Convenient syntheses of 2,3,4,5-tetrahydro-1,4-benzothiazepines, -1,4-benzoxazepines and -1,4-benzodiazepines

Article abstract of DOI:10.1039/b111296c

4-Benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzothiazepines 5a,b, -1,4-benzoxazepine (12) and -1,4-benzodiazepine (20) are obtained via aluminium chloride mediated intramolecular cyclizations of N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)eth

Full text of DOI:10.1039/b111296c

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Convenient syntheses of 2,3,4,5-tetrahydro-1,4-benzothiazepines,
-1,4-benzoxazepines and -1,4-benzodiazepines
Alan R. Katritzky,* Yong-Jiang Xu and Hai-Ying He
1
Center for Heterocyclic Chemistry, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, USA
Received (in Cambridge, UK) 11th December 2001, Accepted 16th January 2002
First published as an Advance Article on the web 11th February 2002
4-Benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzothiazepines 5a,b, -1,4-benzoxazepine (12) and
-1,4-benzodiazepine (20) are obtained via aluminium chloride mediated intramolecular cyclizations of
N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)ethan-1-amines 4a,b, -2-(phenoxy)ethan-1-amine (11)
and -N-[2-(NЈ-methylanilino)ethyl]amine (19), respectively. Subsequent nucleophilic substitutions of the
benzotriazolyl group in 5a,b, 12 and 20 succeeded with Grignard reagents, triethyl phosphite, sodium boro-
hydride, and a silyl enol ether to give novel 2,3,4,5-tetrahydro-1,4-benzothiazepines 6–9, -1,4-benzoxazepines
13 and 14, and -1,4-benzodiazepines 21–23 in good yields.
Introduction
1,4-Benzothiazepine derivatives are of considerable interest
because of their biological activity as inhibitors of HIV-1
integrase, antitumor antibiotics, enzyme inhibitors, muscle
relaxants and anticonvulsants, sedatives and hypnotics.1 1,4-
Benzoxazepines are also of pharmacological interest due
to their activity on the central nervous system, as enzyme
inhibitors, or as analgesics and antitussives.1c,2 1,4-Benzodiaze-
pines are important building blocks in various biologically
active compounds, which show hypolipidermic, central nervous
system, anti-cancer, and anxiolytic activity.3 They are also
effective against Meniere’s disease.4 One recent paper has
shown imidazole-containing tetrahydrobenzodiazepines to be
effective as inhibitors of farnesyltransferase.5
Many synthetic procedures exist for the preparation of
2-oxo-, 3-oxo-, 5-oxo- and 3,5-dioxo-1,4-benzothiazepines6
and for dihydro-1,4-benzothiazepines.7 However, relatively few
publications relate to the preparation of 2,3,4,5-tetrahydro-1,4-
Scheme 1
benzothiazepines containing no carbonyl groups, and most
of these involve reduction of a carbonyl group containing
precursor such as (i) 5-oxo-1,4-benzothiazepine;1c,8a (ii) 3-oxo-
1,4-benzothiazepine;6b and (iii) 2,3-dihydro-7,8-dimethoxy-1,4-
benzothiazepines1d,7d (Scheme 1). We know of only one article
describing a direct ring synthesis of a tetrahydro-1,4-benzo-
thiazepine in 18% yield by condensing 2-BrMgSC6H4CH2-
NHMgBr with BrCH2CH2Br (Scheme 1, iv).8b
Similarly, most syntheses of 2,3,4,5-tetrahydro-1,4-benz-
oxazepines involve reduction of the carbonyl group(s) as in
(i) 5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine;1c (ii) 3-oxo-
2,3,4,5-tetrahydro-1,4-benzoxazepines;9a,b and (iii) 3,5-dioxo-
2,3,4,5-tetrahydro-1,4-benzoxazepine;9c,d or a double bond as
in (iv) 2,3-dihydro-1,4-benzothiazepine.2a (Scheme 2).
Syntheses of 1,4-benzodiazepines have been much studied.10
Most previous preparations of N-substituted-2,3,4,5-tetra-
hydro-1,4-benzodiazepines involved N-substitution of a pre-
existing 2,3,4,5-tetrahydro-1,4-benzodiazepine. For example,
4-acyl-2,3,4,5-tetrahydro-1,4-benzodiazepines were readily
prepared by the selective acylation of 2,3,4,5-tetrahydro-1,4-
benzodiazepines with esters, acid chlorides, carboxylic acids or
sulfonyl chlorides. Reactions of 4-acyl-2,3,4,5-tetrahydro-1,4-
benzodiazepines with 5-formylimidazole and NaBH(OAc)3
Scheme 2
also produced via selective Boc protection at the 4-position,
followed by acylation, deprotection and alkylation.5 1-Benzyl-
4-methyl-2,3,4,5-tetrahydro-1,4-benzodiazepine was previously
gave
1-alkyl-4-acyl-2,3,4,5-tetrahydro-1,4-benzodiazepines.
were
1-Acyl-4-alkyl-2,3,4,5-tetrahydro-1,4-benzodiazepines
592
J. Chem. Soc., Perkin Trans. 1, 2002, 592–598
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b111296c

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BtCH2N and ArCH2N fragments, respectively. The correct
numbers of quaternary carbons for 5a,b, determined by
Attached Proton Test (APT) spectra, further support their
structures.
The benzotriazole moieties in 4-benzotriazolylmethyl-2,3,4,5-
tetrahydro-1,4-benzothiazepines 5a,b were easily substituted by
nucleophiles because of the equilibrium between X and 5a,b.
