A copper(II)-mediated radical cross-dehydrogenative coupling/sulfinic acid elimination approach to 2-quinolones

Article abstract of DOI:10.1016/j.tet.2019.130711

A new cyclisation procedure to prepare 4-carboxy-quinolin-2-ones via a one-pot Cu(II)-mediated radical cross-dehydrogenative coupling/sulfinic acid elimination of linear anilides is described. Extensions to more complex substrates are also reported as are

Full text of DOI:10.1016/j.tet.2019.130711

Tetrahedron 75 (2019) 130711
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A copper(II)-mediated radical cross-dehydrogenative coupling/sulfinic
acid elimination approach to 2-quinolones
Ryan M. Gorman, Timothy E. Hurst**, Wade F. Petersen, Richard J.K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new cyclisation procedure to prepare 4-carboxy-quinolin-2-ones via a one-pot Cu(II)-mediated radical
cross-dehydrogenative coupling/sulfinic acid elimination of linear anilides is described. Extensions to
more complex substrates are also reported as are applications in target synthesis allowing access to
natural products isolated from Oryza sativa and HOFQ.
Received 27 August 2019
Received in revised form
14 October 2019
Accepted 16 October 2019
Available online 21 October 2019
© 2019 Elsevier Ltd. All rights reserved.
Dedicated to Professor Steve Davies to
acknowledge his many seminal research
achievements, his contributions to Tetrahe-
dron: Asymmetry e and his unfailing
friendship over the years
Keywords:
2-Quinolones
Cross-dehydrogenative coupling
Cu(II)-catalysis
Total synthesis
1. Introduction
(psoralens), a class of active sensitisers used in PUVA (psoralen plus
UVA) photochemotherapy and photopheresis for the treatment of
The 2-quinolone scaffold is an attractive synthetic target due to
its presence in a diverse array of both naturally occurring and
biologically active molecules (Fig. 1) [1]. Examples of 2-quinolone
containing natural products range from simple congeners such as
1a-b (isolated from Oryza sativa, also known as purple rice) [2], to
more complex members such as isaindigotidione 2, isolated from
the roots of Isatis indigotica which has found broad utility in
traditional Chinese medicine [3]. Furthermore, 2-quinolones have
been shown to possess potent bioactivity, including as inhibitors of
farnesyl protein transferase (e.g. Zarnestra) [4], as FMS and P38
MAP kinase inhibitors [5], as well as possessing anti-Hepatitis B [6],
anti-bacterial [7], and anti-cancer [8] activities and as a potential
treatment for Chagas disease [9]. In addition, 4-hydroxymethyl-
1,6,8-trimethylfuro[2,3-h]quinolin-2(1H)-one (HOFQ, 3) has been
identified as a promising new member of the furocoumarins
various skin diseases, T-cell lymphoma and organ transplant
rejection [10].
Given their promiscuous bioactivity and utility as synthetic in-
termediates (e.g. as ligand precursors) [11], it is therefore of no
surprise that the synthesis of 2-quinolones has been widely
explored by a variety of methods. In particular, formation of the
C4eC4a bond has emerged as a powerful tool in the preparation of
€
2-quinolones. Examples include via Friedlander cyclisation [12],
iodocyclisation [13], isatin ring expansion [14], metal-free oxidative
* Corresponding author.
** Corresponding author.
E-mail address: richard.taylor@york.ac.uk (R.J.K. Taylor).
Fig. 1. Examples of naturally occurring and biologically active quinolones.
https://doi.org/10.1016/j.tet.2019.130711
0040-4020/© 2019 Elsevier Ltd. All rights reserved.

2
R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
i
k
Scheme 2. Synthesis of anilide cyclisation precursors.
Scheme 1. Synthesis of quinolones via a one-pot cross-dehydrogenative coupling/
sulfinic acid elimination strategy.
cyclisation [15], and superelectrophilic activation [16].
In a related approach, Chuang and coworkers have reported the
manganese(III) acetate mediated oxidative free radical cyclisation
of linear anilides 4 to give 4-carboxy-2-quinolones 6 (Scheme 1)
[17]. The cyclisation itself may be considered as a radical cross-
dehydrogenative coupling (CDC) to give key intermediate 5,
which subsequently undergoes rapid b-elimination of the sulfinic
acid in situ to deliver the 2-quinolone 6. In terms of the substrate
scope, higher yields and lower reaction times were observed when
ketones were used as the substrate (R4 ¼ Alk or Ar, 6 h, 62e88%
yield) compared to the corresponding esters (R4 ¼ OEt, 40 h,
41e53% yield). Furthermore, a large excess of manganese(III) ace-
tate is required (up to 4 equiv), especially in the case of ester sub-
strates. Finally, the reaction must be performed in acetic acid as the
solvent, thereby limiting the potential functional group
compatibility.
In light of our recent work on the copper-catalysed synthesis of
varied 5- and 6-membered nitrogen heterocycles under mild con-
ditions, we sought to develop a copper(II)-mediated approach to
quinolones [18]. In particular, we hoped to reduce the amount of
transition metal salt required and avoid the use of neat acid as a
solvent, while improving the yields and reducing the reaction times
with respect to ester substrates. As such, we wish to report the
synthesis of 4-carboxy-quinolin-2-ones via a one-pot Cu(II)-medi-
ated radical cross-dehydrogenative coupling/sulfinic acid elimina-
tion of linear anilides (Scheme 1) and its extension to related
quinolones and to target synthesis.
2. Results and discussion
The linear substrates required to test the cyclisation were readily
prepared in
2 steps from commercially available materials.
Coupling of anilines 7 with bromoacetyl bromide derivatives 8 gave
the bromoacetamides 9a-l, which underwent alkylation upon
treatment with the appropriate activated methylene compound
under basic conditions to deliver the anilide cyclisation precursors
10a-l (Scheme 2).
With the linear anilide precursors in hand, attention turned to
the key cyclisation/elimination reaction (Scheme 3). Upon treat-
ment of sulfone-containing anilide 10a under our previously
established [18] conditions (10 mol% commercially-available cop-
per(II) 2-ethylhexanoate, 2.4 equiv DIPEA, toluene, reflux under
air), only unreacted starting material was isolated. However, the
a
Scheme 3. Substrate scope in the Cu(II)-mediated synthesis of 2-quinolones 11a-l.
11a was isolated in 84% yield when 10 mol% copper(II) 2-ethylhexanoate was used.
desired quinolone 11a was obtained in 84% yield upon changing the
solvent to mesitylene and increasing the reaction temperature to
165 ꢀC. The yield of 11a was further improved to 96% by increasing
the copper salt loading to 1 equiv (Scheme 3). Although not directly
comparable, the yield of 11a is considerably improved compared to
an almost identical substrate (51% yield with NEt instead of NMe)
prepared under the previously reported Mn(III)-mediated process

R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
3
[17].
With conditions for the one-pot cyclisation/elimination estab-
lished, the substrate scope was next investigated. Incorporation of a
benzyl protecting group on nitrogen led to isolation of quinolone
11b in 54% yield, along with 11% of a by-product that was identified
as
a,b-unsaturated anilide 11b′ arising from elimination of phe-
nylsulfinic acid instead of cyclisation.
The effect of electron-donating and electron-withdrawing
groups on the cyclisation reaction were next examined. N-
Methyl-6-methoxyquinolone 11c was isolated in 71% yield, repre-
senting a minor drop in yield relative to the unsubstituted system
11a. Pleasingly, removable protecting groups on nitrogen were also
tolerated, with 11d and 11e isolated in 69% and 66% yield,
respectively.
In contrast, incorporation of the strongly electron-withdrawing
nitro group on the aromatic ring gave the desired quinolone 11f in
only 23% yield, with the elimination by-product 11f′ isolated as the
major component. Although distant to the site of elimination, the
Scheme 5. Total synthesis of simple natural products 1a and 1b.
acidifying effect of the nitro group on the anilide a-hydrogen ap-
pears sufficient to promote elimination over cyclisation in this case.
The introduction of further substitution into the quinolone
scaffold was next investigated. For example, the synthesis of fused
tricyclic quinolones 11g-h bearing an additional 6- or 7-membered
ring was accomplished in good yields using our method. Further-
more, alkyl substituents were also well-tolerated in the 3-position
of the final product (11i).
smoothly converted into the natural product 1b under the same
conditions (Scheme 5). Further conversion of 1b into the related
natural product 1a was accomplished by demethylation using
excess BBr3 (3 equiv). Simultaneous deprotection of both protecting
groups in 11e could also be achieved in one-pot through the use of a
greater excess of BBr3 (6 equiv), giving 1a in 64% yield.
Finally, in this initial scoping study, the potential to incorporate
electron-withdrawing groups other than an ester into the final
product was also investigated. In analogous fashion to the reported
manganese(III) acetate mediated procedure, replacement of the
ester with a ketone was well-tolerated in the one-pot cyclisation/
elimination reaction. In the event, exposure of anilide 10j to the
standard reaction conditions afforded quinolone 11j in 76% yield,
along with elimination by-product 11j′ in 22% yield. While nitrile-
containing anilide 10k was also a suitable substrate in the reaction
giving quinolone 11k, attempted incorporation of a sulfone gave
only the elimination by-product 11l′. Again, it should be noted that
the copper(II) procedure avoids the requirement for super-
stoichiometric quantities of metal salt and acetic acid as a sol-
vent, as used in the Mn(III) variant.
Finally, the furocoumarin HOFQ 3 was identified as a more
complex candidate to validate our copper-mediated quinolone
procedure. The required linear anilide 12 was prepared in the same
manner as before, via acylation of the aniline derivative with bro-
moacetyl bromide followed by alkylation. Treatment of anilide 12
under the previously optimised conditions (1 equiv copper salt)
delivered the cyclised product 13 in a disappointing 15% yield,
along with 32% of the corresponding alkene 13′ resulting from
premature elimination of phenylsulfinic acid. However, the yield of
the desired product could be increased to 29% (along with 36% of
the elimination by-product 13′) by raising the amount of copper
salt to 2 equiv (Scheme 6). In the final step of the synthesis,
reduction of the ester was accomplished by addition of LiAlH(Ot-
Bu)3, giving the target molecule HOFQ 3 in 60% yield.
In light of our previous one-pot synthesis of oxindoles [18g], a
similar one-pot route to 2-quinolones seemed attainable. Thus,
treatment of a-bromoanilide 9a with the potassium salt of ethyl 2-
3. Conclusions
(phenylsulfonyl)acetate in mesitylene at 60 ꢀC for 1 h, followed by
addition of the copper salt/DIPEA and further heating delivered
quinolone 11a in a respectable 69% yield over the 2 steps (Scheme
4).
A new cyclisation procedure has been developed to prepare 4-
carboxy-quinolin-2-ones from linear anilides via a one-pot Cu(II)-
mediated radical cross-dehydrogenative coupling/sulfinic acid
With conditions for the copper-mediated route to 2-quinolones
successfully established, extension of this methodology to the
preparation of several target molecules was investigated.
First, simple natural products 1a and 1b, isolated from the
purple rice species Oryza sativa [2], were prepared. Although
attempted removal of the benzyl group in 11d with TFA gave only
recovered starting material, PMB protected quinolone 11e was
Scheme 4. Telescoped alkylation/CDC/elimination sequence.
