Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils

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Intramolecular Povarov Reactions for the Synthesis of

Chromenopyridine Fused 2‑Pyridone Polyheterocycles Binding to

α‑Synuclein and Amyloid‑β Fibrils

́

̈

Dan E. Adolfsson, Mohit Tyagi, Pardeep Singh, Adrian Deuschmann, Jorgen Åden, Anna L. Gharibyan,

Sanduni Wasana Jayaweera, Anders E. G. Lindgren, Anders Olofsson, and Fredrik Almqvist *

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ABSTRACT: A BF₃·OEt₂catalyzed intramolecular Povarov reaction

was used to synthesize 15 chromenopyridine fused thiazolino-2-

pyridone peptidomimetics. The reaction works with several O-alkylated

salicylaldehydes and amino functionalized thiazolino-2-pyridones, to

generate polyheterocycles with diverse substitution. The synthesized

compounds were screened for their ability to bind α-synuclein and

amyloid β ﬁbrils in vitro. Analogues substituted with a nitro group bind

to mature amyloid ﬁbrils, and the activity moreover depends on the positioning of this functional group.

Since its discovery, the Povarov reaction⁶has been used

he thiazolino fused 2-pyridone represents a privileged

T_{scaﬀold which can be modiﬁed to display various}widely for the synthesis of nitrogen containing, six-membered

heterocycles with biological relevance.⁷Recently, we utilized

the Lewis acid catalyzed Povarov reaction to construct a

tricyclic pyridine fused 2-pyridone peptidomimetic scaﬀold,^3c

whose analogues have been shown to bind α-synuclein and Aβ

ﬁbrils by ThT displacement⁸in vitro (e.g., compound 4, Figure

1A). We envisioned that performing the Povarov reaction in an

intramolecular fashion⁹could result in the desired chromeno-

pyridine annulated 2-pyridones 11 in a single operation

(Figure 1B). The new scaﬀold 11 being equipped with the

tetrahedral carbon, and the oxygen, could decrease planarity of

the structures and enable increased hydrogen bonding,

respectively.¹⁰In addition, these features could potentially

confer selectivity between diﬀerent amyloid structures, a very

desired property in diagnostic and therapeutic applications of

amyloid binding small molecules.¹¹

We perceived that chromenopyridine ring fused 2-pyridone

scaﬀold 11 would be accessible from amino 2-pyridone 9 and

O-alkylated salicylaldehyde 10. Hence, we began our work by

investigating the feasibility of the reaction between 9a and O-

cinnamyl salicylaldehyde 10a in an intramolecular Povarov

setup using BF₃·OEt₂as catalyst, followed by oxidation with

DDQ (Scheme 1).^3cAs hypothesized, the intramolecular

reaction worked smoothly, and the desired product 11a was

biological activities.¹It was initially designed as a peptidomi-

metic to combat the virulence of uropathogenic E. coli by

inhibiting the formation of pili.^1aWith alternative substitution

patterns, compounds based on this scaﬀold have also

demonstrated activity against Chlamydia trachomatis,^1bListeria

monocytogenes,^1cand Mycobacterium tuberculosis.^1dRigidifying

the scaﬀold by equipping it with sterically demanding aryl

groups provides compounds with the ability to modulate

formation of bacterial and human amyloid ﬁbrils.²Extension of

the bicyclic thiazolino fused 2-pyridone with nitrogen

containing aromatic heterocycles oﬀers another way of

rigidifying the peptidomimetic scaﬀold,³as exempliﬁed by

compounds 1−4 (Figure 1A). These analogues are able to

modulate α-synuclein amyloid ﬁbril formation, which is

associated with Parkinson’s disease, a human neurodegener-

ative disorder,^2a,3a,bor bind to mature α-synuclein ﬁbrils.^3c

Chromenopyridine is a versatile structural motif present in a

variety of polyheterocycles with applications in biology as

estrogenic, antibacterial, and anticancer agents and biosensors

(compounds 5−8, respectively, Figure 1B).⁴Recently, the

merging of two diﬀerent active fragments to develop scaﬀolds

with improved biological properties has received considerable

attention.⁵As mentioned above, annulation of bicyclic

thiazolino fused 2-pyridone with diﬀerent heterocycles has

resulted in scaﬀolds capable of modulating amyloid ﬁbrils.³We

envisaged that fusing thiazolino 2-pyridone and chromenopyr-

idine, by combining units 9 and 10, could aﬀord scaﬀolds with

the ability to target amyloid structures (Figure 1B) and, in

addition, constitute a new central fragment with great potential

for drug discovery in general.

Received: July 16, 2020

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A

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Figure 1. (A) Bicyclic 2-pyridones capable of modulating (compounds 1−3) and binding (compound 4) to α-synuclein and amyloid β ﬁbrils. (B)

Chromenopyridine containing bioactive polyheterocycles 5−8 and retrosynthetic strategy devised for construction of chromenopyridine fused 2-

pyridone polyheterocycle 11.

Scheme 1. Synthesis of 2-Pyridone Based Polyheterocycles 11a−k

isolated in excellent yield. To explore the substrate scope of the

reaction, substituted O-cinnamyl salicylaldehydes 10b−i

(Schemes S1 and S2) were allowed to react with 6-amino-2-

pyridones 9a,b to construct 11b−k in good to excellent yields

(Scheme 1).

Aware of the importance of the 4-nitrophenyl substituent for

amyloid binding activity of the tricyclic scaﬀold 4,^3cwe

prepared 11b−f and 11k with nitro groups in various

positions. Notably, salicylaldehydes with electron withdrawing

R³substituents underwent faster Povarov reaction due to

lowering of LUMO in the electrophilic imine intermediate,

providing 11b−d, 11g, and 11k.¹²Electron donating R⁴

substituents rendered the alkene more nucleophilic and

likewise decreased the reaction times, while electron with-

drawing R⁴substituents increased them. Heating was required

to achieve synthetically useful reaction times for synthesis of

11e and 11h, where, in the former case, the moderate yield

reﬂects a less clean conversion. In the preparation of 11f, the

eﬀect of the electron withdrawing R³substituent compensated

for poor nucleophilicity of the alkene moiety, and heating was

not required to complete the reaction in 1 day. To test the

scalability, 11b was also prepared from 1.6 mmol of 9a. The

yield (88%) is comparable to that at 0.4 mmol scale (86%).

Next, we turned our attention toward the synthesis of C-13

unsubstituted target molecules 13 (Scheme 2). SAR from our

previous study suggested that the best amyloid binding

properties are achieved when the corresponding position is

unsubstituted.^3cIt was approached by Povarov reaction

B

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in organic solvents complicated handling, and these com-

pounds were thus obtained in lower yields.

Scheme 2. Unsuccessful Attempt to Synthesize C-13

Unsubstituted Compound 13a

Scheme 4. Deprotection of Methyl Esters through

Saponiﬁcation of 11a−k and 13a−e

between 9a and O-allyl salicylaldehyde 12. To our dismay, we

were only able to isolate small amounts (7%) of the desired

product 13a, from the complex reaction mixture after 4 days at

70 °C. Microwave irradiation, 120 °C for 3 h, shared the same

lack of success, and 13a was isolated in only 11% yield.

Though fruitful results are reported,^9eattempts with terminal

allyl moieties often suﬀer from low yields.^7a,9a,12a,b

Familiar with the mechanistic features of the Lewis acid

catalyzed Povarov reaction,^{7a,d,e,12c,13}we realized that use of

the terminal allyl group as alkene components would require

the reaction to go via high energy carbocations or operate via

an alternative mechanism.^9a,b,d,14With our previous strives in

mind where we had made use of ethyl vinyl ether as alkene

component, for synthesis of unsubstituted tricyclic analogues

4,^3cwe naturally thought of employing a vinyl ester moiety as

electron donating auxiliary. With 3-bromopropenyl benzoate,¹⁵

we were able to alkylate salicylic aldehydes to synthesize the

required intermediates 14a−d (Schemes 3 and S3). With the

The carboxylic acids 15a−k and 16a−e were initially

screened in an α-synuclein ﬁbrilization assay with Thioﬂavin

T (ThT) to probe for ﬁbril binding and modulation of amyloid

ﬁbril formation (Figure 2A and Figure S1).^8,16Compounds

15b,c, 15e,f, 15k, 16a,b, and 16e bind to the α-synuclein ﬁbrils

and had a signiﬁcant eﬀect on the ﬂuorescence intensity, by

competing with ThT for binding. In addition, compound 15e

has a mild inhibitory eﬀect upon the ﬁbril formation, as the lag

phase was slightly extended. In order to verify that amyloid

ﬁbrils were indeed present, samples were taken upon the end

point of the assay and visualized with transmission electron

microscopy (TEM) (Figure S2). No visible diﬀerence was

observed between the control experiment (black trace) and the

mixture with 16a (green trace) (Figures 2B and S2).

In a similar assay, compounds (15a−c, 15e,f, 15k, 16a−c,

16e) were added after 70 h, when the ﬂuorescence traces had

reached the plateau phase (Figures 3A and S3). The

compounds were observed to bind to the mature α-synuclein

ﬁbrils and displace bound ThT, indicated by reduction of the

ThT ﬂuorescence, to varying degrees (Figures 3B and S4).

Interestingly, all compounds equipped with a nitro group

except 15d showed binding activity. The strongest binding was

observed for compounds with the nitro group situated in

position C-9 (15b, 15c, 16a, and 16b). Moving the nitro group

to position C-8 (16e) or to the 4′ position of the C-13 aryl

group (15e,f) is accompanied by a decrease in ﬁbril binding

ability. Notably, the presence of the C-13 phenyl group

abolishes all binding activity rendered by the nitro group in

position C-8 (15d vs 16e) but not C-9 (15b vs 16a, Figure

S3). The cyclopropyl group appears to be the favored C-14

substituent, over methoxy and proton (15b vs 15c and 15k,

and 16a vs 16b). This observation is in agreement with the

SAR on scaﬀold 4, where cyclopropyl as R¹substituent was

found somewhat superior to phenyl, hydrogen, and methoxy

substituents.^3cTaken together, these observations ﬁt with the

hypothesis that binding sites on amyloid ﬁbrils are made up of

shallow hydrophobic clefts ﬂanked by polar groups, situated

between the rows of side chains and running parallel to the

ﬁber axis.^11a,c,e

Compounds were also evaluated against Aβ40 in a similar

manner (Figure 4 and Figures S5 −S7). Compounds 15b,c,

15f, and 16a, which bind strongly to α-synuclein ﬁbrils, were

found to bind mature Aβ ﬁbrils as well, indicated by reduced

ThT ﬂuorescence, compared to the control experiments.

In summary, we have developed methods to fuse two

privileged scaﬀolds, namely, chromenopyridines and thiazolino

2-pyridones. These new peptidomimetic polyheterocycles

constitute a new scaﬀold with potential for diverse substitution

patterns. The intramolecular Povarov reaction between O-

alkylated salicylaldehydes and amino functionalized thiazolino-

2-pyridones aﬀorded chromenopyridine fused 2-pyridone

polyheterocycles in moderate to excellent yields. Rewardingly,

Scheme 3. Synthesis of C-13 Unsubstituted Compounds

13a−e

a

The benzoate functionality was eliminated during oxidation to

provide the desired products.

alkene component now armed with an ester group, capable of

mesomeric contributions, we attempted Povarov reactions

between 14a−d and 9a,b. Still, heating the reaction mixtures to

70 °C was required to achieve reasonable reaction times.

The desired compounds 13a−e were isolated in low to

moderate yields after 24 h of heating, followed by oxidation

with DDQ at room temperature. The unusually low yield of

13e results from the formation of side products, which

complicated the puriﬁcation. The low to moderate yields

motivated us to try a slightly diﬀerent approach, using CuBr₂

catalysis and O-propargyl salicylaldehyde (Scheme S4).^7b,c,f,9a

Unfortunately, the method suﬀered from undesired side

reactions and 13a was only isolated in 31% yield.

Having both sets of compounds in hand, we hydrolyzed the

methyl ester to deprotect the carboxylic acid and reveal the

peptidomimetic (Scheme 4). The limited solubility of 16a−e

C

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Figure 2. (A) Representative selection of ThT ﬂuorescence traces. Each experiment was performed in triplicate (Figure S1) and normalized to the

average. Compounds 15b and 16a appear to bind ﬁbrils strongly, whereas 15a does not seem to bind to any signiﬁcant extent. 15e and 16b are

borderline. (B) TEM picture of ﬁbrils formed in the presence of compound 16a (green trace).

Figure 3. (A) ThT trace for compound 16a added after 70 h (green), α-Syn control (black), and ThT background ﬂuorescence (gray). (B)

Retained ThT ﬂuorescence 5 h after addition of compounds 15a−c, 15e,f, 15k, 16a−c, and 16e to mature α-synuclein ﬁbrils, compared to the

ﬂuorescence intensity 1 h before addition. For comparison, 15a and 16c were also included.

Figure 4. Retained ThT ﬂuorescence after addition of selected compounds to mature Aβ40 ﬁbrils in vitro. (A) ThT ﬂuorescence trace for addition

of compound 15b (magenta), α-Syn control (black), and ThT background ﬂuorescence (gray). (B) Bar chart representation of the retained

ﬂuorescence (60 h), compared to the intensity before compound addition (40 h).

biological evaluation of chromenopyridine fused thiazolino 2-

pyridones revealed compounds capable of binding to α-

synuclein and Aβ40 amyloid ﬁbrils in vitro. An interesting SAR

was observed with respect to groups at position C-9. The

polyheterocycles equipped with a nitro group at position C-9

showed the strongest binding to α-synuclein and Aβ40

amyloid ﬁbrils. However, changing the position of the nitro

group resulted in decreased binding ability versus both amyloid

ﬁbrils. As binding to mature amyloid ﬁbrils is a property of

pharmacological relevance,¹¹we intend to investigate these

promising compounds further in future biological studies.

EXPERIMENTAL SECTION

■

General. Unless otherwise stated, purchased reactants and

reagents were used as received from commercial suppliers. Molecular

sieves and LiCl were dried at 300 °C under high vacuum for 4 h prior

to use. Acetonitrile was dried over activated 3 Å molecular sieves (5%

w/v) for 48 h, then transferred via syringe to new 3 Å molecular sieves

(5% w/v) for storage until use. DMF, THF, and diethyl ether were

dried using an SG Water solvent drying tower according to the

manufacturer’s instructions and stored over activated 3 Å (DMF) or 4

Å (THF and diethyl ether) MS for 48 h or more before use.

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. Microwave reactions were performed in

D

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sealed vessels using a Biotage Initiator microwave synthesizer,

temperatures were monitored by an internal IR probe, and stirring

was mediated magnetically. TLC was performed on purchased

aluminum 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

prepacked silica gel cartridges (Biotage SNAP Cartridge, KP-Sil).

Preparative HPLC was performed on a Gilson instrument with a

Phenomenex column (250 × 21.2 mm; Gemini 5 μm NX-C18, 110

Å). MeCN/water, with 0.75% HCOOH in the mobile phase. 30−

100% MeCN in water over 30 min with a ﬂow rate of 20 mL/min.

The elution was monitored with UV-abs. at 254 nm. Freeze-drying

was accomplished by freezing the diluted MeCN/water solutions in

liquid nitrogen and then employing a Scanvac CoolSafe freeze-dryer

connected to an Edwards 28 rotary vane oil pump. Optical rotation

was measured with a Rudolph Autopol IV polarimeter 343 at 22 °C

and 589 nm. [α] is reported in deg·mL·g⁻¹·dm⁻¹; concentrations (c)

are given in g/100 mL. IR spectra were recorded on a Bruker Alpha-t

spectrometer. The samples were prepared as KBr pellets or between

CDCl₃): δ 10.60 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.89

(d, J = 8.4 Hz, 1H), 7.44 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H),

7.31 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 15.9 Hz, 1H), 6.43 (dt, J = 15.9,

6.0 Hz, 1H), 4.95 (d, J = 5.9 Hz, 2H). ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 188.4, 161.0, 152.3, 135.8, 135.3, 129.8, 129.0, 128.9,

128.7, 126.9, 122.0, 115.9, 108.5, 70.2. HRMS (ESI-TOF) m/z: [M −

−

H]⁻Calcd for C₁₆H₁₂NO₄282.0772; Found 282.0774.

