J. Org. Chem. 2023, 88, 22, 15989-16006

pubs.acs.
org/joc Note
Ring Opening of Aziridines by Pendant Sulfamates Allows for

Regioselective and Stereospecific Preparation of Vicinal Diamines
Someshwar Nagamalla, Annu Anna Thomas, Appasaheb K. Nirpal, Joel T. Mague,
and Shyam Sathyamoorthi*
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ABSTRACT: The ring opening of aziridines by pendant sulfamates is a viable strategy for the rapid preparation of vicinal diamines.
Our reaction is compatible with both disubstituted cis- and trans-aziridines; unsubstituted, N-alkyl, and N-aryl sulfamates engage
effectively. In all cases examined, the cyclization reaction is perfectly regioselective and stereospecific. Once activated, the product
oxathiazinane heterocycles can be ring opened with a diverse range of nucleophiles.
V icinal diamines (1,2-diamines) are well represented in

molecules of value, including those used as medicines,
ligands, and agrochemicals.1−7 Given their importance to
Scheme 1. Current Strategies To Access Vicinal Diamines
Inspire Our Own Efforts
multiple areas of synthetic chemistry, it is no surprise that

numerous protocols have been invented for their construc-
tion.8−39 Diamination of olefins40−45 and untethered (inter-
molecular) aminolysis46−48 of aziridines are common strategies
for accessing these motifs (Scheme 1). The direct diamination
of olefins is a powerful approach for the construction of vicinal
diamines as it installs both nitrogens in a single synthetic step;
some limitations of existing protocols include harsh reaction
conditions, limited substrate scope, and issues with regiose-
lectivity and stereoselectivity. Intermolecular aminolysis of
aziridines has also been studied in numerous contexts, but
depending on the substrate and reaction conditions, intractable
mixtures of regioisomeric products can result. In contrast to
the first two approaches, aminolysis of aziridines utilizing
detachable tethers has hardly been explored for the synthesis of
1,2-diamines (Scheme 1).49 As part of a larger program on
olefin functionalization50−52 and ring opening of aziridines53,54
and epoxides,55−57 our laboratory is very interested in using
sulfamate tethers as convenient N-nucleophiles. Here, we
present a mild protocol for the intramolecular ring opening of
aziridines by pendant sulfamates, which allows for regiose-
lective and stereospecific syntheses of a variety of vicinal Received: August 1, 2023
diamines. Further, we demonstrate that the product Revised: September 22, 2023
oxathiazinanes are convenient synthons for an array of Accepted: October 18, 2023
polyfunctional targets. Published: October 30, 2023
Before we could begin exploring our envisioned intra-
molecular ring- opening of aziridines by tethered sulfamates,
© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.3c01731

15989 J. Org. Chem. 2023, 88, 15989−16006
The Journal of Organic Chemistry pubs.acs.org/joc Note
we had to develop robust protocols for starting material Scheme 3. Structure−Reactivity Relationship with Various
preparation (Scheme 2). While epoxy-sulfamates can be readily Sulfamate Esters
Scheme 2. Representative Preparation of Aziridine

Sulfamate Substrates
synthesized by mCPBA epoxidation of the corresponding

alkene, alkenyl sulfamates were resistant to several existing
aziridination protocols.58−60 Fortunately, alkenyl alcohols and
alkenyl acetates were amenable to aziridination using Sharpless (Scheme 3, entry 2). With bulkier substituents such as p-
(Scheme 2A),58 Kü rti (Scheme 2B),59 or Komatsu61,62 methoxy-phenyl (Scheme 3, entry 3), the yield of cyclization
(Scheme 2C) reactions. In the case of aziridine acetates dropped, and the reaction time had to be extended to 36 h. We
(Scheme 2A and 2B), carefully monitored hydrolysis gave note that the mass balance of the reaction was excellent and
aziridine alcohols, which were then converted into the was comprised of product and unreacted starting material.
corresponding sulfamates.63,64 Cyclization reactions with p-methyl-phenyl and phenyl
Our laboratory has previously explored the ring-opening of sulfamates were similarly efficient (Scheme 3, entries 4 and
epoxides and aziridines using both sulfamate55 and di-tert- 5). In contrast, N-cyclohexyl sulfamate 11 was completely
butylsilanol tethers.53,54,56,57 It is noteworthy that while di-tert- resistant to cyclization (Scheme 3, entry 6).
butylsilanol epoxides and aziridines cyclize efficiently when We next examined the effect of varying the substituent on
treated with Lewis acids or Brønsted acids, the corresponding the aziridine nitrogen (Scheme 4). In general, to successfully
sulfamate substrates do not react well under these conditions. engage, the aziridine had to be “activated” with an electron-
With epoxy-sulfamates, treatment with aqueous base gave withdrawing group. A variety of such moieties were well
clean and reproducible reactivity.55 Analogously, when tolerated, including methanesulfonyl, 2-thiophenesulfonyl, 4-
aziridine sulfamate 1 was stirred with 1 equiv of Bu4NOH· bromophenylsulfonyl, 4-nitrobenzenesulfonyl, 2,5-difluoroben-
30H2O in a 1:1 mixture of CF3−toluene/H2O at room zenesulfonyl, and 2-naphthalenesulfonyl groups (Scheme 4,
temperature, oxathiazinane 2 formed in an excellent yield of entries 1−6). Tosyl groups can be difficult to remove from
82% (Scheme 3, entry 1). A crystal structure of 2 allowed us to amines, often requiring harsh reagents like lithium aluminum
unambiguously assign its identity and relative stereochemistry hydride or dissolving metal conditions with poor functional
(CCDC 2274209). We wished to study the effect of adding group compatibility. In contrast, nitrobenzenesulfonyl (nosyl)
substituents to the sulfamate nitrogen. Replacing H with a Me groups are much more amenable to removal, often with room
group did not dramatically affect the efficiency of cyclization temperature treatment with thiolate nucleophiles; thus, we
15990 https://doi.org/10.1021/acs.joc.3c01731
J. Org. Chem. 2023, 88, 15989−16006
Scheme 4. Structure−Reactivity Relationship with Various Scheme 5. Substrate Scope

Aziridine N-Substituents
a
Reaction conditions: Bu4NOH·30H2O) (1 equiv)/1:1 CF3−
toluene:H2O/23 °C, 16 h. bIn parentheses: substrate number,
a
product number.
In parentheses: substrate number, product number.
Scheme 6. Cyclization Scales Well with Both cis- and trans-
were pleased that nosylated aziridines were fully compatible Aziridine Sulfamate Substrates
with our optimized protocol. There was no productive reaction
with N-phthalimido-aziridine substrate 24; only decomposition
of starting material was observed (Scheme 4, entry 7). We
hypothesize that the known instability of phthalimide
protecting groups in a basic milieu underlies this.
With all substrates tested (Scheme 5), the cyclization was
perfectly regioselective and stereospecific. In all cases, the
pendant sulfamate auxiliary cleaved the aziridine with 6-exo-
selectivity to give 6-membered oxathiazinane heterocycles
bearing vicinal diamines. trans-Aziridine sulfamate starting
materials gave products with an erythro configuration;
conversely, cis-aziridine sulfamates gave products with a threo
configuration. With our optimized protocol, cis, trans, and
terminal aziridine sulfamates were competent cyclization
substrates but, in some instances, with differing reactivity. example, stirring 6 with NaN3 at room temperature formed
For example, cis-aziridine N-cyclohexyl sulfamate 11 (Scheme azide 47, which is a triamine surrogate (Scheme 7A). When 2
3) gave no reaction, even with extended reaction times; in was reacted with triphosgene and NEt3 at 0 °C, bicyclic
sharp contrast, trans-aziridine N-cyclohexyl sulfamate 27 oxathiazinane urea 48 formed in good yield (Scheme 7B). The
cyclized efficiently (Scheme 5, entry 1). Crystal structures of reactions conditions had to be carefully controlled; when the
products 26 (CCDC 2277022) and 28 (CCDC 2277021) reaction was warmed to room temperature, chloride 49 was the
allowed for unambiguous determination of the relative exclusive product. Crystal structures of 48 (CCDC 2277025)
stereochemistry. The identities of other products were assigned and 49 (CCDC 2277024) have allowed us to confirm the
by analogy. Multifold increases in scale were tolerated without identity and relative stereochemistry. Similar reactions with 26
erosion of yield or selectivity (Scheme 6). allowed for formation of products 50 (CCDC 2279638) and
The oxathiazinane products could be ring opened with a 51, which are epimers of 48 and 49 (Scheme 7B). Bicyclic
variety of nucleophiles, allowing for the rapid transformation of oxathiazinane ureas 48 and 50 could be ring opened with a
these heterocycles into value-added products (Scheme 7). For diverse array of nucleophiles, allowing for the facile
J. Org. Chem. 2023, 88, 15989−16006
Scheme 7. Product Oxathlazinane Heterocycles Are

Amenable to Further Functionalization
■ EXPERIMENTAL SECTION
I. General Considerations. All reagents were obtained
commercially unless otherwise noted. Solvents were purified by
passage under 10 psi N2 through activated alumina columns. Infrared
(IR) spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR
Spectrometer; data are reported in frequency of absorption (cm−1).
1
H NMR spectra were recorded at 400, 500, or 600 MHz. Data are
recorded as chemical shift in ppm referenced internally using residual
solvent peaks, multiplicity (s = singlet, br s = broad singlet, d =
doublet, t = triplet, q = quartet, m = multiplet or overlap of
nonequivalent resonances, qdd = quartet of doublet of doublets, tdt =
triplet of doublet of triplets, dtq = doublet of triplet of quartets, qd =
quartet of doublets, tdq = triplet of doublet of quartets), integration,
coupling constant (Hz). 13C NMR spectra were recorded at 101 or
126 MHz. Exact mass spectra were recorded using an electrospray ion
source (ESI) either in positive mode or in negative mode and with a
time-of-flight (TOF) analyzer on a Waters LCT Premier mass
spectrometer and are given in m/z. Thin layer chromatography
(TLC) was performed on precoated glass plates (Merck) and
visualized either with a UV lamp (254 nm) or by dipping into a
solution of KMnO4−K2CO3 in water followed by heating. Flash
chromatography was performed on silica gel (230−400 mesh) or
Florisil (60−100 mesh).
II. Procedures for Substrate Syntheses. General Procedure A:
Johnson−Magolan Sulfamoylation.
A round-bottom flask was charged with a stir bar, aziridine alcohol

substrate (1 mmol), 1,1,1,3,3,3-hexafluoropropan-2-yl sulfamate
(0.494 g, 2 mmol, 2 equiv), and a 7:3 mixture of CH2Cl2/pyridine
(7 mL of CH2Cl2 and 3 mL of pyridine). The homogeneous mixture
was warmed to 30 °C using an oil bath and kept at this temperature
for 5−16 h (substrate dependent). Following this time, the contents
of the reaction flask were transferred to a separatory funnel with
additional CH2Cl2. The organic layer was washed with one portion of
1 M aqueous HCl solution, collected, dried with MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by chromatography on silica gel (specific conditions are
associated with each compound). Note: quantities are given for a 1
mmol reaction and are modif ied appropriately with changes in scale.
General Procedure B: Sulfamoylation Using N-Cyclohexylsulfa-
moyl Chloride.
A 50 mL round-bottom flask was charged with a stir bar, aziridine

alcohol substrate (1 mmol), and anhydrous CH2Cl2 (5 mL). The
construction of C−C, C−O, C−N, and C−S linkages (Scheme reaction flask was cooled to 0 °C using an ice−water bath.
7C). Subsequently, N-cyclohexylsulfamoyl chloride (0.297 g, 1.5 mmol,
In summary, we have shown that the ring opening of 1.5 equiv, prepared from N-cyclohexylsulfamic acid by the procedure
aziridines by pendant sulfamates is a viable strategy for the of Koek and Leschinsky64) in anhydrous CH2Cl2 (5 mL) was added.
preparation of vicinal diamines. Our reaction is compatible Finally, NEt3 (0.209 mL, 0.152 g, 1.5 mmol, 1.5 equiv) was added
with both cis and trans disubstituted aziridines; unsubstituted, dropwise. The reaction mixture was allowed to warm to room
temperature over a period of 16 h. Following this time, the mixture
N-alkyl, and N-aryl sulfamates engaged effectively. In all cases
was diluted with CH2Cl2, transferred to a separatory funnel, and
examined, the cyclization reaction was perfectly regioselective washed with one portion of a saturated, aqueous NH4Cl solution. The
and stereospecific. The product oxathiazinane heterocycles organic layer was collected, dried over MgSO4 and concentrated
could be activated and ring opened with a diverse range of under reduced pressure. The resulting residue was purified by
nucleophiles. Given the importance of vicinal diamines to chromatography on silica gel (specific conditions are associated with
multiple areas, this strategy is a welcome addition to existing each compound). Note: quantities are given for a 1 mmol reaction and
protocols. are changed appropriately with changes in scale.
J. Org. Chem. 2023, 88, 15989−16006
General Procedure C: Sulfamoylation Using N-Methylsulfamoyl organic layer was collected, dried over MgSO4, and concentrated
Chloride. under reduced pressure. The resulting residue was purified by
chromatography on silica gel (gradient of 5−30% EtOAc/hexanes) to
give 7 as a colorless oil (0.228 g, 0.51 mmol, 27% yield).
Procedure F: Sulfamoylation Using Phenyl-Sulfamoyl Chloride.
A 50 mL round-bottom flask was charged with a stir bar, aziridine

