Para-Functionalization of N-Substituted 4-amino[2.2]paracyclophanes by Regioselective Formylation

Article abstract of DOI:10.1002/ejoc.202100288

Herein, we report a simple and convenient procedure to prepare para-disubstituted [2.2]paracyclophanes in a straightforward manner. Our approach relies on a regioselective formylation of N-substituted 4-amino[2.2]paracyclophanes, which allows an easy access to a series of products incorporating a reactive aldehyde function para to the electron-donating group. These compounds can be engaged in a variety of orthogonal late-stage derivatization processes involving either the carbonyl group or the amine function, and can serve as precursors to rapidly access more complex paracyclophane derivatives. Control of planar chirality is also possible by performing a kinetic resolution of key racemic intermediates through asymmetric transfer hydrogenation. The formylation can be run on a synthetically useful scale, thus confirming the practical applicability of our method.

Full text of DOI:10.1002/ejoc.202100288

Communications
doi.org/10.1002/ejoc.202100288
Para-Functionalization of N-Substituted 4-amino[2.2]
paracyclophanes by Regioselective Formylation
Simon Felder,[a] Laurent Micouin,*[a] and Erica Benedetti*[a]
formed starting form mono-substituted derivatives through
bromination,[6] acetoxylation[7] or amination reactions.[8] In our
ongoing work on the chemistry of [2.2]paracyclophanes,[9] we
became interested in exploring new synthetic routes to access
para-disubstituted pCps in a straightforward manner through
selective carbon-carbon bond formation. Such compounds
could potentially be used to develop original chromophores.[10]
In addition, since substituted [2.2]paracyclophanes can display
planar chirality due to the hindered rotation of their aryl
moieties,[11] para-disubstituted pCps may be employed as
precursors of new chiral ligands and catalysts.[12]
Herein, we report a simple and convenient procedure to
prepare para-disubstituted [2.2]paracyclophanes in a straight-
forward manner. Our approach relies on a regioselective
formylation of N-substituted 4-amino[2.2]paracyclophanes,
which allows an easy access to a series of products incorporat-
ing a reactive aldehyde function para to the electron-donating
group. These compounds can be engaged in a variety of
orthogonal late-stage derivatization processes involving either
the carbonyl group or the amine function, and can serve as
precursors to rapidly access more complex paracyclophane
derivatives. Control of planar chirality is also possible by
performing a kinetic resolution of key racemic intermediates
through asymmetric transfer hydrogenation. The formylation
can be run on a synthetically useful scale, thus confirming the
practical applicability of our method.
Very recently, a palladium-catalyzed para-selective CÀ H
activation/aryl-aryl
coupling
of
4-phenylamino[2.2]
paracyclophane has been reported (Scheme 1a).[13] To the best
of our knowledge, this constitute the sole example of a reaction
allowing the functionalization of paracyclophanes with the
creation of aryl-aryl bonds para to an electron-donating amino
group.
[2.2]Paracyclophane (pCp)[1] and its derivatives constitute a
rather unique class of aromatic compounds characterized by an
unusual three-dimensional framework. These substrates incor-
porate two benzene rings called decks, covalently fixed together
by two ethylene bridges at their para positions. As evidenced
by X-ray diffraction crystallography, the aromatic decks of pCps
are stacked face-to-face and adopt a bent conformation.[2] Due
to their geometrical constraints, steric effects and unique π-
interactions, [2.2]paracyclophanes display an uncommon reac-
tivity. These molecules can in fact undergo Diels-Alder cyclo-
additions, hydrogenations, and ionic additions.[3] Functionalized
pCps also often show remarkable substituent effects in electro-
philic aromatic substitutions: the functional groups on one deck
can induce the incoming electrophile to preferentially attack
the other deck at specific positions.[4] Such transannular
directive effects are, for example, frequently exploited to
selectively access pseudo-gem di-substituted paracyclophanes.[5]
While various methods can be followed to functionalize both
pCp rings, the selective decoration of only one deck is more of a
synthetic challenge. Indeed, only few examples of regioselective
ortho- or para-functionalization of pCps have been reported to
date. Usually, in these cases, carbon-heteroatoms bonds are
Herein we present a practical method to perform a
regioselective para-formylation of N-substituted 4-amino[2.2]
paracyclophanes (Scheme 1b). Our approach is complementary
to the Pd-catalyzed aryl-aryl couplings since it provides reactive
aldehyde derivatives that can serve as intermediates to create
aryl-alkyl or aryl-alkenyl bonds.
