Phosphorous acid promoted isomerization of propargyl alcohols to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2019.06.065

A metal-free and two-phase protocol for the Meyer-Schuster isomerization of propargyl alcohols to the corresponding α,β-unsaturated carbonyl compounds has been achieved in the presence of stoichiometric phosphorous acid aqueous solution, which produces the desired products in high yields with excellent stereoselectivity. Compared with the traditional methods, the procedure features broad scope of the substrates, mild conditions, and easy separation, providing an appealing alternative to the Meyer-Schuster reaction.

Full text of DOI:10.1016/j.tetlet.2019.06.065

Accepted Manuscript
Phosphorous acid promoted isomerization of propargyl alcohols to α,β-unsatu-
rated carbonyl compounds
Xiaotang Gan, Zuqi Fu, Lixin Liu, Yani Yan, Chao Chen, Yongbo Zhou, Jianyu
Dong
PII:
S0040-4039(19)30636-7
https://doi.org/10.1016/j.tetlet.2019.06.065
TETL 50906
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
5 May 2019
25 June 2019
27 June 2019
Please cite this article as: Gan, X., Fu, Z., Liu, L., Yan, Y., Chen, C., Zhou, Y., Dong, J., Phosphorous acid promoted
isomerization of propargyl alcohols to α,β-unsaturated carbonyl compounds, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.06.065
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Phosphorous acid promoted isomerization of
propargyl alcohols to α,β-unsaturated
carbonyl compounds
Xiaotang Gan, Zuqi Fu, Lixin Liu, Yani Yan, Chao Chen, Yongbo Zhou, and Jianyu Dong

1
Tetrahedron Letters
Phosphorous acid promoted isomerization of propargyl alcohols to α,β-unsaturated
carbonyl compounds
Xiaotang Gan,a,║ Zuqi Fu,a,║ Lixin Liu,a Yani Yan,a Chao Chen,c Yongbo Zhou,a and Jianyu Donga,b,

aCollege of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
bDepartment of Educational Science, Hunan First Normal University, Changsha 410205, China
cCollege of Life Sciences, Huzhou University, Huzhou 313000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free and two-phase protocol for the Meyer-Schuster isomerization of propargyl alcohols
to the corresponding α,β-unsaturated carbonyl compounds has been achieved in the presence of
stoichiometric phosphorous acid aqueous solution, which produces the desired products in high
yields with excellent stereoselectivity. Compared with the traditional methods, the procedure
features broad scope of the substrates, mild conditions, and easy separation, providing an
appealing alternative to the Meyer-Schuster reaction.
Available online
Keywords:
Meyer–Schuster rearrangement
H3PO3 aqueous solution
Two-phase
2009 Elsevier Ltd. All rights reserved.
α,β-Unsaturated carbonyl compounds
Introduction
p-toluenesulfonic acid catalyzed Meyer–Schuster rearrangement
of propargyl alcohols into α,β-unsaturated carbonyl
compounds.13b Despite many advances, the Meyer-Schuster
rearrangement has few applications in organic synthesis because
it still suffers from harsh reactions, strong acids, limited substrate
scope, and/or poor stereoselectivity.10b Therefore, facile, efficient,
and stereoselective protocols for Meyer-Schuster rearrangement
are still highly desired.
As versatile structural building blocks, α,β-unsaturated
carbonyl compounds are widely used in the food, agriculture,
medicinal industries, and biologically active compounds.1 This
type of compounds has also attracted increasing interest due to
their broad applications in organic synthesis.2 In the past decades,
a variety of synthetic strategies toward their synthesis have been
developed,3 such as Heck coupling,4 Peterson olefinations,5
formylation,6 cross-aldol condensations,7 Saegusa–Ito oxidation
reaction,8 and the oxidation of allylic alcohols,9 etc.
Among them, the isomerization of readily accessible
propargyl alcohols to α,β-unsaturated carbonyl compounds
provides a straightforward route to these very valuable raw
chemicals with high atom economy.10 This reaction is named
after Meyer and Schuster, which was first reported about 100
years ago. The reaction proceeds under strong Brønsted acids at
elevated temperatures, and the scope of the substrate limits to
tertiary propargyl alcohols that lack β-hydrogen. Over past
decades, many improvements have been made by the use of
transition metals (Ru, Rh, Mo, V, Pd, Ir, Ti, Ag, Au, and Fe)11,12
and organic acids.13 For instances, Douhaibi group developed a
FeCl3-promoted isomerization of propargyl alcohols to the
corresponding α,β-unsaturated carbonyl compounds in 2011.12
Next, Hall and coworkers explored a arylboronic acid catalyzed
synthesis of such compounds.13a Recently, Lee reported
Figure 1. The isomerization of propargyl alcohols.
Herein, we disclose a facile method for Meyer-Schuster
rearrangement promoted by phosphorous acid under metal-free
condition in two-phase system, and the reaction produces the
———
║X.G. and Z.F. contributed equally to this work.
Corresponding author. Tel./Fax: (+) 86-731-88821171. E-mail address: djyustc@hotmail.cn

