Photoinduced Cleavage of N–N Bonds of Aromatic Hydrazines and Hydrazides by Visible Light

Abstract

A photocatalytic system involving [Ru(bpyrz)₃](PF₆)₂·2H₂O, visible light, and air has been developed for cleavage of the N–N bonds of hydrazines and hydrazides. This catalytic system is generally effective for N,N-disubstituted hydrazine and hydrazide derivatives, including arylhydrazides, N-alkyl-N-arylhydrazines, and N,N-diarylhydrazines. The utility of this cleavage reaction has been demonstrated by synthesizing a variety of secondary aromatic amines.

As our society becomes increasingly aware of the issue of environmental sustainability, green chemistry is gaining acceptance in industry and academia. The use of renewable and abundant sources such as visible light is becoming one of the key criteria for developing future ‘green’ methods. As such, the field of visible light photocatalysis has started to attract growing attention from the synthetic organic community.¹ Seminal works from MacMillan, Stephenson, Yoon, and others have shown the versatility of visible light induced reactions in organic synthesis by using ruthenium(II) or iridium(III) complexes or dyes as photocatalysts.^2–6

Amines are routinely used as a sacrificial oxidant in these processes to reduce photoexcited organometallic complexes to ruthenium(I) or iridium(II) complexes while being oxidized to nitrogen radical cations (Scheme 1). Then carbon radicals generated through reduction by the ruthenium(I) or iridium(II) complexes undergo C–C bond formation in most of the reported reactions. On the other hand, the fate of the nitrogen radical cations is relatively unknown. We recently became interested in harnessing the synthetic potential of these nitrogen radical cations generated by visible light photocatalysis. Hydrazines and hydrazides were chosen initially in our studies because they are more easily oxidized than amines. Furthermore, they are useful precursors to generate amines or amides after cleavage of the N–N bonds.⁷ This cleavage is often accomplished under strong reductive,⁸ oxidative,⁹ or other¹⁰ relatively harsh conditions. Herein, we report cleavage of the N–N bonds of hydrazines and hydrazides using visible light photocatalysis under extremely mild conditions.¹¹

Scheme 1.

General catalytic cycle for visible light photocatalysis

Our preliminary studies focused on the cleavage of the N–N bond of N-phenyl-N-benzoyl hydrazine (1a; Table 1). [Ru(bpyrz)₃](PF₆)₂·2H₂O (3a)^12,13 was first examined as the photocatalyst using a 13 watt GE compact fluorescent light bulb as the light source. The reactions were carried out under an air atmosphere. Because the photocatalyst 3a is insoluble or sparingly soluble in most solvents except acetonitrile, the reaction was initially carried out in acetonitrile with 2 mol% of 3a. It was incomplete after 24 hours, providing 42% of the desired cleavage product, N-phenylbenzamide (2a) along with 44% of recovered 1a (Table 1, entry 1). Addition of methanol to the reaction mixture (MeCN–MeOH, 1:1 v/v) greatly facilitated the cleavage and provided 2a in 71% yield (100% conversion) after 24 hours (entry 2). The ratio of MeCN versus MeOH had little effect on the rate of cleavage, and 2a was generated in similar yields (entry 3). Reducing the catalyst loading (1 mol% 3a) reduced the yield of 2a to 59%, with 6% of recovered 1a (entry 4). Little or no conversion was observed when the reaction was conducted either in the absence of 3a or in the dark (entries 5 and 6). Use of degassed MeCN and MeOH dramatically slowed down the reaction, and 2a was isolated in only 13% yield after 40 hours (entry 7). This result hinted that oxygen might play a significant role in the cleavage of the N–N bond. Use of O₂ in the place of air did not improve the reaction and a lower yield (54% yield, 100% conversion) of 2a was obtained after 24 hours (entry 8). Because the N–N bond cleavage of some electron-rich hydrazines is known to be realized by simple exposure to light, we subjected N-methyl-N-phenyl hydrazine (1b) to similar studies to those of 1a. As expected, the cleavage was faster. Using only MeCN and 2 mol% 3a, the desired cleavage product, N-methylaniline was obtained as its N-acetyl derivative 2b in 82% yield after 24 hours (entry 9).¹⁴ The use of MeOH as a co-solvent did not provide any benefit to either the reaction rate or the yield of 2b (entry 10). The background reaction in the absence of the catalyst 3a was faster than that of 1a, yet it was still much slower than the catalyzed reaction (12% conversion after 48 h, entry 11).

Table 1.

Optimization of the Catalyst Systems based on [Ru(bpyrz)₃](PF₆)₂·2H₂O (3a)

Entry	Substrate	Catalyst (mol%)	Conditions	Time (h)	Yield (%)
1	1a	3a (2)	air, MeCN	24	42 (44)a
2	1a	3a (2)	air, MeCN–MeOH (1:1)	24	71
3	1a	3a (2)	air, MeCN–MeOH (2:1)	24	74
4	1a	3a (1)	air, MeCN–MeOH (1:1)	24	59 (6)a
5	1a	3a (0)	air, MeCN–MeOH (1:1)	120	trace
6b	1a	3a (2)	air, MeCN–MeOH (1:1)	48	0
7	1a	3a (2)	N2, degassed MeCN–MeOH (1:1)	40	13
8	1a	3a (2)	O2, MeCN–MeOH (1:1)	24	54
9	1b	3a (2)	air, MeCN	24	82
10	1b	3a (2)	air, MeCN–MeOH (2:1)	24	83
11	1b	3a (0)	air, MeCN–MeOH (2:1)	48	12 (88)a

^aYield of recovered starting material.

^bNo light.

We then compared [Ru(bpyrz)₃](PF₆)₂·2H₂O (3a) against two other known ruthenium complexes (3b^4a and 3c¹⁵) and Rose Bengal (3d)¹⁶ in the cleavage of the N–N bonds of 1a and 1b (Table 2). For hydrazides such as 1a, among the three ruthenium complexes 3a–c (entries 1–3), only 3a showed sufficient efficiency to catalyze the cleavage reaction. Rose Bengal showed similar activity to 3a but gave more side products (entry 4). For hydrazines such as 1b, the three ruthenium complexes (3a–c) and Rose Bengal (3d) all led to completion of the cleavage of the N–N bond. Surprisingly, 3a was the least active catalyst among the three ruthenium complexes (entry 5). Catalyst 3b was more active than 3a and 3c but also gave more side products than the latter (entries 5–7). Rose Bengal (3d) was also more active than 3a (entry 8). Similar to 1a, the reaction catalyzed by Rose Bengal (3d) gave more side products than 3a. Overall, 3a was the optimal catalyst for both the hydrazines and hydrazides.

Table 2.

Comparison of Ruthenium Catalysts 3a–c and Rose Bengal (3d)

Entry	Substrate	Catalyst (mol%)	Conditions	Time (h)	Yield (%)
1	1a	3a (2)	air, MeCN–MeOH (1:1)	24	71
2	1a	3b (2)	air, MeCN–MeOH (1:1)	110	10 (80)a
3	1a	3c (2)	air, MeCN–MeOH (1:1)	110	8 (73)a
4	1a	3d (2)	air, MeCN–MeOH (1:1)	36	49
5	1b	3a (2)	air, MeCN–MeOH (2:1)	24	83
6	1b	3b (2)	air, MeCN–MeOH (2:1)	4	65
7	1b	3c (2)	air, MeCN–MeOH (2:1)	10	85
8	1b	3d (2)	air, MeCN–MeOH (2:1)	10	56

^aYield of recovered 1a.

