Dehydrative Allylation of α C(sp3)-H Bonds of Alkylamines with Allylic Alcohols

Article abstract of DOI:10.1021/acs.orglett.0c01464

Herein reported is a dehydrative coupling reaction of alkyl amines with allylic alcohols promoted by co-operation of photoredox and palladium catalysts. A range of homoallylic amines are efficiently synthesized. A mechanistic study suggests that an in sit

Full text of DOI:10.1021/acs.orglett.0c01464

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Letter
Dehydrative Allylation of α C(sp3)−H Bonds of Alkylamines with
Allylic Alcohols
Yusuke Masuda, Misato Ito, and Masahiro Murakami*
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ABSTRACT: Herein reported is a dehydrative coupling reaction
of alkyl amines with allylic alcohols promoted by co-operation of
photoredox and palladium catalysts. A range of homoallylic amines
are efficiently synthesized. A mechanistic study suggests that an in
situ generated carboxylic acid activates an allylic alcohol to facilitate
its oxidative addition onto palladium.
lkylamines generate α-aminoalkyl radical species when
method to synthesize homoallylic amines from alkylamines and
allylic alcohols through a dehydrative C(sp3)−C(sp3) bond
formation under mild reaction conditions, dispensing with the
use of any stoichiometric activating agents.5
A
subjected to photoredox catalysis.1 Such alkyl radicals are
amenable to coupling with a wide range of organic compounds
in the absence2 or presence of transition-metal catalysts.3
Allylation of α C−H bonds of alkylamines gives straightfor-
ward access to homoallylic amines, which are known as
versatile intermediates for drug synthesis. Xiao and co-workers
showed that the photogeneration of α-amino benzylic radicals
was combined with a palladium catalyzed allylation reaction to
afford homoallylic amines (Figure 1a).3b,4 More atom-
A toluene solution of β-methallyl alcohol (1) and 1-
phenylpyrrolidine (2, 2.0 equiv) was irradiated by LED lamps
(470 nm) in the presence of [Ir(dFCF3ppy)2dtbbpy]PF6 (1
mol %), Pd(OAc)2 (5 mol %), and BrettPhos (5 mol %) at
room temperature. After 12 h, the reaction mixture was
subjected to chromatographic purification to isolate the
coupling product 3 in 75% yield (Table 1, entry 1). Control
experiments confirmed that each of light, photocatalyst, and
palladium was indispensable for the formation of 3.6 It is
known that Pd(OAc)2 reacts with a tertiary phosphine to
generate a palladium(0) species and Ac2O.7 Next, we examined
the use of cyclopentadienyl π-allyl palladium [PdCp(π-allyl)]
as the precursor of palladium(0) together with BrettPhos
instead of Pd(OAc)2/BrettPhos. Only 13% of 3 was formed,
suggesting that generation of a palladium(0) species was
insufficient for the allylation reaction to occur effeciently
(entry 2). Then, acetic acid was added to the reaction
conditions of entry 2, and the yield of 3 rebounded to 75%
(entry 3). We inferred that acetic acid would be generated in
situ to activate the allylic alcohol, accelerating its oxidative
addition onto a palladium center.8
Scheme 1 gives a plausible mechanistic explanation for the
formation of 3 from β-methallyl alcohol (1) and 1-phenyl-
pyrrolidine (2). It consists of four steps: (Step 1) The tertiary
phosphine ligand reduces Pd(OAc)2 to form tertiary
phosphine oxide, a palladium(0) species, and Ac2O.7 Ac2O
Figure 1. Transition-metal/photoredox co-catalytic allylation of α C−
H bonds of amines.
economical reactions were reported by Breit3f and Rovis.3e
Photogenerated α-aminoalkyl radicals were successfully added
onto alkynes, allenes, and 1,3-dienes in the presence of a
rhodium or cobalt catalyst. Herein reported is a dehydrative
allylation reaction of alkylamines with allylic alcohols, which is
cooperatively promoted by photoredox and palladium catalysts
(Figure 1b). The present reaction offers a straightforward
Received: April 28, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01464
© XXXX American Chemical Society
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A

