δ-Selective functionalization of alkanols enabled by visible-light-induced ligand-to-metal charge transfer

Article abstract of DOI:10.1021/jacs.7b13131

We demonstrate the application of ligand-to-metal charge transfer (LMCT) excitation to the direct catalytic generation of energetically challenging alkoxy radicals from alcohols through a coordination-LMCT-homolysis process with an abundant and inexpensive cerium salt as the catalyst. This catalytic manifold provides a simple and efficient way to utilize the characteristic reactivity and selectivity of transient alkoxy radicals for δ-selective C-H bond functionalization. Under mild redox-neutral conditions without the need for prefunctionalization, this method provides a versatile platform to access molecular complexity from simple and abundant alcohols.

Full text of DOI:10.1021/jacs.7b13131

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δ‑Selective Functionalization of Alkanols Enabled by Visible-Light-
Induced Ligand-to-Metal Charge Transfer
Anhua Hu,†,§ Jing-Jing Guo,†,§ Hui Pan,† Haoming Tang,† Zhaobo Gao,‡ and Zhiwei Zuo*,†
†School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
‡Jiuzhou Pharmaceutical, Zhejiang 318000, China
S
* Supporting Information
ABSTRACT: We demonstrate the application of ligand-
to-metal charge transfer (LMCT) excitation to the direct
catalytic generation of energetically challenging alkoxy
radicals from alcohols through a coordination−LMCT−
homolysis process with an abundant and inexpensive
cerium salt as the catalyst. This catalytic manifold provides
a simple and efficient way to utilize the characteristic
reactivity and selectivity of transient alkoxy radicals for δ-
selective C−H bond functionalization. Under mild redox-
neutral conditions without the need for prefunctionaliza-
tion, this method provides a versatile platform to access
molecular complexity from simple and abundant alcohols.
ver the past decade, photoredox catalysis has emerged as
Oa powerful tool for the construction of molecular
Figure 1. Coordination−LMCT−homolysis activation mode allows
complexity, most prominently with the generation of high-
energy heteroatom-centered radicals as an enabling platform.1
Typically, these radicals are accessed via single-electron transfer
(SET) with a triplet excited state of a metal−polypyridyl
photocatalyst generated through visible-light-induced metal-to-
ligand charge transfer (MLCT).2 An alternative excitation
manifold, ligand-to-metal charge transfer (LMCT), has
comparatively been underexploited in the realm of synthetic
organic chemistry, despite holding great promise for the
development of novel photoinduced transformations.
general access to alkoxy radicals.
valuable transformations.8 Thus, a general catalytic platform for
the direct generation of alkoxy radicals from alcohols remains in
high demand.
LMCT excitation promotes homolysis of a metal−ligand
bond to generate ligand-based radical intermediates in a formal
reduction of the metal center,9,10 resulting in oxidation of the
ligand directly, presenting an opportunity for facile photo-
catalytic access to heteroatom-centered radicals. LMCT
catalysis, which proceeds through coordination of the substrate
to an inorganic salt, photoinduced LMCT, and subsequent
homolysis, is a mechanistically distinct photoredox activation
mode that promotes substrate oxidation not through SET by an
excited or oxidized photocatalyst but in the excitation process
itself. This allows for targeted oxidation to occur only at the
transiently coordinated functional group while leaving other,
easier-to-oxidize functionalities intact. Thus, more challenging
oxidations, such as that of alkoxides, can be selectively
accomplished by directly exciting the LMCT band of the
coordination complex, delivering alkoxy radicals in a simplified
and truly general form under mild conditions. This approach
would further improve the ease of application, as only a simple,
photoinactive inorganic salt would be required, with coordina-
tion to the substrate triggering the photocatalytic activity.
