Synthetically amenable amide derivatives of tosylated-amino acids as organocatalysts for enantioselective allylation of aldehydes: Computational rationale for enantioselectivity

Article abstract of DOI:10.1039/c3ob27513b

A phenylalanine derived chiral amide is developed that serves as an effective organocatalyst for the reaction of allyltrichlorosilane with aryl, hetero-aryl and α,β-unsaturated aldehydes to afford the desired homoallylic alcohols in good yield (up to 90%)

Full text of DOI:10.1039/c3ob27513b

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Synthetically amenable amide derivatives of tosylated-
amino acids as organocatalysts for enantioselective
allylation of aldehydes: computational rationale for
enantioselectivity†
Cite this: DOI: 10.1039/c3ob27513b
Debashis Ghosh,a Debashis Sahu,b S. Saravanan,a Sayed H. R. Abdi,*a
Bishwajit Ganguly,*b Noor-ul H. Khan,a Rukhsana I. Kureshya and Hari C. Bajaja
A phenylalanine derived chiral amide is developed that serves as an effective organocatalyst for the reac-
tion of allyltrichlorosilane with aryl, hetero-aryl and α,β-unsaturated aldehydes to afford the desired
homoallylic alcohols in good yield (up to 90%) and high enantioselectivity (up to 99%). The experimental
results and DFT calculations suggest that para substituted aromatic aldehydes as substrate show higher
ee in the product than their ortho/meta counterparts. The 1H and 13C NMR spectra study corroborated
the calculated results. The chiral organocatalyst can be easily synthesized from optically pure phenyl-
alanine in two simple steps with 90% overall yield.
Received 30th December 2012,
Accepted 30th January 2013
DOI: 10.1039/c3ob27513b
www.rsc.org/obc
from amino acids (mostly proline) with N-oxides,4l forma-
Introduction
mides,5 bisformamides6 motifs those worked in the tempera-
The asymmetric allylation reaction of carbonyl compounds is a ture window of 0 °C to RT. However, with these catalysts the
well-known synthetic tool for the production of chirally enantioselectivities were moderate for most substrates, except
enriched homoallyl alcohols which are important building in few selected substrates where the product was obtained
blocks for the construction of biologically active compounds.1 with >90% ee. Notwithstanding these results, as per our con-
Both metal2a,3 and metal-free2,4 asymmetric allylation reaction viction both natural and unnatural α-amino acids with some
protocols have been reported; however, metal-free protocols structural modifications are having great potential in develop-
were preferred in order to avoid metal contamination in the ing efficient enantioselective catalysts for asymmetric allylation
final product. A variety of organocatalysts have been found to reaction of carbonyl compounds. The advantages with these
catalyze the enantioselective allylation of aldehydes4 with allyl- amino acids lie in their easy availability, high optical purity
trichlorosilane. While acknowledging the pioneering advances and affordable costs, as a result they have caught the fancy of
in the use of organocatalysts for the allylation reaction, the researchers to use them (directly or with some modifications)
need for extremely low temperatures4t,u (−80 to −10 °C) and as organocatalysts for a wide range of organic transfor-
elaborate multistep synthesis4u to arrive at an effective catalyst mations.7 In fact natural amino acids (100–200 mol%) have
are major concerns. These concerns are detrimental for overall been used alone8 and in combination with a chiral promoter9
process economics in the production of allylated products to catalyze asymmetric allylation reaction of aldehydes but
with high optical purity at competitive cost. To some extent, could afford products with low to moderate enantioselectivity
these issues were addressed by developing catalysts derived (highest ee being 64%). Ironically, in both these studies allyl-
stannanes were used as allylating agents, which are toxic and
should be avoided for environmental concerns.
aDiscipline of Inorganic Materials and Catalysis, CSIR, Central Salt and Marine
With this backdrop we first screened several natural amino
Chemicals Research Institute (CSMCRI), G. B. Marg, Bhavnagar 364 021, Gujarat,
acids (Table 1) to catalyze asymmetric allylation reaction of
India. E-mail: shrabdi@csmcri.org; Fax: (+91) 0278-2566970
bAnalytical Discipline and Centralised Instrumental Facility, CSIR, Central Salt and
aldehydes using allyltrichlorosilane as relatively safer allylating
agent. Among these amino acids (100 mol%), L-phenylalanine
showed some promising results in the allylation of 4-methoxy
benzaldehyde as a model substrate at RT in 24 h (Table 1,
entry 4). This led us to use tosyl and boc modified L-phenyl-
alanine, catalyst (S)-1 and (S)-2 respectively, those under
Marine Chemicals Research Institute (CSMCRI), G. B. Marg, Bhavnagar 364 021,
Gujarat, India. E-mail: ganguly@csmcri.org; Fax: (+91) 0278-2567562
†Electronic supplementary information (ESI) available: 1H and 13C spectra for all
new and few known compounds, HPLC chromatograms for all homoallyl alco-
hols and quantum chemical calculations details described herein. See DOI:
10.1039/c3ob27513b
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Table 1 Enantioselective allylation of 4-methoxy benzaldehyde with allyl-
trichlorosilane using different L-amino acids based organocatalystsa
Entry Cat.
Time [h] Yieldb [%] eec [%] Config.d
1
2
3
4
5
6
7
8
9
10
L-Isoleucine
L-tert-Leucine
L-Tryptophan
L-Phenylalanine 24
L-Threonine
L-Proline
L-Histidine
L-Valine
(S)-1
24
24
24
18
15
30
25
12
10
10
15
40
20
10
13
25
30
16
0
S
S
S
S
S
—
S
S
S
S
24
36
24
24
24
24
3
11
38
<3
(S)-2
a All the reactions were carried out by using substrate 4-methoxy
benzaldehyde (0.4 mmol), allyltrichlorosilane (1.2 equiv.),
diisopropylethyl amine (2 equiv.) and catalyst (1 equiv.) in CH2Cl2 at
RT. b Isolated yields after column chromatography. c ee determined by
chiral HPLC using Daicel Chiralcel OD-H column. d Absolute
configurations were assigned by comparing both retention time and
optical rotation with the reported reliable data.
similar condition gave the product with ee 38% (Table 1, entry
9) and <3% (Table 1, entry 10) respectively. As tosylated
L-phenylalanine performed better, this catalyst was subjected
to further modifications in order to achieve high performing
catalyst. Accordingly, one pot amidation of tosylated L-phenyl-
alanine with several chiral amines was carried out to get cata-
lysts (S,S)-3 to (S,RS)-810–14 (Fig. 1). To know whether amido
arm or amino acid side of the catalyst play major role in
imparting higher enantioselectivity catalysts (S,RS)-9 and
(S,RS)-10 were also synthesized. Among these organocatalysts,
(S,RS)-3 (15 mol%) was found to be most promising catalyst
that gave allylation products in yield 55–90% and 40–99% ee
under optimized reaction conditions. To have insight into the
mechanism of the allylation reaction, computational analysis
and NMR experiments were performed.
