Exploiting Deep Eutectic Solvents and Organolithium Reagent Partnerships: Chemoselective Ultrafast Addition to Imines and Quinolines Under Aerobic Ambient Temperature Conditions

Article abstract of DOI:10.1002/anie.201609929

Shattering the long-held dogma that organolithium chemistry needs to be performed under inert atmospheres in toxic organic solvents, chemoselective addition of organolithium reagents to non-activated imines and quinolines has been accomplished in green, b

Full text of DOI:10.1002/anie.201609929

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609929
German Edition: DOI: 10.1002/ange.201609929
Organolithium Chemistry
Exploiting Deep Eutectic Solvents and Organolithium Reagent
Partnerships: Chemoselective Ultrafast Addition to Imines and
Quinolines Under Aerobic Ambient Temperature Conditions
Cristian Vidal, Joaquꢀn Garcꢀa-ꢁlvarez,* Alberto Hernꢂn-Gꢃmez, Alan R. Kennedy, and
Eva Hevia*
In memory of Jose Barluenga
Abstract: Shattering the long-held dogma that organolithium
chemistry needs to be performed under inert atmospheres in
toxic organic solvents, chemoselective addition of organo-
lithium reagents to non-activated imines and quinolines has
been accomplished in green, biorenewable deep eutectic
solvents (DESs) at room temperature and in the presence of
air, establishing a novel and sustainable access to amines.
Improving on existing methods, this approach proceeds in the
absence of additives; occurs without competitive enolization,
reduction or coupling processes; and reactions were completed
in seconds. Comparing RLi reactivities in DESs with those
observed in pure glycerol or THF suggests a kinetic anionic
activation of the alkylating reagents occurs, favoring nucleo-
philic addition over competitive hydrolysis.
methods using polar organometallics, require restrictive
reaction conditions. This includes use of inert atmospheres,
dry oxygen-free organic solvents and in many cases low
temperatures (À788C) in order to avoid intermediate degra-
dation and side reactions.[6] Thus, running polar organome-
tallic chemistry under aerobic and/or hydrous conditions is
the ultimate challenge to synthetic chemists.[7] As an opening
gambit towards this target, we recently pioneered use of green
and biorenewable deep eutectic solvents (DESs) combining
ammonium salt choline chloride (ChCl) with water or
glycerol (Gly) (Figure 1) showing they can activate Grignard
N
ucleophilic addition of organolithium derivatives to
carbonyl compounds (e.g., ketones or aldehydes) is
À
a common methodology to access new C C bonds allowing
synthesis of functionalized alcohols.[1] Contrastingly, their use
as nucleophiles to transform imines to amines via direct 1,2-
addition processes has been significantly less developed.[2]
Figure 1. Components of DES mixtures used in this study.
=
Reduced electrophilicity of the C N group, competitive
abstraction of acidic a-hydrogens to give azaenolates and
possible formation of reductive coupling side-products are
some mitigating factors, which can compromise the chemo-
selectivity of this approach.[3] Strategies undertaken to over-
come these limitations include the use of Lewis acids (e.g.,
AlMe3, LiBr)[4,5] as additives that can activate the organic
substrate and of alternative alkylating reagents such as
magnesium zincates ([MgCl][ZnR3]) which appear more
chemoselective than conventional common RLi or RMgX
reagents.[1,2] However, all these protocols, as with nearly all
and organolithium reagents to promote room temperature
chemoselective ketone alkylation/arylation reactions.[8]
Moreover, air could be tolerated in these additions. Subse-
quent insightful studies by Capriati reported lithiation of
diaryltetrahydrofurans in ChCl-based DESs under air, finding
it competitive with protonolysis as well as RMgX- and RLi-
mediated additions to g-chloroketones to furnish 2,2-disub-
stituted tetrahydrofurans.[9] Taking organolithium DES
chemistry into new, more taxing territory, here we describe
the chemoselective addition of organolithium compounds to
both imines and quinolines in DESs under air as a novel
sustainable methodology to amines. This has wide implica-
tions as amine synthesis has been identified as a key area in
green chemistry for pharmaceutical manufacturers.[10]
[*] Dr. C. Vidal, Dr. J. Garcꢀa-ꢁlvarez
Laboratorio de Compuestos Organometꢂlicos y Catꢂlisis (Unidad
Asociada al CSIC), Departamento de Quꢀmica Orgꢂnica e Inorgꢂnica
(IUQOEM), Facultad de Quꢀmica, Universidad de Oviedo
33071, Oviedo (Spain)
E-mail: garciajoaquin@uniovi.es
This study examined adding RLi reagents to a range of
imines at room temperature, in air, using DESs as solvents.[11]
The scope of this green approach considered: 1) the DES
combination, 2) the organometallic reagent; and 3) the imine.
