A General Acid-Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes

Article abstract of DOI:10.1002/anie.201906910

In comparison to the extensively studied metal-catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State-of-the-art protocols for hydroaminomethylation of alkenes rely largely on transition-metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid-mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench-stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.

Full text of DOI:10.1002/anie.201906910

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International Edition: DOI: 10.1002/anie.201906910
German Edition: DOI: 10.1002/ange.201906910
Hydroaminomethylation
A General Acid-Mediated Hydroaminomethylation of Unactivated
Alkenes and Alkynes
Daniel Kaiser+, Veronica Tona+, Carlos R. GonÅalves+, Saad Shaaban, Alberto Oppedisano, and
Nuno Maulide*
Abstract: In comparison to the extensively studied metal-
catalyzed hydroamination reaction, hydroaminomethylation
has received significantly less attention despite its considerable
potential to streamline amine synthesis. State-of-the-art proto-
cols for hydroaminomethylation of alkenes rely largely on
transition-metal catalysis, enabling this transformation only
under highly designed and controlled conditions. Here we
report a broadly applicable, acid-mediated approach to the
hydroaminomethylation of unactivated alkenes and alkynes.
This methodology employs cheap, readily available, and
bench-stable reactants and affords the desired amines with
excellent functional group tolerance and impeccable regiose-
lectivity. The broad scope of this transformation, as well as
mechanistic investigations and in situ domino functionaliza-
tion reactions are reported.
A
mines are key structural moieties in pharmaceuticals,
agrochemicals, natural products, and materials. Probably the
3
À
most powerful approach for the formation of C(sp ) N bonds,
apart from classical SN2 reactions, is the direct addition of
nitrogen-containing fragments to olefins.[1] While, in this
regard, the direct metal-catalyzed hydroamination of alkenes
has been extensively studied,[2] hydroaminomethylation, the
addition of a hydrogen and a (methyleneamino) unit across an
olefin, is often overlooked.[3] Traditional methods to effect net
hydroaminomethylation involve the two-step sequence of
alkene hydroformylation followed by reductive amination
(Scheme 1, A).[4] More recently, several metal-catalyzed
direct hydroaminoalkylation reactions of alkenes have been
reported that employ simple alkylamines as the starting
materials (Scheme 1, B).[5] These approaches, dominated by
early transition-metal catalysts, have shown some restrictions,
in part as a consequence of the thermodynamically challeng-
À
ing C H activation step a to secondary amines and of the
traditional incompatibility of early transition metals with
Scheme 1. Previous approaches to hydroaminomethylation and devel-
opment of a metal-free general hydroaminomethylation of alkenes and
alkynes.
[*] Dr. D. Kaiser,[+] Dr. V. Tona,[+] C. R. GonÅalves,[+] Dr. S. Shaaban,
Dr. A. Oppedisano, Prof. Dr. N. Maulide
University of Vienna, Institute of Organic Chemistry
Währinger Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
oxygen functional groups (with only few notable exception-
s[5a,b]). Attempts to move towards late-transition-metal catal-
ysis typically rely on the use of directing groups.[6] An elegant
exception to this requirement is the ruthenium-catalyzed
hydroaminoalkylation of dienes and allenes developed by
Krische and co-workers (not shown).[7] Recent studies have
harnessed photoredox catalysis,[8] or dual catalysis[9]
(Scheme 1, C): However, while displaying impressive func-
tional group tolerance and mild reaction conditions, such
approaches remain limited to conjugated olefins or otherwise
electronically activated alkenes.[7,8]
[+] These authors contributed equally to this work
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201906910.