Tetrahedron Letters
corresponding α,β-unsaturated carbonyl compounds in high
11 vs entry 8). Investigation of solvents showed that ethyl acetate
(EA), CHCl3, ethyl alcohol (EtOH), tetrahydrofuran (THF),
toluene, and H2O were inferior to CH2Cl2 (Table 1, entries 12–17
and entry 8). Furthermore, a series of acids (HNO3, H2SO4,
H3PO2, H3PO4, CH3COOH, TsOH) were also screened (Table 1,
entries 18–23), the results suggested that H3PO3 was more
suitable for this system (Table 1, entry 8). The reaction also
proceeded smoothly under air, and produced the desired product
in 80% yield (Table 1, entry 24), which was slightly lower than
those in inert condition.
yields with high stereoselectivity (Figure 1).15 H3PO3 is an easily
accessible, stable, and cheap Brønsted acid with moderate acidity,
and it shows unique efficiency in many reactions.14 The use of
H3PO3 in this reaction allows broad scope of the substrates, mild
conditions, and easy separation.
Results and discussion
We commenced our studies with the reaction of
a
commercially available propargyl alcohol 1a (0.2 mmol) and
H3PO3 50 wt% aqueous solution (0.2 mmol, 1.0 equiv) in CH2Cl2
under nitrogen at 80 °C for 12 h, the desired product
cinnamaldehyde 2a was obtained in 70% GC yield with 100% E
isomer (Table 1, entry 1). A brief examination of temperature and
time (Table 1, entries 1–6) indicated that the reaction time could
be shortened from 12 h to 2 h and the cinnamaldehyde (2a) was
obtained in 85% yield (Table 1, entry 4) while raising the
temperature up to 110 °C. Increasing the loading of H3PO3
aqueous solution to 1.5 eq. could lead to higher yield (90%,
Table 1, entry 8; entries 7–9). Then, the screen of different
concentration of H3PO3 aqueous solution demonstrated that the
50 wt% H3PO3 aqueous solution was best (Table 1, entries 10 and
With the optimized conditions in hand, we next investigated
the scope and generality of the reaction. As shown in Table 2,
this phosphorous acid promoted isomerization reaction worked
well for a wide variety of substrates with outstanding functional
group tolerance, producing various (E)-α,β-unsaturated aldehydes
in good to high yields with excellent stereoselectivity. Propargyl
alcohols substituted with alkyl (2b–2f), halogen (2g–2j), and
trifluoromethyl (2k) worked well to give the corresponding (E)-
α,β-unsaturated aldehydes in 62−95% yields. The trans-geometry
of the α,β-unsaturated aldehyde was ascertained by the high
coupling constant of the vinyl protons (J ≈ 15.6–16.4 Hz) in the
1H NMR spectra. The electron effect of substituents played
important roles in the reaction. The electron-donating groups in
the phenyl ring, which favor the formation of propargyl cation A
(vide infra), resulted in higher yields of the desired products [2b
(92%), 2e (93%), and 2f (95%) vs 2g (87%), 2h (85%), 2i (82%),
and 2k (74%)]. The steric hindrance of substituents was
Table 1 Optimization of reaction conditionsa
Entry
1
H3PO3/equiv
1.0
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EA
T/°C
80
t/h
12
12
2
Yieldb(%)
70
Table
2 Substrate scope of α,β-unsaturated carbonyl
compoundsa
2
1.0
100
100
110
120
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
83
3
1.0
79
4
1.0
2
85
5
1.0
2
87
6
1.0
1
80
7
1.3
2
87
90(81)c
8
1.5
2
9
1.7
2
88
10d
11e
12
13
14
15
16
17
18f
19f
20f
21f
22f
23f
24g
1.5
2
70
1.5
2
78
1.5
2
59
1.5
CHCl3
EtOH
2
79
1.5
2
none
none
41
1.5
THF
2
1.5
Toluene
H2O
2
1.5
2
none
none
59
HNO3
H2SO4
H3PO2
H3PO4
CH3COOH
TsOH
1.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
20
2
85
2
none
71
2
2
80
aReaction conditions: 1a (0.2 mmol), H3PO3 50 wt% aqueous solution, N2
atmosphere, solvents (0.5 mL).
bGC yield.
cIsolated yield.
d30 wt % H3PO3 aqueous solution.
e70 wt % H3PO3 aqueous solution.
fOther 50 wt% acid aqueous solutions instead of H3PO3.
gAir.
aReaction conditions: propargylic alcohol (0.2 mmol), H3PO3 50 wt% aqueous
solution (0.3 mmol), N2 atmosphere, 110 °C, 2 h, CH2Cl2 (0.5 mL), isolated
yield.
b10h.

