Synthesis of pyridoacridines through anionic cascade ring closure

Article abstract of DOI:10.1055/s-0033-1338609

A new synthesis of 13-deazaascididemin (AK-37) based on a recently developed anionic cascade ring closure is presented. Although the isolated yields are modest, the approach provides ready access to new substituted derivatives of 13-deazaascididemin. Geor

Full text of DOI:10.1055/s-0033-1338609

PAPER
▌1469
paper
Synthesis of Pyridoacridines through Anionic Cascade Ring Closure
Anionic Cascade Ring Closure towards Pyridoacridines
Ida Nymann Petersen, Jesper Langgaard Kristensen*
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2,
2100 Copenhagen, Denmark
Fax +4535336040; E-mail: jesper.kristensen@sund.ku.dk
Received: 28.01.2014; Accepted after revision: 21.02.2014
utilizing a range of methods, but derivatives with substit-
Abstract: A new synthesis of 13-deazaascididemin (AK-37) based
uents on the A-ring have, to the best of our knowledge, not
on a recently developed anionic cascade ring closure is presented.
yet been accessed.6
Although the isolated yields are modest, the approach provides
ready access to new substituted derivatives of 13-deazaascididemin.
We recently reported a new convergent approach to the
Key words: fused ring systems, natural products, cross coupling, synthesis of ascididemin (1) based on an anionic cascade
ring closure;7 herein, we detail our efforts to extend this
anionic cascade ring closure, oxidation
method to the synthesis of AK-37 and novel derivatives
thereof.
Ascididemin 1 belongs to the family of pyridoacridine
The key substrate 4 required for the anionic ring closure
natural products, which is a group of marine alkaloids iso-
in our synthesis of AK-37 was accessed in 87% yield
lated from corals, tunicates, sponges, and marine inverte-
through a Suzuki cross-coupling reaction between 2-chlo-
ro-4-(2-fluorophenyl) nicotinonitrile (5; available in 81%
brates.1 Ascididemin was first isolated in 1988 by
Kobayashi and co-workers from Okinawan tunicates.2
Many of these pyridoacridines exhibit significant cytotox-
ic activities both in vitro and in vivo against several tumor
cell lines,3 and considerable synthetic effort has been put
into developing robust and convergent routes towards this
class of molecules.4
over three steps from 2′-fluoroacetophenone7a) and o-tol-
ylboronic acid. Initially, we investigated the conditions
used in the synthesis of ascididemin (1) from 3, which in-
volved heating at 95 °C with NaH (10 equiv) in N,N-di-
methylformamide (DMF) for 30 minutes followed by
oxidation of the methylene unit at room temperature by
simply passing a stream of O2 gas through the solution for
three hours, which provided ascididemin (1) in 69% yield
from 3.7a When this protocol was applied to 4, unchanged
starting material was obtained, presumably due to the
lower acidity of the benzylic protons in 4 compared to 3.
Therefore, we gradually raised the temperature to facili-
tate deprotonation, but the instability of DMF towards
NaH at elevated temperature quickly became an issue, as
reactions heated to over 100 °C resulted in extensive de-
composition of the solvent. Thus, similar to the method
development used for the synthesis of ascididemin,7a dif-
ferent conditions with bases such as lithium diisopropyl-
amide (LDA) and lithium 2,2,6,6-tetramethylpiperidide
(LTMP) were also screened, but this only resulted in the
recovery of unchanged starting material. NaHMDS also
reacted with DMF at elevated temperatures.
One of the synthetic derivatives of ascididemin, 13-
deazaascididemin 2 (also known as AK-37), differs from
the natural product by the substitution of a nitrogen with a
CH group in the A-ring (Figure 1).5
N
X
N
X
F
N
A
O
N
N
N
A
A
X
ascididemin (1) X = N
AK-37 (2) X = CH
3 X = N
4 X = CH
Figure 1 Structure of Ascididemin (1) and AK-37 (2) and retrosyn-
thetic analysis based on an anionic cascade ring closure from precur-
sors 3 and 4, respectively
Because NaH was the only base that seemed to initiate the
cascade, other solvents were screened with this base at
145 °C (Table 1, entries 1–5). N,N′-Dimethylpropylene
urea (DMPU) appeared to work well for the ring closure,
being stable at higher temperatures, but the subsequent
room temperature oxidation with O2 was inefficient.
