Conjugate addition - SNAr domino reaction for the synthesis of benzo- or pyridyl-fused lactams and sultams

Article abstract of DOI:10.1055/s-0030-1258302

A versatile domino reaction that can be used for the synthesis of bicyclic benzo- or pyridyl-fused lactam and sultam derivatives is presented, enabling rapid synthesis of a variety of complex structures

Full text of DOI:10.1055/s-0030-1258302

PAPER
4273
Conjugate Addition – SNAr Domino Reaction for the Synthesis of Benzo- or
Pyridyl-Fused Lactams and Sultams
Conjugate
A
dditio
i
n
– S
A
Ne
r
Domino
l
Reactio
s
n
Grøn Nørager,a,b Karsten Juhl*a
a
Medicinal Chemistry Research Denmark, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Fax +4536438237; E-mail: kaju@lundbeck.com
b
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
Received 30 July 2010; revised 21 September 2010
CO2Et
Abstract: A versatile domino reaction that can be used for the syn-
thesis of bicyclic benzo- or pyridyl-fused lactam and sultam deriv-
atives is presented, enabling rapid synthesis of a variety of complex
structures.
F
F
N
R3
1. NaHMDS
2.
N
–
H
N
CO2Et
R2
N
R1
R2
O
R1
R3
Key words: bicyclic compounds, domino reactions, heterocycles,
O
Michael addition, nucleophilic aromatic substitution
CO2Et
N
R3
R2
The domino reaction methodology in organic synthesis
has, in recent years, evolved into an efficient tool for mak-
ing, for example, heterocyclic structures, and has allowed
a rapid increase in molecular complexity, potentially lead-
ing to more efficient and environmentally benign synthet-
ic processes.1
N
O
R1
Scheme 1 Proposed reaction mechanism
Derivatives of benzo- and pyridyl-fused lactams and sul-
tams span several important classes of bicyclic heterocy-
cles. The isoquinolinone and naphthyridinone skeletons
have been found in naturally occurring alkaloids2 such as
dorianine3 and ruprechstyril,4 and a variety of biological
and medicinal activities have been reported, such as NK3
receptor antagonism5 and topoisomerase I inhibition.6
Benzo-fused sultams also show diverse biological activi-
ties, and a number of nonsteroidal anti-inflammatory
agents (NSAIDs) based on the benzo-fused sultam skele-
ton, are commercially available, such as Meloxicam,7
Ampiroxicam,8 and Piroxicam.9
on a conjugate addition – nucleophilic aromatic substitu-
tion domino reaction (Scheme 1).
We hypothesized that a deprotonated amide would add to
a conjugate addition acceptor, creating an enolate inter-
mediate, which would subsequently add to the aromatic
moiety in a nucleophilic aromatic substitution reaction.
2-Fluoro-N-phenylnicotinamide (1a) and ethyl 3-phenyl-
propiolate (2a) were used as model substrates in an initial
optimization study (Table 1). The reaction was carried out
by deprotonation of the amide at room temperature, fol-
lowed by addition of the alkyne and heating. Reaction
temperature and time were the first parameters optimized
(entries 1–6). Formation of the sterically crowded product
required high temperatures; however, full conversion of
the amide was obtained within hours at temperatures at or
above 200 °C using microwave irradiation. Screening of
different solvents showed that the polar aprotic solvents
N,N-dimethylformamide (DMF) and N-methyl-2-pyrroli-
dinone (NMP) gave better results for this reaction (entries
4 and 7–9). Different hexamethyldisilazane (HMDS)
bases were screened, and the results showed that use of
NaHMDS increased the yield slightly (entries 10–12).
Employing a larger excess of base (4 equiv) led to com-
plex mixtures of side products and none of the desired
product was formed (entries 13 and 14). Full conversion
of the amide was obtained when 2.0 equivalents of alkyne
was used (entries 10 and 15–18). The excess was required
because the predominant side products of the reaction re-
sulted from oligomerization of the conjugate addition in-
termediates prior to the ring-closing nucleophilic
aromatic substitution. In these cases, the subsequent lack
Several approaches to the synthesis of isoquinolinone and
naphthyridinone derivatives have been reported, such as
condensation reactions,10 Baylis–Hillman reactions,11 ni-
trogen substitution of isocoumarins,12 aromatic substitu-
tions,13 and a number of transition-metal-based catalytic
reactions.14 Synthesis of benzo- and pyridyl-fused sultams
have not received the same attention, although some syn-
thetic approaches have been reported, such as ring expan-
sion of benzoisothiazoles,15 intramolecular free radical
substitutions,16 and organometallic cyclization reac-
tions.17
The broad applicability of these bicyclic structures justi-
fies continuing research into new approaches to their syn-
thesis. We envisioned, and describe here, a method based
SYNTHESIS 2010, No. 24, pp 4273–4281
x
x.
x
x
.
2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1258302; Art ID: T15710SS
© Georg Thieme Verlag Stuttgart · New York

4274
N. G. Nørager, K. Juhl
PAPER
the ring-closing step. Additionally, attempts were made
using the terminal alkyne ethyl propriolate and the TMS-
protected analogue, ethyl 3-(trimethylsilyl)propiolate;
however, in both cases, oligomerization was the predom-
inant outcome. A modified reaction method (method B),
involving slow addition of a dilute solution of the alkyne
to a pre-heated, deprotonated amide solution, improved
yields in some cases (entry 6). However, temperatures
were restricted to 150 °C because higher temperatures led
to dimerization of the amide substrates. Both simple alkyl
and aryl groups, 1b and 1c, were tolerated as the amide N-
substituent (R2) (entries 2 and 3). Furthermore, a Boc-pro-
tected hydrazide moiety (1f,g,h) was also tolerated; how-
ever, these substrates led to lower yields because reaction
temperatures were restricted to 100 °C, due to decompo-
sition of the Boc group at higher temperatures (entries 7–
9). Surprisingly, double halogenation of the aromatic ring
led to extensive oligomerization, despite further activa-
tion of the nucleophilic aromatic substitution step. In-
creased steric interactions could explanation this
observation, particularly at these lower temperatures.
Table 1 Optimization of Reaction Conditions
CO2Et
N
Ph
Ph
N
F
1. base
Ph
H
N
O
N
Ph
CO2Et
2.
O
1a
2a
3a
Entry Solvent Base (equiv)
Alkyne Temp Time Yield
(equiv) (°C)a (h)
(%)b
24
45
53
81
81
85
8
1
2
NMP
NMP
NMP
NMP
NMP
NMP
NaH (1.2)
NaH (1.2)
NaH (1.2)
NaH (1.2)
NaH (1.2)
NaH (1.2)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.2
1.5
4.0
150
150
200
200
225
250
200
200
200
200
200
200
200
200
200
200
200
200
0.5
4.0
0.5
4.0
0.5
0.5
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3
4
5
6
7
toluene NaH (1.2)
8
THF
NaH (1.2)
67
88
90
81
85
0
Sulfonamides were also investigated as substrates for the
domino reaction and showed similar reactivity, albeit with
notable differences (Table 3). A more facile ring-closing
step was expected, given the more electron-withdrawing
properties of the sulfonamide group. Indeed, shorter reac-
tion times and very little oligomerization of the intermedi-
ate were observed, resulting in better yields without the
need for slow alkyne addition (compare Table 2, entry 6
and Table 3, entry 1). Surprisingly, a domino reaction was
achieved when employing an alkyne with two electron-
withdrawing groups, 2d (Table 3, entry 5). However, ster-
ic interactions between the amide N-substituent and the
alkyne substituent seemed to play a bigger role, impeding
the domino reaction when both were bulky phenyl groups.
