Enantioselective synthesis of dihydro-1 H -benzindoles

Article abstract of DOI:10.1021/jo302798j

The first examples of dihydro-1H-benzindoles by enantioselective γ-lactamization reaction of naphthyl sulfilimines with trichloroacetyl chloride in the presence of ZnCu as catalyst (≥98:2 er and 65-80% yields) are described. Products are obtained by [3,3]-sigmatropic rearrangement of the azasulfonium enolate or followed by a second allylic rearrangement that transfers chirality. The absolute stereochemistry was confirmed by X-ray crystallography, which provides support for the mechanisms proposed.

Full text of DOI:10.1021/jo302798j

Note
pubs.acs.org/joc
Enantioselective Synthesis of Dihydro‑1H‑benzindoles
Gustavo P. Silveira*,⊥ and Joseph P. Marino
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: The first examples of dihydro-1H-benzindoles
by enantioselective γ-lactamization reaction of naphthyl
sulfilimines with trichloroacetyl chloride in the presence of
ZnCu as catalyst (≥98:2 er and 65−80% yields) are described.
Products are obtained by [3,3]-sigmatropic rearrangement of
the azasulfonium enolate or followed by a second allylic
rearrangement that transfers chirality. The absolute stereo-
chemistry was confirmed by X-ray crystallography, which provides support for the mechanisms proposed.
otwithstanding the structural similarity of the sulfilimine
and the sulfoxides, sulfilimines have received less
Then, (S)-sulfilimines 1 and 2 were separately evaluated as γ-
lactamization reagents.19 Reaction of the 1-naphthylsulfilimine
1 with trichloroacetyl chloride, in the presence of zinc−copper
couple as catalyst, in dry THF (−30 °C, 30 min) gave the
(3R,9S)-S-isopropylbenzo[g]indolone 6 in a 65−70% yields
(Scheme 2). Crystallization of naphthyl-γ-lactam 6 by slow
N
attention than sulfoxides as key intermediates in the synthesis
of bioactive molecules.1−4 Over the past three decades, our
group has developed the reaction between chiral vinyl
sulfoxides and dichloroketene as a versatile synthesis of γ-
lactones.5−8 This reaction was pivotal in the synthesis, by our
group9,10 and by others,11−13 of various natural and medicinally
useful compounds. As an extension of this reaction, we14 and
Padwa et al.15,16 used vinylsulfilimines to prepare racemic γ-
lactams. Herein we present the first example of the
enantioselective synthesis of naphthyl-γ-lactams prepared
through the reaction of naphthylsulfilimines with dichloroke-
tene.
Scheme 2. γ-Lactamization from Reaction of (S)-Sulfilimine
1 and Trichloroacetyl Chloride
The naphthylsulfilimines17 1 and 2 were synthesized by the
iodo exchange of 1- or 2-iodonaphthalene (3 or 4) with lithium
isopropylmagnesate followed by the reaction of the magnesium
ate complex18 formed from (R)-N-tosylisopropyloxazolidinone
sulfilimine 5 in 34% and 36% yields, respectively (Scheme 1).
evaporation of ethyl acetate/hexanes, at room temperature,
furnished white granular crystals ([α]20 = +10.1; c = 3.65,
D
CH2Cl2; er ≥99:1). X-ray analysis of these crystals confirmed
the (3R,9S) stereochemistry depicted in Scheme 2.
Scheme 1. Synthesis of Chiral Sulfilimines 1 and 2
In contrast, using the identical experimental conditions as for
1, the same γ-lactamization reaction using (S)-sulfilimine 2
unexpectedly gave the (5S,9R)-benzo[e]indolone 7 as product
in 77−80% yields (Scheme 3).20 Chiral NMR shift reagent
analysis demonstrated this γ-lactam [α]20 = +130; c = 1.6,
D
CHCl3) to have exceptional (er ≥99.5:0.5) enantiomeric purity.
The probable mechanism for the formation of (+)-7 follows
from previous studies.5−8 A [3,3]-sigmatropic rearrangement of
the azasulfonium enolate 8 sets the C-9 stereochemistry of the
intermediate 9. A second allylic rearrangement transfers the
chirality of the isopropylmercaptan group of 9 to give 7
(Scheme 4).