3
detrimental to the reaction [2c (78%) and 2d (62%) vs 2b (92%);
2j (80%) vs 2h (85%)]. In addition, the attachment of methoxy
(2l), and N,N-dimethylamino (2m) that might be protonated by
Brønsted acids resulted in lower yields (58% and 30%,
respectively). Notably, the high efficiency (80–85%) of the
formation of the halogenated products 2h–2j may be applied for
further functionalization toward more complex targets via
stepwise coupling reactions. Treating sterically hindered 1-
(naphthalen-2-yl)prop-2-yn-1-ol (1n) and 1-(naphthalen-1-
yl)prop-2-yn-1-ol (2o) with H3PO3 50 wt% aqueous solution gave
the corresponding products in moderate yields (50% and 45%
yield, respectively). In addition, tertiary propargylic alcohol 1,1-
diphenyl-2-propyn-1-ol was also compatible with this reaction
The mechanism of acid-promoted the Meyer-Schuster
rearrangement was well-accepted,16 which involves formal 1,3-
hydroxyl shift and tautomerization. Firstly, propargyl alcohol 1 is
translated into oxonium salt via rapid protonation step, then takes
off a water molecule to generate propargyl cation A, which
followed by a formal 1,3-cation shift to form the allene cation B.
Finally, attack of a water molecule on the carbocation and
deprotonation is followed by tautomerization to give the α,β-
unsaturated carbonyl compound 2 (Figure 4).
Conclusions
In summary, by the use of relatively weak inorganic acid, we
developed a facile, efficient, and stereoselective procedure for
Meyer-Schuster rearrangement. The reaction proceed under metal
free conditions in two-phase system, which produces a variety of
α,β-unsaturated carbonyl compounds in high yields with
excellent stereoselectivity. The merits of the procedure such as
mild conditions, high yields, excellent stereoselectivity, and easy
separation allow it as an appealing alternative to the Meyer-
Schuster reaction.
system,
and
the
corresponding
product
(3,3-
diphenylacrylaldehyde 2p) was produced in excellent yield
(90%) with 100% E isomer. Furthermore, the α,β-unsaturated
ketones also could be obtained in good yields under the
optimized conditions when terminal alkyne substituted with alkyl
or aryl groups (2q–2t). Unfortunately, the isomerization of the
substrate 4-methyl-1-phenylpent-1-yn-3-ol (1u) did not occur due
to instability of its propargyl cation.
Experimental Section
Interestingly,
the
propargylic
alcohol
(1v,
1-
ethynylcyclohexan-1-ol) with hydrogens in beta-position to the
alcohol proceeded a Rupe rearrangement in this reaction system,
and produced the corresponding enone product (2v) in 85% yield
(Figure 2).
Typical procedure: propargyl alcohols (0.2 mmol), H3PO3 50
