Enantioselective Pd(II)-Catalyzed Intramolecular Oxidative 6- endo Aminoacetoxylation of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.8b03767

A novel asymmetric 6-endo aminoacetoxylation of unactivated alkenes by palladium catalysis, which yields chiral β-acetoxylated piperidines with excellent chemo-, regio- and enantioselectivities under very mild reaction conditions, has been established herein by employing a new designed pyridine-oxazoline (Pyox) ligand. Importantly, introducing a sterically bulky group into the C-6 position of Pyox is crucial to enhance the reactivity of the aminoacetoxylation of alkenes.

Full text of DOI:10.1021/jacs.8b03767

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Communication
Enantioselective Pd(II)-Catalyzed Intramolecular Oxidative
6-endo Aminoacetoxylation of Unactivated Alkenes
Xiaoxu Qi, chaohuang chen, Chuanqi Hou, Liang Fu, Pinhong Chen, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 May 2018
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Enantioselective Pd(II)-Catalyzed Intramolecular Oxidative 6-endo
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Aminoacetoxylation of Unactivated Alkenes
Xiaoxu Qi,† Chaohuang Chen,† Chuanqi Hou, Liang Fu, Pinhong Chen and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
Supporting Information Placeholder
ABSTRACT: A novel asymmetric 6-endo aminoacetoxylation of
unactivated alkenes by palladium catalysis, which yields chiral β-
acetoxylated piperidines with excellent chemo-, regio- and
enantioselectivities under very mild reaction conditions, has been
established herein by employing a new designed pyridine-
oxazoline (Pyox) ligand. Importantly, introducing a sterically
bulky group into the C-6 position of Pyox is crucial to enhance
the reactivity of the amino-acetoxylation of alkenes.
Enantiomer-enriched nitrogen-containing heterocycles, such as 3-
hydroxypiperidines, are frequently found in pharmaceuticals,
1
agrochemicals and natural products. For instance, Jervine,
2
a steroidal alkaloid, isolated from the Veratrum plant genus;
Benidipine, a dihydropyridine calcium channel blocker for curing
3
hypertension (Scheme 1a). Considerable efforts have been
therefore directed toward synthesis of chiral heterocycles, and
many methods have been developed.4 Among them, asymmetric
palladium-catalyzed intramolecular oxidative amination of
alkenes is considered as the one of most prevalent strategy, which
however still remains a big challenge in organic synthesis.5 So far,
some of such transformations have been achieved by the groups
of Yang,6 Zhang,7 Stahl, 8 Michael9 and us,10 which underwent 5-
exo cyclizations to provide five-membered heterocycles with high
enantioselectivities. However, to the best of our knowledge, there
have never been any examples of enantioselective Pd-catalyzed 6-
Scheme 1. Enantioselective Pd(II)-catalyzed oxidative amination
of unactivated alkenes (SE = steric effect).
synthesis of structurally diverse 3-acetoxylated piperidines with
high regioselectivities.13e Thus, we reasoned that, if a chiral ligand
could be explored to carry out the palladium-catalyzed reaction,
the asymmetric 6-endo aminoacetoxylation of unactivated alkenes
giving the chiral 3-acetoxylated piperidines might be realized
(Scheme 1b). Our initial investigations started with the commonly
used nitrogen-based chiral ligands, which however significantly
inhibited the reaction and resulted in poor yields and low
enantioselectivities (For details, see SI). Then, we turned our
attention to exploring some new chiral ligands that would be
helpful to enhance both reactivities and enantioselectivities.
endo oxidative amination of alkenes for the synthesis of chiral
11
piperidines reported in documents to date.
Herein, we
communicate this asymmetric palladium-catalyzed 6-endo
oxidative aminoacetoxylation of unactivated alkenes, which
provides an easy access to enantiomer-enriched 3-acetoxy
piperidines. Notably, we found that a novel sterically bulky
pyridinyl-oxazoline (Pyox) is very essential to achieve a highly
efficient reaction with excellent regio- and enantioselectivities
(Scheme 1b).
