Directed β C-H Amination of Alcohols via Radical Relay Chaperones

Article abstract of DOI:10.1021/jacs.7b05214

A radical-mediated strategy for β C-H amination of alcohols has been developed. This approach employs a radical relay chaperone, which serves as a traceless director that facilitates selective C-H functionalization via 1,5-hydrogen atom transfer (HAT) and enables net incorporation of ammonia at the β carbon of alcohols. The chaperones presented herein enable direct access to imidate radicals, allowing their first use for H atom abstraction. A streamlined protocol enables rapid conversion of alcohols to their β-amino analogs (via in situ conversion of alcohols to imidates, directed C-H amination, and hydrolysis to NH₂). Mechanistic experiments indicate HAT is rate-limiting, whereas intramolecular amination is product- and stereo-determining.

Full text of DOI:10.1021/jacs.7b05214

Communication
pubs.acs.org/JACS
Directed β C−H Amination of Alcohols via Radical Relay Chaperones
Ethan A. Wappes,† Kohki M. Nakafuku,† and David A. Nagib*
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: A radical-mediated strategy for β C−H
amination of alcohols has been developed. This approach
employs a radical relay chaperone, which serves as a
traceless director that facilitates selective C−H function-
alization via 1,5-hydrogen atom transfer (HAT) and
enables net incorporation of ammonia at the β carbon of
alcohols. The chaperones presented herein enable direct
access to imidate radicals, allowing their first use for H
atom abstraction. A streamlined protocol enables rapid
conversion of alcohols to their β-amino analogs (via in situ
conversion of alcohols to imidates, directed C−H
amination, and hydrolysis to NH2). Mechanistic experi-
ments indicate HAT is rate-limiting, whereas intra-
molecular amination is product- and stereo-determining.
he β-amino alcohol is a privileged motif prevalent in
T
pharmaceuticals, agrochemicals, natural products, and
catalyst architectures. Yet, its typical synthesis inelegantly relies
on iterative, functional group manipulation or unselective,
alkene difunctionalization.1 Conversely, directed sp3 C−H
amination2 of an alcohol offers a powerful synthetic alternative
applicable to complex molecules that contain this ubiquitous
functional handle. To date, only the groups of Du Bois, He, and
Lebel have reported methods for β C−H amination of alcohol
derivatives: via Rh or Ag nitrene-mediated, vicinal amination of
carbamates.3 However, metal-based approaches typically afford
γ selectivity, due to requisite metallacycle geometries.4 As part
of our program to develop radical relay strategies for selective
C−H functionalization,5 we hypothesized that an open-shell
pathway might enable valuable, synthetic complementarity.
Remote C−H functionalizations via radical intermediates are
known to exhibit wide functional group tolerance, as well as
robust selectivity via 1,5-hydrogen atom transfer (HAT).6
When radical precursors, or chaperones, are appended to
alcohols, π-cyclizations are typical,7 whereas HAT is much
rarer,8 especially compared with radicals tethered to amines.9,10
Yet, given the synthetic utility of alcohols, it is notable that their
HAT-mediated C−H amination remains unsolved, despite the
propensity for selective C−H amination via N-centered
radicals,6 and recent progress in C−H functionalization of
alcohol derivatives via metal-mediated mechanisms.11
Figure 1. Design of a radical relay chaperone strategy for selective β
C−H amination of alcohols.
prone to β-scission and undesired, competitive mechanisms.12
Thus, we hypothesized that masking the central C of the
chaperone within an imidate should obviate any undesired
degradation. Next, to address the challenge of C−H
functionalization, we noted that although cyclizations of
imine-based sp2 N-centered radicals are known,13 their use in
HAT is rare.14 Furthermore, imidate radicals have never been
reported to effect HAT.15 Thus, to explore the feasibility of
imidate-based chaperones to mediate radical relays, we
performed ground state calculations on the SOMO energies
of imidate radicals with varying substitution (Figure 1b).16 We
were pleased to find that variation of the traceless R′ group in
our proposed imidate chaperone scaffold affords significant
tunability of the SOMO energies of the sp2 N-centered radicals
(e.g., R = Ph, −0.02 eV; Me, −0.69 eV; CCl3, −1.47 eV).
Notably, these open-shell intermediates span a wider range of
energies than related sp3 N-centered radicals that are known to
exhibit variable HAT reactivity (see SI).17 Lastly, upon selective
1,5-HAT, we envisioned in situ iodination of the ensuing C-
C−H functionalization promoted by radical relay enables
robust, predictable selectivity via 1,5-HAT due to a six-
membered, cyclic transition state.6 To exploit this intrinsic
selectivity, we rationalized that a two-atom chaperone, bearing a
terminal N, appended to an alcohol should enable β C−H
amination via 1,5-HAT (Figure 1a). Yet, we were also cognizant
that N-centered radicals, including those of hemiaminals, are
Received: May 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05214
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Journal of the American Chemical Society
Communication
radical and N-displacement,6 or 5-endo-trig radical cyclization
and subsequent oxidation,18 should afford C−H aminated
oxazoline products.
