Azine and Diazine Functionalization Using 2,2,6,6-Tetramethylpiperidino-Based Lithium-Metal Combinations: Application to the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2- c ]pyrimidines

Article abstract of DOI:10.1055/s-0035-1560496

The synthesis of triaryl methanols was investigated by reacting different 4-metalated 2-substituted pyrimidines with diaryl ketones, the latter being generated by deprotocupration-aroylation of azine and diazine substrates. Cyclization of the triaryl meth

Full text of DOI:10.1055/s-0035-1560496

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0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
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Azine and Diazine Functionalization Using 2,2,6,6-Tetrameth-
ylpiperidino-Based Lithium–Metal Combinations: Application to
the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2-c]
pyrimidines
Nada Marquisea
Tan Tai Nguyena
Floris Chevalliera
Laurent Picotb
Valérie Thiéry*b
Olivier Lozachc
Stéphane Bach*c
Sandrine Ruchaudc
Florence Mongin*a
Ar
1) deproto-
cupration
2) aroylation
1) deproto-
metalation
or
O
Ar
(35–90%)
halogen–metal
exchange
Cl
N
Cl
N
7 compounds
N
N
2) cyclization
H or I
N
SMe
N
N
5 compounds
SMe
a Equipe Chimie et Photonique Moléculaires, Institut des Sciences
Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1,
Bâtiment 10A, Case 1003, Campus de Beaulieu, 35042 Rennes,
France
florence.mongin@univ-rennes1.fr
b Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266,
Université de La Rochelle, 17042 La Rochelle, France
valerie.thiery@univ-lr.fr
c USR 3151, CNRS-Université Pierre et Marie Curie, Kinase Inhibitor
Specialized Screening Facility, KISSf, Station Biologique, 29680
Roscoff, France
bach@sb-roscoff.fr
Received: 09.07.2015
MeS
N
Accepted after revision: 18.09.2015
Published online: 30.09.2015
DOI: 10.1055/s-0035-1560496; Art ID: st-2015-s0524-c
N
N
OMe
Li
O
Abstract The synthesis of triaryl methanols was investigated by react-
ing different 4-metalated 2-substituted pyrimidines with diaryl ketones,
the latter being generated by deprotocupration–aroylation of azine and
diazine substrates. Cyclization of the triaryl methanols thus obtained af-
forded pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines, which were evaluat-
ed for kinase inhibition and antiproliferative activities in melanoma
cells.
Cl
N
N
SMe
H2N
N
MeS
MeS
N
N
N
N
N
OMe
N
OH
HO
OMe
Key words diaryl ketone, pyrimidine, deprotometalation, mixed-metal
amide, variolin analogue
N
N
N
N
Cl
N
N
N
N
SMe
NH2
SMe
variolin B
Variolins are a family of marine alkaloids isolated from
the Antartic sponge Kirkpatrickia varialosa.1 Among them,
variolin B is a tricyclic system bearing a substituent at the
5-position endowed with biological properties such as anti-
tumor and antiviral.1a,2 Several total syntheses of variolin
B and analogues have been reported.2b,3 In the convergent
synthesis of Morris,3b,3h,4 the key step involves the tandem
deoxygenation–cyclization of a triaryl methanol, the latter
being for example obtained by reaction of 2-chloro-3-
Scheme 1 Morris synthesis of variolin B
Because of our interest in the synthesis of diaryl ketones
by deprotocupration–aroylation,5 we decided to evaluate
the reactivity of these ketones toward different 4-metalated
2-substituted pyrimidines in order to reach different triaryl
methanols. Thus, the required diaryl ketones were prepared
from azines or diazines as reported previously.5 The latter
were deprotocuprated at room temperature in tetrahydro-
furan (THF) containing N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA) by using (TMP)2CuLi·LiCl (TMP = 2,2,6,6-tet-
lithio-4-methoxypyridine on
(Scheme 1).
a
symmetrical ketone
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N. Marquise et al.
