An efficient synthesis of benzene fused six-, seven- and eight-membered rings containing nitrogen and sulfur by benzyne ring closure reaction

Article abstract of DOI:10.3987/com-04-10169

3,4-Dihydro-2-H-benzo[1,4]thiazines (3a-c), 2,3,4,5-tetrahydro[b]-[1,4] thiazapines (3d-f) and 2,3,4,5-tetrahydro-2H-benzo[b][1,4]thiazocines (3g-i) were prepared by the cyclization of the respective 2-bromophenylsulfanyl derivatives of ethylamine (1a-c), propylamine (2d-f) and butylamine (2g-i).

Full text of DOI:10.3987/com-04-10169

HETEROCYCLES, Vol. 63, No. 10, 2004, pp. 2309 - 2318
Received, 6th July, 2004, Accepted, 19th August, 2004, Published online, 23rd August, 2004
AN EFFICIENT SYNTHESIS OF BENZENE FUSED SIX-, SEVEN- AND
EIGHT-MEMBERED RINGS CONTAINING NITROGEN AND SULFUR
BY BENZYNE RING CLOSURE REACTION
Chandrani Mukherjee and Ed Biehl*
Department of Chemistry, Southern Methodist University, Dallas, TX,
75275 U. S. A. ebiehl@smu.edu
Abstract- 3,4-Dihydro-2-H-benzo[1,4]thiazines (3a–c), 2,3,4,5-tetrahydro[b]-
[1,4]thiazapines (3d–f) and 2,3,4,5-tetrahydro-2H-benzo[b][1,4]thiazocines
(3g–i) were prepared by the cyclization of the respective 2-bromophenylsulfanyl
derivatives of ethylamine (1a–c), propylamine (2d–f) and butylamine (2g–i).
A major portion of our research for the past several years has been concerned with the use of benzyne
chemistry in preparing new heterocycles. For example, we have prepared new heterocycles by
nucleophilic addition to arynes possessing charged substituents,1 by the reaction of benzyne with Barton
esters,2 and by Diels-Alder’s cycloaddition reactions involving 4-haloarynes with furan,3 selenoureas,4
and N,N-diethylthiocarbamic acid S-o-tolyl esters.5 Recently, we turned our attention to the use of
benzyne ring closure reactions in preparation of benzene fused six-membered, seven-membered-, and
eight-membered heterocycles for several reasons. First, many of these heterocycles function as CNS and
cardiovascular agents. Compounds such as diazepam (an auxiolytic 1,4-benzodiazepine,6 nefopam (an
anagesic 1H-2,5-benzoxazocine),7 and diltiazam (a calcium channel blocker)8 are representative of such
agents with clinically interesting biological activity. Second, although many five- and six-membered rings
have been prepared by benzyne ring closure reactions,9 no seven-membered ring and only one eight-
membered ring which contains a single nitrogen atom have been prepared by this route.