Both ascididemin and AK-37 interact with topoisomeras-
es, which are enzymes involved in the uncoiling of DNA
strands prior to replication. However, AK-37 does not in-
duce the formation of harmful reactive oxygen species as
is the case with ascididemin.5 Thus, analogues of AK-37
substituted in the A-ring would be useful for further bio-
logical characterization to potentially develop new anti-
cancer agents. AK-37 has previously been prepared by
Different oxidants were screened (Table 1, entries 5 and
6) but all failed to deliver 2. Attempts to isolate and fully
characterize the presumed deoxy intermediate (see
Scheme 1) were also unsuccessful, although it could be
detected by LC-MS analysis of the crude mixture.
SYNTHESIS 2014, 46, 1469–1474
Advanced online publication: 21.03.2014
To mimic the original conditions, DMF was added after
the ring closure but before oxygen was bubbled through
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338609; Art ID: SS-2014-T0653-OP
© Georg Thieme Verlag Stuttgart · New York

1470
I. N. Petersen, J. L. Kristensen
PAPER
Table 1 Solvent Screening for Ring-Closure/Oxidationa
appropriately substituted o-tolylboronic acids and 5. Ring
closure and oxidation of 6 and 7 was more efficient and
provided 9 and 10 in 29 and 23% yield, respectively. Pre-
cursor 8, bearing a cyano group on the A-ring, gave a
complex mixture of products containing only trace
amounts of the desired product (Scheme 1).
Entry Solvent
Base
NaH
Oxidation
Isolated yield
(%)
1
2
3
4
5
6
7
8
THF
O2
O2
O2
O2
no conversion
no conversion
NMP not stable
trace
THF–DMF NaH
To investigate whether the anionic cascade could be ap-
plied to five-membered heterocycles, we targeted the pre-
viously reported thiophene derivate 1310 (Scheme 2),
which Bracher10b recently fully characterized. The re-
quired precursor 12 was accessed through Negishi cross-
coupling between chloropyridine 5 and commercially
available 2-bromozinc-3-methylthiophene. Cross-coupling
using PEPPSI-iPr as catalyst gave intermediate 12 in 88%
yield. Subsequent ring closure followed by oxidation gave
the desired thiophene derivative 13 in 15% yield.
NMP
NaH
NaH
NaH
NaH
NaH
NaH
DMPU
DMPU
DMPU
DMPU
DMPU
I2, TBHP, pyrdine trace
AcOH, CuI, O2
O2, PhF
trace
3
O2, DMF
12
a All reactions performed at 145 °C in a sealed vessel.
N
the mixture, and this modification gave the desired prod-
uct in 12% yield (Scheme 1, and Table 1, entry 8). The use
of PhF was also investigated a cosolvent for the oxidation
(entry 7), because fluorocarbon solvents are known to dis-
solve oxygen,8 but was this much less efficient than DMF.
We speculate that DMF is involved in the formation of
radicals, which initiate the oxidation of the methylene
bridge, because NaH has previously been shown to trigger
the formation of DMF radicals.9 Although the isolated
yield was modest, the highly convergent nature of the ap-
proach prompted us to investigate whether the protocol
could be extended to other derivatives of AK-37 incorpo-
rating substituents in the A-ring.
F
N
O
a
b, c
ZnBr
88%
15%
S
N
N
S
S
12
13
Scheme 2 Synthesis of thiophene-containing pentacyclic system.
Reagents and conditions: (a) PEPPSI-iPr, THF; (b) NaH, DMPU;
(c) DMF, O2.
The precursor 14 for an isomeric thiophene derivative 15
was prepared via an ate-complex11 derived from 3-bromo-
4-methylthiophene, see Scheme 3. Unfortunately, the
ring-closure/oxidation procedure gave only a mixture of
unidentified products and we were not able to detect the
pentacyclic derivative 15.
OH
B
F
F
N
ref. 7a
81%
a
HO
O
N
F
R
N
Cl
N
Br
b
O
a
5
S
45%
N
N
S
S
14
15
F
N
N
N
O
Scheme 3 Synthesis of 14 and unsuccessful ring closure. Reagents
and conditions: (a) (i) n-BuLi, i-PrMgCl, THF; (ii) ZnCl2; (iii) 5,
PEPPSI-iPr; (b) (i) NaH, DMF, MW 95 °C; (ii) O2, DMF.
c
b
N
N
N
R
R
R
Despite the mixed success with the thiophene derivatives,
we embarked on the synthesis of Kuanoniamine A, which
is another prominent member of the pyridoacridines in
which the A-ring is a thiazole (Scheme 4).12 In the crucial
ring closure the 2-position on the thiazole ring would have
to be protected because this position is relatively acidic.13
Thus, TIPS-protected precursor 18 was targeted as the
crucial intermediate, as this protection group should be
stable under the conditions used for both the cross-
coupling and the ring closure; it should also be readily re-
moved at the end.
