Enantioselective organocatalytic synthesis of the chiral chromenes by domino oxa-Michael-aldol reaction

Article abstract of DOI:10.1016/j.cclet.2017.09.058

The proline based chiral organocatalyst has been found to be an efficient catalyst for the facile synthesis of substituted 2-aryl-2H-chromenes-3-carbaldehyde. We envisioned that the iminium interaction between chiral amino catalysts and α,β-unsaturated ca

Full text of DOI:10.1016/j.cclet.2017.09.058

Accepted Manuscript
Title: Enantioselective organocatalytic synthesis of the chiral
chromenes by domino oxa-Michael-aldol reaction
Authors: Shrikant S. Pendalwar, Avinash V. Chakrawar,
Sudhakar R. Bhusare
PII:
DOI:
Reference:
S1001-8417(17)30408-4
https://doi.org/10.1016/j.cclet.2017.09.058
CCLET 4264
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Chinese Chemical Letters
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24-6-2017
14-9-2017
28-9-2017
Please cite this article as: Shrikant S.Pendalwar, Avinash V.Chakrawar,
Sudhakar R.Bhusare, Enantioselective organocatalytic synthesis of the
chiral chromenes by domino oxa-Michael-aldol reaction, Chinese Chemical
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Communication
Enantioselective organocatalytic synthesis of the chiral chromenes by domino oxa-
Michael-aldol reaction
Shrikant S. Pendalwar, Avinash V. Chakrawar, Sudhakar R. Bhusare
Department of Chemistry, Dnyanopasak College, Parbhani-431 401, MS, India
Graphical Abstract
Enantioselective organocatalytic synthesis of the chiral chromenes by domino oxa-Michael-aldol reaction
Shrikant S. Pendalwar, Avinash V. Chakrawar, Sudhakar R. Bhusare*
Department of Chemistry, Dnyanopasak College, Parbhani-431 401, MS, India
The proline based chiral organocatalyst has been found to be an efficient catalyst for enantioselective domino oxa-Michael-aldol
reaction. This catalytic system provided the synthesis of substituted 2-aryl-2H-chromenes-3-carbaldehyde in good to high yields
(73%-97%) with excellent enantioselectivity (up to 97%) and reasonable reaction times. The atom economy, high yield and mild
reaction conditions are some of the important features of this protocol.
ARTICLE INFO
ABSTRACT
Article history:
Received 24 June 2017
Received in revised form 14 September 2017
Accepted 21 September 2017
Available online
The proline based chiral organocatalyst has been found to be an efficient catalyst for
the facile synthesis of substituted 2-aryl-2H-chromenes-3-carbaldehyde. We
envisioned that the iminium interaction between chiral amino catalysts and α,β-
unsaturated carbonyl group was beneficial along with thiourea group as hydrogen
bond donor, heterocyclic amines as general base in the domino oxa-Michael-aldol
reaction. This catalytic system provided the products in good to high yields (73%-96%)
with excellent enantioselectivity (up to 97%) and reasonable reaction time. The atom
economy, high yield and mild reaction conditions are some of the important features
of this protocol.
Keywords: Asymmetric synthesis
L-Proline
Organocatalyst
2-Aryl-2H-chromenes-3-carbaldehyde
The scope and stereoselectivities achieved by organocatalysts had grown remarkably over the past decade. Organocatalytic reactions
are usually considered as operationally easy and eco-friendly because the use of metals is avoided. Organocatalytic enantioselective
systems have rapidly grown and found to be a very exciting field in organic chemistry and chiral secondary amines are perhaps the most
frequently used organocatalysts, which activate substrates either by raising the highest occupied molecular orbital energy level or
lowering the lowest unoccupied molecular orbital energy level [1].
 Corresponding author.
E-mail address: bhusare71@yahoo.com (S.R. Bhusare)