For C-heteroatom bonds that can be easily generated through
reductive elimination at a Pd(IV) center, a series of palladium-
catalyzed difunctionalizations of alkenes, allowing the efficient
synthesis of nitrogen-containing heterocycles, have been
developed. 12 In recent years, our group disclosed a series of
palladium-catalyzed intramolecular oxidative amination of
alkenes,13 most of which underwent 6-endo aminocyclizations.
For instance, Pd-catalyzed aminoacetoxylation of unactivated
alkenes provided an access to the straightforward and efficient
Reported examples of the oxidative amination reaction
revealed that Pyox/Qox was a privileged ligand;5-10 however, the
ligand HPyox had a detrimental effect on the aminoacetoxylation
reaction of 1a, which was possibly attributed to the strong
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electron-donator (HPyox) to Pd(OAc)2, reducing the Lewis acidity
none
20 mol% Bu NOAc
HPyox
Me Pyox
iPrPyox
L1
4
of the palladium catalyst (eq. 1).14 To enhance the reactivity of the
palladium catalyst, we hypothesized that, if a sterically congested
substituent (R'') was introduced into the C-6 position of the Pyox
ligand, the sterically bulky R'' group makes the interaction
between the pyridinyl group and the palladium center weaker,
thus increasing the PyN-Pd bond length (Scheme 1c).6c,8b The
ligated palladium catalyst will become more electronphilic, which
50 mol% Bu NOAc
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20 mol% HOAc
50 mol% HOAc
no ligand
facilitates the activation of olefins. 15,16
.
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Reaction Time (h)
Reaction Time (h)
Table 1. Ligand screening.a,b
(a)
(b)
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Figure 1. Ligand (a) and additive effects (b) on the reaction rate.
With the optimal reaction conditions in hand, the substrate scope
of this transformation was then examined. As revealed in Table 2,
different nitrogen protecting groups were firstly surveyed.
Substrates with various sulfonyl groups were suitable for the
transformation (see SI) and the substrate 1b bearing the 2,4-
dimethylbenzenesulfonyl protecting group gave the product 2b in
75% yield with the best enantioselectivity (up to 95%) (entries 1-
2). 22 However, the reaction of the substrate 1c with the Boc
protecting group did not occur (entry 3). Then, we turned our
attention to investigating various gem-disubstituted substrates. To
our delight, the reactions of substrates bearing different alkyl
groups, such as Et (1d), n-Pr (1e) and Bn (1f), afforded the
corresponding products in good yields (68-82%) and excellent ee
values (88-93%, entries 4-6). Notably, a slightly decreased
enantioselectivity (80%) was obtained when using the substrate
1g containing two ester moieties (entry 7). The reactions of
substrates bearing gem-diaryl groups (1h-1m), into which acetic
acid was added, afforded the desired products 2h-2m in good
yields (65-86%) and excellent enantioselectivities (89-95%,
entries 8-13). Furthermore, the reaction of substrates with various
ring sizes also proceeded smoothly under the standard conditions
to deliver the spiro-piperidine products 2n-2p and 2t in good
yields (65-85%) and excellent ee values (90-92% for 2o-2p and 2t,
83% for 2n, entries 14-16, 20). Substrates bearing heterocycles,
such as cyclic ether (1q), amide (1r) and ketal (1s), were also
suitable for the reaction, giving the enantiomer-enriched products
2q-2s in good yields with good to excellent enantioselectivities
(91% for 2q-2r, 82% for 2s, entries 17-19). Importantly, the
substrate 1u bearing three allylic moieties also worked well to
yield the olefin-containing 3-acetoxyl piperidine 2u in 48% yield
with 95% ee (entry 21). It is noteworthy that a remarkable
Thrope-Ingold effect was observed in this cyclization. Otherwise,
poor regioselectivity will be obtained. For example, the reaction
of the substrate 1v without any additional substituents on the
carbon chain gave both the 6-endo and 5-exo products 2v and 3v
in 50% and 34% yields with excellent enantioselectivities (90%,
entry 22). Meanwhile, a similar result was also obtained for the
substrate 1w (entry 23). Moreover, 1,1- and 1,2-disbstituted olefin
substrates were ineffective for this enantioselective cyclization
With these hypotheses in mind, the reported ligands, MePyox and
Qox, were examined for the reaction of 1a. As shown in Table 1a,
to our delight, the two ligands exhibited much better reactivities
than HPyox and gave the desired product 2a in both 50% yields
with 83% and 85% ee, respectively. Unfortunately, further
optimizing reaction conditions failed to obtain better results and
the substrate 1a was completely consumed. Inspired by these
results, several new Pyox ligands bearing bulky substituents (R’’)
at the C-6 position were synthesized and tested. Pleasingly, the
ligands BnPyox and iPrPyox gave the aminoacetoxylated product
2a in slightly better yields (52% and 56%, respectively) with
excellent enantioselectivities (91%). Notably, when the Pyox
ligand was further modified by replacing the benzyl and isopropyl
groups with the bulkier diphenylmethyl group, ligand L1
exhibited much better reactivity and the product 2a was obtained
in 83% yield with 92% ee. Furthermore, the yield of 2a could be
further improved by adding HOAc, albeit with slightly diminished
enantioselectivities.
