The direct arylation of allylic sp3 C-H bonds via organic and photoredox catalysis

Article abstract of DOI:10.1038/nature14255

The direct functionalization of unactivated sp³ C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp³ C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.

Full text of DOI:10.1038/nature14255

LETTER
doi:10.1038/nature14255
The direct arylation of allylic sp3 C–H bonds via
organic and photoredox catalysis
James D. Cuthbertson1 & David W. C. MacMillan1
The direct functionalization of unactivated sp3 C–H bonds is still wehypothesizedthatolefinicsubstrates wouldundergohydrogenatom
oneofthemostchallengingproblemsfacingsyntheticorganicchem- abstractionusing our photoredoxconditions to generatetransient allylic
ists. The appeal of such transformations derives from their capacity radicals, which thereafter would participate in a hetero radical–radical
coupling pathway with arene radical anions generated in situ.
A detailed mechanism forthe envisioned fragmentcoupling isdepicted
to facilitate the construction of complex organic molecules via the
coupling ofsimpleandotherwise inertbuilding blocks, withoutintro-
ducingextraneousfunctionalgroups. Despitenotablerecentefforts1, in Fig. 2. Upon irradiation with low-energy visible light (for example,
theestablishmentof generaland mild strategies for theengagement from a 26 W household compact fluorescent lamp (CFL)), the iridium
of sp3 C–H bonds in C–C bond forming reactions has proved diffi- complex Ir(ppy)3 (1) (ppy 5 2-phenylpyridine) is known to undergo a
cult. Within this context, the discovery of chemical transformations metal-to-ligandchargetransferandintersystemcrossingtogeneratethe
that are able to directly functionalize allylic methyl, methylene and long-lived excited state IrIII species 2 (lifetime t 5 1,900 ns)16, which is
IV/
methine carbons in a catalytic manner is a priority. Although proto- a strong reductant:the reduction potential E1/2
*
III is 21.73 V versus
cols fordirect oxidationandamination ofallylicC–H bonds(thatis, thesaturatedcalomelelectrode(SCE)inMeCN, where*IIIindicatesthe
excited state of the IrIII catalyst16. It has long been established that the
photoexcited state of this complex will readily undergo single-electron
C–H bonds where an adjacent carbon is involved in aC5Cbond)have
becomewidely established2,3, the engagementof allylic substratesin
transfer with electron-deficient arenes such as 4-cyanopyridines and
1,4-dicyanobenzene (for example, reductionpotential E1/2red 5 21.61 V
versus SCEfor1,4-dicyanobenzeneinMeCN)17 togenerateapersistent
areneradicalanionalongwiththeoxidizedphotocatalyst3. Thoughthe
IrIV species 3(E1/2IV/III 5 10.77 V versus SCEin MeCN)16 is not likelyto
be sufficiently oxidizing to directly oxidize atypical thiol (E1/2red 511.12 V
versus SCE for butanethiol in MeCN)18, this event should be facilitated
bythepresenceofasuitablebase. Theweaklyacidicthiol(pKa 5 7.91for
methyl 2-mercaptoacetate in H2O)19 is deprotonated to yield the thio-
C–C bond forming reactions has thus far required the use of pre-
functionalizedcouplingpartners4. Inparticular, thedirectarylation
of non-functionalized allylic systems would enable access to a series
of known pharmacophores (molecular features responsible for a
drug’s action), though a general solution to this long-standing chal-
lengeremainselusive. Herewereporttheuseofboth photoredoxand
organic catalysis to accomplish a mild, broadly effective direct allylic
C–H arylation. This C–C bond forming reaction readily accommo-
dates a broad range of alkene and electron-deficient arene reactants,
and has been used in the direct arylation of benzylic C–H bonds.