Heterocycles plays a vital role in the design and discovery of new physiologically active compounds [2]. The benzopyrans also belong
among these privileged structures, as depict and revealed by Nicolaou et al. [3,4]. The condensation reactions between Michael acceptors
and salicylaldehydes have confirmed to be a useful route to benzopyrans [5]. Although asymmetric methods would furnish
enantiomerically enriched chromenes, their development has proven to be a synthetic challenging task. By taking advantage of the
capability of chiral proline derivatives to participate in the reversible formation of enamine and iminium intermediates, Enders
Yamamoto, Jorgenson and List have independently developed novel types of organocatalyzed cascade reactions [1,6,7]. Michael addition
initiated cascade Michael-aldol processes serve as powerful methods for the generation of complex structures.
Compared with the proline amide catalyst, proline with thiourea moiety having pyrrolidine ring, two hydrogen atoms on thiourea
involved in hydrogen bonding and aromatic or cyclic amine as general base are functional centers in the backbone of the catalyst. It exerts
stronger influence on the orientation of the iminium intermediate formed between α,β-unsaturated carbonyl and organocatalyst to
enhance the stereoselectivities for the domino oxa-Michael-aldol reaction.
Herein we reported the asymmetric synthesis of chiral chromenes via organocatalytic domino oxa-Michael-aldol reaction using proline
based chiral organocatalyst. The strategy we presented here is the utilization of a proline based chiral organocatalyst as a promoter for
activation of the Michael acceptor 5 in a highly enantioselective controlled manner (Table 1). As our earlier interest in synthesis and study
of proline based chiral organocatalysts [8], we envisioned that the iminium interaction between chiral amino catalysts and α,β-
unsaturated carbonyl group was beneficial along with thiourea group as hydrogen bond donor, heterocyclic amines as general base in
the domino oxa-Michael-aldol reaction of simple α,β-unsaturated aromatic aldehydes and salicylaldehydes.
All solvents were used as commercial anhydrous grade without further purification. Aluminium sheets 20 cm × 20 cm, Silica gel 60
F254, Merck grade was used for thin layer chromatography to determine the progress of reaction. The column chromatography was
carried out over silica gel (80-120 mesh). Optical rotations were measured on a Polax-2L digital polarimeter. 1H NMR and 13C NMR spectra
were recorded on a Bruker 300 MHz spectrometer. Melting points were measured in open capillary. Enantiomeric purity is determined
on PerkinElmer Series 200 HPLC systems with chiral HPLC.
The procedures for preparing proline based chiral organocatalysts 3a-d were outlined in Scheme 1. First, commercially available Boc-
L-proline reacted with thionyl chloride in DCE solvent and then the solvent was evaporated to remove excess of thionyl chloride and
solvent to obtain chloride of Boc-L-proline. It was then treated with the ammonium isothiocyanate followed by addition of certain amount
of the amine to obtain product. After, the N-Boc protecting group was removed to get proline based chiral organocatalysts 3a-d (detail
information for preparation of 3a-d see Supporting information).
Scheme1. Reagent and conditions: (a) Thionyl chloride, DCE, NH4SCN, PEG-400, Tosyl chloride, Et3N, R-NH2, r.t., 24 h; (b) TFA, DCM, 0 oC.
Preliminary studies were carried out on the model reaction between trans-cinnamaldehyde and salicylaldehyde. The Screening of the
catalyst and catalytic loading on the yield and enantioselectivity of the domino oxa-Michael-aldol reaction between salicylaldehyde and
trans-cinnamaldehyde studied and results were summarized in Table 1. The organocatalysts 3b and 3c were found to be poor catalysts
for this reaction because of less product formation and poor enantioselectivities with 5 mol% catalyst loading (Table 1, entries 2-3). When
the organocatalyst 3d was used, the reaction time was 28 h, moderate improvement in enantioselectivity but the lower yield were
obtained (Table 1, entry 4 vs. 2-3). The organocatalysts 3c and 3d gives low yield due to absence of hydrogen on the nitrogen atom of
amine of the thiourea moiety. When catalyst 3a was used in the reaction, performance of the reaction was better and significant
improvement in yield as well as enantioselectivities (Table 1, entry 1 vs. 2-4).
When organocatalyst 3a loading was increased to 8 mol%, it gives moderate yield and enantioselectivity (Table 1, entry 5). Increasing
the catalytic loading to 10 mol%, the yield and enantioselectivity of product 6a was improved (Table 1, entry 6). So catalyst 3a (10 mol%)
was found to be best in catalytic performance, further we screened different solvents for the domino oxa-Michael-aldol reaction.
Table 1
Screening of the catalyst and catalytic loading for the domino oxa-Michael-aldol reactiona.

