Acid-catalyzed skeletal rearrangement of epoxy alkynes: A fast access to highly functionalized allenes

Article abstract of DOI:10.1021/ol9014199

The acid-catalyzed reaction of epoxy alkyne involves an epoxide ring-opening attacked by π-alkyne, leading to a semipinacol-type rearrangement. In this process, a type of carbon-carbon 3,3-migration of the alkyne system has been discovered, which is promo

Full text of DOI:10.1021/ol9014199

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3214-3217
Acid-Catalyzed Skeletal Rearrangement
of Epoxy Alkynes: A Fast Access to
Highly Functionalized Allenes
Zhao-Jing Zheng, Xing-Zhong Shu, Ke-Gong Ji, Shu-Chun Zhao, and
Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
Received May 20, 2009
ABSTRACT
The acid-catalyzed reaction of epoxy alkyne involves an epoxide ring-opening attacked by π-alkyne, leading to a semipinacol-type rearrangement.
In this process, a type of carbon-carbon 3,3-migration of the alkyne system has been discovered, which is promoted both by epoxide
inducing and hydroxide promoting. This transformation enables the fast synthesis of allenes in mild conditions.
Epoxides, strained three-membered ring heterocycles, are
among the most versatile intermediates in organic chemistry.1
A number of important advances have been achieved in the
chemistry of epoxides over the last years.2 Actually, the
epoxide-opening reaction is one of the most important
procedures in giving potential intermediates for the synthesis
of oxygen-containing natural products and biologically active
compounds. In particular, epoxides can be subjected to a wide
variety by inducing a hydrogen, alkyl, or aryl group to
migrate between adjacent carbons. This skeletal rearrange-
ment induced by epoxide has been thoroughly studied and
plays a very important role in organic synthesis.3
As is known, nucleophilic substitution opening of the
epoxide ring at a saturated carbon is representative of a
reaction of fundamental importance in organic synthesis
(Scheme 1, a). A wide range of applicable nucleophiles,
Scheme 1. Nucleophiles-Promoted Epoxide Opening Reactions
(1) (a) Asahara, H.; Kubo, E.; Togaya, K.; Koizumi, T.; Mochizuki, E.;
Oshima, T. Org. Lett. 2007, 9, 3421. (b) Hanson, R. M. Chem. ReV. 1991,
91, 437. (c) Blay, G.; Cardona, L.; Collado, A. M.; Garca, B.; Pedro, J. R.
J. Org. Chem. 2006, 71, 4929. (d) Yamamoto, K.; Heathcock, C. H. Org.
Lett. 2000, 2, 1709. (e) Nakatani, M.; Nakamura, M.; Suzuki, A.; Inoue,
M.; Katoh, T. Org. Lett. 2002, 4, 4483.
involving group participation by heteroatoms and aryl groups,
has been well-established for epoxide ring-opening.4 Alkyne
is also a reasonable nucleophile. However, addition products
are formed exclusively when terminal alkynes are previously
activated (Scheme 1, b),5 or the epoxides will attack the
(2) (a) Crandall, J. K.; Apparu, M. Org. React. (N.Y.) 1983, 29, 345.
(b) Doris, E.; Dechoux, L.; Mioskowski, C. Synlett 1998, 337. (c) Hodgson,
D. M.; Gras, E. Synthesis 2002, 1625. (d) Hodgson, D. M.; Gras, E. In
Topics in Organometallic Chemistry; Springer: Berlin, Germany, 2003; p
217. (e) Hodgson, D. M.; Bray, C. D. In Aziridine and Epoxides in Organic
Synthesis; Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, Germany,
2006; Chapter 5, p 145.
(3) (a) Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed. 2006,
45, 1429. (b) Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212. (c) Chang,
C.-L.; Kumar, M. P.; Liu, R.-S. J. Org. Chem. 2004, 69, 2793.
(4) (a) Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10, 4383. (b)
Bournaud, C.; Bonin, M.; Micouin, L. Org. Lett. 2006, 8, 3041. (c) Asahara,
H.; Kubo, E.; Togaya, K.; Koizumi, T.; Mochizuki, E.; Oshima, T. Org.
Lett. 2007, 9, 3421.
10.1021/ol9014199 CCC: $40.75
Published on Web 07/08/2009
 2009 American Chemical Society

