Halonium ion triggered rearrangement of unsaturated benzo-annulated bi- and tricyclic sulfonamides

Article abstract of DOI:10.1021/jo401888f

The halonium ion mediated 1,2-Wagner-Meerwein-type rearrangement of a series of benzo-fused bi- and tricyclic sulfonamides is reported. During this rearrangement the carbon-carbon bond that migrates was selectively set in the intramolecular Mizoroki-Heck

Full text of DOI:10.1021/jo401888f

Article
pubs.acs.org/joc
Halonium Ion Triggered Rearrangement of Unsaturated Benzo-
Annulated Bi- and Tricyclic Sulfonamides
Kimberly Geoghegan, Shaun Smullen, and Paul Evans*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The halonium ion mediated 1,2-Wagner−Meerwein-type rearrangement of a series of benzo-fused bi- and tricyclic
sulfonamides is reported. During this rearrangement the carbon−carbon bond that migrates was selectively set in the
intramolecular Mizoroki−Heck (IHR) synthesis of the starting materials. Consequently, this method constitutes a means to
access the regioisomeric series of cyclic sulfonamides not observed during the Mizoroki−Heck reaction.
Paquette, the derivatization of the Heck-derived alkene 2a was
also considered.4 In accordance with Paquette’s findings, the cis-
1,2-dibromination of 2a took place predominantly leading to
3a, in solvents such as chloroform. The stereochemical
outcome was ascribed to bromide interception of a carbocation
from the less hindered convex face of the intermediate, as
opposed to the ring-opening of the bromonium ion (e.g., 5)
from the more hindered, concave face.5
When nonpolar solvents were employed, the same outcome
was observed for dimethoxy-substituted 2b and the cis-1,2-
dibromide 3b was isolated. However, use of chloroform led to
formation of compound 4 as the major product.5 It was
reasoned that 4 resulted from a 1,2-Wagner−Meerwein (W-M)
rearrangement of intermediate 5, whereby the aryl−benzylic
carbon bond, which is appropriately aligned to the C−Br
bromonium ion bond (or the carbocation),6 shifts, generating
secondary carbocation 6 (in a process that may be reversible),
which then is subsequently intercepted, diastereoselectively, by
a bromide ion. The fact that this rearrangement-derived
product was not observed for nonsubstituted alkene 2a
indicates that the methoxy substituents exert influence on the
bond migration.7 Following the rearrangement described, it
should be noted that the bond formed during the IHR
(denoted carbon-a in Scheme 1) migrates to, what was, the
other alkenyl carbon atom in the reaction precursor 1 (i.e.,
carbon-b).
INTRODUCTION
■
Cyclic sulfonamides (sultams) are of interest from both a
chemical and a pharmacological perspective.1 An effective
method for their construction, particularly when benzo-
annulated, is the intramolecular Heck reaction (IHR), a process
that results in formation of the cyclic sulfonamide and a new
alkene (Scheme 1, 1a to 2a, for example).2 We have
investigated this tactic as a means to assemble functionalized
cyclic sulfonamides, which can then be treated under reductive
conditions to excise the sulfonyl group and form a function-
alized amine.3 During this study, following a report from
Scheme 1. Formation of Benzo-Annulated Cyclic
Sulfonamides by the Intramolecular Heck Reaction and
Their Bromination
This latter aspect attracted our attention, since, recently, we
have uncovered that during the IHR of a series of alkyl and aryl
trisubstituted alkenes, carbon−carbon bond formation takes
place with high selectivity at the most substituted alkenyl
carbon (i.e., 7 to 8, Scheme 2).8 During this work, in which the
substitution pattern on the alkenyl carbon dictates bond
formation rather than the size of the newly formed cycle,
Received: August 27, 2013
Published: September 24, 2013
© 2013 American Chemical Society
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Scheme 2. Alkene Substituent Control in the IHR of Cyclic Sulfonamides and the Proposed Application of the 1,2-Wagner−
a
Meerwein Rearrangement
a
EDG = electron donating group.
Scheme 3. Synthesis of Cyclic Sulfonamides 13a and 13b Possessing a Quaternary Center
conditions to reliably overturn the selectivity could not be
identified. Therefore, it was of interest to investigate whether
the bromonium ion triggered 1,2-shift of Heck adducts 8 could
be used to access formally the isomeric series of compounds
not obtainable following IHR.
It was, in fact, felt that the rearrangement of molecules such
as 8 might actually proceed more readily than the example
discussed above (1b to 4), since in going from 8 to 9 steric
compression between the bridgehead substituent (R) and the
peri-aromatic hydrogen would be ameliorated and in addition
the resultant carbocationic intermediate would be tertiary as
opposed to secondary (e.g., 6).
otherwise identical reaction conditions gave an isolated yield of
62% and 68% of 13a and 13b, respectively.
With alkenes 13a and 13b in hand, their behavior in the
presence of bromine was studied (Scheme 4). Treatment of a
chloroform solution of 13a with bromine (10 equiv), which was
warmed from −60 °C to room temperature over a 15 h period,
gave a mixture of products (entry 1). 1,2-Dibromide 16a was
isolated in 33% yield along with 55%10 of a mixture of
rearranged di- and tribromides 14a and 15a (ca. 1:1) that
proved inseparable by flash column chromatography. The
formation of 14a was consistent with diastereoselective
interception of the tertiary carbocation 9 (as observed
previously,5 2b to 4) and it was reasoned that tribromide 15a
formed as a result of bromination of the corresponding alkene
17a (not observed in this reaction), which itself formed on loss
of a proton from the same tertiary carbocation. On reducing the
polarity of the medium, slightly diminished amounts of
rearranged products (14a and 15a) and more of the 1,2-
dibromide 16a (entry 2) were observed. The cis-1,2-dibromo
relationship in 16a was confirmed by NOE. However,
increasing polarity can only be successfully employed in these
reactions to a certain degree, since polar protic solvents
competitively intercept reaction intermediates,5 and solvents
such as DMF, acetonitrile, and propylene carbonate failed to
generate products of bromination in meaningful amounts. Since
the inseparable mixture of rearranged di- and tribromides (14a
and 15a) served to complicate the understanding of this
process, it was felt that if a basic silver salt was added, then the
rate of bromide interception of the tertiary carbocation would
diminish versus alkene formation and that consequently more
tribromide 15a would be isolated. As entry 3 indicates, this
supposition proved incorrect and bromine treatment of 13a in
the presence of silver(I) acetate gave a mixture of 14a and 15a
in approximately the same ratio as observed in the absence of
Ag(I). Reducing the effective bromine concentration11 (entries
RESULTS AND DISCUSSION
■
To investigate the feasibility of the process outlined in Scheme
2, the synthesis of alkenes 13a and 13b was considered.
Dimethoxy-containing 13a was reported in our previous work8b
and was assembled in four steps from 2-bromo-4,5-dimethox-
ybenzenesulfonyl chloride 11a (Scheme 3). It proved more
challenging to assemble dioxolane analogue 13b due to
difficulties associated with the synthesis of the acid-sensitive
2-bromo-4,5-(methylenedioxy)benzenesulfonyl chloride 11b.