Fig. 1 Organocatalysts used in the present study.
Invariably in an organocatalyst, presence of an amide group
play an important role in activation of substrate and reagent
through weak H-bonding interactions.14,15 Therefore, amido
catalyst (S,S)-3 was synthesized by the reaction of (S)-α-methyl
benzylamine with carboxyl group of (S)-1. This modification
resulted in a dramatic improvement of product yield (72%)
and enantioselectivity (ee 65%) (Table 2, entry 1). To know the
effect of configuration of chiral amine on the performance the
catalyst (S,R)-3 was synthesized by the reaction of (S)-1 with
(R)-α-methylbenzylamine. Interestingly, mismatched chiral
centres in the catalyst (S,R)-3 had little or no effect on its cata-
lytic performance (yield 71%, ee 64%; Table 2, entry 2) so
much so that no inversion of the product configuration was
observed. This was further confirmed by using catalyst (S,RS)-3
synthesized from (S)-1 with racemic α-methylbenzylamine that
gave similar performance (Table 2, entry 3). As anticipated, the
catalyst (R,RS)-3 derived from (R)-1 with racemic α-methyl-
benzylamine gave the product with opposite configuration
with no change in yield and ee (Table 2, entry 4). Based on
these results it can be concluded that the enantioinduction in
the product is largely governed by the chirality originated from
L-phenylalanine.
Results and discussion
In quest of highly active and enantioselective catalyst for allyl-
ation reaction of aldehydes, tosylated L-phenylalanine (Table 1,
entry 9) was chosen on its merits for further modifications in
its structure. The catalysts (S,S)-3 to (S,RS)-10 (Fig. 1) were syn-
thesized in a single step by amidation of tosylated L-phenyl-
alanine/L-alanine/L-phenylglycine in excellent yields. These
catalysts (15 mol%) were evaluated for their efficacy in the
asymmetric allylation of aldehydes by using 4-methoxy benz-
aldehyde (0.4 mmol) as a model substrate with allyltrichloro-
silane (1.2 equivalent) as amenable allylating agent in CH2Cl2
at RT. In all the catalytic reactions a base-diisopropylethyl
amine (DIPEA) (2 equiv. with respect to substrate) was used as
an additive.
To know about steric influence (if any) of amine part, the
catalyst (S)-4, (S)-5 and (S,S)-6 were synthesized by the reaction
of (S)-1 with isopropyl amine, diphenylmethyl amine and
(S)-naphthylethyl amine respectively. As a consequence, it was
found that sterically less demanding (S)-4 affected lower
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Table 2 Enantioselective allylation of 4-methoxy benzaldehyde with allyltri-
chlorosilane using catalysts (S,S)-3 to (S,RS)-10a
Table 3 Screening of solvents, reaction temperature and catalyst loadinga
Catalyst Temp. Time Yieldb eec
Entry Solvent
[mol%] [°C]
[h]
[%]
[%]
Entry
Cat.
Time [h]
Yieldb [%]
eec [%]
Config.d
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
CH3CN
CHCl3
15
15
15
15
15
15
15
15
15
15
15
25
25
25
25
25
25
25
25
0
−10
−40
0
0
0
14
15
15
16
14
12
12
10
14
26
40
14
24
14
70
20
50
60
67
75
73
75
70
68
68
70
60
70
64
40
45
46
50
65
73
80
95
96
92
90
95
93
1
2
3
4
5
6
7
8
(S,S)-3
(S,R)-3
(S,RS)-3
(R,RS)-3
(S)-4
(S)-5
(S,S)-6
(S,S,S,S)-7
(S,S,S,S)-8
(S,RS)-9
(S,RS)-10
14
14
14
14
18
14
16
12
12
18
18
72
71
70
70
70
66
67
77
74
42
45
65
64
64
64
53
60
58
61
58
40
50
S
S
S
R
S
S
S
S
S
S
S
THF
CH2Cl2 : THF (1 : 1)
CH2Cl2 : THF (3 : 1)
CH2Cl2 : THF (7 : 3)
CH2Cl2 : THF (7 : 3)
CH2Cl2 : THF (7 : 3)
CH2Cl2 : THF (7 : 3)
9
9
10
11
10
11
12
13
14
CH2Cl2 : THF (7 : 3)d 15
a The reactions were carried out with 15 mol% of organocatalyst in
CH2Cl2 at RT. b Isolated yield after column chromatography. c ee
determined by chiral HPLC using Daicel Chiralcel OD-H column.
d Absolute configurations were assigned by comparing both retention
time and optical rotation with the reported reliable data.
CH2Cl2 : THF (7 : 3)
CH2Cl2 : THF (7 : 3)
10
20
a The reactions were carried out with organocatalyst (S,RS)-3. b Isolated
yield after column chromatography. c ee determined by chiral HPLC
using Daicel Chiralcel OD-H column. d Reaction was carried out in the
absence of freshly activated (at 120 °C) molecular sieves (4 Å).
enantioselectivity (ee, 53%; Table 2, entry 5) in the product.
