Overcoming the Deallylation Problem: Palladium(II)-Catalyzed Chemo-, Regio-, and Stereoselective Allylic Oxidation of Aryl Allyl Ether, Amine, and Amino Acids

Article abstract of DOI:10.1021/acs.orglett.0c02465

We report herein a Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic C-H acetoxylation of aryl allyl ether, amine, and amino acids with the retention of a labile allyl moiety. Mechanistically, the reaction proceeds through a distinct double-bond isomerization from the allylic to the vinylic position followed by intramolecular carboxypalladation and the β-hydride elimination pathway. For the first time, C-H oxidation of N-allyl-protected amino acids to furnish five-membered heterocycles through 1,3-syn-addition is established with excellent diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.0c02465

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Letter
Overcoming the Deallylation Problem: Palladium(II)-Catalyzed
Chemo‑, Regio‑, and Stereoselective Allylic Oxidation of Aryl Allyl
Ether, Amine, and Amino Acids
Kartic Manna, Hasina Mamataj Begam, Krishanu Samanta, and Ranjan Jana*
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ABSTRACT: We report herein a Pd(II)/bis-sulfoxide-catalyzed intra-
molecular allylic C−H acetoxylation of aryl allyl ether, amine, and amino
acids with the retention of a labile allyl moiety. Mechanistically, the
reaction proceeds through a distinct double-bond isomerization from the
allylic to the vinylic position followed by intramolecular carboxypalladation
and the β-hydride elimination pathway. For the first time, C−H oxidation
of N-allyl-protected amino acids to furnish five-membered heterocycles
through 1,3-syn-addition is established with excellent diastereoselectivity.
he palladium-catalyzed Tsuji−Trost reaction with
with the retention of this leaving group is extremely rare.20
Recently, the Gong group reported an intermolecular
asymmetric allylic C−H functionalization of benzyl allyl
ether only (Scheme 1b).21 However, the palladium-catalyzed
extremely labile allylic C−H functionalization of phenolic,
aniline, or aliphatic amines is unknown. Furthermore, the
underlying mechanism of allylic C−H functionalization is
highly ambiguous due to the competitive allylic C−H bond
cleavage/π-allyl Pd complex formation versus olefin isomer-
ization/nucleopalladation/β-hydride elimination pathways
(Scheme 2d).22 However, the latter olefin isomerization relay
is extremely fascinating for the site-selective remote function-
alization.23 For the first time, we have disclosed a Pd(II)/bis-
sulfoxide-catalyzed intramolecular allylic C−H acetoxylation of
salicyclic and anthranilic acid derivatives with the retention of
an extremely labile allyl group, which proceeds through the
allylic to vinylic olefin isomerization/carboxypalladation/β-
hydride elimination pathway (Scheme 1c). Remarkably, a
highly diastereoselective intramolecular cyclization of N-allyl-
protected amino acids through 1,3-syn-addition is also
unveiled. The oxidation takes place chemo-, regio-, and
stereoselectively at the allylic α-proton to furnish six- or five-
T
activated precursors such as allyl acetate, carbonate,
hydroxyl, and halides has been extensively explored for allylic
alkylation.1 In the last decades, the direct allylic C−H
functionalization of simple alkenes with the retention of a
double bond for further synthetic manipulations has stream-
lined this transformation.2 Mechanistically, the crucial π-allyl
Pd complex is formed through concerted metalation
deprotonation (CMD) or concerted proton and two-electron
transfer for a subsequent cross-coupling reaction.3 Because of
their intriguing mechanistic aspects, other metals such as
iridium,4 rhodium,5 and copper6 and transition-metal-free
approaches such as the catalytic heteroene reaction using a
chalcogen oxidant7 and the sodium amide-catalyzed generation
of nucleophilic allyl species8 have been explored. Still, the
development of a highly chemo-, regio-, and stereoselective
allylic C−H bond functionalization is a formidable challenge.
In this vein, the White group has made a significant
contribution to inter- and intramolecular allylic C−H
functionalization by employing a Pd(II)/sulfoxide-benzoqui-
none serial ligand catalyst.9 Subsequently, sulfoxide-oxazo-
line,10 phosphoric acid,11 phosphoramidite,12 4,5-diazafluoren-
9-one,13 and even dimethyl sulfoxide14 were proved to be
effective ligands for allylic C−H functionalization.
