Organocatalytic Asymmetric α-Allylation and Propargylation of α-Branched Aldehydes with Alkyl Halides

Article abstract of DOI:10.1021/acs.joc.1c01394

Enantioselective α-allylation and -propargylation of α-branched aldehydes with alkyl halides was successfully performed using a chiral primary amino acid organocatalyst. This alkylation reaction, involving the generation of a chiral quaternary carbon stereocenter, proceeded smoothly in a mildly basic aqueous solution of potassium hydrogen carbonate to furnish α-allylated or -propargylated aldehydes in a good yield (up to 87%) and high enantioselectivity (up to 96% ee).

Full text of DOI:10.1021/acs.joc.1c01394

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Organocatalytic Asymmetric α‑Allylation and Propargylation of
α‑Branched Aldehydes with Alkyl Halides
Masanori Yoshida*
Cite This: J. Org. Chem. 2021, 86, 10921−10927
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ABSTRACT: Enantioselective α-allylation and -propargylation of α-branched
aldehydes with alkyl halides was successfully performed using a chiral primary
amino acid organocatalyst. This alkylation reaction, involving the generation of a
chiral quaternary carbon stereocenter, proceeded smoothly in a mildly basic aqueous
solution of potassium hydrogen carbonate to furnish α-allylated or -propargylated
aldehydes in a good yield (up to 87%) and high enantioselectivity (up to 96% ee).
nantioselective synthesis of a quaternary carbon stereo-
center is an important research topic in medicinal chemistry
branched aldehydes, leading to the generation of a chiral
quaternary carbon stereocenter, e.g., conjugate addition to
nitroalkenes12a and enones.12b Moreover, Tsuji−Trost allylation
was achieved through synergistic catalysis using a palladium
complex and a primary amino acid.12c−f As discussed in a
previous study by the Rios group,13 transition-metal-free
enamine-based organocatalytic α-alkylation of aldehydes with
alkyl halides still remains challenging since this reaction can
suffer from self-aldolization of substrates and alkylation of an
amine catalyst.3,7 Despite such difficulty of the transition-metal-
free amine catalyzed alkylation of aldehydes, several groups
successfully carried out the alkylation by using unique substrates.
For example, the List group reported that the asymmetric
intramolecular α-alkylation with halo aldehydes proceeded to
give cyclic compounds via the SN2 reaction.14a Cascade
reactions between aldehydes and halo nitroalkenes by Enders’
E
because chiral quaternary carbon stereocenters are found in
biologically active compounds such as pharmaceuticals and
agrochemicals, and their biological properties can be typically
modulated by changing the configuration of the chiral carbon
atoms. Various methods have been developed for the carbon−
carbon bond formation at a tertiary carbon atom, which is a
straightforward procedure to obtain a quaternary carbon atom.
However, the development of a highly enantioselective catalytic
method is challenging in organic synthesis.1,2 Generally, an
aldehyde is a useful substrate for the carbon−carbon bond
formation reaction because the presence of an acidic α-proton of
the formyl group enables the easy formation of an enolate, which
can be used as a carbon nucleophile. However, direct α-
alkylation via an aldehyde enolate typically suffers from side
reactions such as O-alkylation and aldol reactions.3 To avoid
this, aldehydes are generally converted into enolate equivalents,
such as silyl enol ethers4 and enamines,5 and then used as carbon
nucleophiles for the α-alkylation of aldehydes. The aldehyde
enolate equivalents facilitate the asymmetric formation of the
carbon−carbon bond, and a number of reports on the
asymmetric α-alkylation of aldehydes have been published so
far.6,7 Metal enolates of amides8a,b and esters8c are also known as
useful intermediates for synthesizing α-alkylated aldehydes. In
2000, the List, Lerner, and Barbas group reported L-proline as an
excellent catalyst for carrying out the intermolecular asymmetric
aldol reaction.9 Currently, organocatalytic α-alkylation of
aldehydes is recognized as one of the most important methods
for the asymmetric α-alkylation of aldehydes.10 By using amino
acid or amine organocatalysts, direct α-alkylation of aldehydes
can be achieved via the formation of an enamine intermediate. In
recent years, the combined use of organocatalysis and transition-
metal catalysis for the activation of both an electrophile and a
