Unusual sterically controlled regioselective lithiation of 3-bromo-5-(4,4′-dimethyl)oxazolinylpyridine. Straightforward access to highly substituted nicotinic acid derivatives

Article abstract of DOI:10.1021/ol062556i

(Chemical Equation Presented) Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4′-dimethyl)oxazoline with lithium amides is reported. The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4′-dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic acids.

Full text of DOI:10.1021/ol062556i

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6071-6074
Unusual Sterically Controlled
Regioselective Lithiation of
3-Bromo-5-(4,4′-dimethyl)oxazolinylpyridine.
Straightforward Access to Highly
Substituted Nicotinic Acid Derivatives
Nicolas Robert, Anne-Laure Bonneau, Christophe Hoarau, and Francis Marsais*
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, INSA et
UniVersite´ de Rouen, IRCOF-INSA Rouen BP08, 76131 Mont Saint Aignan Cedex,
France
francis.marsais@insa-rouen.fr
Received October 17, 2006
ABSTRACT
Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4′-dimethyl)oxazoline with lithium amides is reported.
The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4 -dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing
′
a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic
acids.
Nicotinic acid (Niacin, Vitamin B3) and nicotinamides are
important members of the B-vitamin group and represent
the active moiety of both coenzymes NAD/NADP involved
in many metabolic processes.1 Niacin is known also as a
very efficient lipid-regulating agent clinically used for the
treatment of severe dyslepidemia and the atherosclerotic
cardiovascular disease.2 Moreover, functionalized nicotinic
acid derivatives, including amide, ester, and oxazoline, have
been used extensively to design pharmacophores in disease
states such as obesity,2 cancer,3 inflammatory,4 and pain,5
as well as pesticides.6 Such scaffolds are also versatile
building blocks for the preparation of complex azahetero-
cycles. The directed orthometalation (DoM) reaction has been
(3) (a) Franchetti, P.; Pasquelini, R.; Petrelli, R.; Ricciutelli, M.; Vita,
P.; Cappellacci, L. Bioorg. Med. Chem. 2004, 14, 4655-4658. (b) Wildiers,
H.; Ahmed, B.; Guetens, G.; De Boeck, G.; De Bruijn, E. A.; Landuyt,
W.; Van Oosterom, A. T. Anticancer Res. 2003, 23, 4055-4060. (c) Cai,
S. X.; Nguyen, B.; Jia, S.; Herich, J.; Guastella, J.; Reddy, S.; Tseng, B.;
Drewe, J.; Kasibhatla, S. J. Med. Chem. 2003, 46, 2474-2481.
(4) (a) Becker, J. W.; Rotonda, J.; Soisson, S. M.; Aspiotis, R.; Bayly,
C.; Francoeur, S.; Gallant, M.; Garcia-Calvo, M.; Giroux, A.; Grimm, E.;
Han, Y.; McKay, D.; Nicholson, D. W.; Peterson, E.; Renaud, J.; Roy, S.;
Thornberry, N.; Zamboni, R. J. Med. Chem. 2004, 47, 2466-2474. (b)
Cutshall, N. S.; Ursino, R.; Kucera, K. A.; Latham, J.; Ihle, N. C. Bioorg.
Med. Chem. Lett. 2001, 11, 1951-1954. (c) Pero, R. W.; Axelsson, B.;
Siemann, D.; Chaplin, D.; Dougherty, G. Mol. Cell. Biochem. 1999, 193,
119-125.
(5) (a) Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med. Chem.
2005, 13, 5717-5732. (b) Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron
2004, 60, 4481-4490. (c) Cocco, M. T.; Congiu, C.; Onnis, V.; Morelli,
M.; Felipo, V.; Cauli, O. Bioorg. Med. Chem. 2004, 12, 4169-4177.
(6) Xue, S.; Ke, S.; Duan, L.; Wang, X.; Guo, Y. J. Ind. Chem. Soc.
2005, 82, 79-82.
(1) Reviews: (a) Offermanns, H.; Kleemann, A.; Tanner, H.; Beschke,
H.; Friedrich, H. In Kirk-Othmer Encyclopedia of Chemical Technology,
3rd ed.; Grayson, M., Eckroth, D., Eds; Wiley: New York, 1983; p 59. (b)
Sharmann, I. M. Nutr. Food Sci. 1982, 77, 17-19.
(2) Reviews: (a) Chan, D. C.; Barett, H. P. R.; Watts, G. F. Am. J.
CardioVasc. Drugs 2004, 4, 227-246. (b) Ganji, S. H.; Kamanna, V. S.;
Kashyap, M. L. J. Nutr. Chem. 2003, 14, 298-305.
10.1021/ol062556i CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/01/2006