2-(Cinnamyloxy)-5-nitrobenzaldehyde (10c). The compound was

prepared by following the general procedure. The reaction mixture

was stirred for 2.75 h. Light yellow solid (446 mg; 87.7%). IR (KBr):

ν 3075, 2908, 1688, 1610, 1588, 1516, 1487, 1450, 1429, 1391, 1340,

1274, 1177, 1157, 1141, 1078, 1063 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃): δ 10.53 (s, 1H), 8.73 (d, J = 2.9 Hz, 1H), 8.43 (dd, J = 9.2,

2.9 Hz, 1H), 7.48−7.41 (m, 2H), 7.41−7.28 (m, 3H), 7.18 (d, J = 9.2

Hz, 1H), 6.85−6.76 (m, 1H), 6.42 (dt, J = 15.9, 6.0 Hz, 1H), 4.97

(dd, J = 6.0, 1.5 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

187.6, 164.8, 141.8, 135.7, 135.3, 130.7, 129.0, 128.9, 126.9, 125.0,

124.9, 121.8, 113.5, 70.4. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd

−

for C₁₆H₁₂NO₄282.0772; Found 282.0767.

2-(Cinnamyloxy)-5-ﬂuorobenzaldehyde (10d). The compound

was prepared by following the general procedure starting from 5-

ﬂuoro-2-hydroxybenzaldehyde (251 mg, 1.79 mmol). The reaction

was stirred for 4.5 h, and the product was puriﬁed with automated

ﬂash column chromatography (50 g cartridge, 3−20% EtOAc in n-

heptane) as white solid in 84% yield (388 mg, 1.51 mmol). IR (KBr):

ν 3415, 3339, 3065, 3030, 2940, 2868, 2054, 1976, 1883, 1780, 1679,

NaCl plates; absorbances are given in reciprocal cm. ¹H, ¹³C, and ¹⁹

F

NMR spectra were recorded on a Bruker Avance III 400 MHz

spectrometer with a BBO-F/H Smartprobe or a Bruker Avance III

HD 600 MHz spectrometer with a CP BBO-H/F, 5 mm cryoprobe, at

298 K, unless another temperature is given. All spectrometers were

operated by Topspin 3.5. Resonances are given in ppm relative to

TMS, and calibrated to solvent residual signals [CDCl₃: δ_H= 7.26

ppm; δ_C= 77.16 ppm. (CD₃)₂SO: δ_H= 2.50 ppm; δ_C= 39.51 ppm.

(CD₃)CO δ_H= 2.05 ppm; δ_C= 29.84 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 with ES⁺and ES⁻ionization. HRMS was performed

on a mass spectrometer with ESI-TOF (ES⁺/ES⁻). Human wild-type

α-synuclein was expressed and puriﬁed as described previously,^3c

expressed and puriﬁed Aβ40 was supplied by Alexotech AB.

1

1610, 1580, 1485, 1461 cm⁻¹. H NMR (400 MHz, CDCl₃) δ 10.54

(d, J = 3.1 Hz, 1H), 7.56 (dd, J = 8.3, 3.3 Hz, 1H), 7.47−7.41 (m,

2H), 7.41−7.34 (m, 2H), 7.34−7.24 (m, 3H), 7.04 (dd, J = 9.1, 3.9

Hz, 1H), 6.78 (dd, J = 16.0, 1.6 Hz, 1H), 6.43 (dt, J = 16.0, 5.8 Hz,

1H), 4.84 (dd, J = 5.8, 1.5 Hz, 2H). ¹³C{¹H} NMR (100 MHz,

CDCl₃) δ 188.7, 188.6, 135.9, 133.8, 128.7, 128.2, 126.6, 126.0, 125.9,

123.1, 122.5, 122.3, 114.7, 114.6, 114.2, 114.0, 77.3, 77.0, 76.7, 69.9.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −122.14. HRMS (ESI-TOF) m/

−

z: [M − H]⁻Calcd for C₁₆H₁₂FO₂255.0827; Found 255.0819.

(E)-4-Nitro-2-((3-(4-nitrophenyl)allyl)oxy)benzaldehyde (10e).

The compound was prepared by following the general procedure

but with 1.8 equiv of alkyl bromide. The reaction mixture was stirred

overnight. During workup, the precipitate was dissolved in DCM

instead of EtOAc. The crude product was puriﬁed with ﬂash column

chromatography (30 × 70 mm silica gel, DCM). Light yellow solid

(431 mg, 73.1%). IR (KBr): ν 3113, 1692, 1596, 1526, 1511, 1391,

1345, 1309, 1248, 1183, 1109 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ

10.61 (d, J = 0.7 Hz, 1H), 8.23 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3

Hz, 1H), 7.92 (dt, J = 11.4, 1.5 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H),

6.91 (d, J = 16.1 Hz, 1H), 6.61 (dt, J = 16.0, 5.5 Hz, 1H), 5.00 (dd, J

= 5.5, 1.6 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 188.1,

160.6, 152.3, 147.7, 142.1, 132.2, 130.1, 129.0, 127.5, 126.9, 124.3,

116.3, 108.3, 69.4. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for

General Procedure for Synthesis of O-Alkylated Salicylal-

dehydes 10a−i. Salicylaldehydes were O-alkylated according to

established procedures with modiﬁcations.¹⁷Under an atmosphere of

nitrogen, cinnamyl bromide II (2.34 mmol, 1.30 equiv) was dissolved

in DMF (1.0 mL) and transferred with a syringe to a mixture of

salicylaldehyde I (1.80 mmol, 1.00 equiv) and K₂CO₃(496 mg, 2.00

equiv) under nitrogen. The reaction mixture was stirred at r.t. until

completion was indicated by TLC analysis. The mixture was then

transferred to a beaker of ice-cold water (60 mL) while stirring; the

resulting precipitate was ﬁltered oﬀ and washed with water (5 mL).

The precipitate was then dissolved in EtOAc (50 mL) and washed

with brine (5 × 25 mL), dried with sodium sulfate, ﬁltered, and

evaporated. Unless otherwise stated, the compounds were used in the

following synthetic step without further puriﬁcation.

−

C₁₆H₁₁N₂O₆327.0622; Found 327.0622.

(E)-2-((3-(4-Nitrophenyl)allyl)oxy)benzaldehyde (10f). The com-

pound was prepared by following the general procedure but with 1.8

equiv of crude alkyl bromide. The reaction mixture was stirred

overnight. The crude product was puriﬁed with automated ﬂash

column chromatography (25 g cartridge, 8−25% EtOAc in heptane.

Oﬀ white solid (311 mg, 61.1%). IR (KBr): ν 3106, 3078, 2869, 1688,

1597, 1513, 1484, 1458, 1450, 1340, 1284, 1251, 1235, 1189, 1165,

1105, 1072, 1041, 1002 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 10.58

(d, J = 0.7 Hz, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.88 (dd, J = 7.7, 1.8 Hz,

1H), 7.62−7.51 (m, 3H), 7.12−6.99 (m, 2H), 6.86 (d, J = 16.1 Hz,

1H), 6.61 (dt, J = 16.1, 5.2 Hz, 1H), 4.89 (dd, J = 5.2, 1.7 Hz, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 189.6, 160.7, 147.4, 142.7,

2-(Cinnamyloxy)benzaldehyde (10a). The compound was pre-

pared by following the general procedure. The mixture was stirred for

6.5 h. The crude product was puriﬁed with automated ﬂash column

chromatography (25 g cartridge, 10−20% EtOAc in heptane). White,

low melting solid (373 mg, 87.2%). IR (KBR): ν 3028, 2862, 1684,

1598, 1580, 1481, 1455, 1375, 1286, 1236 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃): δ 10.58 (s, 1H), 7.86 (dd, J = 7.9, 1.8 Hz, 1H), 7.55 (td, J =

8.0, 1.8 Hz, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H),

7.31−7.27 (m, 1H), 7.05 (dt, J = 7.5, 3.2 Hz, 2H), 6.77 (d, J = 16.0

Hz, 1H), 6.43 (dt, J = 16.0, 5.7 Hz, 1H), 4.84 (dd, J = 5.7, 1.4 Hz,

2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 189.9, 161.1, 136.2, 136.0,

133.7, 128.8, 128.7, 128.3, 126.8, 125.3, 123.6, 121.1, 113.1, 69.3.

136.1, 130.8, 129.0, 128.6, 127.3, 125.3, 124.3, 121.5, 112.9, 68.5.

HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₁₆H₁₂NO₄⁻282.0772;

Found 282.0767.

−

HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₁₆H₁₃O₂237.0921;

Found 237.0917.

2-(Cinnamyloxy)-4-nitrobenzaldehyde (10b). The compound was

prepared by following the general procedure. The reaction mixture

was stirred for 5 h. Light yellow solid (425 mg, 83.6%). IR (KBr): ν

3116, 3042, 2903, 2864, 1693, 1612, 1592, 1527, 1480, 1428, 1408,

1386, 1347, 1301, 1208, 1182, 971 cm⁻¹. ¹H NMR (400 MHz,

(E)-2-((3-(3-(Triﬂuoromethyl)phenyl)allyl)oxy)benzaldehyde

(10g). The compound was prepared by following the general

procedure but with 1.8 equiv of crude alkyl bromide. The reaction

mixture was stirred overnight. The crude product was puriﬁed with

automated ﬂash column chromatography (50 g cartridge, 3−10%

E

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Note

1

EtOAc in heptane). White, low melting solid (434 mg, 78.8%). IR

(KBr): ν 3071, 2936, 2878, 2770, 1682, 1598, 1484, 1459, 1441,

1404, 1378, 1322, 1306, 1287, 1243, 1201, 1164, 1122, 1075, 1041,

yield was calculated from the H NMR spectrum recorded in d6-

DMSO.

Methyl (R)-8-Cyclopropyl-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11a). The compound was prepared by following the

general procedure. The reaction was ﬁnished by TLC analysis after

9.5 h. DDQ was added, and the mixture was stirred for 25 min. The

crude product was puriﬁed with automated ﬂash column chromatog-

raphy (25 g cartridge, 25−75% EtOAc in heptane). Yellow-orange

solid (185 mg, 93%). The compound contained chloroform; yield

1

1007 cm⁻¹. H NMR (400 MHz, CDCl₃): δ 10.58 (d, J = 0.8 Hz,

1H), 7.87 (dd, J = 7.7, 1.9 Hz, 1H), 7.66 (s, 1H), 7.62−7.50 (m, 3H),

7.47 (t, J = 7.7 Hz, 1H), 7.10−7.00 (m, 2H), 6.81 (d, J = 16.1 Hz,

1H), 6.51 (dt, J = 15.9, 5.4 Hz, 1H), 4.86 (dd, J = 5.5, 1.6 Hz, 2H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 189.8, 160.9, 137.1, 136.1,

131.9, 131.3 (q, J = 32.2 Hz), 129.9 (d, J = 1.5 Hz), 129.3, 128.8,

125.7, 125.3, 124.8 (q, J = 3.8 Hz), 124.2 (q. J = 272.4 Hz), 123.4 (q,

J = 3.8 Hz), 121.3, 113.0, 68.8. ¹⁹F NMR (376 MHz, CDCl₃): δ

1

calculated from H NMR sample in (CD₃)₂SO. [α]_D−226° (c 0.35,

−

−62.79. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₁₇H₁₂F₃O₂

305.0795; Found 305.0782.

CHCl₃). IR (KBr): ν 3451, 1001, 2950, 1753, 1666, 1579, 1461,

1436, 1382, 1300, 1258, 1220, 1183, cm⁻¹. H NMR (400 MHz,

1

CDCl₃): δ 8.51 (dd, J = 7.8, 1.7 Hz, 1H), 7.43 (dq, J = 4.7, 3.2, 2.5

Hz, 3H), 7.37−7.28 (m, 2H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 6.91 (dd,

J = 8.1, 1.1 Hz, 1H), 5.73 (dd, J = 8.2, 2.6 Hz, 1H), 5.12−4.98 (m,

2H), 3.81 (s, 3H), 3.69 (dd, J = 11.6, 8.2 Hz, 1H), 3.50 (dd, J = 11.6,

2.6 Hz, 1H), 1.01−0.89 (m, 1H), 0.34−0.11 (m, 4H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 168.8, 159.6, 156.4, 146.9, 143.5, 142.3, 140.8,

137.5, 133.6, 131.8, 130.0, 129.9, 129.5, 128.4, 128.0, 126.5, 123.0,

122.7, 116.6, 109.5, 66.6, 63.5, 53.5, 31.6, 15.7, 11.6, 11.6. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₂₈H₂₃N₂O₄S⁺483.1373;

Found 483.1379.

(E)-2-((3-(3-Methoxyphenyl)allyl)oxy)benzaldehyde (10h). The

compound was prepared by following the general procedure but

with 1.8 equiv of crude alkyl bromide. The reaction mixture was

stirred overnight. The crude product was puriﬁed with automated

ﬂash column chromatography (50 g cartridge, 5−20% diethyl ether in

heptane). The fractions containing the pure desired product were

combined and evaporated. The residue was then co-evaporated with

chloroform twice. White, low melting solid (446 mg, 93%) calculated

from 494 mg containing chloroform. IR (KBr): ν 3003, 2967, 2876,

2839, 1683, 1600, 1575, 1484, 1464, 1435, 1375, 1308, 1290, 1244,

1

1155, 1048, 1002, 972 cm⁻¹. H NMR (400 MHz, CDCl₃): δ 10.57

Methyl 8-Cyclopropyl-3-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11b). The compound was prepared by following the

general procedure. Upon addition of boron triﬂuoride, the stirred

solution turned dark purple and a precipitate emerged within a few

minutes. The resulting suspension thickened so that the stirring was

compromised. The tube was shaken manually with regular intervals

for 20 min until the suspension was lighter and the magnetic stirring

could be continued. The precipitate eventually dissolved completely,

and the reaction was then followed with TLC until complete

consumption of 9a was indicated, after 2 h reaction time. DDQ (197

mg, 2.17 equiv) was added and stirred for 50 min. The residue was

puriﬁed with automated ﬂash column chromatography (25 g SNAP

Cartridge, 20−65% EtOAc in heptane). Yellow solid (181 mg, 85.8%)

The compound contained chloroform; yield calculated from ¹H NMR

sample in (CD₃)₂SO. 11b (746 mg, 88.4%) was also prepared at 1.6

mmol scale, according to the general procedure. The reaction was

complete after 3 h. [α]_D−228° (c 0.289, CHCl₃); IR (KBr): ν 3452,

1752, 1668, 1573, 1526, 1433, 1342, 1227 cm⁻¹; ¹H NMR (400 MHz,

CDCl₃): δ 8.65 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.6, 2.2 Hz, 1H),

7.76 (d, J = 2.2 Hz, 1H), 7.49−7.42 (m, 3H), 7.36−7.30 (m, 1H),

7.24−7.29 (m, 1H), 5.74 (dd, J = 8.3, 2.7 Hz, 1H), 5.22−5.07 (m,

2H), 3.83 (s, 3H), 3.71 (dd, J = 11.7, 8.3 Hz, 1H), 3.52 (dd, J = 11.6,

2.6 Hz, 1H), 1.03−0.90 (m, 1H), 0.36−0.23 (m, 2H), 0.23−0.14 (m,

1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 168.6, 159.4, 156.3, 149.7,

145.3, 144.5, 142.7, 141.2, 137.0, 134.6, 129.9, 129.8, 129.6, 128.74,

128.65, 128.2, 127.1, 117.5, 112.5, 109.4, 67.1, 63.6, 53.5, 31.6, 15.7,

11.68, 11.60. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₈H₂₂N₃O₆S⁺528.1224; Found 528.1229.

