Three-Component Approach to Pyridine-Stabilized Ketenimines for the Synthesis of Diverse Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b01906

Ketenimines are versatile synthetic intermediates capable of performing novel transformations in organic synthesis. They are normally generated in situ due to their inherent instability and high level of reactivity. Herein, we report pyridine-stabilized ketenimine zwitterionic salts, which are prepared through click chemistry from readily accessible alkynes and sulfonyl azides. To demonstrate their synonymous reactivity to ketenimines, these salts have been utilized in a cascade sequence to access highly functionalized quinolines including the core structures of an antiprotozoal agent and the potent topoisomerase inhibitor Tas-103.

Full text of DOI:10.1021/acs.joc.9b01906

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Article
A Three Component Approach to Pyridine Stabilized
Ketenimines for the Synthesis of Diverse Heterocycles
Nicholas P. Massaro, Aayushi Chatterji, and Indrajeet Sharma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01906 • Publication Date (Web): 25 Sep 2019
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A Three Component Approach to Pyridine Stabilized
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Ketenimines for the Synthesis of Diverse Heterocycles
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Nicholas P. Massaro, Aayushi Chatterji and Indrajeet Sharma*
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Department of Chemistry and Biochemistry, and Institute of Natural Products Applications and
Research Technologies, University of Oklahoma, 101 Stephenson Parkway, Norman, OK-73071, USA.
ABSTRACT: Ketenimines are versatile synthetic intermediates capable of performing novel
transformations in organic synthesis. They are normally generated in situ due to their inherent instability
and high level of reactivity. Herein, we report pyridine stabilized ketenimine zwitterionic salts, which are
prepared through click chemistry from readily accessible alkynes and sulfonyl azides. To demonstrate
their synonymous reactivity to ketenimines, these salts have been utilized in a cascade sequence to access
highly functionalized quinolines including the core structures of an antiprotozoal agent and the potent
topoisomerase inhibitor Tas-103.
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INTRODUCTION: Ketenimines are reactive species exhibiting a diverse array of synthetic
applications parallel to their isoelectronic cousins, ketenes and allenes.1 Because of the inherent instability
and reactivity, ketenimines are normally generated in situ for their applications in organic synthesis.2
Current methods to prepare ketenimines include couplings,3a eliminations,3b rearrangements,3c and click
chemistry (Scheme 1a–d).3d
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Scheme 1. In situ preparatory methods for ketenimine synthons.
There are also methods to access ketenimines, which are stable enough to isolate. However, they often
require highly reactive starting materials, multistep processes and chromatographic purification to obtain
the desired ketenimine synthons (Scheme 2a).4 Despite all these methods, ketenimine chemistry is still at
its infancy due to the lack of a stable ketenimine precursor. Therefore, development of a stable precursor
to such reactive intermediates could be attractive to the synthetic community. Herein, we report a bench-
top stable ketenimine salt with synonymous reactivity to its unstable, traditional form (Scheme 2b).
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Scheme 2. Synthesis of stable ketenimine synthons.
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RESULTS AND DISCUSSION: While pursuing the substrate scope of our previously developed
carbene cascade,5 we attempted to synthesize ethyl 1-tosyl-1H-1,2,3-triazole-4-carboxylate via the well-
established click chemistry. To our surprise, instead of isolating the expected triazole, we exclusively
observed a uniquely masked form of ketenimine stabilized as a zwitterionic adduct with 2,6-lutidine. The
structure of organic salt 3a was further confirmed by X-ray diffraction (Scheme 3).6
Scheme 3. Synthesis of benchtop stable ketenimine salt via click chemistry.
These click-chemistry conditions described above were also performed at the gram-scale successfully
(Figure 1, 3a). Encouraged by these findings, we then looked into the substrate scope and screened a
variety of nitrogen bases used in click chemistry. As expected, the reaction proceeded in very high yield
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with 4-dimethylaminopyridine (DMAP), but also proceeded in moderate yield with pyridine as a base
(Figure 1, 3b, 3c). We then screened non-nucleophilic triethyl amine and 2,6-di-tert-butyl-4-
methylpyridine but did not observe formation of ketenimine salt. These results indicate that nucleophilic
pyridine bases with less steric crowding around the nitrogen of the pyridine ring were necessary for salt
formation. We then turned our attention to the alkyne fragment in the click reaction. The reaction tolerated
alkynes bearing the amide and ketone functionalities, albeit in diminished yields. We also attempted the
reaction using phenylacetylene, although we exclusively isolated the triazole product. Finally, we
screened a variety of sulfonyl azides. To our delight, the reaction accommodated electron rich and
sterically encumbered mesitylene in good yield (Figure 1, 3f). Highly electron withdrawing p-
nitrobenzenesulfonyl azide also provided the salt in excellent yield (Figure 1, 3g). The reaction also
worked with functionalized aryl azides such as 4-acetamidobenzenesulfonyl azide (p-ABSA) even in the
presence of unprotected N-H functionality (Figure 1, 3h). In addition to benzenesulfonyl azides,
ketenimine salt formation also happened in good yield with mesyl azide (Figure 1, 3i).
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Figure 1. Scope of ketenimine salt formation; reactions were performed by adding pyridine type bases
(1.2 equiv) to a 0.2 M solution of 1 (0.10 mmol, 1.0 equiv), 2 (0.10 mmol, 1.0 equiv), and CuI in
chloroform at 0 °C (see the supporting information for more details).
To identify the key structural features necessary to stabilize these ketenimine salts, we used
Differential Scanning Calorimetry (DSC), a well-established tool for the characterization of small
molecule thermal behavior7 to perform structure exothermic relationships with our synthesized
ketenimine salts and a well-known coupling reagent EDC which is sold and distributed as the hydrochloric
acid ammonium salt. During our analysis, we encountered very subtle exothermic events and much more
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defined endothermic maxima, so we decided to compare our ketenimines salts and EDC in regard to their
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maximum heat flow temperature. To our delight, the heat traces of 3a‒3c in comparison to EDC suggest
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that these salts exhibit higher thermal stability (Figure 2).
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Figure 2. DSC traces for ketenimine salts 3a‒3c and EDC.
