Phosphine-catalyzed [3 + 2] cycloaddition of phthalazinium dicyanomethanides with allenoates: highly efficient synthesis of 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives

Abstract

The phosphine-catalyzed [3 + 2] cycloaddition between phthalazinium dicyanomethanides and allenoates, has been achieved in dichloromethane at room temperature, providing a broad range of novel heterocyclic compounds, 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives, as single (Z)-isomers in excellent yields (88–99% yield). All reactions are operationally simple and proceed very fast under mild reaction conditions.

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In the past two decades, nucleophilic phosphine-catalyzed annulation reactions have attracted much attention and have intensely been explored.¹ Various reactions including [2 + 2],² [2 + 2 + 1],³ [3 + 2],⁴ [4 + 1],⁵ [2 + 2 + 2],⁶ [3 + 3],⁷ [4 + 2],⁸ [4 + 3],⁹ [6 + 3]¹⁰ and [8 + 2]¹¹ annulations have been achieved.^1,12 These reactions display extensive applications in synthesis of a wide range of biologically useful carbocyclic and heterocyclic compounds,¹ and some of them have served as key step in total synthesis of several natural products.¹³ Generally, phosphine-catalyzed annulation reactions are achieved through stepwise reaction of electrophilic coupling reagent with zwitterionic intermediates formed in situ from the addition of the Lewis basic phosphine to phosphine acceptors such as activated allenes, alkynes, MBH carbonates and acetates.¹ Therefore, the search for new electrophilic coupling reagent are one of key topics in exploring nucleophilic phosphine-catalyzed reactions. In recent five years, it has been demonstrated that a stable 1,3-dipole could serves as an electrophilic coupling reagent to furnish a variety of cycloaddition reactions. In 2011, a kind of readily accessible and stable 1,3-dipoles, N,N′-azomethine imines were first applied in phosphine-catalyzed cycloaddition reaction, leading to development of phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3] and [3 + 2 + 3] cycloadditions of N,N′-cyclic azomethine imines with allenoates, affording biologically important diverse dinitrogen-fused heterocycles, such as tetrahydropyrazolopyrazolone, tetrahydropyrazolopyridazinone, tetrahydropyrazolodiazepinone and tetrahydropyrazolodiazocinone derivatives.¹⁴ This reaction revealed the feasibility of cycloaddition reaction of a stable 1,3-dipole with reactive 1,3-dipolar species generated in situ from phosphine acceptors in the presence of phosphine catalyst, and triggered much attention to this kind of cycloaddition reactions. In 2012, the synthetic potential of C,N-azomethine imine was exploited in phosphine-catalyzed [3 + 2] and [4 + 3] cycloaddition reactions with allenoates to give the tetrahydroisoquinoline derivatives in high yields.¹⁵ The same year, further application of N,N′-azomethine imines was reported in phosphine-catalyzed [3 + 2] and [3 + 3] cycloaddition reactions with ethyl 2-butynoate, providing tetrahydropyrazolopyrazolones and tetrahydropyrazolopyridazinones in moderate to good yields.¹⁶ In 2014, a wide range of azomethine imine variables were used in an efficient phosphine-catalyzed [3 + 2] cycloaddition with diphenylsulfonyl alkenes, providing a practical synthetic method for dinitrogen-fused heterocyclic compounds bearing phenylsulfonyl groups in high yields.¹⁷ Particularly, the function of C,N-cyclic azomethine imines was extended in a phosphine-catalyzed asymmetric [3 + 2] cycloaddition with δ-substituted allenoates, giving functionalized tetrahydroquinoline frameworks in good yields with high diastereoselectivities and good enantioselectivities.¹⁸ In 2015, C,N-cyclic azomethine imines were also employed in phosphine-catalyzed highly enantioselective [3 + 3] cycloaddition with Morita–Baylis–Hillman carbonates to afford a novel class of pharmaceutically interesting 4,6,7,11b-tetrahydro-1H-pyridazino[6,1-a]isoquinoline derivatives in high yields with good to excellent diastereoselectivities and extremely excellent enantioselectivities.¹⁹ Furthermore, the aromatic azomethine imines were identified to be compatible substrates in phosphine-catalyzed [4 + 3] cycloaddition with allenoates, providing dinitrogen-fused heterocyclic compounds in moderate to excellent yields.²⁰ Besides azomethine imines, it was demonstrated that isoquinolinium methylides could act as efficient dipoles in a phosphine-catalyzed dearomatizing [3 + 2] annulation with allenoates or allenones, yielding highly functionalized pyrroloisoquinolines with high regioselectivity in good yields.²¹ Despite of these successful examples above, the scope and type of 1,3-dipoles used for phosphine-catalyzed cycloaddition reactions are still quite limited, thus exploring application of new dipoles in phosphine-catalyzed reactions is still highly desirable. Herein, with the use of phthalazinium dicyanomethanides²² as 1,3-dipole, we investigated phosphine-catalyzed [3 + 2] cycloaddition reaction of α-substituted allenoates for synthesis of biologically important 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives²³ (Scheme 1).

