Conformation-induced remote meta-C-H activation of amines

Article abstract of DOI:10.1038/nature12963

Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds - as far as 11 bonds away - of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

Full text of DOI:10.1038/nature12963

LETTER
doi:10.1038/nature12963
Conformation-induced remote meta-C–H
activation of amines
Ri-Yuan Tang1, Gang Li1 & Jin-Quan Yu1
Achieving site selectivity in carbon–hydrogen (C–H) functionali-
Here we report the rational design of a nitrile-containing template
zation reactions is a long-standing challenge in organic chemistry. that directs C7-selective C–H activation of tetrahydroquinolines (Fig. 1).
The small differences in intrinsic reactivity of C–H bonds in any By systematically modifying the structure of the template, we identified
given organic molecule can lead to the activation of undesired C–H the template conformation as a critical factor in favouring remote meta-
bonds by a non-selective catalyst. One solution to this problem is to or proximate ortho-selectivity(Fig. 1b). Remarkably,bytuningtheprop-
distinguish C–H bonds on the basis of their location in the mole- erties of the Pd(II) catalyst throughuse of N-acetyl-glycine (Ac-Gly-OH)
cule relative to a specific functional group. In this context, the acti- as a ligand, the pre-existing conformational bias in the template can
vation of C–H bonds five or six bonds away from a functional group be further amplified to achieve remote meta-C–H olefination in excel-
by cyclometallation has been extensively studied1–13. However, the lent yield and with high levels of site selectivity (Fig. 1c). This opti-
directed activationof C–H bonds thataredistal to(more than six bonds mized template is broadly applicable to the remote C–H activation of
away) functional groups has remained challenging, especially when 2-phenylpyrrolidines, 2-phenylpiperidines and other aniline-type sub-
the target C–H bond is geometrically inaccessible to directed metal- strates, despite the intrinsic electronic biases in these substrates that
lation owing to the ring strain encountered in cyclometallation14,15
.
favour ortho-functionalization (Fig. 1d). In addition to meta-C–H ole-
Here we report a recyclable template that directs the olefination and fination via a Pd(II)/Pd(0) redox cycle, we were also able to demon-
acetoxylationofdistalmeta-C–Hbonds—asfaras11bondsaway—of strate meta-C–H acetoxylation via Pd(II)/Pd(IV) catalysis using this
anilinesandbenzylicamines. Thistemplateisabletodirectthemeta- template. Thistemplatecanbeeasilyinstalledandlaterrecycled, similar
selective C–H functionalization of bicyclic heterocycles via a highly tochiralauxiliaries thatare widelyused inorganic synthesis, suchas the
strained, tricyclic-cyclophane-like palladated intermediate. X-ray and well-knownEvans oxazolidinone. Thiswork paves theway for practical
nuclear magnetic resonance studies reveal that the conformational applications of remote C–H activation through template control.
biasesinducedbyasinglefluorinesubstitutioninthetemplatecanbe
enhanced by using a ligand to switch from ortho- to meta-selectivity.
