Synthesis of (5R,6R,7S)-6-iodo-1,5,6,7-tetrahydro-4,1-benzoxazonin-3(2H)-ones

Article abstract of DOI:10.1134/S1070428014100121

New 6-iodo-1,5,6,7-tetrahydro-3H-4,1-benzoxazonin-3-ones have been synthesized by reaction of N-tosyl- and N-(2-nitrobenzenesulfonyl)-N-[2-(alkenyl)phenyl]aminoacetic acids with molecular iodine.

Full text of DOI:10.1134/S1070428014100121

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 10, pp. 1472–1479. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © G.G. Mazgarova, K.Yu. Suponitskii, R.R. Gataullin, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 10,
pp. 1487–1493.
Synthesis of (5R*,6R*,7S*)-6-Iodo-1,5,6,7-tetrahydro-
4,1-benzoxazonin-3(2H)-ones
G. G. Mazgarovaa, K. Yu. Suponitskiib, and R. R. Gataullina
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: gataullin@anrb.ru
b Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received May 16, 2014
Abstract—New 6-iodo-1,5,6,7-tetrahydro-3H-4,1-benzoxazonin-3-ones have been synthesized by reaction of
N-tosyl- and N-(2-nitrobenzenesulfonyl)-N-[2-(alkenyl)phenyl]aminoacetic acids with molecular iodine.
DOI: 10.1134/S1070428014100121
Halocyclizations [1–4] are widely used in the syn-
thesis of 2-(1-iodoethyl)dihydroindoles [5], 3-methyli-
deneindoles [6], tetrahydroquinolines [7], and
3,1-benzoxazines [8–10]. However, cyclizations by the
action of halogens with formation of larger rings, in-
cluding benzoxazonine structures, have been reported
in a few publications. In most cases, such heterocycles
are obtained by other methods. For example, known
methods of synthesis of 2,6- [11] and 4,1-benzoxazo-
nine [12] and 1,4-benzothiazonine derivatives [13] do
not utilize halogens.
In this work we studied for the first time iodo-
cyclization of glycine derivatives with a view to ob-
taining benzoxazonines. For this purpose, N-arenesul-
fonyl derivatives IIa–IId [5] were converted into the
corresponding sodium salts by heating with sodium in
benzene, and the subsequent alkylation with methyl
bromoacetate gave esters IIIa–IIId. The latter were
hydrolyzed to acids IVa–IVd by stirring with lithium
hydroxide in aqueous tetrahydrofuran at room tem-
perature. Acids IVa–IVd reacted with molecular iodine
in methylene chloride in the presence of NaHCO3 or
K2CO3 to afford substituted 4,1-benzoxazonin-3-ones
Va–Vd (Scheme 1).
tion should lead to the formation of benzoxazocine
structure B, while in the second case the attack on C4″
should give rise to benzoxazonine derivative V, which
is observed experimentally.
However, we cannot rule out an alternative reaction
path according to which initially formed eight-mem-
bered ring in intermediate B undergoes expansion as
a result of intramolecular attack by the lactone car-
bonyl oxygen atom on the side-chain carbon atom
attached to iodine and migration of halogen to the
neighboring carbon atom. Examples of analogous ring
expansion in iodocyclization products have been
reported [14–16].
In order to elucidate the mechanism of formation of
the 9-endo-cyclization product, we have synthesized
amide VI by heating ester IIIa in methanolic ammonia
under pressure. The reaction of amide VI with iodine
under the same conditions as in the reactions of com-
pounds IVa–IVd gave 4,1-benzoxazonin-2-one Va.
The latter is very likely to be formed via initial halo-
cyclization to 1,4-benzodiazocine D which then iso-
merizes into benzoxazonin-3-imine E whose hydrol-
ysis yields heterocycle Va (Scheme 2). On the other
hand, the direct 9-endo-cyclization of imidic acid H
(which is tautomeric to amide F) to imine E is also
possible (Scheme 3).
Halocyclizations usually involve formation of
onium intermediates like A. In the corresponding
complex formed by compound IV with iodine intra-
molecular attack by the oxygen atom on both C3″ and
C4″ of the alkenyl fragment is possible in the presence
of potassium carbonate. In the first case, 8-exo-cycliza-
The structure of benzoxazonine Va was determined
by X-ray analysis (see figure) and was confirmed by
the NMR and mass spectra, and the structure of the
1472

SYNTHESIS OF (5R*,6R*,7S*)-6-IODO-1,5,6,7-TETRAHYDRO-4,1-BENZOXAZONIN-...
1473
Scheme 1.
