α-Quaternary Chiral Aldehydes from Styrenes, Allylic Alcohols, and Syngas via Multi-catalyst Relay Catalysis

Article abstract of DOI:10.1016/j.chempr.2018.03.010

Mimicking the way nature synthesizes organic molecules, multi-catalyst relay catalysis (MCRC), based on the seamless combination of a series of catalytic reactions, has emerged as a promising strategy for achieving ideal synthesis. In such systems, each step takes place orderly and sequentially. Taken as a whole, the entire process appears indistinguishable from a common one-step reaction but provides a means for extraordinary transformations. Here, we report a one-step transformation of styrenes, allylic alcohols, and syngas to α-quaternary chiral aldehydes in a multi-catalyst system consisting of a rhodium(I) complex, a palladium(0) complex, a chiral Br?nsted acid catalyst, and an achiral amine (20–100 mol %). The cascade hydroformylation and asymmetric allylation reaction was realized with high yields (up to 98%) and high enantioselectivities (up to 99% ee) under mild conditions (1 bar of syngas). The contradiction between the growing demands for chemicals and decreasing fossil resources has prompted chemists to search for ideal synthetic strategies. Living cells produce complicated molecules with an extreme efficiency that organic chemists have long tried to imitate. In recent years, mimicking the way that nature synthesizes organic molecules has emerged as a promising strategy for achieving ideal synthesis. A prominent example of such an approach is multi-catalyst relay catalysis (MCRC), which requires the seamless combination of a series of catalytic reactions. In this paper, using a highly compatible and efficient multi-catalyst system, we have developed a cascade hydroformylation and asymmetric allylation reaction that transforms styrenes, allylic alcohols, and syngas to α-quaternary chiral aldehydes in one step. The current work offers the potential for multi-catalytic approaches and new types of relay processes. Multi-catalyst relay catalysis (MCRC) has emerged as a promising strategy for achieving ideal synthesis. Here, we show that a multi-catalyst system consisting of a rhodium(I) complex, a palladium(0) complex, a chiral Br?nsted acid catalyst, and an achiral amine (20–100 mol %) works ideally to promote a cascade hydroformylation and asymmetric allylation reaction. This method enables the transformation of readily available styrenes, allylic alcohols, and syngas to α-quaternary chiral aldehydes with high yields and enantioselectivities under mild conditions.

Full text of DOI:10.1016/j.chempr.2018.03.010

Article
a-Quaternary Chiral Aldehydes from Styrenes,
Allylic Alcohols, and Syngas via Multi-catalyst
Relay Catalysis
Jing Meng, Lian-Feng Fan,
Zhi-Yong Han, Liu-Zhu Gong
hanzy2014@ustc.edu.cn (Z.-Y.H.)
gonglz@ustc.edu.cn (L.-Z.G.)
HIGHLIGHTS
a-Quaternary chiral aldehydes
synthesized from styrenes, allylic
alcohols, and syngas
Highly compatible and efficient
multi-catalyst system
High yields and
enantioselectivities, mild
conditions, and broad scope
Multi-catalyst relay catalysis (MCRC) has emerged as a promising strategy for
achieving ideal synthesis. Here, we show that a multi-catalyst system consisting of
a rhodium(I) complex, a palladium(0) complex, a chiral Brønsted acid catalyst, and
an achiral amine (20–100 mol %) works ideally to promote a cascade
hydroformylation and asymmetric allylation reaction. This method enables the
transformation of readily available styrenes, allylic alcohols, and syngas to
a-quaternary chiral aldehydes with high yields and enantioselectivities under mild
conditions.
Meng et al., Chem 4, 1–12
May 10, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.03.010

Please cite this article in press as: Meng et al., a-Quaternary Chiral Aldehydes from Styrenes, Allylic Alcohols, and Syngas via Multi-catalyst Relay
Catalysis, Chem (2018), https://doi.org/10.1016/j.chempr.2018.03.010
Article
a-Quaternary Chiral Aldehydes
from Styrenes, Allylic Alcohols, and Syngas
via Multi-catalyst Relay Catalysis
1,2,
Jing Meng,1 Lian-Feng Fan,1 Zhi-Yong Han,1,3, and Liu-Zhu Gong
*
*
The Bigger Picture
SUMMARY
The contradiction between the
growing demands for chemicals
and decreasing fossil resources
has prompted chemists to search
for ideal synthetic strategies.
