Lithium–Bromide Exchange versus Nucleophilic Addition of Schiff's base: Unprecedented Tandem Cyclisation Pathways

Article abstract of DOI:10.1002/chem.201902140

By exploring lithium–bromide exchange reactivity of aromatic Schiff's bases with tert-butyllithium (tBuLi), we have revealed unprecedented competitive intermolecular and intramolecular cascade annulation pathways, leading to valuable compounds, such as iso-indolinones and N-substituted anthracene derivatives. A series of reaction parameters were probed, including solvent, stoichiometry, sterics and organolithium reagent choice, in order to understand the influences that limit such ring-closing pathways. With two viable reactivity options for the organolithium on the imine; namely, nucleophilic addition or lithium–bromide exchange, a surprising competitive nature was observed, where nucleophilic addition dominated, even under cryogenic conditions. Considering the most commonly used solvents for lithium–bromide exchange, tetrahydrofuran (THF) and diethyl ether (Et₂O), contrasting reactivity outcomes were revealed with nucleophilic addition promoted in THF, while Et₂O yielded almost double the conversion of cyclic products than in THF.

Full text of DOI:10.1002/chem.201902140

A Journal of
Accepted Article
Title: Lithium-Bromide Exchange versus Nucleophilic Addition of
Schiff’s base: unprecedented tandem cyclisation pathways S. A.
Orr[a], E. C. Border[b], P. C. Andrews*[a] and V. L. Blair*[a]
Authors: Victoria Louise Blair, Philip C Andrews, Samantha A Orr, and
Emily C Border
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201902140
Link to VoR: http://dx.doi.org/10.1002/chem.201902140
Supported by

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
Lithium-Bromide Exchange versus Nucleophilic Addition of
Schiff’s base: unprecedented tandem cyclisation pathways
S. A. Orr[a], E. C. Border[b], P. C. Andrews*[a] and V. L. Blair*[a]
Dedication ((optional))
Abstract: By exploring lithium-bromide exchange reactivity of
aromatic Schiff’s bases with tert-butyllithium (tBuLi) we have revealed
unprecedented competitive intermolecular and intramolecular
cascade annulation pathways leading to valuable compounds such as
iso-indolinones and N-substituted anthracene derivatives. A series of
reaction parameters were probed including solvent, stoichiometry,
sterics and organolithium reagent choice in order to understand the
influences limiting such ring closing pathways. In the case of having
two viable reactivity options for the organolithium on the imine; namely
nucleophilic addition or lithium-bromide exchange, a surprising
competitive nature was observed where nucleophilic addition
dominated, even under cryogenic conditions. Considering the most
directed lithiation is typically not observed, though it has been
observed in some specific cases.5 More commonly, aryl imines
undergo 1,2 nucleophilic addition providing access to optically
pure amines in the presence of a chiral, non-racemic ligand. The
facile and thermodynamically favoured nature of this 1,2-addition
reaction has been reinforced by recent studies from the groups of
Hevia and Capriati showing such reactivity even in deep eutectic
solvents and water.6
Given the challenge of ring metalation, specifically ortho-
lithiation, an alternative methodology of lithium-bromide exchange
at the ortho- site has been successfully employed. Recent studies
from Tang, Kingsley and Dostál have shown this approach can
generate ortho-lithiated aryl imines in-situ. These can be further
functionalised to give new aluminium,7 titanium8 and benzaborole9
compounds using simple metathesis pathways, and iso-
indolinones from CO insertion followed by cyclisation10 (Scheme
1). However, insight into the structural composition of the lithium
intermediates have, to date, not been crystallographically
determined. In these cases, the possible competing nucleophilic
addition reaction was not observed, perhaps somewhat expected
given the reported and often accepted rapid rate of lithium-
bromide exchange, even at very low temperatures.11 There is,
commonly
used
solvents
for
lithium-bromide
exchange,
tetrahydrofuran (THF) and diethyl ether (Et2O), contrasting reactivity
outcomes were revealed with nucleophilic addition promoted in THF,
while Et2O yielded almost double the conversion of cyclic products
than in THF.
Introduction
Imines, because of the reactivity of the carbon nitrogen double
bond, are valuable precursors for the synthesis of many complex
molecules. The simplicity in preparing functionalised azomethine
derivatives in high yields, with minimal purification, from the
condensation reaction between a primary amine and a carbonyl
containing compound makes them both desirable and versatile
precursors. Also known as Schiff’s bases, they are typically
employed in the preparation of amines,1 in multifunctional ligand
design for metal complexation,2 in polymerisation3 and in the
construction of pharmaceutical-based scaffolds.4 As a result,
there is ongoing interest in developing and establishing new
synthetic strategies for the adaptation and functionalisation of
these valuable N-containing building blocks.
though,
a single example of alternative reactivity, where
employing the bulky lithium reagent, [(HMe2Si)3CLi], led to the
formation of vinylbis(silanes) instead of facilitating lithium-halogen
exchange. 12
To generate new high value molecules, imines are often treated
with an organolithium reagent. In the case of aryl imines, the
carbon-nitrogen functionality is weakly directing hence ortho-
[a]
[b]
Dr S. A. Orr, Prof. P. C. Andrews, Dr V. L. Blair
School of Chemistry
Monash University
Clayton, Melbourne, VIC 3800 (Australia)
Email: victoria.blair@monash.edu
phil.andrews@monash.edu
Scheme 1. Previously reported lithium-bromide exchange of imines and our
work.