With the catalyst system optimized, we next applied it to a variety of hydrazine and hydrazide derivatives (Table 3). This catalytic system was found to be generally effective for N,N-disubstituted hydrazine and hydrazide derivatives including arylhydrazides, N-alkyl-N-arylhydrazines, and N,N-diarylhydrazines. Between the two substituents on the nitrogen atom, one needed to be an aryl group while the second could be an aryl, alkyl, or acyl group. Most of the substrates that meet this criterion gave the desired products in satisfactory yields. Electron-withdrawing substituents on the aromatic rings, such as a trifluoromethyl group, had little effect on the cleavage because 1c behaved very similarly to 1d (entries 1 and 2). Functional groups such as olefins and Cl were compatible with the reaction conditions (entries 3 and 6). Hydrazide derivatives containing heterocycles worked under the optimized conditions although they were not as effective as their counterparts with only aromatic rings (entry 4). The cleavage of a hydrazine substituted with a biaryl group and an alkyl group also afforded the desired secondary amine in modest yield (entry 7). In this case, it appeared that the cleavage product decomposed under the cleavage reactions. To our surprise, tetra-substituted hydrazine derivatives were found to be inert under the optimized conditions (entry 8). Trisubstituted hydrazine derivatives, depending on the pattern of substituents, underwent one of the two types of oxidations to give either hydrazones or azo compounds. One was oxidation of N(H)R to form hydrazones (entries 9 and 10). The other was oxidative cleavage of the N-Me group followed by oxidation of the forming N–N bonds to provide azo compounds (entry 11).

Table 3.

Ruthenium(II)-Catalyzed Photoinduced Cleavage of N–N Bonds^a

Entry	Substrate	Product	Yield (%)
1	1c	2c	82
2	1d	2d	81
3	1e	2e	54
4	1f	2f	47
5	1g	2g	68b
6	1h	2h	51b
7	1i	2i	37
8	1j	–	–
9	1k	2k	36
10	1l	2l	88
11	1m	2m	58

^aReactions were performed on 0.3–0.5 mmol scale in 3–5 mL solvent with 2 mol% 3a. A household 13 W light bulb was used as the light source. Reaction time ranged from 4 to 28 h.

^bDue to the instability of these hydrazine derivatives, the crude products were subjected to the cleavage reaction directly after Boc-deprotection. The yields given refer to overall yields for the two steps.

Secondary aromatic amines are of great interest in many areas of chemistry because of the prevalence of these compounds in pharmaceuticals, materials, etc. Their preparation through nucleophilic amination has been recently popularized by the Goldberg reaction¹⁷ and Buchwald–Hartwig amination.¹⁸ On the other hand, synthesis of the secondary aromatic amines through electrophilic amination has received much less attention. Knochel recently reported an electrophilic amination protocol for the synthesis of diarylamines that involves addition of nucleophilic aryl donors to arylazo tosylates followed by cleavage of N–N bonds (Scheme 2).^7a Excess allyl iodide (3 equiv) and zinc (10 equiv) were required for the cleavage of the N–N bonds. Separately, Mäeorg reported that a number of alkyl and aromatic nucleophiles were efficiently added to N-tert-butoxycarbonylaryldiazenes to generate Boc-protected hydrazines.¹⁹ Although N-tert-butoxycarbonylaryldiazenes are potentially a synthon of ‘ArNH(+)’, the author did not pursue the further conversion of the addition product, Boc-protected hydrazines, to secondary aromatic amines. We felt that, coupled with Mäeorg’s method, our photochemistry could be developed into an efficient electrophilic amination protocol that is complementary to Knochel’s. As shown in Table 4, we were able to add a wide variety of nucleophiles, including aryl boronic acids [catalyzed by Cu(OAc)₂], alkyl lithiums, aryl lithiums, aryl Grignard reagents, and lithium amide enolates, to N-tert-butoxycarbonylaryldiazenes. The Boc group of the hydrazines was easily removed by treatment with trifluoroacetic acid (TFA). Some of the deprotected hydrazines were not stable to silica gel chromatography. For those, the deprotected products were directly subjected to the cleavage reactions. In general, the cleavage step worked as well as those in our substrate scope studies (see above) with one exception where the ruthenium catalyst (3a) was found to decompose with a substrate containing an iodide group (entry 9).

Scheme 2.

Electrophilic amination via aryl azo compounds

Table 4.

Synthesis of Secondary Aromatic Amines^a

Entry	4	RM	5 (Yield %)	2 (Yield %)
1	4n		5n (95)	2n (91)b
2	4o		5o (95)	2o (87)b
3	4p		5p (96)	2p (84)b
4	4q	PhMgBr	5q (96)	2q (85)b
5	4r		5r (79)	2r (65)b
6	4s		5s (73)	2s (55)
7	4t		5t (50)	2t (72)b
8	4u	BuMgCl	5u (92)	2u (70)b
9	4v	BuMgCl	5v (95)	2v (21)b,c
10	4w		5w (71)	2w (51)b

^aReactions were performed on 0.3–0.5 mmol scale in 3–5 mL of MeCN–MeOH (1:1 v/v) with 2 mol% 3a. A household 13 W light bulb was used as the light source. Reaction time ranged from 15 to 48 h.

^bDue to the instability of these hydrazine derivatives, the crude products were subjected to the cleavage reaction directly after Boc-deprotection. The yields refer to overall yields for the two steps.

^cAnother 2 mol% of 3a was added after 10 h; 43% of hydrazine was recovered.

We thought it likely that several competing reaction pathways would operate under the photocatalytic conditions (Scheme 3). Similar to tertiary amines, hydrazine or hydrazide 1 would reductively quench a photoexcited state [Ru(bpyrz)₃]²⁺*, which is generated by exposure of [Ru(bpyrz)₃](PF₆)₂·2H₂O (3a) to visible light. Deprotonation of the resulting nitrogen radical cation 6 would produce radical 7, which could then react with O₂ to form radical 8. Depending on R¹, two different pathways are proposed to diverge from 8. When R¹ is H, a rearrangement of 8 to 10 via 9 is proposed. Similar rearrangements have been observed with nitroso oxides.²⁰ Fragmentation of 10 would provide nitrous acid and amine radical 10, which could be reduced by ruthenium(I) to afford amine 2. On the other hand, when R¹ is non-hydrogen, radical 8 would be reduced by ruthenium(I) to yield 12. Elimination of HOO⁻ would generate diazenium 13, which could undergo two different isomerization processes (cf. Table 3). When R¹ is a benzyl group, isomerization of 13 to hydrazone 2l would be favorable. In contrast, isomerization of 13 to 16 would be favorable when R¹ is a phenyl group. Conversion of 16 into 17 followed by oxidation in situ would provide azobenzene 2m.

Scheme 3.