After some optimization it was found that exposure of a cold
dichloromethane solution of 1-bromo-3,4-(methylenedioxy)-
benzene 10b to chlorosulfonic acid led to formation of the
required sulfonic acid, which immediately precipitated from
solution. In turn, this sulfonic acid could be converted to
sulfonyl chloride 11b with thionyl chloride in dichloromethane
at reflux. A ring-closing metathesis strategy gave the asym-
metrical 3-methyl dihydropyrrole 12b. Subsequent IHR gave
13b as the sole isolable product, the structure of which was
confirmed by X-ray crystallography.9 Microwave irradiation was
briefly investigated as an alternative to standard conductive
heating. Irradiation at 300 W and 125 °C for 25 min under
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Scheme 4. Rearrangement of Cyclic Sulfonamides 13a and 13b
4 and 5) did prove to influence product outcome, particularly
when 0.55 equiv of bromine was used. Whereas use of 1.4 equiv
of bromine (entry 4) gave essentially an identical outcome as
the use of 10 equiv (entry 1), 0.55 equiv (entry 5) gave only a
trace of 1,2-dibromide 16a, none of the rearranged di- and
tribromides (14a and 15a), and the rearranged alkene 17a (in
50% of a maximum 55% yield) as the major product.
dioxolane 13b. Use of 10 equiv of bromine in chloroform at
−60 °C to room temperature (entry 10) led to isolation of 1,2-
dibromide 16a in 38% yield along with a mixture of rearranged
products comprising, predominantly, tribromide 15b and
dibromide 14b (14b:15b, 1:3, 32%). It was interesting to
note that significantly smaller quantities of the rearranged 1,3-
dibromide 14b was observed for the dioxolane series.
Pleasingly, use of NBS also led to the rearrangement, and in
this case alkene 17b, formed in 42% yield, could be isolated
from starting material 13b. Stereoelectronic factors serve to
diminish the interaction between the lone pairs on dioxolane-
substituted aromatic species versus their methoxy-substituted
analogues, which are not similarly conformationally con-
strained.12 This is a possible explanation for the reduction in
amounts of rearrangement products for the dioxolane-
substituted material and the different ratios of di- and
tribromides (14 to 15). It should be noted that the
nonsubstituted analogue (not shown) does not undergo this
type of rearrangement, demonstrating the influence the +M
dimethoxy and dioxolane substituents play in this 1,2-carbon−
carbon bond shift.
This latter observation indicated that proton loss from the
putative intermediate 9 was indeed feasible, and as long as the
resultant alkene could be protected from subsequent
dibromination, it could be effectively isolated. On the basis of
this, the use of N-halosuccinimides was considered in order to
both serve as a source of electrophilic halogen at low
concentration and, due to the shape of the succinimide
anion, a conjugate base to accept a proton from the methyl
group flanking the tertiary carbocation. At room temperature
no reaction with N-bromosuccinimide was realized; however, in
chloroform at reflux 17a was isolated in 66% yield (entry 6). In
a sealed tube (held at 80 °C, oil bath temperature, for 15 h),
90% of 17a was isolated as the sole reaction product. Similarly,
use of NIS (entry 8) gave 82% of 18a. However, the use of
NCS, under otherwise identical reaction conditions, led only to
recovery of starting material (entry 9). Dibromination of 17a
was performed, which gave an isolable sample of 15a (without
14a as a contaminant), serving to confirm both the origin of
15a and its structure assignment.
Following the work outlined in Scheme 4, a means to access
the regioisomeric material, albeit brominated (or iodinated),
from the IHR had been developed.7 To exemplify this, as
shown in Scheme 5, 17a was treated with tri-n-butyltin hydride
in the presence of 2,2′-azoisobutyronylnitrile, leading to the
hoped for reduction of the carbon−bromine bond; however,
this reaction was not clean and the product directly obtained
The chemistry studied and optimized for the dimethoxy-
substituted cyclic sulfonamide 13a was next considered for
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As shown in Scheme 6, exposure of 23a to bromine (10
equiv) using the procedure uncovered (Scheme 4) led to the
reproducible formation of a major product along with two
minor compounds (entry 1). Analysis of the spectroscopic data
recorded for the major product, purified by flash column
chromatography, indicated that its structure was dibromide 24a
(41% yield). Nuclear Overhauser effects were used to correlate
the characteristic methine proton adjacent to nitrogen around
the cyclohexenyl ring to the cis-allylic methine proton. In terms
of mass balance for this reaction, two additional minor reaction
products formed that proved to corun chromatographically.
However, analysis of their nuclear magnetic resonance spectra
indicated that the main component of this mixture was a 1,2-
dibromide, the structure of which was tentatively assigned as
trans-25a. In addition, a diastereoisomer of 24a (epimeric at the
allylic bromide) was also identified. Pleasingly, on increasing
the concentration of bromine to 20 equiv (entry 2)
synthetically useful yields of 24a were observed.
Two aspects associated with the observation and isolation of
24a warrant mention: first, it seems that following the hoped
for rearrangement the initially formed trisubstituted alkene is
reluctant to participate in further 1,2-dibromination, unlike the
1,1-disubstituted alkene 17 formed during the rearrangement of
the bicyclic sulfonamides (as discussed above). Second, the
initially formed trisubstituted alkene evidently undergoes a fast
regio- and diastereoselective allylic bromination.15 Trace
amounts of 1,2-dibromide 25a were detected, and for this
case, again, unlike the bicyclic sulfonamides, NOE indicated
that the 1,2-dibromide was predominantly formed as the trans-
diastereoisomer. On the basis of this it seems reasonable to
speculate that this occurs due to the effect that the additional
cyclohexyl fused ring has on both the stereochemical sense of
bromonium ion formation and on its subsequent reactivity.
The dioxolane containing sulfonamide 23b was next
considered. As indicated in entry 3, use of bromine (10
equiv) gave the desired rearranged product 24b, again featuring
diastereoselective allylic bromination in 33% yield. On the basis
Scheme 5. Reduction of Rearranged Bromide 17a: Reversal
of IHR Regiochemistry
from the reaction was contaminated with 13a, which we
presume arises following fragmentation of the secondary radical
containing intermediate in a process involving a phenyl shift
and generation of a primary radical. Nevertheless, the hoped for
alkene could be obtained in 42% yield following careful
purification to remove 13a and then diastereoselectively further
reduced to afford 19a, the regioisomer of the product of our
one-pot Heck-hydrogenation sequence,13 20a (Scheme 5).
