In-flow photooxygenation of aminothienopyridinones generates iminopyridinedione PTP4A3 phosphatase inhibitors

Article abstract of DOI:10.1039/c9ob00025a

A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones to produce 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-diones has been developed, utilizing ambient air as the sole reactant. N-H Imines are formed as the major products, and excellent functional group tolerance and conversion on gram-scale without the need for chromatographic purification allow for facile late-stage diversification of the aminothienopyridinone scaffold. Several analogs exhibit potent in vitro inhibition of the cancer-associated protein tyrosine phosphatase PTP4A3, and the SAR supports an exploratory docking model.

Full text of DOI:10.1039/c9ob00025a

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In-flow photooxygenation of
aminothienopyridinones generates
Cite this: DOI: 10.1039/c9ob00025a
iminopyridinedione PTP4A3 phosphatase
inhibitors†
a
Nikhil R. Tasker, a Ettore J. Rastelli, a Isabella K. Blanco, b James C. Burnett,
a
Elizabeth R. Sharlow, b John S. Lazo b and Peter Wipf
*
A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones to produce 7-imi-
nothieno[3,2-c]pyridine-4,6(5H,7H)-diones has been developed, utilizing ambient air as the sole reactant.
N-H Imines are formed as the major products, and excellent functional group tolerance and conversion
on gram-scale without the need for chromatographic purification allow for facile late-stage diversification
of the aminothienopyridinone scaffold. Several analogs exhibit potent in vitro inhibition of the cancer-
associated protein tyrosine phosphatase PTP4A3, and the SAR supports an exploratory docking model.
Received 5th January 2019,
Accepted 6th February 2019
DOI: 10.1039/c9ob00025a
rsc.li/obc
ambient conditions.9–11 Therefore, N-H imines are underrepre-
sented in the literature and are frequently only used as transi-
Introduction
Photooxygenations are considered as green alternatives to stan- ent intermediates.12 An exception are natural products such as
dard oxidation methods, as the former involve light and gener- caulibugulone E, where the imine is stabilized by conjugation
ally environmentally innocuous reagents.1,2 Transition metal- to an arene and an electron-rich enamine.13 Caulibugulone E
free conditions with stoichiometric molecular oxygen or air as has distinct biological properties and the N-H imine can be
reactants can eliminate the need for toxic or expensive cata- prepared by treatment of the corresponding carbonyl com-
lysts. Photosensitizers such as Rose Bengal, Methylene Blue, pound, caulibugulone A, with ammonia in the presence of Ti
and tetraphenylporphyrin have been used in several natural (O-i-Pr)4.14 Oxygenation of aryl amines represents another
product syntheses to generate singlet oxygen, which reacts access point to N-unsubstituted imines, but often results in
with electron-rich alkenes and aromatic rings.1,2 For example, hydrolysis under the reaction conditions, or a mechanistically
a
photosensitized singlet oxygen transformation was complex displacement of the amine with dioxygen.1 Examples
implemented in the formal synthesis of daphnane diterpene in the literature where the imine is preserved are scarce and
ortho esters and several alkaloids.2,3 While photooxygenation low yielding.15,16 Fremy’s salt is one of many methods to
is an atom-economical alternative to commonly used reagents mimic singlet oxygen,17 but it is unselective for imine for-
and metal-based oxidation protocols, regioselectivity is often mation and results in hydrolysis.18
difficult to control, especially with alkenes,1 and sometimes
We recently reported that the photooxygenation of thieno-
requires complex reactors,4 photosensitizers,5–7 photocata- pyridone 1 can be performed in high yield, but on limited
lysts,8 or other additives.1,8
scale (<50 mg), to produce a novel nanomolar PTP4A3 phos-
The synthesis of N-unsubstituted imines remains a challen- phatase inhibitor,19 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-
ging problem due to their propensity to hydrolyze under dione 2 (Scheme 1).20 For the further investigation of the intri-
guing biological profile of 2,21 particularly through in vivo
studies, synthetic access to gram-quantities of this material
aDepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
became a critical requirement. Due to the very sluggish reac-
E-mail: pwipf@pitt.edu
bDepartment of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
†Electronic supplementary information (ESI) available: Complete synthesis
schemes, sketch of flow system and additional experimental information, con-
centration-PTP4A3 phosphatase inhibition response curves and assay methods,
photooxygenation optimization studies, drug-likeliness calculations, docking
methods, X-ray diffraction data, fluorescence and UV-VIS spectra, and copies of
1H, 13C, and 19F NMR spectra. CCDC 1880535. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c9ob00025a
tion progress in the batch setup, which was aggravated by the
poor solubility of both substrate and product, a flow process
starting with a diluted, homogeneous solution of the reactant
was investigated. Photochemical flow processes allow for a sig-
nificant decrease in reaction time by increasing the exposure
of the reaction mixture to light while removing light-capturing
products and precipitates.22 Herein, we describe further
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Table 1 Flow photooxygenation of 1 to 2a
Entry
Solvent
Light source
Ratio of 2 to 3b
1
2
3
4
5
6
7
1,2-DCEc
CFL
CFL
CFL
CFL
CFL
CFL
CFL
0 : 1
1.5 : 1
0 : 1
8.7 : 1
10 : 1
7.5 : 1
6 : 1
1,2-DCEd
d
CHCl3
MeOHd
MeOH
i-PrOH
HFIP
8
THF
CFL
6.3 : 1
rsme
6.7 : 1
10 : 1
9
MeOH
i-PrOH
MeOHg
Red (IR) lamp
Red (IR) lamp
CFL
10f
11
Scheme 1 Photooxygenation of thienopyridone 1 and X-ray structure
of hydrolysis product 3 (CCDC 1880535†).
a Optimizations were performed on a 10 mg scale with 30 mL of
solvent (at a concentration of 1.4 mM), utilizing an 18 W compact fluo-
rescent lamp (CFL) with a flow rate of 1.9 mL min−1. The tubing
volume was 80 mL. b Ratios were determined by 1H NMR integration.
c Flow rate = 0.1 mL min−1 d Flow rate = 0.8 mL min−1 e Recovered
. .
starting material. f Three mol% methylene blue added. g Distilled over
Mg turnings and stored over 3 Å molecular sieves for 5 days.
investigations of the scope of the photooxygenation of
4-aminothienopyridones, including the use of a macroflow
photoreactor.
tion band of the 353 nm peak of thienopyridone 1 extended to
500 nm into the visible range of the spectrum. The corres-
ponding absorption maximum of imine 2 was 379 nm, and
Results and discussion
In the original synthesis of 2,20 a minor by-product was this peak extended to 450 nm. Notably, both amine 1 and
observed in the batch photooxygenation process, and the iden- imine 2 exhibited a strong green fluorescence. Combined,
tity of this compound eluded us for some time. Some reports these data suggest that these substrates act as their own photo-
have suggested that these type of transformations result in sensitizers. Experiments with Rose Bengal and Methylene Blue
dimers;23 alternatively, the corresponding carbonyl compound were explored in an attempt enhance the reactivity of 1 and the
is also known to be the major product in related conversions, ratio of 2 to 3, but no substantial changes were observed when
either formed directly or through hydrolysis.18,23a
When the reaction mixture was treated with aqueous sulfu- photosensitizers.
a white CFL or white LED lights were used with these
ric acid, we were able to isolate the by-product as the sole
Chlorinated solvents such as 1,2-dichloroethane (DCE) and
product. Furthermore, an X-ray structure confirmed its assign- CHCl3 exhibited a strong preference for the formation of 3
ment
as
tricarbonyl
compound
3
(Scheme
1). (Table 1, entries 1–3). MeOH showed selectivity for the for-
Photooxygenation of 1 in a methanol/water mixture at neutral mation of 2, and the ratio of 2 to 3 increased when the flow
pH still greatly favored imine formation; therefore, the for- rate was accelerated (entries 4 and 5). The use of dry methanol
mation of tricarbonyl compound 3 in the reaction mixture is did not appreciably affect the outcome (entry 11).
unlikely to proceed substantially through the hydrolysis of 2. Photooxygenation in hexafluoroisopropanol (HFIP) resulted in
While there is only a single previous report on a compound a complex mixture of products. Other protic and polar aprotic
containing the thienopyridinetrione scaffold of 3 in the patent solvents, such as i-PrOH and THF, respectively, resulted in
literature,24 structurally related pyridine-, pyrrolopyridine-, and diminished selectivity (entries 6 and 8). Interestingly, imine
isoquinolinetriones have been obtained by oxidations of pyri- formation was favored in solvents with short singlet oxygen
dines, pyrrolopyridines, and isoquinolines, respectively, as lifetimes.27 Additionally, faster flow rates often provided an
well as via the Beckmann rearrangement or the azido-Schmidt increase in imine formation; although, flow rates above 1.9 mL
reaction of ninhydrin.23b,c,25,26 Some of these compounds are min−1 led to decreased conversion.
of pharmaceutical interest as hepatitis C NS3 proteinase and
caspase inhibitors.23c,26
Optimized conditions required MeOH as the solvent, a
household 18 W CFL light bulb as the light source, and a flow
Thienopyridone 1 was used to optimize the photooxygena- rate of 1.9 mL min−1, resulting in a substrate residence time in
tion conditions leading to 2 in a photo-flow setup (Table 1; see the flow reactor of 42 min, which is a significant improvement
also ESI, Fig. S1, S2, and Table S1†). Solvent, light source, flow over the previous multi-day batch process. With these con-
rate, and additives were varied to minimize the formation of 3. ditions, the desired imine 2 was obtained in a 10 : 1 ratio over
Additives generally increased the content of 3 or decreased the ketone 3. It was also found that white LED lights worked just
rate of conversion of 1, and photosensitizers were not effective. as effectively as the CFL. No additional air or oxygen was
As expected, conversion was not affected by the concentration bubbled through the system; the mole fraction of O2 in MeOH
of the starting material, but the low solubilities of 1 and 2 from exposure to ambient air was sufficient to keep the con-
required moderate to high dilution. In MeOH, the UV-absorp- centration of O2 in the open flow system at any time at least 2
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times higher than the concentration of the substrate (1.4 mM).
Conversely, when the photo-flow reaction was performed
under otherwise optimized conditions but under an atmo-
sphere of argon instead of air, only 17% conversion was
observed by 1H NMR.
In order to examine the substrate scope of the reaction, a
general synthetic route allowing for late-stage diversifica-
tion of the thienopyridone scaffold was accomplished in 5
steps from commercially available aldehyde 4 (Scheme 2;
for a complete schematic overview of intermediates and pro-
ducts, see ESI Schemes S1–8†). A Knoevenagel condensation
using malonic acid afforded 5 in 94% yield. Acyl azide for-
mation, Curtius rearrangement, and concomitant cycliza-
tion provided the thienopyridone scaffold 6 in 52% yield
over 2 steps. Nitration attempts using nitric acid resulted in
poor mass recovery; therefore, nitration was performed with
tert-butyl nitrite to give the nitrated product 7 in 72%
yield.28 A late stage Suzuki–Miyaura coupling with aryl
boronic acids allowed for facile substrate diversifications to
give 8a–p.
Isolation of the enamine after reduction of the nitro group
in 8 proved difficult due to the formation of trace photooxy-
genation products during the purification step. Therefore, a
2-step procedure was implemented to examine the substrate
1
scope (Scheme 3). By H NMR analysis in the presence of an
internal standard (1,3,5-trimethoxybenzene), 8c and 8e were
reduced to the corresponding amine intermediates in 80%
and 67% yield, respectively.
Excellent functional group tolerance was observed, as elec-
tron-rich and -deficient arenes, halides, and amines did not
impede reactivity. Additionally, the photooxygenation of
N-alkylated amides, obtained from 8p20 by alkylation with R’I
in the presence of K2CO3 or under Mitsunobu reaction con-
Scheme 3 Conversion of nitropyridones 8a–p to 7-iminothieno[3,2-c]
pyridine-4,6(5H,7H)-diones 9a–q and attempted conversion of 8p to
acetimide 10.
ditions
with
R’OH,
produced
N-methyl
9p
and
N-methylcyclopropyl 9q in 19% and 31% yield, respectively,
over 3 steps. In contrast, N-acylation of enamine 1 obtained unreactive to photooxygenation, likely due to the decreased
after reduction of the nitro group in 8p rendered the substrate electron density at the α-carbon, and compound 10 was not
observed.
The lower yields in the telescoped conversion of nitroalk-
enes 8 to α-ketoimines 9 vs. the two-step process can be attrib-
uted to product loss in the separation of the imines from
minor ketone side products during chromatography on SiO2.
Imine 9l was exceptionally difficult to purify, resulting in a
poor yield of 8%. Therefore, for scale-up purposes, it became
necessary to develop a method to isolate the imine product
from the ketone without chromatography. Recrystallization to
enrich the imines was not successful. Amines can form
adducts with BF3·OEt2,29 but attempts to generate an imine–
boron complex proved similarly unsuccessful. An aza-Wittig
reaction utilizing P,P,P-triphenylphosphazene,30 or the Ti(O-i-
Pr)4/NH3 protocol14a to convert the imine (2)/ketone (3)
mixture exclusively to the imine also failed. In situ reaction
with hexamethyldisilazene (HMDS) and CsF in DMF, or TBAF
in THF,31 provided the imine 2 in >95% selectivity over ketone
3; however, chromatography was still needed to remove other
trace impurities.
Scheme 2 Synthesis of thienopyridone scaffold enabling late-stage
diversifications with aryl boronic acids.
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Scheme 4 Scale-up of optimized in-flow photooxygenation and tele-
scoped conversion of 8p to give 2.
Scheme 5 Photooxygenation of alternative heterocyclic scaffolds.
Compounds 18 and 19 failed to undergo the desired oxygenation after
nitro group reduction.
Gratifyingly, treatment of a mixture of 2 and 3 with NH4OAc
in MeOH at 65 °C resulted in quantitative formation of the
imine. A homogenous solution was necessary to obtain full
conversion to the imine. When the reaction was performed at
reflux, decomposition was observed, likely due to evaporation
of ammonia; therefore, a sealed reaction vessel was required.
Interestingly, NH4Cl did not react with the ketone, and
NH4OH and methanolic NH3 caused decomposition.
With a modified purification protocol for the final products
9 established, the scalability of the photooxygenation was
investigated next. The synthesis of 8p was performed via an
alternative route than previously reported,20 with the goal
being to facilitate compound throughput (Scheme 4).
Commercially available thiophene 11 was treated with triphos-
gene to give the isocyanate, which was subjected without puri-
fication to stoichiometric ferric chloride in CH2Cl2 to give
lactam 12 in 73% yield over the two steps. C-2 bromination of
12 in acetic acid and Suzuki–Miyaura coupling with phenyl-
boronic acid proceeded in 64% overall yield to give 13. The
coupling product was dehydrogenated with DDQ and nitrated
with tert-butyl nitrite to generate 8p. The two-step nitro group
reduction-photooxygenation was performed on a 500 mg and a
1 g scale, and the combined yields of 2 and 3 in these batches
were 68% and 67%, respectively. Subsequently, imination of
these reaction mixtures using NH4OAc resulted in quantitative
conversions, providing 322 mg and 634 mg, respectively, of
iminothienopyridone 2 (Scheme 4).
We also investigated the photooxygenation of other fused
pyridones (Scheme 5). Unlike the thienopyridones, these sub-
strates were not fluorescent and required photosensitizers
such as Methylene Blue to react with dioxygen.