Dr E. C. Border
Science and Engineering Faculty
Queensland University of Technology
Supporting information for this article is given via a link at the end of
the document.
The lithium-halogen exchange reaction remains one of the most
fundamental synthetic transformation strategies used to
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
regioselectively form new C-C and C-X bonds allowing new
organic molecules to be constructed from simpler organic
scaffolds.13 The highly facile nature of the reaction demands
cryogenic conditions along with excess alkyllithium to control the
equilibria.11 As such, it is often invaluable for protecting sensitive
functional groups, and increasing tolerance towards nucleophilic
addition and/or metalation. The boundaries of lithium-bromide
exchange are continually developing with flow chemistry now
offering an alternative method to overcome any functional group
sensitivity, with rapid transmetalation to more stable
organometallic complexes which can be further functionalised.14
Whilst specially designed organolithium systems allow the
successful lithium-bromide exchange under non-cryogenic
temperatures.15 Surprisingly despite their synthetic relevance, the
study of lithium-bromide exchange of aryl imines prior to further
reactivity remains absent from the literature.
allowed to warm to room temperature (Scheme 3). After one
week, a small crop of red needle crystals deposited from the red
solution.
Scheme 3. Synthesis of Compound 4.
Single crystal X-ray diffraction studies revealed the unexpected
formation of monomeric [anthracene-9,10-(NPhLi.THF3)2] (4)
Figure 1 in which an anthracene unit is substituted at the 9 and
10 positions with a lithium phenylamide moiety with the Li atoms
solvated by three molecules of THF. The planar core of the
anthracene unit confirms a fully delocalised system with average
C=C bond lengths of 1.412 Å which is comparable to literature
values.19 The pendant amido group, C8-N1, is almost co-planar
with the anthracene core (deviation from plane <5o), with the
nitrogen atom sitting in a distorted trigonal planar arrangement
(bond angles ∑ 357.58o), while the phenyl groups are orientated
anti- to the plane of the central anthracene molecule. The lithium
cations adopt a slightly distorted tetrahedral geometry (bond
angles ∑ 653.69o) bonding to the nitrogen atom and three THF
molecules.
Herein we report the unforeseen reactivity of commonplace
ortho-bromo-substituted aryl imine precursors with butyllithium,
revealing an unanticipated competition pathway between the
expected fast lithium-bromide exchange and normally
unfavorable nucleophilic addition, resulting in synthetically
valuable substituted iso-indolinones and anthracenes. Iso-
indolinones are crucial heterocycles in pharmaceutical chemistry
being abundant in numerous natural products and displaying a
wide range of biological properties including activity towards drug
resistant bacteria.16 Whilst substituted polyaromatics have been
reported to possess interesting material chemistry applications in
OLEDs.17 The sequential C-C bond forming mechanistic
pathways for these one pot cascade reactivities are proposed,
with a comprehensive study of reaction parameters.
Results and Discussion
The benchmark imine used in this study was 2-
bromophenylbenzylidene (1) which was prepared according to
our previously reported microwave procedure in high yields from
2-bromobenzaldehdye and aniline in dichloromethane at 50oC for
30 minutes.18 The resulting yellow oil, which displayed light
sensitivity, was fully characterised by 1H and 13C NMR
spectroscopy, with the distinct CH=N imine resonance at 8.87
ppm providing an NMR handle for nucleophilic addition reactivity.
The mesityl (2) and diisopropyl (3) functionalised aniline
derivatives were prepared in the same manner using the
corresponding amine derivative (Scheme 2).
Figure 1. Molecular structure of [anthracene-9,10-(NPhLi.THF3)2] (4) with
thermal ellipsoids drawn at the 50% probability level and hydrogen atoms
omitted for clarity. Symmetry transformations used to generate equivalent
atoms labelled ‘: 1-x, 1-y, 1-z. Bond lengths and angles; Li1-O1, 1.971(2), Li1-
O2, 1.977(2), Li1-O3, 1.961(2), Li1-N1, 1.989(2), N1-C1, 1.3648(16), N1-C8,
1.4129(15), C8-C7, 1.4180(18), C8-C9, 1.4205(18), C9-C10, 1.4326(18), C10-
C11, 1.3657(19), C11-C12, 1.4223(19), C12-C13, 1.3603(19), Li1-N1-C1,
124.50(10), Li1-N1-C8, 114.44(10), C1-N1-C8, 118.64(10), O1-Li1-O2,
104.45(10), O1-Li1-O3, 101.46(11), O2-Li1-O3, 97.55(11), O1-Li1-N1,
120.50(12), O2-Li1-N1, 113.63(11), O3-Li1-N1, 116.09(11), N1-C8-C7,
122.97(11), N1-C8-C9, 119.50(11).
