Organocatalytic regiospecific synthesis of 1H-indene-2-carbaldehyde derivatives: suppression of cycloolefin isomerisation by employing sterically demanding catalysts

Article abstract of DOI:10.1039/c6ob01918h

The regiospecific synthesis of 1H-indene-2-carbaldehyde derivatives was achieved through transition-metal-free, reductive cyclisation of ortho-formyl trans-cinnamaldehydes with Hantzsch ester in the presence of an aminocatalyst. In particular, cycloolefin isomerisation of the resulting products could be inhibited efficiently by the introduction of a sterically demanding stereo-defined aminocatalyst.

Full text of DOI:10.1039/c6ob01918h

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Organocatalytic regiospecific synthesis
of 1H-indene-2-carbaldehyde derivatives:
suppression of cycloolefin isomerisation by
employing sterically demanding catalysts†
Cite this: DOI: 10.1039/c6ob01918h
Hui Mao,‡a Dong Wan Kim,‡a Hun Yi Shin,‡a Choong Eui Song*b and
Jung Woon Yang*a
Received 31st August 2016,
Accepted 8th November 2016
The regiospecific synthesis of 1H-indene-2-carbaldehyde derivatives was achieved through transition-
metal-free, reductive cyclisation of ortho-formyl trans-cinnamaldehydes with Hantzsch ester in the pres-
ence of an aminocatalyst. In particular, cycloolefin isomerisation of the resulting products could be
inhibited efficiently by the introduction of a sterically demanding stereo-defined aminocatalyst.
DOI: 10.1039/c6ob01918h
www.rsc.org/obc
concerning multi-substituted indene derivatives that need to
be addressed. For instance, tert-propargyl acetates gave a
Introduction
Indenes are utilised as building blocks in organic syntheses, mixture of indenes A and B in Pt-catalysed pentannulation
and they often appear as the key structural motif in many (Scheme 1a).10 Re 11 or Rh 12-catalysed, carbonyl-directed func-
natural products with interesting biological activities,1 and in tionalisation of the ortho-C–H bond of aromatic ketones has
functional materials.2 For these reasons, the construction of been reported for the synthesis of indene derivatives through a
an indene ring system has become a hot topic of interest for cascade conjugate addition of α,β-unsaturated ketones and
chemists. To date, a variety of synthetic methods to facilitate
the formation of an indene ring have been reported. Common
approaches for the synthesis of this target molecule include
reduction–dehydration of indanones,3 acid-catalysed dehydra-
tive cyclisation of phenyl-substituted allylic alcohols4 or cycli-
sation of 1,3-dienes,5 ring expansion of certain substituted
cyclopropenes,6 multi-sequence tandem reactions of α-aryl
ketonitriles involving dimerization, heterolytic cleavage of C–C
bonds, intermolecular coupling, and subsequent intra-
molecular cyclisation,7 and Lewis-acid catalysed Friedel–Crafts
cyclisation of aryl allenes.8 In addition, transition-metal (e.g.,
Pd, Ni, Pt, Co, Au, Cu, or Fe)-catalysed carboannulations have
also been established recently as one of the most powerful
methods in this area.9 Although transition-metal catalysis is
widely used in the synthesis of a wide range of different substi-
tuted indenes, there are still important regioselectivity issues
aDepartment of Energy Science, Sungkyunkwan University, 2066 Seobu-ro,
Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea. E-mail: jwyang@skku.edu;
Tel: +82-31-299-4276
bDepartment of Chemistry, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu,
Suwon, Gyeonggi-do 16419, South Korea. E-mail: s1673@skku.edu
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, characterisation data and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/c6ob01918h
Scheme 1 Transition-metal-free, highly regioselective cascade reac-
tions for the synthesis of 1H-indene-2-carbaldehyde.
‡These authors contributed equally to this work.
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aldol condensations. Non-symmetrical ortho-/or meta-substitu- 2-position of the imidazolidinone moiety: tert-butyl > isopropyl
ents on the aromatic ring in acetophenones led to the for- > gem-dimethyl. Cyclic (2d–f) and acyclic (2g) secondary amine
mation of two regioisomers in most cases. Moreover, the regio- catalysts were also subjected to reductive cyclisation of 1a,
chemical outcome relies on catalyst selection, substituent resulting in the formation of the desired product 4a only in
effects, or reaction conditions (Scheme 1b). Therefore, regio- low to moderate yields (7%–44%). We next screened equi-
selective syntheses are still challenging and better strategies valents of Hantzsch ester and various organic solvents. The
that are highly desirable.13
best result (86% yield) was achieved under the following reac-
Herein, we report a highly regiospecific, transition-metal- tion conditions: 2c·HCl salt (20 mol%) and Hantzsch ester 3a
free cascade reaction to access 1H-indene-2-carbaldehyde and (1.2 equiv.) in THF at room temperature (Table 1, entry 13).
its derivatives (Scheme 1c).14 Only a single regioisomer was
Having the optimal conditions in hand, we first explored
detected depending on the choice of the catalyst used, the reaction scope with diverse o-formyl trans-cinnam-
although both possible regioisomeric pathways are aldehydes. Unsubstituted 1a and 4,5-disubstituted aldehydes 1b–c
accompanied by the isomerisation of olefins.
