Synthesis of substituted diazino[c]quinolin-5(6H)-ones, diazino[c]isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)-ones and diazino[c]naphthyridin-5(6H)-ones

Article abstract of DOI:10.1016/j.tet.2013.04.104

Substituted diazino[c]quinolin-5(6H)-ones and -isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)- and -5(6H)-ones were obtained using two synthetic routes: one-pot cross-coupling/cyclisation and two-step cross-coupling/KOH- mediated anionic ring closur

Full text of DOI:10.1016/j.tet.2013.04.104

Tetrahedron 69 (2013) 5393e5400
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted diazino[c]quinolin-5(6H)-ones, diazino[c]
isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)-ones and
diazino[c]naphthyridin-5(6H)-ones
,
c
b
,
c
,
a,
Nathalie Fresneau a, Thomas Cailly b , Frederic Fabis
, Jean-Philippe Bouillon
*
*
ꢀ ꢀ
a
ꢁ
Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesniere, 76821 Mont Saint-Aignan Cedex, France
b
c
ꢀ
Normandie Universite, France
ꢀ
Universite de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel,
F-14032 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2013
Received in revised form 18 April 2013
Accepted 24 April 2013
Available online 28 April 2013
Substituted diazino[c]quinolin-5(6H)-ones and -isoquinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)-
and -5(6H)-ones were obtained using two synthetic routes: one-pot cross-coupling/cyclisation and two-
step cross-coupling/KOH-mediated anionic ring closure. The two strategies gave yields in the same order
of magnitude and their choice depends on the availability of the starting material.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Phenanthridin-6(5H)-ones
Diazines
Cross-coupling
Anionic ring closure
1. Introduction
anionic ring closure.5 If the first methodology constitutes to date
the most straightforward access to substituted phenanthridin-
Phenanthridines and their aza-analogues benzonaphthyridines
have been the subject of many attention owing to their interesting
biological activities, leading to tremendous efforts to obtain
straightforward access to these structures.1 To date, di- and triaza
analogues of phenanthridines remain less studied1b,2 probably
because of the limited access to starting materials, thus preventing
their use as valuable scaffolds in medicinal chemistry.
Substituted (aza)phenanthridin-6(5H)-ones constitute chemical
precursors of choice to obtain the corresponding (aza)phenan-
thridines, offering the possibility to further insert additional sub-
stituents in position 6.1a,b Among the great number of chemical
routes to substituted (aza)phenanthridin-6(5H)-ones, which have
been described, three methods offer a general access to these tri-
cyclic compounds: (1) Pd-catalysed CeH arylation of N-protected
benzamides followed by intramolecular N-arylation,3 (2) one-pot
Pd-catalysed cross-coupling/cyclisation between anilines and
benzoates derivatives1i,2a,4 and (3) Pd-catalysed cross-coupling
with benzonitriles and fluorobenzenes derivatives followed by an
6(5H)-ones, it has never been used to synthesize azaphenan-
thridin-6(5H)-ones derivatives and requires in most cases an ad-
ditional deprotection step.3b,c We thought that the two last
methodologies could be successfully adapted to the synthesis of
new di- and triazaphenanthridin-6(5H)-ones derivatives, and we
wish to report here our efforts toward the synthesis of the un-
known substituted diazino[c]quinolin-5(6H)-ones and -iso-
quinolin-6(5H)-ones, diazino[c]naphthyridin-6(5H)- and -5(6H)-
ones using the two synthetic paths depicted in Fig. 1.
2. Results and discussion
We started our investigations by exploring path A. The three
boronic esters 1aec were prepared in 36e99% yield according to
a literature procedure,6 and starting, respectively, from ethyl ben-
zoate, ethyl 4-trifluoromethylbenzoate and ethyl isonicotinate
(Scheme 1).
The SuzukieMiyaura cross-coupling reactions using commer-
cially available 2-amino-3-chloropyrazine, 5-amino-4-chloropyri-
midine and 4-amino-5-iodopyrimidine as starting materials with
the boronates 1aec were realized using classical conditions with
Pd(PPh3)4 as the catalyst and K3PO4 as the base.7 The expected
* Corresponding authors. E-mail addresses: frederic.fabis@unicaen.fr (F. Fabis),
jean-philippe.bouillon@univ-rouen.fr (J.-P. Bouillon).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.104

5394
N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
LTMP (Lithium 2,2,6,6-TetraMethylPiperidinyl amide) as base and
(R)
(R)
(N)
(N) (R)
O
X/Y
NH
using I2 as the electrophile. The resulting pivalamide 3a was finally
deprotected under acidic conditions to afford 4 in 86% yield. The
coupling of pyridazine 4 with 1a under the previous conditions
gave the expected 2-phenylpyridazino[3,4-c]isoquinolin-6(5H)-
one (5i) in 60% yield (Scheme 2).
(R)
2N
Path A
Y/X
2N
One-pot
Cross-coupling
Cyclisation
CO Et
2
2
N
H
X = Cl or I
Y=B(OR) or SnR
2
3
Ph
Ph
Ph
Ph
I
i
ii
(R)
Y
(R)
N
N
2N
2N
N
(R)
(R)
Path B
N
Cl
N
NHPiv
N
NHPiv
(N)
X
2a, 74 %
(N)
Two-step
F
3a, 78 %
CN
Cross-coupling
O
N
H
Anionic ring closure
iii
Fig. 1. Synthetic paths of diazino[c]quinolin-5(6H)-ones, diazino[c]isoquinolin-6(5H)-
ones, diazino[c]naphthyridin-6(5H)-ones and diazino[c]naphthyridin-5(6H)-ones.
I
Ph
iv
N
N
N
NH2
N
N
H
O
O
B
4, 86 %
i
1a, X = CH, 99%
1b, X = CCF3, 58%
1c, X = N, 36%
X
X
O
5i, 60%
CO2Et
CO2Et
Scheme 2. Synthesis of 2-phenylpyridazino[3,4-c]iso-quinolin-6(5H)-one 5i. Isolated
yields, conditions: (i) 2,2,2-trimethylacetamide 1.2 equiv, Binap 10 mol %, Pd(OAc)2
5 mol %, Cs2CO3, dioxane; (ii) LTMP 8.0 equiv, THF, ꢀ78 ꢁC, over 1.5 h then I2 8.2 equiv;
(iii) H2SO4 (5 M), reflux, overnight; (iv) sealed tube, Pd(PPh3)4 8 mol %, 1a 3.0 equiv,
K3PO4 3.0 equiv, dioxane/H2O 12:1, reflux, overnight.
Scheme 1. Boronic esters 1aec synthesis. Isolated yields starting from the corre-
sponding substituted ethyl benzoates or ethyl isonicotinate: (i) LTMP 1.5 equiv, B(Oi-
Pr)3 2.0 equiv, THF, ꢀ78 ꢁC, over 3.5 h then neopentyl glycol 1.5 equiv, AcOH 1.5 equiv.
pyrazino[2,3-c]-, pyrimidino[5,4-c]- and pyrimidino[4,5-c]iso-
quinolin-6(5H)-ones and their naphthyridin-6(5H)-ones analogues
5aeg were obtained in yields ranging from 11 to 80% (Table 1). For
pyrimidino derivatives 5deg, low yields could be explained by their
higher solubility in MeOH/water medium used for purification pro-
In order to access the unsubstituted analogue of 5i, we first
applied the metallation/iodination sequence as described in
Scheme 2. Unfortunately, this procedure let to degradation of the
starting material 2b. We then prepared the 4-stannylated pyr-
idazine 3b according to the same route as for 3a starting from 3-
iodopyridazine9 and using Bu3SnCl as the electrophile after the
metallation step. Unsubstituted pyridazino[3,4-c]isoquinolinone
(5j) was then obtained in 49% yield according to a Stille cross-
coupling10 between ethyl 2-iodobenzoate and 3b using Pd(OAc)2/S-
Phos in refluxing toluene (Scheme 3).
cess.