Scheme 6. Total synthesis of furocumarin HOFQ 3.

4
R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
elimination sequence. This improved method removes the need to
employ super-stoichiometric quantities of metal salt and acetic acid
as a solvent. Scoping studies have been carried out to prepare
substituted 4-carboxy-quinolin-2-ones, related 4-keto- and 4-
cyano- systems, and related tricyclic analogues. The copper-based
methodology has been validated in target synthesis by preparing
quinolin-2-one natural products isolated from Oryza sativa and
HOFQ.
1634 (C]O), 1567, 1470, 1366, 1176; dH (400 MHz, CDCl3): 7.35e7.32
(3H, m), 7.28e7.24 (3H, m), 7.20e7.17 (2H, m), 7.07e7.03 (2H, m),
4.89 (2H, s), 3.66 (2H, s); dC (100 MHz, CDCl3): 166.5 (C), 141.3 (C),
136.7 (C), 129.9 (CH), 129.0 (CH), 128.8 (CH), 128.6 (CH), 128.3 (CH),
127.8 (CH), 53.8 (CH2), 27.5 (CH2); HRMS [ESþ] found MHþ,
79
304.0321. C
H BrNO requires 304.0332.
15 15
4.1.3. 2-Bromo-N-(4-methoxyphenyl)-N-methylacetamide [21] (9c)
4-Methoxy-N-methylaniline 7c (927 mg, 6.76 mmol), triethyl-
amine (0.95 mL, 6.76 mmol), CH2Cl2 (8 mL) and bromoacetyl bro-
4. Experimental section
mide 8a (589
mL, 6.76 mmol) in CH2Cl2 (12 mL) were subjected to
Except where stated, all reagents were purchased from com-
mercial sources and used without further purification. 1H and 13C
NMR spectra were recorded on a JEOL ECX400 or ECS400 spec-
trometer, operating at 400 MHz and 100 MHz, respectively. All
general procedure A to afford the title compound 9c (1.53 g,
5.93 mmol, 87%) as a brown oil; Rf: 0.38 (1:1 petrol/EtOAc); nmax
/
cmꢁ1 (neat): 2914, 1638 (C]O), 1489, 1419, 1359, 1281, 1230; dH
(400 MHz, CDCl3): 7.20 (2H, d, J ¼ 8.8 Hz), 6.94 (2H, d, J ¼ 8.8 Hz),
3.84 (3H, s), 3.66 (2H, s), 3.27 (3H, s); dC (100 MHz, CDCl3): 166.9 (C),
spectral data was acquired at 295 K. Chemical shifts (d) are quoted
in parts per million (ppm). The residual solvent peak, dH 7.27 and dC
77.0 for CDCl3 was used as a reference. Coupling constants (J) are
reported in Hertz (Hz). The multiplicity abbreviations used are: s
singlet, d doublet, t triplet, q quartet, m multiplet. Signal assign-
ment was achieved by analysis of DEPT, COSY, HMBC and HSQC
experiments where required. Infrared (IR) spectra were recorded
on a PerkinElmer UATR 2 spectrometer as a thin film dispersed
from either CH2Cl2 or CDCl3. Mass-spectra (low and high-
resolution) were obtained by the University of York Mass Spec-
trometry Service, using electrospray ionisation (ESI) on a Bruker
Daltonics, Micro-tof spectrometer. Melting points were determined
using a Gallenkamp apparatus. Thin layer chromatography was
carried out on Merck silica gel 60F254 pre-coated aluminium foil
sheets and were visualised using UV light (254 nm) and stained
with basic aqueous potassium permanganate. Flash column chro-
matography was carried out using slurry packed Fluka silica gel
159.3 (C), 135.7 (C),128.1 (CH),115.0 (CH), 55.5 (Me), 38.2 (Me), 26.8
79
(CH2); HRMS [ESþ] found MHþ 258.0132. C10
258.0124.
H BrNO2 requires
13
4.1.4. N-Benzyl-2-bromo-N-(4-methoxyphenyl)acetamide (9d)
N-Benzyl-4-methoxyaniline 7d (1.28 g, 6.00 mmol), triethyl-
amine (835
mide 8a (521
general procedure A to afford the title compound 9d (1.76 g,
mL, 6.00 mmol), CH2Cl2 (7 mL) and bromoacetyl bro-
mL, 6.00 mmol) in CH2Cl2 (10 mL) were subjected to
5.25 mmol, 88%) as a brown oil; Rf: 0.37 (1:1 Petrol/EtOAc); nmax
/
cmꢁ1 (neat): 3010, 2934, 2837, 1653 (C]O), 1509, 1434, 1401, 1293,
1251; dH (400 MHz, CDCl3): 7.29e7.22 (3H, m), 7.20e7.13 (2H, m),
6.94 (2H, d, J ¼ 8.8 Hz), 6.81 (2H, d, J ¼ 8.8 Hz), 4.84 (2H, s), 3.79 (3H,
s), 3.66 (2H, s); dC (100 MHz, CDCl3): 166.8 (C), 159.3 (C), 136.5 (C),
133.6 (CH), 129.1 (CH), 128.8 (CH), 128.3 (CH), 127.5 (CH), 114.7 (CH),
55.3 (Me), 53.7 (CH2), 27.3 (CH2); HRMS [ESþ] found MHþ 334.0426.
(SiO2), 35e70 mm, 60 Å, under a light positive pressure, eluting with
the specified solvent system.
79
C
H BrNO2 requires 334.0437.
16 17
4.1.5. 2-Bromo-N-(4-methoxybenzyl)-N-(4-methoxyphenyl)
acetamide (9e)
4.1. General procedure A. Synthesis of a-bromoanilides 9a-i
4-Methoxy-N-(4-methoxybenzyl)aniline 7a (2.00 g, 8.22 mmol),
triethylamine (1.14 mL, 8.22 mmol), CH2Cl2 (10 mL) and bromoa-
cetyl bromide 8a (714 mL, 8.22 mmol) in CH2Cl2 (14 mL) were sub-
To a stirred solution of the aniline 7 and triethylamine (1 equiv)
in CH2Cl2 (~0.9 mM) at 0 ꢀC was added acid bromide 8 (1 equiv) in
CH2Cl2 (~0.6 M) via cannula. The solution was allowed to warm to rt
and stirred for 20 h. Further CH2Cl2 was added and the organics
washed with 10% HCl solution, brine, dried (MgSO4) and concen-
trated in vacuo to afford the title compounds 9a-i which could be
used without further purification.
jected to general procedure A. Purification by flash column
chromatography (4:1 Hexane/EtOAc) afforded the title compound
9e (2.64 g, 7.25 mmol, 88%) as a brown oil; Rf: 0.22 (4:1 Hexane/
EtOAc); nmax/cmꢁ1 (neat): 2934, 1658 (C]O), 1509, 1300, 1247,
1175; dH (400 MHz, CDCl3): 7.05 (2H, d, J ¼ 8.5 Hz), 6.88 (2H, d,
J ¼ 8.8 Hz), 6.78 (2H, d, J ¼ 8.8 Hz), 6.74 (2H, d, J ¼ 8.5 Hz), 4.73 (2H,
s), 3.75 (3H, s), 3.72 (3H, s), 3.61 (2H, s); dC (100 MHz, CDCl3): 166.5
(C), 159.2 (C), 158.9 (C), 133.5 (CH), 130.2 (CH), 129.2 (CH), 128.7 (C),
4.1.1. 2-Bromo-N-methyl-N-phenylacetamide [19] (9a)
N-Methylaniline 7a (1.30 mL, 12.0 mmol), triethylamine
(1.67 mL, 12.0 mmol), CH2Cl2 (14 mL) and bromoacetyl bromide 8a
(1.04 mL, 12.0 mmol) in CH2Cl2 (20 mL) were subjected to general
procedure A to afford the title compound 9a (2.15 g, 9.43 mmol,
78%) as a brown solid; Rf: 0.72 (1:1 Petrol/EtOAc); m.p. 45e46 ꢀC
(Lit [19]. 47 ꢀC); nmax/cmꢁ1 (solid): 2997, 2926, 2328, 1622 (C]O),
1570, 1474; dH (400 MHz, CDCl3): 7.44 (2H, tt, J ¼ 7.2, 1.6 Hz), 7.38
(1H, tt, J ¼ 7.2, 1.6 Hz), 7.27 (2H, dt, J ¼ 7.2, 1.6 Hz), 3.65 (2H, s), 3.29
(3H, s); dC (100 MHz, CDCl3): 166.4 (C), 143.0 (C), 130.0 (CH), 128.5
114.6 (CH), 113.6 (CH), 55.3 (Me), 55.0 (Me), 53.0 (CH2), 27.5 (CH2);
79
HRMS [ESþ] found MNaþ 386.0354. C17
386.0362.
H BrNNaO3 requires
18
4.1.6. 2-Bromo-N-methyl-N-(4-nitrophenyl)acetamide [22] (9f)
4-Nitro-N-methylaniline 7f (1.82 g, 12.0 mmol), triethylamine
(1.67 mL, 12.0 mmol), CH2Cl2 (14 mL) and bromoacetyl bromide 7a
(1.04 mL, 12.0 mmol) in CH2Cl2 (20 mL) were subjected to general
procedure A. Purification by flash column chromatography (13:7
Petrol/EtOAc) afforded the title compound 9f (1.59 g, 5.82 mmol,
48%) as a colourless powder; Rf: 0.34 (1:1 petrol/EtOAc); m.p.
84e85 ꢀC (Lit.22 88e89 ꢀC); nmax/cmꢁ1 (solid): 1654 (C]O), 1587,
1518, 1341, 1104, 866; dH (400 MHz, CDCl3): 8.33 (2H, d, J ¼ 9.0 Hz),
7.51 (2H, d, J ¼ 9.0 Hz), 3.74 (2H, s), 3.39 (3H, s); dC (100 MHz,
(CH), 126.9 (CH), 38.0 (Me), 26.8 (CH2); HRMS [ESþ] found MHþ,
79
228.0019. C9H BrNO requires 228.0019.
11
4.1.2. N-Benzyl-2-bromo-N-phenylacetamide [20] (9b)
N-Benzylaniline 7b (2.07 mL, 12.0 mmol), triethylamine
(1.67 mL, 12.0 mmol), CH2Cl2 (14 mL) and bromoacetyl bromide 8a
(1.04 mL, 12.0 mmol) in CH2Cl2 (20 mL) were subjected to general
procedure A to afford the title compound 9b (2.49 g, 8.18 mmol,
68%) as a brown/yellow crystalline solid; Rf: 0.25 (4:1 Petrol/
EtOAc); m.p. 64e65 ꢀC (Lit [20]. 70 ꢀC); nmax/cmꢁ1 (solid): 2325,
CDCl3): 166.1 (C), 148.5 (C), 146.3 (C), 127.5 (CH), 125.2 (CH), 38.1
79
(Me), 26.2 (CH2); HRMS [ESþ] found MHþ 272.9873. C9H BrN2O3
10
requires 272.9869.

