A Photocatalytic Regioselective Direct Hydroaminoalkylation of Aryl-Substituted Alkenes with Amines

Article abstract of DOI:10.1021/acs.orglett.1c01715

A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addition of α-aminoalkyl radicals generated from aniline derivatives or aliphatic amines to the α-position of unsaturated esters. The scope of aromatic alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the aromatic group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method.

Full text of DOI:10.1021/acs.orglett.1c01715

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Letter
A Photocatalytic Regioselective Direct Hydroaminoalkylation of
Aryl-Substituted Alkenes with Amines
Natalia A. Larionova, Jun Miyatake Ondozabal, Emily G. Smith, and Xacobe C. Cambeiro*
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ABSTRACT: A photocatalytic method for the α-selective hydro-
aminoalkylation of cinnamate esters has been developed. The
reaction involves the regioselective addition of α-aminoalkyl
radicals generated from aniline derivatives or aliphatic amines to
the α-position of unsaturated esters. The scope of aromatic alkenes
was extended to styrenes undergoing hydroaminoalkylation with
anti-Markovnikov selectivity, which confirms the importance of the
aromatic group at the β-position. Simple scale-up is demonstrated
under continuous flow conditions, highlighting the practicality of
the method.
hotocatalytic hydroaminoalkylation of electron-poor
1,2
Palkenes has been developed throughout the past decade
taking advantage of the nucleophilic character of α-aminoalkyl
radicals.3 Thus, radicals generated by visible light photo-
oxidation of tertiary amines4 have been shown to engage in
conjugate addition with a variety of Michael acceptors such as
maleimides,5 alkylidene malonates and malononitriles,6 α,β-
unsaturated carbonyl compounds,7 amides8 and esters,9 as well
as alkenylpyridine derivatives.10 In addition, photocatalytic
conjugate additions11 have been described with α-aminoalkyl
radicals generated by different methods, such as oxidative
desilylation12 or decarboxylation,13 among others.14
These transformations proceed generally with high regiose-
lectivity for the β-position with respect to the electron-
withdrawing group (EWG) (Figure 1a), consistent with an
early transition state governed by the SOMO-LUMO
interaction. As a remarkable exception, Sparling observed α-
selectivity in a photocatalytic decarboxylative radical addition
to β-aryl α,β-unsaturated amides (Figure 1b).15 The unusual
selectivity in this case was attributed to a reversible radical
addition, giving place under thermodynamic control to the
more stable benzylic radical. However, this method was limited
to decarboxylative generation of the α-aminoalkyl radical from
α-amino acid substrates, which required a strongly oxidizing
catalyst for decarboxylation.16
Figure 1. Summary of hydroaminoalkylation of electron-poor alkenes
and related transformations.
amines have been reported, based on Mannich-type reactions
of photocatalytically generated iminium ions with silyl enol
ethers18 or with enamines generated in situ using enamine
A method for the direct α-selective aminoalkylation of α,β-
unsaturated carboxylic acid derivatives would provide a
practical, straightforward route for the preparation of β-
amino acids, potentially enabling access to substitution
patterns (β2 and β2,3) which are not easily accessible through
more established routes.17 Alternative photocatalytic methods
for the preparation of β-amino carbonyl compounds from
Received: May 21, 2021
Published: July 1, 2021
https://doi.org/10.1021/acs.orglett.1c01715
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5383−5388
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a
Scheme 1. Hydroaminomethylation of Electron-Poor Alkenes (1) with N,N-Dimethylaniline (2a)
a
Reactions carried out with 1 (0.2 mmol), 2a (1.5 equiv), [Ir(ppy)2(dtbbpy)]PF6 (1 mol %), and Cs2CO3 (20 mol %) in MeCN (2 mL), under
blue light irradiation for 16 h while controlling the temperature at 25 °C. Yields are of isolated product unless otherwise noted. Numbers in
b
c
brackets are α to β ratio determined by 1H NMR of the crude reaction mixture. The ethyl ester was used in this case instead of methyl. Starting
material was the Z-alkene. Yield determined by H NMR using an internal standard.
