Counterion-Enhanced Pd/Enamine Catalysis: Direct Asymmetric α-Allylation of Aldehydes with Allylic Alcohols by Chiral Amines and Achiral or Racemic Phosphoric Acids

Article abstract of DOI:10.1021/acs.joc.0c02385

We report a straightforward and efficient Pd/enamine catalytic procedure for the direct asymmetric α-allylation of branched aldehydes. The use of simple chiral amines and easily prepared achiral or racemic phosphoric acids, together with a suitable Pd-source resulted in a highly active and enantioselective catalyst system for the allylation of various α-branched aldehydes with different allylic alcohols. The reported procedure could provide an easy access to both product antipodes. Furthermore, two possible orthogonal derivatizations of the enantioenriched aldehydes were performed without any decrease in enantioselectivity.

Full text of DOI:10.1021/acs.joc.0c02385

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Article
Counterion-Enhanced Pd/Enamine Catalysis: Direct Asymmetric
α‑Allylation of Aldehydes with Allylic Alcohols by Chiral Amines and
Achiral or Racemic Phosphoric Acids
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́
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Adam Mark Palvolgyi, Jakob Smith, Michael Schnurch, and Katharina Bica-Schroder*
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ABSTRACT: We report a straightforward and efficient Pd/enamine catalytic procedure for the direct asymmetric α-allylation of
branched aldehydes. The use of simple chiral amines and easily prepared achiral or racemic phosphoric acids, together with a suitable
Pd-source resulted in a highly active and enantioselective catalyst system for the allylation of various α-branched aldehydes with
different allylic alcohols. The reported procedure could provide an easy access to both product antipodes. Furthermore, two possible
orthogonal derivatizations of the enantioenriched aldehydes were performed without any decrease in enantioselectivity.
electrophiles.7 Since then, enamine catalysis has played an
INTRODUCTION
■
important role in the field of asymmetric allylation.8−11 A few
Carbon−carbon bond-forming reactions were always in the
elegant procedures have also been found for the asymmetric α-
focus of organic chemistry. The synthesis of asymmetric all-
allylation of branched aldehydes including the synergistic use
carbon quaternary centers is particularly challenging, and
of a Pd-source with modified primary amino acids (Yoshida,
despite the growing numbers of advances in this field, it is still
Scheme 1a) or iridium catalysis with double stereocontrol
a difficult task because of the substantial steric repulsion
(Carreira).12−16 By expanding the use of their previously
between the reactants.1,2
established concept of asymmetric counteranion-directed
Optically active molecules bearing an allylic motif are
catalysis to asymmetric allylations, the List group developed
invaluable intermediates for the total synthesis of biologically
a three-component-catalyst system composed of a Pd-complex,
active compounds.3,4 Based on the pioneering work of Jiro
̅
an amine, and a chiral Brønsted acid known as TRIP (Scheme
1b).17−20 Even though the synthesis of TRIP requires a
multistep procedure and results in a rather pricy catalyst, they
achieved impressive catalytic activities together with a high
degree of enantioselectivity (Scheme 1b).20
Tsuji and Barry M. Trost, the palladium-catalyzed asymmetric
allylation involving an in situ-generated allylpalladium−π
complex is of special interest in this field. Thanks to the
indisputable advantages such as mild reaction conditions and
operational simplicity, it is still a crucial tool for the synthesis
of allylic compounds.5
Herein, we propose a concept of counterion-enhanced
catalysis for the enantioselective α-allylation of α-branched
aldehydes with allylic alcohols (Scheme 1c). The combination
of simple chiral amines together with readily prepared achiral
While the traditional Tsuji−Trost allylation requires both a
good nucleophile and an allylic compound with a suitable
leaving group, several advances have been published to
overcome this problem by merging organo− and transition−-
metal catalyses. In 2003, Krische and coworkers achieved
enone cycloallylations via dual activation of latent nucleophilic
Received: October 8, 2020
and electrophilic partners.6 Three years later, Cordova
́
reported the first Pd/enamine dual catalyst system relying on
Pd(PPh3)4 and pyrrolidine in the direct α-allylation of
nonbranched aldehydes and ketones with activated allylic
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© XXXX American Chemical Society
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A

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Scheme 1. Concepts for the α-Allylation of Branched Aldehydes
Scheme 2. Asymmetric α-Allylation of 2-Phenylpropanal
or racemic phosphoric acids and Pd(PPh3)4 resulted in high
catalytic activities and excellent stereocontrol. As no extensive
catalyst preparation is required, this methodology could
provide a good alternative to current state-of-the-art methods.
the amine source, together with the phosphoric acid P1
(Scheme 2).21 MTBE as an apolar aprotic solvent was used as
its low dielectric constant might facilitate the formation of
stronger contact ion pairs. In accordance with the relevant
literature, high amine loadings were used.20 After the initial
screening for proper concentrations and desiccant, the product
2a could be obtained in good yield, albeit with moderate
enantioselectivity (Table 1, entry 1). Gratifyingly, the ee could
be dramatically increased to 78% by simply changing the amine
source to the C2-symmetric diamine (R,R)-A2, also increasing
RESULTS AND DISCUSSION
■
To establish the new concept, we were initially interested in
the asymmetric α-allylation of 2-phenylpropanal (1a). Based
on our previous observations for asymmetric counterion-
enhanced catalysis, L-valine tert-butyl ester (A1) was chosen as
B
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the use of the phosphoric acid was also found to be crucial, as
both the reactivity and the selectivity drastically decrease in the
absence of compound P1 (Table 1, entry 4).
Table 1. Initial Screening and Proof of Concept
a
b
c
entry
amine
comment
yield (%)
ee (%)
1
2
3
4
5
(S)-A1
82
87
0
37
81
31 (S)
78 (R)
n.d.
35 (R)
0
To further tune our catalytic system, a series of different
achiral or racemic phosphoric acids have been synthesized
following a straightforward one- or two-step reaction
procedure using cheap and easily accessible phenols and
bisphenols as starting materials. The use of P1−P7 yielded the
allylation product 2a in high to excellent yields and
enantioselectivity (Figure 1). The best result was obtained
with the thymol-derived analogue P5, resulting in 98% yield
and 94% ee. To investigate whether the stereochemistry of the
racemic phosphoric acids plays a role in the reaction, the
BINOL-derived acid P8 was tested in the enantiopure form
(both isomers) and also as a racemic mixture. In all three cases,
product 2a was obtained with basically the same enantiose-
lectivity (73%), suggesting that match/mismatch scenarios
between the chiral amine and the racemic phosphoric acid do
not affect the degree of asymmetric induction. This is in good
agreement with our previous observations for organocatalytic
asymmetric transfer hydrogenations.21 Furthermore, diphenyl
phosphate as well as other Brønsted and Lewis acids
traditionally used for organocatalysis were also tested. Only
(R,R)-A2
0 mol % [Pd(PPh3)4]
0 mol % P1
0 mol % (R,R)-A2
a
Performed on a 0.375 mmol scale by using 4.0 mol % Pd(PPh3)4, 50
mol % amine, 6.25 mol % P1, 190 mg 5 Å molecular sieves, and 0.75
b
mmol allyl alcohol in 0.75 mL MTBE at 60 °C for 16 h. Determined
c
by gas chromatography (GC) analysis. Determined by chiral high-
performance liquid chromatography (HPLC) analysis using a Diacel
Chiralcel AS-H column. Absolute configurations were determined by
measuring the optical rotations and comparing with the literature
data.
the yield (Table 1, entry 2). As can be seen, all three catalyst
components are essential for achieving high catalytic activity
and selectivity. In the absence of Pd(PPh3)4, the formation of
2a could not be observed (Table 1, entry 3). Without the
amine source, the reaction presumably follows a pure enol
pathway catalyzed by the phosphoric acid P1, consequently
resulting in a racemic product (Table 1, entry 5). Nevertheless,
Figure 1. Effect of different acidic cocatalysts in the asymmetric α-allylation of 1a. The reaction conditions were identical to those used in Table 1,
entry 2.
