Palladium(II)-Catalyzed Enantioselective Azidation of Unactivated Alkenes

Article abstract of DOI:10.1002/anie.202006757

The first Pd-catalyzed enantioselective azidation of unactivated alkenes has been established by using readily accessible 1-azido-1,2-benziodoxol-3(1H)-one (ABX) as an azidating reagent, which affords a wide variety of structurally diverse 3-N₃

Full text of DOI:10.1002/anie.202006757

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Accepted Article
Title: Palladium(II)-Catalyzed Enantioselective Azidation of Unactivated
Alkenes
Authors: Guosheng Liu, Xiaonan Li, Chuanqi Hou, Pinhong Chen, and
Xiaoxu Qi
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Palladium(II)-Catalyzed Enantioselective Azidation of Unactivated
Alkenes **
Xiaonan Li, a Xiaoxu Qi,a Chuanqi Hou,a Pinhong Chen,*a and Guosheng Liu*a,b
In memory of Professor Kilian Muñiz
Abstract: The first Pd-catalyzed enantioselective azidation of
unactivated alkenes has been established by using readily
accessible 1-azido-1,2-benziodoxol-3(1H)-one (ABX) as an azidating
reagent, which affords a wide variety of structurally diverse 3-N3-
substituted
piperidines
in
good
yields
with
excellent
enantioselectivities. The reaction features good functional group
compatibility and mild reaction conditions. Notably, both an
electrophilic azidating reagent and the sterically bulky chiral
pyridinyl-oxazoline (Pyox) ligand are crucial to the successful
reaction.
Optically pure 3-aminopiperidines widely exist in natural
alkaloids1 (e.g., slaframine)2 and drugs (e.g., ibrutinib, nemonoxacin
and linagliptin)3 as shown in Figure 1, which have been extensively
applied to treat B cell cancers, inhibit DNA gyrase, control blood sugar
and so on. Therefore, the exploration of efficient methods for their
synthesis has received much attention over the last several decades in
organic synthesis, while a multi-step process is often required.4 So far,
an efficient tool for their asymmetric synthesis still remains elusive.5
6
Owing to the diverse transformations of organic azides, 3-
Scheme 1. Asymmetric azidation of unactivated alkenes.
aminopiperidines can be easily prepared from the corresponding 3-
azidopiperidines via a reduction process (Figure 1). In this regard,
asymmetric azidation reaction represents an interesting approach for
their synthesis. Thus, the development of the asymmetric azidation is
highly demand.
Nevertheless, asymmetric azidations are scarcely reported, and mainly
rely on asymmetric Michael addition reaction of deficient alkenes by
using organocatalysts (Jacobsen9a,b and Miller8c-d) or chiral Lewis acids
(Feng).10 So far, the studies on the asymmetric azidation of electro-
neutral or rich alkenes are extremely limited. There is only one elegant
case reported by Burns and coworkers, where the enantioselective
haloazidation of allylic alcohols was accomplished by a chiral Schiff-
based titanium complex.11
Transition-metal catalysis has been regarded as a powerful tool in
asymmetric synthesis. Compared to a series of asymmetric reactions,
transition-metal catalyzed asymmetric azidation is significantly
retarded, which is not surprising considering the following issues: (1)
although a series of azidation of unactivated alkenes have been
reported via radical pathways, second or tertiary sp3 C-N3 bonds were
generally forged through a radical atom transfer process, making
asymmetric azidation extremely challenging (Scheme 1a, i);12 (2) as an
alternative pathway, reductive elimination of organometallic azides
species, such as C-PdII(L)2N3, is a problematic step, leading to an
unsuccessful catalytic azidation (Scheme 1a, ii);13 and (3) owing to a
strong coordination ability, excess amount of azide anion could
promote chiral ligand dissociation from metal centers,14 retarding the
asymmetric azidation.
Figure 1. Representative drugs containing 3-aminopiperidines.
Optically pure organic azides have been recognized as an
important synthon in organic synthesis.5b-c Thus, much efforts have
been paid to develop new methods for their synthesis, such as
asymmetric electrophilic azidation of carbonyl compounds.7 Recently,
azidation of alkenes represents one of the most efficient methods.8
As our ongoing research interests in difunctionalizations of
alkenes, we recently disclosed several palladium-catalyzed
intramolecular amination of alkenes proceeding through 6-endo
cyclization, giving various 3-substituted piperidines;15 meanwhile, an
*a)
X. Li, Dr. X. Qi, C. Hou, Dr. P. Chen, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry, and Shanghai
Hongkong Joint Laboratory in Chemical Synthesis, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences
asymmetric version has also been achieved by employing sterically
16
hindered pyridinyl-oxazoline (Pyox) ligand.
