A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects

Article abstract of DOI:10.1002/chem.202004840

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Full text of DOI:10.1002/chem.202004840

Accepted Article
Accepted Article
Title: A Fast, Green and General Route to Ketones from Amides and
Organolithium Compounds under Aerobic Conditions: Synthetic
and Mechanistic Aspects
Authors: Cristina Prandi, Simone Ghinato, Davide Territo, Andrea
Maranzana, Vito Capriati, and Marco Blangetti
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
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202004840
Link to VoR: https://doi.org/10.1002/chem.202004840
01/2020

10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
A Fast and General Route to Ketones from Amides and
Organolithium Compounds under Aerobic Conditions: Synthetic
and Mechanistic Aspects
Simone Ghinato,[a] Davide Territo,[a] Andrea Maranzana,[a] Vito Capriati,[b]* Marco Blangetti[a]* and
Cristina Prandi[a]*
[a]
Dipartimento di Chimica, Università di Torino, via P. Giuria 7, I-10125 Torino (Italy)
E-mail: cristina.prandi@unito.it; marco.blangetti@unito.it
[b]
Dipartimento di Farmacia–Scienze del Farmaco, Università di Bari “A. Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari (Italy)
E-mail: vito.capriati@uniba.it
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
clustered into three main approaches. One approach relates to
Abstract: We report that the nucleophilic acyl substitution reaction of
the chemical modification of the amide functional group via stable
tetrahedral intermediates.[9] In this context, the use of N,O-
dimethylhydroxyamides, better known as Weinreb amides,
represents nowadays a versatile tool for the chemoselective
synthesis of ketones whose effectiveness relies on the chelation
of the metal into the tetrahedral intermediate to form a five-
membered chelate cycle, which hampers its collapse until the
reaction quench step (Figure 1a).[10] Stable twisted amides have
also been successfully employed by Szostak and co-workers as
effective acylating reagents to promote the chemoselective 1,2-
addition reaction of highly polarised s-block organometallic
reagents by exploiting pyramidalization as a reactive controlling
feature (Figure 1b).[9c, 11] Reaction of Grignard reagents with N-
Boc protected amides under kinetic control[8b] and the
transformation of amides using gem-diborylalkanes as pro-
nucleophiles are other viable alternatives in using modified
amides.[9b] A second approach includes the chemical activation of
the amide functional group via highly electrophilic intermediates
(Figure 1c),[6a, 12] whereas a third synthetic route makes use of
transition metal-catalysed C–N activation reactions of activated
amides delivering a metal acylating agent (Figure 1d).[13] Of note,
Feringa and co-workers have also reported the successful
synthesis of arylaminoketones via a tandem 1,2-nucleophilic
addition of organolithium reagents to benzamide derivatives,
followed by a Buchwald-Hartwig amination reaction in THF, which
is promoted by the in situ released lithium amide.[14]
We have recently thoroughly investigated the reactivity of
benzamides with organolithium reagents[15] and shown that either
directed ortho-metalation (DoM) or nucleophilic acyl substitution
(SNAc) reactions[15b] can smoothly and chemoselectively be
carried out from the same aromatic, sterically hindered tertiary
carboxylic acid amide in the so-called Deep Eutectic Solvents
(DESs) as environmentally friendly reaction media[16] in
combination with cyclopentyl methyl ether (CPME),[17] working
under air, at room temperature (25 °C, RT) or 0 °C (Fig. 1e). The
chemoselectivity of the process was found to be strongly
dependent on the nature of the organolithium reagent: the use of
t-BuLi led to an ortho-lithiation functionalisation, taking advantage
of the directing ability of the amide group, whereas the
employment of less sterically encumbered (or less basic)
organolithium reagents (e.g., MeLi, PhLi, n-BuLi, n-HexylLi)
prompted SNAc pathways.[15b] Ketones, however, always formed
aliphatic and (hetero)aromatic amides by organolithium reagents
proceeds quickly (20
s
reaction time), efficiently, and
chemoselectively with a broad substrate scope in the environmentally
responsible cyclopentyl methyl ether, at ambient temperature and
under air, to provide ketones in up to 93% yield with an effective
suppression of the notorious over-addition reaction. Detailed DFT
calculations and NMR investigations support the experimental results.