Indeed, Grignard reagents replaced the Bt moiety smoothly at
room temperature. Treatment of 5a,b with various Grignard
reagents in THF gave 2,3,4,5-tetrahydro-1,4-benzothiazepines
6a–f in 84–97% yields. With the help of 2 equiv. of ZnBr2 to
coordinate the benzotriazole anion in X, the iminium cations
were trapped by P(OEt)3 to give the derivatives 7a and 7b
in 78% and 77% yield, respectively. Using BF3ؒEt2O instead
of ZnBr2 as the Lewis acid, an analogous reaction of 5a with
1-phenyl-1-(trimethylsilyloxy)ethylene resulted in 3-[2,3,4,5-
tetrahydro-1,4-benzothiazepin-4-yl]-1-phenylpropan-1-one 8 in
48% yield.
Scheme 3 i) R1CO2Et, R1COCl, R1CO2H or R1SO2Cl (X = CO
or SO2); ii) 5-formylimidazole, NaBH(OAc)3; iii) (t-BuOCO)2O;
iv) 1-naphthoyl chloride; v) TFA; vi) same as ii).
We also successfully reduced the Bt moiety with NaBH4.
Treatment of 5a with sodium borohydride in dry THF
furnished the 4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine–
borane complex (9) (Scheme 4). The NMR of 9 showed
restricted rotation as compared to other compounds such as
obtained by the reduction of the corresponding benzoyl-
derivative with LiAlH4 11 (see Scheme 3).
1
6 and 8. All peaks in the aliphatic region of the H NMR
We now report a direct, high-yielding, convenient approach
to 2,3,4,5-tetrahydro-1,4-benzothiazepines, -1,4-benzoxaze-
pines and -1,4-benzodiazepines not involving reduction of a
corresponding carbonyl or unsaturated derivative. 2,3,4,5-
Tetrahydro-1,4-benzothiazepines 6–9, -1,4-benzoxazepines 13
and 14 and -1,4-benzodiazepines 21–23 were obtained in good
yields via the nucleophilic substitutions of 4-benzotriazolyl-
methyl-2,3,4,5-tetrahydro-1,4-benzothiazepines 5a,b, -1,4-benz-
oxazepine 12 and -1,4-benzodiazepine 20. Intermediates 5a,b,
12 and 20 are produced from the intramolecular cyclizations of
N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)ethan-
1-amines 4a,b, -2-(phenoxy)ethan-1-amine 11 and -N-[2-(NЈ-
methylanilino)ethyl]amine 19, respectively.
spectrum were low and broad. All of them became sharper
when the 1H NMR spectrum was recorded at 60 ЊC rather than
at 25 ЊC. The singlet (at 2.45 ppm) ascribed to the NCH3 group
became sharp and distinct. The signal of NCH2Ar, which was a
broad singlet at 25 ЊC, appeared as a distinct doublet (at 4.56
ppm). In the aliphatic region of the 13C NMR spectrum, the
peaks which were low and broad at 25 ЊC, were well shaped at
60 ЊC except for the peak at 46.3 ppm.
We successfully extended this methodology to synthesize
2,3,4,5-tetrahydro-1,4-benzoxazepines.
N,N-Bis(1H-1,2,3-
benzotriazol-1-ylmethyl)-2-(phenoxy)ethan-1-amine 11 and
4-benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine
12 were obtained in 78% and 86% yields, respectively, from
2-phenoxyethylamine 10 using a procedure similar to that
discussed for the syntheses of 4 and 5 (Scheme 5). Pure 11 was
also obtained after a similar work-up procedure. Compound 12
was a mixture of Bt1 and Bt2 isomers in which the Bt1 isomer
predominated. We provide the 1H and 13C NMR data of the Bt1
isomer and the ratio of the two isomers. The cyclized product
12 is well supported by NMR spectra and microanalysis.
When 4-benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benz-
oxazepine (12) was used as the starting material, 2,3,4,5-
tetrahydro-1,4-benzoxazepine derivatives 13a,b and diethyl
2,3,4,5-tetrahydro-1,4-benzoxazepin-4-ylmethylphosphonate
(14) were obtained via procedures similar to those described for
the syntheses of compounds 6 and 7, respectively.
This methodology also works very well in the preparation
of 2,3,4,5-tetrahydro-1,4-benzodiazepine. N-Methyl-N-phenyl-
1,2-ethanediamine 18 was prepared in 90% yield from N-methyl-
aniline 15 as reported via reaction of N-methylbenzenaminium
chloride (16) with oxazolidin-2-one (17).14
Reaction of diamine 18 with 2 equiv. of benzotriazole and
2 equiv. of formaldehyde produced N,N-bis(1H-1,2,3-benzo-
triazol-1-ylmethyl)-N-[2-(NЈ-methylanilino)ethyl]amine 19 in
92% yield as a sole Bt1 isomer. Treatment of 19 with 3 equiv. of
AlCl3 removed only one benzotriazolyl moiety to form
4-benzotriazolylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-1,4-
benzodiazepine 20 via the intramolecular Friedel–Crafts
reaction similar to its oxygen and sulfur analogs. Compound
20 was obtained as a mixture of Bt1 and Bt2 isomers in a 4.4 : 1
ratio and was used directly for the subsequent reactions.
Nucleophilic substitutions of 20 with 1.5 equiv. of a Grignard
Results and discussion
The Mannich condensation of 2-(arylsulfanyl)ethylamine
1a,b,12 benzotriazole (2) and formaldehyde (3) gave N,N-bis-
(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)ethan-1-amines
4a,b in 85% and 81% yields, respectively. When a mixture
of methanol–water was used as the solvent, compounds
4a,b were separated out, essentially pure (determined by NMR
and microanalysis) after washing, and were used directly for
the subsequent reactions.