alcohol substrate (1 mmol), and anhydrous CH2Cl2 (5 mL). The
reaction flask was cooled to 0 °C using an ice−water bath.
Subsequently, N-methylsulfamoyl chloride (0.194 g, 1.5 mmol, 1.5
A 50 mL round-bottom flask was charged with a stir bar, S4 (0.500 g,
equiv, prepared from N-methylsulfamic acid by the procedure of Koek
1.85 mmol, 1 equiv), and anhydrous CH2Cl2 (9 mL). The reaction
and Leschinsky64) in anhydrous CH2Cl2 (5 mL) was added. Finally,
flask was cooled to 0 °C using an ice−water bath. Subsequently,
NEt3 (0.209 mL, 0.152 g, 1.5 mmol, 1.5 equiv) was added dropwise.
phenylsulfamoyl chloride (0.531 g, 2.77 mmol, 1.5 equiv, prepared
The reaction mixture was allowed to warm to room temperature over
from phenylsulfamic acid by the procedure of Koek and Leschinsky64)
a period of 16 h. Following this time, the mixture was diluted with
in anhydrous CH2Cl2 (9 mL) was added. Finally, NEt3 (0.39 mL, 0.28
CH2Cl2, transferred to a separatory funnel, and washed with one
g, 2.8 mmol, 1.5 equiv) was added dropwise. The reaction mixture
portion of a saturated, aqueous NH4Cl solution. The organic layer
was allowed to warm to room temperature over a period of 16 h.
was collected, dried over MgSO4, and concentrated under reduced
Following this time, the mixture was diluted with CH2Cl2, transferred
pressure. The resulting residue was purified by chromatography on
to a separatory funnel, and washed with one portion of a saturated,
silica gel (specific conditions are associated with each compound).
aqueous NH4Cl solution. The organic layer was collected, dried over
Note: quantities are given for a 1 mmol reaction and are changed
MgSO4, and concentrated under reduced pressure. The resulting
appropriately with changes in scale.
residue was purified by chromatography on silica gel (gradient of 5−
Procedure D: Sulfamoylation Using p-Methoxy-Phenylsulfamoyl
Chloride. 30% EtOAc/hexanes) to give 9 as a colorless oil (0.287 g, 0.67 mmol,
36% yield).
III. Procedure for Cyclization Reactions. General Procedure G.
A 50 mL round-bottom flask was charged with a stir bar, S4 (0.269 g,

1 mmol, 1 equiv), and anhydrous CH2Cl2 (5 mL). The reaction flask A 5 mL microwave vial was charged with a stir bar, aziridine substrate
was cooled to 0 °C using an ice−water bath. Subsequently, p- (0.2 mmol, 1 equiv), and 2 mL of CF3−toluene. Bu4NOH·30H2O
methoxy-phenylsulfamoyl chloride (0.331 g, 1.5 mmol, 1.5 equiv, (0.160 g, 0.2 mmol, 1 equiv) was dissolved in 2 mL of H2O and added
prepared from p-methoxy-phenylsulfamic acid by the procedure of to this mixture. The microwave vial was capped, and the reaction was
Koek and Leschinsky64) in anhydrous CH2Cl2 (5 mL) was added. stirred at room temperature for 16−36 h. Following this time, the
Finally, NEt3 (0.21 mL, 0.15 g, 1.5 mmol, 1.5 equiv) was added contents of the reaction flask were transferred to a separatory funnel
dropwise. The reaction mixture was allowed to warm to room with CH2Cl2. The water layer was acidified to pH ≈ 1 using a 1 M
temperature over a period of 16 h. Following this time, the mixture aqueous HCl solution and extracted twice with CH2Cl2 and once with
was diluted with CH2Cl2, transferred to a separatory funnel, and EtOAc. The organic layers were combined, dried with MgSO4, and
washed with one portion of a saturated, aqueous NH4Cl solution. The concentrated under reduced pressure. The resulting residue was
organic layer was collected, dried over MgSO4, and concentrated purified by chromatography on silica gel (specific conditions are
under reduced pressure. The resulting residue was purified by associated with each substrate).
chromatography on silica gel (gradient of 5−30% EtOAc/hexanes) to IV. Characterization of Substrates and Products. Compound
give 5 as a colorless oil (0.136 g, 0.3 mmol, 30% yield). 1.
Procedure E: Sulfamoylation Using p-Methyl-Phenylsulfamoyl
Chloride.
Synthesized using General Procedure A on a 7.43 mmol scale. Purified

using a gradient of 10−40% EtOAc in hexane on silica gel; single
diastereomer (colorless oil, 1.3 g, 3.73 mmol, 50% yield).
1
A 50 mL round-bottom flask was charged with a stir bar, S4 (0.500 g, H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J
1.85 mmol, 1 equiv), and anhydrous CH2Cl2 (9 mL). The reaction = 8.2 Hz, 2H), 5.23 (s, 2H), 4.43−4.09 (m, 2H), 3.04 (ddd, J = 9.7,
flask was cooled to 0 °C using an ice−water bath. Subsequently, p- 7.3, 3.7 Hz, 1H), 2.67 (ddd, J = 8.5, 7.3, 5.2 Hz, 1H), 2.45 (s, 3H),
methyl-phenylsulfamoyl chloride (0.570 g, 2.77 mmol, 1.5 equiv, 2.21−2.08 (m, 1H), 1.80−1.59 (m, 1H), 1.51 (ddd, J = 14.3, 7.4, 5.3
prepared from p-methyl-phenylsulfamic acid by the procedure of Hz, 1H), 1.32 (ddd, J = 14.3, 8.4, 7.3 Hz, 1H), 0.76 (t, J = 7.4 Hz,
Koek and Leschinsky64) in anhydrous CH2Cl2 (9 mL) was added. 3H).
13
Finally, NEt3 (0.39 mL, 0.28 g, 2.8 mmol, 1.5 equiv) was added C{1H} NMR (101 MHz, CDCl3) δ 145.0, 134.2, 129.9, 128.3,
dropwise. The reaction mixture was allowed to warm to room 68.8, 47.4, 41.1, 26.2, 21.8, 20.2, 11.5.
temperature over a period of 16 h. Following this time, the mixture IR ν 3320, 2974, 1597, 1357, 1160, 1012 cm−1.
was diluted with CH2Cl2, transferred to a separatory funnel, and HRMS (ESI) m/z: [M + Na]+ calcd for C13H20N2O5S2Na+
washed with one portion of a saturated, aqueous NH4Cl solution. The 371.0711, found 371.0728 (4.6 ppm error).
J. Org. Chem. 2023, 88, 15989−16006
Compound 2. Compound 5.
Synthesized using General Procedure G on a 0.2 mmol scale. Purified Procedure for synthesis and purification provided in Procedure D.
1
using a gradient of 30−60% EtOAc in hexane on silica gel; single H NMR (400 MHz, CDCl3) δ 7.85−7.76 (m, 2H), 7.38−7.29 (m,
diastereomer (white solid, 0.057 g, 0.164 mmol, 82% yield). 2H), 7.25−7.17 (m, 2H), 6.93−6.84 (m, 2H), 6.65 (s, 1H), 4.26−
1 4.09 (m, 2H), 3.80 (s, 3H), 2.88 (ddd, J = 8.8, 7.3, 4.5 Hz, 1H), 2.68
H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.34−
7.29 (m, 2H), 5.14 (d, J = 8.4 Hz, 1H), 4.75−4.71 (m, 1H), 4.71− (ddd, J = 8.4, 7.3, 5.3 Hz, 1H), 2.44 (s, 3H), 2.00 (dddd, J = 14.6, 8.5,
4.65 (m, 1H), 4.58 (ddd, J = 11.4, 5.2, 1.6 Hz, 1H), 3.76 (ddt, J = 6.0, 4.5 Hz, 1H), 1.67 (ddt, J = 14.2, 8.8, 5.2 Hz, 1H), 1.48 (dqd, J =
12.1, 10.9, 3.0 Hz, 1H), 3.27−3.16 (m, 1H), 2.42 (s, 3H), 2.20 (dtd, J 14.9, 7.5, 5.2 Hz, 1H), 1.34−1.25 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H).
13
= 14.9, 12.8, 5.3 Hz, 1H), 1.64 (dq, J = 14.7, 2.1 Hz, 1H), 1.53 (dt, J = C{1H} NMR (101 MHz, CDCl3) δ 158.1, 144.9, 134.7, 129.9,
14.4, 7.2 Hz, 1H), 1.30−1.22 (m, 1H), 0.60 (t, J = 7.4 Hz, 3H). 128.8, 128.3, 124.7, 114.8, 69.2, 55.7, 46.8, 41.1, 26.7, 21.8, 20.3, 11.6.
13
C{1H} NMR (101 MHz, CDCl3) δ 144.1, 137.3, 130.0, 127.2, IR ν 3430, 2968, 1645, 1508, 1357, 1172, 1020 cm−1.
72.0, 58.1, 57.8, 27.5, 24.9, 21.7, 10.2. HRMS (ESI) m/z: [M + Na]+ calcd for C20H26N2O6S2Na+
IR ν 3430, 2948, 1645, 1434, 1165, 1020 cm−1. 477.1130, found 477.1135 (1.0 ppm error).
HRMS (ESI) m/z: [M + Na]+ calcd for C13H20N2O5S2Na+ Compound 6.
371.0711, found 371.0727 (4.3 ppm error).
Compound 3.
Synthesized using General Procedure G on a 0.2 mmol scale (time =

Synthesized using General Procedure C on a 2 mmol scale. Purified 36 h). Purified using a gradient of 20−60% EtOAc in hexane on silica
using a gradient of 10−30% EtOAc in hexane on silica gel; single gel; single diastereomer (white solid, 51 mg, 0.112 mmol, 56% yield).
diastereomer (colorless oil, 0.218 g, 0.6 mmol, 30% yield). 1
H NMR (500 MHz, CDCl3) δ 7.55−7.49 (m, 2H), 7.42−7.35 (m,
1
H NMR (400 MHz, CDCl3) δ 7.84−7.78 (m, 2H), 7.38−7.31 (m, 2H), 7.23−7.17 (m, 2H), 7.00−6.92 (m, 2H), 4.82 (td, J = 11.5, 2.9
2H), 4.78 (q, J = 5.2 Hz, 1H), 4.22 (ddd, J = 10.2, 5.6, 4.8 Hz, 1H), Hz, 1H), 4.69 (ddd, J = 11.3, 4.8, 2.8 Hz, 1H), 4.41 (d, J = 6.7 Hz,
4.13 (ddd, J = 10.0, 9.0, 4.7 Hz, 1H), 2.99 (ddd, J = 9.2, 7.3, 4.0 Hz, 1H), 4.28 (dt, J = 10.7, 3.7 Hz, 1H), 3.87 (s, 3H), 2.87 (ddt, J = 10.1,
1H), 2.83 (d, J = 5.2 Hz, 3H), 2.71 (ddd, J = 8.5, 7.3, 5.2 Hz, 1H), 6.7, 3.3 Hz, 1H), 2.39 (s, 3H), 2.21−2.00 (m, 2H), 1.68 (ddd, J =
2.45 (s, 3H), 2.09 (dddd, J = 14.7, 9.0, 5.7, 4.0 Hz, 1H), 1.67 (ddt, J = 14.6, 7.3, 2.8 Hz, 1H), 1.08 (dtd, J = 14.4, 7.2, 3.0 Hz, 1H), 0.23 (t, J
14.2, 9.4, 4.8 Hz, 1H), 1.58−1.46 (m, 1H), 1.33 (ddd, J = 14.3, 8.4, = 7.4 Hz, 3H).
13
7.3 Hz, 1H), 0.79 (t, J = 7.4 Hz, 3H). C{1H} NMR (126 MHz, CDCl3) δ 160.1, 144.0, 136.4, 130.5,
13
C{1H} NMR (101 MHz, CDCl3) δ 144.9, 134.6, 129.8, 128.2, 129.7, 129.6, 127.3, 114.9, 72.0, 63.8, 55.8, 55.7, 23.7, 21.7, 21.6, 10.2.
68.4, 47.1, 41.1, 30.2, 26.7, 21.8, 20.3, 11.6. IR ν 3430, 3011, 2948, 1645, 1357, 1172, 1020 cm−1.
IR ν 3300, 2978, 1597, 1357, 1160, 1012 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C20H26N2O6S2Na+
HRMS (ESI) m/z: [M + Na]+ calcd for C14H22N2O5S2Na+ 477.1130, found 477.1138 (1.7 ppm error).
385.0868, found 385.0880 (3.1 ppm error). Compound 7.
Compound 4.
Synthesized using Procedure E on a 1.85 mmol scale. Purified using a