For the purposes of reaction optimization and isolation of a
racemate to verify enantiomeric purity, racemic γ-lactam 7 was
prepared from the racemic sulfilimine ( )-2.17 Unexpectedly,
Similar yields of sulfilimines 1 and 2 were obtained when this
one-pot reaction was carried out on a 2−5 mmol scale.
Compounds 1 and 2 were stored under argon at 4 °C for two
weeks without any decomposition. The chiral center was
assigned as being S by assuming that the sulfilimine is formed
by an SN2 mechanism.17
Received: January 8, 2013
© XXXX American Chemical Society
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Note
Scheme 3. Product of γ-Lactamization for the (S)-Sulfilimine
2 with Dichloroketene
Scheme 6. Proposed Mechanism for the Products 7, 10, and
11
Scheme 4. Proposed Mechanism for Formation of the Chiral
(5S,9R)-Benzoindolone 7
pure crystals of 10 were obtained (38% yield, ≥99.5:0.5 er by
chiral support HPLC and Eu(hfc)3 shift reagent titration,
([α]20 = 8.9; c = 1.2, CH2Cl2), Figure 1. Thus, from the
racemic mixture of compound ( )-10, both enatiomers (+)-10
and (−)-10 selectively crystallized (Scheme 7).
D
the use of longer reaction times and higher temperature (30
min at −30 °C, but allowing the reaction to warm overnight to
room temperature) diminished the isolated yield of 7 to 19%,
with the appearance of two new products. The major product
of the two (isolated yield of 52%) was the S-isopropyl
benzo[e]indolone ( )-10. The third and minor product
(isolated yield 10%) was the aromatic γ-lactam 11 (Scheme
5).21
a
Scheme 5. Products Obtained for γ-Lactamization of ( )-2
a
Reaction conditions: trichloroacetyl chloride, ZnCu couple (5 and 20
Figure 1. X-ray structure for the benzoindolone (5R,9bS)-10.
equiv, respectively), THF dry, 16 h, rt.
However, when the crystals of 10 were resolubilized in ethyl
acetate/hexanes and the yellow solution was allowed to
These observations are consistent with an equilibrium
between γ-lactams 7 and 9 and with 7 as the more stable
isomer. Nonetheless, 9 is the pivotal intermediate leading from
7 to 10 and 11. After the [3,3]-sigmatropic rearragement of the
isopropylmercaptan, intermediate 9 reacts with a second
molecule of dichloroketene resulting to a new [3,3]-sigmatropic
rearrangement yielding benzoindolone 10. Concurrently,
intermediate 9 undergoes gradual aromatization by elimination
of the isopropylmercaptan to give γ-lactam 11 as the overall
themodynamic product (Scheme 6).
Scheme 7. Spontaneous Chiral Crystallization of the
Racemic Benzoindolone ( )-10
Recrystallization of the benzoindolone ( )-10 by slow
evaporation, at room temperature, using 15% of ethyl
acetate/hexanes gave rodlike/blocklike pale yellow crystals.
To our surprise, the X-ray analysis showed that enantiomeric
B
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Note
was washed with 25 mL of brine, dried with MgSO4, and then filtered.
The solvent was removed under rotovap, and the colorless oil was
purified through flash chromatography with elution by 4:6 ethyl
acetate/hexanes. The less polar fraction afforded 5.55 g of the (S)-
sulfilimine 5 (44% yield) as white crystals, and the more polar fraction
gave 4.79 g of the (R)-sulfilimine 5 (38% yield) as colorless bricklike
crystals by slow evaporation of the mixture of solvents at room
evaporate at room temperature for more than 24 h a dark
solution was formed indicating that elimination was occurring
to furnish the thermodynamic product 11.
Finally, the racemic sulfilimine ( )-2 was reacted under
standard lactamization conditions (quench after 30 min of
reaction instead of allowing the reaction to warm overnight to
room temperature) and the expected racemic γ-lactam ( )-7
was obtained in 88% yield.
temperature.