Table 1. Scope and Generality of β C−H Amination
To test our hypothesis, we first synthesized three imidates of
2-phenylethanol by addition into a nitrile, or via transimidation.
Each imidate was then subjected to our recently developed,
triiodide-based C−H amination conditions (Scheme 1).5
Scheme 1. Discovery of β C−H Amination Chaperones
a
b
Cl3CCN, DBU or R(CN)OCH2CF3 NaI, PhI(OAc)2, visible light
c
HCl (aq), MeOH. Isolated yields.
Gratifyingly, these mild conditions (NaI, PhI(OAc)2) convert
all three imidates (1−3) to the desired oxazoline heterocycles
(4−6), albeit with divergent efficiencies (e.g., trace to
quantitative), reflecting a difference in stability of the imidate
intermediates, as well as their respective N-centered radicals.
Fortunately, trichloroacetimidate 3 affords C−H amination
product 6, quantitatively. Given its synthetic convenience and
utility (e.g., Overman rearrangement),19 as well as relative
stability of this precursor and subsequent radical, we chose to
further explore the Cl3C−CN chaperone in our β C−H
amination protocol. Additionally, we expected the resultant
oxazoline (bearing a −CCl3) to be primed for acidic hydrolysis,
allowing direct isolation of free β-amino alcohols via an
exceptionally simple process.20 In practice, we found in situ
subjection of crude oxazoline 6 to HCl (aq) in MeOH
facilitates hydrolysis and chromatography-free isolation (via
acid/base extraction) of pure β-amino alcohol 7 in 87% yield
from 3 (or 80% yield, directly from the alcohol).
With our new protocol in hand for the net installation of
−NH2 to the β position of alcohols, we then subjected this
method to various alcohols bearing a range of sterically and
electronically diverse functionalities (Table 1). As in the case of
phenylethanol, this imidate radical-mediated C−H amination
method proved remarkably efficient, affording nearly quantita-
tive oxazoline formation in all cases, typically with >80%
isolated yields after acidic hydrolysis and purification via
extraction. As shown in Table 1, ortho-, meta-, and para-
substitution of either electronically donating or withdrawing
groups is tolerated (8−15, > 74% yield). Notably, heteroarenes
such as pyridine 16 and thiophene 17 are also tolerant of the
mild, triiodide-based C−H amination reaction conditions. To
prevent HCl-mediated decomposition of the sensitive thio-
phene product, heterobenzyl amide 17 was isolated via a milder
TsOH-based hydrolysis to provide a trichloroacetamide (Ac* =
COCCl3) instead of the free amine. In further probing the
generality of this transformation, we observed that alcohols
with tertiary β C−H bonds are aminated efficiently (18, 19).
Similarly, secondary alcohols are readily β-aminated, affording
remarkably high diastereoselectivity (20−22, >20:1 dr). We
were pleased to find that cholesterol and reduced ibuprofen are
converted to their β-amino alcohol analogs (19, 22), illustrating
the benefit of this approach to drug discovery by enabling
streamlined, postsynthetic modification of medicinal candi-
dates.
Having demonstrated the generality of this imidate-radical-
mediated β-amination for substitution of benzylic and allylic
C−H bonds, we next turned our attention to address the
challenge of alcohols containing stronger C−H bonds (BDE;
aliphatic, 97 vs benzylic, 90 kcal/mol).21 Three key mechanistic
observations enabled us to identify a solution in this regard.
First, we observed that only the trans isomer of 2-phenyl
cyclohexanol is aminated via this protocol (80% yield; see SI),
providing a mixture of diastereomers (2:1). The failure of the
cis imidate to undergo amination suggests HAT is highly
geometry-dependent, and a critical step in this transformation.
Second, to probe the precise role of the HAT step, we
investigated the presence of a kinetic isotope effect (KIE) in the
β C−H amination (eq 1).22 A large primary KIE (8.1) was
observed via intramolecular H/D competition in the imidate
derived from 23, suggesting HAT is likely product- and rate-
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determining. Similarly, intermolecular competition between 3
and its β-d2 analog (of 24) yielded KIE values >2 via single flask
(4.4) and parallel (2.1) experiments.