gave the desired products in good yields using 20 mol% of imid-
azolidinone 2c·HCl catalyst with 1.2 equiv. of Hantzsch ester
3a (Table 2, entries 1–3). When 4- or 5-substituted unsymmetri-
cal substrates (1d–1i) were subjected to the reductive cyclisa-
tion reaction, a mixture of regioisomers 4 and 4′ was observed
in a ca. 67 : 33 ratio regardless of the electronic or positional
nature of the substituents (Table 2, entries 4–9), except for the
5-Me-substituted substrate 1h (Table 2, entry 8). However, to
our surprise, the desired products (up to >99% selectivity)
were obtained regioselectively by using Macmillan’s second
generation catalyst 2h (Table 2, entries 14–19). This catalytic
system exhibited enhanced reactivity and selectivity for a range
of electron-donating and electron-withdrawing groups at
different positions on the phenyl ring, except for 1g. In the
case of 1g, low regioselectivity with poor yield was observed
regardless of the catalyst type (2c or 2h) due to the strong elec-
tron-withdrawing effect of the –NO2 group on the aromatic
ring (Table 2, entries 7 and 17). On the other hand, moderate
regioselectivity was achieved in the presence of alanine-derived
imidazolidinone 2i·HCl catalyst (Table 2, entry 16).
Interestingly, o-acetyl trans-cinnamaldehyde 1j gave product 4j
in good yield and perfect regioselectivity regardless of the cata-
lyst (2c or 2h). Based on our observations and literature pre-
cedence, a reaction mechanism (Scheme 2a) was proposed.
o-Formyl trans-cinnamaldehyde 1a is activated by the second-
ary ammonium salt 2 as an organocatalyst to form iminium
Results and discussion
We began by probing the ability of the secondary amine·HX
catalyst to affect the reaction of o-formyl trans-cinnamaldehyde
1a with Hantzsch ester 3a (Table 1).
A series of imidazolidinone catalysts (2a–c) were first exam-
ined for their catalytic efficiency. Interestingly, the steric bulki-
ness of 2-imidazolidinone played an effective role in greatly
enhancing its catalytic activity. The chemical yield of product
4a increased in the following order of the substituent at the
Table 1 Parameter screening for the synthesis of 1H-indene-2-
carbaldehydea
Entry Catalyst·HX
Hantzsch ester (equiv.) Solvent
THF
Yieldb (%)
species. Subsequently
a hydride was transferred from
1
2a·CF3CO2H 3a (1.1)
20
25
60
75
7
15
44
17
30
36
44
Hantzsch ester 3a to intermediate 5 to give the enamine inter-
mediate 6 and the pyridinium ion 7. At this stage, two
different competitive pathways A (reductive cyclisation) and B
(transfer hydrogenation) are presumably involved with the
enamine intermediate 6. With pathway A, the enamine inter-
mediate 6 reacts with the adjacent carbonyl of the aldehyde to
produce the iminium ion 9, followed by base-promoted de-
hydration to give the α,β-unsaturated iminium ion 10. The
desired product 4 is then formed via hydrolysis of the iminium
ion. In contrast, pathway B can be considered to be a side-
reaction that yields the hydrogenated product 8, if the
enamine intermediate 6 deprotonates the pyridinium ion 7
and the resulting iminium ion then undergoes further hydro-
lysis.15 However, the reaction as per pathway A is more kineti-
cally favoured compared to pathway B because the rate of intra-
molecular nucleophilic addition of enamine to the aldehyde
would be much faster than that of intermolecular proton
2
3
4
5
6
7
8
2a·HCl
2b·HCl
2c·HCl
2d·HCl
2e·HCl
2f·HCl
2g·HCl
3a (1.1)
3a (1.1)
3a (1.1)
3a (1.1)
3a (1.1)
3a (1.1)
3a (1.1)
THF
THF
THF
THF
THF
THF
THF
9
2g·CF3CO2H 3a (1.1)
THF
CHCl3
CH3CN
10
11
12
13
14
15
2c·HCl
2c·HCl
2c·HCl
2c·HCl
2c·HCl
2c·HCl
3a (1.1)
3a (1.1)
3a (1.1)
3a (1.2)
3b (1.2)
3c (1.2)
Toluene 61
THF
THF
THF
86
71
62
a General conditions: 1a (0.5 mmol), catalyst 2a–2g·HX (20 mol%),
Hantzsch ester (1.1 or 1.2 equiv.), solvent (5 mL), r.t. b Isolated yield.
