Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of Chemoselectivity by Organophotocatalysis and Dual Organocatalysis

Article abstract of DOI:10.1021/acs.joc.8b01099

The catalytic and chemoselective oxidation of cinnamaldehyde derivatives having a C=C bond and formyl group was studied by using two organocatalysts. The visible-light-induced catalysis using rhodamine 6G as an organophotocatalyst promoted the methoxyhydr

Full text of DOI:10.1021/acs.joc.8b01099

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Article
Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of
Chemoselectivity by Organophotocatalysis and Dual Organocatalysis
Eito Yoshioka, Maika Inoue, Yuka Nagoshi, Ayumi Kobayashi, Rumiko
Mizobuchi, Akira Kawashima, Shigeru Kohtani, and Hideto Miyabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01099 • Publication Date (Web): 03 Jul 2018
Downloaded from http://pubs.acs.org on July 4, 2018
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Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of Chemoselectivity by
Organophotocatalysis and Dual Organocatalysis
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Eito Yoshioka, Maika Inoue, Yuka Nagoshi, Ayumi Kobayashi, Rumiko Mizobuchi, Akira Kawashima, Shigeru
Kohtani, and Hideto Miyabe*
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuoꢀku, Kobe, 650ꢀ8530, Japan.
Abstract: The catalytic and chemoselective oxidation of cinnamaldehyde derivatives having C=C bond and formyl
group was studied by using two organocatalysts. The visible lightꢀinduced catalysis using rhodamine 6G as an
organophotocatalyst promoted the methoxyhydroxylation of C=C bond in a chemoselective manner. In contrast, the
cooperation between rhodamine 6G and Nꢀheterocyclic carbene (NHC) allowed the oxidative esterification of formyl
group.
TOC
INTRODUCTION
Oxidation is one of the most important organic transformations. Increasingly, much effort has been devoted to
the evolution of catalytic processes in place of traditional methods using stoichiometric quantities of toxic heavy metal
oxidants.1 Particularly, exploring the mild organocatalytic methods is a major challenge in modern organic synthesis.2
In recent years, the visible lightꢀactivated ruthenium or iridium complexes have received much attention as
photocatalysts.3 Furthermore, the use of organic dyes overcomes the need for precious transition metals and enables the
environmentally friendly redox transformations.4ꢀ 10
Cinnamaldehyde derivatives are fragrance ingredients having antifungal properties as well as building
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blocks.11 Our laboratory is interested in developing the organocatalytic protocols for the oxidative functionalization of
C=C bond and formyl group of cinnamaldehydes in a chemoselective manner (Figure 1). The chemoselective oxidation
of C=C bond was achieved by the organophotocatalysis using rhodamine 6G in MeOH. As described below, the
oxidation of 1 led to the formation of acetal product 2 via methoxyhydroxylation intermediate A. In contrast, the
chemoselective oxidation of formyl group was accomplished by dual organocatalysis based on the cooperation between
Nꢀheterocyclic carbene (NHC) and photocatalyst.12 In the oxidative esterification of 1 leading to 3, the photocatalytic
double oxidation of nucleophilic Breslow intermediate B to electrophilic acylium ion equivalent is a key umpolung
process.
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Figure 1. Chemoselective oxidation of cinnamaldehydes.
RESULTS AND DISCUSSION
To study the viability of organic dyes for oxidation processes, our experiments began with the investigation of
methoxyhydroxylation of C=C bond (Table 1). The similar functionalization of C=C bond has been studied by using
iodobenzene diacetate under base conditions.13 We found that the oxidative functionalization of 1a leading to 2a was
promoted by a base such as K2CO3. After a 50 mL roundꢀbottom flask was equipped with 1a (1.0 mmol), BrCCl3 and
rhodamine 6G, K2CO3 and MeOH (10 mL), the flask was capped with argonꢀballoon. Therefore, air (ca 50 mL, ca. 0.45
equivalents of O2) exists in a reaction vessel. In our study, BrCCl3 was used as a quencher toward the photoꢀactivated
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dye species having reductant property. The reduction potential of BrCCl3 (+0.21 V vs. SCE)14 is more positive than that
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of O2 (−0.42 V vs. SCE at pH 7 in H2O),15 indicating that electron accepting ability of BrCCl3 is much better than that
of O2.
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Table 1. Oxidation of carbonꢀcarbon double bond in 1a.a
Entry
1
Organic dye
quencher
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
none
Base
Yield (%)b
NR
27
none
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K2HPO4
Et3N
2
Eosin Y (5 mol%)
3
Fluorescein (5 mol%)
Methylene blue (5 mol%)
9ꢀMesꢀ10ꢀMeꢀacrydinium (5 mol%)
Rhodamine B (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (3 mol%)
Rhodamine 6G (1 mol%)
Eosin Y (5 mol%)
30
4
65
5
69
6
71
7
76
8
67
9
60
10 c
11 c
12 d
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14
15
16
17e
18 f
NR
NR
54
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
none
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
8
61
trace
NR
89
KOH
KOH
29 f
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a In the presence of dye, the reactions of 1a were carried out with BrCCl3 (3 equiv.) and base (2.5 equiv.) in MeOH with
b
white LED light irradiation under argon atmosphere containing air (ca. 50 mL) at rt. Based on isolated yields. 2a was
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obtained as ca. 5:5ꢀ6:4 mixture of syn/antiꢀisomers. c Reactions were carried out in the absence of BrCCl3. d Reaction was
carried in an openꢀvessel under air. e The synꢀ and antiꢀisomers were formed in ratio of 59:41. f Reaction was carried out
after degasification to remove O2.