In order to clarify the ligand effects, the reaction rates were
monitored with various of ligands. As shown in Figure 1a,
reactions using the ligand with a bulky group (R'') exhibited a
faster rate than that using the ligand bearing a small group and the
order was listed as follows: L1 > iPrPyox > MePyox > HPyox.
Meanwhile, the X-ray structure of (R''Pyox)PdCl217 illustrated the
order of PyN-Pd(II) bond lengths as follows: (L1)PdCl2 (2.162
Å) > (MePyox)PdCl2 (2.131 Å)18 > (HPyox)PdCl2 (2.027 Å),18
which is consistent with our hypotheses in Scheme 1c. These
evidences revealed that increasing the size of the R'' group in the
R''Pyox ligand could indeed weaken the PyN-Pd(II) bond, thus
enhancing the electrophilicity of palladium catalyst for alkene
activation. Moreover, the reaction rate could be accelerated by
adding catalytic amounts of HOAc, but slowed down by adding
Bu4NOAc (Figure 1b).19 We reasoned that the dissociation of an
acetate from (L1)Pd(OAc)2 could be promoted by adding HOAc
to generate a cationic palladium/olefin complex, reported by Stahl
and coworkers, 20 which however could be diminished in the
presence of excessive acetates (Scheme 1c).21
reaction.
To demonstrate the preparative utility of this
methodology, our current reaction could be performed on a 5
mmol scale without loss in reaction efficiency (entry 8). The
absolute configuration of the products (R)-2a and (R)-2f were
unambiguously established by X-ray analysis (Figure 2).
Next, we investigated the desymmetrization of diene substrates 4a
and 4b. The reaction of 4a under standard conditions delivered the
two diastereoisomers cis-5a and trans-5a with excellent
regioselectivities (>20:1) and enantioselectivities (88% and 95%
respectively), but poor diastereoselectivities (2.5:1, Scheme 2a).
Interestingly, the desymmetrization of the substrate 4b bearing the
free hydroxyl group furnished the 6-endo product (3S,5R)-5b
in62% yield with >20:1 dr ratio and 98% ee (Scheme 2b).23 These
results indicated that the hydroxyl group is critical to the success
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Table 2. Substrate scope.a
of the desymmetrization, which might be attributed to its
coordination to the palladium catalyst.
In addition, the product 2h could be selectively deprotected under
different reaction conditions, giving the 3-hydroxy-piperidines 6
and 7 in excellent yields without the loss of ee (eq. 2).
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To gain some insight into the reaction mechanism, the
stereochemistry of the reaction was surveyed by employing the
deuterium-labeling substrate trans-1a-d1. Similar to the previous
results, a single isomer trans-2a-d1 was obtained, indicating that
the stereoselective trans-aminopalladation led to an intermediate
int-I and reductive elimination at a Pd (IV) center in int-II
produced the C-OAc bond with stereo-retention (Scheme 3a).24
Therefore, the 6-endo aminopalladation process should be an
enantioselectivity-determining step.
