Palladium-Catalyzed Hydroarylation of Diazoacetic Ester

Abstract

The novel procedure for the Pd-catalyzed hydroarylation of α-diazoacetic ester is reported. In the presence of a catalytic amount of PdCl₂(PPh₃)₂ the three-component reaction of aryl ­iodides, ethyl diazoacetate, and formic acid proceeds smoothly ­resulting in the formation of a series of arylacetates.

The transition-metal-catalyzed transformation of α-diazocarbonyl compounds has become a standard method in organic synthesis. They were used traditionally for carbene generation in reactions such as X–H insertion (X = C, N, O, S), cyclopropanation, and cycloaddition to nitriles and carbonyl compounds.[ ¹ ] More recently, the scope of their application was widened significantly including Pd-catalyzed cross-coupling reactions.[ ² ] Two types of cross-coupling reactions can be carried out depending on the reaction conditions (Scheme [1]). The first proceeds with retention of the diazo group,[ ³ ] whereas the second one ­follows with its loss.[ ⁴ ]

For example, Van Vranken and co-workers have developed a range of Pd-catalyzed three-component reactions[ ⁵ ] which generated organopalladium intermediates followed by capture with secondary amines or active methylene compounds as nucleophiles.

In this work we have elaborated the new Pd-catalyzed three-component coupling: aryl iodides could react with diazoacetate followed by hydrogenation with hydride ­anion generated from formic acid.

Aryl acetic acids and their derivatives compose an important class of organic compounds. Until now their synthesis and biological activity have been a focus of attention in synthetic and medicinal chemistry.[ ⁶ ] In fact, aryl acetic ­acids, for example, indomethancin, sulindac, ibufenac, ­diclofenac, etc. are one of the main categories of nonsteroidal anti-inflammatory drugs[7] [8] [9] [10] (Figure [1]). Therefore, the development of an effective protocol for the synthesis of analogous compounds is noteworthy.

Phenylacetic acid itself is provided by industry, and the main method for the preparation of this compound is the hydrolysis of benzyl cyanide, the letter in turn can be synthesized by interaction of benzyl halide with sodium cyanide.[ ¹¹ ] This preparation is based on application of toxic substances. Alternatively, phenylacetic acid can be prepared by numerous catalytic methods: carbonylation of benzyl alcohol in the presence of rhodium catalysts,[ ¹² ] insertion of ethyl diazoacetate into C–H bond,[ ¹³ ] and Pd-­catalyzed arylation of alkyl acetates.[ ¹⁴ ] The last approach is only presented by a few publications. Therefore elaboration of new synthetic pathways to substituted phenylacetic acid derivatives seems to be an actual problem.

The coupling of methyl 4-iodobenzoate (1a) with ethyl diazoacetate (EDA) in the presence of formic acid and base was selected as model reaction (Scheme [2]). Screening of catalytic systems, solvents, and bases revealed that application zero-valent palladium catalysts Pd₂(dba)₃ and Pd(PPh₃)₄ were less effective comparing to PdCl₂(PPh₃)₂.

The investigated chemical reaction appeared to be sensitive not only to a selected catalyst but also to a choice of solvent and base. To our delight, with acetonitrile as solvent the reaction afforded the cross-coupling product with higher yield (Table [1], entry 3). Triethylamine appeared to be the best base for this reaction, whereas other bases like K₂CO₃, pyridine, or DBU were found to be noneffective in this reaction.

Variation in reaction temperature was investigated further. An attempt to obtain hydroarylated product 2a at room temperature failed. Insignificant increase of reaction temperature dramatically influenced the amount of the synthesized product. It was found that the most favorable temperature was 70 °C, under these conditions isolated yield of 2a reached 69% (Table [1], entry 4). Further ­temperature evaluation reduced the yield of 2a.

