Functionalization of pyridyl ketones using deprotolithiation-: In situ zincation

Article abstract of DOI:10.1039/c6ra11370b

The metallation of aryl ketones was achieved by using LiTMP in the presence of ZnCl₂·TMEDA, as evidenced by subsequent interception with iodine or by a palladium-catalysed cross-coupling reaction. One of the synthesized iodo ketones has been further elaborated to reach derivatives of biological interest.

Full text of DOI:10.1039/c6ra11370b

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Mongin, RSC Adv., 2016, DOI: 10.1039/C6RA11370B.
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DOI: 10.1039/C6RA11370B
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COMMUNICATION
Functionalization of pyridyl ketones using deprotolithiation-in situ
zincation
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Madani Hedidi,a,b,c William Erb,a,* Frédéric Lassagne,a Yury S. Halauko,d,* Oleg A. Ivashkevich,d
Vadim E. Matulis,e Thierry Roisnel,f Ghenia Bentabed-Ababsab,* and Florence Mongina
www.rsc.org/
The metallation of aryl ketones was achieved by using LiTMP in mixing in a 3:1 ratio LiTMP and ZnCl2·TMEDA (TMEDA =
the presence of ZnCl2·TMEDA, as evidenced by subsequent N,N,N’,N’-tetramethylethylenediamine) in THF (THF
=
interception with iodine or by palladium-catalysed cross-coupling tetrahydrofuran), was successfully employed with a large
reaction. One of the synthesized iodo ketones has been further range of sensitive substrates.13 Such a synergy, attributed to
elaborated to reach derivatives of biological interest.
reversible deprotolithiation shifted by zinc-mediated
transmetallation12 (or ‘trans-metal trapping’14), has since been
extended to the use of LiTMP in the presence of ZnCl2·2LiCl,
MgCl2 or CuCN·2LiCl.15
Herein, we report the efficiency of aryl ketones as directing
groups for LiTMP-mediated deprotometallation of pyridines
and other arenes in the presence of ZnCl2·TMEDA as in situ
trap (Scheme 1, Table 1).
Pyridines play a large part in biological processes (nicotine,
niacin, NADP, vitamin B6…), in pharmaceuticals and
agrochemicals,1 as well as in organic materials.2 In addition,
pyridyl ketones bearing a halogen at the position adjacent to
the carbonyl function are key intermediates to access
heterocyclic scaffolds of interest such as azafluorenones,3
azaxanthones,4 naphthyridones,5 and thieno-,6 pyrazolo-7 and
isoxazolo-pyridines.8
Even if deprotonative lithiation9 has been largely used to
regioselectively functionalize pyridines,10 the method has
never been extended to pyridyl ketones due to their low
compatibility with organolithiums. Mixed lithium-nonalkali
metal combinations have been developed to achieve
chemoselective deprotometallation of aromatics.11 In this
context, the 1:1 mixture of homometallic amides LiTMP (TMP
= 2,2,6,6-tetramethylpiperidino) and Zn(TMP)2,12 obtained by
a.Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes,
UMR 6226, Université de Rennes 1-CNRS, Bâtiment 10A, Case 1003, Campus de
Beaulieu, 35042 Rennes, France.
E-mail : william.erb@univ-rennes1.fr
b.Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences, Université
d’Oran 1 Ahmed Ben Bella, BP 1524 El M’Naouer, 31000 Oran, Algeria.
E-mail : badri_sofi@yahoo.fr
c. Present address: Département de Chimie, Faculté des Sciences, Université Hassiba
Benbouali de Chlef, Hay Es-Salem, RN 19, 02000 Chlef, Algeria.
d.UNESCO Chair of Belarusian State University, 14 Leningradskaya Str., Minsk
220030, Belarus.
E-mail : hys@tut.by
e. Research Institute for Physico-Chemical Problems of Belarusian State University,
14 Leningradskaya Str., Minsk 220030, Belarus.
f. Centre de Diffractométrie X, Institut des Sciences Chimiques de Rennes, UMR
6226, Université de Rennes 1-CNRS, Bâtiment 10B, Campus de Beaulieu, 35042
Rennes, France.
Scheme 1
Zincation of aryl ketones 1 using LiTMP in the presence of ZnCl2·TMEDA
followed by iodolysis or palladium-catalysed cross-coupling to afford ketones 2 and 2’.