The described methodology was proven to be amenable to scale-up
and recyclability protocols. Contrasting classical procedures carried
out under inert atmospheres, this work lays the foundation for a
profound paradigm shift of the reactivity of carboxylic acid amides with
organolithiums, with ketones being straightforwardly obtained by
simply combining the reagents under aerobic conditions and with no
need of using previously modified or pre-activated amides, as
recommended.
Introduction
Ketones are a fundamental class of compounds in organic
chemistry,[1] being their reactivity at the crossroad of several
cornerstone transformations such as nucleophilic addition,
reduction and oxidation processes for the obtainment of valuable
derivatives.[2] That is the reason why many researchers focus on
the investigation of their synthesis.[3] In this context, the
chemoselective assembly of ketones by C-C bond formation
constitutes a well-known intriguing challenge in synthesis.[4]
Among the successful strategies the direct conversion of
5]
carboxylic acids,[3e,
and sodium methyl carbonates[3f] into
ketones with organometallic reagents have been reported.
However, the direct 1,2-nucleophilic addition of hard
organometallic reagents onto carboxylic acid derivatives suffers
from a number of limitations depending mostly on the stability of
the tetrahedral intermediate, including over-additions and
reduction side-reactions.[6] Within this framework, amides
exemplify an excellent starting material for the synthesis of
ketones due to their large occurrence in nature and easy
accessibility.[7] Amides, however, are known to be very unreactive
as electrophiles when compared to other carboxylic acids
derivatives.[8] The strategies developed over the years to
overcome their inner inertness towards nucleophiles can be
1
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10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
in combination with the corresponding tertiary alcohols in up to
7:1 ratio (Figure 1e).
Table 1. Nucleophilic acyl substitution reaction promoted by n-BuLi on N-
benzoylpyrrolidine (1a) under various conditions. [a]
Building upon these findings, we herein first report a
systematic investigation showing the potential benefits of using
an environmentally friendly and recyclable solvent like CPME in
the nucleophilic addition of organolithium reagents to cheap and
commercially available amides. Under optimised conditions, a
variety of structurally diversified ketones were isolated as the sole
reaction products, with a broad substrate scope and in short
reaction times (20 s) (i) working in batch conditions, (ii) under air
at RT and, most importantly, (iii) starting from unmodified and
unactivated precursors (e.g., pyrrolidine carboxamide derivatives),
and in the absence of any transition metal catalyst (Figure 1f). A
spectroscopic investigation, supported by density functional
theory (DFT) calculations, provides insights into the stability of the
tetrahedral intermediate involved in the reaction mechanism,
thereby revealing that it is mainly retained in CPME solution.
O
O
OH
n-Bu
n-Bu
n-BuLi (2 equiv.)
N
n-Bu
+
solvent [0.5 M]
RT, 20 s
open air
1a
2a
3a
2a:3a
Entry[a]
Solvent
Conv.(%)[b]
2a yield (%) [c]
ratio[b]
1
2
3
4
5
6
7
8
9
hexane
DEE
88
100
100
100
100
100
5
82:18
92:8
95:5
95:5
96:4
95:5
-
71
88
89
90
89
88
-
DME
TBME
2-MeTHF
1,4-Dioxane
Glycerol
H2O
1. Chemical modification of the amide functional group
O
O
M
O
R
H3O+
R-M
a.
OMe
OMe
Weinreb amide
twisted amide
N
R
R
N
Me
Me
13
50:50
97:3
4
O
O
H3O+
M-O
R
R-M
CPME
100
93
b.
N
N
[a] Reaction conditions: substrate 1a (0.2 mmol), solvent (0.40 mL, DEE =
diethyl ether, DME = 1,2-dimethoxyethane, TBME = tert-butyl methyl ether), n-
BuLi (2 equiv, 2.5 M in hexanes), 20 s, under air. [b] Determined by 1H NMR
analysis on the crude reaction mixture. [c] Determined by 1H NMR using
CH3NO2 as the internal standard.
2. Chemical activation of the amide functional group
O
OTf
O
c.
