Diastereoselective synthesis of novel tetra-and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives: Via intramolecular 1,3-dipolar cycloadditions

Article abstract of DOI:10.1039/c6ra14169b

A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of nitrones or azomethine ylides is described

Full text of DOI:10.1039/c6ra14169b

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Diastereolective synthesis of novel tetra-and pentacyclic
annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine,
pyrrolothiazole and isoxazolidine derivatives via intramolecular
Received 00th January 20xx,
Accepted 00th January 20xx
1
,3-dipolar cycloadditions†
DOI: 10.1039/x0xx00000x
*
Mehdi Ghandi, Nahid Zarezadeh and Alireza Abbasi
www.rsc.org/
A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine,
pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of nitrones or azomethine
ylides is described. These highly functionalized polycyclic scaffolds were obtained with high diastereoselectivity in high
yields via condensation of the initially prepared coumarin-based bifunctional starting materials with sarcosine or N-
phenylglycine, L-proline or L-4-thiazolidinecarboxylic acid, and methyl or benzylhydroxylamine. The proof of the structures
relies on analytical investigation and X-ray crystallography.
the length or position of the tether between the two reaction
centers.
Introduction
1
Sulfonamides have a rich chemical and biological history and are
an important class of compounds in drug discovery due to their
In the domain of cycloaddition, intramolecular 1,3-dipolar
2
3
cycloaddition of azomethine ylides and nitrones with alkenes on
carbo- and heterocyclic systems is one of the most efficient and
reliable strategies for the construction of functionalized and
stereoisomerically pure five-membered pyrrolidines, pyrrolizidines,
pyrrolothiazoles and isoxazolidines. As valuable building blocks, the
10
extensive chemical and biological activities. Significant interest
has been directed toward cyclic sulfonamides, also known as
11
sultams. Although not found in nature, sultams are known as
privileged structures12 in drug discovery due to their diverse
biological properties. Examples include the ampiroxicam (COX-2)
4
5
functionalized derivatives of pyrrolidines, pyrrolizidines and
13
14
6
anti-inflammatory agent, calpain inhibitor 1, benzodithiazine
pyrrolothiazoles have outstanding application in the synthesis of
15
dioxides displaying anti-HIV-1 activity,
sulthiame, brinzolamide for the treatment of glaucoma, and
antiepileptic agent
natural compounds and pharmaceuticals. On the other hand, the
isoxazolidines are valuable precursors, owing to the labile nature of
the N–O bond which can be easily modified to
biologically active β-amino acids, β-lactams, amino sugars, and
16
17
18
MMP-2 inhibitor. Sultams with promising bioactivities such as
19
20
21
22
antiviral,
a23nticancer,
antimicrobial,
antimalarial,
and
7
antileukemic, are also known. As chemically important materials,
sultams have been utilized as efficient chiral auxiliaries and
alkaloids. Thus, it is not surprising that development of synthetic
routes to pyrrolidine-, pyrrolizidine-, pyrrolothiazole-, and
isoxazolidine-containing heterocycles is an interesting challenge in
organic synthesis.
24
reagents.
On the other hand, coumarin derivatives have been the subject
2
5a,b
of recent excellent reviews
structure in many pharmaceuticals and biologically active natural
compounds with wide spectrum of considerable biological
activities such
antioxidant, and antituberculosis.
due to the presence of this core
Whereas intermolecular 1,3-dipolar cycloadditions employing
8
9
azomethine ylides
pyrrolidines/pyrrolizines/pyrrolothiazoles
respectively, in contrast, intramolecular 1,3-dipolar cycloadditions
or nitrones
lead to substituted
and isoxazolidines,
a
25c,d
25e-g
as
anti-inflammatory,
anticancer,
25h
25i
2
,3
give annulated polycyclic ring analogs.
To access this goal,
Given that the synthesis of fused triheterocycles encompassing
bioactive coumarin, δ-sultam and five-membered pyrrolidine,
pyrrolizidine, pyrrolothiazole or isoxazolidine motifs seemed to be
interesting due to their individual widespread known biological
activities and uses, we undertook a study of the synthesis of
heterocyclic scaffolds containing three motifs into one molecule. In
continuation of our previous research based on the cyclization
attention has been dedicated toward synthesis of systems in which
both reacting components are tethered to the starting material so
that polycyclic molecular architecture can be constructed via
intramolecular addition of the in situ generated azomethine ylide or
nitrone to the dipolarophile partner. So, design and synthesis of a
wide variety of polycyclic scaffolds has been carried out by changing
2
6
27
reactions, as well as sultam scaffold, herein, we report an
efficient protocol for the synthesis of novel tetra and pentacyclic
coumarin-based δ-sultam annulated pyrrolidine, pyrrolizine,
pyrrolothiazole and isoxazolidine scaffolds through in situ formation
of nitrones or azomethine ylides followed by an intramolecular 1,3-
dipolar cycloaddition reaction sequence using coumarin-based
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biofunctional starting materials. It is noticeable that two/three new
rings and three/four contiguous stereocentres with high regio- and
stereoselectivity are efficiently created in a single step in this
procedure.
Table 1 Optimization conditions of the 1,3-dipolar cycloaddition reaction of
azomethine ylide
a
Results and discussion
2
8
Initially, 4-chloro-3-formyl coumarin (2) and (E)-N-alkyl-2-
phenylethenesulfonamide 6a-d
2
9
were prepared using the
previously reported procedure (Scheme 1a). In the next step, four
deivatives of (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-
alkylethenesulfonamides 7a-d were synthesized using the method
depicted in scheme 1b.
b
Entry
Solvent
EtOH
Time (h)
Yield (%)
72
(
E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-
propylethenesulfonamide (7a) served for our early exploration of
,3-dipolar cycloaddition reaction. Indeed, 9a was isolated as the
1
2
3
4
5
10
10
7
1
MeOH
Toluene
DCE
75
sole reaction product in 72% upon treatment of 7a with an
equimolar amount of sarcosine 8a in EtOH within 10 h (entry 1,
Table 1). Whereas reaction in MeOH and toluene occurred more
efficiently (entries 2 and 3, Table 1), it was sluggish in DCE and DCM
88
96
96
5
82
DCM
85
(entries 4 and 5, Table 1). It was discovered that reaction proceeded
6
a
MeCN
96
to completion within 5 h in MeCN, affording 9a in 96% yield (entry
6, Table 1).
Reacction conditions: all reactions were carried out using aldehyde (1
mmol), sarcosine (1.1 mmol) with 4Å MS and 15 mL of solvent at reflux.
This new method was then applied to a range of 7a-d, sarcosine
b
Isolated yields.
or N-phenylglycine 8a-b in MeCN at reflux for 5 h. Tetracyclic
coumarino-δ-sultam annulated pyrrolidines 9a-h were obtained in
excellent yields (Table 2).
Table 2 Synthesis of tetracyclic annulated coumarino-δ-sultam pyrrolidines
a,b
9a-h
To explore the generality and the substrate scope of the
developed condensation, sarcosine and N-phenylglycine 8a-b were
replaced with L-proline or L-4-thiazolidinecarboxylic acid 10a-b. The
corresponding pyrrolizine and thiopyrrolizine products 11a-h were
obtained in satisfactory yields (Table 3).
1
R : Pr
Bu
Bn
6 4 2
4-MeC H CH
6
a (96%) 6b (95%) 6c (94%) 6d (95%)
a (26%) 7b (25%) 7c (29%) 7d (27%)
Preparation of (a) aldehyde and (E)-N-alkyl-2-
7
1
Scheme
2
phenylethenesulfonamide 6a-d, and (b) (E)-N-(3-formyl-2-oxo-2H-chromen-
a
4
-yl)-2-phenyl-N-alkylethenesulfonamides 7a-d.
Reacction conditions: aldehyde (1 mmol), cyclic secondary amino acid (1.1
b
mmol) with 4Å MS in MeCN (15 mL) at reflux for 5 h. Isolated yields.
2
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c
Structure of the molecule was further obtained by single crystal X-ray-
Compounds 9a-h, 11a-h and 13a-h were characterized by
1
13
diffraction analysis.
elemental analysis, MS, IR, and H and C NMR spectroscopy.
3
0
31
Unambiguous evidence for the proposed structures of 9h, 11a
3
2
Table 3 Synthesis of pentacyclic annulated coumarino-δ-sultam pyrrolizines and 13h was finally obtained by single crystal X-ray-diffraction
or pyrrolothiazoles 11a-h
a,b
analysis and the ORTEP diagrams are shown in Figure 1, 2 and 3.
Although the precise mechanism is not known, a mechanistic
postulate as shown in Scheme 2 may be invoked to rationalize the
diastereoselective formation of cis-trans 9a-h, 11a-h and 13a-h,
respectively. The dipolar cycloaddition of an azomethine ylide or
nitrone generated from sarcosine, methyl or benzylhydroxylamine
and an aldehyde with a dipolarophile could lead to a mixture of
stereoisomers. Based on the crystal structures of compounds 9h,
1
1a and 13h, the relative stereochemistry of the Ph group and the
adjacent H atom is in the anti orientation, presumably due to the
initial E geometry of the double bond present in compounds 7a-d.
Since the trans stereochemistry of the alkene dipolarophiles 7a-d
has been maintained in pyrrolidines 9a-h, pyrrolizidines 11a-d,
thiopyrrolizines 11e-h and isoxazolidines 13a-h (see Tables 2, 3 and
5
), the cycloadditions have proceeded concerted with both carbon-
carbon σ-bonds being formed at the same time, although not
necessarily to the same extent. It seems justified that the cis-trans
and trans-trans annealated products are expected to be formed via
'
endo-E-ylide I or endo-Z-nitrone I transition states and exo-Z-ylide II
'
or exo-E-nitrone II transition states, respectively (Scheme 2a,b). The
highly diastereoselective formation of cis-trans pyrrolidines 9a-h
and isoxazolidines 13a-h reveals the implication of the endo-E-ylide
'
I or endo-Z-nitrone I transition states, perhaps due to the more
favorable π-interactions in the 1,3-dipolar cycloaddition reaction.
'
Since both endo-E-ylide I or endo-Z-nitrone I transition states
correspond to an endo-orientation of the substitutient Ph and exo-
orientation of the rather bulkier coumarin substituient on the
dipolarophile, reactions in these cases proceed faster in comparison
to those passing respectively through exo-Z-ylide II or exo-E-nitrone
'
II transition states.
Table 4 Optimization conditions of the 1,3-dipolar cycloaddition reaction of
nitrone ylide
a
a
Reacction conditions: aldehyde (1 mmol), cyclic secondary amino acid (1.1
b
mmol) with 4Å MS in MeCN (15 mL) at reflux for 5 h. Isolated yields.
c
Structure of the molecule was further obtained by single crystal X-ray-
diffraction analysis.
