Synthesis of 5-Amino-2,5-dihydro-1H-benzo[b]azepines Using a One-Pot Multibond Forming Process

Article abstract of DOI:10.1021/acs.joc.6b01357

Rapid access to allylic trichloroacetimidates bearing a 2-allylaminoaryl group from readily available 2-iodoanilines combined with a one-pot multibond forming process has allowed the efficient synthesis of a series of 5-amino-2,5-dihydro-1H-benzo[b]azepin

Full text of DOI:10.1021/acs.joc.6b01357

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Article
Synthesis of 5-Amino-2,5-dihydro-1H-benzo[b]azepines
Using a One-Pot Multibond Forming Process
Salaheddin A. I. Sharif, Ewen D. D. Calder, Fábio Godoy Delolo, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01357 • Publication Date (Web): 14 Jul 2016
Downloaded from http://pubs.acs.org on July 14, 2016
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The Journal of Organic Chemistry
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Synthesis of 5ꢀAminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines
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Using a OneꢀPot Multibond Forming Process
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Salaheddin A. I. Sharif, Ewen D. D. Calder, Fábio G. Delolo and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Table of Contents Graphic:
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Abstract: Rapid access to allylic trichloroacetimidates bearing a 2ꢀallylaminoaryl group from readily
available 2ꢀiodoanilines combined with a oneꢀpot multibond forming process has allowed the efficient
synthesis of a series of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines. The potential of these compounds as
synthetic building blocks was demonstrated by the preparation of a lateꢀstage intermediate of the
hyponatremia agent, mozavaptan.
Keywords: Overman rearrangement, ring closing metathesis, 1Hꢀbenzo[b]azepines, mozavaptan.
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INTRODUCTION
1HꢀBenzo[b]azepines are an important class of sevenꢀmembered heterocyclic compound found as a
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key structural element in a wide variety of pharmaceutically active substances.1,2 Within this class, 5ꢀ
aminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepines are of particular significance and include compounds
such as mozavaptan (1), a nonꢀpeptide vasopressin V2ꢀreceptor antagonist used for the treatment of
hyponatremia (low blood sodium levels),3 and 3,5ꢀbis(trifluoromethyl)benzyl protected 2,3,4,5ꢀ
tetrahydroꢀ1Hꢀbenzo[b]azepine 2, developed for the treatment of dyslipidemia (Figure 1).4 The interest
in 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepines has led recently to a detailed analysis of their
conformational bias and a greater understanding of their physicochemical properties.5
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Figure 1. Structures of pharmacologically active 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepines.
Due to the pharmacological importance of 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepines, a
number of methods have been developed for their synthesis.2,3c,6 Traditionally, a Dieckmann
condensation has been used to prepare 1Hꢀbenzo[b]azepinꢀ5ꢀones, followed by introduction of the
amino substituent by reductive amination of the ketone (Scheme 1a).2c More recently, the azepine ring
system in these compounds has been prepared using methods such as the Beckmann rearrangement,6b
the Mitsunobu reaction,6a reductive ringꢀopening of azaꢀbridged azepines,6e and ring closing metathesis
(RCM) (Scheme 1b).6d,7 With the aim of developing new methods for the preparation of highly
functional polycyclic compounds, we have demonstrated that benzannulated alkene derived allylic
alcohols could be used in oneꢀpot multireaction processes for the efficient synthesis of aminoꢀ
substituted indenes, dihydronaphthalenes and 1ꢀbenzoxepines.8 We now report a short and general
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synthesis of allylic trichloroacetimidates bearing a 2ꢀallylaminoaryl group from readily available 2ꢀ
iodoanilines and demonstrate the application of these compounds in a oneꢀpot multibond forming
process for the efficient synthesis of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines (Scheme 1c).
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Scheme 1. Synthetic Approaches for the Preparation of 5-Amino-substituted 1H-
Benzo[b]azepines
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RESULTS AND DISCUSSION
The substrates for the oneꢀpot process, (E)ꢀ(2ꢀallylamino)cinnamyl alcohols were prepared using a
fourꢀstep route from commercially available 2ꢀiodoanilines (Scheme 2). MizorokiꢀHeck reaction of 2ꢀ
iodoanilines 3a–f with methyl acrylate and palladium(II) acetate (5 mol %) under standard conditions
gave the corresponding methyl (E)ꢀ2’ꢀaminocinnamates 4a–f in excellent yields (76–100%).9,10 The
amines were protected with the tosylate group and this allowed monoꢀallylation using allyl bromide and
potassium carbonate.11 Finally, reduction of the (E)ꢀα,βꢀunsaturated methyl esters 5a–f with DIBALꢀH
gave (E)ꢀ(2ꢀallylamino)cinnamyl alcohols 6a–f in high overall yields.
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Scheme 2. Synthesis of Allylic Alcohols 6a–fa
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aIsolated yields are shown.
While this synthetic route allowed access to a range of (E)ꢀ(2ꢀallylamino)cinnamyl alcohols, the
preparation of a 4’ꢀnitro analogue was not possible. Attempted MizorokiꢀHeck coupling of 2ꢀiodoꢀ4ꢀ
nitroaniline with methyl acrylate instead gave the conjugate addition product. An alternative approach
was developed for this compound (Scheme 3). 2ꢀChloroꢀ5ꢀnitrobenzaldehyde (7) was subjected to a
nucleophilic aromatic substitution reaction with pꢀtoluenesulfonamide, which gave 8 in 86% yield.12
HornerꢀWadsworthꢀEmmons reaction of 8 under MasamuneꢀRoush conditions with triethyl
phosphonoacetate (TEPA) gave the ethyl (E)ꢀ2’ꢀaminocinnamate in quantitative yield.13 Analysis of the
1H NMR spectrum of the crude reaction mixture showed exclusive formation of the Eꢀalkene. Allylation
of the amino group was then performed under the same conditions as before. However, due to decreased
nucleophilicity of this compound, the product was isolated in a modest 55% yield. DIBALꢀH reduction
of the ethyl ester then completed the fourꢀstep synthesis of nitroꢀsubstituted cinnamyl alcohol 6g.
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Scheme 3. Synthesis of Allylic Alcohol 6ga
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aIsolated yields are shown.
Having prepared a small library of (E)ꢀ(2ꢀallylamino)cinnamyl alcohols, 6a was used for optimization
of the oneꢀpot process (Table 1). Based on previous work,8,14 the thermally mediated Overman
rearrangement was performed at 140 ºC and the RCM step was done using Grubbs second generation
catalyst (10 mol %) (entry 1).15 While this gave a yield of 69% over the three steps, both the
rearrangement and metathesis stages required reaction times of 48 hours. Increasing the temperature of
the Overman rearrangement to 160 ºC allowed a shorter reaction time (24 h) with a similar overall yield
(entry 2). The catalyst loading and temperature of the RCM step was then investigated. It was found that
a catalyst loading of 5 mol % and a temperature of 60 ºC was optimal for the RCM step, with the
reaction complete after 18 hours (entry 4). Using the optimized conditions for both key steps gave 5ꢀ
aminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine 10a in 81% yield from 6a.
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Table 1.
Optimization of the One-Pot Processa
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Overman
Entry
RCM Reaction
Yield (%)a
Rearrangement
Grubbs II (10 mol %),
50 ºC, 48 h
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160 ºC, 24 h
160 ºC, 24 h
160 ºC, 24 h
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Grubbs II (10 mol %),
50 ºC, 48 h
Grubbs II (2.5 mol %),
60 ºC, 48 h
Grubbs II (5 mol %),
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aIsolated yields are shown.
Using the optimized oneꢀpot procedure, the scope of the process with various (E)ꢀ(2ꢀ
allylamino)cinnamyl alcohol substrates was explored (Scheme 4). Overall, the process was found to be
general and high yielding (79–92%) for the preparation of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines
bearing a range of substituents. Only in the case of the strongly electron deficient 4’ꢀnitrophenyl
analogue 6g did the conditions require significant modification. For this compound, both key steps
entailed longer reaction times and this likely accounts for the lower overall yield of 49%.
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Scheme 4. Synthesis of 5-Amino-2,5-Dihydro-1H-benzo[b]azepines 10b–ga
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b
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aIsolated yields are shown. The RCM step required a reaction time of 24 h. The Overman
rearrangement and RCM step required reaction times of 43 h and 31 h, respectively.
The synthetic potential of these products was demonstrated with the threeꢀstep conversion of 10a to 5ꢀ
aminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepine 12, a lateꢀstage intermediate for the preparation of
mozavaptan and its analogues (Scheme 5).3 A oneꢀpot procedure was used to remove the trichloroacyl
group and reꢀprotect the amine as the Bocꢀderivative. Hydrogenation at atmospheric pressure, followed
by deꢀtosylation with magnesium under mild conditions gave 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀ
benzo[b]azepine 12 in 88% yield. Overall, the highly efficient fourꢀstep route to allylic alcohol 6a,
combined with the oneꢀpot multibond forming strategy has allowed the synthesis of 5ꢀaminoꢀ2,3,4,5ꢀ
tetrahydroꢀ1Hꢀbenzo[b]azepine 12 in 46% overall yield from commercially available 2ꢀiodoaniline (3a).
Mozavaptan is easily prepared from 12 by benzoylation of the 1Hꢀbenzo[b]azepine ring nitrogen,
removal of the Bocꢀprotecting group and reductive amination of the resulting amine with
formaldehyde.3c
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Scheme 5. Formal synthesis of mozavaptan (1)a
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aIsolated yields are shown.
