Ruthenium Pybox-Catalyzed Enantioselective Intramolecular C-H Amination of Sulfamoyl Azides en Route to Chiral Vicinal Diamines

Article abstract of DOI:10.1021/acs.joc.0c02279

Enantioselective C(sp3)-H aminations allow an efficient access to nonracemic chiral amines. This work reports the catalytic asymmetric synthesis of chiral 1,2,5-thiadiazolidine-1,1-dioxides by an enantioselective ring-closing 1,5-C-H amination of sulfamoy

Full text of DOI:10.1021/acs.joc.0c02279

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Ruthenium Pybox-Catalyzed Enantioselective Intramolecular C−H
Amination of Sulfamoyl Azides en Route to Chiral Vicinal Diamines
Xin Nie, Zihan Yan, Sergei Ivlev, and Eric Meggers*
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ABSTRACT: Enantioselective C(sp3)−H aminations allow an efficient access to
nonracemic chiral amines. This work reports the catalytic asymmetric synthesis of
chiral 1,2,5-thiadiazolidine-1,1-dioxides by an enantioselective ring-closing 1,5-C−
H amination of sulfamoyl azides. The reaction is catalyzed by a recently introduced
simple chiral ruthenium bis(oxazoline) (pybox) complex (Angew. Chem. Int. Ed.
2020, 59, 12395) and provides cyclic 5-membered sulfamide products in up to
98% yield and up to 98% ee if the C−H bond is in a benzylic position. Mechanistic
experiments support a stepwise mechanism in which an intermediate ruthenium
nitrenoid species initiates a 1,5-hydrogen atom transfer followed by an immediate
radical rebound. The cyclic sulfamide products are suitable intermediates for the
synthesis of chiral vicinal diamines as has been verified for a representative example.
Our group recently reported in preliminary results a single
example of an enantioselective ring-closing C−H amination
with a sulfamoyl azide using a simple chiral ruthenium
bis(oxazoline) (pybox) catalyst.8 Here, we provide a full
report on this chemistry in which cyclic sulfamides can be
accessed with yields of up to 99% and up to 98% ee (Figure
1c). We further demonstrate that the obtained chiral
sulfamides can be hydrolyzed to provide chiral vicinal diamines
without any loss of enantiomeric excess.
INTRODUCTION
■
The enantioselective direct C(sp3)−H amination of prochiral
methylene groups is a powerful synthetic strategy for the
generation of chiral nitrogen-containing compounds, which are
key structural motifs in natural products, pharmaceuticals,
chiral catalysts, chiral ligands, and auxiliaries, among others.
Within the modality of nitrene insertion, regio- and stereo-
controlled ring-closing C(sp3)−H aminations have been
applied successfully to the catalytic asymmetric generation of
nitrogen heterocycles, some of which such as cyclic
carbamates, cyclic urea, cyclic sulfamidates, and cyclic
sulfamides can be further processed by ring-opening to provide
chiral aminoalcohols and chiral diamines.1,2
RESULTS AND DISCUSSION
■
Initial Experiments and Optimization. Previously, we
reported a simple new chiral transition-metal catalyst in which
a cyclometalated N-(4-nitrophenyl)-imidazo[1,5-a]pyridine
ligand is combined with a standard chiral C2-symmetric
ruthenium pyridine-2,6-bis(oxazoline) (pybox) fragment.8
The strongly electron-donating cyclometalated N-heterocyclic
carbene (NHC) ligand modulates the catalytic activity of the
ruthenium center, and we revealed that such complexes are
suitable for enantioselective nitrene C−H insertion chemistry.
Furthermore, we demonstrated that the catalytic activity and
asymmetric induction can be affected by substituents in the
imidazo[1,5-a]pyridine moiety. For example, sulfamoyl azide
1a was converted to the cyclic sulfamide 2a in 53% yield and
with 70% ee using 5 mol % catalyst Ru1 at 50 °C in 1,2-
Azide-containing compounds are attractive nitrene precur-
sors since molecular nitrogen is the only byproduct in the
course of the C−H amination reaction.3 Sulfonyl azides,4
sulfamoyl azides,5 azidoformates,6 and aliphatic azides7 have
been reported as substrates for enantioselective intramolecular
C(sp3)−H aminations. The ring-closing C(sp3)−H amination
of sulfamoyl azides caught our attention because it generates
cyclic sulfamides, which can subsequently be converted to
chiral diamines. Zhang and co-workers reported an enantio-
selective ring-closing 1,5-C−H amination of sulfamoyl azides
to cyclic sulfamides using metalloradical catalysis (Figure
1a).5a,b Interestingly, depending on the achiral aryl substituents
on the porphyrin core, both enantiomers could be obtained in
an enantiodivergent fashion.5b However, the cobalt catalyst is
structurally very complicated, which hampers its practicability.
Arnold and co-workers, on the other hand, recently reported a
cytochrome P450-catalyzed method for the enantioselective
ring-closing 1,5-C−H amination of sulfamoyl azides but which
comes along with all of the advantages and disadvantages of
enzymatic catalysis (Figure 1b).5c
Received: October 2, 2020
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(entry 12) only resulted in a marginal decrease of yield and
enantiomeric excess, which indicates that it is possible to run
this reaction under open flask conditions.
Substrate Scope. With the optimized conditions in hand
(Table 1, entry 5), we next investigated the substrate scope of
sulfamoyl azides. We started by introducing substituents into
the phenyl moiety of the phenethyl substituent of the initial
sulfamoyl azide 1a (Figure 2). A methyl group in the para- or
meta-position provided the benzylic C−H amination products
2b or 2c in high yields and with high ee values. A methyl group
in the more sterically hindering ortho-position afforded the
cyclic sulfamide 2d with a somewhat reduced yield of 76% and
with 90% ee. A para-phenyl substituent gave the highest
enantioselectivity of all tested substrates, providing cyclic
sulfamide 2e in 98% yield and with 98% ee. An electron-
donating para-methoxy group afforded the cyclic sulfamide 2f
in 92% yield and with 97% ee. Similarly, the electron-rich
benzodioxole group provided the benzylic C−H amination
product 2g in 96% yield and with 96% ee. Electron-
withdrawing substituents in the phenyl moiety decrease both
the yield and the enantioselectivity. For example, a strongly
electron-withdrawing CF3-group in the para-position of the
phenyl moiety gave the corresponding cyclic sulfamide 2h with
just 51% yield and 84% ee. Fluorine or chlorine substituents in
the para-position provided better results with fluorinated cyclic
sulfamide 2i isolated in 89% yield and with 94% ee, while the
chlorinated cyclic sulfamide 2j was isolated in 81% yield and
with 94% ee. Replacing the phenyl moiety with a
benzannulated 2-naphthyl, heteroaromatic 2-thiophene, or N-
Boc-protected 3-indole moiety provided the cyclic sulfamides
2k−m in 83−99% yield and with 95−97% ee. The cyclic
sulfamide 2n bearing two vicinal stereocenters was obtained
with 99% yield and 95% ee by desymmetrization of an indane
substrate. We also tested the C−H amination at allylic and
propargylic positions and found that they occurred with
significantly reduced enantiomeric excess as showcased for the
cyclic sulfamides 2o and 2p.
In all of the examples discussed so far, the cyclic sulfamide
products (2a−p) contained an N-benzyl protection group.
Next, we evaluated the tolerance of the ruthenium pybox
catalysis regarding different N-alkyl groups (Figure 3).
Accordingly, methyl, ethyl, n-propyl, and phenethyl substitu-
ents were well-tolerated and provided the cyclic sulfamides
2q−t in 87−92% yields and with 94−96% ee. Even an N-allyl
substituent provided the cyclic sulfamide 2u with excellent
94% yield and 96% ee without any observation of competing
aziridination. On the other hand, an n-propargyl substituent
provided the cyclic sulfamide 2v with a decreased yield of 55%
but with a still respectable 90% ee.
Additional Experiments. Additional experiments are
shown in Figure 4. First, substrate 1w containing an aliphatic
n-propyl side chain did not undergo any intramolecular C−H
amination and instead provided the reduced acyclic
sulfonamide as the main product (Figure 4a). From this
experiment, we can conclude that an activation of the C(sp3)−
H group by a neighboring aryl, alkenyl, or alkynyl group is a
requirement for an effective C(sp3)−H amination with Ru3.
We also probed the competition between 5- and 6-membered
ring-closing C−H amination. Substrate 1x containing a 3-
phenylpropyl side chain afforded the 6-membered cyclic
sulfamide 3x as the main product without any formation of
the 5-membered product 2x (Figure 4b). However, the
reaction provided just 46% yield of the 6-membered cyclic
Figure 1. Enantioselective intramolecular C(sp3)−H aminations of
sulfamoyl azides to provide cyclic sulfamides.
dichloroethane (DCE) (Table 1, entry 1). Replacing the
trimethylsilyl group with a bromine (Ru2) provided an
improved 80% yield with 93% ee. A chlorine substituent
(Ru3) provided the best results with 93% yield and 95% ee
(entry 3). Thus, we selected Ru3 as the most suitable catalyst
to further optimize the reaction conditions. Increasing the
concentration from 100 to 400 mM improved the yield from
93 to 95% (compare entries 3 and 4). When we further raised
the reaction temperature from 50 to 55 °C, an optimal NMR
yield of 99% and isolated yield of 97% were achieved with a
slightly improved 96% ee (entry 5). Thus, we selected these as
our standard conditions. Other conditions turned out to be
inferior. For example, increasing the temperature further to 80
°C provided slightly reduced yield and enantioselectivity
(entry 6), while reducing the catalyst loading to 2.0 and 1.0
mol % provided a more sluggish conversion with somewhat
reduced enantioselectivities (entries 7 and 8). Other tested
solvents were also less favorable. For example, replacing DCE
with CHCl3 or tetrahydrofuran (THF) both reduced yields
and enantiomeric excess (entries 9 and 10). Interestingly,
adding 1% water (entry 11) or executing the reaction under air
B
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a
Table 1. Initial Experiments and Optimization of Reaction Conditions
b
c
d
entry
catalyst/mol %
T (°C)
solvent
concn (M)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
Ru1 (5.0)
Ru2 (5.0)
Ru3 (5.0)
Ru3 (5.0)
Ru3 (5.0)
Ru3 (5.0)
Ru3 (2.0)
Ru3 (1.0)
Ru3 (5.0)
Ru3 (5.0)
Ru3 (5.0)
Ru3 (5.0)
50
50
50
50
55
80
55
55
55
55
55
55
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
THF
DCE
DCE
0.1
0.1
0.1
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
53
80
93
95
99 (97)
94
76
46
78
74
88
80
70
93
95
95
96
92
94
93
90
89
94
93
e
f
g
h
11
i
12
a
Reaction conditions: Substrate 1a (0.05 mmol) and catalyst (5 mol %) in the indicated solvent at the indicated temperature for 48 h under a
b
c
nitrogen atmosphere unless indicated otherwise. DCE, 1,2-dichloroethane. Yields determined by 1H NMR using 1,1,2,2-tetrachloroethane as the
d
e
internal standard. Determined by high-performance liquid chromatography (HPLC) on the chiral stationary phase. Isolated yield in brackets.
