Telescoped, Divergent, Chemoselective C1 and C1-C1 Homologation of Imine Surrogates: Access to Quaternary Chloro- and Halomethyl-Trifluoromethyl Aziridines

Article abstract of DOI:10.1002/anie.201812525

A conceptually novel, high-yielding, mono- or bis-homologation was realized with lithium halocarbenoids and enables the one-step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAIC

Full text of DOI:10.1002/anie.201812525

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Accepted Article
Title: Telescoped, Divergent, Chemoselective C1 and C1-C1
Homologation of Imines Surrogates: A Straightforward Access to
Quaternary Chloro- and Halomethyl-trifluoromethyl-aziridines
Authors: Laura Ielo, Saad Touqeer, Alexander Roller, Thierry Langer,
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.201812525
Angew. Chem. 10.1002/ange.201812525
Link to VoR: http://dx.doi.org/10.1002/anie.201812525
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10.1002/anie.201812525
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Telescoped, Divergent, Chemoselective C1 and C1-C1
Homologation of Imines Surrogates: A Straightforward Access to
Quaternary Chloro- and Halomethyl-trifluoromethyl-aziridines
Laura Ielo, Saad Touqeer, Alexander Roller, Thierry Langer, Wolfgang Holzer and Vittorio Pace*
Abstract: A conceptually novel, high yielding, mono- or bis-
homologation realized with lithium halocarbenoids enables the one-
step, fully chemocontrolled assembling of a new class of quaternary
trifluoromethyl-aziridines. Trifluoroacetimidoyl chlorides (TFAIC) act
as convenient electrophilic platforms enabling the addition of one or
two homologating elements by simply controlling the stoichiometry of
the process. Mechanistic studies highlighted that the homologation
event - carried out with two different carbenoids (LiCH2Cl and LiCH2F)
- conducts to fluoromethyl-analogues, in which the first nucleophile is
employed for constructing the cycle and, the second for decorating
the resulting molecular architecture.
with standard diazo chemistry.[8] However, as a common feature,
the homologation event is limited to the transfer of one single
carbon unit per transformation.[9] We realized that accomplishing
two consecutive C1-homologations within the same process
would represent a highly significant challenge with the final goal
of reaching quaternary functionalized aziridine derivatives
through a single chemical operation. Our synthetic plan started by
individuating the easily accessible trifluoroacetimidoyl chlorides
(TFAIC)[10] as the proper electrophilic imine surrogate
placeholders on which realizing the bis-functionalization. The
intrinsic reactivity conferred by the chlorine not only would ensure
the smooth addition of the homologating agent but, more
importantly, would be the key to enable the incorporation of two
nucleophilic elements on the sp2 C-N double bond of the TFAIC.
The constitutive presence of a trifluoromethyl group (CF3) within
an organic framework deeply modulates its physico-chemical
properties, thus rendering the scaffold a highly valuable entity
across the chemical sciences.[1] Incorporating such a functionality
within a 3-membered nitrogen cycle would result in unique motifs
(CF3-aziridines)[2] featuring interesting reactivity, synthetic
versatility and pharmacological properties determined by the
interaction of this lipophilic core with biological targets. This innate
potential is reflected in intensive efforts towards the development
of efficient tactics for preparing CF3-aziridines. In 2015 Liu
developed a two-steps Cu-catalyzed trifluoromethylazidation of
alkynes followed by the addition of nucleophiles to the
intermediate azirines (Scheme 1a),[3] while Stirling and Novák
disclosed in 2018 the metal-free alkenylation/cyclization of
amines with trifluoroalkenyl iodonium salts (Scheme 1b).[4] Each
of these strategies leads to structurally different motifs – though
in both cases tertiary CF3-bearing carbons are obtained -
presenting well defined relative placement of substituents: Liu’s
one conducts to α-aryl-α-substituted-trifluoromethylaziridines,
whereas via the Stirling-Novák protocol unsubstituted
trifluoromethylaziridines are formed.
Historically, the conceptual simplicity of ring closure operations
(3-exo-tet) on formal β-substituted CF3-containing amine
derivatives emerged as a valuable tool for accessing the targeted
scaffolds (Scheme 1c).[2a, 2c] Accordingly, the key intermediate I
can be accessed via a C1-homologative transformation carried
out with CF3-nucleophilic synthons on properly activated imines
as shown by Carreira,[5] Xiao[6] and Cahard[7] or, alternatively
through the homologation of electrophilic CF3-containing imines
[*]
Dr. Laura Ielo, MSc. Saad Touqeer, Prof. Dr. Thierry Langer, Prof.
