A new approach to the Nazarov reaction via sequential electrocyclic ring opening and ring closure

Article abstract of DOI:10.1021/ja063421a

Regioselective dichlorocyclopropanation of 2-silyloxydienes furnishes vinylcyclopropanol silyl ethers in good yield. Treatment with silver(I) at room temperature effects disrotatory electrocyclic opening to a 2-chloro-3-silyloxypentadienyl cation, which then undergoes conrotatory (Nazarov) electrocyclization to provide chlorocyclopentenones. This two-step sequence offers a convenient and mild alternative to the standard Nazarov cyclization protocol via a formal 4+1 construction and furnishes products containing useful halogen functionality. In one case possessing a pendant phenyl group, interrupted Nazarov reaction to give a benzohydrindenone was observed. Copyright

Full text of DOI:10.1021/ja063421a

Published on Web 07/04/2006
A New Approach to the Nazarov Reaction via Sequential Electrocyclic Ring
Opening and Ring Closure
Tina N. Grant and F. G. West*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alta., Canada T6G 2G2
Received May 16, 2006; E-mail: frederick.west@ualberta.ca
Scheme 1
The Nazarov reaction, a well-established method for generation
of new cyclopentenone rings from dienone precursors, has enjoyed
considerable recent attention.1 Particular focus has been placed on
its use in tandem or domino processes,2 catalytic approaches,3 and
strategies for stereocontrol in the electrocyclization step.4 As
typically practiced, the Nazarov reaction begins with a 1,4-dien-
3-one, which is activated with protic or Lewis acid to form a
pentadienyl cation. We are interested in alternative methods for
generation of Nazarov-type pentadienyl systems which may permit
novel trapping pathways or greater functional group compatibility.
Here we describe a novel Nazarov process in which 2-chloro-3-
silyloxypentadienyl cations capable of electrocyclization are gener-
Table 1. Preparation of Dichlorocyclopropanol Silyl Ethers 6a
ated from readily available dichlorocyclopropane precursors.
Dihalocyclopropanes are known to undergo 2π disrotatory
electrocyclic opening under thermal conditions or treatment with
silver(I).5 The resulting 2-chloroallyl cations can be trapped by
halide or solvent, aromatic compounds,6 or internal nucleophiles.7
We envisioned a variation of this process as a potential comple-
mentary method for accessing the Nazarov intermediate: if ring-
opening chemistry could be carried out on alkenyl-substituted
dihalocyclopropanes 1, pentadienyl cations 2 potentially capable
of undergoing 4π electrocyclization would result (Scheme 1).
entry
dieneb
R1
R2
R3
product
yield (%)c
Simple dihalogenated vinylcyclopropanes undergo thermal rear-
rangement to dihalocyclopentenes;8 however, these may occur via
a homolytic pathway. To the best of our knowledge, the corre-
sponding cationic process is unknown.9
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
H
H
H
Me
H
H
H
H
H
Pr
Pr
H
6a
6b
6c
6d
6e
7f
93
95
90
91
92
55d
87
71
(CH3)2CH
Ph
(CH2)4
(CH2)3
Ph
Computations have shown that the presence of an alkenyl
substituent on C-2 of a 1,1-dihalocyclopropane should increase the
rate of electrocyclic opening relative to hydrogen.10 The presence
of an oxygen-containing group on the same carbon (Y ) OR)
should also accelerate ring opening and would furnish a pentadienyl
cation quite analogous to the Nazarov intermediate formed from
1,4-dien-3-ones.11 Silyl ethers were chosen for initial investigation,
as the cyclization products 4 would be expected to undergo facile
desilylation to the corresponding cyclopentenone. Thus, cyclopro-
panes 6 were prepared via dichlorocyclopropanation of the readily
available 2-triisopropylsilyloxydienes12 5 under phase-transfer con-
ditions13 (Table 1). Cyclopropanation reactions generally occurred
in high yield, especially in the case of disubstituted silyl enol ethers
(entries 1-5). Silyloxydiene 5f did not react cleanly under phase-
transfer conditions and underwent direct conversion to chlorodi-
enone 7f when treated with potassium t-butoxide in chloroform
(entry 6). Although the anticipated dichlorocyclopropane 6f is the
likely precursor of 7f, none of this material was isolated. Use of
more labile silyl ethers (e.g., triethylsilyl) also led to the unwanted
formation of dienones 7 during purification or the subsequent ring-
opening step.
