Ultrafast amidation of esters using lithium amides under aerobic ambient temperature conditions in sustainable solvents

Article abstract of DOI:10.1039/d0sc01349h

Lithium amides constitute one of the most commonly used classes of reagents in synthetic chemistry. However, despite having many applications, their use is handicapped by the requirement of low temperatures, in order to control their reactivity, as well as the need for dry organic solvents and protective inert atmosphere protocols to prevent their fast decomposition. Advancing the development of air- and moisture-compatible polar organometallic chemistry, the chemoselective and ultrafast amidation of esters mediated by lithium amides is reported. Establishing a novel sustainable access to carboxamides, this has been accomplished via direct C-O bond cleavage of a range of esters using glycerol or 2-MeTHF as a solvent, in air. High yields and good selectivity are observed while operating at ambient temperature, without the need for transition-metal mediation, and the protocol extends to transamidation processes. Pre-coordination of the organic substrate to the reactive lithium amide as a key step in the amidation processes has been assessed, enabling the structural elucidation of the coordination adduct [{Li(NPh2)(OCPh(NMe2))}2] (8) when toluene is employed as a solvent. No evidence for formation of a complex of this type has been found when using donor THF as a solvent. Structural and spectroscopic insights into the constitution of selected lithium amides in 2-MeTHF are provided that support the involvement of small kinetically activated aggregates that can react rapidly with the organic substrates, favouring the C-O bond cleavage/C-N bond formation processes over competing hydrolysis/degradation of the lithium amides by moisture or air.

Full text of DOI:10.1039/d0sc01349h

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DOI: 10.1039/D0SC01349H
ARTICLE
Ultrafast Amidation of Esters using Lithium Amides under
Aerobic Ambient Temperature Conditions in Sustainable
Solvents‡
Michael Fairley,a Leonie J. Bole,b Florian F. Mulks,a,b Laura Main,a Alan R. Kennedy,a Charles T.
O’Hara,a Joaquín García-Alvarez,*c and Eva Hevia*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Lithium amides constitute one of the most commonly used class of reagents in synthetic chemisty. However, despite many
applications, their use is handicapped by their requirements of low temperatures, in order to control their reactivity, as well as
the need of dry organic solvents and protective inert atmosphere protocols to avoid their fast decomposition. Advancing the
development of air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast amidation of
esters mediated by lithium amides is reported. Establishing a novel sustainable access to carboxamides, this has been
accomplished via direct C-O bond cleavage of a range of esters using glycerol or 2-MeTHF as solvents, under air. High yields
and good selectivity are observed while operating at ambient temperature, without the need of transition-metal mediation, and
the protocol extends to transamidation processes. Pre-coordination of the organic substrate to the reactive lithium amide as a
key step in the amidation processes has been assessed, enabling the structural elucidation of the coordination adduct of
[{Li(NPh2)(O=CPh(NMe2)}2] (8) when toluene is employed as a solvent. No evidence for formation of a complex of this type
has been found when using donor THF as a solvent. Structural and spectroscopic insights into the constitution of selected
lithium amides in 2-MeTHF are provided that support the involvement of small kinetically activated aggregates that can react
rapidly with the organic substrates, favouring the C-O bond cleavage/C-N bond formation processes over competing
hydrolysis/degradation of the lithium amides by moisture or air.
been developed for the construction of amide bonds, including
the pre-activation of carboxylic acid partner to promote the
coupling with the relevant amine which allows for the use of
milder reaction conditions.5 Examples of this approach include
Introduction
Amide forming reactions are one of the most commonly found
in pharmaceutical processes.1 Due to this prevalence and their
pivotal role in synthetic processes,2 the investigation of a
sustainable method for their formation has been identified by the
ACS Green Chemistry Institute as a key research area for the
future of pharmaceuticals.3 There is a large variety of elaborate
amide bond forming reactions.4,5 While, conceptually, the
simplest way of preparing amides should be the direct
condensation of carboxylic acids and amines, this amidation
process requires extremely harsh reaction conditions (T 100o )
in order to avoid the formation of unreactive carboxylate
ammonium salts.4b,4m-o Thus several alternative approaches have
the use of more reactive acyl chlorides, carboxylic acid
anhydrides, or other highly activated esters/amides, replacing the
OH group by a better leaving group.5 This strategy has been
successfully employed for peptide synthesis,6 but it suffers from
low
atom
economy.5,7
Transition-metal
catalysed
transformations have also been reported to facilitate amidation
processes, although in many occasions the use of volatile organic
solvents (VOCs) under protective inert atmospheres (N2 or Ar)
are required.8
Li & Szostak 2018
2 eqs. HNR2R3
O
O
3 eqs. LiHMDS
R3
R1
OR/NR2
R1
N
toluene, r.t.
aDepartment of Pure and Applied Chemistry
R2
University of Strathclyde
Glasgow, G1 1XL, United Kingdom
This work
bDepartment für Chemie und Biochemie, Universität Bern,
CH3012, Bern, Switzerland E-mail: eva.hevia@dcb.unibe.ch
c Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al
CSIC). Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento
de Química Orgánica e Inorgánica (IUQOEM), Facultad de Química, Universidad
de Oviedo, E-33071, Oviedo, Spain
Electronic Supplementary Information (ESI) available: [Full experimental details and
copies of NMR spectra are included in the Supporting Information. CCDC 1973293-
1973295 and 1987696 contains supplementary crystallographic data for this paper].