Interestingly, this strategy has not been thoroughly investigated
Heteroatom-centered radicals have traditionally been utilized
as highly versatile synthetic intermediates in transformations
such as the Hoffman−Loffler−Freytag and Barton nitrite ester
reactions.3 Nevertheless, the synthetic potential of their well-
established reactivity and selectivity in 1,5-hydrogen atom
transfer (1,5-HAT) is frequently restrained by the difficulties
inherent in the generation of these transient, high-energy
radicals, which typically relies upon the utilization of
prefunctionalized precursors of alcohols and amines or harsh
conditions.4,5 In contrast, direct homolytic activation of free
alcohols and amines represents the most straightforward and
demanding strategy;2d,e,6 however, this has generally proven
challenging because of the remarkable stability of the X−H
bonds (the O−H bond dissociation energy is ∼105 kcal/mol).7
Through the concerted transfer of a proton and electron,
proton-coupled electron transfer (PCET) catalysis has recently
emerged as a novel and efficient strategy for the general
activation of N−H bonds, as well as O−H bonds in one
catalytic example based on a series of electron-rich arene-
substituted tertiary alcohols, to promote various synthetically
Received: December 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b13131
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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and utilized in the organic synthesis community, likely because
of the popularity of coordinatively saturated photocatalysts.11
Herein we demonstrate the application of LMCT catalysis as a
direct and general method for the catalytic generation of alkoxy
radicals from alcohols and the successful development of an
atom-economical and operationally simple protocol for site-
selective remote C−H bond functionalizations of primary
alcohols (Figure 1).
Given the ubiquity and importance of amines in
pharmaceuticals and natural products, we sought to achieve
the site-selective installation of nitrogenous functionality on
abundant carbinols. We posited that abundant and inexpensive
cerium salts would be ideal catalysts for a sustainable
photocatalytic system;12,13 furthermore, Ce(IV) complexes are
well-precedented in the inorganic chemistry literature to
participate in redox reactions induced by LMCT excitation,
resulting in reduction of the cerium center to Ce(III) and
oxidation of the ligand.14 Intrigued by the ability of alcohols to
ligate to the metal center,15 we envisioned that the coordination
complex could be readily photoexcited by visible-light
irradiation and subsequently undergo Ce(IV)−OR homolysis
to generate the transient alkoxy radical from a simple or
complex alkanol, such as butanol or cholesterol (Figure 2A).
regenerate the active Ce(IV) catalyst and deliver the desired
product.
With this mechanistic hypothesis in hand, we first examined
the proposed C−H bond functionalization using 1-pentanol,
DBAD, tert-butylammonium chloride (TBACl), cerium cata-
lysts, and blue light-emitting diodes (LEDs) (Figure 2B).
Among the commercially available cerium(IV) reagents, we
found that the desired product could be isolated in 13% yield
when cerium(IV) triflate was employed (see the Supporting
Information for further experimental results). With a premade
cerium(IV) chloride complex,17 a light-sensitive yellow
compound, excellent efficiency could be achieved, delivering
the δ-functionalized alcohol in 89% yield. Control experiments
revealed the importance of the cerium catalyst and light, as no
desired product was observed in the absence of either the
catalyst or blue light. Furthermore, operating the reaction in the
dark at elevated temperature led to no observed product
formation, even at a higher catalyst loading. To further simplify
the reaction conditions and build on our previous success of
C−C bond activation of cycloalkanols,13 commercially available
cerium(III) chloride was identified to be a suitable precatalyst,
as a 92% yield of the desired product was observed after 8 h
under neutral conditions without base.
As a means of elucidating the mechanism of this proposed
LMCT-induced transformation, a number of UV−vis experi-
ments were conducted (Figure 3). The absorption spectrum of
the Ce(IV)−alkoxide complex formed from a premade
CeIVCl6 complex and pentanol under basic conditions
2−
according to the protocol reported by the Anwander group15d
displayed a band resembling the LMCT band of analogous
cerium−alkoxide complexes,14a,15d critically, exhibited substan-
tial overlap with the blue LED spectrum, suggesting that the
Ce(IV)−alkoxide species could be photoexcited in this reaction
(Figure S1). We then probed this possibility by analyzing the
absorption spectra of Ce(IV) complexes after irradiation with
blue light at different time points. As shown in Figure 3A, the
absorption spectrum of a solution containing Ce(IV)−alkoxide
complex gradually shifts from λmax = 370 nm to λmax= 330 nm
a
Figure 2. Reaction design and development. Yields were determined
b
by GC analysis of the crude reaction mixtures. The reaction was
performed without base.