d
1
catalysis (Figure 1b).19 However, these methods are limited to
tetrahydroisoquinoline derivatives as the amine partner. A
similar strategy for α-olefination of amines is similarly
restricted to tetrahydroisoquinoline and tetrahydro-β-carbo-
lines.20
In contrast with the well-established Giese-type addition to
electron-poor alkenes, efficient photocatalytic hydroaminoal-
kylation of less polarized alkenes has not been reported to
date.21 This is possibly a consequence of poor chemoselectivity
in the absence of a good matching of the nucleophilic radical
with an electrophilic alkene, giving place to polymerization
side-reactions.22
During our recent investigation on photocatalytic transfer
hydrogenation of cinnamate derivatives we found a kinetic
preference for attack at the α-position in a H atom transfer
from a Hantzsch ester radical cation to the alkene.23 Here we
report a photocatalytic method for the α-selective hydro-
aminoalkylation of cinnamate esters based on the regioselective
addition of α-aminoalkyl radicals, where the reaction is
controlled by the presence of an aromatic group at the β-
position. Moreover, our method is valid for the direct
hydroaminoalkylation of styrenes, which proceeds with high
anti-Markovnikov selectivity (Figure 1c).
Irradiation with blue light of a MeCN solution of cinnamate
ester 1a and dimethylaniline 2a (1.5 equiv) in the presence of
photocatalyst [Ir(ppy)2(dtbbpy)]PF6 (1 mol %) and Cs2CO3
(20 mol %) resulted in quantitative formation of β-amino ester
3aa and its γ-isomer in a 3:1 ratio (Scheme 1), reflecting a
preference for α-addition of the aminoalkyl radical. The use of
the organic, soluble base DBU provided results comparable to
Cs2CO3, as did the use of increased loadings of base. Other
modifications to the reaction conditions resulted generally in
decreased yields (see Supporting Information (SI) section 1.4
for additional details).
To determine the scope of the reaction we first applied it to
a range of cinnamate derivatives (Scheme 1). We probed the
effect of introducing an electron-donating or electron-with-
drawing substituent on the different positions of the aryl ring.
Namely, OMe and CF3 were well tolerated in all cases, leading
to good yields of products 3ba−da and 3ea−ga, respectively.
Although the α-substitution product was favored in all cases,
CF3-substituted substrates led to significantly increased
regioselectivities. In both cases the position of substitution
had no apparent effect on the reaction, suggesting that steric
hindrance was not very relevant. Consistently, ortho-Me-
substituted product 3ha was also readily formed. F, Cl, and Br
were tolerated as well and led to increased regioselectivities
compared to 3aa. These halogen substituents provide useful
handles for further functionalization of the products through
metal-catalyzed cross-couplings or photocatalytic transforma-
tions.24 Similarly, the reaction was compatible with the
presence of several functional groups such as acetal-protected
aldehyde (3na), benzylic alcohol (3oa), tertiary (3pa), and
even secondary amine (3qa). Finally, the reaction worked in
the presence of a dimethylallyl or an allyloxy substituent,
leading to formation of products 3ra and 3sa (starting from the
Z-cinnamate) with no detectable reaction on the allyl groups.
This suggests that the radical formed after addition rapidly
reacts further to provide compound 3.25
Cinnamonitrile was also a valid substrate for the reaction,
although the corresponding product 3ta was obtained with
very poor regioselectivity against its β-addition analogue
(1.3:1). Product 3ua, conversely, was obtained with complete
regioselectivity from the corresponding tetrasubstituted alkene.
A cyclic α,β-unsaturated ester, coumarin, was transformed to
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3va regioselectively albeit in very low yield (10%), and 2-
styrylpyridine gave 3wa in low yield and selectivity, with a
slight preference for the β-addition product (28%, 1:1.6).
Finally, an α,β-unsaturated ester bearing only an aliphatic
substituent reacted to give exclusively the β-addition product
3xa′. More electron-poor substrates such as ketones (e.g.,
3ya′), although generally compatible with the reaction, tended
to give β-addition as the major product.
