Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding

Article abstract of DOI:10.1021/acs.joc.8b03015

We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

Full text of DOI:10.1021/acs.joc.8b03015

Subscriber access provided by ECU Libraries
Article
3
Pyridine fused 2-pyridones via Povarov and A reactions: rapid generation of
highly functionalized tricyclic heterocycles capable of amyloid fibril binding
Pardeep Singh, Dan Erik Adolfsson, Jörgen Ådén, Andrew Gerard Cairns,
Christian Bartens, Kristoffer Brännström, Anders Olofsson, and Fredrik Almqvist
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03015 • Publication Date (Web): 13 Mar 2019
Downloaded from http://pubs.acs.org on March 13, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Pyridine fused 2-pyridones via Povarov and A3 reactions: rapid
generation of highly functionalized tricyclic heterocycles capable of
amyloid fibril binding
Pardeep Singh†, Dan E. Adolfsson†, Jörgen Ådén†, Andrew G. Cairns†, Christian Bartens‡, Kristoffer
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Brännström§, Anders Olofsson§ and Fredrik Almqvist†,*
§
†Umeå University, Department of Medical Biochemistry and Biophysics, Department of Chemistry,
901 87 Umeå, Sweden.
‡Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz
Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
R1
N
R
R
O
R1
S
S
O
(Povarov reaction)
N
+
N
Or
R2
H
R2
H2N
CO2Me
CO2Me
O
R1
new tricyclic central fragment
32 examples
(A3 coupling)
ABSTRACT: We here describe the use of three component reactions to synthesize tricyclic pyridine
ring-fused 2-pyridones. The developed protocols have wide substrate scope and allow the installation of
diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid
polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with
neurodegenerative diseases.
INTRODUCTION
The ring-fused 2,3-dihydrothiazolo-2-pyridone unit has received considerable attention as a
scaffold which can be modified to demonstrate varied biological activities.1,2a–f Particular
substitution patterns show activity against specific bacterial infections,1 while others modulate
the formation of amyloids associated with neurological disorders.2a–f Rigidification of the
bicyclic 2-pyridone, either by decoration with sterically demanding aryl groups2a–d or by
annulation with nitrogen heterocycles2e offers a route to modulators of amyloid formation.
Recently, we reported a nitrene insertion approach for facile synthesis of fluorescent multi ring-
fused 2-pyridone polyheterocycles (Figure 1a).2f The benzoquinoline and benzothienopyridine
annulated polyheterocycles modulated α-synuclein amyloid formation, while indole annulated
2-pyridones were ineffective. These results motivated us to synthesize diverse tricyclic pyridine
ring-fused 2-pyridone scaffolds and identify leads with improved physico-chemical and
biological properties. We perceived that multicomponent coupling reactions of bicyclic 6-
amino-2-pyridones could allow rapid construction of analogues containing a highly
functionalized pyridine fused tricyclic central fragment with the same hydrogen bond donor-
acceptor configurations as in the previously reported polyheterocycles (Figure 1b).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
a. Previous work: Intramolecular nitrene insertion of 6-azido-2-pyridones
3
4
5
R
R1 = -CH2-naphthyl
S
N
6
N
CO2H
7
8
9
O
tricyclic unit important to modulate
a-synuclein aggregation
R
O
R
(i) Nitrene
insertion
R1
N3
R1 = -CH2-benzothiophene
S
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(ii) Hydrolysis
N
N
S
N
CO2Me
CO2H
O
R
S
R1 = -Phenyl
N
N
H
CO2H
O
Inactive
b. This work: A3 and Povarov reactions of 6-amino-2-pyridones
R1
R1
R
9
R
10
8
1
1
Povarov
reaction
9
S
S
8
7
O
2
2
+
or
5
N
4
N
4
5
3
R1
R
2 7
3
R2
6
N
6
H2N
H
CO2Me
CO2Me
A
3 coupling
O
O
Figure 1. Synthesis of ring-fused 2-pyridone polyheterocycles
Multicomponent reactions are a powerful tool for facile assembly of diverse and complex ring-
fused nitrogen heterocycles.3 In particular, transition metal catalyzed three component couplings
of amines, aldehydes and alkynes (A3) and Lewis acid catalyzed three component Povarov
reactions have been widely used for the construction of highly functionalized, biologically
important heterocycles.4,5
Motivated by our interest in the synthesis of thiazolo ring fused 2-pyridone based
heterocycles,2f,6 we herein present A3 and Povarov reactions of 6-amino-2-pyridones for the
efficient synthesis of complex, diversely functionalized pyridine ring-fused 2-pyridones.
Preliminary investigation into the fibril binding of analogues containing these scaffolds suggest
they are capable of binding to amyloid β (Aβ 1–40) and α-synuclein fibrils, which are associated
with Alzheimer’s and Parkinson’s disease respectively.
RESULTS AND DISCUSSION
Our studies began with the synthesis of C-7 unsubstituted bicyclic 6-amino-2-pyridones 5a–d
as substrates. An acyl ketene-imine cyclocondensation between thiazolines7a–b 1a–d and
Meldrum’s acid derivative 27c afforded thiazolo-2-pyridones 3a–d. Subsequent nitration of 3a–d
was followed by reduction to give 6-amino-2-pyridones 5a–d in good yields (Scheme 1).
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
OH
R
R
S
S
O
O
DCE, TFA
+
N
N
MWI, 120 ˚C,
3 min
O
O
CO2Me
CO2Me
O
1a: R = -cyclopropyl
1b: R = -phenyl
1c: R = -OMe
2
3a: 47%; 3b: 49%
3c: 41%; 3d: 51%
1d: R = -H
HNO3/Ac2O
-40 to 0˚C,
2-6 h
8
9
R
O
R
MeOH:THF (2:1)
H2, Pd/C
S
S
10
11
12
13
14
15
16
17
rt, 1-4 h
N
N
H2N
O2N
CO2Me
CO2Me
O
5a: 99%; 5b: 66%
5c: 86%; 5d: 98%
4a: 61%; 4b: 65%
4c: 55%; 4d: 36%
Scheme 1. Synthesis of 6-amino-2-pyridones 5a-5d
Initial investigations of the A3 reaction employed amino-2-pyridone 5a, benzaldehyde and phenyl
acetylene as reactants alongside catalytic copper (II) triflate. The desired pyridine fused 2-pyridone 6a
was attained in 34% yield (Scheme 2). The reaction worked with both aromatic (6a–c and 6f) and
aliphatic (6d–e) aldehydes, and also with aromatic (6a–d) and aliphatic (6e–f) alkynes. The electronic
nature of the reactants did not have a pronounced effect on the yields, however reaction with p-tolyl
benzaldehyde was noticeably slower. The A3 route allowed rapid construction of a diversely
functionalized molecular framework, diversifying the tricyclic central fragment in three positions
simultaneously.
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
R1
R
R
S
S
Cu(OTf)2
+
N
CHCl3, MWI,
120 ˚C, 1 h
N
R2
N
O
H2N
CO2Me
CO2Me
O
5a, 5b
O
6a-f
R2
H
S
S
S
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
a6c: 31%
O
6a: 34%
O
6b: 38%
O
O2N
S
S
S
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
O
6f: 43%
O
6d: 32%
O
6e: 26%
O2N
Scheme 2. A3 reaction of 6-amino-2-pyridones. aReaction mixture heated for 2 hours
We were encouraged by the A3 results, however the utility of this method was limited by harsh
conditions, sometimes leading to complex reaction mixtures and moderate yields. As an
alternative we considered the BF3⋅OEt2 catalyzed Povarov reaction of 6-amino-2-pyridones,
aiming to synthesize the tricyclic scaffold under milder conditions.
For the initial study of the Povarov reaction, 2-pyridone fused aza-diene 7 (Scheme 3) was
synthesized by stirring 6-amino-2-pyridone 5a with p-nitrobenzaldehyde in methanol. Imine 7
then underwent a Povarov reaction with styrene, in the presence of 10 mole percent of BF3⋅OEt2
in DCM at room temperature. Povarov adduct 8 was obtained, and DDQ used to expedite the
slow aerobic oxidation to polyaromatic heterocycle 6b.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
MeOH, rt
S
CHO
S
2 h
+
N
N
68%
H2N
N
O2N
CO2Me
CO2Me
O
5a
O
7
O2N
BF3OEt2,
CH2Cl2, rt,
4 h, 97%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S
S
N
DDQ, CH2Cl2
N
rt, 30 min
75%
N
N
H
CO2Me
CO2Me
O
6b
O
O2N
O2N
8
Scheme 3. Stepwise Povarov reaction with styrene
We next investigated the scope of the Povarov reaction in a multicomponent procedure. Thus, 6-
amino-2-pyridones 5a–d carrying different substituents on C-8 were reacted with various
aldehydes and styrene to establish the substrate scope and prepare suitable analogues for
biological testing (Scheme 4). Gratifyingly, the reaction worked with all aldehydes and 6-
amino-2-pyridones tested. Povarov adducts were oxidized with DDQ to afford pyridine ring-
fused 2-pyridones 6g–o in 50–76% yields. The Povarov reaction proved slow with m-CF3-
styrene, requiring elevated temperature and longer reaction time to obtain moderate yields of
products 6p and 6q respectively.
R3
R3
(i) BF3OEt2,
R
CH2Cl2, rt,
R
S
16 h
S
+
N
(ii) DDQ, CH2Cl2,
rt, 30 min
H2N
N
O
R2
N
CO2Me
O
5a, 5c, 5d
CO2Me
O
R2
H
6g-q
S
S
N
S
N
S
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
O
6g: 50%
O
6h: 51%
O
6i: 53%
O
6j: 54%
F3C
NC
F
O
O
O
O
S
S
S
S
N
N
N
N
S
N
N
N
N
CO2Me
CO2Me
CO2Me
F3C
CO2Me
O
6m: 75%
O
6k: 67%
O
6l: 76%
O
6n: 64%
O2N
CF3
CF3
S
S
S
N
N
N
N
N
N
CO2Me
a6q: 29%
CO2Me
CO2Me
a6p: 49%
O
O
6o: 67%
O
O2N
O2N
Scheme 4. Three component Povarov reaction with styrenes, aHeated to 50 °C for 4 days
To expand the scope of the reaction and investigate the structure activity relationship of this
fragment, we envisioned using ethyl vinyl ether as a dienophile to access a C-9 unsubstituted
and less hydrophobic scaffold. 6-amino-2-pyridones 5a, 5b, 5d reacted with different aldehydes
and ethyl vinyl ether to furnish the desired scaffold 9a–k in 17–59% yield (Scheme 5). The
ACS Paragon Plus Environment

Page 5 of 33
1
The Journal of Organic Chemistry
2
3
4
5
synthesis of 9k was tested on a 1.2 gram (5.30 mmol) scale to confirm the scalability of the
procedure, with the resulting 44% yield comparable to that achieved previously (47%, 0.39
mmol).
6
7
8
9
(i) BF3OEt2,
CH2Cl2, rt,
16 h
R
R
O
S
S
+
(ii) DDQ, CH2Cl2,
rt, 15 min
N
N
R1
N
O
H2N
CO2Me
CO2Me
O
5a, 5b, 5d
O
9a-k
R1
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S
S
S
S
N
N
N
N
N
N
N
N
CO2Me
CO2Me
NC
CO2Me
O
9a: 52%
CO2Me
O
9b: 49%
O
9c: 59%
O
9d: 17%
O2N
F3C
F
S
S
S
S
N
N
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
O
9e: 59%
O
O
O
a9g: 45%
a9f: 46%
a9h: 41%
S
S
S
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
O
9j: 34%
O
9k: 47%
O
9i: 38%
F3C
O2N
O2N
Scheme 5. Three component Povarov reaction with ethyl vinyl ether,
a: Povarov adduct oxidized spontaneously
Observing that the C-10 unsubstituted 9k presented opportunities for late functionalization and efficient
library synthesis, we explored a regioselective halogenation and transition metal coupling approach.
Selective bromination of 9k gave brominated tricyclic intermediate 10, which underwent Suzuki
coupling to furnish products 9l–o in good yields (Scheme 6)
Br
R
R
B(OH)2
PdCl2(PPh3)2, KF
S
S
NBS, CHCl3
9k
N
50 ˚C, 15 min
88%
MeOH, MWI, 120 ˚C
10 min
N
N
N
CO2Me
CO2Me
O
O
O2N
O2N
10
9l: R = 3-OH-phenyl; 80%
9m: R = 3-CH3-phenyl; 85%
9n: R = 3-COCH3-phenyl; 90%
9o: R = 3-thienyl; 92%
Scheme 6. Bromination and Suzuki coupling
Finally, hydrolysis of the methyl esters 6a–q and 9a–o gave carboxylic acids 11a–q and 12a–o
respectively (Scheme 7).
R1
R
R1
R
LiOH (0.1 M aq)
S
S
THF, rt, 2 h
34-81%
N
N
R2
N
R2
N
CO2Me
CO2H
O
O
6a-q, 9a-o
11a-q, 12a-o
Scheme 7. Hydrolysis of methyl esters
The carboxylic acids were evaluated for their ability to modulate α-synuclein amyloid formation by a
fluorescence assay with amyloidophilic dye Thioflavin T (ThT), which produces enhanced fluorescent
emission on binding to fibril structures.8 We postulated that the complexity and diverse substitution of
the analogues may allow selective interaction with amyloidogenic proteins, as previously observed with
related structures.2e,f Even though ThT flourescence signals were low in assays including these
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
compounds (Figure S1), TEM images subsequently showed these samples to contain fibrils
indistinguishable from the control by appearance or seeding behaviour (Figure 2b and S2, S3). Further,
the observed lag phase and results from DLS experiments with 12a (Figure S4) did not suggest
modulatory activity. Given the relatively planar core scaffold, we hypothesized that these analogues
instead competed with ThT binding to fibrils. We conducted a preliminary screen for amyloid binding
using carboxylic acids 11a–q and 12a–o and displacement of ThT bound to α-synuclein and Aβ (1–40)
fibrils as a proxy for binding (Figure S5–7).9 Compounds 11b, 11f, 11o, 11p, 12a, 12i, 12k–o with a p-
nitrophenyl at position C-7 of the tricyclic skeleton bound to both fibril structures, indicated by
reduction of the ThT derived fluorescence (Figure 2a and S5–7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(a)
(b)
Figure 2. Binding of compounds interferes with Thioflavin T. (a) Black trace show α-syn monomers incubated for 70 hours,
forming mature fibers. Then, 100 µM of 11b was added, followed by further incubation, and a loss of fluorescence signal. In
red, 11b was added at time zero. This procedure was repeated for all compounds. (b) Transmission electron microscopy
pictures of α-synuclein fibers formed in the presence of selected compound 11b.
A similar structure activity relationship was observed for both Aβ and α-synuclein fibrils. The
apparent requirement for a C4’ nitro substituent may reflect a polar interaction, as analogues
with alternative electron withdrawing groups were not active (11g and 11h). A C-10 electron
releasing methoxy substituent appears unfavorable, as evidenced by lower binding compared to
analogues with both larger and smaller substituents (11k vs 11b and 11o). Although concurrent
C-9 and C-10 substitution was tolerated, placement of the larger substituent in C-10 appears
favored (11b vs 11k). A range of C-10 aryl substituents were tolerated, at least where C-9 is
unsubstituted (12l–12o). Since all compounds that was shown to bind amyloid fibrils was
equipped with a 4-nitrophenyl substituent, we prepared and tested the fibril binding activity of
bicyclic 2-pyridone 15 (Scheme 8) substituted with a 4-nitrophenyl ring at position C-6. No
significant binding to α-synuclein fibrils was observed upon evaluation (Figure S1). This result
further consolidates that the fused pyridine ring present in the tricyclic scaffold is important for
fibril binding activity.
B(OH)2
Pd(OAc)2
O2N
LiOH (0.1 M aq.)
S
S
S
S
K2CO3
NIS
MeOH
110 °C, MWI
10 min.
N
N
N
N
THF
rt, 2h
26%
MeCN
I
CO2Me
CO2H
CO2Me H2O
rt o.n.
58%
CO2Me
O
O
O
O
O2N
O2N
81%
14
15
3a
13
Scheme 8. Synthesis of bicyclic 2-pyridone 15 equipped with a 4-nitrophenyl substituent.
ACS Paragon Plus Environment

Page 7 of 33
1
The Journal of Organic Chemistry
2
3
CONCLUSION
4
5
6
7
8
9
In summary, we have synthesized C-7 unsubstituted 6-amino-2-pyridones, and used them in A3
and Povarov reactions, allowing synthesis of diversely functionalized pyridine ring-fused 2-
pyridone polyheterocycles. Both methods permit rapid ring construction of new complex
heterocycles with multiple points of variation. The milder Povarov approach proved effective
for accessing compact, less hydrophobic central fragments. The preliminary in-vitro biological
evaluation suggested that eight of the thirty-two tricyclic 2-pyridones tested were able to bind
Aβ and α-synuclein amyloid fibrils. Annulation of bicyclic 2-pyridones with functionalized
pyridine rings therefore provides a straightforward synthetic route to novel tricyclic 2-pyridone
peptidomimetics capable of binding to amyloid fibrils. To build on these promising results we
intend to undertake more detailed appraisal of analogue binding selectivity, properties and
structure activity relationships. Selective binding to mature fibrils is a property of potential
diagnostic and therapeutic value,10 and further development of these molecules as modulators or
probes for neurodegenerative disease may facilitate application in chemical biology or as
clinical diagnostic tools such as PET probes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General information: Unless stated, all reagents and solvents were used as received from commercial
suppliers. All reactions were carried out under an inert atmosphere with dry solvents under anhydrous
conditions, unless otherwise indicated. 4 Å MS were activated at 300 °C under vacuum for 4 h.
