Pd(II)-Catalyzed Enantioselective γ-C(sp3)-H Functionalizations of Free Cyclopropylmethylamines

Article abstract of DOI:10.1021/jacs.0c04801

Prized for their ability to reliably forge stereocenters with precise regiocontrol from simple and abundant starting materials, substrate-directable enantioselective reactions are widely used in modern organic synthesis. As such, enantioselective C(sp3)-H

Full text of DOI:10.1021/jacs.0c04801

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Communication
3
Pd(II)-Catalyzed Enantioselective #-C(sp)-H
Functionalizations of Free Cyclopropylmethylamines
Zhe Zhuang, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04801 • Publication Date (Web): 30 Jun 2020
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Journal of the American Chemical Society
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Pd(II)-Catalyzed Enantioselective γ-C(sp3)−H Functionalizations of
Free Cyclopropylmethylamines
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Zhe Zhuang,† and Jin-Quan Yu*,†
†
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037,
United States
Supporting Information Placeholder
from the strong metal binding properties of the amine8.
ABSTRACT: Prized for their ability to reliably forge
Additionally, free amines are susceptible to oxidative
degradation through β-hydride elimination and N-
substitution reactions towards electrophiles under the
conditions of C−H activation. In this context, extensive studies
have been focused on the design of preinstalled9 or transient10
bidentate directing groups (DGs) on account of their ability to
accelerate cyclometalation and suppress β-hydride
elimination (Scheme 1A). Despite the elegance of DG or TDG
strategies, these reactions are difficult to render
enantioselective due to the persistent racemic background
reactions driven by strong coordination, as well as the lack of
available coordination sites for a chiral ligand. Bidentate
coordination from the substrate also confines the reactivity to
a Pd(II)/Pd(IV) catalytic cycle, owing to the lack of a vacant
coordination site to engage the coupling partner in a
Pd(II)/Pd(0) cycle. Most importantly, the requirement for
substrate DGs precludes the use of native amino groups to
direct C−H activation, which affords superior atom and step
economies in the context of protecting-group-free synthesis.
In fact, reported free aliphatic amine-directed C−H
functionalization reactions are largely limited to bulky
amines; a bulky group at the α position of the free amine is
required to favor dissociation of bis(amine)-Pd(II) complexes
through steric repulsion, hamper oxidative degradation by
blocking the β position, as well as weaken the nucleophilicity
of amino group (Scheme 1A)11.
stereocenters with precise regiocontrol from simple and
abundant starting materials, substrate-directable
enantioselective reactions are widely used in modern organic
synthesis. As such, enantioselective
C(sp3)−H
functionalization reactions directed by innate functional
groups could provide new routes to introduce molecular
complexity within the inert hydrocarbon moiety, but so far
this approach has been met with little success. While free
primary aliphatic amines are common, versatile intermediates
in synthesis, they are traditionally unreactive in C(sp3)−H
activation reactions. Herein we report the Pd-catalyzed
enantioselective C(sp3)−H functionalization of free aliphatic
amines (cyclopropylmethylamines) enabled by
a chiral
bidentate thioether ligand. This ligand’s privileged bidentate
coordination mode and thioether motif favor the generation
of the requisite mono(amine)-Pd(II) intermediate, thus
enabling the enantioselective C−H activation of free amines.
The resulting C−Pd(II) species could engage in either
Pd(II)/Pd(IV) or Pd(II)/Pd(0) catalytic cycles, enabling access
to a diverse range of products through (hetero)arylation,
carbonylation and olefination reactions. Consequently, this
versatile reactivity offers medicinal chemists a general strategy
to rapidly prepare and functionalize biologically relevant
amines.
Scheme 1. C(sp3)−H Functionalization of Aliphatic
Amines
Ligand-controlled enantioselective reactions directed by
innate functional groups (e.g. carboxylic acids, amines, and
alcohols) comprise a classic toolkit to control the regio- and
stereochemical outcomes of organic reactions1, as exemplified
by the Sharpless’s oxidation2, Noyori and Knowles’s
hydrogenation3,4 reactions of alkenes. While such strategies
highlight significant developments in the functionalization of
unsaturated moieties, only recently has serious attention been
directed toward complementary strategies for the
functionalization of saturated hydrocarbons5. Despite
advances in C−H functionalization directed by weakly
coordinating free carboxylic acids6, aliphatic amines bearing
free NH2 groups − ubiquitous structural motifs among
compounds of pharmaceutical, agrochemical, and societal
importance − are less amenable to Pd-catalyzed C−H
functionalization reactions7. This is due to the formation of
stable but unreactive bis(amine)-Pd(II) species, stemming
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A Strategies towards C(sp3) H activation of aliphatic amines
Me

