Oxidative rearrangement of tertiary propargylic alcohols

Article abstract of DOI:10.1055/s-0032-1317711

An oxidative rearrangement of tertiary alcohols mediated by m-CPBA is described that generates tetrasubstituted alkenes with a carboxylic acid substituent. The mechanism of the reaction is proposed to proceed through epoxidation of the alkyne to form an o

Full text of DOI:10.1055/s-0032-1317711

102▌
LETTER
letter
Oxidative Rearrangement of Tertiary Propargylic Alcohols
Rearrangement of Tertiary Propargylic Alcohols
Arantxa Rodríguez,* Wesley J. Moran*
Department of Chemical & Biological Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK
Fax +44(1484)472182; E-mail: a.r.menendez@hud.ac.uk; E-mail: w.j.moran@hud.ac.uk
Received: 09.10.2012; Accepted after revision: 07.11.2012
O
O
O
O
O
Abstract: An oxidative rearrangement of tertiary alcohols mediat-
ed by m-CPBA is described that generates tetrasubstituted alkenes
with a carboxylic acid substituent. The mechanism of the reaction is
proposed to proceed through epoxidation of the alkyne to form an
oxirene that undergoes a 1,2-aryl shift.
Ph
Ph
O
Ph
Ph
5.8%
Ph
19.2%
HO
O
O
Key words: oxidation, rearrangement, propargylic alcohols, car-
boxylic acids, peroxy acid
m-CPBA
Ph
OH
Ph
Ph
Ph
Ph
CCl4
17.1%
6.4%
O
Ph
O
The oxidation of acetylenes with peroxy acids is capri-
cious and can lead to the formation of a variety of products
resulting from either oxidation, rearrangement, or addi-
tion depending on the reaction conditions used. In addi-
tion, only low yields of products have been reported in the
scant number of examples on this topic. McDonald and
Schwab reported that phenylacetylene was oxidised to
five different compounds by perbenzoic acid: ethyl phen-
ylacetate, methyl phenylacetate, benzaldehyde, benzoic
acid, and methyl benzoate (Scheme 1).1 The overall yield
reported was greater than 100%, as the benzoic acid could
also have come from reduction of the perbenzoic acid.
Cl
Ph
O
O
10.7%
Scheme 2 Stille and Whitehurst’s oxidation reaction
have found widespread use in organic synthesis.4 In par-
ticular, the rearrangement of these compounds has gar-
nered significant attention.5,6 During these studies we
discovered a hypoiodite-induced rearrangement to α-io-
doenones (Scheme 3)7 as well as the reaction detailed
herein.
OEt
OMe
Ph
Ph
+
O
O
O
R
m-CPBA (3 equiv)
PhCO3H
I
8.1%
42.5%
Cl3CCO2H (1.5 equiv)
Ph
R
HO
CHCl3
2 d
O
O
NaI (1 equiv)
MeCN, r.t.
+
+
Ph
11.1%
O
Ph
OH
Ph
OMe
3.0%
n
n
43.5%
1
61–85%
n = 1, 2, 3, 4
Scheme 1 McDonald and Schwab’s oxidation reaction
Scheme 3 Our group’s hypoiodite-initiated rearrangement reaction
Stille and Whitehurst reported the oxidation of diphenyl-
acetylene by perbenzoic acid and m-CBPA and obtained a
mixture of products in both cases including benzil and
benzoic peroxyanhydride with ratios which were found to
be solvent dependent (Scheme 2).2 The mechanism for the
formation of these products was proposed to proceed
through epoxidation of the alkyne followed by either ring
opening or rearrangement to the ketene and subsequent
addition or elimination processes.3
With the aim of extending our work utilising in situ gen-
erated iodine(III) species, we aimed to effect an oxidative
rearrangement of propargyl alcohols 1 into diketones 2
through a semipinacol-type process. Accordingly, 1a was
treated with 20 mol% of iodobenzene, 1.5 equivalents of
m-CPBA, and 1.5 equivalents of 4-toluenesulfonic acid
monohydrate in acetonitrile at room temperature (Table
1).8 However, instead of the anticipated oxidative rear-
rangement, elimination of water occurred to generate
enyne 4 (Table 1, entry 1). Replacement of the strong acid
with acetic acid led to no conversion whatsoever (Table 1,
entry 2). However, treatment with trifluoroacetic acid also
led to formation of enyne 4 (Table 1, entry 3). At this
point, it was decided that an acid with a pKa in between
that of trifluoroacetic acid and acetic acid was necessary.