yield
yield
4 R = H
2 R = H
87%
66%
65%
64%
12%
29%
23%
6 R = OMe
7 R = F
9 R = OMe
10 R = F
8 R = CN
11 R = CN
trace
Scheme 1 Synthesis and ring-closure/oxidation of precursors. Re-
agents and conditions: (a) Pd(PPh3)4, K3PO4, i-PrOH, 1,4-dioxane;
(b) NaH, DMPU; (c) O2, DMF.
Precursors 6, 7 and 8 substituted with OMe, F and CN
groups, respectively, on the A-ring, were accessed in a
similar manner to 4 in 64–66% yield through coupling of
Synthesis 2014, 46, 1469–1474
© Georg Thieme Verlag Stuttgart · New York

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Anionic Cascade Ring Closure towards Pyridoacridines
1471
were performed by employing magnetic stirring and a fixed hold-
time using variable power to reach (during 1–2 min) and then main-
tain the desired temperature in the vessel for the programmed time-
period. The temperature was monitored by an IR sensor focused on
a point on the reactor vial glass. The IR sensor was calibrated to in-
Br
Br
a
b
c
S
N
S
S
N
N
75%
74%
45%
NH2
Br
TIPS
ternal solution reaction temperature by the manufacturer. 1H and 13
C
16
17
NMR spectra were recorded with a Bruker Avance 400 or 600 MHz
instrument, using CDCl3 as solvent and with the residual solvent as
the internal reference. Coupling constants (J) are given in hertz
(Hz). Multiplicities of 1H NMR signals are reported as follows: s,
singlet; d, doublet; dd, doublet of doublets; m, multiplet; br, broad
signal. Melting points were measured with an MPA100 Optimelt
melting-point apparatus and are uncorrected. PEPPSI-iPr catalyst
{[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyri-
dyl)palladium(II) dichloride} was obtained from Aldrich. 2-Bro-
mozinc-3-methylthiophene was obtained from Sigma-Aldrich.
F
N
N
O
N
N
S
S
N
N
TIPS
18
kuanoniamine A
Scheme 4 Unsuccessful attempts at the synthesis of kuano-
niamine A. Reagents and conditions: (a) (i) NaNO2, HNO3, H3PO4;
(ii) CuBr, HBr; (b) (i) n-BuLi; (ii) TIPSCl, THF; (c) (i) n-BuLi,
i-PrMgCl, THF; (ii) ZnCl2; (iii) 5, PEPPSI-iPr, MW 110 °C.
Method A: Suzuki Cross-Coupling
In a MW vial were successively added K3PO4 (531 mg, 2.5 mmol,
2.5 equiv), 5 (233 mg, 1.0 mmol, 1 equiv), the appropriately substi-
tuted o-tolylboronic acid (1.2 mmol, 1.2 equiv), Pd(PPh3)4 (58 mg,
5 mol%) and a mixture of 1,4-dioxane–i-PrOH (9:1, 5 mL). The
MW vial was purged with N2 for 5 min then heated at 140 °C for 3 h
under MW conditions. The resulting mixture was filtered through a
pad of Celite and the pad was washed several times with EtOAc.
The filtrate was concentrated in vacuo. The crude material was pu-
rified by column chromatography on silica gel (EtOAc–n-heptane,
1:3) to give the desired product.
2,4-Dibromo-5-methylthiazole 1614 was first accessed
from 2-amino-5-methylthiazole. Subsequent regioselec-
tive Br–Li exchange15 followed by reaction with TIPSCl
provided 4-bromo-2-triisopropylsilyl-5-methylthiazole
17 in 74% yield. Bromine–magnesium exchange followed
by zinc-mediated cross coupling provided the desired pre-
cursor 18 in 45% yield. Despite numerous attempts to pro-
mote the ring-closure/oxidation sequence, we were not
able to identify conditions that promoted the desired con-
version of 18 into Kuanoniamine A. Different bases were
combined with different solvents and oxidants, but at no
point where we able to isolate kuanoniamine A from the
reaction mixture.
