Direct Electrophilic C?H Alkynylation of Unprotected 2-Vinylanilines

Article abstract of DOI:10.1002/chem.201606026

Unprotected aromatic amines can be used as directing groups in metal-catalyzed C?H alkynylations of alkenes. By using low amounts of an Ir^IIIcatalyst in combination with alkynylbenziodoxolones as electrophilic alkyne-transfer reagents, highly desirable 1,3-enynes were isolated in excellent yields of up to 98 % with Z stereoselectivity. A broad substrate scope as well as the high synthetic utility of the 1,3-enynes render this new method an efficient approach for the synthesis of five- and six-membered heterocycles. Further derivatizations of the 1,3-enynes to highly substituted quinolines through Au^I- and N-bromosuccinimide-mediated exo-dig cyclizations were demonstrated.

Full text of DOI:10.1002/chem.201606026

A Journal of
Accepted Article
Title: Direct Electrophilic C-H Alkynylation of Unprotected 2
Vinylanilines
Authors: Lucien D Caspers, Peter Finkbeiner, and Boris J Nachtsheim
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.201606026
Link to VoR: http://dx.doi.org/10.1002/chem.201606026
Supported by

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COMMUNICATION
Direct Electrophilic C-H Alkynylation of Unprotected
2-Vinylanilines
Lucien D. Caspers+,[a] Peter Finkbeiner+,[b] and Boris J. Nachtsheim*[a]
Abstract: Unprotected aromatic amines can be used as directing
first example we recently demonstrated that even unprotected
aromatic phenolic OH-groups can be utilized efficiently in such
transformations.[7a] In this article we want to demonstrate for the
first time, that unprotected aromatic amines can be used as
directing groups in C-H-activating alkynylation reactions very
groups in metal-catalyzed C-H alkynylations of alkenes. Using low
amounts
of
an
Ir(III)-catalyst
in
combination
with
alkynylbenziodoxolones as electrophilic alkyne transfer reagents,
highly desirable 1,3-enynes were isolated in excellent yields of up to
98% and Z-stereoselectivity. A broad substrate scope as well as the
high synthetic utility of the 1,3-enynes renders this novel method an
efficient approach for the synthesis of 5- and 6-membered
heterocycles. We particularly demonstrated further derivatizations of
the 1,3-enyne to highly substituted quinolines via gold(I)- and NBS-
mediated exo-dig cyclizations.
efficiently.
Amine-directed
alkenylations,[8]
arylations,[9]
allylations[10] and azidations[11] are known. Waser and co-workers
described a para-selective alkynylation of N-protected anilines.[12]
The challenge of using free amines in directed alkynylations
becomes clear when looking closer on alkenylations based on
internal alkynes. It has been shown that the nucleophilic amine
directly traps the C-H-inserted metallacycle to give 5- and 6-
membered N-heterocycles showing the non-innocent character of
amines in such transformations.[13]
Directing groups are essential for a high regioselectivity in metal-
catalyzed C-H activation. A potent directing group has a variety of
requirements to fulfill: It must be electron donating enough to
coordinate the transition metal and guide it into close proximity to
the C-H bond that should be modified. At the same time binding
of the directing group to the transition metal must be reversible
and should not deactivate the catalyst or interrupt the catalytic
cycle at any point. Ideally, the directing group should be of
synthetic value itself or it should be readily convertible to a useful
chemical functionality. Common directing groups which fulfill most
of those requirements include nitrogen-containing heterocycles,
imines, amides, carbamates or combinations thereof.[1] While
directing group-mediated arylations, alkenylations and alkylations
have been extensively investigated, directed C-H alkynylations
are less developed due to the low reactivity of common
electrophilic alkyne derivatives. Haloalkynes have proven to be
effective in directing-group-mediated reactions under C-H-
activating conditions.[2,3] In 2014 Chang, Glorius, Li and Loh
independently developed efficient directed alkynylations of
arenes and alkenes utilizing alkynylbenziodoxolones as stable
and reactive electrophilic alkyne transfer reagents.[4-6] These
initial reports were mostly based on common nitrogen-containing
directing groups which have found widespread use in C-H
activation before (Scheme 1 - a). Our group is interested in the
development of directed alkynylations of unactivated double
bonds based on challenging and unusual directing groups. In a
Scheme 1. Recent developments in directing group-mediated alkynylations of
[a]
Lucien D. Caspers, Prof. Dr. Boris J. Nachtsheim
Institut für Organische und Analytische Chemie
Universität Bremen
arenes and alkenes in relationoto this work.
Leobener Straße NW2C
D-28359 Bremen
nachtsheim@uni-bremen.de
Dr. Peter Finkbeiner
Department of Chemistry
University of California
Berkeley, California 94720
These authors contributed equally to this work