f
g
h
i
87% conversion. 72% conversion. In the presence of 1% H2O. Performed under air.
sulfamide 3x with a low enantiomeric excess (20% ee). The
main side product was the formation of the reduced acyclic
sulfamide. Moreover, when we used the substrate 1y in which
both N-alkyl side chains bear a benzylic C−H group, one
leading to a 5-membered (2y) and the other to a 6-membered
ring (3y), only the 5-membered cyclic sulfamide 2y was
formed in 73% yield with 96% ee, demonstrating that the
formation of 5-membered sulfamides is strongly favored. Thus,
these experiments, together with the scope shown in Figures 2
and 3, demonstrate that 2-arylethyl side chains provide the best
results to generate 5-membered cyclic sulfamides in high yields
and with high enantioselectivities. We also confirmed that the
ring-closing C−H amination of sulfamoyl azides can be
performed on a gram scale (Figure 4c). Under standard
conditions, 4 mmol of 1a was converted to (S)-2a in 95% yield
and with 95% ee. At the same time, 65% of the catalyst was
recovered for further use. To demonstrate the utility of this
new method, we converted the cyclic sulfamide 2a to the
diamine 4a in 95% yield with 95% ee using hydrazine at 110
°C (Figure 4d).9,10 The benzylic group could then be removed
by Pd-catalyzed hydrogenation (4a → 5a).
Proposed Mechanism. Finally, we briefly investigated the
expected nitrene mechanism. Transition-metal nitrenoids
typically react in a facile fashion with alkenes to form
aziridines.11 To probe this, we synthesized substrate (E)-8
bearing an internal alkene. Accordingly, when we reacted (E)-8
with Ru3 (8 mol %) at elevated temperature (60 °C), we
obtained the bicyclic aziridine 9 in 34% yield and with 79% ee
(Figure 5a). Thus, this experiment supports the intermediate
formation of a ruthenium nitrenoid species followed by an
intramolecular alkene addition. Such intramolecular formation
of bicyclic aziridine sulfamides has been reported before by
Zhang and co-workers.12 However, to our knowledge, this is
the first example of an enantioselective version of this
transformation. Of note, using catalyst Ru1 instead of Ru3
provided the bicyclic aziridine in a further improved yield of
72% and with an improved 98% ee, thus revealing the synthetic
utility of this asymmetric intramolecular aziridination.
For a further understanding of the reaction mechanism, we
determined the primary kinetic isotope effect (KIE) by
measuring relative rates of two individual reactions (Figure
5b). As a result, the initial rate of the amination of the CH2
group in 1a (kH) was significantly faster compared to the CD2
group in 1a′ (kD) with a determined ratio kH/kD = 3.5. This
KIE value of 3.5 reveals that the cleavage of the C−H bond
occurs during the rate-determining step of the overall C−H
bond amination process. Interestingly, but not unusual, an
intermolecular competition experiment with 1a and 1a′
provided only a diminished KIE of 1.4 as determined from
the product ratio 2a:2a′. This is consistent with a mechanism
in which the two substrates compete for the same binding site
at the catalyst, followed by a fast and irreversible conversion to
a ruthenium nitrenoid intermediate. In contrast, an intra-
molecular competition experiment with the deuterated
substrate 1t′ resulted in a very high KIE value of 12.2 as
determined by the ratio of the two products 2t′ and 2t′′. This
high KIE value demonstrates that the C−H cleavage in this
intramolecular competition experiment is the selectivity-
determining step, and it implicates a stepwise radical
mechanism in which a ruthenium nitrene radical intermediate
abstracts a benzylic hydrogen rather than a concerted nitrene
C−H insertion, generating a diradical intermediate.13,14
Recombination of this diradical then leads to the cyclic
sulfamide. Apparently, this radical rebound must be very rapid
as can be seen for the diastereoretentive allylic C−H
aminations shown in Figure 5c.15 While the E-configured
substrate (E)-1z converts to the E-configured cyclic sulfamide
(E)-2z, the Z-configured substrate (Z)-1z (Z/E > 99:1) leads
to the cyclic sulfamide (Z)-2z as the main product but with a
measurable amount of Z → E isomerization (Z/E = 40:1). The
degree of Z → E isomerization further increases to Z/E = 28:1
at 80 °C.
C
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(Figure 6). The reaction of ruthenium catalyst and sulfamoyl
azide provides a ruthenium nitrenoid intermediate I under
release of molecular nitrogen. This nitrenoid species is initially
formed in its singlet state (IS) and then converts to a triplet
state (IT) to form a nitrenoid radical complex.16,17 This
ruthenium nitrenoid radical then initiates a 1,5-hydrogen atom
transfer (HAT) at the benzylic position to provide the
intermediate diradical II, followed by an instantaneous
radical−radical rebound to the catalyst bound complex III
and release of the product, followed by a new catalytic cycle.
CONCLUSIONS
■
We here demonstrated that a simple chiral ruthenium pybox
catalyst can be used to perform an efficient ring-closing
C(sp3)−H amination of sulfamoyl azides to provide 5-
membered cyclic sulfamides, which are precursors of chiral
vicinal diamines. If the C(sp3)−H bond is in a benzylic
position, the reaction typically proceeds with high yields and
high enantioselectivities. C−H aminations at allylic and
propargylic positions are also possible albeit with reduced
enantioselectivities. Mechanistic experiments support a radical
hydrogen atom abstraction/radical rebound C−H amination
pathway. Future work will investigate other catalytic
asymmetric conversions with this new class of chiral ruthenium
pybox catalysts.
EXPERIMENTAL SECTION
■
All reactions were carried out under an atmosphere of nitrogen with
magnetic stirring unless otherwise stated. The catalytic reactions were
performed using standard Schlenk techniques. Solvents were distilled
under nitrogen from calcium hydride (CH3CN, CH2Cl2) and
sodium/benzophenone (THF, Et2O). HPLC grade of acetone,
methanol, and ethanol was used without further purification. Flash
column chromatography was performed with silica gel 60 M from
Macherey-Nagel (irregular shaped; 230−400 mesh; pH 6.8; pore
volume: 0.81 mL × g−1; mean pore size: 66 Å; specific surface: 492
m2 × g−1; particle size distribution: 0.5% <25 μm and 1.7% >71 μm;
water content: 1.6%). 1H NMR, proton decoupled 13C NMR, and 19
F
NMR spectra were recorded on Bruker Avance 250 (250 MHz),
Bruker Avance 300 (300 MHz), or Bruker AM (500 MHz)
spectrometers at an ambient temperature. NMR yields were
determined using 1,1,2,2-tetrachloroethane as the internal standard.
Figure 2. Substrate scope with N-benzyl sulfamoyl azides.
1
NMR standards were used as follows: H NMR spectroscopy: δ =
7.26 ppm (CDCl3), 5.32 ppm (CD2Cl2); 13C NMR spectroscopy: δ =
77.0 ppm (CDCl3), 53.8 ppm (CD2Cl2); 19F NMR spectroscopy: 0
ppm (CFCl3). Melting points (MPs) were determined on a Mettler
Toledo MP70 using one end closed capillary tubes. IR spectra were
recorded on a Bruker Alpha FT-IR spectrophotometer. High-
resolution mass spectra were recorded on a Bruker En Apex Ultra
7.0 TFT-MS instrument using the ESI/EI technique with an FT-ICR
mass analyzer. Optical rotations were measured on a Kruss P8000-T
̈
22
polarimeter with [α]D values reported in degrees with concen-
trations reported in g/100 mL. Chiral HPLC chromatography was
performed with an Agilent 1200 or Agilent 1260 HPLC system with a
Daicel Chiralpak OD-H, IG, or IA column (250 × 4.6 mm) using n-
hexane/isopropanol as the mobile phase. The catalysts Ru1−Ru38
and the substrates 1a,5b 1f,5b 1h,5b 1j−o,5b 1p−q,15 1r,4a 1x,5a 1y,5b
(E)-1z,15 and (Z)-1z15 were synthesized as reported.
Procedure for the Synthesis of Substrates.5b To a mixture of
amine (1 mmol, 1 equiv) and DBU (1.2 mmol, 1.2 equiv) in CH2Cl2
was added dropwise a solution of N3SO2N35b (2 mmol, 2 equiv, 0.3 M
in CH2Cl2) via a syringe at 0 °C. After the reaction was completed
(monitored by thin-layer chromatography, TLC), the solvent was
removed under reduced pressure at room temperature and the residue
was purified by flash chromatography on silica gel (n-hexane/EtOAc
Figure 3. Substrate scope with sulfamoyl azides bearing different
substituents at the nitrogen.
Together with the existing literature1−7 and the performed
mechanistic experiments, the following mechanism is proposed
D
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a
Figure 4. Additional experiments. Reduction of the azide to an amino group observed as a side reaction.
