Synthesis of Tetrahydroquinoline-Embedded Bridged Benzothiaoxazepine-1,1-dioxides

Article abstract of DOI:10.1002/ejoc.201701152

A diastereoselective synthesis of previously unknown tetrahydroquinoline-containing bridged benzothiaoxazepine-1,1-dioxides is presented. The three-step protocol uses readily available N-aryl-2-fluorobenzenesulfonamides and trans-2,3-epoxy-cinnamyl-alcohol-derived tosylates as the starting materials, involves N-alkylation of sulfonamides, intramolecular epoxide ring-opening, and S_NAr reactions as the reaction steps, and requires only one chromatographic purification to access the desired products in good overall yields.

Full text of DOI:10.1002/ejoc.201701152

A Journal of
Accepted Article
Title: Synthesis of tetrahydroquinoline-embedded bridged
benzothiaoxazepine-1,1-dioxides
Authors: Hemi Borgohain, Runjun Devi, Divya Dheer, Biraj Jyoti Borah,
Ravi Kumar, and Sajal Kumar Das
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701152
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10.1002/ejoc.201701152
European Journal of Organic Chemistry
FULL PAPER
Synthesis of tetrahydroquinoline-embedded bridged
benzothiaoxazepine-1,1-dioxides
Hemi Borgohain,[a] Runjun Devi,[a] Divya Dheer,[b] Biraj Jyoti Borah,[a] Ravi Shankar,[b,c] and Sajal Kumar
Das*[a]
Abstract: A diastereoselective synthesis of previously unknown
tetrahydroquinoline-embedded bridged benzothiaoxazepine-1,1-
dioxides is presented. The three-step protocol utilizes readily
available N-aryl-2-fluorobenzenesulfonamides and trans-2,3-epoxy
cinnamyl alcohol-derived tosylates as the starting materials, involves
N-alkylation of sulfonamides, intramolecular epoxide ring-opening
and SNAr reactions as the reaction steps, and requires only one
chromatographic purification to access the desired products in good
overall yields.
Introduction
To explore broad swaths of the chemical space, diversity-
oriented synthesis of privileged scaffold-based small organic
molecules has been an important goal in modern drug discovery
and chemical biology.[1] In this context, developments of efficient,
scalable and rapid but mild synthetic methods for the
stereoselective construction of highly valuable heterocyclic
scaffolds have attracted a great deal of interest over the years.
The privileged tetrahydroquinoline scaffold is a part of the
molecular frameworks of a wide range of natural products and
synthetic molecules that exhibit
bioactivities.[2] Among several types of tetrahydroquinoline
scaffolds, 4-arenesulfonyl-tetrahydroquinoline (Figure 1)
a
broad spectrum of
represents the core structure of a number of medicinally
important molecules including farnesyltransferase inhibitors,[2a]
antiparasitic agent,[2c] 11-hydroxylase inhibitors,[2e] histone
deacetylase inhibitors,[2f] RORc inverse agonists,[2h] myeloid cell
leukemia-1 inhibitors[2i], etc. On the other hand, sultam is
another privileged heterocyclic unit that is ubiquitously
distributed in a large family of synthetic compounds, including
some clinical drugs, exhibiting versatile bioactivities.[3]
Benzothiaoxazepine-1,1-dioxides (Figure 1), a particular group
of benzosultams, have shown biological activities as modulators
of histamine H3-receptor,[4] positive allosteric modulators,[5] and
KEAP1/NRF2 protein–protein interaction inhibitors.[6] Owing to
their enormous synthetic and pharmacological utilities, 4-
arenesulfonyltetrahydroquinolines and benzothiaoxazepine-1,1-
dioxides have become important synthetic targets for organic
and medicinal chemists.[7,8] However, combination of these two
privileged scaffolds in one single molecule, which may provide a
source of new lead compounds,[9] remains unreported, and is
therefore highly desirable.
Figure
1.
N-arenesulfonyl-tetrahydroquinoline
(upper
panel)
and
benzothiaoxazepine-1,1-dioxide (lower panel) in the core structures of
selected biologically important molecules.
Intramolecular
Friedel-Crafts
epoxide-arene
(IFCEA)
cyclization of aryl-substituted epoxides tethered with
arenes/heteroarenes has been an efficient and powerful tool for
constructing diverse benzo-fused carba- and heterocycles,
largely because of the ready accessibility of aryl-substituted
epoxides in both racemic and single-enantiomeric forms, and
their capability to undergo this cyclization reaction in highly
chemo-, regio-, and stereoselective fashions.[10] Specifically,
notable achievements have been registered in applying IFCEA
reaction as a key step to synthesize diverse chromans,
tetrahydro-1-benzazepines and tetrahydro-2-benzazepines.[10c]
Despite these accomplishments, we believe that IFCEA reaction
is underutilized in synthetic organic chemistry and there are still
many opportunities to exploit it to access benzo-fused carba-
and heterocycles with rich structural complexity and
stereochemical diversity. In continuation of our previous work in
synthesizing structurally diverse benzo-fused heterocycles,[11]
herein, we wish to report the synthesis of tetrahydroquinoline-
embedded bridged benzothiaoxazepine-1,1-dioxides. Examples
of bridged sultams with nitrogen at the bridgehead are scarce
although they have potential applications in medicinal
chemistry.[12]
[a]
[b]
[c]
Department of Chemical Sciences, Tezpur University, Napaam,
Tezpur, Assam, India-784028
Bio-Organic Chemistry Division, Indian Institute of Integrative
Medicine (CSIR), Jammu, India-180001
Academy of Scientific and Innovative Research (AcSIR), Jammu
Campus, India
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701152
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Results and Discussion
showed virtually one spot on TLC, furnishing the desired product
3a in 87% isolated yield. It is important to mention that
Mitsunobu reaction of 1a and trans-((3-(2-bromophenyl)oxiran-2-
yl)methanol also afforded 3a (not shown here); but the
chromatographic purification was problematic.