R1
1. R-M
Tf2O
R1
N
electrophilic activation
N
R
2. H3O+
R2
R2
3. Transition metal-catalysed C–N activation reactions
The picture emerging from the results compiled in Table 1 can be
summarised as follows. The reaction proceeds fast, in satisfactory
yields (88–90%) and with good chemoselectivity in a variety of
ethereal solvents with a ketone (2a)-to-alcohol (3a) ratio of up to
96:4 (Table 1, entries 2–6). Conversely, non-coordinating
solvents like hexane (Table 1, entry 1) provided 2a in moderate
yield only (71%), whereas the SNAc was ineffective in protic
solvents like glycerol and water (Table 2, entries 7,8). Pleasingly,
when 1a was treated n-BuLi (2 equiv) in CPME (0.5 M), under air
at RT, we observed full conversion of the starting material into
valerophenone 2a, which was isolated in 93% yield after 20 s
reaction time, the 2a:3a ratio being 97:3 (Table 1, entry 9). This
last result is particularly satisfying not only in terms of yield and
negligible over-addition reaction, but also because CPME is a well
recognised eco-friendly solvent and represents a sustainable
alternative to the most common ethereal solvents because of its
valuable properties such as a relatively high boiling point, low
toxicity, non-inflammability, low peroxide formation rate and
stability under basic and acidic conditions.[17-18]
O
R1
O
O
d.
R1
Nu
transition metal
M
N
N
transition metal catalysis
R2
R
M
R2
Our previous work:
E
O
O
O
OH
R
R
1. ter-BuLi
iPr
iPr
RLi
DES, CPME
N
N
R
e.
+
DES
CPME
iPr
2. E+
iPr
This work:
f.
O
O
H3O+
Li-O
R
R-Li
30 examples
53–93% yield
N
N
R
CPME, 20 s
RT, under air
broad substrate scope;
cheap and available amides;
high chemoselectivity
very fast reaction
ambient temperature and open air;
recycle and scale-up;
Figure 1. Synthetic strategies available to convert amides into ketones. a.
Weinreb amides. b. Acyl azetidines. c. Electrophilic activation of amides. d.
Metal catalysed C–N bond activation. e. DoM of benzamides in DES. f. This
work: synthesis of ketones starting from unmodified amides under mild
conditions. RT = room temperature.
The next investigation was aimed at the study the effect of
(i) the amount of n-BuLi, (ii) the reaction time, and (iii) the
hexane/CPME ratio on both the conversion of 1a and the yield of
2a (Figure 2). As shown in Figure 2 (top), reaction times longer
than 20 s, as well as a lower amount of n-BuLi than 2 equiv, led
to a significant decrease of the yield of 2a (see Supplementary
Results and Discussion
Reaction development. We began our study by investigating the
reactivity of a simple amide like N-benzoylpyrrolidine (1a) towards
n-BuLi under various reaction conditions (Table 1). First, a 0.5 M
solution of 1a was reacted with n-BuLi (2 equiv) in different
solvents under air, and the reaction mixture was quenched with
water after 20 s reaction time.
Information for details). At the same time,
a 0.2–1.0 M
concentration range of 1a in CPME turned out to be optimal as 2a
was isolated in 91–94% yield after 20 s when using 2 equiv n-BuLi
(Figure 2, bottom). By lowering the CPME:hexane molar fraction,
the yield of 2a gradually decreased up to 71% (pure hexane). A
freshly prepared solution of n-BuLi in CPME (1.9 M)[19] gave
comparable results in terms of yield and conversion.
2
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10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
the reaction of 1i with n-BuLi quickly provided the bis(alkylated)
alcohol 3a in 75% yield as the sole product. Finally, we found that
the treatment of a CPME solution of the Weinreb amide 1j with n-
BuLi gave comparable results to those specified in the case of
amides 1a and 1b as ketone 2a was isolated in 91% yield and
with a 2a:3a ratio of 98:2. All in all, these results disclose that (i)
amides 1a, 1b and 1j stand on the same ground with reference to
their reactivity towards organolithium reagents, and (ii) even in the
absence of a strong internal chelation of the lithium cation (1j) or
of an amide bond twisting (1h) the collapse of the tetrahedral
intermediate[21] can equally be strongly disfavored by simply using
CPME as the solvent, at room temperature and under air, and
commercial solution of RLi reagents, with the SNAc reactions
taking place very fast (20 s) and in high yields.
