Kinetic Resolution of Allyltriflamides through a Pd-Catalyzed C-H Functionalization with Allenes: Asymmetric Assembly of Tetrahydropyridines

Article abstract of DOI:10.1021/jacs.1c01929

Enantioenriched, six-membered azacycles are essential structural motifs in many products of pharmaceutical or agrochemical interest. Here we report a simple and practical method for enantioselective assembly of tetrahydropyridines, which is paired to a ki

Full text of DOI:10.1021/jacs.1c01929

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Kinetic Resolution of Allyltriflamides through a Pd-Catalyzed C−H
Functionalization with Allenes: Asymmetric Assembly of
Tetrahydropyridines
José Manuel González, Borja Cendón, José Luis Mascarenas, and Moisés Gulías*
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ABSTRACT: Enantioenriched, six-membered azacycles are essential structural motifs in many products of pharmaceutical or
agrochemical interest. Here we report a simple and practical method for enantioselective assembly of tetrahydropyridines, which is
paired to a kinetic resolution of α-branched allyltriflamides. The reaction consists of a formal (4+2) cycloaddition between the
allylamine derivatives and allenes and is initiated by a palladium(II)-catalyzed C−H activation process. Both the chiral allylamide
precursors and the tetrahydropyridine adducts were successfully obtained in high yields, with excellent enantioselectivity (up to 99%
ee) and selectivity values of up to 127.
Scheme 1. Kinetic Resolution of α-Branched Amines
he assembly of chiral products through the enantio-
Tselective functionalization of C−H bonds represents one
of the more relevant challenges in modern organic synthesis.1,2
In recent years, a series of brilliant strategies to carry out this
type of reactions using transition metal catalysis, and relying on
the presence of directing groups, have been described. One of
the most relevant approaches to generate asymmetry consists
of the desymmetrization of prochiral C−H bonds using
palladium catalysts and monoprotected amino acids as metal
ligands, a strategy that was pioneered by the group of Yu.3
Inspired by this research, we have recently published a
palladium-catalyzed desymmetrization of diarylmethanamine
triflamides by reaction with allenes to form chiral tetrahydro-
isoquinolines.3e Although these methodologies are appealing,
they require the presence of symmetric groups in the molecule,
which represents a significant restriction in terms of the
structural variability that can be achieved. Furthermore, the
limitation to aromatic substrates reduces possibilities for
subsequent synthetic manipulations.
Alternatively, enantioselective reactions can also be
performed using kinetic resolutions (KRs). These strategies
present the intrinsic limitation of yield, but they enable the
recovery of the precursors in an enantioselective manner and
are very attractive in terms of scope.4 In this context, the group
of Yu has recently reported a palladium-catalyzed kinetic
resolution of α-branched benzyl amine derivatives via C−H
iodination or cross-coupling reactions.5a,b They also reported
the kinetic resolution of racemic alkyltriflamides via cross-
coupling reactions with boronates (Scheme 1A).5c Remark-
ably, related asymmetric reactions using allylamines, or
involving the activation of any type of alkenyl C−H bond,
have never been described. This scarcity might be associated
with the notion that the alkenes could engage in secondary
reactions or the perception that attaining effective chiral
discrimination might be especially challenging in comparison
with reactions involving aromatic Csp2−H bonds (Scheme
Received: February 18, 2021
Published: March 2, 2021
https://dx.doi.org/10.1021/jacs.1c01929
J. Am. Chem. Soc. 2021, 143, 3747−3752
© 2021 American Chemical Society
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a
Table 1. Optimization of Conditions
Scheme 2. Scope of the Formal (4+2) Cycloaddition of
Allyltriflamides and Allenes
a
c
ee (%)
a
b
d
entry deviation from above conditions
C
(%) 3aa
49
45
1a
s
1
none
94
82
88
58
58
54
50
50
20
48
60
94
86
92
84
86
78
80
44
72
90
66
52
99
84
98
70
92
36
22
54
52
8
100
20
26
18
10
14
6
9
2
4
7
54
14
25
15
23
20
40
3
2
3
4
Boc-Val-NHOMe
Boc-Leu-NHOMe
Boc-Phe-OH
37
63
59
64
58
65
64
31
47
36
9
5
Boc-Val-OH
6
Boc-Leu-OH
7
8
Boc-t-Leu-OH
Boc-Ile-OH
9
TcBoc-Phe-OH
Ac-Phe-OH
10
11
12
13
14
15
16
17
18
19
20
2,6-F,F-Bz-Phe-OH
0,5 equiv of Cu(OAc)2·H2O
AgOAc as oxidant
Ag2CO3 as oxidant
THF as solvent
DCE as solvent
i-PrOH as solvent
t-AmylOH as solvent
no base
6
6
25
39
51
55
4
28
56
80
99
2
no DMSO
12
10
7
a
Conditions: rac-1a (0.1 mmol), 2a (0.1 mmol), Pd(OAc)2 (10 mol
%), ligand (40 mol%), Cu(OAc)2·H2O (2 equiv), Cs2CO3 (1.5
equiv), DMSO (15 equiv), PhCH3 (1.2 mL), air, 70 °C, 24h.
b
c
Calculated conversion, C = eeSM/(eeSM + eePR). Enantiomeric excess
(ee) was determined by chiral HPLC analysis of the reaction crude.