C
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Table 2. Different Amines for the Asymmetric α-Allylation of 1a
a
b
c
entry
amine
A1
(R,R)-A2
(S,S)-A2
A3
A4
A5
A6
yield (%)
ee (%)
1
2
3
4
5
6
7
89
98
97
89
89
90
97
31 (S)
94 (R)
94 (S)
37 (R)
21 (R)
60 (R)
44 (R)
a
Performed on a 0.375 mmol scale by using 4.0 mol % Pd(PPh3)4, 50 mol % amine, 6.25 mol % P5, 190 mg 5 Å molecular sieves, and 0.75 mmol
b
c
allyl alcohol in 0.75 mL MTBE at 60 °C for 16 h. Determined by GC analysis. Determined by chiral HPLC analysis using a Diacel Chiralcel AS-
H column. Absolute configurations were determined by measuring the optical rotations and comparing with the literature data.
trifluoroacetic acid led to a comparable result of 75% ee; all
others resulted in significantly inferior results, highlighting the
particular advantages associated with the use of achiral or
racemic phosphoric acids P1−P7 (Figure 1, also see
Supporting Information Tables S2 and S3, pages S4−S6).
Next, a small set of chiral amines (A1−A6) was screened.
While the product 2a was formed in high yields in all cases, the
enantioselectivity was moderate when using an amine other
than (R,R)-A2 (Table 2). Presumably, the high rigidity of
amine (R,R)-A2 results in a significantly increased energy
difference between the diastereomorphic transition states,
therefore results in higher enantioselectivity.
Furthermore, by simply changing the amine source from
(R,R)-A2 to (S,S)-A2, the product (S)-2a could be obtained
with the same excellent enantioselectivity of 94% ee (Table 2,
entries 2−3). However, given the economic considerations, the
(R,R)-A2 analogue was used for further optimizations, as well
as for investigating the scope and limitations.
With the suitable amine [(R,R)-A2] and phosphoric acid
(P5) in hand, we sought to optimize the ratio of these two
components. Eventually, we found that the selectivity of the
product 2a highly depends on the amine-to-acid ratio. As the
allylic aldehyde 2a was obtained in rather high yield even in the
absence of the amine source (Table 1, entry 5), it is likely that
the level of asymmetric induction is determined by competing
enamine- and enol-mediated pathways (see the plausible key
intermediates in Figure 2). Decreasing the amine-to-acid ratio
leads to an increase in the enol-mediated product,
consequently resulting in lower ee values (Figure 2, left side,
see also Supporting Information Table S5, page S8). By
increasing the amine-to-acid ratio, the level of asymmetric
induction increases rapidly. Because of the higher nucleophil-
icity of the enamine, it can suppress the formation of the enol
intermediate and, therefore, lead to an optically active product;
howeverin accordance with the observations of Lista
rather high amine loading was necessary to achieve this. Based
on the results, it seems that the initially used amine-to-acid
ratio of 8:1 gives the best results (Figure 2, middle), while a
further increase in the amine loading could possibly increase
the free amine-to-enamine ratio to an undesired level: this
would lead to the phosphoric acid reacting with the free amine
rather than the enamine, thus hampering the selectivity (Figure
2, right side).
Figure 2. Effect of different amine-to-phosphoric acid ratios in the
asymmetric α-allylation of 1a using amine (R,R)-A2 and phosphoric
acid P5 (bottom), and the plausibly competing key intermediates for
the enol and enamine pathways (top).
Finally, the effect of the solvent was also investigated. Only
slight differences in the catalytic activity and selectivity were
observed (see Supporting Information Table S6, page S9) as
the allylic aldehyde 2a could be obtained in rather high yield
and enantioselectivity even in green, bio-derived solvents like
2-MeTHF. Most importantly, the solvent screening showed
that the use of toluene allowed both the reaction temperature
and the catalyst loadings to be decreased successfully.
Howeversimilar to previous reportsa relatively high
absolute amine loading was necessary to retain a high level
of asymmetric induction.
D
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Having optimized and established the catalytic system, we
explored the scope and limitations of the reaction by testing
different α-branched aldehydes (Scheme 3). Electron-with-
drawing and -donating groups in the meta and the para
positions of the aryl group were well tolerated, resulting in high
yields and enantioselectivity up to >99% ee for the allylic
aldehydes 2c−j under the previously optimized reaction
conditions; however, no reaction was observed when using
the ortho-substituted aldehyde 1b. Eventually, we also tried to
expand the scope to aliphatic aldehydes. Gratifyingly, both a
linear and a cyclic aliphatic substrate could be allylated by
simply increasing the temperature to 90 °C, yielding the
corresponding products (2k−l) with moderate to high yield
and enantioselectivity; even though still no reaction was
observed for short-chained aliphatic aldehydes (2m−n).
Furthermore, our catalyst system was found to well tolerate
different substituted allylic alcohols as well (Scheme 3).
Aliphatic and aromatic primary allylic alcohols readily
furnished the corresponding products (2o, 2r−2t) in good
to excellent yield and in excellent enantiopurity. Moreover,
acyclic and cyclic secondary allylic alcohols were also found to
be suitable reagents for the synthesis of 2p−q and 2u, with the
first two resulting in the rearranged, linear allylic aldehydes 2p
and 2q as major products (Scheme 3). Our procedure could
also give an easy access to both product enantiomers: when
using (S,S)-A2 for the allylation of 1a with allyl alcohol and
cinnamyl alcohol, the (S)-product antipodes [(S)-2a and (S)-
2o] could be obtained with the same excellent 94 and 95% ee,
respectively (Scheme 3).
Scheme 3. Scope and Limitations in the Asymmetric α-
Allylation of α-Branched Aldehydes
a
The proposed reaction mechanism comprises three catalytic
cycles (Figure 3). In the enamine cycle (marked with red), the
substrate 1a reacts with the free amine (R,R)-A2 to form the
enamine I. The allylpalladium−π complex II is generated in
the second catalytic cycle (green) via acidic activation of the
allylic alcohol and subsequent oxidative addition to the Pd0
species. The enamine intermediate I is then allylated with
complex II through the key intermediate III involving all three
catalyst components. This is then dissociated, resulting in the
formation of the imine IV, meanwhile the phosphoric acid and
the Pd0 are regenerated (green and orange cycles). Finally,
hydrolysis of imine IV yields the product 2a. Alternatively, the
free amine (R,R)-A2 could also be allylated directly to give VI;
howevergiven the high catalytic efficiencythis must
dissociate as the reaction proceeds. Based on our observations
and in accordance with the literature, a rather high amine
loading is necessary.20 We suspect that the hydrolysis of the
imine IV is rather slow, therefore a relatively high amine
loading is necessary to speed it up and thus ensure that the
enamine pathway outperforms the competing enol-mediated
reaction (see Figure 3). Our plausible mechanism is supported
by analytical studies, as the mass of the enamine I, the imine
IV, the allylpalladium−π complex II, and the activated allylic
alcohol V intermediates could all be detected via electron spin
ionization-mass spectrometry (ESI-MS) analysis (see Support-
ing Information page S67 for details). A similar study was
carried out by using the amine A1 via GC−MS analysis,
resulting in the same type of proposed catalytic cycle (see
Supporting Information pages S67−S70 for details).