For our initial studies 2-(prop-1-en-2-yl)aniline 1a was used as the
free-amine containing substrate in combination with
benziodoxolone 3a (TIPS-EBX*) as alkyne transfer reagent. First
experiments using [RhCp*Cl2]2 did not result in significant
formation of the desired 1,3-enyne 2a. In sharp contrast to our
recently developed OH-directed alkynylation, only trace amounts
of 2a were observed with Rh(III)-based catalysts (data not shown).
[b]
[+]
Supporting information for this article is given via a link at the end of
the document
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This observation might indicate catalyst inhibition by the primary
acid.[14] This side reaction could be prevented by the additional
amine due to its strong electron donating character. Subsequently, ortho-CH3-substituent present in TIPS-EBX*. Although this
we investigated catalysts based on other group 9 metals. By using
[IrCp*Cl2]2 and AgOAc as additive, we were pleased to find
formation of (Z)-2a in 45% yield (Table 1, entry 1). Addition of
K2CO3 further improved the yield to 75% (Table 1, entry 2). In both
reactions neglectable amounts of (E)-2a were observed.
Substitution of the Lewis acid additive to Zn(OTf)2 improved
overall yield, however, significant amounts of (E)-2a (9%) were
isolated. Since formation of the E-stereoisomer can be observed
only after prolonged reaction times, its formation is likely the result
of an undesired isomerization reaction of initially formed (Z)-2a
(Table 1 – entry 3).
undesired catalyst deactivation is obviously not operational in this
Ir(III)-catalyzed alkynylation, we still observed an unusual high
reaction time of 72 h. Pfeffer and co-workers reported a higher
affinity of free amines to cycloiridated species compared to non-
cyclometallated Ir(III)-complexes.[15] Since these undesired
ligand-exchange processes either by the starting material or by
the reaction product might have a negative influence on the
reactivity of our in situ formed iridacycle, we investigated a variety
of phosphorus and nitrogen–containing heterocycles for an
improved catalyst regeneration. We were pleased to find that
addition of 5 mol% pyridine to the reaction mixture resulted in full
conversion of the starting material after a significantly reduced
reaction time (10 h). Furthermore, we found that the reaction can
be performed as efficient without the exclusion of air and moisture
(Table 1 – entries 7 and 8). In contrast, the use of pyridine in
stoichiometric amounts as both a Brønsted- and a regenerating
Lewis base additive resulted in a complete loss of reactivity (Table
1 – entry 9).
Table 1. Optimization of the reaction conditions.
With the optimized reaction conditions in hand we elaborated the
substrate scope of this transformation (Scheme 2). (Prop-1-en-2-
yl)-substituted anilines with different halogen substitution patterns
(4-Br, 4-Cl or 2,4-(Cl)2) reacted slower than the unsubstituted
substrate 1a. After 24 h full conversion of the starting materials
was observed giving the desired enynes 2b – 2d in high yields of
up to 90%. The more electron rich 5-methyl substituted derivative
2e was isolated in 88% yield after a slightly decreased reaction
time (20 h). It is worth mentioning, that products 2a – 2e were
exclusively isolated in the expected Z-configuration. In contrast,
an inseparable mixture of (Z)- and (E)-2f was obtained from
electron rich compound 1f. Other α-alkyl-substituted vinyl anilines
(R2 = ethyl, isopropyl and cyclohexyl) showed high reaction rates
giving 1,3-enynes 2g-2i in 85-91% yield. Next, a variety of α-aryl-
substituted vinyl anilines (R2 = aryl; 1j-1s were investigated. In all
cases reactivities were decreased significantly indicated by longer
reaction times (48-120 h). The isolated yields, however, were
throughout excellent giving 1,3-enynes 2j-2o in 86-97%
independent of the electronic nature of the substituents. Only the
3,5-(CF3)2-substituted derivative 2p was isolated in significantly
lower yield (64%). Very electron poor substrates 1q-s bearing
either a nitro functionality or a halogen substituent at each of the
aromatic rings reacted well giving the desired products 2q-s in
high yields (78-86%). For 2s the 1,3-enyne was again obtained
as an inseparable mixture of the Z- and the E-isomer (3:2).
Entry[a]
Additive
(mol%)
Base
(equiv.)
Iodane
t
[h]
Yield
(Z)-2a
((E)-2a)
[%][b]
1
AgOAc (10)
-
3a
3a
3a
3a
3a
3b
3b
3b
3b
72
72
72
72
72
72
10
10
72
45 (<1)
75 (<1)
71 (9)
2
AgOAc (10)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
KOAc (0.8)
KOAc (0.8)
KOAc (0.8)
KOAc (0.8)
Pyridine (0.8)
3
Zn(OTf)2 (10)
4
-
84 (8)
5
-
89 (<1)
90 (<1)
93 (<1)
93 (<1)
0 (0)
6
-
7
Pyridine
Pyridine
-
8[c]
9
[a] Reactions were conducted using 0.2 mmol of 1a and 0.24 mmol
benziodoxolone 3a or 3b in 2 ml of 1,2-dichloroethane (DCE). [b] Isolated
yields after column chromatography. Isomeric ratios were determined via
1H-NMR-spectroscopy. [c] Reaction was performed without exclusion of air
or moisture.
We then recognized that the reaction was higher yielding without