Using the
more
hindered
4-amino-5-chloro-2,6-
dimethylpyrimidine, the catalytic system had to be replaced by
Pd(OAc)2/S-Phos to achieve a good conversion to 5h, which was
isolated in a 71% yield (Table 1).8
Table 1
Synthesis of substituted diazino[c](iso)quinolin-6-(5H)-ones and diazino[c]-2,6-
naphthyridin-6-(5H)-ones 5aeh through path A
i
N
9
N
N
NHPiv
N
I
10
8
7
(R)
2
(N)
1
2b, 69 %
(R)
2N
Cl
1a-c
2N
4
6
ii
3
Conditions
i or ii or iii
N
NH2
O
5
H
5 a-h
SnBu3
NHPiv
iii
N
N
N
Coupling partners
Products
N1 N2 N3
Isolated
yields (%)
N
N
O
H
3b, 93 %
R
5j, 49%
2-NH2e3-Clepyrazine/1a
2-NH2e3-Clepyrazine/1b
2-NH2e3-Clepyrazine/1c
5-NH2e4-Clepyrimidine/1a
5-NH2e4-Clepyrimidine/1b
5-NH2e4-Clepyrimidine/1c
4-NH2e5-Iepyrimidine.HCl/1a
4-NH2e5-Cle2,6-diMeepyrimidine/1a
1
1
1
1
1
1
2
2
4
4
4
3
3
3
4
4
d
d
9
d
d
9
d
5a, 61i
5b, 50i
5c, 80i
5d, 40i
5e, 11i
5f, 43i
5g, 41ii
Scheme 3. Synthesis of pyridazino[3,4-c]isoquinolin-6(5H)one 5j. Isolated yields, con-
ditions: (i) 2,2,2-trimethylacetamide 1.2 equiv, Binap 10 mol %, Pd(OAc)2 5 mol %, Cs2CO3,
dioxane; (ii) LTMP 4.0 equiv, THF, ꢀ78 ꢁC, over 1.5 h then Bu3SnCl 2.1 equiv; (iii) ethyl 2-
iodobenzoate 1.1 equiv, Pd(OAc)2 5 mol %, S-Phos 10 mol %, toluene, reflux, overnight.
9-CF3
d
d
9-CF3
d
d
d
The previous one-pot cross-coupling/cyclisation for the syn-
thesis of diaza-analogues of phenanthridinones and benzonaph-
thyridinones 5aej appeared to be efficient, provided that the
starting materials were available. We were then interested in the
alternative route B, for which we have already demonstrated it was
a very general way for the synthesis of phenanthridinones and
benzonaphthyridinones.5 The key-step of this route is the KOH-
mediated anionic ring closure involving a biaryl compound bear-
ing a cyano group in position 2 and a fluorine atom in position 20
(see scheme of Table 2). We first synthesized the biaryl compounds
6aeh using commercially available substituted 2-fluoroarylboronic
acids 1dek (Scheme 4), which were coupled to 3-chloro-2-
cyanopyrazine in the presence of Pd(OAc)2/S-Phos as the catalyst.
d
1,3-diMe 5h, 71iii
Conditions: (i) Sealed tube, Pd(PPh3)4 8 mol %, diazine 1 equiv, boronic species
3.0 equiv, K3PO4 3.0 equiv, dioxane/H2O 12:1, reflux, overnight. (ii) Sealed tube,
Pd(PPh3)4 8 mol %, diazine 1 equiv, boronic species 3.0 equiv, K3PO4 5.0 equiv, di-
oxane/H2O 12:1, reflux, overnight. (iii) Sealed tube, diazine 1 equiv, boronic species
3.0 equiv, K3PO4 3.0 equiv, Pd(OAc)2 5 mol %, S-Phos 10 mol %, dioxane/H2O 12:1,
reflux, overnight.
In the pyridazine series, we first prepared the 3-amino-4-iodo-
6-phenylpyridazine (4) in an overall 50% yield as follows: 3-chloro-
6-phenylpyridazine was aminated with pivalamide using Pd(OAc)2/
BINAP as catalyst affording the aminated pyridazine 2a in 74% yield.
Compound 2a was then iodinated in 78% yield by metallation with

N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
5395
Table 2
3. Conclusion
Synthesis of substituted 3-(2-fluoroaryl or -pyridinyl)pyrazine-2-carbonitriles 6aeh
via Suzuki cross-coupling (path B)
In summary, we have demonstrated that the two routes A and B
are both efficient to provide an easy access to di- and tri-
azaphenanthridin-6(5H)-ones. The one-pot cross-coupling/cycli-
sation method (Path A) gave the expected diazino[c]isoquinolin-
6(5H)-ones and diazino[c]-[2,6]-naphthyridin-6(5H)-ones in
11e80%. The two-step cross-coupling/anionic ring closure route
(path B) afforded pyrazino[2,3-c]quinolin-5(6H)-ones and pyrazino
[2,3-c]-[1,8]-naphthyridin-5(6H)-one in 29e69% overall yields. If
the one-pot procedure can appear more attractive, the two-step
route gave yields in the same order of magnitude and the choice
depends on the availability of the starting material.
N
6'
1'
N
N
N
Cl
5'
4'
1d-k
2'
F
Y
CN
Conditions
i or ii
X
CN
2
3'
6a-h
Boronic species
Products
X
Isolated yield (%)
Y
1d
1e
1f
1g
1h
1i
CH
CF
CH
CH
CH
CH
CH
CH
CF
6a, 83i
6b, 61ii
6c, 69i
6d, 56ii
6e, 55i
6f, 84i
6g, 71ii
6h, 72i
CCl
CCF3
N
COMe
CH
4. Experimental section
4.1. General
1j
1k
CH
CCl
Reagents and solvents were bought from chemical suppliers and
generally used without further purification except compounds 1a,6
3-iodopyridazine9 and 5-iodopyrimidin-4-amine hydrochloride11
prepared from literature procedures. THF and toluene were dried
and distilled over sodium and benzophenone under N2. Reactions
were followed by 1H or 19F NMRof the crude mixture or by Thin Layer
Chromatography (TLC) on silica gel (Merck, Darmstadt, Germany)
and revealed using UV light. Most of the compounds were purified by
Conditions: (i) Pd(OAc)2 5 mol %, S-Phos 10 mol %, 3-chloro-2-cyanopyrazine
1 equiv, boronic species 1.05 equiv, Na2CO3 4 equiv, DME/H2O 2:1, reflux, 15 min.
(ii) Pd(OAc)2 5 mol %, S-Phos 10 mol %, 3-chloro-2-cyanopyrazine 1 equiv, boronic
species 1.5 equiv, Na2CO3 4 equiv, DME/H2O 2:1, reflux, overnight.
B(OH)
F
B(OH)
F
B(OH)
F
2
2
2
B(OH)
F
2
CF
flash silica gel column chromatography (70e200 mm). The purity of
F
Cl
1f
3
synthetic products was established by NMR spectroscopic data, and
MS analysis. MS: Thermo Finnigan, LCQ Advantage Max, Electrospray
Ionisation, Source heater T¼220 ꢁC, capillary voltage¼33 V. High
Resolution Mass Spectra (HRMS) were recorded with a Q-TOF
Micromass Instrument in the positive ESI (CV¼30 V) mode. 1H
(300 MHz), 19F (282 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Bruker Avance DMX 300 instrument. TMS signal or the
residual signal of deuterated solvent was taken as internal reference
for 1H and 13C spectra and CFCl3 signal for 19F spectra. Melting points
were determinate on a Kofler melting point apparatus. IR spectra
were recorded on PerkineElmer IRFT 1650 spectrometer.
1d
1g
1e
B(OH)
F
2
B(OH)
F
B(OH)
2
B(OH)
2
2
Cl
F
F
N
F
OMe
1i
1k
1h
1j
Scheme 4. Commercially available boronic acids 1dek selected for path B.
The biaryl compounds 6aeh were obtained in 55e84% yields
(Table 2).
Biaryls 6aeh were then submitted to KOH-mediated anionic
ring closure in t-BuOH at 150 ꢁC for 1.5 h. The expected pyrazino
[2,3-c]quinolin-5(6H)-ones 7aed,feh were isolated after pre-
cipitation and filtration in 64e97% yields. Using the same condi-
tions, pyrazino[2,3-c]-[1,8]naphthyridin-5(6H)-one 7e was isolated
with a lower 52% yield, probably due to competitive direct sub-
stitution of the fluorine atom adjacent to the nitrogen atom by the
hydroxide anion (Table 3).
4.2. General procedure for the synthesis of boronic esters
(1aec)
To a solution of 2,2,6,6-tetramethylpiperidine (TMPH, 1.5 equiv)
in THF (2 mL/mmol of ester), a solution of n-butyllithium (1.45 M in
hexane,1.5 equiv) was added at ꢀ30 ꢁC over 30 min. After cooling at
ꢀ78 ꢁC, tris(isopropyl)borate (2.0 equiv) was added over 20 min.
