Modular, One-Pot, Sequential Aziridine Ring Opening-SNAr Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams

Article abstract of DOI:10.1021/acs.joc.5b01429

The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.

Full text of DOI:10.1021/acs.joc.5b01429

Article
pubs.acs.org/joc
Modular, One-Pot, Sequential Aziridine Ring Opening−SNAr Strategy
to 7‑, 10‑, and 11-Membered Benzo-Fused Sultams
Joanna K. Loh, Naeem Asad, Thiwanka B. Samarakoon, and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
Center for Chemical Methodologies and Library Development (KU-CMLD), Delbert M. Shankel Structural Biology Center, The
University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States
S
* Supporting Information
ABSTRACT: The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary
pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a
modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is
reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification
pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-
membered benzo-fused sultams for broad-scale screening.
trypsin-like serine protease Factor XIa involved in blood
coagulation22 and, more recently, have been shown to be
modulators of lysosomal acidification involved in critical cellular
function (Figure 1).23 Despite advances in the field,24 methods to
generate functionally rich, medium- to large-sized lactams and
sultams remains a significant challenge.25
We herein report a modular approach utilizing a heretofore-
unknown class of sulfonamide building blocks, namely (o-
fluoroaryl)sulfonyl aziridines, which react with amino alcohols
via a process we term complementary pairing (CP), vide infra,
with high chemo- and regioselectivity enabling access to 10- to
11-membered sultams. Overall, this one-pot protocol involves
sequential aziridine ring opening by the amine component and
intramolecular nucleophilic aromatic substitution (SNAr) via the
alkoxy component. In addition, dual reactivity with primary
amines facilitates access to 7-membered sultams. Taken
collectively, the routes reported herein generate a diverse array
of polycyclic, 10- to 11- and 7-membered benzo-fused sultam
scaffolds.
INTRODUCTION
■
The development of efficient methods for the generation of
medium- and large-sized heterocycles is an important facet of
screening campaigns for facilitating drug discovery.1 In particular,
medium and macrocyclic lactams1,2 constitute an important class
of molecules in compound collections derived from target-
oriented and diversity-oriented3 synthetic approaches. Their
distinct properties, which include conformational constraint,
reduced polarity, increased proteolytic stability, and potential for
higher target binding and selectivity,4 are manifested in improved
pharmacokinetics and pharmacodynamics,4 rendering them as
attractive lead molecules for drug development.5 Taken
collectively, these attributes have inspired production of natural
product like6 medium-sized and macrocyclic ring systems that
are stereochemically rich and enhanced in terms of their fraction
of sp3 carbons,7 enabling efforts to address emerging difficult
drug targets5,8 such as protein−protein interactions9 and
epigenetic targets.10
Synthetic medium-sized (8−11 membered)11 and macrocyclic
lactams have a rich biological profile and have been shown to
exhibit broad activity in a variety of areas ranging from
antitumor,2a antifungal,12 anthelmintic,13 neutral endopeptidase
inhibitory,14 and hepatitis C virus protease inhibitory15 in drug
discovery16 to insecticidal agents in agriculture (Figure 1).17 In
contrast, their sulfonamide-based counterparts (amide surro-
gates),18 medium19 and macrocyclic sultams, are unnatural and
less prevalent in the literature but have been found to exhibit
antiproliferative,20 anti-HIV activity,21 inhibitory activity of
Previously, our group has reported a strategy termed
complementary ambiphile pairing (CAP)26,27 for the synthesis
of skeletally diverse 7- and 8-membered benzo-fused sultams in a
modular and efficient fashion. As shown in Figure 2A, CAP
strategies unite a pair of ambiphilic compounds, possessing both
electrophilic and nucleophilic components, in a synergistic
Received: June 23, 2015
© XXXX American Chemical Society
A
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Figure 1. Bioactive lactams and sultams.
Figure 2. Complementary ambiphile pairing and amphoteric molecules.
Figure 3. Summary of CAP and CP routes to benzo-fused sultams.
complementary manner [(4 + 3) and (4 + 4) cyclizations]. In
contrast, Yudin and co-workers have developed a number of
elegant methods using aziridine aldehydes that contain a
nucleophile and electrophile on the same molecule (Figure
2B) and which they term as amphoteric molecules.28
including Click, Click, Cyclize29 to generate a variety of bridged
and benzo-fused sultams (Figure 3). Based on these studies, we
sought to expand the scope to another unique class of bis-
electrophiles, namely, heretofore unknown o-fluoroaryl-sulfonyl
aziridines for use in complementary pairing to bis-nucleophilic
counterparts, such as amino alcohols, as well as consecutive
coupling with primary amines.30 We envisioned CP of activated
We have previously investigated and reported the use of o-
haloaryl sulfonyl chlorides in a number of pairing strategies
B
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sulfonyl aziridines (simple 6-atom bis-electrophilic synthon) via
“chemo- and regioselective” ring opening by the amino
component of the amino alcohol (bis-nucleophiles) and
subsequent SNAr cyclization with the alcohol component to
furnish unprecedented, functionally rich, medium-sized benzo-
fused sultams in chemoselective “6 + 4” and “6 + 5”
heterocyclization pathways. Moreover, the method can accom-
modate the use of (o-fluoroaryl)sulfonyl aziridines to generate 7-
membered benzo-fused sultams via a “6 + 1” atom cyclization
sequence where primary amines are utilized for sulfonyl aziridine
ring opening and the resulting secondary amines cyclize via a
subsequent SNAr reaction (Figure 3).
Table 1. Optimization of Reaction Conditions
Historically, intramolecular SNAr cyclizations have been
utilized to access common-sized rings or macrocycles comprising
5-membered indoles and indolines,31 macrolactams such as
complestatin (16-membered),32 vancomycin (16-membered and
their modified derivatives),33 and cyclopeptide alkaloids.34
Reports of intramolecular heteroaryl cyclizations en route to
sultams first surfaced in the 1990s, when Giannotti and co-
workers reported Cu-catalyzed reactions on o-halobenzene-
sulfonamides bearing amino side chains.35 In 2010, concurrent
reports from several other laboratories detailed SNAr arylether-
ification protocols to 7- and 8-membered benzo-fused sultams.36
Use of intramolecular SNAr to access 10- and 11-membered
sultams, however, to the best of our knowledge, is void in the
literature, due to several challenging problems including
methods of macrocyclization (cyclization vs oligomerization)
and strain (distortion of standard bond angles, lengths and
unfavorable transannular interactions) in the macrocyclic
products.37
c
a
entry
conc (i−ii M)
time (i, ii min)
yield (%)
b
1
2
3
4
5
0.3
30, 30
30, 40
30, 40
30, 40
30, 40
43
b
0.3
50
b
0.3−0.1
0.3−0.08
0.3−0.05
58
b
66
b,d
34
a
Final isolated yield over two reactions after flash chromatography.
b
Aziridine opening: 1 (1.0 equiv) and 2 (1.05−1.3 equiv) in DMF at
c
130 °C. SNAr: Cs2CO3 (2.5 equiv) in DMF at 150 °C. Reactions were
d
monitored by TLC. Reaction was run only once at 0.05.
facilitate the SNAr reaction and ultimately afford the desired
benzo-oxathiadiazecine 1,1-dioxide 6a in moderate yield (43%
over two reactions; 66% avg/reaction).
With this result in hand, optimization of reaction conditions
was carried out. Notably, it was found that solvent concen-
trations, reaction time, and temperature were key factors since
the aziridine ring opening and SNAr reactions are inter- and
intramolecular pathways, respectively (Table 1 and Scheme 2).
In particular, increased reaction time and temperature were
found to effect reaction decomposition. It should also be noted
that the first reaction (intermolecular aziridine ring opening) was
carried out under relatively high concentrations, while the
subsequent intramolecular SNAr reaction requires dilute
concentrations (Table 1, entries 3−5). Furthermore, it should
also be noted that while aziridine ring opening proceeds at room
temperature, the reaction took 5 days in order to go to
completion, while utilization of μW irradiation allowed for
completion of reaction in 30 min. Efforts to improve this reaction
by screening other bases, for instance, CsF, K2CO3, K3PO4,
DBU, and NaH, revealed that Cs2CO3 was optimal (see the
Supporting Information for more data). After thorough
investigation, the optimized conditions for this one-pot,
sequential aziridine ring opening−SNAr protocol was achieved,
whereby arylsulfonyl aziridine 4a and amino alcohol 5a were
subjected to μW irradiation in DMF at 130 °C for 30 min and
150 °C for 40 min, respectively. This led to 10-membered sultam
6a in good yield (66% over two reactions; 81% avg/reaction)
(Table 1, entry 4). The structure of sultam 6a was confirmed by
X-ray crystallographic analysis (Figure 4). This set of optimized
conditions was also utilized for the synthesis of 7-membered
benzo-fused sultams, with some substrates having a shorter
reaction time for SNAr cyclization.
RESULTS AND DISCUSSION
■
The titled investigation commenced with the preparation of
chiral, nonracemic aziridines 3 via use of a mild Wenker
synthesis38 from the respective amino alcohols, with all
preparations occurring in good to excellent yields. Sulfonylation
of aziridines with o-fluorobenzenesulfonyl chlorides and Et3N in
CH2Cl2 at −30 °C furnished a variety of 1-((2-fluorophenyl)-
sulfonyl)aziridines in good yields (71−94%) (Scheme 1).
Scheme 1. Preparation of Aziridines and Sulfonylation To
Provide (o-Fluoroaryl)sulfonyl Aziridines
Studies on the one-pot, sequential process began with
aziridinyl sulfonamide 4a (aziridine ring opening), which was
reacted with N-methylethanolamine 5a (1.2 equiv) in DMF at
130 °C, using microwave (μW) irradiation for 30 min (Table 1,
entry 1). The reaction was monitored by TLC, and upon
disappearance of starting material, Cs2CO3 (2.5 equiv) was
added to the crude mixture. The mixture was next subjected to 30
additional minutes of μW irradiation at 150 °C in order to
With the optimization conditions in hand, the substrate scope
studies commenced with the synthesis of medium-sized, fused
polycyclic and spirocyclic benzo-fused sultams using several
secondary acyclic and cyclic amino alcohols 5a−e to yield the
corresponding products 6a−p in average to good overall yields
(Scheme 2). Notable applications include both (R)- and (S)-
C
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Scheme 2. “6 + 4” and “6 + 5” Cyclization to Bi- and Tricyclic 10- and 11-Membered Sultams
Figure 4. X-ray structures of 6a, 6p, and 8b.
prolinol, racemic 2-piperidinemethanol, and 2-piperidine-
ethanol to afford the 6,10,5-fused, 6,10,6-fused, and 6,11,6-
fused tricyclic systems, respectively. During the investigation, it
was determined that by increasing the reaction time for some
substrates slightly higher yields were obtained. Thus, sultam 6b
was generated in 70% yield over two reactions (84% avg/
reaction) when the reaction time for SNAr reaction was extended
to 50 min while maintaining all other reaction conditions
(Scheme 2). In addition, two 10-membered benzo-fused sultams
6g and 6m were synthesized from sulfonamides derived from
spiro-cyclohexyl aziridine in good yields. Finally, it is worth
noting that a single diastereomer of the 6,11,6-fused tricyclic
D
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Scheme 3. Spiro- and Stereochemically Rich 10-Membered Sultams
Scheme 4. Substrate Scope of “6 + 1” Cyclization to 7-Membered Sultams
E
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Scheme 5. Utilization of the Mitsunobu Reaction To Access Bridged 7-Membered Sultams
sultam 6p was synthesized, starting with racemic 2-piperidine-
ethanol, suggesting only one diastereomer intermediate under-
went cyclization reaction (or potentially aziridine ring opening).
The relative stereochemistry of 6p was confirmed by X-ray
crystallography (Figure 4, vide infra). Similar sultams 6n and 6o
were also obtained as single diastereomers as observed by NMR.
A proposed plausible mechanism suggests that in all cases the
secondary amino group reacts in a chemoselective fashion for the
aziridine ring opening reaction, rendering the resulting tertiary
amine incapable of executing the cyclization reaction (SNAr) and
thus allowing the unprotected primary or secondary hydroxyl
group to cyclize under basic conditions to provide the various
benzo-oxathiadiazecine 1,1-dioxides. The resulting products
have stereocenters on the core medium-sized rings, which
consequently imparts “non-flatland” architecture.7
Next, we further investigated the scope of this one-pot,
sequential procedure by using chiral, nonracemic, substituted
secondary amino alcohols (Scheme 3). Commercially available
derivatives of ephedrine, 7a−e, were subjected to the “Click”
aziridine ring opening−SNAr reaction conditions, and to our
delight, the secondary alcohols proceeded smoothly to afford
medium-sized sultams (8a−f) in average to good yields over two
reactions, albeit in lower yield for (1S,2S)-(+)-pseudoephedrine-
derived 8c. Sultam 8b was confirmed by X-ray crystallography
where the respective stereocenters (6R,7R) correspond to the
structure as shown in Figure 4. In addition, in all cases studied,
both primary and branched secondary hydroxyl groups were able
to undergo SNAr cyclization to yield their respective sultams.
Also, use of N-(methylamino) cyclohexyl methanol in the
aforementioned method furnished the spiro-benzo-oxathiadia-
zecine-cyclohexane 1,1-dioxide 8f in 46% yield over two
reactions (68% avg/reaction) (Scheme 3).
It is worth noting that the preferred conformations of these
constrained structures are governed by stereoelectronic effects
innate to sulfonamides, which place the nitrogen lone pair
antiperiplanar to the S−Ar bond to maximize the σ* orbital
delocalization and also bisect the OSO internuclear angle.39
The bisection of the OSO internuclear angle by the
nitrogen lone pair has been confirmed in all X-ray crystallo-
graphic structures taken in this study (Figure 4). The
consequence of this stereoelectronic effect/preferred rotomer
of the Ar-SO2NR1R2 moiety is that it renders the core
macrocyclic in a unique conformation, whereby the N−H
bond points to the inner core of the macrocycle (see the circled
highlighted area in 8b of Figure 4).40
whereby their ability to have dual reactivity facilitates access to 7-
membered (common-sized) benzo-fused sultams in an overall “6
+ 1” atom cyclization sequence involving consecutive aziridine
ring opening and SNAr reaction (Scheme 4). The use of simple
alkyl and aromatic amines containing different substituents
furnished benzo-thiadiazepine 1,1-dioxides 10a−e in satisfactory
yields (44−53% over two reactions, 67−73% avg/reaction).
Amines with both cyclic and linear ether moieties were also
employed successfully to provide 7-membered benzo-fused
sultams 10f−i in moderate yields (46−56% over two reactions,
68−75% avg/reactions) (Scheme 4). The primary amines
proceeded with aziridine ring opening, and the secondary
amines generated from the first reaction were then cyclized to
form cyclic sulfonamides.
Similarly, common-sized benzo-fused sultams 10j−p consist-
ing of amines having hydroxyl motifs were generated with
i
different (o-fluoroaryl)sulfonyl aziridines (cyclohexyl, Pr, and
iBu) in albeit slightly lower yields (12−56% over two reactions,
35−75% avg/reaction). On the basis of the results, when primary
amines with unprotected hydroxyl groups are used as the
nucleophile, the resulting secondary amines from the aziridine
ring opening reaction chemoselectively proceed to SNAr
cyclization in preference to the free hydroxyl groups. A high
degree of chemoselectivity was observed in the majority of cases,
although in some cases formation of an unidentified side product
during the SNAr reaction and some final product decomposition
were seen.