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Table 2 Reaction scope for the synthesis of 1H-indene-2-carbaldehydea
Substrate
R
Catalyst 2c·HCl
Catalyst 2h·HCl
Time Yieldc
Time Yieldc
Entry
R′
Product Selectivityb
(h)
(%)
Entry Substrate Product Selectivityb
(h)
(%)
1
2
H
4,5-Di-
MeO
H (1a) 4a = 4′a
H (1b) 4b = 4′b
—
—
20
20
86
65
11
12
1a
1b
4a = 4′a
4b = 4′
b
—
—
2
2
88
71
3
H (1c) 4c = 4′c
—
20
50
13
1c
4c = 4′c
—
2
68
4
5
6
5-F
4-F
4-Cl
H (1d) 4d + 4′d 4d : 4′d = 67 : 33
H (1e) 4′d + 4d 4′d : 4d = 67 : 33
12
12
12
76
74
77
14
1d
1e
1f
4d
4′d
4f
4d : 4′d = 96 : 4
4′d : 4d = 96 : 4
4f : 4′f = 96 : 4
(83 : 17)
1
1
85
79
15
H (1f) 4f + 4′f
4f : 4′f = 56 : 44
16d
1 (6) 80
(77)
16
7
8
4-NO2
5-Me
H (1g) 4g + 4′g 4g : 4′g = 56 : 44
1
12
10
78
17
18
1g
1h
4g + 4′g 4g : 4′g = 56 : 44
4h
1
1
H (1h) 4h + 4′
4h : 4′h =
87.5 : 12.5
4h : 4′h ≥ 99 : 1
86
h
9
10
4-MeO
H
H (1i)
Me
(1j)
4i + 4′i
4j
4i : 4′i = 67 : 33
4j : 4′j ≥ 99 : 1
12
13
67
88
19
20
1i
1j
4i
4j
4i : 4′i ≥ 99 : 1
4j : 4′j ≥ 99 : 1
1
2.5
80
80
a General conditions: 1a (0.5 mmol), catalyst·HCl (20 mol%), Hantzsch ester (1.1 or 1.2 equiv.), solvent (5 mL), r.t. b Determined by 1H NMR spec-
troscopy. c Isolated yield. d Values in parentheses correspond to the selectivity, time, and yield obtained using 20 mol% of catalyst 2i·HCl.
Scheme 2 (a) Plausible mechanism; (b) kinetic study of cycloolefin isomerisation using 4’d.
abstraction from the pyridinium ion 7 by enamine. To validate is used (see the ESI†). To identify the critical cycloolefin iso-
different regioselective natures of the reaction/or product merisation step in this reaction, we carried out the reaction of
using catalyst 2c or 2h, we monitored the reaction of 1e with 4′d with pyridine 7′ in the presence of catalyst 2h or 2c.
Hantzsch ester 3a using 1H NMR spectroscopy. Surprisingly, Comparable results were obtained (Scheme 2b), which are con-
time-dependent cycloolefin isomerisation was observed, sistent with the aforementioned experimental data, thereby
showing that the isomerization is much slower when the providing strong evidence for the main isomerisation step. In
stereo-defined catalyst 2h is used compared to when catalyst 2c the following selection, we provide several postulates to
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Scheme 3 Rational explanations for controlling the cycloolefin isomerisation.
explain the isomerisation process. The olefin isomerisation isomerisation was effectively suppressed by using a sterically
process presumably involves the following steps (much like demanding stereo-defined aminocatalyst and a base. Further
intermediate 10 in Scheme 2a): the acidic proton at the studies on the utilisation of indene derivatives for asymmetric
benzylic position of the indene moiety is abstracted by base 7′, synthesis are ongoing in our laboratories.
and this is a key step in deriving the aromaticity of anionic
indene and the driving force of olefin isomerisation, which
provides the allylic anion intermediate.
After a preferential protonation of the allylic anion that is
formed from the relatively less-hindered tert-butyl substituted
Experimental
General procedures for the synthesis of ortho-formyl
trans-cinnamaldehydes (1a–1f and 1h–1i, procedure A)
imidazolidinone backbone 2c [path (c)] (which greatly affects
The following procedure was modified from a previously
reported protocol:18 to a stirred solution of 2-bromobenz-
aldehyde (5 mmol) in 10 mL of DMF, acrolein diethyl ether acetal
(1.302 g, 10 mmol), n-Bu4NOAc (3.015 g, 10 mmol), K2CO3
(1.04 g, 7.5 mmol), KCl (372.8 mg, 5 mmol), and Pd(OAc)2
(33.7 mg, 0.15 mmol) were added. The mixture was stirred at
90 °C for ca. 2 hours. After cooling, the reaction mixture was
quenched with brine and extracted with diethyl ether. The
combined organic layers were dried using sodium sulphate, fil-
tered, and concentrated in vacuo to afford a crude mixture.
Subsequently, to the solution of the mixture in acetone was
added aqueous 4 N HCl solution slowly at room temperature.
After 30 min, the reaction mixture was quenched using brine
and extracted with diethyl ether. The combined organic layers
were dried using sodium sulphate, filtered, and concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel (ethyl acetate/hexane) to afford the corresponding
o-formyl trans-cinnamaldehydes (1a–1f and 1h–1i).
the selectivity), product 4′d is formed with a slightly improved
selectivity over 4d via hydrolysis of the iminium ion
(Scheme 3a).