H
Pd(TFA)2 (10 mol%)
1
2
3
4
Me
NH2
O
O
O
L
ligand ( ) (10 mol%)
NH2
+
Me
Me
Me
Me
Me
Ag2O (2.0 equiv.)
HFIP, 90 oC, 12 h
N
N
I
N
H
Pd
NH2
DG
TDG
Pd
Pd
H
R
H
R
H
OAc
Pd
OAc
H
OAc
OAc
1a
2a
Me
3a
OAc
OAc
5
Me
Me O
DG strategy
TDG strategy
bulky amine strategy
6
7
8
9
CO2H
L
w/o
Me
Me
NMe2
NHAc
Me
NHOMe
NHAc
NHAc
B Native amine strategy via ligand acceleration
L1
L2
37%, 37:63 er
L3

6%
41%, 85:15 er
37% yield, 47:53 er
R
L
L
NH2
PdII
R
enantioselective
CH activation
amine
NH2
PdII
NH2
OAc
R
dissociation
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R
L
Me
O
Et
AcO
L
PdII
N
Me
AcO
H2N
tBu
Me
N
L

L

AcHN
Me
S
NHAc
NHAc
stable and unreactive
bis(amine)-Pd(II)
requisite
mono(amine)-Pd(II)
versatile
CPd(II) species
tBu
39%, 45:55 er
trans-L4, 35%, 74:26 er
cis-L4, 39%, 43:57 er
L5
L6
68%, 97.5:2.5 er
C Ligand-enabled enantioselective C(sp3) H functionalization of free amines
aConditions: 1a (0.1 mmol), Pd(TFA)2 (10 mol%), ligand(L) (10
mol%), 4-iodotoluene 2a (2.0 equiv.), Ag2O (2.0 equiv.), HFIP
(0.2 mL), 90 °C, 12 h. bThe yields were determined by 1H NMR
analysis of the crude product using CH2Br2 as the internal
standard. The er values of the corresponding Boc-protected
amine 3a’ were determined on the SFC system using
commercially available chiral columns.