c
25
Entry
Catalyst
3a
mol%
Time (h)
26
Yield (%)b
59
[α]
ee (%)d
51
D
1
2
3
4
5
6
5
5
−33.2
-
3b
28
<19
<16
47
ND
ND
62
3c
5
28
-
3d
5
28
−40.4
−46.2
−52.0
3a
8
24
61
71
3a
10
22
68
80
a Reaction was performed with salicylaldehyde (1 mmol), cinnamaldehyde (1.2 mmol), catalyst, 2-NO2-PhCOOH (10 mol%), 100 mg of molecular sieves (MS) of 4Å
in DCM (10 mL) at r.t.
b Isolated yield.
c
25
Measured [α] (c 0.4, CHCl3).
D
d ee values were determined by chiral HPLC.
Toluene was reported to provide moderate yield in similar reactions [9], we also observed similar result in our experiment (Table 2,
entry 1). This was because the low solubility of catalyst 3a in toluene. When used highly polar solvents such as DMF and DMSO, reaction
completed in 48 h giving very poor yields (Table 2, entries 2 and 3), which was in agreement with the literatures [10a,b]. Oxygen containing
less polar solvent such as THF gives low yield and poor enantioselectivity (Table 2, entry 4). Less polar halohydrocarbon solvents, such as
dichloroethane (DCE) and chloroform, gave moderate yields and enantioselectivities (Table 2, entries 5 and 6). When DCM was used as
the solvent, reaction completed in 22 h and gave excellent yield and enantioselectivity. Therefore DCM was chosen as the best solvent
(Table 2, entry 7).
Table 2
Screening of the solvent in domino oxa-Michael-aldol reactiona.
25 c
Entry
Solvent
Toluene
DMF
Time (h)
26
Yield (%)b
[α]
eed (%)
65
D
1
2
3
4
5
6
7
59
<5
<5
48
56
57
71
−42.3
-
48
ND
ND
52
DMSO
THF
48
-
40
−33.8
−34.4
−42.3
−51.4
Chloroform
DCE
30
59
24
65
DCM
22
79
a Reaction was performed with salicylaldehyde (1 mmol), cinnamaldehyde (1.2 mmol), catalyst (10 mol%), 2-NO2-PhCOOH (10 mol%), 100 mg of MS of 4Å in DCM
(10 mL) at r.t.
b Isolated yield.
c
25
Measured [α] (c 0.4, CHCl3).
D
d Determined by chiral HPLC.
Nevertheless, we investigated the influence of various additives on the organocatalytic oxa-Michael-aldol reaction, and the results
were summarized in Table 3. Initially in the absence of any additive we obtained moderate results (Table 3, entry 1). When 2-nitrobenzoic
acid (10 mol%) was used, the enantioselectivity of the reaction in DCM was increased from 79% to 93% ee (Table 3, entry 2). A series of