Me
Me
1''Me
2''
3'
4''
R1
R1
R1
(1) Na, PhH
(2) BrCH2COOMe
Me
Me
M5e''
TsCl or NsCl, Et3N
3''
1'
OMe
5'
A/B
NH2
NH
N
R2
R2
R3
R2
R3
O
Ia, Ib
IIa–IId
IIIa–IIId
I+
I–
Me
Me
R1
R1
LiOH, THF–H2O
I2, K2CO3, CH2Cl2
Me
OH
Me
OK
N
N
R2
R3
O
R2
R3
O
IVa–IVd
A
I
I
I
Me
Me
Me
Me
Me
Me
O
8
R1
R1
R1
6
2
7
5
O
O
7a
9
4O
O
11a
1
10
3
O
11
N
N
N
R2
R2
R2
R3
R3
R3
B
B
Va–Vd
R1 = Me, R2 = H, R3 = 4-MeC6H4SO2 (a); R1 = H, R2 = Me, R3 = 4-MeC6H4SO2 (b); R1 = Me, R2 = H, R3 = 2-O2NC6H4SO2 (c);
R1 = H, R2 = Me, R3 = 2-O2NC6H4SO2 (d).
Scheme 2.
I+
I–
Me
Me
NH3, MeOH
120°C, 5 h
Me
Me
Me
I2, K2CO3, CH2Cl2
Me
Me
IIIa
NH2
NH2
N
N
Ts
VI
O
Ts
F
O
I
I
I
Me
Me
Me
Me
Me
Me
H2O
Me
Me
Va
NH
O
HN
O
O
N
Ts
N
N
NH
Ts
Ts
D
G
E
Scheme 3.
I+
I–
Me
Me
H2O
Me
O
IIIa
VI
E
Va
N
Ts
H
NH
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

MAZGAROVA et al.
1474
other isolated compounds was determined by spectral
methods. Compound Va crystallizes as a racemic twin
(3:1) in Pna21 noncentrosymmetric space group, and
its unit cell contains two molecules in the symmetry-
independent part. Both molecules have quite similar
structures (see figure) with the nine-membered ring
having chair–boat conformation. Despite the presence
of fairly strong electron pair donors, carbonyl and sul-
fonyl oxygen atoms, no intermolecular contacts were
detected between these oxygen atoms and halogen.
The oxygen atoms are involved in fairly weak contacts
C–H···O, and the crystal packing is additionally sta-
bilized by van der Waals interactions. Presumably, the
strongest interaction is intramolecular I···π interaction
between two symmetry-independent molecules with
participation of the phenyl groups [the shortest dis-
tances are as follows: I1 ···C10′ 3.518(3), I1 ···C11′
3.684(3), I1′···C9 3.612(3), I1′···C10 3.451(3), I1′···C11
3.688(3) Å]. Fairly strong intermolecular interactions
involving just symmetry-independent molecules were
observed by us previously [17–19], and we believe that
these interactions are responsible for the presence of
such molecules in the independent part of a unit cell;
their mutual arrangement is not restricted by symmetry
transformations.
as mixtures of syn and anti atropisomers because of
restricted rotation about the Carom–N bond. For in-
stance, compounds IIIa–IIId and IVa–IVd displayed
1
in the H and 13C NMR spectra a fairly well resolved
set of four doublets from the methylene protons in the
glycine fragment (instead of two doublets). The
doublet signals from the side-chain methyl groups and
methoxy group in the aromatic ring were also doubled.
Nevertheless, iodocyclization of mixtures of atrop-
isomeric acids IV afforded benzoxazonines V as only
one stereoisomer.
Thus, the reaction of N-arenesulfonyl-N-{2-[(3E)-
pent-3-en-2-yl]phenyl}aminoacetic acids and -acet-
amide with molecular iodine yields the corresponding
(5R*,6R*,7S*)-1-arenesulfonyl-6-iodo-5,7,9(or
5,7,11)-trimethyl-1,5,6,7-tetrahydro-4,1-benzoxazonin-
3(2H)-ones as a result of regio- and stereoselective
9-endo-cyclization.
EXPERIMENTAL
Single crystals of Va suitable for X-ray analysis
were obtained by slow crystallization from ethanol.
Orthorhombic crystal system, space group Pna21;
C21H24INO4S; M 513.37; unit cell parameters (120 K):
a = 19.9588(6), b = 11.1340(3), c = 19.1203(5) Å;
V = 4248.9(2) Å3; Z = 4; dcalc = 1.605 g/cm3; μ =
1.632 mm–1. Intensities of 54 926 reflections were
measured at 120 K on a Bruker Smart Apex II dif-
1
Some proton and carbon signals in the H and 13C
NMR spectra of esters IIIa–IIId, acids IVa–IVd, and
amide VI were doubled (cf. the data for their N-acetyl
analogs studied previously [20]) due to their existence
C12
C10
C11
C9
C14
C5
I1
C6
C8
C16
C17
O3
S1
C7
C21
C4
C15
C18
C3
N1
C19
O1
O4
C2
O2
C1
C20
C13
Structure of the molecle of (5R*,6R*,7S*)-6-iodo-5,7,9-trimethyl-1-(4-methylbenzenesulfonyl)-1,5,6,7-tetrahydro-4,1-benzoxazonin-
3(2H)-one (Va) according to the X-ray diffraction data. Non-hydrogen atoms are shown as thermal vibration ellipsoids with
a probability of 50%.