Scheme 2. Microwave synthesis of ortho-bromosubstituted imines.
The first reaction studied was that targeting specifically lithium-
bromide exchange. Compound 1 was treated with two equivalents
of tert-butyllithium (tBuLi) at -78oC in tetrahydrofuran (THF) and
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
Scheme 4 illustrates the proposed formation of the anthracene
compound (4). This can be termed as a ‘head to tail’ nucleophilic
addition process. The ortho-lithiated molecule (Scheme 4, I)
undergoes intermolecular 1,2-addition resulting in homocoupling
between two imine molecules (Scheme 4, II), which can then ring
close via a secondary intramolecular addition (Scheme 4, IV).
However, it is also plausible that instead of a sequential two-step
ring closing process a concomitant double addition could occur.
Finally, hydrogen evolution driven by re-aromatisation results in
the anthracene skeleton (Scheme 4, V) confirmed by the isolation
of compound 4. To the best of our knowledge this is the first report
of a lithium-directed approach facilitating anthracene formation.
The closest literature example is a serendipitous result arising
from diorganodiselenides containing an iminoaryl group, which in
the presence of sodium metal and zinc chloride results in the
formation of a cis-9,10-bis(arylamino)-9,10-dihydroanthrancene
species. This is believed to proceed via a radical intermediate.20
A similar result, originating from an ortho-bromo substituted aryl
reaction arises not from exchange process but from the 1,2
addition of tBuLi across the imine bond.
Figure 2. Identified products from the reaction of 1 and tBuLi.
imine,
is
the
formation
of
a
titanium
9,10-
Considering the resulting cyclised products, the major iso-
indolinone 7 and minor N-substituted anthracene 8, it can be
concluded that two concurrent mechanisms are at play. Both
follow the same initial step of Li/Br exchange resulting in species
(Scheme 5, I), however following this, a second competitive
pathway is available as proposed in Scheme 5. In the case of iso-
indolinones, a ‘head to head’ intermolecular nucleophilic addition
can occur to give species (Scheme 5, II), which can then undergo
a further intramolecular addition resulting in ring closing step to
yield species (Scheme 5, III). The elimination of lithium hydride
(LiH) results in the formation of iso-indolinimine (Scheme 5, IV)
which upon work-up undergoes hydrolysis to the desired iso-
indolinone (7).
dihydrophenanthrenediamide accessed via ortho-lithiation and
subsequent transmetallation with TiCl4.8 In our system no other
metal salt is present for metathesis to occur and hence the
reactive lithiated species couples with itself via 1,2 nucleophilic
addition.
Scheme 4. Proposed mechanism for the formation of N-phenyl-substituted
anthracene 4.
The isolation of this unexpected product led us to probe the
reaction process in more depth. The reaction was repeated using
the same conditions and after 18 hours, hydrolysed. The crude
product was then studied by GC-MS, revealing an array of cyclic
and acyclic compounds shown in Figure 2. At least four classes
of compounds could be identified: amines from nucleophilic
addition (5+5a), imine (6) from Li/Br exchange, iso-indolinone
derivatives (7) and anthracene species (8) both resulting from
combined exchange and cyclisation pathways. For simplicity, the
resultant cyclised products have been categorised as 7 and 8
although the composition of these mixtures are further detailed in
the Supporting Information, including the characterisation of a
Scheme 5. Proposed mechanism for the formation of iso-indolinones.
