Catalytic β C-H amination: Via an imidate radical relay

Article abstract of DOI:10.1039/c8sc05685d

The first catalytic strategy to harness imidate radicals for C-H functionalization has been developed. This iodine-catalyzed approach enables β C-H amination of alcohols by an imidate-mediated radical relay. In contrast to our first-generation, (super)stoichiometric protocol, this catalytic method enables faster and more efficient reactivity. Furthermore, lower oxidant concentration affords broader functional group tolerance, including alkenes, alkynes, alcohols, carbonyls, and heteroarenes. Mechanistic experiments interrogating the electronic nature of the key 1,5 H-atom transfer event are included, as well as probes for chemo-, regio-, and stereo-selectivity.

Full text of DOI:10.1039/c8sc05685d

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Catalytic b C–H amination via an imidate radical
relay†
Cite this: DOI: 10.1039/c8sc05685d
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have been paid for by the Royal Society
of Chemistry
Leah M. Stateman, Ethan A. Wappes, Kohki M. Nakafuku, Kara M. Edwards
*
and David A. Nagib
The first catalytic strategy to harness imidate radicals for C–H functionalization has been developed. This
iodine-catalyzed approach enables b C–H amination of alcohols by an imidate-mediated radical relay. In
contrast to our first-generation, (super)stoichiometric protocol, this catalytic method enables faster and
more efficient reactivity. Furthermore, lower oxidant concentration affords broader functional group
tolerance, including alkenes, alkynes, alcohols, carbonyls, and heteroarenes. Mechanistic experiments
interrogating the electronic nature of the key 1,5 H-atom transfer event are included, as well as probes
for chemo-, regio-, and stereo-selectivity.
Received 20th December 2018
Accepted 9th January 2019
DOI: 10.1039/c8sc05685d
rsc.li/chemical-science
photo-mediated method, we hypothesized the key, radical-
generating iodine atom, which is not incorporated in the
Introduction
product, could be continually recycled and ultimately employed
in a catalytic fashion.
At the frontier of organic synthesis, the selective replacement of
an unbiased C–H bond with a more valuable chemical motif
remains
a
vital challenge.1 Specically, incorporation of
In an alternate, thermally initiated sequence, we envisioned
a substoichiometric quantity of I2 may undergo ligand substi-
tution with PhI(OAc)2 (1 equiv. only) to generate AcOI. In the
presence of an alcohol-derived imidate (A), selective formation
of a weak N–I bond (B)16,17 would enable thermal homolysis to
an N-centered radical (C). This transient species (typically
accessed by photolysis)18 should undergo regio-selective 1,5-
HAT to yield b radical (D). Rapid radical recombination (or
chain-propagation with AcOI or N–I) would yield b alkyl iodide
(E). In the presence of PhI(OAc)2 as a terminal oxidant, we
proposed oxazoline (F) formation may accompany regeneration
of the AcOI catalyst by one of two mechanisms: (1) iodide
displacement by the imidate, and re-oxidation of IÀ to I+,19 or (2)
alkyl hypervalent iodane formation, and amination via an I(III)/
I(I) pathway.20 Importantly, we proposed thermal initiation of
this catalytic cycle under low concentrations of I2 (or AcOI) may
improve reaction efficiency and chemoselectivity by precluding
byproduct-forming pathways associated with photolysis of these
promiscuous oxidants.21
a nitrogen atom by C–H amination is an especially important
goal in medicinal chemistry.2,3 Among recent advances toward
directed sp3 C–H functionalization of abundant alcohol deriv-
atives,4 there remain few methods to synthesize b amino alco-
hols (a privileged motif in medicine)5 by C–H amination.6 To
complement state-of-the-art, metal-catalyzed nitrenoid and C–H
insertion pathways for remote C–H amination,7 we sought to
employ a radical-based approach that entails d selective,
hydrogen atom transfer (HAT).8,9 Despite recent advances in
d C–H amination via HAT,10 there remain few catalytic examples
of this transformation.11 Having recently disclosed the rst
method for directed b C–H amination of alcohols by a comple-
mentary imidate radical relay,12,13 we sought to develop an
improved, catalytic strategy (Fig. 1).