Notably, for these
reactions, the related C-heteroatom bonds were generated by the
reductive elimination of high-valent alkyl-Pd(IV) species. Inspired by
these studies, we reasoned that, if an electrophilic azidating reagent can
be used as an azidating source to generate high-valent alkyl-Pd(IV)-N3
species, the efficient catalytic azidation of unactivated alkenes by
alkyl-N3 bond reductive elimination might be feasible (Scheme 1b).17
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn, pinhongchen@mail.sioc.ac.cn
Prof. Dr. G. Liu
Chang-Kung Chuang Institute, East China Normal University
3663 North Zhongshan Road, Shanghai 200062, (China)
b)
*** Supporting information for this article is given via a link at the end of
the document.
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Moreover, owing to the lack of excess amount of azide anion, the
asymmetric azidation might be also expected by introducing chiral
aminooxygenation reaction is difficult to be inhibited completely, and
the reactions afforded C-O bond-forming side product in 5-16% yields
(entries 2-7, for details see SI).
ligands. Herein, we communicate
a
novel Pd-catalyzed
lxn-ligand
Std proton
enantioselective aminoazidation of alkenes proceeding through the 6-
endo cyclization, which provides an easy access to a wide array of
structurally diverse 3-azidopiperidines in good yields with excellent
enantioselectivities (Scheme 1c).18
5
lxn-Metal-1-5
4
lxn-Metal-1-2
3
To test the above-mentioned hypothesis, in the presence of chiral
Pd/Pyox catalysts, the reaction of 1a was selected as the model reaction,
and electrophilic reagent 2a19 was used as an azidating source. As
shown in Table 1, the initial screening of various Pyox ligands revealed
that the chiral Pyox L1 only gave trace desired product 3a with low
enantioselectivities (entry 1). Introducing substituents into the chiral
Pyox ligands at the C6 position proved to be beneficial for both
reaction reactivity and enantioselectivity, and the order is L5 > L4 >
L3 > L2 >> L1 (entries 2-5). Among them, the ligand L5 with the
sterically bulkiest substituent was the best to give 3a in 80% yield with
98% ee. The ligand L6 bearing two phenyl groups on the oxazoline
ring exhibited similar reactivities (entry 6). Decreasing the palladium
catalyst loading to 5 mol% resulted in 3a in 70% yield with 97% ee,
while 2.5 mol% palladium catalyst loading led to a dramatically
decreased yield (24%) with similar enantioselectivity (95% ee, entries
7-8). Moreover, the palladium catalyst exhibited poor reactivity in the
absence of Pyox ligands (entry 9).
lxn-Metal-1-1
2
lxn-Metal
1
6.1
6.0
5.9
5.8
5.7
5.6
5.5
5.4
5.3
5.2
5.1
f1(ppm)
5.0
4.9
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
Figure 2. The reaction of the palladium complex with azide anion.
With the optimal reaction conditions in hand, the substrate scope
of this transformation was then examined. Substrates with different
protecting groups on the nitrogen atom were firstly surveyed, and all
these substrates were suitable for the reaction to give the desired
products in good yields and excellent enantioselectivities (> 90% ee),
except the reaction of the substrate protected by the 2,4-DMPs or Boc
group (in 9% yield or no reaction occurred, for details see SI). Then,
we turned our attention to investigating various gem-disubstituted
substrates. To our delight, reactions of substrates bearing different
alkyl groups, such as Me (1a), n-Pr (1b) and Bn (1d), afforded the
corresponding products 3a-3d in good yields (78-81%) with excellent
enantioselectivities (95-98% ee). Substrate 1c bearing gem-diester
Table 1. Optimization of the Reaction Conditions.a
Table 2. Substrate Scope.a,b
Compared to 2a, ether-type azidating reagent 2b was less effective
(entry 10). Moreover, when 2a was replaced with nucleophilic TMSN3
and PhI(OAc)2 (PIDA), the reaction failed to deliver product 3a (entry
11). Adding extraneous Bu4NN3 to the standard conditions also
completely inhibited the reaction (entry 12 ). In addition, when two or
more equivalents of external Bu4NN3 was added into a solution of
(L5)PdCl2, Pyox L5 was completely dissociated from the palladium
center (Fig. 2), thereby inhibiting the reaction (entry 10, table 1). These
observations indicated that the palladium catalyst was indeed
deactivated by azide anion, and the electrophilic azide reagent was
essential for the asymmetric azidation. Notably, the side
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moieties (AcOCH2) yielded the product 3c with good enantioselectivity
(89% ee), albeit in moderate yield (45%). For the reaction of substrates
(1e-1f) bearing gem-diaryl groups, quinolinyl-oxazoline (Quox) ligand
L7 exhibited better reactivities than L6, giving products 3e-3f in
excellent enantioselectivities (94-96% ee) and moderate yields.