R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
5
4.1.7. 2-Bromo-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone [23]
(9g)
1,2,3,4-Tetrahydroquinoline 7g (1.25 mL, 10.0 mmol), triethyl-
amine (1.39 mL, 6.00 mmol), CH2Cl2 (12 mL) and bromoacetyl bro-
Hexane/EtOAc); m.p. 120e123 ꢀC; nmax/cmꢁ1 (neat): 2936, 1736
(C]O), 1649 (C]O), 1595, 1497, 1449, 1309 (S]O), 1226, 1145 (S]
O); dH (400 MHz, CDCl3): 7.79 (2H, dd, J ¼ 8.2, 1.0 Hz), 7.66 (1H, tt,
J ¼ 7.5, 1.2 Hz), 7.55e7.49 (2H, m), 7.48e7.37 (3H, m), 7.24e7.21 (2H,
m), 4.56 (1H, dd, J ¼ 6.7, 3.9 Hz), 4.10e3.98 (2H, m), 3.24 (3H, s), 2.97
(1H, dd, J ¼ 16.8, 10.7 Hz), 2.84 (1H, dd, J ¼ 10.7, 3.9 Hz), 1.06 (3H, t,
J ¼ 7.1 Hz); dC (100 MHz, CDCl3): 168.4 (C), 165.3 (C), 142.8 (C), 137.8
(C), 134.2 (CH), 130.1 (CH), 129.0 (CH), 128.9 (CH), 128.4 (CH), 127.2
(CH), 66.9 (CH), 62.2 (CH2), 37.5 (Me), 30.8 (CH2), 13.6 (Me); HRMS
[ESþ] found MNaþ, 398.1030. C19H21NNaO5S requires 398.1033.
mide 7a (869
mL, 10.0 mmol) in CH2Cl2 (16 mL) were subjected to
general procedure A to afford the title compound 9g (2.25 g,
8.91 mmol, 88%) as a brown oil; Rf: 0.52 (1:1 Hexane/EtOAc); nmax
/
cmꢁ1 (neat): 2948, 1654 (C]O), 1581, 1491, 1458, 1428, 1389; dH
(400 MHz, CDCl3): 7.23e7.08 (4H, m), 4.03 (2H, s), 3.80 (2H, t,
J ¼ 6.5 Hz), 2.76e2.65 (2H, m), 2.02e1.90 (2H, m); dC (100 MHz,
CDCl3): 166.3 (C), 138.5 (C), 134.3 (C), 128.6 (CH), 126.5 (CH), 126.1
(CH), 123.4 (CH), 43.4 (CH2), 27.5 (CH2), 26.5 (CH2), 23.7 (CH2);
4.2.2. Ethyl 4-(benzyl(phenyl)amino)-4-oxo-2-(phenylsulfonyl)
butanoate (10b)
79
HRMS [ESþ] found MNaþ 275.9984. C11
275.9994.
H BrNNaO requires
12
Ethyl 2-(phenylsulfonyl)acetate (422 mg, 1.85 mmol) and KOtBu
(227 mg, 2.03 mmol) in THF (20 mL) and 2-bromo-N-benzyl-N-
phenylacetamide 9b (727 mg, 2.40 mmol) in THF (4 mL) were
subjected to general procedure B for 18 h. Purification by flash
column chromatography (7:3 Hexane/EtOAc) afforded the title
compound 10b (830 mg, 1.84 mmol, 99%) as a colourless oil; Rf: 0.18
(7:3 Hexane/EtOAc); nmax/cmꢁ1 (neat): 1736 (C]O), 1651 (C]O),
1595, 1494, 1407, 1322 (S]O), 1146 (S]O); dH (400 MHz, CDCl3):
7.78 (2H, dd, J ¼ 7.2, 1.4 Hz), 7.65 (1H, tt, J ¼ 7.4, 1.1 Hz), 7.51 (2H, t,
J ¼ 7.9 Hz), 7.36e7.29 (3H, m), 7.26e7.19 (3H, m), 7.15e7.11 (2H, m),
7.03e6.99 (2H, m), 4.88 (2H, d, J ¼ 14.3 Hz), 4.80 (2H, d, J ¼ 14.3 Hz),
4.62 (1H, dd, J ¼ 10.4, 4.1 Hz), 4.14e4.00 (2H, m), 2.94 (1H, dd,
J ¼ 16.9, 10.4 Hz), 2.85 (1H, dd, J ¼ 16.9, 4.1 Hz), 1.07 (3H, t,
J ¼ 7.1 Hz); dC (100 MHz, CDCl3): 168.4 (C), 165.2 (C), 141.1 (C), 137.8
(C), 136.8 (C), 134.1 (CH), 129.8 (CH), 128.9 (CH), 128.8 (CH), 128.6
(CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 127.4 (CH), 66.9 (CH), 62.2
(CH2), 53.3 (CH2), 31.1 (CH2), 13.6 (Me); HRMS [ESþ] found MNaþ,
474.1337. C25H25NNaO5S requires 474.1346.
4.1.8. 2-Bromo-1-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)
ethanone [24] (9h)
2,3,4,5-Tetrahydroꢁ1H-benzo[b]azepine
3.57 mmol), triethylamine (480 L, 3.57 mmol), CH2Cl2 (5 mL) and
bromoacetylbromide7a(310 L,3.57 mmol)inCH2Cl2 (6.5 mL)were
7h
(525 mg,
m
m
subjected to general procedure A. Purification by flash column chro-
matography (4:1 Hexane/EtOAc) afforded the title compound 9h
(679 mg, 2.53 mmol, 71%) as a colourless solid; Rf: 0.21 (4:1 Hexane/
EtOAc); m.p. 93e95 ꢀC; nmax/cmꢁ1 (neat): 2938, 1654 (C]O), 1492,
1440,1399,1311; dH (400 MHz, CDCl3): 7.27e7.18 (4H, m), 4.69e4.62
(1H,m),3.73(1H,d,J ¼ 10.8 Hz),3.65(1H,d,J ¼ 10.8 Hz),2.94e2.85(1H,
m),2.73e2.61(2H,m),2.03e1.87(2H,m),1.82e1.73(1H,m),1.43e1.31
(1H,m);dC (100 MHz,CDCl3):165.3(C),142.3(C),140.7(C),130.5(CH),
128.6(CH),127.4(CH),126.8(CH),48.0(CH2),34.4(CH2),28.7(CH2),26.9
79
(CH2), 26.3 (CH2); HRMS [ESþ] found MHþ 268.0329. C12
quires268.0332.
H BrNO re-
15
4.1.9. 2-Bromo-N-methyl-N-phenylpropanamide [25,26] (9i)
N-Methylaniline 7a (1.30 mL, 12.0 mmol), triethylamine
(1.67 mL, 12.0 mmol), CH2Cl2 (14 mL) and 2-bromopropionyl bro-
mide 7b (1.26 mL, 12.0 mmol) in CH2Cl2 (20 mL) were subjected to
general procedure A to afford the title compound 9i (2.87 g,
4.2.3. Ethyl 4-((4-methoxyphenyl)(methyl)amino)-4-oxo-2-
(phenylsulfonyl)butanoate (10c)
Ethyl 2-(phenylsulfonyl)acetate (575 mg, 2.52 mmol) and KOtBu
(282 mg, 2.52 mmol) in THF (11 mL) and 2-bromo-N-(4-
methoxyphenyl)-N-methylacetamide 9c (325 mg, 1.26 mmol) in
THF (2 mL) were subjected to general procedure B for 18 h. Purifi-
cation by flash column chromatography (55:45 Hexane/EtOAc)
11.8 mmol, 99%) as an orange oil; Rf: 0.60 (1:1 petrol/EtOAc); nmax
/
cmꢁ1 (neat): 1641 (C]O), 1571, 1472, 1368, 1250, 1104; dH
(400 MHz, CDCl3): 7.48e7.47 (2H, m), 7.40 (1H, tt, J ¼ 7.2, 1.2 Hz),
7.29 (2H, d, J ¼ 7.2 Hz), 4.26 (1H, q, J ¼ 6.8 Hz), 3.29 (3H, s), 1.73 (3H,
d, J ¼ 6.8 Hz); dC (100 MHz, CDCl3): 169.6 (C), 142.8 (C), 129.9 (CH),
afforded the title compound 10c (361 mg, 891 mmol, 71%) as a
brown semi-solid; Rf: 0.12 (55:45 Hexane/EtOAc); nmax/cmꢁ1
(neat): 1738 (C]O), 1655 (C]O), 1512, 1448, 1392, 1323 (S]O),
1249,1148 (S]O); dH (400 MHz, CDCl3): 7.80 (2H, dd, J ¼ 7.2,1.3 Hz),
7.66 (1H, tt, J ¼ 7.5, 1.2 Hz), 7.53 (2H, t, J ¼ 7.5 Hz), 7.15e7.11 (2H, m),
6.96e6.92 (2H, m), 4.54 (1H, dd, J ¼ 10.7, 3.9 Hz), 4.15e3.97 (2H, m),
3.86 (3H, s), 3.20 (3H, s), 2.97 (1H, dd, J ¼ 16.8,10.7 Hz), 2.83 (1H, dd,
J ¼ 16.8, 3.8 Hz), 1.05 (3H, t, J ¼ 7.2 Hz); dC (100 MHz, CDCl3): 168.8
(C), 165.3 (C), 159.3 (C), 137.9 (C), 135.5 (C), 134.1 (CH), 129.0 (CH),
128.8 (CH), 128.3 (CH), 115.2 (CH), 66.9 (CH), 62.2 (CH2), 55.5 (Me),
37.6 (Me), 30.7 (CH2),13.6 (Me); HRMS [ESþ] found MNaþ, 428.1139.
128.4 (CH), 127.1 (CH), 39.0 (CH), 38.1 (Me), 21.8 (Me); HRMS [ESþ]
79
found MHþ 242.0172. C10
H BrNO requires 242.0175.
13
4.2. General procedure B. Synthesis of linear anilides 10a-k
To a stirred solution of activated methylene compound (1e2
equiv) in THF (~0.26 M) was added KOtBu (1e2 equiv). The reaction
mixture was stirred for 5 min, then the anilide (1e2 equiv) in THF
(~0.94 M) was added via cannula. Stirring was continued for 2 h at
room temperature. The reaction mixture was quenched (sat. NH4Cl
solution), the aqueous extracted (EtOAc), and the combined or-
ganics washed (brine), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography afforded the
title compounds.
C20H23NNaO6S requires 428.1138.
