Cross-coupling reaction of aryl diazonium salts with azodicarboxylate using FeCl₂

Abstract

Arene diazonium salts have been employed as the aryl source in reaction with dialkyl azodicarboxylates to form N-aryl hydrazide derivatives. The optimum conditions are developed using FeCl₂ in DMSO at 25 °C for 2 h. Various functional groups were tolerated under the optimum conditions.

---

Introduction

Diazonium compounds are important intermediates due to their high potential for applications in the fields of organic synthesis.^1–3 Besides the classical reactions, aryl diazonium salts also serve as an aryl source in transition metals-catalyzed cross-coupling reactions to form carbon–carbon and carbon–heteroatom bonds.^4–8 Because of the pioneering study of Kikukawa and Matsuda,⁹ the coupling reactions of arene diazonium salts have been well developed over the past decades. Regardless of the long history, these substrates still attract attention and new reports have been emerging constantly. Though arene diazonium salts have been established as the aryl source in catalytic reactions, the main drawback is that they are not commercially available and in most cases have to be prepared before use. In this context, one-pot diazotization^10–12/cross-coupling is obviously more effective.

Dialkyl azodicarboxylates (DAAD) have been employed as the coupling partners in reactions with aryl metals reagents,^13a–c arylboronic reagents,¹⁴ and arenes¹⁵ for the synthesis of N-aryl hydrazides. However, these reactions are typically limited to electron-rich aryl sources. Recently, Yavari and co-workers have also reported novel procedures to form N-aryl hydrazides using various active aryl sources, dialkyl azodicarboxylates and triphenyl phosphine or sodium hydride.^16,17 Based on these findings, we seek to examine the efficiency of arene diazonium salts with dialkyl azodicarboxylates to form N-aryl hydrazides using iron(II) salts.

Results and discussion

We initially examined the coupling of aniline (1a) with diisopropyl azodicarboxylate (2) using Fe(OAc)₂, acetic acid, and tert-butyl nitrite as a model reaction to assess the reaction efficiency. Stirring in DMSO at 25 °C for 2 h resulted diisopropyl 1-(phenyl)-hydrazine-1,2-dicarboxylate in 59% yield together with biphenyl in 19% yield.

To develop the reaction conditions a variety of promoters, solvents, and additives were examined (Table 1). No reaction occurred in the absence of an iron(II) salt (Table 1, entry 21). A catalyst screen also showed that FeCl₂ gave the best result (Table 1, entry 2). Reaction conducted with anhydrous FeCl₂ in extra dry DMSO formed only traces of the desired product (Table 1, entry 3). It could be deduced that H₂O involves on reaction pathway. Other iron salts also promoted the reaction; however, the yields were comparatively lowers (Table 1, entries 4 to 8). CuI was not efficient in this transformation, (Table 1, entry 9) whereas reactions conducted with Zn and SmI₂ occurred to moderate conversion in more than 4 h (Table 1, entries 10 and 11). It is worth mentioning that eosin Y also promotes the reaction with good yield (Table 1, entry 12). Among the solvents examined, DMSO was superior to other solvents (Table 1, entry 2). Reaction in an apolar solvent like toluene resulted in low conversions (Table 1, entry 13). The desired product was obtained only in 23% yield when H₂O was used as the solvent (Table 1, entry 14). This study indicates that the higher amount of H₂O inhibits the reaction. Other protic solvents, such as EtOH, also gave the product in low yield (Table 1, entry 15). Note that when the reaction was conducted in DMSO/H₂O (10 : 1) mixture occurred comparatively in lower yield than those of DMSO. A variety of acids were also considered to evaluate the influence of the acidity and the nature of the counter-ion on reaction progress (Table 1, entries 18 to 20). The results showed that although the tetrafluoroborate anion has been widely used in the literature, it was not the most effective counter-ion for this reaction. Finally, p-TsOH was selected as the acid of choice based on the cost and efficiency. Note that reaction conducted with 1.0 mmol of FeCl₂, formed only traces of the desired product which supports the suggested mechanism pathway.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Acid	Yield (%)
a Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), promoter (2.0 mmol), acid (1.0 mmol), t-BuONO (1.1 mmol), and solvent (3 mL) were stirred at 25 °C for 2 h, under a N2 atmosphere.b Anhydrous FeCl2 was used.c DMSO/H2O was used in a ratio of 10 : 1 as the solvent.d 1.0 mmol of FeCl2 was used.
1	Fe(OAc)2	DMSO	TsOH	59
2	FeCl2	DMSO	TsOH	94
3	FeCl2	DMSO	TsOH	6^b
4	FeF2	DMSO	TsOH	54
5	FeI2	DMSO	TsOH	87
6	FeC2O4	DMSO	TsOH	32
7	Fe(BF4)2	DMSO	TsOH	88
8	FeSO4	DMSO	TsOH	Trace
9	CuI	DMSO	TsOH	Trace
10	Zn	DMSO	TsOH	64
11	SmI2	DMSO	TsOH	41
12	Eosin Y	DMSO	TsOH	91
13	FeCl2	Toluene	TsOH	Trace
14	FeCl2	H2O	TsOH	23
15	FeCl2	EtOH	TsOH	15
16	FeCl2	DMF	TsOH	71
17	FeCl2	DMSO	TsOH	46^c
18	FeCl2	DMSO	HOAc	69
19	FeCl2	DMSO	MsOH	80
20	FeCl2	DMSO	HBF4	46
21	—	DMSO	TsOH	Trace
22	FeCl2	DMSO	TsOH	Trace^d

