One-pot synthesis of new aza- and diaza-aminophenanthrenes

Article abstract of DOI:10.1016/j.tet.2011.05.116

The synthesis of a series of benzo(iso)quinoline and phenanthroline derivatives has been achieved using an efficient one-pot procedure. It proceeds through a Suzuki-Miyaura cross-coupling followed by a Dieckmann-Thorpe ring closure under microwave irradia

Full text of DOI:10.1016/j.tet.2011.05.116

Tetrahedron 67 (2011) 5806e5810
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of new aza- and diaza-aminophenanthrenes
*
ꢀ
Christophe Rochais , Rodrigue Yougnia, Thomas Cailly, Jana Sopkova-de Oliveira Santos, Sylvain Rault,
Patrick Dallemagne
Centre d’Etudes et de Recherche sur le M ꢀe dicament de Normandie (UPRES EA 4258dFR CNRS 3038 INC3M) UFR des Sciences Pharmaceutiques,
Universit ꢀe 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 27 April 2011
Received in revised form 26 May 2011
Accepted 29 May 2011
Available online 2 June 2011
The synthesis of a series of benzo(iso)quinoline and phenanthroline derivatives has been achieved using
an efficient one-pot procedure. It proceeds through a SuzukieMiyaura cross-coupling followed by
a DieckmanneThorpe ring closure under microwave irradiation and provides easy access to building
blocks not readily available through other methods.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azaphenanthrene
Benzoquinoline
Phenanthroline
SuzukieMiyaura cross-coupling
DieckmanneThorpe
Fused ring system
Ring closure
1. Introduction
A
B
Benzo(iso)quinolines are important scaffolds in chemistry either
1
R
R
for their use as metal ligands, or due to their occurrence in nu-
2
merous biological and pharmacological species. More recently
R'
N
N
benzo[h]quinolines have been used widely as rigid substrates to
R'= CHO, NH
2
3
develop CeH functionalization methodology. Because of this im-
C
portance, many syntheses have been explored to access these
scaffolds. Most of the synthesis proceeds through the formation of
the pyridine ring from an already substituted naphthalene pre-
cursor (Fig. 1, route A).4 Contrary to the phenanthrene series, the
construction of the benzo(iso)quinolines central ring has received
less attention. Some approaches have produced such compounds
R
R'
N
5
from aza-stilbene starting materials (Fig. 1, route B), using a radical
6
or a photocyclisationeoxidation processes. More recently, a new
Fig. 1. General access to benzo(iso)quinolines.
approach has been described starting from phenylpyridine pre-
cursors (Fig. 1, route C).7
However, few examples of benzo(iso)quinolines bearing a sub-
stituent on their central ring has been described, and hence efforts
are still needed in order to obtain these new derivatives.
These novel polycyclic systems were generally obtained starting
from o-cyanophenylboronic ester and methyl 2-(2-bromophenyl)
acetate 1 and its analogs (Fig. 2) which were successively in-
volved in
a SuzukieMiyaura cross-coupling followed by an
We have recently described an efficient one-pot synthesis of
intramolecular DieckmanneThorpe ring closure.
8
10-substituted 9-aminophenanthrenes under microwave irradiation.
In order to extend the scope of this methodology, we imagined
applyingtheseconditionstoadequateaza-substrateinordertoobtain
some novel aza and diaza-aminophenanthrenes. Indeed our labora-
tory has already described the synthesis of some ortho-cyanopyr-
idylboronic acids and esters 3aec (Scheme 1), and investigated their
*
Corresponding author. Tel.: þ33 231 566 813; fax: þ33 231 566 803; e-mail
address: christophe.rochais@unicaen.fr (C. Rochais).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.116

C. Rochais et al. / Tetrahedron 67 (2011) 5806e5810
5807
2
- and the 4-positions.9a Unfortunately only the 3-cyano-4-pyridyl
boronic ester 3b could be isolated, due to the well described ten-
NC
EWG
EWG
10
dency of 2-pyridylboronic acids to undergo protodeboronation.
Because of its good reactivity in SuzukieMiyaura cross-cou-
Br
O
B
O
NH2
9a
pling,
3b was chosen to optimize the synthesis of
benzoisoquinolines.
Our first attempt was run according to the optimized conditions
developed in the phenanthrene series: using 1 equiv of the bromide
Fig. 2. Retrosynthetic access to 10-substituted 9-aminophenanthrenes.
1
, 1.1 equiv of the boronic ester 3b, 3 equiv of Cs
2 3
CO as a base, 5% of
8
a
Pd (PPh as a catalyst in dimethylformamide (Scheme 1). Un-
3
3 4
)
ꢀ
fortunately, after 20 min heating at 150 C under microwave irra-
diation, no traces of the expected benzoisoquinoline were detected.
No improvement was found with prolonged reaction time. We
therefore decided to reinvestigate the reaction conditions and more
precisely the influence of the base. The best results were found
when 3 equiv of K
3
PO
4
were used and when the reaction mixture
ꢀ
was heated for 90 min at 150 C under microwave irradiation,
affording the ester 7b in 85% yield (Table 1, entry 3). This procedure
was then applied to the nitrile 2 to afford the requested benzoi-
soquinoline 8b with 65% yield (Table 1, entry 4). The three di-
mensional structure of compound 8b was corroborated by X-ray
11
crystallography (Fig. 3).
