Catalytic Alkene Difunctionalization via Imidate Radicals

Article abstract of DOI:10.1021/jacs.8b07578

The first catalytic strategy to harness imidate radicals has been developed. This approach enables alkene difunctionalization of allyl alcohols by photocatalytic reduction of their oxime imidates. The ensuing imidate radicals undergo consecutive intra- and intermolecular reactions to afford (i) hydroamination, (ii) aminoalkylation, or (iii) aminoarylation, via three distinct radical mechanisms. The broad scope and utility of this catalytic method for imidate radical reactivity is presented, along with comparisons to other N-centered radicals and complementary, closed-shell imidate pathways.

Full text of DOI:10.1021/jacs.8b07578

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Catalytic Alkene Difunctionalization via Imidate Radicals
Kohki M. Nakafuku,† Stacy C. Fosu,† and David A. Nagib*
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: The first catalytic strategy to harness
imidate radicals has been developed. This approach
enables alkene difunctionalization of allyl alcohols by
photocatalytic reduction of their oxime imidates. The
ensuing imidate radicals undergo consecutive intra- and
intermolecular reactions to afford (i) hydroamination, (ii)
aminoalkylation, or (iii) aminoarylation, via three distinct
radical mechanisms. The broad scope and utility of this
catalytic method for imidate radical reactivity is presented,
along with comparisons to other N-centered radicals and
complementary, closed-shell imidate pathways.
n pursuit of a new hydroamination reaction, Overman
serendipitously discovered a synthetically valuable reaction
I
wherein allyl imidates are rapidly converted to allyl amines by
sigmatropic rearrangement.1−3 Nonetheless, the original goal of
converting allyl imidates to 1,2-amino alcohols via hydro-
amination remains unsolved. This is likely because the Brønsted,
Lewis, and π-acids that could activate alkenes toward amination,
efficiently promote rearrangement instead. To solve this
ongoing challenge, we proposed an N-centered radical
mechanism4 may bypass the two-electron pathway and afford
the long-sought hydroamination5 to access valuable β-amino
alcohols (Figure 1a). Moreover, we anticipated imidate radicals
may enable several new classes of reactivity for the synthesis of
functionalized amino alcohols.
In developing a catalytic strategy to harness the reactivity of
imidate radicals,6,7 we proposed allyl imidate A may be
selectively reduced by a single-electron via photocatalysis8
(Figure 1b). We envisioned that such oxime imidates are readily
accessed by the combination of alcohols and imidoyl chlorides in
a modular and tunable manner (to access radical precursors with
variable N−OR bond strengths). In analogy, the incorporation
of weak N−OR bonds within analogs of ketones and amides has
afforded other N-centered radicals (e.g., iminyl, amidyl).9−12 We
thus proposed this tunability may enable us to discover a
catalytic method to access imidate radicals. In our proposed
mechanism, excitation of a photocatalyst (Mn to *Mn) precedes
reductive quenching by an amine to provide a strong reductant
(Mn−1). We postulated single-electron reduction of allyl imidate
A to its radical anion, and subsequent mesolytic cleavage, could
then afford imidate radical B and regenerated photocatalyst
(Mn). Next, rapid, 5-exo-trig cyclization13 of the N-centered
radical would provide C, which contains a C· adjacent to the new
C−N bond. Upon combination with a variety of intermolecular
radical traps, a resulting α-substituted oxazoline D may be
hydrolyzed under acidic conditions to afford a family of 1,2-
amino alcohols. Importantly, we postulated that three distinct
Figure 1. New reactivity modes enabled by imidate radicals.
mechanisms could be employed to intercept the C-centered
radical (Figure 1c). For instance, homolytic substitution (SH2)
of a radical trap containing a weak C−H bond14 may provide
hydroamination. Alternatively, intermolecular radical π-addition
of alkenes would afford aminoalkylation.15 Lastly, a rare,
radical−radical coupling mechanism16 could incorporate γ-
arenes in a net, aminoarylation. Crucially, each of these three
radical termination mechanisms affords reactivity that is
complementary to classic, two-electron strategies.
With this hypothesis in mind, we combined an allyl alcohol
with a pair of imidoyl chlorides (Figure 2). The resulting allyl
imidates were then subjected to reductive, photoredox catalytic
i
conditions in the presence of a reductant, Pr2NEt, an H atom
donor, 1,4-cyclohexadiene (CHD), and a blue LED light.