Even, sterically more demanding catalysts (S)-5 and (S,S)-6 among screened), was subjected to optimization of catalytic
were found to be slightly less enantioselective (ee 60% and reaction conditions. Solvent is known to influence the activity
58% respectively; entries 6, 7), than our reference catalyst and enantioselectivity of a catalytic protocol. Therefore, it was
(S,RS)-3 but, in all these cases the product yield remained natural for us to screen various solvents frequently used for
similar. These results indicate that there exists some steric this type of reaction using allyltrichlorosilane as allylating
influence coming from the amine part of the catalyst and in agent by keeping other process parameters constant (Table 3;
turn affecting the enantioselectivity of the product. Further, entries 1–8). The results showed the promise of CH2Cl2 (entry
condensation of (S)-1 with chiral 1,2-diamines like (S,S)-1,2- 1) and THF (entry 5) for this reaction. Interestingly, mixed
diaminocylohexane and (S,S)-1,2-diphenyl-1,2-diaminoethane solvent system comprising of CH2Cl2 and THF in varying ratios
gave C2-symmetric catalysts (S,S,S,S)-7 and (S,S,S,S)-8 respect- influenced the catalyst activity and enantioselectivity (entries
ively. The idea behind preparing C2-symmetric catalysts was to 6–8) where CH2Cl2 : THF in 7 : 3 ratio (entry, 8) was found to
see if there are any cooperative interactions between the two give highest product yield (75%) and enantioselectivity (ee
units/role of extra element of chirality on the enantioselecti- 80%) in shortest time (10 h). Temperature effect (Table 3,
vity. However, the results showed that these modifications in entries 9–11) on this reaction was our next parameter for
the catalysts were having no distinct advantages on the cataly- optimization study after we fixed the solvent system. At 0 °C,
tic performance (Table 2, entries 8, 9). Until now (S,RS)-3 highest product ee (95%) was obtained albeit with a slight
(derived from phenylalanine) was found to be the most active decreased in yield (70%) and longer reaction time (14 h) (entry
and enantioselective catalyst. To know how crucial is the role 9). Further lowering the temperature to −10 °C gave the
of groups around chiral centre originated from amino acid product with similar ee and yield but reaction time was nearly
part of the catalyst in imparting enantioselectivity in the twice (entry 10). A further decrease in temperature (−40 °C)
product, we replaced it with phenylglycine and alanine to get made the reaction too sluggish with lower product ee (entry
(S,RS)-9 and (S,RS)-10 respectively while retaining other struc- 11). It is to be noted that due to moisture sensitive nature of
tural features. Significant decrease in enantioselectivity in the allylating agent the reaction is required to be done in the pres-
product with catalysts (S,RS)-9 and (S,RS)-10 (Table 2, entries ence of molecular sieves, expectedly in its absence there was a
10 and 11) as compared to (S,RS)-3 (Table 2, entry 3) indicates slight decrease in enantioselectivity (Table 3, entry 12). Sub-
that catalyst performance is sensitive towards steric environ- sequently the reaction conditions of entry 9 was used for vari-
ment around the chiral center of amino acid. Having arrived at ation in catalyst loadings that suggested 15 mol% catalyst is
conclusion that (S,RS)-3 is the most promising among the ideal (yield 70%, ee 95%; Table 3, entry 9) as lowering the cata-
organocatalysts screened in the present study, it was chosen lyst loading to 10 mol% (Table 3, entry 13) caused lower
for further optimization of the reaction conditions.
product yield and longer reaction time. Whereas increasing
In order to further improve yield and enantioselectivity of the catalyst loading to 20 mol% was of no advantage (Table 3,
the allylation product, the catalyst (S,RS)-3 (most promising entry 14).
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Table 4 Effect of different additives on enantioselective allylation of 4-methoxy
benzaldehydea
Table 5 Enantioselective allylation of various aldehydes using catalyst (S,RS)-3a
Time Yieldb eec
[%] Config.d
Amount of
additive [equiv.]
Time
[h]
Yieldb
[%]
eec
[%]
Entry Substrate
[h]
[%]
Entry
Additive
1
2
3
4
5
6
7
8
C6H5CHO (1a)
10
14
15
15
15
12
12
12
12
14
16
14
16
12
8
78
70
65
71
65
70
76
75
73
75
62
80
55
74
90
85
80
82
87
80
95
S
S
4-MeO-C6H4CHO (1b)
4-(C6H5CH2O)-C6H4CHO (1c)
4-(CH3)3C-C6H4CHO (1d)
4-Me-C6H4CHO (1e)
4-NO2-C6H4CHO (1f)
4-F-C6H4CHO (1g)
1
2
3
4
5
6
7
—
—
1
2
3
2
2
2
24
17
14
14
14
14
14
30
55
70
70
75
74
77
70
87
95
95
70
30
20
>99 (−)e
DIPEA
DIEPA
DIEPA
Et3N
DBU
2,6-Lutidine
95
83
86
50
86
80
79
70
40
64
68
65
78
82
79
83
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
R
4-Cl-C6H4CHO (1h)
4-Br-C6H4CHO (1i)
9
a The general reaction procedure was followed. b Isolated yields after
column chromatography. c ee determined by chiral HPLC using Daicel
Chiralcel OD-H column.
10
11
12
13
14
15
16
17
18
19
3-MeO-C6H4CHO (1j)
3-Me-C6H4CHO (1k)
2-MeO-C6H4CHO (1l)
2-Me-C6H4CHO (1m)
2-F-C6H4CHO (1n)
1-Naphthaldehyde (1o)
2-Naphthaldehyde (1p)
Thiophene-2-carbaldehyde (1q) 10
(E)-C6H5CHCHCHO (1r)
(E)-C6H5CHCH(CH3)CHO (1s)
An organic base DIPEA (2 equivalents with respect to sub-
strate) was used as an additive in all the catalytic reactions
carried thus far. In the absence of this base the catalyst
efficiency was markedly lower (Table 4, entry 1).
