Highly efficient syntheses of azetidines, pyrrolidines, and indolines via palladium catalyzed intramolecular amination of C(sp3)-H and C(sp2)-H bonds at γ and δ positions

Article abstract of DOI:10.1021/ja210660g

Efficient methods have been developed to synthesize azetidine, pyrrolidine, and indoline compounds via palladium-catalyzed intramolecular amination of C-H bonds at the γ and δ positions of picolinamide (PA) protected amine substrates. These methods feature relatively a low catalyst loading, use of inexpensive reagents, and convenient operating conditions. Their selectivities are predictable. These methods highlight the use of unactivated C-H bond, especially the C(sp³)-H bond of methyl groups, as functional groups in organic synthesis.

Full text of DOI:10.1021/ja210660g

Communication
pubs.acs.org/JACS
Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines
via Palladium Catalyzed Intramolecular Amination of C(sp3)−H and
C(sp2)−H Bonds at γ and δ Positions
Gang He, Yingsheng Zhao, Shuyu Zhang, Chengxi Lu, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
Table 1. Pd-Catalyzed Intramolecular Amination of
a
γ-C(sp3)−H Bonds
ABSTRACT: Efficient methods have been developed to
synthesize azetidine, pyrrolidine, and indoline compounds
via palladium-catalyzed intramolecular amination of C−H
bonds at the γ and δ positions of picolinamide (PA)
protected amine substrates. These methods feature
relatively a low catalyst loading, use of inexpensive reagents,
and convenient operating conditions. Their selectivities are
predictable. These methods highlight the use of unactivated
C−H bond, especially the C(sp3)−H bond of methyl
groups, as functional groups in organic synthesis.
atalytic functionalization of unactivated sp3 hybridized
C−H bonds under relatively mild reaction conditions
C
remains one of the biggest challenges in organometallic and
synthetic chemistry.1 Compared with the increasingly available
methods for C(sp2)−H functionalizations of various arenes and
heteroarenes, chemo- and stereoselective replacement of
C(sp3)−H bonds of commonly used aliphatic substrates with
C−C and C−heteroatom bonds will provide unique accesses to
a large array of structurally diverse products.2,3 Among these
transformations, amination of C(sp3)−H bonds has been
particularly attractive since N-containing compounds especially
N-heterocycles are ubiquitous in natural products and
pharmaceuticals.4−7 Synthesis of aliphatic N-heterocycles via
the C−H functionalization can be traced back to the classic
a
Hofmann−Loffler−Freytag reaction mediated through the
̈
Reagents and conditions: All the screening reactions were carried out
radical mechanism.8 More recently, metal-catalyzed insertions
of nitrenes and nitrenoids into C(sp3)−H bonds via the “outer-
sphere mechanism” have provided another set of powerful tools
to synthesize complex heterocyclic amines.9 However, the
metal-catalyzed amination of C(sp3)−H bonds via the “inner-
sphere mechanism” remains underdeveloped.10−12 These
transformations could potentially provide different reactivities
and selectivities complementary to those of the radical and
nitrene insertion reactions, which are more amenable to
substrates with relatively weaker secondary and tertiary
C(sp3)−H bonds.13 Herein, we report a new set of methods
to synthesize azetidines, pyrrolidines, and indolines via
palladium-catalyzed picolinamide-directed intramolecular amin-
ation of the C(sp3)−H and C(sp2)−H bonds at the remote γ
and δ positions of amine substrates.
b
in a 10 mL glass vial with a PETF-lined cap at 0.2 mmol scale. The
c
reaction vial was purged with gas (1 atm) and then sealed. Yields were
based on 1H NMR analysis of reaction mixture after 24 h (see
d
Supporting Information (SI)). 1-Fluoro-2,4,6-trimethylpyridinium
triflate. 48 h. Isolated yield.
e
f
in 2005,15 has demonstrated superior directing abilities to enable
a number of transformations including arylation and alkenyla-
tion of γ-C(sp3)−H bonds with aryl and vinyl iodides and
alkylation of γ-C(sp2)−H with β-H containing alkyl halides.