On the basis of the success of the rearrangements for bicyclic
sulfonamides 13a and 13b (Scheme 4), we next turned our
attention to the corresponding tricyclic analogues in which the
quaternary center set following IHR comprises part of a fused
cyclohexyl ring. Compounds required to study the halogen-
triggered rearrangement (23a and 23b) were assembled in four
steps using an iodo-amino cyclization based on a report by
Knight14 and developed by us8a for these compounds. As
before, IHR gave high selectivity for bond formation at the
most substituted carbon atom, although dioxolane 22b gave
poorer conversion than 23a. Optimum yields for this
transformation were achieved using Pd(0) with an electron-
rich phosphine, following which only 40% of 23b was isolated
(along with 50% of recovered starting material, 22b).
Scheme 6. Synthesis and Rearrangement of Benzo-Annulated Tricyclic Sulfonamides 23a and 23b
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Experimental details concerning the preparation of compounds 13a,8b
20a,13 and 21a−23a8a have been previously reported.
of the indication that the efficiency of this process was
improved using 20 equiv of bromine, the yield of 24b was
slightly increased (entry 4). Single crystal X-ray crystallog-
raphy16 served to confirm the relative stereochemistry of the
major dibrominated product (Figure 1).
6-Bromobenzo[d][1,3]dioxole-5-sulfonyl Chloride 11b. At 0
°C solution of 5-bromobenzo[d][1,3]dioxole 10b (1.0 mL, 8.3 mmol,
1.0 equiv) in CH2Cl2 (40 mL) was treated with a solution of HSO3Cl
(0.7 mL, 10.4 mmol, 1.25 equiv) in CH2Cl2 (5 mL) dropwise over 5
min. Stirring was continued for a further 5 min before the reaction
mixture was filtered under suction and the solid washed repeatedly
with CH2Cl2 (5 × 10 mL) to afford 6-bromobenzo[d][1,3]dioxole-5-
sulfonic acid (1.97 g, 85%) as a gray solid. [Mp: 87−89 °C. IR [KBr,
deposited (dep) from CH2Cl2]: 1613, 1503, 1485, 1372, 1337, 1251,
1174, 1038, 938 cm−1. HRMS (ESI): calcd for C7H4O4S79Br ([M −
1
H]−) 278.8963, found 278.8964. H NMR (DMSO-d6, 400 MHz): δ
7.38 (s, 1H), 7.12 (s, 1H), 6.06 (s, 2H). 13C NMR (DMSO-d6, 100
MHz): δ 148.0, 145.9, 140.9, 113.4, 110.7, 109.0, 102.1.] A mixture of
the above sulfonic acid (1.07 g, 3.81 mmol, 1.0 equiv) and SOCl2 (2.76
mL, 38.1 mmol, 10 equiv) in CH2Cl2 (40 mL) was heated to reflux for
15 h. The reaction mixture was cooled and filtered, and the filtrate was
washed with sat. NaHCO3 (20 mL). The aqueous layer was re-
extracted with CH2Cl2 (20 mL). The combined organic layers were
washed with brine, dried over MgSO4, and reduced under pressure to
give sulfonyl chloride 11b (643 mg, 57%) as a pale brown oil, which
gradually solidified. Rf = 0.5 (c-Hex:EtOAc, 3:1). Mp: 54−56 °C. IR
(KBr, dep from CH2Cl2): 3056, 2984, 2917, 1608, 1507, 1476, 1384,
1251, 1180 cm−1. HRMS (ESI): calcd for C7H4O4S79Br35ClNa ([M +
Figure 1. X-ray crystallographic structure of 24b.
As shown in Figure 2, the type of functionalized 3-aryl-
2,3,5,6,7,7a-hexahydroindole skeleton produced is found in a
1
Na])+ 320.8594, found 320.8624. H NMR (CDCl3, 400 MHz): δ
7.62 (s, 1H), 7.23 (s, 1H), 6.16 (s, 2H). 13C NMR (CDCl3, 100
MHz): δ 153.6, 147.6, 136.6, 115.7, 115.1, 110.6, 103.8.
1-[(6-Bromobenzo[d][1,3]dioxol-5-yl)sulfonyl]-3-methyl-2,5-
dihydro-1H-pyrrole 12b. A solution of 11b (1.00 g. 3.31 mmol, 1.0
equiv) and allylamine (0.34 mL, 4.30 mmol, 1.3 equiv) in CH2Cl2 (50
mL) was treated with Et3N (0.6 mL, 4.30 mmol, 1.3 equiv) in a
dropwise fashion at 0 °C. Stirring was continued for 15 h during which
period room temperature was reached. HCl (1 M, 20 mL) was added
to the reaction mixture, and the layers were separated. The organic
layer was washed with H2O (20 mL) and brine (20 mL) and dried
over MgSO4. Filtration followed by solvent removal under pressure
afforded the N-allyl sulfonamide (862 mg, 81%) as a pale yellow solid.
[Rf = 0.4 (c-Hex:EtOAc, 3:1). Mp: 101−104 °C. IR (KBr, dep from
CH2Cl2): 2921, 2853, 1505, 1475, 1329, 1243, 1167, 1034, 924 cm−1.
HRMS (ESI): calcd for C10H11NO4S79Br ([M + H])+ 319.9592, found
319.9599. 1H NMR (CDCl3, 300 MHz): δ 7.58 (s, 1H), 7.13 (s, 1H),
6.10 (s, 2H), 5.74−5.63 (m, 1H), 5.25−5.06 (m, 3H), 3.54 (t, J = 6.0,
2H). 13C NMR (CDCl3, 75 MHz): δ 151.6, 147.7, 135.0, 132.9, 118.5,
114.7, 112.8, 111.7, 102.6, 45.9.] N-Allyl-6-bromobenzo[d][1,3]-
dioxole-5-sulfonamide (400 mg, 1.25 mmol, 1.0 equiv) was dissolved
in DMF (5 mL) and cooled to 0 °C. Sodium hydride (60% w/w in
mineral oil, 75 mg, 1.89 mmol, 1.5 equiv) was added and the mixture
was stirred for 0.5 h. 3-Chloro-2-methylprop-1-ene (0.16 mL, 1.63
mmol, 1.3 equiv) was added in a dropwise fashion. Stirring was
continued for 15 h during which time room temperature was reached.
EtOAc (10 mL) and H2O (10 mL) were added and the phases
separated. The aqueous layer was further extracted with EtOAc (2 ×
10 mL). The combined organic layers were dried over MgSO4. The
crude product, obtained after filtration and solvent removal, was
purified by column chromatography (c-Hex:EtOAc, 6:1 → 3:1), which
gave (430 mg, 93%) as a colorless solid. [Rf = 0.5 (c-Hex:EtOAc, 3:1).
