Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-β-Diketiminates and the Dual Role of LiCH2I

Article abstract of DOI:10.1002/anie.202007954

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation–metalation–acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated β-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH₂Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.

Full text of DOI:10.1002/anie.202007954

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Halogen-Imparted Reactivity in Lithium Carbenoid Mediated
Homologations of Imine Surrogates: Direct Assembly of bis-
Trifluoromethyl-β-Diketiminates and the Dual Role of LiCH2I
Authors: Laura Ielo, Laura Castoldi, Saad Touqeer, Jessica Lombino,
Alexander Roller, Cristina Prandi, Wolfgang Holzer, and
Vittorio Pace
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007954
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10.1002/anie.202007954
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Halogen-Imparted Reactivity in Lithium Carbenoid Mediated
Homologations of Imine Surrogates: Direct Assembly of bis-
Trifluoromethyl-β-Diketiminates and the Dual Role of LiCH2I
Dedicated to Professor José Vicente Sinisterra in the occasion of his 70th birthday
Laura Ielo,a Laura Castoldi,a Saad Touqeer,a Jessica Lombino,b,c Alexander Roller,d Cristina Prandi,e
Wolfgang Holzera and Vittorio Pacea,e*
Abstract: The selective formal insertion (homologation) of a carbon
a carbenoid homologation - Meinwald rearrangement – α-
functionalization approach directly converting vinyl ketones into
homologated α-fully substituted aldehydes.[8a] Notably, the nature
of the halogen (Cl, Br, I) did not influence the outcome of the
process. Later in 2019, we introduced the concept of telescoped
homologation of imine surrogates for accessing – via trivial
stoichiometric control – mono- or di-homologated CF3-aziridines
unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is
reported. The tactic is levered on
a highly chemoselective
homologation – metalation – acyl nucleophilic substitution sequence
which precisely enables to assemble novel trifluoromethylated β-
diketiminates within a single synthetic operation. Unlike previous
homologations conducted with LiCH2Cl furnishing aziridines, herein
we exploit the unique capability of iodomethyllithium to act
contemporaneously as a C1 source (homologating effect) and
metalating agent. The mechanistic rationale grounded on
experimental evidences supports the hypothesized proposal and, the
structural analysis gathers key aspects of this class of valuable
ligands in catalysis.
starting
from
trifluoromethylated
imine
surrogates
(trifluoroacetimidoyl chlorides, TFAICs).[8b, The hypothesized
reaction mechanism based on the experimental evidence points
out that after the first homologation event conducting to
tetrahedral intermediate (TI) I, a selective cyclization of the lithium
amide on the installed chloromethyl-fragment took place, giving
the mono-homologated α-chloro-aziridine (II).[8b] In case of excess
of the reagent (not necessarily LiCH2Cl), the double C1-C1
homologation product (III) is obtained via in situ spontaneous
formation of an electrophilic azirinium ion (IV).[10] The depicted
scenario clearly documents the crucial role displayed by the
9]
Since their introduction in the early 1960s by Closs-Moss[1]
carbenoid reagents attracted wide interest within the synthetic
community for two main reasons: 1) they enable the transfer of a
CH2X fragment into a recipient carbon skeleton under nucleophilic
or electrophilic regime, mainly established by the nature of the
metal;[2] 2) the so-installed, per se reactive, C1-fragment is
amenable of further derivatization within the unique operational
event or, at a later stage of the sequence (Scheme 1 – path a).[3]
This concept is beautifully illustrated in a series of benchmark
transformations achieved with carbenoids and various
electrophilic platforms, e.g. (aza)-carbonyls to oxiranes and
intermediate
I
and, we reasoned that modulating the
homologation phase inserting a distinct halomethyl fragment -
potentially susceptible of further manipulation - could constitute a
tactic for enabling the formal insertion of a carbon conjunctive of
two TFAIC units (Scheme 1 – path d).