9
10
10
It is reported in the literature that with allyltrichlorosilane a The reactions were carried out with organocatalyst (S,RS)-3. b Isolated
yields after column chromatography. c ee determined by chiral HPLC
as an allylating agent, a base is required to promote the cataly-
using Daicel Chiralcel and Chiralpak OD-H, AS-H, IA, IB and IC
tic activity of an organocatalyst.4q,r Therefore, we optimized the
columns according to reported procedures. d Absolute configurations
quantity of DIPEA (1–3 equiv., Table 4, entries 2–4) used in the were assigned by comparing both retention time and optical rotation
with the reported reliable data. e Optical rotation for the product 2c
was negative.
catalytic runs and found that its 2 equivalent is optimum
(entry 3). We also checked the efficacy of couple of other bases
viz., Et3N, 1,8-diazabicycloundec-7-ene (DBU) and 2,6-lutidine
(Table 4, entries 5–7) on the activity and enantioselectivity of
the catalyst (S,RS)-3 in the allylation reaction of 4-methoxy benz-
benzaldehyde. The hetero-aromatic aldehyde (thiophene-2-
carboxaldehyde; Table 5, entry 17) behaved like benzaldehyde
aldehyde by keeping other reaction parameters constant.
by giving only marginally higher yield (80%) and ee (82%).
Experimental results showed that 2 equiv. DIPEA (Table 4,
α,β-Unsaturated aldehydes viz., trans-cinnamaldehyde and
trans-α-methylcinnamaldehyde as substrates works well with
catalyst (S,RS)-3 (Table 5, entries 18 and 19), but the product
configuration was found to be (R) as against for the (S)-pro-
entry 3) was the most suitable among the additives used in the
present study.
After achieving optimum reaction parameters (as per
Table 4, entry 3) for enantioselective allylation reaction, we
ducts obtained with the other aldehydes used in the present
next looked for efficacy of catalyst (S,RS)-3 for various aromatic,
study.
hetero-aromatic as well as α,β-unsaturated aldehydes as sub-
strates (Table 5).
Quantum chemical calculations
Among the various substituted benzaldehydes used in the
To examine the anomalous behaviour of fluoro benzaldehyde
present study, 4-substituted benzaldehydes (Table 5, entries
2–9), irrespective of their electron donating or withdrawing
capabilities, gave the products in higher ee than 3-substituted
dition, a DFT study was performed. Methoxy substituted benz-
(Table 5, entries 10 and 11) followed by 2-substituted (Table 5,
entries 12–14) benzaldehydes. Fluoro substituted benz-
aldehydes showed reversal of the above trend where 2-fluoro-
than the trend obtained with rest of the benzaldehydes for the
allylation reaction with catalyst (S,RS)-3 under optimized con-
aldehyde was chosen as a representative case to explore the
mechanism of the allylation reactions with the catalyst (S,S)-3.
benzaldehyde gave the product in higher ee (68%, Table 5,
entry 14) than 4-fluoro benzaldehyde (50%, Table 5, entry 7).
Computational methods
The ee of unsubstituted benzaldehyde (80%, Table 5, entry 1), Conformational search of the catalyst (S,S)-3 in the gas phase
however lies between 4-substituted and 3-substituted benz-
was performed with the molecular modeling program Macro-
aldehydes. Surprisingly, the bulkier aldehydes like 1- and model16 using the Monte Carlo algorithm for the random vari-
2-naphthaldehydes were found to be more reactive in the ation of all of the rotatable bonds combined with Merck force
field (MMFF94).17–19 For each calculation, 5000 Monte Carlo
present catalytic system gave products with higher yields but
with slightly lower ees (Table 5, entries 15 and 16) than steps had been carried out. The resulting conformations were
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clustered based on torsional RMS using XCluster approach.20
Minimum separation ratio was employed to find the clustering
level at which the distance between members of clusters was
much smaller than the distance between clusters.21 The lowest
energy conformation of catalyst (S,S)-3 was chosen from this
clusterization process. This conformation was optimized with
DFT PBEPBE/6-31G(d) level of theory and taken for further
study. All DFT calculations were performed by using the Gaus-
sian 09 suite of programs.22 Full geometrical optimizations,
frequency calculations had been performed in the gas phase
employing the PBEPBE functional, based on the generalized
gradient functional proposed by Perdew, Burke and Ernzerhof
(PBE) with standard 6-31G(d) basis set.23 The stationary points
were characterized by frequency calculations in order to verify
that the transition structures had one imaginary frequency.
Single point calculations were performed in the same level of
theory in solvent phase. To account for the solvation effects,
the recent universal solvation model, SMD, by Truhlar and co-
workers24 was employed with the dielectric constant corres-
ponding to dichloromethane (ε = 8.93). This model predicts
free energies of solvation with a mean unsigned error well of
about 4 kcal mol−1 for ionic solutes and below 1 kcal mol−1
Scheme 1 Proposed catalytic cycle for enantioselective allylation reaction cata-
lysed by (S,RS)-3.
for neutral solutes.25 Gibbs free energy in solvent phase (Gsol
)
was then calculated using the eqn (1):
Gsol ¼ Ggas þ ΔGsolv þ Gcorr
ð1Þ
Ggas is the Gibbs free energy of the component in the gas
phase. The solvation free energy was calculated as ΔGsolv
=
Esol − Egas, where Esol and Egas are the electronic energies of
component in solution and in the gas phase, respectively.25 Gcorr
is the correction associated with the change in the standard state
from the gas phase (1 atm) to solution (1 mol L−1) and its value
at 298.15 K is 1.89 kcal mol−1 26
.
Results
The carbonyl part of substituted formyl group of catalyst (S,S)-
3 coordinates to the silicon atom of allyltrichlorosilane similar
to the earlier reports.2a,27 This coordination was also observed
in the 13C spectrum analysis (Fig. 5). The nucleophilic carbon
of allyl trichlorosilane attacks the carbonyl carbon of the alde-
hyde through a six membered chair-like transition state (TS)2a
(Scheme 1). The o- and p-methoxy benzaldehydes give R- and
S-transition states with allyltrichlorosilane, which is coordi-
nated to the catalyst (S,S)-3 (Fig. 2). In transition state geo-
metries an intramolecular hydrogen bonding was noticed
between the –NH-proton of amide group and one of the
oxygen of sulphonamide group (Fig. 2 and 3). The 1H NMR
spectrum analysis showed a down field chemical shift for –NH
proton of the catalyst (S,RS)-3 with allyltrichlorosilane and
p-methoxy benzaldehyde (Fig. 4), which corroborates the pres-
ence of intramolecular hydrogen bonding as observed in the
transition state calculations. As the role of the catalyst was our
prime focus, the base DIPEA was not considered in our model
system for computational simplicity. The PBEPBE/6-31G(d)
Fig. 2 PBEPBE/6-31G(d) optimized transition state geometries and corres-
ponding their free energy of activation (kJ mole−1) from reactants to transition
state in CH2Cl2 solvent catalyzed by catalyst (S,S)-3. All distances are in Å. [Gray =
carbon; white = hydrogen; red = oxygen; blue = nitrogen; yellow = sulfur;
green = chlorine; greenish blue = silicon; sky blue = fluorine].
calculated free energy of activation shows that the p-methoxy
substituted S-transition state (ii) is 2.8 kJ mol−1 stable com-
pared to the R-methoxy transition state (i). However, the differ-
ence in the free energy of activation is smaller (1.7 kJ mol−1
)
in the case of o-methoxybenzaldehyde. The lower enantioselec-
tivity observed for o-methoxybenzaldehyde is in agreement
with the calculated results.