O
O
OH
n-BuLi (2 eq.)
R2
n-Bu
n-Bu
N
n-Bu
+
CPME (0.5 M)
RT, 20 s
R1
under air
2a
3a
1a-j
O
O
O
O
O
N
N
N
N
N
1a
1c
1b
1d
1e
k:a ratio 97:3 (93%)
k:a ratio 89:11 (85%)
k:a ratio 97:3 (90%)
k:a ratio 69:31 (64%)
k:a ratio 82:18 (73%)
O
O
O
O
O
O
Figure 2. Effect of n-BuLi equiv and reaction time on the yield of 2a (top). Impact
of the hexane:CPME ratio on conversion (green line) and yield (bars) of 2a after
20 s reaction time and using 2 equiv n-BuLi (bottom). cCPME: 0 (pure hexane),
0.375 (2.0 M in CPME), 0.55 (1.0 M in CPME), 0.71 (0.5 M in CPME), 0.84 (0.2
M in CPME), 1.0 (n-BuLi in pure CPME).
N
N
N
N
N
1f
1g
1h
1j
1i
k:a ratio 0:100 (0%)[a]
k:a ratio 98:2 (91%)
k:a ratio 93:7 (67%)
k:a ratio 93:7 (85%)
k:a ratio 94:6 (90%)
Scheme 1. Nucleophilic acyl substitution reaction on different benzamides 1a–
1j using n-BuLi in CPME at RT under air. Reaction conditions: 1 (0.2 mmol),
CPME (0.4 mL), n-BuLi (2.5 M in hexanes, 0.4 mmol), quench with water after
20 s. Ketone (k)-to-alcohol (a) ratio values were determined by 1H NMR
integration on the crude reaction mixture. Yields in round brackets refer to
valerophenone 2a determined by 1H NMR analysis using CH3NO2 as the
internal standard. [a] Yield of 3a: 75%.
This testifies that the use of commercial solutions of n-BuLi
in hexanes (2.5 M) is both feasible and fruitful.
Cognizant of the above achievements, we next investigated
the effectiveness of the SNAc reaction on different aromatic
carboxylic acid amides 1 (0.5 M in CPME) by varying the nature
of the amide leaving group (Scheme 1). After 20 s reaction time,
similarly to 1a, the simplest N,N-dimethylbenzamide (1b)
delivered ketone 2a in a remarkable 90% yield and with an
excellent 2a-to-3a ratio (97:3) when treated with n-BuLi (2 equiv)
at RT and under air. An increase of the steric hindrance of the
alkyl chains around the nitrogen atom of the amide (1c–e)
reduced both the production of 2a (up to 64%) and the 2a:3a ratio
(up to 69:31). Lower yields (67–85%) were detected when using
N-allylated benzamide 1f or N-benzoylpiperidine 1g as the
substrate, though still with an excellent ketone-to-alcohol ratio
(93:7). Remarkably, the reaction of n-BuLi with a CPME solution
of N-benzoylazetidine 1h, which is characterised by a significant
pyramidalization around the nitrogen atom, at RT and under air,
gave almost similar results (2a: 90% yield; 2a:3a ratio: 94:6)
compared to the ones obtained with simpler and cheaper amides
like 1a and 1b. Conversely, the described protocol does not apply
well to derivatives like N-benzoylpyrrole 1i. Indeed, the peculiar
reactivity of these compounds relies on the exceptional stability of
the corresponding tetrahedral intermediates upon addition of an
organometallic reagent, leading to pyrrolyl carbinols under kinetic
conditions.[20] The latter act as masked carbonyl equivalents
whose carbonyl functionality is revealed under thermodynamic
basic conditions. In addition, the corresponding O-lithiated
pyrrolyl carbinols are known to undergo a fast decomposition at
temperatures higher than -30 °C. It is thus with no surprise that
Mechanistic investigations. 1H-NMR analysis was performed to
investigate the formation and the stability of the tetrahedral
intermediate under our reaction conditions. After the addition of n-
BuLi (2.0 M in cyclohexane, 1.1 equiv) to a 0.5 M solution of 1a
(0.35 mmol, 1.0 equiv) in dry CPME under nitrogen, neither lithium
pyrrolidin-1-ide nor starting material (1a) or valerophenone (2a)
were detected in the 1H NMR spectra (Figure 3). Evidence of the
formation of the tetrahedral intermediate tetr-1a was assessed by
a significant change of the aromatic pattern alongside with a
remarkable upfield shift of the N-a methylenic protons of the
pyrrolidine unit. Partial collapse of the tetrahedral intermediate
1
into valerophenone 2a was observed by H NMR after several
days of experiment (six days), while open-air conditions induced
the instantaneous conversion of tetr-1a into the corresponding
ketone (see Supplementary Information for details).
