Sodium Hydride Induced N-Arylation of Diisopropyl Azodicarboxylate by Aryl Trifluoromethanesulfonates

Abstract

A method for intermolecular N-arylation of the anionic species derived from diisopropyl azodicarboxylate and sodium hydride by aryl trifluoromethanesulfonates, in the presence of a ligand-free copper(I) oxide catalyst at 80 °C in N,N-dimethylformamide, is reported. A variety of functionalized aryl triflouromethanesulfonates were efficiently coupled by this method.

The past decade has witnessed significant progress in the development of cross-coupling reactions.[1] Transition metals are effective catalysts in cross-coupling reactions, particularly C–N bond-formation processes.[2] Several N-nucleophiles, such as amines, amides, hydrazines, and N-heterocycles, participate in C–N cross-coupling reactions,[3] [4] [5] and the application of other compounds as amination reagents have been developed.[6,7] Diisopropyl azodicarboxylate (DIAD) has been used as a suitable amination reagent for the preparation of hydrazides that can be subsequently deprotected to amines. However, this reaction has been limited to electron-rich aromatic systems.[8–10]

Recently, we reported effective systems for the copper-catalyzed coupling of aryl halides with the Mitsunobu reagent.[11] In this Letter, we describe C–N coupling of aryl triflates with the anionic adduct derived from DIAD and NaH, which constitutes a useful method for intermolecular N-arylation with aryl trifluoromethanesulfonates (ArOTfs) in the presence of a ligand-free Cu₂O catalyst and lithium iodide (Scheme [1]).

Initial investigations show that 10 mol% of CuI could accomplish the transformation, and the desired coupling product was obtained in 45% yield, together with reduced DIAD in 20% yield. Phenyl trifluoromethanesulfonate, NaH, and DIAD were selected as prototypical reaction partners for the Cu₂O-catalyzed coupling reaction. The optimized reaction conditions and catalyst system for this transformation involved phenyl trifluoromethanesulfonate (1 mmol), DIAD (1.2 mmol), NaH (1.2 mmol), Cu₂O (10 mol%), and lithium iodide (1.0 mmol) in DMF (2 mL) at 80 °C (see Table [1]).

In addition, 1,10-phenanthroline can be used as a unique ligand for the N-arylation with chlorobenzenes (Table [2]). However, this conversion required higher catalyst loading (30 mol%) compared to those of aryl iodides, bromides, and triflates.

A series of substituted aryl O-triflates, as shown in Table [2], was subjected to the reaction conditions described above. Aryl O-triflates having electron-withdrawing, electron-releasing, and bulky groups on the aromatic ring, afforded moderate to good yields (Table [2]).

Table 2 Reaction Scope for Aryl Sources

Entry	Ar	Product	Yield (%) of 3
1	Ph	3a	83
2	1-naphthyl	3b	80
3	4-MeC6H4	3c	79
4	2-MeC6H4	3d	72
5	3-MeC6H4	3e	80
6	4-MeOC6H4	3f	70
7	2-F3CC6H4	3g	63
8	3-F3CC6H4	3h	81
9	4-NCC6H4	3i	84
10	2-O2NC6H4	3j	67
11	4-O2NC6H4	3k	94
12	2-thienyl	3l	79
13	2-ClC6H4	3m	76

The optimized reaction conditions given above were compatible with the presence of functional groups such as CN, NO₂, CF₃, OMe, and halogens on the aromatic rings of the aryl halides and triflates. With iodobenzene as arylating reagent, the reaction could be carried out at 25 °C in the presence of Cu₂O in DMF to achieve the desired product in 90% yield.

A plausible mechanism for the formation of products 3 [12] is given in Scheme [2]. The copper complex 4, formed from 1 and Cu₂O, undergoes a reduction reaction with NaH to generate the salt 5. This salt is attacked by aryl trifluoromethanesulfonate 2 to afford aryl hydrazide 3.

In conclusion, we have described a novel system for the copper-catalyzed N-arylation of diisopropyl azodicarboxylate in good to excellent yields. This system operates under mild enough conditions and tolerates a wide array of functional groups. Using this procedure iodobenzene was selectively coupled with diisopropyl azodicarboxylate in the presence of bromobenzene and benzene O-triflates.

• References and Notes

• 1 Dai C, Fu GC. J. Am. Chem. Soc. 2001; 123: 2719
  CrossrefPubMedSearch in Google Scholar

