Polymer-supported stereoselective synthesis of tetrahydrobenzopyrazino- thiadiazinone dioxides via N-sulfonyl iminiums

Article abstract of DOI:10.1021/co5000163

The stereoselective synthesis of 1,2,11,11a-tetrahydrobenzo[e]pyrazino[1,2- b][1,2,4]thiadiazin-3(4H)-one 6,6-dioxides on a solid support via tandem N-sulfonyl iminium ion cyclization, followed by nucleophilic addition is reported. The synthesis proceeded

Full text of DOI:10.1021/co5000163

Research Article
pubs.acs.org/acscombsci
Polymer-Supported Stereoselective Synthesis of
Tetrahydrobenzopyrazino-thiadiazinone Dioxides via N‑Sulfonyl
Iminiums
Nadezda Cankarova,† Agustina La Venia,† and Viktor Krchnak*,†,‡
̌
̌
̌
́
̌
́
†Department of Organic Chemistry, Institute of Molecular and Translational Medicine, Faculty of Science, Palacky University, 17
́
Listopadu 12, 771 46 Olomouc, Czech Republic
‡Department of Chemistry and Biochemistry, 251 Nieuwland Science Center, University of Notre Dame, Notre Dame, Indiana
46556, United States
S
* Supporting Information
ABSTRACT: The stereoselective synthesis of 1,2,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-3(4H)-
one 6,6-dioxides on a solid support via tandem N-sulfonyl
iminium ion cyclization, followed by nucleophilic addition is
reported. The synthesis proceeded with full control of
stereoselectivity at the newly formed asymmetric carbon,
under mild conditions, and using commercially available
building blocks. The synthetic route provided high-purity crude products.
KEYWORDS: N-sulfonyl iminiums, polymer-supported, stereoselective, tetrahydrobenzopyrazinothiadiazinone, sp3 carbon
tetrasubstituted 1,2,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b]-
[1,2,4]thiadiazin-3(4H)-one 6,6-dioxides (hereafter referred to
as “tetrahydrobenzopyrazino-thiadiazinone dioxides”) via N-
sulfonyl iminiums. Although N-acyl iminium chemistry has
been documented in numerous examples,13−17 N-sulfonyl
iminiums have been used only sporadically.18−24 To our
knowledge, the use of N-sulfonyl iminiums in the formation of
fused-ring heterocycles has been reported only recently.25
Until now, the synthesis of tetrahydrobenzopyrazino-
thiadiazinone dioxides Ia (Figure 1) had not been described.
The closest related compounds, 1,2,3,4,11,11a-
hexahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazine 6,6-diox-
ides Ib, were patented almost half a century ago, in 1967.26
Since then, little attention has been paid to these compounds,
despite their demonstrated use as central nervous system
depressants and analgesics.26 Other related compounds, II,
contain a cyclic guanidine moiety27 and have exhibited
interesting biological properties, including antitumor, broncho-
lytic,28 antihypertensive,29 and immunosuppressive activities.30
Moreover, the 1,2,4-benzothiadiazine-1,1-dioxide core induced
antagonistic activity toward the chemokine CXCR2 receptor31
and adrenergic system,32,33 as well as activation of potassium
channels.34
INTRODUCTION
■
Recent structural analyses of drugs and compound libraries
used in high-throughput screening have revealed significant
differences in the chemical space covered by individual groups
of compounds.1 Compared to drugs and natural products, the
existing compound collections typically exhibit a low frequency
of sp3-hybridized carbons and chiral centers.2 The incorpo-
ration of a greater proportion of chiral compounds with higher
degrees of saturation has been suggested to possibly improve
clinical outcomes.3,4 Moreover, the hybridization of carbon
atoms can influence the biological and physicochemical
properties of the compounds.2−4 The fraction of sp3-hybridized
carbon atoms out of the total carbon count, which is known as
the Fsp3 value,2 influences the “flatness” of the molecule.3,4
Larger Fsp3 values indicate that the molecule is more likely to
have a nonplanar, three-dimensional architecture.1,2,5 Further-
more, it was suggested and supported by computational analysis
that space coverage originated primarily from the 3D-geometry
correlated with broad biological activity.6−8
Our ongoing research is focused on the design and synthesis
of compound collections with structural features that are largely
missing from traditional compound decks. We have already
developed efficient synthetic routes that lead to fused and
bridged ring systems with 3D architectures as well as to the
formation of asymmetric carbons, with full control over the
stereochemistry.9−12 These synthetic routes have involved the
formation of N-acyl-N-(2,2-dimethoxyethyl)alkylamides, which
were transformed into the target compounds via tandem
iminium-ion cyclization−nucleophilic addition. In this commu-
nication, we have extended the iminium-based chemistry and
have focused on the solid-phase synthesis of 2,4,9,11-
The synthesis of 2,3,10,10a-tetrahydro-1H-benzo[e]pyrrolo-
[1,2-b][1,2,4]thiadiazine 5,5-dioxides III (Figure 1) via
reductive cyclization of appropriate iminium ions has been
reported previously.35 Similarly, the chemical route leading to
compound IV (Figure 1) and its stereoisomer has been shown
Received: January 30, 2014
Published: February 27, 2014
© 2014 American Chemical Society
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Figure 1. Reported related heterocycles.
to involve iminium ions as the key intermediates.36 12H-
Benzo[a]phenothiazine 7,7-dioxides V (Figure 1) were found
to be useful in the treatment of allergy, asthma, cardiovascular
disorders, inflammation, and pain, and they can serve as
cytoprotective agents.37,38 Compounds VIa (Figure 1) have
been reported to be non-nucleoside reverse transcriptase
inhibitors (NNRTIs).39 Benzo[f ]pyrrolo[1,2-b][1,2,5]-
thiadiazepin-11(10H)-one 5,5-dioxides VIb have been synthe-
sized, and their antiviral activity has been evaluated.40 The
effects of the presence of pyrrole and carbonyl moieties have
been investigated. The pyrrole ring was found to be a
determinant for anti-HIV-1 activity, and its replacement with
a saturated pyrrolidine eliminates that activity. Similarly, the
reduction of the carbonyl to a methylene inactivates the
compounds. Sulfonamide VII (Figure 1) has also been
described, and its conformation has been studied in detail.41
Marketed drugs diazoxide (Eudemine, Hyperstat IV,
Proglycem) VIII (Figure 2) and hydrochlorothiazide (Cidrex,
dichloromethane (DCM) to afford the cyclic N-sulfonyl
iminium ion. Subsequent intramolecular attack by the aniline
nitrogen closed the fused rings, and the target structures were
simultaneously released from the resin.