Accordingly, trichloroacetic acid was tested, and a new
product was formed (Table 1, entry 4). Analysis suggested
As part of a wider programme concerned with the reactiv-
ity of polyvalent iodine species, we became interested in
the rearrangement of tertiary propargyl alcohols. Tertiary
propargyl alcohols are useful synthetic intermediates that
SYNLETT 2013, 24, 0102–0104
Advanced online publication: 04.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317711; Art ID: ST-2012-D0870-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Rearrangement of Tertiary Propargylic Alcohols
103
that this was not the anticipated product 2a but that an al-
ternative oxidative rearrangement had taken place to gen-
erate the enoic acid 3a. This rearrangement is completely
unprecedented for this substrate and involves a 1,2-aryl
migration instead of the anticipated 1,2-alkyl migration.
Only a low yield of 3a was obtained, however the remain-
der of the mass balance was unreacted starting material.
Attempts to improve the conversion, and hence the yield
of the product, were unsuccessful. Using either 2- or 4-io-
doanisole as the catalyst led to complete reaction inhibi-
O
Ar
Ar
m-CPBA (1.5 equiv)
HO
HO
Cl3CCO2H (1.5 equiv)
MeCN, r.t.
n
n
1
n = 1, 2
3
R1
R2
3a R1 = R2 = H, 20%
O
3b R1 = Me, R2 = H, 42%
3c R1 = Et, R2 = H, 32%
3d R1 = t-Bu, R2 = H, 40%
3e R1 = OMe, R2 = H, <5%
3f R1 = H, R2 = F, <5%
HO
tion (Table 1, entries
5
and 6), whereas 2-
iodonitrobenzene led to complete conversion into enyne 4
(Table 1, entry 7). During these studies it became evident
that iodobenzene was not required and that the reaction
was mediated by m-CPBA and not a hypervalent iodine
species (Table 1, entry 8). Changing the solvent from ace-
tonitrile to dichloromethane, TFE, or nitromethane af-
forded the dehydrated product 4 whilst methanol gave a
mixture of unidentifiable compounds. Using Oxone® in-
stead of m-CPBA led to complete conversion into enyne
4. Epoxidation of enyne 4 was not observed in any reac-
tions.
O
HO
3g m = 1, 37%
3h m = 2, 0%
m
Scheme 4 Scope of the rearrangement reaction
The rearrangement of a few derivatives with these condi-
tions was investigated in turn (Scheme 4).9 With a 4-meth-
yl substituent, substrate 1b rearranged to provide 42%
yield of isolated product 3b. With a 4-ethyl group, 32%
yield of 3c was obtained and with a 4-tert-butyl group
40% yield of 3d was obtained. Substrates 1e and 1f con-
taining more strongly electron-donating and electron-
withdrawing aromatic substituents, respectively, where
synthesised and submitted to the same reaction conditions
but no desired products could be isolated. The rearrange-
ment of the cyclohexyl substrate 1g proceeded with mod-
erate efficiency furnishing 37% of the acid 3g. However,
cycloheptyl substrate 1h failed to rearrange, and a mixture
of unidentified products was obtained.
The structure of the products was determined with the aid
of NOESY and HMBC NMR experiments (Figure 1). The
NOESY spectrum showed an interaction between the
arene CH and a CH2 in the aliphatic ring. The HMBC
showed interactions between the alkene C and all four of
the CH2 groups in the ring. Subsequently, the methyl ester
of compound 3a was synthesised and the analytical data
matched those in the literature.10
Methyl ether 5 was prepared and subjected to the reaction
conditions, however, no reaction took place (Scheme 5),11
Table 1 Optimization of the Reaction Conditions
Ph
O
Ph
catalyst (20 mol%)
m-CPBA (1.5 equiv)
O
O
Ph
HO
HO
Ph
acid (1.5 equiv)
MeCN, r.t.
1a
2a
3a
4
Entry
Acid
Catalyst
Yield (%)a
1
2
3
4
5
6
7
8
p-toluenesulfonic acid monohydrate
acetic acid
iodobenzene
iodobenzene
iodobenzene
iodobenzene
2-iodoanisole
4-iodoanisole
2-iodonitrobenzene
–
4 83
0
trifluoroacetic acid
trichloroacetic acid
trichloroacetic acid
trichloroacetic acid
trichloroacetic acid
trichloroacetic acid
4 80
3a 20
0
0
4 78
3a 20
a Yield of isolated product.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 102–104

