A Cycloisomerization/Friedel-Crafts Alkylation Strategy for the Synthesis of Pyrano[3,4-b]indoles

Abstract

The synthesis of pyrano[3,4-b]indoles is described. The reaction sequence involves Sonogashira coupling of dihydropyran propargyl ether scaffolds with iodoanilines to afford intermediate indoles. Lewis acid-catalyzed ionization of the dihydropyrans, followed by intramolecular C3 alkylation of the indole, provides the title compounds.

It is well established that compounds containing the “privileged” indole motif exhibit a myriad of biological activities.¹ Building upon our recently reported study of dihydropyran rearrangements,² we developed a program focused on the synthesis of molecules comprising the pyrano[3,4-b]indole framework. Compounds having this skeleton have been used as antiinflammatory and analgesic agents as exemplified by etodolac (1) and pemedolac (2) (Figure 1).³ More recently these compounds have shown promise as inhibitors of hepatitis C virus (HCV) NS5B polymerase (3)⁴ and as potential treatments for lymphoma.⁵

Figure 1.

Biologically active pyrano[3,4-b]indoles

A SciFinder search⁶ of known compounds having the pyrano[3,4-b]indole skeleton revealed 2726 structures with only 55 (2%) bearing substitution at C3 and C4 (cf. 1, Figure 1). Accordingly, methodology providing functionalization at these positions will serve to increase the diversity of this chemotype. Herein, we describe a cycloisomerization/alkylation strategy that affords pyrano[3,4-b]indoles exhibiting both stereochemistry and useful functional groups at C3 and C4.

We envisioned a strategy to pyranoindoles of the type 4 involving intramolecular Friedel-Crafts cyclization of indole 5 (Scheme 1a). Alkylation of allylic alcohol 6 with a substituted bromomethylindole (7) would provide the desired cyclization precursor. Considering our interest in library synthesis, and identifying the indole fragment as a diversity element, we were concerned with the availability and preparation of diverse bromomethylindoles.⁷

Scheme 1.

Proposed a) Intramolecular Indole Alkylation and b) Cycloisomerization/Alkylation Strategies

Alternatively, reports of the intermolecular, electrophilic alkylation of the intermediate metal vinylidenes resulting from metal-catalyzed cycloisomerization of o-alkynylanilines⁸ inspired us to pursue an intramolecular cycloisomerization/alkylation strategy employing o-alkynylanilines (8) (Scheme 1b). Sonogashira coupling⁹ of terminal alkynes (9) with readily available iodoanilines (10) would serve to generate the desired cycloisomerization precursors.

Investigation of our proposed cycloisomerization approach commenced with Sonogashira coupling of terminal alkyne 11 and 2-iodoaniline to provide o-alkynylaniline 12 (Scheme 2).¹⁰ A variety of conditions have been reported to effect cycloisomerization of o-alkynylanilines.^8,11 Our desire to conduct a tandem process and prior experience with related rearrangements² led us to explore conditions that would allow both alkyne activation as well as ring-opening of the dihydropyran. A preliminary screen revealed PtCl₂ and Ph₃PAuCl/AgSbF₆ as candidate catalysts for the transformation. However, upon further investigation, we did not observe the desired pyranoindole. Rather, we isolated both indole 13 and alcohol 14, the latter presumably arising from β-elimination. Furthermore, exposure of indole 13 to Sc(OTf)₃ in CH₃NO₂ resulted in exclusive formation of elimination product 14.

Scheme 2.

Attempted Cycloisomerization/Alkylation Using an Unprotected o-Alkynylaniline

Encouraged by the isolation of indole 13, we anticipated that deactivation of the indole moiety with an electron withdrawing group on the nitrogen would abrogate the formation of alcohol 14. Accordingly, sulfonylation of aniline 12 under standard conditions provided sulfonamide 15 (Scheme 3). A brief catalyst screen revealed a marked dependence of product formation on catalyst choice. Use of π-philic catalysts such as PtCl₂ and Ph₃PAuCl12 generated the desired pyranoindole 16 along with a small amount of the intermediate indole 17 (entries 1 and 2). Alternatively, treatment of 15 with Sc(OTf)₃ and In(OTf)₃, both known to be oxophilic Lewis acids,¹³ provided tetrahydrofuran 18 (stereochemistry not determined).¹⁰ Presumably, tetrahydrofuran 18 arises from initial ionization of the dihydropyran followed by nucleophilic attack by the pendant alkyne to form the C3–C8 bond. The resulting vinyl carbocation may finally be quenched by water present in the reaction medium. Tautomerization of the intermediate enol affords the C9 ketone.¹⁴

Scheme 3.

Catalyst Role in the Tandem Cycloisomerization/Friedel-Crafts Rearrangement^a

^a Conditions: substrate (0.10 mmol), catalyst (0.010 mmol), CH₃NO₂ (1 mL), 3 h. ^b Starting material recovered.