To gain more insights into such a somewhat unexpected
remarkable stability of the tetrahedral intermediate under the
aforementioned conditions and to support the observed 1H NMR
analysis (Figure 3), we investigated its geometry and calculated
the Free Energy barriers of the SNAc reaction by DFT
computations. DFT calculations were run at the M06-2X/aug-cc-
pVTZ//M06-2X/6-311+G(d) level for amides 1a, 1b, and 1j.
3
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10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
Li
O
O
O
n-BuLi (2 equiv)
N
N
n-Bu
+
Li
N
n-Bu
CPME
1a
tetr-1a
2a
Li pyrrolidin-1-ide
Figure 4. Reaction mechanism and calculated Free Energy barriers (kcal mol-
1) for products formation starting from monomeric or coordinated dimeric
structures tetr-1a, tetr-1b, and tetr-1j. 1a: R1 = R2= -(CH2)4-; 1b: R1 = R2 = Me;
1j: R1 = Me, R2 = OMe.
Figure 3. 1H NMR evidence of tetr-1a formation. Experiments were recorded in
dry CPME using CDCl3 as an internal reference. Red arrows indicate the signals
of tetr-1a.
The decomposition rate of the tetrahedral intermediate in
the presence of water was finally evaluated by DFT computations.
Calculations were run on tetr-1b at the same theory level.
Assuming that a fast acid-base equilibrium en route to an
hydroxyamino derivative takes place, the Free Energy barrier for
the amide decomposition into ketone 2a and dimethylamine was
quantitatively evaluated as 10.1 kcal mol-1 by adding one explicit
molecule of water to PCM calculations. This was necessary to
create the cooperative effect which promotes the C–N bond
dissociation that needs to be taken into account to avoid an
overestimation of the Free Energy barrier of about 15 kcal mol-1.
The mechanism involves (i) pre-complexation of the starting
amide by O–Li coordination (TS1, Figure 4), (ii) evolution of TS1
to the corresponding monomeric tetrahedral intermediate (tetr-1,
Figure 4), and (iii) the collapse of tetr-1 into ketone 2a through a
second transition state (TS2, Figure 4). Computational results
revealed that the addition of the organolithium reagent is a fast
reaction (TS1, Free Energy barriers: 9–15 kcal mol-1) producing
rather stable monomeric tetrahedral intermediates (tetr-1a, tetr-
1b, tetr-1j, Figure 4) with respect to the starting reactants. The
cleavage barrier of the C–N bond determines the kinetic stabilities
of the intermediates. By considering the ZPE energy correction,
our results are in fairly good agreement with the previous findings
reported by Boche and co-workers,[6b] where the reactivity of
“classical” and Weinreb amides towards SNAc was studied by
DFT calculations using formamide and N-hydroxyformamide as
model substrates, respectively. However, the Free Energy
barriers of the second step are in contrast with the experimental
stability of the tetrahedral intermediates. As an example, when the
nucleophilic acyl substitution reaction of 1a in dry CPME with n-
BuLi is performed under anhydrous conditions, aqueous quench
after 24 h affords the corresponding ketone 2a with negligible
formation of over-addition products (see Supplementary
Information for details). By contrast, the Free Energy barriers of
about 21 kcal mol-1 correspond to half-life times of the order of
hundreds of seconds. Quantitative agreement with the
experiments is obtained only considering the formation of putative
dimeric aggregates in solution and including two explicit
molecules of CPME in the computations.[22] In this case, the Free
Energy barriers of the second step raise to more than 40 kcal mol-
1 for both 1a and 1b (Figure 4). When CPME was replaced by the
non-coordinating solvent hexane, the Free Energy Barriers of the
dimeric form for the second step dropped down to 19 kcal mol-1,
which suggest low selectivity in hydrocarbons, in agreement with
the experimental results (Table 1, entry 1, see Supplementary
Information for details).