On the other hand, the use of catalyst 2h gives the regio-
specific isomer 4′d owing to the following specific features:16
(i) π–π stacking interaction between the benzyl group within
the imidazolidinone scaffold and the substrate’s indene core is
involved;17 (ii) the sterically demanding benzyl and tert-butyl
groups effectively shield the Si-face of the α,β-unsaturated
iminium ion, which prevents base 7′ from accessing the acidic
proton at the benzylic position of the indene moiety. In order
to demonstrate the vital role of the benzyl group in catalyst 2h,
we synthesized catalyst 2i deriving from alanine. Unlike cata-
lyst 2h, catalyst 2i gave moderate regioselectivity of the product
due to its negligible π–π stacking interaction between the
methyl group and substrate 4′d and relatively high accessibility
from base 7′ compared with catalyst 2h. For the aforemen-
tioned reasons, product 4′d is therefore regioselectively liber-
ated via hydrolysis of the iminium ion without experiencing
significant cycloolefin isomerisation using catalyst 2h
(Scheme 3b).
General procedures for the synthesis of 1H-indene-2-
carbaldehydes (4a–4h and 4′d–4′h, procedure B)
To a stirred solution of o-formyl (or acetyl) trans-cinnam-
aldehydes (0.5 mmol) in 5 mL of THF, Hantzsch ester 3a (1.2
equiv., 0.6 mmol) in combination with either catalyst 2c or 2h
(20 mol%, 0.1 mmol) was added. The mixture was stirred at
Conclusions
We have demonstrated a highly regiospecific fashion for the room temperature for 1–20 h and monitored using thin layer
synthesis of 1H-indene-2-carbaldehyde derivatives through chromatography. The reaction mixture was quenched with
transition-metal-free, cascade reductive cyclisation reactions. water and extracted with diethyl ether. The combined organic
The salient points of this study are as follows: (i) the critical layers were dried over sodium sulphate, filtered, and concen-
cycloolefin isomerisation step was elucidated; and (ii) product trated in vacuo. The residue was purified by flash chromato-
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graphy on silica gel (diethyl ether/pentane) to afford the corres- 1.5 Hz), 131.79 (d, JC–F = 3.8 Hz), 130.44 (d, JC–F = 7.8 Hz),
ponding 1H-indene-2-carbaldehydes (4a–4j and 4′d–4′i). 121.41 (d, JC–F = 21.8 Hz), 120.28 (d, JC–F = 22.3 Hz) ppm;
2-Formyl trans-cinnamaldehyde (1a). The title compound 19F NMR (470 MHz, CDCl3): δ = −107.73 ppm; IR (neat) 1691,
was synthesized according to general procedure A. The physi- 1676, 1597, 1493, 1247, 1133, 982, 878, 819, 775, 713,
cal and spectral data were identical to those previously 678 cm−1; HRMS (ESI) m/z calcd for C10H7FO2Na [M + Na]+
reported for this compound.19,20 White solid; yield 66%; 201.0322, found 201.0323.
1H NMR δ = 10.23 (s, 1H), 9.80 (d, J = 7.8 Hz, 1H), 8.57 (d, J =
4-Chloro-2-formyl trans-cinnamaldehyde (1f). The title com-
16.0 Hz, 1H), 7.91–7.88 (m, 1H), 7.73–7.64 (m, 3H), 6.67 (dd, pound was synthesized according to general procedure A. The
J = 16.0 Hz, 7.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = physical and spectral data were identical to those previously
193.97, 192.95, 149.47, 135.45, 134.80, 134.09, 133.67, 132.37, reported for this compound.21 White solid; yield 30%; mp:
1
130.88, 128.12 ppm.
120–121 °C; H NMR (500 MHz, CDCl3): δ = 10.19 (s, 1H), 9.80
4,5-Dimethoxy-2-formyl trans-cinnamaldehyde (1b). The title (d, J = 7.7 Hz, 1H), 8.48 (d, J = 16.0 Hz, 1H), 7.87 (d, J = 2.1 Hz,
compound was synthesized according to general procedure 1H), 7.69–7.63 (m, 2H), 6.66 (dd, J = 16.0 Hz, 7.7 Hz, 1H) ppm;
A. The physical and spectral data were identical to those pre- 13C NMR (125 MHz, CDCl3): δ = 193.62, 191.32, 147.71, 137.29,
viously reported for this compound.21 White solid; yield 66%; 134.72, 134.13, 134.11, 133.85, 132.73, 129.54 ppm; IR (neat)
1
mp: 153–154 °C; H NMR (500 MHz, CDCl3): δ = 10.24 (s, 1H), 1679, 1482, 1209, 1189, 1133, 977, 906, 823, 732 cm−1
.
9.78 (d, J = 7.7 Hz, 1H), 8.51 (d, J = 15.8 Hz, 1H), 7.38 (s, 1H),
4-Nitro-2-formyl trans-cinnamaldehyde (1g). The title com-
7.15 (s, 1H), 6.66 (dd, J = 15.8 Hz, 7.7 Hz, 1H), 4.02 (s, 3H), pound was synthesized according to general procedure A with
4.01 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ = 193.72, a slight modification (see the ESI†). Pale yellow solid; yield
190.21, 153.53, 151.27, 147.97, 131.23, 130.23, 127.76, 114.02, 30%; mp: 125–127 °C; 1H NMR (500 MHz, CDCl3): δ = 10.30 (s,
109.36, 56.44, 56.41 ppm; IR (neat) 1689, 1584, 1506, 1136, 1H), 9.86 (d, J = 7.5 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.53 (s,
1097, 970, 873, 753 cm−1
.