Reviews:
• 2a Wolfe JP, Wagaw S, Marcoux J.-F, Buchwald SL. Acc. Chem. Res. 1998; 31: 805
  CrossrefSearch in Google Scholar
• 2b Hartwig JF. Angew. Chem. Int. Ed. 1998; 37: 2046
  CrossrefPubMedSearch in Google Scholar
• 2c Muci AR, Buchwald SL. Top. Curr. Chem. 2002; 219: 133
  Search in Google Scholar
• 3 Shafir A, Buchwald SL. J. Am. Chem. Soc. 2006; 128: 8742
  CrossrefPubMedSearch in Google Scholar
• 4 Larsson P, Bolm C, Norrby P. Chem. Eur. J. 2010; 16: 13613
  CrossrefSearch in Google Scholar
• 5 Swapna K, Murthy SN, Nageswar YV. Eur. J. Org. Chem. 2010; 6678
• 6 Monguchi Y, Maejima T, Mori S, Maegawa T, Sajiki H. Chem. Eur. J. 2010; 16: 7372
  CrossrefSearch in Google Scholar
• 7 Terada M, Tsushima D, Nakano M. Adv. Synth. Catal. 2009; 351: 2817
  CrossrefSearch in Google Scholar
• 8 Katritzky AR, Wu J, Verin SV. Synthesis 1995; 651
  Thieme Connect
• 9 Velarde-Ortiz R, Guijarro A, Rieke RD. Tetrahedron Lett. 1998; 39: 9157
  CrossrefSearch in Google Scholar
• 10 Uemura T, Chatani N. J. Org. Chem. 2005; 70: 8631
  CrossrefPubMedSearch in Google Scholar
• 11 Yavari I, Ghazanfarpour-Darjani M, Ahmadian S, Solgi Y. Synlett 2011; 1745
  Thieme Connect
• 12 Typical Procedure for the Preparation of Aryl Hydrazides 3 To a stirred solution of DIAD (1.2 mmol) in DMF (2 mL) at 0 °C, NaH (0.05 g, 1.2 mmol) was added in portions over 20 min. Then, the aryl O-triflate (1.0 mmol), LiI (134 mg, 1mmol), and Cu₂O (15 mg, 0.1 mmol) were added to the reaction mixture, which was stirred at 80 °C for 8 h under N₂. The reaction was cooled and quenched by adding CH₂Cl₂ (2 mL) and sat. aq NH₄Cl (3 mL). The mixture was stirred for an additional 30 min, and two layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 2 mL), the combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel; hexane–EtOAc, 3:1) to give the product. Spectroscopic analyses of all derivatives except 3d and 3m have been reported.¹¹ Diisopropyl 1-o-Tolylhydrazine-1,2-dicarboxylate (3d) Yellow solid; mp 101–103 °C; yield: 0.21 g (72%). IR (KBr): ν_max = 3242, 1541, 1518, 1330, 1140 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.16 (6 H, d, ³ J = 7.1 Hz, 2 Me), 1.25 (6 H, d, ³ J = 7.0 Hz, 2 Me), 2.33 (3 H, s, Me), 4.97–4.99 (2 H, m, 2 CHO), 7.06 (1 H, br s, NH), 7.19–7.22 (3 H, m, 3 CH), 7.44 (1 H, d, ³ J = 7.8 Hz, CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.1 (2 Me), 21.4 (2 Me), 26.1 (Me), 68.9 (CHO), 70.1 (CHO), 113.1 (CH), 119.2 (CH), 126.3 (CH), 129.2 (CH), 130.9 (C), 140.5 (C), 155.7 (C=O), 156.1 (C=O). MS: m/z (%) = 294 (4 [M⁺], 235 (57), 192 (42), 177 (40), 133 (100), 102 (76), 58 (34), 44 (28). Anal. Calcd (%) for C₁₅H₂₂N₂O₄ (294.35): C, 61.21; H, 7.53; N, 9.52. Found: C, 59.89; H, 7.59; N, 9.59. Diisopropyl 1-(2-Chlorophenyl)hydrazine-1,2-dicarboxylate (3m) Colorless solid; mp 103–106 °C; yield 0.24 g (76%). IR (KBr): ν_max = 3286, 1564, 1518, 1332, 1136 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.13 (6 H, d, ³ J = 6.9 Hz, 2 Me), 1.26 (6 H, d, ³ J = 7.0 Hz, 2 Me), 4.98–5.01 (2 H, m, 2 CHO), 7.17 (1 H, br s, NH), 7.46–7.53 (2 H, m, 2 CH), 7.62–7.67 (2 H, m, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.9 (2 Me), 22.3 (2 Me), 70.1 (CHO), 71.0 (CHO), 123.8 (CH), 128.1 (CH), 131.6 (CH), 132.6 (CH), 133.0 (C), 139.4 (C), 154.3 (C=O), 156.0 (C=O). MS: m/z (%) = 314 (1) [M⁺], 225 (12), 212 (53), 197 (45), 152 (100), 102 (64), 111 (12), 58 (35), 44 (19). Anal. Calcd (%) for C₁₄H₁₉ClN₂O₄ (314.76): C, 53.42; H, 6.08; N, 8.90. Found: C, 53.79; H, 6.04; N, 8.98.