H
Me
H
5g
5h
Ph
Ph(CH2)2
6g
6h
a Silyloxydienes 5 were dissolved in CHCl3 (0.12 M) with benzyltri-
ethylammonium chloride (20 mol %), and the resulting solution was stirred
vigorously at room temperature with 50% aqueous NaOH (190 equiv) until
5 was deemed consumed (TLC). b See Supporting Information for prepara-
tion of dienes 5. c All yields are based on isolated product after chroma-
tography. d t-BuOK/CHCl3 used in place of PTC conditions.
halophilic silver(I) ion. Using 6a and 6c as test cases, a variety of
conditions were surveyed. Heating 6a in acetonitrile caused efficient
conversion to chlorodienone 7a (analogous to 7f) as did stirring
with AgBF4 in trifluoroethanol (TFE), while in CH2Cl2, it was
converted to a complex mixture containing 9a. The more highly
substituted 6c was subjected to several silver(I) salts (AgOTf, AgO2-
CCF3, AgBF4) and other Lewis acids (AlCl3, Et2AlCl) in a variety
of solvents, and it was found that AgBF4 in CH2Cl2 gave the optimal
conversion to the desired Nazarov cyclization product 8c. The other
substrates 6a,b,d,e,g,h were then subjected to the same conditions
(Table 2), with varying outcomes.
With cyclopropanes 6a-e and 6g,h in hand, the possibility of
effecting Nazarov cyclization by sequential electrocyclic ring
opening and closure could now be examined.14 Dihalocyclopropanes
can be ionized thermally or with various Lewis acids, especially
As noted above, 6a furnished 9a as part of a mixture that was
not amenable to chromatographic purification. The presence of
additional substituents on either the alkenyl moiety or the cyclo-
propane (entries 2-6) permitted clean conversion to the desired
9
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J. AM. CHEM. SOC. 2006, 128, 9348-9349
10.1021/ja063421a CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. AgBF4-Mediated Rearrangement of Cyclopropanes 6a
Acknowledgment. We thank NSERC for support of this work,
and for a PGS D studentship (T.N.G.).
Supporting Information Available: Experimental procedures and
spectral data for cyclopropanes 6 and their rearrangement products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Reviews: (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React.
1994, 45, 1-158. (b) Pellisier, H. Tetrahedron 2005, 61, 6479-6517. (c)
Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
(2) Recent examples: (a) Yungai, A.; West, F. G. Tetrahedron Lett. 2004,
45, 5445-5448. (b) White, T. D.; West, F. G. Tetrahedron Lett. 2005,
46, 5629-5632. (c) Giese, S.; Mazzola, R. D., Jr.; Amann, C. M.; Arif,
A. M.; West, F. G. Angew. Chem., Int. Ed. 2005, 44, 6545-6549. (d)
Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005, 127, 12472-12473. (e)
Review: Tius, M. A. Eur. J. Org. Chem. 2005, 2193-2206.
(3) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278-
14279. (b) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-
4930. (c) Janka, M.; He, W.; Frontier, A. J.; Eisenberg, R. J. Am. Chem.
Soc. 2004, 126, 6864-6865.
(4) (a) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse,
C.; Haltiwanger, R. C. Synlett 1999, 1612-1614. (b) Kerr, D. J.; Metje,
C.; Flynn, B. L. Chem. Commun. 2003, 1380-1381. (c) Liang, G.; Gradl,
S. N.; Trauner, D. Org. Lett. 2003, 5, 4931-4934. (d) Aggarwal, V. K.;
Belfield, A. J. Org. Lett. 2003, 5, 5075-5078. (e) Prandi, C.; Ferrali, A.;
Guarna, A.; Venturello, P.; Occhiato, E. G. J. Org. Chem. 2004, 69, 7705-
7709. (f) Mazzola, R. D., Jr.; White, T. D.; Vollmer-Snarr, H. R.; West,
F. G. Org. Lett. 2005, 7, 2799-2801.
(5) (a) Kostikov, R. R.; Molchanov, A. P.; Hopf, H. Top. Curr. Chem. 1990,
155 (Small Ring Compounds in Organic Synthesis), 41-80. (b) Banwell,
M. G.; Reum, M. E. In AdVances in Strain in Organic Chemistry; Halton,
B., Ed.; JAI Press: Greenwich, CT, 1991; Vol. 1, pp 19-64. (c)
Fedorynski, M. Chem. ReV. 2003, 103, 1099-1132.
(6) (a) Skattebøl, L.; Boulette, B. J. Org. Chem. 1966, 31, 81-85. (b) Shimizu,
N.; Watanabe, K.; Tsuno, Y. Bull. Chem. Soc. Jpn. 1984, 57, 1165-
1166.
(7) (a) Danheiser, R. L.; Morin, J. M., Jr.; Yu, M.; Basak, A. Tetrahedron
Lett. 1981, 22, 4205-4208. (b) Taylor, R. M. Aust. J. Chem. 2003, 56,
631. (c) Banwell, M. G.; Beck, D. A. S.; Stanislawski, P. C.; Sydnes, M.
O.; Taylor, R. M. Curr. Org. Chem. 2005, 9, 1589-1600.
(8) (a) Ketley, A. D.; Berlin, A. J.; Gorman, E.; Fisher, J. P. J. Org. Chem.
1966, 31, 305-308. (b) Dolbier, W. R.; Sellers, S. F. J. Am. Chem. Soc.