Scheme 1 Phosphine-catalyzed [3 + 2] cycloaddition of phthalazinium dicyanomethanides with allenoates.

Our initial studies focused on the reaction of phthalazinium dicyanomethanide 1a with allenoate 2a with dichloromethane as the solvent (Table 1). First, we investigated the possible background reaction between phthalazinium dicyanomethanide 1a and allenoate 2a. In the absence of phosphine catalyst, after the reaction mixture was stirred for 24 h, a thermal cycloaddition product was obtained in 44% yield and was identified as the compound 3aa′, which was produced through 1,3-dipolar [3 + 2] cycloaddition of 1,3-dipole 1a with double bond between C_α and C_β of allenoate 2a (entry 1). Gratifyingly, in the presence of phosphine catalyst, all phosphines irrespective of their nucleophilic abilities could enable excellent conversion of the phthalazinium dicyanomethanide substrate in relative short reaction time, leading to the desired [3 + 2] cycloaddition product 3aa in 92–95% yield, whose structure is not the same as that of the thermal cycloaddition product 3aa′ (entries 2–6). Different from thermal [3 + 2] cycloaddition of phthalazinium dicyanomethanide 1a with allenoate 2a, in the phosphine-catalyzed formal [3 + 2] cycloaddition, double bond between C_β and C_γ of allenoate 2a underwent stepwise cycloaddition with 1a to give the product 3aa. Of particular note is that the weak nucleophilic Ph₃P needed 48 h of reaction time for full conversion, in contrast, the strong nucleophilic Me₃P only needed 10 min to achieve full conversion, displaying highly efficient catalytic capability (entry 2 vs. 6). Decreasing catalyst loading to 10 mol%, the cycloaddition product 3aa was still obtained in 91% yield, albeit needing 2 h of reaction time (entry 7). The structure of the cycloaddition product 3aa was unambiguously confirmed by X-ray crystallographic data (Fig. 1).²⁴

Table 1 Screening of the reaction conditions^a

Entry	Cat.	t	3	Yield^b (%)
a Reactions were carried out in 1 mL of CH2Cl2 at rt using 0.1 mmol of 1a, 0.15 mmol of 2a and 20 mol% of phosphine.b Isolated yields.c 10 mol% of Me3P was used.
1	—	24 h	3aa′	44
2	Ph3P	48 h	3aa	92
3	MePPh2	6 h	3aa	94
4	Me2PPh	45 min	3aa	93
5	Bu3P	60 min	3aa	92
6	Me3P	10 min	3aa	95
7^c	Me3P	2 h	3aa	91

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Fig. 1 The X-ray crystallographic structure of 3aa.