A number of various aryl iodides were subjected to three-component hydroarylation under optimized reaction conditions (Scheme [3]). The method efficiency was examined upon the variation of the aryl moiety of aryl iodides (Table [2]). In the case of phenyl or aryl group containing an electron-withdrawing substituent the reaction proceeded smoothly giving satisfactory yields. It was not greatly affected by the steric hindrance of the substituents in the benzene ring.

Table 2 Hydroarylation of EDA with Aryl Iodides 1a–g ^a

Entry	Product		Time (h)	Yield (%)b
1		2a	1	69
2		2b	2.5	50
3		2c	2	61
4		2d	1	82
5		2e	1.5	71
6		2f	1.5	65
7		2g	1.5	85
8		2h	1.5	77

^a Reaction conditions: 1a–g (1 mmol), EDA (1.5 mmol), base (2.5 mmol), HCO₂H (1.5 mmol), Pd(PPh₃)₂Cl₂ (0.05 mmol), 70 °C.

^b Isolated yield.

Exploration of nitro- and methoxycarbonyl-containing substrates as well as 3-iodopyridine allowed for the synthesis of a range of ethyl arylacetates 2a–h in respectable yields (61–85%). Aryl iodides containing electron-­donating groups (Me, MeO) provided products in low yields from 5–20%. Aryl bromides and aryl chlorides appeared to be ineffective.

To bring light on the mechanism of interaction two special experiments were performed. Although diazocarboxylate 3 was obtained in some cases along with 2a as byproduct, isolated compound 3 was not converted into 2a (Scheme [4]). Moreover, it was found that diazo compound 3 can also be hydroarylated with aryl iodide 1a in the presence of formic acid resulting in diarylcarboxylate 4 in 60% yield (Scheme [5]).

The proposed mechanism of hydroarylation is presented in Scheme [6]. Palladium dichloride complex can be easily reduced by formic acid resulting in Pd(0) species. The catalytic cycle starts with oxidative addition to form ­aryl­palladium iodide complex A. Then addition of diazocompound to this complex could generate carbene complex B.[ ¹⁵ ] The migration of the aryl group to the carbene center, which is now presented in several publications,[16] [17] would produce benzylic intermediate C.

The exchange complex D can be easily produced by substitution of halogen with formate anion followed by liberation of carbon dioxide (complex E). Reductive elimination should provide the product (arylacetate) ­simultaneously with regeneration of the Pd(0) species.

In conclusion we have demonstrated, for the first time, the possibility of palladium-catalyzed hydroarylation of ethyl diazoacetate with aryl iodides in the presence of formic acid.[18] [19] The described reaction can serve as a pathway for the generation of difficult-to-access arylated carboxylic acid derivatives in satisfactory yield.

Acknowledgment

This research was supported by the Grant-in-Aid of Russian Foundation for Basic Research and NFFD of Ukraine (No 12-03-90421).

• References and Notes


For some reviews, see:
• 1a Ye T, McKervey MA. Chem. Rev. 1994; 94: 1091
  CrossrefSearch in Google Scholar
• 1b Zhang Z, Wang J. Tetrahedron 2008; 64: 6577
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• 1c Doyle MP, Duffy R, Ratnikov M, Zhou L. Chem. Rev. 2010; 110: 704
  CrossrefPubMedSearch in Google Scholar

For recent reviews, see:
• 2a Zhang Y, Wang J. Eur. J. Org. Chem. 2011; 1015
• 2b Zhang Y, Wang J. Chem. Commun. 2009; 5350
• 3 Peng C, Cheng J, Wang J. J. Am. Chem. Soc. 2007; 129: 8708
  CrossrefSearch in Google Scholar

