Oxone promoted dehydrogenative Povarov cyclization of: N -aryl glycine derivatives: An approach towards quinoline fused lactones and lactams

Article abstract of DOI:10.1039/c9ra06212b

Oxone promoted intramolecular dehydrogenative imino Diels-Alder reaction (Povarov cyclization) of alkyne tethered N-aryl glycine esters and amides has been explored, thus affording biologically significant quinoline fused lactones and lactams. The reaction is simple, scalable, and high yielding (up to 88%). The method was further extended to prepare biologically important luotonin-A analogues and the quinoline core of uncialamycin.

Full text of DOI:10.1039/c9ra06212b

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PAPER
Oxone promoted dehydrogenative Povarov
cyclization of N-aryl glycine derivatives: an
approach towards quinoline fused lactones and
lactams†
Cite this: RSC Adv., 2019, 9, 30277
a
Devidas A. More,ab Ganesh H. Shinde,a Aslam C. Shaikh
ab
*
and M. Muthukrishnan
Oxone promoted intramolecular dehydrogenative imino Diels–Alder reaction (Povarov cyclization) of
alkyne tethered N-aryl glycine esters and amides has been explored, thus affording biologically
significant quinoline fused lactones and lactams. The reaction is simple, scalable, and high yielding (up to
88%). The method was further extended to prepare biologically important luotonin-A analogues and the
quinoline core of uncialamycin.
Received 9th August 2019
Accepted 17th September 2019
DOI: 10.1039/c9ra06212b
rsc.li/rsc-advances
Diels–Alder reaction promoted by BF3$OEt2/DDQ for the
construction of quinoline fused lactones employing an alkene
or alkyne as a dienophile.9 Despite the merits, there are
Introduction
Substituted quinolines are a ubiquitous heterocyclic motif
present in a plethora of natural products and medicinal agents,1
among which quinoline fused lactones and lactams are of great
importance due to their presence in complex natural products
and pharmaceutically relevant molecules. In addition, they
serve as a valuable precursor in the synthesis of biologically
active natural products and their analogues such as luotonin-A
(cytotoxic alkaloid),2 uncialamycin (antibiotic),3 aza podo-
phyllotoxin4 analogues (antitumor agents) and quinoline car-
boxamides (radio ligands for molecular imaging).5 (Fig. 1).
Consequently, there is a great deal of attention on the synthesis
of these privileged structures. In general, the synthesis of these
frameworks is associated with multistep processes as well as
usage of toxic reagents.2e,g,6 Therefore, the development of
a general, sustainable and efficient synthetic approach to ach-
ieve these functionalized quinoline-fused lactones/lactams is of
high value, and it would provide an appropriate platform for the
detail biological investigation of these valuable molecules.
In recent years, imino Diels–Alder reaction (Povarov reac-
tion) has received a renewed interest to construct quinoline
scaffolds, in which electron-rich alkenes (or alkynes) were
added to the electron-decient aromatic imines followed by
oxidation.7 However, an intramolecular variant of this trans-
formation is less explored compared to intermolecular.8 In
2009, Weghe et al. elegantly utilized intramolecular imino
certain drawbacks associated with this method such as, non-
ready availability of the requisite starting materials, requiring
a multistep reaction sequences for their synthesis, hazardous
and expensive reagents, limited substrate scope, and the
method have not been explored for the synthesis of quinoline
fused lactams. Later, Jia and Zhang group also explored the
concept of cross dehydrogenative coupling (CDC) for the
construction quinoline fused lactone/lactam in the presence
of TBPA radical cation salt and visible-light photoredox
aDivision of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008,
India. E-mail: m.muthukrishnan@ncl.res.in
bAcademy of Scientic and Innovative Research (AcSIR), Ghaziabad 201002, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra06212b
Fig. 1 Examples of pharmaceuticals and natural products containing
quinoline-fused lactone/lactam moiety.
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Scheme 1 Intramolecular Povarov cyclization for the synthesis of quinoline fused lactones and lactams.
conditions, respectively.10 In the context of our ongoing cyclization of N-aryl glycine ester 1a as a model substrate by
research program dealing with drug discovery, we were employing 5 mol% BF3$OEt2 as a Lewis acid in the presence of
encountered with a need for an efficient methodology for the IBX as an oxidant at room temperature (Table 1, entry 1).12 To
synthesis of quinoline fused lactones and lactams for our our delight, as expected, the reaction proceeded smoothly to
internal screening program. While studying the suitability of give the desired product 3a in 58% yield. Inspired by this
Weghe's method for our library synthesis, we encountered initial result, we screened other Lewis acids and found that
a difficulty in the preparation of starting imine compounds as Cu(OTf)2 is the best among other Lewis acids tried (Table 1,
the procedures are lengthy along with issues pertinent to their entries 1–4). Next, we studied the effect of various oxidants
stability. With regard to practicality, we envisioned that and observed that peroxide-based oxidants also suitable for
alkyne tethered N-aryl glycine derivatives would be an ideal this transformation (Table 1, entries 5–8). Interestingly, the
substrate for our library synthesis as (i) these substrates are reaction proceeded well in the presence of Oxone and 5 mol%
stable and can be easily prepared (ii) in suitable condition, of Cu(OTf)2 at room temperature afforded the required
these substrates can undergo oxidative dehydrogenation11 product 3a in 88% yield (Table 1, entry 9). Notably, Oxone
followed by Povarov cyclization could lead to quinoline fused would be a favourable oxidant as it is cheap, non-toxic, and
lactones/lactams.
In this manuscript, we wish to disclose the successful
realization of this new strategy, which involves Oxone
Table 1 Optimization studiesa,b
promoted oxidative dehydrogenation followed by intra-
molecular Povarov cyclization of alkyne tethered N-aryl
glycine derivatives for the efficient synthesis of quinoline
fused lactones/lactams (Scheme 1). Furthermore, to the best
of our knowledge, Oxone promoted intramolecular Povarov
cyclization of hitherto unknown alkyne tethered N-aryl glycine
derivatives has not been reported.
Entry
Oxidant
Additives
Solvent
Yield (%) 3a
Results and discussion
1
2
3
4
5
6
7
8
IBX
IBX
IBX
IBX
BF3$OEt2
Sc(OTf)3
Cu(OTf)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Toluene
CHCl3
CH3CN
CH3CN
CH3CN
58
53
68
51
23
21
41
49
Accordingly, the required starting material alkyne tethered N-
aryl glycine derivatives were conveniently prepared in two
steps from substituted propargyl alcohols (Scheme 2).
Initially, we examined the dehydrogenative Povarov
PhI(OAc)2
PhI(OCOCF3)2
Na2S2O8
BPO
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
—
9
88
42
10
11
12
13
14
15
Traces
<5
89c
60d
Traces
Cu(OTf)2
a
Reaction conditions: (1) 0.18 mmol 1a, 0.20 mmol oxidant, additive
b
c
(5 mol%) solvent (3.0 mL), 12 h. Isolated yields; rt. 1.3 equiv. of
Oxone was employed. d 24 h; IBX: 2-iodoxybenzoic acid.
Scheme 2 Synthesis of alkyne tethered N-aryl glycine derivatives.
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easy to handle.13 Screening of other solvents for this trans- also gave the desired product in moderate yield (2j, 45%).
formation reveals that CH3CN is the best solvent of choice Furthermore, substitution on the ortho position of the aniline
(Table 1, entry 9 vs. 10–12). Further, not signicant improve- ring provided the desired product in moderate yield (2k, 46%).
ment in the yield has been observed while using more equiv. Moreover, the di-substituted substrate also underwent
of Oxone (Table 1, entry 13). Notably, when we use only Oxone, smoothly, to achieve the desired product 2l in 69% yield. Next,
the desired product formed in a 60% yield albeit in 24 hours we examined the scope of our protocol by altering the substi-
(entry 14), which indicates that the Oxone alone can trigger tution on aryl alkyne part of N-aryl glycine derivatives. Electron
this transformation presumably due to the slightly acidic donating and withdrawing substituents on the aryl alkyne part
nature of Oxone (2KHSO5-KHSO4-K2SO4). Finally, in the of N-aryl glycine derivatives also underwent the reaction
absence of Oxone there is only a trace amount of product smoothly and afforded the product in good yield (2m–2r).
formation has been observed, which reveals the crucial role of Further, the present protocol is suitable for ortho substitution,
Oxone in this transformation (Table 1, entry 15).
disubstitution as well as heteroaryl substitution on aryl alkyne
Aer the optimal reaction condition was established for the part of the glycine derivatives (2s–2v). Alkyl substitution on the
construction of quinoline-fused lactones, the scope and alkyne moiety under optimal condition provided the required
generality of this protocol were investigated (Scheme 3). product 2w, in less yield.
Different electron-donating and electron-withdrawing func-
Aer successful synthesis of quinoline-fused lactones, we
tional groups on the aniline ring as well as the aryl alkyne part further explored the suitability of the present protocol for the
were well tolerated. For example, substrates bearing electron- synthesis of quinoline-fused lactams. Accordingly, we examined
donating groups such as 4-methyl, 4-isopropyl, and 4-tbutyl the intramolecular dehydrogenative Povarov cyclization of N-
on aniline ring were compatible with the reaction conditions aryl glycine amide substrates under our optimized reaction
and provided the desired products 2a, 2b and 2c in 88%, 86% condition and delighted to nd that the present protocol is
and 83% yields, respectively. However, strong electron- suitable for the construction of quinoline fused lactam as well.
ꢀ
donating such as hydroxy, methoxy, and phenoxy substrates However, the reaction requires higher temperature (60 C) for
resulted the desired products in moderate yield (2d–2f, 57– completion. Various electron donating as well as electron
64%). Additionally, substrates bearing halogen atoms such as withdrawing substituents on the aniline ring as well as aryl
F, Cl, and Br successfully reacted under the optimized condi- alkyne part of N-protected glycine amide (Ph- and Bn-) such as
tion to give the desired product (2g–2i) in good yield (75–79%). methyl, methoxy, chloro, di chloro, nitro and thienyl underwent
However, the electron-withdrawing group at the aniline ring cyclization to furnish the corresponding quinoline-fused lac-
tams in moderate to good yields (Scheme 4). It is noteworthy to
mention here that, the substrate bearing a TMS group is also
well tolerated (Scheme 4, 4o) and the resulted product can
conveniently be converted into the natural product luotonin A
in two steps.2 To demonstrate the synthetic practicality of the
present protocol, we conducted a gram-scale experiment by
employing 3c (2.82 mmol, 1.0 g) under the optimal reaction
conditions in which the desired product 4c was obtained in 80%
yield (0.79 g) showing that the present method could be easily
adapted for the large-scale synthesis with high efficiency.
Although the mechanism of this transformation is not fully
understood, however, based on the above experiments (Table 1.
Entry 14 and 15) and previous literature reports,14 a tentative
reaction mechanism is proposed in Scheme 5a. The rst step
involves the in situ generation of highly reactive imine inter-
mediate A, followed by intramolecular cycloaddition to form an
intermediate B.7q–t Further, intermediate B undergoes oxidation
to form the corresponding fused quinoline 2. A radical trapping
experiment was conducted by employing TEMPO as a radical
scavenger and obtained 2a in 48% yield (Scheme 5b), which
indicates that the reaction proceeds via non-radical pathway.
The quinoline fused lactone/lactam produced from the
method described here may nd utility in complex molecule
synthesis. Some representative examples are shown in Scheme
6. We utilized this method for the preparation of quinoline core
precursor of antitumor antibiotic uncialamycin 6.9 Also,
compounds 4c, 4d can easily be converted into cytotoxic alka-
loid luotonin-A analogues.2f
Scheme
3 Intramolecular Povarov cyclization of N-aryl glycine
estersa,b aReaction conditions: 0.18 mmol 1a, 0.20 mmol oxidant,
.
5 mol% of Cu(OTf)2, CH3CN (3.0 mL), rt, 12 h; bisolated yields.
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Scheme 4 Intramolecular Povarov cyclisation of N-aryl glycine amides.a,b. aReaction conditions: 0.14 mmol 3a, 0.15 mmol Oxidant, 5 mol% of
Cu(OTf)2, CH3CN (3.0 mL), 60 ꢀC, 12 h; bisolated yields; creaction carried out at room temperature for 12 h.
Scheme 6 Utility of the reaction.
Scheme 5 A plausible mechanism and control experiment.
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General procedure for the synthesis of substituted N-aryl
glycine ester (1a–1w)
Conclusions
In conclusion, we have demonstrated Oxone promoted intra-
molecular dehydrogenative Povarov cyclization of various
alkyne tethered N-aryl glycine derivatives to furnish biologically
relevant quinoline-fused lactones and lactams. This operation-
ally simple, scalable protocol utilizes non-toxic, inexpensive
Oxone as an oxidant to furnish the required products in high
yield. The method was further utilized for the preparation of
cytotoxic alkaloid luotonin-A analogues and quinoline core of
uncialamycin. Efforts are underway in our laboratory to extend
the application of this method as well as the detail mechanistic
investigation.
A 5 mL Screw Top V vial® was charged with substituted bro-
moacetate (0.39 mmol), Na2CO3 (0.47 mmol), NaI (0.08 mmol),
and substituted aniline (0.38 mmol), DMF (2 mL). The solution
was stirred at room temperature. Aer 1 h, the reaction mixture
was poured into ice water (10 mL) and extracted with EtOAc (2 ꢁ
20 mL). The organic extracts were combined, washed with brine
(15 mL), dried over Na2SO4, concentrated in vacuo and puried
by ash column chromatography by eluting 5–15% of ethyl
acetate/petroleum ether (silica gel, 100–200 mesh), to afford
substituted N-aryl glycine esters (1a–1w).
General procedure for the synthesis of substituted N-aryl
glycine amide (3a–3o)
Experimental section
General information
A 5 mL glass vial® was charged with substituted bromo acet-
amide (0.3 mmol), Na2CO3 (0.36 mmol), NaI (0.061 mmol),
substituted aniline (0.29 mmol), DMF (3 mL). The mixture was
stirred for 12 h at 60 ꢀC. Aer completion of the reaction
(monitored by TLC), the reaction mixture was cooled to room
temperature, then poured into ice water, extracted with ethyl
acetate (20 mL ꢁ 2). The organic extracts were combined,
washed with brine (15 mL), dried over Na2SO4, concentrated in
vacuo and puried by ash column chromatography by eluting
10–20% of ethyl acetate/petroleum ether (silica gel, 100–200
mesh), to afford the substituted N-aryl glycine amides (3a–3o).
