Synthesis of oleophilic electron-rich phenylhydrazines

Phenylhydrazines 1 substituted with two or three long-chain alkyl, alkoxy or alkylsulfanyl groups were successfully prepared by acid-induced removal of the Boc group in hydrazides 2. The reaction is carried out with 5 equivalents of TfOH in CF3CH2OH/CH2Cl2 at −40 °C for 1.5 min. Under these conditions, the deprotected hydrazine 1 is fully protonated, which increases its stability in the reaction medium. The hydrazines were isolated in 60–86% yields and purities >90%. The hydrazides 2 were obtained in 43–71% yields from aryl bromides 5, which were lithiated with t-BuLi and subsequently reacted with di-tert-butyl azodicarboxylate (DTBAD).

The parent phenylhydrazine and many of its electron-deficient derivatives, such as p-nitrophenylhydrazine, are stable under ambient conditions and are conveniently obtained by using classical methods, such as the reduction of diazonium salts [13][14][15].
In contrast, electron-rich arylhydrazines are far less numerous and their preparation is complicated by oxidative instability.
To access functionalized and sensitive arylhydrazines several methods involving the deprotection of hydrazides II have been developed ( Figure 1). Hydrazides II are efficiently obtained by the addition of organometallic reagents III, prepared from aryl halide IV, to azodicarboxylate diesters (AD) [16,17]. Alternatively, II can be obtained in the Pd(0)-or Cu 2+ -catalyzed reaction of arylboronic acid V to AD [18][19][20]. The latter method is especially suited for arylhydrazides substituted with sensitive functional groups. Protected electron-rich arylhydrazines,  hydrazides II, containing the 2,2,2-trichloroethyl group (R = CH 2 CCl 3 ) are conveniently prepared by direct electrophilic amination of arenes VI with bis(2,2,2-trichloroethyl) azodicarboxylate (BTCEAD) under Lewis [21,22] or Brønsted [23] acid conditions. By judicious choice of the substituent R, the removal of the protecting group in II and formation of arylhydrazines I can be accomplished under acidic (R = t-Bu) [16], reductive (R = CH 2 CCl 3 ) [24], or nearly neutral (R = CH 2 CH 2 TMS) conditions [22,25]. Among the three methods, the most straightforward is the removal of the Boc group under acidic conditions. Unfortunately, the literature method for deprotection (HCl in isopropanol, 70 °C) has limited scope, and electron-rich 3,4dimethoxyphenylhydrazine could not be obtained under these conditions, although 4-pentyloxyphenylhydrazine hydrochloride was isolated in 60% yield [16]. The controlled reduction of 2,2,2-trichloroethyl esters (II, R = CH 2 CCl 3 ) with Zn in aqueous MeOH containing NH 4 OAc gave access to a number of small, electron-rich phenylhydrazines, including 3,4dimethoxyphenylhydrazine isolated in 76% yield as hydrochloride [24].
In the context of our research program in liquid-crystalline verdazyl derivatives [26], we needed phenylhydrazines 1 ( Figure 2) substituted with multiple long-chain alkyl, alkoxy and alkylsulfanyl groups. Here we demonstrate an efficient method for the preparation of several hydrophobic di-and trisubstituted phenylhydrazines in purities sufficient for further chemical transformations. Finally, we demonstrate the application of one of the phenylhydrazines for the preparation of a discotic liquid crystal.

Results and Discussion
Our initial attempts at the preparation of 3,4-dioctyloxyphenylhydrazine (1a) focused on deprotection of the trichloroethyl ester 3a under buffered reductive conditions, according to the general literature procedure [24]. In aqueous MeOH hydrazide 3a was practically insoluble, and the reaction mixture was triphasic. Under these conditions no formation of hydrazine 1a was observed. Changing MeOH to EtOH and increasing its volume by two-fold gave homogenous solutions within which the desired hydrazine 1a was formed along with significant quantities of 4 as the major products (Scheme 1). The deamination product 4 was isolated and identified by comparison with the authentic sample. The yield and proportions of the two products, 1a and 4, varied from run to run, according to the 1 H NMR spectra. Therefore, we focused on the acid-catalyzed deprotection of Boc-substituted hydrazines (Scheme 2), hydrazides 2, expecting that the reaction could be performed under fully homogenous conditions. Analysis of the reaction mechanism for the deprotection of 2 under acidic conditions shows that removal of the Boc group generates t-Bu + , which reacts with the solvent, or alternatively it can alkylate the benzene ring of arylhydrazine (Scheme 2). For less reactive arylhydrazines the former process is faster, k 1 << k 2 , and deprotection with HCl in iPrOH is effective [16]. For dialkoxyphenylhydrazines apparently k 1 >> k 2 and the desired hydrazine is not obtained [16].   The nucleophilicity of the hydrazine can be suppressed by its fast and complete protonation with a strong acid (Scheme 2). In this situation, the transient t-Bu + is trapped with the solvent, forming volatile products, which simplifies isolation of the hydrazine as a crude product. We have focused on this approach to arylhydrazines employing trifluoromethanesulfonic acid (TfOH), which was used as an effective catalyst in the deprotection of tert-butyl aryl ethers [27].
Addition of catalytic amounts of the TfOH acid (10 mol %) to solutions of hydrazide 2a ( Figure 3) in a mixture of CF 3 CH 2 OH/CH 2 Cl 2 at −40 °C gave little conversion to hydrazine 1a. With 1.5 equiv of TfOH, hydrazide 2a was only partially converted to hydrazine 1a. With 5 equiv of TfOH the reaction was complete in less than 2 min and the crude hydrazine 1a was isolated as the sole product. Reaction times under 2 min appear to be optimum; the purity of the hydrazine decreased with increasing reaction times.
By using this protocol, hydrazines 1 were isolated as viscous oils in purities >90% and yields of 60-86%, according to 1 H NMR analysis with 1,4-dimethoxybenzene as the internal standard (Scheme 3). Attempts at the preparation of crystalline hydrochlorides of 1 were unsuccessful and the viscous salts rapidly darkened and decomposed. The Boc-protected arylhydrazines, hydrazides 2, were conveniently obtained by direct addition of aryllithium to di-tert-butyl azodicarboxylate (DTBAD, Scheme 3). The latter was prepared by lithiation of aryl bromides 5 with t-BuLi to avoid the formation of n-BuBr with n-BuLi and N-butylation of hydrazide 2. Hydrazide 2a was also obtained by the Cu 2+ -catalyzed addition [18] of arylboronic acid 6a [28] to DTBAD. The yields of both syntheses of 2a were comparable.
The attempted monoiodination of 8 with BTMA·ICl 2 by using a general literature method [35] gave only traces of the product and nearly all of the starting material was recovered. Iodination under the Kern conditions [36,37] (HIO 3 /I 2 ) gave a mixture of mono-and diiodo derivatives, which were difficult to separate. Manipulation of the reaction time and temperature failed to give the desired monoiodo derivative as the major product. The preparation of bromobenzenes substituted with alkylsulfanyl groups, 5c-5f, is described elsewhere [38]. Bromides 5g [39,40] and 5h [41] were obtained according to the respective literature procedures by alkylation of 5-bromopyrogallol.