Microwave reactions were performed in sealed vessels using a Biotage® Initiator microwave
synthesizer; temperatures were monitored by an internal IR probe. TLC was performed on purchased
aluminium backed silica gel plates (median pore size 60 Å, fluorescent indicator 254 nm) and detected
with UV light at 254 and 366 nm. Flash column chromatography was performed using silica gel (0.063–
0.200 mesh). Automated flash column chromatography was performed using a Biotage® Isolera One
system and purchased pre-packed silica gel cartridges (Biotage® SNAP Cartridge, KP-Sil). Preparative
HPLC was performed with a Gilson instrument using a Nucleodur C18 HTec column (25 cm x 21.5
mm; particle size 5 µm). Optical rotation was measured with a Perkin Elmer polarimeter 343 at 25 °C
and 589 nm. IR spectra were recorded on a Bruker Alpha-t spectrometer. The samples were prepared as
1
13
19
KBr pellets or between NaCl plates, absorbances are given in reciprocal cm. H-, C- and F-NMR
spectra were recorded on a Bruker Avance III 400 MHz spectrometer with a BBO-F/H SmartprobeTM, a
Bruker Avance III HD 600 MHz spectrometer with a CP BBO-H/F, 5 mm cryoprobe, or a Bruker
Avance III HD 850 MHz spectrometer with a CP TCI HCN, 5 mm cryoprobe, at 298 K, unless other
temperature is given. All spectrometers were operated by Topspin 3.5.7. Resonances are given in ppm
relative to TMS, and calibrated to solvent residual signals (CDCl3: δH = 7.26 ppm; δC = 77.16 ppm.
(CD3)2SO: δH = 2.50 ppm; δC = 39.51 ppm. CD3OD δH = 3.31 ppm; δC = 49.00 ppm). The following
abbreviations are used to indicate splitting patterns: s = singlet; d = doublet; dd = double doublet; t =
triplet; m = multiplet; bs = broad singlet. LC-MS was conducted on a Micromass ZQ mass spectrometer
using ES+ ionization unless otherwise stated. HRMS was performed on a mass spectrometer with ESI-
TOF (ES+). Amyloid formation was probed by thioflavin T (ThT) fluorescence, with a Fluorostar
Omega instrument (BMG Labtech, Germany), using excitation and emission filters of 440 and 480 nm,
respectively.
Meldrum’s acid derivative (2) was prepared following a published experimental procedure2 with
some modifications: Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (60.0 g; 0.42 mol) was
placed in a round bottomed flask and triethyl orthoformate (195 ml; 1.17 mol) was added. The mixture
was heated with an oil bath at 85 °C, while stirring. The reaction was followed with TLC
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
(CHCl3/MeOH 9:1) and confirmed to be finished after 2 h. The excess triethyl orthoformate was
removed with rotary evaporation. HCl(aq) (2 M; 800 ml) was added to the yellow oily residue while
stirring. A precipitate formed soon after the addition. The mixture was stirred at r.t. for 30 min. and then
filtered. The solid was dissolved in DCM (500 ml) and washed with brine (2 x 250 ml). The organic
phase was dried, filtered and evaporated to give a bright yellow solid (48.3 g, 67%). The aqueous phase
was combined with the filtrate and extracted with DCM (3 x 150 ml). The organic phases were
combined, dried, filtered and evaporated to give a yellow–orange solid (16.4 g; 29%). Total yield (64.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
g, 90%). IR (KBr): ν 1747, 1683, 1592, 1419, 1277, 1259, 1184 cm-1; H-NMR (400 MHz, CDCl3): δ
13
1.76 (s, 6H), 8.54 (s, 1H); C{1H}-NMR (100 MHz, CDCl3): δ 27.4, 95.6, 107.2, 160.7, 168.2, 177.1;
-
−
LC-MS (ESI−): m/z = 171.2 [M−H] , C7H7O5 requires 172.1.
General procedure for synthesis of 3a–d: In a microwave reaction tube equipped with a magnetic
stirrer, thiazoline (1.0 mmol, 1.0 eq.) and Meldrum’s acid derivative (0.60 g, 3.5 mmol, 3.5 eq.) was
dissolved in 1,2-dichloroethane (10ml). TFA (150 µl, 2.0 mmol, 2.0 eq.) was added, the tube was sealed
and heated to 120 °C under microwave irradiations for 3 min. The reaction mixture was cooled to room
temperature diluted with DCM (8 ml) and washed with saturated aqueous sodium bicarbonate solution
(4 ml) followed by brine (4 ml). The aqueous phases were re-extracted with DCM (2 ml each). The
organic phases were combined, dried, filtered and evaporated. The compound was purified with flash
column chromatography.
(R)-Methyl 8-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate (3a):
Prepared by following the general procedure. The product was purified with automated flash column
chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20–100% in 8 CV). Brown solid, 1426
25
mg (47%); [α]D −150 (c 0.52, MeOH). IR (KBr): ν 1753, 1651, 1582, 1502, 1362, 1212, 1007, 822
1
cm-1; H-NMR (600 MHz, CDCl3): δ 0.53–0.59 (m, 2H), 0.80–0.87 (m, 2H), 1.53–1.59 (m, 2H), 3.54
(dd, J = 1.9, 11.7 Hz, 1H), 3.69 (dd, J = 8.4, 11.5 Hz, 1H), 3.79 (s, 3H), 5.60 (dd, J = 1.9, 8.5 Hz, 1H),
6.22 (d, J = 9.2 Hz, 1 H), 7.07 (d, J = 9.2 Hz, 1H); 13C{1H}-NMR (151 MHz, CDCl3): δ 6.1, 6.3, 12.4,
31.8, 53.4, 63.4, 114.5, 115.2, 141.1, 146.6, 161.6, 168.6; LC-MS: m/z = 252.1 [M+H]+, C12H14NO3S+
requires 252.2.
(R)-Methyl
5-oxo-8-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(3b):
Prepared by following the general procedure. The product was purified with automated flash column
chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20–100%). Brown solid, 900 mg
25
(49%); [α]D −83 (c 0.31, CHCl3); IR (CHCl3): ν 1752, 1657, 1586, 1490, 1442, 1370, 1216, 1167,
1068, 821, 767, 701 cm-1; 1H-NMR (400 MHz, CDCl3): δ 3.53 (dd, J = 2.0, 11.6 Hz, 1H), 3.66 (dd, J =
8.4, 11.6 Hz, 1H), 3.83 (s, 3H), 5.70 (dd, J = 2.0, 8.4 Hz, 1H), 6.40 (d, J = 9.2 Hz, 1H), 7.31–7.44 (m,
13
6H); C{1H}-NMR (100 MHz, CDCl3): δ 31.6, 53.4, 63.3, 115.7, 116.1, 127.7 (2C), 128.9, 137.5,
142.3, 145.4, 161.4, 168.5; LC-MS: m/z = 288 [M+H]+, C15H14NO3S+ requires 288.
(R)-Methyl
8-methoxy-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate(3c):
Prepared by following the general procedure. The product was purified with automated flash column
chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20–100%). Brown solid, 263 mg
25
(47%); [α]D −62 (c 0.42, CHCl3); IR (CHCl3): ν 1751, 1664, 1578, 1505, 1440, 1412, 1379, 1278,
1215, 1174, 1068, 816, 729 cm-1; 1H-NMR (400 MHz, CDCl3): δ 3.57 (dd, J = 2.4, 12.0 Hz, 1H), 3.74
(dd, J = 8.4, 12.0 Hz, 1H), 3.75 (s, 3H), 3.79 (s, 3H), 5.60 (dd, J = 2.0, 8.4 Hz, 1H), 6.27 (d, J = 10.0
13
Hz, 1H), 7.26 (d, J = 9.6 Hz, 1H); C{1H}-NMR (100 MHz, CDCl3): δ 32.3, 53.4, 59.1, 63.5, 115.5,
133.2, 135.7, 137.8, 160.3, 168.3; LC-MS: m/z = 242 [M+H]+, C10H12NO4S+ requires 242.
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(R)-Methyl 5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate (3d): Prepared by
following the general procedure. The product was purified with automated flash column
chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20–100%). Brown solid, 344 mg
25
(51%); [α]D −170 (c 5.92, CHCl3); IR (CHCl3): ν 1750, 1658, 1572, 1513, 1437, 1215, 783 cm-1 1H-
NMR (400 MHz, CDCl3): δ 3.54 (dd, J = 2.4, 11.6 Hz, 1H), 3.73 (dd, J = 8.4, 12.0 Hz, 1H), 3.80 (s,
3H), 5.60 (dd, J = 2.0, 8.4 Hz, 1H), 6.12 (dd, J = 0.8, 7.2 Hz, 1H), 6.27 (dd, J = 0.8, 8.8 Hz, 1H), 7.27
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(dd, J = 7.2, 9.2 Hz, 1H); C{1H}-NMR (100 MHz, CDCl3): δ 31.9, 53.4, 63.0, 100.6, 115.3, 140.7,
147.5, 162.2, 168.4; LC-MS: m/z = 212 [M+H]+, C9H10NO3S+ requires 212.
General procedure for preparation of 6-nitro-2-pyridones 4a–d:The 2-pyridone of general
structure 3 (1.0 mmol, 1.0 eq.) was dissolved in acetic anhydride (3.4 ml) and cooled to −40 °C. Acetic
anhydride (1.7 ml) was cooled on ice and HNO3 (65% aq.) (0.10 ml, 1.5 mmol, 1.5 eq.) was added
slowly. The diluted acid was transferred to a dropping funnel and added slowly to the stirred solution.
The reaction mixture was allowed to warm to 0 °C and stirred until completion was indicated by TLC
(EtOAc). The reaction mixture was then quenched with methanol (10 ml) at 0 °C, transferred to a
separation funnel with ice-cold NaHCO3 (sat. aq.) (10 ml) and EtOAc (10 ml). The phases were
separated and the aqueous phase was extracted once more with EtOAc (10 ml). The organic phases
were combined, dried over anhydrous sodium sulphate, filtered and evaporated. The crude product was
purified with flash column chromatography.
(R)-Methyl 8-cyclopropyl-6-nitro-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(4a): Prepared by following the general procedure. The reaction was finished after 105 min. Purified
with flash column chromatography (40 x 120 mm silica; ethyl acetate in heptane, 25–70%). Yellow
25
solid, 1.01 g (61%); [α]D −387 (c 0.40, CHCl3); IR (KBr): ν 1752, 1677, 1496, 1313, 1263, 1219,
1
1002, 772 cm-1; H-NMR (400 MHz, CDCl3): δ 0.62–0.72 (m, 2H), 0.91–1.01 (m, 2H), 1.60–1.68 (m,
1H), 3.67 (dd, J = 2.3, 12.0 Hz, 1H), 3.83 (s, 3H), 3.88 (dd, J = 9.2, 12.0 Hz, 1H), 5.78 (dd, J = 2.3, 9.2
13
Hz, 1H), 8.25 (s, 1H); C{1H}-NMR (100 MHz, CDCl3): δ 6.5, 6.7, 12.4, 32.3, 53.9, 64.3, 113.4,
133.0, 140.4, 153.3, 159.8, 167.6; LC-MS: m/z = 297 [M+H]+, C12H13N2O5S+ requires 297.
(R)-Methyl 6-nitro-5-oxo-8-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate (4b):
Prepared by following the general procedure (1 mmol of HNO3 was used). The reaction was finished
after 2 hours. Purified with automated flash column chromatography (50 g SNAP Cartridge; ethyl
acetate in heptane, 20-100%). Yellow solid, 735 mg (65%); [α]D25 −184 (c 0.52, CHCl3); IR (CHCl3): ν
1
1751, 1682, 1599, 1487, 1441, 1379, 1327, 1260, 1219, 1150, 751, 701 cm-1; H-NMR (400 MHz,
CDCl3): δ 3.66 (dd, J = 2.0, 12.0 Hz, 1H), 3.84–3.89 (m, 4H), 5.86 (dd, J = 2.4, 8.4 Hz, 1H), 7.39–7.46
(m, 5H) 8.52 (s, 1H); 13C{1H}-NMR (100 MHz, CDCl3): δ 32.2, 53.9, 64.4, 114.1, 127.9, 128.9, 129.3,
133.8, 135.3, 141.1, 153.0, 157.4, 167.5; LC-MS: m/z = 333 [M+H]+, C15H13N2O5S+ requires 333.
(R)-Methyl
8-methoxy-6-nitro-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(4c): Prepared by following the general procedure. The reaction was finished after 2 hours. Purified
with automated flash column chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20-
25
100%). Yellow solid, 665 mg (55%); [α]D −187 (c 0.42, CHCl3) IR (CHCl3): ν 1751, 1677, 1586,
1
1511, 1401, 1308, 1259, 1220, 1144, 1089, 935, 765 cm-1; H-NMR (400 MHz, (CD3)2SO): δ 3.76 (s,
3H), 3.82 (dd, J = 2.0, 12.0 Hz, 1H), 3.86 (s, 3H), 4.05 (dd, J = 9.6, 12.0 Hz, 1H), 3.83 (s, 3H), 5.81
13
(dd, J = 2.0, 9.6 Hz, 1H), 8.46 (s, 1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 32.1, 53.2, 58.2, 64.2,
127.6, 130.1, 134.4, 151.0, 151.9, 167.8; LC-MS: m/z = 287 [M+H]+, C10H11N2O6S+ requires 287.
(R)-Methyl 6-nitro-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate (4d): Prepared
by following the general procedure. The reaction was finished after 6 hours. Purified with automated
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
9
flash column chromatography (50 g SNAP Cartridge; ethyl acetate in heptane, 20-100%). Yellow solid,
25
457 mg (36%); [α]D −137 (c 1.6, CHCl3); IR (CHCl3): ν 1749, 1677, 1515, 1439, 1309, 1166, 1219
1
cm-1; H-NMR (400 MHz, CDCl3): δ 3.69 (dd, J = 2.0, 12.0 Hz, 1H), 3.83 (s, 3H), 3.92 (dd, J = 9.2,
12.0 Hz, 1H), 5.75 (dd, J = 2.0, 9.2 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 8.4 Hz, 1H);
13C{1H}-NMR (100 MHz, CDCl3): δ 32.7, 53.9, 63.9, 98.6, 133.5, 140.8, 153.6, 159.0, 167.3; LC-MS:
m/z = 257 [M+H]+, C9H9N2O5S+ requires 257.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for preparation of 6-amino-2-pyridones 5a–d:Pd/C-10 (53 mg, 50 µmol,
0.050 eq.) was placed in a round bottomed flask. The flask was evacuated and back-filled with nitrogen
thrice. MeOH (6 ml) and THF (3 ml) was added. The flask was placed under vacuum until the solvent
started boiling and back-filled with hydrogen. The 6-nitro-2-pyridone of general structure 4 (1 mmol,
1.0 eq.) was dissolved in MeOH (6 ml) and added to the round bottomed flask while stirring. The
reaction mixture was then stirred vigorously at room temperature. When TLC (EtOAc) indicated
completion, chloroform (3 ml) was added. The solution was filtered through a pad of Celite® and
evaporated.
(R)-Methyl
6-amino-8-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-
carboxylate: (5a): Prepared following the general procedure. The reaction was finished after 100 min.
Dark brown solid, 0.89 g (99%); [α]D25 −151 (c 0.19, DMSO). IR (KBr): ν 3448, 3346, 1748, 1643,
1592, 1519, 1292, 1217, 1005, 766 cm-1; 1H-NMR (600 MHz, CDCl3): δ 0.52–0.57 (m, 2H), 0.77–0.83
(m, 2H), 1.50–1.58 (m, 1H), 3.53 (dd, J = 2.2, 11.7 Hz, 1H), 3.68 (dd, J = 8.0, 11.7 Hz, 1H), 3.79 (s,
13
3H), 5.58 (dd, J = 2.2, 8.2 Hz, 1H), 6.31 (s, 1H); C{1H}-NMR (151 MHz, CDCl3): δ 6.2, 6.4, 12.8,
32.4, 53.3, 63.3, 114.9, 115.2, 130.5, 134.0, 157.0, 168.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C12H15N2O3S+ 267.0798; Found 267.0790.
(R)-Methyl
6-amino-5-oxo-8-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(5b): Prepared by following the general procedure. The reaction was finished after 1.5 hours. Purified
with automated flash column chromatography (25 g SNAP Cartridge; ethyl acetate in heptane, 0–60%).
25
Grey solid, 240 mg (66%); [α]D −88 (c 0.5, CHCl3); IR (CHCl3): ν 3454, 3336, 3007, 2954, 1750,
1643, 1596, 1522, 1493, 1442, 1351, 1217, 1156, 1013, 765, 701 cm-1; 1H-NMR (400 MHz, CDCl3): δ
3.52 (dd, J = 2.0, 11.6 Hz, 1H), 3.64 (dd, J = 8.0, 11.6 Hz, 1H), 3.83 (s, 3H), 5.68 (dd, J = 2.4, 8.0 Hz,
13
1H), 6.72 (s, 1H), 7.28–7.41(m, 5H); C{1H}-NMR (100 MHz, CDCl3): δ 32.2, 53.4, 63.3, 115.5,
116.3, 127.5, 127.7, 128.7, 129.9, 134.5, 138.2, 157.1, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C15H15N2O3S+ 303.0798; Found 303.0802.
(R)-Methyl
6-amino-8-methoxy-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(5c): Prepared following the general procedure. The reaction was finished after 3 hours. Black solid,
398 mg (86%); [α]D25 −8 (c 0.062, CHCl3); IR (KBr): 3549, 2956, 1746, 1638, 1617, 1585, 1524, 1452,
1311, 1260, 1217, 1173, 760, 620 cm-1; 1H-NMR (400 MHz, (CD3)2SO)): δ 3.55 (dd, J = 2.4, 12.0 Hz,
1H), 3.68 (dd, J = 8.0, 11.6 Hz, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 4.12 (bs, 1H), 5.59 (dd, J = 2.4, 8.0 Hz,
1H), 6.56 (s, 1H); 13C{1H}-NMR (100 MHz, (CD3)2SO)): δ 32.8, 53.4, 59.0, 63.4, 127.6, 130.1, 134.4,
151.0, 151.9, 167.8; HRMS (ESI-TOF) m/z: [M]+ Calcd for C10H12N2O4S+ 256.0518; Found 256.0518.
