Vinylpyridines as Building Blocks for the Photocatalyzed Synthesis of Alkylpyridines

Article abstract of DOI:10.1002/chem.201701346

The photocatalyzed addition of several hydrogen donors (ethers, aldehydes, alkanes, amides) onto vinylpyridines was achieved. This approach provided access to alkylpyridines, which are important building blocks for the preparation of compounds with biological activity. The strategy was very simple and straightforward because it required only a small amount of a cheap decatungstate salt as photocatalyst. As an added advantage, the reaction could be performed under sunlight irradiation as well as under flow conditions.

Full text of DOI:10.1002/chem.201701346

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Accepted Article
Title: Vinylpyridines as Building Blocks for the Photocatalyzed
Synthesis of Alkylpyridines
Authors: Luca Capaldo, Maurizio Fagnoni, and Davide Ravelli
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Vinylpyridines as Building Blocks for the Photocatalyzed
Synthesis of Alkylpyridines
Luca Capaldo, Maurizio Fagnoni, Davide Ravelli*
Abstract: The photocatalyzed addition of several hydrogen donors
(ethers, aldehydes, alkanes, amides) onto vinylpyridines has been
achieved. This approach gave access to alkylpyridines, important
building blocks for the preparation of compounds having biological
activity. The strategy is very simple and straightforward, since it
requires only a small amount of a cheap decatungstate salt as the
photocatalyst. As an added value, the reaction can be carried out
under sunlight irradiation, as well as under flow conditions.
2-Alkylpyridine alkaloids (e.g. phormidinine A, Figure 1) were
isolated from marine organisms as well.[3i] Substituted
alkylpyridines were recently investigated for their peculiar umami
flavor[4] or as polar surfactants.[5]
From the synthetic point of view, vinylpyridines are useful
substrates for the preparation of alkylpyridines via direct addition
of nucleophiles onto the double bond. Different strategies are
known for the C-alkylation of ethenylpyridines via addition of C-
nucleophiles (benzyl anions[6a] or enolate anions[6b-d]), under
reductive
conditions,[6e]
under
acid-catalyzed,[6f]
NHC-
The pyridine ring is a scaffold of fundamental importance in
many bioactive compounds and it is present in several
antihistamine drugs (acrivastine, pheniramine, triprolidine),
antibiotics (isoniazid) and vitamins (B3, B6).[1] Moreover,
derivatives bearing a pyridine ring substituted with an alkyl chain
were recently isolated from marine sponges of the Niphatidae
(and other) family, showing antibiotic, antimycotic and cytotoxic
activity (Figure 1).[2] Some examples of compounds having the
3-alkylpyridine motif are: nakinadine C,[3a] niphatesine C,[3b]
ikimine A,[3c] haminol-1,[3d] topsendine A,[3e] along with
pyrinodemin A,[3f] cribochalines A and B,[3g] and niphatoxin B.[3h]
catalyzed[6g] or metal-catalyzed[6h-j] conditions. Recently, an
interesting organocatalytic enantioselective addition of
aldehydes onto vinylpyridines has been likewise described.[7]
A milder approach, however, involves the addition of carbon-
centered radicals onto the double bond. A dated example is the
functionalization of 4-vinylpyridine by photodecomposition of
alkylmercury halides (Scheme 1, path a).[8a] In another instance,
the thermal generation of radicals was achieved starting from
alkyl halides, through a Zn-promoted reaction (path b).[8b] Quite
surprisingly, only a few examples were reported for the
functionalization of vinylpyridines by means of photoredox
catalysis (path c), notwithstanding the several examples
published on styrenes.[9] Actually, only -carbonyl,[10a] -oxy[10b]
and -amino radicals[10c,d] were smoothly generated and used for
the preparation of alkylpyridines (path c). Carbon-centered
radicals obtained by a photocatalyzed proton-coupled electron
transfer on N-arylamide derivatives were likewise trapped by 2-
vinylpyridine.[11]
Figure 1. Alkylpyridine motifs in bioactive compounds.
Scheme 1. Generation of carbon based radicals (R•) by cleavage of a R-X
(paths a-c) and
a R-H bond (this work, path d) for the synthesis of
alkylpyridines.
[a]
Mr. L. Capaldo, Prof. M. Fagnoni, Dr. D. Ravelli
PhotoGreen Lab, Department of Chemistry
University of Pavia
In all of the radical-based strategies discussed so far, an X
group must be present in the radical precursor to facilitate the
cleavage of the C-X bond and the ensuing radical formation. By
contrast, the direct generation of radicals by cleavage of a C-H
bond still represents a harsh challenge and has not been
exploited for vinylpyridines derivatization so far.
viale Taramelli 12, 27100 Pavia
E-mail: davide.ravelli@unipv.it
http://www.unipv.it/photochem
Supporting information for this article is given via a link at the end of
the document.
