Palladium-catalyzed enantioselective C-H activation of aliphatic amines using chiral anionic BINOL-phosphoric acid ligands

Article abstract of DOI:10.1021/jacs.6b12234

The design of an enantioselective Pd(II)-catalyzed C-H amination reaction is described. The use of a chiral BINOL phosphoric acid ligand enables the conversion of readily available amines into synthetically valuable aziridines in high enantiomeric ratios.

Full text of DOI:10.1021/jacs.6b12234

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Communication
Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic
Amines using Chiral Anionic BINOL-Phosphoric Acid Ligands
Adam P. Smalley, James D. Cuthbertson, and Matthew J. Gaunt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12234 • Publication Date (Web): 09 Jan 2017
Downloaded from http://pubs.acs.org on January 9, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic
Amines using Chiral Anionic BINOL-Phosphoric Acid Ligands
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Adam P. Smalley, James D. Cuthbertson, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
Supporting Information Placeholder
Our laboratory has been engaged in the development a
series of processes for the Pd-catalyzed C–H functionaliza-
tion of free(NH) aliphatic amines.5 Central to the success of
many of these reactions has been the presence of a putative
hydrogen bond between the NH motif of a ligated amine
and the carbonyl oxygen atom of the Pd-bound carbox-
ylate.5b For example, in the case of tetramethylmorpho-
linone 1a, a hydrogen bond helps to arrange the C–H bond
into the ideal orientation for C–H activation with a second
Pd-bound carboxylate (int-I, Figure 1b). Based on this, we
reasoned that deployment of a chiral carboxylate or related
anionic ligand might lead to a scenario wherein the irre-
versible C–H bond cleavage step would be rendered enanti-
oselective via the desymmetrization of two prochiral methyl
groups, leading ultimately to non-racemic aliphatic amine
products.
ABSTRACT: The design of an enantioselective Pd(II)-
catalyzed C–H amination reaction enabled by a comprehen-
sive understanding of the reaction mechanism is described.
The use of a chiral BINOL phosphoric acid ligand enables
the conversion of readily available amines into synthetically
valuable aziridines in high enantiomeric ratios. The aziri-
dines can be derivatized to afford a range of chiral amine
building blocks incorporating motifs readily encountered in
pharmaceutically relevant molecules.
The development of catalytic enantioselective aliphatic
C–H bond functionalization processes represents an im-
portant challenge for chemical synthesis.1 Most prominent
among the successful advances towards this ideal has been
the use of metallo-carbenoid and –nitrenoid strategies.2 In
contrast, processes that are based on enantioselective metal
insertion into aliphatic C–H bonds remain limited.3 Part of
the reason for this deficiency is the lack of available chiral
ligands that are effective for oxidative C–H functionaliza-
tion with catalysts derived from palladium(II) salts. The
most common classes of ligand for metal-catalyzed enanti-
oselective reactions, chiral phosphines,3 are generally in-
compatible with the reactions conditions required for oxida-
tive Pd-catalyzed C–H bond functionalization. As a result,
the design of novel classes of ligands for Pd(II) catalysts has
been the focus of significant attention in the synthetic com-
munity (Figure 1a).4
(a) A strategy for enantioselective C–H activation
(II)
L
X
Pd
L
X
H3C CH3
DG
H3C
R
R
DG
n
desymmetrization of enantiotopic methyl
groups via C–H bond functionalization
n
(b) Design – enantioselective C–H activation in aliphatic amines
Me Me
H
N
Me
O
Me
O
aliphatic amine 1a
R
O
can chiral
anionic ligands
control
enantioselective
C–H bond
O
H
Me
The catalytic enantioselective desymmetrization of
prochiral methyl groups via Pd-catalyzed Csp3–H activation
represents a potentially useful strategy for the generation of
compounds displaying non-racemic fully substituted carbon
atoms. To date, however, successful examples of this ideal
remain limited. Enantioselective desymmetrization of
prochiral methyl groups has been successfully achieved us-
ing Pd(0)-catalyzed methods; Kagan, Baudoin, Kundig and
Cramer have all reported variations on a C–H amination to
indolines.3 Less common are successful examples of enanti-
oselective oxidative C–H desymmetrization using Pd(II)-
catalysts. For example, Yu and co-workers have reported a
Pd(II)-mediated, chiral auxiliary-controlled disatereoselec-
tive C–H iodination of oxazolines,4a and Pd(II)-catalyzed C–
H functionalizations controlled by amino acid-based ligands
that give moderate but promising levels of enantioselectivity
for alkylation and arylation reactions.4b,c Related to this, our
own efforts identified that similar amino-acid derived lig-
ands enable Pd(II)-catalyzed enantioselective arylation of
tetramethyl-piperidine with moderate enantioselectivity.5c
H-bond controlled
C–H bond cleavage
N
Me
Me
Pd
O
O
O
activation?