4-Nitroisoquinoline 14 provided tricarbonyl product 15 in 17%
yield, but attempts to generate the imine were unsuccessful, in
agreement with previous reports.23a Interestingly, thieno[2,3-c]
pyridin-7(6H)-one 16 behaved very differently compared to the
regioisomeric thieno[3,2-c]pyridin-4(5H)-one 8, despite their
close structural similarity. Unlike 2, the amine derived from 16
fluoresced with a pale-orange colour under a UV light, and was
less reactive, as it required a photosensitizer for further conver-
sion. The reaction profile was not clean, and the only product
that could be isolated was tricarbonyl compound 17.
tion after nitro group reduction, likely due to deactivation of
the pyridone by the fused, electron-withdrawing pyridine ring,
and only starting material was recovered. In contrast, when the
very electron-rich enamine derived from the nitro group
reduction of azacarbazole 19 was subjected to photooxygena-
tion, only decomposition products were observed. These
results suggest that the structure of the pyridone is critically
important for the desired reactivity, and computational and
spectroscopic studies to benchmark the electronic properties
required for the desired reaction pathway are currently
underway.
A proposed mechanism for the enamine oxygenation is
shown in Scheme 6. Upon irradiation, singlet oxygen is gener-
ated, and may react with 20 via an ene-type reaction, in
analogy to the conversion of alkenes.32 In most of these cases,
a hydroperoxide is the main product and is subsequently con-
verted to an alcohol or carbonyl group.1 During the course of
this study, a hydroperoxide intermediate was not observed.
Tautomerization of 21 to 22 should be favored due to aromati-
zation, followed by elimination of water via a vinylogous
Kornblum-DeLaMare rearrangement to give 23.
The value of the photooxygenation of aminothienopyridi-
nones is significantly enhanced by the utility of these
scaffolds. Thienopyridones and their analogs are privileged
structural motifs for the development of biologically active
molecules.33,34 While direct functionalizations on this hetero-
cyclic core are rare, the biological properties of the chemotype
can be significantly improved by such modifications.35 The
relatively simple thienopyridone 1 was shown to be a selective
phosphatase inhibitor and to suppress tumor cell growth.36
Our original entry into photooxygenation20 was inspired by the
Scheme 6 Proposed mechanism for formation of 3-iminopyridine-2,6
Isoquinolin-1(2H)-one 18 was unreactive in the photooxygena- (1H,3H)-diones.
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desire to diversify this scaffold by the introduction of the arene fused to the pyridone is a critical factor for the
additional carbonyl, amine, and imine substituents. inhibitor interaction with the protein. Some of the active halo-
Advanced ovarian cancer and triple negative breast cancer genated analogs, i.e. 9b, 9f, and 9k, which only show minor
respond poorly to existing drugs and, thus, demand new thera- potency variations, may have fewer metabolic liabilities com-
pies. The protein tyrosine phosphatase PTP4A3 (Phosphatase pared to 2 and are therefore worthy of further investigation.
of Regenerating Liver-3, PRL-3) is overexpressed in these N-Alkyl analogs 9p and 9q are of particular note, as this is the
cancer tissues.19 PTP4A3 also promotes cancer cell migration first time we have seen a significant retention of phosphatase
and invasion, and is believed to be the most oncogenic of all inhibition potency with modifications directly on the imino-
tyrosine phosphatases.21 Previously, we found that the imi- pyridone scaffold of 2. Most of the analogs retained drug-like
nothienopyridone, JMS-053 (2), is a specific, cell active small properties as calculated computationally (ESI, Table S3†).
molecule PTP4A3 inhibitor superior to 1 with an in vitro IC50
We next performed exploratory docking studies with the
for PTP4A3 of 30–40 nM.20,21 However, the limited scope of the iminopyridinedione scaffold using the A chain of PTP4A3 PDB
batch-photooxygenation method had hampered our efforts to entry 5TSR (Fig. 1).19c Based on the model, flexible loops
investigate structure–activity relationships (SAR) for this play a significant role in shaping the inhibitor binding site.
scaffold. We were therefore interested to test the new analogs In the closed WPD loop (slate blue cartoon) conformation
generated through in-flow photooxygenation in our biochemi- of the reduced form of the enzyme, the orientation of the
cal potency assay (Table 2, Fig. S3†).
P-Loop (Cys104 – Arg110; cyan cartoon) facilitates two strong
It is remarkable that 16 of the 19 newly investigated analogs hydrogen bonds with the carbonyl oxygens of inhibitor 2,
generated by the flow-photooxygenation process retained the while at the same time providing sufficient steric space to
ability to inhibit the PTP4A3 phosphatase in vitro by at least accommodate small, hydrophobic substitutions on the inhibi-
50% at a concentration <100 nM (IC50). This finding reaffirms
the robustness of this scaffold for further analog development.
Three of the 19 characterized analogs, namely 9e, 9g, and 17
(Table 2, entries 7, 9, and 20), had IC50 values that were signifi-
cantly poorer than 2. The significant loss of potency in 9e and
9g, and the 3-fold reduced activity of 9o, which contain bulky
moieties at the para- and meta-positions of the phenyl substi-
tuent, suggests further modifications at these sites might not
be productive. The >3-fold loss in potency for the inverted thio-
phene scaffold in 17 vs. the isoelectronic 3 also indicates that
Table 2 In vitro inhibition of PTP4A3 phosphatase activitya
Entry
Compound
IC50 (nM)
SEM
N
1
2
3
4
5
6
7
8
JMS-053 (2)
3
34.7
49.5
61.7
41.9
62.5
71.1
255.9
39.1
192.8
65.7
53.4
47.7
36.1
53.4
47.4
67.7
98.2
48.9
85.7
162.2
2.5
2.9
14.2
6
6
3
3
3
3
3
3
3
6
3
3
3
3
3
3
6
6
3
3
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
17
1.2
2.3
2.5
12.3
1.3
6.1
4.1
1.5
2.7
1.4
1.5
2.4
3.0
2.5
12.0
6.0
14.6
9
10
11
12
13
14
15
16
17
18
19
20
Fig. 1 Panel (a) noncovalent docking model of inhibitor 2, shown with
magenta carbons, in the closed WPD loop (slate blue cartoon) confor-
mation of the reduced form of PTP4A3 (PDB entry 5TSR).19c Panel (b)
covalent docking model of inhibitor 2, shown with dark orange carbons,
in the same binding pocket. Hydrogen bonds are shown in yellow dash,
a potential covalent bond forming distance is highlighted in red dash
(Panel (a)), and critical amino acid residues and peptide strands are
labelled.
a Recombinant human PTP4A3 phosphatase was used and the enzy-
matic assay was performed as previously described,20 except that it was
fully automated using an Agilent Bravo Liquid Handling Platform to
increase reproducibility. Results are the mean values of N independent
assays, each comprising 10-point concentration curves conducted with
six replicates (see ESI).
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tor imide nitrogen (e.g.s., 9p and 9q). Moreover, the reorienta- resolves the limitations in scope and scale-up associated with
tion of the P-Loop also repositions the catalytically important the previous light-mediated batch reaction.20 Accordingly, we
Arg 110, such that it can no longer facilitate substrate bin- generated a series of new analogs to elucidate SAR trends,
ding.19d Concomitantly, the loop composed of residues Val47 – and identified several new PTP4A3 phosphatase inhibitors
Lys55 (teal cartoon) orients such that Cys49 can engage in a with low nanomolar IC50 values, thus significantly broaden-
hydrogen bond with the inhibitor’s imine nitrogen. It is ing the utility of this new heterocycle for pharmacological
notable that the same three hydrogen bonds are predicted to investigations. We also generated a binding model and
occur for keto analog 3. At the distal end of the compound, explored a potential covalent active site cysteine interaction
the phenyl ring binds in a pocket surrounded by strictly hydro- mode. Our results suggest that the iminothienopyridone che-
phobic residues, as well as two Trp residues, one of which is motype may be valuable for the development of a first-in-
located in the WPD loop (i.e., Trp68). The properties of this class PTP4A3 inhibitor directed against breast and ovarian
pocket are in agreement with the SAR that was found for the cancer.
new inhibitor series, i.e., the size and location limitations of
the substituents on the phenyl ring. For example, the model
rationalizes the weaker potencies of rigid para-substituents on
the phenyl ring. Based on the general binding mode shown in
Fig. 1, the significantly reduced activity of the large, rigid
Experimental section
General methods
4-OPiv of 9e is predicted to result from both steric and electro- Unless stated otherwise, all reactions were performed under
static incompatibilities with the binding pocket.
an atmosphere of N2 that was passed through a column
An interesting perspective of the docking model of inhibitor (10 × 2 cm) of Drierite®. Air was used for all in-flow photo-
2, shown in Panel (a), lies in its extension to a covalent oxygenation reactions, whereas the batch photooyxygena-
binding mode. Specifically, the more electrophilic imide carbo- tion and the nitration with t-BuONO used oxygen in a
nyl group in 2 is within covalent bond forming distance balloon from an O2 tank. Prior to use, THF was freshly dis-
(Fig. 1, Panel (a), red dashes) to the enzyme’s active site tilled over sodium/benzophenone, and CH2Cl2 was freshly
Cys104 residue (an asterisk in Fig. 1, Panel (b) highlights the distilled over CaH2. Et3N and i-PrNEt2 were distilled over
covalent bond). Upon bond formation, the iminopyridine- CaH2 and stored over KOH. All glassware and stir bars were
dione ring puckers, loosening the hydrogen bond framework. dried in an oven for 3 h prior to use. When necessary,
Therefore, it is possible that the tetrahedral intermediate degassed solvents were prepared by sparging with N2 for 1 h.
would collapse and result in ring opening, converting the Reactions were monitored by TLC analysis (pre-coated silica
reversible covalent adduct into an irreversibly bound inhibitor. gel 60 F254) and spots were visualized (UV lamp 254 nm and
Related binding mechanisms have recently been suggested for 395 nm). Purifications by chromatography were performed on
cysteine protease and serine hydrolase inhibitors.37 A covalent SiO2. 1H/13C NMR spectra were recorded on Bruker Avance
inhibition hypothesis may also aid in explaining the con- 300/75 MHz, Bruker Avance 400/100 MHz or Bruker Avance
sistently potent IC50 values of several substituent variants 500/125 MHz instruments. High resolution mass spectra were
of the iminopyridinedione and pyridinetrione chemotype. obtained on a Micromass UK Limited, Q-TOF Ultima API or a
Furthermore, a covalent Cys104 thiophosphate intermediate Thermo Scientific Exactive Orbitrap LC-MS. Chemical shifts
that is rate-limiting for the turnover of the natural substrate is were reported in parts per million (ppm) with the residual
also postulated for the catalytic cycle of PTP4A;19 therefore, solvent peak (CDCl3: 7.26 ppm for 1H, 77.16 ppm for 13C;
these inhibitors could potentially act as pseudosubstrates of DMSO-d6: 2.50 ppm for 1H, 39.52 ppm for 13C) used as the
the phosphatase.
internal standard. Chemical shifts were tabulated as follows:
Further molecular modeling, biochemical, and in vivo chemical shift, multiplicity (s = singlet, d = doublet, t =
evaluations of these new analogues and their mechanism of triplet, q = quartet, dd = doublet of doublet, dt = doublet of
action are currently underway.
triplet, ddd = doublet of doublet of doublet, m = multiplet,
brs = broad singlet), coupling constant(s), and integration. IR
spectra were obtained using neat samples on a PerkinElmer
100 IR-ATR spectrometer. Melting points were obtained using
a Mel-Temp instrument and are uncorrected. A variable peri-
Conclusions
We have optimized the synthesis of 7-iminothieno[3,2-c]pyri- staltic pump (VWR Model PP3300) was used for the photooxy-
dine-4,6(5H,7H)-diones with photo-flow techniques, and genation reactions. 30 cm of silicone tubing (1/16″ ID, 3/16″
streamlined the conversion of ketone side products to imines OD, 1/16″ wall thickness) in the pump were connected to
to allow for both the preparation of analogs for SAR purposes, 10.5 m of clear FEB tubing (4 mm ID, 5 mm OD, 0.5 mm wall
as well as the generation of gram-scale material for in vivo thickness) via an adapter. The light source was a white house-
biological evaluations. Full conversions were achieved for all hold 18 W CFL or a 40 W-4U BestCircle (AC85-265V) LED for
derivatives, and moderate to satisfactory 3-step yields could the scale-up reactions. For the white CFL and white LED
be obtained when the workup of the flow reaction was lights, the external temperature of the capillary tubing did
coupled with a modified purification protocol. This process not exceed 42 °C.
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General procedure A: photo-flow oxygenation of
thienopyridones
was then added, and the reaction mixture was stirred at 0 °C
for 1.5 h. A solution of NaN3 (2.09 g, 32.1 mmol) in H2O
(16 mL) was added to this reaction mixture slowly at 0 °C (ice-
and bath). The mixture became homogeneous, and then a solid
7-Iminothieno[3,2-c]pyridine-4,6(5H,7H)-dione
(2)
2-phenylthieno[3,2-c]pyridine-4,6,7(5H)-trione (3). The photo- began to precipitate. Stirring was continued for 15 min. The
flow reactor was flushed with MeOH (50 mL). Once the solvent reaction mixture was poured into ice-chilled H2O (30 mL) and
front entered the receiving flask, a solution of 7-amino-2-phe- extracted with EtOAc (3 × 30 mL). The combined organic layers
nylthieno[3,2-c]pyridin-4(5H)-one (1, 10 mg)20 in MeOH were dried (MgSO4), filtered and concentrated to give crude
(30 mL) was passed through the tubing at a rate of 1.9 mL acyl azide as a tan solid that was used for the next step without
min−1 using the peristaltic pump (5 rpm). Subsequently, the further purification.
tubing was flushed with additional MeOH (40 mL). The
A 3-neck flask fitted with a stopper, addition funnel, and
reaction mixture was concentrated to give a mixture of 2 and 3 condenser was charged with Bu3N (6.63 mL, 27.8 mmol) and
(10 mg) and purified by chromatography on SiO2 Ph2O (20 mL). The solution was heated to 240 °C. The addition
(EtOAc : hexanes, 7 : 3, followed by MeOH : EtOAc, 1 : 9) to give funnel was charged with a solution of the crude acyl azide
1
2 (9.1 mg, 91%): H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), (5.53 g, 21.4 mmol) in CH2Cl2 (50 mL). The acyl azide solution
11.59 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J = 8.1, 1.5 Hz, 2H), was added to the hot reaction mixture over a period of ca.
7.53–7.45 (m, 3H). Spectral data were consistent with literature 40 min, allowing the CH2Cl2 to boil off. The mixture was
properties.20
stirred at 240 °C for another 15 min, cooled to rt, and hexanes
2-Phenylthieno[3,2-c]pyridine-4,6,7(5H)-trione (3). To a solu- (20 mL) was added, at which point a solid began to precipitate.
tion of a mixture of 2 and 3 (6 : 1 ratio by 1H NMR analysis, The hexane layer was decanted, and the remaining residue was
0.040 g, 0.16 mmol), prepared according to General Protocol A suspended in EtOAc (15 mL). A tan solid precipitated out of
in THF : H2O (1 : 1, 10 mL) was added H2SO4 (0.083 mL, solution and was filtered to give 6 (2.56 g, 52%): Mp >250 °C;
1.6 mmol). The reaction mixture was allowed to stir at room IR (ATR) νmax 2809, 1637, 1607, 1513, 1472, 1274, 1222, 1144,
1
temperature for 24 h, cooled in an ice bath and filtered. The 994, 928, 803, 762, 692 cm−1; H NMR (400 MHz, DMSO-d6) δ
precipitate was washed with ice-cold H2O and dissolved in 11.54 (brs, 1H), 7.54 (d, J = 0.4 Hz, 1H), 7.28–7.25 (m, 1H), 6.81
THF. The THF solution was concentrated and dried under (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.5,
high vacuum at 45 °C overnight to afford a brown solid that 149.7, 130.7, 130.4, 126.8, 111.4, 100.5; HRMS (ESI+) m/z calcd
was purified by chromatography on SiO2 (EtOAc : hexanes, for C7H5ONSBr (M + H) 229.9270, found 229.9270.