Our strategy closely followed the recently reported stereo-
selective synthesis of benzimidazolinopiperazinones on a
polymer support.9 To achieve diversity at the R1 side chain,
we chose to immobilize the first building blocks on Wang and
Rink amide resins. Rink amide resin was used to attach two
carboxylic acids with carbon chains of different lengths and a
terminal functional group (bromide or amino), specifically,
bromoacetic acid and Fmoc-β-Ala-OH (Scheme 1, structures
1(1) and 1(2)). The target compounds released from the resin
contained an amide. To expand the diversity of the final
compounds at the R1 position, a diamine (ethylenediamine)
and an Fmoc-amino alcohol were immobilized on the Wang
resin (Scheme 1, structures 1(3) and 1(4)) and yielded amines
and alcohols, respectively.
The key intermediates, N-acyl-N-(2,2-dimethoxyethyl)-
amines 3 (Scheme 2), were prepared according to two different
published routes.9 Briefly, route I started with Rink-supported
bromoacetic acid 1 (R1 = −CH2−; X = −Br). The bromine was
substituted with aminoacetaldehyde dimethyl acetal in the
presence of DIEA in DMF to yield the resin-bound N-((2,2-
dimethoxyethyl)amino)amine 2. Acylation of this intermediate
with various Fmoc-amino acids, i.e., Fmoc-Gly-OH, Fmoc-Ala-
OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH,
Fmoc-Tyr(tBu)-OH, and Fmoc-D-Ala-OH afforded the key
intermediates, N-acyl-N-(2,2-dimethoxyethyl)amines 3.
The second route, route II, enabled access to a greater
diversity of compounds; the side chain R1 represents amides
1(2), amines 1(3), or alcohols 1(4) (Scheme 1). Resins 1
(Scheme 2; X = −NH2) were treated with 4-nitrobenzene-
sulfonyl chloride (4-Nos-Cl) to afford the corresponding 4-
nitrobenzenesulfonamides 4. These intermediates, each bearing
an activated nitrogen atom, underwent Mitsunobu alkylation
and yielded alkylated sulfonamides 5. These reactions were
conducted in a solution containing 0.1 M glycolaldehyde
dimethyl acetal, 0.1 M PPh3, and 0.1 M DIAD in anhydrous
tetrahydrofuran (THF) at 50 °C for 16 h.9 Deprotection of the
4-Nos-group followed by acylation with various Fmoc-α-amino
acids (Figure 3, BB2) yielded the N-acyl-N-(2,2-
dimethoxyethyl)amines 3 in high purity. The Fmoc protecting
group was replaced by three 2-nitrobenzenesulfonyl chlorides
that differ in their substitution at the para position.
Unsubstituted 2-Nos-Cl and derivatives substituted with
Figure 2. Marketed drugs containing the 1,2,4-benzothiadiazine-1,1-
dioxide core.
Disalunil, Hydrodiuril, Microzide) IX (Figure 2) contain the
1,2,4-benzothiadiazine-1,1-dioxide core and are used as
antihypertensives (diazoxide and hydrochlorothiazide in
combination with other drugs), as diuretics (hydrochlorothia-
zide), and for the treatment of hypoglycemia (diazoxide).42−44
Here, we describe the solid-phase synthesis of tetrahydro-
benzopyrazino-thiadiazinone dioxides with three diversity
positions and three sp3-hybridized carbon atoms on the
skeleton, two of which are chiral.
RESULTS AND DISCUSSION
■
The key step in our synthetic route was the tandem N-sulfonyl
iminium-ion cyclization−nucleophilic addition reaction. Cyclic
N-sulfonyl iminium intermediates were formed from an
aldehyde and sulfonamide. The aldehyde functionality was
incorporated in protected form as a dimethyl acetal and was
linked via a two-carbon spacer to the amide nitrogen. Dimethyl
acetals were unmasked using 50% trifluoroacetic acid (TFA) in
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a
Scheme 1. Immobilization of the First Building Blocks on a Polymer Support
a
Reagents and conditions: (i) 50% piperidine in DMF, rt, 15 min; (ii) bromoacetic acid (2 equiv), N,N′-diisopropylcarbodiimide (DIC, 1 equiv),
DCM, 5 min, then N,N′-diisopropylethylamine (DIEA, 1 equiv), rt, 2 h; (iii) Fmoc-amino acid (1 equiv), 1-hydroxybenzotriazole hydrate (HOBt, 1
equiv), DIC (1 equiv), DCM/DMF (1:1), rt, 16 h; (iv) 1,1′-carbonyldiimidazole (CDI), pyridine, DCM, rt, 2 h, then ethylenediamine, DCM, rt, 2 h;
(v) CCl3CN, DBU, DCM, rt, 2 h, then 3-(Fmoc-amino)propanol, BF3·Et2O, anhydrous THF, rt, 1 h, then Fmoc-β-Ala-OH (1 equiv), 1-
hydroxybenzotriazole hydrate (HOBt, 1 equiv), DIC (1 equiv), DCM/DMF (1:1), rt, 16 h.
a
Scheme 2. Solid-Phase Stereoselective Synthesis of Tetrahydrobenzopyrazino-thiadiazinone Dioxides 8
a
Reagents and conditions: (i) aminoacetaldehyde dimethyl acetal, DIEA, DMF, rt, 2 h; (ii) Fmoc-α-amino acid (1 equiv), HOBt (1 equiv), DIC (1
equiv), DCM/DMF (1:1), rt, 16 h; (iii) 4-Nos-Cl, 2,6-lutidine, DCM, rt, 4 h; (iv) glycolaldehyde dimethyl acetal, PPh3, diisopropyl azodicarboxylate
(DIAD), anhydrous THF, 0−50 °C, 16 h, repetition; (v) 2-mercaptoethanol, DBU, DMF, rt, 5 min; (vi) 50% piperidine in DMF, rt, 15 min; (vii)
unsubstituted/4-substituted 2-Nos-Cl, 2,6-lutidine, DCM, rt, 4 h; (viii) SnCl2·2H2O, DIEA, DMF (saturated with N2), 50 °C, see Table 1 for
reaction times; (ix) Na2S2O4, tetrabutylammonium hydrogen sulfate (TBAHS), K2CO3, DCM/water (1:1), rt, 2 h; (x) 50% TFA in DCM, rt, 90
min.
electron-withdrawing groups were evaluated (Figure 3, BB3).