We desired to streamline the synthesis of the cycloisomerization precursors (15) in order to provide a route amenable to library preparation. Accordingly, we considered protection of the iodoaniline prior to the Sonogashira coupling in order to provide a more convergent process and to increase flexibility of protecting groups (Scheme 4). However, we did not observe any of the expected protected alkynyl aniline after Sonogashira coupling of alkyne 11 and sulfonamide 19. Instead, we only observed formation of indole 20 arising from cycloisomerization.¹⁵ Subsequent exposure of indole 20 to Sc(OTf)₃ in CH₃NO₂ provided pyranoindoles 21 and 22 in 90% combined yield and 13:1 diastereomeric ratio favoring the trans isomer. An X-ray crystal structure of the analogous methanesulfonyl-protected derivative confirmed the stereochemistry of the major isomer.¹⁰ Due to the convenience and high yield of the two-step procedure, we pursued this strategy for the remainder of our study.

Scheme 4.

Synthesis of Pyranoindoles 21 and 22

An investigation of the scope of the reaction revealed that indoles containing electron withdrawing (Table 1, entries 1–5) or electron donating groups (entry 6) provided the desired pyranoindoles in good yields. The reaction conditions were tolerant of both azide and bromide substituents at R² (entries 7–8). Furthermore, use of iodophenols as coupling partners in the Sonogashira reaction provided intermediate benzofurans, which were smoothly transformed to pyrano[3,4-b]benzofurans¹⁶ using identical conditions (entries 9–10).

Table 1.

Scope of the Sc(OTf)₃-Catalyzed Cyclization^a

entry	substrate (20, 23)	X	R1	R2	yield (%)	drb
1	20	NHTs	H	OMe	90	13:1
2	23a	NHMs	5-F	OMe	95	4:1
3	b	NHTs	5-CF3	OMe	95	2:1
4	c	NHTs	5-NO2	OMe	88	1:1
5	d	NHMs	6-Cl	OMe	77	4:1
6	e	NHTs	5-OMe	OMe	49	>20:1
7	f	NHTs	H	Br	74	17:1
8	g	NHMs	H	N3	44	5:1
9	h	O	H	OMe	80	3:1
10	i	O	5-CO2Me	OMe	60	1:1

^aSee Supporting Information for detailed experimental procedures.

^bDetermined by ¹H NMR analysis of the crude reaction mixture.

An investigation of the reaction scope revealed an interesting relationship between the electronic nature of the indole and the diastereoselectivity of the reaction. Analysis of the results in Table 1 reveals that a decrease in the electron density of the indole is accompanied by a decrease in the diastereoselectivity of the reaction. Our rationale for this trend is illustrated in Scheme 5. We envision two initial pathways for the reaction. Lewis acid-mediated ionization of the dihydropyran may afford the open intermediate 26 (pathway a). Alternatively, S_N2′ attack of the indole on the activated dihydropyran would lead to iminium 27 (pathway b). Bond rotation in 26 to relieve A^1,3-strain would provide 28, which upon ring closure and rearomatization would yield trans-pyranoindole 21. Iminium 27 could also undergo two possible reaction pathways, the first being C–C bond cleavage to return to the open intermediate 26 (pathway c). A second reaction manifold (pathway d) involves deprotonation to furnish cis-pyranoindole 22. We hypothesize that the electron deficiency of the aromatic ring decreases the pKa of the indolic proton prior to rearomatization making pathway d more favorable in these cases, thereby, increasing the proportion of the cis-isomerIncreasing electron density of the indole may favor S_N2′pathway b. However, based on our results we believe that stereodifferentiation to access cis-pyranoindole isomers (cf. 22) occurs during pathways c and d.

Scheme 5.

Proposed Mechanism for Pyranoindole Formation

In order to increase the diversity of structures accessed using this methodology, we proceeded to investigate further reactions of the pyranoindole scaffolds. Precedent for the etherification of alkenols using metal triflates prompted us to investigate further cyclization of 24d (Scheme 6a).¹⁷ Indeed, microwave heating of 24d in the presence of a catalytic amount of Sc(OTf)₃ in 1,2-dichloroethane provided bis-pyran 29 in 93% yield as a single diastereomer. The corresponding cis-isomer (25d) did not cyclize under these conditions and decomposed upon increasing the temperature and catalyst loading.

Scheme 6.

(a) Etherification and (b) Oxidative Rearrangement of Pyranoindoles

Reports of the oxidative rearrangement of 2,3-substituted indoles prompted our investigation of the oxidation of pyranoindole 30 (Scheme 6b).¹⁸ We anticipated that selective epoxidation of the indole 2,3-π bond, followed by ring-contraction would provide a rearranged spirooxindole. Indeed, subjection of pyranoindole 30 to mCPBA in CH₂Cl₂ produced spirooxindole 31 in 49% yield.

In conclusion, we have developed syntheses of pyrano[3,4-b]indoles and pyrano[3,4-b]benzofurans containing an uncommon C3–C4 substitution pattern. The two-step procedure involves Sonogashira coupling of protected iodoanilines with a terminal alkyne followed by Friedel-Crafts alkylation. Conditions to convert pyranoindoles into other scaffolds, including a bis-pyran and a spirooxindole, were devised. Further studies using the methodology to access diverse chemical architectures are currently underway and will be reported in due course.