Conclusion
We have developed a synthetic protocol for the efficient preparation of electron-rich phenylhydrazines 1 substituted with alkylsulfanyl, alkyl and alkoxy groups from Boc hydrazides 2. Experiments demonstrate that the addition of hydrazides 2 to a large excess of TfOH (5 equiv) at −40 °C gives hydrazines 1 in yields ranging from 60-86% and with purity >90%, which is sufficient for subsequent chemical transformations. The optimum reaction time is less than 2 min, typically 90 sec, and longer times lead to a lower purity of the product.
The presented method for the preparation of phenylhydrazines is an attractive alternative to Leblanc's method, which relies on the reductive deprotection of trichloroethyl hydrazide 3 under heterogenous conditions. Our method involves homogenous solutions, low temperatures and short reaction times, and is particularly suited to oleophilic ("greasy") arylhydrazines such as 1, which are important intermediates for the preparation of verdazyls and other heterocycles that may exhibit, e.g., liquidcrystalline properties (e.g., 9). In comparison with Leblanc's protocol, our method is also a regiocontrolled hydrazinylation of the aromatics with the more accessible DTBAD through the organolithium. Although we focus on long-chain-substituted phenylhydrazines, we believe that this method can be used for other electron-rich arylhydrazines.

Experimental
Reagents and solvents were obtained commercially. Reactions were carried out under Ar. 1 H NMR spectra were obtained at 400 MHz in CDCl 3 and referenced to the solvent, unless specified otherwise.

Arylhydrazines 1
General procedure A solution of hydrazide 2 (1 mmol) in a mixture of CH 2 Cl 2 (3 mL)/CF 3 CH 2 OH (1 mL) was rapidly added to a solution of TfOH (0.750 g, 0.44 mL, 5 mmol) in CF 3 CH 2 OH (1 mL) at −40 °C under Ar. The mixture was stirred for 1.5 min, and CH 2 Cl 2 (5 mL) followed by sat. NaHCO 3 (10 mL) were added under very vigorous stirring. The organic layer was separated and the aqueous layer extracted (3 × CH 2 Cl 2 ). Then the extracts were dried (Na 2 SO 4 ) and the solvents were evaporated to give crude arylhydrazine 1 in purities typically >90% as a viscous, yellow to orange oil that darkened upon standing. The quantitative analysis of the deprotection reaction was conducted with 0.2 mmol of 2 as described above. The yield of the hydrazines was established by adding known quantities of 1,4-dimethoxybenzene (2.0 mL of 25 mM solution in CH 2 Cl 2 , 0.05 mmol) to the CH 2 Cl 2 extract, evaporation of the resulting solution, and integration of the low-field 1 H NMR signals.

General procedure
To a solution of the substituted bromobenzene 5 (1.0 mmol) in dry THF (10 mL), t-BuLi (1.7 M in pentane, 2.2 mmol) was added under Ar at −78 °C. After 1.5 h a THF (1 mL) solution of di-tert-butyl azodicarboxylate (DTBAD, 345 mg, 1.5 mmol) was added dropwise. The mixture was stirred at −78 °C for 0.5 h, then 1 h at rt, and quenched with 5% HCl. The organic products were extracted (Et 2 O), the extracts dried (Na 2 SO 4 ), the solvents evaporated, and the residue was passed through a short silica-gel column (hexane/CH 2 Cl 2 then CH 2 Cl 2 ) to give hydrazides 2 as white solids.