Firstly we assessed the reaction of commercially available
nBuLi with aromatic imine N-benzylideneaniline (1a) using
different stoichiometries (entries 1–4, Table 1) in the eutectic
Dr. A. Hernꢂn-Gꢃmez, Dr. A. R. Kennedy, Prof. E. Hevia
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde
Glasgow, G1 1XL (UK)
E-mail: eva.hevia@strath.ac.uk
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609929.
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mixture to favor nBuLi addition to 1a over its competing
hydrolysis is illustrated in entries 7 and 8 of Table 1, whereas
using neat H2O or Gly, in the absence of ammonium salt
ChCl, furnishes 2a in lower 22 and 38% yields, respectively.
Highlighting the exciting potential of these green solvents,
when the addition order of the reagents is reversed and nBuLi
is introduced firstly to the eutectic mixture, which is stirred for
15 s under air before adding imine 1a, product 2a is obtained
in a remarkably high 89% yield. Astonishingly, even if a one-
minute interval is left between these reagents, the yield of 2a
is still good at 63%, emphasising the kinetic stability of nBuLi
in this green solvent. Indeed, it is only after 3.5 min when the
formation of 2a is almost totally suppressed (Scheme 1).
Table 1: Study of the addition reaction of organometallic reagents (RM)
to N-benzylideneaniline (1a) in different DESs.[a,b]
Entry
RM[b]
[mmol][b]
Solvent
Yield [%][c]
1
2
3
4
5
6
7
8
nBuLi
1.3
1.4
1.8
2
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2EG
1ChCl/2H2O
H2O
91
95
97
98
66
54
22
38
1
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
Gly
9
nBuMgCl
nBuMgCl
nBu2Mg
LiMgnBu3
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
10[d]
11
12
8
36
72
[a] Reactions were performed under air, at room temperature and using
1 g of DES. Reaction time 3 s. 1 mmol of the imine 1a was always used.
[b] Commercial solutions of nBuLi (1.6m in hexanes), nBuMgCl (1.0m in
THF) or dibutylmagnesium (1.0m in hexanes) were used. LiMgnBu3 was
prepared in situ by mixing equimolar amounts of nBuLi and nBu2Mg in
hexane. [c] Determined via 1H NMR data using dibromomethane as
internal standard. [d] ZnCl2 (10 mol%) was added to the reaction
mixture.
Scheme 1. Assessing the time-dependent formation of 2a when the
order of addition of reagents is reversed.
The reactivity of 1a with other polar organometallics
under the optimized reaction conditions was also investi-
n
gated. BuMgCl failed to produce 2a, even when ZnCl2 was
n
employed as an additive (entries 9 and 10). Using Bu2Mg,
mixture 1ChCl/2Gly (1:2 mol/mol). Remarkably, under
conditions incompatible with conventional organolithium
chemistry, almost quantitative formation of amine (2a) was
observed employing only slight excess of nBuLi (1.4 equiv,
entry 2), in a very short reaction time (2–3 s). Advantages of
this approach are that: 1) no additives are required to achieve
high conversions; 2) competitive enolization, reduction or
coupling reactions were not observed;[12] 3) edging closer to
which has recently shown promise for addition to bis-
(aryl)methylimines in toluene,[16] yields 2a in a modest 36%
yield (entry 11). Even anionically activated lithium magnesi-
ate LiMgnBu3 showed reduced reactivity (72%, entry 12),
suggesting that under these conditions, the high polarity of
À
Li C bonds in RLi reagents is crucial for success of the 1,2-
addition process.
Our previous work related the enhanced reactivity of
polar organometallics in DESs with studies on the addition of
RMgX reagents to ketones in organic solvents, where chemo-
selectivity can be enhanced by adding substoichiometric
amounts of ammonium salt NnBu4Cl.[8] We attributed this to
forming kinetically activated mixed ammonium magnesiate
salts. Studies here reacting PhLi with 1a in THF in the
presence of NnBu4Cl suggest the formation of related mixed
ammonium lithiate species. However, in this case, these
compounds appear to be extremely reactive in THF solutions,
having a negative effect on addition chemoselectivity. Thus
NMR monitoring of the reaction revealed the formation of
lithium but-3-en-1 oxide 4, resulting from a-deprotonation
and subsequent ring-opening of THF (50% yield) along with
ammonium lithiate complex 5 (Scheme 2(i)), whose consti-
n
stoichiometric conditions, a slight excess of BuLi gave full
conversion to the desired amine 2a, even though hydrolysis
could be expected in the protic solvent; and 4) no imine
decomposition was seen in the eutectic mixture.
Next we assessed the effect of different ChCl-based DESs
on this 1,2-addition reaction. Interestingly, replacing Gly for
HBDs ethylene glycol (EG, entry 5) and water (entry 6)
lowers the yield of amine 2a (to 66 and 54%, respectively).