Mp: 39−40 °C. IR (KBr, dep from CH2Cl2): 3081, 2981, 2916, 1505,
1475, 1369, 1329, 1243, 1164, 1143, 1033, 925 cm−1. HRMS (ESI):
calcd for C14H18NO4S79Br ([M + H])+ 374.0062, found 374.0069. 1H
NMR (CDCl3, 400 MHz): δ 7.63 (s, 1H), 7.12 (s, 1H), 6.09 (s, 2H),
5.63−5.53 (m, 1H), 5.19−5.10 (m, 2H), 4.95−4.86 (m, 2H), 3.88 (s,
2H), 3.83 (d, J = 6.5 Hz, 2H), 1.65 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 151.5, 147.3, 140.1, 133.2, 132.3, 119.5, 115.0, 114.9, 113.5,
112.4, 103.1, 53.2, 48.8, 19.9.] Under N2, a degassed solution of diallyl
compound (430 mg, 1.15 mmol, 1.0 equiv) in anhydrous CH2Cl2 (50
mL) was treated with Hoveyda−Grubbs’ second-generation catalyst
(14 mg, 0.023 mmol, 2.0 mol %). Stirring was continued at 40 °C for
15 h. Once cooled, the solvent was removed under reduced pressure.
Purification by flash column chromatography (c-Hex:EtOAc, 3:1) gave
Figure 2. (−)-Montanine.
family belonging to the amaryllidaceae alkaloid class (mon-
tanine, brunsvigine, and pancracine).17
CONCLUSION
■
In summary, the bromonium ion triggered18 rearrangement of a
series of cyclic benzo-annulated sulfonamides has been
reported. This process features the migration of the benzylic
bond, presumably to generate a tertiary carbocation, which can
then lose a proton to give a new exocyclic alkene. Depending
on the amount of bromine present and the structure of this
alkene, additional 1,2-dibromination may (15), or may not
(24), occur. An additional feature is that for the tricyclic
sulfonamides 23 a further, diastereoselective allylic bromination
is evidently facile.
EXPERIMENTAL SECTION
■
General Directions. Reactions with anhydrous solvents were
carried out under an atmosphere of N2. Glassware was either dried in
an oven or with a heat-gun before use, assembled hot, and cooled to
room temperature under a stream of N2. Anhydrous dichloromethane
(CH2Cl2) and acetonitrile (MeCN) were distilled from CaH2;
anhydrous dimethylformamide (DMF) and chloroform were used as
purchased. Thin layer chromatography (TLC) was carried out using
silica-coated aluminum sheets (60 F254), and silica gel (60 Å, 0.040−
0.063 mm) was used for flash column chromatography, which was
performed at medium pressure. 1H and 13C NMR spectra were
recorded using 300 and 400 MHz instruments as indicated. Reported
assignments are based on a combination of two-dimensional H−1H
1
(gCOSY), 1H−13C (HMQC), and NOESY correlation spectra.
Samples for infrared spectroscopy were recorded as films on KBr
plates using an FT-IR spectrometer. Melting points are uncorrected
and were recorded on recrystallized material (from indicated solvent)
or material directly obtained following purification by flash column
chromatography. High-resolution mass spectra (ESI-HRMS) were
obtained using a mass spectrometer with a TOF mass analyzer.
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12b (324 mg, 82%) as a white solid. Rf = 0.4 (c-Hex:EtOAc, 3:1). Mp:
71−73 °C. IR (KBr, dep from CH2Cl2): 2918, 1483, 1331, 1260, 1164,
1136, 1036, 936, 737 cm−1. HRMS (ESI): calcd for C12H13NO4S79Br
([M + H])+ 345.9749, found 345.9751. 1H NMR (CDCl3, 400 MHz):
δ 7.54 (s, 1H), 7.15 (s, 1H), 6.09 (s, 2H), 5.36−5.34 (m, 1H), 4.22−
4.18 (m, 2H), 4.15−4.04 (m, 2H), 1.73 (s, 3H). 13C NMR (CDCl3,
100 MHz): 151.5, 147.4, 135.0, 132.0, 119.1, 115.2, 113.4, 111.7,
103.1, 57.8, 55.3, 14.3.
5-Methyl-5H-2,5-methano[1,3]dioxolo[4′,5′:4,5]benzo[1,2-
f][1,2]thiazepine 1,1-Dioxide 13b. Under N2, a solution of 12b
(100 mg, 0.29 mmol, 1.0 equiv) in anhydrous DMF (3.0 mL) was
degassed under a steady stream of nitrogen (ca. 0.5 h). To this
solution was added Pd(OAc)2 (6.5 mg, 0.029 mmol, 10 mol %), PPh3
(15 mg, 0.058 mmol, 20 mol %), and K2CO3 (80 mg, 0.58 mmol, 2.0
equiv), and the mixture was heated to 110 °C for 15 h. The reaction
vessel was cooled, and EtOAc (10 mL) and H2O (10 mL) were added.
The resultant aqueous layer was further extracted with EtOAc (2 × 10
mL), and the combined organic extracts were dried over MgSO4.
Filtration followed by solvent removal under reduced pressure gave
the crude product, which was purified by flash column chromatog-
raphy (c-Hex:EtOAc, 2:1), affording the Heck product 13b (72 mg,
80%) as a colorless solid. Rf = 0.3 (c-Hex:EtOAc, 3:1). Mp: 130−132
°C. IR (KBr, dep from CH2Cl2): 3055, 2915, 2859, 1610, 1504, 1475,
1368, 1330, 1243, 1168, 1148, 1094, 1034, 922, 664 cm−1. HRMS
(ESI): calcd for C12H12NO4S ([M + H])+ 266.0487, found 266.0475.
1H NMR (CDCl3, 400 MHz): δ 7.14 (s, 1H), 6.71 (s, 1H), 6.34 (d, J =
was added and the mixture extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (MgSO4). Filtration, followed by
solvent removal under reduced pressure, gave the crude product,
which was purified by flash column chromatography (c-Hex:EtOAc,
6:1), affording compounds 14b and 15b (15 mg, 32%) as a
chromatographically inseparable mixture (14b:15b, 1:3). Rf = 0.6 (c-
Hex:EtOAc, 3:1). IR (NaCl, dep from CH2Cl2): 3053, 2921, 2855,
1504, 1483, 1347, 1251, 1175, 1036, 931 cm−1. HRMS (ESI): calcd for
1
C12H12NO4S79Br2 ([M + H])+ 423.8854, found 423.8835 (14b). H
NMR (CDCl3, 300 MHz): δ 7.20 (s, 1H), 7.18 (s, 1H), 6.89 (s, 1H),
6.70 (s, 1H), 6.34 (d, 1H, J = 1.0 Hz), 6.35 (d, 1H, J = 1.0 Hz), 6.13−
6.11 (m, 4H), 4.54 (d, J = 15.0 Hz, 1H), 4.48 (d, J = 15.0 Hz, 1H),
4.38−4.34 (m, 1H), 4.17−4.14 (m, 1H), 4.12−4.11 (m, 1H), 4.01 (s,
1H), 3.88 (s, 1H), 3.36 (d, J = 11.5 Hz, 1H), 3.14 (d, J = 11.5 Hz, 1H),
1.51 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 151.5, 149.9, 128.5,
127.4, 110.0, 108.4, 105.6, 103.0, 102.8, 65.9, 65.2, 64.9, 63.9, 63.7,
62.9, 61.5, 60.1, 42.3, 33.5. Coincident carbon peaks. Further elution
gave (3R*,4R*,5S*)-3,4-dibromo-5-methyl-4,5-dihydro-3H-2,5-
methano[1,3]dioxolo[4′,5′:4,5]benzo[1,2-f ][1,2]thiazepine 1,1-diox-
ide 16b (15 mg, 38%) as a white solid. Rf = 0.5 (c-Hex:EtOAc,
3:1). HRMS (ESI): calcd for C12H12NO4S79Br2 ([M + H])+ 423.8854,
found 423.8844.