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No reaction occurred in the absence of organic dye as a photocatalyst even employing BrCCl3 under white
LED light irradiation (entry 1). The oxidizing ability of dyes affected the chemical efficiencies (entries 2−7). In general,
the visible lightꢀactivated dyes in a lowest excited singlet state (S1) are rapidly converted into a lowest excited triplet
state (T1) via a spinꢀforbidden singletꢀtriplet intersystem crossing (ISC); thus, the photochemical process occurs from T1.
*
*
Eosin Y5 (Ered in T1 [EY–•/EY*]: +0.83 V vs. SCE in CH3CN16) and fluorescein6 (Ered in T1: +0.77 V vs. SCE in
CH3CN16) possessing less positive reduction potentials have shown the low catalytic activities to give the
methoxyhydroxylated acetal 2a in 27% and 30% yields, respectively (entries 2 and 3). In contrast, the use of methylene
*
*
blue7 (Ered in T1: +1.60 V vs. SCE in CH3CN16) or 9ꢀMesꢀ10ꢀMeꢀacrydinium8 (Ered in T1: +1.45 V vs. SCE in
CH3CN17) having more positive potentials led to an enhancement in chemical yields (entries 4 and 5). We recently
reported the utility of rhodamine B in the cascade radical reactions.18 In our study on rhodamine B, we proposed that
the electronꢀtransfer occurs not from T1 but from S1, because value of quantum yield of ISC is very low (ΦISC
=
*
0.002419) and ISC is slow. As expected from the sufficient positive potential of Ered in S1 (+1.26 V vs. SCE in
CH3CN16), rhodamine B promoted this transformation to give 2a in 71% yield (entry 6). The higher yield of 2a was
*
obtained by rhodamine 6G9 (ΦISC = 0.00220 and Ered in S1: +1.18 V vs. SCE in CH3CN21) (entry 7). Its catalytic
efficiency was confirmed by decreasing the amount of rhodamine 6G (entries 8 and 9). Additionally, this oxidation did
not take place in the absence of BrCCl3 (entries 10 and 11). Next, the reaction was carried in an openꢀvessel under air
(entry 12). However, the chemical yield slightly decreased to 54%. Subsequently, the influence of base was examined
(entries 13−17). The chemical yield increased to 89% by changing a base from K2CO3 to KOH (entry 17). This reaction
proceeded even in the absence of O2, although the chemical yield decreased to 29% yield by degasification to remove
O2 (entry 18).
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Next, the reaction of cinnamaldehyde derivatives 1b−1e was examined (Table 2). Good yields were obtained
in the oxidation of 1b or 1c carrying an electronꢀwithdrawing group on aromatic ring (entries 1−3). We again observed
the positive effect of KOH as a base (entries 1 and 2). The substrates 1d and 1e were also converted into 2d and 2e in
good yields (entries 4 and 5).
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Table 2. Oxidative functionalization of cinnamaldehyde derivatives 1b-e.a
Entry
Substrate
Base
Yield (%)b
1
2
3
4
5
1b (Ar=4ꢀClꢀC6H4)
1b (Ar=4ꢀClꢀC6H4)
1c (Ar=4ꢀFꢀC6H4)
1d (Ar=C6H5)
K2CO3
KOH
KOH
KOH
KOH
67
90
72
89
73
1e (Ar=4ꢀMeꢀC6H4)
a In the presence of rhodamine 6G (5 mol%), the reactions of 1b-e were carried out with
BrCCl3 (3 equiv.) and base (2.5 equiv.) in MeOH with white LED light irradiation under
b
argon atmosphere containing air (ca. 50 mL) at rt. Based on isolated yields (syn:anti =
ca. 6:4; See: SI).
Scheme 1. Reactivity of several substrates and further oxidation of 2a.
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To gain further insight, we next explored the reaction of several substrates (Scheme 1). Introducing methyl
group at αꢀposition did not affected the reactivity. The desired product 5 was obtained in 99% yield from the sterically
hindered substrate 4. Interestingly, the methoxyhydroxylation of polyconjugated substrate 6 proceeded regioselectively
to give the δꢀmethoxyated product 7. Moreover, it is important to note that hydroxylation occurred at αꢀposition. The
activation of C=C bond by formyl group was essential to achieve this methoxyhydroxylation. The simple olefin 8 and
the acetal 9 of 1a did not work well. These results suggest that acetal formation is the final step and the oxidative
process is initiated by Michael addition of MeOH leading to adduct C (Figure 2). Subsequently, the photocatalytic
oxidation of anion D, which is momentarily generated in association with KOH, takes place to give the
resonanceꢀstabilized radical E. Since the photoꢀexcited rhodamine 6G (Rh6G*) has enough positive reduction potential
in S1 (Ered*: +1.18 V21), anion D is easily oxidized to radical E as depicted in photoꢀredox cycle 1. The reduced Rh6G
•
(Rh6G－ ) subsequently reduces BrCCl3 to generate CCl3 radical and Br－, because the reduction potential of rhodamine
6G in the ground state (Ered: −1.14 V vs. SCE in aqueous CH3CN21) is sufficiently negative. In cycle 2, Rh6G* reduces
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BrCCl3 owing to the sufficient oxidation potential of Rh6G* in S1 (Eox*: −1.09 V vs. SCE in CH3CN22). The oxidized
Rh6G (Rh6G+•) possessing enough positive potential in the ground state (Eox: +1.23 V vs. SCE in CH3CN22) oxidizes
the anion D. Consequently, radical E can be generated by both cycles 1 and 2.
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Figure 2. Possible reaction pathway.