4.2.4. Ethyl 4-(benzyl(4-methoxyphenyl)amino)-4-oxo-2-
(phenylsulfonyl)butanoate (10d)
Ethyl 2-(phenylsulfonyl)acetate (1.36 g, 5.98 mmol) and KOtBu
(670 mg, 5.98 mmol) in THF (42 mL) and N-benzyl-2-bromo-N-(4-
methoxyphenyl)acetamide 9d (1.00 g, 2.99 mmol) in THF (9 mL)
were subjected to general procedure B for 4 h. Purification by flash
column chromatography (13:7 Hexane/EtOAc) afforded the title
compound 10d (1.06 g, 2.20 mmol, 74%) as an orange gum; Rf: 0.22
(13:7 Hexane/EtOAc); nmax/cmꢁ1 (neat): 1738 (C]O), 1654 (C]O),
1512, 1447, 1408, 1324 (S]O), 1250, 1148 (S]O); dH (400 MHz,
CDCl3): 7.80 (2H, dd, J ¼ 8.4, 1.2 Hz), 7.66 (1H, tt, J ¼ 7.5, 1.8 Hz), 7.53
(2H, t, J ¼ 7.4 Hz), 7.27e7.21 (3H, m), 7.15e7.12 (2H, m), 6.90 (2H, d,
J ¼ 9.0 Hz), 6.83 (2H, d, J ¼ 9.0 Hz), 4.84 (1H, d, J ¼ 14.2 Hz), 4.73 (1H,
4.2.1. Ethyl 4-(methyl(phenyl)amino)-4-oxo-2-(phenylsulfonyl)
butanoate (10a)
Ethyl 2-(phenylsulfonyl)acetate (2.00 g, 8.76 mmol) and KOtBu
(982 mg, 8.76 mmol) in THF (32 mL) and 2-bromo-N-methyl-N-
phenylacetamide 9a (1.00 g, 4.38 mmol) in THF (6 mL) were sub-
jected to general procedure B for 18 h. Purification by flash column
chromatography (3:2 Hexane/EtOAc) afforded the title compound
10a (1.53 g, 4.07 mmol, 93%) as a colourless solid; Rf: 0.25 (1:1

6
R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
d, J ¼ 14.2 Hz), 4.60 (1H, dd, J ¼ 10.6, 4.0 Hz), 4.13e3.98 (2H, m), 3.81
(3H, s), 2.95 (1H, dd, J ¼ 16.9, 10.6 Hz), 2.84 (1H, dd, J ¼ 16.9, 4.0 Hz),
1.06 (3H, t, J ¼ 7.2 Hz); dC (100 MHz, CDCl3): 168.9 (C), 165.4 (C),
159.4 (C), 138.0 (C), 137.0 (C), 134.3 (CH), 133.8 (C), 129.5 (CH), 129.1
(CH), 129.0 (CH), 128.9 (CH), 128.5 (CH), 127.6 (CH), 115.1 (CH), 67.1
(CH), 62.4 (CH2), 55.6 (Me), 53.5 (CH2), 31.0 (CH2), 13.7 (Me); HRMS
[ESþ] found MHþ, 482.1637. C26H28NO6S requires 482.1632.
(CH2), 31.3 (CH2), 26.5 (CH2), 23.7 (CH2), 13.5 (Me); HRMS [ESþ]
found MHþ, 402.1369. C21H24NO5S requires 402.1370.
4.2.8. Ethyl 4-oxo-2-(phenylsulfonyl)-4-(2,3,4,5-tetrahydro-1H-
benzo[b]azepin-1-yl)butanoate (10h)
Ethyl 2-(phenylsulfonyl)acetate (204 mg, 896
(100 mg, 896 mol) in THF (5 mL) and 2-bromo-1-(2,3,4,5-
tetrahydro-1H-benzo[b]azepin-1-yl)ethanone 9h (120 mg,
448 mol) in THF (2 mL) were subjected to general procedure B for
16 h. Purification by flash column chromatography (3:2 Hexane/
EtOAc) afforded the title compound 10h (119 g, 286 mol, 64%) as a
mmol) and KOtBu
m
4.2.5. Ethyl 4-((4-methoxybenzyl)(4-methoxyphenyl)amino)-4-
oxo-2-(phenylsulfonyl)butanoate (10e)
m
Ethyl 2-(phenylsulfonyl)acetate (1.00 g, 4.40 mmol) and KOtBu
(492 mg, 4.40 mmol) in THF (32 mL) and 2-bromo-N-(4-
methoxybenzyl)-N-(4-methoxyphenyl)acetamide 9e (800 mg,
2.20 mmol) in THF (6 mL) were subjected to general procedure B for
18 h. Purification by flash column chromatography (3:2 Hexane/
EtOAc) afforded the title compound 10e (960 mg, 1.89 mmol, 85%)
as an orange gum; Rf: 0.21 (3:2 Hexane/EtOAc); nmax/cmꢁ1 (neat):
2937, 1738 (C]O), 1654 (C]O), 1512, 1447, 1408, 1323 (S]O), 1248,
1148 (S]O); dH (400 MHz, CDCl3): 7.80 (2H, d, J ¼ 7.5 Hz), 7.66 (1H,
t, J ¼ 7.5 Hz), 7.53 (2H, t, J ¼ 7.5 Hz), 7.04 (2H, d, J ¼ 8.6 Hz),
6.89e6.81 (4H, m), 6.76 (2H, d, J ¼ 8.6 Hz), 4.79 (1H, d, J ¼ 14.1 Hz),
4.66 (1H, d, J ¼ 14.1 Hz), 4.59 (1H, dd, J ¼ 10.6, 4.0 Hz), 4.12e3.98
(2H, m), 3.82 (3H, s), 3.77 (3H, s), 2.93 (1H, dd, J ¼ 16.9, 10.6 Hz),
2.82 (1H, dd, J ¼ 16.9, 4.0 Hz), 1.06 (3H, t, J ¼ 7.2 Hz); dC (100 MHz,
CDCl3): 168.6 (C), 165.3 (C), 159.3 (C), 158.9 (C), 137.9 (C), 134.1 (CH),
133.6 (C), 130.1 (CH), 129.4 (CH), 129.1 (C), 129.0 (CH), 128.8 (CH),
115.0 (CH), 113.7 (CH), 66.9 (CH), 62.2 (CH2), 55.4 (Me), 55.2 (Me),
52.7 (CH2), 31.0 (CH2), 13.6 (Me); HRMS [ESþ] found MNaþ,
534.1530. C27H29NNaO7S requires 534.1557.
m
colourless oil; Rf: 0.22 (3:2 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2938,
1737 (C]O), 1650 (C]O), 1408, 1400, 1322 (S]O), 1145 (S]O); dH
(400 MHz, CDCl3): 7.81e7.77 (2H, m), 7.68e7.62 (1H, m), 7.52 (2H, t,
J ¼ 7.8 Hz), 7.26e7.12 (4H, m), 4.63e4.56 (2H, m), 4.13e3.96 (2H, m),
3.24e3.02 (1H, m), 2.89e2.76 (1H, m), 2.73 (3H, m), 2.01e1.69 (3H,
m), 1.41e1.27 (1H, m), 1.08e1.02 (3H, m); dC (100 MHz, CDCl3):
Mixture of rotamers: 167.5 (C), 167.4 (C), 165.5 (C), 165.2 (C), 142.0
(C), 141.9 (C), 140.9 (C), 140.7 (C), 138.0 (C), 137.9 (C), 134.2 (CH),
130.6 (CH), 129.0 (CH), 128.9 (CH), 128.8 (CH), 128.6 (CH), 128.5
(CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 127.3 (CH), 66.9 (CH), 62.28
(CH2), 62.25 (CH2), 47.70 (CH2), 47.65 (CH2), 34.4 (CH2), 34.2 (CH2),
31.1 (CH2), 31.0 (CH2), 29.0 (CH2), 28.96 (CH2), 26.4 (CH2), 13.7 (Me);
HRMS [ESþ] found MHþ, 438.1349. C22H25NNaO5S requires
438.1346.
4.2.9. Ethyl 3-methyl-4-(methyl(phenyl)amino)-4-oxo-2-
(phenylsulfonyl)butanoate (10i)
Ethyl 2-(phenylsulfonyl)acetate (839 mg, 3.68 mmol) and KOtBu
(448 mg, 3.68 mmol) in THF (14 mL) and 2-bromo-N-methyl-N-
phenylpropanamide 9i (594 mg, 2.45 mmol) in THF (4 mL) were
subjected to general procedure B for 16 h. Purification by flash
column chromatography (17:3 / 3:1 Hexane/EtOAc) afforded the
4.2.6. Ethyl 4-(methyl(4-nitrophenyl)amino)-4-oxo-2-
(phenylsulfonyl)butanoate (10f)
Ethyl 2-(phenylsulfonyl)acetate (399 mg, 1.75 mmol) and KOtBu
(196 mg, 1.75 mmol) in THF (8 mL) and 2-bromo-N-(4-
nitrophenyl)-N-methylacetamide 9f (361 mg, 1.26 mmol) in THF
(1.5 mL) were subjected to general procedure B for 18 h. Purification
by flash column chromatography (1:1 Petrol/EtOAc) afforded the
title compound 10i (208 mg, 535 mmol, 22%) as an orange oil which
was an inseparable (1:1.6) mixture of diastereoisomers; Rf: 0.23
(1:1 Petrol/EtOAc); nmax/cmꢁ1 (neat): 2983, 1732 (C]O), 1651 (C]
O), 1595, 1495, 1448, 1392, 1323 (S]O), 1144 (S]O); dH (400 MHz,
CDCl3): Major diastereoisomer: 7.68 (2H, d, J ¼ 7.6 Hz), 7.57 (2H, t,
J ¼ 7.6 Hz), 7.44e7.25 (4H, m), 7.18 (2H, d, J ¼ 7.6 Hz), 4.25 (1H, d,
J ¼ 10.7 Hz), 3.98e3.90 (2H, m), 3.37e3.24 (1H, m), 3.09 (3H, s),
1.29e1.25 (3H, m), 1.05e0.94 (3H, m); Minor diastereoisomer: 7.82
(2H, d, J ¼ 6.8 Hz), 7.47 (2H, t, J ¼ 6.8 Hz), 7.44e7.25 (6H, m), 4.72
(1H, d, J ¼ 10.7 Hz), 3.85e3.75 (2H, m), 3.37e3.24 (1H, m), 3.23 (3H,
s), 1.29e1.25 (3H, m), 1.05e0.94 (3H, m); dC (100 MHz, CDCl3):
Major diastereoisomer; 173.2 (C), 166.3 (C), 142.8 (C), 137.5 (C),
133.9 (CH), 129.7 (CH), 128.73 (CH), 128.7 (CH), 127.8 (CH), 127.0
(CH), 73.5 (CH), 61.9 (CH2), 37.3 (Me), 36.3 (CH), 16.5 (Me), 13.3
(Me); Minor diastereoisomer: 172.3 (C), 164.5 (C), 143.0 (C), 139.0
(C), 133.8 (CH), 129.7 (CH), 128.8 (CH), 128.3 (CH), 128.1 (CH), 127.3
(CH), 72.7 (CH), 61.7 (CH2), 37.8 (Me), 34.6 (CH), 16.4 (Me), 13.5
(Me); HRMS [ESþ] found MNaþ, 412.1179. C20H23NNaO5S requires
412.1189.
title compound 10f (364 mg, 867 mmol, 66%) as a colourless oil; Rf:
0.19 (1:1 Petrol/EtOAc); nmax/cmꢁ1 (neat): 1737 (C]O),1663 (C]O),
1593, 1522, 1496 1448, 1342 (S]O), 1148 (S]O); dH (400 MHz,
CDCl3): 8.31 (2H, d, J ¼ 8.3 Hz), 7.83 (2H, d, J ¼ 7.8 Hz), 7.69 (1H, t,
J ¼ 7.8 Hz), 7.59 (2H, t, J ¼ 7.8 Hz), 7.45 (2H, d, J ¼ 8.3 Hz), 4.59 (1H,
dd, J ¼ 10.2, 4.2 Hz), 4.14e3.96 (2H, m), 3.30 (3H, s), 3.02 (2H, br s),
1.03 (3H, t, J ¼ 7.2 Hz3); dC (100 MHz, CDCl3): 168.4 (C), 165.3 (C),
148.6 (C), 146.9 (C), 137.9 (C), 134.5 (CH), 129.3 (CH), 129.0 (CH),
128.0 (CH), 125.5 (CH), 66.8 (CH), 62.6 (CH2), 37.8 (Me), 30.9 (CH2),
13.7 (Me); HRMS [ESþ] found MNaþ, 443.0890. C19H20N2NaO7S
requires 443.0883.