Method B: Ring Closure and Oxidation
NaH (60% in mineral oil, 10 equiv) was added to a MW vial and
washed twice with pentane before the precursor dissolved in DMPU
(0.1 M) was added. The reaction was heated under MW conditions
at the indicated temperature for 30 min, then DMF was added in the
same volume as DMPU. The reaction was bubbled with O2 for 30
min and then stirred under an O2 atmosphere for 16 h. The mixture
was poured into sat. aq NH4Cl, extracted with EtOAc, and purified
on activated neutral alumina chromatography (EtOAc).
In summary, a short synthetic strategy for the preparation
of pentacyclic ring systems through an anionic cascade
ring closure has been developed. Using a common inter-
mediate, this convergent strategy allows rapid construc-
tion of novel substituted derivatives of 13-
deazaascididemin (AK-37) in modest yields. A previously
reported heterocyclic analogue of Kuanoniamine A,
wherein the A-ring is transformed into a thiophene, was
also accessed.
Method C: Negishi Cross-Coupling
To a solution of i-PrMgCl (2.0 M in THF, 1 equiv) was added a so-
lution of n-BuLi (1.5 M in hexanes, 0.5 equiv) at –10 °C under N2.
The mixture was stirred at this temperature for 10 min prior to the
addition of a solution of the halogenated compound (1 equiv) in an-
hydrous THF (1 mL). After 30 min, a solution of ZnCl2 (1 M in
THF, 1.05 equiv) was added over 1 min and the reaction mixture
was allowed to warm to r.t. over 40 min then transferred via cannula
to a sealed MW vial containing 5 (0.70 equiv) and PEPPSI-iPr (2
mol%) under N2. The vial was heated at 110 °C for 45 min under
MW conditions, then the resulting mixture was filtered through a
pad of Celite and the pad was washed several times with EtOAc.
The filtrate was concentrated in vacuo and the crude material was
purified by column chromatography to afford the corresponding
pure cross-coupled product.
Starting materials and reagents were obtained from commercial
suppliers and used without further purification. Compound 5 was
prepared as previously described.7a Solvents were either analytical-
or HPLC-grade and were used as received. Anhydrous DMF and
THF for anhydrous reactions were obtained from a Pure Process
Technology Contour solvent purification system (SPS). n-BuLi was
titrated by following the procedure described by Burchat and co-
workers.16 Yields refer to isolated compounds and were estimated
to be >95% pure as determined by 1H NMR and LC-MS analyses,
unless otherwise stated. Thin-layer chromatography (TLC) was car-
ried out on silica gel 60 F254 plates from Merck (Germany). Visual-
ization was accomplished by irradiation with a UV lamp (254 nm).
Column chromatography was performed on chromatography grade
silica 60 Å particle size 15–40 micron (Fisher Scientific) using the
solvent system stated; when otherwise noted activated neutral alu-
mina (ca. 150 mesh) from Aldrich was used.
4-(2-Fluorophenyl)-2-o-tolylnicotinonitrile (4)
Obtained by using method A with o-tolylboronic acid as coupling
partner.
Yield: 250 mg (87%); pale gum; Rf = 0.34 (EtOAc–n-heptane, 1:3).
IR (ATR): 2924, 2229, 1571, 1455, 1221, 844, 755, 726 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.87 (d, J = 5.1 Hz, 1 H), 7.55–
7.26 (m, 9 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.1, 159.3 (JC–F = 249.6 Hz),
151.8, 148.4, 137.7, 136.3, 132.4 (JC–F = 8.3 Hz), 131.01 (JC–F
=
2.3 Hz), 130.98, 129.9, 129.5, 126.2, 125.0 (JC–F = 3.7 Hz), 124.1
(JC–F = 14.3 Hz), 123.4 (JC–F = 1.7 Hz), 116.7 (JC–F = 21.5 Hz),
116.2, 110.2, 20.1.
Microwave-assisted synthesis was carried out in a Biotage Initiator
apparatus operating in single mode; the microwave cavity produc-
ing controlled irradiation at 2.45 GHz (Biotage AB, Uppsala, Swe-
den). The reactions were run in sealed vessels. These experiments
© Georg Thieme Verlag Stuttgart · New York
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1472
I. N. Petersen, J. L. Kristensen
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HRMS (ES, +): m/z [M + H]+ calcd for C19H13FN2: 289.1136;
found: 289.1141.
13C NMR (100 MHz, CDCl3): δ = 182.2, 150.6, 148.8, 146.9, 145.9,
137.9, 136.1, 134.9, 133.1, 132.5, 131.6, 131.2, 130.3, 128.7, 125.8,
123.5, 122.9, 117.1, 115.5.