Based on the results described in Table 1, we propose two pathways leading to the acetal product 2 from
radical E. The oxygenꢀfree pathway is started by the bromine atomꢀtransfer to radical E from BrCCl3 to give the adduct
F.23 The final product 2 would be formed via the substitution reaction of acetal G with HO－ or H2O in a reaction
vessel and/or by workꢀup step, etc. Because this transformation was promoted by air; thus, the oxygenꢀmediated
pathway is also important. The methoxyhydroxylation intermediate I is formed through trapping of E with molecular
oxygen O2 followed by the reduction of radical H. Finally, the acetal product 2 is obtained from intermediate I. No
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reaction of acetal 9 occurred under the standard reaction conditions (Scheme 1); thus, the transformation of aldehyde
into acetal occurred after the formation of adduct F or intermediate I. Additionally, both synꢀ2a and antiꢀ2a were
converted to the same ketone 10 (Scheme 1).
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The inimitable reactivity of NHC has led to the discovery of new organocatalysis.24 In general, the
NHCꢀcatalyzed oxidative esterification of cinnamaldehyde can be performed in combination with a stoichiometric
amount of external oxidant.25 In the absence of oxidant, the esterification of cinnamaldehyde accompanies the
reduction of C=C bond.26 Next, we felt attracted to the cooperative catalysis as a challenging task providing the new
oxidative esterification method.27
In the presence of rhodamine 6G (5 mol%) and BrCCl3 (3 equiv.), the oxidative esterification of 1a was
examined by using several NHCꢀprecatalysts 11Aꢀ11F (entries 1ꢀ7 in Table 3). In the absence of NHCꢀprecatalyst, the
formation of methyl ester 3a was not detected (entry 1). We found that the use of nucleophilic NHC catalyst,26a,28
generated from NꢀMes triazolium 11A and K2CO3, leads to an effective esterification of 1a (entry 2). Next, the effect of
oxidant was examined by replacing BrCCl3 to milder oxidants (entries 8 and 9). However, the use of CCl4 or HCCl3 led
to lower chemical yields. Among them, BrCCl3 is the best oxidant as a quencher toward the photoꢀactivated dye
species.
Table 3. Effects of NHCꢀcatalyst and oxidant on oxidative esterification of 1a.a
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Entry
NHCꢀprecatalyst
none
Oxidant
Solvent
Yield (%)b
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1
2
3
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8
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
BrCCl3
CCl4
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀTHF (1:1)
MeOHꢀHCCl3 (1:1)
ND
99
Triazolium 11A
Triazolium 11B
Triazolium 11C
Thiazolium 11D
Thiazolium 11E
Thiazolium 11F
Triazolium 11A
Triazolium 11A
47
51
ND
9
14
trace
11
9
HCCl3
a
In the presence of NHCꢀprecatalyst (10 mol%) and rhodamine 6G (5 mol%), the reactions of 1a were
carried out with oxidant (3 equiv.) and K2CO3 (2.5 equiv.) with white LED light irradiation under argon
atmosphere at rt. b Based on isolated yields.
In the presence of BrCCl3, the best combination of dye with triazolium 11A was next examined (Table 4). At
first, the reaction was carried out employing BrCCl3 under LED light irradiation in the absence of dye as a
photocatalyst (entry 1). In the absence of photocatalyst, the oxidative esterification of 1a did not occur effectively.
Although it is reported that polyhalides such as C2Cl6 and BrCCl3 are capable to induce the single electronꢀtransfer
(SET) processes of Breslow intermediates under NHCꢀcatalysis without the need of photocatalytic conditions,29 the use
of photocatalyst clearly promoted the present reaction. The combination of 11A and fluorescein led to the formation of
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3a in 68% yield (entry 1). Alizarin red S and rhodamine B worked well (entries 3 and 4). When rhodamine base was
used, the ester 3a was obtained in 52% yield (entry 5). Eosin Y promoted the reaction to give 3a in good yields (entries
6 and 7), although chemical yields decreased at 3 mol% or 1 mol% catalyst loading of 11A (entries 8 and 9). The best
result was obtained by rhodamine 6G (entries 10−14). The competitive oxidation of C=C bond was not observed under
the optimized conditions (entry 11). Even in the presence of lower catalytic amounts of 11A (3 mol%) and rhodamine
6G (1.5 mol%), 3a was obtained in 48% yield (entry 13). The reactivity of product 3a toward methoxyhydroxylation
was also examined. In marked contrast to aldehyde 1a (enrty 18 in Table 1), the methoxyhydroxylation of ester 3a did
not proceed under the methoxyhydroxylation conditions described in Table 1. The ester 3a was recovered in 60% yield,
accompanied with 32% of 4ꢀmethoxycinnamic acid due to hydrolysis by coexisting water. Additionally, the use of
EtOHꢀTHF as solvent led to lower chemical efficiency. The corresponding ethyl ester was obtained in 65% yield when
the reaction carried out at 60 °C.
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Table 4. Selective oxidation of formyl group in 1a.a
Entry
1
Triazolium 11A
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
Dye
Yield (%)b
none
trace
68
83
99
52
99
96
33
13
99
99
92
2
Fluorescein (5 mol%)
Alizarin red S (5 mol%)
Rhodamine B (5 mol%)
Rhodamine base (5 mol%)
Eosin Y (5 mol%)
Eosin Y (5 mol%)
Eosin Y (5 mol%)
Eosin Y (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
Rhodamine 6G (5 mol%)
3
4
5
6
7
8
3 mol%
9
1 mol%
10
11
12
10 mol%
5 mol%
3 mol%
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3 mol%
1 mol%
Rhodamine 6G (1.5 mol%)
Rhodamine 6G (5 mol%)
48
30
14
6
7
8
9
a
In the presence of triazolium 11A and dye, the reactions of 1a were carried out with
BrCCl3 (3 equiv.) and K2CO3 (2.5 equiv.) in MeOHꢀTHF (1:1, v/v) with white LED
light irradiation under argon atmosphere at rt. b Based on isolated yields.