(R)-Methyl
6-amino-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-carboxylate
(5d):
Prepared following the general procedure. The reaction was finished after 4 hours. Black solid, 190 mg
25
(98%); [α]D −13 (c 7.4, CHCl3); IR (CHCl3): ν 3440, 3327, 1746, 1644, 1592, 1437, 1218, 1179 cm-1;
1H-NMR (400 MHz, CDCl3): δ 3.54 (dd, J = 2.0, 11.6 Hz, 1H), 3.71 (dd, J = 8.0, 11.6 Hz, 1H), 3.79 (s,
3H), 4.00 (bs, 3H), 5.75 (dd, J = 2.0, 8.0 Hz, 1H), 6.00 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H);
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13C{1H}-NMR (100 MHz, CDCl3): δ 32.7, 53.3, 63.0, 101.0, 114.6, 131.7, 134.1, 157.7, 168.5; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C9H11N2O3S+ 227.0485; Found 227.0492.
General procedure of the A3-reaction: Preparation of compounds 6a–f : Under air, 6-amino-2-
pyridones of general structure 5 (0.38 mmol, 1.0 eq.) was placed in a 5 ml microwave reaction tube
equipped with a magnetic stirrer and dissolved in chloroform (4 ml). The aldehyde (0.64 mmol, 1.7 eq.)
was added, followed by the acetylene (1.13 mmol, 3.0 eq.) and copper trifluoromethanesulfonate (41
mg, 0.11 mmol, 0.30 eq.). The tube was sealed and heated to 120 °C for 1 h. The tube was opened and
the reaction progress was checked with TLC (ethyl acetate in heptane, 50%) and LC-MS. When no 6-
amino-2-pyridone was left, the mixture was transferred to a separating funnel, diluted with DCM (5 ml)
and washed with NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml). Then dried over anhydrous sodium
sulphate, filtered and evaporated. The crude residue was purified with flash column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl
10-cyclopropyl-5-oxo-7,9-diphenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6a): The compound was prepared following the general
procedure. Purified with flash column chromatography (20 x 120 mm silica; ethyl acetate in toluene, 5–
50%). 101 mg of 5a was converted to 58 mg (34%) of 6a, isolated as a light brown solid. [α]D25 −134 (c
0.22, CHCl3); IR (NaCl): ν 1752, 1663, 1591, 1512, 1491, 1459, 1439, 1380, 1214, 1180, 751, 698 cm-
1
1; H-NMR (400 MHz, CDCl3): δ 0.16–0.25 (m, 4H), 1.14–1.22 (m, 1H), 3.52 (dd, J = 2.7, 11.6 Hz,
1H), 3.72 (dd, J = 8.3, 11.6 Hz, 1H), 3.81 (s, 3H), 5.76 (dd, J = 2.5, 8.3 Hz, 1H), 7.37–7.52 (m, 8H),
7.88 (s, 1H), 8.17–8.24 (m, 2H); 13C{1H}-NMR (100 MHz, CDCl3): δ 10.7, 10.8, 16.1, 31.6, 53.4, 63.5,
109.0, 126.6, 127.4, 127.9, 128.0, 128.8, 129.3, 129.5, 132.7, 138.2, 141.4, 141.8, 143.6, 147.5, 154.4,
159.8, 168.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H23N2O3S+ 455.1423; Found 455.1427.
(R)-Methyl
10-cyclopropyl-7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6b): The compound was prepared following the general
procedure. Purified with flash column chromatography (20 x 120 mm silica; ethyl acetate in toluene, 5–
50%). 100 mg of 5a was converted to 72 mg (38%) of 6b, isolated as a yellow-brown solid. [α]D25 −138
1
(c 0.27, CHCl3); IR (CHCl3): ν 1751, 1665, 1590, 1552, 1520, 1344, 1216, 752 cm-1; H-NMR (400
MHz, CDCl3): δ 0.16–0.26 (m, 4H), 1.15–1.23 (m, 1H), 3.55 (dd, J = 2.6, 11.7 Hz, 1H), 3.75 (dd, J =
8.2, 11.6 Hz, 1H), 3.83 (s, 1H), 5.77 (dd, J = 2.6, 8.3 Hz, 1H), 7.39–7.53 (m, 5H), 7.93 (s, 1H), 8.30 (d,
13
J = 9.0 Hz, 2H), 8.38 (d, J = 8.9 Hz, 2H); C{1H}-NMR (100 MHz, CDCl3): δ 10.8, 10.9, 16.1, 31.6,
53.5, 63.6, 109.0, 124.1, 127.0, 128.1, 128.3, 129.3, 133.7, 141.3, 141.5, 144.1, 145.2, 148.0, 148.4,
151.5, 159.5, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22N3O5S+ 500.1275; Found
500.1295.
(R)-Methyl
10-cyclopropyl-5-oxo-9-phenyl-7-(p-tolyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6c): The compound was prepared following the general procedure
but the reaction mixture was heated for 2 h. Purified with flash column chromatography (20 x 110 mm
silica; ethyl acetate in toluene 5–40%). 101 mg of 5a was converted to 56 mg (31%) of 6c, isolated as a
light brown solid. [α]D25 −141 (c 0.23, CHCl3). IR (CHCl3): ν 1752, 1664, 1591, 1456, 1441, 1214,
1
1181, 751, 701, 664 cm-1; H-NMR (400 MHz, CDCl3): δ 0.15–0.25 (m, 4H), 1.14–1.22 (m, 1H), 2.40
(s, 3H), 3.52 (dd, J = 2.6, 11.6 Hz, 1H), 3.72 (dd, J = 8.3, 11.6 Hz, 1H), 3.81 (s, 3H), 5.76 (dd, J = 2.6,
8.2 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.38–7.52 (m, 5H), 7.86 (s, 1H), 8.12 (d, J = 8.2 Hz, 2H);
13C{1H}-NMR (100 MHz, CDCl3): δ 10.7, 10.8, 16.1, 21.5, 31.6, 53.4, 63.5, 109.1, 126.3, 127.3, 128.0,
129.4, 129.5, 132.5, 135.4, 139.6, 141.3, 141.9, 143.3, 147.4, 154.5, 159.8, 168.9; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C28H25N2O3S+ 469.1579; Found 469.1584.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
8
9
(R)-Methyl
7-cyclohexyl-10-cyclopropyl-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6d): The compound was prepared following the general
procedure. Purified with flash column chromatography (20 x 110 mm silica; ethyl acetate in toluene,
20–60%). 100 mg of 5a was converted to 55 mg (32%) of 6d, isolated as a yellow solid. [α]D25 −115 (c
0.24, CHCl3) IR (CHCl3): ν 2926, 2852, 1753, 1663, 1593, 1459, 1214, 753 cm-1; 1H-NMR (600 MHz,
CDCl3): δ 0.14–0.21 (m, 4H), 1.12–1.18 (m, 1H), 1.23–1.31 (m, 1H), 1.37–1.47 (m, 2H), 1.50–1.59 (m,
2H), 1.72–1.77 (m, 1H), 1.78–1.87 (m, 2H), 2.00–2.06 (m, 2H), 2.97–3.04 (m, 1H), 3.50 (dd, J = 2.8,
11.6 Hz, 1H), 3.67 (dd, J = 8.2, 11.6 Hz, 1H), 3.80 (s, 3H), 5.72 (dd, J = 2.8, 8.7 Hz, 1H), 7.31 (s, 1H),
7.35–7.44 (m, 5H); C{1H}-NMR (151 MHz, CDCl3): δ 10.7, 10.8, 16.2, 26.1, 26.6, 31.6, 33.0, 33.1,
46.5, 53.4, 63.5, 109.0, 127.2, 127.8 (2C), 129.4, 132.1, 140.7, 142.0, 142.6, 147.1, 159.8, 164.5, 169.0;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H28N2NaO3S+ 483.1713; Found 483.1714.
(R)-Methyl 7,9,10-tricyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylate (6e): Prepared by following the general procedure. Purified with flash column
chromatography (20 x 120 mm silica; ethyl acetate in heptane, 10–80%). 96 mg of 5a was converted to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
25
37 mg (26%) of 6e, isolated as a light yellow solid. [α]D −202 (c 0.22, CHCl3); IR (KBr): ν 1754,
1656, 1594, 1454, 1379, 1306, 1212, 1022, 972, 838 cm-1; H-NMR (400 MHz, CDCl3): δ 0.62-0.71
(m, 2H), 0.71-0.80 (m, 2H), 0.96-1.07 (m, 8H), 2.11-2.19 (m, 2H), 2.84-2.91 (m, 1H), 3.47 (dd, J = 2.4,
11.6 Hz, 1H), 3.65 (dd, J = 8.4, 11.6 Hz, 1H), 3.77 (s, 3H), 5.66 (dd, J = 2.4, 8.0 Hz, 1H), 6.87 (s, 1H);
13C{1H}-NMR (100 MHz, CDCl3): δ 10.2, 10.3, 10.4, 10.6, 10.9, 11.0, 15.0, 15.6, 17.6, 31.5, 53.3,
63.3, 109.5, 121.8, 134.2, 140.3, 141.4, 149.0, 159.8, 161.2, 169; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C21H22N2NaO3S+ 405.1243; Found 405.1248.
1
(R)-Methyl
9-cyclopropyl-7-(4-nitrophenyl)-5-oxo-10-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6f): Prepared by following the general procedure, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–30% ethyl acetate in
25
dichloromethane. 80 mg of 5b was converted to 57 mg (43%) of 6f, isolated as a yellow solid. [α]D
−
122 (c 0.31, CHCl3); IR (KBr): ν 1752, 1667, 1592, 1554, 1521, 1493, 1451, 1410, 1344, 1217, 1176,
927, 855, 733, 699 cm-1; H-NMR (400 MHz, CDCl3): δ 0.39–0.47 (m, 2H), 0.52–0.59 (m, 2H), 1.34–
1
1.41 (m, 1H), 3.41 (d, J = 10.0 Hz, 1H), 3.61 (dd, J = 8.8, 11.2 Hz, 1H), 3.77 (s, 3H), 5.80 (d, J = 6.8
Hz, 1H), 7.19–7.42 (m, 5H), 7.53(s, 1H), 8.24 (s, 4H); 13C{1H}-NMR (100 MHz, CDCl3): δ 10.3, 10.8,
17.3, 31.4, 53.5, 63.9, 110.6, 122.2, 124.0, 128.0, 128.3, 128.6, 128.7, 130.5, 130.6, 133.9, 139.7, 140.8,
143.5, 144.4, 148.3, 150.0, 152.4, 159.6, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C27H22N3O5S+ 500.1275; Found 500.1273.
(R,E)-Methyl 8-cyclopropyl-6-(4-nitrostyryl)-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-
carboxylate (7): 6-Amino-2-pyridone 5a (200 mg, 0.75 mmol, 1.0 eq.) and 4-Nitrobenzaldehyde
(136.2 mg, 0.90 mmol, 1.2 eq.) were dissolved in dry methanol (6 mL). A precipitate was formed after
stirring at room temperature for 4 hours. The precipitate was filtered through sintered funnel, washed
with heptane and dried under vacuum to yield compound 7 (205 mg, 68 %) as a red solid. [α]D25 −55 (c
0.26, DMSO); IR (KBr): ν 3417, 2958, 1749, 1629, 1565,1518, 1486, 1399, 1385, 1342, 1272, 1223,
1144, 1105, 842, 992, 622. 1H-NMR (400 MHz, (CD3)2SO, 343K): δ 0.67–0.70 (m, 2H), 0.88–0.90 (m,
2H), 1.62 (broad s, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.76 (s, 3H), 4.00 (dd, J = 9.6, 11.6 Hz, 1H), 5.68 (d,
J = 7.6 Hz, 1H), 7.31 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.30 (d, J = 8.4 Hz, 2H), 9.60 (s, 1H); 13C{1H}-
NMR (100 MHz, (CD3)2SO): δ 5.6, 5.8, 11.8, 30.9, 52.5, 63.0, 113.1, 123.5, 128.5, 131.9, 135.8, 142.4,
145.9, 148.2, 156.0, 156.8, 168.1.
(3R)-Methyl
10-cyclopropyl-7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5,6,7,8,9-hexahydro-2H-
ACS Paragon Plus Environment

Page 13 of 33
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
thiazolo[2,3-g][1,7]naphthyridine-3-carboxylate (8): Compound 7 (100 mg, 0.25 mmol, 1.0 eq.) was
dissolved in dry DCM (4 ml) and styrene (34 µL, 0.30 mmol, 1.2 eq.) was added, followed by BF3⋅OEt2
(3.1 µL, 0.025 mmol, 0.10 eq.) at room temperature. The reaction mixture was stirred at room
temperature for 4 h, diluted with DCM (15 ml) and washed with water (2x10 ml). The combined
aqueous phase was re-extracted with DCM (15 ml). The organic phases were combined, dried over
anhydrous sodium sulphate and evaporated under reduced pressure to yield the crude product. The
product was purified with automated flash column chromatography (25 g SNAP Cartridge) eluting with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25
0–80% ethyl acetate in heptane to yield 123 mg (97%) of 8 as a yellow solid. [α]D −210 (c 0.2,
CHCl3); IR (KBr): ν 3001, 2952, 1755, 1638, 1590, 1518, 1490, 1462, 1401, 1346, 1252, 1211, 1182,
1
854, 699 cm-1; H-NMR (400 MHz, CDCl3): δ 0.49–0.66 (m, 5H), 2.07–2.16 (m, 1H), 2.44–2.50 (m,
1H), 3.47 (dd, J = 2.0, 11.6 Hz, 1H), 3.68 (dd, J = 8.0, 11.6 Hz, 1H), 3.68 (s, 1H), 4.42–4.48 (m, 2H),
5.65 (dd, J = 2.0, 8.0 Hz, 1H), 7.08–7.12 (m, 3H), 7.15–7.26 (m, 2H), 7.52 (d, J = 8.8 Hz, 2H), 8.11
13
(dd, J = 2.0, 8.8 Hz, 2H); C{1H}-NMR (100 MHz, CDCl3): δ 7.5, 9.1, 13.0, 32.0, 42.2, 44.1, 53.3,
55.5, 63.1, 114.6, 123.8, 126.3, 127.5, 128.5 (2C), 132.4, 133.4, 144.9, 147.3, 150.5, 156.4, 168.7; LC-
MS: m/z = 504 [M+H]+, C27H26N3O5S+ requires 504.
Synthesis of compound 6b from Povarov adduct 8: To a solution of Povarov adduct 8 (100 mg,
0.198 mmol, 1.0 eq.) in DCM (4 ml) was added DDQ (45.0 mg, 0.198 mmol, 1.0 eq.) and the reaction
mixture was stirred at room temperature for 30 minutes. After completion, the mixture was diluted with
DCM (20 ml) and washed with water (5x15 ml). The organic phase was dried over anhydrous sodium
sulphate and evaporated under reduced pressure. The crude product was purified by automated flash
column chromatography (25 g SNAP Cartridge) eluting with 0–100% ethyl acetate in heptane to yield
74 mg (75%) of 8 as a yellow solid. The data is the same as for the product prepared via the A3 coupling
reaction.
General procedure for the three component Povarov reaction using styrene as dienophile:
Preparation of compounds 6g–q. Procedure A : Under an atmosphere of nitrogen, 6-aminopyridone of
general structure 5 (0.35 mmol, 1.0 eq.) was placed in an oven dried 5 ml microwave reaction tube or
round bottom flask equipped with a magnetic stirrer, and dissolved in DCM (4 ml). The aldehyde (0.70
mmol, 2.0 eq.) was added while stirring, followed by the styrene (0.70 mmol, 2.0 eq.) and BF3⋅OEt2
(9.4 µl, 0.035 mmol, 0.10 eq.). The tube was sealed with a cap and stirred at room temperature for 16 h.
The reaction was monitored by TLC and LC-MS. When no starting material remained, DDQ (79 mg,
0.35 mmol, 1.0 eq.) was added and the mixture was stirred for 30 min. Upon completion, the mixture
was diluted with DCM (5 ml), washed with NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml), dried
over anhydrous sodium sulphate, filtered and evaporated. The desired product was purified with flash
column chromatography.
Procedure B: Under air, 6-aminopyridone of general structure 5 (0.35 mmol, 1.0 eq.) was placed
in an oven dried 5 ml microwave reaction tube or round bottom flask equipped with a magnetic stirrer,
and dissolved in DCM (4 ml). The aldehyde (0.42 mmol, 1.2 eq.) was added while stirring, followed by
5–10 rods of activated 4Å MS. The styrene (0.42 mmol, 1.2 eq.) and BF3⋅OEt2 (9.4 µl, 0.035 mmol, 0.1
eq.) was subsequently added. The tube was sealed with a cap and stirred at room temperature for 16 h.
The reaction was checked with TLC and LC-MS. When no starting material remained, DDQ (79 mg,
0.35 mmol, 1.0 eq.) was added and the mixture was stirred for 30 min. Upon completion, the mixture
was diluted with DCM (5 ml), washed with NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml), dried
over anhydrous sodium sulphate, filtered and evaporated. The desired product was purified with flash
column chromatography.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
9
(R)-Methyl
10-cyclopropyl-5-oxo-9-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-
thiazolo[2,3-g][1,7]naphthyridine-3-carboxylate (6g): The compound was prepared following general
procedure B. Purified with flash column chromatography (20 x 130 mm silica; ethyl acetate in toluene,
5–30%). 100 mg of 5a was converted to 98 mg (50%) of 6g, isolated as a yellow solid. [α]D −100° (c
0.18, CHCl3); IR (KBr): ν 1750, 1667, 1591, 1458, 1324, 1165, 1123, 1068 cm-1; 1H-NMR (600 MHz,
CDCl3): δ 0.17–0.24 (m, 4H), 1.14–1.22 (m, 1H), 3.53 (dd, J = 2.6, 11.6 Hz, 1H), 3.74 (dd, J = 8.3, 11.6
Hz, 1H), 3.82 (s, 3H), 5.76 (dd, J = 2.6, 8.3 Hz, 1H), 7.38–7.53 (m, 5H), 7.70 (d, J = 8.2 Hz, 2H), 7.90
(s, 1H), 8.32 (d, J = 8.2 Hz, 2H); 13C{1H}-NMR (151 MHz, CDCl3): δ 10.8, 10.9, 16.1, 31.7, 53.5, 63.6,
109.0, 124.3 (q, J = 272 Hz), 125.75 (d, J = 3 Hz), 126.7, 127.7, 128.1 (d, J = 7 Hz), 128.2, 129.3, 131.2
(q, J = 32 Hz), 133.3, 141.5, 141.6, 144.6, 147.9, 152.7, 159.6, 168.7; 19F-NMR (564 MHz, CDCl3): δ −
62.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H22F3N2O3S+ 523.1298; Found 523.1295.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl
7-(4-cyanophenyl)-10-cyclopropyl-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6h): The compound was prepared following general procedure B.