Living cells produce complicated
molecules with an extreme
Mimicking the way nature synthesizes organic molecules, multi-catalyst relay
catalysis (MCRC), based on the seamless combination of a series of catalytic re-
actions, has emerged as a promising strategy for achieving ideal synthesis. In
such systems, each step takes place orderly and sequentially. Taken as a whole,
the entire process appears indistinguishable from a common one-step reaction
but provides a means for extraordinary transformations. Here, we report a one-
step transformation of styrenes, allylic alcohols, and syngas to a-quaternary chi-
ral aldehydes in a multi-catalyst system consisting of a rhodium(I) complex, a
palladium(0) complex, a chiral Brønsted acid catalyst, and an achiral amine
(20–100 mol %). The cascade hydroformylation and asymmetric allylation reac-
tion was realized with high yields (up to 98%) and high enantioselectivities (up to
99% ee) under mild conditions (1 bar of syngas).
efficiency that organic chemists
have long tried to imitate. In
recent years, mimicking the way
that nature synthesizes organic
molecules has emerged as a
promising strategy for achieving
ideal synthesis. A prominent
example of such an approach is
multi-catalyst relay catalysis
(MCRC), which requires the
seamless combination of a series
of catalytic reactions. In this
paper, using a highly compatible
and efficient multi-catalyst
INTRODUCTION
One extraordinary feature of living organisms is their efficient synthesis of numerous
complicated metabolites via a series of enzyme-catalyzed transformations taking
place simultaneously and disciplinarily in one reactor (cell).1 In contrast, multi-step
syntheses in the laboratory and the factory generally require each step to be
performed separately, both in time and space, and usually with the intermediate
products isolated before the next step. In recent years, by mimicking the feature
of biosystems, multi-catalyst relay catalysis (MCRC), on the basis of the combined
use of two or more distinct catalysts, has emerged as a promising strategy for
achieving ideal organic synthesis (Figure 1).2–7 In such systems, different types of cat-
alysts (i.e., metal catalysts, organocatalysts, or enzyme catalysts) work either coop-
eratively or independently to fulfill traditional multi-step synthesis in one operation,
dramatically reducing waste, solvents, time, labor, etc.
system, we have developed a
cascade hydroformylation and
asymmetric allylation reaction that
transforms styrenes, allylic
alcohols, and syngas to
a-quaternary chiral aldehydes in
one step. The current work offers
the potential for multi-catalytic
approaches and new types of
relay processes.
MCRC has achieved successes in important transformations in recent years. For
example, combining olefin hydrogenation and dehydrogenation with olefin metath-
esis has led to successful hydrocarbon upgrading reactions, including an alkane
metathesis process.8,9 Huff and Sanford10 reported the reduction of CO2 to meth-
anol by combining three different metal-catalyzed processes. The Marks group
achieved etheric C–O hydrogenolysis using coupled tandem catalytic cycles.11 Us-
ing the Rh/Ru dual catalyst system, Nozaki and co-workers realized an efficient
transformation from alkenes to linear alcohols,12 and the Shell hydroformylation pro-
cess has used cobalt or phosphine catalyst to convert higher olefins to linear alcohols
for years. The Lautens group combined a Rh-catalyzed alkyne arylation process
and palladium (Pd)-catalyzed C–X (X = O, N) bond coupling process to obtain
Chem 4, 1–12, May 10, 2018 ª 2018 Elsevier Inc.
1

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Cat 1
Cat 2
Cat n
...