Encouraged by these results, we then analyzed the influence carbonyl functionality on the stability of the
ketenimine salts. Although, the yields of salts 3d and 3e were less compared to 3a, their endothermic
maxima still occurred at higher temperatures than EDC and were similar to 3a (Figure 3).
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Figure 3. DSC traces for ketenimine salts 3a, 3d‒3e, and EDC.
It was determined from the DSC traces that electron rich ketenimine salts such as 3f, were significantly
destabilized as compared to parent compound 3a. The DSC trace of 3i also suggests similar destabilizing
effects due to the less stable mesyl group. Surprisingly, p-ABSA derived salt 3h was the least stable
presumably due to its unprotected acetamide functional group. To our delight, the p-nitrobenzene
derivative 3g exhibited significantly higher stability in comparison to our parent compound 3a and EDC
(Figure 4). This suggests that more electron withdrawing sulfonyl groups provide a higher stabilizing
effect.
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Figure 4. DSC traces for ketenimine salts 3a, 3f‒3i, and EDC.
The ketenimine salts presumably form synonymous to previous reports of multicomponent coupling
reactions utilizing click chemistry. The mechanism begins with triazole formation following a stepwise
copper(I) catalyzed alkyne-azide cycloaddition.8 These reactions are believed to incorporate multiple
copper atoms, but one is shown for simplicity.9,10 During these initial stages of the mechanism, copper
acetylide formation provides intermediate A which can coordinate with the sulfonyl azide to subsequently
form adduct B, which then stepwise cyclizes to yield triazole C. This triazole then performs a ring opening
rearrangement to form a reactive ketenimine copper species D,11 which then undergoes protodemetalation
to form unstable ketenimine intermediate E. The pyridine base then performs a nucleophilic addition to
the electrophilic ketenimine E yielding the stabilized zwitterionic salt 3 (Scheme 4).
After the successful synthesis of several bench-top stable ketenimine precursors, we looked into their
synonymous reactivity compared to in situ generated ketenimine synthons. There are mainly five types of
reactions known with ketenimines: nucleophilic additions,12 radical additions,13 cycloadditions,14
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electrocyclic ring-closure reactions,15 and  rearrangements.16 We decided to go with nucleophilic
addition reactions as previously reported by Wang et al.17 for the synthesis of bioactive 2-
aminoquinolines.18
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Scheme 4. Plausible mechanism of ketenimine salt synthesis.
We began our optimization using model substrates 2’-amino acetophenone and ketenimine salt 3a. As
expected, our initial attempts using acetonitrile and DCE as a solvent afforded the synthesis of 2-
aminoquinoline 5a in very high yield (Table 1, entries 1-2). The structure of 5a was confirmed by X-ray
crystallography (Figure 5).19 We did not observe any significant improvement using high boiling point
solvents, sonication conditions, and neat heating (entries 3-5). Therefore, we decided to perform the
substrate scope using DCE reflux conditions.
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Table 1. Optimization of 2-aminoquinolines synthesis
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entry
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solvent
MeCN
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5a yieldb
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aAll optimization reactions were performed by refluxing a 0.2 M solution of 3a (39.0
mg, 0.1 mmol, 1.0 equiv) and 4a (14.0 mg, 0.1 mmol, 1.0 equiv) for 3 h. bYields of
5a obtained after column chromatography. cReaction was performed under
sonication. MeCN = acetonitrile; DCE = 1,2-dichloroethane.
With optimized conditions in hand, we decided to explore the substrate scope of these ketenimine
precursors. As expected, the reaction proceeded in high yield in the presence of a phenyl ketone and
chalcone motifs (Figure 5, 5b‒5c). This reaction also accommodated aldehyde functionality to provide
the unsubstituted 2-aminoquinoline (Figure 5, 5d). The reaction also tolerated the presence of electron-
donating and -withdrawing substituents including a pyridine ring on the 2’-aminoacetophenone fragment
(Figure 5, 5e‒5h). The reaction also accommodated other nucleophiles such as phenols and thiophenols
(Figure 5, 5i‒5j). Interestingly, phenols performed the reaction only with aldehydes and the product
formed was the lactone generated by hydrolysis of the sulfonamide functionality (Figure 5, 5j).
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Figure 5. Scope of 2-aminoquinoline synthesis; all reactions were performed by refluxing a 0.2 M
solution of 3a (39.0 mg, 0.10 mmol, 1.0 equiv) and 4 (0.10 mmol, 1.0 equiv) in DCE for 3 h.
Finally, N-tosyl group was deprotected in quantitative yield under acidic conditions. to provide
medicinally relevant 2-aminoquinolines (Figure 6a). For example, molecules such as LHC165 by Novartis
was recently disclosed to be a potent toll-like receptor 7 agonist.20 In addition, 6-amino-7H-indeno[2,1-
c]quinoline-7-ones are relevant bioactive cores and are present in potent topoisomerase inhibitor Tas-
10321 and antiprotozoal agent22 shown in figure 6b.
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Figure 6. Medicinally relevant 2-aminoquinoline cores and 6-amino-7H-indeno[2,1-c]quinolin-7-one
cores.
To further demonstrate the utility, we then decided to employ the ketenimine salt 3a for the synthesis of
a biologically relevant core scaffolds such as Tas-103; a potent topoisomerase inhibitor. Our strategy
involved a one pot procedure to afford the Tas-103 core 7a, which has previously been accessed in
multiple steps (Scheme 5a).23
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Scheme 5. Synthesis of Tas-103. a) Gram-scale synthesis of ketenimine salt 4a, b) Selective tosyl
deprotection of 4a, c) One-pot procedure for the synthesis of Tas-103 core, d) Stepwise synthesis of
antiprotozoal agent core, [e] example of relevant molecules that contain 2-aminoquinoline core.