Inspired by these results, we decided to study the 1,3-dipolar
cycloaddition reaction of (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-
phenyl-N-alkylethenesulfonamides 7a-d with N-methy or N-
benzylhydroxylamine hydrochlorides 12a-b. To prepare 13a, (E)-N-
(
3-Formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-propylethene sulfon-
amide (7a) was treated with N-methylhydroxylamine hydrochloride Entry
2a and potassium carbonate in methanol at reflux. The
b
Solvent
MeOH
EtOH
Base
Time (h)
15
Yield (%)
54
1
1
2
3
4
5
6
7
8
9
1
K
K
2
2
CO
3
3
isoxazolidine 13a was obtained in 54% yield within 15 h (entry 1,
Table 4). When the reaction was repeated in ethanol and
acetonitrile, isoxazolidine 13a was obtained in 56% and 73% during
CO
15
56
MeCN
MeCN
Toluene
MeCN
EtOH
K2CO3
10
73
1
5 h and 10 h, respectively (entries 2 and 3, Table 4). Changing the
Cs
Cs
2
2
CO
CO
3
3
10
71
base to cesium carbonate showed comparable result in acetonitrile
and lesser yield in toluene (entries 4 and 5, Table 4). It was shown
that reaction with sodium methoxide is sluggish in acetonitrile
10
68
NaOMe
15
52
(
entry 6, Table 4). Triethylamine proved to be an excellent base
especially in acetonitrile on the basis of the obtained results
entries 7 to 10, Table 4). Encouraged by this result, aldehydes 7a-d
Et
3
Et
3
Et
3
Et
3
N
N
N
N
10
68
(
MeOH
Toluene
MeCN
10
70
were then treated with with N-methy or N-benzyllhydroxylamine
hydrochlorides 12a-b, which successfully yielded desired derivatives
1
7
81
0
5
92
3a-h (Table 5).
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a
Reacction conditions: all reactions were carried out using aldehyde (1 of the tethered RN-SO -CH=CHPh group as a good dipolarophile
2
mmol), N-methyl hydroxylamine hydrochloride (1.1 mmol), and base (1.1
mmol) with 4Å MS and 15 mL of solvent at reflux. Isolated yields.
may not be overlooked.
b
Table
isoxazolidines 13a-h
5
Synthesis of tetracyclic annulated coumarino-δ-sultam
a,b
O
O O
H
H
R1
S
H
N
R1
S
N
R3
N
O
OH.HCl
2a-b
O
1
N
O
H
O
R3
CH CN, Et N
O
O
3
3
O
reflux, 5 h
7
a-d
13a-h
O
O
H
O
O
H
O
O
H
H
H
H
Fig. 1 ORTEP diagram of compound 9h with 50% probability displacement
ellipsoids (CCDC 1433802).
S
S
S
N
N
N
O
O
O
N
N
N
H
O
H
H
O
O
O
O
O
13a (92%)
13b (92%)
13c (91%)
O
O
H
O O
H
H
O
O
H
H
H
S
S
S
N
N
N
O
O
O
N
N
N
H
O
H
O
H
O
O
O
O
13d (95%)
13e (90%)
13f (93%)
O
O
H
O O
H
H
H
S
S
N
N
O
O
N
N
H
O
H
O
Fig. 2 ORTEP diagram of compound 11a 50% probability displacement
O
O
ellipsoids (CCDC 998125).
c
13g (94%)
13h (92%)
a
Reacction conditions: aldehyde (1 mmol), N-substituted hydroxylamine
hydrochloride (1.1 mmol) with 4Å MS in the presence of Et N (1.1 mmol) in
3
b
c
MeCN (15 mL) at reflux for 5 h. Isolated yields. Structure of the molecule
was further obtained by single crystal X-ray-diffraction analysis.
Notably, the dipolar cycloaddition reaction of an azomethine
ylide generated from L-proline or L-4-thiazolidinecarboxylic acid and
an aldehyde with a dienophile could lead to a mixture of endo-S-
'
shaped III or exo-W-shaped III ylides, respectively (Scheme 2c).
Inspection of other reported examples together with highly
diastereoselective formation of cis-trans pyrrolizidines 11a-d and
thiopyrrolizines 11e-h in this presentation perhaps shows some
general preference for cycloaddition through an endo-S-shaped
ylide III (Scheme 2c).
Overall, novel tetra-and pentacyclic annulated coumarino-δ-
sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine
derivatives were obtained via highly diastereoselective processes.
These reactions have presumably been proceeded intramolecularly
via the in situ generated azomethine or nitrone ylides, affording the
desired products in excellent yields (Tables 2, 3 and 5). As such, it
can be concluded that azomethine and nitrone ylide intermediates
react with dipolarophile with the least decomposition of the ylides
under the reaction conditions. It implies in turn that both
azomethine and nitrone ylides are rather stable although the nature
Fig. 3 ORTEP diagram of compound 13h 50% probability displacement
ellipsoids (CCDC 1429726).
Conclusions
4
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In conclusion, a number of bifunctional (E)-N-(3-formyl-2-oxo-2H- Scheme 2 Suggested mechanism for the formation of (a) pyrrolidines 9a-h,
b) isoxazolidines 13a-h and (c) pyrrolizidines and thiopyrrolizines 11a-h.
(
chromen-4-yl)-2-phenyl-N-alkylethenesulfonamides 7a-d
were
initially prepared from 4-chloro-3-formyl coumarin (2) and (E)-N-
alkyl-2-phenylethenesulfonamide 6a-d. These starting materials
underwent reactions with secondary amino acids or N-substituted
methyl or benzylydroxylamines in acetonitrile at reflux within 5 h. A
variety of pyrrolidines 9a-h, pyrrolizidines 11a-h and isoxazolidines
Experimental
General information
13a-h were obtained in excellent yields. These reactions were
designed to initially generate in situ an azomethine or nitrone ylides
to accomplish an intramolecular 1,3-dipolar cycloadditions. These
new structures broaden the scaffolds that are accessible through
All commercially available chemicals and reagents were purchased
from Merck Chemical Company and used without further
purification. Melting points were determined with an
Electrothermal model 9100 apparatus and are uncorrected. IR
spectra were recorded on a Shimadzu 4300 spectrophotometer, in
1,3-dipolar cycloadditions reactions and many of them may
represent interesting pharmacophores.
-1
1
13
cm . H and C NMR spectra were recorded on a Bruker DRX-500-
1
13
AVANCE spectrometer at 300 ( H) and 75 MHz ( C) using CDCl as
3
solvent. Mass spectra of the products were obtained with an HP
(
Agilent technologies) 5937 Mass Selective Detector. Elemental
analyses were carried out by a CHN-Rapid Heraeus elemental
analyzer (Wellesley, MA).
General procedure for the synthesis of compounds 6a-d
To a stirring solution of (E)-2-phenylethenesulfonyl chloride 4 (10
mmol) in CH
mmol) and K
3
CN (30 mL) were added primary amines 5a-d (10
CO (1.38 g, 10 mmol) and the reaction mixture was
2
3
stirred at room temperature (25 °C) for 24 h. After completion of
the reaction as indicated by TLC, the solid was filtered, and the
filtrate was concentrated under reduced pressure to afford
products 6a-d as yellowish oil or white solid.
General procedure for the synthesis of compounds 7a-d
To
an
ice-cooled
solution
of
(E)-N-alkyl-2-
phenylethenesulfonamide derivatives 6a-d (10 mmol) in DMF (20
ml) was added 60% sodium hydride in mineral oil (0.88 g, 22 mmol),
and the mixture was stirred for 30 min at room temperature.
Subsequently, 4-chloro-3-formyl coumarin 2 (2.08 g, 10 mmol) was
added, and the mixture was stirred for 2 h at room temperature.
After completion of the reaction as indicated by TLC, the reaction
mixture was poured into ice-water with constant stirring. The
mixture was then extracted with methylene chloride for three
times, and the organic phase was washed with water and brine
solution, and finally dried over Na
evaporated under reduced pressure, and the crude product was
purified by column chromatography (SiO , eluent: 5:1, n-hexane/
EtOAc) to afford products 7a-d as yellow solids.
E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-
propylethenesulfonamide (7a). Yellow solid (103 mg, 26%); mp
2 4
SO . The solvent was then
2
(
-
1
1
R
7
(
66-168 °C; IR (KBr) νmax 1705 (C=O), 1343 (-SO
2
), 1142 (-SO
(33% EtOAc/hexane) 0.47; H NMR (300 MHz, CDCl ) δ 0.85 (t, J =
.4 Hz, 3H, MeCH CH N), 1.46-1.55 (m, 1H, MeCHHCH N), 1.69-1.79
m, 1H, MeCHHCH N), 3.38 (ddd, J = 14.6, 11.0, 5.3 Hz, 1H,
MeCH CHHN), 3.73 (ddd, J = 14.5, 11.3, 5.4 Hz, 1H, MeCH CHHN),
.93 (d, J = 15.3 Hz, 1H, SO CH), 7.39-7.62 (8H, m, Ar and PhCH),
.73 (td, J = 8.5, 1.4 Hz, 1H, Ar), 8.21 (dd, J = 8.1, 1.3 Hz, 1H, Ar),
2
) cm ;
1
f
3
2
2
2
2
2
2
6
7
1
1
1
7
2
1
3
3
0.35 (s, 1H, CHO) ppm; C NMR (75 MHz, CDCl ) δ 11.1, 22.8, 54.1,
16.9, 118.6, 120.7, 124.8, 125.2, 128.5 (2C), 129.1 (2C), 129.3,
31.1, 132.2, 135.3, 143.3, 154.0, 154.3, 161.1, 188.0 ppm; m/z (EI,
0 eV) 398 (19, M +1), 333 (25), 304 (74), 230 (100), 212 (32), 200
+
(
15), 186 (25), 175 (8), 167 (14), 161 (30), 146 (8), 119 (25), 103
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89), 91 (26), 77 (46%); Anal. Calcd for C H NO S: C, 63.46; H, 4.82;
Journal Name
1
(
H NMR (300 MHz, CDCl ) δ 0.97 (t, 3H, J = 7.4 Hz, MeCH CH N),
2
1
19
5
3
2
2
N, 3.52. Found: C, 63.23; H, 4.91; N, 3.34%.
