First C-3 lithiation of DMAP: A new entry into chemical tuning of acylation catalysts

Article abstract of DOI:10.1039/b605170g

A TMSCH₂Li-based reagent promoted the first C-3 lithiation of DMAP opening a direct access to functional diversity in acylation catalysts. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605170g

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First C-3 lithiation of DMAP: a new entry into chemical tuning of
acylation catalysts{
Philippe C. Gros,*a Abdelatif Doudouha and Christopher Woltermannb
Received (in Cambridge, UK) 11th April 2006, Accepted 9th May 2006
First published as an Advance Article on the web 22nd May 2006
DOI: 10.1039/b605170g
A TMSCH2Li-based reagent promoted the first C-3 lithiation
of DMAP opening a direct access to functional diversity in
acylation catalysts.
4-Dimethylaminopyridine (DMAP) (1) is a well-known acylation
catalyst. Numerous reviews have pointed out the important
contribution of this organocatalyst to synthetic organic chemistry.1
From pioneering works to the present, efforts have been made to
Fig. 1 PM3 calculated charge on H-3 and H-2 protons.
elaborate more sophisticated analogues of 1. The amino part has
received attention in terms of electronic properties and chirality
and its modification is well documented.2
method), the H-3 proton exhibits the highest acidity (Fig. 1). Thus
one could conceive of realizing the deprotonation at C-3 by an
The incorporation of chiral moieties at the C-3 or C-2 position
appropriate choice of reagent and conditions.
of the pyridine ring has been the focus of much attention. The C-2
Herein is reported the first direct regioselective C-3 lithiation of
position has been functionalized using two lithiation method-
DMAP using a TMSCH2Li/LiDMAE combination in hexane–
ologies. Vedejs and Chen exploited Kessar’s strategy (BF3
complexation and LiTMP lithiation)3 to introduce carbonyl
THF. A generally applicable methodology is disclosed for the
compounds at C-2.4 This reaction was recently performed in a
preparation of valuable C-3 functional derivatives in good yields.
In the course of a research program aiming at the discovery of
more practical and selective way using the BuLi/LiDMAE
new efficient superbasic reagents, we studied the reaction of 1 with
various TMSCH2Li/LiDMAE combinations in hexane (Scheme 1,
Table 1).
(LiDMAE = Me2N(CH2)2OLi) superbase. A strong coordination
of lithium by pyridine nitrogen and subsequent aggregate
formation placed n-BuLi in adequate position for H-2 proton
abstraction.5
We were surprised to observe that in contrast with BuLi/
LiDMAE which gave exclusive C-2 lithiation (entry 1),5 the C-3
lithiation was observed in significant amount (entries 3 and 4). This
meant that TMSCH2Li was probably not completely chelated by
both LiDMAE and pyridine nitrogen allowing C-3 lithiation to
occur. Interestingly, LiDMAE activated TMSCH2Li since the
latter was found to be inert when used alone (entry 2).
In contrast, the abstraction of H-3 protons by lithium bases has
not been reported due to the low efficiency of Me2N– to
orthodirect the reaction.6 From our knowledge, only a trifluoro-
acetic group7 and bromine8 have been introduced by heating 1
with trifluoroacetyl anhydride or bromine, respectively, in basic
media. While the 3-bromo derivative has been submitted with
success to cross-couplings by Spivey et al.,9 more doubtful was the
effectiveness of the bromine–lithium exchange which was reported
to work fairly well by Vedejs and coworkers10 and sluggishly by
Levacher and coworkers, who turned to bromine–magnesium
exchange.11
Taking into account these limitations in reactivity and
substitution diversity, the development of a general methodology
for the direct introduction of functionalities at C-3 of DMAP
remains a challenging synthetic goal. Thanks to electronic delo-
calisation as attested by charge calculations (PM3 semiempirical
Scheme 1 Lithiation of 1 under various conditions.
Table 1 Lithiation of 1 in hexanea
aSynthe`se Organome´tallique et Re´activite´, UMR CNRS-UHP 7565
Universite´ Henri Poincare´, Faculte´ des Sciences, Boulevard des
Aiguillettes, 54506 Vandoeuvre-le`s-Nancy, France.