This series provided access to the appropriate 2-nitro-
benzenesulfonamides 6. A list of the synthetic building blocks
is shown in Figure 3.
The last step on solid support involved reduction of the nitro
group. The polymer-supported nitroarenes were typically
reduced by tin(II) chloride dihydrate.45 The reduction,
however, was reportedly problematic on several occasions,
with incomplete reduction46 and tin salt contamination9 being
the most severe. We observed both of these problems during
the reduction of intermediates 6. Several derivatives were
incompletely reduced, and LC/MS analysis revealed the
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Figure 3. Building blocks used for the synthesis of tetrahydrobenzopyrazino-thiadiazinone dioxides 8.
Table 1. Synthesized Derivatives of Tetrahydrobenzopyrazino-thiadiazinone Dioxide 8
a
b
c
compound
R1-H
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
R2
R3
reduction
purity (%)
yield (%)
8(1,1,1)
8(1,1,2)
8(1,2,1)
8(1,2,2)
8(1,3,1)
8(1,4,1)
9(1,4,1)
8(1,5,1)
8(1,5,2)
8(1,6,1)
8(2,2,1)
8(2,2,2)
8(2,7,1)
8(2,7,2)
8(3,5,2)
8(3,6,2)
8(4,2,2)
8(4,2,3)
−H
−H
−H
−CF3
−H
−CF3
−H
−H
−H
−H
−CF3
−H
−H
A: rt, 2 days
A: rt, 2 days
A: rt, 2 days
A: rt, 2 days
A: 50 °C, on
A: 60 °C, on
A: 60 °C, on
A: 50 °C, on
A: rt, 2 days
A: rt, 2 days
B: rt, 2 h
93
97
98
96
63
25
46
33
73
20
13
48
36
65
60
53
57
58
27
23
63
74
−(S)-CH3
−(S)-CH3
−(S)-iBu
−(S)-secBu
−(S)-secBu
−(S)-CH2OH
−(S)-CH2OH
−(S)-p-OH-Bn
−(S)-CH3
−(S)-CH3
−(R)-CH3
−(R)-CH3
−(S)-CH2OH
−(S)-p-OH-Bn
−(S)-CH3
d
74
d
49
42
d
−CH2-CONH2
−CH2-CONH2
−CH2-CONH2
79
94
98
93
91
95
95
74
99
83
80
−(CH2)2−CONH2
−(CH2)2-CONH2
−(CH2)2-CONH2
−(CH2)2-CONH2
−(CH2)2-NH2
−(CH2)2-NH2
−(CH2)2-CONH-(CH2)3-OH
−(CH2)2-CONH-(CH2)3-OH
−CF3
−H
B: rt, 2 h
B: rt, 2 h
−CF3
−CF3
−CF3
−CF3
−Cl
B: rt, 2 h
A: rt, 2 days
A: rt, 2 days
B: rt, 2 h
−(S)-CH3
B: rt, 2 h
a
b
c
A: Tin(II) chloride method. B: Dithionite method. Purity of the crude product. Total yield after purification by reverse-phase HPLC.
Incompletely reduced; contained N-hydroxy derivative 9.
d
presence of N-hydroxy derivatives of target compound 8
(referred to as compound 9). In the case of incomplete
reduction, the reaction was repeated overnight (see Table 1).
The reduction of derivative 6(1,4,1), however, did not proceed
quantitatively, even when the temperature was increased to 80
°C. Therefore, we isolated, purified, and fully characterized the
N-hydroxy derivative 9(1,4,1). Moreover, the crude products
were contaminated by tin salts despite thorough washing of the
resin. The tin salts were liberated upon acid cleavage of the
product, thus making the final purification substantially more
complex. Therefore, the crude product solution was passed
through an octadecyl silica plug as a prepurification step (see
Experimental Procedures).
To overcome the problems with tin chloride reduction, we
searched for an alternative reducing agent and obtained
superior results by reducing the nitro group with sodium
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dithionite in DCM−water and TBAHS as a phase-transfer
catalyst.47 Application of this method proceeded with complete
conversion and afforded good yields of the desired products 8
after simple and fast purification.
The target tetrahydrobenzopyrazino-thiadiazinone dioxides 8
were obtained from resin-bound intermediates 7 by acid-
mediated deprotection of acetal with concurrent TFA cleavage
from the acid-labile linkers. With the exception of compounds
suffering from incomplete reduction by tin(II) chloride, the
crude products were obtained in high purity, where the purity
ranged from 74% to 99% (Table 1).
Compounds 8(1,1,1) and 8(1,1,2), which were synthesized
with Fmoc-Gly-OH (BB2 = (1)), formed a racemic mixture.
The absence of a stereogenic center in the ring-forming acyclic
precursor failed to induce stereospecific nucleophilic addition.
In contrast, the synthesis of target tetrahydrobenzopyrazino-
thiadiazinone dioxides 8, which were prepared with chiral
amino acids, proceeded with full stereochemical control. L-
Amino acids in the (S)-configuration yielded tetrahydrobenzo-
pyrazino-thiadiazinone dioxides with an (R)-configuration on
the newly formed stereogenic center (carbon 11a). Only one
diastereoisomer was detected in the LC/MS traces, and the 1H
and 13C NMR spectra of the purified compounds confirmed
their optical purity. These results are consistent with those from
the stereoselective synthesis of related bicyclic tetrahydro-1H-
pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-diones. The configura-
tion was confirmed by ROESY 2D NMR and X-ray
crystallography.48 Furthermore, we have recently described a
related stereoselective, solid-phase synthesis of 1,2,10,10a-
tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-3(4H)-ones.9
To demonstrate the stereochemical diversity provided by this
reaction,49,50 we also prepared target compounds with Fmoc-D-
Ala-OH. As predicted, its (R)-configuration produced an (S)-
configuration on carbon 11a of the products (8(2,7,1) and
8(2,7,2)). These enantiomers differ in their 3D spatial
arrangements while having 2D structures identical to those of
their analogues 8(2,2,1) and 8(2,2,2).
