First one-pot chemo-, regio- and enantioselective functionalisation of pyridine compounds mediated by BuLi-(S)-(-)-N-methyl-2-pyrrolidine methoxide

Article abstract of DOI:10.1016/S0957-4166(01)00454-2

BuLi-(S)-(-)-N-methyl-2-pyrrolidine methoxide (noted BuLi-LiPM*) is the first superbase promoting an unprecedented regioselective C-6 lithiation of pyridine compounds while controlling the asymmetric addition on aldehydes.

Full text of DOI:10.1016/S0957-4166(01)00454-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2631–2635
First one-pot chemo-, regio- and enantioselective
functionalisation of pyridine compounds mediated by
BuLi-(S)-(−)-N-methyl-2-pyrrolidine methoxide
Yves Fort,* Philippe Gros and Alain L. Rodriguez
Synthe`se Organique et Re´activite´, UMR CNRS-UHP 7565, Universite´ Henri Poincare´-Nancy I, BP 239,
54506 Vandoeuvre-Le`s-Nancy, France
Received 2 October 2001; accepted 17 October 2001
Abstract—BuLi-(S)-(−)-N-methyl-2-pyrrolidine methoxide (noted BuLi–LiPM*) is the first superbase promoting an unprece-
dented regioselective C-6 lithiation of pyridine compounds while controlling the asymmetric addition on aldehydes. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
cal nucleophilic addition of BuLi onto the hetero-
aromatic ring. Furthermore, an unprecedented regio-
selective lithiation at C-a of the pyridinic ring is ob-
tained avoiding the classical halogen–metal exchange
on the corresponding brominated derivatives (Scheme
2).
Pyridylalcohols are excellent candidates as chiral sub-
structures of several ligands for asymmetric synthesis
and kinetic resolution (Scheme 1).1 Obviously, the ease
of determining such species in enantiomerically pure
form shows their synthetic usefulness. Two methodolo-
gies have emerged during the past decade. The most
efficient synthesis of non-racemic pyridylalcohols
reported to date is a multistep reaction involving subse-
quent asymmetric reduction of the corresponding
pyridylketones by chiral borane.1a Several diastereose-
lective approaches have also been described based on
trapping organolithium intermediates with optically
active ketones.2
In connection with these studies, we aimed to develop a
new and useful superbase formed by association of
BuLi with chiral vicinal aminoalkoxides.4 The obtained
BuLi–R*OLi reagent should allow direct and regiose-
lective metallation of the pyridinic ring while con-
trolling unprecedented asymmetric addition of the
formed pyridyl lithium to aldehydes.
In our recent work,5 we have shown that the BuLi–
LiDMAE superbase promoted the clean C-6 function-
alisation of 2-chloropyridine. This reaction was chosen
as a model since the CꢀCl bond could also offer further
sources of functionalisation. Thus, we first studied the
reaction with several aminoalkoxides using the best
Recently, our laboratory has reported the usefulness of
BuLi–Me2N(CH2)2OLi (noted BuLi–LiDMAE) for the
metallation of pyridine compounds in apolar solvents.
The aminoalkoxide increases the BuLi basicity/nucle-
ophilicity ratio,3 this superbase then prevents the classi-
Scheme 1.
* Corresponding author. E-mail: yves.fort@sor.uhp-nancy.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00454-2

2632
Y. Fort et al. / Tetrahedron: Asymmetry 12 (2001) 2631–2635
gates is known to be changed by incorporation of
chelating solvents.6 THF was then introduced before
benzaldehyde and a remarkable increase of e.e. (from
35 to 58%) was obtained (Table 1, entry 6/Table 2,
entry 1). A decrease of THF resulted in a dramatic
drop in e.e. (Table 2, entry 2). The asymmetric induc-
tion and yield were not significantly modified by lower-
ing the temperature (Table 2, entry 3). The effect of
cosolvent on e.e. was also crucial and a screening of
various solvents at −78°C revealed THF as the best one
(Table 2, entries 1, 4–7). Finally, the BuLi/LiPM*/2-
chloropyridine ratio was varied (Table 2, entries 8–11).
Even with a large excess of chiral alkoxide, the asym-
metric process was not improved (Table 2, entry 11).7
Scheme 2.
To illustrate the versatility and synthetic value of the
reaction for the preparation of chiral polyfunctional
pyridines, we used the conditions determined in Table 2
conditions previously determined with benzaldehyde as
the electrophile (Scheme 3, Table 1).5
Table 1. Functionalisation of 2-chloropyridine mediated
by BuLi–R*OLi
2. Results and discussion
As previously reported,3a the reaction course was criti-
cally dependent on the aminoalkoxide structure. Except
(S)-(−)-methyl-2-pyrrolidine methanol, which led to
35% e.e. (Table 1, entry 6), no other chiral auxiliary
induced any enantioselection. Some of them (Table 1,
entries 1, 3, 4) even led to complete 2-chloropyridine
degradation by nucleophilic addition. It may be con-
cluded that these aminoalkoxides did not contribute to
increase the BuLi basicity/nucleophilicity ratio and did
not allow the formation of a superbase. In this context,
comparison of entries 1 and 2 indicated the dramatic
effect of substitution at the neighbourhood of the nitro-
gen atom since 2-methyl-2-dimethylamino ethoxide led
to complete substrate degradation, while the 1-methyl-
2-dimethylamino ethoxide produced 1a in good yield.
This difference indicated the probable strong implica-
tion of the nitrogen atom in the lithium aggregates.
Finally, structural modification of the prolinol structure
in order to increase steric hindrance and thus facial
differentiation led to disappointing results. Indeed, even
a slight change in the nitrogen substituent by replacing
methyl with ethyl resulted in complete substrate degra-
dation (Table 1, entry 7). The same observation was
made varying substituents on the side chain (Table 1,
entries 8–10).
Thus, we decided to investigate in more detail the
reaction conditions with the BuLi–Li (S)-(−)-N-methyl-
2-pyrrolidine methoxide (noted BuLi–LiPM*) reagent
(Table 2). At first, we thought that the order of intro-
duction of the cosolvent could have an influence on
enantioselection. Indeed, the structure of lithium aggre-
Scheme 3.