E)-N-Butyl-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-
phenylethenesulfonamide (7b). Yellow solid (103 mg, 25%); mp
2
1.85-2.01 (m, 2H, MeCHHCH N), 2.38 (s, 3H, MeN), 2.61 (dd, J =
1
7
0.1, 9.0 Hz, 1H, MeNCHH), 3.55-3.70 {[2H, consisting dd, J = 8.3,
.9 Hz, 1H (3.58), SO CH]; and ddd, J = 14.2, 10.9, 5.5 Hz, 1H (3.65),
(
2
-1
MeCH CHHN}, 3.97-4.10 {[ddd, J = 14.2, 10.9, 6.0 Hz, 1H (4.02),
1
39-141 °C; IR (KBr) νmax 1705 (C=O), 1347 (-SO
2
), 1139 (-SO
2
) cm ;
2
1
MeCH CHHN]; and dd, J = 9.0, 6.5 Hz, 1H (4.08), MeNCHH}, 4.16-
R (33% EtOAc/hexane) 0.52; H NMR (300 MHz, CDCl ) δ 0.83 (t, J =
2
f
3
4
.29 {[2H, consisting ddd, J = 10.1, 7.9, 7.9 Hz, 1H (4.20), PhCH]; and
7
.3 Hz, 3H, MeCH
2
CH
2
CH
2
2 2
N), 1.19-1.28 (m, 2H, MeCHHCH CH N),
d, J = 8.3 Hz, 1H (4.27), CHN}, 7.28-7.41 (m, 7H, Ar), 7.63 (td, J = 8.5,
1
.40-1.45 (m, 1H, MeCH CHHCH N), 1.65-1.69 (m, 1H,
2 2
1
3
1
.4 Hz, 1H, Ar), 7.81 (dd, J = 8.0, 1.1 Hz, 1H, Ar) ppm; C NMR (75
MHz, CDCl ) δ 11.4, 23.8, 39.4, 47.6, 56.5, 63.0, 63.5, 72.4, 117.2,
18.0, 119.0, 124.5, 124.8, 127.5, 127.7 (2C), 129.0 (2C), 133.2,
2 2
MeCH CHHCH N), 3.40 (ddd, J = 14.6, 11.0, 5.2 Hz, 1H,
MeCH CH CHHN), 3.71-3.79 (ddd, J = 14.5, 11.0, 5.5 Hz, 1H,
3
2
2
1
1
MeCH
2
CH
2
CHHN), 6.91 (d, J = 15.3 Hz, 1H, SO
2
CH), 7.38-7.60 (8H, m,
+
40.0, 153.8, 155.6, 161.5 ppm; m/z (EI, 70 eV) 425 (12, M ), 360
Ar and PhCH), 7.72 (td, J = 8.5, 1.3 Hz, 1H, Ar), 8.19 (dd, J = 8.1, 1.2
13
(9), 345 (17), 331 (14), 317 (41), 302 (8), 288 (28), 274 (16), 256
Hz, 1H, Ar), 10.33 (s, 1H, CHO) ppm; C NMR (75 MHz, CDCl
3
) δ
3.5, 19.9, 31.5, 52.3, 117.0, 118.6, 120.9, 124.9, 125.3, 128.5 (2C),
(
(
100), 240 (20), 226 (53), 214 (41), 198 (29), 133 (61), 115 (19), 104
14), 91 (25%); Anal. Calcd for C H N O S: C, 65.07; H, 5.70; N,
1
1
1
29.1 (2C), 129.4, 131.2, 132.3, 135.3, 143.4, 154.1, 154.4, 161.2,
88.1 ppm; m/z (EI, 70 eV) 412 (11, M +1), 347 (21), 318 (54), 244
23 24
2
4
+
6.60. Found: C, 64.98; H, 5.72; N, 6.61%.
(
(
100), 226 (45), 214 (15), 200 (12), 186 (36), 175 (16), 167 (14), 161
4), 146 (11), 119 (19), 103 (90), 77 (51%); Anal. Calcd for chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
10-Butyl-3-methyl-1-phenyl-1,2,3,3a,10,11a-hexahydro-4H-
11,11-dioxide
22 5
C H21NO S: C, 64.22; H, 5.14; N, 3.40. Found: C, 64.25; H, 5.14; N, (9b). White crystal (413 mg, 94%); mp 166-167 °C; IR (KBr) νmax 1693
-
1
3
.51%.
E)-N-Benzyl-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-
phenylethenesulfonamide (7c). Yellow solid (129 mg, 29%); mp
(C=O), 1351 (-SO
2
), 1144 (-SO
H NMR (300 MHz, CDCl
.27-1.48 (m, 2H, MeCHHCH
MeCH CHHCH N), 2.38 (s, 3H, MeN), 2.61 (dd, J = 10.1, 9.0 Hz, 1H,
2
) cm ; R
f
(33% EtOAc/hexane) 0.50;
1
(
3
) δ 0.95 (t, 3H, J = 7.3 Hz, MeCH
2 2 2
CH CH N),
1
2
CH N), 1.78-1.99 (m, 2H,
2
-1
1
R
1
55-157 °C; IR (KBr) νmax 1706 (C=O), 1336 (-SO
2
), 1142 (-SO
(33% EtOAc/hexane) 0.38; H NMR (300 MHz, CDCl ) δ 4.60 (d, J =
4.3 Hz, PhCHHN), 4.97 (d, J = 14.3 Hz, PhCHHN), 7.01 (d, J = 15.4
Hz, 1H, SO CH), 7.17-7.65 (14H, m, Ar and PhCH), 7.87 (d, J = 8.0 Hz,
2
) cm ;
2
2
1
MeNCHH), 3.57 (dd, J = 8.6, 7.5 Hz, 1H , SO
1.1, 5.1 Hz, 1H, MeCH CH CHHN), 4.02-4.12 {[2H, consisting m,
MeCH CH CHHN]; and dd, J = 9.0, 6.4 Hz, 1H (4.08), MeNCHH}, 4.17-
4.29 {[2H, consisting ddd, J = 10.1, 7.5, 7.5 Hz, 1H (4.20), PhCH]; and
d, J = 8.6 (4.28) Hz, 1H, CHN}, 7.28-7.41 (m, 7H, Ar), 7.63 (td, J = 8.5,
.4 Hz, 1H, Ar), 7.81 (dd, J = 8.0, 1.1 Hz, 1H, Ar) ppm; C NMR (75
MHz, CDCl ) δ 13.7, 20.2, 32.4, 39.4, 47.7, 54.7, 62.9, 63.5, 72.4,
17.2, 118.1, 119.0, 124.5, 124.8, 127.5, 127.7 (2C), 129.0 (2C),
33.2, 140.0, 153.8, 155.7, 161.4 ppm; m/z (EI, 70 eV) 439 (12, M ),
74 (6), 359 (18), 331 (29), 317 (15), 302 (14), 288 (25), 270 (100),
54 (16), 240 (65), 228 (70), 214 (29), 198 (47), 170 (10), 158 (14),
43 (12), 133 (69), 115 (37), 104 (30), 91 (49%); Anal. Calcd for
2
CH), 3.70 (ddd, J = 14.2,
f
3
1
2
2
2
2
2
1
3
1
1
1
1
2
3
H, Ar), 10.22 (s, 1H, CHO) ppm; C NMR (75 MHz, CDCl ) δ 55.4,
16.7, 119.1, 120.3, 124.9, 125.1, 128.6 (4C), 128.7, 129.2 (2C),
29.6 (2C), 131.3, 132.2, 133.8, 135.1, 143.7, 153.4, 154.2, 161.0,
88.2 ppm; m/z (EI, 70 eV) 446 (3, M +1), 381 (8), 352 (9), 278 (92),
62 (5), 248 (6), 220 (4), 167 (4), 103 (31), 91 (100%); Anal. Calcd for
13
1
+
3
1
1
3
2
1
C
+
25 5
C H19NO S: C, 67.40; H, 4.30; N, 3.14. Found: C, 67.65; H, 4.37; N,
3
.03%.
E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-N-(4-methylbenzyl)-2-
phenylethenesulfonamide (7d). Yellow solid (124 mg, 27%); mp
(
-
1
24 26 2 4
H N O S: C, 65.73; H, 5.98; N, 6.39. Found: C, 65.62; H, 5.95; N,
1
R
3
66-167 °C; IR (KBr) νmax 1704 (C=O), 1347 (-SO
2
), 1139 (-SO
(33% EtOAc/hexane) 0.45; H NMR (300 MHz, CDCl ) δ 2.22 (s,
H, Me), 4.60 (d, J = 14.2 Hz, PhCHHN), 4.90 (d, J = 14.2 Hz,
PhCHHN), 6.98-7.04 (5H, m, Ar and SO CH), 7.26-7.65 (9H, m, Ar
and PhCH), 7.92 (dd, J = 8.3, 1.4 Hz, 1H, Ar), 10.18 (s, 1H, CHO) ppm;
2
) cm ;
1
6.40%.
f
3
1
0-Benzyl-3-methyl-1-phenyl-1,2,3,3a,10,11a-hexahydro-4H-
chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
11,11-dioxide
2
(
9c). White crystal (449 mg, 95%); mp 142-144 °C; IR (KBr) νmax 1691
-
1
1
3
(
C=O), 1361 (-SO
H NMR (300 MHz, CDCl
2
), 1143 (-SO
2
) cm ; R
f
(33% EtOAc/hexane) 0.41;
3
C NMR (75 MHz, CDCl ) δ 21.1, 55.1, 116.8, 119.3, 120.3, 124.96,
1
1
1
7
25.03, 128.6 (2C), 129.2 (2C), 129.3 (2C), 129.5 (3C), 130.7, 131.3,
32.3, 135.1, 138.6, 143.7, 153.5, 154.2, 160.9, 188.2 ppm; m/z (EI,
0 eV) 460 (3, M +1), 395 (2), 354 (1), 292 (90), 276 (3), 263 (7), 248
3
) δ 2.40 (s, 3H, MeN), 2.59 (dd, J = 9.6, 8.5
CH), 4.06 (dd, J =
8.5, 6.2 Hz, 1H, MeNCHH), 4.17 (ddd, J = 9.6, 7.6, 7.6 Hz, 1H, PhCH),
.31 (d, J = 8.4 Hz, 1H, CHN), 4.73 (d, J = 14.9 Hz, 1H, PhCHHN), 5.45
d, J = 14.9 Hz, 1H, PhCHHN), 6.97 (t, J = 7.6 Hz, 1H, Ar), 7.16 (t, J =
.8 Hz, 1H, Ar), 7.27-7.37 (m, 11H, Ar), 7.48 (t, J = 7.7 Hz, 1H, Ar)
Hz, 1H, MeNCHH), 3.51 (dd, J = 8.4, 7.6 Hz, 1H , SO
2
+
4
(
(
4), 235 (3), 207 (4), 167 (6), 146 (3), 120 (5), 105 (100), 77 (31%);
Anal. Calcd for C26 S: C, 67.96; H, 4.61; N, 3.05. Found: C,
7.78; H, 5.68; N, 2.90%.
