Interrupted nazarov reactions using dichlorocyclopropanes: A novel mode of arene trapping

Article abstract of DOI:10.1021/ol7015669

2-Siloxy-2-alkenyl-1,1-dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening/Nazarov cyclization. The resulting 2-siloxycyclopentenyl cations are intercepted by the pendant arenes to furnish tricyclic adducts in moderate to good yields. In cases where the arene trap was tethered through the cyclopropane unit, a new mode of trapping occurred to generate unique bridged carbon frameworks.

Full text of DOI:10.1021/ol7015669

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3789-3792
Interrupted Nazarov Reactions Using
Dichlorocyclopropanes: A Novel Mode
of Arene Trapping
Tina N. Grant and F. G. West*
Department of Chemistry, UniVersity of Alberta, Edmonton, AB, Canada T6G 2G2
frederick.west@ualberta.ca
Received July 3, 2007
ABSTRACT
2-Siloxy-2-alkenyl-1,1-dichlorocyclopropanes with aryl-terminated side chains undergo silver-assisted electrocyclic opening/Nazarov cyclization.
The resulting 2-siloxycyclopentenyl cations are intercepted by the pendant arenes to furnish tricyclic adducts in moderate to good yields. In
cases where the arene trap was tethered through the cyclopropane unit, a new mode of trapping occurred to generate unique bridged carbon
frameworks.
Tandem and domino-type reactions have found considerable
utility in organic synthesis,1 due to their potential formation
of multiple carbon-carbon bonds and generation of multiple
stereogenic centers in a single transformation. The Nazarov
cyclization2 can be used to initiate domino reactions involv-
ing capture by nucleophiles or 1,3-dienes of the 2-oxido-
cyclopentenyl cation resulting from electrocyclization. The
“interrupted” Nazarov reaction can involve trapping of the
oxyallyl cation in an intra-3 or intermolecular4 fashion,
allowing the construction of complex ring systems from
surprisingly simple starting materials.
Typically, the Nazarov cyclization is effected by treatment
of a cross-conjugated dienone with stoichiometric Lewis
acid.5 We recently described an alternative route to the
pentadienyl cationic intermediate starting from appropriately
substituted gem-dichlorocyclopropane compounds, 1 (Scheme
1).6 Silver(I)-mediated disrotatory ring opening furnishes
pentadienyl cations, which then undergo the usual conrotatory
electrocyclization and eliminative termination to give chloro-
cyclopentenones 2 and/or 3 analogous to those seen under
more traditional conditions. During these initial studies, we
observed that a substrate 1a with a remote phenyl substituent
surprisingly underwent intramolecular electrophilic aromatic
substitution following electrocyclization to provide benzo-
hydrindenone 4a. Arene trapping in the Nazarov reaction
using dienone substrates was known,3b but this result was
(1) (a) Poli, G.; Gimabastiani, G.; Heumann, A. Tetrahedron 2000, 56,
5959-5989. (b) Padwa, A. Pure Appl. Chem. 2003, 75, 47-62. (c)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551-
564. (d) Tietze, L. F. Domino Reactions in Organic Synthesis; John Wiley:
New York, 2006.
(2) Recent reviews: (a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193-
2206. (b) Pellisier, H. Tetrahedron 2005, 61, 6479-6517. (c) Frontier, A.
J.; Collison, C. Tetrahedron 2005, 61, 7577-7606.
(3) Recent examples: (a) Nair, V.; Bindu, S.; Sreekumar, V.; Chiaroni,
A. Org. Lett. 2002, 4, 2821-2823. (b) Browder, C. C.; Marmsa¨ter, F. P.;
West, F. G. Can. J. Chem. 2004, 82, 375-385. (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) Rostami, A.; Wang, Y.; McDonald, R.; West, F.
G. Org. Lett. 2007, 9, 703-706.
(4) Recent examples: (a) Wang, Y.; Schill, B. D.; Arif, A. M.; West, F.
G. Org. Lett. 2003, 5, 2747. (b) Yungai, A.; West, F. G. Tetrahedron Lett.
2004, 45, 5445. (c) White, T. D.; West, F. G. Tetrahedron Lett. 2005, 46,
5629. (d) Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005, 127, 12472. (e)
Janka, M.; He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.;
Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312.
(5) Catalytic versions of the Nazarov reaction have recently been
developed: (a) He, W.; Sun, X. F.; 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) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5,
5075-5078. (d) Liang, G. X.; Trauner, D. J. Am. Chem. Soc. 2004, 126,
9544-9545. (e) Janka, M.; He, W.; Frontier, A. J.; Eisenberg, R J. Am.
Chem. Soc. 2004, 126, 6864-6865. (f) Malona, J. A.; Colbourne, J. M.;
Frontier, A. J. Org. Lett. 2006, 8, 5661-5664.
(6) Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128, 9348-9349.
10.1021/ol7015669 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/18/2007