7 : 3, followed by MeOH : EtOAc, 1 : 9) to give 3 (0.031 g,
2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7). A solu-
0.120 mmol, 77%) as a bright yellow solid: Mp >250 °C; IR tion of 2-bromothieno[3,2-c]pyridin-4(5H)-one (6, 2.56 g,
(ATR) νmax 3195, 3093, 2921, 2849, 1726, 1700, 1667, 1450, 11.1 mmol) in MeCN (275 mL) was heated to 65 °C in a
1
1417, 1333, 1272 cm−1; H NMR (500 MHz, DMSO-d6) δ 11.91 500 mL round-bottom flask fitted with a condenser under an
(brs, 1H), 8.09 (d, J = 3.5 Hz, 1H), 7.94 (dd, J = 8, 2 Hz, 2H), O2 atmosphere (balloon, 1 atm). After addition of t-BuONO
7.54–7.50 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.7, (5.88 mL, 44.5 mmol), the reaction mixture was stirred for 3 h
159.6, 158.0, 154.4, 141.0, 139.7, 131.5, 130.4, 129.5, 126.5, and turned from a brown heterogeneous mixture to a red
123.1; HRMS (ESI+) m/z calcd for C13H8O3NS (M + H) 258.0219, homogeneous solution. The solution was cooled to room
found 258.0219.
temperature and concentrated. The resulting yellow solid was
(E)-3-(5-Bromothiophen-2-yl)acrylic acid (5). To a solution of suspended in MeCN (10 mL) and placed in a −20 °C freezer
5-bromothiophene-2-carboxaldehyde (4) (10.15 g, 51.53 mmol) for 30 min. The precipitate was filtered to provide 7 as a yellow
in pyridine (128 mL) were added malonic acid (16.25 g, solid (2.21 g, 72%): Mp >250 °C; IR (ATR) νmax 2807, 1648,
154.6 mmol) and piperidine (2.57 mL, 25.76 mmol). The reac- 1617, 1508, 1480, 1336, 1243, 1127, 1038, 890, 764, 706 cm−1
;
tion mixture was heated at reflux for 3 h, cooled to room temp- 1H NMR (400 MHz, DMSO-d6) δ 12.86 (brs, 1H), 8.75 (s, 1H),
erature and concentrated to give a dark oil. The oil was diluted 7.71 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.9, 140.6,
with H2O (30 mL), at which time a solid precipitated. The sus- 135.9, 128.9, 126.9, 126.8, 115.9; HRMS (ESI+) m/z calcd for
pension was then acidified to pH 2 with 6 M HCl. The precipi- C7H4O3N2SBr (M + H) 274.9119, found 274.9121.
tate was filtered and washed with H2O (3 × 15 mL). The filter
General procedure B: Suzuki coupling of 2-bromo-7-
nitrothieno[3,2-c]pyridin-4(5H)-one (7)
cake was dissolved in EtOAc, dried (MgSO4), filtered, and con-
centrated to give 5 (11.29 g, 94%) as a tan solid: 1H NMR
(300 MHz, DMSO-d6) δ 12.41 (brs, 1H), 7.66 (d, J = 15.9 Hz, A 25 mL round-bottom flask was charged inside a glove box
1H), 7.35 (d, J = 3.9 Hz, 1H), 7.27 (d, J = 3.9 Hz, 1H), 6.15 (d, J = with Pd(PPh3)4 (5.0 mol%). The flask was removed from the
15.9 Hz, 1H). Spectral data are consistent with literature glove box and sequentially charged with 2-bromo-7-nitrothieno
properties.38
[3,2-c]pyridin-4(5H)-one (7, 1.0 equiv.), aryl boronic acid (1.1
2-Bromothieno[3,2-c]pyridin-4(5H)-one (6). Et3N (6.02 mL, equiv.), and Na2CO3 (2.3 equiv.). The flask was then purged
42.9 mmol) was added to a solution of (E)-3-(5-bromothio- under a stream of N2, diluted with deoxygenated dioxane and
phen-2-yl)acrylic acid (5, 5.00 g, 21.4 mmol) in acetone (55 mL) H2O (2 : 1, 0.1 M), fitted with a reflux condenser, and heated to
at 0 °C (ice-bath). Ethyl chloroformate (6.25 mL, 64.3 mmol) 90 °C for 16 h. The reaction mixture was cooled to room temp-
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erature and concentrated to give a red oil that was diluted with 1H), 8.79 (s, 1H), 7.84 (s, 1H), 7.79–7.75 (m, 1H), 7.67–7.64 (m,
H2O (10 mL) and treated with 1 M KHSO4 (5 mL). The red oil 1H), 7.49–7.46 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 158.2,
changed to an orange semi-solid suspension, and the mixture 140.7, 139.6, 136.1, 131.7, 131.1, 130.9, 130.6, 130.4, 128.6,
was diluted with EtOAc (40 mL). The layers were separated and 128.0, 127.1, 124.4; HRMS (ESI+) m/z calcd for C13H8O3N2SCl
the aqueous phase was extracted with EtOAc (4 × 20 mL). The (M + H) 306.9939, found 306.9938.
combined organic extracts were washed with saturated
2-(2-Fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8l).
aqueous NaCl, dried (MgSO4), filtered, and concentrated to 2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7, 0.200 g,
give an orange solid that was suspended in MeOH (2 mL), 0.727 mmol) was converted according to general procedure B
sonicated, and heated to the boiling point. The suspension to give 8l (0.140 g, 66%) as a yellow solid: Mp >250 °C; IR
was cooled to room temperature, filtered, and the solids were (ATR) νmax 2823, 1647, 1609, 1500, 1486, 1333, 1245, 1227,
washed with ice-cold MeOH (1 mL) to give the coupling 1137, 757, 711 cm−1 1H NMR (400 MHz, DMSO-d6) δ 12.81
;
product. If residual Ph3P(O) was present, the MeOH trituration (brs, 1H), 8.77 (s, 1H), 8.01–7.96 (m, 2H with an apparent s at
protocol was repeated.
8.00 ppm), 7.48–7.38 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H); 13C NMR
2-(3-Fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8f). (75 MHz, DMSO-d6) δ 160.1 (d, JC–F = 247.5 Hz), 158.0, 147.6,
2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7, 0.075 g, 139.2 (d, JC–F = 6.0 Hz), 137.5 (d, JC–F = 6.0 Hz), 135.7, 130.7 (d,
0.272 mmol) was converted according to general procedure B JC–F = 9.0 Hz), 129.0, 127.1, 125.4 (d, JC–F = 3.0 Hz), 122.7 (d,
to give 8f (0.040 g, 50%) as a yellow solid: Mp >250 °C; IR JC–F = 5.2 Hz), 119.8 (d, JC–F = 12.7 Hz), 116.5 (d, JC–F = 22.5
(ATR) νmax 2798, 1653, 1611, 1502, 1476, 1340, 1263, 1241, 840, Hz); 19F NMR (376 MHz, DMSO-d6) δ −113.2; HRMS (ESI+) m/z
765, 711, 673 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (brs, calcd for C13H8O3N2SF (M + H) 291.0234, found 291.0233.
1H), 8.76 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 10.4 Hz, 1H), 6.67 (d,
2-(4-Chloro-3-fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-
J = 8.0 Hz, 1H), 7.51 (q, J = 6.4 Hz, 1H), 7.26–7.21 (m, 1H); 13C one (8m). 2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7,
NMR (125 MHz, DMSO-d6) δ 162.5 (d, JC–F = 243.7 Hz), 157.8, 0.200 g, 0.727 mmol) was converted according to general pro-
143.0, 138.8, 135.6, 134.4 (d, JC–F = 8.7 Hz), 131.2 (d, JC–F
=
cedure B to give 8m (0.142 g, 60%) as a yellow solid: Mp
8.7 Hz), 129.7, 127.1, 122.1 (d, JC–F = 2.5 Hz), 122.1, 115.4 (d, >250 °C; IR (ATR) νmax 2838, 1655, 1607, 1477, 1335, 1238,
1
JC–F = 21.2 Hz), 112.6 (d, JC–F = 22.5 Hz); 19F NMR (470 MHz, 1187, 1138, 1040, 837, 808, 763, 703 cm−1; H NMR (400 MHz,
DMSO-d6) δ −111.9; HRMS (ESI+) m/z calcd for C13H8O3N2FS DMSO-d6) δ 12.81 (brs, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.02 (dd,
(M + H) 291.0234, found 291.0232.
J = 10.4 Hz, 1.2 Hz, 1H), 7.72–7.64 (m, 2H); 13C NMR
2-(3-Chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8h). (100 MHz, DMSO-d6) δ 158.1, 157.6 (d, JC–F = 246.0 Hz), 141.9,
2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7, 0.200 g, 139.1, 136.2, 133.4 (d, JC–F = 8.0 Hz), 131.4, 129.7, 127.1, 123.1
0.727 mmol) was converted according to general procedure B (d, JC–F = 3.0 Hz), 121.9, 119.6 (d, JC–F = 18.0 Hz), 114.2 (d,
to give 8h (0.161 g, 72%) as a yellow solid: Mp >250 °C; IR JC–F = 23.0 Hz); 19F NMR (376 MHz, DMSO-d6) δ −115.0; HRMS
(ATR) νmax 2790, 2683, 1654, 1614, 1593, 1499, 1475, 1335, (ESI+) m/z calcd for C13H7O3N2SFCl (M + H) 324.9844, found
1
1247, 1232, 1140, 1041, 994, 763, 71 cm−1; H NMR (500 MHz, 324.9844.
DMSO-d6) δ 12.77 (brs, 1H), 8.76 (s, 1H), 8.10 (s, 1H), 7.96 (s,
2-(3-Chloro-4-fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-
1H), 7.80 (d, J = 6.0 Hz, 1H), 7.52–7.45 (m, 2H); 13C NMR one (8n). 2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7,
(125 MHz, DMSO-d6) δ 157.8, 142.7, 138.8, 135.7, 134.3, 134.1, 0.200 g, 0.727 mmol) was converted according to general pro-
131.0, 129.7, 128.5, 127.1, 125.5, 124.6, 121.2; HRMS (ESI+) m/z cedure B to give 8n (0.127 g, 54%) as a yellow solid: Mp
calcd for C13H8O3N2ClS (M + H) 306.9939, found 306.9937.
>250 °C; IR (ATR) νmax 2817, 1655, 1610, 1484, 1336, 1260,
7-Nitro-2-(m-tolyl)thieno[3,2-c]pyridin-4(5H)-one (8i). 2-Bromo- 1227, 1140, 1039, 895, 866, 818, 764, 712, 692 cm−1; H NMR
7-nitrothieno[3,2-c]pyridin-4(5H)-one (7, 0.150 g, 0.545 mmol) (300 MHz, DMSO-d6) δ 12.77 (brs, 1H), 8.74 (s, 1H), 8.12 (dd,
was converted according to general procedure B to give 8i J = 7.0 Hz, 2.1 Hz, 1H), 8.06 (s, 1H), 7.86–7.81 (m, 1H), 7.49 (t,
(0.092 g, 59%) as a yellow solid: Mp >250 °C; IR (ATR) νmax J = 8.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 157.9, 157.2 (d,
2807, 1648, 1619, 1598, 1502, 1476, 1336, 1236, 1135, 1040, JC–F = 248.0 Hz), 141.9, 138.9, 135.8, 130.2, 129.7, 127.9, 127.1,
801, 766, 712 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 12.72 (brs, 126.7 (d, JC–F = 7.0 Hz), 121.4, 120.6 (d, JC–F = 18.0 Hz), 117.7
1H), 8.72 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.63 (d, J = 6.4 Hz, (d, JC–F = 21.0 Hz); 19F NMR (376 MHz, DMSO-d6) δ −116.0;
1H), 7.36 (t, J = 6.4 Hz, 1H), 7.22 (d, J = 6.0 Hz, 1H), 2.38 (s, HRMS (ESI+) m/z calcd for C13H7O3N2SFCl (M + H) 324.9844,
3H); 13C NMR (125 MHz, DMSO-d6): δ 157.8, 144.8, 138.7, found 324.9843.
1
138.2, 135.2, 132.1, 129.8, 129.5, 129.1, 127.2, 126.4, 123.0,
119.6, 20.8; HRMS (ESI+) m/z calcd for C14H11O3N2S (M + H) ethyl)morpholine (24). To a solution of 4-(4,4,5,5-tetramethyl-
287.0485, found 287.0483. 1,3,2-dioxaborolan-2-yl)phenol (0.408 g, 1.85 mmol) in DMF
4-(2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)
2-(2-Chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8k). (5 mL) were added 4-(2-chloroethyl)morpholine hydrochloride
2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one (7, 0.200 g, (0.383 g, 2.03 mmol), Cs2CO3 (1.52 g, 4.63 mmol), and KI
0.727 mmol) was converted according to general procedure B (0.015 g, 0.092 mmol). The reaction mixture was heated to
to give 8k (0.122 g, 55%) as a yellow solid: Mp >250 °C; IR 65 °C for 12 h, cooled to room temperature, diluted with
(ATR) νmax 2852, 1654, 1611, 1500, 1467, 1335, 1242, 1038, 872, EtOAc (100 mL), washed with saturated aqueous NaHCO3
822, 747, 707 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 12.82 (brs, (30 mL) and saturated aqueous NaCl (30 mL), dried (MgSO4),
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filtered, and concentrated to give a brown solid. Purification cooling to room temperature, the desired pyridone was
by chromatography on SiO2 (MeOH : CH2Cl2, 1 : 9) provided 24 obtained as a solid.
(0.519 g, 84%) as an off-white powdery solid: 1H NMR
2-(p-Tolyl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
(25).
(400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, According to procedure C, chromatography on SiO2 (EtOAc) of
2H), 4.13 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 2.80 (t, J = an aliquot of the Suzuki reaction mixture provided 25 as a
5.6 Hz, 2H), 2.57 (t, J = 4.8 Hz, 4H), 1.32 (s, 12H). Spectral data white solid: Mp 210–212 °C; IR (ATR) νmax 2833, 1650, 1480,
are consistent with literature properties.39
1299, 1092, 816, 763, 694 cm−1 1H NMR (500 MHz, CDCl3)
;
2-(4-(2-Morpholinoethoxy)phenyl-7-nitrothieno[3,2-c]pyrdin- δ 7.57 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H),
4(5H)-one (8o). 2-Bromo-7-nitrothieno[3,2-c]pyridin-4(5H)-one 5.76 (brs, 1H), 3.66 (td, J = 6.5 Hz, 2.5 Hz, 2H), 3.06 (t, J =
(7, 0.250 g, 0.908 mmol) was treated according to general pro- 7.0 Hz, 2H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.6,
cedure B to give 8o (0.219 g, 60%) as a yellow solid: Mp 145.0, 142.4, 137.9, 132.9, 130.8, 129.7, 125.7, 120.8, 41.3, 24.5,
>226 °C (dec.); IR (ATR) νmax 2804, 1654, 1611, 1491, 1338, 21.2; HRMS (ESI+) m/z calcd for C14H14ONS (M + H) 244.0791,
1
1248, 1112, 1039, 899, 821, 762, 712 cm−1; H NMR (400 MHz, found 244.0789.
DMSO-d6) δ 12.70 (brs, 1H), 8.71 (s, 1H), 7.83 (s, 1H), 7.76 (d,
2-(4-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 4.15 (t, J = 5.6 Hz, 2H), (26). According to general procedure C, chromatography on
3.59 (t, J = 4.4 Hz, 4H), 2.72 (t, J = 5.6 Hz, 2H), 2.51–2.46 (m, SiO2 (EtOAc) of an aliquot of the crude Suzuki coupling pro-
4H obstructed by DMSO signal); 13C NMR (75 MHz, DMSO-d6) vided 26 as a white solid: Mp 219–221 °C; IR (ATR) νmax 2955,
δ 159.0, 158.0, 144.8, 137.6, 135.1, 130.0, 127.4, 127.3, 124.9, 1652, 1482, 1296, 1094, 822, 775 cm−1 1H NMR (500 MHz,
;
118.4, 115.3, 66.1, 65.5, 56.9, 53.5; HRMS (ESI+) m/z calcd for CDCl3) δ 7.59 (s, 1H), 7.49 (d, J = 11.0 Hz, 2H), 7.34 (d, J =
C19H20N3O5S (M + H) 402.1118, found 402.1116.
