General method for the synthesis of substituted phenanthridin-6(5H)-ones using a KOH-mediated anionic ring closure as the key step

Article abstract of DOI:10.1016/j.tet.2010.05.014

Substituted phenanthridin-6(5H)-ones were obtained in a two-step procedure involving a Suzuki cross-coupling reaction followed by a KOH-mediated anionic ring closure. The influence of the nature and the position of the substituents on the cyclization step were studied. This methodology offers a general and practical route to diversely substituted phenanthridin-6(5H)-ones.

Full text of DOI:10.1016/j.tet.2010.05.014

Tetrahedron 66 (2010) 5008e5016
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
General method for the synthesis of substituted phenanthridin-6(5H)-ones using
a KOH-mediated anionic ring closure as the key step
*
Emmanuelle Dubost, Rosa Magnelli, Thomas Cailly, Rémi Legay, Frédéric Fabis , Sylvain Rault
Centre d’Etudes et de Recherche sur le Médicament de Normandie, UPRES EA 4258, INC3M FR-CNRS 3038, UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie,
boulevard Becquerel, 14032 Caen cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2010
Received in revised form 28 April 2010
Accepted 4 May 2010
Available online 8 May 2010
Substituted phenanthridin-6(5H)-ones were obtained in a two-step procedure involving a Suzuki cross-
coupling reaction followed by a KOH-mediated anionic ring closure. The influence of the nature and the
position of the substituents on the cyclization step were studied. This methodology offers a general and
practical route to diversely substituted phenanthridin-6(5H)-ones.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ones substituted on the benzoyl ring were obtained in modest
overall yields.
The phenanthridin-6(5H)-one framework has been extensively
used for the design of many compounds exhibiting a wide range of
biological activities.1 Even if the synthesis of phenanthridin-6(5H)-
one has been known since the beginning of the 20th century,2 it is
only since the development of palladium-catalyzed chemistry that
more general routes to diversely substituted phenanthridin-6(5H)-
ones have been described. The synthesis of the unsubstituted
phenanthridin-6(5H)-one was reported from N-(2-halophenyl)
benzamide by the palladium-catalyzed formation of the biaryl
bond in a modest yield.3 The scope of this reaction was later ex-
tended to substituted N-(2-iodophenyl)benzamides affording
substituted phenanthridin-6-ones with low diversity regarding the
nature and position of the substituents.4 More recently, starting
from N-benzyl-N-benzoyl-o-iodoanilides, Bernini and co-workers
reported the synthesis of diversely substituted phenanthridin-6
(5H)-ones in good yields.5 This methodology needs the multistep-
formation of the starting materials, including a protection/depro-
tection sequence to afford the NH free phenanthridin-6(5H)-ones.
Other strategies using arylearyl bond formation and subsequent
cyclization were described. Snieckus and Siddiqui described two
examples using a Suzuki cross-coupling reaction between o-bro-
mobenzamides and o-N-Boc-arylboronic acids followed by a TFA-
mediated cyclization.6 Palladium[0]-mediated Ullmann cross-cou-
pling reaction starting from 1-bromo-2-nitrobenzene and 2-hal-
obenzoates followed by a reductive cyclization was described more
Improvements have been recently described by Ferraccioli, who
reported a Pd-catalyzed synthesis of substituted phenanthridin-6
(5H)-ones and heterocyclic analogues from o-substituted iodoar-
enes and o-bromo(hetero)arylcarboxamides.8 This method allows
the creation of both the arylearyl and the NeCO bonds in a one-pot
process, but ortho-electron-donating groups on the iodoarenes
were required for the reaction to work well, limiting thus the scope
of this methodology. More recently, a domino process using two
substituted 2-bromo-N-phenylbenzamides was described.9 Al-
though, some symmetrical substituted phenanthridin-6(5H)-ones
were obtained in good yields in this one-pot procedure, the for-
mation of unsymmetrical products remained tricky.
We have recently reported a two-step synthesis of unsub-
stituted phenanthridin-6(5H)-one, benzo-, and pyridonaphtyr-
idinones involving a Suzuki cross-coupling followed by a new and
high-yielding KOH-mediated anionic ring closure (Scheme 1).10
This procedure has been recently used by Begtrup and Cailly for
the synthesis of some substituted benzo[h]-1,6-naphthyridin-5
(6H)-ones.11 We thought that this methodology could offer a gen-
eral route to diversely substituted phenanthridin-6(5H)-ones and
we wish to report here our efforts to study the influence of the
nature and position of substituents in the KOH-mediated anionic
ring closure from biphenyl derivatives (Scheme 2).
NC
7
NC
(N)
recently by Banwell and co-workers. Only phenanthridin-6(5H)-
(N)
(N)
KOH/MeOH
X
B(OR)
F
2
(N)
(N)
(N)
Suzuki
Cross - Coupling
Microwaves
150°C
N
H
O
F
* Corresponding author. Tel.: þ33 231 56 6808; fax: þ33 231 56 6803; e-mail
Scheme 1. Synthesis of naphtyridinones by Cailly et al.10
address: frederic.fabis@unicaen.fr (F. Fabis).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.014

E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
5009
Table 1
(R)
(R)
Anionic Ring
Closure
Synthesis of substituted 20-fluorobiphenyl-2-carbonitrile 2aes via Suzuki cross-
NC
Suzuki
X
X
F
Cross-Coupling
coupling
+
5
CN
KOH
(R)
(R)
6
4
3
F
N
H
O
X
F
(R)
(R)
6'
3'
(R)
1
X = Br or I or boronic species
(R)
1'
5'
4'
(R)
+
2
X
(R)
2'
Scheme 2. General scheme of the work described herein.
CN
CN
F
X = Br or I or Boronic species
2. Results and discussion
2 a-s
We started our study by the synthesis of the key substituted 20-
fluorobiphenyl-2-carbonitriles via a Suzuki cross-coupling reaction.
Commercially available substituted 2-bromo(iodo)fluoroarenes, 2-
bromobenzonitriles and boronic acids 1a, 1g, and 1l were used.
Boronic acids 1c,12 1e,13 1i,14 and 1j15 were obtained from diversely
substituted fluorobenzenes using previously described conditions.
The synthesis of boronic acids or esters 1b, 1d, 1f, 1h, and 1k was
achieved using ortho-metalation strategy (Scheme 3).
Coupling partners
Conditionsa
Product
Yieldb (%)
Boronic
ArBr(I)
1a
1b
1a
1a
1c
1a
1a
1d
1e
1f
2-Br-1-CN
1-Br-2-F
A 0.5 h 150 ꢀC
m
W
2a
81
78
81
85
63
93
64
50
73
84
73
57
81
67
65
53
78
72
51
A 1.25 h 150 ꢀC
B 48 h Reflux
B 48 h Reflux
A 16 h 105 ꢀC
B 48 h Reflux
C 48 h Reflux
m
W
2b 3-CF3
2c 4-MeO
2d 4-NO2
2e 5-CF3
2f 5-Me
2g 6-Me
2h 30-Cl
2i 30-F
2-Br-5-MeO-1-CN
2-Br-5-NO2-1-CN
1-Br-2-F
2-Br-4-Me-1-CN
2-Br-3-Me-1-CN
2-Br-1-CN
A 1.5 h 150 ꢀC
A 1.25 h 150 ꢀC
A 2 h 150 ꢀC
m
W
2-Br-1-CN
2-Br-1-CN
m
W
m
m
m
W
W
W
2j 30-Me
2k 30-MeO
2l 40-Cl
O
1g
1h
1h
1h
1h
1i
2-Br-1-CN
1-I-4-Cl-2-F
1-Br-2,4-F
1-Br-2-F-4-Me
1-Br-2-F-4-MeO
2-Br-1-CN
A 1 h 150 ꢀ
C
B
D 1 h 110 ꢀC
O
B
B(OH)2
F
O
B(OH)2
F
D 1.25 h 125 ꢀC
m
m
W
W
2m 40-F
F3C
O
D 1.25 h 150 ꢀC
2n 40-Me
2o 40-MeO
2p 50-Cl
2q 50-F
CN
D 2 h 125 ꢀC
A 1 h 150 ꢀC
mW
W
CF3
1b
CN
[12]
Cl
m
1a
i
40%
i
1c
1h
1j
1-Br-2,5-F
2-Br-1-CN
D 1.75 h 130 ꢀC
mW
90%
ii
1d84%
A 2 h 150 ꢀC
A 0.5 h 150 ꢀ
m
C
W
m
2r 50-Me
2s 50-MeO
B(OH)2
B(OH)2
B(OH)2
F
1k
2-Br-1-CN
W
O
B
a
Conditions: (A) Pd(PPh3)4 5 mol %, arylbromide 1 equiv, boronic species
1.2 equiv, K3PO4 2 equiv, DMF; (B) Pd(OAc)2 5 mol %, PPh3 10 mol %, aryl halide
1 equiv, boronic species 1.5 equiv, Na2CO3 4 equiv, DME/H2O 2:1; (C) Pd(OAc)2
5 mol %, S-Phos 10 mol %, arylbromide 1 equiv, boronic species 1.5 equiv, Na2CO3
4 equiv, DME/H2O 2/1; (D) Pd(PPh3)4 5 mol %, arylbromide 1 equiv, boronic species
1.2 equiv, Cs2CO3 2 equiv, toluene/ethanol 9:1.
O
F
F
Me
OMe
F
CN
47%
[13]
iii
iv
1e 78%
1f
1g
48%
i
1h
OMe
MeO
B(OH)2
B(OH)2
F
b
Isolated yields.
Me
Cl
B(OH)2
B(OH)2
F
(Scheme 4). The 3-fluorophenanthridin-6(5H)-one 3m was isolated
in 37% yield. It has to be noticed that the competitive nucleophilic
substitution of the fluorine atom para to the aryl group has not been
observed after the cyclization. The electron-donating effect of the
nitrogen atom on the 3m prevents the SNAr to occur. Under these
conditions the nucleophilic displacement of the fluorine atom ortho
to the aryl group did not occurred before the cyclization. As pre-
viously described, using lower temperature led only to hydrolysis of
the nitrile without cyclization.10b
F
F
[15]
[14]
vi
1j
vii
90%
v
1k
65%
1l
79%
1i
Scheme 3. Boronic species. Isolated yields starting from the corresponding substituted
fluoroarenes or benzonitriles: (i) LTMP 1.2 equiv, B(Oi-Pr)3 1.4 equiv, THF, ꢁ78 ꢀC,
overnight and then pinacol 1.5 equiv, AcOH 1.4 equiv; (ii) s-BuLi 1.05 equiv 1 h, B(Oi-
Pr)3 1.05 equiv 1 h, THF, ꢁ78 ꢀC; (iii) n-BuLi 1.05 equiv 1 h, B(Oi-Pr)3 1.05 equiv 1 h
30 min, THF, ꢁ78 ꢀC; (iv) LiCKOR 1.05 equiv 2 h, B(Oi-Pr)3 1.05 equiv 1 h, THF, ꢁ78 ꢀC;
(v) LTMP 1.05 equiv, B(Oi-Pr)3 1.1 equiv, THF, ꢁ78 ꢀC, 1 h; (vi) s-BuLi 1.05 equiv 1 h, B
(OMe)3 1.05 equiv 2 h, THF, ꢁ78 ꢀC; (vii) LTMP 1.05 equiv, B(Oi-Pr)3 1.2 equiv, THF,
ꢁ78 ꢀC, 1 h.