We
fluorobenzenesulfonamides 1 with readily available trans-2,3-
epoxy cinnamyl alcohol-derived tosylates would provide
compounds 3 which, in turn, would furnish trans-4-aryl-3-
hydroxy-N-(o-fluoroarene)sulfonyl-tetrahydroquinolines via
envisaged
that
N-alkylation
of
N-aryl-2-
2
4
IFCEA reaction (Scheme 1). Our interest in applying IFCEA
reaction to prepare 4 was motivated by their structural similarity
to trans-4-arylchroman-3-ols that have already been synthesized
by us using similar strategy.[11a-c] In contrast to these previously
reported synthesis of chroman derivatives, however, we
suspected that synthesis of 4 would be more challenging owing
to the lower nucleophilicity of the aryl group of a N-tosylaniline
moiety; but the process would be more versatile with additional
diversification positions with three aromatic rings, thus creating
the possibility of synthesizing a wide variety of compounds.
Nevertheless, compounds 4 on treatment with a base should
Scheme 2. Synthesis of 3a by base-mediated N-alkylation of 1a with 2a.
Nevertheless, with compound 3a in hand, we decided to screen
the reaction conditions for the crucial IFCEA reaction by
systematic variations of Brønsted acid, solvent, and reaction
temperature (Table 1). Catalyzed by 20 mol% of TsOH·H2O in
1,2-dichloroethane (DCE) at 80 °C, compound 3a gave
tetrahydroquinoline derivative 4a in 78 % yield (Table 1, entry 1)
without generating even trace amount of the corresponding cis-
isomer.
furnish
tetrahydroquinoline-embedded
bridged
benzothiaoxazepine-1,1-dioxides 5 via an intramolecular SNAr
cycloetherification.[8]
Table 1. Optimization of the reaction conditions for the IFCEA reaction of 3a[a]
entry catalyst
(20 mol%)
TsOH·H2O DCE
solvent
temp time
Yield[b]
(oC)
(min) (%)
Scheme 1. Proposed synthesis of tetrahydroquinoline-embedded bridged
benzothiaoxazepine-1,1-dioxides.
1
50
45
60
78
65
74
79
78
88
90
85
40
75
85
2
H2SO4
TFA
DCE
DCE
DCE
DCE
50
Noteworthy is that synthesis of tetrahydroquinolines and their
derivatives by epoxide-arene cyclization have rarely been
reported in the literature. Kobayashi and Harayama in 2009
reported the synthesis of 3-hydroxy-4-arylquinolin-2(1H)-ones by
leaving group-assisted IFCEA cyclization.[13] Gansäuer, Flowers
II and co-workers recently reported the synthesis of N-alkyl
tetrahydroquinolines via epoxide-arene cyclization involving
homolytic aromatic substitution.[14] However, an operationally
simple method to access compounds of type 4 using the
strategy as outlined in Scheme 1 has not been investigated.
Furthermore, the conception that products from such a method
could be used to prepare the bridged tetrahydroquinolines 5 has
not been apprehended so far.
3
DCE 45
4
TfOH
MsOH
rt
45
45
45
45
60
60
60
60
5
50
70
70
6
TsOH·H2O MeCN
7
TsOH·H2O toluene
8
TsOH·H2O benzene 70
9
TsOH·H2O THF
50
rt
10
11
TsOH·H2O toluene
TsOH·H2O toluene
To examine the feasibility of the strategy outlined above, we
first carried out the N-alkylation of 2-fluorobenzene sulfonamide
derivative 1a (1 equiv) with epoxy tosylate 2a (1 equiv) in the
presence of K2CO3 in DMF at 60 °C (Scheme 2). The reaction
85
[a]Reaction conditions: 3a (0.4 mmol) in 8 mL solvent. [b]Isolated yields
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Delighted by this result, we screened the reaction conditions
by systematic variations of Brønsted acid, solvent, and reaction
temperature (Table 1, entries 2-11). With DCE as the reaction
medium, catalysis of this reaction with other well-known
Brønsted acids such as H2SO4, TFA, TfOH and MsOH also led
to the formation of 4a, albeit in varying yields (entries 2–5).
Notably, yields of the TsOH- and MsOH- catalyzed reaction
were identical (entries 1 and 5). However, given the low cost and
practical advantage of handling of TsOH·H2O, we settled on this
reagent as the preferred catalyst. Furthermore, with TsOH·H2O
as catalyst, the optimal solvent was screened to be toluene
among others, such as MeCN, benzene and THF (entries 1 and
6−9). Finally, the optimal reaction temperature was determined
to be 70 °C (Table 1, entries 7, 10 and 11) with TsOH·H2O in
toluene. The optimized reaction conditions were thus identified
as the treatment of the substrate in toluene at 70 °C for 45 min
in the presence of 20 mol% of TsOH·H2O under which this
cyclization reaction exhibited essentially one spot on TLC (with
traces of polar and nonpolar impurities), and delivered the
desired tetrahydroquinoline derivative 4a in 90% isolated yield.
After gaining efficient access to compound 4a, we decided to
explore its potential in the preparation of tetrahydroquinoline-
embedded bridged benzothiaoxazepine-1,1-dioxide 5a (Table 2).
We carried out the crucial SNAr-based cycloetherification
reaction first with 2.0 equiv of DBU as the base in DMF at 80 °C
for 2 h (Table 2, entry 1). The desired product 5a was isolated,
albiet in lower yield. When the base was switched to KOtBu, 5a
was furnished in higher yields in THF and DMSO (entries 2 and
3) but lower yields were observed in DMF and toluene (entries 4
and 5). Use of Cs2CO3 in DMF at 110 °C for 2 h also gave
inferior result (entry 6). Finally, we employed NaH in different
solvents (entries 7−10) for this transformation. The best result
was obtained when the reaction was performed in DMF in the
presence of NaH at rt for 15 min (entry 9). Interestingly and
surprisingly, this cyclization conditions appeared to be much
milder than that involved in Hanson’s synthesis of
benzothiaoxazepine-1,1-dioxides wherein microwave irradiation
at higher temperature (140-150 °C) was employed.[8b,d]
At this point, the viability of the method to access a
tetrahydroquinoline-embedded bridged benzothiaoxazepine-1,1-
dioxide skeleton had clearly been demonstrated; however, we
wanted to further simplify this three-step synthetic protocol via
process intensification. Given the very clean nature of the first
two steps, we believed that there was the opportunity to avoid
the chromatographic isolation of the intermediate compounds 3a
and 4a, and so we began investigating a modified approach that
would involve a sole chromatographic purification after the final
step (Table 3). Thus, after the completion of the first step, the
reaction mixture was subjected to usual workup to obtain crude
3a which was then exposed for the second step involving an
IFCEA reaction under the optimized conditions. After the
completion of this step, two aspects regarding process
intensification came to our mind. While the first one was
performing the second and final steps in a highly ambitious one-
pot fashion, telescoping these two steps appeared as the
second one. However, ineffectiveness of the cycloetherification
reaction in toluene (entry 10, Table 2) removed the first
possibility.