CONCLUSIONS
In summary, a fourꢀstep synthesis of (E)ꢀ(2ꢀallylamino)cinnamyl alcohols has been developed from
readily available 2ꢀiodoanilines using a highly efficient MizorokiꢀHeck coupling. Following
transformation to the corresponding allylic trichloroacetimidates, these compounds were converted to a
series of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines using a oneꢀpot multibond forming process. As
demonstrated with the straightforward synthesis of 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1Hꢀbenzo[b]azepine 12,
a lateꢀstage intermediate for the synthesis of mozavaptan, these compounds have potential for synthetic
and medicinal chemistry applications. Work is currently underway to investigate further synthetic
applications of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepines and extend the use of oneꢀpot multibond
forming reaction processes.
EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed under an
atmosphere of argon unless otherwise mentioned. Brine refers to a saturated solution of sodium
chloride. Flash column chromatography was performed using silica gel 60 (35–70 ꢀm). Aluminiumꢀ
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backed plates preꢀcoated with silica gel 60F254 were used for thin layer chromatography and were
visualized with a UV lamp or by staining with potassium permanganate. 1H NMR spectra were recorded
on a NMR spectrometer at either 400 or 500 MHz and data are reported as follows: chemical shift in
ppm relative to tetramethylsilane or the solvent (CDCl3, δ 7.26 ppm) as the internal standard,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of nonequivalent
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resonances, integration). C NMR spectra were recorded on a NMR spectrometer at either 101 or 126
MHz and data are reported as follows: chemical shift in ppm relative to tetramethylsilane or the solvent
(CDCl3, δ 77.0 ppm) as internal standard, multiplicity with respect to hydrogen (deduced from DEPT
experiments, C, CH, CH2 or CH3). Infrared spectra were recorded on a FTIR spectrometer;
wavenumbers are indicated in cm–1. Mass spectra were recorded using the electrospray technique.
HRMS spectra were recorded using a dualꢀfocusing magnetic analyzer mass spectrometer. Melting
points are uncorrected.
Methyl (2E)-3-(2'-aminophenyl)prop-2-enoate (4a).10 Methyl acrylate (1.53 mL, 18.3 mmol) was
added to a solution of 2ꢀiodoaniline (3a) (2.00 g, 9.13 mmol), palladium acetate (0.110 g, 0.460 mmol),
triphenylphosphine (0.239 g, 0.913 mmol), potassium carbonate (1.26 g, 9.13 mmol) and
tetrabutylammonium bromide (0.741 g, 2.30 mmol) in N,N’ꢀdimethylformamide (90 mL). The reaction
mixture was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, diluted with water
(50 mL) and extracted with diethyl ether (3 × 50 mL). The organic layer was washed with 5% aqueous
lithium chloride solution (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo.
The residue was purified by column chromatography (diethyl ether/petroleum ether, 1:4) to give methyl
(2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) (1.59 g, 99%) as a yellow solid. Mp 64–66 °C; Rf = 0.33
(diethyl ether/petroleum ether = 1:1); Spectroscopic data were consistent with the literature.10 1H NMR
(400 MHz, CDCl3)
δ 3.80 (s, 3H), 3.98 (br s, 2H), 6.36 (d, J = 15.8 Hz, 1H), 6.70 (dd, J = 8.0, 1.3 Hz,
1H), 6.77 (ddd, J = 8.0, 7.3, 1.3 Hz, 1H), 7.17 (ddd, J = 7.9, 7.3, 1.3 Hz, 1H), 7.38 (dd, J = 7.9, 1.3 Hz,
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1H), 7.83 (d, J = 15.8 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 51.7 (CH3), 116.7 (CH), 117.7 (CH),
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119.0 (CH), 119.9 (C), 128.1 (CH), 131.3 (CH), 140.3 (CH), 145.6 (C), 167.7 (C); MS (ESI) m/z 200
(MNa+, 4), 168 (26), 146 (100), 128 (31).
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Methyl (2E)-3-(2'-amino-5'-methylphenyl)prop-2-enoate (4b).16 The reaction was carried out as
described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) using 4ꢀmethylꢀ2ꢀ
iodoaniline (3b) (2.00 g, 8.58 mmol). Purification by column chromatography (diethyl ether/petroleum
ether, 1:3) gave methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5'ꢀmethylphenyl)propꢀ2ꢀenoate (4b) (1.64 g, 100%) as a
yellow solid. Mp 84–86 °C; Rf = 0.28 (diethyl ether/petroleum ether = 1:1); Spectroscopic data were
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consistent with the literature.16 1H NMR (400 MHz, CDCl3)
δ 2.24 (s, 3H), 3.79 (s, 3H), 3.86 (br s, 2H),
6.34 (d, J = 15.8 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 7.19 (d, J = 1.5 Hz,
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1H), 7.82 (d, J = 15.8 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 20.4 (CH3), 51.6 (CH3), 117.0 (CH),
117.4 (CH), 119.9 (C), 128.2 (C), 128.2 (CH), 132.3 (CH), 140.4 (CH), 143.3 (C), 167.8 (C); MS (ESI)
m/z 214 (MNa+, 100), 192 (11), 182 (23).
Methyl (2E)-3-(2'-amino-5'-methoxyphenyl)prop-2-enoate (4c).17 The reaction was carried out as
described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) using 4ꢀmethoxyꢀ2ꢀ
iodoaniline (3c) (0.170 g, 0.680 mmol) and potassium carbonate (0.188 g, 1.36 mmol). Purification by
column chromatography (diethyl ether/petroleum ether, 1:3) gave methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5'ꢀ
methoxyphenyl)propꢀ2ꢀenoate (4c) (0.141 g, 100%) as a yellow solid. Mp 93–95 °C; Rf = 0.20 (diethyl
ether/petroleum ether = 1:1); Spectroscopic data were consistent with the literature.17 1H NMR (400
MHz, CDCl3)
δ 3.71 (br s, 2H), 3.76 (s, 3H), 3.81 (s, 3H), 6.35 (d, J = 15.8 Hz, 1H), 6.67 (d, J = 8.7 Hz,
1H), 6.82 (dd, J = 8.7, 2.9 Hz, 1H), 6.92 (d, J = 2.9 Hz, 1H), 7.82 (d, J = 15.8 Hz, 1H); 13C NMR (101
MHz, CDCl3)
δ 51.7 (CH3), 55.8 (CH3), 111.6 (CH), 117.9 (CH), 118.4 (CH), 118.7 (CH), 120.8 (C),
139.6 (C), 140.2 (CH), 152.8 (C), 167.6 (C); MS (ESI) m/z 208 (MH+, 100).
Methyl (2E)-3-(2'-amino-5'-fluorophenyl)prop-2-enoate (4d).10 The reaction was carried out as
described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) using 4ꢀfluoroꢀ2ꢀ
iodoaniline (3d) (3.77 g, 16.0 mmol) and potassium carbonate (4.40 g, 32.0 mmol). Purification by
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column chromatography (ethyl acetate/petroleum ether, 1:3) gave methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5'ꢀ
1
2
3
fluorophenyl)propꢀ2ꢀenoate (4d) (2.50 g, 81%) as a yellow solid. Mp 96–98 °C (lit.10 93–95 °C); Rf =
4
5
6
1
0.28 (diethyl ether/petroleum ether = 1:1); H NMR (400 MHz, CDCl3)
δ 3.80 (s, 3H), 3.86 (br s, 2H),
7
8
9
6.33 (d, J = 15.8 Hz, 1H), 6.65 (dd, J = 8.7, 4JHF = 4.8 Hz, 1H), 6.90 (td, J = 8.7, 2.9 Hz, 1H), 7.08 (dd,
3JHF = 9.5, J = 2.9 Hz, 1H), 7.76 (dd, J = 15.8, 5JHF = 1.1 Hz, 1H); 13C NMR (101 MHz, CDCl3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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43
44
45
46
47
48
49
50
51
52
53
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58
59
60
δ
51.8
(CH3), 113.4 (d, 2JCF = 22.7 Hz, CH), 118.0 (d, 3JCF = 7.7 Hz, CH), 118.3 (d, 2JCF = 23.0 Hz, CH), 118.8
(CH), 120.8 (d, 3JCF = 7.2 Hz, C), 139.1 (d, 4JCF = 2.2 Hz, CH), 141.8 (C), 156.2 (d, 1JCF = 237.0 Hz, C),
167.3 (C); MS (ESI) m/z 218 (MNa+, 100), 169 (25), 186 (13), 164 (20).
Methyl (2E)-3-(2'-amino-4'-fluorophenyl)prop-2-enoate (4e).17 The reaction was carried out as
described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) using 5ꢀfluoroꢀ2ꢀ
iodoaniline (3e) (0.926 g, 3.90 mmol) and potassium carbonate (1.08 g, 7.80 mmol). Purification by
column chromatography (ethyl acetate/petroleum ether, 1:3) gave methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ4'ꢀ
fluorophenyl)propꢀ2ꢀenoate (4e) (0.639 g, 84%) as a yellow solid. Mp 107–109 °C; Rf = 0.25 (diethyl
ether/petroleum ether = 1:1); Spectroscopic data were consistent with the literature.17 1H NMR (400
3
MHz, CDCl3)
δ
3.80 (s, 3H), 4.11 (br s, 2H), 6.29 (d, J = 15.8 Hz, 1H), 6.39 (dd, JHF = 10.5, J = 2.5
Hz, 1H), 6.47 (td, J = 8.7, 2.5 Hz, 1H), 7.34 (dd, J = 8.7, 4JHF = 6.4 Hz, 1H), 7.74 (d, J = 15.8 Hz, 1H);
13C NMR (101 MHz, CDCl3) 51.7 (CH3), 102.9 (d, 2JCF = 24.8 Hz, CH), 106.3 (d, 2JCF = 22.2 Hz, CH),
δ
116.0 (d, 4JCF = 2.4 Hz, C), 117.2 (CH), 130.0 (d, 3JCF = 10.6 Hz, CH), 139.3 (CH), 147.4 (d, 3JCF = 11.5
Hz, C), 164.9 (d, 1JCF = 248.9 Hz, C), 167.6 (C); MS (ESI) m/z 218 (MNa+, 100), 186 (59), 164 (6).