As observed the higher S-enantioselectivity with o-substi-
tuted fluoro benzaldehyde, we have performed additional
calculations at the same level of theory.
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lower enantioselectivity observed with p-substituted fluoro benz-
aldehyde in our experimental results.
The calculations performed to account for the dispersion
corrections, B97D functional was used, which contains a semi-
empirical correction for the dispersion interactions.28 The cal-
culated results show that the energy difference obtained with
B97D functional is in agreement with the PBEPBE/6-31G(d)
calculated results (see ESI, Table 2†).
To examine the role of the second chiral centre of this cata-
lyst we have also investigated the allylation reaction with
the catalyst (S,R)-3 for ortho and para substituted fluoro benz-
aldehydes. The transition state calculations suggest that
S-enantiomer is energetically preferred over the corresponding
R-enantiomer as observed for the catalyst (S,S)-3 (see ESI,
Fig. 1†). Therefore, these calculated results corroborate the
experimental observations that the remote chiral centre is not
influencing the enantioselectivity in these cases.
NMR experiments
A series of NMR experiments were conducted for better under-
standing of reaction mechanism of allylation reaction. For this
we looked for any observable changes in NMR spectra of cata-
lyst (S,RS)-3 on addition of allyltrichlorosilane followed by the
addition of the substrate (4-methoxy benzaldehyde). 1H NMR
spectra of catalyst (S,RS)-3, allyltrichlorosilane and substrate
showed a peak at 6.54 ppm, which is significantly downfield
shifted than 6.35 ppm peak for amide proton of virgin catalyst
(Fig. 4). In 13C NMR spectra (Fig. 5) as well, the amide carbon
peak (169.21 ppm) of the catalyst was downfield shifted to
169.92 ppm on the addition of allyltrichlorosilane. However,
on the addition of substrate this peak (169.92 ppm) was
slightly upfield shifted to 169.76 ppm (see full spectra in ESI†).
Spectral changes (191.03 → 191.13 ppm) were also observed in
the aldehyde part of the substrate on its interaction with
allyltrichlorosilane.
Fig. 3 PBEPBE/6-31G(d) optimized transition state geometries and corres-
ponding their free energy of activation (kJ mole−1) from reactants to transition
state in CH2Cl2 solvent catalyzed by catalyst (S,S)-3. All distances are in Å. [Gray =
carbon; white = hydrogen; red = oxygen; blue = nitrogen; yellow = sulfur; green
= chlorine; greenish blue = silicon; sky blue = fluorine].
Fig. 4 1H NMR spectra were taken in CDCl3: (a) catalyst (S,RS)-3; (b) allyl-
trichlorosilane after interaction with catalyst and 4-methoxy benzaldehyde.
The transition states calculated with both o- and p-fluoro-
substituted benzaldehyde with PBEPBE/6-31G(d) suggest that
the S-isomers are energetically preferred over the correspond-
ing R-isomers as obtained with the methoxy substituted benz-
aldehyde (Fig. 2). The free energy of activation calculated for
the R- and S-transition states shows that the o-substituted
fluoro benzaldehyde can give better enantioselectivity com-
pared to the corresponding p-substituted fluoro benzaldehyde.
The o-substituted fluoro S-transition state (viii) is 2.6 kJ mol−1
stable compared to the corresponding R-transition state (vii),
however the difference in the free energy of activation is only
0.5 kJ mol−1 in the case of p-substituted fluoro benzaldehyde
((v) and (vi), Fig. 3). This computed result corroborates the
Fig. 5 13C NMR spectra were taken in CDCl3: (a) 4-methoxy benzaldehyde; (b)
catalyst (S,RS)-3; (c) allyltrichlorosilane after interaction with catalyst (S,RS)-3; (d)
allyltrichlorosilane after interaction with catalyst (S,RS)-3 and 4-methoxy
benzaldehyde.
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The above observed changes clearly indicate that a contact
between amide oxygen and silicon of allyltrichlorosilane has
been established and probably form an intermediate I4r in the
proposed catalytic cycle as shown in Scheme 1. The intermedi-
ate I then form intermediate II by the addition of 4-methoxy
benzaldehyde by establishing intra-molecular hydrogen
bonding between the amide proton and one of the oxygen of
sulphonamide group. The intermediate II is akin to the tran-
sition state obtained during our computational studies. The
intermediate II is transformed into intermediate III, which is
decomposed in the presence of DIPEA to regenerate the cata-
lyst (S,RS)-3 and produce the product oxy-silylated homoallyl
alcohol.4q
Scheme 2 Preparation of tosyl-protected L-phenylalanine.
Step 2: typical procedure for the synthesis of catalyst (S,RS)-
3.14 To the tosyl-protected L-phenylalanine (1 g, 3.13 mmol) in
dry chloroform was added dropwise freshly distilled thionyl
chloride (341 μL, 4.70 mmol), and the resulting mixture was
stirred at room temperature for 1 h. Subsequently, the solution
was refluxed for a further 2 h. The clear yellow solution thus
obtained was distilled completely to give a quantitative yield of
acid chloride as yellow solid. The formed acid chloride was
then immediately dissolved in dry CH2Cl2 under nitrogen
atmosphere and cooled to 0 °C. To the cooled solution was
added D/L-α-methylbenzylamine (398 μL, 3.09 mmol) in CH2Cl2
drop wise under nitrogen atmosphere. After the solution
was stirred for 2 h, the reaction temperature was gradually
increased to room temperature and the mixture was allowed to
stir at room temperature for 12 h. Then, the solution was
extracted with water (50 mL × 5) and dried over anhydrous
Na2SO4. Consequently, the solvent was removed under reduced
pressure, the resulting pale yellow solid was dissolved in a
minimum amount of dichloromethane and an excess amount
of hexane was added to precipitate out the desired product.
