Enantioselective and Regiodivergent Functionalization of N-Allylcarbamates by Mechanistically Divergent Multicatalysis

Article abstract of DOI:10.1002/chem.201602792

A pair of mechanistically divergent multicatalytic reaction sequences has been developed consisting of nickel-catalyzed isomerization of N-allylcarbamates and subsequent phosphoric-acid-catalyzed enantioselective functionalization of the resulting intermediates. By appropriate selection of reaction partners, in situ generated imines and ene-carbamates are mechanistically partitioned to yield opposing functionalized products. Formal α-functionalization to give protected α-arylamines is achieved upon enantioselective Friedel–Crafts reaction with arene nucleophiles, whereas formal β-functionalization is achieved upon reaction with diarylimine electrophiles in an enantioselective Povarov-[4+2] cycloaddition.

Full text of DOI:10.1002/chem.201602792

DOI: 10.1002/chem.201602792
Communication
&
Synthetic Methods
Enantioselective and Regiodivergent Functionalization of N-
Allylcarbamates by Mechanistically Divergent Multicatalysis
Edward Richmond,[a] Ismat Ullah Khan,[a, b] and Joseph Moran*[a]
Abstract: A pair of mechanistically divergent multicatalytic
reaction sequences has been developed consisting of
nickel-catalyzed isomerization of N-allylcarbamates and
subsequent phosphoric-acid-catalyzed enantioselective
functionalization of the resulting intermediates. By appro-
priate selection of reaction partners, in situ generated
imines and ene-carbamates are mechanistically partitioned
to yield opposing functionalized products. Formal a-func-
tionalization to give protected a-arylamines is achieved
upon enantioselective Friedel–Crafts reaction with arene
nucleophiles, whereas formal b-functionalization is ach-
ieved upon reaction with diarylimine electrophiles in an
enantioselective Povarov-[4+2] cycloaddition.
The complex catalytic reaction networks of biosynthesis have
long provided inspiration for chemists looking for efficient ap-
proaches to increasing molecular complexity. On one hand,
nature is capable of achieving mechanistically distinct diver-
gent catalytic reactions from a single biosynthetic intermedi-
Figure 1. Traditional multicatalysis in contrast to mechanistically divergent
multicatalysis and the design concept of a divergent nickel/chiral phospho-
ric-acid-catalyzed functionalization of N-allylcarbamates.
ate, a strategy increasingly copied by chemists interested in di-
versity-oriented synthesis.[1] On the other hand, nature uses
mutually compatible enzymatic catalysts to mediate multiple
catalytic reactions in sequence, the inspiration for the emerg-
ing area of multicatalysis.[2,3,4] Developing abiotic catalytic
lyzed nucleophilic and electrophilic reactivity, respectively.[5,6]
chemistry that simultaneously embodies both of these aspects
compounds that subsequently undergo Brønsted acid cata-
poses a formidable challenge. Here, we report an example of
mechanistically divergent multicatalysis, in which a starting
material is converted by a primary catalyst into an equilibrating
mixture of two molecules possessing mechanistically distinct
reactivity modes. The divergent reactivity of the intermediates
is then unleashed by a secondary catalyst to yield substantial
molecular diversity beginning from a common starting materi-
al and by a common set of catalysts (Figure 1). Specifically, we
describe a nickel-catalyzed isomerization of N-allylcarbamates
to an equilibrating mixture of ene-carbamates and imines,
In 2008, Terada and co-workers reported a multicatalytic se-
quence involving ruthenium-catalyzed isomerization of N-allyl-
carbamates to imines followed by a racemic phosphoric-acid-
catalyzed Friedel–Crafts reaction.[7] However, this Friedel–Crafts
reaction of imines was demonstrated enantioselectively by the
same research group one year prior.[8] This inconsistency high-
lights the non-trivial nature of developing multicatalytic se-
quences capable of delivering enantio-enriched products. Our
interest in developing a regiodivergent enantioselective multi-
catalytic sequence arose from prior work on catalyst discovery
by screening and deconvoluting complex mixtures of catalyst
components.[9] We reasoned that robust catalytic systems dis-
covered in such a manner would have a high likelihood of
being compatible with subsequent catalytic reaction steps. In
our prior investigations, it was noted that (Z)-to-(E)-olefin iso-
merization could be catalyzed by an in situ formed nickel/tri-
phos complex in the presence of zinc.[10] With this information
in hand, we thought that this nickel/triphos complex might
also be an effective catalyst for the positional isomerization of
[a] Dr. E. Richmond, I. U. Khan, Dr. J. Moran
Institut de Science et d’Ingꢀnierie Supramoleculaires (ISIS)
Centre International de Recherche aux Frontiꢁres de la Chimie (icFRC)
Universitꢀ de Strasbourg, CNRS, 8 allꢀe Gaspard Monge
67000, Strasbourg (France)
E-mail: moran@unistra.fr
[b] I. U. Khan
Department of Chemistry, Quaid i Azam University
Islamabad 45320 (Pakistan)
Supporting information and the ORCID number(s) for the author(s) of this
article are available under http://dx.doi.org/10.1002/chem.201602792.