H21NO
5
7
6
1
3
ppm; C NMR (75 MHz, CDCl
3
) δ 39.4, 47.5, 58.9, 63.2, 63.5, 72.0,
1
16.7, 117.8, 119.0, 124.3, 125.4, 127.5, 127.7 (2C), 128.4, 128.6
General procedure for the synthesis of compounds 9a-d and 11a-h (2C), 129.0 (2C), 129.4 (2C), 133.0, 135.9, 140.0, 153.6, 156.1, 161.6
+
ppm; m/z (EI, 70 eV) 473 (0.8, M ), 408 (3), 393 (16), 381 (23), 365
A mixture of aldehyde derivatives 7a-d (1 mmol) and acyclic
(
(
22), 317 (19), 304 (92), 288 (8), 274 (53), 261 (19), 230 (13), 213
58), 158 (8), 133 (38), 115 (21), 104 (12), 91 (100%); Anal. Calcd for
secondary amino acids 8a-b or cyclic secondary amino acids 10a-b
1.1 mmol) in MeCN (15 mL) containing molecular sieves (500 mg,
Å) was heated at reflux with stirring for 5 h. After completion of
the reaction as indicated by TLC, the solvent was removed under
reduced pressure and the residue was recrystallized from 30%
EtOAc in hexane to afford the products 9a-h and 11a-h.
(
4
C
5
27 24 2 4
H N O S: C, 68.62; H, 5.12; N, 5.93. Found: C, 68.61; H, 5.08; N,
.95%.
-Methyl-10-(4-methylbenzyl)-1-phenyl-1,2,3,3a,10,11a-
hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
1,11-dioxide (9d). White crystal (467 mg, 96%); mp 131-133 °C; IR
3
1
3
-Methyl-1-phenyl-10-propyl-1,2,3,3a,10,11a-hexahydro-4H-
-1
(
KBr) νmax 1623 (C=O), 1352 (-SO ), 1144 (-SO ) cm ; R (33%
2 2 f
chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
11,11-dioxide
1
3
EtOAc/hexane) 0.45; H NMR (300 MHz, CDCl ) δ 2.35 (s, 3H, Me),
(
(
9a). White crystal (408 mg, 96%); mp 197-198 °C; IR (KBr) νmax 1693
-
1
2.40 (s, 3H, MeN), 2.56-2.62 (m, 1H, MeNCHH), 3.48-3.53 (m, 1H,
C=O), 1350 (-SO
2
), 1145 (-SO
2
) cm ; R
f
(33% EtOAc/hexane) 0.47;
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 12
Journal Name
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C6RA14169B
ARTICLE
SO CH), 4.03 (br s, 1H, MeNCHH), 4.13-4.19 (m, 1H, PhCH), 4.30 (d, J 129.4 (2C), 129.7 (2C), 133.2, 136.5, 139.7, 146.0, 153.6, 155.5,
2
+
=
1
8.1 Hz, 1H, CHN), 4.70 (d, J = 14.8 Hz, 1H, PhCHHN), 5.40 (d, J = 161.3 ppm; m/z (EI, 70 eV) 534 (11, M ), 443 (15), 366 (100), 275
4.8 Hz, 1H, PhCHHN), 7.00 (t, J = 7.1 Hz, 1H, Ar), 7.11-7.36 (m, 9H, (68), 261 (14), 230 (8), 195 (17), 116 (11), 106 (25), 91 (100%); Anal.
Ar), 7.49 (t, J = 7.3 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
1
3
3
) δ 21.2, Calcd for C32
26 2 4
H N O S: C, 71.89; H, 4.90; N, 5.24. Found: C, 71.78; H,
3
1
1
4
9.4, 47.4, 58.7, 63.2, 63.5, 71.9, 116.6, 117.8, 118.9, 124.3, 125.5, 4.94; N, 5.31%.
257.5, 127.7 (2C), 129.0 (2C), 129.2 (2C), 129.3 (2C), 132.9, 132.9,
38.2, 140.0, 153.6, 156.1, 161.6 ppm; m/z (EI, 70 eV) 487 (7, M ),
22 (4), 407 (17), 381 (31), 318 (76), 302 (4), 288 (32), 275 (22), 213
1
0-(4-Methylbenzyl)-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-
H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one 11,11-dioxide
9h). Yellow crystal (515 mg, 94%); mp 198-200 °C; IR (KBr) ν
+
4
(
max
(31), 133 (26), 105 (100%); Anal. Calcd for C H N O S: C, 69.11; H,
-1
2
8
26
2
4
2 2 f
1698 (C=O), 1340 (-SO ), 1139 (-SO ) cm ; R (33% EtOAc/hexane)
5
.39; N, 5.76. Found: C, 69.10; H, 5.39; N, 5.81%.
,3-Diphenyl-10-propyl-1,2,3,3a,10,11a-hexahydro-4H-
chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one 11,11-dioxide = 15.5 Hz, 1H, PhCHHN), 4.36-4.38 (m, 1H, PhCH), 4.45 (dd, J = 9.7,
9e). Yellow crystal (452 mg, 93%); mp 225-226 °C; IR (KBr) νmax 7.2 Hz, 1H, PhNCHH), 5.47-5.52 (m, 2H, PhCHHN and CHN), 6.90-
1
0
.52; H NMR (300 MHz, CDCl ) δ 2.38 (s, 3H, Me), 3.70 (dd, J = 9.7,
3
1
2
2.3 Hz, 1H, PhNCHH), 4.21 (dd, J = 6.0, 1.5 Hz, 1H, SO CH), 4.26 (d, J
(
-
1
13
1712 (C=O), 1328 (-SO
2
), 1139 (-SO
2
) cm ; R
f
(33% EtOAc/hexane) 7.40 (m, 17H, Ar), 7.46 (t, J = 7.2 Hz, 1H, Ar) ppm; C NMR (75 MHz,
) δ 21.2, 45.0, 55.2, 56.7, 57.5, 74.2, 116.6 (2C), 116.7, 117.8,
1
0.52; H NMR (300 MHz, CDCl ) δ 0.96 (t, J = 7.3 Hz, 3H, CDCl
3
3
MeCH CH N), 1.74-1.97 (m, 2H, MeCHHCH N), 3.47 (ddd, J = 14.0, 120.0, 120.5, 124.3, 125.6, 127.3 (2C), 127.83, 128.78 (2C), 129.3
2
2
2
1
3
5
=
1.8, 4.9 Hz, 1H, MeCH
2
CHHN), 3.40 (d, J = 8.5 Hz, 1H, PhNCHH), (2C), 129.6 (2C), 129.6 (2C), 133.2, 133.4, 138.3, 139.7, 146.0, 153.6,
+
.95-4.05 (ddd, J = 14.0, 11.4, 5.7 Hz, 1H, MeCH CHHN), 4.18 (d, J = 155.4, 161.2 ppm; m/z (EI, 70 eV) 548 (7, M ), 443 (20), 380 (62),
2
.8 Hz, 1H, SO
5.8 Hz, 1H, CHN), 6.92 (t, J = 7.2 Hz, 2H, Ar), 7.02 (d, J = 7.9 Hz, 2H, Anal. Calcd for C33
2
CH), 4.36-4.44 (m, 2H, PhCH and PhNCHH), 5.48 (d, J 288 (41), 275 (80), 260 (8), 195 (10), 116 (9), 105 (100), 77 (42%);
28 2 4
H N O
S: C, 72.24; H, 5.14; N, 5.11. Found: C,
Ar), 7.21 (d, J = 6.8 Hz, 1H, Ar), 7.28-7.38 (m, 7H, Ar), 7.60 (t, J = 7.7 72.21; H, 5.18; N, 4.97%.
1
3
Hz, 1H, Ar), 7.78 (d, J = 8.0 Hz, 1H, Ar) ppm; C NMR (75 MHz,
CDCl ) δ 11.3, 23.7, 45.1, 54.8, 54.9, 57.5, 74.7, 116.6 (2C), 117.2,
7
-Phenyl-5-propyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-
chromeno[4',3':3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one
dioxide (11a): White crystal (388 mg, 86%); mp 156-158 °C; IR (KBr)
3
6,6-
(33%
118.1, 120.1, 120.5, 124.4, 124.9, 127.2 (2C), 127.8, 129.3 (2C),
1
29.6 (2C), 133.3, 139.8, 145.9, 153.7, 154.7, 161.3 ppm; m/z (EI, 70
-1
ν
max 1721 (C=O), 1354 (-SO
2
), 1159 (-SO
EtOAc/hexane) 0.17; H NMR (300 MHz, CDCl ) δ 0.86 (t, J = 7.4 Hz,
CH N), 1.37-1.47 (m,
N), 1.65-1.95 (m, 4H, CH CHHCH and
N), 3.08-3.17 (m, 1H, CH CH CHHN), 3.31-3.39 (m, 1H,
CHHN), 3.64 (ddd, J = 14.6, 11.0, 5.7 Hz, 1H, MeCH CHHN),
11,11-dioxide 3.88 (ddd, J = 14.6, 11.2, 5.8 Hz, 1H, MeCH CHHN), 4.08 (td, J = 8.6,
9f). Yellow crystal (475 mg, 95%); mp 226-228 °C; IR (KBr) νmax 1710 7.4 Hz, 1H, NCHCPh), 4.27 (dd, J = 7.4, 6.1 Hz, 1H, PhCH), 4.39 (dd, J
2 f
) cm ; R
+
1
eV) 486 (9, M ), 443 (4), 318 (100), 289 (32), 276 (48), 260 (12), 240
3
(
(
13), 226 (42), 213 (13), 195 (30), 115 (28), 106 (58), 91 (42), 77
74%); Anal. Calcd for C28 S: C, 69.11; H, 5.39; N, 5.76.
3
1
H, MeCH
H, CHHCH
2
CH
2
N), 1.18-1.31 (m, 1H, CHHCH
2
2
26 2 4
H N O
2
CH
2
2
2
N
Found: C, 68.96; H, 5.45; N, 5.62%.
0-Butyl-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-4H-
chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
MeCHHCH
CH CH
2
2
2
1
2
2
2
2
(
-
1
(
C=O), 1324 (-SO
2
), 1138 (-SO
H NMR (300 MHz, CDCl ) δ 0.91 (t, J = 7.3 Hz, 3H, MeCH
.25-1.46 (m, 2H, MeCHHCH CH N), 1.64-1.91 (m, 2H,
N), 3.54 (ddd, 1H, J = 14.0, 11.9, 4.8 Hz, 1H, 63.6, 66.4, 70.0, 117.0, 117.2, 119.1, 124.4, 124.6, 127.3, 127.9 (2C),
CHHN), 3.70 (d, J = 9.2 Hz, 1H, PhNCHH), 4.02 (ddd, 1H, J 128.8 (2C), 132.6, 138.1, 149.8, 153.1, 161.1 ppm; m/z (EI, 70 eV)
2
) cm ; R
f
(33% EtOAc/hexane) 0.53; = 8.3, 6.1 Hz, 1H, SO
2
CH), 4.78 (d, J = 8.3 Hz, 1H, CHN), 7.22-7.39 (m,
1
3
2
CH CH N), 7H, Ar), 7.56 (t, J = 8.3 Hz, 1H, Ar), 7.73 (d, J = 8.0 Hz, 1H, Ar) ppm;
2
2
1
3
1
2
2
3
C NMR (75 MHz, CDCl ) δ 11.3, 23.2, 26.4, 27.5, 48.1, 55.0, 56.1,
MeCH
MeCH
2
2
CHHCH
CH
2
2
+
=
14.0, 11.4, 5.6 Hz, 1H, MeCH
SO CH), 4.33-4.43 {[2H, consisting m, 1H, PhCH]; and dd, J = 9.5, 6.8 240 (90), 226 (19), 212 (24), 198 (49), 159 (19), 115 (33), 91 (39%);
Hz, 1H (4.41), PhNCHH}, 5.47 (d, J = 5.8 Hz, 1H, CHN), 6.90 (t, J = 7.3 Anal. Calcd for C25 S: C, 66.64; H, 5.82; N, 6.22. Found: C,
Hz, 1H, Ar), 6.99 (d, J = 8.0 Hz, 2H, Ar), 7.20 (d, J = 6.8 Hz, 2H, Ar), 66.61; H, 5.78; N, 6.22%.