Methyl (2E)-3-(2'-amino-5'-chlorophenyl)prop-2-enoate (4f).10 The reaction was carried out as
described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) using 4ꢀchloroꢀ2ꢀ
iodoaniline (3f) (0.975 g, 3.90 mmol) and potassium carbonate (1.08 g, 7.80 mmol). The reaction
mixture was stirred at 80 °C for 8 h. Purification by column chromatography (ethyl acetate/petroleum
ether, 1:3) gave methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5'ꢀchlorophenyl)propꢀ2ꢀenoate (4f) (0.622 g, 76%) as a yellow
solid. Mp 92–94 °C; Rf = 0.18 (diethyl ether/petroleum ether = 1:1); Spectroscopic data were consistent
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The Journal of Organic Chemistry
with the literature.10 1H NMR (400 MHz, CDCl3)
δ 3.81 (s, 3H), 3.97 (br s, 2H), 6.34 (d, J = 15.8 Hz,
1
2
3
1H), 6.64 (d, J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6, 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 15.8
4
5
6
13
Hz, 1H); C NMR (101 MHz, CDCl3)
δ 51.8 (CH3), 117.9 (CH), 119.0 (CH), 121.1 (C), 123.7 (C),
7
8
9
127.3 (CH), 131.0 (CH), 138.9 (CH), 144.0 (C), 167.3 (C); MS (ESI) m/z 234 (MNa+, 64), 202 (46), 186
(100).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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60
Methyl (2E)-3-(2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate.18 pꢀToluenesulfonyl chloride
(2.50 g, 13.0 mmol) was added to a solution of methyl (2E)ꢀ3ꢀ(2'ꢀaminophenyl)propꢀ2ꢀenoate (4a) (1.53
g, 8.70 mmol) in pyridine (43 mL) at 0 °C. The reaction mixture was allowed to warm to room
temperature and stirred for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with
dichloromethane (3 × 50 mL), washed with lithium chloride solution (10 mL) and brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo. Flash column chromatography (diethyl ether/petroleum
ether, 1:1) afforded methyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (2.66 g, 93%)
as a white solid. Mp 156–158 °C (lit.18 160–162 °C); Rf = 0.13 (diethyl ether/petroleum ether = 1:1); 1H
NMR (400 MHz, CDCl3)
δ 2.35 (s, 3H), 3.77 (s, 3H), 6.11 (d, J = 15.8 Hz, 1H), 7.17 (d, J = 8.2 Hz,
2H), 7.20–7.27 (m, 2H), 7.34 (td, J = 8.0, 1.5 Hz, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H), 7.45 (dd, J = 8.0,
13
1.5 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 15.8 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 21.5
(CH3), 51.9 (CH3), 120.1 (CH), 127.1 (CH), 127.2 (CH), 127.3 (2 × CH), 127.6 (CH), 129.6 (2 × CH),
130.6 (C), 130.9 (CH), 134.8 (C), 135.9 (C), 139.3 (CH), 143.9 (C), 167.0 (C); MS (ESI) m/z 354
(MNa+, 100), 233 (8).
Methyl (2E)-3-(5'-methyl-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate.19 The reaction was
carried
out
as
described
for
the
synthesis
of
methyl
(2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate using methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5’ꢀmethylphenyl)propꢀ2ꢀ
enoate (4b) (1.50 g, 7.84 mmol). Purification by column chromatography (ethyl acetate/petroleum ether,
1:4) gave methyl (2E)ꢀ3ꢀ(5'ꢀmethylꢀ2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (2.68 g, 99%)
as a white solid. Mp 164–166 °C (lit.19 160–162 °C); Rf = 0.20 (diethyl ether/petroleum ether = 1:1); 1H
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NMR (400 MHz, CDCl3)
δ
2.32 (s, 3H), 2.35 (s, 3H), 3.77 (s, 3H), 6.10 (d, J = 15.9 Hz, 1H), 6.99 (br s,
1
2
3
4
13
1H), 7.12–7.19 (m, 3H), 7.23–7.26 (m, 2H), 7.50–7.57 (m, 3H); C NMR (101 MHz, CDCl3)
δ 21.0
5
6
7
8
(CH3), 21.5 (CH3), 51.8 (CH3), 119.7 (CH), 127.3 (2 × CH), 127.4 (CH), 128.0 (CH), 129.6 (2 × CH),
130.7 (C), 131.8 (CH), 132.1 (C), 135.9 (C), 137.4 (C), 139.4 (CH), 143.8 (C), 167.0 (C); MS (ESI) m/z
368 (MNa+, 100).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
Methyl (2E)-3-(5'-methoxy-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate. The reaction was
carried
out
as
described
for
the
synthesis
of
methyl
(2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate using methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5’ꢀmethoxyphenyl)propꢀ2ꢀ
enoate (4c) (0.014 g, 0.070 mmol). Purification by column chromatography (ethyl acetate/petroleum
ether, 1:4) gave methyl (2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate
(0.023 g, 93%) as a white solid. Mp 162–164 °C; Rf = 0.23 (petroleum ether/ethyl acetate = 2:1); IR
1
(neat) 3256, 3023, 1701, 1637, 1495, 1214, 1325, 1161, 750 cm−1; H NMR (500 MHz, CDCl3)
δ 2.37
(s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 6.09 (d, J = 15.9 Hz, 1H), 6.53 (br s, 1H), 6.89 (dd, J = 8.8, 2.9 Hz,
1H), 6.95 (d, J = 2.9 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 15.9 Hz,
1H), 7.52 (d, J = 8.2 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 21.5 (CH3), 51.8 (CH3), 55.5 (CH3), 111.4
(CH), 116.7 (CH), 120.1 (CH), 127.3 (C), 127.4 (2 × CH), 129.6 (2 × CH), 130.6 (CH), 133.1 (C), 135.8
(C), 139.2 (CH), 143.9 (C), 158.9 (C), 166.7 (C); MS (ESI) m/z 384 (MNa+, 100); HRMS (ESI) calcd
for C18H19NNaO5S (MNa+), 384.0876, found 384.0864.
Methyl (2E)-3-(5'-fluoro-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate.19 The reaction was
carried
out
as
described
for
the
synthesis
of
methyl
(2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate using methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5’ꢀfluorophenyl)propꢀ2ꢀ
enoate (4d) (2.50 g, 13.0 mmol). Purification by column chromatography (ethyl acetate/petroleum ether,
1:5) gave methyl (2E)ꢀ3ꢀ(5'ꢀfluoroꢀ2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (3.94 g, 88%)
as a white solid. Mp 156–158 °C (lit.19 156–158 °C); Rf = 0.13 (diethyl ether/petroleum ether = 1:1); 1H
NMR (400 MHz, CDCl3)
δ
2.36 (s, 3H), 3.78 (s, 3H), 6.07 (d, J = 15.8 Hz, 1H), 6.96 (br s, 1H), 7.06
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(ddd, J = 8.8, 3JHF = 7.7, J = 2.9 Hz, 1H), 7.14 (dd, 3JHF = 9.2, J = 2.9 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H),
1
2
3
4
5
7.35 (dd, J = 8.8, JHF = 5.2 Hz, 1H), 7.50 (dd, J = 15.8, JHF = 1.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H);
4
5
6
13C NMR (101 MHz, CDCl3)
δ
21.5 (CH3), 52.0 (CH3), 113.3 (d, 2JCF = 23.5 Hz, CH), 117.9 (d, 2JCF
=
=
7
8
22.7 Hz, CH), 121.2 (CH), 127.3 (2 × CH), 129.7 (2 × CH), 130.6 (d, 4JCF = 2.9 Hz, C), 130.7 (d, 3JCF
9
8.8 Hz, CH), 133.4 (d, 3JCF = 8.4 Hz, C), 135.6 (C), 138.2 (d, 4JCF = 2.2 Hz, CH), 144.2 (C), 161.5 (d,
1JCF = 248.4 Hz, C), 166.5 (C); MS (ESI) m/z 372 (MNa+, 100).