1
= 50:1 to 10:1) to afford the sulfamoyl azides. Note: Azides can be
explosive and should be handled carefully.
hexane/EtOAc = 20:1). H NMR (300 MHz, CDCl3) δ 7.44−7.29
(m, 5H), 7.15−7.06 (m, 3H), 7.04−6.95 (m, 1H), 4.47 (s, 2H),
3.38−3.29 (m, 2H), 2.88−2.79 (m, 2H), 2.19 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 136.3, 135.8, 134.7, 130.7, 129.7, 129.1, 128.8,
128.7, 127.2, 126.4, 53.3, 49.0, 32.1, 19.1. HRMS (ESI, m/z) calcd for
C16H18N4O2S1Na [M + Na]+: 353.1043, found: 353.1057. IR (film):
ν (cm−1) 3029, 2927, 2121, 1494, 1457, 1378, 1264, 1205, 1164,
1131, 1113, 1083, 1064, 1030, 983, 935, 908, 850, 797, 733, 698, 608,
588, 553, 533, 503, 452.
1-(2-((Azidosulfonyl)(benzyl)amino)ethyl)-4-methylbenzene
(1b). Colorless oil (290.8 mg, 0.88 mmol, 88% yield; eluent: n-
1
hexane/EtOAc = 20:1). H NMR (300 MHz, CDCl3) δ 7.44−7.29
(m, 5H), 7.09 (d, J = 8.0, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.42 (s, 2H),
3.45−3.35 (m, 2H), 2.86−2.74 (m, 2H), 2.31 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 136.5, 134.7, 134.6, 129.5, 129.1, 128.8, 128.7,
128.6, 53.1, 50.2, 34.0, 21.1. HRMS (ESI, m/z) calcd for
C16H18N4O2S1Na [M + Na]+: 353.1043, found: 353.1048. IR
(film): ν (cm−1) 3029, 2927, 2121, 1515, 1496, 1455, 1377, 1293,
1263, 1203, 1162, 1122, 1085, 1063, 1025, 995, 933, 910, 882, 850,
808, 788, 730, 697, 589, 562, 529, 503, 480, 457.
4-(2-((Azidosulfonyl)(benzyl)amino)ethyl)-1,1′-biphenyl (1e).
White solid (365.0 mg, 0.93 mmol, 93% yield; eluent: n-hexane/
EtOAc = 10:1). MP: 190−191 °C. H NMR (300 MHz, CDCl3) δ
1
7.60−7.48 (m, 4H), 7.47−7.30 (m, 8H), 7.20−7.12 (m, 2H), 4.45 (s,
2H), 3.52−3.42 (m, 2H), 2.94−2.83 (m, 2H). 13C{1H} NMR (75
MHz, CDCl3) δ 140.8, 139.9, 136.8, 134.6, 129.3, 129.1, 129.0, 128.8,
128.7, 127.5, 127.4, 127.1, 53.2, 50.1, 34.2. HRMS (ESI, m/z) calcd
for C21H20N4O2S1Na [M + Na]+: 415.1199, found: 415.1200. IR
(film): ν (cm−1) 3029, 2943, 2125, 1486, 1455, 1406, 1380, 1342,
1293, 1259, 1191, 1158, 1110, 1081, 1056, 1007, 978, 934, 905, 820,
788, 744, 713, 692, 605, 593, 540, 518, 486, 469.
1-(2-((Azidosulfonyl)(benzyl)amino)ethyl)-3-methylbenzene (1c).
Colorless oil (251.1 mg, 0.76 mmol, 76% yield; eluent: n-hexane/
EtOAc = 20:1). 1H NMR (300 MHz, CDCl3) δ 7.44−7.29 (m, 5H),
7.21−7.13 (m, 1H), 7.03 (d, J = 7.5, 1H), 6.94−6.84 (m, 2H), 4.42
(s, 2H), 3.48−3.37 (m, 2H), 2.87−2.74 (m, 2H), 2.31 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 138.5, 137.7, 134.7, 129.6, 129.1,
128.8, 128.7, 128.6, 127.7, 125.8, 53.1, 50.2, 34.4, 21.4. HRMS (ESI,
m/z) calcd for C16H18N4O2S1Na [M + Na]+: 353.1043, found:
353.1047. IR (film): ν (cm−1) 3031, 2928, 2121, 1609, 1493, 1455,
1376, 1265, 1203, 1162, 1122, 1099, 1064, 1028, 1000, 982, 939, 906,
804, 776, 728, 696, 582, 532, 506, 457, 440.
5-(2-((Azidosulfonyl)(benzyl)amino)ethyl)benzo[d][1,3]dioxole
(1g). Colorless oil (320.7 mg, 0.89 mmol, 89% yield; eluent: n-
1
hexane/EtOAc = 30:1). H NMR (300 MHz, CDCl3) δ 7.44−7.29
(m, 5H), 6.74−6.67 (m, 1H), 6.56−6.50 (m, 2H), 5.92 (s, 2H), 4.41
(s, 2H), 3.41−3.32 (m, 2H), 2.78−2.68 (m, 2H). 13C{1H} NMR (75
MHz, CDCl3) δ 147.9, 146.5, 134.6, 131.4, 129.1, 128.8, 128.7, 121.9,
1-(2-((Azidosulfonyl)(benzyl)amino)ethyl)-2-methylbenzene
(1d). Colorless oil (185.0 mg, 0.56 mmol, 56% yield; eluent: n-
E
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Figure 5. Experiments for elucidating the mechanism. Displacement ellipsoids are shown at the 50% probability level at 100 K.
109.2, 108.6, 101.1, 53.3, 50.4, 34.3. HRMS (ESI, m/z) calcd for
C16H16N4O4S1Na [M + Na]+: 383.0784, found: 383.0794. IR (film):
ν (cm−1) 2893, 2122, 1501, 1489, 1443, 1375, 1246, 1190, 1161,
1120, 1102, 1063, 1037, 987, 927, 881, 860, 808, 795, 735, 697, 636,
586, 551, 528, 489, 458, 425.
(2-((Azidosulfonyl)(propyl)amino)ethyl)benzene (1s). Colorless
oil (198.6 mg, 0.74 mmol, 74% yield; eluent: n-hexane/EtOAc =
10:1). 1H NMR (300 MHz, CDCl3) δ 7.36−7.19 (m, 5H), 3.52−3.44
(m, 2H), 3.25−3.17 (m, 2H), 2.99−2.90 (m, 2H), 1.63 (sext, J = 7.6
Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3)
δ 137.8, 128.9, 128.8, 127.0, 51.6, 51.0, 35.0, 21.4, 11.1. HRMS (ESI,
m/z) calcd for C11H16N4O2S1Na [M + Na]+: 291.0886, found:
291.0889. IR (film): ν (cm−1) 2969, 2937, 2878, 2119, 1496, 1456,
1377, 1203, 1178, 1157, 1120, 1080, 1034, 973, 893, 836, 796, 731,
698, 588, 546, 512, 496.
1-(2-((Azidosulfonyl)(benzyl)amino)ethyl)-4-fluorobenzene (1i).
Colorless oil (260.8 mg, 0.78 mmol, 78% yield; eluent: n-hexane/
EtOAc = 10:1). 1H NMR (300 MHz, CDCl3) δ 7.46−7.28 (m, 5H),
7.10−6.90 (m, 4H), 4.41 (s, 2H), 3.44−3.34 (m, 2H), 2.84−2.74 (m,
2H). 13C{1H} NMR (75 MHz, CDCl3) δ 163.6 (C−F, 1JC−F = 245.7
Hz), 160.3 (C−F, 1JC−F = 245.7 Hz), 134.6, 133.4, 133.3, 130.4 (C−
F, 3JC−F = 7.7 Hz), 130.3 (C−F, 3JC−F = 7.7 Hz), 129.1, 128.8, 128.7,
(2-((Azidosulfonyl)(phenethyl)amino)ethyl)benzene (1t). Color-
less oil (280.8 mg, 0.85 mmol, 85% yield; eluent: n-hexane/EtOAc =
2
2
1
115.8 (C−F, JC−F = 21.0 Hz), 115.8 (C−F, JC−F = 21.0 Hz), 53.4,
50.3, 33.8. 19F NMR (235 MHz, CDCl3) δ −116.0. HRMS (ESI, m/
z) calcd for C15H15F1N4O2S1Na [M + Na]+: 357.0797, found:
357.0798. IR (film): ν (cm−1) 2122, 1603, 1510, 1456, 1377, 1219,
1160, 1123, 1102, 1083, 1061, 1015, 985, 940, 910, 882, 857, 825,
796, 730, 697, 589, 562, 530, 511, 478, 458, 424.
10:1). H NMR (300 MHz, CDCl3) δ 7.38−7.14 (m, 10H), 3.53−
3.40 (m, 4H), 2.95−2.84 (m, 4H). 13C{1H} NMR (75 MHz, CDCl3)
δ 137.7, 128.9 (2C), 127.0, 51.6, 34.9. HRMS (ESI, m/z) calcd for
C16H18N4O2S1Na [M + Na]+: 353.1043, found: 353.1048. IR (film):
ν (cm−1) 3028, 2940, 2120, 1603, 1496, 1454, 1377, 1202, 1161,
1126, 1094, 1057, 1030, 963, 909, 845, 736, 696, 600, 515, 495.
F
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Article
1
EtOAc = 10:1). MP: 73−74 °C. H NMR (300 MHz, CDCl3) δ
7.44−7.28 (m, 10H), 6.52 (d, J = 15.8 Hz, 1H), 6.16 (dt, J = 15.8, 7.0
Hz, 1H), 4.49 (s, 2H), 4.99 (d, J = 6.9 Hz, 2H). 13C{1H} NMR (75
MHz, CDCl3) δ 136.1, 136.0, 134.6, 129.1, 128.9, 128.8, 128.6, 128.5,
126.8, 121.7, 51.5, 50.2. HRMS (ESI, m/z) calcd for
C16H16N4O2S1Na [M + Na]+: 351.0886, found: 351.0892. IR
(film): ν (cm−1) 3023, 2145, 1494, 1452, 1433, 1378, 1344, 1245,
1192, 1160, 1111, 1073, 1026, 1002, 972, 927, 899, 841, 772, 741,
718, 693, 598, 560, 541, 524, 489, 474, 456.
