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Cite this: Chem. Commun., 2016,
52, 3520

Brønsted acid-catalysed conjugate addition of
photochemically generated a-amino radicals to
alkenylpyridines†

Received 18th December 2015,
Accepted 29th January 2016

Hamish B. Hepburna and Paolo Melchiorre*ab

DOI: 10.1039/c5cc10401g
www.rsc.org/chemcomm

The conjugate addition of a-amino radicals to alkenylpyridines has
been accomplished by the synergistic merger of Brønsted acid and
visible light photoredox catalysis. Key to reaction development was
the protonation of the alkenylpyridines that transiently generated a
highly reactive, electrophilic pseudo-iminium ion intermediate. Initial
investigations using chiral phosphoric acids provide clues on the
feasibility of an enantioselective catalytic variant.

Nitrogen-containing six-membered heterocycles, such as pyridines,
are essential structural motifs found in an array of pharmaceuticals,
agrochemicals, and natural products.1 This explains why synthetic
methods that facilitate the construction of structurally complex
pyridine-containing molecules are highly sought after. Although
the direct functionalisation of the heterocyclic ring continues to
be the main approach,2 synthetic strategies that feature functionalisation at a remote position have also garnered attention.3 In
particular, alkenylpyridines 1 have long been known as good
Michael acceptors,4 since the embedded CQN imine functionality
can act in analogy to a carbonyl compound, facilitating nucleophilic attack at the b-position. The vast majority of these reactions
involve 2-vinylpyridine (R = H in 1, Scheme 1), as the introduction
of a b-substituent substantially reduces the reactivity of 1. Recently,
transition metal catalysis has been identified as a suitable activation

Scheme 1 Our proposed Brønsted acid-mediated LUMO-lowering activation strategy.

a

ICIQ – Institute of Chemical Research of Catalonia, The Barcelona Institute of
¨sos Catalans 16, 43007 Tarragona, Spain.
Science and Technology, Av. Paı
E-mail: pmelchiorre@iciq.es
b
ICREA – Catalan Institution for Research and Advanced Studies,
´
Pg. Lluıs Companys 23, 08010 Barcelona, Spain
† Electronic supplementary information (ESI) available. CCDC 1450243. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc10401g

3520 | Chem. Commun., 2016, 52, 3520--3523

strategy for promoting the conjugate addition of carbon-centred
nucleophiles to b-substituted alkenylpyridines.5
Given our interest in the field of organocatalysis,6 we were
aware of the power of iminium ion activation for facilitating
conjugate additions.7 We wondered if this activation strategy,
which is classically applied to a,b-unsaturated aldehydes and
ketones, could be further expanded to include alkenylpyridines 1.
We reasoned that the protonation of the basic pyridine nitrogen
in 1 with a Brønsted acid would result in the embedded CQN
imine functioning as a pseudo iminium ion, thus reducing the
energy of the LUMO orbital at the b-carbon atom while facilitating
a metal-free conjugate addition (Scheme 1). While Brønsted acids
have been used to activate pyridines toward the reduction of the
aromatic ring,8 to the best of our knowledge their use to activate
alkenylpyridines towards nucleophilic addition has not been
reported so far.9 Herein, we detail the realisation of this strategy.
The emerging field of light-mediated photoredox catalysis10 had
recently provided an effective way of generating radical intermediates from readily available, bench-stable precursors and under
mild conditions. Using this photoredox strategy, the addition of
nucleophilic open-shell species to simple 2-vinylpyridine have been
recently reported.11 However, there have been no reports describing
the addition of such photochemically-generated radicals to substituted alkenylpyridines 1. We sought to combine this effective
radical generation strategy with Brønsted acid catalysis to develop
a radical conjugate addition to alkenylpyridines.
To test the feasibility of our hypothesis, we investigated the
ability of a variety of Brønsted acids (10 mol%) to catalyse
the light-initiated conjugate addition of dimethylaniline12 2a to
(E)-2-(p-tolylstyryl)pyridine 1a. We used the commercially available photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (A) which, upon
absorption of visible light, can generate nucleophilic a-amino
radicals directly from aniline 2a via single electron transfer
(SET) oxidation.12 The experiments were conducted over 14 hours
in toluene and under irradiation by a strip of blue light-emitting
diodes (blue LEDs strip, lmax = 465 nm).
In the absence of any Brønsted acid, only 9% of the radical
conjugate addition product 3a was observed after 14 hours,

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Table 1

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Screening of Brønsted acid catalystsa

Entry

Brensted acid

Yieldb (%)