Where stated, all reagents were purchased from commercial
sources and used without further purication. All the
substituted propargyl alcohols were prepared using a known
literature procedure.15,16 1H NMR, 13C NMR, and 19F NMR
spectra were recorded on Bruker AV, 200/400/500, JEOL 400
MHz spectrometers in appropriate solvents using TMS as an
internal standard or the solvent signals as secondary standards
and the chemical shis are shown in d scales. Chemical shis
(d) are quoted in parts per million (ppm). The residual solvent
peak, 1H NMR dH 7.26 and 13C {1H} NMR dC 77.0 for CDCl3 were
used as a reference. Coupling constants (J) are reported in Hertz
(Hz) to the nearest 0.1 Hz. Multiplicities of 1H NMR signals are
designated as s (singlet), d (doublet), dd (doublet of doublet), t
(triplet), quin (quintet), sept (septet) bs (broad singlet), m
(multiplet), etc. Melting points were determined using digital
Buchi Melting Point Apparatus B-540 and are uncorrected. Thin
layer chromatography was carried out on Merck silica gel
60F254 pre-coated aluminum foil sheets and was visualized
using UV light (254 nm) and stained with Ninhydrin. Flash
column chromatography was carried out through silica gel
(100–200 mesh) using ethyl acetate/hexane as eluent. Structures
General procedure for the synthesis of quinoline fused
lactones (2a–2w)
To a 5 mL Screw Top V vial® containing a stirring mixture of
substituted N-aryl glycine ester (0.18 mmol), Oxone® (122 mg,
0.20 mmol) in CH3CN (3 mL) was added Cu(OTf)2 (3.25 mg,
0.009 mmol) and the vial cap was wrapped tightly with a Teon.
The solution was then stirred at room temperature. Aer 12 h
(colorless to dark brown color was observed), the solvent was
removed under reduced pressure. The crude reaction mixture
was puried by ash column chromatography by eluting 20–
30% of ethyl acetate/petroleum ether (silica gel, 100–200 mesh),
to afford the pure substituted quinoline fused lactones (2a–2w).
of the products were identied by H NMR, 13C {1H} NMR, 19F
1
NMR, HRMS.
General procedure for the synthesis of quinoline fused
lactams (4a–4o)
General procedure for the synthesis of substituted phenyl
propargyl bromo acetate
To a 5 mL Screw Top V vial® containing a stirring mixture of
substituted N-aryl glycine amide (0.14 mmol), oxone® (92 mg,
To a solution of substituted propargyl alcohol (7.56 mmol) and 0.15 mmol) in CH3CN (3 mL) was added Cu(OTf)2 (2.64 mg,
pyridine (9.0 mmol) in anhydrous DCM (15 mL) was added 2- 0.0073 mmol) and the vial cap was wrapped tightly with
bromoacetyl bromide (8.31 mmol) in DCM (5 mL) at 0 ꢀC under a Teon. The solution was stirred at 60 ꢀC. Aer 12 h (colorless
N2 atmosphere over 30 min. Aer the addition was complete, to dark brown color was observed), the solvent was removed
the reaction mixture was stirred at room temperature for 4 h. under reduced pressure. The crude reaction mixture was puri-
Aer completion of the reaction (monitored by TLC), the crude ed by ash column chromatography by eluting 25–40% of
reaction mixture was then poured into water (30 mL) and ethyl acetate/petroleum ether (silica gel, 100–200 mesh), to
extracted with DCM (3 ꢁ 20 mL). The organic extracts were afford the pure substituted quinoline fused lactams (4a–4o).
dried over Na2SO4 and concentrated in vacuo, affording the
3-Phenylprop-2-yn-1-yl p-tolylglycinate (1a). Compound 1a
substituted phenyl propargyl bromoacetate which was used was isolated in 84% yield (93 mg, yellow solid); mp ¼ 88–90 ꢀC;
directly without further purication.
Rf ¼ 0.55 (VPE/VEA ¼ 90/10); 1H NMR (500 MHz, CDCl3) d ¼ 7.48
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(d, J ¼ 7.3 Hz, 2H), 7.38–7.33 (m, 3H), 7.03 (d, J ¼ 7.8 Hz, 2H),
6.58 (d, J ¼ 8.1 Hz, 2H), 5.02 (s, 2H), 4.18 (bs, 1H), 3.99 (s, 2H),
2.26 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 170.7, 144.6,
131.9, 129.8, 128.8, 128.3, 127.6, 121.9, 113.2, 86.9, 82.3, 53.4,
46.1, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H18NO2
280.1332; found 280.1325.
3-Phenylprop-2-yn-1-yl(4-iso-propylphenyl)glycinate (1b).
Compound 1b was isolated in 81% yield (98 mg, viscous
liquid); Rf ¼ 0.55 (VPE/VEA ¼ 90/10); 1H NMR (500 MHz,
CDCl3) d ¼ 7.48 (d, J ¼ 6.3 Hz, 2H), 7.34 (m, 3H), 7.09 (d, J ¼
8.0 Hz, 2H), 6.61 (d, J ¼ 8.0 Hz, 2H), 5.03 (s, 2H), 4.07 (bs, 1H),
4.00 (s, 2H), 2.83 (sept, J ¼ 6.8 Hz, 1H), 1.23 (d, J ¼ 6.8 Hz,
6H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 170.7, 144.7, 138.9,
131.8, 128.8, 128.3, 127.1, 121.9, 113.2, 86.9, 82.3, 53.4, 46.1,
33.1, 24.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22NO2
308.1645; found 308.1646.
3-Phenylprop-2-yn-1-yl(4-uorophenyl)glycinate (1g). Compound
1g was isolated in 78% yield (87 mg, off white solid); mp ¼ 86–88 ꢀC;
Rf ¼ 0.40 (VPE/VEA ¼ 90/10); 1H NMR (400 MHz, CDCl3) d ¼ 7.48 (d, J
¼ 7.3 Hz, 2H), 7.38–7.34 (m, 3H), 6.92 (t, J ¼ 8.6 Hz, 2H), 6.56 (dd, J
¼ 8.7 Hz, 4.2 Hz, 2H), 5.02 (s, 2H), 4.15 (bs, 1H), 3.95 (s, 2H); 13C
{1H} NMR (100 MHz, CDCl3) d ¼ 170.5, 156.2 (d, J ¼ 235.9 Hz) 143.2,
131.8, 128.8, 128.3, 121.8, 115.7 (d, J ¼ 22.5 Hz), 113.9 (d, J ¼ 7.5 Hz),
86.9, 82.3, 53.4, 46.2; 19F NMR (376 MHz, CDCl3) d ¼ ꢂ126.8; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C17H15FNO2 284.1081; found
284.1075.
3-Phenylprop-2-yn-1-yl(4-chlorophenyl)glycinate (1h).
Compound 1h was isolated in 79% yield (93 mg, off white
solid); mp ¼ 83–85 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 90/10); 1H NMR
(400 MHz, CDCl3) d ¼ 7.45 (d, J ¼ 7.3 Hz, 2H), 7.37–7.31
(m, 3H), 7.14 (d, J ¼ 8.6 Hz, 2H), 6.55 (d, J ¼ 8.6 Hz, 2H),
5.02 (s, 2H), 4.31 (bs, 1H), 3.97 (s, 2H); 13C {1H} NMR (100
MHz, CDCl3) d ¼ 170.3, 145.4, 131.9, 129.2, 128.9, 128.3,
123.1, 121.8, 114.1, 87.1, 82.2, 53.6, 45.8; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H15ClNO2 300.0786; found
300.0780.
3-Phenylprop-2-yn-1-yl(4-bromophenyl)glycinate (1i). Compound
1i was isolated in 78% yield (107 mg, brown solid); mp ¼ 86–88 ꢀC;
Rf ¼ 0.40 (VPE/VEA ¼ 90/10); 1H NMR (500 MHz, CDCl3) d ¼ 7.44 (d, J
¼ 6.8 Hz, 2H), 7.37–7.29 (m, 3H), 7.27 (d, J ¼ 8.5 Hz, 2H), 6.48 (d, J ¼
8.5 Hz, 2H), 5.00 (s, 2H), 4.31 (bs, 1H), 3.94 (s, 2H); 13C {1H} NMR
(125 MHz, CDCl3) d ¼ 170.2, 145.8, 132.0, 131.9, 128.9, 128.3, 121.8,
114.6, 110.1, 87.1, 82.2, 53.6, 45.6; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H15BrNO2 344.0281; found 344.0284.
3-Phenylprop-2-yn-1-yl(4-cyanophenyl)glycinate (1j). Compound
1j crude (90 mg, viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 80/20) Rf ¼ 0.40
(VPE/VEA ¼ 80/20); 1H NMR (500 MHz, CDCl3) d ¼ 7.44 (d, J ¼ 7.2 Hz,
4H), 7.34 (t, J ¼ 8.1 Hz, 3H), 6.58 (d, J ¼ 8.2 Hz, 2H), 5.03 (s, 2H), 4.87
(s, 1H), 4.01 (d, J ¼ 4.9 Hz, 2H); 13C {1H} NMR (125 MHz, CDCl3) d ¼
169.5, 149.9, 133.7, 131.8, 129.0, 128.3, 121.6, 120.0, 112.5, 100.0,
87.2, 81.9, 53.9, 44.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H15N2O2 291.1178; found 291.1140.
3-Phenylprop-2-yn-1-yl(4-(tert-butyl)phenyl)glycinate (1c).
Compound 1c was isolated in 80% yield (102 mg, yellow
1
ꢀ
solid); mp ¼ 89–91 C; Rf ¼ 0.55 (VPE/VEA ¼ 90/10); H NMR
(500 MHz, CDCl3) d ¼ 7.43 (dd, J ¼ 7.7, 1.7 Hz, 2H), 7.29 (m,
3H), 7.20 (d, J ¼ 8.7 Hz, 2H) 6.55 (d, J ¼ 8.7 Hz, 2H), 4.96 (s,
2H), 4.20 (bs, 1H), 3.93 (s, 2H), 1.26 (s, 9H); 13C {1H} NMR
(125 MHz, CDCl3) d ¼ 170.7, 144.4, 140.9, 131.8, 128.8, 128.2,
125.9, 121.8, 112.7, 86.9, 82.4, 53.3, 45.9, 33.7, 31.39; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H24NO2 322.1802; found
322.1801.
3-Phenylprop-2-yn-1-yl(4-hydroxyphenyl)glycinate (1d).
Compound 1d was isolated in 70% yield (78 mg, viscous
liquid); Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (500 MHz,
CDCl3) d ¼ 7.46–7.42 (m, 2H), 7.36–7.30 (m, 3H), 6.68 (d, J
¼ 8.7 Hz, 2H), 6.52 (d, J ¼ 8.7 Hz, 2H), 4.99 (s, 2H), 3.92 (s,
2H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 171.2, 148.7,
140.6, 131.8, 128.8, 128.3, 121.8, 116.2, 114.9, 86.9, 82.3,
53.5, 46.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C
17H16NO3 282.1125; found 282.1126.
3-Phenylprop-2-yn-1-yl(4-methoxyphenyl)glycinate (1e).
Compound 1e was isolated in 60% yield (note: decompo-
sition was observed aer keeping prolong time in column;
brown liquid); Rf ¼ 0.40 (VPE/VEA ¼ 80/20); 1H NMR (500
MHz, CDCl3) d ¼ 7.47–7.44 (m, 2H), 7.37–7.31 (m, 3H), 6.80
(d, J ¼ 8.8 Hz, 2H), 6.61 (d, J ¼ 8.8 Hz, 2H), 5.00 (s, 2H), 3.96
(s, 2H), 3.74 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) d ¼
170.8, 152.7, 141.0, 131.8, 128.8, 128.3, 121.9, 114.9, 114.4,
86.9, 82.4, 55.6, 53.4, 46.7; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C18H18NO3 296.1281; found 296.1280.
3-Phenylprop-2-yn-1-yl(2-chlorophenyl)glycinate (1k).
Compound 1k was isolated in 68% yield (80 mg, off white
solid); mp ¼ 69–71 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 90/10); 1H NMR
(400 MHz, CDCl3) d ¼ 7.54–7.44 (m, 2H), 7.43–7.27 (m,
4H), 7.15 (t, J ¼ 7.7 Hz, 1H), 6.71 (t, J ¼ 7.6 Hz, 1H), 6.56 (d,
J ¼ 8.1 Hz, 1H), 5.04 (s, 2H), 4.98 (bs, 1H), 4.05 (s, 2H); 13
C
{1H} NMR (100 MHz, CDCl3) d ¼ 169.9, 142.7, 131.8, 129.3,
128.9, 128.3, 127.8, 121.8, 119.5, 118.2, 111.2, 87.0, 82.2,
53.6, 45.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
3-Phenylprop-2-yn-1-yl(4-phenoxyphenyl)glycinate (1f).
Compound 1f was isolated in 75% yield (106 mg, off white
solid); mp ¼ 109–111 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 80/20); 1H
NMR (400 MHz, CDCl3) d ¼ 7.48 (dd, J ¼ 7.6, 1.7 Hz, 2H),
7.39–7.27 (m, 5H), 7.04 (t, J ¼ 7.4 Hz, 1H), 6.95 (dt, J ¼ 7.7,
3.4 Hz, 4H), 6.66–6.61 (m, 2H), 5.04 (s, 2H), 4.26 (bs, 1H),
4.00 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) d ¼ 170.6,
158.7, 148.4, 143.3, 131.8, 129.4, 128.9, 128.3, 122.0, 121.8,
121.1, 117.2, 114.1, 87.0, 82.3, 53.5, 46.2; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C23H20NO3 358.1438; found
358.1429.
C
17H15ClNO2 300.0778; found 300.0796.