The precipitate was washed four times with hexane, filtered,
and dried completely to give catalyst (S,RS)-3 as white solid in
86% yield (Scheme 3).
Conclusions
The chiral organocatalyst (S,RS)-3 is highly efficient for cataly-
zing the asymmetric allylation reaction of aromatic, hetero-
aromatic as well as α,β-unsaturated aldehydes with allyl-
trichlorosilane under mild reaction conditions. High yields
and ee’s of homoallyl alcohols were achieved with a wide range
of substrates, in particular, with 4-methoxy-, 4-benzyloxy- and
4-tert-butyl-benzaldehydes where product yields were good (up
to 71%) with excellent ee (up to 99%). The DFT calculations
corroborate the difference in the enantioselectivity observed
with fluoro substituted benzaldehyde in comparison to the
rest of the other aldehydes studied. NMR spectral studies
clearly show the existence of interaction between catalyst, allyl-
trichlorosilane and substrate during asymmetric allylation
reaction.
All other catalysts from (S,S)-3 to (S,S)-10 were synthesized
following above reaction procedure.
Catalyst (S)-1 and (R)-1:14 yield 1.8 g, 95%; white crystals;
mp 163–165 °C; catalyst (S)-1: [α]2D7 = −11.8 (c = 1, CH3COCH3);
catalyst (R)-1: [α]2D7 = 12.3 (c = 1, CH3COCH3); FTIR 3440, 3285,
3036, 2925, 2360, 1956, 1919, 1729, 1673, 1598, 1424, 1336,
Experimental section
Organocatalysts (S)-1, (S,S)-3 to (S,RS)-8 were synthesised from
D- and L-phenylalanine,14,29 whereas catalysts (S,RS)-9 and
(S,RS)-10 based on L-phenylglycine and L-alanine respectively.
Catalyst (S)-2 was directly purchased from Acros Organics. All
the catalysts (except (S)-2) were synthesised following literature
procedure.14
1
1213, 1158, 1077, 910, 813, 746, 675 cm−1; H NMR (500 MHz,
CDCl3): δ = 2.39 (s, 3H), 2.97–3.01 (dd, J = 6.5, 14 Hz, 1H),
3.07–3.11 (dd, J = 5.5, 14 Hz, 1H), 4.18–4.22 (q, J = 6 Hz, 1H),
5.07–5.09 (d, J = 10 Hz, 1H), 7.06–7.08 (m, 2H), 7.20–7.26 (m,
5H), 7.57–7.59 (d, J = 10 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ = 20.4, 38.4, 57.1, 126.6, 126.8, 128.1, 129.3, 136.5, 138.2,
142.8, 171.5; Anal. Calcd for C16H17NO4S: C, 60.17; H, 5.37;
N, 4.39; S, 10.04; O, 20.04. Found: C, 60.14; H, 5.41; N, 4.35; S,
9.99, O, 20.10; TOF-MS (ESI−) calcd for (C16H17NO4S − H+)
318.09, found 318.22.
General procedure for the synthesis of catalysts (S,S)-3 to
(S,RS)-10
Step 1: typical procedure for the preparation of tosyl-
protected L-phenylalanine.14,29 To
a solution of L-phenyl-
alanine (1 g, 6.05 mmol) dissolved in 15 mL of 1.5 N NaOH
was added p-toluenesulfonyl chloride (1.38 g, 7.26 mmol) in
diethyl ether (10 mL) at room temperature. After 10 h of stir-
ring, conc. HCl was added to the viscous white solution until
it became homogeneous. The ether layer was separated, and
the aqueous layer was extracted twice with ether. The crude
product was recrystallised from ether and ethanol mixture
to give pure compound as white crystals (Scheme 2). Other
tosyl-protected-amino acids were synthesised following the
above reaction procedure.14,29
Scheme 3 Preparation of catalyst (S,RS)-3.
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Catalysts (S,S)-3 and (S,R)-3: all the characterization data for
Organic & Biomolecular Chemistry
Catalyst (S,S)-6: yield 0.83 g, 87.8%; white powder; mp
catalysts (S,S)-3 and (S,R)-3 were well matched with the litera- 203 °C, [α]2D7 = −23.2 (c = 1, CHCl3); FTIR 3339, 3259,
ture data.14
3055, 3036, 2975, 2926, 2877, 1933, 1637, 1530, 1445,
Catalyst (S,RS)-3: yield 0.70 g, 86%; white powder; mp 1329, 1160, 1085, 936, 773, 691, cm−1
;
1H NMR (500 MHz,
174 °C; [α]2D7 = −10.3 (c = 1, CHCl3); FTIR 3316, 3249, 2971, CDCl3): δ = 1.47–1.48 (d, J = 7 Hz, 3H), 2.38 (s, 3H),
2925, 2869, 2328, 1948, 1646, 1537, 1443, 1328, 1159, 1089, 2.79–2.84 (dd, J = 7, 14 Hz, 1H), 3.06–3.1 (dd, J = 6, 15 Hz, 1H),
1
932, 747, 699 cm−1; H NMR (500 MHz, CDCl3): δ = 1.32–1.34 3.87–3.91 (q, J = 6.5 Hz, 1H), 4.99–5.01 (d, J = 7.5 Hz,
(m, 3H), 2.42 (s, 3H), 2.78–2.87 (m, 1H), 3.0–3.06 (m, 1H), 1H), 5.75–5.80 (m, 1H), 6.28–6.29 (d, J = 7.5 Hz, 1H), 6.87–6.89
3.85–3.88 (m, 1H), 4.91–4.48 (m, 2H), 6.35–6.36 (m, 1H), (d, J = 7 Hz, 2H), 7.04–7.15 (m, 5H), 7.29–7.54 (m, 6H),
6.88–6.93 (m, 2H), 7.14–7.29 (m, 10 H), 7.55–7.57 (d, J = 7.76–7.78 (d, J = 8 Hz, 1H), 7.86–7.87 (m, 1H), 7.99–8 (d, J =
6.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ = 21.7, 21.9, 38.6, 8 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ = 21.1, 21.4, 38.4,
49.3, 57.9, 126.2, 127.4, 127.5, 128.8, 129.1, 129.2, 129.4, 130, 45, 57.5, 122.3, 123, 125.2, 125.7, 126.3, 127, 127.1, 128.1,
135.3, 136, 142.5, 142.7, 144.1, 169.2; Anal. Calcd for 128.7, 129.1, 129.7, 130.7, 133.8, 135, 137.7, 143.8, 168.7;
C24H26N2O3S: C, 68.22; H, 6.20; N, 6.63; S, 7.59; O, 11.36. TOF-MS (ESI−) calcd for (C28H28N2O3S − H+) 471.18, found
Found: C, 68.24; H, 6.17; N, 6.59; S, 7.50; O, 11.26; TOF-MS 471.28; Anal. Calcd for C28H28N2O3S: C, 71.16; H, 5.97; N, 5.93;
(ESI+) calcd for (C24H26N2O3S + H+) 423.54, found: 423.52.