1982, 104, 2494-2497.
entry
substrate
R1
R2
R3
products
yield (%)b
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6g
6h
H
H
H
Me
H
H
H
H
H
Pr
H
9a
8b + 9b
8c
8d
8e
8g + 9g
10h
c
57d
70
(CH3)2CH
Ph
(CH2)4
(CH2)3
Ph
45
74
Me
H
87e
63f
Ph(CH2)2
a Cyclopropanes 6 were dissolved in CH2Cl2 or TFE (0.05 M) and stirred
with AgBF4 (1.5 equiv) at room temperature until complete consumption
of starting material was observed (TLC). b Yields are based on isolated
product after chromatography. c Compound 9a was present in the crude
reaction mixture, but decomposed during attempted chromatographic
purification (silica or alumina). d Compounds 8b and 9b were isolated in a
1.7:1 ratio. Minor amounts of a dione resulting from trapping by adventitious
water were also obtained (see Supporting Information). e All four possible
regio- and stereoisomers were formed in the ratio 7.7:4.5:3:1 (8g(cis):9g(cis):
8g(trans):9g(trans)). f The simple Nazarov cyclization product 8h was not
isolated.
cyclopentenones 8 or 9.15 In those cases lacking an additional alkyl
substituent on the cyclopropane ring (entries 2-5), complete
regioselectivity in the elimination step was seen in favor of the
more substituted alkene product, except in the case of 6b. This
result contrasts with previous examples of fluorine-directed Nazarov
cyclizations, in which preferential formation of an alkenyl fluoride
was seen.16 The presence of an additional alkyl group on the
cyclopropane (entry 6) led to a mixture of regioisomers 8g and 9g,
in each case as a pair of diastereomers.
The behavior of phenethyl-substituted substrate 6h (entry 7) is
especially notable. In this case, none of the expected cyclopentenone
8h was isolated. Instead, tricyclic product 10h was obtained in good
yield. This product is assumed to form via electrophilic aromatic
substitution involving the 2-silyloxycyclopentenyl cation formed
upon electrocyclization. Such a pathway is precedented,17 but the
participation of a simple phenyl group is striking. Previous examples
of the arene-terminated interrupted Nazarov reaction required the
presence of at least one electron-donating substituent on the
aromatic trap. The eventual formation of the tetrasubstituted alkene
presumably arises via elimination of HCl and CdC migration.
We have described the first examples of an apparent sequential
2π electrocyclic opening/4π electrocyclic closure using alkenyldi-
chlorocyclopropanes as pentadienyl cation precursors. The substrates
are readily available via cyclopropanation of 2-silyloxydienes, and
the process appears to be general. In one case possessing a remote
aryl group, efficient interrupted Nazarov cyclization to a tricyclic
product was seen. Further studies of this process are underway and
will be disclosed in due course.
(9) For an approach to cyclopentenones from dichlorocyclopropylcarbinols
via conjugate elimination to a chloropentadienyl cation, see: Hiyama,
T.; Tsukanaka, M.; Nozaki, H. J. Am. Chem. Soc. 1974, 96, 3713-3714.
(10) Faza, O. N.; Lo´pez, C. S.; AÄ lvarez, R.; de Lera, AÄ . R. J. Org. Chem.
2004, 69, 9002-9010.
(11) Inward disrotation of the Y group, predicted to be slightly favored for
dibromocyclopropanols,10 would lead to a “sickle” or “w” pentadienyl
conformer potentially incapable of 4π cyclization. In the case of a bulky
trialkylsilyl ether, steric factors may favor outward rotation to give 2.
(12) Silyloxydienes were prepared from the corresponding enones by treatment
with TIPSOTf and Et3N. See Supporting Information for details.
(13) (a) Makosza, M.; Wawrzyniewicz, M. Tetrahedron Lett. 1969, 4659-
4662. (b) Futugawa, T.; Nishiyama, N.; Tai, A.; Okuyama, T.; Sugimura,
T. Tetrahedron 2002, 58, 9279-9287.
(14) For a conceptually similar sequence involving 4π electrocyclic opening
of trans-divinylcyclobutenes followed by 8π electrocyclic closure, see:
(a) Paquette, L. A.; Hamme, A. T.; Kuo, L. H.; Doyon, J.; Kreuzholz, R.
J. Am. Chem. Soc. 1997, 119, 1242-1253. (b) Paquette, L. A.; Liu, Z.
S.; Ramsey, C.; Gallucci, J. C. J. Org. Chem. 2005, 70, 8154-8161.
(15) Chlorodienones 7 do not appear to be intermediates in the formation of 8
or 9, as 7b was unreactive under conditions that convert 6b to 8b/9b.
(16) Ichikawa, J. Pure Appl. Chem. 2000, 72, 1685-1689.
(17) Browder, C. C.; Marmsa¨ter, F. P.; West, F. G. Org. Lett. 2001, 3,
3033-3035.
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