Purified with flash column chromatography (20 x 120 mm silica; ethyl acetate in heptane, 20–65%).
25
100 mg of 5a was converted to 92 mg (51%) of 6h, isolated as a yellow solid. [α]D −138 (c 0.27,
CHCl3); IR (CHCl3): ν 2226, 1752, 1665, 1590, 1553, 1457, 1441, 1216, 1180, 749 cm-1; 1H-NMR (600
MHz, CDCl3): δ 0.18–0.25 (m, 4H), 1.16–1.22 (m, 1H), 3.54 (dd, J = 2.6, 11.6 Hz, 1H), 3.74 (dd, J =
8.3, 11.6 Hz, 1H), 3.83 (s, 3H), 5.76 (dd, J = 2.6, 8.3 Hz, 1H), 7.40–7.51 (m, 5H), 7.75 (d, J = 8.5 Hz,
2H), 7.90 (s, 1H), 8.33 (d, J = 8.6 Hz, 2H); 13C{1H}-NMR (151 MHz, CDCl3): δ 10.8, 10.9, 16.1, 31.6,
53.5, 63.6, 109.0, 112.8, 119.0, 126.7, 127.9, 128.1 (2C), 128.3, 129.3, 132.7, 133.6, 141.46, 141.54,
142.3, 145.0, 148.0, 151.9, 159.5, 168.7; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H21N3NaO3S+
502.1195; Found 502.1196.
(R)-Methyl
10-cyclopropyl-7-(4-fluorophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6i): The compound was prepared following general procedure B.
Purified with flash column chromatography (20 x 100 mm silica; ethyl acetate in toluene, 5–40%). 100
25
mg of 5a was converted to 94 mg (53%) of 6i, isolated as a light brown solid. [α]D −135 (c 0.41,
CHCl3); IR (CHCl3): ν 1753, 1663, 1592, 1459, 1221, 751 cm-1; 1H-NMR (400 MHz, CDCl3): δ 0.16–
0.24 (m, 4H), 1.14–1.22 (m, 1H), 3.53 (dd, J = 2.6, 11.6 Hz, 1H), 3.73 (dd, J = 8.4, 11.6 Hz, 1H), 3.81
(s, 3H), 5.76 (dd, J = 2.6, 8.2 Hz, 1H), 7.14 (apparent triplet, J = 8.8 Hz, 2H), 7.39–7.51 (m, 5H), 7.83
(s, 1H), 8.20 (dd, J = 5.5, 8.9 Hz, 2H); 13C{1H}-NMR (100 MHz, CDCl3): δ 10.6, 10.9, 16.1, 31.6, 53.4,
63.5, 109.0, 115.8 (d, J = 22 Hz), 126.3, 128.0, 128.1, 129.3 (2C; d, J = 8 Hz), 132.7, 134.4 (d, J = 3
Hz), 141.3, 141.8, 143.7, 147.7, 153.4, 159.8, 163.9 (d, J = 249 Hz), 168.8; F{1H}-NMR (376 MHz,
CDCl3): δ −112.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22FN2O3S+ 473.1329; Found
19
473.1328.
(R)-Methyl
10-cyclopropyl-7-(naphthalen-1-yl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6j): Prepared by following general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–70% ethyl acetate in
heptane. 70 mg of 5a was converted to 72 mg (54%) of 6j, isolated as an off white solid. [α]D25 −156 (c
0.22, CHCl3); IR (KBr): ν 1751, 1666, 1588, 1555, 1510, 1468, 1439, 1379, 1213, 1148, 1074, 778,
702, 616 cm-1; 1H-NMR (400 MHz, CDCl3): δ 0.22–0.28 (m, 4H), 1.20–1.27 (m, 1H), 3.54 (dd, J = 2.8,
11.6 Hz, 1H), 3.72 (dd, J = 8.4, 11.6 Hz, 1H), 3.81 (s, 3H), 5.79 (dd, J = 2.4, 8.0 Hz, 1H), 7.39-7.42 (m,
3H), 7.46–7.55 (m, 5H), 7.77–7.78 (m, 2H), 7.88–7.90 (m, 2H), 8.31–8.33 (m, 1H); C{1H}-NMR
13
(100 MHz, CDCl3): δ 10.8, 10.9, 16.1, 31.6, 53.4, 63.5, 108.8, 125.3, 125.7, 125.9, 126.8, 127.9, 128.0,
ACS Paragon Plus Environment

Page 15 of 33
1
The Journal of Organic Chemistry
2
3
4
5
128.4, 129.3, 129.4, 131.1, 131.4, 132.5, 134.0, 137.4, 141.4, 141.5, 143.9, 146.9, 156.4, 159.6, 168.8;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H25N2O3S+ 505.1580; Found 505.1583.
(R)-Methyl
10-methoxy-7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
6
7
8
9
g][1,7]naphthyridine-3-carboxylate (6k): Prepared by following general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–100% ethyl acetate in
25
heptane. 90 mg of 5c was converted to 115 mg (67%) of 6k, isolated as a yellow solid. [α]D −174 (c
0.22, CHCl3); IR (KBr): ν 1743, 1665, 1595, 1558, 1522, 1462, 1442, 1343, 1229, 1147, 1070 cm-1; 1H-
NMR (600 MHz, CDCl3): δ 2.96 (s, 3H), 3.62 (dd, J = 1.8, 11.4 Hz, 1H), 3.79 (dd, J = 7.8, 11.4 Hz,
1H), 3.83 (s, 3H), 5.80 (dd, J = 1.8, 8.4 Hz, 1H), 7.45–7.48 (m, 5H), 7.91 (s, 1H), 8.31 (d, J = 9.0 Hz,
2H), 8.38 (d, J = 8.4 Hz, 2H); 13C{1H}-NMR (150 MHz, CDCl3): δ 31.9, 53.6, 60.0, 63.5, 124.1, 126.8,
127.6, 128.1, 128.4, 128.7, 129.2, 132.0, 135.4, 139.1, 141.3, 143.9, 146.2, 148.5, 152.1, 158.6, 168.3;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H20N3O6S+ 490.1067; Found 490.1064.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl 10-methoxy-5-oxo-7,9-diphenyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-
3-carboxylate (6l): Prepared by following general procedure A, purified by automated flash column
chromatography (25 g SNAP Cartridge) eluting with 0–100% ethyl acetate in heptane. 85 mg of 5c was
25
converted to 122 mg (76%) of 6l, isolated as a light yellow solid. [α]D −171 (c 0.21, CHCl3); IR
1
(KBr): ν 1747, 1666, 1606, 1563, 1442, 1362, 1222, 1183, 1076, 1013, 697 cm-1; H-NMR (600 MHz,
CDCl3): δ 2.95 (s, 3H), 3.59 (dd, J = 1.8, 11.4 Hz, 1H), 3.76 (dd, J = 8.4, 11.4 Hz, 1H), 3.82 (s, 3H),
5.80 (dd, J = 2.4, 8.4 Hz, 1H), 7.42–7.48 (m, 8H), 7.86 (s, 1H), 8.21 (dd, J = 1.2, 7.8 Hz, 2H); 13C{1H}-
NMR (150 MHz, CDCl3): δ 31.9, 53.5, 59.9, 63.4, 126.4, 127.4, 127.8, 128.0, 128.8, 129.3, 129.6,
132.2, 133.7, 138.0, 139.6, 141.2, 145.6, 155.1, 158.9, 168.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C25H21N2O4S+ 445.1217; Found 445.1231.
(R)-Methyl
10-methoxy-5-oxo-9-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-
thiazolo[2,3-g][1,7]naphthyridine-3-carboxylate (6m): Prepared by following general procedure A,
purified by automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–100% ethyl
25
acetate in heptane. 92 mg of 5c was converted to 138 mg (75%) of 6m, isolated as a yellow solid. [α]D
−135 (c 0.12, CHCl3); IR (KBr): ν 1746, 1667, 1604,1562, 1454, 1324, 1230, 1066, 854, 744, 702 cm-1;
1H-NMR (600 MHz, CDCl3): δ 2.96 (s, 3H), 3.61 (dd, J = 1.8, 11.4 Hz, 1H), 3.79 (dd, J = 8.4, 12.0 Hz,
1H), 3.83 (s, 3H), 5.80 (dd, J = 1.2, 7.8 Hz, 1H), 7.44–7.48 (m, 5H), 7.71 (d, J = 8.4 Hz, 2H), 7.88 (s,
1H), 8.32 (d, J = 8.4 Hz, 2H); 13C{1H}-NMR (150 MHz, CDCl3): δ 31.9, 53.5, 59.9, 63.5, 123.3 (q, J =
270.4 Hz) 125.8 (q, J = 3.7 Hz), 126.5, 127.5, 127.7, 128.2, 128.4, 129.2, 131.2 (q, J = 32.2 Hz), 132.1,
19
134.7, 139.3, 141.2, 141.3, 146.0, 153.3, 158.7, 168.4; F-NMR: (376 MHz, (CD3)2SO): δ −62.5;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20F3N2O4S+ 513.1090; Found 513.1111.
(R)-Methyl
10-methoxy-5-oxo-9-phenyl-7-(thiophen-2-yl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6n): Prepared by following general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–100% ethyl acetate in
heptane. 84 mg of 5c was converted to 95 mg (64%) of 6n, isolated as a light yellow solid. [α]D25 −79 (c
0.23, CHCl3); IR (KBr): ν 1744, 1663, 1599, 1562, 1531, 1462, 1443, 1352, 1224, 1145, 1071, 748,
701, 617 cm-1; 1H-NMR (400 MHz, CDCl3): δ 2.94 (s, 3H), 3.58 (dd, J = 2.0, 11.6 Hz, 1H), 3.76 (dd, J
= 8.0, 11.6 Hz, 1H), 3.81 (s, 3H), 5.77 (dd, J = 2.0, 8.0 Hz, 1H), 7.11 (dd, J = 4.0, 5.2 Hz, 1H), 7.42–
13
7.48 (m, 6H), 7.71–7.73 (m, 2H); C{1H}-NMR (100 MHz, CDCl3): δ 32.0, 53.5, 59.9, 63.4, 125.2,
126.1, 127.5, 127.7, 128.1(2C), 129.2, 132.3, 133.5, 139.4, 141.0, 143.9, 145.6, 150.6, 158.5, 168.5;
+
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H19N2O4S2 451.0781; Found 451.0794.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
7
8
9
(R)-Methyl
7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (6o): Prepared by following general procedure A, purified by
automated flash column chromatography (10 g SNAP Cartridge) eluting with 0–70% ethyl acetate in
25
heptane. 50 mg of 5d was converted to 68 mg (67%) of 6o, isolated as a yellow solid. [α]D −177 (c
0.28, CHCl3); IR (KBr): ν 1747, 1669, 1596, 1565, 1522, 1461, 1440, 1411, 1344, 1215, 849, 729, 701,
620 cm-1; 1H-NMR (400 MHz, CDCl3): δ 3.62 (d, J = 11.2 Hz, 1H), 3.80–3.85 (m, 4H), 5.77 (d, J = 7.2
Hz, 1H), 6.45 (s, 1H), 7.45–7.56 (m, 5H), 7.94 (s, 1H) 8.30–8.38 (m, 4H); C{1H}-NMR (100 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
CDCl3): δ 32.4, 53.6, 63.0, 95.6, 124.1, 124.5, 128.1, 129.1, 129.2, 132.3, 137.0, 140.2, 142.4, 144.2,
147.5, 148.4, 152.5, 159.9, 168.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18N3O5S+ 460.0962;
Found 460.0963.
(R)-Methyl 10-cyclopropyl-7-(4-nitrophenyl)-5-oxo-9-(3-(trifluoromethyl)phenyl)-3,5-dihydro-
2H-thiazolo[2,3-g][1,7]naphthyridine-3-carboxylate (6p): The compound was prepared following
general procedure B but the reaction mixture was stirred at r.t. for 4 d., followed by addition of DDQ.
Purified with flash column chromatography (20 x 120 mm silica; ethyl acetate in toluene, 10–60%). 100
mg of 5a was converted to 35 mg (16%) of 6p, isolated as a yellow solid. The compound was also
prepared following general procedure B but with stirring at 50 °C for 4 d. followed by addition of DDQ
at room temperature. Purified with flash column chromatography (20 x 120 mm silica; toluene/EtOAc
5-30%). 105 mg of 5a was converted to 110 mg (49%) of 6p, isolated as a yellow solid. [α]D25 −133 (c
1
0.17, CHCl3). IR (CHCl3): ν 1753, 1667, 1589, 1552, 1522, 1458, 1343, 1327, 1167, 1126 cm-1; H-
NMR (400 MHz, (CD3)2SO, 343 K): δ −0.04–0.31 (m, 4H), 1.00–1.09 (m, 1H), 3.60 (dd, J = 2.8, 11.8
Hz, 1H), 3.77 (s, 3H), 3.91 (dd, J = 8.9, 11.8 Hz, 1H), 5.74 (dd, J = 2.8, 8.8 Hz, 1H), 7.68–7.75 (m,
1H), 7.78–7.83 (m, 1H), 7.83–7.89 (m, 1H), 7.95 (bs, 1H), 8.29 (s, 1H), 8.35 (d, J = 9 Hz, 2H), 8.55 (d,
J = 9 Hz, 2H); 13C{1H}-NMR (151 MHz, (CD3)2SO, 343 K): δ 10.2, 10.4, 15.2, 30.4, 52.5, 63.0, 78.8,
106.2, 123.5, 123.9 (q, J = 272 Hz) 124.2, 125.4, 126.5, 127.7, 128.4 (q, J = 32 Hz) 128.5, 132.8, 133.1,
140.4, 141.4, 143.2, 145.1, 146.6, 147.7, 150.0, 157.8, 168.3; 19F-NMR (376 MHz; (CD3)2SO, 343 K):
δ −61.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C28H20F3N3NaO5S+ 590.0969; Found 590.0963.
(R)-Methyl
10-cyclopropyl-5-oxo-7-phenyl-9-(3-(trifluoromethyl)phenyl)-3,5-dihydro-2H-
thiazolo[2,3-g][1,7]naphthyridine-3-carboxylate (6q): The compound was prepared following general
procedure B but the reaction mixture was stirred at r.t. for 11 d., followed by oxidation with DDQ.
Purified with flash column chromatography (20 x 120 mm silica; ethyl acetate in toluene, 10–35%). 100
mg of 5a was converted to 8 mg (4%) of 6q, isolated as a yellow solid. The compound was also
prepared with stirring at 50 °C for 4 d. followed by addition of DDQ at room temperature. Purified with
flash column chromatography (20 x 120 mm silica; ethyl acetate in toluene, 5–30%). 105 mg of 5a was
converted to 60 mg (29%) of 6q, isolated as a yellow solid. [α]D25 −122 (c 0.18, CHCl3); IR (CHCl3): ν
1
1753, 1666, 1591, 1460, 1441, 1325, 1216, 1166, 1125, 1073, 752 cm-1; H-NMR (400 MHz,
(CD3)2SO, 343 K): δ −0.06–0.27 (m, 4H), 0.99–1.08 (m, 1H), 3.58 (dd, J = 2.8, 11.8 Hz, 1H), 3.78 (s,
3H), 3.90 (dd, J = 8.7, 11.8 Hz, 1H), 5.72 (dd, J = 2.8, 8.7 Hz, 1H), 7.44–7.55 (m, 3H), 7.67–7.73 (m,
13
1H), 7.77–7.81 (m, 1H), 7.81–7.88 (m, 1H), 7.92 (bs, 1H), 8.11 (s, 1H), 8.22–8.29 (m, 2H); C{1H}-
NMR (151 MHz, (CD3)2SO, 343 K): δ 10.2, 10.4, 15.3, 30.4, 52.5, 63.0, 106.2, 123.9 (q, J = 272 Hz)
124.1, 125.4, 125.7, 126.6, 128.4, 128.5, 129.1, 131.9, 133.1, 137.3, 140.3, 141.8, 144.8, 145.2, 152.6,
158.0, 168.4; 19F-NMR (376 MHz; (CD3)2SO, 343 K): δ −61.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C28H22F3N2O3S+ 523.1298; Found 523.1283.
ACS Paragon Plus Environment

Page 17 of 33
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
General procedure for preparation of 9a–k: Procedure A: 6-amino-2-pyridones of general structure 5
(0.33 mmol, 1.0 eq.) was placed in an oven dried 5 ml microwave reaction tube or 10 ml round bottom
flask equipped with a magnetic stirrer, and dissolved in dry DCM (4 ml). The aldehyde (0.40 mmol, 1.2
eq.) was added while stirring, and BF3⋅OEt2 (8.9 µl, 0.033 mmol, 0.10 eq.). The tube was sealed and the
mixture stirred for 1 h at room temperature. Ethyl vinyl ether (0.40 mmol, 1.2 eq.) was added and the
mixture was stirred at room temperature until completion of the reaction (16 h). The reaction was
checked with TLC and LC-MS. When no starting material remained, the mixture was diluted with
DCM (5 ml), washed with NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml), dried, filtered and
evaporated. Crude material was dissolved in DCM (5 ml), DDQ (75 mg, 0.33 mmol, 1.0 eq.) was added
and stirred for 30 minutes. Upon completion, the mixture was diluted with DCM (5 ml), washed with
NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml), dried, filtered and evaporated. The desired product
was purified with flash column chromatography.