The low yield in our one-pot procedure is attributed to the presence of an electron rich ketone in 4h,
which may be less susceptible to aldol cyclization. Therefore, we performed a stepwise procedure to
synthesize a core scaffold of an antiprotozoal agent. The two-steps procedure afforded compound 7b in
good yield as shown in Scheme 5b. The structure of product 7b was confirmed by single crystal X-ray
diffraction.24
We propose that the mechanism of our ketenimine salt cascade is initiated by the liberation of 2,6-
lutidine from 1 producing a significantly electrophilic ketenimine 2, this undergoes a nucleophilic addition
to produce intermediate 4 (Scheme 6). This sort of ammonium exchange sequence is known in literature.25
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Then intermediate 4 performs an intramolecular aldol condensation reaction to provide the 2-
aminoquinoline product 5.
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Scheme 6. Plausible mechanism of 2-aminoquinoline synthesis.
CONCLUSIONS: In conclusion, we have synthesized a bench-top stable ketenimine precursor
having the potential for commercialization. We also investigated the structure exothermic
relationship of these ketenimine salts with DSC to identify the key structural features necessary
for their stability. In addition, we explored the synthetic utility of these salts to access a variety of
diverse heterocycles including the core structures of an antiprotozoal agent and a potent
topoisomerase inhibitor Tas-103. New transformations incorporating these stable ketenimine
precursors are being explored and will be communicated in due course.
EXPERIMENTAL SECTION
:
MATERIALS AND METHODS: All reactions were performed in flame-dried glassware under positive
N2 pressure with magnetic stirring unless otherwise noted. Reagents and solvents were obtained from
Sigma-Aldrich, Chem-Impex, VWR International, and Acros Organics and used without further
purification unless otherwise indicated. Dichloromethane was distilled over CaH2 under N2 unless
otherwise indicated. Tetrahydrofuran was distilled over Na under N2 with benzophenone indicator. Thin
layer chromatography (TLC) was performed on 0.25 mm E. Merck silica gel 60 F254 plates and visualized
under UV light (254 nm) or by staining with potassium permanganate (KMnO4), cerium ammonium
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molybdate (CAM), phosphomolybdic acid (PMA), and ninhydrin. Silica flash chromatography was
performed on Sorbtech 230–400 mesh silica gel 60. Sonication was performed using a Bransonic
Ultrasonic Cleaner (Model: M5800H). IR spectra were recorded on a Shimadzu IRAffinity-1 FTIR or a
Nicolet 6700 FTIR spectrometer with peaks reported in cm–1. NMR spectra were recorded on a Varian
VNMRS 400 and 600 MHz NMR spectrometer in CDCl3 unless otherwise indicated. Chemical shifts are
expressed in ppm relative to solvent signals: CDCl3 (1H, 7.26 ppm, 13C, 77.0 ppm); coupling constants
are expressed in Hz. NMR spectra were processed using Mnova (www.mestrelab.com/software/mnova-
nmr). Mass spectra were obtained at the OU Analytical Core Facility on an Agilent 6538 High-Mass-
Resolution QTOF Mass Spectrometer and an Agilent 1290 UPLC. X-ray crystallography analysis was
carried out at the University of Oklahoma using a Bruker APEX ccd area detector and graphite-
monochromated Mo K radiation ( = 0.71073 Å) source and a D8 Quest diffractometer with a Bruker
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Photon II cmos area detector and an Incoatec Is microfocus Mo K source ( = 0.71073 Å). Crystal
structures
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visualized
using
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Mercury
software
(http://www.ccdc.cam.ac.uk/products/mercury/). For further information regarding X-ray structures see
supporting information.
Synthesis of Alkynes 1b−1c
1-morpholinoprop-2-yn-1-one (1b) was prepared using known literature protocol.26
1-phenylprop-2-yn-1-one (1c) was prepared using known literature protocol.27
Synthesis of Sulfonyl Azides 2a−2e
4-methylbenzenesulfonyl azide (2a) was prepared using known literature protocol.28
2,4,6-trimethylbenzenesulfonyl azide (2b) was prepared using known literature protocol.29
4-nitrobenzenesulfonyl azide (2c) was prepared using known literature protocol.30
4-acetamidobenzenesulfonyl azide (2d) was prepared using known literature protocol.28
Methanesulfonyl azide (2e) was prepared using known literature protocol.31
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General Procedure 1 for the Synthesis of Ketenimine Salts 3a−3i
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To a stirring solution of alkyne 1 (0.68−1.53 mmol, 1.2 equiv.), sulfonyl azide 2 (0.57−1.27 mmol, 1.0
equiv.) and CuI (10 mol%) in anhydrous chloroform (0.2 M) at 0 °C was added corresponding pyridine
reagent (0.68−1.53 mmol, 1.2 equiv). The reaction was allowed to stir at this temperature until
consumption of azide 2; reaction times ranged from 3 to 6 hours. Then the chloroform was removed by
rotoevaporator to yield a viscous oil. At this point, approximately 5−10 mL of ethyl acetate was added
followed by brief sonication to mix. Crude residue would solubilize momentarily and be subsequently
followed by immediate precipitation of stabilized ketenimine salt. The organic salt was isolated as a solid
by decanting and further purified by trituration with ethyl acetate and hexane. Solid product obtained was
removed of residual solvent by high vacuum to yield stabilized ketenimine salts 3a−3i without need for
further purification.
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(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-ethoxy-3-oxoprop-1-en-1-yl)(tosyl)amide (3a). White solid
(465.5 mg, 97%, mp 146‒149 °C). TLC: Rf 0.19 (9:1 EtOAc/MeOH). IR (neat): 3066, 2969, 1685, 1570,
1261, 1118. 1H NMR (600 MHz) δ 8.01 (t, J = 7.9 Hz, 1H), 7.97–7.83 (m, 2H), 7.45 (d, J = 7.9 Hz, 2H),
7.28 (d, J = 7.9 Hz, 2H), 5.54 (s, 1H), 3.85 (q, J = 7.1 Hz, 2H), 2.63 (s, 6H), 2.41 (s, 3H), 1.13 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (151 MHz) δ 166.8, 154.8, 152.6, 143.4, 141.8, 129.5, 129.0 (2C), 128.6, 127.2
(2C), 125.7 (2C), 86.2, 59.1, 21.5, 20.0 (2C), 14.3. HRMS (ESI) m/z calcd for C19H23N2O4S ([M+H]+)
375.1379; found 375.1381. Preparation of ketenimine salt 3a was also performed on gram scale without
any modification of general procedure 1.
