Unexpected Prins cyclization: Iron-promoted cyclization/hydration of alkynyl-dimethyl acetals

Article abstract of DOI:10.1016/j.tetlet.2010.11.035

Unexpected products containing acyl-substituted unsaturated seven-membered carbocycle were synthesized by FeCl₃-promoted intramolecular Prins cyclization of alkynyl-dimethylacetals in good yields. It is remarkable that the synthesized 7-exocycl

Full text of DOI:10.1016/j.tetlet.2010.11.035

Tetrahedron Letters 52 (2011) 314–317
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected Prins cyclization: iron-promoted cyclization/hydration
of alkynyl-dimethyl acetals
⇑
⇑
Deping Zheng, Wanchun Gong, Zuodong Ma, Bingzhen Ma, Xiaolong Zhao, Zhixiang Xie , Ying Li
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Unexpected products containing acyl-substituted unsaturated seven-membered carbocycle were synthe-
sized by FeCl3-promoted intramolecular Prins cyclization of alkynyl-dimethylacetals in good yields. It is
remarkable that the synthesized 7-exocyclic vinyl cations generated as a result of Prins-type cyclization
were trapped by H2O (no halogen ion) in CH2Cl2 to give the corresponding enol derivatives. Those enol
derivatives underwent enol-keto tautomerism and then eliminated one molecule of MeOH to give the
corresponding acyl-substituted unsaturated seven-membered carbocycle.
Received 25 August 2010
Revised 29 October 2010
Accepted 9 November 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Prins cyclization
Iron-promoted
Vinyl cation
Hydration
Halogenation
The Prins reaction is an important carbon–carbon bond forming
reaction consisting in the acid-catalyzed condensation of alde-
hydes with alkenes.1 Today the relevance of this reaction as sub-
strates and acid-catalyst has led to the study and application of
many variations.2 Acid catalysts, such as Lewis acids, organic acids,
and supported catalysts have been reported to assist both Prins
acyclic reaction and Prins cyclization. Alkynyl and allenyl group-
attached acetals, ketone, and oxocarbenium ions (generated from
aldehydes and alcohols) have been described as substrates in the
Prins reaction. The Lewis acid-promoted reactions of alkynyl–alde-
hyde or acetals (LA P 1.0 equiv and with halogen) usually gave rise
to the halogen products which formed as the result of vinyl cation
intermediate-trapping by halogen ion (Scheme 1).2,3 However, Le-
wis acid promoted-cyclization reactions of alkynes, using other
nucleophilic reagents such as H2O to capture the vinyl cation inter-
mediates, have received less attention.3e In this Letter, we report an
intramolecular Prins cyclizationfor the synthesisof acyl-substituted
unsaturated seven-membered carbocycle. The reaction features use
of H2O to capture the vinyl cation intermediates, and employment of
inexpensive, environmentally friendly, and stable FeCl3 as catalyst.
provided acyl-substituted unsaturated seven-membered carbocy-
cle 3 in moderate yields (Scheme 1).
To our knowledge, only one example5 has been reported on the
synthesis of acyl-substituted products by TMSOTf promoted Prins-
type cyclization of terminal-substituted alkynyl alcohols with var-
ious aldehydes. Moreover, bicyclo[5.3.0]decane skeletons are also
ubiquitous in nature, occurring in a wide range of biologically ac-
tive substances, such as Bisanhydrolactarorufin A6 and Frondosin
B.7 Therefore, there has been much interest in the development
of methods for synthesis of these subunits from
acetals.
a-hydroxy alkynyl
Firstly, we started our investigation by treating alkynyl-di-
methyl acetals 1a with FeCl3 (0.3 equiv) in CH2Cl2 at 0 °C (Table
1, entry 1). Acyl-substituted unsaturated seven-membered carbo-
cycle 3a was obtained in 36% yield and 1a was recovered in 16%
yield. Increasing the amount of FeCl3 to 1.0 equiv (entry 2) led to
the complete conversion within 30 min. and 3a was obtained in
46% yield with complete conversion of 1a. However, when alky-
nyl-dimethyl acetals 1a was treated with FeCl3 (1.0 equiv) in the
presence of 4 Å molecule sieve in CH2Cl2 at 0 °C, lower yield was
obtained (Table 1, entry 3). We speculated that H2O might play a
role in the reaction. Therefore, 2.0 equiv of H2O was added and
the yield of 3a was increased to 50% (entry 4).When the amount
of H2O was increased to 3.0 equiv, 3a was obtained in 79% yield
(entry 5). However, further raising the amount of H2O to 4.0 equiv,
it did not lead to further improvement (entry 6). These results con-
firmed that H2O (3.0 equiv) was essential to induce this cyclization
reaction. Other iron salt catalysts were used to study the reaction
(entries 7 and 8). FeCl2 would not improve the yield of 3a and
We recently found
a new cascade process to synthesize
spiro[4.5]decane derivatives with high diastereoselectivity by
using FeCl3 promoted Prins cyclization of 2-(5,5-dimethoxypen-
tyl)-1-substituted cyclopentanols (Scheme 1).4 Of late, we explored
the use of this cascade reaction to generate spiro[4.4]nonane deriv-
atives. However, when m = 0, treating compound 1 with FeCl3
⇑
Corresponding authors.
E-mail addresses: xiezx@lzu.edu.cn (Z. Xie), liying@lzu.edu.cn (Y. Li).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.035