Strict γ selectivities were observed in all of these reactions,
presumably due to the formation of a kinetically favored five-
membered palladacycle intermediate. To further expand the
synthetic utility of this PA-directed C−H functionalization
strategy, we investigated whether γ-C(sp3)−H bonds could be
transformed into C−O, C−N, or C−halogen bonds under
Over the past three years, our laboratory has developed
synthetically useful methods based on Pd-catalyzed C−H
functionalizations of picolinamide protected amine substrates.14
The picolinamide (PA) group, originally introduced by Daugulis
Received: November 12, 2011
Published: December 21, 2011
© 2011 American Chemical Society
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certain oxidative conditions through a PdII/PdIV catalytic cycle.16
Accordingly, reactions of the valine substrate 1 and different
oxidizing reagents were examined under palladium catalysis
(Table 1). While oxidants such as Ag+, BQ , NIS, Cu2+, and F+-
based reagents completely failed to promote any useful
transformations, PhI(OAc)2 clearly stood out and afforded
promising initial results (entry 10). To our surprise, the
seemingly unfavorable four-membered azetidine 2 was obtained
as the major product, in an easily separable diastereomeric
mixture (dr ∼6/1), along with minor mono- and diacetoxylated
products 3 and 4. Toluene was found to be the best solvent, and
100−110 °C was the optimal temperature range. The cyclization
reaction performed better under an Ar atmosphere than Air or
O2 (entries 11−13). Interestingly, lowering the Pd(OAc)2
catalysis loading from 10 to 2.5 mol % effected slightly higher
yields (entries 12−14). The reaction using 1 mol % Pd(OAc)2
could afford a 52% yield with a prolonged reaction time of 2
days (entry 16). Finally, addition of 2 equiv of AcOH further
improved the reaction to provide 2 in 85% isolated yield in 24 h
(entry 19). No desired product was formed when Pd(OAc)2 was
replaced with 2 equiv of I2 (entry 20).17
Table 2. Syntheses of Azetidines via Intramolecular
Amination of γ-C(sp3)−H Bonds
With the optimal azetidine formation conditions in hand, we
then tested them on other picolinamide substrates bearing
primary γ-C(sp3)−H bonds (Table 2).18 The OAc-protected
valinol substrate 5 gave a similar cyclization yield but
surprisingly high diastereoselectivity (only one diastereomer
was clearly detected based on 1H NMR, entry 1). Substrates 5,
8, 13, and 16, bearing both α and β substituents, afforded 70−
90% yields (entries 1, 2, 4, 5). In contrast, the substrate 10,
bearing no β substituent, gave only 25% of the cyclized product
11 together with 70% of the acetoxylated product 12 (entry 3).
In fact, 12 could be obtained nearly exclusively in good yield
when the reaction was carried out in AcOH. β-Substituted
aliphatic substrate 18 also gave a satisfying yield (entry 6). We
speculated that a PdIV intermediate was formed via the
PhI(OAc)2 oxidation of the palladacycle intermediate and the
subsequent C−N and C−O reductive elimination pathways
would lead to the formation of the cyclized and acetoxylated
products.19 The rate of the subsequent reductive elimination
processes could be affected by the associated OAc ligand and
the steric effect of the substrates. Only trace amounts of
acetoxylated products (<2%) were observed with substrates 8
and 16 bearing R2 substituents. In contrast, acetoxylated
product 12 predominated for the substrate 10 (R2 = H). One
plausible interpretation for the observed selectivities might be
the torsional strain imposed by the R2 substituent on the β
position and the γ-C−H bonds (and possibly R1 group on the α
position) during the bond reorganization process for the out-of-
palladacycle-plane C−O formation. Such torsional strain might
kinetically favor the in-palladacycle-plane C−N cyclization
despite the ring strain in the resulting azetidine.20 It was also
noteworthy that no β-H elimination product was detected
under the above-mentioned reaction conditions.
a
Negligible amounts of acetoxylated products (<2%) were formed.
No pyrrolidine product was detected.
b
PdIV center. To our delight, the cyclization of the leucine
substrate 21 bearing both primary δ-C(sp3)−H bonds and a
sterically less accessible γ-C(sp3)−H bond proceeded smoothly
to give the pyrrolidine product 22, as a mixture of two dia-
stereomers (dr ∼7/1), in good yield under the same azetidine
formation conditions. The reaction was further optimized with
the addition of 10 equiv of AcOH to suppress the formation of
the undesired acetoxylated product 23 (entry 1, Table 3).22
Substrates 24 and 28, bearing both primary δ-C(sp3)−H bonds
and γ-substituents, also gave satisfying cyclization yields (entries
2, 4). High diastereoselectivity was also obtained for substrate 28.
Similar to the azetidine synthesis, the substrate 26 bearing no γ-
substituents gave only 17% of the pyrrolidine product 27 and a
trace amount of the acetoxylated side product; no azetidine
product was formed, and >70% of unreacted 26 was recovered
(entry 3). It is noteworthy that no pyrrolidine products were
formed in the cyclization reactions of substrates 13 and 18
bearing methyl groups at both γ and δ positions (Table 2). ortho-
tert-Butylaniline substrate 30 also cyclized to give the indoline
product 31 in good yield (entry 5). ortho-Methylbenzylamine
substrate 32, readily prepared from the PA-directed methylation
of the ortho-C(sp2)−H bond of the benzyl amine precursor,14b
gave the cyclized isoindoline product 33 in 56% yield (entry 6).
Encouraged by the success with the PA-directed intra-
molecular amination of a δ-C(sp3)−H bond to synthesize
indoline 31, we went on to explore a similar functionalization of
the ortho C(sp2)−H bonds of phenylethylamine substrates. The
blueprint for this mode of indoline synthesis has been
successfully demonstrated by Yu and co-workers using triflate
protected phenylethylamines.5e Gratifyingly, cyclization of the
phenylalanine 35 proceeded cleanly to afford the indoline
product 36 in 81% yield using 2 mol % of Pd(OAc)2 and
Compared with the ring contraction from a five-membered
palladacycle to a four-membered azetidine product, formation of
a five-membered pyrrolidine product from a six-membered
palladacycle intermediate would be much more favorable.
