C-H Xanthylation: A Synthetic Platform for Alkane Functionalization

Article abstract of DOI:10.1021/jacs.6b09414

Intermolecular functionalizations of aliphatic C-H bonds offer unique strategies for the synthesis and late-stage derivatization of complex molecules, but the chemical space accessible remains limited. Herein, we report a transformation significantly expanding the chemotypes accessible via C-H functionalization. The C-H xanthylation proceeds in useful chemical yields with the substrate as the limiting reagent using blue LEDs and an easily prepared N-xanthylamide. The late-stage functionalizations of complex molecules occur with high levels of site selectivity, and a variety of common functionality is tolerated in the reaction. This approach capitalizes on the versatility of the xanthate functional group via both polar and radical manifolds to unlock a wide array of C-H transformations previously inaccessible in synthesis.

Full text of DOI:10.1021/jacs.6b09414

Communication
pubs.acs.org/JACS
C−H Xanthylation: A Synthetic Platform for Alkane Functionalization
William L. Czaplyski, Christina G. Na, and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
Examples of desirable transformations with no general, practical
ABSTRACT: Intermolecular functionalizations of ali-
phatic C−H bonds offer unique strategies for the synthesis
and late-stage derivatization of complex molecules, but the
chemical space accessible remains limited. Herein, we
report a transformation significantly expanding the chemo-
types accessible via C−H functionalization. The C−H
xanthylation proceeds in useful chemical yields with the
substrate as the limiting reagent using blue LEDs and an
easily prepared N-xanthylamide. The late-stage function-
alizations of complex molecules occur with high levels of
site selectivity, and a variety of common functionality is
tolerated in the reaction. This approach capitalizes on the
versatility of the xanthate functional group via both polar
and radical manifolds to unlock a wide array of C−H
transformations previously inaccessible in synthesis.
approach include the vinylation, allylation, thiolation, hydrox-
ylation, trifluoromethylthiolation, and deuteration of isolated
aliphatic C−H bonds. The development of strategies capable of
achieving these goals would greatly enhance the power of
intermolecular C−H functionalization in complex synthesis and
late-stage functionalization. We reasoned that the sheer number
and diversity of these functional groups would render a single
synthetic approach to achieve these transformations impractical.
Instead, we envisioned an alternative strategy involving the
development of a new intermolecular aliphatic C−H function-
alization that could enable facile access to a wide array of
functional groups via the established chemistry of a single
intermediate.
Previous efforts from our group culminated in the develop-
ment of site-selective C−H halogenations of unactivated
aliphatic C−H bonds using N-haloamides.6 These reactions
use a bulky, electron-poor amidyl radical for site-selective C−H
halogenations with the substrate as the limiting reagent,
enhancing their utility in complex synthesis. We hypothesized
that the combination of the efficiency and site selectivity of our
approach with the transfer of a single, highly versatile functional
group would generate a new, diversity-oriented approach to C−
H functionalization (Figure 1).
nactivated carbon−hydrogen (C−H) bond functionaliza-
U
tion is a powerful tool for chemical synthesis, enabling an
array of new approaches to the construction and late-stage
derivatization of complex molecules.1 In drug discovery and
development, C−H functionalization offers tools to facilitate the
preparation of structural analogs of targets with enhanced
structure−activity relationships (SAR) or other desired phys-
icochemical properties without de novo approaches.2 Owing to
the plethora of different C−H bonds present in most organic
molecules, great effort has been devoted to the site-selective and
predictable functionalization of C−H bonds in complex targets.
Intramolecular, or substrate-directed, C−H functionalizations
are widely used in chemical synthesis, as these reactions benefit
from exquisite site selectivity and improved kinetics provided by
the functionality present in the substrate. However, this approach
is inherently limited by the requisite functionality and lacks
generality in applications to diverse structures. The development
of site-selective, intermolecular C−H functionalizations of
isolated aliphatic C−H bonds is a significantly more daunting
challenge, as these processes lack the advantages of intra-
molecular reactions.