wt% aqueous solution (0.3 mmol), CH2Cl2 (0.5 mL) were placed
in 10 mL sealed Schlenk tube under N2 atmosphere, then stirred
at 110 °C for 2 h and monitored by GC or GC-MS or TLC. After
completion of the reaction, the mixture was cooled to room
temperature, washed with saturated Na2CO3 solution, then
extracted three times with CH2Cl2. The combined organic layer
was dried with anhydrous Na2SO4, subjected to filtration, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel and eluted with petroleum
ether/ethyl acetate to afford the pure products.
Figure 2. Phosphorous acid promoted Rupe-rearrangement.
To further extend the practicability of this reaction, the
isomerization of propargyl alcohols 1a was carried out on much
larger scale (10 mmol). The reaction proceeded smoothly in the
two-phase system, and comparable yield (1.028 g, 78%) of the
desired product was observed. It is worth noted that this reaction
is the first report of two-phase Meyer-Schuster rearrangement,
which allowed easy separation of the product by simple
extraction and concentration, demonstrating the synthetic value
of the procedure in organic synthesis (Figure 3).
Acknowledgments
Financial support by the National Natural Science Foundation
of China (Grant Nos. 21706058, 21573065, and 21878072), NSF
of Hunan Province (grant nos. 2018JJ3031 and 2016JJ1007), and
undergraduate Qing Miao program of Hunan university is
gratefully appreciated.
Supplementary data
Supplementary data (general information and experimental
1
procedures, assigned H, 13C NMR spectral data in table form,
1
copies of H, and 13C NMR spectra) associated with this article
can
be
found,
in
the
online
version,
at
Figure 3. Preparation of cinnamaldehyde at 10 mmol scale.
http://dx.doi.org/10.1016/j.tetlet.xxxx.
References and notes
1. (a) Hidalgo, F. J.; Alcόn, E.; Zamora, R. J. Agric. Food Chem.
2014, 62, 12045–12051; (b) Maddukuri, L.; Shuck, S. C.; Eoff, R.
L.; Zhao, L.; Rizzo, C. J.; Guengerich, F. P.; Marnett, L. J.
Biochemistry 2013, 52, 8766–8776; (c) Zhang, Y.; Tortorella, M.
D.; Wang, Y.; Liu, J.; Liu, X.; Bai, Y.; Wen, D.; Lu, Y.; Talley, J.
J. ACS Med. Chem. Lett. 2014, 5, 1162–1166; (d) Starkenmann,
C.; Brauchli, R.; Maurer, B. J. Agric. Food Chem. 2005, 53,
9244–9248; (e) Goretti, M.; Ponzoni, C.; Marchegiani, E.;
Cramarossa, M. R.; Turchetti, B.; Forti, L.; Buzzini, P. Bioresour.
Technol. 2011, 102, 3993–3998.
2. (a) Gould, E.; Lebl, T.; Slawin, A. M.; Reid, M.; Davies, T.;
Smith, A. D. Org. Biomol. Chem. 2013, 11,7877-7892; (b) Zhu,
Y.; Sun, L.; Lu, P.; Wang, Y. ACS Catal. 2014, 4, 1911–1925; (c)
Jin, X.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2014,
Figure 4. Possible reaction mechanism.