2 2
CH CHHN), 4.18 (d, J = 5.8 Hz, 1H, 451 (8, M ), 357 (4), 343 (6), 317 (100), 288 (46), 274 (40), 260 (19),
2
26 2 4
H N O
7
1
5
1
1
3
1
6
.27-7.38 (m, 7H, Ar), 7.60 (t, J = 7.3 Hz, 1H, Ar), 7.76 (d, J = 8.0 Hz,
5
-Butyl-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-
chromeno[4',3':3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one
dioxide (11b). White crystal (395 mg, 85%); mp 162-164 °C; IR (KBr)
1
3
3
H, Ar) ppm; C NMR (75 MHz, CDCl ) δ 13.6, 20.2, 32.1, 45.1, 53.0,
6,6-
(33%
4.7, 57.4, 74.9, 116.4 (2C), 117.3, 118.1, 120.1, 120.3, 124.3, 124.9,
27.2 (2C), 127.8, 129.3 (2C), 129.6 (2C), 133.3, 139.8, 145.9, 153.7,
-1
ν
max 1722 (C=O), 1353 (-SO
2
), 1157 (-SO
EtOAc/hexane) 0.19; H NMR (300 MHz, CDCl ) δ 0.86 (t, J = 7.4 Hz,
H, MeCH CH CH N), 1.18-1.35 (m, 3H, CHHCH CH and
MeCH CH CH N), 1.38-1.49 (m, 1H, CHHCH CH N), 1.70-1.93 (m,
H, CH CHHCH and MeCH CHHCH N), 3.09-3.18 (m, 1H,
CH CH CHHN), 3.32-3.40 (m, 1H, CH CH CHHN), 3.70 (ddd, J = 14.5,
11,11-dioxide 11.2, 5.3 Hz, 1H, MeCH CH CHHN), 3.93 (ddd, J = 14.5, 11.2, 5.3 Hz,
9g). Yellow crystal (486 mg, 91%); mp 225-227 °C; IR (KBr) νmax 1H, MeCH CH CHHN), 4.08 (td, J = 9.0, 7.4 Hz, 1H, NCHCPh), 4.27
(33% EtOAc/hexane) (dd, J = 7.4, 6.0 Hz, 1H, PhCH), 4.39 (dd, J = 8.3, 6.0 Hz, 1H, SO CH),
) δ 3.73 (dd, J = 9.7, 1.7 Hz, 1H, 4.79 (d, J = 8.3 Hz, 1H, CHN), 7.22-7.42 (m, 7H, Ar), 7.59 (td, J = 8.5,
2 f
) cm ; R
+
54.6, 161.3 ppm; m/z (EI, 70 eV) 500 (20, M ), 443 (3), 332 (100),
1
3
18 (27), 289 (69), 276 (28), 260 (10), 240 (36), 227 (13), 195 (27),
3
2
2
2
2
2
N
16 (16), 106 (42), 91 (24), 77 (41%); Anal. Calcd for C29
9.58; H, 5.64; N, 5.60. Found: C, 69.61; H, 5.58; N, 5.61%.
0-Benzyl-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-4H-
chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one
28 2 4
H N O S: C,
2
2
2
2
2
4
2
2
N
2
2
1
2
2
2
2
2
2
(
2
2
-
1
1
0
701 (C=O), 1353 (-SO
2
), 1141 (-SO
.43; H NMR (300 MHz, CDCl
2
) cm ; R
f
2
1
3
13
PhNCHH), 4.13-4.30 {[2H, consisting d, J = 6.0 Hz, 1H (4.23), SO
and d, J = 15.3 Hz, 1H (4.28), PhCHHN}, 4.39-4.41 (m, 1H, PhCH), MHz, CDCl
2
CH]; 1.4 Hz, 1H, Ar), 7.75 (dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; C NMR (75
) δ 13.5, 20.0, 26.5, 27.6, 31.7, 48.1, 53.3, 56.2, 63.6,
.47 (dd, J = 9.7, 7.4 Hz, 1H, PhNCHH), 5.52-5.57 {[2H, consisting d, J 66.4, 70.0, 117.0, 117.2, 119.2, 124.5, 124.5, 127.3, 127.9 (2C),
15.3 Hz, 1H (5.544), PhCHHN]; and d, J = 6.0 Hz, 1H (5.540), CHN}, 128.8 (2C), 132.5, 138.1, 149.8, 153.1, 161.2 ppm; m/z (EI, 70 eV)
3
5
=
6
1
3
+
.89 (t, J = 7.6 Hz, 1H, Ar), 6.95-7.48 (m, 18H, Ar) ppm; C NMR (75 465 (47, M ), 400 (3), 357 (5), 343 (6), 331 (100), 303 (28), 288 (31),
) δ 45.0, 55.1, 57.0, 57.6, 74.3, 116.7 (3C), 117.8, 120.1, 274 (34), 254 (81), 240 (25), 227 (23), 198 (38), 159 (19), 115 (17),
20.6, 124.4, 125.5, 127.3 (2C), 127.9, 128.4, 128.8 (2C), 128.9 (2C),
MHz, CDCl
3
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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DOI: 10.1039/C6RA14169B
ARTICLE
Journal Name
1
9
1 (25%); Anal. Calcd for C H N O S: C, 67.22; H, 6.07; N, 6.03. EtOAc/hexane) 0.41; H NMR (300 MHz, CDCl ) δ 0.92 (t, J = 7.3 Hz,
2
6
28
2
4
3
Found: C, 67.20; H, 6.12; N, 6.06%.
-Benzyl-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-
chromeno[4',3':3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one
dioxide (11c). White crystal (449 mg, 90%); mp 183-184 °C; IR (KBr)
1H, MeCH
2
CH
2
CH
2
2 2
N), 1.26-1.45 (m, 2H, MeCHHCH CH N), 1.82-1.92
(
m, 2H, MeCH CHHCH N), 2.51-2.63 (m, 2H, SCH C), 3.75-3.93 (m,
2 2 2
5
1
2 2 2 2
H, MeCH CH CHHN), 3.98-4.10 (m, 2H, MeCH CH CHHN and
6,6-
NCHCPh), 4.26 (d, J = 10.3 Hz, 1H, NCHHS), 4.54 (d, J = 10.3 Hz, 1H,
NCHHS), 4.58-4.73 (m, 2H, PhCH and SO CH), 4.89 (d, J = 9.5 Hz, 1H,
CHN), 7.27-7.42 (m, 7H, Ar), 7.62 (td, J = 8.6, 1.5 Hz, 1H, Ar), 7.77
-1
νmax 1712 (C=O), 1355 (-SO2), 1159 (-SO2) cm ; Rf (33%
2
1
3
EtOAc/hexane) 0.13; H NMR (300 MHz, CDCl ) δ 1.13-1.18 (m, 1H,
1
3
(
dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ 13.7,
CHHCH CH N), 1.43-1.46 (m, 1H, CHHCH CH N), 1.65-1.67 (m, 2H,
2
2
2
2
2
1
1
0.1, 32.2, 32.6, 49.2, 53.4, 56.8, 57.7, 65.6, 74.5, 117.3, 117.6,
18.9, 124.4, 124.8, 127.6 (2C), 127.8, 129.0 (2C), 133.2, 136.3,
53.6, 154.1, 161.8 ppm; m/z (EI, 70 eV) 482 (5, M ), 371 (16), 361
CH
2
CHHCH
2
N), 2.91-3.00 (m, 1H, CH
2
CH
2
CHHN), 3.33-3.40 (m, 1H,
CH CH CHHN), 3.71 (br s, 1H, NCHCPh), 4.09 (s, 2H, PhCH and
2
2
+
2
SO CH), 4.49 (d, J = 7.9 Hz, 1H, CHN), 4.78 (d, J = 15.3 Hz, 1H,
(
14), 332 (100), 315 (8), 302 (16), 288 (25), 274 (30), 254 (58), 240
(36), 228 (23), 198 (51), 177 (68), 156 (13), 130 (46), 115 (48), 103
19), 91 (53%); Anal. Calcd for C25 : C, 62.22; H, 5.43; N,
.80. Found: C, 62.23; H, 5.40; N, 5.73%.
5-Benzyl-7-phenyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-
PhCHHN), 5.24 (d, J = 15.3 Hz, 1H, PhCHHN), 6.93-6.95 (m, 2H, Ar),
1
3
7
.19-7.39 (m, 10H, Ar), 7.53-7.62 (m, 2H, Ar) ppm; C NMR (75
MHz, CDCl ) δ 26.8, 27.5, 47.1, 56.4, 56.7, 64.3, 67.0, 69.8, 116.3,
17.1, 120.0, 124.6, 125.1, 127.1, 127.8 (2C), 128.7 (2C), 128.8,
28.9 (2C), 129.1 (2C), 132.6, 134.3, 138.3, 148.8, 153.1, 160.8 ppm;
(
5
26 2 4 2
H N O S
3
1
1
+
m/z (EI, 70 eV) 499 (0.8, M ), 365 (89), 337 (6), 288 (12), 274 (40), chromeno[4,3-c]thiazolo[3',4':1,5]pyrrolo[2,3-e][1,2]thiazin-12-
61 (11), 246 (4), 230 (13), 217 (4), 202 (5), 159 (6), 128 (8), 115 one 6,6-dioxide (11g). White crystal (475 mg, 92%); mp 230-231 °C;
2
-1
(
10), 91 (100%); Anal. Calcd for C29
H
26
N
2
4
O S: C, 69.86; H, 5.26; N, IR (KBr) νmax 1703 (C=O), 1346 (-SO
2
), 1143 (-SO
EtOAc/hexane) 0.34; H NMR (300 MHz, CDCl ) δ 2.48 (d, J = 8.3 Hz,
C), 3.73 (td, J = 8.3, 7.1 Hz, NCHCPh), 4.17 (d, J = 10.2 Hz,
H, NCHHS), 2.35 (dd, J = 8.5, 7.1 Hz, 1H, PhCH), 4.47-4.53 {[2H,
CH]; and d, 1H (4.30), J =
0.2 Hz, NCHHS}, 4.84 (d, J = 9.5 Hz, 1H, CHN), 4.95 (d, J = 14.9 Hz,
2 f
) cm ; R (33%
1
5
.62. Found: C, 69.81; H, 5.31; N, 5.61%.