11.5 Hz, 2H), 5.67 (brs, 1H), 3.67 (td, J = 6.8, 3.0 Hz, 2H), 3.07
(t, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 163.6, 145.9,
141.1, 134.0, 133.4, 132.4, 129.4, 127.1, 122.0, 41.5, 24.7;
HRMS (ESI+) m/z calcd for C13H11ONSCl (M + H) 264.0244,
found 264.0244.
General procedure C: Suzuki coupling of 2-bromo-6,7-
dihydrothieno[3,2-c]pyridin-4(5H)-one
A 100 mL round-bottom flask was charged with Pd(PPh3)4
(5.0 mol%) inside a glove box. The flask was removed from the
glove box and sequentially charged with 2-bromo-6,7-di-
hydrothieno[3,2-c]pyridin-4(5H)-one (41, 1.0 equiv.), aryl
boronic acid (1.1 equiv.), and Na2CO3 (2.3 equiv.). The flask
was purged under a stream of N2, diluted with deoxygenated
dioxane and H2O (2 : 1, 0.1 M), fitted with a reflux condenser,
and heated to 90 °C for 12 h. The resulting dark mixture was
allowed to cool to room temperature, diluted with H2O, and
cooled in an ice-bath. The precipitate was filtered, washed with
H2O, dissolved in CH2Cl2, dried (MgSO4), and concentrated to
give a light coloured solid. Typically, a ca. 10 mg aliquot of the
crude material was purified by chromatography on SiO2
(EtOAc) to characterize the Suzuki products. In some cases,
residual Ph3P(O) was difficult to remove prior to the next step
(DDQ oxidation). Therefore, the entire batch of crude Suzuki
material was purified by chromatography on SiO2. In these
cases, the Suzuki coupling and DDQ oxidation are reported
with separate yields.
2-(4-(Trifluoromethyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridin-
4(5H)-one (27). According to general procedure C, the product
obtained from 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-
one (41, 1.00 g, 4.30 mmol) was purified by chromatography
on SiO2 (EtOAc) to provide 27 (1.03 g, 80%) as an off-white
solid: Mp 227–229 °C; IR (ATR) νmax 3192, 3072, 1653, 1485,
1319, 1163, 1108, 1065, 847, 780 cm−1 1H NMR (500 MHz,
;
CDCl3) δ 7.71 (s, 1H), 7.68–7.61 (m, 4H), 5.74 (brs, 1H), 3.68
(dt, J = 6.8 Hz, 2.8 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 163.3, 146.6, 140.4, 137.0, 133.3, 129.6 (q,
JC–F = 31.2 Hz), 126.0 (q, JC–F = 3.7 Hz), 125.1, 124.0 (q, JC–F
=
270 Hz), 122.8, 41.2, 24.6; 19F NMR (470 MHz, CDCl3) δ −62.6;
HRMS (ESI+) m/z calcd for C14H11F3NOS (M + H) 298.0508,
found 298.0503.
2-(4-Fluorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
(28). According to general procedure C, the product obtained
from 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (41,
0.750 g, 3.23 mmol) was purified by chromatography on SiO2
(EtOAc) to give 28 (0.673 g, 83%) as a light-brown solid: Mp
230–232 °C; IR (ATR) νmax 3211, 1643, 1474, 1134, 1304, 1225,
1162, 823, 780 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H),
General procedure D: DDQ oxidation
The Suzuki coupling product (crude or purified) was sus- 7.54–7.50 m (2H), 7.09–7.05 (m, 2H), 5.69 (brs, 1H), 3.66 (dt,
pended in dioxane (0.1 M) and treated with DDQ (2.0 equiv.). J = 6.5, 2.5 Hz, 2H), 3.07 (t, J = 6.5 Hz, 2H); 13C NMR (125 MHz,
The flask was fitted with a reflux condenser and heated to CDCl3) δ 163.4, 162.5 (d, JC–F = 246.2 Hz), 145.4, 141.1, 133.1,
100 °C for 24 h, allowed to cool to room temperature, and con- 129.8 (d, JC–F = 2.5 Hz), 127.7 (d, JC–F = 7.5 Hz), 121.3, 116.0 (d,
centrated to give a dark solid. The solid was dissolved in EtOAc JC–F = 21.2 Hz), 41.3, 24.5; 19F NMR (470 MHz, CDCl3)
(500 mL), and the orange solution was then washed with satu- δ −113.8; HRMS (ESI+) m/z calcd for C13H11FNOS (M + H)
rated aqueous NaHCO3 (4 × 60 mL) and saturated aqueous 248.0540, found 248.0444.
NaCl, dried (MgSO4), filtered, and concentrated to give a dark
2-(4-Hydroxyphenyl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
solid. The crude residue was purified as a solid by chromato- (29). According to general procedure C, the product obtained
graphy on SiO2 (MeOH : CH2Cl2, 1 : 9), or suspended in CH2Cl2 from 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (41,
(5 mL), sonicated for 2 min, and heated to reflux. Upon 1.06 g, 4.56 mmol) was purified by chromatography on SiO2
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(MeOH : CH2Cl2, 1 : 9) to give 29 (1.02 g, 91%) as a light-orange one (41, 0.625 g, 2.69 mmol) was precipitated from CH2Cl2 to
solid: Mp >250 °C; IR (ATR) νmax 3032, 1638, 1607, 1545, 1483, provide 33 (0.338 g, 48% over two steps) as a tan solid: Mp
1421, 1270, 1242, 1221, 1169, 1102, 983, 826, 771 cm−1 1H >250 °C; IR (ATR) νmax 2834, 1653, 1604, 1482, 1405, 1218,
;
NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.58 (brs, 1H), 7.44 1095, 813, 762, 695 cm−1 1H NMR (400 MHz, DMSO-d6)
;
(d, J = 8.4 Hz, 2H), 7.36 (s, 1H), 6.79 (d, J = 8.4 Hz, 2H), 3.44 δ 11.50 (brs, 1H), 7.90 (s, 1H), 7.79–7.76 (m, 2H), 7.51–7.49 (m,
(td, J = 7.2, 2.4 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H); 13C NMR 2H), 7.28 (d, J = 6.8 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) δ 162.1, 157.3, 143.9, 141.3, 133.3, 126.7, (125 MHz, DMSO-d6) δ 158.5, 147.8, 139.7, 132.7, 131.9, 131.5,
124.2, 119.1, 115.8, 40.2, 23.7; HRMS (ESI+) m/z calcd for 130.2, 129.1, 127.4, 120.7, 100.8; HRMS (ESI+) m/z calcd for
C13H12O2NS (M + H) 246.0583, found 246.0581.
C13H9NOSCl (M + H) 262.0088, found 262.0016.
4-(4-Oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)phenyl piva-
2-(4-(Trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one
late (30). A solution of 2-(4-hydroxyphenyl)-6,7-dihydrothieno (34). According to general procedure D, the product obtained
[3,2-c]pyridin-4(5H)-one (29, 1.03 g, 4.19 mmol) in THF from 2-(4-(trifluoromethyl)phenyl)-6,7-dihydrothieno[3,2-c]
(80 mL) was treated with Et3N (1.18 mL, 8.39 mmol), followed pyridin-4(5H)-one (27, 0.702 g, 2.36 mmol) was purified by
by a solution of Piv2O (1.57 g, 8.39 mmol) in THF (0.5 mL) and chromatography on SiO2 (MeOH : CH2Cl2, 1 : 9) to provide 34
DMAP (0.076 g, 0.629 mmol). The flask was fitted with a reflux (0.539 g, 77%) as a tan solid: Mp >250 °C; IR (ATR) νmax 2830,
condenser and heated to 70 °C for 18 h. The reaction mixture 1643, 1607, 1323, 1106, 1067, 828, 767 cm−1
;
1H NMR
was diluted with EtOAc (200 mL), washed with H2O (50 mL), (400 MHz, DMSO-d6) δ 11.53 (brs, 1H), 8.05 (s, 1H), 7.98 (d, J =
saturated aqueous NaCl (50 mL), dried (MgSO4), filtered, and 8.0 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 6.4 Hz, 1H),
concentrated to give a tan solid. Purification by chromato- 6.89 (d, J = 7.2 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.1,
graphy on SiO2 (dry load, MeOH : CH2Cl2, 1 : 11) provided 30 149.0, 139.6, 137.4, 131.9, 131.3, 128.5 (q, JC–F = 31.2 Hz), 126.3
(1.35 g, 97%) as a tan solid: Mp 233–234 °C; IR (ATR) νmax (q, JC–F = 3.7 Hz), 124.6 (q, JC–F = 271.2 Hz), 122.5, 101.3; 19F
3203, 3070, 2966, 1752, 1655, 1475, 1200, 1162, 1106, 892, 842, NMR (470 MHz, DMSO-d6) δ −61.0; HRMS (ESI+) m/z calcd for
792 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.56 (d, J = C14H9F3NOS (M + H) 296.0351, found 296.0352.
8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 5.72 (brs, 1H), 3.66 (td, J =
2-(4-Fluorophenyl)thieno[3,2-c]pyridin-4(5H)-one
(35).
6.8, 2.8 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 1.35 (s, 9H); 13C NMR According to general procedure D, the product obtained from
(125 MHz, CDCl3) δ 177.2, 163.7, 151.1, 145.7, 141.6, 133.3, 2-(4-fluorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one
131.4, 127.0, 122.3, 121.7, 41.5, 39.4, 27.4, 24.7; HRMS (ESI+) (28, 0.673 g, 2.72 mmol) was purified by chromatography on
m/z calcd for C18H20O3NS (M + H) 330.1158, found 330.1158.
2-(3-(Trifluoromethyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridin- off-white solid: Mp >250 °C; IR (ATR) νmax 2838, 1655, 1605,
4(5H)-one (31). According to general procedure C, chromato- 1505, 1493, 1235, 1150, 822, 750 cm−1 1H NMR (400 MHz,
SiO2 (MeOH : CH2Cl2, 1 : 9) to provide 35 (0.285 g, 41%) as an
;
graphy on SiO2 (EtOAc) of an aliquot of the crude Suzuki coup- DMSO-d6) δ 11.46 (brs, 1H), 7.82 (s, 1H), 7.82–7.78 (m, 2H),
ling product provided 31 as a white solid: Mp 149–151 °C; IR 7.31–7.24 (m, 3H), 6.84 (d, J = 7.2 Hz, 1H); 13C NMR (125 MHz,
(ATR) νmax 3191, 3067, 1650, 1482, 1327, 1121, 791, 690 cm−1
;
DMSO-d6) δ 161.9 (d, JC–F = 245.0 Hz), 158.5, 147.5, 140.0,
1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.73 (d, J = 7.6 Hz, 131.5, 130.0, 129.5 (d, JC–F = 2.5 Hz), 127.8 (d, JC–F = 8.7 Hz),
1H), 7.69 (s, 1H), 7.55–7.49 (m, 2H), 5.57 (brs, 1H), 3.68 (td, J = 120.0, 116.0 (d, JC–F = 21.2 Hz), 100.7; 19F (470 MHz, DMSO-d6)
6.4, 2.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz, δ −113.4; HRMS (ESI+) m/z calcd for C13H9FNOS (M + H)
CDCl3) δ 163.7, 146.5, 140.5, 134.5, 133.3, 131.6 (q, JC–F
=
246.0383, found 246.0381.
32.0 Hz), 129.6, 128.9, 126.7 (q, JC–F = 276.0 Hz), 124.5 (q,
4-(4-Oxo-4,5,dihydrothieno[3,2-c]pyridin-2-yl)phenyl pivalate
JC–F = 4.0 Hz), 122.6, 122.5 (q, JC–F = 4.0 Hz), 41.3, 24.6; 19F (36). According to general procedure D, the product obtained
NMR (376 MHz, CDCl3) δ −62.8; HRMS (ESI+) m/z calcd for from 4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)phenyl
C14H11ONSF3 (M + H) 298.0508, found 298.0507.
pivalate (30, 1.35 g, 4.09 mmol) was purified by chromato-
2-(p-Tolyl)thieno[3,2-c]pyridin-4(5H)-one (32). According to graphy on SiO2 (MeOH : CH2Cl2, 1 : 9) to provide 36 (0.750 g,
general procedures C and D, the product obtained from 56%) as a tan solid: Mp >250 °C; IR (ATR) νmax 2961, 2872,
2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (41, 0.625 g, 2837, 1749, 1637, 1603, 1507, 1491, 1472, 1271, 1205, 1165,
2.69 mmol) was precipitated from CH2Cl2 to provide 32 1112, 891, 840, 757 cm−1 1H NMR (400 MHz, DMSO-d6)
;
(0.344 g, 53% over two steps) as a tan solid: Mp 249–251 °C; IR δ 11.47 (brs, 1H), 7.86 (s, 1H), 7.80–7.77 (m, 2H), 7.26 (t, J =
(ATR) νmax 2811, 1639, 1607, 1507, 1120, 1148, 809, 766, 746, 6.4 Hz,1H), 7.19–7.17 (m, 2H), 6.85 (d, J = 6.8 Hz, 1H), 1.32 (s,
698 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 11.44 (brs, 1H), 7.78 9H); 13C NMR (125 MHz, DMSO-d6) δ 176.2, 158.5, 150.6,
(s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.26–7.25 (m, 3H), 6.83 (d, J = 147.5, 140.2, 131.5, 130.5, 129.9, 126.8, 122.4, 120.1, 100.7,
6.8 Hz, 1H), 2.33 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 38.5, 26.6; HRMS (ESI+) m/z calcd for C18H18O3NS (M + H)
157.9, 146.6, 140.8, 137.2, 131.0, 129.6, 129.2, 129.1, 125.0, 328.1002, found 328.1000.
118.6, 100.2, 20.1; HRMS (ESI+) m/z calcd for C14H12NOS (M +
H) 242.0634, found 242.0511.
2-(3-(Trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one
(37). According to general procedures C and D, the product
2-(4-Chlorophenyl)thieno[3,2-c]pyridin-4(5H)-one
(33). obtained from 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-
According to general procedures C and D, the product one (41, 0.625 g, 2.69 mmol) was precipitated from CH2Cl2 to
obtained from 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)- provide 37 (0.544 g, 69% over two steps) as a tan solid: Mp
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201–204 °C; IR (ATR) νmax 2823, 1648, 1607, 1327, 1166, 1112,
2-(4-Fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8d).
1
1071, 991, 891, 756, 688 cm−1; H NMR (400 MHz, DMSO-d6) According to general procedure E, 2-(4-fluorophenyl)thieno
δ 11.52 (brs, 1H), 8.09 (s, 1H), 8.08–8.04 (m, 2H), 7.70–7.68 (m, [3,2-c]pyridin-4(5H)-one (35, 0.230 g, 0.937 mmol) led to 8d
2H), 7.31 (d, J = 6.8 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H); 13C NMR (0.133 g, 49%) as a yellow solid: Mp >250 °C; IR (ATR) νmax
(125 MHz, DMSO-d6) δ 158.6, 148.2, 139.1, 134.1, 131.6, 130.6, 2807, 1649, 1617, 1491, 1340, 1248, 1226, 1135, 822, 764 cm−1
;
130.4, 129.9 (q, JC–F = 31.2 Hz), 129.7, 124.4 (q, JC–F = 3.7 Hz), 1H NMR (400 MHz, DMSO-d6) δ 12.77 (brs, 1H), 8.75 (s, 1H),
123.8 (q, JC–F = 271.2 Hz), 121.9 (q, JC–F = 3.7 Hz), 121.8, 100.8; 7.97 (s, 1H), 7.93–7.89 (m, 2H), 7.32 (t, J = 8.0 Hz, 2H); 13C
19F NMR (376 MHz, DMSO-d6) δ −61.2; HRMS (ESI+) m/z calcd NMR (125 MHz, DMSO-d6) δ 162.2 (d, JC–F = 245.0 Hz), 157.8,
for C14H9ONSF3 (M + H) 296.0351, found 296.0349.