Substrates
Intermediate 1
Product
Figure 1. The Concept of Multi-catalyst Relay Catalysis (MCRC)
pharmacologically relevant heterocycles.13 Catalytic asymmetric reactions have also
been coupled with other catalytic processes. Within this subfield, the combination of
a metal catalyst (either chiral or achiral) and a chiral organocatalyst has led to a large
number of successful cascade reactions.14–18 As examples, Eilbracht19 and Breit20
and co-workers independently reported Rh/chiral-amine-catalyzed hydroformyla-
tion and asymmetric aldol reactions. Che and co-workers21 and our group22 inde-
pendently developed the Au/chiral-Brønsted-acid-catalyzed hydroamination and
asymmetric reduction process. Through the combination of Rh/chiral Brønsted
acid, the asymmetric hydroaminomethylation of alkenes was reported by Xiao and
coworkers23 and our group.24
Although this area has witnessed continuous success, problems and formidable
challenges still exist: (1) multi-catalyst systems involving more than three distinct
catalysts, which provide opportunities to fulfill more sophisticated transformations
and at the same time may obviously cause much more compatibility issues be-
tween catalysts and intermediates, are rarely seen; (2) the number of successful
multi-catalyst systems, especially those providing general and versatile transforma-
tions, are still limited; and (3) most of the multi-catalyst-system-catalyzed asym-
metric cascade transformations use carefully designed substrates, which require
multi-step synthesis of themselves. With understanding of the state of the art
and the challenges in mind, here, using three (or four) different types of catalysts,
we establish a transformation of readily available styrenes, allylic alcohols, and syn-
gas into chiral a-quaternary functionalized aldehydes through the combination of
Rh-catalyzed hydroformylation and asymmetric allylation catalyzed cooperatively
by Pd and organocatalysts.
Transition-metal-catalyzed hydroformylation is one of the largest homogeneous
catalytic processes in the world (Figure 2A).25–30 Transition-metal-catalyzed allyla-
tion (known as the Tsuji-Trost reaction for the Pd-catalyzed process) is one of the
most versatile transformations to form CꢀC bonds in organic synthesis (Fig-
ure 2B).31,32 The combination of these two important processes, which means
performing the two reactions simultaneously in one reactor, may provide great op-
portunities to develop efficient transformations from simple starting materials. In
our hypothesis (Figure 2C), the alkenes undergo rhodium (Rh)-catalyzed branch-se-
lective hydroformylation, followed by a synergistically Pd- and amine-catalyzed
asymmetric a-allylation of the aldehydes generated in situ to produce a-quaternary
functionalized chiral aldehydes, a class of highly valuable compounds.33–47 How-
ever, such a combined process poses a number of formidable challenges, some
of which even appear to be intrinsic issues and virtually impossible to overcome.
For examples, a careful selection of catalysts and reaction conditions is needed
to inhibit the hydroformylation of the allylating reagent and the product, which
also possess C–C double bonds. The presence of CO gas will almost definitely
deactivate the Pd catalyst and make the whole reaction sluggish. The p-allyl Pd
complex could be reduced by H2 gas or the intermediary Rh hydride48,49 or un-
dergo a carbonylation reaction in the presence of CO.50 List and co-workers re-
ported the direct a-allylation of aldehydes and ketones cooperatively catalyzed
1Hefei National Laboratory for Physical Sciences
at Microscale and Department of Chemistry,
University of Science and Technology of China,
Hefei 230026, China
2Collaborative Innovation Center of Chemical
Science and Engineering, Tianjin 300071, China
3Lead Contact
*Correspondence:
hanzy2014@ustc.edu.cn (Z.-Y.H.),
gonglz@ustc.edu.cn (L.-Z.G.)
https://doi.org/10.1016/j.chempr.2018.03.010
2
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A Transition-Metal-Catalyzed Hydroformylation of Olefins:
CHO
CHO
M (Rh, Co, etc)
CO/H2
R
+
R
R
branched
linear
One of the largest homogeneous catalytic process in the world.
B Transition-Metal-Catalyzed Allylations:
M (Pd, Ir, Mo, etc)
X
Nu
NuH
+
X: OAc, Cl, Br, OH, etc.
One of the most versatile C-C bond forming reactions.
C Cascade Branch-Selective Hydroformylation/Asymmetric Allylation reaction: This Work
CHO
Rh/Pd/Organo, CO/H2
R'
OH
R'
+
R
*
R
one step
1
2
3
up to 98% yield
up to >99% ee
Hydroformylation of the allylic alcohol and the product.
Deactivation of the palladium catalyst by CO coordination.
Carbonylation and hydrogenation of the p-allyl palladium complex.
