Unexpected variations in sites of lithiation of N-(2-methoxybenzyl)- pivalamide

Article abstract of DOI:10.1055/s-0029-1217722

Directed lithiation of N-(2-methoxybenzyl)pivalamide with two mole equivalents of t-BuLi in anhydrous THF at -78 °C followed by reactions with various electrophiles gave ring substitution, but ortho to the methoxy group rather than ortho to the pivaloylam

Full text of DOI:10.1055/s-0029-1217722

2242
LETTER
Unexpected Variations in Sites of Lithiation of N-(2-Methoxybenzyl)-
pivalamide
Unexpected
Varia
e
S
ite
i
s
of
L
i
t
thiation
h
of
N
-(2-Methoxyb
S
enzyl)pivalam
m
ide ith,* Gamal A. El-Hiti, Amany S. Hegazy
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
Fax +44(2920)870600; E-mail: smithk13@cardiff.ac.uk
Received 21 May 2009
(Scheme 1).6 One of these involved carboxylation ortho
to the pivaloylaminomethyl group (2; isolated in 10%
yield by fractional crystallization), and the other involved
carboxylation at the side chain (3; isolated in 14% yield as
Abstract: Directed lithiation of N-(2-methoxybenzyl)pivalamide
with two mole equivalents of t-BuLi in anhydrous THF at –78 °C
followed by reactions with various electrophiles gave ring substitu-
tion, but ortho to the methoxy group rather than ortho to the piv-
aloylaminomethyl group, which was unexpected in view of earlier the methyl ester following treatment of the residue with
diazomethane).6 Again, there was no mention of lithiation
results reported with n-BuLi.
ortho to the methoxy group. Furthermore, the poor regio-
selectivity and low yields achieved in the latter reaction
render the process unattractive as a synthetic method.
Key words: N-(2-methoxybenzyl)pivalamide, directed lithiation,
synthesis, dilithium intermediate, electrophile
Based on our own experience in the use of lithium re-
agents in organic synthesis and in directed lithiation reac-
tions,7 we felt that it might be possible to develop a more
regioselective lithiation procedure for N-(2-methoxyben-
zyl)pivalamide. Therefore, we decided to undertake a
wider investigation of the directed lithiation of this com-
pound. The results, which we now report, show unexpect-
ed variations in the site of lithiation under different
conditions. As a result, we have been able to establish
conditions for a high-yielding and general ring substitu-
tion, but at the position ortho to the methoxy group rather
than ortho to the pivaloylaminomethyl group. Lithiation
at this site was not reported at all under the conditions
used by Simig and Schlosser.6
Regioselective synthesis of substituted aromatics is one of
the classical problems in synthetic chemistry. Simple
electrophilic substitution often leads to various isomers
and polysubstituted aromatics and usually takes place un-
der forcing conditions in the presence of a catalyst. In re-
cent years, many efforts have been made to develop clean
and environmentally friendly processes for the regioselec-
tive production of specific products and it is well recog-
nized that organolithium reagents1,2 can play an important
role in such cases. In particular, lithiation of aromatic
compounds often occurs proximal to substituents that pos-
sess oxygen or nitrogen atoms.3 As a result, lithiation of
aromatics or heterocycles followed by treatment with an
electrophile is one of the most efficient approaches for
synthesis of substituted and/or modified derivatives.4,5 In
connection with other work, we were interested in regi-
oselective substitution of substituted benzylamines and
wished to employ lithiation techniques for this purpose.
Initially, N-(2-methoxybenzyl)pivalamide (1) was lithiat-
ed, followed by reaction with carbon dioxide, under con-
ditions similar to those used by Schlosser. The crude
product was crystallized from ethyl acetate to give pure
white crystals of 3-methoxy-2-(pivaloylaminometh-
1
yl)benzoic acid (2)8 in 11% yield, while the H NMR
Simig and Schlosser have reported that lithiation of N-(4-
methoxybenzyl)pivalamide using n-BuLi at 0 °C, fol-
lowed by treatment with carbon dioxide, results in carbox-
ylation at the 2-position, ortho to the pivaloyl-
aminomethyl group, rather than ortho to the methoxy
group. The product was isolated in 64% yield.6 By con-
trast, following treatment of N-(2-methoxybenzyl)pival-
amide (1) in the same way two products were reported
spectrum of the mother liquor showed the presence of ad-
ditional 2 (19%), along with 3 (40%), residual 1 (17%),
and another compound, subsequently identified as 2-
methoxy-3-(pivaloylaminomethyl)benzoic acid (4; 8%).9
Our initial variation of the procedure involved attempting
the use of alternative lithiating agents, namely s-BuLi and
t-BuLi. The reactions were carried out under the same
CO2H
CO2H
NHCOt-Bu
OMe
1) n-BuLi, 0 °C
2) CO2, 0 °C
NHCOt-Bu
NHCOt-Bu
OMe
+
3) dil. HCl
OMe
1
2
3
Scheme 1 Lithiation of 1 followed by reaction with CO2 as reported by Schlosser6
SYNLETT 2009, No. 14, pp 2242–2244
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.08.2009
DOI: 10.1055/s-0029-1217722; Art ID: D12909ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unexpected Variations in Sites of Lithiation of N-(2-Methoxybenzyl)pivalamide
2243
conditions as used with n-BuLi. Crystallization of the give the corresponding N-(3-substituted 2-methoxyben-
crude product after use of s-BuLi gave 2 in 25% yield, zyl)pivalamides 4-8 in high yields (Table 2).