Moreover, substrates with 3~7 carbon rings also reacted smoothly to
deliver the spiro piperidine products 3g-3k in good yields (60-82%)
and excellent enantioselectivities (94-98% ee); notably, substrate
bearing cyclic alkenes (1l) and spiro heteroatom-cycle substrates (1m-
1n) were also suitable for the reaction to give the products 3l-3n in 68-
78% yields with 95-99% ee. To clarify the Thrope–Ingold effect, the
reaction of non-substituted substrate 1o was investigated, and ligand
L8 provided the desired product 3o in 63% yield with 94% ee. The
absolute configuration of 3d and 3j were unambiguously confirmed by
X-ray analysis.
To examine the regioselectivity, substrates bearing three olefinic
moieties were tested under the standard conditions, the reactions
favorably yielded the six-membered products 3q-3r exclusively in
good yields (63-74%) with 89-98% ee. Moreover, the aniline substrate
1s also was compatible with the reaction conditions to give
tetrahydroquinoline product 3s in 42% yield with 87% ee. For mono-
substituted substrates, as expected, these reactions proceeded smoothly
to give the corresponding products 3t-3v as two diastereoisomers in
good yields (73-91%) with excellent enantioselectivities (70-99% ee),
and the two diastereoisomers could be easily separated by column
chromatography.
Scheme 3. Mechanistic studies of aminoazidation of alkenes.
To elucidate the different selectivities for the desymmetric
reactions in Scheme 2a-2c, the stereochemistry was initially discussed.
As shown in Scheme 3a, the reaction of trans-1a-d1 provided the single
product trans-(R)-3a-d1 with excellent diastereo- and enantioselectivity,
indicating that the reaction was initiated by an asymmetric trans-
aminopalladation to give an enantioenriched intermediate (R)-int-I,
followed by sequential oxidation and direct reductive elimination of
Pd(IV) species (R)-int-I, yielding the predominated azidation (C-N3)
product, along with a small amount of oxygenation (ArCO2-C bond)
product. Meanwhile, it is noteworthy that the X-ray structure for 3w
showed that all the allylic, azidyl and arylsulfonyl groups were
preferentially located at the equatorial orientation. Based on these
observations, we assumed that two intermediates int-II-A and int-II-B
would be involved in the desymmetric/asymmetric trans-
aminopalladation of symmetric dienes 1w-1aa. Given the 1,3-di axial
interaction, the large group in int-II is more favored in equatorial
position than the small group. The steric hindrance of hydrogen (1w),
hydroxyl (1x) and fluoro (1y) is much smaller than that of allyl group,
int-II-A with the allylic group at the equatorial position is much more
stable than int-II-B with the allylic at the axial orientation. Thus, the
desymmetric/asymmetric reaction of 1w-1y proceeded via int-II-A
exclusively, leading to the formation of products cis-3w, trans-3y and
trans-3y selectively. In contrast, the steric hindrance of ethyl and
allylic groups in diene 1z is similar to each other, and the reaction
generated both the int-II-A and int-II-B species, resulting in the
mixture products cis-3z and trans-3z; while the phenyl group is larger
than the allylic group, the int-II-B is more favored to form int-II,
leading to the major product trans-3aa (Scheme 3b).
Scheme 2. Desymmetric/asymmetric aminoazidation of alkenes.
Next, we investigated the desymmetric/asymmetric reactions of
diene substrates. Interestingly, the reaction of 1w provided the single
isomer cis-3w with excellent enantioselectivity (97% ee, Scheme 2a).
The absolute configuration of the products (3R,5R)-3w was determined
by the X-ray analysis. Moreover, for the substrates with small R groups,
such F and OH, the desymmetric reactions of dienes 1x-1y proceeded
very well to provide the desired products trans-3x and trans-3y as a
single isomer in good yields with excellent diastereo- (dr > 20:1) and
enantioselectivities (96-97%, Scheme 2b). For substrates with a larger
R groups, the reactions gave two isomers. For instance, the reaction of
1z with the ethyl group (R) provided the two isomers cis-3z and trans-
3z with excellent enantioselectivities (98% ee) in 1:1 diastereoselective
ratio; however, the reaction of 1aa with the phenyl group (R) afforded
a major isomeric product trans-3aa with excellent enantioselectivities
(95% ee) and 5:1 diastereoselective ratio (Scheme 2c).