General Procedure B: 6-amino-2-pyridones of general structure 5 (0.33 mmol, 1.0 eq.) was
placed in an oven dried 5 ml microwave reaction tube or 10 ml round bottom flask equipped with a
magnetic stirrer, and dissolved in dry DCM (4 ml). The aldehyde (0.40 mmol, 1.2 eq.) was added while
stirring, and BF3⋅OEt2 (8.9 µl, 0.033 mmol, 0.10 eq.). The tube was sealed and the mixture stirred for 1
h at room temperature. Ethyl vinyl ether (0.40 mmol, 1.2 eq.) was added and the mixture was stirred at
room temperature under air balloon until completion of the reaction (16 h). The reaction was monitored
by TLC and LC-MS. When no starting material remained, the mixture was diluted with DCM (5 ml),
washed with NaHCO3 (sat. aq.) (3 ml) followed by brine (3 ml), dried, filtered and evaporated. The
desired product was purified with flash column chromatography.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl
10-cyclopropyl-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9a): Prepared by following the general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–80% ethyl acetate in
25
heptane. 70 mg of 5a was converted to 52 mg (52%) of 9a, isolated as yellow solid. [α]D −120 (c
0.24, CHCl3); IR (KBr): ν 1747, 1665, 1599, 1573, 1525, 1510, 1469, 1411, 1337, 1215, 1179, 852,
1
835, 726 cm-1; H-NMR (400 MHz, CDCl3): δ 0.69–0.76 (m, 2H), 1.04–1.15 (m. 2H), 1.75–1.82 (m,
1H), 3.58 (dd, J = 2.0, 11.6 Hz, 1H), 3.75 (dd, J = 8.4, 11.6 Hz, 1H), 3.80 (s, 3H), 5.78 (dd, J = 2.0, 8.4
13
Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.31–8.36 (m, 4H), 8.46 (dd, J = 1.6, 8.4 Hz, 1H); C{1H}-NMR
(100 MHz, CDCl3): δ 7.5(2C), 10.0, 31.7, 53.4, 63.0, 108.1, 123.9, 124.0, 128.0, 132.8, 135.0, 140.0,
142.8, 144.2, 148.3, 152.3, 159.7, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H18N3O5S+
424.0962; Found 424.0963.
(R)-Methyl
10-cyclopropyl-5-oxo-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9b): Prepared by following the general procedure A, purified by
automated flash column chromatography (10 g SNAP Cartridge) eluting with 0–80% ethyl acetate in
25
heptane. 50 mg of 5a was converted to 41 mg (49%) of 9b, isolated as an off white solid. [α]D −147
(c 0.13, CHCl3); IR (CHCl3): ν 1753, 1666, 1600, 1511, 1473, 1412, 1325, 1216, 1167, 1014, 833, 753,
1
722 cm-1; H-NMR (400 MHz, CDCl3): δ 0.67–0.75 (m, 2H), 1.02–1.13 (m. 2H), 1.74–1.80 (m, 1H),
3.56 (dd, J = 2.0, 11.6 Hz, 1H), 3.76 (dd, J = 8.4, 11.6 Hz, 1H), 3.79 (s, 3H), 5.77 (dd, J = 2.0, 8.4 Hz,
1H), 7.72 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.43 (d, J = 8.8 Hz,
1H); 13C{1H}-NMR (100 MHz, CDCl3): δ 7.4, 7.5, 10.0, 31.7, 53.4, 62.9, 108.1, 122.9 (q, J = 270 Hz),
123.7, 125.7 (q, J = 3.6 Hz), 127.6, 130.9 (q, J = 32.3 Hz), 132.7, 134.7, 140.0, 141.7, 142.1, 153.5,
19
159.8, 168.7; F-NMR (376 MHz, (CD3)2SO): δ −62.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H18F3N2O3S+ 447.0985; Found 447.0992.
(R)-Methyl
7-(4-cyanophenyl)-10-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
g][1,7]naphthyridine-3-carboxylate (9c): Prepared by following the general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–80% ethyl acetate in
heptane. 90 mg of 5a was converted to 80 mg (59%) of 9c, isolated as an off white solid. [α]D25 −177 (c
0.2, CHCl3); IR (CHCl3): ν 2225, 1752, 1665, 1599, 1578, 1527, 1471, 1365, 1216, 832, 747 cm-1; 1H-
NMR (400 MHz, CDCl3): δ 0.67–0.76 (m, 2H), 1.03–1.14 (m, 2H), 1.74–1.81 (m, 1H), 3.57 (dd, J =
2.0, 11.6 Hz, 1H), 3.74 (dd, J = 8.4, 11.6 Hz, 1H), 3.79 (s, 3H), 5.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.75 (dd,
J = 2.0, 6.8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 1H), 8.29 (dd, J = 1.6, 6.8 Hz, 2H), 8.44 (d, J = 8.4 Hz, 1H);
13C{1H}-NMR (100 MHz, CDCl3): δ 7.5(2C), 10.0, 31.7, 53.4, 62.9, 108.1, 112.7, 118.9, 123.7, 127.8,
132.6, 132.8, 134.9, 140.0, 142.5, 142.6, 152.8, 159.7, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H18N3O3S+ 404.1063; Found 404.1065.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl
10-cyclopropyl-7-(4-fluorophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9d): The compound was prepared following general procedure A.
Purified with flash column chromatography (20 x 115 mm silica; ethyl acetate in toluene, 5–40%). 101
25
mg of 5a was converted to 25 mg (17%) of 9d, isolated as a light yellow solid. [α]D −223 (c 0.26,
1
CHCl3). IR (CHCl3) : ν 1752, 1665, 1602, 1473, 1221, 1156, 833, 746 cm-1; H-NMR (400 MHz,
CDCl3): δ 0.65–0.74 (m, 2H), 1.00–1.12 (m, 2H), 1.71–1.79 (m, 1H), 3.54 (dd, J = 2.1, 11.7 Hz, 1H),
3.74 (dd, J = 8.3, 11.7 Hz, 1H), 3.78 (s, 3H), 5.76 (dd, J = 2.1, 8.3 Hz, 1H), 7.14 (apparent triplet, J =
13
8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 8.17 (dd, J = 5.5, 8.8 Hz, 2H), 8.37 (d, J = 8.8 Hz); C{1H}-
NMR (100 MHz, CDCl3): δ 7.4, 7.5, 10.1, 31.8, 53.4, 63.0, 108.2, 115.7 (d, J = 22 Hz), 123.3, 129.3 (d,
J = 9 Hz), 132.5, 134.0, 134.7 (d, J = 3 Hz), 139.8, 141.3, 154.2, 159.9, 163.9 (d, J = 249 Hz), 168.8;
19F{1H}-NMR (376 MHz, CDCl3): δ −112.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H18FN2O3S+
397.1016; Found 397.1017.
(R)-Methyl
10-cyclopropyl-7-(naphthalen-1-yl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9e): Prepared by following the general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–20% ethyl acetate in
25
DCM. 70 mg of 5a was converted to 67 mg (59%) of 9e, isolated as an off white solid. [α]D −226 (c
0.22, CHCl3); IR (KBr): ν 1748, 1669, 1602, 1579, 1514, 1477, 1322, 1221, 1150, 852, 748, 665 cm-1;
1H-NMR (400 MHz, CDCl3): δ 0.76–0.77 (m, 2H), 1.05–1.13 (m. 2H), 1.81–1.84 (m, 1H), 3.57 (d, J =
11.6 Hz, 1H), 3.72 (dd, J = 8.4, 11.2 Hz, 1H), 3.79 (s, 3H), 5.79 (d, J = 6.8 Hz, 1H), 7.47–7.56 (m, 3H),
7.74 (d, J = 7.2 Hz, 1H), 7.86–7.91 (m, 3H), 8.19 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H);
13C{1H}-NMR (100 MHz, CDCl3): δ 7.5(2C), 10.1, 31.8, 53.4, 62.9, 108.1, 125.4, 125.6, 125.9, 126.7,
128.4, 129.2, 131.3, 131.8, 133.9, 134.0, 137.8, 140.0, 141.5, 157.3, 159.8, 168.9; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C25H21N2O3S+ 429.1267; Found 429.1262.
(R)-Methyl
7-cyclohexyl-10-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9f): Prepared by following the general procedure B, purified by
automated flash column chromatography (10 g SNAP Cartridge) eluting with 0–85% ethyl acetate in
heptane. 70 mg of 5a was converted to 47 mg (47%) of 9f, isolated as a light yellow solid. [α]D25 −148
(c 0.36, CHCl3); IR (CHCl3): ν 2926, 2852, 1753, 1666, 1604, 1585, 1523, 1478, 1448, 1389, 1364,
1
1323, 1213, 840, 732 cm-1; H-NMR (400 MHz, CDCl3): δ 0.62-0.71 (m, 2H), 0.97–1.08 (m, 2H),
1.22–1.33 (m, 1H), 1.35–1.46 (m, 2H), 1.48–1.58 (m, 2H), 1.69–1.76 (m, 2H), 1.81–1.85 (m, 2H),
1.97–2.00 (m, 2H), 2.94–3.02 (m, 1H), 3.51 (dd, J = 2.4, 11.6 Hz, 1H), 3.67 (dd, J = 8.4, 11.6 Hz, 1H),
3.75 (s, 3H), 5.72 (dd, J = 2.0. 8.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H); 13C{1H}-
NMR (100 MHz, CDCl3): δ 7.3, 7.4, 10.0, 26.1, 26.5, 31.7, 32.9, 33.0, 46.8, 53.3, 62.8, 108.2, 124.4,
132.0, 133.5, 139.3, 140.1, 160.1, 165.4, 168.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
C21H25N2O3S+ 385.1580; Found 385.1585.
4
5
(R)-Methyl
7,10-dicyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
6
7
8
9
carboxylate (9g): Prepared by following the general procedure B, purified by automated flash column
chromatography (25 g SNAP Cartridge) eluting with ethyl acetate in heptane, 0–85%. 80 mg of 5a was
converted to 46 mg (45%) of 9g, isolated as light brown solid. [α]D25 −155 (c 0.28, CHCl3); IR (CHCl3):
ν 1753, 1663, 1604, 1585, 1482, 1326, 1212, 886, 836, 752 cm-1; 1H-NMR (400 MHz, CDCl3): δ 0.63–
0.67 (m, 2H), 0.97–1.12 (m, 6H), 1.68–1.74 (m, 1H), 2.23–2.28 (m, 1H), 3.51 (dd, J = 2.0, 11.6 Hz,
1H), 3.74 (dd, J = 8.4, 11.6 Hz, 1H), 3.76 (s, 3H), 5.71 (dd, J = 2.0, 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz,
1H), 8.19 (d, J = 8.8 Hz, 1H); 13C{1H}-NMR (100 MHz, CDCl3): δ 7.3, 7.4, 10.0, 10.5, 10.6, 17.9, 31.7,
53.5, 62.8, 108.3, 123.7, 131.6, 133.1, 139.4, 139.6, 159.9, 162.0, 168.9; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H19N2O3S+ 343.1111; Found 343.1111.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-Methyl 10-cyclopropyl-5-oxo-7-propyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylate (9h): Prepared by following the general procedure A, purified by automated flash column
chromatography (25 g SNAP Cartridge) eluting with 0–80% ethyl acetate in heptane. 80 mg of 5a was
25
converted to 42 mg (41%) of 9h, isolated as an off white solid. [α]D −142 (c 0.32, CHCl3); IR
1
(CHCl3): ν 1753, 1663, 1603, 1481, 1213, cm-1; H-NMR (400 MHz, CDCl3): δ 0.65–0.71 (m, 2H),
0.98 (t, J = 7.2 Hz, 3H), 1.00–1.06 (m, 2H), 1.74–1.84 (m, 3H), 2.92–2.95 (m, 2H), 3.52 (dd, J = 2.4,
11.6 Hz, 1H), 3.69 (dd, J = 8.4, 11.6 Hz, 1H), 3.76 (s, 3H), 5.71 (dd, J = 2.0, 8.0 Hz, 1H), 7.42 (d, J =
13
8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H); C{1H}-NMR (100 MHz, CDCl3): δ 7.4 (2C), 10.0, 14.1, 23.3,
31.7, 40.6, 53.3, 62.9, 108.3, 126.4, 131.8, 133.4, 139.6, 140.2, 160.0, 161.3, 168.9; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H21N2O3S+ 345.1267; Found 345.1273.
(R)-Methyl
7-(4-nitrophenyl)-5-oxo-10-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9i): Prepared by following the general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–20% ethyl acetate in
DCM. 100 mg of 5b was converted to 58 mg (38%) of 9i, isolated as a yellow solid. [α]D25 −79 (c 0.23,
CHCl3); IR (CHCl3): ν 1752, 1671, 1599, 1572, 1525, 1493, 1468, 1343, 1217, 726, 704 cm-1; 1H-NMR
(400 MHz, CDCl3): δ 3.56 (dd, J = 2.0, 11.6 Hz, 1H), 3.76 (dd, J = 8.4, 11.6 Hz, 1H), 3.84 (s, 3H), 5.88
(dd, J = 2.4, 8.4 Hz, 1H), 7.36–7.47 (m, 2H), 7.49–7.54 (m, 3H), 7.74 (d, J = 8.8 Hz, 1H), 7.95 (d, J =
13
8.4 Hz, 1H), 8.39–8.35 (m, 4H); C{1H}-NMR (100 MHz, CDCl3): δ 31.8, 53.6, 63.7, 110.8, 124.1,
124.2, 128.1, 128.8, 129.2, 129.4, 130.1, 130.5, 133.3, 133.9, 135.0, 139.9, 141.8, 144.1, 148.4, 152.7,
159.5, 168.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18N3O5S+ 460.0962; Found 460.0956.
(R)-Methyl
5-oxo-10-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9j): Prepared by following the general procedure A, purified by
automated flash column chromatography (25 g SNAP Cartridge) eluting with 0–20% ethyl acetate in
DCM. 100 mg of 5b was converted to 55 mg (34%) of 9j, isolated as a light brown solid. [α]D25 –93 (c
0.32, CHCl3); IR (CHCl3): ν 1753, 1670, 1597, 1583, 1510, 1493, 1443, 1412, 1374, 1326, 1217, 834,
1
754, 723, 702 cm-1; H-NMR (400 MHz, CDCl3): δ 3.54 (dd, J = 2.0, 11.6 Hz, 1H), 3.74 (dd, J = 8.4,
11.6 Hz, 1H), 3.84 (s, 3H), 5.87 (dd, J = 2.0, 8.0 Hz, 1H), 7.36–7.42 (m, 2H), 7.44–7.54 (m, 3H), 7.70–
13
7.73 (m, 3H), 7.91 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.8 Hz, 2H); C{1H}-NMR (100 MHz, CDCl3): δ
31.8, 53.5, 63.8, 110.9, 122.9, 123.9, 125.7 (d, J = 3.7 Hz), 127.6, 128.7, 129.2, 129.4, 130.2, 130.5,
19
133.0 (d, J = 31.9 Hz), 133.1, 133.6, 135.2, 139.8, 141.0, 141.6, 153.9, 159.7, 168.6; F-NMR (376
MHz, (CD3)2SO): δ −62.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H18F3N2O3S+ 483.0985;
Found 483.0983.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
(R)-Methyl
7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylate (9k): Prepared by following the general procedure A, purified by automated flash column
chromatography (50 g SNAP Cartridge) eluting with 0–50% ethyl acetate in DCM. 1200 mg of 5d was
converted to 895 mg (44%) of 9k, isolated as a yellow solid. [α]D –140 (c 0.27, CHCl3). IR (KBr): ν
1747, 1667, 1598, 1582, 1526, 1470, 1439, 1346, 1222, 1066, 847, 723 cm-1; H-NMR (400 MHz,
25
1
9
CDCl3): δ 3.64 (dd, J = 2.0, 11.6 Hz, 1H), 3.81 (s, 3H), 3.84 (dd, J = 8.4, 11.6 Hz, 1H), 5.76 (dd, J =
2.0, 8.0 Hz, 1H), 6.41 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.29–8.35 (m, 4H);
13C{1H}-NMR (100 MHz, CDCl3): δ 32.4, 53.5, 62.9, 97.5, 124.1, 124.4, 128.1, 133.9, 134.5, 139.6,
142.7, 144.2, 148.4, 152.9, 159.9, 168.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H14N3O5S+
384.0649; Found 384.0651.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-methyl
10-bromo-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (10): Compound 9k (800 mg, 2.09 mmol, 1.00 eq.) was dissolved
in chloroform (30 ml), N-bromosuccinimide (371.4 mg, 2.09 mmol, 1.00 eq.) was added and the
reaction mixture was heated at 50 °C for 15 minutes. Completion was confirmed by TLC (80% ethyl
acetate in heptane). The reaction was allowed to reach room temperature and then quenched with a
saturated aqueous sodium thiosulphate solution. Saturated aqueous sodium hydrogen carbonate solution
was added, the phases were separated and the aqueous phase was extracted with dichloromethane (2 x
20 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and the solvent was
removed under reduced pressure. The crude product was recrystallized from dichloromethane and
25
heptane to yield compound 10 (756.0 mg, 1.64 mmol, 78 %) as a yellow solid. [α]D −202 (c 0.35,
CHCl3); IR ν 1740, 1667, 1574, 1526, 1460, 1338, 1239, 853, 833 cm-1; 1H-NMR (400 MHz, CDCl3): δ
3.66 (dd, J = 11.7, 1.9 Hz, 1H), 3.83 (s, 3H), 3.90 (dd, J = 11.7, 8.3 Hz, 1H), 5.93 (dd, J = 8.3, 1.8 Hz,
13
1H), 8.14 (m, 2H), 8.35 (m, 4H); C{1H}-NMR (100 MHz, CDCl3): δ 31.9, 53.8, 64.9, 64.9, 91.0,
124.2 (2C), 125.0, 128.3 (2C), 133.1, 134.2, 139.6, 143.6, 144.1, 148.7, 153.5, 158.9, 168.2 ppm;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H13BrN3O5S+ 461.9754; Found 461.9753.
