Stereoselective preparation of conjugated (Z)-1,3-enynes by dehydration reactions of allenic bromohydrins and the use of the enynes in base-mediated tandem allylation ene-carbocyclization reactions with β-ketoesters

Article abstract of DOI:10.1039/c6ob02178f

A procedure has been developed for the concise, stereoselective synthesis of (Z)-5-bromo-4-aryl-pent-3-en-1-ynes through Sc(OTf)₃ catalyzed dehydration reactions of allenic bromohydrins. (Z)-1,3-Enynes are transformed to methylenecyclopentenes when subjected to a sequential, one-pot process involving base mediated allylation reactions with ethyl acetoacetate followed by ene-carbocyclization reactions. An unprecedented rearrangement reaction involving 1,5-acyl migration takes place when the methylenecyclopentenes are treated with acid to form highly substituted cyclopentadienes.

Full text of DOI:10.1039/c6ob02178f

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Stereoselective Preparation of Conjugated (Z)-1,3-Enynes by Dehydration Reactions of
Allenic Bromohydrins and the Use of the Enynes in Base-Mediated Tandem Allylation
Ene-Carbocyclization Reactions with β-Ketoesters
Mei-Huey Lin,* Yu-Chun Chen, Shih-Hao Chiu, Kung-Yu Liang, Yi-Lin Lee and
Tsung-Hsun Chuang
Department of Chemistry, National Changhua University of Education, Changhua, Taiwan
50007
mhlin@cc.ncue.edu.tw
Abstract: A procedure has been developed for the concise, stereoselective synthesis of
(Z)-5-bromo-4-aryl-pent-3-en-1-ynes through Sc(OTf)3 catalyzed dehydration reactions of
allenic bromohydrins. The (Z)-1,3-enynes are transformed to methylenecyclopentenes when
subjected to a sequential, one-pot process involving base mediated allylation reactions with
ethyl acetoacetate followed by ene-carbocyclization reactions. An unprecedented
rearrangement reaction involving 1,5-acyl migration takes place when the
methylenecyclopentenes are treated with acid to form highly substituted cyclopentadienes.
Introduction
Conjugated enynes are valuable building blocks in synthetic organic1 and medicinal2
chemistry, and in the materials science.3 These conjugated systems are also widely found in
natural product frameworks.4 The conventional method employed to prepare 1,3-enynes (e. g.,
1a) utilizes Sonogashira cross-coupling reactions between stereo-defined alkenyl iodides and
trimethylsilylacetylenes. This approach typically requires a multi-step sequence starting with

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propargylic alcohols (a, Scheme 1).5 An alternative method for stereoselective synthesis of
conjugated enynes 2 starts with allenols 3 and involves initial conversion of the hydroxyl into
a leaving group followed by base induced elimination (b, Scheme 1).6 Although Lewis acid
promoted dehydration of allenols is reported to generate conjugated enynes (c, Scheme 1),7
the process suffers from several drawbacks. Firstly, considerable amounts of enones 4 are
formed as byproducts through Lewis acid promoted rearrangements. Secondly, stoichiometric
amounts of Lewis acids such as indium triflate and boron trifluoride etherate are required for
this reaction. Finally, a rather high loading (20 mol%) of trimethylsilyl triflate is also needed
for conjugated enyne formation.
Scheme 1.
In recent studies, we developed a new method for the preparation of allenic
bromohydrins 5.8 We envisioned that Lewis acid catalyzed reactions of these substances
could serve as a useful process to generate 1,3-enynes 1 (Scheme 2). In addition, we
recognized that C-C bond formation by addition of active methylene compounds to alkynes is
an important process in organic synthesis9 and that recent advances have been made in
developing intramolecular ene-reactions of β-ketoesters and alkynes (d, Scheme 1).10