†
Electronic supplementary information (ESI) available: General procedures,
experimental procedures and compound characterizations, 1H and 13C NMR
spectra of the new compounds, and X-ray crystallographic data. CCDC 1475309
Thus, after optimization of the reaction conditions (using
four different reaction temperatures from -70 to -10 °C and
different amounts of LiTMP from 1 to 3 equiv), treatment of 2-
(
2j’), 1475009 (2k’) and 1475010 (2n’). For ESI and crystallographic data in CIF see
DOI: 10.1039/x0xx00000x
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Journal Name
benzoylpyridine (1a) in THF containing ZnCl2·TMEDA (1 equiv)
with LiTMP (1.5 equiv) at -30 °C for 15 min and then iodine led
to the 3-iodo derivative 2a in 50% yield (entry 1). Similarly, 4-
benzoylpyridine (1b) was converted to the 3-iodo derivative 2b
by using LiTMP (2 equiv); with this substrate benefiting from
two free positions adjacent to the benzoyl group, a second
deprotonation was observed to some extent, as evidenced by
the competitive formation of the diiodo 2b’ (entry 2).
3-Benzoylpyridine (1c) is more prone to nucleophilic attack
onto the ring than its 2- and 4-isomers.16 As a consequence,
deprotolithiation-zincation could only be evidenced by
subsequent iodolysis at temperatures below -50 °C. Using
LiTMP (1.5 equiv) at -55 or -70 °C for 15 min and then iodine
provided the 4-iodo derivative 2c in 30 or 37% yield,
respectively (entry 3).
O
F
I
O
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DOI: 10.1039/C6RA11370B
4
5
6
7
8
9
N
N
F
1d: 1.5 equiv, -55 °C
2d: 63%
O
I
O
N
Cl
N
Cl
1e: 1.5 equiv, -55 °C
2e: 73%
O
Cl
I
O
Cl
N
Cl
N
Cl
O
1f: 1.5 equiv, -55 °C
2f: 78%
When present at pyridine 2-position, halogens are known
to acidify the 4-position, as shown by pKa values calculated in
O
OMe
I
OMe
THF.13a The 2-halogeno 3-benzoylpyridines 1d
-
h
were thus
prepared.17 Accordingly, when similarly reacted by using LiTMP
at -55 °C, the iodo derivatives 2d were isolated in improved
N
Cl
N
Cl
-
g
1g: 1.5 equiv, -55 °C
2g: 70%
yields, in line with the long range effects of fluorine and
chlorine (entries 4-7). In contrast, the reaction from 1h proved
more complex, giving the iodide 2h in a modest yield (entry 8).
The presence of a methoxy group at 2-position of 3-
benzoylpyridine also had a positive impact on the course of
the reaction since involving 1i in the sequence furnished the
iodo derivative 2i in 88% yield (entry 9). Whereas this group
does not acidify remote pyridine 4-position,13b it acts by
making the pyridine ring less sensitive towards competitive
nucleophilic attack. Indeed, based on the 1H NMR chemical
shifts in CDCl3 of 1c (8.12 and 8.82 ppm for H4 and H6,
respectively) and 1i (7.72 and 8.32 ppm for H4 and H6,
respectively), one can predict as shown by Handy and Zhang18
that the partial positive charges at C4 and C6 will be reduced
O
I
O
Ph
Ph
N
Cl
N
Cl
1h: 1.5 equiv, -55 °C
2h: 27%
O
I
O
N
OMe
N
OMe
1i: 1.5 equiv, -55 °C
2i: 88%
O
O
I
35.4
38.6
37.6
40.3
40.7
39.6
for 1i
.
N
39.4
10
11
N
Table 1 Substrates 1a-l, calculated pKa(THF) values for 1j and 1k, conditions
used for the deprotolithiation-zincation, and iodinated aryl ketones 2a-l
obtained.
1j: 1.5 equiv, -55 °C
2j: 33%c
O
I
O
36.0
40.1
Product/yielda (%)
40.9
38.8
36.9
38.4
Entry
Substrate/n/temperature
O
I
O
N
O
35.6
N
O
1k: 1.5 equiv, -55 °C
2k: 60%d
N
N
O
I
O
1
1a: 1.5 equiv, -30 °C
2a: 50%
O
I
O
12
N
S
N
S
1l: 1.5 equiv, -55 °C
2l: 60%
N
N
a
b
2
3
Yield after purification by column chromatography.