a
Reactions were performed on a 0.75 mmol scale by using 1.5 mol %
Pd(PPh3)4, 40 mol % amine(R,R)-A2, 5.0 mol % P5, 190 mg 5 Å
molecular sieves, and 1.50 mmol (substituted) allylic alcohol in 1.50
mL toluene at 40 °C for 16 h. Yields refer to pure products after
isolation by flash column chromatography. The enantioselectivity was
determined by chiral HPLC and chiral GC analysis. Absolute
configurations were determined by measuring the optical rotations
and comparing with the literature data. a(S,S)-A2, as the amine
source, resulting in the formation of (S)-2a. bA higher catalyst loading
of 4.0 mol % Pd(PPh3)4, 50 mol % (R,R)-A2, and 6.25 mol % P5 were
Furthermore, the enantioenriched allylic aldehyde 2a could
be smoothly and orthogonally converted into the correspond-
ing formate 3 and into the dicarbonyl compound 4 via
Baeyer−Villiger oxidation and Wacker-oxidation, respectively,
retaining the excellent enantioselectivity of 2a (Scheme 4).
c
used. Reaction performed at 90 °C.
E
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Figure 3. Plausible reaction mechanism for the direct α-allylation of α-branched aldehyde 1a by using (R,R)-A2, phosphoric acid P5 and
Pd(PPh3)4. The product enantiomer generated in excess [(R)-2a] is illustrated in the cycle for clarity.
a
Scheme 4. Utilization of 2a for the Synthesis of the α-Branched Quaternary Allylic Formate 3 and Dicarbonyl Compound 4
a
(a) Performed on a 2.0 mmol scale by using 40 mol % amine (R,R)-A2, 5.0 mol % P5, 1.5 mol % Pd(PPh3)4, 190 mg 5 Å molecular sieves, and 4.0
mmol allyl alcohol in 4.0 mL toluene at 40 °C for 16 h. Yield refers to pure 2a after flash column chromatography. (b) Performed on a 1.0 mmol
scale by using 2.1 mmol mCPBA, 1.5 mmol NaHCO3, and 1.2 mmol Na2CO3 in anhydrous CH2Cl2 at 25 °C for 24 h. Purified by flash column
chromatography. (c) Performed on a 0.9 mmol scale by using 0.09 mmol PdCl2 and 0.09 mmol CuCl2 in a mixture of DME and water (v/v 9/1).
Purified by flash column chromatography.
relying on a commercially available chiral amine, a readily
synthesized phosphoric acid, and Pd(PPh3)4 resulted in a
simple and rather cheap chiral framework. The catalyst system
was found to be quite versatile, tolerating different aromatic
CONCLUSIONS
■
Herein, we reported a concept of counterion enhanced Pd/
enamine catalysis for the asymmetric α-allylation of α-
branched aldehydes. Our multicomponent catalyst system
F
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and the resulting clear solution was stirred for another 18 h at 95 °C
(heating mantle, IKA). After cooling down to room temperature, 4 N
HCl (25 mL) was slowly added. The precipitate was filtered off, and it
was washed with 4 N HCl. The product was further washed and
hydrolyzed by redissolving it in CH2Cl2 and washing several times
with 4 N HCl. After being dried over Na2SO4, removal of the solvent
yielded the phosphoric acid P2 as a lightly grayish solid (630 mg, 66%
yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.48 (br s, 1H,
POOH), 7.26 (s, 2H, H-arom), 7.02 (s, 2H, H-arom), 2.36 (s, 6H, 2×
CH3), 1.50 (s, 18H, 6× CH3−C); 31P NMR (162 MHz, CDCl3): δ
(ppm) 0.48. Analytical data were in accordance with the literature.
2,4,8,10-Tetra-tert-butyl-6-hydroxydibenzo[d,f ][1,3,2]-
dioxaphosphepine 6-oxide (P3) (Method B). A solution of 3-tert-
butyl-4-hydroxyanisole (2.47 g, 12.0 mmol, 1.0 equiv) in methanol
(75 mL) was prepared and a solution of KOH (2.77 g, 49.0 mmol, 4.1
equiv) and K3Fe(CN)6 (4.58 g, 14.0 mmol, 1.17 equiv) in water (75
mL) was added dropwise over 1 h at room temperature. The mixture
was stirred for 2 h before the addition of 50 mL of water. The
suspension was extracted with ethyl acetate (3 × 50 mL) and the
combined organic phases were washed with brine. After being dried
over Na2SO4, removal of the solvents under reduced pressure afforded
a light brown solid. After washing with n-hexane, 3,3′,5,5′-tetra-tert-
butyl-[1,1′-biphenyl]-2,2′-diol was obtained as an off-white powder
(1.80 g, 73% yield). The subsequent phosphorylation was carried out
according to the synthesis of P2 on a 4.4 mmol scale, yielding
phosphoric acid P3 as an off-white solid (1.97 g, 95% yield). HRMS
[(ESI-time-of-flight (TOF)] m/z: [M + Na]+ calcd for C28H41O4PNa,
495.2640; found, 495.2640; IR ATR (νmax/cm−1): 2955 (O−H),
2867 (C−H), 1615 (CC), 1302 (C−O), 1025 (C−H), 899 (C−H
and aliphatic aldehydes, as well as substituted primary and
secondary allylic alcohols. Furthermore, the possible orthog-
onal derivatization of the enantioenriched aldehydes was
demonstrated through the synthesis of the α-branched
quaternary allylic formate 3 and the dicarbonyl compounds 4.
EXPERIMENTAL SECTION
■
General Experimental Information. All purchased chemicals
from commercial suppliers were used without further purification. Dry
solvents were predistilled and desiccated on aluminum oxide columns
(PureSolv, Innovative Technology). Column chromatography was
performed on standard manual glass columns using Merck (40−60
μm) silica gel with predistilled solvents (EtOAc: ethyl acetate, Et2O:
diethyl ether). For TLC analysis, precoated aluminum-backed plates
were purchased from Merck (silica gel 60 F254). UV-active
compounds were detected at 254 nm. Non UV-active compounds
were detected using Hanessian’s stain solution (cerium molybdate
1
stain). H, 13C, and 31P nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker Advance UltraShield 200 or 400 MHz
spectrometer, and chemical shifts are reported in ppm using TMS
(tetramethylsilane) as the internal standard. Coupling constants (J)
are given in Hz. The following abbreviations are used to explain
multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), brs (broad singlet), dd (doublet of doublets), ddd
(doublets of doublet of doublets), and td (triplet of doublets). GC
measurements were performed on a Thermo Scientific Focus
instrument, by using the BGB5 column and a flame ionization
detector. Chiral HPLC measurements were carried out on a DIONEX
ultraperformance liquid chromatograph equipped with a PDA plus
detector (190−360 nm), using Diacel Chiralcel AS-H, OJ, or IB
columns (250 × 4.60 mm, 5 μm). Chiral GC measurements were
carried out on a Thermo Scientific Focus instrument, by using a
BGB173 column and a flame ionization detector. To determine the
absolute configuration, optical rotation was measured on an Anton
Paar MCP500 polarimeter under the specific conditions and the
results were compared to literature values. Concentrations are given in
g/100 mL. High-resolution MS analysis was performed using a HTC
PAL system autosampler, an Agilent 1100/1200 high-performance
liquid chromatograph, and an Agilent 6230 AJS ESI-time-of-flight
mass spectrometer. Microwave reactions were performed in a Biotage
Initiator Classic microwave reactor in sealed, 20 ml pressure tight
glass vials. Infrared (IR) spectra were recorded on a PerkinElmer
Spectrum 65 Fourier transform IR spectrometer equipped with a
specac MK II Golden Gate Single Reflection ATR unit.