H
R
O
int-I
R
H
Me
O
N
Me
O
Pd
O
O
Me
enantio-enriched
aliphatic
amine products
palladacycle
(c) Pd-catalyzed enantioselective C–H amination to aziridines
Ar
R
R
R
H
O
O
10 mol% Pd(OAc)2
X
N
R
P
Me
N
X
O
20 mol% (R)-TRIP
O
OH
Me
oxidant
Me
O
Ar
e.r. up to 97:3
aziridine
(R)-TRIP
Figure 1. A strategy towards anionic ligand-
controlled enantioselective Pd-catalyzed C–H
activation
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
The use of chiral anionic ligands to control enantioselec-
9). We also found that the addition of 20 equivalents of
AcOH, found to be beneficial in the racemic reaction,5b re-
duced the reaction to an almost racemic process, albeit in
high yield (entry 10). Reducing the concentration to 0.05 M
increased the yield of the product to 71% and the e.r. to
84:16 (entry 11). We next increased the amount of (R)-TRIP
in the reaction to maximize the formation of the chiral-
palladium catalyst, thereby minimizing any non-chiral
background reaction involving Pd(OAc)2; using 10 mol% of
(R)-TRIP with 5 mol% Pd(OAc)2 gave an e.r. of 89:11 with
67% yield of 2a (entry 12). Increasing the loading of
Pd(OAc)2 to 10 mol%, combined with 20 mol% of (R)-TRIP
and the addition of 0.5 equivalents of Ac2O gave 79% yield
of the product with an e.r. of 93.5:6.5 (entry 13, Condition
A). To the best of our knowledge, this represents the first
1
2
3
4
5
6
7
8
tive C–H activation with palladium catalysts has only re-
cently received attention. Aside from the deployment of
chiral amino acid derivatives as bidentate ligands,4 Duan et
al have described the use of BINOL-derived phosphoric ac-
ids6,7 to impart modest enantioselective in a methylene C–H
arylation reaction.8 Based on this seminal discovery, two
further reports detailing chiral BINOL-phosphates as effec-
tive ligands for enantioselective C–H activation recently
emerged; Yu and co-workers detailed a highly selective en-
antiotopic methylene C–H arylation in thioamide deriva-
tives9a and Chen et al reported an auxiliary-directed C–H
arylation of amide derivatives.9b Here, we report our own
studies on the use of a BINOL-phosphoric acid derivative,6
as a chiral anionic ligand,7 to enable the Pd-catalyzed enan-
tioselective C–H amination of aliphatic amines to form
aziridines. High enantioselectivities and yields are obtained
for the aziridination process and the products of the reac-
tion can be readily transformed into novel variants of privi-
leged saturated amine hetereocycles, which we believe will
be of significant interest to practitioners of medicinal chem-
istry (Figure 1c).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
example of
a
highly enantioselective Pd(II)/Pd(IV)-
catalyzed process for desymmetrizing C–H functionalization
of prochiral methyl groups.