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11
12
13
14
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Methyl (2E)-3-(4'-fluoro-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate.17 The reaction was
carried
out
as
described
for
the
synthesis
of
methyl
(2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate using methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ4’ꢀfluorophenyl)propꢀ2ꢀ
enoate (4e) (0.620 g, 3.20 mmol). Purification by column chromatography (ethyl acetate/petroleum
ether, 1:5) gave methyl (2E)ꢀ3ꢀ(4'ꢀfluoroꢀ2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (1.08 g,
97%) as a yellow solid. Mp 157–159 °C; Rf = 0.13 (diethyl ether/petroleum ether = 1:1); Spectroscopic
data were consistent with the literature.17 1H NMR (400 MHz, CDCl3)
δ 2.38 (s, 3H), 3.79 (s, 3H), 6.11
(d, J = 15.8 Hz, 1H), 6.92 (td, J = 8.7, 2.6 Hz, 1H), 7.00 (br s, 1H), 7.20–7.26 (m, 3H), 7.41 (dd, J = 8.7,
4JHF = 6.1 Hz, 1H), 7.48 (d, J = 15.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ
21.5 (CH3), 51.9 (CH3), 112.8 (d, 2JCF = 24.9 Hz, CH), 114.1 (d, 2JCF = 21.8 Hz, CH), 120.5 (CH), 125.1
(d, 4JCF = 3.4 Hz, C), 127.3 (2 × CH), 128.9 (d, 3JCF = 9.5 Hz, CH), 129.9 (2 × CH), 135.7 (C), 136.5 (d,
3JCF = 10.8 Hz, C), 137.8 (CH), 144.4 (C), 163.8 (d, 1JCF = 251.8 Hz, C), 166.7 (C); MS (ESI) m/z 372
(MNa+, 100), 363 (37).
Methyl (2E)-3-(5'-chloro-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate.19 The reaction was
carried
out
as
described
for
the
synthesis
of
methyl
(2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate using methyl (2E)ꢀ3ꢀ(2'ꢀaminoꢀ5’ꢀchlorophenyl)propꢀ2ꢀ
enoate (4f) (0.406 g, 1.90 mmol). The reaction mixture was stirred at room temperature for 18 h.
Purification by column chromatography (ethyl acetate/petroleum ether, 1:5) gave methyl (2E)ꢀ3ꢀ(5'ꢀ
chloroꢀ2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (0.638 g, 91%) as a yellow solid. Mp 152–
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154 °C (lit.19 149–151 °C); Rf = 0.43 (petroleum ether/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3)
1
2
3
4
5
δ
2.36 (s, 3H), 3.78 (s, 3H), 6.09 (d, J = 15.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.28 (br s, 1H), 7.31 (dd,
13
J = 8.6, 2.4 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.50–7.56 (m, 3H); C NMR
6
7
8
(101 MHz, CDCl3)
δ 21.5 (CH3), 52.1 (CH3), 121.3 (CH), 126.9 (CH), 127.3 (2 × CH), 129.1 (CH),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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48
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59
60
129.8 (2 × CH), 130.8 (CH), 132.2 (C), 133.1 (C), 133.3 (C), 135.6 (C), 138.1 (CH), 144.2 (C), 166.7
(C); MS (ESI) m/z 388 (MNa+, 100).
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate (5a). Allyl bromide
(0.830 mL, 9.60 mmol) was added to a stirred solution of methyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (2.66 g, 8.00 mmol) and potassium carbonate (2.21 g, 16.0
mmol) in N,N’ꢀdimethylformamide (50 mL). The reaction mixture was heated to 70 °C for 1 h. The
reaction mixture was cooled to room temperature, diluted with 5% aqueous lithium chloride solution (20
mL) and extracted with diethyl ether (50 mL). The organic layer was washed with 5% aqueous lithium
chloride solution (3 × 10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo.
Purification by column chromatography (diethyl ether/petroleum ether, 1:1) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ
allylꢀNꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (5a) (2.98 g, 100%) as a white solid. Mp 104–
106 °C; Rf = 0.38 (diethyl ether/petroleum ether = 1:1); IR (neat) 2951, 1716, 1636, 1436, 1319, 1164,
1
763 cm−1; H NMR (400 MHz, CDCl3)
δ 2.42 (s, 3H), 3.79 (s, 3H), 4.02 (br s, 1H), 4.27 (br s, 1H),
4.93–5.02 (m, 2H), 5.74 (ddt, J = 17.0, 10.0, 6.8 Hz, 1H), 6.33 (d, J = 16.1 Hz, 1H), 6.84 (dd, J = 7.8,
1.1 Hz, 1H), 7.24–7.35 (m, 4H), 7.56 (d, J = 8.2 Hz, 2H), 7.64 (dd, J = 7.8, 1.5 Hz, 1H), 7.86 (d, J =
13
16.1 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 21.5 (CH3), 51.7 (CH3), 54.9 (CH2), 119.7 (CH), 119.7
(CH2), 127.1 (CH), 128.0 (2 × CH), 128.8 (CH), 129.6 (2 × CH), 129.9 (CH), 130.3 (CH), 132.1 (CH),
135.6 (C), 135.6 (C), 138.3 (C), 140.3 (CH), 143.8 (C), 166.9 (C); MS (ESI) m/z 394 (MNa+, 100);
HRMS (ESI) calcd for C20H21NNaO4S (MNa+), 394.1083, found 394.1067.
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-5'-methylphenyl)prop-2-enoate (5b). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
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toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate
(5a)
using
methyl
(2E)ꢀ3ꢀ(5'ꢀmethylꢀ2'ꢀ[Nꢀ(pꢀ
1
2
3
4
5
6
7
8
9
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (2.00 g, 5.79 mmol) and a reaction time of 3 h.
Purification by column chromatography (ethyl acetate/petroleum ether, 1:5) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ
allylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀmethylphenyl)propꢀ2ꢀenoate (5b) (2.03 g, 91%) as a white solid.
Mp 118–120 °C; Rf = 0.25 (diethyl ether/petroleum ether = 1:1); IR (neat) 2950, 1717, 1639, 1435,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1347, 1160, 759 cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.34 (s, 3H), 2.42 (s, 3H), 3.78 (s, 3H), 3.99 (br s,
1H), 4.26 (br s, 1H), 4.93–5.02 (m, 2H), 5.74 (ddt, J = 17.0, 10.1, 6.8 Hz, 1H), 6.31 (d, J = 16.1 Hz,
1H), 6.71 (d, J = 8.1 Hz, 1H), 7.08 (dd, J = 8.1, 1.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 1.6
Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 16.1 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ 21.2 (CH3),
21.5 (CH3), 51.7 (CH3), 54.9 (CH2), 119.4 (CH), 119.6 (CH2), 127.6 (CH), 128.0 (2 × CH), 129.5 (2 ×
CH), 129.6 (CH), 131.3 (CH), 132.3 (CH), 135.2 (C), 135.7 (C), 135.7 (C), 138.7 (C), 140.5 (CH),
143.7 (C), 167.0 (C); MS (ESI) m/z 408 (MNa+, 100); HRMS (ESI) calcd for C21H23NNaO4S (MNa+),
408.1240, found 408.1220.
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-5'-methoxyphenyl)prop-2-enoate (5c). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (5a) using methyl (2E)ꢀ3ꢀ(5'ꢀmethoxyꢀ2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (0.145 g, 0.400 mmol) and a reaction time of 2 h.
Purification by column chromatography (ethyl acetate/petroleum ether, 1:5) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ
allylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀmethoxyphenyl)propꢀ2ꢀenoate (5c) (0.149 g, 92%) as a white
solid. Mp 153–155 °C; Rf = 0.40 (petroleum ether/ethyl acetate = 2:1); IR (neat) 3022, 1709, 1642,
1
1495, 1289, 1215, 1163, 751 cm−1; H NMR (400 MHz, CDCl3)
δ 2.42 (s, 3H), 3.79 (s, 3H), 3.81 (s,
3H), 3.96–4.01 (m, 1H), 4.24–4.29 (m, 1H), 4.93–5.03 (m, 2H), 5.74 (ddt, J = 16.9, 10.1, 6.8 Hz, 1H),
6.29 (d, J = 16.1 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.8 Hz, 1H), 7.09 (d, J = 2.8 Hz,
1H), 7.26 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 16.1 Hz, 1H); 13C NMR (101 MHz,
CDCl3)
δ
21.5 (CH3), 51.7 (CH3), 55.0 (CH2), 55.5 (CH3), 111.2 (CH), 116.4 (CH), 119.7 (CH2), 119.8
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(CH), 128.0 (2 × CH), 129.6 (2 × CH), 131.0 (CH), 132.3 (CH), 135.7 (C), 136.6 (C), 140.4 (CH), 143.7
(2 × C), 159.3 (C), 166.8 (C); MS (ESI) m/z 424 (MNa+, 100); HRMS (ESI) calcd for C21H23NNaO5S
(MNa+), 424.1189, found 424.1176.
1
2
3
4
5
6
7
8
9
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-5'-fluorophenyl)prop-2-enoate (5d). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
10
11
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14
15
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toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate
(5a)
using
methyl
(2E)ꢀ3ꢀ(5'ꢀfluoroꢀ2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (3.74 g, 11.0 mmol). Purification by column
chromatography (ethyl acetate/petroleum ether, 1:7) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5'ꢀfluorophenyl)propꢀ2ꢀenoate (5d) (3.50 g, 84%) as a white solid. Mp 108–110
°C; Rf = 0.43 (diethyl ether/petroleum ether = 1:1); IR (neat) 2951, 1718, 1650, 1488, 1323, 1275, 1160,
862, 728 cm−1; 1H NMR (400 MHz, CDCl3)
4.95 (dd, J = 17.0, 1.2 Hz, 1H), 5.00 (dd, J = 10.1, 1.2 Hz, 1H), 5.71 (ddt, J = 17.0, 10.1, 6.8 Hz, 1H),
δ 2.40 (s, 3H), 3.77 (s, 3H), 3.95 (br s, 1H), 4.25 (br s, 1H),
4
3
6.28 (d, J = 16.1 Hz, 1H), 6.80 (dd, J = 8.8, JHF = 5.3 Hz, 1H), 6.95 (ddd, J = 8.8, JHF = 7.6, J = 2.9
3
Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.28 (dd, JHF = 9.4, J = 2.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.76
5
13
(dd, J = 16.1, JHF = 1.6 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 21.5 (CH3), 51.8 (CH3), 55.0 (CH2),
113.5 (d, 2JCF = 23.4 Hz, CH), 117.4 (d, 2JCF = 23.0 Hz, CH), 120.1 (CH2), 120.9 (CH), 127.9 (2 × CH),
129.7 (2 × CH), 131.8 (d, 3JCF = 8.9 Hz, CH), 131.9 (CH), 134.2 (d, 4JCF = 3.1 Hz, C), 135.3 (C), 137.8
(d, 3JCF = 8.5 Hz, C), 139.2 (d, 4JCF = 2.0 Hz, CH), 144.0 (C), 162.0 (d, 1JCF = 249.4 Hz, C), 166.5 (C);
MS (ESI) m/z 412 (MNa+, 100); HRMS (ESI) calcd for C20H20FNNaO4S (MNa+), 412.0989, found
412.0969.
