α-Aminoxy-Acid-Auxiliary-Enabled Intermolecular Radical γ-C(sp3)?H Functionalization of Ketones

Article abstract of DOI:10.1002/anie.201712066

A method for site-specific intermolecular γ-C(sp³)?H functionalization of ketones has been developed using an α-aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5-hydrogen ato

Full text of DOI:10.1002/anie.201712066

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Accepted Article
Title: α-Aminoxy Acid Auxiliary Enabled Intermolecular Radical γ-
C(sp3)-H Functionalization of Ketones
Authors: Heng Jiang and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712066
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-Aminoxy Acid Auxiliary Enabled Intermolecular Radical
-C(sp3)H Functionalization of Ketones
Heng Jiang and Armido Studer*
Dedication ((optional))
Abstract: A method for site specific intermolecular -C(sp3)–H
functionalization of ketones has been developed using an -
aminoxy acid auxiliary applying photoredox catalysis.
Regioselective activation of an inert C–H bond is achieved via
1,5-hydrogen atom abstraction by an oxidatively generated
iminyl radical. Tertiary and secondary C-radicals thus formed at
the -position of the imine functionality undergo radical conjugate
addition to various Michael acceptors to provide after reduction
and imine hydrolysis the corresponding -functionalized ketones.
conceived that -imino-oxy acids could also be used as
substrates for -C(sp3)–H functionalization of ketones through a
redox neutral cascade involving two single electron transfer
(SET) steps (Scheme 1c, bottom).[13]
Ketones are valuable substrates in organic synthesis due to
their well understood and broad reactivity.[1] -C(sp3)–H bond
functionalization of ketones, typically achieved via their enolate
intermediates, has been used successfully during the last
century (Scheme 1a, left).[2] The non-activated more challenging
ketone -C(sp3)–H bond could be functionalized using Pd-
catalyzed directed C–H activation with imine type auxiliaries or
other transient directing groups.[3,4] Synergistic photoredox and
enamine catalysis has been successfully used to activate -
C(sp3)–H bonds in cyclic ketones through single electron
oxidation of in situ formed enamines and subsequent -C(sp3)–H
deprotonation (Scheme 1a, middle).[5] However, an efficient
strategy for intermolecular -C(sp3)–H bond functionalization of
ketones has not been disclosed to date (Scheme 1a, right).[6]
A
reliable approach for regioselective C(sp3)–H bond
functionalization is the 1,5-hydrogen atom transfer (HAT) to a
heteroatom centered radical to generate the corresponding
translocated C-radical that can be further functionalized by
established radical methodology.[7] Recent advances in that area
involve photoredox catalyzed distal C(sp3)–H functionalization of
amides, amines and alcohols through 1,5-HAT and
intermolecular C–C bond formation.[8] Iminyl radicals, that are
versatile intermediates for construction of N-heterocycles,[9] have
been shown to engage in 1,5-hydrogen atom abstractions
followed by cyclization[10] or fluorination[11] of the translocated C-
radicals (Scheme 1b). To our knowledge, C–C bond formation
by intermolecular trapping of C-radicals generated by 1,5-HAT to
iminyl radicals has not been reported to date.
We envisioned to apply such an HAT as key step for
intermolecular -C(sp3)–H bond functionalization of ketones.
Leonori et al. and our group independently reported a method
for clean generation of iminyl radicals from -imino-oxy acids by
photoredox catalysis.[12] The cascade affords diverse pyrrolines
through sequential intramolecular carboimination, radical
conjugate addition and reduction (Scheme 1c, top). We
Scheme 1. C(sp3)–H functionalization of ketones.
-Imino-oxy acids readily prepared by condensation of
ketones with -aminoxy acids first react via single electron
oxidation, decarboxylation and acetaldehyde fragmentation to
the corresponding iminyl radicals. HAT from the distal C(sp3)–H
bond to the iminyl radical leads to the -C-radical that can be
trapped intermolecularly by C–C bond formation with a Michael
acceptor to give after reduction and imine hydrolysis a -C(sp3)–
H functionalized ketone. Since the overall cascade requests an
initial SET oxidation step for iminyl radical generation and an
SET reduction step of the Michael adduct radical, the whole
process is redox-neutral and should be realizable with an
appropriate redox catalyst in the absence of any external oxidant
or reductant.[14] Herein we report first results by using an iridium
complex based photoredox catalyst.[15,16,17]
[*]
Dr. H. Jiang, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraß 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de Supporting information for this
article is given via a link at the end of the document.
