Base-mediated intramolecular one-pot double-cyclization of epoxide-tethered 2-fluorobenzenesulfonamides: An avenue to 1,4-benzoxazine-fused benzothiaoxazepine-1,1-dioxides

Article abstract of DOI:10.1039/c9ob02377a

Herein, we describe the synthesis of hitherto unknown 1,4-benzoxazine-fused benzothiaoxazepine-1,1-dioxides by a NaH-promoted intramolecular one-pot double-cyclization of epoxide-tethered 2-fluorobenzene sulfonamides. Mechanistically, the reactions proceed via an intramolecular epoxide ring-opening followed by an intramolecular nucleophilic aromatic substitution. The high yields, mild conditions, complete regio- and diastereoselectivity, and a wide substrate scope render this protocol well suited for drug discovery efforts.

Full text of DOI:10.1039/c9ob02377a

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Base-mediated intramolecular one-pot
double-cyclization of epoxide-tethered
2-fluorobenzenesulfonamides: an avenue to
1,4-benzoxazine-fused benzothiaoxazepine-
1,1-dioxides†
Cite this: Org. Biomol. Chem., 2020,
18, 220
Received 3rd November 2019,
Accepted 3rd December 2019
DOI: 10.1039/c9ob02377a
rsc.li/obc
Jonali Das, Biraj Jyoti Borah
and Sajal Kumar Das
*
Herein, we describe the synthesis of hitherto unknown 1,4-benz- dioxide scaffolds are ubiquitous in a wide range of natural
oxazine-fused benzothiaoxazepine-1,1-dioxides by
NaH-pro- and/or synthetic compounds.5,6 Fig. 1a and b show some pro-
a
moted intramolecular one-pot double-cyclization of epoxide-teth- minent representative examples of compounds based on these
ered 2-fluorobenzene sulfonamides. Mechanistically, the reactions two core structures. Owing to their demonstrated pharmaco-
proceed via an intramolecular epoxide ring-opening followed by logical uses, extensive efforts have been devoted to the develop-
an intramolecular nucleophilic aromatic substitution. The high ment of synthetic methods for diverse 3,4-dihydro-2H-1,4-
yields, mild conditions, complete regio- and diastereoselectivity, benzoxazines and benzothiaoxazepine-1,1-dioxides.7,8
and a wide substrate scope render this protocol well suited for
drug discovery efforts.
Nucleophilic aromatic substitution (SNAr) is one of the most
frequently used reactions that stand tall amongst many recent
innovative reactions.1 Epoxide ring-opening reaction is
another major workhorse in synthetic organic chemistry.2
Despite these attributes, however, a major drawback is that
these two reactions in the intermolecular mode often suffer
from one or more of the following drawbacks: harsh reaction
conditions, excess of reagents, low product yields and long
reaction times. On the other hand, their intramolecular
counterparts not only circumvent these hurdles, but also often
enjoy high to complete regio- and stereocontrol to furnish ring
systems in a straightforward fashion.3,4 In this context, intra-
molecular one-pot double-cyclization involving epoxide ring-
opening followed by SNAr would be a very interesting and
useful method for accessing fused ring systems. Considering
the too frequent usage of SNAr and epoxide ring-opening reac-
tions, one would expect a number of synthetic reports based
on this concept. However, to the best of our knowledge, such
an idea is unprecedented in the chemical literature.
As members of the privileged N-heterocycles, the
3,4-dihydro-2H-1,4-benzoxazine and benzothiaoxazepine-1,1-
Department of Chemical Sciences, Tezpur University, Napaam, Tezpur, Assam, India-
784028. E-mail: sajalkd@tezu.ernet.in
†Electronic supplementary information (ESI) available: Experimental details,
X-ray crystallographic data, figures of 1H, 13C and 19F NMR spectra, and HRMS.
CCDC 1966259. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c9ob02377a
Fig. 1 (a) Representative bioactive 3,4-dihydro-2H-1,4-benzoxazines.
(b) Representative bioactive benzothiaoxazepine-1,1-dioxides. (c)
Designed fused 3,4-dihydro-2H-1,4-benzoxazine–benzothiaoxazepine-
1,1-dioxide hybrids.
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However, the synthesis of hybrid molecules by the combi- intermolecular 2-fluoroarenesulfonamide–epoxide pairing
nation of these two privileged scaffolds remains unreported, strategy (Scheme 1a), we believed that accomplishing this task
despite holding great potential to furnish compounds of new for its intramolecular counterpart (Scheme 1b) would not be
biological profiles. More specifically, synthetic studies to con- as simple as it might seem, since it would need tethering of
struct benzothiaoxazepine-1,1-dioxide fused 3,4-dihydro-2H- two reactive ambiphilic synthons in a single molecule. For
1,4-benzoxazines such as 1 (Fig. 1c) remain elusive. From the example, when we attempted the synthesis of 5t from
vantage point of interest in both synthetic and medicinal compound 6 using epoxy tosylate 7 under typical K2CO3-
chemistry settings, access to such hybrid compounds is highly mediated monoalkylation reaction conditions, we were
desirable.
disappointed to obtain a complex product mixture (Scheme 2).
Meanwhile, in 2010, the research groups of Hanson and This failure to obtain 5t as a major isolated product might be
Cleator almost simultaneously reported the synthesis of attributed to the non-selective generation of sulfonamide N−
diverse benzosultams 4 using 2-fluoroarenesulfonamides 2 as and phenoxide anions as nucleophiles, resulting in the for-
ambiphilic synthons and terminal epoxides 3 as masked ambi- mation of both N- and O-alkylated products (5t and 8), which
philic synthons under harsh reaction conditions and without in turn might have undergone further intramolecular cycliza-
addressing the issues of regio- and diastereoselectivity tion reactions to provide compounds 9 and 10. Thus, the
(Scheme 1a).9,10 We felt that this 2-fluoroarenesulfonamide– complex mixture possibly consisted of unreacted 6, and com-
epoxide pairing strategy should be studied further in organic pounds 5t and 8–10. Moreover, changing the base and other
synthesis to explore the unaddressed issues and could be reaction parameters also did not bring any synthetically accep-
implemented in an intramolecular one-pot double cyclization table result. Therefore, at this stage, we were forced to use an
fashion to access fused benzosultams like 1 from glycidyl alternative strategy involving a late-stage epoxidation strategy.
ether-tethered 2-fluoroarenesulfonamide
Herein, we present the realization of this novel concept.
5
(Scheme 1b). Starting from 2-nitrophenol 11a, first we conducted a three
step reaction sequence involving sequential allylation/prenyla-
At the beginning, we focused on the development of an tion, chemoselective reduction of the NO2 group and 2-fluoro-
effective synthetic route for the double-cyclization precursors benzenesulfonylation of the NH2 group to swiftly generate
5. However, in contrast to the synthesis of substrates for the epoxide-precursor 12a in a high overall yield of 75% (Table 1,
entry 1, column 7). However, epoxidation of 12a using m-CPBA
(1.15 equiv.) in CH2Cl2 at rt failed miserably, resulting in a
complete recovery of 12a (not shown in Table 1). This obser-
vation is consistent with the absence of literature reports (to
our knowledge) on the epoxidation of aryl allyl ethers bearing
an ortho-benzenesulfonamide moiety with m-CPBA. The exact
reason for the observed unreactivity is unclear at present, but
possibly the sulfonamide moiety has a detrimental effect.
Delightfully, however, epoxidation of 12a using excess m-CPBA
(2.5 equiv.) and under more forcing reaction conditions in 1,2-
dichloroethane (DCE) at 80 °C generated 5a, albeit in a moder-
ate yield of 65% (Table 1, entry 1, column 8). Nevertheless,
additional substrates 5b–p, bearing substituents at different
positions of the two benzene rings, were prepared following
the optimized route (Table 1, entries 2–16).
Scheme 1 2-Fluoroarenesulfonamides as ambiphilic synthons in (a) lit-
erature reports and (b) our proposed work.
Scheme 2 Attempted synthesis of 5t.
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Table 1 Synthesis of epoxide substrates of 5 a
The reaction was initially conducted in the presence
of anhydrous K2CO3 (1.5 equiv.) as a base in acetonitrile
(MeCN) at room temperature for 16 h. The desired product 1a
was not detected under these conditions (Table 2, entry 1).
However, increasing the reaction temperature to 80 °C
afforded 1a, albeit in a poor yield of 20% (entry 2). Changing
the solvent to 1,4-dioxane (entry 3) or DMF (entry 4) failed
to show any significant improvements. At 80 °C, the use of
stronger and more soluble but expensive base Cs2CO3
(1.5 equiv.) in 1,4-dioxane (entry 5) or DMF (entry 6) resulted
in improved but still synthetically unsatisfactory yields.
Next, we attempted to utilize strong bases to facilitate the
present domino transformation in a more efficient way.
Delightfully, the treatment of 5a with NaH (1.5 equiv.) in DMF
at rt for 4 h gave 1a in 85% yield (entry 7). It is worth mention-
ing that with NaH (1.5 equiv.) as the base, increasing the
reaction temperature to 80 °C (entry 8) decreased the yield, as
did decreasing the amount of NaH to 0.5 equiv. at rt (entry 9).
Thus, the use of NaH (1.5 equiv.) as the base in DMF at rt
for 4 h (Table 2, entry 7) proved to be the best choice among
all the conditions that we employed for the optimization
studies.
With the optimized conditions in hand, we set out to inves-
tigate the substrate scope of the reaction using the remaining
substrates 5b–p (Table 3). The electronic effect of the substitu-
ent on the Ar1-ring did not significantly affect the reaction
efficiency as evidenced by the fact that substrates 5g–n bearing
an electron-donating methyl or methoxy group or substrates
5o and 5p with an electron-withdrawing bromo substituent on
the Ar1-ring were transformed smoothly into the corres-
ponding tetracyclic hybrid compounds (Table 3, products
1g–p). We also observed similar efficiency of the reaction with
the introduction of additional F or Br atoms on the Ar2-ring
(products 1b and 1c, 1e and 1f, 1h, 1j–l, and 1n and 1p).
Products bearing a Br-substituent (1l, 1o and 1p) hold great
potential for further derivatization using diverse palladium-
catalyzed coupling chemistry. Similarly, products bearing a
fluoro-substituent at the ortho- or para-position with respect to
the electron withdrawing sulfonamide group (products 1b and
1c, 1e and 1f, 1h, 1j and 1k, and 1n and 1p) should be useful
in further elaboration via the intermolecular SNAr reaction pro-
tocol.8 Nevertheless, when the H atoms at the alkene terminus
were changed to methyl groups, no significant changes in the
product yields were observed (products 1d–f and 1i–p). This
indicates that the reaction efficiency was insensitive to the
steric hindrance of the geminal methyl groups around the
in situ generated alkoxy moiety.
Entry
R
R1
R2
R3
R4
Yieldb
1
2
3
4
5
6
7
8
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
Me
Me
H
H
H
H
OMe
OMe
Br
Br
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
F
H
H
F
H
H
H
H
F
H
H
H
H
H
H
F
H
H
F
H
H
F
H
F
H
Br
H
F
H
F
12a (75%)
12b (74%)
12c (71%)
12d (75%)
12e (73%)
12f (70%)
12g (69%)
12h (70%)
12i (71%)
12j (69%)
12k (68%)
12l (70%)
12m (71%)
12n (75%)
12o (73%)
12p (74%)
5a (65%)
5b (62%)
5c (64%)
5d (75%)
5e (73%)
5f (72%)
5g (62%)
5h (64%)
5i (70%)
5j (72%)
5k (70%)
5l (73%)
5m (74%)
5n (74%)
5o (71%)
5p (69%)
H
9
Me
Me
Me
Me
Me
Me
Me
Me
10
11
12
13
14
15
16
H
a Reaction conditions: (a) (i) allyl/prenyl bromide, K2CO3, acetone,
65 °C, 12 h; (ii) Fe powder, NH4Cl, EtOH/H2O, reflux, 2 h; (iii) 2-fluoro-
benzenesulfonyl chlorides, pyridine, 12 h. (b) m-CPBA (2.5 equiv.),
DCE, 80 °C, 12 h. b The values in parentheses indicate the isolated
yields.
From here, we chose compound 5a as the model substrate
for screening bases and optimizing the reaction conditions
required for probing the envisioned double cyclization reac-
tion. The results are summarized in Table 2.