-(4-Methylbenzyl)-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-
2H-chromeno[4',3':3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one 6,6-
3
1
1
H, SCH
2
5
1
consisting dd, J = 9.3, 8.5 Hz, 1H (4.50), SO
2
dioxide (11d). White crystal (451 mg, 88%); mp 207-208 °C; IR (KBr)
-
1
1
ν
max 1716 (C=O), 1356 (-SO
2
), 1161 (-SO
EtOAc/hexane) 0.17; H NMR (300 MHz, CDCl ) δ 1.07-1.20 (m, 1H,
N), 1.60-1.76 (m, 2H,
N), 2.32 (s, 3H, Me), 2.88-2.96 (m, 1H, CH CH CHHN),
CH CHHN), 3.49 (br s, 1H, NCHCPh), 4.01-4.03
m, 1H, CHPh), 4.10-4.17 (m, 1H, SO CH), 4.44 (d, J = 7.8 Hz, 1H,
2
)
cm ;
R
f
(33%
1
1H, PhCHHN), 5.35 (d, J = 14.9 Hz, 1H, PhCHHN), 7.10 (td, J = 8.1, 0.9
Hz, 1H, Ar), 7.20 (d, J = 8.1 Hz, 2H, Ar), 7.30-7.40 (m, 10H, Ar), 7.54
3
CHHCH
CH CHHCH
3
(
2
CH
2
N), 1.44-1.52 (m, 1H, CHHCH
2
CH
2
13
(
td, J = 7.4, 1.4 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ 32.6,
2
2
2
2
4
1
1
4
8.5, 56.7, 56.8, 57.5, 65.5, 74.4, 117.0, 117.1, 118.7, 124.5, 125.2,
27.5 (2C), 127.7, 128.6 (3C), 128.9 (2C), 129.6 (2C), 133.1, 135.6,
36.2, 153.6, 154.2, 161.8 ppm; m/z (EI, 70 eV) 516 (1, M ), 455 (2),
25 (39), 405 (8), 366 (64), 331 (10), 313 (9), 288 (18), 274 (83), 262
.36-3.43 (m, 1H, CH
2
2
2
+
CHN), 4.72 (d, J = 15.1 Hz, 1H, PhCHHN), 5.17 (d, J = 15.1 Hz, 1H,
PhCHHN), 6.87-6.89 (m, 2H, Ar), 7.06 (s, 4H, Ar), 7.37 (d, J = 8.2 Hz,
(
19), 246 (8), 230 (23), 217 (9), 202 (14), 177 (39), 147 (9), 130 (42),
1
H, Ar), 7.56 (t, J = 7.6 Hz, 1H, Ar), 7.67 (d, J = 7.7 Hz, 1H, Ar) ppm;
1
3
28 24 2 4 2
115 (36), 103 (13), 91 (100%); Anal. Calcd for C H N O S : C, 65.09;
C NMR (75 MHz, CDCl
3
) δ 21.1, 27.1, 27.5, 46.7, 56.2, 57.1, 64.6,
H, 4.68; N, 5.42. Found: C, 65.17; H, 4.65; N, 5.38%.
6
1
1
3
1
7.1, 69.7, 116.2, 117.1, 120.1, 124.6, 125.1, 127.1, 127.8 (2C),
28.6 (2C), 129.3 (2C), 129.4 (2C), 130.9, 132.6, 138.6, 138.9, 148.4,
5-(4-Methylbenzyl)-7-phenyl-5,6a,7,7a,8,11a-hexahydro-
+
53.1, 160.7 ppm; m/z (EI, 70 eV) 512 (0.8, M ), 407 (2), 379 (67), 10H,12H-chromeno[4,3-c]thiazolo[3',4':1,5]pyrrolo[2,3-
43 (8), 302 (4), 288 (8), 274 (29), 230 (10), 202 (5), 173 (8), 128 (8), e][1,2]thiazin-12-one 6,6-dioxide (11h). White crystal (482 mg,
15 (10), 105 (100), 91 (19%); Anal. Calcd for C30
H
28
N
2
O
4
S: C, 70.29; 91%); mp 175-177 °C; IR (KBr) νmax 1706 (C=O), 1334 (-SO
2
), 1135 (-
(33% EtOAc/hexane) 0.38; H NMR (300 MHz, CDCl ) δ
.37 (Me), 2.49 (d, J = 8.2 Hz, 1H, SCH C), 3.75 (td, J = 8.2, 7.0 Hz,
NCHCPh), 4.17 (d, J = 10.2 Hz, 1H, NCHHS), 4.36 (dd, J = 8.5, 7.0 Hz,
-
1
1
H, 5.51; N, 5.46. Found: C, 70.33; H, 5.47; N, 5.33%.
SO
2
) cm ; R
f
3
2
2
7
-Phenyl-5-propyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-
chromeno[4,3-c]thiazolo[3',4':1,5]pyrrolo[2,3-e][1,2]thiazin-12-
one 6,6-dioxide (11e). White crystal (421 mg, 90%); mp 2.68-270
1
1
H, PhCH), 4.45 (dd, J = 9.1, 8.5 Hz, 1H, SO
H, NCHHS), 4.82 (d, J = 9.1 Hz, 1H, CHN), 4.90 (d, J = 14.9 Hz, 1H,
2
CH), 4.53 (d, J = 10.2 Hz,
-
1
°
C; IR (KBr) νmax 1715 (C=O), 1345 (-SO
2
), 1141 (-SO
EtOAc/hexane) 0.38; H NMR (300 MHz, CDCl ) δ 0.95 (t, J = 7.4 Hz,
N), 1.85-1.98 (m, 2H, MeCHHCH N), 2.51-2.64 (m,
C), 3.79-3.90 (m, 1H, MeCH CHHN), 3.94-4.10 (m, 2H,
CHHN and NCHCPh), 4.27 (d, J = 10.3 Hz, 1H, NCHHS), 4.53
d, J = 10.3 Hz, 1H, NCHHS), 4.58-4.73 (m, 2H, PhCH and SO CH),
.89 (d, J = 9.5 Hz, 1H, CHN), 7.32-7.43 (m, 7H, Ar), 7.63 (td, J = 8.4,
2 f
) cm ; R (33%
1
PhCHHN), 5.30 (d, J = 14.9 Hz, 1H, PhCHHN), 7.10-7.43 (m, 12H, Ar),
3
1
3
7
2
1
1
5
3
.55 (td, J = 8.4, 1.4 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl ) δ
3
2
H, MeCH
H, SCH
2
CH
2
2
1.2, 32.6, 48.3, 56.7, 56.8, 57.5, 65.3, 74.3, 116.99, 117.04, 118.6,
24.4, 125.3, 127.5 (2C), 127.7, 128.9 (2C), 129.2 (2C), 129.5 (2C),
32.4, 133.1, 136.3, 138.5, 153.6, 154.1, 161.8 ppm; m/z (EI, 70 eV)
2
2
MeCH
(
4
1
2
2
+
30 (2, M ), 425 (52), 400 (4), 380 (27), 333 (12), 313 (7), 295 (69),
1
3
274 (19), 253 (6), 239 (22), 177 (12), 130 (16), 115 (19), 105 (100%);
Anal. Calcd for C29 : C, 65.64; H, 4.94; N, 5.28. Found: C,
5.43; H, 5.03; N, 5.18%.
.4 Hz, 1H, Ar), 7.78 (dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; C NMR (75
) δ 11.3, 23.7, 32.6, 49.2, 55.1, 56.7, 57.6, 65.7, 74.5,
17.3, 117.6, 118.9, 124.4, 124.8, 127.6 (2C), 127.8, 129.0 (2C),
33.3, 136.3, 153.6, 154.1, 161.8 ppm; m/z (EI, 70 eV) 468 (0.8, M ),
57 (11), 318 (100), 288 (36), 274 (31), 260 (14), 240 (68), 228 (25),
14 (19), 198 (50), 177 (58), 156 (16), 130 (63), 115 (69), 103 (25),
26 2 4 2
H N O S
MHz, CDCl
3
6
1
1
3
2
9
+
General procedure for the synthesis of compounds 13a-h
1 (69%); Anal. Calcd for C24
H
24
N
2
O
4
S
2
: C, 61.52; H, 5.16; N, 5.98.
A mixture of aldehyde derivatives 7a-d (1 mmol), N-methyl or
Found: C, 61.50; H, 5.16; N, 6.01%.
benzylhydroxylamines hydrochloride 12a-b (1.1 mmol) and Et
3
N
(
1.1 mmol) in MeCN (15 mL) containing molecular sieves 4Å was
5
-Butyl-7-phenyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-
heated at reflux with stirring for 5 h. After completion of the
reaction as indicated by TLC, the solvent was removed under
reduced pressure, and then H O (10 mL) was added and the mixture
chromeno[4,3-c]thiazolo[3',4':1,5]pyrrolo[2,3-e][1,2]thiazin-12-
one 6,6-dioxide (11f). White crystal (429 mg, 89%); mp 210-213 °C;
IR (KBr) νmax 1716 (C=O), 1345 (-SO ), 1141 (-SO ) cm ; R (33%
2 2 f
-1
2
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 9 of 12
Journal Name
PleaseRd So Cn oA t da vd aj un s ct ems argins
View Article Online
DOI: 10.1039/C6RA14169B
ARTICLE
was extracted with EtOAc (3 × 10 ml). The combined organic phase 2.88 (s, 3H, MeN), 4.20 (br s, 1H, SO CH), 4.57 (d, J = 8.9 Hz, 1H,
2
was dried over Na
2 4
SO , filtered, and evaporated in vacuo and the CHN), 4.65 (d, J = 15.2 Hz, 1H, PhCHHN), 5.55 (d, J = 15.2 Hz, 1H,
residue was recrystallized from 30% EtOAc in hexane to afford the PhCHHN), 5.72 (d, J = 6.5 Hz, 1H, PhCHO), 7.02 (t, J = 7.5 Hz, 1H, Ar),
1
3
products 13a-h.