In our radical relay chaperone strategy, alcohols are readily
converted to imidates by addition to nitriles (Fig. 1a). Upon
combination with stoichiometric oxidant (NaI, PhI(OAc)2; 3
equiv. each), a transient sp2 N-centered radical14,15 is generated
that undergoes selective 1,5-HAT to afford a C-centered radical –
b to the imidate. Subsequent radical trapping and acidic
hydrolysis yields b amino alcohols in a rapid, selective, and
efficient fashion. With the hopes of expanding the synthetic
utility of this new strategy, we proposed development of a cata-
lytic variant (Fig. 1b). To complement our rst-generation,
Results and discussion
In accord with our design, we were pleased to nd the catalytic
b C–H amination of imidate 1 by HAT is indeed possible with
5 mol% I2 and 1.2 equiv. PhI(OAc)2, affording 2 in 95% yield
(Table 1). Crucially, this thermal protocol requires polar, aprotic
solvents (e.g. DMF, MeCN), whereas other solvents (e.g. CH2Cl2,
PhMe) afford inferior yields (entries 1–4). Although rigorous
degassing is not essential, an N2 atmosphere was found to be
superior to an aerobic one (entry 5). Although alkali iodide salts
The Ohio State University, Department of Chemistry and Biochemistry, Columbus, OH
43210, USA. E-mail: nagib.1@osu.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8sc05685d
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Interestingly, we noted this catalytic reaction is completed at
a signicantly faster rate than the rst-generation, photo-
initiated conditions. As shown in Fig. 2, our previous condi-
tions, which are super-stoichiometric in NaI and PhI(OAc)2,
required several hours for reaction completion (purple line).
Conversely, 80% yield is observed in 30 minutes with 5–10% I2
(red and blue lines) or even in as little as 10 minutes with 20% I2
(green line). Although a mere 1% I2 provides full conversion in 6
hours, we found these longer reaction times to be less practical
than the 1–2 hours needed for 5% catalyst loading. Given that
less soluble sources of iodide (e.g. NaI, CsI) do not afford
product as rapidly or efficiently (likely due to slower, incomplete
generation of I2), we presume greater solubility of I2 affords
a higher initial concentration of the active oxidant, AcOI. Taken
together, these data suggest the faster rates shown in Fig. 2 are
consistent with a higher initial concentration of reactive AcOI,
as proposed in the mechanism shown in Fig. 1. Moreover, less
terminal oxidant, and thermal (vs. photolytic) initiation, may be
responsible for ensuring AcOI-based, two-electron reactivity is
more selective for the desired reaction pathway.
Synthetic scope
In order to explore the synthetic utility of our new thermally
initiated, I2-catalyzed protocol, we subjected a series of imidates
to these b C–H amination conditions (5% I2, 1.2 equiv.
PhI(OAc)2, DMF, 50 ꢀC). Upon reaction completion, acidic
hydrolysis of the resulting oxazoline with aq. HCl yielded the
respective b amino alcohol. As shown in Fig. 3, a wide range of
imidates undergo the radical relay mechanism via these cata-
lytic conditions. For trichloroacetimidates (derived from
combination of alcohols and Cl3C–CN), a range of electronically
diverse 2-phenylethanol derivatives could be selectively ami-
nated at the b position. These benzylic C–H aminations (3–10)
are amenable to both electronically rich and decient
Fig. 1 Radical relay strategy for b C–H amination of alcohols: (a)
catalytic vs stoichiometric. (b) Iodine-catalyzed mechanism.
(e.g. NaI, CsI) are competent sources of iodine for this reaction,
they are less efficient than more soluble I2 reagent (entries 6
and 7). Finally, photolysis (entry 8) or non-photolytic initiation
at room temperature (entry 9) afford reactivity, albeit with less
ꢀ
efficiency than standard thermal initiation at 50 C.
Table 1 Development of a catalytic C–H amination of imidates
Entry
Changes from standard conditions
Yield (%)
1
2
3
4
5
6
7
8
9
None
95
31
33
94
61
67
76
50
40
CH2Cl2 instead of DMF
PhMe instead of DMF
MeCN instead of DMF
Air atmosphere instead of N2
NaI instead of I2
CsI instead of I2
2 Â 23 W CFL
Fig. 2 Comparison of the catalytic C–H amination of imidates with
the previous stoichiometric version.
Dark, room temperature
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Fig. 3 Synthetic utility of iodine-catalyzed b C–H amination of imidates. Conditions: 0.4 mmol imidate, I2 (5 mol%), PhI(OAc)2 (1.2 equiv.), DMF
(0.2 M), 50 ꢀC. 1H NMR yield of oxazoline determined vs. standard. Hydrolysis with HCl (2 M) affords amino alcohol (isolated yield, in parenthesis).
aIsolated yield of oxazoline. bStoichiometric NaI (ref. 12). Ac* refers to trichloroacetamide. Functional group robustness: C–H amination yield, %
additive remaining.
substituents (OMe, Me, F, CF3) as well as ortho, meta, and aminated (16). To promote the b amination of stronger,
para substitution. Additionally, medicinally relevant hetero- aliphatic C–H bonds, we employed benzimidates (derived
arenes (thiophene, pyridine, 11–12) are tolerated, as well as from combination of alcohols with Ph-CN or with Ph(CN)
the tertiary C–H of an ibuprofen analog (13). Secondary OCH2CF3). This catalytic protocol is also suitable for the
alcohols are efficiently aminated with excellent diaster- regioselective amination of primary, secondary, and tertiary
eoselectivity (up to >20 : 1 d.r.; 14–15). Finally, the allylic C–H C–H bonds (17–21). Similarly, secondary alcohols are
of a cholesterol analog is also efficiently and stereo-selectively
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tolerated, although greater diastereoselectivity is observed
for cyclic versus acyclic cases (>20 : 1 d.r. vs. 1 : 1 d.r.).