nucleophile to produce a carbon−carbon bond has attracted the
attention of synthetic organic chemists.11 We recently reported
the application of readily available primary amino acids and their
salts as effective catalysts for the asymmetric α-alkylation of α-
group14b and that between α,β-unsaturated aldehydes and
14c
́
bromomalonates by Cordova’s group
also gave cyclic
compounds with high enantioselectivity via the enamine-based
organocatalysis of aldehydes. As for the intermolecular syn-
thesis, the MacMillan group achieved asymmetric α-alkylation
of aldehydes with alkyl halides by photoredox organocatalysis
with an amine catalyst and a transition-metal photosensitizer.15
The Cozzi group16a,b and Nishibayashi group16c also success-
fully carried out α-allylation or -propargylation of aldehydes by
synergistic catalysis with an organocatalyst and a transition-
metal catalyst. Although there are not many reports, transition-
metal-free intermolecular α-alkylation of aldehydes was also
achieved. For example, SN1-type alkylation reactions of
enamine-based organocatalysis with aldehydes were reported
Received: June 11, 2021
Published: July 15, 2021
https://doi.org/10.1021/acs.joc.1c01394
J. Org. Chem. 2021, 86, 10921−10927
© 2021 American Chemical Society
10921

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Note
by Petrini and Melchiorre group,17a,b Cozzi group,17c−e and
Jacobsen group.17f List group achieved α-benzylation of α-
branched aldehydes by SN2-type reaction of enamine-based
organocatalysis.18 Palomo group reported that α-allylation of
aldehydes with electron-deficient allyl halides proceeded in the
presence of a silyl prolinol catalyst and a stoichiometric amount
of tertiary amines.19 Among the works regarding transition-
metal-free intermolecular α-alkylation of aldehydes described
above, Cozzi,17e Jacobsen,17f and List18 successfully synthesized
a chiral quaternary carbon stereocenter with high enantiose-
lectivity by alkylation of α-branched aldehydes. In the context of
these pioneering works, the author turned our attention toward
the transition-metal-free α-alkylation of α-branched aldehydes
with simple alkyl halides through enamine-based organo-
catalysis. Herein, the successful development of an efficient
method for the asymmetric α-alkylation of α-branched
aldehydes with allyl or propargyl halides to generate a chiral
quaternary carbon stereocenter through enamine-based organo-
catalysis by using a primary amino acid as the catalyst is
described.
found that higher enantioselectivity was obtained when the
amount of Bu4NI was low (entry 3). Although the alkylation
reaction proceeded even with a catalytic amount of iodide, it
occurred more smoothly when a stoichiometric amount of
iodide was used (entry 4). The use of allyl methanesulfonate
(2b) instead of 2a led to a slight increase in the yield of 4a.
Likewise, the use of 2-PrOH and tert-butanol (tert-BuOH) as
solvents was found to give a higher yield than other alcohols
(entries 5 and 6).
Next, we screened for the optimal catalyst for the alkylation of
1a with 2b (Table 2). Compared to catalyst 3a, the less hindered
a
Table 2. Catalyst Screening for the Alkylation of 1a with 2b
Initially, alkylation of 2-phenylpropionaldehyde (1a) with
allyl bromide (2a) was performed in the presence of a catalytic
amount of O-(tert-butyldimethylsilyl)-3-hydroxy-D-valine
(3a).12d Because a stoichiometric amount of acid waste would
be generated in this reaction, a base was added to the reaction
mixture to neutralize it. First, a sterically hindered amine,
diisopropylethylamine, was chosen as an organic base to avoid
its N-alkylation by 2a; however, alkylation of catalyst 3a
occurred to stall the alkylation of aldehyde 1a (Supporting
Information). In contrast, alkylation using an inorganic base
such as potassium hydrogen carbonate (KHCO3) in an aqueous
solvent at 0 °C suppressed the catalyst alkylation to
predominantly give 4a while maintaining the enantioselectivity
(Table 1, entry 1). Because the reaction mixture contained
a
The reaction was performed with 1a (0.5 mmol), 2b (1 mmol), 3
(0.1 mmol), KHCO3 (1 mmol), KI (0.25 mmol), Bu4NI (0.25 mmol)
in H2O (1 mL), and 2-PrOH (0.6 mL) at 0 °C for 16 h under Ar. nd
= not determined Enantiomer of 4a was obtained.
b
c
Table 1. Organocatalytic Alkylation of 1a with 2a in the
Presence of KHCO3
amino acids 3b and 3c exhibited lower enantioselectivity, while a
more hindered amino acid 3d resulted in a slower reaction rate.