Ethyl benzoate or 4-(trifluoromethyl)benzoate or ethyl iso-
nicotinate (1.0 equiv) was added via syringe to the reaction mixture
over 10 min and the mixture was stirred at ꢀ78 ꢁC for 3.5 h. After
warming to ꢀ30 ꢁC, glacial acetic acid (1.5 equiv) was added
causing the internal temperature rising to ꢀ10 ꢁC. Neopentyl glycol
(1.5 equiv) was added and the mixture was stirred at room tem-
perature for 2 h. Dichloromethane (20 mL/mmol of ester) was then
added. The organic phase was successively washed three times
with satd aqueous NH4Cl, with satd aqueous NaHCO3 and with
water, dried over MgSO4 and evaporated to give the desired
compounds.
Table 3
Synthesis of substituted pyrazino[2,3-c]quinolin-5(6H)-ones and pyrazino[2,3-c]-
[1,8]naphthyridin-5(6H)-one 7aeh via KOH-mediated anionic ring closure (path B)
N
N
1
N
O
N
2
3
i
Y
Y
CN
X
4
N
H
X
F
6a-h
7a-h
Starting material
Products
Isolated yield (%)
X
Y
6a
6b
6c
6d
6e
6f
CH
CF
CH
CH
CH
CH
CH
CH
CF
7a, 67
7b, 88
7c, 69
7d, 73
7e, 52
7f, 64
7g, 97
7h, 88
4.2.1. Ethyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate (1a).6
Following general procedure 1a was obtained as a yellow oil
CCl
CCF3
N
COMe
CH
(3.30 g, 99%). 1H NMR (300 MHz, CDCl3)
d
7.94 (d, J¼7.8 Hz, 1H),
7.53e7.48 (m, 2H), 7.42e7.34 (m, 1H), 4.38 (q, J¼7.1 Hz, 2H), 3.80 (s,
4H), 1.39 (t, J¼7.1 Hz, 3H), 1.11 (s, 6H).
6g
6h
CH
CCl
4.2.2. Ethyl 2-(5,5-dimethyl-[1,3]-dioxoborinan-2-yl)-4-trifluo
romethylbenzoate (1b). Following general procedure 1b was
Conditions: (i) Sealed tube, KOH 5 equiv, t-BuOH, 150 ꢁC, 1.5 h.

5396
N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
obtained as a dark oil (1.45 g, 58%). IR (neat)
n
(cmꢀ1) 2965, 1714
(7:3)) to give the desired compound 3a as a bright orange powder
(1.17 g, 78%); mp 135e137 ꢁC; IR (neat) (cmꢀ1) 3241 (NH), 2973,
2927, 1656 (C]O), 1485, 1447, 1400, 1180, 1019; 1H NMR (300 MHz,
CDCl3) 9.18 (s, 1H), 8.26 (s, 1H), 7.91e7.87 (m, 2H), 7.56e7.46 (m,
3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3)
177.1, 157.2, 155.7,
136.8, 134.4, 130.4, 129.1 (2C), 127.2 (2C), 101.3, 39.8, 27.4 (3C);
HRMS (ESIþ): calcd for C15H17IN3O m/z 382.0416 [MþH], found
382.0425.
(C]O), 1478, 1343, 1276, 1167, 1124, 1088; 1H NMR (300 MHz,
n
CDCl3)
d
8.01 (d, J¼8.2 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J¼8.2 Hz, 1H),
4.41 (q, J¼7.1 Hz, 2H), 3.80 (s, 4H), 1.41 (t, J¼7.1 Hz, 3H), 1.12 (s, 6H).
d
13C NMR (75 MHz, CDCl3)
d
167.6, 136.6 (q, J¼1.2 Hz), 133.2 (q,
d
2J¼32.6 Hz), 128.8 (2C), 128.3 (q, 3J¼3.6 Hz), 125.4 (q, 3J¼3.8 Hz),
123.8 (d, 1J¼272.9 Hz), 72.6 (2C), 61.8, 31.9, 22.1 (2C), 14.3. 19F NMR
(282 MHz, CDCl3):
158.
d
ꢀ63.5 (s); MS (ESIþ): 331 [MþH], 313, 259, 231,
4.5. Synthesis of N-(4-(tri(n-butyl)stannyl)pyridazin-3-yl)piv-
4.2.3. Ethyl
(1c). Following general procedure 1c was obtained as a yellow oil
(1.88 g, 36%). IR (neat)
(cmꢀ1) 2914, 2863, 1715 (C]O), 1310, 1293,
1095; 1H NMR (300 MHz, CDCl3)
8.95 (d, J¼5.0 Hz, 1H), 8.74 (s,
2-(5,5-dimethyl-[1,3]-dioxoborinan-2-yl)isonicotinate
alamide (3b)
n
A solution of n-butyllithium (17.6 mL, 1.53 M in hexane,
24 mmol, 4.0 equiv) was added to a cold (ꢀ78 ꢁC) and anhydrous
solution of TMPH (4.6 mL, 27 mmol, 4.0 equiv) in THF (40 mL). The
mixture was warmed to 0 ꢁC. After 20 min, the mixture was cooled
to ꢀ78 ꢁC and a solution of N-(pyridazin-3-yl)pivalamide 2b (1.21 g,
6.7 mmol) in THF (20 mL) was added dropwise. The mixture was
then stirred for 1 h 15 min. At ꢀ78 ꢁC, tri(n-butyl)tin chloride
(7.5 mL, 27.7 mmol, 4.1 equiv) was introduced and the stirring was
maintained for 90 min at the same temperature. Hydrolysis was
then carried out at ꢀ78 ꢁC using satd aqueous NH4Cl (50 mL).
Temperature was raised to room temperature and the reaction
mixture was evaporated to dryness. The residue was extracted with
dichloromethane (5ꢂ40 mL). The combined organic extracts were
then dried over magnesium sulfate and evaporated in vacuum. The
residue was purified by column chromatography (eluent: PE/EtOAc
(8:2)) to give the desired compound 3b as a yellow solid (2.94 g,
d
1H), 7.90 (d, J¼5.0 Hz, 1H), 4.15 (q, J¼7.1 Hz, 2H), 3.64 (s, 4H), 1.13 (t,
J¼7.1 Hz, 3H), 0.97 (s, 6H). 13C NMR (75 MHz, CDCl3)
d 164.2, 152.3,
148.7, 142.8, 133.9, 122.9, 72.9 (2C), 62.6, 29.7, 21.5 (2C), 13.6; MS
(ESIþ): 257, 236, 218, 164.
4.3. General procedure for the synthesis of N-(pyridazin-3-yl)
pivalamides (2a,b)
To degassed dioxane (3 mL/mmol of halide), 3-chloro-6-
phenylpyridazine or 3-iodopyridazine (1 equiv), trimethylaceta-
mide (1.2 equiv), Cs2CO3 (2.5 equiv), BINAP (10 mol %) and Pd(OAc)2
(5 mol %) were introduced. The mixture was heated at 100 ꢁC for
24 h under Ar. The resulting solution was filtered and washed with
dioxane. The filtrate was evaporated to dryness and purified by
column chromatography (eluent: PE/AcOEt (7:3)) to afford the
desired compounds.
93%); mp<50 ꢁC; IR (neat)
(C]O), 1498, 1405, 1337, 1279, 1179; 1H NMR (300 MHz, CDCl3)
9.17 (s, 1H), 8.74 (d, J¼5.4 Hz, 1H), 7.57 (d, J¼5.4 Hz, 1H), 1.53e1.43
(m, 6H), 1.36e1.24 (m, 6H), 1.32 (s, 9H), 1.08e1.03 (m, 6H),
n
(cmꢀ1) 3160 (NH), 2957, 2918, 1670
d
4.3.1. N-(6-Phenylpyridazin-3-yl)pivalamide (2a). Following gen-
eral procedure, 2a was obtained as a white powder (199 mg, 74%);
0.92e0.84 (m, 9H); Selected 13C NMR data (75 MHz, CDCl3)
d 178.6,
mp 172e173 ꢁC; IR (neat)
n
(cmꢀ1) 3382 (NH), 2973, 1686 (C]O),
160.2, 147.5, 139.9, 137.7, 39.5, 27.3 (3C); HRMS (ESIþ): calcd for
1509, 1486, 1351, 1294, 1141, 1121; 1H NMR (300 MHz, CDCl3)
d
8.62
C21H40N3OSn m/z 470.2193 [MþH], found 470.2199.
(s, 1H), 8.55 (d, J¼9.3 Hz, 1H), 8.02 (dd, J¼7.9, 1.6 Hz, 2H), 7.87 (d,
J¼9.3 Hz, 1H), 7.56e7.45 (m, 3H), 1.38 (s, 9H); 13C NMR (75 MHz,
4.6. Synthesis of 3-amino-4-iodo-6-phenylpyridazine (4)
CDCl3) d 177.9, 156.7, 154.1, 136.1, 129.7, 129.0 (2C), 126.7 (2C), 125.9,
119.0, 40.1, 27.4; HRMS (ESIþ): calcd for C15H18N3O m/z 256.1450
[MþH], found 256.1451.