Conventionally, an allyl moiety attached to a heteroatom
such as oxygen or nitrogen undergoes deallylation under
palladium catalysis due to facile oxidative addition to the C−O
or C−N bond or hydrolytic cleavage (Scheme 1a).15 Hence, it
has been explored for the chemoselective deprotection of
complex molecules,16 fluorogenic probes,17 prodrug activa-
tion,18 and allyl transfer.19 Therefore, allylic functionalization
Received: July 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02465
© XXXX American Chemical Society
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A

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Letter
a b
,
Scheme 1. Palladium-Catalyzed Functionalization of Allylic
Ether and Amines
Scheme 2. Substrate Scope of Aromatic Acid Derivatives
member rings obviating deallylation or direct carboxypallada-
tion pathways (Scheme 1e).
To optimize the reaction conditions, a mixture of 2-
(allyloxy)benzoic acid 1a, Pd(OAc)2 (10 mol %) as the
catalyst, and Ag2CO3 (2 equiv) as the oxidant was heated in
1,4-dioxane solvent at 120 °C under a N2 atmosphere.
Gratifyingly, we isolated the desired oxinone product, 2a, in
20% yield after 24 h (entry 1, Table 1). Next, we examined
various Pd catalysts such as PdCl2, Pd(TFA)2, Pd-
(CH3CN)2Cl2, Pd(PPh3)4, Pd2(dba)3, and so on. However,
the yield of the desired product was not improved, and the
deallylation product via the C−O bond cleavage was formed.
Subsequently, using various oxidizing agents, for example,
Ag2O, K2S2O8, PIDA, BQ, and so on, did not improve the yield
of the desired product. (For details, see the Supporting
Information.) Interestingly, we observed that in the presence
of Pd(OAc)2, using AgOTf as a Lewis acid and BQ as an
oxidant, the yield of the desired product was increased to 29%
at 70 °C along with the deallylation product (35%) (entry 2,
Table 1). Other additives such as NaOTf, DIPEA, B(C6F5)3,
(BuO)2PO2H, TsOH, and TfOH were proved to be inferior to
AgOTf, predominantly providing the deallylation product.
Among various solvents such as DCM, toluene, DCE, and so
on, THF provided the best results in 30% yield of desired
product along with deallylation (entry 3, Table 1). Commonly
used ligands in allylic C−H activation, such as 2,2′-bipyridine,
diazafluorenone (entry 5, Table 1), 1,10-phenanthroline (entry
6, Table 1), and so on were ineffective in this case. The White
group has shown that bis-sulfoxide/benzoquinone (BQ) serial
ligands on palladium efficiently render allylic C−H oxida-
tion.9c,f Gratifyingly, the formation of the deallylation product
was completely suppressed using the catalytic Pd(II)acetate/
bis-sulfoxide complex (White catalyst, cat. 1), silver triflate,
a
b
Reactions were carried out on a 0.2 mmol scale. Yields refer to the
c
average of isolated yields of two experiments. Reaction time 12 h.
d
e
f
1.0 mmol scale reaction. Diallylated substrate. 3.0 equiv of BQ, 45
g
°C, 72 h. Debromination at the four-position.
and benzoquinone (2 equiv), providing the desired product in
82% yield in THF (entry 8, Table 1).
Subsequently, we explored the substrate scope under the
optimized reaction conditions. Electron-donating substituents
such as methyl (2b, Scheme 2) and methoxy (2g, Scheme 2)
furnished the oxinone product in high yields. Electron-
withdrawing groups such as nitro (2e, Scheme 2) also
furnished the desired product in moderate yield. Halogens
such as chloro (2d, Scheme 2) and fluoro (2f, Scheme 2)
remained intact under the reaction conditions, furnishing
excellent yields. Interestingly, aldehyde functionality (2h,
Scheme 2) was well-tolerated under these mild conditions.
We observed a proximity effect on deallylation versus C−H
oxidation reaction. When 2,6-diallyloxy-benzoic acid was
subjected to the reaction conditions, a monodeallylated
product was obtained in good yield (2i). Furthermore, 2,8-
allyloxy-2-naphthoic acid (1k) furnished a mixture of 8-allyloxy
B
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a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 3. Substrate Scope of Amino Acids
entry
catalyst
additive
solvent
yield (%)
2a/2a′
b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1,4-dioxane
1,4-dioxane
THF
THF
THF
THF
THF
THF
30
89
90
81
68
63
66
82
54
54
10
20/10
29/35
30/60
15/44
07/42
08/39
17/35
82/00
54/00
47/07
00/10
00/12
c
2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
NaOTf
DIPEA
c
3
c
4
c d
,
5
6
7
8
9
c e
,
c f
,
1
1
1
1
1
toluene
DCM
THF
10
11
12
THF
12
a
b
All reactions were carried out on a 0.2 mmol scale. 2 equiv of
Ag2CO3 was used as the oxidant, and the reaction was run at 120 °C
c
for 24 h. Remaining yield was the saturated analogue of 2a (2a′′).
d
e
f
10 mol % DAF was used. 10 mol % 1,10-Phen was used. 20 mol %
DMSO was used.
a
b
All reactions were carried out on a 0.2 mmol scale. Yields refer to
c
the average of isolated yields of at least two experiments. Started
from a racemic substrate; enantiomer with syn (S,S or R,R) product
formed.
