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. 2019 Dec 17;4(27):22601–22612. doi: 10.1021/acsomega.9b03417

Formation of Synthetically Versatile 2-Aminobenzophenones from Readily Accessed Acyl Hydrazides

Nehaal Ahmed 1, André Shamsabadi 1, Vijay Chudasama 1,*
PMCID: PMC6941372  PMID: 31909344

Abstract

graphic file with name ao9b03417_0006.jpg

Herein, we report the transformation of readily accessed acyl hydrazides into protected 2-aminobenzophenones via a two-step process involving an aryne-based molecular rearrangement followed by a one-pot addition–elimination procedure. The assembly of the scaffold is tolerant of a wide variety of functional groups, and the carbamate group on the product can be facilely removed to afford highly valuable 2-aminobenzophenones. Application of the protocol was demonstrated in the synthesis of neurological medicine phenazepam.

Introduction

2-Aminobenzophenones are a very important class of compounds in medicinal and organic chemistry. Compounds bearing this structure have displayed desirable pharmacological use as antimitotic,1 antitumor,2 and antiproliferative3 agents, as well as skeletal muscle relaxants.4 2-Aminobenzophenones are also useful starting materials for the synthesis of a wide variety of fine chemicals such as acridones,5 quinolines,6−8 quinazolines,9−11 quinolinones,12 quinoxalinones,13 fluorenones,14 benzisoxazoles,15 indazoles,16 indoles,17 2-quinazolinones,18 benzothiophenes,19 diaryldibenzodiazocines,20 and (perhaps most noteworthy) benzodiazepines.21−24 As such, various methodologies for the synthesis of 2-aminobenzophenones and their derivatives have been developed, including (i) Friedel–Crafts acylation of para-substituted anilines;25,26 (ii) reaction of 2-aminobenzaldehydes with aryl Grignard reagents followed by oxidation with CuCl2;27 (iii) Pd-catalyzed addition of arylboronic acids28 or sodium arylsulfinates29 to 2-aminobenzonitriles; (iv) Pd-catalyzed C–H bond coupling of ortho-directed anilines;30 and (v) aryl insertion into the C–N of amides31 or imides.32 Unfortunately, however, many of these processes suffer from either poor substrate scope (e.g., Friedel–Crafts processes falter when utilizing electron-poor arenes), require multiple reaction steps (e.g., the Grignard-based route obviates the presence of acidic protons and requires product oxidation to obtain the ketone), or require the use of expensive metal catalysts (e.g., Pd(OAc)2, Pd(TFA)2). Application of aryne insertion chemistry appears to be the most promising of these conditions; however, work here has been primarily focused on the formation of N-aryl 2-aminobenzophenones.31

There has been a substantial number of recent reports for the synthesis of acyl hydrazides and their conversion into a variety of useful chemical functionalities.33 More specifically, facilely accessed acyl hydrazides have been reported as shelf-stable intermediates for the creation of esters, thioesters, amides,34 ketones,35N-acyl carbamates,36 1H- and 2H-indazoles,37 and 1,3,4-oxadiazoles,38 as well as being employed as precursors for the formation of bioactive molecules such as hydroxamic acids39 and macrocyclic enamides.40 Recently, we developed conditions for the reaction of arynes with acyl hydrazides in which a novel molecular rearrangement reaction pathway facilitates the formation of 2-hydrazobenzophenones.37 We envisioned that the transformation of this entity into useful 2-aminobenzophenones would be possible via rupture of the N–N bond in a one-pot alkylation–E1cB elimination procedure (Scheme 1). The cleavage of the N–N bond without the use of hydrogenation procedures involving expensive/undesirable metals was seen as a key aspect in itself; this is particularly well described in related work by Magnus et al.41 Finally, we postulated that our methodology could be applied for the synthesis of medicinally relevant benzodiazepines.

Scheme 1. Synthetic Routes To Access 2-Aminobenzophenones.

Scheme 1

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Results and Discussion

Our study began with the reaction of 2-hydrazobenzophenone 1a with tert-butyl bromoacetate 2a in the presence of a base with the aim of forming protected 2-aminobenzophenone 3a in a two-step one-pot procedure. Initially, the reaction was carried out using an excess of NaH at 20 °C (Table 1, entry 1).36 While these conditions did provide access to desired product 3a, it was only in a modest yield of 45%. Increasing the temperature to 50 °C had a positive effect on yield with 67% of 3a being isolated (Table 1, entry 2).

Table 1. Reaction Optimization for the Formation of Protected 2-Aminobenzophenone 3a.

entry base equiv T (°C) alkylating agent equiv yield 3aa (%) yield 4 (%)
1 NaH 5 20 2a 1.1 45 (72) 0
2 NaH 5 50 2a 1.1 67 0
3 NaH 3 50 2a 1.1 60 12
4b NaH 1 + 1 20 2a 1.1 77 0
5c NaH 1 20 2b 1.1 35 (55) 0
6d NaH 2 20 2b 2 57 10
7d NaH 2.5 20 2b 2.5 53 0
8e NaH 2.5 20 2b 2.5 82 0
9 Cs2CO3 2.5 20 2b 2.5 20 (90) 19
10 NEt3 2.5 20 2b 2.5 0 (2) 0
11 NaOtBu 2.5 20 2b 2.5 23 (44) 0
12 NaOEt 2.5 20 2b 2.5 42 (77) 0
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a

Conversion of starting material 1a given in parentheses when not 100%.

b

Stepwise procedure with intermediate 4a isolated.

c

45% of starting material recovered.

d

Malonate salt observed.

e

Dropwise addition of alkylating agent.

Unfortunately, the efficiency of the reaction was not improved by lowering the number of equivalents of base to 3, where a 60% yield of the desired product and a 12% yield of alkylated-hydrazide intermediate 4a were recovered (Table 1, entry 3). We next decided to try a two-step process, i.e., the use of 1 equiv of NaH and 1.1 equiv of tert-butyl bromoacetate 2a at room temperature to isolate the resulting alkylated acyl hydrazide intermediate 4a and then subjecting this intermediate to an additional equivalent of NaH relative to intermediate isolated. This resulted in an improved overall isolated yield, 77%, of desired product 3a over the two steps (Table 1, entry 4). In an effort to further improve the efficiency of the process, we utilized an alkylating agent with two electron-withdrawing groups in an attempt to promote elimination. We first utilized 1.1 equiv of diethyl bromomalonate 2b as the alkylating agent with 1 equiv of NaH in an attempt to isolate alkylated intermediate 4b (Table 1, entry 5). Interestingly, no intermediate was isolated under these conditions with a 35% yield of the protected 2-aminobenzophenone product 3a and 45% recovery of starting material 1a observed. We suspected that the increased acidity of the α proton in alkylated-hydrazide intermediate 4b resulted in rapid elimination to product 3a. In an attempt to exploit this, a one-pot procedure using 2 equiv of base and alkylating agent was trialed; however, this resulted in only a 57% yield of 3a due to the formation of a significant amount of a malonate salt (Table 1, entry 6). Increasing the equivalents of NaH and malonate 2b to 2.5 resulted in a slight decrease in yield (53%) with even more malonate salt observed (Table 1, entry 7). We therefore added malonate 2b dropwise to minimize the consumption of NaH prior to intermediate 4b formation. Gratifyingly, this resulted in a high yield of the desired product, 82% (Table 1, entry 8), with no intermediate or malonate salt observed. Having established a procedure that led to the formation of 3a in excellent yield, the suitability of other bases was appraised (Table 1, entries 9–12). Unfortunately, the substitution of NaH for weaker bases (i.e., Cs2CO3, NEt3, NaOtBu, NaOEt) proved detrimental to yield with triethylamine not even facilitating the initial alkylation step. The other bases were able to carry out the alkylation and E1cB elimination steps, but gave low yields of the desired product. In the case of using Cs2CO3, we highlight that although compounds 3a and 4b were isolated, the crude reaction mixture appeared to be a complex mixture of many products.

With the optimized conditions for the transformation of 2-hydrazobenzophenones into protected 2-aminobenzophenones in hand, we took the opportunity to investigate the applicability of our protocol for the formation of various protected 2-aminobenzophenones (Scheme 2). A range of 2-hydrazobenzophenones were examined (1a–1j) under the developed reaction conditions. All of the starting 2-hydrazobenzophenones were prepared in good yields using our previously reported procedure for the reaction of acyl hydrazides with benzynes (see the Supporting Information for details).

Scheme 2. Reaction Scope for the Formation of Protected 2-Aminobenzophenones 3.

Scheme 2

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Gram scale.

Reaction conditions: 2-aminobenzophenone 1 (0.50 mmol, 1 equiv) with NaH (1.25 mmol, 2.5 equiv) in tetrahydrofuran (THF) (3 mL) followed by the dropwise addition of diethyl bromomalonate 2b (1.25 mmol, 2.50 equiv) at 20 °C for 4 h.

To our delight, the reaction was tolerant of various functional groups on the aromatic motif (e.g., halo, methyl, methoxy, and trifluoromethyl functionalities) with good to excellent yields (64–82%) observed. The reaction protocol proved to be tolerant of electron-poor, electron-neutral, and electron-rich aromatic rings, with ortho-, meta-, and para-substitutions having no significant effect on yield. The optimized protocol was also shown to be applicable to a gram-scale synthesis, with compound 3a being prepared in a 72% yield.

Having established an efficient protocol for the formation of protected 2-aminobenzophenones, we next investigated conditions for deprotection. Initially, we trialed previously reported Brønsted-acid-based conditions42 and observed that refluxing 3b in HCl (12 M) resulted in the full conversion of starting material with an excellent yield of 2-aminobenzophenone 5b obtained (Table 2, entries 1 and 2). Other previously reported conditions, the use of aqueous KOH in dimethylacetamide,43 did not result in the full conversion of starting material; even increasing the reaction temperature and concentration of KOH did not improve the yield and conversion significantly (Table 2, entries 3–7). Most pleasingly, however, the use of Lewis acid AlCl3 in dichloromethane resulted in the rapid deprotection (45 min) of the isopropyl carbamate with an exceptional isolated yield of product 5b observed, 92% (Table 2, entry 8; a 60% overall yield of 5b from its corresponding acyl hydrazide).44 The assertion of Lewis acidity having a role in the reaction is based on the fact that the use of HCl (12 M) alone (in either 1,4-dioxane or EtOAc) only resulted in complete conversion after 16 h at 110 °C, i.e., rather than being complete in 45 min at 0 °C when using AlCl3. In fact, the reaction when using HCl (12 M) after 16 h at room temperature only resulted in an 11% yield of 5b (17% conversion of 3b). The optimized deprotection conditions were then trialed on electron-poor and electron-rich protected 2-aminobenzophenones 3d and 3h (respectively). To our delight, this afforded the corresponding 2-aminobenzophenones 5d and 5h in excellent yields (>85%, Table 2, inset).

