Lithiation of 2-chloro- and 2-methoxypyridine with lithium dialkylamides: Initial ortho-direction or subsequent lithium ortho-stabilization?

Article abstract of DOI:10.1021/jo026559u

The lithiation pathway of 2-chloro and 2-methoxypyridine with LDA and LTMP has been investigated using deuterated probes. The availability of both H-6 and H-3 protons on the pyridine nucleus was found to be critical to ensure complete C-3 lithiation. We thus concluded that the C-3 lithiation was not a straightforward process. A mechanism involving precomplexation of lithium dialkylamides near the H-6 proton and formation of a 3,6-dilithio pyridine intermediate is proposed.

Full text of DOI:10.1021/jo026559u

Lith ia tion of 2-Ch lor o- a n d 2-Meth oxyp yr id in e w ith Lith iu m
Dia lk yla m id es: In itia l Or th o-Dir ection or Su bsequ en t Lith iu m
Or th o-Sta biliza tion ?
Philippe Gros, Sabine Choppin, and Yves Fort*
Synthe`se Organique et Re´activite´, UMR CNRS-UHP 7565, Faculte´ des Sciences, Universite´ Henri
Poincare´-NancyI, BP 239, 54506, Vandoeuvre-Le`s-Nancy, France
Yves.Fort@sor.uhp-nancy.fr.
Received October 12, 2002
The lithiation pathway of 2-chloro and 2-methoxypyridine with LDA and LTMP has been
investigated using deuterated probes. The availability of both H-6 and H-3 protons on the pyridine
nucleus was found to be critical to ensure complete C-3 lithiation. We thus concluded that the C-3
lithiation was not a straightforward process. A mechanism involving precomplexation of lithium
dialkylamides near the H-6 proton and formation of a 3,6-dilithio pyridine intermediate is proposed.
SCHEME 1
In tr od u ction
For years, directed ortho-metalation (DOM) of aromatic
derivatives has proved to be a powerful synthetic tool for
functionalization (Scheme 1).1 Besides the synthetic
value, many interrogations remain concerning the origin
of the observed ortho-selectivity. Investigations on the
mechanistic pathway revealed that formation of a complex-
induced proximity effect (CIPE)2 is generally admitted.
However, other interpretations involving inductive effects
of substituents as a source of acidification have also been
developed.3
SCHEME 2
More recently, the DOM methodology has been applied
to π-deficient aromatic compounds, especially in the
pyridine series, offering an elegant route to new hetero-
cyclic compounds.4 The DOM mechanism, which has been
the topic of considerable debate, appears even more
complicated with N-containing heteroaromatic com-
pounds, since the nitrogen atom is expected to modify
inductive effects while offering an additional lithium
complexation site. This was clearly demonstrated by the
new regioselectivity obtained using a modified alkyl-
lithium. Indeed, we have already reported that the
superbase BuLi-Me2N(CH2)2OLi (BuLi-LiDMAE) used
in apolar solvents (e.g. hexane) opened access to a new
metalation site.5 We have subsequently shown that the
H-6 proton of 2-chloropyridine 1 and 2-methoxypyridine
6 was directly abstracted by the superbase BuLi-
LiDMAE (Scheme 2).6
lithiated exclusively the C-3 position according to the
DOM selectivity (Figure 1).
Since the PM3-calculated acidity values were very close
for H-3 and H-6, especially in 1,6 only the formation of
(5) (a) Gros, Ph; Fort, Y.; Caube`re, P. J . Chem. Soc., Perkin Trans.
1 1997, 20, 3071. (b) Gros, Ph; Fort, Y.; Caube`re, P. J . Chem. Soc.,
Perkin Trans. 1, 1997, 24, 3597. (c) Gros, Ph.; Ben Youne`s-Millot, C.;
Fort, Y. Tetrahedron Lett. 2000, 41, 303. (d) Choppin, S.; Gros, Ph.;
Fort, Y. Org. Lett. 2000, 2, 803. (e) Choppin, S.; Gros, Ph.; Fort, Y.