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SCE in CH3CN).11 The resulting allyl palladium species C is
described by the two resonance forms, i.e., the palladium(I)
complex and a persistent allylic radical to which a palladium(0)
is located in close proximity.13 Finally, C couples with the α-
amino alkyl radical B to afford 3 along with palladium(0).14
The following experiments were carried out to offer
mechanistic insights. When the deuterium-labeled allylic
alcohol 4 was subjected to the standard reaction conditions,
deuterium atoms were almost equally distributed at both
vinylic and allylic positions of the coupling product 5, which
was suggestive of the formation of a π-allylpalladium
intermediate (Scheme 2a). Next examined was trapping of
Table 1. Dehydrative Coupling Reaction of Allylic Alcohol 1
and Amine 2
a
Scheme 2. Mechanistic Experiments
b c
,
entry
Pd precursor
yield of 3
1
2
3
Pd(OAc)2
PdCp(π-allyl)
PdCp(π-allyl) + AcOH (10 mol %)
83% (75%)
13%
75%
a
Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), [Ir-
(dFCF3ppy)2dtbbpy]PF6 (0.002 mmol), Pd precursor (0.01 mmol),
BrettPhos (0.01 mmol), toluene (2 mL), blue LEDs (470 nm), room
b
temperature, 12 h. Yield determined by 1H NMR analysis with
c
C2H2Cl4 as internal standard. Isolated yield in parentheses.
Scheme 1. Proposed Reaction Pathway
an α-aminoalkyl radical intermediate with methyl vinyl ketone
(6), which generated the alkylated product 7 in 38% yield, as
with the case previously reported (Scheme 2b).2c The
production of 7 indicates that an α-aminoalkyl radical species
would be involved in the reaction mechanism.
A range of alkyl amines was examined for the dehydrative
allylation reaction (Scheme 3). Functional groups such as
cyano (8), ester (9), and fluoro (10) groups were all tolerated
on the aromatic ring of 1-arylpyrrolidines. Sterically hindered
1-(o-tolyl)pyrrolidine also participated in the reaction, and the
allylated product 11 was obtained in 71% yield. 1-Phenyl-
piperidine and 1-benzylindoline gave the corresponding
products 12 and 13 in 50 and 63% yield, respectively. Next,
we examined acyclic amines. N,N-Dimethylaniline underwent
the allylation reaction to afford the product 14 in 78% yield.
When the reaction was carried out with unsymmetrical
dialkylanilines such as N-ethyl-N-methylaniline and N-i-butyl-
N-methylaniline, the allylated products 15 and 16 were
produced in high yield as a mixture with the product allylated
at the secondary C−H bond. N-Methyl-N-i-propylaniline
underwent the allylation reaction selectively at the methyl
group, probably due to steric reasons, to afford the
corresponding product 17 in 74% yield. N-Benzyl-N-
methylaniline derivatives possessing methoxy (19) and chloro
(20) substituents also participated in the dehydrative coupling
reaction. On the other hand, neither trialkylamines nor
electron-rich aniline derivatives afforded the allylated products.
The substrate scope was investigated also with respect to
allylic alcohols (Scheme 4). Allyl alcohol successfully coupled
with the amine 2 to afford the product 21 in 60% yield. β-Alkyl
allylic alcohols participated in the reaction, and the
corresponding products 22 and 23 were generated in 52 and
65% yield, respectively. β-Aryl allylic alcohols were suitable
substrates for the dehydrative coupling reaction. Substituents
reacts with allylic alcohol 1 to generate acetic acid. (Step 2)
Acetic acid protonates the allylic alcohol 1 to assist its oxidative
addition onto palladium(0), furnishing the π-allylpalladium(II)
A.9 (Step 3) Light excites the iridium catalyst to induce single
electron transfer from the amine 2 (E1/2red = +0.70 V vs SCE in
CH3CN)10 to the excited iridium(III) complex (E1/2red[Ir-
(III)*/Ir(II)] = +1.21 V vs SCE in CH3CN),11 forming an
amine radical cation and an iridium(II) species. The radical
cation is deprotonated by an acetate anion to generate the α-
red
amino alkyl radical B. (Step 4) The allyl palladium A [E0
=
−1.35 V vs SCE in DMF for Pd(π-allyl)(PPh3)2(OAc)]12 is