1
2
3
4
5
6
7
8
9

None
PPTS
Benzoic acid
(PhO)2PO2H
(PhO)2PO2H
TFA
pTSA
CSA
(PhO)2PO2H

9
13
31
82
82c
65
34
9
o5d

a
Reaction ran for 14 hours on 0.05 mmol scale of 1, using 1.2 equiv. of
amine 2a, 2 mol% photocatalyst A and 10 mol% of Brønsted acid, under
irridation by a blue LEDs strip (lmax = 465 nm). b Determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as an internal standard. c Performed
using 5 mol% of acid and 1 mol% of A. d Performed in the absence of A or
light illumination. PPTS = pyridinium p-toluenesulfonate; (PhO)2PO2H =
diphenylphosphoric acid; TFA = trifluoroacetic acid; pTSA = p-toluenesulfonic
acid; CSA = camphorsulfonic acid.

optimal conditions (Scheme 2a). This is because, upon protonation of 1b by diphenylphosphoric acid, the lack of conjugation
hampered the LUMO-lowering activating effect at the b-carbon
atom. Conversely, the conjugated 4-alkenylpyridine 1c reacted
smoothly to provide the expected product 3c in 85% yield akin to
a vinylogous 1,6-iminium ion addition.13 These results are
consonant with the protonation of a conjugated nitrogen being
essential for facilitating the radical conjugate addition.
Adopting the optimised conditions described in Table 1,
entry 5, we demonstrated the generality of the diphenylphosphoric
Table 2

Scope of pyridine substratesa

Entry

Substrate 1

Product 3
yieldb (%)
1a R = Me
1d R = H
1e R = OMe
1f R = t-Bu
1g R = Br
1h R = CN
1i R = F

87
63
64
55
84
62
77

8
9

1j R = Cl
1k R = OMe

44
89

10
11

1l R = Me
1m R = F

52
86

12

1n

75

13

1o

75

14

1p

57

15
16
17
18

1q R = n-propyl
1r R = CH2CH2Ph
1s R = –(CH2)6CH3
1t R = cyclohexyl

71c
73
85
84

19

1u

58

20

indicating that the background reaction did not occur readily
(entry 1). The use of the weakly acidic pyridinium p-toluenesulfonate
(PPTS) provided a negligible improvement of reactivity (entry 2).
However, when stronger acids were used, higher yields of 3a were
obtained (entries 3–7). Diphenylphosphoric acid proved as the
optimal catalyst since it afforded a yield as high as 82% (entry 4).
Similar results were observed reducing the acid and the photocatalyst loading to 5 and 1 mol%, respectively (entry 5). Interestingly, when using a very strong acid in the form of CSA the
reaction was completely inhibited and a similar yield to the
background process was observed (entry 8). Finally, no product
formation was detected in the absence of the iridium photocatalyst A, or light, demonstrating that all these components
are needed for this catalytic protocol (entry 9).
Our activation strategy is based on the formation of a pseudoiminium ion, which is generated upon protonation of the pyridyl
nitrogen within 1 (Scheme 1). This means that the position of
the pyridine nitrogen relative to the alkenyl substitution pattern
should have a great influence on the reactivity of the conjugate
addition. Pleasingly, the corresponding 3-alkenylpyridine 1b, a
substrate where the nitrogen is no longer in conjugation with the
olefin, resulted in no product formation when subjected to the

1
2
3
4
5
6
7

1v

o5

a

Scheme 2

The importance of the pyridine nitrogen atom.

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Reaction performed on 0.3 mmol scale, using 2.0 equiv. of 2a, 1 mol%
photocatalyst A and 5 mol% of diphenylphosphoric acid, under irridation by a blue LEDs strip (lmax = 465 nm). b Yield of 3 after isolation by
chromatography. c Using (Z)-1q rather than (E)-1q.