Table 2. Optimization of the reaction conditions for the SNAr reaction of 4a[a]
entry catalyst
(mol%)
solvent
temp
(oC)
80
time
(min)
120
30
yieldb
(%)
60
1
2
3
4
5
6
7
8
9
10
DBU
DMF
KOtBu
KOtBu
KOtBu
KOtBu
Cs2CO3
NaH
THF
rt
75
DMSO
DMF
rt
15
80
rt
15
50
PhMe
DMF
110
110
50
120
120
45
40
45
THF
65
NaH
1,4-dioxane
DMF
50
45
60
NaH
rt
15
87
NaH
toluene
110
120
20
[a]Reaction conditions: 4a (0.2 mmol) and base (0.4 mmol) in solvent (3 mL)
under an argon atmosphere. [b]Isolated yields.
Having been unable to investigate the one-pot protocol, we
briefly investigated the alternative option of telescoping these
two steps by swapping the solvent from toluene to DMF. Thus,
after the completion of the second step, toluene was removed
and a solution of the resulting crude 4a in DMF was treated with
NaH. Unfortunately, this modification resulted in the incomplete
conversion of 4a even with using excess equivalent of NaH. We
were, however, delighted to find that a basic workup (NaHCO3)
after the first step followed by the SNAr reaction with NaH in
DMF afforded 5a in a good 66% overall isolated yield (Table 3,
product 5a).
With these findings, we then turned our attention to explore
the three-step transformation with different substrates under the
optimized conditions, without chromatographic purification of the
intermediate compounds. Towards that objective, additional N-
aryl-2-fluorobenzenesulfonamides
cinnamyl alcohol-derived tosylates
1
and trans-2,3-epoxy
were prepared (see
2
Supporting Information for full details). The scope of the
optimized protocol was then screened with these substrates. As
summarized
in
Table
3,
all
the
corresponding
tetrahydroquinoline-embedded bridged benzothiaoxazepine-1,1-
dioxide 5b−n were obtained in good 65−74% overall yields.
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Table 3. Three-step synthesis of tetrahydroquinoline-embedded bridged benzothiaoxazepine-1,1-dioxides[a,b]
[a]Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol) and K2CO3 (0.3 mmol) in 5 mL DMF for the first step; TsOH·H2O (20 mol%) in 5 mL toluene for the second step;
NaH (0.4 mmol), DMF (3 mL) under an argon atmosphere for the third step. [b]The percentage values indicate overall isolated yields.
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Overall, the synthesized products contain the Ar2-ring as
phenyl (Table 3, products 5a−e, 5k and 5l) or 4-fluorophenyl
group (products 5f−j, 5m and 5n), and the Ar3-ring as phenyl
(products 5b, 5f, 5k and 5m), 2-fluorophenyl (products 5c and
5i), 2-bromophenyl (product 5a), 3-methoxyphenyl (products 5j,
5l and 5n), 4-chlorophenyl (products 5d and 5g), and 4-
bromophenyl (products 5e and 5h) groups. As expected, a
fluorine or a bromine substituent on the ortho-position of the Ar3-
ring did not affect the stereochemical outcome in the first step,
and was found to withstand the SNAr cycloetherification reaction
conditions (products 3b, 3c, and 3g); however, in these cases,
overall yields were slightly diminished. Among all the
synthesized bridged benzosultams, those which contain a
halogen atom (F or Br) on the Ar2 or Ar3 ring should be
potentially useful to introduce additional functionalities via well-
established SNAr or Pd-catalyzed reactions to fit specific
biological targets. All these 14 benzosultams are hydrolytically
stable crystalline solids (in contrast, bridged lactams are highly
prone to hydrolysis) which could be stored.
To evaluate the potential scalability of this approach, gram-
scale transformations of 1c and 2b were carried out under the
optimal reaction conditions. The desired product 5k was
obtained in 68% overall isolated yield (Table 3, product 5k).
Next, an asymmetric version of this highly diastereocontrolled
strategy was also briefly investigated. Thus, enantiomerically
enriched epoxy tosylate (2R,3R)-2b was synthesized using
Sharpless asymmetric epoxidation as the source of chirality
(Scheme 3). Subsequent three-step transformation of (2R,3R)-
2b under the optimized reaction conditions furnished (12R,13S)-
5b in 87:13 e.r.
crucial in the present protocol. However, we believe that, with
the Ar1-ring of moderately electron-rich nature, or bearing more
than one reactive sites, this three-step synthetic route might be
applicable, although purification of the intermediate compounds
would be unavoidable for such cases.
The structures of all the tetracyclic molecules heterocycles
5a−k were assigned on the basis of 1H and 13C NMR
spectroscopy. In addition, the structures of 5a−k are further
supported by the single-crystal X-ray diffraction analysis of 5i,
which unambiguously confirmed its structure. The structure
(Scheme 4, upper panel) clearly shows the relative trans-
stereochemistry between the 12-H and 13-H atoms on the
tetrahydroquinoline ring. Clearly, the stereochemistry observed
herein originates from the second step involving IFCEA reaction
that is assumed to give rise to the corresponding trans-4-aryl-3-
hydroxy tetrahydroquinoline derivative 5i via an SN2 type
epoxide ring opening of protonated epoxide 8 (Scheme 3, lower
panel). However, we could not completely ruled out the
possibility of an SN1 pathway. Fortunately, the carbocation 9
generated from such a reaction mechanism also could provide
the same product 4i via the most favorable conformation of 9.
Scheme 3. Asymmetric version of the developed methodology; enantiomeric
ratio (e.r.) was determined by chiral stationary phase HPLC.
Scheme 4. X-ray single-crystal structure of 5i (upper panel) and rational of the
stereochemistry (lower panel).