Selectivity (s) = ln[(1 − C)(1 − eeSM)]/ln[(1 − C)(1 + eeSM)].
a
Conditions: rac-1a (0.1 mmol), 2 (0.1 mmol), Pd(OAc)2 (10 mol
d
%), ligand (40 mol%), Cu(OAc)2·H2O (2 equiv), Cs2CO3 (1.5
b
equiv), DMSO (15 equiv), PhCH3 (1.2 mL), air, 70 °C, 24 h. 75 °C.
c
d
80 °C. Only the major regioisomer is depicted (see Supporting
1C).6 However, the catalytic asymmetric synthesis of alkene-
containing products is of high interest owing to the elaboration
possibilities offered by the presence of double bonds.
Information for more details).
Herein we report the discovery of a practical and efficient
methodology for the kinetic resolution of α-branched allyl-
triflamides based on a Pd-catalyzed C−H activation process
(Scheme 1B). Very importantly, this resolution is performed
using highly substituted alkenes, which are traditionally
difficult substrates for C−H functionalization reactions.
Furthermore, the activation is coupled to a formal cyclo-
addition rather than to a simple C−H functionalization,
therefore allowing a rapid increase in structural complexity, in
this case, to give enantioenriched tetrahydropyridine skeletons.
Needless to say, tetrahydropyridine and related piperidine
scaffolds form the basic heterocyclic core of many chiral
natural products and bioactive structures (Scheme 1D).
Therefore, the development of practical, direct methods for
the enantioselective synthesis of these types of products is of
major interest.7 Importantly, our reaction also provides a direct
access to enantioenriched allylamine derivatives, which are very
useful for the construction of a variety of optically active
nitrogenated products.
DMSO (10:1), in the presence of 10 mol% of palladium
acetate, 2 equiv of copper acetate, 1.5 equiv of cesium
carbonate, and 40 mol% Boc-L-Phe-NHOMe,5e provides the
desired cycloadduct 3aa with an excellent 94% ee (49%
conversion after 24 h) (Table 1, entry 1). The remaining
starting material was isolated with a 90% ee. Decreasing the
amount of ligand favors the conversion rate but affects the
enantiomeric excess of the product. Not surprisingly, when
Boc-D-Phe-NHOMe was used as ligand, the opposite
enantiomers were obtained with the same enantioselectivity.
Changing the ligand to other diprotected (entries 2 and 3) or
monoprotected amino acids (entries 4−8) resulted in lower
conversions and poorer ee’s. It should be noted that, although
the use of Boc-phenylalanine as ligand led to a moderate
enantioselectivity (58% ee), it made possible to recover the
starting amide with 99% enantioselectivity (entry 4). Indeed,
this ligand gave also good results for some of the other
substrates tested (see below, Scheme 3). Significant decreases
in conversion and enantioselectivity were observed when the
tert-butyloxycarbonyl protecting group of the amino acid was
replaced by an acetyl, trichloro-tert-butyloxycarbonyl, or
difluorobenzoyl group (entries 9−11). Moreover, we found
that, when using less copper acetate, or replacing it with other
We started our research by surveying conditions that could
enable the annulation of racemic allyltriflamide 1a with the
commercially available allene 2a.3g,8 After an extensive
screening, we found that heating this mixture in toluene/
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Communication
a b
,
Scheme 3. Scope of the Formal (4+2) Cycloaddition of Allyltriflamides and Allenes
a
Conditions: rac-1 (0.1 mmol), 2a (0.1 mmol), Pd(OAc)2 (10 mol%), ligand (40 mol%), Cu(OAc)2·H2O (2 equiv), Cs2CO3 (1.5 equiv), DMSO
b
c
d
e
(15 equiv), PhCH3 (1.2 mL), air, 70 °C, 24 h. Hydrogens of crystal structures omitted for clarity. 75 °C. 80 °C. Boc-Phe-OH as ligand, 40 °C.
a
Scheme 4. Derivatization of the Chiral Products
Scheme 5. Derivatization of the Chiral Allylamide Starting
Materials
a
a
Conditions: (a) H2, Pd/C 10 mol%, AcOEt, rt, 24 h. (b) RuCl3 15
mol%, 3.5 equiv NaIO4, H2O/CH3CN/AcOEt 0.75:1:1, rt, 0.5 h. (c)
Red-Al (10 equiv), toluene, 50 °C, 20 h.