Challenges:
Figure 2. Transition-Metal-Catalyzed Hydroformylation of Olefins, Transition-Metal-Catalyzed
Allylation, and Cascade Hydroformylation and Asymmetric Allylation Reaction
by Pd and organocatalysts.51–53 We previously reported Rh/chiral-Brønsted-acid-
catalyzed hydroaminomethylation of alkenes.24 Encouraged by these and other
studies on asymmetric a-allylation of aldehydes,54–59 we initiated the hypothesized
reaction. Allylic alcohols were chosen as the allylating agent because of their easy
accessibility.60 A catalyst system combining Pd and organocatalysts17,52 was
selected to promote the asymmetric a-allylation of the aldehyde generated
in situ. As shown in a detailed mechanism (Figure 3), in the presence of an achiral
Pd(0) catalyst and the BINOL-derived chiral phosphoric acid,61,62 the allylic alcohol
transforms into a p-allyl Pd complex bearing a chiral counter anion63–66 (the chiral
phosphate). The achiral amine (catalytic or stoichiometric amount) forms the
enamine intermediate with the a-branched aldehyde generated from the alkene
hydroformylation process.67,68 The enamine II reacts with the p-allyl Pd complex
IV to form a chiral imine VI, which yields the a-quaternary chiral aldehyde 3 and
releases the amine after in situ hydrolysis. In this proposed catalytic system, asym-
metric hydroformylation is not necessary because of the racemization caused by
the enamine formation process. The chiral phosphoric acid works as the sole chiral
element to control the stereoselectivity in the whole reaction.
RESULTS AND DISCUSSION
We initiated our study by investigating the model reaction of styrene 1a and cin-
namyl alcohol 2a in a syngas atmosphere by using a multi-catalyst system consist-
ing of a Rh complex, Pd(Ph3P)4, a chiral phosphoric acid (R)-TRIP (3,30-bis(2,4,6-trii-
sopropylphenyl)-1,10-binaphthyl-2,20-diyl hydrogenphosphate), and an achiral
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Figure 3. Proposed Mechanism for the Cascade Hydroformylation and Asymmetric Allylation Reaction Catalyzed by Rh, Pd, and Organocatalysts
The multi-catalyst system enables the direct transformation of alkenes, allylic alcohols, and syngas to a-quaternary chiral aldehydes.
amine A1 (Table 1). To diminish the side reactions caused by syngas and suppress
the inactivation effect on the Pd catalyst by CO coordination, we used 1 bar of syn-
gas (CO/H2 = 1:1), which later proved to be a key factor for the reaction.69 Given
that low syngas pressure can also result in a sluggish hydroformylation process, a
Rh complex prepared in situ from Rh(acac)(CO)2 and commercially available rac-
Ph-BPE (1,2-bis(2,5-diphenylphospholano)ethane), which has proven to be highly
active and highly branch-selective for the alkene hydroformylation reaction, was
used. Encouragingly, the expected product 3a was observed in 20% NMR yield
and with 89% ee (entry 1). Surprisingly, lowering the catalyst loading of Rh com-
plex to 1 mol % greatly increased the yield to 78%, albeit with a slightly lower
enantioselectivity (entry 2). This could have resulted from the ligand exchange be-
tween the Rh complex and the Pd complex. The coordination of the excess biden-
tate ligand Ph-BPE to the Pd probably led to poor conversion of the allylation step,
which was supported by a control experiment shown later. Further lowering the Rh
complex loading led to decreased yields, albeit with slightly enhanced enantiose-
lectivities (entries 3 and 4). Then, a detailed evaluation of different achiral amines
was performed. It turned out that the structure of the amines had a great impact on
both the yield and the stereoselectivity of the reaction (entries 5–9). However, the
initial amine A1 still proved optimal for the transformation. Further investigation
revealed that the ligand of the Pd complex was also crucial for the reaction. Using
Pd(dppe)2 or Pd[P(o-tol)3]2 instead of Pd(Ph3P)4 resulted in unproductive reactions
(entries 10 and 11). Increasing the amount of the achiral amine A1, which is readily
available and inexpensive, was found to be beneficial to the reaction in terms of
the yield and enantioselectivity (entries 12 and 13). In the presence of 1 equiv of
A1, the product 3a could be isolated in 87% yield and with 92% ee (entry 13).