Tetrahedron Letters
126, 465–468; (d) Xuan, Y.-N.; Chen, Z.-Y.; Yan, M. Chem.
18.
Commun., 2014, 50, 10471–10473; (e) Franzon, I.; Guénée, L.;
Clément, M. Chem. Sci. 2013, 4, 2619-2624; (f) Zhang, X.; Kang,
J.; Niu, P.; Wu, J.; Yu, W.; Chang, J. J. Org. Chem. 2014, 79,
10170–10178; (g) White, N. A.; Rovis, T. J. Am. Chem. Soc.
2014, 136, 14674–14677; (h) Li, X.; Wang, S.; Li, J.; Li, T.;
Wang, W. Org. Lett. 2013, 15, 5634–5637.
3. (a) McNulty, J.; Velázquez, C. Z.; McLeod, D. Green Chem.
2013, 15, 3146–3149; (b) Chen, H.; Jiang, H.; Cai, C.; Dong, J.;
Fu, W. Org. Lett. 2011, 13, 992–994; (c) Neumann, H.; Sergeev,
A.; Beller, M. Angew. Chem., Int. Ed. 2008, 120, 4965–4969; (d)
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
4. (a) Liu, J.; Zhu, J.; Jiang, H.; Wang, W.; Li, J. Chem. Commun.
2010, 46, 415–417; (b) Yamada, T.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 2005, 70, 5471–5474; (c) Battistuzzi, G.; Cacchi, S.;
Fabrizi, G. Org. Lett. 2003, 5, 777–780.
5. Ager, D. J. Synthesis 1984, 384-398.
6.
(a) Breit, B. Acc. Chem. Res. 2003, 36, 264–275; (b) Neumann,
H.; Sergeev, A.; Beller, M. Angew. Chem., Int. Ed. 2008, 47,
4887–4891.
7. Mackie, P. R.; Foster, C. E. Comprehensive Organic Group
Transformations II, Vol. 3 (Eds.: A. R. Katritzky, R. J. K. Taylor,
S. Jone), Elsevier, Dordrecht, 2004, pp. 59.
8. (a) Ito, Y.; Hirato, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013; (b) Larock, R. C.; Higtower, T. R.; Kraus, G. A.; Hahn, P.;
Zhang, D. Tetrahedron Lett. 1995, 36, 2423–2426; (c) Zhu, J.; Liu,
J.; Ma, R.; Xie, H.; Li, J.; Jiang, H.; Wang, W. Adv. Synth. Catal.
2009, 351, 1229–1232.
9. Tojo, G.; Fernándes, M. In Oxidation of Alcohols to Aldehydes
and Ketones: A Guide to Current Common Practice, ed. G. Tojo,
Springer, Berlin, 2006, pp. 1.
10. (a) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819–821; (b)
Swaminathan, S.; Narayana, K. V. Chem. Rev. 1971, 71, 429–438.
11. Selected examples, see: (a) Engel, D. A.; Dudley, G. B. Org.
Biomol. Chem. 2009, 7, 4149–4158; (b) Cadierno, V.; Garcia-
Garrido, S. E.; Gimeno, J. Adv. Synth. Catal. 2006, 348, 101–110;
(c) Tanaka, K.; Shoji, T. Org. Lett. 2005, 7, 3561–3563; (d) Egi,
M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10,
1867–1870; (e) Álvarez, J. G.; Díez, J.; Vidal, C.; Vicent, C. Inorg.
Chem. 2013, 52, 6533–6542; (f) Cadierno, V.; Crochet, P.;
Garrido, S. E.G.; Gimeno, J. Dalton Trans. 2010, 39, 4015–4031;
(g) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029.
12. Douhaibi, A. S. E.; Judeh, Z. M. A.; Basri, H.; Moussa, Z.;
Messali, M.; Qi, G. Synth. Commun. 2011, 41, 533–540.
13. (a) Zheng, H.; Lejkowski, M.; Hall, D. G. Chem. Sci. 2011, 2,
1305–1310; (b) Park, J.; Yun, J.; Kim, J.; Jang, D.-J.; Park, C. H.;
Lee, K. Synth. Commun. 2014, 44, 1924–1929; (c) Takeshima T. J.
Am. Chem. Soc. 1953, 75, 4107–4108.
14. (a) Li, Z.; Dong, J.; Chen, X.; Li, Q.; Zhou, Y.; Yin, S.-F. J. Org.
Chem. 2015, 80, 9392–9400; (b)Zhou, Y.; Li, Z.; Yang, X.; Chen,
X.; Li, M.; Chen, T.; Yin, S.-F. Synthesis 2016, 48, 231–237.
15. A related patent has been applied, see: Zhou, Y. B.; Liu, L. X.;
Dong, J. Y.; Li, Z. W.; Yin, S.-F.; Han, L.-B. Patent, CN
105130726 A, 2015.
16. (a) Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M.
D. J. Org. Chem. 1977, 42, 3403–3407; (b) Andres, J.; Cardenas,
R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666–674.
Highlights


Metal-free Meyer-Schuster rearrangement
Two-phase system using weak inorganic acid
phosphorous acid as promoter


17.
High yields and excellent stereoselectivity
Scalable synthesis and easy separation
Phosphorous acid promoted isomerization of propargyl
alcohols to α,β-unsaturated carbonyl compounds
Xiaotang Gan, Zuqi Fu, Lixin Liu, Yani Yan, Chao Chen,
Yongbo Zhou, and Jianyu Dong