Highly regio- and enantioselective γ-alkylation of linear α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201700645

Asymmetric alkylation is one of the most useful carbon–carbon bond-forming reactions in synthetic organic chemistry. Chiral-amine-catalyzed alkylation reactions often lack regioselectivity owing to multiple reactive centers. In particular, the alkylation of linear 2-enals through dienamine catalysis produces a mixture of regioisomers owing to reactive α-and γ-positions. A few attempts have been made to mask the α-reactive center to achieve γ-selectivity. Controlling the enantioselectivity at the remote γ-position has also been found to be quite challenging. Herein, we achieved the highly regioselective γ-alkylation of linear α,β-unsaturated aldehydes by using trifluoroethanol (TFE) as a cosolvent. Further, we demonstrated in situ kinetic resolution for enantioenrichment of the γ-alkylated products. This method brings together the activation of an electrophile facilitated by TFE and in situ kinetic resolution to achieve excellent selectivity in dienamine catalysis.

Full text of DOI:10.1002/ejoc.201700645

A Journal of
Accepted Article
Title: Highly Regio- and Enantioselective g-Alkylation of linear a,b-
Unsaturated Aldehydes
Authors: Mahesh S. Kutwal and Chandrakumar Appayee
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700645
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700645
Supported by

10.1002/ejoc.201700645
European Journal of Organic Chemistry
COMMUNICATION
g
a b
Highly Regio- and Enantioselective -Alkylation of Linear , -
Unsaturated Aldehydes**
Mahesh S. Kutwal and Chandrakumar Appayee*
Dedicated to Professor Ronald Breslow on his 86th birthday
Abstract: Asymmetric alkylation is one of the most useful carbon-
carbon bond forming reactions in synthetic organic chemistry. Chiral
amine catalyzed alkylation reactions often lack regioselectivity due to
multiple reactive centers. Particularly, alkylation of linear 2-enals
through dienamine catalysis produces a mixture of regioisomers due
to the reactive a- and g-positions. There are few attempts made to
mask a-reactive center to achieve g-selectivity. Controlling
enantioselectivity at the remote g-position has also been found to be
1).[11] To avoid the formation of regioisomers, a-branched 2-
enals were used to generate selective g-alkylation.[12] Conversely,
g-branching of 2-enals was not sufficient enough to obtain
selective a-alkylation.[11] Very recently, theoretical and NMR
studies have been carried out to explain the ‘E/Z dilemma’ in
dienamine intermediate and the enantioselectivity in g-alkylation
of 2-enals.[13] Nevertheless, the reason for the formation of
significant quantities of a-alkylated products and lower
enantioselectivity of g-alkylated products with longer alkyl chains
is unclear.[11,13] There are reports on kinetic resolution,[15] and
one-pot synthesis of racemic compounds[16] followed by kinetic
resolution in asymmetric catalysis. To the best of our knowledge,
there is no report so far in literature demonstrating asymmetric
catalysis to generate chiral products and in situ kinetic resolution
to enrich product enantiomeric excess. Herein, we report an
asymmetric alkylation of linear a,b-unsaturated aldehydes to
produce single regioisomer, g-alkylated products using
quite challenging. We have achieved
g-alkylation of linear a,b-unsaturated
trifluoroethanol (TFE) as co-solvent. Further, we have
a
highly regioselective
aldehydes using
a
demonstrated an in situ kinetic resolution for the enantioenrichment
of g-alkylated products. This methodology brings a novel activation
of electrophile facilitated by TFE and an in situ kinetic resolution to
achieve excellent selectivity in dienamine catalysis.