Thus, a moderately bulky amino acid was found to be essential
for the efficient catalysis of the alkylation reaction and the
achievement of high enantioselectivity. Next, the methyl ester of
O-silylated L-threonine 3e was used as a catalyst. However, the
reaction was very slow, and only a trace amount of 4a was
obtained. Because the alkylation reaction with its methyl-group-
free amino acid analog, 3f, proceeded smoothly, the carboxy
group of the amino acid was determined to be important for the
efficient promotion of the alkylation reaction. Siloxy-group-free
amino acids 3g−i also did not promote the alkylation reaction
well, and 4a was formed in a low yield. This poor result was
possibly because the solubility of amino acids in the organic
phase affected the reaction rate of the alkylation of 1a with 2b,
and amino acids 3a−d,f, which were soluble in the organic
phase, gave a higher yield than hydrophilic amino acids 3g−i.
Consequently, amino acid 3a was chosen as the catalyst for
further investigation.
a
entry Bu4NI (equiv) KI (equiv)
solvent
yield (%) ee (%)
1
2
3
4
5
6
none
1.0
0.5
0.5
0.5
1.0
none
0.5
none
0.5
0.5
2-PrOH
2-PrOH
2-PrOH
2-PrOH
2-PrOH
tert-BuOH
20
64
60
55
64
64
93
90
92
92
92
92
b
b
0.5
a
The typical reaction was performed with 1a (0.5 mmol), 2a (1
mmol), 3a (0.1 mmol), KHCO3 (1 mmol), KI, Bu4NI in H2O (1 mL)
b
and solvent (0.6 mL) at 0 °C for 16 h under Ar. Allyl
methanesulfonate (2b) was used instead of 2a.
After small optimization of the reaction conditions, it was
found that the increased catalyst loading to 30 mol % was
required for obtaining the alkylated product in a good yield
without prolonging the reaction time. By using tert-BuOH as an
organic solvent instead of 2-PrOH, the use of H2O and an
organic solvent could be reduced to 0.6 and 0.4 mL, respectively,
for the reaction with 0.5 mmol of aldehyde. Then, the substrate
scope of the alkylation reaction was investigated with various α-
branched aldehydes 1 and alkylating reagents 2 (Table 3). The
immiscible organic and aqueous phases, the use of tetrabuty-
lammonium iodide (Bu4NI), a phase transfer catalyst, instead of
KI to promote the alkylation reaction led to the formation of 4a
in higher yield (entry 2). Brief solvent screening led to the
identification of 2-propanol (2-PrOH) as the optimal solvent for
the alkylation reaction, furnishing 4a in good yield and high
enantioselectivity (Supporting Information). The optimal
amounts of Bu4NI and KI were also investigated, and it was
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a
reaction with allyl bromide 2a in the presence of iodide ions
afforded 4a in good yield and high enantioselectivity(entry 3).
However, the same reaction with allyl chloride 2c gave 4a in low
yield, probably because of the slow conversion of 2c to allyl
iodide (entry 4). Next, the alkylation reaction was carried out
with an aldehyde possessing a methyl or a chloro substituent on
the aryl ring. Although no reaction was observed with ortho-
substituted aldehydes, para- and meta-substituted aldehydes
gave the alkylated products in good yield and high
enantioselectivity (Entries 5−10). Likewise, the use of 2-(4-
fluorophenyl)propionaldehyde (1h), 2-(4-methoxyphenyl)-
propionaldehyde (1i), and 2-(naphthalen-2-yl)propion-
aldehyde (1j) led to the formation of alkylated products 4h,
4i, and 4j (entries 11−13). 2-Phenylbutyraldehyde (1k) was
also found to be a good substrate for obtaining alkylated 4k,
although the reaction was slow (entry 14). In contrast to the
above-mentioned successful results, no reaction was observed
when α,α-dialkylacetaldehyde 1l was employed as a substrate
(entry 15). Some additional alkylating reagents were also used
for the alkylation of 1a. Disubstituted and monosubstituted allyl
bromide 2d and 2e also gave the respective alkylated products
4m and 4n in good yield and high enantioselectivity (entries 16
and 17). Since no secondary alkylated products were observed in
the reaction with 2e, it was found that the alkylation of aldehydes
would proceed via the SN2 reaction. Propargylation with 2f was
also investigated, and alkylated products 4o−q were synthesized
in good yield and high enantioselectivity (entries 18−20).