Eur. J . Org. Chem. 2001, 3, 603. (e) For a review see: Gros, Ph.; Fort,
Y. Eur. J . Org. Chem. 2002, 20, 3375.
This unprecedented selectivity strongly contrasted with
those usually obtained with LDA7 or LTMP,8 which
(1) (a) Gwensh, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1. (b)
Snieckus, V. Chem. Rev. 1990, 90, 879.
(2) Anderson, D. R.; Faibish N. C.; Beak, P. J . Am. Chem. Soc. 1999,
121, 7553.
(3) (a) Schlosser, M.; Mongin, F.; Porwisiak, J .; Dmowski, W.; Bu¨ker,
H.; Nibbering, N. M. Chem. Eur. J . 1998, 4, 1281. (b) Chadwick, S. T.;
Rennels, R. A.; Rutherford, J . L.; Collum, D. B. J . Am. Chem. Soc.
2000, 122, 8640.
(4) (a) Marsais, F.; Que´guiner, G.; Snieckus, V.; Epsztajn, J . Adv.
Heterocycl. Chem. 1991, 52, 187. (b) Mongin, F.; Que´guiner, G.
Tetrahedron, 2001, 57, 4059.
(6) Gros, Ph.; Choppin, S.; Mathieu, J .; Fort, Y. J . Org. Chem. 2002,
67, 234.
(7) (a) Comins, D.; La Munyon, D. Tetrahedron Lett. 1988, 29, 773.
(b) Tre´court, F.; Mallet, M.; Marsais, F.; Que´guiner, G. J . Org. Chem.
1988, 53, 1367. (c) Mallet, M. J . Organomet. Chem. 1991, 406, 49. (d)
Comins, D.; Bavevsky, M.; Hong, H. J . Am. Chem. Soc. 1992, 114,
10971. (e) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137.
(8) Lempereur, C., The`se de l’Universite´ de Rouen, France, 2000.
10.1021/jo026559u CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003
J . Org. Chem. 2003, 68, 2243-2247
2243

Gros et al.
SCHEME 4a
F IGURE 1.
F IGURE 2.
SCHEME 3
a
Conditions: (i) LDA (1.2 equiv), THF, -78 °C, 3 h. (ii) TMSCl
(1.5 equiv), THF, -78 °C to rt, 1 h.
SCHEME 5
aggregates at the nitrogen atom could explain the regi-
oselectivity observed with BuLi-LiDMAE.6 This result
again opened interrogations about the lithiation mech-
anism with lithium dialkylamides. Indeed, one could
wonder why these basic systems did not promote lithia-
tion at C-6. The immediate answer is that the lithiation
is initiated at C-3 and follows the DOM principles (path
a, Scheme 3). Another explanation could be the absence
of stabilization of the initially formed 6-lithio intermedi-
ate in the reaction medium, allowing equilibration toward
the more stabilized 3-lithio species (path b, Scheme 3).
From these considerations, we decided to revisit the
metalation of 1 and 6 with LDA and LTMP following the
methodology previously used to study our reagent.6 Thus,
the deuterated compounds 1-d(6), 1-d(3), 6-d(6), and
6-d(3) (Figure 2)9 were chosen as probes to investigate
the lithiation pathway.10 Replacement of the prospective
hydrogens (H-3 or H-6) by a deuterium was expected to
effect protection by KIE.11
Lith ia tion of 1, 1-d (6), a n d 1-d (3) w ith LDA.
Lithiation of 1 and its derivatives was performed with
1.2 equiv of the LDA reagent at -78 °C in THF.7e
(Scheme 4).