aziridines via direct nucleophilic displacement (SN) of
a
tetrahedral intermediate (Scheme 1 – path b).[4] On an analogous
internal SN displacement is levered the Matteson homologation
of boronic esters,[5] a powerful and highly versatile reaction used
recently by Aggarwal to introduce the assembly line synthesis
concept.[6] In general, these classics in carbenoid-mediated
chemistry deliver the expected homologated arrays or thereof
derivatives.[7] The high reactivity of tetrahedral intermediates
formed upon the addition of a carbenoid can be advantageously
exploited for triggering molecular rearrangements, conducting to
complex architectures within
a single synthetic operation
(Scheme 1 – path c).[8] In this context, our group reported in 2017
a
[*]
University of Vienna, Department of Pharmaceutical Chemistry -
Althanstrasse,
14
A-1090,
Vienna,
Austria.
E-mail:
b
vittorio.pace@univie.ac.at Web: http://drugsynthesis.univie.ac.at/;
Fondazione Ri.MED - Via Bandiera 11, 90133 Palermo, Italy; c University
of Palermo, Department STEBICEF - Via Archirafi 32, 90123 Palermo,
d
Italy;
University of Vienna, X-Ray Structure Analysis Center
-
e
Waehringerstrasse 42 A-1090 Vienna, Austria;
University of Turin,
Department of Chemistry - Via P. Giuria 7, 10125 Turin, Italy.
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10.1002/anie.202007954
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COMMUNICATION
Scheme 1. General context of the presented work.
14). We found highly beneficial adding the TFAIC portionwise: at
the beginning of the reaction only 1 equiv was present to ensure
the formation of the TI, thus leaving the second portion to be
added just after the metalation event. Under these conditions, the
desired compound 2 was obtained in an excellent 91% isolated
yield (entry 15). Some practical aspects of the transformation
merit mention: 1) the CH2I2 precursor of the carbenoid was added
in one-pot at the beginning of the reaction because its
transformation into LiCH2I requires minimum a stoichiometric
amount of MeLi-LiBr; 2) this implicitly accounts that the unreacted
CH2I2 remains in reservoir mode before the addition of the second
aliquot of MeLi-LiBr for the metalating phase; 3) an optimal time
of 5 min between the end of the addition of MeLi-LiBr (for forming
the homologating LiCH2I) and, the starting of the second addition
of the same MeLi-LiBr (for forming the metalating LiCH2I)
benefited the process; 4) varying the temperatures for one or both
steps was detrimental for the reaction, giving complex mixtures
(data non shown).
Collectively, our homologative synthetic plan could be regarded
as a tool for bridging two carbon centers with a connecting C1-
unit. Herein, we document the concept of chemoselective
homologation of TFAIC mediated by LiCH2I. We anticipate the
dual (unprecedented) role displayed by the iodocarbenoid: it
delivers the C1 synthon (homologating effect) and, accomplishes
the critical metalation thus, forming a α-iminomethyl lithium
species which attacks the second TFAIC unit, finally yielding the
products. Our strategy would enable a smooth access to
fluorinated β-diketiminates a significantly challenging class of
ligands for which a modular and highly efficient synthetic method
is still underdeveloped.[11] Interestingly, non-fluorinated
analogues (often called NacNac in analogy to more common acac
ligands)[12] emerged recently as versatile ligands (σ-donors) for
stabilizing
low-coordinate
Fe
species[13]
and
Ir-
photoreductants.[14]
The iodo-containing TFAIC (1) was selected as the model
substrate because of gathering information on the
chemoselectivity of a potentially concomitant aryl iodine-metal
exchange (Table 1). Being the expected adduct the homologated
product of two TFAIC building blocks, 2 equiv of them were
required per each CH2 unit supplied. Installing the CH2I unit (via
treatment with CH2I2 / MeLi-LiBr),[15] followed by iodo-metal
exchange with MeLi-LiBr provided a 76:24 ratio mixture of
homologated compounds 2 and 3 (entry 1). Using LiBr-free MeLi
as the metalating agent, resulted in increasing the formation of 3
(55:45 ratio) because of facilitated Ar-I / Li exchange (entry 2),
thus suggesting the presence of LiBr as optimal for the reaction.