A procedure exists for the meta-selective olefination of hydrocinna-
mic acids using a novel end-on 2-aminobenzonitrile template14. Cru-
The selective functionalization of inert C–H bonds at different sites cial for the meta-selectivity, the directing nitrile group is in extended
of organic molecules provides an opportunity for the introduction of conjugation with the carbonyl moiety of the substrate, which positions
diverse structural modifications and the development of novel retro- thenitrilegroupincloseproximitytoandcoplanarwiththetargetmeta-
syntheticdisconnections. However, the widespread application of C–H C–H bond. However, in translating this insight to the meta-selective
functionalizationinorganicsynthesisishamperedbyalackofcatalysts, olefination of tetrahydroquinolines, we needed to design an entirely
reagents and methodologies that enable the site-selective functionali- novel end-on template and we faced several considerable challenges in
zation of C–Hbonds, which oftenhave very subtle differencesin intrinsic determining the optimal structural design. First, the hypothetical pal-
reactivity. We have broadly focused on the development of metal-catalysed ladation intermediate would involve a highly strained intermediate with
C–H activation reactions that are directed byweakly coordinating func- a tricycliccyclophanestructure(Fig. 1a). Second, although a simple amide
tionalgroups1. In analogy to the principles of proximity-driven metallation2, linkage is desirable for practical attachment of the template, we rea-
thistypeofmethodologyenablestheselectivefunctionalizationofC–H lised that the amide group could potentially favour the activation of
bonds that are five or six bonds away from the directing atom, through the ortho-(C8) position, an established mode of reactivity for anilide-
cyclometallation3–13. Although thisapproach has enabled the discovery type substrates19. Moreover, amine substituents are well-known ortho/
of numerous transformations over the past decade, the functionaliza- para directors in electrophilic aromatic substitution reactions, including
tion of C–H bonds that are located farther away from the coordinating electrophilic palladation. Third, to avoid the pitfall of over-engineering,
functional groupremains a largely unsolved problem in organicsynthesis, we hoped to develop a simple amide template with an sp3-hybridized
especially when their locations do not permit cyclometallation owing backbone without having to build in an extended conjugation. We recog-
to geometric strain14–18
.
nized that such a template could lead our substrates to exist in multiple
interconverting conformations, each with a low equilibrium population.
This would translate into a high entropic barrier for formation of the
highly organizedtransitionstate requiredfor cyclopalladation. We there-
fore aimed to acquire an improved understanding of how the confor-
mation of non-constrained atoms in a template can be manipulated to
favour remote C–H activation. In addition, we hoped to develop a cat-
alysttorecognizeandharnesssubtleconformationalbiasesandamplify
pre-existing template-induced preferences for meta-selectivity.
To begin our investigation, we attached the simple nitrile templates
Recently we developed an end-on-coordinating, nitrile-based template
that is able to direct Pd(II)-catalysed meta-selective olefination and aryla-
tion of hydrocinnamic acids14,15. This discovery led us to explore three
keyquestions: first, whether thisnew end-on template approach can be
applied to other substrate classes; second, whether other types of trans-
formation using different catalytic manifolds can be achieved using end-
on templates;and, third, whether there are critical and general underlying
principles for the design of an effective template to direct remote C–H
activation. In this context, we recognized that the selective activation
of C–H bonds at C7 of tetrahydroquinolines is a conceptually intri- T1–T3 to tetrahydroquinoline and tested these substrates in a model
guing and synthetically important challenge. A novel template will be reaction, the Pd(II)-catalysedC–Holefination (Fig. 2a, b). Although the
required to accommodate a highly strained intermediate with a tricy- reaction of 1 did not provide any olefinated products, 2 and 3 afforded
clic cyclophane structure (Fig. 1a).
mixturesofpositionalisomersthataredifficulttoseparate.Theaddition
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
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RESEARCH LETTER
a
Previously inaccessible C–H bonds
Highly strained tricyclic cyclophane intermediates
O
O
N
N
H
( )
Pd
DG
N
Pd
DG
N
n
H
N
H
N
H
H
Pd
( )
( )
n
n
H
DG
b
5
5
8
6
6
7
Pd
7
N
N
N
Me
Me
H
H
N
Pd
Pd
F
H
O
C8
O
O
C7
O
O
O
N
N
Meta-directing
Ortho-directing
c
5
5
8
6
7
6
Pd
N
7
N
N
Ligand
Ligand
H
Me
Me
Highly
ortho-selective
Highly
meta-selective
F
Pd
O
O
O
O
N
d
O
N
H
NH2
N
H
H
NH2
H
N
H
H
N
H
H
H
H
Figure 1
|
Design of a versatile template to direct meta-C–H activation.
of meta-selectivity by use of a ligand. d, Scope of meta-C–H activation:
olefination and acetoxylation. We highlight the C–H bonds and the palladation
intermediate (blue), the newly formed bonds (red) and the importance of
fluorine substitution to this reactivity (magenta).