Table 2. Reaction Optimization for the Formation of 2-Aminobenzophenone 5ba.

entry reagent solvent T (°C) conversion 3b (%) yield 5b (%)
1 HCl (12 M) dioxane 110 100 88
2 HCl (12 M) EtOAc 110 100 83
3 KOH (0.3 M) DMA 60 26 22
4 KOH (0.5 M) DMA 60 42 30
5 KOH (1 M) DMA 110 51 38
6 KOH (4 M) DMA 110 67 59
7 KOH (8 M) DMA 110 56 54
8 AlCl3 (4 equiv) DCM 0 (45 min) 100 92
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a

DMA = N,N-dimethylacetamide. DCM = dichloromethane. All reactions carried out over 16 h unless stated otherwise in parentheses.

Recognizing the potential of the protocol for the synthesis of functional 2-aminobenzophenones, we turned our attention to providing a tangible application of the protocol for the synthesis of a pharmaceutically relevant benzodiazepine (Scheme 3), as a representative example, especially as aryne chemistry is being increasingly employed to synthesize such systems.45 Phenazepam is a member of a class of molecules that have found use in the treatment of various psychiatric and neurological disorders.46 Furthermore, phenazepam can be employed as a precursor for the formation of more complex benzodiazepines such as cinazepam and 3-hydroxyphenazepam.47 We envisioned that phenazepam could be readily accessed via our optimized methodology. More specifically, the chloro entity could be incorporated through the use of starting aldehyde 6 and the bromo substituent could be installed through para-directed bromination of 2-aminobenzophenone 8. Initially, 2-chlorobenzaldehyde 6 was transformed into the corresponding acyl hydrazide 7 via hydroacylation of diisopropyl azodicarboxylate (DIAD). Aryl insertion into the C(O)–N bond utilizing aryne-based molecular transformation resulted in 2-hydrazobenzophenone 1g in a 67% yield. This species was submitted to our addition–elimination protocol to afford protected 2-aminobenzophenone 3g in a 71% yield. Lewis acidic deprotection of the carbamate group afforded 2-aminobenzophenone 5g in a 91% yield. para-Directed electrophilic bromination using NBS introduced bromine at the 7-position to form 8 in a 90% yield. Finally, a one-pot alkylation–cyclization procedure led to an excellent yield of phenazepam (85%). As such, through the application of our novel methodology, we were able to obtain the desired benzodiazepine in good yield (and even without any of the reaction steps being optimized).

Scheme 3. Synthesis of Phenazepam.

Scheme 3

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Reagents and conditions: (a) DIAD (1.1 equiv), H2O, rt, 24 h; (b) 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1.5 equiv), TBAT (2 equiv), toluene, 60 °C, 16 h; (c) NaH (2.5 equiv), THF, diethyl bromomalonate (2.5 equiv, dropwise addition), rt, 4 h; (d) AlCl3 (4 equiv), DCM, rt, 45 min; (e) NBS (1 equiv), DCM, 0 °C, 1 h; (f) bromoacetyl bromide (1.1 equiv), DCM, 0 °C, 1 h, followed by NH3, EtOH, rt, 24 h. TBAT = tetrabutylammonium difluorotriphenylsilicate.

Conclusions

In conclusion, we have shown 2-hydrazobenzophenones to be excellent candidates for the synthesis of functional 2-aminobenzophenones, which have many applications in terms of their pharmacological and synthetic uses (as exemplified by the extensive catalogue of bioactive molecules they can be transformed into).5−24 A one-pot, alkylation–E1cB elimination procedure to produce isopropyl carbamate protected 2-aminobenzophenones from 2-hydrazobenzophenones has been developed. Moreover, the protocol is tolerant of many functional groups, and the deprotection of the isopropyl carbamate has been optimized to produce 2-aminobenzophenones in high yield. Finally, the application of both of these methods was demonstrated in the synthesis of phenazepam.

Experimental Section

General Experimental Methods

All reagents were purchased from Sigma-Aldrich or AlfaAesar and were used as received without further purification unless otherwise stated. Where described below, petrol refers to petroleum ether (b.p. 40–60 °C). All reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel plates. Silica get plates were initially examined under short-wave UV light and then developed with the use of an aqueous potassium permanganate stain. Flash column chromatography was carried out with preloaded GraceResolv flash cartridges on a Biotage Isolera Spektra One flash chromatography system. Quoted yields refer to chromatographically and spectroscopically pure compounds unless otherwise stated. 1H NMR spectra were recorded at 300, 600, or 700 MHz and 13C NMR at 150 or 175 MHz on a Bruker Avance 300, Bruker Avance III 600, or Bruker Avance Neo 700 spectrometer. All spectra were recorded at room temperature unless stated otherwise. The chemical shifts (δ) for 1H and 13C are quoted relative to residual signals of the solvent on the parts per million (ppm) scale. Coupling constants (J values) are reported in hertz (Hz) and are reported as JH–H unless otherwise stated. Signal multiplicities in 13C NMR were determined using the distortionless enhancement by polarization transfer (DEPT) spectral editing technique. Melting points were measured with a Gallenkamp apparatus and are uncorrected.

General Experimental for the Formation of Acyl Hydrazides: Method A

To a solution of azodicarboxylate (6.00 mmol, 1.2 equiv) in H2O (1 mL) was added aldehyde (5.00 mmol, 1.0 equiv), and the reaction mixture was stirred at 21 °C for 48 h. The resulting solution was extracted with EtOAc (3 × 15 mL). The combined extracts were dried (MgSO4) and filtered, and the solvent was evaporated in vacuo. The resultant crude residue was purified as described below.

Diisopropyl 1-(4-Fluorobenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(4-fluorobenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.21 g, 3.70 mmol, 74%). 1H NMR (600 MHz, CDCl3) δ 7.80–7.62 (m, 2H), 7.11 (t, J = 8.5 Hz, 2H), 6.95–6.70 (m, NH, 1H), 5.02 (septet, J = 6.1 Hz, 1H), 4.92 (septet, J = 6.1 Hz, 1H), 1.30 (d, J = 5.2 Hz, 6H), 1.12 (d, J = 5.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 170.3 (C), 165.2 (d, JC–F = 253.4 Hz, C), 155.4 (C), 152.9 (C), 131.3 (d, JC–F = 2.7 Hz, CH), 131.1 (d, JC–F = 9.8 Hz, CH), 115.5 (d, JC–F = 22.1 Hz, CH), 72.8 (CH), 70.9 (CH), 22.0 (CH3), 21.5 (CH3); IR (solid) 3306, 2984, 2939, 1704, 1602, 1507 cm–1.

Diisopropyl 1-Benzoylhydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-benzoylhydrazine-1,2-dicarboxylate as a white solid (1.02 g, 3.30 mmol, 66%). 1H NMR (600 MHz, CDCl3) δ 7.72–7.58 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.15–6.99 (m, NH, 1H), 5.00 (septet, J = 6.3 Hz, 1H), 4.87 (septet, J = 5.9 Hz, 1H), 1.28 (d, J = 5.5 Hz, 6H), 1.04 (d, J = 4.7 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 171.4 (C), 155.5 (C), 153.0 (C), 135.3 (CH), 132.0 (CH), 128.2 (CH), 72.6 (CH), 70.7 (CH), 22.0 (CH3), 21.4 (CH3); IR (solid) 3308, 2983, 2938, 1705, 1601 cm–1.

Diisopropyl 1-(3-Bromobenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(3-bromobenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.20 g, 3.10 mmol, 62%). 1H NMR (600 MHz, CDCl3) δ 7.84–7.73 (m, 1H), 7.67–7.52 (m, 2H), 7.30 (t, J = 7.8 Hz, 1H), 6.99–6.80 (m, NH, 1H), 5.01 (septet, J = 6.0 Hz, 1H), 4.91 (septet, J = 6.0 Hz, 1H), 1.30 (d, J = 5.8 Hz, 6H), 1.10 (d, J = 5.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 169.8 (C), 155.3 (C), 152.6 (C), 137.2 (C), 134.8 (CH), 131.0 (CH), 129.9 (CH), 126.7 (CH), 122.2 (C), 73.0 (CH), 71.0 (CH), 22.0 (CH3), 21.5 (CH3); IR (solid) 3303, 2983, 2938, 1707, 1568 cm–1.

Diisopropyl 1-(4-(Trifluoromethyl)benzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(4-(trifluoromethyl)benzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.17 g, 3.10 mmol, 62%). 1H NMR (600 MHz, CDCl3) δ 7.82–7.74 (m, 2H), 7.73–7.67 (m, 2H), 6.95–6.70 (m, NH, 1H), 5.03 (septet, J = 6.1 Hz, 1H), 4.91 (septet, J = 6.1 Hz, 1H), 1.31 (d, J = 5.8 Hz, 6H), 1.10 (d, J = 5.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 170.2 (C), 155.3 (C), 152.6 (C), 138.8 (C), 133.4 (q, JC–F = 31.9 Hz, C), 128.3 (CH), 125.3 (q, JC–F = 3.0 Hz, CH), 123.7 (q, JC–F = 272.6 Hz, C), 73.1 (CH), 71.1 (CH), 22.0 (CH3), 21.5 (CH3); IR (solid) 3308, 2985, 2941, 1709, 1619, 1514 cm–1.

Diisopropyl 1-(4-Methoxybenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(4-methoxybenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.03 g, 3.05 mmol, 61%). 1H NMR (600 MHz, CDCl3) δ 7.76–7.62 (m, 2H), 6.98–6.64 (m, 3H), 5.00 (septet, J = 6.2 Hz, 1H), 4.92 (septet, J = 6.2 Hz, 1H), 3.86 (s, 3H), 1.29 (d, J = 4.5 Hz, 6H), 1.13 (d, J = 4.5 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 170.8 (C), 163.1 (C), 155.5 (C), 153.3 (C), 131.2 (CH), 127.0 (C), 113.5 (CH), 72.4 (CH), 70.7 (CH), 55.6 (CH3), 22.1 (CH3), 21.6 (CH3); IR (solid) 3310, 2982, 2938, 1733, 1699, 1604, 1510 cm–1.

Diisopropyl 1-(3-Chlorobenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(3-chlorobenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.35 g, 3.95 mmol, 79%). 1H NMR (700 MHz, CDCl3) δ 7.76–7.50 (m, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.96–6.75 (m, NH, 1H), 5.01 (septet, J = 6.2 Hz, 1H), 4.91 (septet, J = 5.6 Hz, 1H), 1.29 (d, J = 5.8 Hz, 6H), 1.14–1.08 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 170.0 (C), 155.3 (C), 152.7 (C), 137.0 (C), 134.4 (CH), 131.9 (CH), 129.6 (CH), 128.2 (CH), 126.3 (C), 73.0 (CH), 71.0 (CH), 22.0 (CH3), 21.5 (CH3); IR (solid) 3287, 2981, 2940, 2921, 1710, 1560 cm–1.

Diisopropyl 1-(2-Chlorobenzoyl)hydrazine-1,2-dicarboxylate 7

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-chlorobenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.49 g, 4.35 mmol, 87%). 1H NMR (700 MHz, CDCl3) δ 7.50–7.42 (m, 1H), 7.41–7.36 (m, 2H), 7.31 (ddd, J = 7.5, 6.8, 1.9 Hz, 1H), 6.82–6.55 (m, NH, 1H), 5.01 (septet, J = 6.1 Hz, 1H), 4.93–4.89 (m, 1H), 1.29 (d, J = 6.1 Hz, 6H), 1.12–1.04 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 167.7 (C), 155.1 (C), 151.8 (C), 136.3 (C), 131.0 (CH), 130.4 (C), 129.5 (CH), 128.1 (CH), 126.8 (CH), 72.9 (CH), 70.9 (CH), 22.0 (CH3), 21.4 (CH3), IR (solid) 3298, 2979, 2944, 2855, 1739, 1710, 1613, 1572 cm–1.

