Sequential Oxidative α-Cyanation/Anti-Markovnikov Hydroalkoxylation of Allylamines

Article abstract of DOI:10.1021/acs.orglett.5b02319

Iron-catalyzed oxidative α-cyanations at tertiary allylamines in the allylic position are followed by anti-Markovnikov additions of alcohols across the vinylic CC double bonds of the initially generated α-amino nitriles. These consecutive reactions generate 2-amino-4-alkoxybutanenitriles from three reactants (allylamines, trimethylsilyl cyanide, and alcohols) in one reaction vessel at ambient temperature.

Full text of DOI:10.1021/acs.orglett.5b02319

Letter
pubs.acs.org/OrgLett
Sequential Oxidative α‑Cyanation/Anti-Markovnikov
Hydroalkoxylation of Allylamines
Alexander Wagner, Nathalie Hampel, Hendrik Zipse, and Armin R. Ofial*
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13, 81377 Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Iron-catalyzed oxidative α-cyanations at tertiary
allylamines in the allylic position are followed by anti-
Markovnikov additions of alcohols across the vinylic CC
double bonds of the initially generated α-amino nitriles. These
consecutive reactions generate 2-amino-4-alkoxybutanenitriles
from three reactants (allylamines, trimethylsilyl cyanide, and alcohols) in one reaction vessel at ambient temperature.
in particular with catalysts based on earth-abundant elements
dditions to alkenes are atom-economic reactions that are
Aused by synthetic chemists in academia and industry to such as iron.8−10
According to the methylenology principle,11 Michael
introduce a broad variety of functional groups into hydro-
carbons.1 However, only a limited number of methods exist so
far for anti-Markovnikov additions of alcohols to simple
aliphatic olefins. Arnold studied the photosensitized generation
of alkene radical cations,2 which were trapped with alcohols to
provide anti-Markovnikov adducts.3 Since then, only a few
related examples for photochemically induced anti-Markovni-
kov alcohol additions have been reported, all of which use 1-
aryl- or 1,1-diarylalkenes as reaction partners (Scheme 1a).4−6
General methods for intermolecular anti-Markovnikov hydro-
alkoxylations under mild and practical conditions are still
lacking because of a shortage of applicable catalytic processes,7
additions of alcohols at intrinsically nucleophilic CC double
bonds could be mediated by linking the electron-rich π-system
with an electron-accepting group through a radical center. As
C-centered radicals are efficiently stabilized by captodative
effects,12 vinyl-substituted α-amino nitriles would be ideal
substrates for testing this approach.
The introduction of nitrile groups at C−H bonds adjacent to
the nitrogen of tertiary amines has recently been achieved with
several catalyst-oxidant combinations and various cyanide
sources.13−15 Hence, allylamines may serve as potential
precursors for vinyl-substituted α-amino nitriles. Indeed, it
has been reported that allylamines can be used in oxidative α-
cyanations under various conditions16,17 (Scheme 1b). The few
examples show, however, that oxidation occurs preferentially at
aliphatic or benzylic α-positions of the amines,17a−c and only
Mizuno and co-workers detected small amounts of α-cyanated
products that originated from reaction at the allyl group.17d,18
In recent years, we have developed iron-catalyzed oxidative
α-cyanations of a variety of tertiary amines.19,20 Here, we report
that FeCl2-catalyzed direct α-cyanations at tertiary allylamines
in the allylic position are followed by anti-Markovnikov
additions of alcohols across the vinylic CC double bonds of
the initially generated α-amino nitriles (Scheme 1c).
Scheme 1. Direct Anti-Markovnikov Additions of Alcohols
a
to Alkenes and Oxidative α-Cyanations of Allylamines
Monitoring the oxidative cyanation of N,N-diallylaniline 1a
under our standard conditions in methanol [10 mol % FeCl2, 2
equiv of Me3SiCN, 2.5 equiv of tBuOOH (5.5 M in decane), dry
N2 atmosphere, ambient temperature]19c,21 by GC−MS
indicated that significant amounts of the α-cyanation product
2a accumulated in the reaction mixture only during the initial
phase of the reaction. The cyanation product 2a was
accompanied by the generation of compounds with a molecular
mass of 2a·MeOH. While 2a was isolated in low yield (21%)
when the reaction was worked-up after 4 h reaction time, the
a
b
SET, single electron transfer; HAT, hydrogen atom transfer. For
reaction conditions, see notes in ref 17.
Received: August 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02319
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
product of the addition of methanol to 2a was obtained in 86%
yield after 16 h (Scheme 2). 2D-NMR spectroscopic character-
Scheme 3. Suggested Mechanism for the Oxidative C1-
Cyanation of the N-Allyl Group with Subsequent Anti-
Markovnikov Hydroalkoxylation
Scheme 2. Sequential Oxidative Cyanation/Hydro-
a
alkoxylation of N,N-Diallylanilines 1a−d
a
Yields refer to isolated products after chromatographic purification.
ization of 2a·MeOH showed the presence of a terminal
methoxy group, in agreement with structure 3a. N,N-Diallylani-
lines 1b,c with electron donating p-methyl (σp = −0.17)22 or p-
chemically calculated radical stabilization energies (RSEs),25
transfer of a hydrogen atom from C to radical F is
thermodynamically feasible and exothermic by 38 kJ mol−1
(in the gas phase, for details see Supporting Information).
Both radicals D and F involved in the proposed catalytic
