Synthesis of spiro[4.5]trienones by intramolecular ipso-halocyclization of 4-(p-methoxyaryl)-1-alkynes

Article abstract of DOI:10.1021/ja053079m

A wide variety of 3-halospiro[4.5]trienones are readily prepared in good to excellent yields by the intramolecular ipso-halocyclization of 4-(p-methoxyaryl)-1-alkynes under mild reaction conditions. ICl, I₂, and Br₂ are all effective electrophiles for this process under carefully optimized reaction conditions. Copyright

Full text of DOI:10.1021/ja053079m

Published on Web 08/11/2005
Synthesis of Spiro[4.5]trienones by Intramolecular ipso-Halocyclization of
4-(p-Methoxyaryl)-1-alkynes
Xiaoxia Zhang and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received May 11, 2005; E-mail: larock@iastate.edu
Table 1. Synthesis of Spirotrienones by the Reaction of
Arylalkynes and Halogen Electrophiles
Annulated arene heterocycles and carbocycles can be conve-
niently prepared by the electrophilic cyclization of arenes bearing
heteroatom- or carbon-tethered olefins, respectively.1 However, only
a few examples of the analogous chemistry of alkynes have been
reported, although this would appear to be a very efficient route to
a wide range of useful, functionally substituted heterocycles and
carbocycles.2 All previously reported reactions of this type have
employed ortho-substituted arenes. We wish to report a very useful
route to spiro[4.5]trienones via intramolecular ipso-halocyclization
of simple methoxy-substituted 4-aryl-1-alkynes.
During our study of the cyclization of simple N-propargylic
anilines to quinolines,2d we had occasion to examine the reaction
of N-(4-methoxyphenyl)-N-(3-phenyl-2-propyn-1-yl)triflamide (1)
with 2 equiv of ICl in CH2Cl2 at -78 °C for 0.5 h (Conditions A).
To our surprise, the 1-azaspirotrienone 3 was produced exclusively
in an 88% yield and none of the expected dihydroquinoline 2 was
observed (eq 1 and Table 1, entry 1).3 This is a rare example of an
iodonium ion-induced intramolecular ipso-cyclization of an alkyne
onto an arene under extremely mild reaction conditions.4 Since the
spiro[4.5]decane skeleton is a key structural feature present in a
number of interesting natural products,5 this process represents a
powerful new tool for the synthesis of such compounds, which may
be difficult to prepare by any other present method.6 We therefore
chose to study this cyclization in more detail.
When the cyclization of 1 was performed at room temperature,
the spirotrienone 3 was obtained in only a 46% yield together with
a 48% yield of 2. This suggests that ipso-cyclization is a kinetically
favored process. The corresponding N-acetyl derivative 15 also
cyclized efficiently at -78 °C to produce spiroamide 16 in a 66%
yield (Table 1, entry 9). However, analogous anilines with the acetyl
group replaced by a hydrogen or methyl group failed to generate
the corresponding ipso-cyclization products. In these two cases,
the presence of electron-releasing groups on the nitrogen facilitated
electrophilic aromatic substitution ortho to the nitrogen to produce
the corresponding quinolines.2d
ICl proved to be an efficient electrophile for this and a number
of related spirocyclizations, as indicated in Table 1 (entries 1 and
4-8). The reaction accommodates various substituents at the remote
end of the triple bond of the N-triflanilide. Electron-rich or electron-
poor aryl- and alkyl-substituted alkynes (entries 4-6) are readily
accommodated, producing the expected spirocyclic products in good
yields. The presence of a sterically hindered silyl group presents
no difficulty, and the reaction proceeds without desilylation,
a All reactions were run on a 0.3 mmol scale. b See the text and
Supporting Information for Conditions A-C. c Three equivalents of ICl was
required. d Four equivalents of ICl was required.
although 3 equiv of ICl was required to get a good yield (entry
7).7 The presence of an olefin on the end of the triple bond presented
no difficulties (entry 8). We were also pleased to see that the
p-methoxy group in acetanilide 15 could be replaced by a
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10.1021/ja053079m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
attack on the electron-rich aromatic ring to form intermediate B.
The methyl group of B is removed via nucleophilic displacement
by the X-, HCO3- (Conditions B), or MeO- (Conditions C) present
in the reaction mixture.
In summary, a simple, very versatile new approach to a wide
variety of 3-halospirotrienones bearing a spiro[4.5]decane ring
system has been developed. The reaction proceeds under very mild
conditions and tolerates considerable functionality. A systematic
study of the reaction has revealed that different “optimal” reaction
conditions are required for different substrates and electrophiles.
Further work to better understand the effect of the base and the
solvent on the reaction path and utilization of these spirotrienones
as pivotal intermediates in the preparation of biologically active
compounds is presently underway.
p-dimethylamino group, and spirotrienone 16 was obtained in a
comparable yield after acid hydrolysis (entry 10).
Acknowledgment. We gratefully acknowledge the donors of
the Petroleum Research Fund, administered by the American
Chemical Society, and the National Institute of General Medical
Sciences (GM 070620) for partial support of this research, and
Kawaken Fine Chemicals Co., Ltd., and Johnson Matthey, Inc. for
donating the palladium acetate.
I2 has also successfully been employed in this process as an
electrophile. When 1 was initially treated with 2 equiv of I2 in
MeCN at room temperature, dihydroquinoline 2 was obtained in
an 80% yield without any formation of spirotrienone 3. Interestingly,
by simply adding 2 equiv of NaHCO3 (Conditions B), spirotrienone
3 can be formed in a 90% yield in 2 h, although a longer reaction
time was required than when ICl was employed (entry 2). It is
noteworthy that, by this minor modification in the reaction
conditions, we can switch the ipso/ortho cyclizations “on” or “off”
at will. Bromo-substituted spirotrienone 4 was also obtained in an
excellent yield under similar ipso reaction conditions when Br2 was
employed as the electrophile (entry 3).
The synthetic utility of this process would be greatly increased
if we could vary the nature of the substitution between the alkyne
and the arene. We have, in fact, been able to replace the nitrogen
moiety by a ketone, ester, or amide moiety and still obtain excellent
yields using reaction Conditions B (entries 11-13). The reaction
with a ketone linkage is substantially faster than that with the
corresponding amide (10 min versus 12 h). With an ethane linkage,
careful optimization of the reaction conditions indicated that the
reaction temperature, the base, and the presence of a protic solvent
are all crucial for the success of the reaction. Thus, when 4-(4-
methoxyphenyl)-1-phenyl-1-butyne was treated with 5 equiv of
electrophile and 2 equiv of NaOMe in a mixed solvent system of
3:4 CH2Cl2/MeOH at -78 °C (Conditions C), iodo- (25) and
bromotrienone (26) were obtained in almost quantitative yields.
These halogen-promoted aromatic cyclizations not only quickly
construct a complex, highly functionalized carbon skeleton but also
provide a very useful handle for further structural manipulation.
For example, the iodospirotrienone 3 produced by this strategy can
be employed in palladium-catalyzed reactions, such as the car-
boannulation of alkynes,8 to quickly achieve additional molecular
complexity (eq 2).
Supporting Information Available: General experimental proce-
dures and spectral data for all of the starting materials and products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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A tentative mechanistic interpretation to explain the formation
of the spirotrienone might reasonably assume an initial interaction
of electrophilic iodine with the alkyne residue to give the iodonium
intermediate A (Scheme 1). A can then undergo intramolecular ipso-
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