The acid free asymmetric intermolecular α-alkylation of aldehydes in fluorinated alcohols

Article abstract of DOI:10.1039/c2cc30261f

The acid free asymmetric intermolecular α-alkylation of aldehydes with alcohols has been discovered using trifluoroethanol as solvent. This unprecedented system affords the enantioenriched functionalized primary alcohols (after NaBH₄ reduction) in high yields and good to excellent enantioselectivities with wide substrate scope in the absence of any acid additive.

Full text of DOI:10.1039/c2cc30261f

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COMMUNICATION
The acid free asymmetric intermolecular a-alkylation of aldehydes in
fluorinated alcoholsw
Jian Xiao,ab Kai Zhaoa and Teck-Peng Loh*a
Received 12th January 2012, Accepted 8th February 2012
DOI: 10.1039/c2cc30261f
The acid free asymmetric intermolecular a-alkylation of aldehydes
with alcohols has been discovered using trifluoroethanol as solvent.
This unprecedented system affords the enantioenriched functionalized
primary alcohols (after NaBH4 reduction) in high yields and good to
excellent enantioselectivities with wide substrate scope in the absence
of any acid additive.
generated cationic species in water or fluorinated alcohols could
be trapped by a chiral enamine intermediate to implement
asymmetric alkylation of aldehydes.
Herein, we present trifluoroethanol, which acts as a reaction
medium to allow the elusive asymmetric intermolecular a-alkylation
of aldehydes proceed smoothly only with an amine catalyst.
Inspired by the unique chemical reactivity and selectivity in
water reactions discovered by our group8 and others,9 reaction
of propanal 1a with xanthydrol 2a catalyzed by different
secondary amine catalysts I–VIII was carried out in water at
80 1C initially. Pyrrolidine I can afford the recemate product in
67% yields, and chiral catalysts II–VII afforded product 3a in
a range of 35–82% yields with visible ee (Table 1, entries 2–7).
When the solvent was changed to TFE, the yields and ee are
higher than in water for all the tested catalysts at 80 1C
(Table 1, entries 8–10). Our designed catalysts II and III can
afford the product in 67% and 89% yields, respectively, albeit
with low ee (Table 1, entries 8 and 9). MacMillan catalyst IV
gave moderate ee, but low yield (Table 1, entry 10). Intriguingly,
catalyst VII could furnish the product in 67% yield and 90% ee
(Table 1, entry 11). Surprisingly, this reaction could proceed
smoothly at room temperature and impart high yield and high
stereocontrol in TFE (Table 1, entry 12). However, the more acidic
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) gave less desirable
results and only afforded the product in 33% yields and
18% ee (Table 1, entry 13). This probably attributes to
stronger acidity of HFIP, which induces more side reactions.
Decreasing the temperature improved the enantioselectivity
and the best result (96% yield and 96% ee) was obtained
at À10 1C (Table 1, entries 14 and 15). At room temperature, the
other catalysts also work, but only MacMillan catalyst IV gave
good yields and good enantioselectivities (Table 1, entries 16–20).
Comparison of results of catalysts V, VI and VII implies that the
CF3 substituent group is crucial to get high yields and high
enantioselectivities. To our surprise, this reaction in TFE at room
temperature affords 3a with 56% yield in the absence of catalysts,
which indicates that a strong background reaction occurs
(Table 1, entry 21). Despite the strong background reaction,
this asymmetric reaction was not sensitive to temperature and
comparable high enantioselectivity could be obtained at high
temperature (Table 1, entry 11), room temperature as well as
low temperature (Table 1, entry 12).
The catalytic asymmetric intermolecular a-alkylation of aldehydes
has been a long-standing challenge and highly sought-after
goal in asymmetric catalysis, in view of its synthetic value for
the construction of versatile building blocks in organic synthesis.1
Until recently, this elusive reaction has been addressed by use of
asymmetric aminocatalysis.2 As readily available and versatile
starting materials, alcohols have been used as alkylating reagents
via the SN1 pathway to implement asymmetric alkylation of
aldehydes and most of these developments rely on the complicated
system of aminocatalysis with metal catalysis or Brønsted catalysis.3
From the viewpoint of energy-saving and green chemistry, it is
highly valuable to develop efficient methods for asymmetric
alkylation of aldehydes with alcohols without any acid additive.
Fluorinated alcohols (hexafluoro-2-propanol, HFIP;
trifluoroethanol, TFE) are well known as ‘‘magic solvents’’
to facilitate reactions with poor nucleophiles without resort to
Lewis acid or metal catalysis.4 Their high ionizing power and
strong ability to donate hydrogen bonds easily generate
