Iminyl Radical-Mediated Controlled Hydroxyalkylation of Remote C(sp3)-H Bond via Tandem 1,5-HAT and Difunctionalization of Aryl Alkenes

Article abstract of DOI:10.1002/adsc.201801198

A visible-light mediated γ-hydroxyalkylation of ketones via C(sp³)-H functionalization has been developed under redox neutral conditions. This protocol relies on the iminyl radical-triggered 1,5-HAT followed by oxyalkylation of alkenes, wherein C?C and C?O bonds were constructed in one step. This three-component reaction features mild conditions, wide substrate scope and excellent functional group tolerance, thus providing a facile and highly efficient access to complex valuable ketones. (Figure presented.).

Full text of DOI:10.1002/adsc.201801198

Title: Iminyl Radical-Mediated Controlled Hydroxyalkylation of Remote
C(sp3)-H Bond via Tandem 1,5-HAT and Difunctionalization of
Aryl Alkenes
Authors: Zhi-Yong Ma, Li-Na Guo, Yu-Rui Gu, Li Chen, and Xin-Hua
Duan
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801198
Link to VoR: http://dx.doi.org/10.1002/adsc.201801198

10.1002/adsc.201801198
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iminyl Radical-Mediated Controlled Hydroxyalkylation of
Remote C(sp3)-H Bond via Tandem 1,5-HAT and
Difunctionalization of Aryl Alkenes
Zhi-Yong Ma,a Li-Na Guo,a Yu-Rui Gu,a Li Chen,a and Xin-Hua Duan a,*
a
Department of Chemistry, School of Science and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation
of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, People’s Republic of China
Fax: +86-29-8266-3914; Tel: +86-29-8266-3914; E-mail: duanxh@xjtu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
year, Studer reported an iminyl radical enabled γ-
Abstract. A visible-light mediated γ-hydroxyalkylation of
ketones via C(sp3)-H functionalization has been developed alkylation of ketones using Michael acceptors as
alkylating reagents (Scheme 1c).[5e] In those reactions,
under redox neutral conditions. This protocol relies on the
iminyl
radical-triggered
1,5-HAT
followed
by
the reactive iminyl radicals could be easily generated
from oxime derivatives by visible light-induced
single electron transfer (SET).[7] However, the
selective C(sp3)-H bond abstraction and radical
alkylation under mild conditions remains at an
underexplored level. Furthermore, the development
of elegant radical cascades for the construction of
more complex molecules is still desirable and
challenging. It is well known that the
difunctionalization of alkenes is an extremely
powerful tool for C-C and C-heteroatom bonds
formation.[7d,8] We questioned that whether the C-
centered radicals generated through 1,5-HAT process
could engage in the difunctionalization of alkenes to
provide diverse ketones. Herein, we present a visible-
light driven three-component γ-hydroxyalkylation of
ketones through tandem iminyl radical-initiated 1,5-
HAT and oxyalkylation of unactivated alkenes. In
this transformation, water not only assists imine
hydrolysis, but also serves as a nucleophile to
participate the reaction.
oxyalkylation of alkenes, wherein C-C and C-O bonds were
constructed in one step. This three-component reaction
features mild conditions, wide substrate scope and excellent
functional group tolerance, thus providing a facile and
highly efficient access to complex valuable ketones.
Keywords: iminyl radical; 1,5-HAT; difunctionalization;
multicomponent reactions; γ C-H functionalization.
The direct functionalization of C(sp3)-H bonds
represents an elegant and promising strategy to
modify the organic molecules. Due to their high bond
strength and ubiquity, it is quite challenging to
activate the specified C(sp3)-H bonds, especially
remote and inert C(sp3)-H bonds in organic
synthesis.[1] Compared with the transition-metal-
catalyzed C(sp3)-H activation, the radical-mediated
functionalization of C(sp3)-H bonds via hydrogen
atom transfer (HAT) process have received much
attention owing to their mild reaction conditions,
excellent selectivity control as well as avoiding the
requirement of directing groups.[2] Over the past few
years, significant progress has been made in the C-,[3]
O-[4] and N-centered[5] radicals triggered selective
C(sp3)-H bonds functionalization via HAT process.