3-Phenylprop-2-yn-1-yl(2,4-dimethylphenyl)glycinate (1l).
Compound 1l was isolated in 72% yield (83 mg, viscous
liquid); Rf ¼ 0.50 (VPE/VEA ¼ 90/10); 1H NMR (500 MHz,
CDCl3) d ¼ 7.47 (d, J ¼ 7.7 Hz, 2H), 7.38–7.31 (m, 3H), 6.94 (s,
1H), 6.92 (s, 1H), 6.43 (d, J ¼ 7.9 Hz, 1H), 5.02 (s, 2H), 4.03 (s,
2H) 2.24 (s, 3H), 2.21 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3)
d ¼ 170.9, 142.6, 131.9, 131.2, 128.9, 128.3, 127.3, 127.2,
122.8, 121.9, 110.2, 86.9, 82.3, 53.5, 46.1, 20.3, 17.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H20NO2 294.1489, found
294.1476.
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3-(p-Tolyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)glycinate (1m).
RSC Advances
MHz, CDCl3) d ¼ 170.7, 147.4, 144.3, 141.2, 132.5, 128.7,
126.1, 123.5, 112.8, 87.6, 84.8, 52.9, 45.9, 33.8, 31.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H23N2O4 367.1652; found
367.1658.
Compound 1m was isolated in 77% yield (97 mg, off white
solid); mp ¼ 85–87 ꢀC; Rf ¼ 0.55 (VPE/VEA ¼ 90/10); 1H NMR (500
MHz, CDCl3) d ¼ 7.34 (d, J ¼ 7.8 Hz, 2H), 7.21 (d, J ¼ 8.3 Hz, 2H),
7.11 (d, J ¼ 7.7 Hz, 2H), 6.57 (d, J ¼ 8.3 Hz, 2H), 4.99 (s, 2H), 3.96
(s, 2H), 2.34 (s, 3H), 1.27 (s, 9H); 13C {1H} NMR (125 MHz,
CDCl3) d ¼ 170.8, 144.4, 141.1, 139.1, 131.8, 129.0, 126.1, 118.8,
112.8, 87.2, 81.7, 53.6, 46.0, 33.8, 31.5, 21.4; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C22H26NO2 336.1958; found 336.1969.
3-(4-iso-Propylphenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)gly-
cinate (1n). Compound 1n was isolated in 76% yield (93 mg, off
white solid); mp ¼ 86.5–88.5 ꢀC; Rf ¼ 0.55 (VPE/VEA ¼ 90/10); 1H
NMR (500 MHz, CDCl3) d ¼ 7.38 (d, J ¼ 8.2 Hz, 2H), 7.21 (d, J ¼
8.6 Hz, 2H), 7.17 (d, J ¼ 8.1 Hz, 2H), 6.58 (d, J ¼ 8.6 Hz, 2H), 4.99
(s, 2H), 3.96 (s, 2H), 3.86 (bs, 1H), 2.89 (sept, J ¼ 6.9 Hz, 1H), 1.26
(s, 9H), 1.23 (d, J ¼ 6.9 Hz, 6H); 13C {1H} NMR (125 MHz, CDCl3)
d ¼ 170.8, 149.9, 144.4, 141.1, 131.9, 126.4, 126.1, 119.2, 112.8,
87.2, 81.6, 53.6, 46.0, 34.0, 33.8, 31.4, 23.7; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C24H30NO2 364.2271; found 364.2272.
3-(4-Methoxyphenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)glyci-
nate (1o). Compound 1o was isolated in 75% yield (93 mg,
viscous liquid); Rf ¼ 0.45 (VPE/VEA ¼ 90/10); 1H NMR (400 MHz,
CDCl3) d ¼ 7.49 (d, J ¼ 7.7 Hz, 2H), 7.29 (d, J ¼ 7.5 Hz, 2H), 6.93
(d, J ¼ 7.9 Hz, 2H), 6.67 (d, J ¼ 8.1 Hz, 2H), 5.08 (s, 2H), 4.31 (bs,
1H), 4.05 (s, 2H), 3.86 (s, 3H), 1.38 (s, 9H); 13C {1H} NMR (100
MHz, CDCl3) d ¼ 170.7, 159.9, 144.4, 140.9, 133.3, 125.9, 114.7,
113.8, 112.7, 86.9, 81.0, 55.1, 53.5, 45.8, 33.7, 31.4; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H26NO3 352.1907; found
352.1906.
3-(3-Chloro-4-methylphenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)
glycinate (1s). Compound 1s was isolated in 68% yield (83 mg, off
1
ꢀ
white solid); mp ¼ 66.5–68.5 C; Rf ¼ 0.55 (VPE/VEA ¼ 90/10); H
NMR (500 MHz, CDCl3) d ¼ 7.47 (d, J ¼ 1.0 Hz, 1H), 7.29–7.24 (m,
3H), 7.20 (d, J ¼ 7.8 Hz, 1H), 6.62 (d, J ¼ 8.6 Hz, 2H), 5.02 (s, 2H),
4.01 (s, 2H), 3.46 (bs, 1H), 2.40 (s, 3H), 1.30 (s, 9H); 13C {1H} NMR
(125 MHz, CDCl3) d ¼ 170.8, 144.4, 141.2, 137.3, 134.2, 132.2,
130.8, 130.0, 126.1, 120.9, 112.8, 85.7, 82.8, 53.4, 46.0, 33.9, 31.5,
20.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H25ClNO2
370.1568; found 370.1570.
3-(3,5-Dimethylphenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)glyci-
nate (1t). Compound 1t was isolated in 69% yield (86 mg, off white
solid); mp ¼ 89–91 ꢀC; Rf ¼ 0.55 (VPE/VEA ¼ 90/10); 1H NMR (400
MHz, CDCl3) d ¼ 7.21 (d, J ¼ 8.2 Hz, 2H), 7.08 (s, 2H), 6.96 (s, 1H),
6.57 (d, J ¼ 8.1 Hz, 2H), 4.97 (s, 2H), 3.95 (s, 2H), 2.27 (s, 6H), 1.26
(s, 9H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 170.7, 144.4, 141.0,
137.8, 130.7, 129.5, 126.0, 121.5, 112.8, 87.3, 81.6, 53.5, 45.9, 33.8,
31.4, 20.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H28NO2
350.2115; found 350.2109.
3-(2-Methoxyphenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)glyci-
nate (1u). Compound 1u was isolated in 69% yield (86 mg,
1
ꢀ
yellow solid); mp ¼ 96–98 C; Rf ¼ 0.45 (VPE/VEA ¼ 90/10); H
NMR (400 MHz, CDCl3) d ¼ 7.42 (d, J ¼ 7.5 Hz, 1H), 7.30 (t, J ¼
7.9 Hz, 1H), 7.21 (d, J ¼ 8.4 Hz, 2H), 6.88 (dd, J ¼ 7.5 Hz, 8.5 Hz,
2H), 6.57 (d, J ¼ 8.3 Hz, 2H), 5.05 (s, 2H), 4.18 (bs, 1H), 3.96 (s,
2H), 3.86 (s, 3H), 1.27 (s, 9H); 13C {1H} NMR (100 MHz, CDCl3)
d ¼ 170.7, 160.2, 144.4, 140.9, 133.9, 130.4, 126.0, 120.4, 112.7,
110.9, 110.6, 86.2, 83.4, 55.7, 53.7, 45.9, 33.8, 31.4; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H26NO3 352.1907; found
352.1899.
3-(4-Fluorophenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)gly-
cinate (1p). Compound 1p was isolated in 72% yield (90 mg,
ꢀ
off white solid); mp ¼ 78.5–80.5 C; Rf ¼ 0.50 (VPE/VEA ¼ 90/
1
10); H NMR (500 MHz, CDCl3) d ¼ 7.42 (dd, J ¼ 8.7, 5.4 Hz,
2H), 7.21 (d, J ¼ 8.6 Hz, 2H), 7.00 (t, J ¼ 8.7 Hz, 2H), 6.58 (d, J
¼ 8.6 Hz, 2H), 4.98 (s, 2H), 3.97 (s, 2H), 1.27 (s, 9H); 13C {1H}
NMR (125 MHz, CDCl3) d ¼ 170.8, 162.8 (d, J ¼ 250.2 Hz),
144.4, 141.2, 133.9 (d, J ¼ 8.5 Hz), 126.1, 117.9 (d, J ¼ 3.4 Hz),
115.6 (d, J ¼ 22.2 Hz), 112.8, 85.9, 82.1, 53.3, 45.9, 33.8, 31.4;
19F NMR (376 MHz, CDCl3) d ¼ ꢂ109.8; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C21H23FNO2 340.1707; found 340.1709.
3-(4-Chlorophenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)gly-
cinate (1q). Compound 1q was isolated in 72% yield (89 mg,
3-(Thiophen-2-yl)prop-2-yn-1-yl(4-iso-propylphenyl)glycinate
(1v). Compound 1v was isolated in 69% yield (84 mg, viscous
liquid); Rf ¼ 0.50 (VPE/VEA ¼ 95/5); H NMR (500 MHz, CDCl3)
1
d ¼ 7.28 (d, J ¼ 5.1 Hz, 1H), 7.25 (d, J ¼ 3.8 Hz, 1H), 7.06 (d, J ¼
8.4 Hz, 2H), 6.97 (dd, J ¼ 4.9, 3.9 Hz, 1H), 6.57 (d, J ¼ 8.4 Hz,
2H), 5.01 (s, 2H), 3.97 (s, 2H), 3.54 (bs, 1H), 2.80 (sept, J ¼ 6.9 Hz,
1H), 1.20 (d, J ¼ 6.9 Hz, 6H); 13C {1H} NMR (125 MHz, CDCl3) d ¼
170.7, 144.8, 138.9, 133.1, 128.0, 127.2, 126.9, 121.8, 113.2, 86.4,
80.4, 53.5, 46.1, 33.1, 24.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H20NO2S 314.1209; found 314.1210.
ꢀ
off white solid); mp ¼ 76–78 C; Rf ¼ 0.52 (VPE/VEA ¼ 90/10);
1H NMR (400 MHz, CDCl3) d ¼ 7.39 (d, J ¼ 8.6 Hz, 2H), 7.30
(d, J ¼ 8.5 Hz, 2H), 7.23 (d, J ¼ 8.7 Hz, 2H), 6.59 (d, J ¼ 8.7 Hz,
2H), 5.00 (s, 2H), 4.00 (s, 2H), 1.28 (s, 9H); 13C {1H} NMR (100
MHz, CDCl3) d ¼ 170.8, 144.4, 141.2, 135.0, 133.1, 128.7,
126.1, 120.4, 112.8, 85.8, 83.3, 53.3, 46.0, 33.9, 31.5; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H23ClNO2 356.1412;
found 356.1405.
But-2-yn-1-yl p-tolylglycinate (1w). Compound 1w was iso-
lated in 60% yield (94 mg, viscous liquid); Rf ¼ 0.5 (VPE/VEA ¼ 90/
10); 1H NMR (500 MHz, CDCl3) d ¼ 6.99 (d, J ¼ 8.1 Hz, 2H), 6.52
(d, J ¼ 8.3 Hz, 2H), 4.72 (s, 2H), 4.09 (bs, 1H), 3.91 (s, 2H), 2.23 (s,
3H), 1.85 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 170.7,
144.5, 129.7, 127.4, 113.1, 83.7, 72.6, 53.4, 45.9, 20.3, 3.5; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C13H16NO2 218.1178.; found
218.1176.
3-(4-Nitrophenyl)prop-2-yn-1-yl(4-(tert-butyl)phenyl)glyci-
nate (1r). Compound 1r was isolated in 70% yield (86 mg,
yellow solid); mp ¼ 76.5–78.5 ꢀC; Rf ¼ 0.45 (VPE/VEA ¼ 90/10);
1H NMR (400 MHz, CDCl3) d ¼ 8.17 (d, J ¼ 8.6 Hz, 2H), 7.57 (d,
J ¼ 8.6 Hz, 2H), 7.22 (d, J ¼ 8.4 Hz, 2H), 6.58 (d, J ¼ 8.4 Hz,
2H), 5.02 (s, 2H), 4.00 (s, 2H), 1.27 (s, 9H); 13C {1H} NMR (100
N-Phenyl-N-(3-phenylprop-2-yn-1-yl)-2-(p-tolylamino)acetamide
(3a). Compound 3a was isolated in 73% yield (79 mg, off white
1
ꢀ
solid); mp ¼ 94.2–96.2 C; Rf ¼ 0.40 (VPE/VEA ¼ 70/30); H NMR
(500 MHz, CDCl3) d ¼ 7.55–7.47 (m, 3H), 7.38 (d, J ¼ 7.0 Hz, 2H),
7.35 (d, J ¼ 7.3 Hz, 2H), 7.32–7.26 (m, 3H), 6.93 (d, J ¼ 8.0 Hz, 2H),
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6.39 (d, J ¼ 8.0 Hz, 2H), 4.77 (s, 2H), 4.59 (bs, 1H), 3.58 (s, 2H), 2.21
(s, 3H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 169.3, 145.1, 140.0,
131.6, 129.9, 129.6, 129.1, 128.4, 128.3, 128.2, 126.9, 122.6, 113.1,
84.5, 83.9, 46.6, 39.4, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C24H23N2O 355.1805; found 355.1807.