(2k) and 8-hydroxy (2k′) oxinone. However, 3-(allyloxy)-2-
naphthoic acid (1c) and 2-(allyloxy)-1-naphthoic acid (1j)
provided the corresponding oxinone in high to moderate yield,
and the products were unambiguously characterized by X-ray
crystallography (2j; CCDC 2009840).
observed that because of steric hindrance, the isopropyl group
exhibits an anisotropic effect in the solid state. A 1:1
diastereoisomeric mixture of compound 4f was obtained
from the corresponding 1:1 diastereoisomeric starting material
3f. Furthermore, racemic 3j and 3k provided the correspond-
ing cyclized products in racemic mixtures. However, no
product is formed in the absence of any substitution at the α-
position (4i). Likewise, the yield of the desired product
increases with the increase in steric bulk at the α-substitution,
for example, methyl, propyl, benzyl, and isobutyl (4a, 4b, 4c,
4d, Scheme 3) and valine versus isoleucine (4e, 4f). For the
lysine substrate bearing two N-allyl groups at α- and ε-carbon,
C−H cleavage selectively took place at the α-N-allyl moiety
(4j). Whereas L-(S) amino acid derivatives exclusively
provided the (S,S) product, the racemic substrates (R/S)
provided exclusive R,R and S,S (4j, 4k) stereochemistry,
indicating the highly diastereoselective syn addition of the
pendant carboxylic acid.
As hypothesized, the reaction may proceed through two
distinct mechanistic pathways. In path a, a palladium-catalyzed
allylic C−H bond cleavage to generate a π-allyl Pd species
followed by the intramolecular nucleophilic addition of
carboxylic acid to furnish the desired product is plausible.
Alternatively, a palladium-catalyzed double-bond isomerization
from the allylic to the vinylic position followed by
carboxypalladation and β-hydride elimination may also lead
to the desired product (Scheme 4a). From control studies, we
observed that the reaction with a saturated analogue 1a′ or
with an internal olefin 1a′′ did not furnish any desired product
(Scheme 4b). Interestingly, a mixture of desired product 2a,
deallylation product 2a′, and saturated analogue 2a′′ was
obtained under both Lewis acid and Bronsted acid conditions
using Pd(OAc)2 in lieu of cat. 1 (Scheme 4c). This saturated
Next, we were motivated to examine the feasibility of the
allylic C−H oxidation of N-allyl anthranilic acids. We observed
the prominent role of the protecting group of the N-allyl
moiety on the reaction outcome, where free or allyl, methyl,
and −Boc groups were unsuccessful. We assumed that the N-
center should be comparably electronegative to the oxygen
atom to effect an α-C−H bond cleavage. As anticipated, the
corresponding −NTs (1l) furnished the desired product in
46% yield under the previously optimized reaction conditions.
Furthermore, after stirring the reaction mixture for 72 h at 45
°C in toluene using 3.0 equiv of BQ, the yield was increased to
70%. Under these optimized conditions, a wide range of
anthranilic acid derivatives underwent intramolecular allylic
C−H oxidation to provide the corresponding oxazinones (2l−
2s). Although fluoro- (2n) and chloro- (2o) substituents were
intact, bromo- was dehaloganated under the reaction
conditions, presumably via the oxidative addition of the in
situ-generated Pd(0).