We were conscious that using PIDA as oxidant generates
two equivalents of AcOH, whose increasing concentration
throughout the reaction may compromise the enantioselec-
tivity of the process (entry 10). Accordingly, we found that
use of ‘acetate-free’ oxidants such as iodosylbenzene or io-
dine,4a,10 resulted in an improved enantiomeric ratio of
86:14 and 95:5 respectively, but the yields were dramatically
reduced (entries 14,15).11 Multiple oxidants were investigat-
ed in order to attain catalytic turnover and it was found that
addition of AgOAc improved the yield and maintained the
e.r. of the product (entry 16). After further optimization of
the reaction parameters (lowering concentration, increasing
catalyst loading and increasing temperature) we found that
88% yield of aziridine product with an e.r. of 96.5:3.5 could
be obtained (entry 17, Condition B). It is clear that the enan-
tioselectivity depends on a delicate balance between the
concentration of AcOH and the chiral TRIP ligand, suggest-
ing that AcO– can replacing the TRIP ligand on the palladi-
um(II) center at high concentrations of AcOH, leading to
racemic turnovers. Therefore, it is possible that using 20
mol% of the TRIP ligand offsets this problem, particularly
towards the end of the reaction. Furthermore, by using
AgOAc, which is heterogeneous in this reaction, we suggest
At the outset of our studies, we tested the enantioselec-
tive C–H amination of morpholinone 1a, to give aziridine
2a, by screening a range of chiral acids in combination with
5 mol% Pd(OAc)2 and phenyliodosyldiacetate (PIDA) in
toluene at 70 ˚C (see supporting information for details).
Unfortunately, none of these reactions resulted in signifi-
cant enantioselectivity in the product. However, we did find
that when 5 mol% of BINOL-derived phosphoric acid (BPA,
3a) was added to the reaction, a 16% yield and a low enanti-
omeric ratio (e.r.) of 53:47 was observed (Table 1, entry 1).
Based on this, we tested the 3,3’-diaryl-BINOL phosphoric
acid, (R)-TRIP 3b, under the same conditions and found
that although the e.r. had risen slightly to 55:45, the yield
(by GC) was improved to 70% (entry 2). A screen of solvents
revealed that reaction in EtOAc or 1,4-dioxane increased the
e.r. of the products to 79:21 and 86.5:23.5 respectively, and
with moderate yields (entries 4,5); notably, the reaction in
dioxane did not reach completion. The addition of 2 equiva-
lents of Ac2O did not significantly affect the reaction (entry
Table 1. Selected optimization data for enantioselective Pd-catalyzed C–H amination to aziridines
entry
Pd(OAc)2, mol%
(R)ꢀTRIP,
Solvent
Oxidant
Additives /
Conc., M
Yield (GC)
e.r. (GC)
mol%
comments
1
2
5
5
5 (of 3a)
PhMe
PhMe
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PhI=O
I2
–
0.1
0.1
16
65
70
64
44
64
4
53:47
55:45
5
5
–
3
5
1,2ꢀDCE
EtOAc
1,4ꢀdioxane
MeOAc
TBME
DMA
–
0.1
61:39
4
5
5
–
0.1
79:21
5
5
5
–
0.1
86.5:23.5
80:20
6
5
5
–
0.1
7
5
5
–
0.1
80:20
8
5
5
–
0.1
32
75
82
71
67
79
10
4
57.5:42.5
78.5:21.5
52:48
9
5
5
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
2 equiv. Ac2O
0.1
10
11
12
13a
14
15
16
17b
5
5
20 equiv. AcOH
0.1
5
5
–
0.05
0.05
0.05
0.1
84:16
5
10
20
5
–
89:11
10
5
0.5 equiv. Ac2O
–
93.5:6.5
86:14
5
10
10
20
0.5 equiv. Ac2O
0.05
0.05
0.033
95:5
5
I2, AgOAc
86
88
95:5
ACS Paragon Plus Environment
10
EtOAc
I2, AgOAc
90 ˚C
96.5:3.5
aCondition A. bCondition B.

Page 3 of 5
Journal of the American Chemical Society
that its insolubility is beneficially modulating the concentra-
flash column chromatography. Chiral analysis was carried
out using GC or HPLC.
tion of AcO–/AcOH.12 Taken together, the optimization
studies revealed two sets of reaction conditions (A and B)
for a Pd-catalyzed enantioselective C–H amination to aziri-
dines.