1
(R)-5: mp = 123−124 °C; [α]20 = −391 (c = 0.68, CHCl3); H
D
In conclusion, we have disclosed the first example of an
enantioselective γ-lactamization reaction between naphthylsul-
filimine isomers and trichloroacetyl chloride. We are currently
exploring this reaction for the synthesis of natural products,22,23
and our results will be reported in due course.
NMR (300 MHz, CDCl3) δ ppm 0.90 (d, J = 6.46 Hz, 3 H), 1.27 (d, J
= 7.04 Hz, 3 H), 1.37 (d, J = 7.04 Hz, 3 H), 2.42 (s, 3 H), 4.56−4.61
(m, 1 H), 4.64 (spt, J = 7.04 Hz, 1 H), 5.49 (d, J = 7.92 Hz, 1 H), 7.18
(m, 2 H), 7.29 (m, 2 H), 7.37−7.43 (m, 3 H), 7.83 (d, J = 8.22 Hz, 2
H); 13C NMR (75 MHz, CDCl3) δ ppm 16.3, 17.0, 17.3, 21.3, 51.4,
56.6, 80.4, 80.6, 125.8, 126.3, 128.2, 128.5, 128.9, 129.3, 133.0, 140.0,
142.4, 153.6; HRMS (ESI) m/z calcd 421.1250 for C20H24N2O4S2,
EXPERIMENTAL SECTION
found 421.1256.
■
1
(S)-5: mp = 147−148 °C; [α]20 = −198.5 (c = 0.85, CHCl3); H
D
Commercial grade reagents and solvents were used without further
purification except as indicated below. Anhydrous tetrahydrofuran
(THF) was distilled from sodium and benzophenone. Reactions were
carried out in oven- or flame-dried glassware under an atmosphere of
dry argon only when specified in the experimental details. All reactions
were magnetically stirred and monitored by analytical thin-layer
chromatography using silica gel 60 F-254 plates. Visualization was
accomplished by UV light (256 nm), and phosphomolybdic acid 10%
solution. Flash chromatography was performed by mixing the crude
with silica gel 60 (230−400 mesh) in a proportion of 1:4 using a
NMR (300 MHz, CDCl3) δ ppm 0.90 (d, J = 6.80 Hz, 3 H), 1.29 (d, J
= 6.80 Hz, 3 H), 1.35 (d, J = 6.97 Hz, 3 H), 2.41 (s, 3 H), 3.41 (spt, J
= 6.80 Hz, 1 H), 4.74 (pt, J = 7.13 Hz, 1 H), 5.45 (d, J = 8.13 Hz, 1
H), 7.22 (dd, J = 7.46, 1.82 Hz, 2 H), 7.32 (d, J = 7.96 Hz, 2 H), 7.37−
7.44 (m, 3 H), 7.84 (d, J = 8.29 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ ppm 16.5, 17.4, 17.5, 20.1, 21.7, 50.6, 54.2, 82.1, 85.5, 126.1,
126.2, 127.0, 129.0, 129.2, 129.3, 129.8, 133.6, 139.4, 143.2, 158.4;
HRMS (ESI) m/z calcd 421.1250 for C20H24N2O4S2, found 421.1254.
General Preparation of Chiral 1- and 2-Naphthylsulfilimines.
n-BuLi (1.26 mL, 2.54 M in hexanes, 3.2 mmol) was added to 0.82 mL
of i-PrMgCl (1.95 M in THF, 1.6 mmol) at −5 °C, and the mixture
was allowed to stir until the Mg−ate complex was formed (15−30
min). The ate complex was cooled to −20 °C, and 1.6 mmol of iodide
in 4 mL of dry THF was transferred by cannula. The reaction mixture
was allowed to stir for another 30 min at −5 °C and recooled to −30
°C. Then, 420 mg of the sulfilimine chiral auxiliary 5 (0.7 equiv) in 10
mL of THF was added to the naphthyl Mg−ate complex. After 30 min
of reaction at −30 °C the mixture was quenched with 5 mL of
saturated NH4Cl and extracted with 15 mL of ethyl acetate. The
organic layer was washed with 10 mL of brine. Purification by flash
column chromatography with elution by ethyl acetate/hexanes 10−
60% provided a mixture of the desired product and Evan’s auxiliary in
a proportion of 55:45. Second purification of the mixture by flash
chromatography with elution by ethyl acetate/hexanes 30−60% gave
the desired product. Alternatively, the solid can be recrystallized by
slow evaporation at room temperature in a mixture of ethyl acetate/
hexanes.