Figure 3. Mechanistic studies. (A) UV−vis spectral changes observed
upon photolysis of a solution of CeIV(OC5H11)Cln complex in CH3CN
under blue light (0−20 min). (B) Operando IR experiments with a
solution of (n-Bu4N)2CeCl6 and 2-methyl-1-phenyl-2-propanol in the
dark (0−15 min) and with blue-light irradiation (15−25 min). (C)
Reaction profiles for the δ-C−H amination of 1-pentanol catalyzed by
(n-Bu4N)2CeCl6 and CeCl3. See the Supporting Information for
experimental details.
We anticipated that the δ-C−H bond would then be selectively
activated via a thermodynamically favorable 1,5-HAT to
generate the highly nucleophilic alkyl radical, which would
readily undergo coupling with di-tert-butyl azodiformate
(DBAD) to forge a new C−N bond with the formation of a
nitrogen-centered radical.16 Single-electron reduction of this
radical by the reduced form of the cerium catalyst would
B
DOI: 10.1021/jacs.7b13131
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a
Figure 4. Reaction scope. General reaction conditions: DBAD (0.4 mmol), alcohol substrate (1.2 mmol), CeCl3 (0.004 mmol), TBACl (0.02
mmol), CH3CN (4 mL), 90 W blue LEDs. All yields are isolated yields. Diastereoselectivity was determined by 1H NMR or HPLC analysis. See the
b
Supporting Information for full reaction scope and experimental details. The reaction was performed with 2 mol % CeCl3 and 10 mol % TBACl.
upon irradiation, indicative of a photoinduced homolysis event
to generate a Ce(III) complex,14c while the Ce(IV)−alkoxide
complex is completely stable in the dark (Figure S3), indicating
that ground-state SET is not operative. To further elucidate the
alkoxy radical formation process via LMCT, operando IR
experiments with a solution of (n-Bu4N)2CeIVCl6 and 2-methyl-
1-phenyl-2-propanol was performed. In this case, the oxidation
of the tertiary alcohol would lead to a fast β-scission pathway to
generate acetone, which is easily quantified by IR spectroscopy,
as the C−C bond cleavage product. No acetone formation was
detected in the dark (0−15 min), but when the light was turned
on (15−25 min), acetone formation (10% yield in 5 min) via
photoinduced LMCT generation of the transient tert-alkoxy
radical was observed (Figure 3B). When the reaction profiles of
this remote functionalization transformation with the cerium-
(IV) chloride complex and cerium(III) chloride are compared,
a marked induction period is observed for CeCl3 (Figure 3C).
These observations indicate that CeCl3 was functionalized as
the precatalyst. We reasoned that Ce(III) species (E1/2(CeIII/
CeIV) = 0.41 V vs SCE in CH3CN) can be activated in situ by a
photoinduced single-electron oxidation with DBAD18 (E* =
1.66 V vs SCE in CH3CN; see the Supporting Information). In
combination, these studies describe a unique approach to the
mild catalytic generation of alkoxy radicals using a simple,
commercially available earth-abundant metal salt as a photo-
catalyst.
We next evaluated the generality of this atom-economical
and operationally simple protocol. As partially shown in Figure
4, diverse classes of alcohols could be selectively and
predictably functionalized under mild and redox-neutral
conditions (see the Supporting Information for expanded
reaction scope). Because of the high reactivity of alkoxy
radicals, primary (2), secondary (3−12), and tertiary (13−18)
carbon centers could all be functionalized with good efficiency.
Critically, for substrates in which weaker, activated C−H bonds
were present, only δ-functionalized products were observed in
all cases (8−12, 15, 17, and 18). These results further
emphasize the exquisite control that a catalytic 1,5-HAT
mechanistic pathway affords for C−H abstraction. Further-
more, the highly electrophilic nature of the alkoxy radical offers
additional polarity-based selectivity. Thus, a substrate contain-
ing multiple electronically differentiated δ-C−H bonds under-
goes selective functionalization at the most electron-rich carbon
center, as exemplified by product 13. As expected, easily
oxidized moieties, such as electron-rich arenes (4) and alkenes
(17), were not oxidized in this system because of the
C
DOI: 10.1021/jacs.7b13131
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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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.7b13131.
■
S
Experimental procedures and additional data (PDF)
AUTHOR INFORMATION
Corresponding Author
*zuozhw@shanghaitech.edu.cn
ORCID
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21772121) and the “Thousand Plan” Youth Program for
financial support and J. M. Lipshultz (Princeton University) for
discussions.
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