General procedure for the synthesis of compound 9l–9o: Compound 10 (0.13 mmol, 1.0 eq.)
was dissolved in methanol (5 mL). Under a nitrogen atmosphere, boronic acid (0.26 mmol, 2.0 eq.), KF
(0.25 mmol, 1.8 eq.) and lastly Pd(PPh3)2Cl2 (0.013 mmol, 0.1 eq.) were added. The reaction was
heated to 120 °C under MWI for 10 minutes. Completion was confirmed by LC-MS. The reaction
mixture was diluted with DCM and washed with brine (5 mL). The aqueous phase was extracted with
DCM (2 x 15 mL), dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude product was purified by silica gel flash column chromatography.
(R)-methyl
10-(3-hydroxyphenyl)-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9l): Prepared by following the general procedure, purified by flash
column chromatography (ethyl acetate in DCM, 80–100%) and recrystallization from DCM and
25
heptane. 60 mg of 10 was converted to 41 mg (79%) of 9l, isolated as a yellow solid. [α]D −122 (c
1
0.22, DMSO); IR: ν 3224, 1747, 1648, 1574, 1523, 1470, 1339, 1220, 750, 725 621 cm-1; H-NMR
(600 MHz, (CD3)2SO): δ 3.61 (broad d, J = 11.5 Hz, 1H), 3.79 (s, 3H), 3.91 (m, 1H), 5.85 (d, J = 8.3
Hz, 1H), 6.79 (m, 2H), 6.89 (broad t, J = 7.2 Hz, 1H), 7.37 (broad t, J = 8.3 Hz, 1H), 7.75 (d, J = 8.6
13
Hz, 1H), 8.42 (m, 5H), 9.72 (s, 1H); C{1H}-NMR (151 MHz, (CD3)2SO): δ 30.9, 53.1, 63.3, 109.1,
115.7, 116.8, 120.5, 124.2 (2C), 124.8, 127.8 (2C), 130.4, 132.9, 133.4, 135.9, 138.9, 142.5, 143.6,
147.9, 151.4, 157.9, 158.2, 168.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18N3O6S+ 476.0916;
Found 476.0912.
(R)-methyl
7-(4-nitrophenyl)-5-oxo-10-(m-tolyl)-3,5-dihydro-2H-thiazolo[2,3-
ACS Paragon Plus Environment

Page 21 of 33
1
The Journal of Organic Chemistry
2
3
4
5
6
7
g][1,7]naphthyridine-3-carboxylate (9m): Prepared by following the general procedure, purified by
flash column chromatography (ethyl acetate in DCM, 0–50%) and recrystallization from MeOH. 44.4
25
mg of 10 was converted to 38.5 mg (85%) of 9m, isolated as an orange solid. [α]D −115 (c 0.36,
1
CHCl3); IR: ν 2955, 1752, 1669, 1600, 1575, 1513, 1468, 1344, 1216, 839, 753 cm-1; H-NMR (400
MHz, CDCl3): δ 2.45 (s, 3H), 3.55 (dd, J = 11.61, 1.74 Hz, 1H), 3.75 (dd, J = 11.57, 8.25 Hz, 1H), 3.84
(s, 3H), 5.87 (dd, J = 7.97, 1.40 Hz, 1H), 7.30 (m, 4H), 7.75 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.6 Hz,
1H), 8.31 (d, J = 8.9 Hz, 2H), 8.35 (d, J = 8.9 Hz, 2H); 13C{1H}-NMR (100 MHz, CDCl3): δ 21.5, 31.8,
53.6, 63.7, 110.8, 124.1 (3C), 128.2 (2C), 129.9, 130.0, 130.2, 130.4, 132.0, 133.4, 134.1, 138.8, 139.9,
141.7, 144.2, 148.4, 152.7, 159.6, 168.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H20N3O5S+
474.1124; Found 474.1121.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-methyl
10-(3-acetylphenyl)-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9n): Prepared by following the general procedure, purified by
flash column chromatography (ethyl acetate in DCM, 80–100%) and recrystallization from DCM and
heptane. 47 mg of 10 was converted to 46 mg (90%) of 9n, isolated as an orange solid. [α]D25 −100 (c
1
0.25, DMSO); IR ν 3016, 2956, 1752, 1673, 1601, 1573, 1526, 1468, 1343,1217, 840, 753 cm-1; H-
NMR (400 MHz, (CD3)2SO, 343 K): δ 2.63 (s, 3H), 3.62 (dd, J = 11.7, 1.8 Hz, 1H), 3.80 (s, 3H), 3.94
(dd, J = 11.7, 8.9 Hz, 1H), 5.85 (dd, J = 8.4, 1.8 Hz, 1H), 7.71 (m, 3H), 7.97 (s, 1H), 8.09 (m, 1H), 8.32
13
(d, J = 9.2 Hz, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.45 (d, J = 8.7 Hz, 1H); C{1H}-NMR (100 MHz,
(CD3)2SO, 343 K): δ 26.4, 30.8, 52.6, 62.2, 108.0, 123.7 (2C), 124.5, 127.6, (2C), 128.0, 129.4, 129.5,
132.4, 133.0, 134.5, 135.1, 137.6, 138.8, 142.9, 143.4, 147.8, 151.3, 157.9, 168.3, 197.1; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C26H20N3O6S+ 502.1073; Found 502.1079.
(R)-methyl
7-(4-nitrophenyl)-5-oxo-10-(thiophen-3-yl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylate (9o): Prepared by following the general procedure, purified by
flash column chromatography (ethyl acetate in heptane, 0–20%) and recrystallization from DCM and
heptane. 61.2 mg of 10 was converted to 56.6 mg (92%) of 9o, isolated as an orange solid. [α]D25 −127
1
(c 0.28, CHCl3) IR: ν 2955, 1752, 1669, 1600, 1575, 1513, 1468, 1344, 1216, 839, 753 cm-1; H-NMR
(400 MHz, CDCl3): δ 3.55 (dd, J = 11.6, 1.9 Hz, 1H), 3.77 (m, 1H), 3.83 (s, 3H), 5.86 (dd J = 8.2, 1.9
Hz, 1H), 7.13 (dd, J = 4.8, 1.1 Hz, 1H), 7.39 (dd, J = 2.9, 1.1 Hz, 1H), 7.52 (dd, J = 4.8, 2.9 Hz, 1H),
13
7.81 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 8.31 (m, 4H); C{1H}-NMR (100 MHz, CDCl3): δ
31.6, 53.6, 63.8, 105.9, 124.1, 124.2 (2C), 125.9, 127.0, 128.1 (2C), 128.7, 133.3, 134.0, 134.8, 139.8,
+
142.4, 144.1, 148.4, 152.7, 159.4, 168.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H16N3O5S2
466.0531; Found 466.0527.
General procedure for preparation of acids 11a–q and 12a–o: Procedure A. The ester was dissolved in
THF (2 ml) and LiOH (0.1 M aq.; 1.4 eq.) was added while stirring. The reaction mixture was left
stirring at r.t. while monitored with TLC (EtOAc). Upon completion, the reaction was quenched with
HCl (1 M aq.; 1.5 eq.). The mixture was evaporated and the watery residue was partioned between
chloroform (10 ml) and brine (5 ml). The phases were separated and the aqueous phase was extracted
with another portion of CHCl3 (10 ml). The organic phases were combined, dried, filtered and
evaporated. The residue was re-dissolved in DMSO (1 ml) and purified with preparative HPLC
(H2O/MeCN + 0.75% HCOOH; 30–100% in 25 min., 100% for 10 min.) The fraction containing the
desired product was diluted with H2O (1:1) and freeze-dried.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
General Procedure B. The ester was dissolved in THF (2 ml) and LiOH (0.1 M aq.; 1.4 eq.) was
added while stirring. The reaction mixture was left stirring at r.t. while monitored with TLC (EtOAc).
Upon completion, the reaction was quenched with HCl (1 M; 1.5 eq.). The mixture was diluted with
EtOAc (15 ml) and washed with brine (10 ml). The aqueous phase was extracted with EtOAc (10 ml).
The organic phases were combined, dried, filtered and evaporated. The residue was re-dissolved in
DMSO (1 ml) and purified with preparative HPLC (H2O/MeCN + 0.75% HCOOH; 30–100% in 25
min., 100% for 10 min.) The fraction containing the desired product was diluted with H2O (1:1) and
freeze-dried.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure C. Upon complete saponification the reaction mixture was neutralised with
prewashed* Amberlyst® 15 until around pH = 6 by pH-paper, then filtered through a pad of wet (THF)
Celite®. The amberlyst and Celite® was rinsed with MeOH until the filtrate was transparent. The
filtrate was evaporated and extracted according to the general procedure. The residue was trituated in
Et2O (2 ml) and filtered through a cotton-plug in a Pasteur pipet. The solid was washed with more Et2O
(2 ml) and dried under vacuum o.n.
* The Amberlyst® was rinsed prior to use with THF/MeOH 1:1 in a cylindrical sintered funnel until the
filtrate was transparent, then dried briefly by passing air through the funnel.
(R)-10-Cyclopropyl-5-oxo-7,9-diphenyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (11a): The compound was prepared and purified according to general procedure C. 50
25
mg of 6a was converted to 26 mg (53%) of 11a, isolated as a dark yellow solid. [α]D −36 (c 0.17,
1
DMSO); IR (KBr): ν 1622, 1588, 1557, 1462, 1442, 1382, 1134, 701 cm-1; H-NMR (400 MHz,
CD3OD (+ CDCl3)): δ 0.12–0.27 (m, 4H), 1.15–1.23 (m, 1H), 3.62 (dd, J = 1.0, 11.3 Hz, 1H), 3.79 (dd,
J = 8.5, 11.3 Hz, 1H), 5.65 (dd, J = 0.9, 8.1 Hz, 1H), 7.39–7.59 (m, 8H), 7.93 (s, 1H), 8.21 (d, J = 7.3
Hz, 2H); 13C{1H}-NMR (100 MHz, CD3OD): δ 11.4, 11.5, 17.0, 32.4, 65.1, 110.6, 127.8, 128.4, 129.0,
129.1, 129.8, 130.5 (2C), 134.0, 139.4, 141.8, 142.9, 146.2, 149.4, 155.8, 161.8, 171.2; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C26H21N2O3S+ 441.1266; Found 441.1265.
(R)-10-Cyclopropyl-7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11b): Prepared by following the general procedure B, 49 mg
25
of 6b was converted to 20 mg (49%) of 11b, isolated as a yellow solid. [α]D −28 (c 0.21, CHCl3); IR
(KBr): ν 3434, 3097, 1742, 1635, 1585, 1553, 1521, 1460, 1442, 1410, 1342, 1229, 830, 735, 702, 621
cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 0.04–0.22 (m, 4H), 1.10–1.17 (m, 1H), 3.49 (dd, J = 2.0, 11.6
Hz, 1H), 3.82 (dd, J = 8.8, 11.6 Hz, 1H), 5.74 (dd, J = 2.0, 8.8 Hz, 1H), 7.46–7.58 (m, 5H) 8.24 (s, 1H),
8.37 (d, J = 8.8 Hz, 2H), 8.50 (d, J = 8.8 Hz, 2H), 13.57 (s, 1H); 13C{1H}-NMR (100 MHz, (CD3)2SO):
δ 10.3, 10.4, 15.6, 31.0, 63.3, 106.7, 123.9, 126.5, 127.7, 127.9, 129.2, 133.1, 140.6, 140.8, 143.6,
146.6, 147.1, 147.7, 149.9, 158.1, 169.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20N3O5S+
486.1118; Found 486.1114.
(R)-10-Cyclopropyl-5-oxo-9-phenyl-7-(p-tolyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11c): The compound was prepared according to general
procedure A. 25 mg of 6c was converted to 14.3 mg (59%) of 11c, isolated as a bright yellow powder.
25
[α]D −44 (c 0.25, DMSO). IR (KBr): ν 1626, 1589, 1556, 1509, 1490, 1460, 1442, 1380, 1278, 823,
735, 701 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 0.02–0.22 (m, 4H), 1.08–1.16 (m, 1H), 2.38 (s, 3H),
3.56 (dd, J = 1.9, 11.9 Hz, 1H), 3.86 (dd, J = 8.8, 11.8 Hz, 1H), 5.63 (dd, J = 1.8, 8.7 Hz, 1H), 7.33 (d, J
= 8.1 Hz, 2H), 7.40–7.60 (m, 5H), 8.02 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H). 13.55 (bs, 1H). 13C{1H}-NMR
(151 MHz, (CD3)2SO): δ 10.3, 10.5, 15.7, 20.9, 31.0, 63.2, 106.8, 125.4, 126.8, 127.7, 127.8, 129.2,
ACS Paragon Plus Environment

Page 23 of 33
1
The Journal of Organic Chemistry
2
3
4
5
129.3, 129.4, 132.1, 134.9, 139.1, 140.5, 141.2, 144.9, 146.9, 152.6, 158.4, 169.7; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C27H23N2O3S+ 455.1423; Found 455.1424.
(R)-7-Cyclohexyl-10-cyclopropyl-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
6
7
8
9
g][1,7]naphthyridine-3-carboxylic acid (11d): The compound was prepared and purified according to
general procedure C. 60 mg of 6d was converted to 23 mg (39%) of 11d, isolated as a dark yellow
25
solid. [α]D −67 (c 0.90, DMSO). IR (CHCl3): ν 2928, 2853, 1740, 1662, 1590, 1557, 1513, 1463,
1443, 1388, 1265, 737, 703 cm-1; H-NMR (400 MHz, CD3OD): δ 0.11–0.22 (m, 4H), 1.13–1.22 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1H), 1.28–1.41 (m, 1H), 1.41–1.55 (m, 2H), 1.57–1.72 (m, 2H), 1.72–1.81 (m, 1H), 1.83–1.92 (m, 2H),
1.93–2.02 (m, 2H), 2.88–2.98 (m, 1H), 3.60 (d, J = 11.3 Hz, 1H), 3.81 (dd, J = 8.5, 11.3 Hz, 1H), 5.70
(d, J = 7.9 Hz, 1H), 7.37–7.52 (m, 5H); C{1H}-NMR (100 MHz, CD3OD): δ 10.4, 10.5, 15.7, 25.5,
26.0, 31.5, 32.1, 32.2, 45.4, 64.2, 106.1, 126.8, 127.5, 127.6, 127.7, 129.0, 129.1, 131.4, 140.2, 141.4,
144.6, 146.1, 158.4, 162.5, 169.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H27N2O3S+ 447.1737;
Found 447.1737.
(R)-7,9,10-Tricyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (11e): The compound was prepared according to general procedure A. 45 mg of 6e was
converted to 16 mg (37%) of 11e, isolated as a yellow powder. [α]D25 −113 (c 0.19, CHCl3). IR (KBr): ν
13
1
3413, 1735, 1655, 1593, 1530, 1472, 1386, 1222, 1031, 959, 886, 809, 732 cm-1; H-NMR (600 MHz,
(CD3)2SO): δ 0.45–0.50 (m, 1H), 0.54–0.59 (m, 1H), 0.81–0.90 (m, 2H), 0.95 (d, J = 6.0 Hz, 4H), 0.97–
1.60 (m, 2H), 1.10 (dd, J = 2.2, 8.4 Hz, 2H), 2.11–2.17 (m, 2H), 2.88–2.93 (m, 1H), 3.50 (dd, J = 2.4,
11.7 Hz, 1H), 3.79 (dd, J = 8.7, 11.6 Hz, 1H), 5.49 (dd, J = 1.2, 8.4 Hz, 1H), 7.11 (s, 1H), 13.44 (bs,
1H); C{1H}-NMR (151 MHz, (CD3)2SO): δ 9.9, 10.0, 10.6, 10.7, 10.9, 11.0, 14.6, 15.0, 16.6, 30.8,
63.0, 107.6, 121.6, 133.4, 139.6, 142.4, 148.9, 158.3, 159.7, 169.7; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C20H20N2NaO3S+ 391.1087; Found 391.1088.
13
(R)-9-Cyclopropyl-7-(4-nitrophenyl)-5-oxo-10-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11f): Prepared by following the general procedure B, 48 mg of
25
6f was converted to 23 mg (42%) of 11f, isolated as a yellow solid. [α]D −97 (c 0.22, DMSO); IR
(KBr): ν 3429, 2863, 1752, 1616, 1579, 1554, 1521, 1493, 1466, 1411, 1344, 1218, 854, 732, 701, cm-1;
1H-NMR (400 MHz, (CD3)2SO): δ 0.35–0.40 (m, 2H), 0.80–0.84 (m, 2H), 1.33-1.40 (m, 1H), 3.49 (dd,
J = 1.6, 11.6 Hz, 1H), 3.82 (dd, J = 8.8, 11.6 Hz, 1H), 5.74 (dd, J = 1.6, 8.8 Hz, 1H), 7.38–7.54 (m, 5H)
13
7.46 (s, 1H), 8.37 (dd, J = 2.0, 9.7 Hz, 2H), 8.50 (d, J = 2.0, 9.7 Hz, 2H); C{1H}-NMR (100 MHz,
(CD3)2SO): δ 10.1, 10.6, 16.9, 30.8, 63.7, 108.7, 121.5, 123.8, 127.9, 128.4, 130.3, 130.5, 133.3, 139.5,
139.9, 143.8, 144.6, 147.7, 149.4, 150.8, 158.2, 169.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C26H20N3O5S+ 486.1118; Found 486.1114.
(R)-10-Cyclopropyl-5-oxo-9-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11g): The compound was prepared and purified according to
general procedure C. 60 mg of 6g was converted to 26 mg (44%) of 11g, isolated as a dark yellow solid.