Diisopropyl 1-(2,3,4-Trimethoxybenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2,3,4-trimethoxybenzoyl)hydrazine-1,2-dicarboxylate as a white solid (797 mg, 2.00 mmol, 40%). Mp 110–112 °C; 1H NMR (600 MHz, CDCl3) δ 7.25–7.08 (m, 1H), 6.88 (s, NH, 1H), 6.69 (d, J = 8.7 Hz, 1H), 5.00–4.88 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 1.26 (d, J = 5.8 Hz, 6H), 1.20–1.12 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 168.0 (C), 156.4 (C), 155.1 (C), 152.5 (C), 151.4 (C), 141.7 (C), 124.3 (CH), 122.9 (C), 107.0 (CH), 72.3 (CH), 70.5 (CH), 62.1 (CH3), 61.1 (CH3), 56.2 (CH3), 22.0 (CH3), 21.6 (CH3); IR (solid) 3310, 2982, 2940, 1737, 1710, 1596 cm–1; LRMS (ESI) 399 (30, [M + H]+), 195 (100, [M – C8H15N2O4 + H]+); HRMS (ESI) calcd for C18H27N2O8 [M + H]+ 399.1762; observed 399.1760.

Diisopropyl 1-(3,4-Dimethylbenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(3,4-dimethylbenzoyl)hydrazine-1,2-dicarboxylate as a white solid (891 mg, 2.65 mmol, 53%). 1H NMR (700 MHz, CDCl3) δ 7.47–7.32 (m, 2H), 7.14 (d, J = 7.8 Hz, 1H), 7.10–7.00 (m, NH, 1H), 4.99 (septet, J = 6.3 Hz, 1H), 4.88 (septet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 1.30–1.23 (m, 6H), 1.15–1.04 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 171.4 (C), 155.5 (C), 153.3 (C), 141.5 (C), 136.6 (C), 132.6 (C), 129.6 (CH), 129.4 (CH), 126.2 (CH), 72.3 (CH), 70.6 (CH), 22.0 (CH3), 21.5 (CH3), 20.1 (CH3), 19.7 (CH3); IR (thin film) 3278, 3010, 2986, 1713, 1531, cm–1; LRMS (ESI) 337 (100, [M + H]+); HRMS (ESI) calcd for C15H20N3O7 [M + H]+ 337.3959, observed 337.3961.

Diisopropyl 1-(3-Iodobenzoyl)hydrazine-1,2-dicarboxylate

Compound prepared according to method A. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(3-iodobenzoyl)hydrazine-1,2-dicarboxylate as a white solid (1.11 g, 2.55 mmol, 51%). 1H NMR (700 MHz, CDCl3) δ 8.01–7.90 (m, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.71–7.53 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H), 5.01 (septet, J = 6.2 Hz, 1H), 4.92 (septet, J = 6.1 Hz, 1H), 1.30 (d, J = 5.9 Hz, 6H), 1.13–1.08 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 169.6 (C), 155.3 (C), 152.6 (C), 140.8 (CH), 136.8 (CH), 129.9 (CH), 127.3 (CH), 93.4 (CH), 73.0 (CH), 71.0 (CH), 22.1 (CH3), 21.5 (CH3); IR (solid) 3300, 2975, 2941, 1711, 1535 cm–1.

(2-Bromophenoxy)trimethylsilane

To a solution of 2-bromophenol (603 μL, 5.70 mmol) in THF (10 mL) was added hexamethyldisilazane (1.57 mL, 7.50 mmol). The solution was refluxed for 2 h and then allowed to cool down to room temperature. The solvent was then removed in vacuo to afford (2-bromophenoxy)trimethylsilane as an orange oil (1.24 g, 5.10 mmol, 89%). 1H NMR (600 MHz, CDCl3) δ 7.53 (dd, J = 7.9, 1.6 Hz, 1H), 7.18 (td, J = 8.0, 1.6 Hz, 1H), 6.88 (dd, J = 8.0, 1.5 Hz, 1H), 6.85 (td, J = 7.8, 1.5 Hz, 1H), 0.31 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 152.6 (C), 133.4 (CH), 128.4 (CH), 122.8 (CH), 120.9 (CH), 115.7 (C), −0.5 (CH3); IR (thin film) 3056, 2986, 1584 cm–1.

2-(Trimethylsilyl)phenyl Trifluoromethanesulfonate

To a solution of (2-bromophenoxy)trimethylsilane (2.00 g, 8.60 mmol) in THF (20 mL) at −78 °C was added dropwise n-BuLi (2.5 M, 3.91 mL, 12.2 mmol). The reaction mixture was stirred for 20 min. After this time, to the solution was added dropwise Tf2O (1.90 mL, 12.2 mmol). The reaction was allowed to warm slowly to room temperature and stirred for a further 30 min. The solution was quenched with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and filtered, and the solvent removed in vacuo. Purification by column chromatography (10–80% EtOAc/petrol) afforded 2-(trimethylsilyl)phenyl trifluoromethanesulfonate as a yellow oil (1.46 g, 4.90 mmol, 57%). 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.3 Hz, 1H), 7.45 (td, J = 7.8, 1.5 Hz, 1H), 7.36–7.33 (m, 2H), 0.37 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 155.2 (C), 136.4 (CH), 132.7 (CH), 131.4 (CH), 127.6 (CH), 119.6 (CH), 118.6 (q, JC–F = 319.9 Hz, C), −0.7 (CH3); IR (thin film) 3054, 2987 cm–1.

General Experimental for the Formation of 2-Hydrazobenzophenones 1a–j: Method B

To a solution of acyl hydrazide (500 μmol, 1.0 equiv) and TBAT (1.00 mmol, 540 mg, 2.0 equiv) in toluene (6 mL) was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (750 μmol, 182 μL, 1.5 equiv). The reaction mixture was stirred at 50 °C for 16 h. The resulting solution was then allowed to cool down to room temperature, and the solvent was evaporated in vacuo. The resultant crude residue was purified as described below. These 2-hydrazobenzophenone compounds exist as rotamers, and this leads to broadness in peaks + additional peaks (the stereodynamics of the N–N bond about hydrazide-type molecules is well known in the literature; see for example: ref (40)). As such, we conducted VT NMR experiments on a model compound (i.e., compound 1a) to prove that the additional peaks for the 2-hydrazobenzophenones at room temperature were indeed very likely to be due to the rotameric nature of these molecules.

Diisopropyl 1-(2-(4-Fluorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1a

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(4-fluorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a pale yellow oil (173 mg, 430 μmol, 86%). 1H NMR (700 MHz, CDCl3) δ 7.83–7.81 (m, 2H), 7.77–7.76 (m, 1H), 7.57–7.54 (m, 1H), 7.42–7.35 (m, 2H), 7.12 (t, J = 7.6 Hz, 2H), 7.12 (br s, 1H, NH), 5.00–4.93 (m, 1H), 4.79 (septet, J = 6.1 Hz, 1H), 1.31–1.22 (m, 6H), 1.16–0.90 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 195.1 (C), 194.5 (C), 166.1 (d, JC–F = 253.8 Hz, C), 165.9 (d, JC–F = 253.7 Hz, C), 156.1 (C), 155.8 (C), 155.0 (C), 154.5 (C), 141.0 (C), 135.4 (C), 133.5 (C), 133.4 (C), 133.1 (CH), 132.4 (CH), 130.1 (CH), 129.8 (CH), 129.4 (CH), 128.9 (CH), 127.7 (CH), 127.4 (CH), 115.7 (d, JC–F = 21.7 Hz), 71.2 (CH), 70.8 (CH), 70.0 (CH), 22.1 (CH3), 22.0 (CH3), 21.8 (CH3); IR (thin film) 3323, 2921, 2834, 1711, 1666, 1622, 1599, 1574 cm–1; LRMS (ESI) 403 (100, [M + H]+); HRMS (ESI) calcd for C21H24FN2O5 [M + H]+ 403.1664; observed 403.1658.

1H NMR (400 MHz, CDCl3, −57 °C) δ 7.88–7.72 (m, 3H), 7.62–7.58 (m, 1H), 7.45–7.35 (m, 3H), 7.20–7.13 (m, 2H), 5.00–4.72 (m, 2H), 1.38–0.75 (m, 12H).

1H NMR (400 MHz, DMSO-d6, 120 °C) δ 8.84 (br s, 1H), 7.78–7.75 (m, 2H), 7.59 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 7.54 (ddd, J = 8.1, 1.2, 0.5 Hz, 1H), 7.39 (ddd, J = 7.6, 7.4, 1.2 Hz, 1H), 7.38 (ddd, J = 7.6, 1.6, 0.5 Hz, 1H), 7.29–7.25 (m, 2H), 4.84 (septet, J = 6.3 Hz, 1H), 4.79 (septet, J = 6.3 Hz, 1H), 1.21 (d, J = 6.3 Hz, 6H), 1.06 (d, J = 6.3 Hz, 6H).

13C NMR (100 MHz, DMSO-d6, 120 °C) δ 193.0 (C), 165.1 (d, JC–F = 252.1 Hz, C), 155.7 (C), 153.9 (C), 140.4 (C), 134.8 (C), 133.8 (d, JC–F = 2.8 Hz, C), 132.4 (d, JC–F = 9.5 Hz, CH), 131.1 (CH), 129.0 (CH), 126.5 (CH), 126.5 (CH), 115.3 (d, JC–F = 22.2 Hz, CH), 70.2 (CH), 68.9 (CH), 21.7 (CH3), 21.4 (CH3).

Diisopropyl 1-(2-Benzoylphenyl)hydrazine-1,2-dicarboxylate 1b

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-benzoylphenyl)hydrazine-1,2-dicarboxylate as a pale brown oil (161 mg, 420 μmol, 84%). 1H NMR (700 MHz, CDCl3) 7.80–7.49 (m, 5H), 7.46–7.35 (m, 4H), 7.10–6.87 (m, 1H, NH), 5.06–4.92 (m, 1H), 4.92–4.76 (m, 1H), 1.32–1.22 (m, 6H), 1.18–0.92 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 196.7 (C), 196.1 (C), 156.1 (C), 155.8 (C), 154.9 (C), 154.5 (C), 153.0 (C), 141.0 (C), 137.3 (C), 137.1 (C), 135.6 (C), 133.6 (CH), 133.2 (C), 132.3 (CH), 132.0 (CH), 130.4 (CH), 130.3 (CH), 129.7 (CH), 129.5 (CH), 128.5 (CH), 128.3 (CH), 127.6 (CH), 127.4 (CH), 120.8 (CH), 72.6 (CH), 71.2 (CH), 70.8 (CH), 70.0 (CH), 69.9 (CH), 22.1 (CH3), 22.1 (CH3), 22.0 (CH3), 21.7 (CH3), 21.5 (CH3); IR (thin film) 3301, 2981, 2937, 1883, 1716, 1659, 1598, 1579 cm–1; LRMS (ESI) 385 (100, [M + H]+); HRMS (ESI) calcd for C21H25N2O5 [M + H]+ 385.1758; observed 385.1755.