Table 1. gem-Dichlorocyclopropanation of Siloxydienesa
Scheme 1. Ring Opening/Ring Closure Sequence with
gem-Dichlorocyclopropanes
time
yield
entry substrate
R1
R2 (min) product (%)b
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
H
H
H
H
H
H
H
Me
Me
30
30
20
30
40
45
7
1a
1b
1c
1d
1e
1f
1g
1h
1i
87
75
79
71
85
70
86
91
88
3-MeO-Ph
4-MeO-Ph
2-Me-Ph
2-Br-Ph
4-TIPSO-Ph
2-furyl
Ph
3-MeO-Ph
45
75
a Silyloxydienes 5 were dissolved in CHCl3 (0.12M) and benzyltriethyl-
ammonium chloride (0.3 equiv) was subsequently added. To this solution
was added 50% NaOH aq (190 equiv). The reaction was allowed to stir
vigorously at room temperature and was monitored (TLC) for the disap-
pearance of starting material. b Yields given are for isolated product after
purification.
notable for the participation of an unactivated phenyl group
under mild reaction conditions; previous examples had been
limited to electron-rich arenes. Here we describe a prelimi-
nary study of this intriguing chemistry, in which simple
siloxydienes with a variety of pendent aryl groups are
converted in good yields via a two-step sequence to complex
fused or bridged bicyclic products.
Ring-opening reactions of gem-dichlorocyclopropanes
under strictly thermal conditions are known, leading to
dichloroalkene products.10 With this in mind, we examined
higher temperatures together with halophilic silver(I) to
sequester free chloride anions in the reaction mixture. We
were gratified to find that treatment of 1b and 1c with 1
equiv of AgBF4 in MeCN at reflux led to the production of
tricyclic products 4b and 4c in 53% and 76%, respectively.
These conditions were subsequently applied to the remaining
substrates, including 1a (Table 2).
Remarkably, an electron-poor aromatic ring (entry 5) can
participate in this reaction, generating the desired tricyclic
product, 4e, albeit in a decreased yield of 48%. A silyl-
protected phenol was also found to trap the cationic Nazarov
intermediate to provide 4f; however, the yield of this reaction
was reduced and the reaction time required for complete
conversion of starting material was substantially increased.
Premature loss of the labile phenolic protecting group may
have some detrimental effect upon the yield of this reaction,
suggesting further investigation into the use of more robust
protecting groups on these substrates (note the good yield
obtained for methoxy counterpart 4c, entry 3). In all of these
cases (entries 1-6), the tricyclic products 4 had suffered
dehydrochlorination, and possessed a ring-fusing alkene
adjacent to the arene and the ketone.
A number of substrates were synthesized to examine the
effects of aromatic substitution, as well as the substitution
pattern of the vinylcyclopropane precursor. The required
siloxydiene substrates could be easily prepared by exhaustive
reduction of the corresponding hydrocinnamic acids, fol-
lowed by a one-pot Swern oxidation/Wittig olefination
reaction7 to provide the desired R,â-unsaturated ketones in
moderate to good yield. The ketones were cleanly converted
to the 2-triisopropylsiloxy dienes, 5a-i, under standard
conditions using triethylamine and triisopropylsilyl trifluoro-
methanesulfonate (see the Supporting Information).
Dichlorocyclopropanation of 2-triisopropylsiloxy dienes
can be carried out under phase transfer catalysis conditions6,8
in order to install the gem-dichlorocyclopropane moiety with
complete regioselectivity (Table 1). Notably, the cyclopro-
panation of the 2-furyl-substituted compound (entry 7) could
be accomplished in good yield after a very brief reaction
time and without any evidence of over-cyclopropanation on
the furan.
With the gem-dichlorocyclopropane substrates 1a-i in
hand, we could examine the tandem electrocyclic opening/
electrocyclic closure/electrophilic aromatic substitution pro-
cess. Unfortunately, application of the optimized conditions
from the original study (1.5 equiv of AgBF4, CH2Cl2, rt) to
substrates 1b and 1c led to a complex mixture of inseparable
products. Replacement of CH2Cl2 with the more polar
CF3CH2OH failed to improve the outcome.9
Attempts to involve a furan moiety in the interrupted
Nazarov reaction were unsuccessful (entry 7), leading to
(9) CF3CH2OH has found some utility in the silver(I)-mediated Nazarov
reaction, although its effectiveness was determined to be very substrate
specific.
(10) (a) Kostikov, R. R.; Molchanov, A. P.; Hopf, H. Small Ring
Compounds in Organic Synthesis. Top. Curr. Chem. 1990, 155, 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.
(7) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-2200.
(8) (a) Makosza, M.; Wawryniewicz, M. Tetrahedron Lett. 1969, 4659-
4662. (b) Futugawa, T.; Nishiyama, N.; Tai, A.; Okuyama, T.; Sugimura,
T. Tetrahedron 2002, 58, 9279-9287.
3790
Org. Lett., Vol. 9, No. 19, 2007