cationic intermediates by solvolysis of SN1-active substrates.
It has been found that hot water has similar properties and can also
act as a mild acid catalyst at elevated temperature.5,6 Direct
substitution of activated alcohols with different nucleophiles
‘‘on water’’ or in fluorinated alcohols has been realized by Cozzi
and Zoli.6 In our recent report on enantioselective Michael addition
of aldehydes to nitroalkenes in water by our rationally designed
enzyme-like organocatalyst,7d hydrogen bonding interaction has
been reported to be crucial to activate the substrate and stabilize
the transition state. As our efforts are ongoing to develop a new
catalytic system and new reactions,7 we envisage that the
a Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore, 637371. E-mail: teckpeng@ntu.edu.sg;
Fax: +65 6515 8229; Tel: +65 63168899
b Dalian Institute of Chemical Physics, The Chinese Academy of
Sciences, Dalian, P. R. China, 116023
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. See DOI: 10.1039/
c2cc30261f
With the optimized conditions in hand, we proceeded to
examine the substrate scope using 10 mol% catalyst VII in
c
3548 Chem. Commun., 2012, 48, 3548–3550
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Table 1 Reaction of propanal with xanthydrola
Table 2 Catalytic asymmetric reaction of aldehydes with alcoholsa
T/
Yieldb
eec
(%)
Entry Substrates
1
Product
1C (%)
RT 92
0
90
92
96
À10 96
96
Entry
Catalyst
Solvent
T/1C
Yieldb (%)
eec (%)
2
3
40
60
41
78
70
65
1
2
3
4
5
6
7
8
I
II
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
(CF3)2CHOH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
80
80
80
80
80
80
80
80
80
80
80
rt
67
71
82
76
36
56
35
67
89
29
67
92
33
92
96
42
50
71
42
42
56
—
À7
À20
10
10
10
10
0
13
51
90
90
18
92
96
—
24
78
39
32
—
III
IV
V
VI
VII
II
III
IV
VII
VII
VII
VII
VII
II
80
83
55
40
60
48
78
73
65
80
91
56
9
10
11
12
13
14
15
16
17
18
19
20
21
rt
0
4
5
6
40
40
40
92
93
30
78
84
58
À10
rt
III
IV
V
VI
—
rt
rt
rt
rt
rt
a
Reactions were conducted with propanal (0.4 mol), xanthydrol
b
(0.1 mmol), catalyst (0.01 mmol). Isolated yield after column
c
chromatography. ee was determined by HPLC analysis on a chiral
stationary phase.
TFE (Table 2). At the outset, various aldehydes were reacted
with xanthydrol 2a. Although propanal can react with 2a at
room temperature or lower temperature, aldehydes with longer
chains cannot react with xanthydrol 2a at room temperature
and the reaction can proceed at 40 1C or even higher tempera-
ture (Table 2, entries 1–6). At higher temperature, higher yields
but lower ee were observed. Various aldehydes could be
tolerated and gave the products in good yields and moderate
to good enantioselectivities. 9H-Thioxanthen-9-ol 2b and bis-
(4-(dimethylamino)phenyl)methanol 2c also can act as alcohol
substrates and afforded the desired product 3g and 3h in good
yields and good enantioselectivities, respectively (Table 2,
entries 7 and 8). Importantly, ferrocene-based alcohol 2d and
indole-based alcohol 2e were well tolerated with propanal at
room temperature to afford the corresponding products 3i and
3j in good yields and good enantioselectivities (Table 2, entries 9
and 10), since ferrocene-based chiral ligands and catalysts are
important in asymmetric catalysis10 and indole skeleton plays
vital role in natural products and pharmaceutical chemistry.11
In summary, we have disclosed that using TFE as solvent,
for the first time, the asymmetric intermolecular a-alkylation
7
8
9
rt
rt
rt
54
76
74
55
89
85
(syn)
(dr 50 : 50)d 90
(anti)
45
81
(syn)
(dr 35 : 65)d 91
(anti)
10
rt
a
Reactions were conducted with 0.4 mmol aldehyde, 0.1 mmol alcohol with
0.01 mmol catalyst VII in 0.5 mL CF3CH2OH. b Isolated yield. c ee was
determined by HPLC analysis on a chiral stationary phase. d dr (syn : anti)
was determined by chiral HPLC on a chiral stationary phase.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3548–3550 3549

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of aldehydes with alcohols was realized without resort to any
acid additive and the reaction was only catalyzed by a chiral
secondary amine. This acid free and efficient methodology
delivers good to excellent enantioselectivities with good yields
for a wide range of aldehydes and alcohols. The success of this
reaction expands the applicability of fluorinated alcohols in
enantioselective organocatalytic reactions and opens up new
insight into fluorinated alcohols in organocatalysis.
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We gratefully acknowledge Nanyang Technological
University, Ministry of Education Academic Research Fund
Tier 2 (No. T207B1220RS) and NSFC (No. 21102142) for the
funding of this research.
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3550 Chem. Commun., 2012, 48, 3548–3550
This journal is The Royal Society of Chemistry 2012