Diisopropyl 1-(2-(3-Bromobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1c

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(3-bromobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a clear oil (183 mg, 395 μmol, 79%). 1H NMR (600 MHz, CDCl3) δ 8.02–7.82 (m, 1H), 7.77–7.67 (m, 2H), 7.62–7.56 (m, 1H), 7.55–7.10 (m, 4H), 7.08–6.65 (m, NH, 1H), 5.06–4.77 (m, 2H), 3.96–3.93 (m, 3H), 1.31–0.94 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 195.0 (C), 194.6 (C), 156.2 (C), 155.8 (C), 154.9 (C), 154.5 (C), 142.0 (C), 141.1 (C), 139.1 (C), 136.4 (CH), 136.1 (CH), 134.8 (CH), 133.3 (CH), 132.7 (CH), 130.1 (CH), 128.9 (CH), 128.7 (CH), 127.7 (CH), 127.4 (CH), 126.1 (C), 122.8 (C), 71.3 (CH), 71.0 (CH), 70.1 (CH), 22.2 (CH3), 22.1 (CH3), 22.0 (CH3), 21.8 (CH3); IR (thin film) 3312, 2980, 2880, 1715, 1660, 1622, 1595, 1575 cm–1; LRMS (ESI) 487 (30, [M81Br + Na]+), 485 (31, [M79Br + Na]+), 465 (100, [M79Br + H]+), 463 (98, [M79Br + H]+); HRMS (ESI) calcd for C21H24BrN2O5 [M79Br + H]+ 463.0863; observed 463.0858.

Diisopropyl 1-(2-(4-(Trifluoromethyl)benzoyl)phenyl)hydrazine-1,2-dicarboxylate 1d

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(4-(trifluoromethyl)benzoyl)phenyl)hydrazine-1,2-dicarboxylate as a clear oil (161 mg, 355 μmol, 71%). 1H NMR (600 MHz, CDCl3) δ 7.94–7.85 (m, 2H), 7.83–7.63 (m, 3H), 7.62–7.57 (m, 1H), 7.42–7.34 (m, 2H), 7.09–6.84 (m, NH, 1H), 5.03–4.94 (m, 1H), 4.85–4.75 (m, 1H), 1.30–1.23 (m, 6H), 1.18–0.92 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 195.4 (C), 194.9 (C), 155.9 (C), 154.9 (C), 141.1 (C), 140.2 (C), 134.7 (C), 132.9 (CH), 130.6 (CH), 130.0 (CH), 129.9 (CH), 129.2 (CH), 128.7 (CH), 127.7 (CH), 127.4 (CH), 125.6 (CH), 123.7 (q, JC–F = 272.2 Hz, C), 119.0 (CH), 71.3 (CH), 71.0 (CH), 70.1 (CH), 22.1 (CH3), 21.9 (CH3); IR (thin film) 3323, 2921, 2834, 1711, 1666, 1622, 1599, 1574 cm–1; LRMS (ESI) 453 (100, [M + H]+); HRMS (ESI) calcd for C22H24F3N2O5 [M + H]+ 453.1632; observed 453.1630.

Diisopropyl 1-(2-(4-Methoxybenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1e

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(4-methoxybenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a pale brown oil (151 mg, 365 μmol, 73%). 1H NMR (700 MHz, CDCl3) δ 7.77–7.57 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H), 7.41–7.35 (m, 2H), 7.17–7.04 (m, 1H, NH), 6.92 (d, J = 8.6 Hz, 1H), 5.02–4.93 (m, 1H), 4.90–4.75 (m, 1H), 3.87–3.82 (m, 3H), 1.31–1.20 (m, 6H), 1.16–0.90 (m, 6H); 13C NMR (175 MHz, CDCl3) δ 195.4 (C), 194.7 (C), 164.0 (C), 163.9 (C), 163.1 (C), 156.0 (C), 156.1 (C), 155.7 (C), 155.0 (C), 154.6 (C), 140.8 (C), 136.3 (C), 132.9 (C), 131.9 (CH), 131.1 (CH), 131.1 (CH), 129.8 (CH), 129.6 (CH), 128.9 (CH), 127.6 (CH), 127.4 (CH), 120.8 (CH), 113.8 (CH), 113.5 (CH), 72.6 (CH), 72.3 (CH), 70.7 (CH), 70.6 (CH), 69.9 (CH), 55.7 (CH3), 55.6 (CH3), 55.6 (CH3), 22.1 (CH3), 22.1 (CH3), 22.0 (CH3), 21.7 (CH3), 21.6 (CH3); IR (thin film) 3302, 2981, 2937, 2842, 1717, 1652, 1597, 1577 cm–1; LRMS (ESI) 437 (30, [M + Na]+), 415 (100, [M + H]+); HRMS (ESI) calcd for C22H27N2O6 [M + H]+ 415.1864; observed 415.1862.

Diisopropyl 1-(2-(3-Chlorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1f

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(3-chlorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a pale yellow oil (170 mg, 405 μmol, 81%). 1H NMR (700 MHz, CDCl3) δ 7.80–7.64 (m, 2H), 7.62–7.46 (m, 2H), 7.45–7.34 (m, 3H), 7.34–7.14 (m, 1H), (m, 1H, NH), 5.07–4.80 (m, 2H), 1.30–0.94 (m, 12H); 13C NMR (175 MHz, CDCl3) δ 195.1 (C), 194.7 (C), 156.2 (C), 156.1 (C), 155.9 (C), 154.9 (C), 154.5 (C), 142.0 (C), 141.0 (C), 138.9 (C), 138.7 (C), 134.8 (C), 133.5 (CH), 133.2 (CH), 132.7 (CH), 130.4 (CH), 130.0 (CH), 129.9 (CH), 129.2 (CH), 128.7 (CH), 128.4 (CH), 127.8 (CH), 127.4 (CH), 126.2 (CH), 120.8 (CH), 71.3 (CH), 71.0 (CH), 70.1 (CH), 22.1 (CH3), 22.1 (CH3), 22.0 (CH3), 22.0 (CH3), 21.8 (CH3); IR (thin film) 3305, 2985, 2884, 1718, 1658, 1619, 1599, 1580 cm–1; LRMS (ESI) 443 (8, [M37Cl + Na]+), 441 (25, [M35Cl + Na]+), 421 (30, [M37Cl + H]+), 419 (100, [M35Cl + H]+); HRMS (ESI) calcd for C21H24ClN2O5 [M35Cl + H]+ 419.1368; observed 419.1367.

Diisopropyl 1-(2-(2-Chlorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1g

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(2-chlorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a clear oil (140 mg, 335 μmol, 67%). 1H NMR (700 MHz, CDCl3) δ 7.78–6.70 (m, 9H), 5.05–4.86 (m, 2H), 1.29–1.04 (m, 12H); 13C NMR (175 MHz, CDCl3) δ 195.5 (C), 195.1 (C), 156.0 (C), 155.8 (C), 155.1 (C), 154.6 (C), 151.8 (C), 138.2 (C), 136.3 (C), 135.3 (CH), 135.1 (CH), 134.7 (CH), 134.1 (CH), 134.1 (CH), 133.9 (CH), 133.8 (CH), 132.2 (CH), 132.1 (CH), 132.0 (CH), 131.9 (CH), 131.0 (CH), 130.8 (CH), 130.7 (CH), 130.6 (CH), 130.5 (CH), 130.4 (CH), 129.9 (CH), 129.5 (CH), 128.2 (CH), 128.1 (CH), 120.8 (CH), 127.8 (CH), 126.8 (CH), 72.8 (CH), 71.1 (CH), 70.9 (CH), 70.1 (CH), 69.9 (CH), 69.8 (CH), 22.1 (CH3), 22.0 (CH3), 22.0 (CH3), 21.4 (CH3); IR (thin film) 3308, 2992, 2888, 1723, 1653, 1617, 1606 cm–1; LRMS (ESI) 443 (9, [M37Cl + Na]+), 441 (26, [M35Cl + Na]+), 421 (31, [M37Cl + H]+), 419 (100, [M35Cl + H]+); HRMS (ESI) calcd for C21H24ClN2O5 [M35Cl + H]+ 419.1368; observed 419.1370.

Diisopropyl 1-(2-(2,3,4-Trimethoxybenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1h

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(2,3,4-trimethoxybenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a clear oil (171 mg, 360 μmol, 72%). 1H NMR (700 MHz, CDCl3) δ 7.70–7.52 (m, 1H), 7.52–7.46 (m, 1H), 7.44–7.27 (m, 3H), 7.18–7.10 (m, 1H), 6.65 (d, J = 8.7 Hz, 1H), 4.94–4.78 (m, 2H), 3.87–3.66 (m, 9H), 1.27–1.03 (m, 12H); 13C NMR (175 MHz, CDCl3) δ 195.2 (C), 194.9 (C), 157.4 (C), 157.2 (C), 155.9 (C), 155.6 (C), 155.0 (C), 154.6 (C), 153.7 (C), 142.4 (C), 136.9 (C), 132.6 (CH), 132.3 (CH), 130.9 (CH), 130.6 (CH), 130.1 (CH), 129.9 (CH), 127.6 (CH), 127.0 (CH), 126.7 (CH), 126.2 (CH), 106.8 (CH), 106.7 (CH), 70.9 (CH), 70.5 (CH), 69.7 (CH), 69.6 (CH), 62.1 (CH3), 61.7 (CH3), 61.7 (CH3), 61.1 (CH3), 61.0 (CH3), 56.2 (CH3), 24.0 (CH3), 22.2 (CH3), 22.1 (CH3), 22.0 (CH3), 21.8 (CH3); IR (thin film) 3300, 2899, 2815, 1720, 1666, 1614, 1598, 1562 cm–1; LRMS (ESI) 475 (100, [M + H]+); HRMS (ESI) calcd for C24H31N2O8 [M + H]+ 475.2275 observed 475.2280.

Diisopropyl 1-(2-(3,4-Dimethylbenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1i

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(3,4-dimethylbenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a yellow oil (151 mg, 365 μmol, 73%). 1H NMR (600 MHz, CDCl3) δ 7.76–7.13 (m, 8H), 5.00–4.77 (m, 2H), 2.31–2.26 (m, 6H), 1.30–0.92 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 189.9 (C), 189.4 (C), 149.4 (C), 149.1 (C), 148.2 (C), 147.9 (C), 146.5 (C), 136.5 (CH), 136.2 (CH), 134.8 (C), 134.2 (CH), 130.2 (CH), 129.3 (CH), 128.3 (CH), 125.8 (CH), 125.3 (CH), 124.6 (CH), 122.9 (CH), 121.8 (CH), 121.6 (CH), 120.8 (CH), 119.4 (CH), 65.6 (CH), 64.3 (CH), 63.9 (CH), 63.2 (CH), 15.3 (CH3), 14.0 (CH3), 13.4 (CH3); IR (thin film) 3329, 2921, 2840, 1711, 1653, 1622, 1591, 1569 cm–1; LRMS (ESI) 413 (100, [M + H]+); HRMS (ESI) calcd for C23H29N2O5 [M + H]+ 413.2071; observed 413.2068.