143.5, 138.3, 135.3, 129.8, 128.9 (d, JC–F = 2.5 Hz), 128.7 (d,
JC–F = 8.7 Hz), 127.2, 120.0, 116.2 (d, JC–F = 21.2 Hz); 19F NMR
(470 MHz, DMSO-d6) δ −112.6; HRMS (ESI+) m/z calcd for
General procedure E: nitration of pyridones
A suspension of the DDQ oxidation product (1.0 equiv.) in C13H8FN2O3S (M + H) 291.0234, found 291.0233.
MeCN (0.04 M) was heated to 65 °C in a round-bottom flask 4-(7-Nitro-4-oxo-4,5,dihydrothieno[3,2-c]pyridin-2-yl)phenyl
fitted with a condenser under an atmosphere of O2 (balloon, pivalate (8e). According to general procedure E, 4-(4-oxo-4,5,
1 atm). Neat t-BuONO (4.0 equiv.) was added, and the reaction dihydrothieno[3,2-c]pyridin-2-yl)phenyl pivalate (36, 0.854 g,
mixture was stirred for 3–5 h, or until consumption of starting 2.60 mmol) led to 8e (0.791 g, 81%) as a yellow solid: Mp
material was observed by TLC analysis. Typically, the reaction >250 °C; IR (ATR) νmax 3264, 3085, 2979, 1720, 1671, 1609,
mixture stayed heterogeneous, but slightly darkened. The solu- 1515, 1481, 1330, 1204, 1167, 1131, 776 cm−1 1H NMR
;
tion was cooled to room temperature and concentrated to (400 MHz, DMSO-d6) δ 12.78 (brs, 1H), 8.75 (d, J = 6.4 Hz, 1H),
approximately 1/2 volume. The precipitate was filtered to give 7.99 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H),
the pure nitration product. In some cases when the solid was 1.32 (s, 9H); 13C NMR (125 MHz, DMSO-d6) δ 176.2, 157.8,
not pure, it was resuspended in MeCN, sonicated for 5 min, 151.1, 143.8, 138.4, 135.3, 129.8, 127.1, 122.5, 120.0, 38.5, 26.6;
and filtered.
HRMS (ESI+) m/z calcd for C18H17O5N2S (M + H) 373.0853,
7-Nitro-2-(p-tolyl)thieno[3,2-c]pyridin-4(5H)-one
(8a). found 373.0851.
According to general procedure E, 2-(p-tolyl)thieno[3,2-c]
7-Nitro-2-(3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4
pyridin-4(5H)-one (32, 0.175 g, 0.725 mmol) led to 8a (0.082 g, (5H)-one (8g). According to general procedure E, 2-(3-(trifluoro-
39%) as a yellow solid: Mp >250 °C; IR (ATR) νmax 2825, 1649, methyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one (37, 0.354 g,
1
1492, 1250, 1027, 806, 765 cm−1; H NMR (500 MHz, DMSO- 1.19 mmol) led to 8g (0.307 g, 75%) as a yellow solid: Mp
d6) δ 12.73 (brs, 1H), 8.73 (s, 1H), 7.91 (s, 1H), 7.74 (d, J = >250 °C; IR (ATR) νmax 2793, 1665, 1615, 1498, 1477, 1329,
8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H); 13C NMR 1247, 1228, 1158, 1109, 996, 892, 764 cm−1
;
1H NMR
(125 MHz, DMSO-d6) δ 157.9, 144.9, 138.6, 138.0, 135.2, 129.9, (300 MHz, DMSO-d6) δ 12.80 (brs, 1H), 8.78 (s, 1H), 8.22–8.14
129.5, 127.3, 125.9, 119.2, 20.7; HRMS (ESI+) m/z calcd for (m, 3H), 7.78–7.68 (m, 2H); 13C NMR (100 MHz, d6-DMSO) δ
C14H11O3 N2S (M + H) 287.0485, found 287.0483.
157.9, 142.6, 139.1, 136.0, 133.4, 130.5, 130.1 (q, JC–F =
2-(4-Chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8b). 35.0 Hz), 130.0, 129.8, 127.2, 125.1 (q, JC–F = 5.0 Hz), 123.9 (q,
According to general procedure E, 2-(4-chlorophenyl)thieno JC–F = 271.0 Hz), 122.3 (q, JC–F = 4.0 Hz), 121.8; 19F NMR
[3,2-c]pyridin-4(5H)-one (33, 0.164 g, 0.626 mmol) led to 8b (376 MHz, DMSO-d6) δ −61.1; HRMS (ESI+) m/z calcd for
(0.108 g, 56%) as a yellow solid: Mp >250 °C; IR (ATR) νmax C14H8O3N2F3S (M + H) 341.0202, found 341.0200.
2806, 1655, 1482, 1335, 1255, 1231, 1093, 815, 764, 706 cm−1
;
2-(3-Methoxyphenyl)-7-nitrothieno[3,2-c]pyridin-4(5H)-one (8j).
1H NMR (400 MHz, DMSO-d6) δ 12.79 (brs, 1H), 8.76 (s, 1H), According to general procedure E, 2-(3-methoxyphenyl)thieno
8.03 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H); [3,2-c]pyridin-4(5H)-one (0.085 g, 0.330 mmol) led to 8j
13C NMR (125 MHz, DMSO-d6) δ 157.8, 143.2, 138.6, 135.6, (0.053 g, 53%) as a yellow solid: Mp >250 °C; IR (ATR) νmax
133.3, 131.1, 129.8, 129.2, 127.7, 127.2, 120.6; HRMS (ESI+) m/z 2823, 1674, 1595, 1469, 1338, 1241, 1037, 763, 679 cm−1
;
1H
calcd for C13H8O3 N2ClS (M + H) 306.9939, found 306.9937.
NMR (400 MHz, DMSO-d6) δ 12.77 (brs, 1H), 8.76 (s, 1H), 8.04
7-Nitro-2-(4-(trifluoromethyl)phenyl)thieno[3,2-c]pyridin-4(5H)- (s, 1H), 7.40–7.38 (m, 3H), 7.00–6.96 (m, 1H), 3.85 (s, 3H); 13C
one (8c). According to general procedure E, 2-(4-(trifluoro- NMR (125 MHz, DMSO-d6) δ 159.9, 157.9, 144.5, 138.4, 135.4,
methyl)phenyl)thieno[3,2-c]pyridin-4(5H)-one (34, 0.447 g, 133.5, 130.4, 129.8, 127.2, 120.3, 118.3, 115.0, 110.9, 55.3;
1.51 mmol) led to 8c (0.406 g, 79%) as a yellow solid: Mp HRMS (ESI+) m/z calcd for C14H11O4N2S (M + H) 303.0434,
>250 °C; IR (ATR) νmax 2803, 1664, 1611, 1494, 1322, 1231, found 303.0297.
1109, 1065, 832, 766 cm−1 1H NMR (500 MHz, DMSO-d6)
;
δ 12.82 (brs, 1H), 8.78 (s, 1H), 8.17 (s, 1H), 8.10 (d, J = 8.0 Hz,
2H), 7.81 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, DMSO-d6)
General procedure F: nitro reduction and in-flow
photooxygenation
δ 157.9, 142.5, 139.3, 136.1, 136.0, 129.7, 128.5 (q, JC–F
31.2 Hz), 127.1, 126.5, 126.1 (q, JC–F = 3.7 Hz), 124.0 (q, JC–F
=
=
A suspension of nitro-compound (1.0 equiv.) in MeOH : EtOAc
(3 : 1, 0.05 M) was treated under a nitrogen atmosphere with
270.0 Hz), 121.9; 19F NMR (470 MHz, DMSO-d6) δ −61.1; 10% Pd/C (15 mol%). H2 was bubbled through the mixture.
HRMS (ESI+) m/z calcd for C14H8F3N2O3S (M + H) 341.0202, The suspension was stirred at room temperature under H2
found 341.0201.
(1 atm, balloon) for 6 h, filtered through Celite, and the Celite
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pad was washed with MeOH (50 mL). The Pd/C was removed graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9d (0.025 g,
from the Celite, boiled in PhMe (40 mL), filtered over Celite, 25%) as a yellow solid: Mp 239–241 °C; IR (ATR) νmax 3259,
and eluted with MeOH. This procedure was performed twice. 2970, 1698, 1608, 1596, 1437, 1377, 1362, 1148, 908, 824 cm−1
;
The combined filtrates were concentrated under reduced 1H NMR (400 MHz, DMSO-d6) δ 11.87 (brs, 1H), 11.60 (s, 1H),
pressure to afford a brown solid that was used in the in-flow 7.97–7.92 (m, 3H), 7.34 (t, J = 8.8 Hz, 2H); 13C NMR (125 MHz,
photooxygenation without further purification. A solution of DMSO-d6) δ 162.6 (d, JC–F = 246.0 Hz), 159.9, 157.7, 153.3,
the crude solid in MeOH (ca. 2–3 mL mg−1) was passed 148.1, 141.9, 136.8, 128.5 (d, JC–F = 2.5 Hz), 122.2, 116.3 (d,
through the tubing at a rate of 1.9 mL min−1 using the peristal- JC–F = 22.5 Hz); 19F NMR (470 MHz, DMSO-d6) δ −111.4; HRMS
tic pump (5 RPM) under white LED irradiation. The tubing (ESI+) m/z calcd for C13H8N2O2FS (M + H) 275.0285, found
was flushed with MeOH (40 mL). The mixture was concen- 275.0283.
trated to give a brown solid that was purified by chromato-
graphy on SiO2 (dry loaded, acetone : hexanes, 1 : 2 to 1 : 1) to yl)phenyl pivalate (9e). According to general procedure F, the
yield the desired imine. product obtained from 4-(7-nitro-4-oxo-4,5,dihydrothieno[3,2-c]
4-(7-Imino-4,6-dioxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-
2-(p-Tolyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-dione (9a). pyridin-2-yl)phenyl pivalate (8e, 0.175 g, 0.469 mmol) was puri-
According to general procedure F, the product obtained from fied by chromatography on SiO2 (acetone : hexanes, 1 : 2) to
7-nitro-2-(p-tolyl)thieno[3,2-c]pyridin-4(5H)-one (8a, 0.080 g, give 9e (0.029 g, 17%) as a tan solid: Mp 249–251 °C; IR (ATR)
0.279 mmol) was purified by chromatography on SiO2 νmax 3240, 3094, 1746, 1719, 1695, 1608, 1439, 1245, 1218,
(acetone : hexanes, 1 : 2) to give 9a (0.032 g, 42%) as a yellow 1164, 1113, 792 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s,
solid: Mp 254–255 °C; IR (ATR) νmax 3288, 3225, 1712, 1687, 1H), 11.60 (s, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.23 (d,
1612, 1391, 1301, 1194, 1153, 781 cm−1 1H NMR (400 MHz, J = 8.8 Hz, 2H), 1.32 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ
;
DMSO-d6) δ 11.85 (brs, 1H), 11.56 (s, 1H), 7.92 (s, 1H), 7.76 (d, 176.3, 160.1, 157.8, 153.4, 151.6, 148.4, 142.0, 136.8, 129.6,
J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H); 13C NMR 127.5, 122.7, 122.3, 38.6, 26.7; HRMS (ESI+) m/z calcd for
(125 MHz, DMSO-d6) δ 160.0, 157.8, 153.3, 149.6, 141.3, 139.4, C18H17N2O4S (M + H) 357.0904, found 357.0903.
136.8, 129.9, 129.2, 126.0, 121.4, 20.8; HRMS (ESI+) m/z calcd
for C14H11N2O2S (M + H) 271.0536, found 271.0535.
2-(3-Methoxyphenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-
dione (9f). According to general procedure F, the product
2-(4-Chlorophenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- obtained from 2-(3-fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4
dione (9b). According to general procedure F, the product (5H)-one (8f, 0.085 g, 0.292 mmol) was purified by chromato-
obtained from 2-(4-chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4 graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9f (0.028 g,
(5H)-one (8b, 0.095 g, 0.309 mmol) was purified by chromato- 35%) as a yellow solid: Mp 235–236 °C; IR (ATR) νmax 3251,
graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9b (0.030 g, 3187, 3097, 1692, 1611, 1579, 1431, 1310, 1271, 1226, 1156,
33%) as a yellow solid: Mp 237–238 °C; IR (ATR) νmax 3186, 962, 778 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.87 (brs, 1H),
1
1730, 1669, 1614, 1441, 1241, 1161, 1093, 815 cm−1; H NMR 11.64 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 13.6 Hz, 1H), 7.70 (d, J =
(400 MHz, DMSO-d6) δ 11.87 (brs, 1H), 11.63 (s, 1H), 8.03 (s, 11.2 Hz, 1H), 7.57–7.49 (m, 1H), 7.32–7.25 (m, 1H); 13C NMR
1H), 7.91 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 162.5 (d, JC–F = 243.7 Hz), 159.8, 157.6,
(125 MHz, DMSO-d6) δ 160.0, 157.8, 153.4, 147.7, 142.2, 136.8, 153.3, 147.5 (d, JC–F = 1.2 Hz), 142.4, 136.7, 134.1 (d, JC–F
=
134.1, 130.8, 129.3, 127.9, 122.7; HRMS (ESI+) m/z calcd for 8.7 Hz), 131.3 (d, JC–F = 8.7 Hz), 123.1, 122.3 (d, JC–F = 1.2 Hz)
C13H8N2O2ClS (M + H) 290.9990, found 290.9989.
116.1 (d, JC–F = 20.0 Hz), 112.9 (d, JC–F = 23.7 Hz); 19F NMR
7-Imino-2-(4-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine- (376 MHz, DMSO-d6) δ −111.8; HRMS (ESI+) m/z calcd for
4,6(5H,7H)-dione (9c). According to general procedure F, the C13H8N2O2FS (M + H) 275.0285, found 275.0283.
product obtained from 7-nitro-2-(4-(trifluoromethyl)phenyl)
7-Imino-2-(3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine-
thieno-[3,2-c]pyridin-4(5H)-one (8c, 0.125 g, 0.367 mmol) was 4,6(5H,7H)-dione (9g). According to general procedure F, the
purified by chromatography on SiO2 (acetone : hexanes, 1 : 2) product obtained from 7-nitro-2-(3-(trifluoromethyl)phenyl)
to give 9c (0.041 g, 34%) as a greenish/yellow solid: Mp thieno-[3,2-c]pyridin-4(5H)-one (8g, 0.128 g, 0.376 mmol) was
>250 °C; IR (ATR) νmax 3249, 3181, 1692, 1615, 1325, 1247, purified by chromatography on SiO2 (acetone : hexanes, 1 : 2)
1
1158, 1132, 1068, 831, 787 cm−1; H NMR (400 MHz, DMSO- to give 9g (0.029 g, 23%) as a yellow solid: Mp 236–238 °C; IR
d6) δ 11.90 (s, 1H), 11.70 (s, 1H), 8.16 (s, 1H), 8.11 (d, J = (ATR) νmax 3188, 3103, 1731, 1680, 1617, 1426, 1335, 1242,
1
8.0 Hz, 2H), 7.84 (d, J = 8.40 Hz, 2H); 13C NMR (125 MHz, 1177, 1161, 1128, 800, 689 cm−1; H NMR (400 MHz, DMSO-
DMSO-d6) δ 159.9, 157.7, 153.4, 147.0, 143.1, 136.8, 135.8, d6) δ 11.89 (s, 1H), 11.68 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 8.17
129.2 (q, JC–F = 31.2 Hz), 126.9, 126.1 (q, JC–F = 3.7 Hz), 124.0 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz,
(q, JC–F = 270 Hz), 123.9; 19F NMR (470 MHz, DMSO-d6) δ 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.0, 157.8, 153.4,
−61.2; HRMS (ESI+) m/z calcd for C14H8F3N2O2S (M + H) 147.1, 142.9, 136.8, 133.1, 130.6, 130.3 (q, JC–F = 33.0 Hz), 125.8
325.0253, found 325.0252.