Third, upon exploring the feasibility of β-amination of an
alcohol containing a stronger tertiary C−H bond (Figure 2,
Notably, even an alcohol with strong, primary β C−H bonds
(BDE: 101 kcal/mol),21 such as ethanol, affords β-amido
alcohol 33. Longer alcohols with unbiased, secondary β C−H
bonds (34, 35) provide even greater efficiency−consistent with
our observation that triiodide-based C−H amination enables
methylene functionalization.5 Orthogonal functionality is
tolerated under these mild, radical-mediated conditions,
including ethers, esters, and amines (36−38). Secondary
alcohols can also undergo β-amination (39, 40), complemen-
tary to metal-mediated approaches.3 Last, subjecting enantio-
pure (S)-2-methyl-butanol to the C−H amination provides
amide 41 with complete stereoablation (0% es), reinforcing the
presence of planar radical or cationic intermediates.
A synthetic benefit of our radical chaperone strategy is the
intermediacy of an oxazoline heterocycle that can be easily
derivatized to many, useful synthetic functionalities.23 To
demonstrate this wide utility, the β C−H amination products
were converted to several valuable motifs (Scheme 2). First, in
Figure 2. New radical chaperone enables extension to aliphatic
alcohols.
Scheme 2. Synthesis of a Family of β-Amines
27), we observed successful HAT from the radical of imidate
28 to afford β-iodide 30 (53% yield). This interception of
intermediate 29 supports our proposed mechanistic hypothesis
of I· trap, and explains the importance of subsequent
nucleophilic I− displacement by the imidate for overall β-
amination (since substitution is more facile for benzyl iodides
than nonbenzyl iodides).
This observation, coupled with an understanding of the
viability, and importance, of HAT in overall amination,
encouraged us to investigate benzimidate 28 (R = Ph), which
simultaneously has a more reactive N-radical (Figure 1b) and
more nucleophilic N. In this case, oxazoline 31 is obtained
exclusively (62% yield), without any iodide 29 remaining after
24 h. Finally, in contrast to the trichloroacetimidate-derived
products, benzimidates afford protected β-amido alcohols.
However, free amino alcohol 32 can also be obtained upon
hydrolysis with NaOH, or via acyl migration (e.g., 37, 38).
With a second-generation, benzimidate chaperone enabling β
C−H amination of aliphatic alcohols, we sought to explore the
scope and generality of this alternate approach (Table 2).
situ hydrolysis of the oxazoline with TsOH provides acetamide
42 as a complementary product to the unprotected β amino
alcohols shown in Table 1 (via HCl hydrolysis). Next,
subjecting 42 to NaOH afforded carbamate 43. Importantly,
oxazoline 6 could be isolated in 88% yield, enabling several
further derivatizations. For example, DDQ oxidation provides a
unique method of synthesizing oxazole 44 from an alcohol and
nitrile. Additionally, nucleophilic ring-opening of oxazoline 6
provides access to a family of β-amines, including thioester 45
(via KSAc), azide 46 (via Me3Si−I, then NaN3), and halides
47−49 (via Me3Si-X). Lastly, deoxygenation via iodination and
Raney Ni reduction affords alkane 50, wherein the alcohol is a
traceless activator in a formal β C−H amination.
Table 2. β C−H Amination of Aliphatic Alcohols
In summary, this radical relay chaperone strategy for rapidly
converting ubiquitous alcohols into β-amino analogs, in a single
afternoon, provides a powerful synthetic alternative to access
these privileged motifs. We expect this broadly applicable β C−
H amination scheme, and its wide product versatility, will
enable streamlined syntheses of complex, amine-containing
molecules from their abundant alcohol precursors. Finally,
building on this first example of imidate-mediated HAT, we
anticipate the use of radical relay chaperones will enable further
discovery of regioselective C−H functionalizations.
C
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N.; Mieczkowski, A.; Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2010, 132, 5568.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05214.
■
S
(10) Amidine HAT affords C−O or C−N: (a) Wang, Y.-F.; Chen,
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H. Angew. Chem., Int. Ed. 2016, 55, 14546. (b) Kim, S.; Joe, G. H.; Do,
J. Y. J. Am. Chem. Soc. 1993, 115, 3328.
Experimental procedures, spectroscopic data for all new
1
compounds, including H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*nagib.1@osu.edu
ORCID
■
(13) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603.
(14) (a) Forrester, A. R.; Gill, M.; Thomson, R. H. J. Chem. Soc.,
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David A. Nagib: 0000-0002-2275-6381
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
(16) DFT calculations indicate N-H BDE’s are nearly identical for all
imidates in Figure 1b (100
1 kcal/mol), suggesting that HAT is
ACKNOWLEDGMENTS
■
more likely related to the SOMO energies. Ground state calculations
on the SOMO energies of imidate radicals, as well as N−H BDE
calculations, performed using the ωB97X-D/6-31G(D) hybrid func-
tional.
We thank The Ohio State University, National Institutes of
Health (NIH R35 GM119812), and American Chemical
Society Petroleum Research Fund for financial support.
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Overman, L. E. Tetrahedron 2009, 65, 6432.
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require carbamate N-deprotection via two subsequent steps.
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(22) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
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DOI: 10.1021/jacs.7b05214
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