When compounds 4a,b were treated with 3 equiv. of AlCl3
in CH2Cl2, one of the benzotriazole moieties was removed to
form the cyclization products 4-benzotriazolylmethyl-2,3,4,5-
tetrahydro-1,4-benzothiazepines 5a,b in 86% and 91% yields,
respectively (Scheme 1). Although starting materials 4a,b were
Bt1 (benzotriazol-1-yl) isomers only, compounds 5a,b were each
obtained as a mixture of Bt1 and Bt2 (benzotriazol-2-yl) isomers
in which the Bt1 isomer predominated. This indicated that there
was an equilibrium between the cyclization products 5a,b and X
(Scheme 4). We report the 1H and 13C NMR data of the major
Bt1 isomers and the ratio of Bt1 and Bt2 isomers determined by
1H NMR spectroscopy (see Experimental section). According
to our previous work,13 Bt1 and Bt2 are both good leaving
groups, and removal of benzotriazolyl groups from Bt1 and Bt2
isomers in the presence of a Lewis acid results in the same
iminium cation X. Therefore, compounds 5a,b were each used
as mixtures of two isomers for the subsequent reactions. Com-
1
pounds 4a,b and 5a,b were characterized by their H and 13C
NMR spectra and microanalysis. The aliphatic region of the 1H
NMR spectra of 4a,b showed one singlet ascribed to two
BtCH2N (at 5.65 ppm). In the spectra of 5a,b, two singlets were
observed (at ca. 5.40 ppm and 4.20 ppm) which were ascribed to
reagent (p-ClC H MgBr, CH ᎐CHMgBr, or PhCH MgCl) in
᎐
6
4
2
2
THF gave 1-methyl-4-substituted-2,3,4,5-tetrahydro-1H-1,4-
benzodiazepines 21a–c in 68–76% yields. Compounds 21a–c
were fully characterized by 1H and 13C NMR spectra and
J. Chem. Soc., Perkin Trans. 1, 2002, 592–598
593

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Scheme 4 i) Benzotriazole (BtH), HCHO; ii) AlCl3; iii) Grignard reagents; iv) P(OEt)3, ZnBr2; v) BF3ؒEt2O,
; vi) NaBH4.
Scheme 5 i) BtH, HCHO; ii) AlCl3; iii) RMgBr; iv) P(OEt)3, ZnBr2.
microanalysis or HRMS results. Treatment of 20 with 1.2
equiv. of triethyl phosphite in the presence of ZnBr2 furnished
Scheme 6 i) HCl–EtOAc (1 M); ii) oxazolidin-2-one (17), neat; iii) 1 M
NaOH; iv) BtH, HCHO; v) Grignard reagents; vi) P(OEt)3, ZnBr2; vii)
NaBH4.
diethyl (1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-
ylmethyl)phosphonate (22) in 69% yield (Scheme 6).
Reaction of 20 with 2 equiv. of NaBH4 at room temperature
replaced the benzotriazolyl group with hydrogen to afford 1,4-
dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (23) in 73%
yield. The methylene protons, the 5-position, in 23 appear at
4.31 and 3.79 ppm in 1NMR spectra as an AB system with 13.6
Hz coupling constants.
ethyl]amine are followed by nucleophilic substitutions of the
remaining benzotriazolyl groups in the cyclized products with
Grignard reagents, triethyl phosphite, sodium borohydride,
and a silyl enol ether.
The methodology discussed in this paper allows the substitu-
ents at the 4-position of 1,4-benzothiazepines, 1,4-benzoxaze-
pines and 1,4-benzodiazepines to be varied easily. The nature
and orientation of substitutents at the other positions are
derived from the starting materials.
Conclusion
In summary, we have developed efficient and convenient
methods for the syntheses of diverse 4-substituted 2,3,4,5-
tetrahydro-1,4-benzothiazepines, -1,4-benzoxazepines and
-1,4-benzodiazepines. Intramolecular cyclizations of N,N-bis-
(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(arylthio)ethan-1-amines,
-2-(phenoxy)ethan-1-amine and -N-[2-(NЈ-methylanilino)-
Experimental
THF was distilled from sodium–benzophenone prior to use. All
mps were determined using a Bristoline hot-stage microscope
594
J. Chem. Soc., Perkin Trans. 1, 2002, 592–598

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1
and are uncorrected. H (300 MHz) and 13C (75 MHz) NMR
129.5, 128.5, 127.4, 127.1, 124.0, 119.1, 110.3, 67.3, 58.4, 55.9,
spectra were recorded on a 300 NMR spectrometer in CDCl3
(with TMS for 1H and CDCl3 for 13C as the internal reference);
J values are given in Hz. All of the reactions were carried out
under N2. Column chromatography was performed on silica gel
(230–400 mesh).
32.1, 21.9.
4-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 6a
To a solution of 5a (0.30 g, 1 mmol) in anhydrous THF (15 mL)
at 0 ЊC, 4-methoxyphenylmagnesium bromide (3 ml, 1.5 mmol,
0.5 M in THF) was added dropwise. The solution was stirred
for 2 h at 0 ЊC, and for 10 h at room temperature. Then the
solvent was evaporated. The residue was dissolved in Et2O,
washed with 20% NH4Cl, 2 M NaOH and brine. The organic
solution was dried over anhydrous Na2SO4. After removal of
the solvent in vacuo, the residue was purified by column
chromatography (eluent: EtOAc : hexanes : Et3N = 1 : 7 : 0.05)
and recrystallized from Et2O to give the product as colorless
prisms (0.25 g, 88%); mp 85–86 ЊC (Found: C, 71.59; H, 6.98; N,
4.89. C17H19NOS requires C, 71.54; H, 6.71; N, 4.91%); δH (300
MHz, CDCl3, Me4Si) 7.55 (1H, t, J 4.7), 7.22–7.15 (4H, m),
7.02 (1H, t, J 5.0), 6.86 (2H, d, J 8.2), 4.11 (2H, s, PhCH2N),
3.81 (3H, s, CH3O), 3.49 (2H, s, 4-CH3OPhCH2N), 3.33–3.30
(2H, m), 2.81–2.78 (2H, m); δC (75 MHz, CDCl3) 158.6, 143.2,
137.1, 132.2, 130.9, 130.7, 129.9, 127.2(2), 113.6, 59.2, 57.7,
56.0, 55.2, 30.3.
