'Counter-intuitive' regioselectivity, subtle steric and solvation effects in lithiation of cyclic tertiary aralkylamines

Article abstract of DOI:10.1016/j.tetlet.2005.07.110

Lithiation of a series of cyclic aralkyl tertiary amines with sec-BuLi in various solvents has been studied. There is a subtle sensitivity to steric factors and lithium coordinating solvents/additives have an adverse effect. ortho-Lithiation is observed only in the case of an eight-membered cyclic amine and the ease of benzylic lithiation with respect to nitrogen is in the surprising order γ > β ? α, δ. These observations are discussed in the context of nitrogen coordination promoted lithiation.

Full text of DOI:10.1016/j.tetlet.2005.07.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6753–6755
‘Counter-intuitive’ regioselectivity, subtle steric and solvation
effects in lithiation of cyclic tertiary aralkylaminesI
Satinder V. Kessar,* Paramjit Singh, Kamal Nain Singh, P. Venugopalan, Amarjit Kaur,
Manu Mahendru and Rajiv Kapoor
Department of Chemistry, Panjab University, Chandigarh 160014, India
Received 10 May 2005; revised 8 July 2005; accepted 22 July 2005
Available online 15 August 2005
Abstract—Lithiation of a series of cyclic aralkyl tertiary amines with sec-BuLi in various solvents has been studied. There is a subtle
sensitivity to steric factors and lithium coordinating solvents/additives have an adverse effect. ortho-Lithiation is observed only in
the case of an eight-membered cyclic amine and the ease of benzylic lithiation with respect to nitrogen is in the surprising order
c > b ꢀ a, d. These observations are discussed in the context of nitrogen coordination promoted lithiation.
Ó 2005 Elsevier Ltd. All rights reserved.
The deprotonative lithiation-electrophile reaction
sequence is a widely used method for forming new bonds
at weakly acidic carbon centers.1–5 Heteroatoms play a
pivotal role in such metalations through their electronic
effects and by coordination with lithium in the transition
state and, arguably,6 in a prelithiation complex (Scheme
1). In spite of studies spread over seven decades, some
aspects of this chemistry remain unsettled. Notably,
there is a surprising lack of understanding and systema-
tic data on regioselectivity and its correlation with
through space distance between heteroatom coordinated
lithium and the reacting C–H center.7,8 For cyclic sys-
tems, where conformational variations in distance may
be less, even qualitative level studies are rare.9 The area
is complicated by superimposition of electronic effects,10
the presence of multiple rapidly equilibrating moieties
and other variables, which are difficult to delineate pre-
cisely. Lithium coordination itself can vary with the
donor ability and steric environment of the substrate
heteroatom. Solvents/additives which coordinate
strongly with RLi can increase its reactivity due to de-
aggregation but this can be countered by many factors,
including sequestration of the substrate and net effect
may vary among the different classes of compounds.11
The state of RLi aggregation can also have a role in
regioselectivity, particularly in promoting distal
lithiation.12
X
X
X
C
(LiR)n
Li
(RLi)n
+
R
C H
H
C H
H
precomplex
H
H
H
H
H
The lithiations reported here are of synthetic interest, for
tertiary amines in general, and cyclic aralkylamines in
particular,13 and could be especially revealing in the
context discussed above because (i) competing benzylic
and aryl sites amenable to easy lithiation are present;
(ii) the heteroatom is part of a medium-sized ring; (iii)
the net electronic effect of nitrogen, unlike those of O,
S, and P is not marked,14,15 and coordinative effects
might be more important. In the event, treatment of
amines 1a–4a in toluene–Et2O (1:1) with 2.2 equiv of
sec-BuLi (ꢁ78 ! 0 °C, 1 h ! ꢁ78 °C) followed by reac-
tion with benzophenone (2.2 equiv) afforded alcohols
1c–4c (Table 1, entries 1–4).16,17 The relative ease of
lithiation at competing benzylic sites, with respect
to nitrogen, is in the surprising order c > b ꢀ a, d.
X
X
E+
C Li
C E
-RH
H
H
H
H
Heteroatom-assisted deprotonation, X = heteroatom, E+ = electrophile
Scheme 1.
Keywords: Regioselectivity; Lithiation; Amines; Solvent effects; Steric
effects.
q Details of the experimental procedure are available in Supplementary
data.
*
Corresponding author. Tel.: +91 17 22554435; fax: +91 17
22545074; e-mail: svkessar@pu.ac.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.110