The results obtained were surprising when considering
the classical interpretation of ortho-lithiation. Indeed, C-3
lithiation was obtained only when H-3 and H-6 were
present on the pyridine ring. The absence of any reactiv-
ity of 1-d(6) strongly supported the involvement of the
H-6 proton in the lithiation process, since the starting
material was recovered with an unchanged deuterium
content (>98%). In the same way, the metalation of 1-d-
(3) did not give any metalation product. According to the
result obtained above with 1-d(6) and taking into account
our hypothesis of a possible metalation at C-6, a 6-sily-
lated product should have been detected at least in small
amounts from 1-d(3). An explanation could be the pro-
tonation of the 6-lithio intermediate 1-d(3)-Li(6) by
diisopropylamine delivered in the reaction medium before
electrophilic quenching (Scheme 5).
Thus, we studied the reaction with the more basic
LTMP (pKa ) 37.3; pKa ) 35.7 for LDA).4b With such a
reagent, the delivery of a less acidic conjugated amine
(TMP) in the reaction medium could be expected to
prevent protonation of lithiated intermediates and thus
to allow efficient trapping by electrophile. The metalation
was performed with 1.2 equiv of LTMP (Scheme 6).
As expected, LTMP led to 2 in better yield (95%) than
LDA (68%, Scheme 4), and compounds 1-d(3) and 1-d(6)
underwent metalation. Surprisingly, the lithiation of 1-d-
(3) resulted in a mixture of regioisomers. Deuterium at
C-3 induced a strong decrease in the yield of 2 (25%) as
well as the formation of 4-silyl and 3,6-disilyl derivatives
4-d(3) and 5, respectively, in notable amounts. The 6-silyl
derivative 3-d(3) was also obtained in significant yield
(6%), underlining the ability of LTMP to lithiate the 6
position.12 Finally, 2-d(6) was obtained in lower yield from
1-d(6) than was 2 from 1. Indeed, this compound was
obtained in 80% yield besides 15% of unreacted 1-d(6),
which displayed unchanged deuterium content. Although
this result did not allow us to exclude direct lithiation at
C-3, it also revealed the role of H-6 in the lithiation
process.
We then studied the metalation of 2-methoxypyridine
derivatives 6, 6-d(6), and 6-d(3) with the aim to examine
(9) 1-d(6), 6-d(6), 1-d(3), and 6-d(3) were prepared according to refs
5d, 5a, 7e, and 8, respectively
(10) The reported yields are average values calculated for at least
two runs. A reproducibility of (2% was observed.
(11) Examples using KIE to elucidate reaction pathways have been
reported. See for instance: (a) Kopach, M.; Meyers, A. I. J . Org. Chem.,
1996, 61, 6764. (b) Clayden, J .; Pink, J .; Westlund, N.; Wilson, F.
Tetrahedron Lett. 1998, 39, 303.
(12) Recently, Kondo and co-workers have reported a C-6 silylation
of 2-bromopyridine with LTMP in Et2O using an in situ trapping
technique. Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo, Y. Chem.
Commun. 2001, 23, 2450.
2244 J . Org. Chem., Vol. 68, No. 6, 2003

Lithiation of 2-Chloro- and 2-Methoxypyridine
SCHEME 6 a
a
Conditons: (i) LTMP (1.2 equiv), THF, -78 °C, 1.5 h. (ii) TMSCl (1.5 equiv), THF, -78 °C to rt, 1 h.
SCHEME 7a
SCHEME 8 a
a
Conditions: (i) (1) LTMP (1.2 equiv), THF, -78 °C, 1 h; (2)
ClSiMe3 (1.5 equiv), THF, -78 °C, 1 h.
a
Conditions: (i) (1) LDA (1.2 equiv), THF, 0 °C, 1 h; (2) TMSCl
(1.5 equiv) THF, -78 °C to rt, 1 h.
TABLE 1. P M3-Ca lcu la ted Mu llik en Ch a r ges for 1 a n d
6a
the effect of the methoxy group, known as a better
lithium complexing agent than chlorine, on the selectiv-
ity.
substrate
H-3
H-4
H-5
H-6
1
6
0.126
0.125
0.109
0.104
0.117
0.118
0.121
0.117
Lith ia tion of 6, 6-d (6), a n d 6-d (3) w ith LDA.
a
Calculated with PM3 method.