See DOI: 10.1039/x0xx00000x
O
O
1.5 eqs. LiNR2R3
R3
R1
OR/NR2
R1
N
R2
20 s, 2-MeTHF, r.t.,
in air
Scheme 1. State of the art for transition-metal free amidation procedures.4j,k
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Journal Name
Breaking new ground in this evolving field, Szostak has reported several DESs combinations (entries 6-9) and water (entry 10).
View Article Online
DOI: 10.1039/D0SC01349H
an effective amidation procedure using the utility amide As 2a is a solid, in all cases it was employed as a 1 M solution
LiHMDS (HMDS= 1,1,1,3,3,3-hexamethyldisilazide) to in 2-MeTHF. Using neat 2-MeTHF as a reaction medium, at
mediate the amidation of esters and amides, at room temperature, room temperature, under air allowed for the isolation of 3a in
by simply activating the amine component. However, reactions high yields (80%) upon adding 1.5 equivalents of the lithium
need to be carried out in toluene under inert atmosphere amide.18 Switching to the eutectic mixture 1ChCl/2Gly similar
conditions, while using excess lithium amide and the relevant yields were obtained although a three molar excess of 2a was
amine (Scheme 1).4j,k,9
required (83%, entry 6). Good to excellent yields were also
Towards more sustainable, safer chemical transformations, our obtained employing eutectic mixtures containing other H-bond
group has been one of the pioneers in using organolithium donors, including ethylene glycol (EG) and water (59% and
reagents in non-conventional renewable solvents such as 81%, entries 7 and 8, respectively). Comparable yields were also
glycerol (Gly) and Deep Eutectic Solvents (DES), which obtained when ChCl in the glycerol-based DES was replaced by
combine the non-toxic ammonium salt choline chloride (ChCl, lithium chloride (79%, entry 9), although, due to the greater
as hydrogen-bond acceptor) with glycerol or water as sustainable viscosity of this mixture, heating was required to ensure adequate
hydrogen bond-donors. Under these conditions not only can stirring. Moving to water as polar medium, the reaction still
higher yields and greater chemoselectivites be accomplished proceeded, albeit, with a significantly reduced yield (36%, entry
than those obtained using toxic organic solvents, but reactions 10) due to an increased rate of hydrolysis of the lithium amide.
can also be performed at ambient temperature, in the presence of Interestingly, and as we have previously observed in the addition
moisture and air, a trio of conditions normally incompatible with of organolithium reagents to aromatic nitriles,11c glycerol gave
polar organometallic chemistry.10,11 Thus, we have applied equal or better yields than the eutectic mixtures in the amidation
fruitfully this sustainable approach for the chemoselective and of esters, enabling similar conversions to 3a to those observed
ultrafast alkylation and arylation of ketones,11a imines11b and for 2-MeTHF when using just 1.5 equivalents of 2a.
nitriles11c as well as the anionic polymerization of different
Table 1. Addition of lithium N-methylanilide 2a to ethyl benzoate 1a in various molecular
styrenes.11d,12 Taking a step forward towards developing
sustainable, mechanistically well-supported aerobic polar
organometallic chemistry, here we report our findings on the
mechanism and application of lithium-mediated amidation and
transamidation reactions of ethyl esters and a N-Boc-substituted
benzamide under air using the biomass derived solvents glycerol
and 2-methyltetrahydrofuran (2-MeTHF, Scheme 1).13,14
solvents and eutectic mixtures.[a]
LiNMePh 2a
(in 2-MeTHF)
O
O
OEt
N
20 s, solvent,
r.t., in air
1a
3a
Solvents are estimated to make up from 56% to 85% of the mass
involved in pharmaceutical processes.15 Therefore, solvent
choice is critical when considering the development of more
environmentally benign processes. Biomass-derived solvents
such as glycerol (Gly) and 2-MeTHF, have emerged as greener
alternatives to volatile organic compounds (VOCs) in organic
synthesis.16 Thus, for example, 2-MeTHF can be renewably
produced from furfural without the use of petrochemicals and
shares many of the same properties that make THF a widely used
solvent in organic synthesis.14,17 Furthermore, its immiscibility
with water, enables liquid extractions without the need of toxic
classical organic solvents for extracting reaction products.
Entry
Solvent
THF[d]
LiNMePh[b]
Yield[c]
[%]
93
[eqs.]