L
cat. Pd/
C6F5
O
NHR2
PdII
CH
activation
H
R
R1
L
NR2
NHR2
NHR2
NH2
R1
L

R1
R1
R1

R2 = H, alkyl
Pd(II)/Pd(IV)
(hetero)arylation
Pd(II)/Pd(0)
carbonylation
olefination
L
L
i-Pr
SPh
NHAc
two steps, single
recrystallization
Our previous research has disclosed two enantioselective
C(sp3)−H functionalization reactions using a monodentate
triflamide
DG:
the
γ-C(sp3)−H
arylation
of
In light of our approach using the combination of
monodentate practical DGs and bidentate ligands to enable
enantioselective C−H activation reactions12, we were
particularly interested in applying this concept to the
otherwise challenging chemical feedstocks such as aliphatic
amines (Scheme 1B). We reasoned that due to the bidentate
chelation mode of the ligand, unreactive bis(amine)-Pd(II)
species would readily dissociate as a result of strong
coordination from the ligand, generating the desired reactive
mono(amine)-Pd(II) intermediate for cyclopalladation. The
bidentate ligand also creates a rigid framework that is ideal for
the transfer of chiral information to the substrate during C−H
activation. Moreover, the privileged amidate group (N-acyl)
on the ligand can not only participate as an internal base to
facilitate C(sp3)−H activation over β-hydride elimination but
is also labile enough to generate a vacant coordination site for
coupling partners used in Pd(II)/Pd(0) chemistry. Herein we
report the design of a thioether-based chiral bidentate ligand
that enables Pd(II)-catalyzed enantioselective C−H
functionalization reactions of free cyclopropylmethylamines
(Scheme 1C). Arylation via a Pd(II)/Pd(IV) catalytic cycle
afforded chiral free aliphatic amines bearing aryl groups,
including aza-heterocycles, at the γ-position. Preliminary
results also showed that this catalyst enables the olefination
and carbonylation reactions of primary and secondary free
amines through a Pd(II)/Pd(0) catalytic cycle, providing
valuable γ-olefinated free amines and γ-lactams respectively.
cyclopropylmethylamine enabled by a mono-N-protected
amino acid (MPAA) ligand13 and the γ-C(sp3)−H cross-
coupling of 3-aminopentane enabled by acetyl-protected
aminomethyl oxazoline ligands (APAO) ligand14. Bidentate
picolinamide-directed benzylic C(sp3)−H arylation has also
been reported using a BINOL phosphoric acid ligand with
limited scope15. Due to the widespread presence of cyclopropyl
moieties among drug and agrochemical molecules16, we
selected free cyclopropylmethylamine 1a as a model substrate
for our initial investigations. Upon extensive studies of the
reaction conditions in the absence of ligand, a combination of
Pd(TFA)2, 4-iodotoluene 2a, Ag2O, and 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) solvent produced a 6% 1H NMR yield of the
desired cis-γ-arylation product 3a with a considerable amount
of the degradation product cyclopropane aldehyde. To test
our hypothesis, chiral bidentate ligands that previously
promoted enantioselective C(sp3)−H activation, including
MPAA L15c,13, O-methylhydroxamic acid L212c, dimethylamine
L36b, oxazoline L412b,14, and quinoline L512a, were investigated
under the standard reaction conditions (Table 1). To our
delight, these ligands generally promoted the arylation
reaction, delivering the arylation product 3a in 30% to 40%
yield with MPAA ligand L1 being the superior ligand (40%
yield, 85:15 er). However, further modifications of the ligand
structure and optimization of the reaction conditions failed to
improve the yield and er. Therefore, we turned our attention
to using thioethers as soft σ-donors, believing that thioethers
might facilitate dissociation of bis(amine)-Pd(II) complexes,
as well as stabilize the Pd catalysts through their strong
coordination. The racemic ligand L7 developed for the
olefination of free carboxylic acids17 significantly improved the
reaction to 57% yield (see Supporting Information Table S5).
Through systematic modifications of the backbone of the
thioether ligand we found that introduction of an isopropyl
group gave optimal reactivity with 97.5:2.5 er in 68% yield (see
Supporting Information Table S5). Notably, this optimal