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SYNTHESIS OF (5R*,6R*,7S*)-6-IODO-1,5,6,7-TETRAHYDRO-4,1-BENZOXAZONIN-...
1475
fractometer (MoKα radiation, θmax = 30.1°). The initial
array of reflection intensities was processed using
SAINT and SADABS programs included in APEX2
software package [21]; a correction for absorption was
applied. The structure was solved by the direct method
and was refined against F2hkl by the full-matrix least-
squares procedure in anisotropic approximation for
non-hydrogen atoms. Hydrogen atoms were placed
into geometrically calculated positions which were
refined according to the riding model [Uiso(H) =
nUeq(C), where n = 1.5 for methyl carbon atoms and
n = 1.2 for the other carbons]. The structure was
125.37, 128.34, 128.55, 129.00, 130.55, 133.55,
135.29 (C3, C4, C5, C6 C3′, C4′ C5′, C3″, C4″); 131.57,
135.38, 138.22, 141.16, 144.96 (C1, C2, C6′, C1′, C2′).
Mass spectrum, m/z: 360.1 [M]+, 174.1 [M – H –
SO2C6H4NO2]+. Found, %: C 59.88; H 5.52; N 7.68;
S 8.82. C18H20N2O4S. Calculated, %: C 59.98; H 5.59;
N 7.77; S 8.90.
Methyl N-{4-methyl-2-[(3E)-pent-3-en-2-yl]-
phenyl}-N-(4-methylbenzenesulfonyl)aminoacetate
(IIIa). Metallic sodium, 0.069 g (3 mmol), was added
to a solution of 0.77 g (2.34 mmol) of compound IIa in
6 mL of anhydrous benzene, the walls of the flask were
rinsed with 3 mL of anhydrous benzene, the mixture
was heated for 3 h under reflux with protection from
atmospheric moisture, 0.359 g (2.35 mmol) of methyl
bromoacetate was added, and the mixture was heated
for 2 h at 80°C. The mixture was cooled, 55 mL of
benzene and 20 mL of water were added, and the
organic phase was separated, dried over MgSO4, and
evaporated under reduced pressure. The residue was
purified by silica gel column chromatography using
benzene as eluent, followed by recrystallization from
methanol. Yield 0.675 g (73%), colorless crystals,
refined from 12442 independent reflections (Rint
=
0.0665). The final divergence factors were wR2 =
0.0697 for all independent reflections and R1 = 0.0348
for 10418 reflections with I > 2σ(I). All calculations
were performed on an IBM PC using SHELXTL [22].
The coordinates of atoms and their temperature factors
were deposited to the Cambridge Crystallographic Data
Centre (entry no. CCDC 998999) and are available at
http://www.ccdc.cam.ac.uk/products/csd/request/.
The spectral and analytical data were obtained
using the equipment of the Khimiya Shared Use Center
(Institute of Organic Chemistry, Ufa Research Center,
1
mp 122–124°C. Rf 0.43 (C6H6). H NMR spectrum, δ,
1
Russian Academy of Sciences). The H and 13C NMR
ppm: 1.18 d and 1.23 d (3H each, 1″-H, J = 6.6,
7.7 Hz), 1.65 d and 1.70 d (3H each, 5″-H, J = 6.2,
4.4 Hz), 2.33 s and 2.45 s (3H each, 4′-CH3), 3.66 s
and 3.69 s (3H each, OCH3), 3.77–3.84 m (2H, 2″-H),
4.00 d and 4.13 d (1H each, HA, J = 17.6 Hz), 4.47 d
and 4.63 d (1H each, HB, J = 17.6 Hz), 5.30–5.54 m
(4H, 3″-H, 4″-H), 6.74–7.62 m (14H, Harom). 13C NMR
spectrum, δC, ppm: 17.92, 18.10, 21.27, 21.36, 21.54,
21.66, 27.02, 27.03 (CH3); 34.90, 36.04 (C2″); 51.89,
51.98 (OCH3), 53.24, 53.48 (NCH2); 122.84, 123.50,
127.12, 128.26, 128.32, 128.41, 128.92, 129.07,
129.16, 129.31, 129.52, 130.24, 135.30, 136.89 (C3″,
C4″, C3′, C5′, C6′, C2, C6, C3, C5); 134.58, 134.64,
137.01, 138.74, 138.76, 143.09, 143.18, 146.17,
146.19, 147.28 (C1′, C2′, C4′, C1, C4); 168.94, 169.18
(C=O). Mass spectrum, m/z: 246.2 [M – H –
SO2C6H4CH3]+. Found, %: C 65.73; H 6.67; N 3.41;
S 7.92. C22H27NO4S. Calculated, %: C 65.81; H 6.78;
N 3.49; S 7.99.
spectra were recorded on Bruker AM 300 [300.13 (1H)
and 75.47 MHz (13C)] and Bruker Avance III 500
instruments (500.13 and 125.73 MHz) from solutions
in CDCl3 using tetramethylsilane as internal reference.