However, examples of the formation of kinetically less favored
six-membered palladacycles via C(sp3)−H palladation are
scarce.21 Despite the unanimous γ-selectivity observed in our
previous studies, we decided to test the possibility of the
δ-C(sp3)−H activation under these oxidative conditions, in view
of the unique driving force for C−N reductive elimination from a
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Communication
a
Table 3. Syntheses of Pyrrolidines via Intramolecular
Scheme 2. Substrate Deuteration Studies
Amination of δ-C(sp3)−H Bonds
a
Deuterium incorporation of substrates 13, 26, and 21 under the
conditions of 2.5 mol % of Pd(OAc)2, AcOD (10 equiv), toluene
(solvent), at 110 °C for 24 h. The resulting deuterated products were
1
purified and then analyzed by H NMR (see SI).
substrate 21 exclusively occurred at the δ-CH3 at the 25% level.
The following order of relative reactivities of different C(sp3)−
H bonds under these reaction conditions was concluded:
primary γ-C−H > primary δ-C−H > secondary and tertiary
γ-C−H bonds.23
Although the picolinamide group could be readily installed via
the standard amide coupling, its cleavage under mild reaction
conditions was quite challenging. In our previous report of the
PA-directed arylation of γ-C(sp3)−H bonds, a more easily
removable auxiliary PAre 42 was introduced to enable its
deprotection under mild acidic conditions, which significantly
improved its synthetic utility (Scheme 3).14a Here, PAre-
Scheme 3. Employment of a More Easily Removable PA
Group
a
b
>70% of unreacted starting material 26 was recovered. 10 mol % of
Pd(OAc)2 was used.
2.5 equiv of PhI(OAc)2 in toluene at 60 °C in 24 h (Scheme 1).
A similar yield was obtained with 5 mol % of Pd(OAc)2 at 50 °C
Scheme 1. Syntheses of Indolines via Intramolecular
Amination of δ-C(sp2)−H Bonds
protected leucine substrate 43 underwent the desired
C−N cyclization under slightly different conditions, in which
10 equiv of AcOH was omitted to avoid the unwanted cleavage
of the TBS group.24 To our delight, cleavage of the PAre group
using 5 equiv of 1 M aq. HCl in dioxane proceeded smoothly
even at room temperature to give the product 45 following the
subsequent Cbz protection.25
In summary, we have developed a new set of methods to
synthesize azetidine, pyrrolidines, and indolines via Pd-
catalyzed picolinamide-directed intramolecular C−H amina-
tion. Complementary to the reactivity patterns observed in the
radical and nitrene-mediated C−H activation reactions, primary
C(sp3)−H bonds of methyl groups on both γ and δ positions
could be readily functionalized in a selective and predictable
manner, even with high diastereoselectivity in certain germinal
dimethyl substrates. These methods are efficient, economical,
and practical in the laboratory. More detailed mechanistic
studies, new development of picolinamide auxiliaries, and
applications of these methods in the synthesis of complex
molecules are currently under investigation.24
in 24 h. Furthermore, cyclization of the unsubstituted phenyl-
ethylamine substrate 37 also performed well to give 38, which
was readily hydrolyzed to afford the free indoline 39 by
treatment of 1.5 equiv of NaOH in MeOH/THF/H2O at 50 °C.
The following substrate deuteration experiments were
performed to map the relative reactivities of different C(sp3)−H
bonds under the Pd-catalyzed C−H activation conditions
in the absence of PhI(OAc)2 (Scheme 2). Isoleucinol substrate
13 showed >60% deuteration at the γ-CH3, 22% deuteration at
the γ′-CH2, and ∼20% deuteration at the δ-CH3. However, no
pyrrolidine product was formed under the corresponding
oxidative conditions with PhI(OAc)2 (entry 4, Table 2).
Substrate 26 showed that both the γ-CH2 and δ-CH3 groups
were deuterated to a smaller extent (14% and 9% respectively);
however, only the pyrrolidine product 27 was formed in 17%
yield under the corresponding oxidative amination conditions
(entry 3, Table 3). Deuteration incorporation of the leucine
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Communication
Jones, J. E.; Wojtas, L.; Zhang, X. P. Org. Lett. 2010, 12, 1248−1251.
(e) Du Bois, J. Org. Process Res. Dev. 2011, 15, 758−762. (f) Lu, H.;
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AUTHOR INFORMATION
■
Corresponding Author
Guc11@psu.edu
(10) For selected examples of Pd-catalyzed aminations of allylic
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ACKNOWLEDGMENTS
■
We gratefully acknowledge The Pennsylvania State University
and the U.S. National Science Foundation (CAREER CHE-
1055795) for financial support of this work.
(11) For Pd-catalyzed aminations of unactivated C(sp3)−H bonds,
see: (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006,
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