Finally, we have explored a novel stereoselective allylic C−H
oxidation of N-allyl amino acids to access 2-vinyloxazolidin-5-
one derivatives. Hence, an enantiomerically pure N-allyl, N-
tosyl substrate 3a was prepared from (S)-alanine and subjected
to the reaction condition to afford the cyclized product in 47%
yield.24 Subsequently, a series of substrates from natural and
unnatural amino acids were synthesized and examined under
the optimized conditions to provide the corresponding 2-
vinyloxazolidin-5-one in moderate to high yields with high
(>20:1) diastereoselectivity (Scheme 3). From the X-ray
crystal structure analysis (4e; CCDC 2009842), it was
observed that the newly formed C−O bond is syn to the α-
carboxylic acid, exclusively providing S,S-isomer. It was also
C
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reaction conditions, a mixture of 3-ethyl-1H-isochromen-1-
one, 7a, and 3-vinylisochroman-1-one, 7b, was obtained after
12 h. However, stirring the reaction mixture for 72 h led to the
formation of the thermodynamically more stable 7a exclusively
through double-bond isomerization (Scheme 4e). In contrast
with the previous report, we demonstrate here that Pd(II)/bis-
sulfoxide/benzoquinone prefers a double-bond isomerization/
nucleopalladation pathway for allylic ether or amine sub-
strates.22b
Scheme 4. Mechanistic Possibilities and Control
Experiments
From our control experiments, we propose that initially, a
palladium complex is localized to the carboxylate site, and a
palladium-assisted double-bond isomerization from the allylic
to the vinylic position takes place to generate intermediate II
(Scheme 5). Subsequently, intramolecular carboxypalladation
Scheme 5. Plausible Catalytic Cycle for Allylic Oxidation
to form III followed by β-hydride elimination furnishes the
desired product (Scheme 5). Finally, Pd(0) is oxidized to
Pd(II) by benzoquinone to complete the catalytic cycle.
The product was further functionalized to demonstrate the
utility of the terminal double bond (Scheme 6). A Heck−
Scheme 6. Product Derivatization
analogue may form either through protodemetalation of the
incipient alkyl-palladium species, which is formed through
carboxypalladation, or through acid-catalyzed carboxylation of
vinylic ether. However, the reaction in the presence of triflic
acid predominantly led to the formation of the deallylation
product. This could be attributed to the unavailability of the
carboxylate anion for nucleophilic addition due to the
protonation under a strong acidic medium. Hence, deleterious
palladium-catalyzed C−O bond activation may take place. To
probe the olefin isomerization pathway, a vinylic ether 5 was
separately prepared and subjected to the reaction conditions,
furnishing 70% of the desired product (Scheme 4d). From the
kinetic studies with allylic (1b) and vinylic substrates (5), it
was observed that the reaction proceeds at a faster rate in the
initial stage with 5 compared with 1b and at a similar rate in
the later stage. (For details, see the SI.) Thus palladium-
catalyzed olefin isomerization could be the slow step;
subsequently, carboxypalladation/β-hydride elimination pro-
vides the desired product. The propensity of olefin isomer-
ization under the reaction conditions was further probed using
a homoallylic carbon analogue 6. When 6 was subjected to the
Matsuda reaction of 2a with diazonium salt 9 afforded the
corresponding arylation product in 85% yield. Furthermore, a
cross-olefin metathesis reaction with methyl acrylate 11 using
Grubb’s II catalyst afforded the metathesis product in 65%
yield.
In conclusion, we have developed a palladium-catalyzed
highly chemo-, regio-, and stereoselective allylic C−H
oxidation of allyl ether, amine, and amino acids. A conven-
tional palladium-catalyzed deallylation problem through C−O/
C−N bond cleavage is overcome and tuned toward allylic C−
H bond oxidation. Moreover, competitive π-allyl Pd formation
via allylic C−H bond cleavage versus olefin isomerization/
D
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1846−1913. (c) Trost, B. M.; Machacek, M. R.; Aponick, A.
Predicting the Stereochemistry of Diphenylphosphino Benzoic Acid
(DPPBA)-Based Palladium-Catalyzed Asymmetric Allylic Alkylation
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carboxypalladation has been elucidated to probe whether the
latter pathway is operative. Remarkably, a highly stereo-
selective 1,3-syn-addition is established for the C−H oxidation
of N-allyl-protected amino acids. We anticipate that the
present transformation and mechanistic insight will be helpful
for further research.
ASSOCIATED CONTENT
* Supporting Information
■
sı
(2) For reviews, see: (a) Fernandes, R. A.; Nallasivam, J. L. Catalytic
allylic functionalization via π-allyl palladium chemistry. Org. Biomol.
Chem. 2019, 17 (38), 8647−8672. (b) Lorion, M. M.; Oble, J.; Poli,
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Lorion, M. M.; Poli, G. Direct Allylic Functionalization Through Pd-
Catalyzed C-H Activation. Eur. J. Org. Chem. 2014, 2014 (27), 5863−
5883. (d) Davies, H. M. L.; Nikolai, J. Catalytic and enantioselective
allylic C-H activation with donor-acceptor-substituted carbenoids.
Org. Biomol. Chem. 2005, 3 (23), 4176−4187. For seminal work, see:
(e) Kitching, W.; Rappoport, Z.; Winstein, S.; Young, W. G. Allylic
Oxidation of Olefins by Palladium Acetate. J. Am. Chem. Soc. 1966,
88, 2054−2055. (f) Chen, M. S.; White, M. C. A Sulfoxide-Promoted,
Catalytic Method for the Regioselective Synthesis of Allylic Acetates
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2004, 126, 1346−1347. (g) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang,
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02465.