The elemental analyses were obtained on a EURO EA-
3000 CHNS Elemental Analyzer. The mass spectra
(electron impact, 70 eV) were recorded on a Thermo
Finnigan MAT 95 XP mass spectrometer (ion source
temperature 250°C); samples were introduced through
an HP 6890 gas chromatograph. Sorbfil PTSKh-AF-V-
UF or PTSKh-P-V-UF plates were used for qualitative
TLC analysis; spots were detected under UV light
(λ 254 nm) or by treatment with iodine vapor.
N-{2-Methyl-6-[(3E)-pent-3-en-2-yl]phenyl}-
2-nitrobenzenesulfonamide (IId) was synthesized
according to the procedure described in [5] for the syn-
thesis of sulfonamide IIb from 1.99 g (11.37 mmol) of
compound Id. The product was isolated by column
chromatography using benzene as eluent. Yield 3.19 g
Methyl N-{2-methyl-6[(3E)-pent-3-en-2-yl]-
phenyl}-N-(4-methylbenzenesulfonyl)aminoacetate
(IIIb) was synthesized in a similar way from 2.55 g
(7.77 mmol) of compound IIb. Yield 2.07 g (69%),
1
(78%), viscous liquid, Rf 0.62 (PhH). H NMR spec-
trum, δ, ppm: 1.11 d (3H, CH3, J = 7.0 Hz), 1.60 d
(3H, CH3, J = 4.8 Hz), 2.23 s (3H, 2′-CH3), 3.55–
3.66 m (1H, 2″-H), 5.25–5.36 m (2H, HC=CH), 7.04–
7.96 m (8H, Harom, NH). 13C NMR spectrum, δC, ppm:
17.89, 19.41, 20.79 (CH3); 36.82 (C2″); 124.29, 125.10,
1
viscous liquid, Rf 0.55 (PhH). H NMR spectrum, δ,
ppm: 1.10 d and 1.14 d (3H each, 1″-H, J = 4.3,
6.8 Hz), 1.58 d and 1.68 d (3H each, 5″-H, J = 6.5 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

MAZGAROVA et al.
1476
2.13 s and 2.45 s (3H each, 2′-CH3), 3.69 s and 3.73 s
(3H each, OCH3), 3.52–3.96 m (2H, 2″-H), 4.14 d and
4.20 d (1H each, HA, J = 17.6 Hz), 4.30 d and 4.41 d
(1H each, HB, J = 17.6 Hz), 5.06–5.46 m (4H, 3″-H,
4″-H), 6.97–7.74 m (14H, Harom). Found, %: C 65.74;
H 6.71; N 3.41; S 7.89. C22H27NO4S. Calculated, %:
C 65.81; H 6.78; N 3.49; S 7.99.
0.48 g (1.197 mmol) of ester IIIa in 16 mL of THF–
H2O (3:1), the mixture was stirred for 3 h, and 50 mL
of tert-butyl methyl ether and 50 mL of water were
added. The aqueous phase was separated and extracted
with 20 mL of tert-butyl methyl ether, the organic
phase was separated, and the aqueous phase was
shaken with 30 mL of 1 N aqueous HCl and extracted
with 70 mL of tert-butyl methyl ether. The organic
phase was dried over MgSO4 and the solvent was
removed under reduced pressure. Yield 0.427 g (92%),
Methyl N-{4-methyl-2-[(3E)-pent-3-en-2-yl]-
phenyl}-N-(2-nitrobenzenesulfonyl)aminoacetate
(IIIc) was synthesized in a similar way from 1.78 g
(4.96 mmol) of compound IIc. Yield 1.6 g (75%),
1
white amorphous powder. H NMR spectrum, δ, ppm:
1
1.16 d and 1.28 d (3H each, 1″-H, J = 6.8, 5.5 Hz),
1.63 d and 1.69 d (3H each, 5″-H, J = 6.3, 4.8 Hz),
2.31 s and 2.33 s (3H each, 4′-CH3), 3.69–3.97 m (2H,
2″-H), 4.05 d and 4.18 d (1H each, HA, J = 18.2 Hz),
4.44 d and 4.60 d (1H each, HB, J = 18.0, 18.4 Hz),
5.26–5.54 m (4H, 3″-H, 4″-H), 6.72–7.26 m (14H,
viscous liquid, Rf 0.54 (PhH). H NMR spectrum, δ,
ppm: 0.74 d and 1.20 d (3H each, 1″-H, J = 7.0 Hz),
1.51 d and 1.63 d (3H each, 5″-H, J = 6.3, 4.1 Hz),
3.71 s and 3.73 s (3H each, OCH3), 3.52–3.76 m (2H,
2″-H), 3.96 d and 4.00 d (1H each, HA, J = 18.4 Hz),
4.88 d and 4.94 d (1H each, HB, J = 18.4 Hz), 5.37–
5.44 m (4H, 3″-H, 4″-H), 6.94–7.69 m (14H, Harom).