N,N-Bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-(phenylthio)ethan-
1-amine 4a
2-(Phenylsulfanyl)ethylamine (1, 1.53 g, 10 mmol) and benzo-
triazole (2, 2.39 g, 20 mmol) were dissolved in methanol–water
(40 : 10 mL). Formaldehyde (3, 1.62 g, 20 mmol, 37% aqueous
solution) was then slowly added to the solution. The reaction
mixture was stirred for 12 h at room temperature. The precipi-
tate was filtered off, washed with cold Et2O, and dried to give
the product as a white powder (3.74 g, 90%); mp 89–90 ЊC
(colorless plates from CH2Cl2–Et2O) (Found: C, 63.56; H, 5.08;
N, 23.79. C22H21N7S requires C, 63.59; H, 5.09; N, 23.60%);
δH (300 MHz, CDCl3, Me4Si) 8.09 (2H, d, J 8.2), 7.64 (2H, d,
J 8.5), 7.52 (2H, t, J 8.0), 7.41 (2H, t, J 8.0), 7.27–7.21 (5H, m),
5.64 (4H, s, 2 BtCH2N), 3.19 (2H, t, J 6.7), 3.08 (2H, t, J 6.7);
δC (75 MHz, CDCl3) 146.0, 134.9, 133.0, 129.4, 129.1, 128.0,
126.4, 124.3, 120.0, 109.8, 64.4, 50.1, 32.1.
4-(3-Phenylprop-2-yn-1-yl)-2,3,4,5-tetrahydro-1,4-benzothiaze-
pine 6b
N,N-Bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-[(2-methyl-
phenyl)thio]ethan-1-amine 4b
Following the same procedure as 6a using (phenylethynyl)-
magnesium bromide (1.5 ml, 1.0 M in THF) as Grignard
reagent, compound 6b (0.25 g, 90%) was obtained as a yellow
oil; δH (300 MHz, CDCl3, Me4Si) 7.54 (1H, dd, J 7.3, 1.5), 7.46–
7.43 (2H, m), 7.35–7.30 (4H, m), 7.25–7.17 (2H, m), 4.24 (2H, s,
PhCH2N), 3.53 (2H, s, CCH2N), 3.44–3.41 (2H, m), 2.87–2.83
(2H, m); δC (75 MHz, CDCl3) 142.4, 137.0, 132.3, 131.6(2),
130.8, 128.2(2), 128.1, 127.5, 127.4, 122.9, 85.2, 84.9, 59.5, 57.9,
44.5, 31.2. HRMS calcd for C18H18NS (M ϩ 1): 280.1160.
Found: 280.1148.
Following the same procedure as 4a using 2-[(2-methylphenyl)-
thio]ethylamine as starting material, the title compound (3.78 g,
88%) was obtained as colorless plates; mp 124–125 ЊC (from
CH2Cl2–Et2O) (Found: C, 64.32; H, 5.65; N, 23.16. C23H23N7S
requires C, 64.31; H, 5.40; N, 22.83%); δH (300 MHz, CDCl3,
Me4Si) 8.09 (2H, d, J 8.2), 7.66 (2H, d, J 8.2), 7.51 (2H, t, J 7.3),
7.41 (2H, t, J 7.6), 7.14–7.07 (4H, m), 5.65 (4H, s, 2 BtCH2N),
3.21 (2H, t, J 6.7), 3.06 (2H, t, J 7.0), 2.26 (3H, s); δC (75 MHz,
CDCl3) 146.1, 137.8, 134.3, 133.1, 130.3, 128.2, 128.0, 126.5,
126.1, 124.2, 120.0, 109.8, 64.4, 50.1, 31.3, 20.3.
4-(4-Chlorobenzyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 6c
4-Benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
5a
Following the same procedure as 6a using 4-chlorophenyl-
magnesium bromide (1.5 ml, 1.0 M in ether) as Grignard reagent,
compound 6c (0.27 g, 93%) was purified by recrystallization;
mp 83–84 ЊC (colorless prisms from CH2Cl2) (Found: C, 66.28;
H, 5.64; N, 4.61. C16H16ClNS requires C, 66.31; H, 5.56; N,
4.83%); δH (300 MHz, CDCl3, Me4Si) 7.57–7.54 (1H, m), 7.30–
7.21 (4H, m), 7.17–7.14 (2H, m), 6.97–6.94 (1H, m), 4.09 (2H, s,
PhCH2N), 3.50 (2H, s, 4-ClPhCH2N), 3.33–3.30 (2H, m), 2.79–
2.76 (2H, m); δC (75 MHz, CDCl3) 142.9, 137.3, 137.1, 132.6,
132.3, 130.8, 130.0, 128.4, 127.3, 127.2, 59.0, 58.0, 55.8, 30.3.
A mixture of 4a (3.35 g, 8 mmol) and AlCl3 (3.2 g, 24 mmol) in
dry CH2Cl2 (60 mL) was stirred at 25 ЊC for 12 h. Then 2 M
NaOH solution (40 mL) was added to quench the reaction. The
aqueous phase was extracted with CH2Cl2. The combined
organic layer was washed with 1 M NaOH, brine, and dried
over anhydrous Na2SO4. Removal of the solvent in vacuo gave
the crude product, which was purified by column chrom-
atography (eluent: EtOAc : hexanes = 1 : 4–1 : 2) to give a
mixture of Bt1 and Bt2 isomers in a 5.2 : 1 ratio (1.92 g, 81%);
mp 117–118 ЊC (from EtOAc–hexanes) (Found: C, 64.72; H,
5.50; N, 19.07. C16H16N4S requires C, 64.84; H, 5.44; N,
18.90%); δH (300 MHz, CDCl3, Me4Si) 8.08 (1H, d, J 8.2), 7.64
(1H, d, J 8.2), 7.56 (1H, d, J 6.7), 7.50 (1H, t, J 7.0), 7.40 (1H, d,
J 7.9), 7.26–7.15 (3H, m), 5.40 (2H, s, BtCH2N), 4.20 (2H, s,
PhCH2N), 3.42–3.39 (2H, m), 2.86–2.84 (2H, m); δC (75 MHz,
CDCl3) 146.2, 142.2, 136.7, 132.9, 132.7, 132.5, 130.7, 127.8,
127.4, 124.0, 120.0, 110.2, 66.9, 57.9, 56.5, 32.1.
