Lateral lithiation in deep eutectic solvents: regioselective functionalization of substituted toluene derivatives

Article abstract of DOI:10.1039/d0cc00593b

The heteroatom-directed lateral lithiation of functionalized toluenes in a choline chloride-based eutectic mixture is reported. The metalations proceed within ultrafast reaction times, with a broad substrate and electrophile scope. The directing groups pr

Full text of DOI:10.1039/d0cc00593b

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Lateral Lithiation in Deep Eutectic Solvents: Regioselective
Functionalization of Substituted Toluene Derivatives
Davide Arnodo,† Simone Ghinato,† Stefano Nejrotti,† Marco Blangetti* and Cristina Prandi*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract. The heteroatom-directed lateral lithiation of lithiation (LL) of substituted toluenes.2d, 3-4 However, owing to
functionalized toluenes in choline chloride-based eutectic their well-known air and moisture sensitivity, strictly controlled
a
mixture is reported. The metalations proceed within ultrafast experimental conditions are usually required to avoid both the
reaction times, with a broad substrate and electrophile scope. The degradation of intermediate lithiated species and undesired
directing groups provide a rapid and high regioselective access to side reactions.6 Thus, the identification of new synthetic
functionalized aromatic derivatives of remarkable synthetic value. strategies involving polar organometallic reagents under
aerobic and protic conditions nowadays represents
a
The directed ortho-metalation (DoM) and the lateral metalation
(LM) of aromatic compounds have assumed a pivotal role in
synthesis since the seminal report by Gilman and Morton.1
Nowadays these strategies represent a powerful and well-
consolidated methodology for the construction of
polysubstituted aromatics and heteroaromatics, which have
overtaken the classical electrophilic aromatic substitution for
the assembly of regiospecifically substituted aromatic rings. The
ongoing development of novel metalation reagents for the
ortho-aryl deprotonation (DoM), which has been extensively
reviewed in the literature, clearly illustrates the continued
importance of this class of transformation.2 In strong
relationship with the DoM strategies, of equal synthetic utility
is the development of methodologies for the lateral metalation
fascinating and ultimate challenge in this area. Additionally, the
transition to synthetic methodologies where traditional
solvents are replaced by water or low-impact alternatives
strongly concurs to the goal of attaining sustainability.7 For this
purpose, Deep Eutectic Solvents (DESs) represent a novel and
promising class of unconventional, green solvents, that can
potentially replace the classical petroleum-derived volatile
organic compounds, VOCs.8 In this context, the chemistry of
polar organometallic compounds has recently experienced a
deep revolution by virtue of the independent investigations by
Hevia, García-Álvarez and Capriati on the reactivity of Grignard
and organolithium reagents in the alkylation/arylation of
ketones, imines and nitriles, at room temperature (RT), under
air, and in DESs or glycerol (Gly) or water.9 Furthermore, regio-
and chemoselective DoM reactions using cyclopentyl methyl
ether (CPME) and choline chloride (ChCl)-based eutectic
mixtures as solvents under air have been recently reported,10
while to the best of our knowledge only one example of
regioselective lateral lithiation of diaryl-THF derivatives has
been described hitherto in protic media under hydrous
conditions (Scheme 1, B).11 Building on our long-standing
interest in polar organometallic chemistry12 and our recent
findings in using heterogeneous bio-based solvent mixtures for
the chemoselective DoM of hindered benzamides,10b we now
report a systematic study on the usefulness of DESs as
sustainable media for promoting the regioselective lateral
lithiation of substituted toluene derivatives (Scheme 1, C).
Notable features of our report include a) the use of
environmentally friendly conditions (absence of VOCs and
open-air conditions), b) screening and identification of the most
of benzylic alkyl groups promoted by heteroatom-containing
4
substituents (directing groups, DGs).3,
Overall, extensive
investigations have clearly established that, for either class of
reaction, amides, carbonates and oxazolines are the most
powerful directors.2b-c, 2e Due to the obvious competition with
the ortho-deprotonation process resulting from the presence of
similar DGs, LM often suffers of cumbersome regioselectivity
issues. Hence, of particular interest is the development of
synthetic methods for the selective benzylic metalation of alkyl-
substituted aromatic compounds minimizing the competitive
DoM pathway (Scheme 1, A).5 Organolithium reagents are
elective organometallic species for promoting the lateral
Dipartimento di Chimica
Università di Torino, Via P. Giuria 7, I-10125, Torino, Italy.