(100−200 mesh, 1.0 mmol/g) were used. Individual synthetic
steps for the synthesis of resins 3 were described in our recent
publications.9
Cleavage of the Fmoc-Protecting Group and Reaction
with Unsubstituted/4-Substituted 2-Nos-Cl (Resins 6).
Resins 3 (1 g), which were prepared according to a reported
protocol,9 were washed with DCM 3× and DMF 3× and
treated with 50% piperidine in DMF for 15 min. After the
resins were washed with DMF 3× and DCM 3×, a solution of
2-Nos-Cl (3 mmol) and 2,6-lutidine (3.3 mmol, 382 μL) in 10
mL of DCM was added to the resin, and the resulting slurry
was shaken at rt for 16 h. The resin was subsequently washed
with DCM 3×.
Reduction of the Nitro Group with Tin(II) Chloride
Dihydrate (Resins 7). Resins 6 (0.25 g) were swollen in
DCM and washed with N2-saturated DMF 3×. A solution
containing tin(II) chloride dihydrate (2.5 mmol, 564 mg) and
DIEA (2.5 mmol, 433 μL) in 2.5 mL of N2-saturated DMF was
then added to the resin. The temperatures and reaction times
for individual compounds are listed in Table 1. The resins were
washed thoroughly with DMF 7× and DCM 5×.
Cleavage, Cyclization, and Isolation of the Products
(8). Resins 7 (0.25 g) were treated with 3 mL of 50% TFA in
DCM at rt for 90 min. The cleavage products were collected,
and the resins were washed with 50% TFA in DCM 3×. All
washes were combined and evaporated by a stream of nitrogen.
Isolation after Tin(II) Chloride Reduction. The oily residue
was dissolved in 1 mL of MeCN and was diluted with 15 mL of
water. Depending on the compound used, a solution or an
opalescent solution, occasionally with precipitation, was
formed. A 3 mL of octadecyl cartridge (Applied Separations)
was wetted with 3 mL of MeCN and washed with 3 mL of
distilled water. Half the volume of the solution of the target
compound was passed through the column, and the column
was washed with 3 mL of distilled water. The target compound
was eluted with 3−5 mL of MeCN. The MeCN was
evaporated, and the oily residue was concentrated on a freeze
drier for 16 h; the residue was then weighed and dissolved in
0.7 mL of DMSO-d6 for NMR analysis. The solution was
purified by semipreparative reversed-phase HPLC.
CONCLUSION
■
We described the stereoselective, solid-phase synthesis of
tetrahydrobenzopyrazino-thiadiazinone dioxides via N-sulfonyl
iminium ion cyclization−nucleophilic addition. The target
compounds have three diversity positions and were prepared
from simple, commercially available building blocks, including
L- and D-amino acids, to generate stereochemical diversity.
These chiral amino acids controlled the configuration of the
newly formed chiral center and afforded optically pure
products. Given their favorable structural properties, which
include a nonplanar scaffold, chiral carbons, and a sulfonamide
moiety, as well as the biological activity observed for several of
their analogues, tetrahydrobenzopyrazino-thiadiazinone diox-
ides represent heterocycles with potential therapeutic activity.
Isolation after Dithionite Reduction. The oily residue was
dissolved in 1 mL of MeCN and purified by semipreparative
reversed-phase HPLC.
2-(6,6-Dioxido-3-oxo-3,4,11,11a-tetrahydrobenzo[e]-
pyrazino[1,2-b][1,2,4]thiadiazin-2(1H)-yl)acetamide 8-
(1,1,1).
Yield: 18.6 mg (63%) of amorphous solid. 1H NMR (600 MHz,
DMSO-d6): δ 7.60−7.53 (m, 2 H), 7.47 (s, 1 H), 7.40 (ddd, J =
1.5, 7.8 Hz, 1 H), 7.22 (br. s., 1 H), 6.89 - 6.81 (m, 2 H), 5.47−
5.41 (m, 1 H), 4.32 (d, J = 16.4 Hz, 1 H), 3.95 (dd, J = 3.4, 13.4
Hz, 1 H), 3.74 (d, J = 16.4 Hz, 1 H), 3.65 (d, J = 16.4 Hz, 1 H),
3.51 (dd, J = 1.8, 13.4 Hz, 1 H), 3.09 (d, J = 16.4 Hz, 1 H). 13C
NMR (151 MHz, DMSO-d6): δ 169.6, 163.1, 142.6, 133.9,
125.6, 117.9, 116.2, 116.1, 62.5, 50.6, 48.6, 44.9. HRMS (ESI-
TOF): m/z calcd for C12H15N4O4S [M + H]+ 311.0809, found
311.0893.
EXPERIMENTAL PROCEDURES
■
The solid-phase syntheses were carried out in plastic reaction
vessels (syringes, each equipped with a porous disc) using a
manually operated synthesizer.51 The volume of the wash
solvent was 10 mL per 1 g of resin. For washing, the resin slurry
was shaken with fresh solvent for at least 1 min before changing
the solvent. All reactions were carried out at ambient
temperature unless stated otherwise. Commercially available
Rink resin (100−200 mesh, 0.66 mmol/g) and Wang resin
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2-(6,6-Dioxido-3-oxo-9-(trifluoromethyl)-3,4,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)acetamide 8(1,1,2).
1.0, 7.1, 8.0 Hz, 1 H), 6.75 (dd, J = 1.0, 8.5 Hz, 1 H), 5.47−5.36
(m, 1 H), 4.07−3.97 (m, 3 H), 3.66 (dd, J = 2.8, 14.2 Hz, 1 H),
3.45−3.39 (m, 1 H), 1.84−1.74 (m, 2 H), 1.74−1.66 (m, 1 H),
0.87 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 6.5 Hz, 3 H). 13C NMR
(151 MHz, DMSO-d6): δ 171.2, 167.5, 143.2, 133.8, 125.0,
117.2, 116.4, 116.2, 63.9, 56.3, 49.5, 48.2, 44.9, 23.6, 23.4, 22.0.