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ramethylpiperidino), prepared in situ from CuCl and LiTMP
(2 equiv). Trapping with aroyl chlorides after two hours fur-
nished the compounds 1a–i (Scheme 2).
1) base prepared from
ZnCl2⋅TMEDA (1 equiv)
and LiTMP (3 equiv)
THF, 0 °C or r.t., 2 h
I
N
N
N
N
Cl
Cl
2) I2
1) base prepared from
R2
O
R2
4a 0 °C: 18%
4a r.t.: 0%
CuCl (1 equiv)
and LiTMP (2 equiv)
TMEDA (1 equiv)
THF, r.t., 2 h
2
X
Ar
X
Ph
N
OH
R3
N
R1
R3
N
R1
1) TMPMgCl·LiCl
(1 equiv)
THF, –60 °C or –40 °C, 2 h
O
2)
N
1
Cl
N
Ar
Cl
2
Cl
2) 1a
O
O
O
4b –60 °C: 33%
4b –40 °C: 51%
3) hydrolysis
Ph
Ph
Scheme 3 Functionalization of 2-chloropyrimidine (2)
Cl
N
Cl
N
Cl
N
Cl
N
Cl
O
1a: 90%
1b: 41%
1c: 80%
Cl
O
O
1) base prepared from
MCl2⋅TMEDA (0.5 equiv)
and LiTMP (1.5 equiv)
I
N
N
N
N
N
THF, r.t., 2 h
MeO
Cl
Cl
N
F3C
Cl
N
N
SMe
SMe
2) I2
1d: 80%
1e: 80%
1f: 65%
5a M = Zn: 77%
5a M = Cd: 59%
3
O
O
Cl
Cl
O
OMe
N
Ph
N
N
N
N
Ph
OH
1) TMPMgCl⋅LiCl
(1 equiv)
THF, –60 °C, 2 h
Cl
Cl
Cl
1h: 21%
OMe
1g: 35%
1i: 58%
N
N
Cl
N
3
Scheme 2 Synthesis of the diaryl ketones 1a–i
SMe
2) 1a
3) hydrolysis
5b: 21%
Scheme 4 Functionalization of 2-(methylthio)pyrimidine (3)
We next considered the formation of 4-metalated
2-chloropyrimidine from 2 and its trapping. The pyrimi-
dine 2 being prone to nucleophilic attacks,6 we first tried to
use the base prepared in situ by mixing ZnCl2·TMEDA
and LiTMP in a 1:3 ratio,7 and supposed to be a 1:1
LiTMP·2LiCl(±TMEDA)–Zn(TMP)2 mixture.8 It proved not
appropriate, with the iodide 4a isolated in a low 18% yield
when the deprotonation step was performed at 0 °C
and only degradation noticed at higher temperatures.
TMPMgCl·LiCl being a suitable base for 2 in THF at –60 °C,
as evidenced by subsequent iodolysis after two hours,9 we
thus employed it in order to attempt the interception of the
deprotomagnesated species with the ketone 1a. The ex-
pected triaryl methanol 4b was obtained in a moderate 33%
yield by carrying out the reaction at –60 °C, but its forma-
tion could be improved with a deprotonation step at –40 °C
(Scheme 3).
4-Metalated derivatives of 2-(methylthio)pyrimidine (3)
could be formed at room temperature in THF by using ei-
ther the previous lithium–zinc base or the corresponding
lithium–cadmium base, prepared in situ by mixing
CdCl2·TMEDA (0.5 equiv) and LiTMP (1.5 equiv).10 This was
evidenced by iodolysis to afford 5a in correct yields. When
TMPMgCl·LiCl was employed at –60 °C, the alcohol 5b re-
sulting from a quenching with the ketone 1a was obtained
in a moderate 21% yield (Scheme 4).