Generating LiCH2I with n-BuLi-LiBr benefited the formation of 2
(entry 3), though the addition of the facilitating lithiating ligand
TMEDA inverted the ratio in favour of 3 (entry 4). Switching to
other common organolithiums (s-BuLi-LiBr and t-BuLi-LiBr) had
little effect on the reaction outcome (entries 5-6) while,
bromomethyllithium (LiCH2Br,[16] generated from BrCH2I and
MeLi-LiBr) could be used as a competent C1-unit donor (entry 7),
giving 2 in slightly lower yield. Pleasingly, these experimental
evidences – i.e. different homologating behaviour of both LiCH2I
and LiCH2Br compared with LiCH2Cl reported before - fully
support the hypothesized logic harnessed on rendering further
reactive the TI. Increasing the loading of both reactants LiCH2I
and MeLi-LiBr improved both the 2:3 ratio and the isolated yield
of 2, though a considerable excess did not further boost the
transformation (entries 8-9). A significant solvent dependence
was noticed using diethyl ether and toluene (entries 10-11) in
place of THF. A remarkable improvement was achieved when
using the same LiCH2I as C1 source (homologating role) and as
I/Li exchange agent (metalating role).[17] This unprecedented
double effect of the carbenoid reagent was subjected to further
investigation to maximize both ratio and conversion (vide infra for
mechanistic details). Cognizant that – constitutively - the
existence time of a carbenoid is very limited[18] and, its productive
employment requires the adoption of Barbier-type conditions at -
78 °C, a careful optimization of the carbenoid loading was secured.
Using 1.8 equiv of LiCH2I in each of the steps gave a 93:7 2:3
ratio at 87% conversion (entry 12), whereas a slight excess during
the homologation (entry 13) was slightly detrimental compared to
inverting the excess in favour of the metalation step (entries 13-
Table 1. Reaction optimization.
Homologa-
Metalating agent
(equiv)
Conve
rsionb
Ratio
Yield
of
2 (%)c
Entry
ting
agent
2 / 3
(equiv)a
1
LiCH2I (1.2)
LiCH2I (1.2)
LiCH2I (1.2)
LiCH2I (1.2)
LiCH2I (1.2)
LiCH2I (1.2)
LiCH2Br (1.2)
LiCH2I (1.8)
LiCH2I (2.3)
LiCH2I (1.8)
LiCH2I (1.8)
LiCH2I (1.8)
LiCH2I (1.8)
LiCH2I (1.3)
LiCH2I (1.3)
MeLi-LiBr (1.2)
MeLi (1.2)
41
36
39
35
31
36
33
72
74
18
27
87
83
89
95
76:24
55:45
68:32
41:59
63:37
72:29
70:30
81:19
80:20
83:17
79:21
93:7
26
2
14
3
4d
n-BuLi-LiBr (1.2)
n-BuLi-LiBr (1.2)
s-BuLi-LiBr (1.2)
t-BuLi-LiBr (1.2)
MeLi-LiBr (1.2)
MeLi-LiBr (1.8)
MeLi-LiBr (2.3)
MeLi-LiBr (1.8)
MeLi-LiBr (1.8)
LiCH2I (1.8)
22
11
5
15
6
23
7
19
8
54
9
55
10e
11f
12
13
14
15
10
16
76
LiCH2I (1.3)
90:10
98:2
70
LiCH2I (1.8)
83
LiCH2I (1.5)
>99:1
91
a
Unless stated otherwise (entries 2-6), LiCH2I was generated under Barbier
conditions in THF starting from CH2I2 and MeLi-LIBr at -78 °C for 1 h. The
metalating agent was added after 5 min from the end of the homologation step.
b
The ratio has been calculated by 1H-NMR analysis using 1,3,5-
trimethylbenzene as internal standard. c Isolated yield. d TMEDA (1.2 equiv) was
added. e Reaction run in Et2O. f Reaction run in toluene.