To establish the scope of this reaction, phthalazinium dicyanomethanide (1a) was reacted with a variety of allenoates (2a–2q) in dichloromethane at room temperature under phosphine catalysis conditions. As shown in the Table 2, in the presence of 20 mol% of Me₃P, all allenoates very efficiently underwent [3 + 2] cycloaddition reaction at room temperature to give 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives (3) as single (Z)-isomers in excellent yields (91–99%). The electronic properties and the substitution pattern of substituents in allenoates have not remarkable influence on the reaction process. Generally, the reactions proceeded very fast and could complete in no more than 30 minutes except the reaction of 4-(methoxycarbonyl)phenyl-substituted allenoate 2k, which proved to be less reactive, needing relatively longer 70 minutes to complete the reaction.

Table 2 Scope of allenoates^a

Entry	R (2)	t (min)	3	Yield^b (%)
a Reactions were performed in 1 mL of CH2Cl2 at rt using 0.1 mmol of 1a, 0.15 mmol of 2 and 20 mol% of Me3P.b Isolated yields.
1	C6H5 (2a)	10	3aa	95
2	2-FC6H4 (2b)	7	3ab	91
3	3-FC6H4 (2c)	15	3ac	96
4	4-FC6H4 (2d)	15	3ad	99
5	3-ClC6H4 (2e)	15	3ae	98
6	4-ClC6H4 (2f)	30	3af	95
7	2-BrC6H4 (2g)	5	3ag	96
8	3-BrC6H4 (2h)	3	3ah	98
9	4-BrC6H4 (2i)	30	3ai	99
10	3-CF3C6H4 (2j)	15	3aj	96
11	4-CO2MeC6H4 (2k)	70	3ak	99
12	2-MeC6H4 (2l)	4	3al	99
13	3-MeC6H4 (2m)	20	3am	98
14	4-MeC6H4 (2n)	20	3an	98
15	4-t-BuC6H4 (2o)	20	3ao	92
16	2-Naphthyl (2p)	20	3ap	97
17	CO2Et (2q)	20	3aq	94

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Next, we studied the reaction of allenoate (2a) with different phthalazinium dicyanomethanides (1) (Table 3). Phthalazinium dicyanomethanides were conveniently synthesized through reaction of phthalazine or phthalazine derivative with TCNEO.^22m,n,25 For nonsymmetric substituted phthalazines, both nitrogen atoms can attack tetracyanoethyleneoxide, thus leading to two positional isomeric phthalazinium-2-dicyanomethanide derivatives in nearly quantitative total yield (Table 3). Since both isomers could not be separated by flash column, the mixture of two isomeric phthalazinium dicyanomethanides was employed in the [3 + 2] cycloaddition reaction with allenoates, giving a mixture of cycloadducts, which could be separated by using flash column. The cycloaddition yields were determined through HPLC analysis of two isomeric substrates. In the presence of 20 mol% of Me₃P, [3 + 2] cycloadditions of phthalazinium dicyanomethanides 1 with allenoate 2a were performed at room temperature to afford the cycloadducts in 93–99% yield. A range of phthalazinium dicyanomethanides smoothly underwent the reaction irrespective of electron-donating groups, electron-withdrawing groups, or their substitution pattern. It is noted that 6,7-dimethyl substituted phthalazinium dicyanomethanide 3e needed longer reaction time. As indicated in Scheme 2, dicyano(isoquinolin-2-ium-2-yl)methanide 1g was also a compatible substrate. Exposing it to the standard reaction conditions led to the corresponding product 3ga in 88% yield. In particular, in the presence of 50 mol% of Me₃P, dicyano(pyridazin-1-ium-1-yl)methanide 4 underwent [3 + 2] cycloaddition with allenoate 2a to give the 5,6-dihydropyrrolo[1,2-b]pyridazine-7,7(4aH)-dicarbo-nitrile product 5 in 79% yield and a aromatized product 6 in 19% yield.

Table 3 Scope of phthalazinium dicyanomethanides^a,b

a Reactions were performed in 1 mL of CH₂Cl₂ at rt using 0.1 mmol of 1, 0.15 mmol of 2a and 20 mol% of Me₃P.b Isolated yields.c 1b : 1c = 33 : 67.