Scope of the reaction. With satisfactory conditions in place, we
sought to capitalize on this process by exploring the scope of this
transformation. By reacting
a
variety of aliphatic and
(hetero)aromatic N-acyl pyrrolidines 1a, 1k–1x with commercially
available aliphatic and (hetero)aromatic organolithium reagents
ranging from n-BuLi to s-BuLi, t-BuLi, n-HexylLi, PhLi and 2-
thienylLi (Scheme 2), a wide range of ketones 2b–2ad were
synthesized in very satisfactory yields (53–93%). Unsubstituted
2b–2f, as well as ketones decorated with electron-donating (MeO,
2g–2j), neutral (Me, 2k–2m) or electron-withdrawing (Br, 2n,o;
CF3, 2q,r) substituents, were smoothly obtained with different ring
substitution patterns [ortho- (2g,h, 2m), meta- (2i,j) and para-
(2k,l, 2n,o, 2q,r)] in 60–88% yields. Of note, all the
aforementioned transformations proved to be highly
chemoselective, and do not suffer competitive pathways such as
DoM (2g–2j), lateral lithiation (2k–2m) or lithium-halogen
exchange (2n,o) reactions. Assorted (hetero)aryl derivatives with
a fluorine substituent (2p), electron-deficient (pyridine: 2s,t), and
electron-rich
(thiophene:
2u,v,
N-methylindole:
2w,x)
heterocycles served as competent reaction partners as well,
thereby delivering the desired ketones in 53–93% yield. It is worth
noting that, under the above conditions, even (cyclo)alkyl (2y–
2ab), bicyclic (2ac) and sterically hindered adamantyl (2ad)
ketones could be obtained from the corresponding acyl
pyrrolidines in 55–89% yield. These results thus testify to the
generality of the described protocol for the ketone synthesis from
amides.[23]
4
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10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
O
O
R2-Li
O
Reaction crude
2d, pyrrolidine
in CPME/hexane
(CPME/hex = 0.7)
n-HexLi
(2.3 M in hexanes)
R1
R1 = (Hetero)Aryl, (Cyclo)Alkyl
R2 = Alkyl, (Hetero)Aryl
N
R1
R2
CPME, 20 s
RT, under air
N
1a, 1k-x
2
CPME (0.5 M)
RT, 20 s
R1 = (Hetero)Aryl
1a
O
O
O
O
O
O
O
fractional
distillation
gram scale
s-Bu
t-Bu
n-Hex
n-Bu
S
2b
2c
2d
2e
2f
2g
(78%)
(61%)
(86%)
(85%)
(71%)
(83%)
O
O
O
O
O
O
O
O
O
O
(74%)
t-Bu
n-Hex
t-Bu
n-Bu
t-Bu
n-Hex
O
HN
2h
(64%)
2i
(60%)
2j
(64%)
2k
(88%)
2l
(75%)
2m
(87%)
Ph
Cl
O
O
O
O
O
2d
(86%)
in
Et3N
n-Bu
n-Hex
n-Bu
s-Bu
CPME/Hex
S
Br
Br
F
CF3
CF3
2n
(70%)
2o
(80%)
2p
(74%)
2q
(77%)
2r
(84%)
O
O
O
O
S
n-Bu
s-Bu
Scheme 3. Gram-scale synthesis of 2d and recycling procedure of CPME and
pyrrolidine from the acylation reaction. Reaction conditions: 1a (1 g, 5.7 mmol),
n-HexLi (4.96 mL, 11.4 mmol), CPME (11 mL), 20 s. Yields refer to products
isolated after flash-column chromatography.