D. Zheng et al. / Tetrahedron Letters 52 (2011) 314–317
315
X
R
EtO
O
FeX3 (1 equiv)
TiCl4
O
R
Y
Y
OEt
OEt
X= Cl, Br
~91%
Cl
R'
OEt
Y = O, NTs, C(CO2Et)2
R = aryl, alkyl
R'
I
RO OR
n
n = 0; onee xample
n = 1; R = Me, Pr, Bn
OH
H
OH
Cl
TMSI
OR
TiCl4
CH(OMe)2
n
OMe
Ham's work
i
O
R
R
FeCl3, 3H2O
FeCl3
R
HO
n
MeO OMe
m
OMe
CH2Cl2
CH2Cl2, 0 oC
0oC
m
n
m
n
2
3
n = 1; m =1
Our Previous Work
1
n = 1,2; m = 0
This work
Scheme 1. Lewis acid promoted Prins cyclization of alkynyl acetals.
Table 1
Optimization of intramolecular Prins cyclization conditionsa
O
conditions
HO
OMe
OMe
1a
3a
Entry
Cat./equiv
Solvent
H2O/equiv
Temp (°C)
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
FeCl3/0.3
FeCl3/1.0
FeCl3/1.0
FeCl3/1.0
FeCl3/1.0
FeCl3/1.0
FeCl2/1.0
Fe2(SO4)3/1.0
TMSOTf/1.0
TiCl4/1.0
SnCl4/1.0
FeCl3Á6H2O/1.0
AgOTf/0.1
ZnBr2/1.0
CuCl2/1.0
TsOH/1.0
FeCl3/1.0
FeCl3/1.0
CH2Cl2
CH2Cl2
—
—
—
2
3
4
3
3
3
3
3
—
3
3
3
3
3
3
0
0
0
0
0
0
0
rt
À23
À78
À78
0
0
0
rt
0
0
0
50
30
60
30
30
30
60
120
20
20
30
40
40
60
120
120
60
36
46
37
50
79
61
32
—
73
32
16
Trace
—
b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
—
—
—
—
MeCN
60
—
a
b
c
Reactions were conducted with 0.2 mmol of 3a, in 5 mL of solvent.
4 Å molecule sieve was added in reaction.
Isolated yield.
Fe2(SO4)3 was inactive. And then, the effects of other Lewis and
Brønsted acids were investigated (entries 9–16). Use of TMSOTf
failed to improve the yield of 3a (entry 7). TiCl4, SnCl4, and
FeCl3Á6H2O showed low catalytic activity while AgOTf, ZnBr2,
CuCl2, and TsOH were inactive. When THF or MeCN was employed
as solvents, no desired product was observed (Table 1, entries 17
and 18). Thus, the optimized cyclization conditions were found
to be using 1.0 equiv of 1a, 1.0 equiv of FeCl3 and 3.0 equiv of
H2O in CH2Cl2 at 0 °C for 30 min.
conditions. And the results were summarized in Table 2.
Electron-donating substituents at para-position of the aryl group
did not obviously affect the yields of the desired products (entries
1–3). The reactions of substrates containing six-member rings
were also investigated. As expected, the corresponding a,b-unsat-
urated keto bicyclo[5.4.0]hendecanes 3d and 3e were obtained in
good yields (entries 4 and 5).
When substrate containing an electron-withdrawing group at
ortho-position of the aryl ring was used, no cyclized product was
observed (entry 6); instead, aldehyde 3f was detected as a major
product. It was probable that the 2-trifluoromethyl on aryl group
To explore the scope of the Prins cyclization, a variety of
alkynyl-dimethyl acetals 1 were examined under the optimized