Email: marco.blangetti@unito.it ; cristina.prandi@unito.it
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: experimental details,
compounds characterization. See DOI: 10.1039/x0xx00000x
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5
A
: Regioselective LL of substituted toluenes under conventional conditions
Table 1. Metalation reaction of N,N-diisopropyl-2-methylbenzamide 1a under different
View Article Online
conditions.a
DOI: 10.1039/D0CC00593B
DG
Li
DG
E
E+
DG
RLi
THF or Et2O
T = from -78 °C to RT
under N2
N(iPr)2
N(iPr)2
N(iPr)2
N(iPr)2
1) t-BuLi, 2 s
R-Li, 2 s
MeI
O
D
O
O
Li
O
RLi
= n-BuLi, sec-BuLi, LDA, TMPLi, LIC-KOR or LiNK
CPME/DES, RT
2) CD3OD
DGs = CO2NR2, oxazolines, X, OR, CO2R, SO2R
under air
under air
Bn-D-1a
1a
Bn-Li-1a
2a
11
B
C
: Regioselective LL of diaryl-THF derivatives in CPME/DES (2015)
Ar
E
Entry
1
2
3
4
5
6
7
8
DES
R-Li (eq.)
t-Bu (2)
t-Bu (2)
t-Bu (2)
t-Bu (2)
t-Bu (2)
t-Bu (2)
t-Bu (1)
t-Bu (1.2)
t-Bu (1.5)
t-Bu (1.5)
n-Bu (1.5)
s-Bu (1.5)
E+ (eq.)
Product (yield %)b
2a (62)
-
Ar
Ar
RLi, then E+
RLi
OH
O
O
Li
CPME/DESs
0 °C, under air
CPME/DESs
0 °C, under air
ChCl/Gly
ChCl/Glyc
ChCl/Glyd
ChCl/urea
ChCl/H2O
ChCl/Gly
ChCl/Gly
ChCl/Gly
ChCl/Gly
ChCl/Gly
ChCl/Gly
ChCl/Gly
MeI (5)
MeI (5)
MeI (5)
MeI (5)
MeI (5)
MeI (3)
MeI (5)
MeI (5)
MeI (5)
CD3OD (5)
MeI (5)
MeI (5)
R
This work
2a (52)
2a (59)
-
2a (41)
2a (50)
2a (58)
2a (70)
Bn-D-1ae
2a (26)
2a (38)
:
: regioselective LL of substituted toluene derivatives in CPME/DES
DG
DG
E+
DG
t-BuLi
Li
E
CPME/DES
RT, under air
CPME/DES
RT, under air


Absence of VOCs, room temperature, under air
Clean reactions and easy work up


High regioselectivity
Wide substrates and electrophiles scope
9
Scheme 1. State-of-the-art of the heteroatom-directed lateral lithiation of alkyl-
10
11
12
substituted aromatic compounds.
suitable directing groups for regioselective LL, c) clean reactions
and easy work-up procedures and d) wide substrates and
electrophiles scope.
a Reaction conditions: 1.0 g DES per 0.2 mmol of 1a, CPME (0.2 mL); DES: ChCl/Gly
(1:2 mol mol–1); ChCl/urea (1:2 mol mol–1); ChCl/H2O (1:2 mol mol–1). b Determined
c
d
by 1H NMR using CH3NO2 as the internal standard. No CPME was added. T = 0
°C. e Bn-D-1a: 80% isolated yield, 80% D incorporation.