---

After having defined the optimum reaction conditions, we sought to explore the scope of the reaction (Table 2). Cross-coupling of electron-neutral aryl diazonium salts proceeded with good yields (entries 1 and 2). The reactions conducted with 3- and 4-methyl substituted aniline proceeded in high conversion (entries 1 and 2). This reaction is not sensitive to steric effects as ortho-substituted diazonium salt also afforded the desired product in high yield (entry 5). Electron-poor substrates resulted in slightly lower yields (entries 7 to 11) than those of electron-neutral and electron-rich substrates, which are probably due to the lower nucleophilicity of the aromatic ring. In the presence of 4-bromo and 2-bromo benzenamine (1l, 1m), amination occurred exclusively at the amine position (entry 12). Note that the tolerance for bromide on the aromatic ring offers an opportunity for subsequent cross-coupling, facilitating expedient synthesis of highly complex aryl hydrazides. Heteroaromatic substrate 1n also achieved the desired product in acceptable yield (entry 14). The presence of OH moiety on aromatic ring was not compatible with this amination reaction.

Table 2 Reaction scope for arene diazonium salts^a

Entry	1	Ar	Yield (%)
a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), FeCl2 (2.0 mmol), TsOH (1.0 mmol), t-BuONO (1.1 mmol), and DMSO (3 mL) were stirred at 25 °C for 2 h, under a N2 atmosphere.
1	a	Ph	3a, 94
2	b	1-Naphthyl	3b, 91
3	c	4-Tol	3c, 94
4	d	3-Tol	3d, 90
5	e	2-Tol	3e, 91
6	f	4-MeO–C6H4	3f, 97
7	g	2-F3C–C6H4	3g, 86
8	h	3-F3C–C6H4	3h, 87
9	i	4-NC–C6H4	3i, 83
10	j	4-NO2–C6H4	3j, 81
11	k	2-NO2–C6H4	3k, 86
12	l	4-Br–C6H4	3l, 93
13	m	2-Br–C6H4	3m, 87
14	n	5-Methyl thienyl	3n, 75

---

It is worth mentioning that when 2 mmol of phenyl diazonium salt was treated with 2 (1 mmol) at the optimum conditions, diisopropyl 1,2-(diphenyl)-1,2-hydrazinedicarboxylate (4) was achieved in 91% yield (Scheme 1). This result suggests that the mechanism involves reductive coupling of the aryldiazonium salt and azodicarboxylate with the oxidation of the Fe²⁺ ion.

Scheme 1 Formation of 1,2-diphenyl hydrazides.