Scheme 1. General synthesis of novel aza-aminophenanthrenes. Reagents and con-
ꢀ
ꢀ
ditions: (i) (a) LTMP ꢁ78 C; (b) B(O-iPr)
3
ꢁ78 C; (c) pinacol rt, 18e95% (ii) Pd(PPh
3
)
4
,
Using the boronic ester 3c, the reaction led to two novel ben-
zoisoquinolines 7c and 8c (Table 1, entry 5 and 6). Unfortunately
when the boronic ester 3a was used, no traces of the expected
tricycles were found. Under these conditions 3-cyanopyridine was
isolated, resulting from the protodeboronation of 3a.
ꢀ
K
3
PO
4
, DMF, 150 C, MW, 25e85%. (iii) KOAc, PdCl
2
(dppf), bis(pinacolato)diboron,
CH Cl , 75e95%.
2
2
reactivity.9 Herein we wish to describe the optimization of the re-
Because of the instability of the ortho-cyanopyridylboronic es-
ters and in order to obtain the two benzoquinoline isomers, bearing
a nitrogen atom in position 1 and 4 (Table 1), we decided to explore
the feasibility of a reverse process. Hence we applied our one-pot
methodology to the coupling of ortho-halogenocyanopyridine 4
and the boronic esters 5 and 6 (Scheme 1). The latter were obtained
from the corresponding bromides 1 and 2 through the palladium-
catalyzed cross-coupling reaction with bis(pinacolato)diboron de-
action conditions and the synthesis of unknown aminobenzo(iso)
quinolines from these reactive substrates.
2
. Results and discussion
ortho-Cyanopyridylboronic esters are obtained using an ortho-
metalation procedure from the corresponding cyanopyridines, us-
ing triisopropylborate as an electrophile, followed by addition of
12
veloped by Miyaura. The reactions proceeded with moderate to
good yields to give four novel benzoquinoline derivatives 7a,d and
8a,d (Table 1, entry 7 to 10), whose structures were confirmed by
9
b
pinacol to afford 3aec in a one-pot procedure (Scheme 1).
Starting from 3-cyanopyridine, the lower yield observed for the
synthesis of 3b, could be explained by the lithiation in both the
11
X-ray crystallography.
Table 1
General synthesis of aza-aminophenanthrenes according to Scheme 1
Entry
EWG
2
8
1
6
NC
Y
3
4
9
7
N
5
6a
10
EWG
NH2
10a
10b
6
X
3
a-c, 4a,b
1
, 2, 5, 6
1
5
4
a
N
2
4
3
7
a-d, 8a-d
No
X
EWG
No
N position
2
Y
No
N position
4
EWG
Time (min)
Yield (%)a
/
1
1
CO
CN
2
CH
3
3a
7a
CO CH
2
CN
3
90
2
3
4
5
6
2
1
2
1
2
3a
3b
3b
3c
3c
2
3
3
4
4
8a
7b
8b
7c
8c
4
3
3
2
2
90
90
90
90
90
/
CO
CN
2
CH
3
3
CO CH
2
CN
3
3
85
65
25
77
Br
O
B
CO
CN
2
CH
O
CO CH
2
CN
7
8
9
1
5
6
5
6
CO
CN
2
CH
3
3
4b
4b
4a
4a
5
5
2
2
7d
8d
7a
8a
1
1
4
4
CO
CN
2
CH
3
3
90
90
90
90
60
67
72
67
O
B
Cl
CO
CN
2
CH
CO
CN
2
CH
0
O
a
Isolated yield.

5808
C. Rochais et al. / Tetrahedron 67 (2011) 5806e5810
70e200
mm) or on neutral alumina gel (Merck 90, 63e200 mm). IR
spectra were recorded on KBr disks with a PerkineElmer BX FTIR
1
13
apparatus. H and CNMRspectrawere recorded, respectively, at400
and 100 MHz with a Jeol Lambda 400 NMR spectrometer. Chemical
shifts d are reported inparts per millionwith the solvent resonance as
the internal standard; coupling constants J are given in hertz. Multi-
plicityisgivenasfollows:s(singlet), d(doublet), t(triplet), q(quartet),
m (multiplet). The microwave reactions were performed using
a Biotage Initiator Microwave oven using 2e5 mL sealed vials. Tem-
perature was measured with an IR-sensor and reaction times are
given as hold times. LC/MS (ESI) analyses were realized with a Waters
alliance 2695 as separating module using the following gradient: A
(
3
95%)/B (5%) to A (5%)/B(95%) in 10 min. This ratio was hold during
min before return to initial conditions in 1 min. Initial conditions
were then maintained for 5 min (A: H O, B: CH CN; each containing
2
3
HCOOH: 0.1%; Column: C18 Xterra MSC118/2.1_50mm). MSdetection
was performed with a Micromass ZMD 2000 by positive ESI. High
Resolution Mass Spectra were performed at 70 eV by electronic im-
pact (HREIMS) or positive or negative electrospray (HRESIMS).
Melting points were determined on Kofler melting point apparatus.
