Efficient and rapid synthesis of phenolic analogs of 4-phenylbutanoic acid using microwave-assisted Michael addition as a key reaction

Article abstract of DOI:10.1080/00397911.2016.1155714

ABSTRACT: The addition of phenols to acrylonitrile in the presence of aqueous benzyltrimethylammonium hydroxide or tetramethylammonium hydroxide under microwave irradiation yielded the corresponding Michael adducts. The obtained adducts were easily transformed to phenolic analogs of 4-phenylbutanoic acids via the hydrolysis of nitrile groups.

Full text of DOI:10.1080/00397911.2016.1155714

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient and Rapid Synthesis of Phenolic
Analogues of 4-phenylbutanoic Acid Using
Microwave–Assisted Michael Addition as a Key
Reaction
Hirokazu Iida, Yusuke Akatsu, Kazushi Mizukami, Sho Natori, Minako
Matsukawa & Kie Takahashi
To cite this article: Hirokazu Iida, Yusuke Akatsu, Kazushi Mizukami, Sho Natori, Minako
Matsukawa & Kie Takahashi (2016): Efficient and Rapid Synthesis of Phenolic Analogues of 4-
phenylbutanoic Acid Using Microwave–Assisted Michael Addition as a Key Reaction, Synthetic
Communications, DOI: 10.1080/00397911.2016.1155714
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1155714
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Date: 15 March 2016, At: 07:29

Efficient and Rapid Synthesis of Phenolic Analogues of 4-Phenylbutanoic Acid using
Microwave–Assisted Michael Addition as a Key Reaction
Hirokazu Iida1,, Yusuke Akatsu1, Kazushi Mizukami1, Sho Natori1, Minako Matsukawa1,
Kie Takahashi1
1Department of Biosciences, Kanto Gakuin University College of Science and Technology,
Yokohama, Kanagawa, 236-8501, Japan
Corresponding author: Hirokazu Iida E-mail: hiida@kanto-gakuin.ac.jp
Abstract
The addition of phenols to acrylonitrile in the presence of aqueous
benzyltrimethylammonium hydroxide or tetramethylammonium hydroxide under
microwave irradiation yielded the corresponding Michael adducts. The obtained adducts
were easily transformed to phenolic analogous of 4-phenylbutanoic acids via the
hydrolysis of nitrile groups.
KEYWORDS: Michael addition, Microwave irradiation, 4-PBA
1

Several human diseases are caused by defects in protein folding. Potential therapeutic
strategies that rescue the native protein conformation and/or induce the stabilization of
intermediates have been developed for protein misfolding diseases.[1] The sodium salt of
4-phenylbutanoic acid (4-PBA) is supposedly one of the chemical compounds that has
been used to recover the native protein conformation and/or to stabilize intermediates.[2-6]
The synthesis of 4-PBA analogues and their structure–activity relations were reported by
Hamana et al. in 2012.[7] They synthesized 3-phenylpropanoic acid, 5-phenylpentanoic
acid, and 6-phenylhexanoic acid, and investigated their protective effects against neuronal
cell death. We recently reported the synthesis of 4-PBA analogues wherein heteroaromatic
groups such as pyrrole and indole replace the phenyl group of 4-PBA.[8] During our study
on the synthesis of 4-PBA analogues and their protective effects against heat damage in
Arabidopsis thaliana, we recognized that phenolic analogues of 4-PBA exhibited unique
effects. [9] We hypothesized that Michael addition reactions between phenols and
acrylonitrile followed by the hydrolysis of adducts would be an efficient synthetic method
for phenolic analogues of 4-PBA. The Michael addition between phenol and acrylonitrile
was reported by Gunnoe et al. using Cu(I) catalysts, however, the long reaction time (40 h)
of this reaction was problematic.[10,11] The same Michael addition reactions were also
reported by Askin et al. using potassium carbonate and tert-butanol as catalysts, and by
2