Methyl (R)-3-Nitro-13-oxo-7-phenyl-6, 10, 11, 13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11c). The compound was prepared by following the

general procedure. A precipitate emerged after 10 min stirring upon

addition of boron triﬂuoride. The magnetic stirring was compromised

as the mixture got viscous, and the tube was shaken manually for 10

min, until the viscosity had decreased to a point where magnetic

stirring was possible. The reaction was ﬁnished after 5.8 h. DDQ was

added, and the mixture was stirred for 10 min. The crude product was

dissolved in a larger volume of DCM and loaded onto a column (30 ×

80 mm silica gel, equilibrated with DCM) and puriﬁed with ﬂash

column chromatography (0−70% EtOAc in heptane). Yellow solid

(179 mg, 92%). The compound contained chloroform; yield was

calculated from ¹H NMR spectrum recorded in (CD₃)₂SO. [α]_D

−256° (c 0.55, CHCl₃). IR (KBr): ν 3443, 1754, 1680, 1595, 1535,

1514, 1451, 1432, 1342, 1322, 1222, 1179, 1041 cm⁻¹. ¹H NMR [400

MHz, (CD₃)₂SO]: δ 8.48 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 8.6, 2.3

Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.66−7.53 (m, 3H), 7.37 (ddt, J =

(d, J = 0.7 Hz, 1H), 7.86 (dd, J = 8.0, 1.9 Hz, 1H), 7.55 (ddd, J = 8.3,

7.4, 1.9 Hz, 1H), 7.30−7.21 (m, 1H), 7.09−6.98 (m, 3H), 6.95 (t, J =

2.1 Hz, 1H), 6.84 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.74 (d, J = 15.9 Hz,

1H), 6.42 (dt, J = 16.0, 5.7 Hz, 1H), 4.83 (dd, J = 5.7, 1.6 Hz, 2H),

3.83 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 189.9, 161.1,

160.0, 137.7, 136.0, 133.5, 129.8, 128.7, 125.3, 123.9, 121.1, 119.4,

114.0, 113.1, 112.1, 69.2, 55.4. HRMS (ESI-TOF) m/z: [M + Na]⁺

+

Calcd for C₁₆H₁₆NaO₃291.0997; Found 291.1003.

(E)-2-((3-(4-Ethoxyphenyl)allyl)oxy)benzaldehyde (10i). The

compound was prepared by following the general procedure but

with 1.8 equiv of crude alkyl bromide. The reaction mixture was

stirred overnight. Only about 50% conversion of salicylaldehyde was

indicated by TLC, but the alkyl bromide was consumed. The crude

product was puriﬁed with automated ﬂash column chromatography

(25 g cartridge, 5−20% diethyl ether in heptane). Oﬀ white solid (124

mg, 24.5%). IR (KBr): ν 2980, 2934, 2879, 1681, 1599, 1512, 1485,

1455, 1388, 1287, 1239, 1179, 1047, 978, cm⁻¹. ¹H NMR (400 MHz,

CDCl₃): δ 10.59 (s, 1H), 7.88 (dd, J = 8.0, 1.8 Hz, 1H), 7.60−7.52

(m, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.89 (d, J

= 8.7 Hz, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.31 (dt, J = 15.9, 5.9 Hz,

1H), 4.83 (dd, J = 6.0, 1.5 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 1.44 (t, J

= 7.0 Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.0, 161.3,

159.2, 136.0, 133.6, 128.8, 128.6, 128.0, 125.3, 121.1, 121.0, 114.8,

113.1, 69.6, 63.7, 15.0. HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd for

+

C₁₈H₁₈NaO₃305.1154; Found 305.1160.

General Procedure for Synthesis of C-13 Aryl Substituted

Povarov Reaction Products 11a−j. The 6-amino thizolo-2-

pyridone 9 (0.40 mmol, 1.00 equiv) and 2-(cinnamyloxy)-

benzaldehyde 10 (0.48 mmol, 1.20 equiv) were weighed up in a

Biotage Microwave reaction tube and dissolved in DCM (4 mL). 4 Å

MS (8−10 pellets) was added, followed by BF₃·OEt₂(10.8 μL; 0.100

equiv), whereupon the tube was sealed and left stirring at r.t. The

reaction was monitored with TLC until complete consumption of 1,

and the corresponding imine intermediate, was indicated. The tube

was then opened and DDQ (182 mg; 2.00 equiv) was added. The

reaction mixture was stirred until complete oxidation was visible by

TLC, then transferred to a separation funnel and diluted with DCM

(25 mL). The mixture was washed with saturated aqueous

bicarbonate solution (2 × 10 mL), followed by brine (10 mL). The

aq. phases were re-extracted once each with DCM (3 mL). The

organic phase was dried over sodium sulfate, ﬁltered, and evaporated

to dryness. The crude residue was redissolved in DCM and puriﬁed

with automated ﬂash column chromatography. The fractions

containing pure desired product were combined, evaporated, and

co-evaporated with distilled chloroform twice. The residue was put

under high vacuum for several hours before storage at −20 °C. The

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Note

13.3, 7.8, 1.7 Hz, 2H), 6.02 (s, 1H), 5.75 (dd, J = 8.7, 2.0 Hz, 1H),

5.20 (d, J = 3.4 Hz, 2H), 3.94 (dd, J = 11.9, 8.7 Hz, 1H), 3.75 (s, 3H),

3.66 (dd, J = 11.9, 2.0 Hz, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

168.4, 159.8, 156.4, 149.8, 145.2, 142.6, 142.3, 139.6, 133.9, 133.5,

129.5, 129.5, 129.4, 129.0, 128.8, 128.5, 128.5, 127.1, 117.5, 112.7,

96.1, 66.9, 63.0, 53.6, 32.4. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd

for C₂₅H₁₈N₃O₆S⁺488.0911; Found 488.0901.

11.9, 8.8 Hz, 1H), 3.76 (s, 3H), 3.66 (dd, J = 11.8, 2.0 Hz, 1H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO]: δ 168.6, 158.3, 155.9, 149.1,

147.9, 144.7, 143.5, 139.9, 139.6, 138.6, 133.1, 130.8, 130.6, 128.3,

128.1, 125.9, 124.3 (2C), 117.5, 112.3, 94.2, 79.2, 66.3, 62.5, 53.1,

31.5. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₂₅H₁₇N₄O₈S⁺

533.0762; Found 533.0748.

Methyl (R)-8-Cyclopropyl-2-ﬂuoro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11g). The compound was prepared by following the

general procedure starting from 9a (106 mg, 0.40 mmol). The

reaction was stirred for 4.5 h, and the product was puriﬁed with

automated ﬂash column chromatography (50 g cartridge, 10−70%

EtOAc in n-heptane) in 92% yield as a light-yellow powder (170 mg,

0.36 mmol). [α]_D−160° [c 0.33, (CD₃)₂SO]. IR (KBr): ν 3548,

3473, 3414, 3081, 3000, 2953, 2844, 2041, 1752, 1665, 1617, 1578,

1550, 1520, 1494, 1483, 1461, 1429 cm⁻¹. ¹H NMR [400 MHz,

(CH₃)₂SO] δ 7.66 (dd, J = 9.0, 3.2 Hz, 1H), 7.27 (ttd, J = 7.7, 5.6,

5.1, 3.0 Hz, 4H), 7.15 (dt, J = 5.6, 3.0 Hz, 1H), 7.05 (td, J = 8.6, 3.2

Hz, 1H), 6.84 (dd, J = 8.9, 4.5 Hz, 1H), 5.50 (dd, J = 8.8, 2.5 Hz,

1H), 4.99−4.75 (m, 2H), 3.65 (dd, J = 11.8, 8.8 Hz, 1H), 3.55 (s,

3H), 3.36 (dd, J = 11.9, 2.6 Hz, 1H), 0.72−0.61 (m, 1H), 0.10 to

−0.08 (m, 3H), −0.12 to −0.24 (m, 1H). ¹³C{¹H} NMR [100 MHz,

(CD₃)₂SO] δ 169.2, 158.5, 152.5, 145.9, 144.6, 142.4, 140.4, 137.0,

134.2, 130.3, 130.2, 129.4, 128.8, 128.3, 128.2, 119.1, 119.0, 108.0,

79.6, 66.63, 63.64, 53.4, 31.1, 15.7, 11.5, 11.4. ¹⁹F{¹H} NMR [376

MHz, (CD₃)₂SO] δ −120.83. HRMS (ESI-TOF) m/z: [M + H]⁺

Calcd for C₂₈H₂₂FN₂O₄S⁺501.1279; Found 501.1287.

Methyl (R)-8-Cyclopropyl-2-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11d). The compound was prepared by following the

general procedure. The reaction was ﬁnished after 6.6 h. DDQ was

added, and the mixture was stirred for 20 min. The crude product was

puriﬁed with automated ﬂash column chromatography (25 g

cartridge, 15−55% EtOAc in heptane). Yellow solid (148 mg,

70%). The compound contained chloroform; yield was calculated

from ¹H NMR spectrum recorded in (CD₃)₂SO. [α]_D−197° (c 0.29,

CHCl₃). IR (KBr): ν 3444, 3001, 2953, 1753, 1669, 1618, 1580,

1549, 1518, 1494, 1482, 1459, 1443, 1384, 1340, 1299, 1250, 1229,

1088, 1022 cm⁻¹; ¹H NMR [400 MHz, (CD₃)₂SO]: δ 8.99 (d, J = 2.9

Hz, 1H), 8.26 (dd, J = 9.0, 2.9 Hz, 1H), 7.55−7.44 (m, 3H), 7.36 (dt,

J = 5.4, 2.9 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 5.72 (dd, J = 8.8, 2.6

Hz, 1H), 5.39−5.14 (m, 2H), 3.86 (dd, J = 11.8, 8.8 Hz, 1H), 3.76 (s,

3H), 3.58 (dd, J = 11.8, 2.6 Hz, 1H), 0.87 (m, 1H), 0.32−-0.02 (m,

4H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 168.6, 160.8, 159.3, 145.0,

144.4, 143.4, 142.6, 141.2, 137.0, 134.4, 129.8, 129.7, 128.7, 128.4,

128.2, 126.8, 123.3, 122.4, 117.6, 109.2, 67.3, 63.5, 53.5, 31.6, 15.7,

11.7, 11.6. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₈H₂₂N₃O₆S⁺528.1224; Found 528.1216.

Methyl (R)-8-Cyclopropyl-13-oxo-7-(3-(triﬂuoromethyl)phenyl)-

6,10,11,13-tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]-

naphthyridine-11-carboxylate (11h). The compound was prepared

by following the general procedure, but the mixture was heated in an

oil bath at 70 °C for 8 h. DDQ was added, and the mixture was stirred

at room temperature for 10 min. The crude product was puriﬁed with

automated ﬂash column chromatography (25 g cartridge, 20−65%

EtOAc in heptane). Yellow solid (163 mg, 74%). The compound

Methyl (R)-8-Cyclopropyl-7-(4-nitrophenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11e). The compound was prepared by following the

general procedure, but the mixture was heated in an oil bath at 70 °C

for 23 h. DDQ was added, and the mixture was stirred at room

temperature for 15 min. The crude product was puriﬁed with

automated ﬂash column chromatography (25 g cartridge, 15−60%

EtOAc in heptane). Yellow solid (114 mg, 54%). The compound

1

contained chloroform; yield was calculated from H NMR spectrum

1

contained chloroform; yield was calculated from H NMR spectrum

recorded in (CD₃)₂SO. [α]_D−165° (c 0.37, CHCl₃). IR (KBr): ν

3552, 3475, 3414, 3236, 3002, 2955, 1753, 1668, 1611, 1580, 1553,

1518, 1489, 1464, 1437, 1382, 1329, 1296, 1257, 1221, 1178, 1168,

recorded in (CD₃)₂SO. [α]_D−163° (c 0.21, CHCl₃). IR (KBr): ν

2999, 2953, 2848, 1752, 1667, 1579, 1552, 1519, 1491, 1462, 1438,

1381, 1347, 1299, 1258, 1220, 1179, 1149, 1107, 1070, 1035, 1005

1

1126, 1108, 1073, 1046 cm⁻¹. H NMR [400 MHz, (CD₃)₂SO]: δ

1

cm⁻¹. H NMR [400 MHz, (CD₃)₂SO]: δ 8.33 (dt, J = 6.4, 2.3 Hz,

8.21 (dd, J = 7.8, 1.7 Hz, 1H), 7.96−7.64 (m, 4H), 7.40 (td, J = 7.7,

1.7 Hz, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H),

5.71 (d, J = 8.7 Hz, 1H), 5.20−4.89 (m, 2H), 3.86 (ddd, J = 11.9, 8.7,

6.4 Hz, 1H), 3.75 (s, 3H), 3.57 (ddd, J = 11.8, 4.0, 2.6 Hz, 1H), 0.77

(m, 1H), 0.39 to −0.16 (m, 4H). ¹³C{¹H} NMR [100 MHz,

(CD₃)₂SO, 343 K]: δ 168.4 (d, J = 3.3 Hz), 157.8, 155.5, 145.1,

144.8, 139.9, 139.7, 137.6, 133.6 (d, J = 10.1 Hz), 132.9 (d, J = 6.0

Hz), 131.4, 128.7 (d, J = 7.5 Hz), 128.6 (d, J = 2.7 Hz), 126.26−

125.97 (m), 124.6, 124.6 (d, J = 4.0 Hz), 122.1 (d, J = 7.4 Hz), 116.4,

106.7 (d, J = 7.2 Hz), 78.8, 65.6, 63.0 (d, J = 4.7 Hz), 52.5, 30.3 (d, J

= 4.2 Hz), 14.9 (d, J = 5.7 Hz), 11.0, 10.9. The multiplets in the¹³C

NMR spectrum are caused by atropoisomers. ¹⁹F NMR (376 MHz,

CDCl₃) δ −62.68. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₉H₂₂F₃N₂O₄S⁺551.1247; Found 551.1249.

Methyl (R)-8-Cyclopropyl-7-(3-methoxyphenyl)-13-oxo-

6,10,11,13-tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]-

naphthyridine-11-carboxylate (11i). The compound was prepared

by following the general procedure. The reaction was ﬁnished after 5.5

h. DDQ was added, and the mixture was stirred for 10 min. The crude

product was puriﬁed with automated ﬂash column chromatography

(25 g cartridge, 20−70% EtOAc in heptane). Yellow solid (172 mg,

83.7%). The compound contained chloroform; yield was calculated

from ¹H NMR spectrum recorded in (CD₃)₂SO. [α]_D−160° (c 0.31,

CHCl₃). IR (KBr): ν 3442, 3000, 2953, 2837, 1753, 1667, 1606,

1579, 1552, 1517, 1489, 1463, 1436, 1381, 1371, 1298, 1284, 1260,

1217, 1180, 1149, 1107, 1071, 1035 cm⁻¹. ¹H NMR [400 MHz,

(CD₃)₂SO, 343 K]: δ 8.23 (dd, J = 7.8, 1.7 Hz, 1H), 7.45−7.33 (m,

2H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 7.07−6.94 (m, 3H), 6.94−6.87

(m, 1H), 5.68 (dt, J = 8.7, 3.1 Hz, 1H), 5.19−4.95 (m, 2H), 3.89−

3.79 (m, 4H), 3.76 (s, 3H), 3.54 (dd, J = 11.8, 2.8 Hz, 1H), 1.02−

2H), 8.21 (dd, J = 7.7, 1.7 Hz, 1H), 7.79 (dd, J = 8.7, 2.0 Hz, 1H),

7.69 (dd, J = 8.7, 2.0 Hz, 1H), 7.41 (td, J = 7.7, 1.7 Hz, 1H), 7.20 (td,

J = 7.5, 1.1 Hz, 1H), 7.00 (dd, J = 8.2, 1.1 Hz, 1H), 5.73 (dd, J = 8.7,

2.5 Hz, 1H), 5.20−4.97 (m, 2H), 3.86 (dd, J = 11.9, 8.8 Hz, 1H), 3.76

(s, 3H), 3.58 (dd, J = 11.9, 2.6 Hz, 1H), 0.92−0.80 (m, 1H), 0.34−

0.17 (m, 3H), 0.07 (q, J = 7.2, 6.1 Hz, 1H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 168.6, 159.3, 156.3, 147.8, 147.1, 145.0, 144.4,

141.0, 139.3, 133.2, 132.1, 131.1, 131.1, 128.9, 126.5, 123.3, 122.9,

122.7, 116.7, 108.3, 66.2, 63.6, 53.5, 31.6, 16.0, 12.3, 12.2. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₂₈H₂₂N₃O₆S⁺528.1224;

Found 528.1228.