Fig. 3. X-ray structure of compound 8b: CCDC 822920.11
4.2. General one-pot procedure
Having assessed the feasibility of the synthesis of 4 novel ben-
4
.2.1. Methyl 5-aminobenzo[h]quinoline-6-carboxylate (7a). To
zo(iso)quinolines, we decided to explore the introduction of a nitro-
genatominthe otherring. Thus, we prepared ethyl (3-bromopyrid-4-
yl) acetate 10 by treatment of 3-bromo-4-methylpyridine 9 with
LHMDS inTHF followed by the addition of diethyl carbonate (Scheme
a solution of aryl halide 4a (48 mg, 0.35 mmol) in 2 mL dime-
thylformamide were added boronic ester 5 (106 mg, 0.385 mmol),
Pd(PPh
mixture was irradiated at 150 C for 90 min using a microwave
reactor. The reaction mixture was then diluted with EtOAc, filtrated
on a small pad of Celite, and concentrated under vacuum. The crude
mixture was then purified by column chromatography (DCM/
3
)
4
(20 mg, 5 mol %), and K
3
PO
4
(242 mg, 1.11 mmol). The
ꢀ
13
2
). Gratifyingly, when the one-pot protocol, was applied to the
coupling of 10 with ortho-cyanophenylboronic ester 11 and led to the
novel benzisoquinoline 12 in 85% yield.
CyHex 7/3) to afford 63 mg of the corresponding phenanthrene 7a
ꢀ
(
72% yield). Off-white solid; mp 90 C; IR (KBr)
n
3479, 3355 (NH
2
),
N
Br
2941, 2851 (CH), 1672 (CO), 1538, 1515, 1419, 1304, 1226, 776,
ꢁ1 1
9
7
36 cm ; H NMR (400 MHz, CDCl
J¼8.8 Hz, 1H, H10), 8.39 (d, J¼7.8 Hz, 1H, H
1H, H ), 7.43 (br s, 2H, NH
), 7.53 (dd, J¼8.0, 7.8 Hz,1H, H
), 4.04 (s, 3H, OCH
169.9 (CO), 148.0, 147.4, 140.0, 131.1(2C), 128.1, 127.4, 125.6, 123.9,
3
)
d
8.84 (m, 2H, H
), 7.61 (dd, J¼8.8, 4.9 Hz,
), 7.38 (dd,
3
); C NMR (100 MHz, CDCl )
1 3
, H ), 8.48 (d,
7
i
N
2
8
2
N
CO2C2H5
13
J¼8.8, 8.0 Hz, 1H, H
9
3
CO2C2H5
NH2
ii
NC
CO2C2H5
ii
d
NH2
13
N
Br
NC
þ
þ
N
123.2, 123.0, 122.5, 101.4, 51.6; LCMS: ES
MþH] m/z 253.0975 (calcd for C15
253.13 (M ); HRESIMS
O
N
10
O
1
2
þ
B
O
B
[
13 2 2
H N O 253.0977).
O
3c
11
4.2.2. 5-Aminobenzo[f]quinoline-6-carbonitrile (8a). Starting from
Scheme 2. General synthesis of novel aza- and diaza-10-substituted 9-
aminophenanthrenes Reagents and conditions: (i) EtO
2
CO, LHMDS, THF, rt, 63%. (ii)
the halide 4a (48 mg, 0.35 mmol) and the boronic ester 6 (94 mg,
ꢀ
Pd(PPh
3
)
, K
4 3
PO
4
, DMF, 150 C, MW, 50e83%.
0.385 mmol), following the general procedure described for 7a, 8a
ꢀ
was obtained as an off-white solid (51 mg, 67%); mp 210 C; IR (KBr)
n
3
2
462, 3350 (NH ), 2208 (CN), 1641 (CO), 1493, 1393, 1289, 1169, 791,
The reaction was then repeated with pyridylboronic ester 3c to
efficiently afford the novel phenanthroline aminoester 13 in 50%
yield (Scheme 2).
ꢁ1 1
3 1 3
744, 732 cm ; H NMR (400 MHz, CDCl ) d 8.84 (m, 2H, H , H ), 8.41
(
1
d, J¼8.8 Hz,1H, H10), 8.00 (d, J¼8.8 Hz,1H, H
7
), 7.67 (dd, J¼8.8, 4.9 Hz,
H, H
2
), 7.64 (dd, J¼8.8, 7.8 Hz,1H, H
8
), 7.48 (dd, J¼8.8, 7.8 Hz,1H, H
); C NMR (100 MHz, CDCl 149.1(C ),148.6(C
), 130.2(C6a), 129.1(C ), 127.6(C10b), 124.3(C
9
3
2
),
),
),
13
6.17 (br s, 2H, NH
2
3
)
d
5
3
. Conclusion
138.6(C4a), 131.4(C
1
8
1
24.3(C ),123.9(C
9
7
),123.1(C10a),122.7(C10),117.5(CN), 85.4(C
6
);LCMS:
þ
þ
In summary we have demonstrated that our one-pot sequence
ES 220.39; HRESIMS [MþH] m/z 220.0865 (calcd for C14
10 3
H N
11
incorporating a SuzukieMiyaura coupling followed by a Die-
ckmanneThorpe ring closure, is an efficient and fast method for the
synthesis of a large variety of novel benzoquinolines, benzoiso-
quinolines, and phenanthrolines.
