Organic chemistry: Functionalization of C(sp3)-H bonds using a transient directing group

Article abstract of DOI:10.1126/science.aad7893

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C-H bonds. Arylation of a wide range of aldehydes and ketones at the β or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C-H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.

Full text of DOI:10.1126/science.aad7893

RESEARCH
| REPORTS
confirmation by Kaguya and LADEE of the lunar
Na trend between November and April provides
the strongest evidence yet for an annual varia-
tion of the Na exosphere. This trend is likely the
cumulative response of Na to meteoroid streams,
whose annual activity peaks from November through
January and then subsides until the summer. The
substantial residence time for Na at the surface
suggested by this interpretation inevitably leads
to the conclusion that Na migrates toward the
poles like other volatiles (e.g., water) in these cycles
of adsorption and redesorption. The K measure-
ments show a strong but, contrary to Na, short-
lived response to the Geminids meteoroid shower.
Outside of the meteoroid streams, K shows a
regular variation across a lunation that correlates
strongly with the abundance of potassium in the
lunar bulk soil. Combined, these results and re-
cent studies of the Mercurian exosphere (23, 24)
indicate a pronounced role for meteoroid impact
vaporization and surface exchange in determining
the composition of surface-bounded exospheres.
However, the details of how the exosphere depends
on surface composition and responds to meteo-
roid streams are not yet understood.
for M.S. was through NASA grants NNX14AG14A, NNX13AP94G,
and NNX13AO74G. All LADEE UVS data are available online at the NASA
Planetary Data System (PDS), including all raw and calibrated
spectra and derived sodium and potassium line strengths.
Supplementary Text
Figs. S1 to S5
References (25–34)
SUPPLEMENTARY MATERIALS
13 August 2015; accepted 30 November 2015
Published online 17 December 2015
10.1126/science.aad2380
www.sciencemag.org/content/351/6270/249/suppl/DC1
Materials and Methods
ORGANIC CHEMISTRY
Functionalization of C(sp3)–H bonds
using a transient directing group
Fang-Lin Zhang,* Kai Hong,* Tuan-Jie Li,* Hojoon Park, Jin-Quan Yu†
Proximity-driven metalation has been extensively exploited to achieve reactivity and
selectivity in carbon–hydrogen (C–H) bond activation. Despite the substantial
improvement in developing more efficient and practical directing groups, their
stoichiometric installation and removal limit efficiency and, often, applicability as well.
Here we report the development of an amino acid reagent that reversibly reacts with
aldehydes and ketones in situ via imine formation to serve as a transient directing
group for activation of inert C–H bonds. Arylation of a wide range of aldehydes and
ketones at the b or g positions proceeds in the presence of a palladium catalyst
and a catalytic amount of amino acid. The feasibility of achieving enantioselective
C–H activation reactions using a chiral amino acid as the transient directing group
is also demonstrated.
REFERENCES AND NOTES
1. R. C. Elphic et al., Space Sci. Rev. 185, 3–25 (2014).
2. A. Colaprete et al., Space Sci. Rev. 185, 63–91 (2014).
3. A. E. Potter, T. H. Morgan, Science 241, 675–680 (1988).
4. A. S. Stern, Rev. Geophys. 37, 453–491 (1999).
5. A. L. Sprague, M. Sarantos, D. M. Hunten, R. E. Hill,
R. W. H. Kozlowski, Can. J. Phys. 90, 725–732 (2012).
6. D. Hunten, A. L. Sprague, Adv. Space Res. 19, 1551–1560
(1997).
7. M. Sarantos, R. M. Killen, A. S. Sharma, J. A. Slavin, Icarus 205,
364–374 (2010).
8. M. Kagitani et al., Earth Planets Space 61, 1025–1029
(2009).
9. M. Kagitani et al., Planet. Space Sci. 58, 1660–1664
(2010).
10. R. W. H. Kozlowski, A. L. Sprague, D. M. Hunten, Geophys. Res.
Lett. 17, 2253–2256 (1990).