While the well-known Heck reaction can be employed to generate
allyl-substituted aromatics with high levels of efficiency via p-addition,
olefin transposition sequences, there are few known examples of direct
allylic arylationviathefunctionalizationofC–H bonds5,6. Indeed, a liter-
ature survey reveals an isolated report on the Fe-catalysed coupling
of Grignard reagents with simple olefins as the only transition-metal-
mediated allylic arylation reported to date7. Given the state of the art of
allylic C–H arylation (or for allylic C–C bond formation in general),
we considered that a mild and widely applicable solution to this chal-
lenge would be useful.
red
lateanion(E1/2 5 –0.85 VversusSCEfor butanethiolateinMeCN)18,
which is readily oxidized by the photocatalyst. Based on the reported
BDEsfortypicalthiolsandallylicC–Hbonds, wereasonedthattheelec-
trophilic thiyl radical 5 would readily abstract an allylic hydrogen atom
from the alkene substrate (cyclohexene allylic C–HBDE583.2 kcal mol21
a Arylation of pre-functionalized allylic substrates – well known
N
X
Transition metal
N
catalysis
Y
Therapidlygrowingfieldofvisible-light-mediatedphotoredoxcatal-
ysis offers a valuable platform for the design or discovery of new syn-
thetic transformations8–10. The ability of photoredox catalysts to act as
both strong oxidants and reductants upon irradiation with low-energy
visiblelighthasenabledtheinventionofaseriesofusefulbondconstruc-
tions, previouslythoughttobeunattainableviaconventionalpathways.
In our laboratory, the synergistic merger of visible-light photoredox catal-
ysis with organocatalysis has been instrumental in the development of
a numberof methods forthe direct functionalizationof unactivated sp3
C–Hbonds11–13. Usingthis powerful dual-catalysisparadigm, we recently
reported the direct arylation of benzylic ethers via a C–H abstraction
mechanism that proceeds through the heterocoupling of two cataly-
tically generated radical species14. With this mechanistic blueprint in
hand, we recently considered whether the combination of photoredox
catalysis and organocatalysis could provide asolution to the long-standing
and more significant challenge of direct allylic arylation (Fig. 1). Given
that the allylic C–H bonds of simple alkenes are relatively weak (the allylic
b Direct allylic C–H oxidation or amination – well known
H
Transition metal
OH
NHR
catalysis or
stoichiometric [O]
c Direct allylic C–H arylation – remains elusive (this research)
N
Photoredox
H
N
and organic catalysis
Y
Figure 1
|
The direct arylation of allylic C–H bonds via the synergistic
merger of photoredox and organic catalysis. a, Arylation of allylic bonds is
generally accomplished via transition-metal-catalysed couplings with pre-
functionalized substrates. b, Installation of heteroatoms via direct allylic C–H
functionalization is widely known. c, Direct C–H arylation is proposed via the
C–H bond dissociationenergy (BDE)incyclohexeneis83.2 kcal mol21)15, synergistic merger of photoredox and organic catalysis.
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.
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LETTER RESEARCH
alkenes coupled with 1,4-dicyanobenzene in excellent yields (12–16,
71–87%yield). Notably, cyclicsubstrates bearingalkylsubstituentsalso
provide high levels of coupling efficiency, although the production of
minorquantities of regioisomeric adducts can typically be detected due
to the presence of secondary sites of hydrogen atom abstraction. Not
surprisingly, installation of a tert-butyl group on the cyclohexene ring
afforded only one major product, with only trace quantities of regio-
isomers being observed (17, 92% yield). Similarly useful levels of regio-
selectivity were obtained when a-pinene was employed as the olefinic
substrate (18, 93% yield). The observed selectivity is attributed to the
expectationthattheelectrophilicthiylradicalabstractsthemosthydridic
hydrogenatom(thatis, thehydrogenatomthathasthegreatesthydride
character) and subsequent coupling of the radical proceeds through the
least hindered secondary radical position.