(Z)-(1-(4-(dimethyliminio)pyridin-1(4H)-yl)-3-ethoxy-3-oxoprop-1-en-1-yl)(tosyl)amide (3b). Light
brown solid (493.3 mg, 95%, mp 145‒147 °C). TLC: Rf 0.15 (9:1 EtOAc/MeOH). IR (neat): 3076, 2928,
1640, 1567, 1121, 1080. 1H NMR (500 MHz) δ 7.93 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.24
(d, J = 7.9 Hz, 2H), 6.67 (d, J = 7.1 Hz, 2H), 5.32 (s, 1H), 3.89 (q, J = 7.1 Hz, 2H), 3.23 (s, 6H), 2.38 (s,
3H), 1.14 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz) δ 166.3, 156.6, 156.5, 155.6, 141.0, 140.7 (2C),
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139.0, 128.5 (2C), 126.4 (2C), 105.5 (2C), 58.3, 40.0 (2C), 20.9, 13.9. HRMS (ESI) m/z calcd for
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C19H24N3O4S ([M+H]+) 390.1488; found 390.1472.
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(Z)-(3-ethoxy-3-oxo-1-(pyridin-1-ium-1-yl)prop-1-en-1-yl)(tosyl)amide (3c). Pale yellow solid (313.2
mg, 71%, mp 123‒125 °C). TLC: Rf 0.19 (9:1 EtOAc/MeOH). IR (neat): 3117, 2980, 1692, 1593, 1269,
1125. 1H NMR (400 MHz) δ 8.57 (d, J = 5.5 Hz, 2H), 8.41 (tt, J = 7.8, 1.4 Hz, 1H), 7.91–7.86 (m, 4H),
7.29–7.26 (m, 2H), 5.44 (s, 1H), 3.86 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (151 MHz, CD2Cl2) δ 166.0, 145.4, 143.4, 141.7, 129.1, 128.8 (2C), 128.0, 126.5 (2C), 126.1 (2C),
84.1, 58.9, 20.9, 13.7, 13.4. HRMS (ESI) m/z calcd for C17H19N2O4S ([M+H]+) 347.1066; found
347.1066.
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(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-morpholino-3-oxoprop-1-en-1-yl)(tosyl)amide
(3d).
Gray/white solid (102.1 mg, 43%, mp 120‒123 °C). TLC: Rf 0.04 (9:1 EtOAc/MeOH). IR (neat): 3065,
2840, 1616, 1557, 1270, 899. 1H NMR (600 MHz) δ 7.97 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H),
7.42 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 5.77 (s, 1H), 3.64‒3.49 (m, 4H), 3.48‒3.29 (m, 4H),
2.62 (s, 6H), 2.39 (s, 3H). 13C{1H} NMR (151 MHz) δ 164.8, 154.7 (2C), 151.1, 143.3, 141.8, 128.9 (2C),
127.1 (2C), 125.4 (2C), 121.7, 85.5, 66.8 (2C), 22.7, 21.4 (2C), 20.2 (2C). HRMS (ESI) m/z calcd for
C21H26N3O4S ([M+H]+) 416.1644; found 416.1641.
(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-oxo-3-phenylprop-1-en-1-yl)(tosyl)amide (3e). Gray/white
solid (168.1 mg, 48%, mp 115‒117 °C). TLC: Rf 0.29 (9:1 EtOAc/MeOH). IR (neat): 3066, 2969, 1625,
1521, 1135, 906. 1H NMR (500 MHz) δ 8.05 (t, J = 7.9 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.80–7.75 (m,
2H), 7.48 (dd, J = 11.1, 7.7 Hz, 3H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 6.77 (s, 1H), 2.63
(s, 6H), 2.41 (s, 3H). 13C{1H} NMR (151 MHz) δ 186.0, 154.6, 152.8, 143.4, 142.4, 139.5, 131.8, 129.2
(2C), 128.6, 128.5, 128.4 (2C), 127.6 (2C), 127.3 (2C), 125.8 (2C), 91.5, 21.5, 20.1 (2C). HRMS (ESI)
m/z calcd for C23H23N2O3S ([M+H]+) 407.1429; found 407.1426.
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(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-ethoxy-3-oxoprop-1-en-1-yl)(mesitylsulfonyl)amide (3f). Pale
yellow solid (421.2 mg, 87%, mp 91‒94 °C). TLC: Rf 0.31 (9:1 EtOAc/MeOH). IR (neat): 2980, 2933,
1689, 1577, 1107, 1039. 1H NMR (300 MHz) δ 8.02 (t, J = 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 6.92
(s, 2H), 5.30 (s, 1H), 3.85 (q, J = 7.1 Hz, 2H), 2.78 (s, 6H), 2.77 (s, 6H), 2.28 (s, 3H), 1.11 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (75 MHz) δ 166.7, 154.6 (2C), 152.7, 143.5, 140.5, 138.4, 137.0, 131.8, 131.4 (2C),
125.7 (2C), 85.8, 58.9, 22.9 (2C), 20.8, 20.0 (2C), 14.3. HRMS (ESI) m/z calcd for C21H27N2O4S
([M+H]+) 403.1692; found 403.1679.
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(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-ethoxy-3-oxoprop-1-en-1-yl)((4-nitrophenyl)sulfonyl)amide
(3g). Pale yellow solid (506.3 mg, 98%, mp 148‒149 °C). TLC: Rf 0.29 (9:1 EtOAc/MeOH). IR (neat):
3101, 2983, 1687, 1601, 1351, 1133. 1H NMR (500 MHz, CD2Cl2) δ 8.32 (d, J = 8.8 Hz, 2H), 8.13 (d, J
= 8.9 Hz, 2H), 8.08 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 5.51 (s, 1H), 3.84 (q, J = 7.1 Hz, 2H),
2.59 (s, 6H), 1.11 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CD2Cl2) δ 165.4, 154.0 (2C), 151.5, 148.9,
148.2, 143.7, 127.7 (2C), 125.6 (2C), 123.4 (2C), 87.6, 58.9, 19.4 (2C), 13.6. HRMS (ESI) m/z calcd for
C18H20N3O6S ([M+H]+) 406.1073; found 406.1053.