4.2.7. Ethyl 4-(3,4-dihydroquinolin-1(2H)-yl)-4-oxo-2-
(phenylsulfonyl)butanoate (10g)
Ethyl 2-(phenylsulfonyl)acetate (381 mg, 1.67 mmol) and KOtBu
(187 mg, 1.67 mmol) in THF (9 mL) and 2-bromo-1-(3,4-
dihydroquinolin-1(2H)-yl)ethanone 9g (316 g, 1.25 mmol) in THF
(2 mL) were subjected to general procedure B for 18 h. Purification
by flash column chromatography (13:7 Hexane/EtOAc) afforded the
4.2.10. N-Methyl-4-oxo-N,4-diphenyl-3-(phenylsulfonyl)
butanamide (10j)
1-Phenyl-2-(phenylsulfonyl)ethanone (274 mg, 1.05 mmol) and
KOtBu (118 mg, 1.05 mmol) in THF (4 mL) and 2-bromo-N-methyl-
N-phenylacetamide 9a (120 mg, 0.526 mmol) in THF (1.5 mL) were
subjected to general procedure B for 18 h. Purification by flash
column chromatography (4:1 Hexane/EtOAc) afforded the title
title compound 10g (339 mg, 845 mmol, 68%) as a yellow oil; Rf: 0.23
(13:7 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2942, 1737 (C]O), 1650
(C]O), 1492, 1400, 1323 (S]O), 1240, 1147 (S]O); dH (400 MHz,
CDCl3): 7.87e7.75 (2H, m), 7.68e7.61 (1H, m), 7.56e7.49 (2H, m),
7.22e7.03 (4H, m), 4.64e4.56 (1H, m), 4.08e3.96 (2H, m),
3.83e3.64 (2H, m), 3.45e3.16 (2H, m), 2.75e2.63 (2H, m), 2.01e1.79
(2H, m), 1.07e0.99 (3H, m); dC (100 MHz, CDCl3): 168.1 (C), 165.2
(C), 138.1 (C), 137.6 (CH), 134.2 (CH), 129.0 (CH), 128.8 (CH), 128.6
(CH), 126.3 (CH), 126.0 (CH) 124.4 (C), 67.1 (CH), 62.2 (CH2), 43.0
compound 10j (213 mg, 523 mmol, 99%) as a colourless solid; Rf:
0.22 (4:1 Hexane/EtOAc); nmax/cmꢁ1 (neat): 3061, 1681 (C]O),
1654 (C]O), 1596, 1496, 1448, 1377, 1310 (S]O), 1150 (S]O); dH
(400 MHz, CDCl3): 7.90 (2H, d, J ¼ 7.3 Hz), 7.54e7.30 (11H, m), 7.21
(2H, d, J ¼ 7.3 Hz), 5.61 (1H, dd, J ¼ 10.9, 3.1 Hz), 3.17e3.09 (1H, m),

R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
7
3.16 (3H, s), 2.89 (1H, dd, J ¼ 16.7, 3.1 Hz); dC (100 MHz, CDCl3):
191.8 (C), 168.6 (C), 142.7 (C), 136.7 (C), 134.1 (CH), 133.5 (CH), 130.1
(CH), 129.2 (CH),129.1 (CH), 128.8 (CH), 128.5 (CH), 128.4 (CH), 127.2
(CH), 66.4 (CH), 37.4 (Me), 33.3 (CH2); HRMS [ESþ] found MNaþ,
430.1070. C23H21NNaO4S requires 430.1083.
(8 mL), dried (MgSO4), filtered and concentrated in vacuo. Purifi-
cation by flash column chromatography (3:2 Hexane/EtOAc)
afforded the title compound 11a (42 mg, 182 mmol, 83%) as a brown
solid.
4.3.2. Ethyl 1-benzyl-2-oxo-1,2-dihydroquinoline-4-carboxylate
(11b)
Ethyl 4-(benzyl(phenyl)amino)-4-oxo-2-(phenylsulfonyl)buta-
noate 10b (162 mg, 0.359 mmol), copper(II) 2-ethylhexanoate
4.2.11. 3-Cyano-N-methyl-N-phenyl-3-(phenylsulfonyl)
propanamide (10k)
2-(Phenylsulfonyl)acetonitrile (191 mg, 1.05 mmol) and KOtBu
(118 mg, 1.05 mmol) in THF (4 mL) and 2-bromo-N-methyl-N-phe-
nylacetamide 9a (120 mg, 0.526 mmol) in THF (1.5 mL) were sub-
jected to general procedure B for 18 h. Purification by flash column
chromatography (4:1 Hexane/EtOAc) afforded the title compound
(126 mg, 100 mol%) and DIPEA (150 mL, 0.862 mmol) in mesitylene
(11 mL) were subjected to general procedure C at 165 ꢀC for 18 h.
Purification by flash column chromatography (5:1 Hexane/EtOAc)
afforded the title compound 11b (60 mg, 195 mmol, 54%) as a col-
10k (123 mg, 302
m
mol, 57%) as a colourless solid; Rf: 0.24 (4:1
ourless oil; Rf: 0.17 (5:1 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2978,
1736 (C]O), 1656 (C]O), 1595, 1495, 1449, 1407; dH (400 MHz,
CDCl3): 8.25 (1H, d, J ¼ 8.2 Hz), 7.39 (1H, t, J ¼ 8.2 Hz), 7.28e7.04
(8H, m), 5.51 (2H, s), 4.40 (2H, q, J ¼ 7.3 Hz), 1.37 (3H, t, J ¼ 7.3 Hz);
dC (100 MHz, CDCl3): 165.3 (C), 161.5 (C), 139.7 (C), 139.5 (C), 135.7
(C), 131.0 (CH), 128.7 (CH), 127.3 (CH), 127.1 (CH), 126.5 (CH), 123.7
(CH), 122.7 (CH), 117.7 (C), 115.5 (CH), 62.0 (CH2), 46.2 (CH2), 14.2
(Me); HRMS [ESþ] found MHþ, 308.1282. C19H18NO3 requires
308.1281.
Hexane/EtOAc); nmax/cmꢁ1 (neat): 2925, 1656 (C]O), 1596, 1496,
1333 (S]O), 1157 (S]O); dH (400 MHz, CDCl3): 7.97e7.93 (2H, m),
7.83e7.73 (1H, m), 7.68e7.59 (2H, m), 7.54e7.40 (3H, m), 7.23 (2H,
d, J ¼ 7.6 Hz), 4.73e4.65 (1H, m), 3.31 (3H, s), 3.06 (1H, dd, J ¼ 16.4,
4.6 Hz), 2.73 (1H, dd, J ¼ 16.4, 9.2 Hz); dC (100 MHz, CDCl3): 166.0
(C), 142.2 (C), 135.6 (C), 135.4 (CH), 130.4 (CH), 129.6 (CH), 129.4
(CH), 127.8 (CH), 127.2 (CH), 114.0 (C), 53.8 (CH), 37.8 (Me), 31.5
(CH2); HRMS [ESþ] found MHþ, 329.0947. C17H17N2O3S requires
329.0954.
Also isolated was ethyl (E)-4-(benzyl(phenyl)amino)-4-oxobut-
2-enoate [28] 11b′ (19 mg, 61 mmol, 11%) as a yellow oil; Rf: 0.21
4.3. General procedure C. Copper mediated synthesis of quinolones
11a-k
(5:1 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2980, 1720 (C]O), 1659
(C]O), 1634, 1594, 1494, 1389, 1293, 1160; dH (400 MHz, CDCl3):
7.36e7.16 (8H, m), 7.01e6.96 (2H, m), 6.90 (1H, d, J ¼ 15.3 Hz), 6.80
(1H, d, J ¼ 15.3 Hz), 4.98 (2H, s), 4.14 (2H, q, J ¼ 7.1 Hz), 1.23 (3H, t,
J ¼ 7.1 Hz); dC (100 MHz, CDCl3): 165.7 (C), 164.1 (C), 141.1 (C), 136.9
(C), 134.4 (CH), 131.6 (CH), 129.8 (CH), 128.8 (CH), 128.6 (CH), 128.5
(CH), 128.2 (CH), 127.7 (CH), 61.1 (CH2), 53.6 (CH2), 14.2 (Me); HRMS
[ESþ] found MNaþ, 332.1251. C19H19NNaO3 requires 332.1257.
To a stirred solution of the anilide 10a-k and copper(II) 2-
ethylhexanoate (10 mol% to 100 mol%) in mesitylene (0.03 M) was
added DIPEA (2.4 eq). The reaction was stirred at reflux under an
atmosphere of air. Upon completion of the reaction, the solvent was
removed under reduced pressure and EtOAc was added. The solu-
tion was washed with 10% HCl solution, 10% aqueous NH4OH so-
lution, brine, dried (MgSO4), filtered and concentrated in vacuo.
Purification by flash column chromatography afforded the title
compounds.
4.3.3. Ethyl 6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-
carboxylate [29] (11c)
Ethyl 4-((4-methoxyphenyl)(methyl)amino)-4-oxo-2-(phenyl-
sulfonyl)butanoate 10c (166 mg, 410
mmol), copper(II) 2-
4.3.1. Ethyl 1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylate
[27] (11a)
ethylhexanoate (144 mg, 100 mol%) and DIPEA (171
m
L, 984 mol)
m
in mesitylene (15 mL) were subjected to standard procedure C at
From 10a: Ethyl 4-(methyl(phenyl)amino)-4-oxo-2-(phenyl-
165 ꢀC for 18 h. Purification by flash column chromatography (1:1
sulfonyl)butanoate 10a (100 mg, 266
ethylhexanoate (93.3 mg, 100 mol%) and DIPEA (111
in mesitylene (8 mL) were subjected to general procedure C at
165 ꢀC for 18 h. Purification by flash column chromatography (3:2
Hexane/EtOAc) afforded the title compound 11a (59.0 mg,
m
mol), copper(II) 2-
Hexane/EtOAc) afforded the title compound 11c (77 mg, 293 mmol,
m
L, 638 mol)
m
71%) as a yellow solid; Rf: 0.17 (1:1 Petrol/EtOAc); m.p. 99e100 ꢀC
(Lit [29]. 105 ꢀC); nmax/cmꢁ1 (neat): 1723 (C]O), 1658 (C]O), 1620,
1586, 1563,1463, 1430; dH (400 MHz, CDCl3): 7.97 (1H, d, J ¼ 2.9 Hz),
7.34 (1H, d, J ¼ 9.3 Hz), 7.29 (1H, s), 7.23 (1H, dd, J ¼ 9.3, 2.9 Hz), 4.44
(2H, q, J ¼ 7.1 Hz), 3.87 (3H, s), 3.74 (3H, s), 1.43 (3H, t, J ¼ 7.1 Hz); dC
(100 MHz, CDCl3): 165.4 (C), 160.9 (C), 155.0 (C), 137.6 (C), 135.0 (C),
125.2 (CH), 120.1 (CH), 118.3 (C), 115.7 (CH), 108.8 (CH), 61.9 (CH2),
55.6 (Me), 29.9 (Me), 14.1 (Me); HRMS [ESþ] found MHþ, 262.1069.