1
arom), 701 (C−H arom); H NMR (400 MHz, CDCl3): δ (ppm)
10.57 (br s, 1H), 7.42 (br s, 2H), 7.12 (d, J = 2.0 Hz, 2H), 1.45 (s,
18H), 1.27 (s, 18H); 31P NMR (162 MHz, CDCl3): δ (ppm) 0.40;
13C{1H} NMR (100 MHz, CDCl3): δ 147.9, 144.3, 144.1, 140.2,
140.1, 130.1, 126.5, 125.3, 35.5, 34.7, 31.5, 31.3.
4,8-Di-tert-butyl-6-hydroxy-1,11-dimethyldibenzo[d,f ]-[1,3,2]-
dioxaphosphepine 6-oxide (P4). 3,3′-Di-tert-butyl-6,6′-dimethyl-
[1,1′-biphenyl]-2,2′-diol was prepared via method A on a 12.0
mmol scale. Column chromatography (silica gel, 1.5% EtOAc in light
petrol) afforded the diol as a white solid (910 mg, 45% yield). The
subsequent phosphorylation was carried out according to the
synthesis of P2 on a 3.4 mmol scale, yielding phosphoric acid P4
as a white solid (900 mg, 69% yield). HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C22H29O4PNa, 411.1701; found, 411.1732; IR ATR
(νmax/cm−1): 2961 (O−H), 2872 (C−H), 1610 (CC), 1308 (C−
1
O), 1023 (C−H), 901 (C−H arom), 700 (C−H arom); H NMR
(400 MHz, CDCl3): δ (ppm) 7.38 (dd, J = 8.0, 1.5 Hz, 2H), 7.11 (dd,
J = 11.8, 8.2 Hz, 2H), 2.01 (d, J = 27.3 Hz, 6H), 1.48 (d, J = 12.4 Hz,
18H); 31P NMR (162 MHz, CDCl3): δ (ppm) 3.99; 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 144.5, 144.3, 140.8, 140.7, 134.8, 130.1,
129.9, 128.9, 35.2, 31.3, 21.1.
Amine(S)-A1, (R,R)-A5, and (R,R)-A6 were prepared according to
literature procedures.22−24
General Procedures for the Phosphoric Acid Synthesis.
Phosphoric acids P1, P7, and P8 were prepared by direct
phosphorylation of the corresponding diols.25 Phosphoric acids
P2−P6 were prepared in a two-step fashion via oxidative coupling
of the corresponding phenols (method A or B) followed by
subsequent phosphorylation.26−28
6-Hydroxy-4,8-diisopropyl-1,11-dimethyldibenzo[d,f ][1,3,2]-di-
oxaphosphepine-6-oxide (P5). 3,3′-Diisopropyl-6,6′-dimethyl-[1,1′-
biphenyl]-2,2′-diol was prepared via method A on a 20.0 mmol scale.
Column chromatography (silica gel, 2.0% EtOAc in light petrol)
afforded the diol as a pale yellow liquid (2.03 g, 68% yield). The
subsequent phosphorylation was carried out according to the
synthesis of P2 on a 6.7 mmol scale, yielding phosphoric acid P5
as an amorphous brown solid (2.0 g, 83% yield). HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C20H25O4PNa, 383.1388; found, 383.1389;
IR ATR (νmax/cm−1): 2963 (O−H), 2872 (C−H), 1610 (CC),
1204 (C−O), 967 (C−H), 818 (C−H arom), 696 (C−H arom); 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.24 (br s, 1H), 7.27 (d, J = 8.0
Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.49−3.45 (m, 2H), 2.14 (s, 6H),
1.27 (dd, J = 25.5, 6.9 Hz, 12H); 31P NMR (162 MHz, CDCl3): δ
(ppm) 2.40; 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 145.4,
137.7, 136.1, 128.0, 127.1, 126.3, 26.6, 24.1, 22.8, 19.7.
4,8-Di-tert-butyl-6-hydroxy-2,10-dimethyldibenzo[d,f ]-[1,3,2]-
dioxaphosphepine 6-oxide (P2) (Method A). In a pressure-tight
MW-vial, 2-(tert-butyl)-4-methylphenol (1.5 g, 12.0 mmol, 1.0 equiv)
was dissolved in chlorobenzene (7.2 mL, 1.66 M solution) and di-tert-
butyl peroxide (2.3 mL, 12.6 mmol, 1.05 equiv) was added. The vial
was sealed, and it was stirred for 15 min at room temperature. The
vial was then placed in a microwave reactor and the reaction mixture
was stirred for 15 min (160 °C, high absorption setting and 10 bar
pressure limit to avoid safety issues). The reaction mixture was
allowed to cool down, and volatiles were removed in vacuo. Column
chromatography (silica gel, 1.5% EtOAc in light petrol) afforded 3,3′-
di-tert-butyl-5,5′-dimethyl-[1,1′-biphenyl]-2,2′-diol as a pale yellow
solid (845 mg, 56% yield). To the solution of this diol (800 mg, 2.45
mmol, 1.0 equiv) in pyridine (7 mL), POCl3 (0.51 mL, 5.4 mmol, 2.2
equiv) was slowly added via a syringe at 0 °C. The reaction mixture
was stirred for 24 h at 95 °C (heating mantle, IKA). After being
cooled down to room temperature, distilled H2O (4 mL) was added,
4,8-Di-tert-butyl-6-hydroxy-2,10-dimethoxydibenzo[d,f ]-[1,3,2]-
dioxaphosphepine-6-oxide (P6). 3,3′-Di-tert-butyl-5,5′-dimethoxy-
[1,1′-biphenyl]-2,2′-diol was prepared according to literature
procedure (method B) on a 4.0 mmol scale. The subsequent
G
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Article
phosphorylation was carried out according to the synthesis of P2 on a
0.8 mmol scale, yielding phosphoric acid P6 as a light brown solid
(300 mg, 89% yield). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C22H29O6PNa, 443.1599; found, 443.1595; IR ATR (νmax/cm−1):
2971 (O−H), 2870 (C−H), 1613 (CC), 1210 (C−O), 1002 (C−
H), 822 (C−H arom), 703 (C−H arom); 1H NMR (400 MHz,
CDCl3): δ (ppm) 10.88 (br s, 1H), 6.96 (d, J = 2.0 Hz, 2H), 6.66 (d,
J = 2.0 Hz, 2H), 3.74 (s, 6H) 1.42 (s, 18H); 31P NMR (162 MHz,
CDCl3): δ (ppm) 1.64; 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
156.4, 142.7, 142.6, 140.4, 140.2, 131.0, 115.1, 113.0, 55.7, 35.5, 31.1.
General Procedure for Parameter Optimization. All reactions
were carried out in flame-dried Schlenk tubes (25 mL, VWR) by using
the standard Schlenk technique. A flame-dried Schlenk tube was
charged with finely ground and freshly activated 5 Å molecular sieves
(190 mg), Pd(PPh3)4 (17.3 mg, 0.015 mmol, 4.0 mol %), amine or
amino-acid ester (50 mol %), phosphoric acid (6.25 mol %), and
solvent (0.75 mL). Allyl alcohol (50 μL, 0.75 mmol, 2.0 equiv) and 2-
phenylpropanal (50 μL, 0.375 mmol, 1.0 equiv) were added and the
reaction mixture was stirred at the specific temperature for 16 h (in a
preheated and stirred oil bath). Upon completion, Et2O (3 mL) and 2
N HCl (5 mL) were added, and the reaction mixture was vigorously
stirred for 30 min. A sample for GC and chiral HPLC analysis was
taken to determine the yield and the enantioselectivity.