1
SimpliFlash with BSR pump system. H NMR and 13C NMR spectra
were recorded at ambient temperature with the residual solvent and
TMS peaks as internal standards. The line positions of multiplets are
given in ppm (δ), and the coupling constants (J) are given as absolute
values in hertz. Infrared spectra were recorded with an FT-IR
spectrometer and reported as cm−1. X-ray diffraction analysis of a
single crystal was performed using a combination of ω- and φ-scans of
0.3°. Specific rotations were measured at 589 nm and 20 °C. All
melting points were recorded uncorrected. High-resolution mass
spectra (HRMS) were quantified with a LTQ-FT instrument using ES
ionization. Enentiomeric ratios (er) were determined using chiral
HPLC (0.02% of Et2NH was added to the spectroscopic ethanol) with
chiralcel OD column and detector at 235 nm or by Eu shift reagents.
Yields refer to chromatographically and spectrographically pure
compounds, unless otherwise noted.
(4R,5S)-3-(Isopropylthio)-4-methyl-5-phenyloxazolidin-2-
one (13). To a solution of 2.5 g of the Evan’s oxazolidinone24 (14.1
mmol) in 40 mL of dry THF at 0 °C was slowly added 1 equiv of n-
BuLi. The color of the solution turned from colorless to dark red. After
the reaction mixture was allowed to react for 30 min at 0 °C, a solution
of 2.5 g of S-isopropyl isopropanesulfonothioate25 (14.4 mmol) in 40
mL of dry THF was added by cannula, at once, and the reaction was
allowed to stir overnight at room temperature. The white mixture was
quenched with 50 mL of saturated NH4Cl and extracted with 50 mL of
ethyl acetate. The organic layer was washed with 50 mL of H2O and
brine, dried with MgSO4, and then filtered.26 The solvent was removed
via rotovap, and the colorless oil was purified through flash
chromatography with elution by 1:9 ethyl acetate/hexanes to provided
(S)-Isopropyl(4-methylphenylsulfonamido)(naphthalen-2-yl)-
1
sulfonium (1): 134 mg (36% yield); mp = 146−147 °C; H NMR
(300 MHz, CDCl3) δ ppm 1.15 (d, J = 6.70 Hz, 3 H), 1.21 (d, J = 6.70
Hz, 3 H), 2.27 (s, 3 H), 3.37 (sept, J = 6.70 Hz, 1 H), 7.07 (d, J = 8.61
Hz, 2 H), 7.54−7.66 (m, 3 H), 7.72 (d, J = 8.61 Hz, 2 H), 7.90−7.96
(m, 1 H), 8.00 (d, J = 8.61 Hz, 2 H), 8.06−8.12 (m, 1 H); 13C NMR
(75 MHz, CDCl3) δ ppm 15.1, 21.6, 53.7, 122.0, 125.8, 126.5, 128.3,
128.7, 129.4, 132.8, 135.2, 141.7; HRMS (ESI) m/z calcd for
C20H22NO2S2 372.1086, found 372.1086.
(S)-Iisopropyl(4-methylphenylsulfonamido)(naphthalen-1-yl)-
sulfonium (2). Chiral assay for 2 indicated ≥98:2% er according to
HPLC analysis with a Chiralpak OD column using EtOH/hexanes
15% (t = 12.4−14.0 min).
1
2.51 g of the oxazolidine sulfide 13 (73% yield) as a colorless oil: H
NMR (300 MHz, CDCl3) δ ppm 0.87 (d, J = 6.70 Hz, 3 H), 1.27 (d, J
= 6.94 Hz, 3 H), 1.32 (d, J = 6.70 Hz, 3 H), 3.36 (spt, J = 6.70 Hz, 1
H), 4.08−4.19 (m, 1 H), 5.65 (d, J = 7.89 Hz, 1 H), 7.23− 7.29 (m, 2
H), 7.31−7.44 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ ppm 15.6,
20.6, 21.3, 41.1, 60.5, 79.0, 126.1, 128.8, 128.8; HRMS (ESI) m/z
calcd for C13H17NO2S 251.0980, found 251.0985.