In sealed tube, 3a (1.0 g, 2.6 mmol) was dissolved into aqueous
5 M H2SO4 (7.9 mL, 3 mL/mmol) and the resulting solution was
heated at 95 ꢁC for 7 h. After cooling to room temperature, the
mixture was diluted with water (30 mL) and the aqueous phase was
washed with ethyl acetate (3ꢂ20 mL). The pH of combined aqueous
phase was fixed at 10 with an aqueous 2 M sodium hydroxide solu-
tion (20 mL) and the resulting aqueous phase was extracted with
ethyl acetate (3ꢂ20 mL). The combined organic phase was dried over
magnesium sulfate and evaporated to dryness, giving the desired
compound 4 as a bright brown solid (0.67 g, 86%); mp 178e179 ꢁC; IR
4.3.2. N-(Pyridazin-3-yl)pivalamide (2b).12 Following general pro-
cedure 2b was obtained as a white powder (1.21 g, 69%). 1H NMR
(300 MHz, CDCl3):
d
8.91 (dd, J¼4.6, 1.5 Hz, 1H), 8.52 (s, 1H), 8.48
(dd, J¼9.0,1.5 Hz,1H), 7.47 (dd, J¼9.0, 4.6 Hz,1H),1.25 (s, 9H). HRMS
(ESIþ): calcd for C9H14N3O m/z 180.1137 [MþH], found 180.1140.
4.4. Synthesis of N-(4-iodo-6-phenylpyridazin-3-yl)piv-
alamide (3a)
(neat)
n
(cmꢀ1) 3468, 3276, 1636, 1510, 1490, 1450, 1433, 1262, 1184,
8.13 (s, 1H), 7.92 (dd, J¼8.0,1.5 Hz,
1015; 1H NMR (300 MHz, CDCl3)
d
A solution of n-butyllithium (24.1 mL, 1.3 M in hexane,
31.3 mmol, 8.0 equiv) was added to a cold (ꢀ78 ꢁC) and anhydrous
solution of TMPH (5.3 mL, 31.3 mmol, 8.0 equiv) in THF (25 mL). The
mixture was warmed to 0 ꢁC. After 30 min, the mixture was cooled
to ꢀ78 ꢁC and a cold (ꢀ78 ꢁC) solution of N-(6-phenylpyridazin-3-
yl)pivalamide (2a) (1.01 g, 3.9 mmol) in THF (20 mL) was added
dropwise. Then, the mixture was stirred for 90 min. At ꢀ78 ꢁC,
iodine (8.20 g, 32.1 mmol, 8.2 equiv) was introduced and stirring
was maintained for 90 min at the same temperature. Hydrolysis
was then carried out at ꢀ78 ꢁC using satd aqueous NH4Cl (50 mL).
Temperature was raised to room temperature and the solution was
decolorized with satd aqueous sodium thiosulfate (30 mL) and
evaporated nearly to dryness. The residue was extracted with
dichloromethane (4ꢂ40 mL), then the combined organic extracts
were dried over magnesium sulfate and evaporated in vacuum. The
residue was purified by column chromatography (eluent: PE/EtOAc
2H), 7.52e7.39 (m, 3H), 5.34 (s, 2H); 13C NMR (75 MHz, CDCl3)
d 158.7,
152.2, 135.7, 135.4, 129.1, 128.9 (2C), 126.2 (2C), 89.7; HRMS (ESIþ):
calcd for C10H9IN3 m/z 297.9841 [MþH], found 297.9833.
4.7. General procedure for tandem Suzuki cross cou-
plingecyclisation reactions (compounds 5aei)13
In a sealed tube and under argon atmosphere, the appropriate
diazine (1.0 equiv) and the corresponding boronic ester (3.0 equiv)
were dissolved in a mixture of dioxane/water 12:1 (7.7 mL/mmol of
diazine), then K3PO4 (3.0 or 5.0 equiv) and palladium catalyst
(Pd(PPh3)4 8 mol % or Pd(OAc)2 5 mol %þS-Phos 10 mol %) were
added. The reaction mixture was refluxed overnight and then
cooled to room temperature. The crude product was evaporated to
dryness and purified using column chromatography or precipitated
in MeOH/water (2:1) (20 mL/mmol of diazine).

N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
5397
4.7.1. Pyrazino[2,3-c]isoquinolin-6(5H)-one (5a). Starting from 2-
amino-3-chloropyrazine (100 mg, 0.77 mmol) and boronic ester
1a, following general procedure, 5a was obtained after pre-
(neat)
1408, 1359, 1319, 1180, 1108; 1H NMR (300 MHz, DMSO-d6)
n
(cmꢀ1) 3410 (NH), 3018, 2753, 1680 (C]O), 1593, 1547,
d
12.28 (s, 1H), 9.98 (s, 1H), 9.14 (s, 1H), 9.06 (d, J¼5.2 Hz, 1H), 8.85
cipitation as a yellow powder (94 mg, 61%); mp>260 ꢁC; IR (neat)
n
(s, 1H), 8.18 (d, J¼5.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
(cmꢀ1) 3010, 2876, 1653 (C]O), 1607, 1504, 1414, 1341, 1073; 1H
NMR (300 MHz, DMSO-d6)
d 159.1, 152.4, 151.7, 146.9, 145.4, 139.6, 134.8, 130.8, 127.2, 119.9;
d
12.34 (s, 1H), 8.70 (d, J¼7.6 Hz, 1H),
HRMS (ESIþ): calcd for C10H7N4O m/z 199.0620 [MþH], found
8.58 (d, J¼2.4 Hz, 1H), 8.56 (d, J¼2.4 Hz, 1H), 8.33 (d, J¼7.6 Hz, 1H),
199.0626.
7.97 (dd, J ¼7.6, 7.6 Hz, 1H), 7.82 (dd, J ¼7.6, 7.6 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6):
d
161.0, 144.6, 143.7, 139.1, 133.6, 133.3, 131.9,
4.7.7. Pyrimido[4,5-c]isoquinolin-6(5H)-one (5g). Starting from 4-
amino-5-iodopyrimidine hydrochloride (326 mg, 1.30 mmol) and
boronic ester 1a, following general procedure, 5g was obtained
after precipitation as a brown powder (103 mg, 41%); mp>260 ꢁC;
130.5, 127.4 (2C), 123.4; HRMS (ESIþ): calcd for C11H8N3O m/z
198.0667 [MþH], found 198.0668.
4.7.2. 9-(Trifluoromethyl)pyrazino[2,3-c]-isoquinolin-6(5H)-one
(5b). Starting from 2-amino-3-chloropyrazine (91 mg, 0.70 mmol)
and boronic ester 1b, following general procedure, 5b was obtained
after precipitation as a white powder (94 mg, 50%); mp>260 ꢁC; IR
IR (neat)
n
(cmꢀ1) 3342 (NH), 3036, 2869, 1686 (C]O), 1594, 1419,
1405, 1316, 1147; 1H NMR (300 MHz, DMSO-d6)
d
12.40 (s, 1H), 9.72
(s, 1H), 8.97 (s, 1H), 8.64 (d, J¼7.9 Hz, 1H), 8.33 (d, J¼7.9 Hz, 1H), 7.93
(dd, J ¼7.9, 7.9 Hz, 1H), 7.74 (dd, J ¼7.9, 7.9 Hz, 1H); 13C NMR
(neat)
n
(cmꢀ1) 3300 (NH), 2926, 2868, 1690, 1664 (C]O), 1409,
(75 MHz, DMSO-d6) d 162.6, 157.7, 152.7, 143.1, 133.5, 131.3, 129.5,
1351, 1298, 1254, 1179, 1125, 1067; 1H NMR (300 MHz, DMSO-d6)
127.9, 126.2, 122.8, 111.4; HRMS (ESIþ): calcd for C11H8N3O m/z
198.0667 [MþH], found 198.0659.
d
12.60 (s, 1H), 8.89 (s, 1H), 8.63 (d, J¼2.4 Hz, 1H), 8.62 (d, J¼2.4 Hz,
1H), 8.50 (d, J¼8.3 Hz, 1H), 8.12 (dd, J¼8.3, 1.1 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6):
d
160.6, 145.1, 144.8, 139.5, 134.3, 132.9 (q,
4.7.8. 1,3-Dimethylpyrimido[4,5-c]isoquinolin-6(5H)-one
(5h). Starting from 4-amino-5-chloro-2,6-dimethylpyrimidine
(151 mg, 0.96 mmol), boronic ester 1a, following general pro-
cedure, 5h was obtained after precipitation as a grey powder
2J¼32.2 Hz), 131.0, 130.3, 129.1, 126.4 (q, 3J¼3.2 Hz), 123.6 (q,
1J¼266.6 Hz), 120.2 (q, 3J¼4.1 Hz); 19F NMR (282 MHz, DMSO-d6):
d
ꢀ61.7 (s); HRMS (ESIþ): calcd for C12H7F3N3O m/z 266.0541
[MþH], found 266.0550.