4-Benzoyl-3,5-
1b: 2 equiv, -30 °C
2b: 45%b
diiodopyridine (2b’) was also obtained in 10% yield. c 1,5-Diiodo-4-azafluorenone
d
(2j’) was also obtained in 20% yield. 1,6-Diiodo-4-azaxanthone (2k’) was also
O
I
O
obtained in 10% yield.
The behaviour of the ketones 1j-l, possessing reduced
flexibility on carbonyl direction, was similarly examined. 4-
azafluorenone (1j) was converted to the 1-iodo derivative 2j in
N
N
1c: 1.5 equiv, -55 °C
1c: 1.5 equiv, -70 °C
2c: 30%
2c: 37%
a
moderate yield, similar to that obtained from 3-
2 | RSC Adv., 2016, 00, 1-3
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Journal Name
benzoylpyridine (1c). In the case of 1j, the phenyl ring was also
COMMUNICATION
Interestingly, the deprotolithiation-in situ zincation could
View Article Online
attacked to a lesser extent at a position facing the pyridine be combined with
a
subsequent NeDgOisI:h1i0.1c0r3o9s/Cs-6cRoAu11p3l7in0Bg
nitrogen to afford the diiodide 2j’ (entry 10, Figure 1). In reaction.20 Thus, using catalytic amounts of PdCl2 as palladium
contrast with the reaction from 1j, the sequence using 4- source and 1,1’-diphenylphosphinoferrocene (dppf) as ligand
azaxanthone (1k) and 4-azathioxanthone (1l) provided the with 2-chloropyridine12a allowed 2’m to be formed from 9-
iodides 2k and 2l in higher 60% yields (entries 11 and 12).
xanthone (1m) in 76% yield (Scheme 1).
CH acidities are in general useful data to better understand
deprotometallation outcomes, in particular regarding
regioselectivity issues. We thus calculated selected pKa values
in THF solution by means of quantum chemistry at the DFT
B3LYP level of theory.13 After geometry optimization and
calculation of the vibrational frequencies by using the 6-31G(d)
basis set, the single point energies were obtained using the 6-
311+G(d,p) basis set. The solvent influence was treated
through the polarized continuum model (PCM) with the
default parameters for THF. Finally, the pKa values were
reached from the Gibbs energy of the homodesmic reaction
between the studied and probe heterocycles.
That both sets of CH acidity values for 1m and 1n are
rather similar (Table 2) supports the role of the carbonyl
direction on the course of the reaction through coordination.
Analogously, the difference observed between the pKa values
of 1j and 1k is not significant enough to allow for a
rationalization of the distinct yields noted, rather suggesting a
more efficient stabilization of the metallated compound by the
carbonyl group in the case of 1k at the origin of the higher
yield. Besides, the formation of dimetallated products from 1j
and 1k, as demonstrated by isolation of 2j’ and 2k’ (Figure 1),
could be favoured for the former by a nitrogen assistance and,
for the latter, by a relatively low pKa value (35.6) at the 6-
position (Table 1).
Figure 1 ORTEP diagrams (30% probability) of compounds 2j’ and 2k’
.
In order to evaluate the scope of the method, we chose
other aromatic substrates.19 When compared with its 4-aza
analogue 1k, xanthone (1m) similarly led to the 1-iodo 2m in
72% yield. On the contrary, as previously noted between 1j
and 1k, the reaction from 1n was less efficient than from 1m
.
Indeed, 1-iodofluorenone (2n) was obtained in 52% yield, but
together with the ketone 2n’ (35% yield) resulting from an
addition of the metallated product to 1n (Scheme 1, Table 2).
As organozincs hardly react with ketones, the product 2n’
could rather result from an addition of 1-lithiofluorenone to 1n
more rapid than its trapping by the zinc species. These results
suggest that the carbonyl direction in the metallated derivative
coming from 1n is less prone to stabilize a 1-lithio compound
than that from 1m
.
Table 2 Substrates 1m and 1n and their calculated pKa(THF) values, conditions
used for the deprotolithiation-zincation, iodinated aryl ketones 2m and 2n
obtained, and ORTEP diagram (30% probability) of compound 2n’.