Dr. Wolfgang Holzer, Prof. Dr. Vittorio Pace*
University of Vienna, Department of Pharmaceutical Chemistry,
Althanstrasse, 14, A-1090, Vienna (Austria)
Scheme 1. General context of the presented work.
E-mail: vittorio.pace@univie.ac.at; web: drugsynthesis.univie.ac.at/
Ing. Alexander Roller
University of Vienna, X-Ray Structure Analysis Center,
Waehringerstrasse 42, A-1090 Vienna (Austria)
Recently, our group documented that homologation processes
mediated by lithium carbenoids (LiCH2X)[11] might forge complex
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10.1002/anie.201812525
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molecular architectures in an extremely convenient and effective
way by simply selecting the reaction conditions,[12] thus making
flexible and modular the strategy to a given target.[13] By
introducing the unprecedented concept of C1-C1-double
homologation – eventually realized with two distinct homologating
agents - within a unique chemical event, herein we present a
straightforward tactic enabling the construction of unkown α-halo-
α-trifluoromethylaziridines and α-halomethyl-α-trifluoromethyl
aziridines.[2c, 14]
Table 1. Optimization of the reaction
Entry
Homologating
agent
Equiv
2
3
Yield (%)[a]
Yield (%)[a]
We commenced our investigations reacting the electrophilic
TFAIC 1a – featuring a potentially exchangeable bromine - with
LiCH2Cl (1.2 equiv) under standard homologation conditions: the
α-chloroaziridine 2 was formed as the unique product in an
excellent 90% yield (Table 1 – entry 1). The increase of carbenoid
loading to 1.5 and 2.3 equiv respectively, evidenced the
contemporaneous formation of the bis-homologated adduct
chloromethylaziridine 3, though as the minor product (entries 2-
3). The indicative decrease of the formation of 2 at progressively
higher amounts of LiCH2Cl was symptomatic of the strict
dependence on the stoichiometry of the process. Thus, having
ascertained the initial hypothesis of employing 1 as placeholder
for two simultaneous functionalizations, the desired compound 3
was the exclusive reaction product – 91% isolated yield - when
2.8 equiv of carbenoid were used (entry 4). Significantly, the
putative intermediate compound 4 formed upon homologation of
1 followed by acidic quenching could not be observed, thus
suggesting an extremely high reactivity for this species (vide infra
for mechanistic details). Some additional points merit mention: a)
The reaction reach completion within 1 h, thus allowing to
selectively obtain the mono- or the bis-homologated product by
simply selecting the stoichiometry; b) Chemoselectivity is fully
preserved in the presence of the reactive bromine, suggesting
high versatility and flexibility; c) a tamed nucleophilic but more
stable carbenoid (i.e. ClMgCH2Cl-LiCl)[15] does not induce the
transformation even at higher temperature (entries 5-6); d)
Running the reaction in Et2O sensitively dropped the yield (entry
7), confirming the preference for the more polar THF; e) Replacing
TFAIC 1a with the corresponding imidate 1b was not possible
(entry 8), suggesting the process requires an activated imine
surrogate to proceed.
1
2
LiCH2Cl
LICH2Cl
1.2
1.5
2.3
2.8
2.8
2.8
2.8
2.8
90
57
22
-
< 2
23
73
91
-
3
LICH2Cl
4
LICH2Cl
5[b]
6[b,c]
7[d]
8[e]
ClMgCH2Cl
ClMgCH2Cl
LICH2Cl
-
-
-
-
82
-
LiCH2Cl
-
Otherwise indicated LiCH2Cl was generated under Barbier conditions in
THF at -78 °C starting from ICH2Cl and MeLi-LiBr 1.5 M and compound 1a
was used as the starting agent. [a] Isolated yield. [b] Formed from ICH2Cl and
i-PrMgCl-LiCl (ref. 15). [c] Run at -30 °C. [d] Et2O was used as the solvent.
Compound 1b was used.