(153 mg, 71%); mp>260 ꢁC; IR (neat) (cmꢀ1) 3359 (NH), 2843,
n
2702, 1679 (C]O), 1588, 1570, 1440, 1417, 1324; 1H NMR (300 MHz,
DMSO-d6)
4.7.3. Pyrazino[2,3-c]-2,6-naphthyridin-6(5H)-one
(5c). Starting
d
12.23 (s, 1H), 8.45 (d, J¼8.3 Hz, 1H), 8.39 (dd, J¼7.6,
from 2-amino-3-chloropyrazine (142 mg, 1.08 mmol) and boronic
1.3 Hz, 1H), 7.92 (ddd, J ¼ 8.3, 8.3 Hz and J¼1.3 Hz, 1H), 7.70 (dd,
ester 1c, following general procedure, 5c was obtained after pre-
J¼8.3, 7.6 Hz, 1H), 2.98 (s, 3H), 2.57 (s, 3H); 13C NMR (75 MHz,
cipitation as a yellow powder (172 mg, 80%); mp>260 ꢁC; IR (neat)
n
DMSO-d6) d 164.7,164.0,161.9,154.1,133.3,132.3,128.2,127.9,126.9,
(cmꢀ1) 3372 (NH), 2665, 1672 (C]O), 1538, 1397, 1326, 1107, 1019;
126.5, 107.6, 27.7, 25.2; HRMS (ESIþ): calcd C13H12N3O m/z 226.0980
[MþH], found 226.0985.
1H NMR (300 MHz, DMSO-d6)
d
12.66 (s, 1H), 9.94 (s, 1H), 8.98 (d,
J¼5.2 Hz, 1H), 8.64 (d, J¼2.2 Hz, 1H), 8.63 (d, J¼2.2 Hz, 1H), 8.15 (d,
J¼5.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6):
d
160.7, 150.4, 146.8,
4.7.9. 2-Phenylpyridazino[3,4-c]isoquinolin-6(5H)-one (5i). Starting
from 3-amino-4-iodo-6-phenylpyridazine 4 (84 mg, 0.28 mmol)
and boronic ester 1a, following general procedure, and using col-
umn chromatography (eluent: PE/EtOAc (6:4)) 5i was obtained as
145.2, 144.4, 139.6, 133.1, 130.8, 127.7, 119.8; HRMS (ESIþ): calcd for
C10H7N4O m/z 199.0620 [MþH], found 199.0609.
4.7.4. Pyrimido[5,4-c]isoquinolin-6(5H)-one (5d). Starting from 5-
amino-4-chloropyrimidine (91 mg, 0.69 mmol) and boronic ester
1a, following general procedure, 5d was obtained after pre-
cipitation as a dark brown powder (55 mg, 40%); mp>260 ꢁC; IR
a yellow powder (46 mg, 60%); mp>260 ꢁC; IR (neat) (cmꢀ1) 3322
n
(NH), 3080, 1678 (C]O), 1605, 1480, 1388, 1344, 1310, 1161, 1135; 1H
NMR (300 MHz, DMSO-d6) 11.35 (s, 1H), 9.03 (s, 1H), 8.90 (d,
d
J¼7.6 Hz, 1H), 8.49 (d, J¼7.6 Hz, 1H), 8.32 (d, J¼7.1 Hz, 2H), 7.99 (dd,
(neat)
n
(cmꢀ1) 3014, 2877, 1667 (C]O), 1610, 1585, 1434, 1398,
J ¼7.6, 7.6 Hz, 1H), 7.91 (dd, J ¼ 7.6, 7.6 Hz, 1H), 7.61e7.52 (m, 3H);
1355, 1334, 1300; 1H NMR (300 MHz, DMSO-d6)
d
11.97 (s, 1H), 9.08
13C NMR (75 MHz, DMSO-d6):
d 161.2, 154.4, 150.1, 135.9, 133.4,
(s,1H), 8.81 (s,1H), 8.76 (dd, J¼7.7,1.0 Hz,1H), 8.36 (dd, J¼7.7, 1.0 Hz,
131.4, 130.8, 129.6, 128.9 (2C), 127.7, 127.5, 126.7 (2C), 125.3, 118.2,
117.9; HRMS (ESIþ): calcd for C17H12N3O m/z 274.0980 [MþH],
found 274.0985.
1H), 8.00 (ddd, J ¼ 7.7, 7.7 Hz and J¼1.0 Hz, 1H), 7.90 (ddd, J ¼ 7.7, 7.7
Hz and J¼1.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d 160.0, 152.0,
145.0, 140.6, 133.4, 133.1, 131.8, 130.3, 129.1, 127.4, 123.7; HRMS
(ESIþ): calcd for C11H8N3O m/z 198.0667 [MþH], found 198.0668.
4.8. Synthesis of pyridazino[3,4-c]isoquinolin-6(5H)-one (5j)
4.7.5. 9-(Trifluoromethyl)pyrimido[5,4-c]-isoquinolin-6(5H)-one
(5e). Starting from 5-amino-4-chloropyrimidine (92 mg,
0.71 mmol) and boronic ester 1b, following general procedure, 5e
was obtained after precipitation as a grey powder (21 mg, 11%);
S-Phos (13 mg, 0.03 mmol, 10 mol %) was introduced in dry
toluene (0.5 mL) under Argon, then Pd(OAc)2 (4 mg, 0.02 mmol,
5 mol %) was added. The resulting solution was heated at 80 ꢁC for
10 min. A solution of N-(4-(tri(n-butyl)stannyl)pyridazin-3-yl)piv-
alamide 3b (150 mg, 0.32 mmol, 1.0 equiv) in dry toluene (0.8 mL)
mp>260 ꢁC; IR (neat) (cmꢀ1) 3375 (NH), 2874, 1675 (C]O), 1407,
n
1314, 1289, 1262, 1174, 1121, 1066; 1H NMR (300 MHz, DMSO-d6)
and ethyl 2-iodobenzoate (80 mL, 0.48 mmol, 1.5 equiv) were suc-
d
12.19 (s,1H), 9.08 (s,1H), 8.88 (s,1H), 8.81 (s,1H), 8.47 (d, J¼8.3 Hz,
cessively added. The solution was refluxed overnight and the
resulting mixture was evaporated to dryness. The crude product
was purified by column chromatography (eluent: PE/EtOAc (6:4))
to give the desired product 5j (31 mg, 49%) as a yellow powder;
1H), 8.16 (dd, J¼8.3, 1.6 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d
159.1, 152.2, 145.6, 139.5, 133.7, 132.9 (q, 2J¼32.5 Hz), 131.9, 130.7,
129.1, 127.7 (q, 3J¼3.3 Hz), 123.6 (q, 1J¼273.1 Hz), 120.4 (q,
3J¼4.0 Hz); 19F NMR (282 MHz, DMSO-d6):
d
ꢀ61.8 (s); HRMS
mp>260 ꢁC; IR (neat)
n
(cmꢀ1) 3156 (NH), 3047, 2918, 1654 (C]O),
(ESIþ): calcd for C12H7F3N3O m/z 266.0541 [MþH], found 266.0547.
1606, 1479, 1436, 1345, 1324; 1H NMR (300 MHz, DMSO-d6)
d 12.55
(s, 1H), 9.17 (d, J¼5.3 Hz, 1H), 8.67 (d, J¼7.9 Hz, 1H), 8.60 (d,
J¼5.3 Hz, 1H), 8.36 (d, J¼7.9 Hz, 1H), 7.97 (dd, J¼7.9, 7.5 Hz, 1H), 7.84
4.7.6. Pyrimido[5,4-c]-2,6-naphthyridin-6(5H)-one
(5f). Starting
from 5-amino-4-chloropyrimidine (146 mg, 1.13 mmol) and bo-
ronic ester 1c, following general procedure, 5f was obtained after
precipitation as a brown powder (96 mg, 43%); mp>260 ꢁC; IR
(dd, J¼7.9, 7.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d 161.3, 151.0,
147.2, 133.5, 131.3, 130.7, 127.7, 127.5, 124.7, 120.4, 116.8; HRMS
(ESIþ): calcd for C11H8N3O m/z 198.0667 [MþH], found 198.0673.