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-4'-fluorophenyl)prop-2-enoate (5e). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate
(5a)
using
methyl
(2E)ꢀ3ꢀ(4’ꢀfluoroꢀ2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (1.07 g, 3.00 mmol). Purification by column
chromatography (ethyl acetate/petroleum ether, 1:7) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ4'ꢀfluorophenyl)propꢀ2ꢀenoate (5e) (0.946 g, 79%) as a white solid. Mp 111–
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113 °C; Rf = 0.38 (diethyl ether/petroleum ether = 1:1); IR (neat) 2951, 1712, 1602, 1497, 1353, 1256,
1164, 908, 730 cm−1; 1H NMR (400 MHz, CDCl3)
1
2
3
4
δ
2.43 (s, 3H), 3.78 (s, 3H), 4.02 (br s, 1H), 4.21 (br
5
6
7
8
s, 1H), 4.95–5.05 (m, 2H), 5.72 (ddt, J = 16.9, 10.1, 6.8 Hz, 1H), 6.27 (d, J = 16.1 Hz, 1H), 6.57 (dd,
3JHF = 9.2, J = 2.8 Hz, 1H), 7.06 (td, J = 8.8, 2.8 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz,
9
4
13
10
11
12
13
14
15
16
17
18
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21
22
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31
32
33
34
35
36
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39
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42
43
44
45
46
47
48
49
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51
52
53
54
55
56
57
58
59
60
2H), 7.62 (dd, J = 8.8, JHF = 6.2 Hz, 1H), 7.78 (d, J = 16.1 Hz, 1H); C NMR (101 MHz, CDCl3)
δ
21.6 (CH3), 51.7 (CH3), 54.9 (CH2), 116.4 (d, 2JCF = 21.6 Hz, CH), 117.0 (d, 2JCF = 21.9 Hz, CH), 119.5
(CH), 120.2 (CH2), 128.0 (2 × CH), 128.6 (d, 3JCF = 9.4 Hz, CH), 129.7 (2 × CH), 131.7 (CH), 132.1 (d,
4JCF = 3.7 Hz, C), 135.1 (C), 139.3 (CH), 139.8 (d, 3JCF = 9.2 Hz, C), 144.2 (C), 163.1 (d, 1JCF = 253.1
Hz, C), 166.7 (C); MS (ESI) m/z 412 (MNa+, 100); HRMS (ESI) calcd for C20H20FNNaO4S (MNa+),
412.0989, found 412.0970.
Methyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-5'-chlorophenyl)prop-2-enoate (5f). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate
(5a)
using
methyl
(2E)ꢀ3ꢀ(5'ꢀchloroꢀ2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (0.600 g, 1.60 mmol). Purification by column
chromatography (ethyl acetate/petroleum ether, 1:5) gave methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5'ꢀchlorophenyl)propꢀ2ꢀenoate (5f) (0.664 g, 100%) as a yellow solid. Mp 104–
106 °C; Rf = 0.58 (petroleum ether/ethyl acetate = 2:1); IR (neat) 2951, 1720, 1610, 1353, 1164, 908,
730 cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.44 (s, 3H), 3.80 (s, 3H), 3.99 (br s, 1H), 4.26 (br s, 1H), 4.97
(dd, J 17.0, 1.1 Hz, 1H), 5.03 (dd, J = 10.1, 1.1 Hz, 1H), 5.73 (ddt, J = 17.0, 10.1, 6.8 Hz, 1H), 6.31 (d,
J = 16.1 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.6, 2.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.57
(d, J = 8.2 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 16.1 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ
21.6 (CH3), 51.8 (CH3), 54.9 (CH2), 120.2 (CH2), 121.0 (CH), 127.1 (CH), 128.0 (2 × CH), 129.7 (2 ×
CH), 130.3 (CH), 131.2 (CH), 131.8 (CH), 134.7 (C), 135.3 (C), 136.7 (C), 137.4 (C), 139.0 (CH),
144.1 (C), 166.5 (C); MS (ESI) m/z 428 (MNa+, 100); HRMS (ESI) calcd for C20H2035ClNNaO4S
(MNa+), 428.0694, found 428.0673.
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(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]phenyl)prop-2-en-1-ol (6a). Diisobutylaluminium
hydride (4.1 mL, 4.1 mmol, 1 M in hexane) was added dropwise with stirring to a solution of methyl
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (5a) (0.690 g, 1.86 mmol) in
dichloromethane (19 mL) at −78 °C. The solution was stirred at −78 °C for 2 h and then allowed to
warm to room temperature over 16 h. The reaction was quenched with 10% aqueous potassium sodium
tartrate solution (5 mL), extracted with diethyl ether (2 × 10 mL), washed with water (20 mL), brine (20
mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (ethyl
acetate/petroleum ether, 1:2) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀ
ol (6a) (0.611 g, 96%) as a colorless oil. Rf = 0.13 (diethyl ether/petroleum ether = 1:1); IR (neat) 3491,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
2924, 1597, 1341, 1161, 726 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.97 (br s, 1H), 2.43 (s, 3H), 4.00 (br
s, 1H), 4.18–4.29 (m, 3H), 4.93–5.01 (m, 2H), 5.72 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 6.33 (dt, J = 16.0,
5.4 Hz, 1H), 6.68 (dd, J = 7.8, 1.3 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H), 7.12 (td, J = 7.8, 1.3 Hz, 1H),
7.23–7.30 (m, 3H), 7.55–7.61 (m, 3H); 13C NMR (101 MHz, CDCl3)
δ 21.5 (CH3), 54.8 (CH2), 63.8
(CH2), 119.4 (CH2), 126.5 (CH), 126.7 (CH), 127.8 (CH), 127.9 (2 × CH), 128.6 (CH), 129.4 (CH),
129.5 (2 × CH), 130.8 (CH), 132.4 (CH), 136.1 (C), 136.6 (C), 137.8 (C), 143.6 (C); MS (ESI) m/z 366
(MNa+, 100); HMRS (ESI) calcd for C19H21NNaO3S (MNa+), 366.1134, found 366.1119.
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-5'-methylphenyl)prop-2-en-1-ol (6b). The reaction
was
carried
out
as
described
for
the
(6a)
synthesis
of
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol
using methyl
toluenesulfonyl)amino]ꢀ5'ꢀmethylphenyl)propꢀ2ꢀenoate (5b) (1.50 g, 3.89 mmol). Purification by
column chromatography (ethyl acetate/petroleum ether, 1:2) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5'ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀol (6b) (1.37 g, 98%) as a colorless oil. Rf = 0.10
(diethyl ether/petroleum ether = 1:1); IR (neat) 3510, 2921, 1598, 1491, 1340, 1159, 859, 734 cm−1; 1H
NMR (400 MHz, CDCl3)
δ 2.15 (br s, 1H), 2.31 (s, 3H), 2.42 (s, 3H), 3.96 (br s, 1H), 4.19–4.28 (m,
3H), 4.93–5.01 (m, 2H), 5.72 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 6.31 (dt, J = 16.0, 5.7 Hz, 1H), 6.56 (d, J
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= 8.1 Hz, 1H), 6.79 (d, J = 16.0 Hz, 1H), 6.92 (dd, J = 8.1, 1.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.40
1
2
3
4
13
(d, J = 1.3 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H); C NMR (101 MHz, CDCl3)
δ 21.2 (CH3), 21.5 (CH3),
5
6
7
8
54.8 (CH2), 63.8 (CH2), 119.2 (CH2), 126.7 (CH), 127.0 (CH), 127.9 (2 × CH), 128.7 (CH), 129.1 (CH),
129.5 (2 × CH), 130.5 (CH), 132.5 (CH), 134.1 (C), 136.2 (C), 137.3 (C), 138.4 (C), 143.5 (C); MS
(ESI) m/z 380 (MNa+, 100); HRMS (ESI) calcd for C20H23NNaO3S (MNa+), 380.1291, found 380.1279.
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10
11
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49
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54
55
56
57
58
59
60
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-5'-methoxyphenyl)prop-2-en-1-ol
reaction was carried out as described for the synthesis of (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol (6a) using methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(6c).