When either of the phenyl groups was replaced by a small-
er methyl group the domino reaction could proceed
(Table 3, entries 1 and 4).
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NaH (1.2)
10
11
12
13
14
15
16
17
18
NaHMDS (1.2)
KHMDS (1.2)
LiHMDS (1.2)
NaH (4.0)
NaHMDS (4.0)
NaHMDS (1.2)
NaHMDS (1.2)
NaHMDS (1.2)
NaHMDS (1.2)
0
50
55
65
88
a The reaction was heated by microwave irradiation.
b The reaction was evaluated using LC/MS analysis before workup.
The product yield was determined by comparing the peak area to an
internal standard solution using authentic samples as reference.
Unsuccessful attempts were made with both amides and
sulfonamides to utilize activated olefins as the conjugate
acceptors. No conjugate addition of the amides were ob-
served despite heating to 250 °C using microwave irradi-
ation and adding various Lewis acid catalysts.
Intermediate analogues, 6a and 6b, were synthesized and
subjected to the optimized reaction conditions, resulting
in complete retro-conjugate addition at room temperature
within minutes (Scheme 2). This indicates that the retro
addition is faster than the ring-closing step.
of alkyne led to incomplete amide conversion or to dimer-
ization of the amide substrates.
Having obtained a set of optimal conditions, we then ex-
plored the scope of the reaction, starting with various
amide substrates (Table 2).
The range of aromatic rings tolerated by the reaction was
found to extend from simple 2-fluoro-benzene (1b) to
more activated fluoropyridines 1a and 1d, as well as to
less activated 3-methoxy-2-fluorobenzene (1e), in yields
ranging from 40 to 65% (Table 2, entries 1, 2, 4, and 5).
Variation of the alkyne substituent (R3) revealed a notable
influence on the reaction outcome. Simple electron-donat-
ing alkyl and aryl groups were tolerated (entries 1, 6, and
10). However, electron-withdrawing groups, which acti-
vate the alkyne more towards conjugate addition, led to
extensive oligomerization of the intermediate, instead of
To extend the range of target structures, the domino reac-
tion product 3b was hydrolyzed and decarboxylated to
yield 2,3-diphenyl-2H-isoquinolin-1-one (9; Scheme 3).
Complete hydrolysis was achieved in a mixture of meth-
anol and aqueous sodium hydroxide at room temperature
within hours. The carboxylic acid was subsequently de-
carboxylated using microwave-assisted copper-catalyzed
protodecarboxylation in a yield of 89%.18
Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York

PAPER
Conjugate Addition – SNAr Domino Reaction
4275
Table 2 Reaction Scope with Amides
Entry Amide
Alkyne
Product
Methoda Temp
(°C)
Time
(h)
Yield
(%)b
CO2Et
Ph
F
N
CO2Et
N
H
N
1
2
1a
1b
1c
1d
1e
1a
1f
2a
3a
A
A
A
A
A
200
200
200
200
200
4
65
61
52
40
63
N
Ph
Ph
Me
Ph
Ph
O
F
O
CO2Et
Ph
H
N
2a
2a
2a
2a
2b
2b
2b
2b
2c
3b
3c
3d
3e
3f
4
4
4
4
N
Ph
O
F
O
CO2Et
Ph
H
N
3
N
Me
O
O
CO2Et
Ph
F
N
N
H
4
N
N
Ph
Ph
O
O
OMe
OMe CO2Et
Ph
F
5
H
N
N
Ph
Ph
O
O
CO2Et
CO2Et
N
A
B
200
150
4
16
36
48
6
N
O
Ph
CO2Et
F
N
N
N
H
N
N
N
7
3g
3h
3i
B
B
B
A
100
100
100
200
16
16
16
4
41
24
18
53
Pr
N
Pr
N
N
N
N
N
O
F
Boc
O
Boc
CO2Et
H
N
8
1g
1h
1a
Pr
N
Pr
N
F
O
F
Boc
O
Boc
F
CO2Et
H
N
9
Pr
N
Pr
N
Cl
O
Boc
O
Cl
Boc
CO2Et
CO2Et
N
Pr
10
3j
N
Ph
Pr
O
a Method A: Alkyne addition at r.t., and heating using microwave irradiation. Method B: Slow alkyne addition at the reported temperatures.
b Yield of isolated product.
Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York

4276
N. G. Nørager, K. Juhl
PAPER
Table 3 Reaction Scope with Sulfonamides
Entry Amide
Alkyne
Product
Methoda Temp (°C) Time (h) Yield (%)b
CO2Et
N
F
S
N
N
H
1
2
3
4
5
4a
4b
4c
4d
4b
2b
5a
A
A
B
A
B
200
200
150
200
150
1
1
64
75
38
46
36c
N
Ph
Ph
S
Ph
O
O
O
O
O
O
CO2Et
F
S
H
2b
2b
2a
2d
5b
5c
5d
5e
N
N
S
Ph
O
F
O
F
CO2Et
F
S
H
16
4
N
N
Ph
S
Ph
O
O
O
O
O
O
O
CO2Et
Ph
F
S
H
N
N
Me
S
Me
O
O
CO2Et
CF3
CO2Et
16
N
F3C
S
Ph
O
F
a Method A: Alkyne addition at r.t., and heating using microwave irradiation. Method B: Slow alkyne addition at the reported temperatures.
b Yield of isolated product.
c Regioselectivity of the conjugate addition was established using NOESY and ROESY spectroscopic analysis.
CO2Et
the target structures has been extended by decarboxyla-
tion of the domino reaction products.
F
F
CO2Et
NaHMDS
DMF, r.t.
+
H
N
N
8
Me
Me
Oven-dried glassware was used when the reactions were performed
under argon atmosphere. DMF, NMP and THF were dried using
molecular sieves. NaHMDS, LiHMDS and KHMDS were titrated
against 2,6-di-tert-butyl-4-methylphenol with fluorine as indicator.
A solution of L-tryptophan in DMF was used as the internal stan-
dard in the optimization study. All reagents were obtained from
commercial sources and used as received. 1H and 13C NMR spectra
were recorded at either 500 MHz (1H) and 126 MHz (13C), or 600
MHz (1H) and 151 MHz (13C). The solvent (CDCl3, DMSO, or
CD3OD) was used as internal reference. Chemical shifts (d) and
coupling constants (J) are expressed in ppm and Hertz respectively.
