Asymmetric α-Allylation of Aldehydes with Alkynes by Integrating Chiral Hydridopalladium and Enamine Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b00740

A palladium-catalyzed asymmetric α-allylation of aldehydes with alkynes has been established by integrating the catalysis of enamine and chiral hydridopalladium complex that is reversibly formed from the oxidative addition of Pd(0) to chiral phosphoric acid. The ternary catalyst system, consisting of an achiral palladium complex, a primary amine, and a chiral phosphoric acid allows the reaction to tolerate a wide scope of α,α-disubstituted aldehydes and alkynes, affording the corresponding allylation products in high yields and with excellent levels of enantioselectivity.

Full text of DOI:10.1021/acs.orglett.8b00740

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric α‑Allylation of Aldehydes with Alkynes by Integrating
Chiral Hydridopalladium and Enamine Catalysis
Yong-Liang Su,† Lu-Lu Li,† Xiao-Le Zhou,† Zhen-Yao Dai,† Pu-Sheng Wang,*,†
and Liu-Zhu Gong*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed asymmetric α-allylation of aldehydes with alkynes has been established by integrating the
catalysis of enamine and chiral hydridopalladium complex that is reversibly formed from the oxidative addition of Pd(0) to chiral
phosphoric acid. The ternary catalyst system, consisting of an achiral palladium complex, a primary amine, and a chiral
phosphoric acid allows the reaction to tolerate a wide scope of α,α-disubstituted aldehydes and alkynes, affording the
corresponding allylation products in high yields and with excellent levels of enantioselectivity.
Scheme 1. Transition-Metal-Catalyzed Asymmetric Allylic
Functionalization by Using Alkynes as Allylic Precursors
he discovery of completely atom-economic chemical
Treactions has been a long-standing research target in
modern synthetic organic chemistry.1 The transition-metal-
catalyzed allylic substitution reaction2 has been one of the most
fundamentally important transformations,3 with widespread
applications to the synthesis of pharmacologically important
molecules.4 However, the general requirement of high
oxidation state allylic precursors, along with the generation of
stoichiometric amounts of waste, poses constant constraints on
the synthetic efficiency. In recent decades, transition-metal
hydride-mediated addition of nucleophiles to alkynes5 has been
a versatile alternative to generate allylmetal complexes, allowing
the creation of atom-economic allylic substitution reactions for
building structural complexity from easily accessible starting
materials (Scheme 1a). With the use of chiral phosphine
ligands, Rh-catalyzed enantioselective allylic substitution trans-
formations of alkynes for the formation of C−O,6 C−N,7 and
C−C8 bonds have been successfully developed by Breit and
Dong. However, only Pd-catalyzed enantioselective intra-
molecular allylic amination reactions have been reported,
based on palladium hydride-mediated addition to the
carbon−carbon triple bond (Scheme 1b).9 Herein, we will
report an asymmetric α-allylation of aldehydes with alkynes by
integrating the chiral hydridopalladium complex and enamine
catalysis (Scheme 1c).
hydridopalladium complex,10 which then reacts with acetylenes
to form electrophilic π-allylpalladium complexes.11 Inspired by
Trost revealed that the palladium(0) complex is able to
undergo oxidative addition to acetic acid to generate a
Received: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
these elegant precedents, we discerned that a chiral
hydridopalladium phosphate I would be generated from
palladium(0) complex and a chiral phosphoric acid and then
might isomerize an alkyne to an allene II. Subsequently,
another hydropalladation between the allene II with the chiral
hydridopalladium I may proceed to form a chiral π-
allylpalladium phosphate species III. As indicated by previous
asymmetric counteranion-directed catalysis12,13 and our own
study on the oxidative coupling of an enolizable aldehyde and a
terminal alkene by using a triple catalytic system,14 the enamine
IV reversibly generated from the aldehyde and the amine
catalyst would undergo asymmetric allylic substitution with
chiral π-allylpalladium phosphate III via the transition state TS-
112 to give a coupling product V stereoselectively, which finally
undergoes the hydrolysis to furnish the allylation product 3 and
regenerates the amine catalyst (Scheme 2a). As such, the
Table 1. Optimization of Reaction Conditions
b
c
d
entry
L
amine (A)
yield (%)
E:Z
ee (%)
1
2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
A1
A2
A3
A4
A5
A6
A7
A3
A3
A3
A3
A3
A3
A3
A3
A3
55
60
9:1
9:1
83
86
92
56
35
44
64
2
3
80
10:1
5:1
4
56
5
36
4:1
Scheme 2. Mechanistic Rationale for the Asymmetric
Allylation of Enolizable Aldehydes with Alkynes by
Integrating the Catalysis of Enamine and Hydridopalladium
Phosphate, Reversibly Formed from Palladium(0) and
Chiral Phosphoric Acid
6
20
6:1
7
46
6:1
8
PCy3
75
2:1
9
xantphos
dppf
50
12:1
5:1
89
87
10
11
12
36
(S)-BINAP
dppe
trace
trace
75
e
13
10:1
10:1
9:1
94
94
91
ef
,
g
14
fh
80 (73)
15 ,
63
7
fi
16 ,
a
Reaction conditions: unless indicated otherwise, the reaction of 1a
(0.20 mmol), 2a (0.40 mmol), Pd(OAc)2 (10 mol %), L (40 mol %),
A (60 mol %), and (R)-TRIP (10 mol %) was carried out in toluene (2
b
mL) for 48 h at 100 °C. Yield was determined by 1H NMR analysis of
the crude reaction mixture by using trimethylbenzene-1,3,5-tricarbox-
c
1
ylate as an internal standard. The E/Z was determined by H NMR
d
analysis of the crude reaction mixture. The ee value was determined
by HPLC, and the absolute configuration was assigned by comparing
e
the optical rotation with the literature value. 10 mol % Pd(PPh3)4 was
f
g
h
used. 80 mol % A3 and 0.6 mmol 2a was used. Isolated yield. 7.5
i
mol % Pd(PPh3)4 and 7.5 mol % (R)-TRIP were used. 5 mol %
Pd(PPh3)4 and 5 mol % (R)-TRIP were used.