nitro substituted benzoic acids were used, such as 3-nitrobenzoic acid and 4-nitrobenzoic acid, we obtained low yields and
enantioselectivity (Table 3, entries 3 and 4). When, trifluoroacetic acid (10 mol%) was used, there was no improvement in yield or
enantioselectivity for the reaction (Table 3, entry 5). We increased the concentration of 2-nitrobenzoic acid, but the yield and
enantioselectivity were decreased (Table 3, entry 2 vs. entries 6 and 7). Eventually, 10 mol% 2-nitrobenzoic acid was identified as the
optimal additive.
Table 3
Effect of the additives on domino oxa-Michael-aldol reactiona.
c
25
Entry
Additives
mol%
10
Time (h)
22
Yield (%)b
[α]
ee (%)d
79
D
1
2
3
4
5
6
7
No Additives
69
84
46
43
51
61
60
−51.4
2-NO2-PhCOOH
3-NO2-PhCOOH
4-NO2-PhCOOH
CF3COOH
10
22
−54.0
−38.4
−43.1
−8.4
93
10
24
59
10
24
54
10
24
59
2-NO2-PhCOOH
2-NO2-PhCOOH
15
22
−47.5
−48.1
73
20
22
74
a Reaction was performed with salicylaldehyde (1 mmol), cinnamaldehyde (1.2 mmol), catalyst (10 mol%), 2-NO2-PhCOOH (10 mol%), 100 mg of MS of 4Å in DCM
(10 mL) at r.t.
b Isolated yield.
c
25
Measured [α] (c = 0.4, CHCl3).
D
d Determined by chiral HPLC.
Having established 3a as a suitable organocatalyst, DCM as the solvent and 2-nitrobenzoic acid as an effective additive, then we studied
the substrate scope for the enantioselective domino oxa-Michael-aldol reaction. The catalytic system worked well for a variety of
substituted salicylaldehyde derivatives, although the yields and enantioselectivities varied with the electronic and steric properties of the
substrates. The α,β-unsaturated aromatic aldehydes bearing electron-withdrawing groups, such as a nitro group and fluorine were good
Michael acceptors, generally affording the desired products 6a-j.
Compound 6a: Isolated yield 93%, [α]D25 -60.1 (c 0.4, CHCl3), 1H NMR (300 MHz, DMSO-d6): δ 5.50 (s, 1H), 6.99-7.05 (d, 2H, J = 7.9, 1.2
Hz), 7.16-7.24 (m, 1H), 7.40-7.45 (t, 2H, J = 7.2, 1.3 Hz), 7.56 (s, 1H), 7.68-7.72 (d, 1H, J = 7.2, 1.3 Hz), 8.07-8.17 (m, 2H), 8.30-8.32 (d, 1H,
J = 7.5, 1.1 Hz), 9.46 (s, 1H). 13C NMR (75 MHz, DMSO-d6): δ 74.41, 113.45, 114.34, 118.16, 126.34, 127.89, 129.89, 131.09, 136.49, 142.19,
143.56, 154.43, 160.03, 190.01. HPLC (Daicel Chiralpak AD, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 25.36 min (major), 30.45 min
(minor).
Table 4
Asymmetric domino oxa-Michael-aldol reactions of various salicylaldehydes and substituted cinnamaldehydes.
c
Entry
1
R1
H
R2
H
Product
Time (h)
22
Yield (%)a
93
ee (%)b
[α]25
D
6a
92
−60.4

2
3
3,5-Br
3,5-I
3-Cl, 5-I
5-Br
H
H
6b
6c
6d
6e
6f
23
23
24
20
20
24
20
24
24
73
76
74
96
95
81
83
80
79
97
94
97
78
78
75
85
96
91
+34.1
+102.3
−20.8
−32.3
−55.5
+27.3
−36.5
−26.5
−55.6
H
4
H
5
4-NO2
4-NO2
4-OMe
4-F
6
7
5-Br
H
6g
6h
6i
8
9
H
4-Br
4-Cl
10
H
6j
a Isolated yield.
b Determined by chiral HPLC analysis.
c
25
Measured [α] (c 0.4, CHCl3).
D
The enantioselectivity was also affected by the electronic properties of the substituent’s of salicylaldehydes as 3,5-dibromo and 3,5-
diiodo salicylaldehydes showed higher ee than the un-substituted salicylicaldehyde (Table 4, entries 2-4 and 8–10), while 4-methoxy
cinnamaldehyde gives moderate yields and relative lower ee value (Table 4, entry 7).
In summary, A group of novel proline based organocatalysts derived from Boc-L-proline, 3a-d, have been obtained via a simple
synthesis. The catalytic performance of the resultant synthetic products for the domino oxa-Michael-aldol reactions between
salicylaldehyde and cinnamaldehyde has been evaluated. It has been found that, out of all four organocatalysts, 3a was found to be
efficient for the oxa-Michael-aldol reactions under investigation. It has excellent catalytic activity affording excellent enantioselectivity
and moderate to high yields even at low dosages of 10 mol% along with the 2-NO2-PhCOOH (10 mol%) as additives and 100 mg of MS 4Å.
Acknowledgments
We acknowledge, Dr. Smt. S. S. Kadam, Principal and Prof. W. N. Jadhav, Head Department of Chemistry, Dnyanopasak College,
Parbhani for providing necessary facilities and University Grant Commission, Delhi for the award of the Junior Research Fellowship.
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