High-resolution mass spectrometry (HRMS) was conducted with a
MicroTOF mass spectrometer. Microwave-assisted reactions were
performed with a Biotage Initiator 60 instrument.
O
O
6a
1c
CO2Et
F
F
NaHMDS
DMF, r.t.
CO2Et
H
+
N
N
S
Me
S
8
Me
O
O
F
O
O
F
7
6b
Scheme 2 Retro-conjugate addition
CO2Et
Ph
Ph
Ph
1. MeOH, NaOH, r.t.
2-Fluoro-N-phenylnicotinamide (1a)
N
2. Cu2O, phenanthroline
NMP, quinoline
N
Ph
Aniline (1.5 mL, 16 mmol) was added to 2-fluoronicotinic acid
(2.15 g, 15.2 mmol), N-(3-dimethylaminopropyl)-N¢-ethylcarbodi-
imide hydrochloride (2.91 g, 15.3 mmol) and 1-hydroxybenzotriaz-
ole (2.14 g, 15.8 mmol) in THF (60 mL). The reaction was stirred
at r.t. for 16 h, then the reaction mixture was poured into H2O (50
mL), extracted with EtOAc (3 × 50 mL), washed with sat. aq
NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, fil-
tered and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel (heptane–EtOAc) to obtain 2-
fluoro-N-phenylnicotinamide (1a). Yield: 2.93 g (89%).
O
190 °C, MW
O
3b
9
(89%)
Scheme 3 Decarboxylation of 3b
In conclusion, a versatile domino reaction has been devel-
oped for the synthesis of bicyclic benzo- or pyridyl-fused
lactam and sultam derivatives. Additionally, the scope of
Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York

PAPER
Conjugate Addition – SNAr Domino Reaction
4277
1H NMR (600 MHz, CDCl3): d = 8.67 (ddd, J = 9.8, 7.5, 2.0 Hz,
1 H), 8.54 (d, J = 13.6 Hz, 1 H), 8.44–8.34 (m, 1 H), 7.66–7.63 (m,
2 H), 7.43 (ddd, J = 7.4, 4.8, 2.4 Hz, 1 H), 7.42–7.38 (m, 2 H), 7.20
(ddd, J = 8.5, 2.1, 1.0 Hz, 1 H).
13C NMR (151 MHz, CDCl3): d = 159.7 (d, J = 234 Hz), 159.6,
150.7, 143.8, 137.2, 129.2, 125.3, 122.8, 120.7, 116.4 (d,
J = 27 Hz).
1H NMR (500 MHz, CDCl3): d = 8.40 (d, J = 14.1 Hz, 1 H), 7.70
(m, 3 H), 7.40 (t, J = 7.9 Hz, 2 H), 7.20 (m, 3 H), 3.97 (s, 3 H).
13C NMR (126 MHz, CDCl3): d = 161.7, 150.9 (d, J = 247 Hz),
148.3 (d, J = 13 Hz), 138.1, 129.5, 125.2, 150.0, 123.0, 120.9,
116.9, 57.0.
HRMS (EI): m/z [M + H]+ calcd for C14H13FNO2: 246.0925; found:
246.0921.
HRMS (EI): m/z [M + H]+ calcd for C12H10FN2O: 217.0779; found:
217.0772.
tert-Butyl N¢-(3-Fluoropyridine-4-carbonyl)-N-propylhydra-
zinecarboxylate (1f)
2-Fluoro-N-phenylbenzamide (1b)
Synthesized as for 1a using 2-fluorobenzoic acid and aniline. Yield:
Synthesized as for 1a using 3-fluoronicotinic acid and tert-butyl N-
propylhydrazinecarboxylate.19 Yield: 84%.
86%.
1H NMR (600 MHz, CDCl3): d = 8.67–8.56 (m, 2 H), 8.32 (s, 1 H),
7.87 (s, 1 H), 3.56 (t, J = 7.3 Hz, 2 H), 1.67–1.58 (m, 2 H), 1.58–
1.34 (m, 9 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 161.1, 161.0, 156.0 (d,
J = 259 Hz), 146.9, 139.4 (d, J = 27.0 Hz), 124.6, 82.0, 52.1, 28.3,
20.9, 11.2.
1H NMR (600 MHz, CDCl3): d = 8.56–8.31 (m, 1 H), 8.19 (td,
J = 8.0, 1.8 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 2 H), 7.53 (dddd, J = 8.3,
7.2, 5.3, 1.9 Hz, 1 H), 7.42–7.36 (m, 2 H), 7.35–7.29 (m, 1 H), 7.18
(dddd, J = 9.5, 5.1, 2.2, 1.0 Hz, 2 H).
13C NMR (151 MHz, CDCl3): d = 161.2, 160.4 (d, J = 246 Hz),
137.7, 133.8, 132.4, 129.1, 125.1, 124.8, 120.6, 116.2 (d,
J = 25.1 Hz).
HRMS (EI): m/z [M + H]+ calcd for C17H20N3O2: 298.1550; found:
298.1565.
HRMS (EI): m/z [M + H]+ calcd for C13H11FNO: 216.0822; found:
216.0819.
tert-Butyl N-Propylhydrazinecarboxylate
Prepared following the literature procedure.19
2-Fluoro-N-methylbenzamide (1c)
Two drops of DMF were added to 2-fluorobenzoic acid (4.83 g,
32.7 mmol) and oxalyl chloride (10.0 mL, 118 mmol) in THF (80
mL), and the mixture was stirred at r.t. for 16 h. The reaction mix-
ture was concentrated in vacuo and the residue was redissolved in
THF (50 mL). The reaction mixture was added dropwise to a cooled
mixture of methylamine (2 M in THF, 150 mL) and H2O (50 mL) at
0 °C, and the mixture was stirred for 16 h. The reaction mixture was
concentrated in vacuo, poured into H2O (100 mL), made basic with
sat. aq NaHCO3 (200 mL), extracted with EtOAc (5 × 100 mL),
dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by chromatography on silica gel (heptane–
EtOAc) to obtain 2-fluoro-N-methylbenzamide (1c). Yield: 4.31 g
(86%).
1H NMR (500 MHz, CDCl3): d = 8.12 (td, J = 7.9, 1.9 Hz, 1 H),
7.46 (dddd, J = 8.2, 7.3, 5.3, 1.9 Hz, 1 H), 7.30–7.22 (m, 1 H), 7.11
(ddd, J = 12.2, 8.3, 0.9 Hz, 1 H), 6.75 (s, 1 H), 3.04 (dd, J = 4.8,
1.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 163.9, 160.6 (d, J = 247 Hz),
133.2, 132.1, 124.8, 121.0 (d, J = 11 Hz), 116.0 (d, J = 25 Hz),
26.8.
tert-Butyl N¢-(3,5-Difluoropyridine-4-carbonyl)-N-propylhy-
drazinecarboxylate (1g)
Synthesized as for 1a using 3,5-difluoronicotinic acid and tert-butyl
N-propylhydrazinecarboxylate. Yield: 64%.