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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Challenges commonly associated with metal-catalyzed
hydroaminomethylation range from the control of regiose-
lectivity and the threat of double functionalization to the
development of conditions that allow the functionalization of
alkynes. Seeking to address these challenges, we became
interested in the development of a hydroaminomethylation
protocol using iminium ions. This transformation was envi-
sioned to proceed by an entirely different mechanism, thus
circumventing the need for transition-metal catalysis. Mayr
and co-workers have shown that iminium ions paired with
noncoordinating anions can be employed for hydroamino-
methylation of highly activated p-systems (Scheme 1, D).[10]
Cohen and Onopchenko investigated the in situ formation of
iminium ions by treating bis(dimethylamino)methane with
a Brønsted acid (Scheme 1, E).[11] The reaction of simple
alkenes under these conditions resulted in a mixture of
aliphatic secondary and allylic tertiary amines formed
through competing hydride transfer and ene reaction.[12–14]
Similar reactivity was observed serendipitously during Heath-
cock and co-workersꢀ synthesis of methyl homosecodaphni-
phyllate,[15] as well as by Manninen and co-workers, who
reported reactions of iminium ions with norbornene deriva-
tives, obtaining mixtures of products in most cases.[16] Hoping
to develop a more general approach, we designed a system
able to suppress competing elimination which would result in
undesired alkene formation. In our synthetic plan, the
nucleophilic addition of a p-system onto an iminium ion (I)
would trigger an internal redox event by 1,5-hydride transfer
to the resulting carbenium ion of intermediate II, affording
the desired hydroaminomethylated products (III) or products
of direct functionalization with nucleophiles (IV) (Scheme 1,
F).[17]
no)methane (2a), derivatives of which are common reagents
in transition-metal catalysis.[7a,c,18] When trifluoroacetic acid
(TFA) was employed at slightly elevated temperatures (see
the Supporting Information for details on optimization), the
desired secondary amine product was isolated in high yield
after aqueous, hydrolytic workup (Scheme 3, Method B).
While the precise reasons for the increased selectivity
observed when using this solvent remain unclear, we suspect
the solvating properties of TFA, as well as the low nucleo-
philicity and low basicity of the corresponding conjugate base,
to play important roles in dictating the reaction outcome by
facilitating the hydride transfer event.[19] Using these con-
ditions, a wide range of aminals and alkenes were found to be
suitable reactants in this novel hydroaminomethylation pro-
tocol (Scheme 3). Initially focusing on substitution at nitro-
gen, we observed the formation of a range of secondary
amines in high yields (3a–f, 73–92% yield) starting from
several readily available aminals. Particularly appealing is the
possibility of obtaining benzylated or allylated amines (3e,
3 f), ripe for easy deprotection and downstream functional-
ization (4 f). The formation of 3e is complementary to
transition-metal catalysis, where the use of benzylamines
tends to lead to branched products resulting from activation
[5b,e]
À
of the benzylic C H bond,
and which thus relies most
commonly on less flexible N-aryl substrates (and products).
With respect to the olefinic substrates, a wide variety of
substitution patterns were accommodated by our protocol,
including unactivated linear, branched, and cyclic alkenes
(3g–l, 36–91% yield). It is worth mentioning that all linear
and cyclic alkenes provided only a single isolable product,
while the reaction of a branched alkene showed the occur-
rence of an ene-reaction-derived side product, leading to
a diminished yield of 3h. Styrenes also proved to be viable
partners for this transformation, providing the products of
hydroaminomethylation in good to excellent yields (3m–u,
39–86% yield, up to 50 mmol scale). As shown by 3t, the
effect of the double-bond geometry is negligible, as the amine
was isolated in good yield starting from either stereoisomer.
More telling, however, are the results of a functional-group
tolerance study: an unusually broad range of polar moieties is
tolerated by this protocol, including esters, phosphonates,
amides, nitriles and halides (3v–3aa, 40–93% yield). Remark-
ably, an alkene containing a free alcohol also proved to be
a viable substrate for this transformation, affording the
corresponding product in 82% yield (3ab). This stands in
strong contrast with the early-transition-metal-catalyzed
procedures that are state of the art in hydroaminomethyla-
tion: the oxophilicity of the catalysts employed is difficult to
reconcile with a free alcohol. Even more striking is the
successful hydroaminomethylation of amine-containing sub-
strates under our conditions (3ac and 3ad, 60% and 75%
yield), as free amine functionalities generally lie beyond the
scope of state-of-the-art direct hydroaminomethylation
through metal- and photoredox-catalytic procedures.[8,9] Fur-
thermore, it is worth noting that complete selectivity for the
linear (vs. branched) products is observed throughout. Having
explored the performance of this approach with alkenes, we
became interested in the possibility of achieving the hydro-
aminomethylation of alkynes. Pleasingly, our protocol enables
At the outset, we hypothesized that the use of Eschen-
moserꢀs salt (N,N-dimethylmethylideneammonium iodide) or
derivatives thereof would be amenable to realizing the plan
outlined in Scheme 1. While we were pleased to find that the
treatment of styrene with Eschenmoserꢀs salt led to the
formation of amine 3m in up to quantitative yield (Method
A), we soon became aware of limitations in the reaction scope
accessible with this class of reagents (see Scheme 2 and the
Supporting Information for further information).
We therefore turned to alternative iminium ion precursors
such as the commercially available aminal bis(dimethylami-
Scheme 2. Eschenmoser’s salt enabled initial success. Reactions were
run on 0.5 mmol scale. Yields refer to isolated material after purifica-
tion. *: Yield determined by 1H NMR analysis using an internal
standard. † : Eschenmoser’s chloride was employed. HFIP=1,1,1,3,3,3-
hexafluoro-2-propanol.
