Aminoalkoxide-mediated formation and stabilization of phenylpyridyllithium: Straightforward access to phenylpyridine derivatives

Article abstract of DOI:10.1021/jo026706o

It is shown that lithium aggregates promoted the efficient metalation of phenylpyridines and stabilization of phenylpyridyllithium. The BuLi-LiDMAE superbase prevented dimerization or nucleophilic addition encountered with t-BuLi or n-BuLi. The reported s

Full text of DOI:10.1021/jo026706o

TABLE 1. Rea ction of 1 w ith Lith iu m Ba sesa
Am in oa lk oxid e-Med ia ted F or m a tion a n d
Sta biliza tion of P h en ylp yr id yllith iu m :
Str a igh tfor w a r d Access to P h en ylp yr id in e
Der iva tives
Philippe Gros and Yves Fort*
Synthe`se Organique et Re´activite´, UMR CNRS-UHP 7565,
Faculte´ des Sciences, Universite´ Henri Poincare´, BP 239,
54506 Vandoeuvre-Le`s-Nancy, France
yield, %
yves.fort@sor.uhp-nancy.fr
Received November 13, 2002
base (equiv)
conditions
2a b
3b
4b
LDA (2-4)
LTMP (4)
t-BuLi (1.2)
t-BuLi (1.2)
t-BuLi (1.2)
THF, -78 °C, 1 h
THF, -78 °C, 1 h
THF, -78 °C, 1 h
Et2O, -78 °C, 1 h
hexane, 0 or -78 °C,
1-3 h
15 (3a )
Abstr a ct: It is shown that lithium aggregates promoted
the efficient metalation of phenylpyridines and stabilization
of phenylpyridyllithium. The BuLi-LiDMAE superbase
prevented dimerization or nucleophilic addition encountered
with t-BuLi or n-BuLi. The reported selective pyridine ring
lithiation of 2-, 3-, and 4-phenylpyridine R to nitrogen opens
a straightforward access to their derivatives.
25
n-BuLi (2-4)
n-BuLi (2-4)
THF, -78 °C, 1 h
hexane, 0 or -78 °C,
1-3 h
24 (3b)
2 (3b)
n-BuLi-TMEDA (2)
n-BuLi-LiDMAE (2) hexane, 0 °C, 1 h
n-BuLi-LiDMAE (3) hexane, 0 °C, 1 h
hexane, 0 °C, 1 h
17 (3b)
75c
>99c
Phenylpyridines and their derivatives are important
compounds1 for their agrochemical2 and pharmaceutical3
applications. Functional phenylpyridines have been pre-
pared by metal-catalyzed cross-coupling of substituted
aryl and pyridyl partners,4 amino-dienes ring closure
processes,5 or modification of the parent phenylpyridines.
The latter methodology refers essentially to substitution
of the phenyl group, particularly with 2-phenylpyridine
1 whose ortho-aromatic activated C-H bond is easily
cleaved by transition metal complexes.6
On the other hand, the functionalization of the pyridyl
group has been far less studied. A zirconium-mediated
C-H activation via nitrogen complexation has been
reported leading to introduction of some substituents R
to nitrogen.7 Aryl groups were also coupled in low yield
at the 6-position via nucleophilic addition of aryl-
lithiums.8 Curiously, metalation of unsubstituted phenyl-
pyridines by lithium reagents, a widely used methodology
to introduce functionalities onto heterocycles, has not
a
b
All reactions performed on 2 mmol (310 mg) of 1. GC yields.
For each run the remaining part is unreacted 1. c Reaction of
MeSSMe (3-7.2 mmol) performed at -78 °C in the same solvent
as used for metalation.
been mentioned yet. Our laboratory has reported a new
reagent (BuLi-LiDMAE) for the selective R lithiation of
pyridine derivatives in apolar solvents (hexane or tolu-