Diisopropyl 1-(2-(3-Iodobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 1j

Compound prepared according to method B. Purification by column chromatography (10–50% EtOAc/petrol) afforded diisopropyl 1-(2-(3-iodobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a clear oil (179 mg, 350 μmol, 70%). 1H NMR (600 MHz, CDCl3) δ 8.20–8.04 (m, 1H), 7.95–7.87 (m, 1H), 7.82–7.67 (m, 2H), 7.60–7.57 (m, 1H), 7.47–7.30 (m, 3H), 7.22–7.17 (m, 1H), 7.08–6.84 (m, NH, 1H), 5.02–4.79 (m, 2H), 1.39–0.96 (m, 12H); 13C NMR (150 MHz, CDCl3) δ 194.9 (C), 194.6 (C), 156.2 (C), 156.1 (C), 155.9 (C), 154.9 (C), 154.5 (C), 142.3 (C), 141.9 (C), 141.1 (C), 141.0 (C), 139.2 (CH), 138.7 (CH), 136.7 (CH), 132.7 (CH), 130.2 (CH), 129.8 (CH), 129.5 (CH), 129.2 (CH), 128.7 (CH), 127.7 (CH), 127.4 (CH), 120.8 (CH), 94.2 (C), 93.4 (C), 71.3 (CH), 71.0 (CH), 70.1 (CH), 22.1 (CH3), 21.1 (CH3), 21.1 (CH3), 22.0 (CH3) 21.8 (CH3), 21.6 (CH3), 21.5 (CH3); IR (thin film) 3310, 2906, 2844, 1711, 1652, 1619, 1597 cm–1; LRMS (ESI) 511 (100, [M + H]+); HRMS (ESI) calcd for C21H24IN2O5 [M + H]+ 511.0725; observed 511.0720.

General Experimental for the Formation of Isopropyl Carbamate Protected 2-Aminobenzophenones 3a–j: Method C

To a stirring solution of sodium hydride (60% mineral oil dispersion, 50 mg, 1.25 mmol, 2.5 equiv) in anhydrous THF (0.5 mL) under an atmosphere of argon was added dropwise a solution of 2-hydrazobenzophenone (0.5 mmol, 1 equiv) predissolved in anhydrous THF (1 mL), and the reaction mixture was stirred for 5 min. After this time, to the reaction mixture was added diethyl bromomalonate (205 μL, 1.25 mmol, 2.5 equiv) predissolved in 1.5 mL anhydrous THF via a syringe pump (over 30 min, 5.7 μL min–1). The reaction mixture was then stirred at 20 °C for 4 h and monitored via TLC till completion and poured over sat. aq. NH4Cl (10 mL). The resulting solution was extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried (MgSO4) and filtered, and the solvent was evaporated in vacuo. The resultant residue was purified as described below.

Isopropyl (2-(4-Fluorobenzoyl)phenyl)carbamate 3a

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(4-fluorobenzoyl)phenyl)carbamate as a yellow oil (123 mg, 0.410 mmol, 82%). 1H NMR (500 MHz, CDCl3) δ 9.99 (br s, NH, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.8, 5.4 Hz, 2H), 7.59–7.53 (m, 1H), 7.49 (dd, J = 7.9, 1.5 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H), 7.03 (t, J = 8.1 Hz, 1H), 5.01 (septet, J = 6.3 Hz, 1H), 1.30 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 197.7 (C), 165.4 (d, JC–F = 254.4 Hz, C), 153.5 (C), 141.1 (C), 135.0 (C), 134.3 (CH), 133.2 (CH), 132.6 (d, JC–F = 9.2 Hz, CH), 123.0 (CH), 121.1 (CH), 120.2 (C), 115.5 (d, JC–F = 21.8 Hz, CH), 68.9 (CH), 22.1 (CH3); IR (thin film) 3302, 2981, 2935, 1729, 1633, 1580, 1519 cm–1; LRMS (ESI) 302 (100, [M + H]+); HRMS (ESI) calcd for C17H16FNO3 [M + H]+ 302.1192; observed 302.1193.

Isopropyl (2-Benzoylphenyl)carbamate 3b

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-benzoylphenyl)carbamate as a colorless oil (110 mg, 0.390 mmol, 78%). 1H NMR (500 MHz, CDCl3) δ 10.17 (br s, NH, 1H), 8.44 (d, J = 8.7 Hz, 1H), 7.70 (dt, J = 8.4, 1.5 Hz, 2H), 7.61–7.43 (m, 5H), 7.04–6.98 (m, 1H), 5.02 (septet, J = 6.3 Hz, 1H), 1.30 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 199.4 (C), 153.6 (C), 141.3 (C), 138.9 (C), 134.3 (CH), 133.7 (CH), 132.5 (CH), 130.0 (CH), 128.4 (CH), 122.9 (C), 121.0 (CH), 120.0 (CH), 68.9 (CH), 22.2 (CH3); IR (thin film) 3318, 2979, 2934, 1728, 1635, 1580, 1518 cm–1; LRMS (ESI) 284 (100, [M + H]+); HRMS (ESI) calcd for C17H18NO3 [M + H]+ 284.1287; observed 284.1286.

Isopropyl (2-(3-Bromobenzoyl)phenyl)carbamate 3c

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(3-bromobenzoyl)phenyl)carbamate as a brown oil (123 mg, 0.340 mmol, 68%). 1H NMR (700 MHz, CDCl3) δ 10.11 (br s, NH, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 1.7 Hz, 1H), 7.70 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.60–7.58 (m, 1H), 7.56 (dd, J = 8.6, 7.5, 1.5 Hz, 1H), 7.49 (dd, J = 7.9, 1.5 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.03 (m, 1H), 5.02 (septet, J = 6.3 Hz, 1H), 1.30 (d, J = 6.3 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 197.8 (C), 153.5 (C), 141.5 (C), 140.8 (C), 135.3 (CH), 134.8 (CH), 133.5 (CH), 132.7 (CH), 129.9 (CH), 128.5 (CH), 122.7 (C), 122.3 (C), 121.2 (CH), 120.1 (CH), 69.1 (CH), 22.2 (CH3); IR (thin film) 3310, 3082, 2977, 2934, 1723, 1633, 1603, 1577, 1560, 1510 cm–1; LRMS (ESI) 364 (100, [M81Br + H]+), 362 (98, [M79Br + H]+); HRMS (ESI) calcd for C17H16BrNO3 [M79Br + H]+ 362.0392; observed 362.0374.

Isopropyl (2-(4-(Trifluoromethyl)benzoyl)phenyl)carbamate 3d

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(4-(trifluoromethyl)benzoyl)phenyl)carbamate as a yellow oil (125 mg, 0.355 mmol, 71%). 1H NMR (700 MHz, CDCl3) δ 10.25 (br s, NH, 1H), 8.47 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.57–7.55 (m, 1H), 7.45 (dd, J = 7.9, 1.5 Hz, 1H), 7.01–6.99 (m, 1H), 5.02 (septet, J = 6.3 Hz, 1H), 1.30 (d, J = 6.4 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 198.3 (C), 153.3 (C), 142.4 (C), 141.8 (CH) 135.0 (CH), 133.7 (CH), 133.6 (q, JC–F = 31.0 Hz, C), 125.4 (q, JC–F = 3.7 Hz, CH), 123.8 (q, JC–F = 272.6 Hz, C), 121.9 (CH), 121.2 (CH), 120.1 (CH), 69.1 (CH), 22.2 (CH3); IR (thin film) 3340, 2969, 2920, 1727, 1628, 1590, 1579 cm–1; LRMS (ESI) 352 (100, [M + H]+); HRMS (ESI) calcd for C18H17F3NO3 [M + H]+ 352.1155; observed 352.1159.

Isopropyl (2-(4-Methoxybenzoyl)phenyl)carbamate 3e

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(4-methoxybenzoyl)phenyl)carbamate as a red oil (119 mg, 0.380 mmol, 76%). 1H NMR (500 MHz, CDCl3) δ 9.85 (br s, NH, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.76–7.68 (m, 2H), 7.56–7.47 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.98–6.91 (m, 2H), 5.00 (septet, J = 6.3 Hz, 1H), 3.88 (s, 3H), 1.28 (d, J = 6.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 197.7 (C), 163.4 (C), 153.6 (C), 140.6 (C), 133.6 (CH), 132.9 (CH), 132.7 (CH), 131.2 (C), 123.9 (C), 121.1 (CH), 120.2 (CH), 113.7 (CH), 68.8 (CH), 55.6 (CH3), 22.2 (CH3); IR (thin film) 3317, 2980, 2935, 2839, 1728, 1628, 1595, 1580 cm–1; LRMS (ESI) 314 (100, [M + H]+); HRMS (ESI) calcd for C18H19NO4 [M + H]+ 314.1392; observed 314.1385.

Isopropyl (2-(3-Chlorobenzoyl)phenyl)carbamate 3f

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(3-chlorobenzoyl)phenyl)carbamate as a yellow oil (102 mg, 0.320 mmol, 64%). 1H NMR (700 MHz, CDCl3) δ 10.12 (br s, NH, 1H), 8.45 (dd, J = 8.5, 0.7 Hz, 1H), 7.68 (t, J = 1.7 Hz, 1H), 7.61–7.53 (m, 3H), 7.49 (dd, J = 7.9, 1.5 Hz, 1H), 7.44–7.38 (m, 1H), 7.06–6.99 (m, 1H), 5.02 (septet, J = 6.3 Hz, 1H), 1.30 (d, J = 6.3 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 197.9 (C), 153.6 (C), 141.5 (C), 140.6 (C), 134.8 (CH), 134.7 (C), 133.5 (CH), 132.3 (CH), 129.8 (CH), 129.7 (CH), 128.0 (CH), 122.3 (C), 121.2 (CH), 120.1 (CH), 69.1 (CH), 22.2 (CH3); IR (thin film) 3313, 3022, 2982, 2936, 1729, 1637, 1604, 1580 cm–1; LRMS (ESI) 320 (40, [M37Cl + H]+), 318 (100, [M35Cl + H]+); HRMS (ESI) calcd for C17H16ClNO3 [M35Cl + H]+ 318.0897; observed 318.0893.

Isopropyl (2-(2-Chlorobenzoyl)phenyl)carbamate 3g

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(2-chlorobenzoyl)phenyl)carbamate as a yellow oil (114 mg, 0.36 mmol, 71%). 1H NMR (700 MHz, CDCl3) δ 10.94 (br s, NH, 1H), 8.57 (d, J = 8.5 Hz, 1H), 7.59–7.54 (m, 1H), 7.48–7.45 (m, 1H), 7.44 (td, J = 7.8, 1.6 Hz, 1H), 7.37 (td, J = 7.4, 1.0 Hz, 1H), 7.32 (ddd, J = 13.7, 7.8, 1.5 Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 5.05 (septet, J = 6.3 Hz, 1H), 1.33 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 198.8 (C), 153.6 (C), 142.8 (C), 139.1 (C), 135.9 (CH), 134.8 (CH), 131.1 (CH), 131.0 (C), 130.2 (CH), 128.8 (CH), 126.8 (CH), 121.2 (CH), 121.0 (C), 119.2 (CH), 69.1 (CH), 22.2 (CH3); IR (thin film) 3320, 3028, 2981, 2936, 1743, 1721, 1635, 1603, 1582 cm–1; LRMS (ESI) 320 (30, [M37Cl + H]+), 318 (100, [M35Cl + H]+); HRMS (ESI) calcd for C17H16ClNO3 [M35Cl + H]+ 318.0897; observed 318.0894.