a, The challenge of remote meta-C–H activation of bicyclic heterocycles,
illustrated by previously inaccessible C–H bonds and highly strained
tricyclic cyclophane intermediates. DG, directing group. b, Proposed
conformation-controlled meta-C–H activation. Me, methyl. c, Amplification
of our previously identified ligand, Ac-Gly-OH, did not improve the In contrast, the amide C–N bond in 5 can more freely rotate, leading to
level of selectivity with these templates. We attributed the poor site selec- some of the meta-C–H olefination product. Notably, introduction of
tivity to either a lack of conformational rigidity in the template back- the a-fluorine substitution in 6a leads to a conformationalswitchwherein
bones (T1 and T2) or the template being too short to reach the target the carbonyl group is directed away from the ortho-C–H bond. Increas-
C–H bond (T3). We subsequently explored the a-hydroxy template ing the proportion of this conformation seems to improve the rate of
structure (T4, T5 and T6) and observed an encouraging trend favour- meta-C–H activation; however, a low barrier for interconversion between
ing C7 selectivity in C–H olefination (Fig. 2b). Although exclusive C8- thepro-metaandpro-orthoconformers stillresults insubstantial levels
olefination was observed using template T4 (substrate 4), the use of of ortho-C–H activation.
templatesT5 (substrate5) and T6 (substrate 6a) afforded C7-olefinated
product with selectivities of 11% and 20%, respectively. Although the
level of meta-selectivity was still poor with these templates, the obser-
vation that a single fluorine substituent, in T6, nearly doubles the meta-
selectivity prompted us to investigate the origin of this phenomenon.
Wereasonedthatthemeta-selectivityof6acouldbeamplifiedbythe
use of a bulkierandmore electron-rich catalyst because the C7position
is less sterically hindered and more electron poor than C8 (ref. 22). In
fact,wefoundthattheuseofAc-Gly-OHas aligandinconjunctionwith
template T6 improves the level of meta-selectivity from 20% to 92%
Becausefluorinesubstituents can lead to pronounced changes in mole- (Fig. 2b). After deprotection, the meta-olefinated product 7a was iso-
cular conformation20,21, we studied the conformations of 4–6 in the lated in 75% yield. Under these ligand-enhanced reaction conditions, the
solid state and in solution. X-ray crystal structures of 4 and 5 showed meta-selectivity of substrate5 is also markedly increased (11% to 84%).
thatthecarbonylgroupisperfectlyorientedtoperformortho-C–Hacti- In contrast, olefination of substrate 4 with Ac-Gly-OH as a ligand pro-
vation. However, inthe X-raycrystal structure of6athecarbonylgroup vides the olefinated product with 91% ortho-selectivity (92% yield). These
is oriented away from C7, which presumably makes it better suited for results suggest that, although the Ac-Gly-OH ligand can promote meta-
the nitrile moiety to approach the meta-C–H bond (C8). Studies of the selectivity, the appropriate conformation of the template is a prerequisite
nuclear Overhauser effect showed that a similar conformational trend for achieving high levels of meta-selectivity. We have also tested the ana-
is present in solution (Supplementary Information). Steric hindrance logue of T6 that contains a-difluoro substituents, in an attemptto improve
from the gem-dimethyl substituents in 4 probably raises the activation the meta-selectivity further. We obtained a yield and meta-selectivity sim-
energy for amide N–C bond rotation, leading to highly restricted intercon- ilar to those gained using T6, indicating that electronic effect does not have
version between the pro-ortho (ground state) and pro-meta conformations. a major role in controlling meta-selectivity (Supplementary Information).
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LETTER RESEARCH
a
b
5
8
(1) Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%)
AgOAc (3 equiv.), HFIP, 90 °C, 24–40 h
X
6
7
CO2Et
X
+
N
T
N
H
(2) HCl/EtOH (1:5)
90 °C, 2–4 h
1.5 equiv.
