Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation

Article abstract of DOI:10.1002/chem.201702593

An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophi

Full text of DOI:10.1002/chem.201702593

A Journal of
Accepted Article
Title: Barbier Continuous Flow Preparation and Reactions of
Carbamoyllithiums for Nucleophilic Amidation
Authors: Maximilian Andreas Ganiek, Matthias Richard Becker,
Guillaume Berionni, Hendrik Zipse, and Paul Knochel
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Barbier Continuous Flow Preparation and Reactions of
Carbamoyllithiums for Nucleophilic Amidation
Maximilian A. Ganiek, Matthias R. Becker, Guillaume Berionni, Hendrik Zipse and Paul Knochel*
Abstract: An ambient temperature continuous flow method for
nucleophilic amidation and thioamidation is described. Deprotonation
of formamides by lithium diisopropylamine (LDA) affords
carbamoyllithium intermediates that are quenched in situ with
various electrophiles such as ketones, allyl bromides, Weinreb and
morpholino amides. The nature of the reactive lithium intermediates
and the thermodynamics of the metalation were further investigated
by ab initio calculations and kinetic experiments.
Scheme 1. Continuous flow methods using either an in situ metalation
procedure (a) or a new Barbier procedure (b).
The amide group is an ubiquitous functionality, present in one
third of commercial drugs.[1] Also, analogous thioamide
derivatives have gained attention as antibiotics as well as bio-
isosteric optical labels in proteins and versatile synthons for
heterocyclic synthesis or C-H activation.[2] Numerous protocols
for amidations and, to a lesser extent, thioamidations have been
developed.[3] Of special interest are amidations and
thioamidations involving carbamoyllithium intermediates.[4]
Recently, Reeves has utilized carbamoyllithiums for the
synthesis of α-amino amides with high stereoselectivity.[5] On the
other hand, Yoshida has shown that carbamoyllithiums can be
generated from carbamoyl chlorides via reductive lithiation with
lithium naphthalenide at -78 °C under continuous flow conditions
for the synthesis of functionalized α-ketoamides.[6] The use of
continuous flow set-ups has been shown to be highly promising
for organic synthesis,[7] although special custom-made
equipment is sometimes necessary.[8] A more classical approach
has been to generate a transient organometallic species in the
presence of trapping agents (Barbier conditions)[9] like
aldehydes, ketones, Me3SiCl or B(OiPr)3.[10] Recently, we have
shown that in situ trapping of highly reactive polyfunctional
aryllithiums can be realized using a metallic salt (MetXn) as in
Thus, if
a mixture of N,N-diethyl formamide (1a) and
cyclohexanone (2a, 0.7 equiv.) in THF is mixed in a simple T-
mixer with LDA (1.2 equiv.),[12] after a residence time of 1 min at
25 °C the α-hydroxy amide (4a) is obtained in 95% yield (Table 1,
entry 1). In contrast, all attempts to generate carbamoyllithiums
of type 3 in the absence of an electrophile at non-cryogenic
temperatures led to extensive decomposition.
Table 1. Continuous flow generation of carbamoyllithium of type 3 in the
presence of a carbonyl electrophile (2a-h) leading to α-hydroxy amides (4a-k).
Product of Type 4[a]
Entry
Formamide
Electrophile[b]
1
2
1a
1b
2a
2a
4a: 95%
4b: 72%
situ trapping reagent (MetXn
= ZnCl2·2LiCl, MgCl2·2LiCl,
CuCN·2LiCl, LaCl3·2LiCl; Scheme 1).[11] Thus, we have found
that a range of aromatic and heterocyclic substrates (Ar-H) can
be converted to various organometallics (Ar-Met) by treating a
mixture of Ar-H and MetXn with TMPLi (TMP = 2,2,6,6-
tetramethylpiperidyl).[11] Herein, we wish to report an extension
of this methodology by performing the in situ metalation of a
substrate (R-H) not in the presence of a metallic salt but directly
in the presence of an organic electrophile (E-X, such as a
ketone, an aldehyde, a Weinreb amide, an allylic bromide or a
disulfide) leading to a variety of useful organic molecules (R-E).
This Barbier approach has been applied on the generation and
trapping of unstable carbamoyl- and thiocarbamoyl-lithium
intermediates of type 3 (Table 1).