1H NMR (500 MHz, CDCl3): d = 8.49 (s, 2 H), 3.58 (t, J = 7.2 Hz,
2 H), 1.71–1.60 (m, 2 H), 1.50 (s, 9 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 155.6 (d, J = 266 Hz), 146.3,
137.4, 137.3, 129.9, 82.4, 28.6, 21.1, 14.6, 11.6.
HRMS (EI): m/z [M + H]+ calcd for C14H20F2N3O3: 316.1467;
found: 316.1450.
tert-Butyl N¢-(3-Chloro-5-fluoropyridine-4-carbonyl)-N-prop-
ylhydrazinecarboxylate (1h)
Synthesized as for 1a using 3-chloro-5-fluoronicotinic acid20 and
tert-butyl N-propylhydrazinecarboxylate. Yield: 88%.
1H NMR (500 MHz, CDCl3): d = 8.51 (s, 1 H), 8.47 (s, 1 H), 8.03
(s, 1 H), 3.58 (t, J = 7.2 Hz, 2 H), 1.71–1.60 (m, 2 H), 1.50 (s, 9 H),
0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 156.9, 154.9, 154.8, 146.3, 137.4,
137.2, 129.9, 82.4, 28.6, 21.1, 14.6, 11.6.
HRMS (EI): m/z [M + H]+ calcd for C8H8FNO: 154.0663; found:
154.0665.
HRMS (EI): m/z [M + H]+ calcd for C14H20ClFN3O3: 332.1177;
found: 332.1177.
3-Fluoro-N-phenylnicotinamide (1d)
Synthesized as for 1a using 3-fluorobenzoic acid and aniline. Yield:
76%.
3-Chloro-5-fluoronicotinic Acid
Prepared following a literature procedure.20
1H NMR (600 MHz, CDCl3): d = 8.66 (d, J = 2.7 Hz, 1 H), 8.64 (dd,
J = 4.9, 1.4 Hz, 1 H), 8.36 (t, J = 22.5 Hz, 1 H), 8.03 (dd, J = 6.6,
4.9 Hz, 1 H), 7.66 (dd, J = 8.5, 0.9 Hz, 2 H), 7.44–7.38 (m, 2 H),
7.24–7.19 (m, 1 H).
13C NMR (151 MHz, CDCl3): d = 159.1, 156.0 (d, J = 256 Hz),
147.2, 139.5 (d, J = 28 Hz), 136.9, 129.3, 128.0 (d, J = 9.6 Hz),
125.5, 124.8, 120.7.
Domino Reactions: General Procedure
Method A: NaHMDS (1.0 M in THF, 1.20 mL, 1.20 mmol) was add-
ed to a solution of the amide/sulfonamide (1.00 mmol) in DMF
(10.0 mL) under an atmosphere of argon, and the mixture was
stirred for 30 min, while cooling to 0 °C. The alkyne (2.00 mmol)
was added dropwise to the mixture, which was heated by micro-
wave irradiation using an Emry Optimizer instrument. The reaction
mixture was poured into H2O (100 mL), extracted with EtOAc–
Et2O (1:1, 3 × 100 mL), washed with diluted brine (H2O–brine, 1:1;
3 × 100 mL), dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by chromatography on silica gel
(heptane–EtOAc) to obtain the product.
HRMS (EI): m/z [M + H]+ calcd for C12H10FN2O: 217.0772; found:
217.0774.
2-Fluoro-3-methoxy-N-phenylbenzamide (1e)
Synthesized as for 1a using 2-fluoro-3-methoxybenzoic acid and
aniline. Yield: 71%.
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Method B: NaHMDS (1.0 M in THF, 1.20 mL, 1.20 mmol) was add-
ed to a solution of the amide/sulfonamide (1.00 mmol) in DMF
(10.0 mL) under an atmosphere of argon, and the mixture was
stirred for 30 min, while heating to the addition temperature. A so-
lution of the alkyne (2.00 mmol) in DMF (5.0 mL) was added drop-
wise to the mixture at a rate of 0.4 mL/h, while continuing the
heating. The reaction mixture was cooled to r.t. and poured into H2O
(100 mL), extracted with EtOAc–Et2O (1:1, 3 × 100 mL), washed
with diluted brine (H2O–brine, 1:1; 3 × 100 mL), dried over
MgSO4, filtered and concentrated in vacuo. The crude product was
purified by chromatography on silica gel (heptane–EtOAc).
1H NMR (600 MHz, CDCl3): d = 8.61 (d, J = 5.2 Hz, 1 H), 8.35 (s,
1 H), 8.29 (dd, J = 5.2, 0.8 Hz, 1 H), 7.42–7.32 (m, 3 H), 7.25–7.13
(m, 7 H), 4.02 (q, J = 7.1 Hz, 2 H), 0.92 (t, J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 173.4, 165.5, 152.7, 143.9, 142.2,
137.3, 137.2, 132.4, 130.3, 129.9, 129.7, 129.4, 127.9, 120.3, 118.2,
61.3, 13.7.
HRMS (EI): m/z [M + H]+ calcd for C23H19N2O3: 371.1390; found:
371.1398.
Ethyl 5-Methoxy-1-oxo-2,3-diphenyl-1,2-dihydroisoquinoline-
4-carboxylate (3e)
Synthesized by method A using 2-fluoro-3-methoxy-N-phenyl-
benzamide (1e) and ethyl phenylpropiolate (2a). Heating for 4 h at
200 °C. Yield: 63%.
1H NMR (500 MHz, CDCl3): d = 8.20 (d, J = 8.1 Hz, 1 H), 7.38 (t,
J = 8.0 Hz, 1 H), 7.22–7.10 (m, 8 H), 7.06 (d, J = 7.9 Hz, 1 H), 7.00
(m, 2 H), 3.99 (q, J = 7.1 Hz, 2 H), 3.29 (s, 3 H), 0.92 (t, J = 7.1 Hz,
3 H).
13C NMR (126 MHz, CDCl3): d = 174.8, 166.5, 153.7, 150.4, 143.8,
133.8, 133.4, 130.2, 129.2, 129.1, 129.0, 128.1, 127.8, 127.8, 125.4,
119.2, 116.1, 61.3, 56.7, 14.1.
Ethyl 5-Oxo-6,7-diphenyl-5,6-dihydro-1,6-naphthyridine-8-
carboxylate (3a)
Synthesized by method A using 2-fluoro-N-phenylnicotinamide
(1a) and ethyl phenylpropiolate (2a). Heating for 4 h at 200 °C.
Yield: 65%.
1H NMR (500 MHz, CDCl3): d = 8.81 (dt, J = 16.6, 8.3 Hz, 1 H),
8.62 (dd, J = 4.4, 1.8 Hz, 1 H), 7.37 (tt, J = 15.7, 7.9 Hz, 2 H), 7.32–
7.23 (m, 4 H), 7.22–7.15 (m, 3 H), 7.12–7.05 (m, 2 H), 4.01 (q,
J = 7.1 Hz, 2 H), 0.91 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 175.1, 165.9, 153.2, 151.7, 138.6,
136.3, 133.2, 130.3, 129.5, 129.3, 129.1, 128.8, 128.0, 121.2, 120.7,
120.2, 61.4, 13.9.