Scheme 3. Hydroaminomethylation of Styrene Derivatives
(4) with N,N-Dimethylaniline (2a)
a
Scheme 2. Hydroaminomethylation of Methyl Cinnamate
(1a) with Amines (2) (Reaction Conditions Same as in
Scheme 1; [Ir]+ = [Ir(ppy)2(dtbbpy)]PF6)
a
Reactions carried out with 4 (0.2 mmol), 2a (2 equiv),
[Ir(ppy)2(dtbbpy)]PF6 (1 mol %), and Cs2CO3 (20 mol %) in
MeCN (8 mL), under blue light irradiation for 24 h while controlling
the temperature at 25 °C. Yields are of isolated product. [Ir]+
=
b
[Ir(ppy)2(dtbbpy)]PF6. Yield determined by 1H NMR using an
internal standard.
anti-Markovnikov regioselectivity.27 Similarly, 1,1-diphenyle-
thene provided product 5j in 77% yield. β-Methylstyrene
reacted with the same selectivity but providing a very poor
yield of 5k. It is worth noting that, while these examples show
that an electron-withdrawing group directly bound to the
alkene was not necessary, high electron density was still
detrimental to the reaction: Thus, p-aminostyrene did not react
and p-methoxystyrene provided only low yields of the product
(5l, 5m). A m-methoxy substituent, having an overall electron-
withdrawing effect (Hammet σm = +0.115 vs. σp = −0.268),
provided 5n in 70% yield.
The simple conditions employed allowed for the straightfor-
ward translation into a readily scalable continuous flow
method. Thus, a MeCN solution of alkene, amine, and catalyst
containing 20 mol % of DBU was pumped through a coil of
PTFE tube which was irradiated with blue LEDs. The collected
solution, after workup and purification, afforded the corre-
sponding β-amino ester product. This method was applied,
with excellent results, to the preparation of compounds 3aa,
3ae, and 3ag (Scheme 4).
A plausible mechanism for the reaction (Figure 2) would
involve reductive quenching of the excited catalyst (E° Ir/*Ir+
= 0.76 V) by amine 2 (E° 2+/2 = 0.71 V) followed by
deprotonation to form and aminoalkyl radical B,28,29 which
would then add across the alkene substrate (1 or 4) double
bond. Reduction of the resulting benzylic radical Cα followed
by protonation would lead to product 3 or 5. Control
experiments supported the formation of the α-aminoalkyl
radical under our reaction conditions, promoted by the
presence of Cs2CO3 (Figure S3, SI). Also, deuteration at the
benzylic position was observed when the reaction was
performed in the presence of D2O (Figure S4).
a
b
0.2 mmol of 2 and 3 equiv of 1a were used. Product was obtained
c
as a mixture of diastereoisomers (see SI). Product was obtained as a
7:1 mixture of regioisomers. Characterized as mixture of α/β.
d
Then, we explored the reactivity of different amines
(Scheme 2). The reaction proceeds well with a variety of
substituted dimethylaniline derivatives (3ab to 3ae) as well as
with methyldiphenylamine (3af). N-Phenylpyrrolidine and
N,N-diethylaniline provided products 3ag and 3ah in excellent
yields and regioselectivities, although with poor diastereose-
lectivity. Similar to the above-mentioned observations for
products 3ra and 3sa, an alkene-substituted diphenylamine
derivative resulted in formation of product 3ai with no
cyclization of the pendant terminal alkene. Nonsymmetrically
substituted anilines tended to react at the position leading to
the least stable radical. Thus, N-ethyl-N-methylaniline gave 3aj
as the major product, while N-methyl-N-isopropylaniline and
N-methyl-N-benzylaniline gave 3ak and 3al, with no reaction
observed at the isopropyl and benzyl substituents, respectively.
Remarkably, the reaction was not limited to aniline derivatives:
products 3am and 3an were readily obtained from their parent
amines in good yields and selectivities. This opens the way for
the application of the present reaction to more diverse and
useful products; however, further optimization is still needed
to extend the scope to diverse aliphatic amines.26
Finally, we explored the reactivity under our conditions of
styrene derivatives, not bearing the electron-withdrawing group
on the alkene (Scheme 3). Both styrene and a range of
substituted derivatives reacted smoothly with N,N-dimethyla-
niline to give the corresponding hydroaminomethylation
products 5a−i in good yields (54 to 81%) and with complete
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observations, combined with the absence of cyclization
products in the reactions leading to compounds 3ra, 3sa,
and 3ai, provide support for kinetic control of the
regioselectivity rather than a reversible radical addition under
thermodynamic control. It is likely that this observation may
extend to other radical additions to moderately electron-poor
alkenes.
