Br?nsted acid-catalyzed meyer-schuster rearrangement for the synthesis of α, β -unsaturated carbonyl compounds

Article abstract of DOI:10.1080/00397911.2013.879314

An efficient and simple protocol for the Meyer-Schuster rearrangement of propargyl alcohols into α,β-unsaturated carbonyl compounds has been developed using catalytic amounts of p-toluenesulfonic acid in 1,2-dichloroethane.

Full text of DOI:10.1080/00397911.2013.879314

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Brønsted Acid–Catalyzed Meyer–Schuster
Rearrangement for the Synthesis of α,β-
Unsaturated Carbonyl Compounds
Jungmin Park a , Jihee Yun a , Jaehyun Kim a , Dong-Jin Jang b c
Cheol Ho Park a b & Kooyeon Lee a b
,
a Department of Bio-health Technology , Kangwon National
University , Chuncheon , Republic of Korea
b Institute of Bioscience and Biotechnology , Kangwon National
University , Chuncheon , Republic of Korea
c Samyang Pharmaceutical Research and Development Center ,
Daejeon , Republic of Korea
Accepted author version posted online: 18 Mar 2014.Published
online: 29 May 2014.
To cite this article: Jungmin Park , Jihee Yun , Jaehyun Kim , Dong-Jin Jang , Cheol Ho
Park & Kooyeon Lee (2014) Brønsted Acid–Catalyzed Meyer–Schuster Rearrangement for the
Synthesis of α,β-Unsaturated Carbonyl Compounds, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:13, 1924-1929, DOI:
10.1080/00397911.2013.879314
To link to this article: http://dx.doi.org/10.1080/00397911.2013.879314
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Synthetic Communications1, 44: 1924–1929, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.879314
BRØNSTED ACID–CATALYZED MEYER–SCHUSTER
REARRANGEMENT FOR THE SYNTHESIS OF a,b-
UNSATURATED CARBONYL COMPOUNDS
Jungmin Park,1 Jihee Yun,1 Jaehyun Kim,1 Dong-Jin Jang,2,3
Cheol Ho Park,1,2 and Kooyeon Lee1,2
1Department of Bio-health Technology, Kangwon National University,
Chuncheon, Republic of Korea
2Institute of Bioscience and Biotechnology, Kangwon National University,
Chuncheon, Republic of Korea
3Samyang Pharmaceutical Research and Development Center, Daejeon,
Republic of Korea
GRAPHICAL ABSTRACT
Abstract An efficient and simple protocol for the Meyer–Schuster rearrangement of
propargyl alcohols into a,b-unsaturated carbonyl compounds has been developed using
catalytic amounts of p-toluenesulfonic acid in 1,2-dichloroethane.
Keywords a,b-Unsaturated carbonyl compounds; Brønsted acid; Meyer–Schuster
rearrangement; p-toluenesulfonic acid; propargyl alcohols
INTRODUCTION
a,b-Unsaturated carbonyl compounds are key structural units for the synthesis
of biologically active natural products, pharmaceuticals, and other useful materials.[1]
The traditional methods for synthesizing a,b-unsaturated carbonyls—which are
based on aldol condensation,[2] Horner–Wadsworth–Emmons reaction,[3] Claisen–
Schmidt condensation,[4] etc.—involve multiple steps and exhibit overall poor atom
economy. The Meyer–Schuster rearrangement,[5] which involves the rearrangement
of propargyl alcohols into a,b-unsaturated carbonyl compounds, is considered a
highly efficient reaction because of its high atom economy; however, this reaction
Received October 23, 2013.
Address correspondence to Kooyeon Lee, Department of Bio-health Technology, Kangwon
National University, Chuncheon 200–701, Republic of Korea. E-mail: lky@kangwon.ac.kr
1924