Proposed pathways

To support the hypothesis that hydrazine or hydrazide 1 would be initially oxidized by a photoexcited state [Ru(bpyrz)₃]²⁺*, we performed two series of fluorescence quenching experiments (Stern–Volmer studies²¹) using substrates 1a and 1b (Figure 1). The ratio of the fluorescene intensity without a quencher (I_o) versus that with a quencher (I) was shown to be first order dependent on the concentration of 1a or 1b, indicating that both act as reductive quenchers of the excited state of [Ru(bpyrz)₃]²⁺. Hydrazine 1b is expected to be a stronger reducing agent than hydrazide 1a because the latter compound is substituted with a benzoyl group instead of a methyl group. The slope of the line for hydrazine 1b was larger than that for hydrazide 1a, which was consistent with this expectation. Furthermore, protonation of hydrazines such as 1b would remove one of the two lone pairs on the two nitrogen atoms, rendering 1b an ineffective quencher of [Ru(bpyrz)₃]²⁺*. Indeed, the HCl salt of hydrazine 1b was found to be inert under the optimized conditions.

Figure 1.

Fluorescence quenching of [Ru(bpyrz)₃](PF₆)₂·2H₂O (3a)by hydrazide 1a and hydrazines 1b

In conclusion, we have developed a photocatalytic method for cleavage of the N–N bonds of hydrazines and hydrazides. The method, using 2 mol% ruthenium(II) catalyst, visible light, and air, is operationally very simple. The utility of this method has been demonstrated by the synthesis of secondary aromatic amines through electrophilic amination. Furthermore, this study has shed some light on the fate of nitrogen radical cations generated by quenching the photoexcited state [Ru(bpyrz)₃]²⁺*.

All reactions were carried out under a nitrogen atmosphere unless otherwise stated. Anhydrous solvents were purchased and used as received except THF, CH₂Cl₂, Et₂O, and toluene, which were rigorously purged with argon for 2 h and then further purified by passing through two packed columns of neutral alumina (for THF and Et₂O) or through neutral alumina and copper(II) oxide (for toluene and CH₂Cl₂) under argon from a solvent purification system. All new compounds were characterized by ¹H NMR, ¹³C NMR, and IR spectroscopy (thin film on NaCl plates), in addition to elemental analysis and/or high resolution mass spectroscopy. Melting points are uncorrected. For starting materials and intermediates, copies of the ¹H and ¹³C NMR spectra are given in the Supporting Information. Copies of the ¹H and ¹³C NMR spectra for all the final products are given in the Supporting Information. NMR spectra were recorded in deuterated solvents. All ¹H NMR experiments are reported in δ units in parts per million (ppm) and were measured relative to the signals for residual chloroform (δ = 7.26 ppm), DMSO-d₆ (δ = 2.50 ppm), CD₃CN (δ = 1.96 ppm), or CD₃OD (δ = 3.34 ppm). All ¹³C NMR spectra (obtained with ¹H decoupling) are reported in ppm relative to CDCl₃ (δ = 77.00 ppm), DMSO-d₆ (δ = 39.51 ppm), CD₃CN (δ = 118.26 ppm), or CD₃OD (δ = 49.86 ppm). The following abbreviations are used to designate multiplicities of NMR signals: s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quint = quintet, and dd (doublet of doublet). Coupling constants (J values) are reported in hertz (Hz).

Deprotection of N-tert-Butoxycarbonyl N′,N′-Disubstituted Hydrazines and Hydrazides; General Procedure A

To a solution of a Boc-hydrazine or hydrazide derivative (0.3 mmol) in CH₂Cl₂ (5 mL) was added TFA (0.5 mL) at 0 °C. The flask was placed in a fridge until no starting material was observed by TLC. Sat. aq Na₂CO₃ (10 mL) was added and the resulting mixture was stirred at 0 °C for 5 min, then the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic solution was washed with H₂O (1 × 5 mL), brine (1 × 5 mL) and dried over anhydrous MgSO₄. The solvents were removed under reduced pressure to afford the crude N′,N′-disubstituted hydrazine or hydrazide, which was purified by silica gel column chromatography. If the hydrazine or hydrazide was not stable on silica gel, it was then used directly in the next step.

Ruthenium(II)-Catalyzed Photolytic Cleavage of N–N Bonds; General Procedure B

A screw-capped, disposable test tube with a stir bar was charged with [Ru(bpyrz)₃](PF₆)₂·2H₂O (2 mol%), substituted hydrazine or hydrazide (0.5 mmol), and solvent (5 mL). A 20-gauge 11/2″ needle was pierced through the Teflon cap of the tube so that the reaction system was exposed to air. The reddish solution was stirred at r.t. under the irradiation of a 13 W GE compact fluorescent light bulb. The reaction was monitored by TLC. When the reaction was complete, the mixture was filtered through a short silica pad and eluted with Et₂O (20 mL) and EtOAc (5 mL). The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography to afford the product. A photograph of the setup is shown in the Supporting Information.

N-Benzoylaniline (2a)²²

Following general procedure B, 1a (106 mg, 0.5 mmol) in MeCN (2.5 mL) and MeOH (2.5 mL) was subjected to the reaction for 12 h. Purification on silica gel column chromatography (hexanes–Et₂O, 5:1) gave the product.

Yield: 70 mg (71%); white crystals; mp 165–166 °C (Lit.²² 165–167 °C).

¹H NMR (400 MHz, DMSO-d₆): δ = 10.25 (s, 1 H), 7.94–7.97 (m, 2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.51–7.61 (m, 3 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 1 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 165.6, 139.2, 135.0, 131.6, 128.6, 128.4, 127.7, 123.7, 120.4.

N-Acetyl-N-methylaniline (2b)²³

Following general procedure B, N-methyl phenylhydrazine (35 μL, 0.30 mmol) in MeCN (2 mL) and MeOH (1 mL) was subjected to the reaction for 24 h. The crude product was dissolved in EtOAc (5 mL), and AcCl (47 μL, 0.66 mol) was added. The solution was heated at 50 °C for 20 min, and then diluted with Et₂O (60 mL). After washing with sat. aq NaHCO₃ (1 × 5 mL), H₂O (1 × 5 mL), and brine (1 × 5 mL), the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexanes–acetone, 4:1) to give the product.

Yield: 37 mg (83%); white crystals; mp 108–109 °C (Lit.²⁴ 106–108 °C). The ¹H and ¹³C NMR data are consistent with those reported.²³

N-tert-Butoxycarbonylaniline (2c)²⁵

Based on general procedure B, 1c (103 mg, 0.5 mmol) was subjected to the reaction in MeCN (2.5 mL) and MeOH (2.5 mL) for 24 h. After purification by silica gel column chromatography (hexanes–EtOAc, 10:1), the product was obtained.

Yield: 79 mg (82%); white crystals; mp 140–143 °C (Lit.²⁶ 134–136 °C). The ¹H and ¹³C NMR data are consistent with those reported.²⁵

N-tert-Butoxycarbonyl-4-trifluoromethylaniline (2d)²⁷

Based on general procedure B, compound 1d (122 mg, 0.44 mmol) in MeCN (2.5 mL) and MeOH (2.5 mL) was subjected to the reaction for 28 h. Purification by silica gel column chromatography (hexanes–EtOAc, 20:1) gave the desired product.

Yield: 93 mg (81%); white crystals; mp 120–123 °C (Lit.²⁷ 121–122 °C). The ¹H and ¹³C NMR data are consistent with those reported.²⁷

N-Styrylacetylaniline (2e)²⁸

Following the general procedure B, 1e (101 mg, 0.4 mmol) in MeCN (2.0 mL) and MeOH (2.0 mL) was subjected to the reaction for 10 h. Purification by silica gel column chromatography (hexanes–EtOAc, 6:1) gave the product.