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Table 2. Variation of the -imino-oxy acids.[a],[b]
Table 1. Reaction optimization.
entry[a]
photocatalyst R1, R2
yield (%)[b]
51
PC1
PC1
PC1
PC1
PC2
PC3
–
H, H (1a)
1
Me, Me (1b)
H, Me (1c)
H, Ph (1d)
H, Me (1c)
H, Me (1c)
H, Me (1c)
H, Me (1c)
H, Me (1c)
73
2
81 (75)[c]
77
3
4
11
5
31
6
n.d.
n.d.
n.d.
7
8[d]
9[e]
PC1
PC1
[a] Reaction conditions: A mixture of 1 (0.1 mmol, 1.0 equiv), 2a (0.2 mmol,
2.0 equiv), photocatalyst (0.001 mmol, 1.0 mol%), base (0.2 mmol, 2.0 equiv)
in CHCl3 (1.0 mL, 0.1 M) was irradiated by a 10 W blue LEDs at 26 °C for 24 h.
For imine hydrolysis, 1.0 mL H2O was added and the mixture was stirred for
30 minutes at room temperature. [b] The yield was determined by 1H NMR
analysis using CH2Br2 as an internal standard. [c] Isolated yield at 0.2 mmol
scale. [d] Conducted in the absence of CsF. [e] Conducted in the dark.
Optimization studies were conducted using four different α-
aminoxy acids as auxiliaries, three Ir-based photocatalysts (PC1,
PC2, and PC3) in combination with 3-methylbutyl phenyl ketone
and methyl 2-phenylacrylate (2a) as radical acceptor. Oxime
ethers 1a-d were prepared by condensation of the
corresponding -aminoxy acid with 3-methylbutyl phenyl ketone.
Blue LED light irradiation of a CHCl3 solution containing 1a, 2a,
PC1 (1 mol%) and CsF for 16 h afforded the -C(sp3)–H
functionalized ketone 3a in 51% yield (Table 1, entry 1). With 2-
imino-oxy isobutyric acid 1b, 3a was obtained in 73% yield
(Table 1, entry 2). A further improvement was achieved by using
2-aminoxy propionic acid as the auxiliary (81%, Table 1, entry 3).
The 2-imino-oxy 2-phenylacetic acid 1d was also a competent
substrate providing a comparable yield (77%, Table 1, entry 4).
Other solvents and potassium or sodium salts such as K2CO3,
KOAc, NaOAc, and Na2HPO4 provided worse results (see
Supporting Information). The catalysts PC2 and PC3 led to
significantly lower yields (Table 1, entries 5, 6). In control
experiments, 3a was not detected in the absence of either
photocatalyst or CsF (Table 1, entries 7, 8). As a signature of a
photoredox catalyzed process, this cascade did not proceed in
the dark (Table 1, entry 9).
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1.0 equiv), 2a (0.4 mmol,
2.0 equiv), PC1 (0.002 mmol, 1.0 mol%), CsF (0.4 mmol, 2.0 equiv) in CHCl3
(2.0 mL, 0.1 M) was irradiated by a 10 W blue LED at 26 °C for 16 h. For imine
hydrolysis, 1.0 mL H2O was added and the mixture was stirred for 30 minutes
at room temperature. [b] Isolated yields are provided.
Under optimized conditions, we examined the scope with
respect to the ketone moiety keeping 2a as the radical acceptor
(Table 2). The phenyl group in the oxime ether in 1c could be
replaced by electron rich or electron poor para-substituted
phenyl groups and the targeted -C(sp3)–H functionalized
ketones 3b-e were obtained in good yields. 2-Naphthyl, 2-thienyl
and 3-pyridyl were also tolerated as R1-substituents to afford 3f-
h in 67-80% yields. Importantly, the cascade is not restricted to
aryl alkyl oxime ethers and di-alkyl oxime ethers also work. For
i
t
instance, the Me, Pr and Bu-substituted oxime ethers provided
3i-k in 47-84% yield. Functional group tolerance was
documented by the successful transformation of anisole (3l),
ester (3m) and Cbz-piperidine (3n) containing substrates (51-
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81%). The tert-alkyl moiety to be functionalized was varied next
and we found that C–H bonds in cyclic and acyclic systems
could be functionalized (3o-q). We further showed that
secondary benzylic C–H bonds can be modified, as documented
by the preparation of 3r (83%). Due to the lower stability of a
secondary alkyl radical and accordingly less efficient 1,5-HAT,
yield for methylene C–H bond functionalization was significantly
lower (3s, 31%). As expected, in these two cases, C–C bond
formation occurred with poor diastereoselectivity and -C(sp3)–H
alkylation of an -substituted ketone also proceeded without any
selectivity (see 3t).
reason for the observed lower yields. Other Michael acceptors
such as acrylonitrile, methyl acrylate and nitroethene did not
engage in the remote functionalization.