5398
N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
4.9. General procedure for Suzuki cross-coupling (com-
135.2 (d, 3J¼1.4 Hz),130.6 (d, J¼1.0 Hz),129.9 (qd, 3J¼4.5, 3J¼1.9 Hz),
124.7 (d, J¼4.7 Hz),124.5 (d, 2J¼13.4 Hz),122.1 (q,1J¼272.8 Hz),119.6
pounds 6aeh)14
(qd, 2J¼33.4, 2J¼12.4 Hz), 114.8; 19F NMR (282 MHz, CDCl3):
ꢀ61.8
d
In a degassed solution of DME/H2O (2:1) (12 mL/mmol of dia-
zine), were successively introduced S-Phos (10 mol %) and Pd(OAc)2
(5 mol %). The solution was heated at 80 ꢁC for 10 min then sodium
carbonate (4.0 equiv), appropriate boronic acid (1.05 or 1.5 equiv)
and appropriate diazine (1.0 equiv) were added. The solution was
then refluxed (15 min or overnight) under Ar. The resulting mixture
was filtered on Celite and washed with ethyl acetate and water. The
aqueous phase was then extracted three times with ethyl acetate.
The combined organic phase was dried over MgSO4 and evaporated
to dryness. The residue was purified by column chromatography
(eluent: PE/EtOAc) to give the desired product.
(d, J¼13.1 Hz, 3F), ꢀ116.1 (m, 1F); HRMS (ESIþ): calcd for
C12H5F4N3Na m/z 290.0317 [MþNa], found 290.0316.
4.9.5. 3-(20-Fluoropyridin-3-yl)pyrazine-2-carbonitrile
(6e). Starting from 2-chloro-3-cyanopyrazine (80 mg, 0.58 mmol)
and boronic acid 1h, following general procedure, 6e was obtained
after purification by column chromatography (eluent: PE/EtOAc
(75:25)) as a yellow powder (63 mg, 55%); mp 84e86 ꢁC; IR (neat)
n
(cmꢀ1) 2922, 2851, 2241 (CN), 1608, 1571, 1446, 1410, 1392, 1254; 1H
NMR (300 MHz, CDCl3)
8.91 (d, J¼2.3 Hz, 1H), 8.76 (d, J¼2.3 Hz,
d
1H), 8.46e8.44 (m, 1H), 8.12 (ddd, J¼9.2, 7.5, 1.9 Hz, 1H), 7.50e7.39
(m, 1H); 13C NMR (75 MHz, CDCl3)
d
160.0 (d, 1J¼242.1 Hz), 152.0 (d,
4.9.1. 3-(20-Fluorophenyl)pyrazine-2-carbonitrile (6a). Starting from
2-chloro-3-cyanopyrazine (81 mg, 0.58 mmol) and boronic acid 1d,
following general procedure, 6a was obtained after purification by
column chromatography (eluent: PE/EtOAc (85:15)) as a yellow
3J¼5.8 Hz), 150.4 (d, J¼15.0 Hz), 146.6, 144.1, 142.2 (d, J¼2.8 Hz),
130.3, 122.0 (d, J¼4.6 Hz), 118.0 (d, 2J¼29.3 Hz), 114.8; 19F NMR
(282 MHz, CDCl3):
C10H6FN4Na m/z 201.0576 [MþNa], found 201.0578.
d
ꢀ67.5 (d, J¼9.2 Hz); HRMS (ESIþ): calcd for
powder (95 mg, 83%); mp 72e73 ꢁC; IR (neat)
n
(cmꢀ1) 3055, 2246
4.9.6. 3-(20-Fluoro-30-methoxyphenyl)pyrazine-2-carbonitrile
(6f). Starting from 2-chloro-3-cyanopyrazine (80 mg, 0.58 mmol)
and boronic acid 1i, following general procedure, 6f was obtained
after purification by column chromatography (eluent: PE/EtOAc
(CN),1615,1496,1458,1429,1388,1217,1170,1102; 1H NMR (300 MHz,
CDCl3)
8.88 (d, J¼2.4 Hz,1H), 8.70 (d, J¼2.4 Hz,1H), 7.63 (ddd, J ¼7.5,
d
7.5 Hz and J¼1.6Hz,1H)7.59e7.52(m,1H), 7.35 (ddd, J ¼7.5, 7.5 Hz and
J¼1.6 Hz,1H), 7.30e7.25 (m,1H); 13C NMR (75 MHz, CDCl3)
d 159.8 (d,
(8:2)) as a white powder (111 mg, 84%); mp 124e125 ꢁC; IR (neat)
n
1J¼251.8Hz),153.5(d,3J¼1.1Hz),146.5,143.5,132.9(d,J¼8.5Hz),131.4
(d, J¼2.1 Hz), 130.6 (d, 4J¼1.2 Hz), 124.8 (d, J¼3.7 Hz), 122.9 (d,
2J¼13.8 Hz), 116.4 (d, 2J¼21.4 Hz), 115.2 (d, 5J¼1.2 Hz); 19F NMR
(cmꢀ1) 3094, 2949, 2243 (CN), 1587, 1486, 1430, 1398, 1275, 1065,
1026; 1H NMR (300 MHz, CDCl3)
d
8.87 (d, J¼2.3 Hz, 1H), 8.71 (d,
J¼2.3 Hz, 1H), 7.31e7.21 (m, 1H), 7.22e7.10 (m, 2H), 3.96 (s, 3H); 13C
(282 MHz, CDCl3):
calcd for C11H7FN3 m/z 200.0624 [MþH], found 200.0625.
d
ꢀ114.2 (ddd, J¼10.2, 7.2, 5.2 Hz); HRMS (ESIþ):
NMR (75 MHz, CDCl3)
d
153.5, 149.9 (d, 1J¼252.0 Hz), 148.2 (d,
2J¼10.4 Hz), 146.5, 143.6, 130.6, 124.7 (d, J¼4.8 Hz), 123.6 (d,
4.9.2. 3-(20,30-Difluorophenyl)pyrazine-2-carbonitrile (6b). Starting
from 2-chloro-3-cyanopyrazine (101 mg, 0.72 mmol) and boronic
acid 1e, following general procedure, 6b was obtained after puri-
fication by column chromatography (eluent: PE/EtOAc (8:2)) as
2J¼11.3 Hz), 122.0 (d, J¼0.8 Hz), 115.9 (d, J¼2.4 Hz), 115.2, 56.5; 19
F
NMR (282 MHz, CDCl3):
d
ꢀ136.8 (dd, J¼10.2, 3.7 Hz); HRMS (ESIþ):
calcd for C12H8FN3ONa m/z 252.0549 [MþNa], found 252.0555.
4.9.7. 3-(20,40-Difluorophenyl)pyrazine-2-carbonitrile (6g). Starting
from 2-chloro-3-cyanopyrazine (502 mg, 3.58 mmol) and boronic acid
1j, following general procedure, 6g was obtained after purification by
column chromatography (eluent: PE/EtOAc (85:15)) as a yellow pow-
a brown oil (96 mg, 61%); IR (neat)
1490, 1477, 1393, 1269, 1057; 1H NMR (300 MHz, CDCl3)
J¼2.3 Hz, 1H), 8.68 (d, J¼2.3 Hz, 1H), 7.39e7.27 (m, 2H), 7.27e7.17
n
(cmꢀ1) 3097, 3056, 2245 (CN),
8.83 (d,
d
(m, 1H); Selected 13C NMR data (75 MHz, CDCl3)
d 152.4, 150.7 (dd,
der (554 mg, 71%); mp 100e102 ꢁC; IR (neat) (cmꢀ1) 3050, 2927, 2243
n
1J¼249.0, 2J¼11.0 Hz), 148.3 (dd, 1J¼254.4, 2J¼14.1 Hz), 146.6, 144.0,
(CN), 1596, 1430, 1387, 1270, 1154, 1101; 1H NMR (300 MHz, CDCl3)
130.4, 126.0 (d, J¼3.8 Hz), 124.9 (d, J¼4.8 Hz), 119.9 (d, 2J¼17.1 Hz),
114.9; 19F NMR (282 MHz, CDCl3):
d
ꢀ136.5 (dm, J¼20.5 Hz), ꢀ139.1
d
8.88 (d, J¼2.3 Hz, 1H), 8.72 (d, J¼2.3 Hz, 1H), 7.65 (ddd, J ¼8.4, 8.4 Hz
and J¼6.2 Hz,1H), 7.18e6.95 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 164.7
(ddd, J¼20.5, 9.9, 3.6 Hz); HRMS (ESIþ): calcd for C11H6F2N3 m/z
(dd, 1J¼254.6, 3J¼12.2 Hz), 160.3 (dd, 1J¼254.6, 3J¼12.2 Hz), 152.7,
146.6, 143.6, 132.7 (dd, J¼10.2, 3.7 Hz), 130.5, 119.3 (dd, J¼14.0, 3.9 Hz),
218.0530 [MþH], found 218.0542.