To reach the triaryl methanols, it also proved possible to
involve the iodide 5a in a butyllithium-mediated halogen–
metal exchange reaction in the presence of the ketone 1a or
1b. Performing this reaction in THF at –95 °C, as previously
documented by Morris,3b,h,4 led to the alcohol 5b or 6b in
72% or 45% yield, respectively. Replacing methanol quench-
ing with acetyl chloride afforded the corresponding acetate
5b′. Finally, treating both 5b and 5b′ with triethylsilane and
trifluoroacetic acid at 100 °C in 1,2-dichloroethane fur-
nished the phenyl-substituted tricycle 7b in 45% yield
(Scheme 5). Because no improvement was here noted by
using the acetate 5b′ as intermediate,4 we kept the se-
quence involving triaryl methanols for the rest of the study.
In order to prepare analogues of 9-(methylthio)-5-
phenylpyrido[3′,2′;4,5]pyrrolo[1,2-c]pyrimidine (7b), we
aimed at synthesizing various triaryl methanols (Table 1).
When 2-chloro-4-iodopyrimidine (4a) was involved instead
of 5a in the reaction with 1a, a lower 24% yield was noticed
(Table 1, entries 1 and 2). With the other aryl(2-chloro-3-
pyridyl)methanones 1c–e, the expected alcohols were iso-
lated in yields ranging from 52–70% (Table 1, entries 3–5).
The position of chlorine on the (2-chloro-3-pyridyl)(chloro-
3-pyridyl)methanone is an important parameter for the
success of the reaction. Indeed, whereas a good 75% yield
was registered by using 1f (compound 5f, Table 1, entry 6),
a complex mixture without the expected derivative togeth-
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Table 1 (continued)
Ph
N
OH
I
1) BuLi, THF
–95 °C, 1.5 h
Entry
Substrate X
1
Product
Yield (%)
N
N
N
+ 1a or 1b
Cl
N
R
F3C
2) MeOH
SMe
SMe
5a
5b R = H: 72%
6b R = Cl: 45%
OH
4
5a SMe
1d
59
5a + 1a
N
N
Et3SiH (8 equiv)
TFA (2 equiv)
DCE
Cl
N
R = H
Ph
SMe
1) BuLi, THF
–95 °C, 1.5 h
2) AcCl
5d
100 °C, 48 h
MeO
Ph
OAc
Et3SiH (8 equiv)
TFA (2 equiv)
OH
N
N
N
N
5
5a SMe
1e
52
DCE
100 °C, 48 h
Cl
N
N
SMe
N
N
SMe
Cl
N
5b': 68%
7b: 45%
SMe
5e
Scheme 5 Synthesis of 9-(methylthio)-5-phenylpyrido[3′,2′:4,5]pyrro-
lo[1,2-c]pyrimidine (7b)
N
Cl
OH
6
5a SMe
1f
75
er with starting material was obtained from 1g (Table 1, en-
try 7). With the ketones 1h and 1i bearing a pyrimidyl
group, things become difficult, probably in relation with
ring sensitivity to nucleophilic attacks; as a consequence,
the alcohol 5i was the only to be formed, in a very low 8%
yield (Table 1, entries 8 and 9).
N
N
Cl
N
SMe
5f
Cl
N
OH
7
8
9
5a SMe
5a SMe
5a SMe
1g
1h
1i
0
0
8
Table 1 Synthesis of the Triaryl Methanols 4b and 5b–i
N
N
Cl
N
SMe
R
Ar
N
OH
5g
I
1) BuLi, THF
–95 °C, 1.5 h
Z
Cl
N
Ph
N
OH
N
N
+
1
N
Cl
Y
N
2) hydrolysis
X
X
N
4a: X = Cl
5a: X = SMe
4b
5b–i
Cl
SMe
5h
Entry
1
Substrate X
1
Product
Yield (%)
24
MeO
N
OMe
OH
Ph
OH
N
N
N
4a Cl
1a
1a
Cl
N
N
N
Cl
Cl
N
4b
SMe
5i
Ph
OH
2
3
5a SMe
72
70
N
N
In order to progress toward the corresponding 5-aryl
tricycles, the triaryl methanols were submitted to the ac-
tion of triethylsilane and trifluoroacetic acid as before (Ta-
ble 2). Under these conditions, the targets 7b–f were gener-
ated in moderate yields (Table 2, entries 2–6). No cycliza-
tion was noticed from the dichloride 4b (Table 2, entry 1).