N
O
N
S
O
S
S
S
N
N
2s
(74%)
2t
(79%)
2u
(53%)
2v
(91%)
2w
(86%)
2x
(93%)
R1 = (Cyclo)Alkyl
O
O
O
O
n-Hex
n-Hex
S
2y
(55%)
2z
(70%)
2aa
(78%)
2ab
(84%)
Conclusions
O
In summary, this work discloses that there is no need to
make use of chemically modified or activated amides as well as
transition metal-catalysed C–N activation processes to promote
and privilege nucleophilic acyl substitution reactions by
O
2ac
(84%)
2ad
(89%)
Scheme 2. Synthesis of ketones 2 through the nucleophilic acyl substitution
reaction between aliphatic and (hetero)aromatic N-acylpyrrolidines 1 and
aliphatic and (hetero)aromatic organolithium reagents in CPME, at RT and
under air. Reaction conditions: 1 (0.2 mmol), R2Li (0.4 mmol), CPME (0.4 mL),
20 s. Yields refer to products isolated after flash-column chromatography. 1k:
N-2-methoxybenzoyl pyrrolidine; 1l: N-3-methoxybenzoyl pyrrolidine; 1m: N-4-
methylbenzoyl pyrrolidine; 1n: N-2-methylbenzoyl pyrrolidine; 1o: N-4-
bromobenzoyl pyrrolidine; 1p: N-4-fluorobenzoyl pyrrolidine; 1q: N-4-
trifluoromethylbenzoyl pyrrolidine; 1r: N-nicotinoyl pyrrolidine; 1s: N-thiophene-
2-carbonyl pyrrolidine; 1t: N-1-methyl-1H-indole-2-carbonyl pyrrolidine; 1u: N-
octanoyl pyrrolidine; 1v: N-cyclohexanecarbonyl pyrrolidine; 1w: N-
norbornenecarbonyl pyrrolidine; 1x: N-adamantanoyl pyrrolidine.
organolithium
reagents.
Indeed,
both
aliphatic
and
(hetero)aromatic N-acylpyrrolidines have been found to
successfully react with commercial solution of aliphatic and
(hetero)aromatic organolithiums, with the desired ketones
obtained in up to 93% yield (30 cases investigated and discussed)
and with an effective suppression of the notorious over-addition
reaction, when using CPME (0.5
M
solution) as an
environmentally responsible solvent. Valuable points of practical
interest of the presented protocol are (i) reactions run in open air
and at room temperature with extremely fast reaction times (20 s),
(ii) tolerance of several electron-donating, electron-deficient and
sterically hindered functional groups, and (iii) high
chemoselectivity with no competition with potential DoM, lateral
and halogen-exchange pathways.
The utility and the sustainability of the process was further
highlighted by its scalability and the recyclability/reusability of
both the solvent and the pyrrolidine leaving group to prepare
additional starting material. The experimental results are nicely
supported by detailed DFT calculations that show how CPME
stabilizes the dimeric tetrahedral intermediate, and by NMR
spectroscopic investigations, which provide insights into the
stability of the tetrahedral intermediate in CPME solution.
Scalability and recycle. To further explore the utility, the
versatility and the robustness of this new sustainable synthetic
protocol and to improve its atom economy, we investigated the
scalability of the process. To this end, we carried out a gram scale
synthesis of 2d starting from 1a. By reacting a solution of 1a (11.4
mmol, 2 g, in 22 mL CPME) with n-HexylLi (2 equiv, 2.3 M in
hexanes), the reaction proceeded uneventfully in 20 s at RT under
air, and resulted in the formation of 2d in 90% yield (2 g) and with
a 97:3 ketone-to-alcohol ratio. Furthermore, in order to prepare
additional starting material, we also investigated the recyclability
and the reusability of both the solvent (CPME) and the pyrrolidine
leaving group (b.p. = 87 °C) by distillation (Scheme 3). To this end,
a solution of 1a (5.7 mmol, 1 g, in 11 mL CPME) was reacted with
n-HexylLi (2 equiv, 2.3 M in hexanes). The resulting crude
reaction mixture was carefully fractionally distilled. This favored
an easy recovery of the CPME/hexane fraction containing the
pyrrolidine. The latter was finally successfully acylated with
benzoyl chloride, thereby affording the starting material 1a in 74%
isolated yield and allowing, at the same time, the recovery of
ketone 2d in 86% yield (1 g) after purification.