Due to the importance of the iso-indolinone skeleton many
methods have been described for their synthesis. Among the suite
of synthetic methodologies available, two main approaches
dominate namely; functionalisation of pre-constructed bicyclic
scaffolds, such as phthalimide derivatives,21 or the synthesis of a
g-lactam core via cyclisation reactions.22 Relevant examples
include lithiation and annulation methodologies,23 with a recent
report describing ortho-bromo-substituted aryl-alkyl imines as a
route to iso-indolinones (Scheme 1).10,24 In contrast to our
hydroxyl iso-indolinone (7a) and
a bromo-aryl substituted
isoindolinone (9). Given the inherent rapid nature of lithium-
bromide exchange, it is surprising that the major species from the
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
intermolecular cyclisation pathway, the imine undergoes selective
lithium-bromide exchange to which toxic carbon monoxide inserts
into the C-Li bond which upon rearrangement yields an iso-
indolinone. Interestingly no evidence of a competing nucleophilic
addition pathway was described suggesting Schiff bases display
differing reactivity dependent on their substituents being alkyl or
aromatic. The cascade reactivity observed in this work is also
reliant upon the ortho-position of the bromine. This is
demonstrated by previous studies whereby tBuLi will undergo
solvent of choice for typical Li/Br exchange reactions in the
literature,(11,26) hence it was surprising to find that the highest
conversion to addition products (combined 62% yield of amines 5
and 5a, entry 1, Table 1) was observed for THF. A point to note is
once the addition or exchange step has occurred, neither site
being lithiated limits the other process from occurring. From the
initial results, it is possible to observe the effects of several
competing reaction pathways. Lithium-bromide exchange is the
fastest to occur, however the consequent intermolecular
cyclisation step is slower and thus ends up in competition with
nucleophilic addition. This is problematic since once the imine has
undergone nucleophilic addition the two-step cyclisation pathway
is inhibited. Relating these outcomes to the choice of solvent
medium, it can be deduced that there are two possible factors at
play; polarity and Lewis donor stabilisation.
In relatively polar solvents homogeneous solutions help
facilitate cyclisation, whereas with less polar solvents, such as
hexane (entry 6, Table 1), lower solubility and precipitation of
reaction intermediates impedes the cyclisation pathway. However,
the outcome is not wholly attributed to the solubility. The strength
of the metal-donor interaction in solution appears to be crucial as
it can shut down the metal atom site for reactivity. In the presence
of strongly coordinating Lewis donor solvents, such as
monodentate THF (entry 1, Table 1) and bidentate TMEDA (entry
5, Table 1), it would appear the lithiated intermediate is stabilised
thereby hindering cyclisation. In the case of bulkier tridentate
PMDETA (entry 4, Table 1) an increase in cyclised product is
observed. Interestingly, diethyl ether, which is a low polarity, labile,
monodentate Lewis donor, provides the best solvent for inhibiting
addition reactivity while promoting lithium-bromide exchange and
subsequent cyclisation (entry 2, Table 1).
clean nucleophilic addition of
a
para-bromo-substituted
diarylimine with no lithium-bromide exchange observed.6
Alternatively increasing the sterics surrounding the bromine atom,
such as a bromo-substituted bis(imino)phenyl NCN ligand, can
switch off the nucleophilic addition site for reactivity and facilitate
solely lithium-bromide exchange.25 Given the importance of the
resultant cyclised products, a range of reaction parameters were
probed in a bid to understand the reaction pathways.
Solvent studies
To determine the effect solvent may have on both the diversity
and ratio of final products obtained, we studied a range of solvents
with differing polarities (e = 1.9 - 7.6) alongside the addition of
Lewis
bases,
including
and
TMEDA
PMDETA
(N,N,N’,N’-
(N,N,N’,N’’-
tetramethylethylenediamine)
pentamethyldiethylenetriamine), as co-solvents, as summarised
in Table 1.
Table 1. Influence of solvent on Li/Br exchange of compound 1.[a]
Stoichiometric effect
5
(%)
5a
(%)
6
(%)
7 and 8
Other
(%)
Entry
Solvent
(%)[b]
To validate the observation that the addition and exchange
processes are competitive and not stepwise due to using two
equivalents of tBuLi, studies investigating the effect of
stoichiometry were carried out. Reactions using the two most
contrasting solvents - THF and Et2O - were conducted using both
a 2:1 and1:1 ratio of tBuLi:imine, as summarised in Table 2.
1
2
3
THF
Et2O
6
0
0
56
23
29
0
1
0
38
72
64
0
4
7
toluene
hexane/
4
0
37
0
61
2
PMDETA[c]
Table 2. Varying stoichiometry of tBuLi with compound 1 in Et2O and THF.[a]
hexane/
5
6
16
14
39
30
0
0
45
53
0
3
TMEDA[c]
hexane
5
(%)
5a
(%)
6
(%)
7 and 8
Other
(%)
[a] Determined by GC-MS. [b] Combined conversion of cyclic derivatives,
see SI for full ratios. [c] Reaction in bulk hexane with 2 equivalents of donor.
[d] Commercial solution of tBuLi (1.7M in pentane).
Entry
X
solvent
(%)[b]
1
2
3
4
1
2
1
2
Et2O
Et2O
THF
THF
3
0
12
23
17
56
0
1
0
0
77
72
12
38
8
4
0
0
All reactions were performed under the same conditions only
varying the bulk solvent. The resulting mixtures were hydrolysed
and the organic components extracted and analysed by GC-MS.