The
toluenesulfonyl)amino]ꢀ5'ꢀmethoxyphenyl)propꢀ2ꢀenoate (5c) (0.140 g, 0.350 mmol). Purification by
column chromatography (ethyl acetate/petroleum ether, 1:2) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5'ꢀmethoxyphenyl)propꢀ2ꢀenꢀ1ꢀol (6c) (0.104 g, 80%) as a colorless oil. Rf =
0.18 (petroleum ether/ethyl acetate = 2:1); IR (neat) 3523, 2944, 1601, 1495, 1345, 1161, 752 cm−1; 1H
NMR (400 MHz, CDCl3) δ 2.07 (t, J = 5.4 Hz, 1H), 2.42 (s, 3H), 3.79 (s, 3H), 3.91–3.98 (m, 1H), 4.18–
4.28 (m, 3H), 4.93–5.01 (m, 2H), 5.72 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 6.30 (dt, J = 16.0, 5.4 Hz, 1H),
6.58 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.9 Hz, 1H), 6.77 (dt, J = 16.0, 1.5 Hz, 1H), 7.07 (d, J = 2.9
Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 21.5 (CH3),
54.9 (CH2), 55.4 (CH3), 63.7 (CH2), 110.7 (CH), 113.9 (CH), 119.3 (CH2), 126.6 (CH), 127.9 (2 × CH),
129.4 (C), 129.7 (2 × CH), 130.4 (CH), 130.9 (CH), 132.5 (CH), 136.2 (C), 138.8 (C), 143.5 (C), 159.2
(C); MS (ESI) m/z 396 (MNa+, 100); HRMS (ESI) calcd for C20H23NNaO4S (MNa+), 396.1240, found
396.1223.
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-5'-fluorophenyl)prop-2-en-1-ol (6d). The reaction
was
carried
out
as
described
for
the
(6a)
synthesis
of
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol
using methyl
toluenesulfonyl)amino]ꢀ5'ꢀfluorophenyl)propꢀ2ꢀenoate (5d) (3.30 g, 8.50 mmol). Purification by column
chromatography
(ethyl
acetate/petroleum
ether,
1:3)
gave
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
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toluenesulfonyl)amino]ꢀ5'ꢀfluorophenyl)propꢀ2ꢀenꢀ1ꢀol (6d) (2.99 g, 98%) as a colorless oil. Rf = 0.10
1
2
3
(diethyl ether/petroleum ether = 1:1); IR (neat) 3507, 2920, 1600, 1488, 1345, 1161, 752 cm−1; 1H NMR
4
5
6
(400 MHz, CDCl3)
δ 2.35 (t, J = 5.6 Hz, 1H), 2.42 (s, 3H), 3.95 (dd, J = 13.4, 6.8, 1H), 4.17–4.28 (m,
7
8
3H), 4.91–5.01 (m, 2H), 5.70 (ddt, J = 16.9, 10.1, 6.8 Hz, 1H), 6.30 (dt, J = 16.0, 5.5 Hz, 1H), 6.65 (dd,
9
4
3
J = 8.8, JHF = 5.4 Hz, 1H), 6.73–6.83 (m, 2H), 7.24 (dd, JHF = 10.0, J = 2.9 Hz, 1H), 7.27 (d, J = 8.3
Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H); 13C NMR (101 MHz, CDCl3)
112.8 (d, 2JCF = 23.3 Hz, CH), 114.7 (d, 2JCF = 23.1 Hz, CH), 119.7 (CH2), 125.4 (d, 4JCF = 1.7 Hz, CH),
127.9 (2 × CH), 129.6 (2 × CH), 131.2 (d, 3JCF = 9.1 Hz, CH), 132.1 (CH), 132.3 (CH), 132.4 (d, 4JCF
10
11
12
13
14
15
16
17
18
19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
21.5 (CH3), 54.9 (CH2), 63.4 (CH2),
=
2.8 Hz, C), 135.9 (C), 140.2 (d, 3JCF = 8.6 Hz, C), 143.8 (C), 162.2 (d, 1JCF = 247.9 Hz, C); MS (ESI)
m/z 384 (MNa+, 100); HRMS (ESI) calcd for C19H20FNNaO3S (MNa+), 384.1040, found 384.1023.
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-4'-fluorophenyl)prop-2-en-1-ol (6e). The reaction
was
carried
out
as
described
for
the
(6a)
synthesis
of
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol
using methyl
toluenesulfonyl)amino]ꢀ4'ꢀfluorophenyl)propꢀ2ꢀenoate (5e) (0.790 g, 2.00 mmol). Purification by
column chromatography (ethyl acetate/petroleum ether, 1:3) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ4'ꢀfluorophenyl)propꢀ2ꢀenꢀ1ꢀol (6e) (0.728 g, 99%) as a colorless oil. Rf = 0.08
(diethyl ether/petroleum ether = 1:1); IR (neat) 3507, 2923, 1600, 1495, 1347, 1161, 908, 727 cm−1; 1H
NMR (400 MHz, CDCl3)
δ 2.18 (t, J = 5.6 Hz, 1H), 2.43 (s, 3H), 3.96 (br s, 1H), 4.09–4.27 (m, 3H),
4.94–5.03 (m, 2H), 5.69 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 6.25 (dt, J = 16.0, 5.3 Hz, 1H), 6.41 (dd, 3JHF
= 9.3, J = 2.6 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H), 6.99 (td, J = 8.6, 2.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H),
4
13
7.55 (dd, J = 8.6, JHF = 6.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H); C NMR (101 MHz, CDCl3)
δ 21.6
2
2
(CH3), 54.7 (CH2), 63.6 (CH2), 116.0 (d, JCF = 21.2 Hz, CH), 116.2 (d, JCF = 21.2 Hz, CH), 119.8
(CH2), 125.7 (CH), 127.7 (d, 3JCF = 8.9 Hz, CH), 127.9 (2 × CH), 129.7 (2 × CH), 130.7 (d, 5JCF = 1.8
Hz, CH), 131.9 (CH), 134.3 (d, 4JCF = 3.7 Hz, C), 135.7 (C), 137.7 (d, 3JCF = 8.8 Hz, C), 144.0 (C),
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161.5 (d, 1JCF = 248.9 Hz, C); MS (ESI) m/z 384 (MNa+, 100); HRMS (ESI) calcd for C19H20FNNaO3S
(MNa+), 384.1040, found 384.1023.
1
2
3
4
5
6
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-5'-chlorophenyl)prop-2-en-1-ol (6f). The reaction
7
8
9
was
carried
out
as
described
for
the
(6a)
synthesis
of
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol
using methyl
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14
15
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17
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21
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58
59
60
toluenesulfonyl)amino]ꢀ5'ꢀchlorophenyl)propꢀ2ꢀenoate (5f) (0.660 g, 1.60 mmol). Purification by
column chromatography (ethyl acetate/petroleum ether, 1:3) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5'ꢀchlorophenyl)propꢀ2ꢀenꢀ1ꢀol (6f) (0.566 g, 92%) as a colorless oil. Rf = 0.28
(petroleum ether/ethyl acetate = 2:1); IR (neat) 3505, 2923, 1597, 1478, 1343, 1161, 907, 727 cm−1; 1H
NMR (400 MHz, CDCl3)
δ 2.23 (br s, 1H), 2.43 (s, 3H), 3.94 (br s, 1H), 4.17–4.29 (m, 3H), 4.92–5.02
(m, 2H), 5.69 (ddt, J = 17.0, 10.1, 6.8 Hz, 1H), 6.32 (dt, J = 16.0, 5.1 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H),
6.75 (dt, J = 16.0, 1.5 Hz, 1H), 7.07 (dd, J = 8.6, 2.4 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.54–7.59 (m,
3H); 13C NMR (101 MHz, CDCl3)
δ 21.6 (CH3), 54.8 (CH2), 63.4 (CH2), 119.8 (CH2), 125.2 (CH),
126.5 (CH), 127.8 (CH), 127.9 (2 × CH), 129.7 (2 × CH), 130.7 (CH), 132.0 (CH), 132.4 (CH), 134.5
(C), 135.0 (C), 135.8 (C), 139.6 (C), 143.9 (C); MS (ESI) m/z 400 (MNa+, 100); HRMS (ESI) calcd for
C19H2035ClNNaO3S (MNa+), 400.0745, found 400.0729.
5-Nitro-2-[N-(p-toluenesulfonyl)amino]benzaldehyde (8). pꢀToluenesulfonamide (0.148 g, 0.865
mmol) was added to a solution of 2ꢀchloroꢀ5ꢀnitrobenzaldehyde (7) (0.0800 g, 0.432 mmol), and
potassium carbonate (0.107 g, 0.780 mmol) in N,N’ꢀdimethylformamide (2 mL) and heated to 90 °C for
2 h. The reaction mixture was cooled to room temperature, diluted with water (2 mL) and extracted with
ethyl acetate (10 mL). The organic layer was washed with 1 M hydrochloric acid solution (3 × 2 mL)
and brine (2 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column
chromatography
(ethyl
acetate/petroleum
ether,
1:5)
gave
5ꢀnitroꢀ2ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]benzaldehyde (8) (0.122 g, 86%) as a white solid. Mp 172–174 °C; Rf = 0.38
(petroleum ether/ethyl acetate = 2:1); IR (neat) 3164, 1673, 1586, 1345, 1215, 1164, 749 cm−1; 1H NMR
(400 MHz, CDCl3)
δ
2.40 (s, 3H), 7.31 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 9.3 Hz, 1H), 7.83 (d, J = 8.2 Hz,
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2H), 8.34 (dd, J = 9.3, 2.6 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 9.94 (d, J = 0.6 Hz, 1H), 11.19 (br s, 1H);
13C NMR (101 MHz, CDCl3)
1
2
3
4
δ
21.6 (CH3), 117.3 (CH), 120.5 (C), 127.4 (2 × CH), 130.2 (2 × CH),
5
6
7
8
130.5 (CH), 131.5 (CH), 135.6 (C), 142.1 (C), 145.0 (C), 145.3 (C), 193.5 (CH); MS (ESI) m/z 343
(MNa+, 100); HRMS (ESI) calcd for C14H12N2NaO5S (MNa+), 343.0359, found 343.0350.