Procedure for the Amination Reactions. A 10 mL Schlenk
tube was charged with catalyst Ru3 (5.4 mg, 0.005 mmol, 5 mol %)
under an atmosphere of nitrogen. Subsequently, 1,2-dichloroethane
(0.25 mL) containing sulfamoyl azide (0.1 mmol, 1 equiv) was added
via a syringe under a nitrogen atmosphere. The resulting solution was
stirred under a nitrogen atmosphere at a 55 °C oil bath temperature
for 48 h. Afterward, the reaction solution was directly purified by flash
chromatography on silica gel (n-hexane/EtOAc = 10:1 to 3:1) to
afford the product. The enantiomeric excess was determined by chiral
HPLC analysis. The absolute configuration of 2j was determined by
single-crystal X-ray structure analysis as S-configuration (see the
Supporting Information), and all other products were assigned
accordingly.
Figure 6. Proposed mechanism. HAT, hydrogen atom transfer.
(2-(Allyl(azidosulfonyl)amino)ethyl)benzene (1u). Colorless oil
(210.4 mg, 0.79 mmol, 79% yield; eluent: n-hexane/EtOAc = 10:1).
1H NMR (300 MHz, CDCl3) δ 7.40−7.16 (m, 5H), 5.90−5.75 (m,
1H), 5.35−5.25 (m, 2H), 3.84 (d, J = 6.5 Hz, 2H), 3.54−3.45 (m,
2H), 2.98−2.89 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 137.8,
131.6, 128.9, 128.8, 127.0, 120.5, 52.2, 50.0, 34.8. HRMS (ESI, m/z)
calcd for C11H15N4O2S1 [M + H]+: 267.0910, found: 267.0913. IR
(film): ν (cm−1) 3029, 2938, 2121, 1603, 1497, 1454, 1420, 1378,
1284, 1202, 1164, 1116, 1086, 1055, 984, 929, 902, 878, 837, 780,
733, 699, 644, 600, 576, 512, 496.
(S)-2-Benzyl-4-phenyl-1,2,5-thiadiazolidine-1,1-dioxide (2a).5b
Starting from 1a (31.6 mg, 0.1 mmol) according to the general
procedure, 2a was afforded as a white solid (28.0 mg, 0.097 mmol,
97% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
96% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
75:25, flow rate 1.0 mL/min, 25 °C, tr (major) = 14.5 min, tr (minor)
= 13.1 min). [α]D22 = −69.4° (c 1.0, CH2Cl2). MP: 123−124 °C. 1H
NMR (300 MHz, CDCl3) δ 7.44−7.29 (m, 10H), 4.85−4.75 (m,
1H), 4.69 (d, J = 6.1 Hz, 1H), 4.37 (d, J = 13.6 Hz, 1H), 4.01 (d, J =
13.6 Hz, 1H), 3.56 (dd, J = 9.6, 7.1 Hz, 1H), 3.13 (dd, J = 9.5, 8.2 Hz,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.5, 135.0, 129.2, 128.9,
128.8, 128.4, 56.1, 55.2, 50.7.
(2-((Azidosulfonyl)(prop-2-yn-1-yl)amino)ethyl)benzene (1v).
White solid (235.2 mg, 0.89 mmol, 89% yield; eluent: n-hexane/
1
EtOAc = 10:1). MP: 46−47 °C. H NMR (300 MHz, CDCl3) δ
7.38−7.20 (m, 5H), 4.02 (d, J = 2.5 Hz, 2H), 3.66−3.58 (m, 2H),
3.01−2.93 (m, 2H) 2.45 (t, J = 2.5 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3) δ 137.5, 128.9 (2C), 127.1, 76.5, 75.0, 49.8, 38.6, 34.5.
HRMS (ESI, m/z) calcd for C11H13N4O2S1 [M + H]+: 265.0754,
found: 265.0757. IR (film): ν (cm−1) 3294, 2938, 2131, 1492, 1454,
1423, 1380, 1340, 1283, 1206, 1162, 1126, 1093, 1057, 1030, 985,
924, 908, 835, 774, 756, 724, 702, 681, 662, 639, 596, 558, 540, 506,
468.
(S)-2-Benzyl-4-(p-tolyl)-1,2,5-thiadiazolidine-1,1-dioxide (2b).
Starting from 1b (33.0 mg, 0.1 mmol) according to the general
procedure, 2b was afforded as a white solid (29.9 mg, 0.099 mmol,
99% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 95%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 75:25,
flow rate 1.0 mL/min, 25 °C, tr (major) = 13.6 min, tr (minor) = 15.0
(((Azidosulfonyl)(propyl)amino)methyl)benzene (1w). Colorless
22
1
min). [α]D = −89.3° (c 1.0, CH2Cl2). MP: 134−135 °C. H NMR
(300 MHz, CDCl3) δ 7.40−7.24 (m, 7H), 7.20−7.12 (m, 2H), 4.75
(dd, J = 14.6, 7.1 Hz, 1H), 4.61 (d, J = 6.2 Hz, 1H), 4.36 (d, J = 13.7
Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.52 (dd, J = 9.6, 7.1 Hz, 1H),
3.13 (dd, J = 9.4, 8.4 Hz, 1H), 2.33 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 138.9, 135.4, 135.1, 129.8, 128.9, 128.8, 128.4, 126.5, 55.9,
55.3, 50.7, 21.2. HRMS (ESI, m/z) calcd For C16H18N2O2S1Na [M +
Na]+: 325.0981, found: 325.0999. IR (film): ν (cm−1) 3249, 3066,
3034, 2919, 2881, 2859, 1515, 1497, 1474, 1455, 1403, 1370, 1355,
1343, 1311, 1297, 1275, 1249, 1213, 1200, 1185, 1150, 1111, 1083,
1057, 1023, 1009, 944, 924, 900, 818, 782, 738, 719, 695, 644, 625,
586, 542, 511, 474, 430, 416.
oil (216.2 mg, 0.85 mmol, 85% yield; eluent: n-hexane/EtOAc =
10:1). H NMR (300 MHz, CDCl3) δ 7.44−7.30 (m, 5H), 4.46 (s,
1
2H), 3.19 (t, J = 7.7 Hz, 2H), 1.58 (sext, J = 7.7 Hz, 2H), 0.85 (t, J =
7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 134.9, 129.0, 128.6,
128.5, 52.6, 50.5, 20.8, 11.1. HRMS (ESI, m/z) calcd for
C10H14N4O2S1Na [M + Na]+: 277.0730, found: 277.0734. IR
(film): ν (cm−1) 2970, 2937, 2878, 2120, 1496, 1455, 1375, 1256,
1204, 1178, 1158, 1120, 1079, 1020, 939, 911, 887, 783, 733, 697,
587, 526, 457.
(2-((Azidosulfonyl)(2-phenylethyl-2,2-d2)amino)ethyl)benzene
(1t′). Colorless oil (302.5 mg, 0.91 mmol, 91% yield; n-hexane/
EtOAc = 10:1). 1H NMR (300 MHz, CDCl3) δ 7.40−7.15 (m, 10H),
3.52−3.42 (m, 4H), 2.94−2.84 (m, 2H). 13C{1H} NMR (75 MHz,
CDCl3) δ 137.7, 128.9 (2C), 127.0, 51.6, 51.5, 34.9. HRMS (ESI, m/
z) calcd for C16H16D2N4O2S1Na [M + Na]+: 355.1168, found:
355.1173. IR (film): ν (cm−1) 3027, 2120, 1496, 1452, 1377, 1202,
1164, 1107, 1072, 1028, 962, 911, 840, 796, 731, 696, 596, 514, 494.
(((Azidosulfonyl)(2-phenylethyl-2,2-d2)amino)methyl)benzene
(1a′). Colorless oil (264.3 mg, 0.83 mmol, 83% yield; n-hexane/
EtOAc = 10:1). 1H NMR (300 MHz, CDCl3) δ 7.45−7.20 (m, 8H),
7.14−7.04 (m, 2H), 4.42 (s, 2H), 3.42 (s, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 137.6, 134.6, 129.1, 128.9, 128.8 (2C), 128.7, 126.9,
53.1, 50.0, 33.8 (quint, J = 19.9 Hz). HRMS (ESI, m/z) calcd for
C15H14D2N4O2S1Na [M + Na]+: 341.1012, found: 341.1020. IR
(film): ν (cm−1) 2122, 1496, 1451, 1376, 1201, 1164, 1108, 1077,
982, 937, 906, 803, 770, 731, 695, 590, 531, 497, 458.
(S)-2-Benzyl-4-(m-tolyl)-1,2,5-thiadiazolidine-1,1-dioxide (2c).
Starting from 1c (33.0 mg, 0.1 mmol) according to the general
procedure, 2c was afforded as a white solid (30.0 mg, 0.099 mmol,
99% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 97%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 85:15,
flow rate 1.0 mL/min, 25 °C, tr (major) = 18.6 min, tr (minor) = 20.9
22
1
min). [α]D = −85.6° (c 1.0, CH2Cl2). MP: 110−111 °C. H NMR
(300 MHz, CDCl3) δ 7.40−7.30 (m, 5H), 7.28−7.10 (m, 4H), 4.76
(dd, J = 14.5, 7.2 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.37 (d, J = 13.6
Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.53 (dd, J = 9.6, 7.1 Hz, 1H),
3.13 (dd, J = 9.3, 8.6 Hz, 1H), 2.34 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 139.1, 138.4, 135.1, 129.7, 129.1, 128.9, 128.8, 128.4, 127.1,
123.6, 56.1, 55.2, 50.7, 21.5. HRMS (ESI, m/z) calcd for
C16H18N2O2S1Na [M + Na]+: 325.0981, found: 325.0992. IR
(film): ν (cm−1) 3241, 3032, 2919, 2883, 2858, 1607, 1491, 1474,
(E)-(3-((Azidosulfonyl)(benzyl)amino)prop-1-en-1-yl)benzene
((E)-8). White solid (308.7 mg, 0.94 mmol, 94% yield; n-hexane/
G
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1453, 1405, 1372, 1342, 1297, 1277, 1251, 1203, 1151, 1108, 1082,
1054, 1009, 961, 929, 900, 829, 779, 738, 718, 693, 634, 614, 585,
511, 479, 448, 428.