Having set the optimal conditions for the transformation, we next
studied the scope (Scheme 2). Confirming the chemoselective
profile of the method, different halogen substituted TFAICs were
amenable substrates for the methodology. Regardless the
position on the aromatic ring (ortho, meta, para), also the
potentially exchangeable bromo analogues reacted in high yield
giving the homologated substrates 4 and 5. An analogous
outcome was observed when chlorinated (6-8), monofluoro (9),
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10.1002/anie.202007954
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difluoro (10) or trifluoromethyl (11) TFAICs derivatives were
employed. Genuine chemoselectivity was deducted when multi-
electrophilic TFAICs were tested, thus demonstrating the
chemical integrity of nitrile (12) and esters [t-Bu (13) and Et (14)].
The reaction of the naphthyl-derivative was crucial for obtaining
the analogue (15) whose X-ray analysis gave fundamental details
on the structure of these new synthesized motifs (vide infra).
Notably, scaling-up the preparation of 15 at 20 mmol scale was
possible in comparable yield. Decorating the starting TFAICs with
aliphatic residues of variable steric hindrance [4-n-Bu (16), 2,5-di-
Me (17) and i-Pr (18)] did not alter the efficiency of the technique.
The potentially cyclopropyl-manifold vinyl motif (19) remained
untouched during the whole sequence, as well as, the terminal
alkyne (20) - amenable of deprotonation under the basic
conditions required. Introducing nitrogen-centered functionalities
was permitted, as observed in the case of the morpholino- (21),
nitro- (22) and diazo- (23) containing substrates. Incorporating
electron-donating groups such as ethers [3-ethoxy- (24), 2,5-
dimethoxy- (25)], cyclic acetal [1,3-benzodioxolane (26)] and
fluorinated ether [4-trifluoromethoxy- (27)] further extended the
scope of the method.
Scheme 2. Scope of the reaction for preparing bis-CF3-β-diketiminates.
TFAICs presenting sulfur substituents reacted equally well,
yielding the 4-sulfonamido- (28) and 4-thiomethyl (29) analogues.
Interestingly, the 4-phenylseleno- substituted TFAIC did not
undergo any concomitant Se/Li exchange,[19] furnishing the
desired compound (30) in 90% yield. We consider these findings
highly relevant for establishing a robust and flexible route towards
bis-CF3-β-diketiminates with vistas to their high-throughput
screening in catalysis.
Mechanistically, the nucleophilic addition of LiCH2I to TFAIC (A)
results in the formation of a tetrahedral intermediate (B), which
through the elimination of a chloride ion, conducts to the α-
iodomethylimine (C). As
a
consequence of the tamed
electrophilicity of the azacarbonyl carbon (compared to the
starting TFAIC) of this non isolable species, the subsequent
addition of the organolithium reagent furnishes the α-iminomethyl
lithium (D). This nucleophilic fragment reacts with the second
TFAIC building block according to an analogous addition-
elimination pathway (E), yielding the homologated adduct (F).
Finally, the intervention of a tautomeric equilibrium delivers the
compound in the observed form G. The plausibility of the
prospected mechanism is grounded on the following experimental
evidences: 1) the GC-MS analysis of the reaction crude indicates
the presence of CH2I2 at the end of the reaction, indicating that
although a part of it has been consumed for providing the C1
homologating unit, it is re-formed after the metalating step; 2)
when the metalation was conducted with MeLi, n-BuLi and
LiCH2Br (entries 2, 3, 7 - Table 1), the GC-MS analysis of the
crude showed the peaks of MeI, n-BuI and BrCH2I diagnostic for
the metalating mechanism suggested; 3) additionally, the
relatively highly boiling n-BuI (bp 130 °C) could be recovered and
unambiguously elucidated after chromatography on silica gel of
the reaction crude. Collectively, in the optimized reaction only 1
equiv of CH2I2 (of the 3.0 equiv initially present) is used for the
transformation, being at least 2.0 equiv regenerated during the
metalating step.