Household
CFL
Cyanopyridine 6
CN
Arene coupling
partner
N
*IrIII(ppy)3
2
Reductant
SET
Photoredox
catalytic
cycle
CN
IrIII(ppy)3
1
N–
Photoredox catalyst
8
[IrIV(ppy)3]+
Oxidant
3
Radical–radical
coupling
SET
—H+
Importantly, acyclic alkenes alsoserve as effectiveallyl couplingpart-
ners in this protocol while generally exhibiting high levels of regiocon-
trol with respect to the C–C bond forming step (19–23, 63–90% yield;
Fig. 3a). For example, implementation of 2-pentene leads predomi-
nantlytotheformationofthebranchedarylationproductwithexcellent
efficiency (20, 85% yield), with only trace quantities of linear arylation
adducts arising from hydrogen atom abstraction of the terminal meth-
ylenegroup. Exposureof2-methyl-2-pentenetothesephotoredoxcon-
ditions afforded two arylation isomers in a 1.4:1 ratio: the major isomer
arisesfromcouplingoftheallylicradicalthroughthemorenucleophilic
tertiary substituted carbon, to generate a quaternary centre with useful
efficiency (21, 90% combined yield for both isomers). In contrast, the
reaction with 2,29-dimethyl-3-hexene yielded onlyasingle product, result-
ing from coupling at the least hindered terminus of the allylic radical
(22, 81% yield). With respect to medicinal chemistry applications, it is
importanttonotethatheteroatomscanbeincorporatedintothealkene
RSH
4
Thiol catalyst
Organocatalytic
cycle
9
RS
5
Thiyl radical
HAT
—CN
N
H
Synergistic catalysis
Photoredox
Cyclohexene 7
Arylation product 10
Organic catalysis
Figure 2
|
Proposedmechanismforthedirectarylationofallylic C–H bonds substrateswith no deleterious effecton reaction efficiency (compare 19
via photoredox and organic catalysis. The photoredox catalytic cycle is
initiated via excitation of photocatalyst 1 to give the excited state 2. Single-
electron reduction of 4-cyanopyridine (6) via SET generates the radical anion
8alongwithoxidant3. Inthepresenceofabase, oxidant3iscapableofinitiating
the organocatalytic cycle via oxidation of the thiol catalyst 4 to give the thiyl
radical 5 along with the regenerated photocatalyst 1. The thiyl radical
5 abstracts an allylic hydrogen atom (HAT, hydrogen atom transfer) from
cyclohexene (7) to generate allylic radical 9. A radical–radical coupling and
subsequenteliminationofcyanideservetoconstructthenewC–Cbondandform
the arylation product 10 while completing the two synergistic catalysis cycles.
and 23). Thus, coupling of 4-penten-1-olafforded thedesired arylation
productinusefulyield(23, 66%yield). Inclusionofaphenylsubstituent
onthealkenemoietyresultedinalowerisolatedyield, presumablyowing
to decreased hydridicity of the allylic C–H bonds (24, 76% yield); how-
ever, an analogous substrate bearing a 4-MeO substituent on the phenyl
ring underwent efficient, regioselective coupling with 1,4-dicyanobenzene
(25, 95%yield). Intriguingly, anaturallyoccurringheteroatom-substituted
terpene could be employed directly to generate an arylated derivative
in only one step and in good yield (26, 84% yield).
Thisnewphotoredox–organocatalytic methodologycanalsobeapplied
to a one-stepsynthesisof b-arylketones.Forexample,whenthetrimeth-
ylsilyl enol ether of cyclohexanone was exposed to these new arylation
conditions, the resultant b-aryl ketone was isolated in high yield (27,
83% yield). Furthermore, direct reaction of the corresponding allylic
alcohol (2-cyclohexen-1-ol) also furnished ketone 27 via regioselective
hydrogenatomabstractionadjacenttothealcoholandsubsequentcou-
pling at the allylic b-enol position (see Supplementary Information).
Finally, b,c-unsaturatedestersareviablesubstrates, affordingamixture
of b,c- and c,d-unsaturated products (28, 81% yield).