Y. Fort et al. / Tetrahedron: Asymmetry 12 (2001) 2631–2635
Table 2. Functionalisation of 2-chloropyridine mediated by BuLi–LiPM*
2633
Entry
BuLi/LiPM*/substrate
T (°C)
Cosolventa
E.e.b
1a (%)c
1
2
3
4
5
6
7
8
3/3/1
3/3/1
3/3/1
3/3/1
3/3/1
3/3/1
3/3/1
1/1/1
2/2/1
4/4/1
3/6/1
−78
−78
−110
−78
−78
−78
−78
−78
−78
−78
−78
THF (1/1)
THF (10/1)
THF (1/1)
Et2O (1/1)
DMM (1/1)
DME (1/1)
58
28
58
0
41
13
0
39
46
53
28
59
59
63
55
63
65
63
23
51
59
57
d
–
THF (1/1)
THF (1/1)
THF (1/1)
THF (1/1)
9
10
11
a Hexane/cosolvent ratio given in parentheses.
b Determined by 31P NMR spectroscopy, see Section 3.
c Yields of isolated product, after column chromatography.
d Without cosolvent.
(entry 1) to examine the condensation of several pyri-
dine compounds with various representative aldehydes
(Table 3). As shown, products 1b–f were generally
obtained in good yields and moderated e.e.s. 3-Picoline
(Table 3, entry 4) had to be metalated at 0°C to ensure
efficient functionalisation. The instability of the 6-
lithio-2-fluoropyridine implied to perform both metalla-
tion and condensation of 2-fluoropyridine at −100°C
(Table 3, entry 5). Note that the BuLi–LiPM* super-
base promoted the clean C-6 functionalisation of 3-
picoline (Table 3, entry 4), according to our previous
observations with BuLi–LiDMAE.3f As recently
reported by Collum,8 the key step of stereocontrol can
be connected to the incorporation of aldehyde in a
precomplex including chiral alkoxide and a lithiated
compound. The formation of this precomplex seems to
be unfavourable when the aldehyde is substituted by an
electron-withdrawing group, the incorporation being
prevented by increasing the reactivity of aldehyde
(Table 3, entry 3).
Table 3. Functionalisation of pyridine compounds mediated by aBuLi–LiPM*

