Efficient synthesis of 1,4-thiazepanones and 1,4-thiazepanes as 3d fragments for screening libraries

Article abstract of DOI:10.1021/acs.orglett.0c01230

1,4-Thiazepanes and 1,4-thiazepanones represent seven-membered ring systems with highly 3D character and are currently underrepresented in fragment screening libraries. A nuclear magnetic resonance (NMR) fragment screen identified 1,4-acylthiazepanes as new BET (bromodomain and extraterminal domain) bromodomain ligands; however, an efficient and readily diversified synthesis for library development has not been reported. Here we report a one-pot synthesis using α,β-unsaturated esters and 1,2-amino thiols to form 1,4-thiazepanones as precursors to 1,4-thiazepanes with high 3D character. This reaction proceeds in reasonable time (0.5-3 h) and in good yield and tolerates a broad scope of α,β-unsaturated esters. Several 1,4-thiazepanes were synthesized by a two-step transformation and were characterized as new BET bromodomain ligands using protein-observed ¹⁹F NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries.

Full text of DOI:10.1021/acs.orglett.0c01230

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Letter
Efficient Synthesis of 1,4-Thiazepanones and 1,4-Thiazepanes as 3D
Fragments for Screening Libraries
Anil K. Pandey,† Steven E. Kirberger,† Jorden A. Johnson, Jennifer R. Kimbrough, Danika K. D. Partridge,
and William C. K. Pomerantz*
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ABSTRACT: 1,4-Thiazepanes and 1,4-thiazepanones represent seven-membered ring systems with highly 3D character and are
currently underrepresented in fragment screening libraries. A nuclear magnetic resonance (NMR) fragment screen identified 1,4-
acylthiazepanes as new BET (bromodomain and extraterminal domain) bromodomain ligands; however, an efficient and readily
diversified synthesis for library development has not been reported. Here we report a one-pot synthesis using α,β-unsaturated esters
and 1,2-amino thiols to form 1,4-thiazepanones as precursors to 1,4-thiazepanes with high 3D character. This reaction proceeds in
reasonable time (0.5−3 h) and in good yield and tolerates a broad scope of α,β-unsaturated esters. Several 1,4-thiazepanes were
synthesized by a two-step transformation and were characterized as new BET bromodomain ligands using protein-observed 19F
NMR. This synthesis should provide ready access to diverse 3D fragments for screening libraries.
materials for library synthesis and undesired regioisomer
production18 hinder their effectiveness. Conjugate additions
into α,β-unsaturated lactones and lactams yield 1,4-thiazepa-
nones, but these methods force hydroxyl or amino substituents
in the seven-position, limiting the scope for product diversity.19
Methyl-3-mercaptopropionate cyclizes using aziridine with
sodium methoxide. This pathway requires several days and
may not be compatible with base-sensitive functional
groups.20,21 Thiazepanones are also synthesized from cycliza-
tion with cysteamine or derivatives under basic conditions with
α,β-unsaturated esters, taking 3−7 days and often resulting in
low yield.21−25 Our synthesis of 1a using this approach gave
similar yields (32%) and reaction time (3 days).7 Here we
develop cysteamine cyclization reactions with α,β-unsaturated
esters to produce 1,4-thiazepanones in short (<3 h) reaction
times (Figure 1, bottom). The significant improvement stems
from the moderate reactivity of trifluoroethyl esters and milder
reaction conditions to increase the substrate scope. Using our
improved conditions, a broad scope of 1,4-thiazepanones is
achieved, in many cases without chromatography. These
ragment-based ligand discovery (FBLD) is an efficient
Fapproach for inhibitor discovery against difficult drug
targets.1 The premise of FBLD is a reduction of chemical space
that is efficiently sampled through screening low-molecular
weight molecules. Retrospective analyses identified a need for
increasing the fragment library diversity.2 Fragment libraries
are largely composed of flat molecular scaffolds, with a high
prevalence of aromatic rings.3,4 Ring systems, such as saturated
seven-membered rings, are underrepresented.5 Fragments with
increased 3D character have shown improved specificity in
protein-binding assays, offering an additional metric for library
design.6 We recently screened a 3D-enriched library against the
protein, BRD4,7 an anticancer drug target.8,9 One lead 3D
fragment hit, 1a, was an acylated 1,4-thiazepane. The
structure−activity relationship (SAR) study was limited due
to the lack of a robust and easily diversified synthetic route for
creating a library of thiazepane molecules. To address this
need, we report an optimized synthesis of 1,4-thiazepanes for
fragment library development (Figure 1).