Scheme 3. Stereochemistry and chiral model of the reaction.
To elucidate the origins of enantioselective aminopalladation
step, the complex (L1)PdCl2 was synthesized and determined by
the X-ray crystallography (Scheme 3b). Steric repulsion between
the phenyl group in L1 and tosylamide in substrate caused an
unfavored 6-endo-aminopalladation of model B, and the favored
trans-aminopalladation of model
A
generated
a
chiral
intermediate [(R)-int-I] containing C-N bond with high
enantioselectivity, which affords the chiral product (R)-2a via a
sequential oxidation and reductive elimination (Scheme 3c).25
In conclusion, we have developed a novel enantioselective Pd-
catalyzed 6-endo aminoacetoxylation of unactivated alkenes,
providing an easy access to structurally diverse 3-acetoxylated
piperidines with excellent regio- and enantioselectivities.
Moreover, we found that introducing a sterically bulky group at
the C-6 position of Pyox is crucial to enhance the reactivity of
palladium catalysts as well as enantioselectivities for the
aminoacetoxylated products.
Figure 2. X-ray structure of the products 2a (left) and 2f (right)
ASSOCIATED CONTENT
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gliu@mail.sioc.ac.cn
Scheme 2. The desymmetric/asymmetric aminoacetoxylation.
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Notes
The authors declare no competing financial interest.
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Equal Contribution
†These authors contribute equally.
Vol 1. P63, Thieme: Stuttgart, New York, 2013. For some examples, see:
(f) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127,
7690. (g) Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am.
Chem. Soc. 2005, 127, 14586. (h) Muñiz, K. J. Am. Chem. Soc. 2007, 129,
14542. (h) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E.
J. Am. Chem. Soc., 2009, 131, 9488. (i) Sibbald, P. A.; Michael, F. E. Org.
Lett. 2009, 11, 1147.
(13) (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354. (b)
Yin, G.; Wu, T.; Liu, G. Chem. Eur. J. 2012, 18, 451. (c) Zhu, H.; Chen,
P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 1766. (d) Chen, C.; Chen, P.; Liu,
G. J. Am. Chem. Soc. 2015, 137, 15648. (e) Zhu, H.; Chen, P.; Liu, G. Org.
Lett. 2015, 17, 1485.
(14) Our initial studies on the asymmetric aminoacetoxylation were based
on our previously reported H2O2/HOAc system, in which reactions using
chiral ligands always provided the product in poor yields and low
enantioselectivities; in addition, significant side reactions took place. For
details, see the S1 in the Supporting Information.
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8
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ACKNOWLEDGMENT
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the National
Nature Science Foundation of China (Nos. 21532009, 21472217,
21790330 and 21761142010), the Science and Technology
Commission of Shanghai Municipality (Nos. 17XD1404500 and
17JC1401200), and the strategic Priority Research Program (No.
XDB20000000) and the Key Research Program of Frontier
Science (QYZDJSSW-SLH055) of the Chinese Academy of
Sciences.
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significantly decreased enantioselectivity (73% ee, 33% yield) was
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due to the extra acetate. The explanation was provided in SI, and Geier, M.
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(22) For the substrates with different protecting group (Pg), the reactions
gave the desired products as following: Pg = p-MeOC6H4SO2, 73% yield
(93% ee); Pg = p-tBu C6H4SO2, 69% yield (92% ee); Pg = p-NO2 C6H4SO2,
45% yield (81% ee); Pg = o-NO2 C6H4SO2, 9% yield (81% ee); Pg =
Cl3CCH2OSO2, 24% yield (ee nd).
(23) The reaction also yielded small amounts of 5-exo cyclization product
(10%), which was inseparable from other unidentified side products.
(24) The stereochemistry of the reaction is the same as the I(III)-mediated
alkenes, but with different mechanism (ref. 11), see the SI for details.
(25) Although we cannot exclusively rule out the possibility that the
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trans aminopalladation, we favor the mechanism proposed here.
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ACS Paragon Plus Environment

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Journal of the American Chemical Society
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ACS Paragon Plus Environment