Table 2 Screening of the reaction conditions for the one-pot double-
cyclization of 5a a
Entry Base (equiv.) Solvent
Temp. (°C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5) Dioxane 80
Cs2CO3 (1.5) DMF
NaH (1.5)
NaH (1.5)
NaH (0.5)
MeCN
MeCN
Dioxane 80
DMF 80
rt
80
16
16
16
16
16
16
4
nrc
20
22
24
35
42
85
67
40
Meanwhile, to demonstrate the synthetic practicality of this
intramolecular one-pot double-cyclization method, a scale-up
experiment with 5.0 mmol of 5d was performed, affording the
desired product 1d in 78% yield.
It is to be mentioned that the structures of tetracyclic pro-
ducts 1a–p were confirmed by the 1H NMR, 13C NMR and
HRMS data. X-ray single-crystal diffraction analysis of represen-
tative compound 1l was performed to further confirm their
structures (Fig. 2).
80
rt
80
rt
DMF
DMF
DMF
4
6
a All reactions were conducted with 0.2 mmol of 5a in 2.0 mL of
solvent. b The values in parentheses indicate the isolated yields. c No
reaction.
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Table 3 Substrate scope of the intramolecular one-pot double-cycliza-
tion of 5a a,b
Now, our methodology in principle should be applicable to
benzothiaoxazepine-1,1-dioxides fused to various other aza-
heterocycles such as pyrrolidines, piperidines, indolines, tetra-
hydroquinolines etc. To delineate one of many such possi-
bilities, we further extended the strategy to the synthesis of
indoline-fused benzothiaoxazepine-1,1-dioxides (Scheme 3).
Thus, compound 13 was converted into epoxides 5q–s via inter-
mediate alkenes 12q–s following a sequential chemoselective
NO2-reduction–2-fluorophenylsulfonylation–epoxidation reaction
sequence (Scheme 3). The intramolecular one-pot double-cycliza-
tion of 5q–s proceeded efficiently under the standard conditions,
affording indoline-fused benzothiaoxazepine-1,1-dioxides 12q–s
in high isolated yields.
Although we could successfully carry out the double cycliza-
tion, we sensed that the incorporation of a stereodefined
epoxide moiety into the substrate might be troublesome owing
to the already-described difficulty in the late stage epoxidation
process. Thus, despite our initial failure as shown in
Scheme 1, the focus of our study then turned back again
towards the desire of using a preformed epoxide building
block in the synthesis. Along this line, we performed alkylation
of 11a with epoxy tosylate 7 furnishing 14 in excellent yield
(Scheme 4). Chemoselective reduction of the NO2 group of 14
under transfer hydrogenation conditions (Et3SiH, Pd–C)11
followed by 2-fluorobenzenesulfonylation of the resulting
crude amine provided the corresponding glycidyl ether-
tethered 2-fluoroarenesulfonamide 5t which, without purifi-
cation, was treated with NaH under the optimized reaction
conditions to afford the corresponding diastereomerically pure
tetracyclic product 1t in a high overall yield.
In summary, we have established a base-mediated one-pot
double cyclization of glycidyl ether-tethered 2-fluoroarenesul-
fonamides to furnish 1,4-benzoxazine-fused benzothiaoxaze-
pine-1,1-dioxides as
a new class of hybrid compounds.
Mechanistically, the reaction involves an intramolecular
epoxide ring-opening followed by an intramolecular nucleo-
philic aromatic substitution – a scenario unprecedented in the
chemical literature. The notable features of this protocol com-
a Reactions were conducted with 0.2 mmol of 5b–p in 2.0 mL of DMF
at rt under a N2 atmosphere. b The values in parentheses indicate the
isolated yields. c 78% yield was observed when the reaction was con-
ducted with 5 mmol of 5d.
Fig. 2 ORTEP diagram of compound 1l as determined by X-ray analysis
Scheme 3 Synthesis of indoline-fused benzothiaoxazepine-1,1-
(ellipsoid contour probability, 35%).
dioxides.
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prise mild conditions, a broad substrate scope (multiple diver-
sification points), complete regio- and diastereoselectivity, and
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge the financial support provided by the
Department of Biotechnology, New Delhi as a DBT-Twinning
project grant (BT/PR25173/NER/95/1055/2017). JD is also
thankful to Tezpur University for providing a research and
innovation grant (2018–19).
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