Yield: 51 mg (54%); white crystals; mp 95–97 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.52 (m, 2 H), 7.41–7.44 (m, 2 H), 7.27–7.37 (m, 5 H), 7.11 (t, J = 7.4 Hz, 1 H), 6.65 (d, J = 15.9 Hz, 1 H), 6.39 (dt, J = 15.8, 7.3 Hz, 1 H), 3.34 (dd, J = 7.3, 1.2 Hz, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.8, 137.6, 136.4, 135.4, 129.0, 128.7, 128.0, 126.4, 124.5, 121.8, 119.9, 41.9.

(N-Phenylcarboxamido)pyrazine (2f)²⁹

Following general procedure B, compound 1f (62 mg, 0.29 mmol) in MeCN (1.5 mL) and MeOH (1.5 mL) was irradiated for 28 h. Purification by silica gel column chromatography (hexanes–EtOAc, 2:1) gave the product.

Yield: 27 mg (47%); white crystals; mp 128–130 °C (Lit.³⁰ 123–125 °C). The ¹H and ¹³C NMR data are consistent with those reported.²⁹

N-Benzylaniline (2g)³¹

Based on general procedure B, crude 1g in MeCN (2.6 mL) and MeOH (1.3 mL) was subjected to the reaction for 24 h. After purified by silica gel column chromatography (hexanes–CH₂Cl₂, 2:1) the product was obtained as a yellow oil (51 mg, 68%). The ¹H and ¹³C NMR data are consistent with those reported.³¹

N-Benzyl-2-chloroaniline (2h)³²

Following general procedure B, crude 1h was subjected to the reaction in MeCN (3 mL) and MeOH (1.5 mL) for 15 h. After purification by silica gel column chromatography (hexanes–CH₂Cl₂, 10:1→8:1), the desire product (43 mg, 51%) was obtained as a colorless oil. The ¹H and ¹³C NMR data are consistent with those reported.³²

N-Butyl-(3′-chlorobiphenyl-4-yl)amine (2i)

Following general procedure B, compound 1i (87 mg, 0.32 mmol) in MeCN (2.0 mL) and MeOH (1.0 mL) was subjected to the reaction for 15 h. Purification by silica gel column chromatography (hexanes–EtOAc, 50:1) gave the product.

Yield: 31 mg (37%, two steps); colorless oil.

IR (neat): 3416, 3063, 3030, 2962, 2931, 2869, 1615, 1594, 1530, 1478, 1330, 824, 782 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.53 (t, J = 1.9 Hz, 1 H), 7.40–7.44 (m, 3 H), 7.31 (t, J = 7.8 Hz, 1 H), 7.21–7.24 (m, 1 H), 6.65–6.69 (m, 2 H), 3.75 (br s, 1 H), 3.17 (t, J = 7.1 Hz, 2 H), 1.60–1.68 (m, 2 H), 1.46 (sext, J = 7.4 Hz, 2 H), 0.99 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.4, 143.1, 134.5, 129.8, 128.2, 127.9, 126.2, 125.8, 124.2, 112.8, 43.5, 31.6, 20.3, 13.9.

Anal. Calcd for C₁₆H₁₈ClN: C, 73.98; H, 6.98; N, 5.39. Found: C, 73.99; H, 7.12; N, 5.51.

2-Methyl-1-methylene-2-phenylhydrazine (2k)³³

Following general procedure B, compound 1k (68 mg, 0.5 mmol) in MeCN (2.5 mL) and MeOH (2.5 mL) was subjected to the cleavage reaction for 15 h. After purification by silica gel column chromatography (hexanes–CH₂Cl₂, 2:1), 2k was isolated as the major product.

Yield: 24 mg (36%); colorless oil. The ¹H and ¹³C NMR data are consistent with those reported.³³

1-Benzylidene-2-methyl-2-phenylhydrazine (2l)³⁴

Following general procedure B, compound 1l (105 mg, 0.49 mmol) in MeCN (5 mL) was subjected to the cleavage reaction for 36 h. After purification by silica gel chromatography (hexanes–EtOAc, 30:1), 2l was obtained.

Yield: 91 mg (88%); white crystals; mp 107–109 °C (Lit.³⁵ 106–107 °C). The ¹H and ¹³C NMR data are consistent with those reported.³⁴

Azobenzene (2m)

Following general procedure B, 1m (67 mg, 0.34 mmol) in MeCN (1.5 mL) and MeOH (1.5 mL) was subjected to the reaction for 2 d. After purification by silica gel column chromatography (hexanes–EtOAc, 100:1), the product was obtained.

Yield: 36 mg (58%); yellow crystals.

¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.98 (m, 4 H), 7.48–7.57 (m, 6H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.6, 131.0, 129.1, 122.8. NMR spectra are identical to those from an authentic sample.

N-tert-Butoxycarbonyl-N′-(2-chlorophenyl)-N′-(4-fluorophenyl)hydrazine (5n)

Based on the literature procedure,^19b a solution of 4n (300 mg, 1.25 mmol), 4-fluorophenylboronic acid (280 mg, 2.0 mmol), and Cu(OAc)₂·H₂O (12.5 mg, 0.0625 mmol) in dried MeOH (5 mL) was heated at reflux for 5 min in an atmosphere of N₂. The solution was cooled to r.t. and 100 mg of silica gel was added. After stirring for 5 min, the solvent was removed and the residue was subjected to silica gel column chromatography (hexanes–EtOAc, 25:1) to give the pure product.

Yield: 398 mg (95%); white crystals; mp 107–109 °C.

IR (neat): 3307, 3067, 2983, 2935, 1729, 1708, 1509, 1481, 1370, 1230, 1160, 831 cm⁻¹.

¹H NMR (400 MHz, CD₃OD): δ = 7.55 (d, J = 7.6 Hz, 1 H), 7.47 (dd, J = 8.0, 1.5 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 6.93 (t, J = 8.7 Hz, 2 H), 6.65–6.68 (m, 2 H), 1.48/1.37 (rotamers, 2 × s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.2 (d, J = 240.0 Hz), 154.7, 143.4, 141.7, 131.9, 130.7, 130.2, 128.1, 127.9, 115.36 (d, J = 22.5 Hz), 114.7, 81.3, 28.1.

Anal. Calcd for C₁₇H₁₈ClFN₂O₂: C, 60.63; H, 5.39; N, 8.32. Found: C, 60.48; H, 5.29; N, 8.24.

N-(2-Chlorophenyl)-N-(4-fluorophenyl)hydrazine (1n)

Compound 5n (110 mg, 0.33 mmol) was subjected to general procedure A to give crude 1n as a reddish oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.50 (m, 1 H), 7.28–7.35 (m, 2H), 7.20–7.24 (m, 1 H), 6.87–6.95 (m, 4 H), 4.23 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.9 (d, J = 236.2 Hz), 146.1 (d, J = 1.5 Hz), 146.0, 131.9, 131.1, 128.1 (d, J = 22.2 Hz), 127.5, 115.7 (d, J = 7.5 Hz), 115.2, 115.0.

N-(2-Chlorophenyl)-4-fluoroaniline (2n)³⁶

The crude compound 1n in MeCN (3.0 mL) and MeOH (1.5 mL) was subjected to general procedure B. Purification by silica gel column chromatography (hexanes–CH₂Cl₂, 6:1) gave the product.