EtO2C
1–6h
1a–7h
N
O
S
O
N
O
O
N
NC
NC
NC
O
T2
2
T1
1
T3
3
Without Ac-Gly-OH: 0% without ligand
~80% yield
Multiple products
~30% yield
Multiple products
With Ac-Gly-OH: 0% with ligand
~71% yield
Multiple products
~30% yield
Multiple products
C7
C7
C7
N
N
N
C8
C8
F
H
C8
Me
Me
H
H
O
O
O
O
O
O
CN
T6
CN
CN
T4
4
T5
5
6a
Without Ac-Gly-OH: 7% yield
26% yield
C7:C8 = 11:89
74% yield
C7:C8 = 20:80
C7:C8 = 0:100
With Ac-Gly-OH:
92% yield
C7:C8 = 9:91
45% yield
C7:C8 = 84:16
85% yield
C7:C8 = 92:8
Me
Cl
c
N
H
N
H
N
H
N
H
EtO2C
EtO2C
EtO2C
EtO2C
7d, 70%
7a, 75%
C7:C8 = 92:8
7b, 80%
C7:C8 = 97:3
7c, 71%
C7:(C6 + C8) = 88:12
C7:(C6 + C8) = 92:8
MeO
F
O
N
H
N
H
N
H
N
H
Me
EtO2C
EtO2C
EtO2C
EtO2C
7e, 52%
C7:(C5 + C8) = 93:7
7f, 53%
C7:C5 = 88:12
7gC7, 52%
7h, 71%
C7:(C5 + C6 + C8) = 87:13
C7:C6 = 78:22
Figure 2
|
Development of templates to direct meta-C–H olefination.
yields of other olefinated products are shown along with the selectivity
(combined yields are shown in b). See Supplementary Information for
experimental details. Selectivity of the olefinated products was determined by
1H NMR analysis or gas chromatography mass spectrometry (GCMS) using a
flame ionization detector. The variance is estimated to be within 5%. HFIP,
a, Olefination of tetrahydroquinoline derivatives. b, Six representative
templates designed to screen the meta-C–H olefination.
c, Tetrahydroquinolines with a variety of substitution patterns appended
with template T6 (6a–6h) undergo facile meta-C–H olefination. The yields
of 2 and 3 are NMR yields with CH2Br2 as the internal standard. The selectivity hexafluoroisopropanol.
is not determined, owing to multiple olefinated products detected. The isolated
Having established an optimal system for meta-selective C–H ole- acetanilides demonstrates the high reactivity of the ortho-position of
fination, we proceeded to investigatethe scope of tetrahydroquinolines thesesubstratestowardspalladation19. Ameta-selectiveC–Holefination
(Fig. 2c). Substitution at C2 improves the meta-selectivity (7b, 97:3). of anilines would offer a complementary retrosynthetic disconnection
Substitutions at the C5 and C6 positions were well tolerated (7c–7f). for the synthesis of substituted anilines. Thus, aniline was attached to
C8 substitution decreases the level of meta-selectivity to 78:22, presumably the optimized template T6 and subjected to the established olefination
owing to the sterichindrance of the C7 position(7g). Dihydrobenzoxazine
6h was also selectively meta-olefinated to give the desired product in
71% isolated yield (7h). It is worthnoting that the C7 positions of these
heterocyclic skeletons are very difficult to functionalize, and that this
methodologycouldenable thesynthesisofa newsubclassofthesemed-
ically active heterocycles.
conditions (Fig. 3). A mixture of mono- and di-olefinated products
(9amono and 9adi) was obtained in 88%combined yield with 99% meta-
selectivity, suggesting that this template can successfully override an
electronic biastowards ortho-palladation. A variety ofelectron-richand
electron-poormeta-substitutedanilines gavethemono-olefinatedpro-
ducts ingood to high yieldswiththe meta-selectivity ranging from 94%
Wesubsequentlyexploredtheuseofourtemplatesysteminthemeta- to 99% (9b–9g). Ortho-substituted anilines were selectively olefinated
selective olefination of anilines. The directed ortho-C–H olefination of at the less hindered position to give mono-olefinated products (9hmono
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X
a
b
CN
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%)
R'
F
X
T6
=
O
R'
N
N
+
O
AgOAc (3 equiv.)