Selected results:
• 4a Greenman KL, Van Vranken DL. Tetrahedron 2005; 61: 6438
  CrossrefSearch in Google Scholar
• 4b Peng C, Wang Y, Wang J. J. Am. Chem. Soc. 2008; 130: 1566
  CrossrefPubMedSearch in Google Scholar
• 4c Peng C, Yan G, Wang Y, Jiang Y, Zhang Y, Wang J. Synthesis 2010; 4154
  Thieme Connect
• 5a Devine SK. J, Van Vranken DL. Org. Lett. 2007; 2047
• 5b Devine SK. J, Van Vranken DL. Org. Lett. 2008; 1909
• 5c Kadirka R, Devine SK. J, Adams CS, Van Vranken DL. Angew. Chem. Int. Ed. 2009; 48: 3677
  CrossrefPubMedSearch in Google Scholar

For selected examples, see:
• 6a Takeda T, Gonda R, Hatano K. Chem. Pharm. Bull. 1997; 45: 697
  CrossrefSearch in Google Scholar
• 6b Kimura Y, Nishibe M, Nakajima H, Hamasaki T. Agric. Biol. Chem. 1991; 55: 1137
  CrossrefSearch in Google Scholar
• 7 Curhan SG, Eavey R, Shargorodsky J, Curhan GC. Am. J. Med. 2010; 123: 231
  CrossrefSearch in Google Scholar
• 8 Harrington PJ, Lodewijk E. Org. Process Res. Dev. 1997; 1: 72
  CrossrefSearch in Google Scholar
• 9 Musa KA. K, Matxain JM, Eriksson LA. J. Med. Chem. 2007; 50: 1735
  CrossrefSearch in Google Scholar
• 10 Bandgar BP, Sarangdhar RJ, Ahamed FA, Viswakarma S. J. Med. Chem. 2011; 54: 1202
  CrossrefSearch in Google Scholar
• 11 Adams R, Thal AF. Org. Synth., Coll. Vol. I 1941; 436
• 12 Duan J, Jiang J, Gong J, Fan Q, Jiang D. J. Mol. Catal. A: Chem. 2000; 159: 89
  CrossrefSearch in Google Scholar
• 13 Fructos MR, Belderrain TR, de Fremont P, Scott NM, Nolan SP, Diaz-Requejo MM, Perez PJ. Angew. Chem. Int. Ed. 2005; 44: 5284
  Search in Google Scholar
• 14a Hama T, Hartwig JF. Org. Lett. 2008; 1545
• 14b Biscoe MR, Buchwald SL. Org. Lett. 2009; 1773
• 15 Broering M, Brandt CD, Stellwag S. Chem. Commun. 2003; 2344
• 16 Albeniz AC, Espinet P, Manrique R, Perez-Mateo A. Angew. Chem. Int. Ed. 2002; 41: 2363
  CrossrefPubMedSearch in Google Scholar
• 17 Sole D, Vallverdu L, Solans X, Font-Bardia M, Bonjoch J. Organometallics 2004; 23: 1438
  CrossrefSearch in Google Scholar
• 18 Typical Procedure for the Pd-Catalyzed Cross-Coupling between Aryl Iodides and EDA To a mixture of aryl iodide 1a–h (1 mmol), PdCl₂(PPh₃)₂ (35 mg, 0.05 mmol) in a Schlenk flask under argon atmosphere, Et₃N (254 mg, 2.5 mmol) and formic acid (69 mg, 1.5 mmol) in MeCN (3 mL) were added. The mixture was stirred and heated to 70 °C, then EDA (171 mg, 1.5 mmol) in MeCN (2 mL) was added in small portions for 40–60 min. The mixture was stirred at the same temperature until 1a–h disappeared (the total time of heating indicated in Table 2). The solvent was evaporated in vacuo. Purification of the mixture by column chromatography (EtOAc–hexane = 1:10 v/v) gave the pure compounds 2a–h.
• 19 Selected Data for Synthesized Compounds Compound 2a: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, 2 H, J = 7.2 Hz), 7.35 (d, 2 H, J = 7.2 Hz), 4.14 (q, 2 H, J = 7.0 Hz), 3.88 (s, 3 H), 3.65 (s, 2 H), 1.23 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.8, 166.8, 139.3, 129.8, 129.3, 129.0, 61.0, 52.0, 41.3, 14.1. IR (film): 1733, 1615, 1290 cm^–1. Anal. Calcd for C₁₂H₁₄O₄: C, 64.85; H, 6.35. Found: C, 64.92; H, 6.39. Compound 2e: yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (m, 2 H), 7.62 (m, 1 H), 7.51 (m, 1 H), 4.18 (q, 2 H, J = 7.0 Hz), 3.73 (s, 2 H), 1.27 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.3, 148.2, 136.0, 135.6, 129.4, 124.4, 122.2, 61.4, 41.0, 14.1. IR (film): 1740, 1540, 1360 cm^–1. Anal. Calcd for C₁₀H₁₁NO₄: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.48; H, 5.39; N, 6.75. Compound 2g: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.52 (m, 2 H), 7.64 (d, 1 H, J = 7.8 Hz), 7.25 (m, 1 H), 4.16 (q, 2 H, J = 7.0 Hz), 3.61 (s, 2 H), 1.25 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.6, 150.3, 148.5, 136.7, 129.8, 128.5, 123.3, 61.1, 38.5, 14.1. IR (film): 1730, 1600 cm^–1. Anal. Calcd for C₉H₁₁NO₂: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.54; H, 6.66; N, 8.57.