We were thus particularly interested in preparing 3,4-dihydro-2H-benzo[1,4]thiazines, 2,3,4,5-
tetrahydrobenzo[b][1,4]thiazepines, and 2,3,4,5-tetrahydro-2H-benzo[b][1,4]thiazocines. Since
the
nitrogen and sulfur atoms of the heterocylic portion of these compounds are on adjacent carbons of the
benzene fused ring, they should, in principle, be capable of being synthesized by aryne ring closure
reactions. Furthermore, of the sulfur and nitrogen containing seven-membered and eight-membered
rings, only the unsubstituted 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (3d) is known.10–13

We selected 2-bromophenylsulfanyl derivatives of ethylamine (2a–c), propylamine (2d–f) and
butylamine (2g–i) to be the aryne precursors. They were prepared according to equation 1 by the reaction
Br(CH ) NH
2 n
SH
Br
S
NH
2
n
2
R
R
(1)
NaH/THF/rt
n = 2,3, or 4
Br
1a. R = H
b. R = 4-Me
c. R = 5-MeO
2 (a–i)
of the respective 2-bromobenzenethiol (1a-c) with the HBr salts of 2-bromoethyl-, 3-bromopropyl- and
4-bromobutylamine and NaH and THF at room temperature. The first two amines are commercially
available whereas 4-bromobutylamine was prepared by treatment of 4-aminobutyl alcohol with HBr
(48%).14
Next, as shown in equation 2 and Table 1, compounds (2a–c) underwent cyclization with LDA to give
S
S
NH
2
n
LDA
R
R
n
(2)
N
H
Br
2 (a–i)
3(a–i)
3,4-dihydro-2H-benzo[1,4]thiazines (3a–c) in 87–93% yields. However, and more importantly,
compounds (2d–f) afforded seven-membered rings (3d–f) and 2g–i gave eight-membered rings (3g–i)
1
in yields of 85–95% and 64–70%, respectively. The products were identified on the basis of H NMR
and 13C NMR spectroscopy and, in the case of 3e, by X-Ray crystallography. An ORTEP drawing of 3e is
shown below in Figure 1.
Figure 1 ORTEP drawing of compound (3e)

On the basis of entropy, one might expect the formation of seven- and especially eight-membered rings to
be disfavored. Indeed this expectation might be one of the major reasons why aryne ring closure
reactions have not been applied to such rings. However, the use of the sterically demanding base LDA
and the non-nucleophilic solvent THF enables the ring closure reaction to occur.
Conclusions
In conclusion, we have found benzyne ring closure reactions to be a valuable method for the preparation
of six-, seven- and eight-membered rings possessing nitrogen and sulfur atoms. Of the compounds
reported here, only the parent seven-membered ring compound (3d) was previously known. The yield
of 3d reported in Table 1 is higher than those from previous methods which generally involved a ring
expansion of thio-4-chromanones13 or the corresponding oximes by reduction12 or N-deoxygenation.11
Thus, the high yields and the facile synthesis of substituted 2-bromobenzenethiols from the
corresponding bromoanilines15 shown in this study suggest that the benzyne ring closure reaction is the
method of choice for the preparation of the titled compounds.
EXPERIMENTAL
1
General Data Melting points were taken on a Melt-Temp capillary apparatus and are uncorrected. H
13
and C NMR spectra were recorded on a 400 MHz Bruker AVANCE DRX-400 Multi-nuclear NMR
spectrometer. Chemical shift are reported in reference to TMS as internal standard. HMRS were
measured by the Washington University Mass Spectrometry Resource, an NIH Research Resource (Grant
No.P41RR0954). Routine MS were recorded on a Hewlett-Packard GC/MS Model GCD Series II. THF
was freshly distilled using sodium-benzophenone method and all reactions were monitored by TLC.
Concentrations were performed by rotary evaporator using water aspirator system. Low pressure
chromatography was carried out by applying air pressure to pyrex column packed with silica gel 60
(0.040-0.063 mm particle size, 230-400 mesh). Na2SO4 was used as drying agent. The solvents, reagents,
and starting materials, including 2-bromobenzenethiol (1a) were purchased from commercial sources. 2-
Bromo-4-methyl- (1b), and 2-bromo-6-methoxybenzenethiol (1c) were prepared as follows.
Procedure for the synthesis of 2-bromobenzenethiols (1b,c)
A mixture of 2-bromo-4-methylaniline or 2-bromo-6-methoxyaniline (26.8 mmol), concd HCl (5
mL) and ice (10 g) was cooled at –5 °C and slowly treated with solution of sodium nitrite (1.88 g, 26.8
mmol) in water (10 mL), the temperature being maintained below 0 °C . The cold solution of the
diazonium salt was added dropwise (1 h) to a stirring aqueous (10 mL) solution of potassium ethyl
xanthate (8.6 g, 53.7 mmol) maintained at 70–78 °C. After stirring for an additional 1 h, the mixture was
cooled to rt, the pH of the solution adjusted to 8 by the addition of NaHCO3, and extracted with CH2Cl2.