A notable feature of these 7-membered sultams possessing a
free N−H is their ability to undergo an additional facile
Mitsunobu reaction to synthesize bridged [3.2.2] bicyclic benzo-
fused sultams. Hence, sultam 10l was treated with Ph3P and
DIAD in THF at room temperature, stirred overnight, and upon
completion, provided ethanobenzothiadiazepine 1,1-dioxide 11a
in 87% yield (Scheme 5). The structure of sultam 10m was
confirmed by X-ray crystallography and shown to display an
optimal positioning of the hydroxyl group in order to participate
in facile intramolecular Mitsunobu alkylation to afford sultam
11b bearing a two-carbon bridgehead. Further demonstration of
the intramolecular Mitsunobu reaction was realized in the
production of the spiro-cyclohexyl-containing [3.2.2] bridged
benzo-fused sultam 11c, albeit in a lower yield of 40%. The
structure of 11c was confirmed by X-ray crystallography
(Scheme 5). Sultam 10o, on the other hand, was unsuccessful
in yielding the two-carbon bridged sultam after several attempts
using similar reaction conditions. The recovery of starting
material and several side products present in Mitsunobu
With the aforementioned results in hand, the one-pot,
sequential strategy was extended to several primary amines 9,
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reactions as well as excess reagents that were used in the reaction
were collected.
A key finding during the studies was the isolation of the
intermediate, aziridine ring opened product, which was
observable on 19F NMR (Scheme 6). A major difference between
one step (Scheme 7). Hence, both (R)- and (S)-benzyl glycidyl
ethers were subjected to “Click” epoxide ring opening30 with
TBS-protected D-alaninol to furnish elaborate amino alcohols 16
and 17. The chiral, nonracemic building blocks were then utilized
in the established aziridine ring opening−SNAr procedure to
afford 10-membered sultams 18 and 19 with three stereocenters,
along with pendant free hydroxy group, in moderate yields. In
this regard, it should be noted that the TBS-ether protecting
group was removed during the reaction, presumably by the
displaced fluoride anion in the SNAr reaction, thus representing
an overall one-pot, sequential aziridine ring opening−SNAr−
desilylation protocol.
Scheme 6. 19F NMR Studies: Comparison between
a
Sulfonamide A, Ring-Opened B, and Product C
In summary, we have developed a one-pot CP strategy
introducing (o-fluoroaryl)sulfonyl aziridine building blocks as
versatile bis-electrophilic species for reaction with amino
alcohols/amines for the preparation of common and medium-
sized benzo-fused sultams containing up to three stereocenters.
This approach was extended to the utilization of elaborate chiral,
nonracemic building blocks as well as cyclic and spirocyclic
amino alcohols to afford a diverse array of polycyclic scaffolds.
Furthermore, the method is highly modular and adaptable for the
preparation of sultam libraries in a one-pot, sequential manner.
Work in this regard is underway and will be reported in due
course.
a
See the 19F spectra in the Supporting Information.
EXPERIMENTAL SECTION
the intermediate and the final product is the presence of the
fluorine atom, and use of 19F NMR provided a convenient way to
monitor the progression of the SNAr reaction. In this experiment,
aziridinyl-sulfonamide A was chosen and shown to contain a
single resonance (triplet) in the 19F NMR spectrum (Figure 1a,
Supporting Information). Reaction with racemic 2-piperidine-
methanol furnished the ring opened intermediate B, which was
detected as a single resonance (triplet) in the 19F NMR spectrum
(Figure 1b, Supporting Information) but shifted marginally
upfield due to the electronic changes within the sulfonamide.
After SNAr reaction, the 19F NMR of the desired product C (6n)
was obtained and showed complete disappearance of the fluorine
resonance (Figure 1c, Supporting Information).41
■
General Information. All air- and moisture-sensitive reactions were
carried out in flame- or oven-dried glassware under argon atmosphere
using standard gastight syringes, cannula, and septa. Stirring was
achieved with oven-dried, magnetic stir bars. CH2Cl2 was purified by
passage through the purification system employing activated Al2O3.42
Et3N was purified by passage over basic alumina and stored over KOH.
Flash column chromatography was performed with SiO2. The crude
mixture was also purified using an automated flash column
chromatography system. Thin-layer chromatography was performed
on silica gel plates. Deuterated solvents were purchased from
1
commercial sources. H and 13C NMR spectra were recorded on a
400 MHz spectrometer as well as a 500 spectrometer operating at 500
MHz and 126 MHz, respectively. High-resolution mass spectrometry
(HRMS) spectra were obtained on a TOF-MS operating on ESI.
Microwave-assisted reactions were carried out in 1 dram vials utilizing a
reaction heating block in an Anton Paar Synthos 3000 synthesizer and
also Biotage Initiator both using an external calibrated external infrared
Encouraged by these results, and in an effort to further
highlight the efficiency of this modular approach, studies were
focused toward the extension of the method using readily
available chiral, nonracemic building blocks that were obtained in
Scheme 7. “Click, Click, Click, Cyclize” to Stereochemically Rich, 10-Membered Sultams
G
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(IR) sensor. All NMR peak assignments were assigned on the basis of
both COSY and HSQC NMR methods.
hexane); [α]2D0 = −5.0 (c = 1.43, CHCl3); FTIR (thin film) 3103, 2964,
1603, 1481, 1429, 1335, 1167, 854, 741, 727 cm−1; 1H NMR (500 MHz,
CDCl3) δ ppm 8.10−7.85 (m, 1H, aromatic), 7.12−6.88 (m, 2H,
aromatic), 2.80 (dd, J = 7.1, 1.1 Hz, 1H, NCHaHbCH), 2.70 (ddd, J =
7.3, 7.2, 4.6 Hz, 1H, NCHCH), 2.24 (d, J = 3.8 Hz, 1H, NCHaHbCH),
1.61−1.43 (m, 1H, CH3CHCH3), 0.96 (d, J = 6.8 Hz, 3H,
CH3CHCH3), 0.90 (d, J = 6.7 Hz, 3H, CH3CHCH3); 13C NMR (126
MHz, CDCl3) δ ppm 166.3 (dd, J = 258.5, 11.4 Hz), 160.4 (dd, J =
260.8, 12.8 Hz), 132.4 (dd, J = 10.6, 1.6 Hz), 111.9 (dd, J = 22.0, 3.8 Hz),
105.8 (dd, J = 25.5, 25.4 Hz), 105.4 (dd, J = 26.0, 25.9 Hz), 46.5, 33.7,
30.1, 19.4, 18.9; HRMS calcd for C11H13F2NO2SH (M + H)+ 262.0713,
found 262.0720 (TOF MS ES+).
(S)-10-Bromo-3-isobutyl-5-methyl-2,3,4,5,6,7-hexahydrobenzo-
[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide (6a). According to the
reaction protocol described in general procedure B from 4a (49.8
mg), compound 6a (66%, 38.7 mg) was isolated after chromatography
as a white solid: mp 192−195 °C; Rf = 0.44 (2:1 EtOAc/hexane); [α]D20
= +167.5 (c = 1.02, CHCl3); FTIR (thin film) 3267, 3090, 2966, 1576,
1558, 1462, 1400, 1323, 1165, 1059, 824, 781, 748, 725 cm−1; 1H NMR
(500 MHz, CDCl3) δ ppm 7.85 (d, J = 8.3 Hz, 1H, aromatic), 7.34−7.28
(m, 2H, aromatic), 7.09 (s, 1H, NH), 4.41−4.31 (m, 2H, OCH2CH2),
2.73 (dddd, J = 9.2, 9.0, 4.7, 4.6 Hz, 1H, NHCHCH2N), 2.66 (dd, J =
12.6, 4.9 Hz, 1H, NHCHCHaHbN), 2.58 (ddd, J = 14.8, 10.8, 3.3 Hz,
1H, NCHaHbCH2O), 2.46 (s, 3H, NCH3), 2.34 (ddd, J = 15.2, 1.7, 1.6
Hz, 1H, NCHaHbCH2O), 2.24 (dd, J = 12.6, 10.5 Hz, 1H,
NHCHCHaHbN), 1.85 (ddd, J = 13.7, 9.4, 4.2 Hz, 1H, NHCHCHaHb),
1.62−1.49 (m, 1H, CH3CHCH3), 1.33 (ddd, J = 13.8, 8.8, 5.0 Hz, 1H,
NHCHCHaHb), 0.86 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.73 (d, J = 6.6
Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 155.1,
132.8, 129.3, 128.4, 125.7, 120.6, 69.7, 60.0, 53.2, 49.8, 44.3, 43.1, 24.4,
23.6, 21.9; HRMS calcd for C15H23BrN2O3SH (M + H)+ 391.0691,
found 391.0670 (TOF MS ES+).
General Procedure A: Preparation of (o-Fluoroaryl)sulfonyl
Aziridines. To a round-bottom flask containing a solution of aziridine
(2.2 mmol, 2.0 equiv) in dry CH2Cl2 (0.5 M) was added Et3N (2.2
mmol, 2.0 equiv). The reaction mixture was cooled to −40 °C and
stirred for 10 min, and sulfonyl chloride (1.1 mmol, 1.0 equiv) was
added to the reaction mixture in a dropwise fashion. The reaction was
then stirred for 30 min after which conversion of starting material was
monitored by TLC. Upon completion of the reaction, the mixture was
warmed to rt and quenched with cold water (2.2 mL), and the layers
were separated. The organic portion was washed with cold 10% aq HCl,
and the resulting layers were separated. This partitioning was then
repeated with cold water, cold satd NaHCO3, cold water again, and
finally brine. The final organic layer was dried (Na2SO4) and
concentrated under reduced pressure to afford the desired aziridinyl
sulfonamide.
General Procedure B: One-Pot, Sequential (Aziridine Ring
Opening and SNAr). To a microwave vial containing a solution of
sulfonamide (1.0 equiv) in DMF (0.3 M) was added amine/amino
alcohol (1.05−1.2 equiv). The reaction vessel was capped and heated in
the Biotage Initiator microwave at 130 °C for 30−40 min, after which
conversion of starting material was monitored by TLC. To the crude
mixture were added DMF (0.08 M) and Cs2CO3 (2.5 equiv), and the
mixture underwent microwave irradiation again at 150 °C for 30−50
min. Water was added to the crude mixture, which was extracted with
EtOAc (4×). The organic layer was separated, and the combined
organic layers were washed with water and brine, dried (Na2SO4), and
concentrated under reduced pressure to afford the crude product, which
was purified by an automated flash column chromatography system.
General Procedure C: One-Pot, Sequential (Aziridine Ring
Opening and SNAr). To a microwave vial containing a solution of
sulfonamide (1.0 equiv) in DMF (0.3 M) was added amine/amino
alcohol (1.05−1.2 equiv). The reaction vessel was capped and heated in
a Biotage Initiator microwave at 130 °C for 30−40 min, after which
conversion of starting material was monitored by TLC. To the crude
mixture was added Cs2CO3 (2.5 equiv), and the mixture underwent
microwave irradiation again at 150 °C for 30−50 min. Water was added
to the crude mixture, which was extracted with EtOAc (4×). The organic
layer was separated, and the combined organic layers were washed with
water and brine, dried (Na2SO4), and concentrated under reduced
pressure to afford the crude product, which was purified by the
automated flash column chromatography system.
(S)-10-Bromo-3-isopropyl-5-methyl-2,3,4,5,6,7-hexahydrobenzo-
[b][1,4,5,8]oxathiadiazecine-1,1-Dioxide (6b). According to the
reaction protocol described in general procedure B from 4b (50.0
mg), compound 6b (70%, 41.0 mg) was isolated after chromatography
as a white solid: mp 175−180 °C; Rf = 0.45 (2:1 EtOAc/hexane); [α]D20
= +170.4 (c = 0.545, CHCl3); FTIR (thin film) 3263, 3099, 2968, 1578,
1560, 1452, 1371, 1323, 1163 1057, 820, 737 cm−1; 1H NMR (500 MHz,
CDCl3) δ ppm 7.84 (d, J = 8.4 Hz, 1H, aromatic), 7.36−7.29 (m, 2H,
aromatic), 7.05 (s, 1H, NH), 4.43−4.27 (m, 2H, OCH2CH2), 2.68 (ddd,
J = 11.2, 4.6, 4.5 Hz, 1H, NHCHCH2N), 2.60 (ddd, J = 14.5, 10.6, 3.5
Hz, 1H, NHCHCHaHbN), 2.49 (dd, J = 12.7, 5.1 Hz, 1H,
NCHaHbCH2O), 2.46 (s, 3H, NCH3), 2.38−2.23 (m, 3H,
NHCHCHaHbN, NCHaHbCH2O, CH3CHCH3), 0.98 (d, J = 6.9 Hz,
3H, CH3CHCH3), 0.79 (d, J = 7.3 Hz, 3H, CH3CHCH3); 13C NMR
(126 MHz, CDCl3) δ ppm 155.2, 132.9, 129.2, 128.3, 125.7, 120.7, 69.7,
55.6, 53.7, 53.1, 44.3, 28.9, 18.3, 15.6; HRMS calcd for
C14H21BrN2O3SH (M + H)+ 377.0535, found 377.0495 (TOF MS ES+).
(S)-10-Fluoro-3-isobutyl-5-methyl-2,3,4,5,6,7-hexahydrobenzo-
[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide (6c). According to the
reaction protocol described in general procedure C from 4c (52.0
mg), compound 6c (43%, 26.8 mg) was isolated after chromatography
as a white solid: mp 145−148 °C; Rf = 0.33 (2:1 EtOAc/hexane); [α]D20
= +148.7 (c = 0.87, CHCl3); FTIR (thin film) 3265, 2962, 1603, 1587,
1458, 1350, 1323, 1163, 1057, 818, 785, 733, 704 cm−1; 1H NMR (400
MHz, CDCl3) δ ppm 7.99 (dd, J = 8.6, 6.4 Hz, 1H, aromatic), 7.07 (s,
1H, NH), 6.92−6.78 (m, 2H, aromatic), 4.46−4.19 (m, 2H,
OCH2CH2), 2.70 (dddd, J = 9.0, 8.8, 4.6, 4.4 Hz, 1H, NHCHCH2N),
2.65 (dd, J = 12.4, 4.9 Hz, 1H, NHCHCHaHbN), 2.58 (ddd, J = 14.9, 8.9,
5.5 Hz, 1H, NCHaHbCH2O), 2.46 (s, 3H, NCH3), 2.34 (ddd, J = 15.1,
1.8, 1.7 Hz, 1H, NCHaHbCH2O), 2.23 (dd, J = 12.4, 10.5 Hz, 1H,
NHCHCHaHbN), 1.85 (ddd, J = 13.7, 9.5, 3.9 Hz, 1H, NHCHCHaHb),
1.61−1.52 (m, 1H, CH3CHCH3), 1.33 (ddd, J = 13.8, 8.6, 5.0 Hz, 1H,
NHCHCHaHb), 0.86 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.72 (d, J = 6.6
Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 166.3 (d,
1JC−F = 254.8 Hz), 156.3 (d, 3JC−F = 10.5 Hz), 133.7 (d, 3JC−F = 10.8 Hz),
General Procedure D: Mitsunobu Reaction. To a flame-dried
round-bottom flask containing a solution of sultam (0.047 mmol, 1.0
equiv) in dry THF (0.05 M) was added triphenylphosphine (0.140
mmol, 3.0 equiv). The reaction mixture was stirred for 10 min, and
diisopropyl azodicarboxylate (0.12 mmol, 2.5 equiv) was added to the
mixture in a dropwise fashion. The reaction was then stirred overnight at
rt, and conversion of starting material was monitored by TLC. The
solvent was removed in vacuo to yield a yellow oil and was purified by an
automated flash column chromatography system.