(Z)-((4-acetamidophenyl)sulfonyl)(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-ethoxy-3-oxoprop-1-en-1-
yl)amide (3h). Pale yellow solid (521.3 mg, 98%, mp 127‒130 °C). TLC: Rf 0.10 (9:1 EtOAc/MeOH).
IR (neat): 3341, 3099, 2984, 1687, 1265, 1122. 1H NMR (500 MHz) δ 8.51 (s, 1H), 8.01 (t, J = 7.9 Hz,
1H), 7.85 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 5.47 (s, 1H), 3.84 (q, J =
7.1 Hz, 2H), 2.57 (s, 6H), 2.19 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz) δ 169.6, 166.2,
154.3 (2C), 152.1, 143.8, 141.8, 135.9, 127.8 (2C), 125.8 (2C), 119.0 (2C), 87.1, 59.3, 24.5, 19.8 (2C),
14.2. HRMS (ESI) m/z calcd for C20H24N3O5S ([M+H]+) 418.1437; found 418.1418.
(Z)-(1-(2,6-dimethylpyridin-1-ium-1-yl)-3-ethoxy-3-oxoprop-1-en-1-yl)(methylsulfonyl)amide
(3i).
Yellow solid (310.5 mg, 90%, mp 98‒100 °C). TLC: Rf 0.15 (9:1 EtOAc/MeOH). IR (neat): 3068, 2979,
1678, 1578, 1260, 1093. 1H NMR (400 MHz) δ 8.06 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 5.57
(s, 1H), 3.90 (q, J = 7.1 Hz, 2H), 3.03 (s, 3H), 2.87 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (75
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MHz) δ 166.5, 154.3 (2C), 153.0, 143.8, 125.8 (2C), 85.9, 59.0, 38.9, 20.0 (2C), 14.2. HRMS (ESI) m/z
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calcd for C13H19N2O4S ([M+H]+) 299.1066; found 299.1058.
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Synthesis of Starting Materials 4a−4h
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(2-aminophenyl)(phenyl)methanone (4a) was prepared using known literature protocol.32
(E)-1-(2-aminophenyl)-3-phenylprop-2-en-1-one (4b) was prepared using known literature protocol.33
2-aminobenzaldehyde (4c) was prepared using known literature protocol.34
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1-(2-amino-5-bromophenyl)ethan-1-one (4d) was prepared using known literature protocol.35
1-(2-amino-5-methoxyphenyl)ethan-1-one (4e) was prepared using known literature protocol.36
3-acetyl-4-aminobenzonitrile (4f) was prepared using known literature protocol.37
1-(2-mercaptophenyl)ethan-1-one (4g) was prepared using known literature protocol.38
2-amino-4-methoxyphenyl)(phenyl)methanone (4h). To a stirring solution of commercially available 4-
methoxy-2-nitrobenzaldehyde (300 mg, 1.66 mmol, 1.0 equiv, 0.2 M) in THF was added
phenylmagnesium bromide solution (608 L, 1.1 equiv, 3.0 M) at 0 °C. The reaction was stirred at this
temperature for three hours and quenched at 0 °C with saturated ammonium chloride solution. Crude
alcohol was extracted three times with ethyl acetate and dried over sodium sulfate. The crude product was
concentrated to volume and redissolved in 30 mL of dichloromethane (0.05 M). To this solution was
added MnO2 (2.16 g, 24.88 mmol, 15 equiv) at room temperature and reaction was allowed to stir for six
hours upon which the crude reaction was filtered over celite and concentrated to volume. This crude
residue was then redissolved in methanol (0.3 M), Pd/C (20.1 mg, 10 mol%) was added and the reaction
was purged under hydrogen atmosphere (1 atm with H2 balloon). After three hours of stirring at room
temperature, crude reaction was filtered over celite and concentrated to volume. The crude residue was
immediately purified by flash column chromatography eluting with 2:5 EtOAc: hexanes gradient to 2:1
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EtOAc:hexanes affording (2-amino-4-methoxyphenyl)(phenyl)methanone (4h) as a pale yellow solid
(291.7 mg, 78%, mp 111–113 °C). TLC: Rf 0.28 (2:3 hexanes/EtOAc). IR (neat): 3474, 3344, 3016,
2975, 1608, 1225. 1H NMR (300 MHz) δ 7.63–7.55 (m, 2H), 7.52–7.34 (m, 4H), 6.38 (s, 2H), 6.20–6.13
(m, 2H), 3.79 (s, 3H). 13C{1H} NMR (75 MHz) δ 197.6, 164.4, 153.6, 140.6, 136.9, 130.4, 128.6 (2C),
128.0 (2C), 112.2, 104.0, 99.2, 55.2. LRMS (ESI) m/z calcd for C14H14NO3 ([M+H2O]-) 244.1; found
244.0. Values match literature known values.39
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General Procedure 2 for the Synthesis of Products 5a−5k
To a 4 mL scintillation vial was added ketenimine salt 3 (0.05–0.27 mmol, 1.0 equiv.) and 5 (0.05–0.27
mmol, 1.0 equiv.) and anhydrous DCE (0.2 M). The reaction was stirred at 90 °C with a heating block
until complete consumption of 5. Reaction times ranged from 6 to 12 hours. The crude reaction mixture
was concentrated and then purified using flash column chromatography eluting with 1:10 ethyl acetate:
hexanes gradient to 3:7 EtOAc:hexanes affording products 5a−5k.
Ethyl (Z)-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5a). White solid (18.4 mg, 91%,
mp 146–149 °C). TLC: Rf 0.19 (7:3 hexanes/EtOAc). IR (neat): 3237, 3068, 2976, 1733, 1622, 1272.
1H NMR (500 MHz) δ 11.89 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 8.4,
1H), 7.35 (t, J = 8.3 Hz, 1H), 7.33–7.29 (m, 1H) 7.21 (d, J = 8.1 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 2.47
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(s, 3H), 2.35 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). C{1H} NMR (126 MHz) δ 165.3, 150.7, 146.2, 142.4,
140.1, 135.1, 132.5, 132.1, 129.3, 129.1, 126.4, 125.9, 125.0, 124.8, 120.8, 117.1, 61.9, 21.3, 16.3, 14.0.