-Methyl-1-phenyl-10-propyl-1,3a,10,11a-
tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
1,11-dioxide (13a). White crystal (392 mg, 92%); mp 182-183 °C; IR
7.14-7.54 (m, 12H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ 21.2, 43.2,
9.4, 66.3, 74.0, 82.1, 115.1, 116.8, 117.5, 124.4, 125.7, 126.7 (2C),
5
1
1
3
29.0 (2C), 129.1 (3C), 129.4 (2C), 132.7, 133.5, 136.8, 138.4, 153.7,
57.1, 161.0 ppm; m/z (EI, 70 eV) 488 (9, M ), 378 (39), 317 (14),
289 (14), 274 (30), 246 (8), 230 (19), 213 (18), 202 (13), 136 (51),
105 (100), 91 (21), 77 (78%); Anal. Calcd for C H N O S: C, 66.38;
H, 4.95; N, 5.73. Found: C, 66.40; H, 4.96; N, 5.71%.
+
1
-1
(
KBr) νmax 1697 (C=O), 1328 (-SO ), 1144 (-SO ) cm ; R (33%
2 2 f
1
EtOAc/hexane) 0.45; H NMR (300 MHz, CDCl
3
) δ 0.99 (t, J = 7.4 Hz,
27 24 2 5
3
H, MeCH CH N), 1.95-2.05 (m, 2H, MeCHHCH N), 2.85 (s, 3H,
2
2
2
MeN), 3.69 (ddd, J = 14.3, 10.2, 6.4 Hz, 1H, MeCH
2
CHHN), 4.11 (ddd,
3-Benzyl-1-phenyl-10-propyl-1,3a,10,11a-
J = 14.3, 10.2, 6.6 Hz, 1H, MeCH CHHN), 4.25 (dd, J = 9.1, 6.7 Hz, 1H, tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
2
2
SO CH), 4.55 (d, J = 9.1 Hz, 1H, CHN), 5.71 (d, J = 6.7 Hz, 1H, PhCHO), 11,11-dioxide (13e). White crystal (452 mg, 90%); mp 158-159 °C; IR
-
1
7
1
1
1
1
.37-7.46 (m, 5H, Ar), 7.52-7.54 (m, 2H, Ar), 7.65 (td, J = 8.4, 1.2 Hz, (KBr) νmax 1696 (C=O), 1357 (-SO
2
), 1147 (-SO
2 f
) cm ; R (33%
13
1
H, Ar), 7.81 (d, J = 8.1 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ EtOAc/hexane) 0.43; H NMR (300 MHz, CDCl ) δ 1.01 (t, J = 7.3 Hz,
1.3, 23.8, 43.2, 56.8, 66.0, 74.4, 82.0, 115.1, 117.4, 117.6, 124.5, 1H, MeCH CH N), 1.98-2.10 (m, 2H, MeCHHCH N), 3.80 (ddd, J =
CHHN), 4.12-4.31 {[4H, consisting s, 2H
60.9 ppm; m/z (EI, 70 eV) 426 (49, M ), 380 (19), 338 (31), 316 (4.17), PhCH N]; [m, 1H, MeCH CHHN]; and dd, 1H, J = 8.8, 6.5 Hz,
3
2
2
2
25.0, 126.7 (2C), 128.9 (2C), 129.1, 133.7, 136.7, 153.9, 156.2, 14.2, 10.8, 6.5 Hz, 1H, MeCH
2
+
2
2
(
100), 304 (13), 288 (21), 274 (80), 255 (36), 240 (22), 227 (80), 214 1H (4.28), SO
2
CH}, 4.85 (d, J = 8.8 Hz, 1H, CHN), 5.74 (d, J = 6.4 Hz,
(
94), 198 (51), 185 (18), 134 (70), 115 (25), 105 (35), 91 (35%); Anal. 1H, PhCHO), 7.22-7.54 (m, 12H, Ar), 7.66 (t, J = 7.6 Hz, 1H, Ar), 7.83
13
Calcd for C22
H
22
N
2
O
5
S: C, 61.96; H, 5.20; N, 6.57. Found: C, 61.97; H, (d, J = 7.8 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
56.9, 60.1, 64.6, 74.3, 82.1, 115.3, 117.3, 117.7, 124.6, 125.0, 126.7
2C), 127.4, 128.2 (2C), 128.4 (2C), 128.9 (2C), 129.0, 133.8, 136.8,
3
) δ 11.3, 23.9,
5
.17; N, 6.61%.
0-Butyl-3-methyl-1-phenyl-1,3a,10,11a-
tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
(
1
+
1
(
2
36.9, 153.9, 156.3, 161.2 ppm; m/z (EI, 70 eV) 502 (17, M ), 411
42), 380 (8), 369 (7), 331 (15), 316 (70), 303 (8), 288 (16), 274 (31),
49 (21), 227 (26), 212 (12), 198 (42), 105 (36), 91 (100%); Anal.
1
1,11-dioxide (13b). White crystal (405 mg, 92%); mp 151-153 °C;
-1
IR (KBr) νmax 1701 (C=O), 1352 (-SO
EtOAc/hexane) 0.50; H NMR (300 MHz, CDCl
3
2
), 1144 (-SO
) δ 0.97 (t, J = 7.4 Hz,
CH N), 1.85-2.04
N), 2.85 (s, 3H, MeN), 3.72 (ddd, J = 14.3,
CH CHHN), 4.17 (ddd, J = 14.3, 11.0, 5.7 Hz, tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
CHHN), 4.25 (dd, J = 9.0, 6.7 Hz, 1H, SO CH), 4.55 (d, J 11,11-dioxide (13f). White crystal (480 mg, 93%); mp 199-200 °C; IR
9.0 Hz, 1H, CHN), 5.71 (d, J = 6.7 Hz, 1H, PhCHO), 7.37-7.45 (m, (KBr) νmax 1711 (C=O), 1346 (-SO
2 f
) cm ; R (33%
1
28 26 2 5
Calcd for C H N O S: C, 66.91; H, 5.21; N, 5.57. Found: C, 66.90; H,
3
5
.25; N, 5.68%.
H, MeCH
2
CH
2
CH
CHHCH
1.0, 5.5 Hz, 1H, MeCH
H, MeCH CH
2
N), 1.30-1.50 (m, 2H, MeCHHCH
2
2
(m, 2H, MeCH
2
2
3-Benzyl-10-butyl-1-phenyl-1,3a,10,11a-
1
1
=
5
2
2
2
2
2
-
1
2
), 1140 (-SO
H, Ar), 7.52-7.54 (m, 2H, Ar), 7.66 (td, J = 8.5, 1.3 Hz, 1H, Ar), 7.81 EtOAc/hexane) 0.45; H NMR (300 MHz, CDCl ) δ 0.98 (t, J = 7.3 Hz,
N), 1.35-1.49 (m, 2H, MeCHHCH CH N), 1.94-2.05
CHHCH N), 3.87 (ddd, J = 14.0, 11.4, 5.6 Hz, 1H,
CHHN), 4.12-4.32 {[4H, consisting AB-q, J = 14.9 Hz, 2H
N]; [m, 1H, MeCH CH CHHN]; and dd, 1H, J = 8.9, 6.8
88 (19), 274 (69), 240 (18), 227 (88), 214 (49), 198 (46), 185 (14), Hz, 1H (4.29), SO CH}, 4.84 (d, J = 9.0 Hz, 1H, CHN), 5.73 (d, J = 6.8
34 (63), 115 (28), 105 (34), 115 (30), 105 (36), 91 (38), 77 (74%); Hz, 1H, PhCHO), 7.22-7.54 (m, 12H, Ar), 7.66 (t, 1H, J = 7.6 Hz, Ar),
2
) cm ; R
f
(33%
1
3
1
3
(d, J = 8.1 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ 13.7, 20.1, 1H, MeCH
2.4, 43.2, 55.2, 66.0, 74.4, 82.1, 115.2, 117.4, 117.6, 124.5, 125.0, (m, 2H, MeCH
26.7 (2C), 128.9 (2C), 129.1, 133.7, 136.8, 153.9, 156.2, 160.9 ppm; MeCH CH
2
CH
2
CH
2
2
2
3
1
2
2
2
2
+
m/z (EI, 70 eV) 440 (20, M ), 394 (12), 359 (9), 338 (31), 330 (100), (4.17), PhCH
2
1
2
2
2
2
1
3
Anal. Calcd for C23
H
24
N
2
O
5
S: C, 62.71; H, 5.49; N, 6.36. Found: C, 7.82 (d, J = 7.8 Hz, 1H, Ar) ppm; C NMR (75 MHz, CDCl
3
) δ 13.7,
6
2.74; H, 5.50; N, 5.54%.
0-Benzyl-3-methyl-1-phenyl-1,3a,10,11a-
tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
1,11-dioxide (13c). White crystal (431 mg, 91%); mp 175-176 °C; IR
20.2, 32.5, 55.0, 60.1, 64.6, 74.4, 82.1, 115.3, 117.4 117.7, 124.5,
1
1
25.0, 126.7 (2C), 127.3, 128.2 (2C), 128.4 (2C), 128.9 (2C), 129.0,
1
33.8, 136.8, 136.9, 153.9, 156.2, 161.2 ppm; m/z (EI, 70 eV) 516 (5,
+
M ), 425 (36), 394 (7), 369 (8), 345 (14), 330 (95), 303 (22), 288 (17),
1
-1
2
74 (44), 249 (28), 220 (29), 198 (65), 105 (58), 91 (100%); Anal.
(KBr) νmax 1705 (C=O), 1346 (-SO
2
), 1141 (-SO
EtOAc/hexane) 0.45; H NMR (300 MHz, CDCl ) δ 2.89 (s, 3H, MeN),
.23 (br s, 1H, SO CH), 4.59 (d, J = 8.9 Hz, 1H, CHN), 4.68 (d, J = 15.2
Hz, 1H, PhCHHN), 5.60 (d, J = 15.2 Hz, 1H, PhCHHN), 5.72 (d, J = 6.5
Hz, 1H, PhCHO), 6.97 (t, J = 7.4 Hz, 1H, Ar), 7.13 (d, J = 7.6 Hz, 1H, c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one 11,11-dioxide (13g). White
2 f
) cm ; R (33%
1
29 28 2 5
Calcd for C H N O S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.50; H,
3
5
.46; N, 5.48%.
4
2
3,10-Dibenzyl-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-
1
3
3
Ar), 7.30-7.52 (m, 12H, Ar) ppm; C NMR (75 MHz, CDCl ) δ 43.2, crystal (517 mg, 94%); mp 195-197 °C; IR (KBr) νmax 1721 (C=O),
-
1
1
5
1
1
3
1
9.6, 66.3, 74.1, 82.2, 115.2, 116.8, 117.4, 124.5, 125.6, 126.7 (2C), 1385 (-SO
28.6, 128.8 (2C), 129.0 (2C), 129.1 (3C), 133.5, 135.8, 136.7, 153.7, (300 MHz, CDCl
57.0, 161.0 ppm; m/z (EI, 70 eV) 474 (39, M ), 364 (72), 319 (8), (4.25) PhCH
03 (43), 286 (8), 274 (49), 246 (10), 230 (24), 213 (52), 202 (14), PhCHHNSO ), 4.92 (d, J = 8.8 Hz, 1H, CHN), 5.70 (d, J = 15.1 Hz, 1H,
36 (88), 105 (25), 91 (100%); Anal. Calcd for C26 S: C, 65.81; PhCHHNSO ), 5.77 (d, J = 6.4 Hz, 1H, PhCHO), 6.92 (t, J = 7.5 Hz, 1H,
2
2
), 1148 (-SO
) δ 4.19-4.31 {[3H, consisting AB-q, J = 14.7 Hz, 2H
N]; and br s, 1H (4.31), SO CH}, 4.74 (d, J = 15.1 Hz, 1H,
2 f
) cm ; R (33% EtOAc/hexane) 0.41; H NMR
3
+
2
2
2
H
22
N
2
O
5
1
3
H, 4.67; N, 5.90. Found: C, 62.80; H, 5.71; N, 5.79%.