255 mmol, 96%) as a brown solid; Rf: 0.19 (3:2 Hexane/EtOAc); m.p.
132 ꢀC (Lit [27]. 134e135 ꢀC); nmax/cmꢁ1 (neat): 2919, 1714 (C]O),
1643 (C]O), 1583, 1454, 1416, 1399, 1334, 1235; dH (400 MHz,
CDCl3): 8.35 (1H, dd, J ¼ 8.2, 1.1 Hz), 7.64e7.58 (1H, m), 7.41 (1H, d,
J ¼ 8.6 Hz), 7.24e7.18 (1H, m), 7.16 (1H, s), 4.43 (2H, q J ¼ 7.1 Hz),
3.73 (3H, s), 1.41 (3H, t, J ¼ 7.1 Hz); dC (100 MHz, CDCl3): 165.3 (C),
161.4 (C),140.3 (C),138.9 (C),131.1 (CH),127.1 (CH),124.2 (CH),122.7
(CH), 117.5 (C), 114.5 (CH), 62.0 (CH2), 29.8 (Me), 14.1 (Me); HRMS
[ESþ] found MHþ, 232.0965. C13H14NO3 requires 232.0968.
C14H16NO4 requires 262.1074.
4.3.4. Ethyl 1-benzyl-6-methoxy-2-oxo-1,2-dihydroquinoline-4-
carboxylate (11d)
Ethyl
sulfonyl)butanoate 10d (241 mg, 501
ethylhexanoate (175 mg, 100 mol%) and DIPEA (209 m
4-(benzyl(4-methoxyphenyl)amino)-4-oxo-2-(phenyl-
mol), copper(II) 2-
L,
One-pot synthesis from 7a: To a stirred solution of ethyl 2-
m
(phenylsulfonyl)acetate (50 mg, 219
was added KOtBu (27.0 mg, 241 mol) and held for 5 min. 2-Bromo-
mol) in mesitylene
mmol) in mesitylene (2.25 mL)
m
1.20 mmol) in mesitylene (15 mL) were subjected to standard
procedure C at 165 ꢀC for 18 h. Purification by flash column chro-
matography (7:3 Hexane/EtOAc) afforded the title compound 11d
N-methyl-N-phenylacetamide 7a (50 mg, 439
m
(0.5 mL) was added and stirring continued for 1 h at 60 ꢀC under an
atmosphere of air. Copper(II) 2-ethylhexanoate (77 mg, 100 mol%),
(117 mg, 344 mmol, 69%) as an orange solid; Rf: 0.18 (7:3 Hexane/
DIPEA (89
m
L, 526
m
mol) and mesitylene (1.75 mL) were added to
EtOAc); nmax/cmꢁ1 (neat): 1723 (C]O), 1655 (C]O), 1617, 1590,
1563, 1496, 1454, 1431; dH (400 MHz, CDCl3): 7.91 (1H, d, J ¼ 2.8 Hz),
7.34 (1H, s), 7.30e7.13 (5H, m), 7.04 (1H, dd, J ¼ 9.3, 2.9 Hz), 5.54
(2H, br s), 4.44 (2H, q, J ¼ 7.1 Hz), 3.80 (3H, s), 1.42 (3H, t, J ¼ 7.1 Hz);
dC (100 MHz, CDCl3): 165.3 (C), 161.0 (C), 154.9 (C), 138.2 (C), 135.8
the reaction mixture and stirred at 165 ꢀC for 16 h under an at-
mosphere of air. The solvent was removed under reduced pressure
and EtOAc (10 mL) was added. The solution was washed with 10%
HCl solution (8 mL), 10% aqueous NH4OH solution (8 mL), brine

8
R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
(C), 134.2 (C), 128.7 (CH), 127.3 (CH), 126.4 (CH), 124.8 (CH), 119.9
(CH), 118.5 (C), 116.5 (CH), 108.8 (CH), 61.9 (CH2), 55.5 (Me), 46.2
(CH2), 14.1 (Me); HRMS [ESþ] found MNaþ, 360.1211. C20H19NNaO4
requires 360.1206.
4.42 (2H, q, J ¼ 7.1 Hz), 4.19 (2H, t, J ¼ 6.0 Hz), 2.98 (2H, t, J ¼ 6.0 Hz),
2.09 (2H, quint, J ¼ 6.0 Hz), 1.41 (3H, t, J ¼ 7.1 Hz); dC (100 MHz,
CDCl3): 165.5 (C), 160.9 (C), 138.9 (C), 137.0 (C), 130.5 (CH), 125.0
(CH), 124.9 (CH), 123.4 (CH), 122.2 (C), 117.3 (C), 61.9 (CH2), 42.7
(CH2), 27.9 (CH2), 20.4 (CH2), 14.1 (Me); HRMS [ESþ] found MHþ,
258.1125. C15H16NO3 requires 258.1125.
4.3.5. Ethyl 6-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-
dihydroquinoline-4-carboxylate (11e)
Ethyl 4-((4-methoxybenzyl)(4-methoxyphenyl)amino)-4-oxo-
4.3.8. Ethyl 3-oxo-5,6,7,8-tetrahydro-3H-azepino[3,2,1-ij]
2-(phenylsulfonyl)butanoate 10e (491 mg, 960
mmol), copper(II) 2-
quinoline-1-carboxylate (11h)
ethylhexanoate (336 mg, 100 mol%) and DIPEA (400
m
L, 2.30 mmol)
Ethyl
benzo[b]azepin-1-yl)butanoate ethyl 4-oxo-2-(phenylsulfonyl)-4-
(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)butanoate 10h
(72 mg, 173 mol), copper(II) 2-ethylhexanoate (60.0 mg, 100 mol%)
and DIPEA (72.3
4-oxo-2-(phenylsulfonyl)-4-(2,3,4,5-tetrahydroꢁ1H-
in mesitylene (27 mL) were subjected to standard procedure C at
165 ꢀC for 18 h. Purification by flash column chromatography (7:3
Hexane/EtOAc) afforded the title compound 11e (232 mg, 631
mmol,
m
66%) as an orange solid; Rf: 0.19 (7:3 Hexane/EtOAc); m.p.
84e86 ꢀC; nmax/cmꢁ1 (neat): 2937, 1725 (C]O), 1656 (C]O), 1513,
1431,1247; dH (400 MHz, CDCl3): 7.91 (1H, d, J ¼ 2.9 Hz), 7.33 (1H, s),
7.25 (1H, d, J ¼ 9.5 Hz), 7.11 (2H, d, J ¼ 8.7 Hz), 7.07 (1H, dd, J ¼ 9.5,
2.9 Hz), 6.80 (2H, d, J ¼ 8.7 Hz), 5.48 (2H, s), 4.44 (2H, q, J ¼ 7.1 Hz),
3.82 (3H, s), 3.73 (3H, s), 1.43 (3H, t, J ¼ 7.1 Hz); dC (100 MHz, CDCl3):
165.4 (C), 161.0 (C), 158.8 (C), 154.9 (C), 138.2 (C), 134.3 (C), 127.9 (C),
127.8 (CH), 125.0 (CH), 120.0 (CH), 118.6 (C), 116.6 (CH), 114.2 (CH),
108.8 (CH), 62.0 (CH2), 55.6 (Me), 55.2 (Me), 45.7 (CH2), 14.1 (Me);
HRMS [ESþ] found MNaþ, 390.1301. C21H21NNaO5 requires
390.1312.
mL, 416 mmol) in mesitylene (5.5 mL) were sub-
jected to standard procedure C at 165 ꢀC for 18 h. Purification by
flash column chromatography (13:7 Hexane/EtOAc) afforded the
title compound 10h (36 mg, 311 mmol, 77%) as an orange oil; Rf: 0.22
(13:7 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2937, 1728 (C]O), 1655
(C]O), 1587, 1448, 1243; dH (400 MHz, CDCl3): 8.01 (1H, d,
J ¼ 7.6 Hz), 7.30 (1H, d, J ¼ 7.6 Hz), 7.12 (1H, t, J ¼ 7.6 Hz), 7.07 (1H, s),
4.46e4.38 (4H, m), 3.17e3.11 (2H, m), 2.14e2.05 (2H, m), 2.02e1.93
(2H, m), 1.39 (3H, t, J ¼ 7.3 Hz); dC (100 MHz, CDCl3): 165.7 (C), 162.4
(C), 141.7 (C), 139.8 (C), 133.7 (CH), 130.7 (C), 124.7 (CH), 123.4 (CH),
122.7 (CH), 118.7 (C), 61.9 (CH2), 44.8 (CH2), 33.2 (CH2), 25.4 (CH2),
23.8 (CH2), 14.1 (Me); HRMS [ESþ] found MNaþ, 294.1093.
4.3.6. Ethyl 1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-
C16H17NNaO3 requires 294.1101.
carboxylate (11f)
Ethyl
sulfonyl)butanoate 10f (141 mg, 336
ethylhexanoate (117 mg, 100 mol%) and DIPEA (140
4-(methyl(4-nitrophenyl)amino)-4-oxo-2-(phenyl-
mol), copper(II) 2-
L, 336 mol)
4.3.9. Ethyl 1,3-dimethyl-2-oxo-1,2-dihydroquinoline-4-
carboxylate (11i)
m
m
m
Ethyl
sulfonyl)butanoate 10i (167 mg, 429
ethylhexanoate (150 mg, 100 mol%) and DIPEA (179
3-methyl-4-(methyl(phenyl)amino)-4-oxo-2-(phenyl-
mol), copper(II) 2-
L, 1.03 mmol)
in mesitylene (10 mL) were subjected to standard procedure C at
m
165 ꢀC for 18 h. Purification by flash column chromatography (3:2
m
Hexane/EtOAc) afforded the title compound 11f (21 mg, 76
m
mol,
in mesitylene (12 mL) were subjected to standard procedure C at
23%) as yellow solid; Rf: 0.26 (1:1 Hexane/EtOAc); m.p.
a
165 ꢀC for 18 h. Purification by flash column chromatography (5:2
147e151 ꢀC; nmax/cmꢁ1 (neat): 1725 (C]O),1671 (C]O),1607,1524,
1342, 1301; dH (400 MHz, CDCl3): 9.44 (1H, d, J ¼ 2.6 Hz), 8.44 (1H,
dd, J ¼ 9.4, 2.6 Hz), 7.50 (1H, d, J ¼ 9.4 Hz), 7.40 (1H, s), 4.49 (2H, q,
J ¼ 7.1 Hz), 3.80 (3H, s), 1.46 (3H, t, J ¼ 7.1 Hz); dC (100 MHz, CDCl3):
171.3 (C), 164.2 (C), 161.2 (C), 144.1 (C), 137.8 (C), 126.7 (CH), 125.6
(CH), 123.8 (CH), 117.2 (C), 115.1 (CH), 62.6 (CH2), 30.4 (Me), 14.1
(Me); HRMS [ESþ] found MHþ, 277.0820. C13H13N2O5 requires
277.0819.
