Selective Reductive Elimination at Alkyl Palladium(IV) by Dissociative Ligand Ionization: Catalytic C(sp3)?H Amination to Azetidines

Article abstract of DOI:10.1002/anie.201800519

A palladium(II)-catalyzed γ-C?H amination of cyclic alkyl amines to deliver highly substituted azetidines is reported. The use of a benziodoxole tosylate oxidant in combination with AgOAc was found to be crucial for controlling a selective reductive elimination pathway to the azetidines. The process is tolerant of a range of functional groups, including structural features derived from chiral α-amino alcohols, and leads to the diastereoselective formation of enantiopure azetidines.

Full text of DOI:10.1002/anie.201800519

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Selective Reductive Elimination at Alkyl Pd(IV) via Dissociative
Ligand Ionization Enables Catalytic C(sp3)-H Amination to
Azetidines
Authors: Matthew James Gaunt, Manuel Nappi, Chuan He, William
Whitehurst, and Ben Chappell
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800519
Angew. Chem. 10.1002/ange.201800519
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10.1002/anie.201800519
Angewandte Chemie International Edition
COMMUNICATION
Selective Reductive Elimination at Alkyl Pd(IV) via Dissociative
Ligand Ionization Enables Catalytic C(sp3)–H Amination to
Azetidines
Manuel Nappi,+ Chuan He,+ William G. Whitehurst, Ben G. N. Chappell and Matthew J. Gaunt*
Abstract: A Pd(II)-catalyzed γ-C–H amination of cyclic alkyl amines
to highly substituted azetidines is reported. The use of a benziodoxole
tosylate oxidant in combination with AgOAc was found to be crucial
for controlling a selective reductive elimination pathway to the
azetidines. The process is tolerant of a range of functional groups,
including structural features derived from chiral a-amino alcohols, and
leads to the diastereoselective formation of enantiopure azetidines.
aliphatic cyclic amine products from aminoalkyl-Pd(IV) species
remains a challenge.
Here, we detail a Pd(II)-catalyzed intramolecular C–H amination
process in which a distinct oxidation system exerts control over
competitive reductive elimination pathways leading to the
formation of azetidines (Scheme 1c). The C–H amination
converts a class of synthetically versatile alkyl amines into highly
substituted, functionally complex and stereochemically defined
azetidines, which could be useful as novel building blocks.8
The development of new methods for the synthesis of aliphatic N-
heterocycles based on metal-catalyzed C–H activation has
stimulated intense research effort.1 Among these processes,
intramolecular C–H amination using Pd(II) catalysts represents an
attractive way to access saturated N-heterocycles from free(NH)
amines. Key to the success of such a strategy would be the
oxidation of an amine-ligated Pd(II) palladacycle to an alkyl-
Pd(IV) species,2 from which C–N reductive elimination would form
the cyclic amine. Despite its apparent simplicity, the successful
realization of this tactic is hindered by two factors. Firstly,
oxidation of the amine-ligated palladacyle results in a Pd(IV)
species displaying a number of different anionic ligands, meaning
that the selectivity of reductive elimination can be difficult to
control, leading to multiple products (Scheme 1a).3 Secondly,
Pd(II)-catalyzed C–H activation on free(NH) alkyl amines can be
hampered by substrate degradation connected to the use of the
strong oxidants required to affect the transition between
Pd(II)/(IV) intermediates.4 While a number of elegant solutions
have emerged for C(sp2)–H amination,5 examples of Pd(II)-
catalyzed C–H amination to aliphatic N-heterocycles are rare. In
2012, Daugulis and Chen independently reported that Pd(II)-
catalyzed intramolecular C(sp3)–H amination to 5- and 4-
membered N-heterocycles could be affected by a hypervalent
iodine oxidant (Scheme 1b).1,6 However, the amine substrate
required protection with a picolinamide auxiliary and, in some
cases, the reaction led to product mixtures arising from non-
selective reductive elimination. In 2014, our laboratory reported a
Pd(II)-catalyzed C–H amination to aziridines, also using an I(III)
oxidant.7 In this case, the reaction could not accommodate amine
substrates containing C–H bonds at the α-position to the amine.
