Sequential Cu(I)/Pd(0)-Catalyzed Multicomponent Coupling and Annulation Protocol for the Synthesis of Indenoisoquinolines

Abstract

Copper-catalyzed coupling of imines, vinylstannanes or alkynes and o-bromoaroyl chlorides followed by Pd(0)-catalyzed annulations afforded indenoisoquinolines. Protocols requiring minimal purifications were developed, providing new methods for the construction of combinatorial libraries.

The prevalance of N-heterocycles among established pharmaceutical agents¹ continues to inspire the development of new synthetic methods. We have been exploring a protocol based on an assembly of α-N-substituted amides followed by various intramolecular cyclizations,² opening up access to combinatorial libraries of hexahydro-1H-isoindolones (Figure 1).³

Figure 1.

The general strategy

Herein, we describe a powerful novel combination of the Cu(I)-catalyzed three-component coupling and an intramolecular Pd(0)-catalyzed 1,2-bisarylation of an olefin or an alkyne in amides IV and V to deliver substituted indenoisoquinolines VI and VII (Figures 1 and 2). The protocol allows a rapid increase in molecular complexity in only two steps.

Figure 2.

Strategy toward indenoisoquinolines

Structurally related indenoisoquinolines have been shown to possess potent biological activities.⁴ Our protocol provides a more efficient alternative to the established preparations of indenoisoquinolines, particularly those substituted at the angular position or the benzylic carbon in the indene ring.⁵ The method reported herein opens up a modular access to indenoisoquinolines, and is well amenable to automation.

Initial studies were focused on extending the scope of the known Cu(I)-catalyzed coupling⁶ to o-bromoaroyl chlorides III as well as to 1,1-disubstituted vinylstannanes II (Figure 2). We were able to decrease the molar excess of stannane 3a,⁷ from 2.0 equiv to 1.5 equiv⁸ and realize the coupling to imine 1a and aroyl chloride 2a providing amide 4a in good yields (Scheme 1). An increase in the CuCl catalyst load improved the yield of amide 4a from 67% (with 10 mol % CuCl) and to 82% (with 20 mol % CuCl, Scheme 1).⁹ Next, the Pd-catalyzed cyclization of amide 4 a was explored, anticipating that an intramolecular Heck reaction would afford intermediate VIII poised for electrophilic arylation to yield dihydroindeno[1,2-c]isoquinolines VI (Figure 2).¹⁰ The treatment of amide 4a with Pd(OAc)₂ (5 %) and NaOAc (1 equiv) afforded the indenoisoquinoline 5a in a 93% yield as a single diastereomer (Scheme 1).¹¹

Scheme 1.

Protocol utilizing an isolated amide

Aiming to establish a protocol amenable to automated synthesis, we sought to eliminate chromatographic purification of amide 4a. The addition of solid KF and small quantities of water, followed by filtration was employed to remove tin residues from the reaction mixtures. The resulting crude amide 4a was treated with Pd(OAc)₂ catalyst under conditions reported in Scheme 1 to afford indenoisoquinoline 5a in 75% yield over two steps (entry 1, Table 1, Method A). A brief survey revealed that sodium acetate was the optimum base for the Pd-catalyzed cyclization.¹⁰ The replacement of NaOAc with Na₂CO₃/n-Bu₄NCl applying modified Jeffery's conditions¹² (compare Methods A and B, entries 1, 3 and 4, Table 1) resulted in a decrease in the reaction yields, particularly severe for the electronically deactivated imines 1c (R² = H) and 1d (R² = Cl) (entries 3 and 4, Method B, Table 1). Overall, the optimized sequential protocol afforded the corresponding indenoisoquinolines 5a-5e in 38-75% yields over two steps (entries 1-5, Table 1, Method A). The lower yields of the electronically deactivated chloro and ester-substituted indenoisoquinolines 5d-e are in agreement with the proposed involvement of electrophilic palladation in the key step, although the less facile iminolysis of the acyl chlorides may also be a contributing factor. The 3,4-disubstituted imines 1f and 1g afforded single regioisomers of heterocycles 5f (77%) and 5g (71%) arising from palladation at the least hindered position in the aromatic ring (entries 6 and 7, Table 1). A contiguous 1,2,3,4,5-substitution pattern was achieved in an activated imine yielding indenoisoquinoline 5h in 64% yield (entry 8, Table 1). Efficient preparation of indenoisoquinolines 5 i and 5 j demonstrated the compatibility of the method with heteroatoms other than oxygen (entries 9 and 10, Table 1).

Table 1.

Angularly Substituted Indenoisoquinolines

entry	R1	R2	R3	prdtb	yieldc (%)
1	H	OMe	H	5a	75 (71)d
2	H	Me	H	5b	69
3	H	H	H	5c	67 (17)d
4	H	Cl	H	5d	49 (11)d
5	H	COOMe	H	5e	38
6	H	OMe	OMe	5f	77
7	H	-OCH2CH2O-		5ge	71
8	OMe	OMe	OMe	5h	64
9	H	NMe2	H	5i	59
10	thiophene-2-yl			5j	74

^aMethod A: was used for all the entries: (i) CuCl (20%), MeCN/CH₂Cl₂, 45 °C, 6 h, imine : acyl chloride : stannane = 1.0 : 1.2 : 1.5 (mol); (ii) aqueous KF, filtration, evaporation; (iii) Pd(OAc)₂ (5%), NaOAc (1.0 equiv), DMF, 120 °C, 24 h.