2
4
4.9.3. 3-(30-Chloro-20-fluorophenyl)pyrazine-2-carbonitrile
(6c). Startingfrom 2-chloro-3-cyanopyrazine(80mg, 0.58mmol)and
boronic acid 1f, following general procedure, 6c was obtained after
purification by column chromatography (eluent: PE/EtOAc (85:15)) as
115.1, 112.6 (dd, J¼21.9, J¼3.8 Hz), 105.0 (dd, 2J¼25.5, 25.5 Hz); 19F
NMR (282 MHz, CDCl3):
d
ꢀ104.8 (m, 1F), ꢀ109.2 (m,1F); HRMS (ESIþ):
calcd for C12H6F2N3 m/z 218.0530 [MþH], found 218.0537.
4.9.8. 3-(40-Chloro-20-fluorophenyl)pyrazine-2-carbonitrile
(6h). Starting from 2-chloro-3-cyanopyrazine (80 mg, 0.57 mmol)
and boronic acid 1k, following general procedure, 6h was obtained
after purification by column chromatography (eluent: PE/EtOAc
(85:15)) as a yellow powder (97 mg, 72%); mp 144e146 ꢁC; IR (neat)
yellow crystals (92 mg, 69%); mp 131e132 ꢁC; IR (neat) (cmꢀ1) 3079,
n
2926, 2242 (CN),1457,1429,1391,1237,1140,1041; 1H NMR (300 MHz,
CDCl3)
8.89 (d, J¼2.3 Hz, 1H), 8.75 (d, J¼2.3 Hz, 1H), 7.66e7.60 (m,
d
1H), 7.52 (ddd, J ¼6.5, 6.5 Hz and J¼1.7 Hz,1H), 7.30 (ddd, J ¼8.0, 8.0 Hz
and J¼0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d
155.5 (d, 1J¼254.1 Hz),
n
(cmꢀ1) 3051, 2929, 2243 (CN), 1610, 1574, 1417, 1385, 1217, 1117,
152.8 (d, 3J¼1.4 Hz),146.5,144.0,133.4,130.5,129.6 (d, J¼1.5 Hz),125.2
1086; 1H NMR (300 MHz, CDCl3)
d
8.88 (d, J¼2.2 Hz, 1H), 8.72 (d,
(d, J¼4.9Hz),124.4 (d, 2J¼13.9 Hz),122.4 (d, 2J¼17.8 Hz), 114.9; 19FNMR
J¼2.2 Hz, 1H), 7.59 (dd, J¼8.4, 8.0 Hz, 1H), 7.39e7.30 (m, 2H); 13C
(282 MHz, CDCl3):
C11H6ClFN3 m/z 234.0234 [MþH], found 234.0231.
d
ꢀ116.2 (dd, J¼6.7, 6.5 Hz); HRMS (ESIþ): calcd for
NMR (75 MHz, CDCl3)
d
159.6 (d, 1J¼255.5 Hz), 152.6 (d, 3J¼1.6 Hz),
146.6, 143.8, 138.4 (d, 3J¼10.3 Hz), 132.2 (d, 3J¼3.0 Hz), 130.5, 125.5
(d, J¼3.7 Hz), 121.5 (d, 2J¼14.0 Hz), 117.3 (d, 2J¼25.0 Hz), 115.0; 19F
4.9.4. 3-(20-Fluoro-30-(trifluoromethyl)phenyl)pyrazine-2-
carbonitrile (6d). Starting from 2-chloro-3-cyanopyrazine (400 mg,
2.87 mmol) and boronic acid 1g, following general procedure, 6d
was obtained after purification by column chromatography (eluent:
NMR (282 MHz, CDCl3):
d
ꢀ111.3 (m); HRMS (ESIþ): calcd for
C11H6ClFN3 m/z 234.0234 [MþH], found 234.0229.
PE/EtOAc (85:15)) as a yellow oil (467 mg, 56%); IR (neat)
3098, 3059, 2240 (CN),1457,1624,1470,1330,1302,1218,1133,1037;
n )
(cmꢀ1
4.10. General procedure for KOH-mediated anionic ring clo-
sure (compounds 7aeh)
1H NMR (300 MHz, CDCl3)
d
8.91 (d, J¼2.3 Hz, 1H), 8.77 (d, J¼2.3 Hz,
1H), 7.84e7.82 (m, 2H), 7.48 (dd, J ¼7.8, 7.8 Hz, 1H); 13C NMR
In a sealed tube were successively introduced substituted biaryl
6aeh (1.0 equiv), KOH (5.0 equiv) and t-BuOH (6 mL/mmol of
(75 MHz, CDCl3)
d
157.1 (dq, 1J¼261.5, 3J¼1.9 Hz), 152.2, 146.6, 144.2,

N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
5399
substrate). The tube was sealed and the suspension was heated at
150 ꢁC for 1.5 h. After cooling, the mixture was diluted with water
and aqueous solution of HCl 2 M was added until complete pre-
cipitation. The product was then filtered and washed with water
affording the desired compound.
HRMS (ESIþ): calcd for C10H7N4O m/z 199.0620 [MþH], found
199.0622.
4.10.6. 7-Methoxypyrazino[2,3-c]quinolin-5(6H)-one (7f). Starting
from 3-(20-fluoro-30-methoxyphenyl)pyrazine-2-carbonitrile 6f
(548 mg, 2.39 mmol), following general procedure except that the
reaction mixture was evaporated to dryness and washed with
water (17 mL), 7f was isolated as a yellow powder (346 mg, 64%);
4.10.1. Pyrazino[2,3-c]quinolin-5(6H)-one (7a). Starting from 3-(20-
fluorophenyl)pyrazine-2-carbonitrile 6a (345 mg, 1.73 mmol), fol-
lowing general procedure, 7a was isolated as a white powder
mp 240 ꢁC; IR (neat)
n
(cmꢀ1) 3393 (NH), 3073, 1679 (C]O), 1495,
11.18
(228 mg, 67%); mp>260 ꢁC; IR (neat)
n
(cmꢀ1) 3340 (NH), 3064,
1390, 1266, 1246, 1052, 1022; 1H NMR (300 MHz, DMSO-d6)
d
2908, 1686 (C]O), 1670, 1455, 1385, 1202, 1019; 1H NMR (300 MHz,
DMSO-d6)
(s, 1H), 9.10 (d, J¼2.1 Hz, 1H), 8.97 (d, J¼2.1 Hz, 1H), 8.15 (dd, J¼5.4,
d
12.07 (s, 1H), 9.08 (d, J¼1.7 Hz, 1H), 8.96 (d, J¼1.7 Hz,
4.0 Hz, 1H), 7.41e7.02 (m, 2H), 3.95 (s, 3H); 13C NMR (75 MHz,
1H), 8.53 (d, J¼7.6 Hz, 1H), 7.62 (dd, J ¼7.6, 7.6 Hz, 1H), 7.40 (d,
DMSO-d6) d 159.2, 148.7,146.6,146.2, 145.5, 137.3,127.6,122.7,118.4,
J¼7.6 Hz,1H), 7.32 (dd, J ¼7.6, 7.6 Hz,1H); 13C NMR (75 MHz, DMSO-
115.7, 112.7, 56.2; HRMS (ESIþ): calcd for C12H10N3O2 m/z 228.0773
[MþH], found 228.0764.
d6)
d 159.6, 148.5, 146.5, 145.3, 137.8, 137.1, 131.9, 124.2, 122.6, 117.8,
115.9; HRMS (ESIþ): calcd for C11H8N3O m/z 198.0667 [MþH], found
198.0676.