Found, %: C 58.24; H 5.51; N 6.39; S 7.32.
C21H24N2O6S. Calculated, %: C 58.32; H 5.59; N 6.48;
S 7.41.
H
arom), 8.25 br.s (2H, OH). 13C NMR spectrum, δC,
ppm: 17.92, 18.10, 21.30, 21.42, 21.57, 21.66, 26.99,
27.00 (CH3); 34.90, 36.10 (C2″); 53.06, 53.36 (NCH2);
122.96, 123.73, 127.21, 127.23, 128.23, 128.25,
128.38, 128.98, 129.19, 129.25, 129.61, 130.25,
135.18, 136.74 (C3″, C4″, C3′, C5′, C6′, C2, C6, C3, C5);
134.43, 134.45, 136.08, 138.92, 138.94, 143.30,
143.39, 146.03, 147.27, 147.28 (C1′, C2′, C4′, C1, C4);
174.34, 174.61 (C=O). Found, %: C 65.01; H 6.42;
N 3.49; S 8.17. C21H25NO4S. Calculated, %: C 65.09;
H 6.50; N 3.61; S 8.28.
Methyl N-{2-methyl-6-[(3E)-pent-3-en-2-yl]-
phenyl}-N-(2-nitrobenzenesulfonyl)aminoacetate
(IIId) was synthesized in a similar way from 1.78 g
(4.96 mmol) of compound IId. Yield 1.7 g (82%),
1
viscous liquid, Rf 0.34 (PhH). H NMR spectrum, δ,
ppm: 0.93 d and 1.14 d (3H each, 1″-H, J = 7.0 Hz),
1.60 d and 1.64 d (3H each, 5″-H, J = 6.3 Hz), 2.10 s
and 2.28 s (3H each, 4′-CH3), 3.73 s and 3.75 s (3H
each, OCH3), 3.67–4.15 m (2H, 2″-H), 4.32 d and
4.39 d (1H each, HA, J = 18.0 Hz), 4.56 d and 4.66 d
(1H each, HB, J = 18.0 Hz), 5.14–5.46 m (4H, 3″-H,
4″-H), 7.01–7.69 m (14H, Harom). 13C NMR spectrum,
δC, ppm: 17.95, 18.13, 18.79, 19.32, 21.30, 22.80
(CH3); 35.50, 36.43 (C2″); 52.13, 52.22 (OCH3); 54.08,
54.23 (NCH2); 123.05, 123.85, 123.88, 126.49, 127.39,
128.32, 129.22, 129.31, 129.46, 129.67, 131.19,
131.25, 132.27, 132.30, 133.59, 133.68, 135.24,
137.10 (C3″, C4″, C3′, C4′, C5′, C3, C4, C5, C6); 133.05,
133.23, 135.63, 135.81, 138.62, 139.58, 139.61,
146.41, 148.19, 148.21 (C1′, C2′, C6′, C1, C2); 169.00,
169.09 (C=O). Mass spectrum, m/z: 246.2 [M – H –
SO2C6H4NO2]+, 186.1 [M – SO2C6H4CH3 – COOCH3 –
3H]+. Found, %: C 58.21; H 5.50; N 6.41; S 7.32.
C21H24N2O6S. Calculated, %: C 58.32; H 5.59;
N 6.48; S 7.41.
N-{2-Methyl-6-[(3E)-pent-3-en-2-yl]phenyl}-N-
(4-methylbenzenesulfonyl)aminoacetic acid (IVb)
was synthesized in a similar way from 0.580 g
(1.5 mmol) of ester IIIb. Yield 0.491 g (88%), amor-
phous powder, mp 120–122°C (from petroleum ether).
1H NMR spectrum, δ, ppm: 1.12 d and 1.14 d (3H
each, 1″-H, J = 5.9, 6.6 Hz), 1.57 d and 1.70 d (3H
each, 5″-H, J = 6.4, 4.4 Hz), 1.93 s and 2.12 s (3H
each, 2′-CH3), 3.48–4.00 m (2H, 2″-H), 4.05 d and
4.18 d (1H each, HA, J = 18.2 Hz), 4.44 d and 4.60 d
(1H each, HB, J = 18.0, 18.4 Hz), 5.03–5.49 m (4H,
3″-H, 4″-H), 6.96–7.67 m (14H, Harom), 8.23 br.s (2H,
OH). 13C NMR spectrum, δC, ppm: 17.95, 18.19,
18.88, 19.30, 21.64, 21.85, 22.42, 22.66 (CH3); 35.81,
36.83 (C2″); 53.54, 53.66 (NCH2); 122.72, 123.59,
126.47, 127.16, 128.26, 128.28, 128.83, 128.95,
129.28, 129.37, 129.43, 129.55, 135.60, 137.22 (C3″,
C4″, C3′, C4′, C5′, C2, C6, C3, C5); 136.83, 137.02,
137.04, 137.13, 138.09, 139.32, 143.60, 143.62,
146.42, 148.49 (C1′, C2′, C6′, C1, C4); 175.00, 175.02
(C=O). Found, %: C 64.98; H 6.41; N 3.54; S 8.18.