We started our investigations using the N,N-diisopropyl-2-
methylbenzamide 1a as a model substrate, since a) we have
already demonstrated that this directing group can efficiently
promote the ortho-lithiation in CPME/DESs heterogeneous
mixtures10b and b) the LL of tertiary o-alkylbenzamides is
generally performed using LDA13 or sec-BuLi/TMEDA14 in VOCs
at low temperatures in order to avoid self-condensation of the
lithiated species. Based on our previous findings,10b a vigorously
stirred suspension of amide 1a (0.2 mmol, 1 M in CPME)15 in a
ChCl/Gly (1:2 mol/mol) eutectic mixture was treated with a
commercial 1.7 M pentane solution of t-BuLi (2 eq.) at RT under
air. Instantaneous quench of the reaction mixture with MeI (5
eq.) afforded the corresponding N,N-diisopropyl-2-
ethylbenzamide 2a in 62% yield (Table 1, entry 1) alongside with
6% of α,α-dimethylated byproduct (see ESI for details). Notably,
in the absence of CPME as an additive no lithiation occurred and
the starting material 1a was quantitatively recovered after
workup (Table 1, entry 2). The regioselectivity of the metalation
was assessed by 1H and 2H NMR analyses of the products arising
from the deuteration of Bn-Li-1a with CD3OD. Under these
conditions the reaction gave almost exclusively benzylic
deuterated product Bn-D-1a (91% D) with no detectable
incorporation of D in the ortho-position (see ESI).16 Efforts were
made to further improve the conversion of the starting material
and suppress the formation of the undesired bis-functionalized
byproduct. No improvements were observed when the reaction
was performed at 0 °C (Table 1, entry 3) or switching ChCl/urea
(1:2 mol/mol) for ChCl/Gly (Table 1, entry 4), whereas the use
of water as the hydrogen bond donor was ineffective (Table 1,
entry 5). Lowering the equivalents of electrophile (Table 1,
entries 6) led to a decrease of conversion, while reducing the
amount of lithiating agent to 1.5 eq. gave the best results in
terms of yield and suppression of byproduct, as confirmed by 1H
and 2H NMR analysis of the corresponding deuterated product
Bn-D-1a (Table 1, entries 9-10 and Figure S12, ESI).
Notably, other organolithiums such as n-BuLi and s-BuLi were
considerably less effective in promoting the lateral metalation
under these conditions (Table 1, entries 11-12). The half-life of
Bn-Li-1a in the above protic medium was then evaluated by
quenching multiple reaction samples with MeI at different
times. The estimated half-life for Bn-Li-1a from the first-order
plot obtained is 6.57 s, which is consistent with the ortho-Li N,N-
diisopropylbenzamide10b in the same heterogeneous solvent
system (see ESI for details). The selectivity of the lithiation
reaction was then investigated for a series of ortho-, meta- and
para-substituted toluenes bearing different DGs (Scheme 2).
The substrates were treated with t-BuLi (1.5 equiv.) in
CPME/DES (ChCl/Gly 1:2) mixture at RT under air followed by
DG
DG
DG
DG
DG
t-BuLi (1.5 eq.)
2 s, RT
Li
D
Li
CD3OD
D
+
+
ChCl/Gly 1:2
CPME
under air
-1a-h
o-Li-1a-h
Bn-D-1a-h
o-D-1a-h
1a-h
Bn-Li
D
N(iPr)2
N(iPr)2
N(iPr)2
N(iPr)2
N
O
D
O
O
O
O
D
+
D
D
Bn-D-1a (80%)
Bn:o ratio 100:0
80% D
o-D-1b + o'-D-1b (93%)
Bn:o ratio 0:100
64% D
o-D-1c (89%)
Bn:o ratio 0:100
54% D
Bn-D-1d (85%)
Bn:o ratio 92:8
42% D
D
SO2NEt2
SO2NEt2
D
OMOM
D
OMOM
D
o-D-1e (72%)
Bn:o ratio 0:100
80% D
2-Bn-D-1f (78%)
Bn:o ratio 80:20
92% D
o-D-1g (91%)
Bn:o ratio 0:100
59% D
o-D-1h (92%)
Bn:o ratio 0:100
38% D
Scheme 2. Metalation reaction of substituted toluenes 1a-h using t-BuLi in CPME/DES at
RT under air. Reaction conditions: 1a-h (0.2 mmol), CPME (0.2 mL), DES (1.0 g), CD3OD (5
eq.). DES: ChCl/Gly (1:2 mol mol–1). Ratios and D incorporation are based on 1H NMR
integration and confirmed with 2H NMR. Yields in brackets refer to products isolated
after flash column chromatography.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC00593B
1a