The combined CH2Cl2 extracts were washed with water, dried over Na2SO4, and the solvent evaporated

to give an oily residue. The residue was mixed with a solution of 6 g of KOH in 30 mL of ethanol then
hydrolyzed by refluxing for 12 h under nitrogen atmosphere. After the evaporation of the solvent, the
Table 1 Preparation of Compounds (3a-i)
Entry 2 Aryne Precursor
Yield, % 3 Product
Yield, %
89
S
S
NH
2
1
a
84
a
Br
N
H
S
S
NH
2
2
3
b
c
79
82
b
c
93
87
Me
Br
Me
N
H
MeO
S
MeO
S
NH
2
Br
N
H
4
d
87
d
85
S
NH
S
2
Br
N
H
S
NH
S
2
5
6
e
f
84
82
e
f
95
92
Me
Br
Me
N
H
MeO
S
S
NH
2
MeO
Br
N
H
S
S
NH
2
7
g
67
g
68
Br
N
H
S
S
NH
2
8
9
h
i
74
80
h
i
70
64
Me
Br
Me
N
H
S
MeO
MeO
S
NH
2
N
H
Br
reaction mixture was diluted with water, and the resulting solution was washed with ether. The aqueous
layer was acidified by the slow addition of 3N sulfuric acid and extracted with CH2Cl2. The CH2Cl layer
was washed with water, dried over Na2SO4 and the solvent evaporated. The resulting crude product was
purified by column chromatography with hexane as eluent to give 1b and 1c in nearly quantitative

yields.15
General procedure for the synthesis of 2-(bromophenylsulfanyl)amines (2a–i)
To a well stirred solution of NaH (60% suspension in hexanes, 0.25g, 10.5 mmol) and THF (10 mL) kept
under argon atmosphere at rt, the appropriate 2-bromobenzenethiol (2.6 mmol) in THF (5 mL) was
slowly added through a needle-syringe system. The reaction mixture was stirred for 30 min then the
appropriate 2-bromoethylamine hydrobromide salt (39 mmol) was added in small portions under
continuous argon purging. After the addition of the salt, the reaction mixture was stirred for another 6 h.
°
Then ice-water was added at 0 C, and the mixture extracted with CH2Cl2 (3x75 mL). The combined
CH2Cl2 extracts were washed with water, dried over Na2SO4, and the solvent removed under reduced
pressure. The resulting crude product (2a–i), which was purified by column chromatography using 5%
ethyl acetate-hexane as eluent. The physical and spectral properties for 2a–i are shown below.
2-(2-Bromophenylsulfanyl)ethylamine (2a)
1
This compound was obtained as a colorless oil. H NMR (CDCl3) δ 1.44 (s, 2H, -NH2), 3.01(t, J = 5.7
Hz, 2H, -CH2), 3.08 (t, J = 5.7 Hz, 2H, -CH2), 7.06 (dd, J = 7.0, 7.4 Hz, 1H, Ar-H-6), 7.31(m, 2H, Ar-
H-4, Ar-H-5), 7.57 (d, J = 7.6 Hz, 1H, Ar-H-3). 13C NMR (CDCl3) δ 37.6, 40.9, 124.8, 127.4 128.2,
129.3, 133.5, 137.5. MS (EI) m/z, (relative intensity): 233 (M+ 7), 231 (M+, 7), 204 [(M+–CH2NH), 100],
,
202 [(M+–CH2NH), 100], 152 [(M+–Br), 53]. Anal. Calcd for C7H8NBrS: C, 38.55; H, 3.70; N, 6.42.
Found: C, 38.66; H, 3.79; N, 6.45.