1H), 8.51–8.48 (m, 2H), 7.89 (d, J = 8.5 Hz, 1H), 6.74 (dd, J =
4,5-Methylenedioxy-2-formyl trans-cinnamaldehyde (1c). 16.1 Hz, 7.5 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ =
The title compound was synthesized according to general pro- 192.97, 190.46, 148.98, 146.25, 141.32, 135.01, 134.36, 129.71,
1
cedure A. White solid; yield 47%; mp: 185–186.5 °C; H NMR 128.88, 128.31 ppm; IR (neat) 1687, 1524, 1349, 1209, 1116,
[500 MHz, (CD3)2SO]: δ = 10.29 (s, 1H), 9.73 (d, J = 7.7 Hz, 1H), 977, 833, 742, 650, 640 cm−1; HRMS (ESI) m/z calcd for
8.62 (d, J = 15.7 Hz, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 6.88 (dd, J = C10H7NO4Na [M + Na]+ 228.0267, found 228.0265.
15.6 Hz, 7.7 Hz, 1H), 6.24 (s, 2H), 3.34 (s, 6H) ppm; 13C NMR
5-Methyl-2-formyl trans-cinnamaldehyde (1h). The title com-
[125 MHz, (CD3)2SO]: δ = 194.69, 190.68, 152.32, 149.98, pound was synthesized according to general procedure A. The
147.96, 132.29, 130.97, 129.69, 109.31, 106.86, 103.00 ppm; IR physical and spectral data were identical to those previously
(neat) 1689, 1671, 1591, 1495, 1447, 1370, 1186, 1128, 1063, reported for this compound.21 White solid; yield 48%; mp:
1030, 985, 928, 889, 786, 657 cm−1; HRMS (ESI) m/z calcd for 61–63 °C; 1H NMR (500 MHz, CDCl3): δ = 10.16 (s, 1H), 9.79 (d,
C11H8O4Na [M + Na]+ 227.0315, found 227.0311.
J = 7.8 Hz, 1H), 8.58 (d, J = 15.8 Hz, 1H), 7.78 (d, J = 7.8 Hz,
5-Fluoro-2-formyl trans-cinnamaldehyde (1d). The title com- 1H), 7.51 (brs, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.66 (dd, J = 15.9
pound was synthesized according to general procedure Hz, 7.8 Hz, 1H), 2.49 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3):
1
A. White solid; yield 28%; mp: 94–94.5 °C; H NMR (500 MHz, δ = 194.05, 192.59, 149.77, 145.21, 135.42, 135.14, 132.15,
CDCl3): δ = 10.18 (s, 1H), 9.82 (d, J = 7.6 Hz, 1H), 8.55 (dd, J = 131.57, 131.50, 128.78, 21.90 ppm; IR (neat) 1689, 1597, 1199,
16.0 Hz, 0.8 Hz, 1H), 7.94 (dd, J = 8.5 Hz, 5.7 Hz, 1H), 7.39 (dd, 1128, 979, 827, 748 cm−1
.
J = 9.4 Hz, 2.4 Hz, 1H), 7.35–7.32 (m, 1H), 6.65 (dd, J = 16.0 Hz,
4-Methoxy-2-formyl trans-cinnamaldehyde (1i). The title
7.6 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ = 193.53, compound was synthesized according to general procedure
191.23, 165.67 (d, JC–F = 258.1 Hz), 147.74 (d, JC–F = 2.0 Hz), A. The physical and spectral data were identical to those pre-
138.62 (d, JC–F = 9.0 Hz), 137.46 (d, JC–F = 10.0 Hz), 133.18, viously reported for this compound.21 Yellow solid; yield 65%;
1
130.34 (d, JC–F = 2.9 Hz), 117.84 (d, JC–F = 22.1 Hz), 115.27 (d, mp: 116–119 °C; H NMR (500 MHz, CDCl3): δ = 10.23 (s, 1H),
JC–F = 23.2 Hz) ppm; 19F NMR (470 MHz, CDCl3): δ = 9.75 (d, J = 7.7 Hz, 1H), 8.49 (d, J = 15.9 Hz, 1H), 7.70 (d, J = 8.6
−102.08 ppm; IR (neat) 1687, 1602, 1574, 1490, 1256, 1225, Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.18 (dd, J = 8.6 Hz, 2.6 Hz,
1165, 1120, 977, 883, 821, 642 cm−1; HRMS (ESI) m/z calcd for 1H), 6.63 (dd, J = 15.9 Hz, 7.7 Hz, 1H), 3.94 (s, 3H) ppm;
C10H7FO2Na [M + Na]+ 201.0322, found 201.0327.