N-[(1E)-Ethyl[(4R,5S)-4-phenyl-5-methyl-2-oxo-1,3-oxazoli-
din-3-yl](1-methylethyl)-λ4-sulfanylidene]-4-methylbenzene-
sulfonamide ((R)- and (S)-5). To a solution of 7.54 g of the
oxazolidinone sulfide 13 (30 mmol) in 150 mL of CH3CN was added
10.15 g of chloramine-T (1.2 equiv), and the reaction mixture was
allowed to stir overnight at room temperature. A white solid was
formed on the bottom of the round flask. The reaction was quenched
with H2O and extracted with 25 mL of ethyl acetate. The organic layer
(R)-2: [α]20D = +227 (c = 3.46, CHCl3); 126 mg (34% yield). (S)-
2: [α]20D = −170 (c = 2.57, CHCl3); 119 mg (32% yield); mp = 129−
130 °C; 1H NMR (300 MHz, CDCl3) ppm 1.18 (d, J = 6.70 Hz, 3 H),
1.23 (d, J = 6.70 Hz, 3 H), 2.26 (s, 3 H), 3.28 (d, J = 6.70 Hz, 1 H),
7.09 (d, J = 8.61 Hz, 2 H), 7.53−7.66 (m, 3 H), 7.71−7.78 (m, 2 H),
7.81−7.96 (m, 3 H), 8.15 (d, J = 1.67 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ ppm 15.5, 16.9, 21.5, 54.5, 121.9, 126.4, 126.4, 127.8, 128.1,
128.8, 128.8, 129.2, 129.6, 129.6, 130.1, 132.7, 141.6; HRMS (ESI) m/
z calcd for C20H22NO2S2 372.1086, found 372.1086.
General Procedure to Prepare the Racemic Sulfilimines 1
and 2. Isopropyl(4-methylphenylsulfonamido)(naphthalen-2-yl)-
sulfonium (( )-2). To a solution of 577 mg of the naphthyl isopropyl
C
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Note
sulfide27 (2.85 mmol) in 25 mL of CH3CN, at room temperature, was
added 1.2 g of chloramine-T (1.5 equiv), and the reaction mixture was
allowed to stir overnight. The mixture was diluted with 20 mL of H2O,
and the organic phase was extracted with 25 mL of ethyl acetate and
washed with 20 mL of brine. The solvent was removed under rotovap,
and the colorless oil was purified through flash chromatography with
elution by (30−60% ethyl acetate/hexanes) to give 930 mg of the
naphthyl sulfilimine 2 (88% yield) as a white solid.
General Lactamization Procedure. To 480 mg of zinc powder
(7.35 mmol) in a dry flask equipped with a magnetic stir bar and a
condenser was added 728 mg of CuCl (7.35 mmol) and 4 mL of
anhydrous THF. The reaction mixture was refluxed under nitrogen
until the formation of a dark gray solid (1.5−2 h). The reaction was
cooled to the temperature indicated. To the zinc−copper mixture was
added 0.37 mmol of the respective naphthylsulfilimine in 3 mL of dry
THF by cannula and allowed to stir for 15 min. Finally, 205 μL of
trichloroacetyl (1.84 mmol) chloride was added via syringe pump
during 30 min. After the reaction mixture was allowed to stir for the
indicated time, it was filtered through a Celite pad into 5 mL of
sodium bicarbonate solution, followed by extraction with 20 mL of
ethyl acetate. The organic layer was washed with 10 mL of brine and
dried over magnesium sulfate. The solvent was removed via rotovap,
and the crude was purified by silica gel chromatography with ethyl
acetate/hexanes to give the desired lactam.