Similarly, cyclization of the dichloride 6b did not take place
under the conditions used (Table 2, entry 7). In both cases,
starting material was recovered.
Cl
N
SMe
5b
Cl
OH
5a SMe
1c
N
N
Cl
N
SMe
5c
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Table 2 Synthesis of the Tricycles 7b–f
Variolin B was characterized as a potent inhibitor of cy-
clin-dependent kinases (CDK), key actors involved notably
in the regulation of the cell-division cycle, programmed
cell-death by apoptosis, transcription as well as differentia-
tion.2a This chemical scaffold was consequently used to de-
sign new inhibitors of CDK.11 In this study we thus tested
the new derivatives on a panel of nine protein kinases in-
cluding CDK5: HsAurora B, HsCDK5/p25, HsRIPK3 (receptor
interacting protein kinase), HsHaspin; porcine (Sus scrofa)
SsGSK-3 (glycogen synthase kinase-3) and SsCK1 (casein ki-
nase 1); kinases from the protozoan parasites, Leishmania
major LmCK1, Plasmodium falciparum PfGSK-3, and from
Leishmania donovani LdTLK (tousled-like kinase). These ki-
nases were not significantly affected by the tested chemical
compounds (5b–e and 7c–f) with none of the molecules
causing more than 50% inhibition of enzymatic activity at
10–5 M.
The antiproliferative activity of the 5,9-disubstituted
pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines 5b–e and 7c–f
was studied in the A2058 (ATCC® CRL-11147) melanoma
cell line (Figure 1). A2058 are highly invasive human epi-
thelial adherent melanoma cells, derived from lymph nodes
metastatic cells obtained from a 43 years male patient.
They are tumorigenic at 100% frequency in nude mice and
considered as very resistant to anticancer drugs.
Ar
N
Ar
N
OH
Et3SiH (8 equiv)
TFA (2 equiv)
N
N
N
DCE
100 °C, 48 h
R
Cl
N
X
X
4b
5b–f
6b
7b–f
R
Entry
1
Substrate X, R
Product
Yield (%)
Ph
N
N
4b Cl, H
0a
N
Cl
7a
Ph
2
3
5b SMe, H
45
23
N
N
N
SMe
7b
Cl
5c SMe, H
N
N
The compounds 5 exerted low antiproliferative activity
in A2058 melanoma cells, with 0–13% growth inhibition in
cells treated for 72 h at 10–5 M. In contrast, the compounds
7 exhibited 23–44% growth inhibition and were considered
as moderately antiproliferative. This activity was not cor-
related to CDK inhibition, as all molecules were inactive at
10–5 M in the CDK inhibition assay. Because of the presence
of the sp3 carbon, the compounds 5 are not planar in con-
trast to the compounds 7. This observation indicates that
the planar structure improves the antiproliferative activity
and suggests that the cytotoxicity of these new compounds
may be related to a DNA intercalating activity, as previously
reported with variolin analogues.1a,b The nature of the ring
N
N
N
SMe
7c
CF3
4
5d SMe, H
36
N
N
SMe
7d
OMe
5
5e SMe, H
18
N
N
SMe
7e
N
Cl
6
7
5f SMe, H
21
N
N
N
SMe
7f
Ph
N
N
6b SMe, Cl
0a
N
SMe
Figure 1 Antiproliferative activity of the compounds 5b–e and 7c–f in
A2058 human melanoma cells grown for 72 h in a cell-culture medium
containing 10–5 M molecule
Cl
7g
a Only starting material was recovered.