Noteworthy is that that all the tested substrates contain the
Ar1-ring as highly potent 3,5-dimethoxyphenyl or 3,5-
dimethylphenyl group only, as our prior studies[11a-c] indicated
that Brønsted acid-catalyzed IFCEA cyclization reactions of aryl-
substituted epoxides tethered to arenes are highly efficient when
the reacting arene group is 3,5-dimethoxyphenyl or 3,5-
dimethylphenyl ring. To avoid the purification of the intermediate
compounds, such a selection of the Ar1 group was extremely
Conclusions
In summary, we have developed
diastereoselective synthetic route for accessing biologically
a
regio- and
relevant
tetrahydroquinoline-embedded
bridged
benzothiaoxazepine-1,1-dioxides via
a
three-step reaction
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Third step: Finally, to a stirred solution of the above crude product in
freshly dried DMF (4 mL) was added powdered NaH (9.6 mg, 0.4 mmol)
at 0 °C under an argon atmosphere. After stirring for 15 min at room
temperature, the reaction mixture was quenched with saturated aq.
NH4Cl solution (20 mL), and diluted with EtOAc (20 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL).
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the crude product by silica gel column chromatography (5-
10% EtOAc/hexanes) afforded the desired bridged benzosultam 5.
sequence. The synthetic route that was used involved three key
steps: first the synthesis of epoxide-tethered N-aryl-N-(2-
fluoroarene)sulfonyl anilines via N-alkylation of N-ary-2-
fluorobenzenesulfonamides with trans-2,3-epoxy cinnamyl
alcohol-derived tosylates, then the intramolecular Friedel-Crafts
epoxide-arene reaction to afford trans-4-aryl-3-hydroxy
tetrahydroquinoline derivatives, and finally the NaH-mediated
cycloetherification reaction to afford the target bridged
benzosultams. The protocol is experimentally convenient, rapid,
and scalable, and requires easily available starting materials,
reagents, and catalyst. Further application of this procedure to
synthesize analogous polycyclic bridged structures is underway
in our laboratory.
(±)-(12R,13R/12S,13S)-13-(2-Bromophenyl)-1,3-dimethoxy-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5a): Prepared from compounds 1a and 2a according to the general
procedure; white solid; yield = 66%; mp = 197–199 °C; Rf = 0.45 (silica
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.64-7.62 (m,
1H), 7.50 (dd, J = 7.8 Hz, 1.4 Hz, 1H), 7.46-7.41 (m, 1H), 7.37-7.35 (m,
1H), 7.09-7.05 (m, 3H), 6.80 (d, J = 2.3 Hz, 1H), 6.45-6.43 (m, 1H), 6.13
(d, J = 2.3 Hz, 1H), 4.69-4.64 (m, 1H), 4.60 (s, 1H), 4.53 (d, J = 2.3 Hz,
1H), 3.82 (s, 3H), 3.56 (d, J = 15.1 Hz, 1H), 3.30 (s, 3H); 13C NMR (100
MHz, CDCl3):  159.1, 157.6, 151.2, 143.5, 138.8, 134.2, 133.1, 132.4,
129.6, 128.2, 128.1, 127.5, 125.4, 124.6, 124.1, 111.5, 103.3, 98.4, 74.7,
55.6, 55.5, 46.7, 41.2; Anal. calcd. for C23H20BrNO5S: C, 54.99; H, 4.01;
N, 2.79, found: C, 54.92; H, 4.05; N, 2.84.
Experimental Section
All dry reactions were carried out under nitrogen in oven-dried glassware.
Commercial reagents were used without further purification unless
otherwise stated. Progress of reactions was monitored by TLC on pre-
coated Merck silica gel plates (60F-254). Visualization of reactants and
products was accomplished with UV light. Column chromatography was
performed over silica gel (60–120 mesh) procured from Merck using
freshly distilled solvents. Melting points were determined with a Buchi-
535 apparatus and are not corrected. Perkin Elmer 20 analyzer was
utilized for elemental analysis of all compounds. Optical rotations were
measured by a Rudolph Autopol V polarimeter. HPLC data were
(±)-(12S,13R/12R,13S)-1,3-Dimethoxy-13-phenyl-12,13-dihydro-5,12-
methanodibenzo[b,f][1,4,5]oxathiazonine 6,6-dioxide (5b): Prepared
from compounds 1a and 2b according to the general procedure; white
solid; yield = 74%; mp = 186–188 °C; Rf = 0.39 (silica gel, 15% EtOAc in
hexane); 1H NMR (400 MHz, CDCl3):  7.51 (dd, J = 7.8 Hz, 1.6 Hz, 1H),
7.41 (td, J = 7.9 Hz, 1.8 Hz, 1H), 7.28-7.23 (m, 4H), 7.20-7.17 (m, 1H),
7.07 (td, J = 7.8 Hz, 1.8 Hz, 1H), 6.97 (d, J = 7.1 Hz, 2H), 6.79 (d, J = 2.3
Hz, 1H), 4.62-4.58 (m, 2H), 4.21 (s, 1H), 3.81 (s, 3H), 3.62 (d, J = 13.7
Hz, 1H), 3.29 (s, 3H); 13C NMR (100 MHz, CDCl3):  158.9, 157.9, 151.2,
143.9, 138.5, 134.0, 132.4, 129.6, 128.6, 127.3, 126.6, 125.2, 124.7,
111.7, 103.3, 98.4, 76.8, 55.5, 55.4, 46.2, 42.3; Anal. calcd. for
C23H21NO5S: C, 65.23; H, 5.00; N, 3.31, found: C, 65.11; H, 5.07; N, 3.24.
1
recorded using Dionex (Ultimate 3000) HPLC Instruments. H NMR and
13C NMR spectra were run on a JEOL 400 MHz spectrometer or Bruker
Advance III-400 MHz in CDCl3 as solvent. Chemical shifts are expressed
in  ppm with the abbreviations s, d, t, q, dd, dt and m denoting singlet,
doublet, triplet, quartet, doublet of doublets, doublet of triplets, and
multiplet, respectively. Tetramethylsilane ( 0.00 ppm) or residual
chloroform ( 7.27 ppm) served as an internal standard in 1H NMR and
CDCl3 (77.0 ppm) in 13C NMR. All spectra were recorded at 25 °C.