13C NMR (125 MHz, CDCl3): δ = 193.96, 192.20, 161.84, 148.54,
4-Fluoro-2-formyl trans-cinnamaldehyde (1e). The title com- 135.08, 130.64, 129.73, 127.85, 119.93, 118.53, 55.88 ppm; IR
pound was synthesized according to general procedure (neat) 1676, 1598, 1501, 1266, 1137, 1101, 1039, 982, 924, 826,
A. White solid; yield 51%; mp: 105.5–106 °C; 1H NMR 770 cm−1
.
(500 MHz, CDCl3): δ = 10.23 (s, 1H), 9.79 (d, J = 7.7 Hz, 1H),
2-Acetyl trans-cinnamaldehyde (1j). The title compound was
8.47 (d, J = 15.9 Hz, 1H), 7.75 (dd, J = 8.6 Hz, 5.1 Hz, 1H), 7.61 synthesized according to general procedure A with a slight
(dd, J = 8.3 Hz, 2.7 Hz, 1H), 7.40 (td, J = 8.2 Hz, 2.7 Hz, 1H), modification (see the ESI†). Yellow solid; yield 40%; mp:
1
6.65 (dd, J = 15.9 Hz, 7.7 Hz, 1H) ppm; 13C NMR (125 MHz, 48–49 °C; H NMR (500 MHz, CDCl3): δ = 9.74 (d, J = 7.8 Hz,
CDCl3): δ = 193.57, 190.99 (d, JC–F = 1.5 Hz), 163.95 (d, JC–F
254.8 Hz), 147.66, 135.48 (d, JC–F = 5.9 Hz), 132.39 (d, JC–F
=
=
1H), 8.14 (d, J = 15.9 Hz, 1H), 7.84 (dd, J = 7.7 Hz, 1.3 Hz, 1H),
7.68–7.61 (m, 1H), 7.58 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.53 (td, J =
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7.5 Hz, 1.4 Hz, 1H), 6.57 (dd, J = 15.9 Hz, 7.8 Hz, 1H), 2.66 (s, 1H NMR (500 MHz, CDCl3): δ = 9.99 (s, 1H), 7.68 (s, 1H), 7.48
3H) ppm; 13C NMR (125 MHz, CDCl3): δ = 200.83, 194.20, (dd, J = 8.2 Hz, 4.9 Hz, 1H), 7.29 (dd, J = 8.4 Hz, 2.2 Hz, 1H),
152.25, 137.61, 134.65, 132.49, 131.03, 130.38, 129.96, 128.63, 7.12–7.08 (m, 1H), 3.64 (s, 2H) ppm; 13C NMR (125 MHz,
29.18 ppm; IR (neat) 1683, 1621, 1596, 1565, 1479, 1358, 1257, CDCl3): δ = 188.21, 162.52 (d, JC–F = 244.2 Hz), 149.03, 146.66
1133, 1111, 971, 764 cm−1
C11H10O2Na [M + Na]+ 197.0573, found 197.0578.
;
HRMS (ESI) m/z calcd for (d, JC–F = 3.5 Hz), 143.95 (d, JC–F = 9.1 Hz), 140.50 (d, JC–F = 2.4
Hz), 125.95 (d, JC–F = 8.9 Hz), 116.08 (d, JC–F = 23.3 Hz), 110.95
1H-Indene-2-carbaldehyde (4a). The title compound was syn- (d, JC–F = 23.0 Hz), 35.17 ppm; 19F NMR (470 MHz, CDCl3): δ =
thesized according to general procedure B. Colorless oil; yield: −115.51 ppm; IR (neat) 2921, 2848, 2721, 1725, 1666, 1599,
88% (using catalyst 2h), 86% (using catalyst 2c); 1H NMR 1471, 1390, 1351, 1250, 1200, 1182, 942, 875, 812 cm−1; HRMS
(500 MHz, CDCl3): δ = 9.99 (s, 1H), 7.74 (s, 1H), 7.61 (dd, J = (EI-Magnetic Sector) m/z calcd for C10H7FO 162.0475, found
6.6 Hz, 1.1 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.42–7.36 (m, 2H), 162.0473.
3.67 (d, J = 1.2 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3): δ =
5-Chloro-1H-indene-2-carbaldehyde (4f). The title com-
188.44, 148.00, 147.20, 145.23, 142.38, 129.07, 127.32, 125.00, pound was synthesized according to general procedure
124.42, 35.66 ppm; IR (neat) 2922, 2854, 1724, 1666, 1558, B. White solid; yield: 80% (using catalyst 2h); mp: 92–96 °C;
1461, 1384, 1349, 1128, 1050, 969, 929, 866 cm−1; HRMS 1H NMR (500 MHz, CDCl3): δ = 9.99 (s, 1H), 7.67 (s, 1H), 7.59
(EI-Magnetic Sector) m/z calcd for C10H8O 144.0570, found (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.1 Hz,
144.0571.