(5S*,10S*)-10-Bromo-7,8-dimethoxy-4-methylene-4,5-dihy-
dro-3H-2,5-methanobenzo[f ][1,2]thiazepine 1,1-Dioxide 17a.
A mixture of 13a (40 mg, 0.14 mmol, 1 equiv) and N-
bromosuccinimide (27 mg, 0.154 mmol, 1.1 equiv) in CHCl3 (0.8
mL, 0.178 M) was heated (oil bath temperature 80 °C) in a sealed
tube for 15 h. Once cooled, CH2Cl2 (10 mL) and H2O (10 mL) were
added and the layers partitioned. The organic layer was washed
successively with H2O and brine and dried over MgSO4. Filtration
followed by solvent removal under reduced pressure gave the crude
product, which was purified by flash column chromatography (c-
Hex:EtOAc, 4:1) affording the title compound 17a (45 mg, 90%) as a
colorless solid. Rf = 0.3 (c-Hex:EtOAc, 2:1). Mp: 48−50 °C. IR (KBr,
dep from CH2Cl2): 3063, 2938, 2848, 1704, 1599, 1511, 1343, 1268,
1173, 1151, 1047, 1047, 916, 753 cm−1. HRMS (ESI): calcd for
4.0 Hz, 1H), 6.22 (d, J = 4.0 Hz, 1H), 6.01−6.00 (m, 2H), 4.36 (d, J =
12.0 Hz, 1H), 3.74 (d, J = 12.0 Hz, 1H), 1.49 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 150.1, 148.1, 140.7, 138.2, 133.8, 125.8, 107.6,
103.9, 102.1, 68.9, 45.2, 17.7.
(4R*,5S*,10S*)-4,10-Dibromo-7,8-dimethoxy-4-methyl-4,5-
dihydro-3H-2,5-methanobenzo[f ][1,2]thiazepine 1,1-Dioxide
14a and (4R*,5S*,10S*)-4,10-Dibromo-4-(bromomethyl)-7,8-
dimethoxy-4,5-dihydro-3H-2,5-methanobenzo[f ][1,2]-
thiazepine 1,1-Dioxide 15a. A solution of alkene 13a (40 mg, 0.142
mmol, 1 equiv) in CHCl3 (0.8 mL) was treated with bromine (0.7 mL,
1.42 mmol, 10 equiv) at −60 °C (dry ice−acetone cold bath) and
allowed to stir for 15 h during which time room temperature was
reached. The reaction was quenched with aq sat. Na2S2O3 solution (10
mL) and extracted with CH2Cl2 (3 × 10 mL), and the combined
organic layers were dried (MgSO4). Filtration, followed by solvent
removal under reduced pressure, gave the crude product, which was
purified by flash column chromatography (c-Hex:EtOAc, 5:1),
affording compounds 14a and 15a (37 mg, 55%) as a chromato-
graphically inseparable mixture (14a:15a; 1:1). Rf = 0.5 (c-Hex:EtOAc,
3:1). IR (KBr, dep from CH2Cl2): 3010, 2960, 2937, 2849, 1598, 1509,
1
C13H15NO4S79Br ([M + H])+ 359.9905, found 359.9918. H NMR
(CDCl3, 400 MHz): δ 7.18 (s, 1H), 6.64 (s, 1H), 6.30 (s, 1H), 5.35 (s
(br), 1H), 5.11 (s (br), 1H), 4.43−4.25 (m, 2H), 3.93 (s, 3H), 3.90 (s,
3H), 3.87 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 153.2, 149.9,
144.6, 130.6, 125.6, 109.4, 108.3, 107.5, 67.3, 57.7, 56.5, 50.1. Anal.
Calcd for C13H14NO4BrS: C, 43.35; H, 3.92; N, 3.89. Found: C, 43.20;
H, 3.62; N, 3.71.
Method Using Bromine. A solution of alkene 13a (30 mg, 0.107
mmol, 1 equiv) in CHCl3 (0.6 mL) was treated with bromine (3.0 μL,
0.058 mmol, 0.55 equiv) at −60 °C (dry ice−acetone cold bath) and
allowed to stir for 15 h. Over this period room temperature was
reached and the reaction was quenched with aq sat. Na2S2O3 solution
(10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried (MgSO4). Filtration, followed by solvent
removal under reduced pressure, gave the crude product, which was
purified by flash column chromatography (c-Hex:EtOAc, 4:1)
affording the title compound 17a (19 mg, 50%) as a colorless solid
with data as above.
1464, 1347, 1271, 1154 cm−1
. HRMS (ESI): calcd for
C13H16NO4S79Br2 ([M + H])+ 439.9167, found 439.9146 (14a).
HRMS (ESI): calcd for C13H14NO4S79Br2 ([M − HBr + H])+
1
437.9010, found 437.9019 (15a). H NMR (CDCl3, 400 MHz): δ
7.21 (s, 1H), 7.19 (s, 1H), 6.94 (s, 1H), 6.67 (s, 1H), 6.36 (s, 1H),
6.35 (s, 1H), 4.58 (d, J = 15.5 Hz, 1H), 4.49 (d, J = 15.0 Hz, 1H),
4.38−4.35 (m, 1H), 4.33−4.31 (m, 1H), 4.18−4.14 (m, 1H), 4.12−
4.11 (m, 1H), 4.05 (s, 1H), 3.97−3.92 (m, 13H), 3.41 (d, J = 11.5 Hz,
1H), 3.04 (d, J = 11.5 Hz, 1H), 1.48 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 152.8, 152.1, 150.9, 150.4, 128.4, 126.9, 126.7, 126.3, 112.6,
110.5, 107.4, 65.8, 65.6, 65.5, 64.0, 62.8, 61.7, 60.7, 56.7, 43.3, 33.6.
Further elution gave (3R*,4,R*,5S*)-3,4-dibromo-7,8-dimethoxy-5-
methyl-4,5-dihydro-3H-2,5-methanobenzo[f ][1,2] thiazepine 1,1-di-
oxide 16a (21 mg, 33%) as a white solid. Rf = 0.5 (c-Hex:EtOAc,
2:1). HRMS (ESI): calcd for C13H15NO4S79Br2Na ([M + Na])+
461.8981, found 461.8988.
