Light-Induced Alkylation of (Hetero)aromatic Nitriles in a Transition-Metal-Free C-C-Bond Metathesis

Article abstract of DOI:10.1021/acs.orglett.7b00652

A light-induced C-C-σ-bond metathesis was achieved through transition-metal-free activation of an unstrained C(sp³)-C(sp³)-σ-bond in 1-benzyl-1,2,3,4-tetrahydroisoquinolines. A photoredox-mediated single-electron oxidation of these precursor amines yield radical cations which undergo a homolytic cleavage of a C(sp³)-C(sp³)-σ-bond rather than the well-known α-C-H-scission. The resulting carbon-centered radicals are used in the ipso-substitution of (hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C-C-bond cleavage and formation.

Full text of DOI:10.1021/acs.orglett.7b00652

Letter
pubs.acs.org/OrgLett
Light-Induced Alkylation of (Hetero)aromatic Nitriles in a Transition-
Metal-Free C−C-Bond Metathesis
Benjamin Lipp,† Alexander Lipp,† Heiner Detert, and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: A light-induced C−C-σ-bond metathesis was
achieved through transition-metal-free activation of an un-
strained C(sp3)−C(sp3)-σ-bond in 1-benzyl-1,2,3,4-
tetrahydroisoquinolines. A photoredox-mediated single-elec-
tron oxidation of these precursor amines yield radical cations
which undergo a homolytic cleavage of a C(sp3)−C(sp3)-σ-
bond rather than the well-known α-C−H-scission. The resulting carbon-centered radicals are used in the ipso-substitution of
(hetero)aromatic nitriles proceeding through another single-electron transfer-mediated C−C-bond cleavage and formation.
Scheme 1. Reactions Involving a Cleavage of an Unstrained
C(sp3)−C(sp3)-σ-Bond in 1,2-Dihydro- and 1,2,3,4-
Tetrahydroisoquinolines
ue to their thermodynamic stability and their low degree
Dof polarization, the activation of unstrained C−C-bonds
is still among the most difficult challenges in organic
chemistry.1 Significant progress has been made in this field in
recent decades, yet most examples rely on the use of transition
metals.1,2 The cleavage of unstrained C(sp3)−C(sp3)-σ-bonds
is particularly demanding, and relatively few examples are
known to date.1 A possible strategy for the cleavage of such
strong bonds is the fragmentation of radical cations.3 In 1963,
Knabe and co-workers reported an acid-promoted, stereo-
specific rearrangement of N-methyl-1,2-dihydropapaverine
(Scheme 1a).4 Kinetic studies by Langhals and Ruchardt5
̈
provided strong evidence for a radical chain reaction via the
homolytic cleavage of an unstrained C(sp3)−C(sp3)-σ-bond in
an intermediate radical cation.6 We have found a related 1,3-
benzyl migration in 1-benzyl-1,2,3,4-tetrahydroisoquinolines
(Scheme 1b) and, together with the Straub group, presented
evidence for a free radical chain mechanism under kinetic
entropy control.7 Again, a homolytic cleavage of an unstrained
C(sp3)−C(sp3)-σ-bond is involved.
It is well established that light-induced single-electron
transfer (SET) reactions provide access to radical cations
under exceptionally mild conditions.3a Over the past decade,
photoredox catalysis has emerged as one of the most vital
research areas within organic chemistry.8 Upon excitation by
light, a photoredox catalyst (e.g., transition metal complex,9
organic dye,10 or semiconductor11) undergoes two successive
SET steps, thereby returning to its electronic ground state. By
engaging in these redox reactions, components of the reaction
mixture can experience unique, net redox-neutral trans-
formations.8 N-Substituted 1,2,3,4-tetrahydroisoquinolines be-
long to the most frequently used electron donors in
photoredox-catalyzed reactions.8,12 The initially formed amine
radical cations are usually converted to the corresponding
iminium ions by abstraction of a hydrogen atom or by
deprotonation and subsequent one-electron oxidation of the
resulting neutral radical.12
With the mentioned previous work on σ-bond fragmentation
taken into consideration (Scheme 1b), the installation of a
suitable 1-substituent on the tetrahydroisoquinoline core
should favor the cleavage of a C(sp3)−C(sp3)-σ-bond over
the scission of the adjacent α-C−H bond upon abstraction of
an electron from nitrogen. The produced alkyl radicals could
subsequently engage in a C−C-bond-forming reaction with a
suitable radical acceptor. The radical ipso-substitution of
Received: March 3, 2017
© XXXX American Chemical Society
A
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Scheme 2. Plausible Reaction Mechanism of the Designed C−C-σ-Bond Metathesis
(hetero)aromatic nitriles would be an option in this respect.13
The combination of both processes would result in the net
redox-neutral formation of a new C(sp3)−C(sp3)-σ-bond when
light-induced SET steps serve to form both a transient (from
the σ-bond fragmentation) and a persistent radical (from the
reduction of the cyanoarene) which undergo a selective
recombination (Scheme 1c).14 Ideally, the cyanide anion
liberated in the rearomatization of intermediate 7a sub-
sequently combines with iminium salt 5a to form α-
aminonitrile 9a, completing a new type of σ-bond metathesis
in which two C−C bonds are broken and two new C−C bonds
are formed. To the best of our knowledge, this constitutes the
first report of a light-induced C−C-σ-bond metathesis.