HRMS (ESI-TOF): m/z calcd for C16H23N4O4S [M + H]+
367.1435, found 367.1431.
Yield: 12.5 mg (25%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 7.96 (s, 1 H), 7.81 (d, J = 8.2 Hz, 1 H), 7.56 (br.
s., 1 H), 7.23 (br. s., 1 H), 7.17 (s, 1 H), 7.11 (d, J = 8.2 Hz, 1
H), 5.56−5.46 (m, 1 H), 4.32 (d, J = 16.4 Hz, 1 H), 3.98 (dd, J
= 3.4, 13.6 Hz, 1 H), 3.77 (d, J = 16.4 Hz, 1 H), 3.66 (d, J =
16.4 Hz, 1 H), 3.53 (d, J = 13.6 Hz, 1 H), 3.18 (d, J = 16.4 Hz,
1 H). 13C NMR (75 MHz, DMSO-d6): δ 169.5, 162.8, 143.2,
133.6 (q, J = 31.5 Hz), 127.5, 123.3 (q, J = 271.5 Hz), 119.1,
113.5, 113.0, 62.5, 50.5, 48.6, 44.8. HRMS (ESI-TOF): m/z
calcd for C13H14F3N4O4S [M + H]+ 379.0682, found 379.0684.
2-((4S,11aR)-4-Methyl-6,6-dioxido-3-oxo-3,4,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)acetamide 8(1,2,1).
2-((4S,11aR)-4-((R)-sec-Butyl)-6,6-dioxido-3-oxo-
3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]-
thiadiazin-2(1H)-yl)acetamide 8(1,4,1).
Yield: 5.6 mg (20%) of amorphous solid. 1H NMR (600 MHz,
DMSO-d6): δ 7.76−7.69 (m, 2 H), 7.54 (dd, J = 1.5, 7.9 Hz, 1
H), 7.37 (ddd, J = 1.5, 7.2, 8.5 Hz, 1 H), 7.33 (br. s., 1 H), 6.80
(ddd, J = 1.0, 7.2, 7.9 Hz, 1 H), 6.75 (dd, J = 1.0, 8.5 Hz, 1 H),
5.49−5.43 (m, 1 H), 4.05−3.98 (m, 2 H), 3.98 (dd, J = 2.1,
14.1 Hz, 1 H), 3.61 (dd, J = 2.8, 14.1 Hz, 1 H), 3.37 (d, J = 3.2
Hz, 1 H), 2.12−1.98 (m, 1 H), 1.47−1.38 (m, 1 H), 1.27−1.18
(m, 1 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.81 (t, J = 7.3 Hz, 3 H).
13C NMR (151 MHz, DMSO-d6): δ 171.1, 165.4, 143.1, 133.9,
125.2, 117.3, 116.1, 116.0, 63.8, 60.7, 49.9, 48.2, 41.4, 26.3,
13.3, 11.9. HRMS (ESI-TOF): m/z calcd for C16H23N4O4S [M
+ H]+ 367.1435, found 367.1429.
Yield: 38.6 mg (46%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 7.73 (br. s., 1 H), 7.69 (d, J = 1.8 Hz, 1 H), 7.55
(dd, J = 1.5, 7.9 Hz, 1 H), 7.43−7.33 (m, 2 H), 6.85−6.74 (m,
2 H), 5.44−5.38 (m, 1 H), 4.10−3.94 (m, 3 H), 3.63 (dd, J =
2.6, 13.8 Hz, 1 H), 3.33 (q, J = 6.9 Hz, 1 H), 1.49 (d, J = 6.9
Hz, 3 H). 13C NMR (75 MHz, DMSO-d6): δ 170.9, 168.0,
143.1, 133.9, 125.3, 117.4, 116.1, 116.0, 63.4, 53.5, 49.6, 48.3,
22.4. HRMS (ESI-TOF): m/z calcd for C13H17N4O4S [M +
H]+ 325.0965, found 325.0992.
2-((4S,11aR)-4-((R)-sec-Butyl)-11-hydroxy-6,6-dioxido-
3-oxo-3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b]-
[1,2,4]thiadiazin-2(1H)-yl)acetamide 9(1,4,1).
2-((4S,11aR)-4-Methyl-6,6-dioxido-3-oxo-9-(trifluoro-
methyl)-3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b]-
[1,2,4]thiadiazin-2(1H)-yl)acetamide 8(1,2,2).
Yield: 3.6 mg (13%) of amorphous solid. 1H NMR (600 MHz,
DMSO-d6): δ 10.59 (s, 1 H), 7.96 (br. s, 1 H), 7.59 (dd, J = 1.5,
7.9 Hz, 1 H), 7.57−7.53 (m, 2 H), 7.30 (dd, J = 0.6, 8.5 Hz, 1
H), 7.05−7.01 (m, 1 H), 5.52−5.49 (m, 1 H), 4.05 (d, J = 16.1
Hz, 1 H), 4.02−3.96 (m, 2 H), 3.84 (dd, J = 1.5, 14.4 Hz, 1 H),
3.76 (d, J = 3.2 Hz, 1 H), 2.14−2.08 (m, 1 H), 1.53−1.47 (m, 1
H), 1.32−1.25 (m, 1 H), 0.92 (d, J = 7.0 Hz, 3 H), 0.84 (t, J =
7.3 Hz, 3 H). 13C NMR (151 MHz, DMSO-d6): δ 172.0, 165.2,
145.6, 134.1, 124.9, 121.0, 120.3, 116.0, 71.4, 61.4, 48.9, 48.5,
41.5, 26.3, 13.3, 11.9. HRMS (ESI-TOF): m/z calcd for
C16H23N4O5S [M + H]+ 383.1384, found 383.1394.