Consequently, the development of catalytic processes to form
(a) Reductive elimination to N-heterocycles from alkyl-Pd(IV) complexes
H
n
N
X
Y
R
X
Me
Me
R
N
O
O
R
N
reductive
X–Y
O
O
Pd(
Pd(
)
IV
H
H
R
N
)
II
n
oxidative
addition
elimination
n
n
Y
R
N
H
n
selectivity of reductive elimination depends on nature of X and Y
(b) Direct C–N reductive elimination in a C–H amination reactions to heterocycles
Me
Me
Me
O
O
Me
O
O
O
O
N
Pd
N
O
) O
Pd(
N
IV
O
O
Me
n
O
Me
Me
Chen & Daugulis – auxiliary controlled
azetidines & pyrrolidines
Gaunt – sterically controlled
aziridines
C–N vs C–OAc reductive elimination
can be a problem
selective C–N reductive elimination
but requires fully substituted amines
(c) This work – Oxidant-controlled Pd(II)-catalyzed C–H activation to azetidines
R3
R3
R2
OTs
O
R2
10 mol% Pd(OAc)2
AgOAc, DCE
O
I
N
N
O
H
O
O
1R
O
1R
Me
distinct and selective
amine
oxidant
reductive elimination pathway
azetidine
Scheme 1. Pd-catalyzed C–H amination to N-heterocycles.
Recently, we described a Pd(II)-catalyzed process for β-C–H
amination on hindered alkyl amines to form aziridines, which
proceeded by direct intramolecular C–N reductive elimination
from an aminoalkyl Pd(IV) intermediate.7 We speculated that
reaction of a related homologated amine 1a should undergo γ-C–
H amination to form the corresponding azetidine 2a (Scheme 2).
We were surprised to find, however, that reaction of amine 1a
produced only the γ-C–H acetoxylation product 3a, with no sign
of azetidine 2a, when treated under identical conditions to the
aziridine forming process.7a Notably, Chen et al observed
competitive C–H acetoxylation as an (often significant) by-product
in their related azetidine-forming reaction.6b Drawing analogy with
our mechanistic work on aziridine formation,7b we assumed
aminoalkyl-Pd(IV) species int-I (from oxidation of palladacycle 4,
Scheme 3) would precede C–O reductive elimination and provide
[*]
[+]
Manuel Nappi, Chuan He, William G. Whitehurst, Ben G. N.
Chappell and Prof. Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Rd, Cambridge CB2 1EW (UK)
E-mail: mjg32@cam.ac.uk
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201800519
Angewandte Chemie International Edition
COMMUNICATION
Me
a starting point for computational studies. We were cognizant of
the important effect imparted by the adjacent carbonyl motif; while
its precise role remains uncertain, we believe that it modulates the
reactivity of the NH group and affects both the steps leading to C–
H activation as well as modulating the pathways leading to
reductive elimination. Although a number of catalytic C(sp3)–H
acetoxylation methods have been reported via alkyl-Pd(IV)
intermediates, the salient features of the crucial C(sp3)–O
reductive elimination step have proved difficult to elucidate.9
Towards the formation of 3a, computational interrogation of the
fate of int-I surprisingly showed that the lowest energy pathway
did not involve direct C–O reductive elimination.
O
Me
O
Me
Me
Me
Me
Pd
Me
O
O
“TsO “ oxidant
O
O
O
)
Pd
N
O
N
(
IV
H
O
H
O
Et
O
O
Et
S
O
Ar
int-III
what oxidant will load
a single OTs group to
the Pd(IV) center ?
4
generated from
Pd(OAc)2 and 1a
dissociative
ionization
of TsO–
κ2
binding
of OAc
will the H-bonded TsO–
group be capable of
attacking the C–Pd(IV)
bond ?
Me
Me
O
Me
Me
Me
displacement of Pd(II)
by tosylate
O
O
O
Pd
N
H
O
(
)
IV
N
O
O
H
O
O
Et
Et
(formal reductive
elimination)
Me
O
S
Me
O
OTs
Ar
Me
5
int-IV
Me
O
Me
Me
H
O
Me
H
10 mol% Pd(OAc)2
O
N
internal displacement
by amine group
Me
O
N
Me
O
N
azetidine 2a
O
N
Et
PhI(OAc)2, PhMe, 80 ˚C
O
Et
O
Et
Et
Me
OAc
azetidine, 2a
not observed
acetoxylated
amine 3a, 75%
Scheme 3. Proposed C–H Amination to Azetidines.
amine, 1a
putative pathway based on preliminary DFT calculations
C–H bond
cleavage
&
loss
of
Pd(OAc)2
catalyst
Me
Me
We proposed that replacing one of the acetate ligands on the
aminoalkyl-Pd(IV) species with a OTs group (int-III) would
promote dissociative ionization of the better leaving group.