Coupling constants (J values) are given in hertz (Hz).
(12S,13R)-1,3-Dimethoxy-13-phenyl-12,13-dihydro-5,12-
General procedure for the synthesis of bridged benzosultams 5a-n
by the three-step (involving only one chromatographic purification)
method (Table 3):
methanodibenzo[b,f][1,4,5]oxathiazonine 6,6-dioxide {(12S,13R)-5b}:
Prepared from compounds 1a and (2R,3R)-2b according to the general
procedure; [α]20 = +12.34° (c = 0.55, CHCl3); enantiomeric ratio (87:13)
D
was determined by HPLC analysis: (Daicel Chiralpak IA column, n-
hexane:isopropanol = 85:15, flow rate = 1.0 mL/min, temp. = 25 °C,
wavelength = 254 nm, major enantiomer: tR = 9.7 min, minor enantiomer:
tR = 10.85 min); spectral data and other physical data of (12S,13R)-5b
were identical with that of racemic 5b.
First step: A mixture of sulfonamide 1 (0.2 mmol), epoxy tosyalte 2 (0.2
mmol) and anhydrous K2CO3 (45 mg, 0.325 mmol) in dry DMF (6 mL)
was heated at 60°C under N2 atmosphere for 12 h. The reaction was
terminated by the addition of water (10 mL) and diethyl ether (20 mL)
was added. The organic layer was separated, washed by brine (20 mL)
and dried over anhyd. Na2SO4. After filtration, the solution was
evaporated to dryness under reduced pressure. The resulting crude
product was further dried by a high vacuum pump, and then subjected to
the next step without further purification.
(±)-(12R,13R/12S,13S)-13-(2-Fluorophenyl)-1,3-dimethoxy-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5c): Prepared from compounds 1a and 2c according to the general
procedure; brown solid; yield = 68%; mp = 180–182 °C; Rf = 0.45 (silica
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.51 (dd, J =
7.7 Hz, 1.5 Hz, 1H), 7.44-7.40 (m, 1H), 7.30 (dd, J = 8.1 Hz, 1.1 Hz, 1H),
7.22-7.17 (m, 1H), 7.13-7.05 (m, 2H), 6.95-6.91 (m, 1H), 6.80 (d, J = 2.6
Hz, 1H), 6.48-6.44 (m, 1H), 6.15 (d, J = 2.6 Hz, 1H), 4.67-4.62 (m, 1H),
4.57-4.56 (m, 2H), 3.82 (s, 3H), 3.58 (d, J = 14.7 Hz, 1H), 3.32 (s, 3H);
Second step: To a stirred solution of the crude product (obtained from
the first step) in AR grade toluene (5 mL) was added TsOH.H2O (6.9 mg,
0.04 mmol). The resulting mixture was then heated at 70 °C for 45 min.
The mixture was cooled to room temperature, and then poured in beaker
containing EtOAc (20 mL) and saturated aq. NaHCO3 solution (15 mL)
with vigorous stirring. The combined organic layer was washed with brine
(20 mL) and dried over anhydrous Na2SO4. After filtration, the solution
was evaporated to dryness under reduced pressure. The resulting crude
product was further dried by a high vacuum pump, and then subjected to
the next step without further purification.
1
13C NMR (100 MHz, CDCl3):  159.4 (d, JC−F = 246.6 Hz), 159.2, 157.7,
2
151.2, 138.9, 134.1, 132.6, 130.6 (d, JC−F = 13.9 Hz), 129.6, 128.3 (d,
3
3JC−F = 8.5 Hz), 128.0 (d, JC−F = 3.8 Hz), 125.4, 124.7, 124.0 (d, 4JC−F
=
2
3.1 Hz), 115.3 (d, JC−F = 22.3 Hz), 110.6, 103.6, 98.4, 75.1, 55.6, 55.4,
46.7, 35.0 (d, 3JC−F = 3.8 Hz); Anal. calcd. for C23H20FNO5S: C, 62.57; H,
4.57; N, 3.17, found: C, 62.62; H, 4.48; N, 3.19.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701152
European Journal of Organic Chemistry
FULL PAPER
(±)-(12S,13R/12R,13S)-13-(4-Chlorophenyl)-1,3-dimethoxy-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5d): Prepared from compounds 1a and 2d according to the general
procedure; white solid; yield = 67%; mp = 198–200 °C; Rf = 0.42 (silica
Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.81-6.76 (m, 2H), 6.17 (d, J = 2.2 Hz,
1H), 4.65-4.60 (m, 1H), 4.57-4.56 (m, 1H), 4.16 (s, 1H), 3.82 (s, 3H), 3.56
(d, J = 15.1 Hz, 1H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3):  165.3 (d,
1JC−F = 256.6 Hz), 159.4, 157.8, 153.1 (d, 3JC−F = 12.3 Hz), 149.7, 142.8,
138.4, 131.8, 131.4 (d, 3JC−F = 10.8 Hz), 128.9, 128.7, (d, 4JC−F = 3.8 Hz),
120.6, 112.7 (d, 2JC−F = 23.1 Hz), 112.1 (d, 2JC−F = 22.3 Hz), 110.8, 103.5,
98.4, 77.1, 55.6, 55.4, 46.0, 41.8; Anal. calcd. for C23H19BrFNO5S: C,
53.09; H, 3.68; N, 2.69, found: C, 52.93; H, 3.74; N, 2.66.
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.52 (dd, J =
7.8 Hz, 1.6 Hz, 1H), 7.42 (td, J = 7.8 Hz, 1.6 Hz, 1H), 7.27-7.22 (m, 3H),
7.10-7.06 (m, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 2.3 Hz, 1H), 6.15
(d, J = 2.3 Hz, 1H), 4.64-4.54 (m, 2H), 4.18 (s, 1H), 3.82 (s, 3H), 3.56 (d,
J = 15.2 Hz, 1H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3):  159.2,
157.8, 151.1, 142.5, 138.5, 134.1, 132.48, 132.45, 129.7, 128.8, 128.6,
125.1, 124.7, 111.1, 103.5, 98.4, 76.6, 55.6, 55.4, 46.1, 41.8; Anal. calcd.
for C23H20ClNO5S: C, 60.33; H, 4.40; N, 3.06, found: C, 60.25; H, 4.44; N,
3.00.