Received: July 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b07578
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Having developed the first catalytic reaction of an imidate
radical, we sought to investigate the generality and utility of this
hydroamination on a range of allyl imidates (Figure 4). To this
Figure 2. Hydroamination of allyl alcohols via imidate radicals.
Unsurprisingly, the N-OMe oxime 1a, which has a large
reduction potential (Ered > −2 V),17,18 affords minimal
hydroamination, yielding 10% oxazoline 2′, only with a highly
reducing catalyst (III). Alternatively, the N-OPh oxime 1b is
more easily reduced (−1.6 V) and efficiently provides 2′ (up to
80% yield) with commercially available Ir photocatalysts (II or
III). Notably, subsequent hydrolysis of oxazoline 2′ with HCl
(aq) unveils the privileged 1,2-amino alcohol pharmacophore 2.
Interestingly, when imidate 1b is combined with a Pd catalyst,
rearrangement to an allyl amide is observed exclusively, instead
(97% yield),19 demonstrating the divergent reactivity of one-
and two-electron pathways for imidates.
We were also intrigued by the complementarity of imidate
radical reactivity with other N-centered radicals, such as those of
imines and amides.9,10 First, they are synthetically orthogonal, as
these imidate-based radicals are accessed from alcohols, whereas
iminyl and amidyl radicals are derived from ketones or acid
chlorides, respectively (Figure 3). Moreover, we noted each of
Figure 4. Hydroamination of allyl imidates. Isolated yields of
hydroamination (and hydrolysis) are indicated.
end, we found that allyl alcohols with both terminal and internal
olefins are hydroaminated smoothly (2−4), as well as
trisubstituted olefins (5). These results illustrate that primary,
secondary, benzylic, and tertiary radicals are all viable
intermediates in the translocation of an imidate N-centered
radical to a γ C-radical. If chloro- or silyl-substituted olefins are
employed (gray circles), products bearing heteroatom function-
ality at three adjacent carbons are obtained (6−7). Several
natural products are also hydroaminated (8−10), including
those containing multiple alkenes−demonstrating chemo-
selectivity of this protocol for allyl alcohols. In the case of
secondary alcohols, exclusive syn-diastereoselectivity (>20:1) is
observed in all cases (11−15), likely due to geometric
constraints of the five-membered oxazoline intermediate.
Interestingly, and complementary to our previous studies on
H atom abstraction by imidate radicals,7 hydroamination
outcompetes β C−H abstraction−even of weak, allyl or benzyl
C−H bonds (13−14, highlighted with gray circles). Addition-
ally, 5-exo-trig (vs 6-exo-trig) cyclization is solely observed. The
imidate of gibberellic ester is also efficiently converted to its β
amino-alcohol (15), illustrating chemoselectivity in the
presence of esters, lactones, and unprotected allyl alcohols, as
Figure 3. Comparison of N-centered radical precursors.
these N-centered radical precursors reacts differently. For
example, when a simple N-OPh is incorporated, a competition
between all three radical precursors exclusively results in
cyclization of the imidate radical. In this case, only oxazoline
2′ is formed among all three possible hydroamination products,
with both the imine and amide radical precursors remaining.
This competitive hydroamination of the imidate (versus iminyl
or amidyl) precursor is also observed with strongly reducing
catalyst III (−2.2 V).
B
DOI: 10.1021/jacs.8b07578
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Journal of the American Chemical Society
Communication
well as orthogonal selectivity to other radical-mediated hydro-
amination methods.10d
Given the scarcity of such a cascade (radical cyclization
terminated by radical−radical coupling), we further probed this
mechanism by employing several regioisomers of dicyanoben-
zene in the reaction (Figure 6). We proposed if a conjugate
The robust reactivity observed for these imidate radicals in the
case of hydroamination via SH2 led us to question if other
trapping mechanisms might also be viable by this catalytic
pathway. Replacing CHD with various olefins, we investigated
the amino-alkylation of imidates by radical π-addition (Figure
5). Notably, both acrylates (16−18) and styrenes (19−23)
Figure 6. Mechanistic support for radical−radical coupling.
addition mechanism is operative, then an arene with reinforcing
1,3-disubstituted electron-withdrawing groups (e.g., CN)
should be an especially efficient radical trap. However, no
aminoarylation is observed with 1,3-dicyanobenzene. Instead,
1,2- or 1,4- dicyano-benzene, which are more easily reduced (by
up to 200 mV),20 affords significant product formation, likely as
a result of a greater concentration of cyclohexadienyl radical
anion formed by the Ir photoreductant. Moreover, ortho- and
para- CN disubstitution are not as conducive to conjugate
addition as the meta isomer, further supporting a radical−radical
coupling mechanism.
