63)

Τηε χηεµιχαλ σηιϕτσ (δ) αρε εξπρεσσεδ ιν ππµ ρελατιϖε το ΤΜΣ, ανδ Χ₆Δ₆ ωασ υσεδ ασ τηε σολϖεντ. Αλλ οργανοµεταλλιχ οπερατιονσ ωερε περϕορµεδ υνδερ α δρψ νιτρογεν ατµοσπηερε ωιτη στανδαρδ Σχηλενκ τεχηνιθυεσ. Αλλ οϕ τηε γλασσ ϕλασκσ ωερε ϕλαµεδ υνδερ ϖαχυυµ ανδ ϕιλλεδ ωιτη νιτρογεν πριορ το υσε. Χολυµν χηροµατογραπηψ ωασ περϕορµεδ ωιτη σιλιχα γελ (40∠140 µεση). Ανηψδρουσ γραδε σολϖεντσ ωερε πυρχηασεδ ϕροµ Αλδριχη Χηεµιχαλσ ανδ υσεδ ωιτηουτ ϕυρτηερ πυριϕιχατιονσ. Αλλ ινδολε εστερσ ωερε σψντηεσιζεδ βψ κνοων προχεδυρε. [4] Τολυενε σολυτιονσ οϕ τριµετηψλαλυµινυµ ανδ ΔΙΒΑΛ−Η ωερε πυρχηασεδ ϕροµ Αλδριχη Χηεµιχαλ χοµπανψ ανδ υσεδ ασ ρεχειϖεδ.

Synthesis of Amidoaluminum Complexes in Toluene: ( S )-(-)-1-(2-Pyrrolidinylmethyl)pyrrolidinylamino-dimethyl Aluminum (3h); Typical Procedure

A solution of (S)-(-)-1-(2-pyrrolidinylmethyl)pyrrolidine (3.0 g, 0.019 mol) in toluene (100 mL) was added to a 250 mL reaction flask under N₂ to form a clear yellow solution. Me₃Al in toluene (2 M, 9.7 mL, 0.019 mol) was added to the solution over 15 min at 0-5 ˚C, resulting in gas evolution and a mild exotherm. The reaction mixture retained a clear yellow appearance. The reaction mixture was allowed to warm to r.t., then allowed to stir until gas evolution ceased (1-2 h). The solution was used directly with no further purification.

Synthesis of N -(Phenylsulfonyl)indole-3-carboxamides: ( S )-[1-(Phenylsulfonyl)-1 H -indol-3-yl][2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methanone (5h); Typical Procedure

Ethyl (N-phenylsulfonyl)indole-3-carboxylate (4a; 1.75 g, 0.006 mol) was dissolved in toluene (3 mL) inside a 100 mL reaction flask under N₂. A toluene solution of 3h (20 mL, 0.006 mol, ˜0.28 M) was added to the slurry over 10 min at r.t., resulting in a 2-3 ˚C exotherm. The reaction mixture was heated to reflux for 18 h, allowed to cool to r.t., then H₂O (2 mL) was added to the reaction mixture over 10 min, resulting in gas evolution and a mild exotherm. Solids were removed by filtration to yield a dark biphasic filtrate. The organics were collected, washed with H₂O (5 mL) and brine (5 mL), and then dried over anhydrous Na₂SO₄. The organics were concentrated under reduced pressure, then purified by flash chromatography on silica gel (THF-EtOH, 10:1) to give a dark, tacky solid. Triturating the tacky solid with cyclohexane (50 mL) yielded 5h.

Yield: 1.5 g (64%); light-brown powder.

^¹H NMR (400 MHz, C₆D₆): δ = 8.23 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 7.7 Hz, 1 H), 7.68 (m, 1 H), 7.66 (m, 1 H), 7.55 (s, 1 H), 7.04 (t, J = 7.3 Hz, 2 H), 6.61 (m, 3 H), 4.17 (dd, J = 13.3, 1.3 Hz, 1 H), 3.18 (d, J = 13.4 Hz, 1 H), 2.70 (td, J = 8.2, 2.3 Hz, 1 H), 2.59 (dd, J = 11.2, 4.7 Hz, 1 H), 2.50-2.32 (m, 6 H), 1.89 (q, J = 8.9 Hz, 1 H), 1.78 (m, 1 H), 1.53 (m, 5 H).

^¹³C NMR (100 MHz, C₆D₆): δ = 138.6, 136.0, 132.8, 128.6, 126.4, 124.7, 124.1, 123.0, 122.3, 120.9, 113.8, 62.7, 61.9, 54.7, 54.6, 50.0, 30.3, 23.5, 22.6.

Anal. Calcd for C₂₄H₂₇N₃O₃S: C, 65.8; H, 6.22; N, 9.6. Found: C, 66.1; H, 6.43; N, 9.4.

Reduction of Indole-3-carboxamides Using DIBAL-H: 3-[(3-Methylpiperidin-1-yl)methyl]-1 H -indole (7f); Typical Procedure

(1H-Indol-3-yl)(3-methylpiperidin-1-yl)methanone (2f; 2.3 g, 9.5 mmol) was dissolved in toluene (50 mL) inside a 100 mL reaction flask, under nitrogen. A solution of n-BuLi (2.5 M in hexanes, 3.8 mL, 9.5 mmol) was added to the reaction mixture over a 10 min period at 0-5 ˚C, resulting in a mild exotherm. After stirring for an additional 15 min, a solution of DIBAL-H in toluene (1.5 M, 6.6 mL, 10 mmol) was added to the reaction mixture over a 5 min period at 0-5 ˚C. No exotherm was observed. The reaction mixture was allowed to warm to r.t., then stirred at 50 ˚C for 16 h. After cooling to r.t., MeOH (1.9 mL) was added to the reaction mixture over a 10 min period, resulting in the formation of solids that were removed by Buchner filtration. The filtrate was concentrated under reduced vacuum, then purified by flash chromatography on silica gel (THF-EtOH, 10:1) to give 7f.

Yield: 1.7 g (75%); light-brown powder; mp 145-148 ˚C (Lit. [9] 144-146 ˚C).

IR (ATR): 3230 (NH), 2510 (CH), 1555, 1501, 1335, 885, 730 cm^-l.

^¹H NMR (400 MHz, DMSO-d ₆): δ = 10.88 (s, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 7.18 (d, J = 2.2 Hz, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 6.96 (t, J = 7.3 Hz, 1 H), 3.56 (s, 2 H), 2.82-2.72 (br, 2 H), 1.86-1.76 (br t, 1 H), 1.66-1.34 (br, 5 H), 0.86-0.73 (m, 4 H).

^¹³C NMR (100 MHz, DMSO-d ₆): δ = 136.7, 128.1, 124.8, 121.3, 119.5, 118.7, 111.7, 111.6, 61.8, 54.2, 53.8, 33.2, 31.1, 25.6, 20.1.

Anal. Calcd for C₁₅H₂₀N₂: C, 78.90; H, 8.83; N, 12.27. Found: C, 78.56; H, 8.59; N, 12.33.

Synthesis of 1 H -Indole-3-carboxamides: ( S )-(1 H -Indol-3-yl)[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]methanone (2h); Typical Procedure

Ethyl indole-3-carboxylate (1a; 3.4 g, 0.019 mol) was dissolved in toluene (60 mL) inside a 250 mL reaction flask under a N₂ atmosphere. A toluene solution of 3h (100 mL, 0.019 mol, ˜0.19 M) was added to the slurry over 10 min at r.t., resulting in substantial gas evolution. The reaction mixture was refluxed for 16 h, then allowed to cool to r.t. with stirring. H₂O (7 mL) was added to the reaction mixture over 5 min to give a slurry (the addition of H₂O was moderately exothermic with moderate gas evolution). Solids were removed by filtration and washed with THF (100 mL). The filtrates were combined and concentrated to a solid under reduced pressure and the residue was purified by flash chromatography on silica gel (THF-EtOH, 10:1) to give 2h.

Yield: 4.5 g (75%); free-flowing, white powder; mp 139-140 ˚C.