C21H25NO4S. Calculated, %: C 65.09; H 6.50;
N 3.61; S 8.28.
N-{4-Methyl-2-[(3E)-pent-3-en-2-yl]phenyl}-N-
(4-methylbenzenesulfonyl)aminoacetic acid (IVa).
Lithium hydroxide, 0.057 g (2.394 mmol), was added
under stirring at room temperature to a solution of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

SYNTHESIS OF (5R*,6R*,7S*)-6-IODO-1,5,6,7-TETRAHYDRO-4,1-BENZOXAZONIN-...
1477
treated as described above in a. Yield 0.034 g (10%);
the properties of the products obtained as described in
a and b were identical.
N-{4-Methyl-2-[(3E)-pent-3-en-2-yl]phenyl}-N-
(2-nitrobenzenesulfonyl)aminoacetic acid (IVc) was
synthesized in a similar way from 0.580 g (1.5 mmol)
of ester IIIc. Yield 0.467 g (84%), viscous liquid.
1H NMR spectrum, δ, ppm: 0.93 d and 1.14 d (3H
each, 1″-H, J = 7.0 Hz), 1.60 d and 1.64 d (3H each,
5″-H, J = 6.3 Hz), 2.10 s and 2.28 s (3H each, 4′-CH3),
4.04–4.15 m (2H, 2″-H), 4.33 d and 4.40 d (1H each,
HA, J = 18.0 Hz), 4.57 d and 4.72 d (1H each, HB, J =
18.0 Hz), 5.12–5.46 m (4H, 3″-H, 4″-H), 7.01–7.69 m
(14H, Harom). Found, %: C 57.29; H 5.22; N 6.61;
S 7.58. C20H22N2O6S. Calculated, %: C 57.40; H 5.30;
N 6.69; S 7.66.
(5S*,6R*,7R*)-6-Iodo-5,7,11-trimethyl-1-
(4-methylbenzenesulfonyl)-1,5,6,7-tetrahydro-
4,1-benzoxazonin-3(2H)-one (Vb) was synthesized in
a similar way from 0.425 g (1.09 mmol) of acid IVb.
Yield 0.125 g (22%), mp 146–148°C (from MeCN),
1
Rf 0.7 (PhH). H NMR spectrum, δ, ppm: 1.38 d (3H,
3
3
7-CH3, J = 7.0 Hz), 1.58 d (3H, 5-CH3, J = 5.9 Hz),
1.69 s and 2.47 s (3H each, CH3), 3.80 d (1H, 2-H, J =
2
3
12.9 Hz), 3.65 d.q (1H, 7-H, J = 4.5, J = 6.8 Hz),
4.08–4.18 m (1H, 5-H), 4.51 d.d (1H, 6-H, J = 4.0,
2
3J = 10.7 Hz), 4.92 d (1H, 2-H, J = 12.9 Hz), 7.02 d
(1H, Harom, J = 8.1 Hz), 7.24–7.34 m (3H, Harom, J =
8.1 Hz), 7.33 d (2H, Harom, J = 8.5 Hz), 7.64 d (2H,
Harom, J = 8.5 Hz), 7.79 d (1H, Harom). 13C NMR spec-
trum, δC, ppm: 18.27, 20.01, 21.63, 25.19 (CH3); 32.92
(C7), 49.94 (C6), 52.43 (CH2), 77.50 (C5); 127.06,
127.18, 128.77, 129.84, 130.41 (C8, C9, C10, C2′, C6′,
C3′, C5′); 134.79, 138.05, 138.44, 143.24, 143.57 (C7a,
C11, C11a, C1′, C4′); 168.19 (C3). Found, %: C 49.02;
H 4.64; I 24.64; N 2.67; S 6.19. C21H24INO4S. Calcu-
lated, %: C 49.13; H 4.71; I 24.72; N 2.73; S 6.25.
(5S*,6R*,7R*)-6-Iodo-5,7,9-trimethyl-1-(2-nitro-
benzenesulfonyl)-1,5,6,7-tetrahydro-4,1-benzoxazo-
nin-3(2H)-one (Vc). a. Compound Vc was synthesized
as described above for Va (method a) from 0.338 g
(0.808 mmol) of acid IVc. Yield 0.088 g (20%).