3
4
1c
1d
2a
2b
4c: 63%
4d: 69%
5
6
1e
1f
2c
2d
4e: 72%
4f: 58%
7
8
1g
1a
2e
2f
4g: 79%
4h: 76%
[*]
M. A. Ganiek, Dr. M. R. Becker, Dr. G. Berionni, Prof. Dr. Hendrik
Zipse, Prof. Dr. P. Knochel, Ludwig-Maximilians-Universität
München, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
9
1h
2g
4i: 63%
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10
11
1a
1i
2h
2h
4j: 91%
4k: 61%
8
9
1e
1j
5g
5h
6h: 61%
6i: 54%
[a] Yield of isolated product. The reactions were performed on a 1 or
2 mmol scale.
10
1i
5i
6j: 60%c
This Barbier flow procedure proved to be quite general and a
range of N,N-dialkyl formamides (1a-i) add to various ketones
(2a-g), leading to α-hydroxy amides (4a-i) in 58-95% yield
(entries 1-9, Table 1). Although additional functional groups like
11
12
1h
1d
5i
5j
6k: 58%c
6l: 88%
an epoxide, an ester or a cyano group were not tolerated,[4,6]
a
ketal, an acetal or an aryl halide proved to be compatible with
the flow reaction conditions (entries 5, 7, 9). Pivaldehyde (2h)
was found to be an excellent electrophile, furnishing the α-
hydroxy-amides 4j-k in 61-91% yield (entries 10-11; Table 1).
The procedure was also readily extended to Weinreb amides[13]
and to the related N-morpholino amides[14] of type 5, providing a
range of α-keto amides of type 6 in 61-82% yield (Table 2).
These acylations were usually performed on a 1 mmol scale
(runtime: 2 min), but a scale-up was possible without any further
optimization.[15] Thus, the preparation of α-keto amide 6b was
performed on a 35 mmol scale (runtime: 70 min) in comparable
yield (65%) as the small scale reaction (entries 1-2). Similarly,
this Barbier flow method could be performed with an isocyanate
(5h), leading to the unsymmetrical 1,2-diamide (6i) in 54% yield
(entry 9). Allylations using 3-bromocyclohexene (5i) furnished
the allylic amides (6j-k) in 58-60% yield (entries 10-11). Finally,
using dibutyl disulfide (5j) as quenching electrophile led to S-
butyl dibutylcarbamothioate (6l) in 88% yield (entry 12).
[a] Yield of isolated product. The reactions were performed on a 1 or
2 mmol scale. [b] Yield on a 35 mmol scale. [c] The reaction was
performed in the presence of 10 % CuCN.2LiCl.
A further extension to the generation of nucleophilic thioamides
of type 8 using the flow lithiation of N,N-dimethyl thioformamide
(7a) was possible by increasing the overall flow rate from
2 mL/min to 20 mL/min (Scheme 2).[16] Under the optimized
conditions N,N-dimethyl thioformamide (7a) and ketone 2i
(0.7 equiv.) were mixed in a simple T-mixer with LDA (1.2 equiv.)
and furnished, after a residence time of 48 sec at 25 °C the α-
hydroxy thioamide (9a) in 70% yield (Scheme 2).
Scheme 2. Continuous flow lithiation of N,N-dimethyl thioformamide (7a) in
the presence of norcamphor (2i).
Table 2. Continuous flow generation of carbamoyllithiums (3) in the presence
of Weinreb amides and other electrophiles (5a-j) leading to products 6a-l at
25 °C in THF.
This flow Barbier lithiation of thioformamides (7a-b) in the
presence of N-morpholine benzamides gives a reliable access to
valuable [4f] α-keto thioamides 9b-g in 41-98% yield (Scheme 3).
Products of type 7[a]
Entry
Formamide
Electrophile[b]
1
2
1g
1g
5a
5b
6a: 63%
6b: 65%b
Scheme 3. Flow Barbier reactions of thioformamides 7a-b with various aryl
morpholine amides (5).
3
1h
5a
6c: 76%
Interestingly,[4e] under these optimized flow conditions, no side-
products derived from a lithiation of the electrophile (E-X) were
found.[17] To explain the preferential formamide lithiation, we
have determined the relative free energies of lithiation of
formamide 1a in comparison with other well-known C-H acids[18]
such as 2-phenyl-1,3-dithiane (10a), 3,5-difluoroanisole (10b),
3,5-difluorobenzene (10c) and benzothiazole (10d) by
performing competition experiments using pivaldehyde (2h) as
electrophile (Scheme 4). The relative free energies ΔΔG° of
deprotonation (with 1a taken as reference) show that formamide
1a is located between the dithiane (10a) and 1,3-fluorobenzenes
(10b-c) with respect to its lithiation preference (Scheme 4).