Methyl (R)-3-Nitro-7-(4-nitrophenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11f). The compound was prepared by following the

general procedure. A red precipitate emerged upon addition of boron

triﬂuoride. The mixture got thick, so the tube was sonicated in an

ultrasonic water bath at room temperature for 5 min, then shaken

manually with regular intervals during several hours, until the viscosity

had decreased to a point where magnetic stirring was no longer

compromised. The reaction was ﬁnished after 24.5 h. DDQ was

added, and the mixture was stirred for 10 min. The crude product was

puriﬁed with ﬂash column chromatography (80 × 30 mm SiO₂, 0−

17% EtOAc in DCM. Orange solid (167 mg, 78.5%). The compound

1

contained chloroform; yield was calculated from H NMR spectrum

recorded in (CD₃)₂SO. [α]_D−239° (c 0.28, CHCl₃). IR (KBr): ν

1

3447, 1756, 1670, 1595, 1532, 1433, 1348, 1227, 1042 cm⁻¹. H

NMR [400 MHz, (CD₃)₂SO]: δ 8.51−8.40 (m, 3H), 8.07 (dd, J =

8.7, 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.75−7.66 (m, 2H), 6.06

(s, 1H), 5.79−5.72 (m, 1H), 5.22 (d, J = 1.6 Hz, 2H), 3.94 (dd, J =

G

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Note

0.93 (m, 1H), 0.30 (m, 3H), 0.21−0.09 (m, 1H). ¹³C{¹H} NMR [100

MHz, (CD₃)₂SO, 343 K]: 168.4, 158.4 (d, J = 7.5 Hz), 157.9, 155.6,

144.8, 144.3, 141.4, 139.9, 137.8, 133.0, 131.3, 128.7 (d, J = 7.9 Hz),

128.5, 124.6, 122.3, 122.0, 121.9, 116.4, 115.4 (d, J = 13.4 Hz), 113.6,

107.3, 78.8, 65.8, 62.9, 55.1, 52.5, 30.3, 14.7, 10.83−10.45 (m). The

multiplets in the¹³C NMR spectrum are caused by atropoisomers. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₂₉H₂₅N₂O₅S⁺513.1479;

Found 513.1476.

General Procedure for Synthesis of Povarov Reaction

Products 13a−e. The 6-amino thizolo-2-pyridone 9 (0.40 mmol,

1.00 equiv) and O-(propenyl benzoate)-salicylaldehyde 14 (0.48

mmol, 2.00 equiv) were weighed up in a Biotage Microwave reaction

tube and dissolved in DCM (4 mL). 4 Å MS (8−10 pellets) was

added, followed by BF₃·OEt₂(10.8 μL; 0.10 equiv), whereupon the

tube was sealed and left stirring in an oil bath at 70 °C. The reaction

was monitored with TLC until complete consumption of 9 was

indicated. The tube was then cooled down to r.t., opened, and DDQ

(182 mg; 2.00 equiv) was added. The reaction mixture was stirred for

5 min; complete oxidation was indicated by TLC. Then it was

transferred to a separation funnel and diluted with DCM (25 mL).

The mixture was washed with saturated aqueous bicarbonate solution

(2 × 10 mL), followed by brine (10 mL). The aq. phases were re-

extracted once each with DCM (3 mL). The organic phase was dried

over sodium sulfate, ﬁltered, and evaporated to dryness. The crude

residue was redissolved in DCM and puriﬁed with automated ﬂash

column chromatography. The fractions containing pure desired

product were combined, evaporated, and co-evaporated with distilled

chloroform twice. The residue was put under high vacuum for several

Methyl (R)-8-Cyclopropyl-7-(4-ethoxyphenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11j). The compound was prepared by following the

general procedure. The reaction was ﬁnished after 70 min. DDQ was

added, and the mixture was stirred for 10 min. The crude product was

puriﬁed with automated ﬂash column chromatography (25 g

cartridge, 20−60% EtOAc in heptane). The column was colored

orange as the desired product eluted; we are hence suspecting that the

compound binds to or breaks down on silica gel. Yellow solid (112

mg, 53.0%). The compound contained chloroform; yield was

calculated from ¹H NMR spectrum recorded in (CD₃)₂SO. [α]_D

−188° (c 0.32, CHCl₃). IR (KBr): ν 3443, 2979, 1753, 1666, 1607,

1581, 1507, 1437, 1381, 1245, 1176, 1108, 1044 cm⁻¹. ¹H NMR [400

MHz, (CD₃)₂SO]: δ 8.19 (dd, J = 7.8, 1.7 Hz, 1H), 7.43−7.30 (m,

2H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.18 (td, J = 7.5, 1.1 Hz, 1H),

7.05−6.95 (m, 3H), 5.69 (dd, J = 8.7, 2.5 Hz, 1H), 5.22−5.00 (m,

2H), 4.09 (d, J = 7.0 Hz, 2H), 3.85 (dd, J = 11.8, 8.7 Hz, 1H), 3.75 (s,

3H), 3.56 (dd, J = 11.8, 2.6 Hz, 1H), 1.37 (t, J = 6.9 Hz, 3H), 0.98−

0.84 (m, 1H), 0.40−0.26 (m,1H), 0.26−0.03 (m, 3H). ¹³C{¹H}

NMR [100 MHz, (CD₃)₂SO]: δ 168.8, 158.4, 158.3, 155.8, 145.1,

144.6, 141.8, 140.0, 133.6, 131.7, 131.1, 129.1, 128.7, 125.0, 122.8,

122.5, 116.8, 113.7, 113.5, 107.8, 79.2, 66.0, 63.1, 52.9, 30.6, 15.1,

14.6, 10.9, 10.9. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₃₀H₂₇N₂O₅S⁺527.1635; Found 527.1632.

1

hours before storage at −20 °C. The yield was calculated from H

NMR spectrum recorded in d6-DMSO.

Methyl 8-Cyclopropyl-3-nitro-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (13a). The compound was prepared by following the

general procedure starting from 9a (106 mg, 0.40 mmol). The

reaction mixture was stirred for 24 h, and the product was puriﬁed on

automated ﬂash column chromatography (50 g cartridge, 10−75%

EtOAc in n-heptane) in 37% yield (66 mg, 0.146 mmol), isolated as a

light yellow solid. [α]_D−235° (c 0.264, CHCl₃); IR (KBr): ν 3086,

6005, 2955, 2924, 2852, 1754, 1670, 1577, 1531, 1460, 1343, 1237,

1032, 918, 805, 738 cm⁻¹; ¹H NMR (600 MHz, CDCl₃): δ 8.64 (d, J

= 8.6 Hz, 1H), 8.09 (s, 1H), 7.96−7.91 (m, 1H), 7.84−7.80 (m, 1H),

5.77 (dd, J = 8.2, 1.8 Hz, 1H), 5.45 (s, 2H), 3.80 (s, 3H), 3.76 (dd, J

= 11.5, 8.4 Hz, 1H), 3.58 (d, J = 11.6 Hz, 1H), 1.79−1.73 (m, 1H),

1.15−1.04 (m, 2H), 0.76−0.68 (m, 2H). ¹³C{¹H} NMR (151 MHz,

CDCl₃): δ 168.6, 159.5, 156.6, 149.7, 144.9, 143.3, 140.2, 135.9,

130.4, 128.2, 127.3, 126.8, 117.5, 112.9, 108.1, 68.6, 63.1, 53.5, 31.8,

10.1, 7.7, 7.6. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₂H₁₈N₃O₆S⁺452.0911; Found 452.0911.

(R)-Methyl 8-Methoxy-3-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (11k). The compound was prepared by following the

general procedure. The reaction was ﬁnished after 2 h. DDQ was

added, and the mixture was stirred for 10 min. The crude product was

puriﬁed with automated ﬂash column chromatography (25 g

cartridge, 0−100% EtOAc in heptane). Yellow solid (155 mg,

25

73%). [α]_D−241 (c 0.4, CHCl₃). IR (KBr): ν 3468, 3000, 1742,

Methyl (R)-3-Nitro-13-oxo-6,10,11,13-tetrahydrochromeno[4,3-

b]thiazolo[2,3-g][1,7]naphthyridine-11-carboxylate (13b). The

compound was prepared by following the general procedure starting

from 9a (106 mg, 0.40 mmol). The reaction mixture was stirred for

24 h, and the product was puriﬁed on automated ﬂash column

chromatography (50 g cartridge, 10−50% EtOAc in n-heptane) in

54% yield (89 mg, 0.216 mmol) as a yellow powder. [α]_D−216° [c

0.16, (CH₃)₂SO]. IR (KBr): ν 3548, 3415, 3083, 3006, 2955, 2851,

1749, 1672, 1605, 1589, 1533, 1514, 1457, 1433 cm⁻¹. ¹H NMR [400

MHz, (CD₃)₂SO] δ 8.38 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.6, 2.3

Hz, 1H), 7.87 (d, J = 1.1 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 6.71 (s,

1H), 5.73 (dd, J = 8.7, 2.0 Hz, 1H), 5.54 (s, 2H), 3.98 (dd, J = 11.8,

8.7 Hz, 1H), 3.75 (s, 3H), 3.69 (dd, J = 11.9, 2.0 Hz, 2H). ¹³C{¹H}

NMR [100 MHz, (CD₃)₂SO] δ 169.1, 156.6, 149.4, 144.0, 138.9,

135.2, 131.5, 130.1, 117.8, 112.8, 97.2, 68.0, 62.9, 53.5, 32.0. HRMS

(ESI-TOF) m/z: [M + Na]⁺Calcd for C₁₉H₁₃N₃NaO₆S⁺434.0423;

Found 434.0428.

1667, 1592, 1552, 1531, 1494, 1456, 1410, 1375, 1226, 922, 799, 740,

705 cm⁻¹. ¹H NMR (600 MHz, CDCl₃): δ 8.68 (d, J = 8.3 Hz, 1H),

7.94 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.52−7.43 (m,

3H), 7.28 (d, J = 6.5 Hz, 2H), 5.78 (d, J = 6.2 Hz, 1H), 5.03 (q, J =

15.0 Hz, 2H), 3.83 (s, 3H), 3.81−3.76 (m, 1H), 3.61 (d, J = 11.1 Hz,

1H), 2.98 (s, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 168.2, 158.4,

156.4, 149.8, 145.0, 140.9, 140.4, 135.8, 135.7, 132.5, 130.0, 129.9,

128.5, 128.2, 128.2, 128.2, 128.1, 127.1, 117.4, 112.6, 66.8, 63.4, 60.1,

53.6, 32.0. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₆H₂₀N₃O₇S⁺518.1016; Found 518.1016.

2-(Allyloxy)-4-nitrobenzaldehyde (12). Under an atmosphere of

nitrogen, 2-hydroxy-4-nitrobenzaldehyde Ib (300 mg, 1.00 equiv) and

K₂CO₃(498 mg, 2.01 equiv) were suspended in DMF (1.5 mL).

While stirring at r.t., allyl bromide (198 μL, 1.30 equiv) was added.

The reaction mixture was stirred for 3:40 h at r.t. until completion was

indicated by TLC analysis. The mixture was transferred to a beaker of

ice-cold water (60 mL) while stirring; the resulting precipitate was

ﬁltered oﬀ and washed with water (5 mL). The precipitate was then

dissolved in EtOAc (50 mL) and washed with brine (5 × 25 mL),

dried with sodium sulfate, ﬁltered, and evaporated. Yellow solid (326

mg, 87.7%). IR (KBr): ν 3102, 3086, 2886, 1689, 1614, 1590, 1532,

1482, 1433, 1420, 1395, 1369, 1350, 1308, 1270, 1246, 1184, 1111,

Methyl (R)-8-Cyclopropyl-2-ﬂuoro-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (13c). The compound was prepared by following the

general procedure starting from 9a (106 mg, 0.40 mmol). The

reaction mixture was stirred for 24 h, and the product was puriﬁed on

automated ﬂash column chromatography (50 g cartridge, 10−50%

EtOAc in n-heptane) isolated in 43% yield (73 mg, 0.172 mmol) as a

light-yellow powder. [α]_D−200° [c 0.33, (CH₃)₂SO]. IR (KBr): ν

3549, 3473, 3415, 3004, 2247, 1753, 1663, 1606, 1582, 1523, 1490,

1

1087, 995, 937, 88, 815, 747 cm⁻¹. H NMR (600 MHz, CDCl₃): δ

10.57 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.85

(s, 1H), 6.09 (ddt, J = 16.6, 10.6, 5.3 Hz, 1H), 5.51 (d, J = 17.3 Hz,

1H), 5.42 (d, J = 10.5 Hz, 1H), 4.78 (d, J = 4.7 Hz, 2H). ¹³C{¹H}

NMR (151 MHz, CDCl₃): δ 188.4, 160.9, 152.2, 131.3, 129.7, 129.0,

119.6, 115.8, 108.5, 70.2. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd

1

1470 cm⁻¹. H NMR [600 MHz, (CD₃)₂SO] δ 8.29 (s, 1H), 7.90−

7.79 (m, 1H), 7.26 (d, J = 3.3 Hz, 1H), 7.09 (dd, J = 8.9, 4.5 Hz, 1H),

5.71 (dd, J = 8.9, 2.1 Hz, 1H), 5.52−5.42 (m, 2H), 3.88 (dd, J = 11.8,

8.9 Hz, 1H), 3.74 (s, 3H), 3.62 (dd, J = 11.8, 2.2 Hz, 1H), 1.83−1.74

−

for C₁₀H₈NO₄206.0459; Found 206.0465.

H

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Note

(m, 1H), 1.13−0.99 (m, 2H), 0.70−0.55 (m, 2H). ¹³C{¹H} NMR

[151 MHz, (CD₃)₂SO] δ 169.3, 158.7, 158.7, 157.1, 153.1, 145.2,

145.2, 143.2, 139.2, 135.5, 130.8, 128.1, 124.0, 124.0, 119.4, 119.4,

118.9, 118.7, 110.5, 110.3, 107.2, 67.9, 63.0, 53.4, 31.2, 10.2, 7.9, 7.7.

¹⁹F NMR [565 MHz, (CD₃)₂SO] δ −120.86 (td, J = 8.8, 8.3, 4.4 Hz).

107.7, 66.6. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for

−

C₁₇H₁₂NO₆[M − H]⁻326.0670; Found 326.0657.

(E)-3-(2-Formyl-5-nitrophenoxy)prop-1-en-1-yl Benzoate (14b).

The compound was prepared by following the general procedure

starting from 4-nitro-2-hydroxybenzaldehyde (334 mg, 2.00 mmol).

The reaction mixture was stirred for 2.0 h, and the product was

puriﬁed with automated ﬂash column chromatography (50 g

cartridge, 10−90% EtOAc in n-heptane) in 68% yield (450 mg,

1.37 mmol) as a white powder. (E)-3-Bromoprop-1-en-1-yl benzoate

was prepared according to literature reports and crystallized from

heptane.^15aIR (KBr): ν 3420, 3098, 3086, 3036, 2953, 2868, 2756,

1730, 1694, 1613, 1601, 1586, 1523, 1493, 1477, 1452, 1428 cm⁻¹.