Wenextsoughttoinvestigatethescopeofthearomaticcouplingpart-
ner in the arylation protocol. As shown in Fig. 3b, a range of electron-
deficient arenes are well tolerated in this new photoredox protocol.
Derivatives of dicyanobenzene, including those bearing ortho-substituents,
readily coupled with the cyclohexenyl allylic radical to affordthe corre-
sponding arylation adducts in good to excellent yield (29–31, 50–83%
yield). Moreover, extended aromatic systems, such as a biphenyl deriv-
ative,werealsofoundtoparticipateefficiently(32, 66%yield). Although
the presence of one cyano-substituent was a requirement for the viab-
ility of the aryl coupling component, additional electron-withdrawing
substituents,suchassulfones,maybereadilyincorporatedwithoutissue
(33, 69% yield). Notably, a range of cyanopyridine derivatives under-
versusS–HBDE5 87.0 kcalmol21 15,20 toprovideallylicradical9along
)
with regenerated organocatalyst 4. At this time, an intermolecular radical–
radicalcoupling wouldservetoforgethenewC–C bond, withtheresulting
pyridienylorcyclohexadienylanionundergoing rapidrearomatization
via elimination of cyanide.
We began our direct allylic C–H arylation studies with an evaluation
of a range of photocatalysts, thiols, solvents, and bases in the presence
ofcyclohexeneand1,4-dicyanobenzeneasrepresentativecouplingpart-
ners. We found that the use of light (from two 26-W CFLs) in the
presence of Ir(ppy)3, triisopropylsilanethiol, and K2CO3 enabled the
desired aryl–allylfragmentcoupling in excellentyield (87%) to furnish
the desired arylcyclohexene. The necessity of each of the key reaction
components—photocatalyst, thiol, and light—was demonstrated through
a series of control experiments (Supplementary Information). While
trace amounts of product were formed in the absence of thiol and
photocatalyst5, no reaction was observed upon exclusion of light. It should
be noted that theseoptimal conditions employstandard household 26 W
CFLs and proceed readily at room temperature with low loadings of
both the photocatalyst (1 mol%) and organocatalyst (5 mol%).
With these optimized conditions in hand, wenext examined the scope
of olefins that can be employed in thisdirect allylic arylation reaction. As
shown in Fig. 3a, this simple arylation protocol permits the direct cou- went coupling with cyclohexene to afford the corresponding hetero-
pling of electron-deficientarenes witha wide range ofunfunctionalized arylation adductswithusefullevelsofefficiency(34–37, 70–84%yield).
alkenes. Importantly, bothcyclic and acyclic olefinsare readily accom- Additionally, halide substituents at the 2- and 3-positions of pyridine
modated in this transformation. For example, a series of simple cyclic were also tolerated. In these cases it is important to note that the thiol
5
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RESEARCH LETTER
Figure 3
|
Substrate scope for the
Catalyst combination
direct allylic arylation reaction.
A range of alkenes are efficiently
arylated under the standard reaction
conditions (top, generalized
1 mol% Ir(ppy)3
5 mol% catalyst 11
1
R2
R2
Me
Me
N
Ir
EWG
R1
H
R1
EWG
Me
Si
Me
N
N
K2CO3
acetone, 23 °C
26 W light
NC
R3
R4
SH
Me
R3
R4
Me
reaction). EWG, electron-
Arene
Alkene
(
)-allylic arene
withdrawing group. a, The substrate
scope includes both cyclic and
acyclic alkenes. b, A range of arenes
bearing electron-withdrawing
Ir(ppy)3
1
Organocatalyst 11
a
CN
CN
CN
CN
CN
CN
substituents can be employed as
coupling partners under the standard
conditions. Isolated yields are
t-Bu
indicated below each entry. *Isomers
observed; in all cases the major
isomer is depicted. Yields refer to the
combined yield of all isomers. Ratios
of isomers where applicable:
(
)-12 79%
(
)-13 87%
(
)-14 73%
(
)-15 86%
(
)-16 71%*
(
)-17 92%*
CN
CN
CN
CN
CN
CN
Me
(6)-16(2.2:1.0 E:Z), (6)-17(.20:1),
18 (.10:1), (6)-19 (1.4:1.0),
Me
Me
Me Me
Me
Me
Me
Me
t-Bu
OH
Me
(6)-20 (4.9:1.0), (6)-21 (1.4:1.0),
(6)-23 (1.1:1.0), (6)-24 (2.1:1.0),
(6)-25 (.19:1), (6)-26 (,1:1),
(6)-28 (1.2:1.0), (6)-29 (1.1:1.0).