(S)-1-((4-Bromo-2-fluorophenyl)sulfonyl)-2-isopropylaziridine
(4b). According to general procedure A from 2-fluoro-4-bromosulfonyl
chloride (1 g), 4b (854.4 mg, 72%) was isolated as a yellow oil: Rf = 0.60
(1:3 EtOAc/hexane); [α]2D0 = −47.6 (c = 0.675, CHCl3); FTIR (thin
1
film) 3094, 2962, 1589, 1472, 1398, 1333, 1167, 879, 735 cm−1; H
NMR (500 MHz, CDCl3) δ ppm 7.88−7.76 (m, 1H, aromatic), 7.53−
7.41 (m, 2H, aromatic), 2.80 (dd, J = 7.1, 1.1 Hz, 1H, NCHaHbCH), 2.72
(ddd, J = 7.3, 7.2, 4.8 Hz, 1H, NCHCH), 2.24 (d, J = 4.8 Hz, 1H,
NCHaHbCH), 1.59−1.39 (m, 1H, CH3CHCH3), 0.96 (d, J = 6.8 Hz,
3H, CH3CHCH3), 0.91 (d, J = 6.7 Hz, 3H, CH3CHCH3); 13C NMR
(126 MHz, CDCl3) δ ppm 159.1 (d, 1JC−F = 262.2 Hz), 131.4, 129.4 (d,
3JC−F = 9.0 Hz), 127.9 (d, 3JC−F = 3.8 Hz), 121.0 (d, 2JC−F = 24.5 Hz),
120.5 (d, 2JC−F = 24.2 Hz), 46.6, 33.8, 30.1, 19.5, 18.9; HRMS calcd for
C11H13BrFNO2SH (M + H)+ 321.9913, found 321.9888 (TOF MS
ES+).
(S)-1-((2,4-Difluorophenyl)sulfonyl)-2-isopropylaziridine (4d). Ac-
cording to general procedure A from 2,4-difluorosulfonyl chloride (1 g),
4d (889.4 mg, 72%) was isolated as a yellow oil: Rf = 0.51 (1:3 EtOAc/
126.2 (d, 4JC−F = 3.2 Hz), 109.7 (d, 2JC−F = 22.1 Hz), 104.9 (d, 2JC−F
=
25.0 Hz), 69.7, 60.0, 53.2, 49.9, 44.4, 43.1, 24.4, 23.6, 21.8; HRMS calcd
H
DOI: 10.1021/acs.joc.5b01429
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
for C15H23FN2O3SH (M + H)+ 331.1492, found 331.1519 (TOF MS
ES+).
119.5 (d, 4JC−F = 3.2 Hz), 113.4 (d, 2JC−F = 24.5 Hz), 59.5, 58.9, 50.1,
42.7, 26.4 (2C), 25.0, 22.4, 22.1 (2C); HRMS calcd for
C16H23FN2O3SH (M + H)+ 343.1492, found 343.1485 (TOF MS ES+).
(6S,14aR)-11-Bromo-6-isobutyl-1,2,3,5,6,7,14,14a-
octahydrobenzo[b]pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine 8,8-Di-
oxide (6h). According to the reaction protocol described in general
procedure C from 4a (81.8 mg), compound 6h (57%, 57.7 mg) was
isolated after chromatography as a colorless oil: Rf = 0.34 (1:1 EtOAc/
hexane); [α]2D0 = −48.1 (c = 1.805, CHCl3); FTIR (thin film) 3275,
2955, 1578, 1466, 1317, 1159, 1063, 852, 733, 702 cm−1; 1H NMR (400
MHz, CDCl3) δ ppm 7.93−7.71 (m, 1H, aromatic), 7.26−7.18 (m, 2H,
aromatic), 5.69 (s, 1H, NH), 4.48 (dd, J = 11.5, 3.3 Hz, 1H,
OCHaHbCHN), 3.90 (dd, J = 11.4, 11.3 Hz, 1H, OCHaHbCHN), 3.40−
3.26 (m, 1H, NHCHCH2N), 3.17 (ddt, J = 12.0, 8.1, 3.8 Hz, 1H,
NCHCH2O), 3.14−3.03 (m, 1H, NCHaHbCH2CH2), 2.50−2.38 (m,
3H, NHCHCH2N, NCHaHbCH2CH2), 2.01−1.90 (m, 1H,
NCH2CH2CHaHb), 1.88−1.77 (m, 3H, NCH2CH2CH2, CH3CHCH3),
1.67 (ddd, J = 14.3, 8.4, 6.2 Hz, 1H, NHCHCHaHb), 1.40 (td, J = 11.4,
4.6 Hz, 1H, NCH2CH2CHaHb), 1.10 (ddd, J = 14.0, 7.8, 6.2 Hz, 1H,
NHCHCHaHb), 0.90 (dd, J = 6.9, 6.8 Hz, 6H, CH3CHCH3); 13C NMR
(126 MHz, CDCl3) δ ppm 156.0, 131.1, 130.8, 128.0, 124.5, 118.2, 74.0,
62.8, 61.4, 56.7, 55.5, 40.9, 27.4, 24.7, 24.7, 22.7, 22.3; HRMS calcd for
C17H25BrN2O3SH (M + H)+ 417.0848, found 417.0836 (TOF MS ES+).
(6S,14aR)-11-Fluoro-6-isopropyl-1,2,3,5,6,7,14,14a-
octahydrobenzo[b]pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine 8,8-Di-
oxide (6i). According to the reaction protocol described in general
procedure C from 4d (54.3 mg), compound 6i (37%, 26.1 mg) was
isolated after chromatography as a semiwhite sticky oil: Rf = 0.28 (1:1
EtOAc/hexane); [α]2D0 = −6.6 (c = 1.33, CHCl3); FTIR (thin film)
(S)-10-Fluoro-3-isopropyl-5-methyl-2,3,4,5,6,7-hexahydrobenzo-
[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide (6d). According to the
reaction protocol described in general procedure C from 4d (94.2
mg), compound 6d (40%, 44.6 mg) was isolated after chromatography
as a white solid: mp 183−188 °C; Rf = 0.30 (2:1 EtOAc/hexane); [α]D20
= +128.8 (c = 0.745, CHCl3); FTIR (thin film) 3257, 2974, 1603, 1587,
1470, 1448, 1373, 1323, 1163, 1067, 818, 777, 756, 729 cm−1; 1H NMR
(400 MHz, CDCl3) δ ppm 7.99 (dd, J = 8.6, 6.4 Hz, 1H, aromatic), 7.04
(s, 1H, NH), 6.93−6.73 (m, 2H, aromatic), 4.43−4.25 (m, 2H,
OCH2CH2), 2.71−2.56 (m, 2H, NHCHCH2N, NHCHCHaHbN), 2.50
(dd, J = 12.8, 5.0 Hz, 1H, NCHaHbCH2O), 2.47 (s, 3H, NCH3), 2.37−
2.29 (m, 3H, NHCHCHaHbN, NCHaHbCH2O, CH3CHCH3), 0.99 (d,
J = 6.9 Hz, 3H, CH3CHCH3), 0.80 (d, J = 7.2 Hz, 3H, CH3CHCH3); 13
C
NMR (126 MHz, CDCl3) δ ppm 166.3 (d, 1JC−F = 254.7 Hz), 156.4 (d,
3JC−F = 10.6 Hz), 133.7 (d, 3JC−F = 10.8 Hz), 126.2 (d, 4JC−F = 3.4 Hz),
109.7 (d, 2JC−F = 22.1 Hz), 105.1 (d, 2JC−F = 25.0 Hz), 69.7, 55.7, 53.8,
53.1, 44.4, 28.9, 18.4, 15.6; HRMS calcd for C14H21FN2O3SH (M + H)+
317.1335, found 317.1320 (TOF MS ES+).
(S)-11-Chloro-3-isopropyl-5-methyl-2,3,4,5,6,7-hexahydrobenzo-
[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide (6e). According to the
reaction protocol described in general procedure B from 4e (75.0
mg), compound 6e (51%, 45.8 mg) was isolated after chromatography
as a yellow oil: Rf = 0.32 (1:1 EtOAc/hexane); [α]2D0 = +89.0 (c = 0.125,
CHCl3); FTIR (neat) 3149, 2962, 1587, 1469, 1371, 1307, 1222, 1161,
1107, 1060, 835, 821, 729 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm
7.95 (d, J = 2.7 Hz, 1H, aromatic), 7.50 (dd, J = 8.8, 2.7 Hz, 1H,
aromatic), 7.14 (s, 1H, NH), 7.12 (d, J = 8.9 Hz, 1H, aromatic), 4.39−
4.29 (m, 2H, OCH2CH2), 2.75−2.69 (m, 1H, NHCHCH2N), 2.56
(ddd, J = 14.5, 10.5, 3.6 Hz, 1H, NCHaHbCH2O), 2.48 (dd, J = 12.6, 5.1
Hz, 1H, NCHaHbCH2O), 2.45 (s, 3H, NCH3), 2.38−2.25 (m, 3H,
NHCHCHaHb, NHCHCHaHbN, CH3CHCH3), 0.98 (d, J = 6.9 Hz, 3H,
CH3CHCH3), 0.81 (d, J = 7.2 Hz, 3H, CH3CHCH3); 13C NMR (126
MHz, CDCl3) δ ppm 153.2, 134.1, 131.6, 131.3, 127.5, 118.7, 69.7, 55.4,
53.6, 53.0, 44.2, 28.9, 18.3, 15.5; HRMS calcd for C14H21ClN2O3SH (M
+ H)+ 333.1040, found 333.1022 (TOF MS ES+).
1
3300, 2961, 1603, 1587, 1468, 1387, 1323, 1157, 1070, 839 cm−1; H
NMR (500 MHz, CDCl3) δ ppm 7.99−7.76 (m, 1H, aromatic), 6.82−
6.64 (m, 2H, aromatic), 4.84 (d, J = 6.9 Hz, 1H, NH), 4.45 (dd, J = 11.6,
3.1 Hz, 1H, OCHaHbCHN) 3.99 (dd, J = 11.2, 11.1 Hz, 1H,
OCHaHbCHN), 3.32 (ddd, J = 11.3, 5.9, 5.7 Hz, 1H, NHCHCH2N),
3.08 (dddd, J = 11.2, 8.7, 5.8, 3.1 Hz, 1H, NCHCH2O), 2.97 (ddd, J =
9.6, 6.2, 4.5 Hz, 1H, NCHaHbCH2CH2), 2.71 (dd, J = 14.4, 5.6 Hz, 1H,
NHCHCHaHbN), 2.56−2.43 (m, 2H, NCHaHbCH2CH2,
NHCHCHa Hb N), 2. 00−1. 85 (m, 2H, CH3 CH CH3 ,
NCH2CH2CHaHb), 1.79−1.69 (m, 2H, NCH2CH2CH2), 1.45−1.31
(m, 1H, NCH2CH2CHaHb), 0.97 (dd, J = 6.9, 4.4 Hz, 6H,
(S)-3-((S)-sec-Butyl)-11-chloro-5-methyl-2,3,4,5,6,7-
hexahydrobenzo[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide (6f). Ac-
cording to the reaction protocol described in general procedure B from
4f (78.7 mg), compound 6f (45%, 42.1 mg) was isolated after
chromatography as a white solid: mp 138−142 °C; Rf = 0.31 (1:1
EtOAc/hexane); [α]2D0 = −93.2 (c = 0.125, CHCl3); FTIR (neat) 2962,
1588, 1467, 1371, 1159, 1060, 831, 819, 750 cm−1; 1H NMR (500 MHz,
CDCl3) δ ppm 7.95 (d, J = 2.7 Hz, 1H, aromatic), 7.50 (dd, J = 8.8, 2.7
Hz, 1H, aromatic), 7.11 (d, J = 8.8 Hz, 1H, aromatic), 7.05 (s, 1H, NH),
4.44−4.24 (m, 2H, OCH2CH2), 2.83−2.72 (m, 1H, NHCHCH2N),
2.58 (ddd, J = 14.5, 10.6, 3.5 Hz, 1H, NCHaHbCH2O), 2.50 (dd, J = 12.6,
5.1 Hz, 1H, NCHaHbCH2O), 2.44 (s, 3H, NCH3), 2.35−2.25 (m, 2H,
NHCHCHa Hb N, NHCHCHa Hb ), 2.01−1.92 (m, 1H,
CH3CHCHaHbCH3), 1.92−1.82 (m, 1H, CH3CHCHaHbCH3), 1.03−
0.95 (m, 1H, CH3CHCHaHbCH3), 0.95−0.90 (m, 3H,
CH3CHCH2CH3), 0.80 (d, J = 7.1 Hz, 3H, CH3CHCH2CH3); 13C
NMR (126 MHz, CDCl3) δ ppm 153.3, 134.1, 131.6, 131.3, 127.5,
118.6, 69.6, 55.7, 54.6, 52.8, 44.2, 36.0, 23.0, 15.3, 12.4; HRMS calcd for
C15H23ClN2O3SH (M + H)+ 347.1196, found 347.1200 (TOF MS ES+).
12-Fluoro-5-methyl-4,5,6,7-tetrahydro-2H-spiro[benzo[b]-
[1,4,5,8]oxathiadiazecine-3,1′-cyclohexane] 1,1-Dioxide (6g). Ac-
cording to the reaction protocol described in general procedure B
from 4g (77.7 mg), compound 6g (46%, 42.6 mg) was isolated after
chromatography as a brownish oil: Rf = 0.35 (1:1 EtOAc/hexane); FTIR
(neat) 3245, 2956, 2931, 1591, 1488, 1458, 1319, 1153, 1062, 891, 821,
705 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (ddd, J = 8.2, 8.2,
5.9 Hz, 1H, aromatic), 7.13 (ddd, J = 8.2, 1.1, 1.0 Hz, 1H, aromatic), 6.98
(ddd, J = 10.5, 8.4, 1.1 Hz, 1H, aromatic), 6.55 (s, 1H, NH), 5.61−5.56
(m, 1H, OCHaHbCH2), 3.79 (dd, J = 5.1, 4.9 Hz, 1H, OCHaHbCH2),
3.38 (d, J = 5.8 Hz, 2H, NCH2CH2O), 3.25−3.09 (m, 2H, NHCCH2N),
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 166.0 (d, 1JC−F
=
253.8 Hz), 157.5 (d, 3JC−F = 10.8 Hz), 132.0 (d, 3JC−F = 10.9 Hz), 126.7
(d, 4JC−F = 3.2 Hz), 107.9 (d, 2JC−F = 22.2 Hz), 102.6 (d, 2JC−F = 25.6
Hz), 74.0, 64.9, 62.8, 59.4, 57.5, 31.3, 27.2, 23.8, 18.7, 18.2; HRMS calcd
for C16H23FN2O3SH (M + H)+ 343.1492, found 343.1492 (TOF MS
ES+).
(6S,14aR)-6-((S)-sec-Butyl)-10-chloro-1,2,3,5,6,7,14,14a-
octahydrobenzo[b]pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine 8,8-Di-
oxide (6j). According to the reaction protocol described in general
procedure B from 4f (78.8 mg), compound 6j (54%, 54.4 mg) was
isolated after chromatography as a yellow oil: Rf = 0.37 (1:1 EtOAc/
hexane); [α]2D0 = −68.4 (c = 0.125, CHCl3); FTIR (neat) 2962, 2875,
1
1598, 1467, 1407, 1380, 1338, 1163, 1064, 786, 761 cm−1; H NMR
(500 MHz, CDCl3) δ ppm 7.91 (d, J = 2.7 Hz, 1H, aromatic), 7.46 (dd, J
= 8.8, 2.7 Hz, 1H, aromatic), 7.06 (d, J = 8.8 Hz, 1H, aromatic), 6.85 (d, J
= 5.7 Hz, 1H, NH), 4.35 (dd, J = 11.8, 3.2 Hz, 1H, OCHaHbCHN), 3.90
(t, J = 11.6 Hz, 1H, OCHaHbCHN), 3.20−2.95 (m, 2H, NHCHCH2N,
NCHCH2O), 2.92−2.78 (m, 1H, NCHaHbCH2CH2), 2.63−2.50 (m,
2H, NHCHCHaHbN, NCHaHbCH2CH2), 2.41 (dd, J = 13.5, 5.1 Hz,
1H, NHCHCHaHbN), 2.02−1.86 (m, 1H, NCH2CHaHbCH2), 1.86−
1.75 (m, 2H, NCH2CHaHbCH2, NCH2CHaHbCHaHb), 1.76−1.62 (m,
2H, NCH2CHaHbCHaHb, CH3CHCHaHbCH3), 1.40−1.29 (m, 1H,
CH3CHCHaHbCH3), 1.11−0.97 (m, 1H, CH3CHCHaHbCH3), 0.95 (d,
J = 6.8 Hz, 3H, CH3CHCH2CH3), 0.90 (t, J = 7.3 Hz, 3H,
CH3CHCH2CH3); 13C NMR (126 MHz, CDCl3) δ ppm 153.1,
133.6, 131.6, 130.3, 126.7, 116.4, 73.5, 61.9, 58.0, 57.2, 55.7, 37.0, 27.0,
25.4, 24.2, 15.8, 11.6; HRMS calcd for C17H25ClN2O3SH (M + H)+
373.1353, found 373.1334 (TOF MS ES+).