PTSA–CATALYZED MEYER–SCHUSTER REARRANGEMENT
1925
Scheme 1. PTSA–catalyzed Meyer–Schuster rearrangement.
traditionally requires strongly acidic media and harsh conditions, both of which often
result in the formation of a mixture of E and Z stereoisomers.[5b] The recently
developed synthesis methods catalyzed by transition metals such as Au,[6] Ru,[7]
Rh,[8] Ir,[9] Pd,[10] and other metals[11] proceed under mild conditions with high
efficiency and selectivity; however, in most cases, expensive catalysts, some of which
require preparation and special handling, are required. Recently, we developed the
indirect hydration of alkynes catalyzed by FeCl2 ꢀ 4H2O in the presence of methane-
sulfonic acid[12] and found that 1-phenylprop-2-yn-1-ol reacts smoothly to produce
cinnamaldehyde in good yield, via the Mayer–Schuster rearrangement by
FeCl2 ꢀ 4H2O in the presence of methanesulfonic acid. Although the results of Meyer–
Schuster rearrangement by triflic acid (TfOH) or p-toluenesulfonic acid (PTSA) as a
Brønsted acid in tetrahydrofuran (THF) have been reported,[13] the disadvantages
were poor yield and poor stereoselectivity. However, when using 1,2-dichloroethane
(DCE) as the solvent, 1-phenyl-2-propyn-1-ol 1a readily reacted with catalytic
amounts of PTSA to selectively afford E-cinnamaldehyde 2a in good yield. Herein,
we describe an efficient PTSA-catalyzed rearrangement of propargyl alcohols into
a,b-unsaturated carbonyl compounds (Scheme 1).
RESULTS AND DISCUSSION
Initially, a variety of Lewis and Brønsted acids were screened using 1-phenyl-2-
propyn-1-ol 1a as the model substrate (Table 1). The use of various iron salts as the
catalyst was investigated for the formation of a cinnamaldehyde 2a in DCE. Catalytic
amounts of FeCl3, FeCl2 ꢀ 4H2O, and Fe(ClO4)3 ꢀ xH2O were inactive at 60 ꢁC for the
Meyer–Schuster rearrangement (entries 1–3). The reaction of 1a and 10 mol%
of Fe(OTf)3 gave 2a in 41% yield, exclusively in the E configuration, at 60 ꢁC
(entry 4); however, at room temperature, only trace amounts of the product could
be detected by 1H NMR analysis (entry 5). When using Bi(OTf)3 as the catalyst a rela-
tively poor yield of 2a (44%) was obtained (entry 6), while no reaction occurred when
using Sc(OTf)3 (entry 7). The reaction with In(OTf)3 gave a 17:1 mixture of the E and
Z stereoisomers, and that too in poor yields (entry 8). Cu(OTf)2 also gave the desired
product in poor yield (entry 9).
Next, the effects of various Brønsted acids were investigated for the Meyer–
Schuster rearrangement. Brønsted acids such as CSA and TfOH were inefficient in
the presence of 30 mol% (entries 10 and 11). However, when using MsOH, 2a was
1
obtained in a moderate yield of 68% (entry 12). To our delight, the H NMR yield
of 2a increased to 89% when using PTSA instead of MsOH (Table 1, entry 13). When
the amount of PTSA was decreased to 10 mol%, the yield of 2a decreased to 46%
(entry 14). Further, at room temperature, only trace amounts of the product could
be detected (entry 15). Then, various solvents were screened to determine the optimal

1926
J. PARK ET AL.
Table 1. Optimization of reaction conditions for the rearrangement of propargyl alcoholsa
Entry
Catalyst (mol %)
Solvent
DCE
DCE
Temp. (ꢁC)
Time (h)
Yield (%)b
E=Z ratioc
1
2
FeCl3(10)
60
60
60
60
25
60
60
60
60
60
60
60
60
60
25
60
60
60
60
60
16
16
16
1
0
FeCl2 ꢀ 4H2O (10)
Fe(ClO4)3 ꢀ xH2O (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
In(OTf)3(10)
Cu(OTf)2(10)
CSA (30)
0
0
3
DCE
DCE
4
41
Trace
44
(E only)
3:1
(E only)
5
DCE
DCE
10
1
6
7
DCE
DCE
10
6
0
36
8
17:1
9
DCE
DCE
3
32
4
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
(E only)
10
11
12
13
14
15
16
17
18
19
20
10
3
TfOH (30)
DCE
DCE
Trace
68
89 (84)d
46
MsOH (30)
PTSA (30)
PTSA (10)
5
DCE
DCE
1
2.2
10
24
10
10
8
PTSA (30)
PTSA (30)
DCE
THF
Trace
21
PTSA (30)
PTSA (30)
Toluene
CH3CN
Chlorobenzene
EtOH
8
10
PTSA (30)
PTSA (30)
60
0
10
aReaction conditions: 1-phenyl-2-propyn-1-ol (1a, 1.0 mmol), solvent (3.0 mL), in air.
bYields are based on 2a, determined by crude 1H NMR using dibromomethane as the internal standard.
cAs observed by 1H NMR.
dIsolated yield.
solvent for the reaction with PTSA. The use of THF, toluene, CH3CN, and chloro-
benzene resulted in poor yields (entries 16–19); furthermore, no reaction occurred
when using EtOH (entry 20).
Next, we investigated the scope and limitation of the Meyer–Schuster
rearrangement catalyzed by PTSA in DCE, using a variety of propargyl alcohols.
The obtained results are shown in Table 2. Electron-rich aromatic propargyl alcohols
afforded the desired products in good to excellent yields (entries 2 and 4). However,
the use of propargyl alcohol with an ortho-methoxy substituent on the aromatic ring
gave the desired product 2c in poor yield (entry 3). When using this substrate, other
products were not obtained, but the starting material disappeared within 3 h, prob-
ably because of steric hindrance and decomposition. Moreover, substitution of an
electron-withdrawing group such as trifluoromethyl, chloro, and bromo on the
phenyl ring resulted in reasonable yields of the product (entries 5–8). However, when
propargyl alcohol 1i bearing a naphthyl moiety was used, 2i was obtained in only 39%
yield (entry 9). We could not obtain other products; however, the starting material
disappeared (probably decomposed) within 1 h. The use of 2-phenylbut-3-yn-2-ol 1j
resulted in a 1.3:1 mixture of the E and Z stereoisomers in 85% yield, as determined