(4R*,5S*,11S*)-4,11-Dibromo-4-methyl-4,5-dihydro-3H-2,5-
methano[1,3]dioxolo[4′,5′:4,5]benzo[1,2-f ][1,2]thiazepine 1,1-
Dioxide 14b and (4R*,5S*,11S*)-4,11-Dibromo-4-(bromo-
methyl)-4,5-dihydro-3H-2,5-methano[1,3]-dioxolo[4′,5′:4,5]-
benzo[1,2-f ][1,2]thiazepine 1,1-Dioxide 15b. A solution of
alkene 13b (30 mg, 0.094 mmol, 1 equiv) in CHCl3 (1 mL) was
treated with bromine (0.05 mL, 0.94 mmol, 10 equiv) at −60 °C (dry
ice−acetone cold bath) and allowed to stir for 15 h, over which time
room temperature was reached. An aq sat. Na2S2O3 solution (10 mL)
(5S*,10S*)-10-Iodo-7,8-dimethoxy-4-methylene-4,5-dihy-
dro-3H-2,5-Methanobenzo[f][1,2]thiazepine 1,1-Dioxide 18a.
A mixture of 13a (40 mg, 0.14 mmol, 1 equiv) and N-iodosuccinimide
(39 mg, 0.18 mmol, 1.25 equiv) in CHCl3 (0.8 mL, 0.178 M) was
heated (oil bath temperature 80 °C) in a sealed tube for 15 h. Once
cooled, CH2Cl2 (10 mL) and H2O (10 mL) were added and the layers
partitioned. The organic layer was washed successively with H2O and
brine and dried over MgSO4. Filtration followed by solvent removal
under reduced pressure gave the crude product, which was purified by
flash column chromatography (c-Hex:EtOAc, 4:1), affording the title
compound 18a (47 mg, 82%) as a colorless solid. Rf = 0.3 (c-
Hex:EtOAc, 2:1). Mp: 174−176 °C. IR (KBr, dep from CH2Cl2):
2882, 1598, 1508, 1463, 1339, 1267, 1219, 1150, 1046, 1011, 912, 746,
639 cm−1. HRMS (ESI): calcd for C13H14NO4SINa ([M + Na])+
1
429.9599, found 429.9586. H NMR (CDCl3, 400 MHz): δ 7.18 (s,
1H), 6.61 (s, 1H), 6.60 (s, 1H), 5.34−5.33 (m, 1H), 5.13 (s, 1H),
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4.42−4.29 (m, 2H), 3.95−3.89 (m, 7H). 13C NMR (CDCl3, 100
MHz): δ 152.8, 149.9, 145.5, 130.8, 125.6, 109.0, 107.9, 107.7, 59.8,
56.4, 50.4, 42.4.
cm−1. HRMS (ESI): calcd for C15H19NO4S79Br ([M + H])+ 388.0218,
found 388.0235. 1H NMR (CDCl3, 400 MHz): δ 7.60 (s, 1H), 7.13 (s,
1H), 6.10 (s, 2H), 5.47 (s (br), 1H), 5.06 (t, J = 6.0 Hz, 1H), 2.94 (q, J
= 6.0 Hz, 2H), 2.11 (t, J = 6.0 Hz, 2H), 1.99 (s (br), 2H), 1.76 (s (br),
2H), 1.67−1.48 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 151.5,
147.4, 133.3, 131.9, 125.1, 114.4, 112.2, 111.6, 102.9, 40.6, 37.1, 27.5,
25.2, 22.6, 22.2.
(5S*,11S*)-11-Bromo-4-methylene-4,5-dihydro-3H-2,5-
methano[1,3]dioxolo[4′,5′:4,5]benzo[1,2-f ][1,2]thiazepine 1,1-
Dioxide 17b. A mixture of 13b (40 mg, 0.15 mmol, 1 equiv) and N-
bromosuccinimide (269 mg, 1.51 mmol, 10 equiv) in CHCl3 (0.85
mL, 0.178 M) was heated (oil bath temperature 80 °C) in a sealed
tube for 15 h. Once cooled, CH2Cl2 (10 mL) and H2O (10 mL) were
added and the layers partitioned. The organic layer was washed
successively with H2O and brine and dried over MgSO4. Filtration,
followed by solvent removal under reduced pressure, gave the crude
product, which was purified by flash column chromatography (c-
Hex:EtOAc, 4:1), affording the title compound 17b (22 mg, 42%) as a
light brown solid. Rf = 0.5 (c-Hex:EtOAc, 3:1). Mp: 211−213 °C. IR
(KBr, dep from CH2Cl2): 2918, 1614, 1504, 1481, 1342, 1246, 1159,
1120, 1036, 916, 668 cm−1. HRMS (ESI): calcd for C12H11NO4S79Br
([M + H])+ 343.9583, found 343.9592. 1H NMR (CDCl3, 400 MHz):
δ 7.16 (s, 1H), 6.66 (s, 1H), 6.29 (s, 1H), 6.06 (d, J = 1.5 Hz, 1H),
6.05 (d, J = 1.5 Hz, 1H), 5.33−5.31 (m, 1H), 5.12 (s (br), 1H), 4.43−
4.25 (m, 2H), 3.83 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 151.8,
148.5, 144.4, 132.3, 127.1, 109.2, 106.2, 105.6, 102.6, 66.9, 57.9, 49.9.
(4S*,5S*)-7,8-Dimethoxy-4-methyl-4,5-dihydro-3H-2,5-
methanobenzo[f ][1,2]thiazepine 1,1-Dioxide 19a. A solution of
17a (100 mg, 0.28 mmol, 1 equiv) in anhydrous toluene (6 mL) was
treated with n-Bu3SnH (0.097 mL, 0.363 mmol, 1.3 equiv) and AIBN
(cat.). The reaction mixture was heated to reflux for 15 h (oil bath
temperature 110 °C). Once cooled, Et2O (50 mL) and 2% KF
solution (100 mL) were added, and the reaction mixture was stirred
for 2 h, after which the layers were separated. The aqueous layer was
extracted with Et2O (2 × 50 mL), and the combined ethereal layers
were dried (MgSO4). Filtration followed by solvent removal gave the
crude material, which was purified by column chromatography (c-
Hex:EtOAc, 4:1) to afford the debrominated compound (33 mg, 42%)
as a brown viscous oil. [7,8-Dimethoxy-4-methylene-4,5-dihydro-3H-
2,5-methanobenzo[f ][1,2] thiazepine 1,1-dioxide: Rf = 0.3 (c-
Hex:EtOAc, 2:1). HRMS (ESI): calcd for C13H16NO4S ([M + H])+
1-((6-Bromobenzo[d][1,3]dioxol-5-yl)sulfonyl)-2,4,5,6,7,7a-
hexahydro-1H-indole 22b. A solution of 21b (1.0 g, 2.58 mmol, 1.0
equiv) in distilled MeCN (20 mL) was treated with powdered K2CO3
(1.31 g, 9.48 mmol, 3.6 equiv). The mixture was stirred for 1 h at
room temperature. Finely ground I2 (907 mg, 9.48 mmol, 3.6 equiv)
was added in one portion and the reaction stirred for 4 h. A solution of
sat. Na2SO3 (50 mL) was added and the combined mixture was
extracted with CH2Cl2 (2 × 50 mL). The combined extracts were
dried over MgSO4, filtered, and reduced under pressure to afford the
crude iodide. The crude material was directly dissolved in CH2Cl2 (30
mL) and treated with DBU (0.77 mL, 5.16 mmol, 2.0 equiv) at room
temperature. Stirring was maintained for 2 h before 1 M HCl (15 mL)
was added, and the layers were separated. The resulting aqueous layer
was extracted with CH2Cl2 (2 × 20 mL), and the combined organic
layers were dried over MgSO4. The crude product, obtained after
filtration, solvent removal, and purification by column chromatography
(c-Hex:EtOAc, 4:1), was 22b (750 mg, 75%), a brown viscous oil. Rf =
0.5 (c-Hex:EtOAc, 2:1). IR (KBr, dep from CH2Cl2): 2933, 2853,
1610, 1505, 1475, 1368, 1327, 1242, 1166, 1142, 1082, 1034, 922, 671
cm−1. HRMS (ESI): calcd for C15H16NO4S79BrNa ([M + Na])+
1
407.9876, found 407.9880. H NMR (CDCl3, 400 MHz): δ 7.51 (s,
1H), 7.14 (s, 1H), 6.08 (s, 2H), 5.26 (s (br), 1H), 4.31−4.25 (m, 2H),
4.22−4.18 (m, 2H), 2.50−2.44 (m, 2H), 2.20−2.16 (m, 2H), 2.00−
1.96 (m, 2H), 1.32−1.19 (m, 3H). 13C NMR (CDCl3, 100 MHz): δ
151.4, 147.8, 142.1, 132.8, 115.2, 114.3, 113.6, 111.3, 102.9, 66.5, 55.5,
35.6, 28.6, 26.5, 24.0.