4-Pentyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 6d
Following the same procedure as 6a using butylmagnesium
bromide (0.75 ml, 2.0 M in ether) as Grignard reagent, com-
pound 6d (0.21 g, 89%) was obtained as a yellowish oil (Found:
C, 71.34; H, 8.71; N, 6.32. C14H21NS requires C, 71.44; H, 8.99;
N, 5.95%); δH (300 MHz, CDCl3, Me4Si) 7.53 (1H, d, J 7.0),
7.23–7.11 (3H, m), 4.13 (2H, s, PhCH2N), 3.33–3.30 (2H, m),
2.76–2.73 (2H, m), 2.35 (2H, t, J 7.4), 1.54–1.45 (2H, m), 1.34–
1.22 (4H, m), 0.88 (3H, t, J 6.7); δC (75 MHz, CDCl3) 143.1,
136.9, 132.2, 130.6, 127.2, 127.1, 59.4, 58.1, 52.2, 30.0, 29.5,
27.0, 22.5, 14.0.
4-Benzotriazolylmethyl-9-methyl-2,3,4,5-tetrahydro-1,4-benzo-
thiazepine 5b
Following the same procedure as for 5a using 4b as the starting
material, compound 5b (2.03 g, 82%) was obtained as a mixture
of Bt1 and Bt2 isomers in a 6.1 : 1 ratio; mp 86–87 ЊC (colorless
prisms from EtOAc–hexanes) (Found: C, 65.70; H, 5.99.
C17H18N4S requires C, 65.78; H, 5.84%); δH (300 MHz, CDCl3,
Me4Si) 8.09 (1H, d, J 8.2), 7.65 (1H, d, J 8.2), 7.50 (1H, t, J 7.0),
7.39 (1H, t, J 7.3), 7.13 (3H, br s), 5.42 (2H, s, BtCH2N), 4.23
(2H, s, ArCH2N), 3.36–3.34 (2H, m), 2.84–2.81 (2H, m), 2.47
(3H, s); δC (75 MHz, CDCl3) 146.2, 142.5, 140.2, 136.7, 133.0,
4-(4-Methoxybenzyl)-9-methyl-2,3,4,5-tetrahydro-1,4-benzo-
thiazepine 6e
Following a similar procedure as for 6a using 5b instead of 5a,
compound 6e (0.26 g, 87%) was purified by recrystallization;
mp 71–72 ЊC (colorless prisms from Et2O) (Found: C, 71.99; H,
7.41; N, 4.66. C18H21NOS requires C, 72.20; H, 7.07; N, 4.68%);
δH (300 MHz, CDCl3, Me4Si) 7.21 (2H, d, J 8.5), 7.10–7.02 (2H,
J. Chem. Soc., Perkin Trans. 1, 2002, 592–598
595

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m), 6.87–6.83 (3H, m), 4.11 (2H, s, PhCH2N), 3.81 (3H, s), 3.51
(2H, s, 4-CH3OPhCH2N), 3.27–3.24 (2H, m), 2.79–2.76 (2H,
m), 2.47 (3H, s); δC (75 MHz, CDCl3) 158.5, 143.2, 139.4, 137.1,
130.8, 129.8, 128.8, 128.7, 126.4, 113.5, 59.5, 57.1, 56.4, 55.1,
30.4, 21.9.
128.0, 127.5, 127.4, 59.5, 58.2, 47.0, 37.0, 30.1. HRMS calcd for
C18H20NOS (M ϩ 1): 298.1266. Found: 298.1264.
4-Methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine–borane
complex 9
A mixture of 5a (0.60 g, 2 mmol) and NaBH4 (0.15 g, 4 mmol)
was stirred at 25 ЊC for 12 h in dry THF (20 mL). After evap-
oration of the solvent in vacuo, the residue was dissolved in
EtOAc. The organic phase was washed with 1 M NaOH, brine,
and dried over anhydrous Na2SO4. After removal of the EtOAc
in vacuo, the residue was purified by column chromatography
(eluent: EtOAc : hexanes : Et3N = 1 : 9 : 0.05) to afford 9 (0.13 g,
67%); mp 111–112 ЊC (colorless prisms from EtOAc–hexanes)
(Found: C, 62.23; H, 8.68; N, 7.26. C10H16NSB requires C,
62.19; H, 8.35; N, 7.25%); δH (300 MHz, CDCl3, Me4Si) 7.52–
7.48 (1H, m), 7.27–7.26 (3H, m), 4.56 (1H, d, J 13.8), 4.16 (1H,
d, J 13.8), 3.42 (1H, dd, J 11.7, 11.4), 3.24–3.18 (1H, m), 3.14–
3.09 (1H, m), 2.94 (1H, dd, J 13.2, 10.3), 2.45 (3H, s, NCH3),
2.40–1.21 (3H, br s, BH3); δC (75 MHz, CDCl3) 137.5, 136.1
(br), 133.2, 132.7, 129.7, 128.3, 66.0, 63.7 (br), 48.0 (br), 28.4.
9-Methyl-4-pentyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 6f
Following a similar procedure as for 6e using butylmagnesium
bromide (0.75 ml, 2.0 M in ether) as Grignard reagent, com-
pound 6f (0.22 g, 88%) was obtained as a yellowish oil (Found:
C, 72.44; H, 9.67; N, 5.86. C15H23NS requires C, 72.23; H, 9.29;
N, 5.62%); δH (300 MHz, CDCl3, Me4Si) 7.26 (3H, br s), 4.12
(2H, s, ArCH2N), 3.29–3.26 (2H, m), 2.75–2.73 (2H, m), 2.46
(3H, s), 2.37 (2H, t, J 7.4), 1.56–1.46 (2H, m), 1.36–1.22 (4H,
m), 0.89 (3H, t, J 7.1); δC (75 MHz, CDCl3) 143.3, 139.6, 137.0,
128.9, 128.6, 126.6, 59.8, 57.7, 52.9, 30.3, 29.6, 27.2, 22.6, 22.0,
14.1.