2
20.0875). X-ray structure available in Supplementary data.
4
.2.3. Methyl 5-aminobenzo[f]isoquinoline-6-carboxylate
(7b). Starting from the halide 1 (80 mg, 0.35 mmol) and the bo-
ronic ester 3b (89 mg, 0.385 mmol), following the general pro-
4
4
. Experimental part
cedure described for 7a,b was obtained as an orange solid (75 mg,
ꢀ
8
5%); mp 212 C; IR (KBr)
n
3427, 3396 (NH
2
), 3002, 2947,1680 (CO),
ꢁ
1
1
.1. General
1631, 1610, 1446, 1318, 1269, 1221, 1006, 780 cm
400 MHz, CDCl 9.38 (s,1H, H
), 8.82 (d, J¼5.8 Hz, 1H, H
(d, J¼7.8 Hz,1H, H10), 8.37 (d, J¼5.8 Hz,1H, H ), 8.31 (d, J¼8.8 Hz,1H,
), 7.61 (dd, J¼8.8, 6.8 Hz, 1H, H ), 7.44 (dd, J¼7.8, 6.8 Hz, 1H, H ),
3 3
6.45 (s, 2H, NH ), 4.03 (s, 3H, OCH ); C NMR (100 MHz, CDCl )
;
H NMR
(
3
)
d
4
1
), 8.49
All commercial solvents and reagents were used as-received ex-
2
cept THF, which was distilled over Na/benzophenone under argon.
Flash chromatography was realized on silica gel (SDS AAC 60,
H
7
8
9
13
2

C. Rochais et al. / Tetrahedron 67 (2011) 5806e5810
5809
ꢁ
d
169.7 (CO), 147.5, 145.9, 145.1, 137.8, 132.5, 129.6, 125.9, 123.8,
725 cm 1; 1H NMR(400MHz, CDCl
3
)
d
9.13 (d, J¼7.8 Hz,1H, H10), 9.09
þ
1
2
23.3, 123.1, 119.5, 116.3, 105.9, 51.9; HRESIMS [MþH] m/z
(dd, J¼1.96, 3.8 Hz, 1H, H
J¼7.8 Hz, 1H, H
.8 Hz,1H, H
), 7.56 (d, J¼7.8, 6.8 Hz,1H, H
NMR (100 MHz, CDCl
124.9, 124.9, 123.3, 121.8, 117.6, 117.3, 75.0; LCMS: ES 220.10 (M );
2
); 8.21 (d, J¼8.8 Hz, 1H, H
7
), 7.99 (d,
53.0979 (calcd for C15
H
13
N
2
O
2
253.0977).
4
), 7.72 (dd, J¼8.8, 6.8 Hz, 1H, H
8
), 7.61 (dd, J¼3.8,
1
3
7
3
9
), 5.23 (br s, 2H, NH
2
);
C
4
.2.4. 5-Aminobenzo[f]isoquinoline-6-carbonitrile
(8b). Starting
3
) d 151.4,148.3,147.5,131.4,130.1,129.8, 126.2,
þ
þ
from the halide 2 (69 mg, 0.35 mmol) and the boronic ester 3b
ꢁ
ꢁ
þ
(
89 mg, 0.385 mmol), following the general procedure described for
ES 218.11 (M ); HRESIMS[MþH] m/z 220.0866 (calcd for C14
10 3
H N
ꢀ
11
7
a, 8b was obtained as a yellow solid (50 mg, 65%); mp 220 C; IR
220.0875). X-ray structure available in Supplementary data.
(
1
2
KBr) n 3421, 3327 (NH ), 3157, 2923, 2205 (CN), 1658, 1615, 1569,
445, 1188, 832, 757, 727, 621 cm ; H NMR (400 MHz, acetone-
ꢁ
1 1
4.2.9. Ethyl 6-aminobenzo[h]isoquinoline-5-carboxylate
(12). Starting from the halide 10 (85 mg, 0.35 mmol) and the bo-
ronic ester 11 (88 mg, 0.385 mmol), following the general pro-
d
H
6
): 9.74 (s, 1H, H
10), 8.62 (d, J¼5.8 Hz, 1H, H
J¼7.8, 6.8 Hz, 1H, H ), 7.52 (dd, J¼7.8, 6.8 Hz, 1H, H
); C NMR (100 MHz, DMSO-d 149.4, 148.5, 147.1, 137.2,
4
), 8.87 (d, J¼5.8 Hz, 1H, H
), 7.91 (d, J¼7.8 Hz, 1H, H
), 6.84 (br s, 2H,
1
), 8.71 (d, J¼7.8 Hz, 1H,
2
7
), 7.75 (dd,
8
9
cedure described for 7a, 12 was obtained as a colorless solid (77 mg,
13
ꢀ
NH
2
6
)
d
83%); mp 172 C; IR (KBr)
n
3361, 3203 (NH
2
), 2982, 2933,1668 (CO),
ꢁ1 1
132.9, 130.4, 129.9, 124.8, 123.1, 122.0, 121.7, 117.6, 116.5, 82.3;
1626, 1597, 1544, 1260, 1211, 1190, 1096, 763, 540 cm
(400 MHz, CDCl 9.74 (s, 1H, H
), 8.72 (d, J¼7.8 Hz, 1H, H10), 8.53
(d, J¼5.8 Hz, 1H, H ), 8.30 (d, J¼5.8 Hz, 1H, H
), 7.79 (t, J¼7.8 Hz, 1H, H
NH
), 4.53 (q, J¼6.8 Hz, 2H, OCH
NMR (100 MHz, CDCl
; H NMR
þ
HRESIMS [MþH] m/z 220.0879 (calcd for C14
H
10
N
3
220.0875).