1
2
2
3
2-MeTHF
80
3
2
81
4
1.5
1
80
5
78
6
1ChCl/2Gly
1ChCl/2EG
1ChCl/2H2O
1LiCl/3Gly[e]
H2O
3
83
7
3
59
8
3
81
9
3
79
10
11
12
3
36
Gly
3
85
1.5
79
Results and discussion
[a] Reactions performed under air at ambient temperature using 1 g of solvent,
1 mmol of ester. Reactions stirred for 20 s, then quenched with sat. Rochelle’s salt
soln. (5 mL). [b] Lithium amide was added as a 1 M soln. in 2-MeTHF. [c] Isolated
yields are given. [d] Lithium amide 2a was added as a 0.2 M soln. in THF. [e]
Reactions carried out at 53 °C due to viscosity issues.
Bearing all these precedents in mind, we started our studies on
the sustainable formation of aromatic amides by selecting, as a
model process, the reaction of ethyl benzoate 1a with lithium N-
methylanilide (2a), at room temperature and in the presence of
air (see Table 1).
As a control experiment, we first employed THF as the reaction
solvent at room temperature, using two equivalents of 2a, which
furnished N-methyl-N-phenylbenzamide 3a in excellent yield
(93%, Table 1) in as little as 20 s while working under aerobic
conditions. We next compared these results by replacing THF by
a more sustainable reaction medium, which included biomass-
derived 2-MeTHF (entries 2-5) and glycerol (entry 11) as well as
Encouraged by these initial findings that show for the first time
the potential of lithium amides to enable ester amidations in the
company of air and moisture, which are generally antagonists of
these reagents, we next explored the kinetic stability of
LiNMePh in Gly and 2-MeTHF.
These two sustainable solvent systems were chosen on the basis
of their similar performances when using just 1.5 equivalents of
2a (Table 1). For these studies the order of addition of reagents
2 | J. Name., 2012, 00, 1-3
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was reversed, thus 2a (1.5 eq. of a 1 M solution in 2-MeTHF) Firstly, the feasibility of the in-situ formation oVfietwhAerticlilethOinulimne
was added to the relevant solvent system, and allowed to stir amides through addition of n-butyllithiumDtoOIt:h1e0.r1e0a3c9t/iDo0nSCm0i1x3t4u9rHe
under air for a set period of time before introducing ethyl containing ester 1a and the relevant amine was assessed (Scheme
benzoate 1a (Table 2, see SI for details). Remarkably, while only 3), encouraged by previous work by Pace that has shown the
traces of 3a were observed after 30 seconds when Gly was suitability of 2-Me THF for the preparation and manipulation of
employed (entry 2, Table 2),19 in 2-MeTHF, after 1 minute, 3a lithium amides.13c,13d
forms in a 70% yield (entry 3) which is comparable to that
1) 1.5 eqs. HNMePh
O
observed when the order of addition of reagents is reversed
(80%, entry 4, Table 1). Highlighting the impressive kinetic
stability of 2a in 2-MeTHF against decomposition under air and
moisture, it was only after 10 minutes that formation of 3a was
almost completely suppressed (13% yield, entry 6).
2) 1.5 eqs. n-BuLi
OH
O
Ph
+
Bu
Bu
Ph
N
Ph
Ph
OEt
20 s, 2-MeTHF,
r.t., in air
3a
4
1a
Another advantage of 2-MeTHF over Gly was witnessed on
dispensing 2a as a solid rather than as a 2-MeTHF solution
(Scheme 2). While the reaction ran smoothly, with reagents
quickly mixing into 2-MeTHF, to give 3a in 82% yield with no
significant difference to that when adding the lithium amide as a
solution (entry 4, Table 1), using neat Gly, partial decomposition
of 2a occurs, affording 3a in a diminished 47% yield.
Furthermore, the high solubility of 2a in 2-MeTHF allows the
reaction to be scaled up to a 10 mmol scale using just 6 mL of a
2.5 M solution of 2a, yielding 3a in an 89% yield (see SI for
details).
Scheme 3. In-situ formation of 2a and 2f and their subsequent reactions with 1a in
2-MeTHF.
While full conversion of starting material 1a was observed, the
amidation reaction does not take place selectively, thus 3a is
obtained in a 74% yield along with 26% of the double addition
product 5-phenylnonan-5-ol (4) (Scheme 3).
Next, we explored the scope of this air- and moisture-compatible
methodology by reacting 2a with assorted esters 1a–m bearing
different functional groups. In all cases reactions were carried
out using 2-MeTHF and under air, at room temperature using a
small excess of 2a (1.5 equivalents) and quenching the reaction
crudes after just 20 seconds, affording amides 3a-3m (Table 3).
Reactions involving halogen pendant aromatic esters furnished
good yields (67–83%) of 3b–e, demonstrating a tolerance of
mildly electron withdrawing groups. A slight decrease in yield is
apparent when an ortho-substituent is introduced, even as small
as fluorine. When a methoxy group is present in the para and
meta positions, good yields are found in 3f and 3g (74–89%).
Again, ortho-substituents lead to a decreased yield (63%) for 3h.