The outcomes of these reactions emphasise the competing
nature of the nucleophilic addition pathway, whereby all systems
resulted in a considerable amount of amine products 5 and 5a
being isolated in the range of 23 - 62%, with the lowest formation
being in diethyl ether (entry 2, Table 1). THF is typically the
71
6
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
addition is observed which would suggest that the competing
addition step is slow in Et2O. In the case of THF (entries 3 and 4,
Table 3) when two equivalents of tBuLi are employed, almost
selectively the addition and exchange product 5a was observed
(89%). Alternatively using a 1:1 ratio a mixture of products was
obtained, 33% of which addition product 5 was observed
highlighting the rapidness of the addition pathway. Comparing
these two solvents it can be seen that THF promotes the addition
pathway and is quicker than in Et2O, confirmed by the presence
of species 5 in THF reactions. There is also no cyclisation
observed with THF, whereas in Et2O the slower addition pathway
is less competitive, and facilitates cyclisation.
As the mesityl group was not sterically demanding enough
to protect the C=N functionality, the bulkier diisopropyl substituted
imine 3 was tested. The reaction in Et2O, (entries 5 and 6, Table
3) revealed almost exclusively Li/Br exchange as the major
product with 99% of 6 being obtained when one equivalent of
tBuLi was employed. This was consistent in THF (entries 7 and 8,
Table 3) with 88% of 6 recorded. As predicted, providing steric
protection of the imine functionality reduced or completely
inhibited 1,2 nucleophilic addition, however this also blocked the
site for intermolecular cyclisation.
[a] Determined by GC-MS. [b] Combined conversion of cyclic derivatives,
see SI for full ratios. [c] Commercial solution of tBuLi (1.7M in pentane).
Even when only one equivalent of tBuLi was used the addition-
only product 5 was observed for both systems, revealing the
addition and exchange pathways to be truly competitive, and
hence detrimental to the cyclisation pathway. The high yield of
cyclised products for both reactions in Et2O (entries 1 and 2, Table
2) indicates that the exchange process dominates over addition
of the lithium reagent, while the relatively low yields of cyclised
products from the THF reactions indicate the addition reaction to
be more favourable, as highlighted by when only one equivalent
of tBuLi is employed (entry 3, Table 2). Thus, in THF the addition
occurs faster than Li/Br exchange on the same molecule, and the
addition step then prevents cyclisation.
Steric influences
To confirm that the suppression of the addition pathway allows
the Li/Br exchange to occur successfully we prepared two
substituted imines, compounds 2 and 3, bearing a mesityl (Mes)
or diisopropylphenyl (Dipp) group as the aniline moiety. The
reaction was then performed in the same manner as previous
studies employing both one and two equivalents of tBuLi in Lewis
base donor solvents THF and Et2O (Table 3).
Importance of organolithium reagent
Finally, a series of experiments were conducted to determine
whether the ratio of addition, exchange, and cyclisation products
could be varied based on the nucleophilicity of the organolithium
reagent. The results are summarised in Table 4, with the outcome
using tBuLi under optimised conditions for cyclisation presented
in entries 1 and 2. Using two equivalents of nBuLi in diethyl ether
at -78oC, product nBu-5a dominates, resulting from nucleophilic
addition and Li/Br exchange on the same molecule (entry 6, Table
4). Using only one equivalent of nBuLi (entry 5, Table 4) led
almost exclusively to the addition product (nBu-5), confirming that
addition is favoured over exchange in this case. Comparatively,
sBuLi, offering an in-between nucelophilicity and basicity of tBuLi
and nBuLi, behaves similarly to tBuLi in the presence of 1
equivalent (entry 3, Table 4). Although, in the presence of 2
equivalents a trend is observed for the addition and exchange
product R-5a which gradually decreases from nBu>sBu>tBu
(entries 2, 4 and 6, Table 4).
Table 3. Effect of varying sterically protected imines 2 and 3 with 1 and 2 eq
of tBuLi in Et2O and THF.[a]
7 and
5
(%)
5a
(%)
6
(%)
Other
(%)
8
Entry
imine
X
Solvent
(%)[b]
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
1
2
1
2
1
2
1
2
Et2O
Et2O
THF
THF
Et2O]
Et2O
THF
THF
0
0
0
31
6
48
42
45
2
35
20
0
17
7
33
3
16
6
89
0
0
Table 4. Effect of varying organolithium reagents with 1 in Et2O.[a]
0
99
85
89
88
0
1
0
10
2
4
1
0
4
5
0
6
2
4
R-7
R-5
(%)
R-5a
(%)
R-6
(%)
Other
(%)
and 8
Entry
R
X
(%)[b]
[a] Determined by GC-MS. [b] Combined conversion of cyclic derivatives,
see SI for full ratios. [c] Commercial solution of tBuLi (1.7M in pentane).