1
2
3
4
5
6
7
8
We were pleased to observe that methylene C–H amina-
tion to the spirocyclic aziridine 2c product was also success-
ful with an excellent e.r. of 94.7:5.3, the low yield being
comparable to that of the racemic reaction. Aziridine 2c was
also crystalline, enabling determination of its absolute con-
figuration via X-ray diffraction. We also investigated the
corresponding piperazinone scaffold, wherein the heterocy-
clic oxygen of the morpholinone is replaced by a nitrogen
containing group; successful C–H activation on these sub-
strates would substantially broaden the scope of the reac-
tion and provide access to more medicinally relevant heter-
ocyclic products. We were pleased to find that a series of
functionalized N-alkyl derivatives containing benzyl, glyci-
nyl, and hydroxylethyl motifs all worked well in the reac-
tion, delivering the aziridine products (2d-f) in good yield
and high e.r’s. N-Aryl substrates also worked well in the
reaction and a range of electronic and steric properties were
tolerated, with electron rich (2g-j), electron deficient (2k-
m) and even Lewis basic heterocyclic motifs (2n) all provid-
ing the corresponding aziridines in good yields and high
e.r’s.
With optimal conditions in hand, we explored the scope
of the Pd-catalyzed enantioselective C–H amination (Table
2). First, we assessed simple derivatives of the morpho-
linone scaffold and found that variations at both sides of the
free(NH) amine were accommodated. In addition to the
tetramethyl morpholinone 1a, a cyclohexyl-derived sub-
strate worked effectively in the reaction giving a 95:5 enan-
tiomeric ratio in the product aziridine 2b with moderate
yield.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of enantioselective C–H amina-
tion
Ar
R
R
R
10 mol% Pd(OAc)2
H
O
20 mol% (R)-TRIP
X
N
O
O
R
P
Me
N
X
Conditions A or B
O
OH
Me
Me
O
Ar
amine 1
aziridine 2
(R)–TRIP 3b
Me
In considering the pathway through which this enanti-
oselective transformation proceeds, it was important to ra-
tionalize the observation that a high concentration of ace-
tate leads to a low enantioselectivity, while an acetate-free
system results in a low yield of product. An explanation for
this effect could involve an active Pd(II) complex displaying
one acetate and one TRIP ligand. It seems unlikely, based
on the size of TRIP, that two of these ligands could be ac-
commodated around the Pd(II) center; attempts to synthe-
size Pd(TRIP)2 were unsuccessful. We also noticed a varia-
tion in e.r. depending on the electronic properties of the N-
aryl group in amines 2g-l. When the log(e.r.) of the aziri-
Me
Me
O
Me
O
O
N
O
N
N
O
O
Me
Me
O
2a, 70% yield (B)
e.r. 96.6:3.4
2b, 54% yield (A)
e.r. 94.9:5.1
2c, 23% yield (A)
e.r. 94.7:5.3
BnO
O
N
Me
Me
Me
N
Me
N
O
N
O
Me
Me
dines is plotted against the Hammett
σ constant of the aryl
2d, 74% yield (B)
e.r. 91.9:8.1
2e, 76% yield (B)
e.r. 93.1:6.9
substituent, one can draw a linear correlation between the
enantioselectivity and electronic properties of the group.13
Furthermore, it is noticeable that the e.r. in the correspond-
ing morpholinones are higher than the lactam series, possi-
bly reflecting the more electronegative nature of the lactone
oxygen atom.