One of the greatest challenges in synthetic organic
trifluoroethanol (TFE) as
a co-solvent and in situ kinetic
chemistry
is
to
achieve
highly
selective
recent emphasis on
organic
resolution to obtain high enantioselectivity.
transformations.[1] There has been
a
During g-alkylation of hex-2-enal 1b in water, various organic
co-solvents have been used to enhance the solubility of the
electrophile, Michler’s hydrol 2a.
enantioselective reactions due to the increasing demand of
single enantiomer drugs.[2] Primary[3] and secondary amine chiral
catalysts have been utilized for variety of functionalization of
carbonyl compounds.[4-9] In amine catalysis, it is often found to
be difficult to control regioselectivity[5,11] due to the generation of
reactive nucleophilic intermediates[4i] such as enamine,[4b,4i]
dienamine,[6] trienamine[7] and tetraenamine[8] having multiple
reactive centers. In asymmetric dienamine catalysis where
active a- and g-positions are generated, it is quite challenging to
obtain highly regioselective g-functionalized products.[9,11-14]
Furthermore, controlling enantioselectivity at the remote g-
position becomes a much greater task in dienamine catalysis.[4k]
Asymmetric dienamine catalysis was first demonstrated by
Jørgensen and co-workers for the regioselective g-amination of
linear a,b-unsaturated aldehydes (2-enals) via a proposed [4+2]
cycloaddition pathway.[9] Though a-alkylation of aldehydes and
ketones have been carried out with excellent selectivity,[10] SN-
type alkylation of linear a,b-unsaturated aldehydes has been
reported with a mixture of a- and g-alkylated products (Scheme
Previous work:
Less selective γ- and α-alkylation of linear 2-enals[11]
O
Ar
R
O
O
N
H
OH
Ar
H
Ar
Ar
H
H
:
α
+
Ar
acid additive
+
Ar
γ
R
R
Regioselectivity = 72 to 84
28 to 16
70 to 92% ee
Highly selective γ-alkylation of α-branched 2-enals[12a]
O
O
R1
R1
R
N
OH
Ar
Ar
H
H
H
α
α
+
acid additive
Ar
Ar
γ
R
single regioisomer
90 to 96% ee
This work:
Highly selective γ-alkylation of linear 2-enals
[*]
M. S. Kutwal, Dr. Chandrakumar Appayee
Discipline of Chemistry
Indian Institute of Technology Gandhinagar
Palaj, Gandhinagar, Gujarat 382355, India
E-mail: a.chandra@iitgn.ac.in
O
O
N
OH
H
H
Ar
H
+
Ar
Ar
acid additive
Ar
γ
Homepage: www.iitgn.ac.in/faculty/chemistry/chandrakumar.htm
trifluoroethanol
R
R
&
[**] The authors are grateful to the SERB, India for Extra Mural
Research funding (EMR/2014/000207) and IIT Gandhinagar for
financial support.
single regioisomer
90 to 94% ee
kinetic resolution
Scheme 1. Alkylation of a,b-unsaturated aldehydes (2-enals) through
dienamine catalysis.
Supporting information for this article can be found under:
is given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700645
European Journal of Organic Chemistry
COMMUNICATION
Addition of trifluoroethanol (TFE) as
a
co-solvent
and the same was true with trifluoroethanol as the only solvent
(entry 13).
serendipitously produced only g-alkylated product and no trace
of a-alkylated product was observed in 1H-NMR of the crude
reaction mixture (Table 1, entry 1).[17] This level of
regioselectivity was retained even in the absence of the catalyst,
proline 4a (entry 2). Whereas achiral and diastereoselective
alkylation reactions in TFE has been reported recently, exact
role of TFE in alkylation is still unclear.[18] Changing the solvent
system from water/TFE to toluene/TFE led to shorter reaction
times, but without any change in enantioselectivity (entry 3).
Table 1: Reaction optimization for the asymmetric g-alkylation of hex-2-enal
1b.
Though g-alkylation reactions take only few hours, by
continuing the same reactions for longer period of time, we have
observed an increase in product ee along with decrease in yield
(kinetic resolution) in almost all reactions catalyzed by 4d and
acid additives. During the longer reaction times, we observed a
more polar unidentified mixture of products that was later
removed by a short silica gel filtration of the reaction mixture
using diethyl ether. As compared to other acids, benzoic acid
was again found to be the best additive that resulted in 74% ee
with 37% product yield after 28 h (entry 14). Lowering the
o
reaction temperature from rt to 0 C showed better yield (52%)
o
with the same ee (entry 15). But further lowering to –20 C did
O
O
catalyst
acid additive
not show any improvement in product yield and ee (entry 16).