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N-allylcarbamates,[11] and show compatibility with chiral Brønst-
ed acid catalysts.
Table 1. Generality of the multicatalytic isomerization/arylation.[a]
In our initial studies, treatment of N-allylcarbamates with
a slight excess of arene, 10 mol% NiCl2·dme, 10 mol% triphos,
10 mol% of the commercially available BINOL-derived phos-
phoric acid ((Æ)-3) with 5 equiv of zinc, and HCO2H gave
access to a range of a-aryl carbamates in good to excellent iso-
lated yields (Table 1, racemic protocol). The developed catalytic
conditions proved applicable to arylation of both tert-butoxy-
carbonyl- and carboxybenzyl-protected (Boc and Cbz, respec-
tively) N-allylcarbamates with a range of electron-rich arene
nucleophiles in good to excellent yields. 2-Methylfuran and
2-methylthiophene proved compatible nucleophiles (2a–c),
providing the desired a-heteroaryl carbamates in excellent
yields. 1,3,5-Trimethoxy- and 1,3-dimethoxybenzene proved to
be excellent nucleophiles in this catalytic system, yielding the
expected a-aryl carbamates 2e–k.
Internal unsaturated carbamates could also be employed as
starting materials with arylated products 2g–i, isolated in 67–
78% yield. In a survey of other aromatic nucleophiles, 1- and
2- naphthol were both well tolerated by the reaction (2d and
2l, respectively). Intriguingly, it was observed that allylcarba-
mate isomerization occurred in the absence of formic acid
when MeCN was used as solvent under an argon atmos-
phere.[12] Enantioselective reactivity could thus be achieved
with indole nucleophiles by employing a sequential multicatal-
ysis protocol without the necessity to isolate reaction inter-
mediates.[13] The chiral phosphoric acid (R)-TRIP [(R)-3,3’-
bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’-diyl hydrogen
phosphate], in combination with N-Boc allylcarbamates 1a
and 1c, allowed the desired a-indolyl carbamates 2m–r to be
obtained in good yields and uniformly excellent enantioselec-
tivities (Table 1, enantioselective protocol).
With a reliable procedure for the multicatalytic enantioselec-
tive a-functionalization of N-allylcarbamates established, we
next sought to apply the same catalytic reaction conditions to
a formal b-functionalization of N-allylcarbamates simply by var-
iation of the reaction partner. Considering that Masson, Zhu,
and co-workers have recently demonstrated a phosphoric-acid-
catalyzed enantioselective Povarov reaction[14] between ene-
carbamates and imines,[15] we elected to probe the develop-
ment of a multicatalytic version of this reaction using N-allyl-
carbamates as starting materials. Initial experiments employing
the aforementioned reaction conditions resulted in poor yields
of the expected tetrahydroquinoline product. It was found that
improved yields could be obtained by reducing the formic
acid equivalents and by pre-isomerization of the N-allylcarba-
mate for 1 h at 408C. According to the newly optimized ‘se-
quential multicatalysis’ reaction procedure, and employing rac-
emic (Æ)-3, a range of racemic tetrahydroquinolines were pre-
pared in good yields and good diastereoselectivities (see the
Supporting Information for details of racemic scope).[16]
[a] Isolated yield after column chromatography. [b] Performed at 608C.