We sought to establish a high-yielding synthesis of 1,4-
thiazepane and thiazepanones for BRD4 inhibitor develop-
ment. Whereas multiple approaches have been described for
forming benzothiazepinones,10−13 which benefit from the
rigidified amino thiols for optimizing cyclization, far fewer
methods for non-ring-fused thiazepanones are reported (Figure
1, top). Tetrahydro-1,4-thiapyranones undergo Beckmann
rearrangements14,15 or Schmidt reactions.16,17 These pathways
yield the desired seven-membered rings, but access to starting
Received: April 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01230
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Table 1. Reaction Optimization with Solvent and Base
entry
base
time (h) % yield temp (°C) imidazole
solvent
1
2
3
4
5
6
7
8
9
Et3N
DIEA
NaOH
DBU
DBU
DBU
DBU
DBU
DBU
18
18
18
18
18
24
18
18
18
0
0
0
11
53
25
27
53
56
60
60
60
60
60
60
60
60
rt
no
no
no
no
yes
no
no
yes
yes
THF
THF
THF
THF
THF
CH3OH
DMF
CH3CN
CH3CN
a
Reactions performed with 2a.1 (1.0 equiv), cysteamine (1.2 equiv),
base (2.0 equiv), and imidazole (0−20 mol %) in solvent (5 mL).
Yields and temperature indicated.
acylation. We tested methyl (2a.1), 2,2,2-trifluoroethyl (2a.2),
and hexafluoroisopropyl (2a.3) esters (Table 2).27 Ester 2a.2
was the best-suited, yielding 3a in higher yields (70%, entry 4,
Table 2) and shorter reaction times (0.5 h) relative to the
much slower methyl ester (56%, entry 1, 18 h). Under these
conditions, alternative bases could be used but with reduced
yield or extended reaction times. Unlike the methyl ester, the
trifluoroethyl ester cyclization worked efficiently, forming
thiazepanone 3a without imidazole (71%, entry 5, Table 2).
Figure 1. General scheme for 1,4-thiazepanone and 1,4-thiazepane
synthesis.
Table 2. Optimization of Cyclization for 1,4-
a
Thiazepanones
thiazepanones are subsequently reduced and functionalized to
generate bromodomain ligands.
Our initial attempt to synthesize the 1,4-thiazepanone
included a two-step reaction, creating an amide bond with
aryl-substituted acrylic acids, followed by an intramolecular
conjugate addition (Scheme S2). Here the conjugate addition
step was not successful, presumably due to the reduced
electrophilicity of the β-carbon. Conducting the conjugate
addition first on 3-(2-thienyl)acrylic acid with N-Boc-cyste-
amine, followed by deprotection and intramolecular acylation
to form 3a led to a mixture of side products. We ultimately
focused our attempts instead on a one-pot conjugate addition
and acylation reaction (Figure 1).
The initial optimization of the tandem conjugate addition/
cyclization reaction used the methyl ester of 3-(2-thienyl)-
acrylic acid to favor conjugate addition prior to cyclization. A
base screen showed DBU to yield the cyclized 1,4-
thiazepanone, albeit in low yields (11%, Table 1). Other
bases, DIEA, Et3N, and NaOH, did not yield product. NaOH
has been previously used; however, the reaction times took 5
days with modest yield.24 Finally, we tested the effect of acyl
transfer additives26 and found 0.2 equiv of imidazole to
increase the yield (53%, entry 5, Table 1). The reaction was
further improved through solvent choice. Tetrahydrofuran and
acetonitrile were well-suited for this reaction. Acetonitrile was
optimal, as the reaction worked efficiently at ambient
temperature (entry 9) and excluded the need for heating to
solubilize reagents, as required for tetrahydrofuran.
entry
R
base
time (h) % yield imidazole
1
2
3
4
5
6
−CH3 (2a.1)
DBU
DIEA
NaOH
DBU
DBU
DBU
18
18
18
56
71
22
70
71
50
yes
yes
yes
yes
no
−CH2CF3 (2a.2)
−CH2CF3 (2a.2)
−CH2CF3 (2a.2)
−CH2CF3 (2a.2)
−CH(CF3)2 (2a.3)
0.5
0.5
1
yes
a
Reactions performed with ester (1 equiv), cysteamine (1.2 equiv),
base (2 equiv), and imidazole (0−20 mol %) in CH3CN (5 mL) at rt
for 0.5−18 h. Yields are indicated.