2.82 (s, 3H, NCH3), 1.99−1.87 (m, 4H, cyclohexyl), 1.70−1.44 (m, 6H,
(6S,14aR)-6-((S)-sec-Butyl)-9-fluoro-1,2,3,5,6,7,14,14a-
octahydrobenzo[b]pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine 8,8-Di-
oxide (6k). According to the reaction protocol described in general
1
cyclohexyl); 13C NMR (126 MHz, CDCl3) δ ppm 160.3(d, JC−F
=
257.2 Hz), 154.5, 133.5 (d, 3JC−F = 11.2 Hz), 123.8 (d, 3JC−F = 10.2 Hz),
I
DOI: 10.1021/acs.joc.5b01429
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
procedure B from 4h (74.4 mg), compound 6k (57%, 54.9 mg) was
isolated after chromatography as a yellowish white solid: mp 152−156
°C; Rf = 0.41 (1:1 EtOAc/hexane); [α]2D0 = −58.3 (c = 0.125, CHCl3);
FTIR (neat) 2962, 2875, 1598, 1467, 1380, 1338, 1163, 1064, 786, 761
cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.42 (ddd, J = 8.4, 5.8 Hz,
1H, aromatic), 7.07 (d, J = 6.2 Hz, 1H, NH), 6.89 (ddd, J = 8.5, 1.1, 1.1
Hz, 1H, aromatic), 6.82 (ddd, J = 9.6, 8.4, 1.0 Hz, 1H, aromatic), 4.42
(dd, J = 11.8, 3.2 Hz, 1H, OCHaHbCHN), 3.92 (dd, J = 11.5, 11.2 Hz,
1H, OCHaHbCHN), 3.19−3.04 (m, 2H, NHCHCH2N, NCHCH2O),
3.03−2.93 (m, 1H, NCHaHbCH2CH2), 2.64 (dd, J = 13.8, 5.4 Hz, 1H,
NHCHCHaHbN), 2.57 (ddd, J = 9.3, 9.2, 6.1 Hz, 1H,
NCHaHbCH2CH2), 2.46 (dd, J = 13.8, 4.9 Hz, 1H, NHCHCHaHbN),
1.99−1.88 (m, 1H, NCH2CHaHbCH2), 1.88−1.61 (m, 4H,
NCH2CHaHbCH2, NCH2CHaHbCH2, CH3CHCHaHbCH3), 1.38
(dddd, J = 13.1, 6.8, 3.6, 3.5 Hz, 1H, CH3CHCHaHbCH3), 1.10−1.00
(m, 1H, CH3CHCHaHbCH3), 0.99 (d, J = 6.8 Hz, 3H,
CH3CHCH2CH3), 0.89 (t, J = 7.3 Hz, 3H, CH3CHCH2CH3); 13C
chromatography as a sticky colorless oil: Rf = 0.52 (1:1 EtOAc/hexane);
[α]2D0 = +30.1 (c = 0.59, CHCl3); FTIR (thin film) 3259, 2934, 1578,
1464, 1391, 1327, 1159, 1063, 812, 762, 733, 702 cm−1; 1H NMR (400
MHz, CDCl3) δ ppm 7.80 (d, J = 8.3 Hz, 1H, aromatic), 7.29 (d, J = 1.8
Hz, 1H, aromatic), 7.20 (d, J = 1.8 Hz, 1H, aromatic), 4.39 (dd, J = 10.7,
4.6 Hz, 1H, OCHaHbCHN), 3.75−3.60 (m, 1H, OCHaHbCHN), 3.42−
3.25 (m, 1H, NCHCH2O), 2.79−2.60 (m, 4H, NCH2CH2CH2CH2,
NHCHCH2 N, NHCHCHa Hb N), 2.49−2.31 (m, 1H,
NHCHCHaHbN), 1.99−1.86 (m, 1H, CH3CHCH3), 1.87−1.77 (m,
1 H , N C H 2 C H 2 C H a H b C H 2 ) , 1 . 5 9 − 1 . 3 6 ( m , 4 H ,
NCH2CH2CHaHbCHaHb), 1.30−1.16 (m, 1H, NCH2CH2CH2CHaHb),
0.94 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.89 (d, J = 7.0 Hz, 3H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 156.5, 131.9, 127.7,
127.7, 125.7, 120.3, 73.7, 59.4, 57.4 (2C), 54.2, 31.2, 23.8, 22.9, 21.6,
18.3, 17.2; HRMS calcd for C17H25BrN2O3SH (M + H)+ 417.0848,
found 417.0838 (TOF MS ES+).
(7S)-2-Bromo-7-isobutyl-6,7,8,10,11,12,13,13a,14,15-
d e c a h y d r o b e n z o [ b ] p y r i d o [ 1 , 2 - h ] [ 1 , 4 , 5 , 8 ] -
oxathiadiazacycloundecine 5,5-Dioxide (6o). According to the
reaction protocol described in general procedure C from 4a (53.6
mg), compound 6o (20%, 14.5 mg) was isolated after chromatography
as a light yellow oil: Rf = 0.20 (2:1 EtOAc/hexane); [α]2D0 = +132.4 (c =
0.69, CHCl3); FTIR (thin film) 3202, 2935, 1580, 1470, 1389, 1325,
1163, 1065, 812, 733 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.82 (d,
J = 8.3 Hz, 1H, aromatic), 7.21 (dd, J = 8.3, 1.7 Hz, 1H, aromatic), 7.13
(d, J = 1.7 Hz, 1H, aromatic), 6.68 (s, 1H, NH), 4.56 (ddd, J = 11.9, 9.9,
4.4 Hz, 1H, OCHaHbCH2CHN), 4.43 (ddd, J = 11.9, 4.7, 4.6 Hz, 1H,
OCHaHbCH2CHN), 3.20−2.99 (m, 2H, NHCHCHaHbN,
NCHaHbCH2CH2CH2), 2.81 (ddd, J = 12.8, 8.9, 4.3 Hz, 1H,
NHCHCH2N), 2.50 (dt, J = 14.1, 3.9 Hz, 1H, NCHaHbCH2CH2CH2),
2.35 (dt, J = 12.9, 4.4 Hz, 1H, NCHCH2CH2O), 2.15−2.05 (m, 2H,
NHCHCHaHbN, NCHCHaHbCH2O), 2.01 (dt, J = 15.1, 5.0 Hz, 1H,
NCHCHaHbCH2O), 1.94 (ddd, J = 13.6, 9.2, 4.1 Hz, 1H,
NCH2CH2CHaHbCH2), 1.77−1.68 (m, 1H, NCH2CH2CH2CHaHb),
1.68−1.50 (m, 4H, NCH2CH2CH2CH2, CH3CHCH3, NHCHCHaHb),
1.38−1.28 (m, 2H, NCH2CH2CHaHbCH2, NHCHCHaHb), 1.22−1.13
(m, 1H, NCH2CH2CH2CHaHb), 0.87 (d, J = 6.6 Hz, 3H, CH3CHCH3),
0.79 (d, J = 6.6 Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ
ppm 154.5, 132.3, 128.1, 126.3, 123.7, 116.2, 65.5, 55.5, 50.5 (2C), 49.0,
43.6, 28.1, 24.7, 23.9, 23.5, 22.0, 21.3, 20.6; HRMS calcd for
C19H29BrN2O3SH (M + H)+ 445.1161, found 445.1157 (TOF MS ES+).
(7S,13aS)-2-Bromo-7-isopropyl-6,7,8,10,11,12,13,13a,14,15-
d e c a h y d r o b e n z o [ b ] p y r i d o [ 1 , 2 - h ] [ 1 , 4 , 5 , 8 ] -
oxathiadiazacycloundecine 5,5-Dioxide (6p). According to the
reaction protocol described in general procedure C from 4b (78.1
mg), compound 6p (22%, 23.3 mg) was isolated after chromatography
as a white solid: mp 152−157 °C; Rf = 0.21 (2:1 EtOAc/hexane); [α]D20
= +107.4 (c = 0.81, CHCl3); FTIR (thin film) 3205, 2934, 1580, 1470,
1387, 1327, 1163, 1065, 821, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ
ppm 7.81 (d, J = 8.3 Hz, 1H, aromatic), 7.20 (dd, J = 8.3, 1.7 Hz, 1H,
aromatic), 7.13 (d, J = 1.7 Hz, 1H, aromatic), 6.62 (s, 1H, NH), 4.54
(ddd, J = 11.6, 9.4, 4.4 Hz, 1H, OCHaHbCH2CHN), 4.40 (ddd, J = 11.6,
5.0, 4.9 Hz, 1H, OCHaHbCH2CHN), 3.17−3.03 (m, 1H,
NCHaHbCH2CH2CH2), 2.96 (dd, J = 12.9, 4.6 Hz, 1H,
NHCHCHaHbN), 2.73 (ddd, J = 10.4, 4.6, 4.4 Hz, 1H, NHCHCH2N),
2.51 (d, J = 14.3 Hz, 1H, NCHaHbCH2CH2CH2), 2.47−2.32 (m, 2H,
CH3CHCH3, NCHCH2CH2O), 2.29−2.08 (m, 2H, NHCHCHaHbN,
NCHCHaHbCH2O), 1.95 (dddd, J = 14.6, 9.3, 5.1, 4.9 Hz, 1H,
NCHCHaHbCH2O), 1.81−1.67 (m, 1H, NCH2CH2CH2CHaHb),
1.67−1.45 (m, 3H, NCH2CHaHbCH2CH2), 1.37−1.20 (m, 1H,
NCH2CHaHbCH2CH2), 1.19−1.09 (m, 1H, NCH2CH2CH2CHaHb),
0.98 (d, J = 6.9 Hz, 3H, CH3CHCH3), 0.87 (d, J = 7.2 Hz, 3H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 154.8, 132.4, 128.1,
126.3, 123.7, 116.3, 66.0, 55.1, 50.4, 50.2, 49.4, 29.1, 28.4, 23.6, 21.1,
20.5, 18.9, 15.6; HRMS calcd for C18H27BrN2O3SH (M + H)+ 431.1004,
found 431.0976 (TOF MS ES+).
1
NMR (126 MHz, CDCl3) δ ppm 161.1 (d, JC−F = 259.8 Hz), 155.6,
133.5 (d, 3JC−F = 11.0 Hz), 119.2 (d, 3JC−F = 13.1 Hz), 110.6 (d, 2JC−F
24.2 Hz), 109.9 (d, JC−F = 3.6 Hz), 73.5, 62.1, 58.5, 57.6, 55.6, 36.8,
27.1, 25.6, 24.3, 15.9, 11.5; HRMS calcd for C17H25FN2O3SH (M + H)+
357.1648, found 357.1635 (TOF MS ES+).
=
4
(6S,14aS)-11-Fluoro-6-isopropyl-1,2,3,5,6,7,14,14a-
octahydrobenzo[b]pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine 8,8-Di-
oxide (6l). According to the reaction protocol described in general
procedure B from 4d (47.0 mg), compound 6l (42%, 25.7 mg) was
isolated after chromatography as a colorless oil: Rf = 0.1 (1:1 EtOAc/
hexane); [α]2D0 = +74.4 (c = 0.36, CHCl3); FTIR (thin film) 3286, 2962,
1603, 1587, 1475, 1383, 1329, 1163, 1070, 847, 735, 698 cm−1; 1H NMR
(500 MHz, CDCl3) δ ppm 7.94 (dd, J = 8.6, 6.5 Hz, 1H, aromatic),
6.92−6.76 (m, 3H, aromatic, NH), 4.33 (dd, J = 11.9, 3.3 Hz, 1H,
OCHaHbCHN), 3.92 (dd, J = 11.8, 11.7 Hz, 1H, OCHaHbCHN), 3.16
(ddd, J = 10.2, 5.5, 4.8 Hz, 1H, NHCHCH2N), 3.06 (ddt, J = 11.9, 8.6,
3.1 Hz, 1H, NCHCH2O), 2.71 (dt, J = 11.9, 5.9 Hz, 1H,
NCHaHbCH2CH2), 2.64−2.50 (m, 2H, NCHaHbCH2CH2,
NHCHCHaHbN), 2.37 (dd, J = 13.5, 5.0 Hz, 1H, NHCHCHaHbN),
2.02−1.89 (m, 2H, CH3CHCH3, NCH2CH2CHaHb), 1.87−1.78 (m,
2H, NCH2CH2CH2), 1.36 (ddt, J = 12.6, 6.6, 3.4 Hz, 1H,
NCH2CH2CHaHb), 0.95 (dd, J = 17.2, 6.8 Hz, 6H, CH3CHCH3); 13
C
NMR (126 MHz, CDCl3) δ ppm 166.0 (d, 1JC−F = 254.3 Hz), 156.2 (d,
3JC−F = 10.5 Hz), 132.5 (d, 3JC−F = 10.8 Hz), 126.4 (d, 4JC−F = 3.3 Hz),
108.8 (d, 2JC−F = 22.2 Hz), 103.1 (d, 2JC−F = 25.4 Hz), 73.7, 62.0, 59.1,
57.3, 55.2, 30.5, 27.0, 25.6, 19.6, 17.5; HRMS calcd for C16H23FN2O3SH
(M + H)+ 343.1492, found 343.1459 (TOF MS ES+).
(R)-10-Chloro-2,3,5,7,14,14a-hexahydro-1H-spiro[benzo[b]-
pyrrolo[1,2-h][1,4,5,8]oxathiadiazecine-6,1′-cyclohexane] 8,8-Diox-
ide (6m). According to the reaction protocol described in general
procedure B from 4i (82.0 mg), compound 6m (51%, 53.0 mg) was
isolated after chromatography as a white solid: mp 154−159 °C; Rf =
0.37 (1:1 EtOAc/hexane); [α]2D0 = −24.0 (c = 0.125, CHCl3); FTIR
1
(neat) 2937, 1585, 1465, 1315, 1228, 1157, 1064, 819, 732 cm−1; H
NMR (500 MHz, CDCl3) δ ppm 7.92 (d, J = 2.7 Hz, 1H, aromatic), 7.45
(dd, J = 8.8, 2.7 Hz, 1H, aromatic), 7.05 (d, J = 8.8 Hz, 1H, aromatic),
6.30 (s, 1H, NH), 4.46 (dd, J = 11.9, 3.2 Hz, 1H, OCHaHbCHN), 3.93
(dd, J = 11.8, 11.5 Hz, 1H, OCHaHbCHN), 3.24−3.18 (m, 1H,
NCHCH2O), 3.13 (dddd, J = 12.2, 9.3, 3.4, 3.3 Hz, 1H,
NCHa Hb CH2 CH2 ), 2.50−2.37 (m, 2H, NHCCHa Hb N,
NCHaHbCH2CH2), 2.17 (d, J = 14.1 Hz, 1H, NHCCHaHbN), 2.03−
1.86 (m, 2H, NCH2CHaHbCHaHb, NCH2CH2CHaHb), 1.84−1.76 (m,
2H, NCH2CHaHbCHaHb, NCH2CH2CHaHb), 1.75−1.63 (m, 2H,
cyclohexyl), 1.58−1.50 (m, 1H, cyclohexyl), 1.50−1.41 (m, 1H,
cyclohexyl), 1.41−1.20 (m, 5H, cyclohexyl), 1.14−1.04 (m, 1H,
cyclohexyl); 13C NMR (126 MHz, CDCl3) δ ppm 153.0, 133.6, 133.3,
129.6, 126.5, 116.3, 73.6, 63.7, 60.3, 59.6, 38.4, 31.3, 27.3, 26.1, 25.4,
21.6, 21.4 (2C); HRMS calcd for C18H25ClN2O3SH (M + H)+
385.1353, found 385.1336 (TOF MS ES+).
(7S)-2-Bromo-7-isopropyl-7,8,10,11,12,13,13a,14-octahydro-6H-
benzo[b]pyrido[1,2-h][1,4,5,8]oxathiadiazecine 5,5-Dioxide (6n).
According to the reaction protocol described in general procedure C
from 4b (95.6 mg), compound 6n (36%, 44.7 mg) was isolated after
(3S,6S,7R)-10-Fluoro-3-isopropyl-5,6-dimethyl-7-phenyl-
2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide
(8a). According to the reaction protocol described in general procedure
C from 4d (52.0 mg), compound 8a (46%, 37.2 mg) was isolated after
J
DOI: 10.1021/acs.joc.5b01429
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatography as a sticky colorless oil: Rf = 0.67 (1:1 EtOAc/hexane);
[α]2D0 = +43.1 (c = 1.145, CHCl3); FTIR (thin film) 3267, 2962, 1603,
1585, 1475, 1454, 1371, 1323, 1163, 1068, 812, 764, 737, 704 cm−1; 1H
NMR (500 MHz, CDCl3) δ ppm 8.02 (dd, J = 8.8, 6.5 Hz, 1H,
aromatic), 7.60−7.54 (m, 2H, aromatic), 7.48 (s, 1H, NH), 7.45−7.35
(m, 3H, aromatic), 6.94 (dd, J = 10.3, 2.4 Hz, 1H, aromatic), 6.87 (ddd, J
= 8.7, 7.7, 2.3 Hz, 1H, aromatic), 5.25 (d, J = 2.5 Hz, 1H, OCHPh), 2.93
(qd, J = 7.1, 2.6 Hz, 1H, NCHCH3), 2.63 (ddd, J = 11.3, 4.6, 4.5 Hz, 1H,
NHCHCH2N), 2.55 (dd, J = 12.9, 5.2 Hz, 1H, NHCHCHaHbN), 2.32
(m, 1H, CH3CHCH3), 2.11 (dd, J = 12.1, 12.0 Hz, 1H,
NHCHCHaHbN), 1.51 (s, 3H, NCH3), 1.09 (d, J = 7.1 Hz, 3H,
NCHCH3), 0.98 (d, J = 6.9 Hz, 3H, CH3CHCH3), 0.78 (d, J = 7.2 Hz,
3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 166.3 (d, 1JC−F
= 254.6 Hz), 155.6 (d, 3JC−F = 10.7 Hz), 135.0, 134.0 (d, 3JC−F = 10.8
Hz), 128.4, 128.3 (2C), 127.1 (2C), 125.1 (d, 4JC−F = 3.4 Hz), 109.5 (d,
2JC−F = 22.0 Hz), 104.3 (d, 2JC−F = 25.2 Hz), 85.3, 56.7, 55.1, 52.9, 38.9,
13.6, 3.4 Hz, 1H, NHCHCHaHbN), 2.26 (s, 3H, NCH3), 2.22−2.14 (m,
1H, NHCHCHaHbN), 1.94 (dt, J = 13.3, 6.7 Hz, 1H, CH3CHCH3), 1.50
(dd, J = 14.0, 7.0 Hz, 1H, NHCHCHaHb), 1.32 (ddd, J = 13.9, 7.7, 6.0
Hz, 1H, NHCHCHaHb), 1.04 (d, J = 6.6 Hz, 3H, CH3CHCH3), 1.02 (d,
J = 6.8 Hz, 3H, CH3CHCH3), 0.77 (d, J = 7.0 Hz, 3H, NCHCH3); 13
C
NMR (126 MHz, CDCl3) δ ppm 165.9 (d, 1JC−F = 253.3 Hz), 158.7 (d,
3JC−F = 11.0 Hz), 138.6, 131.6 (d, 3JC−F = 10.9 Hz), 129.0 (2C), 128.6,
127.9 (d, 4JC−F = 3.5 Hz), 126.7 (2C), 107.3 (d, 2JC−F = 22.3 Hz), 103.2
(d, 2JC−F = 25.5 Hz), 86.9, 60.9, 60.7, 52.5, 45.4, 37.2, 24.7, 23.1, 22.8,
10.9; HRMS calcd for C22H29FN2O3SH (M + H)+ 421.1956, found
421.1956 (TOF MS ES+).
(3S,6S)-10-Fluoro-3,6-diisobutyl-5-methyl-2,3,4,5,6,7-
hexahydrobenzo[b][1,4,5,8]oxathiadiazecine-1,1-Dioxide (8e). Ac-
cording to the reaction protocol described in general procedure B from
4c (49.2 mg), compound 8e (39%, 26.6 mg) was isolated after
chromatography as a white solid: mp 133−137 °C; Rf = 0.66 (1:1
EtOAc/hexane); [α]2D0 = +106.8 (c = 0.825, CHCl3); FTIR (thin film)
28.6, 18.3, 15.5, 10.6; HRMS calcd for C21H27FN2O3SH (M + H)+
1
2957, 1601, 1585, 1475, 1387, 1325, 1165, 1068, 849, 731 cm−1; H
407.1805, found 407.1790 (TOF MS ES+).
NMR (500 MHz, CDCl3) δ ppm 8.04−7.96 (m, 1H, aromatic), 7.22 (s,
1H, NH), 6.89−6.83 (m, 2H, aromatic), 4.22−4.08 (m, 2H,
OCH2CHN), 2.86 (dd, J = 13.0, 4.8 Hz, 1H, NHCHCHaHbN),
2.74−2.63 (m, 1H, NHCHCH2N), 2.51 (tdd, J = 9.0, 5.3, 3.5 Hz, 1H,
NCHCH2), 2.35 (s, 3H, NCH3), 2.13 (dd, J = 13.0, 11.0 Hz, 1H,
NHCHCHaHbN), 1.87 (ddd, J = 13.7, 9.8, 3.7 Hz, 1H, NHCHCHaHb),
1.64−1.44 (m, 2H, NHCHCH2CH, NCHCH2CH), 1.39−1.20 (m, 2H,
NHCHCHaHb, NCHCHaHb), 1.10 (ddd, J = 14.2, 8.7, 5.8 Hz, 1H,
NCHCHaHb), 0.91 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.85 (d, J = 6.6 Hz,
3H, CH3CHCH3), 0.77 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.71 (d, J = 6.5
Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 166.2 (d,
1JC−F = 254.8 Hz), 156.6 (d, 3JC−F = 10.5 Hz), 133.6 (d, 3JC−F = 10.6 Hz),
(3S,6R,7R)-10-Fluoro-3-isopropyl-5,6-dimethyl-7-phenyl-
2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide
(8b). According to the reaction protocol described in general procedure
B from 4d (53.0 mg), compound 8b (47%, 39.0 mg) was isolated after
chromatography as a white solid: mp 87−93 °C; Rf = 0.72 (1:1 EtOAc/
hexane); [α]2D0 = +12.8 (c = 0.69, CHCl3); FTIR (thin film) 3300, 2962,
1603, 1583, 1479, 1456, 1369, 1325, 1157, 1068, 843, 770, 735, 700
cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.97 (dd, J = 8.8, 6.6 Hz, 1H,
aromatic), 7.56−7.45 (m, 2H, aromatic), 7.45−7.32 (m, 3H, aromatic),
6.76 (ddd, J = 8.7, 7.7, 2.4 Hz, 1H, aromatic), 6.66 (dd, J = 10.6, 2.4 Hz,
1H, aromatic), 6.47 (s, 1H, NH), 4.78 (d, J = 9.9 Hz, 1H, OCHPh), 3.10
(dq, J = 9.8, 6.5 Hz, 1H, NCHCH3), 2.82−2.59 (m, 2H, NHCHCH2N,
NHCHCHaHbN), 2.40 (dd, J = 13.9, 7.2 Hz, 1H, NHCHCHaHbN),
2.15 (s, 3H, NCH3), 1.98−1.79 (m, 1H, CH3CHCH3), 0.97 (d, J = 6.9
Hz, 6H, CH3CHCH3), 0.86 (d, J = 6.6 Hz, 3H, NCHCH3); 13C NMR
126.1 (d, 4JC−F = 3.4 Hz), 109.6 (d, 2JC−F = 22.1 Hz), 104.6 (d, 2JC−F
=
25.0 Hz), 71.4, 57.7, 55.0, 49.4, 42.8, 36.1, 34.8, 25.3, 24.4, 23.7, 23.1,
22.0, 21.5; HRMS calcd for C19H31FN2O3SH (M + H)+ 387.2118, found
387.2093 (TOF MS ES+).
(126 MHz, CDCl3) δ ppm 165.9 (d, 1JC−F = 253.7 Hz), 158.7 (d, 3JC−F
=
3
10.8 Hz), 138.5, 133.0 (d, JC−F = 10.7 Hz), 129.0 (2C), 128.8, 127.1
(S)-10-Fluoro-3-isobutyl-5-methyl-3,4,5,7-tetrahydro-2H-spiro-
[benzo[b][1,4,5,8]oxathiadiazecine-6,1′-cyclohexane] 1,1-Dioxide
(8f). According to the reaction protocol described in general procedure
B from 4c (46.2 mg), compound 8f (46%, 30.9 mg) was isolated after
chromatography as a sticky colorless oil: Rf = 0.58 (1:1 EtOAc/hexane);
[α]2D0 = +8.7 (c = 0.695, CHCl3); FTIR (thin film) 2953, 1605, 1589,
(2C), 124.2 (d, 4JC−F = 3.2 Hz), 108.5 (d, JC−F = 22.0 Hz), 104.7 (d,
2
2JC−F = 25.3 Hz), 88.3, 67.8, 58.4, 52.5, 37.7, 32.1, 19.0, 17.7, 10.6;
HRMS calcd for C21H27FN2O3SH (M + H)+ 407.1805, found 407.1765
(TOF MS ES+).
(3S,6S,7S)-10-Bromo-3-isopropyl-5,6-dimethyl-7-phenyl-
2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide
(8c). According to the reaction protocol described in general procedure
C from 4b (52.3 mg), compound 8c (13%, 9.7 mg) was isolated after
chromatography as a colorless oil: Rf = 0.55 (1:1 EtOAc/hexane); [α]D20
= +73.2 (c = 0.335, CHCl3); FTIR (thin film) 3285, 2964, 1578, 1468,
1452, 1319, 1155, 1064, 804, 756, 727, 702 cm−1; 1H NMR (400 MHz,
CDCl3) δ ppm 7.78 (d, J = 8.4 Hz, 1H, aromatic), 7.52−7.47 (m, 2H,
aromatic), 7.46−7.40 (m, 2H, aromatic), 7.40−7.33 (m, 1H, aromatic),
7.07 (dd, J = 8.4, 1.8 Hz, 1H, aromatic), 6.95 (d, J = 1.8 Hz, 1H,
aromatic), 4.71 (d, J = 9.3 Hz, 1H, OCHPh), 4.41 (s, 1H, NH), 4.01 (bs,
1H, NHCHCH2N), 3.19−3.08 (m, 1H, NCHCH3), 2.78 (dd, J = 13.3,
2.9 Hz, 1H, NHCHCHaHbN), 2.23 (m, 4H, NHCHCHaHbN, NCH3),
1.96−1.79 (m, 1H, CH3CHCH3), 1.09 (d, J = 6.8 Hz, 3H,
CH3CHCH3), 1.00 (d, J = 6.9 Hz, 3H, CH3CHCH3), 0.75 (d, J = 7.0
Hz, 3H, NCHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 157.8, 138.5,
131.0, 130.8, 128.9 (2C), 128.6, 127.7, 126.7 (2C), 123.4, 118.8, 87.0,
60.4, 58.8, 58.0, 37.3, 32.3, 19.0, 18.0, 10.4; HRMS calcd for
C21H27BrN2O3SH (M + H)+ 467.1004, found 467.1004 (TOF MS ES+).
(3S,6S,7S)-10-Fluoro-3-isobutyl-5,6-dimethyl-7-phenyl-
2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]oxathiadiazecine 1,1-Dioxide
(8d). According to the reaction protocol described in general procedure
C from 4c (71.9 mg), compound 8d (30%, 33.2 mg) was isolated after
chromatography as a white solid: mp 165−169 °C; Rf = 0.52 (1:1
EtOAc/hexane); [α]2D0 = +20.0 (c = 0.145, CHCl3); FTIR (thin film)
3265, 2960, 1602, 1586, 1473, 1451, 1373, 1323, 1163, 1066, 815, 762,
734, 706 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (dd, J = 8.8, 6.6
Hz, 1H, aromatic), 7.51−7.31 (m, 5H, aromatic), 6.65 (ddd, J = 8.5, 8.3,
2.4 Hz, 1H, aromatic), 6.52 (dd, J = 10.4, 2.4 Hz, 1H, aromatic), 4.68 (d,
J = 9.3 Hz, 1H, OCHPh), 4.40 (d, J = 7.3 Hz, 1H, NH), 4.18 (bs, 1H,
NHCHCH2N), 3.17 (dd, J = 8.8, 7.1 Hz, 1H, NCHCH3), 2.79 (dd, J =
1
1468, 1425, 1391, 1317, 1159, 1070, 847, 733 cm−1; H NMR (500
MHz, CDCl3) δ ppm 7.97 (dd, J = 8.7, 6.5 Hz, 1H, aromatic), 6.84 (ddd,
J = 8.8, 7.9, 2.4 Hz, 1H, aromatic), 6.79 (dd, J = 9.9, 2.4 Hz, 1H,
aromatic), 4.69 (d, J = 10.2 Hz, 1H, OCHaHbC), 3.70 (d, J = 9.8 Hz, 1H,
OCHaHbC), 2.99−2.84 (m, 2H, NHCH, NCHaHb), 2.43 (s, 3H,
NCH3), 2.25−2.12 (m, 1H, NCHaHb), 1.94−1.66 (m, 8H,
NHCHCH2CH, NHCHCHaHb, cyclohexyl), 1.64−1.47 (m, 1H,
cyclohexyl), 1.43 (d, J = 12.8 Hz, 1H, cyclohexyl), 1.36−1.11 (m, 3H,
NHCHCHaHb, cyclohexyl), 0.84 (dd, J = 6.6, 6.5 Hz, 6H, CH3CHCH3);
13C NMR (126 MHz, CDCl3) δ ppm 165.9 (d, 1JC−F = 254.3 Hz), 157.7
(d, 3JC−F = 10.6 Hz), 132.5 (d, 3JC−F = 10.7 Hz), 124.8, 109.3 (d, 2JC−F
=
22.0 Hz), 104.2 (d, 2JC−F = 24.9 Hz), 73.2, 59.8, 52.5, 49.3, 47.3, 36.8,
30.6, 28.1, 25.5, 24.3, 23.1, 22.8, 22.7, 22.4; HRMS calcd for
C20H31FN2O3SH (M + H)+ 399.2118, found 399.2126 (TOF MS ES+).
(S)-3-Isopropyl-7-methyl-5-propyl-2,3,4,5-tetrahydrobenzo[f ]-
[1,2,5]thiadiazepine 1,1-Dioxide (10a). According to the reaction
protocol described in general procedure B from 4j (65.3 mg),
compound 10a (44%, 33.1 mg) was isolated after chromatography as
a yellowish oil: Rf = 0.40 (1:1 EtOAc/hexane); [α]2D0= −140.3 (c = 0.125,
CHCl3); FTIR (neat) 3267, 2927, 1595, 1461, 1325, 1161, 790, 732
1
cm−1; H NMR (500 MHz, CDCl3) δ ppm 7.77 (d, J = 8.1 Hz, 1H,
aromatic), 6.84 (s, 1H), 6.81 (ddd, J = 8.0, 1.5, 0.7 Hz, 1H), 4.18 (d, J =
9.2 Hz, 1H, NHCHCH2N), 3.46 (dd, J = 14.8, 2.5 Hz, 1H,
NHCHCH2 N), 3.41−3.24 (m, 2H, NHCHCHa Hb N,
NCHaHbCH2CH3), 3.18 (ddd, J = 13.1, 7.1, 6.9 Hz, 1H,
NCHaHbCH2CH3), 3.01 (dd, J = 14.9, 9.4 Hz, 1H, NHCHCHaHbN),
2.35 (s, 3H, PhCH3), 2.02−1.85 (m, 1H, CH3CHCH3), 1.66 (ddddd, J =
7.3, 7.3, 7.3, 7.3, 7.3 Hz, 2H, NCH2CH2CH3), 1.04 (dd, J = 6.8, 5.0 Hz,
6H, CH3CHCH3), 0.99 (t, J = 7.3 Hz, 3H, NCH2CH2CH3); 13C NMR
(126 MHz, CDCl3) δ ppm 148.6, 143.5, 131.1, 128.4, 121.7, 119.8, 61.4,
K
DOI: 10.1021/acs.joc.5b01429
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
56.9, 56.0, 30.3, 21.7, 21.5, 19.6, 19.0, 11.5; HRMS calcd for
C15H24N2O2SH (M + H)+ 297.1637, found 297.1615 (TOF MS ES+).
(S)-7-Bromo-5-butyl-3-isobutyl-2,3,4,5-tetrahydrobenzo[f ][1,2,5]-
thiadiazepine 1,1-Dioxide (10b). According to the reaction protocol
described in general procedure B from 4a (50.4 mg), compound 10b
(50%, 29.0 mg) was isolated after chromatography as a colorless oil: Rf =
0.48 (1:4 EtOAc/hexane); [α]2D0 = −90.2 (c = 3.3, CHCl3); FTIR (neat)
2H, aromatic), 6.78−6.69 (m, 2H, aromatic), 4.68 (d, J = 14.7 Hz, 1H,
NCHaHbPh), 4.44 (d, J = 14.7 Hz, 1H, NCHaHbPh), 4.32 (d, J = 9.1 Hz,
1H, NH), 3.43 (dd, J = 14.8, 2.2 Hz, 1H, NHCHCH2N), 3.29−3.14 (m,
1H, NHCHCHaHbN), 3.13−2.96 (m, 1H, NHCHCHaHbN), 1.85−
1.66 (m, 1H, CH3CHCH3), 0.86 (d, J = 6.8 Hz, 3H, CH3CHCH3), 0.79
(d, J = 6.7 Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm
165.3 (d, 1JC−F = 253.5 Hz), 150.6 (d, 3JC−F = 10.1 Hz), 140.9 (d, 4JC−F
=
1
3258, 2957, 1578, 1468, 1369, 1319, 1151, 802, 733 cm−1; H NMR
0.9 Hz), 130.8 (d, 3JC−F = 10.9 Hz), 130.2 (q, 2JC−CF3 = 32.6 Hz), 130.1,
128.5 (2C), 125.8 (q, 3JC−CF3 = 3.7 Hz, 2C), 124.0 (q, 1JC−CF3 = 273.1
Hz), 108.7 (d, 2JC−F = 22.6 Hz), 106.5 (d, 2JC−F = 24.4 Hz), 60.7, 58.0,
56.4, 30.0, 19.0, 18.7; HRMS calcd for C19H20F4N2O2SH (M + H)+
417.1260, found 417.1271 (TOF MS ES+).
(400 MHz, CDCl3) δ ppm 7.68 (d, J = 8.5 Hz, 1H, aromatic), 7.12 (d, J =
1.8 Hz, 1H, aromatic), 7.07 (dd, J = 8.5, 1.7 Hz, 1H, aromatic), 4.33 (d, J
= 8.1 Hz, 1H, NH), 3.68−3.55 (m, 1H, NHCHCH2N), 3.51 (dd, J =
15.2, 2.9 Hz, 1H, NHCHCHaHbN), 3.45−3.34 (m, 1H,
NCHaHbCH2CH2CH3), 3.28−3.17 (m, 1H, NCHaHbCH2CH2CH3),
3.05 (dd, J = 15.2, 8.3 Hz, 1H, NHCHCHaHbN), 1.86 (ddq, J = 12.9, 8.3,
6.5 Hz, 1H, CH3CHCH3), 1.68−1.57 (m, 2H, NCH2CH2CH2CH3),
1.57−1.49 (m, 1H, NHCHCHaHbCH), 1.48−1.36 (m, 2H,
NCH2CH2CH2CH3), 1.29 (ddd, J = 13.9, 8.5, 5.5 Hz, 1H,
NHCHCHaHbCH), 1.01−0.94 (m, 9H); 13C NMR (126 MHz,
CDCl3) δ ppm 149.3, 131.9, 129.7, 127.0, 123.1, 121.4, 58.5, 54.3,
53.9, 40.8, 29.8, 24.6, 23.0, 21.9, 20.1, 13.9; HRMS calcd for
C16H25BrN2O2SH (M + 2+H)+ 391.0873, found 391.0872 (TOF MS
ES+).
(S)-3-Isopropyl-7-methyl-5-(oxetan-3-yl)-2, 3, 4, 5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10f). According
to the reaction protocol described in general procedure B from 4j (69.5
mg), compound 10f (55%, 46.1 mg) was isolated after chromatography
as a white solid: mp 145−148 °C; Rf = 0.38 (1:1 EtOAc/hexane); [α]D20
= −27.0 (c = 0.125, CHCl3); FTIR (neat) 3267, 2960, 1602, 1471, 1369,
1326, 1218, 1145, 1068, 815, 729 cm−1; 1H NMR (500 MHz, CDCl3) δ
ppm 7.79 (d, J = 8.0 Hz, 1H, aromatic), 7.27−7.24 (m, 1H, aromatic),
7.13 (bs, 1H, aromatic), 3.80 (ddd, J = 14.6, 7.7, 1.6 Hz, 1H,
NCHCHaHbOCH2), 3.70−3.62 (m, 1H, NCHCH2OCHaHb), 3.59 (dd,
J = 10.9, 9.2 Hz, 1H, NCHCHaHbOCH2), 3.54−3.42 (m, 1H,
NCHCH2OCHaHb), 3.31 (dddd, J = 9.7, 9.7, 7.7, 1.6 Hz, 1H,
NHCHCH2N), 3.20−3.12 (m, 1H, NCHCH2OCH2), 2.94 (dd, J =
14.5, 9.6 Hz, 1H, NHCHCHaHbN), 2.70 (dd, J = 14.5, 10.0 Hz, 1H,
NHCHCHaHbN), 2.56 (s, 1H, NH), 2.40 (s, 3H, PhCH3), 1.92−1.80
(m, 1H CH3CHCH3), 1.09 (d, J = 6.5 Hz, 3H, CH3CHCH3), 0.84 (d, J =
6.6 Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 144.5,
141.1, 140.1, 130.4, 129.1, 128.7, 61.9, 60.1, 58.7, 47.6, 41.1, 29.3, 21.3,
20.6, 18.5; HRMS calcd for C15H22N2O3SH (M + H)+ 311.1429, found
311.1415 (TOF MS ES+).
(S)-5-Benzyl-7-bromo-3-isobutyl-2,3,4,5-tetrahydrobenzo[f ]-
[1,2,5]thiadiazepine 1,1-Dioxide (10c). According to the reaction
protocol described in general procedure C from 4a (65.4 mg),
compound 10c (50%, 41.1 mg) was isolated after chromatography as
a white solid: mp 140−144 °C; Rf = 0.46 (1:3 EtOAc/hexane); [α]D20
=
−75.5 (c = 0.14, CHCl3); FTIR (thin film) 3275, 2957, 1578, 1458,
1325, 1155, 800, 783, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm
7.76 (d, J = 8.5 Hz, 1H, aromatic), 7.42−7.29 (m, 5H, aromatic), 7.23 (d,
J = 1.8 Hz, 1H, aromatic), 7.16 (dd, J = 8.4, 1.8 Hz, 1H, aromatic), 4.65
(d, J = 14.3 Hz, 1H, NCHaHbPh), 4.38 (d, J = 14.3 Hz, 1H, NCHaHbPh),
4.30−4.17 (m, 1H, NH), 3.51−3.28 (m, 2H, NHCHCH2N,
NHCHCHaHbN), 3.01−2.79 (m, 1H, NHCHCHaHbN), 1.59−1.48
(m, 1H, CH3CHCH3), 1.35 (ddd, J = 14.2, 7.4, 7.0 Hz, 1H,
NHCHCHaHb), 1.09−0.96 (m, 1H, NHCHCHaHb), 0.79 (d, J = 6.5
Hz, 3H, CH3CHCH3), 0.70 (d, J = 6.6 Hz, 3H, CH3CHCH3); 13C NMR
(126 MHz, CDCl3) δ ppm 149.8, 136.7, 129.7, 128.9 (2C), 128.3 (2C),
127.9, 127.4, 127.35 124.2, 122.4, 58.3, 57.8, 53.7, 41.0, 24.5, 22.4, 22.0;
HRMS calcd for C19H23BrN2O2SH (M + H)+ 423.0742, found
423.0742 (TOF MS ES+).
(S)-9-Fluoro-3-isopropyl-5-(3-methoxypropyl)-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10g). Accord-
ing to the reaction protocol described in general procedure B from 4k
(70.6 mg), compound 10g (56%, 50.0 mg) was isolated after
chromatography as a yellow oil: Rf = 0.37 (1:1 EtOAc/hexane); [α]D20
= −140.7 (c = 0.125, CHCl3); FTIR (neat) 3263, 2962, 1608, 1569,
1
1456, 1386, 1319, 1201, 1149, 1068, 723 cm−1; H NMR (500 MHz,
CDCl3) δ ppm 7.85 (dd, J = 8.8, 6.5 Hz, 1H, aromatic), 6.74 (dd, J =
11.5, 2.4 Hz, 1H, aromatic), 6.66 (ddd, J = 8.8, 7.5, 2.4 Hz, 1H,
aromatic), 4.54 (d, J = 7.2 Hz, 1H, NH), 3.58−3.42 (m, 4H,
NHCHCHaHbN, NHCHCH2N, NCH2CH2CH2OCH3), 3.34 (s, 3H,
NCH2CH2CH2OCH3), 3.33−3.30 (m, 1H, NCHaHbCH2CH2OCH3),
3.28−3.19 (m, 2H, NHCHCHaHbN, NCHaHbCH2CH2OCH3), 2.01−
1.93 (m, 1H, CH3CHCH3), 1.92−1.83 (m, 2H, NCH2CH2CH2OCH3),
1.06 (d, J = 6.8 Hz, 3H, CH3CHCH3), 1.03 (d, J = 6.7 Hz, 3H,
(S)-7-Bromo-3-isobutyl-5-(4-isopropylbenzyl)-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10d). Accord-
ing to the reaction protocol described in general procedure C from 4a
(58.0 mg), compound 10d (42%, 23.5 mg) was isolated after
chromatography as a light yellow solid: mp 155−161 °C; Rf = 0.54
(1:3 EtOAc/hexane); [α]2D0 = −102.9 (c = 0.485, CHCl3); FTIR (thin
film) 3258, 2959, 1578, 1468, 1375, 1325, 1155, 843, 798, 700 cm−1; 1H
NMR (500 MHz, CDCl3) δ ppm 7.74 (dd, J = 8.4, 2.0 Hz, 1H,
aromatic), 7.32 (d, J = 7.9 Hz, 2H, aromatic), 7.26 (d, J = 5.0 Hz, 2H,
aromatic), 7.27−7.21 (m, 1H, aromatic), 7.19−7.11 (m, 1H, aromatic),
4.60 (d, J = 13.9 Hz, 1H, NCHaHbPh), 4.32 (d, J = 13.9 Hz, 1H,
NCHaHbPh), 4.23 (s, 1H, NH), 3.41 (dd, J = 14.9, 2.4 Hz, 1H,
NHCHCH2N), 3.38−3.30 (m, 1H, NHCHCHaHbN), 3.03−2.80 (m,
1H, NHCHCHaHbN), 1.60−1.46 (m, 1H, CH3CHCH3), 1.40−1.26
(m, 1H CCHCH3), 1.25 (d, J = 6.9 Hz, 6H, CH3CHCH3), 1.06−0.93
(m, 1H, NHCHCHaHb), 0.95−0.83 (m, 1H, NHCHCHaHb), 0.76 (d, J
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 165.2 (d, 1JC−F
=
252.1 Hz), 150.3 (d, 3JC−F = 10.5 Hz), 130.8 (d, 3JC−F = 10.9 Hz), 129.2,
107.7 (d, 2JC−F = 22.7 Hz), 105.6 (d, 2JC−F = 24.7 Hz), 69.7, 61.6, 58.7,
56.8, 51.0, 30.2, 28.0, 19.6, 19.0; HRMS calcd for C15H23FN2O3SH (M +
H)+ 331.1492, found 331.1481 (TOF MS ES+).
(S)-3-((S)-sec-Butyl)-8-chloro-5-(3-methoxypropyl)-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10h). Accord-
ing to the reaction protocol described in general procedure B from 4f
(78.7 mg), compound 10h (46%, 44.8 mg) was isolated after
chromatography as a colorless oil: Rf = 0.42 (1:1 EtOAc/hexane);
[α]2D0 = +132.5 (c = 0.125, CHCl3); FTIR (neat) 3267, 2931, 1506, 1488,
= 6.6 Hz, 3H, CH3CHCH3), 0.64 (d, J = 6.6 Hz, 3H, CH3CHCH3); 13
C
1
1458, 1386, 1326, 1220, 1157, 1058, 821 cm−1; H NMR (500 MHz,
NMR (126 MHz, CDCl3) δ ppm 150.0 (2C), 148.7, 134.0, 129.6, 128.5
(2C), 127.4, 126.9 (2C), 124.0, 122.3, 57.9, 57.5, 53.8, 41.0, 33.9, 24.6,
24.0, 23.9, 22.3, 22.1; HRMS calcd for C22H29BrN2O2SH (M + H)+
465.1211, found 465.1184 (TOF MS ES+).
(S)-9-Fluoro-3-isopropyl-5-(4-(trifluoromethyl)benzyl)-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10e). According
to the reaction protocol described in general procedure B from 4k (70.5
mg), compound 10e (53%, 59.6 mg) was isolated after chromatography
as a brown oil: Rf = 0.42 (1:1 EtOAc/hexane); [α]2D0 = −149.9 (c = 0.125,
CHCl3); FTIR (neat) 3267, 2968, 1604, 1573, 1477, 1433, 1325, 1161,
854, 742 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.93 (dd, J = 8.8, 6.4
Hz, 1H, aromatic), 7.65 (d, J = 8.0 Hz, 2H, aromatic), 7.55 (d, J = 8.0 Hz,
CDCl3) δ ppm 7.83 (d, J = 2.5 Hz, 1H, aromatic), 7.34 (dd, J = 8.8, 2.6
Hz, 1H, aromatic), 7.05 (d, J = 8.8 Hz, 1H, aromatic), 4.49 (d, J = 9.4 Hz,
1H, NH), 3.60−3.48 (m, 2H, NHCHCH2N, NCH2CH2CHaHbOCH3),
3 . 4 8 − 3 . 4 2 ( m , 2 H , N C H 2 C H 2 C H a H b O C H 3
,
NCHaHbCH2CH2OCH3), 3.38 (dd, J = 14.8, 2.5 Hz, 1H,
NHCHCHaHbN), 3.33 (s, 3H, NCH2CH2CH2OCH3), 3.29 (dd, J =
13.5, 6.8 Hz, 1H, NCHaHbCH2CH2OCH3), 3.04 (dd, J = 14.8, 9.6 Hz,
1H, NHCHCHaHbN), 1.90−1.78 (m, 2H, NCH2CH2CH2OCH3),
1.74−1.64 (m, 1H, CH3CHCH2CH3), 1.59−1.49 (m, 1H,
CH3CHCHaHbCH3), 1.36−1.25 (m, 1H, CH3CHCHaHbCH3), 1.01−
0.93 (m, 6H, CH3CHCH2CH3); 13C NMR (126 MHz, CDCl3) δ ppm
L
DOI: 10.1021/acs.joc.5b01429
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
146.7, 134.8, 132.6, 128.1, 125.9, 120.7, 77.2, 69.8, 61.5, 58.7, 57.1, 51.2,
30.2, 28.2, 19.6, 18.9; HRMS calcd for C16H25ClN2O3SH (M + H)+
361.1353, found 361.1338 (TOF MS ES+).
calcd for C14H21BrN2O3SH (M + H)+ 377.0535, found 377.0515 (TOF
MS ES+).
(S)-7-Bromo-5-((R)-1-hydroxypropan-2-yl)-3-isobutyl-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10m). Accord-
ing to the reaction protocol described in general procedure C from 4a
(146.3 mg), compound 10m (12%, 20.2 mg) was isolated after
chromatography as a white solid: mp 150−154 °C; Rf = 0.55 (1:1
EtOAc/hexane); [α]2D0 = −143.5 (c = 0.365, CHCl3); FTIR (thin film)
3475, 3253, 2957, 1576, 1470, 1381, 1321, 1161, 1055, 808, 777, 727,
694 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (d, J = 8.4 Hz, 1H,
aromatic), 7.35 (d, J = 1.8 Hz, 1H, aromatic), 7.27−7.24 (m, 1H,
aromatic), 3.98 (s, 1H, NH), 3.88−3.74 (m, 1H, NCHCH3), 3.62 (s,
1H, OH), 3.58−3.47 (m, 3H, NHCHCH2N, NHCHCHaHbN,
HOCHaHb), 3.40 (dd, J = 11.0, 10.4 Hz, 1H, HOCHaHb), 2.47−2.26
(m, 1H, NHCHCHaHbN), 1.95−1.78 (m, 1H, CH3CHCH3), 1.40−
1.19 (m, 5H, CH3CHN, NHCHCH2), 1.00 (dd, J = 6.3 Hz, 6H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 150.7, 134.6, 129.5,
127.8, 125.7, 125.5, 65.6, 60.9, 54.0, 51.7, 41.1, 24.7, 23.0, 21.9, 13.9;
HRMS calcd for C15H23BrN2O3SH (M + H)+ 391.0691, found
391.0656 (TOF MS ES+).
(S)-7-Bromo-5-(1-(hydroxymethyl)cyclohexyl)-3-isopropyl-
2,3,4,5-tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10n).
According to the reaction protocol described in general procedure C
from 4b (96.4 mg), compound 10n (26%, 34.0 mg) was isolated after
chromatography as a white solid: mp 164−168 °C; Rf = 0.66 (1:1
EtOAc/hexane); [α]2D0 = −187.1 (c = 1.29, CHCl3); FTIR (thin film)
3445, 3261, 2959, 1574, 1462, 1398, 1321, 1163, 1063, 808, 733 cm−1;
1H NMR (400 MHz, CDCl3) δ ppm 7.76 (d, J = 8.5 Hz, 1H, aromatic),
7.68 (d, J = 1.8 Hz, 1H, aromatic), 7.35 (dd, J = 8.4, 1.8 Hz, 1H,
aromatic), 4.06 (d, J = 9.2 Hz, 1H, NH), 3.92−3.77 (m, 2H,
NCHaHbCHNH, CHaHbOH), 3.68 (dd, J = 12.6, 4.8 Hz, 1H,
CHaHbOH), 3.45 (ddd, J = 8.9, 8.8, 8.6 Hz, 1H, NHCHCH2N),
3.36−3.21 (m, 1H, OH), 2.35 (dd, J = 15.6, 10.4 Hz, 1H,
NCHaHbCHNH), 2.09 (d, J = 12.9 Hz, 1H, cyclohexyl), 1.88−1.68
(m, 6H, cyclohexyl, CH3CHCH3), 1.57 (ddd, J = 13.1, 12.8, 3.7 Hz, 1H,
cyclohexyl), 1.48−1.34 (m, 2H, cyclohexyl), 1.31−1.17 (m, 1H,
cyclohexyl), 1.06 (d, J = 6.8 Hz, 3H, CH3CHCH3), 1.00 (d, J = 6.9
Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 147.9,
139.0, 131.8, 129.3, 127.6, 126.2, 63.6, 61.5, 61.2, 50.3, 31.6, 31.2, 30.1,
25.5, 23.0, 22.8, 19.3, 18.2; HRMS calcd for C18H27BrN2O3SH (M +
H)+ 431.1004, found 431.1019(TOF MS ES+).
9-Fluoro-5-(3-methoxypropyl)-4,5-dihydro-2H-spiro[benzo[f ]-
[1,2,5]thiadiazepine-3,1′-cyclohexane] 1,1-Dioxide (10i). According
to the reaction protocol described in general procedure B from 4g (77.7
mg), compound 10i (56%, 54.0 mg) was isolated after chromatography
as a brownish oil: Rf = 0.38 (1:1 EtOAc/hexane); FTIR (neat) 3326,
1
2928, 1612, 1573, 1469, 1338, 1147, 1041, 773 cm−1; H NMR (500
MHz, CDCl3) δ ppm 7.27−7.22 (m, 1H, aromatic), 6.97 (s, 1H, NH),
6.48 (d, J = 8.8, Hz, 1H, aromatic), 6.35 (ddd, J = 11.2, 8.1, 1.0 Hz, 1H,
aromatic), 5.61−5.54 (m, 1H, NCH2CH2CHaHbOCH3,), 4.95 (dd, J =
6.6, 6.5 Hz, 1H, NCH2CH2CHaHbOCH3), 3.54−3.44 (m, 4H,
NHCCH2N, NCH2CH2CH2OCH3), 3.36 (s, 3H, OCH3), 3.25 (ddd,
J = 6.7, 6.6, 5.0 Hz, 2H, NCH2CH2CH2OCH3), 2.00−1.84 (m, 5H,
cyclohexyl), 1.65−1.55 (m, 1H, cyclohexyl), 1.54−1.39 (m, 4H,
1
cyclohexyl); 13C NMR (126 MHz, CDCl3) δ ppm 161.1 (d, JC−F
=
248.9 Hz), 148.6 (d, 4JC−F = 3.4 Hz), 134.2 (d, 3JC−F = 12.7 Hz), 109.4
(d, 3JC−F = 14.0 Hz), 107.8, 101.1 (d, 2JC−F = 23.5 Hz), 70.2, 58.8, 50.0,
40.8, 29.0, 26.2 (2C), 25.0, 22.3, 21.9 (2C); HRMS calcd for
C17H25FN2O3SH (M + H)+ 357.1648, found 357.1627 (TOF MS ES+).
7-Bromo-5-(2-hydroxyethyl)-4,5-dihydro-2H-spiro[benzo[f ]-
[1,2,5]thiadiazepine-3,1′-cyclohexane] 1,1-Dioxide (10j). According
to the reaction protocol described in general procedure C from 4l (47.6
mg), compound 10j (46%, 24.8 mg) was isolated after chromatography
as a white solid: mp 178−182 °C; Rf = 0.44 (1:1 EtOAc/hexane); FTIR
(thin film) 3454, 3263, 2934, 1580, 1487, 1369, 1312, 1150, 1057, 795,
733, 694 cm−1; 1H NMR (400 MHz, CDCl3) δ ppm 7.68 (dd, J = 8.4, 1.7
Hz, 1H, aromatic), 7.25 (s, 1H, aromatic), 7.19 (dd, J = 8.4, 1.7 Hz, 1H,
aromatic), 4.44 (s, 1H, NH), 3.81−3.66 (m, 2H, NCH2CH2OH), 3.57
(bs, 2H, NCH2CH2OH), 3.26 (bs, 2H, NCH2CNH), 2.85 (s, 1H, OH),
1.75−1.53 (m, 6H, cyclohexyl), 1.50−1.27 (m, 4H, cyclohexyl); 13C
NMR (126 MHz, CDCl3) δ ppm 148.1, 129.5, 127.1, 125.8, 125.3,
122.6, 65.3, 59.5, 59.1, 56.5, 25.6 (2C), 21.0 (3C); HRMS calcd for
C15H21BrN2O3SH (M − H)+ 387.0383, found 387.0372 (TOF MS
ES−).
(S)-7-Bromo-5-(2-hydroxyethyl)-3-isopropyl-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10k). According
to the reaction protocol described in general procedure C from 4b (97.6
mg), compound 10k (46%, 50.4 mg) was isolated after chromatography
as a colorless oil: Rf = 0.35 (1:1 EtOAc/hexane); [α]2D0 = −175.5 (c =
0.125, CHCl3); FTIR (thin film) 3466, 3252, 2964, 1578, 1470, 1371,
1319, 1157, 1059, 795, 731, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ
ppm 7.74 (dd, J = 8.6, 2.1 Hz, 1H, aromatic), 7.37 (d, J = 2.0 Hz, 1H,
aromatic), 7.29−7.22 (m, 1H, aromatic), 4.17 (d, J = 9.4 Hz, 1H, NH),
3.88−3.76 (m, 1H, HOCHaHb), 3.68−3.57 (m, 2H, NCH2CH2), 3.51−
3.36 (m, 3H, NCHaHBCHNH, NHCHCH2, OH), 3.33−3.22 (m, 1H,
HOCHaHb), 2.85 (dd, J = 15.0, 10.4 Hz, 1H, NCHaHBCHNH), 1.92−
1.79 (m, 1H, CH3CHCH3), 1.06 (d, J = 6.8 Hz, 3H, CH3CHCH3), 1.02
(d, J = 6.9 Hz, 3H, CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm
148.9, 135.6, 129.6, 127.7, 126.1, 125.5, 60.9, 60.0, 58.9, 57.9, 30.0, 19.5,
18.3; HRMS calcd for C13H19BrN2O3SH (M + H)+ 363.0378, found
363.0375 (TOF MS ES+).
(S)-7-Bromo-5-((S)-1-hydroxy-4-methylpentan-2-yl)-3-isobutyl-
2,3,4,5-tetrahydrobenzo[f ]-[1,2,5]thiadiazepine 1,1-Dioxide (10o).
According to the reaction protocol described in general procedure C
from 4a (258.0 mg), compound 10o (21%, 70.0 mg) was isolated after
chromatography as a white solid: mp 86−90 °C; Rf = 0.47 (1:1 EtOAc/
hexane); [α]2D0 = +117.3 (c = 0.92, CHCl3); FTIR (thin film) 3470,
1
3250, 2955, 1578, 1470, 1402, 1323, 1163, 1068, 876, 812 cm−1; H
NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J = 8.1 Hz, 1H, aromatic),
7.25−7.14 (m, 2H, aromatic), 6.70 (d, J = 6.4 Hz, 1H, NH), 4.41 (dd, J =
11.7, 2.9 Hz, 1H, NCHCHaHbOH), 3.87 (dd, J = 11.8, 11.0 Hz, 1H,
NCHCHaHbOH), 3.16−2.99 (m, 1H, NHCHCH2N), 2.77−2.57 (m,
2H, NCHCH2OH, NCHaHbCHNH), 2.40 (dd, J = 13.6, 4.8 Hz, 1H,
NCHaHbCHNH), 1.80−1.68 (m, 2H, CH3CHCH3, CH3CHCH3), 1.63
(ddd, J = 14.1, 7.2, 7.1 Hz, 1H, NHCHCHaHb), 1.24 (dd, J = 7.8, 6.3 Hz,
2H, NCHCH2), 1.13 (ddd, J = 13.7, 7.0, 6.9 Hz, 1H, NHCHCHaHb),
0.98−0.88 (m, 9H, CH3CHCH3, CH3CHCH3), 0.84 (d, J = 6.6 Hz, 3H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 155.2, 131.8, 129.7,
128.0, 124.9, 118.5, 75.2, 54.0, 51.4, 51.3, 43.4, 42.0, 24.9, 24.3, 23.0,
22.7, 22.5, 22.4; HRMS calcd for C18H29BrN2O3SH (M + H)+ 435.1136,
found 435.1147 (TOF MS ES+).
(S)-7-Bromo-5-((R)-4-hydroxy-3-methylbutyl)-3-isobutyl-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10p). Accord-
ing to the reaction protocol described in general procedure C from 4a
(81.1 mg), compound 10p (43%, 43.1 mg) was isolated after
chromatography as a colorless oil: Rf = 0.45 (1:1 EtOAc/hexane);
[α]2D0 = −103.1 (c = 0.66, CHCl3); FTIR (thin film) 3512, 3252, 2957,
1578, 1543, 1470, 1371, 1315, 1150, 1040, 800, 731, 700 cm−1; 1H NMR
(500 MHz, CDCl3) δ ppm 7.67 (d, J = 8.5 Hz, 1H, aromatic), 7.20 (d, J =
1.8 Hz, 1H, aromatic), 7.10 (dd, J = 8.5, 1.8 Hz, 1H, aromatic), 4.41 (d, J
(S)-7-Bromo-5-(2-hydroxyethyl)-3-isobutyl-2,3,4,5-
tetrahydrobenzo[f ][1,2,5]thiadiazepine 1,1-Dioxide (10l). According
to the reaction protocol described in general procedure C from 4a (63.5
mg), compound 10l (43%, 31.0 mg) was isolated after chromatography
as a colorless oil: Rf = 0.45 (1:1 EtOAc/hexane); [α]2D0 = −120.8 (c =
0.085, CHCl3); FTIR (thin film) 3454, 3250, 2957, 1576, 1470, 1367,
1
1319, 1155, 1061, 808, 789, 745, 700 cm−1; H NMR (500 MHz,
CDCl3) δ ppm 7.69 (d, J = 8.4 Hz, 1H, aromatic), 7.36 (d, J = 1.8 Hz, 1H,
aromatic), 7.23 (dd, J = 8.5, 1.8 Hz, 1H, aromatic), 4.27 (d, J = 9.0 Hz,
1H, NH), 3.82 (ddd, J = 13.6, 5.6, 3.9 Hz, 1H, HOCHaHb), 3.73−3.57
(m, 3H, NHCHCH2, NCH2CH2OH), 3.42 (s, 1H, OH), 3.36 (dd, J =
15.0, 2.1 Hz, 1H, NHCHCHaHbN), 3.32−3.21 (m, 1H, HOCHaHb),
2.85−2.71 (m, 1H, NHCHCHaHbN), 1.93−1.79 (m, 1H,
CH3CHCH3), 1.36 (ddd, J = 14.3, 9.1, 5.7 Hz, 1H, NHCHCHaHb),
1.30−1.18 (m, 1H, NHCHCHaHb), 0.98 (dd, J = 6.5, 6.4 Hz, 6H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 148.9, 135.6, 129.6,
127.7, 126.1, 125.5, 61.3, 60.1, 58.0, 54.1, 40.7, 24.6, 23.0, 21.9; HRMS
M
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The Journal of Organic Chemistry
Article
= 8.2 Hz, 1H, NH), 3.68−3.56 (m, 2H, NHCHCH2N,
NCHaHbCH2CHMe), 3.55−3.49 (m, 1H, HOCHaHbCHMe), 3.46
(dd, J = 15.1, 2.7 Hz, 1H, NHCHCHaHbN), 3.43−3.39 (m, 1H,
HOCHaHbCHMe), 3.21 (ddd, J = 13.7, 8.3, 5.9 Hz, 1H,
NCHaHbCH2CHMe), 2.95 (dd, J = 15.1, 9.0 Hz, 1H, NHCHCHaHbN),
1.91−1.79 (m, 2H, HOCH2CHMe, CH3CHCH3), 1.79−1.70 (m, 2H,
NCH2CHaHbCHMe, OH), 1.53−1.43 (m, 2H, NHCHCHaHbCH,
NCH2CHaHbCHMe), 1.27 (ddd, J = 14.0, 8.4, 5.6 Hz, 1H,
NHCHCHa Hb CH), 1.03−0.93 (m, 9H, CH3 CHCH3 ,
HOCH2CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 149.3, 132.4,
129.7, 127.3, 123.8, 122.1, 67.7, 59.2, 54.0, 52.3, 40.9, 33.4, 31.4, 24.6,
22.9, 21.9, 17.0; HRMS calcd for C17H27BrN2O3SH (M + H)+ 421.0979,
found 421.0980 (TOF MS ES+).
(3S)-7-Bromo-3-isobutyl-3,4-dihydro-2,5-ethanobenzo[f ][1,2,5]-
thiadiazepine 1,1-Dioxide (11a). According to the reaction protocol
described in general procedure D from 10l (17.6 mg), compound 11a
(87%, 14.6 mg) was isolated after chromatography as a colorless oil: Rf =
0.53 (1:2 EtOAc/hexane); [α]2D0 = −29.1 (c = 0.945, CHCl3); FTIR
(thin film) 2957, 1574, 1448, 1391, 1333, 1165, 839, 797, 694 cm−1; 1H
NMR (500 MHz, CDCl3) δ ppm 7.74 (d, J = 8.4 Hz, 1H, aromatic), 7.56
(dd, J = 8.4, 2.0 Hz, 1H, aromatic), 7.48 (d, J = 2.0 Hz, 1H, aromatic),
3.97−3.82 (m, 1H, NCHCH2N), 3.72 (dddd, J = 14.7, 8.6, 2.4, 1.7 Hz,
1H, SNCHaHb), 3.42 (ddd, J = 14.1, 7.7, 2.5 Hz, 1H,
CNCHaHbCH2NS), 3.39−3.32 (m, 1H, CNCHaHbCH2NS), 3.26−
3.21 (m, 1H, NCHaHbCHN), 3.21−3.16 (m, 1H, SNCHaHb), 2.73 (dd,
J = 14.4, 9.1 Hz, 1H, NCHaHbCHN), 1.89−1.75 (m, 1H, CH3CHCH3),
1.68 (ddd, J = 14.3, 9.8, 4.7 Hz, 1H, NCHCHaHbCH), 1.14 (ddd, J =
13.8, 9.0, 4.6 Hz, 1H, NCHCHaHbCH), 0.95 (d, J = 6.8 Hz, 3H,
CH3CHCH3), 0.93 (d, J = 6.5 Hz, 3H, CH3CHCH3); 13C NMR (126
MHz, CDCl3) δ ppm 148.1, 143.2, 133.9, 131.3, 129.8, 126.8, 53.3, 51.1,
51.07, 39.1, 38.3, 24.6, 23.2, 21.6; HRMS calcd for C14H19BrN2O2SH
(M + H)+ 359.0429, found 359.0430 (TOF MS ES+).
(4R,11S)-7-Bromo-11-isobutyl-4-methyl-3,4-dihydro-2,5-
ethanobenzo[f ][1,2,5]thiadiazepine 1,1-dioxide (11b). According to
the reaction protocol described in general procedure D from 10m (28.5
mg), compound 11b (46%, 12.5 mg) was isolated after chromatography
as a colorless oil: Rf = 0.66 (1:2 EtOAc/hexane); [α]2D0 = −2.1 (c = 0.25,
CHCl3); FTIR (thin film) 2957, 1574, 1456, 1381, 1331, 1161, 816, 789,
756, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm 7.72 (d, J = 8.4 Hz,
1H, aromatic), 7.59 (dd, J = 8.4, 2.0 Hz, 1H, aromatic), 7.45 (d, J = 1.9
Hz, 1H, aromatic), 4.09−3.90 (m, 1H, NCHCH2N), 3.51−3.29 (m, 4H,
SNCH2CHCH3, NCHCHaHbN), 2.81 (dd, J = 14.3, 6.6 Hz, 1H,
NCHCHaHbN), 1.84−1.77 (m, 1H, CH3CHCH3), 1.73 (ddd, J = 13.9,
10.2, 4.7 Hz, 1H, NCHCHaHbCH), 1.21 (ddd, J = 14.1, 9.0, 5.0 Hz, 1H,
NCHCHaHbCH), 0.96 (dd, J = 6.5, 3.8 Hz, 9H, NCHCH3,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 144.3, 143.6,
136.0, 131.6, 129.1, 126.6, 56.2, 54.5, 49.2, 44.8, 40.3, 25.1, 23.2, 21.5,
20.2; HRMS calcd for C15H21BrN2O2SH (M + H)+ 373.0585, found
373. 0565 (TOF MS ES+).
(42%, 33.4 mg) was isolated after chromatography as a white solid: mp
50−55 °C; Rf = 0.50 (1:1 EtOAc/hexane); [α]2D0 = +22.5 (c = 1.315,
CHCl3); FTIR (thin film) 3514, 2953, 1601, 1587, 1477, 1454, 1389,
1321, 1155, 1070, 808, 741, 700 cm−1; 1H NMR (500 MHz, CDCl3) δ
ppm 7.98 (dd, J = 8.8, 6.5 Hz, 1H, aromatic), 7.41−7.25 (m, 5H,
aromatic), 6.79 (ddd, J = 8.7, 7.8, 2.4 Hz, 1H, aromatic), 6.72 (dd, J = 9.9,
2.4 Hz, 1H, aromatic), 5.75 (s, 1H, NH), 4.46 (d, J = 11.8 Hz, 1H,
OCHaHbC), 4.40 (d, J = 11.9 Hz, 1H, OCHaHbC), 4.37 (dd, J = 12.3, 5.1
Hz, 1H, OCHCHaHbO), 3.90 (dd, J = 11.9 Hz, 1H, OCHCHaHbO),
3.64 (bs, 1H, NHCHCH2N), 3.37−3.23 (m, 2H, OCHCH2O,
NCHCH3), 3.14 (dd, J = 9.4, 4.1 Hz, 1H, HOCHaHbCH), 3.09−2.99
(m, 2H, NHCHCHaHbN, HOCHaHbCH), 2.53 (d, J = 12.7 Hz, 1H,
NCHaHbCHO), 2.36−2.28 (m, 2H, NCHaHbCHO, OH), 2.14 (dd, J =
15.1, 10.8 Hz, 1H, NHCHCHaHbN), 1.95−1.81 (m, 1H, CH3CHCH3),
1.42 (ddd, J = 13.7, 7.7, 6.0 Hz, 1H, NHCHCHaHb), 1.14 (ddd, J = 13.6,
7.9, 5.6 Hz, 1H, NHCHCHaHb), 0.98 (d, J = 6.5 Hz, 3H, NCHCH3),
0.93 (d, J = 6.5 Hz, 3H, CH3CHCH3), 0.89 (d, J = 6.6 Hz, 3H,
CH3CHCH3); 13C NMR (126 MHz, CDCl3) δ ppm 165.7 (d, 1JC−F
=
254.0 Hz), 157.2, 137.7, 132.2 (d, 3JC−F = 10.8 Hz), 128.5 (2C), 127.9
(2C), 127.7 (2C), 108.6 (d, 2JC−F = 22.2 Hz), 104.1 (d, 2JC−F = 24.5 Hz),
73.4, 72.2, 71.9, 69.4 (2C), 57.4, 56.3, 53.7, 46.1, 24.2, 23.0, 22.5, 9.5;
HRMS calcd for C25H35FN2O5SH (M + H)+ 495.2329, found 495.2348
(TOF MS ES+).
(3S,7S)-7-((Benzyloxy)methyl)-10-fluoro-5-((R)-1-hydroxypropan-
2-yl)-3-isobutyl-2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]-
oxathiadiazecine 1,1-Dioxide (19). According to the reaction protocol
described in general procedure B from 4c (40.0 mg), compound 19
(42%, 30.5 mg) was isolated after chromatography as a colorless sticky
oil: Rf = 0.35 (1:1 EtOAc/hexane); [α]2D0 = +45.9 (c = 0.535, CHCl3);
FTIR (thin film) 3450, 3259, 2957, 1603, 1587, 1477, 1454, 1387, 1323,
1161, 1070, 808, 733, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ ppm
7.96 (ddd, J = 8.6, 6.4, 1.6 Hz, 1H, aromatic), 7.53−7.44 (m, 2H,
aromatic), 7.44−7.37 (m, 2H, aromatic), 7.38−7.29 (m, 1H, aromatic),
6.87−6.79 (m, 1H, aromatic), 6.79 (ddd, J = 10.0, 1.8 Hz, 1H, aromatic),
6.42 (s, 1H, NH), 4.66 (s, 2H, OCH2C), 4.56 (dd, J = 5.4, 3.1 Hz, 1H,
OCHCH2O), 4.01 (dd, J = 10.5, 5.1 Hz, 1H, OCHCHaHbO), 3.98−3.89
(m, 1H, OCHCHaHbO), 3.44−3.26 (m, 2H, HOCH2CH), 3.06−2.96
(m, 1H, NHCHCH2N), 2.95−2.87 (m, 3H, NCH2CHO, OH), 2.77−
2.64 (m, 1H, NCHCH3), 2.33 (dd, J = 14.8, 4.9 Hz, 1H,
NHCHCHaHbN), 2.26 (dd, J = 14.9, 3.8 Hz, 1H, NHCHCHaHbN),
1.65−1.53 (m, 1H, CH3CHCH3), 1.54−1.43 (m, 1H, NHCHCHaHb),
0.96 (ddd, J = 13.5, 7.9, 5.6 Hz, 1H, NHCHCHaHb), 0.84 (dd, J = 6.5,
1.5 Hz, 3H, CH3CHCH3), 0.81 (dd, J = 6.7, 1.6 Hz, 3H, NCHCH3),
0.72 (dd, J = 6.6, 1.5 Hz, 3H, CH3CHCH3); 13C NMR (126 MHz,
CDCl3) δ ppm 165.9 (d, 1JC−F = 254.8 Hz), 155.5, 136.2, 132.3 (d, 3JC−F
= 10.2 Hz), 129.0 (2C), 128.6 (2C), 128.4, 127.3, 109.2 (d, 2JC−F = 22.0
Hz), 104.1 (d, 2JC−F = 25.2 Hz), 78.6, 75.0, 71.0, 64.8, 61.4, 55.8, 53.5,
51.6, 43.4, 24.1, 23.1, 21.8, 10.0; HRMS calcd for C25H35FN2O5SH (M +
H)+ 495.2329, found 495.2298 (TOF MS ES+).
7-Bromo-4H-spiro[2,5-ethanobenzo[f ][1,2,5]thiadiazepine-3,1′-
cyclohexane] 1,1-Dioxide (11c). According to the reaction protocol
described in general procedure D from 10j (21.2 mg), compound 11c
(40%, 8.1 mg) was isolated after chromatography as a white solid: Rf =
0.51 (1:2 EtOAc/hexane); mp 182−185 °C; FTIR (thin film) 2935,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1574, 1452, 1393, 1327, 1167, 804, 694 cm−1; H NMR (500 MHz,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01429.
CDCl3) δ ppm 7.67 (d, J = 8.4 Hz, 1H, aromatic), 7.53 (dd, J = 8.4, 2.0
Hz, 1H, aromatic), 7.47 (d, J = 2.0 Hz, 1H, aromatic), 3.88 (ddd, J = 14.8,
6.9, 5.7 Hz, 1H, SNCHaHb), 3.44 (ddd, J = 14.7, 8.5, 7.1 Hz, 1H,
SNCHaHb), 3.38−3.30 (m, 2H, CNCH2CH2NS), 3.15 (ddd, J = 14.3,
1.3, 1.2 Hz, 1H, NCHaHbCNS), 2.94 (dd, J = 14.5, 0.9 Hz, 1H,
NCHaHbCNS), 2.20−2.09 (m, 1H, cyclohexyl), 1.89−1.77 (m, 3H,
cyclohexyl), 1.75−1.65 (m, 1H, cyclohexyl), 1.49−1.35 (m, 3H,
cyclohexyl), 1.34−1.21 (m, 2H, cyclohexyl); 13C NMR (126 MHz,
CDCl3) δ ppm 148.9, 144.8, 133.7, 131.2, 128.7, 126.8, 60.5, 58.8, 49.8,
41.3, 37.1, 36.9, 25.1, 22.8, 22.4; HRMS calcd for C15H19BrN2O2SH (M
+ 2 + H)+ 373.0403, found 373. 0399 (TOF MS ES+).
1
Optimization table and H, 19F, and 13C NMR spectral
data (PDF)
X-ray crystallographic data for 6a, 6p, 8b (CIF), 10m, and
11c
AUTHOR INFORMATION
■
Corresponding Author
(3S,7R)-7-((Benzyloxy)methyl)-10-fluoro-5-((R)-1-hydroxypropan-
2-yl)-3-isobutyl-2,3,4,5,6,7-hexahydrobenzo[b][1,4,5,8]-
oxathiadiazecine 1,1-Dioxide (18). According to the reaction protocol
described in general procedure B from 4c (44.2 mg), compound 18
*E-mail: phanson@ku.edu.
Notes
The authors declare no competing financial interest.
N
DOI: 10.1021/acs.joc.5b01429
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The Journal of Organic Chemistry
Article
(10) (a) Mai, A. ChemMedChem 2014, 9, 415−417. (b) Knapp, S.;
Weinmann, H. ChemMedChem 2013, 8, 1885−1891.
ACKNOWLEDGMENTS
■
This investigation was supported by funds provided by the NIH
Center for Chemical Methodologies and Library Development at
the University of Kansas (P50 GM069663) and NIGMS Pilot-
Scale Libraries Program (NIH P41 GM076302). We thank Justin
Douglas and Sarah Neuenswander in the University of Kansas
NMR Laboratory (NSF Grant Nos. 9512331, 9977422, and
0320648 and NIH Center Grant Nos. P20 GM103418,
S10RR024664, and S10OD016360) and Victor Day in the X-
ray Crystallography Laboratory (NSF-MRI Grant No. CHE-
0923449). We also acknowledge Patrick Porubsky and Benjamin
Neuenswander for providing assistance with mass spectrometry
as well as Gerald Lushington for computational analysis and data.
We also thank The University of Kansas and the State of Kansas
for partial student support (J.K.L., N.A., and T.B.S.).
(11) (a) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131−9166.
(b) See refs 1 and 2.
(12) Hegde, V. R.; Patel, M. G.; Gullo, V. P.; Ganguly, A. K.; Sarre, O.;
Puar, M. S. J. Am. Chem. Soc. 1990, 112, 6403−6405.
(13) (a) Ayers, S.; Zink, D. L.; Mohn, K.; Powell, J. S.; Brown, C. M.;
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