These results suggest that sterics may have a more prominent
role than electronic effects in this type of transformations. The
ester substrate scope was also extended successfully to
heterocyclic substituents. 3-Furyl in 3j and 3-pyridyl in 3k gave
high yields (73 and 72%). Aliphatic esters (39–72%, 3l–m)
showed no deprotonation of the acidic -C–H bond. The scope
was limited to less bulky esters. Di-ortho-substituted ethyl
o,o-dimethylbenzoate and the quaternary carbon centre adjacent
to the carbonyl functionality in ethyl pivalate prove to be too
sterically encumbered to allow amidation. Esters bearing
stronger acidic protons such as ethyl 4-hydroxybenzoate (ethyl
paraben) and ethyl 4-aminobenzoate (benzocaine) were
incompatible with this method. In all failed reactions, the starting
esters were recovered almost quantitatively, likely after
hydrolysis during workup. It should also be noted that the
reaction of 2a with phenylbenzoate furnished 3a in comparable
yields to those found using 1a. These results align well with
Szostak studies using LiHMDS in toluene that show the
compatibility of his approach with several alcohol-derived
esters.4k
Table 2. Assessment of forming 3a in 2-MeTHF and Gly when the order of addition of
reagents is 2a then 1a.[a]
1) stirring, time
2) 1 eq. 1a, 20 s
Me
N
O
Li
N
solvent,
r.t., in air
1.5 eqs.
1 M in 2-MeTHF
3a
2a
Entry
Solvent
Time
Yield
[%]
32
1
2
3
4
5
6
Gly
10 s
30 s
3
2-MeTHF
1 min
2 min
5 min
10 min
70
62
42
13
[a] Reactions performed under air at ambient temperature using 1 g of solvent,
1 mmol of 1a. Lithium amide 2a was added as a 1 M soln. in 2-MeTHF and stirred
for the specified time before addition of 1a. Reactions stirred for another 20 s, then
quenched with sat. Rochelle’s salt soln. (5 mL). Isolated yields are given.
Building on these results, along with the fact that 2-MeTHF can
also be used as the extraction solvent for the isolation of 3a, we
chose this solvent to carry out our remaining studies.
1.5 eqs. LiNMePh 2a
O
O
(solid)
OEt
N
20 s, solvent,
r.t., in air
1a
3a
47%
82%
Gly
2-MeTHF
Scheme 2. Addition of solid LiNMePh 2a to a solution of ethyl benzoate 1a in Gly
and 2-MeTHF.
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J. Name., 2013, 00, 1-3 | 3
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Table 3. Addition of lithium N-methylanilide 2a to various esters 1a–m.[a]
suppressed. Ethyl trifluoroacetate 1n was found to be a better
View Article Online
DOI: 10.1039/D0SC01349H
electronic match with less basic lithium diphenylamide and
produced a better yield of 5i (70%), while 5h was only afforded
in a poor 6% yield. Using lithium morpholide led to the
formation of 5d in poor yields (17%), which is attributed to the
limited solubility of this amide in 2-MeTHF, so the reaction had
to be carried under much more dilute conditions (see SI for
details). Interestingly it should be noted that the synthesis of 5d
has been recently reported via transamidation of an N-Boc
activated amide and free morpholine in acetonitrile at room
temperature.4l
O
O
1.5 eqs. LiNMePh 2a
R1
OEt
R1
N
20 s, 2-MeTHF,
r.t., in air
1am
3am
O
O
Ph
Ph
N
N
Cl
3a
80%
3b
85%
Table 4. Addition of various lithium amides 2a–i to ethyl benzoate 1a or ethyl
trifluoroacetate 1n. [a]
O
O
F
O
Ph
F
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
O
1.5 eqs. LiNR2R3 2ah
O
F
R1
OEt
R1
NR2R3
3c
77%
3d
70%
3e
67%
20 s, 2-MeTHF,
r.t., in air
1a R1 = Ph
3a, 5bh'
O
O
OMe O
R1 = CF3
Ph MeO
1n
N
MeO
3f
74%
3g
89%
3h
63%
O
O
O
n-Bu
Ph
N
Ph
N
H
Ph
N
O
O
O
n-Bu
Ph
3a
81%
5b
71%
5c
77%
N
[b]
O
N
O
3i
3j
3k
O
O
58%
73%
72%
Ph
N
Ph
N
Ph
N
O
O
3
O
Ph
N
Ph
N
5d
17%
5e
79%
5f
58%
[c]
O
O
3l
3m
72%
39%
O
Ph
N
CF3
N
Ph
N
[a] Reactions performed under air at ambient temperature using 1 g of solvent,
1 mmol of ester. Reactions stirred for 20 s, then quenched with sat. Rochelle’s salt
soln. (5 mL). Lithium amide 2a was added as a 1 M soln. in 2-MeTHF. Isolated
yields are given.
5g
63%
5h
6%
5h'
70%
[a] Reactions performed under air at ambient temperature using 1 g of solvent,
1 mmol of esters 1a or 1n. Reactions stirred for 20 s, then quenched with sat.