gradient of 5−25% EtOAc/hexanes on silica gel; single diastereomer
Synthesized using General Procedure G on a 0.2 mmol scale. Purified (colorless oil, 0.228 g, 0.52 mmol, 28% yield).
using a gradient of 30−50% EtOAc in hexane on silica gel; single 1
H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.32 (d, J
diastereomer (white solid, 0.051 g, 0.14 mmol, 70% yield). = 8.3 Hz, 2H), 7.18−7.09 (m, 4H), 6.85 (s, 1H), 4.26−4.08 (m, 2H),
1
H NMR (400 MHz, CDCl3) δ 7.80−7.72 (m, 2H), 7.35−7.28 (m, 2.86 (ddd, J = 8.6, 7.2, 4.6 Hz, 1H), 2.67 (ddd, J = 8.4, 7.2, 5.2 Hz,
2H), 4.86 (d, J = 6.3 Hz, 1H), 4.61−4.52 (m, 2H), 3.91 (ddd, J = 1H), 2.43 (s, 3H), 2.33 (s, 3H), 1.99 (dddd, J = 14.6, 8.4, 6.0, 4.6 Hz,
10.6, 8.5, 3.5 Hz, 1H), 3.49−3.40 (m, 1H), 2.66 (s, 3H), 2.43 (s, 3H), 1H), 1.67 (d, J = 5.8 Hz, 1H), 1.47 (ddd, J = 14.2, 7.4, 5.3 Hz, 1H),
2.05−1.94 (m, 1H), 1.79−1.61 (m, 2H), 1.35−1.23 (m, 1H), 0.72 (t, 1.30 (ddd, J = 14.3, 8.4, 7.2 Hz, 1H), 0.80 (t, J = 7.4 Hz, 3H).
13
J = 7.4 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 144.8, 135.4, 134.6, 133.6,
13
C{1H} NMR (126 MHz, CDCl3) δ 143.9, 137.9, 129.9, 127.1, 130.1, 129.8, 128.2, 121.2, 69.2, 46.7, 41.1, 26.6, 21.8, 20.9, 20.2, 11.5.
71.4, 61.1, 55.5, 32.7, 23.7, 21.7, 20.0, 8.5. IR ν 3273, 2968, 2926, 1514, 1457, 1405, 1363, 1320, 1174, 1157,
IR ν 3436, 2978, 1645, 1487, 1165, 1020 cm−1. 1092, 932, 815, 724, 673, 573 cm−1.
HRMS (ESI) m/z: [M + Na]+ calcd for C14H22N2O5S2Na+ HRMS (ESI) m/z: [M + Na]+ calcd for C20H26N2O5S2Na+
385.0868, found 385.0878 (2.6 ppm error). 461.1181, found 461.1192 (2.4 ppm error).
J. Org. Chem. 2023, 88, 15989−16006
Synthesized using General Procedure G on a 0.182 mmol scale.

Purified using a gradient of 5−30% EtOAc/hexanes on silica gel; Synthesized using General Procedure B on a 1.5 mmol scale. Purified
single diastereomer (colorless crystalline solid, 0.039 g, 0.089 mmol, using a gradient of 10−30% EtOAc in hexane on silica gel; single
48% yield). diastereomer (colorless oil, 0.206 g, 0.48 mmol, 32% yield).
1 1
H NMR (500 MHz, CDCl3) δ 7.54−7.50 (m, 2H), 7.35−7.31 (m, H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.34 (d, J
2H), 7.27−7.24 (m, 2H), 7.21−7.17 (m, 2H), 4.81 (td, J = 11.3, 3.1 = 8.1 Hz, 2H), 4.47 (d, J = 7.5 Hz, 1H), 4.19−3.99 (m, 2H), 3.32
Hz, 1H), 4.70 (ddd, J = 11.4, 4.8, 3.0 Hz, 1H), 4.51 (d, J = 6.8 Hz, (dtd, J = 10.5, 6.9, 3.6 Hz, 1H), 2.93 (ddd, J = 8.7, 7.3, 4.5 Hz, 1H),
1H), 4.29 (dt, J = 10.5, 3.9 Hz, 1H), 2.86 (ddt, J = 10.1, 6.8, 3.4 Hz, 2.73 (ddd, J = 8.3, 7.3, 5.3 Hz, 1H), 2.45 (s, 3H), 2.04 (dddt, J = 13.1,
1H), 2.42 (s, 3H), 2.39 (s, 3H), 2.22−2.05 (m, 2H), 1.68 (ddt, J = 11.0, 9.2, 4.7 Hz, 3H), 1.84−1.64 (m, 3H), 1.62−1.46 (m, 2H),
14.5, 7.5, 3.8 Hz, 1H), 1.09 (ddq, J = 14.4, 10.1, 7.2 Hz, 1H), 0.23 (t, 1.41−1.18 (m, 6H), 0.83 (t, J = 7.4 Hz, 3H).
J = 7.4 Hz, 3H). 13
C{1H} NMR (101 MHz, CDCl3) δ 144.8, 134.8, 129.8, 128.3,
13
C{1H} NMR (126 MHz, CDCl3) δ 144.0, 139.3, 136.4, 134.8, 68.0, 53.9, 46.7, 41.2, 33.87, 33.80, 26.8, 25.3, 24.8 (2C), 21.8, 20.3,
130.3, 129.7, 129.0, 127.2, 72.0, 63.7, 55.8, 23.6, 21.7, 21.6, 21.3, 10.1. 11.6.
IR ν 3408, 1651, 1636, 1508, 1457, 1363, 1317, 1174, 1163, 1092, IR ν 3299, 2943, 1597, 1457, 1172, 1020 cm−1.
1018, 901, 812, 781, 664, 550 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C19H30N2O5S2Na+
HRMS (ESI) m/z: [M + Na]+ calcd for C20H26N2O5S2Na+ 453.1494, found 453.1510 (3.5 ppm error).
Compound 9.
Synthesized using Procedure F on a 1.85 mmol scale. Purified using a

gradient of 5−25% EtOAc/hexanes on silica gel; single diastereomer Synthesized using General Procedure A on a 2 mmol scale. Purified
(colorless oil, 0.287 g, 0.67 mmol, 36% yield). using a gradient of 10−30% ethyl acetate in CH2Cl2 on silica gel;
1
H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.37− single diastereomer (colorless oil, 191 mg, 0.7 mmol, 35% yield).
1
7.30 (m, 4H), 7.24−7.15 (m, 3H), 7.15−7.09 (m, 1H), 4.24−4.12 H NMR (400 MHz, CDCl3) δ 5.42 (s, 2H), 4.32 (tdd, J = 9.9, 9.0,
(m, 2H), 2.86 (ddd, J = 8.6, 7.3, 4.7 Hz, 1H), 2.66 (ddd, J = 8.3, 7.3, 4.8 Hz, 2H), 3.08 (s, 3H), 2.97 (ddd, J = 9.2, 7.4, 3.8 Hz, 1H), 2.76
5.2 Hz, 1H), 2.43 (s, 3H), 2.07−1.94 (m, 1H), 1.68 (ddt, J = 14.1, (td, J = 7.8, 5.6 Hz, 1H), 2.19−2.05 (m, 1H), 1.82−1.68 (m, 1H),
8.7, 5.2 Hz, 1H), 1.45 (dtd, J = 14.9, 7.4, 5.1 Hz, 1H), 1.36−1.24 (m, 1.66−1.44 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H).
13
1H), 0.79 (t, J = 7.5 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 68.7, 46.7, 41.0, 39.6, 26.3,
13
C{1H} NMR (101 MHz, CDCl3) δ 144.9, 136.4, 134.5, 129.8, 20.3, 11.7.
129.6, 128.2, 125.2, 120.4, 69.3, 46.7, 41.0, 26.6, 21.7, 20.2, 11.5. IR ν 3368, 3259, 1371, 1303, 1183, 1146, 932 cm−1.
IR ν 3436, 2971, 1654, 1636, 1599, 1488, 1363, 1320, 1174, 1157, HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C7H16N2O5S2Na
1092, 929, 815, 755, 673, 573 cm−1. 295.0398, found 295.0403 (1.7 ppm error).
HRMS (ESI) m/z: [M + Na]+ calcd for C19H24N2O5S2Na+ Compound 13.
447.1024, found 447.1031 (1.6 ppm error).
Compound 10.
Synthesized using General Procedure G on a 0.31 mmol scale. Synthesized using General Procedure G on a 0.2 mmol scale. Purified
Purified using a gradient of 10−35% EtOAc/hexanes on silica gel; using a gradient of 10−30% ethyl acetate in dichloromethane on silica
single diastereomer (white solid, 0.059 g, 0.14 mmol, 45% yield). gel; single diastereomer (colorless oil, 0.045 g, 0.165 mmol, 83%
1
H NMR (500 MHz, CDCl3) δ 7.31−7.28 (m, 2H), 7.28−7.24 (m, yield).
1
4H), 7.25−7.21 (m, 1H), 7.00−6.96 (m, 2H), 4.68−4.59 (m, 1H), H NMR (500 MHz, CDCl3) δ 5.13 (d, J = 8.7 Hz, 1H), 4.94 (d, J
4.57−4.47 (m, 1H), 4.35 (d, J = 11.5 Hz, 1H), 4.14 (dt, J = 9.5, 4.3 = 11.0 Hz, 1H), 4.69 (ddd, J = 13.0, 11.6, 2.3 Hz, 1H), 4.59 (ddd, J =
Hz, 1H), 2.68−2.58 (m, 1H), 2.18 (s, 3H), 1.95 (tdd, J = 14.5, 10.2, 11.4, 5.2, 1.6 Hz, 1H), 3.76 (dddd, J = 12.1, 10.9, 4.3, 2.5 Hz, 1H),
4.1 Hz, 2H), 1.45 (dt, J = 12.0, 7.6 Hz, 1H), 0.88 (ddq, J = 14.3, 10.2, 3.39 (tdd, J = 8.4, 6.4, 4.2 Hz, 1H), 3.06 (s, 3H), 2.12 (dtd, J = 14.6,
7.1 Hz, 1H), −0.03 (t, J = 7.5 Hz, 3H). 12.7, 5.2 Hz, 1H), 1.78−1.69 (m, 1H), 1.69−1.60 (m, 2H), 1.03 (t, J
13
C{1H} NMR (126 MHz, CDCl3) δ 144.0, 137.5, 136.3, 129.75, = 7.4 Hz, 3H).
13
129.72, 129.3, 129.2, 127.2, 72.1, 63.8, 55.8, 23.6, 21.6 (2C), 10.1. C{1H} NMR (126 MHz, CDCl3) δ 72.0, 58.4, 58.3, 42.0, 27.5,
IR ν 3422, 2971, 1654, 1636, 1559, 1457, 1363, 1317, 1174, 1092, 25.3, 10.7.
1018, 901, 801, 735, 664, 550 cm−1. IR ν 3299, 3265, 1434, 1348, 1317, 1172, 1126, 932 cm−1.
HRMS (ESI) m/z: [M + Na]+ calcd for C19H24N2O5S2Na+ HRMS (ESI-TOF) m/z: [M + H]+ calcd for C7H17N2O5S2+
J. Org. Chem. 2023, 88, 15989−16006

diastereomer (colorless oil, 0.302 g, 0.89 mmol, 68% yield). Synthesized using General Procedure G on a 0.2 mmol scale. Purified
1
H NMR (400 MHz, CDCl3) δ 7.75−7.69 (m, 2H), 7.19−7.12 (m, using a gradient of 10−30% ethyl acetate in dichloromethane on silica
1H), 5.16 (s, 2H), 4.39−4.23 (m, 2H), 3.06 (ddd, J = 9.6, 7.3, 3.8 Hz, gel; single diastereomer (white solid, 63 mg, 0.152 mmol, 76% yield).
1
1H), 2.73 (ddd, J = 8.3, 7.3, 5.3 Hz, 1H), 2.21−2.10 (m, 1H), 1.72 H NMR (400 MHz, acetone-d6) δ 7.85−7.81 (m, 2H), 7.79 (d, J
(ddd, J = 15.2, 9.5, 4.6 Hz, 1H), 1.60−1.50 (m, 1H), 1.40 (ddd, J = = 8.6 Hz, 2H), 6.56 (d, J = 8.8 Hz, 1H), 5.59 (d, J = 11.0 Hz, 1H),
14.2, 8.3, 7.1 Hz, 1H), 0.84 (t, J = 7.5 Hz, 3H). 4.67−4.53 (m, 2H), 3.83 (dddd, J = 12.1, 11.0, 4.4, 2.6 Hz, 1H),
13
C{1H} NMR (101 MHz, CDCl3) δ 137.1, 134.5, 134.0, 127.8, 3.50−3.39 (m, 1H), 2.05−1.93 (m, 1H), 1.76−1.57 (m, 2H), 1.39
68.7, 47.9, 42.0, 26.2, 20.3, 11.4. (dt, J = 14.0, 7.4 Hz, 1H), 0.69 (t, J = 7.4 Hz, 3H).
13
IR ν 3380, 2978, 1680, 1362, 1155, 1023 cm−1. C{1H} NMR (101 MHz, acetone-d6) δ 142.1, 133.2, 129.7,
HRMS (ESI) m/z: [M + Na]+ calcd for C10H16N2O5S3Na+ 127.4, 72.5, 59.0, 58.8, 27.5, 25.0, 10.3.
363.0119, found 363.0126 (1.9 ppm error). IR ν 3259, 2920, 1434, 1360, 1189, 1006, 738 cm−1.
Compound 15. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H17BrN2O5S2Na+
434.9660, found 434.9647 (3.0 ppm error).
Compound 18.
Synthesized using General Procedure G on a 0.2 mmol scale. Purified