OH
Ar
H
Ar
H
o
Surprisingly, addition of brine to the reaction at 0 C resulted in
+
Ar
solvent, time
rt
Ar
49% yield with 94% ee and 100% g-selectivity (entry 17). But the
combination of toluene/TFE/water as the reaction solvents not
only lowered the product yield and ee but also resulted in a
mixture of g- and a-alkylated products as 92:8 ratio (entry 18).
Et
Et
2a
1b
3b
Ar = 4-(NMe2)-C6H4
F3C
CF3
CF3
Ph
Ph
Ph
Ph
catalyst 4d (20 mol%)
PhCO2H (50 mol%)
CO2H
O
O
N
H
N
N
H
N
H
H
OH
4b
OTMS
OH
Ar
OTMS
H
Ar
H
CF3
toluene, TFE, brine
0 oC, 25 h
+
4a
4c
4d
Ar
Ar
Entry[a]
Catal
yst
Acid
Solvents
t
Yield[b]
[%]
ee[c]
[%]
R
R
[h]
2a
3[a]
Ar = 4-(NMe2)-C6H4
O
O
1[d]
2[d]
3[e]
4[e]
4[e]
6[e]
7
4a
-
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
4-NBA
PhCO2H
H2O/TFE
H2O/TFE
12
36
1
2
2
2
2
2
54
38
81
68
53
70
58
77
0
0
0
16
18
50
52
62
1
O
O
4a
4b
4c
4d
4d
4d
Toluene/TFE
Toluene/TFE
Toluene/TFE
Toluene/TFE
Toluene/TFE
Toluene/TFE
Ar
H
Ar
H
Ar
H
Ar
H
Ar
Ar
Ar
Ar
Me
Me
Me
8
Me
3b
3
2
9[f]
10[g]
11[g]
12[g]
13
4d
4d
4d
4d
4d
4d
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
DCE/TFE
CHCl3/TFE
PhF/TFE
PhCl/TFE
TFE
1
2
3
1
9
58
74
65
67
40
37
40
26
52
34
26
74
3a[b]
3c
3d
40% yield
40% yield
49% yield
43% yield
90% ee
91% ee
94% ee
94% ee
O
O
O
14
Toluene/TFE
28
Ar
Ar
H
Ar
H
15[h]
16[i]
4d
4d
4d
PhCO2H
PhCO2H
PhCO2H
Toluene/TFE
Toluene/TFE
Toluene/TFE
/Brine
Toluene/TFE
/H2O
33
43
25
52
47
74
64
94
Ar
H
Ar
Ar
17[h,j,k]
49[l]
Me
Me
Me
4
6
5
18[h,j,m]
4d
PhCO2H
18
40
80
3e
3f
3g
40% yield
44% yield
43% yield
[a] Reactions were carried out with 2a (0.16 mmol), 1b (0.24 mmol), catalyst
(0.016 mmol), acid (0.016 mmol) in solvent (0.8 mL) and TFE (116 μL) at rt
unless otherwise mentioned. [b] Obtained from 1H NMR of the crude reaction
mixture with internal standard, 1,3-dinitrobenzene. [c] Determined by HPLC
with a chiral stationary phase. [d] H2O/TFE (1:1) were used. [e] Toluene/TFE
(3:1) were used. [f] TFE (24 μL) was used. [g] TFE (58 μL) was used. [h]
Reaction was carried out at 0 oC. [i] Reaction was carried out at –20 oC. [j] 1b
(0.16 mmol), 4d (0.032 mmol), PhCO2H (0.08 mmol) were used. [k] Brine
(0.35 mL) was also added. [l] lsolated yield of product 3b. [m] H2O (0.35 mL)
was also added and a mixture of g- and a-alkylated products was formed
(92:8).
94% ee
93% ee
94% ee
O
O
O
Ar
H
Ar
H
Ar
H
Ar
Ar
Ar
OBn
3
3j
3i[c]
40% yield
94% ee
3h
48% yield
93% ee
40% yield
90% ee
Scheme 2. Substrate scope for asymmetric g-alkylation of linear 2-enals.