1
2
3
tBu
tBu
sBu
1
2
1
3
0
4
12
23
13
0
1
0
77
72
78
8
4
4
In the case of the mesityl functionality (2), in diethyl ether (entries
1 and 2, Table 3), nucleophilic addition was not notably different
in comparison to the non-substituted imine 1. The addition occurs
concurrently with Li/Br exchange when two equivalents of tBuLi
are used. Interestingly when only one equivalent is used no
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
Conclusions
4
5
sBu
nBu
2
1
2
1
2
1
2
0
36
2
0
0
0
0
0
0
0
58
7
6
0
In this fundamental study of the lithium-bromide exchange
reaction in bromo-substituted diaryl imines, it is revealed that the
expected superior chemoselectivity of the Li/Br exchange is
challenged by competitive addition pathways. In the presence of
traditionally used THF, the unprecedented amine product is a
result of the unsaturated functionality of the imine moiety
undergoing nucleophilic addition, even under cryogenic
conditions. Alternatively employing diethyl ether the rapidity of
Li/Br exchange versus nucleophillic addition is generally
maintained. Remarkably, in this case the lithiated imine is
consumed in cascade cyclisation pathways. The new C-C bond
formation arises through a two-step 1,2-nucleophilic addition
process of the lithiated imine; either in a ‘head to head’ or a ‘head
to tail’ manner forming iso-indolinones and N-phenyl-anthracenes,
respectively.
91
0
6
nBu
96
0
0
4
7
CH2SiMe3
CH2SiMe3
Mes
68
64
83
68
0
32[c]
0
8
36
7
0
9
10
2
0
10
Mes
21
9
[a] Determined by GC-MS. [b] Combined conversion of cyclic derivatives,
see SI for full ratios. [c] Starting material. [d] Commercial solution of tBuLi
(1.7M in pentane), nBuLi (1.6M in hexanes), sBuLi (1.4M in cyclohexane),
LiCH2SiMe3 (1M in hexanes).
Interestingly, with (trimethylsilyl)methyllithium, employing both
one and two equivalents of organolithium reagent, nucleophilic
addition dominates over Li/Br exchange with no cyclisation
observed (entry 7 and 8, Table 4). In an attempt to inhibit
nucleophilic addition of the organolithium reagent and to preserve
the imine functionality for ring closing, a less nucleophilic aryl
lithium reagent was studied, mesityllithium. However, on treating
the imine with mesityllithium the addition product (Mes-5) was
again identified as the major species, suggesting sterics of the
lithium reagent has little influence in hindering the addition
pathway (entry 9 and 10, Table 4). In summary, employing either
one or two equivalents of tBuLi in diethyl ether at -78oC remains
the optimum reaction conditions for obtaining the highest ratio of
iso-indolinone products.
Experimental Section
General considerations
All reactions and manipulations were carried out under a protective
nitrogen atmosphere using either standard Schlenk techniques or an
MBraun glove box fitted with a gas purification and recirculation unit. NMR
measurements were conducted in a J. Youngs tube oven dried and flushed
with nitrogen prior to use. Solvents were obtained from an MBraun SPS-
800 solvent purification system and stored over 4 Å molecular sieves under
nitrogen.
NMR spectra were recorded on a Bruker AVANCE DRX 400
spectrometer operating at 400.13 MHz for 1H, 100.62 MHz for 13C and
155.5 MHz for 7Li. All 13C spectra were proton decoupled. 1H and 13C NMR
spectra were referenced against the appropriate solvent signal.
Crystallographic data of compound 4 was collected at the MX1
beamline at the Australian Synchrotron, Melbourne, Victoria, Australia (γ
= 0.71073 A). All data was collected at 100 K, maintained using an open
flow of nitrogen. The software used for data collection and reduction of the
data was performed using XDS. Multi-scan absorption corrections
(SADABS) were applied. Crystallographic data for compound 9 were
collected on a Bruker X8 Nonius Kappa CCD diffractometer with graphite-
Overall, a powerful solvent, stoichiometric and nucleophilic
dependence is apparent in determining the resulting products in
what would appear
a
simple textbook organolithium
transformation. From this lithium-bromide exchange study of
ortho-bromo-substituted diaryl imines, we can generalise reaction
conditions to obtain various products as summarised in Scheme
6. Future work within our group will probe the scope of the
cyclisation pathways to introduce further functionality on the imine
precursors to access a range of privileged N-heterocycles.
monochromated Mo Kα (λ = 0.71073 Å) radiation at 123 (1) K. Data was
0
collected and processed using the Bruker Apex2 v.2012.2.0 software;
Lorentz, polarisation and absorption corrections (multi-scan – SADABS])
were applied. Structures were solved and refined using SHELX-2016 or
Olex2. All non-hydrogen atoms were refined using anisotropic thermal
parameters. Selected crystallographic details and refinements are
provided in table S5. CCDC 1914306 and 1914307 contains the
supplementary crystallographic data for this structure. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
General reaction method
To a flame dried Schlenk flask 5 mL of the desired solvent was added
along with the corresponding imine (1-3). The reaction mixture was then
cooled to -78oC and the lithium reagent was added. The reaction mixture
was left to stir for approximately 18 hours warming to room temperature.