2787, 1503, 1491, 1442, 1401, 1352, 1311, 1278, 1260, 1213, 1185,
1150, 1104, 1084, 1042, 964, 923, 897, 878, 818, 771, 716, 696, 645,
623, 610, 589, 564, 511, 474, 420.
(S)-2-Benzyl-4-(o-tolyl)-1,2,5-thiadiazolidine-1,1-dioxide (2d).
Starting from 1d (33.0 mg, 0.1 mmol) according to the general
procedure, 2d was afforded as a white solid (23.0 mg, 0.076 mmol,
76% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
90% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
80:20, flow rate 1.0 mL/min, 25 °C, tr (major) = 15.9 min, tr (minor)
(S)-2-Benzyl-4-(4-(trifluoromethyl)phenyl)-1,2,5-thiadiazolidine-
1,1-dioxide (2h).5b Starting from 1h (38.4 mg, 0.1 mmol) according
to the general procedure, 2h was afforded as a white solid (18.2 mg,
0.051 mmol, 51% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess
was determined by HPLC analysis on a Chiralpak IG column, ee =
84% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
85:15, flow rate 1.0 mL/min, 25 °C, tr (major) = 10.6 min, tr (minor)
= 15.1 min). [α]D22 = −50.1° (c 1.0, CH2Cl2). MP: 133−134 °C. 1H
NMR (300 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3
Hz, 2H), 7.40−7.30 (m, 5H), 4.92−4.76 (m, 2H), 4.40 (d, J = 13.6
Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.63 (dd, J = 9.9, 7.3 Hz, 1H),
3.06 (dd, J = 9.6, 7.9 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ
142.8, 134.7, 131.4 (C−F, 2JC−F = 32.9 Hz), 130.9 (C−F, 2JC−F = 32.9
22
1
= 13.3 min). [α]D = −52.9° (c 1.0, CH2Cl2). MP: 73−74 °C. H
NMR (300 MHz, CDCl3) δ 7.65−7.56 (m, 1H), 7.40−7.28 (m, 5H),
7.28−7.18 (m, 2H), 7.15−7.09 (m, 1H), 5.05 (dd, J = 14.7, 7.2 Hz,
1H), 4.59 (d, J = 6.5 Hz, 1H), 4.37 (d, J = 13.6 Hz, 1H), 4.03 (d, J =
13.6 Hz, 1H), 3.56 (dd, J = 9.6, 7.2 Hz, 1H), 3.10 (dd, J = 9.5, 8.1 Hz,
1H), 2.28 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 136.5, 135.2,
135.0, 130.8, 128.9, 128.8, 128.6, 128.4, 127.1, 126.1, 54.3, 52.6, 50.1,
19.1. HRMS (ESI, m/z) calcd for C16H18N2O2S1Na [M + Na]+:
325.0981, found: 325.0989. IR (film): ν (cm−1) 3249, 3028, 2960,
2922, 2866, 1491, 1457, 1407, 1381, 1351, 1323, 1301, 1218, 1146,
1117, 1094, 1076, 1054, 1011, 917, 899, 782, 745, 695, 637, 602, 572,
551, 535, 509, 484, 454, 438.
3
Hz), 129.0, 128.8, 128.5, 126.9, 126.2 (C−F, JC−F = 3.9 Hz), 126.1
(C−F, 3JC−F = 3.9 Hz), 125.7 (C−F, 1JC−F = 271.8 Hz), 122.1 (C−F,
1JC−F = 271.8 Hz), 55.3, 54.8, 50.7. 19F NMR (235 MHz, CDCl3) δ
−62.7 (s, 3F).
(S)-2-Benzyl-4-(4-fluorophenyl)-1,2,5-thiadiazolidine-1,1-dioxide
(2i). Starting from 1i (33.4 mg, 0.1 mmol) according to the general
procedure, 2i was afforded as a white solid (27.3 mg, 0.089 mmol,
89% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
94% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
85:15, flow rate 1.0 mL/min, 25 °C, tr (major) = 15.5 min, tr (minor)
= 17.3 min). [α]D22 = −79.8° (c 1.0, CH2Cl2). MP: 136−137 °C. 1H
NMR (300 MHz, CDCl3) δ 7.41−7.29 (m, 7H), 7.09−7.00 (m, 2H),
4.86−4.62 (m, 2H), 4.38 (d, J = 13.6 Hz, 1H), 3.99 (d, J = 13.6 Hz,
1H), 3.56 (dd, J = 9.6, 7.1 Hz, 1H), 3.08 (dd, J = 9.5, 8.1 Hz, 1H).
13C{1H} NMR (75 MHz, CDCl3) δ 164.6 (C−F, 1JC−F = 248.2 Hz),
(S)-4-([1,1′-Biphenyl]-4-yl)-2-benzyl-1,2,5-thiadiazolidine-1,1-di-
oxide (2e). Starting from 1e (39.2 mg, 0.1 mmol) according to the
general procedure, 2e was afforded as a white solid (35.7 mg, 0.098
mmol, 98% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
98% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
70:30, flow rate 1.0 mL/min, 25 °C, tr (major) = 20.5 min, tr (minor)
= 31.4 min). [α]D22 = −158.0° (c 1.0, CH2Cl2). MP: 190−191 °C. 1H
NMR (300 MHz, CDCl3) δ 7.62−7.52 (m, 4H), 7.49−7.41 (m, 4H),
7.40−7.29 (m, 6H), 4.84 (dd, J = 14.5, 7.3 Hz, 1H), 4.71 (d, J = 6.4
Hz, 1H), 4.40 (d, J = 13.6 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.59
(dd, J = 9.6, 7.2 Hz, 1H), 3.17 (dd, J = 9.5, 8.3 Hz, 1H). 13C{1H}
NMR (75 MHz, CDCl3) δ 142.0, 140.4, 137.4, 135.0, 129.0, 128.9,
128.8, 128.4, 127.9, 127.8, 127.2, 127.0, 55.8, 55.2, 50.7. HRMS (ESI,
m/z) calcd for C21H21N2O2S1 [M + H]+: 365.1324, found: 365.1322.
IR (film): ν (cm−1) 3278, 3029, 2923, 2854, 1485, 1454, 1395, 1363,
1344, 1307, 1278, 1208, 1152, 1118, 1063, 1007, 938, 903, 836, 809,
765, 726, 694, 648, 611, 587, 563, 546, 518, 499, 480, 426.
(S)-2-Benzyl-4-(4-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-di-
oxide (2f).5b Starting from 1f (34.6 mg, 0.1 mmol) according to the
general procedure, 2f was afforded as a white solid (29.3 mg, 0.092
mmol, 92% yield; n-hexane/EtOAc = 5:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 97%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 15.2 min, tr (minor) = 17.8
min). [α]D22 = −101.1° (c 1.0, CH2Cl2). MP: 113−114 °C. 1H NMR
(300 MHz, CDCl3) δ 7.40−7.27 (m, 7H), 6.92−6.84 (m, 2H), 4.74
(dd, J = 14.3, 7.2 Hz, 1H), 4.60 (d, J = 5.5 Hz, 1H), 4.36 (d, J = 13.6
Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.51 (dd, J = 9.6, 7.1
Hz, 1H), 3.13 (dd, J = 9.5, 8.3 Hz, 1H). 13C{1H} NMR (75 MHz,
CDCl3) δ 160.1, 135.1, 130.4, 128.9, 128.8, 128.4, 127.9, 114.5, 55.7,
55.5, 55.4, 50.6.
1
161.4 (C−F, JC−F = 248.2 Hz), 134.9, 134.4 (2C), 129.0, 128.9,
3
3
128.4 (C−F, JC−F = 8.8 Hz), 128.3 (C−F, JC−F = 8.8 Hz), 116.3
2
2
(C−F, JC−F = 21.9 Hz), 116.0 (C−F, JC−F = 21.9 Hz), 55.4, 55.2,
50.6. 19F NMR (235 MHz, CDCl3) δ −112.8. HRMS (ESI, m/z)
calcd for C15H15F1N2O2S1Na [M + Na]+: 329.0730, found: 329.0738.
IR (film): ν (cm−1) 3264, 2923, 2855, 1606, 1510, 1478, 1455, 1404,
1360, 1337, 1288, 1224, 1205, 1150, 1120, 1086, 1056, 1015, 945,
899, 832, 789, 754, 739, 719, 695, 645, 620, 582, 541, 513, 498, 474,
427.
(S)-2-Benzyl-4-(4-chlorophenyl)-1,2,5-thiadiazolidine-1,1-diox-
ide (2j).5b Starting from 1j (35.1 mg, 0.1 mmol) according to the
general procedure, 2j was afforded as a white solid (26.1 mg, 0.081
mmol, 81% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 94%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 8.9 min, tr (minor) = 10.6
min). [α]D22 = −114.0° (c 1.0, CH2Cl2). MP: 160−161 °C. 1H NMR
(300 MHz, CDCl3) δ 7.40−7.29 (m, 9H), 4.77 (dd, J = 14.4, 7.2 Hz,
1H), 4.69 (d, J = 6.5 Hz, 1H), 4.38 (d, J = 13.6 Hz, 1H), 3.98 (d, J =
13.6 Hz, 1H), 3.56 (dd, J = 9.7, 7.3 Hz, 1H), 3.06 (dd, J = 9.6, 8.1 Hz,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ 137.2, 134.9, 134.8, 129.4,
129.0, 128.9, 128.5, 127.9, 55.4, 55.0, 50.7.