Diethyl 2,3,4,5-tetrahydro-1,4-benzothiazepin-4-ylmethylphos-
phonate 7a
To a solution of 5a (0.30 g, 1.0 mmol) in dry THF (15 mL) at
0 ЊC, ZnBr2 (0.45 g, 2 mmol) was added. The solution was
stirred for 20 min before triethyl phosphite (0.2 g, 1.2 mmol)
was added dropwise. After stirring at room temperature for 10
h, the solvent was evaporated. The residue was dissolved in
EtOAc, and the solution was washed with 2 M NaOH and
water. The organic layer was dried over Na2SO4. After removal
of the solvent in vacuo, the residue was purified by column
chromatography (eluent: EtOAc : hexanes = 1 : 3–2 : 1) to give
7a (0.25 g, 79%) as a yellowish oil (Found: C, 53.01; H, 7.02; N,
4.82. C14H22NO3PS requires C, 53.32; H, 7.03; N, 4.44%);
δH (300 MHz, CDCl3, Me4Si) 7.56 (1H, dd, J 7.0, 1.5), 7.32 (1H,
dd, J 7.0, 1.5), 7.24–7.15 (2H, m), 4.28 (2H, s, PhCH2N), 4.15
(4H, q, J 7.4, 2OCH2CH3), 3.50–3.47 (2H, m), 2.75–2.72 (2H,
m), 2.72 (2H, s, PCH2N), 1.33 (6H, t, J 7.0); δC (75 MHz,
CDCl3) 142.3, 137.0, 132.5, 131.3, 127.4, 127.3, 62.0 (d, J 6.9),
60.5 (d, J 7.4), 59.4 (d, J 8.6), 46.9 (d, J 168.9), 29.8, 16.4 (d,
J 5.7).
N,N-Bis(1H-1,2,3-benzotriazol-1-ylmethyl)-2-phenoxyethan-1-
amine 11
Following the same procedure as for 4a using 2-phenoxy-
ethylamine 10 instead of 1, the title compound (3.11 g, 78%)
was obtained as a white solid; mp 94–95 ЊC (colorless prisms
from MeOH) (Found: C, 66.27; H, 5.29; N, 24.77. C22H21N7O
requires C, 66.15; H, 5.30; N, 24.54%); δH (300 MHz, CDCl3,
Me4Si) 8.09 (2H, d, J 8.2), 7.73 (2H, d, J 8.2), 7.48 (2H, t, J 7.1),
7.40 (2H, d, J 7.5), 7.27 (2H, t, J 8.2), 6.97 (1H, t, J 7.3), 6.82
(2H, d, J 7.9), 5.77 (4H, s, 2 BtCH2N), 4.10 (2H, t, J 4.8), 3.83
(2H, t, J 4.8); δC (75 MHz, CDCl3) 158.0, 146.1, 133.2, 129.6,
127.9, 124.2, 121.3, 119.9, 114.3, 110.1, 66.9, 64.8, 49.7.
4-Benzotriazolylmethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine 12
Following the same procedure as 5a using 11 instead of 4a,
compound 12 was obtained as a mixture of Bt1 and Bt2 isomers
in a 5.6 : 1 ratio (1.48 g, 66%); mp 67–69 ЊC (colorless prisms
from EtOAc–hexanes) (Found: C, 68.52; H, 5.80; N, 20.20.
C16H16N4O requires C, 68.55; H, 5.75; N, 19.99%); δH (300
MHz, CDCl3, Me4Si) 8.07 (1H, d, J 7.9), 7.65 (1H, d, J 7.9),
7.50 (1H, t, J 7.6), 7.39 (1H, t, J 7.6), 7.18 (2H, dd, J 7.6, 7.3),
7.09 (2H, dd, J 7.3, 6.4), 5.51 (2H, s, BtCH2N), 4.10 (2H, t,
J 4.1), 3.97 (2H, s, PhCH2N), 3.20–3.18 (2H, m); δC (75 MHz,
CDCl3) 159.6, 145.9, 133.2, 130.6, 130.3, 128.9, 127.5, 124.0,
123.5, 120.8, 119.9, 110.1, 70.8, 68.1, 56.7, 55.9.
Diethyl [9-methyl-2,3,4,5-dihydro-1,4-benzothiazepin-4-
ylmethyl]phosphonate 7b
Following a similar procedure as for 7a using 5b instead of 5a,
compound 7b (0.25 g, 76%) was obtained as a yellowish oil;
δH (300 MHz, CDCl3, Me4Si) 7.20–7.17 (1H, m), 7.15–7.10 (2H,
m), 4.34 (2H, s, ArCH2N), 4.16 (4H, q, J 7.3), 3.50–3.48 (2H,
m), 2.83 (2H, d, J 10.8), 2.76–2.73 (2H, m), 2.46 (3H, s), 1.33
(6H, t, J 7.0); δC (75 MHz, CDCl3) 141.4, 139.9, 136.9, 129.4
(2), 126.7, 62.0 (d, J 6.3), 60.6 (d, J 8.5), 58.5 (d, J 8.4), 47.0 (d,
J 167.4), 29.6, 21.8, 16.4 (d, J 5.3). HRMS calcd for
C15H25NO3SP (M ϩ 1): 330.1293. Found: 330.1263.