2-(2-Bromo-4-methylphenylsulfanyl)ethylamine (2b)
This compound was obtained as a viscous liquid. 1H NMR (CDCl3) δ 1.45(br s, 2H, -NH2), 2.31(s, 3H,
-CH3), 2.93 (t, J = 6.0 Hz, 2H, -CH2), 3.02 (t, J = 5.8 Hz, 2H, -CH2), 7.08 (d, J = 7.8 Hz, 1H, Ar-H-6),
7.25 (dd, J = 2.5, 7.8 Hz, 1H, Ar-H-5), 7.42 (d, J = 2.5 Hz, 1H, Ar-H-3). 13C NMR (CDCl3) δ 21.0, 38.6,
41.1, 124.8, 129.1, 130.7, 133.5, 134.1, 138.2. MS (EI) m/z, (relative intensity): 247 (M+ 2), 245 (M+2),
,
234 [(M+–CH2NH), 37], 232 [(M+–CH2NH), 37], 166 [(M+–Br), 100]. Anal. Calcd for C8H10NBrS: C,
41.39; H, 4.34; N, 6.03. Found: C, 41.51; H, 4.40; N, 6.21.
2-(2-Bromo-5-methoxyphenylsulfanyl)ethylamine (2c)
This compound was obtained as a light yellow oil. 1H NMR (CDCl3) δ 1.43 (br s, 2H, -NH2), 3.01 (t,
J = 5.8 Hz, 2H, -CH2), 3.05 (t, J = 5.8 Hz, 2H, -CH2), 3.81(s, 3H, -OMe), 6.62(dd, J = 2.4, 8.6 Hz, 1H,
13
Ar-H-4), 6.88 (d, J = 2.4 Hz, 1H, Ar-H-6), 7.45 (d, J = 8.6 Hz, 1H, Ar-H-3). C NMR (CDCl3) δ 33.8,
39.5, 55.7, 113.5, 115.3, 116.0, 133.9, 136.6, 159.5. MS (EI) m/z, (relative intensity): 263 (M+ 3), 261
,
(M+, 3), 182 [(M+–79), 100]. Anal. Calcd for C8H10NOBrS: C, 38.72; H, 4.06; N, 5.64. Found: C,
38.66; H, 4.11; N, 5.41.
3-(2-Bromophenylsulfanyl)propylamine (2d)

This compound was obtained as a viscous liquid. 1H NMR (CDCl3) δ 1.28 (br s, 2H, -NH2), 1.87 (m,
2H, -CH2), 2.88 (m, 2H, -CH2), 3.01(t, J = 6.1 Hz, 2H, -CH2),7.03 (dd, J = 2.4 Hz, 7.8 Hz, 1H, Ar-H-6),
13
7.27 (m, 2H, Ar-H-5, H-6), 7.55 (d, J = 7.7 Hz, 1H, Ar-H-3). C NMR (CDCl3) δ 30.7, 32.6, 41.5,
123.9, 126.8, 128.1, 128.3, 133.4, 138.5. MS (EI) m/z, (relative intensity): 247 (M]+, 9), 245 (M+, 9), 166
[(M+–Br), 34], 57 [(CH2CH2CH2NH)+, 100]. Anal. Calcd for C8H10NBrS: C, 41.39; H, 4.34; N, 6.03.
Found: C, 41.44; H, 4.41; N, 6.05.
3-(2-Bromo-4-methylphenylsulfanyl)propylamine (2e)
This compound was obtained as a colorless oil. 1H NMR (CDCl3) δ 1.27 (br s, 2H, -NH2), 1.82(m, 2H, -
CH2), 2.31 (s, 3H, -CH3), 2.87 (m, 2H, -CH2), 2.98 (t, J = 6.3 Hz, 2H, -CH2), 7.08 (d, J = 7.9 Hz, 1H,
Ar-6H), 7.21 (dd, J = 2.5, 7.9 Hz, 1H, Ar-5H), 7.41 (d, J = 2.5 Hz, 1H, Ar-H-3). 13C NMR δ (CDCl3)
20.9, 31.3, 32.8, 41.5, 124.6, 129.0, 129.5, 134.0, 134.4, 137.6. MS (EI) m/z, (relative
intensity): 261 (M+, 4), 259 (M+, 4), 194 (M+, 20), 57 [(CH2CH2CH2NH)+, 100]. Anal. Calcd for
C9H12NBrS: C, 43.91; H, 4.91; N, 5.69. Found: C, 43.98; H, 4.77; N, 5.55.