multiple catalyst system12,14,15 of palladium, a primary amine,
and a chiral phosphoric acid16 would enable the asymmetric α-
allylation of aldehydes with alkynes by integrating the catalytic
activity of enamine and chiral hydridopalladium phosphate
(Scheme 2).
π-allyl-Pd phosphate moiety in the transition state and thereby
could alter the reactivity and stereoselectivity.3b,c For instance,
an electron-rich alkylphosphine resulted in a similar yield but
with much diminished E/Z and enantioselectivity (Table 1,
entry 8). Notably, a clear effect of diphosphine ligand bite
angles on the reaction was observed,19 and the wider bite angle
was beneficial to the reactivity and the control of alkene
geometry. Xantphos (Table 1, entry 9, bite angle = 108°) could
smoothly give 3aa in 50% yield, 12:1 E/Z and 89% ee, and dppf
(bite angle = 99°) also afforded 3aa with reduced yield and E/Z
selectivity (Table 1, entry 10), yet only trace amount of product
3aa was obtained when either BINAP (bite angle = 93°) or
dppe (bite angle = 86°) was used (Table 1, entries 11 and 12).
The absence of achiral counteranion, such as acetate, could
further improve the enantioselectivity (Table 1, entry 13). A
slightly improved yield with maintained stereoselectivity was
obtained by increasing the stoichiometry of the aldehyde 2a
and in the presence of 80 mol % of amine catalyst A3 (Table 1,
entry 14). However, much diminished results were observed
when 7.5 mol % Pd(PPh3)4 and 7.5 mol % (R)-TRIP were used
(Table 1, entry 15), and almost trace amounts of product were
obtained at an even lower catalyst loading (Table 1, entry 16).
Because of the synthetic versatility and prevalence of
conjugated dienes in biologically relevant molecules,17
a
skipped enyne18 1a was selected as a model substrate for the
hypothesis (Scheme 2b). The preliminary study was evaluated
by the treatment of pent-4-en-1-yn-1-ylbenzene (1a) and 2-
phenylpropanal (2a) in the presence of Pd(OAc)2 (10 mol %),
PPh3 (40 mol %), achiral amine A1 (60 mol %), and (R)-TRIP
(10 mol %) at 100 °C, affording the desired allylation product
3aa in 55% yield, 9:1 E/Z and with good enantiomeric excess
(Table 1, entry 1). Fine tuning of the aryl group of the achiral
amine significantly improved the yield and enantioselectivity
(Table 1, entries 2 and 3). In consideration of the obvious
impact of the amine catalyst on the reaction performance, other
chiral amines were investigated. However, a variety of amine
catalysts provided allylation product 3aa in moderate to low
yield and with significantly reduced enantioselectivity (Table 1,
entries 4−7). The examination of various phosphine ligands
revealed that the pattern of phosphine ligands could
dramatically influence the electronic and steric feature of the
B
DOI: 10.1021/acs.orglett.8b00740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Having established the optimized conditions, the substrate
scope for alkynes was explored next (Scheme 3). A wide scope
Scheme 4. Scope, with Respect to Aldehydes
a
Scheme 3. Scope, with Respect to Alkynes
a
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), Pd(PPh3)4 (10
mol %), (R)-TRIP (10 mol %), A3 (80 mol %), toluene (2 mL), 48 h
at 100 °C, under N2. Yield was determined after separation by silica gel
chromatography. The ee value was determined by HPLC. The E/Z
1
was determined by H NMR analysis of the crude reaction mixture.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), Pd(PPh3)4 (10
stereoselective allylation. For example, commercially available
substances such as cyclamen aldehyde (2l) and helional (2m)
were able to undergo stereoselective coupling with skipped
enyne 1a, giving chiral α,α-disubstituted aldehydes in good
yields and with excellent levels of enantioselectivity. It was
noteworthy that simple 2-ethylpropanal (2n) and 2-cyclohexyl
propanal (2o) also afforded the corresponding products in
moderate to good yields and with good enantioselectivities.