^bWith one exception, a single diastereomer was isolated.

^cIsolated yield of heterocycles 5 obtained via Method A calculated per imine as the limiting reagent.

^dYield of heterocycle 5 obtained by Method B is given in parentheses. Method B: same as Method A, but substituting Na₂CO₃ (1.0 equiv)/n-Bu₄NCl (1.0 equiv) for NaOAc.

^eProduct was isolated as a 4 : 1 mixture of diastereomers (by ¹H NMR), the major diastereomer is shown.

To expand the reaction scope, imines 1a and 1b were coupled to substituted aroyl chlorides 2b-c and vinylstannanes 3a and 3b-c¹³ bearing aliphatic (Me) and aromatic (Ph) substituents. Indenoisoquinolines 5k-o were obtained in good yields (59-76%) over two steps (Table 2). Heterocycles 5k-o were isolated as single diastereomers following chromatography and trituration of the crude products. The relative stereochemistry in heterocycles 5 (R⁴ = COOEt and Ph, Tables 1 and 2) was assigned based on analogy with indenoisoquinolines 5j and 5n, the structure of which was elucidated via single crystal X-ray crystallographic analyses. The relative stereochemistry in products 5 m and 5 o (R⁴ = Me) was assigned via spectroscopic methods.¹⁴

Table 2.

Diversification of Additional Building Blocks

entry	R1	R2	R3	R4	prdtb	yieldc (%)
1	Me	OMe	H	COOEt	5k	62
2	OMe	F	F	COOEt	5l	76
3	OMe	H	H	Me	5m	68
4	OMe	H	H	Ph	5n	59
5	Me	H	H	Me	5o	54

^aReaction conditions: (i) CuCl (20%), MeCN/ CH₂Cl₂, 45 °C, 6 h, imine : acyl chloride : stannane = 1.0 : 1.2 : 1.5 (mol); (ii) treatment with aqueous KF, filtration, evaporation; (iii) Pd(OAc)₂ (5%), NaOAc (1.0 equiv), DMF, 120 °C, 24 h.

^bSingle diastereomer was isolated.

^cIsolated yield of heterocycles 5 calculated per imine as the limiting reagent.

To access a distinct substitution pattern in the indenoisoquinolines, propargyl amide 7 a was prepared from imine 1a, aroyl chloride 2a and alkyne 6a in a good yield (54%) using conditions reported by Arndtsen¹⁵ (Scheme 2). We envisioned that Pd-catalyzed intramolecular bisfunctionalization of the alkyne¹⁶ would proceed via intermediate IX to afford indenoisoquinolines VII (Figure 2). Conceivably, a 1,3-shift of the allylic hydrogen in the intermediate I X would provide an organopalladium intermediate poised for the terminal electrophilic palladation.

Scheme 2.

Protocol utilizing an isolated propargyl amide

Indeed, the treatment of amide 7a with Pd(OAc)₂ catalyst and Na₂CO₃/n-Bu₄NCl additive mixture for a prolonged time period (36 h at 120 °C in DMF) afforded the corresponding indenoisoquinoline 8a in an excellent yield (91%) (Scheme 2). Ultimately, the isolation of amide 7a was avoided, limiting the purification of the crude reaction mixtures to the removal of excess alkyne via filtration through a short plug of silica. The resulting crude product was directly subjected to Pd-catalysis, affording indenoisoquinoline 8a in a good yield (66%) over two steps (entry 1, Table 2). This protocol was then applied to the coupling of imines 1a, 1b and 1j with aroyl chloride 2a and aryl acetylenes 6a-6c to provide indenoisoquinolines 8a-e in good yields (51-68%) over two steps (Table 2). Single crystal X-ray crystallographic studies on heterocycle 8c unequivocally established the structure, including the position of the double bond within the isoquinoline ring.¹⁷

The new synthetic protocol described here rapidly and efficiently assembles indenoisoquinolines with distinct substitution patterns from three simple building blocks. The modular strategy is particularly well suited for the construction of combinatorial libraries of indenoisoquinolines.

Table 3.

Indenoisoquinolines with a benzylic substituent

entry	R1	R2 (aryl)	prdtb	yieldc (%)
1	OMe	C6H5-	8a	66
2	Me	C6H5-	8b	51
3	thiophene-2-yl	C6H5-	8c	68
4	OMe	p-CH3C6H4-	8d	63
5	OMe	p-FC6H4-	8e	57

^aReaction conditions: (i) CuCl (20%), i-PrEt₂N (1.5 equiv) MeCN, rt. 1 h, imine : acyl chloride : alkyne = 1.0 : 1.2 : 1.5 (mol); (ii) treatment with aqueous KF, filtration, evaporation; (iii) Pd(OAc)₂ (5%), Na₂CO₃(1.0 equiv), n-Bu₄NCl (1.0 equiv), DMF, 120 °C, 36 h.

^bSingle diastereomer was isolated.

^cIsolated yield of heterocycles 8 calculated per imine as the limiting reagent.