124.2, 118.2, 52.8, 41.2, 22.3, 18.2; chiral HPLC analysis: (Diacel
Chiralcel AS-H column, n-hexane/2-propanol 99.8/0.2 v/v %, 0.4
mL/min, λ = 210 nm) tR (R) = 18.0 min, no minor enantiomer was
detected.
(R)-2-(3-Chlorophenyl)-2-methylpent-4-enal (2e).12 Column
chromatography (silica gel, light petrol/Et2O 10:1) afforded 2e as a
colorless oil (145 mg, 93% yield, 91% ee). [α]2D0 −65.5 (c 1.0,
CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm), 9.43 (s, 1H), 7.24−
7.21 (m, 3H), 7.07−7.03 (m, 1H), 5.56−5.35 (m, 1H), 5.03−4.94
(m, 2H), 2.57−2.54 (m, 2H), 1.36 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 201.1, 141.7, 134.9, 132.6, 130.0, 127.6,
125.5, 119.1, 53.6, 40.6, 18.8; chiral HPLC analysis: (Diacel Chiralcel
AS-H column, n-hexane/2-propanol 99.8/0.2 v/v %, 0.5 mL/min, λ =
210 nm) tR (S) = 21.8 min, tR (R) = 23.0 min.
(R)-2-(4-Chlorophenyl)-2-methylpent-4-enal (2f).19 Column
chromatography (silica gel, light petrol/Et2O 10:1) afforded 2f as a
colorless oil (140 mg, 90% yield, 95% ee). [α]2D0 −72.1 (c 1.0,
1
CHCl3); H NMR (200 MHz, CDCl3): δ (ppm) 9.40 (s, 1H), 7.25
(d, J = 8.0 Hz, 2H), 7.11−7.07 (d, J = 8.0 Hz, 2H), 5.53−5.33 (m,
1H), 4.99−4.91 (m, 2H), 2.56−2.51 (m, 2H), 1.34 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 201.3, 138.0, 133.4, 132.7, 129.0,
128.6, 119.0, 53.2, 40.6, 18.9; chiral HPLC analysis: (Diacel Chiralcel
OJ column, n-heptane/2-propanol 99.8/0.2 v/v %, 0.7 mL/min, λ =
235 nm) tR (R) = 20.1 min, tR (S) = 22.2 min.
General Procedure for Scope and Limitation. A flame-dried
Schlenk tube (25 mL, VWR) was charged with finely ground and
freshly activated 5 Å molecular sieves (190 mg), Pd(PPh3)4 (13.0 mg,
0.01125 mmol, 1.5 mol %), (1R,2R)-diaminocyclohexane [(R,R)-A2,
34.2 mg, 0.30 mmol, 40 mol %], phosphoric acid P5 (13.50 mg,
0.0375 mmol, 5.0 mol %), and toluene (1.5 mL). The corresponding
allylic alcohol (1.5 mmol, 2.0 equiv) and aldehyde (0.75 mmol, 1.0
equiv) were added, and the reaction mixture was stirred at 40 °C for
16 h (in a preheated and stirred oil bath). Upon completion, Et2O (6
mL) and 2 N HCl (10 mL) were added, and the mixture was
vigorously stirred for 30 min. The reaction mixture was filtered
through a short pad of Celite, and it was washed with Et2O several
times. The phases of the filtrate were separated, and the aqueous layer
was extracted with Et2O (2×). The combined organic phases were
washed with water, dried over Na2SO4, and concentrated in vacuo.
Purification by flash column chromatography (light petrol/Et2O 15:1
or 9:1, UV and Henessian’s stain visualization) afforded the pure
products. The enantioselectivity was determined by chiral HPLC
analysis.
(R)-2-Methyl-2-(4-methoxyphenyl)pent-4-enal (2g).18 Column
chromatography (silica gel, light petrol/Et2O 8:1) afforded 2g as a
colorless oil (136 mg, 89% yield, 93% ee). [α]2D0 −58.1 (c 1.0,
1
CHCl3); H NMR (200 MHz, CDCl3): δ (ppm) 9.38 (s, 1H), 7.09
(d, J = 10.0 Hz, 2H), 6.83 (d, J = 10.0 Hz, 2H), 5.58−5.41 (m, 1H),
5.01−4.93 (m, 2H), 3.72 (s, 3H), 2.58−2.56 (m, 2H), 1.34 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 210.9, 158.8, 133.3,
131.2, 128.3, 118.5, 114.2, 55.2, 52.9, 40.5, 18.9; chiral HPLC
analysis: (Diacel Chiralcel AS-H column, n-hexane/2-propanol 99.5/
0.5 v/v %, 1.0 mL/min, λ = 235 nm) tR (major) = 10.9 min, tR
(minor) = 11.8 min.
(R)-2-(4-Isobutylphenyl)-2-methylpent-4-enal (2h).19 Column
chromatography (silica gel, light petrol/Et2O 13:1) afforded 2h as a
colorless oil (158 mg, 92% yield, 91% ee). [α]2D0 −70.3 (c 1.0,
1
CHCl3); H NMR (200 MHz, CDCl3): δ (ppm) 9.42 (s, 1H), 7.07
(s, 4H), 5.58−5.38 (m, 1H), 5.01−4.92 (m, 2H), 2.59−2.54 (m, 2H),
2.38 (d, J = 8.0 Hz, 2H), 1.78 (sept., J = 8.0 Hz, 1H) 1.35 (s, 3H),
0.82 (d, J = 8.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 202.0, 140.8, 136.6, 133.4, 129.6, 126.9, 118.4, 53.3, 44.9, 40.6,
30,1, 18.9; chiral HPLC analysis: (Diacel Chiralcel AS-H column, n-
hexane/2-propanol 99.8/0.2 v/v %, 0.5 mL/min, λ = 235 nm) tR (R)
= 13.0 min, tR (S) = 14.4 min.
2-Phenyl-2-methylpent-4-enal (2a).19 Column chromatography
(silica gel, light petrol/Et2O 10:1) afforded 2a as a colorless oil [(R)-
enantiomer: 122 mg, 93% yield, 94% ee], [(S)-enantiomer: 124 mg,
94% yield, 94% ee]. [α]2D0 −69.0 (c 1.0, CHCl3), [(R)-enantiomer]
(R)-2-(Naphtalen-2-yl)-2-methylpent-4-enal (2i).19 Column chro-
matography (silica gel, light petrol/Et2O 9:1) afforded 2i as a
colorless oil (151 mg, 90% yield, 88% ee). [α]2D0 −109.2 (c 1.0,
CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm) 9.45 (s, 1H), 7.73−
7.58 (m, 4H), 7.37−7.21 (m, 3H), 5.55−5.34 (m, 1H), 4.99−4.88
(m, 2H), 2.75−2.52 (m, 2H), 1.42 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 201.9, 136.9, 133.5, 133.2, 132.5, 128.6,
128.1, 127.6, 126.4, 126.3, 125.0, 118.7, 53.8, 40.6, 19.0; chiral HPLC
analysis: (Diacel Chiralcel AS-H column, n-hexane/2-propanol 99.8/
0.2 v/v %, 1 mL/min, λ = 235 nm) tR (R) = 15.9 min, tR (S) = 18.4
min.