Finally, when 2-benzoylthiophene (1o) was submitted to
LiTMP in the presence of ZnCl2·TMEDA as before, the reaction
took place next to sulphur to afford after iodolysis the iodo
derivative 2o in 80% yield (Scheme 2).
Entry
Substrate/n/temperature
Product/yielda (%)
1) ZnCl2·TMEDA (1 equiv)
O
I
O
O
41.2
O
O
2) LiTMP (1.5 equiv)
THF, -55 °C, 15 min
41.0
39.5
S
S
I
O
36.2
1
3) I2 (1.5 equiv)
-55 °C to rt
1o
2o
1m: 1.5 equiv, -55 °C
2m: 72%
80% yield
O
O
Scheme 2
Zincation of phenyl 2-thienyl ketone (1o) using LiTMP in the presence of
I
39.8
41.6
ZnCl2·TMEDA followed by iodolysis to afford the iodinated 2-thienyl ketone 2o.
40.5
39.3
2
To move towards nitrogen-containing derivatives of
biological interest, 2-benzoyl-3-iodopyridine (2a) was involved
in further reactions (Scheme 3). A catalyst-base system was
first optimized to perform guanidine copper-catalysed N-
arylation.21 Upon treatment with K3PO4 as base and CuI as
catalyst source in the presence of DMSO, the iodide 2a was
converted to the pyrido[3,2-d]pyrimidine 3a in 77% yield.
Besides, cyclizing Suzuki coupling22 was performed from the
1n: 1.5 equiv, -55 °C
2n: 52%
OH
O
ketone 2a and 2-aminophenylboronic acid under palladium
2n’: 35%
23
catalysis to provide 5-phenylbenzo[f][1,7]naphthyridine (4a
)
a Yield after purification by column chromatography.
in 68% yield.
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COMMUNICATION
Journal Name
(H2N)2C=NH·HCl (2 equiv)
K3PO4 (2 equiv)
Morimoto, K.-i. Kasahara, S. Ohashi, H. Suzuki, TV.ieHwaAyraticslhe iOannlinde
I
N
NH2
S. Miyoshi, Bioorg. Med. Chem. Lett., 2014, 24, 1327.
DOI: 10.1039/C6RA11370B
CuI (10 mol.%)
8
9
E. J. Hanan, R. V. Fucini, M. J. Romanowski, R. A. Elling, W.
Lew, H. E. Purkey, E. C. VanderPorten and W. Yang, Bioorg.
Med. Chem. Lett., 2008, 18, 5186.
O
N
N
N
Ph
Ph
DMSO, 110 °C, 24 h
2a
3a
(a) H. W. Gschwend and H. R. Rodriguez, Org. React., 1979,
26, 1; (b) P. Beak and V. Snieckus, Acc. Chem. Res., 1982, 15
77% yield
,
K2CO3 (8 equiv)
EtOH, H2O
306; (c) V. Snieckus, Chem. Rev., 1990, 90, 879; (d) T. G. Gant
and A. I. Meyers, Tetrahedron, 1994, 50, 2297; (e) M.
Schlosser, Organometallics in Synthesis, 2002, 2nd ed. (Ed.:
M. Schlosser).
(HO)2B
Pd(PPh3)4 (5 mol.%)
toluene, reflux, 24 h
NH2·HCl
(2 equiv)
10 (a) G. Queguiner, F. Marsais, V. Snieckus and J. Epsztajn, Adv.
Heterocycl. Chem., 1991, 52, 187; (b) F. Mongin and G.
Queguiner, Tetrahedron, 2001, 57, 4059; (c) M. Schlosser
and F. Mongin, Chem. Soc. Rev., 2007, 36, 1161.
11 (a) R. E. Mulvey, Acc. Chem. Res., 2009, 42, 743; (b) B. Haag,
M. Mosrin, H. Ila, V. Malakhov and P. Knochel, Angew. Chem.
Int. Ed., 2011, 50, 9794; (c) F. Mongin and A. Harrison-
Marchand, Chem. Rev., 2013, 113, 7563. A few carbonyl-
containing five-membered heteroaromatics proved
N
N
Ph
4a
68% yield
Scheme 3
interest.