Yield: 19.6 mg (33%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 8.16 (d, J = 1.8 Hz, 1 H), 7.80 (d, J = 8.3 Hz, 1
H), 7.73 (br. s., 1 H), 7.41 (br. s., 1 H), 7.09 (dd, J = 1.3, 8.3
Hz, 1 H), 7.05 (s, 1 H), 5.51−5.46 (m, 1 H), 4.15−4.05 (m, 2
H), 4.00−3.91 (m, 1 H), 3.66 (dd, J = 2.8, 14.2 Hz, 1 H), 3.43−
3.36 (m, 1 H), 1.50 (d, J = 7.0 Hz, 3 H). 13C NMR (75 MHz,
DMSO-d6): δ 170.9, 167.6, 143.5, 133.7 (q, J = 31.5 Hz), 127.2,
123.3 (q, J = 273.0 Hz), 118.9, 113.1, 112.7, 63.5, 53.5, 49.4,
48.4, 22.3. HRMS (ESI-TOF): m/z calcd for C14H16F3N4O4S
[M + H]+ 393.0839, found 393.0864.
2-((4S,11aR)-4-(Hydroxymethyl)-6,6-dioxido-3-oxo-
3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]-
thiadiazin-2(1H)-yl)acetamide 8(1,5,1).
2-((4S,11aR)-4-Isobutyl-6,6-dioxido-3-oxo-3,4,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)acetamide 8(1,3,1).
Yield: 12.3 mg (48%) of amorphous solid. 1H NMR (600 MHz,
DMSO-d6) δ 7.77 (br. s., 1 H), 7.64 (br. s., 1 H), 7.53 (dd, J =
1.5, 7.9 Hz, 1 H), 7.46 (br. s., 1 H), 7.37 (ddd, J = 1.5, 7.0, 8.5
Hz, 1 H), 6.82−6.75 (m, 2 H), 5.51−5.47 (m, 1 H), 4.08 (d, J =
17.0 Hz, 1 H), 4.01−3.93 (m, 2 H), 3.87 (dd, J = 2.5, 11.0 Hz,
1 H), 3.77 (dd, J = 2.1, 11.0 Hz, 1 H), 3.63 (dd, J = 2.9, 13.5
Hz, 1 H), 3.34 (t, J = 2.1 Hz, 1 H). 13C NMR (151 MHz,
Yield: 20.0 mg (73%) of amorphous solid. 1H NMR (600 MHz,
DMSO-d6): δ 7.78 (d, J = 2.3 Hz, 1 H), 7.75 (br. s., 1 H), 7.53
(dd, J = 1.8, 8.0 Hz, 1 H), 7.39−7.32 (m, 2 H), 6.79 (ddd, J =
298
dx.doi.org/10.1021/co5000163 | ACS Comb. Sci. 2014, 16, 293−302

ACS Combinatorial Science
Research Article
DMSO-d6): δ 171.1, 166.4, 143.2, 133.9, 125.1, 117.2, 116.2,
116.0, 65.1, 63.5, 59.9, 49.5, 48.8. HRMS (ESI-TOF): m/z
calcd for C13H17N4O5S [M + H]+ 341.0914, found 341.0920.
2-((4S,11aR)-4-(Hydroxymethyl)-6,6-dioxido-3-oxo-9-
(trifluoromethyl)-3,4,11,11a-tetrahydrobenzo[e]-
pyrazino[1,2-b][1,2,4]thiadiazin-2(1H)-yl)acetamide 8-
(1,5,2).
3-((4S,11aR)-4-Methyl-6,6-dioxido-3-oxo-9-(trifluoro-
methyl)-3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b]-
[1,2,4]thiadiazin-2(1H)-yl)propanamide 8(2,2,2).
Yield: 14.8 mg (53%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 8.43 (br. s., 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.58
(br. s., 1 H), 7.21 (s, 1 H), 7.03 (d, J = 8.6 Hz, 1 H), 6.94 (br.
s., 1 H), 5.53−5.42 (m, 1 H), 3.92 (dd, J = 2.1, 13.8 Hz, 1 H),
3.74−3.70 (m, 1 H), 3.68 (dd, J = 2.8, 13.8 Hz, 1 H), 3.41−
3.33 (m, 2 H), 2.38 (t, J = 7.0 Hz, 2 H), 1.48 (d, J = 6.7 Hz, 3
H). 13C NMR (101 MHz, DMSO-d6): δ 172.7, 166.7, 143.6,
133.6 (q, J = 32 Hz), 127.0, 123.3 (q, J = 273 Hz), 118.7, 112.8
(q, J = 3 Hz), 112.4 (q, J = 4 Hz), 63.1, 53.3, 49.0, 44.1, 33.0,
22.4. HRMS (ESI-TOF): m/z calcd for C15H18F3N4O4S [M +
H]+ 407.0995, found 407.0979.
Yield: 19.3 mg (36%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 8.21 (br. s, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.64
(br. s, 1 H), 7.53 (br. s, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 7.04 (s,
1 H), 5.60 - 5.52 (m, 2 H), 4.11 (d, J = 17.0 Hz, 1 H), 4.01 (dd,
J = 1.5, 13.5 Hz, 1 H), 3.98 (d, J = 17.0 Hz, 2 H), 3.84 (dd, J =
2.1, 5.6 Hz, 1 H), 3.79 (dd, J = 1.8, 6.2 Hz, 1 H), 3.66 (dd, J =
2.5, 13.5 Hz, 1 H), 3.43 - 3.38 (m, 1 H). 13C NMR (75 MHz,
DMSO-d6): δ 171.2, 166.1, 143.6, 133.7 (q, J = 31.5 Hz), 127.1,
123.3 (q, J = 271.5 Hz), 119.1 (d, J = 1.5 Hz), 112.8 (q, J = 4.5
Hz), 65.1, 63.7, 59.9, 49.4, 48.8, 40.4. HRMS (ESI-TOF): m/z
calcd for C14H16F3N4O5S [M + H]+ 409.0788, found 409.0816.
2-((4S,11aR)-4-(4-Hydroxybenzyl)-6,6-dioxido-3-oxo-
3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]-
thiadiazin-2(1H)-yl)acetamide 8(1,6,1).
3-((4R,11aS)-4-Methyl-6,6-dioxido-3-oxo-3,4,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)propanamide 8(2,7,1).