cycle are unusually stable in absolute terms, which implies weak
C−H bonds in the closed shell parent systems C and G. On the
basis of bond dissociation energies (BDEs), the relevant C−H
bond of 2a (+310 kJ/mol) is slightly weaker than that of 2-
methoxy substituents (σp = −0.27)22 at the phenyl rings
−
analogously gave 2-anilino-4-methoxybutanenitriles 3b,c in
yields of 85% and 93%, respectively. The electron-withdrawing
p-bromo-substituted aniline 1d (σp (Br) = 0.25)22 gave 3d in a
−
moderate yield of 67%.
Changing the solvent from CH3OH to CD3OD for the
reaction of 1a under otherwise identical conditions of Scheme 2
yielded the d3-methyl ether 3a′ in 88% yield.
phenylmalononitrile (+322
4 kJ/mol, from ref 26), which
was successfully used as the H atom donor in intramolecular
anti-Markovnikov hydroetherifications.5g,6a The relevant C−H
bond of 2a is also weaker than in reaction product 3a (+348 kJ/
mol) and much weaker than the allylic C−H bond in propene
(+369 kJ/mol)27 or the α−C-H bond in the glycine-derivative
(+364 kJ/mol) depicted in Figure 1.25,28 Interestingly, the α−
C-H bond in 3a is of comparable strength as the O−H bond in
tBuOOH (BDE = +353 9 kJ/mol, from ref 29).
While the 1H and 13C NMR spectra of 3a′ indicate a
quantitative OCD3 incorporation, the methylene group at C3 of
the 4-methoxybutanenitrile branch shows a ca. 42% uptake of D
(see Supporting Information). Because of fast H/D exchange
between CD3OD and tBuOOH under the conditions applied, it
is presently not possible to unequivocally assign the source of
the H or D that adds to the C3 position.
To rationalize the selective anti-Markovnikov addition of
methanol, we suggest that iron-catalyzed oxidation converts the
allyl-substituted amines A into α,β-unsaturated iminium ions B,
which are then trapped by kinetically controlled attack of
cyanide ions at the iminium carbon (Scheme 3).23 Further
oxidation of the intermediate α-amino nitriles C generates the
donor/acceptor-substituted radicals D, which enter a radical
chain reaction. In accord with the methylenology principle,11
radicals D show reactivity comparable to the π-electron-
deficient acrylonitriles. Therefore, Michael-type addition of
alcohols to the terminal C-4 may generate intermediates E, in
which the negative charge is delocalized and efficiently
stabilized by the electron-withdrawing cyano group. Fast
proton transfer converts E to radicals F, which benefit from
captodative stabilization.12 Deuteration at C2 in product 3a′
was not observed (see above). Therefore, we conclude that O−
H of tBuOOH or C−H of methanol do not act as hydrogen
atom donors toward radicals F. The catalytic cycle may be
closed, however, by direct or indirect hydrogen atom transfer24
from α-amino nitriles C to radicals F to generate the final
products G as well as the radicals D that take part in the next
cycle of the radical chain reaction. On the basis of the quantum-
Figure 1. Comparison of C−H bond dissociation energies (BDEs) in
α-amino nitriles 2a and 3a with those in structurally analogous
compounds and in 2-phenylmalononitrile.
When ethanol was used as the solvent instead of methanol,
the 4-ethoxy-substituted 2-aminobutanenitrile 4 (68%) was
obtained from 1a by the cyanation/hydroalkoxylation sequence
(Scheme 4). Ethyl ether 4 was accompanied by the 2-
aminopropanenitrile 5 (31% isolated yield), whose formation
is rationalized in analogy to the previously described oxidative
dealkylation/cyanomethylation of N,N-dialkylanilines in meth-
anol:19c Oxidative degradation of 1a via hydrolysis of the
intermediate α,β-unsaturated iminium ions forms N-allylaniline,
which condenses with acetaldehyde, generated by oxidation of
the solvent ethanol,30 to yield iminium ions, which are finally
trapped by cyanide to yield 5 (Scheme 4).
Reactions with N-allyl-N-ethylaniline (6a) and triallylamine
(9) showed that the scope of the oxidative α-cyanation/-
hydroalkoxylation can be extended to mono- and triallyl-
B
DOI: 10.1021/acs.orglett.5b02319
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Letter
the π-system of the vinyl-substituted α-amino nitrile
intermediate. Thus, this reaction combines three components32
in one pot to yield 2-amino-4-alkoxybutanenitriles under mild
conditions. Such ether-functionalized α-amino nitriles may
further extend the rich synthetic versatility of α-amino nitriles.33
Detailed studies of the mechanism including further character-
ization of highly stabilized radicals of structural type D, as well
as broadening the scope of this novel type of anti-Markovnikov
hydroalkoxylation are currently underway.
Scheme 4. Oxidative Cyanation of N,N-Diallylaniline (1a) in
Ethanol
a
ASSOCIATED CONTENT
■
S
* Supporting Information
a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02319.
Yields refer to isolated products after separation and purification by
column chromatography.
Scheme 5. Oxidative Cyanation/Hydroalkoxylation of the
Experimental details, discussion of the quantum-chemi-
cally calculated RSEs, and spectroscopic characterization
data (PDF)
Monoallylamines 6a,b, Triallylamine (8) and N,N-
a
Diallylbenzylamine (11)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ofial@lmu.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support of this work by Prof. Herbert Mayr (LMU
Munchen, Germany) and the Deutsche Forschungsgemein-
schaft (SFB 749, projects B1 and C6) is gratefully acknowl-
edged.
̈
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