N-Benzyl-2-((4-methoxyphenyl)amino)-N-(3-phenylprop-2-yn-
1-yl)acetamide (3e). Compound 3e crude (note: crude was
ꢀ
recrystallize in n-hexane) mp ¼ 79–81 C; Rf ¼ 0.35 (VPE/VEA
¼
1
70/30); H NMR (400 MHz, CDCl3, rotameric mixture found in
1 : 0.97 ratio) d ¼ 7.45–7.26 (m, 20H, aromatic) (rotameric),
6.85–6.72 (m, 4H, aromatic) (rotameric), 6.66 (d, J ¼ 8.6 Hz, 2H,
aromatic) and 6.56 (d, J ¼ 8.5 Hz 2H, aromatic) (rotameric), 4.80
(s, 2H, CH2) and 4.74 (s, 2H, CH2) (rotameric), 4.53 (s, 2H, CH2)
and 3.95 (s, 2H, CH2), (rotameric), 4.19 (s, 2H, CH2) and 4.11 (s,
2H, CH2) (rotameric), 3.75 (s, 3H, OMe) and 3.73 (s, 3H, OMe)
(rotameric); 13C {1H} NMR (100 MHz, CDCl3, rotamers) d ¼
169.7 and 169.6 (rotameric C]O), 152.3 and 152.2 (rotameric),
141.7 and 141.6 (rotameric), 136.4 and 135.5 (rotameric), 131.7
(rotameric), 129.1 and 128.3 (rotameric), 128.8 and 128.7
(rotameric), 128.5 and 128.4 (rotameric), 128.0 and 127.8
(rotameric), 126.7 (rotameric), 122.5 and 121.9 (rotameric),
114.9 and 114.9 (rotameric), 114.4 (rotameric), 84.9 and 84.3
(rotameric Calkyne), 83.6 and 82.6 (rotameric Calkyne), 55.8
(OMe) 49.2 and 49.1 (rotameric CH2), 46.5 and 46.4 (rotameric
CH2), 36.3 and 35.5 (rotameric CH2); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C25H25N2O2 385.1911; found 385.1911.
2-((4-Methoxyphenyl)amino)-N-phenyl-N-(3-phenylprop-2-yn-1-
yl)acetamide (3b). Compound 3b was isolated in 41% yield (46 mg,
1
brown liquid); Rf ¼ 0.35 (VPE/VEA ¼ 70/30); H NMR (400 MHz,
CDCl3, starting material was not stable) d ¼ 7.49 (d, J ¼ 7.3 Hz, 2H),
7.39–7.33 (m, 5H), 7.32–7.25 (m, 3H), 6.71 (d, J ¼ 8.8 Hz, 2H), 6.43
(d, J ¼ 8.8 Hz, 2H), 4.75 (s, 2H), 3.69 (s, 3H), 3.55 (s, 2H); 13C {1H}
NMR (100 MHz, CDCl3) d ¼ 169.4, 152.3, 141.6, 139.9, 131.7, 131.6,
129.9, 129.1, 128.8, 128.4, 128.3, 128.2, 114.7, 114.3, 84.4, 83.9,
55.7, 47.1, 39.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C24H23N2O2 371.1754; found 371.1755.
N-Benzyl-2-(phenylamino)-N-(3-phenylprop-2-yn-1-yl)acetamide
(3c).17,18 Compound 3c was isolated in 76% yield (79 mg, off white
1
ꢀ
solid); mp ¼ 95.5–97.5 C; Rf ¼ 0.40 (VPE/VEA ¼ 70/30); H NMR
(500 MHz, CDCl3, rotameric mixture found in 1 : 0.98 ratio) d ¼
7.44–7.39 (rotameric m, 6H, aromatic) 7.34 (rotameric m, 14H,
aromatic), 7.21 (rotameric quin, 4H, aromatic), 6.79–6.73 (rota-
meric m, 2H, aromatic), 6.71 (d, J ¼ 8.0 Hz, 2H, aromatic) and 6.61
(d, J ¼ 7.9 Hz, 2H, aromatic) (rotameric), 4.93 (rotameric bs, 2H,
NH), 4.84 (s, 2H, CH2) and 4.76 (s, 2H, CH2) (rotameric), 4.56 (s,
2H, CH2) and 4.00 (s, 2H, CH2) (rotameric), 4.21 (s, 2H, CH2) and
4.16 (s, 2H, CH2) (rotameric); 13C {1H} NMR (125 MHz, CDCl3) d ¼
169.5 and 162.4 (rotameric C]O), 147.4 and 147.3 (rotameric),
136.5 and 135.6 (rotameric), 131.9 (rotameric), 129.4 and 129.4
(rotameric), 129.2 and 128.9 (rotameric), 128.8 and 128.6 (rota-
meric), 128.5 and 128.4 (rotameric), 128.2 and 127.9 (rotameric),
126.8 (rotameric), 122.6 and 122.0 (rotameric), 117.8 (rotameric),
113.2 and 113.1 (rotameric), 85.2 and 84.5 (rotameric Calkyne),
83.7 and 82.7 (rotameric Calkyne), 49.4 and 49.3 (rotameric CH2),
45.6 and 45.5 (rotameric CH2), 36.4 and 35.7 (rotameric CH2);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H23N2O; 355.1805
found 355.1798.
N-Benzyl-2-((4-chlorophenyl)amino)-N-(3-phenylprop-2-yn-1-
yl)acetamide (3f). Compound 3f was isolated in 74% yield
ꢀ
(42 mg, brown solid); mp ¼ 91–93 C; Rf ¼ 0.40 (VPE/VEA ¼ 70/
30); 1H NMR (400 MHz, CDCl3, rotameric mixture found in
1 : 0.98 ratio) d ¼ 7.40–7.26 (m, 20H, aromatic) (rotameric), 7.11
(dd, J ¼ 11.5, 8.6 Hz, 4H, aromatic) (rotameric), 6.59 (d, J ¼
8.3 Hz, 2H) and 6.48 (d, J ¼ 8.4 Hz, 2H, aromatic) (rotameric),
4.80 (s, 2H, CH2) and 4.73 (s, 2H, CH2) (rotameric), 4.53 (s, 2H,
CH2) and 3.93 (s, 2H, CH2) (rotameric), 4.17 (s, 2H, CH2) and
4.09 (s, 2H, CH2) (rotameric); 13C {1H} NMR (100 MHz, CDCl3,
rotamers) d ¼ 169.0 and 168.8 (rotameric C]O), 145.8 and
145.7 (rotameric), 136.2 and 135.3 (rotameric), 131.7 (rota-
meric), 129.1 (rotameric) 129.1 and 129.0 (rotameric), 128.8 and
128.7 (rotameric), 128.5 and 128.3 (rotameric), 128.4 and 128.3
(rotameric), 128.1 and 127.8 (rotameric), 126.6 (rotameric),
122.4 and 122.2 (rotameric), 114.0 and 114.0 (rotameric), 85.1
and 84.5 (rotameric Calkyne), 83.4 and 82.4 (rotameric Cal-
kyne), 49.2 (rotameric CH2), 45.4 (rotameric CH2), 36.3 and 35.6
(rotameric CH2); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
N-Benzyl-N-(3-phenylprop-2-yn-1-yl)-2-(p-tolylamino)acetamide
(3d). Compound 3d was isolated in 74% yield (80 mg, off white
solid); mp ¼ 93–95 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 70/30); 1H NMR (500
MHz, CDCl3, rotameric mixture found in 1 : 0.98 ratio) d ¼ 7.43
(rotameric m, 6H, aromatic), 7.35 (rotameric m, 14H, aromatic),
7.06 (d, J ¼ 8.0 Hz, 2H, aromatic) and 7.02 (d, J ¼ 8.0 Hz, 2H,
aromatic) (rotameric), 6.66 (d, J ¼ 8.1 Hz, 2H, aromatic) and 6.56
(d, J ¼ 8.1 Hz, 2H, aromatic) (rotameric), 4.85 (s, 2H, CH2) and 4.76
(s, 2H, CH2) (rotameric), 4.57 (s, 2H, CH2) and 4.00 (s, 2H, CH2)
(rotameric) 4.21 (s, 2H, CH2) and 4.15 (s, 2H, CH2) (rotameric), 2.29
(s, 3H, 4-CH3 aniline) and 2.27 (s, 3H, 4-CH3 aniline) (rotameric);
13C {1H} NMR (125 MHz, CDCl3 rotamers) d ¼ 169.5 and 169.4
(rotameric C]O), 145.1 and 145.0 (rotameric) 136.4 and 135.5
(rotameric), 131.7, 129.7 and 129.6 (rotameric), 129.0 and 128.7
(rotameric), 128.6 and 128.4 (rotameric), 128.3 and 128.2 (rota-
meric), 127.9 and 127.7 (rotameric), 126.8 and 128.6 (rotameric),
122.4 and 121.9 (rotameric), 113.1, 84.9 and 84.2 (rotameric Cal-
kyne), 83.6 and 82.6 (rotameric Calkyne), 49.2 and 49.1 (rotameric
CH2), 45.8 and 45.7 (rotameric CH2), 36.2 and 35.5 (rotameric
CH2), 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25N2O
369.1961; found 369.1958.
C
24H22ClN2O 389.1415; found 389.1422.
N-Benzyl-2-((2,5-dichlorophenyl)amino)-N-(3-phenylprop-2-
yn-1-yl)acetamide (3g). Compound 3g was isolated in 61% yield
1
(76 mg, viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 70/30); H NMR
(400 MHz, CDCl3, rotameric mixture found in 1 : 0.97 ratio) d ¼
7.49–7.28 (m, 20H, aromatic) (rotameric), 7.18 (t, J ¼ 7.9 Hz, 2H,
aromatic), (rotameric), 6.62 (t, J ¼ 8.1 Hz, 2H, aromatic) (rota-
meric), 6.58 (s, 1H, aromatic) and 6.41 (s, 1H, aromatic) (rota-
meric), 5.72 (bs, 2H, NH) (rotameric), 4.83 (s, 2H, CH2) and 4.76
(s, 2H, CH2) (rotameric), 4.56 (s, 2H, CH2) and 4.20 (s, 2H, CH2)
(rotameric), 4.13 (s, 2H, CH2) and 3.98 (s, 2H, CH2) (rotameric);
13C {1H} NMR (100 MHz, CDCl3, rotamers) d ¼ 168.4 and 168.3
(rotameric C]O), 144.0, 136.3 and 135.3 (rotameric), 133.6 and
133.5 (rotameric), 131.9, 130.1 and 129.4 (rotameric), 129.0,
128.9 and 128.7 (rotameric), 128.6 and 128.4 (rotameric), 128.3
and 128.1 (rotameric), 126.8, 122.5 and 121.9 (rotameric), 118.0,
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117.3, 111.3 and 111.2 (rotameric), 85.5 and 84.6 (rotameric 2.28 (s, 3H, 4-Me aniline) and 2.26 (s, 3H, 4-Me aniline) (rotameric);
Calkyne), 83.4 and 82.4 (rotameric Calkyne), 49.5 and 49.4 13C {1H} NMR (100 MHz, CDCl3 rotamers) d ¼ 169.5 and 169.4
(rotameric CH2), 45.0, 36.5 and 35.9 (rotameric CH2); HRMS (rotameric C]O), 145.1 and 145.0 (rotameric), 138.9 and 138.5
(ESI-TOF) m/z: [M + H]+ calcd for C24H21Cl2 N2O (M + H)+ (rotameric), 136.4 and 135.5 (rotameric), 131.6, 129.7 and 129.7
423.1025; found 423.1016.
(rotameric), 129.1 and 129.0 (rotameric), 128.9, 128.6 and 128.4
N-Benzyl-2-((4-methoxyphenyl)amino)-N-(3-(p-tolyl)prop-2-yn-1- (rotameric), 127.9 and 128.4 (rotameric), 126.8 and 126.7 (rota-
yl)acetamide (3h). Compound 3i was isolated in 68% yield (76 mg, meric), 119.3 and 118.8 (rotameric), 113.2, 85.1 and 84.4 (rotameric
off white solid); mp ¼ 115.5–117.5 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 70/30); Calkyne), 82.8 and 81.9 (rotameric Calkyne), 49.1 and 49.0 (rota-
1H NMR (500 MHz, CDCl3, rotameric mixture found in 1 : 0.98 meric CH2), 45.8 and 45.8 (rotameric CH2), 36.3 and 35.5 (rota-
ratio) d ¼ 7.41–7.31 (m, 14H aromatic) (rotameric), 7.15 (d, J ¼ meric CH2), 21.4 and 20.3 (rotameric, N–CH2, 4-PhCH3); HRMS
7.9 Hz, 4H, aromatic) (rotameric), 6.81 (dd, J ¼ 9.0, 8.1 Hz, 4H, (ESI-TOF) m/z: [M + H]+ calcd for C26H27N2O 383.2118; found
aromatic) (rotameric), 6.69 (d, J ¼ 7.8 Hz, 2H, aromatic) and 6.58 383.2115.
(d, J ¼ 7.8 Hz, 2H, aromatic) (rotameric), 4.83 (s, 2H, CH2) and 4.75
N-Benzyl-N-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-2-(p-tolylamino)
(s, 2H, CH2) (rotameric), 4.63 (bs, 2H, NH) (rotameric), 4.55 (s, 2H, acetamide (3k). Compound 3k was isolated in 71% yield (76 mg,
1
CH2) and 3.96 (s, 2H, CH2) (rotameric), 4.19 (s, 2H, CH2) and 4.12 viscous liquid); Rf ¼ 0.35 (VPE/VEA ¼ 60/40); H NMR (400 MHz,
(s, 2H, CH2) (rotameric), 3.76 (s, 3H, OCH3) and 3.75 (s, 3H, OCH3) CDCl3, rotameric mixture found in 1 : 0.96 ratio) d ¼ 7.39–7.24 (m,
(rotameric), 2.37 (s, 3H, 4-MePh) and 2.36, (s, 3H, 4-MePh), (rota- 14H, aromatic) (rotameric), 6.98 (dd, J ¼ 13.3, 8.1 Hz, 4H, aromatic)
meric); 13C {1H} NMR (125 MHz, CDCl3 rotamers) d ¼ 169.6 and (rotameric), 6.80 (dd, J ¼ 7.9, 6.0 Hz, 4H, aromatic) (rotameric), 6.60
169.5 (rotameric C]O), 152.2, 141.7 and 141.6 (rotameric), 138.9 (d, J ¼ 8.0 Hz, 2H, aromatic) and 6.49 (d, J ¼ 8.0 Hz, 2H, aromatic)
and 138.5 (rotameric), 136.4 and 135.5 (rotameric), 131.5, 129.0 (rotameric), 4.78 (s, 2H, CH2) and 4.70 (s, 2H, CH2) (rotameric), 4.50
and 128.9 (rotameric), 128.6 and 128.3 (rotameric), 127.8 and 127.6 (s, 2H, CH2) and 3.93 (s, 2H, CH2) (rotameric), 4.13 (s, 2H, CH2) and
(rotameric), 126.6, 119.3 and 118.8 (rotameric), 114.8 and 114.8 4.09 (s, 2H, CH2) (rotameric), 3.76 (s, 6H, OCH3) (rotameric), 2.23 (s,
(rotameric), 114.2, 85.0 and 84.3 (rotameric Calkyne), 82.8 and 81.9 3H, PhCH3) and 2.21 (s, 3H, PhCH3) (rotameric); 13C {1H} NMR (100
(rotameric Calkyne), 55.6, 49.1 and 49.0 (rotameric CH2), 46.4 and MHz, CDCl3, rotamers) d ¼ 169.5 and 169.3 (rotameric), 159.8 and
46.3 (rotameric CH2), 36.3 and 35.5 (rotameric CH2), 21.3; HRMS 159.6 (rotameric), 145.0 and 144.9 (rotameric), 136.4 and 135.5
(ESI-TOF) m/z: [M + H]+ calcd for C26H27N2O2 399.2067; found (rotameric), 133.1, 129.7 and 129.6 (rotameric), 128.9 and 128.7
399.2065.