(5R*,6R*,7S*)-6-Iodo-5,7,9-trimethyl-1-(4-meth-
ylbenzenesulfonyl)-1,5,6,7-tetrahydro-4,1-benzoxaz-
onin-3(2H)-one (Va). a. A mixture of 0.39 g
(1.02 mmol) of compound IVa, 0.33 g (1.3 mmol) of
iodine, and 0.114 g (1.35 mmol) of sodium hydrogen
carbonate in 12 mL of methylene chloride was stirred
for 24 h at room temperature. The mixture was treated
with a CHCl3–H2O mixture, the organic extract was
washed with a 5% aqueous solution of Na2SO3 or
Na2S2O3 (2×20 mL) and with water, dried over
MgSO4, and evaporated under reduced pressure, and
the residue was subjected to column chromatography
on silica gel using benzene as eluent. Yield 0.12 g
(23%), colorless crystals, mp 174–176°C (from
1
MeCN), Rf 0.73 (PhH). H NMR spectrum, δ, ppm:
3
1.35 d (3H, 7-CH3, J = 7.0 Hz), 1.60 d (3H, 5-CH3,
3J = 5.9 Hz), 2.37 s and 2.48 s (3H each, CH3), 3.63 d
2
b. A mixture of 0.33 g (0.789 mmol) of acid IVc,
0.4 g (1.6 mmol) of I2, and 0.235 g (1.7 mmol) of
K2CO3 was stirred for 24 h at room temperature. The
mixture was treated with CHCl3–H2O, the organic
phase was separated and washed twice with an aque-
ous solution of Na2SO3 or Na2S2O3 and then with
water, dried over MgSO4, and evaporated under
reduced pressure, and the residue was purified by silica
gel column chromatography using benzene as eluent.
Yield 0.183 g (66%, calculated on the reacted acid
IVc, conversion 64%), colorless crystals, mp 193–
195°C (from MeCN), Rf 0.44 (PhH). Further elution
(1H, 2-H, J = 12.9 Hz), 3.83 d.q (1H, 7-H, J = 4.5,
3J = 6.8 Hz), 4.07–4.17 m (1H, 5-H), 4.52 d.d (1H, 6-H,
2J = 4.0, 3J = 10.7 Hz), 4.88 d (1H, 2-H, J = 12.9 Hz),
6.31 d (1H, Harom, J = 8.1 Hz), 6.88 d (1H, Harom, J =
8.1 Hz), 7.33 d (2H, Harom, J = 8.5 Hz), 7.57 d (2H,
Harom, J = 8.5 Hz), 7.72 s (1H, Harom). 13C NMR spec-
trum, δC, ppm: 20.03, 21.66, 21.68, 24.77 (CH3); 31.89
(C7), 49.90 (C6), 55.14 (CH2), 78.00 (C5); 127.82,
127.97, 128.72, 129.71, 130.07 (C8, C10, C11, C2′, C6′,
C3′, C5′); 134.23, 135.91, 139.05, 142.29, 143.64 (C7a,
C9, C11a, C1′, C4′); 168.41 (C3). Mass spectrum, m/z:
386.2 [M – H – I]+. Found, %: C 49.05; H 4.61;
I 24.61; N 2.66; S 6.18. C21H24INO4S. Calculated, %:
C 49.13; H 4.71; I 24.72; N 2.73; S 6.25.
1
gave 0.12 g (36%) of initial acid IVc. H NMR spec-
3
trum, δ, ppm: 1.33 d (3H, 7-CH3, J = 6.6 Hz), 1.60 d
3
(3H, 5-CH3, J = 6.1 Hz), 2.36 s (3H, 9-CH3), 3.76–
3
By subsequent elution with benzene–ethyl acetate
(4:1) we isolated unreacted initial acid IVa.
b. A mixture of 0.247 g (0.639 mmol) of amide VI,
0.325 g (1.28 mmol) of I2, and 0.18 g (1.3 mmol) of
K2CO3 in 10 mL of methylene chloride was stirred for
24 h at room temperature. The mixture was then
3.84 m (1H, 7-H), 4.13 d (1H, 2-H, J = 13.6 Hz),
4.22 d.q (1H, 5-H, 2J = 4.5, 3J = 6.8 Hz), 4.50 d.d (1H,
2
3
6-H, J = 4.2, J = 10.8 Hz), 4.95 d (1H, 2-H, J =
13.6 Hz), 6.61 d (1H, Harom, J = 8.1 Hz), 6.91 d (1H,
Harom, J = 6.3 Hz), 7.53 d (2H, Harom, J = 2.5 Hz) 7.69 s
(2H, Harom), 7.77 s (1H, Harom). Mass spectrum:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

MAZGAROVA et al.
1478
C5″, C6′, C2, C6, C3, C5); 134.13, 134.19, 135.33,
135.35, 138.86, 138.95, 144.20, 144.22, 145.76,
147.07 (C1′, C2′, C4′, C1, C4); 170.65, 171.01 (C=O).