Yield: 66 mg (91%); yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.35 (dd, J = 7.9, 1.4 Hz, 1 H), 7.01–7.17 (m, 6 H), 6.77–6.81 (m, 1 H), 6.01 (br s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 159.0 (d, J = 240.7 Hz), 141.0, 137.3 (d, J = 2.5 Hz), 129.7, 127.5, 123.2 (d, J = 8.0 Hz), 120.8, 120.0, 116.1 (d, J = 22.4 Hz), 114.5.

N-tert-Butoxycarbonyl-N′-(4-trifluoromethylphenyl)-N′-(3-chlorophenyl)hydrazine (5o)

This compound was prepared according to the literature procedure.^19b A mixture of 4o (300 mg, 1.09 mmol), 3-chlorophenylboronic acid (274 mg, 1.75 mmol), and Cu(OAc)₂·H₂O (11 mg, 0.055 mmol) in anhydrous MeOH (5 mL) was heated at reflux for 2 h. The solvent was removed with a rotary evaporator and the residue was purified by silica gel column chromatography (hexanes–EtOAc, 5:1) to give the product.

Yield: 400 mg (95%); white crystals; mp 119–121 °C.

IR (neat): 3284, 3072, 2986, 2936, 1710, 1619, 1597, 1524, 1480, 1372, 1329, 1251, 1163, 1117, 1075, 838 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 8.6 Hz, 2 H), 7.26 (t, J = 8.2 Hz, 1 H), 7.22–7.24 (m, 1 H), 7.13 (d, J = 8.6 Hz, 2 H), 7.09–7.11 (m, 2 H), 6.92/6.69 (rotamers, 2 × br s, 1 H), 1.50/1.32 (rotamers, 2 × br s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.5, 148.6, 146.1, 135.0, 130.3, 126.4, 124.3 (q, J = 270.5 Hz), 124.5/124.3, 123.9 (q, J = 31.7 Hz), 121.4, 119.4/119.1, 116.9, 82.4/82.1, 28.2/28.0.

HRMS (ESI): m/z [M − H]⁻ calcd for C₁₈H₁₈ClF₃N₂O₂: 385.0925; found: 385.0928.

N′-(4-Trifluoromethylphenyl)-N′-(3-chlorophenyl)hydrazine (1o)

According to general procedure A, 5o (120 mg, 0.31 mmol) afforded crude 1o after 4 h at r.t.

Yield: 85 mg; yellow oil.

IR (neat): 3359, 3076, 2928, 1620, 1592, 1517, 1478, 1327, 1166, 1117, 1073, 839, 785 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J = 8.6 Hz, 2 H), 7.31 (t, J = 1.9 Hz, 1 H), 7.28–7.24 (m, 3 H), 7.18–7.15 (m, 1 H), 7.08–7.05 (m, 1 H), 4.20 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.9, 148.8, 135.0, 130.3, 126.2 (q, J = 3.8 Hz), 124.5 (q, J = 269.4 Hz), 123.7, 122.6 (q, J = 32.5 Hz), 121.3, 119.3, 117.0.

N-(3-Chlorophenyl)-4-trifluoromethylaniline (2o)

According to general procedure B, crude 1o obtained above (ca. 0.31 mmol) in MeCN (1.5 mL) and MeOH (1.5 mL) was subjected to the cleavage reaction for 15 h to give 2o.

Yield: 73 mg (87%, 2 steps); off-white crystals; mp 60–63 °C.

IR (neat): 3414, 1597, 1584, 1532, 1327, 1117, 1070, 844, 769 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.51 (d, J = 8.6 Hz, 2 H), 7.23 (t, J = 8.1 Hz, 1 H), 7.13 (t, J = 2.1 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 2 H), 7.00 (dd, J = 8.1, 2.1 Hz, 2 H), 5.92 (br s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.6, 142.7, 135.1, 130.5, 126.8 (q, J = 3.7 Hz), 124.4 (q, J = 269.2 Hz), 122.6 (q, J = 32.6), 122.4, 118.9, 117.2, 116.3.

Anal. Calcd for C₁₃H₉ClF₃N: C, 57.47; H, 3.34; N, 5.16. Found: C, 57.71; H, 3.23; N, 5.11.

N-tert-Butoxycarbonyl-N′-(3-fluorophenyl)-N′-phenylhydrazine (5p)

Isopropylmagnesium chloride (2 M in THF, 1.1 mL, 2.2 mmol) was added dropwise to a solution of 1-fluoro-3-iodobenzene (235 μL, 2 mmol) in THF (5 mL) at −20 °C. After 30 min, the solution was cooled to −95 °C and a solution of 4p (412 mg, 2 mmol) in THF (2 mL) was added. The reaction was quenched with sat. aq NH₄Cl (5 mL) after 5 min. The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL) and dried over anhydrous MgSO₄. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (hexanes–EtOAc, 20:1) to give 5p.

Yield: 581 mg (96%); white crystals; mp 123–125 °C.

IR (neat): 3289, 3071, 3040, 3006, 2983, 2936, 1711, 1613, 1594, 1493, 1374, 1252, 1164, 759 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.87/9.46 (rotamers, 2 × br s, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.27 (q, J = 7.8 Hz, 1 H), 7.16–7.20 (m, 2 H), 7.07–7.12 (m, 1 H), 6.63–6.77 (m, 3 H), 1.42/1.21 (rotamers, 2 × s, 9 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 162.8 (d, J = 240.3 Hz), 155.1, 148.5 (d, J = 10.1 Hz), 145.1, 130.5 (d, J = 9.8 Hz), 129.2, 123.8, 121.1, 112.3, 107.2 (d, J = 21.0 Hz), 103.0 (d, J = 25.9 Hz), 79.8, 28.4.

Anal. Calcd for C₁₇H₁₉FN₂O₂: C, 67.53; H, 6.33; N, 9.27. Found: C, 67.42; H, 6.31; N, 9.18.

N-(3-Fluorophenyl)-N-phenylhydrazine (1p)

This crude compound was obtained from compound 5p (100 mg, 0.33 mol) following general procedure A.

¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.39 (m, 2 H), 7.27–7.30 (m, 2 H), 7.15–7.21 (m, 1 H), 7.09–7.13 (m, 1 H), 6.90–6.95 (m, 2 H), 6.57–6.62 (m, 1 H), 4.18 (br s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.5 (d, J = 242.0 Hz), 151.0 (d, J = 10.0 Hz), 148.4, 129.8 (d, J = 9.9 Hz), 129.4, 123.8, 121.8, 112.6 (d, J = 2.5 Hz), 107.0 (d, J = 21.4 Hz), 104.3 (d, J = 25.6 Hz).

N-(3-Fluorophenyl)aniline (2p)³⁷

Following general procedure B, after 18 h, crude 1p in MeCN (2.0 mL) and MeOH (1.0 mL) gave the desired product after silica gel column chromatography (hexanes–Et₂O, 8:1).