HRMS (EI): m/z [M + H]+ calcd for C25H22NO4: 400.1543; found:
400.1539.
HRMS (EI): m/z [M + H]+ calcd for C23H19N2O3: 371.1390; found:
371.1392.
Ethyl 7-Methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyridine-
8-carboxylate (3f)
Synthesized by method B using 2-fluoro-N-phenylnicotinamide
(1a) and ethyl 2-butynoate (2b). Heating at 150 °C for 16 h. Yield:
48%.
1H NMR (600 MHz, CDCl3): d = 8.95 (dt, J = 4.6, 2.3 Hz, 1 H),
8.61 (dd, J = 8.0, 1.9 Hz, 1 H), 7.59–7.54 (m, 2 H), 7.53–7.48 (m,
1 H), 7.40 (dt, J = 8.0, 4.0 Hz, 1 H), 7.26–7.22 (m, 2 H), 4.51 (q,
J = 7.2 Hz, 2 H), 2.08 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 167.4, 162.8, 155.1, 151.1, 142.3,
138.0, 136.4, 130.0, 129.3, 128.3, 121.9, 120.2, 114.4, 61.9, 19.5,
14.3.
Ethyl 1-Oxo-2,3-diphenyl-1,2-dihydroisoquinoline-4-carboxy-
late (3b)
Synthesized by method A using 2-fluoro-N-phenylbenzamide (1b)
and ethyl phenylpropiolate (2a). Heating for 4 h at 200 °C. Yield:
61%.
1H NMR (600 MHz, CDCl3): d = 8.54 (dd, J = 8.1, 1.4 Hz, 1 H),
7.48 (ddd, J = 8.7, 7.0, 1.7 Hz, 1 H), 7.40 (ddd, J = 8.0, 7.1, 1.0 Hz,
1 H), 7.37–7.28 (m, 3 H), 7.22–7.14 (m, 5 H), 7.14–7.08 (m, 2 H),
6.80 (d, J = 8.5 Hz, 1 H), 4.01 (q, J = 7.1 Hz, 2 H), 0.94–0.89 (m,
3 H).
13C NMR (125 MHz, CDCl3): d = 174.5, 166.3, 151.8, 146.7, 142.0,
138.5, 133.2, 132.4, 130.0, 129.6, 129.5, 129.2, 128.9, 127.7, 126.7,
126.1, 124.4, 119.0, 118.2, 61.0, 13.8.
HRMS (EI): m/z [M + H]+ calcd for C18H17N2O3: 309.1234; found:
309.1238.
HRMS (EI): m/z [M + H]+ calcd for C24H20NO3: 370.1438; found:
370.1439.
Ethyl 2-(tert-Butoxycarbonylpropylamino)-3-methyl-1-oxo-1,2-
dihydro-2,6-naphthyridine-4-carboxylate (3g)
Synthesized by method B using tert-butyl N¢-(3-fluoropyridine-4-
carbonyl)-N-propylhydrazinecarboxylate (1f) and ethyl 2-butyn-
oate (2b). Heating at 100 °C for 16 h. Yield: 41%.
Ethyl 2-Methyl-1-oxo-3-phenyl-1,2-dihydroisoquinoline-4-car-
boxylate (3c)
1H NMR (600 MHz, CDCl3): d (mixtures of two rotamers) = 9.35
(d, J = 8.1 Hz, 1 H), 8.70 (dd, J = 10.9, 5.5 Hz, 1 H), 8.36 (dd,
J = 5.4, 3.2 Hz, 1 H), 4.62–4.42 (m, 2 H), 3.88–3.76 (m, 1 H), 3.47–
3.38 (m, 1 H), 2.53 (d, J = 7.3 Hz, 3 H), 1.71–1.51 (m, 6 H), 1.46
(dt, J = 16.0, 7.1 Hz, 3 H), 1.35 (s, 5 H), 0.93 (dt, J = 11.4, 7.4 Hz,
3 H).
13C NMR (151 MHz, CDCl3): d (mixtures of two rotamers) = 158.6,
153.7, 145.9, 145.7, 142.5, 141.9, 129.5, 122.3, 83.5, 82.8, 62.5,
53.1, 51.7, 28.2, 27.9, 21.5, 20.9, 17.3, 14.2, 11.4.
Synthesized by method A using 2-fluoro-N-methyl-benzamide (1c)
and ethyl phenylpropiolate (2a). Heating for 4 h at 200 °C. Yield:
52%.
1H NMR (600 MHz, CDCl3): d = 8.55 (dd, J = 8.0, 1.6 Hz, 1 H),
7.74 (ddd, J = 8.7, 7.1, 1.7 Hz, 1 H), 7.55 (d, J = 8.6 Hz, 1 H), 7.53–
7.48 (m, 3 H), 7.46 (ddd, J = 8.0, 7.1, 0.9 Hz, 1 H), 7.44–7.40 (m,
2 H), 3.99 (q, J = 7.1 Hz, 2 H), 3.54 (s, 3 H), 0.92 (t, J = 7.1 Hz,
3 H).
13C NMR (151 MHz, CDCl3): d = 174.1, 166.3, 152.2, 141.2, 133.6,
132.9, 129.9, 128.8, 127.3, 126.9, 124.3, 119.3, 115.9, 100.0, 60.9,
37.1, 13.8.
HRMS (EI): m/z [M + H]+ calcd for C20H28N3O5: 390.2033; found:
390.2012.
HRMS (EI): m/z [M + H]+ calcd for C19H18NO3: 308.1281; found:
Ethyl 2-(tert-Butoxycarbonylpropylamino)-8-fluoro-3-methyl-
1-oxo-1,2-dihydro-2,6-naphthyridine-4-carboxylate (3h)
Synthesized by method B using tert-butyl N¢-(3,5-difluoropyridine-
4-carbonyl)-N-propylhydrazinecarboxylate (1g) and ethyl 2-bu-
tynoate (2b). Heating at 100 °C for 16 h. Yield: 24%.
1H NMR (500 MHz, CDCl3): d (mixtures of two rotamers) = 8.92
(d, J = 15.2 Hz, 1 H), 8.50 (d, J = 13.8 Hz, 1 H), 4.51 (m, 2 H),
308.1291.
Ethyl 1-Oxo-2,3-diphenyl-1,2-dihydro-2,6-naphthyridine-4-
carboxylate (3d)
Synthesized by method A using 3-fluoro-N-phenylnicotinamide
(1d) and ethyl phenylpropiolate (2a). Heating for 4 h at 200 °C.
Yield: 40%.
Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York

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Conjugate Addition – SNAr Domino Reaction
4279
3.94–3.74 (m, 1 H), 3.49–3.34 (m, 1 H), 2.47 (d, J = 6.6 Hz, 3 H),
1.76–1.57 (m, 2 H), 1.57 (s, 5 H), 1.46 (m, 3 H), 1.38 (s, 4 H), 0.94
(q, J = 7.3 Hz, 3 H).
2,6-Difluoro-N-phenylbenzenesulfonamide (4b)
Synthesized as for 4a using 2,6-difluorobenzenesulfonyl chloride
and aniline. Yield: 85%.
13C NMR (126 MHz, CDCl3): d (mixtures of two rotamers) = 166.3,
156.6, 156.4, 154.9, 154.7, 147.8, 147.6, 143.8, 134.9, 134.7, 83.6,
83.0, 62.7, 62.5, 53.5, 52.0, 28.6, 28.4, 21.9, 21.4, 17.5, 17.3, 14.6,
11.7, 11.6.
HRMS (EI): m/z [M + H]+ calcd for C20H27FN3O5: 408.1929; found:
408.1937.
1H NMR (500 MHz, CDCl3): d = 7.49 (tt, J = 8.4, 6.0 Hz, 1 H), 7.29
(dd, J = 9.2, 6.5 Hz, 2 H), 7.20 (d, J = 7.8 Hz, 2 H), 7.16 (t,
J = 7.4 Hz, 1 H), 7.01 (m, 3 H).
13C NMR (126 MHz, CDCl3): d = 160.2 (d, J = 259 Hz), 135.9,
135.4 (t, J = 11 Hz), 129.9, 126.3, 121.5, 117.1, 113.5 (d,
J = 23 Hz).
Ethyl 2-(tert-Butoxycarbonylpropylamino)-8-chloro-3-methyl-
1-oxo-1,2-dihydro-2,6-naphthyridine-4-carboxylate (3i)
Synthesized by method B using tert-butyl N¢-(3-chloro-5-fluoropy-
ridine-4-carbonyl)-N-propylhydrazinecarboxylate (1h) and ethyl 2-
butynoate (2b). Heating at 100 °C for 16 h. Yield: 18%.
1H NMR (500 MHz, CDCl3): d (mixtures of two rotamers) = 8.92
(d, J = 16.7 Hz, 1 H), 8.63 (d, J = 13.3 Hz, 1 H), 4.50 (m, 3 H),
3.95–3.79 (m, 1 H), 3.44–3.29 (m, 1 H), 2.45 (d, J = 8.5 Hz, 3 H),
1.72–1.63 (m, 2 H), 1.57 (s, 5 H), 1.50–1.43 (m, 3 H), 1.39 (s, 4 H),
0.94 (m, 3 H).
13C NMR (151 MHz, CDCl3): d (mixtures of two rotamers) = 166.1,
166.0, 157.4, 157.2, 154.5, 154.4, 147.5, 147.4, 146.8, 146.6, 145.9,
145.8, 130.9, 130.7, 130.5, 125.8, 125.5, 108.3, 108.1, 83.2, 82.6,
62.3, 62.2, 53.0, 51.7, 29.7, 28.2, 27.9, 21.7, 21.1, 17.2, 16.9, 14.2,
14.2, 11.4, 11.3.
2-Fluoro-N-phenylbenzenesulfonamide (4c)
Synthesized as for 4a using 2-fluorobenzenesulfonyl chloride and
aniline. Yield: 79%.
1H NMR (600 MHz, CDCl3): d = 7.82 (t, J = 7.5 Hz, 1 H), 7.53
(ddd, J = 8.3, 7.4, 5.1 Hz, 1 H), 7.25–7.15 (m, 4 H), 7.14–7.07 (m,
3 H), 6.74 (s, 1 H).
13C NMR (151 MHz, CDCl3): d = 158.7 (d, J = 254 Hz), 135.6,
135.5, 131.0, 129.4, 125.8, 124.6, 121.6, 116.9.
2-Fluoro-N-methylbenzenesulfonamide (4d)
2-Fluorobenzenesulfonyl chloride (0.70 mL, 5.3 mmol) was dis-
solved in THF (50 mL), and the mixture was cooled to 0 °C. Meth-
ylamine (2.0 M in THF, 8.0 mL, 16 mmol) was added dropwise, and
the mixture was stirred for 1 h. The mixture was concentrated in
vacuo, dissolved in Et2O (50 mL), washed with 1 M HCl (2 × 50
mL) and brine (2 × 50 mL), dried over MgSO4, filtered and concen-
trated in vacuo. The crude product was purified by chromatography
on silica gel (heptane–EtOAc) to obtain 2-fluoro-N-methyl-
benzenesulfonamide (4c). Yield: 0.77 g (77%).
1H NMR (500 MHz, CDCl3): d = 7.92 (td, J = 7.7, 1.5 Hz, 1 H),
7.61 (ddd, J = 7.8, 5.2, 1.5 Hz, 1 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.27–
7.19 (m, 1 H), 4.81 (d, J = 3.5 Hz, 1 H), 2.72 (d, J = 5.3 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 159.2 (d, J = 254 Hz), 135.5,
131.2, 127.1, 124.9, 117.4, 29.7.
HRMS (EI): m/z [M + H]+ calcd for C20H27ClN3O5: 424.1634;
found: 424.1642.
tert-Butyl 7-Methyl-5-oxo-6-phenyl-5,6-dihydro-1,6-naphthyri-
dine-8-carboxylate (3j)
Synthesized by method A using 2-fluoro-N-phenylnicotinamide
(1a) and ethyl hexynoate (2c). Heating for 4 h at 200 °C. Yield:
53%.
1H NMR (500 MHz, CDCl3): d = 8.96 (dd, J = 4.6, 1.7 Hz, 1 H),
8.62 (dd, J = 8.0, 1.7 Hz, 1 H), 7.56 (m, 3 H), 7.42 (dd, J = 8.0,
4.6 Hz, 1 H), 7.30 (m, 2 H), 4.54 (q, J = 7.1 Hz, 2 H), 2.49–2.37 (m,
2 H), 1.52 (dt, J = 11.8, 7.6 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H), 0.72
(t, J = 7.3 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 167.8, 163.4, 155.5, 151.7, 146.7,
137.9, 136.8, 130.1, 129.6, 129.2, 122.3, 120.6, 114.7, 62.24, 34.2,
23.1, 14.7, 14.5.
Ethyl 1,1-Dioxo-2,3-diphenyl-1,2-dihydro-1(6)-thia-2,5-diaza-
naphthalene-4-carboxylate (5a)
Synthesized by method A using 2-fluoropyridine-3-sulfonic acid
phenylamide (4a) and ethyl 2-butynoate (2b). Heating for 1 h at
200 °C. Yield: 64%.
1H NMR (500 MHz, CDCl3): d = 8.89 (dd, J = 4.8, 1.4 Hz, 1 H),
8.14 (dd, J = 8.0, 1.4 Hz, 1 H), 7.53–7.46 (m, 3 H), 7.43 (dd,
J = 7.9, 4.8 Hz, 1 H), 7.31 (dd, J = 6.3, 3.2 Hz, 2 H), 4.48 (q,
J = 7.1 Hz, 2 H), 2.14 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H).