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Further investigations were performed (Table 5). The esters 3c-3e were obtained without any problems. The
substrate 1f having a methoxy group at oꢀposition of aromatic ring worked well. The substrate 1g bearing furan and
2ꢀnaphthaldehyde 12 produced the corresponding esters 3g and 13, allowing facile incorporation of structural variety.
Table 5. Reaction of cinnamaldehydes 1c-g and 2ꢀnaphthaldehyde 12.a
a
In the presence of 11A (5 mol%) and rhodamine 6G (5 mol%), the reactions were
carried out with BrCCl3 (3 equiv.) and K2CO3 (2.5 equiv.) in MeOHꢀTHF (1:1, v/v)
with white LED light irradiation under argon atmosphere at rt.
The cooperative organocatalysis is initiated by the formation of Breslow intermediate B, which is
photocatalytically oxidized to afford the radical J via deprotonation (Figure 3). Particularly, electronꢀrich Breslow
*
intermediate B is easily oxidized, which is supported by sufficient positive potential of Ered in S1 of rhodamine 6G
(+1.18 V21). The oxidation potential of the Breslow intermediate was reported (Eox: around −0.49 V vs. SCE).30 The
oxidation potential of the azaꢀBreslow intermediate (Eox: +0.49 V vs. SCE in CH2Cl2) was also shown by T. Rovis.31
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The second photocatalytic oxidation of J leads to acylium ion equivalent K. Finally, cation K reacts with MeOH to
give the ester 3 and NHC catalyst.
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Figure 3. Cooperative organocatalysis.
CONCLUSION
We have developed new organocatalysis for the chemoselective methoxyhydroxylation and oxidative
esterification of cinnamaldehydes. The organophotocatalysis using rhodamine 6G promoted the methoxyhydroxylation
of C=C bond of cinnamaldehydes under visible light irradiation. In contrast, the oxidative esterification of formyl group
was achieved by the dual organocatalysis based on the cooperation between rhodamine 6G and Nꢀheterocyclic carbene
(NHC).
EXPERIMENTAL SECTION
General. Melting points were taken on a Yanaco MPꢀJ3 and are uncorrected. Infrared spectra were measured on a
JASCO FT/IRꢀ4100. 1HꢀNMR spectra were measured on a JEOL ECXꢀ400 PSK (400 MHz) or Varian NMRS 600 (600
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MHz) with CDCl3 as an internal standard (7.26 ppm). 13CꢀNMR spectra were measured on a JEOL ECXꢀ400 PSK (101
MHz) or Varian NMRS 600 (162 MHz) with CDCl3 as an internal standard (77.0 ppm). 19FꢀNMR spectra were
measured on a JEOL ECXꢀ400 PSK (376 MHz) with C6F6 as an internal standard (–162.2 ppm). Highꢀresolution mass
spectra were recorded on a timeꢀofꢀflight (TOF) mass spectrometer by use of Thermo Fisher Scientific Exactive
LC/MS spectrometer. For silica gel column chromatography, SiliCycle Inc. SiliaFlash F60 was used. Preparative TLC
separations were carried out on precoated silica gel plates (E. Merck 60F254). Products 2d,13a 3a,32 3c,33 3d,34 3e,33,35
3f,33 3g36 and 1337 are known compounds.
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General procedure for methoxyhydroxylation: A 50 mL roundꢀbottom flask was equipped with crashed KOH (140
mg, 2.5 mmol), undegassing MeOH (10 mL), 1a-e, 4 or 6 (1.0 mmol), bromotrichloromethane (296 ꢀL, 3.0 mmol) and
rhodamine 6G (24 mg, 0.050 mmol) at room temperature. After the flask was capped with argonꢀballoon, the stirring
reaction mixture was irradiated with white LED lamp (1000 lm) at room temperature. After being stirred for 5 hours,
the reaction mixture was filtrated with folded filter paper which was then wasched with MeOH several times. The
filtrate was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography
(AcOEt:hexanes = 1:4–1:0) afforded the products 1a-e, 5 or 7 as a mixture of syn/antiꢀ isomers. The ratio of products
was determined by 1H NMR analysis of the mixture. In the case of 1a-e and 5, second purification of the mixture by
preparative TLC afforded the isolated isomers.
2-Hydroxy-3-methoxy-3-(4-methoxyphenyl)propanal dimethylacetal (2a) Following general procedure, the reaction
of 1a was carried out. First purification by flash silica gel column chromatography afforded the product 2a (227 mg,
89%) as a mixture of 59:41 syn/antiꢀisomers. The syn/antiꢀisomers was separated by second purification by preparative
TLC (AcOEt:hexanes = 1:2, 2ꢀfold development). Syn-isomer: Colorless oil. IR (KBr) 3489 (br), 2935, 1611, 1512,
1247 cmꢀ1. 1H NMR (CDCl3) δ 7.27 (2H, d, J = 8.7 Hz), 6.91 (2H, d, J = 8.7 Hz), 4.27 (1H, d, J = 4.6 Hz), 4.21 (1H, d,
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J = 5.5 Hz), 3.81 (3H, s), 3.68 (1H, m), 3.40 (6H, s), 3.25 (3H, s), 2.52 (1H, br s). C NMR (CDCl3) δ 159.4, 130.3,
128.6, 113.8, 103.8, 82.3, 75.1, 56.8, 55.5, 55.2, 54.7. HRMS (ESI+) calcd for C13H20O5Na (M+Na+): 279.1203, Found:
279.1232. Anti-isomer: Colorless oil. IR (KBr) 3476 (br), 2935, 1611, 1512, 1249 cmꢀ1. 1H NMR (CDCl3) δ 7.29 (2H,
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d, J = 8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 4.22 (1H, d, J = 5.5 Hz), 4.12 (1H, d, J = 5.5 Hz), 3.94 (1H, m), 3.81 (3H, s),
3.45 (3H, s), 3.38 (3H, s), 3.23 (3H, s), 2.20 (1H, br s). 13C NMR (CDCl3) δ 159.4, 129.5, 129.4, 113.6, 103.7, 82.5,
73.4, 56.5, 55.2, 55.0, 54.7. HRMS (ESI+) calcd for C13H20O5Na (M+Na+): 279.1203, Found: 279.1225.