As a testament to the synthetic utility provided by these mild,
catalytic conditions, several functional groups that were not
previously tolerated in our stoichiometric protocol can now be
aminated (22–26). Most interestingly, the reactive p-systems of
alkenes and alkynes, which are prone to deleterious reaction
with large amounts of oxidant, are now amenable as substrates.
For example, whereas alkene 25 was previously accessible in
only 43% yield under the stoichiometric, photochemical
protocol, these catalytic, thermal conditions provide amination
in 88% yield. Additionally, alkynes, which had previously not
been tolerated (0%), are now suitable substrates for this b C–H
amination (26, 63% yield).
To further probe this improved functional group tolerance,
we conducted an additive robustness screen22 for both the
stoichiometric and catalytic protocols – employing synthetically
and medicinally relevant functionalities that appeared unlikely
to withstand strong oxidative conditions. As shown in Fig. 3,
this catalytic method is superior for the b C–H amination of
imidate 1 to 2 in the presence of various functional groups,
including alkenes, alcohols, ketones, aldehydes, thiophenes,
pyrroles, and halides (catalytic: 85–100%; stoichiometric:
0–82% yield). Illustrating the mildness of the new catalytic
protocol, these additives are recovered in up to 95% yield,
whereas they are frequently decomposed in the highly oxidative
environment of the stoichiometric conditions (0–43%) (see ESI†
for complete table of functional groups tolerated, including
those that are tolerated in both conditions).
Fig. 4 Regioselectivity probes of b selectivity via 1,5-HAT.
one another). Interestingly, these catalytic conditions afford
greater diastereoselectivity (5 : 1 d.r.) than the stoichiometric
protocol (2 : 1 d.r.). Moreover, b benzyl iodide intermediate 31
was observed for the rst time, only in the catalytic case. Taken
together, these results suggest divergent mechanisms are
operative in the radical trapping steps of these two protocols. A
possible explanation is that the higher oxidant concentration of
the (super)stoichiometric method more rapidly oxidizes the
benzyl radical to a cation, which is unselectively cyclized to
afford the thermodynamically favored cis product in only a 2 : 1
excess. On the other hand, a stepwise iodine trapping and
subsequent cyclization mechanism under the low oxidant
concentration of the catalytic conditions allow for greater 5 : 1
diastereoselectivity. This likely occurs via slower conversion of
the observed alkyl iodide intermediate 31, which enables
greater, overall stereocontrol. Oxidation of benzyl iodide 31 to
its hypervalent iodane nucleofuge may also afford cyclization –
with either retention or inversion.26
Mechanistic investigations
To gain a deeper understanding of this reaction mechanism, we
conducted a series of competitive rate studies interrogating
various stereoelectronic effects. First, we probed the regiose-
lectivity of the imidate radical-mediated amination in the
presence of weaker C–H bonds. Although our reaction design is
based on the entropic and enthalpic favorability of 1,5-HAT,8a
there are notable examples of 1,6-HAT mediated pathways that
are governed by substrate geometry23 or thermodynamics.24 To
test the inuence of the latter, the b selectivity of this C–H
amination was investigated for alcohols bearing a weaker g C–H
bond (Fig. 4). In each case, b selectivity (via 1,5-HAT) was
observed in preference to g selectivity (via 1,6-HAT). When the g
C–H bond is signicantly weaker (benzylic: 90 vs. secondary:
98 kcal molÀ1),25 the b amine 27 is still preferentially formed
(2 : 1 b : g selectivity). However, when g ÀC1–H bond is only
marginally weaker (3ꢀ: 96 vs. 2ꢀ: 98 kcal mol ),25 the b amine 28
is obtained exclusively (>20 : 1 b : g selectivity).
Next, we investigated the observed diastereoselectivity of the
b C–H amination by employing cis and trans isomers of 2-
phenyl-cyclohexanol 29 as stereochemical probes in the
formation of b amino alcohol 30 (Fig. 5). Whereas the tri-
chloroacetimidate of cis-29 does not afford C–H amination
(likely because the imidate radical is conformationally con-
strained to the opposite side of the ring), trans-29 efficiently
undergoes HAT (since the imidate radical and b C–H are syn to Fig. 5 Diastereoselectivity via divergent trapping mechanisms.
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Acknowledgements
We thank the National Institutes of Health (NIH R35
GM119812) and National Science Foundation (NSF CAREER
1654656) for nancial support. LMS is supported by the NSF
GRFP Fellowship.
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Conflicts of interest
There are no conicts to declare.
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