¹H NMR (600 MHz, CDCl₃) δ 10.58 (s, 1H), 8.15 (dt, J = 8.2, 0.9

Hz, 2H), 8.03 (d, J = 8.9 Hz, 1H), 7.93 (dq, J = 5.0, 2.0 Hz, 2H), 7.83

(dd, J = 12.5, 1.2 Hz, 1H), 7.70−7.59 (m, 1H), 7.52 (t, J = 7.7 Hz,

2H), 5.96 (dt, J = 12.6, 7.0 Hz, 1H), 4.87 (d, J = 7.0 Hz, 2H).

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 188.1, 163.2, 160.5, 140.9,

134.0, 130.1, 129.7, 128.8, 128.6, 128.2, 115.9, 108.1, 107.9, 66.4.

HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₁₇H₁₂NO₆⁻326.0670;

Found 326.0668.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₂₂H₁₈FN₂O₄S⁺

425.0966; Found 425.0972.

M e t h y l ( R ) - 8 - C y c l o p r o p y l - 1 3 - o x o - 6 , 1 0 , 1 1 , 1 3 -

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (13d). The compound was prepared by following the

general procedure starting from 9a (106 mg, 0.40 mmol). The

reaction mixture was stirred for 24 h, and the product was puriﬁed

with automated ﬂash column chromatography (50 g cartridge, 20−

80% EtOAc in n-heptane) isolated in 51% yield (85 mg, 0.20 mmol)

as a yellow powder. [α]_D−135° [c 0.33, (CH₃)₂SO]. IR (KBr): ν

3415, 3082, 3003, 2953, 2927, 2844, 1747, 1663, 1603, 1588, 1578,

1

1519, 1493, 1461 cm⁻¹. H NMR [600 MHz, (CD₃)₂SO] δ 8.27 (s,

1H), 8.21 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (td, J = 7.7, 1.7 Hz, 1H),

7.18 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 5.71 (dd, J = 8.8,

2.2 Hz, 1H), 5.50−5.45 (m, 2H), 3.89 (dd, J = 11.8, 8.8 Hz, 1H), 3.74

(s, 3H), 3.62 (dd, J = 11.8, 2.2 Hz, 1H), 1.85−1.75 (m, 1H), 1.10−

1.05 (m, 2H), 0.71−0.56 (m, 2H). ¹³C{¹H} NMR [151 MHz,

(CD₃)₂SO] δ 169.3, 158.8, 156.9, 146.2, 142.6, 139.3, 135.0, 132.2,

130.8, 127.9, 125.0, 122.8, 122.8, 117.6, 107.2, 67.8, 63.0, 53.4, 31.2,

10.2, 7.9, 7.7. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₂H₁₉N₂O₄S⁺407.1060; Found 407.1063.

Methyl (R)-8-Cyclopropyl-2-nitro-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylate (13e). The compound was prepared by following the

general procedure starting from 9a (106 mg, 0.40 mmol). The

reaction mixture was stirred for 24 h, and the product was puriﬁed

with automated ﬂash column chromatography (50 g cartridge, 10−

50% EtOAc in n-heptane) in 14% yield (25 mg, 0.05 mmol) as a

yellow powder. [α]_D−83° [c 0.12, (CH₃)₂SO]. IR (KBr): ν 3417,

3082, 30009, 2954, 2852, 2247, 1753, 1665, 1617, 1606, 1592, 1578,

1520, 1488, 1467 cm⁻¹. ¹H NMR [600 MHz, (CD₃)₂SO] δ 8.98 (d, J

= 2.9 Hz, 1H), 8.34 (s, 1H), 8.27 (dd, J = 9.0, 2.9 Hz, 1H), 7.27 (d, J

= 9.0 Hz, 1H), 5.78−5.67 (m, 3H), 3.91 (dd, J = 11.8, 8.9 Hz, 1H),

3.75 (s, 3H), 3.64 (dd, J = 11.8, 2.2 Hz, 1H), 1.85−1.78 (m, 1H),

1.15−1.05 (m, 2H), 0.73−0.60 (m, 2H). ¹³C{¹H} NMR [151 MHz,

(CD₃)₂SO] δ 169.2, 161.6, 158.6, 143.8, 143.8, 142.7, 139.4, 135.8,

130.1, 128.4, 127.3, 122.8, 120.4, 119.0, 107.2, 68.6, 63.0, 53.4, 31.2,

10.2, 7.9, 7.7. HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd for

C₂₂H₁₇N₃NaO₆S⁺474.0736; Found 474.0714.

General Procedure for Synthesis of O-Alkylated Salicylal-

dehydes 14a−d. Under an atmosphere of nitrogen, 3-bromopro-

penyl benzoate (868 mg, 3.60 mmol, 1.80 equiv) was dissolved in

DMF (2.0 mL) and transferred with a syringe to a mixture of

salicylaldehyde I (2.00 mmol, 1.00 equiv) and K₂CO₃(553 mg, 2.00

equiv) under nitrogen. The reaction mixture was stirred at r.t. until

completion was indicated by TLC analysis. The mixture was diluted

with CH₂Cl₂(50 mL) and washed with brine (5 × 50 mL), ﬁltered

through sodium sulfate, and evaporated. The crude product was

puriﬁed with automated ﬂash column chromatography.

(E)-3-(2-Formyl-4-nitrophenoxy)prop-1-en-1-yl Benzoate (14a).

The compound was prepared by following the general procedure

starting from 5-nitro-2-hydroxybenzaldehyde (334 mg, 2.00 mmol).

The reaction mixture was stirred for 1.0 h, and the product was

puriﬁed with automated ﬂash column chromatography (50 g

cartridge, 5−85% EtOAc in n-heptane) in 61% yield (400 mg, 1.22

mmol) as a white powder. (E)-3-Bromoprop-1-en-1-yl benzoate was

prepared according to literature reports and crystallized from

heptane.^15aIR (KBr): ν 3412, 3111, 3069, 2947, 2898, 2631, 1718,

1687, 1609, 1588, 1526, 1481, 1451, 1428, 1406 cm⁻¹. ¹H NMR (600

MHz, CDCl₃) δ 10.51 (s, 1H), 8.75 (d, J = 2.9 Hz, 1H), 8.47 (dd, J =

9.1, 2.9 Hz, 1H), 8.18−8.10 (m, 2H), 7.83 (d, J = 12.4 Hz, 1H), 7.67

(t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.19 (d, J = 9.1 Hz, 1H),

5.95 (dt, J = 12.5, 7.1 Hz, 1H), 4.89 (d, J = 7.1 Hz, 2H). ¹³C{¹H}

NMR (151 MHz, CDCl₃) δ 187.3, 164.3, 163.2, 141.8, 141.1, 130.5,

130.1, 130.1, 128.7, 128.5, 128.3, 128.2, 127.0, 124.9, 124.8, 113.0,

(E)-3-(4-Fluoro-2-formylphenoxy)prop-1-en-1-yl Benzoate (14c).

The compound was prepared by following the general procedure

starting from 5-ﬂuoro-2-hydroxybenzaldehyde (251 mg, 1.79 mmol).

The reaction mixture was stirred for 2.5 h, and the product was

puriﬁed with automated ﬂash column chromatography (50 g

cartridge, 2−50% EtOAc in n-heptane) as a white powder in 84%

yield (388 mg, 1.51 mmol). (E)-3-Bromoprop-1-en-1-yl benzoate was

prepared according to literature reports and crystallized from

heptane.^15aIR (KBr): ν 3548, 3415, 3091, 3059, 2946, 2892, 2870,

2766, 1727, 1685, 1614, 1599, 1584, 1495, 1452 cm⁻¹. ¹H NMR (600

MHz, CDCl₃) δ 10.48 (s, 1H), 8.18−8.09 (m, 2H), 7.76 (dd, J = 12.5,

1.3 Hz, 1H), 7.70−7.62 (m, 1H), 7.56 (dd, J = 8.2, 3.3 Hz, 1H), 7.52

(t, J = 7.8 Hz, 2H), 7.31−7.27 (m, 3H), 7.04 (dd, J = 9.1, 3.9 Hz,

1H), 5.92 (dt, J = 12.5, 7.0 Hz, 1H), 4.74 (dd, J = 7.0, 1.2 Hz, 2H).

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 188.58, 188.57, 163.3, 157.9,

156.98, 156.97, 156.3, 140.2, 133.9, 130.10, 128.6, 128.4, 122.5, 122.3,

114.68, 114.63, 114.3, 114.1, 108.9. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −121.79. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for

−

C₁₇H₁₂FO₄299.0725; Found 299.0725.

3-(2-Formylphenoxy)prop-1-en-1-yl Benzoate (14d). The com-

pound was prepared by following the general procedure starting from

2-hydroxybenzaldehyde (244 mg, 2.00 mmol). The reaction mixture

was stirred for 1.5 h, and the product was puriﬁed with automated

ﬂash column chromatography (50 g cartridge, 2−25% EtOAc in n-

heptane) in 79% yield as a white powder (450 mg, 1.59 mmol). 3-

Bromoprop-1-en-1-yl benzoate was prepared by following literature

reports.^15aInstead of recrystallization, it was puriﬁed on automated

ﬂash column chromatography (50 g cartridge, 0−10% EtOAc in n-

heptane) and isolated as a mixture of E and Z isomers. Thus, the

alkylated salicylaldehyde was also isolated as a mixture of E and Z

isomers. IR (KBr): ν 3415, 3093, 3067, 2941, 2859, 2761, 1734, 1691,

1

1599, 1582, 1482, 1453, 1400 cm⁻¹. H NMR (400 MHz, CDCl₃) δ

10.55 (s, 1H), 10.25 (s, 1H), 8.30−8.23 (m, 1H), 8.19−8.09 (m, 2H),

8.00−7.98 (m, 1H), 7.90−7.87 (m, 1H), 7.80−7.42 (m, 9H), 7.37−

7.35 (m, 1H), 7.12−7.02 (m, 2H), 5.98−5.91 (m, 1H), 5.42−5.37

(m, 1H), 5.03−5.01 (m, 1H), 4.77−4.75 (m, 1H). ¹³C{¹H} NMR

(100 MHz, CDCl₃) δ 189.7, 189.6, 188.4, 164.9, 163.3, 162.8, 160.7,

152.3, 140.0, 137.1, 135.8, 135.8, 135.3, 134.0, 134.0, 133.9, 130.3,

130.2, 130.1, 130.0, 128.7, 128.7, 128.6, 128.6, 128.6, 128.5, 128.4,

128.3, 126.5, 125.2, 125.2, 123.5, 121.1, 121.0, 112.8, 112.7, 109.2,

108.7, 65.4, 62.2. HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for

−

C₁₇H₁₃O₄281.0819; Found 281.0819.

General Procedure for Hydrolysis of Methyl Esters. Syn-

thesis of 15a−j and 16a−e. The methyl ester was dissolved in

THF (4 mL), and LiOH (0.10 M, 1.40 equiv) was added to the

stirred solution. The hydrolysis was monitored with TLC. Upon

completion, HCl (1.00 M, 1.50 equiv) was added. The resulting

mixture was stirred for 5 min, then concentrated partially, until most

of the THF was removed. The residue was partitioned between water

and CHCl₃/MeOH 9:1 (10 mL). The phases were separated, and the

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Note

aqueous phase was extracted once more (5 mL). The combined

organic extracts were dried with sodium sulfate, ﬁltered, and

evaporated. The residue was redissolved in DMSO (1−3 mL) and

puriﬁed with preparative HPLC. The fractions containing the pure

desired product were combined, diluted with water, and freeze-dried.

( R ) - 8 - C y c l o p r o p y l - 1 3 - o x o - 7 - p h e n y l - 6 , 1 0 , 1 1 , 1 3 -

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15a). The compound was prepared by following the

general procedure. 50 mg of 11a was hydrolyzed. The reaction was

ﬁnished after 42 min. Orange solid (32.6 mg, 67.2%). [α]_D−90.40 [c

0.20, (CD₃)₂SO]; IR (KBr): ν 3441, 3003, 1743, 1648, 1610, 1576,

1519, 1493, 1463, 1437, 1382, 1299, 1253, 1221, 1182, 1036 cm⁻¹.

¹H NMR [600 MHz, (CD₃)₂SO]: δ 13.52 (s, 1H), 8.21 (dd, J = 7.7,

1.6 Hz, 1H), 7.55−7.31 (m, 6H), 7.19 (t, J = 7.5 Hz, 1H), 6.99 (d, J =

8.0 Hz, 1H), 5.60 (dd, J = 8.7, 1.9 Hz, 1H), 5.13 (d, J = 14.7 Hz, 1H),

5.00 (d, J = 14.6 Hz, 1H), 3.83 (dd, J = 11.7, 8.7 Hz, 1H), 3.54 (dd, J

= 11.9, 1.9 Hz, 1H), 0.85−0.75 (m, 1H), 0.30 to −0.01 (m, 4H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO] δ 169.6, 158.2, 155.8, 145.1,

145.0, 141.7, 140.1, 136.8, 133.3, 131.7, 129.9, 129.8, 128.7, 128.3,

127.8, 127.7, 125.0, 122.7, 122.5, 116.8, 107.3, 66.0, 63.2, 30.9, 15.2,

11.2, 11.0. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₇H₂₁N₂O₄S⁺469.1217; Found 469.1228.

8-Cyclopropyl-3-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15b). The compound was prepared by following the

general procedure. 62 mg of methyl ester 11b was hydrolyzed. The

reaction was found complete after 50 min. Yellow solid (30.9 mg,

51.2%). [α]_D−122.3° [c 0.308, (CD₃)₂SO]; IR (KBr): ν 3448, 1638,

1573, 1530, 1438, 1343, 1226, 1042, 741 cm⁻¹. ¹H NMR [600 MHz,

(CD₃)₂SO]: δ 13.63 (bs, 1H), 8.42 (dd, J = 8.6, 1.8 Hz, 1H), 8.05

(dd, J = 8.6, 2.2 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.54−7.41 (m,

4H), 7.40−7.33 (m, 1H), 5.61 (d, J = 8.7 Hz, 1H), 5.31−5.09 (m,

2H), 3.84 (dd, J = 11.7, 8.7 Hz, 1H), 3.56 (dd, J = 11.7, 1.9 Hz, 1H),

0.90−0.82 (m, 1H), 0.30−0.15 (m, 3H), 0.12−0.00 (m, 1H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO]: δ 169.5, 157.9, 155.7, 149.1,

MHz, (CD₃)₂SO]: δ 169.5, 160.6, 158.0, 146.3, 142.5, 142.4, 142.2,

140.2, 136.4, 134.1, 129.7, 129.7, 128.5, 128.0, 127.9, 127.8, 126.9,

122.6, 120.2, 118.2, 107.2, 66.9, 63.4, 31.0, 15.2, 11.2, 11.1. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₂₇H₂₀N₃O₆S⁺514.1068;

Found 514.1088.

(R)-8-Cyclopropyl-7-(4-nitrophenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15e). The compound was prepared by following the

general procedure. 50 mg of 11e was hydrolyzed. The reaction was

ﬁnished after 30 min. Yellow solid (34.5 mg, 70.9%). [α]_D−94.72° [c

0.26, (CD₃)₂SO]. IR (KBr): ν 3442, 3075, 3002, 2850, 2578, 1758,

1665, 1605, 1561, 1519, 1491, 1464, 1442, 1385, 1348, 1298, 1258,

1

1225, 1183, 1109, 1045 cm⁻¹. H NMR [600 MHz, (CD₃)₂SO]: δ

13.58 (s, 1H), 8.37−8.27 (m, 2H), 8.21 (d, J = 7.7 Hz, 1H), 7.78 (d, J

= 7.7 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.20

(t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.62 (d, J = 8.6 Hz, 1H),

5.17−4.97 (m, 2H), 3.89−3.78 (m, 1H), 3.55 (d, J = 11.6 Hz, 1H),

0.89−0.82 (m, 1H), 0.32−0.17 (m, 3H), 0.10−0.03 (m, 1H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO]: δ 169.5, 158.0, 155.8, 147.2,

146.1, 144.9, 143.7, 140.1, 139.4, 133.0, 131.8, 131.4, 131.3, 128.5,

125.0, 123.0, 122.9, 122.6, 122.5, 116.8, 106.7, 65.8, 63.3, 31.0, 15.5,

11.8, 11.7. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₇H₂₀N₃O₆S⁺514.1068; Found 514.1072.