diastereomer (white solid, 0.058 g, 0.17 mmol, 85% yield). Synthesized using General Procedure A on a 2.26 mmol scale. Purified
1
H NMR (500 MHz, acetone-d6) δ 7.86 (dd, J = 5.0, 1.3 Hz, 1H), using a gradient of 10−30% ethyl acetate in CH2Cl2 on silica gel;
7.66 (dd, J = 3.7, 1.3 Hz, 1H), 7.19 (dd, J = 5.0, 3.8 Hz, 1H), 6.61 (d, single diastereomer (colorless oil, 250 mg, 0.66 mmol, 29% yield).
1
J = 8.7 Hz, 1H), 5.58 (d, J = 10.9 Hz, 1H), 4.68−4.54 (m, 2H), 3.87 H NMR (400 MHz, acetone-d6) δ 8.57−8.44 (m, 2H), 8.27 (dq, J
(dddd, J = 12.1, 11.0, 4.1, 2.6 Hz, 1H), 3.47 (dddd, J = 8.8, 7.7, 6.6, = 9.2, 2.1 Hz, 2H), 6.70 (s, 2H), 4.21 (dt, J = 10.2, 5.7 Hz, 1H), 4.11
4.0 Hz, 1H), 2.05−2.02 (m, 1H), 1.76−1.61 (m, 2H), 1.40 (dq, J = (ddd, J = 10.1, 8.3, 5.3 Hz, 1H), 3.09 (td, J = 7.6, 5.2 Hz, 1H), 3.00−
13.4, 7.5 Hz, 1H), 0.73 (t, J = 7.4 Hz, 3H). 2.88 (m, 1H), 2.16−2.02 (m, 1H), 1.85 (ddt, J = 14.7, 8.0, 5.3 Hz,
13
C{1H} NMR (126 MHz, acetone-d6) δ 143.7, 132.9, 132.7, 1H), 1.67 (dtd, J = 14.8, 7.4, 5.1 Hz, 1H), 1.44 (ddq, J = 14.6, 8.4, 7.4
128.4, 72.6, 59.0, 58.9, 27.4, 24.9, 10.2. Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H).
13
IR ν 3410, 2948, 1645, 1434, 1165, 1020 cm−1. C{1H} NMR (101 MHz, acetone-d6) δ 151.8, 144.6, 130.4,
HRMS (ESI) m/z: [M + Na]+ calcd for C10H16N2O5S3Na+ 125.4, 68.1, 47.8, 43.4, 27.2, 20.8, 11.8.
363.0119, found 363.0134 (4.1 ppm error). IR ν 3341, 3291, 1699, 1537, 1351, 1161, 929 cm−1.
Compound 16. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H17N3O7S2Na+
402.0406, found 402.0403 (0.8 ppm error).
Compound 19.

using a gradient of 10−30% ethyl acetate in CH2Cl2 on silica gel;
single diastereomer (colorless oil, 459 mg, 1.11 mmol, 60% yield).
1
H NMR (400 MHz, CDCl3) δ 7.85−7.76 (m, 2H), 7.75−7.64 (m, Synthesized using General Procedure G on a 0.2 mmol scale. Purified
2H), 5.22 (s, 2H), 4.38−4.21 (m, 2H), 3.09 (ddd, J = 9.4, 7.3, 3.8 Hz, using a gradient of 10−30% ethyl acetate in dichloromethane on silica
1H), 2.73 (ddd, J = 8.4, 7.3, 5.2 Hz, 1H), 2.14 (dddd, J = 14.9, 8.8, gel; single diastereomer (white solid, 0.056 g, 0.147 mmol, 73% yield).
1
4.9, 3.7 Hz, 1H), 1.69 (dddd, J = 14.7, 9.3, 5.1, 4.1 Hz, 1H), 1.53 H NMR (400 MHz, acetone-d6) δ 8.49−8.39 (m, 2H), 8.23−8.12
(dqd, J = 14.9, 7.4, 5.2 Hz, 1H), 1.41−1.22 (m, 1H), 0.78 (t, J = 7.5 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.60 (d, J = 11.1 Hz, 1H), 4.59−
Hz, 3H). 4.52 (m, 2H), 3.82 (dddd, J = 12.0, 11.0, 4.8, 2.6 Hz, 1H), 3.52 (tt, J
13
C{1H} NMR (101 MHz, CDCl3) δ 136.5, 132.6, 129.7, 129.2, = 8.3, 5.4 Hz, 1H), 2.04−1.88 (m, 1H), 1.78−1.60 (m, 2H), 1.51−
68.7, 47.8, 41.5, 26.2, 20.2, 11.6. 1.35 (m, 1H), 0.71 (t, J = 7.4 Hz, 3H).
IR ν 3359, 3271, 1380, 1317, 1170, 1157, 932 cm−1. 13
C{1H} NMR (126 MHz, acetone-d6) δ 150.0, 147.5, 128.3,
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H17BrN2O5S2Na+ 124.3, 71.6, 58.3, 58.1, 26.5, 24.2, 9.4.
434.9660, found 434.9672 (2.8 ppm error). IR ν 3100, 2917, 1522, 1348, 1340, 1166, 1009, 738 cm−1.
J. Org. Chem. 2023, 88, 15989−16006
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H17N3O7S2Na+ 1H), 1.48 (dqd, J = 14.9, 7.4, 5.2 Hz, 1H), 1.37−1.20 (m, 1H), 0.70
402.0406, found 402.0409 (0.75 ppm error). (t, J = 7.4 Hz, 3H).
13
Compound 20. C{1H} NMR (101 MHz, CDCl3) δ 135.3, 134.1, 132.0, 129.7,
129.5, 129.4, 128.0, 127.8, 123.1, 68.7, 47.4, 41.5, 26.2, 20.1, 11.4.
IR ν 3368, 3276, 1505, 1362, 1317, 1155, 932 cm−1.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H20N2O5S2Na+
407.0711, found 407.0701 (2.5 ppm error).
Compound 23.

1
H NMR (400 MHz, CDCl3) δ 7.62 (ddd, J = 7.3, 5.1, 3.2 Hz, 1H),
7.34 (ddt, J = 9.0, 7.0, 3.5 Hz, 1H), 7.29−7.18 (m, 1H), 5.25 (s, 2H),
4.39−4.24 (m, 2H), 3.22 (ddd, J = 9.0, 7.3, 4.1 Hz, 1H), 3.00−2.90
(m, 1H), 2.16 (dddd, J = 14.6, 9.2, 5.2, 4.1 Hz, 1H), 1.83−1.70 (m,
1H), 1.63−1.37 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H). Synthesized using General Procedure G on a 0.2 mmol scale. Purified
13
C{1H} NMR (101 MHz, CDCl3) δ 157.9 (dd, J = 234.9, 2.9 Hz), using a gradient of 10−30% ethyl acetate in dichloromethane on silica
155.4 (dd, J = 240.4, 2.9 Hz), 127.1 (dd, J = 17.1, 7.2 Hz), 122.8 (dd, gel; single diastereomer (white solid, 0.045 g, 0.117 mmol, 58% yield).
1
J = 23.9, 8.5 Hz), 118.9 (dd, J = 24.3, 7.9 Hz), 117.3 (d, J = 27.0 Hz), H NMR (400 MHz, acetone-d6) δ 8.48 (d, J = 1.8 Hz, 1H), 8.11
68.5, 48.5, 42.0, 26.2, 20.2, 11.3. (dd, J = 8.0, 3.9 Hz, 2H), 8.05−7.98 (m, 1H), 7.91 (dd, J = 8.7, 1.9
IR ν 3390, 3285, 1699, 1362, 1328, 1155, 932 cm−1. Hz, 1H), 7.74−7.62 (m, 2H), 6.54 (d, J = 8.7 Hz, 1H), 5.60 (d, J =
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H16F2N2O5S2Na+ 10.9 Hz, 1H), 4.65−4.50 (m, 2H), 3.84 (dddd, J = 11.9, 10.9, 4.2, 2.6
393.0366, found 393.0363 (0.8 ppm error). Hz, 1H), 3.48 (dtd, J = 8.7, 6.9, 4.1 Hz, 1H), 2.11−1.94 (m, 1H),
Compound 21. 1.70−1.55 (m, 2H), 1.42−1.27 (m, 1H), 0.59 (t, J = 7.4 Hz, 3H).
13
C{1H} NMR (126 MHz, acetone-d6) δ 139.7, 135.6, 133.1,
130.2, 130.1, 129.6, 128.8, 128.6, 128.4, 123.5, 72.5, 58.9, 58.7, 27.5,
25.0, 10.3.
IR ν 3282, 2971, 1505, 1420, 1363, 1180, 1012, 861 cm−1.
407.0711, found 407.0702 (2.2 ppm error).
Compound 24.

using a gradient of 10−30% ethyl acetate in dichloromethane on silica
gel; single diastereomer (white solid, 59 mg, 0.16 mmol, 80% yield).
1
H NMR (500 MHz, acetone-d6) δ 7.58 (ddd, J = 7.7, 5.5, 3.2 Hz,
1H), 7.51−7.46 (m, 1H), 7.43 (td, J = 9.2, 4.1 Hz, 1H), 6.91 (d, J =
9.2 Hz, 1H), 5.63 (d, J = 11.0 Hz, 1H), 4.66−4.55 (m, 2H), 3.86
(dddd, J = 11.9, 11.0, 5.0, 2.6 Hz, 1H), 3.53 (dddd, J = 9.2, 8.0, 6.3,
5.0 Hz, 1H), 2.03−1.92 (m, 1H), 1.78−1.63 (m, 2H), 1.55−1.42 (m, Synthesized using General Procedure A on a 1.08 mmol scale. Purified
1H), 0.78 (t, J = 7.4 Hz, 3H). using a gradient of 10−30% ethyl acetate/dichloromethane on silica
13
C{1H} NMR (126 MHz, acetone-d6) δ 158.6 (dd, J = 245.1, 2.6 gel; single diastereomer (colorless oil, 0.170 g, 0.5 mmol, 46% yield).
Hz), 155.7 (dd, J = 249.7, 2.8 Hz), 131.9 (dd, J = 16.8, 6.8 Hz), 122.2 1
(dd, J = 24.4, 9.0 Hz), 119.7 (dd, J = 24.5, 8.3 Hz), 117.0 (d, J = 26.9 2H), 5.32 (s, 2H), 4.83 (td, J = 9.5, 4.5 Hz, 1H), 4.58 (ddd, J = 9.7,
Hz), 72.4, 59.0, 58.9, 27.4, 25.0, 10.1. 5.6, 4.4 Hz, 1H), 2.77 (ddd, J = 10.0, 8.2, 3.1 Hz, 1H), 2.66 (dt, J =
IR ν 3196, 2917, 1488, 1445, 1346, 1160, 1092, 738 cm−1. 8.2, 6.9 Hz, 1H), 2.25 (dddd, J = 15.2, 9.7, 5.6, 3.1 Hz, 1H), 1.96−
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H16F2N2O5S2Na+ 1.75 (m, 2H), 1.58 (dp, J = 14.4, 7.4 Hz, 1H), 1.22 (d, J = 7.5 Hz,
393.0366, found 393.0359 (1.8 ppm error). 3H).
Compound 22. 13
C{1H} NMR (101 MHz, CDCl3) δ 165.4, 134.3, 130.2, 123.1,
69.0, 49.9, 45.2, 26.9, 20.7, 11.4.
IR ν 3386, 2925, 1615, 1524, 1054, 966, 808 cm−1.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H18N3O5S+
340.0967, found 340.0958 (2.6 ppm error).
Compound 25.