11. A. L. Sprague, R. W. Kozlowski, D. M. Hunten, W. K. Wells,
F. A. Grosse, Icarus 96, 27–42 (1992).
12. D. M. Hunten et al., Icarus 136, 298–303 (1998).
13. S. M. Smith, J. K. Wilson, J. Baumgardner, M. Mendillo,
Geophys. Res. Lett. 26, 1649–1652 (1999).
14. S. Verani, C. Barbieri, C. Benn, G. Cremonese, Planet. Space
Sci. 46, 1003–1006 (1998).
15. V. Tenishev, M. Rubin, O. J. Tucker, M. R. Combi, M. Sarantos,
Icarus 226, 1538–1549 (2013).
16. A. A. Berezhnoy et al., Planet. Space Sci. 96, 90–98
(2014).
17. M. Matta et al., Icarus 204, 409–417 (2009).
18. Materials and methods are available as supplementary
materials on Science Online
19. A. E. Potter, R. M. Killen, T. H. Morgan, J. Geophys. Res. 105
(E6), 15073–15084 (2000).
20. B. L. Jolliff, J. J. Gillis, L. A. Haskin, R. L. Korotev,
M. A. Wieczorek, J. Geophys. Res. 105 (E2), 4197–4216
(2000).
21. D. J. Lawrence et al., Science 281, 1484–1489 (1998).
22. T. J. Stubbs et al., Influence of Meteoroid Streams on the
Lunar Environment: Results from LADEE, 46th Lunar
and Planetary Science Conference, held March 16–20, 2015,
in The Woodlands, Texas. LPI Contribution No. 1832, p. 2984
(2015).
recoordination of a metal with functional
groups in substrates has been extensively
exploited to control selectivity and promote
reactivity in metal-catalyzed or -mediated
reactions (1–5). The same approach has
ketones via a vinyl C–H activation step, featuring
an enamine intermediate with a pyridine moiety
as the transient directing group (13). Bedford et al.
developed a Rh-catalyzed ortho-arylation through
reversible in situ transesterification of catalytic
amounts of phosphinite ligands with the phenol
substrate (14). The strategy of using catalytic
directing groups has also been employed by
Lightburn et al. (15) and Grünanger and Breit (16)
to achieve selectivity in Rh-catalyzed hydroformyla-
tion reactions.
In conjunction with our efforts to develop
Pd-catalyzed C(sp3)–H functionalizations (17, 18),
we have extensively investigated the feasibility of
Pd(II)-catalyzed C(sp3)–H activation of aldehydes
and ketones using a wide range of potential
transient directing groups, including those pre-
viously developed for Rh(I) catalysts. Unfortu-
nately, the resultant Pd(II) complexes bound to
the bidentate iminopyridine or iminooxazoline
are unreactive toward cleavage of sp3 C–H bonds
under various conditions. The development of
monoprotected amino acid ligands (19, 20) and
the recent use of amino acids as bidentate di-
recting groups in C–H functionalizations of pep-
tides (21) led us to speculate that an amino acid
could serve as a suitable transient directing group.
We reasoned that the amino acid could be re-
versibly tethered to an aldehyde or ketone sub-
strate via an imine linkage under appropriate
conditions. In a similar manner to that operative
in our dipeptide chemistry, the imine moiety and
the carboxylate could form a bidentate directing
group to enable subsequent C–H functionaliza-
tion (Fig. 1C).
P
been successfully implemented in directed C–H
activation reactions (6–11). However, the cova-
lent installation and removal of directing groups
is a major drawback for synthetic applications.
First, an additional two steps must be added to
the synthetic sequence. Second, the conditions
for installation or removal of the directing groups
are sometimes incompatible with other functional
groups present in advanced synthetic intermedi-
ates. It is therefore highly desirable to devise a
functionally tolerant reagent that can be reversi-
bly linked to the substrate and can serve as a
directing group. Upon C–H activation and sub-
sequent functionalization, this reagent would
dissociate from the product and transiently link
to another substrate molecule so that only a cata-
lytic quantity of the directing group would be
needed (Fig. 1A). This approach has been success-
fully implemented in Rh(I)-catalyzed C(sp2)–H
activation reactions in a number of pioneering
examples. Jun et al. reported the use of 2-amino
pyridine as a transient directing group for Rh-
catalyzed activation of aldehydic C–H bonds (12)
(Fig. 1B). Recently, using a related strategy, Mo
and Dong reported a Rh-catalyzed a-alkylation of
23. M. Horányi et al., Nature 522, 324–326 (2015).
24. R. M. Killen, J. Hahn, Icarus 250, 230 (2015).
ACKNOWLEDGMENTS
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA.