We began our investigations with the synthesis of racemic
4-dimethylamino[2.2]paracyclophane. Compound (�)-2 was
prepared first, starting from commercially available [2.2]
paracyclophane, and following a two-step nitration/reduction
procedure previously reported in the literature (Scheme 2).[14]
Reductive methylation of derivative (�)-2 then afforded product
(�)-3a in 90% yield (Scheme 2).
[a] S. Felder, Dr. L. Micouin, Dr. E. Benedetti
Laboratoire de Chimie et Biochimie Pharmacologiques
et Toxicologiques – UMR8601 CNRS
Université de Paris
45 rue des Saints Pères,
75006 Paris, France
E-mail: laurent.micouin@u-paris.fr
erica.benedetti@u-paris.fr
Scheme 1. Access to para-disubstituted pCps through selective carbon-
carbon bond formation.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100288
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any appreciable loss of efficiency, thus confirming the practical
applicability of our method.
The relative position of the substituents in compound
(�)-4a (formyl group para to the amino group) was deduced
from NMR studies, and subsequently confirmed by chemical
correlation. Indeed, 4-amino[2.2]paracyclophane (�)-2 was
converted into para-iodinated compound (�)-5 using a pre-
viously described synthetic protocol.[18] N,N-Dimethylation of
amine (�)-5, followed by iodine-lithium exchange and formyla-
tion with DMF afforded product (�)-4a in 35% overall yield
(Scheme 4). The proton and carbon NMR spectra of this
aldehyde and the one obtained through the direct formylation
pathway showed identical signal patterns.
The Vilsmeier-Haack reaction proved to be a robust method
to functionalize N-substituted 4-amino[2.2]paracyclophanes at
their para position. In fact, the formylation was successfully
employed to selectively decorate compounds (�)-3b and
(�)-3c, easily obtained through a mono- or di-benzylation of 4-
amino[2.2]paracyclophane (�)-2 (Scheme 5).[19]
Scheme 2. Synthesis of racemic compound (�)-3a.
Having pCp (�)-3a in hand, we considered the possibility of
performing selective formylation reactions. By taking inspiration
from a protocol frequently employed to decorate pCps with
aldehyde groups,[15] Rieche’s conditions were tested in a first
assay (Scheme 3a). The introduction of an aldehyde group at
the para position of 4-methoxy[2.2]paracyclophane has indeed
been described to occur in a chemical yield of 90% after only
4 hours of reaction.[16] However, N-substituted analog (�)-3a
was regioselectively formylated in only 15% chemical yield after
3 days using similar conditions. Amines are known to interact
with TiCl4 to form metal-nitrogen bonds.[17] Such reactivity may
hamper the activation of dichloromethyl methyl ether and
explain the low conversion observed when performing Rieche’s
formylation. Different conditions were therefore screened to
optimize this transformation, and we were pleased to find that
the Vilsmeier-Haack protocol could afford aldehyde (�)-4a in a
short reaction time and 90% yield (Scheme 3b). The reaction
could be run on a synthetically useful scale (750 mg) without
N,N-Diallyl substituted 4-amino[2.2]paracyclophane(�)-3d
reacted as well to form product (�)-4d in 50% yield (Scheme 5).
Interestingly, when Fmoc-protected amine (�)-3e was sub-
jected to formylation under the same conditions, product
(�)-4d could be isolated in 42% yield (Scheme 5). This last
example clearly shows that the reaction also tolerates sub-
strates incorporating mild electron-withdrawing groups on the
nitrogen atom. All transformations are supposed to proceed
through the mechanism proposed to explain the Vilsmeier-
Haack formylation of more common benzene derivatives.[20]
The formylated products (�)-4a–d incorporate both an
electron-donating and an electron-withdrawing group, and
exhibit interesting UV-Vis absorption and fluorescence emission
properties.[19] In addition, due to the presence of the reactive
aldehyde group, these compounds can undergo a variety of
derivatization reactions. To exemplify different possibilities,
compound (�)-4a was reduced to the corresponding benzylic
alcohol (�)-7, engaged in a reductive amination reaction, and
submitted to Grignard addition (Scheme 6). Wittig reactions
Scheme 3. Selective formylation of compound (�)-3a.