E-mail: philippe.gros@sor.uhp-nancy.fr; Fax: +33 3836 84785;
Tel: +33 3836 84979
LiDMAE
(equiv.)
Entry RLi (eq.)
Conv. (%) 1ab (%) 1bb (%)
1
2
3
4
a
BuLi (2)
2
—
1
100
0d
37
60
96c
—
18
44
—
—
18
15
TMSCH2Li (2)
TMSCH2Li (2)
TMSCH2Li (2)
bFMC Corporation, Lithium Division, Highway 161 Box 795, Bessemer
City, NC, 28016, USA. E-mail: CHRIS_WOLTERMANN@fmc.com;
Fax: +1 704 868 5496; Tel: +1 704 868 5421
2
Metallation performed on 1.84 mmol of 1 in hexane at r.t. for 4 h.
Isolated yields. Metallation at 0 uC for 1 h. No reaction
occurred.
b
c
d
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterization of compounds 1a–g. See DOI: 10.1039/
b605170g
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2673–2674 | 2673

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synthetically useful functionalities suitable for cross-couplings or
Table 2 Lithiation of
hexane–THFa
1
with TMSCH2Li-based reagents in
Conv. 1ab 1bb
asymmetric transformations (Scheme 2). A range of C-3 functional
derivatives has been prepared efficiently using only a stoichio-
metric amount of electrophile in each case even for sensitive
moieties such as aldehyde12 or tin halide indicating the very low
nucleophilicity of the basic reagent.
TMSCH2Li LiDMAE Additive
Entry (equiv.)
(equiv.)
(equiv.)
(%)
(%) (%)
1
2
3
4
5
6
7
8
a
1
1
1
1
2
2
2
2
0
—
—
55
51
—
—
—
—
—
—
—
—
55
50
49
48
55
85
75
70
0.05
—
1
0
1
DIA (0.05)c 50
In summary, the first direct C-3 lithiation of DMAP has been
realized. The TMSCH2Li/LiDMAE reagent effected a highly
regioselective metallation process when used in a hexane–THF
medium. When compared with current methodologies that allow
the introduction of only a few substituents, this lithiation is of
particular interest to design new DMAP-based acylation catalysts
by broadening functional diversity.
—
—
—
—
49
56
86
76
2
—
TMEDA (2) 79
Metallation performed on 1.84 mmol of 1 in hexane–THF (1 : 1)
b
c
at 0 uC for 4 h. GC yields. DIA: Diisopropylamine.
The authors would like to thank FMC Corporation, Lithium
Division for financial support and Sandrine Adach (Nancy) for
recording the mass spectra.
Notes and references
{ General procedure for C-3 functionalisation of 1. TMSCH2Li (6 mL of a
0.92 M solution in hexane, 5.52 mmol) was added dropwise to a solution of
2-dimethylaminoethanol (164 mg, 1.84 mmol) in hexane (6 mL) at 0 uC.
After 30 min of stirring, a solution of 1 (1.84 mmol) in THF (12 mL) was
then added dropwise. The solution was then stirred for 4 h at the same
temperature then treated at 278 uC with a solution of the appropriate
electrophile (2.02 mmol) in THF (1 mL). The temperature was maintained
at 278 uC for 1 h and at 0 uC for 30 min. Hydrolysis was then performed at
this temperature with water (10 mL). Then the reaction medium was
extracted twice with diethyl ether (25 mL), the organic layer dried over
MgSO4 and evaporated under vacuum. Finally, the crude product was
subjected to GC analysis and purified by column chromatography eluting
with hexane–AcOEt mixtures. See ESI{ for characterization of compounds
1a–g.
Scheme 2 Preparation of C-3 functional 4-DMAP. Reagents and
conditions: (i) TMSCH2Li (2 equiv.)–LiDMAE (1 equiv.), hexane–THF,
0 uC, 4 h; (ii) MeSSMe, CBr4, I2, ClSnBu3, PhCHO, –(CH2)5–NCHO or
PhCONMe2 (1.1 equiv.), THF, 278 uC, 1 h then r.t.