At this stage, we investigated the effect of the pressure of the syngas. As ex-
pected, probably as a result of the deactivation effect caused by CO coordination
to the Pd catalyst, increasing the syngas pressure to 2 bar led to a sluggish reac-
tion (entry 14). Syngas at 4 bar rendered the reaction completely unproductive
(entry 15). Finally, a slightly higher yield and maintained enantioselectivity were
obtained by reducing the reaction time to 48 hr (entry 16). At 60ꢁC, similar levels
of yield and enantioselectivity were observed (entry 17).
Having established the optimized reaction conditions, we first investigated the
scope of allylic alcohols for the reaction with styrene 1a (Scheme 1; see also
4
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Table 1. Optimization of Catalysts and Reaction Conditions
Rh(acac)(CO)2 (x mol %)
rac-Ph-BPE (y mol %)
[Pd]/L (3 mol %), amine
(R)-TRIP (10 mol %)
CHO
Ph
Ph
Ph
OH
H2/CO
(1:1)
Ph
3 Å MS, MTBE, 30-60 oC
1a
3a
2a
Ar
O
NH2
NH2
NH2
R1
Ph
Ph
Ph
O
R2
A4
P
P
P
OH
A1: R1 = Me, R2 = Me
A2: R1 = H, R2 = Ph
A3: R1 = Ph, R2 = Ph
O
Ph Ph
A6
Ar
A5
rac-Ph-BPE
x/y
(R)-TRIP: Ar = 2,4,6-(iPr)3C6H2
NH2
Entry
1
[Pd]/L
Amine (mol %)
A1 (40)
H2/CO (bar)
Yield (%)a
20
ee (%)b
89
75
90
91
11
5
2/2.4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppe)2
Pd[P(o-tol)3]2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
1
1
1
1
1
1
1
1
1
1
1
1
1
2
4
1
1
2
1/1.2
A1 (40)
A1 (40)
A1 (40)
A2 (40)
A3 (40)
A4 (40)
A5 (40)
A6 (40)
A1 (40)
A1 (40)
A1 (80)
A1 (100)
A1 (100)
A1 (100)
A1 (100)
A1 (100)
78
3
0.5/0.6
45
4
0.25/0.3
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
27
5
50
6
51
7
72
31
60
49
–
8
43
9
83
10
11
12
13
14
15
16d
17e
trace
NR
78
–
91
92
91
–
87c
47c
trace
93c
91c
92
92
Unless indicated otherwise, the reaction was carried out under a CO/H2 (1:1, 1–4 bar) atmosphere in the scale of 1a (0.2 mmol), 2a (0.4 mmol), Rh(acac)(CO)2 (0.25–
˚
2 mol %), ligand (0.3–2.4 mol %), (R)-TRIP (10 mol %), and 3 A molecular sieve (150 mg) in tert-butyl methyl ether (2.0 mL). NR, no reaction.
aNMR yield with trimethyl benzene-1,3,5-tricarboxylate as the internal standard.
bDetermined by chiral high-performance liquid chromatography.
cIsolation yield.
dThe reaction was carried out for 48 hr.
eThe reaction was carried out at 60ꢁC.
Figures S1–S36 and S71–S106). A series of cinnamyl alcohols with either electron-
withdrawing or electron-donating substituents at the para, ortho, or meta position
of the arene moiety underwent the reactions smoothly to give the corresponding
a-quaternary aldehydes in moderate to excellent yields (57%–97%) and high to
excellent enantioselectivities (86%–99% ee, 3b–3i). An apparent trend was that
allylic alcohols bearing electron-withdrawing groups provided higher yields than
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Scheme 1. Substrate Scope for Allylic Alcohols
Unless indicated otherwise, the reaction was carried out under a CO/H2 (1:1, 1 bar) atmosphere in the scale of 1a (0.2 mmol), 2a (0.4 mmol),
ꢁ
˚
Rh(acac)(CO)2 (1 mol %), ligand (1.2 mol %), (R)-TRIP (10 mol %) and 3 A molecular sieve (150 mg) in tert-butyl methyl ether (2.0 mL) at 40 C for 48 hr.