Hexane/EtOAc) afforded the title compound 11i (90 mg, 367 mmol,
86%) as an orange solid; Rf: 0.34 (1:1 Hexane/EtOAc); m.p.
68e70 ꢀC; nmax/cmꢁ1 (neat): 2982, 1730 (C]O), 1646 (C]O), 1600,
1590, 1464, 1226; dH (400 MHz, CDCl3): 7.52 (1H, t, J ¼ 8.5 Hz), 7.42
(1H, d, J ¼ 8.5 Hz), 7.34 (1H, d, J ¼ 8.5 Hz), 7.22 (1H, t, J ¼ 8.5 Hz),
4.50 (2H, q, J ¼ 7.2 Hz), 3.74 (3H, s), 2.23 (3H, s), 1.43 (3H, t,
J ¼ 7.2 Hz); dC (100 MHz, CDCl3): 167.0 (C), 162.0 (C), 139.0 (C), 138.7
(C),130.0 (CH), 126.9 (C), 125.5 (CH), 122.4 (CH), 117.1 (C), 114.4 (CH),
61.9 (CH2), 30.0 (Me), 14.9 (Me), 14.2 (Me); HRMS [ESþ] found
MNaþ, 368.0943. C14H15NNaO3 requires 268.0944.
Also isolated was ethyl (E)-4-(methyl(4-nitrophenyl)amino)-4-
oxobut-2-enoate 11f′ (32 mg, 115 mmol, 34%) as a brown solid; Rf:
0.37 (1:1 Hexane/EtOAc); nmax/cmꢁ1 (neat): 2983, 1720 (C]O),
1665 (C]O), 1592, 1521, 1496, 1341, 1301, 1177; dH (400 MHz,
CDCl3): 8.30 (2H, d, J ¼ 8.3 Hz), 7.35 (2H, d, J ¼ 8.3 Hz), 6.86 (2H, s),
4.16 (2H, q, J ¼ 7.3 Hz), 3.44 (3H, s), 1.25 (3H, t, J ¼ 7.3 Hz); dC
(100 MHz, CDCl3): 165.2 (C), 163.8 (C), 148.2 (C), 146.2 (C), 133.3
(CH), 132.4 (CH), 127.2 (CH), 125.2 (CH), 61.2 (CH2), 37.5 (Me), 14.0
(Me); HRMS [ESþ] found MHþ, 279.0971. C13H15N2O5 requires
279.0975.
4.3.10. 4-Benzoyl-1-methylquinolin-2(1H)-one [30] (11j)
N-Methyl-4-oxo-N,4-diphenyl-3-(phenylsulfonyl)butanamide
10j (100 mg, 245
mmol), copper(II) 2-ethylhexanoate (85.9 mg,
100 mol%) and DIPEA (102
m
L, 589 mmol) in mesitylene (7 mL) were
subjected to standard procedure C at 165 ꢀC for 18 h. Purification by
flash column chromatography (13:7 Hexane/EtOAc) afforded the
title compound 11j (49 mg, 186 mmol, 76%) as an orange solid; Rf:
0.19 (13:7 Hexane/EtOAc); m.p. 83e85 ꢀC; nmax/cmꢁ1 (neat): 1656
(C]O), 1589, 1452, 1250; dH (400 MHz, CDCl3): 7.94 (2H, d,
J ¼ 8.0 Hz), 7.67e7.59 (2H, m), 7.56e7.44 (4H, m), 7.19 (1H, t,
J ¼ 8.0 Hz), 6.72 (1H, s), 3.79 (3H, s); dC (100 MHz, CDCl3): 194.7 (C),
161.2 (C), 147.2 (C), 140.3 (C), 135.7 (C), 134.5 (CH), 131.4 (CH), 130.2
(CH), 128.8 (CH), 127.0 (CH), 122.6 (CH), 120.5 (CH), 118.1 (C), 114.7
(CH), 29.7 (Me); HRMS [ESþ] found MNaþ, 286.0833. C17H13NNaO2
requires 286.0838.
4.3.7. Ethyl 5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-7-
carboxylate (11g)
Ethyl 2-(benzenesulfonyl)-4-oxo-4-(1,2,3,4-tetrahydroquinolin-
1-yl)butanoate
10g
(230 mg,
574
m
mol),
copper(II)
2-
L,
ethylhexanoate (201 mg, 100 mol%) and DIPEA (240
m
1.38 mmol) in mesitylene (12 mL) were subjected to standard
procedure C at 165 ꢀC for 18 h. Purification by flash column chro-
matography (1:1 Hexane/EtOAc) afforded the title compound 11g
Also isolated was (E)-N-methyl-4-oxo-N,4-diphenylbut-2-
(80 mg, 311
m
mol, 54%) as an orange solid; Rf: 0.24 (1:1 Hexane/
enamide [31] 11j′ (14 mg, 52.8 mmol, 22%) as an orange solid; Rf:
EtOAc); m.p. 134e136 ꢀC; nmax/cmꢁ1 (neat): 2937, 1718 (C]O), 1641
(C]O), 1582, 1431, 1232, 1066; dH (400 MHz, CDCl3): 8.13 (1H, d,
J ¼ 8.0 Hz), 7.32 (1H, d, J ¼ 7.7 Hz), 7.16 (1H, t, J ¼ 7.7 Hz), 7.15 (1H, s),
0.26 (13:7 Hexane/EtOAc); m.p. 65e68 ꢀC; nmax/cmꢁ1 (neat): 1644
(C]O), 1594, 1495, 1374, 1306; dH (400 MHz, CDCl3): 7.98 (1H, d,
J ¼ 15.3 Hz), 7.98 (2H, d, J ¼ 7.6 Hz), 7.59 (1H, t, 7.6 Hz), 7.48 (2H, t,

R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
9
J ¼ 7.6 Hz), 7.45 (2H, t, J ¼ 7.6 Hz), 7.37 (1H, t, J ¼ 7.6 Hz), 7.20 (2H, d,
J ¼ 7.6 Hz), 6.93 (1H, d, J ¼ 15.3 Hz), 3.44 (3H, s); dC (100 MHz,
CDCl3): 189.8 (C), 164.7 (C), 142.8 (C), 137.0 (C), 133.8 (CH), 133.7
(CH), 133.4 (CH), 130.0 (C), 128.91 (C), 128.88 (C), 128.3 (CH), 127.2
(CH), 38.0 (CH); HRMS [ESþ] found MNaþ, 288.0989. C17H15NNaO2
requires 288.0995.
(37 mg, 101
m
mol) in CH2Cl2 (1.01 mL) at ꢁ78 ꢀC was added BBr3
(1 M solution in CH2Cl2, 605 mL, 605 mmol). The solution was
allowed to warm to room temperature and stirred for 16 h. The
reaction mixture was quenched with brine (5 mL) and extracted
with EtOAc (3 ꢂ 5 mL). The combined organic extracts were washed
with brine (5 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography afforded the
4.3.11. 1-Methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile [32]
(11k)
title compound 1a (15 mg, 64.4 mmol, 64%) as a colourless solid.
3-Cyano-N-methyl-N-phenyl-3-(phenylsulfonyl)propanamide
4.4. 2-Bromo-N-(2,7-dimethylbenzofuran-4-yl)-N-
methylacetamide
10k (76 mg, 231
mmol), copper(II) 2-ethylhexanoate (81.0 mg,
100 mol%) and DIPEA (96.6
m
L, 555 mmol) in mesitylene (7 mL) were
subjected to standard procedure C at 165 ꢀC for 18 h. Purification by
flash column chromatography (3:2 Hexane/EtOAc) afforded the ti-
N,2,7-Trimethylbenzofuran-4-amine (1.13 g, 6.42 mmol), trie-
thylamine (971
mL, 6.98 mmol), CH2Cl2 (7 mL) and bromoacetyl
tle compound 11k (24 mg, 130
mmol, 56%) as an orange solid; Rf:
bromide (607 L, 6.98 mmol) in CH2Cl2 (10 mL) were subjected to
m
0.22 (3:2 Hexane/EtOAc); m.p. 127e129 ꢀC (Lit [32]. 165e166 ꢀC);
nmax/cmꢁ1 (neat): 1659 (C]O), 1593, 1457; dH (400 MHz, CDCl3):
7.96 (1H, dd, J ¼ 7.6, 1.5 Hz), 7.72 (1H, t, J ¼ 8.4 Hz), 7.46 (1H, d,
J ¼ 8.4 Hz), 7.41 (1H, t, J ¼ 7.6 Hz), 7.17 (1H, s), 3.76 (3H, s); dC
(100 MHz, CDCl3): 159.8 (C), 140.0 (C), 132.5 (CH), 128.8 (CH), 126.8
(CH),123.3 (CH),122.5 (C),117.6 (C),114.8 (C),114.3 (C-5), 29.8 (C-7);
HRMS [ESþ] found MNaþ, 207.0531. C11H8N2NaO requires 207.0529.
general procedure A. Purification by flash column chromatography
(3:2 Hexane/EtOAc) afforded the title compound (1.670 g,
5.64 mmol, 88%) as a colourless solid; Rf: 0.21 (3:2 Hexane/EtOAc);
m.p. 64e66 ꢀC; nmax/cmꢁ1 (neat): 3107, 2917, 1672 (C]O), 1505,
1371, 1186; dH (400 MHz, CDCl3): 7.02 (1H, d, J ¼ 7.8 Hz), 6.98 (1H, d,
J ¼ 7.8 Hz), 6.31 (1H, s), 3.66e3.64 (2H, m), 3.31 (3H, s), 2.51 (3H, s),
2,48 (3H, s); dC (100 MHz, CDCl3): 166.9 (C), 156.8 (C), 154.3 (C),
131.9 (C), 125.9 (C), 124.5 (CH), 121.7 (C), 121.1 (CH), 100.1 (CH), 37.3
4.3.12. Ethyl 6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate
[2] (1b)
(Me), 27.1 (CH2), 14.8 (Me), 14.1 (Me); HRMS [ESþ] found MHþ
79
296.0281. C13H BrNO2 requires 296.0281.
15
Ethyl
6-methoxy-1-(4-methoxybenzyl)-2-oxo-1,2-
mol) in TFA
dihydroquinoline-4-carboxylate 11e (100 mg, 272
m
4.5. Ethyl 4-((2,7-dimethylbenzofuran-4-yl)(methyl)amino)-4-oxo-
2-(phenylsulfonyl)butanoate (12)
(2 mL) was stirred at 85 ꢀC for 18 h. The reaction mixture was added
dropwise to cold saturated NaHCO3 solution (20 mL) then extracted
with EtOAc (3 ꢂ 10 mL). The combined organic layers were washed
with brine (20 mL) and concentrated in vacuo. Purification by flash
column chromatography (3:1 Hexane/EtOAc) afforded the title
compound 1b (55 mg, 0.22 mmol, 82%) as a yellow solid; Rf: 0.27
Ethyl 2-(phenylsulfonyl)acetate (578 mg, 2.54 mmol) and KOtBu
(303 mg, 2.70 mmol) in THF (20 mL) and 2-bromo-N-(2,7-
dimethylbenzofuran-4-yl)-N-methylacetamide
(500 mg,
1.69 mmol) in THF (7.5 mL) were subjected to general procedure B
for 18 h. Purification by flash column chromatography (7:3 Hexane/
(1:3 Hexane/EtOAc); m.p. 140e143 ꢀC (Lit [2]. 183e186 ꢀC); nmax
/
cmꢁ1 (neat): 2991, 1726 (C]O), 1681 (C]O), 1623, 1503, 1448,
1234; dH (400 MHz, DMSO‑d6): 12.04 (1H, s), 7.60 (1H, d, J ¼ 2.6 Hz),
7.31 (1H, d, J ¼ 8.9 Hz), 7.24 (1H, dd, J ¼ 8.9, 2.6 Hz), 6.92 (1H, s), 4.38
(2H, q, J ¼ 6.9 Hz), 3.33 (3H, s), 1.35 (3H, t, J ¼ 6.9 Hz); dC (100 MHz,
DMSO‑d6): 165.6 (C), 160.9 (C), 154.9 (C), 139.8 (C), 134.6 (C), 125.4
(CH), 120.8 (CH), 117.8 (CH), 116.6 (C), 108.0 (CH), 62.4 (CH2), 55.9
(Me), 14.5 (Me); HRMS [ESþ] found MNaþ, 270.0743. C13H13NNaO4
requires 270.0737.