4-(2-Fluorophenyl)-2-(4-methoxy-2-methylphenyl)nicotinoni-
trile (6)
11-Methoxy-9H-benzo[b]pyrido[4,3,2-mn]acridin-9-one (9)
Obtained by using method B. 4-(2-Fluorophenyl)-2-o-tolylnicoti-
nonitrile 6 (124 mg, 0.39 mmol) was heated to 145 °C to give 9.
Obtained by using method A with 4-methoxy-o-tolylboronic acid as
coupling partner.
Yield: 210 mg (66%); pale gum; Rf = 0.31 (EtOAc–n-heptane, 1:3).
Yield: 35 mg (29%); yellow-orange flakes; mp 305–307 °C;
IR (ATR): 2227, 1607, 1387, 1573, 1243, 759, 729 cm–1.
Rf = 0.65 (CH2Cl2–EtOAc, 1:1).
IR (ATR): 1677, 1597, 1418, 1273, 1026, 841, 771, 751 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.9 (d, J = 5.1 Hz, 1 H), 7.55–7.48
(m, 2 H), 7.42–7.25 (m, 4 H), 6.88–6.86 (m, 2 H), 3.86 (s, 3 H),
2.34 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 9.02 (d, J = 5.7 Hz, 1 H), 8.80 (d,
J = 8.8 Hz, 1 H), 8.63 (m, 2 H), 8.34 (d, J = 5.8 Hz, 1 H), 7.98 (m,
1 H), 7.93 (d, J = 2.76 Hz, 1 H), 7.90 (m, 1 H), 7.38 (dd, J = 8.8,
2.8 Hz, 1 H), 4.03 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 182.1, 162.2, 150.7, 148.9, 147.0,
145.9, 137.7, 133.9, 133.0, 131.4, 130.2, 129.4, 127.7, 123.6, 122.9,
122.8, 116.3, 114.5, 110.8, 55.9.
13C NMR (100 MHz, CDCl3): δ = 163.8, 160.5, 158.0 (JC–F
=
250.5 Hz), 151.4, 148.4, 138.0, 132.0 (JC–F = 8.4 Hz), 130.9, 130.7
(JC–F = 2.2 Hz), 130.1, 124.6 (JC–F = 3.7 Hz), 124.1 (JC–F = 14.7 Hz),
122.8 (JC–F = 1.8 Hz), 116.4 (JC–F = 21.6 Hz), 116.2, 116.1, 111.3,
110.1, 55.2, 20.0.
HRMS (ES, +): m/z [M + H]+ calcd for C20H15FN2O: 319.1241;
found: 319.1246.
HRMS (ES, +): m/z [M + H]+ calcd for C20H12N2O2: 313.0972;
found: 313.0972.
2-(4-Fluoro-2-methylphenyl)-4-(2-fluorophenyl)nicotinonitrile
11-Fluoro-9H-benzo[b]pyrido[4,3,2-mn]acridin-9-one (10)
Obtained by using method B. 4-(2-Fluorophenyl)-2-o-tolylnicoti-
nonitrile 7 (163 mg, 0.53 mmol) was heated to 125 °C, and purified
by chromatography using silica gel.
(7)
Obtained by using method A with 4-fluoro-o-tolylboronic acid as
coupling partner.
Yield: 197 mg (65%); pale gum; Rf = 0.34 (EtOAc–n-heptane, 1:3).
IR (ATR): 2229, 1572, 1496, 1231, 908, 759, 728 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.92 (d, J = 5.1 Hz, 1 H), 7.56–7.4
Yield: 37 mg (23%); yellow flakes; mp 254–257 °C; Rf = 0.70
(CH2Cl2–EtOAc, 1:1).
IR (ATR): 2229, 1676, 1598, 1259, 1414, 894, 749, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 5.7 Hz, 1 H), 8.94 (m,
1 H), 8.67 (m, 1 H), 8.44 (m, 2 H), 8.16 (m, 1 H), 8.02 (m, 1 H),
7.94 (m, 1 H), 7.55 (m, 1 H).
13C NMR (150 MHz, CDCl3): δ = 181.3, 163.0 (JC–F = 254.2 Hz),
149.8, 148.8, 146.7, 145.9, 138.0, 134.5 (JC–F = 7.15 Hz), 133.1,
132.1 (JC–F = 3.3 Hz), 131.8, 130.6, 128.7 (JC–F = 8.25 Hz), 123.5,
122.9, 122.4 (JC–F = 22.0 Hz), 116.7, 115.4, 114.8 (JC–F = 23.1 Hz).