104
A. Rodríguez, W. J. Moran
LETTER
Acknowledgment
O
O
We thank the University of Huddersfield for funding.
HO
HO
Supporting Information for this article is available online at
NOESY
interaction
HMBC
interactions
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Figure 1 Structure determination by NMR experiments
References and Notes
(1) McDonald, R. N.; Schwab, P. A. J. Am. Chem. Soc. 1964,
86, 4866.
(2) Stille, J. K.; Whitehurst, D. D. J. Am. Chem. Soc. 1964, 86,
4871.
O
Ph
Ph
m-CPBA (1.5 equiv)
HO
MeO
(3) (a) Ortiz de Montellano, P. R.; Kunze, K. L. J. Am. Chem.
Soc. 1980, 102, 7373. (b) Crandall, J. K.; Conover, W. W. II.
J. Org. Chem. 1978, 43, 1323. (c) Csizmadia, I. G.; Font, J.;
Strausz, O. P. J. Am. Chem. Soc. 1968, 90, 7360.
(4) For a review, see: Bauer, E. B. Synthesis 2012, 44, 1131.
(5) For example, see: (a) Angara, G. J.; Bovonsombat, P.;
McNelis, E. Tetrahedron Lett. 1992, 33, 2285.
(b) Bovonsombat, P.; McNelis, E. Tetrahedron 1993, 49,
1525. (c) Chen, J.-M.; Huang, X. Synthesis 2004, 2459.
(d) Bovonsombat, P.; McNelis, E. Synth. Commun. 1995,
25, 1223. (e) Djuardi, E.; Bovonsombat, P.; McNelis, E.
Tetrahedron 1994, 50, 11793. (f) Bovonsombat, P.;
McNelis, E. Tetrahedron Lett. 1993, 34, 4277.
(g) Bovonsombat, P.; McNelis, E. Tetrahedron Lett. 1993,
34, 8205.
Cl3CCO2H (1.5 equiv)
MeCN, r.t.
5
3a
Scheme 5 Mechanistic investigation
thus demonstrating that the presence of the hydroxyl
group is crucial for the reaction to occur. Presumably, the
hydroxyl group preorganises and directs the epoxidation
of the alkyne through a hydrogen-bonding interaction.12
The mechanism of this rearrangement is proposed to pro-
ceed through hydroxyl-directed epoxidation of the alkyne
to form an oxirene that undergoes a 1,2-aryl shift to form
a ketene intermediate (Scheme 6). Addition of water fol-
lowed by elimination of water generates the final product.
An acid is required for the reaction to occur, however, a
fine balance exists between formation of products 3 and 4.
(6) For a review of the Meyer–Schuster rearrangement, see:
Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7,
4149.
(7) Moran, W. J.; Rodríguez, A. Org. Biomol. Chem. 2012, 10,
8590.
(8) Rodríguez, A.; Moran, W. J. Org. Lett. 2011, 13, 2220.
(9) Typical Experimental Procedure
C6H4-3-Cl
1-[(4-tert-Butylphenyl)ethynyl]cyclopentanol (1a, 50 mg,
0.21 mmol), m-CPBA (54 mg, 0.31 mmol), and
trichloroacetic acid (51 mg, 0.31 mmol) were dissolved in
MeCN (1 mL) at r.t. under a nitrogen atmosphere. The
mixture was stirred overnight until solid precipitation was
evident (typically less than 15 h). The reaction mixture was
quenched with sat. aq Na2S2O3 solution and extracted with
CH2Cl2. The organic layer was washed with sat. aq NaHCO3
solution, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (silica gel; 20:1 PE–EtOAc) to afford 2-(4-
tert-butylphenyl)-2-cyclopentylideneacetic acid (3a) as a
pale yellow solid (22 mg, 40%); mp 193–195 °C. IR (neat):
1252 (s), 1284 (s), 1618 (m), 1674 (s), 2955 (w) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.32 (9 H, s), 1.58 (2 H, quin,
J = 6.8 Hz), 1.76 (2 H, quin, J = 6.9 Hz), 2.23 (2 H, t, J = 7.2
Hz), 2.89 (2 H, t, J = 7.3 Hz), 7.10 (2 H, d, J = 8.4 Hz), 7.35
(2 H, d, J = 8.4 Hz), 11.35 (1 H, br). 13C NMR (100 MHz,
CDCl3): δ = 26.1, 27.1, 31.7 (3 C), 34.8, 34.9, 36.5, 125.1,
125.4 (2 C), 129.2 (2 C), 135.9, 149.9, 168.1, 173.0. MS: m/z
= 281.2 [M + 23]. HRMS: m/z calcd for C17H22NaO2:
281.1512; found: 281.1518.
Ar
m-CPBA
O
O
O
H
HO
HO
O
O
H
Ar
Ar
1
O
Ar
1,2-aryl
migration
O
HO
HO
HO
O
Ar
Ar
H+
O
Ar
OH2
Ar
H2O
HO
O
3
Scheme 6 Postulated rearrangement mechanism
(10) Martín-Vaca, B.; Rudler, H. J. Chem. Soc., Perkin Trans. 1
1997, 3119.
In conclusion, an unprecedented oxidative rearrangement
of tertiary propargylic alcohols to enoic acids is presented.
This process converts readily accessible compounds into
tetrasubstituted alkenes with a carboxylic acid substituent.
The reaction likely proceeds through a hydrogen-bond di-
rected alkyne epoxidation followed by a 1,2-aryl migra-
tion.
(11) Zhang, H.; Fu, X.; Chen, J.; Wang, E.; Liu, Y.; Li, Y. J. Org.
Chem. 2009, 74, 9351.
(12) For a review, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. Rev. 1993, 93, 1307.
Synlett 2013, 24, 102–104
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