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N. Marquise et al.
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connected to the tricycle also plays an important role, as the
absence of cycle leads to a complete loss of activity, as ob-
served with variolin D.1c Moreover, the presence of ring ni-
trogens or/and amino function is also critical for CDK inhi-
bition.2a
As a conclusion, 2-substituted pyrimidines could be
functionalized at their 4-position by using a lithium–metal
TMP-based deprotonating agent.12–14 The triaryl methanols
obtained either after subsequent quenching, or through io-
dine–lithium exchange with in situ ketone trap, were cy-
clized to afford new pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimi-
dines.
Hill, J. B.; Morris, J. C. J. Org. Chem. 2005, 70, 6204. (i) Baeza, A.;
Mendiola, J.; Burgos, C.; Alvarez-Builla, J.; Vaquero, J. J. Tetrahe-
dron Lett. 2008, 49, 4073. (j) Baeza, A.; Mendiola, J.; Burgos, C.;
Alvarez-Builla, J.; Vaquero, J. J. Eur. J. Org. Chem. 2010, 5607.
(k) Layek, M.; Syam Kumar, Y.; Islam, A.; Karavarapu, R.;
Sengupta, A.; Halder, D.; Mukkanti, K.; Pal, M. MedChemComm
2011, 2, 478.
(4) Anderson, R. J.; Morris, J. C. Tetrahedron Lett. 2001, 42, 311.
(5) For a review on the topic, see: Harford, P. J.; Peel, A. J.;
Chevallier, F.; Takita, R.; Mongin, F.; Uchiyama, M.; Wheatley, A.
E. H. Dalton Trans. 2014, 43, 14181.
(6) See, for example: Wang, X.; Xu, F.; Xu, Q.; Mahmud, H.; Houze,
J.; Zhu, L.; Akerman, M.; Tonn, G.; Tang, L.; McMaster, B. E.;
Dairaghi, D. J.; Schall, T. J.; Collins, T. L.; Medina, J. C. Bioorg. Med.
Chem. Lett. 2006, 16, 2800.
(7) L’Helgoual’ch, J. M.; Seggio, A.; Chevallier, F.; Yonehara, M.;
Jeanneau, E.; Uchiyama, M.; Mongin, F. J. Org. Chem. 2008, 73,
177.
(8) García-Álvarez, P.; Mulvey, R. E.; Parkinson, J. A. Angew. Chem.
Int. Ed. 2011, 50, 9668.
(9) Mosrin, M.; Knochel, P. Chem. Eur. J. 2009, 15, 1468.
(10) (a) Mongin, F.; Uchiyama, M. Curr. Org. Chem. 2011, 15, 2340.
(b) Armstrong, D. R.; Kennedy, A. R.; Mulvey, R. E.; Parkinson, J.
A.; Robertson, S. D. Chem. Sci. 2012, 3, 2700.
(11) Bettayeb, K.; Tirado, O. M.; Marionneau-Lambot, S.; Ferandin,
Y.; Lozach, O.; Morris, J. C.; Mateo-Lozano, S.; Drueckes, P.;
Schaechtele, C.; Kubbutat, M. H. G.; Liger, F.; Marquet, B.;
Joseph, B.; Echalier, A.; Endicott, J. A.; Notario, V.; Meijer, L.
Cancer Res. 2007, 67, 8325.
Acknowledgment
We gratefully acknowledge financial support from the Institut Uni-
versitaire de France (to F.M.), MESR of France (to T.T.N.), Rennes
Métropole, and French Cancer League (Comité 17). We also thank the
Cancéropôle Grand Ouest (axis: natural sea products in cancer treat-
ment) for scientific support and Biogenouest (Western France life sci-
ence and environment core facility network) for supporting KISSf
screening facility. S.B. is supported by ANR/Investissements d’Avenir
program by means of the OCEANOMICs project (grant # ANR-11-
BTBR-0008). F.M. thanks Thermo Fisher for generous gift of 2,2,6,6-
tetramethylpiperidine. We thank Edouard Dean for his contribution
to the synthesis experimental work.