Under these optimized conditions, we tested the order of the
two-step reaction sequence. When the ester group was
replaced by an amide via first acylating with cysteamine, the
subsequent conjugate addition product was not formed using
the optimized conditions. (Scheme S2).28 This result is
consistent with conjugate addition preceding cyclization
when using the trifluoroethyl ester.
With a set of conditions in hand, we explored the reaction
scope with respect to the α,β-unsaturated ester (Table 3). In
the case of cinnamic esters, the syntheses worked efficiently.
For para substitution, electron-donating and -withdrawing
Finally, we sought to tune the electrophilicity of the α,β-
unsaturated esters while favoring conjugate addition before
B
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a
We next tested the generality of this reaction using cysteine,
penicillamine, and 1,4-aminothiophenol (Table 4).22 For
Table 3. Scope of Cyclization for 1,4-Thiazepanones
a
Table 4. Cyclization with Different 1,2-Aminothiols
entry compd
1,2-aminothiol
base/catalyst time (h) % yield
b
1
2
3
4
3x
3y
3a.1
3c.1
L-cysteine
DBU
DBU
DBU
TBAF
18
18
18
24
67
62
0
b
c
L-penicillamine
2-aminothiophenol
2-aminothiophenol
d
65
a
For 3x and 3y, reactions were performed with 1.0 equiv of ester, 1,2-
aminothiol (1.2 equiv), base (2 equiv), dimethylsulfate (1.5 equiv),
and imidazole (0−20 mol %) in CH3CN (5 mL). For 3c.1, the
reaction was performed with cinnamic acid (1 equiv), 2-amino-
thiophenol (2 equiv), and TBAF (0.1 equiv) at 80 °C for 24 h. Yields
b
c
indicated. Obtained as a mixture of diastereomers. Predominant
d
disulfide formation under optimized conditions. Synthesized using
the previously reported protocol.29
cysteine derivatives, the free carboxylic acid was converted to
a methyl ester prior to isolation to yield 3x and 3y. A moderate
to high degree of diastereoselectivity was observed (i.e., 3x, dr
= 2.3:1; 3y, dr = >95:1). Additionally, we reacted 2-
aminothiophenol with either a trifluoroethyl or a methyl
ester of cinnamic acids. The reaction was unsuccessful with
predominant disulfide formation. Alternately, compound 3c.1
was synthesized via a reported protocol using TBAF as a
catalyst under neat conditions.29 In our hands, these
conditions were not compatible with the synthesis of non-
ring-fused 1,4-thiazepanones, demonstrating the complemen-
tary nature of both methods.
a
Reactions performed with ester (1.0 equiv), cysteamine (1.2 equiv),
base (2 equiv), and imidazole (0−20 mol %) in CH3CN (5 mL) at rt,
b
0.5−3 h. Yields indicated. Product obtained using methyl ester and
c
d
no imidazole. No imidazole was added. Product isolated as a
diastereomeric mixture; R2 = CH3
To produce 1,4-thiazepanes for bromodomain inhibition
experiments, the 1,4-thiazepanones 3a, 3c, 3g, and 3h were
reduced using sodium borohydride/iodine (Table 5) or borane
groups led to isolated yields of 50−83% for 3f−k. For p-nitro
groups, reduced yields and increased side products were
obtained. The yield of 3l could be improved to 40% by
excluding the acyl transfer catalyst or by using the less reactive
methyl ester. Ortho- and meta-substituted cinnamic esters
provided modest to high yields of 50−87% (e.g., 3m−o) and
trisubstituted α,β-unsaturated esters 3p and 3s. High-yielding
reactions (i.e., 3f, 3g, 3h, 3j, 3m, and 3n) did not require
chromatographic purification. A few reactions showed modest
conversion of 50% (3i and the disubstituted aryl ether 3t)
primarily due to unreacted cinnamic ester, even after several
hours of reaction. For the heterocyclic substituent nitrofuryl-
containing 3d, the reaction did not form the major product.