IR (ATR): 3230, 2510 (NH, CH), 1725, 1654, 1555, 1501, 1335, 885, 730 cm^-¹.

^¹H NMR (400 MHz, C₆D₆): δ = 10.90 (s, 1 H), 8.35 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.20-7.13 (m, 2 H), 6.91 (br, 1 H), 4.75-4.48 (br, 1 H), 3.31-3.03 (br, 2 H), 2.98-2.72 (br, 1 H), 2.63-2.24 (br, 5 H), 1.75 (1 H, m), 1.66 (m, 1 H), 1.52 (br, 4 H), 1.40 (m, 1 H), 1.32-1.14 (br, 1 H).

^¹³C NMR (100 MHz, C₆D₆): δ = 166.6, 136.3, 122.3, 121.3, 120.7, 112.0, 111.9, 58.7, 54.4, 30.1, 28.8, 27.6, 23.6.

Anal. Calcd for C₁₈H₂₃N₃O: C, 72.7; H, 7.8; N, 14.13. Found: C, 72.31; H, 7.56; N, 14.35.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.

Acknowledgment

The authors wish to thank Aldrich Chemicals for their very generous supply of starting materials and analytical support.

References

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References

• 1 Mavunkel BJ. Chakravarty S. Perumattam JJ. Luedtke GR. Xi L. Lim D. Xu Y. Laney M. Liu DY. Schreiner GF. Lewicki JA. Dugar S. Bioorg. Med. Chem. Lett.  2003,  13:  3087 
  CrossrefSearch in Google Scholar
• 2a Saxton JE. The Alkaloids   The Chemical Society; London: 1971. ; Specialist Periodical Reports:
• 2b Saxton JE. Nat. Prod. Rep.  1989,  6:  1 
  Search in Google Scholar
• 2c Hesse M. Alkaloid Chemistry   Wiley; New York: 1978. 
• 2d Cordell GA. Introduction to Alkaloids: A Biogenetic Approach   Wiley; New York: 1981. 
• 2e Gilchrist TL. Heterocyclic Chemistry   Pitman; London: 1981. 
• 2f Pindur AR. J. Heterocycl. Chem.  1988,  25:  1 
  Search in Google Scholar
• 3a Joule JA. Mills K. Heterocyclic Chemistry   University Press; Cambridge: 2000. 
• 3b Sundberg RJ. The Chemistry of Indoles   Academic Press; New York: 1970.  p.142 
• 3c Jones AR. Comprehensive Heterocyclic Chemistry   Vol. 4:  Katrizky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.334 
  Search in Google Scholar
• 3d Gupta RR. Heterocyclic Chemistry   Vol. 2:  Springer Publishing; New York: 1999.  p.199 
  Search in Google Scholar
• 3e Nakazaki M. Yamamoto K. J. Org. Chem.  1976,  41:  1877 
  Search in Google Scholar
• 4 Islam M. Brennan C. Wang Q. Hossain MM. J. Org. Chem.  2006,  71:  4675 
  CrossrefSearch in Google Scholar
• 5a Basha A. Lipton M. Weinreb SM. Tetrahedron Lett.  1977,  48:  4171 
  Search in Google Scholar
• 5b Ko D. Kim KH. Ha D. Org. Lett.  2002,  4:  3759 
  Search in Google Scholar
• 6 Lindsay FB. Ferrando F. Christensen KL. Overgaard J. Roca T. Bennasar ML. Skrydstrup T. J. Org. Chem.  2007,  72:  4181 
  CrossrefSearch in Google Scholar
• 7 Germain C. Bourdais J. J. Heterocycl. Chem.  1976,  13:  1209 
  CrossrefSearch in Google Scholar
• 8 Collman JP. Hegedus LL. Norton JR. Finke RG. Principles and Applications of Organotransition Metal Chemistry   University Science Books; Mill Valley, CA: 1987. 
• 9 Orth RE. Bennett JW. Ma OH. Young L. J. Pharm. Sci.  1968,  57:  1814 
  CrossrefSearch in Google Scholar

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