Experimental Section
Experimental Details
Preparation of 2-thienyllithium solution in CPME. In a Schlenk tube
under a positive pressure of nitrogen, t-BuLi (1.7 M in pentane, 2.0 mmol,
2.0 equiv) was added dropwise to a precooled (-78 °C) stirred solution of
2-bromothiophene (1.0 mmol, 1.0 equiv, 97 µL) in dry CPME (1 mL, 1 M).
The reaction was stirred at -78 °C for 1 h to yield a pale-yellow solution of
2-thienyllithium (2-ThLi). The exact concentration was determined by
titration with diphenylacetic acid prior to use.
5
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10.1002/chem.202004840
Chemistry - A European Journal
RESEARCH ARTICLE
the computations. The optimisations were followed by aug-cc-pVTZ[29]
single-point energy calculations (including PCM), and free energies were
estimated by adding the thermochemical contributions obtained at M06-
2X/6-311+G(d) level. These DG (at 298K) values at DFT(M06-2X)/aug-cc-
pVTZ are reported throughout in the text. A complete set of critical point
geometries and energies is reported in the Supporting Information. All
calculations were carried out by using the GAUSSIAN16 system of
programs.[30]
Preparation of n-butyllithium solution in CPME. A solution of n-BuLi
(2.5 M in hexanes, 5 mL) in dry CPME (5 mL) was added to a test tube
fitted with a septum and flushed with dry argon. The tube was then placed
under vacuum (45 mmHg) until 5 mL of concentrated solution was
obtained. The resulting solution was diluted again with freshly distilled
CPME (5 mL) and concentrated under vacuum up to a 5 mL residual
volume. This procedure was repeated three times to completely remove
residual traces of hexane. The final n-BuLi solution in CPME was titrated
with diphenylacetic acid in anhydrous THF prior to use.
Acknowledgements
General procedure for SNAc and synthesis of compounds 2b-2ad.
Reactions were performed under air at room temperature. In an open
screw cap vial, N-acylpyrrolidines 1a, 1k–1x (0.2 mmol, 1 equiv) were
dissolved in CPME (0.4 mL, 0.5 M). The selected organolithium reagent
(n-BuLi 2.5 M in hexanes, s-BuLi 1.4 M in cyclohexane, t-BuLi 1.7 M in
pentane, n-HexLi 2.3 M in hexanes, PhLi 1.9 M in di-n-butyl ether, freshly
prepared 2-ThLi, 0.4 mmol, 2.0 equiv) was rapidly spread over the mixture,
which was kept under vigorous stirring for 20 s (60 s for PhLi and 2-ThLi),
and then diluted with water. The mixture was washed twice with 1 M HCl
(5 mL) and extracted with Et2O (3 x 5 mL). The combined organic layers
were dried over Na2SO4 and the solvent removed under reduced pressure.
The crude products were purified by flash column chromatography on
silica gel.
We would like to acknowledge Prof. Vittorio Pace for helpful
discussions and suggestions, Dr. Emanuele Priola for technical
support. Huvepharma Italia srl, Regione Piemonte and Cassa di
Risparmio di Torino for financial support. V.C. thanks the
Interuniversity Consortium C.I.N.M.P.I.S. and the University of
Bari for supporting this work.
Keywords: ketones • amides • organolithiums • chemoselectivity
• carbanions
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RESEARCH ARTICLE
Entry for the Table of Contents
SNAc with organolithiums under air achieved: Aliphatic and (hetero)aromatic ketones are straightforwardly, chemoselectively and quickly
(20s reaction time) obtained in up to 93% yield and with a broad substrate scope by reacting organolithium reagents with a variety of amides at
ambient temperature and under air in the environmentally friendly cyclopentyl methyl ether (CPME). Gram scale preparations and recyclability
of the reagents have also been successfully accomplished.
Institute and/or researcher Twitter usernames: @Capriati_V @farmuniba @LabPrandi @kristinaprandi
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