PTSA–CATALYZED MEYER–SCHUSTER REARRANGEMENT
1927
Table 2. PTSA–catalyzed Meyer–Schuster rearrangementa
Entry
1
Substrate
Product
Time (h)
1
Yieldb (%)
84
96
2
3
4
2
3
2
32
82
5
6
5
2
50
67
7
8
9
1
2
1
83
65
39
10
11
12
8
6
1
85 (E=Z ¼ 1.3:1)
83
70
aReaction conditions: propargyl alcohols (1.0 mmol), PTSA (30 mol%), DCE (3.0 mL), in air.
bIsolated yields.

1928
J. PARK ET AL.
by 1H NMR analysis of the crude mixture before column chromatography (entry 10).
Rearrangement of the internal alkynyl alcohol proceeded efficiently to give the corre-
sponding a,b-unsaturated ketone 2k in good yield, although this reaction required a
longer time to complete as compared to those with terminal alkynes (entry 11).
1-Phenylprop-2-ynyl acetate 1l, too, reacted smoothly to produce cinnamaldehyde
2a in good yield (entry 12). Finally, we tested 2ꢁ-aliphatic propargyl alcohols such
as undec-1-yn-3-ol and 5-phenylpent-1-yn-3-ol, but no reaction was observed. More-
over, internal propargyl alcohols such as 3-phenyl-1-p-tolylprop-2-yn-1-ol did not
afford the desired product but gave the dimeric ether.[14]
CONCLUSIONS
In conclusion, we have demonstrated that PTSA is a very effective catalyst that
promotes the Meyer–Schuster rearrangement. Various propargyl alcohols were toler-
ated in this reaction, which was applicable to internal alkynyl alcohols as well. This
reported catalytic procedure for the synthesis of a,b-unsaturated carbonyl com-
pounds is a very simple, efficient, and selective methodology involving readily avail-
able propargyl alcohols as precursors and proceeding in an atom-economical manner.
EXPERIMENTAL
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a
Bruker Avance III 400 NMR spectrometer. Deuterated chloroform was used as the
solvent, and chemical shift values (d) are reported in parts per million relative to the
residual signals of this solvent (d 7.26 for 1H and d 77.0 for 13C). 1,2-Dichloroethane
was distilled from CaCl2. Commercially available reagents were used without purifi-
cation. Propargyl alcohols were prepared by Grignard addition to aldehyde.
General Procedure for the Synthesis of a,b-Unsaturated Carbonyl
Compounds from Aryl Propargyl Alcohols
1-Phenyl-2-propyn-1-ol (66.08 mg, 0.5 mmol) was added to a suspension of p-
toluenesulfonic acid (98%, Alfa Aesar, 28.35 mg, 30 mol%) in dry 1,2-dichloroethane
(3.0 mL). The stirred solution was heated at 60 ꢁC for 1 h. Then, the solvent was
removed at reduced pressure and the residue was purified by column chromatography
with n-Hex=EtOAc (7=1) as the eluent to give cinnamaldehyde (2a, 55.70 mg, 84%) as
a yellow color oil. 1H NMR (400 MHz, CDCl3) d 9.70 (d, J ¼ 7.7 Hz, 1H), 7.58–7.55
(m, 1H), 7.50 (d, J ¼ 16.0 Hz, 1H), 7.45–7.43 (m, 4H), 6.72 (dd, J ¼ 16.0, 7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 193.6, 152.6, 133.9, 131.1, 129.0, 128.5, 128.4.
All products reported in this article are known compounds, and their full data
can be obtained from the reported literature.
FUNDING
This work was supported by the 2013 Research Grant from the Kangwon
National University (No. 120131489) and by the ‘‘Leaders Industry–University
Cooperation’’ Project, supported by the Ministry of Education, Science, and Tech-
nology (MEST).

PTSA–CATALYZED MEYER–SCHUSTER REARRANGEMENT
1929
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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