a Lewis acid additive and KOAc turned out to be a superior base
yielding (Z)-2a in 89% (Table 1 – entries 4 and 5). Substituting the
benziodoxolone to 3b (TIPS-EBX) resulted in similar yields (Table
1 – entry 6). In our previous studies TIPS-EBX* was found to be
superior in comparison to TIPS-EBX due to a potential C-H-
insertion of the Rh(III)-catalyst into the emerging 2-iodo benzoic
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Scheme 3. Gram scale synthesis of 1,3-enyne 2j.
1,3-Enynes are versatile structural motifs, not only as target
structures in optoelectronical devices,[16] but also as synthetic
intermediates for the synthesis of a variety of carbo- and
heterocycles.[16-19] To demonstrate the high synthetic value of the
obtained 1,3-enynes, we further investigated a variety of chemical
transformations with compound 2j as model substrate. Addition of
TBAF yielded the terminal unfunctionalized 1,3-enyne 4 in 98 %
yield. Protection as mesylamide followed by NBS-induced 6-exo-
dig bromocyclization resulted in formation of 2-(dibromomethyl)-
substituted quinoline 5 in 50 % overall yield. Copper(I)-catalyzed
[3+2]-cycloaddition with benzyl azide gave triazole
quantitative yields.
6 in
Scheme 2. Substrate scope. Reactions were performed at room temperature
with 0.20 mmol of 1, 0.24 mmol of 3b, 0.16 mmol KOAc, 2.5 mol% [IrCp*Cl2]2
and 5 mol% pyridine in 2 mL of 1,2-dichloroethane. [a] inseparable mixture.
To demonstrate the importance of the free amino group ortho to
the exocyclic double bond as a directing group, we also performed
the reaction with meta- and para-substituted anilines 1t and 1u.
In both cases, no product formation was observed (2t and 2u) and
the starting materials were almost completely recovered after
48 h. To prove the economic viability of our method, we performed
a gram scale alkynylation of 1j while simultaneously decreasing
catalyst loading to 1 mol% (Scheme 3). Even though a notably
prolonged reaction time was observed (8 d) the product 2j was
isolated in excellent yield of 91%.
Scheme 4. Further derivatizations of 1,3-enynes. [4c, 7a, 20]
A terminal phenyl group could be introduced via Sonogashira-
coupling to yield enyne in 69% yield. No concurring
7
intramolecular cyclization reaction was observed between the
1,3-enyne and the free amine. Such a transformation could be
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triggered by treatment of 2j with an Au(I)-catalyst.[20] Under these
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quinoline 8 in 77% yield. In situ conversion of the free amine into
the azide via Sandmeyer-reaction directly results in an
intramolecular [3+2]-cycloaddition to give the multisubstituted
triazolo[1,5-a]quinoline 9 in an highly effective manner 89% yield.
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In summary we have developed
a unique NH2-directed
alkynylation of a sp2-hybridized C-H-bond. This novel method
gives direct access to 1,3-enyne-substituted anilines in excellent
Z-stereoselectivity. As demonstrated the free amine can not only
be used as a directing group but can also be used as a functional
group in a plethora of further synthetic modifications. In particular,
syntheses of highly substituted quinolines through 6-exo-dig
cyclizations were achieved under a variety of conditions. In future
developments we want to focus our studies on the partially
observed isomerization of the exocyclic double bond. A controlled
one-pot procedure that would involve an effective in situ Z to E-
isomerization would give direct access to the otherwise difficult to
obtain E-isomer through the same mode of activation.
Furthermore, deeper mechanistic investigations are underway.
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Acknowledgements
We thank the DFG (NA 955/1-1), the Fonds der Chemischen
Industrie (Sachkostenzuschuss) and the Carl-Zeiss-Stiftung
(PhD-scholarship for PF) for financial support. We further like to
thank Prof. Christina Nevado (University of Zürich) for helpful
discussions during ICHIC 2016 in Les Diablerets.
Keywords: C-H activation • alkynes • iridium • iodine • enynes
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10.1002/chem.201606026
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Lucien D. Caspers+,[a] Peter
Finkbeiner+,[b] and Boris J.
Nachtsheim*[a]
Page No. – Page No.
Direct Electrophilic C-H Alkynylation of
Unprotected 2-Vinylanilines
Text for Table of Contents
A swiss knife that isn’t sharp Free amines can be used as directing groups in C-H activating
alkynylation reactions. The free amine in 2-vinylanilines can act as a Lewis-base to guide an Ir(III)-
catalyst to the exocyclic double bond to generate highly useful 1,3-enynes with excellent Z-
regioselectivity after further reaction with alkynylbenziodoxolones.
[a]
Lucien D. Caspers, Prof. Dr. Boris J. Nachtsheim
Institut für Organische und Analytische Chemie
Universität Bremen
Leobener Straße NW2C
This article is protected by copyright. All rights reserved.