Accompanied by the anchimeric κ2 binding of the trans (axial)
acetate, the dissociation of the OTs from the aminoalkyl-Pd(IV)
center generates the octahedral Pd(IV) intermediate int-IV, in
which the H-bonded tosylate is primed for displacement at the
electrophilic C–Pd(IV) bond to form the γ-amino tosylate 5.9e-f,10
Cyclization of the amine to displace the γ-tosylate completes the
formal C–N reductive elimination process to azetidine 2a.
Me
O
O
Me
Me
O
oxidation
Me
O
O
Me
O
O
Pd
N
O
)
(
IV
O
)
Pd
N
H
O
(
IV
H
O
O
Et
Et
Me
int-II
O
O
O
O
Me
int-I
Me
dissociative ionization of AcO–
& Κ2 binding of OAc to Pd(IV)
displacement at C–Pd(IV) bond
by proximal H-bonded AcO–
Scheme 2. Rationalization of C–H acetoxylation.
Guided by this mechanistic blueprint, we first considered an
oxidant capable of transferring the single tosylate group required
to form crucial aminoalkyl-Pd(IV) species int-III. We began by
testing conditions related to the C–H acetoxylation process
(Scheme 2), wherein TsOH was added in expectation that the
desired pathway could be triggered by the substitution of acetate
on a Pd(IV) intermediate with a TsO ligand (Table 1, entry 1);
unfortunately, none of the desired azetidine was observed.
Similarly, the use of NFSI in combination with TsOH, conditions
reported independently by Dong10 as part of C(sp3)–H
oxysulfonylation processes, also failed to give the azetidine 2a.
Our first success was realized through the use of Koser’s reagent,
a tosylate-containing hypervalent iodine oxidant (entry 2).11 We
were pleased to observe the formation of azetidine 2a, albeit in
6% yield. We were surprised to find that addition of AgOAc
increased the yield of 2a to 27% with only trace acetoxylation
observed (entry 3). With this in mind and based on Rao’s use of
benziodoxoles in Pd(II)-reactions,12 reaction of 1a with a tosylate
derivative of these reagents (6), retaining AgOAc, increased the
yield of 2a to 52% (entry 4). Further improvements were made by
increasing the amount of AgOAc and 6 (entry 5). Reaction without
AgOAc gave trace amounts of 2a and there was no reaction in the
absence of Pd(OAc)2 (entries 6,7). These results point to an
important role for both the oxidant 6 and AgOAc. The use of 6
suggests oxidative transfer of the tosylate to form aminoalkyl-
Instead, we found that 3a could be formed via a two-step reaction
at the Pd(IV) center; dissociative ionization of an axial acetate
from Pd(IV) in int-I and simultaneous k2 binding of the axial
acetate forms an octahedral complex int-II. Notably, the
dissociated acetate remains hydrogen bonded to the ligated
amino group in int-II, which aids the displacement of the high
valent metal group, installing the acetoxy motif at the g-position.
This pathway draws an important parallel with the elegant work of
Sanford et al, who recently reported C–O reductive elimination
from stoichiometric alkyl Pd(IV) complexes based on
a
dissociative ionization mechanism.9e,f In light of these preliminary
computational studies, we re-evaluated our design hypothesis for
azetidine formation (Scheme 3).
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10.1002/anie.201800519
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COMMUNICATION
Ar1
Pd(IV) species, int-III. Interestingly, use of AgOTs precludes any
reaction (entry 8).
Me
Me
Me
O
Me
O
Me
O
O
O
O
Me
Me
Me
O
O
Pd
O
O
N
N
O
H
H
O
)
O
Pd
N
Ar1
(
IV
Et
H
O
Et
2Ar
HI
Table 1. Optimization of reaction conditions.
O
Et
O
O
OTs
S
5
S
O
Ar2
int-V
O
Me
O
PIDA = PhI(OAc)2
HTIB = PhIOH(OTs)
OTs
Me
Me
Pd(II) catalyst
oxidant
O
Me
H
O
int-VI
N
N
O
additive, solvent
temperature
O
I
Et
2a
Et
O
Me
6
O
amine, 1a
azetidine, 2a
TS-2 ΔE = 15.66 kcalmol-1
TS-1 ΔE = 9.83 kcalmol-1
Entry
Catalyst
Oxidant
(equiv.)