316
D. Zheng et al. / Tetrahedron Letters 52 (2011) 314–317
reduced the electron density of the carbon–carbon triple bond to
prevent it from attacking the oxonium ion, which was generated
from acetal in the presence of FeCl3. Additionally, acetal 1g with
a linker chain was examined; the desired product 3g was obtained
in 10% yield. When trimethylsilanealkynyl 1h was used, the
starting material decomposed and no product was observed under
Table 2 (continued)
Entry
8
Substrates 1
Products 3
Yield (%)b
TMS
HO
OMe
OMe
Decompose
1h
Table 2
(CH2)5CH3
(CH2)5CH3
Cl
The scope of the synthesis of acyl-substituted unsaturated seven-membered carbo-
cycles by FeCl3-promoted intramolecular Prins cyclizationa
HO
Yield (%)b
9
39
Entry
Substrates 1
Products 3
CH(OMe)2
1i
3i
O
a
Optimized conditions: 1 (0.2 mmol), FeCl3 (1.0 equiv), H2O (3.0 equiv), CH2 Cl2
(5 ml), 0 °C, 30–40 min.
HO
1
79
OMe
OMe
b
Isolated yield.
1a
3a
the optimized conditions. Additionally, when the alkyne was at-
tached to an alkyl group instead of an aryl ring (entry 9), the chlo-
rovinyl bicarbocycles 3i was obtained in 39% yield as the main
product.
Me
Me
O
Based on these results, a reaction mechanism is proposed as
shown in Scheme 2. The reaction was initiated by eliminating one
molecule of H2O from 4 in the presence of FeCl3,8 giving rise to 5.
The compound 5 was transformed by the action of FeCl3 to the oxo-
nium ion intermediate 6 with Denmark9 and Yu’s3h work as litera-
ture precedents. Nucleophilic attack of C–C triple bond on the
cation center in 6 would lead to the formation of 7. It was noted that
when the C–C double bond was also present in 6, the attack on the
cation center at double bond seemed more easily than at triple
bond, since the relative rate for Prins cyclization is in the order of
alkene > alkyne.3b,4 In our cases, however, the products containing
bicyclo[5.3.0]decane or bicyclo[5.4.0]hendecane formed more
easily than that the spiro[4.4]decane derivatives. When R was the
electron-rich aryl group, the H2O attacks the vinyl cation interme-
diate 7 to give enol derivatives (path a). Those enol derivatives then
underwent enol-keto tautomerism and eliminated one molecule
of MeOH to give the corresponding acyl-substituted unsaturated
seven-membered carbocycles. If R was aryl group attached to an
2
72
HO
OMe
OMe
3b
1b
1c
1d
OMe
OMe
O
3
4
5
72
81
77
HO
HO
HO
OMe
OMe
3c
Me
Me
O
OMe
OMe
3d
R
FeCl3
OMe
Fe3+
HO
OMe
R
-H2O
OMe
OMe
O
OMe
OMe
5
OMe
4
-FeCl2(OMe)
R
OMe
3e
R
1e
1f
R
OH2
OMe
Path a
F3C
F3C
OMe
OMe
H2O
6
7
HO
HO
6
7
48
10
8
Path c
H2O
R
Path b
Cl
OMe
OMe
CHO
O
R
3f
Cl
R
O
OH
O
3a~3c
Scheme 2. A plausible mechanism for the formation of products.
3f
3i
OMe
OMe
3g
1g