(m, 4 H), 7.36–7.26 (m, 2 H), 7.08–7.02 (m, 2 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.8 (JC–F = 249.6 Hz), 162.8,
157.7 (JC–F = 250.2 Hz), 151.3, 148.1, 138.7 (JC–F = 8.7 Hz), 133.3
(JC–F = 2.9 Hz), 131.8 (JC–F = 8.4 Hz), 130.9 (JC–F = 8.8 Hz), 130.4
(JC–F = 2.2 Hz), 124.4 (JC–F = 3.7 Hz), 123.5 (JC–F = 14.4 Hz), 122.2
(JC–F = 1.8 Hz), 117.1 (JC–F = 21.6 Hz), 116.1 (JC–F = 21.6 Hz),
115.4, 112.6 (JC–F = 21.6), 109.8, 19.5.
HRMS (ES, +): m/z [M + H]+ calcd for C19H12F2N2: 307.1041;
found: 307.1037.
HRMS (ES, +): m/z [M + H]+ calcd for C19H9FN2O; 301.0772;
found: 301.0780.
2-(4-Cyano-2-methylphenyl)-4-(2-fluorophenyl)nicotinonitrile
Attempted Synthesis of 9-Oxo-9H-benzo[b]pyrido[4,3,2-mn]ac-
ridine-11-carbonitrile (11)
(8)
Obtained by using method A with 4-cyano-o-tolylboronic acid as
coupling partner.
To a MW vial containing 2-(4-cyano-2-methylphenyl)-4-(2-fluoro-
phenyl)nicotinonitrile (8; 50 mg, 0.16 mmol) and anhydrous DMF
(with a concentration of 0.1 M) was added NaH (60% in mineral oil,
64 mg, 10 equiv). The vial was sealed and heated at 110 °C for
30 min under MW conditions (Caution: Great care should be taken
with this pressurized system and the procedure is generally not rec-
ommended). After cooling to r.t., the resulting mixture was bubbled
with O2 for 30 min, stirred for 16 h under an O2 atmosphere, and
concentrated in vacuo. The crude material was purified by column
chromatography on activated neutral alumina to afford trace
amounts of 11 as green-yellow flakes contaminated with aliphatic
impurities.
Yield: 199 mg (64%); clear gum; Rf = 0.29 (EtOAc–n-heptane,
1:3).
IR (ATR): 2231, 1575, 1220, 907, 760, 727 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.92 (d, J = 5.1 Hz, 1 H), 7.67–
7.64 (m, 2 H), 7.58–7.49 (m, 4 H), 7.37–7.29 (m, 2 H), 2.36 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 158.0 (JC–F = 250.5 Hz),
151.9, 148.6, 141.7, 137.9, 134.2, 132.4 (JC–F = 8.44 Hz), 130.6
(JC–F = 2.2 Hz), 130.2, 129.6, 124.8 (JC–F = 4.0 Hz), 123.9 (JC–F
=
1.8 Hz), 123.3 (JC–F = 14.3 Hz), 116.5 (JC–F = 21.6 Hz), 115.3,
113.5, 109.8, 19.5.
HRMS (ES, +): m/z [M + H]+ calcd for C20H12FN3: 314.1088;
1H NMR (400 MHz, CDCl3): δ = 9.17 (d, J = 5.8 Hz, 1 H), 9.07 (d,
J = 8.3 Hz, 1 H), 8.88 (m, 1 H), 8.70 (m, 2 H), 8.55 (d, J = 5.7 Hz,
1 H), 8.06 (m, 1 H), 7.98 (m, 2 H).
found: 314.1096.
4-(2-Fluorophenyl)-2-(3-methylthiophen-2-yl)nicotinonitrile
(12)
9H-Benzo[b]pyrido[4,3,2-mn]acridin-9-one (2)
To a sealed MW vial containing 5 (162 mg, 0.7 mmol, 0.7 equiv)
and PEPPSI-iPr (13 mg, 0.02 mmol, 2 mol%) under N2 was added
a solution of (3-methylthiophen-2-yl)zinc bromide (0.5 M in THF;
1 mmol, 1 equiv, 2 mL). The vial was heated at 110 °C for 45 min
under MW conditions, then the resulting mixture was filtered
through a pad of Celite and the pad was washed several times with
EtOAc. The crude material was purified by column chromatogra-
phy (n-heptane–EtOAc, 1:3) to furnish 12.