Additive
T
˚C
Solvent
2a
(equiv.)
TsOH (2)
–
(%)[a]
Scheme 4. Computational validation of C–H amination.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
PIDA (2)
HTIB (2)
HTIB (2)
6 (2)
80
80
80
80
60
60
60
60
PhMe
PhMe
PhMe
PhMe
DCE
0
6
1
2
3
4
5
6
7
8
Table 2 shows that a range of fully substituted morpholinones
displaying an a-ethyl group alongside functionalized a’-
sidechains undergo efficient C–H amination to azetidines 2a-h;
sidechain groups compatible with the reaction comprised
hydroxymethyl derivatives (2c,d), fluoromethyl (2e), protected
amines (2f), esters (2g) and arenes (2h). In addition, an amine
containing a spiro-cyclohexane motif provided the corresponding
azetidine 2i in 83% yield. The C–H amination of a cyclic amide
derivative lead to the piperazinone 2j in moderate yield.
AgOAc (2)
AgOAc (2)
AgOAc (3)
–
27
52
81
trace
–
6 (3)
6 (3)
DCE
6 (3)
AgOAc (3)
AgOTs (3)
DCE
Pd(OAc)2
6 (3)
DCE
–
Typically, the C(sp3)–H functionalization of unprotected alkyl
amines via classical cyclopalladation/Pd(IV) pathways is often
restricted to molecules displaying fully substituted carbon atoms
around the free(NH) motif. This is, partly, because deleterious
oxidation reactions at the a-position to the amine are initiated by
the requisite oxidant, leading to decomposition. On the basis that
the benziodoxole 6 is less oxidizing than its acyclic counterparts,16
we reasoned that amine substrates with fewer substituents might
be compatible with the modified reagent. This feature would be
attractive for two reasons: chiral amino alcohols could be used to
assemble the morpholinones; and a chiral center adjacent to the
[a] Yields by 1HNMR using Ph3CH or (Cl2CH)2 as internal standard.
Although the precise role of the AgOAc is unclear, it could be
responsible for converting any non-acetate Pd(II) species, formed
at the end of the cycle, back to the essential Pd(OAc)2 catalyst.13
We validated our hypothesis through computation (Scheme 4).
Probing the fate of aminoalkyl-Pd(IV) species int-V (formed from
4 and 6) revealed a low energy pathway involving the dissociative
ionization of tosylate (TSdiss=9.83 kcalmol-1), via TS-1, assisted by
the concerted κ2 binding of the 2-iodobenzoate ligand to form int-
VI. The tosylate then attacks the γ-carbon atom (in int-VI, via TS-
2), displacing the nucleofugal Pd(IV) species (TSdispl=15.66
kcalmol-1) to form the C–OTs bond in 5.10 Following
decomplexation of Pd(II), displacement of tosylate with the amine
forms azetidine 2a.14,15 With the optimal conditions, we examined
the scope of the γ-C–H amination.
NH motif would introduce
diastereoselectivity question to the C–H activation step.
Accordingly, range of enantioenriched substrates were
a
previously unexplored
a
prepared starting from different amino alcohols. At 80 ˚C, the C–
H amination delivered the azetidines in useful yields and excellent
diastereoselectivity (2k-x).
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10.1002/anie.201800519
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COMMUNICATION
Table 1. Substrate ccope for C–H amination to azetidines[a]
OTs
O
N
10 mol% Pd(OAc)2
O
I
N
O
H
O
AgOAc, DCE, 60–80˚C
O
O
Me
amine 1
6
azetidine 2
Me
Me
Me
Me
Me
Me
O
Me
O
O
Me
Me
O
O
Me
Me
O
N
O
N
Me
N
N
O
N
O
N
O
O
O
O
O
Et
OTIPS
OAc
F
N
Me
2b, 62%
Me
Me
2a, 81%
Me
2c, 66%
2d,61%
2e, 53%
2f, 54%
O
O2N
O
Ph
O
Me
Me
Me
Me
N
O
N
O
N
O
N
O
O
N
N
N
O
O
Et
O
Et
Et
Et
EtO2C
MeO
2g, 56%
2h, 53%
2i, 83%
2j, 83%
2k, 55%, dr > 20:1 (gram scale)
2l, 50%, dr = 13:1
OTIPS
Me
O
OTIPS
Me
Ph
Me Me
O
N
O
Me
Me
NH
O
N
O
N
O
N
O
O
N
O
Et
O
O
O
Et
Et
Et
Me
2p, 64%
Me
Me
2r, 55%
Me
2n, 54%, dr > 20:1
2o, 56%, dr > 20:1
1q, no reaction
2m, 57%, dr = 11:1
Ts
N
TsHN
O
Me
N
Me
Me
N
Me
N
Ph
O
O
O
O
O
N
O
O
O
O
N
O
N
O
O
N
O
EtO2C
Me
Me
Me
Me
2s, 62%
2t, 35%
2u, 47%
2v, 82%
2w, 61%
2x, 52%
[a] Yields are of isolated products. See Supporting Information for details. [b] Stoichiometric reaction over 2 steps. TIPS = triisopropylsilyl, Ts = p-toluenesulfonyl.