1
H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 1.7 Hz, 1H), 8.02− Synthesized using General Procedure A on a 1.86 mmol scale
7.86 (m, 4H), 7.62 (dddd, J = 19.1, 8.1, 6.9, 1.3 Hz, 2H), 5.38 (s, (reaction time of 6 h at a temperature of 30 °C). Purified using a
2H), 4.35−4.18 (m, 2H), 3.10 (ddd, J = 9.2, 7.3, 4.0 Hz, 1H), 2.82− gradient of 10−40% EtOAc in hexane on silica gel; single
2.72 (m, 1H), 2.16−2.01 (m, 1H), 1.69 (ddt, J = 14.3, 9.4, 4.6 Hz, diastereomer (colorless oil, 0.200 g, 0.57 mmol, 31% yield).
J. Org. Chem. 2023, 88, 15989−16006
1
H NMR (400 MHz, CDCl3) δ 7.87−7.78 (m, 2H), 7.39−7.29 (m, Hz, 1H), 1.83−1.72 (m, 2H), 1.69−1.58 (m, 2H), 1.39−1.26 (m,
2H), 4.96 (s, 2H), 4.39−4.27 (m, 2H), 2.85 (dt, J = 7.9, 4.8 Hz, 1H), 4H), 1.13−0.95 (m, 2H), 0.39 (t, J = 7.5 Hz, 3H).
13
2.67 (td, J = 6.5, 4.5 Hz, 1H), 2.44 (s, 3H), 2.41−2.26 (m, 1H), 2.10 C{1H} NMR (126 MHz, CDCl3) δ 143.9, 138.0, 129.9, 127.3,
(ddt, J = 15.0, 7.9, 4.6 Hz, 1H), 1.82−1.68 (m, 1H), 1.63 (dp, J = 70.3, 61.7, 58.9, 56.0, 32.0, 31.6, 26.2, 26.0, 25.3, 25.2, 23.0, 21.7, 9.9.
14.3, 7.3 Hz, 1H), 0.87 (t, J = 7.5 Hz, 3H). IR ν 3430, 2972, 1640, 1597, 1451, 1165, 1020, 930 cm−1.
13
C{1H} NMR (101 MHz, CDCl3) δ 144.5, 137.2, 129.8, 127.7, HRMS (ESI) m/z: [M + Na]+ calcd for C19H30N2O5S2Na+
68.9, 50.9, 45.5, 29.6, 23.0, 21.8, 11.7. 453.1494, found 453.1500 (1.3 ppm error).
IR ν 3420, 2978, 1597, 1357, 1160, 1024 cm−1.
Compound 29.
HRMS (ESI) m/z: [M + Na]+ calcd for C13H20N2O5S2Na+
371.0711, found 371.0725 (3.8 ppm error).
Compound 26.
Synthesized using General Procedure A on a 1 mmol scale. Purified

Synthesized using General Procedure G on a 0.2 mmol scale. Purified 1
5H), 7.27−7.22 (m, 2H), 5.34 (s, 2H), 4.49 (dd, J = 7.0, 4.9 Hz, 2H),
diastereomer (white solid, 0.052 g, 0.15 mmol, 75% yield).
1
H NMR (500 MHz, acetone-d6) δ 7.81−7.73 (m, 2H), 7.41 (d, J 3.28−3.01 (m, 4H), 2.64 (s, 3H), 2.51 (dtd, J = 14.2, 7.0, 5.3 Hz,
= 8.1 Hz, 2H), 6.62 (d, J = 8.6 Hz, 1H), 5.81 (d, J = 10.7 Hz, 1H), 1H), 2.43−2.29 (m, 1H).
13
4.64−4.54 (m, 2H), 3.66 (tdd, J = 10.6, 6.6, 3.6 Hz, 1H), 3.35 (tdd, J C{1H} NMR (101 MHz, CDCl3) δ 144.4, 137.4, 136.9, 129.7,
= 8.5, 6.6, 4.5 Hz, 1H), 2.42 (s, 3H), 1.92−1.76 (m, 2H), 1.66−1.53 128.8, 128.7, 127.5, 126.7, 68.7, 49.7, 45.6, 36.0, 29.3, 21.7.
(m, 1H), 1.50−1.35 (m, 1H), 0.62 (t, J = 7.4 Hz, 3H). IR ν 3376, 3271, 1597, 1371, 1183, 1155, 926 cm−1.
13
C{1H} NMR (126 MHz, acetone-d6) δ 144.2, 139.6, 130.5, HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H22N2O5S2Na+
127.9, 72.6, 59.2, 58.4, 26.2, 24.9, 21.4, 9.7. 433.0868, found 433.0888 (4.6 ppm error).
IR ν 3430, 2948, 1645, 1434, 1165, 1020 cm−1. Compound 30.
371.0711, found 371.0726 (4.0 ppm error).
Compound 27.

gel; single diastereomer (white solid, 0.068 g, 0.16 mmol, 83% yield).
1
H NMR (400 MHz, acetone-d6) δ 7.54−7.48 (m, 2H), 7.24 (d, J
Synthesized using General Procedure B on a 1.5 mmol scale. Purified
using a gradient of 10−30% EtOAc in hexane on silica gel; single = 8.0 Hz, 2H), 7.18−7.07 (m, 3H), 7.07−6.99 (m, 2H), 6.62 (d, J =
diastereomer (colorless oil, 0.194 g, 0.45 mmol, 30% yield). 8.5 Hz, 1H), 5.99 (d, J = 10.3 Hz, 1H), 4.67−4.51 (m, 2H), 3.76−
1
H NMR (400 MHz, CDCl3) δ 7.90−7.75 (m, 2H), 7.32 (d, J = 3.62 (m, 2H), 2.96−2.86 (m, 1H), 2.69 (dd, J = 13.9, 7.3 Hz, 1H),
7.9 Hz, 2H), 4.61 (br s, 1H), 4.25−4.08 (m, 2H), 3.28 (dtt, J = 10.9, 2.39 (s, 3H), 2.03−1.86 (m, 2H).
13
7.4, 3.6 Hz, 1H), 2.82−2.74 (m, 1H), 2.69 (td, J = 6.3, 4.2 Hz, 1H), C{1H} NMR (126 MHz, acetone-d6) δ 143.9, 138.9, 137.6,
2.43 (s, 3H), 2.33−2.12 (m, 2H), 2.04−1.96 (m, 2H), 1.79−1.65 (m, 130.5, 130.3, 129.2, 127.5, 127.2, 72.5, 58.9, 58.6, 37.7, 25.9, 21.4.
3H), 1.63−1.52 (m, 2H), 1.40−1.08 (m, 5H), 0.87 (td, J = 7.5, 1.4 IR ν 3268, 2965, 1425, 1360, 1183, 1157, 1089, 704 cm−1.
Hz, 3H). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H23N2O5S2+
13
C{1H} NMR (101 MHz, CDCl3) δ 144.3, 137.5, 129.7, 127.6, 411.1046, found 411.1063 (4.1 ppm error).
68.1, 53.7, 50.6, 46.0, 33.7, 29.5, 25.2, 24.8, 23.4, 21.7, 11.6. Compound 31.
IR ν 3310, 2958, 1597, 1457, 1172, 1012 cm−1.
453.1494, found 453.1510 (3.5 ppm error).
Compound 28.

1
4H), 6.89−6.81 (m, 2H), 4.86 (s, 2H), 4.44−4.34 (m, 2H), 3.04 (dd,
using a gradient of 30−60% EtOAc in hexane on silica gel; single J = 14.2, 5.2 Hz, 1H), 2.94 (pd, J = 4.2, 1.6 Hz, 2H), 2.63 (dd, J =
diastereomer (white solid, 0.067 g, 0.156 mmol, 78% yield). 14.2, 6.6 Hz, 1H), 2.47 (s, 3H), 2.42−2.18 (m, 2H).
13
1
H NMR (500 MHz, CDCl3) δ 7.79−7.73 (m, 2H), 7.31 (d, J = C{1H} NMR (101 MHz, CDCl3) δ 144.6, 136.7, 136.4, 131.7,
8.0 Hz, 2H), 5.06−4.97 (m, 1H), 4.51 (d, J = 9.0 Hz, 1H), 4.44 (ddt, 130.5, 129.7, 127.5, 120.8, 68.9, 49.3, 45.9, 35.9, 29.1, 21.8.
J = 12.1, 5.4, 1.7 Hz, 1H), 4.04−3.94 (m, 1H), 3.72 (ddt, J = 11.5, 7.0, IR ν 3376, 3282, 1488, 1371, 1180, 1156, 1089, 932 cm−1.
3.7 Hz, 1H), 3.17 (dd, J = 10.4, 5.8 Hz, 1H), 2.44−2.41 (m, 4H), HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H21BrN2O5S2Na+
2.09−2.05 (m, 1H), 2.05−1.95 (m, 1H), 1.89 (dqd, J = 15.1, 7.3, 3.2 510.9973, found 510.9984 (2.2 ppm error).
J. Org. Chem. 2023, 88, 15989−16006
Compound 32. HRMS (ESI) m/z: [M + Na]+ calcd for C19H21F3N2O5S2Na+

501.0742, found 501.0753 (2.2 ppm error).
Compound 35.

gel; single diastereomer (white solid, 0.088 g, 0.18 mmol, 90% yield).
1
H NMR (500 MHz, acetone-d6) δ 7.42−7.36 (m, 2H), 7.22−7.15
(m, 4H), 7.00−6.92 (m, 2H), 6.74−6.69 (m, 1H), 6.13−6.07 (m, Synthesized using General Procedure A on a 0.6 mmol scale. Purified
1H), 4.70−4.57 (m, 2H), 3.77−3.66 (m, 2H), 3.01 (dd, J = 14.0, 3.4 using a gradient of 10−30% ethyl acetate in dichloromethane on silica
Hz, 1H), 2.66 (dd, J = 14.0, 8.7 Hz, 1H), 2.44 (s, 3H), 2.08−1.92 (m, gel; single diastereomer (colorless oil, 0.128 g, 0.277 mmol, 46%
2H). yield).
1
13
C{1H} NMR (126 MHz, acetone-d6) δ 143.0, 138.1, 136.4, H NMR (400 MHz, CDCl3) δ 7.89−7.83 (m, 1H), 7.81−7.76 (m,
131.5, 131.1, 129.4, 126.5, 120.1, 71.7, 58.9, 57.8, 36.4, 25.5, 20.8. 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.56−7.48 (m, 2H), 7.48−7.41 (m,
IR ν 3196, 2971, 1420, 1340, 1157, 1097, 932 cm−1. 2H), 7.31−7.20 (m, 1H), 7.15 (dd, J = 7.1, 1.2 Hz, 1H), 7.06 (d, J =
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H22BrN2O5S2+ 8.2 Hz, 2H), 5.00 (s, 2H), 4.33−4.21 (m, 2H), 3.45 (dd, J = 14.7, 6.1
489.0154, found 489.0160 (1.2 ppm error). Hz, 1H), 3.26 (dd, J = 14.7, 6.5 Hz, 1H), 3.13 (td, J = 6.3, 4.3 Hz,
Compound 33. 1H), 3.02 (ddd, J = 7.3, 6.0, 4.4 Hz, 1H), 2.37 (s, 3H), 2.34−2.17 (m,
2H).
13
C{1H} NMR (101 MHz, CDCl3) δ 144.2, 136.5, 133.8, 133.7,
131.7, 129.5, 128.7, 127.5, 127.3, 127.1, 126.4, 125.8, 125.6, 123.6,
68.7, 49.1, 46.3, 33.1, 29.0, 21.7.
IR ν 3286, 2946, 1430, 1363, 1089, 778 cm−1.
483.1024, found 483.1019 (1.0 ppm error).
Compound 36.
Synthesized using General Procedure A on a 1.32 mmol scale; purified
using a gradient of 10−45% EtOAc/hexanes on silica gel; single
diastereomer (white solid, 0.285 g, 0.59 mmol, 44% yield).
1
1H), 7.28 (t, J = 7.7 Hz, 1H), 7.26−7.22 (m, 2H), 7.21−7.17 (m,
2H), 4.96 (s, 2H), 4.40−4.34 (m, 2H), 3.15 (dd, J = 14.5, 5.7 Hz, Synthesized using General Procedure G on a 0.060 mmol scale.
1H), 2.98 (dddd, J = 21.3, 7.5, 5.7, 4.4 Hz, 2H), 2.83 (dd, J = 14.5, 6.8 Purified using a gradient of 10−30% ethyl acetate in dichloromethane
Hz, 1H), 2.41 (s, 3H), 2.40−2.34 (m, 1H), 2.22 (ddt, J = 15.0, 7.4, on silica gel; single diastereomer (colorless oil, 0.025 g, 0.054 mmol,
90% yield).
4.6 Hz, 1H). 1
13 H NMR (400 MHz, CDCl3) δ 7.75−7.71 (m, 1H), 7.66 (d, J =
C{1H} NMR (126 MHz, CDCl3) δ 144.6, 138.3, 136.6, 132.3,
8.1 Hz, 1H), 7.43 (dd, J = 8.0, 6.6 Hz, 2H), 7.35−7.27 (m, 2H),
131.0 (q, J = 32.2 Hz), 129.7, 129.2, 127.4, 125.5 (q, J = 3.7 Hz),
7.15−7.05 (m, 3H), 6.72 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 10.6 Hz,
125.1 (q, J = 277 Hz), 123.7 (q, J = 3.8 Hz), 68.8, 48.9, 45.4, 35.9,
1H), 5.13 (d, J = 6.6 Hz, 1H), 4.77 (td, J = 12.1, 2.1 Hz, 1H), 4.70
29.1, 21.6.
(ddd, J = 11.6, 5.2, 1.7 Hz, 1H), 3.96−3.84 (m, 1H), 3.77−3.61 (m,
IR ν 3276, 2968, 1597, 1451, 1371, 1334, 1157, 1123, 1075, 929,
1H), 3.35 (dd, J = 14.3, 4.9 Hz, 1H), 2.85 (dd, J = 14.3, 10.2 Hz, 1H),
812, 712, 550 cm−1. 2.40−2.26 (m, 1H), 2.22 (s, 3H), 1.89−1.81 (m, 1H).
HRMS (ESI) m/z: [M + Na]+ calcd for C19H21F3N2O5S2Na+ 13
C{1H} NMR (101 MHz, CDCl3) δ 143.6, 134.1, 134.0, 131.3,
501.0742, found 501.0752 (2 ppm error). 130.9, 129.4, 129.0, 128.6, 128.0, 126.7, 126.6, 125.9, 125.4, 122.8,
Compound 34. 71.4, 58.8, 56.3, 36.5, 23.8, 21.7.
IR ν 3245, 2923, 1425, 1363, 1186, 1155, 1089, 778 cm−1.
483.1024, found 483.1031 (1.4 ppm error).
Compound 37.