(rotameric), 128.6 and 128.3 (rotameric), 127.8 and 127.6 (rota-
N-Benzyl-2-((4-chlorophenyl)amino)-N-(3-(p-tolyl)prop-2-yn-1-yl) meric), 126.7 and 126.6 (rotameric), 114.4 and 114.3 (rotameric),
acetamide (3i). Compound 3j was isolated in 71% yield (80 mg, off 113.9 and 113.8 (rotameric), 113.2 and 113.1 (rotameric), 84.8 and
white solid); mp ¼ 96–98 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 70/30); 1H NMR 84.1 (rotameric Calkyne), 82.0 and 81.2 (rotameric Calkyne), 55.14
(400 MHz, CDCl3, rotameric mixture found in 1 : 0.9 ratio) d ¼ 1H (rotameric OCH3), 49.1 and 49.0 (rotameric CH2), 45.8 and 45.7
NMR (400 MHz, DMSO) d 7.44–7.28 (m, 14H, aromatic) (rota- (rotameric CH2), 36.3 and 35.5 (rotameric CH2), 20.3; HRMS (ESI-
meric), 7.13 (t, J ¼ 8.5 Hz, 8H, aromatic) (rotameric), 6.61 (d, J ¼ TOF) m/z: [M + H]+ calcd for C26H27N2O2 (M + H)+ 399.2067;
8.5 Hz, 2H, aromatic) and 6.50 (d, J ¼ 8.5 Hz, 2H, aromatic) found 399.2075.
(rotameric), 4.96 (bs, 2H, NH) (rotameric), 4.82 (s, 2H, CH2) and
N-Benzyl-N-(3-(4-chlorophenyl)prop-2-yn-1-yl)-2-(p-tolylamino)
4.74 (s, 2H, CH2) (rotameric), 4.54 (s, 2H, CH2) and 3.93 (s, 2H, acetamide (3l). Compound 3l was isolated in 73% yield (81 mg,
1
CH2) (rotameric), 4.18 (s, 2H, CH2) and 4.10 (s, 2H, CH2) (rota- viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 70/30); H NMR (400 MHz,
meric), 2.36 (s, 6H, NHCH2 4-MePh) (rotameric); 13C {1H} NMR CDCl3, rotameric mixture found in 1 : 0.88 ratio) d ¼ 7.42–7.21
(100 MHz, CDCl3, rotamers) d ¼ 169.0 and 168.9 (rotameric C]O), (m, 18H, aromatic) (rotameric), 6.99 (dd, J ¼ 12.0, 8.2 Hz, 4H,
145.8 and 145.7 (rotameric), 139.0 and 138.6 (rotameric), 136.3 and aromatic) (rotameric), 6.60 (d, J ¼ 8.1 Hz, 2H, aromatic) and 6.51
135.4 (rotameric), 131.6, 129.1 and 129.0 (rotameric), 128.7 and (d, J ¼ 8.1 Hz, 2H, aromatic) (rotameric), 4.78 (s, 2H, CH2) and
128.4 (rotameric), 128.0 and 127.8 (rotameric), 126.6, 122.2, 119.3 4.71 (s, 2H, CH2) (rotameric), 4.50 (s, 2H, CH2) and 3.96 (s, 2H,
and 118.7 (rotameric), 114.0, 85.3 and 84.5 (rotameric Calkyne), CH2) (rotameric), 4.16 (s, 2H, CH2) and 4.09 (s, 2H, CH2) (rota-
82.6 and 81.7 (rotameric Calkyne), 49.2, 45.4 and 45.3 (rotameric meric), 2.24 (s, 3H, NHPhCH3) and 2.22 (s, 3H, NHPhCH3)
CH2), 36.3 and 35.7 (rotameric CH2), 21.4; HRMS (ESI-TOF) m/z: [M (rotameric); 13C {1H} NMR (100 MHz, CDCl3, rotamers) d ¼ 169.5,
+ H]+ calcd for C25H24ClN2O 403.1572; found 403.1570.
145.0 and 144.9 (rotameric), 136.3 and 135.4 (rotameric), 134.8
N-Benzyl-N-(3-(p-tolyl)prop-2-yn-1-yl)-2-(p-tolylamino)acetamide and 134.4 (rotameric), 132.9, 129.7 and 129.6 (rotameric), 129.0,
(3j). Compound 3h was isolated in 77% yield (83 mg, off white 128.7, 128.6 and 128.4 (rotameric), 128.0 and 127.7 (rotameric),
solid); mp ¼ 106–108 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 70/30); 1H NMR (400 126.9 and 126.6 (rotameric), 120.9 and 120.3 (rotameric), 113.16,
MHz, CDCl3, rotameric mixture found in 1 : 0.97 ratio) d ¼ 7.42– 84.7 and 83.0 (rotameric Calkyne), 83.8 and 83.7 (rotameric Cal-
7.29 (m, 14H, aromatic) (rotameric), 7.14 (t, J ¼ 7.1 Hz, 4H, kyne), 49.3 and 49.2 (rotameric CH2), 45.81, 36.2 and 35.5 (rota-
aromatic) (rotameric), 7.03 (dd, J ¼ 12.4, 8.1 Hz, 4H, aromatic) meric CH2), 20.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
(rotameric), 6.65 (d, J ¼ 7.9 Hz, 2H, aromatic) and 6.54 (d, J ¼ C25H24ClN2O (M + H)+ 403.1572; found 403.1584.
7.9 Hz, 2H, aromatic) (rotameric), 4.83 (s, 2H, CH2) and 4.76 (s, 2H,
N-Benzyl-N-(3-(4-nitrophenyl)prop-2-yn-1-yl)-2-(p-tolylamino)
CH2) (rotameric), 4.55 (s, 2H, CH2) and 3.98 (s, 2H, CH2) (rota- acetamide (3m). Compound 3m was isolated in 65% yield (69 mg,
1
meric), 4.20 (s, 2H, CH2) and 4.14 (s, 2H, CH2) (rotameric), 2.38 (s, viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 70/30); H NMR (500 MHz,
3H, NHCH2 4-MePh) and 2.37 (s, 3H, NHCH2 4-MePh) (rotameric), CDCl3, rotameric mixture found in 1 : 0.86 ratio) d ¼ 8.20 (m, 4H,
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aromatic) (rotameric), 7.52 (d, J ¼ 7.5 Hz, 4H, aromatic) (rota- 90.5 and 89.6 (rotameric), 49.1 and 49.0 (rotameric), 45.4 and 45.3
meric), 7.46–7.29 (m, 10H, aromatic) (rotameric), 7.08–6.99 (m, (rotameric), 36.4 and 35.7 (rotameric), ꢂ0.2 and 0.3 (rotameric
4H, aromatic) (rotameric), 6.65 (d, J ¼ 6.8 Hz, 2H, aromatic) and TMS); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H27N2OSi
6.56 (d, J ¼ 7.4 Hz, 2H, aromatic) (rotameric), 4.84 (s, 2H, CH2) 351.1878; found 351.1895.
and 4.77 (s, 2H, CH2) (rotameric), 4.58 (s, 2H, CH2) and 4.28 (s,
5-(Benzyloxy)pent-3-yn-2-yl(4-methoxyphenyl)glycinate
2H, CH2), (rotameric), 4.15 (s, 2H, CH2) and 4.03 (s, 2H, CH2) (5). Compound 5 was isolated in 62% yield (70 mg, viscous
(rotameric), 2.27 (s, 6H, NHPhCH3) (rotameric). 13C {1H} NMR liquid); Rf ¼ 0.35 (VPE/VEA ¼ 70/30); 1H NMR (400 MHz,
(100 MHz, CDCl3, rotamers) d ¼ 169.7 and 169.5 (rotameric C] CDCl3) d ¼ 7.33–7.27 (m, 5H), 6.76 (d, J ¼ 8.9 Hz, 2H), 6.62
O), 147.4 and 147.2 (rotameric), 145.0 and 144.9 (rotameric), (d, J ¼ 8.9 Hz, 2H), 5.56 (q, J ¼ 6.7 Hz, 1H), 4.73 (bs, 1H),
136.1 and 135.2 (rotameric), 132.5 and 132.4 (rotameric), 129.8 4.54 (s, 2H), 4.16 (d, J ¼ 1.6 Hz, 2H), 3.87 (s, 2H), 3.68 (s,
and 129.7 (rotameric), 129.3 and 129.1 (rotameric), 128.8 and 3H), 1.50 (d, J ¼ 6.7 Hz, 3H); 13C {1H} NMR (100 MHz,
128.4 (rotameric), 128.2 and 127.9 (rotameric), 127.2 and 127.1 CDCl3) d ¼ 169.9, 152.9, 139.9, 137.0, 128.2, 127.9, 127.7,
(rotameric), 126.8 and 126.7 (rotameric), 123.6 and 123.5 (rota- 114.9, 114.6, 84.2, 81.1, 71.4, 61.1, 56.9, 55.4, 46.9, 21.0;
meric), 113.2 (rotameric), 89.3 and 88.1 (rotameric Calkyne), 83.1 HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24NO4
and 82.3 (rotameric Calkyne), 49.7 and 49.1 (rotameric CH2), 45.9 354.1700; found 354.1692.
and 45.8 (rotameric CH2), 36.3 and 35.7 (rotameric CH2), 20.3;
7-Methyl-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2a). Compound
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H24N3O3 (M + H)+ 2a was isolated in 88% yield (43 mg, off white solid); mp ¼ 198–
414.1812; found 414.1817.
200 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (400 MHz, CDCl3) d ¼
N-Benzyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)-2-(p-tolylamino) 8.30 (d, J ¼ 8.7 Hz, 1H), 7.67 (dd, J ¼ 8.7, 1.7 Hz, 1H), 7.64–7.57 (m,
acetamide (3n). Compound 3n was isolated in 74% yield (79 mg, 4H), 7.46–7.42 (m, 2H), 5.35 (s, 2H), 2.50 (s, 3H); 13C {1H} NMR (100
viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 70/30); 1H NMR (500 MHz, MHz, CDCl3) d ¼ 168.9, 149.3, 143.2, 142.8, 139.9, 133.7, 133.1,
CDCl3, rotameric mixture found in 1 : 0.98 ratio) d ¼ 7.36–7.26 132.5, 130.9, 129.4, 129.3, 128.8, 127.9, 124.2, 67.8, 22.1; HRMS (ESI-
(m, 8H) (rotameric), 7.20 (dd, J ¼ 13.2, 6.2 Hz, 3H, aromatic) TOF) m/z: [M + H]+ calcd for C18H14NO2 276.1019; found 276.1016.
(rotameric), 7.15 (dd, J ¼ 9.0, 4.6 Hz, 3H, aromatic) (rotameric),
7-iso-Propyl-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2b).
6.98 (d, J ¼ 7.9 Hz, 2H, aromatic) and 6.94 (d, J ¼ 7.9 Hz, 2H, Compound 2b was isolated in 86% yield (43 mg, off white
aromatic) (rotameric), 6.92–6.88 (m, 2H, aromatic) (rotameric), solid); mp ¼ 197–199 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR
6.58 (d, J ¼ 8.0 Hz, 2H, aromatic) and 6.47 (d, J ¼ 8.0 Hz, 2H, (400 MHz, CDCl3) d ¼ 8.37 (d, J ¼ 8.8 Hz, 1H), 7.77 (d, J ¼
aromatic) (rotameric), 4.74 (s, 2H, CH2) and 4.61 (s, 2H, CH2) 8.8 Hz, 1H), 7.67–7.58 (m, 4H), 7.45 (d, J ¼ 6.7 Hz, 2H), 5.37
(rotameric), 4.47 (s, 2H, CH2) and 3.89 (s, 2H, CH2) (rotameric), (s, 2H), 3.05 (Sept, J ¼ 6.9 Hz, 1H), 1.28 (d, J ¼ 6.9 Hz, 6H);
4.11 (s, 2H, CH2) and 4.03 (s, 2H, CH2) (rotameric), 2.22 (s, 3H, 13C {1H} NMR (100 MHz, CDCl3) d ¼ 168.9, 150.5, 149.7,
NHPhCH3) and 2.20 (s, 3H, NHPhCH3) (rotameric); 13C {1H} 143.4, 143.1, 133.8, 132.4, 131.3, 130.5, 129.4, 129.3, 128.8,
NMR (125 MHz, CDCl3, rotamers) d ¼ 169.7 and 169.6 (rota- 127.9, 121.7, 67.8, 34.5, 23.6; HRMS (ESI-TOF) m/z: [M + H]+
meric C]O), 145.3 and 145.2 (rotameric), 136.5 and 135.6 calcd for C20H18NO2 304.1332; found 304.1328.
(rotameric), 132.9 and 132.6 (rotameric), 129.9 and 129.9
7-(tert-Butyl)-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2c).