reduced by iridium(II) (E1/2red[Ir(III)/Ir(II)] = −1.37 V vs
B
https://dx.doi.org/10.1021/acs.orglett.0c01464
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a
Scheme 3. Scope with Respect to Amines
Scheme 5. Reactions with α- and γ-Substituted Allylic
Alcohols
(diphenylphosphino)biphenyl (BIPHEP) as the ligand sig-
nificantly improved the efficiency, and the allylated amine 29
was produced in 63% yield as a mixture of the linear and
branched isomers with preference for a linear one (linear:-
branched = 91:9).15 The same linear:branched ratio was
observed with 3-butene-2-ol (30), which was consistent with
the proposed mechanism involving the allyl palladium
intermediate. 2-Penten-1-ol (31) afforded the linear product
32 selectively. The site-selectivity is accounted for by assuming
that C−C bond formation at the sterically less hindered site is
more favored when the allyl palladium C and the α-amino
radical B couple.
a
Reaction conditions: 1 (0.20 mmol), amine (0.40 mmol), [Ir-
(dFCF3ppy)2dtbbpy]PF6 (0.002 mmol), Pd(OAc)2 (0.01 mmol),
BrettPhos (0.01 mmol), toluene (2 mL), blue LEDs (470 nm), room
temperature, 12 h. Isolated yield. (b) 0.60 mmol of amine.
a
Scheme 4. Scope with Respect to Allylic Alcohols
In conclusion, we have disclosed that a photoredox/
Pd(OAc)2/biarylphosphine system enables dehydrative C-
(sp3)−C(sp3) bond formation between alkylamines and allylic
alcohols. In situ generated acetic acid would accelerate
oxidative addition of allylic alcohols onto palladium to form
the allyl palladium for coupling with the alkyl radical species,
dispensing with the need for derivatization to the correspond-
ing esters or carbonates.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01464.
a
Reaction conditions: 1 (0.20 mmol), amine (0.40 mmol), [Ir-
(dFCF3ppy)2dtbbpy]PF6 (0.002 mmol), Pd(OAc)2 (0.01 mmol),
BrettPhos (0.01 mmol), toluene (2 mL), blue LEDs (470 nm), room
temperature, 12 h. Isolated yield.
Experimental procedures, mechanistic experiments, and
NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3, 7−27, 29, and 32 (ZIP)
on the aromatic ring such as 2-methyl (25), 4-methoxy (26),
and 4-fluoro (27) groups were all tolerated under the reaction
conditions.
Next, the reaction of α- and γ-substituted allylic alcohols was
studied (Scheme 5). 2-Buten-1-ol (28) hardly reacted with
N,N-dimethylaniline under the optimized reaction conditions
using BrettPhos. To our delight, the use of 2,2′-bis-
AUTHOR INFORMATION
Corresponding Author
■
Masahiro Murakami − Department of Synthetic Chemistry and
Biological Chemistry, Kyoto University, Katsura, Kyoto 615-
8510, Japan; Email: murakami@sbchem.kyoto-u.ac.jp
C
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Authors
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Letter
D.-F.; Adele, A.; Gong, L.-Z. J. Am. Chem. Soc. 2013, 135, 9255.
(g) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W.
Angew. Chem., Int. Ed. 2014, 53, 6776. (h) Pupo, G.; Properzi, R.; List,
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Yusuke Masuda − Department of Synthetic Chemistry and
Biological Chemistry, Kyoto University, Katsura, Kyoto 615-
8510, Japan; orcid.org/0000-0002-0386-9989
Misato Ito − Department of Synthetic Chemistry and Biological
Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01464
Notes
The authors declare no competing financial interest.
(12) Zhang, P.-P.; Zhang, W.-C.; Zhang, T.-F.; Wang, Z.-Q.; Zhou,
W.-J. J. Chem. Soc., Chem. Commun. 1991, 491.
ACKNOWLEDGMENTS
■
(13) Reviews about persistent radical: (a) Studer, A. Chem. Soc. Rev.
2004, 33, 267. (b) Fischer, H. Chem. Rev. 2001, 101, 3581.
(14) (a) Lang, S. B.; O’Nele, K. M.; Tunge, J. A. J. Am. Chem. Soc.
2014, 136, 13606. (b) Lang, S. B.; O’Nele, K. M.; Tunge, J. A. Chem. -
Eur. J. 2015, 21, 18589. (c) Zhang, H.-H.; Zhao, J.-J.; Yu, S. J. Am.
Chem. Soc. 2018, 140, 16914.
This work was supported by JSPS KAKENHI Grant Numbers
15H05756 (M.M.) and 19K15562 (Y.M.).
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