hexanes, and the solvents were slowly evaporated at room temperature
during 18 h to give 42 mg (19% yield) of (+)-10 and 42 mg (19%
yield) of (−)-10 as rodlike/blocklike pale yellow crystals. The
compound spontaneously chirally resolves upon crystallization. The
sample randomly selected was assigned as the (5R,9bS) enantiomer by
X-ray crystallography with Flack parameter = 0.02(3). An assay of
chirality indicated er ≥99.5:0.5 according to HPLC analysis with a
Chiralcel OD column using 3% EtOH/hexanes and Eu(hfc)3 shift
20
reagent titration: mp = 170 °C; [α]D = 8.9 (c = 1.2, CH2Cl2); IR
3115, 2978, 1785, 1700, 1653, 1392, 1189, 1172; 1H NMR (400 MHz,
CDCl3) δ ppm 1.40 (d, J = 6.97 Hz, 3 H), 1.42 (d, J = 6.97 Hz, 3 H),
2.46 (s, 3 H), 3.71 (spt, J = 6.91 Hz, 1 H), 4.46 (t, J = 2.65 Hz, 1 H),
4.81 (dd, J = 6.05, 2.74 Hz, 1 H), 6.74 (dd, J = 6.05, 2.74 Hz, 1 H),
7.34−7.40 (m, 3 H), 7.41−7.48 (m, 2 H), 7.89 (d, J = 7.63 Hz, 1 H),
8.01 (d, J = 8.62 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ ppm 22.1,
22.6, 37.7, 51.6, 52.8, 82.0, 95.1, 107.7, 126.8, 128.1, 128.5, 130.3,
130.9, 131.4, 131.6, 134.2, 136.0, 146.9, 164.2, 195.0; HRMS (ESI) m/
z calcd for C24H21Cl4NNaO4S2 613.9564, found 613.9558.
1,1-Dichloro-3-tosyl-1H-benzo[e]indol-2(3H)-one (11). Using
nonstandard (reaction time of 16 h, reaction temperature of 25 °C)
lactamization conditions, purification by flash column chromatography
with elution by 30% ethyl acetate/hexanes gave 15 mg (10% yield) of
the product 11 as dark green oil: IR 1771, 1574, 1518, 1378, 1262,
1
1178, 1089, 815; H NMR (600 MHz, CDCl3) δ ppm 2.45 (s, 3 H),
7.04 (ddd, J = 8.51, 7.04, 1.47 Hz, 1 H), 7.30−7.31 (m, 1 H), 7.31−
7.33 (m, 2 H), 7.69 (d, J = 8.51 Hz, 1 H), 7.76 (d, J = 9.10 Hz, 1 H),
7.78 (d, J = 8.22 Hz, 1 H), 7.83 (d, J = 8.80 Hz, 1 H), 7.84−7.85 (m, 1
H), 7.85−7.87 (m, 1 H); 13C NMR (150 MHz, CDCl3) δ ppm 21.8,
105.0, 112.5, 124.2, 125.2, 127.0, 128.3, 128.7, 129.5, 129.8, 131.4,
133.8, 134.4, 138.2, 145.9, 168.1; HRMS (ESI) m/z calcd for
C19H13Cl2NO3S 406.0066, found 406.0066.
(3aR,9bS)-3,3-Dichloro-9b-(isopropylthio)-1-tosyl-3,3a-dihydro-
1H-benzo[g]indol-2(9bH)-one (6). Using standard (reaction time of
30 min, reaction temperature of −30 °C) lactamization conditions,
purification by flash column chromatography with elution by ethyl
acetate/hexanes provided 116−125 mg of 6 as a colorless solid (65−
70% yields). Recrystallization by slow evaporation of ethyl acetate/
hexanes at room temperature gave white granular crystals which were
used to have the structure solved by X-ray crystallography with Flack
parameter = 0.01(3). Chiral assay indicated 98:2 er according to
HPLC analysis with a Chiralcel OD column using 3% EtOH/hexanes
(t = 9.6−10.6 min): mp = 143−144 °C dec; [α]20D = +10.1 (c = 3.65,
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray tables and discussions for (R)-5, (3R,9S)-6, and
(5R,9bS)-10, 1H and 13C NMR for the new compounds herein
presented, as well as chiral HPLC data for (S)-2, (3R,9S)-6, and
(5R,9bS)-10.] This material is available free of charge via the
Internet at http://pubs.acs.org.