Obtained by using method B. 4-(2-Fluorophenyl)-2-o-tolylnicoti-
nonitrile 4 (110 mg, 0.38 mmol) was heated to 145 °C to give 2 with
analytical data consistent with previously published values.6
Yield: 12 mg (12%); yellow flakes; mp 266–268 °C; Rf = 0.63
(CH2Cl2–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 5.7 Hz, 1 H), 8.90 (m,
1 H), 8.65 (m, 2 H), 8.51 (m, 1 H), 8.41 (d, J = 5.8 Hz, 1 H), 7.99
(m, 1 H), 7.95–7.84 (m, 2 H), 7.68 (m, 1 H).
Synthesis 2014, 46, 1469–1474
© Georg Thieme Verlag Stuttgart · New York

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Anionic Cascade Ring Closure towards Pyridoacridines
1473
Yield: 180 mg (88%); clear gum/solid; Rf = 0.48 (EtOAc–n-hep-
tane, 1:3).
with EtOAc followed by column chromatography (EtOAc–n-hep-
tane, 1:9) afforded 18.
IR (ATR): 2228, 1570, 1450, 1221, 907, 725 cm–1.
Yield: 0.50 g (74%); slightly yellow oil; Rf = 0.71 (EtOAc–n-hep-
tane, 1:4).
1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 1.42 (hept,
J = 7.5 Hz, 3 H), 1.14 (d, J = 7.7 Hz, 18 H).
1H NMR (400 MHz, CDCl3): δ = 8.87 (d, J = 5.0 Hz, 1 H), 7.56–
7.46 (m, 3 H), 7.41–7.40 (m, 1 H), 7.36–7.26 (m, 2 H), 7.01–7.00
(d, J = 5.0 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 158.0 (JC–F = 250.2 Hz), 157.1,
13C NMR (100 MHz, CDCl3): δ = 168.3, 130.9, 127.8, 18.4, 12.8,
11.5.
148.8, 138.9, 133.9, 132.1 (JC–F = 8.4 Hz), 130.8, 130.8 (JC–F
=
2.2 Hz), 127.6, 124.7 (JC–F = 3.7 Hz), 123.8 (JC–F = 14.3 Hz), 122.9
(JC–F = 1.8 Hz), 116.4 (JC–F = 21.7 Hz), 116.0, 110.0, 15.8.
HRMS (ES, +): m/z [M + H]+ calcd for C17H11FN2S: 295.0700;
4-(2-Fluorophenyl)-2-[5-methyl-2-(triisopropylsilyl)thiazol-4-
yl]nicotinonitrile (18)
Obtained by using method C starting with 4-bromo-5-methyl-2-(tri-
isopropylsilyl)thiazole 17 (167 mg, 0.5 mmol) and 5 (233 mg, 2
equiv, 1.0 mmol).
found: 295.0699.
9H-Pyrido[4,3,2-mn]thieno[2,3-b]acridin-9-one (13)10
Obtained by using method B. 4-(2-Fluorophenyl)-2-(3-methylthio-
phen-2-yl)nicotinonitrile (121 mg, 0.41 mmol) was heated to
145 °C to give 13.
Yield: 101 mg (45%); Rf = 0.48 (EtOAc–n-heptane, 1:3).
1H NMR (400 MHz, CDCl3): δ = 8.84 (d, J = 5.1 Hz, 1 H), 7.54 (m,
2 H), 7.4 (dd, J = 5.1, 1.34 Hz, 1 H), 7.33–7.23 (m, 2 H), 2.76 (s,
3 H), 1.48 (hept, J = 7.7 Hz, 3 H), 1.18 (d, J = 7.5 Hz, 18 H).
Yield: 18 mg (15%); orange flakes; mp 294–296 °C; Rf = 0.63
13C NMR (100 MHz, CDCl3): δ = 166.8, 158.0 (JC–F = 250.2 Hz),
158.4, 150.8, 150.2, 149.4, 139.0, 131.7 (JC–F = 8.07 Hz), 130.9
(JC–F = 2.6 Hz), 124.5 (JC–F = 3.7 Hz), 124.2 (JC–F = 14.7 Hz), 123.0
(JC–F = 2.2 Hz), 116.2 (JC–F = 21.6 Hz), 115.7, 109.8, 18.5, 12.6,
11.7.
(CH2Cl2–EtOAc).
