Efficient synthesis of functionalized olefins by Wittig reaction using Amberlite resin as a mild base

Article abstract of DOI:10.1080/00397911.2016.1276191

A convenient procedure for the synthesis of olefins by the reaction of stabilized, semistabilized, and nonstabilized phosphorous ylides with various aldehydes or ketone using Amberlite resin as a mild base is described. Our developed method offers facile and racemization-free synthesis of α,β-unsaturated amino esters and chiral allylic amine. The developed methodology offers mild reaction conditions, high efficiency, and facile isolation of the final products, a practical alternative to known procedures.

Full text of DOI:10.1080/00397911.2016.1276191

An Efficient Synthesis of Functionalized Olefins by Wittig Reaction Using Amberlite
Resin as a Mild Base
Tushar R. Valkute1, Eswar K. Aratikatla1,2, Asish K. Bhattacharya1,2
1Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune,
Maharashtra, India, 2Academy of Scientific and Innovative Research (AcSIR), CSIR-
National Chemical Laboratory (CSIR-NCL), Pune, India
Corresponding Author: Asish K. Bhattacharya, Division of Organic Chemistry, CSIR-
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411 008, Maharashtra,
India. Email: ak.bhattacharya@ncl.res.in
Abstract
A convenient procedure for the synthesis of olefins by the reaction of stabilized, semi-
stabilized, and non-stabilized phosphorous ylides with various aldehydes or ketone
employing Amberlite resin as a mild base is described. Our developed method offers
facile and racemization free synthesis of , -unsaturated amino esters and chiral allylic
amine. The developed methodology offers mild reaction conditions, high efficiency and
facile isolation of the final products, a practical alternative to known procedures.
Graphical Abstract:
1

KEYWORDS: Wittig reaction; phosphonium ylides; Amberlite resin; aldehyde; alkene
INTRODUCTION
Carbon-carbon bond formation reactions play a major role in the total synthesis of
bioactive molecules. Several C-C bond-forming reactions are known in the literature
however, Wittig olefination remains one of the most favored when an alkene group is to
be introduced with specificity of bond placement. In the classical Wittig method1-3 forms
a phosphorous ylide is formed upon treatment with appropriate base, which then reacts
with a ketone or aldehyde to furnish the corresponding alkene. However, the Wittig
method has a few drawbacks4 such as substrate sensitivity to base, racemization of the
adjacent stereogenic centre, and self-condensation of the carbonyl to name a few. Several
new modifications of Wittig reaction conditions employing various bases such as tertiary
amines,5 lithium 1,1,1,3,3,3-hexafluoro-isopropoxide,6 LiCl/DBU,7 KOSiMe3,8 LiOH,9 or
KH10 have been reported. Recently Ag2CO3 as a mild base for ylide formation for the
Wittig reaction has been reported.11 Using K2CO3 as a mild base, Wittig olefination of
non-stabilized ylides under solid-state ball milling conditions has been reported.12 Wittig
olefination in solution-phase chemistry has been applied using NaHCO313 or K2CO3.14
Synthesis of unsaturated amino acids employing Wittig olefination has been
accomplished using K3PO4 and a phase-transfer catalyst at 90 C without losing optical
activity or enantiomeric excess.15-16
In recent years, use of resins as solid catalysts in organic transformations17 has garnered
attention of organic chemists worldwide due to their nontoxicity, low cost, reusability,18
2

and recovery by simple filtration after completion of the reaction. Amberlite IR-400 (OH–
) resin has emerged as an efficient heterogeneous catalyst for various chemical
transformations.19
During the course of our work on the synthesis of antimalarial natural products,20 the
development of a mild base-catalyzed Wittig reaction for the synthesis of styrenes
became a necessary. It was anticipated that the numerous advantages associated with
Amberlite IR-400 (OH–) resin could render it as a mild base for the Wittig olefination of
aldehydes and ketones including base-sensitive substrates.
RESULTS AND DISCUSSION
In order to optimize the reaction conditions for the Wittig olefination, 3,4-dimethoxy
benzaldehyde 1a was allowed to react with methylphosphonium bromide 2a in the
presence of various bases under different reaction conditions (Table 1). It was observed
that when the experiment was performed at 95 C for 10 h with Amberlite IR-400 (OH–)
in DMF as solvent (Table 1, entry 17), the corresponding alkene product 3a was obtained
in high yield (85%). The requirement of Amberlite IR-400 (OH–) to effect this
transformation was evident from the fact that no product was formed in the absence of
Amberlite IR-400 (OH–) (Table 1, entry 11 and 12).
The generality of the synthetic methodology was further demonstrated using various
aldehydes and ketone (1a-u) including aromatic, heterocyclic, aliphatic, -amino esters
3