Al-Awadi et al. using aqueous benzyltrimethylammonium hydroxide as a catalyst;
however, as mentioned above, both reported reaction times exceed 20 h. [12,13]
In some cases, microwave irradiation methods are useful to accelerate reaction rate. [14] We
are interested in organic reactions under non-conventional conditions such as high pressure
and microwave irradiation. Recently, we reported that the 1,2-addition reaction between
trimethylsilyl cyanide (TMSCN) and acetophenone occurred without solvent under
microwave irradiation conditions but did not occur under high–pressure conditions.[15] We
also reported that microwave irradiation might facilitate the conjugate additions of
TMSCN and chalcones without additives or solvent.[16] Interestingly, when we applied
microwave irradiation to the Michael addition of phenols and acrylonitrile, the reaction
rates were strongly accelerated, and Michael adducts were rapidly produced compared to
the abovementioned report. The obtained adducts were easily transformed into 4-PBA
analogues. We briefly report these results herein.
First, we investigated the Michael addition reaction of phenol (10 mmol) and acrylonitrile
(60 mmol) in the presence of 40% aqueous benzyltrimethylammonium hydroxide (R = Bn;
1 mL) or 10% tetramethylammonium hydroxide (R = Me; 1 mL) without solvent under
3

microwave irradiation conditions (Scheme S1). The reactions rapidly proceeded with the
assistance of microwave irradiation to yield the corresponding adducts (Table S1). The
microwave irradiation power was 12–18 W for all reactions, as shown in Table S1.
Both longer reaction time and higher reaction temperature seemed enhance the formation
of compound 2 (data not shown). The reaction occurring under microwave irradiation in
the presence of 40% aqueous benzyltrimethylammonium hydroxide at 60°C in 60 min
showed 55% conversion to 1a (Table S1 entry 4, determined by 1H NMR), while the
reaction at 60°C in 120 min in the presence of the same catalyst showed 46% conversion to
1a (Table S1 entry 5). These results suggest that along with the Michael reaction of water
and acrylonitrile, an unusual dephenylation reaction from 1a to 2 occurred under the
present reaction conditions. We will report about the unusual dephenylation reaction
separately in the near future.
Next, we investigated different catalysts for the addition reaction. When the above
reactions were repeated using a 40% methanol solution of benzyltrimethylammonium
hydroxide as catalyst, 3-methoxypropionitrile was obtained as the main product. This
suggests that the Michael addition of methanol and acrylonitrile mainly occurred under
4

these reaction conditions. In contrast, when we used benzyltrimethylammonium chloride
or tetramethylammonium chloride to catalyze the reaction between phenol and
acrylonitrile under microwave irradiation, no reactions were observed.
To clarify the scope and limitation of the microwave–assisted Michael addition, we applied
the microwave conditions to several phenols (Scheme S2).
All reactions proceeded to give the corresponding Michael adducts 1a–f. The results are
summarized in Table 2. Entries 5 and 6 suggest that the presence of an
electron-withdrawing group at the 4–position of the phenyl group decreased the reactivity
of the Michael addition.
Finally, we transformed the obtained Michael adducts into 4-PBA analogues by
hydrolyzing the nitrile group to carboxylic acid (Scheme S3). The concentrated
hydrochloric acid–assisted hydrolysis of 1 smoothly proceeded to give the corresponding
phenolic analogues of 4-PBA 3 in 45–98% yield (Table S3).
5

In conclusion, we presented a highly efficient and rapid method for preparing phenolic
analogues of 4-PBA by microwave–assisted Michael addition without solvent followed by
hydrolysis. Further investigations of the protective effects of the sodium or potassium salts
of 3 against heat damage in Arabidopsis thaliana are currently in progress and will be
reported in due course.
Experimental section
Representative experimental procedure for the synthesis of 1a–f: 10% aqueous
tetramethylammonium hydroxide (1 mL) was added to a mixture of phenol (1.08 g, 10
mmol) and acrylonitrile (4 mL, 60 mmol), and the suspension was irradiated at 60°C for 30
min. During irradiation, the microwave apparatus indicated a power of 18–20 W. The
organic layer was extracted with diethyl ether (20 mL, 3 times), and the combined organic
layer was successively washed with 5% aq. HCl (30 mL), 5% aq. NaHCO3 (30 mL), and
brine (30 mL). Finally, the resulting organic layer was dried over MgSO4, and the solvent
was removed in vacuo. Reaction conversion was determined by 1H NMR analysis of the
residue. The residue was further purified by column chromatography on silica gel (30 g)
using ethyl acetate and hexane (1:4, v/v) as an eluent to afford Michael adduct 1a (1.01 g,
68 %) as a colorless solid. The analytically pure sample was obtained by recrystallization
6