3-(2-Bromo-5-methoxyphenylsulfanyl)propylamine (2f)
°
1
This compound was isolated as a white powder, mp 134-135 C (EtOAc/hexanes). H NMR (CDCl3) δ
1.69 (br s, 1H, -NH2), 1.89 (m, 2H, -CH2), 2.89 (m, 2H, -CH2), 3.01 (t, J = 6.4 Hz, 2H, -CH2), 3.81 (s,
3H, -OMe), 6.60 (dd, J = 2.4, 8.0 Hz, 1H, Ar-H-4), 6.84 (d, J = 2.4 Hz, 1H, Ar-H-6), 7.42 (d, J = 8.0 Hz,
13
1H, Ar-H-3). C NMR (CDCl3) δ 30.5, 30.7, 40.4, 55.8, 112.4, 114.3, 114.8, 133.7, 138.8, 159.5. MS
+
(m/z) (relative intensity): 277 (M+, 4), 275 (M , 4), 196 [(M+–Br), 100]. Anal. Calcd for
C9H12NOBrS: C, 41.23; H, 4.61; N, 5.34. Found: C, 41.18; H, 4.69; N, 5.19.
4-(2-Bromophenylsulfanyl)butylamine (2g)
This compound was isolated as a yellow viscous liquid. 1H NMR (CDCl3) δ 1.29 (br s, 1H, -NH2),
1.66 (m, 2H, -CH2), 1.77 (m, 2H, -CH2), 2.88 (m, 2H, -CH2), 3.48 (t, J = 6.4 Hz, 2H -CH2), 7.08 (dd, J
= 2.5, 7.8 Hz, 1H, Ar-H-6), 7.28 (dd, J = 7.8, 8.0 Hz, 1H, Ar-H-5), 7.43 (dd, J = 7.8, 8.0 Hz, 1H, Ar-H-
13
4), 7.59 (d, J = 7.8 Hz, 1H, Ar-H-3). C NMR (CDCl3) δ 21.5, 40.0, 40.4, 40.6, 127.9, 128.1, 129.2,
131.8, 133.6, 137.3. MS (EI) m/z, (relative intensity): 261 (M+, 4), 259. (M+, 4), 180 [(M+–Br), 16], 56
([CH2CH2CH2N]+, 100). Anal. Calcd for C9H12NBrS: C, 43.91; H, 4.91; N, 5.69. Found: C, 43.69; H,
4.98; N, 5.67.
4-(2-Bromo-4-methylphenylsulfanyl)butylamine (2h)
This compound was isolated as a yellow viscous liquid. 1H NMR (CDCl3) δ 1.52(br s, 1H, -NH2), 1.74
(m, 4H, -CH2x2), 2.31 (s, 3H, -CH3), 2.73 (m, 2H, -CH2), 2.93 (t, J = 6.2, Hz, 2H, -CH2), 7.07(dd, J =
2.7, 7.7 Hz, 1H, Ar-H-5), 7.18 (d, J = 7.7 Hz, 1H, Ar-H-6), 7.40 (d, J = 2.6 Hz, 1H, Ar-H-3). 13C NMR
(CDCl3) δ 20.9, 27.1, 30.5, 33.6, 51.2, 124.3, 129.0, 129.1, 133.9, 134.8, 137.3. MS (EI) m/z, (relative

intensity): 275 (M+, 1), 273 (M +, 1), 194 [(M+–Br), 100]. Anal. Calcd for C10H14NBrS: C, 46.16; H,
5.42; N, 5.38. Found: C, 46.31; H, 5.41; N, 5.46.