Scheme 4. Chemical correlation studies.
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Scheme 7. Transformations involving reactive substituents at the nitrogen
atom.
converted to the corresponding primary amine (�)-4g upon
treatment with piperidine in DMF (Scheme 7), thus opening up
a plethora of possibilities for further functionalization at the
nitrogen atom.
Scheme 5. Para-formylation of pCps (�)-3b–e.
All the transformations described above have been con-
ducted on racemic material. It is however possible to prepare
enantiopure 4-amino[2.2]paracyclophane (Sp)-2 taking advant-
age of a method previously optimized in our laboratory.[9a] In a
first step, the kinetic resolution of racemic 4-formyl[2.2]
paracyclophane (�)-11 was performed by asymmetric transfer
hydrogenation using RuCl(p-cymene)[(S,S)-Ts-DPEN] as the cata-
lyst, and t-BuOK as the base, in a 1:1 i-PrOH/MeCN mixture
(Scheme 8).
The resulting enantiopure aldehyde (Sp)-11 was converted
into the corresponding oxime (Sp)-12 through a classical
condensation reaction. Treatment of compound (Sp)-12 with
Scheme 6. Late-stage derivatization of compound (�)-4a.
were also successfully conducted starting from compound
(�)-4a (Scheme 6).[21]
Derivatization reactions involving reactive substituents at
the nitrogen atom can also be performed. For instance,
compound (�)-4d, showing a N,N-diallyl moiety, was success-
fully submitted to ring-closing metathesis (RCM) in the presence
of a 2nd generation Hoveyda-Grubbs catalyst (HG cat, Scheme 7)
to generate cyclized product (�)-4f in 72% yield (Scheme 7).
The Fmoc-protected derivative (�)-4e, on its side, was easily
Scheme 8. Access to enantiopure 4-amino[2.2]paracyclophane (Sp)-2.
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Koser’s reagent[22] and NaOH finally led to the formation of the
desired enantiopure amine (Sp)-2, which was isolated in 58%
yield (Scheme 8). Starting from this precursor, it will clearly be
easy to prepare a variety of para-disubstituted pCps in their
enantiopure form simply by using our regioselective formyla-
tion protocol as a key synthetic step.
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In conclusion, we reported a practical method to regiose-
lectively synthesize para-disubstituted [2.2]paracyclophanes in
few steps, and good overall yields. Our approach is based on
the Vilsmeier-Haack formylation of differently substituted 4-
amino[2.2]paracyclophanes, which allows the introduction of a
reactive aldehyde function para to the electron-donating
groups. The formylated products exhibit interesting spectro-
scopic properties, and can be engaged in a variety of late-stage
functionalization processes leading to more complex para-
cyclophane derivatives. All synthesized compound can be easily
obtained in their enantiopure form. We are convinced that our
convenient formylation reaction will reveal particularly useful as
a key step to access planar chiral paracyclophanes showing
interesting photophysical or catalytic properties. The possibility
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emitters is currently under investigation in our laboratory.
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We gratefully thank the Agence Nationale de la Recherche (ANR
PhotoChiraPhane), CNRS, Université de Paris and the Ministère de
l’Enseignement Supérieur et de la Recherche for financial support.
Patrice Gerardo is kindly acknowledged for his help with mass
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: Formylation
·
[2.2]Paracyclophanes
·
Para-
[18] C. Braun, M. Nieger, W. R. Thiel, S. Bräse, Chem. Eur. J. 2017, 23, 15474–
15483.
[19] For more details, see the Supporting information.
disubstitution · Planar chirality · Regioselective reactions
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Manuscript received: March 8, 2021
Revised manuscript received: March 25, 2021
Accepted manuscript online: March 26, 2021
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COMMUNICATIONS
A regioselective formylation of N-
substituted 4-amino[2.2]
S. Felder, Dr. L. Micouin*, Dr. E.
Benedetti*
paracyclophanes is described, which
allows an easy access to key
synthetic intermediates which are
useful for the preparation of a large
variety of para di-substituted paracy-
clophanes in a straightforward
manner.
1 – 5
Para-Functionalization of N-Substi-
tuted 4-amino[2.2]paracyclophanes
by Regioselective Formylation