(Due to possible resonance and equilibrium forms of this molecule, S/N ratio of some aromatic peaks
were drastically reduced). HRMS (ESI) m/z calcd for C20H21N2O4S ([M+H]+) 385.1222; found 385.1220.
Ethyl (Z)-4-phenyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5b). White solid (19.3 mg, 82%,
mp 65–68 °C). TLC: Rf 0.35 (7:3 hexanes/EtOAc). IR (neat): 3244, 2923, 1618, 1597, 1271, 1132. 1H
NMR (600 MHz) δ 12.13 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.47 (s, 3H), 7.41 (s, 1H), 7.35 (d, J = 8.2
Hz, 2H), 7.27 (d, J = 7.9 Hz, 5H), 4.04 (s, 2H), 2.39 (s, 3H), 0.95 (s, J = 8.7 Hz, 3H). 13C{1H} NMR (151
MHz) δ 164.9, 150.5, 142.8, 139.4, 134.1, 132.1, 129.1, 129.0, 128.9, 128.6, 128.3, 127.7, 126.6, 124.8,
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121.4, 61.5, 21.4, 13.4. (Due to possible resonance and equilibrium forms of this molecule, S/N ratio of
some aromatic peaks were drastically reduced). HRMS (ESI) m/z calcd for C25H23N2O4S ([M+H]+)
447.1379; found 447.1374.
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Ethyl (Z)-4-((E)-styryl)-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5c). Pale yellow solid (23.5
mg, 94%, mp 73–75 °C). TLC: Rf 0.31 (7:3 hexanes/EtOAc). IR (neat): 3244, 2978, 1616, 1595, 1075,
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667. H NMR (400 MHz) δ 12.02 (s, 1H), 7.91–7.85 (m, 2H), 7.65 (t, J = 7.7 Hz, 1H), 7.53–7.49 (m,
2H), 7.43–7.34 (m, 5H), 7.28–7.21 (m, 4H), 7.15–7.04 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H),
1.22 (t, J = 7.1 Hz, 3H). C{1H} NMR (151 MHz) δ 165.0, 151.2, 146.1, 142.5, 140.1, 139.5, 135.6,
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132.3, 129.4, 129.2, 128.9, 128.4, 127.1, 126.4, 126.0, 124.8, 120.1, 117.2, 62.0, 21.5, 14.1. (Due to
possible resonance and equilibrium forms of this molecule, S/N ratio of some aromatic peaks were
drastically reduced). HRMS (ESI) m/z calcd for C27H25N2O4S ([M+H]+) 473.1535; found 473.1519.
Ethyl (Z)-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5d). White solid (16.8 mg, 86%, mp 187–
190 °C). TLC: Rf 0.46 (7:3 hexanes/EtOAc). IR (neat): 3194, 2923, 1679, 1444, 1157, 1079. 1H NMR
(400 MHz) δ 10.77 (s, 1H), 8.75 (s, 1H), 8.21 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.75–7.69 (m,
2H), 7.40 (t, J = 8.2 Hz 1H), 7.29 (d, J = 8.1 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.45 (t, J =
7.1 Hz, 3H). C{1H} NMR (101 MHz) δ 166.4, 148.5, 143.9, 142.2, 137.2, 132.8, 129.2 (2C), 128.9
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(3C), 128.8, 127.7, 125.4, 123.7, 110.8, 62.3, 21.6, 14.2. HRMS (ESI) m/z calcd for C19H19N2O4S
([M+H]+) 371.1066; found 371.1061.
Ethyl (Z)-6-bromo-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5e). White solid (49.6
mg, 80%, mp 160–162 °C). TLC: Rf 0.36 (7:3 hexanes/EtOAc). IR (neat): 3197, 2992, 1732, 1621, 1591,
1075. 1H NMR (600 MHz) δ 11.97 (s, 1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.26
(s, 4H), 4.39 (s, 2H), 2.47 (s, 3H), 2.39 (s, 3H), 1.31 (s, 3H).13C{1H} NMR (151 MHz) δ 165.1, 150.4,
145.0, 142.8, 139.6, 134.9, 134.2, 129.1, 127.5, 126.1, 122.4, 118.8, 117.9, 62.1, 21.4, 14.0. (Due to
possible resonance and equilibrium forms of this molecule, S/N ratio of some aromatic peaks were
drastically reduced). HRMS (ESI) m/z calcd for C20H20BrN2O4S ([M+H]+) 463.0327; found 463.0318.
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Ethyl (Z)-6-methoxy-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5f). White solid (48.4
mg, 87%, mp 119–122 °C). TLC: Rf 0.12 (7:3 hexanes/EtOAc). IR (neat): 3185, 2985, 1734, 1600, 1251,
824. 1H NMR (600 MHz) δ 11.97 (s, 1H), 7.84 (s, 1H), 7.33–7.22 (m, 5H), 7.14 (d, J = 2.5 Hz, 1H), 4.41
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145.6, 142.4, 129.1, 126.1, 121.5, 106.3, 62.0, 55.7, 21.4, 16.6, 14.0. (Due to possible resonance and
equilibrium forms of this molecule, S/N ratio of some aromatic peaks were drastically reduced). HRMS
(ESI) m/z calcd for C21H23N2O5S ([M+H]+) 415.1328; found 415.1325.
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Ethyl (Z)-6-cyano-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5g, major isomer). Pale
yellow solid (30.0 mg, 27%, mp 179–181°C). TLC: Rf 0.16 (7:3 hexanes/EtOAc). IR (neat): 3192, 2901,
2227, 1733, 1608, 1073. 1H NMR (600 MHz) δ 12.06 (s, 1H), 8.09 (s, 1H), 7.82 (d, J = 7.9 Hz, 4H), 7.43
(d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 4.39 (d, J = 7.5 Hz, 2H), 2.50 (s, 3H), 2.40 (s, 3H), 1.30 (t, J = 7.3 Hz,
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3H). C{1H} NMR (151 MHz) δ 164.6, 150.7, 143.4, 139.2, 137.8, 134.1, 130.4, 129.6, 129.3, 129.2,
128.7, 126.4, 126.2, 125.5, 118.3, 108.6, 108.5, 62.3, 21.5, 14.0, 14.0. (Due to possible resonance and
equilibrium forms of this molecule, S/N ratio of some aromatic peaks were drastically reduced). HRMS
(ESI) m/z calcd for C21H20N3O4S ([M+H]+) 410.1175; found 410.1176.