from ethanol. Selected spectral data of synthetic Michael adducts: 1a: colorless needles,
mp 56°C –58°C (EtOH, lit.[17] 59°C –60°C), 1H NMR (DMSO-d6
2.98 (2H, t, J = 6.0
Hz), 4.16 (2H, t, J = 6.5 Hz), 6.94–7.00 (2H, m), 7.26–7.32 (2H, m); 13C NMR (DMSO-d6)
: 18.0 (CH2), 62.7 (CH2), 114.6 (CH), 119.0 (CN), 121.3 (CH), 129.7 (CH), 157.7 (C);
ESI-TOFMS m/z: 148.0774 ([M+H]+, 148.0762 calcd for C9H10NO).
Representative experimental procedure for the synthesis of 3a–f: Amixture of 1c (0.59 g, 3
mmol) and conc-HCl (5 mL) was refluxed for 2 h and then cooled to 0°C for 1 h. The
resulting solid was collected to yield analytically pure 3c (0.63 g, 98%) as colorless needles.
Selected spectral data of synthetic 4-PBA analogues: 3c: colorless needles, mp 145°C
–147°C (lit.[18] 144°C –145°C), 1H NMR (DMSO-d6
2.21 (3H, s), 2.65 (2H, t, J = 6.5
Hz), 4.10 (2H, t, J = 6.5 Hz), 6.79 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz), 12.30 (1H,
br.s); 13C NMR (CDCl3) : 20.7, 34.5, 63.4, 114.7, 130.1, 130.6, 156.4, 176.4;
ESI-TOFMS m/z: 181.0869 ([M+H]+, 181.0865 calcd for C10H13O3).
ACKNOWLEDGMENTS
This work was financially supported by the Institute of Science and Technology, Kanto
Gakuin University, in 2013. The authors are grateful to MEXT, Japan, for purchasing the
7

high-field NMR instrument (JNM-ECX500II) with the Matching Fund Subsidy for Private
Universities (to H.I. as a representative in 2013). H. I. extends his gratitude to Sasakawa
Scientific Research (Grant Nos. 6–182 and 7–199 K) and Sasakawa Grants for Science
Fellows (No. F02–109) from the Japan Science Society for supporting his research.
Supporting Information: Experimental detail and 1H and 13C NMR spectra. This material
can be found via the “Supplementary Content” section of this article’s webpage.
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Table S1. Microwave–assisted Michael addition of phenol and acrylonitrile in the presence
of a catalyst (% conversion determined by 1H NMR spectroscopy)
entry R
time
temp (°C)
%
Conversion
46a
1
Bn
60 min
120 min
60 min
60 min
120 min
60 min
60 min
30 min
30 min
60 min
240 min
70
70
65
60
60
60
55
60
70
70
70
2
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
42a
3
43a
4
55a
5
46a
6
47a
7
30a
8
67
9
31 a
41 a
68a
10
11
a) Formation of compound 2 was observed by 1H NMR analysis.
11

Table S2. Microwave–assisted Michael addition of phenols and acrylonitrile in the
presence of a catalyst (% conversion determined by 1H NMR)
Entry R
R’
Time
%
product
(min) Conversion
1
2
3
4
5
6
H
Me 30
Me 30
Me 40
75
1a
1b
1c
1d
1e
1f
2-Me
4-Me
69a
69a
80
4-OMe Bn
4-Cl Me 30
4-NO2 Bn 60
30
7a
0.1a
a Formation of compound 2 was observed by 1H NMR analysis.
12

Table S3. Synthesis of carboxylic acids 3 from 1
Entr
y
R
Yielda (%) product
1
H
60
82
98
3a
3b
3c
3d
3e
3f
2
2-Me
4-Me
3
4
4-OMe 73
5
4-Cl
47
45
6
4-NO2
a Isolated yields, not optimized.
13

Scheme S1. The reaction between phenol and acrylonitrile in the presence of a catalyst
14

Scheme S2. The reaction between phenols and acrylonitrile in the presence of a catalyst
15

Scheme 3. Hydrolysis of 1 to carboxylic acids 3
16