2,3,4,4a-Tetrahydro-1H-5,11b-etheno[1,3]dioxolo[4′,5′:4,5]-
benzo[1,2-e]benzo[c][1,2]thiazine 6,6-Dioxide 23b. Under N2, a
premixed solution (1 h at 50 °C) of Pd(dba)2 (8 mg, 0.014 mmol, 10
mol %) and t-BuBrett-Phos (13 mg, 0.03 mmol, 21 mol %) in
anhydrous DMF (2 mL) was treated with a solution of 22b (53 mg,
0.14 mmol, 1 equiv) in anhydrous DMF (0.5 mL) and K2CO3 (39 mg,
0.28 mmol, 2 equiv), and the mixture was heated to 110 °C for 15 h.
The reaction vessel was cooled, and EtOAc (10 mL) and H2O (10
mL) were added. The resultant aqueous layer was further extracted
with EtOAc (2 × 10 mL), and the combined organic extracts were
dried over MgSO4. Filtration followed by solvent removal under
reduced pressure gave the crude product, which was purified by flash
column chromatography (c-Hex:EtOAc, 6:1→1:1), affording the Heck
product 23b (17 mg, 40%, 80% brsm) as a light brown viscous oil. Rf =
0.3 (c-Hex:EtOAc, 2:1). IR (KBr, dep from CH2Cl2): 2932, 1609,
1504, 1482, 1346, 1249, 1176, 1161, 1036, 944, 757, 673 cm−1. HRMS
(ESI): calcd for C15H16NO4S ([M + H])+ 306.0800, found 306.0809.
1H NMR (CDCl3, 400 MHz): δ 7.14 (s, 1H), 6.70 (s, 1H), 6.20 (d, J =
1
282.0800, found 282.0812. H NMR (CDCl3, 400 MHz): δ 7.20 (s,
1H), 6.65 (s, 1H), 5.19 (s, 1H), 4.93 (s, 1H), 4.29 (dd, J = 12.5 Hz, 2.5
Hz, 1H), 4.02−3.97 (m, 1H), 3.93 (s, 3H), 3.90 (s, 4H), 3.53−3.51
(m, 1H), 3.44 (dd, J = 12.5, 3.0 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ 152.5, 149.9, 148.3, 132.6, 125.7, 108.7, 108.1, 106.7, 57.6,
56.4, 56.3, 52.3, 47.1.] A mixture of the alkene (18 mg, 0.064 mmol,
1.0 equiv) and 20% w/w Pd/C (1.4 mg, 0.013 mmol) in EtOH:EtOAc
(1:1, 10 mL) was stirred under an atmosphere of hydrogen (1 atm) for
15 h. The mixture was filtered through Celite (washed with EtOAc, 3
× 20 mL) and solvent removal afforded the alkane compound 19a (16
mg, 89%) as a colorless viscous oil. Rf = 0.3 (c-Hex:EtOAc, 2:1). IR
(KBr, dep from CH2Cl2): 2958, 2924, 2853, 1602, 1509, 1463, 1322,
1264, 1146 cm−1. HRMS (ESI): calcd for C13H17NO4SNa ([M +
1
Na])+ 306.0776, found 306.0768. H NMR (CDCl3, 400 MHz): δ
7.22 (s, 1H), 6.56 (s, 1H), 4.26 (dd, J = 12.5, 1.5 Hz, 1H), 3.90 (s,
6H), 3.66 (dd, J = 13.5, 9.5 Hz, 1H), 3.34 (dd, J = 3.0, 1.5 Hz, 1H),
3.26−3.22 (m, 1H), 2.94−2.92 (m, 1H), 2.69−2.60 (m, 1H), 0.78 (d, J
= 7.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 151.7, 149.1, 129.9,
127.3, 111.2, 108.2, 58.2, 56.3, 54.0, 44.6, 38.9, 16.4.
3.5 Hz, 1H), 6.12 (d, J = 3.5 Hz, 1H), 6.00 (app. d, J = 4.5 Hz, 2H),
4.46−4.42 (m, 1H), 2.36 (d, J = 13.5 Hz, 1H), 2.16−2.10 (m, 1H),
1.88−1.49 (m, 4H), 1.42−1.09 (m, 2H). 13C NMR (CDCl3, 100
MHz): δ 150.1, 147.8, 140.8, 138.3, 132.8, 126.4, 107.4, 103.4, 102.1,
72.4, 48.6, 28.5, 27.7, 22.9, 21.7.