A mechanistic proposal for the designed reaction is depicted
in Scheme 2. Upon excitation by UV-light, aromatic nitriles
such as dicyanobenzenes and cyanopyridines become strong
electron acceptors.13 It can thus be anticipated that excited 4-
cyanopyridine [E1/2(3[1a]*/2a) = +1.65 V vs SCE, calculated
for the triplet state according to the literature, consequently
higher for the singlet state]15 is capable of directly oxidizing 1,2-
dialkylated 1,2,3,4-tetrahydroisoquinolines such as ( )-lauda-
nosine [3a, typically: E1/2(R3N•+/R3N) ≤ +1.1 V vs SCE15c and
E1/2(4a/3a) = +0.55 V vs Ag/AgNO3/+0.86 V vs SCE16] to the
corresponding radical cations 4a without any external photo-
redox catalyst being added. Alternatively, phenanthrene can be
used as a photoredox catalyst, which proved to be suitable for
radical alkylations of aromatic nitriles.17 Fluorescence quench-
ing experiments17a indicate that the excited singlet state of
phenanthrene [E1/2(Phen•+/1[Phen]*) = −2.1 V vs SCE]18
readily reduces aromatic nitriles such as 4-cyanopyridine [1a,
E1/2(1a/2a) = −1.66 V vs SCE]15b to the corresponding radical
anions 2a (oxidative quenching). The resulting phenanthrene
radical cation is a strong electron acceptor [E1/2(Phen•+/Phen)
= +1.50 V vs SCE]15c capable of oxidizing tertiary amines such
as ( )-laudanosine (3a).15c Fluorescence quenching studies19
also suggest that the excited singlet state of phenanthrene
[E1/2(1[Phen]*/Phen•−) = +1.14 V vs SCE, calculated
according to the literature]15a,c is capable of oxidizing tertiary
amines such as 3a to the corresponding radical cations
(reductive quenching). The emerging phenanthrene radical
anion is a strong reductant [E1/2(Phen/Phen•−) = −2.44 V vs
SCE]15c and easily transfers an electron to aromatic nitriles
such as 4-canopyridine (1a). Cleavage of a C(sp3)−C(sp3)-σ-
bond in the intermediate radical cation 4a and subsequent
selective radical recombination, followed by elimination of
cyanide from the anionic intermediate 7a and trapping of
iminium ion 5a by liberated cyanide anions, finally affords
pyridine 8a and α-aminonitrile 9a.14,17,20 A detailed mechanistic
discussion is provided in the Supporting Information.
An extensive screening of reaction conditions was under-
taken using 4-cyanopyridine (1a) and ( )-laudanosine (3a) as
a model system (see the Supporting Information, Tables S1−
S6, S10). Although ipso-substitution product 8a could be
obtained in the absence of an additional photoredox catalyst
(36% yield, via direct SET, see Scheme 2), improved results
were obtained in the presence of phenanthrene (25 mol %, 45%
yield). α-Aminonitrile 9a is kinetically labile and reforms
iminium ion 4a, which then competes with the nitrile’s radical
anions 2a for the liberated benzylic radicals 6a or can engage in
further photochemistry. Thus, the yield of 8a could be further
increased by the addition of TMSCN (2.0 equiv, 64% yield) as
an external cyanide source to improve trapping of the
intermediate iminium ion 5a (see the Supporting Information,
Table S10). TMSCN was found to be superior to KCN,
presumably due to its excellent solubility in organic solvents
such as acetonitrile (see the Supporting Information, Table S4).
Based on unchanged UV/vis-absorption spectra, a potential
coordination of the pyridine’s nitrogen to the TMS group,
which would significantly lower the pyridine’s LUMO, appears
unlikely (see the Supporting Information, section 4).