3
)
d
1
1
1
X-ray structure available in Supplementary data.
3
4
), 7.99 (d, J¼7.8 Hz, 1H,
H
7
9
), 7.67 (t, J¼7.8 Hz, 1H, H
8
), 7.14 (br s, 2H,
1
3
4
.2.5. Methyl 5-aminobenzo[h]isoquinoline-6-carboxylate
2
2
), 1.51 (t, J¼6.8 Hz, 3H, CH
3
);
C
(7c). Starting from the halide 1 (80 mg, 0.35 mmol) and the bo-
3
)
d
169.5, 150.3, 145.9, 136.2, 131.9, 130.1,
ronic ester 3c (89 mg, 0.385 mmol), following the general procedure
described for 7a,c was obtained as a yellow solid (22 mg, 25%); mp
128.4, 127.5, 124.0, 122.7, 122.0, 120.1, 118,6, 99.1, 61.0, 14.4; LCMS:
þ
þ
ꢁ
ꢁ
þ
ES 267.19 (M ); ES 265.20 (M ); HRESIMS [MþH] m/z 267.1130
ꢀ
1
1
52 C; IR (KBr)
n
3431, 3336 (NH
2
), 3204, 3075, 2951 (CH),1706 (CO),
(calcd for C16 267.1134).
15 2 2
H N O
ꢁ
1 1
659, 1606, 1588, 1436, 1408, 1237, 1193 cm ; H NMR (400 MHz,
CDCl 10.00 (s,1H, H ), 8.63 (d, J¼8.8 Hz,
), 8.76 (d, J¼5.8 Hz,1H, H
H, H10), 8.24 (d, J¼7.8 Hz,1H, H ), 7.71 (d, J¼5.8 Hz,1H, H ), 7.57 (dd,
J¼7.8, 6.8 Hz, 1H, H ), 7.48 (d, J¼8.8, 6.8 Hz, 1H, H ), 6.16 (br s, 2H,
NH ), 4.06 (s, 3H, OCH 169.7, 147.4,
45.5, 143.1, 132.1, 132.0, 130.7, 128.1, 125.7, 124.3, 124.0, 121.9, 114.8,
3
)
d
1
3
4.2.10. Ethyl 6-amino-2,9-phenanthroline-5-carboxylate
(13). Starting from the halide 10 (85 mg, 0.35 mmol) and the bo-
ronic ester 3c (89 mg, 0.385 mmol), following the general pro-
1
7
4
8
9
13
2
3
); C NMR (100 MHz, CDCl
3
)
d
cedure described for 7a, 13 was obtained as a yellow solid (47 mg,
ꢀ
1
1
(
50%); mp 214 C; IR (KBr)
n
3462, 3420 (NH
2
), 2923, 2849, 1636
þ
þ
þ
ꢁ1
1
06.1, 52.0; LCMS: ES 253.15 (M ); HRESIMS [MþH] m/z 253.0968
(CO), 1261, 1201, 1112, 1022, 801, 623 cm
CDCl 10.12 (s, 1H, H10), 9.90 (s, 1H, H
.62 (d, J¼5.8 Hz, 1H, H
J¼4.8 Hz, 1H, H ), 7.00 (br s, 2H, NH
1.52 (t, J¼6.8 Hz, 3H, CH
; H NMR (400 MHz,
calcd for C15 253.0977).
H
13
N
2
O
2
3
)
d
1
), 8.86 (d, J¼4.8 Hz, 1H, H
8
),
8
3
), 8.32 (d, J¼5.8 Hz, 1H, H
4
), 7.75 (d,
4.2.6. 5-Aminobenzo[h]isoquinoline-6-carbonitrile
(8c). Starting
7
2
), 4.56 (q, J¼6.8 Hz, 2H, OCH
2
),
13
fromthehalide2(69mg, 0.35mmol)andtheboronicester3c(89mg,
3
3
); C NMR (100 MHz, CDCl ) d 168.8 (CO),
0
.385 mmol), following the general procedure described for 7a, 8c
148.0, 146.9, 146.8, 146.6, 145.3, 136.1, 128.8, 125.9, 118.8, 114.7,
ꢀ
þ
þ
þ
was obtained as a yellow solid (59 mg, 77%); mp >260 C; IR (KBr)
n
103.7, 101.7, 61.5, 14.4; LCMS: ES 268.42 (M ); HRESIMS [MþH]
3
7
418, 3355 (NH
2
), 3225, 2924 (CH), 2205 (CN),1665,1580,1466,1117,
54 cm ; H NMR (400 MHz, acetone-d 10.13 (s,1H, H ), 8.85 (d,
), 8.25 (d, J¼5.8Hz,1H, H ),
), 7.71 (dd, J¼7.8, 6.8 Hz,1H, H ), 7.55 (d, J¼8.8,
); C NMR (100 MHz, acetone-d
148.5, 147.0, 132.7, 132.6, 130.0, 129.5, 129.3, 127.1, 125.6, 124.2,
m/z 268.1082 (calcd for C15 268.1086).