(±)-(12S,13S/12R,13R)-9-Fluoro-13-(2-fluorophenyl)-1,3-dimethoxy-
12,13-dihydro-5,12-methanodibenzo[b,f][1,4,5]oxathiazonine
6,6-
dioxide (5i): Prepared from compounds 1b and 2c according to the
general procedure; brown solid; yield = 71%; mp = 176–178 °C; Rf = 0.44
(silica gel, 15% EtOAc in hexane); 1H NMR (400 MHz, CDCl3):  7.50 (dd,
J = 8.8 Hz, 6.2 Hz, 1H), 7.23-7.18 (m, 1H), 7.13-7.08 (m, 1H), 7.02 (dd, J
= 9.2 Hz, 2.6 Hz, 1H), 6.95-6.91 (m, 1H), 6.81-6.76 (m, 2H), 6.47-6.43 (m,
1H), 6.17 (d, J = 2.2 Hz, 1H), 4.67-4.59 (m, 2H), 4.56 (s, 1H), 3.82 (s, 3H),
3.58 (d, J = 15.1 Hz, 1H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3): 
(±)-(12S,13R/12R,13S)-13-(4-Bromophenyl)-1,3-dimethoxy-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5e): Prepared from compounds 1a and 2e according to the general
procedure; brown solid; yield = 70%; mp = 190–192 °C; Rf = 0.44 (silica
1
1
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.52 (dd, J =
165.4 (d, JC−F = 256.6 Hz), 159.7 (d, JC−F = 246.6 Hz), 159.3, 157.7,
3
3
7.8 Hz, 1.6 Hz, 1H), 7.43-7.37 (m, 3H), 7.27-7.24 (m, 1H), 7.08 (td, J =
7.4 Hz, 1.2 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 2.3 Hz, 1H),
6.14 (d, J = 2.3 Hz, 1H), 4.64-4.53 (m, 2H), 4.16 (s, 1H), 3.82 (s, 3H),
3.56 (d, J = 15.2 Hz, 1H), 3.33 (s, 3H); 13C NMR (100 MHz, CDCl3): 
159.2, 157.8, 151.0, 143.1, 138.6, 134.1, 132.5, 131.8, 129.7, 129.0,
128.5, 127.7, 125.1, 124.8, 120.5, 111.0, 103.5, 98.4, 76.5, 55.6, 55.4,
46.1, 41.9; Anal. calcd. for C23H20BrNO5S: C, 54.99; H, 4.01; N, 2.79,
found: C, 55.12; H, 4.05; N, 2.86.
153.2 (d, JC−F = 12.3 Hz), 138.7, 131.3 (d, JC−F = 10.8 Hz), 130.4 (d,
2JC−F = 13.8 Hz), 128.8 (d, JC−F = 3.1 Hz), 128.5 (d, JC−F = 8.5 Hz),
4
3
127.9 (d, 3JC−F = 3.8 Hz), 124.1 (d, 4JC−F = 3.0 Hz), 115.4 (d, 2JC−F = 22.3
2
2
Hz), 112.9 (d, JC−F = 23.1 Hz), 112.0 (d, JC−F = 22.3 Hz), 110.3, 103.5,
98.4, 75.7, 55.6, 55.4, 46.6, 41.8, 35.0 (d, 3JC−F = 3.8 Hz); Anal. calcd. for
C23H19F2NO5S: C, 60.12; H, 4.17; N, 3.05, found: C, 60.16; H, 4.16; N,
3.07.
(±)-(12S,13R/12R,13S)-9-Fluoro-1,3-dimethoxy-13-(3-
(±)-(12S,13R/12R,13S)-9-Fluoro-1,3-dimethoxy-13-phenyl-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5f): Prepared from compounds 1b and 2b according to the general
procedure; white solid; yield = 72%; mp = 174–176 °C; Rf = 0.51 (silica
methoxyphenyl)-12,13-dihydro-5,12-methanodibenzo[b,f][1,4,5]
oxathiazonine 6,6-dioxide (5j): Prepared from compounds 1b and 2f
according to the general procedure; off white solid; yield = 73%; mp =
185–187 °C; Rf = 0.42 (silica gel, 15% EtOAc in hexane); 1H NMR (400
MHz, CDCl3):  7.49 (dd, J = 8.7 Hz, 6.4 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H),
6.99 (dd, J = 9.1 Hz, 2.3 Hz, 1H), 6.79-6.72 (m, 3H), 6.54 (d, J = 7.8 Hz,
1H), 6.50 (s, 1H), 6.16 (d, J = 2.3 Hz, 1H), 4.62-4.58 (m, 2H), 4.18 (s, 1H),
3.81 (s, 3H), 3.76 (s, 3H), 3.64 (d, J = 15.6 Hz, 1.8 Hz, 1H), 3.35 (s, 3H);
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.45 (dd, J =
8.8 Hz, 6.2 Hz, 1H), 7.27-7.19 (m, 3H), 6.99-6.94 (m, 3H), 6.79-6.75 (m,
2H), 6.15 (d, J = 2.6 Hz, 1H), 4.63-4.59 (m, 2H), 4.21 (s, 1H), 3.80 (s, 3H),
3.62 (dd, J = 15.7 Hz, 1.5 Hz, 1H), 3.31 (s, 3H); 13C NMR (100 MHz,
CDCl3):  165.2 (d, 1JC−F = 255.8 Hz), 159.2, 158.0, 153.2 (d, 3JC−F = 12.3
1
13C NMR (100 MHz, CDCl3):  165.3 (d, JC−F = 255.9 Hz), 159.8, 159.1,
3
4
Hz), 143.7, 138.3, 131.3 (d, JC−F = 10.8 Hz), 128.7 (d, JC−F = 3.08 Hz),
128.6, 127.2, 126.7, 112.8 (d, 2JC−F = 23.1 Hz), 111.9 (d, 2JC−F = 22.3 Hz),
111.5, 103.4, 98.5, 77.4, 55.5, 55.4, 46.1, 42.3; Anal. calcd. for
C23H20FNO5S: C, 62.57; H, 4.57; N, 3.17, found: C, 62.47; H, 4.61; N,
3.19.