Br
BnO
Me
N
Me
Me
Me
N
N
Me
Me
N
N
N
O
O
O
Me
Me
Me
Figure 2. Correlation between e.r. and Hammett
constant
1.50
2f, 87% yield (B)
e.r. 92.8:7.2
2g, 78% yield (B)
e.r. 93.6:6.4
2h, 68% yield (B)
e.r. 93.9:6.1
MeO
t-Bu
O2N
1.45
Me
Me
Me
Me
Me
Me
N
N
N
1.40
1.35
1.30
1.25
1.20
1.15
1.10
1.05
1.00
p-NO2
p-CN
N
N
N
R² = 0.9783
p-Br
O
O
O
Me
Me
Me
2i, 81% yield (B)
e.r. 92.1:7.9
2j, 80% yield (B)
e.r. 92.4:7.6
2k, 76% yield (B)
e.r. 96.1:3.9
NC
CN
Me
N
H
Me
Me
N
Me
Me
N
Me
F3C
N
p-tBu
N
N
O
O
N
O
p-OMe
Me
Me
Me
2l, 91% yield (B)
e.r. 95.4:4.6
2m, 67% yield (B)
e.r. 94.1:5.9
2n, 71% yield (B)
e.r. 95.7:4.3
-0.5
0.0
0.5
1.0
Hammett σ constants
Conditions A: Substrate (1.0 equiv.), 10 mol% Pd(OAc)2,
PhI(OAc)2 (2.5–4.0 equiv.), Ac2O (0.5 equiv.), 20 mol% (R)-
TRIP, EtOAc (0.05 M). Conditions B: Substrate (1.0 equiv.),
10 mol% Pd(OAc)2, AgOAc (3.0 equiv.), I2 (2.0 equiv.), 20
mol% (R)-TRIP, EtOAc (0.033 M). Yields are quoted after
Figure 3. Possible pathways for the enantioselec-
tive C–H activation
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
In conclusion, we have developed a Pd-catalyzed enanti-
1
2
3
4
5
6
7
8
oselective C–H amination to aziridines using anionic
BINOL phosphate ligands. A range of amines, displaying
prochiral methyl groups, undergo enantioselective desym-
meterizing C–H activation to produce highly substituted
and functionalized products that can be transformed into
non-racemic saturated heterocyclic building blocks. While
the precise nature of the enantiocontrol imparted by the
TRIP ligands remains unclear, we believe that this asym-
metric C–H activation process will be of significant utility to
practitioners of synthetic and medicinal chemistry.
We have previously shown that the Pd(II)-catalyst coor-
dinates the free(NH) of the amine through the nitrogen lone
pair in the pseudo-axial position,5b which means that the
subsequent C–H activation is only possible at the methyl
group that is syn to the coordinated metal (pseudo-
equatorial on the ring), leading to the four-membered ring
cyclopalladation complex. As a result, one scenario could
involve a hydrogen bond between the NH and the phos-
phate ligand, providing a rigid transition structure for C–H
bond cleavage via a concerted-metallation-deprotonation
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data. The Supporting
Information is available free of charge on the ACS Publica-
tions website at
type pathway utilizing the acetate group (Figure 3a).14
A
AUTHOR INFORMATION
Corresponding Author
second possibility involves an acetate hydrogen bonding to
the ligated amine and the irreversible and enantiodetermin-
ing C–H bond cleavage mediated by the phosphate ligand
(Figure 3b). While these models lay out a preliminary un-
derstanding of the factors that influence this reaction, it was
not possible, at this stage, to further elucidate which path-
way is prevalent, nor the nature of the excellent enantiose-
lectivity observed in this reaction.15 Computational studies
to elucidate the stereocontrolling elements of this catalyst-
ligand combination are ongoing and will be reported in due
course.
*mjg32@cam.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to the EPSRC and Pfizer Global Research and
Development for an iꢀCASE studentship (A.P.S.), the European
Commission for a Marie Curie International Outgoing Fellowship
(J.D.C.), the ERC, Royal Society Wolfson Merit Award and
EPSRC for Fellowships (M.J.G.). Mass spectrometry data were
acquired at the EPSRC UK National Mass Spectrometry Facility
at Swansea University.
We previously demonstrated that the aziridine ring in
the morpholinone-derived products could be opened in the
presence of nucleophiles. To test whether the corresponding
lactam-aziridines were also compatible with this ring open-
ing transformation, we subjected 2d to treatment with py-
razole in the presence of p-toluenesulfonic acid to reveal the
amide product in 72% yield. Reduction of the lactam was
achieved using LiAH4 in THF to afford highly substituted
piperazine 4 in good yield. We also showed that after open-
ing 2d with MeOH, a second diastereoselective C–H amina-
tion takes place to form aziridine 5 in good yield. Aziridine
ring opening with pyrazole and subsequent lactam reduc-
tion affords piperazine 6 in good yield. We believe that the-
se non-racemic highly functionalized saturated amine het-
erocycles would be difficult to form by other methods and
should be attractive building blocks in medicinal chemistry
programs.16
REFERENCES
(1). For an early overview covering enantioselective C–H activation;
see Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041.