NC
NC
KOH 5 equiv.
+
The Suzuki cross-coupling conditions were adjusted depending
on the starting materials. Compounds 2aeb and 2hes were syn-
thesized using microwave heating conditions, Pd(PPh3)4 with ei-
ther K3PO4 in DMF or Cs2CO3 in a toluene/ethanol mixture. The
microwave heating allowed a dramatic decrease in the reaction
times16 and afforded the expected biaryls in 50e84% yields (Table 1,
conditions A and D). For compound 2e, conditions A were used with
conventional heating, microwaves heating leading to a lower yield.
Compounds 2c, 2d, and 2f were obtained in 81e93% yields using
Na2CO3 as base and DME/H2O as solvent (Table 1, conditions B).
Finally, the sterically hindered 20-fluoro-6-methylbiphenyl-2-car-
bonitrile 2g was synthesized in 64% yield using S-Phos as the ligand
(Table 1, conditions C).17
We then explored the anionic ring closure reaction starting from
20,40-difluorobiphenyl-2-carbonitrile 2m. When we applied the
previously described conditions (KOH, MeOH, 150 ꢀC),10b the com-
plete conversion of the starting material was observed but led to an
1:1 mixture (1H NMR) of the expected 3-fluorophenanthridin-6
(5H)-one 3m and 20-fluoro-40-methoxybiphenyl-2-carbonitrile 2o
MeOH 0.75 h
microwave, 150°C
2m
F
N
H
O
F
F
MeO
F
3m
2o
isolated yield = 37%
1 : 1
Scheme 4. Cyclization of compound 2m in MeOH.
In order to avoid the formation of 2o, we decided to use non-
nucleophilic solvents. Using non-protic solvents, such as NMP or
DMF led to mixtures of products. Finally we were pleased to find
that the use of t-BuOH instead of methanol allowed the isolation of
3m in a good 87% yield without formation of by-products (Table 2).
We then applied these conditions to biphenyls 2aes. Substituted
phenanthridin-6(5H)-ones 3aes were isolated pure after a simple
dilution of the reaction mixture with water and filtration. In all
cases, total conversion of the starting material to the expected
substituted phenanthridin-6(5H)-one was observed (TLC monitor-
ing). All the compounds were obtained in 78e99% yields except
compounds 3b, 3c, 3e, and 3g for which the lower yields are due to

5010
E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
Table 2
a general methodology for the synthesis of substituted phenan-
KOH-mediated anionic ring closure
thridin-6(5H)-ones. This reaction has been shown to work with
both electron-withdrawing and electron-donating groups and al-
lows a practical synthesis of phenanthridin-6(5H)-ones substituted
in all positions.
5
4
6
9
10
8(R)
6'
3'
(R)
1
1'
2'
3
1
5'
4'
KOH 5 equiv.
2
7
(R) 2
(R)
CN
6
t-BuOH
150°C microwave
F
3
4. Experimental section
4.1. General methods
N
O
H5
4
2 a-s
3a-s
Starting material
Time (min)a
Product
Yieldb (%)
Melting points were determined on a Kofler melting point ap-
paratus. IR spectra were recorded on KBr discs. 1H and 13C NMR
spectra were recorded, respectively, at 400 and 100 MHz or at 500
and 125 MHz, using CDCl3 or DMSO-d6 as solvents. High Resolution
Mass Spectra (HRMS-EI) were performed at 70 eV. Elemental
Analyses were performed at ‘Institut de Recherche en Chimie
Organique Fine’ (Rouen, France). For microwave reactions temper-
ature were measured with an IR-sensor and reaction times given as
hold times. THF was distilled from Na/benzophenone under N2. All
commercially available compounds were used as received except
n-butyllithium and sec-butyllithium commercial solutions, which
were titrated prior to use.18
2a
10
25
5
11
8
13
5
30
30
60
5
20
30
60
40
20
60
40
75
3a
99
33
67
99
70
99
61
85
90
96
85
99
87
94
88
86
99
97
78
2b 3-CF3
2c 4-MeO
2d 4-NO2
2e 5-CF3
2f 5-Me
2g 6-Me
2h 30-Cl
2i 30-F
3b 7-CF3
3c 8-MeO
3d 8-NO2
3e 9-CF3
3f 9-Me
3g 10-Me
3h 4-Cl
3i 4-F
2j 30-Me
2k 30-MeO
2l 40-Cl
3j 4-Me
3k 4-MeO
3l 3-Cl
2m 40-F
2n 40-Me
2o 40-MeO
2p 50-Cl
2q 50-F
3m 3-F
3n 3-Me
3o 3-MeO
3p 2-Cl
3q 2-F
3r 2-Me
3s 2-MeO
4.2. Synthesis of boronic species 1bed, 1f, 1h and 1k
2r 50-Me
2s 50-MeO
2-Fluorobenzeneboronic
acid
1a,
2-fluoro-3-methoxy-
benzeneboronic acid 1g, and 2-fluoro-6-methoxybenzeneboronic
acid 1l were bought from chemical suppliers. 2,3-Difluoro-
benzeneboronic acid 1e,13 5-chloro-2-fluorobenzeneboronic acid
1i14 and 2-fluoro-5-methylbenzeneboronic acid 1j15 were prepared
according to literature methods.
a
The poor solubility in t-BuOH of some phenanthridin-6(5H)-ones may cause
vials breakage due to the formation of hotspots under elongated microwave heating
times (especially for 3c, 3e, 3g, and 3k).
b
Isolated yields.
their partial solubility in water and poor solubility in organic sol-
vents. Even for compound 3b, no formation of by-products was
observed (TLC monitoring). Interestingly, this anionic ring closure
occurred even with electron-donating groups (3j,k, 3n,o, and 3r,s).
The quantitative formation of 3a in a shorter time clearly demon-
strates the superiority of t-BuOH over MeOH in this KOH-mediated
anionic ring closure.10b The very short reaction times observed for
some compounds (3c, 3e, 3g, and 3k) could be correlated to the
very poor solubility of these phenanthridin-6(5H)-ones in t-BuOH,
favoring thus the ring closure. Moreover, the reaction proceeds via
an addition/elimination mechanism as the formation of an aryne
intermediate is excluded from biaryls 2hek.
As substituted phenanthridin-6(5H)-ones were isolated after
a very simple work-up, we thought that these two steps could be
achieved in a sequential procedure without purification of the bi-
phenyl compound. As an example, the Suzuki cross-coupling of 2-
fluoro-6-methoxyphenylboronic acid 1l and 2-bromobenzonitrile
followed by the KOH-mediated anionic ring closure of the crude
intermediate led to isolation of the pure 1-methoxyphenanthridin-
6(5H)-one 3t in 34% overall yield (Scheme 5). This modest yield was
mainly due to the poor conversion (1H NMR, 55%) observed in the
cross-coupling step, which has not been further investigated.
4.2.1. 6-Trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-
2-yl)benzonitrile 1b. n-BuLi 2.5 M in n-hexane (2.80 mL,
7.01 mmol) was added to a solution of 2,2,6,6-tetramethylpiper-
idine (1.18 mL, 7.01 mmol) in 10 mL of THF under N2 at ꢁ10 ꢀC. The
solution was stirred for 15 min, cooled to ꢁ78 ꢀC and B(Oi-Pr)3
(1.89 mL, 8.18 mmol) was added. After 10 min, a solution of 4-tri-
fluoromethylbenzonitrile (1.00 g, 5.84 mmol) in 5 mL of THF was
added via syringe. The mixture was stirred at ꢁ78 ꢀC for 2 h and
subsequently warm to room temperature over 2 h. The reaction
was quenched with AcOH (0.47 mL, 8.18 mmol) and pinacol (1.04 g,
8.76 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h, diluted with water (100 mL), and extracted
with dichloromethane (3ꢂ100 mL). The combined organic layers
were washed with a 15% KH2PO4 solution (3ꢂ50 mL), dried over
MgSO4, filtrated, and concentrated in vacuo. The crude product was
recrystallized from n-heptane to give 6-trifluoromethyl-2-(4,4,5,5-
tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1b as white
crystals (600 mg, 40%); mp 78e79 ꢀC; IR (KBr) (cmꢁ1) 2989, 2230
n
(CN), 1372, 1126; 1H NMR (400 MHz, CDCl3)
d 1.40 (s, 12H), 7.69 (t,
J¼7.8 Hz, 1H), 7.85 (d, J¼7.8 Hz, 1H), 8.06 (t, J¼7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
27.8, 85.3, 114.7, 115.0, 122.6 (q, 1J¼273 Hz),
128.4 (q, J¼5 Hz), 131.5, 133.6 (q, 2J¼32 Hz), 138.7; HRMS-EI m/z
[Mþ] calcd for C14H15BNO2F3 297.11478, found 297.11591.
OMe
Pd(OAc) 5 mol %
2
OMe
S-Phos 10 mol %
B(OH)
2
OMe
KOH 5 equiv.
5 min
Na CO 4 equiv.
2
3
+
Br
4.2.2. 4-Trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-
2-yl)benzonitrile 1c12. n-BuLi 2.5 M in n-hexane (2.80 mL,
7.01 mmol) was added to a solution of 2,2,6,6-tetramethylpiperidine
(1.18 mL, 7.01 mmol) in 10 mL of THF under N2 at ꢁ10 ꢀC. The solu-
tion was stirred for 15 min, cooled to ꢁ78 ꢀC and B(Oi-Pr)3 (1.89 mL,
F
t-BuOH
microwave, 150 °C
N
H
O
CN
DME/H O 2/1
2
CN
3t
1l1.5 equiv.
1 equiv.
F
Reflux
24h
34%overall
1
H NMR conversion : 55%
Scheme 5. Sequential synthesis of 1-methoxyphenanthridin-6(5H)-one 3t.