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Consequently, we believed that 1,3-enynes 1, which containing allylic bromide moieties and
have (Z)-stereochemistry at the ene center, might be excellent substrates for one-pot,
sequential base mediated allylation reactions with β-ketoesters and ene-carbocyclization
reactions to produce methylenecyclopentenes 6 (Scheme 2). In the studies pursuing these
proposals, we developed
a
procedure for concise, stereoselective synthesis of
(Z)-5-bromo-4-aryl-pent-3-en-1-ynes by using Sc(OTf)3-catalyzed dehydration reactions of
allenic bromohydrins. In addition, we demonstrated that the (Z)-1,3-enynes, formed in this
manner, are transformed to methylenecyclopentenes. Moreover, we observed that an
unprecedented rearrangement reaction involving 1,5-acyl migration takes place to form
highly substituted cyclopentadienes when the methylenecyclopentenes are treated with acid.
Scheme 2.
Results and Discussion
Our initial studies of the enyne forming process proposed above focused on an
exploration the dehydration reaction of bromohydrin 5a promoted by triflic acid. We
observed that enyne 1a is generated in this process along with significant amounts of enone
1a’, which can be easily separated by using chromatography (Table 1, entry 1). Next, we
probed the use of metal triflates such as scandium triflate and bismuth triflate to promote the

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Lewis acid mediated dehydration reaction of 5a. As can be seen by viewing the results in
Table 1 (entries 2-4), reactions using a water tolerant and highly active Lewis acid catalyst
scandium triflate gave high yields of enyne 1a. It is noteworthy that enyne 1a generated in
the bismuth triflate catalyzed dehydration reaction contains an inseparable impurity (Table 1,
entry 4). The results of further studies showed that optimal conditions for the dehydration
reaction involve the use of 0.5 mol% of scandium triflate and that enyne 1a gradually
decomposes at room temperature but it is relatively stable when stored below 0 oC.
Table 1. Lewis Acid-Catalyzed Dehydration Reaction of Allenic Bromohydrin 5a Giving
1,3-Enyne 1aa
b
aConditions: 5a (0.4 mmol), Lewis acid (as indicated), solvent (2.5 mL). Ratio was
determined by using 1H NMR.
With optimal conditions in hand, Sc(OTf)3 promoted reactions of a variety of
aryl-substituted allenic bromohydrins 5 were explored (Table 2). The starting bromohydrins
5 were prepared by using the known indium mediated allenylation reactions of arylacyl
bromides with propargyl bromide.8a Allenic bromohydrins 5a and 5g, obtained by using the
previously described chromatographic procedure,8a were observed to undergo Sc(OTf)3
mediated dehydration reactions to give the respective enynes 1a and 1g in high yields (Table

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2, entries 2 and 10). Alternatively, the crude bromohydrins 5 generated in the indium
mediated allenylation reactions can be directly subjected to the Sc(OTf)3 promoted
dehydration. The results (Table 2, entries 3-5, 9 and 11) show that enynes 1 are produced in
modest yields even when purification of the intermediate allenic bromohydrins 5 is not
performed. However, reaction of pure allenic bromohydrin 5e is an exception in that its
Sc(OTf)3 mediated dehydration reaction, even when conducted using at low catalyst loading,
leads to a significant amount of enone 1’ (Table 2, entry 6 vs 1; entry 7 vs 9 and 10). Finally,
Sc(OTf)3-mediated dehydration reactions of 5 not only occur with high levels of
regioselectivity but they also form Z-stereoisomers selectively, as is demonstrated by using
X-ray crystallographic analysis of 1b.11
Table 2. Sc(OTf)3 Catalyzed Conjugated 1,3-Enyne 1 Formationa
OH
Br
Br
Ar
Br
Ar
O
In
Sc(OTf)3
Ar
+
O
+
Br
Br
Ar
5
1
1'
5
Sc(OTf)3
1, yield (%)a; Time; (5:1:1')b
Ar
entry
yield (%)
(mol%)
2
1a, 63; 1 h; (0:80:20)
1a, 84; 1 h; (0:92:8)
1
2
5a, 62
0.5
0.5
5a, 62
1b, 60c; 2 h
Br
3
4
5
--
--
--
Cl
1c, 51c; 3 h
0.5
0.5
Me
1d, 50c; 15 min
2
1e, 22; 1 h; (0:33:67)
5e, 60
6
7
8
0.5
0.1
1e, 48; 5 min; (0:56:44)
MeO
5e
, 60
1e, 46; 10 min; (0:59:41)
5e, 60
MeO
1f, 42c; 1 h
0.5
9
--
OMe
0.5
0.5
1g, 88; 1 h; (0:98:2)
1h, 41c; 0.5 h
5g, 66
10
11
--
aConditions: 5a (0.4 mmol), Sc(OTf)3 (as indicated), ClCH2CH2Cl (2.5 mL), reflux.

