Research Article
Cite This: ACS Catal. 2018, 8, 6401−6406 pubs.acs.org/acscatalysis
Visible Light Mediated, Redox Neutral Remote 1,6-
Difunctionalizations of Alkenes
Wei Shu,† Estíbaliz Merino,† and Cristina Nevado*,†
†
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
*
S Supporting Information
ABSTRACT: A photoinduced cascade strategy is presented
here for the remote functionalization of alkenes under redox
neutral conditions. A broad portfolio of alkyl groups has been
added to double bonds to produce, upon 1,5-HAT, remote C-
Downloaded from pubs.acs.org by UNIV OF ZURICH on 07/18/18. For personal use only.
centered radicals which can be harvested in the presence of O-
or C-nucleophiles to efficiently form Csp3−O and Csp3−Csp2
bonds at room temperature.
KEYWORDS: photocatalysis, redox neutral, remote functionalization, alkene, radical, oxy-alkylation, carbo-alkylation
1. INTRODUCTION
Alkene difunctionalizations play a prominent role in the
ACS Catal. 2018.8:6401-6406.
efficient assembly of molecular complexity.1 A large degree of
diversity in terms of the functional groups added across double
bonds has been achieved by means of oxidative conditions,
including, but not limited to oxy-arylation,2 carbo-alkylation,3
amino-alkylation,4 and oxy-alkylation5,6 reactions (Scheme 1A).
Scheme 1. Strategies for the Difunctionalization of Alkenes
1,n-Hydrogen atom transfer (HAT) processes provide an
exceptional opportunity for the remote functionalization of
inert Csp3−H bonds.7 However, examples of 1,n-difunctional-
izations of alkenes as a result of the combination of olefin
functionalization and 1,n-HAT are still scarce (Scheme 1B).8
Multiple challenges hamper the successful development of
these transformations including the promiscuous reactivity of
different intermediates (M1/M1′, M2/M2′) as well as their
propensity to undergo competitive side reactions. Thus,
intermediates M1 and M2 might undergo radical atom-transfer
processes to deliver hydroalkylation or haloalkylation prod-
ucts,9 whereas carbocationic intermediates M1′ and M2′ tend
to undergo elimination reactions.10 Elegant work by Liu et al. in
© 2018 American Chemical Society
this context resulted in successful 1,6-oxy- and 1,6-azidotri-
fluoromethylations of alkenes.11 These protocols utilize
stoichiometric amounts of hypervalent iodine reagents12 at
elevated temperature to trigger the addition of the trifluor-
omethyl group onto the alkene. The remote functionalization
of the Csp3−H bonds requires a vicinal heteroatom-containing
functionality (such as O, N, CO) in combination with
MeOH and TMSN3 as nucleophiles (Scheme 1B, left).11a,c,d
Photoredox catalysis has emerged as a powerful tool to
enable single electron transfer (SET) reactions under mild
conditions by taking advantage of photoexcited catalysts.6,7e−j,13
Thus, as part of our ongoing interest in the remote
functionalization of Csp3−H bonds,14 we set out to develop a
visible-light mediated, redox neutral 1,6-difunctionalization of
unactivated alkenes. The mild reaction conditions enabled us to
expand the portfolio of C-based functionalities that can be
added across the π-system. Further, the functionalization of the
remote Csp3−H bonds could be performed with both O- as
well as, for the first time, C-based nucleophiles, thus
demonstrating the complementarity and extended functional
group compatibility of this light-mediated protocol.
2. RESULTS AND DISCUSSION
The reaction of diethyl 2-allyl-2-(4-methoxyphenethyl)-
malonate in the presence of ethyl 2-bromo-2,2-difluoroacetate
was selected to find the optimal conditions. After initial
screening of different photocatalysts to reduce the C−Br
bond,15 we found that the desired 1,6-acetoxy alkylation
product 1 could be obtained in 59% yield using 2 mol % of
Ir(ppy)3 upon irradiation with blue LED (34 W) in the
presence of AgOAc in acetonitrile at room temperature (Table
1, entries 1−3). Different solvents were tested next: while
toluene or DMF decreased the reaction efficiency (Table 1,
Received: February 20, 2018
Revised: May 31, 2018
Published: June 14, 2018
6401 DOI: 10.1021/acscatal.8b00707
ACS Catal. 2018, 8, 6401−6406
ACS Catalysis
Table 1. Optimization of the Reaction Conditionsa
entry catalyst
1 Ir(ppy)3
2 [Ir{dF(CF3)ppy}2(dtbpy)]PF6
3 Ru(bpy)3Cl·6H2O
4 Ir(ppy)3
5 Ir(ppy)3
6 Ir(ppy)3
7 Ir(ppy)3
8 Ir(ppy)3
9 Ir(ppy)3
10b Ir(ppy)3
11 No [Ir] or no light
a
Alkene (0.1 mmol), alkyl bromide (2 equiv), MOAc (2 equiv) in solvent (0.1 M), 34 W blue LED. The yield was determined by crude 1H NMR
using mesitylene as internal standard. In brackets: isolated yield after column chromatography. bAgOAc (1.5 equiv).
entries 4 and 5), chlorinated solvents had a positive effect on
the reaction outcome (Table 1, entries 6 and 7). Different
additives were also investigated (Table 1, entries 8−9). The
best yield in 1 was obtained when 1.5 equiv of AgOAc were
used (Table 1, entry 10). In contrast, in the absence of either Ir-
catalyst or light, 1 was not observed (Table 1, entry 11) thus
confirming the important role of both parameters (metal and
light) for a successful outcome in these transformations.