(q, JC–F = 4.0 Hz), 123.9, 123.8 (q, JC–F = 270.0 Hz), 122.7 (q, JC–F =
2-(4-Fluorophenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- 4.0 Hz); 19F NMR (376 MHz, DMSO-d6) δ −61.3; HRMS (ESI+) m/z
dione (9d). According to general procedure F, the product calcd for C14H8N2O2F3S (M + H) 325.0253, found 325.0251.
obtained from 2-(4-fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4
2-(3-Chlorophenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-
(5H)-one (8d, 0.105 g, 0.361 mmol) was purified by chromato- dione (9h). According to general procedure F, the product
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obtained from 2-(3-chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4 1732, 1678, 1615, 1571, 1428, 1237, 1166, 812, 794, 760, 751,
(5H)-one (8h, 0.040 g, 0.130 mmol) was purified by chromato- 721 cm−1 1H NMR (400 MHz, DMSO-d6) δ 11.89 (brs, 1H),
;
graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9h (0.013 g, 11.65 (s, 1H), 8.06–7.99 (m, 2H), 7.56–7.40 (m, 2H), 7.35 (t, J =
34%) as a yellow solid: Mp 226–228 °C; IR (ATR) νmax 3211, 7.0 Hz 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.0, 158.5 (d,
3079, 1725, 1676, 1610, 1565, 1433, 1300, 1236, 1220, 1156, JC–F = 248.0 Hz), 157.8, 153.4, 142.9 (d, JC–F = 6.0 Hz), 141.6 (d,
772, 678 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.87 (brs, 1H), JC–F = 3.0 Hz), 140.0, 131.4 (d, JC–F = 9.0 Hz), 129.2, 125.5 (d,
11.65 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.85–7.81 (m, 1H), JC–F = 3.0 Hz), 124.6 (d, JC–F = 4.0 Hz), 119.6 (d, JC–F = 12.0 Hz),
7.52–7.50 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 159.9, 116.6 (d, JC–F = 22.0 Hz); 19F NMR (376 MHz, DMSO-d6)
157.7, 153.4, 147.3, 142.5, 136.7, 134.2, 133.9, 131.2, 129.2, δ −112.7; HRMS (ESI+) m/z calcd for C13H8N2O2SF (M + H)
125.7, 124.9, 123.3; HRMS (ESI−) m/z calcd for C13H6N2O2SCl 275.0285, found 275.0283.
(M − H) 288.9833, found 288.9842.
7-Imino-2-(m-tolyl)thieno[3,2-c]pyridine-4,6(5H,7H)-dione (9i). (5H,7H)-dione (9m). According to general procedure F, the
According to general procedure F, the product obtained from product obtained from 2-(4-chloro-3-fluorophenyl)-7-
2-(4-Chloro-3-fluorophenyl)-7-iminothieno[3,2-c]pyridine-4,6
7-nitro-2-(m-tolyl)thieno[3,2-c]pyridin-4(5H)-one (8i, 0.075 g, nitrothieno-[3,2-c]pyridin-4(5H)-one (8m, 0.155 g, 0.477 mmol)
0.261 mmol) was purified by chromatography on SiO2 was purified by chromatography on SiO2 (acetone : hexanes,
(acetone : hexanes, 1 : 2) to give 9i (0.018 g, 25%) as a yellow 1 : 2) to give 9m (0.027 g, 18%) as a yellow solid: Mp >250 °C;
solid: Mp 234–235 °C; IR (ATR) νmax 3208, 3092, 1714, 1686, IR (ATR) νmax 3184, 1731, 1678, 1611, 1467, 1429, 1419, 1306,
1
1610, 1379, 1307, 1172, 1153, 888, 772, 684 cm−1
;
1H NMR 1226, 1155, 1068, 961, 865, 808, 781 cm−1; H NMR (400 MHz,
(300 MHz, DMSO-d6) δ 11.84 (brs, 1H), 11.57 (s, 1H), 7.95 (s, DMSO-d6) δ 11.89 (s, 1H), 11.67 (s, 1H), 8.13 (s, 1H), 8.07 (dd,
1H), 7.71 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, J = 10.6, 1.6 Hz, 1H), 7.76–7.67 (m, 2H); 13C NMR (75 MHz,
1H), 7.26 (d, J = 7.5 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 159.9, 157.7, 157.5 (d, JC–F = 245.2 Hz), 153.4,
DMSO-d6) δ 160.1, 157.8, 153.4, 149.5, 141.7, 138.8, 136.7, 146.4 (d, JC–F = 3.0 Hz), 142.8, 136.7, 133.0 (d, JC–F = 7.5 Hz),
131.9, 130.3, 129.3, 126.7, 123.3, 121.9, 20.9; HRMS (ESI+) m/z 131.5, 123.8, 123.4 (d, JC–F = 3.7 Hz), 120.3 (d, JC–F = 17.2 Hz),
calcd for C14H11N2O2S (M + H) 271.0536, found 271.0533.
114.5 (d, JC–F = 22.5 Hz); 19F NMR (376 MHz, DMSO-d6) δ
2-(3-Methoxyphenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- −114.9; HRMS (ESI+) m/z calcd for C13H7N2O2SClF (M + H)
dione (9j). According to general procedure F, the product 308.9895, found 308.9895.
obtained
pyridin-4(5H)-one (8j, 0.040 g, 0.132 mmol) was purified by (5H,7H)-dione (9n). According to general procedure F, the
chromatography on SiO2 (acetone : hexanes, 1 : 2) to give 9j product obtained from 2-(3-chloro-4-fluorophenyl)-7-
from
2-(3-methoxyphenyl)-7-nitrothieno[3,2-c]
2-(3-Chloro-4-fluorophenyl)-7-iminothieno[3,2-c]pyridine-4,6
(0.008 g, 23%) as a tan solid: Mp 226–227 °C; IR (ATR) νmax nitrothieno-[3,2-c]pyridin-4(5H)-one (8n, 0.180 g, 0.554 mmol)
3210, 1694, 1614, 1593, 1463, 1437, 1260, 1230, 1158, 1028, was purified by chromatography on SiO2 (acetone : hexanes,
1
783, 680 cm−1; H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 1 : 2) to give 9n (0.036 g, 21%) as a yellow solid: Mp
11.59 (s, 1H), 8.04 (s, 1H), 7.41–7.37 (m, 3H), 7.03–7.00 (m, 235–236 °C; IR (ATR) νmax 3223, 2997, 2823, 1710, 1605, 1501,
1H), 3.85 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 159.9, 1461, 1434, 1374, 1235, 1185, 1155, 908, 855, 820, 775,
1
157.8, 153.4, 149.2, 141.8, 136.7, 133.2, 130.5, 122.4, 118.5, 734 cm−1; H NMR (500 MHz, DMSO-d6) δ 11.87 (s, 1H), 11.64
115.6, 111.1, 55.4; HRMS (ESI+) m/z calcd for C14H11N2O2S (s, 1H), 8.19 (d, J = 7.0 Hz, 1H), 8.07 (s, 1H), 7.90–7.87 (m, 1H),
(M + H) 287.0485, found 287.0484.
7.53 (t, J = 9.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 159.9,
2-(2-Chlorophenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- 157.7, 157.6 (d, JC–F = 248.2 Hz), 153.3, 146.4, 142.5, 136.7,
dione (9k). According to general procedure F, the product 129.8 (d, JC–F = 3.7 Hz), 128.2, 127.0 (d, JC–F = 7.5 Hz), 123.4,
obtained from 2-(2-chlorophenyl)-7-nitrothieno[3,2-c]pyridin-4 120.7 (d, JC–F = 18.0 Hz), 117.8 (d, JC–F = 21.0 Hz); 19F NMR
(5H)-one (8k, 0.111 g, 0.361 mmol) was purified by chromato- (470 MHz, DMSO-d6) δ −114.9; HRMS (ESI+) m/z calcd for
graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9k (0.033 g, C13H7N2O2SClF (M + H) 308.9895, found 308.9895.
31%) as a yellow solid: Mp 220–221 °C; IR (ATR) 3226, 3192,
3080, 1724, 1678, 1608, 1408, 1307, 1224, 1165, 914, 887, 758, 4,6(5H,7H)-dione (9o). According to general procedure F, the
731 cm−1 1H NMR (300 MHz, DMSO-d6) δ 11.88 (brs, 1H), product obtained from 2-(4-(2-morpholinoethoxy)phenyl-7-
7-Imino-2-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-c]pyridine-
;
11.66 (s, 1H), 7.84 (s, 1H), 7.83–7.78 (m, 2H), 7.68–7.64 (m, nitrothieno[3,2-c]pyrdin-4(5H)-one (8o, 0.125 g, 0.311 mmol)
1H), 7.53–7.47 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 160.0, was purified by chromatography on SiO2 (acetone : hexanes,
157.8, 153.5, 144.9, 143.5, 135.6, 131.7, 131.1, 131.0, 130.7, 1 : 1) to give 9o (0.028 g, 23%) as a brown solid: Mp >250 °C; IR
130.6, 128.1, 126.5; HRMS (ESI+) m/z calcd for C13H8N2O2SCl (ATR) νmax 3212, 3084, 2927, 2835, 1693, 1601, 1460, 1437,
(M + H) 290.9990, found 290.9984.
1290, 1254, 1180, 1149, 1107, 824, 800, 777 cm−1 1H NMR
;
2-(2-Fluorophenyl)-7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- (300 MHz, DMSO-d6) δ 11.82 (brs, 1H), 11.49 (s, 1H), 7.84 (s,
dione (9l). According to general procedure F, the product 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 4.16 (t, J =
obtained from 2-(2-fluorophenyl)-7-nitrothieno[3,2-c]pyridin-4 5.7 Hz, 2H), 3.60–3.56 (m, 4H), 2.71 (t, J = 5.7 Hz, 2H),
(5H)-one (8l, 0.138 g, 0.475 mmol) was purified by chromato- 2.51–2.46 (m, 4 H covered in part by DMSO signal); 13C NMR
graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9l (0.011 g, 8%) (100 MHz, DMSO-d6) δ 160.1, 159.6, 157.9, 153.3, 149.6, 140.7,
as a yellow solid: Mp 225–226 °C; IR (ATR) νmax 3191, 3100, 136.9, 127.7, 124.6, 120.7, 115.3, 66.2, 65.6, 56.9, 53.6; HRMS
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(ESI+) m/z calcd for C19H20N3O4S (M + H) 386.1169, found (0.066 g, 56%) as a yellow solid: Mp 193–194 °C; IR (ATR) νmax
386.1162. 3219, 3099, 1713, 1667, 1605, 1453, 1427, 1334, 1298, 1176,
5-Methyl-7-nitro-2-phenylthieno[3,2-c]pyridin-4(5H)-one (38). 878, 830, 752, 687 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 11.75
A solution of 8p (0.200 g, 0.735 mmol) and K2CO3 (0.507 g, (s, 1H), 8.04 (s, 1H), 7.89 (dd, J = 8.4, 1.5 Hz, 2H), 7.52–7.45
3.67 mmol) in DMF (9 mL) was treated dropwise with iodo- (m, 3H), 3.74 (d, J = 7.0 Hz, 2H), 1.19–1.10 (m, 1H), 0.48–0.46
methane (0.23 mL, 3.7 mmol). The reaction mixture was (m, 2H), 0.36–0.33 (m, 2H); 13C NMR (125 MHz) δ 159.5, 157.7,
stirred at 90 °C for 2 d, quenched with saturated aqueous 152.3, 149.2, 140.9, 136.3, 131.8, 129.6, 129.4, 126.2, 122.5,
NH4Cl (5 mL) and stirred for 5 min. The mixture was diluted 44.5, 9.7, 3.7; HRMS (ESI+) m/z cald for C17H15O2N2S (M + H)
with EtOAc (100 mL). The layers were separated, and the 311.0849, found 311.0847.
organic layer was washed with H2O (5 × 5 mL) and saturated
N-(4-Oxo-2-phenyl-4,5-dihydrothieno[3,2-c]pyridin-7-yl)acetamide
aqueous NaCl (2 × 5 mL), dried (MgSO4) and purified by (40). Through a suspension of 10% Pd/C (15 mol%) and
chromatography on SiO2 (dry-load, EtOAc : hexanes, 1 : 1) to 7-nitro-2-phenylthieno[3,2-c]pyridin-4(5H)-one (8p, 0.200 g,
yield 38 (0.146 g, 69%) as a yellow solid: Mp >250 °C; IR (ATR) 0.735 mmol) in MeOH (18 mL, N2 sparged) was bubbled H2
νmax 3079, 1655, 1603, 1482, 1296, 1256, 1075, 1044, 879 cm−1
;
gas for 10 min. The reaction mixture was stirred at room temp-
1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.00 (s, 1H), 7.86 erature under an atmosphere of H2 (1 atm, balloon) for 6 h
(d, J = 7.6 Hz, 2H), 7.48 (t, J = 8.4 Hz, 2H), 7.41 (t, J = 7.2 Hz, and filtered through Celite. The Celite pad was washed with
1H), 3.69 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 157.7, 144.9, MeOH (50 mL). The Pd/C layer was removed from the Celite,
139.6, 137.8, 132.3, 129.4, 128.9, 128.8, 126.5, 126.0, 120.1, heated at reflux in PhMe (40 mL), filtered over Celite, and
37.5; HRMS (ESI+) m/z calcd for C14H11O3N2S (M + H) eluted with MeOH. This procedure was performed twice. The
287.0483, found, 287.0485.
combined filtrates were concentrated under reduced pressure
7-Imino-5-methyl-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)- to afford a brown solid that was dissolved in Ac2O (7 mL) and
dione (9p). According to general procedure F, the product THF (7 mL), and stirred at room temperature in the dark for
obtained from 5-methyl-7-nitro-2-phenylthieno[3,2-c]pyridin-4 16 h. The reaction mixture was concentrated under reduced
(5H)-one (38, 0.120 g, 0.419 mmol) was purified by chromato- pressure. Purification by chromatography on SiO2 (dry-load,
graphy on SiO2 (acetone : hexanes, 1 : 2) to give 9p (0.025 g, MeOH : EtOAc, 1 : 9) provided 40 (0.130 g, 62%) as a beige
22%) as a brown solid: Mp 236–237 °C; IR (ATR) νmax 3234, solid: Mp >250 °C; IR (ATR) νmax 3253, 3160, 3054, 2972, 2938,
3100, 1711, 1670, 1606, 1455, 1432, 1329, 1281, 1183, 1105, 2809, 1652, 1617, 1508, 1384, 1374, 1291, 1145, 1035, 1012,
1
1
878 cm−1; H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.03 976, 947, 871, 803, 751, 687; H NMR (500 MHz, DMSO-d6) δ
(s,1H), 7.90–7.77 (m, 2H), 7.53–7.45 (m, 3H), 3.23 (s, 3H); 11.46 (brs, 1H), 9.71 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.5 Hz,
13C NMR (75 MHz, DMSO-d6) δ 159.6, 157.9, 152.4, 149.1, 2H), 7.46 (t, J = 6.9 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.30 (s,
140.7, 136.5, 131.9, 129.6, 129.4, 126.2, 122.5, 27.0; HRMS 1H), 2.06 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 169.0, 157.4,
(ESI+) m/z calcd for C14H11O2N2S (M + H) 271.0534, found, 146.0, 141.5, 132.8, 130.9, 129.3, 128.4, 125.7, 120.3, 113.8
271.0536.