Table 1. Ligand Investigation for γ-C(sp3)−H Arylation of
Free Cyclopropylmethylaminea,b
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thioether ligand L6 could be easily synthesized in two steps
with single recrystallization in 92% yield from the
commercially available Evans’ oxazolidinone chiral auxiliary
(see Supporting Information preparation of ligand section).
tetrahydropyran (3h), benzyl (Bn)-protected hydroxyl (3k),
1
2
3
4
5
6
7
8
a
methoxy (3l), and phenolic ether (3m) were all well tolerated,
and products were obtained in moderate yields (45% to 66%)
and high ers (greater than 96:4). Phenyl groups (3a and 3n−3s)
were compatible under the current conditions, and remained
intact despite the potentially reactive aryl C(sp2)−H or
benzylic C(sp3)−H bonds. A range of substituents on the aryl
ring from electron-withdrawing (fluoro and chloro) (3n, 3o,
and 3p) to electron-donating (methoxy) (3q) groups were also
well tolerated, providing arylation products in good yields (up
to 73%) and excellent ers (up to 99:1 er). The less reactive
unsubstituted cyclopropylmethylamine 1t also reacted in a
synthetically useful yield (42%) and correspondingly high er
(96.5:3.5). Extension of this desymmetrization protocol to
isobutylamine and 3-pentanamine also afforded desired
arylation products in good yields and moderate ers (see
Table 2. Free Cyclopropylmethylamine Scope for γ-
C(sp3)−H arylationa,b
Me
Pd(TFA)2 (10 mol%)
H
Me
L6
(10 mol%)
+
NH2
Ag2O (2.0 equiv.)
HFIP, 90 oC, 12 h
I
NH2
R
R
1
2a
3
9
10
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Me
Me
Me
Me
NHBoc
NHBoc
NHBoc
NHBoc
( )3
( )5
Me
Me
Me
Me
Supporting
Information
Table
S9).
However,
3b'
63%, 97:3 er
3c'
67%, 97:3 er
3d'
3e'
54%, 97.5:2.5 er
61%, 97.5:2.5 er
cyclobutylmethylamine substrates were not reactive under
these conditions.
Me
Me
Me
Me
Next, we surveyed the scope of aryl and heteroaryl iodides
using 1a as the model substrate (Table 3). γ-Arylation of 1a
with simple iodobenzene 2b resulted in good yield (71%) and
excellent er (97.5:2.5). A wide range of para substituents on
the aryl iodides from electron-donating (Me and isopropyl) to
electron-withdrawing (CF3, ester, and halide) groups were
well tolerated, delivering γ-arylated products (3a and 4c−4g)
with high ers (greater than 96:4 er) in moderate to good yields
(46% to 72%). Meta-substituted aryl iodides bearing methyl or
coordinating OCF3 and NO2 groups consistently provided
useful yields (51% to 68%) and ers greater than 94.5:5.5
(4h−4j). Indeed, the above products featured additional
reactive groups such as esters (in 4e) and halogens (chloro in
4g) that could serve as useful synthetic handles for subsequent
derivatizations. Given the ubiquity of heteroaromatics,
especially pyridine-containing heterocycles, in small molecule
drug discovery18, we examined the reactivity of aza-heteroaryl
iodides under the aforementioned conditions. Although
heteroaryl iodides were incompatible with the previously
reported MPAA-enabled arylation of triflamide13, we reasoned
that when switching to a strongly coordinating thioether
ligand, catalyst poisoning by coordination of these aza-
heterocycles might be dramatically suppressed. While
unsubstituted 4-iodopyridine 2t failed to give any desired
arylation product under the standard conditions, we were
NHBoc
NHBoc
NHBoc
NHBoc
( )4
F
O
3f'
3g'
70%, 98:2 er
3h'
3i'
55%, 97.5:2.5 er
58%, 98.5:1.5 er
66%, 97:3 er
Me
Me
Me
Me
NHBoc
NHBoc
( )4
CF3
NHBoc
NHBoc
( )3
OMe
( )3
OBn
PhO
3j'
3k'
48%, 97:3 er
3l'
3m'
65%, 96:4 er
54%, 97.5:2.5 er
45%, 96.5:3.5 er
Me
Me
Me
Me
NHBoc
NHBoc
NHBoc
F
NHBoc
F
Cl
F
3n'
3a'
68%, 97.5:2.5 er
3o'
3p'
48%, 99:1 er
61%, 96:4 er
73%, 97:3 er
Me
Me
Me
Me
NHBoc
NHBoc
OMe
NHBoc
( )3
NHBz
3q'
66%, 96:4 er
3r'
52%, 97.5:2.5 er
3s'
3t'
42%, 96.5:3.5 er
74%, 96:4 er
pleased to find that
a broad range of 2-substituted
iodopyridines (2k−2r) proceeded smoothly with excellent ers
(up to 97.5:2.5). A variety of functional groups including fluoro
(4k), chloro (4l and 4m), bromo (4n), methoxy (4o), and CF3
(4p−4r) were compatible with the optimal conditions,
yielding valuable cis-γ-heteroaryl cyclopropylmethylamines.
