Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes

Article abstract of DOI:10.1039/c5ob01837d

A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold fo

Full text of DOI:10.1039/c5ob01837d

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Lewis acid-promoted [2 + 2] cycloadditions of
alkenes with aryl ketenes†
Cite this: DOI: 10.1039/c5ob01837d
E. M. Rigsbee,‡a C. Zhou,‡b C. M. Rasik,b A. Z. Spitz,c A. J. Nicholsd and
Received 2nd September 2015,
Accepted 22nd September 2015
M. K. Brown*b
DOI: 10.1039/c5ob01837d
www.rsc.org/obc
A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes
is presented. The process involves the in situ generation of a
ketene in the presence of a Lewis acid. The utility of products is
demonstrated towards the synthesis of a common scaffold found
in several natural product families.
Ketene–alkene [2 + 2] cycloadditions have been established to
be important reactions for chemical synthesis.1 These reac-
tions, however, do not function well with poorly reactive and
unstable monosubstituted aryl ketenes.2,3 For example, cyclo-
addition of phenylketene with cyclopentadiene only provides
the cycloadduct in 26% yield (Scheme 1).2 Cycloaddition of
this type are significant, as the cyclobutanone products gene-
rated would represent an important scaffold for chemical syn-
thesis.4 Herein, we provide a solution to this problem through
the development of a Lewis acid-promoted [2 + 2] cyclo-
addition with monosubstituted aryl ketenes (Scheme 2b). The
utility of this method is also demonstrated by the synthesis of
a scaffold that is common to several natural product families.
Scheme 2 Lewis acid-promoted ketene–alkene [2 + 2] cycloadditions.
As part of a program toward developing new methods for
the synthesis of cyclobutanes, we have introduced Lewis acid-
promoted ketene–alkene [2 + 2] cycloadditions.5 In our initial
installment, we developed a method for cycloaddition of
“stable” disubstituted ketenes (Scheme 2a).5a In these reac-
tions the ketene is fully generated prior to addition of alkene
and Lewis acid. To extend the utility of this method towards
use of unstable ketenes, like monosubstitued aryl ketenes, a
new protocol was developed as pregeneration of the ketene was
not possible. This initiative led to the identification of con-
ditions that allow for the in situ generation of a monosubsti-
tuted aryl ketene in the presence of a Lewis acid (Scheme 2b).6
Due to efforts towards the total synthesis of gracilioether
F (5), a method for cycloaddition with an “unstable” vinyl-
ketene (Scheme 3) was developed.5c In this reaction, because
mono-substituted ketenes undergo dimerization, the ketene
needed to be generated in situ at low concentrations. This was
achieved by slow addition of acid chloride 1 to a solution of
Lewis acid, i-Pr2NEt, and alkene 2.5b
Scheme 1 [2 + 2] Cycloadditions with aryl ketenes.
aSSCI, A Division of Albany Molecular Research Inc, 3065 Kent Avenue West
Lafayette, IN 47906-1076, USA
bIndiana University, Department of Chemistry, 800 E. Kirkwood Ave, Bloomington,
IN 47405, USA. E-mail: brownmkb@indiana.edu
cAlbert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
dEli Lilly and Co., 307 Merrill St., Indianapolis, IN 46225, USA
Due to the known instability of monosubstituted aryl
ketenes, the method illustrated in Scheme 3 seemed appropri-
ate for initial reaction development.5c The optimization of the
test reaction is outlined in Table 1. We found that the dropwise
†Electronic supplementary information (ESI) available. CCDC 1421862. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c5ob01837d
‡These authors contributed equally to the completion of this work.
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Scheme 3 Summary of related work.
Table 1 Optimization of reactions conditionsa
Chart 1 Substrate scope. See the ESI† for experimental details, yield
refers to yield of isolated product. dr = diastereomeric ratio – deter-
mined by 1H NMR analysis of the unpurified reaction mixtures. In all
cases, expect where noted, the dr of the unpurified reaction mixtures
b
and purified samples are the same. a Reactions with two equiv. alkene.
Entry Lewis acid Acid chloride equiv. Alkene equiv. Yieldb (%)
c
dr of the purified mixture, dr of the unpurified mixture is 14 : 1. Reac-
tion run for 3 h. ∼10% of a regioisometric product was performed.
1
2
3
4
5
EtAlCl2
Me2AlCl
Me3Al
Me3Al
Me3Al
1
1
1
1
3
20
20
20
2
22
20
91
74
40
but useful yield. This method has proven successful with both
cyclic and acyclic alkenes. The scope of this reaction includes
both activated (e.g., diene, allyl silane) and unactivated alkenes
(e.g., 1-hexene, cyclopentene). Trisubstituted olefins are also
suitable substrates for this reaction (product 13). Aryl acid
chlorides of varying steric (vide infra, product 20) and elec-
tronic properties (products 15–16) were also found to be viable