Reactions were carried out with 2a (0.16 mmol), 1 (0.16 mmol), 4d (0.032
mmol), PhCO2H (0.08 mmol) in toluene (0.8 mL), TFE (116 μL) and Brine
(0.35 mL). [a] Yields are referred to that of isolated after column
chromatography and ee was determined by HPLC with a chiral stationary
phase. [b] 1a (0.24 mmol) was used. [c] Reaction was stopped after 23 h.
Several linear 2-enals were tested under the optimized
reaction conditions and found only g-alkylated products. No trace
of a-alkylated products was observed in 1H-NMR of the crude
reaction mixture. Pent-2-enal 1a was found to be decomposing
in this reaction conditions and hence 1.5 equivalent of enal 1a
was used to obtain 40% isolated yield of g-alkylated product 3a
Various chiral catalysts have been screened to obtain better
enantioselectivity (entry 4-6 and see Support Information, Table
S1, entry 5-7). Catalyst 4d was found to be more suitable in
these conditions to give 70% yield of g-alkylated product and
50% ee in 2 h (entry 6). Other fluorinated alcohols were found to
be less effective as compared to TFE as a co-solvent (see
Supporting Information, Table S1, entry 2-4). Amongst the acid
additives screened (Table 1, entry 6-8 and see Supporting
Information, Table S2), benzoic acid resulted in higher yield and
ee of the g-alkylated product (entry 8). Replacing toluene by
other organic solvents failed to improve product ee (entry 9-12)
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10.1002/ejoc.201700645
European Journal of Organic Chemistry
COMMUNICATION
with 91% ee (Scheme 2). Other alkyl 2-enals 1b-g having
different chain length produced g-alkylated products 3b-g with
excellent ee and moderate yields. Terminal double bond (3h),
benzylic group (3i) and benzyloxy group (3j) containing products
were conveniently synthesized without disturbing those
functional groups. Under these reaction conditions, other less
reactive electrophiles[19] were found to be unreactive, but
thioxanthydrol 2d in reaction with enal 1b produced a 50:50
mixture of a- and g-alkylated products (see Supporting
Information Table S5).
3e after 25 h with the loss of 44% yield to unidentified products
(Figure 1b). These studies reveal a selective decomposition of
‘S’ enantiomer of product 3e by the catalyst 4d (kinetic
resolution) that accounts for the increase in ee with decrease in
the yield of product 3e.
Though [4+2] cycloaddition pathway was proposed[9] for the
regioselective g-functionalization, our attempts to trap the
cationic intermediate[19]
A
(Scheme 4), generated from
electrophiles 2, as the [4+2] cycloadducts were unsuccessful.
Nevertheless, the results of highly regioselective g-alkylated
products from 2a and a 50:50 mixture of a- and g-alkylated
products from 2d in presence of TFE suggest
a novel
a)
mechanism for the activation of electrophiles by TFE that needs
to be further studied in detail.
O
O
catalyst 4d (20 mol%)
PhCO2H (50 mol%)
OH
Ar
H
Ar
H
R
+
Ar
Ar
toluene, TFE, brine
0 o
C
Me
Me
4
2a
4
Ar = 4-(NMe2)-C6H4
N
3e[a]
A
1e
O
H2O
Ar
H
Ar
H
R
Ar
Ar
H
R
C
R
R-3
(major)
O
OH
N
A
R
H
N
A
H
H2O
Ar
Ar
Ar
N
2a
H2O
1
H
R
N
Ar
A
E
H
R
4
H
N
B
A
Unidentified
mixture of
products
b)
H2O
Ar
O
N
O
O
catalyst 4d (20 mol%)
PhCO2H (50 mol%)
Ar
H
H
Ar
H
Ar
H
n
S
o
i
t
R, S
R
u
l
Ar
Ar
so
re
Ar
Ar
H
R
toluene, TFE, brine
D
c
i
R
t
e
n
0 o
C
Me
4
S-3
(minor)
Me
Ki
4
A
3e[a]
Ar = 4-(NMe2)-C6H4
racemic-3e
Ar = 4-(NMe2)-C6H4
Scheme 4. Proposed reaction mechanism for the selective g-alkylation of
linear 2-enals.