(R)-3-Nitro-7-(4-nitrophenyl)-13-oxo-6,10, 11, 13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15f). The compound was prepared by following the

general procedure but with 1.60 equiv of LiOH. 50 mg of 11f was

hydrolyzed. The reaction was ﬁnished after 2 h, whereupon 1.72 equiv

of HCl was added. The mixture was partitioned between DCM/n-

BuOH (1:1) and brine/water (1:1). Yellow solid (26.1 mg, 53.6%)

[α]_D−3.55 [c 0.51, (CD₃)₂SO]. IR (KBr): ν 3435, 3107, 1748, 1666,

1592, 1566, 1533, 1453, 1431, 1384, 1346, 1227, 1180, 1043 cm⁻¹.

¹H NMR [400 MHz, (CD₃)₂SO]: δ 13.74 (s, 1H), 8.54−8.35 (m,

3H), 8.04 (dd, J = 8.7, 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.73−

7.67 (m, 1H), 5.98 (s, 1H), 5.62 (dd, J = 8.6, 1.5 Hz, 1H), 5.20 (s,

2H), 3.90 (dd, J = 11.8, 8.6 Hz, 1H), 3.62 (dd, J = 11.8, 1.6 Hz, 1H).

¹³C{¹H} NMR [100 MHz, (CD₃)₂SO]: δ 169.4, 158.3, 155.8, 149.0,

146.7, 142.7, 142.1, 140.4, 136.4, 134.3, 129.8, 129.7, 129.2, 128.5,

128.4, 127.9, 127.8, 126.0, 117.5, 112.0, 107.3, 66.7, 63.3, 31.1, 15.2,

11.2, 11.1. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for

C₂₇H₂₀N₃O₆S⁺514.1068; Found 514.1062.

147.9, 144.9, 143.2, 140.0, 139.5, 138.6, 133.1, 130.8, 130.6, 128.1,

128.0, 125.8, 124.3, 117.5, 112.2, 93.9, 66.3, 62.8, 31.9. HRMS (ESI-

TOF) m/z: [M + H]⁺Calcd for C₂₄H₁₅N₄O₈S⁺519.0605; Found

519.0612.

(R)-3-Nitro-13-oxo-7-phenyl-6,10,11,13-tetrahydrochromeno-

[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-carboxylic Acid (15c).

The compound was prepared by following the general procedure but

with 1.60 equiv of LiOH. 50 mg of 11c was hydrolyzed. The reaction

was ﬁnished after 2 h, whereupon 1.72 equiv of HCl was added. The

mixture was partitioned between DCM/n-BuOH (2:1) and brine/

water (1:1). Yellow solid (38 mg, 78%). [α]_D−6.79 [c 0.18,

(CD₃)₂SO]. IR (KBr): ν 3440, 3082, 2935, 1754, 1666, 1623, 1592,

1577, 1536, 1517, 1226, 1043 cm⁻¹. ¹H NMR [400 MHz, (CD₃)₂SO,

343 K]: δ 8.50 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.6, 2.3 Hz, 1H),

7.74 (d, J = 2.3 Hz, 1H), 7.65−7.55 (m, 3H), 7.40−7.32 (m, 2H),

5.95 (s, 1H), 5.62 (dd, J = 8.5, 1.8 Hz, 1H), 5.19 (s, 2H), 3.93 (dd, J

= 11.8, 8.5 Hz, 1H), 3.62 (dd, J = 11.7, 1.8 Hz, 1H). ¹³C{¹H} NMR

[100 MHz, (CD₃)₂SO, 343 K]: δ 168.9, 158.1, 155.6, 148.9, 144.0,

143.1, 141.3, 138.6, 133.2, 132.8, 128.82, 128.79, 128.75, 128.5, 128.4,

128.1, 127.7, 125.6, 116.9, 111.8, 93.6, 66.3, 62.6, 31.6. HRMS (ESI-

TOF) m/z: [M + H]⁺Calcd for C₂₄H₁₆N₃O₆S⁺474.0755; Found

474.0757.

(R)-8-Cyclopropyl-2-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15d). The compound was prepared by following the

general procedure. 50 mg of 11d was hydrolyzed. The reaction was

ﬁnished after 40 min. Yellow solid (36.9 mg, 75.8%). [α]_D−92.47 [c

0.23, (CH₃)₂SO]. IR (KBr): ν 3442, 3082, 3002, 1743, 1631, 1589,

1574, 1550, 1518, 1494, 1481, 1460, 1443, 1385, 1341, 1297, 1251,

1201, 1091, 1023 cm⁻¹. ¹H NMR [600 MHz, (CD₃)₂SO]: δ 13.62 (s,

1H), 9.00 (d, J = 2.9 Hz, 1H), 8.25 (dd, J = 8.9, 2.5 Hz, 1H), 7.47

(dd, J = 17.9, 4.9 Hz, 4H), 7.36 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 8.8

Hz, 1H), 5.62 (d, J = 8.5 Hz, 1H), 5.27 (dd, J = 87.1, 14.9 Hz, 2H),

3.84 (dd, J = 11.7, 8.7 Hz, 1H), 3.56 (d, J = 11.6 Hz, 1H), 0.86 (s,

1H), 0.30−0.15 (m, 3H), 0.10−0.00 (m, 1H). ¹³C{¹H} NMR [151

(R)-8-Cyclopropyl-2-ﬂuoro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15g). The compound was prepared by following the

general procedure starting from 11g (50 mg, 0.09 mmol). The

reaction mixture was stirred for 4 h, and the product was isolated as a

yellow powder in 38% yield (38 mg, 0.07 mmol). [α]_D−113° [c 0.12,

(CH₃)₂SO]. IR (KBr): ν 3415, 3081, 3001, 2921, 2852, 1713, 1656,

1619, 1575, 1550, 1520, 1494, 1482, 1462, 1429 cm⁻¹. ¹H NMR [600

MHz, (CD₃)₂SO] δ 7.67 (dd, J = 9.0, 3.2 Hz, 1H), 7.31−7.19 (m,

5H), 7.14 (dt, J = 6.8, 2.4 Hz, 1H), 7.03 (td, J = 8.6, 3.2 Hz, 1H), 6.83

(dd, J = 8.9, 4.5 Hz, 1H), 5.25 (t, J = 7.8 Hz, 1H), 4.94−4.76 (m,

2H), 3.54 (dd, J = 11.3, 8.4 Hz, 1H), 3.33 (dt, J = 11.5, 2.9 Hz, 1H),

0.70−0.55 (m, 1H), 0.15 to −0.10 (m, 3H), −0.13 to −0.25 (m, 1H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO] δ 169.5, 158.8, 158.46, 158.44,

157.2, 152.4, 146.8, 144.0, 142.0, 140.7, 140.6, 137.2, 134.06, 134.04,

130.3, 130.25, 130.22, 128.9, 128.7, 128.2, 128.16, 128.12, 124.6,

124.5, 119.0, 118.9, 118.6, 118.5, 110.8, 110.7, 107.1, 66.64, 66.62,

64.8, 32.1, 15.67, 15.65, 11.6, 11.5. ¹⁹F NMR [565 MHz, (CD₃)₂SO]

δ −120.83 HRMS (ESI) m/z: [M + H]⁺Calcd for C₂₇H₂₀FN₂O₄S⁺

487.1123; Found 487.1103.

(R)-8-Cyclopropyl-13-oxo-7-(3-(triﬂuoromethyl)phenyl)-

6,10,11,13-tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]-

naphthyridine-11-carboxylic Acid (15h). The compound was

prepared by following the general procedure, but upon complete

saponiﬁcation, the mixture was neutralized with Amberlyst 15 until

around pH = 6 by pH paper, then ﬁltered through a pad of THF-wet

Celite. The amberlyst and Celite were rinsed with MeOH until the

ﬁltrate was transparent. The ﬁltrate was evaporated and extracted

according to the general procedure. The residue was triturated with

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1

Et₂O (0.5 mL) and ﬁltered. The solid was washed with more Et₂O

(0.5 mL) and dried under vacuum overnight. 25 mg of 11h was

hydrolyzed to provide 15h (15.45 mg, 63.4%) as a yellow solid. [α]_D

−51.71° [c 0.29, (CD₃)₂SO]. IR (KBr): ν 3442, 3082, 3003, 1734,

1458, 1430, 1382, 1229, 1181, 925, 820, 740, 707 cm⁻¹. H NMR

[600 MHz, (CD₃)₂SO] δ 8.51−8.37 (m, 1H), 8.04 (dd, J = 8.6, 2.2

Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.49−7.48 (m, 3H), 7.39−7.36 (m,

2H), 5.63 (d, J = 8.5 Hz, 1H), 5.10−5.01 (m, 2H), 3.90 (dd, J = 11.6,

8.6 Hz, 1H), 3.64 (d, J = 11.3 Hz, 1H), 2.88 (s, 3H). ¹³C{¹H} NMR

[151 MHz, (CD₃)₂SO] δ 169.2, 157.1, 155.7, 149.0, 143.0, 140.1,

139.6, 137.2, 135.5, 130.6, 129.6, 129.4, 128.3, 128.1, 128.0, 127.7,

127.6, 125.9, 117.4, 112.1, 66.3, 63.4, 59.4, 31.7. HRMS (ESI-TOF)

m/z: [M + H]⁺Calcd for C₂₅H₁₈N₃O₇S⁺504.0860; Found 504.0842.

8-Cyclopropyl-3-nitro-13-oxo-6,10,11,13-tetrahydrochromeno-

[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-carboxylic Acid (16a).

The compound was prepared by following the general procedure. 33

mg of 13a was hydrolyzed. The reaction was ﬁnished after 40 min.

Orange solid (9.1 mg, 28.5%). [α]_D−162.3° [c 0.186, (CD₃)₂SO]; IR

(KBr): ν 3438, 1731, 1652, 1578, 1531, 1432, 1345, 1238, 1034, 919,

1

1629, 1577, 1518, 1490, 1446, 1382, 1330, 1169, 1127 cm⁻¹. H

NMR [600 MHz, (CD₃)₂SO, 343 K]: δ 8.25 (dd, J = 7.7, 1.8 Hz,

1H), 7.85−7.65 (m, 4H), 7.37 (td, J = 7.8, 1.7 Hz, 1H), 7.17 (t, J =

7.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.38 (d, J = 8.2 Hz, 1H), 5.14−

4.92 (m, 2H), 3.68 (dt, J = 10.0, 7.3 Hz, 1H), 3.55 (d, J = 10.9 Hz,

1H), 0.80−0.70 (m, 1H), 0.34 to −0.07 (m, 4H). ¹³C{¹H} NMR

[151 MHz, (CD₃)₂SO, 343 K]: δ 168.4, 157.7, 155.4, 146.6, 144.0,

140.3, 137.9, 133.6, 132.6 (d, J = 13.3 Hz), 131.0, 128.6 (d, J = 9.9

Hz), 127.8, 126.1, 124.7, 124.6, 124.3, 122.9, 122.5, 122.0, 116.3,

105.3, 65.6, 65.1, 31.8 (d, J = 8.3 Hz), 14.8 (d, J = 9.5 Hz), 11.2−0.9

(m). The multiplets in the¹³C NMR spectrum are caused by

atropoisomerism. ¹⁹F NMR [565 MHz, (CD₃)₂SO, 343 K]: δ

739 cm⁻¹. H NMR [600 MHz, (CD₃)₂SO]: δ 8.38 (dd, J = 8.6, 2.1

1

+

H]⁺Calcd for

Hz, 1H), 8.29 (s, 1H), 8.01 (dd, J = 8.6, 2.3 Hz, 1H), 7.80 (d, J = 2.2

Hz, 1H), 5.63−5.60 (m, 3H), 3.86 (dd, J = 11.7, 8.7 Hz, 1H), 3.61

(dd, J = 11.7, 1.6 Hz, 1H), 1.80−1.74 (m, 1H), 1.12−1.02 (m, 2H),

0.68−0.63 (m, 1H), 0.56−0.51 (m, 1H). ¹³C{¹H} NMR [151 MHz,

(CD₃)₂SO]: δ 169.6, 158.2, 156.3, 148.9, 144.1, 143.3, 139.6, 135.5,

130.6, 128.2, 127.7, 125.6, 117.3, 112.3, 106.5, 67.9, 62.8, 31.3, 9.7,

7.5, 7.3. HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₂₁H₁₆N₃O₆S⁺

438.0755; Found 438.0769.

−61.20. HRMS (ESI-TOF) m/z: [M

C₂₈H₂₀F₃N₂O₄S⁺537.1091; Found 537.1094.

(R)-8-Cyclopropyl-7-(3-methoxyphenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15i). The compound was prepared by following the

general procedure, but upon complete saponiﬁcation, the mixture was

neutralized with Amberlyst 15 until around pH = 6 by pH paper, then

ﬁltered through a pad of THF-wet Celite. The amberlyst and Celite

were rinsed with MeOH until the ﬁltrate was transparent. The ﬁltrate

was evaporated and extracted according to the general procedure. The

residue was triturated in Et₂O (0.5 mL) and ﬁltered. The solid was

washed with more Et₂O (0.5 mL) and dried under vacuum overnight.

25 mg of 11i was converted to 15i (17.5 mg, 72%) isolated as a yellow

solid. [α]_D−91.56° [c 0.21, (CD₃)₂SO]. IR (KBr): ν 3442, 3390,

2941, 2836, 1757, 1646, 1608, 1577, 1519, 1463, 1439, 1439, 1218,

1038 cm⁻¹. ¹H NMR [600 MHz, (CD₃)₂SO, 343 K]: δ 8.24 (dd, J =

7.8, 1.7 Hz, 1H), 7.44−7.33 (m, 2H), 7.16 (td, J = 7.5, 1.1 Hz, 1H),

7.03 (dd, J = 8.2, 2.5 Hz, 1H), 7.00−6.87 (m, 3H), 5.51−5.45 (m,

1H), 5.17−4.96 (m, 2H), 3.82 (d, J = 8.6 Hz, 3H), 3.78−3.71 (m,

1H), 3.53 (dd, J = 11.3, 2.0 Hz, 1H), 0.99−0.92 (m, 1H), 0.34−0.21

(m, 3H), 0.20−0.09 (m, 1H). ¹³C{¹H} NMR [151 MHz, (CD₃)₂SO,

343 K]: δ 168.7, 158.4 (d, J = 9.2 Hz), 157.8, 155.5, 145.2, 144.3,

141.0, 140.1, 138.0, 132.8, 131.1, 128.6 (d, J = 10.8 Hz), 128.0, 124.6,

122.5, 121.9, 116.3, 115.4 (d, J = 12.2 Hz), 113.5, 106.4, 65.8, 64.1,

55.1, 31.2, 14.6, 11.14−10.10 (m). The multiplets in the¹³C NMR

spectrum are caused by atropoisomerism. HRMS (ESI-TOF) m/z: [M +

H]⁺Calcd for C₂₈H₂₂N₂O₅S⁺499.1322; Found 499.1326.