Yield: 13.1 mg (57%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 7.51 (d, J = 7.9 Hz, 1 H, H7), 7.49 (br. s., 1 H,
−CONH2), 7.38−7.35 (m, 1H, H10), 7.34 (s, 1 H, −NH10−),
6.98 (br. s., 1 H, −CONH2), 6.84−6.73 (m, 2 H, H8 and H9),
5.46−5.37 (m, 1 H, H11a), 3.90 (dd, J = 1.8, 13.5 Hz, 1 H, ···
H1), 3.74 (dt, J = 13.5, 6.8 Hz, 1 H, H3′), 3.57 (dd, J = 2.1, 13.5
Hz, 1 H, H1), 3.36−3.28 (m, 2 H, H4, H3′), 2.37 (t, J = 6.9
Hz, 2 H, H2′), 1.47 (d, J = 6.7 Hz, 3 H, C4−CH3). 13C NMR
(101 MHz, DMSO-d6): δ 172.8 (CONH2), 167.0 (C3), 143.3
(C6a), 133.8 (C10), 125.1 (C7), 117.1 (C8 or C9), 115.7 (C8 or
C9 and C10a), 63.0 (C11a), 53.3 (C4), 49.3 (C1), 44.1 (C3′), 33.0
(C2′), 22.5 (C4-CH3). NOESY 1D spectra: NOE interactions
between protons from methyl group with H11a and ···H1.
HRMS (ESI-TOF): m/z calcd for C14H19N4O4S [M + H]+
339.1122, found 339.1145
Yield: 35.0 mg (65%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 9.36 (br. s., 1 H), 7.70 (br. s, 1 H), 7.63−7.56
(m, 2 H), 7.44 (br. s, 1 H), 7.42−7.32 (m, 1 H), 6.93 (d, J = 8.5
Hz, 2 H), 6.83 (t, J = 7.5 Hz, 1 H), 6.75−6.64 (m, 3 H), 5.32−
5.23 (m, 1 H), 4.19 (d, J = 16.7 Hz, 1 H), 3.62−3.47 (m, 2 H),
3.35 (dd, J = 2.6, 13.8 Hz, 1 H), 3.10 (dd, J = 5.6, 13.8 Hz, 1
H), 3.00 (dd, J = 2.6, 13.5 Hz, 1 H), 2.72−2.61 (m, 1 H). 13C
NMR (75 MHz, DMSO-d6): δ 171.4, 166.6, 156.4, 143.1,
133.9, 131.3, 125.2, 125.2, 117.6, 116.4, 116.3, 114.8, 63.4, 58.6,
48.7, 47.3. HRMS (ESI-TOF): m/z calcd for C19H21N4O5S [M
+ H]+ 417.1227, found 417.1239.
3-((4R,11aS)-4-Methyl-6,6-dioxido-3-oxo-9-(trifluoro-
methyl)-3,4,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b]-
[1,2,4]thiadiazin-2(1H)-yl)propanamide 8(2,7,2).
3-((4S,11aR)-4-Methyl-6,6-dioxido-3-oxo-3,4,11,11a-
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)propanamide 8(2,2,1).
Yield: 16.2 mg (58%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 8.10 (s, 1 H), 7.76 (d, J = 8.6 Hz, 1 H), 7.53 (br.
s., 1 H), 7.17 (s, 1 H), 7.04 (d, J = 8.6 Hz, 1 H), 6.97 (br. s., 1
H), 5.56−5.39 (m, 1 H), 4.00−3.88 (m, 1 H), 3.74 (dd, J = 7.0,
13.6 Hz, 1 H), 3.63 (dt, J = 2.4, 14.1 Hz, 1 H), 3.41−3.30 (m, 2
H), 2.38 (t, J = 7.0 Hz, 2 H), 1.48 (d, J = 7.3 Hz, 3 H). 13C
NMR (101 MHz, DMSO-d6): δ 172.7, 166.7, 143.6, 133.6 (q, J
= 32 Hz), 127.0, 123.3 (q, J = 273 Hz), 118.8, 112.8 (q, J = 3
Hz), 112.4 (q, J = 4 Hz), 63.1, 53.3, 49.0, 44.1, 33.0, 22.4.
HRMS (ESI-TOF): m/z calcd for C15H18F3N4O4S [M + H]+
407.0995, found 407.1010.
Yield: 13.9 mg (60%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 7.51 (dd, J = 1.4, 7.9 Hz, 1 H), 7.48 (br. s., 1 H),
7.35 (ddd, J = 1.4, 7.1, 8.4 Hz, 1 H), 7.33 (s, 1 H), 6.97 (br. s., 1
H), 6.82−6.74 (m, 2 H), 5.46−5.40 (m, 1 H), 3.90 (dd, J = 2.2,
13.8 Hz, 1 H), 3.74 (dt, J = 7.1, 13.5 Hz, 1 H), 3.57 (dd, J = 2.6,
13.8 Hz, 1 H), 3.37−3.27 (m, 2 H), 2.37 (t, J = 7.1 Hz, 2 H),
1.47 (d, J = 6.7 Hz, 3 H). 13C NMR (101 MHz, DMSO-d6): δ
172.8, 167.0, 143.3, 133.8, 125.1, 117.1, 115.7, 115.7, 63.0, 53.3,
49.3, 44.1, 33.0, 22.5. HRMS (ESI-TOF): m/z calcd for
C14H19N4O4S [M + H]+ 339.1122, found 339.1142.
2-((4S,11aR)-4-(Hydroxymethyl)-6,6-dioxido-3-oxo-9-
(trifluoromethyl)-3,4,11,11a-tetrahydrobenzo[e]-
299
dx.doi.org/10.1021/co5000163 | ACS Comb. Sci. 2014, 16, 293−302

ACS Combinatorial Science
Research Article
pyrazino[1,2-b][1,2,4]thiadiazin-2(1H)-yl)ethanaminium
2,2,2-trifluoroacetate 8(3,5,2).
thiadiazin-2(1H)-yl)-N-(3-hydroxypropyl)propanamide
8(4,2,3).