*These authors contributed equally to this work.
We thank R. Killen for constructive discussions and the three reviewers
who helped to greatly improve this paper. LADEE UVS was
supported through the NASA Lunar Quest Program. Additional funding
†Corresponding author. E-mail: yu200@scripps.edu
252 15 JANUARY 2016 • VOL 351 ISSUE 6270
sciencemag.org SCIENCE

RESEARCH
| REPORTS
We chose arylation of 2-methylbenzaldehyde
1a with 4-iodoanisole as the model reaction for
optimization. Benzaldehyde derivatives are known
to readily form imine linkages with amino acids
(22). After extensive experimentation, we found
that the desired C(sp3)–H selective mono-arylation
product 2a could be observed in 18% nuclear
magnetic resonance (NMR) yield when the reac-
tion was conducted in hexafluoroisopropyl alco-
hol (HFIP) with 10 mol % Pd(OAc)2 (OAc, acetate),
40 mol % glycine, and 1.5 equivalents of silver
trifluoroacetate (see table S1, entry 5). The use of
acetic acid (AcOH) as the solvent improved the
yield to 52%, albeit with considerable decom-
position of the starting material (table S1, entry
6). We speculated that the low mass balance
stemmed from a rate mismatch between the
imine formation step and the following C–H
cleavage step, leading to decomposition of the
accumulated imine species. Therefore, we rea-
soned that the addition of water would reduce
the concentration of the imine intermediate and
prevent decomposition during the reaction. In-
deed, when a 9:1 mixture of AcOH and H2O was
used as the solvent, we were able to achieve 93%
conversion and 71% NMR yield, along with for-
mation of the diarylated product in 11% yield
(table S1, entry 8). By switching the limiting
reagent to the aryl iodide, we obtained the de-
sired mono-arylated product exclusively in 81%
NMR yield (table S1, entry 10). We also evaluated
a variety of amino acids and found that the side
chain of the amino acid does not have a marked
effect on the efficiency of this transformation
(table S1, entries 10 to 13). As expected, N-protected
glycine led to a complete loss of reactivity, con-
sistent with the hypothesis that imine formation
is crucial for enabling C–H activation (table S1,
entry 14).
Under optimal conditions, we next examined
the scope of C–H arylation (Fig. 2). The arylation of
2-methylbenzaldehyde 1a proceeded with a wide
range of aryl iodides in good yields. Both electron-
donating (2a to 2c) and electron-withdrawing
(2f to 2n) substituents are well tolerated at
either the para or meta position of the aryl io-
dide (72 to 83% yield). The use of a sterically
hindered ortho-substituted aryl iodide led to
a reduced yield (2d, 43%). The reaction can ac-
commodate a range of functional groups, includ-
ing halides (F and Br), nitro groups, aldehydes,
ketones, esters, and even free carboxylic acid
groups. More importantly, this reaction is
compatible with heteroaryl iodides as coupling
partners (2o to 2v), overriding the strong co-
ordination of heteroatoms to the metal catalyst.
This feature renders the reaction particularly
useful for the synthesis of biologically active
compounds bearing heterocycles. Finally, benzal-
dehydes with various ortho, meta, and para
substituents were effectively arylated with 1-iodo-
3-nitrobenzene, providing the corresponding pro-
ducts in good yields under the standard conditions
(2w to 2ad). The use of the analogous ketone
substrate 2′-methylacetophenone produced the
arylated product in low yield, presumably be-
cause that ketimine is more difficult to form.