while crystallization of the crude product from the t-BuLi
reaction allowed isolation of two components, 2 (5%
OLi
O
yield) and 4 (40%), the structure of which was confirmed
by X-ray crystallography (Figure 1). Inspection of the 1H
NMR spectra of the residual mother liquors allowed the
overall yields of all components obtained in the reactions
to be analyzed, and the results are presented in Table 1.
N
OMe
t-BuLi
t-Bu
N
H
t-Bu
t-BuLi
–78 °C
OMe
1
–78 °C
O
OLi
1) E+
2 h, –78 °C
N
H
t-Bu
N
t-Bu
2) H3O+
OMe
OMe
E
Li
4–8 (73–86%)
Scheme 2 Lithiation of 1 with t-BuLi at –78 °C followed by reac-
tions with electrophiles
Figure 1 X-ray crystal structure of 4
Table 2 Synthesis of Products 4–8 According to Scheme 2
Product Electrophile
E
Yield
(%)a
Table 1 Yields of Components from Lithiation of 1 with RLi at
0 °C Followed by Reactions with Carbon Dioxide
4b
5c
6
CO2
CO2H
80
RLi
Approximate yields of the components of the
total product (%)a
4-MeOC6H4CHO
PhCHO
Ph2CO
4-MeOC6H4CH(OH)
PhCH(OH)
Ph2C(OH)
D
76d
75
1
2
3
4
n-BuLi
s-BuLi
t-BuLi
17
9
30
48
19
40
38
26
8
7
73e
86
–
8
D2O
a Yield of isolated product after purification by column chromatogra-
phy unless otherwise indicated.
–
49
a By combination of weights of the crystallized materials and the
quantities estimated by 1H NMR to be present in the mother liquors.
b Compound 4 was purified by crystallization from EtOAc.
c The structure of compound 5 was confirmed by X-ray crystallogra-
phy.
d Compound 9 (Figure 2) was obtained as a byproduct in 2% yield.
e Compound 10 (Figure 2) was obtained as a byproduct in 3% yield.
The results in Table 1 showed interesting variations in
product proportions. In an attempt to increase the selectiv-
ity, the reactions were each carried out at –78 °C. Lithia-
tion was conducted over four hours, the cooling bath was
then removed, and solid carbon dioxide was then added to
the reaction mixture. The reaction mixture was stirred for
a further 30 minutes while warming to room temperature,
and the products were worked up as before. The n-BuLi
reaction resulted in quantitative recovery of 1, suggesting
that lithiation with n-BuLi did not take place under these
conditions. The reaction with s-BuLi gave 2 and 3 in low-
er yields than at 0 °C, along with residual 1. However, the
reaction with t-BuLi was extremely interesting.
MeO
OH
OH
Ph
Ph
NHCOt-Bu
NHCOt-Bu
OMe
OMe
10
9
Figure 2 Structures of compounds 9 and 10
1
The H NMR spectra of 5 and 6 showed the CH2 hydro-
In this case it was possible to isolate pure 4 in 80% yield
following crystallization of the crude product. The mother
liquor showed the presence of additional 4 along with a
small quantity of 3 and traces of 1. The reaction clearly
had potential as a synthetic method, and therefore, the
same lithiation procedure was used for reactions with a
range of different electrophiles (Scheme 2). Following
workup of the reaction mixtures the crude products were
purified by column chromatography (silica gel; Et2O–
hexane, 1:3) or direct crystallization from ethyl acetate to
gens as two separated double doublets, verifying that they
are diastereotopic.