those with electron-donating substituents (entries 3b–3d versus 3e and 3f). Cin-
namyl alcohol incorporating a heteroarene (i.e., entry 3j) was also tolerated and
converted to the expected product in moderate yield and excellent enantioselec-
tivity. For some substrates (i.e., 3e and 3j), elevating the reaction temperature from
40ꢁC to 60ꢁC led to higher yields and similar levels of enantioselectivity. Allylic al-
cohols with a terminal double bond, e.g., 1-arylallyl alcohol, were not tolerated for
the reaction, probably because of their high activity to undergo hydroformylation
under the reaction conditions. However, 2-aryl allylic alcohols bearing a disubsti-
tuted terminal olefin moiety, because of their lower tendency to participate in
the hydroformylation process, were well tolerated for the reaction (3k–3n).
Compared with those of the linear cinnamyl alcohol substrates, generally higher
enantioselectivities (95%–99% ee) were observed. To improve the functional group
diversity of the reaction, 4-CN, 4-CH2OH, and 3,4,5-trimethoxyl-substituted
cinnamyl alcohols were also tested and were all well tolerated for the reaction
(3p and 3r).
Next, the generality of styrenes was investigated with 2-phenylprop-2-en-1-ol and
cinnamyl alcohols as the counterparts (Scheme 2; see also Figures S37ꢀS64 and
6
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CHO
Rh(acac)(CO)2 (1 mol %)
rac-Ph-BPE (1.2 mol %)
Pd(PPh3)4 (3 mol %)
A1 (100 mol %)
(R)-TRIP (10 mol %)
OH
Ar'
Ar
Ar'
or
or
CHO
H2/CO
Ar
Ar'
3 Å MS, MTBE, 40 o
C
Ar'
OH
Ar
(1 bar, 1:1)
1
3
2
CHO
CHO
CHO
CHO
CHO
Me
MeO
F
Cl
Br
3v, 85%, 84% ee
3u, 60%, 94% ee
3w, 80%, 98% ee
3s, 77%, 99% ee
3t, 88%, 99% ee
CHO
CHO
CHO
MeO
CHO
CHO
F
Br
Cl
Me
3aa, 79%, 92% ee
3bb, 84%, 92% ee
3x, 73%, 94% ee
3y, 74%, 94% ee
3z, 74%, 93% ee
Cl
Cl
Cl
OMe
CHO
CHO
CHO
CHO
F3C
MeO
Br
CF3
3ff, 91%, 83% ee
3cc, 81%, 93% ee
3dd, 88%, 85% ee
3ee, 83%, 89% ee
Scheme 2. Substrate Scope for Styrenes
Unless indicated otherwise, the reaction was carried out under a CO/H2 (1:1, 1 bar) atmosphere in the scale of 1a (0.2 mmol), 2a (0.4 mmol),
ꢁ
˚
Rh(acac)(CO)2 (1 mol %), ligand (1.2 mol %), (R)-TRIP (10 mol %), and 3 A molecular sieve (150 mg) in tert-butyl methyl ether (2.0 mL) at 40 C for 48 hr.
S107ꢀS134). Generally, the reactions of 2-phenylprop-2-en-1-ol with various sty-
rene derivatives took place smoothly, giving the corresponding a-quaternary chiral
aldehydes in moderate to high yields with high to excellent enantioselectivities
(84%–99% ee, 3sꢀ3aa). Surprisingly, bromo-substituted styrenes were also well
tolerated for the cascade reaction involving Pd(0), giving bromo-containing prod-
ucts with excellent enantioselectivities (3w and 3y). This was probably because the
oxidative addition of Pd(0) to the bromoarene was suppressed in the CO atmo-
sphere. 4-Iodo-substituted styrene was also examined but failed to provide the
product. A number of substituted styrenes were also tested in the reactions with
cinnamyl alcohol and p-chlorocinnamyl alcohol and showed satisfying results
(3bbꢀ3ff). An arylalkene bearing two strong electron-withdrawing substituents
was also applicable to the reaction (3cc). Notably, in the presence of a catalytic
amount of amine A1 (40 or 20 mol %), the model reaction of 1a and 2a could pro-
ceed completely at a higher temperature and prolonged reaction time, and pro-
vided the product 3a with satisfying yields and enantioselectivities (Scheme 3).