To further investigate the different radical-trapping mecha-
nisms employed in this study, we appended a 1,6-diene on the
allyl imidate to serve as a radical clock (Figure 7). In the
Figure 5. Aminoalkylation and aminoarylation of imidates.
function as capable partners to effect a three-component radical
coupling of imidates, alkenes, and an H atom. In these cases,
both 1,1- and 1,2- disubstitution is tolerated, as well as
incorporation of heteroarenes, such as 2- and 4- vinylpyridines.
Although tertiary radicals (from trisubstituted allyl alcohols)
afford greater efficiency in this radical π-addition, simple allyl
alcohols (that incorporate a primary radical intermediate) are
also suitable for this aminoalkylation (e.g., 20 vs 21).
In the hopes of incorporating an aryl trap within this cascade,
we sought to develop an aminoarylation by a radical−radical
coupling mechanism (Figure 5). Although such a mechanism is
rare, especially in the absence of persistent radicals as traps,16 we
proposed cyanoarenes may selectively combine with the
transient, imidate-derived tertiary radicals. This hypothesis
was realized by aminoarylation with various aryl precursors, such
as dicyano-benzene (DCB; 24−25), its perfluorinated analog
(26), and 4-cyano-pyridine (27). In these unique couplings, we
propose that a radical anion of the arene is photocatalytically
generated in parallel with formation of the imidate radicals, both
by reductive quenching mechanisms. The ensuing cyclo-
hexadienyl radical and the translocated alkyl radical selectively
combine with one another to afford the observed products in
preference to dimerization of either radical.
Figure 7. Radical clock experiments for each mechanism indicate the
following rates: acrylate addition > cyclization > SH2.
presence of CHD, rapid cyclization (kcyc > 1 × 105 s−1)13
precedes trapping, thereby interrupting the hydroamination
with an intermediary radical cyclization cascade. However, in the
presence of an acrylate trap, aminoalkylation is uninterrupted,
indicating intermolecular radical π-addition is faster than
intramolecular cyclization.
In summary, a series of catalytic reactions have been
developed that harness imidate radicals. Oxime imidates, readily
C
DOI: 10.1021/jacs.8b07578
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(d) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075.
(e) Silvi, M.; Melchiorre, P. Nature 2018, 554, 41.
prepared from alcohols, are mildly and selectively reduced by an
Ir photocatalyst in the presence of visible light to generate
imidate radicals. Subsequent cyclization and trapping with (a)
an H atom, (b) an electronically diverse range of olefins (e.g.,
acrylates, styrenes), or (c) a cyanoarene enables access to the
following transformations: hydroamination, aminoalkylation,
and aminoarylation. We expect this strategy will facilitate further
development of radical mechanisms that are complementary to
the classic, two-electron reactivity of imidates.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b07578.
■
S
Experimental procedures and characterization for all new
compounds (PDF)
1H and 13C NMR spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*nagib.1@osu.edu
■
(11) Notably, refs 10c−e contain examples of carbamate radicals,
which can be prepared from alcohols, albeit via a complementary
synthesis, activation, and deprotection manifold.
(12) For other relevant examples of N-centered radical reactivity, see:
(a) Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012,
134, 11980. (b) Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A.
Angew. Chem., Int. Ed. 2016, 55, 9974. (c) Becker, P.; Duhamel, T.;
ORCID
David A. Nagib: 0000-0002-2275-6381
Author Contributions
†K.M.N. and S.C.F. contributed equally.
Notes
Stein, C. J.; Reiher, M.; Muniz, K. Angew. Chem., Int. Ed. 2017, 56, 8004.
̃
The authors declare no competing financial interest.
(13) (a) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J. Am.
Chem. Soc. 1998, 120, 7738. (b) Newcomb, M. Radicals in Organic
Synthesis; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2001; pp
317−336. (c) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
3925.
ACKNOWLEDGMENTS
■
We thank The Ohio State University, National Institutes of
Health (NIH R35 GM119812), National Science Foundation
(NSF CAREER 1654656), and American Chemical Society
Petroleum Research Fund for financial support. S.C.F. is
supported by an HHMI Gilliam Fellowship. We are grateful to
Dr. Xin Yang and Andrew Chen for assistance with CV and DFT
experiments.
(14) (a) Binmore, G.; Walton, J. C.; Cardellini, L. J. Chem. Soc., Chem.
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D
DOI: 10.1021/jacs.8b07578
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX