Angewandte
Communications
Chemie
Reaction Mechanisms
Fundamental Difference in Reductive Lithiations with Preformed
Radical Anions versus Catalytic Aromatic Electron-Transfer Agents:
N,N-Dimethylaniline as an Advantageous Catalyst
Nicole Kennedy,* Peng Liu, and Theodore Cohen*
[
6]
Abstract: The reductive lithiation of phenyl thioethers, or alkyl
chlorides, by either preformed aromatic radical anions or by
lithium metal and an aromatic electron-transfer catalyst, is
commonly used to prepare organolithiums. Revealed herein is
that these two methods are fundamentally different. Reductions
with radical anions occur in solution, whereas the catalytic
reaction occurs on the surface of lithium, which is constantly
reactivated by the catalyst, an unconventional catalyst function.
The order of relative reactivity is reversed in the two methods as
the dominating factor switches from electronic to steric effects
of the alkyl substituent. A catalytic amount of N,N-dimethy-
laniline (DMA) and Li ribbon can achieve reductive lithiation.
DMA is significantly cheaper than alternative catalysts, and
conveniently, the Li ribbon does not require the removal of the
oxide coating when DMA is used as the catalyst.
laboratory to address the decomposition of LDMAN above
[
7]
À458C. This widely accepted method was expanded by Yus
and co-workers to include 1–5 mol% of p,p’-di-tert-butylbi-
phenyl (DBB), or naphthalene (Np),
[
8–11]
and a large excess of
for their catalytic
[12]
specially prepared lithium powder
reductive lithiation of alkyl chlorides and phenyl sulfides.
It has been implicitly assumed that the mechanism for
both the aromatic radical anion method (Scheme 1) and the
catalytic method are the same. However, these mechanisms
are very different. This surprising discovery came about while
developing a novel type of reductive lithiation catalyst, N,N-
dimethylaniline (DMA), which has been found to be at least
as effective as DBB, the most commonly used reductive
lithiation catalyst. DMA has significant advantages over
DBB, such as an immensely lower cost and the ability to be
recycled from the reductive lithiation mixture by a simple
aqueous extraction.
DMA was compared to DBB and 1-(N,N-dimethylami-
no)naphthalene (DMAN) in the reductive lithiation of
methyl phenyl sulfide (1) with lithium ribbon (Table 1).
The methyl lithium intermediate 2 was trapped with benzal-
dehyde to produce 1-phenylethanol (3). As shown in Table 1,
DMA catalyzed the reductive lithiation of 1 almost as well as
DMAN and considerably better than DBB (entries 1–3).
N,N-dimethyl-o-toluidine (DMOT), which is also commer-
[
13]
T
he replacement of a C–heteroatom bond with a CÀLi bond
using aromatic radical anions, known as reductive lithiation, is
a practical method for the synthesis of organolithium com-
pounds. Specifically, the reductive lithiation of phenyl thio-
ethers in which aromatic radical anions, including lithium
naphthalenide (LN), lithium p,p’-di-tert-butylbiphenylide
[
14]
(
(
LDBB), or lithium 1-(N,N-dimethylamino)naphthalenide
[
1–4]
[5]
LDMAN),
are the source of electrons (Scheme 1).
A catalytic method, which employs a catalytic amount of
[13]
the aromatic hydrocarbon necessary for the electron transfer
from the lithium to the substrate rather than a stoichiometric
amount of the aromatic radical anion, was developed in this
cially available but slightly more expensive,
produced
a result comparable to that of DMA (entry 4). Isopropyl
benzene, which is structurally similar to DMA but lacks
a nitrogen atom, did not catalyze the reductive lithiation of
1
(entry 5). Increasing the equivalents of lithium ribbon led to
an increase in the yield of 3 (entry 7).
Table 1: Catalytic reductive lithiation of 1.
Scheme 1. Reductive lithiation of phenyl thioethers with aromatic
radical anions. THF=tetrahydrofuran.
[b]
Entry
Catalyst
Yield [%]
1
2
3
4
5
6
7
DBB
DMAN
DMA
DMOT
isopropyl benzene
none
48
72
68
65
42
39
[
*] Dr. N. Kennedy, Prof. P. Liu, Prof. T. Cohen
Department of Chemistry, University of Pittsburgh
2
19 Parkman Avenue, Pittsburgh, PA 15260 (USA)
[c]
none
65
E-mail: nmk28@pitt.edu
[a] Oxide coating on lithium ribbon was scraped off prior to the reaction.
b] Yield of isolated 3 after chromatographic purification. [c] 5 equiv of
lithium ribbon.
[
Angew. Chem. Int. Ed. 2016, 55, 383 –386
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
383