Isopropyl (2-(2,3,4-Trimethoxybenzoyl)phenyl)carbamate 3h

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(2,3,4-trimethoxybenzoyl)phenyl)carbamate as a yellow oil (134 mg, 0.36 mmol, 72%). 1H NMR (700 MHz, CDCl3) δ 10.74 (br s, NH, 1H), 8.46 (d, J = 7.9 Hz, 1H), 7.51–7.47 (m, 1H), 7.43 (dd, J = 8.0, 1.5 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.92–6.90 (td, J = 7.4, 1.0 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.00 (septet, J = 6.3 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 198.8 (C), 156.1 (C), 153.7 (C), 152.3 (C), 142.1 (C), 141.7 (C), 134.8 (CH), 134.3 (CH), 127.1 (C), 124.6 (CH), 123.0 (C), 120.9 (CH), 119.1 (CH), 106.8 (CH), 68.8 (CH), 61.9 (CH), 61.0 (CH), 56.2 (CH), 22.2 (CH3); IR (thin film) 3301, 3012, 2977, 2929, 1740, 1639, 1593, 1589 cm–1; LRMS (ESI) 374 (100, [M + H]+); HRMS (ESI) calcd for C20H23NO6 [M + H]+ 374.1598; observed 374.1601.

Isopropyl (2-(3,4-Dimethylbenzoyl)phenyl)carbamate 3i

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(3,4-dimethylbenzoyl)phenyl)carbamate as a brown oil (103 mg, 0.330 mmol, 66%). 1H NMR (500 MHz, CDCl3) δ 10.04 (br s, NH, 1H), 8.40 (m, 1H), 7.53 (m, 3H), 7.43 (dd, J = 7.8, 1.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.06–6.99 (m, 1H), 5.00 (septet, J = 6.3 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 199.2 (C), 153.6 (C), 142.1 (C), 140.9 (C), 136.8 (C), 136.5 (C), 133.8 (CH), 133.4 (CH), 131.2 (CH), 129.5 (CH), 128.0 (CH), 123.5 (C), 120.9 (CH), 120.0 (CH), 68.8 (CH), 22.1 (CH3), 20.1 (CH3), 19.8 (CH3); IR (thin film) 3286, 2978, 2923, 2853, 1730, 1633, 1600, 1580, 1518 cm–1; LRMS (ESI) 312 (100, [M + H]+); HRMS (ESI) calcd for C19H21NO3 [M + H]+ 312.1594; observed 312.1596.

Isopropyl (2-(3-Iodobenzoyl)phenyl)carbamate 3j

Compound prepared according to method C. Purification by column chromatography (10–50% EtOAc/petrol) yielded isopropyl (2-(2-chlorobenzoyl)phenyl)carbamate as a yellow oil (139 mg, 0.34 mmol, 68%). 1H NMR (700 MHz, CDCl3) δ 10.11 (br s, NH, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.88 (ddd, J = 7.9, 1.7, 1.1 Hz, 1H), 7.61–7.60 (m, 1H), 7.55 (ddd, J = 8.6, 7.5, 1.4 Hz, 1H), 7.47 (dd, J = 7.9, 1.5 Hz, 1H), 7.19 (t, J = 7.8 Hz, 2H), 7.02–7.00 (m, 1H), 5.01 (septet, J = 6.3 Hz, 1H), 1.29 (d, J = 6.3 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 197.6 (C), 153.5 (C), 141.5 (C), 141.1 (C), 140.8 (CH), 138.5 (CH), 134.8 (CH), 133.5 (C), 130.0 (CH), 129.0 (CH), 122.2 (CH), 121.2 (CH), 120.1 (C), 94.1 (C), 69.0 (CH), 22.2 (CH3); IR (thin film) 3318, 3025, 2984, 2940, 1737, 1719, 1640, 1603 cm–1; LRMS (ESI) 410 (100, [M + H]+); HRMS (ESI) calcd for C17H17INO3 [M + H]+ 410.0248; observed 410.0251.

General Experimental for the Deprotection of Isopropyl Carbamate Protected 2-Aminobenzophenones 5: Method D

To a stirring solution of aluminum chloride (4 mmol, 4 equiv) in dichloromethane (2 mL) was added dropwise isopropyl carbamate protected 2-aminobenzophenone (1 mmol, 1 equiv) predissolved in dichloromethane (0.5 mL). The mixture was then stirred for 1 h and monitored via TLC till completion. The reaction mixture was then poured into ice water (10 mL). If a solid precipitate was formed, the mixture was filtered and the solid was washed with water (3 × 3 mL) and dried in vacuo. If no solid was formed, the mixture was then extracted with EtOAc (3 × 4 mL). The combined organic extracts were then washed with water (3 × 4 mL), dried (MgSO4), and concentrated in vacuo. The resultant residue was purified as described below.

(2-Aminophenyl)(phenyl)methanone 5b

Compound prepared according to method D. Purification by column chromotography (10–25% EtOAc/petrol) yielded (2-aminophenyl)(phenyl)methanone as a yellow crystalline solid (180 mg, 0.920 mmol, 92%). Mp 103–104 °C; 1H NMR (700 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.1 Hz, 2H), 7.46 (t, J = 7.1 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.10 (br s, NH, 2H); 13C NMR (175 MHz, CDCl3) δ 199.2 (C), 151.1 (C), 140.3 (C), 134.7 (CH), 134.4 (CH), 131.2 (CH), 129.3 (CH), 128.2 (CH), 118.3 (C), 117.2 (CH), 115.7 (CH); IR (solid) 3502, 3087, 3056, 3031, 1669, 1593, 1575 cm–1; LRMS (ESI) 198 (100, [M + H]+); HRMS (ESI) calcd for C13H11NO [M + H]+ 198.0919; observed 198.0916.

(2-Aminophenyl)(4-(trifluoromethyl)phenyl)methanone 5d

Compound prepared according to method D. Purification by column chromotography (10–25% EtOAc/petrol) yielded (2-aminophenyl)(4-(trifluoromethyl)phenyl)methanone as a yellow crystalline solid (236 mg, 0.890 mmol, 89%). Mp 98–99 °C; 1H NMR (700 MHz, CDCl3) δ 7.74–7.70 (m, 4H), 7.35 (dd, J = 8.1, 1.3 Hz, 1H), 7.32 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 6.75 (dd, J = 8.4, 1.0 Hz, 1H), 6.60 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.21 (br s, NH, 2H); 13C NMR (175 MHz, CDCl3) δ 197.8 (C), 151.4 (C), 143.6 (C), 135.0 (CH), 134.5 (CH), 132.6 (q, JC–F = 32.7 Hz, C), 129.3 (CH), 125.3 (q, JC–F = 3.8 Hz, CH), 123.9 (q, JC–F = 272.4 Hz, CH), 117.4 (C), 117.3 (CH), 115.8 (CH); IR (solid) 3487, 3069, 3040, 3021, 1672, 1590, 1575 cm–1; LRMS (ESI) 266 (100, [M + H]+); HRMS (ESI) calcd for C14H11F3NO [M + H]+ 266.0787; observed 266.0789.

(2-Aminophenyl)(2,3,4-trimethoxyphenyl)methanone 5h

Compound prepared according to method D. Purification by column chromatography for (10–25% EtOAc/petrol) yielded (2-aminophenyl)(2,3,4-trimethoxyphenyl)methanone as a yellow crystalline solid (247 mg, 0.860 mmol, 86%). Mp 123–125 °C; 1H NMR (700 MHz, CDCl3) δ 7.30 (dd, J = 8.1, 1.5 Hz, 1H), 7.21 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.66 (d, J = 8.3, 0.8 Hz, 1H), 6.51 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.35 (br s, NH, 2H), 3.88 (s, 3H), 3.88 (s, 3H), 3.78 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 198.0 (C), 155.1 (C), 151.6 (C), 151.1 (C), 142.1 (C), 134.9 (C), 134.6 (CH), 128.2 (CH), 123.7 (CH), 118.9 (C), 116.9 (CH), 115.5 (CH), 106.9 (CH), 61.8 (CH3), 61.1 (CH3), 56.2 (CH3); IR (solid) 3500, 3084, 3065, 3029, 1670, 1593, 1571 cm–1; LRMS (ESI) 288 (100, [M + H]+); HRMS (ESI) calcd for C16H17NO4 [M + H]+ 288.1231; observed 288.1235.

(2-Aminophenyl)(2-chlorophenyl)methanone 5g

Compound prepared according to method D with 0.36 mmol of isopropyl (2-(2-chlorobenzoyl)phenyl)carbamate 3g. Purification by column chromotography for (10–25% EtOAc/petrol) yielded (2-aminophenyl)(2-chlorophenyl)methanone as a yellow crystalline solid (75 mg, 0.33 mmol, 91%). Mp 57–59 °C; 1H NMR (700 MHz, CDCl3) δ 7.47–7.43 (m, 1H), 7.38 (ddd, J = 8.0, 7.3, 1.9 Hz, 1H), 7.34 (td, J = 7.4, 1.2 Hz, 1H), 7.32–7.30 (m, 1H), 7.28 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.17 (dd, J = 8.1, 1.5 Hz, 1H), 6.72 (m, 1H), 6.54 (ddd, J = 8.1, 7.0, 1.1 Hz) 6.47 (br s, NH, 2H); 13C NMR (175 MHz, CDCl3) δ 197.4 (C), 151.6 (C), 140.0 (C), 135.4 (CH), 134.8 (CH), 130.8 (C), 130.5 (CH), 130.0 (CH), 128.6 (CH), 126.8 (CH), 117.5 (C), 117.2 (CH), 115.9 (CH); IR (solid) 3450, 3070, 3041, 3029, 1665, 1591, 1580 cm–1.

(2-Amino-5-bromophenyl)(2-chlorophenyl)methanone 8

To a solution of (2-aminophenyl)(2-chlorophenyl)methanone 5g (75 mg, 0.33 mmol, 1 equiv) in dichloromethane (10 mL) was added N-bromosuccinimide (59 mg, 0.33 mmol, 1 equiv) at 0 °C. The mixture was stirred for 1 h at this temperature. After completion of the reaction, the resulting mixture was quenched with sat. aq. NaHCO3 (20 mL) and extracted into DCM (3 × 15 mL). The combined organic layers were then dried (MgSO4), and the solvent was removed in vacuo. Purification by column chromotography (10–25% EtOAc/petrol) yielded (2-amino-5-bromophenyl)(2-chlorophenyl)methanone as a yellow crystalline solid (92 mg, 0.30 mmol, 90%). Mp 88–90 °C; 1H NMR (700 MHz, CDCl3) δ 7.45 (dd, J = 8.0, 0.7 Hz, 1H), 7.40 (td, J = 7.8, 1.7 Hz, 1H), 7.34 (td, J = 7.5, 1.1 Hz, 1H), 7.32 (d, J = 8.9, 2.3 Hz, 1H), 7.29 (dd, J = 7.5, 1.5 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 6.52 (br s, NH, 2H); 13C NMR (175 MHz, CDCl3) δ 196.5 (C), 150.5 (C), 139.1 (C), 138.0 (C), 136.3 (C), 131.0 (C), 130.2 (CH), 128.6 (CH), 127.0 (CH), 119.1 (C), 118.7 (CH), 106.8 (CH); IR (solid) 3350, 3041, 3022, 1627, 1570 cm–1.