The side-chain-substituted byproduct formed in the reac-
tion with 4-anisaldehyde would be expected to be formed
as a mixture of diastereoisomers; however, its NMR spec-
tra showed what appeared to be a single set of signals, in-
dicating that the isolated product was probably a single
diastereomer. Its structure was established as 9 (Figure 2)
by X-ray crystallography. However, since this byproduct
was isolated in only 2% yield, it is possible that a small
Synlett 2009, No. 14, 2242–2244 © Thieme Stuttgart · New York

2244
K. Smith et al.
LETTER
Ducki, S. Tetrahedron 2008, 64, 6329. (f) Porcs-Makkay,
M.; Komáromi, A.; Lukács, G.; Simig, G. Tetrahedron
2008, 64, 1029. (g) Castanet, A.-S.; Tilly, D.; Véron, J.-B.;
Samanta, S. S.; Ganguly, T.; Mortier, J. Tetrahedron 2008,
64, 3331. (h) Michon, C.; Murai, M.; Nakatsu, M.; Uenishi,
J.; Uemura, M. Tetrahedron 2009, 65, 752.
amount of the other diastereoisomer was formed but not
isolated.
Clearly, the procedure outlined in Scheme 2 represents a
simple, efficient, and high yielding route for substitution
of N-(2-methoxybenzyl)pivalamide (1) ortho to the meth-
oxy group. It is not clear why lithiation of 1 with t-BuLi
in THF at –78 °C gives substitution ortho to the methoxy
group while n-BuLi and s-BuLi give mixtures containing
two main substitution products, neither of which involves
lithiation ortho to this group. It could have something to
do with the way the reagents aggregate, their ability to
chelate the two substituents, or the relative bulk of the
alkyl groups, but without further information it is not easy
to decide. However, whatever the explanation, the method
has practical significance.
(5) Recent examples for substituted heterocycles: (a)Philipova,
I.; Dobrikov, G.; Krumova, K.; Kaneti, J. J. Heterocycl.
Chem. 2006, 43, 1057. (b) Robert, N.; Bonneau, A.-L.;
Hoarau, C.; Marsais, F. Org. Lett. 2006, 8, 6071.
(c) Aliyenne, A. O.; Khiari, J. E.; Kraïem, J.; Kacem, Y.;
Hassine, B. B. Tetrahedron Lett. 2006, 47, 6405.
(d) Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron 2006, 62,
6036. (e) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org.
Lett. 2007, 9, 1263. (f) Clayden, J.; Hennecke, U. Org. Lett.
2008, 10, 3567. (g) McLaughlin, M.; Marcantonio, K.;
Chen, C.; Davies, I. W. J. Org. Chem. 2008, 73, 4309.
(h) Capriati, V.; Florio, S.; Luisi, R.; Mazzanti, A.; Musio,
B. J. Org. Chem. 2008, 73, 3197. (i) Affortunato, F.; Florio,
S.; Luisi, R.; Musio, B. J. Org. Chem. 2008, 73, 9214.
(6) Simig, G.; Schlosser, M. Tetrahedron Lett. 1988, 29, 4277.
(7) See, for example: (a) Smith, K.; El-Hiti, G. A.; Abdo, M. A.;
Abdel-Megeed, M. F. J. Chem. Soc., Perkin Trans. 1 1995,
1029. (b) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.;
Abdo, M. A. J. Org. Chem. 1996, 61, 647. (c) Smith, K.;
El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A. J. Org.
Chem. 1996, 61, 656. (d) Smith, K.; El-Hiti, G. A.;
In summary, N-(2-methoxybenzyl)pivalamide (1) under-
goes lithiation with t-BuLi at –78 °C, followed by treat-
ment with electrophiles, to give high yields of the
corresponding substituted products 4–8 having the sub-
stituent ortho to the methoxy group. This contrasts with
earlier results using other lithiating agents.
Acknowledgment
Pritchard, G. J.; Hamilton, A. J. Chem. Soc., Perkin Trans. 1
1999, 2299. (e) Smith, K.; El-Hiti, G. A.; Shukla, A. P.
J. Chem. Soc., Perkin Trans. 1 1999, 2305. (f) Smith, K.;
El-Hiti, G. A.; Hawes, A. C. Synthesis 2003, 2047.
(g) Smith, K.; El-Hiti, G. A.; Mahgoub, S. A. Synthesis
2003, 2345. (h) El-Hiti, G. A. Synthesis 2003, 2799.
(i) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F. Synthesis
2004, 2121. (j) El-Hiti, G. A. Synthesis 2004, 363.
We thank Dr Benson Kariuki, X-ray crystallography service at Car-
diff School of Chemistry, and the EPSRC National Crystallography
Service for the crystal structures. A. S. Hegazy thanks Cardiff Uni-
versity for financial support.
References and Notes
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2951. (l) Smith, K.; Barratt, M. L. J. Org. Chem. 2007, 72,
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(1) (a) Clayden, J. Organolithiums: Selectivity for Synthesis,
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(2) See, for example: (a) Gschwend, H. W.; Hamdan, A. J. Org.
Chem. 1975, 40, 2008. (b) Fitt, J. J.; Gschwend, H. W.
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Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255.
(f) Schlosser, M. Angew. Chem. Int. Ed. 2005, 44, 376.