As mentioned previously, one unusual observation was that a higher loading of Rh
catalyst (2/2.4 mol % Rh precursor and ligand) resulted in a much slower reaction.
To verify our hypothesis that the presence of the excess bidentate phosphine ligand
might prohibit the Pd-catalyzed allylation process, we performed a control experi-
ment starting from the aldehyde 4 with rac-Ph-BPE instead of Ph3P as the ligand
(Figure 4A). In accordance with our hypothesis, the reaction turned out to be
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Scheme 3. Cascade Reaction Using a Catalytic Amount of Amine
completely unproductive. To gain insight into the pathway of the reaction and also
to clarify the impact of CO and H2 on the asymmetric allylation process, we per-
formed a serial of control experiments with racemic 2-phenylpropanal 4 as the reac-
tant in the absence of Rh catalyst under various gas atmospheres (Figure 4B). In the
nitrogen atmosphere, the reaction of 4 and 2a provided (S)-3a in 84% yield and with
93% ee after a 10-hr reaction time (entry 1). The results strongly supported that the
cascade reaction of alkene and allylic alcohol proceeded through a hydroformyla-
tion and asymmetric allylation pathway. In the same reaction time, replacement
of the nitrogen gas with CO (1, 2, or 4 bar) severely suppressed the reaction and
slightly eroded the enantioselectivity (entries 2–4). Hydrogen gas (1 bar) also led
to a diminished yield, although the impact was much milder in comparison with
CO gas (entry 5). Switching to a syngas atmosphere (1 bar, 1:1), a serious inhibition
effect was observed as well (entry 6). However, 86% yield and 90% ee could also be
achieved in a prolonged reaction time (entry 7). In contrast, performing the reaction
with 2 bar of syngas (1:1) for 48 hr provided the product only in 41% yield (entry 8),
also indicating that low syngas pressure was a key factor for the cascade reaction.
To illustrate the synthetic utility of the reaction, we performed a series of transfor-
mations of the a-quaternary chiral aldehyde 3k (Figure 5; see also Figures
S65ꢀS70 and S135ꢀS140). The aldehyde 3k could also be applied to the Wittig
reaction to give chiral compound 5 bearing two C=C double bonds. The treat-
ment of 3k with hydroxylamine hydrochloride followed by heating at 70ꢁC in
the presence of carbonyldiimidazole afforded chiral nitrile 6 with the conservation
of the stereochemical information. A one-pot sequential reductive amination of 3k
with 4-methoxylbenzyl amine furnished chiral amine 7 with excellent stereochem-
ical fidelity.
In summary, we have successfully developed a cascade transformation of styrenes,
allylic alcohols, and syngas to a-quaternary chiral aldehydes in a multi-catalyst sys-
tem consisting of a Rh(I) complex, a Pd(0) complex, a chiral Brønsted acid, and an
achiral amine (20–100 mol %). The reaction proceeds through an alkene hydroforma-
tion and asymmetric allylation sequence. Under a 1 bar syngas atmosphere, which
was demonstrated to be crucial for the reaction, Rh-catalyzed branched-selective hy-
droformylation and Pd- and organo-catalyzed asymmetric allylation occur simulta-
neously and orderly, allowing for the generation of a-quaternary chiral aldehydes
in high yields (up to 98%) and enantioselectivities (up to 99% ee).