Phenazepam

To a solution of (2-amino-5-bromophenyl)(2-chlorophenyl)methanone 8 (92 mg, 0.30 mmol, 1 equiv) in THF (10 mL) was added bromoacetyl bromide (29 μL, 0.33 mmol, 1.1 equiv) at 0 °C. The mixture was stirred for 1 h at this temperature. After this time, ammonium hydroxide (1.5 mL) in EtOH (2 mL) was added dropwise, and the reaction was allowed to stir for 2 h. After the completion of the reaction, the resulting mixture was quenched with sat. aq. NaHCO3 (20 mL) and extracted into EtOAc (3 × 15 mL). The combined organic layers were then dried (MgSO4) and the solvent was removed in vacuo. Purification by column chromatography (0–10% MeOH/DCM) yielded (2-amino-5-bromophenyl)(2-chlorophenyl)methanone as a yellow crystalline solid (89 mg, 0.260 mmol, 85%). Mp 222–235 °C; 1H NMR (700 MHz, CDCl3) δ 8.61 (br s, NH, 1H), 7.57 (dd, J = 8.6, 2.3 Hz, 1H), 7.54–7.50 (m, 1H), 7.41–7.37 (m, 3H), 7.20 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 4.38 (s, 2H); 13C NMR (175 MHz, CDCl3) δ 170.9 (C), 169.3 (C), 138.4 (C), 136.9 (C), 134.9 (C), 133.3 (C), 132.3 (CH), 131.2 (CH), 131.2 (CH), 130.4 (CH), 129.8 (CH), 127.2 (CH), 122.7 (C), 116.9 (CH), 56.6 (CH2); IR (solid) 3253, 2900, 1670, 1505 cm–1.

Diisopropyl 1-(2-(tert-Butoxy)-2-oxoethyl)-2-(2-(4-fluorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate 4a

To a stirring solution of sodium hydride (60% mineral oil dispersion, 40 mg, 1.00 mmol, 1.0 equiv) in anhydrous THF (0.5 mL) was added dropwise a solution of diisopropyl 1-(2-(4-fluorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate (0.5 mmol, 1 equiv) predissolved in anhydrous THF (1 mL) under an atmosphere of argon, and the reaction mixture was stirred for 5 min. After this time, to the reaction mixture was added tert-butyl bromoacetate (162 μL, 1.10 mmol, 1.1 equiv) dropwise, predissolved in a 1.5 mL anhydrous THF. The reaction mixture was then stirred at 20 °C for 1 h and monitored via TLC till completion and poured over saturated aqueous NH4Cl (10 mL). The resulting solution was extracted with EtOAc (3 × 15 mL). The combined extracts were dried (MgSO4) and filtered, and the solvent was evaporated in vacuo. Purification by column chromatography (10–50% EtOAc/petrol) yielded diisopropyl 1-(2-(tert-butoxy)-2-oxoethyl)-2-(2-(4-fluorobenzoyl)phenyl)hydrazine-1,2-dicarboxylate as a yellow oil (230 mg, 0.445 mmol, 89%). 1H NMR (400 MHz, CDCl3) δ 7.80–7.88 (m, 3H), 7.49–7.55 (m, 1H), 7.26 (dd, 2H, J = 7.2, 5.9 Hz), 7.09 (t, 2H, J = 8.2 Hz), 5.05 (m, 1H), 4.74 (septet, 1H, J = 6.3 Hz), 4.20–4.60 (m, 2H), 0.96–1.42 (m, 21H). 13C NMR (150 MHz, CDCl3) δ 193.8 (C), 167.7 (C), 166.6 (d, JC–F = 253.4 Hz, CH), 156.0 (C), 153.8 (C), 139.0 (C), 134.3 (C), 133.3 (CH), 131.8 (CH), 131.6 (CH), 128.9 (CH), 128.2 (CH), 127.0 (CH), 126.3 (CH), 125.9 (CH), 115.5 (d, JC–F = 22.0 Hz, CH), 81.3 (C), 71.0 (CH), 52.5 (CH), 28.2 (CH), 22.2 (CH); IR (thin film) 3341, 2989, 2967, 1743, 1620, 1583, 1523 cm–1; LRMS (ESI) 517 (100, [M + H]+), HRMS (ESI) calcd for C27H34FN2O7 [M + H]+ 517.2342; observed 517.2348.

Acknowledgments

The authors gratefully acknowledge the UCL Graduate School for funding A.S. The authors also acknowledge the UCL Chemistry Mass Spectrometry Facility (Dr. K. Karu/Dr. X. Yang) and the EPSRC U.K. National MS Facility (Swansea).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03417.

  • Copies of characterization data (1H and 13C NMR) of all featured compounds; and detailed experimental procedure, NMR (1H and 13C), IR, LRMS (ESI), and HRMS (ESI) of all featured compounds (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. N.A. and A.S. contributed equally.

The authors declare no competing financial interest.

Supplementary Material

ao9b03417_si_001.pdf (4MB, pdf)