Among them, 1,5-HAT is commonly favorable
pathway, wherein the newly formed C-centered
radicals could be trapped by various reactive partners
to form C-C or C-heteroatom bonds.[3-6] For instance,
Nevado et al recently demonstrated an iminyl radical-
promoted remote C(sp3)-H bond functionalization
through
a
1,5-HAT/intramolecular cyclization
process, producing a variety of elaborated fused
ketones (Scheme 1a).[5b] Later on, Leonori et al
disclosed an iminyl radical-induced direct γ-
fluorination of ketones (Scheme 1b).[5d] In the same
Scheme 1. Photoinduced iminyl radical-triggered 1,5-HAT
reactions.
1
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10.1002/adsc.201801198
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.[a]
Table 2. Scope of the styrenes.[a]
Entry Deviation of standard conditions
Yield[%][b]
1
2
none
68
2 mol% of [Ru(bpy)3](PF6)2 as
the photocatalyst
0
3
5 mol% of Eosin Y as the
photocatalyst
0
4
5
6
7
8
9
DMF as the solvent
acetone as the solvent
25
46
40
65
43
0
THF as the solvent
1 equiv of HOAc was added
1 equiv of KOAc was added
w/o photocatalyst or light
[a]
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.4
mmol, 2.0 equiv), photocatalyst (2 mol %) and water (20
mmol, 100.0 equiv) in 2.0 mL MeCN was irradiated by 30
o
W blue light-emitting diodes (LEDs) at 25 C for 24 h
under N2, [b] Isolated yield.
[a] The reaction were carried out under the standard reaction
[b]
conditions.
Yield on a 2 mmol scale is given in
parentheses. [c] 4 mL MeCN was used.
Based on our recent studies in iminyl radical
chemistry,[9] we initially examined the reactions of
several oxime esters 1 and styrene 2a with water
(100.0 equiv) as a nucleophile, using 2 mol % of fac-
[Ir(ppy)3] as the photoredox catalyst in MeCN (0.1
M) under 30 W blue LED irradiation (Table 1).
Primary investigations indicated that pentafluoro-
benzoyl oxime 1a was the most efficient iminyl
radical precursor for this reaction and afforded the
desired γ-hydroxyalkylated ketone 3a in 68% yield.
Other O-acyl oximes with leaving groups such as
BzO, 4-CF3BzO, 4-NO2BzO, and AcO were less
effective or inert for this reaction (see Table S1 in the
Supporting Information). Thus, the oxime ester 1a
and styrene 2a were chosen as the model substrates to
survey other reaction parameters. The screening of
photoredox catalysts demonstrated that except fac-
[Ir(ppy)3], [Ru(bpy)3](PF6)2 and Eosin Y didn’t show
any catalytic activity (entries 2 and 3). Among the
solvents tested, DMF, acetone, and THF led to
inferior yields (entries 4-6), while DCM and PhCF3
were found to be ineffective solvents. Furthermore,
the use of 1.0 equiv of HOAc or KOAc as additives
did not improve the yield of 3a (entries 7 and 8).
Control experiments disclosed that both the
photoredox catalyst and the light irradiation are
crucial for the success of the reaction (entry 9).
substrates with electron-withdrawing groups (3b-e vs
3f-g). A wide range of functional groups, including
halogens (3f, 3g, 3j), ether (3d), ester (3e) and a
boronic acid pinacol ester (3h) all survived well
under the present conditions. It is worth mentioning
that 2-vinylnaphthalene 2k was the efficient substrate,
affording the desired product 3k in 53% yield, but 1-
vinylnaphthalene was inert for this transformation.
Besides styrenes, 1,1-disubstituted olefins 2l-2q were
also efficient substrates, producing the corresponding
products 3l-3q in 55-83% yields. It should be noted
that the reaction could also be scaled up to 2 mmol,
and the desired product 3l was obtained in 63 % yield.