8.18 mmol) was added. After 10 min,
a solution of 4-tri-
3. Conclusions
fluoromethylbenzonitrile (1.00 g, 5.84 mmol) in 5 mL of THF was
added via syringe. The mixture was stirred at ꢁ78 ꢀC for 2 h and
subsequently warm to room temperature over 2 h. The reaction was
quenched with AcOH (0.47 mL, 8.18 mmol) and pinacol (1.04 g,
In summary, we have shown that the KOH-mediated anionic
ring closure of substituted 20-fluorobiphenyl-2-carbonitriles offers

E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
5011
8.76 mmol) was added. The reaction mixture was stirred at room
temperature for one hour, diluted with water (100 mL), and
extractedwith dichloromethane (3ꢂ100 mL). The combined organic
layers were washed with a 15% KH2PO4 solution (3ꢂ50 mL), dried
over MgSO4, filtrated, and concentrated in vacuo. The crude product
was recrystallized from petroleum ether to give 4-trifluoromethyl-
2-(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1c as
tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1h as white
crystals (520 mg, 47%); mp 85e86 ꢀC; IR (KBr) (cmꢁ1) 2984, 2226
1.39 (s, 12H),
n
(CN), 1332, 1352; 1H NMR (400 MHz, CDCl3)
d
7.51e7.60 (m, 2H), 7.70 (d, 3J¼8.8 Hz, 1H), 7.89 (dd, J¼6.8, 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 24.8, 84.8, 117.3, 119.0, 131.1, 131.6,
133.4, 135.8; HRMS-EI m/z [Mþ] calcd for C13H16BNO2 229.1274,
found 229.12684. Anal. Calcd for C13H16BNO2: C, 68.16; H, 7.04; N,
6.11. Found: C, 68.03; H, 7.24; N, 6.43.
a yellow powder (1.69 g, 90%); mp 208e209 ꢀC; IR (KBr)
2973, 2235 (CN), 1682, 1330, 1130; 1H NMR (400 MHz, CDCl3)
n
(cmꢁ1
1.40
)
d
(s, 12H), 7.78e7.84 (m, 2H), 8.15 (s, 1H); 13C NMR (100 MHz, CDCl3)
4.2.6. 2-Fluoro-5-methoxybenzeneboronic acid 1k. n-BuLi 2.5 M in
n-hexane (68 mL, 0.17 mol) was added to a solution of 2,2,6,6-tet-
ramethylpiperidine (29 mL, 0.17 mol) in 200 mL of THF under N2 at
ꢁ10 ꢀC. The solution was stirred for 15 min, cooled to ꢁ78 ꢀC and B
(Oi-Pr)3 (43.8 mL, 0.19 mol) was added. After 5 min, a solution of 4-
methoxyfluorobenzene (18 mL, 0.16 mol) in 10 mL of THF was
added via syringe. The mixture was stirred at ꢁ78 ꢀC for 1 h and
subsequently warmed to room temperature over 1 h. Water
(200 mL) was added and the resulting mixture was washed with
diethyl ether (3ꢂ100 mL), the aqueous layer was acidified with a
HCl 3 M solution until pH¼1. The product was extracted with
diethyl ether (3ꢂ300 mL), the organic layers were dried over
MgSO4, filtrated, and concentrated in vacuo. 2-Fluoro-5-methox-
ybenzeneboronic acid 1k was obtained as a white powder after
recrystallization from petroleum ether (17.4 g, 65%); mp
d
24.8, 85.3, 117.7,120.7, 123.2 (q, 1J¼272 Hz), 127.8 (q, J¼4 Hz), 132.6
(q, J¼4 Hz), 133.3 (q, 2J¼33 Hz), 133.7; HRMS-EI m/z [Mþ] calcd for
C14H15BNO2F3 297.11478, found 297.11462.
4.2.3. 3-Chloro-2-fluorobenzeneboronic acid 1d. A solution of s-BuLi
1.3 M in cyclohexane/hexane 92:8 (6.18 mL, 8.04 mmol) was added
to
a stirred solution of 1-chloro-2-fluorobenzene (0.80 mL,
7.66 mmol) in 10 mL of THF at ꢁ78 ꢀC. The reaction mixture was
stirred at ꢁ78 ꢀC for 1 h, and B(Oi-Pr)3 (1.86 mL, 8.04 mmol) was
added. The solution was stirred for 1 h and warmed to room tem-
perature. HCl 3 M was added until pH¼1, the resulting mixture was
extracted with ethyl acetate (3ꢂ100 mL). The combined organic
layers were dried over MgSO4, filtered, and evaporated. 3-Chloro-2-
fluorobenzeneboronic acid 1d was obtained as a white powder
(1.13 g, 84%); mp 246e247 ꢀC; IR (KBr)
n
(cmꢁ1) 3295, 1603, 1446,
195e196 ꢀC; IR (KBr)
(400 MHz, DMSO-d6)
n
(cmꢁ1) 3286, 2964, 1492, 1029; 1H NMR
3.71 (s, 3H), 6.90e6.95 (m, 1H), 7.00 (t,
1332, 729; 1H NMR (400 MHz, CDCl3)
d
5.20 (s, 1H), 5.21 (s, 1H), 7.16
d
(t, J¼7.8 Hz, 1H), 7.52 (t, J¼7.8 Hz, 1H), 7.72e7.75 (m, 1H); 13C NMR
4J¼8.8 Hz, 1H), 7.04e7.06 (m, 1H), 8.22 (s, 2H); 13C NMR (100 MHz,
(100 MHz, CDCl3)
d
120.7 (d, 2J¼21 Hz), 125.2 (d, J¼4 Hz), 134.0,
DMSO-d6)
d
55.5, 115.6 (d, 2J¼26 Hz), 116.7 (d, 3J¼9 Hz), 119.4 (d,
134.4, 135.0 (d, J¼6 Hz), 162.7 (d, 1J¼244 Hz); HRMS-EI m/z [Mþ]
3J¼9 Hz), 122.8, 155.0 (d, 4J¼2 Hz), 159.8 (d, 1J¼236 Hz). Anal. Calcd
calcd for C6H5BO2FCl 174.0055, found 174.0059.
for C7H8BFO3: C, 49.47; H, 4.74. Found: C, 49.36; H, 4.77.
4.2.4. 2-Fluoro-3-methylbenzeneboronic acid 1f. n-BuLi 2.5 M in
n-hexane (3.81 mL, 9.53 mmol) was added to a solution of t-BuOK
(1.07 g, 9.53 mmol) in 10 mL of THF under N2 at ꢁ78 ꢀC. The solu-
tion was stirred for 15 min and 1-fluoro-2-methylbenzene
(1.00 mL, 9.08 mmol) was added in 10 mL of THF at ꢁ78 ꢀC. Stirring
was continued for 2 h before B(Oi-Pr)3 (2.20 mL, 9.53 mmol) was
added neat via syringe. The mixture was stirred at ꢁ78 ꢀC for 1 h
and subsequently warm to room temperature over 3e4 h. The re-
action mixture was quenched with water and a solution of HCl 1 M
until pH¼1. Extraction with ethyl acetate (3ꢂ50 mL), drying of the
combined organic layers other MgSO4, and evaporation of solvents
led to 2-fluoro-3-methylbenzeneboronic acid 1f as a white powder.
Recrystallization from petroleum ether gave white crystals
4.3. General procedures for the synthesis of substituted
20-fluorobiphenyl-2-carbonitriles 2aes
Conditions A: To a degassed solution of aryl halide (1 equiv) in
DMF (5 mL/mmol of aryl halide) were added K3PO4$H2O (2 equiv),
boronic species (1.2 equiv), and Pd(PPh3)4 (5 mol %). The suspen-
sion was heated under N2 (conditions described in Table 1). The
resulting mixture was partitioned in water and ethyl acetate and
filtrated through a short pad of Celite. The organic layer was
washed with water, dried over MgSO4, filtrated, and evaporated.
The crude product was then purified by silica gel chromatography.
Conditions B: To a degassed solution of triphenylphosphine
(10 mol %) in a mixture of DME/water 2:1 (12 mL/mmol of aryl
halide) was added Pd(OAc)2 (5 mol %) at room temperature. The
resulting mixture was heated at 80 ꢀC for 10 min. Aryl halide
(1 equiv), boronic species (1.5 equiv), and Na2CO3 (4 equiv) were
added. The suspension was then heated under N2 (conditions de-
scribed in Table 1). The mixture was poured in water and extracted
with ethyl acetate. The combined layers were filtrated through
a short pad of Celite. The organic layer was washed with water,
dried over MgSO4, filtrated, and evaporated. The crude product was
then purified by silica gel chromatography.
Conditions C: To a degassed solution of 2-dicyclohexylphosphino-
20,60-dimethoxybiphenyl (S-PHOS) (10 mol %) in a mixture of DME/
water2:1 (12 mL/mmol of aryl halide) was added Pd(OAc)2 (5 mol %)
at room temperature. The resulting mixture was heated at 80 ꢀC for
10 min. Aryl halide (1 equiv), boronic species (1.5 equiv), and
Na2CO3 (4 equiv) were added. The suspension was heated under N2
(conditions described in Table 1). The mixture was poured in water
and extracted with ethyl acetate. The combined layers were filtrated
through a short pad of Celite. The organic layer was washed with
water, dried over MgSO4, filtrated, and evaporated. The crude
product was then purified by silica gel chromatography.
(670 mg, 48%); mp 160e161 ꢀC; IR (KBr)
n
(cmꢁ1) 3301, 1615, 1429,
2.28 (s, 3H), 5.46 (s, 1H),
1322, 742; 1H NMR (400 MHz, CDCl3)
d
5.48 (s, 1H), 7.10 (t, J¼6.8 Hz, 1H), 7.31 (t, J¼7.8 Hz, 1H), 7.66 (t,
J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
14.4 (d, J¼4 Hz), 123.4
(d, 2J¼29 Hz), 123.4 (d, J¼4 Hz), 132.7 (d, J¼9 Hz), 132.8 (d, J¼5 Hz),
163.8 (d, 1J¼242 Hz); HRMS-EI m/z [Mþ] calcd for C7H8BO2F
154.06013, found 154.06067.
4.2.5. 2-(4,4,5,5-Tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile
1h. n-BuLi 2.5 M in n-hexane (2.33 mL, 5.82 mmol) was added to
a solution of 2,2,6,6-tetramethylpiperidine (0.98 mL, 5.82 mmol) in
10 mL of THF under N2 at ꢁ10 ꢀC. The solution was stirred for
15 min, cooled to ꢁ78 ꢀC and B(Oi-Pr)3 (1.57 mL, 6.79 mmol) was
added. After 10 min,
a solution of benzonitrile (0.50 mL,
4.85 mmol) in 2.5 mL of THF was added via syringe. The mixture
was stirred at ꢁ78 ꢀC and warmed to room temperature overnight.