Unfortunately, no reaction was observed in the case of reaction
with ethylmethanesulfonate (2g), probably because of the lower
reactivity of a simple alkyl halide than that of allyl or propargyl
halides (entry 21). Although the reaction with cyclohexenyl
bromide 2h was very slow, corresponding alkylated product 4r
was obtained with high enantioselectivity (entry 22). Finally, a
larger scale synthesis was conducted, and a good yield of 4a was
obtained from 2.5 mmol of 2a (entry 23).
The plausible reaction mechanism for the alkylation of 1a with
2b is proposed in Scheme 1. By comparing the specific rotation
with those reported previously, it was found that 4a was an S-
enantiomer.12c,17d Initially, 3a, the amino acid catalyst, was
converted to its potassium or tetrabutylammonium salt (3a-
OM) in the presence of KHCO3 or Bu4NI, respectively (Scheme
1a). Then, 3a-OM reacted with 1a to give imine Im-1, which
generated enamine Im-2 by tautomerization. Concurrently, allyl
iodide was generated by the reaction of 2b with the iodide ion.
Enamine Im-2 then underwent alkylation by allyl iodide to give
imine Im-3, which was, in turn, converted to α-alkylated
aldehyde 4a and catalyst 3a-OM by hydrolysis. An acid waste,
hydrogen iodide (HI), generated during the alkylation of Im-2,
was neutralized by KHCO3 to generate KI. A plausible
mechanism for the stereocontrol is depicted in Scheme 1b.12f
To avoid steric repulsion between the enamine moiety and the
carboxylate group, the large amino acid side chain (Y) was
oriented perpendicular to the re face of the α-carbon atom of the
enamine moiety. Consequently, the allyl iodide approached the
enamine from its si face, assisted by an electrostatic interaction
between allyl iodide and the carboxylate group to furnish the S-
enantiomer of alkylated 4a.
Table 3. Substrate Scope
b
c
entry
1
2
3
4
5
6
7
8
1
2
4
yield (%)
ee (%)
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
2b
2b
2a
2c
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2d
2e
2f
4a
4a
4a
4a
4b
4c
80
31
76
22
84
84
nr
80
77
nr
79
82
83
67
nr
71
81
87
80
85
nr
92
94
91
92
90
92
nd
96
93
nd
92
88
92
91
nd
79
86
90
88
92
nd
87
94
d
4e
4f
9
10
11
12
13
4h
4i
4j
e
14
e
4k
15
16
17
1a
1a
1a
1h
1i
4m
4n
4o
4p
4q
f
18
f
19
f
2f
2f
20
21
1a
1i
1a
2g
2h
2b
g
22
h
4r
4a
13
87
23
a
The typical reaction was performed with 1 (0.5 mmol), 2 (1 mmol),
3a (0.15 mmol), KHCO3 (1 mmol), KI (0.25 mmol), Bu4NI (0.25
mmol) in H2O (0.6 mL), and tert-BuOH (0.4 mL) at 0 °C for 24 h
b
c
d
under Ar. nr = no reaction nd = not determined The reaction was
performed with 1a (0.5 mmol), 2b (1 mmol), 3a (0.15 mmol),
KHCO3 (1.25 mmol), Bu4NHSO4 (0.25 mmol) in H2O (0.6 mL),
e
and tert-BuOH (0.4 mL) at 0 °C for 87 h under Ar. The reaction was
performed for 72 h. The reaction was performed for 64 h. The
reaction was performed for 54 h. The reaction was performed with 1
(2.5 mmol), 2 (5 mmol), 3a (0.75 mmol), KHCO3 (5 mmol), KI
(1.25 mmol), Bu4NI (1.25 mmol) in H2O (3.0 mL), and tert-BuOH
(2.0 mL) at 0 °C for 24 h under Ar.