1.9 Hz, 1H), 3.65 (d, J = 1.3 Hz, 2H) ppm; 13C NMR (125 MHz,
5,6-Dimethoxy-1H-indene-2-carbaldehyde (4b). The title CDCl3): δ = 188.24, 148.53, 146.34, 143.94, 143.21, 133.32,
compound was synthesized according to general procedure 128.94, 125.97, 124.28, 35.41 ppm; IR (neat) 2960, 1668, 1560,
B. Pale yellow solid; yield: 71% (using catalyst 2h), 65% (using 1353, 1253, 1140, 1060, 994, 915 cm−1; HRMS (EI-Magnetic
1
catalyst 2c); mp: 112–113.5 °C; H NMR (500 MHz, CDCl3): δ = Sector) m/z calcd for C10H7 ClO 178.0185, found 178.0185.
9.89 (s, 1H), 7.67 (s, 1H), 7.10 (d, J = 2.0 Hz, 2H), 3.96 (s, 3H),
6-Chloro-1H-indene-2-carbaldehyde (4′f). The title com-
3.94 (s, 3H), 3.62 (d, J = 1.4 Hz, 2H) ppm; 13C NMR (125 MHz, pound was synthesized along with an inseparable mixture of
CDCl3): δ = 187.47, 151.03, 149.13, 148.59, 146.09, 139.39, 4f and 4′f using catalyst 2c according to general procedure
134.97, 107.82, 106.58, 56.28, 56.27, 35.69 ppm; IR (neat) 2959, B. H and 13C NMR assignments of the title compound were
1
2930, 1658, 1549, 1490, 1351, 1315, 1209, 1190, 1131, 1101, carried out with a small amount of compound 4f after inten-
992, 882, 825 cm−1; HRMS (EI-Magnetic Sector) m/z calcd for sive chromatographic purification. 1H NMR (500 MHz, CDCl3):
C12H12O3 204.0781, found 204.0783.
δ = 9.98 (s, 1H), 7.69 (brs, 1H), 7.54 (brs, 1H), 7.53 (d, J =
5,6-Methylenedioxy-1H-indene-2-carbaldehyde (4c). The title 8.2 Hz, 1H), 7.36 (dd, J = 8.1 Hz, 1.9 Hz, 1H), 3.67 (s, 2H) ppm;
compound was synthesized according to general procedure 13C NMR (125 MHz, CDCl3): δ = 188.00, 147.24, 146.60, 146.52,
B. Pale yellow solid; yield: 68% (using catalyst 2h), 50% (using 140.74, 135.16, 127.71, 125.33, 125.04, 35.61 ppm; HRMS
1
catalyst 2c); mp: 130–135 °C; H NMR (500 MHz, CDCl3): δ = (EI-Magnetic Sector) m/z calcd for C10H7ClO 178.0185, found
9.86 (s, 1H), 7.63 (s, 1H), 7.03 (s, 1H), 7.01 (s, 1H), 6.03 (s, 2H), 178.0188.
3.59 (d, J = 1.3 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3): δ =
5-Nitro-1H-indene-2-carbaldehyde (4g) and 6-nitro-1H-
187.36, 149.64, 148.16, 147.73, 146.36, 141.04, 136.21, 105.89, indene-2-carbaldehyde (4′g). The title compounds were syn-
104.15, 101.76, 35.63 ppm; IR (neat) 2927, 2855, 1722, 1644, thesized along with an inseparable mixture of 4g and 4′g using
1554, 1478, 1355, 1288, 1167, 1114, 1037, 907, 883, 838 cm−1
HRMS (EI-Magnetic Sector) m/z calcd for C11H8O3 188.0468, yield 16%; H NMR (500 MHz, CDCl3): δ = 10.06 (d, J = 3.5 Hz,
found 188.0468. 1H), 8.46–8.41 (m, 1H), 8.30–8.28 (m, 1H), 7.78–7.69 (m, 2H),
;
catalyst 2h according to general procedure B. Yellow solid;
1
6-Fluoro-1H-indene-2-carbaldehyde (4d). The title com- 3.80 (d, J = 5.8 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3): δ =
pound was synthesized according to general procedure 187.98, 187.90, 151.29, 151.27, 149.40, 148.24, 148.15, 148.04,
B. White solid; yield: 85% (using catalyst 2h); mp: 91–92 °C; 145.59, 145.21, 144.71, 143.50, 125.54, 124.53, 123.86, 123.36,
1H NMR (500 MHz, CDCl3): δ = 9.95 (s, 1H), 7.69 (s, 1H), 7.56 120.29, 119.24, 36.39, 36.18 cm−1; IR (neat) 1667, 1564, 1517,
(dd, J = 8.4 Hz, 5.1 Hz, 1H), 7.25 (d, J = 1.1 Hz, 1H), 7.09 (td, J = 1386, 1337, 1138, 1067, 900, 827, 803, 739, 706, 672, 637 cm−1
9.0 Hz, 2.4 Hz, 1H), 3.67 (s, 2H) ppm; 13C NMR (125 MHz, HRMS (EI-Magnetic Sector) m/z calcd for C1oH7NO3 189.0426,
;
CDCl3): δ = 187.88, 163.81 (d, JC–F = 249.3 Hz), 147.66 (d, JC–F
=
found 189.0422.