{Additional thiol or base required;
see Supplementary Information for
experimental details. {Yield from
silyl enol ether 83%, yield from
2-cyclohexen-1-ol 62%.
18 93%*
(
)-19 63%*†
(
)-20 85%*
(
)-21 90%*
(
)-22 81%†
(
)-23 66%*†
CN
CN
MeO
CN
CN
CN
Me
O
O
Me
OEt
Me
Me
OAc
(
)-24 76%*†
(
)-25 95%*
(
)-26 84%*
(
)-27 83%‡
(
)-28 81%*†
b
CN
CN
Me
Me
CN
NC
SO2Ph
Me
(
(
)-29 83%*
(
)-30 74%
(
(
)-31 50%
(
(
)-32 66%
(
(
)-33 69%†
Cl
N
N
N
N
N
Cl
NBoc
Me
)-34 84%
(
)-35 73%†
)-36 70%
)-37 80%
)-38 70%
catalyst didnotparticipate in a non-productivepyridine addition SNAr
Wenextsoughttodemonstratetheutilityofthis methodologyforthe
pathway (an initial concern that did not prove to be valid for the preparation of high-value and versatile building blocks, and at the same
2-chloropyridine system). Finally, it was shown that a 7-azaindole deriv- time demonstrate the mild nature of the conditions employed (Fig. 4a).
ative functions as a viable coupling partner (38, 70% yield), a notable More specifically, we have found that boronic ester-substituted cyclo-
findingwithrespecttopotentialapplicationsofthistechnologyinmedi- hexenes are stable to these photoredox conditions and, more impor-
cinal chemistry.
tantly, undergo regioselective arylation at the carbon centre adjacent
to the C–B bond (39, 73% yield). Moreover, incorporation of a boronic
ester substituent on the arene coupling component can also be toler-
ated in this transformation (40, 60% yield).
Finally, acentraladvantageofthismild, visible-light-mediatedaryla-
tionprotocolisthe potential forthelate-stage diversificationofadvanced,
highly functionalized synthetic intermediates. As an illustration of this
strategy, we subjected 5-pregnen-3b-ol-20-one, a complex biologically
active molecule, to our standard reaction conditions. In the event, this
compound underwent fragment coupling with 1,4-dicyanobenzene in
a highly regioselective and diastereoselective fashion to deliver the aryl
functionalized steroid framework 41 in good yield (Fig. 4b).
Beyondregiocontrol,amoreremarkableselectivityphenomenonthat
we have observed in these photoredox coupling studies is that mono-
arylation adducts are observed exclusively, despite the fact that the allyl
substituted arylproduct containsa C–Hbond that isfarweaker than the
allylicpositionofthestartingmaterialolefin.Twomechanisticscenarios
could account for this unique (and valuable) form of chemoselectivity.