alkynes.6 This limitation greatly restricts the application of
epoxy alkyne, which is an important substance and also an
interesting topic in organic synthesis.7 In continuation of our
interest in the development of new methodologies for
R-hydroxy epoxide ring-opening,8 we found the first member
of this family that deviates from this requirement, wherein
the π-system of one molecule (alkyne) combines with a
functional group and has no multiple bonds (epoxide),
affording synthetically useful allenes (Scheme 2).9,10 To the
Table 1. Optimization of Reaction Conditionsa
entry catalyst (mol %) solvent temp, °C time, min yield,b
%
1
2
3
4
5
6
7
8
TsOH (5)
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
-78
20
20
10
10
15
15
15
10
10
10
30
60
79
76
77
87
77
81
83
73
71
67
67
66
CF3CO2H (5)
CH3SO3H (5)
TsOH (10)
TsOH (10)
TsOH (10)
TsOH (10)
AlCl3 (5)
FeCl3 (5)
AuCl3 (5)
BF3·OEt2 (5)
TiCl4 (5)
Scheme 2
9
10
11
12
a Reactions were conducted with 0.3 mmol of 1a, in 2 mL of solvent.
b Isolated yield.
best of our knowledge, there are only a few successful
examples of this system.11 Herein, we report a novel catalytic
method for synthesis of allenes via acid-catalyzed skeletal
rearrangement of epoxy alkynes. The π-system of the alkyne
attacking at the epoxide ring acted as the key step.
Initially, we started our investigation by using epoxy
alkyne 1a (0.3 mmol), treated with TsOH (5 mol %) in
CH3CN (2 mL) at room temperature. To our delight, the
expected allene 2a (Figure 1)12 was obtained in 79% yield
(entries 2 and 3). When the amount of TsOH was increased
to 10 mol %, a satisfying yield of 87% was obtained in 10
min (entry 4). However, when a change was made to other
solvents for this reaction, no superior results were obtained
(entries 5-7). Lewis acids, such as AlCl3, AuCl3, FeCl3,
BF3·OEt2, and TiCl4, were also investigated, and we were
pleased to find that similar results were obtained with lower
catalyst loading (entries 8-12). Thus the use of TsOH (10
mol %) in CH3CN (conditions A) and AlCl3 (5 mol %) in
CH2Cl2 (conditions B) at room temperature were both used
as the standard conditions.
With the optimal conditions in hand, we investigated more
examples. The results are summarized in Table 2. In
conditions A, the analogous substrates 1b and 1c were
prepared and also successfully converted to the corresponding
products 2b and 2c in 51% and 89% yields, respectively
(entries 2 and 3). Successively, the more complex cyclic
substrates 1e-g demonstrated the efficiency of this rear-
rangement and gave the synthetically valuable allenes 2e-g
in 66-92% yields (entries 5-7). Experiments with acyclic
substrates 1h-n14 were also examined, and the correspond-
ing products 2h-n were obtained in 41-65% yields (entries
Figure 1. The X-ray structure of 2a.
in 20 min (Table 1, entry 1). Then the catalysis conditions
were optimized by changing the catalysts and solvents, as
shown in Table 1.13 Protic acids, including CF3CO2H and
CH3SO3H, also catalyzed this reaction, and the desired
product 2a was obtained in 76% and 77% yields, respectively
(9) (a) Trost, B. M.; Pinkerton, A. B.; Seidel, M. J. Am. Chem. Soc.
2001, 123, 12466. (b) Baner, K. Liebigs Ann. l997, 2005.
(10) (a) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M.,
Eds.; John Wiley & Sons: New York, 1984. (b) The Chemistry of Ketenes,
Allenes, and Related Compounds, Part 1; Patai, S., Ed.; John Wiley & Sons:
New York, 1980. (c) Modern Allene Chemistry; Krause, N., Hashmi,
A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(5) (a) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126,
2495. (b) Kim, K.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 67.
(6) (a) Lin, M.-Y.; Maddirala, S. J.; Liu, R.-S. Org. Lett. 2005, 7, 1745.
(b) Lin, G.-Y.; Li, C.-W.; Hung, S.-H.; Liu, R.-S. Org. Lett. 2008, 10, 5059.
(c) Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.; Liu, X.-G.; Shi, M. Org. Lett. 2007, 9,
3191.
(11) Madhushaw, R. J.; Li, C.-L.; Shen, K.-H.; Hu, C.-C.; Liu, R.-S.
J. Am. Chem. Soc. 2001, 123, 7427.
(12) The molecular structure of the corresponding product 2a was
determined by X-ray crystallography (Figure 1). Crystallographic data have
been described in the Supporting Information.
(7) Arcadi, A. Chem. ReV. 2008, 108, 3266.
(13) For detailed optimization of reaction conditions, see the Supporting
Information.
(14) Syn/anti mixtures of the substrates were used and the ratio was
determined by 1H NMR spectroscopic analysis. For a full explanation and
definition of the terms syn and anti as used herein see: Marson, C. M.;
Benzies, D. W. M.; Hobson, A. D. Tetrahedron 1991, 47, 5491.
(8) (a) Shu, X.-Z.; Liu, X.-Y.; Ji, K.-G.; Xiao, H.-Q.; Liang, Y.-M.
Chem.sEur. J. 2008, 14, 5282. (b) Ji, K.-G.; Shen, Y.-W.; Shu, X.-Z.;
Xiao, H.-Q.; Bian, Y.-J.; Liang, Y.-M. AdV. Synth. Catal. 2008, 350, 1275.
(c) Ji, K.-G.; Shu, X.-Z.; Chen, J.; Zhao, S.-C.; Zheng, Z.-J.; Liu, X.-Y.;
Liang, Y.-M. Org. Biomol. Chem. 2009, 7, 2501.
Org. Lett., Vol. 11, No. 15, 2009
3215