14 3 2
H N O
ꢁ
1 1
6
)
d
1
J¼8.8Hz,1H, H10);8.82 (d, J¼5.8 Hz,1H, H
3
4
4.3. Boronic ester synthesis
7
5
.93 (d, J¼7.8 Hz,1H, H
8
8
13
.8 Hz, 1H, H
9
), 6.74 (br s, 2H, NH
2
6
)
4.3.1. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
(3b). In a dry 500 mL flask under N 2,2,6,6-tetramethylpiperidine
d
2
þ
þ
ꢁ
ꢁ
123.5, 117.4, 116.4, 99.1; LCMS: ES 220.12 (M ); ES 218.09 (M );
(57.6 mmol) was dissolved in dry THF (200 mL) and the mixture
þ
ꢀ
HRESIMS [MþH] m/z 220.0862(calcd for C14
H N
10 3
220.0875). X-ray
was cooled to ꢁ10 C before n-BuLi (57.6 mmol, 2.5 M in n-hexane)
11
structure available in Supplementary data.
was added over 2 min. The mixture was stirred for 10 min before
ꢀ
ꢀ
cooling to ꢁ78 C. At ꢁ78 C, B(O-i-Pr)
3
(65.3 mmol) was added
ꢀ
4
.2.7. Methyl 5-aminobenzo[h]quinoline-6-carboxylate
over 2 min and stirred for 5 min at ꢁ78 C before 3-cyanopyridine
(48 mmol) dissolved in dry THF (50 mL) was added dropwise over
5 min. The reaction was left in the dry ice bath, allowed to reach
room temperature overnight and quenched with glacial acetic acid
(67.2 mmol) followed by addition of pinacol (72 mmol). The mix-
ture was stirred for 2 h at room temperature and then transferred to
(7d). Starting from the halide 4b (48 mg, 0.35 mmol) and the bo-
ronic ester 5 (106 mg, 0.385 mmol), following the general pro-
cedure described for 7a, 7d was obtained as a yellow solid (53 mg,
ꢀ
6
(
0%); mp 144 C; IR (KBr)
n
3477, 3403 (NH
2
), 2947, 2924, 2850
ꢁ
1
1
CH), 1679 (CO), 1610, 1434, 1305, 1241, 1233, 787, 727 cm
; H
NMR (400 MHz, CDCl
3
)
d
9.17 (d, J¼6.8 Hz,1H, H10), 9.02 (dd, J¼1.96,
); 8.30 (d, J¼8.8 Hz, 1H, H ), 8.24 (dd, J¼1.96, 6.8 Hz,
), 7.59 (dd, J¼8.8, 6.8 Hz, 1H, H ), 7.51 (dd, J¼5.8, 8.8 Hz, 1H,
), 7.46 (dd, J¼6.8 Hz, 1H, H ), 6.32 (br s, 2H, NH ), 4.04 (s, 3H,
); C NMR (100 MHz, CDCl 170.0, 150.7, 148.4, 145.1, 132.1,
30.0, 129.0, 126.6, 125.0, 124.5, 123.7, 121.5, 119.0, 103.0, 51.8;
a separating funnel with CH
KH PO
(10 w/v %) (4ꢂ60 mL). The combined aqueous layers was
back-extracted once with CH Cl (15 mL), the combined organic
phase was dried over MgSO , and the solvents were evaporated to
2 2
Cl (75 mL) and washed with aqueous
5
1
.8 Hz, 1H, H
H, H
2
7
2
4
4
8
2
2
H
OCH
3
9
2
4
13
3
3
)
d
give cyanopyridineboronic ester 3b as a yellow solid with 18% yield;
ꢀ
1
mp 88 C; IR (KBr)
n
3097, 2968, 2930, 2238 (CN), 1618, 1522, 1476,
þ
þ
ꢁ
ꢁ
þ
LCMS: ES 253.12 (M ); ES 251.15 (M ); HRESIMS [MþH] m/z
1464, 1421, 1385, 1373, 1337, 1201, 1113, 1046, 963, 882, 849, 778,
ꢁ
1 1
2
53.0965 (calcd for C15
H
13
N
2
O
2
253.0977).
765, 714, 655, 578 cm ; H NMR (400 MHz, CDCl
3
)
d
8.86 (s, 1H,
), 7.70 (d, J¼4.6 Hz, 1H, H ), 1.34 (s,
153.3, 152.1, 129.3, 117.1, 114.2,
H
2
), 8.74 (d, J¼4.6 Hz, 1H, H
6
5
13
4.2.8. 5-Aminobenzo[h]quinoline-6-carbonitrile (8d). Starting from
12H); C NMR (100 MHz, CDCl
85.8, 83.1, 25.0.