S, 6.78; O, 10.16. Found: C, 71.13; H, 6.02; N, 5.88; S, 6.71; O,
Catalyst (R,RS)-3: yield 0.70 g, 86%; white powder; mp 10.25.
185 °C; [α]2D7 = 11.2 (c = 1, CHCl3); FTIR 3313, 3247, 3059, 2971,
Catalysts (S,S,S,S)-7 and (S,S,S,S)-8: all the characterization
2924, 2872, 2360, 1946, 1644, 1537, 1444, 1328, 1159, 1088, data for catalysts (S,S,S,S)-7 and (S,S,S,S)-8 were well matched
933, 815 746, 698 cm−1 1H NMR (500 MHz, CDCl3): δ = with literature data.14
1.31–1.34 (m, 3H), 2.41 (s, 3H), 2.79–2.88 (m, 1H), 2.98–3.04
;
Catalyst (S,RS)-9: pre-catalyst: N-tosyl-protected L-phenylgly-
(m, 1H), 3.85–3.89 (m, 1H), 4.91–4.99 (m, 1H), 5.03–5.11 (m, cine:13 yield 1.8 g, 89.1%; white crystal; mp 165 °C; [α]D27 = 25.1
1H), 6.37–6.41 (m, 1H), 6.89–6.93 (m, 2H), 7.14–7.29 (m, 10H), (c = 1, CH3COCH3); FTIR 3592, 3535, 3293, 3060, 3060 2977,
7.55–7.57 (m, 2H); 13C NMR (125 MHz, CDCl3): δ = 21.5, 21.7, 2921, 2541, 1920, 1725, 1602, 1458, 1328, 1168, 1089, 925, 811,
38.5, 49, 57.7, 126, 127.1, 127.3, 128.6, 128.9, 129.2, 129.8, 692 cm−1 1H NMR (500 MHz, CD3COCD3): δ = 2.36 (s, 3H),
;
135.2, 135.9, 143.6, 150.7, 169; Anal. Calcd for C24H26N2O3S: C, 5.06–5.07 (br, 1H), 7.27–7.36 (m, 7H), 7.67–7.69 (d, J = 8 Hz,
68.22; H, 6.20; N, 6.63; S, 7.59; O, 11.36. Found: C, 68.26; H, 2H); 13C NMR (125 MHz, CD3COCD3): δ = 21.5, 60.5, 128,
6.18; N, 6.59; S, 7.50; O, 11.29; TOF-MS (ESI+) calcd for 128.3, 129, 129.5, 130.3, 137.7, 139.4, 140.2, 143.9, 171.5;
(C24H26N2O3S + H+) 423.54, found: 423.50.
TOF-MS (ESI−) calcd for (C15H15NO4S − H+) 304.07, found
Catalyst (S)-4: yield 0.60 g, 83%; white powder; mp 156 °C; 304.16; Anal. Calcd for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59;
[α]2D7 = −5.2 (c = 1, CHCl3); FTIR 3370, 3264, 3131, 3062, 2970, S, 10.50; O, 20.96. Found: C, 59.04; H, 5.00; N, 4.55; S, 10.44;
2928, 2363, 1940, 1638, 1531, 1431, 1327, 1161, 1091, 950, 810, O, 21.06.
744, 670 cm−1
;
1H NMR (500 MHz, CDCl3): δ = 0.98 (s, 6H),
Catalyst (S,RS)-9: yield 1.18 g, 88.8%; pale yellow powder;
2.42 (s, 3H), 2.81–2.85 (dd, J = 6, 13 Hz, 1H), 2.99–3.03 (dd, J = mp 155 °C; [α]2D7 = 19.6 (c = 1, CHCl3); FTIR 3322, 3257, 3059,
6.5, 13.5 Hz, 1H), 3.78–3.79 (m, 1H), 3.89–3.90 (m, 1H), 4.98 3034, 2972, 2926, 1943, 1793, 1647, 1538, 1446, 1335, 1161,
(br, 1H), 5.78 (br, 1H), 6.97 (m, 2H), 7.21–7.26 (m, 6H), 1090, 1024, 940, 816, 692, 674 cm−1 1H NMR (500 MHz,
;
7.57–7.58 (d, J = 7 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ = CDCl3): δ = 1.33–1.36 (m, 3H), 2.38 (s, 3H) 4.73–4.79 (m, 1H),
23.8, 40.1, 43, 59.2, 128.6, 130.3, 130.6, 131.2, 136.8, 170.2; 4.93–5.03 (m, 1H), 6.99–7.26 (m, 13H), 7.58–7.59 (d, J = 8 Hz,
TOF-MS (ESI+) calcd for (C19H24N2O3S + H+) 361.15, found 2H); 13C NMR (125 MHz, CDCl3): δ = 22.6, 23.2, 50.8, 61.9, 62,
361.22; Anal. Calcd for C19H24N2O3S: C, 63.31; H, 6.71; N, 7.77; 127, 128.7, 128.8, 129, 130, 130.1, 130.4, 130.9, 131, 138, 143.7,
S, 8.90; O, 13.32. Found: C, 63.36; H, 6.76; N, 7.73; S, 8.82; O, 144.9, 169.3; TOF-MS (ESI−) calcd for (C23H24N2O3S − H+)
13.40.