Using diethyl 2-allyl-2-(4-methoxyphenethyl)malonate and
ethyl 2-bromo-2,2-difluoroacetate, different oxygen-based nu-
cleophiles were explored (Scheme 2). AgOBz delivered the
corresponding 1,6-oxocarbofunctionalization product 2 in 65%
yield. Interestingly, the reaction could be carried out in the
presence of Ag2CO3 and 2 equiv of propanoic or p-toluic acid,
to deliver the corresponding esters in comparable yields
(compounds 3 and 4). The nature of the alkyl halide was
explored next under the optimized conditions with AgOAc as
Scheme 2. Reaction Scope on Alkyl Halide and O-Based
Reagent for 1,6-Oxy-alkylation
a
See Table 1, entry 10 for detailed conditions. bAg2CO3 (0.75 equiv)
was used. c36 h. dOne mmol scale. e48 h. fPerfluorohexyl iodide was
used.
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additive, solvent 1 (yield, %)
AgOAc, CH3CN 36
AgOAc, CH3CN 0
AgOAc, CH3CN 0
AgOAc, toluene 31
AgOAc, DMF 33
AgOAc, 1,2-DCE 66
AgOAc, CH2Cl2 71
K/LiOAc, CH2Cl2 0
TBAOAc, CH2Cl2 31
AgOAc, CH2Cl2 71 (67)
AgOAc, CH2Cl2 0
O-donor. 2-Bromo-2,2-difluoro-1-(piperidin-1-yl)ethan-1-one
delivered 5 in 84% yield. Less activated bromides also proved
to be compatible with the reaction protocol. Thus, 2-bromo-1-
(piperidin-1-yl)ethan-1-one delivered 6 in 56% yield, whereas
ethyl 2-bromo-2-fluoroacetate furnished 7 in 72% as a 1:1
mixture of diastereoisomers. Simple alkyl and aryl 2-
bromoacetates efficiently furnished the desired remote
difunctionalization products 8-11 in good yields, albeit in
some cases, longer reaction times were required to obtain
complete conversion of the starting material. Interestingly, the
reaction could be scaled up to 1 mmol without erosion of the
isolated yield. The structure of the remote 1,6-difunctionaliza-
tion products was confirmed by X-ray diffraction analysis of 9’
stemming from the basic hydrolysis of compound 9.16 α-Bromo
butyrolactone furnished the corresponding lactone derivative
12 in 58% as a 1:1 mixture of diastereoisomers. α-Bromo-
aromatic as well as -alkyl ketones could be efficiently employed
in these transformations, delivering the remote functionalized
ketones 13−16 in excellent yields with complete regioselectiv-
ity. Finally, we also demonstrated that perfluoroalkyl-containing
alkyl bromides and iodides could be efficiently engaged in the
reaction as shown by the efficient formation of compounds 17−
19 under the standard reaction conditions. These examples
showcase the high functional group compatibility of this redox
neutral remote difunctionalization as esters, amides, lactones,
ketones, C−Cl bonds were well tolerated under the optimized
protocols. For a summary of substrates that did not work, see
section S3.3 in the Supporting Information, SI.
Next, we decided to interrogate the flexibility of the reaction
in terms of the olefinic partner (Scheme 3). Alkenes bearing
electronically diverse groups on the remote aromatic ring
delivered the desired oxocarbofunctionalization products 20−
28 in excellent yields. In the presence of methyl 2-
bromoacetate, 1,6-oxyalkylation products 29 and 30 could be
obtained in good yields. Interestingly, halogen substituents in
the aromatic ring both in ortho, meta, and para position proved
to be well tolerated as demonstrated by the efficient reaction to
produce the corresponding remote oxocarbofunctionalization
products in synthetically useful yields (26−28, 31−33).
Substrates with different substituents on the aliphatic chain
were also accommodated in the reaction as demonstrated by
the isolation of 34 and 35 in 58% and 54% yield, respectively.
DOI: 10.1021/acscatal.8b00707
ACS Catal. 2018, 8, 6401−6406
ACS Catalysis
Scheme 3. Reaction Scope on Alkene
a
See Table 1, entry 10 for detailed conditions.
Fully linear or heteroatom bridged alkyl chains did not furnish
the desired products, thus signalizing the importance of
Thorpe-Ingold effects in the reaction (see section S3.3 in the
SI).15,17
As discussed earlier, one of the major drawbacks of existing
alkene remote difunctionalizations stems from the use of
oxidative conditions, incompatible with C-based nucleophiles.11
Given the mild, redox neutral conditions of our protocol, we set
out to explore the incorporation of C-based nucleophiles in the
reaction (Scheme 4).