Scheme 3. Mechanistic rationale and proof of the metalating capability of LiCH2I.
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10.1002/anie.202007954
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COMMUNICATION
The X-ray analysis of compound 15 shows interesting
characteristics of the β-diketiminate skeleton, being firstly evident
the asymmetry of the conjugated planar system. The two TFAIC
units connected to the homologating element are not equal: the
bond lengths of N1-C1 (1.343 Å) and N3-C3 (1.289 Å) are
different and they are intermediate between an average sp2 N-C
(1.280 Å) and an average sp3 N-C (1.460 Å).[20] The β-diketiminate
array is also featured by a hydrogen atom attached to N1 placed
at H-bond distance with N3, thus forming the N1-H-N3 angle of
136.94°. Bond lengths of C1-C2 (1.368 Å) and C2-C3 (1.436 Å) –
again not equal – fully supports the partial double bond character
of these elements [cfr. average sp3 C-C (1.540 Å), average sp2 C-
C (1.340 Å)].[20] Merged together, this information are consistent
with an extended conjugation across the central motif (N1-C1-C2-
C3-N3) with the final result of rendering it almost planar, as a
consequence of the small torsion angles (N1-C1-C2-C3, 2.65 °)
and (N3-C3-C2-C1, 6.95 °), respectively.
Scheme 4. Consecutive homologation-diversification of a Weinreb amide
decorated TFAIC.
In summary, we have documented the formal insertion of a carbon
atom between two TFAICs arrays, resulting in the one-step
assembly of the novel bis-trifluomethylated β-diketiminate
backbone. The strategy relies on the stoichiometry controlled
homologation of one TFAIC unit with the nucleophilic carbenoid
Figure 1. X-ray structural analysis of compound 15 (CCDC 2007131).
iodomethyllithium acting contemporaneously as
a
C1
(homologating) and metalating (of the intermediate α-
iodomethylimine) agent. The fine tuning of the reaction conditions
guarantees a high level of chemocontrol as deducted from the
substrate scope underlining the tolerance for functionalities
whose chemical integrity could enable late-stage derivatization.
The structural analysis diagnostic for an extended planar
conjugate system secured insights valuable for further designing
and developing new applications of these ligands in synthetic
chemistry.
Acknowledgements
We thank the University of Vienna and Fondazione Ri.MED for
generous support; OEAD is acknowledged for praedoctoral
fellowship to S.T.
Spurred by the highly chemoselective profile observed in the
reaction with esters (13-14, Scheme 2), we wondered if installing
a Weinreb amide (per se less reactive than esters)[21] on the
TFAIC would have allowed to realize sequential additions of
different organometallics in order to rapidly diversify – without
isolating - the flexible β-diketiminate backbone (Scheme 4). This
Keywords: Homologation • Metalation • Carbenoids • Imines •
Chemoselectivity.
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10.1002/anie.202007954
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COMMUNICATION
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10.1002/anie.202007954
Angewandte Chemie International Edition
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Laura Ielo, Laura Castoldi, Saad
Touqeer, Jessica Lombino, Alexander
Roller, Cristina Prandi, Wolfgang Holzer
and Vittorio Pace*
Halogen-Imparted
Lithium Carbenoid
Homologations of Imine Surrogates:
Direct Assembly of bis-
Reactivity
in
Mediated
Trifluoromethyl-β-Diketiminates and
the Dual Role of LiCH2I
The treatment of a trifluoroacetimidoyl chloride (TFAIC) with the carbenoid iodomethyllithium results in
the chemoselective formation of a bis-trifluoromethyl-β-diketiminate. This sequential two-events strategy
involves the homologation of the imine surrogate followed by the lithiation of the intermediate operated
by the same carbenoid and attack of a second TFAIC unit.
This article is protected by copyright. All rights reserved.