4-(2-Bromo-4-methoxyphenylsulfanyl)butylamine (2i)
This compound was isolated as a colorless viscous liquid. 1H NMR (CDCl3) δ 1.32 (s, 1H, -NH2),
1.74(m, 4H, -CH2x2), 2.89 (m, 2H, -CH2), 3.12 (t, J = 6.4 Hz, 2H, -CH2), 3.90 ( s, 3H, -OMe), 6.64 (d, J
13
= 2.7 Hz, 1H, Ar-H-6), 6.94 (dd, J = 2.7, 8.0 Hz, 1H, Ar-H-4), 7.45 (d, J = 8.0 Hz, 1H, Ar-H-3). C
NMR (CDCl3) δ 29.4, 30.6, 30.7, 40.5, 55.9, 112.1, 114.3, 114.8, 133.7, 138.8, 159.6. MS (EI) m/z,
(relative intensity): 291 (M+, 3), 289 (M+, 3), 210 [(M+–Br), 40], 73 (100). Anal. Calcd for
C10H14NOBrS: C, 43.49; H, 5.11; N, 5.07. Found: C, 43.38; H, 5.22; N, 5.19.
Typical procedure for the synthesis of 3a–3i
Diisopropylamine (0.5 mL, 5 mmol) was added through a needle syringe system to a well stirred solution
°
of THF (5 mL) and n-BuLi (2.4 mL of 1.6 M solution in hexanes, 3.8 mmol) kept at –78 C under argon
°
atmosphere. The reaction mixture was then cooled to –20 C and kept at that temperature for 45 min.
°
The reaction mixture was the cooled to –78 C and a solution of the appropriate 2-(2-bromophenyl-
sulfanyl)amine (1.3 mmol) in THF (5 mL) was slowly added to the reaction mixture which was allowed
to warm to rt. After stirring for 5 h, a saturated NH4Cl solution was added, and the resulting mixture was
extracted with ethyl acetate, and the extract was washed with water, and dried (Na2SO4). The solvent was
removed and the remaining crude product was purified by column chromatography using silica gel
(400 mesh) and 10% ethyl acetate-hexane. The physical and spectral properties of 3a–i are given below.
3,4-Dihydro-2H-benzo[1,4]thiazine (3a)
This compound was isolated as a colorless oil. 1H NMR (CDCl3) δ 3.07 (t, J = 5.0 Hz, 2H, -CH2), 3.65 (t,
J = 5.0 Hz, 2H, -CH2), 4.00 (br s, 1H, -NH), 6.48 (dd, J = 1.8, 7.9 Hz, 1H, Ar-H-5), 6.63 (dd, J = 7.4 Hz,
7.5 Hz, 1H, Ar-H-7), 6.96 (dd, J = 7.4, 7.8 Hz, 1H, Ar-H-6), 7.00 (dd, J = 1.7, 7.8 Hz, 1H, Ar-H-8). 13C
NMR (CDCl3) δ 26.5, 42.7, 115.8, 118.5, 125.9, 127.1, 128.1, 128.9. HRMS calcd for C8H9NS: 151.046.
Found: 151.047. Anal. Calcd for C8H9NS: C, 63,54; H, 6.00; N, 9.26. Found: C, 63.66; H, 6.07; N, 9.36.
6-Methyl-3,4-dihydro-2H-benzo[1,4]thiazine (3b)
This compound was isolated as a colorless oil. 1H NMR (CDCl3) δ 2.21 (s, 3H, -CH3), 3.06 (t, J=6.2 Hz,
2H, -CH2), 3.60 (t, J=6.2 Hz, 2H, -CH2), 3.94 (br s, 1H, -NH), 6.31 (d, J = 2.2 Hz, 1H, Ar-H-5), 6.47 (dd,
13
J = 2.2, 7.6 Hz, 1H, Ar-H-7), 6.89 (d, J = 7.6 Hz, 1H, Ar-H-8). C NMR (CDCl3) δ 21.4, 26.5, 42.9,
116.4, 119.6, 127.9, 130.2, 135.8, 141.9. HRMS calcd for C9H11NS: 165.061. Found: 165.060. Anal:
Calcd for C9H11NS: C, 65.41; H, 6.71; N, 8.48. Found: C, 65.32; H, 6.61; N, 8.56.