1
and +68.2 (c 1.0, CHCl3), [(S)-enantiomer]; H NMR (200 MHz,
CDCl3): δ (ppm) 9.40 (s, 1H), 7.23−7.11 (m, 5H), 5.55−5.34 (m,
1H), 4.98−4.89 (m, 2H), 2.58−2.52 (m, 2H), 1.33 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 201.9, 139.5, 133.2, 128.9, 127.2,
118.6, 53.6, 40.6, 18.5; chiral HPLC analysis: (Diacel Chiralcel AS-H
column, n-heptane/2-propanol 99.8/0.2 v/v %, 1 mL/min, λ = 210
nm) tR (R) = 21.2 min, tR (S) = 26.0 min.
(R)-2-(3-Methylphenyl)-2-methylpent-4-enal (2c).19 Column
chromatography (silica gel, light petrol/Et2O 10:1) afforded 2c as a
colorless oil (130 mg, 92% yield, 90% ee). [α]2D0 −75.1 (c 1.0,
CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm): 9.41 (s, 1H), 7.18−
7.14 (m, 1H), 6.99−6.96 (m, 3H), 5.58−5.37 (m, 1H), 5.01−4.92
(m, 2H), 2.59−2.51 (m, 2H), 2.33 (s, 3H), 1.33 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 202.0, 139.4, 138.5, 133.3, 128.7,
128.1, 124.2, 118.5, 53.5, 40.6, 21.6, 18.8; chiral HPLC analysis:
(Diacel Chiralcel AS-H column, n-hexane/2-propanol 99.8/0.2 v/v %,
1 mL/min, λ = 210 nm) tR (R) = 8.1 min, tR (S) = 9.6 min.
(R)-2-(4-Methylphenyl)-2-methylpent-4-enal (2d).19 Column
chromatography (silica gel, light petrol/Et2O 12:1) afforded 2d as a
colorless oil (126 mg, 90% yield, >99% ee). [α]2D0 −61.3 (c 1.0,
CHCl3); 1H NMR (200 MHz, CDCl3): δ (ppm) 9.40 (s, 1H), 7.13−
7.03 (m, 4H), 5.58−5.37 (m, 1H), 5.00−4.91 (m, 2H), 2.66−2.46
(m, 2H), 2.25 (s, 3H), 1.34 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 201.9, 140.1, 138.0, 133.7, 128.5, 128.3, 128.0,
(R)-2-(4-(tert-Butyl)benzyl)-2-methylpent-4-enal (2j). Column
chromatography (silica gel, light petrol/Et2O 12:1) afforded 2j as a
colorless oil (160 mg, 87% yield, 80% ee). [α]2D0 −67.6 (c 1.0,
CHCl3); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H25O,
245.1905; found, 245.1902; IR ATR (νmax/cm−1): 3035 (C−H), 2965
(C−H arom), 2935 (C−H), 2160 (CC alkene), 1718 (CO),
1600 (CC arom), 1495 (C−H), 1446 (C−H), 840 (C−H arom),
764 (C−H arom), 700 (C−H arom); 1H NMR (200 MHz, CDCl3):
δ (ppm) 9.52 (s, 1H), 7.19 (d, J = 4.0 Hz, 2H), 6.95 (d, J = 4.0 Hz,
2H), 5.77−5.56 (m, 1H), 5.05−4.97 (m, 2H), 2.70 (d, J = 12.0 Hz,
2H), 2.33−2.04 (m, 2H), 1.21 (s, 9H), 0.94 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 206.1, 149.4, 133.5, 133.1, 129.9, 125.1,
118.8, 50.1, 41.4, 39.9, 34.4, 31.4, 18.6; chiral HPLC analysis: (Diacel
H
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Chiralcel OJ column, n-heptane/2-propanol 99.8/0.2 v/v %, 0.7 mL/
min, λ = 235 nm) tR (major) = 11.4 min, tR (minor) = 12.0 min.
(−)-2-Allyl-2-methylundecanal (2k). Column chromatography
(silica gel, light petrol/Et2O 50:1) afforded 2k as a colorless oil
(138 mg, 82% yield, 85% ee). [α]2D0 −10.2 (c 1.0, CHCl3); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H29O, 225.2218; found,
225.2210; IR ATR (νmax/cm−1): 2923 (C−H arom), 2854 (C−H),
(R)-2-Phenylpent-2,4-dimethyl-4-enal (2s).30 Column chromatog-
raphy (silica gel, light petrol/Et2O 15:1) afforded 2s as a colorless oil
(116 mg, 82% yield, 91% ee). [α]2D0 −51.8 (c 1.0, CHCl3); H NMR
1
(200 MHz, CDCl3): δ (ppm) 9.47 (s, 1H), 7.33−7.19 (m, 5H), 4.73
(s, 1H), 4.54 (s, 1H) 2.61 (dd, J = 20 Hz, 14 Hz, 2H), 1.39 (s, 3H),
1.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 202.3,
139.9 129.2, 128.8, 127.2, 125.4, 53.9, 39.3, 19.1, 17.9; chiral HPLC
analysis: (Chiralcel AS-H column, n-hexane/2-propanol 99.8/0.2 v/v
%, 0.5 mL/min, λ = 210 nm) tR (R) = 18.1 min, tR (S) = 23.6 min.
2-Phenylhex-2-methyl-4-enal (2t).19 Column chromatography
(silica gel, light petrol/Et2O 15:1) afforded 2t as a colorless oil
(120 mg, 85% yield, dr.: 4/1, 34% ee/91% ee). 1H NMR (200 MHz,
CDCl3, major diast.): δ (ppm) 9.42 (s, 1H, CHO), 7.28−7.13 (m,
5H, H-arom), 5.45−5.37 (m, 1H), 5.14−5.02 (m, 1H), 2.53−2.49
(m, 2H), 1.50 (d, J = 8.0 Hz, 3H), 1.32 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3, major diast.): δ (ppm) 202.3, 139.9, 129.2, 128.8,
127.2, 125.4, 53.9, 39.3, 19.1, 17.9; chiral HPLC analysis: (Chiralcel
AS-H column, n-hexane/2-propanol 99.8/0.2 v/v %, 0.5 mL/min, λ =
210 nm) tR (minor diast.) = 13.9 min, 14.4 min, tR (major diast.) =
16.2 min, 18.1 min.
1
1727 (CO), 1456 (C−H), 1191 (C−H), 840 (C−H arom); H
NMR (400 MHz, CDCl3): δ (ppm) 9.39 (s, 1H), 5.69−5.59 (m, 1H),
5.03−4.96 (m, 2H), 2.22−2.05 (m, 2H), 1.39−1.38 (m, 2H), 1.26−
1.10 (m, 14H) 0.95 (s, 3H), 0.81 (t, J = 6.0 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 206.4, 133.2, 118.3, 72.15, 49.0, 39.6,
35.3, 31.9, 30.2, 29.5, 29.3, 23.9, 22.7, 18.4, 14.1; chiral GC analysis
(BGB 173 column, 160 °C isothermal 70 min, 30 °C/min to 220 °C)
tR (major) = 70.3 min, tR (minor) = 71.6 min.