Notwithstanding, although the addition process is less effi-
cient, its excellent chemoselectivity is maintained, without
forming by-products, as only unreacted imine 1a and amine
2a were seen in the reaction crudes (see the Supporting
Information (SI)).[13] Contrastingly, when using HBDs con-
taining carbonyl functionalities (such as urea or lactic acid),
1
complex mixtures of products were observed from adding
tution was established by H DOSY NMR experiments (see
n
=
BuLi across the C O bond of these H-donor molecules,
SI). Contrastingly, using PhLi the addition reaction occurs
quantitatively to form amide [(THF)3LiNPh(CHPh2)] (3),
whose structure was elucidated by X-ray crystallography
(Scheme 2(ii) and SI). This significant increase in the basicity
of PhLi in THF on the addition of NnBu4Cl contrasts with
results observed using DESs, where no substantial metallation
of the glycerol (HBD component of the DES) is seen, hinting
along with traces of 2a.[14] Crucially, the use of inert-
atmosphere Schlenk techniques or low temperature (0 to
À788C), mandatory when these additions are carried out in
ethereal solvents, are not required using DESs (these solvent
mixtures have a high heat capacity, so low temperatures are
not needed to cool reactions).[15] The propensity of the DES
2
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Table 2: Addition of organolithium (RLi) reagents to imines in the
eutectic mixture 1ChCl/2Gly.[a]
Scheme 2. Deleterious effect of ammonium salt on addition reaction
between imine 1a and phenyllithium.
that though the formation of reactive ammonium lithiate
species (via anionic activation by possible co-complexation
with ChCl) can explain high efficiency of the addition
reactions, other subtle effects such as the choice of HBD
component or the nature of the ammonium salt employed
should also play an important role in tuning the chemo-
selectivity of the reaction. Moreover, the different HBD
abilities of water and alcohols cannot be disregarded, as
recently shown by Capriati for “in water” RMgX mediated-
additions to g-chloroketones.[9c] Advancing the understanding
of the interactions between the different components of DESs
attracts widespread interest and debate,[11a] and to date only
the structure of the DES reline (1ChCl/2Urea) has been
elucidated using neutron diffraction.[17]
Encouraged by these findings we then ran the reaction
using other RLi reagents and imines, to probe the scope of
this transformation (see Table 2). For each substrate tested,
the addition reaction in the eutectic mixture 1ChCl/2Gly was
complete in a very short reaction time (3 s) and with high
selectivity, as only unreacted imine and the desired amine
(2a–s) were observed in the reaction crudes (see SI). Imine 1a
was chosen as the benchmark to study the addition of
different organolithium reagents. Thus, under the previously
optimized reaction conditions (1.4 equiv of RLi, room
temperature, under air, Table 1) both aliphatic (nBuLi,
MeLi, sBuLi, tBuLi) and aromatic (PhLi) organolithium
reagents successfully add to imine 1a yielding amines (2a–
e) in excellent yields (86–95%). Results are particularly
remarkable with sterically demanding sBuLi and tBuLi, which
in general have a greater tendency to undergo b-hydride
elimination, especially when employed at room temperature.
But here, they chemoselectively produce amines (2c,d and
2h,i, 80–94% yield), without need of a large excess of RLi
(1.4 equiv) or long reaction times (3 s). The method also
offers an excellent substrate scope, showing similar amine
conversions for N-aryl- or N-alkyl-substituted aldimines
(Table 2). High chemoselectivity is also apparent as elec-
tron-withdrawing (Br; 2m, 2q and 2s) and electron-donating
substituents (MeO or Me; 2k, 2l, 2n, 2o, 2p and 2r) are
tolerated on imine Ar groups, without observing possible
competing processes such as Li–Br exchange (2m, 2q and 2s)
or a-metallation.
[a] Reactions were run under air, at room temperature using 1 g of the
eutectic mixture 1ChCl/2Gly. Reaction time 3 s. 1 mmol of imine was
n
always used. Commercial solutions of BuLi (1.6m in hexanes), MeLi
(1.6m in diethyl ether), sBuLi (1.4m in cyclohexane), tBuLi (1.9m in
pentane) and PhLi (1.8m in dibutyl ether) were used. Yields were
1
determined by H NMR data using dibromomethane as internal
standard.
reagents to aza-aromatic heterocyclic compounds which takes
place with concomitant dearomatization of the heterocycle.