7-Methoxy-3,4-dihydro-2H-benzo[1,4]thiazine (3c)

This compound was isolated as a light yellow oil. 1H NMR (CDCl3) δ 3.10 (t, J = 5.1 Hz, 2H, -CH2), 3.59
(t, J = 5.1 Hz, 2H, -CH2), 3.73 (br s, 1H, -NH), 3.75 (s, 3H, -OMe), 6.45 (dd, J = 2.6, 8.5 Hz, 1H, Ar-
H-6), 6.52 (d, J = 2.6 Hz, 1H, Ar-H-8), 6.60 (d, J = 8.5 Hz, 1H, Ar-H-5). 13C NMR (CDCl3) δ 38.4, 53.9,
55.6, 110.3, 113.5, 113.6, 133.3, 140.1, 150.1. HRMS calcd for C9H11NOS: 181.056. Found: 181.058.
Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12; N, 7.73. Found: C, 59.80; H, 6.18; N, 7.83.
2,3,4,5-Tetrahydrobenzo[b][1,4]thiazepine (3d)
This compound was isolated as a colorless oil. 1H NMR (CDCl3) δ 2.10 (m, 2H, -CH2), 2.86 (m, 2H,
-CH2), 3.30 (t, J = 5.4 Hz, 2H, -CH2), 3.90 (br s, 1H, -NH), 6.76 (d, J = 7.0 Hz, 1H, Ar-H-6), 6.81(dd, J
=7.0, 7.5 Hz, 1H, Ar- H-8), 7.07 (dd, J = 7.2, 7.5 Hz, 1H, Ar-H-7), 7.40 (d, J = 7.2 Hz, 1H, Ar-H-9).
13C NMR (CDCl3) δ 32.2, 33.4, 47.6, 120.4, 121.3, 125.5, 128.9, 133.3, 152.1. HRMS calcd for
C9H11NS: 165.061. Found: 165.063. Anal. Calcd for C9H11NS: C, 65.41; H, 6.71; N, 8.48. Found: C,
65.49; H, 6.81; N, 8.57.
7-Methyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (3e)
°
1
This compound was isolated as a colorless needles, mp 48–49 C (EtOAc/hexanes). H NMR (CDCl3) δ
2.09 (m, 2H, -CH2), 2.26 (s, 3H, -CH3), 2.79 (m, 2H, -CH2), 3.24 (m, 2H, -CH2), 3.91 (br s, 1H, -NH),
6.59 (d, J = 2.8 Hz, 1H, Ar-H-6), 6.63 (dd, J = 2.8,7.6 Hz, 1H, Ar-H-8), 7.28 (d, J = 7.6 Hz, 1H, Ar-H-
9). 13C NMR (CDCl3) δ 21.3 32.4, 33.7, 47.9, 121.2, 122.4, 122.4, 133.3, 138.4, 152.1. HRMS calcd
for C10H13NS: 179.077. Found: 179.075. Anal. Calcd for C10H13NS: C, 66.99; H, 7.31; N, 7.81. Found: C,
67.18; H, 7.40; N, 7.88.