HFIP, 90 °C, 24–48 h
R
R
T
6
T6
1.2–2.0 equiv.
8a–8t
9a–9t
OMe
o'
Me
F
m'
o'
o'
EtO2C
EtO2C
EtO2C
EtO2C
m
N
N
m
N
N
m
m
o
o
o
o
T6
T6
T6
T6
9amono, 43%
9ba, 83%
9c, 81%
9d, 84%
m:(o + p) = 99:1
m:(o + o' + p) = 99:1
m:(o + o' + p) = 98:2
m:(o + o' + p) = 96:4
9adi, 45%
(m, m'):others = 99:1
m'
Br
CF3
Cl
Me
o'
o'
o'
EtO2C
m
N
o
EtO2C
EtO2C
EtO2C
N
N
N
m
o
T6
o
o
T6
9f, 67%
T6
T6
9e, 78%
9g, 80%
9hmono, 53%
m:(o + o' + p) = 96:4
m'
m:(o + o' + p) = 94:6
di: 8%
m:(o + o' + p) = 94:6
m:(o + m' + p) = 95:5
9hdi, 19%
(m, m'):others = 98:2
m'
m'
m'
OCF
3
MeO
Me
F
EtO2C
EtO2C
EtO2C
EtO2C
m
N
m
N
m
N
N
m
o
o
o
o
T6
T6
T6
T6
9imono, 80%
m:(o + m' + p) = 98:2
9idi, 5%
9jmono, 46%
m:o = 99:1
9jdi, 40%
9kmono, 72%
m:o = 99:1
9kdi, 12%
9lmono, 45%
m:o = 98:2
l
di, 22%
(m, m'):others = 99:1
(m, m'):others = 95:5
(m, m'):others = 96:4
(m, m'):others = 94:6
O
O
Me
Br
m'
m'
m'
Cl
MeO
EtO2C
EtO2C
EtO2C
EtO2C
m
m
N
N
m
N
N
m
o
o
o
o
T6
T6
T6
T6
9mmono, 56%
m:o = 99:1
9mdi: 5%
9nmono, 52%
m:o = 99:1
9ndi, 8%
9omono, 35%
m:o = 99:1
9odi, trace
9p, 56%
m:(o + p) = 95:5
(m, m'):others = 98:2
(m, m'):others = 97:3
Me
F
Me
Me
Me
Cl
o'
EtO2C
EtO2C
EtO2C
EtO2C
m
m
N
m
N
N
N
m
o
o
o
o
T6
T6
T6
T6
9q, 73%
m:(o + p) = 92:8
9r, 82%
m:(o + p) = 97:3
9s, 63%
m:(o + o' + p) = 90:10
9tmono, 38%
m:o = 95:5
9tdi, 32%
(m, m'):others = 94:6
Me
Me
Me
o'
o'
o'
O
O
N
m
o
P
m
N
S
m
o
N
o
O
EtO
T6
OEt
T6
Ph
T6
F3C
Me
9b1, 76%
m:(o + o' + p) = 99:1
9b2, 78%
m:(o + o' + p) = 99:1
9b3, 51%
m:(o + o' + p) = 99:1
Me
Me
Me
O
O
o'
o'
MeO
o'
o'
MeO
EtO
m
N
N
m
N
m
N
m
o
o
o
o
O
T6
O
T6
T6
T6
9b4, 50%
m:(o + o' + p) = 95:5
9b5, 60%
m:(o + o' + p) = 99:1
9b6, 82%
m:(o + o' + p) = 99:1
9b7, 84%
m:(o + o' + p) = 99:1
Figure 3
|
Template-directed remote C–H olefination of N-methylanilines. of the di-olefinated product, when applicable) are shown along with the
a, Anilines with a variety of substitution patterns were found to undergo facile selectivity. See Supplementary Information for experimental details. Selectivity
meta-C–H olefination. b, In the box, electron-deficient olefins and various
di-and tri-substituted olefins were compatible with the transformation in a.