Notably, a gram-scale reaction of 1a and 2a was successful
and afforded α-quaternary aldehyde 3aa in 76% yield, 10:1 E/Z
and 94% ee. After the condensation with 4-methoxybenzyl-
amine and followed by reduction with LiAlH4,20 the aldehyde
3aa was converted to a secondary amine 4 in excellent yield and
maintained enantioselectivity. Alternatively, under the con-
ditions of Pinnick oxidation,21 the aldehyde 3aa was trans-
formed to a carboxylic acid, which underwent methylation with
(trimethylsilyl)diazomethane (TMSCH2N2) to yield the
corresponding ester 5. On the other hand, α-quaternary nitrile
6 was accessed by sequential treatment of 3aa with hydroxyl-
amine hydrochloride and CDI (1,1′-carbonyldiimidazole).
Furthermore, a chiral tetrahydropyran 7 could also be furnished
in excellent yield via the reduction and a gold-catalyzed
intramolecular cyclization, despite having low diastereoselectiv-
ity. (A derivation of chiral aldehydes is given in Scheme 5.)
In conclusion, we have established a palladium-catalyzed
atom-economic asymmetric α-allylation of aldehydes with
alkynes by using a ternary catalyst system of achiral
palladium(0) complex, primary amine, and chiral phosphoric
acid to integrate enamine and chiral hydridopalladium
phosphate catalysis. The protocol enables a wide range of
alkynes and enolizable aldehydes to give a diverse spectrum of
mol %), (R)-TRIP (10 mol %), A3 (80 mol %), toluene (2 mL), 48 h
at 100 °C, under N2. The yield was determined after separation by
silica gel chromatography. The ee value was determined by HPLC. The
E/Z was determined by 1H NMR analysis of the crude reaction
mixture.
of phenyl-substituted skipped enynes (1b−1l) bearing both
electron-donating and electron-withdrawing groups at the
para-, meta-, and ortho-position of the phenyl moiety gave the
desired allylation products in moderate to good yields and with
excellent E/Z and enantioselectivities. In addition, skipped
enynes with aromatic and heteroaromatic substituents,
including 2-naphthlalene (1m) and 3-thiophene (1n), could
be tolerated to undergo efficient and stereoselective allylation.
Moreover, a series of 1-arylpropynes (1o−1r) were also able to
participate in the asymmetric allylation reaction, providing the
allylation product with excellent yields and enantioselectivities.
Moreover, 1-phenyl-1-butyne (1s) afforded comparable yield
and enantioselectivity to the 1-arylpropynes, albeit with
unsatisfactory diastereoselectivity.
The generality for α,α-disubstituted aldehydes then was
examined under the optimized reaction conditions (see Scheme
4). Significantly, the protocol was amenable to a wide range of
enolizable aldehydes. In addition to the α-methyl-substituted 2-
arylacetaldehyde (2b−2j), the reaction was tolerant of both
electron-donating and electron-withdrawing substituents at
different positions of the aryl moiety. The α-ethyl-substituted
aldehyde (2k) underwent the reaction to give a good yield, but
with only acceptable enantioselectivity. Remarkably, a series of
aliphatic aldehydes were also suitable coupling partners for the
C
DOI: 10.1021/acs.orglett.8b00740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 5. Derivatization of Chiral Aldehydes
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chiral α-quaternary aldehydes in high yields and with high levels
of enantioselectivity. Moreover, the chiral α-quaternary
aldehydes can serve as a platform molecule for the synthesis
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trapping chiral π-allylpalladium phosphates.
ASSOCIATED CONTENT
■
S
* Supporting Information
(15) Chen, D. F.; Han, Z. Y.; Zhou, X. L.; Gong, L. Z. Acc. Chem. Res.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00740.
2014, 47, 2365.
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Complete experimental procedures and characterization
data for the prepared compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pusher@ustc.edu.cn (P.-S. Wang).
*E-mail: gonglz@ustc.edu.cn (L.-Z. Gong).
(18) Gao, S.; Liu, H.; Yang, C.; Fu, Z.; Yao, H.; Lin, A. Org. Lett.
2017, 19, 4710.
ORCID
Pu-Sheng Wang: 0000-0002-7229-3426
Liu-Zhu Gong: 0000-0001-6099-827X
Notes
(19) (a) van Leeuwen, P.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P.
Chem. Rev. 2000, 100, 2741. (b) Birkholz, M.-N.; Freixa, Z.; van
Leeuwen, P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099.
(20) Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 15303.
(21) (a) Lindgren, B. O.; Nilsson, T.; Husebye, S.; Mikalsen, O.;
Leander, K.; Swahn, C.-G. Acta Chem. Scand. 1973, 27, 888. (b) Kraus,
G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. (c) Kraus, G. A.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from MOST (973 Project
No. 2015CB856600), NSFC (No. 21602214), and the China
Postdoctoral Science Foundation (Nos. 2015M580534 and
2017T100449).
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DOI: 10.1021/acs.orglett.8b00740
Org. Lett. XXXX, XXX, XXX−XXX