6754
S. V. Kessar et al. / Tetrahedron Letters 46 (2005) 6753–6755
Table 1. Lithiation/benzophenone reaction of amines 1a–4a,d, 5, 6a, and 7a in toluene–Et2O (1:1) (conditions A), with addition of 2.2 equiv of
TMEDA (conditions B), in THF (conditions C), and in pure toluene (conditions D)
Entry
Substrate (available sites)a
Lithiation positionb
Product (conditions, % yield)c
1
2
3
4
5
6
7
8
9
1a (a, b, o)
2a (a, c, o)
3a (b, c, o)
4a (a, d, o)
4d (a, d)
5 (a, c, o)
6a (a, o)
7a (a, o)
b
c
c
o
1c (A, 60); (B, 62); (C, 62)
2c (A, 31); (C, 5)
3c (A, 42); (B, –); (C, –); (D, –)
4c (A, 55); (B, –); (C, –); (D, –)
(A, –)
(A, –); (C, –)
6c (A, 63); (B, 20); (C, 60)
(A, –); (C, –)
(–)
(–)
o
(–)
a
(–)
10a (a, c, o)
11a
10d (A, 50)
(A, –)
10
a o Denotes ortho position.
b (–) Denotes insignificant product formation (HPLC/TLC).
c Yields are for isolated pure compounds.
ortho-Lithiation was observed only in the case of 4a
although directed ortho-metalation (DoM) is the norm
with open chain benzylamines or if the nitrogen is di-
rectly attached to the aromatic ring.3 It seems that in
4a, but not in 3a, the greater flexibility of an eight-mem-
bered ring allows coordination-assisted lithiation at an
ortho position. Although 4a delineates the minimum
proximity requirement for ortho-lithiation in this series,
the relevant centers still seem to remain, in models,
somewhat far apart. In the case of 4d, in which the reac-
tive ortho-position is blocked by a trimethylsilyl group,
lithiation at neither the a nor d position was observed.
In fact, products corresponding to lithiation at the a-
benzylic position, for example, 8c from 1a, were not
formed to an appreciable extent in any of the amine
reactions in toluene–ether (1:1), in contrast to oxygen
and sulfur analogues 9 and 10 (Table 1, entry 9 and
Ref. 18). It may be inferred that not only the electronic
but also the coordinative effects of nitrogen do not favor
a-lithiation. Amines 5 and 7a were inert (Table 1, entries
6 and 8), which could be due to steric inhibition of coor-
dinative lithiation. The steric demand of 7a is only
slightly higher than that of 2a and it could also undergo
ortho-lithiation on the appended benzene ring, but it was
unreactive under the conditions studied (Fig. 1).
suppression of lithiation by TMEDA was to be
expected,11 the dramatic curtailment in THF seemed
surprising especially in comparison with the open-chain
amine 6a (Table 1, entry 7). The adverse effect of THF
on the yield of the major product was also observed in
the lithiation of cyclic amine 3a and to a lesser extent
in the case of 2a (Table 1, entries 3 and 2). In contrast
to lithiation of 2a–4a, metalation of the analogous six-
membered ring amine 1a proceeded readily in THF
(Table 1, entry 1 and Ref. 20), which is a remarkable
reversal of solvent effect within a closely related series
of substrates (1a–4a). Moreover, addition of other
strongly lithium coordinating additives (TMEDA,
PMDTA, and HMPA) or the use of SchlosserÕs base
in THF had no adverse effect on the major product of
this reaction,16 a feature characteristic of acidity-driven
metalations.21 Whatever the factors are in 1b or the
transition state leading to it, which are responsible for
the distinctive lithiation of 1a is not clear at this stage.22
In conclusion, we have found that lithiation of these cyc-
lic tertiary amines (a) exhibits subtle sensitivity to steric
factors, (b) strongly lithium coordinating solvents/addi-
tives have an adverse effect except in the case of 1a. In
terms of regioselectivity (c) ortho-lithiation is observed
only in 4a while benzylic lithiation prevails in 1a–3a
and (d) its relative ease is c > b ꢀ a, d. Some findings
of this comparative study, apparently the first in which
the heteroatom is enclosed in a ring, are indeed surpris-
ing but may be specific to an extent to the chosen set.
There is an urgent need for additional studies on the
spatial dependence of the coordinative component of
the heteroatom effect and its related areas.23
To study the effect of solvents and additives on the
metalation of these amines, reactions of 4a were carried
out in pure toluene, in toluene–Et2O (1:1) alone or with
added TMEDA and in THF (Table 1, entry 4).19 While
R
R
R
N
N
N
N
CH3
CH3
CH3
N
CH3
Acknowledgements
1
2
3
R
CH3
4
Financial support from DST and CSIR, New Delhi, is
gratefully acknowledged.
R
CH3
N
(
)
n
N
X
R1
CH2Ph
R2
R
R
6, R1 = CH3, R2 = H
5
8
9, X = O, n = 1
10, X = S, n = 2
11, X = CH2, n = 1
Supplementary data
R2 = (CH2)4
1
7,
R
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.07.110.
a) R = H b) R = Li c) R = C(OH)Ph2 d) R = SiMe3
Figure 1.

S. V. Kessar et al. / Tetrahedron Letters 46 (2005) 6753–6755
6755
Chandrachood, P. S.; Shete, N. R. T. Tetrahedron 1981,
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References and notes
14. Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721–737.
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16. The general experimental procedure, spectroscopic data of
the products and starting amines can be found in the
Supplementary data. Substituent position in the products
was additionally confirmed by X-ray crystallography (3c,
4c) or by comparison with authentic a-substituted prod-
ucts obtained from 1a and 2a by the BF3 activation route
(Ref. 14). The question of kinetic versus thermodynamic
control was not addressed. However, in reactions in which
the temperature was not raised to 0 °C, yields were lower
but no change in the product profile was detected.
17. Crystallographic data (excluding structure factors) for the
structures 3c and 4c in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 266706 and 266707.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 (0)12223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
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23. Exploratory studies with conformationally rigid or
restricted systems to chart patterns of regioselectivity and
in-depth spectroscopic, rate law, and computational stud-
ies are needed for further understanding.