of the mono- and di-olefinated products was determined by 1H NMR analysis
and GCMS analysis using a flame ionization detector. The variance is estimated
The isolated yields of the mono-olefinated product (and also the isolated yields to be less than 5%. Ph, phenyl.
and 9imono) accompaniedbysmallamountsof the di-olefinatedbypro- wasalsocarriedoutusing5 mol%Pd(OAc)2 togivethedesiredproduct,
ducts. Despite the steric hindrance, excellent meta-selectivity was also 9d, in 60% isolated yield (Supplementary Information). The replace-
obtained for a number of para-substituted anilines, albeit with varied ment oftheN-methyl group by a readily removable benzyl-type protect-
mono- or di-selectivity (9j–9o). Polysubstituted anilines were also smoothly ing group was also tolerated, thus improving the utility of this reaction
olefinatedattheremainingmeta-positionstoaffordanilines9p–9rcon- (9s and 9t). The hydrogenolysis of the benzyl-type protecting group also
taining complex 1,2,3,5-substitution patterns. Meta-olefination of 8d reduced the installed olefin unit to corresponding alkyl (Supplementary
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LETTER RESEARCH
a
b
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%)
X
CN
O
F
X
T6 =
O
PhI(OAc)2 (2 equiv.)
Ac2O (7 equiv.)
HFIP, 90 °C, 30–40 h
N
AcO
N
T6
T6
8
10
Me
Cl
o'
o'
AcO
AcO
AcO
m
m
N
N
N
m
o
o
o
T6
T6
T6
10a, 60%
10b, 66%
10e, 51%
m:o = 92:8
m:o = 91:9
m:o = 94:6
Br
CF3
m'
Me
o'
o'
AcO
AcO
AcO
m
m
m
o
N
N
N
o
o
T6
T6
T6
10f, 47%
m:o = 98:2
10g, 32%
m:o = 99:1
10h, 65%
m:o = 91:9
Cl
m'
OCF3
Me
Me
AcO
AcO
AcO
m
m
o
N
N
N
m
o
o
T6
T6
T6
10i, 65%
m:o = 95:5
10j, 60%
m:o = 90:10
10q, 64%
m:o = 98:2
c
d
Pd(OAc)2 (10 mol%)
Ac-Gly-OH (20 mol%)
CN
F
T6 =
O
PhI(OAc)2 (2 equiv.)
Ac2O (7 equiv.)
HFIP, 90 °C, 30–40 h
N
N
O
AcO
T6
T6
11a–11d
12a–12d
N
N
N
N
T6
o
o
m
o
o
m
m
m
AcO
AcO
AcO
AcO
T6
T6
T6
12a, 54%
m:o = 96:4
12b, 56%
m:o = 98:2
12c, 51%
m:o = 94:6
12d, 58%
m:o = 96:4
Figure 4
|
Meta-C–H acetoxylation of N-methylanilines and benzylamine
acetoxylated benzylamine derivative is shown along with the selectivity. See
derivatives. a, Anilines(8) witha variety ofsubstitution patterns undergo facile Supplementary Information for experimental details. The selectivities of the
meta-C–H acetoxylation. b, The isolated yield of the acetoxylated aniline is
shown along with the selectivity. c, Benzylamines derivatives (11a–11d) were
found to undergo facile meta-C–H acetoxylation. d, The isolated yield of the
acetoxylated products were determined by 1H NMR analysis and GCMS
analysis using a flame ionization detector. The variance is estimated to be less
than 5%.