• References and Notes

• 1 Dai C, Fu GC. J. Am. Chem. Soc. 2001; 123: 2719
  CrossrefPubMedSearch in Google Scholar

Reviews:
• 2a Wolfe JP, Wagaw S, Marcoux J.-F, Buchwald SL. Acc. Chem. Res. 1998; 31: 805
  CrossrefSearch in Google Scholar
• 2b Hartwig JF. Angew. Chem. Int. Ed. 1998; 37: 2046
  CrossrefPubMedSearch in Google Scholar
• 2c Muci AR, Buchwald SL. Top. Curr. Chem. 2002; 219: 133
  Search in Google Scholar
• 3 Shafir A, Buchwald SL. J. Am. Chem. Soc. 2006; 128: 8742
  CrossrefPubMedSearch in Google Scholar
• 4 Larsson P, Bolm C, Norrby P. Chem. Eur. J. 2010; 16: 13613
  CrossrefSearch in Google Scholar
• 5 Swapna K, Murthy SN, Nageswar YV. Eur. J. Org. Chem. 2010; 6678
• 6 Monguchi Y, Maejima T, Mori S, Maegawa T, Sajiki H. Chem. Eur. J. 2010; 16: 7372
  CrossrefSearch in Google Scholar
• 7 Terada M, Tsushima D, Nakano M. Adv. Synth. Catal. 2009; 351: 2817
  CrossrefSearch in Google Scholar
• 8 Katritzky AR, Wu J, Verin SV. Synthesis 1995; 651
  Thieme Connect
• 9 Velarde-Ortiz R, Guijarro A, Rieke RD. Tetrahedron Lett. 1998; 39: 9157
  CrossrefSearch in Google Scholar
• 10 Uemura T, Chatani N. J. Org. Chem. 2005; 70: 8631
  CrossrefPubMedSearch in Google Scholar
• 11 Yavari I, Ghazanfarpour-Darjani M, Ahmadian S, Solgi Y. Synlett 2011; 1745
  Thieme Connect
• 12 Typical Procedure for the Preparation of Aryl Hydrazides 3 To a stirred solution of DIAD (1.2 mmol) in DMF (2 mL) at 0 °C, NaH (0.05 g, 1.2 mmol) was added in portions over 20 min. Then, the aryl O-triflate (1.0 mmol), LiI (134 mg, 1mmol), and Cu₂O (15 mg, 0.1 mmol) were added to the reaction mixture, which was stirred at 80 °C for 8 h under N₂. The reaction was cooled and quenched by adding CH₂Cl₂ (2 mL) and sat. aq NH₄Cl (3 mL). The mixture was stirred for an additional 30 min, and two layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 2 mL), the combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel; hexane–EtOAc, 3:1) to give the product. Spectroscopic analyses of all derivatives except 3d and 3m have been reported.¹¹ Diisopropyl 1-o-Tolylhydrazine-1,2-dicarboxylate (3d) Yellow solid; mp 101–103 °C; yield: 0.21 g (72%). IR (KBr): ν_max = 3242, 1541, 1518, 1330, 1140 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.16 (6 H, d, ³ J = 7.1 Hz, 2 Me), 1.25 (6 H, d, ³ J = 7.0 Hz, 2 Me), 2.33 (3 H, s, Me), 4.97–4.99 (2 H, m, 2 CHO), 7.06 (1 H, br s, NH), 7.19–7.22 (3 H, m, 3 CH), 7.44 (1 H, d, ³ J = 7.8 Hz, CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.1 (2 Me), 21.4 (2 Me), 26.1 (Me), 68.9 (CHO), 70.1 (CHO), 113.1 (CH), 119.2 (CH), 126.3 (CH), 129.2 (CH), 130.9 (C), 140.5 (C), 155.7 (C=O), 156.1 (C=O). MS: m/z (%) = 294 (4 [M⁺], 235 (57), 192 (42), 177 (40), 133 (100), 102 (76), 58 (34), 44 (28). Anal. Calcd (%) for C₁₅H₂₂N₂O₄ (294.35): C, 61.21; H, 7.53; N, 9.52. Found: C, 59.89; H, 7.59; N, 9.59. Diisopropyl 1-(2-Chlorophenyl)hydrazine-1,2-dicarboxylate (3m) Colorless solid; mp 103–106 °C; yield 0.24 g (76%). IR (KBr): ν_max = 3286, 1564, 1518, 1332, 1136 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.13 (6 H, d, ³ J = 6.9 Hz, 2 Me), 1.26 (6 H, d, ³ J = 7.0 Hz, 2 Me), 4.98–5.01 (2 H, m, 2 CHO), 7.17 (1 H, br s, NH), 7.46–7.53 (2 H, m, 2 CH), 7.62–7.67 (2 H, m, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.9 (2 Me), 22.3 (2 Me), 70.1 (CHO), 71.0 (CHO), 123.8 (CH), 128.1 (CH), 131.6 (CH), 132.6 (CH), 133.0 (C), 139.4 (C), 154.3 (C=O), 156.0 (C=O). MS: m/z (%) = 314 (1) [M⁺], 225 (12), 212 (53), 197 (45), 152 (100), 102 (64), 111 (12), 58 (35), 44 (19). Anal. Calcd (%) for C₁₄H₁₉ClN₂O₄ (314.76): C, 53.42; H, 6.08; N, 8.90. Found: C, 53.79; H, 6.04; N, 8.98.