Upon surveying functional groups for transfer to maximize
molecular diversity, the xanthate (dithiocarbonate) group
appeared ideally suited for this purpose. Zard and others have
demonstrated the versatility of alkyl xanthates in radical-
mediated synthesis to access an impressive array of valuable
Important recent studies have sought to address this challenge
and have provided a number of practical methods for
intermolecular C−H functionalizations using a substrate as the
limiting reagent with good efficiency. For example, trans-
formations achieving the oxidation,3 azidation,4 and halogen-
ation5 of isolated aliphatic C−H bonds have appeared with good
site selectivities, functional group compatibilities, and notable
application to the derivatization of complex molecules and
natural products. However, the limited set of molecular
functionality accessible via these strategies restricts the chemical
space and subsequent utility of C−H functionalizations.
Figure 1. Approaches to site-selective, intermolecular C−H function-
alization.
Received: September 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b09414
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Journal of the American Chemical Society
Communication
functionality.7 The diverse array of aliphatic C−H functionaliza-
tions potentially accessible via alkyl xanthates includes many
unknown transformations (e.g., C−H to C−S).8 Therefore, we
hypothesized that a site-selective aliphatic C−H xanthylation
would significantly increase the power of intermolecular C−H
functionalization in synthesis and facilitate new late-stage
modifications of complex molecules.9
Since the xanthate functionality participates in radical-
mediated group transfer processes, we targeted the preparation
of N-xanthylamide 1 as an initial goal. We anticipated that a
successful aliphatic C−H xanthylation using 1 would display the
notable site selectivity and chemoselectivity of our prior C−H
halogenation, as both processes would involve similar amidyl
radical intermediates. The synthesis of 1 via the direct N-
xanthylation of amides with strong base was unsuccessful,10 but
we were able to develop a new approach that avoids the use of
strongly basic conditions and is also amenable to large-scale
preparation: the reaction of the parent N-chloroamide of 1 with
inexpensive potassium ethyl xanthate provided facile access to
shelf-stable N-xanthylamide 1 on decagram scale.11
for the 2-position. The xanthylation of norbornane provided 7 as
the single exo diastereomer in 49% yield. The sterically dictated
site selectivity of 1 is clear from the reactions of adamantane and
trans-decalin: the functionalization of adamantane greatly
favored the less hindered 3° C−H sites, providing xanthate 8
as a single product in 70% yield. The reaction of trans-decalin
proceeded with a high methylene/methine site selectivity (ks/kt
= >99).
We next surveyed a range of heterocycles and functionalized
acyclic substrates to study the site selectivity and functional
group compatibility of the C−H xanthylation (Figure 2).
Xanthylation adjacent to heteroatoms was efficient across a
number of substrates, with hyperconjugation likely assisting in
the site selectivity. For example, the xanthylations of
tetrahydrofuran and 1,4-dioxane delivered 10 and 11,
respectively, in useful yields. Although reagent 1 possesses
similar C−H bonds adjacent to oxygen, no products resulting
from such abstraction were observed. The reactions of important
nitrogen heterocycles were successful, as demonstrated by the
functionalizations of 2-methoxypyridines to afford 12 and 13 in
addition to N-methyl pyrrole giving 14. These substrates
demonstrate that the system tolerates nitrogen functionality
that can pose a challenge to metal-oxo catalysts. The electron-
withdrawing N-phthalimide functionality of linear substrate 15
dictates selective functionalization of the distal methylene sites,
with a δ selectivity of 64% (68% combined yield). In addition, the
xanthylation of 15-crown-5 afforded 16 in good yield (67%),
providing a new approach to the derivatization of crown ethers.
The electronic site selectivity of the C−H xanthylation across a
number of acyclic compounds (17−20) indicates a preference
for reaction at the most electron-rich methylene sites, consistent
with our previous studies involving amidyl radicals. These C−H
xanthylations proceed in good overall yields, with site selectivities
comparable (or superior) to those of most metal-catalyzed
processes.
With key reagent 1 in hand, we commenced our studies of the
aliphatic C−H xanthylation with a number of simple hydro-
carbons using the substrate as the limiting reagent to ensure
reaction practicality (Figure 2).12 Reactions of 1 with cyclo-
We were keenly interested in ascertaining the potential for site-
selective C−H xanthylations of complex molecules owing to the
range of structures accessible via the xanthate functional group. A
number of diverse complex natural products and drug precursors
were studied in this context (Figure 3). The C−H xanthylations
Figure 2. Products of C−H xanthylation. Yields refer to NMR yield with
hexamethyldisiloxane (HMDS) as an internal standard or GC yield with
dodecane as an internal standard. *Isolated yield.