(S)-4-(Benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,5-thiadiazolidine-
1,1-dioxide (2g). Starting from 1g (36.0 mg, 0.1 mmol) according to
the general procedure, 2g was afforded as a white solid (31.9 mg,
0.096 mmol, 96% yield; n-hexane/EtOAc = 5:1). Enantiomeric excess
was determined by HPLC analysis on a Chiralpak OD-H column, ee
= 96% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
70:30, flow rate 1.0 mL/min, 25 °C, tr (major) = 13.1 min, tr (minor)
= 16.0 min). [α]D22 = −123.3° (c 1.0, CH2Cl2). MP: 130−131 °C. 1H
NMR (300 MHz, CDCl3) δ 7.40−7.30 (m, 5H), 6.92 (d, J = 1.6 Hz,
1H), 6.83−6.72 (m, 2H), 5.96 (s, 2H), 4.71 (dd, J = 13.1, 7.3 Hz,
1H), 4.61 (d, J = 5.7 Hz, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.01 (d, J =
13.6 Hz, 1H), 3.51 (dd, J = 9.6, 7.1 Hz, 1H), 3.09 (dd, J = 9.6, 8.1 Hz,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ 148.5, 148.2, 135.0, 132.3,
128.9, 128.8, 128.4, 120.2, 108.6, 106.9, 101.5, 55.9, 55.3, 50.7.
HRMS (ESI, m/z) calcd for C16H17N2O4S1 [M + H]+: 333.0904,
found: 333.0918. IR (film): ν (cm−1) 3227, 3088, 3064, 3033, 2909,
(S)-2-Benzyl-4-(naphthalen-2-yl)-1,2,5-thiadiazolidine-1,1-diox-
ide (2k).5b Starting from 1k (36.6 mg, 0.1 mmol) according to the
general procedure, 2k was afforded as a white solid (28.1 mg, 0.083
mmol, 83% yield; n-hexane/EtOAc = 5:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 97%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 14.2 min, tr (minor) = 17.9
min). [α]D22 = −119.9° (c 1.0, CH2Cl2). MP: 163−164 °C. 1H NMR
(300 MHz, CDCl3) δ 7.90−7.76 (m, 4H), 7.55−7.46 (m, 3H), 7.42−
7.28 (m, 5H), 4.96 (dd, J = 14.4, 7.4 Hz, 1H), 4.78 (d, J = 6.4 Hz,
1H), 4.41 (d, J = 13.6 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.63 (dd, J
= 9.7, 7.2 Hz, 1H), 3.21 (dd, J = 9.6, 8.3 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3) δ 135.7, 135.0, 133.5, 133.3, 129.4, 129.0, 128.9, 128.4,
128.1, 127.9, 126.9, 126.8, 125.9, 123.7, 56.2, 55.1, 50.7.
(R)-2-Benzyl-4-(thiophen-2-yl)-1,2,5-thiadiazolidine-1,1-dioxide
(2l).5b Starting from 1l (32.2 mg, 0.1 mmol) according to the general
H
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The Journal of Organic Chemistry
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Article
procedure, 2l was afforded as a white solid (27.4 mg, 0.093 mmol,
93% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
96% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
80:20, flow rate 1.0 mL/min, 25 °C, tr (major) = 20.9 min, tr (minor)
= 16.0 min). [α]D22 = −94.8° (c 1.0, CH2Cl2). MP: 112−113 °C. 1H
NMR (300 MHz, CDCl3) δ 7.42−7.31 (m, 5H), 7.29 (dd, J = 5.1, 1.2
Hz, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 5.06
(t, J = 7.1 Hz, 1H), 4.32 (d, J = 13.6 Hz, 1H), 4.13 (d, J = 13.6 Hz,
1H), 3.58 (dd, J = 9.6, 6.8 Hz, 1H), 3.54 (br s, 1H), 3.30 (dd, J = 9.6,
7.4 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 141.4, 135.0, 129.0,
128.8, 128.4, 127.3, 126.4, 126.1, 55.3, 52.1, 50.7.
procedure, 2q was afforded as a white solid (18.5 mg, 0.087 mmol,
87% yield; n-hexane/EtOAc = 3:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
94% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
70:30, flow rate 1.0 mL/min, 25 °C, tr (major) = 16.7 min, tr (minor)
= 14.5 min). [α]D22 = −14.2° (c 1.0, CH2Cl2). MP: 119−120 °C. 1H
NMR (300 MHz, CDCl3) δ 7.50−7.30 (m, 5H), 4.84 (dd, J = 13.9,
7.2 Hz, 1H), 4.66 (d, J = 5.0 Hz, 1H), 3.69 (dd, J = 9.3, 7.3 Hz, 1H),
3.24 (t, J = 8.7 Hz, 1H), 2.76 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 138.7, 129.2, 129.0, 126.6, 58.0, 55.9, 32.9.
(S)-2-Ethyl-4-phenyl-1,2,5-thiadiazolidine-1,1-dioxide (2r).4a
Starting from 1r (25.4 mg, 0.1 mmol) according to the general
procedure, 2r was afforded as a white solid (20.1 mg, 0.089 mmol,
89% yield; n-hexane/EtOAc = 3:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 96%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 9.2 min, tr (minor) = 14.3
tert-Butyl (S)-3-(5-Benzyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)-
1H-indole-1-carboxylate (2m).5b Starting from 1m (45.6 mg, 0.1
mmol) according to the general procedure, 2m was afforded as a
white solid (42.3 mg, 0.099 mmol, 99% yield; n-hexane/EtOAc =
3:1). Enantiomeric excess was determined by HPLC analysis on a
Chiralpak IG column, ee = 95% (absorbance at 210 nm, mobile
phase: n-hexane/isopropanol = 70:30, flow rate 1.0 mL/min, 25 °C, tr
22
1
min). [α]D = −18.8° (c 1.0, CH2Cl2). MP: 97−98 °C. H NMR
(300 MHz, CDCl3) δ 7.50−7.30 (m, 5H), 4.83 (dd, J = 14.3, 7.2 Hz,
1H), 4.64 (d, J = 4.5 Hz, 1H), 3.73 (dd, J = 9.4, 7.2 Hz, 1H), 3.28−
3.14 (m, 2H), 3.10−2.94 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 138.7, 129.2, 129.0, 126.6, 56.0, 55.6, 41.8,
13.2.
22
(major) = 12.1 min, tr (minor) = 16.8 min). [α]D = −90.8° (c 1.0,
CH2Cl2). MP: 59−60 °C. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J =
8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.44−7.22 (m,
7H), 5.06 (dd, J = 14.8, 7.1 Hz, 1H), 4.60 (d, J = 6.7 Hz, 1H), 4.38
(d, J = 13.6 Hz, 1H), 4.14 (d, J = 13.6 Hz, 1H), 3.57 (dd, J = 9.6, 7.1
Hz, 1H), 3.44 (dd, J = 9.5, 8.3 Hz, 1H), 1.66 (s, 9H). 13C{1H} NMR
(75 MHz, CDCl3) δ 149.4, 136.1, 135.1, 129.0, 128.9, 128.4, 127.6,
125.4, 124.2, 123.2, 119.3, 117.3, 115.8, 84.5, 53.3, 50.7, 49.7, 28.3.
(3aS,8aR)-1-Benzyl-3,3a,8,8a-tetrahydro-1H-indeno[1,2-c]-
[1,2,5]thiadiazole 2,2-dioxide (2n).5b Starting from 1n (32.8 mg, 0.1
mmol) according to the general procedure, 2n was afforded as a white
solid (29.7 mg, 0.099 mmol, 99% yield; n-hexane/EtOAc = 4:1).
Enantiomeric excess was determined by HPLC analysis on a
Chiralpak OD-H column, ee = 95% (absorbance at 210 nm, mobile
phase: n-hexane/isopropanol = 75:25, flow rate 1.0 mL/min, 25 °C, tr
(major) = 13.3 min, tr (minor) = 10.6 min). [α]D22 = −154.7° (c 1.0,
(S)-4-Phenyl-2-propyl-1,2,5-thiadiazolidine-1,1-dioxide (2s).
Starting from 1s (26.8 mg, 0.1 mmol) according to the general
procedure, 2s was afforded as a white solid (21.1 mg, 0.088 mmol,
88% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
96% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
80:20, flow rate 1.0 mL/min, 25 °C, tr (major) = 15.8 min, tr (minor)
22
1
= 13.7 min). [α]D = −28.7° (c 1.0, CH2Cl2). MP: 88−89 °C. H
NMR (300 MHz, CDCl3) δ 7.50−7.30 (m, 5H), 4.83 (dd, J = 14.0,
7.0 Hz, 1H), 4.60 (d, J = 5.1 Hz, 1H), 3.77−3.66 (m, 1H), 3.22 (t, J =
8.7 Hz, 1H), 3.16−3.02 (m, 1H), 2.98−2.84 (m, 1H), 1.66 (sext, J =
7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 138.8, 129.2, 129.0, 126.6, 56.0 (2C), 48.8, 21.3, 11.5.
HRMS (ESI, m/z) calcd for C11H17N2O2S1 [M + H]+: 241.1005,
found: 241.1015. IR (film): ν (cm−1) 3282, 2966, 2930, 2875, 1495,
1460, 1390, 1363, 1347, 1329, 1309, 1272, 1202, 1174, 1138, 1083,
1050, 1029, 988, 939, 906, 890, 805, 772, 746, 718, 695, 626, 608,
572, 518, 455.
1
CH2Cl2). MP: 135−136 °C. H NMR (300 MHz, CDCl3) δ 7.45−
7.34 (m, 6H), 7.33−7.23 (m, 2H), 7.16−7.08 (m, 1H), 5.11 (t, J =
7.8 Hz, 1H), 4.50 (d, J = 13.8 Hz, 1H), 4.31 (d, J = 8.0 Hz, 1H),
4.19−4.09 (m, 2H), 3.02−2.90 (m, 1H), 2.88−2.76 (m, 1H).
13C{1H} NMR (75 MHz, CDCl3) δ 141.6, 138.3, 135.3, 130.0, 129.3,
128.9, 128.4, 128.0, 125.6, 125.3, 63.4, 61.1, 50.2, 38.1.
(S)-2-Phenethyl-4-phenyl-1,2,5-thiadiazolidine-1,1-dioxide (2t).