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bRatio was determined by using 1H NMR. cTwo-step overall yield.
Tandem, methylenecyclopentene forming, allylation and ene-carbocyclization reactions
of ethyl acetoacetate with (Z)-1,3-enynes were examined using 1b. Among the various bases
explored to promote this process (Table 3), potassium carbonate, cesium carbonate and
tripotassium phosphate induce formation of the target methylenecyclopentene 6b in moderate
to high yields. However, 6b was found to contain a small amount of an impurity, which
defied removal even by using meticulous chromatography (Table 3, entries 1-9). Among
these bases, potassium carbonate mediates reaction of 1b in DMF at ambient temperature
(Table 3, entry 6 versus 1, 7 and 8). The results of an exploration of the effects of additives
demonstrated that the presence of silver carbonate but not potassium iodide significantly
enhances the yield of the tandem reaction (Table 3, entries 9 and 10).
The scope of the base promoted tandem allylation and ene-carbocyclization reaction of
ethyl acetoacetate with aryl-substituted-1,3-enynes 1 was evaluated. As can be seen by
viewing the results in Scheme 3, silver carbonate assisted reaction takes place quickly (0.5 h)
and efficiently at ambient temperature. In addition, other active methylene compounds,
including ethyl benzoylacetate, ethyl cyanoacetate, allyl acetoacetate, dimethyl malonate and
isopropylidene malonate, also participate in this process (Scheme 4). Note that formation of
7a by potassium carbonate promoted reaction of 1b with ethyl benzoylacetate was performed
o
at elevated temperature (75 C) because only the allylation intermediate is generated at room
temperature. In addition, the formation of 7b indicates that other active methylene
compounds in addition to 1,3-dicarbonyl compounds serve as suitable substrates for the

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base-mediated tandem allylation ene-carbocyclization.
Table 3. Base Promoted Tandem Allylation Ene-Carbocyclization Reactions of Ethyl
Acetoacetate with 1,3-Enyne 1ba
O
O
Br
O
O
base
OEt
+
4-BrC6H4
OEt
solvent
4-BrC6H4
1b
6b
6b
entry
solvent, Temp, Time
base/ additive
yield (%)
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K3PO4
CH3CN, rt, 20 h
CH3CN, rt, 0.5 h
1
2
3
4
5
77
61
13
46
67
CH3CN, 87 oC, 0.5 h
CH3CN, 87 oC, 0.5 h
CH3CN, 87 oC, 0.5 h
K2CO3
6
DMF, rt, 0.5 h
DMF, rt, 0.5 h
DMF, rt, 0.5 h
DMF, rt, 0.5 h
DMF, rt, 0.5 h
69
51
54
69
90
Cs2CO3
7
K3PO4
8
K2CO3/KIb
K2CO3/Ag2CO3
9
c
10
Ag2CO3
Ag2CO3
11
12
DMF, rt, 0.5 h
0
5
DMF, 87 oC, 0.5 h
aConditions: 1b (0.63 mmol), ethyl acetoacetate (0.6 mmol) and indicated base (1.74
mmol) in solvent (0.6 mL). bKI (0.66 mmol). cAg2CO3 (0.12 mmol).
Scheme 3. Scope of Enynes in Tandem Allylation Ene-Carbocyclization Reactionsa
Br
a) cat. Ag2CO3
EtO
O
O
O
EtO
K2CO3, DMF
Ar
1
Ac
or
b) K2CO3, DMF
OEt
+
O
O
Ar
Ar
6
O
O
O
O
O
O
OEt
OEt
OEt
Br
Cl
6a, 87%a, (70 %)b
6b, 90%a, (69 %)b
6c, 83%a, (66 %)b
O
O
O
O
OEt
OEt
MeO
6d, 89%a, (70 %)b
6e, 82%a, (56 %)b
O
O
O
O
OEt
OEt
MeO
6f, 83%a, (56 %)b
6h, 85%a, (55 %)b
aConditions: 1 (0.63 mmol), ethyl acetoacetate (0.6 mmol), K2CO3 (1.74 mmol), Ag2CO3