f
g
h
alkylation reaction proceeded in a two-phase reaction mixture
consisted of organic and aqueous phases under the best reaction
conditions. The progress of the reaction was monitored by TLC,
and workup was performed after no further change was
observed. Under the optimized reaction conditions, the
alkylation reaction of 1a with 2b was completed within 24 h
and afforded 4a in 80% yield and 92% ee (entry 1). Because the
alkylation was slow in the absence of iodide ions, it is likely that
the alkylation of 1a with allyl iodide, which is presumed to be
generated by the reaction of 2b and the iodide ion, proceeded
faster than that with 2b (entry 2). Likewise, the alkylation
In conclusion, the asymmetric α-alkylation of α-branched
aldehydes with allyl or propargyl halides was successfully
achieved using O-(tert-butyldimethylsilyl)-3-hydroxy-D-valine,
a chiral primary-amino-acid-based enamine organocatalyst. By
carrying out the alkylation reaction in an aqueous solvent, it was
found that the catalyst alkylation was suppressed to give an
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small plug of silica gel, eluted with Et2O (1 mL × 3), and concentrated
under reduced pressure. (S)-2-Methyl-2-phenylpent-4-enal (4a) was
isolated by column chromatography (silica gel, hexane−Et2O 19:1) in
80% yield (69.8 mg) as a colorless oil. The enantioselectivity was
determined by chiral HPLC analysis (92% ee). The absolute
configuration was determined by comparison of the specific rotation
Scheme 1. Plausible Reaction Mechanism
with those of the literatures:12c,d colorless oil; [α] = +53.4 (c 1.0,
16.5
589
1
CHCl3); Rf = 0.71 (n-hexane−EtOAc, 9:1); H NMR (400 MHz,
CDCl3) 9.52 (1H, s), 7.41−7.24 (5H, m), 5.60−5.49 (1H, m), 5.09−
5.02 (2H, m), 2.73−2.60 (2H, m), 1.45 (3H, s); 13C{1H} NMR (100
MHz, CDCl3) 202.0, 139.4, 133.1, 128.8, 127.3, 127.1, 118.6, 53.6,
40.5, 18.8. Spectroscopic data of 4a−h,j,k12c,d and 4m23 are in
agreement with the published data.
Larger-Scale Synthesis of 4a. In a 20 mL vial, 3a (186 mg, 0.75
mmol), tetrabutylammonium iodide (461 mg, 1.25 mmol), potassium
iodide (208 mg, 1.25 mmol), and potassium hydrogen carbonate (500
mg, 5 mmol) were placed. The vial was capped with a rubber septum,
and the atmosphere in the vial was replaced with argon. Then a bubbler
was attached to the vial with a needle, a mixture of water (3.0 mL) and
tert-butanol (2.0 mL) was added, and the mixture was stirred for 5 min
at room temperature. After 1a (335 mg, 2.5 mmol) and 2b (680 mg, 5
mmol) were added to the mixture at 0 °C, the whole reaction mixture
was stirred for 24 h at the same temperature. The resulting mixture was
extracted with Et2O (5 mL × 4), and the combined organic phase was
filtered through a small plug of silica gel, eluted with Et2O (5 mL × 3),
and concentrated under reduced pressure. Allylated product 4a was
isolated by column chromatography (silica gel, hexane−Et2O 19:1) in
87% yield (376.8 mg) with 94% ee.
2-Methyl-2-(4-methylphenyl)pent-4-enal (4b): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 84% yield
(78.8 mg), 90% ee, colorless oil; [α]15869.7 = +72.3 (c 1.0, CHCl3); Rf =
0.58 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.49
(1H,s), 7.21−7.19 (2H, m), 7.15−7.13 (2H, m), 5.60−5.50 (1H, m),
5.08−5.01 (2H, m), 2.71−2.58 (2H, m), 2.34 (3H, s), 1.42 (3H, s);
13C{1H} NMR (100 MHz, CDCl3) 202.0, 137.0, 136.2, 133.3, 129.5,
127.0, 118.5, 53.2, 40.5, 20.9, 18.8.
2-Methyl-2-(3-methylphenyl)pent-4-enal (4c): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 84% yield
(78.8 mg), 92% ee, colorless oil; [α]15869.9 = +77.8 (c 1.0, CHCl3); Rf =
0.49 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.50 (1H,
s), 7.29−7.28 (1H, m), 7.12−7.04 (3H, m), 5.60−5.50 (1H, m), 5.09−
5.01 (2H, m), 2.71−2.59 (2H, m), 2.36 (3H, s), 1.43 (3H, s); 13C{1H}
NMR (100 MHz, CDCl3) 202.0, 139.3, 138.5, 133.3, 128.7, 128.1,
127.9, 124.1, 118.5, 53.5, 40.5, 21.6, 18.8.