(2). For selected reviews and examples of enantioselective carbene
C–H insertion; see (a) Davies, H. M. L., Manning, J. D. Nature
2008, 451, 417; (b) Doyle, M. P., Duffy, R., Ratnikov, M., Zhou, L.
Chem. Rev. 2010, 110, 704; (c) Davies, H. M. L., Morton, D. Chem.
Soc. Rev. 2011, 40, 1857; (d) Liao, K., Negretti, S., Musaev, D. G.,
Bacsa, J. Davies, H. M. L., Nature 2016, 533. For selected reviews
of enantioselective nitrene C–H insertion; see (e) Du Bois, J. Org.
Process Res. Dev. 2011, 15, 758; (f) Collet, F., Lescot, C., Dauban, P.
Chem. Soc. Rev. 2011, 40, 1926.
(3). Examples of enantioselctive Pd(0)-catalyzed desymmetrization
via C(sp3)–H activation: Examples on Me groups: (a) Anas, S.,
Cordi, A. Kagan, H. B. Chem. Commun. 2011, 47, 11483; (b) Mar-
tin, N., Pierre, C., Davi, M., Jazzar, R., Baudoin, O. Chem. Eur. J.
2012, 18, 4480; (c) Saget, T., Lemouzy, S., Cramer, N. Angew.
Chem. Int. Ed. 2012, 51, 2238; (d) Yang, L., Melot, R., Neuberger,
M., Baudoin, O. Chem Sci. 2016, advance article, DOI.
10.1039/C6SC04006C. Examples on cycloalkanes: (e) Saget, T.,
Cramer, N. Angew. Chem. Int. Ed. 2012, 51, 12842; (f) Pedroni, J.,
Donets, P. A., Cramer, N. Chem. Sci. 2015, 6, 5164; (g) Nakanishi,
M., Katayev, D., Besnard, C., Kundig, E. P. Angew. Chem. Int. Ed.
2011, 50, 7438
Scheme 1. Synthesis of complex amines
Me
Ph
Ph
N
Me
H
Me
Me
(i) pyrazole, p-TsOH (72%)
(ii) LiAlH4, THF (83%)
N
N
Me
N
O
N
Me
2d
4
N
(iii) MeOH, p-TsOH (66%)
enantio-enriched
highly substituted
saturated amine
heterocycles
(iv) 5 mol% Pd(OAc)2, PIDA
AcOH, Ac2O, EtOAc (69%)
[iterative C–H aziridination]
(4). Examples of Pd(II)-catalyzed desymmetrization via C(sp3)–H
activation. Examples on Me groups: (a) Giri, R., Chen, X., Yu, J. –Q.
Angew. Chem. Int. Ed. 2005, 44, 2112; (b) Shi, B. –F., Maugel, N.,
Zhang, Y. –H., J. –Q. Yu Angew. Chem. Int. Ed. 2008, 47, 4882;
(c) Xiao, K.-J., Lin, D. W., Miura, M., Zhu, R. –Y., Gong, W., Wasa,
M., Yu, J. –Q. J. Am. Chem. Soc. 2014, 136, 8138; (d) Examples on
cycloalkanes: (d) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 19598; (e) Xiao, K.-J., Lin, D.
W., Miura, M., Zhu, R. –Y., Gong, W., Wasa, M., Yu, J. –Q. J. Am.
Chem. Soc. 2014, 136, 8138; (f) Chan, K. S. L., Fu, H. –Y., Yu, J. –
Me
Ph
Me
Ph
MeO
N
Me
H
N
(i) pyrazole, p-TsOH (78%)
(ii) LiAlH4, THF (61%)
N
Me
N
O
N
N
OMe
5
6
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
Q. J. Am. Chem. Soc. 2015, 136, 2042. Enantioselective methylene
C–H activation: (g) Chen, G., Gong, W., Zhuang, Z., Andra, M. S.,
Chen, Y. –Q., Hong, X., Yang, Y. –F., Liu, T. Houk, K. N., Yu, J. –Q.