These substrates were lithiated according to literature
procedures. The classical conditions required 1.2 equiv
of LDA in THF at 0 °C (Scheme 7).
resulted in the strong decrease of the yield of the C-3
silylated derivative.
As shown, like with 2-chloropyridine derivatives, LDA
gave no reaction with both 6- and 3-deuterated deriva-
tives 6-d(6) and 6-d(3), which were totally recovered with
unchanged deuterium content. This again supported the
high probability of the H-6 proton involvement in the
lithiation pathway.
Interestingly, 6-d(3) did not give a mixture of regioi-
somers such as was observed with 1-d(3). Particularly,
no silylation at C-4 was detected, while such product
was obtained in 46% yield from 1-d(3). To explain such
a difference the net atomic charges on hydrogens in 1
and 6 have been calculated (PM3 method) as a reflection
of the relative acidities of the prospective protons
(Table 1).
As shown, H-4 displayed higher acidity in both sub-
strates. Thus, acidities did not allow us to explain
lithiation at C-4 exclusively with 1. We thought that the
selectivity was here rather governed by the ability of
heteroatoms at C-2 to chelate lithium. Thus the better
complexation by the methoxy group probably led to
localization of lithium dialkylamide near the oxygen atom
and the pyridine nitrogen impeding lithiation at a
position other than H-3 or H-6. With chlorine, the level
of complexation was probably much lower, consequently
Lith ia tion of 6, 6-d (6), a n d 6-d (3) w ith LTMP .
As already observed with LDA, H-3 and H-6 had to be
present to ensure the complete C-3 lithiation of 6 with
LTMP (Scheme 8).
Expectedly, the reaction of 6-d(3) allowed us to trap of
the 6-lithio intermediate, leading to compound 8-d(3) in
63% yield, underlining the ability of LTMP to directly
abstract H-6. This supported the hypothesis of the
intermediate protonation in previous reaction with LDA.
Protection of the C-3 position by deuterium was here
noteworthy, allowing a complete reversal of usual selec-
tivity. In addition, introduction of deuterium at C-6
J . Org. Chem, Vol. 68, No. 6, 2003 2245

Gros et al.
TABLE 2. Mon itor in g of 6-Li2(3,6) F or m a tion fr om
6-Li(6)
SCHEME 9
T (°C)
time (h)
6 (%)a
9 (%)a
10 (%)a
-78
-40
0
1
1
0.5
1
2
98
98
80
70
68
5
12
13
10
15
15
0
0
a
GC yields.
SCHEME 10
In agreement with eq 2a in Scheme 9, the above
experiments revealed that 6-Li2(3,6) can be formed from
6-Li(6) at 0 °C. Prolonged reaction times did not produce
larger amounts of 10, thus supporting an equilibrated
process (eq 3a). Finally, we also verified that DIA could
protonate 6-Li(6) selectively (Scheme 10). This result also
revealed the higher stability of 6-Li(3) in the reaction
medium.
allowing free lithium dialkylamide to abtract the more
acidic H-4 proton.
This study revealed the involvement of the H-6 proton
in the lithiation pathway of 1 and 6 with LDA and LTMP
and that C-3 lithiation appeared to be partly or totally
initiated at C-6 with regard to the basic reagent (Scheme
9). Thus, 1-Li(6) or 6-Li(6) could react with itself (eq 2a)
or with lithium dialkylamides (eq 2b) to give the dilithio
intermediate 1-Li2(3,6) or 6-Li2(3,6). These intermediates
then could be turned into 1-Li(3) or 6-Li(3) following two
pathways: reaction with 1 or 6 (eq 3a) or protonation at
C-6 by DIA or TMPH (eq 3b). It can be seen that
introduction of deuterium at C-6 prevents formation of
the 6-lithio intermediate, leading to the absence of
reaction with LDA or a drop of the C-3 functionalization
yield with LTMP. In the same way introduction of
deuterium at C-3 produces the 6-lithio derivative that is
totally or partially protonated with regard to acidity of
the conjugated amine delivered in the reaction medium.