• References and Notes


For some reviews, see:
• 1a Ye T, McKervey MA. Chem. Rev. 1994; 94: 1091
  CrossrefSearch in Google Scholar
• 1b Zhang Z, Wang J. Tetrahedron 2008; 64: 6577
  CrossrefSearch in Google Scholar
• 1c Doyle MP, Duffy R, Ratnikov M, Zhou L. Chem. Rev. 2010; 110: 704
  CrossrefPubMedSearch in Google Scholar

For recent reviews, see:
• 2a Zhang Y, Wang J. Eur. J. Org. Chem. 2011; 1015
• 2b Zhang Y, Wang J. Chem. Commun. 2009; 5350
• 3 Peng C, Cheng J, Wang J. J. Am. Chem. Soc. 2007; 129: 8708
  CrossrefSearch in Google Scholar

Selected results:
• 4a Greenman KL, Van Vranken DL. Tetrahedron 2005; 61: 6438
  CrossrefSearch in Google Scholar
• 4b Peng C, Wang Y, Wang J. J. Am. Chem. Soc. 2008; 130: 1566
  CrossrefPubMedSearch in Google Scholar
• 4c Peng C, Yan G, Wang Y, Jiang Y, Zhang Y, Wang J. Synthesis 2010; 4154
  Thieme Connect
• 5a Devine SK. J, Van Vranken DL. Org. Lett. 2007; 2047
• 5b Devine SK. J, Van Vranken DL. Org. Lett. 2008; 1909
• 5c Kadirka R, Devine SK. J, Adams CS, Van Vranken DL. Angew. Chem. Int. Ed. 2009; 48: 3677
  CrossrefPubMedSearch in Google Scholar