3
) d
the halide 4b (48 mg, 0.35 mmol) and the boronic ester 6 (94 mg,
0
.385 mmol), following the general procedure described for 7a, 8d
ꢀ
was obtained as an off-white solid (51 mg, 67%);mp 190 C; IR (KBr)
n
4.3.2. 2-(4,4,5,5-Tetramethyl-[1,2]-dioxoborolan-2-yl)benzonitrile
3
443, 3321 (NH
2
), 3214, 2198 (CN), 1650, 1597, 1491, 1406, 756,
(11). Compound 11 was obtained according to the same procedure

5810
C. Rochais et al. / Tetrahedron 67 (2011) 5806e5810
1
starting from benzonitrile, as a colorless solid with 50% yield. H
References and notes
NMR (400 MHz, CDCl
J¼8.8 Hz, 1H, H ), 7.51e7.60(m, 2H, H
analyses are consistent with the previously described product.
3
)
d
7.89(dd, J¼6.8, 2.0 Hz, 1H, H
6
), 7.70(d,
1
. (a) Haghighi, M. G.; Rashidi, M.; Nabavizadeh, S. M.; Jamali, S.; Puddephatt, R. J.
3
4
, H ), 1.39(s, 12H). Other
5
DaltonTrans. 2010, 39,11396e11402; (b) Baratta, W.; Fanfoni, L.; Magnolia, S.; Siega,
K.; Rigo, P. Eur. J. Inorg. Chem. 2010, 1419e1423; (c) Baratta, W.; Ballico, M.; Baldino,
S.; Chelucci, G.; Herdtweck, E.; Siega, K.; Magnolia, S.; Rigo, P. Chem.dEur. J. 2008,
14
9
148e9160; (d) Prema, D.; Wiznycia,A. V.; Scott, B. M.; Hilborn, J.;Desper, J.; Levy, C.
4
.3.3. Methyl [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]
acetate (5). To a solution of methyl 2-(2-bromophenyl)acetate
300 mg, 1.31 mmol) in 4.3 mL of dioxane were successively added
J. Dalton Trans. 2007, 4788e4796.
2
. (a) Atatreh, N.; Stojkoski, C.; Smith, P.; Booker, G. W.; Dive, C.; Frenkel, A. D.;
Freeman, S.; Bryce, R. A. Bioorg. Med. Chem. Lett. 2008, 18, 1217e1222; (b)
Cappelli, A.; Giuliani, G.; Gallelli, A.; Valenti, S.; Anzini, M.; Mennuni, L.; Ma-
kovec, F.; Cupello, A.; Vomero, S. Bioorg. Med. Chem. 2005, 13, 3455e3460; (c)
Murthy, M.; Pedemonte, N.; MacVinish, L.; Malietta, L.; Cuthbert, A. Eur. J.
Pharmacol. 2005, 516, 118e124; (d) Szkotak, A. J.; Murthy, M.; MacVinish, L. J.;
Duszyk, M.; Cuthbert, A. W. Br. J. Pharmacol. 2004, 142, 531e542; (e) Kerry, M.
A.; Boyd, G. W.; Mackay, S. P.; Meth-Cohn, O.; Platt, L. J. Chem. Soc., Perkin Trans.
(
at room temperature bis(pinacoloto)diboron (382 mg, 1.5 mmol)
and potassium acetate (553 mg, 5.63 mmol) The reaction mixture
was the then flushed twice with argon and PdCl
2
(dppf) (76 mg,
0
.1 mmol) was then added. The reaction mixture was heated for 3 h
under reflux before cooling and diluting with Et
2
O. The organic
1
1999, 2315e2321; (f) Cappelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.; Ma-
phase was washed with H
2
O and brine and dried (MgSO
4
). The
Cl
CyHex 6/4) to afford 5 as colorless oil (345 mg, 95%). H NMR
400 MHz, CDCl
kovec, F.; Doucet, E.; Hamon, M.; Bruni, G.; Romeo, M. R.; Menziani, M. C.; De
Benedetti, P. G.; Langer, T. J. Med. Chem. 1998, 41, 728e741.
3. (a) Tsai, A. S.;Tauchert, M. E.;Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011,133,
1
M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009,131,11310e11311; (c) Yu, W. Y.;
Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2008,130, 3304e3306;
crude product was purified by silica gel chromatography (CH
2
2
/
1
248e1250; (b) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.;Sato,
(
1
3
3
)
d
7.83 (d, J¼5.8 Hz, 1H, H
), 7.26 (dd, J¼7.8, 6.9 Hz, 1H, H ), 7.18 (d, J¼6.9 Hz, 1H, H
.98 (s, 2H, CH ), 3.66 (s, 3H, OCH ), 1.31 (s, 12H). Other analyses are
3
), 7.38 (dd, J¼7.8, 5.8 Hz,
H, H
4
5
6
),
(d) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300e2301.
2
3
4
. (a) Aramoto, H.; Obora, Y.; Ishii, Y. J. Org. Chem. 2009, 74, 628e633; (b) Wang,
X.-S.; Li, Q.; Yao, C.-S.; Tu, S.-J. Eur. J. Org. Chem. 2008, 3513e3515; (c) Kozlov, N.
G.; Gusak, K. N. Russ. J. Org. Chem. 2008, 44, 1049e1053; (d) Hewlins, M. J. E.;
Salter, R. Synthesis 2007, 2157e2163; (e) Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.;
Crew, A. P.; Dong, H.-Q.; Jin, M.; Ma, L.; Panicker, B.; Siu, K. W.; Steinig, A. G.;
Stolz, K. M.; Tavares, P. A. R.; Volk, B.; Weng, Q.; Werner, D.; Mulvihill, M. J. Org.