157.9, 153.1 (d, 3JC−F = 12.4 Hz), 145.4, 138.2, 131.3 (d, 3JC−F = 10.5 Hz),
129.6, 128.9, (d, 4JC−F = 2.8 Hz), 119.6, 113.5, 112.7 (d, 2JC−F = 23.0 Hz),
112.0 (d, 2JC−F = 22.0 Hz), 111.3, 103.3, 98.4, 87.0, 77.3, 55.5, 55.4, 55.2,
46.2, 42.2; Anal. calcd. for C24H22FNO6S: C, 61.14; H, 4.70; N, 2.97,
found: C, 61.03; H, 4.74; N, 2.92.
(±)-(12S,13R/12R,13S)-13-(4-chlorophenyl)-9-fluoro-1,3-dimethoxy-
12,13-dihydro-5,12 methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-
dioxide (5g): Prepared from compounds 1b and 2d according to the
general procedure; white solid; yield = 69%; mp = 187–189 °C; Rf = 0.53
(silica gel, 15% EtOAc in hexane); 1H NMR (400 MHz, CDCl3):  7.50 (dd,
J = 8.4 Hz, 6.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.98 (dd, J = 9.2 Hz, 2.6
Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.81-6.76 (m, 2H), 6.16 (d, J = 2.6 Hz,
1H), 4.65-4.61 (m, 1H), 4.57-4.56 (m, 1H), 4.18 (s, 1H), 3.82 (s, 3H), 3.57
(dd, J = 15.1 Hz, 0.7 Hz, 1H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3): 
(±)-(12S,13R/12R,13S)-1,3-Dimethyl-13-phenyl-12,13-dihydro-5,12-
methanodibenzo[b,f][1,4,5]oxathiazonine 6,6-dioxide (5k): Prepared
from compounds 1c and 2b according to the general procedure; brown
solid; yield = 72%; mp = 181–183 °C; Rf = 0.59 (silica gel, 15% EtOAc in
hexane); 1H NMR (400 MHz, CDCl3):  7.46 (dd, J = 7.8 Hz, 1.4 Hz, 1H),
7.39 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.29-7.25 (m, 4H), 7.23-7.19 (m, 1H),
7.04 (td, J = 7.8 Hz, 1.8 Hz, 1H), 6.92 (br s, 2H), 6.67 (s, 1H), 4.62-4.56
(m, 2H), 4.18 (s, 1H), 3.65 (d, J = 14.7 Hz, 1H), 2.26 (s, 3H), 1.57 (s, 3H);
13C NMR (100 MHz, CDCl3):  151.1, 142.7, 137.3, 136.8, 136.6, 133.8,
132.8, 130.5, 129.7, 129.0, 127.9, 127.1, 125.8, 125.2, 124.82, 124.80,
77.2, 45.5, 45.2, 20.9, 19.3; Anal. calcd. for C23H21NO3S: C, 70.56; H,
5.41; N, 3.58, found: C, 70.48; H, 5.47; N, 3.62.
1
3
165.2 (d, JC−F = 255.8 Hz), 159.4, 157.8, 153.1 (d, JC−F = 12.3 Hz),
3
142.3, 138.3, 132.6, 131.4 (d, JC−F = 10.8 Hz), 128.9, 128.6, 112.7 (d,
2
2JC−F = 21.6 Hz), 112.1 (d, JC−F = 22.3 Hz), 110.8, 103.5, 98.4, 77.4,
55.6, 55.4, 46.0, 41.8; Anal. calcd. for C23H19ClFNO5S: C, 58.05; H, 4.02;
N, 2.94, found: C, 58.09; H, 4.04; N, 2.99.
(±)-(12S,13R/12R,13S)-13-(3-Methoxyphenyl)-1,3-dimethyl-12,13-
dihydro-5,12 methanodibenzo[b,f][1,4,5]oxathiazonine 6,6-dioxide
(5l): Prepared from compounds 1c and 2f according to the general
procedure; off white solid; yield = 70%; mp = 172–174 °C; Rf = 0.44
(silica gel, 15% EtOAc in hexane); 1H NMR (400 MHz, CDCl3):  7.46 (dd,
J = 7.8 Hz, 1.4 Hz, 1H), 7.39 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.27-7.25 (m,
2H), 7.19 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.75 (dd, J = 8.2 Hz,
2.3 Hz, 1H), 6.66 (s, 1H), 6.47 (br s, 2H), 4.62-4.56 (m, 2H), 4.13 (s, 1H),
(±)-(12S,13R/12R,13S)-13-(4-Bromophenyl)-9-fluoro-1,3-dimethoxy-
12,13-dihydro-5,12-methanodibenzo[b,f][1,4,5]oxathiazonine
6,6-
dioxide (5h): Prepared from compounds 1b and 2e according to the
general procedure; brown solid; yield = 70%; mp = 182–184 °C; Rf = 0.51
(silica gel, 15% EtOAc in hexane); 1H NMR (400 MHz, CDCl3):  7.50 (dd,
J = 8.8 Hz, 6.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 9.2 Hz, 2.2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701152
European Journal of Organic Chemistry
FULL PAPER
3.75 (s, 3H), 3.66 (d, J = 14.7 Hz, 1H), 2.26 (s, 3H), 1.60 (s, 3H). 13C
NMR (100 MHz, CDCl3):  160.0, 151.1, 144.4, 137.3, 136.7, 136.6,
133.8, 132.7, 130.5, 130.1, 129.7, 125.8, 125.1, 124.8, 120.33, 120.30,
114.3, 111.7, 77.1, 55.2, 45.7, 45.1, 20.9, 19.3; Anal. calcd. for
C24H23NO4S: C, 68.39; H, 5.50; N, 3.32, found: C, 68.37; H, 5.58; N, 3.28.