(−)-1-Allylcyclohex-3-ene-1-carbaldehyde (2l).29 Column chro-
matography (silica gel, light petrol/Et2O 20:1) afforded 2l as a
colorless oil (62 mg, 55% yield, 59% ee). [α]2D0 −5.6 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3): δ (ppm) 9.42 (s, 1H), 5.68−5.60 (m,
3H), 5.02−4.97 (m, 2H), 2.28−2.14 (m, 3H), 2.00−1.94 (m, 2H),
1.88−1.80 (m, 2H), 1.54−1.47 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 205.8, 132.7, 126.8, 124.4, 118.6, 47.9, 39.8, 29.5,
27.0, 22.0; chiral HPLC analysis: (Diacel Chiralcel OJ column, n-
hexane/2-propanol 99.5/0.5 v/v %, 0.3 mL/min, λ = 235 nm) tR
(minor) = 14.4 min, tR (major) = 15.3 min.
2-Phenyl-2-(cyclohex-2-en-1-yl)propanal (2u).29 Column chro-
matography (silica gel, light petrol/Et2O 20:1) afforded 2u as a
colorless oil (108 mg, 67% yield, dr.: 9/1, 43% ee/99% ee). 1H NMR
(200 MHz, CDCl3, major diast.): δ (ppm) 9.49 (s, 1H), 7.28−7.16
(m, 5H), 5.72−5.46 (m, 1H), 5.40−5.05 (m, 1H), 3.06−3.01 (m,
1H), 1.86 (br s, 2H), 1.71−1.01 (m, 7H); 13C NMR (100 MHz,
CDCl3, major diast.): δ (ppm) 202.7, 139.2, 130.0, 128.8, 127.7,
127.2, 126.7, 56.8, 41.0, 40.5, 24.9, 24.4, 14.9, 14.3; chiral HPLC
analysis: (Chiralcel AS-H column, n-hexane/2-propanol 99.8/0.2 v/v
%, 0.5 mL/min, λ = 210 nm) tR (minor diast.) = 19.3 min, 23.3 min,
tR (major diast.) = 20.7 min, 29.1 min.
(R)-2-Cinnamyl-2-methylundecanal (2v). Column chromatogra-
phy (silica gel, light petrol/Et2O 50:1) afforded 2v as a colorless oil
(164 mg, 73% yield, 66% ee). [α]2D0 −19.0 (c 1.0, CHCl3); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C21H33O, 301.2531; found,
301.2535; IR ATR (νmax/cm−1): 2923 (C−H arom), 2853 (C−H),
1702 (CO), 1184 (C−H), 700 (C−H arom); 1H NMR (400 MHz,
CDCl3): δ (ppm) 9.45 (s, 1H), 7.27−7.14 (m, 5H), 6.35 (d, J = 16.0
Hz, 1H), 6.05−5.97 (m, 1H), 2.37−2.25 (m, 2H), 1.48−1.41 (m,
2H), 1.26−1.12 (m, 14H) 1.00 (s, 3H), 0.81 (t, J = 6.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 206.4, 137.2, 133.4,
128.5, 127.3, 126.1, 124.9, 49.6, 38.8, 35.5, 31.9, 30.2, 29.5, 29.3, 24.0,
22.7, 18.7, 14.1; chiral HPLC analysis: (Chiralcel OJ column, n-
hexane/2-propanol 98/2 v/v %, 1 mL/min, λ = 254 nm) tR (R) = 6.2
min, tR (S) = 8.3 min.
Derivatization of the Enantioenriched Product 2a. Synthesis
of 2-Phenyl-2-methylpent-4-enal (2a) on 2.0 mmol Scale. The
synthesis was carried out in accordance with the general procedure for
scope and limitation in a 50 mL VWR Schlenk tube (in a preheated
and stirred oil bath). The reaction mixture was stirred at 40 °C for 16
h. The standard work-up procedure and the subsequent column
chromatographic purification yielded the product 2a as a colorless oil
(332 mg, 95% yield), which was used quantitively for the synthesis of
3 and 4, respectively.
(E)-2,5-Diphenylpent-2-methyl-4-enal (2o).19 Column chroma-
tography (silica gel, light petrol/Et2O 10:1) afforded 2o as a colorless
oil [(R)-enantiomer: 170 mg, 91% yield, 93% ee], [(S)-enantiomer:
167 mg, 89% yield, 95% ee]. [α]2D0 −100.2 (c 1.0, CHCl3), [(R)-
enantiomer] and +101.0 (c 1.0, CHCl3), [(S)-enantiomer]; 1H NMR
(200 MHz, CDCl3): δ (ppm) 9.46 (s, 1H), 7.34−7.09 (m, 10H), 6.30
(d, J = 16.0 Hz, 1H), 5.92−5.76 (m, 1H), 2.73−2.66 (m, 2H), 1.39
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 202.0, 139.5,
137.2, 133.6, 129.0, 128.5, 127.5, 127.3, 127.2, 126.2, 123.4, 54.1,
39.9, 19.0; chiral HPLC analysis: (Chiralcel AS-H column, n-hexane/
2-propanol 99/1 v/v %, 1 mL/min, λ = 210 nm) tR (R) = 9.8 min, tR
(S) = 12.0 min.
(R,E)-2-Methyl-2-phenyl-5-(thiophen-2-yl)pent-4-enal (2p).16
Column chromatography (silica gel, light petrol/Et2O 15:1) afforded
1
2p as a light yellow oil. (162 mg, 84% yield, 74% ee), H NMR (400
MHz, CDCl3): δ (ppm) 9.46 (s, 1H), 7.33−7.30 (m, 2H), 7.24−7.17
(m, 3H), 6.99 (d, J = 8.0 Hz, 1H), 6.83−6.81 (m, 1H), 6.74 (d, J =
8.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 5.73−5.65 (m, 1H), 2.69−
2.66 (m, 2H), 1.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 201.8, 142.3, 139.3, 130.0, 129.0 127.5, 127.2, 126.7, 124.9,
123.7, 54.1, 39.9, 18.9; chiral HPLC analysis: (Chiralcel AS-H
column, n-heptane/2-propanol 93/7 v/v %, 1 mL/min, λ = 254 nm)
tR (R) = 6.6 min, tR (S) = 7.6 min.
(R,E)-5-Cyclohexyl-2-methyl-2-phenylpent-4-enal (2q).16 Col-
umn chromatography (silica gel, light petrol/Et2O 15:1) afforded
1
2q as a colorless oil (148 mg, 77% yield, >99% ee). H NMR (400
MHz, CDCl3): δ (ppm) 9.45 (s, 1H), 7.32−7.05 (m, 5H), 5.34−5.28
(m, 1H) 5.07−5.04 (m, 1H), 2.52−2.50 (m, 2H), 1.78−1.50 (m,
6H), 1.33 (s, 3H), 1.11−1.07 (m, 4H), 0.93−0.90 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 202.4, 141.0, 140.0, 128.8, 127.2,
121.6, 54.0, 40.8, 39.4, 33.1, 26.1, 19.0; chiral HPLC analysis:
(Chiralcel AS-H column, n-heptane/2-propanol 99.8/0.2 v/v %, 1
mL/min, λ = 210 nm) tR (major) = 17.5 min, no minor enantiomer
was detected.