[c] Performed at 1008C. Enantiomeric ratios (e.r.) determined by use of
analytical HPLC analysis over a chiral stationary phase. Triphos=bis(di-
phenylphosphino-ethyl)phenylphosphine, PA=generic phosphoric acid,
1,2-DCE=1,2-dichloroethane.
enantiomeric excess (ee). This decrease was established to be
caused by a competing racemic background reaction catalyzed
by residual HCO2H. Gratifyingly, simply by adding solid NaHCO3
after completion of the isomerization step, a series of enan-
tioenriched tetrahydroquinolines (4a–h) could be prepared in
good yield, diastereomeric (d.r.) and enantiomeric ratios (e.r.)
(Table 2). To demonstrate that no erosion of enantiocontrol oc-
cured as a consequence of the sequential catalytic protocol,
tetrahydroquinoline 4 f was prepared from an isolated sample
of the requisite ene-carbamate using catalyst (R)-5. Indeed, the
discrete Povarov reaction and the sequential procedure fur-
nished tetrahydroquinoline 4 f with almost identical e.r. values
(92:8 vs 90:10, respectively) and comparable yields (85% over
one step vs 76% over two steps, respectively).
Optimization of the sequential catalysis procedure for the
enantioselective preparation of tetrahydroquinolines then fol-
lowed. Phosphoric acid (R)-5, similar to the optimal catalyst
structure of Zhu and Masson, delivered promising initial results
in combination with N-Cbz allylcarbamates, albeit with reduced
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2) formal b- functionalization through a [4+2]-Povarov cycload-
dition. Divergence of the nascent ene-carbamate intermediate
prior to a second catalytic event, as part of a mechanistically
divergent multicatalysis scenario, allows this opposing reactivi-
ty to be realized. In addition, such a scenario has been demon-
strated to be fully compatible with enantioselective catalysis.
The two reaction systems described here are rare examples of
the productive combination of nickel and organocatalysis.[19,20]
The system involving the cycloaddition represents the first tel-
escoped exploitation of the inherent nucleophilicity of ene-car-
bamates after a catalytic isomerization event. Further studies
will seek to apply the concept of mechanistically divergent
multicatalysis in related transformations and to achieve pro-
gressively longer sequences.
Table 2. Scope of sequential multicatalytic isomerization/enantioselective
Povarov reaction.[a]
Acknowledgements
This work was supported in part by grants from LabEx CSC
and the Marie Curie Actions FP7-PEOPLE Program (CIG-2012-
326112). E.R. and I.U.K thank the Leverhulme Trust and the
HEC-Pakistan/French Embassy for fellowships, respectively.
Keywords: Brønsted acids
·
carbamates
·
imines
·
isomerization · multicatalysis · nickel
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Received: June 13, 2016
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COMMUNICATION
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Synthetic Methods
E. Richmond, I. U. Khan, J. Moran*
&& – &&
Enantioselective and Regiodivergent
Functionalization of N-Allylcarbamates
by Mechanistically Divergent
Multicatalysis
Simple divergence: A pair of mechanis-
tically divergent multicatalytic reaction
sequences has been developed consist-
ing of nickel-catalyzed isomerization of
N-allylcarbamates and subsequent phos-
phoric-acid-catalyzed enantioselective
functionalization of the resulting inter-
mediates. Formal a-functionalization to
give protected a-arylamines is achieved
upon enantioselective Friedel–Crafts re-
action with arene nucleophiles, whereas
formal b-functionalization is achieved
upon reaction with diarylimine electro-
philes in an enantioselective Povarov-
[4+2] cycloaddition.
Chem. Eur. J. 2016, 22, 1 – 5
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