As shown in Scheme 2, the proposed mechanism starts with the formation of an aryl radical 5 by electron transfer from Fe(II) to the aryldiazonium salt. Addition of the aryl radical to diisopropyl azodicarboxylate gives radical intermediate 6. This intermediate is further transformed to the final coupling product 3 by two possible pathways: (a) reduction of the radical intermediate 6 by Fe(II) to give 7, followed by protonation with H₂O or (b) direct hydrogen radical transfer from H₂O to 6. The radical mechanism is further supported by the fact that 2,2,6,6-tetramethylpiperidinoxyl (TEMPO) effectively inhibits the reaction.

Scheme 2 Plausible mechanism for the formation of N-aryl hydrazide derivatives.

Experimental

Amines, azodicarboxylate, promoters, t-BuONO, acids, and solvents were obtained from Merck and were used without further purification. Mp: electrothermal-9100 apparatus. IR spectra: Shimadzu IR-460 spectrometer. ¹H and ¹³C NMR spectra: Bruker DRX-500 AVANCE instrument; in CDCl₃ at 500.1 and 125.7 MHz, respectively; δ in ppm, J in Hz. EI-MS (70 eV): Finnigan-MAT-8430 mass spectrometer, in m/z. Elemental analyses (C, H, N) were performed with a Heraeus CHN-O-Rapid analyzer. The results agreed favourably with the calculated values. All known compounds gave satisfactory spectroscopic data and were consistent with that reported in the literature^13,14 (see ESI† for characterization data for all products).

General procedure for synthesis of compound 3 or 4

A sample tube containing aryl amine (1.0 or 2.0 mmol), t-BuONO (1.1 mmol), p-TsOH (1.0 mmol), and DMSO (3 mL) was stirred for 10 min at 25 °C. Afterwards, DIAD (1.0 mmol) and FeCl₂ (2.0 mmol) were added to the resulting mixture with the ambient conditions. The mixture was then evacuated, and backfilled with N₂ (three times) and stirred for 2 h at 25 °C. The crude reaction mixture was diluted with EtOAc (5 mL) and a saturated NH₄Cl solution (3 mL). The mixture was stirred for an additional 30 min and the two layers were separated. The aqueous layer was extracted with EtOAc (2 mL × 3). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo to yield the crude product 3 (purity 84%). The crude product was further purified by recrystallization from diethyl ether.

Diisopropyl 1-(2-methylphenyl)-1,2-hydrazinedicarboxylate (3e). Colorless solid, mp: 109–110.5 °C; yield: 0.27 g (91%). IR (KBr) (ν_max, cm⁻¹): 3242, 3035, 2978, 1541, 1518, 1330, 1140. ¹H NMR (500.1 MHz, CDCl₃): δ_H = 1.16 (6H, d, ³J = 7.1 Hz, 2 Me), 1.22 (6H, d, ³J = 7.0 Hz, 2 Me), 2.33 (3H, s, Me), 4.97–5.02 (2H, m, 2 CHO), 6.96 and 7.04 (H, br s, NH), 7.14–7.25 (3H, m), 7.44 (1H, br). ¹³C NMR (125.7 MHz, CDCl₃): δ_C = 21.1 (2 Me), 21.4 (2 Me), 26.1 (Me), 68.9 (CHO), 70.1 (CHO), 113.1 (CH, br), 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 (M⁺, 4), 235 (37), 207 (26), 192 (65), 133 (100), 105 (72), 102 (87), 60 (31). Anal. calcd for C₁₅H₂₂N₂O₄ (294.35): C, 61.21; H, 7.53; N, 9.52%. Found: C, 61.37; H, 7.70; N, 9.57%.