Rochelle’s salt soln. (5 mL). Lithium amides 2a-i were added as a 1 M soln. in
2-MeTHF. Isolated yields are given. [b] 3 eqs. lithium anilide 2b solution. [c]
0.08 M. lithium morpholide 2d solution. Isolated yields are given.
After assessing the range of ester functionalities that could be
tolerated by the system, the variation of lithium amides that
could be successfully employed was also examined (Table 4).
The aromatic primary lithium anilide 2b was found to achieve a
good yield of 5b (71%) with a higher amide load of 3
equivalents, whereas when using 1.5 equivalents a modest 36%
yield was observed. Interestingly, if the reaction is carried out
under identical conditions (1.5. eq of 2b, 20s, RT) but under
strict inert atmosphere conditions using dry 2-MeTHF, 5b is
obtained in a superior 59%. These findings suggest that the lower
yields observed for LiNHPh are not only a consequence of its
reduced basicity in comparison to 2a but also due to its partial
degradation under the conditions of the study.
While esters are easier to access as starting materials, the
transamidation of amides is of particular importance in
biochemical and pharmaceutical applications.4a The examples
3a, 5c, and 5e–5h have, therefore, also been synthesised by
transamidation from 6 (Table 5). They afforded fair to good
yields (53–77%) which match those observed with the ethyl ester
1a. Interestingly, in the case of lithium diphenylamide, the use
of the stabilized NBoc2 leaving group in 6 circumvented the
reactivity problems observed earlier furnishing 5h in a 72%
yield, whereas starting from ester 1a, 5h was obtained in a poor
6% yield (vide supra).
A range of secondary aliphatic amides were found to give
moderate to good yields (58–79%, 5c–f) and even in the case of
cis-2,6-dimethylpiperidide the steric bulk seems to have little
effect on yield (63%, 5g). However, when using bulkier 2,2,6,6,-
tetramethylpiperidide the amidation reaction was completely
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Table 5. Addition of various lithium amides 2a,c, e-h to N,N-di(Boc)-benzamide 6.[a]
View Article Online
DOI: 10.1039/D0SC01349H
O
1.5 eqs. LiNR2R3 2a,c,eh
O
NR2R3
Ph
NBoc2
Ph
20 s, 2-MeTHF,
r.t., in air
6
3a, 5c,eh
O
O
O
n-Bu
Ph
N
Ph
N
Ph
N
n-Bu
3a
77%
5c
70%
5e
65%
O
O
O
Ph
N
Ph
N
Ph
N
Figure 1 Assessing solvent effects for the co-complexation reaction of LiNPh2 (2h) and
PhC(=O)NMe2 (7) in: A) D8-THF and B) D8-toluene using 1H DOSY NMR experiments
(see SI for details).
5f
53%
5g
73%
5h
72%
Since the amidation and transamidation reactions presented in
Tables 1-5 are very fast, we chose the less nucleophilic lithium
amide 2h partnered with tertiary N,N-dimethylbenzamide 7,
which lacking of an activated leaving group could maximise
opportunities for the detection of a possible coordination adduct
prior to the nucleophilic addition step. Interestingly using
deuterated THF, a donor solvent with similar capabilities to those
of 2-MeTHF, no interaction between 2h and 7 is observed in
solution, as is evidenced by the two distinct diffusion coefficients
determined for both compounds by DOSY NMR (D = 7.638x10-
[a] Reactions performed under air at ambient temperature using 1 g of solvent,
1 mmol of benzamide 6. Reactions stirred for 20 s, then quenched with sat.
Rochelle’s salt soln. (5 mL). Lithium amides 2a,c,e-h were added as a 1 M soln. in
2-MeTHF. Isolated yields are given.
Motivated by the fast reactivity and air- and moisture-resistance
of the lithium amide reagents in 2-MeTHF, our focus next turned
to the characterization of a selection of these reactive
intermediates to give insights into the possible mechanism/s
operating in these reactions. Previous work by Yoon has shown
that KOtBu can mediate ester amidations in technical grade THF
under air.20 These reactions seem to operate via a radical
mechanism where the presence of oxygen and moisture are
crucial for the formation of a reactive acyl radical derived from
the ester which, in turn, can react with the amine. Accordingly,
when the reaction is performed using an anhydrous solvent under
argon the amidation process is completely suppressed. In
contrast, we found that carrying out the reaction of ester 1a and
LiNMePh (2a) under strict inert atmospheric conditions and
stringently dry 2-MeTHF resulted in an 85% yield (almost
identical to that when performing the same reaction under air
with wet solvent, 81%, Table 1, entry 4). Thus, it seems very
unlikely that a related radical mechanism could be in operation
here.