We next investigated whether the same strat-
egy could be applied to aliphatic ketone sub-
strates, which are versatile and widely used
synthetic intermediates (23). Although b-arylation
of ketones via reaction pathways other than
b-metal insertion has been limited to the sub-
strates without a-substitution (24, 25), directed
C(sp3)–H activation of ketones has only been stu-
died through the intermediacy of preformed
oximes (9, 26, 27). We were aware that direct
arylation of ketones using a transient directing
Two Strategies for Directed C–H Activation
Fig. 1. C‒H activation using transient directing
groups. (A) Two strategies for directed C‒H acti-
vation. M, metal. (B) Pioneering examples of
reversibly linked directing groups. Me, methyl; X,
leaving group. (C) C(sp3)‒H arylation using an
amino acid as a transient directing group. Phth,
phthalimido; Et, ethyl; TFA, trifluoroacetic acid.
pre-installed directing groups
transient directing groups
[M] DG
C H
C H
[M] DG
DG: directing group
Disadvantage: requires installation
and removal of the directing group
[M] DG
C H
Pioneering Examples of Reversibly Linked Directing Groups
Me
Me
R
N
O
N
O
R
OH
H
H2N
N
PR2X
[Rh]
O
H
N
P
[Rh]
N
N
N
H
R
H
[Rh]
Mo (Ref. 13)
[Rh]
Jun (Ref. 12)
[Rh]
H
R
[Rh]
H
H
Bedford (Ref. 14)
C(sp3)–H Arylation Using Amino Acid as Transient Directing Group
C(sp3)–H Activation of Peptides
Design of Transient Amino Acid Directing Group
O
O
R
R
H2N
PhthN
O
O
OH
N
N
n
O
n
O
O
Pd
Pd
Pd(OAc)2
H
H
H
OAc
OAc
This Work
O
O
R
R''
via:
via:
cat. Pd(OAc)2
amino acid
O
O
N
R'
R
+
+
R'
H
O
AgTFA
AcOH/HFIP/H2O
I
Pd
OAc
R H
R
up to 98:2 er
O
Me
cat. Pd(OAc)2
amino acid
O
H
Et
Et
Me
Et
N
Me
AgTFA
AcOH/HFIP
O
I
Pd
H
R
OAc
SCIENCE sciencemag.org
15 JANUARY 2016 • VOL 351 ISSUE 6270 253

RESEARCH
| REPORTS
10 mol% Pd(OAc)2
40 mol% glycine
O
O
Fig. 2. Palladium-catalyzed
benzylic C(sp3)‒H arylation
of aldehydes. Ar(Het),
(hetero)aryl.
+
Ar(Het)
I
1.5 equiv. AgTFA
AcOH:H2O (9:1)
90oC, 36–48 h
R
R
Ar(Het)
H
1a–1i (1.2 equiv.)
1.0 equiv.
OH
2a–2ad
O
O
O
O
O
Me
OMe
Me
2a, 72%
2b, 82%
2c, 74%
2d, 43%
2e, 70%
O
O
Me
O
O
O
O
NO2
O
F
F
Cl
2f, 81%
2g, 79%
2h, 83%
2i, 81%
2j, 76%
O
CO2H
O
O
CO2Me
O
O
CO2Me
CO2H
N
2o, 71%
O
CF3
2k, 74%
2l, 78%
2m, 73%
2n, 74%
O
Cl
O
O
CF3
O
CF3
Cl
Cl
N
N
N
N
N
Cl
Ts
2p, 68%
2q, 52%
2r, 57%
2s, 47%
2t, 72%
O
NO2
O
O
O
O
NO2
NO2
Me
O
O
S
O
Me
Cl
Me
H
Me
2y, 73%
2u, 58%
2v, 54%
2w, 77%
2x, 84%
O
NO2
O
NO2
O
NO2
O
NO2
F
O
NO2
F
Br
F
2ac, 60%
2ad, 68%
2z, 64%
2aa, 76%
2ab, 81%
For each entry number (in boldface), data are reported as isolated yield. See supplementary materials for experimental
details.