The reaction was quenched with AcOH (0.39 mL, 6.79 mmol) and
pinacol (859 mg, 7.27 mmol) was added. The reaction mixture was
stirred at room temperature for 1 h, diluted with water (100 mL),
and extracted ethyl acetate (3ꢂ50 mL). The combined organic
layers were dried over MgSO4, filtrated, and evaporated to afford an
orange solid. Recrystallization from n-heptane gave 2-(4,4,5,5-
Conditions D: To a degassed solution of aryl halide (1 equiv) in
a mixture of toluene/ethanol (9:1, 5 mL/mmol of aryl halide) were

5012
E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
added Cs2CO3 (2 equiv), boronic species (1.2 equiv), and Pd(PPh3)4
(5 mol %). The suspension was heated under N2 (conditions de-
scribed in Table 1). The resulting mixture was partitioned in water
and ethyl acetate and filtrated through a short pad of Celite. The
organic layer was washed with water, dried over MgSO4, filtrated,
and evaporated. The crude product was then purified by silica gel
chromatography.
bromofluorobenzene (0.13 mL, 1.14 mmol), following general
procedure A and using cyclohexane/EtOAc (95:5) as eluent, 20-flu-
oro-5-trifluoromethylbiphenyl-2-carbonitrile 2e was obtained as
a yellow oil (190 mg, 63%); IR (KBr)
n
(cmꢁ1) 2235 (CN), 1488, 1333,
7.23e7.33 (m, 2H), 7.44 (dt,
1123, 764; 1H NMR (500 MHz, CDCl3)
d
J¼7.5, 2.0 Hz, 1H), 7.48e7.52 (m, 1H), 7.75e7.78 (m, 2H), 7.91e7.93
(m, 1H); 13C NMR (125 MHz, CDCl3)
d
116.6 (d, 2J¼21 Hz), 116.9,
123.1 (q, 1J¼273 Hz), 124.6 (d, J¼15 Hz), 124.8 (d, J¼4 Hz), 125.2 (q,
J¼4 Hz), 128.1 (m), 131.2, 131.8 (d, J¼7 Hz), 132.8, 134.0, 134.6 (q,
2J¼33 Hz), 140.7, 159.4 (d, 1J¼250 Hz); HRMS-EI m/z [Mþ] calcd for
C14H7NF4 265.05145, found 265.05063.
4.3.1. 20-Fluorobiphenyl-2-carbonitrile 2a19. Starting from 2-bro-
mobenzonitrile (867 mg, 4.76 mmol) and 2-fluorobenzeneboronic
acid 1a (1.00 g, 7.15 mmol) following general procedure A and using
cyclohexane/EtOAc (9:1) as eluent, 20-fluorobiphenyl-2-carbon-
itrile 2a was obtained as
a
white powder (763 mg, 81%);
4.3.6. 20-Fluoro-5-methylbiphenyl-2-carbonitrile 2f. Starting from
2-bromo-4-methylbenzonitrile (2.00 g, 10.20 mmol) and 2-fluo-
robenzeneboronic acid 1a (2.13 g, 15.30 mmol), following general
procedure B and using cyclohexane/EtOAc (9:1) as eluent, 20-flu-
oro-5-methylbiphenyl-2-carbonitrile 2f was obtained as a white
mp¼83e84 ꢀC; IR (KBr)
n
(cmꢁ1) 3064, 2235 (CN), 1579, 1439; 1H
NMR (400 MHz, CDCl3) d 7.20e7.29 (m, 2H), 7.41e7.52 (m, 4H), 7.67
(m, 1H), 7.79 (d, J¼7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d
112.8, 116.1 (d, 2J¼21 Hz), 118.0, 124.3 (d, J¼3 Hz), 125.8 (d,
2J¼15 Hz), 128.2, 130.8, (d, J¼7 Hz), 130.9 (d, J¼2 Hz), 131.2 (d,
J¼3 Hz),132.5, 133.2,139.5, 159.4 (d, 2J¼248 Hz); HRMS-EI m/z [Mþ]
calcd for C13H8NF 197.06407, found 197.06394.
powder (2.0 g, 93%); mp 70e71 ꢀC; IR (KBr)
n
(cmꢁ1) 2917, 2221
2.44 (s, 3H),
(CN), 1608, 1216; 1H NMR (400 MHz, DMSO-d6)
d
7.34e7.41 (m, 2H), 7.44e7.51 (m, 3H), 7.53e7.58 (m, 1H), 7.86 (d,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 21.2, 108.9, 115.8 (d,
4.3.2. 20-Fluoro-3-trifluoromethylbiphenyl-2-carbonitrile 2b. Start-
ing from 6-trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,2]-dioxobor-
olan-2-yl)benzonitrile 1b (418 mg, 1.41 mmol) and 2-
bromofluorobenzene (0.13 mL, 1.17 mmol), following general pro-
cedure A and using cyclohexane/EtOAc (9:1) as eluent, 20-fluoro-3-
trifluoromethylbiphenyl-2-carbonitrile 2b was obtained as a yellow
2J¼22 Hz), 118.1, 124.7 (d, J¼3 Hz), 125.6 (d, 2J¼15 Hz), 129.5, 131.1
(d, J¼8 Hz), 131.4 (d, J¼6 Hz), 131.5, 133.0, 138.6, 144.0, 158.9 (d,
1J¼246 Hz); HRMS-EI m/z [Mþ] calcd for C14H10NF 211.07972, found
211.08007.
4.3.7. 20-Fluoro-6-methylbiphenyl-2-carbonitrile 2g. Starting from
2-bromo-3-methylbenzonitrile (200 mg, 1.02 mmol) and 2-fluo-
robenzeneboronic acid 1a (210 mg, 1.53 mmol), following general
procedure B and using cyclohexane/EtOAc (9:1) as eluent, 20-
fluoro-6-methylbiphenyl-2-carbonitrile 2g was obtained as
oil (242 mg, 78%); IR (KBr)
n
(cmꢁ1) 3087, 2234 (CN), 1464, 759; 1H
NMR (400 MHz, DMSO-d6)
d
7.39e7.47 (m, 2H), 7.56e7.65 (m, 2H),
7.95e7.97 (m, 1H), 8.02e8.07 (m, 1H), 8.09e8.12 (m, 1H); 13C NMR
(100 MHz, DMSO-d6)
d
109.0 (q, J¼2 Hz), 114.3, 116.0 (d, J¼22 Hz),
122.6 (q, 1J¼274 Hz), 124.4 (d, J¼15 Hz), 125.0 (d, J¼4 Hz), 126.6 (q,
J¼5 Hz), 131.5 (q, 2J¼32 Hz), 131.6 (d, J¼2 Hz), 132.0 (d, J¼8 Hz),
134.1, 135.2, 141.6, 158.7 (d, 1J¼246 Hz); HRMS-EI m/z [Mþ] calcd for
C14H7NF4 265.05145, found 265.05219.
a yellow oil (209 mg, 64%); IR (KBr)
n
(cmꢁ1) 2927, 2228 (CN),
2.18 (s, 3H), 7.21 (t,
1459, 754; 1H NMR (400 MHz, DMSO-d6)
d
J¼8.8 Hz, 1H), 7.26e7.29 (m, 1H), 7.39 (t, J¼7.8 Hz, 1H), 7.42e7.48
(m, 2H), 7.52 (d, J¼7.8 Hz, 1H), 7.61 (d, J¼7.7 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6)
d
20.0 (d, 5J¼2 Hz), 113.5, 115.9 (d,
4.3.3. 20-Fluoro-4-methoxybiphenyl-2-carbonitrile 2c. Starting from
2-bromo-5-methoxybenzonitrile (500 mg, 2.36 mmol) and 2-fluo-
robenzeneboronic acid 1a (493 mg, 3.54 mmol), following general
procedure B and using cyclohexane/EtOAc (95:5) as eluent, 20-flu-
oro-4-methoxybiphenyl-2-carbonitrile 2c was obtained as a white
2J¼21 Hz), 118.0, 124.3 (d, J¼4 Hz), 124.9 (d, J¼16 Hz), 128.3, 130.3,
130.6 (d, J¼8 Hz), 131.0 (d, J¼3 Hz), 134.2, 138.5, 138.9, 159.2 (d,
1J¼246 Hz); HRMS-EI m/z [Mþ] calcd for C14H10NF 211.07972,
found 211.07944.
powder (433 mg, 81%); mp 80e81 ꢀC; IR (KBr)
(CN),1482,1260; 1H NMR (400 MHz, CDCl3)
3.88 (s, 3H), 7.17e7.25
55.7, 113.4,
n
(cmꢁ1) 2964, 2227
4.3.8. 30-Chloro-20-fluorobiphenyl-2-carbonitrile 2h. Starting from
3-chloro-2-fluorobenzeneboronic acid 1d (575 mg, 3.30 mmol) and
2-bromobenzonitrile (500 mg, 2.75 mmol), following general pro-
cedure A and using cyclohexane/EtOAc (9:1) as eluent, 30-chloro-20-
fluorobiphenyl-2-carbonitrile 2h was obtained as white crystals
d
(m, 4H), 7.38e7.42 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
116.0 (d, 2J¼22 Hz), 117.6, 118.0, 119.2, 124.3 (d, J¼4 Hz), 125.5 (d,
2J¼16 Hz), 130.4 (d, J¼8 Hz), 131.4 (d, J¼2 Hz), 131.8, 132.2 (d,
J¼2 Hz), 159.0, 159.6 (d, 1J¼246 Hz); HRMS-EI m/z [Mþ] calcd for
C14H10NFO 227.07463, found 227.07352.
(320 mg, 50%); mp 114e115 ꢀC; IR (KBr)
n
(cmꢁ1) 2222 (CN), 1447,
7.21 (dt, J¼7.9, 1.2 Hz,
1431, 1230, 759; 1H NMR (400 MHz, CDCl3)
d
1H), 7.33 (ddd, J¼7.8, 6.5, 1.7 Hz, 1H), 7.48e7.54 (m, 3H), 7.68 (dt,
4.3.4. 20-Fluoro-4-nitrobiphenyl-2-carbonitrile 2d. Starting from
2-bromo-5-nitrobenzonitrile (500 mg, 2.20 mmol) and 2-fluo-
robenzeneboronic acid 1a (460 mg, 3.30 mmol), following general
procedure B and using cyclohexane/EtOAc (9:1) as eluent, 20-flu-
oro-4-nitrobiphenyl-2-carbonitrile 2d was obtained as a yellow
J¼7.8, 1.4 Hz, 1H), 7.80 (ddd, J¼7.6, 1.4, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
112.8, 117.8, 122.0 (d, 2J¼18 Hz), 124.7 (d,
J¼5 Hz), 127.3 (d, 2J¼15 Hz), 128.7, 129.6 (d, J¼2 Hz), 130.8
(d, J¼2 Hz), 131.4, 132.5, 133.4, 138.5, 155.0 (d, 1J¼250 Hz); HRMS-EI
m/z [Mþ] calcd for C13H7FNCl 231.0251, found 231.02534.
powder (453 mg, 85%); mp 136e137 ꢀC; IR (KBr)
n
(cmꢁ1) 3064,
2233 (CN), 1524, 1352; 1H NMR (400 MHz, CDCl3)
d
7.26e7.36 (m,
4.3.9. 20,30-Difluorobiphenyl-2-carbonitrile 2i. Starting from 2,3-
difluorobenzeneboronic acid 1e (521 mg, 3.30 mmol) and 2-bro-
mobenzonitrile (500 mg, 2.75 mmol), following general procedure
A and using cyclohexane/EtOAc (9:1) as eluent, 20,30-difluor-
obiphenyl-2-carbonitrile 2i was obtained as white crystals
2H), 7.46 (dt, J¼7.8, 2.0 Hz, 1H), 7.51e7.57 (m, 1H), 7.75 (d, J¼8.8 Hz,
1H), 8.51 (dd, J¼8.8, 2.0 Hz, 1H), 8.65 (d, J¼3.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
114.3, 116.0, 116.6 (d, 2J¼21 Hz), 123.8 (d,
2J¼15 Hz), 124.8 (d, J¼4 Hz), 127.1, 128.3, 130.8 (d, J¼2 Hz), 132.3 (d,
J¼8 Hz), 132.4 (d, J¼2 Hz), 145.6, 147.1, 159.2 (d, 1J¼250 Hz); HRMS-
EI m/z [Mþ] calcd for C13H7N2O2F 242.04914, found 242.04929.