1
CH2Cl2); IR 1754, 1371, 1225, 1174. H NMR (400 MHz, CDCl3) δ
ppm 0.45 (d, J = 6.80 Hz, 3 H), 1.30 (d, J = 7.13 Hz, 3 H), 2.48 (s, 3
H), 3.17 (spt, J = 6.97 Hz, 1 H), 3.26 (dd, J = 5.89, 0.75 Hz, 1 H), 6.03
(dd, J = 9.79, 5.80 Hz, 1 H), 6.90 (d, J = 9.79 Hz, 1 H), 7.16 (dd, J =
7.46, 1.33 Hz, 1 H), 7.35 (td, J = 7.46, 1.33 Hz, 1 H), 7.39 (d, J = 8.46
Hz, 2 H), 7.41−7.45 (m, 1 H), 8.04 (d, J = 7.80 Hz, 1 H), 8.25 (d, J =
8.46 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ ppm 22.0, 23.3, 24.5,
39.1, 59.1, 76.9, 77.2, 77.6, 118.3, 127.7, 128.0, 129.5, 129.5, 129.7,
130.2, 131.0, 131.4, 133.1, 135.1, 145.9, 164.9; HRMS (ESI) m/z calcd
for C22H21Cl2NNaO3S2 504.0238, found 504.0232.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gustavo.silveira@iq.ufrgs.br.
■
Present Address
Departamento de Quımica Organica, Instituto de Quımica,
Universidade Federal do Rio Grande do Sul, Porto Alegre/RS,
91501-970, Brazil.
(5S,9bR)-1,1-Dichloro-5-(isopropylthio)-3-tosyl-5,9b-dihydro-1H-
benzo[e]indol-2(3H)-one (7). Using standard (reaction time of 30
min, reaction temperature of −30 °C) lactamization conditions,
purification by flash column chromatography with elution by 15%
ethyl acetate/hexanes provided 137−143 mg (77−80% yields) of 7 as
colorless needle crystals, er ≥99.5:0.5 using Eu(FOD) + Ag(FOD).
(5S,9bR)-7 from (S)-2: [α]20D = +130 (c = 0.85, CHCl3). (5R,9bS)-
⊥
́
́
̂
Notes
The authors declare no competing financial interest.
7 from (R)-2: [α]20 = −137 (c = 1.6, CHCl3); IR 1755, 1371, 1173.
D
ACKNOWLEDGMENTS
1H NMR (400 MHz, CDCl3) δ ppm 1.11 (d, J = 6.80 Hz, 3 H), 1.33
■
We thank the University of Notre Dame for its generous
support of this program, especially Dr. Allen Oliver for the X-
ray analysis and the Mass Spectrometry Facility (Bill Boggess,
Nonka Sevova). G.P.S. thanks Dr. Jed. Fisher for regular and
lasting scientific discussions.
(d, J = 6.97 Hz, 3 H), 2.46 (s, 3 H), 3.44 (d, J = 6.80 Hz, 1 H), 4.00 (s,
1 H), 6.57−6.65 (m, 2 H), 7.26 (dd, 1 H), 7.33−7.45 (m, 4 H), 7.48
(dd, J = 7.30, 0.83 Hz, 1 H), 8.12 (d, J = 8.11 Hz, 2 H); 13C NMR
(150 MHz, CDCl3) δ ppm 22.0, 24.3, 25.2, 36.1, 59.8, 74.8, 123.0,
126.5, 127.9, 128.7, 129.2, 129.7, 129.7, 129.8, 130.0, 132.0, 134.9,
146.1, 164.2; HRMS (ESI) m/z calcd for C22H21Cl2NO3S2 481.0340,
found 481.0340.
S-Isopropyl 2,2-Dichloro-2-(1,1-dichloro-2-oxo-3-tosyl-2,3,5,9b-
tetrahydro-1H-benzo[e]indol-5-yl)ethanethioate (( )-10). Using
nonstandard (reaction time of 16 h, reaction temperature of 25 °C)
lactamization conditions, purification by flash column chromatography
with elution by 15% ethyl acetate/hexanes provided 114 mg of the
product ( )-10 as a yellow solid.
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■
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yellow solid ( )-10 was dissolved in a mixture of 15% ethyl acetate/
D
dx.doi.org/10.1021/jo302798j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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E
dx.doi.org/10.1021/jo302798j | J. Org. Chem. XXXX, XXX, XXX−XXX