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Scheme 3. Reaction development and scope of the hydroaminomethylation reaction. Reactions were run on 0.5 mmol scale. Yields refer to
isolated material after purification. +: Yield after acylative protection with Boc2O to facilitate isolation. **: DCE used as co-solvent. Æ: Reaction was
run for 5 h. °: Reaction was run at room temperature. See Supporting Information for details.
this reaction with no trace of double hydroaminomethylation.
In this context, we were delighted to find that terminal
alkynes afforded the secondary allylic amines 6a and 6b in
good yields exclusively as the E-stereoisomers, as a conse-
quence of the syn-nature of the hydride transfer. The reaction
proceeded selectively even in the presence of an additional
alkene (6c, 68% yield) or a cyclopropane moiety (6d, 85%
yield). Importantly, owing to the formation of the most stable
carbocationic intermediate, the use of internal alkynes leads
to single isomeric trisubstituted alkene products (6e and 6j,
The iminium ion V, ultimately resulting from the pivotal
1,5-hydride shift, can be easily engaged in domino function-
alization processes (Scheme 4). The addition of simple
ketones to the acidic reaction mixture results in the formation
of trisubstituted amines in good yields via Mannich reaction
(7a–g, 52–71% yield), whereas capture with an electron-rich
arene via Friedel–Crafts reaction delivers a tertiary benzylic
amine product (7h, 54% yield). Furthermore, employing
Method A, we were able to perform domino hydroamino-
methylation–functionalization reactions using hydridic reduc-
41% and 48% yield). As before, aryl substitution (6 f–j, 31– tants (7i, 74% yield) and organozinc nucleophiles (7j and 7k,
57% yield) and a range of functional groups were tolerated
(6k–m, 41–97% yield), including a propargyl silane (6n).
These results establish our procedure for hydroaminomethy-
lation as a simple synthesis of stereodefined di- and trisub-
stituted allylic amines.
66% and 63% yield, respectively) that are incompatible with
more acidic conditions.
The presented method also enables a straightforward and
unusual disconnection towards bioactive amines such as the
broad-spectrum antimycotic Naftifine (8) (Scheme 5),[20]
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higher for styrene (Scheme 6, B). This result suggests that,
while the hydride transfer event is not rate-determining, it has
a higher relative contribution to the reaction rate in the case
of the more electron-rich, and therefore more reactive,
styrene substrate.[21] Moreover, it is likely that the relative
increase in stabilization of the benzylic cation contributes to
the higher KH/KD observed for styrene.
In conclusion, we have developed an acid-mediated
hydroaminomethylation of unactivated alkenes and alkynes.
The methodology displays an unconventionally broad func-
tional group tolerance and allows the synthesis of secondary
and, after nucleophilic quenching, tertiary amines. Given the
natural abundance of both alkenes and alkynes, we anticipate
that this practical, cheap, and direct amination will find broad
application in synthetic chemistry and feedstock-chemical
processing alike.
Acknowledgements
We thank the ERC (CoG VINCAT), FWF (P 30226),
Austrian Academy of Sciences (DOC fellowship to D.K.)
and the University of Vienna for financial support. The
fundamental expertise of the NMR and the mass spectrom-
etry departments of the University of Vienna is acknowl-
edged.
À
À
Scheme 4. Domino C C and C H bond formation. Reactions were run
on 0.2 mmol scale. Yields refer to isolated material after purification.
Conflict of interest
Scheme 5. Concise synthesis of Naftifine (8).
N.M. and co-workers own a patent on the hydroaminome-
thylation process (Pct/EP2019/062867).
accessible in a simple two-step sequence from phenylacety-
lene.
Keywords: amines ·hydroaminoalkylation ·
Additional observations provide support for the mecha-
nism proposed above and showcase interesting features of the
system at hand (Scheme 6). As expected, the use of perdeu-
terated bis(dimethylamino)methane (2a-d12) led to regiose-
lective and complete deuterium incorporation, confirming an
intramolecular hydride transfer event (9a, Scheme 6, A).
Additionally, treatment of both styrene (1m) and aliphatic
olefin 1a with the isotopically mixed aminal (2b-d18) show-
cases a kinetic isotope effect (KH/KD), shown to be slightly
hydroaminomethylation
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Angew. Chem. 2019, 131, 14781–14785
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Revised manuscript received: July 27, 2019
Version of record online: September 4, 2019
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