1H NMR (400 MHz, CDCl3): δ = 8.93 (d, J = 5.8 Hz, 1 H), 8.62 (m,
2 H), 8.35 (d, J = 5.9 Hz, 1 H), 8.00 (m, 1 H), 7.92 (m, 1 H), 7.86
(d, J = 5.1 Hz, 1 H), 7.55 (d, J = 5.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 177.4, 149.6, 149.0, 148.4, 147.7,
146.0, 139.7, 137.5, 133.2, 131.7, 130.6, 129.3, 127.4, 123.0, 122.8,
115.9, 115.6.
Acknowledgment
4-(2-Fluorophenyl)-2-(4-methylthiophen-3-yl)nicotinonitrile
The authors thank Dr. François Crestey for his valuable contribu-
tions to this project.
(14)
Obtained by using method C starting with 3-bromo-4-methylthio-
phene (1 mmol, 177 mg).
Supporting Information for this article is available online at
Yield: 110 mg (48%); clear gum; Rf = 0.42 (EtOAc–n-heptane,
1:3).
IR (ATR): 2227, 1570, 1222, 908, 730, 759 cm–1.
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra. SnugIoipfn
m
r
iot
SatrnufpgIori
m
p
nitart
1H NMR (400 MHz, CDCl3): δ = 8.87 (d, J = 5.1 Hz, 1 H), 7.75 (m,
1 H), 7.56–7.48 (m, 2 H), 7.41 (m, 1 H), 7.36–7.26 (m, 2 H), 7.01
(m, 1 H), 2.37 (s, 3 H).
References
(1) Marshall, K. M.; Barrows, L. R. Nat. Prod. Rep. 2004, 21,
731.
(2) Kobayashi, J.; Cheng, J.; Nakamura, H.; Ohizumi, Y.;
Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. Tetrahedron Lett.
1988, 29, 1177.
13C NMR (100 MHz, CDCl3): δ = 157.7 (JC–F = 250.5 Hz), 158.77,
151.2, 148.5, 137.8, 136.8, 131.7 (JC–F = 8.07 Hz), 130.4 (JC–F
=
2.6 Hz), 127.8, 124.4 (JC–F = 3.7 Hz), 123.6 (JC–F = 14.3 Hz), 122.5
(JC–F = 1.8 Hz), 122.4, 116.1 (JC–F = 21.3 Hz), 116.0, 108.9, 14.9.
HRMS (ES, +): m/z [M + H]+ calcd for C17H11FN2S: 295.0700;
(3) (a) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
(b) Delfourne, E.; Kiss, R.; Le Corre, L.; Merza, J.; Bastide,
J.; Frydman, A.; Darro, F. Bioorg. Med. Chem. 2003, 11,
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M.; Cardenas, D. J.; Echavarren, A. M. J. Chem. Soc., Perkin
Trans. 1 2002, 1360. (c) Cuerva, J. M.; Cardenas, D. J.;
Echavarren, A. M. Chem. Commun. 1999, 1721.
(d) Gellerman, G.; Rudi, A.; Kashman, Y. Synthesis 1994,
239. (e) Moody, C. J.; Rees, C. W.; Thomas, R. Tetrahedron
1992, 48, 3589. (f) Alvarez, M.; Feliu, L.; Ajana, W.; Joule,
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found: 295.0698.
2,4-Dibromo-5-methylthiazole (16)14
2-Amino-5-methylthiazole (2.0 g, 17.6 mmol) was dissolved in
H3PO4 (20 mL) and HNO3 (10 mL). The mixture was cooled to 0 °C
before NaNO2 (3.8 g, 55 mmol) in H2O (8 mL) was added. After
20 min, the solution was slowly added to a cooled solution CuBr
(2.6 g, 18 mmol) in HBr (19 mL). This mixture was stirred for 1.5 h
then neutralized with NaOH. Sat. aq NaHCO3 (50 mL) was added
and the mixture was extracted with EtOAc (3 × 40 mL), dried with
MgSO4, and evaporated. Heptane was added and the mixture was
decanted and evaporated to give 17.
Yield: 6.6 g (75%); mp 40–43 °C; Rf = 0.59 (EtOAc–n-heptane,
1:4).
1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 133.0, 132.7, 122.9, 12.9.
4-Bromo-5-methyl-2-(triisopropylsilyl)thiazole (17)
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stirred at –78 °C for 15 min, then TIPSCl (0.46 mL, 1.95 mmol) was
added and the mixture was slowly warmed to r.t. Standard work-up
© Georg Thieme Verlag Stuttgart · New York
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1474
I. N. Petersen, J. L. Kristensen
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Synthesis 2014, 46, 1469–1474
© Georg Thieme Verlag Stuttgart · New York