-Methyl-10-(4-methylbenzyl)-1-phenyl-1,3a,10,11a-
tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
1,11-dioxide (13d). White crystal (464 mg, 95%); mp 150-152 °C;
Ar), 7.05 (d, J = 7.7 Hz, 1H, Ar), 7.27-7.55 (m, 17H, Ar) ppm; C NMR
75 MHz, CDCl ) δ 60.0, 60.1, 65.1, 73.9, 82.4, 115.2, 116.7, 117.6,
(
3
3
1
24.4, 125.6, 126.7 (2C), 127.5, 128.3 (2C), 128.5 (2C), 128.6, 128.88
(
2C), 128.94 (2C), 129.1, 129.2 (2C), 133.6, 135.9, 136.7, 136.8,
1
+
-1
153.7, 157.4, 161.3 ppm; m/z (EI, 70 eV) 550 (7, M ), 459 (11), 364
IR (KBr) νmax 1705 (C=O), 1346 (-SO ), 1141 (-SO ) cm ; R (33%
EtOAc/hexane) 0.50; H NMR (300 MHz, CDCl ) δ 2.36 (s, 3H, Me),
3
2
2
f
1
(44), 289 (20), 275 (75), 230 (22), 220 (26), 202 (12), 106 (38), 91
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J. Name., 2013, 00, 1-3 | 9
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DOI: 10.1039/C6RA14169B
ARTICLE
100%); Anal. Calcd for C H N O S: C, 69.80; H, 4.76; N, 5.09.
Journal Name
(
Florentino, F. Delgado and J. Tamariz, Synthesis, 2016, 48
1055.
,
3
2
26
2
5
Found: C, 69.82; H, 4.71; N, 4.95%.
-Benzyl-10-(4-methylbenzyl)-1-phenyl-1,3a,10,11a-
tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one
1,11-dioxide (13h). White crystal (519 mg, 92%); mp 210-212 °C;
3
For some recent examples on intramolecular 1,3-dipolar
cycloadditions of nitrone ylides, see: (a) U. Chiacchio, A.
Corsaro, G. Gumina, V. Pistará, A. Rescifina, M. Alessi, A.
3
1
Piperno, G. Pomeo and R. Roberto, Tetrahedron, 1997, 53
,
-1
IR (KBr) νmax 1712 (C=O), 1345 (-SO ), 1148 (-SO ) cm ; R (33%
2
2
f
13855; (b) E. M. Beccalli, G. Broggini, G. La Rosa, D.
Passarella and T. Pilati, J. Org. Chem., 2000, 65, 8924; (c) Q,
Zaho, F. Han and D. L. Romero, J. Org. Chem., 2000, 67, 3317;
(d) G. K. Tranmer and W. Tam, J. Org. Chem., 2001, 66, 5113;
1
3
EtOAc/hexane) 0.46; H NMR (300 MHz, CDCl ) δ 2.38 (s, 3H, Me),
4
.23-4.29 {[3H, consisting s, 2H (4.24) PhCH N]; and br s, 1H (4.30),
2
SO
2
2
CH}, 4.70 (d, J = 15.1 Hz, 1H, PhCHHNSO ), 4.90 (d, J = 8.8 Hz,
(
e) K. Singha, A. Roy, P. K. Dutta, S. Tripathi, S. Sahabuddin, B.
1
H, CHN), 5.65 (d, J = 15.1 Hz, 1H, PhCHHNSO ), 5.76 (d, J = 6.5 Hz,
2
Achari and S. B. Mandal, J. Org. Chem., 2004, 69, 6507; (f) P.
K. Kalita, B. Baruah and P. J. Bhuyan, Tetrahedron Lett., 2006,
1
H, PhCHO), 6.96 (t, J = 7.6 Hz, 1H, Ar), 7.14-7.53 (m, 17H, Ar) ppm;
1
3
C NMR (75 MHz, CDCl ) δ 21.2, 60.0, 60.1, 65.0, 73.9, 82.3, 115.1,
3
4
7
, 7779; (g) A. Chatterjee and P. K. Bhattacharya, J. Org.
Chem., 2006, 71, 345; (h) G. Singh, M. P. S. Ishar, V. Gupta, G.
Singh, M. Kalyan and S. S. Bhella, Tetrahedron, 2007, 63
1
1
1
16.7, 117.6, 124.4, 125.7, 126.7 (2C), 127.4, 128.3 (2C), 128.4 (2C),
28.9 (2C), 129.0, 129.1 (2C), 129.5 (2C), 132.8, 133.5, 136.7, 136.9,
38.4, 153.7, 157.4, 161.3 ppm; m/z (EI, 70 eV) 564 (5, M ), 378
,
+
4
2
773; (i) M. Bakthadoss and G, Murugan, Eur. J. Org. Chem.,
010, 5825; (j) S. Saubern, J. M. Macdonald, J. H. Ryan, R. C.
(
C
25), 289 (34), 274 (12), 220 (8), 105 (100), 91 (83%); Anal. Calcd for
S: C, 70.19; H, 5.00; N, 4.96. Found: C, 70.23; H, 5.06; N,
33
H
28
N
2
O
5
J. Woodgate, T. S. Louie, M. J. Fuchter, J. M. White and A. B.
Holmes, Tetrahedron, 2010, 66, 2761; (k) S. Majumder and P.
J. Bhuyan, Tetrahedron Lett., 2012, 53, 762; (l) E. H. Krenske,
S. Agopcan, V. Aviyente, K. N. Houk, B. A. Johnson and A. B.
Holmes, J. Am. Chem. Soc., 2012, 134, 12010; (m) M.
Bakthadoss, G, Sivakumar and D. S. Sharada, Synthesis, 2013,
45, 237; (n) R. Rajesh, M. Suresh and R. Raghunathan,
Tetrahedron Lett., 2014, 55, 69; (o) M. Bakthadoss and J.
5.01%.
Acknowledgements
We acknowledge the University of Tehran for financial support of
this research.
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Notes and references
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For reviews on 1,3-dipolar cycloaddition reactions, see: (a) A.
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For some recent examples on intramolecular 1,3-dipolar
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2
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(
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1
0 | J. Name., 2012, 00, 1-3
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PleaseRd So Cn oA t da vd aj un s ct ems argins
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DOI: 10.1039/C6RA14169B
ARTICLE
1
2 For recent reviews on sultam chemistry, see: (a) A.
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1
1
1
1
1
1
28 K.-T. Li, Y.-B. Lin and D.-Y. Yang, Org. Lett., 2012, 14, 1190.
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30 The CCDC deposition number for compound 9h is 1433802.
23, 365.
8 R. J. Cherney, R. Mo, D. T. Meyer, K. D. Hardman, R.-Q. Liu,
M. B. Covington, M. Qian, Z. R. Wasserman, D. D. Christ, J. M.
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Formula: C33
b = 16.285(3) Å, c = 17.991(6) Å, α = 90.00°, β = 133.170(18)°,
γ = 90.00°, space group P 2 /c.
31 The CCDC deposition number for compound 11a is 998125.
Formula: C25 S. Unit cell parameters: a = 8.790(2) Å, b
= 15.553(2) Å, c = 16.313(2) Å, α = 90.00°, β = 90.00°, γ =
90.00°, space group P 2
0 A. Scozzafava, T. Owa, A. Mastrolorenzo and C. T. Supuran, 32 The CCDC deposition number for compound 13h is 1429726.
28 2 4
H N O S. Unit cell parameters: a = 13.148(3) Å,
1
2
004, 47, 2981.
1
9 R. Di Santo1, R. Costi1, M. Artico1, S. Massa, M. E. Marongiu,
26 2 4
H N O
A. G. Loi, A. De Montis and P. La Colla, Antiviral Chem.
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9, 127.
1 1 1
2 2 .
2
2
2
2
Curr. Med. Chem., 2003, 10, 925.
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Formula: C33
b = 11.159(2) Å, c = 17.179(3) Å, α = 90.00°, β = 108.33(3)°, γ
= 90.00°, space group P 2 /n.
28 2 5
H N O S. Unit cell parameters: a = 14.898(3) Å,
1
2 C. Valente, R. C. Guedes, R. Moreira, J. Iley, J. Gut and P.
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2
2
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.
5 For recent reviews on coumarin chemistry, see: (a) F. G.
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Córdova-Guerrero, A. G. Teissier García and S. Osegueda-
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5,
38892; (d) G. Kayal, K. Jain, S. Malviya and A. Kharia, Int. J.
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(
e) S. Emami and S. Dadashpour, Eur. J. Med. Chem., 2015,
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Dosedel, R. Hrdina, P. Anzenbacher, T. Filipsky, M. Riha and
P. Mladenka, Curr. Top. Med. Chem., 2015, 15, 830. For
antituberculosis activity, see: (i) R. S. Keri, B. S. Sasidhar, B. M
and Nagaraja, M. A. Santos, Eur. J. Med. Chem., 2015, 100
2
,
57.
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2
Tabatabaei Rezaei and A. Taheri, Tetrahedron Lett., 2009, 50
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4
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Mohammadimehr, M. Sadeghzadeh and A. Hasani
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J. Name., 2013, 00, 1-3 | 11
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DOI: 10.1039/C6RA14169B
ARTICLE
Journal Name
Graphical abstract
Diastereolective synthesis of novel tetra-and pentacyclic annulated coumarino-δ-
sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives via
intramolecular 1,3-dipolar cycloadditions
*
Mehdi Ghandi, Nahid Zarezadeh and Alireza Abbasi
OH
O
O
O O
S
H
H
R1
O
N
H
N
R2
OH
N
O O
S
H
H
O
R2
H
R1
O
N
O
3
O
N
R NHOH.HCl
CH CN
3
R1
S
H
O
R3
O
O
H
N
H
CH3CN, Et3N
reflux, 5 h
O
R1
O
reflux, 5 h
S
X
N
O
CO H
R1 = Pr, Bu, Bn, 4-MeC6H4CH2
R2 = Me, Ph
2
N
H
N
O
O
X
H
O
X = CH2, S
R3 = Me, Bn
O
1
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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