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We surmised that the formation of (carbon-centered) radicals
could be attained by a homolytic C-H cleavage via a hydrogen
atom transfer (HAT)[12] by using a decatungstate salt (TBADT,
(nBu4N)4[W10O32]) as the photocatalyst (Scheme 1, path d).[13,14]
Firstly, we optimized the reaction conditions by studying the
photocatalyzed addition of cyclohexane (1g) onto 4-vinylpyridine
(2a) to give 4-(2-cyclohexylethyl)pyridine (9) as a model reaction.
As reported in Table S1, the highest yield of 9 (68%) was
obtained by irradiating (IRR centered at 310 nm; 10×15 W
phosphor-coated lamps were used) a MeCN solution of 2a (0.1
M) for 16 h in the presence of TBADT (2 mol%; MAX = 323 nm)
and an excess of 1g (5 equiv.). We then investigated the scope
of our approach by testing several hydrogen donors (ethers 1a,b,
acetal 1c, amides 1d,e, nitrile 1f, cyclohexane 1g, silane 1h and
aldehydes 1i-m, Figure 2) in the reaction with vinylpyridines 2a-
g, adopting the optimized conditions by using the minimum
excess of 1.
under flow conditions[15] (flow rate = 0.2 mL min-1). The flow
photoreactor (total volume: 12 mL) employed here is based on a
PTFE tubing (internal diameter: 1.3 mm) wrapped around an
immersion well apparatus (125 W Hg vapors lamp as the light
source).[14f]
Table 1. TBADT photocatalyzed synthesis of alkylpyridines 3-20.[a]
Figure 2. Hydrogen donors (1a-m) and vinylpyridines (2a-g) used in this work.
[a] Conditions: A MeCN solution (15 mL) of 1a-m (1.5-7.5 mmol, 0.1-0.5 M, 1-5
equiv.) and 2a-c (1.5 mmol, 0.1 M, 1 equiv.), in the presence of TBADT
(2×10−3 M, 2 mol%) irradiated with 10×15 W phosphor-coated lamps (IRR
centered at 310 nm) for 16 h. Isolated yields reported, see SI for details.
4-Vinylpyridine (2a) was first tested and in most cases the
expected products were formed in good to excellent yields
(Table 1). As for ethers, tetrahydrofuran (1a) and 1,4-dioxane
(1b) gave the Giese adducts 3 and 4 in 68 and 62% yields,
respectively. A similar yield (64%; compound 5) was achieved
when shifting to 1,3-benzodioxole (1c) as hydrogen donor.
Elective substrates for this reaction appeared to be aliphatic
amides, since both N,N-dimethylformamide (1d) and N-
methylformamide (1e) gave excellent yields of 6 and 7 (94 and
87%, respectively). Accordingly, the reactivity of 1d was also
investigated under different conditions, by changing the light
source. As an example, formamide 6 was obtained in a very
good yield (77%) when the reaction was performed in a solar
simulator and in 83% yield when the solution was irradiated with
direct sunlight in a Pyrex vessel on a window ledge (Table 1).
Isocapronitrile (1f) reacted with 2a to afford 8 as the only product
in 92% yield, with a regioselective C-H cleavage at the methine
site. Noteworthy, in the preparation of alkylpyridine 9 a higher
yield (86% vs 68%) was obtained when carrying out the reaction
[b]
Irradiation carried out by placing the solution (50 mL) in a solar simulator
[c]
(500 W·m–2).
Irradiation carried out by placing the solution (50 mL) in a
[d] [e]
Pyrex vessel exposed on a window ledge for 8 h.
1.6 M 1f.
Reaction
carried out under flow conditions (see text and SI). [f] TBADT 4 mol%.
4-Vinylpyridine was also capable of trapping silyl radicals, even
though a higher amount of TBADT was required (4 mol%). Thus,
the Si-H bond in dimethylphenylsilane (1h) was homolytically
broken and trapping of the thus-formed radical afforded silane
10 in a modest yield (39%). Activation of C(sp2)-H bonds in
aldehydes (whether aliphatic or aromatic) allowed the
preparation of unsymmetrical ketones. In particular, heptanal (1i)
gave ketone 11 in 56% yield, whereas aromatic aldehydes gave
contrasting results. While unsubstituted benzaldehyde (1j)
reacted quite well with 2a, giving 12 in 46% yield, the reaction of
salicylaldehyde (1k) to give 13 failed, probably due to the
presence of the phenolic group.[14g] Protection of the -OH group
as TBDMS ether restored the usual reactivity (product 14 formed
in 42% yield, Table 1, and 13 from it by basic treatment, see SI).