9
Ethyl (2E)-3-(5'-nitro-2'-[N-(p-toluenesulfonyl)amino]phenyl)prop-2-enoate. Lithium bromide
(0.043 g, 0.50 mmol) was added to a solution of triethyl phosphonoacetate (0.085 mL, 0.43 mmol) and
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (0.064 mL, 0.43 mmol) in acetonitrile (2 mL) and stirred at room
temperature for 0.5 h. 5ꢀNitroꢀ2ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]benzaldehyde (8) (0.040 g, 0.13 mmol)
was added and the solution was stirred at room temperature for 3 h. The reaction was quenched with
10% aqueous potassium sodium tartrate solution (2 mL), concentrated to half volume in vacuo and
extracted with diethyl ether (3 × 5 mL). The combined organic layers were washed with water (2 mL),
brine (2 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column
chromatography (ethyl acetate/petroleum ether, 1:3) gave ethyl (2E)ꢀ3ꢀ(5'ꢀnitroꢀ2'ꢀ[Nꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (0.048 g, 99%) as a white solid. Mp 158–160 °C; Rf = 0.28
(petroleum ether/ethyl acetate = 2:1); IR (neat) 3255, 2980, 1700, 1640, 1527, 1344, 1166, 908, 757
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11
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43
44
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48
49
50
51
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53
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55
56
57
58
59
60
cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.34 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 4.27 (q, J = 7.1 Hz, 2H), 6.35
(d, J = 15.7 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 15.7 Hz, 1H), 7.65–7.72 (m, 4H), 8.16 (dd, J
13
= 9.0, 2.6 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 14.2 (CH3), 21.6 (CH3),
61.3 (CH2), 123.0 (CH), 123.1 (CH), 124.3 (CH), 125.5 (CH), 127.2 (2 × CH), 127.9 (C), 130.1 (2 ×
CH), 135.6 (C), 136.5 (CH), 140.6 (C), 144.7 (C), 144.9 (C), 165.9 (C); MS (ESI) m/z 413 (MNa+, 100);
HRMS (ESI) calcd for C18H18N2NaO6S (MNa+), 413.0778, found 413.0760.
Ethyl (2E)-3-(2'-[N-allyl-N-(p-toluenesulfonyl)amino]-5'-nitrophenyl)prop-2-enoate (9). The
reaction was carried out as described for the synthesis of methyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenoate (5a) using ethyl (2E)ꢀ3ꢀ(2'ꢀ[Nꢀ(pꢀtoluenesulfonyl)amino]ꢀ
5'ꢀnitrophenyl)propꢀ2ꢀenoate (0.020 g, 0.047 mmol). Purification by column chromatography (ethyl
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acetate/petroleum ether, 1:10) gave ethyl (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀ
nitrophenyl)propꢀ2ꢀenoate (9) (0.012 g, 55%) as a white solid. Mp 128–130 °C; Rf = 0.50 (petroleum
ether/ethyl acetate = 2:1); IR (neat) 2956, 1716, 1529, 1349, 1215, 908, 730 cm−1; 1H NMR (400 MHz,
1
2
3
4
5
6
7
8
CDCl3)
δ 1.35 (t, J = 7.1 Hz, 3H), 2.44 (s, 3H), 4.16 (br s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.98 (dd, J =
9
17.0, 1.1 Hz, 1H), 5.04 (dd, J = 10.0, 1.1 Hz, 1H), 5.72 (ddt, J = 17.0, 10.0, 6.8 Hz, 1H), 6.47 (d, J =
10
11
12
13
14
15
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17
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21
22
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27
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30
31
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59
60
16.1 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.80 (d, J =
13
16.1 Hz, 1H), 8.11 (dd, J = 8.8, 2.6 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H); C NMR (101 MHz, CDCl3)
δ
14.3 (CH3), 21.6 (CH3), 54.8 (CH2), 60.9 (CH2), 120.7 (CH2), 122.3 (CH), 122.9 (CH), 124.3 (CH),
127.9 (2 × CH), 129.9 (2 × CH), 131.1 (CH), 131.4 (CH), 134.9 (C), 137.6 (C), 138.0 (CH), 143.6 (C),
144.6 (C), 147.4 (C), 165.7 (C); MS (ESI) m/z 453 (MNa+, 100); HRMS (ESI) calcd for
C21H22N2NaO6S (MNa+), 453.1091, found 453.1073.
(2E)-3-(2'-[N-Allyl-N-(p-toluenesulfonyl)amino]-5'-nitrophenyl)prop-2-en-1-ol (6g). The reaction
was
carried
out
as
described
for
the
(6a)
synthesis
using
of
ethyl
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
(2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol
toluenesulfonyl)amino]ꢀ5’ꢀnitrophenyl)propꢀ2ꢀenoate (9) (0.143 g, 0.330 mmol). Purification by column
chromatography (ethyl acetate/petroleum ether, 1:2) gave (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀ
toluenesulfonyl)amino]ꢀ5’ꢀnitrophenyl)propꢀ2ꢀenꢀ1ꢀol (6g) (0.110 g, 85%) as a colorless oil. Rf = 0.18
(petroleum ether/ethyl acetate = 2:1); IR (neat) 3537, 2924, 1525, 1347, 1162, 748 cm−1; 1H NMR (400
MHz, CDCl3)
δ 2.05 (br s, 1H), 2.45 (s, 3H), 4.12 (br s, 2H), 4.33 (br d, J = 4.9 Hz, 2H), 4.92–5.04 (m,
2H), 5.69 (ddt, J = 17.0, 10.1, 6.8 Hz, 1H), 6.49 (dt, J = 16.0, 4.9 Hz, 1H), 6.85 (dt, J = 16.0, 1.6 Hz,
1H), 6.86 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.95 (dd, J = 8.8, 2.7
Hz, 1H), 8.43 (d, J = 2.7 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ 21.6 (CH3), 54.7 (CH2), 63.2 (CH2),
120.4 (CH2), 121.7 (CH), 122.1 (CH), 124.4 (CH), 127.9 (2 × CH), 129.8 (2 × CH), 130.5 (CH), 131.5
(CH), 134.1 (CH), 135.4 (C), 139.9 (C), 142.0 (C), 144.3 (C), 147.5 (C); MS (ESI) m/z 411 (MNa+,
100); HRMS (ESI) calcd for C19H20N2NaO5S (MNa+), 411.0985, found 411.0970.
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N-(p-Toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-benzo[b]azepine
(10a). (2E)ꢀ3ꢀ(2'ꢀ[NꢀAllylꢀNꢀ(pꢀtoluenesulfonyl)amino]phenyl)propꢀ2ꢀenꢀ1ꢀol (6a) (0.313 g, 0.911
mmol) was dissolved in dichloromethane (45 mL) and cooled to 0 °C under argon with stirring.
Trichloroacetonitrile (0.137 mL, 1.37 mmol) was added to the solution, followed by 1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (0.0685 mL, 0.460 mmol) and the reaction was allowed to warm to
room temperature over 2 h. The reaction mixture was filtered through a short pad of alumina (neutral,
Brockman V) with diethyl ether (150 mL) and concentrated in vacuo to yield the crude allylic
trichloroacetimidate as a yellow oil. This was used without further purification. The allylic
trichloroacetimidate was transferred to a dry Schlenk tube containing a stirrer bar and potassium
carbonate (0.0300 g, 5 mg/mL) to which pꢀxylene (6 mL) was then added. The tube was purged with
argon, sealed and heated to 160 °C for 24 h. The reaction mixture was allowed to cool to room
temperature and Grubbs 2nd generation catalyst (0.0391 g, 0.0460 mmol) and pꢀxylene (51 mL) were
added. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was concentrated in
vacuo and purified by column chromatography (diethyl ether/petroleum ether, 1:3) to give Nꢀ(pꢀ
1
2
3
4
5
6
7
8
9
10
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51
52
53
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58
59
60
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
(0.339 g, 81%) as a white solid. Mp 160–163 °C (decomposition); Rf = 0.28 (diethyl ether/petroleum
ether = 1:1); IR (neat) 3337, 2925, 1701, 1496, 1341, 1159, 906, 727 cm−1; 1H NMR (400 MHz, CDCl3)
δ
2.47 (s, 3H), 3.86 (br s, 1H), 4.66 (br s, 1H), 5.58 (br t, J = 7.7 Hz, 1H), 5.84 (br d, J = 9.0 Hz, 1H),
6.04 (br s, 1H), 6.82 (br s, 1H), 7.23 (td, J = 8.4, 1.6 Hz, 1H), 7.31 (td, J = 8.4, 1.3 Hz, 1H), 7.36 (d, J =
8.2 Hz, 2H), 7.42 (br d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 8.37 (br s, 1H); 13C NMR (101 MHz,
CDCl3)
δ 21.6 (CH3), 49.0 (CH2), 52.7 (CH), 92.5 (C), 125.8 (CH), 127.4 (2 × CH), 128.2 (CH), 129.3
(CH), 129.7 (CH), 130.0 (2 × CH), 130.8 (2 × CH), 137.7 (C), 138.1 (C), 139.2 (C), 144.2 (C), 161.4
(C); MS (ESI) m/z 481 (MNa+, 49); HRMS (ESI) calcd for C19H1735Cl3N2NaO3S (MNa+), 480.9918,
found 480.9904.