Table 2. Transformation of Epoxy Alkynes to Allenes
a
Syn/anti mixtures of the substrates were used and the ratio was determined by H NMR spectroscopic analysis. b Reactions were conducted with 0.3
mmol of 1, 10 mol % of TsOH in 2 mL of CH3CN at room temperature. c Reactions were conducted with 0.3 mmol of 1, 5 mol % of AlCl3 in 2 mL of
CH2Cl2 at room temperature. d Isolated yield.
1
8-14). This transformation followed the same rules under
conditions B; however, lower yields were always obtained
(entries 1-7).
Substrates 1o and 1p with aliphatic R1 and R2 groups
afforded no allene product (entries 15 and 16).
An epoxy alkyne with a five-membered ring was inves-
tigated under conditions A. However, no desired product was
obtained. When Lewis acid was induced, a mixture (10:7)
of 2r and 3r was isolated in 60% yield under conditions B
(Scheme 3).15 The reason for the formation of 3r was that
the chloride ion attacked epoxide leading to the epoxide ring-
opening instead of alkyne. Epoxy alkyne 1s also afforded
the same result (Scheme 3). The same phenomenon was not
observed by TLC with other substrates, and it might be
caused by the ring strain.
As seen, various aryl groups R2 on the epoxy ring were
tolerated (entries 1-3). An electron-withdrawing aryl group
gave a better result relative to the electron-rich substituent
(entries 2 vs. 3 and 6 vs. 7). This might be explained by
assuming that an electron-withdrawing group increased the
electrophilicity of the intermediate oxonium ions (Scheme
5, C and D), thus making the alkyne attack a favored process.
Substitution on the ring was also tolerated (entry 4). Better
results were always obtained when conjugated systems were
applied (entries 5-7), whereas acyclic substrates always
afforded lower yields of desired products (entries 8-14);
this might be due to steric configuration, and syn-diastere-
oisomer favored allene formation (Scheme 5, E vs. F).
(15) The structure of 3r was confirmed by X-ray crystallographic
analyses, the X-ray structure of 3r and crystallographic data are described
1
in the Supporting Information. 2r was confirmed by analysis of H NMR
spectroscopy of the mixture and 3r. The proportion of 2r and 3r was
1
confirmed by analysis of H NMR spectroscopy.
3216
Org. Lett., Vol. 11, No. 15, 2009

Scheme 3
.
Reactions of 1r and 1s
Scheme 5. Proposed Mechanism
mation was observed based on results in Table 1 and Scheme
4. This observation was also reasoned in Scheme 5. For
intermediate F from the anti-isomer, due to configurational
orientation of the alkyne away from the epoxide, its attacking
on the carbon of the epoxide ring is hindered, whereas this
attacking process is favored for intermediate E (Scheme 5,
E vs. F).
To uncover the stereoselectivity of this transformation, we
investigated the reaction of syn-isomer 1h-1 and anti-isomer
1h-2 under conditions A, respectively (Scheme 4). Only one
Scheme 4
In conclusion, we developed a new acid-promoted epoxide
ring-opening with an alkynyl group. In this reaction, π-alkyne
rearranged allene through a carbon-carbon 3,3-migration
acted as a nucleophilic reagent. Therefore, a convenient and
efficient method for constructing varieties of ready terminal
allenes was achieved. We envisioned that this keto-hydroxyl-
allene product could be applied to the synthesis of some
natural products when proper substrates and catalysts were
used.16 Further investigations on this acid-catalyzed skeletal
rearrangement and the application of these keto-hydroxyl-
allene products are ongoing.
relative configuration allene product 2h was obtained deter-
mined by NMR. The syn-diastereoisomer 1h-1 afforded a
better yield (77%) compared to the anti-diastereoisomer 1h-2
(31%). These experimental results were consistent with our
proposed mechanism.
Acknowledgment. We thank the NSF (NSF-20621091,
NSF-20732002) for financial support.
With the above experimental results in hand, a possible
sequential mechanism of this rearrangement reaction is
proposed, as depicted in Scheme 5. Activated by protic acid
or Lewis acid, the five-membered-ring intermediates C and
D might be formed. Under the dual role of promoting by
hydroxy group and inducing of the activated epoxide ring, a
carbon-carbon 3,3-migration leads to the formation of final
keto-hydroxyl-allene product 2. Although the two isomers
gave the same product, the stereoselectivity of this transfor-
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds, and
CIF files for 2a and 3r. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL9014199
(16) (a) Ma, S.-M. Chem. ReV. 2005, 105, 2829. (b) Smith, N. D.;
Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100, 3257. (c) Widenhoefer,
R. S. Chem.sEur. J. 2008, 14., 5382.
Org. Lett., Vol. 11, No. 15, 2009
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