Found, %: C 65.18; H 6.70; N 7.16; S 8.19.
C21H26N2O3S. Calculated, %: C 65.26; H 6.78; N 7.25;
S 8.30.
m/z 544.0 [M]+. Found, %: C 44.04; H 3.80; I 23.24;
N 5.06; S 5.81. C20H21IN2O6S. Calculated, %: C 44.13;
H 3.89; I 23.31; N 5.15; S 5.89. M 544.36.
(5S*,6R*,7R*)-6-Iodo-5,7,11-trimethyl-1-(2-nitro-
benzenesulfonyl)-1,5,6,7-tetrahydro-4,1-benzoxazo-
nin-3(2H)-one (Vd). A mixture of 0.724 g
(1.73 mmol) of acid IVd, 0.9 g (3.56 mmol) of I2, and
0.55 g (4 mmol) of K2CO3 was stirred for 24 h at room
temperature. The mixture was then treated as described
above for the synthesis of Vc (method b). Yield
0.396 g (56% on the reacted acid IVd, conversion
75%), mp 138–140°C (from MeCN), Rf 0.66 (PhH).
REFERENCES
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3
1H NMR spectrum, δ, ppm: 1.39 d (3H, 7-CH3, J =
3. Cardillo, C. and Orena, M., Tetrahedron, 1990, vol. 46,
3
6.6 Hz), 1.60 d (3H, 5-CH3, J = 5.9 Hz), 1.75 s (3H,
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11-CH3), 3.70–3.78 m (1H, 7-H), 4.22 d (1H, 2-H, J =
13.2 Hz), 4.16–4.24 m (1H, 5-H), 4.54 d.d (1H, 6-H,
2J = 3.6, 3J = 10.6 Hz), 5.04 d (1H, 2-H, J = 13.2 Hz),
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13
H
arom), 7.85 d (1H, Harom, J = 7.7 Hz). C NMR spec-
5. Mazgarova, G.G., Absalyamova, A.M., and Gataul-
trum, δC, ppm: 17.74, 19.72, 24.96 (CH3); 32.87 (C7),
49.65 (C6), 54.08 (CH2), 77.45 (C5); 124.10, 127.45,
129.10, 130.54, 131.59, 131.83, 134.01 (C8, C9, C10,
C3′, C4′, C5′, C6′); 133.17, 133.41, 138.30, 143.18,
147.61 (C7a, C11, C11a, C1′, C2′); 168.35 (C3). Mass
spectrum: m/z 544.0 [M]+. Found, %: C 44.01; H 3.80;
I 23.21; N 5.07; S 5.79. C20H21IN2O6S. Calculated, %:
C 44.13; H 3.89; I 23.31; N 5.15; S 5.89. M 544.36.
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Further elution with benzene–ethyl acetate (4:1)
gave 0.183 g (25%) of initial acid IVd.
[{4-Methyl-2-[(3E)-pent-3-en-2-yl]phenyl}-
(4-methylbenzenesulfonyl)amino]acetamide (VI).
A suspension of 0.96 g (2.406 mmol) of ester IIIa in
15 mL of a saturated solution of ammonia in methanol
was heated for 5 h at 120°C in a high-pressure reactor.
The mixture was cooled and evaporated under reduced
pressure, and the product was isolated by silica gel
column chromatography using benzene as eluent. Yield
10. Gataullin, R.R., Afon’kin, I.S., Fatykhov, A.A., Spiri-
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1
0.75 g (81%), amorphous powder. H NMR spectrum,
1979, vol. 57, p. 3296.
δ, ppm: 1.22 d and 1.27 d (3H each, 1″-H, J = 7.0,
6.8 Hz), 1.62 d and 1.72 d (3H each, 5″-H, J = 6.1,
2.6 Hz); 2.31 s, 2.33 s, and 2.46 s (12H, CH3); 3.96–
4.03 m (2H, 2″-H), 3.82 d and 3.91 d (1H each, HA, J =
16.9, 16.7 Hz), 4.20 d and 4.27 d (1H each, HB, J =
16.9, 16.7 Hz), 5.23–5.60 m (4H, 3″-H, 4″-H),
5.68 br.s and 5.77 br.s (2H, CONH2), 6.65 br.s and
6.87 br.s (2H, CONH2), 6.44–7.58 m (14H, Harom).
13C NMR spectrum, δC, ppm: 17.95, 18.13, 21.28,
21.33, 21.39, 21.60, 21.63, 21.87 (CH3); 35.38, 36.13
(C2″); 53.09, 56.56 (NCH2); 123.56, 124.21, 127.51,
127.60, 127.81, 128.32, 128.53, 128.55, 129.37,
129.58, 129.61, 134.85, 136.44, 136.46 (C2″, C3″, C3″,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 10 2014

SYNTHESIS OF (5R*,6R*,7S*)-6-IODO-1,5,6,7-TETRAHYDRO-4,1-BENZOXAZONIN-...
1479
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