Science 2016, 353, 1023.
(5). (a) McNally, A., Haffemayer, B., Collins, B. S. L., Gaunt, M. J.
Nature 2014, 510, 129; (b) Smalley, A. P., Gaunt, M. J. J. Am.
Chem. Soc. 2015, 137, 10632; (c) He, C., Gaunt, M. J. Angew.
Chem. Int. Ed. 2015, 54, 15840; (d) Calleja, J., Pla, D., Gorman, T.
W., Domingo, V., Haffemayer, B., Gaunt, M. J. Nat. Chem. 2015, 7,
1009. (d) Willcox, D., Chappell, B. G. N., Hogg, K. F., Calleja, J.,
Smalley, A. P., Gaunt, M. J. Science 2016, 354, 851.
(6) (a) Akiyama, T., Itoh, J., Yokota, K., Fuchibe, K. Angew. Chem.
Int. Ed. 2004, 43, 1566; (b) Uraguchi, D., Terada, M. J. Am. Chem.
Soc. 2004, 126, 5356; (c) Parmar, D., Sugiono, E., Raja, S. &
Rueping, M. Chem. Rev. 2014, 114, 9047.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Hamilton, G. L., Kang, E. J., Mba, M., Toste, F. D. Science
2007, 317, 496; (b) Mukherjee, S., List, B. J. Am. Chem. Soc. 2007,
129, 11336; (c) Jiang, G., Halder, R., Fang, Y., List, B. Angew.
Chem. Int. Ed. 2011, 50, 9752; (d) Chai, Z., Rainey, T. J. J. Am.
Chem. Soc. 2012, 134, 3615; (e) Wang, P.-S., Lin, H.-C., Zhai, Y.-J.,
Han, Z.-Y.; Gong, L.-Z. Angew. Chem. Int. Ed. 2014, 53, 11218.
(8) Yan, S.-B., Zhang, S., Duan, W.-L. Org. Lett. 2015, 17, 2458.
(9) (a) Jain, P., Verma, P., Xia, G. Yu, J. –Q. Nat. Chem. 2016, 353,
1023. (b) Wang, H., Tong, H. –R., He, G., Chen, G. Angew. Chem.
Int. Ed. 10.1002/anie.201609337.
(10). Rubottom, G. M., Mott, R. C. J. Org. Chem. 1979, 44, 1731.
(11) Use of PhIO generates water, which we determined degrades
the catalyst.5b Use of I2 leads to inactive PdI2 being formed at the
end of the catalytic cycle.
(12) The lower pH resulting from generation of AcOH could affect
the concentration of the putative 3•Pd(OAc) species, thereby affect-
ing stereoinduction
(13) Neel, A., Millo, A., Toste, F. D., Sigman, M. S. Science, 2015,
347, 737.
(14) (a) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 10692. (b) García-Cuadrado, D.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2006, 128, 1066. (c) Balcells, D.; Clot, E.; Eisenstein, O. Chem.
Rev. 2010, 110, 749. (c) Davies, D. L., Donald, S. M. A., Macgregor,
S. A. J. Am. Chem. Soc. 2005, 127, 13754.
(15) Simon, L. Goodman, J. M. J. Org. Chem. 2011, 76, 1775.
(16) (a) Lovering, F., Bikker, J., Humblet J. Med. Chem. 2009, 52,
6752; (b) Roughley, S. D., Jordan, A. M. J. Med. Chem. 2011. 54,
3451.
TOC
Ar
R
R
R
H
O
10 mol% Pd(OAc)2
X
N
O
O
R
P
Me
N
X
20 mol% (R)-TRIP
O
OH
Me
oxidant
Me
O
Ar
14 examples, e.r. up to 97:3
(R)-TRIP
ACS Paragon Plus Environment