(432 mg, 73%); mp 94e95 ꢀC; IR (KBr)
n
(cmꢁ1) 2226 (CN), 1465,
758; 1H NMR (500 MHz, CDCl3)
d 7.18e7.30 (m, 3H), 7.51e7.55 (m,
2H), 7.69 (dt, J¼7.8, 1.4 Hz, 1H), 7.80e7.81 (m, 1H); 13C NMR
4.3.5. 20-Fluoro-5-trifluoromethylbiphenyl-2-carbonitrile 2e. Start-
ing from 4-trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,2]-dioxobor-
olan-2-yl)benzonitrile 1c (406 mg, 1.37 mmol) and 2-
(100 MHz, CDCl3)
5 Hz), 126.0 (d, J¼4, 1.2 Hz), 127.9 (d, J¼9 Hz), 128.7, 130.9 (d,
J¼1 Hz), 132.7, 133.4, 138.2 (d, J¼3 Hz), 147.8 (dd, J¼251 Hz,
d
112.8, 117.8, 118.0 (d, 2J¼17 Hz), 124.4 (dd, J¼7,

E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
5013
2J¼14 Hz), 150.9 (d, 1J¼248 Hz, 2J¼13 Hz); HRMS-EI m/z [Mþ] calcd
1h (437 mg, 1.91 mmol), following general procedure D and using
cyclohexane/EtOAc (9:1) as eluent, 20-fluoro-40-methylbiphenyl-
2-carbonitrile 2n was obtained as white crystals (226 mg, 67%);
for C13H7NF2 215.05464, found 215.05441.
4.3.10. 20-Fluoro-30-methylbiphenyl-2-carbonitrile 2j. Starting from
2-fluoro-3-methylbenzeneboronic acid 1f (508 mg, 3.30 mmol) and
2-bromobenzonitrile (500 mg, 2.75 mmol), following general pro-
cedure A and using cyclohexane/EtOAc (9:1) as eluent for the chro-
matography, 20-fluoro-30-methylbipheny-2-carbonitrile 2j was
mp 89e90 ꢀC; IR (KBr) (cmꢁ1) 2925, 2225 (CN), 1627, 1438,
n
1266, 1127, 765; 1H NMR (400 MHz, CDCl3)
d 2.41 (s, 3H),
7.02e7.05 (m, 2H), 7.07 (ddd, J¼7.8, 1.6, 0.7 Hz, 1H), 7.30 (t,
J¼7.8 Hz, 1H), 7.46 (dt, J¼7.6, 1.2 Hz, 1H), 7.49 (ddt, J¼7.9, 1.2,
0.6 Hz, 1H), 7.64 (dt, J¼7.6, 1.4 Hz, 1H), 7.76 (ddd, J¼7.7, 1.4, 0.6 Hz,
obtained as white crystals (489 mg, 84%); mp 70e71 ꢀC; IR (KBr)
n
1H); 13C NMR (100 MHz, CDCl3)
d
21.2, 112.8, 116.6 (d, 2J¼22 Hz),
(cmꢁ1) 3063, 2235(CN),1462,1203; 1H NMR (400 MHz, CDCl3)
d
2.32
118.2, 125.1 (d, J¼3 Hz), 127.9, 130.8 (d, J¼4 Hz), 131.0 (d, J¼2 Hz),
132.5, 133.2, 139.8, 141.61 (d, J¼8 Hz), 141.62, 159.2 (d,
1J¼248.0 Hz); HRMS-EI m/z [Mþ] calcd for C14H10FN 211.07972,
found 211.07967.
(d, J¼2.0 Hz, 3H), 7.26 (t, J¼7.6 Hz, 1H), 7.31 (dt, J¼7.2, 1.6 Hz, 1H),
7.42e7.46 (m, 1H), 7.60 (d, J¼8.0 Hz, 1H), 7.65 (dt, J¼7.6, 1.2 Hz, 1H),
7.82 (dt, J¼8.0, 1.6 Hz, 1H), 7.98 (dd, J¼7.6, 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d
14.2 (d, J¼4 Hz), 30.7,111.8,117.9,124.3 (d, J¼4 Hz),
124.9 (d, 2J¼18 Hz), 125.2 (d, 2J¼16 Hz), 128.8 (d, J¼2 Hz), 129, 130.9,
132.5 (d, J¼5 Hz), 133.3 (d, J¼15 Hz), 139.0, 157.2 (d, 1J¼245 Hz);
HRMS-EI m/z [Mþ] calcd for C14H10NF 211.07972, found 211.08049.
4.3.15. 20-Fluoro-40-methoxybiphenyl-2-carbonitrile
2o. Starting
from 1-bromo-2-fluoro-4-methoxybenzene (600 mg, 2.93 mmol)
and 2-(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1h
(805 mg, 3.52 mmol), following general procedure D and using
cyclohexane/EtOAc (9:1) as eluent, 20-fluoro-40-methoxybiphenyl-
2-carbonitrile 2o was obtained as white crystals (410 mg, 65%); mp
4.3.11. 20-Fluoro-30-methoxybiphenyl-2-carbonitrile
2k. Starting
from 2-fluoro-3-methoxybenzeneboronic acid 1g (800 mg,
4.71 mmol) and 2-bromobenzonitrile (715 mg, 3.93 mmol), fol-
lowing general procedure A and using cyclohexane/EtOAc (8:2) as
eluent, 20-fluoro-30-methoxybiphenyl-2-carbonitrile 2k was
obtained as white crystals (654 mg, 73%); mp 133e134 ꢀC; IR (KBr)
69e70 ꢀC; IR (KBr)
n
(cmꢁ1) 3079, 2223 (CN), 1624, 1477, 1125, 757;
1H NMR (400 MHz, CDCl3)
d
3.86 (s, 3H), 6.77 (dd, J¼11.8, 2.0 Hz,
1H), 6.82 (ddd, J¼8.0, 2.0, 0.7 Hz, 1H), 7.34 (t, J¼8.7 Hz, 1H), 7.45 (dt,
J¼7.7, 1.3 Hz, 1H), 7.48 (dd, J¼8.3, 2.0 Hz, 1H), 7.63 (dt, J¼7.8, 1.4 Hz,
1H), 7.76 (ddd, J¼8.0, 1.4, 0.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
n
(cmꢁ1) 3016, 2224 (CN), 1483, 1275; 1H NMR (500 MHz, CDCl3)
d
3.93 (s, 3H), 6.97 (dt, J¼6.3, 1.3 Hz, 1H), 7.06 (dt, J¼8.2, 1.6 Hz, 1H),
d
55.7, 102.1 (d, 2J¼26 Hz), 110.4 (d, J¼3 Hz), 112.9, 117.9, 118.2 (d,
7.18 (dt, J¼7.8, 1.5 Hz, 1H), 7.46e7.52 (m, 2H), 7.65 (dt, J¼7.8, 1.4 Hz,
2J¼22 Hz), 127.8, 131.1 (d, J¼2 Hz), 131.7 (d, J¼4 Hz), 132.5, 133.2,
139.6, 160.1 (d, 1J¼248 Hz), 161.7; HRMS-EI m/z [Mþ] calcd for
C14H10NOF 227.07463, found 227.07538.
1H), 7.77 (ddd, J¼7.8, 1.4, 0.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
56.3, 112.7, 113.9 (d, J¼2 Hz), 118.0, 122.2, 124.0, 126.5 (d,
2J¼12 Hz), 128.2, 130.9, 132.4, 133.2 (d, J¼3 Hz), 139.3, 148.1 (d,
J¼11 Hz), 149.3 (d, 1J¼249 Hz); HRMS-EI m/z [Mþ] calcd for
C14H10ONF 227.07463, found 227.07359.
4.3.16. 50-Chloro-20-fluorobiphenyl-2-carbonitrile 2p. Starting from
5-chloro-2-fluorobenzeneboronic acid 1i (575 mg, 3.30 mmol)
and 2-bromobenzonitrile (500 mg, 2.75 mmol), following gen-
eral procedure A and using cyclohexane/EtOAc (95:5) as eluent,
50-chloro-20-fluorobiphenyl-2-carbonitrile 2p was obtained as
4.3.12. 40-Chloro-20-fluorobiphenyl-2-carbonitrile 2l. Starting from
4-chloro-1-iodo-2-fluorobenzene (500 mg, 1.95 mmol) and 2-
(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile
1h
white crystals (300 mg, 53%); mp 108e109 ꢀC; IR (KBr)
3074, 2221(CN), 1466, 1215, 808, 760; 1H NMR (500 MHz, CDCl3)
7.17 (t, J¼8.9 Hz, 1H), 7.38e7.45 (m, 2H), 7.48 (d, J¼7.8 Hz, 1H),
n )
(cmꢁ1
(536 mg, 2.34 mmol), following general procedure D and using cy-
clohexane/EtOAc (9:1) as eluent, 40-chloro-20-fluorobiphenyl-2-
carbonitrile 2l was obtained as white crystals (256 mg, 57%); mp
d
7.52 (t, J¼7.7 Hz, 1H), 7.66e7.70 (m, 1H), 7.79 (d, J¼7.9 Hz, 1H);
107e108 ꢀC; IR (KBr)
n
(cmꢁ1) 3435, 2932, 2224 (CN), 1609, 1402,
13C NMR (125 MHz, CDCl3)
d
112.9, 117.5 (d, 2J¼24 Hz), 117.6,
1215, 767; 1H NMR (400 MHz, CDCl3)
d
7.25e7.29 (m, 2H), 7.37 (t,
127.3 (d, 2J¼17 Hz), 127.6, 128.8, 129.5 (d, J¼4 Hz), 130.7 (d,
J¼8 Hz), 130.8 (d, J¼1 Hz), 130.9 (d, J¼3 Hz), 134.3, 138.2, 157.9 (d,
1J¼247 Hz); HRMS-EI m/z [Mþ] calcd for C13H7ClFN 231.0251,
found 231.0244.