EXPERIMENTAL PROCEDURES
To a flame-dried, nitrogen-filled Schlenk tube equipped with a stir bar were added
alkene 1 (20.8 mg, 0.2 mmol), allylic alcohol 2 (0.4 mmol, 2.0 equiv), 2-phenylpro-
pan-2-amine (5.4–27.0 mg, 0.2–1.0 equiv), Rh(acac)(CO)2 (0.52 mg, 0.002 mmol,
0.01 equiv), Pd(Ph3P)4 (6.9 mg, 0.006 mmol, 0.03 equiv), (R)-TRIP (15.1 mg,
˚
0.02 mmol, 0.1 equiv), a 3 A molecular sieve (150 mg). Then, rac-Ph-BPE
8
Chem 4, 1–12, May 10, 2018

Please cite this article in press as: Meng et al., a-Quaternary Chiral Aldehydes from Styrenes, Allylic Alcohols, and Syngas via Multi-catalyst Relay
Catalysis, Chem (2018), https://doi.org/10.1016/j.chempr.2018.03.010
(R)-TRIP (10 mol%), A1 (100 mol %),
Pd(dba)2 (3 mol%), (rac)-Ph-BPE (6 mol %)
CHO
A
Ph
OH
Ph
CHO
Ph
Ph
MTBE (2 mL) , 3 Å MS
40°C, 48 h then 2 N HCl, 30 min
2a, 0.4 mmol
( )-4, 0.2 mmol
(S)-3a, not observed
Gas (1-4 Bar)
(R)-TRIP (10 mol %)
A1 (100 mol%), Pd(PPh3)4 (3 mol %)
CHO
Ph
B
Ph
OH
Ph
CHO
Ph
MTBE (2 mL) , 3 Å MS
40°C, 10-48 h then 2 N HCl, 30 min
2a, 0.4 mmol
( )-4, 0.2 mmol
3a
(S)-
Entry
Gas
Yield (%)
ee (%)
1
N2 (1 bar), 10 h
84
93
2
3
4
5
6
7
8
CO (1 bar), 10 h
CO (2 bar), 10 h
CO (4 bar), 10 h
H2 (1 bar), 10 h
7
89
87
87
90
90
90
90
7
6
57
12
86
41
H2/CO (1 bar), 10 h
H2/CO (1 bar), 48 h
H2/CO (2 bar), 48 h
Figure 4. Control Experiments Using rac-2-Phenylpropanal as Substrate
(A) The inhibition effect of Ph-BPE ligand to asymmetric allylation catalyzed by Pd and organocatalysts.
(B) Influence of CO and H2 on the allylation reaction.
(0.0024 mmol, 0.012 equiv) in 0.25 mL of toluene and 2.0 mL of tert-butyl methyl
ether were added under nitrogen. After that, oxygen was removed by a freeze-
pump-thaw process three times. The Schlenk tube was refilled with 1 bar of syngas
(CO:H2 = 1:1). After being stirred at 40ꢁC for 48 hr, the vial was cooled down to
room temperature, and the reaction mixture was acidified with 2 N HCl (2 mL) at
room temperature for 30 min and extracted with ethyl ether (4 3 5 mL). The com-
bined organic layers were dried over anhydrous Na2SO4. The mixture was filtered
and concentrated in vacuo. The residue was purified through flash column chroma-
tography (SiO2, hexanes/acetonitrile = 8/1) to provide product 3. See the Supple-
mental Information for more detailed experimental procedures and characteriza-
tion data for all products.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures and 140
figures and can be found with this article online at https://doi.org/10.1016/j.chempr.
2018.03.010.
Chem 4, 1–12, May 10, 2018
9

Please cite this article in press as: Meng et al., a-Quaternary Chiral Aldehydes from Styrenes, Allylic Alcohols, and Syngas via Multi-catalyst Relay
Catalysis, Chem (2018), https://doi.org/10.1016/j.chempr.2018.03.010
CO2Et
(EtO)2POCH2COOEt, LiCl
DBU, CH3CN
5, 64%, 99% ee
CN
CHO
1) NH2OH HCl NaOAc, EtOH
2) CDI, THF, heat, then H2O
6, 62%, 99% ee
3k, 99% ee
PMBHN
1) PMBNH2, toluene, 4Å MS
2) LiAlH4, Et2O, 0 o
C
7, 46%, 98% ee
Figure 5. Transformations of a-Quaternary Chiral Aldehyde Products
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Natural Science Founda-
tion of China (grants 21502183 and 21772184) and the Chinese Academy of Science
(grant XDB20000000).
AUTHOR CONTRIBUTIONS
J.M. carried out the experimental and data-analysis work. L.-F.F. performed the deri-
vation reactions of the product. Z.-Y.H. and L.-Z.G. designed the reaction and
directed the project. Z.-Y.H. and L.-Z.G. wrote the paper with the assistance of
J.M. and L.-F.F.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: December 17, 2017
Revised: February 11, 2018
Accepted: March 12, 2018
Published: April 5, 2018
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