ene).9 The regioselectivity was a consequence of a co-
operative chelation of lithium by pyridine nitrogen and
lithium dimethylaminoalkoxide (LiDMAE).10 We have
now investigated if such a reagent could promote the
metalation of the pyridine ring of phenylpyridines.
We first studied the lithiation of 2-phenylpyridine 1.
As no data were available about this reaction, we also
examined the reactivity of 1 toward some commonly used
lithium bases (Table 1).
The less basic lithium dialkylamides did not metalate
1 in THF even when used in excess, implying the use of
stronger bases such as n-BuLi or t-BuLi. Unfortunately,
none of these reagents led to the expected compound 2a
with main recovery of unreacted 1. In hexane, no meta-
lation occurred and n-BuLi led to limited nucleophilic
addition product 3b while in THF addition products 3a ,b
were substantial. The reactivity of t-BuLi in Et2O was
of interest since no addition product was detected, and
dimer 4 was produced in 25% yield. This indicated that
lithiation actually occurred at C-6 of the pyridine ring
and the formation of 4 could be explained by nucleophilic
addition of the lithio derivative onto the azomethine bond
of unreacted 1 before introduction of electrophile. The
metalation was next attempted with n-BuLi-TMEDA in
hexane expecting an increase of basicity of n-BuLi as well
(1) Degussa, H. B. Aldrichim. Acta 1981, 14, 13.
(2) (a) Nakajima, T.; Komyoji, T.; Akagi, T.; Nagatani, K.; Haga,
T.; Matsuo, N.; Suzuki, K. ACS Symp. Ser. 1995, 584, 443. (b) Schaefer,
P.; Hamprecht, G.; Heistracher, E.; Klintz, R.; Koenig, H.; Walter, H.;
Westphalen, K.-O.; Mislitz, U. Ger. Offen. DE 19500760, 1996; Chem.
Abstr. 1996, 125, 167793.
(3) (a) Okada, T.; El-Mehasseb, I. M.; Kodaka, M.; Tomohiro, T.;
Okamoto, K.; Okuno, H. J . Med. Chem. 2001, 44, 4661. (b) Pasquinet,
E.; Rocca, P.; Richalot, S.; Gueritte, F.; Guenard, D.; Godard, A.;
Marsais, F.; Queguiner, G. J . Org. Chem. 2001, 66, 2654.
(4) (a) Choppin, S.; Gros, Ph.; Fort, Y. Org. Lett. 2000, 6, 803. (b)
Liu, S.-Y.; Choi, M. J .; Fu, G. C. Chem. Commun. 2001, 23, 2408. (c)
Alami, M.; Peyrat, J .-F.; Belachmi, L.; Brion, J .-D. Eur. J . Org. Chem.
2001, 22, 4207. (d) Chapman, G. M.; Stanforth, S. P.; Tarbit, B.;
Watson, M. D. J . Chem. Soc., Perkin Trans. 1 2002, 5, 581.
(5) Church, R.; Trust, R.; Albright, J . D.; Powell, D. W. J . Org. Chem.
1995, 60, 3750.
(6) (a) Ryabov, A. D. Chem. Rev. 1990, 90, 403. (b) Lim, Y.-G.; Kang,
J .-B.; Kim, Y. H. J . Chem. Soc., Perkin Trans. 1 1996, 17, 2201. (c)
Djukic, J .-P.; Maisse, A.; Pfeffer, M.; Do¨tz, K. H.; Nieger, M. Organo-
metallics 1999, 18, 2786. (d) Oi, S.; Fukita, S.; Hirata, N.; Watanuki,
N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 16, 2579.
(9) For a review see: Gros, Ph.; Fort, Y. Eur. J . Org. Chem. 2002,
20, 3375.
(7) Guram, A. S.; J ordan, R. F. Organometallics 1991, 10, 3470.
(8) Overberger, C. G.; Herin, L. P. J . Org. Chem. 1962, 27, 2423.
(10) Gros, Ph.; Choppin, S.; Mathieu, J .; Fort, Y. J . Org. Chem. 2002,
67, 234.
10.1021/jo026706o CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/30/2003
2028
J . Org. Chem. 2003, 68, 2028-2029