(12) 2-Chloro-α-(2-chloro-3-pyridyl)-α-phenyl-4-pyrimidine-
methanol (4b)
Supporting Information
i-PrMgCl·LiCl (about 1.3 M THF solution, 1.2 mmol) was stirred
with 2,2,6,6-tetramethylpiperidine (0.21 mL, 1.2 mmol) at r.t.
for 48 h. The resulting solution was cooled at –60 °C before
introduction of a cooled solution of 2-chloropyrimidine (2, 0.11
g, 1.0 mmol) in THF (2 mL). After 2 h at –40 °C, a solution of the
ketone 1a (0.26 g, 1.2 mmol) in THF (4 mL) was added at –60 °C.
The mixture was stirred overnight at r.t. before addition of H2O
(0.5 mL) and dilution with EtOAc (20 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification was performed by chromatography on
silica gel (eluent: heptane–EtOAc, 7:3) to afford 4b in 51% yield
as a yellow powder; mp 90 °C. 1H NMR (300 MHz, CDCl3): δ =
4.97 (s, 1 H), 7.18 (dd, 1 H, J = 7.8, 4.7 Hz), 7.33 (dd, 1 H, J = 7.8,
1.9 Hz), 7.36 (d, 1 H, J = 5.2 Hz), 8.37 (dd, 1 H, J = 4.7, 1.9 Hz),
7.35–7.45 (m, 5 H), 8.60 (d, 1 H, J = 5.2 Hz) ppm. 13C NMR (75
MHz, CDCl3): δ = 80.5 (C), 117.6 (CH), 122.3 (CH), 127.5 (2 CH),
128.7 (CH), 128.8 (2 CH), 138.2 (C), 139.9 (CH), 140.7 (C), 149.4
(CH), 150.8 (C), 160.1 (CH), 161.0 (C), 175.0 (C) ppm. ESI-HRMS:
m/z calcd for C16H1135Cl2N3NaO [M + Na]+: 354.0177; found:
354.0178.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560496.
S
u
p
p
ortiInfogrmoaitn
S
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References and Notes
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(13) 4-Iodo-2-(methylthio)pyrimidine (5a)
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperi-
dine (0.50 mL, 3.0 mmol) in THF (6 mL) were successively added
BuLi (about 1.6 M hexanes solution, 3.0 mmol) and, 5 min later,
ZnCl2·TMEDA7 (0.26 g, 1.0 mmol). The mixture was stirred for
15 min at 0 °C before introduction of 2-(methylthio)pyrimidine
(3, 0.25 g, 2.0 mmol). After 2 h at this temperature, a solution of
I2 (0.76 g, 3.0 mmol) in THF (10 mL) was added. The mixture
was stirred overnight before addition of an aqueous saturated
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2811–2816

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solution of Na2S2O3 (10 mL) and extraction with EtOAc (3 × 20
mL). The combined organic layers were dried over MgSO4, fil-
tered, and concentrated under reduced pressure. Purification
was performed by chromatography on silica gel (eluent:
heptane–EtOAc, 95:5) to afford 5a in 77% yield as a beige
powder; mp 52 °C (ref. 14: 52–53 °C). 1H NMR (300 MHz,
CDCl3): δ = 2.54 (s, 3 H), 7.40 (d, 1 H, J = 5.1 Hz), 8.00 (d, 1 H,
J = 5.1 Hz) ppm.
(14) Majeed, A. J.; Antonsen, O.; Benneche, T.; Undheim, K. Tetrahe-
dron 1989, 45, 993.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2811–2816