8-Methoxy-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine (3f)
This compound was isolated as a yellow oil. 1H NMR (CDCl3) δ 2.01(m, 2H, -CH2), 2.78 (m, 2H,
-CH2), 3.14 (t, J = 5.0 Hz, 2H, -CH2), 3.75 (br s, 1H, -NH), 3.77 (s, 3H, -OMe), 6.69 (dd, J = 2.3, 8.4 Hz,
1H, Ar-H-7), 6.77 (d, J = 8.4 Hz, 1H, Ar-H-6), 7.04 (d, J = 2.3 Hz, 1H, Ar-H-9). 13C NMR (CDCl3) δ
32.5, 34.0, 48.5, 56.0, 114.7, 117.9, 122.0, 128.1, 146.2, 154.5. HRMS. calcd for C10H13NOS: 195.072.
Found: 195.074. Anal. Calcd for C10H13NOS: C, 61.50; H, 6.71; N, 7.17. Found: C, 67.12; H, 7.40; N,
7.91.
3,4,5,6-Tetrahydro-2H-benzo[b][1,4]thiazocine (3g)
This compound was isolated as a colorless oil. 1H NMR (CDCl3) δ 1.36 (m, 2H, -CH2), 2.01 (m,
2H, CH2), 3.06 (m, 2H, -CH2), 3.64 (m, 2H, -CH2), 3.95 (br s, 1H, -NH), 6.73 (d, J = 7.7 Hz, 1H, Ar-H-7),
6.80 (dd, J = 7.6, 7.8 Hz, 1H, Ar-H-9), 7.06 (dd, J = 7.7, 7.8 Hz, 1H, Ar-H-8), 7.38 (d, J = 7.6 Hz, 1H,
13
Ar-H-10). C NMR (CDCl3) δ 30.2, 40.5, 41.7, 46.6, 120.1, 121.3, 124.0, 128.3, 133.7, 152.3. HRMS
calcd for C10H13NS: 179.077. Found: 179.079. Anal. Calcd for C10H13NS: C, 66.99; H, 7.31; N, 7.81.
Found: C, 66.89; H, 7.30; N, 7.90.

8-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4]thiazocine (3h)
This compound was isolated as a yellow oil. 1H NMR (CDCl3) δ 1.34 (m, 2H, -CH2), 2.03 (m, 2H, -CH2),
2.26 (s, 3H, -CH3), 2.99 (m, 2H, -CH2), 3.58 (m, 2H, -CH2), 3.87 (br s, 1H, -NH), 6.57 (d, J = 1.2 Hz, 1H,
Ar-H-7), 6.64 (dd, J = 1.2, 7.6 Hz, 1H, Ar-H-9), 7.28 (d, J = 7.6 Hz, 1H, Ar-H-10). 13C NMR (CDCl3) δ
15.2, 28.8, 30.1, 34.5, 51.2, 112.9, 116.5, 117.9, 127.5, 142.1, 133.9. HRMS calcd for C11H15NS: 193.093.
Found: 193.096. Anal. Calcd for C11H15NS: C, 68.35; H, 7.82; N, 7.25. Found: C, 68.40; H, 7.88; N, 7.30.
9-Methoxy-3,4,5,6-tetrahydro-2H-benzo[b][1,4]thiazocine (3i)
This compound was isolated as a yellowish oil. 1H NMR (CDCl3) δ 1.33 (m, 2H, -CH2), 2.14 (m, 2H, -CH2),
2.98 (m, 2H, -CH2), 3.68 (m, 2H, -CH2), 3.77 (br s, 1H, -NH), 3.92 (s, 3H, -OMe), 6.77(d, J = 7.8 Hz,
1H, Ar-H-7), 6.79 (dd, J = 2.6, 7.8 Hz, 1H, Ar-H-8), 7.28 (d, J = 2.6 Hz, 1H, Ar-H-10). 13C NMR (CDCl3)
δ 28.0, 29.1, 34.5, 51.2, 55.6, 113.1, 116.3, 118.0, 127.5, 142.1, 155.9. HRMS calcd for C11H15NOS:
209.087. Found: 209.089. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 63.22; H,
7.31; N, 6.61.
ACKNOWLEDGEMENTS
This research was supported in part by the Robert Welch Foundation, Houston, TX.
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