Figure 3. Aliphatic C−H xanthylations of complex molecules. Yields
refer to isolated yields. *NMR yield.
alkanes in PhCF3 using blue LED irradiation provided alkyl
xanthates 2−5 in good yields (59−85%). A competition
experiment between cyclohexane and d12-cyclohexane indicated
a kinetic isotope effect of 6.3, comparable to our C−H
halogenations and consistent with irreversible C−H abstraction
by an amidyl radical. The C−H xanthylation of n-hexane favored
the methylene sites with ksecondary/kprimary (ks/kp) ≈ 11 after
correcting for the number of hydrogen atoms, with a preference
of the terpenoids (+)-sclareolide and (−)-ambroxide delivered
xanthates 21 and 22 in 55% and 80% yield, respectively.13 The
xanthylation reaction is amenable to scale-up, delivering xanthate
21 in 54% yield on gram scale. In both cases we observed
functionalization at a single site, with (+)-sclareolide reacting at
the sterically most accessible, electron-rich methylene site and
(−)-ambroxide reacting at the position activated by hyper-
B
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Journal of the American Chemical Society
Communication
conjugation. Functionalization of a precursor to the topical
retinoid differin occurred at the most accessible tertiary C−H
site, giving xanthate 23 in 51% yield. Notably, this xanthylation
succeeds in the presence of an electron-rich aromatic ring, which
would likely pose a major challenge for alternative strategies
involving oxidizing intermediates. The reaction of 5α-cholestane
occurred on the steroidal A-ring, with a 3:1 site selectivity
favoring the C3 position to give product 24; this selectivity is
remarkable since the substrate contains seven tertiary C−H
bonds and 13 methylene sites for functionalization with no
inherent substrate electronic bias. Steroid trans-androsterone
acetate underwent xanthylation to afford C6 and C2
functionalization products 25 in a 1:1 ratio as single
diastereomers (56% combined yield). We next questioned
whether electronic deactivation of the steroidal A-ring would
enable site-selective functionalization of the B-ring. Steroid 5α-
androstanedione, with ketone deactivation of the A-ring,
exhibited perfect diastereoselectivity and site selectivity on the
B-ring, delivering xanthate 26 as a single product in 44% yield. As
a comparison, the C−H oxidation of this substrate with a number
of Fe-catalysts proceeded with poor site selectivity involving
several methylene and methine positions,3e highlighting the
unique capabilities of our system in the steric and electronic
differentiation of the C−H sites.14 As a final challenge, we
examined the C−H xanthylation of the terpenoid (+)−
longifolene, a classic target for studies in organic synthesis.
This substrate poses a significant chemoselectivity challenge for
alternative C−H functionalizations involving oxidizing inter-
mediates, as the alkene is known to undergo facile oxidation and
skeletal rearrangement.15 The xanthylation of (+)-longifolene
with reagent 1 under solvent-free conditions provides xanthate
27 as a single diastereomer with excellent site selectivity. The
regioselectivity of the reaction can be rationalized by selective
C−H abstraction of the less hindered ring system away from the
quaternary centers in the substrate, and the mild conditions of
the C−H xanthylation minimize any undesired alkene
functionalization.
Figure 4. Aliphatic C−H transformations of complex substrates. Yields
refer to isolated yields.
oxidation of alcohols to ketones is a major concern.20
A
functional group interconversion from an alkyl xanthate could
enable control of the product oxidation state, and the mild
conditions of our approach would allow C−H oxidation of
substrates containing oxidation-sensitive functionality. We have
developed a xanthate to hydroxyl group interconversion,
constituting a formal C−H hydroxylation using xanthylamides.
The reaction of C6-functionalized steroidal xanthate 25 with
persistent radical TEMPO and tris(trimethylsilyl)silane followed
by mild reduction of the intermediate alkoxyamine delivered
alcohol 31 in good yield (56%).21 Alternatively, oxidation of the
alkoxyamine using mCPBA selectively yields a ketone product
(59% yield).22 This approach allows complete reagent control of
the product oxidation state, offering an attractive solution to
major challenges in aliphatic C−H oxidation.