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3-(4-Chlorophenyl)-2-hydroxy-3-methoxypropanal dimethylacetal (2b) Following general procedure, the reaction
of 1b was carried out. First purification by flash silica gel column chromatography afforded the product 2b (234 mg,
90%) as a mixture of 61:39 syn/antiꢀisomers. The syn/antiꢀisomers was separated by second purification by preparative
TLC (AcOEt:hexanes = 1:2, 2ꢀfold development). Syn-isomer: Colorless oil. IR (KBr) 3463 (br), 2935, 1491 cmꢀ1. 1H
NMR (CDCl3) δ 7.35 (2H, d, J = 8.7 Hz), 7.30 (2H, d, J = 8.7 Hz), 4.32 (1H, d, J = 4.1 Hz), 4.28 (1H, d, J = 5.5 Hz),
3.64 (1H, m), 3.43 (3H, s), 3.41 (3H, s), 3.27 (3H, s) , 2.45 (1H, br s). 13C NMR (CDCl3) δ 137.1, 133.7, 128.8, 128.6,
103.8, 81.9, 74.9, 57.1, 55.6, 54.6. HRMS (ESI+) calcd for C12H1735ClO4Na (M+Na+): 283.0708, Found: 283.0706.
HRMS (ESI+) calcd for C12H1737ClO4Na (M+Na+): 285.0682, Found: 285.0675. Anti-isomer: Colorless oil. IR (KBr)
3465 (br), 2935, 1490 cmꢀ1. 1H NMR (CDCl3) δ 7.36ꢀ7.29 (4H, m), 4.24 (1H, d, J = 5.5 Hz), 4.11 (1H, d, J = 5.5 Hz),
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3.92 (1H, m), 3.45 (3H, s), 3.37 (3H, s), 3.24 (3H, s), 2.27 (1H, br s). C NMR (CDCl3) δ 136.3, 133.8, 129.6, 128.4,
103.5, 82.4, 73.3, 56.8, 55.1, 54.6. HRMS (ESI+) calcd for C12H1735ClO4Na (M+Na+): 283.0708, Found: 283.0705.
HRMS (ESI+) calcd for C12H1737ClO4Na (M+Na+): 285.0682, Found: 285.0676.
3-(4-Fluorophenyl)-2-hydroxy-3-methoxypropanal dimethylacetal (2c) Following general procedure, the reaction of
1c was carried out. First purification by flash silica gel column chromatography afforded the product 2c (177 mg, 72%)
as a mixture of 61:39 syn/antiꢀisomers. The syn/antiꢀisomers was separated by second purification by preparative TLC
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(AcOEt:hexanes = 1:1). Syn-isomer: Colorless oil. IR (KBr) 3463 (br), 2935, 1604, 1509 cmꢀ1. H NMR (CDCl3) δ
7.33 (2H, m), 7.06 (2H, m), 4.32 (1H, d, J = 4.1 Hz), 4.26 (1H, d, J = 5.5 Hz), 3.64 (1H, m), 3.42 (3H, s), 3.41 (3H, s),
3.26 (3H, s), 2.49 (1H, br d, J = 3.7 Hz). 13C NMR (CDCl3) δ 162.5 (d, J = 247 Hz), 134.2 (d, J = 4 Hz), 129.0 (d, J = 8
Hz), 115.3 (d, J = 21 Hz), 103.7, 81.9, 74.9, 57.0, 55.6, 54.6. 19F NMR (CDCl3) δ −115.0 (1F, s). HRMS (ESI+) calcd
for C12H17FO4Na (M+Na+): 267.1003, Found: 267.1011. Anti-isomer: Colorless oil. IR (KBr) 3465 (br), 2935, 1604,
1509 cmꢀ1. 1H NMR (CDCl3) δ 7.34 (2H, m), 7.05 (2H, m), 4.25 (1H, d, J = 5.5 Hz), 4.10 (1H, d, J = 5.0 Hz), 3.94 (1H,
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m), 3.45 (3H, s), 3.37 (3H, s), 3.23 (3H, s), 2.27 (1H, br d, J = 3.6 Hz). 13C NMR (CDCl3) δ 162.2 (d, J = 247 Hz),
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133.3 (d, J = 4 Hz), 129.8 (d, J = 8 Hz), 115.1 (d, J = 22 Hz), 103.5, 82.3, 73.2, 56.7, 55.0, 54.6. F NMR (CDCl3) δ
−115.0 (1F, s). HRMS (ESI+) calcd for C12H17FO4Na (M+Na+): 267.1003, Found: 267.0998.