6-Bromo-N-(2-(cyclohex-1-en-1-yl)ethyl)benzo[d][1,3]-
dioxole-5-sulfonamide 21b. A mixture of sulfonyl chloride 11b
(600 mg, 2.02 mmol, 1.0 equiv) and 2-cyclohex-1-enyethylamine (0.37
mL, 2.42 mmol, 1.2 equiv) in CH2Cl2 (15 mL) was treated with Et3N
(0.34 mL, 2.42 mmol, 1.2 equiv) in a dropwise fashion at 0 °C. Stirring
was continued for 15 h during which period room temperature was
reached. HCl (1 M, 10 mL) was added to the reaction mixture, and
the layers were separated. The organic layer was washed successively
with sat. NaHCO3 (10 mL), H2O (10 mL), and brine and was dried
over MgSO4. Filtration followed by solvent removal under pressure
afforded the crude product. Purification through a plug of silica (c-
Hex:EtOAc, 2:1) afforded the title compound (743 mg, 95%) as a
brown viscous oil. Rf = 0.2 (c-Hex:EtOAc, 4:1). IR (KBr, dep from
CH2Cl2): 2925, 1504, 1475, 1369, 1329, 1243, 1167, 1136, 1034, 653
(6aR*,9S*,11S*,12S*)-9,12-Dibromo-2,3-dimethoxy-
7,8,9,11-tetrahydro-6aH-6,11-methanodibenzo[c,f ][1,2]-
thiazepine 5,5-Dioxide 24a. A solution of 23a (18 mg, 0.056 mmol,
1 equiv) in CHCl3 (0.8 mL, 0.178 M) was treated with Br2 (57 μL,
1.12 mmol, 20 equiv) at −60 °C (dry ice−acetone cold bath) and
allowed to stir at this temperature for 1.5 h (reaction monitored by
TLC). The reaction was quenched with aq sat. Na2S2O3 solution (10
mL) and the reaction mixture allowed to warm to room temperature.
The reaction micture was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic layers were dried (MgSO4). Filtration followed by
solvent removal under reduced pressure gave the crude product, which
was purified by flash column chromatography (c-Hex:EtOAc, 4:1),
affording initially (6aR*,10aR*,11R*,12S*)-11,12-dibromo-2,3-dime-
thoxy-7,8,9,10-tetrahydro-6aH-6,10a-ethanodibenzo[c,e][1,2]thiazine
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5,5-dioxide 25a (3 mg, 11%) as a white solid. Rf = 0.6 (c-Hex:EtOAc,
2:1). HRMS (ESI): calcd for C16H19NO4S79Br2Na ([M + Na])+
501.9294, found 501.9314. Further elution gave title compound 24a
(21 mg, 77%) as a colorless solid. Rf = 0.5 (c-Hex:EtOAc, 2:1). Mp:
181−183 °C. IR (KBr, dep from CH2Cl2): 2932, 1609, 1504, 1482,
1346, 1249, 1176, 1161, 1036, 944, 757, 673 cm−1. HRMS (ESI): calcd
for C16H18NO4S79Br2 ([M + H])+ 477.9323, found 477.9332. 1H
NMR (CDCl3, 400 MHz): δ 7.19 (s, 1H), 6.62 (s, 1H), 6.35 (s, 1H),
6.17 (s, 1H), 4.90 (s, 1H), 4.38−4.32 (m, 1H), 3.92 (s, 3H), 3.91 (s,
3H), 3.86 (s (br), 1H), 2.46−2.39 (m, 2H), 2.33−2.26 (m, 1H), 2.18−
2.08 (m, 1H). 13C NMR (CDCl3, 100 MHz): δ 159.2, 150.6, 140.2,
128.2, 126.1, 125.1, 109.6, 108.0, 66.8, 59.3, 56.6, 56.5, 56.1, 46.4, 32.3,
24.3.
(6aR*,9S*,11S*,13S*)-9,13-Dibromo-7,8,9,11-tetrahydro-
6aH-6,11-methano-[1,3]-dioxolo[4′,5′:4,5]benzo[1,2-f ]benzo-
[c][1,2]thiazepine 5,5-Dioxide 24b. A solution of 23b (20 mg,
0.066 mmol, 1 equiv) in CHCl3 (0.35 mL, 0.178 M) was treated with
Br2 (64 μL, 1.24 mmol, 20 equiv) at −60 °C (dry ice−acetone cold
bath) and allowed to stir at this temperature for 1.5 h. The reaction
was quenched with aq sat. Na2S2O3 solution (10 mL) and the solution
allowed to warm to room temperature. The mixture was extracted with
CH2Cl2 (3 × 10 mL), and the combined organic layers were dried
(MgSO4). Filtration followed by solvent removal under reduced
pressure gave the crude product, which was purified by flash column
chromatography (c-Hex:EtOAc, 4:1), affording initially
(5aR*,11bR*,12R*,13S*)-12,13-dibromo-2,3,4,4a-tetrahydro-1H-
5,11b-ethano[1,3]dioxolo[4′,5′:4,5]benzo[1,2-e]benzo[c][1,2]thiazine
6,6-dioxide 25b (5 mg, 16%) as a colorless solid. Rf = 0.5 (c-
Hex:EtOAc, 2:1). HRMS (ESI): calcd for C15H15NO4S79Br2Na ([M +
Na])+ 485.8981, found 485.8992. Further elution gave the title
compound 24b (12 mg, 40%) as a colorless solid. Rf = 0.4 (c-
Hex:EtOAc, 2:1). Mp: 172−175 °C. IR (KBr, dep from CH2Cl2):
2960, 2923, 1609, 1504, 1481, 1342, 1249, 1178, 1160, 1036, 944, 821,
756 cm−1. HRMS (ESI): calcd for C15H13NO4S79Br2Na ([M + Na])+
483.8824, found 483.8841. 1H NMR (CDCl3, 400 MHz): δ 7.17
(s,1H), 6.65 (s, 1H),6.34 (s, 1H), 6.14 (s, 1H), 6.07−6.05 (m, 2H),
4.09 (s (br), 1H), 4.38−4.31 (m, 1H), 3.82 (s, 1H), 2.48−2.38 (m,
2H), 2.32−2.26 (m, 1H), 2.17−2.08 (m, 1H). 13C NMR (CDCl3, 100
MHz): δ 151.9, 148.7, 139.9, 129.9, 127.7, 125.7, 107.7, 106.2, 102.3,
66.4, 59.2, 56.8, 48.5, 32.5, 24.1. Crystals suitable for X-ray diffraction
were obtained from (CH2Cl2−c-Hex).
REFERENCES
■
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ASSOCIATED CONTENT
J. C.; Estev
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■
M. A.; Per
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* Supporting Information
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̈
Copies of proton and carbon NMR spectra, NOE correlation
for compounds 14, 15, and 19 and X-ray crystallographic data
for 13b and 24b. This material is available free of charge via the
Internet at: http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.evans@ucd.ie. Tel: +353-1-716-2291
(11) Bromination charge-transfer complex which is susceptible to
concentration of molecular bromine: Ruasse, M.-F. Adv. Phys. Org.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors would like to thank University College Dublin for
financial support and the National University of Ireland for an
NUI Travelling Studentship (K.G.). We also thank Dr. Helge
Muller-Bunz for X-ray crystallography and Drs. Yannick Ortin
̈
and Dilip Rai for assistance with NMR spectroscopy and mass
spectrometry, respectively. Ms. Lenka Fujakova and Mr.
Chigozie Achara are thanked for efforts associated with the
synthesis of 11b. Membership (P.E.) of COST action CM0804
is acknowledged.
(16) CCDC 947372 available via www.ccdc.cam.ac.uk.
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