[e]
Having determined the conditions for achieving full chemocontrol,
the scope of the mono-homologation technique en route to
valuable α-chloroaziridines was evaluated (Scheme 2). The
protocol turned to be highly versatile, chemoselective and of
general applicability, as documented by the structural diversity of
the synthesized compounds. The following points underline the
potential of the methodology: 1) neither the substituents’
electronic behaviour and their position across the aromatic ring
influence the outcome; 2) no concomitant halogen-lithium
exchange occurs in systems featuring these substituents,
including bromine, chlorine and fluorine (2, 5-7) The superb
chemocontrol is clearly evidenced in reactions carried out with
substrates presenting functionalities notoriously highly sensitive
to organolithium reagents such as nitrile (8-9), ester (10-11) or
even a Weinreb amide (12). Taken together these examples
showcase the formidable electrophilicity of TFAICs, enabling the
selective homologation exactly on the targeted carbon. Aromatic
(13-16), as well as unsaturated (17) and aliphatic (18-19) groups
on the aromatic ring were perfectly tolerated including in the
presence of sterically relevant elements (20). Nitrogen-featuring
substituents on the aromatic ring such as morpholine (21), a diazo
moiety (22) and a lactam (23) further demonstrate the potential of
the tactic.
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10.1002/anie.201812525
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in case of significant steric hindrance (42). Unsaturated motifs
such as an olefin (43) or alkyne (44) were perfectly tolerated.
Neither
the
carbenoid-mediated
Simmons-Smith-type
cyclopropanation on the olefin[16] and abstraction of the acidic
proton of the terminal alkyne were observed. A series of nitrogen-
containing groups – e.g. morpholine (45), pyrrolidine (46), lactam
(47), diazo (48) - could be placed on the ring, further expanding
the scope of the protocol. Remarkably, recrystallization of
compound 48 provided enantiomerically pure (S)-48 as
unambiguously ascertained by X-ray structural analysis. Ethers
(49-50) or cyclic acetal (51) are compatible with the reaction
conditions, as well as, diversely oxidized sulfur substituents of
opposite electronic characteristics such as sulfide (52, electron-
donating) and sulfoxide (53, electron-withdrawing and potentially
reactive with an organolithium).
Scheme 2. C1-homologation for preparing chloro-trifluoromethylaziridines.
Crystal structures are deposited at CCDC ([10] 186913; [21] 186914; [22]
186911).
The conceptually novel C1-C1 double homologation was then
applied for the synthesis of α-chloromethyl-α-trifluoromethyl
aziridines (Scheme 3). Pleasingly, the optimized conditions found
in Table 1 were of general applicability, thus allowing the
straightforward preparation of these unknown scaffolds featuring
a quaternary all-substituted carbon through a single synthetic
operation. TFAICs reacted extremely well with independence
from the electronic or sterical properties of substituents.
Accordingly, all halogens (3, 24-27) – including the reactive iodine
(28) or the trifluoromethyl group (29-30) – furnished the bis-
homologated adducts in high yields after short reaction times.
Chloromethyllithium proved to be highly selective, as observed in
the cases of nitriles regardless their relative position (31-33) - and
an ester (34). This is quite noteworthy since these functionalities
are known to be highly susceptible to the attack of carbanions.
Embodying hydrocarbon functionalities such as aryl (35, 37-38),
or aliphatic groups (39-41) does not alter the efficiency including
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Scheme 3. C1-C1 bis-homologation for preparing chloromethyl-
trifluoromethylaziridines. Crystal structures are deposited at CCDC ([45]
186915; [48] 186912.
Scheme 5. Synthesis of fluoromethyl-trifluoromethylaziridines via the
homologation with two different carbenoids.
No variation of the reactivity profile of the starting TFAICs was
noticed, thus confirming the general outcome discussed for
chloromethyl analogues. Importantly and, as a further evidence of
the mechanism, exchanging the order of addition of the two
carbenoids resulted in the formation of the sole mono-
homologated aziridine. The tamed nucleophilicity of LiCH2F[18]
compared to LiCH2Cl results in no attack to TFAIC, thus
demonstrating that the monohomologated chloroaziridine
obtained (2) is formed in 74% yield during the second
homologation event with LiCH2Cl. Notably, such a second
homologation is limited at the insertion of only one carbon unit
because of the stoichiometry employed.