The synthesis of 2-substituted dihydroquinolines, through
adding RLi reagents to quinoline, is a commonly used
methodology for the production of tetrahydroquinoline-
containing alkaloids.[18] Using conventional methods limited
by low temperatures, an inert atmosphere and scrupulously
dry solvents, these reactions usually yield mixtures of re-
aromatized 2-substituted quinoline and C2- and C4-dihydro-
quinolines.[19] In contrast, we found that under the same
optimized reaction conditions (1ChCl/2Gly as solvent, at
room temperature in air, 1.4 equiv RLi in Table 3) aliphatic
s
t
(MeLi, BuLi, BuLi) organolithium reagents add instanta-
neously (5 s) to quinoline to furnish exclusively C2-substi-
tuted dihydroquinolines 6a–d. Although reaction yields are
moderate (30–54%), chemoselectivities are remarkable, as
no by-products were seen in reaction crudes, only unreacted
quinoline and target 2-substituted dihydroquinolines (see SI).
In summary, this work has shown that replacing conven-
tional toxic ethereal solvents by green, biorenewable deep
Next we extended this greener and air-compatible proto-
col to the even more challenging addition of organolithium
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b) J. Clayden, Organolithiums: Selectivity for Synthesis, Perga-
mon, Elsevier, Oxford, 2002.
Table 3: Addition of organolithium (RLi) reagents to quinolines in the
eutectic mixture 1ChCl/2Gly.[a]
[2] Selected examples of 1,2-addition of organolithiums to imines:
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J. Org. Chem. 2015, 6779 and references therein.
[8] C. Vidal, J. Garcꢂa-ꢃlvarez, A. Hernꢁn-Gꢀmez, A. R. Kennedy,
E. Hevia, Angew. Chem. Int. Ed. 2014, 53, 5969; Angew. Chem.
2014, 126, 6079.
[a] Reactions were performed under air, at room temperature using 1 g of
the eutectic mixture 1ChCl/2Gly. Reaction time 5 s. 1 mmol of quinoline
was always employed. Commercial solutions of MeLi (1.6m in diethyl
ether), sBuLi (1.4m in cyclohexane), and tBuLi (1.9m in pentane) were
used. Yields were determined by 1H NMR data using dibromomethane
as internal standard.
[9] a) V. Mallardo, R. Rizzi, F. C. Sassone, R. Mansueto, F. M.
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[10] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
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eutectic solvents facilitates the successful chemoselective
addition of organolithium reagents to imines and quinolines
under standard bench experimental conditions (room temper-
ature and under air), thus edging closer towards reaching
aerobic/hydrous polar organometallic chemistry and at the
same time advancing main-group based green chemistry.
Experimental Section
Full experimental details and copies of NMR spectra are included
in the Supporting Information. CCDC 1503241 contains supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
[12] R. Bloch, Chem. Rev. 1998, 98, 1407.
[13] It should be noted that benzaldehyde (the hydrolyzed product of
imine 1a) was not formed in the reaction using eutectic mixture
1ChCl/2H2O.
Acknowledgements
[14] A similar behavior has been noted by us for the addition of
RMgX to ketones using DESs, see Ref. [8].
We are indebted to Spanish MINECO (RYC-2011-08451,
CTQ2013-40591-P, CTQ2014-51912-REDC), Gobierno del
Principado de Asturias (GRUPIN14-006), and the EU COST
SIPs-CM1302 for financial support. J.G.-A. thanks MINECO
and the European Social Fund for award of a “Ramꢀn
y Cajal” contract. E.H. and A.H.G. thank the ERC (Stg
MixMetApps) for its generous sponsorship of this research.
We also thank Professor Robert E. Mulvey for his insightful
comments.
[15] Molar heat capacity for DESs based on quaternary ammonium
salts and several hydrogen bond donors (i.e. Gly) have been
recently reported in the temperature range of 298.15 – 353.15 K.
J. Naser, F. S. Mjalli, Z. S. Gano, J. Chem. Eng. Data 2016, 61,
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Tetrahedron 2004, 60, 8221; c) A. OꢅByrne, P. Evans, Tetrahedron
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Keywords: deep eutectic solvents · green chemistry · imines ·
organolithium reagents · salt activation
[1] a) The Chemistry of Organolithium Compounds (Eds.: Z.
Rappoport, I. Marek), Patai Series, Wiley, Chichester, 2004;
Manuscript received: October 10, 2016
Final Article published: && &&, &&&&
4
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Communications
Organolithium Chemistry
The green(air), the better! Moving closer
to the dream of hydrous/aerobic organo-
lithium chemistry, replacing toxic organic
solvents by green and biorenewable deep
eutectic solvents (DESs) enables regio-
selective addition of organolithium
reagents to non-activated imines at room
temperature in air.
C. Vidal, J. Garcꢁa-ꢂlvarez,*
A. Hernꢃn-Gꢄmez, A. R. Kennedy,
E. Hevia*
&&&& — &&&&
Exploiting Deep Eutectic Solvents and
Organolithium Reagent Partnerships:
Chemoselective Ultrafast Addition to
Imines and Quinolines Under Aerobic
Ambient Temperature Conditions
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!