J¼7.8 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.51 (dt, J¼7.8, 1.0 Hz, 1H), 7.67
(dt, J¼7.8,1.0 Hz,1H), 7.79 (dd, J¼7.8,1.0 Hz,1H); 13C NMR (100 MHz,
CDCl3)
d
112.8, 117.0 (d, 2J¼26 Hz), 117.8, 124.4 (d, J¼15 Hz), 124.9 (d,
J¼4 Hz), 128.5, 130.9 (d, J¼2 Hz), 131.9 (d, J¼3 Hz), 132.6, 133.3,
136.00 (d, J¼10 Hz),138.45,159.2 (d, 1J¼252 Hz); HRMS-EI m/z [Mþ]
calcd for C13H7ClFN 231.0251, found 231.0251.
4.3.17. 20,50-Difluorobiphenyl-2-carbonitrile
1-bromo-2,5-difluorobenzene (0.58 mL, 5.18 mmol) and 2-(4,4,5,5-
tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1h (1.42 g,
2q. Starting
from
4.3.13. 20,40-Difluorobiphenyl-2-carbonitrile 2m. Starting from 1-
bromo-2,4-difluorobenzene (0.14 mL, 1.24 mmol) and 2-(4,4,5,5-
tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile 1h (340 mg,
1.49 mmol), following general procedure D and using cyclohexane/
EtOAc (9:1) as eluent, 20,40-difluorobiphenyl-2-carbonitrile 2m was
6.22 mmol), following general procedure D and using cyclohexane/
EtOAc (9:1) as eluent, 20,50-difluorobiphenyl-2-carbonitrile 2q was
obtained as white crystals (862 mg, 78%); mp 87e88 ꢀC; IR (KBr)
n
(cmꢁ1) 2224 (CN),1471, 1180; 1H NMR (400 MHz, CDCl3)
d 7.13e7.22
(m, 3H), 7.47e7.54 (m, 2H), 7.68 (dt, J¼7.7, 1.4 Hz, 1H), 7.79 (dd,
obtained as white crystals (217 mg, 81%); mp 102e103 ꢀC; IR (KBr)
(cmꢁ1) 3067, 2235 (CN), 1593, 960, 856, 768; 1H NMR (400 MHz,
CDCl3)
6.95e7.03 (m, 2H), 7.41 (dt, J¼8.6, 6.3 Hz, 1H), 7.47e7.52
n
J¼7.7, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 112.8, 117.3 (dd,
2J¼24 Hz, J¼8 Hz), 117.4 (dd, 2J¼25 Hz, J¼9 Hz), 117.8 (dd, 2J¼25 Hz,
J¼3 Hz), 117.8, 127.0 (dd, 2J¼17 Hz, J¼8.1 Hz), 128.7, 130.8 (d,
J¼1 Hz), 132.7, 133.3, 138.4, 155.5 (dd, 1J¼241 Hz, 4J¼2 Hz), 158.5
(dd, 1J¼243 Hz, 4J¼2 Hz); HRMS-EI m/z [Mþ] calcd for C13H7F2N
215.05464, found 215.05561.
d
(m, 2H), 7.67 (dt, J¼7.7, 1.4 Hz, 1H), 7.78 (ddd, J¼7.7, 1.4, 0.6 Hz, 1H);
13C NMR (100 MHz, CDCl3)
d
104.5 (t, 2J¼26 Hz), 112.0, 112.3 (dd,
2J¼21 Hz, J¼4 Hz,), 117.8, 122.1 (dd, J¼15, 4 Hz), 129.1, 131.1, 132.8
(dd, J¼10, 4 Hz), 133.3, 133.5, 137.9, 159.1 (dd, 1J¼248 Hz, 3J¼12 Hz),
162.8 (dd, 1J¼248 Hz, 3J¼12 Hz); HRMS-EI m/z [Mþ] calcd for
C13H7NF2 215.05464, found 215.05473.
4.3.18. 20-Fluoro-50-methylbiphenyl-2-carbonitrile 2r. Starting from
2-fluoro-5-methylbenzeneboronic acid 1j (305 mg, 1.98 mmol) and
2-bromobenzonitrile (300 mg, 1.65 mmol), following general pro-
cedure A and using cyclohexane/EtOAc (9:1) as eluent, 20-fluoro-50-
methylbiphenyl-2-carbonitrile 2r was obtained as white crystals
4.3.14. 20-Fluoro-40-methylbiphenyl-2-carbonitrile
2n. Starting
from 1-bromo-2-fluoro-4-methylbenzene (0.20 mL, 1.59 mmol)
and 2-(4,4,5,5-tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile
(251 mg, 72%); mp 77e78 ꢀC; IR (KBr) (cmꢁ1) 3038, 2233 (CN),
n

5014
E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
1487, 1217, 769; 1H NMR (500 MHz, CDCl3)
d
2.38 (s, 3H), 7.09 (dd,
159.0, 160.6; HRMS-EI m/z [Mþ] calcd for C14H11NO2 225.07896,
J¼9.8, 8.3 Hz, 1H), 7.19e7.23 (m, 2H), 7.47 (dt, J¼7.7, 1.3 Hz, 1H), 7.49
found 225.07809.
(m, 1H), 7.65 (dt, J¼7.7, 1.3 Hz, 1H), 7.77 (ddd, J¼7.7, 1.4, 0.6 Hz, 1H);
13C NMR (125 MHz, CDCl3)
d
20.7, 112.8, 115.8 (d, 2J¼22 Hz), 118.1,
4.4.4. 8-Nitrophenanthridin-6(5H)-one 3d21. Starting from 20-flu-
oro-4-nitrobiphenyl-2-carbonitrile 2d (100 mg, 0.41 mmol) 3d was
125.3 (d, 2J¼15 Hz), 128.1, 130.9 (d, J¼2 Hz), 131.2 (d, J¼2 Hz), 131.5
(d, J¼3 Hz), 132.5, 133.2, 133.8 (d, J¼4 Hz), 139.8, 157.6 (d,
1J¼245 Hz); HRMS-EI m/z [Mþ] calcd for C14H10FN 211.07972, found
211.07973.
obtained as a white powder (100 mg, 99%); mp >260 ꢀC; IR (KBr)
n
(cmꢁ1) 2892, 1685(CO), 1340, 746; 1H NMR (400 MHz, DMSO-d6)
d
7.34 (d, 3J¼8.0 Hz, 1H), 7.42 (d, 3J¼8.0 Hz, 1H), 7.63 (t, 3J¼8.0 Hz,
1H), 8.49 (d, 3J¼8.0 Hz, 1H), 8.59 (dd, 3J¼8.8 Hz, 4J¼2.4 Hz, 1H), 8.78
4.3.19. 20-Fluoro-50-methoxybiphenyl-2-carbonitrile
2s. Starting
(d, 3J¼8.8 Hz, 1H), 9.00 (d, 3J¼2.4 Hz, 1H), 12.05 (s, 1H); 13C NMR
from 2-fluoro-5-methoxybenzeneboronic acid 1k (224 mg,
1.32 mmol) and 2-bromobenzonitrile (200 mg, 1.10 mmol), fol-
lowing general procedure A and using cyclohexane/EtOAc (9:1) as
eluent, 20-fluoro-50-methoxybiphenyl-2-carbonitrile 2s was
(100 MHz, DMSO-d6) d 116.2, 116.5, 122.9 (2C), 124.6, 124.8, 126.1,
126.4, 131.7, 137.7, 139.4, 146.3, 159.6; HRMS-EI m/z [Mþ] calcd for
C13H8N2O3 240.05347, found 240.05334.
obtained as white crystals (127 mg, 51%); mp 81e82 ꢀC; IR (KBr)
n
4.4.5. 9-Trifluoromethylphenanthridin-6(5H)-one 3e. Starting from
20-fluoro-5-trifluoromethylbiphenyl-2-carbonitrile 2e (100 mg,
0.38 mmol) 3e was obtained as a white powder (70 mg, 70%); mp
(cmꢁ1) 2222 (CN), 1475, 1215, 761; 1H NMR (500 MHz, CDCl3)
d 3.83
(s, 3H), 6.92e6.96 (m, 2H), 7.13 (t, J¼9.1 Hz, 1H), 7.49e7.52 (m, 2H),
7.66 (dt, J¼7.7, 1.2 Hz, 1H), 7.78 (dd, J¼7.7, 1.2 Hz, 1H); 13C NMR
>260 ꢀC; IR (KBr)
(500 MHz, DMSO-d6)
n
(cmꢁ1) 1675 (CO), 1347, 1284, 1119; 1H NMR
(125 MHz, CDCl3)
d
55.9, 112.8, 115.8 (d, J¼2 Hz), 116.0 (d, J¼8 Hz),
d
7.27e7.31 (m, 1H), 7.40 (d, J¼7.5 Hz, 1H),
116.8 (d, 2J¼24 Hz), 118.0, 126.1 (d, 2J¼17 Hz), 128.3, 130.9 (d,
J¼2 Hz), 132.6, 133.3, 139.6, 153.7 (d, 1J¼241 Hz), 155.6 (d, J¼2 Hz);
HRMS-EI m/z [Mþ] calcd for C14H10NOF 227.07463, found
227.07553.
7.53e7.56 (m, 1H), 7.92 (d, J¼8.3 Hz, 1H), 8.50 (d, J¼8.3 Hz, 1H), 8.53
(d, J¼7.9 Hz, 1H), 8.82 (s, 1H), 11.84 (s, 1H); 13C NMR (125 MHz,
DMSO-d6)
d
116.2, 116.7, 120.2 (q, J¼4 Hz), 122.5, 123.8 (q, J¼3 Hz),
123.9, 123.9 (q, 1J¼274 Hz), 128.4, 129.0, 130.5, 132.7 (q, 2J¼31 Hz),
134.9, 136.9, 159.9; HRMS-EI m/z [Mþ] calcd for C14H8NOF3
263.05578, found 263.05559.
4.4. General procedure for the synthesis of substituted
phenanthridin-6(5H)-ones 3aes
4.4.6. 9-Methylphenanthridin-6(5H)-one 3f22. Starting from 20-flu-
oro-5-methylbiphenyl-2-carbonitrile 2f (1.8 g, 8.53 mmol) 3f was
obtained as a white powder (1.77 g, 99%); mp 250e251 ꢀC; IR (KBr)
In a microwave vial were introduced a substituted 20-fluo-
robiphenyl-2-carbonitrile (1 equiv) and KOH (5 equiv) in t-BuOH
(6 mL/mmol of substituted 20-fluorobiphenyl-2-carbonitrile). The
vial was sealed and the suspension was heated under microwaves
at 150 ꢀC for the time reported in Table 2. The mixture was diluted
with HCl 1 M until complete precipitation. The product was fil-
trated and washed with water.
n
(cmꢁ1) 2883, 1670 (CO), 1617, 1366, 753; 1H NMR (400 MHz,
DMSO-d6)
d
2.52 (s, 3H), 7.24 (t, J¼7.8 Hz, 1H), 7.34 (d, J¼7.8 Hz, 1H),
7.44e7.47 (m, 2H), 8.19 (d, J¼7.8 Hz, 1H), 8.32 (s, 1H), 8.36 (d,
J¼7.8 Hz, 1H), 11.58 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 21.6,
116.1,117.5,122.2,122.5,123.2,123.4,127.5,129.2,129.5,134.3,136.7,
143.0, 160.8; HRMS-EI (g molꢁ1) calcd for C14H11NO 209.08405,
found 209.08421.