First, the doubly activated (benzylic and allylic) C–H bond of the pro-
duct is significantly less hydridic than the starting material allylic C–H,
and is thereby sufficiently less susceptible to hydrogen atom abstrac-
tionbythe electrophilicthiylradicaloftheorganocatalyst (therebygov-
erned by the inherent exchange rate constant). Second, it is possible
that hydrogen abstraction does indeed occur from the mono-arylation
Anoverarching goal of this researchprogrammeistodefinea widely
adduct;however, theresultantstabilizedradicalisinsufficientlyreactive applicable mode of catalytic activation based on well-established physical
to participate in a second radical–radical coupling event (a persistent properties (that is, BDEs, hydrogen atom transfer exchange constants,
radical effect), and hydrogen atom re-abstraction from solvent or thiol oxidation potentials), which permits activation of any given substrate
would reconstitute the initial arylation product. Given that we do not in a predictable manner. Although the primary focus of this work has
observe the formation of any olefin-transposed styrenyl side products, been the direct arylation of allylic C–H bonds, we reasoned that this
which would arise from the hydrogen atom quenching of a persistent genericactivationmodecouldbeextendedtoencompassadiversemenu
benzylic–allylic radical species, we presume that the former, exchange- of substrates. In theory, any substrate possessing hydridic C–H bonds of
constant-gated mechanism is operative.
an appropriate strength (,80–90 kcal mol21) should have the potential
7 6
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LETTER RESEARCH
hydridic C–H bond than the benzylic position. It cannot be ruled out
that some degree of benzylic radical formation may occur; however, a
rapidhydrogenatomexchangewiththecyclohexenesubstratemaypre-
dominate over the rate of productive radical–radical coupling.
We have developed a reaction manifold that permits the direct func-
tionalization and arylation of allylic sp3 C–H bonds under mild and
operationally simple conditions. This new C–C bond forming process,
which relies on the mechanistic merger of photoredox and thiol-based
organic catalysis, readily accommodates a diverse range of alkene and
electron-deficient arene coupling partners. These studies havealso estab-
lished the versatility of this activation mode for the direct arylation of
both complex and sensitive olefin-containing molecules.
a
b
O
Me
Me Me
N
O
Me
Me
Me
Me
H
O
O
CN
B
B
O
H
H
HO
Me
Me
Me Me
CN
( )-39 73% yield*
( )-40 60% yield
41 67% yield*
c
1 mol% Ir(ppy)3
5 mol% catalyst 11
1
O
CN
OTBS
+
O
O
K2CO3, 26 W light
acetone, 23 °C
Received 2 November 2014; accepted 22 January 2015.
CN
CN
Silyl ketene acetal
(1.1 equiv.)
1. He, J. et al. Ligand-controlled C(sp3)–H arylation and olefination in synthesis of
unnatural chiral a-amino acids. Science 343, 1216–1220 (2014).
2. Eames, J. & Watkinson, M. Catalytic allylic oxidation of alkenes using an
asymmetric Kharasch-Sosnovsky reaction. Angew. Chem. Int. Edn 40, 3567–3571
(2001).
CN
68% yield
Me
d
Me
1 mol% Ir(ppy)3
1
10 mol% catalyst 11
3. Johannsen, M. & Jørgensen, K. A. Allylic amination. Chem. Rev. 98, 1689–1708
(1998).
H
+
Na2CO3, 26 W light
acetone, 23 °C
4. Trost, B. M. & Van Vranken, D. L. Asymmetric transition metal-catalyzed allylic
alkylations. Chem. Rev. 96, 395–422 (1996).
CN
CN
Ethylbenzene
(5 equiv.)
69% yield
5. Borg, R. M., Arnold, D. R. & Cameron, T. S. Radical ions in photochemistry. 15. The
photosubstitution reaction between dicyanobenzenes and alkyl olefins. Can.
J. Chem. 62, 1785–1802 (1984).
6. Hoshikawa, T. & Inoue, M. Photoinduced direct 4-pyridination of C(sp3)–H bonds.
Chem. Sci. 4, 3118–3123 (2013).
e
1,4-dicyanobenzene
Me
H
NC
H
7. Sekine, M., Ilies, L. & Nakamura, E. Iron-catalyzed allylic arylation of olefins via
C(sp3)–H activation under mild conditions. Org. Lett. 15, 714–717 (2013).
8. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox
catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011).
9. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with
transition metal complexes: applications in organic synthesis. Chem. Rev. 113,
5322–5363 (2013).
1 mol% Ir(ppy)3
1
+
10 mol% catalyst 11
Na2CO3, 26 W light
acetone, 23 °C
78% yield
Only product
Cyclohexene
(2.5 equiv.)
Ethylbenzene
(2.5 equiv.)
10. Schultz, D. M. & Yoon, T. P. Solarsynthesis: prospects invisible light photocatalysis.
Science 343, 1239176 (2014).
11. Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with
organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322,
77–80 (2008).
12. Nagib, D. A., Scott, M. E. & MacMillan, D. W. C. Enantioselective
a-trifluoromethylation of aldehydes via photoredox organocatalysis. J. Am. Chem.
Soc. 131, 10875–10877 (2009).
13. Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox
activation for the direct b-arylation of ketones and aldehydes. Science 339,
1593–1596 (2013).
14. Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for
organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation
of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014).
15. Khursan, S. L., Mikhailov, D. A., Yanborisov, V. M. & Borisov, D. I. AM1 Calculations of
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61, 91–95 (1997).
Figure 4
|
Expanding the scope of the direct C–H arylation protocol.
a, Substrates bearing boronic esters substituents are tolerated, providing a
means to rapidly access functionalized building blocks. b, The mild conditions
allow for late-stage functionalization of advanced synthetic intermediates and
bioactive natural products. c, Silyl ketene acetals are compatible with the
reaction conditions, yieldingb-aryllactones. d, Arylationis notlimited toallylic
C–H bonds; benzylic C–H bonds can also be arylated. e, The reactivity is
governed by bond strengths, with the weaker allylic bond undergoing exclusive
functionalization in a direct competition experiment. *Isomers observed; in all
cases the major isomer is depicted. Yields refer to the combined yield of all
isomers. Ratios of isomers where applicable: (6)-39 (6:1), 41 (.10:1). See
Supplementary Information for experimental details.
to serve as a viable coupling partner in this arylation manifold. Along
these lines, we found that silyl ketene acetalsare also readily arylated to
produce the corresponding b-aryl lactones (Fig. 4c). It is important to
consider that lactones represent a high-value substrateclass that is incom-
patible with contemporary enamine mediated b-arylation technologies13.
Moreover, this fragment couplingprotocol can be extended to benzylic
substrates such as ethylbenzene to generate the corresponding benzhy-
dryl systems in excellent yields (Fig. 4d).
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The predictable and highly useful nature of this hydrogen atom acti-
vation mode is exemplified in a direct competition experiment con-
ducted with cyclohexene and ethylbenzene. As shown in Fig. 4e, when
both olefinic and benzylic substrates were combined in the samevessel,
only the product of allylic arylation was observed (78% yield) with no
competitive formation of the benzylic arylation product to any degree.
This is a striking result given that ethylbenzene is in fact a suitable
substrate for this arylation protocol (see Fig. 4d). The exclusive forma-
tion of the allylic arylation product can be readily rationalized by con-
sideration of the BDEs for the two substrates (cyclohexene allylic
C–HBDE 5 83.2 kcalmol21 versusethylbenzenebenzylicC–HBDE 5
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Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support was provided by NIHGMS (R01
GM103558-03), and we also thank Merck and Amgen for funding. J.D.C. thanks Marie
Curie Actions for an International Outgoing Fellowship.
Author Contributions J.D.C. performed and analysed experiments. J.D.C. and D.W.C.M.
designed experiments to develop this reaction and probe its utility, and also prepared
this manuscript.
85.4 kcal mol21 15,21, along with an appreciation of the hydridic nature
)
of the respective C–H bonds involved. On this basis, it can be readily
anticipated that the thiyl radical will preferentially abstract a hydrogen
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www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper.
Correspondence and requests for materials should be addressed to
atom from the allylic substrate, which possesses the weaker and more D.W.C.M. (dmacmill@princeton.edu).
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