Starting from 1t (33.0 mg, 0.1 mmol) according to the general
procedure, 2t was afforded as a white solid (27.8 mg, 0.092 mmol,
92% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
96% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
70:30, flow rate 1.0 mL/min, 25 °C, tr (major) = 19.0 min, tr (minor)
= 15.2 min). [α]D22 = −36.2° (c 1.0, CH2Cl2). MP: 120−121 °C. 1H
NMR (300 MHz, CDCl3) δ 7.43−7.33 (m, 5H), 7.32−7.18 (m, 5H),
4.79 (dd, J = 13.9, 7.2 Hz, 1H), 4.59 (d, J = 6.1 Hz, 1H), 3.66 (dd, J =
9.4, 7.1 Hz, 1H), 3.47−3.34 (m, 1H), 3.30−3.16 (m, 2H), 2.97 (t, J =
7.6 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.6, 138.4, 129.2,
129.0, 128.8, 128.7, 126.8, 126.6, 56.3, 56.0, 48.4, 34.6. HRMS (ESI,
m/z) calcd for C16H18N2O2S1Na [M + Na]+: 325.0981, found:
325.0980. IR (film): ν (cm−1) 3279, 3031, 2953, 2925, 2859, 1603,
1494, 1477, 1454, 1399, 1350, 1328, 1309, 1295, 1276, 1210, 1150,
1132, 1090, 1060, 1027, 967, 940, 913, 894, 842, 751, 696, 632, 619,
586, 563, 516, 491, 443.
(S)-2-Benzyl-4-(cyclohex-1-en-1-yl)-1,2,5-thiadiazolidine-1,1-di-
oxide (2o).5b Starting from 1o (32.0 mg, 0.1 mmol) according to the
general procedure, 2o was afforded as a white solid (22.2 mg, 0.076
mmol, 76% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IA column, ee = 77%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 90:10,
flow rate 1.0 mL/min, 25 °C, tr (major) = 14.5 min, tr (minor) = 17.1
min). [α]D = −40.7° (c 1.0, CH2Cl2). MP: 108−109 °C. H NMR
(300 MHz, CDCl3) δ 7.42−7.28 (m, 5H), 5.80−5.71 (m, 1H), 4.32
(br s, 1H), 4.31 (d, J = 13.7 Hz, 1H), 3.98 (d, J = 13.7 Hz, 1H), 4.16
(dd, J = 14.7, 7.2 Hz, 1H), 3.29 (dd, J = 9.4, 7.1 Hz, 1H), 3.01 (dd, J
= 9.2, 8.5 Hz, 1H), 2.12−1.82 (m, 4H), 1.72−1.44 (m, 4H). 13C{1H}
NMR (75 MHz, CDCl3) δ 135.3, 134.1, 128.9, 128.8, 128.3, 126.4,
57.9, 52.0, 50.6, 25.1, 23.9, 22.4, 22.2.
22
1
(S)-2-Benzyl-4-(phenylethynyl)-1,2,5-thiadiazolidine-1,1-dioxide
(2p).15 Starting from 1p (34.0 mg, 0.1 mmol) according to the general
procedure, 2p was afforded as a colorless oil (30.6 mg, 0.098 mmol,
98% yield; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak IG column, ee = 68%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 11.5 min, tr (minor) = 14.4
(S)-2-Allyl-4-phenyl-1,2,5-thiadiazolidine-1,1-dioxide (2u). Start-
ing from 1u (26.6 mg, 0.1 mmol) according to the general procedure,
2u was afforded as a white solid (22.4 mg, 0.094 mmol, 94% yield; n-
hexane/EtOAc = 4:1). Enantiomeric excess was determined by HPLC
analysis on a Chiralpak OD-H column, ee = 96% (absorbance at 210
22
min). [α]D = −107.1° (c 1.0, CH2Cl2). 1H NMR (300 MHz,
CDCl3) δ 7.47−7.27 (m, 10H), 4.74−4.54 (m, 2H), 4.31 (d, J = 13.8
Hz, 1H), 4.20 (d, J = 13.8 Hz, 1H), 3.55 (dd, J = 9.6, 6.7 Hz, 1H),
3.42 (dd, J = 9.6, 7.2 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ
135.0, 132.0, 129.3, 129.0, 128.8, 128.5, 128.4, 121.5, 86.5, 84.2, 54.0,
50.7, 44.6.
nm, mobile phase: n-hexane/isopropanol = 70:30, flow rate 1.0 mL/
22
min, 25 °C, tr (major) = 12.5 min, tr (minor) = 10.1 min). [α]D
=
−29.7° (c 1.0, CH2Cl2). MP: 61−62 °C.1H NMR (300 MHz, CDCl3)
δ 7.48−7.30 (m, 5H), 5.98−5.80 (m, 1H), 5.38−5.22 (m, 2H), 4.90−
4.74 (m, 2H), 3.84−3.66 (m, 2H), 3.53 (dd, J = 14.0, 6.8 Hz, 1H),
3.19 (dd, J = 9.6, 8.0 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ
(S)-2-Methyl-4-phenyl-1,2,5-thiadiazolidine-1,1-dioxide (2q).15
Starting from 1q (24.0 mg, 0.1 mmol) according to the general
I
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138.6, 132.0, 129.2, 128.9, 126.6, 120.1, 56.1, 55.4, 49.7. HRMS (ESI,
m/z) calcd for C11H14N2O2S1Na [M + Na]+: 261.0668, found:
261.0670. IR (film): ν (cm−1) 3266, 2924, 2881, 1495, 1470, 1456,
1421, 1397, 1360, 1347, 1310, 1277, 1211, 1200, 1147, 1113, 1083,
1058, 1013, 980, 925, 895, 802, 776, 754, 721, 696, 642, 584, 563,
517, 451.
resulting suspension was filtered through a pad of Celite. The filtrate
was extracted with HCl (1 M, 2 × 2 mL), and the combined aqueous
layers were adjusted to pH 14 by adding aqueous NaOH (6 M). The
aqueous phase was extracted with EtOAc (2 × 3 mL), and the
combined organic layers were washed with brine (4 mL) and dried
over Na2SO4 and concentrated under reduced pressure to afford the
benzyl-protected diamine 4a as a yellow oil (43.0 mg, 0.19 mmol, 95%
yield). [α]D22 = +12.1° (c 1.0, CH2Cl2). The analytical data of 4a are
in accordance with the literature.18 1H NMR (300 MHz, CDCl3) δ
7.35−7.20 (m, 10H), 4.05 (dd, J = 8.3, 4.8 Hz, 1H), 3.81 (s, 2H),
2.85 (dd, J = 11.8, 4.8 Hz, 1H), 2.75 (dd, J = 11.8, 8.3 Hz, 1H), 1.82
(s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 144.6, 140.4, 128.7,
128.5, 128.2, 127.3, 127.1, 126.5, 57.1, 55.7, 53.9.
(S)-4-Phenyl-2-(prop-2-yn-1-yl)-1,2,5-thiadiazolidine-1,1-dioxide
(2v). Starting from 1v (26.4 mg, 0.1 mmol) according to the general
procedure, 2v was afforded as a yellow oil (13.0 mg, 0.055 mmol, 55%
yield; n-hexane/EtOAc = 3:1). Enantiomeric excess was determined
by HPLC analysis on a Chiralpak OD-H column, ee = 90%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, 25 °C, tr (major) = 9.3 min, tr (minor) = 10.8
min). [α]D22 = −33.3° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3)
δ 7.48−7.32 (m, 5H), 4.97−4.85 (m, 1H), 4.66 (d, J = 6.2 Hz, 1H),
3.98 (dd, J = 17.1, 2.5 Hz, 1H), 3.90 (dd, J = 9.9, 7.2 Hz, 1H), 3.83
(dd, J = 17.1, 2.5 Hz, 1H), 3.50 (dd, J = 9.9, 8.5 Hz, 1H), 2.38 (t, J =
2.5 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 138.2, 129.3, 129.1,
126.6, 74.5, 56.2, 55.4, 36.7. HRMS (ESI, m/z) calcd for
C11H12N2O2S1Na [M + Na]+: 259.0512, found: 259.0512. IR
(film): ν (cm−1) 3280, 2923, 2854, 1455, 1395, 1293, 1204, 1158,
1067, 1027, 925, 903, 754, 698, 637, 610, 555, 496, 455.
Competition of 5- vs 6-Membered Ring Formation. Starting
from 1x (33.0 mg, 0.1 mmol) according to the general procedure, 2-
benzyl-5-phenyl-1,2,6-thiadiazinane-1,1-dioxide 3x was afforded as a
white solid (13.9 mg, 0.046 mmol, 46% yield; n-hexane/EtOAc =
4:1). Enantiomeric excess was determined by HPLC analysis on a
Chiralpak IG column, ee = 20% (absorbance at 210 nm, mobile
phase: n-hexane/isopropanol = 70:30, flow rate 1.0 mL/min, 25 °C, tr
(major) = 18.2 min, tr (minor) = 15.6 min). MP: 126−127 °C. The
analytical data of 3x are in accordance with the literature.5a 1H NMR
(300 MHz, CDCl3) δ 7.46−7.30 (m, 10H), 4.84−4.72 (m, 1H), 4.52
(d, J = 13.8 Hz, 1H), 4.22 (d, J = 7.9 Hz, 1H), 4.13 (d, J = 13.8 Hz,
1H), 3.52 (td, J = 13.2, 3.1 Hz, 1H), 3.28−3.17 (m, 1H), 2.08−1.90
(m, 1H), 1.90−1.80 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ
139.4, 135.6, 129.1, 129.0, 128.9, 128.7, 128.2, 126.4, 59.9, 52.1, 47.6,
29.5.
The free diamine was converted to the corresponding hydro-
chloride salt by addition of 4 M HCl in 1,4-dioxane (2 equiv). The
suspension of hydrochloride salt (29.9 mg, 0.1 mmol) and 15 mg of
palladium hydroxide on carbon (20 wt % loading) in methanol (3
mL) was stirred under a hydrogen atmosphere (H2 balloon) for 14 h.