Yield: 52 mg (84%); yellow oil. The ¹H and ¹³C NMR data are consistent with those reported.³⁷

N-tert-Butoxycarbonyl-N′-(4-trifluoromethylphenyl)-N′-phenylhydrazine (5q)

According to the literature procedure,^19a a solution of phenylmagnesium bromide (3 M in THF, 317 μL, 0.95 mmol) was added drop-wise to a solution of 4o (200 mg, 0.73 mmol) in anhydrous THF (5 mL) at −100 °C. After 15 min, the reaction was quenched by addition of sat. aq NH₄Cl (5 mL). The mixture was extracted with Et₂O (3 × 20 mL) and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL), and dried over anhydrous MgSO₄. After the solvents were removed by rotary evaporation, the residue was purified by silica gel column chromatography (hexanes–EtOAc, 10:1) to give the desired product.

Yield: 246 mg (96%); white crystals; mp 112–115 °C.

IR (neat): 3289, 2988, 2938, 1711, 1622, 1327, 1165, 1117, 1071, 836 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.97/9.55 (rotamers, 2 × br s, 1H), 7.57 (d, J = 8.6, 2 H), 7.41 (t, J = 7.7 Hz, 2 H), 7.26–7.29 (m, 2 H), 7.16–7.21 (m, 1 H), 7.00 (d, J = 8.6 Hz, 2 H), 1.43/1.22 (rotamers, 2 × s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.2/155.0, 149.4, 144.6, 129.3, 126.1, 125.1/124.8, 124.5 (q, J = 269.2 Hz), 122.8/122.3, 122.3 (q, J = 32.5 Hz), 115.4/115.2, 82.0/81.5, 28.1/27.9.

Anal. Calcd for C₁₈H₁₉F₃N₂O₂: C, 61.36; H, 5.44; N, 7.95. Found: C, 61.39; H, 5.36; N, 7.99.

N-(4-Trifluoromethylphenyl)aniline (2q)³⁸

According to general procedure A, 5q (120 mg, 0.34 mmol) was subjected to the deprotection reaction for 1 h. The crude hydrazine 1q in MeCN (2.0 mL) and MeOH (1.0 mL) was subjected to the cleavage reaction for 4 h following general procedure B. After purification by silica gel column chromatography (hexanes–EtOAc, 40:1), compound 2q was obtained.

Yield: 69 mg (85%, two steps); yellow oil.

IR (neat): 3351, 3224, 3066, 3042, 2931, 2858, 1620, 1597, 1517, 1493, 1327, 1280, 1164, 1114, 1070, 839, 702.

The ¹H and ¹³C NMR data are consistent with those reported.³⁸

Anal. Calcd for C₁₃H₁₀F₃N: C, 65.82; H, 4.25; N, 5.90. Found: C, 65.82; H, 4.27; N, 5.84.

N-tert-Butoxycarbonyl-N′-(2-methoxyphenyl)-N′-(4-trifluoromethylphenyl)hydrazine (5r)

To a solution of anisole (218 μL, 2 mmol) and TMEDA (362 μL, 2.4 mmol) in THF (10 mL), was added n-BuLi (1.6 M in THF, 1.5 mL, 2.4 mmol) at 0 °C. The solution was stirred at r.t. for 2 h, then 1.8 mL of the above solution was added to a solution of 4o (137 mg, 0.5 mmol) in THF (5 mL) at −78 °C. The reaction was quenched with sat. aq NH₄Cl (5 mL) after 20 min. Purification by silica gel column chromatography (hexanes–Et₂O, 4:1) afforded the desired product.

Yield: 151 mg (79%); yellow oil.

IR (neat): 3371, 3306, 3008, 2981, 2940, 2845, 1734, 1620, 1525, 1501, 1469, 1373, 1329, 1248, 1162, 1117, 1067, 834, 760 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.75/9.27 (2 × br s, 1 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.42 (d, J = 6.8 Hz, 1 H), 7.31–7.36 (m, 1 H), 7.14–7.16 (m, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.61 (d, J = 7.8 Hz, 2H), 3.72 (s, 3 H), 1.42 (br s, 9 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 155.2, 154.6, 150.7, 131.8, 128.6, 127.8, 126.0 (q, J = 3.6 Hz), 125.1 (q, J = 270.2 Hz), 121.1, 118.3 (q, J = 32.0 Hz), 112.8, 112.1, 79.8, 55.5, 28.1.

Anal. Calcd for C₁₉H₂₁F₃N₂O₃: C, 59.68; H, 5.54; N, 7.33. Found: C, 59.74; H, 5.48; N, 7.31.

N-(2-Methoxyphenyl)-N-(4-trifluoromethylphenyl)hydrazine (1r)

Following general procedure A, compound 5r (135 mg, 0.35 mmol) afforded crude 1r.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.40 (m, 2 H), 7.31–7.35 (m, 1 H), 7.26–7.29 (m, 1 H), 6.97–7.07 (m,4 H), 4.29 (br s, 2 H), 3.83 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.3, 153.0, 135.1, 128.6, 128.5, 125.9 (q, J = 3.8 Hz), 125.0 (q, J = 270.5 Hz), 121.3, 119.4 (q, J = 32.2 Hz), 112.8, 112.4, 55.5.

N-(2-Methoxyphenyl)-(4-trifluoromethyl)aniline (2r)

Following general procedure B, crude 1r in MeCN (2 mL) and MeOH (1 mL) was subjected to the cleavage reaction for 12 h. Another 2 mol% of the catalyst 3a was added and the reaction was complete after another 12 h. Purification by silica gel column chromatography (hexanes–Et₂O, 10:1) afforded the desired product.

Yield: 61 mg (65%, two steps); pink crystals; mp 60–62 °C.

IR (neat): 3415, 3077, 3009, 2970, 2946, 2845, 1622, 1602, 1533, 1465, 1323, 1246, 1115, 1070, 1029, 750 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J = 8.7 Hz, 2 H), 7.36–7.39 (m, 1 H), 7.14 (d, J = 8.7 Hz, 2 H), 6.92–7.02 (m, 3 H), 3.90 (s, 3H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.3, 146.3, 130.8, 126.6 (q, J = 3.8 Hz), 124.6 (q, J = 270.6 Hz), 122.0, 121.7 (q, J = 32.7 Hz), 120.7, 117.2, 116.0, 110.8, 55.6.

Anal. Calcd for C₁₄H₁₂F₃NO: C, 62.92; H, 4.53; N, 5.24. Found: C, 63.20; H, 4.31; N, 5.33.

N-tert-Butoxycarbonyl-N′-(2-bromo-4-methylphenyl)-N′-(pyridn-3-yl)hydrazine (5s)

According to the literature procedure,^19a i-PrMgCl·LiCl (1.3 M in THF, 1.5 mL, 2.0 mmol) was added dropwise to a solution of 3-bro-mopyridine (193 μL, 2.0 mmol) in THF (2 mL) at 0 °C. The solution was stirred at r.t. for 30 min, then cooled to −100 °C and a solution of 5i (598 mg, 2.0 mmol) in THF (5 mL) was added. The reaction was quenched after 20 min with sat. aq NH₄Cl (5 mL). The mixture was extracted with Et₂O (3 × 20 mL) and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL), and dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes–EtOAc, 5:1→1:1) to give 5s.

Yield: 277 mg (73%); white crystals; mp 58–61 °C.

IR (neat): 3159, 2978, 2933, 1732, 1581, 1491, 1369, 1242, 1164 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.91/9.49 (rotamers, 2 × br s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H), 7.84 (br s, 1 H), 7.55–7.57 (m, 1 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.22 (dd, J = 8.5, 4.7 Hz, 1 H), 6.83 (d, J = 7.0 Hz, 1 H), 2.33 (s, 3 H), 1.42 (br s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.6, 143.4, 140.9, 140.1, 139.2, 135.2, 134.2, 131.0, 129.7, 123.2, 122.6, 119.3, 81.6, 28.2, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₁BrN₃O₂: 378.0812; found: 378.0812.