suggests that a dehydrohalogenation process leading to
benzohydrindenones 4a-f requires the presence of a hydro-
gen atom at the bridgehead position of the initial tricyclic
product, 6 (Scheme 2).
Table 2. Silver(I)-Mediated Interrupted Nazarov Reactionsa
Scheme 2. Proposed Mechanism of Arene Trapping and
Elimination
Product formation is presumed to involve silver-assisted
opening of the dichlorocyclopropane and 4π electrocycliza-
tion of the resulting pentadienyl cation as in Scheme 1. Once
the cyclopentenyl cation is formed, electrophilic aromatic
substitution and rearomatization can proceed to give cycliza-
tion products 7, which may suffer HBF4-mediated desilyl-
ation under the reaction conditions to furnish R-chloro-
cyclopentanones 6. In the absence of substitution at the
R-position of the vinyl substituent, 6 can then undergo
elimination of HCl to provide the cyclopentenones 4.
Notably, since methyl-substituted product 6i does not
undergo this process, we surmise that the elimination may
proceed via a second oxyallyl cation (A), followed by
elimination with the Zaitsev selectivity typically seen in the
simple Nazarov reaction.12
a gem-Dichlorocyclopropanes 1 were dissolved in freshly distilled MeCN
(0.05M) and stirred with AgBF4 (1 equiv) at reflux. The reactions were
monitored (TLC) for complete consumption of starting material (6-48 h).
b Yields given are for isolated product after purification. c None of the
tricyclic product was observed, even after prolonged reaction time.
In light of the possible intermediacy of a second cyclo-
pentenyl cation, we envisaged a substrate with two pendent
aryl groups capable of undergoing sequential trapping
reactions. Substituted vinylcyclopropane 8a was synthesized
via Horner-Wadsworth-Emmons olefination13 followed by
formation of the triisopropylsiloxy diene using the previously
outlined method (Scheme 3). Silyloxy diene 8a was then
subjected to phase transfer cyclopropanation conditions to
generate the gem-dichlorocyclopropane intermediate 9a. This
more substituted cyclopropane substrate was found to be very
sensitive to decomposition during attempted chromatographic
purification (silica or alumina), and was submitted directly
to AgBF4 in refluxing MeCN without isolation. Under these
rapid consumption of starting material with no discernible
formation of the desired tricyclic product. A likely explana-
tion for this is the instability of the furyl moiety in the
presence of the HBF4 that is generated during this process.11
Finally, the effect of substitution at the R-position of the
vinyl substituent was investigated. When a methyl substituent
was added to the substrate with a pendant phenyl trap, only
the product of the simple Nazarov reaction, 2h, was isolated
in excellent yield (entry 8). However, when the more
nucleophilic 3-methoxyphenyl moiety was employed on a
similar substrate (entry 9) the desired tricyclic product, 6i,
was isolated in very good yield. The relative stereochemistry
of this product was confirmed by single-crystal X-ray
crystallography. Retention of the chloro-substituent in 6i
(12) Harmata has observed cyclopentenone elimination byproducts from
the dehydrochlorination of chlorocyclopentanones during intramolecular
[4+3]-cycloaddition reactions: Harmata, M.; Elomari, S.; Barnes, C. L. J.
Am. Chem. Soc. 1996, 118, 2860-2871.
(13) Mitoshi, K.; Nakae, T.; Sakuyama, S.; Nishizaki, M.; Odagaki, Y.;
Nakai, H.; Hamanaka, N. Bioorg. Med. Chem. 1997, 5, 1621-1647.
(11) Control experiments show that the enone precursor to diene 5g is
destructively consumed in the presence of HBF4.
Org. Lett., Vol. 9, No. 19, 2007
3791