Based on the reaction results and kinetic studies, we
propose a mechanism for the selective g-alkylation of linear a,b-
unsaturated aldehydes (Scheme 4). Accordingly,
a stable
cationic intermediate A, derived from 2a and acid (A–H) in
presence of TFE, reacts with dienamine B, derived from 2-enal 1
and catalyst 4, to produce alkylated iminium intermediate C and
its isomer D. These iminium intermediates C and D hydrolyze to
regenerate catalyst 4 along with g-alkylated enals R-3 (major)[13]
and S-3 (minor) respectively. The proposed mechanism is
supported by the initial observation of 52% ee of product 3e after
2.5 h (Figure 1a).
Figure 1. Kinetic study on g-alkylation under the optimized reaction conditions.
1a) Formation of 3e from 1e and 2a in different time intervals. 1b) Reactivity of
Racemic-3e in different time intervals. [a] Product yield was obtained from 1H
NMR of the crude reaction mixture and ee was determined by HPLC with a
chiral stationary phase.
In a longer reaction time, due to chiral match, minor
enantiomer S-3 reacts faster with catalyst 4 to reform iminium
ion
D that further gets converted to dienamine E upon
deprotonation. Dienamine E may either get converted into the
major enantiomer R-3 via iminium ion D (dynamic kinetic
resolution) or decompose into an unidentified mixture of
products (kinetic resolution) during the longer reaction time.
Kinetic studies performed with racemic-3e support kinetic
resolution more than dynamic kinetic resolution due to
increasing ee of 3e with a loss of product yield (Figure 1b).
Thus, we have carried out a kinetic study on g-alkylation of
dec-2-enal 1e under the optimized reaction conditions and
observed increase in ee with decrease in product yield (kinetic
resolution) during the course of reaction (Figure 1a). When a
racemic g-alkylated product racemic-3e was subjected to the
optimized reaction conditions in the absence of 1e and 2a, we
observed a similar kinetic resolution that resulted in 56% ee of
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10.1002/ejoc.201700645
European Journal of Organic Chemistry
COMMUNICATION
5053; c) Z.-J. Jia, Q. Zhou, Q.-Q. Zhou, P.-Q. Chen, Y.-C. Chen,
Angew. Chem. Int. Ed. 2011, 50, 8638.
In summary, we have developed a methodology for a highly
regio- and enantioselective g-alkylation of linear a,b-unsaturated
aldehydes. Trifluoroethanol (TFE) was found to be an effective
co-solvent for the excellent g-selectivity. We have demonstrated
an in situ kinetic resolution that is responsible for the substantial
increase in enantiomeric excess of g-alkylated products 3. It was
further confirmed by converting racemic-3e into chiral 3e under
the optimized reaction conditions. The observed moderate yields
of other g-alkylation[11] and g-amination[9] reactions of linear a,b-
unsaturated aldehydes reported in the literature suggest that
similar kinetic resolution might have contributed to the
enantioenrichment of those products. As our attempts to form
the [4+2] adduct of 2 were unsuccessful, and simple SN-type
alkylation of linear a,b-unsaturated aldehydes are reported to
give a mixture of regioisomers[11], there may be a different
reaction pathway for the selective g-alkylation in TFE. Further
work to understand the role of TFE in the regioselective g-
alkylation may reveal new type of electrophile activation in
dienamine catalysis.
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10.1002/ejoc.201700645
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Mahesh S. Kutwal and Chandrakumar
Appayee*
In#situ#kinetic'resolution
N
H
O
O
N
Ar
Ar
PhCO2
H
H
Ar
H
Page No. – Page No.
+
H
α
OH
Ar
γ
γ
R
Ar
Ar
R
Highly Regio- and Enantioselective -
g
R
single regioisomer
trifluoroethanol
90 to 94% ee
Alkylation of Linear
Aldehydes
, -Unsaturated
a b
Perfect regioselectivity was achieved for the g-alkylation of linear a,b-unsaturated
aldehydes in presence of trifluoroethanol. An in situ kinetic resolution was
demonstrated for the enantioenrichment of remote stereoselective g-alkylated
products using chiral secondary amine catalyst. This methodology brings a novel
activation of electrophiles facilitated by trifluoroethanol and an in situ kinetic
resolution to achieve excellent selectivity in dienamine catalysis.
This article is protected by copyright. All rights reserved.