Scheme 4. Continuous-Flow Production of β-Amino Esters
In conclusion, the methodology presented allows the
hydroaminoalkylation of a wide variety of moderately
electron-poor alkenes, including styrene derivatives, with
aniline derivatives as well as aliphatic amines. Besides, the
method is readily scalable under continuous flow conditions.
Computational data suggest that the reaction is driven by the
presence of the aromatic substituent, which controls reactivity
and regioselectivity. An accurate balance between the aromatic
substituent and the electron-withdrawing group is necessary
for selectivity, with stronger EWGs leading to Giese-type
addition, which will be of importance for the development of
related regioselective methodologies further expanding the
scope of these transformations.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01715.
Further details on reaction optimization, character-
ization of all new compounds, and copies of NMR
spectra (PDF)
Figure 2. Plausible mechanism for the hydroaminoalkylation.
AUTHOR INFORMATION
Corresponding Author
■
Xacobe C. Cambeiro − School of Science, University of
Greenwich, Chatham Maritime ME4 4TB, United Kingdom;
Department of Chemistry, School of Biological and Chemical
Sciences, Queen Mary University of London, London E1 4NS,
United Kingdom; orcid.org/0000-0002-7365-7201;
Email: x.cambeiro@gre.ac.uk
Authors
Natalia A. Larionova − Department of Chemistry, School of
Biological and Chemical Sciences, Queen Mary University of
London, London E1 4NS, United Kingdom; orcid.org/
0000-0003-4668-6717
Jun Miyatake Ondozabal − Department of Chemistry, School
of Biological and Chemical Sciences, Queen Mary University
of London, London E1 4NS, United Kingdom
Emily G. Smith − Department of Chemistry, School of
Biological and Chemical Sciences, Queen Mary University of
London, London E1 4NS, United Kingdom
Figure 3. DFT-calculated energy profile for the radical addition
[PBE0-GD3/6-31+G(d,p), ΔG: Gibbs free energies in solution
(SMD model for MeCN) relative to sum of separate reagents
reported in kcal/mol]. E°: Calculated reduction potentials vs SCE
reported in V.
DFT calculations (PBE0-GD3/6-31+G(d,p), SMD model
for MeCN, Figure 3) were consistent with our mechanistic
hypothesis: Transition states for the radical addition at
positions α and β were both energetically accessible, with
addition at α favored by 1.0 kcal/mol, a small but significant
difference consistent with the observed regioselectivity.
Furthermore, the radical addition step was exergonic by
−10.2 and −5.2 kcal/mol, respectively, for the α and β
additions, and the calculated reduction potentials of the
resulting benzylic or enol radical (−1.47 and −0.94 V) indicate
an easy reduction to the corresponding anions by the reduced
form of the catalyst (E° = −1.51 V vs SCE).28 These
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01715
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Queen Mary University of London for
partially funding this research. N.A.L. thanks the European
Commission for an MSCA fellowship (Project LIONCAT,
799664). J.M.O. thanks QMUL for a PhD scholarship.
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Alkenes and the Formal Conversion of Methylamine. Angew. Chem.,
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hydroaminomethylation using formaldehyde aminals as starting
material, see: (b) Kaiser, D.; Tona, V.; Goncalves, C. R.; Shaaban,
S.; Oppedisano, A.; Maulide, N. A General Acid-Mediated Hydro-
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(24) Iodine-substituted substrates provided complex mixtures with
only low yield of the hydroaminoalkylation product.
(25) Newcomb, M. Radical Kinetics and Clocks. In Encyclopedia of
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(26) For example, N-methylpyrrolidine and N-methylpiperidine
both reacted with good conversions to give mixtures of regio- and
diastereomeric hydroaminoalkylation products.
(27) The only detected byproducts were double alkylation of the
amine with two units of the alkene, and a dehydrogenated derivative
of product 5.
(28) This process is well-precedented; see for example: Prier, C. K.;
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