Yield: 22.4 mg (74%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 8.03 (t, J = 5.4 Hz, 1 H), 7.67 (s, 1 H), 7.55 (d, J
= 8.6 Hz, 1 H), 6.84 (d, J = 2.0 Hz, 1 H), 6.80 (dd, J = 2.0, 8.6
Hz, 1 H), 5.46−5.43 (m, 1 H), 3.90 (dd, J = 2.3, 13.7 Hz, 1 H),
3.78 (dt, J = 6.9, 13.7 Hz, 1 H), 3.73 (t, J = 6.7 Hz, 2 H), 3.54
(dd, J = 2.6, 13.8 Hz, 1 H), 3.31−3.26 (m, 2 H), 3.15−3.05 (m,
2 H), 2.41−2.30 (m, 2 H), 1.65 (quin, J = 6.7 Hz, 2 H), 1.46
(d, J = 6.9 Hz, 3 H). 13C NMR (126 MHz, DMSO-d6): δ 170.3,
166.7, 144.4, 138.3, 127.3, 117.0, 114.6, 114.5, 63.1, 58.4, 53.3,
49.1, 44.3, 35.8, 33.3, 32.3, 22.4. HRMS (ESI-TOF): m/z calcd
for C17H23ClN4NaO5S [M + Na]+ 453.0970, found 453.0947.
Yield: 28.6 mg (27%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 7.73 (d, J = 8.2 Hz, 1 H), 7.22 (s, 1 H), 7.01 (d, J
= 8.2 Hz, 1 H), 5.61−5.49 (m, 1 H), 3.95 (d, J = 13.4 Hz, 1 H),
3.83 (dd, J = 2.4, 11.2 Hz, 1 H), 3.78 (dd, J = 2.4, 11.2 Hz, 1
H), 3.68 (dd, J = 1.9, 13.4 Hz, 1 H), 3.54 (dd, J = 6.0, 13.4 Hz,
1 H), 3.46−3.32 (m, 2 H), 2.91−2.76 (m, 2 H). 13C NMR (75
MHz, DMSO-d6): δ 173.4, 165.9, 144.1, 133.7 (q, J = 31.5 Hz),
126.7, 123.4 (q, J = 271.5 Hz), 118.7, 112.5 (q, J = 3.8 Hz),
64.8, 63.7, 60.1, 48.9, 47.4, 38.2. HRMS (ESI-TOF): m/z calcd
for C14H18F3N4O4S [M + H]+ 395.0995, found 395.1016.
2-((4S,11aR)-4-(4-Hydroxybenzyl)-6,6-dioxido-3-oxo-
9-(trifluoromethyl)-3,4,11,11a-tetrahydrobenzo[e]-
pyrazino[1,2-b][1,2,4]thiadiazin-2(1H)-yl)ethanaminium
2,2,2-trifluoroacetate 8(3,6,2).
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of the experimental procedures and the NMR spectra
associated with this article. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vkrchnak@nd.edu.
■
Yield: 28.5 mg (23%) of amorphous solid. 1H NMR (300 MHz,
DMSO-d6): δ 7.78 (d, J = 8.2 Hz, 1 H), 7.19 (s, 1 H), 7.04 (d, J
= 8.2 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 2 H), 6.70 (d, J = 8.4 Hz, 2
H), 5.38−5.32 (m, 1 H), 3.67 (t, J = 3.6 Hz, 1 H), 3.38 (dd, J =
2.2, 13.5 Hz, 1 H), 3.33−3.27 (m, 1 H), 3.22−3.06 (m, 3 H),
3.02 (dd, J = 2.7, 13.5 Hz, 1 H), 2.73−2.61 (m, 2 H). 13C NMR
(75 MHz, DMSO-d6): δ 173.0, 165.8, 156.6, 143.9, 133.6 (q, J
= 32.3 Hz), 131.3, 126.7, 124.9, 123.4 (q, J = 271.5 Hz), 118.8,
114.8, 112.6 (q, J = 4.5 Hz), 63.4, 58.5, 48.4, 47.8, 39.6, 38.4.
HRMS (ESI-TOF): m/z calcd for C20H22F3N4O4S [M + H]+
471.1308, found 471.1334.
Funding
This research was supported by the Department of Chemistry
and Biochemistry at the University of Notre Dame, by projects
P207/12/0473 from the Czech Science Foundation (GACR),
and CZ.1.07/2.3.00/20.0009 from the European Social Fund.
The infrastructure of this project (Institute of Molecular and
Translational Medicine) was supported by the Operational
Programme Research and Development for Innovations
(Project CZ.1.05/2.1.00/01.0030).
Notes
The authors declare no competing financial interest.
N-(3-Hydroxypropyl)-3-((4S,11aR)-4-methyl-6,6-dioxi-
d o - 3 - o x o - 9 - ( t r i fl u o r o m e t h y l ) - 3 , 4 , 1 1 , 1 1 a -
tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-
2(1H)-yl)propanamide 8(4,2,2).
ACKNOWLEDGMENTS
We are grateful for the use of the NMR facility at the University
of Notre Dame.
■
REFERENCES
■
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Yield: 20.6 mg (63%) of amorphous solid. 1H NMR (500 MHz,
DMSO-d6): δ 8.04 (t, J = 5.4 Hz, 1 H), 7.88 (s, 1 H), 7.76 (d, J
= 8.0 Hz, 1 H), 7.13 (d, J = 1.4 Hz, 1 H), 7.07−7.04 (m, 2 H),
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H). 13C NMR (126 MHz, DMSO-d6): δ 170.3, 166.7, 143.7,
133.6 (q, J = 32.2 Hz), 127.0, 123.3 (q, J = 273.8 Hz), 118.7,
112.7 (q, J = 3.4 Hz), 112.4 (q, J = 4.2 Hz), 63.1, 58.4, 53.3,
49.0, 44.3, 35.8, 33.4, 32.3, 22.4. HRMS (ESI-TOF) m/z calcd
for C18H24F3N4O5S [M + H]+ 465.1414, found 465.1425.
3-((4S,11aR)-9-chloro-4-methyl-6,6-dioxido-3-oxo-
3,4,11,11a-tetrahydrobenzo[e] pyrazino[1,2-b][1,2,4]-
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