group would pose several challenges: First, in
situ formation of ketimines is generally less fa-
vored than that of aldimines. Second, one of the
ketimine E/Z isomers may not be reactive if the
orientation of the imino acid directing group is
not suitable for directing palladium in proximity
to the target C–H bond. Third, tautomerization
of imines to enamines may occur as a competing
pathway, which would generate an ineffective
directing group. With these considerations in
mind, we further optimized the reaction con-
ditions for ketone arylation. Although the initial
investigation with 3-methyl-2-pentanone (3a)
provided <2% yield of the desired product under
the optimal conditions for aldehydes (table S2,
entry 1), we found that by using 50 mol % glycine
and a 3:1 mixture of HFIP:AcOH as the solvent,
the yield of b-arylation product 4a could be
substantially improved to 71% (table S2, entry 7).
However, a variety of amino acids with side chains
proved inferior and led to diminished yields
(table S2, entries 9 to 11).
lead to the decomposition of the starting mate-
rial under the current conditions.
Because carrying out Pd-catalyzed enantiose-
lective C–H insertion reactions remains a sub-
stantial challenge (19, 28–30), we wondered
whether the enantioselective C–H arylation
could be achieved by using a chiral reversible
directing agent. Thus, benzaldehydes bearing
methylene C(sp3)–H bonds were investigated in
the presence of a chiral amino acid. This trans-
formation is difficult due to the more sluggish
C–H activation, as well as the requirement of
discrimination between the two enantiotopic
C–H bonds. On the basis of our proposed inter-
mediate in Fig. 1C, we envisioned that the enan-
tioselection could be realized through the steric
interaction between the R group (R ≠ H) and
the bulky side chain R′′ of the amino acid.
Indeed, when 40 mol % L-valine (R′′ = isopropyl)
We then explored the scope of ketones and
aryl iodides under the new conditions. As il-
lustrated in Fig. 3, a wide range of aryl iodides
with electron-donating or -withdrawing substit-
uents were well tolerated (4a to 4f). Moderate
to good yields were achieved after conducting
the reaction with a variety of linear, a-branched,
and cyclic ketones (4g to 4r). We found that
this method can activate methylene C(sp3)–H
bonds in cyclic substrates, producing the corre-
sponding syn products with excellent diaster-
eoselectivity (4o to 4q). Furthermore, one example
of g-arylation was observed when b-C(sp3)–H
bonds were absent in the substrate (4s). How-
ever, aliphatic aldehydes are not suitable sub-
strates because competing reaction pathways
254 15 JANUARY 2016 • VOL 351 ISSUE 6270
sciencemag.org SCIENCE

RESEARCH
| REPORTS
Fig. 3. Palladium-catalyzed C(sp3)‒H arylation of
ketones. Pr, propyl; Bu, butyl; Hex, hexyl; dr, diastere-
omeric ratio.
O
10 mol% Pd(OAc)2
50 mol% glycine
O
H
R1
R2
I
R1
R2
R3
+
1.5 equiv. AgTFA
HFIP:AcOH (3:1)
110°C, 36 h
R3
3a–3n (1.0 equiv.)
2.0 equiv.
4a–4s
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
Me
NO2
CO2Me
NO2
Me
4a, 71%
4b, 65%
4c, 62%
4d, 60%*
O
O
O
O
Me
Me
Me
Me
Me
Me
CO2Me
CO2Me
Ph
4h, 59% mono
4h', 26% di
4e, 53%
n-Pr
4f, 47%
n-Bu
4g, 47%
O
O
O
O
Me
c-Hex
Me
CO2Me
CO2Me
CO2Me
4k, 40%
CO2Me
4l, 57% mono
4l', 21% di
4i, 60%
4j, 48%
O
O
O
O
Me
n-Bu
Ph
Me
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
4m, 38% mono
4m',15% di
4n, 55%
4o, 39%, 20:1 dr
4p, 52%, >20:1 dr
O
Me
Me
O
O
Me
Me
CO2Me
CO2Me
4s, 49% mono
4s', 12% di
CO2Me
4q, 54%, >20:1 dr
4r, 60%
For each entry number (in boldface), data are reported as isolated yield. See
supplementary materials for experimental details. * Reaction performed at 130°C with 3.0
equiv. aryl iodide.
was used instead of glycine, the arylation of
2-ethyl-5-(trifluoromethyl)benzaldehyde (5a) pro-
vided the desired product 6a with an enantio-
meric ratio (er) of 85:15 (table S3, entry 4).