[α]D25 −43 (c 0.24, DMSO). IR (CHCl3): ν 1741, 1637, 1587, 1556, 1464, 1325, 1170, 1123, 1068, 737
cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 0.05–0.25 (m, 4H), 1.06–1.22 (m, 1H), 3.57 (d, J = 11.3, 1H),
3.88 (dd, J = 8.9, 11.1 Hz, 1H), 5.64 (d, J = 7.6 Hz, 1H), 7.40–7.64 (m, 5H), 7.86 (d, J = 7.8 Hz, 2H),
8.14 (s, 1H), 8.48 (d, J = 7.8 Hz, 2H), 13.26 (bs, 1H); C{1H}-NMR: (100 MHz, (CD3)2SO): δ 10.3,
13
10.5, 15.7, 31.0, 63.2, 106.8, 125.66, 125.68, 126.2, 127.5, 127.7, 127.9, 129.3, 132.9, 140.6, 140.9,
19
141.4, 146.0, 147.2, 150.8, 158.2, 169.6; F{1H}-NMR (376 MHz, (CD3)2SO): δ −61.0; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C27H20F3N2O3S+ 509.1141; Found 509.1140.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
(R)-7-(4-Cyanophenyl)-10-cyclopropyl-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11h): The compound was prepared and purified according to
general procedure C but extracted with CHCl3/IPA 10:1. 50 mg of 6h was converted to 29 mg (60%) of
25
11h, isolated as a dark yellow solid. [α]D −106 (c 0.67, DMSO). IR (CHCl3): ν 3467, 3058, 3003,
1
2227, 1736, 1658, 1588, 1553, 1490, 1461, 1382, 1266, 848, 734, 702 cm-1; H-NMR (400 MHz,
9
CH3OD (+ CDCl3)): δ 0.17–0.25 (m, 4H), 1.16–1.24 (m, 1H), 3.63 (dd, J = 1.6, 11.6 Hz, 1H), 3.81 (dd,
J = 8.5, 11.6 Hz, 1H), 5.73 (dd, J = 1.4, 8.2 Hz, 1H), 7.38–7.56 (m, 5H), 7.80 (d, J = 8.4 Hz, 2H), 7.98
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(s, 1H), 8.38 (d, J = 8.3 Hz, 2H); C{1H}-NMR (151 MHz, CH3OD (+ CDCl3)): δ 11.1, 11.2, 16.4,
32.3, 109.8, 112.8, 119.2, 127.5, 128.4, 128.50, 128.52, 128.7, 129.7, 133.1, 134.2, 141.4, 141.7, 143.1,
146.8, 148.8, 152.5, 161.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H20N3O3S+ 466.1219; Found
466.1214.
(R)-10-Cyclopropyl-7-(4-fluorophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11i): The compound was prepared and purified according to
general procedure C but extracted with CHCl3/IPA 10:1. 44 mg of 6i was converted to 22 mg (52%) of
25
11i, isolated as a dark yellow solid. [α]D −104 (c 0.53, DMSO). IR (CHCl3): ν 1737, 1635, 1589,
1
1559, 1518, 1464, 1442, 1413, 1229, 1163, 739 cm-1; H-NMR (400 MHz, CH3OD + CDCl3): δ 0.10–
0.24 (m, 4H), 1.12–1.20 (m, 1H), 3.57 (dd, J = 1.6, 11.7 Hz, 1H), 3.73 (dd, J = 8.3, 11.5 Hz, 1H), 5.72
(dd, J = 1.9, 8.2 Hz, 1H), 7.13 (apparent triplet, J = 8.7, 2H), 7.32–7.49 (m, 5H), 7.82 (s, 1H), 8.18 (dd,
J = 5.4, 8.7 Hz, 2H); 13C{1H}-NMR (100 MHz, CD3OD): δ 11.5 (2C), 17.0, 33.6, 67.6, 110.0, 116.5 (d,
J = 22 Hz), 127.3, 128.95, 129.01, 130.4, 130.6 (d, J = 8 Hz), 134.0, 136.1 (d, J = 2 Hz), 142.0, 143.1,
19
147.3, 149.2, 154.3, 161.8, 165.1 (d, J = 248 Hz) 174.3; F{1H}-NMR (376 MHz, (CD3)2SO): δ −
112.5; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H19FN2NaO3S+ 481.0992; Found 481.0991.
(R)-10-Cyclopropyl-7-(naphthalen-1-yl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11j): Prepared by following the general procedure B, 33 mg of
25
6j was converted to 18 mg (56%) of 11j, isolated as a yellow solid. [α]D −24 (c 0.13, DMSO); IR
(KBr): ν 3055, 3003, 1740, 1663, 1587, 1558, 1510, 1470, 1440, 1398, 1294, 1238, 864, 779, 702, 616
cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 0.02–0.28 (m, 4H), 1.12–1.21 (m, 1H), 3.58 (dd, J = 1.6, 11.6
Hz, 1H), 3.87 (dd, J = 8.4, 11.6 Hz, 1H), 5.64 (dd, J = 1.6, 8.8 Hz, 1H), 7.43–7.46 (m, 3H), 7.52–7.59
(m, 4H), 7.63 (t, J = 7.6 Hz, 1H), 7.76–7.80 (m, 2H), 8.04 (t, J = 7.6 Hz, 2H), 8.30 (dd, J = 0.8, 8.8 Hz,
13
1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 10.3, 10.5, 15.7, 31.0, 63.3, 106.6, 125.4, 125.5, 126.0,
126.7, 127.8, 128.0, 128.3, 129.1, 130.1, 130.5, 132.0, 133.4, 136.7, 140.4, 140.9, 145.5, 146.5, 154.9,
158.3, 169.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H23N2O3S+ 491.1424; Found 491.1423.
(R)-10-Methoxy-7-(4-nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11k): Prepared by following the general procedure C, 70 mg of
6k was converted to 52 mg (76%) of 11k, isolated as a light yellow solid. [α]D25 −4 (c 0.2, DMSO); IR
(KBr): ν 2932, 2589, 1742, 1639, 1591, 1560, 1522, 1491, 1467, 1443, 1410, 1343, 1228, 886, 754,
735, 698 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 2.98 (s, 3H), 3.66 (d, J = 11.6 Hz, 1H), 3.93 (dd, J =
8.4, 11.6 Hz, 1H), 5.70 (d, J = 7.2 Hz, 1H), 7.46–7.55 (m, 5H), 8.23 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H),
8.37 (d, J = 8.8 Hz, 2H); 13C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.4, 59.3, 63.2, 123.9, 126.5, 127.1,
127.8, 128.0, 128.1, 129.2, 130.3, 136.6, 138.8, 140.3, 143.4, 145.3, 147.8, 150.5, 157.3, 169.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H18N3O6S+ 476.0911; Found 476.0910.
(R)-10-Methoxy-5-oxo-7,9-diphenyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (11l): Prepared by following the general procedure B, 73 mg of 6l was converted to 36
25
mg (51%) of 11l, isolated as a light yellow solid. [α]D −20 (c 0.25, DMSO); IR (KBr): ν 3055, 2929,
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2591, 1740, 1649, 1592, 1514, 1491, 1467, 1444, 1383, 1362, 1280, 1228, 887, 752, 735, 699 cm-1; 1H-
NMR (400 MHz, (CD3)2SO): δ 2.84 (s, 3H), 3.64 (dd, J = 1.6, 12.0 Hz, 1H), 3.91 (dd, J = 8.4, 11.6 Hz,
1H), 5.67 (dd, J = 1.2, 8.4 Hz, 1H), 7.42–7.54 (m, 8H), 8.02 (s, 1H), 8.25 (dd, J = 1.2, 8.0 Hz, 2H);
13C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.4, 59.2, 63.2, 125.6, 126.9, 127.1, 127.3, 127.7, 128.8,
129.1, 129.5, 130.4, 135.1, 137.5, 139.1, 140.3, 145.0, 153.1, 157.5, 169.5; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C24H19N2O4S+ 431.1060; Found 431.1058.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-10-Methoxy-5-oxo-9-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11m): Prepared by following the general procedure B, purified
by recrystallization from methanol (2 ml). 60 mg of 6m was converted to 38 mg (65%) of 11m, isolated
25
as a light yellow solid. [α]D −4 (c 0.19, DMSO); IR: ν 3434, 1741, 1651, 1595, 1491, 1468, 1412,
1324, 1230, 168, 1126, 1066, 886, 746, 701, 620 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 2.86 (s, 3H),
3.66 (d, J = 11.6 Hz, 1H), 3.93 (dd, J = 8.4, 11.6 Hz, 1H), 5.69 (d, J = 8.4 Hz, 1H), 7.47–7.53 (m, 5H),
13
7.89 (d, J = 8.0 Hz, 2H), 8.17 (s, 1H), 8.50 (d, J = 8.0 Hz, 2H), 13.67 (bs, 1H); C{1H}-NMR (100
MHz, (CD3)2SO): δ 31.9, 59.7, 63.6, 126.2, 126.7, 127.6, 128.1, 128.3, 128.4, 129.7, 130.1, 130.8,
136.5, 139.4, 140.8, 141.8, 145.7, 151.9, 157.8, 169.9; 19F-NMR (376 MHz, (CD3)2SO): δ −61.0;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H18F3N2O4S+ 499.0934; Found 499.0938.
(R)-10-Methoxy-5-oxo-9-phenyl-7-(thiophen-2-yl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11n): Prepared by following the general procedure B, 73 mg
of 6n was converted to 34 mg (48%) of 11n, isolated as light yellow solid. [α]D25 −25 (c 0.27, DMSO);
IR (KBr): ν 3435, 3101, 1743, 1640, 1592, 1506, 1468, 1327, 1223, 846, 738, 699, 616 cm-1; 1H-NMR
(400 MHz, (CD3)2SO): δ 2.84 (s, 3H), 3.63 (dd, J = 2.0, 12.0 Hz, 1H), 3.92 (dd, J = 8.8, 11.6 Hz, 1H),
5.64 (dd, J = 1.6, 8.4 Hz, 1H), 7.18 (dd, J = 4.0, 7.8 Hz, 1H) 7.43–7.50 (m, 5H), 7.71 (dd, J = 1.2, 7.8
13
Hz, 1H), 8.00 (dd, J = 1.2, 4.0 Hz, 1H), 8.02 (s, 1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.3,
59.2, 63.1, 124.4, 126.8, 127.1, 127.2, 127.7, 128.5, 129.0, 129.5, 130.5, 134.8, 138.9, 139.9, 143.6,
+
144.9, 149.4, 157.1, 169.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H17N2O4S2 437.0624; Found
437.0634.
(R)-7-(4-Nitrophenyl)-5-oxo-9-phenyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid 11o): Prepared by following the general procedure B, 27 mg of 6o was converted to 11
25
mg (42%) of 11o, isolated as a yellow solid. [α]D −3 (c 0.4, DMSO). IR (KBr): ν 3471, 3414, 2950,
1
1740, 1642, 1594, 1567, 1519, 1464, 1442, 1406, 1342, 1218, 862, 728, 702, 621 cm-1; H-NMR (400
MHz, (CD3)2SO): δ 3.65 (d, J = 11.6 Hz, 1H), 3.93 (dd, J = 8.4, 11.6 Hz, 1H), 5.62 (d, J = 8.4 Hz, 1H),
6.41 (s, 1H), 7.54-7.62 (m, 5H), 8.30 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H), 8.56 (d, J = 9.2 Hz, 2H);
13C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.0, 62.9, 93.4, 123.9, 124.4, 127.9, 128.8, 129.2, 131.8,
136.6, 139.4, 143.8, 144.1, 146.4, 147.7, 150.8, 158.6,169.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H16N3O5S+ 446.0805; Found 446.0805.
(R)-10-Cyclopropyl-7-(4-nitrophenyl)-5-oxo-9-(3-(trifluoromethyl)phenyl)-3,5-dihydro-2H-
thiazolo[2,3-g][1,7]naphthyridine-3-carboxylic acid (11p): The compound was prepared and purified
according to general procedure C but extracted with CHCl3/IPA 10:1. 36 mg of 6p was converted to 15
25
mg (43%) of 11p, isolated as a dark yellow solid. [α]D −83 (c 0.32, DMSO); IR (CHCl3): ν 1751,
1
1618, 1580, 1553, 1520, 1340, 1326, 1122 cm-1; H-NMR (400 MHz, (CD3)2SO, 343 K): δ −0.02–0.3
(m, 4H), 0.99–1.09 (m, 1H), 3.59 (dd, J = 2.0, 11.8 Hz, 1H), 3.90 (dd, J = 8.8, 11.7, 1H ), 5.66 (dd, J =
2.0, 8.8 Hz, 1H), 7.67–7.76 (m, 1H), 7.77–7.89 (m, 2H), 7.90–8.00 (m, 1H), 8.28 (s, 1H), 8.36 (d, J =
8.8 Hz, 2H), 8.56 (d, J = 8.8 Hz, 2H); 13C{1H}-NMR (100 MHz, (CD3)2SO, 343 K): δ 10.2, 10.4, 15.2,
30.8, 63.1, 106.0, 123.5, 123.9 (q, J = 273 Hz), 124.8, 125.4, 126.4, 127.7, 128.5, 132.8, 133.1, 140.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
141.5, 143.3, 145.0, 146.9, 147.7, 149.9, 157.7, 169.0. 19F-NMR (376 MHz, (CD3)2SO): δ −61; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C27H19F3N3O5S+ 554.0992; Found 554.0979.
(R)-10-Cyclopropyl-5-oxo-7-phenyl-9-(3-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (11q): The compound was prepared and purified according to
general procedure C but extracted with CHCl3/IPA 10:1. 39 mg of 6q was converted to 22.6 mg (60%)
5
6
7
8
25
of 11q, isolated as a dark yellow solid. [α]D −119 (c 0.31, DMSO); IR (CHCl3): ν 1735, 1660, 1623,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1587, 1443, 1381, 1326, 1167, 1126, 704 cm-1; H-NMR (600 MHz, (CD3)2SO, 333 K: δ −0.04–0.24
(m, 4H), 0.96–1.02 (m, 1H), 3.58 (d, J = 10.8 Hz, 1H), 3.70–3.76 (m, 1H), 5.43 (d, J = 7.9 Hz, 1H),
7.46 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.5, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.83 (d,
J = 7.1 Hz, 1H), 7.90 (s, 1H), 8.06 (s, 1H), 8.26 (d, J = 7.5 Hz, 1H); C{1H}-NMR (151 MHz,
13
(CD3)2SO, 333 K): δ 10.4, 10.5, 15.3, 31.8, 64.9, 104.9, 123.9 (d, J = 3 Hz), 124.0 (q, J = 272 Hz),
125.2, 125.4 (d, J = 3 Hz), 126.6, 128.3, 128.4, 128.5, 128.9, 131.8, 133.1 (d, J = 1.4 Hz), 137.7, 140.7,
19
142.1, 144.4, 146.6, 151.9, 157.9, 168.5; F-NMR (564 MHz, (CD3)2SO): δ −61.0; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C27H20F3N2O3S+ 509.1141;Found 509.1148.
(R)-10-Cyclopropyl-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-
3-carboxylic acid (12a): Prepared by following the general procedure B, purified by recrystallization
from methanol (2 ml), 27 mg of 9a was converted to 17 mg (65%) of 12a, isolated as yellow solid.
25
[α]D −64 (c 0.16, DMSO); IR (KBr): ν 3417, 2921, 2851, 1740, 1638, 1596, 1573, 1472, 1412, 1384,
1337, 1232, 853, 726, 623 cm-1; H-NMR (400 MHz, (CD3)2SO): δ 0.59–0.64 (m, 2H), 1.08 (m, 2H),
1.82 (m, 1H), 3.61 (d, J = 11.6 Hz, 1H), 3.87 (dd, J = 9.2, 11.6 Hz, 1H), 5.64 (d, J = 8.0 Hz, 1H), 8.38–
8.51 (m, 6H), 13.60 (s, 1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 7.1, 7.3, 9.6, 31.1, 62.7, 106.3,
124.0, 124.2, 127.7, 132.8, 134.6, 139.2, 143.6, 143.8, 147.7, 150.8, 158.3, 169.6; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C20H16N3O5S+ 410.0805; Found 410.805.
(R)-10-Cyclopropyl-5-oxo-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12b): Prepared by following the general procedure B , 24 mg
1
13
25
of 9b was converted to 13 mg (56%) of 12b, isolated as a light yellow solid. [α]D −38 (c 0.06,
DMSO); IR (KBr): ν 3435, 1743, 1635, 1574, 1514, 1479, 1385, 1325, 1231, 1170, 1124, 1068, 834,
753 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 0.57–0.67 (m, 2H), 1.07–1.11 (m, 2H), 1.79–1.86 (m, 1H),
3.61 (dd, J = 1.2, 11.6 Hz, 1H), 3.87 (dd, J = 8.8, 12.0 Hz, 1H), 5.64 (dd, J = 1.2, 8.4 Hz, 1H), 7.91 (d, J
= 8.4 Hz, 2H), 8.42 (d, J = 8.4 Hz, 3H), 8.49 (d, J = 8.4 Hz, 1H); 13C{1H}-NMR (100 MHz, (CD3)2SO):
δ 7.1, 7.3, 9.6, 31.1, 62.6, 106.3, 122.9 (q, J = 270 Hz), 123.9, 125.7 (d, J = 3.6 Hz), 127.3, 129.1 (d, J =
31.1 Hz), 132.7, 134.4, 139.1, 141.6, 143.1, 151.7, 158.4, 169.6; 19F-NMR: (376 MHz, (CD3)2SO): δ −
61.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H16F3N2O3S+ 433.0828; Found 433.0840.
(R)-7-(4-Cyanophenyl)-10-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12c): Prepared by following the general procedure C, 17 mg of
25
9c was converted to 13 mg (81%) of 12c, isolated as a yellow solid. [α]D −168 (c 0.17, DMSO); IR
(KBr): ν 3431, 2226, 1759, 1654, 1625, 1577, 1524, 1476, 1408, 1300, 1216, 834, 763 cm-1; H-NMR
1
(400 MHz, (CD3)2SO): δ 0.56–0.68 (m, 2H), 1.03–1.11 (m, 2H), 1.79–1.84 (m, 1H), 3.61 (dd, J = 1.2,
11.6 Hz, 1H), 3.85 (dd, J = 8.8, 12.0 Hz, 1H), 5.62 (dd, J = 1.6, 8.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H),
8.40 (d, J = 8.4 Hz, 2H), 8.44 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H); 13C{1H}-NMR (100 MHz,
(CD3)2SO): δ 7.1, 7.3, 9.6, 31.2, 62.7, 106.2, 111.5, 118.7, 124.0, 127.3, 132.7, 132.8, 134.5, 139.1,
142.0, 143.4, 151.2, 158.4, 169.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H16N3O3S+ 390.0907;
Found 390.0908.
