Pd-free Sonogashira coupling: one pot synthesis of phthalide via domino Sonogashira coupling and 5-exo-dig cyclization

Abstract

Phthalides have been synthesized exclusively in one pot via Pd-free Sonogashira coupling. A Cu-catalyzed domino Sonogashira coupling and 5-exo-dig cyclization between suitable substituted ortho-bromobenzoic acids and terminal alkynes afforded phthalides in good yields under mild reaction conditions.

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Phthalides are the core structural subunits of many drug candidates.¹ Though many phthalide derivatives are used in clinical medicine, the two most important marketed drugs are antiarthritic agent talniflumate² and the immunosuppressant drug mycophenolate mofetil.³ Particularly C3-substituted phthalides are exemplified by the natural products cytosporone E (1),⁴ fuscinarin (2),⁵ cryphonectric acid (3)⁶ (Fig. 1) an important intermediate in synthesis of complex natural products.⁷

Fig. 1 Bioactive phthalide derivatives.

Therefore, owing to their pharmacological importance and synthetic utility in organic synthesis development of efficient and economic method of preparation is of considerable interest for last few decades.

A number of methods for the synthesis of 3-substituted phthalide have been developed, most of them involved the cyclization of ortho-substituted arylaldehydes⁸ or C3-alkylation of phthalides.⁹ Recently, several transition-metal mediated syntheses of phthalide such as, Ru-catalysed cross-dehydrogenative coupling¹⁰ and Ru- or Rh-catalyzed intramolecular hydroacylation¹¹ have been reported. In literature there are few reactions involving Pd-free Sonogashira coupling for the synthesis of heterocycles and carbocycles. We envisaged that regio-selectively 3-substituted phthalides could be obtained by domino Sonogashira coupling and 5-exo-dig cyclization (Scheme 1).

Scheme 1 Retro-synthetic analysis.

Consequently, in this report we have described an interesting method for one-pot synthesis of 3-substituted phthalides exclusively starting from o-bromobenzoic acid and terminal alkyne (Scheme 2).

Scheme 2 Synthesis of phthalides.

The precursor 2-bromobenzoic acids were prepared in moderate to good yields via Pinnick oxidation¹² from the corresponding aldehydes. We started the investigation of the domino process with simple 2-bromobenzoic acid (1 mmol) and phenylacetylene (0.1 mmol) (Table 1). While screening with different Cu-salt, we identified CuI (10 mmol%) as a convenient and inexpensive catalyst that is more effective over the other. DMF gave the better yields of the product compared to other solvents. Addition of ligands (such as, 1, 10-phenanthroline) did not have marked effect on the reaction yields (Table 1, entry 6). Amine base triethylamine have prominent effect on reaction among the organic and inorganic bases. Some increment of the product yields was resulted with elevation of temperature from 60 °C to 80 °C (Table 1, entry 7). Further elevation temperature to 100 °C did not affect the yields of the reaction.

Table 1 Optimization of reaction conditions for the domino process^a

Entry	Catalyst	Base	Solvent	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: o-bromobenzoic acids (1 mmol), phenylacetylene (0.1 mmol), base (3.0 mmol), Cu-salt (10 mol%), solvent (3 mL).b Isolated yield.c With 1,10-phenanthroline ligand.
1	CuI	Et3N	DMF	60	3	75
2	CuBr	Et3N	DMF	60	3	45
3	CuCl	Et3N	DMF	60	3	30
4	Cu(OTf)2	Et3N	DMF	60	3	25
5	Cu(OAc)2	Et3N	DMF	60	3	0
6	CuI	Et3N	DMF	60	3	74^c
7	CuI	Et3N	DMF	80	3	90
8	CuI	Et3N	DMF	80	5	65
9	CuI	Et3N	DMA	80	3	65
10	CuI	Et3N	DMSO	80	3	53
11	CuI	NaOAc	DMF	80	3	50
12	CuI	Na2CO3	DMF	80	3	41
13	CuI	K2CO3	DMF	80	3	44
14	CuI	Et3N	DMF	100	3	90

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We found that prolonged reaction time did not give better conversion of phthalides. Optimal conditions for the domino reaction were finalized to be CuI (10 mol%), Et₃N (3.0 mmol), DMF (3 mL), 80 °C, 3 h.