Electron-rich 5-iodoindole 2s was also a suitable coupling
partner, affording product 4s in moderate yield (51%) with
excellent er (96.5:3.5).
aConditions: 1 (0.1 mmol), Pd(TFA)2 (10 mol%), L6 (10 mol%),
4-iodotoluene 2a (3.0 equiv.), Ag2O (2.0 equiv.), HFIP (0.2
b
mL), 90 °C, 12 h. Isolated yields of the corresponding Bz or
Boc-protected amines. The er values were determined on the
SFC system using commercially available chiral columns.
With the optimal ligand and conditions in hand, we next
explored the scope of aliphatic amines (Table 2). The γ-
arylated products were isolated in the form of tert-
butyloxycarbonyl (Boc) or benzoyl (Bz)-protected amines for
their
Cyclopropylmethylamines (1b−1g) bearing various aliphatic
chains at the position, including cyclobutanes (1e),
ease
of
purification
and
analysis.
Table 3. Aryl and Heteroaryl Iodide Scope for γ-C(sp3)−H
Arylationa,b
β
cyclopentanes (1f), and cyclohexanes (1g), were all compatible
with the optimal protocol, affording the arylation products
(3b−3g) in yields ranging from modest to good (54% to 70%)
with excellent ers (greater than 97.5:2.5). A range of
functionalities such as fluoro (3i), trifluoromethyl (3j),
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and secondary amines (1u−1w) with pentafluorostyrene
H
R
Pd(TFA)2 (10 mol%)
L6
1
2
3
4
proceeded smoothly, delivering the γ-olefinated aliphatic
amines (6a−6e) with good to excellent ers (94:6 to 98.5:1.5).
Under current conditions, other olefins such as acrylate and
styrene failed to deliver desired olefination product.
NH2
(10 mol%)
NH2
R
+
Ag2O (2.0 equiv.)
HFIP, 90 oC, 12 h
I
1a
2
4
Table
4.
Free
Primary
Scope
and
for
Secondary
5
6
7
8
Me
Me
γ-C(sp3)−H
Me
CF3
Cyclopropylmethylamine
Carbonylation and Olefinationa,b
NHBoc
NHBoc
NHBoc
Pd(OAc)2 (15 mol%)
L6
styrene (3.0 equiv.)
Pd(OAc)2 (15 mol%)
L6
Mo(CO)6 (0.3 equiv.)
NHBoc
C6F5
(15 mol%)
O
(15 mol%)
H
9
NR2
NHR2
Ag2O (2.0 equiv.)
HFIP, 90 oC, 6 h
Ag2O (2.0 equiv.)
NaOAc (1.0 equiv.)
HFIP, 90 oC, 12 h
NHR2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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32
33
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60
R1
R1
R1
3a'
4b'
4c'
4d'
68%, 97.5:2.5 er
71%, 97.5:2.5 er
61%, 96:4 er
72%, 96:4 er
5
1
6
CO2Me
F
Cl
A carbonylation
Me
NHBoc
O
NHBoc
NHBoc
NHBoc
O
O
O
NH
N
R
N
Me
N ( )3
R
Me
4e'
4f'
4g'
4h'
46%, 96:4 er
51%, 97.5:2.5 er
62%, 96:4 er
68%, 97:3 er
5a
5b
5d
63%, 95:5 er
5e
R = F,
N
N
45%, 89.5:10.5 er
45%, 95:5 er
5c
33%, 93:7 er
R = Cl,
43%, 97:3 er
OCF3
NHBoc
NO2
NHBoc
F
Cl
NHBoc
NHBoc
B olefination
C6F5
C6F5
C6F5
C6F5
H
N
H
N
4i'
4j'
4k'
4l'
NHBoc
57%, 94.5:5.5 er
51%, 96.5:3.5 er
42%, 94.5:5.5 er
46%, 96.5:3.5 er
NHBoc
R
R
Me
Me
Cl
N
Me
N
N
N
Me
6b'
33% yield, 94:6 er
Br
NHBoc
OMe
NHBoc
CF3
NHBoc
6a'
6c
6e
30%, 98.5:1.5 er
R = F,
51%, 96:4 er
6d
Cl
NHBoc
39%, 95.5:4.5 er
R = Cl,
40%, 98.5:1.5 er
aConditions for carbonylation: 1 (0.1 mmol), Pd(OAc)2 (15
mol%), L6 (15 mol%), Mo(CO)6 (0.3 equiv.), Ag2O (2.0 equiv.),
NaOAc (1.0 equiv.), HFIP (0.1 mL), 90 °C, 12 h. Conditions for
olefination: 1 (0.1 mmol), Pd(OAc)2 (15 mol%), L6 (15 mol%),
pentafluorostyrene (3.0 equiv.), Ag2O (2.0 equiv.), HFIP (0.1
mL), 90 °C, 6 h. bIsolated yields for secondary amines or
isolated yields of the corresponding Boc-protected amines for
primary amines. The er values were determined on the SFC
system using commercially available chiral columns.
4m'
4n'
4o'
4p'
37%, 95.5:4.5 er
41%, 96.5:3.5 er
43%, 97:3 er
39%, 96.5:3.5 er
Ts
N
CF3
N
N
N
CF3
NHBoc
NHBoc
NHBoc
NHBoc
4q'
4r'
4s'
4t'
52%, 95.5:4.5
62%, 97.5:2.5 er
51%, 96.5:3.5 er
<5%, er n.d.
In summary, we have realized effective and general Pd-
catalyzed enantioselective C(sp3)−H functionalizations of free
aliphatic amines enabled by a single Pd(II) catalyst bearing a
bidentate chiral thioether ligand. Both Pd(II)/Pd(IV) and
Pd(II)/Pd(0) catalytic cycles are compatible with this chiral
ligand, as demonstrated by (hetero)arylation, carbonylation
and olefination reactions respectively. A broad range of chiral
γ-(hetero)aryl, γ-olefinated free amines and γ-lactams could
be easily accessed without installing exogenous directing