Purified using a gradient of 10−50% EtOAc/hexanes on silica gel;
single diastereomer (white solid, 90 mg, 0.188 mmol, 89% yield).
1
(m, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.13 (d, J
= 8.1 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 10.5 Hz, 1H), Synthesized using General Procedure A on a 0.65 mmol scale. Purified
4.67 (ddd, J = 11.6, 5.0, 2.4 Hz, 1H), 4.61 (td, J = 11.8, 2.7 Hz, 1H), using a gradient of 10−30% ethyl acetate in CH2Cl2 on silica gel;
3.81 (tdd, J = 8.8, 7.2, 3.8 Hz, 1H), 3.73 (tdd, J = 10.4, 7.2, 3.0 Hz, single diastereomer (colorless oil, 157 mg, 0.35 mmol, 54% yield).
1H), 3.16 (dd, J = 14.0, 3.8 Hz, 1H), 2.83−2.78 (m, 1H), 2.36 (s, 1
3H), 2.03 (q, J = 2.7 Hz, 1H), 1.95 (dtd, J = 14.5, 11.6, 5.0 Hz, 1H). 7H), 5.06 (s, 2H), 4.45 (s, 2H), 4.38−4.22 (m, 2H), 3.59−3.40 (m,
13
C{1H} NMR (126 MHz, acetone-d6) δ 143.7, 139.4, 138.9, 2H), 2.91 (td, J = 6.6, 3.4 Hz, 2H), 2.46 (s, 3H), 2.31−1.95 (m, 4H).
13
134.3, 130.7 (q, J = 32.8 Hz), 130.3, 129.9, 127.2, 127.1 (q, J = 4.3 C{1H} NMR (101 MHz, CDCl3) δ 144.5, 138.0, 137.2, 129.8,
Hz), 125.2 (q, J = 271.6 Hz), 123.9 (q, J = 4.0 Hz), 72.5, 59.8, 58.7, 128.7, 128.0, 127.9, 127.6, 73.1, 68.6, 67.7, 47.2, 45.6, 29.8, 29.5, 21.8.
37.6, 26.5, 21.3. IR ν 3378, 3278, 1371, 1183, 1157, 1089, 924 cm−1.
IR ν 3410, 1655, 1630, 1517, 1453, 1317, 1174, 1160, 1092, 901, HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H26N2O6S2Na+
812, 735, 598 cm−1. 477.1130, found 477.1129 (0.2 ppm error).
J. Org. Chem. 2023, 88, 15989−16006

using a gradient of 10−30% ethyl acetate in dichloromethane on silica Synthesized using General Procedure A on a 3.02 mmol scale. Purified
gel; single diastereomer (colorless oil, 0.063 g, 0.139 mmol, 70%
using a gradient of 5−30% EtOAc/hexanes on silica gel; single
yield).
1 diastereomer (white solid, 0.643 g, 1.70 mmol, 56% yield).
H NMR (500 MHz, acetone-d6) δ 7.79−7.71 (m, 2H), 7.42−7.31 1
(m, 4H), 7.30−7.25 (m, 3H), 6.64 (dd, J = 8.6, 2.4 Hz, 1H), 5.88 (d,
J = 10.7 Hz, 1H), 4.66−4.55 (m, 2H), 4.29−4.16 (m, 2H), 3.79−3.69 = 8.1 Hz, 2H), 5.18 (s, 2H), 4.31 (ddt, J = 19.0, 9.5, 5.3 Hz, 2H), 3.03
(m, 1H), 3.60 (tdd, J = 8.3, 6.4, 4.4 Hz, 1H), 3.33−3.20 (m, 2H), (ddd, J = 10.6, 7.5, 3.5 Hz, 1H), 2.70 (td, J = 7.9, 5.3 Hz, 1H), 2.45 (s,
2.40 (s, 3H), 1.92−1.82 (m, 3H), 1.67 (ddt, J = 14.6, 8.2, 4.9 Hz, 3H), 2.14 (dddd, J = 14.4, 8.8, 5.1, 3.6 Hz, 1H), 1.64 (dt, J = 14.5, 4.9
1H). Hz, 1H), 1.46 (tdd, J = 8.6, 7.4, 5.3 Hz, 1H), 1.30 (ddd, J = 13.2, 8.1,
13
C{1H} NMR (126 MHz, acetone-d6) δ 143.4, 138.6, 138.4, 6.7 Hz, 1H), 1.24−1.14 (m, 2H), 1.14−1.04 (m, 2H), 0.76 (t, J = 7.2
129.7, 128.2, 127.3, 127.2, 127.0, 72.3, 71.7, 66.0, 58.8, 53.9, 30.9, Hz, 3H).
13
25.4, 20.6. C{1H} NMR (101 MHz, CDCl3) δ 145.0, 134.2, 129.8, 128.3,
IR ν 3273, 2874, 1457, 1363, 1189, 1160, 1092, 778 cm−1. 68.8, 45.9, 40.9, 29.3, 26.4, 26.2, 22.2, 21.7, 13.9.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H26N2O6S2Na+ IR ν 3368, 3268, 2957, 2871, 1651, 1597, 1559, 1457, 1371, 1317,
477.1130, found 477.1140 (2.1 ppm error). 1183, 1157, 1089, 926, 815, 715 cm−1.
Compound 39. HRMS (ESI) m/z: [M + Na]+ calcd for C15H24N2O5S2Na+
399.1024, found 399.1039 (3.7 ppm error).
Compound 42.

using a gradient of 5−30% EtOAc/hexanes on silica gel; single Synthesized using General Procedure G on a 0.60 mmol scale.
diastereomer (colorless oil, 0.173 g, 0.41 mmol, 22% yield). Purified using a gradient of 10−30% EtOAc/hexanes on silica gel;
1
H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.34 (d, J single diastereomer (white solid, 0.147 g, 0.39 mmol, 65% yield).
1
= 8.0 Hz, 2H), 5.02 (br s, 2H), 4.40−4.27 (m, 2H), 2.83 (dt, J = 8.6, H NMR (500 MHz, CDCl3) δ 7.79−7.72 (m, 2H), 7.35−7.29 (m,
4.5 Hz, 1H), 2.72 (ddd, J = 7.6, 5.9, 4.5 Hz, 1H), 2.44 (s, 3H), 2.42− 2H), 5.02 (d, J = 8.3 Hz, 1H), 4.69 (ddd, J = 13.3, 11.4, 2.3 Hz, 2H),
2.31 (m, 1H), 2.04 (ddt, J = 15.4, 8.8, 4.7 Hz, 1H), 1.71−1.45 (m, 4.58 (ddd, J = 11.4, 5.2, 1.6 Hz, 1H), 3.79−3.69 (m, 1H), 3.26 (qd, J
7H), 1.19−1.01 (m, 4H), 0.94−0.79 (m, 2H). = 7.3, 3.2 Hz, 1H), 2.43 (s, 3H), 2.29−2.16 (m, 1H), 1.71−1.57 (m,
13
C{1H} NMR (101 MHz, CDCl3) δ 144.5, 137.1, 129.7, 127.7, 1H), 1.49 (ddt, J = 13.9, 9.0, 6.9 Hz, 1H), 1.28−1.17 (m, 1H), 1.02
68.8, 48.4, 45.8, 36.9, 36.4, 33.6, 32.6, 29.7, 26.3, 26.2, 26.0, 21.7. (dtd, J = 14.3, 7.2, 2.3 Hz, 2H), 0.95−0.84 (m, 2H), 0.65 (t, J = 7.3
IR ν 3368, 3382, 2923, 2852, 1597, 1448, 1371, 1314, 1183, 1157, Hz, 3H).
1086, 992, 921, 815, 712, 553 cm−1. 13
C{1H} NMR (126 MHz, CDCl3) δ 144.2, 137.2, 130.0, 127.2,
HRMS (ESI) m/z: [M + Na]+ calcd for C18H28N2O5S2Na+ 71.9, 58.1, 56.7, 31.5, 27.67, 27.64, 22.1, 21.6, 13.7.
439.1337, found 439.1357 (4.5 ppm error). IR ν 3422, 2957, 2869, 1654, 1505, 1457, 1417, 1363, 1337, 1186,
Compound 40. 1160, 1015, 941, 864, 778 cm−1.
399.1024, found 399.1048 (6 ppm error).
Compound 43.

Purified using a gradient of 10−30% EtOAc/hexanes on silica gel;
single diastereomer (white crystalline solid, 0.086 g, 0.206 mmol, 72%
yield).
1
(m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 5.85 (dd, J = 10.9, 2.6 Hz, 1H), Synthesized using General Procedure A on a 3.38 mmol scale. Purified
4.65−4.58 (m, 2H), 3.62 (dddd, J = 11.6, 10.7, 5.3, 3.0 Hz, 1H), 3.40 using a gradient of 10−40% EtOAc/hexanes on silica gel; single
(dddd, J = 10.1, 7.9, 5.4, 3.8 Hz, 1H), 2.44 (s, 3H), 2.01−1.91 (m, diastereomer (white solid, 0.726 g, 2.17 mmol, 64% yield).
1
1H), 1.90−1.84 (m, 1H), 1.56−1.47 (m, 2H), 1.42 (dtt, J = 9.2, 5.9, H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J
1.9 Hz, 3H), 1.32−1.27 (m, 2H), 1.03−0.94 (m, 2H), 0.85 (tdd, J = = 8.1 Hz, 2H), 5.19 (br s, 2H), 4.38−4.20 (m, 2H), 2.99 (dddd, J =
9.4, 7.3, 3.8 Hz, 1H), 0.77−0.66 (m, 2H), 0.56 (tdd, J = 12.6, 10.8, 8.9, 7.0, 3.9, 1.5 Hz, 1H), 2.84 (dq, J = 7.5, 5.9 Hz, 1H), 2.45 (s, 3H),
3.4 Hz, 1H). 2.20−2.05 (m, 1H), 1.66 (dq, J = 14.3, 4.6 Hz, 1H), 1.16 (d, J = 5.9
13
C{1H} NMR (126 MHz, acetone-d6) δ 144.3, 139.3, 130.6, Hz, 3H).
13
127.9, 72.5, 60.6, 54.7, 40.4, 34.5, 33.8, 32.9, 27.0, 26.8, 26.4, 25.9, C{1H} NMR (101 MHz, CDCl3) δ 144.9, 134.5, 129.9, 128.0,
21.4. 68.7, 41.0, 40.9, 26.0, 21.7, 12.0.
IR ν 3276, 2926, 2851, 1508, 1420, 1363, 1337, 1189, 1160, 1092, IR ν 3399, 1654, 1559, 1505, 1457, 1371, 1363, 1183, 1157, 1092,
1015, 869, 778, 547 cm−1. 918, 804, 721, 673, 550 cm−1.
J. Org. Chem. 2023, 88, 15989−16006
Compound 44. V. Scale-up Reactions and Further Transformation of

Products. Scale-up Reactions. Compound 2.