4.4.1. Phenanthridin-6(5H)-one
3a20. Starting from 20-fluo-
robiphenyl-2-carbonitrile 2a (700 mg, 3.55 mmol), 3a was obtained
as a white powder (693 mg, 99%); mp >260 ꢀC; IR (KBr)
3047, 1663 (CO), 1369, 748; 1H NMR (500 MHz, DMSO-d6)
n
(cmꢁ1
7.25 (t,
)
4.4.7. 10-Methylphenanthridin-6(5H)-one 3g. Starting from 20-flu-
oro-6-methylbiphenyl-2-carbonitrile 2g (100 mg, 0.47 mmol) and
d
3J¼7.8 Hz, 1H), 7.36 (d, 3J¼8.7 Hz, 1H), 7.48 (t, 3J¼7.8 Hz, 1H), 7.63 (t,
3J¼7.8 Hz,1H), 7.84 (t, 3J¼7.8 Hz,1H), 8.31 (d, 3J¼7.8 Hz,1H), 8.38 (d,
3J¼8.8 Hz, 1H), 8.50 (d, 3J¼8.8 Hz, 1H), 11.69 (s, 1H); 13C NMR
obtained as a white powder (61 mg, 61%); mp >260 ꢀC; IR (KBr)
n
(cmꢁ1) 2858, 1654 (CO), 1377, 731; 1H NMR (400 MHz, DMSO-d6)
2.92 (s, 3H), 7.25 (t, J¼7.8 Hz, 1H), 7.40 (d, J¼7.8 Hz, 1H), 7.45e7.54
d
(100 MHz, DMSO-d6)
d
115.9, 117.4, 122.0, 122.3, 123.0, 125.6, 127.3,
(m, 2H), 7.70 (d, J¼7.8 Hz, 1H), 8.31 (d, J¼7.8 Hz, 1H), 8.43 (d,
127.6, 129.3, 132.5, 134.1, 136.4, 160.6; HRMS-EI m/z [Mþ] calcd for
J¼8.8 Hz, 1H), 11.61 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 25.3,
C13H9NO 195.0684, found 195.06911.
116.0, 118.6, 121.4, 125.8, 126.9, 127.2, 127.3, 128.5, 133.1, 134.9, 136.7,
136.9, 160.7; HRMS-EI m/z [Mþ] calcd for C14H11NO 209.08405,
found 209.08472.
4.4.2. 7-Trifluoromethylphenanthridin-6(5H)-one 3b. Starting from
20-fluoro-3-trifluoromethylbiphenyl-2-carbonitrile 2b (100 mg,
0.38 mmol) 3b was obtained as a white powder (33 mg, 33%); mp
4.4.8. 4-Chlorophenanthridin-6(5H)-one 3h. Starting from 30-
chloro-20-fluorobiphenyl-2-carbonitrile 2h (100 mg, 0.43 mmol)
3h was obtained as a white powder (83 mg, 85%); mp 222e223 ꢀC;
>260 ꢀC; IR (KBr)
n
(cmꢁ1) 2921, 1675 (CO), 1303, 750; 1H NMR
(500 MHz, DMSO-d6)
d
7.27 (t, 3J¼7.5 Hz, 1H), 7.39 (d, 3J¼8.5 Hz,
1H), 7.53 (t, 3J¼7.5 Hz, 1H), 7.98 (t, 3J¼8.5 Hz, 1H), 8.05 (d, 3J¼7.5 Hz,
IR (KBr)
(400 MHz, DMSO-d6)
n
(cmꢁ1) 3056, 1656 (CO), 1608, 1360, 748; 1H NMR
1H), 8.42 (d, 3J¼8.0 Hz, 1H), 8.85 (d, 3J¼8.0 Hz, 1H), 11.66 (s, 1H); 13
C
d
7.28 (t, J¼7.8 Hz, 1H), 7.64 (d, J¼7.8 Hz, 1H),
NMR (125 MHz, DMSO-d6)
d
115.4, 116.3, 122.0, 123.1, 123.6, 123.8
7.69 (t, J¼7.8 Hz, 1H), 7.89 (t, J¼7.8 Hz, 1H), 8.34 (d, J¼7.8 Hz, 1H),
(q, 1J¼271 Hz), 127.2 (q, J¼7 Hz), 127.4, 128.7 (q, 2J¼32 Hz), 130.2,
131.9, 136.7, 137.0, 158.0; HRMS-EI m/z [Mþ] calcd for C14H8NOF3
263.05578, found 263.05509.
8.42 (d, J¼8.8 Hz, 1H), 8.54 (d, J¼8.8 Hz, 1H), 10.78 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 119.3, 113.6, 122.5, 122.8, 123.1, 125.5, 127.6,
128.8, 129.8, 132.8, 133.4, 133.6, 160.8; HRMS-EI m/z [Mþ] calcd for
C13H8NOCl 229.02943, found 229.02918.
4.4.3. 8-Methoxyphenanthridin-6(5H)-one 3c5. Starting from 20-
fluoro-4-methoxybiphenyl-2-carbonitrile 2c (100 mg, 0.44 mmol)
3c was obtained as a white powder (67 mg, 67%); mp 248e249 ꢀC;
4.4.9. 4-Fluorophenanthridin-6(5H)-one 3i. Starting from 20,30-
difluorobiphenyl-2-carbonitrile 2i (100 mg, 0.46 mmol) 3i was
obtained as a white powder (88 mg, 90%); mp 257e258 ꢀC; IR (KBr)
IR (KBr)
DMSO-d6)
n
(cmꢁ1) 2902, 1667 (CO), 1368, 750; 1H NMR (400 MHz,
d
3.90 (s, 3H), 7.23 (t, J¼7.8 Hz, 1H), 7.33 (d, J¼8.8 Hz, 1H),
n
(cmꢁ1) 1653 (CO), 1430, 1354, 1261, 750; 1H NMR (400 MHz,
7.40e7.42 (m, 2H), 7.74 (s, 1H), 8.29 (d, J¼7.8 Hz, 1H), 8.43 (d,
DMSO-d6)
d
7.27 (dt, J¼8.1 Hz, 5.3 Hz, 1H), 7.42 (ddd, J¼10.8, 8.1,
J¼8.8 Hz, 1H), 11.71 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
55.4,
1.1 Hz, 1H), 7.70 (dt, J¼7.2, 1.0 Hz, 1H), 7.89 (dt, J¼7.2, 1.4 Hz, 1H),
8.24 (d, J¼8.2 Hz, 1H), 8.36 (dd, J¼6.8, 1.1 Hz, 1H), 8.52 (d, J¼8.1 Hz,
108.6, 116.0, 117.7, 121.6, 122.3, 122.7, 124.6, 127.1, 127.7, 128.5, 135.5,

E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
5015
1H), 11.62 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
114.9 (d,
DMSO-d6)
d
3.82 (s, 3H), 6.86 (dd, 3J¼6.3 Hz, 4J¼1.3 Hz, 1H), 6.90 (d,
2J¼17 Hz), 119.0 (d, J¼4 Hz), 119.9 (d, J¼3 Hz), 122.0 (d, J¼7 Hz),
123.1, 125.2 (d, 2J¼13 Hz), 125.9, 127.7, 128.6, 133.1, 133.6 (d, J¼2 Hz),
149.5 (d, 1J¼245.3 Hz),160.6; HRMS-EI m/z [Mþ] calcd for C13H8NOF
213.05898, found 213.05881.
J¼2.4 Hz, 1H), 7.52e7.56 (m, 1H), 7.76e7.81 (m, 1H), 8.24e8.28 (m,
2H), 8.34 (d, J¼8.1 Hz, 1H), 11.58 (s, 1H); 13C NMR (100 MHz, DMSO-
d6)
d 55.2, 99.5, 110.1, 111.1, 121.9, 124.4, 124.7, 126.7, 127.4, 132.7,
134.5, 138.0, 160.3, 161.1; HRMS-EI m/z [Mþ] for C14H11NO2
225.07896, found 225.07864.
4.4.10. 4-Methylphenanthridin-6(5H)-one 3j8. Starting from 20-flu-
oro-30-methylbiphenyl-2-carbonitrile 2j (300 mg, 1.42 mmol) 3j
was obtained as a white powder (286 mg, 96%); mp 241e243 ꢀC; IR
4.4.16. 2-Chlorophenanthridin-6(5H)-one 3p1c. Starting from 50-
chloro-20-fluorobiphenyl-2-carbonitrile 2p (100 mg, 0.43 mmol) 3p
was obtained as a white powder (85 mg, 86%); mp >260 ꢀC; IR
(KBr)
DMSO-d6)
n
(cmꢁ1) 3054, 1674 (CO), 1368, 741; 1H NMR (400 MHz,
d
2.51 (s, 3H), 7.20 (t, J¼6.8 Hz, 1H), 7.36 (d, J¼7.8 Hz, 1H),
(KBr)
DMSO-d6)
n
(cmꢁ1) 2865, 1682 (CO), 1359, 772; 1H NMR (400 MHz,
7.65 (t, J¼6.8 Hz, 1H), 7.87 (t, J¼6.8 Hz, 1H), 8.28 (d, J¼7.8 Hz, 1H),
d
7.36 (d, J¼8.8 Hz, 1H), 7.51 (dd, J¼8.8 Hz, 2.0 Hz, 1H),
8.35 (d, J¼7.8 Hz, 1H), 8.53 (d, J¼8.8 Hz, 1H), 10.73 (s, 1H); 13C NMR
7.66 (t, J¼6.8 Hz, 1H), 7.84 (t, J¼7.8 Hz, 1H), 8.30 (d, J¼7.8 Hz, 1H),
(100 MHz, DMSO-d6)
d 17.7, 117.6, 121.2, 122.1, 122.8, 124.2, 125.4,
8.45 (d, J¼2.0 Hz, 1H), 8.54 (d, J¼7.8 Hz, 1H), 11.80 (s, 1H); 13C NMR
127.5, 127.9, 131.1, 133.0,134.6, 134.8, 161.2; HRMS-EI m/z [Mþ] calcd
(100 MHz, DMSO-d6) d 117.8, 119.0, 122.7, 122.9, 125.7, 126.4, 127.3,
for C14H11NO 209.08405, found 209.08318.
128.5, 129.3, 132.8, 133.1, 135.3, 160.5; HRMS-EI m/z [Mþ] calcd for
C13H8NOCl 229.02943, found 229.02916.