4.10.7. 8-Fluoropyrazino[2,3-c]quinolin-5(6H)-one
(7g). Starting
from 3-(20,40-difluorophenyl)-pyrazine-2-carbonitrile 6g (36 mg,
0.17 mmol), following general procedure, 7g was isolated as a yel-
4.10.2. 7-Fluoropyrazino[2,3-c]quinolin-5(6H)-one
(7b). Starting
from 3-(20,30-difluorophenyl)pyrazine-2-carbonitrile 6b (457 mg,
2.10 mmol), following general procedure, 7b was isolated as a yel-
low powder (35 mg, 97%); mp>260 ꢁC; IR (neat) (cmꢀ1) 3358
n
(NH), 3073,1709 (C]O),1675,1626,1450,1379,1269,1210; 1H NMR
low powder (399 mg, 88%); mp>260 ꢁC; IR (neat)
n
(cmꢀ1) 3325
(300 MHz, DMSO-d6) d 12.19 (s, 1H), 9.09 (m, 1H), 8.96 (m, 1H), 8.59
(NH), 3027, 2866, 1672 (C]O), 1494, 1443, 1389, 1356, 1219, 1203,
(dd, J¼8.5, 6.5 Hz, 1H), 7.24e7.15 (m, 2H); Selected 13C NMR data
1039; 1H NMR (300 MHz, DMSO-d6)
d
12.11 (s, 1H), 9.11 (m, 1H),
(75 MHz, DMSO-d6)
d
159.8,148.7,146.1,145.3,139.5 (d, 3J¼12.2 Hz),
9.01 (m, 1H), 8.38 (d, J¼7.9 Hz), 7.64e7.48 (m, 1H), 7.36e7.29 (m,
136.7, 127.1 (d, 3J¼10.5 Hz), 114.8, 110.7 (d, 2J¼23.0 Hz), 102.1 (d,
1H); 13C NMR (75 MHz, DMSO-d6)
d
159.5, 149.2 (d, 1J¼245.7 Hz),
2J¼25.8 Hz); 19F NMR (282 MHz, DMSO-d6):
d
ꢀ107.0 (m); HRMS
148.8, 146.1 (d, 4J¼3.4 Hz), 146.0, 137.5, 126.5 (d, 2J¼14.1 Hz), 122.6
(ESIþ): calcd for C11H7FN3O m/z 216.0573 [MþH], found 216.0573.
(d, 3J¼6.9 Hz), 120.2 (d, J¼2.8 Hz), 120.0 (d, J¼3.7 Hz), 117.3 (d,
2J¼17.5 Hz); 19F NMR (282 MHz, DMSO-d6):
d
ꢀ129.6 (dd, J¼10.8,
4.10.8. 8-Chloropyrazino[2,3-c]quinolin-5(6H)-one
(7h). Starting
4.7 Hz); HRMS (ESIþ): calcd for C11H7FN3O: m/z 216.0573 [MþH],
from 3-(40-chloro-20-fluorophenyl)pyrazine-2-carbonitrile 6h (92
mg, 0.39 mmol), following general procedure, 7h was isolated as
found 216.0569.
a yellow powder (80 mg, 88%); mp>260 ꢁC; IR (neat) (cmꢀ1) 3346
n
4.10.3. 7-Chloropyrazino[2,3-c]quinolin-5(6H)-one
(7c). Starting
(NH), 3039, 2890, 1674 (C]O), 1611, 1447, 1371, 1204, 1089; 1H NMR
(300 MHz, DMSO-d6)
12.17 (s, 1H), 9.09 (d, J¼2.1 Hz, 1H), 8.98 (d,
from 3-(30-chloro-20-fluorophenyl)pyrazine-2-carbonitrile 6c (240
mg, 1.03 mmol), following general procedure, 7c was isolated as
d
J¼2.1 Hz, 1H), 8.53 (d, J¼8.6 Hz, 1H), 7.43 (d, J¼1.9 Hz, 1H), 7.38 (dd,
a yellow powder (164 mg, 69%); mp>260 ꢁC; IR (neat)
n
(cmꢀ1
)
J¼8.6, 1.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d 159.7, 148.7, 146.0,
3350 (NH), 3194, 3137, 3060, 1678 (C]O), 1610, 1488, 1390, 1348,
145.7, 138.8, 137.2, 136.2, 126.2, 122.8, 116.8, 115.2; HRMS (ESIþ):
1236, 1178, 1030; 1H NMR (300 MHz, DMSO-d6)
d
11.32 (s, 1H), 9.13
calcd for C11H7ClN3O m/z 232.0278 [MþH], found 232.0284.
(m, 1H), 9.02 (m, 1H), 8.57 (d, J¼7.9 Hz, 1H), 7.79 (d, J¼7.9 Hz, 1H),
7.35 (dd, J ¼7.9, 7.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d 159.6,
Acknowledgements
148.9,146.1,146.0,137.1,134.3,132.1,123.4,123.3,119.8,119.1; HRMS
(ESIþ): calcd for C11H6ClN3ONa m/z 254.0097 [MþNa], found
254.0089.
ꢀ
The authors thank Pr. N. Ple and Dr. C. Fruit for interesting dis-
ꢀ
cussion related to diazine chemistry, Dr. D. Harakat (Universite de
Reims Champagne Ardennes) for HRMS. This work has been par-
4.10.4. 7-(Trifluoromethyl)pyrazino[2,3-c]quinolin-5(6H)-one
(7d). Starting from 3-(20-fluoro-30-(trifluoromethyl)phenyl)-pyr-
azine-2-carbonitrile 6d (393 mg, 1.47 mmol), following general
procedure, 7d was isolated as a yellow powder (286 mg, 73%);
ꢀ
tially supported by Universite de Rouen, CNRS, CRUNCH and LABEX
SYNORG (ANR-11-LABX-0029).
References and notes
mp>260 ꢁC; IR (neat)
n
(cmꢀ1) 3398 (NH), 3123, 1696 (C]O), 1436,
10.92
1330, 1297, 1147, 1117, 1029; 1H NMR (300 MHz, DMSO-d6)
d
1. (a) Dubost, E.; Dumas, N. B.; Fossey, C.; Magnelli, R.; Butt, S.; Ballandonne, C.;
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Chua, P. C.; O’Brien, S. E.; Siddiqui-Jain, A.; Bourbon, P.; Haddach, M.; Michaux,
J.; Nagasawa, J.; Schwaebe, M. K.; Stefan, E.; Vialettes, A.; Whitten, J. P.; Chen, T.
K.; Darjania, L.; Stansfield, R.; Anderes, K.; Bliesath, J.; Drygin, D.; Ho, C.; Omori,
M.; Proffitt, C.; Streiner, N.; Trent, K.; Rice, W. G.; Ryckman, D. M. J. Med. Chem.
2011, 54, 635e654; (c) Feng, W.; Satyanarayana, M.; Tsai, Y. C.; Liu, A. A.; Leroy,
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(s, 1H), 9.15 (d, J¼2.0 Hz, 1H), 9.04 (d, J¼2.0 Hz, 1H), 8.93 (d,
J¼7.8 Hz, 1H), 8.02 (d, J¼7.8 Hz, 1H), 7.52 (dd, J¼7.8, 7.8 Hz, 1H);
Selected 13C NMR data (75 MHz, DMSO-d6)
d 159.6, 149.1, 146.5,
145.7, 136.8, 134.3, 129.5 (q, J¼5.7 Hz), 129.3, 122.4, 119.8; 19F NMR
(282 MHz, DMSO-d6)
d
ꢀ58.7 (s); HRMS (ESIþ): calcd for
C12H7F3N3O m/z 266.0541 [MþH], found 266.0549.
4.10.5. Pyrazino[2,3-c]-1,8-naphthyridin-5(6H)-one
(7e). Starting
from 3-(20-fluoropyridin-3-yl)pyrazine-2-carbonitrile 6e (165 mg,
0.82 mmol), following general procedure, 7e was isolated as a yel-
low powder (84 mg, 52%); mp>260 ꢁC; IR (neat)
n
(cmꢀ1) 3365
(NH), 2970, 2842, 1679 (C]O), 1600, 1431, 1384, 1320, 1206, 1192;
1H NMR (300 MHz, DMSO-d6)
d
12.50 (s, 1H), 9.13 (d, J¼2.1 Hz, 1H),
9.02 (d, J¼2.1 Hz, 1H), 8.89 (dd, J¼7.8, 1.7 Hz, 1H), 8.64 (dd, J¼4.8,
1.7 Hz, 1H), 7.42 (dd, J¼7.8, 4.8 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) d 160.4, 151.8, 149.3, 148.7, 146.0, 145.6, 137.4, 133.2, 119.1, 113.5;

5400
N. Fresneau et al. / Tetrahedron 69 (2013) 5393e5400
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ꢀ
5. (a) Dubost, E.; Magnelli, R.; Cailly, T.; Legay, R.; Fabis, F.; Rault, S. Tetrahedron 2010,
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13. See Table 1 and Scheme 2 for details.
14. See Table 2 for details.