2-(4-Chlorophenyl)-2-methylpent-4-enal (4e): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 80% yield
(83.0 mg), 96% ee, colorless oil; [α]15899.0 = +83.0 (c 1.0, CHCl3); Rf =
0.56 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.49 (1H,
s), 7.37−7.34 (2H, m), 7.20−7.17 (2H, m), 5.57−5.46 (1H, m), 5.08−
5.03 (2H, m), 2.69−2.57 (2H, m), 1.44 (3H, s); 13C{1H} NMR (100
MHz, CDCl3) 201.4, 137.9, 133.4, 132.6, 129.0, 128.6, 119.0, 53.2,
40.5, 18.8.
2-(3-Chlorophenyl)-2-methylpent-4-enal (4f): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 77% yield
(79.9 mg), 93% ee, colorless oil; [α]58917.1 = +74.1 (c 1.0, CHCl3); Rf =
0.43 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.51 (1H,
s), 7.34−7.25 (3H, m), 7.14−7.12 (1H, m), 5.58−5.47 (1H, m), 5.10−
5.05 (2H, m), 2.70−2.58 (2H, m), 1.44 (3H, s); 13C{1H} NMR (100
MHz, CDCl3) 201.3, 141.6, 134.9, 132.5, 130.0, 127.6, 127.4, 125.4,
119.1, 53.6, 40.5, 18.8.
alkylated product in a good yield. In this reaction, a chiral
quaternary carbon stereocenter was generated with high
enantioselectivity.
EXPERIMENTAL SECTION
■
Materials. Aldehydes 1, alkylating reagents 2, and amino acids 3
used in this study are known compounds. Aldehyde 1a was purchased
and used after column chromatography (silica gel, hexane−Et2O 19:1);
other aldehydes 1b,20a 1c,18 1d,20b 1e,20c 1f,g,20b 1h,20c 1i−k,20a and
1l20d were synthesized according to the literature procedure.20a
Alkylating reagents 2a,c−h were purchased and used after distillation;
2b was synthesized from allyl alcohol and methane sulfonyl chloride by
a general procedure for the transformation of an alcohol to a
sulfonate.21 O-Silylated amino acids 3a,12d 3b,c,22 3d,12d 3e,12f and
3f22 were synthesized according to the literature procedures; other
amino acids 3g−i were purchased and used without purification.
Purification of alkylated products 4 was accomplished by column
chromatography on Kanto Chemical Co., Inc. silica gel, 60 N (spherical,
neutral; 63−210 μm). Proton NMR (1H NMR), fluorine NMR (19F
NMR), and proton-decoupled carbon NMR [13C{1H} NMR] spectra
were recorded on a JNM-ECS400 FT NMR unit. Chemical shifts, δ of
1H NMR, and 13C{1H} NMR are referred to TMS and that of 19F NMR
was referred to CF3CO2H (−76.55 ppm). The specific rotation was
measured by a HORIBA SEPA-500 polarimeter. HPLC was carried out
using a JASCO PU-2089 Plus intelligent pump and a UV-2075 Plus UV
detector. HRMS were measured on a JMS-T100-LP for 4o and on a
Thermo Scientific Exactive for 4i,n,p−r.
Typical Procedure for the Alkylation Reaction. In a 7 mL vial,
3-(tert-butyldimethylsiloxy)-D-valine (3a, 35.1 mg, 0.15 mmol),
tetrabutylammonium iodide (92 mg, 0.25 mmol), potassium iodide
(42 mg, 0.25 mmol), and potassium hydrogen carbonate (100 mg, 1
mmol) were placed. The vial was capped with a rubber septum, and the
atmosphere in the vial was replaced with argon. Then a bubbler was
attached to the vial with a needle, a mixture of water (0.6 mL) and tert-
butanol (0.4 mL) was added, and the mixture was stirred for 5 min at
room temperature. After 2-phenylpropionaldehyde (1a, 67 mg, 0.5
mmol) and allyl methanesulfonate (2b, 136 mg, 1 mmol) were added to
the mixture at 0 °C, the whole reaction mixture was stirred for 24 h at
the same temperature. The resulting mixture was extracted with Et2O
(1 mL × 4), and the combined organic phase was filtered through a
2-(4-Fluorophenyl)-2-methylpent-4-enal (4h): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 79% yield
(75.6 mg), 92% ee, colorless oil; [α]25819.8 = +71.7 (c 1.0, CHCl3); Rf =
0.56 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.49 (1H,
s), 7.25−7.20 (2H, m), 7.10−7.05 (2H, m), 5.58−5.47 (1H, m), 5.08−
5.03 (2H, m), 2.70−2.57 (2H, m), 1.44 (3H, s); 13C{1H} NMR (100
MHz, CDCl3) 201.6, 162.0 (d, J 246 Hz), 135.0, 132.8, 128.9 (d, J 7.7
Hz), 118.9, 115.7(d, J 21 Hz), 53.1, 40.7, 18.9; 19F NMR (376 MHz,
CDCl3) − 116.0.