TABLE 2. P r ep a r a tion of C-6 Su bstitu ted
2-P h en ylp yr id in esa
In summary we have shown that BuLi-LiDMAE is a
powerful base for the direct pyridine ring metalation of
2-, 3-, and 4-phenylpyridines offering a straightforward
access to derivatives. This work also revealed the ability
of lithium aggregates to prevent dimerization by efficient
stabilization of phenylpyridyllithium.
Exp er im en ta l Section
electrophile
product
FG
yield,b %
Et2O, THF, and hexane were distilled and stored on sodium
wire before use. 2-Dimethylaminoethanol was distilled under
nitrogen and stored on molecular sieves. t-BuLi was used as a
1.5 M solution in pentane. n-BuLi was used as a 1.6 M solution
in hexanes. LDA and LTMP were prepared respectively by
reaction of diisopropylamine and 2,2,6,6-tetramethylpiperidine
with n-BuLi in THF.
MeSSMe
C2Cl6
CBr4
ClSnBu3
ClPPh2
2a
2b
2c
2d
2e
SMe
Cl
Br
SnBu3
PPh2
92
81
89
72
55c
a
b
All reactions performed on 2.66 mmol (412 mg) of 1. Isolated
P r oced u r e for lith ia tion of p h en ylp yr id in es 1 or 3. A
solution of 2-dimethylaminoethanol (0.8 mL, 8 mmol) in hexane
(10 mL) was cooled at 0 °C and treated dropwise with n-BuLi
(10 mL, 16 mmol). After 30 min at 0 °C, a solution of appropriate
phenylpyridine (412 mg, 2.66 mmol) in hexane (5 mL) was added
dropwise. After 1 h at 0 °C, the red brown reaction mixture was
cooled to -78 °C and treated with a solution of appropriate
electrophile (9.6 mmol) in hexane (5 mL). After 1 h at -78 °C
the temperature was allowed to raise to room temperature. The
hydrolysis was then performed at 0 °C with H2O. The organic
layer was then extracted twice with diethyl ether, dried over
MgSO4, and evaporated under vacuum. The crude products 2
or 4 were then purified by column or radial chromatography with
hexane/AcOEt mixtures as eluent.
yields after column chromatography (hexanes-AcOEt mixtures).
c Air-sensitive 2e has been fully oxidized (H2O2) into the corre-
sponding phosphine oxide and analyzed as such.
SCHEME 1. Meta la tion of 3- a n d
4-P h en ylp yr id in ea
2a . Column chromatography (95:5 hexanes/AcOEt) yielded 2a
1
(592 mg, 92%) as a yellow oil. H NMR δH 2.67 (s, 3H), 7.13 (d,
J ) 7.6 Hz, 1H), 7.39-7.56 (m, 5H), 8.05 (br d, J ) 8 Hz, 2H).
13C NMR δC 13.3, 115.6, 120.2, 126.9, 128.8, 129.2, 136.6, 156.1,
159.5 ppm. MS (EI) m/z 201 (M+, 100), 200 (68), 155 (28), 154
(49), 127 (20), 77 (14), 51 (23). Anal. Calcd for C12H11NS: C, 71.60;
H, 5.51; N, 6.96. Found C, 71.51; H, 5.62; N, 7.12.
a
Reagents and conditions: (a) (i) BuLi-LiDMAE (3 equiv for
3; 4 equiv for 5), hexane, 0 °C, 1 h; (ii) MeSSMe or CBr4 (3.6 equiv
for 3; 4.8 equiv for 5), hexane, -78 °C to rt.
4a . Radial chromatography (95:5 hexanes/AcOEt) yielded 4a
1
(409 mg, 77%) as a yellow oil. H NMR δH 2.61 (s, 3H), 7.22 (br
as a stabilization of pyridyllithium by diamine. Only
addition product 3b was obtained in this case with low
conversion of 1.
On the other hand, the reaction with BuLi-LiDMAE
in hexane at 0 °C induced the unprecedented clean C-6
lithiation of the pyridine ring. Compound 2a was ob-
tained as a single product in good to excellent yield in
sharp contrast with standard alkyllithiums.
d, J ) 7.4 Hz, 1H), 7.55-7.60 (m, 5H), 7.71 (dd, J ) 7.4 and 0.7
Hz, 1H), 8.68 (d, J ) 0.7 Hz, 1H). 13C NMR δC 13.5, 113.1, 121.5,
126.9, 127.9, 129.1, 129.2, 134.5, 147.9, 163.5 ppm. MS(EI) m/z
202 (M+ + 1, 17), 201 (M+,100), 200 (46), 168 (26), 154 (30), 77
(18), 51 (18). Anal. Calcd for C12H11NS: C, 71.60; H, 5.51; N,
6.96. Found C, 71.74; H, 5.41; N, 7.05.
P r oced u r e for Lith ia tion of 4-P h en ylp yr id in e 5. The
procedure used with 1 and 3 was modified as follows: 5 (310
mg, 2 mmol) was added as a solid through a powder addition
funnel.
To illustrate the scope of this new lithiation process,
we performed the condensation of some typical electro-
philic reagents (Table 2).
6a .11 Radial chromatography (95:5 hexanes/AcOEt) yielded
1
6a (320 mg, 80%) as a yellow oil. H NMR δH 2.52 (s, 3H), 7.16
We next examined the ability of our reagent to meta-
late the other phenylpyridine isomers 3 and 5 whose,
from our knowledge, direct lithiation has not been
reported (Scheme 1). As shown 3 and 5 were efficiently
lithiated R to nitrogen and functionalities could be
introduced in very good yields at this position. While the
selective C-2 lithiation obtained with 5 could be expected,
more interesting was the exclusive lithiation at C-6 of 3.
Indeed, no regiosiomer resulting from a lithiation at C-2
was detected. Curiously, with 5 a larger amount of base
had to be used to ensure completion of reaction. An
explanation could be the slight solubility of 5 in hexane.
(dd, J ) 5.4 and 1.6 Hz, 1H), 7.36-7.49 (m, 4H), 7.55 (d, J ) 1.6
Hz, 1H), 7.61 (m, 1H), 8.45 (dd, J ) 5.5 and 0.8 Hz, 1H). 13C
NMR δC 13.4, 113.1, 115.5, 117.8, 119.3, 127.1, 127.2, 128.6,
129.2, 138.1, 149.9, 160.7 ppm. MS (EI) m/z 201 (M+, 100), 200
(60), 155 (44), 127 (21), 77 (15), 51 (18).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 2b-e, 4b, and 6b. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026706O
(11) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43, 2273.
J . Org. Chem, Vol. 68, No. 5, 2003 2029