HRMS (EI): m/z [M + H]+ calcd for C20H21N2O3: 337.1547; found:
337.1551.
2-Fluoropyridine-3-sulfonic Acid Phenylamide (4a)
13C NMR (126 MHz, CDCl3): d = 166.9, 153.7, 149.3, 134.9, 130.9,
2-Fluoropyridine-3-sulfonyl chloride21 (0.71 g, 3.6 mmol) was add-
ed to pyridine (100 mL) under an atmosphere of argon, and the mix-
ture was cooled to 0 °C. Aniline (0.35 mL, 3.8 mmol) was added,
and the mixture was stirred for 16 h while returning to r.t. The reac-
tion mixture was concentrated in vacuo and the residue was purified
by chromatography on silica gel (heptane–EtOAc) to obtain 2-fluo-
ropyridine-3-sulfonic acid phenylamide (4a). Yield: 0.76 g (84%).
130.1, 130.0, 129.6, 127.5, 122.4, 118.9, 62.3, 19.8, 14.6.
HRMS (EI): m/z [M + H]+ calcd for C17H17N2O4S: 345.0904; found:
345.0904.
Ethyl 8-Fluoro-3-methyl-1,1-dioxo-2-phenyl-1,2-dihydro-
1l(6)-1,2-benzothiazine-4-carboxylate (5b)
Synthesized by method A using 2,6-difluoro-N-phenylbenzene-
sulfonamide (4b) and ethyl 2-butynoate (2b). Heating for 1 h at
200 °C. Yield: 75%.
1H NMR (500 MHz, CDCl3): d = 7.60 (td, J = 8.2, 5.3 Hz, 1 H),
7.47–7.40 (m, 4 H), 7.27 (dd, J = 6.7, 2.9 Hz, 2 H), 7.23–7.16 (m,
1 H), 4.43 (q, J = 7.1 Hz, 2 H), 2.12 (s, 3 H), 1.41 (t, J = 7.1 Hz,
3 H).
13C NMR (126 MHz, CDCl3): d = 167.2, 159.5 (d, J = 245 Hz),
143.2, 135.4, 133.8, 133.7, 129.9, 129.7, 129.4, 122.2, 117.3, 115.8,
115.6, 113.4, 107.9, 62.3, 20.2, 14.5.
1H NMR (600 MHz, DMSO): d = 10.85 (s, 1 H), 8.47 (ddd, J = 4.9,
1.8, 0.9 Hz, 1 H), 8.36 (ddd, J = 9.6, 7.6, 1.9 Hz, 1 H), 7.54 (ddd,
J = 7.6, 4.9, 1.6 Hz, 1 H), 7.28–7.21 (m, 2 H), 7.14–7.09 (m, 2 H),
7.09–7.00 (m, 1 H).
13C NMR (151 MHz, DMSO): d = 158.1 (d, J = 242 Hz), 152.9 (d,
J = 15 Hz), 142.8, 137.1, 129.8, 125.1, 123.5, 122.7 (d, J = 30 Hz),
120.63.
2-Fluoropyridine-3-sulfonyl Chloride
Prepared according to the literature procedure.21
HRMS (EI): m/z [M + H]+ calcd for C18H17FNO4S: 362.0857;
found: 362.0864.
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PAPER
Ethyl 3-Methyl-1,1-dioxo-2-phenyl-1,2-dihydro-1l(6)-1,2-ben-
zothiazine-4-carboxylate (5c)
HRMS (EI): m/z [M + H]+ calcd for C14H19FNO3: 268.1343; found:
268.1331.
Synthesized by method B using 2-fluoro-N-phenylbenzenesulfon-
amide (4c) and ethyl 2-butynoate (2b). Heating at 150 °C for 16 h.
Yield: 38%.
Ethyl 3-[(2,6-Difluorobenzenesulfonyl)methylamino]butyrate
(6b)
Ethyl 3-(methylamino)butynoate (0.74 g, 5.1 mmol) and N,N-diiso-
propylethylamine (0.97 mL, 5.6 mmol) were dissolved in THF (50
mL) and cooled to 0 °C. 2,6-Difluorobenzenedulfonyl chloride
(1.05 g, 4.9 mmol) was added and the reaction mixture was allowed
to return to r.t. while stirring overnight. The reaction mixture was
filtered and concentrated in vacuo and the crude product was puri-
fied by chromatography on silica gel (heptane–EtOAc) to obtain 6b.
Yield: 0.60 g (38%).
1H NMR (600 MHz, CDCl3): d = 7.49 (tt, J = 8.4, 5.9 Hz, 1 H), 7.01
(t, J = 8.5 Hz, 2 H), 4.61–4.53 (m, 1 H), 4.09–4.01 (m, 2 H), 2.91 (s,
3 H), 2.53 (dd, J = 14.9, 7.1 Hz, 1 H), 2.44 (dd, J = 14.9, 7.7 Hz,
1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 170.3, 159.7 (dd, J = 258.6,
4.2 Hz), 134.2 (t, J = 11.0 Hz), 118.3 (t, J = 16.3 Hz), 113.1 (dd,
J = 23.8, 3.7 Hz), 60.8, 50.5, 39.8, 28.1, 17.8, 14.1.
HRMS (EI): m/z [M + H]+ calcd for C13H18F2NO4S: 322.0919;
found: 322.0908.
1H NMR (600 MHz, CDCl3): d = 7.86 (d, J = 7.8 Hz, 1 H), 7.68–
7.62 (m, 2 H), 7.52–7.48 (m, 1 H), 7.44–7.38 (m, 3 H), 7.25–7.22
(m, 2 H), 4.41 (q, J = 7.1 Hz, 2 H), 2.13 (s, 3 H), 1.39 (dd, J = 8.5,
5.8 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 167.0, 142.5, 135.2, 132.3, 131.3,
130.9, 129.5, 129.2, 128.9, 127.9, 126.1, 122.3, 116.6, 61.8, 19.8,
14.2.
HRMS (EI): m/z [M + H]+ calcd for C18H18NO4S: 344.0951; found:
344.0951.
Ethyl 2-Methyl-1,1-dioxo-3-phenyl-1,2-dihydro-1l(6)-1,2-ben-
zothiazine-4-carboxylate (5d)
Synthesized by method A using 2-fluoro-N-methylbenzenesulfon-
amide (4d) and ethyl phenylpropiolate (2a). Heating for 4 h at
200 °C. Yield: 46%.
1H NMR (600 MHz, CDCl3): d = 8.19 (d, J = 8.2 Hz, 1 H), 7.95 (dd,
J = 7.8, 1.3 Hz, 1 H), 7.71–7.65 (m, 1 H), 7.59–7.52 (m, 3 H), 7.50–
7.45 (m, 3 H), 3.89 (q, J = 7.1 Hz, 2 H), 3.02 (s, 3 H), 0.75 (t,
J = 7.1 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 167.1, 146.0, 134.1, 132.3, 130.7,
130.3, 129.2, 129.0, 128.8, 128.2, 126.0, 121.9, 116.0, 61.3, 34.8,
13.3.