Purified using a gradient of 10−35% EtOAc/hexanes on silica gel; A 100 mL round-bottom flask was charged with a stir bar, 1 (1.1 g,
single diastereomer (white solid, 0.091 g, 0.27 mmol, 93% yield). 3.16 mmol, 1 equiv), and 16 mL of CF3−toluene. Bu4NOH·30H2O
1
H NMR (500 MHz, acetone-d6) δ 7.82−7.71 (m, 2H), 7.41 (d, J (2.53 g, 3.16 mmol, 1 equiv) was dissolved in 16 mL of H2O and
= 8.1 Hz, 2H), 6.39 (d, J = 8.6 Hz, 1H), 5.58 (d, J = 10.7 Hz, 1H), added to this mixture. The biphasic reaction mixture was stirred at
4.64−4.53 (m, 2H), 3.69 (dddd, J = 12.1, 10.7, 4.6, 2.7 Hz, 1H), 3.53 room temperature for 16 h. Following this time, the contents of the
(dtd, J = 8.6, 6.8, 4.6 Hz, 1H), 2.42 (s, 3H), 2.04−1.95 (m, 1H), 1.71 reaction flask were transferred to a separatory funnel with CH2Cl2.
(dd, J = 14.5, 2.3 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H). The water layer was acidified to pH ≈ 1 using a 1 M aqueous HCl
13
C{1H} NMR (126 MHz, acetone-d6) δ 144.1, 139.7, 130.5, solution (30 mL) and extracted with CH2Cl2 (2 × 50 mL) and once
127.7, 72.4, 61.0, 52.7, 27.1, 21.3, 17.5. with EtOAc (20 mL). The organic layers were combined, dried over
IR ν 3399, 1651, 1636, 1559, 1542, 1420, 1363, 1337, 1186, 1155, MgSO4, and concentrated under reduced pressure. The resulting
1092, 983, 815, 778, 664, 550 cm−1. residue was purified using a gradient of 20−60% EtOAc/hexanes on
HRMS (ESI) m/z: [M + Na]+ calcd for C12H18N2O5S2Na
silica gel to give 2 as a white semisolid (880 mg, 2.53 mmol, 80%
357.0555, found 357.0572 (4.8 ppm error).
yield).
Compound 45.
Compound 26.

using a gradient of 5−30% EtOAc/hexanes on silica gel (colorless oil, A 100 mL round-bottom flask was charged with a stir bar, 25 (0.7 g,
0.234 g, 0.73 mmol, 17% yield). 2.01 mmol, 1 equiv), and 10 mL of CF3−toluene. Bu4NOH·30H2O
1
H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.36 (d, J (1.6 g, 2.00 mmol, 1 equiv) was dissolved in 10 mL of H2O and added
= 8.1 Hz, 2H), 5.18 (s, 2H), 4.35−4.21 (m, 2H), 2.98 (ddt, J = 8.6, to this mixture. The biphasic reaction mixture was stirred at room
7.1, 4.1 Hz, 1H), 2.60 (d, J = 7.1 Hz, 1H), 2.45 (s, 3H), 2.25 (dddd, J temperature for 16 h. Following this time, the contents of the reaction
= 15.0, 8.7, 5.2, 3.6 Hz, 1H), 2.14 (d, J = 4.4 Hz, 1H), 1.55 (ddt, J = flask were transferred to a separatory funnel with CH2Cl2. The water
14.7, 9.0, 4.4 Hz, 1H). layer was acidified to pH ≈ 1 using a 1 M aqueous HCl solution (20
13
C{1H} NMR (101 MHz, CDCl3) δ 145.2, 134.1, 130.0, 128.2, mL) and extracted with CH2Cl2 (2 × 50 mL) and once with EtOAc
68.4, 36.3, 34.7, 30.7, 21.8. (20 mL). The organic layers were combined, dried over MgSO4, and
IR ν 3390, 1645, 1636, 1363, 1320, 1183, 1160, 1092, 929, 784, concentrated under reduced pressure. The resulting residue was
664, 550 cm−1. purified using a gradient of 20−60% EtOAc/hexanes on silica gel to
HRMS (ESI) m/z: [M + Na]+ calcd for C11H16N2O5S2Na give 26 as a white solid (0.532 g, 1.53 mmol, 76% yield).
343.0398, found 343.0409 (3.2 ppm error). Further Transformations. Compound 47.
Compound 46.

Purified using a gradient of 10−40% EtOAc/hexanes on silica gel
(white solid, 0.071 g, 0.222 mmol, 61% yield).
1
H NMR (500 MHz, acetone-d6) δ 7.79−7.74 (m, 2H), 7.45−7.35 A 20 mL microwave vial was charged with a stir bar, 6 (91 mg, 0.2
(m, 2H), 6.91 (dd, J = 8.7, 4.4 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 4.30 mmol, 1 equiv), NaN3 (26 mg, 0.4 mmol, 2 equiv), and DMSO (2
(ddd, J = 13.0, 5.8, 2.8 Hz, 1H), 4.23 (ddd, J = 13.1, 9.4, 1.8 Hz, 1H), mL). The heterogeneous mixture was stirred at room temperature for
3.60 (tddd, J = 9.1, 7.9, 4.6, 3.5 Hz, 1H), 3.22 (dddd, J = 14.9, 4.6, 16 h. Following this time, the reaction was diluted with EtOAc (10
3.5, 1.2 Hz, 1H), 3.12 (dt, J = 14.9, 8.8 Hz, 1H), 2.42 (s, 3H), 2.08 mL) and chilled H2O (10 mL). The contents of the reaction flask
(tt, J = 4.6, 1.5 Hz, 1H), 1.94 (dtd, J = 15.4, 9.3, 2.8 Hz, 1H). were transferred to a separatory funnel with additional EtOAc (5 mL).
13
C{1H} NMR (126 MHz, acetone-d6) δ 144.1, 139.6, 130.6, The organic layer was separated, and the aqueous layer was extracted
127.7, 67.3, 52.8, 46.8, 36.0, 21.4. with additional EtOAc (5 mL). The organic layers were combined,
IR ν 3282, 1654, 1559, 1505, 1457, 1363, 1337, 1177, 1157, 1089, dried with MgSO4, and concentrated under reduced pressure. The
924, 815, 664, 550 cm−1. resulting residue was purified by chromatography on silica gel
HRMS (ESI) m/z: [M + Na]+ calcd for C11H16N2O5S2Na (gradient of 50−100% EtOAc/hexanes) to give 47 as a white solid
343.0398, found 343.0408 (2.9 ppm error). (62 mg, 0.15 mmol, 75% yield).
J. Org. Chem. 2023, 88, 15989−16006
the mixture was diluted with CH2Cl2, transferred to a separatory

funnel, and washed with one portion of a saturated, aqueous NH4Cl
solution. The organic layer was collected, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by chromatography on silica gel (gradient of 15−40%
EtOAc/hexanes) to give 49 as a white solid (0.064 g, 0.193 mmol,
75% yield).
1
H NMR (400 MHz, acetone-d6) δ 7.83−7.75 (m, 2H), 7.40
(d, J = 8.0 Hz, 2H), 6.78−6.69 (m, 2H), 6.67−6.59 (m, 2H),
6.41 (d, J = 7.8 Hz, 1H), 4.39 (d, J = 9.5 Hz, 1H), 3.70 (s,
3H), 3.62 (tt, J = 9.8, 3.3 Hz, 1H), 3.46 (ddd, J = 12.6, 7.9, 5.0
Hz, 1H), 3.39−3.23 (m, 2H), 2.41 (s, 3H), 1.98 (ddt, J = 13.8,
8.0, 4.0 Hz, 1H), 1.70−1.56 (m, 2H), 1.24 (ddq, J = 14.4, 9.7,
7.3 Hz, 1H), 0.56 (t, J = 7.4 Hz, 3H). 1
H NMR (500 MHz, CDCl3) δ 7.93−7.87 (m, 2H), 7.31 (d, J =
13
C{1H} NMR (101 MHz, acetone-d6) δ 152.6, 143.8, 143.0, 8.1 Hz, 2H), 6.66 (s, 1H), 3.97 (dt, J = 7.8, 2.9 Hz, 1H), 3.59−3.48
140.1, 130.4, 128.0, 115.6, 114.7, 58.1, 55.8, 55.0, 49.8, 22.8, 21.4, (m, 3H), 2.42 (s, 3H), 1.94−1.78 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H).
11.2. 13
C{1H} NMR (126 MHz, CDCl3) δ 155.5, 144.8, 136.3, 129.6,
IR ν 3282, 2974, 2160, 1731, 1597, 1363, 1257, 1093, 775 cm−1. 128.1, 63.6, 51.7, 40.3, 38.8, 27.4, 21.7, 8.2.
HRMS (ESI) m/z: [M + Na]+ calcd for C20H27N5O3SNa+ IR ν 3291, 2974, 1725, 1685, 1363, 1092, 815 cm−1.
440.1732, found 440.1743 (2.5 ppm error). HRMS (ESI) m/z: [M + Na]+ calcd for C14H19ClN2O3SNa+
Compound 48.
353.0703, found 353.0717 (4.0 ppm error).
Compound 50.
A 50 mL round-bottom flask was charged with a stir bar, 2 (0.290 g,

0.83 mmol), and anhydrous CH2Cl2 (16 mL). The reaction flask was
A 50 mL round-bottom flask was charged with a stir bar, substrate 26
cooled to 0 °C using an ice−water bath. Subsequently, NEt3 (0.58
(0.110 g, 0.316 mmol, 1 equiv), and anhydrous CH2Cl2 (6 mL). The
mL, 0.42 g, 4.16 mmol, 5 equiv) and triphosgene (0.370 g, 1.25 mmol,
reaction flask was cooled to 0 °C using an ice−water bath.
1.5 equiv) were added. The reaction mixture was stirred at 0 °C for 1
Subsequently, NEt3 (0.22 mL, 0.159 g, 1.58 mmol, 5 equiv) and
h. Following this time, the mixture was diluted with CH2Cl2,
triphosgene (0.140 g, 0.472 mmol, 1.5 equiv) were added. The
transferred to a separatory funnel, and washed with one portion of a
saturated, aqueous NH4Cl solution. The organic layer was collected, reaction mixture was stirred at 0 °C for 1 h. Following this time, the
dried over MgSO4, and concentrated under reduced pressure. The mixture was diluted with CH2Cl2, transferred to a separatory funnel,
resulting residue was purified by chromatography on silica gel and washed with one portion of a saturated, aqueous NH4Cl solution.
(gradient of 25−80% EtOAc/hexanes) to give 48 as a white solid The organic layer was collected, dried over MgSO4, and concentrated
(0.233 g, 0.62 mmol, 75% yield). under reduced pressure. The resulting residue was purified by
chromatography on silica gel (gradient of 25−60% EtOAc/hexanes)
to give 50 as a white solid (0.071 g, 0.19 mmol, 60% yield).
1
H NMR (400 MHz, CDCl3) δ 7.99−7.92 (m, 2H), 7.35 (d, J =
8.1 Hz, 2H), 4.86 (ddd, J = 13.0, 11.7, 2.3 Hz, 1H), 4.60 (ddd, J = 1
11.8, 5.2, 1.5 Hz, 1H), 4.28 (ddd, J = 12.2, 3.4, 1.2 Hz, 1H), 4.00 H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.39−
(ddd, J = 8.3, 3.3, 1.3 Hz, 1H), 2.45 (s, 3H), 2.11 (dtd, J = 14.5, 12.8, 7.29 (m, 2H), 4.82−4.60 (m, 2H), 4.46 (td, J = 7.2, 3.7 Hz, 1H), 4.38
5.2 Hz, 1H), 1.94 (ddq, J = 15.1, 7.5, 3.7 Hz, 1H), 1.90−1.78 (m, (ddd, J = 12.3, 7.3, 3.1 Hz, 1H), 2.45 (s, 3H), 2.28−2.10 (m, 1H),
2H), 0.93 (t, J = 7.5 Hz, 3H). 2.01−1.85 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H).
13
13
C{1H} NMR (101 MHz, CDCl3) δ 146.8, 146.0, 134.9, 130.0, C{1H} NMR (101 MHz, CDCl3) δ 148.5, 146.0, 135.0, 130.0,
128.8, 72.8, 60.8, 59.6, 28.0, 25.9, 21.9, 8.6. 128.7, 72.8, 59.4, 59.2, 24.6, 22.6, 21.9, 9.6.
IR ν 2974, 1771, 1600, 1540, 1354, 1194, 1083, 963 cm−1. IR ν 2965, 1770, 1590, 1540, 1365, 1194, 1090, 962 cm−1.
A 50 mL round-bottom flask was charged with a stir bar, substrate 26