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Scheme 2 [3 + 2] cycloaddition reactions of dicyanomethanide 1g and 4.

To explore the feasibility of an enantioselective variant of this reaction, an array of commercially available chiral phosphines were screened in [3 + 2] cycloaddition of phthalazinium dicyanomethanide 1a with allenoate 2a. As shown in Table 4, unfortunately, although reasonable conversions were observed in all cases, only moderate enantioselectivities were achieved (entries 1–6). The spirocyclic chiral phosphine P6 catalyzed the reaction to give the product in 60% yield with the highest 55% ee (the absolute configuration of the product 3aa has not been determined) (entry 6). The bifunctional chiral phosphine P7 displayed excellent catalytic activity, albeit with moderate enantioselectivity (entry 7). Decreasing the reaction temperature to 0 °C, the enantiomeric excess was slightly increased to 55% (entry 8). Further attempts to improve enantioselectivity through optimizing the reaction conditions failed.

Table 4 Screening of enantioselective reaction conditions^a

Entry	Cat.	t (h)	Yield^b (%)	ee^c (%)
a Reactions were carried out in 1 mL of CH2Cl2 using 0.1 mmol of 1a, 0.15 mmol of 2a and 20 mol% of phosphine.b Isolated yields.c Determined by chiral HPLC analysis.d The reaction was performed at 0 °C.
1	P1	120	86	25
2	P2	3	95	20
3	P3	7	96	45
4	P4	16	87	30
5	P5	48	94	25
6	P6	120	60	55
7	P7	3	97	50
8^d	P7	24	92	55

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To further demonstrate the synthetic utility of the reaction, we performed the reaction of 1a with allenoate 2a under the standard reaction conditions on the gram scale. To our delight, one gram of the phthalazinium dicyanomethanide 1a could smoothly convert into the corresponding product 3aa in 45 min with 98% isolated yield (Scheme 3). Treatment of cycloadduct 3ai using palladium catalyst in 1,2-dimethoxyethane (DME) at 80 °C afforded the aromatized product 7 in 78% yield (Scheme 3).

Scheme 3 Reaction on the gram-scale and further transformation of the product.

Conclusions

In summary, we have developed phosphine-catalyzed [3 + 2] cycloaddition of phthalazinium dicyanomethanides with allenoates to give 1,2,3,10b-tetrahydropyrrolo[2,1-a]phthalazine derivatives in excellent yields. The reactions of various allenoates with phthalazinium dicyanomethanides proceed very fast under mild conditions, providing a highly efficient method to heterocyclic compounds.

Experimental

Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Reactions were monitored through thin-layer chromatography (TLC). Chromatograms were visualized by fluorescence quenching under UV light at 254 nm. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200–300 mesh). Infrared spectra were recorded using a Bruker Optics TENSOR 27 instrument. ¹H and ¹³C NMR spectra were recorded using a Bruker-300 spectrometer. Accurate mass measurements were performed using an Agilent instrument with the ESI-MS technique.

General procedure for the phosphine-catalyzed [3 + 2] cycloaddition reaction: to an oven-dried 15 mL of Schlenk tube was added phthalazinium dicyanomethanide (0.1 mmol), 2 mL of CH₂Cl₂ and allenoate (0.15 mmol) at room temperature, then phosphine (0.02 mmol) was added to the above solution. The resulting mixture was stirred at room temperature for specified time depending on the TLC monitoring, and then was concentrated. The residue was purified by flash column (ethyl acetate/petroleum ether) to afford the corresponding cycloadduct.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21172253, 21372256, 21572264), the National S&T Pillar Program of China (2015BAK45B01), Research Fund for the Doctoral Program of Higher Education of China (No. 20120008110038), Chinese Universities Scientific Fund (No. 2016QC090).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1455366, 1455369, 1455370, 1455373 and 1465124. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra13643e

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