The trifluoromethylthiol group has become invaluable in the
preparation of bioactive compounds owing to its high electro-
negativity and ability to modulate the lipophilicity of drug
molecules.23 Recent reports of aliphatic C−H trifluoromethylth-
iolation using AgSCF3 and persulfate oxidants have emerged, but
are generally selective for tertiary C−H bonds and often require
excess substrate to obtain synthetically useful yields.24 We have
developed simple conditions to introduce the trifluoromethylth-
iol group from alkyl xanthates using an easily accessible reagent
developed by Shen, as shown in the preparation of 32.25 This
provides a general approach to formal aliphatic C−H trifluoro-
methylthiolation using the substrate as the limiting reagent,
appropriate for late-stage functionalizations of complex sub-
strates.
We view the aliphatic C−H xanthylation herein as a platform
technology serving to unlock an array of important C−H
transformations, including many with no synthetic precedent.
Our approach exploits the impressive versatility of alkyl xanthates
in a broad range of radical-mediated as well as polar bond-
forming reactions. An initial demonstration of this approach is
outlined in Figure 4. For example, the product of C−H
vinylation, 28, is readily accessed from differin precursor xanthate
23 via radical coupling with ethyl styryl sulfone.16 Lewis acid
mediated addition of bistrimethylsilyl thymine to (−)-ambroxide
xanthate 22 delivers N-alkyl thymine derivative 29 in high yield
(87%), highlighting the utility of the xanthate group in polar
reactions.17
The selective deuteration of aliphatic C−H bonds represents
another attractive yet undeveloped transformation. Such a
process would expedite the preparation of isotopically labeled
compounds for mechanistic and metabolic studies and offer an
attractive route to deuterated drugs with enhanced pharmaco-
kinetic properties.18 The reaction of amino acid derivative
xanthate 20 with CD3OD using Et3B/O2 initiation provides
deuterated product 30 in good yield (71%, 85% deuterium
incorporation).19 Thus, the xanthylation−deuteration sequence
constitutes a formal, site-selective monodeuteration of aliphatic
C−H bonds, which, to our knowledge, does not exist.
The thiol−ene addition is useful for bioconjugation, offering a
bioorthogonal alternative to azide−alkyne cycloadditions, with
additional applications in polymer synthesis and materials
science.26 In this light, a site-selective, aliphatic C−H thiolation
would enable a formal thiol−ene from alkane starting materials.
The C−H xanthylation is ideal for such a transformation: simple
workup with an amine base provides thiols in excellent yield. As a
Oxidations of unactivated aliphatic C−H bonds are likely the
most studied intermolecular C−H transformation, but over-
C
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coupling of (+)-longifolene xanthate 27 with a glucose-derived
allyl glycoside. Following quantitative conversion of 27 to its
thiol derivative, photochemical thiol−ene delivered glycoconju-
gated (+)-longifolene adduct 33 in 62% yield. Considering the
mild conditions and functional group compatibility of the C−H
xanthylation and the broad utility of the thiol−ene process, we
expect this tactic will offer major opportunities in the conjugation
of complex molecules. We would also note that while Figure 4
offers a number of attractive avenues for molecular derivatization
via C−H xanthylation, this is certainly not comprehensive.
Alkylation, alkynylation,16 and acylation reactions,27 among
others, are also possible using alkyl xanthates.
Applying different transformations to a single xanthate
substrate provides facile access to a wide range of derivatives
via a C−H diversification approach. As an example, (+)−
sclareolide xanthate 21 is converted to seven different derivatives
in a single step following the initial C−H xanthylation (Figure 4).
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only does the xanthylation unlock new aliphatic C−H trans-
formations, it also facilitates the synthesis of diverse analogs via a
simple switch of reagent in the product elaboration rather than
through the application of a new C−H functionalization.
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addition to our previous efforts in C−H halogenation, clearly
highlights the unique capabilities of functionalized amides in
enabling a broad range of practical aliphatic C−H trans-
formations. These studies also demonstrate the potential for
enhanced site selectivity and functional group compatibility with
respect to other aliphatic C−H functionalizations. We anticipate
that these characteristics will lead to powerful applications in
molecular derivatization for the synthesis and study of
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1
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(14) Oxidation at the C6 site of cholestanol acetate has been reported
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b09414.
■
in very low yield (1.6%): Barton, D. H. R.; Gokturk, A. K.; Morzycki, J.
̈
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Experimental procedures and spectral data for all new
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AUTHOR INFORMATION
Corresponding Author
*eja@email.unc.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the ACS PRF (55108-ND1),
Award R01 GM 120163 from the National Institute of General
Medical Sciences, an Eliel Award (W.L.C.), and a Royster
Fellowship (C.G.N.).
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