Diisopropyl 1-(4-bromophenyl)-1,2-hydrazinedicarboxylate (3l). Colorless solid, mp: 126–128 °C; yield: 0.33 g (93%). IR (KBr) (ν_max, cm⁻¹): 3267, 3053, 2982, 1557, 1531, 1308, 1107, 658. ¹H NMR (500.1 MHz, CDCl₃): δ_H = 1.23 (6H, d, ³J = 6.3 Hz, 2 Me), 1.25 (6H, d, ³J = 6.7 Hz, 2 Me), 4.96–5.03 (2H, m, 2 CHO), 6.97 (1H, br s, NH), 7.30 (2H, m, 2 CH), 7.43 (2H, d, ³J = 6.5 Hz, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ_C = 21.3 (2 Me), 21.6 (2 Me), 70.1 (CHO), 72.3 (CHO), 114.4 (C), 119.1 (2 CH, br), 131.5 (2 CH), 137.8 (C), 154.6 (C=O), 156.1 (C=O). MS: m/z (%) = 359 (M⁺, 7), 361 ((M + 2)⁺, 7), 279 (36), 270 (52), 183 (35), 155 (100), 115 (78), 103 (63), 59 (81). Anal. calcd for C₁₄H₁₉BrN₂O₄ (359.22): C, 46.81; H, 5.33; N, 7.90; Br, 22.24%. Found: C, 46.89; H, 5.46; N, 7.99; Br, 22.35%.

Diisopropyl 1-(2-bromophenyl)-1,2-hydrazinedicarboxylate (3m). Colorless solid, mp: 109–111 °C; yield: 0.31 g (87%). IR (KBr) (ν_max, cm⁻¹): 3267, 3053, 2982, 1557, 1531, 1308, 1107, 658. ¹H NMR (500.1 MHz, CDCl₃): δ_H = 1.21 (6H, d, ³J = 6.4 Hz, 2 Me), 1.22 (6H, d, ³J = 6.6 Hz, 2 Me), 4.98–5.02 (2H, m, 2 CHO), 6.95 and 7.09 (1H, br s, NH), 7.25–7.81 (4H, m, 4 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ_C = 21.9 (2 Me), 22.2 (2 Me), 70.1 (CHO), 70.9 (CHO), 124.2 (CH, br), 126.5 (CH), 131.9 (CH), 132.0 (CH), 133.0 (C), 139.4 (C), 154.3 (C=O), 156.0 (C=O). MS: m/z (%) = 359 (M⁺, 2), 361 ((M + 2)⁺, 5), 279 (21), 270 (38), 183 (30), 155 (100), 115 (78), 103 (63), 59 (81). Anal. calcd for C₁₄H₁₉BrN₂O₄ (359.22): C, 46.81; H, 5.33; N, 7.90; Br, 22.24%. Found: C, 46.85; H, 5.38; N, 7.94; Br, 22.30%.

Diisopropyl 1-(5-methyl-thiophen-2-yl)-1,2-hydrazinedicarboxylate (3n). Yellow solid, mp: 98–100 °C; yield: 0.22 g (75%). IR (KBr) (ν_max, cm⁻¹): 3242, 3048, 2976, 1552, 1523, 1321, 1127. ¹H NMR (500.1 MHz, CDCl₃): δ_H = 1.25 (6H, d, ³J = 6.8 Hz, 2 Me), 1.29 (6H, d, ³J = 7.0 Hz, 2 Me), 2.42 (3H, s, Me), 4.99–5.04 (2H, m, 2 CHO), 6.42–6.78 (3H, m). ¹³C NMR (125.7 MHz, CDCl₃): δ_C = 21.3 (2 Me), 21.5 (2 Me), 41.7 (Me), 69.4 (CHO), 71.3 (CHO), 105.7 (CH, br), 114.3 (CH), 129.1 (C), 139.7 (C), 156.1 (C=O), 156.6 (C=O). MS: m/z (%) = 300 (M⁺, 2), 241 (13), 203 (34), 183 (16), 97 (100), 59 (34). Anal. calcd for C₁₃H₂₀N₂O₄S (300.37): C, 51.98; H, 6.71; N, 9.33; S, 10.68%. Found: C, 52.13; H, 6.89; N, 9.28; S, 10.84%.

Diisopropyl 1,2-bis(phenyl)-1,2-hydrazinedicarboxylate (4). Colorless solid, mp: 155–158 °C; yield: 0.34 g (94%). IR (KBr) (ν_max, cm⁻¹): 3042, 2978, 1567, 1551, 1320, 1118. ¹H NMR (500.1 MHz, CDCl₃): δ_H = 1.26–1.29 (12H, m, 4 Me), 5.05–5.10 (2H, m, 2 CHO), 7.17–7.51 (10H, m, 10 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ_C = 21.9 (4 Me), 70.8 (2 CHO), 123.1 (2 CH, br), 126.4 (2 CH, br), 128.4 (2 CH), 131.7 (2 CH), 132.6 (2 CH), 141.2 (2 C), 155.3 (2 C=O). MS: m/z (%) = 356 (M⁺, 1), 269 (18), 182 (25), 87 (12), 77 (100). Anal. calcd for C₂₀H₂₄N₂O₄ (356.42): C, 67.40; H, 6.79; N, 7.86%. Found: C, 67.69; H, 6.84; N, 8.10%.

Conclusion

We have developed a new cross-coupling reaction for the synthesis of N-aryl hydrazides using readily available and easily prepared starting materials with ambient conditions and a short reaction time. Using this procedure, a simple recrystallization from ether would suffice to isolate the pure titled product. The electronic and steric variations of substrates did not change the yield in an appreciable manner. The reaction is completely selective for a cross-coupling reaction and no compounds arising from benzene homo-coupling are detected by crude GC-MS analysis using the optimal conditions.

Acknowledgements

This study was supported by the Islamic Azad University of IRAN, buinzahra branch (research grant).

Notes and references

1. S. Mahouche-Chergui, S. Gam-Derouich, C. Mangeneya and M. M. Chehim, Chem. Soc. Rev., 2011, 40, 4143.
2. M. Hartmann, Y. Li and A. Studer, J. Am. Chem. Soc., 2012, 134, 16516.
3. A. Wetzel, G. Pratsch, R. Kolb and M. R. Heinrich, Chem.–Eur. J., 2010, 16, 2547.
4. H. Bonin, D. Delbrayelle, P. Demonchaux and E. Gras, Chem. Commun., 2010, 46, 2677.
5. M. B. Andrus and C. Song, Org. Lett., 2001, 3, 3761.
6. F. Mo, D. Qiu, Y. Jiang, Y. Zhang and J. Wang, Tetrahedron Lett., 2010, 52, 518.
7. H. Bonin, E. Fouquet and F. X. Felpin, Adv. Synth. Catal., 2011, 353, 3063.
8. F. X. Felpin, K. Miqueu, J. M. Sotiropoulos, E. Fouquet, O. Ibarguren and J. Laudien, Chem.–Eur. J., 2010, 16, 5191.
9. G. K. Kikukawa and T. Matsuda, Chem. Lett., 1977, 159.
10. S. Tang, D. Zhou and Y. C. Wang, Eur. J. Org. Chem., 2014, 3656.
11. L. Malet-Sanz, J. Madrzak, S. V. Ley and I. R. Baxendale, Org. Biomol. Chem., 2010, 8, 5324.
12. L. He, G. Qiu, Y. Gao and J. Wu, Org. Biomol. Chem., 2014, 12, 6965.
13. (a) J. P. Demers and D. H. Klaubert, Tetrahedron Lett., 1987, 28, 4933; (b) A. R. Katritzky, J. Wu and S. V. Verin, Synthesis, 1995, 651; (c) I. Zaltsgendler, Y. Leblanc and M. A. Bernstein, Tetrahedron Lett., 1993, 34, 2441.
14. T. Uemura and N. Chatani, J. Org. Chem., 2005, 70, 8631.
15. L. Gu, S. Neo and Y. Zhang, Org. Lett., 2011, 13, 1872.
16. I. Yavari, M. Ghazanfarpour-Darjani, S. Ahmadian and Y. Solgi, Synlett, 2011, 1745.
17. I. Yavari, M. Ghazanfarpour-Darjani, M. Bayat and A. Malekafzali, Synlett, 2015, 942.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra15875c

---