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Note
2-Methyl-2-(4-methoxyphenyl)pent-4-enal (4i): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 82% yield
(83.6 mg), 88% ee, colorless oil; [α]15869.6 = +92.3 (c 1.0, CHCl3); Rf =
0.53 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.46 (1H,
s), 7.19−7.15 (2H, m), 6.94−6.90 (2H, m), 5.60−5.50 (1H, m), 5.08−
5.01 (1H, m), 3.81 (3H, s), 2.70−2.57 (2H, m), 1.42 (3H, s); 13C{1H}
NMR (100 MHz, CDCl3) 201.9, 158.7, 133.3, 131.1, 128.3, 118.5,
114.2, 55.2, 52.9, 40.5, 18.8.; ν(neat)/cm−1 1720 (CO); HRMS
(APCI/Orbitrap) m/z [M + H]+ calcd for C13H17O2+ 205.1223, found
205.1224.
2-Methyl-2-(naphthalen-2-yl)pent-4-enal (4j): isolated by
column chromatography (silica gel, hexane−Et2O 19:1); 83% yield
(93.5 mg), 92% ee, colorless oil; [α]15879.2 = +124.0 (c 1.0, CHCl3); Rf =
0.54 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.59 (1H,
s), 7.87−7.81 (3H, m), 7.711−7.707 (1H, m), 7.53−7.46 (2H, m),
7.38−7.35 (1H, m), 5.61−5.51 (1H, m), 5.11−5.01 (2H, m), 2.85−
2.69 (2H, m), 1.55 (3H, s); 13C{1H} NMR (100 MHz, CDCl3) 202.0,
136.7, 133.3, 133.1, 132.4, 128.6, 128.0, 127.5, 126.4, 126.3, 125.0,
118.7, 53.8, 40.5, 18.9.
0.49 (n-hexane−EtOAc, 9:1); 1H NMR (400 MHz, CDCl3) 9.47 (1H,
s), 7.21−7.17 (2H, m), 6.95−6.91 (2H, m), 3.81 (3H, s), 2.81−2.68
(2H, m), 1.97 (1H, t, J 2.4 Hz), 1.59 (3H, s); 13C{1H} NMR (100 MHz,
CDCl3) 200.3, 159.0, 129.9, 128.2, 114.2, 80.2, 71.3, 55.2, 52.5, 26.3,
19.1; ν(neat)/cm−1 1722 (CO), 2115 (CC), 3289 (CH);
HRMS (ESI/Orbitrap) m/z [M + Na]+ calcd for C13H14O2Na+
225.0886, found 225.0886.
2-(1-Cyclohexen-3-yl)-2-phenylpropanal (4r): obtained as a
mixture of diastereomers by column chromatography (silica gel,
16.5
hexane−Et2O 19:1); 81% yield (75.7 mg), 86% ee, colorless oil; [α]
589
1
= +2.7 (c 1.0, CHCl3); Rf = 0.66 (n-hexane−EtOAc, 9:1); H NMR
(400 MHz, CDCl3) 9.54 (1H, s), 9.52 (1H, s), 7.40−7.36 (2H, m),
7.31−7.23 (3H, m), 5.59−5.44 (1H, m), 5.23−5.14 (1H, m), 2.68−
2.66 (2H, m), 2.62−2.60 (2H, m), 1.61−1.59 (3H, m), 1.57−1.55 (3H,
m), 1.44 (3H, s), 1.41 (3H, s); 13C{1H} NMR (100 MHz, CDCl3)
202.5, 202.3, 139.8, 139.6, 129.3, 128.8, 127.24, 127.19, 127.1, 125.3,
124.5, 54.1, 53.8, 39.2, 33.2, 19.0, 18.8, 18.0, 12.9; ν(neat)/cm−1 1717
(CO); HRMS (ESI/Orbitrap) m/z [M + Na]+ calcd for
C16H20O2Na+ 267.1356, found 267.1356.