groups.
aConditions: 1a (0.1 mmol), Pd(TFA)2 (10 mol% or 15 mol% for
heteroaryl iodides), L6 (10 mol% % or 15 mol% for heteroaryl
iodides), aryl or heteroaryl iodide 2 (3.0 equiv.), Ag2O (2.0
equiv.), HFIP (0.2 mL), 90 °C, 12 h. bIsolated yields of the
corresponding Boc-protected amines. The er values were
determined on the SFC system using commercially available
chiral columns.
To test the feasibility of extending this Pd(II)/thioether
catalyst system to a Pd(II)/Pd(0) catalytic cycle, we embarked
on the enantioselective carbonylation and olefination of free
primary and secondary aliphatic amines (Table 4). Reported
works on C(sp3)−H carbonylation19 and olefination20 are
largely limited to DG strategies, and no asymmetric version
has been achieved to date. Using Mo(CO)6 as a nonhazardous
and air-stable solid source of CO, carbonylation of primary
amine 1a delivered bicyclic γ-lactam 5a in a synthetically
useful yield (45%) and moderate er (89.5:10.5). A range of
secondary amines (1u−1x) were also reactive using the optimal
protocol, affording the valuable cyclopropane fused
pyrrolidones (5b−5e) in moderate yields (up to 63%) and good
ers (up to 97:3 er). Olefination of primary amines (1a and 1i)
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Full experimental details and characterization of new
compounds (PDF)
AUTHOR INFORMATION
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Journal of the American Chemical Society
Chem. 2017, 9, 26−32. (b) Wu, Y.; Chen, Y.-Q.; Liu, T.; Martin, D. E.;
Corresponding Author
Yu, J.-Q. Pd-catalyzed γ‑C(sp3)−H arylation of free amines using a
transient directing group. J. Am. Chem. Soc. 2018, 140, 10363−10367. (c)
Li, B.; Seth, K.; Niu, B.; Pan, L.; Yang, H.; Ge, H. Transient-ligand-
enabled ortho-arylation of five-membered heterocycles: facile access
to mechanochromic materials. Angew. Chem., Int. Ed. 2018, 57,
3401−3405. (d) Li, B.; Lawrence, B.; Li, G.; Ge, H. Ligand-controlled
direct γ-C−H arylation of aldehydes. Angew. Chem., Int. Ed. 2020, 59,
3078−3082.
1
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*yu200@scripps.edu
ORCID
Zhe Zhuang: 0000-0001-6679-0496
Jin-Quan Yu: 0000-0003-3560-5774
Notes
The authors declare no competing financial interests.
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Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Ligand-accelerated
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alkenylation, and alkynylation. Science 2017, 355, 499−503. (c) Xiao,
K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, W.; Wasa, M.; Yu, J.-Q.
Palladium(II)-catalyzed enantioselective C(sp3)−H activation using a
chiral hydroxamic acid ligand. J. Am. Chem. Soc. 2014, 136, 8138−8142.
(13) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. Palladium(II)-catalyzed
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Am. Chem. Soc. 2015, 137, 2042−2046.
(14) Shao, Q.; Wu, Q.-F.; He, J.; Yu, J.-Q. Enantioselective γ-
C(sp3)−H activation of alkyl amines via Pd(II)/Pd(0) catalysis. J. Am.
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(15) Wang, H.; Tong, H. R.; He, G.; Chen, G. An enantioselective
bidentate auxiliary directed palladium-catalyzed benzylic C−H
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(16) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition metal
chemistry of cyclopropenes and cyclopropanes. Chem. Rev. 2007, 107,
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(17) Zhuang, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.; Hsiao, Y.; Joe, C. L.;
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ACKNOWLEDGMENT
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We gratefully acknowledge The Scripps Research Institute
and NIH (NIGMS, R01GM084019) for financial support. Z. Z.
thanks Alastair N. Herron for proofreading.
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C6F5
NH2
O
H
NH2
L
cat. Pd/
R
L
1
2
PdII
NH
NH2
NH2
L

R
R
R
R
3
4
5
i-Pr
Pd(II)/Pd(IV)
(hetero)arylation
up to 99:1 er
Pd(II)/Pd(0)
carbonylation
olefination
SPh
NHAc
two steps, single
recrystallization
up to 98.5:1.5 er
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