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The reaction was also extended to 3-vinyl (2b) and 2-
vinylpyridine (2c, Table 1). Alkylated pyridines 15 and 16 were
formed in 50 and 42% yield, respectively, in the photocatalyzed
addition of 1a and 1g onto 2b. By contrast, 2-vinylpyridine gave
results comparable with those of 2a (products 17-20 obtained in
up to 82% yield, Table 1). Attempted alkylation of 2-
vinylpyrazine failed due to polymerization.
observed in compound 2f is similar to that found in the
cyclohexyl radical addition onto ethyl cinnamate.[16]
With the aim to prepare compounds of potential industrial
interest, 2c was reacted with protected salicylaldehydes 1l and
1m to give ketones 21 and 22 (Scheme 2). In the former case,
compound 21 was formed in roughly the same yield under flow
conditions in only 5 h. In the latter case, treatment of crude 22
under basic conditions (LiOH) formed phenol 23. Notably,
compounds 21 and 23 belong to a class of compounds
mimicking the umami flavour.[4]
Scheme 4. Regioselectivity in the addition of radicals onto substituted
vinylpyridines.
As for the mechanism, the formation of carbon-centered radicals
is promoted by excited TBADT via a hydrogen atom transfer
reaction (Scheme 5).[12,13] Vinylpyridines behave as radical traps
and regioselective addition at the  position smoothly took place.
The efficient back hydrogen donation from [HW10O32]4- to the
adduct radical hampered the otherwise fast polymerization of 2
to poly(vinylpyridines).[17]
Scheme 2. Photocatalyzed synthesis of derivatives 21 and 23 having umami
flavor.
We then tested phenyl substituted vinylpyridines 2d and 2e
(Scheme 3). Photocatalytic addition of cyclohexane onto 2d led
to compound 24 in a good yield (71%). The versatility of our
approach made possible the smooth preparation of 25
(precursor of the antihistamine drug pheniramine, see Figure 1)
in a single step and in 68% yield starting from DMF and 2e.
Scheme 5. Proposed reaction mechanism.
Moreover, the high absorptivity of TBADT at the wavelength
used prevented the light absorption of the starting vinylpyridines
(see Figures S1, S2) and of the end compounds. This was
beneficial to the overall process, since it avoided again a
photopolymerization of 2[17] and at the same time made
negligible intramolecular hydrogen abstraction side reactions
from the resulting 2-alkylpyridines.[18] The presence of a COOEt
or a CN group on the double bond of vinylpyridines makes them
more electrophilic, but shifts (at least in part) the regioselectivity
of radical attack to the  position.
Scheme 3.
Finally, vinylpyridines bearing an electron-withdrawing group
such as 2f and 2g were subjected to the photocatalyzed reaction
with 1g (Scheme 4). Cyclohexyl radical attacked both the  and
the  (preferred) position with respect to the pyridyl ring.
Compound 2f gave ethyl esters 26 as a mixture of isomers (
ratio of 14:86) in a 71% overall yield, whereas olefin 2g afforded
nitriles 27 ( ratio of 34:66) in a 60% yield. The regioselectivity
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Experimental Section
Typical Procedure for the TBADT-Photocatalyzed Functionalization
of Vinylpyridines. An acetonitrile solution (15 mL) of cyclohexane 1g
(808 μL, 7.5 mmol, 0.5 M, 5 equiv.) and vinylpyridine 2a (161 μL,1.5
mmol, 0.1 M, 1 equiv.), in the presence of TBADT (2∙10−3 M, 2 mol%)
was poured in a quartz tube and then purged for 3 min with nitrogen,
capped with a septum, and irradiated for 16 h in a multi-lamp apparatus
fitted with 10×15 W phosphor-coated lamps (emission centered at 310
nm). The solvent was removed under reduced pressure from the
photolyzed solution and the product isolated by purification of the residue
by column chromatography to yield 194 mg of 9 (68% yield) as an oil.
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Keywords: Decatungstate anion
•
Hydrogen transfer
•
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COMMUNICATION
Luca Capaldo, Maurizio Fagnoni, Davide
Ravelli*
Page No. – Page No.
Vinylpyridines as Building Blocks for
the Photocatalyzed Synthesis of
Alkylpyridines
The flavor of photocatalysis. The photocatalyzed addition of several hydrogen
donors (R-H) onto vinylpyridines has been achieved. This approach gave access to
alkylpyridines, important building blocks for the preparation of compounds having
biological activity, including derivatives showing an umami flavor.
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