Notably, the reaction of 1-phenyl-1,3-butadiene with
1a and water proceeded regioselectively to give the
sole product 3r in 45% yield, which was probably
attributed to the stability of newly formed benzyl
radical. When ethyl cinnamate 2s was subjected to
the reaction system, the desired product 3s was
isolated in 36% yield with excellent stereoselectivity.
Satisfactorily, the olefinic 1,3-dicarbonyls 2t also
delivered the desired product 3t, albeit in only 28%
yield, wherein the intramolecular carbonyl groups
were compatible.[9e,10] Remarkably, the terminal
olefins 2u and 2v derived from estrone participated
this reaction well to provide the desired products 3u
and 3v in 58% and 55% yield, respectively, which
further demonstrated the potential applications of this
protocol. Unfortunately, heteroaromatic styrenes,
such as 2-vinylquinoline and pyridine were not
applicable in this transformation (not shown).
With the optimal conditions in hand, we explored
the scope of the styrenes with 1a using water as a
nucleophile. A variety of styrenes reacted efficiently
with 1a and water to give the corresponding products
3b-3j in moderate to good yields (Table 2). The
styrenes bearing electron-donating groups at the para
position of the phenyl ring gave better yields than the
2
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10.1002/adsc.201801198
Advanced Synthesis & Catalysis
Table 3. Scope of the oxime esters.
functionalization of benzylic C(sp3)-H bonds in
oxime esters also proceeded smoothly to furnish the
desired products 4l and 4m in 47% and 60% yields,
respectively. However, oxime ester 1o having
primary C-H bond did not gave the desired product.
Finally, we examined the scope of O nucleophiles
in our oxyalkylation strategy (Table 4). Besides water,
i
the common alcohols such as MeOH, EtOH, PrOH,
and BnOH were also efficient nucleophiles, affording
the corresponding products 5a-5b in moderate yields.
Unfortunately, the sterically hindered alcohols,
amines or indoles failed to give any desired products
(not shown).
To verify the probable mechanism of this reaction,
radical trapping experiments were conducted
carefully (eqs 1 and 2). Addition of TEMPO (1.0
equiv) to the reaction of 1a and 2a with water
dramatically decreased the yield of 3a and the adduct
6a was isolated in 56% yield. These results indicated
that the C-centered radical generated through 1,5-
HAT should be involved in this transformation.
Furthermore, the addition of BHT (1.0 equiv) also
suppressed this reaction completely. On the other
hand, when 1a and (1-cyclopropylvinyl)benzene 2w
were used as the substrates, the ring expanded
product 7a was isolated in 33% yield as sole product,
which provided further evidence for a radical
pathway (eq 3).
Subsequently, the generality of oxime esters 1 was
evaluated using α-methylstyrene 2l as the radical
acceptor in the presence of water (Table 3).
Gratifyingly, a series of oxime esters containing
tertiary γ-C(sp3)-H bonds reacted smoothly with 2l
and water to give the target products 4a-4g in
moderate yields. The exclusive formation of 4a
indicated that the iminyl radical H-abstraction of
tertiary C-H bonds is more favorable than secondary
and primary C-H bonds. Notably, the carbamate N-
Boc in the oxime ester was compatible with the
reaction conditions, whereas the N-Cbz substrate
afforded the deprotected product 4f. It is noteworthy
that the oxime esters having a phenyl or thiophen-2-
yl substituent at the -position delivered the
cycloketone 4h' or 4i' as sole product in 75% and
70% yields, respectively, which suggested that the
intramolecular radical cyclization process is preferred
over the intermolecular radical addition.[5b] The
oxime esters with secondary γ-C(sp3)-H bonds also
gave the anticipated products (4j and 4k), but in
relatively lower yields. Satisfactorily, the
Based on the above results and literatures, a
possible mechanism is proposed in Scheme 2. First,
the IrIII is excited to IrIII* upon visible-light
irradiation. Subsequently, single-electron reduction of
1a by IrIII* affords the iminyl radical I through N-O
bond cleavage and delivers the oxidized photocatalyst
Table 4. Scope of the O nucleophiles. [a]
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), fac-
[Ir(ppy)3] (2 mol %) and alcohols (2 mmol, 10.0 equiv) in
2.0 mL MeCN was irradiated by 30 W blue LEDs at 25 oC
for 24 h under N2, After the reaction completed, 0.5 mL
water was added and the mixture was stirred at room
temperature for 1 h. Isolated yield.