: N,N-diisopropyl-2-methylbenzamide
DG
DG
1) t-BuLi, 2 s
1d
1f
1i
1j
: 4,4-dimethyl-2-(o-tolyl)-4,5-dihydrooxazole
: N,N-diethyl-2,4-dimethylbenzenesulfonamide
: N,N-diisopropyl-2,4-dimethylbenzamide
: N,N-diisopropyl-2,6-dimethylbenzamide
2) E+
E
ChCl/Gly (1:2), CPME
RT, under air
1a, 1d, 1f, 1i-k
2b-r
1k
: N,N-diisopropyl-2,4,6-trimethylbenzamide
O
O
O
N(iPr)2
O
O
N(iPr)2
N(iPr)2
O
N(iPr)2
N(iPr)2
N(iPr)2
OH
H
N
H
Ph
Ph
N
Bn
COOH
Ph
OH
S
O
Ph
2f
(BnNCS, 34%)
2b
2d
2e
2c
2g
(Weinreb amide, 59%)b
(PhCHO, 66%)
(propylene oxide, 56%)
O
N(iPr)2
(CO2, 50%)a
(PhCH=NPh, 53%)
O
O
O
N(iPr)2
N(iPr)2
N(iPr)2
O
O
O
N(iPr)2
N(iPr)2
N(iPr)2
H
Ph
Ph
N
D
COOH
P(OPh)2
D
Ph
O
OH
Ph
O
2h
(DPPCl, 26%)c
2i
2j
(Weinreb amide, 57%)b (CD3OD, 80%, 71%D)
1j
2k
2l
Bn-D-
1i
Bn-D-
(CD3OD, 90%, 86%D)
(CO2, 37%)a
(PhCHO, 70%)
(PhCH=NPh, 67%)
O
O
N(iPr)2
N(iPr)2
O
N(iPr)2
SO2NEt2
OH
SO2NEt2
Ph
OH
N
O
N
O
Ph
D
OH
OH
O
Ph
2r
2o
(MeI, 78%)
2p
2q
2m
(propylene oxide, 54%)
2n
(Weinreb amide, 53%)b
1k
Bn-D-
(PhCHO, 60%)
(PhCOMe, 60%) (propylene oxide, 65%)
(CD3OD, 73%, 60%D)
Scheme 3. Scope of the lateral lithiation reaction of substituted toluenes 1a, 1d, 1f, and 1i-k in CPME/DES (ChCl/Gly 1:2 mol mol–1) mixture. Reaction conditions: substrate (0.2
mmol), t-BuLi (1.7 M in pentane, 0.4 mmol), CPME (0.2 mL), DES (1.0 g), electrophile (5 eq.). Reported yields refer to products isolated after flash column chromatography. a CO2 was
bubbled for 15 s. b Weinreb amide: N-methoxy-N-methylbenzamide. c DPPCl: diphenyl phosphoryl chloride.
quenching with CD3OD after 2 s, and analyzed by 1H and 2H NMR both ortho- (1g) and meta-OMOM (1h) substituted toluenes in
(Figure S17, ESI). The strongest DG of the series, namely the CPME/DES, however with low D incorporation (Scheme 2, o-D-
tertiary amide group, efficiently promoted the sole ortho- 1g and o-D-1h).
lithiation of both meta- and para-substituted derivatives 1b and Based on data reported in Scheme 2, derivatives of substrates
1c under these conditions (Scheme 2, o-D-1b and o-D-1c). These 1a, 1d and 1f were than selected to evaluate the generality of
results are coherent with those reported for the same reactions this transformation (Scheme 3). Carbonyl electrophiles such as
run under conventional metalation conditions,17 as a matter of aldehydes and imines reacted smoothly with anion Bn-Li-1a,
fact regioselective lateral lithiation of 1c entails the use of thereby providing the expected lateral functionalized adducts
hindered lithium amides2a, 5e while the benzylic lithiation of 1b 2b and 2c in good yields (66% and 53% respectively). The
has never been described so far. On the other hand, the benzylic anion Bn-Li-1a promoted the regioselective ring
oxazolinyl moiety is a versatile coordinating DG able to opening of 1,2-propylene oxide affording the corresponding
efficiently promote both DoM of benzene derivatives and the homologation product 2d in 56% yield. Acylation of Bn-Li-1a
lithiation of tolyl methyl groups.18 Pleasingly, treatment of the successfully proceeded using CO2 and the aromatic Weinreb
ortho-tolyl oxazoline 1d with t-BuLi at RT under air gave almost amide (N-methoxy-N-methylbenzamide) as electrophiles,
complete regioselective benzylic metalation (Scheme 2, Bn-D- affording the corresponding substituted phenylacetic acid 2e
1d) with an overall 42% D incorporation. Tertiary sulfonamides and ketone 2g in 50% and 59% yield respectively (Scheme 3).21
also represent powerful DGs for DoM and LL processes. Under The quenching reaction of Bn-Li-1a with base-sensitive
these conditions, lithiation of the para-methyl tertiary functional groups (e.g. isothiocyanates and diphenyl phosphoryl
sulfonamide 1e afforded the sole kinetic ortho-lithiation o-D-1e chloride) was less favorable and furnished the thioamide 2f and
product,19 while treatment of the 2,4-dimethyl derivative 1f the phosphonate derivative 2h in lower yields (34% and 26%).