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b
(0.12 mmol), DMF (0.6 mL), rt, 0.5 h. Conditions: 1 (0.63 mmol), ethyl acetoacetate (0.6
mmol), K2CO3 (1.74 mmol), DMF (0.6 mL), rt, 0.5 h.
Finally, a brief exploration of synthetic utility of this chemistry showed that the
methylenecyclopentenes serve as precursors of highly substituted cyclopentadienes 8 and 9.
For example, in the presence of NaOEt/HOEt, methylenecyclopentene 6b undergoes
deacylation to form cyclopentadiene 8b (a in Scheme 5). Moreover, an unprecedented
rearrangement reaction occurs when the methylenecyclopentenes are treated with
HCl/CH2Cl2. This process forms the corresponding highly substituted cyclopentadienes 9. (b,
Scheme 5). Assignment of the structures of the rearrangement products were made by using
X-ray crystallographic analysis of 9b.12 The unique acid promoted rearrangement reactions of
methylenecyclopentenes 6 likely take place via 1,5-acyl migration pathway shown in Scheme
6.
Scheme 4. Scope of Active Methylene Compounds in Tandem Allylation
Ene-Carbocyclization Reactions a
Br
O
Y
a) cat. Ag2CO3
OR
K2CO3, DMF
1b
Br
+
O
or
b) K2CO3, DMF
Br
7a-e
Y
OR
Ph
O
O
NC
O
OEt
OEt
Br
Br
7a, rt, 0.5 h, 83 %a
7a, 75 oC, 2 h, 65 %b
7b, rt, 0.5 h, 80 %a
7b, rt, 0.5 h, 34 %b
O
O
O
O
O
O
MeO
O
O
OMe
Br
O
Br
Br
7c, rt, 0.5 h, 81 %a
7c, rt, 0.5 h, 56 %b
7d, rt, 1 h, 81 %a
7d, rt, 6 h, 73 %b
7e, rt, 0.5 h, 74 %a
7e, rt, 0.5 h, 62 %b
aConditions: 1b (0.63 mmol), active methylene compound (0.6 mmol), K2CO3 (1.74

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mmol), Ag2CO3 (0.12 mmol for 7a; 0.30 mmol, for 7b; 0.18 mmol, for 7c; 0.12 mmol, for 7d;
b
0.30 mmol, for 7e), DMF (0.6 mL). Conditions: 1b (0.63 mmol), active methylene
compound (0.6 mmol), K2CO3 (1.74 mmol), DMF (0.6 mL).
Scheme 5. Reactions of Methylenecyclopentenes 6
O
O
O
OEt
NaOEt, EtOH
(a)
OEt
rt, 15 min
75%
Br
Br
8b
6b
O
O
O
5
O
OEt
HCl, CH2Cl2
rt, 10 min
1
5
1
OEt
(b)
2
Ar
4
Ar
3
9a, Ar = phenyl, 91%;
9b, Ar = 4-bromophenyl, 93%;
9c, Ar = 4-chlorophenyl, 93%;
9e, Ar = 4-methoxyphenyl, 90%;
9h, Ar = naphthyl, 91%;
6
9
Scheme 6. 1,5-Acyl Migration Mechanism.
Conclusions
In conclusion, the studies described above led to (1) the development of a new and
simple method for preparation of (Z)-1,3-enynes, (2) the use of these enynes in base mediated,
one-pot tandem allylation and ene-carbocyclization reactions with active methylene
compounds to generate methylenecyclopentenes, and (3) the discovery of novel routes for
formation of highly substituted cyclopentadienes.
Acknowledgment Financial support from the Ministry of Science and Technology of the