Scheme 2. Proposed mechanism.
3
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10.1002/adsc.201801198
Advanced Synthesis & Catalysis
IrIV.[11] Then, iminyl radical I triggers a 1,5-hydrogen
atom transfer to give the C-centered radical II. The
radical II attacks the C=C bond of styrene 2a
regioselectively to furnish the benzyl radial III,
which is oxidized by IrIV to give the carbocation
intermediate IV and regenerates the photocatalyst IrIII.
Finally, nucleophilic attack of H2O onto the cation IV
followed by hydrolysis leads to the γ-
hydroxyalkylated ketone 3a. Finally, we also
determined a quantum yield of 0.13 for the reaction.
The low quantum yield and an on/off studies were
consistent with the proposed absence of a chain
process (For details, see the Supporting
Information).[11c]
In summary, we have developed the first visible-
light driven three-component γ-hydroxyalkylation of
ketones under concise, redox neutral conditions. In
this protocol, tandem iminyl radical-triggered 1,5-
HAT and subsequent oxyalkylation of unactivated
alkenes enabled the controlled γ-C(sp3)-H bonds
functionalization of ketones. Besides water, simple
alcohols were also efficient nucleophiles, leading to
the corresponding γ-carboetherification of ketones in
good yields. Further studies to explore new remote
C(sp3)-H bond functionalization reactions by merging
radical chemistry are currently underway in our
laboratory.
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Experimental Section
General procedure for iminyl radical-mediated controlled
hydroxyalkylation of remote C(sp3)-H bond: An oven-
dried 10 mL reaction tube equipped with a magnetic stir
bar was charged with oximes 1 (0.2 mmol, 1.0 equiv), fac-
[Ir(ppy)3] (0.004 mmol, 0.02 equiv), then the tube was
evacuated and backfilled with nitrogen (three times).
Subsequently, alkene (0.4 mmol, 2.0 equiv), 2.0 mL of
MeCN and 0.36 mL of distilled water were injected into
the tube by syringe under nitrogen atmosphere. The
reaction mixture was stirred under the irradiation of a 30
W Blue LEDs at room temperature for 24 h. After reaction
completed, the mixture was quenched with brine and
extracted with ethyl acetate (3 x 10 mL). The combined
organic extracts were washed with brine (10 mL), dried
over Na2SO4 and concentrated in vacuo. Purification of the
crude product by flash chromatography on silica gel
(petroleum ether/ethyl acetate 5:1 to 2:1) to give the
corresponding products 3 or 4 in yields list in Table 2 and
Table 3.
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Financial support from the Natural Science Basic Research Plan
in Shaanxi Province of China (No. 2016JZ002), the Fundamental
Research Funds of the Central Universities (No. zrzd2017001,
xjj2016056 and 1191329724) is greatly appreciated. We also
thank Miss Lu at Instrument Analysis Center of Xi’an Jiaotong
University for their assistance with HRMS analysis.
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10.1002/adsc.201801198
Advanced Synthesis & Catalysis
COMMUNICATION
Iminyl Radical-Mediated Controlled Hydroxy-
alkylation of Remote C(sp3)-H Bond via Tandem
1,5-HAT and Difunctionalization of Aryl Alkenes
Adv. Synth. Catal. Year, Volume, Page – Page
Zhi-Yong Ma,a Li-Na Guo,a Yu-Rui Gu,a Li Chen,a
and Xin-Hua Duan a,*
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This article is protected by copyright. All rights reserved.