(rotameric), 129.2 and 129.0 (rotameric), 128.9 and 128.6 Compound 2c was isolated in 83% yield (41 mg, off white
(rotameric), 128.2 and 127.5 (rotameric), 127.92 and 127.84 solid); mp ¼ 236–238 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR
(rotameric), 127.2 and 127.1 (rotameric), 126.9 and 126.9 (500 MHz, CDCl3) d ¼ 8.33 (d, J ¼ 8.9 Hz, 1H), 7.93 (dd, J ¼ 8.9,
(rotameric), 122.6 and 121.9 (rotameric), 113.4 and 113.3 1.9 Hz, 1H), 7.82 (d, J ¼ 1.9 Hz, 1H), 7.64–7.57 (m, 3H), 7.46
(rotameric), 88.0 and 86.9 (rotameric Calkyne), 78.5 and 77.7 (dd, J ¼ 5.0, 2.8 Hz, 2H), 5.37 (s, 2H), 1.32 (s, 9H); 13C {1H}
(rotameric Calkyne), 49.5 and 49.4 (rotameric CH2), 45.9, 36.6 NMR (125 MHz, CDCl3) d ¼ 168.9, 152.6, 149.2, 143.4, 133.6,
and 35.8 (rotameric CH2), 20.6; HRMS (ESI-TOF) m/z: [M + H]+ 132.4, 130.7, 129.8, 129.4, 129.2, 128.8, 127.5, 120.3, 67.8,
calcd for C23H23N2OS (M + H)+ 375.1526; found 375.1533.
35.3, 30.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20NO2
318.1489; found 318.1483.
N-Benzyl-2-(phenylamino)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)
acetamide (3o). Compound 3k was isolated in 65% yield (64 mg,
7-Hydroxy-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2d).
1
viscous liquid); Rf ¼ 0.40 (VPE/VEA ¼ 80/20); H NMR (400 MHz, Compound 2d was isolated in 57% yield (28 mg, off white
CDCl3, rotameric mixture found in 1 : 0.96 ratio) d ¼ 1H NMR solid); mp ¼ 259–261 ꢀC; Rf ¼ 0.30 (VPE/VEA ¼ 50/50); 1H
(400 MHz, CDCl3) d 7.21–6.96 (m, 14H) (rotameric), 6.59–6.54 (m, NMR (400 MHz, CDCl3) d ¼ 9.73 (s, 1H), 8.16 (d, J ¼ 9.2 Hz,
2H) (rotameric), 6.50 (d, J ¼ 7.8 Hz, 2H) and 6.39 (d, J ¼ 7.6 Hz, 1H), 7.64 (m, 2H), 7.61–7.57 (m, 3H), 7.54 (dd, J ¼ 9.2,
2H) (rotameric), 4.71 (bs, 2H, NH) (rotameric), 4.57 (s, 2H, CH2) 2.7 Hz, 1H), 7.17 (d, J ¼ 2.7 Hz, 1H), 5.43 (s, 2H); 13C {1H}
and 4.50 (s, 2H, CH2) (rotameric), 4.17 (s, 2H, CH2) and 3.88 (s, NMR (100 MHz, CDCl3) d ¼ 169.1, 158.9, 146.6, 142.4,
2H, CH2) (rotameric), 3.79 (s, 2H, CH2) and 3.75 (s, 2H, CH2) 141.4, 134.8, 134.3, 133.3, 130.3, 129.8, 129.7, 129.6, 124.0,
(rotameric), 0.00 (s, 9H, TMS) and 0.00 (s, 9H, TMS) (rotameric); 106.8, 68.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
13C {1H} NMR (100 MHz, CDCl3, rotamers) d ¼ 169.3 and 169.1
C
17H12NO3 278.0812; found 278.0809.
7-Methoxy-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2e).
(rotameric C]O), 147.3 and 147.2 (rotameric), 136.3 and 135.4
(rotameric), 129.2 and 129.1 (rotameric), 128.9 and 126.6 (rota- Compound 2e was isolated in 61% yield (30 mg, off white
meric), 128.6 and 128.4 (rotameric), 127.9 and 127.7 (rotameric), solid); mp ¼ 242.5–244.5 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 60/40); 1H
117.6 (rotameric), 112.9 (rotameric), 99.7 and 98.8 (rotameric), NMR (500 MHz, CDCl3) d ¼ 8.31 (d, J ¼ 9.3 Hz, 1H), 7.61 (m,
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3H), 7.49 (dd, J ¼ 9.3, 2.6 Hz, 1H), 7.45 (d, J ¼ 7.1 Hz, 2H), 1.6 Hz, 2H), 5.39 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3)
7.10 (d, J ¼ 2.6 Hz, 1H), 5.34 (s, 2H), 3.80 (s, 3H); 13C {1H} d ¼ 167.9, 147.1, 144.7, 135.8, 133.2, 130.8, 129.8, 129.4,
NMR (125 MHz, CDCl3) d ¼ 168.9, 160.1, 147.0, 141.8, 141.7, 129.3, 128.9, 128.8 (two 13C), 124.9, 67.5; HRMS (ESI-TOF)
133.9, 133.1, 132.8, 129.5, 129.4 (two 13C), 128.6, 123.9, m/z: [M + H]+ calcd for C17H11ClNO2 296.0478.; found
102.9, 67.7, 55.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 296.0480.
C
18H14NO3 292.0968; found 292.0965.
5,7-Dimethyl-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2l).
7-Phenoxy-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2f). Compound 2l was isolated in 69% yield (34 mg, off white
Compound 2f was isolated in 64% yield (32 mg, off white solid); mp ¼ 177–179 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR
solid); mp ¼ 232–234 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 50/50); 1H (400 MHz, CDCl3) d ¼ 7.63–7.54 (m, 3H), 7.52 (s, 1H), 7.45 (s,
NMR (400 MHz, CDCl3) d ¼ 8.39 (d, J ¼ 9.3 Hz, 1H), 7.55 (m, 1H), 7.43–7.41 (m, 2H), 5.33 (s, 2H), 2.90 (s, 3H), 2.45 (s, 3H);
4H), 7.43–7.33 (m, 5H), 7.16 (t, J ¼ 7.4 Hz, 1H), 7.04 (d, J ¼ 13C {1H} NMR (100 MHz, CDCl3) d ¼ 169.3, 148.6, 142.7,
7.9 Hz, 2H), 5.38 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3) 142.0, 139.5, 139.1, 134.1, 133.1, 132.4, 129.2, 129.1, 128.8,
d ¼ 168.7, 158.0, 155.7, 147.5, 143.0, 142.4, 133.3, 133.3, 128.0, 122.2, 67.7, 22.1, 18.5; HRMS (ESI-TOF) m/z: [M + H]+
132.9, 130.0, 129.5, 129.3 (two 13C), 128.7, 124.5, 123.9, calcd for C19H16NO2 290.1176; found 290.1173.
119.6, 110.9, 67.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
23H16NO3 354.1125; found 354.1121.
7-(tert-Butyl)-9-(p-tolyl)furo[3,4-b]quinolin-3(1H)-one (2m).
Compound 2m was isolated in 80% yield (39 mg, pale yellow
C
1
ꢀ
7-Fluoro-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2g). Compound solid); mp ¼ 205–207 C; Rf ¼ 0.40(VPE/VEA ¼ 60/40); H NMR
2g was isolated in 79% yield (39 mg, off white solid); mp ¼ 218– (400 MHz, CDCl3) d ¼ 8.33 (d, J ¼ 8.8 Hz, 1H), 7.93 (dd, J ¼ 9.0,
220 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (400 MHz, CDCl3) d ¼ 2.1 Hz, 1H), 7.86 (d, J ¼ 2.0 Hz, 1H), 7.41 (d, J ¼ 8.0 Hz, 2H),
8.40 (dd, J ¼ 9.4, 5.6 Hz, 1H), 7.65–7.58 (m, 4H), 7.49 (dd, J ¼ 9.8, 7.35 (d, J ¼ 8.0 Hz, 2H), 5.37 (s, 2H), 2.49 (s, 3H), 1.33 (s, 9H);
2.8 Hz, 1H), 7.46–7.42 (m, 2H), 5.39 (s, 2H); 13C {1H} NMR (100 MHz, 13C {1H} NMR (100 MHz, CDCl3) d ¼ 169.0, 152.4, 149.3, 143.6,
CDCl3) d ¼ 168.4, 162.2 (d, J ¼ 253.1 Hz), 147.7, 143.8 (d, J ¼ 2.8 Hz), 143.4, 139.5, 132.4, 130.7, 130.6, 129.9, 129.7, 128.7, 127.6,
143.3 (d, J ¼ 6.4 Hz), 133.9 (d, J ¼ 9.6 Hz), 132.9 (d, J ¼ 5.9 Hz), 129.8, 120.4, 67.9, 35.4, 30.9, 21.4; HRMS (ESI-TOF) m/z: [M + H]+
129.5, 129.0 (d, J ¼ 9.9 Hz), 128.6, 121.4 (d, J ¼ 26.5 Hz), 109.1 (d, J ¼ calcd for C22H22NO2 332.1645; found 332.1642.
23.6 Hz), 67.7; 19F NMR (376 MHz, CDCl3) d ¼ ꢂ107.1; HRMS (ESI-
7-(tert-Butyl)-9-(4-isopropylphenyl)furo[3,4-b]quinolin-3(1H)-one
TOF) m/z: [M + H]+ calcd for C17H11FNO2 280.0768; found 280.0765. (2n). Compound 2n was isolated in 76% yield (38 mg, off white
7-Chloro-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2h). solid); mp ¼ 239–241 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (500
Compound 2h was isolated in 76% yield (38 mg, off white MHz, CDCl3) d ¼ 8.35 (d, J ¼ 9.0 Hz, 1H), 7.94 (d, J ¼ 9.1 Hz, 1H),
solid); mp ¼ 216–218 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H 7.89 (s, 1H), 7.46 (d, J ¼ 7.8 Hz, 2H), 7.38 (d, J ¼ 7.9 Hz, 2H), 5.40 (s,
NMR (400 MHz, CDCl3) d ¼ 8.23 (d, J ¼ 9.1 Hz, 1H), 7.80 (s, 2H), 3.05 (sept, J ¼ 6.8 Hz, 1H), 1.36 (d, J ¼ 7.1 Hz, 6H), 1.35 (s, 9H);
1H), 7.72–7.65 (m, 1H), 7.65–7.55 (m, 3H), 7.47–7.42 (m, 13C {1H} NMR (125 MHz, CDCl3) d ¼ 169.1, 152.4, 150.3, 149.4,
2H), 5.36 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 168.2, 143.6, 143.5, 132.5, 131.0, 130.8, 129.7, 128.9, 127.7, 127.3, 120.5,
148.7, 144.3, 143.0, 135.6, 133.1, 132.7, 132.5, 131.6, 129.7, 68.0, 35.4, 34.0, 30.9, 23.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
129.4, 128.7, 128.3, 124.4, 67.7; HRMS (ESI-TOF) m/z: [M + C24H26NO2 360.1958; found 360.1953.
H]+ calcd for C17H11ClNO2 296.0473; found 296.0469.
7-(tert-Butyl)-9-(4-methoxyphenyl)furo[3,4-b]quinolin-3(1H)-
7-Bromo-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2i). Compound one (2o). Compound 2o was isolated in 57% yield (28 mg, off
1
ꢀ
2i was isolated in 75% yield (37 mg, yellow solid); mp ¼ 219–221 ꢀC; white solid); mp ¼ 262–264 C; Rf ¼ 0.35 (VPE/VEA ¼ 60/40); H
Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (500 MHz, CDCl3) d ¼ 8.26 (d, J NMR (400 MHz, CDCl3) d ¼ 8.34 (d, J ¼ 9.0 Hz, 1H), 7.93 (dd, J ¼
¼ 9.1 Hz, 1H), 8.03 (d, J ¼ 1.2 Hz, 1H), 7.90 (d, J ¼ 9.0 Hz, 1H), 7.65– 9.0, 1.7 Hz, 1H), 7.88 (s, 1H), 7.40 (d, J ¼ 8.5 Hz, 2H), 7.13 (d, J ¼
7.59 (m, 3H), 7.44 (d, J ¼ 7.4 Hz, 2H), 5.39 (s, 2H); 13C {1H} NMR (125 8.5 Hz, 2H), 5.39 (s, 2H), 3.94 (s, 3H), 1.35 (s, 9H); 13C {1H} NMR
MHz, CDCl3) d ¼ 168.2, 149.2, 144.6, 143.1, 134.3, 133.1, 132.8, (100 MHz, CDCl3) d ¼ 169.1, 160.4, 152.4, 149.3, 143.5, 143.3,
129.9, 129.5, 128.9, 128.7, 127.9, 124.2, 67.7; HRMS (ESI-TOF) m/z: 132.5, 130.8, 130.3, 129.7, 127.8, 125.7, 120.4, 114.7, 67.9, 55.4,
[M + H]+ calcd for C17H11BrNO2 339.9968; found 339.9963.
3-Oxo-9-phenyl-1,3-dihydrofuro[3,4-b]quinoline-7-carbonitrile 348.1594; found 348.1589.
35.4, 30.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H22NO3
(2j). Compound 2j was isolated in 45% yield (23 mg, viscous
7-(tert-Butyl)-9-(4-uorophenyl)furo[3,4-b]quinolin-3(1H)-one
1
liquid); Rf ¼ 0.40 (VPE/VEA ¼ 50/50); H NMR (400 MHz, CDCl3) (2p). Compound 2p was isolated in 78% yield (39 mg, yellow
1
ꢀ
d ¼ 8.51 (d, J ¼ 8.8 Hz, 1H), 8.30 (d, J ¼ 1.5 Hz, 1H), 7.97 (dd, J ¼ solid); mp ¼ 299–301 C; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); H NMR
8.7, 1.7 Hz, 1H), 7.71–7.62 (m, 3H), 7.47–7.42 (m, 2H), 5.45 (s, 2H); (400 MHz, CDCl3) d ¼ 8.31 (d, J ¼ 9.0 Hz, 1H), 7.93 (dd, J ¼ 9.0,
13C {1H} NMR (100 MHz, CDCl3) d ¼ 167.7, 151.2, 146.9, 145.1, 2.1 Hz, 1H), 7.76 (d, J ¼ 2.0 Hz, 1H), 7.50–7.44 (m, 2H), 7.33 (m,
133.5, 132.8, 132.4, 131.9, 130.9, 130.4, 129.7, 128.7, 127.2, 117.9, 2H), 5.34 (s, 2H), 1.33 (s, 9H); 13C {1H} NMR (100 MHz, CDCl3) d ¼
112.9, 67.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H11N2O2 168.7, 163.2 (d, J ¼ 250.2 Hz), 152.8, 149.2, 143.4, 142.3, 132.5,
287.0778.; found 287.0824.