Alternatively, 3d was obtained using the less reactive methyl
ester but in low yield. Imidazole-containing ester was
nonreactive toward these conditions to form 3e, indicating
sensitivity toward more electron-deficient heterocycles. α,β-
Unsaturated esters substituted without aromatic groups are
also substrates and yield 3q and 3r in comparable yield.
Finally, we tested polar and acid- and base-sensitive
functional groups. Thiazepanones with acid- or base-labile
protecting groups, Boc and trifluoroacetamide, respectively,
also formed (3w, 3v). A methyl ester was also tolerated (3u).
In contrast, previously reported protocols using either strongly
basic or acidic conditions provide limited access to these acid-
or base-labile functional groups.20−25
a
Table 5. Synthesis of 1,4-Thiazepanes
a
Reduction conditions: thiazepanone (1.0 equiv), NaBH4 (5 equiv),
iodine (2 equiv) in THF (5 mL). Carbamoylation and acylation
conditions: amine (1 equiv), triethylamine (1.2 to 1.5 equiv), and
electrophile (1.2 to 1.5 equiv) for 0.5 to 2 h, rt. Yields indicated.
C
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dimethylsulfide28 to the corresponding 1,4-thiazepanes 4a, 4c,
4g, and 4h and converted to carbamates or amides (Table 5
and Table S1).28 Using this approach, we significantly
improved the prior synthesis of parent compound 1a over
the reported synthesis.7 The current methodology should be
preferable for the synthesis of 1,4-thiazepanes to other
approaches with an improvement in time, yield, and scope.
With several 1,4-thiazepanes and thiazepanones in hand, we
tested for BRD4-D1 binding. These molecules possess a
significant 3D character with a plane-of-best fit of 0.84 to 1.0
and 0.61 to 1.1, respectively (Table S2),31 above the threshold
of 0.25 for describing a 3D fragment.6 We used 19F NMR to
quantify ligand binding to fluorinated BRD4-D1 by measuring
a change in chemical shift of a fluorinated tryptophan (W81)
resonance located in the protein binding site (Figure 2B).30
Full experimental details and spectral characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
William C. K. Pomerantz − Department of Chemistry,
University of Minnesota, Minneapolis, Minnesota 55455,
United States; orcid.org/0000-0002-0163-4078;
Email: wcp@umn.edu
Authors
Anil K. Pandey − Department of Chemistry, University of
Minnesota, Minneapolis, Minnesota 55455, United States
Steven E. Kirberger − Department of Chemistry, University of
Minnesota, Minneapolis, Minnesota 55455, United States
Jorden A. Johnson − Department of Chemistry, University of
Minnesota, Minneapolis, Minnesota 55455, United States
Jennifer R. Kimbrough − Department of Chemistry, University
of Minnesota, Minneapolis, Minnesota 55455, United States;
orcid.org/0000-0003-0221-3088
Danika K. D. Partridge − Department of Chemistry, University
of Minnesota, Minneapolis, Minnesota 55455, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01230
Author Contributions
†A.K.P. and S.E.K. contributed equally.
Notes
The authors declare the following competing financial
interest(s): We have submitted a provisional patent on this
work: Pomerantz, W. C. K.; Johnson, J.; Kirberger, S. E.;
Pandey, A. Improved Synthesis of Substituted 1,4-Thiazepan-
5-ones. UMN Provisional Patent 2020-042, filed 2019.
ACKNOWLEDGMENTS
■
We acknowledge the NIH Biotechnology training grant
5T32GM008347-23 and the Masonic Cancer Center for
funding.
Figure 2. (A) Fluorine NMR titration. (B) BRD4-D1 with the 5-
fluorotrytophans labeled in blue (PDB ID: 3MXF). (C) Binding
isotherm of 1g (black circles) and 1h (purple squares). (D) Structure
and corresponding ligand affinities.
REFERENCES
■
(1) Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti,
H. Twenty Years on: The Impact of Fragments on Drug Discovery.
Nat. Rev. Drug Discovery 2016, 15 (9), 605−619.
We tested 11 compounds at a single concentration, including
six thiazepanones and five thiazepanes. Thiazepanes 1g, 1h,
and 6a induced a significant chemical shift and were titrated to
obtain a Kd value of 120−210 μM (Figure 2 and Figures S1
and S2), demonstrating good affinity. These titration experi-
ments also demonstrate the good water solubility of the
thiazepane scaffold.