For selected examples, see:
• 6a Takeda T, Gonda R, Hatano K. Chem. Pharm. Bull. 1997; 45: 697
  CrossrefSearch in Google Scholar
• 6b Kimura Y, Nishibe M, Nakajima H, Hamasaki T. Agric. Biol. Chem. 1991; 55: 1137
  CrossrefSearch in Google Scholar
• 7 Curhan SG, Eavey R, Shargorodsky J, Curhan GC. Am. J. Med. 2010; 123: 231
  CrossrefSearch in Google Scholar
• 8 Harrington PJ, Lodewijk E. Org. Process Res. Dev. 1997; 1: 72
  CrossrefSearch in Google Scholar
• 9 Musa KA. K, Matxain JM, Eriksson LA. J. Med. Chem. 2007; 50: 1735
  CrossrefSearch in Google Scholar
• 10 Bandgar BP, Sarangdhar RJ, Ahamed FA, Viswakarma S. J. Med. Chem. 2011; 54: 1202
  CrossrefSearch in Google Scholar
• 11 Adams R, Thal AF. Org. Synth., Coll. Vol. I 1941; 436
• 12 Duan J, Jiang J, Gong J, Fan Q, Jiang D. J. Mol. Catal. A: Chem. 2000; 159: 89
  CrossrefSearch in Google Scholar
• 13 Fructos MR, Belderrain TR, de Fremont P, Scott NM, Nolan SP, Diaz-Requejo MM, Perez PJ. Angew. Chem. Int. Ed. 2005; 44: 5284
  Search in Google Scholar
• 14a Hama T, Hartwig JF. Org. Lett. 2008; 1545
• 14b Biscoe MR, Buchwald SL. Org. Lett. 2009; 1773
• 15 Broering M, Brandt CD, Stellwag S. Chem. Commun. 2003; 2344
• 16 Albeniz AC, Espinet P, Manrique R, Perez-Mateo A. Angew. Chem. Int. Ed. 2002; 41: 2363
  CrossrefPubMedSearch in Google Scholar
• 17 Sole D, Vallverdu L, Solans X, Font-Bardia M, Bonjoch J. Organometallics 2004; 23: 1438
  CrossrefSearch in Google Scholar
• 18 Typical Procedure for the Pd-Catalyzed Cross-Coupling between Aryl Iodides and EDA To a mixture of aryl iodide 1a–h (1 mmol), PdCl₂(PPh₃)₂ (35 mg, 0.05 mmol) in a Schlenk flask under argon atmosphere, Et₃N (254 mg, 2.5 mmol) and formic acid (69 mg, 1.5 mmol) in MeCN (3 mL) were added. The mixture was stirred and heated to 70 °C, then EDA (171 mg, 1.5 mmol) in MeCN (2 mL) was added in small portions for 40–60 min. The mixture was stirred at the same temperature until 1a–h disappeared (the total time of heating indicated in Table 2). The solvent was evaporated in vacuo. Purification of the mixture by column chromatography (EtOAc–hexane = 1:10 v/v) gave the pure compounds 2a–h.
• 19 Selected Data for Synthesized Compounds Compound 2a: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, 2 H, J = 7.2 Hz), 7.35 (d, 2 H, J = 7.2 Hz), 4.14 (q, 2 H, J = 7.0 Hz), 3.88 (s, 3 H), 3.65 (s, 2 H), 1.23 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.8, 166.8, 139.3, 129.8, 129.3, 129.0, 61.0, 52.0, 41.3, 14.1. IR (film): 1733, 1615, 1290 cm^–1. Anal. Calcd for C₁₂H₁₄O₄: C, 64.85; H, 6.35. Found: C, 64.92; H, 6.39. Compound 2e: yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (m, 2 H), 7.62 (m, 1 H), 7.51 (m, 1 H), 4.18 (q, 2 H, J = 7.0 Hz), 3.73 (s, 2 H), 1.27 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.3, 148.2, 136.0, 135.6, 129.4, 124.4, 122.2, 61.4, 41.0, 14.1. IR (film): 1740, 1540, 1360 cm^–1. Anal. Calcd for C₁₀H₁₁NO₄: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.48; H, 5.39; N, 6.75. Compound 2g: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.52 (m, 2 H), 7.64 (d, 1 H, J = 7.8 Hz), 7.25 (m, 1 H), 4.16 (q, 2 H, J = 7.0 Hz), 3.61 (s, 2 H), 1.25 (t, 3 H, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.6, 150.3, 148.5, 136.7, 129.8, 128.5, 123.3, 61.1, 38.5, 14.1. IR (film): 1730, 1600 cm^–1. Anal. Calcd for C₉H₁₁NO₂: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.54; H, 6.66; N, 8.57.

• Supplementary Material