9.3 Hz), 147.09 (d, JC–F = 4.0 Hz), 146.91, 138.47 (d, JC–F = 2.3
6-Methyl-1H-indene-2-carbaldehyde (4h). The title com-
Hz), 125.52 (d, JC–F = 9.3 Hz), 114.90 (d, JC–F = 23.5 Hz), 112.57 pound was synthesized according to general procedure
(d, JC–F = 23.5 Hz), 35.94 (d, JC–F = 2.6 Hz) ppm; 19F NMR B. Colorless oil; yield 86%; 1H NMR (500 MHz, CDCl3): δ = 9.95
(470 MHz, CDCl3): δ = −111.08 ppm; IR (neat) 2907, 2855, (s, 1H), 7.70 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.19
1728, 1680, 1611, 1562, 1472, 1392, 1348, 1252, 1195, 1137, (d, J = 7.8 Hz, 1H), 3.63 (s, 2H), 2.44 (s, 3H) ppm; 13C NMR
1119, 1093, 944, 877, 805 cm−1; HRMS (EI-Magnetic Sector) (125 MHz, CDCl3): δ = 188.33, 148.16, 146.43, 145.69, 139.85,
m/z calcd for C10H7FO 162.0475, found 162.0474.
139.61, 128.30, 125.75, 124.12, 35.40, 21.98 ppm; IR (neat)
5-Fluoro-1H-indene-2-carbaldehyde (4′d). The title com- 2922, 2854, 1662, 1608, 1556, 1389, 1345, 1126, 929, 855,
pound was synthesized according to general procedure 820 cm−1; HRMS (EI-Magnetic Sector) m/z calcd for C11H10O
B. White solid; yield: 79% (using catalyst 2h); mp: 82–84.5 °C; 158.0726, found 158.0725.
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5-Methoxy-1H-indene-2-carbaldehyde (4i). The title com-
pound was synthesized according to general procedure B. Pale
yellow solid; yield 80%; mp: 60–64 °C; 1H NMR (500 MHz,
CDCl3): δ = 9.97 (s, 1H), 7.68 (brs, 1H), 7.43 (d, J = 8.3 Hz, 1H),
7.12 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 3.85
(s, 3H), 3.60 (d, J = 1.6 Hz, 2H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 188.35, 159.37, 148.33, 147.92, 143.58, 137.47,
125.50, 115.99, 108.74, 55.68, 34.91 ppm; IR (neat) 2958, 2925,
M. V. Lakshmikantham, M. P. Cava, D. Lorcy and
J. R. Bethelot, J. Org. Chem., 2000, 65, 6739–6742;
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H. Yan, K.-i. Kanno, K. Nakajima and T. Takahashi, J. Org.
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1723, 1661, 1352, 1288, 1210, 1155, 1107, 1030, 883, 807 cm−1
;
HRMS (EI-Magnetic Sector) m/z calcd for C11H10O2 174.0675,
found 174.0675.
6-Methoxy-1H-indene-2-carbaldehyde (4′i). The title com-
pound was synthesized along with an inseparable mixture of
4i and 4′i using catalyst 2c according to general procedure
1
B. H and 13C NMR assignments of the title compound were
carried out with a small amount of compound 4i after inten-
sive chromatographic purification. 1H NMR (500 MHz, CDCl3):
δ = 9.90 (s, 1H), 7.69 (brs, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.10
(brs, 1H), 6.93 (dd, J = 8.4 Hz, 2.3 Hz, 1H), 3.87 (s, 3H), 3.65 (s,
2H) ppm; 13C NMR (125 MHz, CDCl3): δ = 187.90, 161.32,
148.32, 147.91, 145.40, 135.46, 125.34, 114.09, 110.35, 55.72,
35.76 ppm; HRMS (EI-Magnetic Sector) m/z calcd for C11H10O2
174.0675, found 174.0677.
3-Methyl-1H-indene-2-carbaldehyde (4j). The title compound
was synthesized according to general procedure B. The physi-
cal and spectral data were identical to those previously
reported for this compound.22 1H NMR (500 MHz, CDCl3): δ =
10.24 (s, 1H), 7.60–7.58 (m, 1H), 7.55–7.53 (m, 1H), 7.44–7.39
(m, 2H), 3.64 (d, J = 2.2 Hz, 2H), 2.57 (t, J = 2.3 Hz, 3H) ppm;
13C NMR (125 MHz, CDCl3): δ = 187.30, 156.06, 144.91, 144.52,
139.69, 129.27, 127.08, 124.76, 121.84, 35.91, 10.98 ppm.
8 Selected recent examples: (a) S. Yamazaki, Y. Yamamoto,
Y. Fukushima, M. Takebayashi, T. Ukai and Y. Mikata,
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3527–3529; (b) D. Zhang, E. K. Yum, Z. Liu and
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Acknowledgements
J. W. Y. thanks the NRF Nano Material Technology
Development Program (2012M3A7B4049652) for financial
support. C. E. S. acknowledges the support from the Ministry
of
Science,
ICT
and
Future
Planning
(NRF-2014R1A2A1A01005794). J. W. Y. and C. E. S. acknowl-
edge the support from the NRF Basic Research Laboratory
Program (2016R1A4A1011451).
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