widely used as a powerful and efficient method for regio-
selective functionalization of aromatics and heteroaromatics.7
Selective C-4 lithiation of nicotinamides,8 3-(4,4′-dimethyl)-
oxazolinylpyridine,9 3-cyanopyridine,10 and unprotected nico-
tinic acid11 has been successfully accomplished using lithium
dialkylamides and Hauser bases. With these achievements,
we recently sought to identify the simplest scaffold to prepare
highly functionalized niacin analogues. We selected the
5-bromonicotinic acid 1 due to the presence of two meta-
directed metalation groups (DMGs), allowing three possible
ortho substitutions using DoM methodology. Further func-
tionalizations could be also achieved exploiting the C-Br
bond synthetic value.
The bulky secondary and tertiary amides 3-5 (Scheme
2) were prepared from 5-bromonicotinic acid 1 via the
Scheme 2
The regiochemical lithiation of the 1,3-inter-related-
DMGs system specifically at the less favored ortho positions
not located between the two DMGs has been scarcely
studied.7a,12 The choice of suitable lithiating agents in the
case of the lithiation of bromopyridine models as 1 is
restricted mainly to lithium amides which avoid competitive
side reactions such as C-Br exchange and nucleophilic
addition to the pyridine nucleus. The lithiation of 5-bro-
monicotinic acid 1 using 2,2′,6,6′-tetramethylpiperidinyl-
lithium (LTMP) occurred selectively at the most hindered
C-4 position (Scheme 1).11b We further reasoned that the
corresponding acid chlorides. Treatment of 3-bromo-5-
cyanopyridine 2 with the appropriate amino alcohol in the
presence of catalytic amounts of zinc chloride cleanly
afforded multigram quantities of 3-bromo-5-(4,4′-dimethyl)-
oxazolinylpyridine 6 in excellent 95% yield.14
A first set of lithiation experiments was achieved using
LTMP at -78 °C in THF. Each lithio intermediate was
quenched with D2O (Table 1, entries 1-4). All bulky
carboxamides 3-5 showed exclusive deuterium incorporation
at the C-4 position (entries 1-3) providing deuterated
compounds 3a-5a in high isolated yields. On the other hand,
we found that the 3-bromo-5-(4,4′-dimethyl)oxazolinylpy-
ridine 6 was selectively deuterated at the C-2 position (entry
4).15 We then tried to modify the lithiation regioselectivity
of 6 from the C-2 to C-4 position. Thus, deprotonation of 6
with LTMP at -78 °C, warming at different temperatures,
and trapping the lithio intermediates with D2O clearly showed
that the C-2 lithio species slowly isomerized to the thermo-
dynamically more stable C-4 lithio isomer at -50 °C (entry
5).
We also observed that the 4-lithiopyridine previously
formed at -50 °C underwent degradation at -40 °C (entry
6). The lithiation of 3-bromo-5-(4,4′-dimethyl)oxazolinylpy-
ridine 6 was carried out with a less hindered amide base,
lithium diisopropylamine (LDA), at -78 °C in THF.
Surprisingly, quenching the lithio intermediate with D2O led
exclusively to isolation of the C-4 deuterated product 6a in
90% yield (entry 7). Thus, steric hindrance appeared to be
the major factor controlling the regioselectivity of deproto-
nation of 6. To gain further support for this assumption, we
examined the lithiation of the less hindered oxazoline 7,
prepared from 3-bromo-5-cyanopyridine 2 in 56% yield
(Scheme 2).
Scheme 1. C-4 Lithiation of 5-Bromonicotinic Acid 1
addition of external (base) and/or internal (DMG) steric
effects might drive the challenging ortho lithiation at less
hindered sites.
As a preliminary assay, the unprotected nicotinic acid 1
was reacted with the most highly hindered lithium (tert-
butyldimethylsilyl)-tert-butylamide (LiBSBA)13 in THF for
30 min at -50 °C followed by D2O quenching to provide
exclusively the C-4 deuterated product in 82% yield. Herein
we report our results from a thorough screening of bulky
carboxylic acid derived DMGs which identified the (4,4′-
dimethyl)oxazoline as a suitable DMG to control the ortho
lithiation at both C-Br ortho positions.
(7) (a) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376-393. (b)
Anctil, E. J. G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling Reactions;
2nd ed.; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; p 761. (c) Snieckus, V. Chem ReV. 1990, 90, 879-933.
(8) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059-4090.
(9) Meyers, A. I.; Gabel, R. A. J. Org. Chem. 1982, 47, 2633-2637.
(10) Cailly, T.; Fabis, F.; Lemaˆıtre, S.; Bouillon, A.; Rault, S. Tetrahe-
dron Lett. 2005, 46, 135-137.
As expected, treatment of 7 with LTMP (entry 8) followed
by quenching with D2O mainly provided the C-4 deuterated
compound 7a (entry 8).
(11) (a) Lazaar, J.; Rebstock, Hoarau, C.; Mongin, F; Tre´court, F.;
Godard, A.; Marsais, F.; Que´guiner, G. Tetrahedron Lett. 2005, 46, 3811-
3813. (b) Lazaar, J.; Rebstock, A.-S.; Mongin, F.; Godard, A.; Tre´court,
F.; Marsais, F.; Que´guiner, G. Tetrahedron 2002, 58, 6723-6728.
(12) Nguyen, T.-N.; Chau, N. T. C.; Castanet, A.-S.; Nguyen, K. P. P.;
Mortier, J. Org. Lett. 2005, 7, 2445-2448.
(14) Witte, H.; Seeliger, W. Liebigs Ann. Chem. 1974, 996-1009.
(15) 1H NMR spectra of C2 deuterated product 6b showed two
characteristic doublets corresponding to the H-4 and H-6 protons, which
both correlate in the HMBC NMR spectra with the quaternary carbon C-5′
of the oxazolinyl group.
(13) Cameron, W.; Guay, B.; Scheuermeyer, F. J. Org. Chem. 1997,
62, 758-760.
6072
Org. Lett., Vol. 8, No. 26, 2006