The reaction mixture was then hydrolysed with 10 mL of deionised water
and extracted (3 x 15 mL) with diethyl ether. The organic layer was dried
with anhydrous MgSO4 and volatiles removed, the crude sample was
analysed by GC-MS.
Full details are provided in the electronic supporting information.
Scheme 6. Summary of reaction conditions for obtaining desired product. [a] =
combined conversion of iso-indolinone derivatives.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
The authors thank Monash University, the Australian Research
Council (DP170104722) for financial support. The authors also
acknowledge Dr Craig Forsyth for his assistance with the
crystallography. This research was undertaken on the MX1
beamline at the Australian Synchrotron, part of ANSTO. We would
also like to thank the Monash Analytical Platform, Australia
(School of Chemistry, Monash University).
[18] E. C. Border, V. L. Blair, P. C. Andrews, Aust. J. Chem. 2015, 68, 844-
848.
[19] (a) C. Lambert, C. Risko, V. Coropceanu, J, Schelter, S. Amthor, N. E.
Gruhn, J. C. Durivage, J.-L. Brédas, J. Am. Chem. Soc. 2005, 127, 8508-
8516; (b) T. Nishiumi, Y. Chimoto, Y. Hagiwara, M. Higuchi, K.
Yamamoto, Macromolecules 2004, 37, 2661-2664.
[20] A. Pöllnitz, C. Silvestru, J.-F. Carpentier, A. Silvestru, Dalton Trans. 2012,
41, 5060-5070.
[21] (a) J. M. Dennis, C. M. Calyore, J. S. Sjoholm, P. Lutz, J. J. Gair, J. B.
Johnson, Synlett 2013, 24, 2567-2570; (b) R. K. Dempster, F. A. Luzzio,
Tetrahedron Letters 2011, 52, 4992-4995; (c) A. B. Nejma, M. Znati, A.
Daich, M. Othman, A. M. Lawson, H. B. Jannet, Steroids 2018, 138, 102-
107.
Keywords: lithium-bromide exchange • nucleophilic addition •
imines • cyclisation • iso-indolinones
[1]
(a) R. Bloch, Chem. Rev. 1998, 98, 1407-1438; (b) K. Yamada, K.
Tomioka, Chem. Rev. 2008, 108, 2874-2886; (c) S. E. Denmark, C. M.
Stiff, J. Org. Chem. 2000, 65, 5875-5878; (d) S. E. Denmark, N. Nakajima,
O. J.-C. Nicaise, J. Am. Chem. Soc. 1994, 116, 8797-8798; (e) T. Franz,
M. Hein, U. Veith, V. Jäger, E.-M. Peters, K. Peters, H. G. von Schnering,
Angew. Chem. Int. Ed. 1994, 33, 1298-1301; (f) K. Higashiyama, H.
Inoue, T. Yamauchi, H. Takahashi, J. Chem. Soc. Perkin Trans. 1995,
111-115; (g) G. Wu, M. Huang, Chem. Rev. 2006, 106, 2596-2616. (h)
S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069-1094.
(a) J. F. Beck, J. A. R. Schmidt, Dalton Trans. 2012, 41, 860-870; (b) A.
M. Preda, C. I. Rat, C. Silvestru, H. J. Breunig, H. Lang, T. Rüffer, M.
Mehring, Dalton Trans. 2013, 42, 1144-1158; (c) M. Novák, L. Dostál, J.
Turek, M. Alonso, F. De Proft, A. Ružička, R. Jambor, Chem. Eur. J. 2016,
22, 5620-5628; (d) D. L. Davies, F. Lelj, M. P. Lowe, K. S. Ryder, K.
Singh, S. Singh, Dalton Trans. 2014, 43, 4026-4039.
[22] A. Di Mola, l. Palombi, A. Massa, Curr. Org. Chem. 2012, 16, 2302-2320.
[23] (a) C. K. Bradsher, D. A. Hunt, J. Org. Chem. 1981, 46, 327-330; (b) J.
B. Campbell, R. F. Dedinas, S. A. Trumbower-Walsh, J. Org. Chem.
1996, 61, 6205-6211; (c) K. Smith, G. A. El-Hiti, A. S. Hegazy, Chem.
Commun. 2010, 46, 2790-2792.
[24] Y. Xu, X.-Y. Liu, Z.-H. Wang, L.-F. Tang, Tetrahedron 2017, 73, 7245-
7253.
[25] (a) S.-P. Chia, H.-W. Xi, Y. Li, K. H. Lim, C.-W. So, Angew. Chem. Int.