Conversion of 2-benzoyl-3-iodopyridine (2a) to derivatives of biological
compatible: (d) W. Lin, O. Baron and P. Knochel, Org. Lett.,
2006, 8, 5673; (e) S. H. Wunderlich and P. Knochel, Angew.
Chem. Int. Ed., 2007, 46, 7685; (f) M. Mosrin and P. Knochel,
Org. Lett., 2009, 11, 1837; (g) T. Bresser, M. Mosrin, G.
Monzon and P. Knochel, J. Org. Chem., 2010, 75, 4686.
12 (a) J. M. L'Helgoual'ch, A. Seggio, F. Chevallier, M. Yonehara,
E. Jeanneau, M. Uchiyama and F. Mongin, J. Org. Chem.,
2008, 73, 177; (b) P. García-Álvarez, R. E. Mulvey and J. A.
Parkinson, Angew. Chem. Int. Ed., 2011, 50, 9668.
13 For previous examples in the pyridine series, see: (a) K.
Snégaroff, T. T. Nguyen, N. Marquise, Y. S. Halauko, P. J.
Harford, T. Roisnel, V. E. Matulis, O. A. Ivashkevich, F.
Chevallier, A. E. H. Wheatley, P. C. Gros and F. Mongin,
Chem. Eur. J., 2011, 17, 13284; (b) M. Hedidi, G. Bentabed-
Ababsa, A. Derdour, Y. S. Halauko, O. A. Ivashkevich, V. E.
Matulis, F. Chevallier, T. Roisnel, V. Dorcet and F. Mongin,
Tetrahedron, 2016, 72, 2196.
In summary, we have reported a short and simple access to
iodinated aryl ketones. Additionally, transition metal-mediated
reactions occurring with cyclization led to elaborated scaffolds.
Applications towards the synthesis of libraries of compounds
for biological evaluation are currently under investigation in
our laboratory.
We thank the Ministère de l'Enseignement supérieur et de
la Recherche scientifique Algérien (M. H.), the Centre national
de la recherche scientifique and the Institut Universitaire de
France (F. M.). We acknowledge FEDER founds (D8 VENTURE
Bruker AXS diffractometer) and Thermo Fisher (generous gift
of 2,2,6,6-tetramethylpiperidine). This research has been
partly performed as part of the CNRS PICS project “Bimetallic
synergy for the functionalization of heteroaromatics”.
14 M. A. Fuentes, A. R. Kennedy, R. E. Mulvey, J. A. Parkinson, T.
Rantanen, S. D. Robertson and V. Snieckus, Chem. Eur. J.,
2015, 21, 14812.
15 M. R. Becker and P. Knochel, Angew. Chem. Int. Ed., 2015,
54, 12501.
16 For Lewis acid-catalysed nucleophilic additions at C4 onto 3-
substituted pyridines, see: Q. Chen, X. Mollat du Jourdin and
P. Knochel, J. Am. Chem. Soc., 2013, 135, 4958.
17 T. T. Nguyen, N. Marquise, F. Chevallier and F. Mongin,
Chem. Eur. J., 2011, 17, 10405.
18 S. T. Handy and Y. Zhang, Chem. Commun., 2006, 299.
19 Concerning the deprotonation of benzophenone using a
lithium-cadmium base, see: K. Snégaroff, J. M. L'Helgoual'ch,
G. Bentabed-Ababsa, T. T. Nguyen, F. Chevallier, M.
Yonehara, M. Uchiyama, A. Derdour and F. Mongin, Chem.
Eur. J., 2009, 15, 10280.
20 On the topic, see: (a) E. Negishi, A. O. King and N. Okukado, J.
Org. Chem., 1977, 42, 1821; (b) E. Negishi, Acc. Chem. Res.,
1982, 15, 340.
Notes and references
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21 For reviews on the topic, see: (a) F. Monnier and M. Taillefer,
Angew. Chem. Int. Ed., 2009, 48, 6954; (b) I. P. Beletskaya
and A. V. Cheprakov, Organometallics, 2012, 31, 7753.
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Chem. Rev., 1995, 95, 2457; (b) S. Kotha, K. Lahiri and D.
Kashinath, Tetrahedron, 2002, 58, 9633.
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4 | RSC Adv., 2016, 00, 1-3
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