2-Fluoro-N-methylbenzamide (1c) by Retro-Conjugate Addi-
tion
NaHMDS (2.0 M in THF, 0.100 mL, 0.200 mmol) was added to a
solution of ethyl 3-[(2-fluorobenzoyl)methylamino]butyrate (6a; 49
mg, 0.18 mmol) in DMF (2.0 mL). The mixture was stirred at r.t. for
1 h, then concentrated in vacuo and the crude mixture was purified
by chromatography on silica gel (heptane–EtOAc) to obtain 1c.
Yield: 89%.
HRMS (EI): m/z [M + H]+ calcd for C18H18NO4S: 344.0951; found:
344.0952.
Ethyl 8-Fluoro-1,1-dioxo-2-phenyl-3-trifluoromethyl-1,2-dihy-
dro-1l(6)-1,2-benzothiazine-4-carboxylate (5e)
NMR spectra matched those obtained previously.
Synthesized by method B using 2,6-difluoro-N-phenylbenzene-
sulfonamide (4b) and ethyl 4,4,4-trifluoro-2-butynoate (2d). Heat-
ing at 150 °C for 16 h. Yield: 36%.
2,6-Difluoro-N-methyl-benzenesulfonamide (7)
Synthesized above using ethyl 3-[(2,6-difluorobenzenesulfo-
nyl)methylamino]butyrate (6b). Yield: 91%.
1H NMR (600 MHz, CDCl3): d = 7.71 (td, J = 8.3, 5.1 Hz, 1 H),
7.51 (d, J = 8.0 Hz, 1 H), 7.40–7.33 (m, 4 H), 7.18–7.13 (m, 2 H),
4.46 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, CDCl3): d = 163.8, 157.7 (d, J = 261 Hz),
135.7, 134.4 (d, J = 9 Hz), 130.5, 129.6, 129.4, 127.4, 127.2, 123.5
(d, J = 4 Hz), 122.5 (d, J = 15 Hz), 121.0, 119.6 (d, J = 21 Hz),
119.1, 63.4, 13.9.
1H NMR (500 MHz, CDCl3): d = 7.60–7.50 (m, 1 H), 7.07 (t,
J = 8.9 Hz, 2 H), 4.98 (s, 1 H), 2.83 (d, J = 5.3 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 160.0 (d, J = 258 Hz), 135.1 (dd,
J = 81, 70 Hz), 117.5 (t, J = 16 Hz), 113.5 (d, J = 24 Hz), 29.8.
HRMS (EI): m/z [M + H]+ calcd for C7H8F2NO2S: 208.0238; found:
208.0230.
+
HRMS (EI): m/z [M + NH4 ] calcd for C18H17F4N2O4S: 433.0834;
found: 433.0847.
2,3-Diphenyl-2H-isoquinolin-1-one (9)
Ethyl 1-Oxo-2,3-diphenyl-1,2-dihydroisoquinoline-4-carboxylate
(3b; 51 mg, 0.14 mmol) was dissolved in a mixture of MeOH (1.0
mL) and aq NaOH (2.00 M, 0.20 mL). The mixture was heated to
reflux for 2 h then aq HCl (1 M) was added until pH 3–4 was
reached. The mixture was extracted with EtOAc (3 × 10 mL) and
concentrated in vacuo. The residue was dissolved in a mixture of N-
methylpyrrolidinone (3 mL) and quinoline (1.5 mL). To this mix-
ture was added copper(I) oxide (2 mg, 0.01 mmol) and o-phenan-
throline (6 mg, 0.03 mmol) under an atmosphere of argon. The
reaction mixture was heated by microwave irradiation using an
Emry Optimizer instrument (1 h at 190 °C). The mixture was dilut-
ed with aq HCl (1 M, 10 mL), extracted with EtOAc–Et2O (1:1,
3 × 10 mL), washed with a H2O–brine mixture (1:1, 3 × 10 mL),
dried over MgSO4 and concentrated in vacuo. The crude product
was purified by chromatography on silica gel (heptane–EtOAc) to
obtain 2,3-diphenyl-2H-isoquinolin-1-one (9). Yield: 36 mg (89%).
Ethyl 3-[(2-Fluorobenzoyl)methylamino]butyrate (6a)
Ethyl 3-(methylamino)butynoate (0.55 g, 3.8 mmol) was added to
2-fluorobenzoic acid (0.50 g, 3.56 mmol), N-(3-dimethylaminopro-
pyl)-N¢-ethylcarbodiimide hydrochloride (0.77 g, 4.0 mmol) and 1-
hydroxybenzotriazole (0.50 g, 3.7 mmol) in THF (20 mL). The re-
action mixture was stirred at r.t. for 16 h then the mixture was
poured into H2O (20 mL), extracted with EtOAc (3 × 50 mL),
washed with sat. aq NaHCO3 (3 × 50 mL) and brine (3 × 50 mL),
dried over MgSO4, filtered and concentrated in vacuo. The crude
product was purified by chromatography on silica gel (heptane–
EtOAc) to obtain 6a. Yield: 0.21 g (22%).
1H NMR (600 MHz, CDCl3): d = 7.43–7.30 (m, 2 H), 7.23–7.16 (m,
1 H), 7.13–7.03 (m, 1 H), 5.21–5.12 (m, 1 H), 4.20–4.09 (m, 2 H),
2.99 (s, 3 H), 2.72–2.66 (m, 1 H), 2.55 (m, 1 H), 1.31 (d, J = 6.7 Hz,
2 H), 1.30–1.19 (m, 3 H).
1H NMR (600 MHz, CDCl3): d = 8.52 (dd, J = 8.1, 1.7 Hz, 1 H),
7.48 (ddd, J = 8.7, 7.0, 1.7 Hz, 1 H), 7.41–7.31 (m, 4 H), 7.22–7.14
(m, 7 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.45 (s, 1 H).
13C NMR (151 MHz, CDCl3): d = 170.9, 166.8, 158.9, 131.1, 128.9,
125.2, 124.5, 115.8, 60.8, 51.3, 47.0, 18.8, 17.6, 14.2.
Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York

PAPER
Conjugate Addition – SNAr Domino Reaction
4281
13C NMR (151 MHz, CDCl3): d = 177.9, 153.9, 142.6, 139.2, 135.7,
131.9, 130.1, 129.6, 129.2, 128.9, 128.6, 127.9, 126.3, 126.1, 123.8,
118.1, 112.6.
HRMS (EI): m/z [M + H]+ calcd for C21H16NO: 298.1226; found:
298.1225.
304. (b) Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J. Org.
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Roy, A.; Nivorozhkin, A.; Landrau, N.; Desisto, K.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Synthesis 2010, No. 24, 4273–4281 © Thieme Stuttgart · New York