Biomol. Chem. 2007, 5, 61e64; (f) Alajarin, M.; Vidal, A.; Ortin, M.-M. Tetrahe-
dron 2005, 61, 7613e7621; (g) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2004,
15
consistent with the previously described product.
4.3.4. 2-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ace-
tonitrile (6). Compound 6 was obtained according to the same
procedure and starting from 2 (300 mg, 1.53 mmol) as colorless oil
1
(
279 mg, 75%); H NMR (400 MHz, CDCl
3
)
d
7.88 (d, J¼6.8 Hz, 1H),
6
, 353e355; (h) Mahata, P. K.; Venkatesh, C.; Kumar, U. K. S.; Ila, H.; Junjappa, H.
J. Org. Chem. 2003, 68, 3966e3975.
5. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol. Chem. 2003, 1,
7.46 (m, 2H), 7.33 (m, 1H), 4.11 (s, 2H), 1.37 (s, 12H). Other analyses
16
are consistent with the previously described product.
4
047e4057; (b) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron Lett.
2001, 42, 9061e9064.
6
. (a) Abbott, B. M.; Ferrari, F. D.; Harnor, S. J.; Barnes, J. C.; Marquez, R. Tetrahedron
008, 64, 5072e5078; (b) Hewlins, M. J. E.; Salter, R. Synthesis 2007, 2164e2174;
c) Lewis, F. D.; Algutkar, R. S.; Yang, J.-S. J. Am. Chem. Soc. 2001, 123, 3878e3884.
7. (a) Basle, O.; Bidange, J.; Shuai, Q.; Li, C. L. Adv. Synth. Catal. 2010, 352,
145e1149; (b) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J. N. J. Org. Chem.
008, 73, 495e501; (c) Mamane, V.; Lou e€ rat, F.; Iehl, J.; Abboud, M.; Fort, Y.
4
.4. Ethyl 2-(3-bromopyridin-4-yl)acetate (10)
2
(
ꢀ
LiHMDS (1 M in THF, 10 mL, 10.1 mmol) was added at 0 C to
a solution of pyridine derivative (1.16 g, 6.8 mmol) and Et CO
1.03 mL, 8.51 mmol) in THF (20 mL). After 5 h LiHMDS (5 mL,
1
2
2
3
(
Tetrahedron 2008, 64, 10699e10705.
ꢀ
5
mmol) was added at 20 C. The solution was then stirred for 2 h
Cl was added. The aqueous layer
O and the combined organic layers were
washed with brine and dried over MgSO . Evaporation of the sol-
8. (a) Rochais, C.; Yougnia, R.; Dallemagne, P.; Rault, S. Tetrahedron Lett. 2009, 50,
5704e5708; (b) Yougnia, R.; Rochais, C.; Dallemagne, P.; Rault, S. Tetrahedron
and a saturated solution of NH
was washed with Et
4
2010, 66, 2803e2808.
2
9
. (a) Cailly, T.; Fabis, F.; Lemaître, S.; Bouillon, A.; Sopkov aꢀ , J.; Rault, S. Synlett 2006,
53e56; (b) Cailly, T.; Lemaître, S.; Fabis, F.; Rault, S. Synthesis 2007, 3247e3251.
4
10. Fuller, A. A.; Hester, H. R.; Salo, E. V.; Stevens, E. P. Tetrahedron Lett. 2003, 44,
vent and flash chromatography (cyclohexane/EtOAc: 3/1) afforded
the title compound as a yellow oil (1.03 g, 62% yield). H NMR
1
2935e2938.
1
1. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 822921 for 8a, CCDC 822920 for 8b, CCDC
(
(
400 MHz, CDCl
3
)
d
8.71 (s, 1H, H
2
), 8.47 (d, J¼4.9 Hz, 1H, H
6
), 7.26
d, J¼4.9 Hz, 1H, H ), 4.19 (q, J¼7.1 Hz, 2H), 3.78 (s, 2H), 1.27 (t,
5
822919 for 8c, and CCDC 822922 for 8d. Copies of the data can be obtained, free
J¼7.1 Hz, 3H). Other analyses are consistent with the previously
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk. X-ray structures and
summary are available in Supplementary data.
described product.1
3c
1
1
2. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508e7510.
3. (a) Hansen, J. F.; Kamata, K.; Meyers, A. I. J. Heterocycl. Chem. 1973, 10, 711e714;
b) Bremner, D. H.; Dunn, A. D.; Wilson, K. A.; Sturrock, K. R.; Wishart, G.
Supplementary data
(
Synthesis 1997, 949e952; (c) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.;
Peglion, J. L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 30, 15157e15166.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.05.116. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
1
4. Dubost, E.; Magnelli, R.; Cailly, T.; Legay, R.; Fabis, F.; Rault, S. Tetrahedron 2010,
6, 5008e5016.
5. Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227e4230.
16. Baudoin, O.; Guenard, D.; Gu eꢀ ritte, F. J. Org. Chem. 2000, 65, 9268e9271.
6
1