5-(Cyclopropylmethyl)-7-nitro-2-phenylthieno[3,2-c]pyridin-4 285.0692, found 285.0690.
(5H)-one (39). solution of 7-nitro-2-phenylthieno[3,2-c] 6,7-Dihydrothieno[3,2-c]pyridin-4(5H)-one (12). A solution of
22.8; HRMS (ESI+) m/z calcd for C15H13O2N2S (M + H)
A
pyridin-4(5H)-one (8p, 0.220 g, 0.727 mmol) in THF (15 mL) thiophene-2-ethylamine (11, 10.0 mL, 84.5 mmol) in CH2Cl2
was treated with cyclopropane methanol (0.0770 mL, (30 mL) was added slowly over 10 min to a solution of triphos-
0.945 mmol) and PPh3 (0.250 g, 0.0945 mmol), cooled to 0 °C, gene (9.58 g, 32.1 mmol) in CH2Cl2 (150 mL) in a three neck
and treated dropwise with DIAD (0.187 mL, 0.945 mmol). The 1 L round-bottom flask (N2 inlet, glass stopper, an outlet con-
reaction mixture was warmed to room temperature, stirred for nected to an aqueous NH4OH trap) at 0 °C under N2. Then,
1
4
20 h, diluted with MeOH (15 mL), concentrated to volume saturated aqueous NaHCO3 (180 mL) was added to the reaction
in vacuo, cooled to 0 °C, and filtered. The precipitate was dried mixture and the resulting biphasic mixture was stirred vigor-
to afford 39 (0.130 g, 55%) as a yellow solid: Mp 229–231 °C; IR ously at 0 °C (ice-bath) under N2 for 2.5 h. The organic layer
(ATR) νmax 3087, 1654, 1595, 1514, 1484, 1449, 1333, 1304, was dried (MgSO4), filtered, and concentrated to provide a
1230, 1137, 1025 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 9.08 (s, crude product as a dark yellow oil. IR showed the presence of
1H), 8.03 (s, 1H), 7.95 (dd, J = 8.4, 1.2 Hz, 2H), 7.55–7.43 (m, an isocyanate peak at 2259 cm−1. A solution of this material
3H), 4.50 (d, J = 7.2 Hz, 2H), 1.45–1.36 (m, 1H), 0.67–0.62 (m, (13.0 g, 84.6 mmol) in CH2Cl2 (150 mL) was added dropwise
2H), 0.47–0.45 (m, 2H); 13C NMR (125 MHz) δ 157.3, 145.0, by addition funnel (2–3 drops per second) over 2 h to a
138.2, 137.7, 132.2, 129.3, 129.2, 128.9, 126.8, 126.0, 120.2, mixture of ferric chloride (14.4 g, 88.8 mmol) in CH2Cl2
53.4, 10.7, 3.5; HRMS (ESI+) m/z calcd for C17H14O3N2S (M + H) (450 mL) under N2 at 50 °C in a flask connected to a reflux
327.0798, found 327.0794.
condenser. After an additional 2 h, the mixture was cooled to
5-(Cyclopropylmethyl)-7-imino-2-phenylthieno[3,2-c]pyridine- 0 °C (ice-bath) and diluted with aqueous citric acid (30 g of
4,6(5H,7H)-dione (9q). According to general procedure F, the citric acid monohydrate in 250 mL of H2O), and the resulting
product obtained from 5-(cyclopropylmethyl)-7-nitro-2-phe- biphasic mixture was stirred for 15 min. The two layers were
nylthieno[3,2-c]pyridin-4(5H)-one (39, 0.125 g, 0.383 mmol) separated and the aqueous layer was extracted with CH2Cl2
was purified by chromatography on SiO2 (CH2Cl2) to give 9q (100 mL). The combined organic layers were washed with satu-
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rated aqueous NaCl (350 mL), dried (MgSO4), and concen- mixture was sonicated and filtered. The filtrate was concen-
trated to a dark oil. Purification by chromatography on basic trated, the process was repeated, and the precipitates were
Al2O3 (CH2Cl2 to load the sample, elution with combined to provide 42 as a tan solid (2.88 g). The aqueous
MeOH : CH2Cl2, 1 : 19) provided 12 (9.90 g, 73% over two steps) phase was extracted with CH2Cl2 until the suspended solid was
1
as a brown liquid: H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 5.5 no longer present. The combined CH2Cl2 washes were dried
Hz, 1H), 7.11 (d, J = 5.5 Hz, 1H), 5.57 (brs, 1H), 3.65 (dt, J = 6.5, (MgSO4), filtered, and concentrated to provide additional 42
1
2.5 Hz, 2H), 3.08 (t, J = 6.5 Hz, 2H). Spectral data were consist- (4.94 g; combined yield: 7.82 g, 82%) as a tan solid: H NMR
ent with literature properties.20
(300 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.85 (s, 1H), 7.75 (d, J =
2-Bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (41). In a 7.2 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.38–7.34 (m, 1H), 7.26
250 mL round-bottom flask, solution of 12 (4.80 g, (dd, J = 6.6, 5.4 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H). Spectral data
31.3 mmol) in AcOH (60 mL) was treated with Br2 (1.77 mL, were consistent with literature properties.20
a
34.5 mmol). The red reaction mixture was shielded from light
7-Nitro-2-phenylthieno[3,2-c]pyridin-4(5H)-one (8p). To a 1 L
with foil and stirred at room temperature. Reaction progress round-bottom flask charged with a stir bar were added 42
was monitored by LC-MS. Additional Br2 (1.00 mL) was added (2.80 g, 12.3 mmol), MeCN (246 mL) and t-BuONO (6.51 mL,
every 24 h until starting material was consumed. The reaction 49.3 mmol), and the flask was flushed with O2 and stirred at
mixture was diluted with PhMe (250 mL) and concentrated. room temperature under O2 (1 atm, balloon, 10 min flush) for
The resulting brown solid was dissolved in CH2Cl2 (300 mL), 24 h. Reaction progress was monitored by TLC analysis (50%
washed with saturated aqueous NaHCO3 (100 mL), 1 M EtOAc : hexanes, Rf = 0.70). The solution was partially concen-
Na2S2O3 (100 mL), and saturated aqueous NaCl (100 mL), trated (ca. 1/4 volume). The resulting slurry was cooled in an
dried (MgSO4), and concentrated to give a crude tan solid that ice bath for 20 min and filtered. The precipitate was washed
was purified by chromatography on SiO2 (CH2Cl2 to load with MeOH (3 × 5 mL) and dried under high vacuum to
sample, EtOAc : hexanes, 4 : 1 to 1 : 0) to provide 41 (4.70 g, provide 8p (1.78 g, 53%) as a yellow-brown solid: 1H NMR
1
65%) as a tan solid: H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), (300 MHz, DMSO-d6) δ 12.76 (brs, 1H), 8.74 (d, J = 6.9 Hz, 1H),
5.69 (brs, 1H), 3.64 (dt, J = 6.8, 2.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 7.98 (s, 1H), 7.85 (dt, J = 6.9,1.5 Hz, 2H), 7.52–7.41 (m, 3H).
2H). Spectral data were consistent with literature properties.20
Spectral data were consistent with literature properties.20
2-Phenyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (13). To
7-Imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione (2).
a 1 L round-bottom flask containing Pd(PPh3)4 (1.72 g, A suspension of 8p (1.00 g, 3.67 mmol) in MeOH (90 mL) was
1.64 mmol,) were added 41 (9.77 g, 42.1 mmol), phenylboronic bubbled with N2 for 5 min, and then treated with 10% Pd/C
acid (6.28 g, 50.5 mmol), and Na2CO3 (10.3 g, 96.8 mmol). The (0.597 g, 0.551 mmol). The reaction mixture was bubbled with
flask was evacuated and purged with N2 (3×), diluted with H2 for 10 min, stirred at room temperature under a H2 atmo-
deoxygenated dioxane and H2O (2 : 1, 420 mL), fitted with a sphere (1 atm, balloon) for 16 h, and filtered through Celite.
reflux condenser, and heated to 90 °C for 15 h. The resulting The Celite pad was washed with MeOH (100 mL). The Pd/C
dark mixture was cooled to room temperature, diluted with layer was removed from the Celite, boiled in PhMe (40 mL), fil-
H2O (1 L), cooled in an ice-bath, and filtered. The brown tered over Celite, and eluted with MeOH. This procedure was
residue was washed with cold H2O (2 × 100 mL) and dissolved performed twice. The combined filtrates were concentrated
in EtOAc. The H2O washes were extracted with CH2Cl2 (2 × under reduced pressure to afford a brown solid that was dis-
50 mL), and the combined organic layers were dried (MgSO4), solved in MeOH (2 L). The solution was passed through the
filtered, concentrated, and dried under high vacuum to afford tubing at a rate of 1.9 mL min−1 using the peristaltic pump (5
a black solid that was purified by chromatography on SiO2 RPM) under LED irradiation. The tubing was flushed with
(CH2Cl2 to load sample, EtOAc : hexanes, 1 : 1 to 1 : 0) to MeOH (40 mL). The mixture was concentrated to give a brown
provide 13 (9.58 g, 99%) as a tan solid: 1H NMR (300 MHz, solid that was filtered through a short SiO2 plug (dry load,
CDCl3) δ 7.59 (s, 1H), 7.58 (d, J = 5.1 Hz, 2H), 7.38 (tt, J = 9.0, MeCN : CH2Cl2, 1 : 6) to provide the imine/ketone mixture as a
1.2 Hz, 2H), 7.33–7.29 (m, 1H), 5.65 (brs, 1H), 3.67 (dt, J = 6.8, dark orange solid (0.634 g, 2.47 mmol). A solution of this
2.8 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H). Spectral data were consist- mixture and NH4OAc (3.81 g, 49.5 mmol) in MeOH (180 mL)
ent with literature properties.20
in an oven-dried pressure vessel was stirred at 60–65 °C. Due
2-Phenylthieno[3,2-c]pyridin-4(5H)-one (42). In a 500 mL to residual solid still present after 24 h, the solution was dec-
round-bottom flask equipped with a condenser, a solution of anted and additional MeOH (180 mL) and NH4OAc (3.81 g,
13 (9.58 g, 41.8 mmol) and DDQ (19.0 g, 83.6 mmol) in 1,4- 49.5) were added. The reaction mixture was stirred for an
dioxane (260 mL) was stirred at 100 °C for 36 h. The reaction additional 24 h. The process was repeated until the solution
mixture was cooled to room temperature, concentrated, was homogeneous. The reaction mixture was cooled to room
diluted with EtOAc (300 mL), saturated aqueous NaHCO3 and temperature and concentrated. The solid residue was sus-
H2O (4 : 1, 500 mL), and stirred for 24 h. The organic layer was pended in EtOAc (300 mL) and saturated aqueous NaHCO3
washed with saturated aqueous NaHCO3 (3 × 100 mL) and (150 mL), and vigorously stirred until all solids dissolved. The
saturated aqueous NaCl (100 mL), dried (MgSO4), filtered, and layers were separated, and the aqueous layer was extracted
concentrated give a light brown solid. Acetone was added to with EtOAc (2 × 50 mL). The combined organic layers were
the solid to yield a black solution with a tan precipitate. The washed with H2O (2 × 50 mL) and concentrated to provide 2
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(0.634 g, 67% over three steps) as a reddish-brown solid: 1H
(E)-3-(5-Bromothiophen-3-yl)acrylic acid (44). To a solution
NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 11.59 (s, 1H), 7.98 of 43 (3.39 g, 17.7 mmol) in a round-bottom flask equipped
(s, 1H), 7.88 (dd, J = 8.1, 1.5 Hz, 2H), 7.53–7.44 (m, 3H). with a reflux condenser were added pyridine (40 mL) and
Spectral data were consistent with literature properties.20
malonic acid (5.59 g, 53.2 mmol). At 110 °C, piperidine
4-Nitroisoquinolin-1(2H)-one (14). To a solution of 1-hydroxy- (0.88 mL, 8.9 mmol) was added. After 3 h (reaction progress
isoquinoline (2.00 g, 13.5 mmol) in AcOH (13.5 mL) was added was monitored by TLC, EtOAc : hexanes, 1 : 9), the reaction
HNO3 (2.68 mL, 40.5 mmol). The solution was stirred at room mixture was concentrated, diluted with H2O (45 mL), and neu-
temperature for 5 min, then heated to 65 °C for 16 h in a tralized with 6 M HCl to pH 2. The precipitate was filtered,
round-bottom flask equipped with a reflux condenser. The washed with H2O (3 × 10 mL), and dissolved in MeOH. This
reaction mixture was poured over ice and filtered. The residue solution was concentrated and dried under high vacuum to
was washed with ice-cold H2O (2 × 5 mL) and dried under high provide 44 (2.35 g, 57%) as a tan solid: 1H NMR (300 MHz,
vacuum to provide 14 (1.53 g, 59%) as a yellow solid: Mp CDCl3) δ 12.34 (brs, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.71 (d, J =
236–237 °C; IR (ATR) νmax 3061, 2864, 1655, 1631, 1509, 1470, 1.5 Hz, 1H), 7.48 (d, J = 15.9 Hz, 1H), 6.37 (d, J = 15.9 Hz, 1H).
1
1439, 1317, 1285, 1225, 1139, 1039 cm−1; H NMR (300 MHz, Spectral data were consistent with literature properties.37
DMSO-d6) δ 12.42 (brs, 1H), 8.64 (d, J = 6.3 Hz, 1H), 8.57 (dd,
2-Bromothieno[2,3-c]pyridin-7(6H)-one (45). A solution of
J = 7.2, 0.3 Hz, 1H), 8.31 (ddd, J = 8.1, 1.5, 0.6 Hz, 1H), 7.94 (td, Et3N (2.81 mL, 20.2 mmol) and 44 (2.35 g, 10.1 mmol) in
J = 7.2, 1.5 Hz, 1H), 7.68 (td, J = 7.2, 0.9 Hz, 1H); 13C NMR acetone (21 mL) was treated at 0 °C with ethyl chloroformate
(75 MHz, DMSO-d6) δ 161.4, 136.2, 134.3, 129.4, 128.2, 128.0, (2.94 mL, 30.2 mmol). The reaction mixture was stirred at 0 °C
127.7, 124.2, 123.1; HRMS (ESI+) m/z calcd for C9H7O3N2 (M + for 1 h. A solution of NaN3 (0.983 g, 15.1 mmol) in H2O (6 mL)
H) 191.0451, found, 191.0451.
was added slowly at 0 °C, and stirring was continued at 0 °C
Isoquinoline-1,3,4(2H)-trione (15).