130.8, 130.7, 129.9, 129.6 (d, J ¼ 3.6 Hz), 127.6, 120.0, 116.5 (d, J ¼
5-Chloro-9-phenylfuro[3,4-b]quinolin-3(1H)-one (2k). 21.8 Hz), 67.7, 35.4, 30.8; 19F NMR (376 MHz, CDCl3) d ¼ ꢂ110.9;
Compound 2k was isolated in 51% yield (25 mg, off white HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H18FNO2Na 358.1214;
solid); mp ¼ 246–248 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 50/50); 1H found 358.1208.
NMR (400 MHz, CDCl3) d ¼ 7.96 (dd, J ¼ 7.4, 0.8 Hz, 1H),
7-(tert-Butyl)-9-(4-chlorophenyl)furo[3,4-b]quinolin-3(1H)-one
7.86–7.80 (m, 1H), 7.64–7.55 (m, 4H), 7.45 (dd, J ¼ 7.7, (2q). Compound 2q was isolated in 77% yield (38 mg, pale yellow
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1
ꢀ
solid); mp ¼ 265–267 C; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); H NMR 128.7, 128.3, 127.8, 121.7, 68.2, 34.5, 23.6; HRMS (ESI-TOF) m/z: [M +
(400 MHz, CDCl3) d ¼ 8.33 (d, J ¼ 9.0 Hz, 1H), 7.94 (dd, J ¼ 8.9, H]+ calcd for C18H16NO2S 310.0896; found 310.0891.
1.9 Hz, 1H), 7.76 (d, J ¼ 2.1 Hz, 1H), 7.61 (d, J ¼ 8.4 Hz, 2H), 7.42
7,9-Dimethylfuro[3,4-b]quinolin-3(1H)-one (2w). Compound
(d, J ¼ 8.4 Hz, 2H), 5.35 (s, 2H), 1.34 (s, 9H); 13C {1H} NMR (100 2w was isolated in 17% yield (11 mg, brown solid); mp ¼ 213–
MHz, CDCl3) d ¼ 168.7, 152.9, 149.2, 143.5, 142.1, 135.7, 132.4, 215 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 50/50); 1H NMR (400 MHz, CDCl3)
132.1, 130.8, 130.2, 130.0, 129.6, 127.3, 119.9, 67.6, 35.4, 30.8; d ¼ 8.25 (d, J ¼ 8.8 Hz, 1H), 7.85 (s, 1H), 7.67 (dd, J ¼ 8.7, 1.6 Hz,
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H19ClNO2 352.1099; 1H), 5.49 (s, 2H), 2.69 (s, 3H), 2.63 (s, 3H); 13C {1H} NMR (100
found 352.1096.
MHz, CDCl3) d ¼ 169.2, 148.5, 143.0, 139.7, 138.7, 133.0, 131.5,
7-(tert-Butyl)-9-(4-nitrophenyl)furo[3,4-b]quinolin-3(1H)-one 129.1, 122.4, 67.7, 22.3, 14.6; HRMS (ESI-TOF) m/z: [M + H]+
(2r). Compound 2r was isolated in 75% yield (37 mg, yellow calcd for C13H12NO2 214.0878; found 214.0869.
1
ꢀ
solid); mp ¼ 310–312 C; Rf ¼ 0.35 (VPE/VEA ¼ 60/40); H NMR
7-Methyl-2,9-diphenyl-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-3-
(500 MHz, CDCl3) d ¼ 8.50 (d, J ¼ 8.6 Hz, 2H), 8.37 (d, J ¼ 9.0 Hz, one (4a). Compound 4a was isolated in 80% yield (39 mg, brown
1H), 7.99 (dd, J ¼ 9.0, 2.0 Hz, 1H), 7.70 (d, J ¼ 8.6 Hz, 2H), 7.65 solid); mp ¼ 247–249 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 40/60); 1H NMR (500
(d, J ¼ 1.9 Hz, 1H), 5.35 (s, 2H), 1.34 (s, 9H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 8.32 (d, J ¼ 8.7 Hz, 1H), 7.88 (d, J ¼ 7.9 Hz, 2H),
MHz, CDCl3) d ¼ 168.2, 153.7, 149.3, 148.5, 143.6, 140.7, 140.5, 7.66–7.58 (m, 4H), 7.54 (s, 1H), 7.51–7.47 (m, 2H), 7.40 (t, J ¼
132.2, 131.1, 130.4, 130.1, 126.9, 124.5, 119.5, 67.3, 35.5, 30.8; 8.0 Hz, 2H), 7.18 (t, J ¼ 7.4 Hz, 1H), 4.79 (s, 2H), 2.48 (s, 3H); 13
C
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H19N2O4 363.1339; {1H} NMR (125 MHz, CDCl3) d ¼ 165.6, 150.0, 148.7, 142.8, 139.4,
found 363.1333.
138.7, 134.6, 132.5, 130.9, 129.3 (two 13C), 129.2, 129.1, 127.9,
7-(tert-Butyl)-9-(3-chloro-4-methylphenyl)furo[3,4-b]quinolin-
127.7, 125.3, 124.5, 119.7, 48.3, 22.1; HRMS (ESI-TOF) m/z: [M + H]+
3(1H)-one (2s). Compound 2s was isolated in 73% yield (36 mg, calcd for C24H19N2O 351.1492; found 351.1494.
off white solid); mp ¼ 241–243 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 60/40); 1H
7-Methoxy-2,9-diphenyl-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-3-
NMR (400 MHz, CDCl3) d ¼ 8.36 (d, J ¼ 9.0 Hz, 1H), 7.96 (dd, J ¼ one (4b). Compound 4b was isolated in 52% yield (26 mg, yellow
9.0, 2.1 Hz, 1H), 7.81 (d, J ¼ 2.0 Hz, 1H), 7.48 (d, J ¼ 7.8 Hz, 1H), solid); mp ¼ 236–238 ꢀC; Rf ¼ 0.30 (VPE/VEA ¼ 30/70); 1H NMR (400
7.46 (d, J ¼ 1.7 Hz, 1H), 7.27 (dd, J ¼ 7.8, 1.8 Hz, 1H), 5.38 (s, 2H), MHz, CDCl3) d ¼ 8.33 (d, J ¼ 9.3 Hz, 1H), 7.88 (d, J ¼ 8.0 Hz, 2H),
2.52 (s, 3H), 1.35 (s, 9H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 7.61 (m, 3H), 7.50 (d, J ¼ 6.8 Hz, 2H), 7.45–7.38 (m, 3H), 7.17 (t, J ¼
168.7, 152.9, 149.3, 143.5, 141.9, 137.7, 135.4, 132.7, 132.4, 131.8, 7.3 Hz, 1H), 7.04 (d, J ¼ 2.5 Hz, 1H), 4.78 (s, 2H), 3.78 (s, 3H); 13
C
130.9, 129.9, 129.2, 127.4, 127.1, 120.0, 67.7, 35.4, 30.9, 20.1; {1H} NMR (100 MHz, CDCl3) d ¼ 165.5, 159.2, 148.4, 146.1, 141.7,
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H21ClNO2 366.1255; 139.2, 134.6, 132.5, 129.3, 129.2, 129.1, 129.1, 128.8, 128.1, 125.1,
found 366.1251.
7-(tert-Butyl)-9-(3,5-dimethylphenyl)furo[3,4-b]quinolin-3(1H)-
one (2t). Compound 2t was isolated in 74% yield (37 mg, yellow
122.7, 119.5, 103.3, 55.5, 48.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C24H19 N2O2 367.1441 found 367.1435.
2-Benzyl-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-3-one
solid); mp ¼ 214.5–216.5 ꢀC; Rf ¼ 0.45 (VPE/VEA ¼ 60/40); 1H NMR (4c). Compound 4c was isolated in 84% yield (41 mg, yellow solid);
(500 MHz, CDCl3) d ¼ 8.34 (d, J ¼ 9.0 Hz, 1H), 7.93 (dd, J ¼ 9.0, mp ¼ 192–194 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 30/70); 1H NMR (500 MHz,
1.0 Hz, 1H), 7.86 (s, 1H), 7.19 (s, 1H), 7.05 (s, 2H), 5.38 (s, 2H), 2.43 CDCl3) d ¼ 8.45 (d, J ¼ 8.4 Hz, 1H), 7.78 (t, J ¼ 8.5 Hz, 2H), 7.58–
(s, 6H), 1.34 (s, 9H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 169.0, 7.50 (m, 4H), 7.38 (m, 2H), 7.34–7.27 (m, 5H), 4.89 (s, 2H), 4.24 (s,
152.3, 149.3, 143.8, 143.5, 138.9, 133.6, 132.3, 130.9, 130.7, 129.7, 2H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 166.4, 150.7, 149.6, 143.5,
127.7, 126.5, 120.6, 67.9, 35.3, 30.9, 21.3; HRMS (ESI-TOF) m/z: [M 136.2, 134.3, 131.1, 129.8, 128.9, 128.8, 128.3 (two 13C), 128.0,
+ H]+ calcd for C23H24NO2 346.1802; found 346.1797.
127.9, 127.5, 125.6, 47.2, 46.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd
7-(tert-Butyl)-9-(2-methoxyphenyl)furo[3,4-b]quinolin-3(1H)- for C24H19N2O 351.1492; found 351.1487.
one (2u). Compound 2u was isolated in 56% yield (28 mg, off
2-Benzyl-7-methyl-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-b]
1
ꢀ
white solid); mp ¼ 257–259 C; Rf ¼ 0.30 (VPE/VEA ¼ 60/40); H quinolin-3-one (4d). Compound 4d wꢀas isolated in 82% yield
NMR (400 MHz, CDCl3) d ¼ 8.35 (d, J ¼ 9.0 Hz, 1H), 7.92 (dd, J ¼ (40 mg, yellow solid); mp ¼ 204–206 C; Rf ¼ 0.40 (VPE/VEA
¼
9.0, 1.9 Hz, 1H), 7.68 (d, J ¼ 1.6 Hz, 1H), 7.57–7.53 (m, 1H), 7.30– 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.29 (d, J ¼ 8.7 Hz, 1H),
7.27 (m, 1H), 7.20–7.13 (m, 2H), 5.35 (d, J ¼ 15.0 Hz, 1H), 5.25 (d, 7.58 (dd, J ¼ 8.7, 1.5 Hz, 1H), 7.55–7.46 (m, 4H), 7.36–7.33 (m,
J ¼ 15.0 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H); 13C {1H} NMR (100 2H), 7.29–7.23 (m, 5H), 4.85 (s, 2H), 4.19 (s, 2H), 2.43 (s, 3H);
MHz, CDCl3) d ¼ 169.2, 156.4, 152.1, 149.2, 143.3, 140.5, 133.7, 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.5, 149.7, 148.1,
131.2, 130.9, 130.7, 129.6, 128.2, 121.9, 120.9, 120.6, 111.6, 68.3, 142.6, 138.2, 136.3, 134.4, 132.1, 130.6, 128.9 (two 13C), 128.8,
55.4, 35.3, 30.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 128.8, 128.4, 128.2, 127.8, 127.4, 124.3, 47.0, 46.7, 21.9;
C
22H22NO3 348.1594; found 348.1590.
7-iso-Propyl-9-(thiophen-2-yl)furo[3,4-b]quinolin-3(1H)-one (2v). found 365.1653.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H21N2O 365.1648;
Compound 2v was isolated in 77% yield (38 mg, brown solid); mp ¼
2-Benzyl-7-methoxy-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-
157–159 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 60/40); 1H NMR (400 MHz, CDCl3) b]quinolin-3-one (4e). Compound 4e was isolated in 59%
d ¼ 8.33 (d, J ¼ 8.8 Hz, 1H), 8.07 (d, J ¼ 1.8 Hz, 1H), 7.77 (dd, J ¼ 8.8, yield (29 mg, brown solid); mp ¼ 179–181 ꢀC; Rf ¼ 0.35 (VPE
/
1.9 Hz, 1H), 7.67 (dd, J ¼ 5.1, 1.1 Hz, 1H), 7.38 (dd, J ¼ 3.5, 1.2 Hz, VEA ¼ 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.31 (d, J ¼
1H), 7.33 (dd, J ¼ 5.1, 3.5 Hz, 1H), 5.50 (s, 2H), 3.11 (sept, J ¼ 6.9 Hz, 9.2 Hz, 1H), 7.57–7.51 (m, 3H), 7.43–7.39 (m, 3H), 7.31–7.27
1H), 1.32 (d, J ¼ 6.9 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ (m, 5H), 6.98 (d, J ¼ 2.6 Hz, 1H), 4.87 (s, 2H), 4.21 (s, 2H),
168.7, 150.9, 149.7, 143.3, 136.1, 133.6, 132.6, 131.3, 130.7, 129.9, 3.75 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.6,
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158.9, 148.3, 145.6, 141.7, 136.3, 134.5, 132.4, 129.0, 128.9, 21.9, 21.3; HRMS (ESI-TOF) m/z: [M
+
H]+ calcd for
128.8, 128.7 (two 13C), 128.2, 127.8, 122.4, 103.3, 55.4, 46.9,
46.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H21N2O2;
381.1598 found 381.1597.
C
26H23N2O 379.1805; found 379.1801.