Consequently, we speculated that a more steri-
cally encumbered amino acid should lead to
superior enantioselectivity. When we performed
the reaction using L-tert-leucine (R′′ = tert-butyl),
we achieved excellent enantioselectivity (98:2 er),
albeit in only 30% NMR yield (table S3, entry 5).
Reducing the ratio of ligand-to-Pd from 4:1 to
2:1 resulted in a substantially enhanced yield
(87%), without any erosion of enantioselectivity
(table S3, entry 6). Apparently, sterically bulky
L-tert-leucine is less prone to imine formation,
allowing the free form of the amino acid to
coordinate with Pd(II) and deactivate the
catalyst. Finally, the addition of 3 equivalents
of water led to nearly identical results (table
S3, entry 8). However, the presence of water
has proved to be beneficial to other aldehyde
substrates.
wide range of aryl iodides bearing various func-
tional groups at the para or meta position (6a to
6i in Fig. 4). With respect to the scope of al-
dehydes, the reaction is compatible with ester
(6j), trifluoromethyl (6k), and halogen substituents
(6l to 6n). Halogen-substituted benzaldehydes
exhibited higher reactivity, and the palladium
catalyst loading could be reduced to 5 mol %.
Moreover, the methylene C(sp3)–H bond on lon-
ger side chains could also be activated (6o and
6p), thus greatly expanding the scope of aldehydes
for this reaction.
Under optimized conditions, the enantioselec-
tive arylation of 5a proceeded effectively with a
SCIENCE sciencemag.org
15 JANUARY 2016 • VOL 351 ISSUE 6270 255

RESEARCH
| REPORTS
10 mol% Pd(OAc)2
20 mol% L-tert-leucine
2.0 equiv. AgTFA
Fig. 4. Palladium-catalyzed
enantioselective benzylic
C(sp3)‒H arylation of
aldehydes. HPLC,
high-performance liquid
chromatography.
O
O
R3
R1
R3
R1
+
H
3.0 equiv. H2O
HFIP:AcOH (9:1)
100oC, 24 h
I
R2
R2
6a–6p
5a–5h (1.0 equiv.)
3.0 equiv.
O
O
O
O
F3C
F
F3C
Cl F3C
Br F3C
CO2Me
Me
Me
Me
Me
6a, 80%, 98:2 er
6b, 72%, 97:3 er
6c, 77%, 98:2 er
6d, 73%, 98:2 er
O
CO2Me
O
CF3
O
O
F3C
F3C
F3C
NO2
F3C
Me
Me
Me
Me
6f, 77%, 98:2 er*
6g, 63%, 98:2 er*
6h, 62%, 98:2 er
6e, 88%, 98:2 er
O
O
CF3
O
F
O
F3C
OMe MeO2C
F
F
F
Me
Me
6j, 71%, 96:4 er
Me
Me
6k, 69%, 97:3 er*
6l, 64%, 96:4 er†
6i, 63%, 95:5 er
Cl
O
Cl
O
Cl
O
Br
O
F
F
F
F
Me
6o, 68%, 97:3 er
OBn
6p, 54%, 98:2 er*
Me
Me
6m, 67%, 97:3 er†
6n, 60%, 97:3 er†
For each entry number (in boldface), data are reported as isolated yield. Enantiomeric ratios (er) were determined
by chiral HPLC analysis. See supplementary materials for experimental details. * Reaction performed at 110oC.
† Reaction performed with 5 mol% Pd(OAc)2 and 10 mol% L-tert-leucine.
REFERENCES AND NOTES
16. C. U. Grünanger, B. Breit, Angew. Chem. Int. Ed. 47, 7346–7349
(2008).
17. D.-H. Wang, M. Wasa, R. Giri, J.-Q. Yu, J. Am. Chem. Soc. 130,
7190–7191 (2008).