substrates. Attempted cycloaddition with either acetyl chloride
or butanoyl chloride resulted in low yields of the cycloaddition.
This can be attributed to the slower rate of ketene formation
with the less acidic acid chloride. Finally, the observed
diastereomeric ratios are likely, in part, due to equilibration
1
a See the ESI for experimental details. b Yield determined by 1HNMR
analysis of the unpurified reaction mixture with an internal standard.
addition of a solution of acid chloride 6 to a mixture of alkene,
base, and Lewis acid at −78 °C then warming to −45 °C was
critical to success for formation of cyclobutanone 8. Entries
1–3 show that weaker aluminum Lewis acids provided the
highest yield of the cycloadduct 8, which led to our use of
Me3Al. Higher equivalents of alkene afforded the cyclobuta-
none product 8 in excellent yields; however, as low as two
equivalents of alkene still provided good yields of the desired
product (Table 1, entries 3 and 4). We propose the success of
this method is due to the ephemeral formation of a highly
reactive monosubstituted ketene-Lewis acid adduct (e.g., inter-
mediate analogous to 3, Scheme 3). By maintaining a low con-
centration of the reactive intermediate and relatively high
concentration of the alkene, [2 + 2] cycloadditions can occur
with low rates of ketene dimerization and decomposition.
Alternatively, the acid chloride can be used in excess if desired
(Table 1, entry 5), albeit with lower yields.
Chart 1 displays the substrate scope of the optimized reac-
tion. All reactions, except where noted, were performed with
20 equivalents of alkene. However, as noted in Table 1, entry 4,
fewer equivalents of alkene provided the product in reduced
Scheme 4 Reaction with chiral alkene.
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the synthesis of a scaffold that is common to several natural
product families.
Acknowledgements
Indiana University and the National Institutes of Health
(R01GM110131) are also acknowledged for generous financial
support.
Notes and references
1 For excellent reviews, see: (a) B. B. Snider, Chem. Rev., 1988,
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Wiley, New York, N.Y., 1995; (d) T. T. Tidwell, Ketenes II,
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Eur. J. Org. Chem., 2006, 563–576; (f) R. L. Danheiser,
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2 (a) M. Rey, S. Roberts, A. Dieffenbacher and A. S. Dreiding,
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Scheme 5 Synthesis of a common scaffold.
3 Cycloadditions with aryl-substituted ketene iminium salts
and alkenes are known. J. B. Falmagne, J. Escudero,
S. Taleb-Sahraoui and L. Ghosez, Angew. Chem., Int. Ed.,
1981, 20, 879.
4 (a) E. Lee-Ruff and G. Mladenova, Chem. Rev., 2003, 103,
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under the reaction or workup conditions. This is due to the
known configurationally instability of the aryl substituted
stereocenter.7,8 Furthermore, equilibrium diastereomeric ratios
for bicyclic systems such as 8 are known to be near 1 : 1 dr.7
Reaction with chiral allylsilane 17 led to formation of cyclo-
butanone 18 with excellent levels of diastereoselectivity
(Scheme 4).9 In this example, the precious alkene component
was used as the limiting reagent.
To demonstrate the utility of the method, a scaffold that is
prevalent in several natural product families was prepared. The
synthesis commences with [2 + 2] cycloaddition of o-bromoaryl
substituted ketene derived from acid chloride 19. Cyclobuta-
none 20 was accessed in 80% yield on gram scale. Subsequent
deprotonation with KHMDS and alkylation with methyl iodide
afforded a single diastereomer of product. Baeyer–Villiger oxi-
dation provided lactone 21 in good yield over two steps.5c
Upon addition of t-butyllithium, lithium–halogen exchange
occurred followed by an intramolecular acyl substitution to
generate 22. Structures related to 22 are common to several
natural products such as 25,10 24,11 and 23 (Scheme 5).12
Ed., 2014, 53, 14522–14526; (d)
For a DFT studies
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Y. J. Hong, D. J. Tantillo and M. K. Brown, Org. Lett., 2014,
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6 For examples of ketene generation in the presence of a
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Conclusions
7 M. Rey, S. M. Roberts, A. S. Dreiding, A. Roussel,
H. Vanlierde, S. Toppet and L. Ghosez, Helv. Chim. Acta,
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In summary, we have developed a method for the cycloaddition
of aryl ketenes and alkenes. This process shows broad scope,
includes highly diastereoselective variants, and has enabled
8 See the ESI† for details.
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Org. Biomol. Chem.
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