(R)-2-Phenylpent-4-en-2-yl Formate (3). Prepared according to
the literature procedure.31 To a solution of the enantioenriched allylic
aldehyde 2a (174.5 mg, 1.0 mmol) in anhydrous CH2Cl2 (15 mL),
mCPBA (70% assay, 394 mg, 2.10 mmol, 2.10 equiv), NaHCO3 (138
mg, 1.50 mmol, 1.50 equiv), and Na2CO3 (138 mg, 1.20 mmol, 1.20
equiv) were added, and the resulting suspension was stirred for 24 h
at room temperature. The reaction mixture was diluted with 10%
NaHCO3 and CH2Cl2 and the phases were separated. The aqueous
layer was extracted with CH2Cl2 (3×), and the combined organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. Flash column chromatography (light petrol/
Et2O 95:5) afforded the product 3 as a colorless liquid (152 mg, 80%
(R)-2-Methyl-2,4-diphenylpent-4-enal (2r).29 Column chromatog-
raphy (silica gel, light petrol/Et2O 10:1) afforded 2r as a colorless oil
(173 mg, 92% yield, 93% ee). [α]2D0 −93.6 (c 1.0, CHCl3); H NMR
1
(400 MHz, CDCl3): δ (ppm) 9.34 (s, 1H), 7.20−7.09 (m, 10H), 5.10
(s, 1H), 4.80 (s, 1H) 3.19 (d, J = 12.0 Hz, 1H) 4.80 (d, J = 12.0 Hz,
1H), 1.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
201.4, 145.0 142.3, 139.5, 128.6, 128.2, 127.4, 127.2, 126.6, 117.7,
54.4, 41.7, 18.9; chiral HPLC analysis (Chiralcel IB column, n-
hexane/2-propanol 99.5/0.5 v/v %, 1 mL/min, λ = 235 nm) tR (S) =
7.0 min, tR (R) = 7.8 min.
yield, 93% ee). [α]2D0 −55.2 (c 1.0, CHCl3); H NMR (200 MHz,
1
CDCl3): δ (ppm) 7.98 (s, 1H), 7.29−7.17 (m, 5H), 5.61−5.44 (m,
1H), 5.03−4.85 (m, 2H), 2.83−2.63 (m, 2H), 1.78 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ (ppm) 160.2, 143.6, 132.3, 128.4, 127.4,
I
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124.9, 119.1, 84.2, 46.8, 25.1; chiral HPLC analysis: (Chiralcel IB
column, n-hexane/2-propanol 99.8/0.2 v/v %, 1 mL/min, λ = 210
nm) tR (R) = 8.8 min, tR (S) = 9.3 min.
388−401. (f) Trost, B. M.; Jiang, C. Catalytic Enantioselective
Contruction of All-Carbon Quaternary Stereocenters. Synthesis 2006,
369−396. (g) Feng, J.; Holmes, M.; Krische, M. J. Acyclic Quaternary
Carbon Stereocenters via Enantioselective Transition Metal Catalysis.
Chem. Rev. 2017, 117, 12564−12580.
(R)-2-Methyl-4-oxo-2-phenylpenatal (4). Prepared according to
the literature procedure.32 To a solution of the enantioenriched allylic
aldehyde 2a (157.0 mg, 0.9 mmol, 1.0 equiv) in a mixture of H2O and
dimethoxyethane (4.5 mL, 1/9 v/v) was added PdCl2 (15.9 mg, 0.09
mmol, 0.1 equiv) and CuCl2 (12.1 mg, 0.09 mmol, 0.1 equiv) and the
resulting suspension was stirred overnight. The solvent was
evaporated in vacuo and the crude product was purified by flash
column chromatography (light petrol/EtOAc 5:1) affording the
product 4 as a light yellow oil (124 mg, 72% yield, 94% ee). [α]D20
(2) For selected advances, see: (a) Mikami, K.; Motoyama, Y.;
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Enantioselective Formation of All-Carbon Quaternary Stereocenters
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Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P. Asymmetric
catalytic formation of quaternary carbons by iminium ion trapping of
radicals. Nature 2016, 532, 218−222.
1
−66.0 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3): δ (ppm) 9.49
(s, 1H), 7.31−7.16 (m, 5H), 3.04 (dd, J = 26.0 Hz, 18.0 Hz, 2H),
2.00 (s, 3H), 1.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 206.0, 201.0, 139.2, 129.0, 127.5, 126.8, 51.8, 50.4, 30.9, 19.9;
chiral HPLC analysis: (Chiralcel IB column, n-hexane/2-propanol 95/
5 v/v %, 1 mL/min, λ = 220 nm) tR (S) = 10.3 min, tR (R) = 11.8
min.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02385.
■
sı
Detailed parameter optimization, NMR spectra, and
chiral HPLC traces (PDF)
(3) Trost, B. M.; Chisholm, J. D.; Wrobleski, S. T.; Jung, M.
Ruthenium-Catalyzed Alkene-Alkyne Coupling: Synthesis of the
Proposed Structure of Amphidinolide A. J. Am. Chem. Soc. 2002,
124, 12420−12421.
AUTHOR INFORMATION
Corresponding Author
■
̈
Katharina Bica-Schroder − Institute of Applied Synthetic
(4) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-
Catalyzed Allylic Alkylations: Applications in Total Synthesis. Chem.
Rev. 2003, 103, 2921−2944.
Chemistry, TU Wien, A-1060 Vienna, Austria; orcid.org/
0000-0002-2515-9873; Email: katharina.schroeder@
tuwien.ac.at
(5) For selected reviews, see: (a) Trost, B. M. Metal Catalyzed
Allylic Alkylation: Its Development in the Trost Laboratories.
Tetrahedron 2015, 71, 5708−5733. (b) Trost, B. M.; Van Vranken,
D. L. Asymmetric Transition Metal-Catalyzed Allylic Alkylations.
Authors
́
́
́
́
̈
Adam Mark Palvolgyi − Institute of Applied Synthetic
Chemistry, TU Wien, A-1060 Vienna, Austria
Jakob Smith − Institute of Applied Synthetic Chemistry, TU
Wien, A-1060 Vienna, Austria
́
Chem. Rev. 1996, 96, 395−422. (c) Dieguez, M.; Oscar, P. Biaryl
Phosphites: New Efficient Adaptative Ligands for Pd-Catalyzed
Asymmetric Allylic Substitution Reactions. Acc. Chem. Res. 2010,
43, 312−322. (d) Hong, A. Y.; Stoltz, B. M. The Construction of All-
Carbon Quaternary Stereocenters by Use of Pd-Catalyzed Asym-
metric Allylic Alkylation Reactions in Total Synthesis. Eur. J. Org.
Chem. 2013, 2745−2759.
Michael Schnurch − Institute of Applied Synthetic Chemistry,
̈
TU Wien, A-1060 Vienna, Austria; orcid.org/0000-
0003-2946-9294
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02385
(6) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. Catalytic Enone
Cycloallylation via Concomitant Activation of Latent Nucleophilic
and Electrophilic Partners: Merging Organic and Transition Metal
Catalysis. J. Am. Chem. Soc. 2003, 125, 7758−7759.
Notes
́
(7) Ibrahem, I.; Cordova, A. Direct Catalytic Intermolecular α-
The authors declare no competing financial interest.
Allylic Alkylation of Aldehydes by Combination of Transition-Metal
and Organocatalysis. Angew. Chem., Int. Ed. 2006, 45, 1952−1956.
(8) Weix, D. J.; Hartwig, J. F. Regioselective and Enantioselective
Iridium-Catalyzed Allylation of Enamines. J. Am. Chem. Soc. 2007,
129, 7720−7721.
ACKNOWLEDGMENTS
■
Financial support by the Austrian Science Fund (project
P29146-N34) is gratefully acknowledged. The authors thank F.
Scharinger for kindly providing phosphoric acids P6−P7.
(9) Liu, D.; Xie, F.; Zhang, W. Palladium-catalyzed asymmetric
allylic alkylation with an enamine as the nucleophilic reagent.
Tetrahedron Lett. 2007, 48, 7591−7594.
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