18. J. He et al., Science 343, 1216–1220 (2014).
19. B.-F. Shi, N. Maugel, Y.-H. Zhang, J.-Q. Yu, Angew. Chem. Int.
Ed. 47, 4882–4886 (2008).
20. D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science 327,
315–319 (2010).
21. W. Gong, G. Zhang, T. Liu, R. Giri, J.-Q. Yu, J. Am. Chem. Soc.
136, 16940–16946 (2014).
22. F. C. McIntire, J. Am. Chem. Soc. 69, 1377–1380 (1947).
23. R. C. Larock, in Comprehensive Organic Transformations (Wiley,
ed. 2, 1999), pp. 1197–1620.
24. M. T. Pirnot, D. A. Rankic, D. B. C. Martin, D. W. C. MacMillan,
Science 339, 1593–1596 (2013).
25. Z. Huang, G. Dong, J. Am. Chem. Soc. 135, 17747–17750
(2013).
ACKNOWLEDGMENTS
1. J. M. Brown, Chem. Soc. Rev. 22, 25–41 (1993).
2. A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 93,
1307–1370 (1993).
3. C. G. Hartung, V. Snieckus, in Modern Arene Chemistry,
D. Astruc, Ed. (Wiley, 2004), pp. 330–367.
4. R. A. Johnson, K. B. Sharpless, in Catalytic Asymmetric
Synthesis, I. Ojima, Ed. (Wiley, ed. 2, 2005), pp. 231–280.
5. Z. Li, H. Yamamoto, Acc. Chem. Res. 46, 506–518 (2013).
6. X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int.
Ed. 48, 5094–5115 (2009).
7. O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 42,
1074–1086 (2009).
8. L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed.
48, 9792–9826 (2009).
9. L. V. Desai, K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 126,
9542–9543 (2004).
10. D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 110,
624–655 (2010).
We gratefully acknowledge The Scripps Research Institute and
the NIH (National Institute of General Medical Sciences grant
2R01GM084019) for financial support. F.-L.Z. thanks Wuhan
University of Technology and T.-J.L. thanks Jiangsu Normal
University for financial support. J.-Q.Y. and F.-L.Z. conceived
the experimental concept; F.-L.Z. performed the arylation of
primary C–H bonds; K.H. developed the enantioselective C–H
arylation; T.-J.L. developed conditions for the b-arylation of
ketones; and H.P. performed enantioselective C–H arylation.
Metrical parameters for the structure of compound S2
(see supplementary materials) are available free of charge
from the Cambridge Crystallographic Data Centre under reference
number CCDC 1434263.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/351/6270/252/suppl/DC1
Supplementary Text
Tables S1 to S9
NMR Spectra
HPLC Spectra
26. T. Kang, Y. Kim, D. Lee, Z. Wang, S. Chang, J. Am. Chem. Soc.
136, 4141–4144 (2014).
27. P. Gao et al., J. Am. Chem. Soc. 137, 12231–12240 (2015).
28. M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Angew.
Chem. Int. Ed. 50, 7438–7441 (2011).
11. J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev.
40, 4740–4761 (2011).
12. C.-H. Jun, H. Lee, J.-B. Hong, J. Org. Chem. 62, 1200–1201 (1997).
13. F. Mo, G. Dong, Science 345, 68–72 (2014).
14. R. B. Bedford, S. J. Coles, M. B. Hursthouse, M. E. Limmert,
Angew. Chem. Int. Ed. 42, 112–114 (2003).
X-ray Crystallographic Data
Reference (31)
29. S. Anas, A. Cordi, H. B. Kagan, Chem. Commun. 47,
11483–11485 (2011).
15. T. E. Lightburn, M. T. Dombrowski, K. L. Tan, J. Am. Chem. Soc.
130, 9210–9211 (2008).
30. T. Saget, S. J. Lemouzy, N. Cramer, Angew. Chem. Int. Ed. 51,
2238–2242 (2012).
2 November 2015; accepted 4 December 2015
10.1126/science.aad7893
256 15 JANUARY 2016 • VOL 351 ISSUE 6270
sciencemag.org SCIENCE