In the presence of 2-bromo-2,2-difluoroacetate and trime-
thoxybenzene, different substitution patterns on the aromatic
Scheme 4. Extension to 1,6-Carbo-alkylation of Alkene
a
Alkene (0.1 mmol), alkyl bromide (0.3 mmol), arene (0.3 mmol), in
the presence of 3 mol % of Ir(ppy)3 and Ag2CO3 (0.075 mmol) in
DCM (0.1 M) at 25 °C. bEtCN was used as solvent.
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ring of the 6-aryl-1-hexene partner could be tolerated (36−38).
Both 2-bromo-2,2-difluoroketones and cyclohexyl amides could
also be successfully employed as alkyl partners in the
dicarbofunctionalization reaction (39−40). This 1,6-carbo-
alkylation process is also compatible with less activated alkyl
radical precursors (41−42) as well as with different substitution
patterns on the alkyl chain of the olefinic partner (43).
Different indoles were also tested yielding the desired reaction
products (44−47) in synthetically useful yields under the
standard reaction conditions with EtCN as solvent.
Mechanistic studies were also performed (Scheme 5).
Reactions in the presence of well-established radical traps
Scheme 5. Deuterium Labelling Experiments, DFT
Calculations and Proposed Reaction Mechanisma
a
Intermediates and transition states computed at B3LYP/6-311+
+G(d,p) (iefpcm, solvent = dichloromethane) level. Energies are given
in kcal/mol (relative to the sum of the starting materials, GI + Galkene =
0 kcal/mol).
showed no desired 1,6-difunctionalization products whereas the
alkene could be completely recovered, which is indicative of
radical intermediates along the reaction pathway (see SI).15
Deuterium labeling studies involving 48 and d2-48 yielded KIE
values of 1.2 and 1.0 for parallel (two-flask) and competitive
(one-pot) intermolecular experiments, respectively (Scheme
5a.1). In contrast, a KIE = 3.3 could be determined for the
intramolecular competition experiment with substrate d1-48
(Scheme 5a.2).18 DFT calculations15 revealed a slightly higher
energy barrier for the addition of the C-centered radical I to the
alkene (TSI−II, ΔG‡ = 16.1 kcal/mol) compared to that of the
1,5-HAT taking place on intermediate II (TSII−III, ΔG‡ = 11.8
kcal/mol). Interestingly, the latter process is exergonic (ΔG =
DOI: 10.1021/acscatal.8b00707
ACS Catal. 2018, 8, 6401−6406
ACS Catalysis
−11.7 kcal/mol) as a result of the stabilized benzylic radical
produced in III.19
In line with these results, our mechanistic proposal involves
the activation of the Ir(III)-photocatalyst upon irradiation
which in turn, reduces the C−Br bond delivering an alkyl
radical I under redox neutral conditions. Subsequent addition
of I onto the double bond produces C-centered radical II. A
1,5-Hydrogen atom transfer, presumably aided by the
preorganization of the starting material,17 takes place to
produce a more stable C-centered benzylic radical III in a
remote and site-selective manner. Oxidation of the radical to
the corresponding carbocation takes place in the presence of an
Ir(IV) complex intermediate to produce IV, which is thus
subsequently quenched in the presence of either an O- or a C-
based nucleophile to produce the remote dicarbo- or
oxocarbofunctionalization products observed in these trans-
formations. The results of the deuterium labeling experiments,
consistent with this proposal, point toward the Csp3−H bond
cleavage via 1,5-HAT being irreversible (with a primary KIE
observed in the intramolecular experiment, Scheme 5a.2), but
taking place after the RDS, which involves the irreversible
functionalization of the substrate bearing the C−H/D bond
(i.e., no primary KIE observed in the two intermolecular
deuterium labeling experiments summarized in Scheme 5a.1).20
3. CONCLUSIONS
In summary, a visible light mediated, redox neutral protocol is
presented here toward the efficient remote functionalization of
alkenes. The mild reaction conditions enable the addition of a
wide variety of C-centered radicals to the double bond
producing a vicinal radical intermediate that is not quenched
under the reaction conditions. A subsequent 1,5-HAT results in
the site selective generation of a remote benzylic radical which
can be trapped with O- or C-nucleophiles to produce, in a
highly efficient manner, new Csp3−O and Csp3−Csp2 bonds at
room temperature.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b00707.
General information, experimental procedures, DFT
calculations, detailed descriptions for products, and
copies of NMR spectra (PDF)
Crystallographic data (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: cristina.nevado@chem.uzh.ch (C.N.).
ORCID
Estíbaliz Merino: 0000-0002-2960-5404
Cristina Nevado: 0000-0002-3297-581X
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We thank the European Research Council (ERC Starting grant
agreement no. 307948) and the Swiss National Science
Foundation (SNF 200020_146853) for financial support. We
thank Prof. Anthony Linden for the X-ray diffraction analysis of
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9′. The authors would like to acknowledge the support by the
COST Action CHAOS (CA15106).
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6406 DOI: 10.1021/acscatal.8b00707

ACS Catal. 2018, 8, 6401−6406