The resulting solution was filtered through a pad of Celite, and the
filtrate was concentrated under reduced pressure. The residue was
washed with EtOAc (2 × 3 mL) and dried under a vacuum to afford
the desired chiral vicinal diamine hydrochloride salt 5a as a white
22
solid (18.8 mg, 0.09 mmol, 90% yield). [α]D = −19.1° (c 1.0,
EtOH). The analytical data of 5a are in accordance with the
literature.19 1H NMR (300 MHz, DMSO-d6) δ 8.86 (br s, 6H), 7.66−
7.55 (m, 2H), 7.51−7.41 (m, 3H), 4.67 (t, J = 6.4 Hz, 1H), 3.53 (dd,
J = 13.4, 6.8 Hz, 1H), 3.25 (dd, J = 13.4, 6.1 Hz, 1H). 13C{1H} NMR
(125 MHz, DMSO-d6) δ 134.8, 129.9, 129.5, 128.4, 52.6, 42.3. An
enantiomeric excess of 95% ee was determined after conversion of the
diamine hydrochloride salt to its cyclic urea13d according to a
literature procedure.20
Procedure for the Asymmetric Aziridination Reaction. A 10
mL Schlenk tube was charged with sulfamoyl azide (E)-8 (32.8 mg,
0.1 mmol) and Ru1 (8.9 mg, 0.008 mmol, 8 mol %) under an
atmosphere of nitrogen. 1,2-Dichloroethane (0.25 mL) was added via
a syringe under a nitrogen atmosphere, and the resulting solution was
stirred under a nitrogen atmosphere at a 60 °C oil bath temperature
for 60 h. The reaction solution was directly purified by flash
chromatography on silica gel (n-hexane/EtOAc = 10:1 to 3:1) to
afford the bicyclic aziridine 9 (21.6 mg, 0.072 mmol, 72% yield) as a
white solid. The absolute configuration of the product 9 was
confirmed by single-crystal X-ray diffraction as R,R-configuration (see
the Supporting Information). Enantiomeric excess was determined by
HPLC analysis on a Chiralpak OD-H column, ee = 98% (absorbance
at 210 nm, mobile phase: n-hexane/isopropanol = 70:30, flow rate 1.0
Starting from 1y (34.4 mg, 0.1 mmol) according to the general
procedure, (S)-4-phenyl-2-(3-phenylpropyl)-1,2,5-thiadiazolidine-1,1-
dioxide 2y was afforded as a white solid (23.1 mg, 0.073 mmol, 73%
yield; n-hexane/EtOAc = 5:1). Enantiomeric excess was determined
by HPLC analysis on a Chiralpak OD-H column, ee = 96%
(absorbance at 210 nm, mobile phase: n-hexane/isopropanol = 60:40,
flow rate 1.0 mL/min, 25 °C, tr (major) = 19.5 min, tr (minor) = 14.4
22
min). [α]D = −238.5° (c 1.0, CH2Cl2). MP: 91−92 °C. The
analytical data of 2y are in accordance with the literature.5b 1H NMR
(300 MHz, CDCl3) δ 7.48−7.12 (m, 10H), 4.87−4.76 (m, 1H), 4.69
(d, J = 6.0 Hz, 1H), 3.69 (dd, J = 9.4, 7.1 Hz, 1H), 3.28−3.08 (m,
2H), 3.02−2.90 (m, 1H), 2.73 (t, J = 7.4 Hz, 1H), 1.97 (quint, J = 7.4
Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 141.1, 138.7, 129.2,
129.0, 128.6 (2C), 126.6, 126.2, 56.1, 56.0, 46.5, 30.1, 29.4.
Gram-Scale Reaction. A 50 mL flask was charged with catalyst
Ru3 (216.4 mg, 0.2 mmol, 5 mol %) under an atmosphere of
nitrogen. Subsequently, 1,2-dichloroethane (10 mL) containing
sulfamoyl azides 1a (1.26 g, 4.0 mmol) was added via a syringe
under a nitrogen atmosphere. The resulting solution was stirred under
a nitrogen atmosphere at a 55 °C oil bath temperature for 48 h.
Afterward, the reaction solution was directly purified by flash
chromatography on silica gel (n-hexane/EtOAc = 10:1 to 3:1) to
afford 2a as a white solid (1.10 g, 95% yield). Then, the catalyst
(140.7 mg, 0.13 mmol, 65%) was reisolated by changing the eluent to
CH2Cl2/CH3CN (100:1 to 20:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
95% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
75:25, flow rate 1.0 mL/min, 25 °C, tr (major) = 14.5 min, tr (minor)
= 13.1 min).
22
mL/min, 25 °C, tr (major) = 10.8 min, tr (minor) = 13.9 min). [α]D
1
= −123.0° (c 1.0, CH2Cl2). MP: 156−157 °C. H NMR (300 MHz,
CDCl3) δ 7.45−7.27 (m, 10H), 4.52 (d, J = 13.7 Hz, 1H), 3.92 (d, J =
13.7 Hz, 1H), 3.81 (d, J = 3.4 Hz, 1H), 3.57 (d, J = 10.3 Hz, 1H),
3.36 (dd, J = 10.3, 4.0 Hz, 1H), 3.17 (t, J = 3.8 Hz, 1H). 13C{1H}
NMR (75 MHz, CDCl3) δ 134.9, 133.9, 129.1, 128.9, 128.8 (2C),
128.6, 126.7, 49.2, 46.5, 45.5, 45.1. HRMS (ESI, m/z) calcd for
C16H16N2O2S1Na [M + Na]+: 323.0825, found: 323.0826. IR (film):
ν (cm−1) 1497, 1455, 1334, 1165, 1134, 1093, 1047, 1018, 993, 937,
872, 842, 816, 796, 767, 744, 720, 694, 657, 610, 570, 530, 487, 470,
421.
Kinetic Isotope Experiments. Two parallel reactions: Ring-
closing C−H aminations 1a → 2a and 1a′ → 2a′ were performed
independently following the general procedure, and partial con-
versions were determined after 2 h reaction time from 1H NMR using
1,1,2,2-tetrachloroethane as the internal standard. The KIE was
determined from the ratio of these relative initial rates. Intermolecular
competition reaction: A 1:1 mixture of 1a (15.8 mg, 0.05 mmol) and
1a′ (15.9 mg, 0.05 mmol) was converted to a mixture of 2a and 2a′
following the general procedure. After a reaction time of 2 h, the ratio
of 2a and 2a′ was determined by 1H NMR (Figure S1 of the
Supporting Information). Intramolecular competition reaction: The
ring-closing amination of 1t′ (33.2 mg, 0.1 mmol) following the
general procedure provided a mixture of 2t′ and 2t″, and the ratio was
Follow-up Chemistry. The cyclic 5-membered sulfamide 2a
(57.6 mg, 0.2 mmol) was dissolved in hydrazine monohydrate (3 mL)
and stirred for 14 h at a 110 °C oil bath temperature. After removing
the solvent under reduced pressure, EtOAc (4 mL) was added and the
1
determined by H NMR (Figure S2 of the Supporting Information).
J
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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Article
Diastereochemistry of Allylic C−H Amination. (E)-2-Benzyl-
4-(but-1-en-1-yl)-1,2,5-thiadiazolidine-1,1-dioxide ((E)-2z). Starting
from (E)-1z (29.4 mg, 0.1 mmol) according to the general procedure,
(E)-2z was afforded as a colorless oil (25.8 mg, 0.097 mmol, 97%
yield, E:Z > 99:1; n-hexane/EtOAc = 4:1). Enantiomeric excess was
determined by HPLC analysis on a Chiralpak OD-H column, ee =
63% (absorbance at 210 nm, mobile phase: n-hexane/isopropanol =
90:10, flow rate 1.0 mL/min, 25 °C, tr (major) = 11.0 min, tr (minor)
= 13.5 min). [α]D22 = −33.0° (c 1.0, CH2Cl2). The analytical data of
(E)-2z are in accordance with a literature report.15 1H NMR (300
MHz, CDCl3) δ 7.40−7.28 (m, 5H), 5.78 (dt, J = 15.3, 6.2 Hz, 1H),
5.41 (dd, J = 15.3, 7.8 Hz, 1H), 4.45 (br s, 1H), 4.28 (d, J = 13.7 Hz,
1H), 4.04 (d, J = 13.7 Hz, 1H), 4.19 (quint, J = 7.1 Hz, 1H), 3.33 (dd,
J = 9.4, 6.8 Hz, 1H), 2.99 (dd, J = 9.3, 7.9 Hz, 1H), 2.03 (quint, J =
7.1 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 138.2, 135.3, 128.9, 128.7, 128.3, 125.6, 54.9, 53.7, 50.6,
25.2, 13.1.
Zihan Yan − Fachbereich Chemie, Philipps-Universität
Marburg, 35043 Marburg, Germany
Sergei Ivlev − Fachbereich Chemie, Philipps-Universität
Marburg, 35043 Marburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02279
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge funding from the Deutsche
Forschungsgemeinschaft (ME 1805/15-1).
(Z)-2-Benzyl-4-(but-1-en-1-yl)-1,2,5-thiadiazolidine-1,1-dioxide
((Z)-2z). Starting from (Z)-1z (29.4 mg, 0.1 mmol) according to the
general procedure, (Z)-2z was afforded as a colorless oil (25.3 mg,
0.095 mmol, 95% yield, Z/E = 40:1; n-hexane/EtOAc = 4:1).
Enantiomeric excess was determined by HPLC analysis on a
Chiralpak OD-H column, ee = 73% (absorbance at 210 nm, mobile
phase: n-hexane/isopropanol = 90:10, flow rate 1.0 mL/min, 25 °C, tr
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02279.
NMR spectra, HPLC traces, and crystallographic data
(2j and 9); NMR spectra of the intermolecular
competition KIE experiment (Figure S1); NMR spectra
of the intramolecular competition KIE experiment
(Figure S2); diastereochemistry and Z/E ratio at 55
and 80 °C (Figure S3); selected crystallographic data
and details of the structure determination for 2j (Table
S1); selected crystallographic data and details of the
structure determination for 9 (Table S2) (PDF)
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Accession Codes
CCDC 2026683−2026684 contain the supplementary crys-
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AUTHOR INFORMATION
Corresponding Author
■
Eric Meggers − Fachbereich Chemie, Philipps-Universität
Marburg, 35043 Marburg, Germany; orcid.org/0000-
0002-8851-7623; Email: meggers@chemie.uni-
marburg.de
Authors
Xin Nie − Fachbereich Chemie, Philipps-Universität Marburg,
35043 Marburg, Germany
K
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