1
Experimental procedures, spectroscopic data, H and
13C NMR spectra for all synthesized compounds (PDF)
Accession Codes
CCDC 2009840 and 2009842 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
■
Ranjan Jana − Organic and Medicinal Chemistry Division,
CSIR-Indian Institute of Chemical Biology, Kolkata 700032,
West Bengal, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India;
orcid.org/0000-0002-5473-0258; Email: rjana@iicb.res.in
(3) Engelin, C.; Jensen, T.; Rodriguez-Rodriguez, S.; Fristrup, P.
Mechanistic Investigation of Palladium-Catalyzed Allylic C−H
Activation. ACS Catal. 2013, 3, 294−302.
(4) (a) Lei, H.; Rovis, T. Ir-Catalyzed Intermolecular Branch-
Selective Allylic C−H Amidation of Unactivated Terminal Olefins. J.
Am. Chem. Soc. 2019, 141, 2268−2273. (b) Knecht, T.; Mondal, S.;
Ye, J.-H.; Das, M.; Glorius, F. Intermolecular, Branch-Selective, and
Redox-Neutral Cp*IrIII-Catalyzed Allylic C-H Amidation. Angew.
Chem., Int. Ed. 2019, 58, 7117−7121. (c) Wang, Z.; He, Z.; Zhang, L.;
Huang, Y. Iridium-Catalyzed Aerobic α, β-Dehydrogenation of γ,δ-
Unsaturated Amides and Acids: Activation of Both α- and β-C-H
bonds through an Allyl-Iridium Intermediate. J. Am. Chem. Soc. 2018,
140, 735−740. (d) Sharma, A.; Hartwig, J. F. Enantioselective
Functionalization of Allylic C-H Bonds Following a Strategy of
Functionalization and Diversification. J. Am. Chem. Soc. 2013, 135,
17983−17989.
Authors
Kartic Manna − Organic and Medicinal Chemistry Division,
CSIR-Indian Institute of Chemical Biology, Kolkata 700032,
West Bengal, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
Hasina Mamataj Begam − Organic and Medicinal Chemistry
Division, CSIR-Indian Institute of Chemical Biology, Kolkata
700032, West Bengal, India
Krishanu Samanta − Organic and Medicinal Chemistry
Division, CSIR-Indian Institute of Chemical Biology, Kolkata
700032, West Bengal, India; Academy of Scientific and
Innovative Research (AcSIR), Ghaziabad 201002, Uttar
Pradesh, India
(5) (a) Harris, R. J.; Park, J.; Nelson, T. A. F.; Iqbal, N.; Salgueiro,
D. C.; Bacsa, J.; MacBeth, C. E.; Baik, M.-H.; Blakey, S. B. The
Mechanism of Rhodium-Catalyzed Allylic C-H Amination. J. Am.
Chem. Soc. 2020, 142, 5842−5851. (b) Archambeau, A.; Rovis, T.
Rhodium(III)-Catalyzed Allylic C(sp(3))-H Activation of Alkenyl
Sulfonamides: Unexpected Formation of Azabicycles. Angew. Chem.,
Int. Ed. 2015, 54, 13337−13340. (c) Li, Q.; Yu, Z.-X. Conjugated
Diene-Assisted Allylic C-H Bond Activation: Cationic Rh(I)-
Catalyzed Syntheses of Polysubstituted Tetrahydropyrroles, Tetrahy-
drofurans, and Cyclopentanes from Ene-2-Dienes. J. Am. Chem. Soc.
2010, 132, 4542−4543. (d) Li, Q.; Yu, Z.-X. Enantioselective
Rhodium-Catalyzed Allylic C−H Activation for the Addition to
Conjugated Dienes. Angew. Chem., Int. Ed. 2011, 50, 2144−2147.
(6) (a) Li, J.; Zhang, Z.; Wu, L.; Zhang, W.; Chen, P.; Lin, Z.; Liu,
G. Site-specific allylic C−H bond functionalization with a copper-
bound N-centred radical. Nature 2019, 574, 516−521. (b) Qin, L.;
Sharique, M.; Tambar, U. K. Controllable, Sequential, and Stereo-
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02465
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by DST, SERB, Govt. of India, core
research grant no. EMR/2014/000469 and Ramanujan
fellowship, award no. SR/S2/RJN-97/2012. K.M., H.M.B.,
and K.S. thank CSIR and UGC for their fellowships.
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