In conclusion, we report the efficient synthesis of 1,4-
thiazepane and 1,4-thiazepanones with an improved substrate
scope. Several thiazepanes maintain affinity for BRD4. Ready
access to this scaffold will increase the diversity of 3D fragment
screening libraries. The versatility of this short approach will be
used for library generation for screening against diverse
proteins and for improving binding efficiency to BRD4.
̈
(2) Fuller, N.; Spadola, L.; Cowen, S.; Patel, J.; Schonherr, H.; Cao,
Q.; McKenzie, A.; Edfeldt, F.; Rabow, A.; Goodnow, R. An Improved
Model for Fragment-Based Lead Generation at AstraZeneca. Drug
Discovery Today 2016, 21 (8), 1272−1283.
̈
(3) Brown, D. G.; Bostrom, J. Analysis of Past and Present Synthetic
Methodologies on Medicinal Chemistry: Where Have All the New
Reactions Gone? J. Med. Chem. 2016, 59 (10), 4443−4458.
(4) Feher, M.; Schmidt, J. M. Property Distributions: Differences
between Drugs, Natural Products, and Molecules from Combinatorial
Chemistry. J. Chem. Inf. Comput. Sci. 2003, 43 (1), 218−227.
(5) Giordanetto, F.; Jin, C.; Willmore, L.; Feher, M.; Shaw, D. E.
Fragment Hits: What Do They Look Like and How Do They Bind? J.
Med. Chem. 2019, 62 (7), 3381−3394.
(6) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J.
A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small
Molecules of Different Origins Have Distinct Distributions of
Structural Complexity That Correlate with Protein-Binding Profiles.
Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (44), 18787−18792.
(7) Johnson, J. A.; Nicolaou, C. A.; Kirberger, S. E.; Pandey, A. K.;
Hu, H.; Pomerantz, W. C. K. Evaluating the Advantages of Using 3D-
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Enriched Fragments for Targeting BET Bromodomains. ACS Med.
Chem. Lett. 2019, 10, 1648−1654.
Esters: Expeditious Access to (R)-Thiazesim. Org. Lett. 2013, 15 (13),
3448−3451.
(8) Smith, S. G.; Zhou, M.-M. The Bromodomain as an Acetyl-
Lysine Reader Domain. In Chromatin Signaling and Diseases; Elsevier,
2016; pp 97−111.
(28) Refer to the Supporting Information.
(29) Zhang, P.; Ye, D.; Chu, Y. An Efficient One-Pot Procedure for
the Synthesis of 1,5-Benzothiazepinones Catalyzed by Tetrabutylam-
monium Fluoride (TBAF). Tetrahedron Lett. 2016, 57 (33), 3743−
3745.
(30) Gee, C. T.; Arntson, K. E.; Urick, A. K.; Mishra, N. K.; Hawk,
L. M. L.; Wisniewski, A. J.; Pomerantz, W. C. K. Protein-Observed
19F-NMR for Fragment Screening, Affinity Quantification and
Druggability Assessment. Nat. Protoc. 2016, 11 (8), 1414−1427.
(31) Colomer, I.; Empson, C. J.; Craven, P.; Owen, Z.; Doveston, R.
G.; Churcher, I.; Marsden, S. P.; Nelson, A. A Divergent Synthetic
Approach to Diverse Molecular Scaffolds: Assessment of Lead-
Likeness Using LLAMA, an Open-Access Computational Tool. Chem.
Commun. 2016, 52 (45), 7209−7212.
(9) Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.;
Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T. T.; Felletar, I.;
Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.;
West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; et al.
Selective Inhibition of BET Bromodomains. Nature 2010, 468
(7327), 1067−1073.
(10) Meninno, S.; Volpe, C.; Lattanzi, A. Catalytic Enantioselective
Synthesis of Protecting-Group-Free 1,5-Benzothiazepines. Chem. -
Eur. J. 2017, 23 (19), 4547−4550.
(11) Fang, C.; Lu, T.; Zhu, J.; Sun, K.; Du, D. Formal [3 + 4]
Annulation of α,β-Unsaturated Acyl Azoliums: Access to Enantioen-
riched N− H -Free 1,5-Benzothiazepines. Org. Lett. 2017, 19 (13),
3470−3473.
(12) Fukata, Y.; Asano, K.; Matsubara, S. Facile Net Cycloaddition
Approach to Optically Active 1,5-Benzothiazepines. J. Am. Chem. Soc.
2015, 137 (16), 5320−5323.