Notably, the imine functionality in the crude products can be
conserved by in situ benzoyl protection. As an example, Bz-
imine 5 was obtained in 71% yield in the reaction of 1c with 2a
by adding benzoyl chloride to the crude product after visible light
irradiation further documenting the synthetic value of the method
since the activated imine functionality in 5 offers a rich
downstream chemistry (Eq. 1).[17]
Table 3. Variation of the radical acceptor.[a],[b]
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0
equiv), PC1 (0.002 mmol, 1.0 mol%), CsF (0.4 mmol, 2.0 equiv) in CHCl3 (2.0
mL, 0.1 M) was irradiated by a 10 W blue LED at 26 °C for 16 h. For imine
hydrolysis, 1.0 mL H2O was added and the mixture was stirred for 30 minutes
at room temperature. [b] Isolated yields are provided. [c] DCM was used
instead of CHCl3 and 3.0 equiv Michael acceptor was used.
Scheme 2. Suggested mechanism.
The suggested mechanism is depicted in Scheme 2. Photo-
We next varied the radical acceptor mainly using 1c as the
substrate. Various 2-arylacrylates show good reactivity and the
ketones 4a-g were obtained in 53-77% yield (Table 3). The
methyl ester in 2a can be replaced by a benzyl ester and -
C(sp3)–H modification worked with similar efficiency (4h, 81%).
Ⅲ
excitation of Ir (dFCF3ppy)2(dtbbpy)PF6 by visible light leads to
Ⅲ
the excited *Ir (dFCF3ppy)2(dtbbpy)PF6 complex, which is SET
reduced by carboxylate A, formed by deprotonation of substrate
1, to generate the carboxyl radical
Ⅱ
B
along with
Ir (dFCF3ppy)2(dtbbpy)PF6. Sequential fragmentation of CO2
and acetaldehyde from B generates the iminyl radical C.
Hydrogen transfer from the distal C–H bond to the iminyl radical
provides C-radical D which then reacts via intermolecular
conjugate addition to give the adduct radical E. The photoredox
Phenyl 1-phenylvinyl ketone is also
a competent radical
acceptor providing 4i in 55% yield. In addition, methyl vinyl
ketone and ethyl vinyl ketone reacted with 1c to the
corresponding ketones 4k (31%) and 4l (33%), albeit yield
significantly decreased. The same observation was made for
functionalization of the secondary benzylic C–H bond with
methyl vinyl ketone (see 4j). These alkyl vinyl ketones are
known to readily undergo polymerization what is likely the
cycle is closed through SET reduction of
E
by
Ⅱ
Ir (dFCF3ppy)2(dtbbpy)PF6 to provide F thereby regenerating the
Ⅲ
ground-state
photocatalyst
Ir (dFCF3ppy)2(dtbbpy)PF6.
Protonation and imine hydrolysis of F eventually afford 3 or 4.
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In summary, we have developed a photoredox catalyzed -
C(sp3)–H functionalization of ketones using the readily
accessible -aminoxy propionic acid as an auxiliary.
Condensation of a ketone with the auxiliary provides the
substrate oxime ether which upon SET oxidation with an iridium
photocatalyst provides the corresponding iminyl radical. H-atom
abstraction from a distal C–H bond to the iminyl radical allows
for site selective generation of secondary and tertiary alkyl
radicals, which undergo conjugate addition to provide after
reduction and imine hydrolysis the corresponding -
functionalized ketones. The overall redox neutral transformation
proceeds under mild conditions and a wide range of functional
groups are tolerated.
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This work was supported by the Alexander von Humboldt
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Conflict of Inerest
The authors declare no conflict of interest.
Keywords: C-H bond functionalization • photoredox chemistry •
iminyl radical • redox-neutral • ketone
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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H. Jiang, A. Studer*
Page No. – Page No.
α-Aminoxy Acid Auxiliary Enabled
Intermolecular Radical
C(sp3)H Functionalization of
Ketones
γ-
Auxiliary and Light! A method for site specific intermolecular γ-C(sp3)-H
functionalization of ketones has been developed using an -aminoxy acid auxiliary
applying photoredox catalysis.
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