2-Ethyl-2-phenylpent-4-enal (4k): isolated by column chroma-
tography (silica gel, hexane−Et2O 19:1); 67% yield (63.0 mg), 91% ee,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01394.
■
17.4
colorless oil; [α] = +50.8 (c 1.0, CHCl3); Rf = 0.60 (n-hexane−
589
sı
1
EtOAc, 9:1); H NMR (400 MHz, CDCl3) 9.50 (1H, s), 7.40−7.20
(5H, m), 5.57−5.47 (1H, m), 5.10−5.02 (2H, m), 2.77−2.64 (2H, m),
2.06−1.92 (2H, m), 1.80 (3H, t, J 7.6 Hz); 13C{1H} NMR (100 MHz,
CDCl3) 202.5, 138.5, 132.9, 128.8, 127.6, 127.3, 118.4, 57.5, 36.1, 24.5,
8.0.
1
HPLC data; H, 13C{1H}, and 19F NMR spectra of 4
(PDF)
2,5-Dimethyl-2-phenylhex-4-enal (4m): isolated by column
chromatography (silica gel, hexane−Et2O 19:1); 71% yield (72.2 mg),
79% ee. Light yellow oil; [α]15879.5 = +37.1 (c 1.0, CHCl3); Rf = 0.61 (n-
AUTHOR INFORMATION
Corresponding Author
1
■
hexane−EtOAc, 9:1); H NMR (400 MHz, CDCl3) 9.53 (1H, s),
7.40−7.25 (5H, m), 4.96−4.91 (1H, m), 2.67−2.56 (2H, m), 1.65 (3H,
d, J 0.8 Hz), 1.56 (3H, s), 1.42 (3H, s); 13C{1H} NMR (100 MHz,
CDCl3) 202.6, 140.0, 135.0, 128.7, 127.1, 118.6, 118.4, 54.4, 34.4, 25.9,
19.0, 17.9.
Masanori Yoshida − Liberal Arts and Sciences, National
Institute of Technology (KOSEN), Asahikawa, Hokkaido 071-
8142, Japan; orcid.org/0000-0001-9481-6462;
Email: yoshida@edu.asahikawa-nct.ac.jp
2-Methyl-2-phenylhex-4-enal (4n): obtained as a mixture of (E)-
and (Z)-isomers by column chromatography (silica gel, hexane−Et2O
19:1); 81% yield (75.7 mg), 86% ee, colorless oil; [α]15869.8 = +39.3 (c 1.0,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01394
1
CHCl3); Rf = 0.66 (n-hexane−EtOAc, 9:1); H NMR (400 MHz,
CDCl3) 9.54 (1H, s), 9.52 (1H, s), 7.40−7.36 (2H, m), 7.31−7.23 (3H,
m), 5.59−5.44 (1H, m), 5.23−5.14 (1H, m), 2.68−2.66 (2H, m),
2.62−2.60 (2H, m), 1.61−1.59 (3H, m), 1.57−1.55 (3H, m), 1.44 (3H,
s), 1.41 (3H, s); 13C{1H} NMR (100 MHz, CDCl3) 202.5, 202.3,
139.8, 139.6, 129.3, 128.8, 127.24, 127.19, 127.1, 125.3, 124.5, 54.1,
53.8, 39.2, 33.2, 19.0, 18.8, 18.0, 12.9.; ν(neat)/cm−1 1722 (CO);
HRMS (APCI/Orbitrap) m/z [M + H]+ calcd for C13H17O+ 189.1274,
found 189.1276.
Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (JP17K05872).
The author thanks Dr. Tomohiro Hirose (Instrumental Analysis
Division, Global Facility Center, Creative Research Institution,
Hokkaido University) for the measurements of HRMS.
2-Methyl-2-phenylpent-4-ynal (4o): isolated by column chro-
matography (silica gel, hexane−Et2O 19:1); 87% yield (74.6 mg), 90%
ee, colorless oil; [α]51879.5 = +98.9 (c 1.0, CHCl3); Rf = 0.53 (n-hexane−
1
EtOAc, 9:1); H NMR (400 MHz, CDCl3) 9.53 (1H, s), 7.43−7.38
REFERENCES
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(2H, m), 7.35−7.27 (3H, m), 2.85−2.71 (2H, m), 1.97 (1H, t, J 2.8
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