Most recently, insightful DFT studies on LiHMDS mediated
transamidation reactions by Hong and Szostak have proposed
that these processes take place via the formation of a mixed co-
complex between the relevant lithium anilide and LiHMDS
(which is present in excess in the reaction media, Scheme 1),4j to
which the tertiary amide organic substrate coordinates. This pre-
coordination facilitates an intramolecular nucleophilic attack
which is the rate determining step of the reaction.4k To
investigate if similar substrate pre-coordination could also be in
operation in our studies we carried out 1H DOSY NMR studies
of 1:1 mixtures of lithium diphenyl amide 2h with the N,N-
dimethylbenzamide 7 in D8-THF and D8-toluene solutions (see
Figure 1 and SI for details).
10
m2/s and 1.263x10-9 m2/s for 2h and 7, respectively—see
Figure 1A) which are consistent with the presence in solution of
free N,N-dimethylbenzamide (MWdet = 153 g/mol MWdiff = -3%)
and the formation of monomeric trisolvated [Li(NPh2)(THF)3]
(MWdet = 363 g/mol MWdiff = 8%) (see SI for details).
Contrastingly, when 2h and 7 are combined in toluene, a solvent
with a significantly lower donor ability,21 coordination complex
[{Li(NPh2)(O=CPh(NMe2)}2] (8) is obtained as a crystalline
solid in 40 % yield. X-ray crystallographic studies established
the dimeric constitution of 8 (Figure 2) comprising a planar
Li2N2 ring (sum of endocyclic angles: 360°). The Li-N distance
in 8 (1.993(2) Å) is noticeably shorter to those found for the
related dimeric TMEDA-solvate of 2a [{LiNPh2}(TMEDA)}2]
(TMEDA= N,N’-tetramethylethylendiamine) (mean Li-N, 2.139
Å),22 being closer to that reported in monomeric
[Li(NPh2)(THF)3] (1.960(2) Å) by Williard.23 Tertiary amide 7
coordinates to Li via its oxygen atom forming a relatively short
bond (Li-O, 1.827(2) Å) consistent with the high Lewis basicity
of the amide oxygen atoms. 24, 25 Interestingly, this Li-O bond is
1
retained in toluene solution as revealed by H DOSY NMR
experiments which show that both {NPh2} and {O=CPh(NMe2)}
fragments diffuse together in solution as part of the same
molecular entity (D = 6.52x10-10 m2/s, see Figure 1B and SI for
details). While complexes of this type have been predicted in
computational studies,4k 8 represents to the best of our
knowledge the first example known of a coordination adduct of
a lithium amide and a tertiary aromatic amide to be structurally
characterised.26
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DOI: 10.1039/D0SC01349H
Figure 2 Molecular structure of [{LiNPh2}(O=CPh(NMe2)}2] (8) crystallised from
toluene. Displacement ellipsoids at 50% probability and hydrogen atoms omitted for
clarity.
Collectively these findings suggest that while in the non-Lewis
donor solvent toluene, transamidation reactions may take place
via the initial formation of a pre-coordination adduct similar to
8, that brings the organic substrate in close proximity to the
lithium amide, facilitating nucleophilic addition to its C=O bond,
this type of activation seems unlikely when using donor solvents
like THF (or 2-MeTHF). Alternatively, a plausible explanation
of the fast reactivities observed in these solvents could be the
formation of kinetically activated smaller aggregates of the
lithium amide (vide infra) which could then preferentially
undergo transamidation (or ester amidation) reactions over
competing degradation processes by air and/or moisture.
Figure 3. Molecular structures of dimeric (left to right) lithium anilide 2b-S4, lithium
diphenylamide 2h-S3 and lithium 2,2’-bipyridylamide 2i-S2 crystallised from 2-MeTHF.
Displacement ellipsoids at 50% probability and hydrogen atoms omitted for clarity
(except those on the nitrogen atoms in 2b-S4).
Seminal studies by Jackman28 and Williard23 on the constitution
of lithium amides in ethereal solvents have proposed a
progression of solvation from dimeric Li2A2S2 (A = amide, S =
solvent) to LiAS3 when increasing the steric hindrance on the
amide ligand and the donor solvent. A closer look into the
structures of 2b-S4, 2h-S3 and 2i-S2 shows that along with the
steric demands of the amide, electronic effects can also play a
role in the degree of solvation. Thus, in centrosymmetric 2i-S2,
multidentate 2,2’-bipyridylamide ligands adopt a syn-syn
conformation,29 with two N(amido) bridges connecting the Li
centers, with each ligand forming two additional dative
N(pyridyl)–Li interactions. Contrasting with diphenylamide
derivative 2h-S3, here the higher hapticity of the amide group
favours the formation of a disolvated dimer, with only one
molecule of 2-MeTHF coordinated per Li atom. Interestingly 2i
failed to undergo transamidation when reacted with 1a, which
can be attributed to a certain extent to its reduced nucleophilicity
To further investigate solvent effects in these reactions and the
possible constitution of the reactive lithium amides in 2-MeTHF,
we next prepared and isolated as crystalline solids the 2-MeTHF
solvates of lithium N-anilide 2b, N-diphenylamide 2h and 2,2’-
bipyridylamide 2i.27 Compounds were prepared by reacting the
n
relevant amine with an equimolar amount of BuLi, affording
white solids that could then be recrystallised in 2-
MeTHF/hexane solvent mixtures furnishing [{Li(NHPh)}2(2-
MeTHF)4] (2b-S4), [{Li(NPh2)}2(2-MeTHF)3] (2h-S3) and
[{Li(Npy2)}2(2-MeTHF)2] (2i-S2) (py= 2-pyridyl) in 21, 54 and
66% yields respectively and whose structures were established
by X-ray crystallography (Figure 3).