The conceptual novelty of the strategy elaborated was then
complemented with a survey on the chemical behaviour of these
non-previously reported scaffolds (Scheme 6). The substituents
on the aromatic rings act as versatile platforms for selective
functionalizations. The alkyne 44 serves as an expeditious naked
source of the corresponding methyl ketone 60 generated upon
Au(I)-catalyzed Wacker-type hydration (path a).[19] The Pd-
catalyzed Feringa cross-coupling of PhLi with iodo- (28) or
bromoarenes (54) was suitable for both chloromethyl- (61) and
fluoromethyl-aziridines (62) with comparable yields (path b).[20]
The electrophilic activation of the lactam moiety of compound
23,[21] followed by in situ reduction under Huang’s conditions[22]
delivered the corresponding reduced pyrrolidinyl system 63 (path
c). Finally, the aziridine Ag-mediated ring-opening with an amine
in the presence of an allylating agent gave with excellent
regioselectivity the 1,2-diamine scaffold 64 featuring full
substitution at the initial aziridine carbon (path d).[23]
Mechanistically, the telescoped homologation can be rationalized
via the expected addition of the 1st equiv of LiCH2Cl to form the
tetrahedral intermediate B (Scheme 4). Presumably, the internal
coordination between the lithium cation of the amidic functionality
and the chlorine2c, 8c introduced during the homologation event
would then trigger an internal nucleophilic displacement leading
to the mono-homologated chloroaziridine C. Whenever an excess
of homologating agent is present (2.8 equiv) and no quenching is
realized, the intermediate chloroaziridine spontaneously
evolves[8c, 17] to the highly electrophilic azirinium ion D which then
undergoes the second homologation to finally yield
chloromethylaziridine E.
Scheme 4. Plausible mechanism for the C1 and C1-C1 homologations.
In order to provide evidence for the mechanistic rationale, a
telescoped homologation accomplished with two different agents,
- LiCH2Cl and LiCH2F[18] – was designed (Scheme 5). The first
carbenoid was used as a C1 source for constructing the aziridinyl
ring, while the fluorinated carbenoid was conveniently used to
install the functionalizing CH2F motif. With much of our delight a
series of fluoromethyl-trifluoromethylaziridines (54-59) could be
easily accessed in a modular and divergent way via a single
synthetic operation consisting in the controlled generation and
employment of these two carbenoids during the same sequence.
Scheme 6. Manipulation of synthesized compounds.
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In summary, we have documented the assembling of quaternary
all-substituted trifluoromethylaziridines via a single synthetic
operation consisting in the lithium halocarbenoids-mediated
mono- or bis-homologation of trifluoroacetimidoyl chlorides.
These easily accessible electrophilic substrates act as convenient
placeholders for installing up to two nucleophilic elements: the fine
tuning of the reaction stoichiometry accounts for excellent levels
of chemocontrol. As such, the use of an excess of homologating
agent enables to formally install two carbon units, namely the
methylene fragment of the aziridinyl ring and, the functionalizing
exocyclic halomethylenic moiety. Based on mechanistic
–
experimental evidences two different carbenoids can be
advantageously used for the process. Uniformly high yields,
superb chemoselectivity and efficiency make the overall
sequence a straightforward and modular route towards a new
class of chemical entities assembled and functionalized within a
unique synthetic event.
Acknowledgements
[12] V. Pace, L. Castoldi, E. Mazzeo, M. Rui, T. Langer, W. Holzer, Angew.
Chem. Int. Ed. 2017, 56, 12677-12682.
The University of Vienna is gratefully acknowledged for financial
support. L. Ielo and S. Touqeer thank OEAD for postdoctoral and
predoctoral grants, respectively. The Authors are indebted to
Albemarle Corporation and ABCR Germany for generous gifts of
organolithiums and fluoroiodomethane, respectively.
[13] For accounts on the authors' research on carbenoid chemistry, see:a) L.
Castoldi, S. Monticelli, R. Senatore, L. Ielo, V. Pace, Chem. Commun. 2018, 54,
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28, 879-888. Illuminating work on constructing complex, highly functionalized
molecular architectures with different organometallic species has been
developed by Marek. See for example: c) J. Bruffaerts, D. Pierrot, I. Marek, Nat.
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Keywords: Homologation • Aziridines • Carbenoid •
Trifluoromethylation • Chemoselectivity.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
Layout 2:
COMMUNICATION
Laura Ielo, Saad Touqeer, Alexander
Roller, Thierry Langer, Wolfgang Holzer
and Vittorio Pace*
Telescoped,
Chemoselective
Divergent,
and C1-C1
C1
Homologation of Activated Imines
Surrogates: A Straightforward Access
Text for Table of Contents
to
Quaternary
Chloro-
and
Halomethyl-trifluoromethyl-aziridines
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