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Republic of China, Taiwan (MOST 105-2113-M-018-004) is gratefully acknowledged. We
also thank the assistance from professor Jui-Hsien Huang’s group for the x-ray structure
determination.
Notes and References
1. (a) K. C. Nicolaou, W. M. Dai, S. C. Tsay, V. A. Estevez, W. Wrasidlo, Science 1992, 256,
1172. (b) B. M. Trost, Angew. Chem., Int. Ed. 1995, 34, 259. (c) K. C. Nicolaou, A. L.
Smith, In Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995. (d) J. Henkelmann, In Applied Homogeneous Catalysis with Organometallic
Compounds; B. Cornils, W. A. Herrman, Eds.; VCH: New York, 1996. (e) S. Saito, Y.
Yamamoto, Chem. Rev. 2000, 100, 2901. (f) Y. Wu, W. Lin, C. Liu, C. Wu, Adv. Synth.
Catal. 2008, 350, 1841. (g) T. Sakurada, Y. Sugiyama, S. Okamoto, J. Org. Chem. 2013,
78, 3583. (h) G. C. Midya, B. Parasar, K. Dhara, J. Dash, Org. Biomol. Chem. 2014, 12,
1812.
2. (a) N. Zein, A. M. Sinha, W. J. McGahren, G. A. Ellestad, Science 1988, 240, 1198. (b) P.
Nussbaumer, L. Leitner, K. Marz, A. Stutz, J. Med. Chem. 1995, 38, 1831.
3. (a) Y. Liu, M. Nishiura, Y. Wang, Z. Hou, Z. J. Am. Chem. Soc. 2006, 128, 5592. (b) R.
Kaminker, B. P. Biro, M. E. Boom, Angew. Chem., Int. Ed. 2011, 50, 3224.
4. (a) S. Tsukamoto, M. Takahashi, S. Matsunaga, N. Fusetani, R. W. M. Van Soest, J. Nat.
Prod. 2000, 63, 682. (b) L. M. Autunes, M. G. Organ, Tetrahedron Lett. 2003, 44, 6805.
(c) P. Lan, L. E. White, E. S. Taher, P. E. Guest, M. G. Banwell, A. C. Willis, J. Nat.
Prod. 2015, 78, 1963.

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5. Y. Peng, M. Yu, L. Zhang, Org. Lett. 2008, 10, 5187.
6. (a) Y. Choe, P. H. Lee, Org. Lett. 2009, 11, 1445. (b) Y. Deng, X. Jin, C. Fu, S. Ma, Org.
Lett. 2009, 11, 2169. (c) B. Alcaide, P. Almendros, del Campo T. Martínez, Org. Biomol.
Chem. 2012, 10, 7603.
7. P. H. Lee, A Jae-Myung, Bull. Korean Chem. Soc. 2009, 30, 471.
8. (a) M. -H. Lin, Y.-C. Huang, C.-K. Kuo, C.-H. Tsai, Y.-S. Li, T.-C. Hu, T.-H. Chuang, J.
Org. Chem. 2014, 79, 2751. (b) M.-H. Lin, C.-K. Kuo, Y.-C. Huang, Y.-T. Tsai, C.-H.
Tsai, K.-Y. Liang, Y.-S. Li, T.-H. Chuang, Tetrahedron 2014, 70, 5513. (c) M.-H. Lin,
Y.-S. Li, C.-K. Kuo, C.-H. Chen, Y.-C. Huang, K.-Y. Liang, Y.-C. Chen, C.-H. Tsai,
T.-H. Chuang, J. Org. Chem. 2015, 80, 2462.
9. Intermolecular ene reaction: (a) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem. Soc.
2003, 125, 13002. (b) Y. Xi, D. Wang, X. Ye, N. G. Akhmedov, J. L. Petersen, X. Shi,
Org. Lett. 2014, 16, 306. Asymmetric Conia-Ene reaction: (c) A. Matsuzawa, T.
Mashiko, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 7616. (d) S. Shaw,
J. D. White, J. Am. Chem. Soc. 2014, 136, 13578.
10. (a) J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2004, 126, 4526. (b)
Y. Kuninobu, A. Kawata, K. Takai, Org. Lett. 2005, 7, 4823. (c) Q. Gao, B.-F. Zheng,
J.-H. Li, D. Yang, Org. Lett. 2005, 7, 2185. (d) X. Meng, S. Kim, Synlett 2012, 23, 1960.
(e) R. Stammler, M. Malacria, Synlett 1994, 1, 92. (f) C.-L. Deng, R.-J. Song, Y.-L. Liu,
J.-H. Li, Adv. Synth. Catal. 2009, 351, 3096. (g) M. Li, T. Yang, D. J. Dixon, Chem.
Commun. 2010, 46, 2191. (h) C.-L. Deng, T. Zou, Z.-Q. Wang, R.-J. Song, J.-H. Li, J.

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Org. Chem. 2009, 74, 412.
11. The structure has been deposited with the Cambridge Crystallographic Data Centre (1b:
CCDC 1500489). These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
12. These structures have been deposited with the Cambridge Crystallographic Data Centre
(9b: CCDC 1500488) (9a (enol form): CCDC 1500487). These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.