A 50 mL round-bottom flask was charged with a stir bar, substrate 2 (0.090 g, 0.26 mmol, 1 equiv), and anhydrous CH2Cl2 (5 mL). The
(0.090 g, 0.258 mmol), and anhydrous CH2Cl2 (5 mL). The reaction reaction flask was cooled to 0 °C using an ice−water bath.
flask was cooled to 0 °C using an ice−water bath. Subsequently, NEt3 Subsequently, NEt3 (0.18 mL, 0.131 g, 1.29 mmol, 5 equiv) and
(0.18 mL, 0.13 g, 1.29 mmol, 5 equiv) and triphosgene (0.114 g, 0.38 triphosgene (0.114 g, 0.38 mmol, 1.5 equiv) were added. The reaction
mmol, 1.5 equiv) were added. The reaction mixture was allowed to mixture was allowed to warm to room temperature over a period of 6
warm to room temperature over a period of 6 h. Following this time, h. Following this time, the mixture was diluted with CH2Cl2,
J. Org. Chem. 2023, 88, 15989−16006
transferred to a separatory funnel, and washed with one portion of a (10 mL) and chilled H2O (10 mL). The contents of the reaction flask
saturated, aqueous NH4Cl solution. The organic layer was collected, were transferred to a separatory funnel with additional EtOAc (5 mL).
dried over MgSO4, and concentrated under reduced pressure. The The organic layer was separated, and the aqueous layer was extracted
resulting residue was purified by chromatography on silica gel with EtOAc (5 mL). The organic layers were combined, dried with
(gradient of 50−100% EtOAc/hexanes) to give 51 as a white solid MgSO4, and concentrated under reduced pressure. The resulting
(50 mg, 0.15 mmol, 58% yield). residue was purified by chromatography on silica gel (gradient of 30−
60% EtOAc/hexanes) to give 53 as a white solid (0.051 g, 0.144
mmol, 72% yield).
1
= 8.2 Hz, 2H), 6.17 (s, 1H), 4.38 (ddd, J = 7.7, 6.3, 4.2 Hz, 1H), 4.02
1
(ddd, J = 9.0, 7.7, 4.5 Hz, 1H), 3.70−3.51 (m, 2H), 2.43 (s, 3H), H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.34−
2.08−1.99 (m, 2H), 1.95−1.78 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H). 7.28 (m, 2H), 5.41 (s, 1H), 4.23 (ddd, J = 12.2, 8.2, 4.2 Hz, 1H),
13
C{1H} NMR (101 MHz, CDCl3) 156.5, 144.8, 136.4, 129.7, 4.04−3.96 (m, 2H), 3.33 (dddd, J = 8.6, 4.8, 2.4, 1.3 Hz, 1H), 2.43 (s,
128.3, 61.6, 52.9, 41.9, 31.6, 22.7, 21.8, 9.7. 3H), 2.06 (s, 3H), 1.86 (ddt, J = 15.5, 7.9, 5.9 Hz, 2H), 1.81−1.73
IR ν 3295, 2974, 1720, 1690, 1363, 1094, 815 cm−1. (m, 1H), 1.73−1.65 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H).
13
HRMS (ESI) m/z: [M + Na]+ calcd for C14H19ClN2O3SNa+ C{1H} NMR (126 MHz, CDCl3) δ 171.2, 154.5, 144.8, 136.5,
353.0703, found 353.0713 (2.8 ppm error). 129.7, 128.1, 63.9, 60.5, 51.7, 35.7, 27.5, 21.8, 21.0, 8.3.
Compound 52. IR ν 3310, 2978, 1720, 1715, 1690, 1363, 1092, 815 cm−1.
HRMS (ESI) m/z: [M + Na]+ calcd for C16H22N2O5SNa+
377.1147, found 377.1154 (1.9 ppm error).
Compound 54.
A 20 mL microwave vial was charged with a stir bar, 48 (75 mg, 0.2
mmol, 1 equiv), and CH3CN (2 mL). Dimethyl malonate (0.048 mL,
0.055 g, 0.42 mmol, 2.1 equiv) and cesium carbonate (0.136 g, 0.42
A 20 mL microwave vial was charged with a stir bar, 48 (0.075 g, 0.2
mmol, 2.1 equiv) were added. The reaction mixture was stirred for 36
mmol, 1 equiv), NaN3 (0.026 g, 0.4 mmol, 2 equiv), and DMSO (2
h at room temperature. Following this time, the reaction was diluted mL). The heterogeneous mixture was stirred at room temperature for
with EtOAc (10 mL) and chilled H2O (10 mL). The contents of the 1 h. Following this time, the reaction was diluted with EtOAc (10
reaction flask were transferred to a separatory funnel with additional mL) and chilled H2O (10 mL). The contents of the reaction flask
EtOAc (5 mL). The organic layer was separated, and the aqueous were transferred to a separatory funnel with additional EtOAc (5 mL).
layer was extracted with additional EtOAc (5 mL). The organic layers The organic layer was separated, and the aqueous layer was extracted
were combined, dried with MgSO4, and concentrated under reduced with additional EtOAc (5 mL). The organic layers were combined,
pressure. The resulting residue was purified by chromatography on dried with MgSO4, and concentrated under reduced pressure. The
silica gel (gradient of 50−100% EtOAc/hexanes) to give 52 as a white resulting residue was purified by chromatography on silica gel
solid (0.055 g, 0.13 mmol, 65% yield). (gradient of 50−100% EtOAc/hexanes) to give 54 as a white solid
(0.055 g, 0.163 mmol, 82% yield).
1
1
2H), 5.21 (s, 1H), 3.97 (td, J = 5.7, 2.4 Hz, 1H), 3.75 (s, 3H), 3.74 (s, H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.33 (d, J
3H), 3.30 (t, J = 7.1 Hz, 1H), 3.25 (td, J = 7.4, 2.1 Hz, 1H), 2.43 (s, = 8.0 Hz, 2H), 6.33 (s, 1H), 3.94 (dt, J = 7.0, 3.4 Hz, 1H), 3.42 (td, J
3H), 1.84 (dtd, J = 15.1, 7.2, 5.1 Hz, 4H), 1.42 (dtd, J = 13.1, 6.5, 2.9 = 6.5, 2.6 Hz, 1H), 3.34 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 1.93−1.72
Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). (m, 2H), 1.61 (q, J = 6.5 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H).
13
13
C{1H} NMR (101 MHz, CDCl3) δ 169.4, 169.3, 154.5, 144.7, C{1H} NMR (101 MHz, CDCl3) δ 155.4, 145.0, 136.3, 129.8,
136.5, 129.7, 128.2, 63.6, 53.7, 52.9 (2C), 51.0, 34.1, 27.7, 24.0, 21.8, 128.1, 63.8, 52.3, 47.5, 35.3, 27.4, 21.8, 8.2.
8.3. IR ν 3320, 2970, 2094, 1748, 1585, 1365, 1256, 1092, 815 cm−1.
IR ν 3300, 2974, 1731, 1717, 1610, 1365, 1100, 820 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for C14H19N5O3SNa+
HRMS (ESI) m/z: [M + Na]+ calcd for C19H26N2O7SNa+ 360.1106, found 360.1113 (1.9 ppm error).
Compound 53.

A 20 mL microwave vial was charged with a stir bar, 48 (0.075 g, 0.2 mmol, 1 equiv), and CH3CN (2 mL). tBuSH (0.050 mL, 0.040 g,
mmol, 1 equiv), KOAc (0.040 g, 0.4 mmol, 2 equiv), and DMF (2 0.44 mmol, 2.2 equiv) and potassium carbonate (0.064 g, 0.46 mmol,
mL). The heterogeneous reaction mixture was stirred for 4 h at room 2.3 equiv) were added. The reaction mixture was stirred for 48 h at
temperature. Following this time, the reaction was diluted with EtOAc room temperature. Following this time, the reaction was diluted with
J. Org. Chem. 2023, 88, 15989−16006
EtOAc (10 mL) and chilled H2O (10 mL). The contents of the Accession Codes
reaction flask were transferred to a separatory funnel with additional CCDC 2274209, 2277021−2277022, 2277024−2277025, and
EtOAc (5 mL). The organic layer was separated, and the aqueous 2279638 contain the supplementary crystallographic data for
layer was extracted with additional EtOAc (5 mL). The organic layers this paper. These data can be obtained free of charge via
were combined, dried with MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by chromatography on
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
silica gel (gradient of 50−100% EtOAc/hexanes) to give 55 as a white request@ccdc.cam.ac.uk, or by contacting The Cambridge
solid (0.062 g, 0.161 mmol, 81% yield). Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Shyam Sathyamoorthi − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66047, United
1
H NMR (400 MHz, CDCl3) δ 7.95−7.87 (m, 2H), 7.31 (d, J = States; orcid.org/0000-0003-4705-7349;
8.2 Hz, 2H), 5.48 (s, 1H), 3.94 (ddd, J = 6.9, 3.9, 2.5 Hz, 1H), 3.48− Email: ssathyam@ku.edu
3.26 (m, 1H), 2.49 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.87−1.81 (m,
2H), 1.75−1.55 (m, 2H), 1.29 (s, 9H), 0.91 (t, J = 7.4 Hz, 3H). Authors
13
C{1H} NMR (101 MHz, CDCl3) δ 154.8, 144.7, 136.5, 129.7, Someshwar Nagamalla − Department of Medicinal Chemistry,
128.1, 63.9, 53.4, 42.6, 36.1, 31.0, 27.6, 23.8, 21.8, 8.3. University of Kansas, Lawrence, Kansas 66047, United States
IR ν 3359, 2965, 1748, 1597, 1363, 1169, 1093, 815 cm−1. Annu Anna Thomas − Department of Medicinal Chemistry,
407.1439, found 407.1445 (1.5 ppm error).
University of Kansas, Lawrence, Kansas 66047, United States
Compound 56. Appasaheb K. Nirpal − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66047, United States
Joel T. Mague − Department of Chemistry, Tulane University,
New Orleans, Louisiana 70118, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.3c01731
mmol, 1 equiv), NaN3 (0.013 g, 0.2 mmol, 1 equiv), and DMSO (2 Notes
mL). The heterogeneous mixture was stirred at room temperature for
The authors declare no competing financial interest.
1 h. Following this time, the reaction was diluted with EtOAc (10
mL) and chilled H2O (10 mL). The contents of the reaction flask
were transferred to a separatory funnel with additional EtOAc (5 mL).
The organic layer was separated, and the aqueous layer was extracted
■ ACKNOWLEDGMENTS
This work was supported by a National Institutes of Health
with additional EtOAc (5 mL). The organic layers were combined, grant (R35GM142499) and a CMADP pilot project grant
dried with MgSO4, and concentrated under reduced pressure. The (P30GM145499) awarded to S.S. Justin Douglas and Sarah
resulting residue was purified by chromatography on silica gel Neuenswander (KU NMR Lab) are acknowledged for help
(gradient of 50−100% EtOAc/hexanes) to give 56 as a white solid with structure elucidation. Lawrence Seib and Anita Saraf (KU
(0.051 g, 0.15 mmol, 75% yield).
Mass Spectrometry Facility) are acknowledged for help
acquiring HRMS data. J.T.M. thanks Tulane University for
support of the Tulane Crystallography Laboratory.
■ REFERENCES
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1
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8.1 Hz, 2H), 5.76 (s, 1H), 4.43−4.30 (m, 1H), 3.87 (td, J = 8.3, 4.5 Applications in Asymmetric Synthesis and Molecular Recognition.
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IR ν 3340, 2980, 2110, 1745, 1585, 1365, 1256, 1090, 815 cm−1. Diamino Acids: Biological Significance and Synthetic Approaches.
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360.1106, found 360.1112 (1.7 ppm error). (4) Kizirian, J.-C. Chiral Tertiary Diamines in Asymmetric Synthesis.
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■ ASSOCIATED CONTENT
Data Availability Statement
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https://pubs.acs.org/doi/10.1021/acs.joc.3c01731. B. S.; Hanna, M. M. B.; Bloomfield, A. J.; Montgomery, T. D. [3 + 2]
Cycloadditions of Tertiary Amine N-Oxides and Silyl Imines as an
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Ring Opening of Aziridines by Pendant Sulfamates Allows for

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V icinal diamines (1,2-diamines) are well represented in

multiple areas of synthetic chemistry, it is no surprise that

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.3c01731

Scheme 2. Representative Preparation of Aziridine

synthesized by mCPBA epoxidation of the corresponding

Scheme 4. Structure−Reactivity Relationship with Various Scheme 5. Substrate Scope

Scheme 7. Product Oxathlazinane Heterocycles Are

A round-bottom flask was charged with a stir bar, aziridine alcohol

A 50 mL round-bottom flask was charged with a stir bar, aziridine

A 50 mL round-bottom flask was charged with a stir bar, aziridine

A 50 mL round-bottom flask was charged with a stir bar, S4 (0.269 g,

Synthesized using General Procedure A on a 7.43 mmol scale. Purified

Synthesized using General Procedure G on a 0.2 mmol scale (time =

Synthesized using Procedure E on a 1.85 mmol scale. Purified using a

Compound 8. Compound 11.

Synthesized using General Procedure G on a 0.182 mmol scale.

Synthesized using Procedure F on a 1.85 mmol scale. Purified using a

Compound 14. Compound 17.

Synthesized using General Procedure A on a 1.3 mmol scale. Purified

Synthesized using General Procedure G on a 0.2 mmol scale. Purified

Synthesized using General Procedure A on a 1.85 mmol scale. Purified

Synthesized using General Procedure A on a 1.95 mmol scale. Purified

Synthesized using General Procedure G on a 0.2 mmol scale. Purified

Synthesized using General Procedure A on a 1.73 mmol scale. Purified

Synthesized using General Procedure A on a 1 mmol scale. Purified

Synthesized using General Procedure G on a 0.2 mmol scale. Purified

Synthesized using General Procedure A on a 0.97 mmol scale. Purified

Compound 32. HRMS (ESI) m/z: [M + Na]+ calcd for C19H21F3N2O5S2Na+

Synthesized using General Procedure G on a 0.2 mmol scale. Purified

Synthesized using General Procedure G on a 0.209 mmol scale.

Compound 38. Compound 41.

Synthesized using General Procedure G on a 0.2 mmol scale. Purified

Synthesized using General Procedure A on a 1.84 mmol scale. Purified

Synthesized using General Procedure G on a 0.286 mmol scale.

Compound 44. V. Scale-up Reactions and Further Transformation of

Synthesized using General Procedure G on a 0.29 mmol scale.

Synthesized using General Procedure A on a 4.14 mmol scale. Purified

Synthesized using General Procedure G on a 0.365 mmol scale.

the mixture was diluted with CH2Cl2, transferred to a separatory

A 50 mL round-bottom flask was charged with a stir bar, 2 (0.290 g,

A 50 mL round-bottom flask was charged with a stir bar, substrate 26

A 20 mL microwave vial was charged with a stir bar, 48 (0.075 g, 0.2

(52) Nagamalla, S.; Mague, J. T.; Sathyamoorthi, S. Progress towards

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