Information). Finally, a range of olefin coupling partners, including (10f and 10g). Meta-selective acetoxylation of an ortho,meta-di-
1,2-di-substituted olefins, were shown tobe compatible withthis trans- substituted anilinewas also successful (10q).Theversatilityofournewly
formation, demonstrating broader scope than the majority of directed developed methodology is further demonstrated by the meta-selective
ortho-C–H olefination reactions (9b1–9b7).
acetoxylation of acyclic and cyclic benzylamines (Fig. 4c, d). Notably,
the C–H bonds that are cleaved in these in benzylamine substrates are
11 bonds away from the directing nitrogen atom, which is an unpre-
cedentedly long distance for direct C–H activation. Meta-selective ace-
toxylation of 2-phenylpyrrolidine 11c and 2-phenylpiperidine 11d is a
potentially powerful methodology for accessing diverse structures of
medicinallyimportantheterocycles. The hydrolyticremoval ofthetem-
plate also converted the acetate to hydroxyl group in one pot (Sup-
plementary Information).
Theutilityofourtemplate-directedremoteC–Hactivationapproach
in developing other types of C–C and C–heteroatom bond-forming
reactionsviadifferentcatalyticmanifoldsremainedtobedemonstrated.
Thus, amine substrate 8a was subjected to various C–H oxidation reac-
tion conditions (Fig. 4a, b). Notably, these transformations proceed via
a Pd(II)/Pd(IV) redox chemistryas opposed tothePd(0)/Pd(II) catalytic
cycle of C–H olefination. We found that the use of PhI(OAc)2 oxidant8
affords meta-acetoxylated amine 10a as the major product in 60% iso-
lated yield. Excellentlevelsof meta-selectivity (90%–98%) were obtained
Preliminary mechanistic studies of the acetoxylation of aniline also
with various substituted anilines. A variety of ortho-, meta- and para- revealed that conformation of templates, again, has a decisive role in
substituents were tolerated in this transformation (10b–10j) although controllingthesiteselectivity.ControlexperimentsshowedthatAc-Gly-
more electron-withdrawing substituents led to a depreciation in yield OH had only a minor beneficial effect on the yield of acetoxylation and
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RESEARCH LETTER
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a negligible influence on the site selectivity. Remarkably, we found that
thelevelsofmeta-selectivityoftheacetoxylationofaniline wererespec-
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the absence of an amino-acid ligand, reflecting the intrinsic conforma-
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with the commercially available 2-(2-cyanophenoxy)-2-fluoroacetic
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METHODS SUMMARY
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as follows. A 35-ml sealed tube (with a Teflon cap) equipped with a magnetic stir
bar was charged with amide substrate (0.10 mmol, 1.0 equiv.), Pd(OAc)2 (2.3 mg,
0.01 mmol, 10 mol%), Ac-Gly-OH(2.4 mg, 0.02 mmol, 20 mol%)andAgOAc(50 mg,
0.30 mmol, 3.0 equiv.). HFIP (0.5 ml) was added to the mixture, followed by ethyl
acrylate (1.2–2.0 equiv.) and, finally, another portion of HFIP (0.5 ml). The tube
was then capped and submerged into an oil bath pre-heated to 90 uC. The reaction
was stirred for 24–48 h and cooled to room temperature (,25 uC). The crude reac-
tion mixture was diluted with EtOAc (5 ml) and filtered through a short pad of
Celite. The sealed tube and Celite pad were washed with an additional 20 ml of
EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was puri-
fiedbypreparativethin-layerchromatography usinghexanes,EtOAcanddichlor-
omethane as the eluent. The positional selectivity was determined by GCMS with
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Received 31 August; accepted 18 December 2013.
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Supplementary Information is available in the online version of the paper.
Acknowledgements We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 1R01 GM102265) for their financial support. R.-Y.T. is a visiting
scholar from Wenzhou University and is sponsored by the National Natural Science
Foundation of China (21202121).
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Author Contributions R.-Y.T. and G.L. performed the experiments and developed the
reactions. R.-Y.T. and J.-Q.Y. designed the templates. J.-Q.Y. had the idea for this work
and prepared this manuscript with feedback from R.-Y.T. and G.L.
Author Information Reprints and permissions information is available at
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 J.-Q.Y. (yu200@scripps.edu).
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