(g) Chadwick, S. T.; Ramirez, A.; Gupta, L.; Collum, D. B.
J. Am. Chem. Soc. 2007, 129, 2259.
(3) See, for example: (a) Beak, P.; Zajdel, W. J.; Reitz, D. B.
Chem. Rev. 1984, 84, 471. (b) Snieckus, V. Chem. Rev.
1990, 90, 879. (c) El-Hiti, G. A. Heterocycles 2000, 53,
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4059. (e) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G.
Tetrahedron 2001, 57, 4489. (f) Anctil, E. J.-G.; Snieckus,
V. J. Organomet. Chem. 2002, 653, 150. (g) Smith, K.; El-
Hiti, G. A. Curr. Org. Synth. 2004, 1, 253. (h) Chinchilla,
R.; Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667.
(i) Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459.
(j) Rathman, T. L.; Bailey, W. F. Org. Process Res. Dev.
2009, 13, 141.
(4) Recent examples for substituted benzenes: (a) Clayden, J.;
Turner, H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7,
3147. (b) Chodakowski, J.; Kliś, T.; Serwatowski, J.
Tetrahedron Lett. 2005, 46, 1963. (c) Clayden, J.; Dufour, J.
Tetrahedron Lett. 2006, 47, 6945. (d) Burgos, P. O.;
Fernández, I.; Iglesias, M. J.; García-Granda, S.; Ortiz, F. L.
Org. Lett. 2008, 10, 537. (e) Wilkinson, J. A.; Raiber, E.-A.;
(8) Analytical Data for Compound 2: Mp 170–171 °C (lit.6
168–169 °C). 1H NMR (500 MHz, DMSO-d6): d = 7.43 (t,
J = 6 Hz, exch., 1 H, NH), 7.34 (app. t, J = 8 Hz, 1 H, H-5),
7.27 (dd, J = 2, 8 Hz, 1 H, H-6), 7.19 (br d, J = 8 Hz, 1 H, H-
4), 4.47 (d, J = 6 Hz, 2 H, CH2), 3.82 (s, 3 H, OCH3), 1.05 [s,
9 H, C(CH3)3] ppm. 13C NMR (125 MHz, DMSO-d6):
d = 177.5 (s, C=O), 169.7 (s, CO2H), 158.4 (s, C-3), 134.3 (s,
C-2), 128.7 (d, C-5), 126.7 (s, C-1), 121.6 (d, C-6), 114.6 (d,
C-4), 56.5 (q, OCH3), 38.4 [s, C(CH3)3], 35.7 (t, CH2), 27.8
[q, C(CH3)3] ppm. MS (ES+): m/z (%) = 553 (34) [2 M +
Na]+, 531 (42) [2 M + H]+, 329 (32) [M + MeCNNa]+, 304
(3) [M + K]+, 266 (100) [MH]+. HRMS (ES+): m/z calcd for
C14H20NO4 [MH]+: 266.1392; found: 266.1392. FT-IR:
n
max = 3401, 2965, 1698, 1611, 1539, 1467, 1385, 1219
cm–1.
(9) Analytical Data for Compound 4: Mp 156–157 °C. 1H
NMR (500 MHz, DMSO-d6): d = 8.03 (t, J = 6 Hz, exch., 1
H, NH), 7.57 (dd, J = 2, 8 Hz, 1 H, H-6), 7.32 (dd, J = 2, 8
Hz, 1 H, H-4), 7.16 (app. t, J = 8 Hz, 1 H, H-5), 4.32 (d, J = 6
Hz, 2 H, CH2), 3.79 (s, 3 H, OCH3), 1.15 [s, 9 H, C(CH3)3]
ppm. 13C NMR (500 MHz, DMSO-d6): d = 178.1 (s, C=O),
167.8 (s, CO2H), 157.1 (s, C-2), 134.6 (s, C-3), 131.5 (d,
C-4), 129.6 (d, C-6), 126.1 (s, C-1), 123.9 (d, C-5), 62.1 (q,
OCH3), 38.6 [s, C(CH3)3], 37.3 (t, CH2), 27.9 [q, C(CH3)3]
ppm. MS (ES+): m/z (%) = 569 (12) [2 M + K]+, 553 (100)
[2 M + Na]+, 548 (32) [2 M + NH4]+, 329 (25) [M +
MeCNNa]+, 304 (27) [M + K]+, 288 (70) [M + Na]+, 266 (71)
[MH]+. HRMS (ES+): m/z calcd for C14H20NO4 [MH]+:
266.1392; found: 266.1386. FT-IR: nmax = 3377, 2972, 1698,
1610, 1540, 1427, 1368, 1247 cm–1.
Synlett 2009, No. 14, 2242–2244 © Thieme Stuttgart · New York