7-Methyl-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10b). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
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toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
1
2
3
4
5
6
7
8
using (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀmethylphenyl)propꢀ2ꢀenꢀ1ꢀol (6b) (0.170 g,
0.480 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:3) gave 7ꢀ
methylꢀNꢀ(pꢀtoluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀ
9
benzo[b]azepine (10b) (0.179 g, 80%) as a white solid. Mp 174–176 °C; Rf = 0.30 (diethyl
10
11
12
13
14
15
16
17
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ether/petroleum ether = 1:1); IR (neat) 3333, 2923, 1701, 1505, 1340, 1155, 1112, 909, 727 cm−1; H
NMR (400 MHz, CDCl3)
δ 2.33 (s, 3H), 2.47 (s, 3H), 3.82 (br s, 1H), 4.67 (br s, 1H), 5.53 (br t, J = 7.8
Hz, 1H), 5.84 (br d, J = 8.6 Hz, 1H), 6.04 (br s, 1H), 6.67 (br s, 1H), 7.02 (dd, J = 8.1, 1.4 Hz, 1H), 7.23
13
(br s, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 8.43 (br s, 1H); C NMR (101 MHz,
CDCl3)
δ 21.1 (CH3), 21.6 (CH3), 49.1 (CH2), 52.7 (CH), 92.5 (C), 125.8 (CH), 127.4 (2 × CH), 127.9
(CH), 130.0 (2 × CH), 130.2 (2 × CH), 130.9 (CH), 135.4 (C), 137.8 (C), 138.8 (C), 139.4 (C), 144.1
(C), 161.4 (C); MS (ESI) m/z 495 (MNa+, 48); HRMS (ESI) calcd for C20H1935Cl3N2NaO3S (MNa+),
495.0074, found 495.0053.
7-Methoxy-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10c). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
using (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀmethoxyphenyl)propꢀ2ꢀenꢀ1ꢀol (6c) (0.076 g,
0.20 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:3) gave 7ꢀ
methoxyꢀNꢀ(pꢀtoluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀ
benzo[b]azepine (10c) (0.079 g, 79%) as a white solid. Mp 190–195 °C (decomposition); Rf = 0.20
(diethyl ether/petroleum ether = 1:1); IR (neat) 3337, 2935, 1701, 1502, 1215, 1156, 749 cm−1; 1H NMR
(400 MHz, CDCl3)
δ 2.46 (s, 3H), 3.61–3.84 (m, 4H), 4.72 (br s, 1H), 5.51 (br t, J = 7.6 Hz, 1H), 5.85
(br s, 1H), 6.05 (br s, 1H), 6.64 (br s, 1H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.93 (br s, 1H), 7.35 (d, J = 8.2
Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 8.58 (br s, 1H); 13C NMR (101 MHz, CDCl3)
δ
21.6 (CH3), 49.2
(CH2), 52.9 (CH), 55.6 (CH3), 92.5 (C), 114.9 (CH), 125.5 (CH), 127.4 (2 × CH), 129.2 (CH), 130.0 (2
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× CH), 130.4 (CH), 131.2 (CH), 137.7 (C), 140.5 (C), 144.1 (C), 159.7 (2 × C), 161.4 (C); MS (ESI)
1
2
3
37
m/z 513 (MNa+, 51); HRMS (ESI) calcd for C20H1935Cl2 ClN2NaO4S (MNa+), 512.9994, found
4
5
6
512.9973.
7
8
9
7-Fluoro-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10d). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
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11
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15
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49
50
51
52
53
54
55
56
57
58
59
60
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
using (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀfluorophenyl)propꢀ2ꢀenꢀ1ꢀol (6d) (0.189 g,
0.520 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:3) gave 7ꢀ
fluoroꢀNꢀ(pꢀtoluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀ
benzo[b]azepine (10d) (0.204 g, 82%) as a white solid. Mp 181–183 °C; Rf = 0.25 (petroleum
ether/diethyl ether = 3:1); IR (neat) 3333, 3034, 1705, 1503, 1344, 1159, 907, 729 cm−1; 1H NMR (400
MHz, CDCl3) δ 2.47 (s, 3H), 3.81 (br s, 1H), 4.62 (br s, 1H), 5.52 (br t, J = 7.4 Hz, 1H), 5.85 (br s, 1H),
5.98 (br s, 1H), 6.81 (br s, 1H), 6.91 (td, J = 8.2, 2.9 Hz, 1H), 7.12 (br s, 1H), 7.36 (d, J = 8.2 Hz, 2H),
13
7.75 (d, J = 8.2 Hz, 2H), 8.40 (br s, 1H); C NMR (101 MHz, CDCl3)
δ 21.6 (CH3), 48.9 (CH2), 52.2
(CH), 92.4 (C), 116.1 (CH), 116.4 (CH), 125.4 (CH), 127.4 (2 × CH), 130.1 (3 × CH), 131.1 (CH),
133.9 (C), 137.3 (C), 141.6 (C), 144.4 (C), 161.4 (C), 162.1 (d, 1JCF = 250.6 Hz, C); MS (ESI) m/z 499
(MNa+, 49); HRMS (ESI) calcd for C19H1635Cl3FN2NaO3S (MNa+), 498.9823, found 498.9809.
8-Fluoro-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10e). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
using (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ4'ꢀfluorophenyl)propꢀ2ꢀenꢀ1ꢀol (6e) (0.222 g,
0.610 mmol). Purification by column chromatography (diethyl ether/petroleum ether, 1:3) gave 8ꢀ
fluoroꢀNꢀ(pꢀtoluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀ
benzo[b]azepine (10e) (0.269 g, 92%) as a white solid. Mp 147–149 °C; Rf = 0.28 (diethyl
ether/petroleum ether = 1:1); IR (neat) 3340, 2925, 1704, 1599, 1501, 1343, 1160, 909, 731 cm−1; H
1
NMR (400 MHz, CDCl3)
δ
2.48 (s, 3H), 3.86 (br d, J = 17.8 Hz, 1H), 4.62 (br d, J = 17.8 Hz, 1H), 5.56
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The Journal of Organic Chemistry
(br t, J = 7.8 Hz, 1H), 5.85 (ddd, J = 11.4, 4.5, 1.8 Hz, 1H), 6.02 (dd, J = 11.4, 7.8 Hz, 1H), 6.55 (br d,
3JHF = 8.0 Hz, 1H), 7.02 (td, J = 8.2, 2.6 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 8.2, 4JHF = 6.4
1
2
3
4
5
6
Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 8.24 (br s, 1H); 13C NMR (101 MHz, CDCl3)
δ 21.7 (CH3), 48.8
7
8
2
2
(CH2), 52.1 (CH), 92.4 (C), 115.6 (d, JCF = 22.9 Hz, CH), 116.2 (d, JCF = 21.0 Hz, CH), 125.6 (CH),
9
127.4 (2 × CH), 130.2 (2 × CH), 130.7 (CH), 132.0 (CH), 135.3 (d, 4JCF = 3.5 Hz, C), 137.2 (C), 139.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
1
(d, JCF = 9.9 Hz, C), 144.6 (C), 161.4 (C), 162.5 (d, JCF = 230.0 Hz, C); MS (ESI) m/z 499 (MNa+,
49); HRMS (ESI) calcd for C19H1635Cl3FN2NaO3S (MNa+), 498.9823, found 498.9804.
7-Chloro-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10f). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
using (2E)ꢀ3ꢀ(2'ꢀ[NꢀallylꢀNꢀ(pꢀtoluenesulfonyl)amino]ꢀ5'ꢀchlorophenyl)propꢀ2ꢀenꢀ1ꢀol (6f) (0.290 g,
0.770 mmol). The RCM step was heated to 60 °C for 24 h. Purification by column chromatography
(diethyl
ether/petroleum
ether,
1:3)
gave
7ꢀchloroꢀNꢀ(pꢀtoluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀ
trichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine (10f) (0.300 g, 79%) as a white solid.
Mp 158–160 °C; Rf = 0.25 (diethyl ether/petroleum ether = 1:1); IR (neat) 3341, 2925, 1705, 1495,
1343, 1159, 908, 730 cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.47 (s, 3H), 3.88 (br s, 1H), 4.60 (br s, 1H),
5.51 (br t, J = 7.6 Hz, 1H), 5.84 (br d, J = 9.0 Hz, 1H), 5.97 (br s, 1H), 6.79 (br s, 1H), 7.20 (dd, J = 8.4,
13
2.4 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.40 (br s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 8.26 (br s, 1H); C
NMR (101 MHz, CDCl3)
δ 21.7 (CH3), 48.9 (CH2), 52.1 (CH), 92.3 (C), 125.4 (CH), 127.4 (2 × CH),
129.6 (2 × CH), 130.2 (2 × CH), 131.0 (2 × CH), 134.9 (C), 136.5 (C), 137.2 (C), 141.0 (C), 144.5 (C),
161.4 (C); MS (ESI) m/z 515 (MNa+, 42); HRMS (ESI) calcd for C19H1635Cl4N2NaO3S (MNa+),
514.9528, found 514.9515.
7-Nitro-N-(p-toluenesulfonyl)-5-(2',2',2'-trichloromethylcarbonylamino)-2,5-dihydro-1H-
benzo[b]azepine (10g). The reaction was carried out as described for the synthesis of Nꢀ(pꢀ
toluenesulfonyl)ꢀ5ꢀ(2',2',2'ꢀtrichloromethylcarbonylamino)ꢀ2,5ꢀdihydroꢀ1Hꢀbenzo[b]azepine
(10a)
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