References

  1. Liou J.-P.; Chang C.-W.; Song J.-S.; Yang Y.-N.; Yeh C.-F.; Tseng H.-Y.; Lo Y.-K.; Chang Y.-L.; Chang C.-M.; Hsieh H.-P. Synthesis and Structure–Activity Relationship of 2-Aminobenzophenone Derivatives as Antimitotic Agents. J. Med. Chem. 2002, 45, 2556–2562. 10.1021/jm010365+. [DOI] [PubMed] [Google Scholar]
  2. Singh R. K.; Prasad D. N.; Bhardwaj T. R. Design, Synthesis and Evaluation of Aminobenzophenone Derivatives Containing Nitrogen Mustard Moiety as Potential Central Nervous System Antitumor Agent. Med. Chem. Res. 2013, 22, 5901–5911. 10.1007/s00044-013-0582-8. [DOI] [Google Scholar]
  3. Castellano S.; Taliani S.; Viviano M.; Milite C.; Da Pozzo E.; Costa B.; Barresi E.; Bruno A.; Cosconati S.; Marinelli L.; Greco G.; Novellino E.; Sbardella G.; Da Settimo F.; Martini C. Structure–Activity Relationship Refinement and Further Assessment of 4-Phenylquinazoline-2-Carboxamide Translocator Protein Ligands as Antiproliferative Agents in Human Glioblastoma Tumors. J. Med. Chem. 2014, 57, 2413–2428. 10.1021/jm401721h. [DOI] [PubMed] [Google Scholar]
  4. Singh R. K.; Devi S.; Prasad D. N. Synthesis, Physicochemical and Biological Evaluation of 2-Amino-5-Chlorobenzophenone Derivatives as Potent Skeletal Muscle Relaxants. Arab. J. Chem. 2015, 8, 307–312. 10.1016/j.arabjc.2011.11.013. [DOI] [Google Scholar]
  5. Wu H.; Zhang Z.; Liu Q.; Liu T.; Ma N.; Zhang G. Syntheses of Acridones via Copper(II)-Mediated Relay Reactions from o-Aminoacetophenones and Arylboronic Acids. Org. Lett. 2018, 20, 2897–2901. 10.1021/acs.orglett.8b00957. [DOI] [PubMed] [Google Scholar]
  6. Shirini F.; Akbari-Dadamahaleh S.; Mohammad-Khah A. Rice Husk Ash Supported FeCl2·2H2O: A Mild and Highly Efficient Heterogeneous Catalyst for the Synthesis of Polysubstituted Quinolines by Friedländer Heteroannulation. Chinese J. Catal. 2013, 34, 2200–2208. 10.1016/S1872-2067(12)60684-6. [DOI] [Google Scholar]
  7. Zakerinasab B.; Nasseri M. A.; Kamali F. Efficient Procedure for the Synthesis of Quinoline Derivatives by NbCl5.PEG and NbCl5 in Glycerol as Green Solvent. Iran. Chem. Commun. 2015, 3, 335–347. [Google Scholar]
  8. Reddy B. P.; Iniyavan P.; Sarveswari S.; Vijayakumar V. Nickel Oxide Nanoparticles Catalyzed Synthesis of Poly-Substituted Quinolines via Friedlander Hetero-Annulation Reaction. Chinese Chem. Lett. 2014, 25, 1595–1600. 10.1016/j.cclet.2014.06.026. [DOI] [Google Scholar]
  9. Karnakar K.; Kumar A. V.; Murthy S. N.; Ramesh K.; Nageswar Y. V. D. Recyclable Graphite Oxide Promoted Efficient Synthesis of 2-Phenyl Quinazoline Derivatives in the Presence of TBHP as an Oxidant. Tetrahedron Lett. 2012, 53, 4613–4617. 10.1016/j.tetlet.2012.06.098. [DOI] [Google Scholar]
  10. Zhang J.; Zhu D.; Yu C.; Wan C.; Wang Z. A Simple and Efficient Approach to the Synthesis of 2-Phenylquinazolines via Sp3 C-H Functionalization. Org. Lett. 2010, 12, 2841–2843. 10.1021/ol100954x. [DOI] [PubMed] [Google Scholar]
  11. Dabiri M.; Salehi P.; Bahramnejad M. Ecofriendly and Efficient One-Pot Procedure for the Synthesis of Quinazoline Derivatives Catalyzed by an Acidic Ionic Liquid Under Aerobic Oxidation Conditions. Synth. Commun. 2010, 40, 3214–3225. 10.1080/00397910903395250. [DOI] [Google Scholar]
  12. Park K. K.; Lee J. J. Facile Synthesis of 4-Phenylquinolin-2(1H)-One Derivatives from N-Acyl-o-Aminobenzophenones. Tetrahedron 2004, 60, 2993–2999. 10.1016/j.tet.2004.02.001. [DOI] [Google Scholar]
  13. Shobha D.; Chari M. A.; Mukkanti K.; Kim S. Y. Synthesis and Anti-Neuroinflammatory Activity Studies of Substituted 3,4-Dihydroquinoxalin-2-Amine Derivatives. Tetrahedron Lett. 2012, 53, 2675–2679. 10.1016/j.tetlet.2012.03.057. [DOI] [Google Scholar]
  14. Zhang Z.; Kodumuru V.; Sviridov S.; Liu S.; Chafeev M.; Chowdhury S.; Chakka N.; Sun J.; Gauthier S. J.; Mattice M.; Ratkay L. G.; Kwan R.; Thompson J.; Cutts A. B.; Fu J.; Kamboj R.; Goldberg Y. P.; Cadieux J. A. Discovery of Benzylisothioureas as Potent Divalent Metal Transporter 1 (DMT1) Inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 5108–5113. 10.1016/j.bmcl.2012.05.129. [DOI] [PubMed] [Google Scholar]
  15. Chiarini M.; Del Vecchio L.; Mainelli F.; Rossi L.; Arcadi A. Synthesis of 3-Substituted 2,1-Benzisoxazoles by the Oxidative Cyclization of 2-Aminoacylbenzenes with Oxone. Synthesis 2016, 48, 3017–3030. 10.1055/s-0035-1561471. [DOI] [Google Scholar]
  16. Mochalov S. S.; Khasanov M. I.; Fedotov A. N.; Trofimova E. V. 2H-Indazoles from 2-Aminobenzophenones. Chem. Heterocycl. Compd. 2008, 44, 229–230. 10.1007/s10593-008-0020-x. [DOI] [Google Scholar]
  17. Paul N.; Muthusubramanian S. Reaction of Diphenacylanilines with 2-Aminobenzophenone: An Abnormal Friedlander Reaction Yielding Indoles. Synth. Commun. 2013, 43, 1200–1209. 10.1080/00397911.2011.627524. [DOI] [Google Scholar]
  18. Sbei N.; Batanero B.; Barba F.; Haouas B.; Benkhoud M. L.; Barba I. Facile Preparation of 3-Substituted 2-Quinazolinones via Electrogenerated Base. Tetrahedron 2018, 74, 2068–2072. 10.1016/j.tet.2018.03.010. [DOI] [Google Scholar]
  19. Park K. K.; Lee J. H. Efficient Synthesis of 2,3-Disubstituted Benzo[b]Thiophenes Starting from 2-Aminobenzophenone. Bull. Korean Chem. Soc. 2008, 29, 2502–2504. 10.5012/bkcs.2008.29.12.2502. [DOI] [Google Scholar]
  20. Acharya B. P.; Rao Y. R. Synthesis of Unsymmetrically Substituted 6,12-Diaryldibenzo[b,f][1,5]Diazocines and Their Precursor Schiff Bases. Synthesis 1986, 324–326. 10.1055/s-1986-31601. [DOI] [Google Scholar]
  21. Reddy D. R.; Ballante F.; Zhou N. J.; Marshall G. R. Design and Synthesis of Benzodiazepine Analogs as Isoform-Selective Human Lysine Deacetylase Inhibitors. Eur. J. Med. Chem. 2017, 127, 531–553. 10.1016/j.ejmech.2016.12.032. [DOI] [PubMed] [Google Scholar]
  22. Cheng P.; Zhang Q.; Ma Y. B.; Jiang Z. Y.; Zhang X. M.; Zhang F. X.; Chen J. J. Synthesis and in Vitro Anti-Hepatitis B Virus Activities of 4-Aryl-6-Chloro-Quinolin-2-One and 5-Aryl-7-Chloro-1,4-Benzodiazepine Derivatives. Bioorg. Med. Chem. Lett 2008, 18, 3787–3789. 10.1016/j.bmcl.2008.05.065. [DOI] [PubMed] [Google Scholar]
  23. Huang Y.; Khoury K.; Chanas T.; Dömling A. Multicomponent Synthesis of Diverse 1,4-Benzodiazepine Scaffolds. Org. Lett. 2012, 14, 5916–5919. 10.1021/ol302837h. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fier P. S.; Whittaker A. M. An Atom-Economical Method to Prepare Enantiopure Benzodiazepines with N-Carboxyanhydrides. Org. Lett. 2017, 19, 1454–1457. 10.1021/acs.orglett.7b00417. [DOI] [PubMed] [Google Scholar]
  25. Cortez-Maya S.; Cortes Cortes E.; Hernández-Ortega S.; Apan T. R.; Martínez-García M. Synthesis of 2-Aminobenzophenone Derivatives and Their Anticancer Activity. Synth. Commun. 2012, 42, 46–54. 10.1080/00397911.2010.521435. [DOI] [Google Scholar]
  26. Tran P. H.; Phung H. Q.; Hansen P. E.; Tran H. N.; Le T. N. Efficient Friedel–Crafts Benzoylation of Aniline Derivatives with 4-Fluorobenzoyl Chloride Using Copper Triflate in the Synthesis of Aminobenzophenones. Synth. Commun. 2016, 46, 893–901. 10.1080/00397911.2016.1148164. [DOI] [Google Scholar]
  27. Yan Y.; Wang Z. Metal-Free Intramolecular Oxidative Decarboxylative Amination of Primary α-Amino Acids with Product Selectivity. Chem. Commun. 2011, 47, 9513–9515. 10.1039/c1cc12885j. [DOI] [PubMed] [Google Scholar]
  28. Chen J.; Ye L.; Su W. Palladium-Catalyzed Direct Addition of Arylboronic Acids to 2-Aminobenzonitrile Derivatives: Synthesis, Biological Evaluation and in Silico Analysis of 2-Aminobenzophenones, 7-Benzoyl-2-Oxoindolines, and 7-Benzoylindoles. Org. Biomol. Chem. 2014, 12, 8204–8211. 10.1039/C4OB00978A. [DOI] [PubMed] [Google Scholar]
  29. Chen J.; Li J.; Su W. Palladium-Catalyzed Direct Addition of 2-Aminobenzonitriles to Sodium Arylsulfinates: Synthesis of o-Aminobenzophenones. Molecules 2014, 19, 6439–6449. 10.3390/molecules19056439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Szabó F.; Simkó D.; Novák Z. A One-Pot Process for Palladium Catalyzed Direct C-H Acylation of Anilines in Water Using a Removable Ortho Directing Group. RSC Adv. 2014, 4, 3883–3886. 10.1039/C3RA45160G. [DOI] [Google Scholar]
  31. Pintori D. G.; Greaney M. F. Insertion of Benzene Rings into the Amide Bond: One-Step Synthesis of Acridines and Acridones from Aryl Amides. Org. Lett. 2010, 12, 168–171. 10.1021/ol902568x. [DOI] [PubMed] [Google Scholar]
  32. Wright A. C.; Haley C. K.; Lapointe G.; Stoltz B. M. Synthesis of Aryl Ketoamides via Aryne Insertion into Imides. Org. Lett. 2016, 18, 2793–2795. 10.1021/acs.orglett.6b00994. [DOI] [PubMed] [Google Scholar]
  33. Shamsabadi A.; Chudasama V. An Overview of the Synthesis of Acyl Hydrazides from Aldehydes and Reactions of the Products Thereof. Org. Biomol. Chem. 2017, 15, 17–33. 10.1039/C6OB02099B. [DOI] [PubMed] [Google Scholar]
  34. Maruani A.; Lee M. T. W.; Watkins G.; Akhbar A. R.; Baggs H.; Shamsabadi A.; Richards D. A.; Chudasama V. A Facile, One-Pot Procedure for the Conversion of Aromatic Aldehydes to Esters, as well as Thioesters and Amides, via Acyl Hydrazide Intermediates. RSC Adv. 2016, 6, 3372–3376. 10.1039/C5RA26842G. [DOI] [Google Scholar]
  35. Akhbar A. R.; Chudasama V.; Fitzmaurice R. J.; Powell L.; Caddick S. Acyl Hydrazides as Acyl Donors for the Synthesis of Diaryl and Aryl Alkyl Ketones. Chem. Commun. 2014, 50, 743–746. 10.1039/C3CC47967F. [DOI] [PubMed] [Google Scholar]
  36. Shamsabadi A.; Ren J.; Chudasama V. Enabling the Facile Conversion of Acyl Hydrazides into: N-Acyl Carbamates via Metal-Free Ionic-Based Rupture of the N-N Linkage. RSC Adv. 2017, 7, 27608–27611. 10.1039/C7RA04178K. [DOI] [Google Scholar]
  37. Shamsabadi A.; Chudasama V. A Facile Route to 1H- and 2H-Indazoles from Readily Accessible Acyl Hydrazides by Exploiting a Novel Aryne-Based Molecular Rearrangement. Chem. Commun. 2018, 54, 11180–11183. 10.1039/C8CC06556J. [DOI] [PubMed] [Google Scholar]
  38. Sugimoto O.; Arakaki T.; Kamio H.; Tanji K. The Use of a Mitsunobu Reagent for the Formation of Heterocycles: A Simple Method for the Preparation of 3-Alkyl-5-Aryl-1,3,4-Oxadiazol-2(3H)-Ones from Carboxylic Acids. Chem. Commun. 2014, 50, 7314–7317. 10.1039/C4CC01971G. [DOI] [PubMed] [Google Scholar]
  39. Papadopoulos G. N.; Kokotos C. G. Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes. Chem. Eur. J. 2016, 22, 6964–6967. 10.1002/chem.201600333. [DOI] [PubMed] [Google Scholar]
  40. Kim Y. J.; Lee D. Use of N–N Bond Stereodynamics in Ring-Closing Metathesis to Form Medium-Sized Rings and Macrocycles. Org. Lett. 2004, 6, 4351–4353. 10.1021/ol048136f. [DOI] [PubMed] [Google Scholar]
  41. Magnus P.; Garizi N.; Seibert K. A.; Ornholt A. Synthesis of Carbamates from Diethoxycarbonyl Hydrazine Derivatives by E1cB Eliminative Cleavage of the N-N′-Bond Rather than Reduction. Org. Lett. 2009, 11, 5646–5648. 10.1021/ol902313v. [DOI] [PubMed] [Google Scholar]
  42. Takemoto Y.; Matsumoto T.; Ito Y.; Terashima S. An Expeditious Synthesis of (3S,4S)-Statine and (3S,4S)- Cyclohexylstatine. Tetrahderon Lett. 1990, 31, 217–218. 10.1016/S0040-4039(00)94374-0. [DOI] [Google Scholar]
  43. Gaboardi M.; Castaldi G.; Castaldi M.. Process and Intermediates for the Preparation of Linagliptin. WO Patent WO0675392015.
  44. Chee G.-L. Selective Deprotection of Isopropyl Esters, Carbamates and Carbonates with Aluminium Chloride. Synlett 2001, 1593–1595. 10.1055/s-2001-17466. [DOI] [Google Scholar]
  45. Yang Y.; Xu Y.; Jones C. R. A Ring Expansion Route to Benzofused N-Heterocycles Through Aryne Insertion into 1,3-Diaza-Heterocycles. Eur. J. Org. Chem. 2019, 5196–5200. 10.1002/ejoc.201900570. [DOI] [Google Scholar]
  46. Lukashov O. I.; Kazakov P. V.; Mirzabekova N. S. Optimization of Phenazepam Production Technology. Pharm. Chem. J. 2018, 52, 641–643. 10.1007/s11094-018-1874-6. [DOI] [Google Scholar]
  47. Andronati S. A.; Makan S. Y.; Neshchadin D. P.; Yakubovskaya L. N.; Sava V. M.; Andronati K. S. Bioaccessibility of Cinazepam Introduced as Inclusion Complex with Beta-Cyclodextrin. Pharm. Chem. J. 1998, 32, 513–515. 10.1007/BF02465736. [DOI] [Google Scholar]

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