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2-Hydroxy-3-methoxy-3-phenylpropanal dimethylacetal (2d)13a Following general procedure, the reaction of 1d
was carried out. First purification by flash silica gel column chromatography afforded the product 2d (201 mg, 89%) as
a mixture of 63:37 syn/antiꢀisomers. The syn/antiꢀisomers was separated by second purification by preparative TLC
(AcOEt:hexanes = 1:2, 2ꢀfold development). Syn-isomer: Colorless oil. IR (KBr) 3465 (br), 2933, 1452, 1197 cmꢀ1. 1H
NMR (CDCl3) δ 7.40ꢀ7.30 (5H, m), 4.33 (1H, d, J = 4.6 Hz), 4.25 (1H, d, J = 5.5 Hz), 3.70 (1H, m), 3.42 (3H, s), 3.41
(3H, s), 3.28 (3H, s), 2.50 (1H, br d, J = 4.1 Hz). 13C NMR (CDCl3) δ 138.4, 128.4, 128.0, 127.3, 103.7, 82.6, 75.0,
57.1, 55.5, 54.6. HRMS (ESI+) calcd for C12H18O4Na (M+Na+): 249.1097, Found: 249.1094. Anti-isomer: Colorless oil.
IR (KBr) 3466 (br), 2932, 1453, 1192 cmꢀ1. 1H NMR (CDCl3) δ 7.37ꢀ7.30 (5H, m), 4.28 (1H, d, J = 5.5 Hz), 4.14 (1H,
d, J = 5.5 Hz), 3.97 (1H, m), 3.45 (3H, s), 3.38 (3H, s), 3.25 (3H, s), 2.24 (1H, br d, J = 3.7 Hz). 13C NMR (CDCl3) δ
137.5, 128.2 (2C), 128.1, 103.5, 83.0, 73.4, 56.7, 55.0, 54.6. HRMS (ESI+) calcd for C12H18O4Na (M+Na+): 249.1097,
Found: 249.1094.
2-Hydroxy-3-methoxy--3-(4-methylphenyl)propanal dimethylacetal (2e) Following general procedure, the reaction
of 1e was carried out. First purification by flash silica gel column chromatography afforded the product 2e (176 mg,
73%) as a mixture of 60:40 syn/antiꢀisomers. The syn/antiꢀisomers was separated by second purification by preparative
TLC (AcOEt:hexanes = 1:2, 2ꢀfold development). Syn-isomer: Colorless oil. IR (KBr) 3459 (br), 2930, 1513, 1449,
1196 cmꢀ1. 1H NMR (CDCl3) δ 7.24 (2H, br d, J = 8.2 Hz), 7.18 (2H, br d, J = 8.2 Hz), 4.30 (1H, d, J = 4.6 Hz), 4.23
(1H, d, J = 5.5 Hz), 3.68 (1H, m), 3.42 (3H, s), 3.41 (3H, s), 3.27 (3H, s), 2.49 (1H, br d, J = 3.7 Hz), 2.36 (3H, s). 13C
NMR (CDCl3) δ 137.7, 135.2, 129.1, 127.3, 103.7, 82.5, 75.1, 56.9, 55.5, 54.7, 21.2. HRMS (ESI+) calcd for
C13H20O4Na (M+Na+): 263.1254, Found: 263.1255. Anti-isomer: Colorless oil. IR (KBr) 3474 (br), 2929, 1513, 1449,
1191 cmꢀ1. 1H NMR (CDCl3) δ 7.25 (2H, br d, J = 8.2 Hz), 7.18 (2H, br d, J = 8.2 Hz), 4.24 (1H, d, J = 5.5 Hz), 4.14
(1H, d, J = 5.0 Hz), 3.95 (1H, m), 3.45 (3H, s), 3.38 (3H, s), 3.24 (3H, s), 2.35 (3H, s), 2.21 (1H, br d, J = 3.7 Hz). 13C
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NMR (CDCl3) δ 137.8, 134.4, 128.9, 128.1, 103.6, 82.8, 73.4, 56.6, 55.0, 54.6, 21.2. HRMS (ESI+) calcd for
C13H20O4Na (M+Na+): 263.1254, Found: 263.1250.
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2-Hydroxy-3-methoxy-2-methyl-3-phenylpropanal dimethylacetal (5) Following general procedure, the reaction of
4 was carried out. First purification by flash silica gel column chromatography afforded the product 5 (237 mg, 99%) as
a mixture of 75:25 two isomers. The syn/antiꢀisomers was separated by second purification by preparative TLC
(AcOEt:hexanes = 1:2, 2ꢀfold development), although the stereostructure of each isomers has not been determined.
Major isomer: Colorless oil. IR (KBr) 3501 (br), 2937, 1452 cmꢀ1. 1H NMR (CDCl3) δ 7.38ꢀ7.30 (5H, m), 4.41 (1H, s),
4.24 (1H, s), 3.60 (3H, s), 3.58 (3H, s), 3.23 (3H, s), 2.28 (1H, s), 0.91 (3H, s). 13C NMR (CDCl3) δ 137.4, 128.8, 127.9
(2C), 108.1, 85.5, 58.2, 58.1, 56.9, 17.6. One carbon peak is missing due to overlapping peak of CDCl3. HRMS (ESI+)
calcd for C13H20O4Na (M+Na+): 263.1254, Found: 263.1277. Minor isomer: Colorless oil. IR (KBr) 3500 (br), 2937,
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1452 cmꢀ1. H NMR (CDCl3) δ 7.38ꢀ7.28 (5H, m), 4.21 (1H, s), 3.96 (1H, s), 3.54 (3H, s), 3.42 (3H, s), 3.24 (3H, s),
2.22 (1H, br s), 1.17 (3H, s). 13C NMR (CDCl3) δ 137.4, 128.7, 127.8, 127.7, 107.5, 85.6, 76.7, 58.6, 57.1, 56.8, 18.2.