EtOAc) afforded the title compound 12 (678 mg,1.53 mmol, 90%) as a
colourless gum; Rf: 0.35 (1:1 Hexane/EtOAc); nmax/cmꢁ1 (neat):
2925, 1738 (C]O), 1658 (C]O), 1324 (S]O), 1188, 1148 (S]O); dH
(400 MHz, CDCl3): 7.72 (2H, d, J ¼ 7.8 Hz), 7.62 (1H, t, J ¼ 7.8 Hz), 7.47
(2H, t, J ¼ 7.8 Hz), 7.01 (1H, d, J ¼ 7.8 Hz), 6.96e6.89 (1H, m), 6.27
(1H, s), 4.54e4.47 (1H, m), 4.12e3.96 (2H, m), 3.23 (3H, s),
3.10e3.61 (2H, m), 2.52 (3H, s), 2.46 (3H, s), 1.04 (3H, t, J ¼ 7.15 Hz);
dC (100 MHz, CDCl3): 168.7 (C), 165.2 (C), 156.6 (C), 154.3 (C), 137.6
(C), 134.0 (CH), 131.6 (C), 128.8 (CH), 128.7 (CH), 126.0 (C), 124.7
(CH), 121.4 (C), 121.2 (CH), 100.0 (CH), 66.7 (CH), 62.1 (CH2), 36.7
(Me), 30.6 (CH2), 14.8 (Me), 14.1 (Me), 13.6 (Me); HRMS [ESþ] found
MHþ, 444.1479. C23H26NO6S requires 444.1475.
4.3.13. Ethyl 6-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate
[2] (1a)
From 1b: To a stirred solution of ethyl 6-methoxy-2-oxo-1,2-
dihydroquinoline-4-carboxylate 1b (28 mg, 113 mmol) in CH2Cl2
(1.13 mL) at ꢁ78 ꢀC was added BBr3 (1 M solution in CH2Cl2, 340
m
L,
4.6. Ethyl 1,6,8-trimethyl-2-oxo-1,2dihydrofuro[2,3-h]quinoline-4-
carboxylate (13)
340
m
mol). The solution was allowed to warm to room temperature
and stirred for 16 h. The reaction mixture was quenched with brine
(5 mL) and extracted with EtOAc (3 ꢂ 5 mL). The combined organic
extracts were washed with brine (5 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatog-
Ethyl 4-((2,7-dimethylbenzofuran-4-yl)(methyl)amino)-4-oxo-
2-(phenylsulfonyl)butanoate 12 (270 mg, 609
mmol), copper(II) 2-
ethylhexanoate (416 mg, 200 mol%) and DIPEA (254
mL,
raphy afforded the title compound 1a (25 mg, 107
m
mol, 95%) as a
1.46 mmol mmol) in mesitylene (18 mL) were subjected to standard
colourless solid; Rf: 0.22 (19:1 Hexane/EtOAc); m.p. > 200 ꢀC; nmax
/
procedure C at 165 ꢀC for 18 h. Purification by flash column chro-
matography (13:7 Hexane/EtOAc) afforded the title compound 13
cmꢁ1 (neat): 3289 (OeH), 1712 (C]O), 1654 (C]O), 1615, 1423,
1254; dH (400 MHz, DMSO‑d6): 11.93 (1H, s), 9.54 (1H, s), 7.46 (1H,
d, J ¼ 2.6 Hz), 7.22 (1H, d, J ¼ 8.9 Hz), 7.06 (1H, dd, J ¼ 8.9, 2.6 Hz),
6.85 (1H, s), 4.36 (2H, q, J ¼ 6.9 Hz), 1.34 (3H, t, J ¼ 6.9 Hz); dC
(100 MHz, DMSO‑d6): 166.1 (C), 161.1 (C), 153.4 (C), 140.2 (C), 133.7
(C), 125.0 (CH), 121.6 (CH), 117.8 (CH), 117.2 (C), 110.4 (CH), 62.7
(CH2), 14.8 (Me); HRMS [ESþ] found MNaþ, 256.0577. C12H11NNaO4
requires 256.0580.
(52 mg, 174 mmol, 29%) as an orange oil; Rf: 0.22 (1:1 Hexane/
EtOAc); nmax/cmꢁ1 (neat): 2924, 1726 (C]O), 1652 (C]O), 1590,
1236; dH (400 MHz, CDCl3): 7.86 (1H, s), 7.06 (1H, s), 6.91 (1H, s),
4.46 (2H, q, J ¼ 7.3 Hz), 4.03 (3H, s), 2.53 (6H, s), 1.44 (3H, t,
J ¼ 7.3 Hz); dC (100 MHz, CDCl3): 166.4 (C), 162.0 (C), 155.9 (C), 154.6
(C), 140.4 (C), 134.4 (C), 122.5 (CH), 120.4 (CH), 117.8 (C), 113.0 (C),
104.5 (CH), 62.2 (CH2) 33.5 (Me), 15.2 (Me), 14.4 (Me), 14.1 (Me);
HRMS [ESþ] found MNaþ, 322.1043. C17H17NNaO4 requires
322.1050.
From 11e: To a stirred solution of ethyl 6-methoxy-1-(4-
methoxybenzyl)-2-oxo-1,2-dihydroquinoline-4-carboxylate
11e

10
R.M. Gorman et al. / Tetrahedron 75 (2019) 130711
C. Schubert, M.A. Chaikin, C. Crysler, I.P. Petrounia, R.R. Donatelli, E.J. Yurkow,
Also isolated was ethyl (E)-4-((2,7-dimethylbenzofuran-4-
yl)(methyl)amino)-4-oxobut-2-enoate 13′ (66 mg, 285 mol, 36%)
L. Boczon, M. Mazzulla, M.R. Player, R.J. Patch, C.L. Manthey, C. Molloy,
B. Tomczuk, C.R. Illig, Bioorg. Med. Chem. Lett 18 (2008) 2097;
b) M.H. Chen, P. Fitzgerald, S.B. Singh, E.A. O'Neill, C.D. Schwartz,
C.M. Thompson, S.J. O'Keefe, D.M. Zaller, J.B. Doherty, Bioorg. Med. Chem. Lett
18 (2008) 2222.
m
as an orange oil; Rf: 0.61 (1:1 Hexane/EtOAc); nmax/cmꢁ1 (neat):
2927, 1720 (C]O), 1661 (C]O), 1508, 1369, 1293; dH (400 MHz,
CDCl3): 7.00 (1H, d, J ¼ 7.6 Hz), 6.86 (1H, d, J ¼ 7.6 Hz), 6.86 (1H, d,
J ¼ 15.3 Hz), 7.68 (1H, d, J ¼ 15.3 Hz), 6.24 (1H, s), 4.12 (2H, q,
J ¼ 7.3 Hz), 3.38 (3H, s), 2.51 (3H, s), 2.46 (3H, s), 1.21 (3H, t,
J ¼ 7.3 Hz); dC (100 MHz, CDCl3): 165.6 (C), 164.3 (C), 156.6 (C), 154.2
(C), 134.2 (CH) 131.5 (C), 130.8 (CH), 125.9 (C), 124.5 (CH), 121.4 (C),
121.3 (CH), 100.1 (CH), 60.8 (CH2) 36.9 (Me), 14.8 (Me), 14.1 (Me),
13.9 (Me); HRMS [ESþ] found MNaþ, 324.1206. C17H19NNaO4 re-
quires 324.1212.
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h]quinoline-4-carboxylate 13 (40 mg, 0.13 mmol) in dry THF (5 mL)
at 0 ꢀC under Ar atmosphere, was added in one portion, LiAl-
H(OtBu)3 (70 mg, 0.27 mmol). The reaction was warmed slowly to
room temperature and stirred for 36 h. A solution of 10% aqueous
HCl (6 mL) was then added and the mixture stirred at this tem-
perature for 1 h before the THF was removed in vacuo. The solid was
filtered and washed with cold MeOH afford the title compound
ꢀ
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ꢀ
DMSO‑d6): 7.40 (1H, s), 7.24 (1H, s), 6.64 (1H, s), 5.50 (1H, t,
J ¼ 5.6 Hz), 4.78 (2H, dd, J ¼ 5.6, 1.1 Hz), 3.90 (3H, s), 2.52 (3H, br s),
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258.1125. The data obtained was consistent with those previously
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Acknowledgments
We thank the EPSRC for postdoctoral support (T. E. H., EP/
J000124/1). We also thank CHEM21 for postgraduate support (R. M.
G.). The research for this work has received funding from the
Innovative Medicines Initiative joint undertaking project CHEM21
(https://www.chem21.eu/) grant agreement no. 115360, resources
of which are composed of financial contribution from the European
Union's Seventh Framework Programme (FP7/2007e2013) and
EFPIA companies in kind contribution. We are also grateful to the
South African National Research Foundation (NRF/95404, W.F.P) for
their financial support. The accompanying Electronic Supplemen-
tary Information (ESI) contains additional spectroscopic data.
f) P. Drouhin, T.E. Hurst, A.C. Whitwood, R.J.K. Taylor, Org. Lett. 16 (2014)
4900;
g) T.E. Hurst, R. Gorman, P. Drouhin, A. Perry, R.J.K. Taylor, Chem. Eur J. 20
(2014) 14063;
ꢁ
h) C.L. Moody, V. Franckevicius, P. Drouhin, J.E.M.N. Klein, R.J.K. Taylor, Tet-
rahedron Lett. 53 (2012) 1897;
i) D.S. Pugh, J.E.M.N. Klein, A. Perry, R.J.K. Taylor, Synlett (2010) 934;
j) A. Perry, R.J.K. Taylor, Chem. Commun. 3249 (2009);
k) For a photoredox approach to related systems from our laboratories see:
W.F. Petersen, R.J.K. Taylor, J.R. Donald Org. Lett. 19 (2017) 874;
l) W.F. Petersen, R.J.K. Taylor, J.R. Donald, Org. Biomol. Chem. 15 (2017) 5831.
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Appendix A. Supplementary data
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