4-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine 13a
Following a similar procedure as 6a using 12 instead of 5a as
starting material, compound 13a (0.20 g, 74%) was purified by
recrystallization; mp 80–82 ЊC (colorless needles from Et2O)
(Found: C, 75.63; H, 7.39; N, 5.16. C17H19NO2 requires C,
75.81; H, 7.11; N, 5.20%); δH (300 MHz, CDCl3, Me4Si) 7.24–
7.16 (3H, m), 7.03–6.98 (3H, m), 6.87 (2H, d, J 8.5), 4.09–4.06
(2H, m), 3.81 (3H, s), 3.80 (2H, s, PhCH2N), 3.58 (2H, s,
4-CH3OPhCH2N), 3.09–3.06 (2H, m); δC (75 MHz, CDCl3)
160.0, 158.7, 131.9, 130.8, 130.6, 130.1, 128.5, 123.3, 120.7,
113.6, 70.2, 58.1, 58.0, 57.9, 55.2.
3-[2,3-Dihydro-1,4-benzothiazepin-4-yl]-1-phenylpropan-1-one 8
BF3ؒEt2O (0.43 g, 3 mmol) was added dropwise to a stirred
solution of the compound 5a (0.30 g, 1.0 mmol) in CH2Cl2
(15 mL) at 0 ЊC. The yellow mixture was stirred for 10 min
before the addition of 1-phenyl-1-(trimethylsilyloxy)ethylene
(0.29 g, 1.5 mmol). The mixture was stirred at 0 ЊC for 2 h and
overnight at 25 ЊC. The reaction was quenched with water, and
washed with 2 M NaOH and water. The organic layer was dried
over MgSO4. After removal of CH2Cl2 in vacuo, the residue was
purified by column chromatography (eluent: EtOAc : hexanes =
1 : 8–1 : 5) to give the product 8 (0.13 g, 44%) as a yellowish oil;
δH (300 MHz, CDCl3, Me4Si) 7.96 (2H, d, J 7.3), 7.57–7.53 (2H,
m), 7.47 (2H, dd, J 7.8, 7.3), 7.27–7.25 (1H, m), 7.23–7.14 (2H,
m), 4.19 (2H, s, PhCH2N), 3.38–3.35 (2H, m), 3.18 (2H, t,
J 7.1), 2.86 (2H, t, J 7.1), 2.81–2.76 (2H, m); δC (75 MHz,
CDCl3) 199.1, 142.9, 136.9, 136.8, 133.1, 132.4, 130.6, 128.6,
4-(4-Chlorobenzyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine 13b
Following the same procedure as 13a using 4-chlorophenyl-
magnesium bromide (1.5 ml, 1.0 M in ether) as Grignard reagent,
compound 13b (0.23 g, 84%) was obtained as a yellowish oil
(Found: C, 70.19; H, 6.21; N, 5.45. C16H16ClNO requires C,
70.20; H, 5.89; N, 5.12%); δH (300 MHz, CDCl3, Me4Si)
7.31–7.23 (4H, m), 7.20 (1H, dd, J 8.1, 4.1), 7.03 (1H, d, J 7.9),
6.99 (2H, d, J 4.1), 4.07 (2H, dd, J 4.3, 4.1), 3.78 (2H, s), 3.60
596
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(2H, s), 3.08 (2H, dd, J 4.3, 4.0); δC (75 MHz, CDCl3) 160.0,
137.2, 132.8, 131.6, 130.6, 130.2, 128.6, 128.5, 123.4, 120.8,
70.1, 58.1, 58.0, 57.9.
5.14 (2H, m), 3.76 (2H, s), 3.08 (2H, d, J 6.1), 2.98–2.89 (4H,
m), 2.88 (3H, s); δC (75 MHz, CDCl3) 152.4, 135.9, 130.8, 130.2,
127.8, 120.5, 117.6, 115.4, 58.9, 58.0, 56.3, 54.4, 42.8.
Diethyl 2,3,4,5-tetrahydro-1,4-benzoxazepin-4-ylmethylphos-
phonate 14
1-Methyl-4-phenylethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiaze-
pine (21c)
Following a similar procedure as for 7a using 12 instead of 5a
as starting material, compound 14 (0.21 g, 70%) was obtained
as a yellowish sticky oil (Found: C, 55.77; H, 7.76; N, 4.83.
C14H22NO4P requires C, 56.18; H, 7.41; N, 4.68%); δH (300
MHz, CDCl3, Me4Si) 7.27–7.17 (2H, m), 7.04–7.00 (2H, m),
4.18 (4H, q, J 7.0), 4.04 (2H, s), 4.04 (2H, t, J 4.3), 3.29 (2H, t,
J 4.3), 2.84 (2H, d, J 11.3), 1.33 (6H, t, J 7.0); δC (75 MHz,
CDCl3) 159.9, 131.1, 131.0, 128.8, 123.5, 120.9, 69.2, 62.1 (d,
J 6.9), 59.5 (d, J 9.2), 59.2 (d, J 9.2), 48.6 (d, J 166.6), 16.5 (d,
J 5.7).
Following a similar procedure as for 21a using benzylmagne-
sium chloride (1.5 mL, 1.0 M in ether) as Grignard reagent,
compound 21c (0.20 g, 76%) was obtained as a colorless oil
(Found: N, 10.85. C18H22N2 requires N, 10.52%); δH (300 MHz,
CDCl3, Me4Si) 7.25–7.14 (7H, m), 6.89 (2H, d, J 7.0), 3.88 (2H,
s), 3.00–2.96 (4H, m), 2.88 (3H, s), 2.96–2.82 (2H, m), 2.69–2.62
(2H, m); δC (75 MHz, CDCl3) 152.3, 140.3, 130.7, 130.1, 128.6,
128.3, 127.9, 125.9, 120.6, 115.5, 59.0, 56.5, 56.0, 53.9, 42.9,
34.2. HRMS calcd for C18H23N2 (M ϩ 1): 267.1861. Found:
267.1850.