Ethyl (Z)-4-methyl-2-(tosylimino)-1,2-dihydro-1,8-naphthyridine-3-carboxylate (5h). Pale orange solid
(34.5 mg, 80%, mp 124–126 °C). TLC: Rf 0.28 (7:3 hexanes/EtOAc). IR (neat): 3212, 2980, 1719, 1619,
1076. 1H NMR (300 MHz) δ 11.91 (s, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.08 (ddd, J = 8.1, 1.7, 0.7 Hz,
1H), 7.90–7.80 (m, 2H), 7.34 (ddd, J = 8.1, 4.7, 0.7 Hz, 1H), 7.25–7.22 (m, 2H), 4.38 (qd, J = 7.1, 0.7 Hz,
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2H), 2.46 (d, J = 0.7 Hz, 3H), 2.37 (s, 3H), 1.30 (td, J = 7.1, 0.7 Hz, 3H). C{1H} NMR (75 MHz) δ
164.9, 152.4, 142.8, 133.7, 129.2, 126.2, 120.7, 62.1, 21.5, 15.8, 14.0. (Due to possible resonance and
equilibrium forms of this molecule, S/N ratio of some aromatic peaks were drastically reduced). HRMS
(ESI) m/z calcd for C19H20N3O4S ([M+H]+) 386.1175; found 386.1176.
Ethyl (Z)-4-methyl-2-(tosylimino)-2H-thiochromene-3-carboxylate (5i). White solid (40.9 mg, 92%, mp
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139–140 °C). TLC: Rf 0.24 (7:3 hexanes/EtOAc). IR (neat): 2983, 1727, 1597, 1425, 1280, 1083. H
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NMR (400 MHz) δ 7.91 (d, J = 8.0 Hz, 1H), 7.89–7.85 (m, 2H), 7.60–7.48 (m, 3H), 7.28–7.25 (m, 2H),
4.31 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 2.39 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz) δ
166.2, 165.1, 145.8, 143.5, 137.6, 133.6, 130.5, 130.5, 129.2 (2C), 127.9, 127.6, 127.0 (2C), 126.8, 126.4,
62.0, 21.5, 19.1, 13.9. HRMS (ESI) m/z calcd for C20H20NO4S2 ([M+H]+) 402.0834; found 402.0836.
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Ethyl 2-oxo-2H-chromene-3-carboxylate (5j). Amber grease (10.3 mg, 44%). TLC: Rf 0.41 (7:3
hexanes/EtOAc). IR (neat): 3110, 2979, 1755, 1605, 1209, 1037. 1H NMR (400 MHz) δ 8.52 (d, J = 0.7
Hz, 1H), 7.68–7.56 (m, 2H), 7.40–7.30 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz) δ 163.1, 156.7, 155.2, 148.6, 134.3, 129.5, 124.8, 118.4, 117.9, 116.8, 62.0, 14.2.
LRMS (ESI) m/z calcd for C12H11O4 ([M+H]+) 241.0; found 240.4. Matches literature known values.40
Ethyl (Z)-6-bromo-4-phenyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (5k, major isomer).
White solid (46.6 mg, 82% mp 157–160 °C). TLC: Rf 0.52 (7:3 hexanes/EtOAc). IR (neat): 3243, 3060,
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2980, 1733, 1617, 1074. H NMR (600 MHz) δ 12.12 (s, 1H), 8.21 (s, 1H), 7.85 (d, J = 26.5 Hz, 1H),
7.71 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 6.3 Hz, 4H), 7.30 (s, 4H), 7.18 (s, 1H), 4.00 (s, 2H), 2.40 (s, 3H),
1.00–0.67 (m, 3H). 13C{1H} NMR (151 MHz) δ 167.5, 163.9, 151.7, 150.7, 149.0, 147.6, 145.8, 144.1,
142.7, 139.8, 137.1, 137.1, 136.4, 135.1, 130.0, 129.4, 129.4, 129.2, 128.6, 126.9, 126.1, 119.0, 118.5,
61.8, 31.6, 22.6, 21.5. (Due to possible resonance and equilibrium forms of this molecule, S/N ratio of
some aromatic peaks were drastically reduced. Some peaks from both isomers could not be differentiated
as well causing an excess number of carbon peaks.). HRMS (ESI) m/z calcd for C25H22BrN2O4S
([M+H]+) 525.0484; found 525.0473.
Selective deprotection of 5a to synthesize 6a.
ethyl 2-amino-4-methylquinoline-3-carboxylate (6a). To a stirring solution of 5a (20.9 mg ,0.05 mmol,
0.02 M) in CH2Cl2 at 0 °C was added three drops of concentrated H2SO4. The ice bath was removed, and
the reaction was allowed to stir at room temperature for 7 hours. Then the reaction mixture was basified
with saturated NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted
three times with dichloromethane. The combined organic layers were dried over sodium sulfate and
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concentrated to volume. The crude ethyl 2-amino-4-methylquinoline-3-carboxylate (6a) was isolated
as a pure white solid without need for further purification. (12.3 mg, 98%, mp 133–136 °C). TLC: Rf 0.70
(7:3 hexanes/EtOAc). IR (neat): 3428, 3127, 2991, 1705, 1234, 1094. 1H NMR (500 MHz) δ 7.89 (ddd,
J = 8.4, 1.4, 0.7 Hz, 1H), 7.65–7.56 (m, 2H), 7.29 (ddd, J = 8.3, 6.6, 1.6 Hz, 1H), 5.74 (s, 2H), 4.47 (q, J
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= 7.2 Hz, 2H), 2.73 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). C{1H} NMR (126 MHz) δ 168.3, 154.6, 147.4,
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131.2, 126.2, 124.7, 123.3, 123.0, 114.4, 61.7, 16.8, 14.2. HRMS (ESI) m/z calcd for C13H15N2O2
([M+H]+) 231.1134; found 231.1137.