ring (para to the MeO), and subsequent protiodesilylation
from the exo face. The relative stereochemistry of these
products was confirmed by single-crystal X-ray crystal-
lography of 12d and 12e. Remarkably, the selectivity is also
observed when the silyl enol ether portion of the diene exists
as a mixture of E/Z isomers (8d, E:Z ) 1:6.5). This
observation suggests that under the reaction conditions the
more substituted double bond experiences E/Z isomerization
upon ring opening of the gem-dichlorocyclopropane, and
equilibrates to the more stable E-isomer prior to 4π elec-
trocyclization.14 The unique carbon framework that is gener-
ated as a result of this reaction is inherent in the Galbulimima
belgraVeana family of alkaloids.15 This novel mode of
trapping offers a potential strategy toward advanced inter-
mediates needed for the synthesis of these natural products.
In summary, we have found that gem-dichlorocyclo-
propane compounds undergo efficient interrupted Nazarov
reaction with arene traps. Under these conditions, electron-
rich, neutral, and electron-poor aromatic moieties can
intercept the intermediate oxyallyl cationic species, providing
an expedient route to benzohydrindenone skeletons. We have
also developed a new mode of trapping using electron-rich
aromatic rings tethered through the cyclopropane moiety.
This new trapping pathway provides a stereoselective route
to adducts possessing unique bridged bicyclic skeletons.
Additional studies of the halocyclopropane-mediated Nazarov
reaction involving other trapping modes are currently
underway, and will be disclosed in due course.
Scheme 3. A New Mode of Arene Trapping in the Interrupted
Nazarov Reaction
conditions, 9a was converted to benzohydrindenones 10a and
11a in a 2.7:1 ratio and a combined yield of 68% (2 steps).
This result suggested that the nucleophilicity of the second
arene moiety was insufficient to trap the putative intermediate
carbocationic species. Bearing this in mind, we next prepared
8b with a more electron-rich arene appended to the cyclo-
propane ring. After cyclopropanation and direct treatment
with AgBF4, we were surprised to observe clean conversion
to the unexpected bridged bicyclic compound 12b in 57%
yield (Scheme 3).
Generation of 12b appears to be the result of trapping of
the initial cyclopentenyl cation by the more electron-rich
arene unit, with complete regioselectivity in favor of
6-membered ring-closure on the unchlorinated terminus. The
bridged architecture precludes elimination of HCl to generate
a second cyclopentenyl cation in this case. To our knowledge,
this trapping process is without precedent. To explore its
generality, substrates 8c-e were synthesized and the two-
step cyclopropanation/silver(I)-mediated Nazarov procedure
was applied. All three substrates were cleanly converted to
bridged bicyclic products 12c-e, respectively, in moderate
to good yield over the two-step sequence. The silver(I)-
mediated Nazarov reaction appears to proceed stereoselec-
tively in each case, providing a single product as a result of
conrotatory 4π electrocyclization, electrophilic aromatic
substitution at the least hindered position on the aromatic
Acknowledgment. We thank NSERC for support of this
work, and T.N.G. gratefully acknowledges NSERC for a
PGSD studentship and the University of Alberta for a Queen
Elizabeth II scholarship. We also thank Dr. Bob McDonald
and Dr. Michael Ferguson (X-ray Crystallography Lab,
Department of Chemistry, University of Alberta) for the
crystal structure determination of compounds 6i, 12d, and
12e.
Supporting Information Available: Experimental pro-
cedures, physical data, and NMR spectra for all compounds
and synthetic intermediates as well as CIF data for 6i, 12d,
and 12e. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL7015669
(14) This phenomenon has previously been observed: (a) Denmark, S.
E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990, 55, 5543-5545.
(b) Giese, S.; West, F. G. Tetrahedron Lett. 1998, 44, 4043-4060. (c) Giese,
S.; West, F. G. Tetrahedron 2000, 56, 10221-10228.
(15) Mander, L. N.; Wells, A. P. Tetrahedron Lett. 1997, 38, 5709-
5712.
3792
Org. Lett., Vol. 9, No. 19, 2007