N-(2-Bromo-4-methylphenyl)-N-(pyridin-3-yl)hydrazine (1s)

Compound 5s (78 mg, 0.21 mmol) was subjected to general procedure A. Purification by silica gel column chromatography (CH₂Cl₂–Et₂O, 2:1) gave 1s.

Yield: 24 mg (42%); colorless oil.

IR (neat): 3338, 3310, 3167, 3037, 2959, 2926, 2856, 1584, 1488, 1428, 1319, 1249, 1044, 800, 710 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 2.8 Hz, 1 H), 8.05 (dd, J = 4.6, 1.3 Hz, 1 H), 7.52–7.53 (m, 1 H), 7.17–7.22 (m, 3 H), 7.08 (ddd, J = 8.4, 4.6, 0.7 Hz, 1 H), 4.19 (s, 2 H), 2.38 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.7, 143.2, 139.8, 139.4, 136.0, 134.8, 130.0, 128.7, 123.1, 122.5, 119.9, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₃BrN₃: 278.0288; found: 278.0287.

N-(Pyridn-3-yl)-2-bromo-4-methylaniline (2s)

Following general procedure B, 1s (58 mg, 0.21 mmol) in MeCN (2.0 mL) and MeOH (1.0 mL) was subjected to the cleavage reaction for 6 h. After purification by silica gel column chromatography (hexanes–acetone, 4:1) the product was obtained.

Yield: 30 mg (55%); yellow oil.

IR (neat): 3393, 3235, 3032, 2923, 1587, 1517, 1485, 1314, 806, 710 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (s, 1 H), 8.22 (d, J = 4.3 Hz, 1 H), 7.38–7.41 (m, 2 H), 7.20 (dd, J = 8.2, 4.6 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.01–7.04 (m, 1 H), 5.90 (s, 1 H), 2.29 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.7, 141.0, 139.1, 137.5, 133.5, 132.6, 128.9, 124.8, 123.7, 117.4, 113.8, 20.3.

HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₁BrN₂: 262.0106; found: 262.0101.

N-tert-Butoxycarbonyl-N′-(2-byphenyl)-N′-phenylhydrazine (5t)

To a solution of 2-bromobiphenyl (259 μL, 1.5 mmol) in THF (5 mL) was added i-PrMgCl·LiCl (1.3 M in THF, 1.3 mL, 1.65 mmol) at 0 °C. The solution was stirred at r.t. for 15 h (GC analysis showed incomplete halogen exchange) and cooled to −78 °C. A solution of 4p (309 mg, 1.5 mmol) in THF (2 mL) was added and the reaction was quenched with sat. aq NH₄Cl (5 mL) after 30 min. The mixture was extracted with Et₂O (3 × 20 mL), and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL) and then dried over anhydrous MgSO₄. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (hexanes–CH₂Cl₂, 3:1→1:1) to give 5t.

Yield: 270 mg (50%); colorless oil.

IR (neat): 3373, 3320, 3065, 2982, 2934, 1744, 1726, 1706, 1599, 1500, 1477, 1162, 750, 705 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 9.71/9.08 (2 × s, 1 H), 7.50–7.68 (m, 3 H), 7.41–7.47 (m, 1 H), 7.29–7.33 (m, 2 H), 7.18 (t, J = 7.3 Hz, 2 H), 7.07–7.12 (m, 1 H), 6.91–6.99 (m, 2 H), 1.45/1.31 (2 × s, 9 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 155.6, 146.9, 142.6, 139.4, 136.7, 130.9, 128.8, 128.1, 127.8, 126.7, 126.1, 125.1, 119.3, 114.5, 79.4, 28.2.

Anal. Calcd for C₂₃H₂₄N₂O₂: C, 76.64; H, 6.71; N, 7.77. Found: C, 76.50; H, 6.61; N, 7.78.

N-(2-Biphenyl)-N-phenylhydrazine (1t)

Following general procedure A, 5t (180 mg, 0.5 mmol) was treated at 0 °C for 3 h to give crude 1t (126 mg).

¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.51 (m, 3 H), 7.32–7.41 (m, 6 H), 7.23–7.28 (m, 2 H), 7.05–7.08 (m, 2 H), 6.81–6.86 (m, 1 H), 3.63 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.3, 146.4, 139.5, 139.1, 131.7, 128.7 (2 × C), 128.6, 128.3, 127.4, 126.9, 126.6, 118.2, 113.8.

N-(2-Biphenyl)aniline (2t)³⁹

Following general procedure A, crude 1t in MeCN (3 mL) and MeOH (1.5 mL) was subjected to the cleavage reaction for 24 h. After purification by silica gel column chromatography (hexanes–Et₂O, 5:1), 2t was obtained.

Yield: 88 mg (72%, two steps); as yellow oil.

IR (neat): 3409, 3053, 3029, 1584, 1593, 1516, 1503, 1474, 1438, 1314, 747, 705 cm⁻¹.

The ¹H and ¹³C NMR data are consistent with those reported.³⁹

N-tert-Butoxycarbonyl-N′-(2-bromo-4-methylphenyl)-N′-butylhydrazine (5u)

According to the literature procedure,^19a n-butylmagnesium bromide (2 M in THF, 0.35 mL, 0.67 mmol) was added to a solution of 4s (200 mg, 0.67 mmol) in THF (5 mL) at −100 °C. The color of the reactant turned from red to yellow during the addition. The reaction was quenched with sat. aq NH₄Cl (5 mL) after 15 min, the mixture was extracted with Et₂O (3 × 20 mL), and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL) and then dried over MgSO₄. After being concentrated in vacuo, the residue was purified by silica gel column chromatography to give the product.

Yield: 220 mg (92%); yellow oil.

IR (neat): 3247, 2965, 2933, 2874, 1701, 1493, 1371, 1169 cm⁻¹.

¹H NMR (400 MHz, DMSO-d₆): δ = 8.78/8.40 (rotamers, 2 × s, 1H), 7.36 (s, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 2.96–3.13 (m, 2 H), 2.23/2.17 (rotamers, 2 × s, 3 H), 1.47–1.55 (m, 2 H), 1.26–1.44 (m, 11 H), 0.87 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 154.4, 147.3, 134.6, 133.4, 128.6, 122.1, 116.9, 78.5, 55.7, 29.2, 28.1, 19.8, 19.5, 14.1.

Anal. Calcd for C₁₆H₂₅BrN₂O₂: C, 53.79; H, 7.05; N, 7.84. Found: C, 54.05; H, 7.14; N, 7.82.

N-Butyl-N-(2-bromo-4-methylphenyl)hydrazine (1u)

Following general procedure A, 5u (120 mg, 0.34 mmol) afforded the crude product (85 mg) as a yellow oil that was used directly in the next step.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.39 (m, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 7.06–7.10 (m, 1 H), 3.56 (br s, 2 H), 3.01–3.05 (m, 2 H), 2.28 (s, 3 H), 1.60–1.69 (m, 2 H), 1.40 (quin, J = 7.4 Hz, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.5, 134.9, 133.9, 128.6, 120.7, 118.9, 59.6, 29.5, 20.3, 20.1, 14.0.