́
(13) Troelsen, N. S.; Shanina, E.; Gonzalez-Romero, D.; Dankova,
D.; Jensen, I. S. A.; Sniady, K. J.; Nami, F.; Zhang, H.; Rademacher,
́
C.; Cuenda, A.; Gotfredsen, C. H.; Clausen, M. H. The 3F Library:
Fluorinated Fsp 3 -Rich Fragments for Expeditious 19 F NMR Based
Screening. Angew. Chem., Int. Ed. 2020, 59 (6), 2204−2210.
(14) Barkenbus, C.; Diehl, J. F.; Vogel, G. R. The Beckmann
Rearrangement of Some Heterocyclic Ketoximes. J. Org. Chem. 1955,
20 (7), 871−874.
(15) Shankaran, K.; Donnelly, K. L.; Shah, S. K.; Caldwell, C. G.;
Chen, P.; Hagmann, W. K.; MacCoss, M.; Humes, J. L.; Pacholok, S.
G.; Kelly, T. M.; Grant, S. K.; Wong, K. K. Synthesis of Analogs of
(1,4)-3- and 5-Imino Oxazepane, Thiazepane, and Diazepane as
Inhibitors of Nitric Oxide Synthases. Bioorg. Med. Chem. Lett. 2004,
14 (23), 5907−5911.
(16) Mull, R. P.; Egbert, M. E.; Dapero, M. R. Guanidines with
Antihypertensive Activity. J. Org. Chem. 1960, 25 (11), 1953−1956.
(17) Evans, P. A.; Modi, D. P. Novel Approach to Lactams via
(Triisopropylsilyl) Azidohydrin Formation and Photoinduced
Schmidt Rearrangement. J. Org. Chem. 1995, 60 (21), 6662−6663.
́
(18) Szostak, M.; Yao, L.; Aube, J. Cation-n Control of
Regiochemistry of Intramolecular Schmidt Reactions En Route to
Bridged Bicyclic Lactams. Org. Lett. 2009, 11 (19), 4386−4389.
̈
(19) Bohrisch, J.; Faltz, H.; Patzel, M.; Liebscher, J. Chiral 1,4-
Diazepinones and 1,4-Thiazepinones by Diastereoselective Ring
Chain Transformation of α,β Unsaturated Lactones or Lactams.
Tetrahedron 1994, 50 (36), 10701−10708.
(20) Jakob, F.; Schlack, P. 5-Oxo-1-Thia-4-Aza-Cycloheptan-
Synthesen. Chem. Ber. 1963, 96 (1), 88−92.
(21) Arya, V. P.; Kaul, C. L.; Grewal, R. S.; David, J.; Talwaker, P.
K.; Shesoy, S. J. Antihypertensive Agents: Part V* - Synthesis &
Antihypertensive Activity of 3-Arylimino-2,3,5,6-Tetrahydro-4H-1,4-
Thiazines & Related Cyclic Amidines. Indian J. Chem. B 1977, 15,
720−726.
(22) Leonard, N. J.; Ning, R. Y. The Synthesis and Stereochemistry
of Substituted 1,4-Thiazepines Related to the Penicillins. J. Org. Chem.
1966, 31 (12), 3928−3935.
(23) Blondeau, P.; Berse, R. G. C.; Gravel, D. Synthesis of Some
Stable 7-Halo-1,4-Thiazepines. Potential Substituted Penam Precur-
sors. Can. J. Chem. 1971, 49, 3866−3876.
(24) Wamhoff, H.; Theis, C. H. Perhydro-l,4-Thiazepin-5-Onen.
Chem. Ber. 1980, 113, 995−1009.
(25) Karimova, N. M.; Glazkov, A. A.; Ignatenko, A. V.; Kolomiets,
A. F. Addition of Thiols to Ethyl 4,4,4-Trifluorocrotonate. Russ. Chem.
Bull. 2003, 52 (7), 1621−1622.
(26) Yang, X.; Birman, V. B. Acyl Transfer Catalysis with 1,2,4-
Triazole Anion. Org. Lett. 2009, 11 (7), 1499−1502.
(27) Fang, X.; Li, J.; Wang, C. J. Organocatalytic Asymmetric Sulfa-
Michael Addition of Thiols to α,β-Unsaturated Hexafluoroisopropyl
E
https://dx.doi.org/10.1021/acs.orglett.0c01230
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