and enantiomerically pure protected amine with various phosphonium ylides (2a-f) to
furnish the corresponding styrene products (3a-3ac) (Table 2).
Methyltriphenylphosphonium bromide was initially allowed to react with various
substituted aromatic aldehydes (1a-i) to furnish the corresponding styrene products (3a-i)
in 76-89% yield (entries 1-9, Table 2). However, when ethylphosphonium ylide 2b was
treated with 3,4-dimethoxy benzaldehyde, a mixture21 of (E)- and (Z)-3j in the ratio of
3:2 was obtained (entry 10, Table 2). The isomeric products were inseparable by column
chromatography. Also, reaction of isovaleraldehyde 1t with semi-stabilized ylide 2f
furnished an inseparable E/Z-mixture21 (4:3) of the product 3ab (entry 28, Table 2).
The scope of the developed synthetic method was further elaborated by examining
reactions of stabilized, non-stabilized and semi-stabilized ylides with various aldehydes
in the presence of Amberlite IR-400 (OH–). Reaction of 2-chlorocyclohexanone 1q with
stabilized ylide 2c using the generalized method afforded the desired product 3t in 60%
yield (entry 20, Table 2). Interestingly, when 2-oxo-2-phenylacetaldehyde 1o was treated
with stabilized 2c and semi-stabilized ylide 2f, the aldehyde carbonyl group participated
in the Wittig reaction and the corresponding products 3r and 3aa were obtained,
respectively with exclusively E-selectivity (entries 18 and 27, respectively, Table 2). It is
pertinent to mention here that synthesis of chalcone 3aa22 could be achieved using this
method.
4

Vinylogous amino acids i.e. , -unsaturated amino acids constitute an essential
ubiquitous motif in several peptide natural products.23 The synthesis of functionalized -
amino acids requires , -unsaturated amino acids as substrates in various organic
reactions such as Diels-Alder reactions,24 1,4-conjugate additions25 and epoxidation
reactions.26 Most of the reported Wittig olefination conditions have a major drawback i.e.
they cause racemization of the stereogenic centre.27 It is pertinent to mention here that the
present method can be used for the synthesis of , -unsaturated amino esters and
enantiomerically pure allylic amines with complete E-selectivity. When N-Boc protected
D-phenylalanal 1r was reacted with stabilized ylide 2c and 2d, corresponding , -
unsaturated amino esters 3u and 3x were obtained, respectively with exceptional E-
selectivity (entries 21 and 24, respectively, Table 2). Similarly, N-Boc protected L-
phenylalanal 1s on reaction with stabilized ylide 2c and 2d furnished , -unsaturated
amino esters 3v and 3w, respectively with E-selectivity (entries 22 and 23, respectively,
Table 2). Allylic amines have been found to be useful synthetic intermediates in the
synthesis of biologically active molecules.28 N-Boc N,O-isopropyllidene L-serinal 1u also
furnished the pure allylic amine 3ac (entry 29, Table 2) when treated with semi-stabilized
phosphonium ylide 2f with E-selectivity. It is pertinent to mention here that synthesis of
, -unsaturated amino esters and enantiomerically pure allylic amine by the developed
method was achieved without racemization as proved by HPLC analysis on a chiral
column (see SI).
5

CONCLUSION
In conclusion, we have developed a practical method utilizing Amberlite IR-400 (OH–)
resin as a mild base for stabilized, semi-stabilized and non-stabilized ylide formation for
the Wittig olefination. The developed method yielded exclusively E-olefination products
with stabilized ylides. In case of Wittig reaction with semi-stabilized ylides, mostly E-
isomeric products were obtained. Further, we have shown the utility of our developed
protocol in the synthesis of chalcone 3aa, which is a useful bioactive molecule. We have
demonstrated the facile and racemization free synthesis of , -unsaturated amino esters
and chiral allylic amine. The main advantages associated with Amberlite IR-400 (OH–)
resin are low cost, non-toxicity and easy work up by simple filtration.
EXPERIMENTAL
General. All melting points were recorded on a Büchi melting point apparatus in open
capillaries and are uncorrected. Commercially available reagents and solvents were used
as received. All dry reactions were carried out under argon atmosphere and flash
chromatography was performed with CombiFlash R 200i with UV/VIS and ELSD, Isco
f
Teledyne Inc., USA using RediSep column (SiO2). 1H NMR spectra were recorded on
500 or 400 or 200 MHz spectrometer and 13C NMR spectra were recorded at 125 or 100
or 50 MHz. Chemical shifts are reported as δ values (ppm) relative to internal standard
tetramethylsilane in CDCl3. HRMS (ESI) were recorded on an Orbitrap (quadrupole plus
ion trap) and TOF mass analyser. Optical rotations were recorded on a JASCO P-1020
polarimeter.
6