409.51, found 409.45; Anal. Calcd for C23H24N2O3S: C, 67.62;
Catalyst (S)-5:12 yield 0.82 g, 84.5%; white powder; mp H, 5.92; N, 6.86; S, 7.85; O, 11.75. Found: C, 67.65; H, 5.98; N,
186 °C; [α]2D7 = −12.8 (c = 1, CHCl3);12 FTIR 3303, 3060, 3032, 6.80; S, 7.79; O, 11.82.
2924, 2870, 2361, 1949, 1652, 1531, 1443, 1325, 1154, 1089,
Catalyst
(S,RS)-10:
pre-catalyst:
N-tosyl-protected
933, 816, 744, 699 cm−1; H NMR (500 MHz, CDCl3): δ = 2.41 L-alanine:14,29 yield 2.4 g, 87.8%; white crystal; mp = 170 °C;
(s, 3H), 2.82–2.86 (dd, J = 6, 14 Hz, 1H), 3.01–3.05 (dd, J = 6.5, [α]2D7 = 7.8 (c = 1, H2O); FTIR 3433, 3282, 2932, 2361, 1922,
14 Hz, 1H), 3.95–3.99 (q, J = 6.5 Hz, 1H), 4.97–4.98 (d, J = 7 Hz, 1721, 1638, 1519, 1459, 1340, 1217, 1161, 1043, 1014, 813,
1H), 6.11–6.13 (d, J = 8 Hz, 1H), 6.87–6.95 (m, 3H), 7.07–7.28 685 cm−1; 1H NMR (500 MHz, CD3COCD3): δ = 1.31–1.31 (d, J =
(m, 15H), 7.54–7.56 (d, J = 8 Hz, 2H); 13C NMR (125 MHz, 7 Hz, 3H), 2.41 (s, 3H), 3.93–3.99 (m, 1H), 7.36–7.38 (d, J =
CDCl3): δ = 21.6, 38.1, 57.2, 57.5, 57.6, 127.1, 127.2, 127.4, 8 Hz, 2H), 7.74–7.76 (d, J = 8.5 Hz, 2H); 13C NMR (50 MHz,
127.5, 128.6, 129, 129.2, 129.9, 134.9, 135.6, 140.6, 141, 143.9, CD3COCD3, D2O): δ = 18.2, 20.6, 51.3, 125.6, 126.7, 129.7,
169.1; TOF-MS (ESI+) calcd for (C29H28N2O3S + H+) 485.18, 137.2 143.8, 174.3; TOF-MS (ESI−) calcd for (C10H13NO4S − H+)
found 485.29; Anal. Calcd for C29H28N2O3S: C, 71.87; H, 5.82; 242.06, found 242.12; Anal. Calcd for C10H13NO4S: C, 49.37; H,
N, 5.78; S, 6.62; O, 9.90. Found: C, 71.82; H, 5.86; N, 5.74; S, 5.39; N, 5.76; S, 13.18; O, 26.31. Found: C, 49.33; H, 5.34; N,
1
6.57; O, 10.1.
5.83; S, 13.14; O, 26.41.
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Catalyst (S,RS)-10: yield 1.3 g, 91.2%; yellow powder; mp =
158 °C; [α]2D7 = 3.5 (c = 1, CHCl3); FTIR 3321, 3256, 3063, 2965,
2925, 2363, 1945, 1742, 1646, 1542, 1448, 1331, 1262, 1158,
1091, 1025, 808, 698, 668 cm−1; 1H NMR (500 MHz, CDCl3): δ =
1.23–1.24 (d, J = 7 Hz 3H), 1.37–1.46 (td, J = 7, 24 Hz, 3H),
2.41–2.42 (d, J = 4.5 Hz, 3H), 3.73–3.77 (m, 1H), 4.91–5.01 (m,
1H), 5.11–5.17 (m, 1H), 6.41–6.49 (td, J = 4.5, 26 Hz, 1H),
7.20–7.33 (m, 8H), 7.70–7.74 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ = 19.2, 21.5, 21.7, 49, 52.5, 125.9, 126, 127.1, 127.2,
127.4, 128.7, 129.9, 144, 170.1; TOF-MS (ESI−) calcd for
(C28H22N2O3S − H+) 345.14, found 345.12; Anal. Calcd for
C28H22N2O3S: C, 62.40; H, 6.40; N, 8.09; S, 9.26; O, 13.85.
Found: C, 62.46; H, 6.31; N, 8.01; S, 9.31; O, 13.96.
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In a N2 atmosphere glovebox 25.32 mg (0.06 mmol) of catalyst
(S,RS)-3 was weighed out to a oven dried 5 mL reactor. To it
24 mg of powdered activated 4 Å MS was immediately added.
To it 1 mL of dry mixed solvent (CH2Cl2 : THF in 7 : 3 ratio)
was added. The reactor was sealed with a septum and Teflon
tape and taken out of glovebox. It was then cooled to 0 °C
temperature. To it allyltrichlorosilane (1.2 equiv. with respect
to aldehyde) was added dropwise. After
1 h aldehyde
(0.4 mmol) was added during 15 minutes followed by DIEPA
(2 equiv. with respect to aldehyde) was added and the reaction
was allowed to stir for 14 h at this temperature. The reaction
was quenched with aqueous NaHCO3 (1 mL) and extracted
with dichloromethane (3 × 10 mL). The combined organic
layers were washed with brine and dried over Na2SO4. The
products were purified by flash chromatography using silica
gel 100–200 mesh. Products were confirmed by NMR data
corresponded to those published.
Acknowledgements
Authors thank CSIR and UGC for financial support. Debashis
Ghosh and Debashis Sahu are thankful to AcSIR for their
Ph.D. degree enrolment. Analytical Discipline and Centralized
Instrumental Facility is gratefully acknowledged for instrumen-
tal facilities.
Notes and references
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