(R)-8-Cyclopropyl-7-(4-ethoxyphenyl)-13-oxo-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15j). The compound was prepared by following the

general procedure. 50 mg of 11j was hydrolyzed. The reaction was

ﬁnished after 65 min. Yellow powder (35.5 mg, 72.9%). [α]_D−78.30°

[c 0.19, (CD₃)₂SO]. IR (KBr): ν 3413, 2980, 1745, 1640, 1608, 1577,

1508, 1463, 1441, 1383, 1299, 1283, 1245, 1223, 1178, 1111, 1045

cm⁻¹. ¹H NMR [600 MHz, (CD₃)₂SO] δ 13.52 (s, 1H), 8.19 (d, J =

7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.24

(d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.07−6.95 (m, 3H), 5.59

(d, J = 8.7 Hz, 1H), 5.21−5.01 (m, 2H), 4.09 (q, J = 6.8 Hz, 2H),

3.86−3.78 (m, 1H), 3.53 (d, J = 11.6 Hz, 1H), 1.37 (t, J = 6.9 Hz,

3H), 1.00−0.90 (m, 1H), 0.36−0.08 (m, 4H). ¹³C{¹H} NMR [151

MHz, (CD₃)₂SO] δ 169.6, 158.4, 158.2, 155.8, 144.9, 144.9, 141.7,

140.1, 133.5, 131.6, 131.1, 129.0, 128.8, 125.0, 122.8, 122.4, 116.8,

113.6, 113.5, 107.5, 66.0, 63.2, 63.1, 30.9, 15.0, 14.6, 11.0, 10.9.

HRMS (ESI-TOF) m/z: [M + H]⁺Calcd for C₂₉H₂₅N₂O₅S⁺

513.1479; Found 513.1496.

(R)-3-Nitro-13-oxo-6,10,11,13-tetrahydrochromeno[4,3-b]-

thiazolo[2,3-g][1,7]naphthyridine-11-carboxylic Acid (16b). The

compound was prepared by following the general procedure starting

from 13b (28 mg, 0.07 mmol). The reaction mixture was stirred for

0.5 h, and the product was isolated as a yellow powder in 15% yield

(4.200 mg, 0.01 mmol). [α]_D−100° [c 0.10, (CD₃)₂SO]. IR (KBr): ν

3418, 3085, 2927, 2597, 1742, 1642, 1614, 1584, 1535, 1516, 1456

cm⁻¹. H NMR [600 MHz, (CD₃)₂SO] δ 8.41 (d, J = 8.6 Hz, 1H),

1

8.03 (dd, J = 8.6, 2.3 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 2.2 Hz, 1H),

6.68 (s, 1H), 5.55 (d, J = 17.8 Hz, 3H), 3.93 (dd, J = 11.5, 8.5 Hz,

1H), 3.66 (d, J = 11.4 Hz, 1H). ¹³C{¹H} NMR [151 MHz,

(CD₃)₂SO] δ 169.3, 158.5, 156.2, 148.9, 144.0, 143.5, 138.7, 134.7,

130.8, 129.5, 128.2, 125.6, 117.3, 112.3, 96.3, 67.6, 63.0, 32.1. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₁₈H₁₂N₃O₆S⁺398.0442;

Found 398.0439.

( R ) - 8 - C y c l o p r o p y l - 2 - ﬂ u o r o - 1 3 - o x o - 6 , 1 0 , 1 1 , 1 3 -

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (16c). The compound was prepared by following the

general procedure starting from 13c (47 mg, 0.11 mmol). The

reaction mixture was stirred for 1 h, and the product was isolated as a

yellow powder in 43% yield (20 mg, 0.04 mmol). [α]_D−145° [c 0.22,

(CD₃)₂SO]. IR (KBr): ν 3415, 3070, 3002, 2846, 1744, 1626, 1601,

1569, 1525, 1473 cm⁻¹. ¹H NMR [400 MHz, (CD₃)₂SO] δ 13.49 (s,

1H), 8.27 (s, 1H), 7.85 (dd, J = 9.0, 3.2 Hz, 1H), 7.26 (td, J = 8.6, 3.2

Hz, 1H), 7.09 (dd, J = 8.9, 4.6 Hz, 1H), 5.61 (dd, J = 8.8, 1.6 Hz,

1H), 5.47 (s, 2H), 3.86 (dd, J = 11.8, 8.7 Hz, 1H), 3.60 (dd, J = 11.8,

1.7 Hz, 1H), 1.85−1.70 (m, 1H), 1.13−1.02 (m, 2H), 0.70−0.54 (m,

2H). ¹³C{¹H} NMR [100 MHz, (CD₃)₂SO] δ 170.1, 159.1, 158.7,

156.7, 153.0, 145.0, 143.5, 139.4, 135.4, 130.6, 127.9, 124.1, 124.0,

119.4, 119.3, 118.8, 118.6, 110.5, 110.3, 106.9, 67.9, 63.2, 31.6, 10.2,

7.9, 7.7. ¹⁹F{¹H} NMR [376 MHz, (CD₃)₂SO] δ −120.90. HRMS

(ESI-TOF) m/z: [M + H]⁺Calcd for C₂₁H₁₆FN₂O₄S⁺411.0810;

Found 411.0801.

(R)-8-Cyclopropyl-13-oxo-6,10,11,13-tetrahydrochromeno[4,3-

b]thiazolo[2,3-g][1,7]naphthyridine-11-carboxylic Acid (16d). The

compound was prepared by following the general procedure starting

from 13d (47 mg, 0.11 mmol). The reaction mixture was stirred for 2

h, and the product was isolated as a white powder in 28% yield (13

mg, 0.03 mmol). [α]_D−60° [c 0.16, (CD₃)₂SO]. IR (KBr): ν 3432,

3001, 2548, 1742, 1625, 1599, 1582, 1565, 1524, 1493, 1467 cm⁻¹.

¹H NMR [600 MHz, (CD₃)₂SO] δ 8.26 (s, 1H), 8.21 (dd, J = 7.8, 1.7

(R)-8-Methoxy-3-nitro-13-oxo-7-phenyl-6,10,11,13-

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (15k). The compound was prepared by following the

general procedure. Compound precipitated during the workup and

was ﬁltered through a sintered funnel and dried. The compound was

redissolved in DMSO (3 mL) and puriﬁed with preparative HPLC.

105 mg of 11k was hydrolyzed. The reaction was ﬁnished after 16 h.

Yellow powder (66 mg, 64.6%). [α]_D−52° [c 0.4, (CD₃)₂SO]. IR

(KBr): ν 3449, 3057, 1740, 1665, 1635, 1583, 1556, 1533, 1515,

Hz, 1H), 7.40 (td, J = 7.7, 1.7 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04

(d, J = 8.1 Hz, 1H), 5.61 (dd, J = 8.8, 1.6 Hz, 1H), 5.47 (d, J = 1.5 Hz,

2H), 3.86 (dd, J = 11.7, 8.7 Hz, 1H), 3.59 (dd, J = 11.7, 1.6 Hz, 1H),

1.83−1.74 (m, 1H), 1.13−1.02 (m, 2H), 0.70−0.54 (m, 2H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO] δ 168.0, 156.7, 154.7, 143.9,

K

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Note

140.7, 137.3, 132.9, 130.0, 128.5, 125.6, 122.9, 120.75, 120.73, 115.5,

104.8, 65.7, 61.0, 29.4, 8.1, 5.7, 5.6. HRMS (ESI-TOF) m/z: [M +

Na]⁺Calcd for C₂₁H₁₆N₂NaO₄S⁺415.0729; Found 415.0712.

( R ) - 8 - C y c l o p r o p y l - 2 - n i t r o - 1 3 - o x o - 6 , 1 0 , 1 1 , 1 3 -

tetrahydrochromeno[4,3-b]thiazolo[2,3-g][1,7]naphthyridine-11-

carboxylic Acid (16e). The compound was prepared by following the

general procedure starting from 13e (20.76 mg, 0.046 mmol). The

reaction was stirred for 1.5 h, and the product was isolated as yellow

powder in 20% yield (4.200 mg, 0.009 mmol). [α]_D−198° [c 0.10,

(CD₃)₂SO]. IR (KBr): ν 3550, 3475, 3414, 3236, 3079, 2844, 2497,

NH₄Cl solution (sat. aq.) (40 mL). The aq. phase was extracted with

diethyl ether (2 × 30), and the combined organic phase was dried

over sodium sulfate, ﬁltered, and concentrated by rotary evaporation.

The residue was redissolved in DCM and puriﬁed with automated

ﬂash column chromatography.

Ethyl (E)-3-(3-Methoxyphenyl)acrylate (IVa). The compound was

prepared by following the general procedure. The reaction was

ﬁnished after 3.5 h. The crude product was puriﬁed with automated

ﬂash column chromatography (50 g cartridge, 5−15% EtOAc in

heptane). Transparent oil (1.94 g, 94%). IR (KBr): ν 2981, 2940,

2906, 2837, 1712, 1638, 1581, 1490, 1466, 1434, 1367, 1311, 1293,

1261, 1179, 1041, 982 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d,

J = 16.0 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.12 (dt, J = 7.7, 1.2 Hz,

1H), 7.04 (s, 1H), 6.93 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.42 (d, J =

16.0 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.34 (t, J = 7.1

Hz, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 167.1, 160.0, 144.6,

136.0, 130.0, 120.9, 118.7, 116.3, 113.0, 60.7, 55.4, 14.5. The NMR

data are in agreement with published data for this compound.^20a

Ethyl (E)-3-(3-(Triﬂuoromethyl)phenyl)acrylate (IVb). The com-

pound was prepared by following the general procedure. The reaction

was ﬁnished after 1.3 h. The crude product was puriﬁed with

automated ﬂash column chromatography (50 g cartridge, 5% EtOAc

in heptane). Colorless oil that crystallizes at room temperature (1.20

g, 89%). IR (KBr): ν 3048, 2986, 2912, 1715, 1675, 1642, 1478, 1441,

1367, 1335, 1308, 1281, 1202, 1157, 1125, 1098, 1079, 1035, 996

1

1754, 1634, 1617, 1587 cm⁻¹. H NMR [600 MHz, (CD₃)₂SO] δ

8.95 (d, J = 2.8 Hz, 1H), 8.24 (dd, J = 9.0, 2.9 Hz, 1H), 7.25 (d, J =

9.0 Hz, 1H), 5.69−5.59 (m, 4H), 3.87−3.84 (m, 1H), 3.61 (dd, J =

11.6, 1.7 Hz, 1H), 1.79−1.75 (m, 1H), 1.11−1.03 (m, 2H), 0.68−

0.56 (m, 2H). ¹³C{¹H} NMR [151 MHz, (CD₃)₂SO] δ 169.5, 161.1,

158.2, 143.7, 143.0, 142.2, 139.0, 135.2, 129.3, 127.7, 126.7, 122.3,

119.8, 118.5, 106.3, 68.1, 62.9, 31.2, 9.7, 7.4, 7.2. HRMS (ESI-TOF)

m/z: [M + H]⁺Calcd for C₂₁H₁₆N₃O₆S⁺438.0755; Found 438.0766.

2-(Hydroxymethyl)-5-nitrophenol. The compound was prepared

from 2-hydroxy-4-nitro-benzoic acid by following a published

procedure¹⁸but with only 3 equiv of BH₃·SMe₂. 10.00 g was

converted to 8.39 g (91%) after puriﬁcation. NMR data were in

agreement with published data.

2-Hydroxy-4-nitrobenzaldehyde (Ib). 2-(Hydroxymethyl)-5-nitro-

phenol (8.20 g, 1.00 equiv) was dissolved in THF (100 mL).

(Diacetoxyiodo)benzene (17.27 g, 1.11 equiv) and TEMPO (158 mg,

0.02 equiv) were weighed up and added. The resulting suspension was

stirred at r.t. After 30 min, a clear solution remained, but TLC

indicated some remaining acid. No further progress was indicated

after 65 min, whereupon (diacetoxyiodo)benzene (3.14 g, 0.20 equiv)

was added. After 50 min of stirring, the reaction was found complete

by TLC. Saturated aqueous sodium thiosulfate solution (100 mL) was

added, and the mixture was stirred for 5 min, then transferred to a

separation funnel and extracted with EtOAc (150 + 50 + 50 mL). The

organic phases were combined, washed with brine (200 mL), and

evaporated. The residue was redissolved in chloroform (300 mL) and

extracted with aqueous potassium hydroxide solution (5% w/v, 3 ×

200 mL). The combined extracts were cooled in an ice-water bath and

neutralized with HCl (12 M, 44 mL). The precipitate was ﬁltered oﬀ

and dissolved in EtOAc, dried with sodium sulfate, ﬁltered, and

evaporated. The residue was redissolved in DCM/MeOH (99:1) and

puriﬁed with ﬂash column chromatography (70 × 120 mm silica gel,

DCM/MeOH 99:1). 5.23 g (64.5%) isolated as a light-yellow powder.

NMR data recorded in (CD₃)₂CO are in close agreement with

published data,¹⁸and the phenolic proton is visible as well. ¹H NMR

(600 MHz, (CD₃)₂CO): δ 11.06 (s, 1H), 10.27 (s, 1H), 8.10 (d, J =

8.4 Hz, 1H), 7.93−7.81 (m, 1H), 7.76 (s, 1H). IR (KBr): ν 3452,

3224, 3110, 3046, 2885, 1676, 1537, 1476, 1353, 1299, 1219, 1172,

1116, 958, 882, 827, 793, 740 cm⁻¹. ¹H NMR (600 MHz, CDCl₃): δ

11.16 (s, 1H), 10.08 (s, 1H), 7.79−7.89 (m, 3H). ¹³C{¹H} NMR

(151 MHz, CDCl₃): δ 196.1, 162.0, 152.6, 134.9, 123.8, 114.5, 113.6.

1

cm⁻¹. H NMR (400 MHz, CDCl₃): δ 7.77 (s, 1H), 7.74−7.66 (m,

2H), 7.63 (d, J = 7.8 Hz, 0H), 7.52 (t, J = 7.8 Hz, 1H), 6.50 (d, J =

16.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 166.6, 142.9, 135.4, 131.6 (q, J

= 32.5 Hz), 131.2 (d, J = 1.4 Hz), 129.6, 126.7 (q, J = 3.7 Hz), 124.7

(q, J = 3.8 Hz), 123.9 (q, J = 272.5 Hz), 120.4, 60.9, 14.4. ¹⁹F NMR

(376 MHz, CDCl₃) δ −62.9. The NMR data are in agreement with

published data for this compound.^20b

Ethyl (E)-3-(4-Ethoxyphenyl)acrylate (IVc). The compound was

prepared by following the general procedure but at 15 mmol scale.

The reaction was ﬁnished after 2.2 h. The crude product was puriﬁed

with automated ﬂash column chromatography (50 g cartridge, 5%

EtOAc in heptane). White solid (3.03 g, 91%). IR (KBr): ν 3395,

2988, 2932, 1710, 1631, 1604, 1573, 1482, 1425, 1394, 1364, 1289,

1253, 1168, 1043 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 7.64 (d, J =

15.9 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.8 Hz 2H), 6.30

(d, J = 15.9 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.0 Hz,

2H), 1.43 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 167.5, 160.9, 144.5, 129.8, 127.2, 115.8, 114.9,

63.8, 60.5, 14.9, 14.52.

General Procedure for Synthesis of Cinnamyl Alcohols Va−

d. The cinnamyl alcohols were synthesized according to a literature

procedure.^19cThe cinnamyl ester IV (10 mmol, 1.0 equiv) was

weighed up in an oven-dried 100 mL round-bottom ﬂask, put under

nitrogen, and dissolved in dried THF (30 mL). The reaction mixture

was cooled to −78 °C in a dry ice/acetone bath, and DiBAl-H (1 M

in toluene, 24 mL, 24 mmol. 2.4 equiv) was added slowly with a

syringe. The mixture was stirred at −78 °C while the reaction was

monitored with TLC. Upon complete consumption of the cinnamyl

ester, saturated Rochelle salt solution (20 mL) was added to the

mixture at −78 °C. The mixture was allowed to warm up to room

temperature, transferred to a separation funnel, and extracted with

EtOAc (5 × 40 mL). The organic phases were combined, dried over

sodium sulfate, ﬁltered through a pad of EtOAc-wet Celite, and

concentrated by rotary evaporation.

−

HRMS (ESI-TOF) m/z: [M − H]⁻Calcd for C₇H₄NO₄166.0146;

Found 166.0145.