A
suspension of 14 for 1 h. The mixture was poured into ice-cold H2O, extracted
(0.200 g, 1.05 mmol) in EtOH : EtOAc (8 mL, 1 : 1) was bubbled with EtOAc, dried (MgSO4), and concentrated to give the crude
with N2 for 10 min before adding 10% Pd/C (0.171 g, azide intermediate as a tan solid. To a solution of Bu3N
0.158 mmol). Then, H2 was bubbled through the mixture for (3.15 mL, 13.1 mmol) in Ph2O (10 mL) heated to 240 °C was
5 min. The solution was stirred at room temperature under H2 added a solution of the crude azide (2.60 g, 10.1 mmol) in
(1 atm, balloon) for 24 h and filtered over Celite. The Celite pad CH2Cl2 (20.2 mL) over a period of ca. 30 min, allowing the
was washed consecutively with PhMe and MeOH until coloured CH2Cl2 to boil off. The reaction mixture was stirred at 240 °C
material stopped eluting. The filtrate was concentrated to give a for another 1 h, cooled to room temperature, diluted with
solid that was dissolved in in MeOH (400 mL) and treated with hexanes (70 mL), and stirred for 15 min. The precipitate was
methylene blue (0.010 g, 0.032 mmol). The solution was passed filtered, washed with hexanes (2 × 10 mL) and dried under
through the tubing under at a rate of 1.9 mL min−1 using the vacuum to give the crude product as a sticky brown solid.
peristaltic pump (5 RPM) under LED irradiation. The tubing Purification by chromatography on SiO2 (CH2Cl2 to load
was flushed with MeOH (50 mL). The reaction mixture was con- sample, EtOAc to elute impurities, then MeOH : EtOAc, 1 : 9)
centrated to give a blue solid which was purified by chromato- provided 45 (1.29 g, 56%) as a brown solid: Mp 246–248 °C; IR
graphy on SiO2 (dry load, EtOAc : hexanes, 1 : 2.5) to give 15 (ATR) νmax 3131.3, 2957.1, 2838.5, 1627.6, 1609.6, 1521.9,
(0.032 g, 17%) as a green solid: Mp 226–228 °C; IR (ATR) νmax 1470.6, 1418.7, 1238.5, 1059.5, 948.3, 935.8, 888.1 cm−1 1H
;
3194, 3114, 2923, 1685, 1589, 1332, 1272, 1129, 974, 823, NMR (300 MHz, DMSO-d6) δ 11.65 (brs, 1H), 7.57 (s, 1H), 7.29
794 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 11.94 (brs, 1H), 8.13 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 6.9, 1H); 13C NMR (100 MHz,
(dd, J = 8.4, 1.2 Hz, 1H), 8.05 (dd, J = 7.2, 1.2, Hz, 1H), DMSO-d6) δ 157.1, 146.7, 131.4, 130.1, 128.4, 121.0, 101.5;
7.95–7.85 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 175.5, 163.2, HRMS (ESI+) m/z calcd for C7H5BrNOS (M + H) 229.9275,
157.5, 134.9, 134.0, 132.3, 129.8, 128.1, 126.7; HRMS (ESI−) m/z found, 229.9266.
calcd for C9H4O3N (M-H) 174.0192, found, 174.0186.
2-Bromo-4-nitrothieno[2,3-c]pyridin-7(6H)-one (46). To a
5-Bromothiophene-3-carbaldehyde (43). To a solution of solution of 45 (1.20 g, 5.21 mmol) in MeCN (104 mL) was
thiophene-3-carbaldehyde (2.00 mL, 22.1 mmol) in CH2Cl2 added t-BuONO (2.76 mL, 20.9 mmol). The flask was flushed
(80 mL) was added AlCl3 (8.86 g, 66.4 mmol). The dark solu- with O2 and the solution was stirred for 15 h at rt under O2
tion was stirred for 10 min, and Br2 (1.25 mL, 24.4 mmol) was (1 atm, balloon), concentrated, and suspended in MeCN
added. The mixture was stirred at room temperature for 12 h, (10 mL). The resulting slurry was filtered and washed with
and slowly quenched with H2O at 0 °C. The aqueous phase MeCN (3 × 5 mL) to provide 46 (0.730 g, 51%) as a tan solid:
was extracted with CH2Cl2 (2 × 30 mL). The combined organic Mp 203–205 °C; IR (ATR) νmax 3189, 3083, 1744, 1700, 1674,
phases were washed with saturated aqueous Na2S2O3 (30 mL) 1519, 1430, 1389, 1369, 1260, 880, 867, 821, 797, 746 cm−1
;
and saturated aqueous NaCl (30 mL), dried (MgSO4), and con- 1H NMR (300 MHz, DMSO-d6) δ 12.88 (brs, 1H), 8.69 (s, 1H),
centrated. The dark oil was purified by chromatography on 8.06 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 157.1, 138.4,
SiO2 (EtOAc : hexanes, 1 : 19) to provide 43 (2.85 g, 67%) as a 137.3, 130.7, 128.2, 127.5, 124.8; HRMS (ESI+) m/z calcd for
1
yellow liquid: H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 7.99 C7H4BrN2O3S (M + H) 274.9126, found, 274.9106.
(d, J = 1.5 Hz, 1H), 7.50 (d, J = 1.2 Hz, 1H). Spectral data were
4-Nitro-2-phenylthieno[2,3-c]pyridin-7(6H)-one (16). To a
100 mL round-bottom flask containing Pd(PPh3)4 (0.134 g,
consistent with literature properties.40
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0.127 mmol) were added 46 (0.700 g, 2.54 mmol), phenyl- washed with saturated aqueous NaCl (10 mL), dried (MgSO4),
boronic acid (6.28 g, 50.5 mmol), and Na2CO3 (0.623 g, concentrated, and dried under high vacuum to give 47 (1.27 g,
1
5.85 mmol). The flask was evacuated and purged with N2 (3×), 89%) as a light red solid: H NMR (300 MHz, DMSO-d6) δ 8.48
diluted with deoxygenated dioxane and H2O (2 : 1, 26 mL), (s, 1H), 8.22 (dd, J = 6, 0.6 Hz, 1H), 7.83 (d, J = 13.2 Hz, 1H),
fitted with a reflux condenser, and heated to 90 °C for 16 h. 7.45 (d, J = 6 Hz, 1H), 5.05 (d, J = 13.2 Hz, 1H), 2.98 (s, 6H).
The solution was concentrated to give a red oil that was Spectral data were consistent with literature properties.41,42
diluted with H2O (50 mL) and 1 M KHSO4 (5 mL), at which
2,7-Naphthyridin-1(2H)-one (48). To a solution of 47 (1.27 g,
time the red oil converted to an orange semi-solid suspension. 7.33 mmol) in AcOH (3.50 mL) was added H2SO4 (3.50 mL).
The mixture was diluted with EtOAc (40 mL), and the layers The reaction mixture was stirred at 110 °C for 1 h, cooled to
were separated. The aqueous phase was extracted with EtOAc room temperature, diluted with H2O (10 mL), and then slowly
(3 × 100 mL). The combined organic extracts were washed with added to NH4OH (15 mL). The solution was neutralized to pH
saturated aqueous NaCl (50 mL), dried (MgSO4), filtered, and 7–8 with additional NH4OH and was cooled in an ice bath.
concentrated to give a yellow solid. The solid was then partially The precipitate was filtered and washed with small amounts of
dissolved in MeOH (15 mL), sonicated, and heated to reflux, cold H2O (2 × 3 mL) and dried under high vacuum to afford 48
1
cooled to room temperature, and kept in a −20 °C freezer for (0.899 g, 84%) as a tan solid: H NMR (300 MHz, DMSO-d6) δ
30 min. The yellow precipitate was filtered and washed with 11.61 (brs, 1H), 9.31 (t, J = 0.8 Hz, 1H), 8.70 (d, J = 5.4 Hz, 1H),
cold MeOH to give 16 (0.354 g, 52%): Mp >250 °C; IR (ATR) 7.59 (dd, J = 5.4, 0.8 Hz, 1H), 7.42 (dd, J = 6.9, 6.0 Hz, 1H), 6.56
νmax 3308, 1646, 1626, 1530, 1504, 1489, 1459, 1439, 1401, (d, J = 7.2 Hz, 1H). Spectral data were consistent with literature
1348, 1306, 1246, 1153, 1100, 1064, 1025, 998, 964 cm−1
NMR (300 MHz, DMSO-d6) δ 12.75 (brs, 1H), 8.70 (s, 1H), 8.28
;
1H properties.42
4-Nitro-2,7-naphthyridin-1(2H)-one (18). To a microwave vial
(s, 1H), 7.88 (dd, J = 8.1, 1.8 Hz, 2H), 7.57–7.50 (m, 3H); 13C charged with a stir bar were added 48 (0.882 g, 6.03 mmol)
NMR (75 MHz, DMSO-d6) δ 157.5, 152.6, 138.4, 136.6, 132.0, and H2SO4 (5.50 mL), followed by HNO3 (1.20 mL, 18.1 mmol).
130.0, 129.5, 127.9, 127.6, 126.6, 120.0; HRMS (ESI+) m/z calcd The vial was capped and stirred at 85 °C for 16 h. The reaction
for C13H9O3N2S (M + H) 273.0328, found, 273.0334.
mixture was cooled to 0 °C (ice-bath), diluted with H2O
2-Phenylthieno[2,3-c]pyridine-4,5,7(6H)-trione (17). To a sus- (10 mL), and basified to pH 7 with NH4OH. The resulting pre-
pension of 16 (0.170 g, 0.468 mmol) in degassed MeOH cipitate was filtered, washed with minimal amounts of cold
(10 mL) was added 10% Pd/C (0.076 g, 0.070 mmol). Then, H2 H2O (2 × 5 mL), and dried under high vacuum to provide 18
was bubbled through the mixture for 5 min. The suspension (0.393 g, 34%) as a yellow solid: Mp >250 °C; IR (ATR) νmax
was stirred at room temperature under H2 (1 atm, balloon) for 3187, 3130, 3060, 2879, 1677, 1631, 1589, 1509, 1471, 1415,
17 h, and filtered over Celite. The Pd/C layer was removed, 1348, 1296, 1247, 1204, 1187, 1107, 1038, 895, 790 cm−1 1H
;
boiled in PhMe (10 mL) for 10 seconds, filtered over Celite, NMR (300 MHz, DMSO-d6) δ 12.66 (brs, 1H), 9.38 (s, 1H), 8.91
and washed with MeOH. The process was repeated two more (t, J = 5.5 Hz, 2H), 8.41 (d, J = 5.5 Hz, 1H); 13C NMR (75 MHz,
times. The combined filtrates were concentrated under DMSO-d6) δ 161.7, 152.9, 150.4, 141.7, 135.5, 125.9, 118.4,
reduced pressure to give a residue that was suspended in 115.9; HRMS (ESI+) m/z calcd for C8H6O3N3 (M + H) 191.0403,
MeCN (20 mL) and treated with meso-tetraphenylporphine found, 191.0404.
(0.0086 g, 0.014 mmol). The solution was irradiated with two
2,5-Dihydro-1H-pyrido[4,3-b]indol-1-one (49). A solution of
CFL lamps, flushed with O2, and allowed to stir under O2 (1 2,4-dihydroxypyridine (0.500 g, 4.41 mmol) and phenylhydra-
atm, balloon) for 6 d. The reaction mixture was concentrated zine (1.49 mL, 14.7 mmol) in Ph2O (3.5 mL) was stirred for
and purified by chromatography on SiO2 (dry load, 15 h at 240 °C. The solution was cooled to room temperature
MeCN : CH2Cl2, 0 : 1 to 1 : 6) to provide 17 (0.025 g, 21%) as a and diluted with hexanes (20 mL), stirred for 15 min, and fil-
yellow solid. The reaction was also performed in-flow following tered. The solid was washed with hexanes and collected to give
the general procedure F with 3% methylene blue to provide 17 crude 49 as a dark gray solid that was washed with MeOH (2 ×
(11%) as a yellow solid: Mp >250 °C; IR (ATR) νmax 3079, 2851, 3 mL) and filtered to provide 49 (0.393 g, 48%) as a black
1
1737, 1701, 1671, 1535, 1502, 1454, 1415, 1360, 1265, 1120, solid: H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.08 (s,
1078, 998, 954 cm−1 1H NMR (300 MHz, DMSO-d6) δ 12.01 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.30–7.25
;
(brs, 1H), 8.05 (s, 1H), 7.90 (dd, J = 8.1, 2.1 Hz, 2H), 7.53–7.47 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 6.9 Hz, 1H).
(m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 170.1, 159.0, 158.1, Spectral data were consistent with literature properties.43
151.1, 141.6, 140.1, 131.5, 129.9, 129.5, 126.4, 121.3; HRMS
(ESI+) m/z calcd for C13H6O3NS (M + H) 256.0063, found, solution of 49 (0.100 g, 0.543 mmol) in MeCN (11 mL) was
256.0063. added t-BuONO (0.287 mL, 2.17 mmol). The flask was flushed
4-Nitro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (19). To a
(E)-4-(2-(Dimethylamino)vinyl)nicotinonitrile (47). A solu- with O2, and the solution was stirred for 15 h at room tempera-
tion of 3-cyano-4-methylpyridine (1.00 g, 8.21 mmol) and ture under O2 (1 atm, balloon). The solvent was evaporated,
Bredereck’s reagent (2.07 mL, 9.03 mmol) in DMF (12 mL), and the orange residue was purified by chromatography on
was heated at 140 °C under N2 in a 20 mL microwave vial for 2 SiO2 (dry load, EtOAc : hexanes, 1 : 1 to 1.5 : 1) to provide 19
d. After addition of EtOAc (200 mL), the mixture was washed (0.052 g, 42%) as a yellow-orange powder: Mp >250 °C; IR
with H2O (5 × 24 mL). The combined organic layers were (ATR) νmax 3376, 3013, 2924, 2815, 1630, 1608, 1509, 1250,
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1191, 1020 cm−1; H NMR (400 MHz, DMSO-d6) δ 12.41 (brs, 14 (a) P. Wipf, B. Joo, T. Nguyen and J. S. Lazo, Org. Biomol.
1H), 12.29 (brs, 1H), 8.72 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.72
(d, J = 8.1 Hz, 1H), 7.39 (td, J = 8.1, 0.9 Hz, 1H), 7.28 (t, J = 8.4
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 159.3, 137.7, 137.1,
Chem., 2004, 2, 2173; (b) M. Brisson, C. Foster, P. Wipf,
B. Joo, R. J. Tomko Jr., T. Nguyen and J. S. Lazo, Mol.
Pharmacol., 2007, 71, 184.
135.7, 124.7, 123.3, 122.0, 121.8, 120.3, 112.8, 106.1; HRMS 15 H. H. Wasserman and J. L. Ives, J. Org. Chem., 1985, 50,
(ESI+) m/z calcd for C11H8O3N3 (M + H) 230.0559, found,
3573.
230.0560.
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Conflicts of interest
The authors are co-inventors of patents on the composition of
matter and the use of 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)- 19 (a) J. S. Lazo, K. E. McQueeney, J. C. Burnett, P. Wipf and
diones and related compounds, filed and held by the
University of Pittsburgh and the University of Virginia.
E. R. Sharlow, Int. J. Biochem. Cell Biol., 2018, 96, 171;
(b) E. R. Sharlow, P. Wipf, K. E. McQueeney, A. Bakan and
J. S. Lazo, Expert Opin. Invest. Drugs, 2014, 23, 1;
(c) H. Zhang, G. Kozlov, X. Li, H. Wu, I. Gulerez, H. Zhang
and K. Gehring, Sci. Rep., 2017, 7, 48; (d) M. Wei,
K. V. Korotkov and J. S. Blackburn, Pharmacol. Ther., 2018,
190, 128; (e) M. Fontanillo and M. Koehn, Adv. Exp. Med.
Biol., 2016, 917, 209.
Acknowledgements
The authors thank the Department of Defense (Award
W81XWH-18-1-0011, BC170507) for support of this research,
and T. Maskrey (University of Pittsburgh) for QC analyses and 20 J. M. Salamoun, K. E. McQueeney, K. Patil, S. J. Geib,
compound repository management.
E. R. Sharlow, J. S. Lazo and P. Wipf, Org. Biomol. Chem.,
2016, 14, 6398.
21 (a) K. E. McQueeney, J. M. Salamoun, J. C. Burnett,
N. Barabutis, S. L. Lewandowski, D. C. Llaneza,
R. Cornelison, Y. Bai, Z.-Y. Zhang, J. D. Catravas,
C. N. Landen, P. Wipf, J. S. Lazo and E. R. Sharlow,
Oncotarget, 2018, 9, 8223; (b) K. E. McQueeney,
J. M. Salamoun, J. G. Ahn, P. Pekic, I. K. Blanco,
H. L. Struckman, E. R. Sharlow, P. Wipf and J. S. Lazo,
FASEB J., 2018, 32, 5661.
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