Under the optimized conditions, the scope of this
unprecedented reaction was investigated (Scheme 3). Since a
longer lifetime of the radicals 6 should increase their probability
of coupling with the cyanoarene-derived radical anions 2, an
increase in yields of ipso-substitution products 8 with the
increase in stability of the intermediate alkyl radicals was
expected. Moreover, a higher stabilization of radicals 6 would
also favor their liberation from the parent amine radical cations
B
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a
Scheme 3. Scope of the Light-Induced Alkylation of (Hetero)aromatic Nitriles in a C−C-Bond Metathesis
a
b
All reactions were performed according to the general procedure (see the Supporting Information). All yields are those of isolated products. After
c
d
purification via preparative HPLC. Irradiation with sunlight. Using 1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline as a radical
precursor. 0.80 mmol scale, simultaneously irradiated with two CFL bulbs. Product not isolated.
e
f
4 over the competing α-C−H-activation. Indeed, a range of
precursors of secondary benzylic radicals furnished the desired
alkylation products 8b−8d in high yields (70−75%). The
reaction proceeded smoothly using methoxy-substituted,
primary benzylic radicals (as liberated from natural benzyliso-
quinoline alkaloids) affording compounds 8a, 8e, and 8f in
yields of 44−64%. The reaction of 4-cyanopyridine (1a) with
( )-laudanosine (3a) could also be effected using sunlight as
the sole energy source (66% yield).21 Replacing the 3′,4′-
methoxy groups by alkyl moieties afforded moderate yields
(43−48%, 8g and 8h), most likely due to the lower stability of
the intermediate radicals. Remarkably, even unsubstituted
benzylic radicals can serve as intermediates in the σ-bond
metathesis, although the yield can be increased by extension of
the arene moiety (8i vs 8j). Electron-withdrawing substituents
in the benzylic radical (8u and 8v) and nonstabilized alkyl
radicals (8w) are however not tolerated. Compound 8a could
also be obtained using 1-(3,4-dimethoxybenzyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline as a radical precursor (58%
yield) proving that the electron-donating 6,7-dimethoxy
substitution pattern at the tetrahydroisoquinoline core is not
a prerequisite for this unusual C−C-bond cleavage.
A range of alkylated and arylated cyanopyridines afforded the
desired products 8k−8n in high yields (62−71%). Electron-
withdrawing substituents in the pyridine core were tolerated as
well (8o). Even the selective replacement of cyanide in the
presence of a chlorine substituent in an activated position could
be achieved (8p; loss of chlorine or double alkylation not
observed). When 2-cyanopyridines were submitted to the
standard procedure (8q and 8r), the desired products were
obtained in moderate yields (27−34%), which are satisfactory
in view of the largest LUMO-coefficient usually being located in
the 4-position of the pyridine core.6,17b The ipso-substitution
protocol was also successfully applied to 1-cyanoisoquinoline
(8s). While 9,10-dicyanoanthracene afforded the desired
product in moderate yield (8t, 27%), 1,4-dicyanobenzene did
not engage in the C−C-bond-metathesis (8y). The alkylation
of cyanopyridines bearing strongly electron-donating substitu-
ents is not feasible (8x), presumably due to their poor electron
acceptor quality or the low stability of intermediate 2.
C
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Finally, an iridium-based photoredox catalyst was tested in
place of phenanthrene, which would allow the process to be
induced by visible light.22 Again, an extensive optimization was
undertaken (see the Supporting Information, Tables S7−S9).
The visible-light-induced reaction proceeded smoothly with fac-
Ir(ppy)3 (1.5 mol %), although the yields were lower than
those for the phenanthrene-based protocol (up to 53%).
In summary, the cleavage of an unstrained C(sp3)−C(sp3)-σ-
bond in 1-substituted N-alkyltetrahydroisoquinolines could be
effected by means of a light-induced single-electron oxidation.
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this C−C-bond cleavage could exemplarily be used in the ipso-
substitution of (hetero)aromatic nitriles proceeding through
another single-electron transfer-mediated C−C-bond cleavage
and formation. Overall, two C−C-bonds are formed at the
expense of two others, which represents the first example of a
light-induced C−C-σ-bond metathesis.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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Soc. Jpn. 1984, 57, 763.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00652.
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(20) (a) Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136,
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2016, ahead of print (doi: 10.1002/ejoc.201601394).
(22) Nakajima, K.; Nojima, S.; Sakata, K.; Nishibayashi, Y.
ChemCatChem 2016, 8, 1028.
Optimization studies, experimental procedures, a mech-
anistic discussion, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: opatz@uni-mainz.de.
ORCID
Till Opatz: 0000-0002-3266-4050
Author Contributions
†B.L. and A.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Johannes C. Liermann (Mainz, NMR spectros-
copy), Dr. Norbert Hanold (Mainz, deceased, mass spectrom-
etry), Natalie Tober and Nico Roder (Mainz, technical advice),
̈
and the Carl Zeiss Foundation (project ChemBioMed, financial
support).
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