General Procedure for Synthesis of Cinnamyl Esters IVa−c.

The cinnamyl esters were synthesized according to a literature

procedure with slight modiﬁcations.¹⁹LiCl (509 mg; 12 mmol, 1.2

equiv) was weighed up in an oven-dried 100 mL round-bottom ﬂask

and put under vacuum. The ﬂask was heated with a hot air gun for

several minutes and allowed to cool down to room temperature, then

back-ﬁlled with nitrogen. The ﬂask was put under vacuum and back-

ﬁlled with nitrogen twice more. Dried MeCN (30 mL) was added

with a syringe, and the resulting suspension was cooled to 0 °C in an

ice-water bath. Triethylphosphonoacetate (2.4 mL, 12 mmol, 1.2

equiv) was added with a syringe while stirring. After 20 min was

added benzaldehyde III (10 mmol, 1.0 equiv), followed by DBU (1.8

mL, 12 mmol, 1.2 equiv) dropwise. The resulting reaction mixture

was allowed to warm up to room temperature and stirred until

completion was indicated by TLC analysis. Upon complete

consumption of the aldehyde, the mixture was concentrated under

reduced pressure and partitioned between diethyl ether (30 mL) and

(E)-3-(3-Methoxyphenyl)prop-2-en-1-ol (Va). The compound was

prepared at 9.30 mmol scale by following the general procedure. The

reaction was ﬁnished after 1 h. Transparent liquid (1.54 g, quant.). IR

(KBr): ν 3361, 2939, 2836, 1599, 1580, 1490, 1465, 1454, 1433,

1289, 1257, 1156, 1046, 1011, 970 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃): δ 7.27−7.20 (m, 1H), 7.02−6.96 (m, 1H), 6.93 (t, J = 2.1

Hz, 1H), 6.81 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.59 (d, J = 15.9 Hz,

1H), 6.36 (dt, J = 15.9, 5.7 Hz, 1H), 4.33 (dd, J = 5.7, 1.5 Hz, 2H),

3.82 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 159.9, 138.3,

L

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Note

131.1, 129.7, 129.0, 119.3, 113.5, 111.9, 63.8, 55.4. The NMR data are

in agreement with published data for this compound.^20c

procedure. The reaction was ﬁnished after 5 min. White solid (1.10 g,

91% crude yield). ¹H NMR (400 MHz, CDCl₃): δ 7.31 (d, J = 8.6 Hz,

2H), 6.85 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 15.6 Hz, 1H), 6.26 (dt, J =

15.6, 7.9 Hz, 1H), 4.17 (dd, J = 7.9, 1.0 Hz, 2H), 4.04 (q, J = 7.0 Hz,

2H), 1.41 (t, J = 7.0 Hz, 3H). This compound is unstable and has to

be used in the next step immediately.

(E)-1-(3-Bromoprop-1-en-1-yl)-4-nitrobenzene (IId). The com-

pound was prepared at 6.0 mmol scale by following the general

procedure but with DCM as solvent and 1.22 equiv of PBr₃used. The

reaction was complete after 40 min. Light yellow solid (1.39 g, 96%

crude yield). IR (KBr): ν 1595, 1515, 1341, 1197, 1107, 971 cm⁻¹. ¹H

NMR (400 MHz, CDCl₃): δ 8.20 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8

Hz, 2H), 6.71 (d, J = 15.7 Hz, 1H), 6.61−6.51 (m, 1H), 4.16 (dd, J =

7.5, 0.9 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 147.5, 142.3,

132.2, 130.0, 127.4, 124.2, 32.0. The NMR data are in agreement with

published data for this compoud.²⁰ⁱ

2-(Prop-2-yn-1-yloxy)benzaldehyde (VI). Under an atmosphere of

nitrogen, salicylaldehyde Ia (1.07 mL, 1.00 equiv) and K₂CO₃(2.76 g,

2.00 equiv) were suspended in DMF (5.0 mL). While stirring at r.t.,

propargyl bromide (80% w/w in toluene, 1.45 mL, 1.30 equiv) was

added. The reaction mixture was stirred for 2.5 h at r.t. until

completion was indicated by TLC analysis, then diluted with DCM

(100 mL) and washed with water (50 mL), followed by brine (3 × 50

mL). The organic phase was dried, ﬁltered, and concentrated. The

crude product was puriﬁed with automated ﬂash column chromatog-

raphy (50 g cartridge, 0−4% EtOAc in heptane). Oﬀ white solid (1.50

g, 94%). NMR spectra were in agreement with published data.²¹

(R)-8-Cyclopropyl-6-nitro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]-

pyridine-3-carboxylic Acid (VII). The ester (methyl (R)-8-cyclo-

propyl-6-nitro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-car-

boxylate, 50 mg, 0.169 mmol, 1.0 equiv) was dissolved in THF (4

mL) and put under stirring at r.t. LiOH solution (2.36 mL, 0.1M, 1.4

equiv) was added. TLC after 70 min indicated complete conversion.

HCl (1 M aq., 253 μL, 1.5 equiv) was added. After 5 min stirring, the

mixture was evaporated to water, diluted with brine (3 mL), and

extracted with CHCl₃/IPA 9:1 (10 + 5 mL). The organic phases were

combined, dried, ﬁltered, and evaporated (47.4 mg). The residue was

trituated with diethyl ether (2 × 2,5 mL) and dried under vacuum.

Yellow solid (35 mg, 74%). [α]_D−1.3° [c 0.15, (CD₃)₂SO]. IR

(KBr): ν 3393, 3010, 1738, 1679, 1496, 1391, 1313, 1266, 1240, 1008

cm⁻¹. ¹H NMR [600 MHz, (CD₃)₂SO] δ 13.84 (s, 1H), 8.13 (s, 1H),

5.67 (dd, J = 9.6, 1.9 Hz, 1H), 4.03 (dd, J = 12.1, 9.6 Hz, 1H), 3.75

(dd, J = 12.1, 1.9 Hz, 1H), 1.63 (tt, J = 8.3, 5.1 Hz, 1H), 0.92−0.84

(m, 2H), 0.73−0.66 (m, 1H), 0.66−0.60 (m, 1H). ¹³C{¹H} NMR

[151 MHz, (CD₃)₂SO] δ 168.8, 161.1, 152.2, 138.7, 132.1, 112.2,

64.2, 32.3, 11.9, 6.4, 6.2. HRMS (ESI-TOF) m/z: [M + Na]⁺Calcd

for C₁₁H₁₀N₂NaO₅S⁺305.0208; Found 305.0198.

(E)-3-(3-(Triﬂuoromethyl)phenyl)prop-2-en-1-ol (Vb). The com-

pound was prepared at 8.89 mmol scale by following the general

procedure. The reaction was complete after 1 h. Transparent liquid

(1.76 g, quant.). IR (KBr): ν 3345, 2869, 1487, 1441, 1334, 1270,

1199, 1165, 1125, 1099, 1072, 1011, 967 cm⁻¹. ¹H NMR (400 MHz,

CDCl₃): δ 7.63 (s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.52−7.39 (m, 2H),

6.71−6.61 (m, 1H), 6.44 (dt, J = 15.9, 5.4 Hz, 1H), 4.36 (dd, J = 5.4,

1.6 Hz, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 137.6, 131.2, (q, J

= 32.3 Hz), 130.7, 129.7 (d, J = 1.4 Hz), 129.5, 129.2, 124.3 (q, J =

3.8 Hz), 124.2 (q, J = 136.2 Hz), 123.2 (q, J = 3.8 Hz), 63.5. ¹⁹F

NMR (376 MHz, CDCl₃): δ −62.81. The NMR data are in

agreement with published data for this compound.^20d

(E)-3-(4-Ethoxyphenyl)prop-2-en-1-ol (Vc). The compound was

prepared at 8.57 mmol scale by following the general procedure. The

reaction was complete after 2 h. White solid (1.52 g, quant.). IR

(KBr): ν 3363, 3274, 2979, 2931, 1605, 1512, 1476, 1447, 1397,

1305, 1269, 1246, 1175, 1114, 1087, 1048, 1007, 970 cm⁻¹. ¹H NMR

(400 MHz, CDCl₃): δ 7.38−7.29 (m, 2H), 6.92−6.80 (m, 2H),

6.62−6.48 (m, 1H), 6.23 (dt, J = 15.9, 6.0 Hz, 1H), 4.35−4.27 (m,

2H), 4.04 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H). ¹³C{¹H}

NMR (100 MHz, CDCl₃): δ 158.9, 131.2, 129.4, 127.8, 126.2, 114.7,

64.1, 63.6, 15.0. The NMR data are in agreement with published data

for this compound.^20e

(E)-3-(4-Nitrophenyl)prop-2-en-1-ol (Vd). The compound was

prepared at 10.4 mmol scale by following the general procedure. The

reaction was ﬁnished after 1 h. Light yellow solid (1.89 g, quant.). IR

(KBr): ν 3508, 3108, 3080, 1652, 1596, 1504, 1455, 1411, 1338,

1101, 972, 958 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ 8.23−8.10 (m,

2H), 7.59−7.44 (m, 2H), 6.72 (dt, J = 16.0, 1.8 Hz, 1H), 6.54 (dt, J =

16.0, 5.1 Hz, 1H), 4.40 (dd, J = 5.1, 1.7 Hz, 2H). ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 147.1, 143.4, 133.7, 128.4, 127.1, 124.2, 63.3. The

NMR data are in agreement with published data for this compound.^20f

General Procedure for Synthesis of Cinnamyl Bromides

IIa−d. The cinnamyl bromides were synthesized according to a

literature procedure with slight modiﬁcations.^19cThe cinnamyl

alcohol V (2.0 mmol, 1.0 equiv) was weighed up in an oven-dried

Biotage microwave reaction tube and put under nitrogen. Dried

diethyl ether (4 mL) was added, and the resulting suspension was

cooled to 0 °C in an ice/water bath. PBr₃(0.20 mL, 2.0 mmol, 1.0

equiv) was added dropwise with a syringe. The resulting mixture was

stirred at 0 °C until complete consumption of the starting material

was indicated by TLC. The reaction was quenched at 0 °C by slow

and careful addition of a concentrated phosphate buﬀer at pH 7.4 (4

mL). The reaction mixture was transferred to a separation funnel, and

the phases were separated. The aq. phase was extracted with diethyl

ether (2 × 5 mL). The combined organic phases were dried over

sodium sulfate, ﬁltered, and concentrated by rotary evaporation. The

crude cinnamyl bromide was used for the next step without further

puriﬁcation or storage.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c01699.

■

sı

(E)-1-(3-Bromoprop-1-en-1-yl)-3-methoxybenzene (IIa). The

compound was prepared at 4.45 mmol scale by following the general

procedure but with 0.915 equiv of PBr₃used. The reaction was

complete after 5 min. Transparent liquid (0.938 g, 92.8% crude yield).

¹H NMR (400 MHz, CDCl₃): δ 7.25 (t, J = 7.9 Hz, 1H), 6.98 (dt, J =

7.6, 1.2 Hz, 1H), 6.92 (t, J = 2.1 Hz, 1H), 6.86−6.80 (m, 1H), 6.62

(d, J = 15.5 Hz, 1H), 6.39 (dt, J = 15.5, 7.7 Hz, 1H), 4.16 (dd, J = 7.8,

1.0 Hz, 2H), 3.82 (s, 3H). The NMR data are in agreement with

published data for this compound.^20g

1

Schemes S1−S4; H NMR, ¹³C NMR, and ¹⁹F NMR

spectra for all new compounds; and ﬁbrils binding

results for carboxylic acids 15a−k and 16a−e (PDF)

AUTHOR INFORMATION

Corresponding Author

■

(E)-1-(3-Bromoprop-1-en-1-yl)-3-(triﬂuoromethyl)benzene (IIb).

The compound was prepared at 3.98 mmol scale by following the

general procedure. The reaction was complete after 25 min. Oﬀ white

Fredrik Almqvist − Umeå University, Department of Chemistry,

901 87 Umeå, Sweden; orcid.org/0000-0003-4646-0216;

Email: fredrik.almqvist@umu.se

1

solid (0.977 g, 92.6% crude yield). H NMR (600 MHz, CDCl₃): δ

7.63 (s, 1H), 7.54 (ddd, J = 19.3, 7.7, 1.7 Hz, 2H), 7.45 (t, J = 7.7 Hz,

1H), 6.67 (d, J = 15.6 Hz, 1H), 6.47 (dt, J = 15.5, 7.7 Hz, 1H), 4.15

(dd, J = 7.7, 1.1 Hz, 2H). The NMR data are in agreement with

published data for this compound.^20h

(E)-1-(3-Bromoprop-1-en-1-yl)-4-ethoxybenzene (IIc). The com-

pound was prepared at 5.03 mmol scale by following the general

Authors

Dan E. Adolfsson − Umeå University, Department of

Chemistry, 901 87 Umeå, Sweden

Mohit Tyagi − Umeå University, Department of Chemistry, 901

87 Umeå, Sweden

M

https://dx.doi.org/10.1021/acs.joc.0c01699

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Note

Weise, C.; Nordvall, L.-M.; Prasad, G. K.; Olofsson, A.; Larsson, G.;

Almqvist, F.; Wittung-Stafshede, P. Modulation of α -Synuclein

Fibrillization by Ring-Fused 2-Pyridones: Templation and Inhibition

Involve Oligomers with Different Structure. Arch. Biochem. Biophys.

2013, 532 (2), 84−90 and references cited within.

Pardeep Singh − Umeå University, Department of Chemistry,

901 87 Umeå, Sweden

Adrian Deuschmann − Umeå University, Department of

Chemistry, 901 87 Umeå, Sweden

̈

́

Jorgen Åden − Umeå University, Department of Chemistry, 901

(3) (a) Singh, P.; Chorell, E.; Krishnan, K. S.; Kindahl, T.; Åden, J.;

Wittung-Stafshede, P.; Almqvist, F. Synthesis of Multiring Fused 2-

Pyridones via a Nitrene Insertion Reaction: Fluorescent Modulators

of α -Synuclein Amyloid Formation. Org. Lett. 2015, 17 (24), 6194−

6197. (b) Sellstedt, M.; Almqvist, F. Synthesis of a Novel Tricyclic

Peptidomimetic Scaffold. Org. Lett. 2008, 10 (18), 4005−4007.

87 Umeå, Sweden

Anna L. Gharibyan − Umeå University, Department of

Chemistry, 901 87 Umeå, Sweden

Sanduni Wasana Jayaweera − Umeå University, Department of

Chemistry, 901 87 Umeå, Sweden

Anders E. G. Lindgren − Umeå University, Department of

Chemistry, 901 87 Umeå, Sweden

Anders Olofsson − Umeå University, Department of Chemistry,

901 87 Umeå, Sweden

́

(c) Singh, P.; Adolfsson, D. E.; Åden, J.; Cairns, A. G.; Bartens, C.;

̈

Brannstrom, K.; Olofsson, A.; Almqvist, F. Pyridine-Fused 2-

Pyridones via Povarov and A3 Reactions: Rapid Generation of

Highly Functionalized Tricyclic Heterocycles Capable of Amyloid

Fibril Binding. J. Org. Chem. 2019, 84 (7), 3887−3903.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c01699

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Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

F.A. is grateful to the Swedish Research Council (2017-02339,

2017-00695, and 2018-04589), the Knut and Alice Wallenberg

■

̈

foundation (KAW 2013.0031), the Goran Gustafsson

foundation, the Kempe Foundation (SMK-1755), the Swedish

Foundation for Strategic Research (SB12-0070), the National

Institutes of Health (R01AI134847-01A1), the Erling Perssons

Stiftelse and the Michael J Fox foundation for ﬁnancial

support. The authors acknowledge the facilities and technical

assistance of the Umeå Core Facility Electron Microscopy

(UCEM) at the Chemical Biology Centre (KBC), Umeå

University, a part of the National Microscopy Infrastructure

(NMI).

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Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β Fibrils

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