One pot procedure for the synthesis of 7a
6-amino-3-methoxy-7H-indeno[2,1-c]quinolin-7-one (7a). Ketenimine salt 3a (39.4 mg, 0.11 mmol, 1
equiv) and aniline 4h (24.0 mg, 0.11 mmol, 1 equiv) were heated neat at 90 °C with a heating block in a
scintillation vial for 2 hours. The homogenous oil was then cooled to room temperature and 0.5 mL of
concentrated H2SO4 was added. The reaction was then heated at 90 °C for 3 hours. Reaction was then
cooled to 0 °C and basified with saturated NaHCO3 solution. The quenched reaction was then extracted
three times with ethyl acetate and the combined organic layers were filtered over sodium sulfate and
concentrated to volume yielding a red powder solid. The crude solid was then purified by flash column
chromatography eluting with 3:10 ethyl acetate: hexanes gradient to 2:3 hexanes:ethyl acetate affording
6-amino-3-methoxy-7H-indeno[2,1-c]quinolin-7-one (7a) as an orange solid (5.5 mg, 19%). TLC: Rf
0.28 (2:3 hexanes/EtOAc). IR (neat): 3406, 3286, 2952, 1685, 1637, 1272. 1H NMR (600 MHz) δ 8.15
(d, J = 9.2 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.58–7.53 (m, 1H), 7.45 (t, J = 7.4
Hz, 1H), 7.02 (s, 1H), 6.99 (dd, J = 9.2, 2.5 Hz, 1H), 6.11 (s, 2H), 3.94 (s, 3H). 13C{1H} NMR (151 MHz)
δ 193.8, 163.9, 155.6, 154.1, 153.0, 141.6, 134.8, 133.7, 130.7, 126.4, 124.5, 123.6, 117.3, 114.8, 109.6,
105.6, 55.6. HRMS (ESI) m/z calcd for C17H13N2O2 ([M+H]+) 277.0977; found 277.0970.
Stepwise procedure for the synthesis of 7b
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ethyl 2-amino-6-bromo-4-phenylquinoline-3-carboxylate (6b). To a 4 mL scintillation vial containing 5k
(46.6 mg, 0.09 mmol) prepared from general procedure 2 was added H2SO4 (443 L, 0.2 M). This was
allowed to stir at room temperature for 3 hours. Once starting material was consumed on TLC, reaction
was cooled to 0 °C and basified with saturated NaHCO3 solution and extracted with CH2Cl2 three times.
The combined organic layers were dried over sodium sulfate and concentrated to volume yielding ethyl
2-amino-6-bromo-4-phenylquinoline-3-carboxylate (6b) as a pale-yellow solid (24.1 mg, 73%, mp
154–156 °C) without need for further purification. TLC: Rf 0.68 (7:3 hexanes/EtOAc). IR (neat): 3460,
3297, 3155, 1698, 1638, 1090. 1H NMR (600 MHz) δ 7.64 (dd, J = 8.9, 2.2 Hz, 1H), 7.53 (dd, J = 8.9,
1.4 Hz, 1H), 7.47 (td, J = 3.8, 3.3, 1.7 Hz, 4H), 7.29–7.25 (m, 2H), 5.91 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H),
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0.73 (t, J = 7.2 Hz, 3H). C{1H} NMR (151 MHz) δ 167.9, 155.2, 150.6, 147.2, 136.9, 134.5, 129.3,
128.8 (2C), 128.3, 128.3 (2C), 127.8, 124.1, 116.1, 113.9, 61.3, 13.1. HRMS (ESI) m/z calcd for
C18H16BrN2O2 ([M+H]+) 371.0395; found 371.0388.
6-amino-2-bromo-7H-indeno[2,1-c]quinolin-7-one (7b). To a 4 mL scintillation vial containing 6b was
added (21.5 mg, 0.06 mmol) was added H2SO4 (579 L, 0.1 M). This was set to stir at 90 °C with a heating
block for 3 hours. Once starting material was consumed on TLC, reaction was cooled to 0 °C and basified
with saturated NaHCO3 solution and extracted with ethyl acetate three times. The combined organic layers
were dried over sodium sulfate and concentrated to volume yielding a red solid. This crude solid was
washed with a 1:1 mixture of dichloromethane and hexane. The solvent was decanted and residual solvent
was removed via high vacuum providing pure 6-amino-2-bromo-7H-indeno[2,1-c]quinolin-7-one (7b)
as a an orange solid (14.6 mg, 78%, mp 254–257 °C). TLC: Rf 0.72 (7:3 hexanes/EtOAc). IR (neat):
3432, 3104, 2923, 1692, 1641, 745. 1H NMR (600 MHz) δ 8.40 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.73 (s,
2H), 7.62 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), NH2 signal is absent. 13C{1H} NMR (151 MHz)
δ 136.1, 134.4, 131.1, 127.2, 124.6, 124.1. (Due to poor solubility in deuterated solvents, 1H NMR signals
were broadened and an effective 13C spectra was not obtained so the structure was also confirmed by X-
ray crystallography). HRMS (ESI) m/z calcd for C16H10BrN2O ([M+H]+) 324.9977; found 324.9986.
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ACKNOWLEDGEMENTS: We thank Dr. Susan Nimmo, Dr. Steven Foster, and Dr. Douglas
R. Powell from the Research Support Services, University of Oklahoma, for expert NMR, mass
spectral, and X-ray crystallographic analyses, respectively. The work was supported by NSF
CHE-1753187, the American Chemical Society Petroleum Research Fund (ACSPRF) Doctoral
New Investigator grant (PRF No. 58487-DNI1) and Robberson Research and Creative Endeavors
Grant to N. P. Massaro. We also thank Matthew Houck for assistance with the DSC
experimentation.
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CONFLICTS OF INTEREST: There are no conflicts of interest to declare
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website.
X-ray crystallography data, CIF files and relevant spectra for all important compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
Indrajeet Sharma; Email: isharma@ou.edu;
Key Words: Ketenimine, click chemistry, multicomponent reactions, quinolines, heterocycles
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