2634
Y. Fort et al. / Tetrahedron: Asymmetry 12 (2001) 2631–2635
M+ −15), 166 (7), 143 (91), 142 (100), 114 (4), 113 (15),
’
In summary, we have shown that BuLi–LiPM* is the
first ambivalent superbase allowing regioselective metal-
lation of pyridine rings and asymmetric addition of
lithiated pyridine reagents to aldehydes. This valuable
one-pot method was found to be a simple route to
chiral functional pyridine derivatives. Work is now in
progress to elucidate the mechanism of the lithiation
and the structure of aggregate(s) in order to optimise
and extend this new regio- and enantioselective process.
112 (4), 78 (7), 57 (14), 52 (5), 51 (7). [h]2D0=+7.1 (c
1.11, CHCl3). E.e. 35%.
Data for 1c: 1H NMR (CDCl3, 300 K): l=7.58 (t,
J=7.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.21 (d, J=7.6
Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.8 Hz,
2H), 5.71 (d, J=4.2 Hz, 1H), 4.50 (d, J=4.5 Hz, 1H),
3.79 (s, 3H). 13C NMR (CDCl3, 300 K): l=163.3,
159.7, 150.5, 139.8, 134.9, 128.7, 123.2, 119.9, 114.4,
75.1, 55.7. MS (EI) m/z (rel. int.): 250 (40), 249 (100,
+
’
M ), 137 (100), 113 (34), 112 (31), 94 (18), 78 (18), 77
3. Experimental
(25), 66 (10). [h]2D0=+80.2 (c 1.50, CHCl3). E.e. 45%.
The reactions were carried out under a nitrogen atmo-
sphere. All solvents were distilled and stored over
sodium. Column chromatography was carried out at
normal pressure, using silica gel 60 (0.063–0.200 nm,
Merck). Optical rotation ([h]2D0) measurements were
obtained using a Perkin–Elmer 141 polarimeter. The
e.e.s were determined by 31P NMR spectroscopy after
derivatisation with (R,R)-N,N%-diisopropylcyclohexane-
1,2-diazaphospholidine.9 Mass spectra were recorded
on a Hewlett Packard 5871, and are reported as frag-
mentation in m/z with relative intensities (%) in paren-
theses. NMR spectra were recorded on a Bruker 400
(1H at 400.1 MHz, 13C at 100.6 MHz, 31P at 162.0
MHz).
Data for 1d: 1H NMR (CDCl3, 300 K): l=7.60 (t,
J=7.8 Hz, 1H), 7.34–7.28 (m, 4H), 7.22 (d, J=7.8 Hz,
1H), 7.13 (d, J=7.8 Hz, 1H), 5.73 (s, 1H), 4.70 (bs,
1H). 13C NMR (CDCl3, 300 K): l=162.5, 150.7, 141.1,
140.1, 134.2, 129.2, 128.7, 123.6, 119.9, 74.8. MS (EI)
+
’
m/z (rel. int.): 255 (57), 254 (64, M ), 253 (100), 142
(26), 141 (32), 140 (20), 114 (31), 113 (73) 78 (27), 77
(40). [h]2D0=+37.9 (c 0.98, CHCl3). E.e. 23%.
Data for 1e: 1H NMR (CDCl3, 300 K): l=8.31 (s,
1H),7.39–7.23 (m, 6H), 7.04 (d, J=8.0 Hz), 5.71 (s,
1H), 2.26 (s, 3H). 13C NMR (CDCl3, 300 K): l=158.8,
148.5, 143.9, 138.0, 132.3, 128.9, 128.1, 127.4, 121.2,
+
’
75.3, 18.5. MS (EI) m/z (rel. int.): 199 (92, M ), 198
(100), 180 (19), 122 (32), 93 (40), 92 (30), 77 (23), 65
3.1. General procedure for the preparation of 1a–f
(14). [h]2D0=+56.4 (c 1.41, CHCl3). E.e. 39%.
n-BuLi (6 mL of a 1.6 M solution in hexanes; 9.6
mmol) was added dropwise to a solution of (S)-(−)-N-
methyl-2-pyrrolidine methanol (552 mg, 4.8 mmol) in
hexane (3 mL) cooled at 0°C. After 30 min at 0°C, the
reaction medium was cooled at −78°C and a solution of
pyridine compound (1.6 mmol) in hexane (1 mL) was
added. After 1 h at this temperature, THF (10 mL) was
added dropwise to the orange solution, and stirred for
10 min. The dark-red solution was treated with a
solution of the appropriate aldehyde (8 mmol) in THF
(2 mL). The reaction mixture was maintained at −78°C
for 30 min. Hydrolysis was then performed at this
temperature with water (5 mL) followed by extractions
at room temperature with diethyl ether (2×20 mL).
After drying over MgSO4 and evaporation of solvents,
the crude product was purified by chromatography on
silica gel using hexane–AcOEt as eluent.
Data for 1f: 1H NMR (CDCl3, 300 K): l=7.73 (q,
J=7.6 Hz, 1H), 7.42–7.28 (m, 5H), 7.15 (dd, J=7.6, 2.4
Hz, 1H), 6.82 (dd, J=7.6, 2.4 Hz, 1H), 5.75 (s, 1H),
4.32 (bs, 1H). 13C NMR (CDCl3, 300 K): l=163.2 (d,
J
CꢀF=242.0 Hz), 161.4 (d, JCꢀF=10.8 Hz), 142.7, 142.3
(d, JCꢀF=7.6 Hz), 129.0, 128.4, 127.3, 118.6 (d, JCꢀF
=
+
’
35.9 Hz), 75.4. MS (EI) m/z (rel. int.): 203 (100, M ),
202 (80), 184 (21), 174 (14), 126 (14), 107 (15), 97 (76),
77 (51), 51 (32). [h]2D0=+37.1 (c 1.01, CHCl3). E.e. 30%.
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