a
Conditions: (a) RuCl3 3 mo%, NaIO4, CCl4/CH3CN/H2O, 1:1:1.6,
rt. (b) K2CO3, propargyl bromide, 60 °C. (c) 7.5 mol% [IrCp*Cl2],
dichloroethane, reflux. (d) Optimized conditions are shown in Table
1 using Boc-D-Phe-NHOMe.
oxidants, such as silver acetate or silver carbonate, the
conversions and enantioselectivities were poorer (entries 12−
14). The use of solvents other than toluene, such as THF,
DCE, or isopropanol, clearly gave worse results in both
conversion and selectivity (entries 15−17), while with tert-
amyl alcohol we obtained an ee of 80% for the product and an
excellent 99% ee for the recovered starting material (entry 18).
We also found that, without base or DMSO, the reaction
hardly progresses (entries 19 and 20), and the enantio-
selectivity is greatly diminished.
The scope of the reaction with respect to the allene
component was studied using the above optimized conditions,
albeit with small adjustments in temperature, and the results
are summarized in Scheme 2. Therefore, when the allyl-
triflamide was tested with a different 1,1-disubstituted allene
(5-vinylidenenonane), it resulted in the formation of the
cycloadduct 3ba with a 90% ee, while the starting amide was
recovered with 82% ee (selectivity factor of 48).
The reaction also works very nicely with monosubstituted
allenes such as commercially available propa-1,2-dien-1-
ylcyclohexane (2c), the silyl-protected buta-2,3-dien-1-ol 2d,
or allenes containing acetate (2f) and phthalimide (2e)
functional groups, leading to enantioselectivities up to 94%
in the products and over 96% in the corresponding starting
materials. In contrast, buta-2,3-dien-1-ol failed to participate in
the annulation, and the reaction provided a complex mixture of
products. In the case of allenes with aromatic substituents (2g
and 2h), we observed very good enantiomeric excess in the
products (up to 94% ee) but more modest enantioselectivities
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for the starting materials (62−78% ee). Remarkably, trisub-
stituted allenes (2i) can also work with only a slight erosion of
the enantioselectivity of the product (86% ee). In this reaction
we also observed the formation of a small proportion of a
different regioisomer.
Gratifyingly, in most of the cases the products were formed
with high E:Z diastereoselectivity. The preferred formation of
the Z-isomer with monosubstituted allenes is likely a
consequence of steric effects associated to the interaction of
the phenyl group of the alkene with the substituent of the
allene.
allyltriflamides can be easily manipulated owing to the
presence of the double bond. For example, compound (S)-
1a (99% ee) can be converted into the chiral keto amino
product 7 under oxidative conditions (Scheme 5). Amine (S)-
1a can be also alkylated with propargyl bromide, and the
resulting enyne can be cyclized to the interesting piperidine 9
using iridium catalysis. This optically active product (99% ee),
obtained as a single diastereoisomer, exhibits up to four
stereocenters.9 Finally, we also demonstrated that enantioen-
riched compounds like (S)-1a can participate in the (4+2)
annulation reaction with allene 2a under standard conditions,
using the D-amino acid ligand derivative, to give the
corresponding enantiomer (S)-3aa (88% yield), which exhibit
the same enantiomeric excess as the starting material.
Overall, we have discovered a new enantioselective
annulation process based on a Pd(II)-catalyzed reaction of
allylamine derivatives and allenes and relying on an asymmetric
C−H activation step. The reaction allows very efficient kinetic
resolutions and provides an unprecedented access to a broad
range of enantioenriched piperidines and highly substituted
allyl amines. These enantioenriched products can be easily
converted into several appealing azacycles and different
nitrogenated derivatives. The methodology provides a power-
ful atom- and step-economical approach to this type of
optically active products
The optimized conditions were also used for further
evaluating the scope of the reaction with regard to the
allyltriflamide precursors. Pleasingly, we found that allylamine
derivatives with other groups at the α-position, including
methyl, butyl, and isobutyl, are well tolerated. In all cases the
reactions took place with good yields and excellent enantio-
selectivities (Scheme 3, 1b−1d, up to 94% ee for products and
starting materials). The crystallization of compounds 3ba and
1b allowed determination of the absolute configuration R and
S, respectively, through X-ray crystallographic analysis
(Scheme 3, top right). [Their crystal structure data are
deposited to the CCDC.]