Scheme 3. C-2 and C-4 Substitution of 6a
Table 1. Lithiation of 3-Bromo-5-carboxypyridines 3-7a
a Base (1 equiv), electrophiles (1-6 equiv). The superscripts b-h
depict the following electrophiles: bCl2, cI2, dSiMe3Cl, eCNCO2Et,
f3,4,5-trimethoxybenzaldehyde, gN-tosylbenzylimine, hallyl bromide.
iIsolated yield of 9g. Yields are isolated yields. See the Supporting
Information for details.
1
a Percent of deuterium incorporation estimated by H NMR. b Isolated
overyields. c Isolated overyield is 56%.
product 8g in 70% yield. Interestingly, the same procedure
could be used to improve the yield of the C-4 allylation after
lithiation with LDA, leading to the C-4 allylated compound
9g in 82% yield (Scheme 4).
Application of the regiocontrolled lithiation of 6 using
LTMP or LDA followed by trapping the respective C-2 or
C-4 lithio intermediates at -78 °C with various electrophiles
led to a large panel of C-2 and C-4 substituted 3-bromo-5-
oxazolylpyridines. Halogenation, carboxyethoxylation, amino
and hydroxyl alkylation, and trimethylsilylation of 6 could
be thus achieved either at C-2 or C-4 positions in moderate
to excellent yields using the appropriate electrophiles as
depicted in Scheme 3. However, the C-2 allylated compound
8g could not be obtained by treating the C-2 lithio derivative
of 6 neither with allylbromide nor with allyliodide at -78
°C whatever the reaction time. Allylation of 6 was also
successfully realized at the C-4 position, affording 9g in
moderate 56% yield.
Warming the reaction to room temperature led to prior
isomerization of the C-2 lithio species to the C-4 lithio isomer
with subsequent allylation to give 9g in 40% yield (Scheme
3).
Regioselective C-2 lithiation of 6 followed by Li/Zn
transmetalation and subsequent copper-catalyzed allylation
was envisaged for achieving C-2 allylation (Scheme 4).16
Treatment of 6 with LTMP at -78 °C, reaction with
anhydrous ZnCl2, and warming immediately to room tem-
perature for 1 h before addition of allylbromide in the
presence of CuCN‚2LiCl afforded the expected C-2 allylated
Scheme 4. C-2 and C-4 Allylation of 6a
a Base (1 equiv), ZnCl2 (1.1 equiv), CuCN‚2LiCl (1.1 equiv),
allyl bromide (1.1 equiv). See the Supporting Information for details.
The intermediate C-2 and C-4 pyridylzinc chlorides are
stable at room temperature and are thus potential candidates
for palladium-catalyzed cross-coupling reactions. Thus, both
C-2 and C-4 pyridylzinc chlorides were treated with various
phenyliodides (1 equiv) in the presence of Pd(PPh3)4 (5 mol
%) as catalyst in refluxing THF for 20 h (Scheme 5). Further
treatment with EDTA allowed isolation of expected 2- and
4-phenyl products 10a-c and 11a-c in good to high yields
as depicted in Scheme 5.
(16) For a unique example of bromopyridine lithiation and subsequent
Li/Zn transmetalation followed by Pd-mediated Negishi coupling, see:
Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3, 835-838.
The usefulness of this strategy was later illustrated by the
synthesis of 4- and 6-arylated 5-bromonicotinic acids as
Org. Lett., Vol. 8, No. 26, 2006
6073