HRMS (ESI+) calcd for C13H20O4Na (M+Na+): 263.1254, Found: 263.1253.
(E)-2-Hydroxy-5-methoxyhex-3-enal dimethylacetal (7) Following general procedure, the reaction of 6 was carried
out. First purification by flash silica gel column chromatography afforded the product 7 (118 mg, 62%) as a mixture of
about 1:1 syn/antiꢀisomers. The syn/antiꢀisomers cannot be separated by second purification by preparative TLC
(AcOEt:hexanes = 1:2, 2ꢀfold development). Colorless oil. IR (KBr) 3441 (br), 2930, 1450 cmꢀ1. The presence of
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diastereomers precluded a comprehensive assignment of all proton and carbon resonances. H NMR (CDCl3) δ
5.76ꢀ5.66 (2H, m), 4.18ꢀ4.14 (2H, m), 3.80ꢀ3.73 (1H, m), 3.46 (3H, s), 3.433 (3/2H, s), 3.431 (3/2H, s), 3.27 (3H, s),
2.28 (1H, br s), 1.25 (3H, dd, J = 6.4, 1.8 Hz). 13C NMR (CDCl3) δ 134.6, 134.4, 129.1 (2C), 106.5, 106.4, 77.4 (2C),
71.4 (2C), 56.0, 55.9, 55.4 (2C), 55.2, 55.1, 21.2 (2C). HRMS (ESI+) calcd for C9H18O4Na (M+Na+): 213.1097, Found:
213.1103.
Procedure for oxidation of anti-2a and syn-2a: To a solution of antiꢀ2a (100 mg, 0.39 mmol) in CH2Cl2 (1.0 mL)
were added saturated NaHCO3 solution (1.0 mL), 2ꢀhydroxyꢀ2ꢀazaadamantane (3.0 mg, 0.020 mmol), KBr (4.6 mg,
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0.039 mmol), tetraꢀnꢀbutylammonium bromide (6.3 mg, 0.020 mmol) and NaClO.5H2O (96 mg, 0.59 mmol) at room
temperature. After being stirred for 4 hours, the reaction mixture was diluted with water and extracted with AcOEt. The
organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue by
preparative TLC (AcOEt:hexanes = 1:2) afforded the product 10 (49 mg, 49%) as colorless oil. The product 10 was
obtained in 44% yield (67 mg) as colorless oil from synꢀ2a (155 mg, 0.60 mmol) by the same procedure.
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1,1,3-Trimethoxy-3-(4-methoxyphenyl)propan-2-one (10) IR (KBr) 2939, 1743, 1609, 1512, 1253 cmꢀ1. H NMR
(CDCl3) δ 7.30 (2H, br d, J = 8.7 Hz), 6.90 (2H, br dt, J = 8.7 Hz), 5.09 (1H, s), 4.57 (1H, s), 3.81 (3H, s), 3.35 (3H, s),
3.32 (3H, s), 3.23 (3H, s). 13C NMR (CDCl3) δ 201.1, 160.0, 129.6, 126.8, 114.2, 100.8, 84.8, 56.9, 55.3, 54.1 (2C).
HRMS (ESI+) calcd for C13H18O5Na (M+Na+): 277.1046, Found: 277.1059.
General procedure for oxidative esterification: A suspension of powdered K2CO3 (346 mg, 2.5 mmol) in dehydrated
THFꢀMeOH (1:1 v/v, 10 mL) was degassed using three pumpꢀthaw cycles under argon atmosphere at 0 °C. To this
suspension were added 1a, 1c-g or 12 (1.0 mmol), bromotrichloromethane (296 ꢀL, 3.0 mmol), triazolium 11A (13.2
mg, 0.050 mmol) and rhodamine 6G (24 mg, 0.050 mmol) at room temperature. The stirring reaction mixture was
irradiated with white LED lamp (1000 lm) at room temperature. After being stirred for 3 hours, the reaction mixture
was filtrated with folded filter paper which was then wasched with MeOH several times. The filtrate was concentrated
under reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt:hexanes = 1:10–
1:1) afforded the products 3a, 3c-g or 13.
(E)-3-(4-Methoxyphenyl)-2-propenoic acid methyl ester (3a)32 Following general procedure, the reaction of 1a was
carried out. Purification by flash silica gel column chromatography afforded the product 3a (190 mg, 99%) as colorless
crystals. Mp 85ꢀ86 °C (hexane). IR (KBr) 2952, 1716, 1604, 1513, 1255 cmꢀ1. 1H NMR (CDCl3) δ 7.65 (1H, d, J = 16.0
Hz), 7.47 (2H, d, J = 8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 6.30 (1H, d, J = 16.0 Hz), 3.84 (3H, s), 3.79 (3H, s). 13C NMR
(CDCl3) δ 167.8, 161.4, 144.5, 129.7, 127.1, 115.3, 114.3, 55.4, 51.6. HRMS (ESI+) calcd for C11H12O3Na (M+Na+):
215.0679, Found: 215.0689.
(E)-3-(4-Fluorophenyl)-2-propenoic acid methyl ester (3c)33 Following general procedure, the reaction of 1c was
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carried out. Purification by flash silica gel column chromatography afforded the product 3c (154 mg, 85%) as colorless
crystals. Mp 40ꢀ42 °C (hexane). IR (KBr) 2954, 1705, 1637,1601, 1511, 1436, 1320 cmꢀ1. 1H NMR (CDCl3) δ 7.66 (1H,
d, J = 16.0 Hz), 7.51 (2H, m), 7.08 (2H, m), 6.36 (1H, d, J = 16.0 Hz), 3.81 (3H, s). 13C NMR (CDCl3) δ 167.3, 163.9
(d, J = 252 Hz), 143.6, 130.6 (d, J = 3 Hz), 129.9 (d, J = 9 Hz), 117.6 (d, J = 2 Hz), 116.0 (d, J = 22 Hz), 51.7. 19F
NMR (CDCl3) δ −110.1 (1F, s). HRMS (ESI+) calcd for C10H10FO2 (M+H+): 181.0659, Found: 181.0657.