4.4.11. 4-Methoxyphenanthridin-6(5H)-one 3k. Starting from 20-
fluoro-30-methoxybiphenyl-2-carbonitrile 2k (100 mg, 0.44 mmol)
3k was obtained as a white powder (84 mg, 85%); mp 167e168 ꢀC;
4.4.17. 2-Fluorophenanthridin-6(5H)-one 3q. Starting from 20,50-
difluorobiphenyl-2-carbonitrile 2q (650 mg, 3.02 mmol) 3q was
IR (KBr)
n
(cmꢁ1) 3394, 1661 (CO), 1266, 1021, 746; 1H NMR
obtained as a white powder (644 mg, 99%); mp >260 ꢀC; IR (KBr)
n
(400 MHz, DMSO-d6)
d
3.93 (s, 3H), 7.15 (d, J¼7.7 Hz, 1H), 7.22 (t,
(cmꢁ1) 2876, 1690 (CO), 1507, 1151, 769; 1H NMR (400 MHz, DMSO-
d6)
7.37e7.39 (m, 2H), 7.68 (t, J¼7.2 Hz, 1H), 7.84e7.88 (m, 1H),
8.25e8.28 (m, 1H), 8.32 (dd, J¼8.0, 1.2 Hz, 1H), 8.51 (d, J¼8.4 Hz,
J¼8.0 Hz, 1H), 7.65 (t, J¼7.8 Hz, 1H), 7.83e7.87 (m, 1H), 7.95 (d,
J¼7.7 Hz, 1H), 8.35 (dd, J¼8.0, 0.8 Hz, 1H), 8.46 (d, J¼8.4 Hz, 1H),
d
10.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
56.0, 110.4, 114.7,
1H), 11.74 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 109.1 (d,
117.9, 121.9, 122.7, 125.7, 126.0, 127.4, 127.8, 132.6, 134.1, 146.0, 160.1;
HRMS-EI m/z [Mþ] calcd for C14H11NO2 225.07896, found
225.07855.
2J¼24 Hz), 117.1 (d, 2J¼24 Hz), 117.8 (d, J¼9 Hz), 118.8 (d, J¼8 Hz),
123.2, 125.8, 127.4, 128.6, 132.8, 133.1, 133.5 (d, J¼3 Hz), 157.8 (d,
1J¼238 Hz), 160.5; HRMS-EI m/z [Mþ] calcd for C13H8NOF
213.05898, found 213.05901.
4.4.12. 3-Chlorophenanthridin-6(5H)-one 3l. Starting from 40-
chloro-20-fluorobiphenyl-2-carbonitrile 2l (100 mg, 0.43 mmol) 3l
was obtained as a white powder (99 mg, 99%); mp >260 ꢀC; IR
4.4.18. 2-Methylphenanthridin-6(5H)-one 3r23. Starting from 20-
fluoro-50-methylbiphenyl-2-carbonitrile 2r (400 mg, 1.89 mmol) 3r
was obtained as a white powder (386 mg, 97%); mp 256e258 ꢀC; IR
(KBr)
DMSO-d6)
n
(cmꢁ1) 2858, 1663 (CO), 1609, 762; 1H NMR (400 MHz,
d
7.28 (dd, J¼8.8, 2.0 Hz, 1H), 7.37 (d, J¼2.0 Hz, 1H), 7.65
(KBr)
DMSO-d6)
n
(cmꢁ1) 3012, 1657 (CO), 1608, 770; 1H NMR (400 MHz,
(t, J¼7.8 Hz, 1H), 7.85 (t, J¼7.8 Hz, 1H), 8.29 (d, J¼7.8 Hz, 1H), 8.39 (d,
d
2.40 (s, 3H), 7.24e7.31 (m, 2H), 7.61 (t, J¼7.8 Hz, 1H),
J¼8.8 Hz, 1H), 8.47 (d, J¼8.8 Hz, 1H), 11.76 (s, 1H); 13C NMR
7.83 (t, J¼7.8 Hz, 1H), 8.19 (s, 1H), 8.30 (d, J¼7.8 Hz, 1H), 8.47 (d,
(100 MHz, DMSO-d6)
d
115.3, 116.6, 122.2, 122.8, 125.3, 125.5, 127.5,
J¼7.8 Hz, 1H), 11.60 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 20.7,
128.3, 133.1, 133.5, 133.7, 137.6, 160.8; HRMS-EI m/z [Mþ] calcd for
116.0, 117.4, 122.6, 123.1, 125.7, 127.5, 127.8, 130.6, 131.2, 132.7, 134.2,
134.4, 160.7; HRMS-EI m/z [Mþ] calcd for C14H11NO 209.08405,
found 209.08402.
C13H8NOCl 229.02943, found 229.0294.
4.4.13. 3-Fluorophenanthridin-6(5H)-one 3m. Starting from 20,40-
difluorobiphenyl-2-carbonitrile 2m (100 mg, 0.47 mmol) 3m was
4.4.19. 2-Methoxyphenanthridin-6(5H)-one 3s. Starting from 20-
fluoro-50-methoxybiphenyl-2-carbonitrile 2s (300 mg, 1.32 mmol)
3s was obtained as a white powder (233 mg, 78%); mp 167e168 ꢀC;
obtained as a white powder (88 mg, 87%); mp >260 ꢀC; IR (KBr)
n
(cmꢁ1) 2873, 1693 (CO), 1358, 759; 1H NMR (400 MHz, DMSO-d6)
d
7.13e7.15 (m, 2H), 7.62e7.66 (m, 1H), 7.84e7.88 (m, 1H), 8.30 (dd,
IR (KBr)
DMSO-d6)
n
(cmꢁ1) 2875, 1674 (CO), 1506, 766; 1H NMR (400 MHz,
J¼8.0 Hz, 1.2 Hz, 1H), 8.44e8.48 (m, 2H), 11.78 (s, 1H); 13C NMR
d
3.86 (s, 3H), 7.14 (dd, J¼8.8 Hz, 2.9 Hz, 1H), 7.29 (d,
(100 MHz, DMSO-d6)
d
102.1 (d, 2J¼25 Hz), 110.0 (d, 2J¼23 Hz),
J¼8.8 Hz, 1H), 7.63 (t, J¼7.8 Hz, 1H), 7.82e7.86 (m, 2H), 8.30 (d,
114.5, 122.7, 125.0, 125.9 (d, J¼10 Hz), 127.5, 127.9, 133.1, 133.8, 138.1
(d, J¼11 Hz),161.0,162.5 (d, 1J¼246 Hz); HRMS-EI m/z [Mþ] calcd for
C13H8NOF 213.05898, found 213.05899.
J¼7.8 Hz, 1H), 8.54 (d, J¼7.8 Hz, 1H), 11.58 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 55.6, 106.1, 106.2, 117.3, 117.8, 118.3, 123.0,
125.9, 127.5, 128.0, 130.7, 132.6, 134.1, 154.8, 160.4; HRMS-EI m/z
[Mþ] calcd for C14H11NO2 225.07896, found 225.07836.
4.4.14. 3-Methylphenanthridin-6(5H)-one 3n. Starting from 20-flu-
oro-40-methylbiphenyl-2-carbonitrile 2n (100 mg, 0.47 mmol) 3n
was obtained as a white powder (94 mg, 94%); mp >260 ꢀC; IR
4.5. Sequential synthesis of 1-methoxyphenanthridin-6
(5H)-one 3t
(KBr)
DMSO-d6)
n
(cmꢁ1) 1653 (CO), 1430, 1354, 1261, 750; 1H NMR (400 MHz,
d
2.37 (s, 3H), 7.07 (d, J¼7.8 Hz, 1H), 7.14 (s, 1H), 7.59 (t,
To a
solution of 2-dicyclohexylphosphino-20,60-dimethox-
ybiphenyl (S-PHOS) (49 mg, 0.12 mmol) in 15 mL of a DME/water
mixture (2:1) was added Pd(OAc)2 (13 mg, 0.06 mmol) at room
temperature. The solution was heated at 80 ꢀC for 10 min. 2-bro-
J¼7.8 Hz, 1H), 7.81 (t, J¼7.8 Hz, 1H), 8.24 (d, J¼7.8 Hz, 1H), 8.28 (d,
J¼7.8 Hz, 1H), 8.43 (d, J¼8.8 Hz, 1H), 11.60 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 21.1, 115.2, 116.0, 122.3, 123.1, 123.5, 125.3,
127.4 (2C), 132.7, 134.4, 136.6, 139.4, 161.0; HRMS-EI m/z [Mþ] calcd
mobenzonitrile
(200 mg,
1.10 mmol),
2-fluoro-6-methox-
for C14H11NO 209.08405, found 209.08485.
ybenzeneboronic acid 1l (374 mg, 2.20 mmol), and Na2CO3
(175 mg, 1.65 mmol) were added. The resulting mixture was heated
at reflux for 24 h, and partitioned in 30 mL of water and 30 mL of
ethyl acetate. The combined layers were filtrated through a short
pad of Celite. The organic layer was washed with water (2ꢂ30 mL),
dried over MgSO4, filtrated, and evaporated. The crude was then
4.4.15. 3-Methoxyphenanthridin-6(5H)-one 3o. Starting from 20-
fluoro-40-methoxybiphenyl-2-carbonitrile 2o (410 mg, 1.80 mmol)
3o was obtained as a white powder (359 mg, 88%); mp 250e251 ꢀC;
IR (KBr)
n
(cmꢁ1) 2875, 1673 (CO), 1506, 766; 1H NMR (400 MHz,

5016
E. Dubost et al. / Tetrahedron 66 (2010) 5008e5016
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filtrated through a short pad of silica gel using cyclohexane/EtOAc
(95:5) as eluent. The crude was introduced in a microwave vial with
KOH (309 mg, 5.50 mmol) in 3 mL of t-BuOH. The vial was sealed
and the suspension was heated under microwaves at 150 ꢀC for
5 min. A solution of HCl 1 M was added to the reaction mixture
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(cmꢁ1) 2964, 1672 (CO),1606; 1H NMR (400 MHz, DMSO-d6)
d
4.02 (s, 3H), 6.92 (d, J¼8.8 Hz, 1H), 7.01 (d, J¼7.8 Hz, 1H), 7.42 (dt,
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J¼7.8 Hz, 1H), 7.60 (t, J¼6.8 Hz, 1H), 7.80 (t, J¼7.8 Hz, 1H), 8.36 (d,
J¼7.8 Hz, 1H), 9.17 (d, J¼7.8 Hz, 1H), 11.70 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 55.8, 105.0, 107.0, 108.9, 125.6, 126.8, 127.0,
127.4, 129.5, 132.3, 133.9, 138.2, 158.3, 160.6; HRMS-EI m/z [Mþ]
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Supplementary data
Supplementary data that may be helpful in the review process
should be prepared and provided as a separate electronic file. That
file can then be transformed into PDF format and submitted along
with the manuscript and graphic files to the appropriate editorial
office. Supplementary data associated with this article can be found
in online version at doi:10.1016/j.tet.2010.05.014.
15. Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem.
1995, 60, 3020e3027.
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References and notes
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