We also analyzed the reactivity of the precursors with other
substituents at the terminal and internal positions of the alkene
moiety. As illustrated with the formation of products 3ea−3ia
and enantioenriched precursors 1e−1i, enantioselectivities up
to 96% and almost enantiopure allylsulfonamides were
obtained (selectivities up to 127). Even reactants with the
alkene embedded in a cyclohexyl ring, such as 1h and 1i, were
effective substrates, generating chiral bicyclic structures.
Substrates bearing terminal alkenes (1j and 1k) also led to
good results, although in this case with slightly lower
conversions and enantioselectivities, perhaps because there is
less steric encumbrance (3ja and 3ka, up to 90% ee).
Remarkably, homoallylamide substrates like 1l and 1m, in
which the chiral center is in the β-position relative to the
amine, also participated in the cycloaddition. In this case, as for
the formation of 3ka, N-Boc-phenylalanine was a more suitable
ligand. Of course, different allylsulfonamides can be combined
with different allenes, and therefore a great variety of products
can be formed with similar levels of enantioselectivity (see, for
instance, 3hc, with 90% ee). As can be deduced from the
reaction conditions (Scheme 3), the optimal temperature
depends on the type of precursors, likely because of steric
factors.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01929.
■
sı
Experimental details and characterization data for all
new compounds (PDF)
Accession Codes
CCDC 2043705 and 2043710 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Moisés Gulías − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain; orcid.org/0000-0001-8093-2454;
Email: moises.gulias@usc.es
The presence of unsaturations in the cyclic products
provides for performing divergent manipulations. For instance,
treatment of 3ac with hydrogen gas in the presence of
palladium over carbon led to product 4 in an excellent 91%
yield (Scheme 4). Therefore, the hydrogenation is accom-
panied by an isomerization process which makes it possible to
create a new stereocenter in a fully diastereoselective manner.
The product 3ac can also react selectively with ruthenium
trichloride to give, in 66% yield, the tetrahydropyridine 5,
exhibiting an α,β-unsaturated motif. Importantly, the triflyl
group of the amide can be successfully removed using Red-Al
in quantitative yield. In all cases the enantiopurity of the
product was intact.
Authors
José Manuel González − Centro Singular de Investigación en
Química Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Borja Cendón − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain
As commented before, one of the advantages of this type of
kinetic resolution strategies is that the recovered precursor
might also be an invaluable platform to produce different types
of enantioenriched derivatives. In our case, the chiral
José Luis Mascarenas − Centro Singular de Investigación en
̃
Química Biolóxica e Materiais Moleculares (CIQUS) and
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Diarylmethylamines with Organoborons. Angew. Chem., Int. Ed. 2015,
54, 11143−11146. (e) Han, H.; Zhang, T.; Yang, S.-D.; Lan, Y.; Xia,
J.-B. Palladium-Catalyzed Enantioselective C−H Aminocarbonyla-
tion: Synthesis of Chiral Isoquinolinones. Org. Lett. 2019, 21, 1749−
1754. (f) Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J. Palladium-
Catalyzed Enantioselective C−H Activation of Aliphatic Amines
Using Chiral Anionic BINOL-Phosphoric Acid Ligands. J. Am. Chem.
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain; orcid.org/0000-0002-7789-700X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01929
Soc. 2017, 139, 1412−1415. (g) Vidal, X.; Mascarenas, J. L.; Gulías,
̃
Notes
M. Palladium-Catalyzed, Enantioselective Formal Cycloaddition
between Benzyltriflamides and Allenes: Straightforward Access to
Enantioenriched Isoquinolines. J. Am. Chem. Soc. 2019, 141, 1862−
1866.
(4) For recent examples of kinetic resolutions in metal catalysis, see:
(a) Xiao, K.-J.; Chu, L.; Yu, J.-Q. Enantioselective C−H Olefination
of α-Hydroxy and α-Amino Phenylacetic Acids by Kinetic Resolution.
Angew. Chem., Int. Ed. 2016, 55, 2856−2860. (b) Brauns, M.; Cramer,
N. Efficient Kinetic Resolution of Sulfur-Stereogenic Sulfoximines by
Exploiting CpXRhIII-Catalyzed C−H Functionalization. Angew.
Chem., Int. Ed. 2019, 58, 8902−8906.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has received financial support from Spanish grants
(SAF2016-76689-R, CTQ2016-77047-P, PID2019-108624RB-
I00, PID2019-110385GB-I00, and FPI fellowship to B.C.), the
Consellería de Cultura, Educación e Ordenación Universitaria
(ED431C 2017/19, 2015-CP082 and Centro Singular de
Investigación de Galicia accreditation 2019-2022, ED431G
2019/03 and J. M. G fellowship), the European Regional
Development Fund (ERDF), and the European Research
Council (Advanced Grant No. 340055). The orfeo-cinqa
network CTQ2016-81797-REDC is also kindly acknowledged.
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