While all three compounds exhibit dimeric structures in the solid
state, displaying a planar Li2N2 core similar to that described for
8, different degrees of solvation are observed. In every case the
Me groups of the 2-MeTHF solvent ligands point away from the
Li2N2 planes. Thus, for anilide 2b-S4, the symmetrically
equivalent Li atoms are tetracoordinated, being solvated by two
2-MeTHF molecules; whereas increasing the steric hindrance in
the amide group in diphenylamide 2h-S3, a rare trisolvated dimer
is observed with two different Li atoms, one tricoordinate and
the other tetracoordinate (Figure 3). As far as we can ascertain
the only precedent of a structurally authenticated lithium amide
solvated by 2-MeTHF is lithium N-methylanilide, which also
exhibits a dimeric arrangement, equivalent to 2b-S4 with each
lithium coordinated to two molecules of the ethereal solvent.23
as
a consequence of partial delocalization within the
dipyridylamide scaffold.
Previous seminal structural studies by Mulvey30,31 and Stalke32
have established the structural diversity of lithium anilide
complexes solvated by THF spanning from hexameric
[{Li(NHPh)}6(THF)8] (which can be envisaged as a partially dis-
assembled ladder motif)31 to a dimeric arrangement similar to
2b-S4 where each lithium binds to two molecules of THF,
precluding further association.32 Contrastingly the trisolvated
dimeric structure lithium diphenylamide in 2-MeTHF (Li2A2S3)
(vide supra) differs notably to that of the same amide in THF
which displays a monomeric LiAS3 motif.23 These differences in
aggregation illustrate the subtle effects that small variations on
the steric hindrance of the solvent can play in the constitution of
the lithium amide.33
6 | J. Name., 2012, 00, 1-3
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In order to get a better understanding on the constitution of these observed, although the degree of THF solvation VcieowuAldrticnleoOtnlbinee
1
lithium amides in solution, we then carried out detailed H established.38
DOI: 10.1039/D0SC01349H
DOSY NMR studies of LiNMePh (2a), LiNHPh(2b) and LiNPh2 Collectively, these investigations show that while in the solid
(2h) in deuterated THF and in non-deuterated 2-Me THF state some subtle variations in the degree of aggregation and
solutions (see Table 6 and SI for details). It should be noted that solvation of the lithium amides using either 2-MeTHF or THF as
for D8-THF the external calibration curve (ECC) method a donor are observed, nearly identical constitutions are detected
developed by Stalke was employed.34,35 Since ECC for the in solution when using both of these ethereal solvents, favoring
estimation of molecular weights of small molecules by DOSY trisolvated LiAS3 monomers. Considering the close interplay of
NMR using 2-Me THF as a solvent has not yet been developed, aggregation and solvent effects with reactivity patterns in lithium
for this solvent we used internal calibration curves (ICC) using amide chemistry,39 a plausible rationale for the fast amidation
1,2,3,4-tetraphenylnaphthalene (TPhN), 1-phenylnapthtalene (1- (and transamidation) reactions observed in our study could be the
PhN) and TMS as internal reference standards.36
formation of kinetically activated aggregates of the lithium
amides in 2-MeTHF solution. Monomer formation should lead
to more powerful nucleophilic lithium amides that can react
faster with the unsaturated organic substrate (ester or amide) to
add across its C=O bond, favoring addition over competing
degradation by oxygen or moisture.
Table 6. Solution-state studies of 2a, 2b and 2h by 1H DOSY NMR using ECCDSE in D8-
THF and ICC in 2-MeTHF to estimate their constitution and solvation in these donor
solvents.
A
A
A
II
S
S
Li
Li
S
Li
Li
S
S
A
I
Conclusions
A = N(R)Ph (R = H, Me, Ph)
S = THF or 2-MeTHF
To conclude, pushing forward the development of more
sustainable and air- and moisture-compatible organolithium
chemistry, here we introduce renewable and polar 2-MeTHF as
a reaction medium to access a wide range of synthetically
relevant carboxamides via ester amidation or amide
transamidation using lithium amides as metal precursors.
Reactions take place at room temperature without the need of
external additives in just 20 seconds. 2-MeTHF seems to play a
key role in these reactions, ensuring full solubilization of the
lithium reagent and favouring the formation of small kinetically
activated aggregates that can react rapidly with the organic
substrate before decomposition reactions by air or moisture can
compete.