N,N-Bis(1H-1,2,3-benzotriazol-1-ylmethyl)-N-[2-(NЈ-methyl-
anilino)ethyl]amine 19
Diethyl (1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-
ylmethyl)phosphonate 22
Following the same procedure as 4a using 18 instead of 1, the
title compound (3.80 g, 92%) was purified by recrystallization;
mp 132–133 ЊC (colorless prisms from EtOAC) (Found: C,
66.70; H, 6.05; N, 27.27. C23H24N8 requires C, 66.97; H, 5.86; N,
27.16%); δH (300 MHz, CDCl3, Me4Si) 8.09 (2H, d, J 8.0), 7.57–
7.38 (6H, m), 7.16 (2H, t, J 6.8), 6.70 (1H, t, J 6.8), 6.54 (2H, d,
J 6.7), 5.66 (4H, s, 2 BtCH2N), 3.40–3.32 (2H, m), 3.16–3.08
(2H, m), 2.74 (3H, s); δC (75 MHz, CDCl3) 148.5, 146.0, 133.0,
129.3, 127.9, 124.2, 120.0, 116.7, 112.2, 109.7, 65.0, 51.4, 47.7,
38.8.
Following a similar procedure as for 7a using 20 instead of 5a
as starting material, compound 22 (0.22 g, 69%) was obtained
as a colorless oil (Found: C, 57.64; H, 8.28; N, 9.26. C15H25-
N2O3P requires C, 57.68; H, 8.07; N, 8.97%); δH (300 MHz,
CDCl3, Me4Si) 7.23–7.15 (2H, m), 6.90 (2H, d, J 7.7), 4.20–4.10
(4H, m), 3.98 (2H, s), 3.14–3.11 (2H, m), 2.94–2.91 (2H, m),
2.88 (3H, s), 2.78 (2H, d, J 11.0), 1.33 (6H, t, J 7.0); δC (75 MHz,
CDCl3) 152.3, 131.1, 129.4, 127.9, 120.4, 115.5, 61.8 (d, J 6.9),
60.2 (d, J 9.2), 57.3 (d, J 8.6), 52.9, 48.1 (d, J 167.8), 42.8, 16.3
(d, J 5.7).
4-Benzotriazolylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-1,4-
benzodiazepine 20
1,4-Dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine 23
Following a similar procedure as for 9 using 20 instead of 5a as
starting material, compound 23 (0.26 g, 73%) was obtained as a
colorless oil; δH (300 MHz, CDCl3, Me4Si) 7.31 (1H, td, J 7.8,
1.1), 7.12 (1H, d, J 6.7), 6.91 (2H, t, J 7.3), 4.31, 3.79 (2H, AB,
J 13.6), 3.46 (1H, dd, J 13.7, 5.9), 3.30–3.22 (1H, m), 3.07–2.99
(1H, m), 2.91–2.85 (1H, m), 2.89 (3H, s), 2.48 (3H, s); δC (75
MHz, CDCl3) 151.1, 132.1, 129.9, 123.8, 120.6, 115.7, 64.6,
61.2, 50.9, 47.3, 41.5. HRMS calcd for C11H16N2: 176.1313.
Found: 176.1305.
Following the same procedure as for 5a using 19 instead of 4a,
compound 20 (2.02 g, 86%) was obtained as a mixture of Bt1
and Bt2 isomers in a 4.4 : 1 ratio; mp 130–131 ЊC (colorless
crystals from CHCl3–Et2O) (Found: C, 69.48; H, 6.62; N, 23.65.
C17H19N5 requires C, 69.60; H, 6.53; N, 23.87%); δH (300 MHz,
CDCl3, Me4Si) Bt1: 8.08 (1H, d, J 7.7), 7.67 (1H, d, J 7.8), 7.50
(1H, t, J 7.3), 7.38 (1H, t, J 7.3), 7.24–7.15 (2H, m), 6.91 (2H, d,
J 7.7), 5.50 (2H, s), 3.93 (2H, s), 3.03 (4H, s), 2.88 (3H, s); Bt2:
7.96–7.85 (2H, m), 7.43–7.33 (2H, m), 7.24–7.15 (2H, m), 6.91
(2H, d, J 7.7), 5.67 (2H, s), 3.98 (2H, s), 3.03 (4H, s), 2.88 (3H,
s); δC (75 MHz, CDCl3) Bt1: 152.3, 146.0, 133.3, 130.6, 129.6,
128.2, 127.3, 123.8, 120.8, 119.8, 115.7, 110.3, 68.0, 57.8, 55.0,
54.2, 42.7.
References
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4-(4-Chlorobenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzo-
diazepine 21a
Following a similar procedure as for 6a using 20 instead of 5a
as starting material, and 4-chlorophenylmagnesium bromide
(1.5 mL, 1.0 M in ether) as Grignard reagent, compound 21a
(0.21 g, 72%) was obtained as a colorless oil (Found: C, 70.80;
H, 6.77; N, 9.87. C17H19ClN2 requires C, 71.19; H, 6.68; N,
9.77%); δH (300 MHz, CDCl3, Me4Si) 7.26 (4H, s), 7.26–7.18
(1H, m), 6.96–6.82 (3H, m), 3.74 (2H, s), 3.52 (2H, s), 2.98–2.90
(4H, m), 2.88 (3H, s); δC (75 MHz, CDCl3) 152.5, 137.5, 132.5,
130.8, 130.3, 130.2, 128.3, 127.9, 120.6, 115.5, 58.8, 57.7, 56.3,
54.1, 42.9.
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4-Allyl-1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
(21b)
Following a similar procedure as for 21a using vinylmagnesium
bromide (1.5 mL, 1.0 M in THF) as Grignard reagent, com-
pound 21b (0.14 g, 68%) was obtained as a colorless oil (Found:
C, 76.87; H, 9.29; N, 14.03. C13H18N2 requires C, 77.18; H, 8.97;
N, 13.85%); δH (300 MHz, CDCl3, Me4Si) 7.22–7.17 (1H, m),
7.10 (1H, d, J 7.1), 6.88–6.83 (2H, m), 5.97–5.83 (1H, m), 5.20–
J. Chem. Soc., Perkin Trans. 1, 2002, 592–598
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