More importantly, owing to both allylic and azidyl groups at the
equatorial orientation, the products 3p and 3r could be easily converted
to the 3,6-diazabicyclo[3.3.1]nonane derivatives 4a and 4b in good
yields, which involves a tricycle intermediate int-4, followed by a
20
sequential nitrogen elimination (Scheme 4a).
In addition, the
asymmetric azidation reaction of 1a could be conducted on a gram
scale to give product 3a in slightly lower yield (72%) without any
erosion in enantiomeric excess (98% ee, Scheme 4b), which could be
efficiently transformed into alkyl amine 5 and amides 6-7. Moreover,
the enantiomerically enriched 3a could also be converted to the related
N-aniline product 8 in good yields. Notably, the azidyl group could
undergo sequential reduction/condensation with CS2 to provide product
9 in 65% yield with 98% ee. Lastly, triazole 10 was obtained in 76%
yield with 96% ee through a click reaction of 3a with an aryl alkyne.
These examples demonstrated the applicability of this aminoazidation
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reaction for the synthesis of optically pure 3-amino-piperidines as a
synthon.
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Reaction conditions: (a) In, NaI, allyl bromide, r.t. (b) Pd/C (10% wt),
H2, Boc2O, EtOAc, r.t. (c) P(OMe)3, toluene, 80°C. (d) Pd/C (10% wt),
H2, CuI, 2-acetylcyclohexanone, Cs2CO3, 4-iodofluorobenzene, DMF,
r.t. (e) PPh3, toluene, 50°C, then CS2, 50 °C. (f) CuI, phenylacetyene,
THF, r.t.
In conclusion, we have developed the first enantioselective Pd(II)-
catalyzed intramolecular aminoazidation of unactivated alkenes, which
provides an easy access to a variety of enantio-enriched 3-azido
piperidines in good to excellent yields with excellent
enantioselectivities. In addition, employing Pyox ligand with a larger
sterically bulky group is critical to the success of this process. Our
current protocol represents the first example of the enantioselective
alkyl C-N3 bond formation via reductive elimination at a transition-
metal center. Moreover, employing the electrophilic azidating reagent
makes this catalytic amino-azidation reaction of alkenes particularly
useful.
Acknowledgements
13 F. M. Miloserdov, C. L. McMullin, M. M. Belmonte, J. Benet-Buchholz,
V. I. Bakhmutov, S. A. Macgregor, V. V. Grushin, Organometallics 2014,
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We are grateful for financial support from the National Nature Science
Foundation of China (Nos. 21532009, 21971255, 21821002, 21790330
and 21761142010), the Science and Technology Commission of
Shanghai Municipality (Nos. 19590750400 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.
16 (a) X. Qi, C. Chen, C. Hou, L. Fu, P. Chen, G. Liu, J. Am. Chem. Soc.
2018, 140, 7415; (b) C. Chen, P. M. Pfluger, P. Chen, G. Liu, Angew. Chem.
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Conflict of interest
17 The sp2 C-N3 bond formation via reductive elimination of Pd(IV)
species was proposed by Jiao and coworkers. For details, see: Q. Zheng, P.
Feng, Y. Liang, N. Jiao, Org. Lett. 2013, 15, 4262.
The authors declare no competing financial interest.
Keywords: Asymmetric azidation • Palladium-Catalyzed • Oxidative
amination • Unactivated alkenes • Azidopiperidines
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18 Racemic intramolecular aminoazidation of alkenes via radical pathways
was reported, however, which afforded achiral exo-cyclization products,
see: K. Shen, Q. Wang, J. Am. Chem. Soc. 2017, 139, 13110.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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X. Li, X. Qi, C. Hou, P. Chen, G. Liu*
Page No. – Page No.
Palladium(II)-Catalyzed
Enantioselective Azidation of
Unactivated Alkenes
The first Pd-catalyzed enantioselective intramolecular aminoazidation of unactivated alkenes using readily accessible 1-azido-
1,2-benziodoxol-3(1H)-one (ABX) as an azidating source has been established herein, which affords a wide variety of
structurally diverse 3-N3-substituted piperidines in good yields with excellent enantioselectivities. The reaction features good
functional group compatibility and mild reaction conditions. Notably, the employment of both an electrophilic azidating reagent
and the sterically bulky chiral pyridinyl-oxazoline (Pyox) ligand is crucial to the successful reaction.
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