Note that such a C-6 to C-3 isomerization pathway can
be related to previous works dealing with lithiation of
3-chloro and 3-fluoropyridine, where lithio intermediates
isomerization from C-2 to C-4 were also observed.13
To check the ability of the 6-lithio intermediate to
produce the 3,6-dilithio derivative, 6-Li(6) was prepared
unambiguously from 6-bromo-2-methoxypyridine and the
reaction mixture was quenched at various times and
temperatures with TMSCl (Table 2).
Con clu sion
This study reveals the ability of LDA or LTMP to first
abstract the H-6 proton of 2-chloro and 2-methoxypyri-
dine. Thus, the lithiation pathway could be not a direct
ortho-direction but rather subsequent lithium ortho-
stabilization in the reaction medium after initial lithia-
tion at C-6. Due to its higher basicity, LTMP was found
to be able to directly abstract H-3; H-6 was nevertheless
probably also involved in the metalation. It is hoped that
this study brings another argument to the open debate
of the ortho-lithiation mechanism. Work is now in
progress to investigate the structure of the proposed
intermediates as well as the lithiation process with other
ortho-directing groups in various positions of the pyridine
nucleus.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 400 and 100 MHz, respectively, with TMS as internal
standard and CDCl3 as solvent.Coupling constants (J ) are
given in hertz. GC/MS spectra were recorded in EI mode.
Ma ter ia ls a n d Solven ts. BuLi (1.6 M solution in hexane),
2-chloropyridine, 2-methoxypyridine, and dimethylaminoet-
hanol were purchased from Acros. Hexane and THF were
distilled and stored on sodium wire before use. All other
reagents were commercially available and were purified or
used as received. Compounds 27e and 77a were found to be
identical to authentic samples.
(13) (a) Marsais, F.; Bre´ant, P.; Ginguene, A.; Que´guiner, G. J .
Organomet. Chem. 1981, 216, 139. (b) Marsais, F.; Que´guiner, G.
Tetrahedron 1983, 39 (12), 2009.
2246 J . Org. Chem., Vol. 68, No. 6, 2003

Lithiation of 2-Chloro- and 2-Methoxypyridine
P r oced u r e for Meta la tion w ith LDA. To a solution of
diisopropylamine (0.34 mL, 2.4 mmol) in THF (20 mL) cooled
at -78 °C, under a nitrogen atmosphere, was added dropwise
n-BuLi (1.5 mL, 2.4 mmol). After addition, the mixture was
stirred at 0 °C for 30 min and then cooled to -78 °C and
treated dropwise by a solution of the 2-chloropyridine deriva-
tive (2 mmol) in THF (5 mL). After 3 h of stirring, TMSCl (0.45
mL, 3 mmol) in THF (5 mL) was added dropwise. After one
additional hour at -78 °C, the hydrolysis was performed at
-10 °C with diluted aqueous HCl (10%). The aqueous layer
was then extracted twice with ether. After drying (MgSO4) and
evaporation of solvents, the crude product was purified by
column chromatography (hexane/AcOEt 95:5).
1H). 13C NMR δ: -1.9, 122.8, 122.9, 123.0, 127.3, 136.7, 151.3,
170.2 ppm. MS (EI) m/z (%): 187 (M+ + 1, 20), 186 (M+, 31),
171 (100), 151 (44), 93 (59), 72 (44), 63 (19).
1
2-Ch lor o-[3-2H]-4-p yr id yl(tr im eth yl)sila n e, 4-d (3). H
NMR δ: 0.3 (s, 9H), 7.3 (d, J ) 4.8 Hz, 1H), 8.35 (d, J ) 4.8
Hz, 1H). 13C NMR δ: 2.1, 126.1, 127.2, 128.3, 128.9, 148.5,
151.1, 154.4 ppm. MS (EI) (m/z): 186 (M+) (23), 171 (100), 93
(7), 83 (5), 73 (20), 63 (10), 52 (5).