gave high D incorporation in the benzylic position proximal to However, attempted halogenation of Bn-Li-1a using
the DG together with a 20% D incorporation in the ortho- chlorinating, brominating or iodinating agents resulted in low
position (Scheme 2). The weaker methoxymethoxy (OMOM) conversions and only the corresponding homocoupling
DG, which offers a remarkable regiocontrol of the lithiation products were detected in the reaction mixture.12e The directing
reaction under conventional conditions with high selectivity for ability of the tertiary amide group was then exploited for the
DoM over LL,20 was finally investigated. Unsurprisingly, full regioselective lateral lithiation of substituted xylenes 1i-k.
ortho-selectivity was observed for the lithiation/deuteration of Deuterium labelling experiments (metalation followed by
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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deuteration of Bn-Li-1i-k) showed high benzylic selectivity with
no detectable D incorporation at the para- position for 2,4-
dimethyl and mesityl derivatives 1i and 1k, while notably no bis-
deuterated products were observed upon lithiation of substrate
1j. Hence, electrophilic quench of Bn-Li-1i-k with aldehydes,
imines, amides and epoxides provided the corresponding
products 2j-n with good overall yields (53-70%) (Scheme 3). On
the other hand, acylation of Bn-Li-1i with CO2 proceeded with
lower yield, affording the substituted phenylacetic acid 2i in
37% yield. The scope of this transformation was also extended
to the other previously investigated DGs, as such o-tolyl
oxazoline 1d and o,p-dimethyl sulfonamide 1f. The lithiation
efficiently occurred proximal to the DGs moiety and led to the
formation of adducts 2o-r in good yields (60-78%) upon
quenching of the corresponding Bn-Li-1d and Bn-Li-1f anions
with alkylating agents, such as iodomethane and propylene
oxide, and carbonyl electrophiles (Scheme 3).
In summary, we have reported the directed lateral lithiation on
functionalized toluene derivatives under air, at RT, within a
reaction time of 2 s and using environmentally friendly deep
eutectic mixtures in combination with cyclopentyl methyl ether
(CPME). The reaction conditions are exceedingly mild, reaction
times very fast and work-up straightforward. The most widely
used DGs in ortho- and lateral lithiation reactions (tertiary
amides, sulfonamides and oxazolines) preserve their relative
directing abilities and efficiently promote the LL under these
conditions. The scope has been extended to various substrates
and electrophiles, thus providing rapid access to functionalized
aromatic derivatives suitable for further synthetic
transformations. Taken together our results represent an
important advance in the chemistry of polar organometallic
reagents in unconventional protic media as an alternative and
green paradigm to traditional anhydrous, low temperatures and
inert conditions. We expect that in the near future this
approach will be expanded to other broadly used
organometallic mediated transformations, thus paving the way
to more general applications of green chemistry principles.
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15 For a recent review on the use of CPME as a green solvent,
see: U. Azzena, M. Carraro, L. Pisano, S. Monticelli, R.
Bartolotta and V. Pace, ChemSusChem, 2019, 12, 40.
16 Metalation of N,N-diisopropyl-2-ethylbenzamide with t-BuLi
in THF at -78 °C affords only the ortho-Li product as reported
by: D. R. Armstrong, S. R. Boss, J. Clayden, R. Haigh, B. A.
Kirmani, D. J. Linton, P. Schooler and A. E. H. Wheatley,
Angew. Chem. Int. Ed., 2004, 43, 2135.
17 P. Beak and R. A. Brown, J. Org. Chem., 1982, 47, 34.
18 a) N. Tahara, T. Fukuda and M. Iwao, Tetrahedron Lett., 2002,
43, 9069; b) H. W. Gschwend and A. Hamdan, J. Org. Chem.,
1975, 40, 2008.
19 Treatment of 1e with n-BuLi in THF under thermodynamic
control conditions affords the kinetic ortho-Li product, which
slowly equilibrates over 2 h into the thermodynamic Bn-Li
species. See S. L. MacNeil, O. B. Familoni and V. Snieckus, J.
Org. Chem. 2001, 66, 3662.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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R. D. Clark and A. Jahangir, Org. React., 2004, 47, 1.
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21 Quenching the intermediate Bn-Li-1a using a base sensitive
electrophile such as ethyl benzoate afforded the same ketone
2g, although with lower yields.
5
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