N-Butyl-2-bromo-4-methylaniline (2u)⁴⁰

Based on general procedure B, compound 1u (crude, 85 mg, ca. 0.33 mol) in MeCN (2.0 mL) and MeOH (1.0 mL) was subjected to the cleavage reaction for 15 h and then purified by silica gel column chromatography (hexanes–EtOAc, 50:1) to give the desired product.

Yield: 57 mg (70%).

¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.25 (m, 1 H), 6.97–7.00 (m, 1H), 6.55 (d, J = 8.3 Hz, 1 H), 4.10 (br s, 1 H), 3.13 (q, J = 6.7 Hz, 2 H), 2.22 (s, 3 H), 1.61–1.68 (m, 2 H), 1.45 (quin, J = 7.4 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.9, 132.7, 128.9, 126.9, 111.2, 109.5, 43.8, 31.4, 20.3, 20.0, 13.9.

MS (CI): m/z [M + H]⁺ calcd for C₁₁H₁₇BrN₂: 242; found: 242.

N-tert-Butoxycarbonyl-N′-butyl-N′-(4-iodophenyl)hydrazine (5v)

According to the literature procedure,^19a n-butylmagnesium chloride (2.0 M in THF, 375 μL, 0.75 mmol) was added dropwise to a solution of 4v (250 mg, 0.75 mmol) in THF (10 mL) at −100 °C. The solution color turned from orange to green. After 5 min, the reaction was quenched with sat. aq NH₄Cl (5 mL), the mixture was extracted with Et₂O (3 × 20 mL), and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL), and dried over anhydrous MgSO₄. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (hexanes–EtOAc, 100:5) to give the product.

Yield: 280 mg (95%); yellow crystals; mp 72–75 °C.

IR (neat): 3299, 2965, 2934, 2874, 1709, 1590, 1489, 1368, 1251, 1163, 813 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.49 (m, 2 H), 6.56–6.60 (m, 2 H), 6.42/6.23 (rotamers, 2 × br s, 1 H), 3.34–3.48 (m, 2 H), 1.56–1.64 (m, 2 H), 1.32–1.48 (m, 11 H), 0.95 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.6, 149.0, 137.8, 114.8, 81.1, 80.5, 52.1, 28.6, 28.3, 20.2, 14.0.

Anal. Calcd for C₁₅H₂₃IN₂O₂: C, 46.16; H, 5.94; N, 7.18. Found: C, 46.36; H, 6.03; N, 7.25.

N-Butyl-N-(4-iodophenyl)hydrazine (1v)

Based on general procedure A, 5v (170 mg, 0.436 mmol) gave the crude product (115 mg, 91%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.49 (m, 2 H), 6.73–6.77 (m, 2 H), 3.54 (br s, 2 H), 3.56 (t, J = 7.5 Hz, 2 H), 1.57–1.64 (m, 2 H), 1.38 (sext, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 151.1, 137.5, 115.2, 78.8, 55.1, 27.6, 20.1, 14.0.

N-Butyl-4-iodoaniline (2v)⁴¹

The crude product 1v (ca. 0.4 mmol) was subjected to the cleavage reaction in MeCN (4.0 mL) following general procedure B. After 10 h, another 2 mmol% of catalyst was added. After another 10 h, the reaction mixture was loaded onto a silica gel column (hexanes–CH₂Cl₂, 3:1→2:1) to give the desired product.

Yield: 23 mg (21%); yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.42 (m, 2 H), 6.36–6.40 (m, 2 H), 3.63 (br s, 1 H), 3.07 (t, J = 7.1 Hz, 2 H), 1.55–1.62 (m, 2 H), 1.42 (sext, J = 7.2 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CD₃CN): δ = 149.8, 138.5, 115.6, 76.5, 43.8, 31.9, 20.9, 14.1.

1-(N-tert-Butoxycarbonylamino-N-phenyl-DL-alanyl)pyrrolidine (5w)

Freshly prepared LDA in THF (0.26 M, 1.83 mmol) was added to 1-propionylpyrrolidine (234 mg, 1.83 mmol) in THF (5 mL) at −20 °C. After 1 h, the solution was cooled to −78 °C and a solution of 4p (170 mg, 0.825 mmol) in THF (2 mL) was added. The reaction was quenched with sat. aq NH₄Cl (5 mL) after 30 min, the mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were washed with H₂O (1 × 5 mL), brine (1 × 5 mL) and then dried over anhydrous MgSO₄. After being concentrated in vacuo, the residue was purified by silica gel column chromatography (hexanes–EtOAc, 3:2) to give 5w.

Yield: 195 mg (71%); colorless oil.

IR (neat): 3472, 3362, 3258, 3065, 2981, 2934, 2881, 1738, 1637, 1456, 1234, 1168, 759 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.72 (br s, 1 H), 7.21–7.31 (m, 2H), 6.79–6.89 (m, 3 H), 4.67 (q, J = 6.9 Hz, 1 H), 3.33–3.57 (m, 4H), 1.98–2.06 (m, 2 H), 1.76–1.88 (m, 2 H), 1.43–1.54 (m, 11 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 156.2, 149.6, 129.1, 120.5, 114.2, 79.9, 56.7, 46.1, 45.6, 28.3, 26.2, 23.9, 14.7.

Anal. Calcd for C₁₈H₂₇N₃O₃: C, 64.84; H, 8.16; N, 12.6. Found: C, 64.82; H, 8.26; N, 12.33.

1-(N-Amino-N-phenyl-DL-alanyl)pyrrolidine (1w)

Following general procedure A, 5w (120 mg, 0.36 mmol) afforded crude 1w (78 mg).

¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.28 (m, 2 H), 7.03–7.06 (m, 2 H), 6.79–6.83 (m, 1 H), 4.60 (q, J = 6.8 Hz, 1 H), 3.73 (br s, 2 H), 3.40–3.55 (m, 4 H), 1.77–1.95 (m, 4 H), 1.39 (d, J = 6.8 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 170.8, 150.8, 129.1, 118.9, 114.0, 57.4, 46.2, 45.9, 26.2, 24.0, 11.7.

1-(N-Phenyl-DL-alanyl)pyrrolidine (2w)⁴²

Following general procedure B, crude 1w in MeCN (2 mL) and MeOH (2 mL) was subjected to the cleavage reaction for 24 h. After purification by silica gel column chromatography (hexanes–EtOAc, 1:1), the product 2w was obtained.

Yield: 40 mg (51%, two steps); white crystals; mp 111–112 °C (Lit.⁴² 113–115 °C).

IR (neat): 3320, 3116, 3050, 2976, 2923, 2872, 2854, 1643, 1427, 1643, 1332, 756, 693 cm⁻¹.

¹H NMR (400 MHz, CDCl₃): δ = 7.14–7.19 (m, 2 H), 6.68–6.73 (m, 1 H), 6.56–6.63 (m, 2 H), 4.63 (br s, 1 H), 4.25 (q, J = 6.6 Hz, 1 H), 3.44–3.63 (m, 4 H), 1.97–2.03 (m, 2 H), 1.84–1.91 (m, 2 H), 1.38 (d, J = 6.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 146.7, 129.3, 117.7, 113.5, 50.5, 46.2, 46.0, 26.1, 24.1, 18.0.

MS (CI): m/z (%) = 219 (100) [M + H]⁺.