2-Ch lor o-3,6-bis(tr im eth ylsilyl)p yr id in e, 5. 1H NMR δ:
0.3 (s, 9H), 0.35 (s, 9H), 7.4 (d, J ) 7.1 Hz, 1H), 7.65 (d, J )
7.1 Hz, 1H). 13C NMR δ: 1.8, -1.3, 127, 133.9, 142.9, 157.6
(C2), 170.5 (C6). MS (EI) (m/z): 258 (M+ + 1, 17), 257 (M+, 28),
256 (M+ - 1, 5), 243 (90), 223 (79), 185 (17), 151 (22), 93 (33).
P r oced u r e for Meta la tion w ith LTMP . To a solution of
2,2,6,6-tetramethylpiperidine (0.41 mL, 2.4 mmol) in THF (10
mL) cooled at -30 °C, under a nitrogen atmosphere, was added
dropwise n-BuLi (1.5 mL, 2.4 mmol). After addition, the
mixture was stirred at 0 °C for 30 min, cooled to -78 °C, and
Lith ia tion of 2-Meth oxyp yr id in es 6, 6-d (6), a n d 6-d (3).
The procedure was identical to that with 2-chloropyridines,
excepted that the metalation with LDA was carried out at 0
°C.
2-Meth oxy-[6-2H]-3-p yr id yl(tr im eth yl)sila n e, 7-d (6). 1H
NMR δ: 7.64 (d, J ) 7.2 Hz, 1H), 6.84 (d, J ) 7.2 Hz, 1H),
3.93 (s, 3H), 0.26 (s, 9H). 13C NMR δ: -2.1, 53.9, 120.2, 127.8,
136.5, 152.9, 153.5, 154.2, 167.3 ppm. MS (EI) m/z (%): 183
(M+ + 1) (2), 182 (M+) (14), 167 (40), 137 (100), 59 (11).
2-Meth oxy-[3-2H]-6-p yr id yl(tr im eth yl)sila n e, 8-d (3). 1H
NMR δ: 7.44 (d, J ) 8.0 Hz, 1H), 7.11 (d, J ) 8.0 Hz, 1H),
3.93 (s, 3H), 0.27 (s, 9H).13C NMR δ: -1.8, 53.9, 108.7, 109.3,
109.95, 125.7, 130.3, 162.9, 170.7 ppm. MS (EI) m/z (%): 183
(M+ + 1) (5), 182 (M+) (30), 167 (100), 137 (42), 59 (13).
treated dropwise with
a solution of the 2-chloropyridine
derivative (2 mmol) in THF (5 mL). After 1.5 h of stirring,
TMSCl (0.45 mL, 3 mmol) in THF (5 mL) was introduced
dropwise. After one additional hour at -78 °C, the hydrolysis
was performed at -10 °C with diluted aqueous HCl (10%). The
workup was identical to that described above.
2-Ch lor o-[6-2H]-3-p yr id yl(tr im eth yl)sila n e, 2-d (6).1H
NMR δ: 0.35 (s, 9H), 7.2 (d, J ) 7.5 Hz, 1H), 7.75 (d, J ) 7.5
Hz, 1H). 13C NMR δ: -1.33 (C3), 121.8, 135.2, 144.9, 152.3,
153.2, 153.9 156.8 ppm. MS (EI) m/z (%): 186 (M+, 5), 171 (100),
135 (20), 107 (6), 93 (14), 78 (7), 63 (20), 53 (6).
1
2-Ch lor o-[3-2H]-6-p yr id yl(tr im eth yl)sila n e, 3-d (3). H
NMR δ: 0.3 (s, 9H), 7.40 (d, J ) 7 Hz, 1H), 7.55 (d, J ) 7 Hz,
J O026559U
J . Org. Chem, Vol. 68, No. 6, 2003 2247