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acid-catalysed radical conjugate addition by evaluating a variety of
alkenylpyridines 1 (Table 2).
A wide range of aromatic substituents were tolerated at the
b position, providing the corresponding products 3 in good yields.
Both electron-donating (entries 1–4) and electron-withdrawing
substituents (entries 5–7) at the para position were readily accommodated. A range of meta (entries 8 and 9) and ortho substituents
(entries 10 and 11) were also tolerated with similar yields. Aryl
groups featuring multiple substitution patterns were also successfully subjected to the reaction conditions (entry 12). The presence
of sterically demanding groups, such as naphthyl and mesityl, did
not affect the reactivity (entries 13 and 14). Importantly, alkyl
substituted alkenylpyridines, including short chain (entry 15),
longer chain (entries 16 and 17) and sterically demanding alkyl
species (entry 18), also performed well under the optimised
conditions. A quinoline substrate was also successfully used,
but provided a slightly reduced yield (entry 19). A limitation of
the methodology is that disubstituted alkenylpyridines did not
react under the optimal conditions (entry 20).
It was also possible to successfully vary the amine component
of the reaction (Scheme 3). We found that both mixed N-alkyl-Naryl (adducts 4a–d) and N,N-diaryl tertiary amines (4e) efficiently
participated in the radical conjugate addition. Substituents of
different electronic nature were easily accommodated at the aryl
para (4a,b) or meta position (4c,d), without affecting the efficiency
of the process, while the use of cyclic amines afforded compounds
4f and 4g, bearing two vicinal stereogenic centres.
We found that other electron deficient alkenyl heterocycles 5
readily participated in the radical conjugate addition (Scheme 4).
Although a longer irradiation time was required (24 h), the products
6 were achieved in good yields. Interestingly, benzothiazoles were
not suitable substrates (6e).
Fig. 1 details our proposed mechanism, which features both
an organocatalytic and a photoredox catalytic cycle working in
concert to furnish the product 3. Protonation of the pyridine 1
generates the activated pyridinium intermediate 7. Simultaneously,
irradiation of the photoredox catalyst leads to the formation of an
excited Ir(III) species, which generates a nucleophilic a-amino radical
8 from dimethylaniline by means of single electron transfer

Fig. 1

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Scheme 3 Scope of amine. Reaction performed on 0.3 mmol scale of 1a,
using 2.0 equiv. of amine 2, 1 mol% of photocatalyst A and 5 mol% of
diphenylphosphoric acid, under irridation by a blue LEDs strip (lmax =
465 nm). Yield of 4 after isolation by chromatography.

Scheme 4 Other alkenylheterocycles that participate in the process.
Reaction performed on 0.3 mmol scale of 1a, using 2.0 equiv. of amine
2, 1 mol% of A and 5 mol% of diphenylphosphoric acid. Yield of 6 after
isolation by chromatography.

Proposed mechanism.

3522 | Chem. Commun., 2016, 52, 3520--3523

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Notes and references

Scheme 5

Enantioselective variant.

(SET) oxidation followed by deprotonation. Upon radical conjugate
addition to 7, the resulting radical intermediate 9 participates in a
second SET event with the reduced Ir(II) species to regenerate the
photocatalyst and, after protonation of 10, liberate the product 3 and
the organocatalyst. When performing our studies, we noticed that
any unreacted 1a was always recovered as a mixture of the E- and
Z-isomers, despite the starting material having exclusively an E
geometry. Intrigued by this observation further analysis was undertaken. We found that simple irradiation of E-1a did not lead to
isomerisation, which occurred instead upon addition of the iridium
photocatalyst A. Stern–Volmer fluorescence quenching experiments,
detailed in the ESI,† have demonstrated that the excited state of the
photocatalyst A is quenched by both the amine 2a and the pyridine
substrate 1a.14 Thus, the excited A participates in two different
pathways: a non-productive energy transfer mechanism, which only
leads to the isomerisation of the alkenylpyridine, and an electron
transfer mechanism with the dimethylaniline 2a, leading to the
formation of product 3.
Finally, we envisaged that the use of a chiral phosphoric acid
could potentially infer enantio-induction through the formation of
a chiral ion pair of type 7.15 Pleasingly, after substantial optimization, detailed in the ESI,† we found that the BINOL-based chiral
acid 10 catalysed the generation of 3a with 35% ee, indicating the
feasibility of a stereocontrolled variant of the radical conjugate
addition (Scheme 5).16 Notably, using either E-1a or Z-1a resulted in
the formation of the same enantiomer of 3a, which suggests a
Curtin–Hammett type kinetic situation, sustained by the energy
transfer isomerisation process, where an isomer of the alkenylpyridine reacts faster than the other.
In summary, a Brønsted acid-catalysed conjugate addition of
photochemically generated a-amino radicals to alkenylpyridines
has been accomplished. We also demonstrated the feasibility of
an enantioselective version of the chemistry.
This work was supported by the ICIQ Foundation, MINECO
(project CTQ2013-45938-P), the AGAUR (2014 SGR 1059), and the
European Research Council (ERC 278541 – ORGA-NAUT). H. H.
thanks the Marie Curie COFUND action (2015-1-ICIQ-IPMP) and
Severo Ochoa Excellence Accreditation 2014–2018, SEV-20130319 for a postdoctoral fellowship. Dr Suva Paria is thanked
for assistance with the Stern–Volmer studies.

This journal is © The Royal Society of Chemistry 2016

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Chem. Commun., 2016, 52, 3520--3523 | 3523