2-Benzyl-9-(4-methoxyphenyl)-7-methyl-1,2-dihydro-3H-pyr-
rolo [3,4-b]quinolin-3-one (4k). Compound 4k was isolated in
2-Benzyl-7-chloro-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-b] 75% yield (37 mg, yellow solid); mp ¼ 190–192 ꢀC; Rf ¼ 0.35
1
quinolin-3-one (4f). Compound 4f was isolated in 81% yield (VPE/VEA ¼ 30/70); H NMR (400 MHz, CDCl3) d ¼ 8.29 (d, J ¼
(40 mg, brown solid); mp ¼ 224–226 ꢀC; Rf ¼ 0.40 (VPE/VEA
¼
8.6 Hz, 1H), 7.58 (dd, J ¼ 8.7, 1.8 Hz, 1H), 7.54 (s, 1H), 7.34–7.27
30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.33 (d, J ¼ 8.6 Hz, (m, 7H), 7.07 (d, J ¼ 8.7 Hz, 2H), 4.86 (s, 2H), 4.22 (s, 2H), 3.90 (s,
1H), 7.70 (s, 1H), 7.68 (d, J ¼ 2.3 Hz, 1H), 7.59–7.51 (m, 3H), 3H), 2.46 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.54,
7.37 (m, 2H), 7.33–7.27 (m, 5H), 4.88 (s, 2H), 4.24 (s, 2H); 13
C
159.91, 149.66, 148.11, 142.47, 138.03, 136.29, 131.98, 130.57,
{1H} NMR (100 MHz, CDCl3) d ¼ 165.9, 150.9, 147.8, 142.7, 130.30, 128.75, 128.53, 128.23, 127.74, 127.67, 126.41, 124.34,
136.0, 134.1, 133.5, 132.5, 130.8, 129.3, 129.2, 129.1, 128.9 114.36, 55.31, 47.00, 46.82, 21.90; HRMS (ESI-TOF) m/z: [M + H]+
(two 13C), 128.3, 128.1, 127.9, 124.4, 47.1, 46.7; HRMS (ESI- calcd for C26H23N2O2 395.1754; found 395.1762.
TOF) m/z: [M + H]+ calcd for C24H18ClN2O 385.1102; found
385.1100.
2-Benzyl-9-(4-chlorophenyl)-7-methyl-1,2-dihydro-3H-pyrrolo
[3,4-b]quinolin-3-one (4l). Compound 4l was isolated in 81%
2-Benzyl-5,8-dichloro-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-b] yield (40 mg, yellow solid); mp ¼ 193–195 ꢀC; Rf ¼ 0.40 (VPE/VEA
quinolin-3-one (4g). Compound 4g was isolated in 43% yield ¼ 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.27 (d, J ¼ 8.6 Hz, 1H),
(21 mg, yellow solid); mp ¼ 231–233 ꢀC; Rf ¼ 0.45 (VPE/VEA ¼ 30/ 7.59 (dd, J ¼ 8.5, 1.3 Hz, 1H), 7.53 (d, J ¼ 8.3 Hz, 2H), 7.43 (s,
70); 1H NMR (500 MHz, CDCl3) d ¼ 7.80 (d, J ¼ 8.1 Hz, 1H), 7.53 1H), 7.36–7.26 (m, 7H), 4.85 (s, 2H), 4.19 (s, 2H), 2.46 (s, 3H); 13
C
(d, J ¼ 8.1 Hz, 1H), 7.47–7.44 (m, 3H), 7.34–7.26 (m, 7H), 4.85 (s, {1H} NMR (100 MHz, CDCl3) d ¼ 166.3, 149.6, 147.9, 141.3,
2H), 4.10 (s, 2H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 165.3, 138.5, 136.1, 135.1, 132.8, 132.2, 130.7, 130.4, 129.3, 128.8,
151.0, 147.1, 144.2, 136.3, 136.0, 135.1, 132.3, 130.4, 129.7, 128.4, 128.3, 127.9, 127.2, 123.9, 47.0, 46.6, 21.9; HRMS (ESI-
129.5, 128.8, 128.6, 128.4, 128.2, 128.1, 127.9, 125.8, 47.2, 46.9; TOF) m/z: [M + H]+ calcd for C25H20ClN2O 399.1259; found
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H17Cl2N2O (M + H)+ 399.1271.
419.0712; found 419.0703.
2-Benzyl-7-methyl-9-(4-nitrophenyl)-1,2-dihydro-3H-pyrrolo
[3,4-b]quinolin-3-one (4m). Compound 4m was isolated in 71%
2-Benzyl-9-(4-methoxyphenyl)-7-methyl-1,2-dihydro-3H-
pyrrolo [3,4-b]quinolin-3-one (4h). Compound 4h was iso- yield (35 mg, yellow solid); mp ¼ 200–202 ꢀC; Rf ¼ 0.30 (VPE/VEA
lated in 57% yield (28 mg, yellow solid); mp ¼ 197–199 ꢀC; Rf ¼ 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.43 (d, J ¼ 8.8 Hz, 2H),
¼ 0.35 (VPE/VEA ¼ 30/70); 1H NMR (500 MHz, CDCl3) d ¼ 8.31 8.34 (d, J ¼ 8.7 Hz, 1H), 7.65 (dd, J ¼ 8.7, 1.8 Hz, 1H), 7.60 (d, J ¼
(d, J ¼ 9.3 Hz, 1H), 7.41 (dd, J ¼ 9.2, 2.0 Hz, 1H), 7.34 (d, J ¼ 8.8 Hz, 2H), 7.36–7.29 (m, 6H), 4.86 (s, 2H), 4.18 (s, 2H), 2.48 (s,
7.6 Hz, 2H), 7.31–7.27 (m, 7H), 7.03 (d, J ¼ 1.7 Hz, 1H), 4.87 3H). 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.10, 149.92, 148.32,
(s, 2H), 4.20 (s, 2H), 3.76 (s, 3H), 2.46 (s, 3H); 13C {1H} NMR 148.19, 141.38, 140.16, 139.33, 136.10, 132.75, 131.06, 130.30,
(125 MHz, CDCl3) d ¼ 166.7, 158.9, 148.4, 145.7, 141.9, 129.03, 128.49, 128.31, 128.12, 126.74, 124.40, 123.63, 47.26,
138.8, 136.4, 132.4, 131.5, 129.7, 128.9, 128.9, 128.8, 128.7, 46.55, 22.11; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
128.2, 127.7, 122.4, 103.4, 55.4, 47.0, 46.8, 21.3; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C26H23N2O2 395.1754; found
395.1750.
C
25H20N3O3 410.1499; found 410.1505.
2-Benzyl-7-methyl-9-(thiophen-2-yl)-1,2-dihydro-3H-pyrrolo
[3,4-b]quinolin-3-one (4n). Compound 4n was isolated in 73%
yield (36 mg, yellow solid); mp ¼ 221–223 ꢀC; Rf ¼ 0.40 (VPE/VEA
2-Benzyl-7-chloro-9-(p-tolyl)-1,2-dihydro-3H-pyrrolo[3,4-
b]quinoline-3-one (4i). Compound 4i was isolated in 80% ¼ 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.31 (d, J ¼ 8.7 Hz, 1H),
yield (39 mg, yellow solid); mp ¼ 187–189 ꢀC; Rf ¼ 0.45 (VPE
/
7.84 (s, 1H), 7.61 (dd, J ¼ 8.7, 1.9 Hz, 1H), 7.59–7.56 (m, 1H),
VEA ¼ 30/70); 1H NMR (400 MHz, CDCl3) d ¼ 8.28 (d, J ¼ 7.36–7.31 (m, 4H), 7.31–7.23 (m, 4H), 4.90 (s, 2H), 4.36 (s, 2H),
9.0 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J ¼ 9.0 Hz, 1H), 7.37–7.27 2.51 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.42, 149.87,
(m, 9H), 4.87 (s, 2H), 4.24 (s, 2H), 2.46 (s, 3H); 13C {1H} NMR 148.32, 138.82, 136.35, 135.73, 134.26, 132.42, 130.88, 129.55,
(100 MHz, CDCl3) d ¼ 165.9, 150.8, 147.8, 142.8, 139.3, 129.27, 128.96, 128.41, 128.01, 127.97, 127.95, 127.72, 124.34,
136.0, 133.9, 132.3, 130.7, 130.5, 129.8, 129.2, 128.8, 128.2, 47.41, 47.20, 22.16; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
128.1, 127.8, 124.5, 113.9, 47.1, 46.8, 21.3; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C25H20ClN2O 399.1259; found
399.1261.
C
23H19N2OS 371.1213; found 371.1221.
2-Benzyl-9-(trimethylsilyl)-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-
3-one (4o). Compound 4o was isolated in 67% yield (33 mg, off
white solid); mp ¼ 202–204 ꢀC; Rf ¼ 0.40 (VPE/VEA ¼ 30/70); 1H NMR
2-Benzyl-7-methyl-9-(p-tolyl)-1,2-dihydro-3H-pyrrolo[3,4-
b]quinolin-3-one (4j). Compound 4j was isolated in 79% (400 MHz, CDCl3) d ¼ 8.42 (d, J ¼ 8.2 Hz, 1H), 8.16 (d, J ¼ 8.3 Hz,
yield (39 mg, yellow solid); mp ¼ 203–205 ꢀC; Rf ¼ 0.40 (VPE
/
1H), 7.75 (ddd, J ¼ 8.3, 7.0, 1.3 Hz, 1H), 7.62 (ddd, J ¼ 8.3, 7.0,
VEA ¼ 30/70); 1H NMR (500 MHz, CDCl3) d ¼ 8.33 (d, J ¼ 1.3 Hz, 1H), 7.41–7.27 (m, 5H), 4.94 (s, 2H), 4.46 (s, 2H), 0.51 (s, 9H);
8.7 Hz, 1H), 7.61 (d, J ¼ 7.8 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J ¼ 13C {1H} NMR (100 MHz, CDCl3) d ¼ 166.0, 149.3, 148.1, 142.9,
7.7 Hz, 2H), 7.33–7.25 (m, 7H), 4.89 (s, 2H), 4.23 (s, 2H), 2.47 136.2, 135.7, 132.3, 132.1, 129.1, 128.9, 128.3, 127.9, 127.8, 127.4,
(s, 6H); 13C {1H} NMR (125 MHz, CDCl3) d ¼ 166.6, 149.8, 49.3, 47.1, 1.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H23N2OSi
148.2, 142.8, 138.8, 138.1, 136.4, 132.1, 131.5, 130.7, 129.6, (M + H)+ 347.1578; found 347.1581.
128.9, 128.8, 128.5, 128.3, 127.8, 127.6, 124.4, 47.1, 46.8,
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Paper
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9-((Benzyloxy)methyl)-7-methoxy-1-methylfuro[3,4-b]quino-
lin-3(1H)-one (6). Compound 7 was isolated in 41% yield
(21 mg, yellow solid); mp ¼ 174–176 ꢀC; Rf ¼ 0.35 (VPE/VEA ¼ 30/
70); 1H NMR (400 MHz, CDCl3) d ¼ 8.26 (d, J ¼ 9.3 Hz, 1H), 7.47
(dd, J ¼ 9.3, 2.7 Hz, 1H), 7.41–7.36 (m, 5H), 7.18 (d, J ¼ 2.7 Hz,
1H), 5.88 (q, J ¼ 6.5 Hz, 1H), 5.06 (ABq, J ¼ 13.20 Hz, 2H), 4.71
(ABq, J ¼ 11.74 Hz, 2H), 3.92 (s, 3H), 1.68 (d, J ¼ 6.5 Hz, 3H); 13
C
{1H} NMR (100 MHz, CDCl3) d ¼ 168.2, 160.1, 146.3, 142.3,
137.8, 136.7, 136.3, 133.2, 129.0, 128.7, 128.4, 128.1, 123.7,
101.2, 76.8, 73.7, 65.9, 55.7, 21.1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C21H20NO4 350.1387; found 350.1380.
9-Phenyl-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-3-one (7).
Compound 7 was isolated in 88% yield (65 mg, grey solid);
mp ¼ 279–281 ꢀC (decomposed); Rf ¼ 0.40 (VDCM/VMeOH ¼ 90/
10); 1H NMR (400 MHz DMSO d6) d ¼ 9.26 (bs, 1H), 8.26 (d, J ¼
8.4 Hz, 1H), 7.87 (t, J ¼ 7.4 Hz, 1H), 7.79 (d, J ¼ 8.3 Hz, 1H),
7.67 (t, J ¼ 7.4 Hz, 1H), 7.58–7.62 (m, 5H), 4.38 (s, 2H); 13C
{1H} NMR (100 MHz, DMSO d6) d ¼ 167.6, 151.4, 148.7, 142.9,
133.9, 131.0, 130.3, 129.7, 129.2, 128.9 (two 13C), 128.1, 126.6,
125.4, 42.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
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G. D. Tamagnan, A. J. Chalmers, D. Dewar, S. L. Pimlott
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A. Blair, L. Stevenson, D. Dewar, S. L. Pimlott and
A. Sutherland, MedChemComm, 2013, 4, 1461–1466; (c)
L. Stevenson, A. A. S. Tavares, A. Brunet, F. I. McGonagle,
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C
17H13N2O 261.1022; found 261.1019.
7-Methyl-9-phenyl-1,2-dihydro-3H-pyrrolo[3,4-b]quinolin-3-
one (8). Compound 8 was isolated in 86% yield (65 mg, grey
solid); mp ¼ 317–319 ꢀC (decomposed); Rf ¼ 0.40 (VDCM/VMeOH
¼ 90/10); 1H NMR (400 MHz, DMSO d6) d ¼ 9.19 (bs, 1H), 8.15
(d, J ¼ 8.5 Hz, 1H), 7.70 (d, J ¼ 8.4 Hz, 1H), 7.62–7.52 (m, 6H),
4.34 (s, 2H), 2.45 (s, 3H); 13C {1H} NMR (100 MHz, DMSO d6) d ¼
168.2, 151.0, 147.9, 142.7, 138.3, 134.5, 132.4, 131.7, 130.6,
129.7, 129.4, 129.3, 127.0, 124.3, 42.5, 22.0; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C18H15N2O 275.1179; found 275.1176.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Generous nancial support from CSIR-New Delhi (HCP0008) is
gratefully acknowledged. DAM and ACS thank UGC and CSIR
for the award of a senior research fellowship.
6 (a) L. Stevenson, A. A. S. Tavares, A. Brunet, F. I. McGonagle,
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Lett., 2010, 20, 954–957; (b) D. Osborne and P. J. Stevenson,
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RSC Adv., 2019, 9, 30277–30291 | 30291