Ed. 2013, 52, 6298-6301; (b) M. T. Nguyen, B. Gabidullin, G. I. Nikonov,
Dalton Trans. 2018, 47, 4607-4612; (c) I. Vránová, R. Jambor, A.
Ružička, R. Jirásko, L. Dostál, Organometallics 2015, 34, 534-541.
[26] (a) L. Bonnafoux, F. Leroux, F. Colobert, Beilstein J. Org. Chem. 2011,
7, 1278-1287; (b) K. S. Feldman, I. Y. Gonzalez, J. E. Brown,
Tetrahedron Lett. 2015, 56, 3564-3566.
[2]
[3]
(a) T. R. Forder, M. D. Jones, New J. Chem. 2015, 39, 1974-1978; (b) M.
C. Joseph, A. J. Swarts, S. F. Mapolie, Dalton Trans. 2018, 47, 12209-
12217; (c) C. Bariashir, Z. Wang, H. Suo, M. Zada, G. A. Solan, Y. Ma,
T. Liang, W.-H. Sun, European Polymer Journal 2019, 110, 240-251.
S. F. Martin, Pure Appl. Chem. 2009, 81, 195-204.
[4]
[5]
(a) F. E. Zieglar, K. W. Fowler, J. Org. Chem. 1976, 41, 1564-1566; (b)
J. F. Beck, A. Neshat, J. A. R. Schmidt, Eur. J. Inorg. Chem. 2010, 5146-
5155; (c) A. Neshat, C. L. Seambos, J. F. Beck, J. A. R. Schmidt, Dalton
Trans. 2009, 4987-5000.
[6]
[7]
(a) C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R. Kennedy, E.
Hevia, Angew. Chem. Int. Ed. 2016, 55, 16145-16148; (b) G. Dilauro, M.
Dell’Aera, P. Vitale, V. Capriati, F. M. Perna, Angew. Chem. Int. Ed. 2017,
56, 10200-10203.
N. B. Kingsley, T. J. Doyon, L. E. Shephard, J. Organomet. Chem. 2016,
48-53.
[8]
[9]
D. Zhao, W. Gao, Y. Mu, L. Ye, Chem. Eur. J. 2010, 16, 4394-4401.
M. Hejda, A. Lyčka, R. Jambor, A. Ružička, L. Dostál, Dalton Trans. 2014,
43, 12678-12688
[10] (a) H.-J. Li, Y.-Q. Zhang, L.-F. Tang, Tetrahedron 2015, 71, 7681-7686;
(b) Y. Xi, X.-Y. Liu, Z. -H. Wang, L.-F. Tang, Tetrahedron 2017, 73, 7245-
7253.
[11] Organolithiums: selectivity for synthesis, Chapter 3, Vol. 23 (Ed.; J.
Clayden), Elsevier, Oxford, 2002.
[12] Y. M. Oskoei, A. Mousavi-azar, A. Madram, A. Hassanpour, M. Hayaty,
Silicon 2012, 4, 251-257.
[13] (a) L. Bonnafoux, F. R. Leroux, F. Colobert, Beilstein J. Org. Chem. 2011,
7, 1278-1287; (b) M. Schlosser, Angew. Chem. Int. Ed. 2005, 44, 376-
393.
[14] (a) M. Ketels, M. A. Ganiek, N. Weidmann, P. Knochel, Angew. Chem.
Int. Ed. 2017, 56, 12770-12773; (b) H. Kim, H.-J. Lee, D.-P. Kim, Angew.
Chem. Int. Ed. 2015, 54, 1877-1880; (c) H. Kim, A. Nagaki, J.-I. Yoshida,
Nat. Commun. 2011, 2, 264-269.
[15] P. C. Gros, F. Elaachbouni, Chem. Commun. 2008, 4813-4815.
[16] M. Dutta, S. M. Mandal, R. Pegu, S. Pratihar, J. Org. Chem. 2017, 82,
2193-2198.
[17] Y.-H. Yu, C.-H. Huang, J.-M. Yeh, P.-T. Huang, Organic Electronics 2011,
12, 694-702.
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
This article is protected by copyright. All rights reserved.

10.1002/chem.201902140
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Book-Breaking
Standard textbook methodology of
rapid, selective lithium-bromide
Boundaries:
S. A. Orr, E. C. Border, P. C. Andrews*
and V. L. Blair*
exchange has been challenged in the
case of bromo-substituted imines.
Employing tBuLi, five products are
identified, revealing an unprecedented
Page No. – Page No.
Lithium-bromide exchange versus
nucleophilic addition of Schiff’s
bases: unprecedented tandem
cyclisation pathways
competitive
nucleophilic
addition
pathway, along with tandem inter/intra-
molecular cyclisations.
Layout 2:
FULL PAPER
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.