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(±)-(12S,13R/12R,13S)-9-Fluoro-1,3-dimethyl-13-phenyl-12,13-
dihydro-5,12-methanodibenzo[b,f][1,4,5] oxathiazonine 6,6-dioxide
(5m): Prepared from compounds 1d and 2b according to the general
procedure; white solid; yield = 73%; mp = 186–188 °C; Rf = 0.59 (silica
1
gel, 15% EtOAc in hexane); H NMR (400 MHz, CDCl3):  7.45 (dd, J =
8.7 Hz, 5.9 Hz, 1H), 7.30-7.20 (m, 4H), 6.99 (dd, J = 9.1 Hz, 2.7 Hz, 1H),
6.92 (br s, 2H), 6.78-6.74 (m, 1H), 6.71 (s, 1H), 4.66-4.57 (m, 2H), 4.18
(s, 1H), 3.66 (d, J = 14.7 Hz, 1H), 2.27 (s, 3H), 1.61 (s, 3H); 13C NMR
1
3
(100 MHz, CDCl3):  165.2 (d, JC−F = 255.9 Hz), 153.1 (d, JC−F = 12.5
3
[4]
V. J. Santora, J. A. Covel, J. B. Ibarra, G. Semple, B. Smith, J. Smith, M.
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Hz), 142.4, 137.4, 136.8, 136.6, 131.5 (d, JC−F = 11.5 Hz), 130.7, 129.1,
4
128.9 (d, JC−F = 3.8 Hz), 127.94, 127.92, 127.2, 125.8, 125.0, 112.4 (d,
2JC−F = 23.9 Hz), 112.1 (d, JC−F = 22.0 Hz), 87.1, 77.7, 45.4, 45.1, 20.9,
2
[5] A. Cordi, P. Desos, P. Lestage, L. Danober, Can. Pat. Appl. CA 2752131
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19.4; Anal. calcd. for C23H20FNO3S: C, 67.46; H, 4.92; N, 3.42, found: C,
67.32; H, 4.89; N, 3.47.
[6] T. G. Davies, W. E, Wixted, J. E. Coyle, C. Griffiths-Jones, K. Hearn, R.
McMenamin, D. Norton, S. J. Rich, C. Richardson, G. Saxty, H. M.
Willems, A. J. Woolford, J. E. Cottom, J P. Kou, J. G. Yonchuk, H. G.
Feldser, Y. Sanchez, J. P. Foley, B. J. Bolognese, G. Logan, P. L.
Podolin, H. Yan, J. F. Callahan, T. D. Heighman, J. K. Kerns, J. Med.
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((±)-(12S,13R/12R,13S)-9-Fluoro-13-(3-methoxyphenyl)-1,3-dimethyl-
12,13-dihydro-5,12-methanodibenzo[b,f][1,4,5]oxathiazonine
6,6-
dioxide (5n): Prepared from compounds 1d and 2f according to the
general procedure; off white solid; yield = 71%; mp = 179–181 °C; Rf =
0.44 (silica gel, 15% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): 
7.45 (dd, J = 9.1 Hz, 6.4 Hz, 1H), 7.28-7.27 (m, 1H), 7.23-7.19 (m, 1H),
7.00 (dd, J = 9.1 Hz, 2.3 Hz, 1H), 6.79-6.74 (m, 2H), 6.70 (s, 1H), 6.48
(br s, 2H), 4.67-4.66 (m, 2H), 4.63-4.58 (m, 1H), 4.14 (s, 1H), 3.76 (s,
3H), 3.68 (d, J = 15.1 Hz, 1H), 2.27 (s, 3H), 1.64 (s, 3H); 13C NMR (100
MHz, CDCl3):  165.3 (d, 1JC−F = 255.9 Hz), 160.1, 153.1 (d, 3JC−F = 11.5
[7]
For reviews on the synthesis of tetrahydroquinolines, see: a) B.
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7157–7259; c) A. R. Katritzky, S. Rachwal, B. Rachwal, Tetrahedron
1996, 52, 15031–15070.
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a) S. Faisal, P. K. Maity, Q. Zang, T. B. Samarakoon, R. L. Sourk, P. R.
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K. Loh, A. Rolfe, L. S. Le, S. Y. Yoon, G. H. Lushington, P. R. Hanson,
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Klimberg, M. Brzozowski, B. Neuenswander, G. H. Lushington, P. R.
Hanson, J. Comb. Chem. 2010, 12, 850-854; d) A. Rolfe, T. B.
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4992–5000.
3
Hz), 144.1, 137.5, 131.4 (d, JC−F = 10.5 Hz), 130.7, 130.1, 128.9, (d,
2
4JC−F = 2.9 Hz), 125.8, 124.9, 120.3, 120.2, 119.6, 114.2, 112.3 (d, JC−F
= 23.9 Hz), 112.1 (d, 2JC−F = 22.0 Hz), 111.8, 77.7, 55.2, 55.4, 45.6, 45.1,
20.9, 19.4; Anal. calcd. for C24H22FNO4S: C, 65.59; H, 5.05; N, 3.19,
found: C, 65.47; H, 5.02; N, 3.26.
Acknowledgements
SKD is grateful to the Science and Engineering Research Board,
Department of Science and Technology (DST SERB), New Delhi,
for financial assistance (Grant No. SB/FT/CS 073/2013). We are
thankful to Prof. S. C. Pan, IIT-Guwahati for the HPLC data.
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Keywords: Tetrahydroquinolines • benzothiaoxazepine-1,1-
dioxides • Intramolecular Friedel-Crafts epoxy arene cyclization •
SNAr reaction • Bridged-benzosultams
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701152
European Journal of Organic Chemistry
FULL PAPER
COMMUNICATION
Synthesis of previously
unknown
Polycyclic Bridged
heterocycles
tetrahydroquinoline-
Hemi Borgohain,
implanted
bridged
Runjun Devi, Divya
Dheer, Biraj Jyoti
Borah,Ravi Shankar,
and Sajal Kumar Das*
benzothiaoxazepine-1,1-
dioxides is presented. The
three-step protocol utilizes
readily available N-ary-2-
fluorobenzenesulfonamides
Synthesis of
tetrahydroquinoline-
embedded bridged
benzothiaoxazepine-
1,1-dioxides
and
cinnamyl
tosylates as the starting
materials, involves N-
alkylation of sulfonamides,
intramolecular epoxide
trans-2,3-epoxy
alcohol-derived
ring-opening and SNAr
reactions as the reaction
steps, and requires only
one
chromatographic
purification to access the
desired products in good.
overall yields
This article is protected by copyright. All rights reserved.