General method for Wittig olefination: A round bottom flask was charged with the
suspension of ylide (1.5 mmol) in DMF (4 mL) and then Amberlite IR-400 (OH–)(1.2 g)
was added to it. The content was stirred for the next 20 min at 95 °C under inert
atmosphere then appropriate aldehyde (1 mmol) was added to the reaction mixture and
heating was continued for next 10 hours. On completion of the reaction (TLC), the resin
was filtered off and the crude reaction mixture was evaporated to dryness. Isolation of the
product was carried out by flash chromatography (CombiFlash Rf 200i with UV/VIS and
ELSD, Isco Teledyne Inc., USA) using RediSep® column (SiO2,). All the products were
identified on the basis of their spectral data. The spectral data of all the synthesized
compounds have been provided in the Supporting Information.
ACKNOWLEDGMENT
Generous financial support received from Science and Engineering Research Board
(SERB), Department of Science & Technology (SR/S1/OC-02/2011) and Council of
Scientific and Industrial Research (CSIR), New Delhi (NaPAHA, CSC0130) is gratefully
acknowledged. EKA is grateful to the University Grants Commission (UGC), New Delhi
for the award of a Senior Research Fellowship (SRF).
SUPPORTING INFORMATION
Full experimental detail with spectral data of all the synthesized compounds, copies of
1H, 13C NMR and DEPT spectra, HRMS of all the compounds, HPLC chromatogram of
chiral compounds. This material can be found via the “Supplementary Content”
7

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10

Table 1. Reaction conditions for optimization of Wittig olefination
Reaction conditions, Time Yield (%)a
Entry Solvent Base
1
THF
THF
THF
THF
THF
THF
Et3N
Et3N
Et3N
Et3N
DMF
DMF
DMF
DMF
Amberlite IR-400 (300 mg) RT, 12 h
Amberlite IR-400 (300 mg) Reflux, 12 h
No Reaction
15%
2
3
Piperidine
Piperidine
Pyrrolidine
Pyrrolidine
-
RT, 12 h
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
No Reaction
20%
4
Reflux, 12 h
RT, 12 h
5
6
Reflux, 12 h
RT, 12 h
7
8
-
Reflux, 12 h
9
Amberlite IR-400 (300 mg) RT, 12 h
Amberlite IR-400 (300 mg) Reflux, 12 h
10
11
12
13
14
-
-
RT, 12 h
Reflux, 12 h
Amberlite IR-400 (300 mg) RT, 12 h
Amberlite IR-400 (300 mg)
Amberlite IR-400 (500 mg)
Amberlite IR-400 (1.0 g)
Amberlite IR-400 (1.2 g)
80 C, 30 h
80 C, 24 h
80 C, 18 h
95 C, 10 h
15
16
17
DMF
DMF
DMF
40%
50%
85%
aIsolated yield.
11

Table 2. Synthesis of various olefins using Amberlite-400 (OH-)
H
C
Amberlite-400(OH )
R'X
R
R-CHO
Ph3P
DMF, 95°C, 10 h
R'
3a-ac
2a-e
1a
Entry
Substrate
Ylide
Product
Yield E:Z
(%)a
ratio
85
1
2a
2a
3a
3b
1a
86
2
1b
1c
87
84
3
4
2a
2a
3c
3d
1d
83
5
2a
3e
1e
1f
89
80
6
7
2a
2a
3f
1g
3g
12

79
8
2a
2a
1h
3h
3i
76
82
9
1i
1a
3:2
10
2b
3j
86
80
E only
11
12
1a
1e
2c
2c
3k
E only
3l
83
E only
13
2c
1j
1k
1l
3m
3n
72
71
E only
E only
14
15
2c
2c
3o
3p
78
E only
16
2c
1m
13

74
76
E only
17
18
2c
2c
1n
3q
E only
1o
1p
3r
3s
89
60
E only
19
20
2c
2c
1q
1r
3t
81
88
E only
21
22
2c
2c
3u
E only
1s
1s
3v
3w
3x
77
85
78
E only
E only
E only
23
24
25
2d
2d
1r
1f
2e
3y
14

87
90
E only
E only
26
27
1p
1o
2e
3z
2f
2f
3aa
3ab
75
79
4:3
28
29
1t
E only
2f
1u
3ac
aIsolated yield.
15