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(E)-3-Phenyl-2-propenoic acid methyl ester (3d)34 Following general procedure, the reaction of 1d was carried out.
Purification by flash silica gel column chromatography afforded the product 3d (178 mg, 79%) as colorless crystals.
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Mp 33ꢀ35 °C (hexane).. IR (KBr) 2952, 1719, 1637, 1315, 1278 cmꢀ1. H NMR (CDCl3) δ 7.70 (1H, d, J = 16.0 Hz),
7.53 (2H, m), 7.39 (3H, m), 6.45 (1H, d, J = 16.0 Hz), 3.81 (3H, s). 13C NMR (CDCl3) δ 167.4, 144.9, 134.4, 130.3,
128.9, 128.1, 117.8, 51.7. HRMS (ESI+) calcd for C10H10O2Na (M+Na+): 185.0573, Found: 185.0571.
(E)-3-(4-Methylphenyl)-2-propenoic acid, methyl ester (3e)33,35 Following general procedure, the reaction of 1e was
carried out. Purification by flash silica gel column chromatography afforded the product 3e (169 mg, 96%) as colorless
1
crystals. Mp 56ꢀ57 °C (hexane). IR (KBr) 2949, 1712, 1634, 1607, 1514, 1436, 1319 cmꢀ1. H NMR (CDCl3) δ 7.67
(1H, d, J = 16.0 Hz), 7.42 (2H, br d, J = 7.8 Hz), 7.19 (2H, br d, J = 7.8 Hz), 6.40 (1H, d, J = 16.0 Hz), 3.80 (3H, s),
13
2.37 (3H, s). C NMR (CDCl3) δ 167.6, 144.9, 140.7, 131.6, 129.6, 128.0, 116.7, 51.6, 21.5. HRMS (ESI+) calcd for
C11H12O2Na (M+Na+): 199.0730, Found: 199.0732.
(E)-3-(2-Methoxyphenyl)-2-propenoic acid methyl ester (3f)33 Following general procedure, the reaction of 1f was
carried out. Purification by flash silica gel column chromatography afforded the product 3f (121 mg, 63%) as colorless
oil. IR (KBr) 2950, 1714, 1631, 1490, 1437, 1249 cmꢀ1. 1H NMR (CDCl3) δ 8.00 (1H, d, J = 16.0 Hz), 7.50 (1H, dd, J
= 7.8, 1.8 Hz), 7.35 (1H, ddd, J = 8.2, 7.3, 1.8 Hz), 6.98ꢀ6.90 (2H, m), 6.53 (1H, d, J = 16.0 Hz), 3.89 (3H, s), 3.80 (3H,
13
s). C NMR (CDCl3) δ 167.9, 158.3, 140.3, 131.5, 128.9, 123.3, 120.7, 118.3, 111.1, 55.4, 51.6. HRMS (ESI+) calcd
for C11H12O3Na (M+Na+): 215.0679, Found: 215.0671.
(E)-3-(Furan-2-yl)-2-propenoic acid methyl ester (3g)36 Following general procedure, the reaction of 1g was carried
out. Purification by flash silica gel column chromatography afforded the product 3g (79 mg, 52%) as colorless oil. IR
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(KBr) 2956, 1729, 1439 cmꢀ1. 1H NMR (CDCl3) δ 7.48 (1H, d, J = 1.8 Hz), 7.43 (1H, d, J = 15.8 Hz), 6.61 (1H, d, J =
3.7 Hz), 6.46 (1H, dd, J = 3.7, 1.8 Hz), 6.31 (1H, d, J = 15.8 Hz), 3.78 (3H, s). 13C NMR (CDCl3) δ 167.5, 150.9, 144.7,
131.2, 115.4, 114.8, 112.2, 51.7. HRMS (ESI+) calcd for C8H9O3 (M+H+): 153.0546, Found: 153.0536.
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(E)-2-Naphthalenecarboxylic acid methyl ester (13)37 Following general procedure, the reaction of 12 was carried
out. Purification by flash silica gel column chromatography afforded the product 13 (125 mg, 67%) as colorless crystals.
Mp 74ꢀ76 °C (hexane). IR (KBr) 3062, 2950, 1712, 1469, 1441, 1355, 1297 cmꢀ1. 1H NMR (CDCl3) δ 8.62 (1H, d, J =
0.6 Hz), 8.06 (1H, dd, J = 8.5, 1.7 Hz), 7.96 (1H, dd, J = 8.2, 0.6 Hz), 7.89ꢀ7.87 (2H, m), 7.59 (1H, ddd, J = 7.9, 6.7,
1.2 Hz), 7.54 (1H, ddd, J = 8.2, 6.7, 1.2 Hz), 3.99 (3H, s). 13C NMR (CDCl3) δ 167.2, 135.5, 132.4, 131.0, 129.3, 128.2,
128.1, 127.7, 127.3, 126.6, 125.2, 52.2. HRMS (ESI+) calcd for C12H10O2Na (M+Na+): 209.0573, Found: 209.0594.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Assignment of synꢀ and antiꢀisomers and 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: miyabe@huhs.ac.jp
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI GrantꢀinꢀAid for Scientific Research (C) Grant Number 16K08188 (to
H.M.).
Notes and References
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