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(R)-10-Cyclopropyl-7-(4-fluorophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12d): The compound was prepared and purified according to
general procedure C but was extracted with CHCl3/IPA 10:1. 29 mg of 9d was converted to 9.4 mg
25
(34%) of 12d, isolated as a dark yellow solid. [α]D −58 (c 0.34, DMSO); IR (NaCl): ν 1743, 1628,
1590, 1576, 1474, 1221, 1181, 1135 cm-1; 1H-NMR (600 MHz, (CD3)2SO): δ 0.55–0.61 (m, 1H), 0.62–
0.67 (m, 1H), 1.02–1.12 (m, 2H), 1.79–1.85 (m, 1H), 3.59 (dd, J = 1.1, 11.6 Hz, 1H), 3.83 (dd, J = 8.7,
11.7 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 7.38 (apparent triplet, J = 8.8 Hz, 2H), 8.26 (dd, J = 5.6, 8.7 Hz,
2H), 8.32 (d, J = 8.6 Hz, 1H), 8.44 (d, J =8.6 Hz, 1H); 13C{1H}-NMR (151 MHz, (CD3)2SO): δ 7.1, 7.3,
9.6, 31.3, 62.9, 106.2, 115.7 (d, J = 22 Hz), 123.3, 128.9 (d, J = 8 Hz), 132.5, 133.7, 134.5, 139.1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
142.5, 152.4, 158.6, 163.0 (d, J = 247 Hz), 169.6; F{1H}-NMR (376 MHz, (CD3)2SO): δ −112.6;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H16FN2O3S+ 383.0860; Found 383.0868.
(R)-10-Cyclopropyl-7-(naphthalen-1-yl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12e): Prepared by following the general procedure B, 25 mg of
25
9e was converted to 17 mg (70%) of 12e, isolated as a light yellow solid. [α]D −47 (c 0.13, DMSO);
IR (KBr): ν 3414, 1737, 1617, 1580, 1516, 1481, 1398, 1384, 1244, 803, 778, 620 cm-1; 1H-NMR (400
MHz, (CD3)2SO): δ 0.26–0.72 (m, 2H), 1.07–1.18 (m. 2H), 1.83–1.90 (m, 1H), 3.61 (dd, J = 1.2, 11.6
Hz, 1H), 3.84 (dd, J = 8.4, 11.6 Hz, 1H), 5.60 (d, J = 7.6 Hz, 1H), 7.51–7.60 (m, 2H), 7.64–7.71 (m,
13
2H), 8.02–8.07 (m, 3H), 8.14 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H); C{1H}-NMR (100 MHz,
(CD3)2SO): δ 7.1, 7.2, 9.6, 31.2, 62.7, 106.3, 125.4, 126.0, 126.6, 127.7, 128.1, 128.3, 129.0, 130.5,
132.1, 133.4, 133.6, 137.3, 139.0, 142.5, 155.9, 158.6, 169.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H19N2O3S+ 415.1111; Found 415.1114.
(R)-7-Cyclohexyl-10-cyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (12f): Prepared by following the general procedure B, 36 mg of 9f was converted to 20
25
mg (58%) of 12f, isolated as a light yellow solid. [α]D −77 (c 0.17, DMSO); IR (KBr): ν 3434, 2927,
2850, 1738, 1665, 1601, 1583, 1524, 1482, 1448, 1390, 1326, 1223, 852, 623 cm-1; H-NMR (400
1
MHz, (CD3)2SO): δ 0.55–0.58 (m, 2H), 1.02 (m, 2H), 1.25–1.44 (m, 3H), 1.54–1.57 (m, 2H), 1.71–1.88
(m, 6H), 2.77–2.83 (m, 1H), 3.55 (d, J = 11.6 Hz, 1H), 3.81 (dd, J = 9.2, 10.8 Hz, 1H), 5.56 (d, J = 8.4
13
Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ
7.0, 7.2, 9.6, 25.5, 25.9, 31.0, 32.1, 32.2, 45.7, 62.5, 106.3, 124.8, 131.8, 133.1, 138.5, 141.0, 158.6,
163.7, 169.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H23N2O3S+ 371.1424; Found 371.1427.
(R)-7,10-Dicyclopropyl-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-carboxylic
acid (12g): Prepared by following the general procedure B, 30 mg of 9g was converted to 15 mg (52%)
25
of 12g, isolated as a light yellow solid. [α]D −208 (c 0.18, DMSO); IR (KBr): ν 3416, 2924, 2851,
1728, 1673, 1635, 1542, 1526, 1403, 1362, 1315, 1224, 845, 631 cm-1; 1H-NMR (400 MHz, (CD3)2SO):
δ 0.51–0.60 (m, 2H), 0.99–1.03 (m, 6H), 1.72–1.78 (m, 1H), 2.21–2.26 (m, 1H), 3.54 (dd, J = 1.2, 12.0
Hz, 1H), 3.80 (dd, J = 8.4, 11.6 Hz, 1H), 5.25 (dd, J = 1.2, 8.4 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 8.24
13
(d, J = 8.4 Hz, 1H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 7.0, 7.2, 9.6, 10.1, 10.2, 17.0, 31.0, 62.6,
106.3, 124.7, 131.3, 132.7, 138.8, 140.5, 158.4, 160.5, 169.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H17N2O3S+ 329.0954; Found 329.0953.
(R)-10-Cyclopropyl-5-oxo-7-propyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (12h): Prepared by following the general procedure B, 28 mg of 9h was converted to 12
mg (45%) of 12h, isolated as a light yellow solid. [α]D25 −27 (c 0.21, DMSO); IR (KBr): ν 3432, 3082,
2961, 2930, 1735, 1655, 1600, 1583, 1525, 1485, 1388, 1332, 1286, 1223, 1185, 853, 616 cm-1; H-
1
NMR (400 MHz, (CD3)2SO): δ 0.51–0.63 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H), 0.99–1.08 (m, 2H), 1.68–
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
1.80 (m, 3H), 2.83 (t, J = 7.6 Hz, 2H) 3.56 (dd, J = 1.6, 11.6 Hz, 1H), 3.82 (dd, J = 8.8, 11.6 Hz, 1H),
13
5.58 (dd, J = 1.6, 8.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H); C{1H}-NMR (100
MHz, (CD3)2SO): δ 7.0, 7.2, 9.6, 13.6, 22.5, 31.0, 38.8, 62.5, 106.3, 126.4, 131.7, 133.0, 138.6, 141.1,
158.5, 159.8, 169.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H19N2O3S+ 331.1111; Found
331.1136.
5
6
7
8
(R)-7-(4-Nitrophenyl)-5-oxo-10-phenyl-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
carboxylic acid (12i): Prepared by following the general procedure B, 30 mg of 9i was converted to 18
mg (62%) of 12i, isolated as a yellow solid. [α]D25 −58 (c 0.22, DMSO); IR (KBr): ν 1740, 1652, 1577,
1524, 1493, 1470, 1443, 1411, 1372, 1343, 1223, 854, 839, 777 cm-1; 1H-NMR (400 MHz, (CD3)2SO):
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 3.59 (dd, J = 1.4, 12.2 Hz, 1H), 3.89 (dd, J = 8.6, 11.6 Hz, 1H), 5.75 (dd, J = 1.4, 8.6 Hz, 1H), 7.37–
13
7.43 (m, 2H), 7.45–7.59 (m, 3H), 7.64 (d, J = 8.8 Hz, 1H) 8.35–8.47 (m, 5H); C{1H}-NMR (100
MHz, (CD3)2SO): δ 31.3, 63.4, 108.8, 124.1, 124.6, 127.7, 128.5, 129.2, 130.1, 132.7, 133.3, 134.8,
139.0, 142.9, 143.6, 147.8, 151.2, 158.2, 169.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H16N3O5S+ 446.0805; Found 446.0808.
(R)-5-Oxo-10-phenyl-7-(4-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12j): Prepared by following the general procedure B, purified
by recrystallization from methanol (2ml), 27 mg of 9j was converted to 14 mg (53%) of 12j, isolated as
a light yellow solid. [α]D25 −46 (c 0.20, DMSO); IR (KBr): ν 3449, 1743, 1658, 1618, 1584, 1493, 1325,
1243, 1167, 1123, 1067, 1014, 860, 703 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 3.57 (d, J = 11.6 Hz,
1H), 3.90 (t, J = 9.2, 11.2 Hz, 1H), 5.74 (d, J = 7.6 Hz, 1H), 7.42–7.68 (m, 6H), 7.89 (d, J = 8.4 Hz,
13
2H), 8.26 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 7.2 Hz, 2H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.2,
63.3, 108.8, 124.3, 125.6, 125.8, 127.4, 128.4, 129.2, 129.5, 130.1, 132.7, 133.1, 134.9, 138.9, 141.5,
19
142.4, 152.0, 158.3, 169.6; F-NMR (376 MHz, (CD3)2SO): δ −61.0; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C24H16F3N2O3S+ 469.0828; Found 469.0835.
(R)-7-(4-Nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-carboxylic acid
(12k): Prepared by following the general procedure B but was extracted with CHCl3/IPA 10:1. 50 mg of
25
9k was converted to 17 mg (58%) of 12k, isolated as yellow solid. [α]D −10 (c 0.08, DMSO); IR
1
(KBr): ν 3416, 1747, 1654, 1578, 1510, 1471, 1401, 1375, 1343, 1226, 851, 818, 622 cm-1; H-NMR
(400 MHz, (CD3)2SO): δ 3.67 (d, J = 11.5 Hz, 1H), 3.97 (dd, J = 11.4, 8.9 Hz, 1H), 5.63 (d, J = 8.1 Hz,
13
1H), 6.72 (s, 1H), 8.12 (d, 1H), 8.43 (m, 5H); C{1H}-NMR (400 MHz, (CD3)2SO): δ 31.9, 62.6,
96.4, 124.1 (2C), 124.7, 127.8 (2C), 134.0, 134.9, 138.6, 143.5, 143.9, 147.8, 151.3, 158.8, 169.6;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H12N3O5S+ 370.0498; Found 379.0504.
(R)-10-(3-hydroxyphenyl)-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12l): The compound was prepared according to general
procedure B but extracted with CHCl3/IPA 7:3. Purified by recrystallization from methanol. 31.2 mg of
9l was converted to 18.3 mg (60%) of 12l, isolated as an orange solid. [α]D25 −3 (c 0.29, DMSO); IR: ν
3019, 1728, 1648, 1571, 1512, 1466, 1442, 1411, 1335, 1213, 914, 752, 709 cm-1; 1H-NMR (400 MHz,
(CD3)2SO, 343 K): δ 3.57 (dd, J = 11.5, 1.6 Hz, 1H), 3.84 (dd, J = 11.6, 8.5 Hz, 1H), 5.66 (dd, J = 8.4,
1.6 Hz, 1H), 6.78 (m, 2H), 6.8 (dd, J = 8.6, 2.3 Hz, 1H), 7.34 (t, J = 8.7 Hz, 1H), 7.73 (d, J = 8.7 Hz,
13
1H), 8.29 (d, J = 8.7 Hz, 1H), 8.36 (m, 2H), 8.45 (m, 2H); C{1H}-NMR (100 MHz, (CD3)2SO, 343
K): δ 31.3, 63.9, 108.4, 115.2, 116.7, 120.3, 123.7 (2C), 124.0, 127.5 (2C), 129.9, 132.4, 133.1, 135.9,
138.9, 142.8, 143.7, 147.7, 150.8, 157.7, 157.9, 168.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H16N3O6S+ 462.0760; Found 462.0764.
(R)-7-(4-nitrophenyl)-5-oxo-10-(m-tolyl)-3,5-dihydro-2H-thiazolo[2,3-g][1,7]naphthyridine-3-
ACS Paragon Plus Environment

Page 29 of 33
1
The Journal of Organic Chemistry
2
3
4
5
carboxylic acid (12m): The compound was prepared according to general procedure B but extracted
with CHCl3/IPA 7:3. Purified by recrystallization from methanol. 42.5 mg of 9m was converted to 21.2
25
mg (52%) of 12m, isolated as an orange solid. [α]D −47 (c 0.04, DMSO); IR: ν 1747, 1634, 1578,
1510, 1471, 1401, 1343, 1226, 851, 725 cm-1; 1H-NMR (400 MHz, (CD3)2SO): δ 2.41 (s, 3H), 3.58 (dd,
J = 11.8, 1.3, 1H), 3.89 (dd, J = 11.8, 8.6 Hz, 1H), 5.75 (dd, J = 8.7, 1.3 Hz, 1H), 7.31 (m, 4H), 7.68 (d,
J = 8.7 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 9.0 Hz, 2H), δ 8.44 (d, J = 9.0 Hz, 2H);
13C{1H}-NMR (100 MHz, (CD3)2SO): δ 20.9, 31.2, 63.4, 108.8, 124.1 (2C), 124.6, 127.8 (2C), 129.8
(2C), 130.0 (2C), 131.9, 132.8, 133.5, 137.9, 139.1, 142.9, 143.7, 147.8, 151.2, 158.2, 169.6; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H18N3O5S+ 460.0967; Found 460.0962.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)-10-(3-acetylphenyl)-7-(4-nitrophenyl)-5-oxo-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12n): The compound was prepared according to general
procedure B but extracted with CHCl3/IPA 7:3. Purified by recrystallization from methanol. 41.6 mg of
9n was converted to 18.1 mg (45%) of 12n, isolated as an orange solid. [α]D25 −6 (c 0.3, DMSO); IR: ν
1760, 1679, 1599, 1572, 1525, 1470, 1412, 1343 1259, 839, 754 cm-1; 1H-NMR (400 MHz, (CD3)2SO,
343 K): δ 2.63 (s, 3H), 3.60 (dd, J = 11.6, 1.5 Hz, 1H), 3.89 (dd, J = 11.7, 8.5 Hz, 1H), 5.73(dd, J =
8.5, 1.4 Hz, 1H), 7.71 (m, 3H), 7.96 (broad s, 1H), 8.07 (m, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.36 (d, J =
8.9 Hz, 2H), 8.45 (d, J = 8.9 Hz, 2H); 13C{1H}-NMR (100 MHz, (CD3)2SO, 343 K): δ 26.4, 31.3, 63.6,
107.6, 123.7 (2C), 124.3, 127.6 (2C), 127.9, 129.4, 129.5, 132.2, 132.9, 134.6, 135.3, 137.6, 138.9,
143.3, 143.5, 147.7, 151.1, 157.9, 168.9, 197.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C25H18N3O6S+ 488.0916; Found 488.0911.
(R)-7-(4-nitrophenyl)-5-oxo-10-(thiophen-3-yl)-3,5-dihydro-2H-thiazolo[2,3-
g][1,7]naphthyridine-3-carboxylic acid (12o): The compound was prepared according to general
procedure B but extracted with CHCl3/IPA 7:3. Purified by recrystallization from methanol. 60.6 mg of
9o was converted to 56.2 mg (96%) of 12o, isolated as an orange solid. [α]D25 −75 (c 0.08, DMSO); IR:
1
ν 1741, 1636, 1576, 1470, 1339, 851, 725 cm-1; H-NMR (400 MHz, (CD3)2SO): δ 3.59 (dd, J = 11.6,
1.2 Hz, 1H), 3.89 (dd, J = 11.7, 8.7 Hz, 1H), 5.74 (dd, J = 8.9, 1.3 Hz, 1H), 7.22 (dd, J = 4.8, 1.2 Hz,
1H), 7.69 (dd, J = 2.8, 1.2 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 5.0, 2.8 Hz, 1H), 8.39 (d, J =
13
8.8 Hz, 1H), 8.42 (m, 4H); C{1H}-NMR (100 MHz, (CD3)2SO): δ 31.2, 63,5, 104.1, 124.1 (2C),
124.7, 126.2, 127.4, 127.8 (2C), 128.8, 132.9, 133.5, 134.5, 138.9, 143.4, 143.6, 147.8, 151.2, 158.1,
+
169.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H14N3O5S2 452.0369; Found 452.0377.
Methyl (R)-8-cyclopropyl-6-iodo-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate
(13): 2-pyridone 3a (4.8 g, 19 mmol, 1.0 eq.) was dissovled in acetonitrile (190 ml) in a round bottomed
flask. N-iodosuccinimide (5.2 g, 23 mmol, 1.2 eq.) was added while stirring. Water (41 µl, 2.3 mmol,
0.12 eq.) was added, the flask was covered with a septum and the reaction mixture was stirred at r.t. The
reaction was followed with TLC (80% ethyl acetate in heptane) and found complete after stirring over
night. Upon completion, saturated aqueous sodium thiosulfate solution (80 ml) was added and the
resulting mixture was stirred for 5 min. The mixture was subsequently partitioned between ethyl acetate
(350 ml) and brine (200 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and
evaporated. The product was purified with automated flash column chromatography (100 g cartridge;
15–35% ethyl acetate in heptane) to provide 4.2 g (58%) of the title compound 13 as a light yellow
solid. [α]D25 −234 (c 0.665, CHCl3). IR (KBr cm-1): ν 3012, 2953, 1738, 1715, 1649, 1578, 1482, 1436,
1370, 1353, 1330, 1265, 1244, 1218, 1180, 1149, 1017. 1H-NMR (600 MHz, CDCl3): δ 0.61–0.54 (m,
2H), 0.89–0.82 (m, 2H), 1.59–1.53 (m, 1H), 3.52 (dd, J = 2.4, 11.6 Hz, 1H), 3.73 (dd, J = 8.6, 11.6 Hz,
1H), 3.80 (s, 3H), 5.61 (dd, 2.4, 8.8 Hz, 1H), 7.66 (s, 1H). 13C{1H}-NMR (100 MHz, CDCl3): δ 6.2,
6.5, 12.3, 32.1, 53.5, 64.7, 84.4, 116.2, 148.3, 149.7, 158.7, 168.3; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C12H13INO3S+ 377.9655; Found 377.9661.
ACS Paragon Plus Environment