Scheme 5. C-4 and C-6 Arylation of 6a
Scheme 6. Niacin Analogue Synthesisa
a Base (1 equiv), Ar-I (1 equiv), Pd(PPh3)4 (5% mol). Yields
are isolated yields. See the Supporting Information for details.
niacin analogues. The 4-arylated 5-bromonicotinic acids may
be also selected precursors to design new 5-bromo-4-aryl-
N-benzylnicotinamide as neurokinin-1 (NK1) receptor an-
tagonists.17 Hydrolysis of the oxazoline group was achieved
under either acidic or basic conditions after prior specific
chlorination18 of the oxazoline nitrogen atom. Expected
nicotinic acids 12a-c and 13a-c were obtained in 59-43%
overall yields in four-step synthesis from 2 (Scheme 6).
In summary, we have developed a regioselective lithiation
of 3-bromo-5-(4,4′-dimethyloxazolynyl)pyridine 6 which
provides a new versatile pathway to various substituted
5-bromonicotinic acid derivatives by electrophilic quench,
Cu(II)-catalyzed allylation, or Negishi cross-coupling after
Li/Zn transmetalation. The method was used as an efficient
a Yields are isolated yields. See the Supporting Information for
details.
entry to novel 4- and 6-aryl-5-bromonicotinic acids as novel
niacin analogues. Further substitutions of these unprotected
nicotinic acid analogues at the C-5 position may be consid-
ered, taking advantage of the broad synthetic value of the
C-Br bond.19
(17) Ishichi, Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004, 60, 4481-
4490.
Acknowledgment. This work has been supported by the
(18) Weinreb, S. H.; Levin, J. I. Tetrahedron Lett. 1982, 23, 2347-
2350.
CNRS, INSA of Rouen, and University of Rouen (I.U.T.).
(19) For C-Br arylation of 5-bromonicotinic acid, see: (a) Ferna`ndez,
J.-C.; Feu, L. S.; Ferna´ndez, D.; de la Figuera, N.; Forns, P.; Alberico, F.
Tetrahedron Lett. 2005, 46, 581-585. (b) Daku, K. M. L.; Newton, R. F.;
Pearce, S. P.; Vile, J.; Williams, J. M. J. Tetrahedron Lett. 2003, 44, 5095-
5098. (c) Hone, N. D.; Payne, L. J.; Tice, C. M. Tetrahedron Lett. 2001,
42, 1115-1118. (d) Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahe-
dron Lett. 1998, 39, 4175-4178.
Supporting Information Available: Experimental de-
tails. The material is available free of charge via the Internet
at http://pubs.acs.org.
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