isomer returning starting material 1q. A possible explanation
involves binding Pd(OAc)2 to the less sterically hindered face of
the cyclic amine, placing the key C–H bond in a syn-orientation to
the Pd(II) center (Scheme 5).
Me
Me
anti
H Me
O
H Me
O
Me
versus
complex
from
opposite
isomer
O
O
O
O
O
H
H
Pd(OAc)2
NH
Pd
Pd
N
N
O
O
O
nPr
O
nPr
O
O
O
Me
Me
H
nPr
Me
C–H & PdOAc are
C–H & PdOAc are
syn
C–H activation is
2v
H
anti
Pd(OAc)2 binds
anti to Me group
(a) LiAlH4, THF
(b) MeNH2
EtOH
(c) NaOH, MeOH
60˚C
(d) (c) then
Pb(OAc)4
C–H activation is
geometrically prevented
facilitated by proximity
Me
OH
Me
Me
Me
Me
Me
Me
Me
Me
O
Scheme 5. Stereoselective C–H Activation.
HO
HO
NH
HO
HO
N
N
HO2C
N
MeO
N
Interestingly, the highest diastereoselectivity was observed when
using morpholinones based on alaninol (2k), in comparison to
phenylalanine and serine-derived amines (2l-m). To probe the
stereochemical features of the C–H activation step, we prepared
isomeric substrates that displayed the reactive ethyl group both
syn and anti to the stereogenic center. We found that only the
anti-isomer produced the desired azetidine 2p, with the syn-
Me
7, 76%
Me 8, 91%
Me 9, 96%
Me 10, 54%
Scheme 6. Derivatization of Azetidines.
Further examples of the C–H amination demonstrated that
substituents can be accommodated on either side of the amine
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10.1002/anie.201800519
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COMMUNICATION
[3]
[4]
[5]
a) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936-946; b)
M. H. Perez-Temprano, J. M. Racowski, J. W. Kampf, M. S. Sanford, J.
Am. Chem. Soc. 2014, 136, 4097-4100.
linkage forming azetidines 2r-x displaying functional groups
useful for downstream synthetic modification. Azetidine 2x was
crystalline, enabling unambiguous confirmation of the absolute
configuration of the product by X-ray diffraction.17 Acyclic amines
proved to be poor substrates, requiring stoichiometric amounts of
Pd(OAc)2 to afford 2y in modest yield.18
a) K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem., Int.
Ed. 2003, 42, 4077-4082. b) C. de Graaff, L. Bensch, M. J. van Lint, E.
Ruijter, R. V. A. Orru, Org. Biomol. Chem. 2015, 13, 10108-10112.
a) J. Jiao, K. Murakami, K. Itami, ACS Catal. 2016, 6, 610-633. b) R.
Narayan, S. Manna, A. Antonchick, Synlett 2015, 26, 1785-1803. c) M.
Baeten, B. U. W. Maes, Adv. Organometal. Chem. 2017, 67, 401-481.
See also ref. 1
Finally, we showed that the azetidine products serve as
substrates for a selection of simple transformations to potentially
useful products (Scheme 6). Reduction of the lactone of 2t with
LiAlH4 generated diol 7; aminolysis of the lactone gave amide 8 in
very good yield; hydrolysis of the morpholinone delivered the
corresponding hydroxy-acid 9. We also found that oxidative
decarboxylation of 9 delivered the 4-membered ring cyclic-
hemiaminal 10 as a stable, single diastereomer.
[6]
a) E. T. Nadres, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 7-10; b) G.