1 G. Ho¨fle, W. Steglich and H. Vorbruggen, Angew. Chem., 1978, 90, 602;
G. Ho¨fle, W. Steglich and H. Vorbruggen, Angew. Chem., Int. Ed. Engl.,
1978, 17, 569; F. V. Scriven, Chem. Soc. Rev., 1983, 12, 129;
U. Ragnarsson and L. Grehn, Acc. Chem. Res., 1998, 31, 494;
R. Murugan and E. F. V. Scriven, Aldrichimica Acta, 2003, 36, 21.
2 A. Spivey, A. Maddaford, T. Fekner, A. J. Redgrave and
C. S. Frampton, J. Chem. Soc., Perkin Trans. 1, 2000, 3460;
S. Wagaw and S. L. Buchwald, J. Org. Chem., 1996, 61, 7240;
J. P. Wolfe and S. L. Buchwald, J. Am. Chem. Soc., 1997, 119, 6054;
H. Hotsuki, H. Sakai and T. Shinohara, Synlett, 2000, 116.
3 For a review on BF3-assisted lithiations, see: S. Kessar and P. Singh,
Chem. Rev., 1997, 97, 721, and references therein.
4 E. Vedejs and X. Chen, J. Am. Chem. Soc., 1996, 118, 1809.
5 D. Cuperly, Ph. Gros and Y. Fort, J. Org. Chem., 2002, 67, 238. For
related work, see also: F. Loue¨rat, Ph. Gros and Y. Fort, Tetrahedron,
2005, 61, 4761; D. Martineau, M. Beley and Ph. C. Gros, J. Org. Chem.,
2006, 71, 566.
6 For an evaluation of the orthodirecting ability of heteroaromatic
substituents in lithiation, see: V. Snieckus, Chem. Rev., 1990, 90, 879.
7 M. Kawase, J. Koyanagi and S. Saito, Chem. Pharm. Bull., 1999, 47,
718.
8 W. W. Paudler and M. V. Jovanovic, J. Org. Chem., 1983, 48, 1064;
M. P. Groziak and L. M. Melcher, Heterocycles, 1987, 26, 2905.
9 A. C. Spivey, T. Fekner, S. E. Spey and H. Adams, J. Org. Chem., 1999,
64, 9430.
From these results, we guessed that preventing the formation of
aggregates between pyridine nitrogen and the lithiating agent using
a strongly coordinating solvent could direct the reaction towards
the C-3 lithiation. We found that THF nicely accomplished this
task since the metallation performed in a hexane–THF mixture
resulted in exclusive C-3 lithiation (Table 2). This reactivity in
THF was in sharp contrast with those of lithium dialkylamides
LDA or LiTMP which failed in lithiating 1 while BuLi/LiDMAE
gave nucleophilic addition.5
Thus TMSCH2Li was found to be sufficiently basic and non-
nucleophilic to perform the clean abstraction of the more acidic
H-3 proton even when used in stoichiometric amount (entry 1).
The incorporation of 1–2 equiv. of LiDMAE or TMEDA
dramatically improved the yields with 1b formed exclusively in
70–85% yields. However, the TMEDA-containing mixtures
exhibited poor solubility complicating the stirring process and
lowering the yield. Extended reaction times did not give higher
yields probably due to a partial protonation of the intermediate
3-lithiopyridine by THF. The TMSCH2Li/LiDMAE (2 : 1)
combination offered the best result yielding 1b in 85% yield as a
single product (entry 6).
10 S. A. Shaw, P. Aleman and E. Vedejs, J. Am. Chem. Soc., 2003, 125,
13368.
11 T. Poisson, M. Penhoat, C. Papamicae¨l, G. Dupas, V. Dalla, F. Marsais
and V. Levacher, Synlett, 2005, 15, 2285.
12 Compound 1f has been prepared in 45% yield by C-3 lithiation of
4-fluoropyridine and subsequent quenching with DMF, see: F. Marsais,
F. Tre´court, P. Bre´ant and G. Que´guiner, J. Heterocycl. Chem., 1988,
25, 81.
Then the above conditions were applied for investigating the
scope of this new lithiation.{ The reaction was then examined
using several electrophilic reagents with the aim to introduce
2674 | Chem. Commun., 2006, 2673–2674
This journal is ß The Royal Society of Chemistry 2006