Exclusive formation of the phthalide was unambiguously confirmed by the single crystal structure analysis of the product formed with an exo-cyclic double. CCDC of the compound 3a is 1000643† and ORTEP of the compound is shown in Fig 2.

Fig. 2 The X-ray crystal structure of compound 3a.

The scope and generality of the reaction was demonstrated by synthesizing a number of structurally diverse phthalide derivatives with varying substituents (Table 2). Results described in the Table 2 shows that our synthetic protocol has a wide range functional group tolerance, including amine, alkyl, halogens, methoxy and primary alcoholic OH. Influence of the electron-donating and withdrawing functional groups on both the coupling partner is quite clear from the results in Table 2. Electron withdrawing group such as F and pyridyl ring in combination with COOH in the 2-bromobenzoic acid part increase the reactivity of the C–Br bond producing good yields of phthalides (3b, 3l). In contrast, electron-donating group methyl, methoxy, ^tBu in both acids and alkyne part decrease the reactivity of alkyne moiety as well as C–Br bond resulting lower yields of phthalides (3c, 3d, 3f). A steric factor may be operating in the o-chloro substituent and the bulky aryl group in the alkyne part which afforded quite lower amount the phthalide formation (3g, 3i, 3j)‡.

Table 2 Synthesis of phthalide derivatives^a

Entry	Substrate	Alkyne	Product^b (% yields)
a Reaction conditions: o-bromobenzoic acids (1 mmol), terminal alkyne (0.1 mmol), Et3N (3.0 mmol), CuI (10 mol%), DMF (3 mL), 80 °C, 3 h.b Isolated yield in parenthesis.c Isocumarin (10%) was isolated.
1
2
3
4
5
6
7
8
9
10
11
12
13
14

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We propose that the reaction proceeds via domino reaction of Cu-mediated Sonogashira coupling and intramolecular 5-exo-dig cyclization (Scheme 3). Firstly, CuI in presence of Et₃N base formed Cu-acetylide which undergoes a Sonogashira type coupling with the C–Br bond to afford the o-alkynylcarboxylate (I). Intramolecular attack of the carboxylate on the Cu(I) co-ordinated electrophilic o-alkyne moiety in a 5-exo-dig fashion to give the intermediate II. The intermediate II finally produced our desired compound III and Cu(I) which enters into the catalytic cycle.

Scheme 3 Proposed reaction pathway.

Conclusions

In conclusion, we have developed a very short and efficient methodology for the regio-selective synthesis of 3-substituted phthalide using very cheap starting materials and under mild reaction conditions. Our methodology is a very convenient one to be applied in the total synthesis of complex molecules of prevalent pharmacological values.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1000643. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra07639g

‡ General procedure of the preparation of 3-substituted phthalides: o-bromobenzoic acids (1 mmol), terminal alkyne (0.1 mmol), Et₃N (3.0 mmol), CuI (10 mol%) and 3 mL of DMF were taken in a 25 mL round bottomed flask in argon atmosphere. The mixture was heated to 80 °C temperature for 3 h. The completion of the reaction was monitored by TLC checking. After completion of the reaction mixture was cooled to room temperature and diluted with water. It was then extracted with ethyl acetate (3 × 50 mL). Combined organic layer was washed with brine and evaporated to dryness under reduced pressure. The desired phthalide was isolated by usual column chromatography with a mixture of ethyl acetate and petroleum ether (1 : 20) as eluent. Spectral data of the representative compound 3-benzylideneisobenzofuran-1(3H)-one (3a): white solid; mp: 84–86 °C; yield: 90%; ¹H NMR (200 MHz, CDCl₃): 6.40 (1H, s), 7.29–7.44 (3H, m), 7.48–7.56 (1H, m), 7.66–7.76 (2H, m), 7.82–7.92 (3H, m); ¹³C NMR (50 MHz, CDCl₃): 107.2, 120.0, 123.4, 125.6, 128.5, 128.9 (2C), 129.8, 130.2 (2C), 133.2, 134.6, 140.7, 144.7, 167.2; elemental analysis: C: 81.07%; H: 4.54%; found: C: 81.00%; H: 4.49%; HRMS of C₁₅H₁₁O₂⁺ [M + H⁺]: 223.0754; observed: 223.0750.

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