D. Zheng et al. / Tetrahedron Letters 52 (2011) 314–317
317
electron-withdrawing group, the oxonium ion was attacked by nei-
References and notes
ther double bond nor triple bond. H2O attacked the oxonium ion to
give aldehyde 3f. When R was an alkyl group, the ClÀ attacked the
vinyl cation intermediate 7 to give the halogen product 3i.
In conclusion, a new strategy is developed for the synthesis of
the acyl-substituted unsaturated seven-membered carbocycle by
employing the FeCl3-promoted intramolecular Prins cyclization.
This is convenient, economical, and environmentally friendly. The
process would serve as a good complement to the existing
methodologies and its mild reaction condition must be useful in
the synthesis of nature products with such skeletons. Efforts
toward this goal are in progress in our laboratory.
1. (a) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 51, 505–555; (b) Snider, B. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
1991; Vol. 2, pp 527–561.
2. Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925–957.
3. (a) Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K. Synlett
2001, 293–295; (b) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66,
4679–4686; (c) Kim, Y.-H.; Lee, K.-Y.; Oh, C.-Y.; Yang, J.-G.; Ham, W.-H.
Tetrahedron Lett. 2002, 43, 837–841; (d) Miranda, P. O.; Díaz, D. D.; Padrón, J. I.;
Bermejo, J.; Martín, V. S. Org. Lett. 2003, 5, 1979–1982; (e) Miranda, P. O.; Díaz,
D. D.; Padrón, J. I.; Ramírez, M. A.; Martín, V. S. J. Org. Chem. 2005, 70, 57–62; (f)
Miranda, P. O.; Carballo, R. M.; Ramírez, M. A.; Martín, V. S.; Padrón, J. I. Arkivoc
2007, 331–343; (g) Miranda, P. O.; Ramírez, M. A.; Martín, V. S.; Padrón, J. I.
Chem. Eur. J. 2008, 14, 6260–6268; (h) Xu, T. Y.; Yu, Z. K.; Wang, L. D. Org. Lett.
2009, 11, 2113–2116.
4. Zheng, D. P.; Ma, Z. D.; Gong, W. C.; Xie, Z. X.; Li, Y. Synlett 2010, 14, 2169–2173.
5. Chavre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Cho, Y. S. J. Org. Chem. 2008,
73, 7467–7471.
Acknowledgments
6. (a) Daniewski, W. M.; Gumulka, M.; Skibicki, P.; Krajewski, J.; Gluzifiski, P.
Phytochemistry 1991, 30, 1326–1328; (b) Daniewski, W. M.; Gumulka, M.;
Ptaszyn´ ska, K.; Skibicki, P.; Jacobsson, U.; Norin, T. Phytochemistry 1992, 31,
3933–3936.
7. Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz, A. J.; Johnson, R.
K. Tetrahedron 1997, 53, 5047–5060.
We are grateful for the financial support of the National Natural
Science Foundation of China (Grant Nos. 20872053 and 21072084).
We also thank Dr. Wei Yu of Lanzhou University for helpful
discussions.
8. (a) Keinan, E.; Mazur, Y. J. Org. Chem. 1978, 43, 1020–1022; (b) Fadel, A.; Salaun
Tetrahedron 1985, 41, 413–420; (c) Díaz, D. D.; Miranda, P. O.; Padrón, J. I.;
Martín, V. S. Curr. Org. Chem. 2006, 10, 457–476.
Supplementary data
9. Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089–8110.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.035.