4
5
1c
1j
5c
5d
6d: 72%
6e: 76%
6
7
1g
1k
5e
5f
6f: 75%
6g: 82%
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ΔΔG of metallation are following similar trends as the reported
pKa values of the selected C-H reference acids.[18,20]
Scheme 4. Relative free energy of LDA-mediated lithiation of 1a taken as
reference compared to other CH acids (10a-d) in THF at 25 °C. ΔΔG° = 1.364
log Krel. Control experiments demonstrated that the results of the competition
experiments were independent of the concentration and the time before
quenching (t = 1 or 10 min).
Scheme 5. Theoretically calculated relative free energies of LDA-mediated
lithiation taking LDA as the reference in THF at 25 °C.[21] Left scale: Assuming
monomeric structures; Right scale: dimeric structures.
We have observed that the free energy difference for lithiation of
0.4 kcal mol-1 between 1,3-difluorobenzenes 10b and 10c is
similar to the reported value of 0.48 kcal mol-1 in the case of the
lithiation with TMPLi in THF at -75 °C.[20] According to these
competition experiments, the thermodynamic acidity of
formamide 1a was estimated to be pKa = 30 (between 10a and
10c, Scheme 4)[18]. This ranking was further confirmed by ab
initio calculations.
It remains striking that the lithiation of 1a can be performed in
the presence of enolizable ketones like 2a-d which are much
stronger C-H acids (pKa ~ 20).
This demonstrates that the lithiation of 1a by LDA is much faster,
presumably due to an exceptionally strong complex induced
proximity effect.[23] The coordination of the formamide moiety to
LDA is thus a kinetically determining factor which surpasses C-H
acidity and thermodynamic considerations. Similar coordination
effects were recently described for rationalizing the
regioselectivities of the lithiation of a series of aromatic dithianes,
which was mainly controlled by coordination effects and kinetics,
rather by than the thermodynamics of lithiation.[18b] Thus, the
successful development of this Barbier continuous flow
metalation of formamides relies more on favourable kinetics of
lithiation than on a thermodynamically highly acidic formamide
C-H bond. This Barbier continuous flow procedure constitutes a
significant extension of the previously reported in situ trapping
metalations[11] and it opens the way to design other Barbier type
reactions involving unstable intermediates.
In line with earlier theoretical studies[5a] the structure of
monomeric carbamoyllithiums such as the one derived from
DMF is that of a side-on complex (Scheme 5). Reaction free
energies for generation of lithiated DMF from monomeric LDA
are positive (that is, unfavorable) by 7.2 kcal mol-1, which is in
obvious disagreement with the synthetic and equilibration
experiments. However, much more favorable lithiation energies
are obtained starting from the dimeric LDA structure, whose
relevance in THF solution has been demonstrated repeatedly.[22]
The lithiation of DMF is exergonic by 2.5 kcal mol-1 under these
conditions due to favorable Lewis acid/Lewis base interactions
between the amide lone pair electrons and the second lithium
cation. Applying this dimer model to the lithiation of 1,3-
difluorobenzene (10c) and benzothiazole (10d) predicts reaction
free energies in the same order as observed in the lithiation
experiments, which further supports the relevance of these
aggregates in THF solution (Scheme 5). Furthermore, the
experimental (Scheme 4) and theoretical (Scheme 5, right scale)
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749, B2
and C6) for financial and Vapoutec Ltd for technical support. M.
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Keywords: flow chemistry• lithiation• acidity• amidation • Barbier
reaction
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COMMUNICATION
Maximilian A. Ganiek, Matthias R.
Becker, Guillaume Berionni, Hendrik
Zipse, Paul Knochel*
Page No. – Page No.
Barbier Continuous Flow Preparation
and Reactions of Carbamoyllithiums
for Nucleophilic Amidation
Hot chemistry at room temperature: An ambient temperature continuous flow
method for nucleophilic amidation and thioamidation is described. Deprotonation of
formamides in the presence of various electrophiles by lithium diisopropylamine
(LDA) affords carbamoyllithium intermediates that are quenched in situ with various
electrophiles. Insight into the thermodynamics of their metalation was gained by
kinetic experiments an ab initio calculations.
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