S
S
A
A
S
S
S
Li
Li
Li
A
Li
A
S
S
S
S
V
IV
III
MWdet
V
IV
III
D8-THF
[g/mol]
MWdiff [%]
MWdiff [%]
MWdiff[%]
LiN(Me)Ph (2a)
LiN(H)Ph (2b)
LiNPh2 (2h)
335
331
393
-2
-5
-23
-27
-19
54
47
87
<1
MWdet
MWdiff
[%]
MWdiff
[%]
MWdiff
[%]
2-MeTHF
[g/mol]
LiN(Me)Ph (2a)
LiN(H)Ph (2b)
LiNPh2 (2h)
363
393
451
2
-21
-31
-23
57
38
54
-9
-4
Experimental
General procedure for (trans)amidation of esters and
amides
D8-THF: Molecular weights derived from 1H DOSY-ECC-MW determinations at 15 nM
concentrations in 0.5 mL D8-THF against tetramethylsilane (TMS) as a reference
standard.[27a] 2-MeTHF: Molecular weights derived from 1H DOSY-ICC-MW
Additions were performed under air at room temperature in an
determinations at 0.2
M concentrations in 0.5 mL 2-MeTHF with 1,2,3,4- open Schlenk flask (25 mL) and 1 g of solvent. Lithium amide 2
tetraphenylnaphthalene (TPhN), 1-phenylnapthtalene (1-PhN) and TMS as internal
reference standards. [29] See SI for full details.
(1.5 mmol, 1.5 eq.) was added to a stirring solution (960 rpm) of
ester 1/amide 6 (1 mmol). After 20 s the reaction was quenched
by the addition of sat. Rochelle’s salt sol. (sodium potassium
tartrate tetrahydrate, 5 mL) before being extracted into 2-
MeTHF (3 x 10 mL). Extracts were combined, dried over
MgSO4 and concentrated under vacuum.
Crude products were purified by silica column chromatography,
eluted by hexane:EtOAc (10:1 – 2:1 gradient). Products were
identified by GCMS and 1H NMR. Yields were obtained by 1H
NMR spectroscopy by integration against a ferrocene internal
standard.
Focusing first on 2-Me THF, the solvent employed for the
reactivity studies (vide supra), the dimeric tetrasolvated Li2A2S4
and trisolvated Li2A2S3 structures found in the solid state for 2a,
2b and 2h respectively do not seem to be retained in solution
(MWdiff 57, 38 and 35% respectively, Table 6 and SI). A much
better fit is found instead considering the presence of trisolvated
LiAS3 monomers (MWdiff 2, -9 and -4% respectively). Mirroring
this trend, a preference for the formation of smaller monomeric
aggregates in deuterated THF solutions is also observed for the
three lithium amides (see Table 6).37 These findings are
consistent with previous work by Collum assessing the
constitution of LiNPh2 (2h) in THF/toluene solutions which
proposed a dimer/monomer equilibrium in solution. At high
concentrations of THF only the monomeric version of 2h is
General procedure for the synthesis of lithium amides
n-BuLi (19 mL, 30 mmol) was added dropwise to a stirring
solution of amine (30 mmol) in hexane (60 mL) and left to stir
for 1 h. The resultant suspension was filtered and washed with
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2002, 58, 2155.(o) B. S. Jursic and Z. Zdravkovdki, Synth.
hexane (3 x 10 mL) before being dried under vacuum. The white
solid product obtained was stored in an argon filled glovebox and
analyzed by 1H and 7Li NMR spectroscopy (see ESI for details).
View Article Online
Commun., 1993, 23, 2761.
DOI: 10.1039/D0SC01349H
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
6
We thank the EPSRC (EP/S020837/1) and the University of
Strathclyde for their generous sponsorship of this research as
well as Dr. Ross McLellan (University of Strathclyde) and
Pasquale Mastropierro (Universität Bern) for their assistance in
the structural studies. We are indebted to the MINECO of Spain
(Projects CTQ2014-51912-REDC and CTQ2016-75986-P), the
Gobierno del Principado de Asturias (Project GRUPIN14-006)
and the Fundación BBVA for the award of a “Beca Leonardo a
Investigadores y Creadores Culturales 2017” to JGA. The X-ray
crystal structure determination service unit of the Department of
Chemistry and Biochemistry of the University of Bern is
acknowledged for measuring, solving, refining and summarizing
the structure of compound 8. The Synergy diffractometer was
partially funded by the Swiss National Science Foundation
(SNF) within the R'Equip programme (project number
206021_177033).
7
8
9
G. Li, M. Szostak, Chem. Rec. 2019, 19, 1.
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Notes and references
‡
a visionary organolithium chemist and an inspiring mentor to Joaquin Garcia-Alvarez,
Charlie O’Hara and Eva Hevia
Dedicated to Professor Robert (Rab) Mulvey on the occasion of his 60th birthday,
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Chemical Science
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DOI: 10.1039/D0SC01349H
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Using 2-methyl THF as a sustainable reaction medium enables the efficient
chemoselective and ultrafast amidation of esters by lithium amides at room
temperature in air, edging closer towards reaching air- and moisture-compatible
polar organometallic chemistry