He, Y. Zhao, S. Zhang, C. Lu, G. Chen, J. Am. Chem. Soc. 2012, 134,
3-6; c) G. He, G. Lu, Z. Guo, P. Liu, G. Chen, Nat. Chem. 2016, 8, 1131-
1136. For related studies, see: X. Ye, Z. He, T. Ahmed, K. Weise, N. G.
Akhmedov, J. L. Petersen, X. Shi, Chem. Sci. 2013, 4, 3712-3716.
a) A. McNally, B. Haffemayer, B. S. L. Collins, M. J. Gaunt, Nature 2014,
510, 129-133. b) A. P. Smalley, M. J. Gaunt, J. Am. Chem. Soc. 2015,
137, 10632-10641.
[7]
[8]
a) A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008, 108, 3988-
4035; b) B. Alcaide, P. Almendros, C. Aragoncillo, Curr. Opin. Drug
Discov. Devel. 2010, 13, 685-697. c) F. Couty, G. Evano, Synlett 2009,
3053-3064.
In conclusion, we have developed a Pd(II)-catalyzed γ-C–H
amination process in which cyclic secondary alkyl amines are
converted into highly substituted azetidines. The use of a
benziodoxole tosylate as oxidant, in combination with AgOAc,
was crucial in delivering the azetidines. We propose that the C–H
amination to azetidines is facilitated by a selective reductive
elimination that involves dissociative ionization of a tosylate and
anchimeric k2 carboxylate binding to form an octahedral
aminoalkyl-Pd(IV) complex. Nucleophillic attack of the tosylate at
the carbon atom bearing the Pd(IV) group forms the C–OTs bond,
which in turn is displaced by the proximal amino group to form the
azetidine. The reaction displays a broad tolerance to functional
groups, including structural features derived from chiral α-amino
alcohols, which leads to a diastereoselective process forming
enantiopure azetidines. We believe that the distinct reductive
elimination pathway will be applicable to other C–H
functionalization processes.
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Acknowledgements
[13] See supporting information for details. See also; a) X. Chen, C. E.
Goodhue, J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 12634–12635. b) J.-
J. Li, T.-S. Mei, J.-Q. Yu, Angew. Chem. Int. Ed. 2008, 47, 6452 –6455.
[14] Alternative mechanisms for direct C–O or C–N reductive elimination (to
3a & 2a, respectively) from int-VI were significantly higher in energy. See
supporting information, figure S2, for details.
We are grateful to EPSRC (EP/N031792/1), Royal Society for a
Wolfson Merit Award (M.J.G.), H2020 European Research
Council (M.N & C.H.), the Herchel Smith Foundation (B.G.N.C.)
and EPSRC and AstraZeneca (W.G.W) for funding. Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
[15] Although we were unable to isolate tosylate 5, support for the proposed
pathway is demonstrated via the preparation of the corresponding
chloride, by the same pathway, and observation of the formation of
azetidine 2a. See supporting information for details.
Keywords: keyword 1 • keyword 2 • keyword 3 • keyword 4
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[17] 2x was obtained as a single crystal, whose structure was confirmed by
X-ray diffraction, see supporting information for details.
[18] Acyclic amine (1y) formed the corresponding azetidine (2y) in 47% yield
over two steps using a stoichiometric amount of palladium.
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100 mol% Pd(OAc)2
H
N
N
PivO
Me
H
then
PivO
6, AgOAc, DCE, 80˚C, 47%
Me
Me
Me
Me
1y
2y
This article is protected by copyright. All rights reserved.

10.1002/anie.201800519
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Manuel Nappi,+ Chuan He,+
William G. Whitehurst, Ben G.
N. Chappell and Matthew J.
Gaunt*
Page No. – Page No.
A Pd(II)-catalyzed γ-C–H amination of cyclic alkyl amines to highly substituted
azetidines is reported. The use of a benziodoxole tosylate oxidant in combination
with AgOAc was found to be crucial for controlling a selective reductive elimination
pathway to the azetidines. The process is tolerant of a range of functional groups,
including structural features derived from chiral a-amino alcohols, and leads to the
diastereoselective formation of enantiopure azetidines.
Selective Reductive Elimination at
Alkyl Pd(IV) via Dissociative Ligand
Ionization Enables Catalytic C(sp3)–H
Amination to Azetidines
O
10 mol% Pd(OAc)2, AgOAc, DCE
OTs
O
N
N
O
H
O
I
Me
O
O
dissociative ionization
of TsO– leads to C–O
reductive elimination
selective reductive elimination pathway
23 examples
amine
azetidine
This article is protected by copyright. All rights reserved.