C-Alkynylation of Cyclopropanols

Article abstract of DOI:10.1021/acs.orglett.5b01789

Alkynylation of cyclopropanols with 1-bromo-1-alkynes has been devised for easy access to synthetically useful alk-4-yn-1-ones. This method broadens the utility of attractively functionalized cyclopropanols as a new class of homoenolate equivalent in C-C bond formation.

Full text of DOI:10.1021/acs.orglett.5b01789

Letter
pubs.acs.org/OrgLett
C‑Alkynylation of Cyclopropanols
R. V. N. S. Murali, Nagavaram Narsimha Rao, and Jin Kun Cha*
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: Alkynylation of cyclopropanols with 1-bromo-1-alkynes has been
devised for easy access to synthetically useful alk-4-yn-1-ones. This method broadens
the utility of attractively functionalized cyclopropanols as a new class of homoenolate
equivalent in C−C bond formation.
Scheme 2. Alkynylation of Cyclopropanols 1a−c
lkylation of ketones, esters, and other carboxylic acid
Aderivatives is a staple of frequently utilized C−C bond-
Scheme 1. Homoenolate Alkylation and Acylation
forming reactions. Asymmetric alkylation reactions of carbox-
ylic acid derivatives are typically achieved under the aegis of
chiral auxiliaries.1,2 Recent advances in organocatalysis offer a
convenient method for enantioselective alkylation of alde-
hydes.3 Analogous C−C bond formation of homoenolates gives
a useful alternative but has received less attention. Previous
work was limited primarily to homoenolates bearing less
electrophilic esters, amides, and nitriles.4 The keto homo-
enolates are prone to cyclize to the corresponding cyclo-
propoxides, thus requiring a more demanding balance between
stability and reactivity for applications to C−C bond formation.
Keto homoenolates are more advantageous than ester
homoenolates for the rapid assembly of two large segments.
We recently combined ring opening of readily available
cyclopropanols5 with transmetalation to shift the otherwise
unfavorable equilibrium for in situ generation of β-keto
homoenolates. Specifically, we first developed SN2′ alkylation
of cyclopropanols with allylic halides or propargylic sulfonates
and C-acylation of cyclopropanols.6 We report herein facile
alkynylation of cyclopropanols with 1-bromo-1-alkynes for the
preparation of alk-4-yn-1-ones to broaden the utility of
cyclopropanols as a homoenolate equivalent (Scheme 1).
Cross-coupling of cyclopropanols with readily available
bromoalkynes7 was next chosen to utilize cyclopropanols as a
new class of attractively functionalized keto homoenolates. The
use of bromoalkynes or alkynyliodoniium salts as electrophilic
alkynes was well documented in combination with various
Received: June 20, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Preparation of Furans from γ-Alkynones
Scheme 4. Elaboration of γ-Alkynones
Figure 1. Additional examples of alkynylation.
nucleophiles, including mixed zinc−copper reagents,8 for C−C
and C−heteroatom bond formation.9−11 Notwithstanding the
aforementioned SN2′ alkylation and C-acylation reactions of
cyclopropanols, the reactivity profile of cyclopropanols as a
homoenolate equivalent in the C−C bond formation remains
to be fully defined.12 Additionally, the resulting adducts, γ-
alkynones, have long been known to be valuable intermediates
for organic synthesis. The juxtaposition of the keto and alkyne
functionalities in alk-4-yn-1-ones is well suited for elaboration,
especially in light of recent progress in gold- and platinum-
catalyzed transformations of alkynes.13
By adaptation of coupling reaction conditions for SN2′
alkylation of cyclopropanols, a THF solution of cyclopropanol
1a was treated at rt with commercially available Et2Zn, followed
by CuCN·2LiCl and 1-bromo-1-hexyne, to yield the expected
coupling product 2a in 75% yield (Scheme 2). Both Et2Zn and
CuCN·2LiCl were required, and in their absence, a complex
mixture was found with no alkynylation product. Substituents
on 1-bromo-1-alkynes exerted little influence: irrespective of
the nature of R6 (an alkyl, phenyl, or ester group), the resultant
γ-alkynones 2a, 3a, and 4a were isolated in comparable yields.
Similarly, the alkynylation reactions of cyclopropanols 1b and
1c proceeded cleanly. Additional examples show a wide
substrate scope and compatibility with common functional
groups, such as an enyne and an α,β-unsaturated ester (e.g., 12,
15, 16, and 20), under mild conditions (Figure 1). An alcohol
substituent (e.g., 9 from 6-bromo-5-hexyn-1-ol) is also tolerated
and can thus be introduced without a protecting group. Also
included is the convenient preparation of enantiopure adducts
10−20.
As for synthetic applications, cyclization of the γ-alkynone
adducts to furans was selected in part owing to the utility of
attractively substituted furans.14 Furans are embedded in a
number of natural products and have been employed as useful
intermediates in organic synthesis. Among a plethora of known
methods for preparing furans, cyclization of γ-alkynones to
furans is a reliable approach and has been effected under acidic
or basic conditions, as well as by transition-metal-catalyzed
cycloisomerization reactions.15,16 The latter method allows easy
preparation of furans under mild reaction conditions, but ready
access to judiciously substituted γ-alkynones has been lacking.
B
DOI: 10.1021/acs.orglett.5b01789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.; Ashton, K.;
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As shown in Scheme 3, the present method denotes a
convergent, efficient route to both functionalized γ-alkynones
and 2,5-disubstituted/2,3,5- trisubstituted furans.
Cyclization of 2a took place smoothly under conventional
acidic conditions (the use of p-TsOH) in toluene at 85 °C to
give 2,3,5-trisubstituted furan 21 in 75% yield (Scheme 3, entry
1). The corresponding cyclization of 3a having a phenyl-
acetylene was significantly slower under identical conditions
(Scheme 3, entry 2). An effective solution was found in Au(I)
catalysis by the method of Krause to yield 22 in 70% yield at rt
(Scheme 3, entry 3).15a When alkynoate 4a was subjected to
acidic conditions, formation of 23 (70%) was accompanied by
that of 24 (28%) due to surprisingly facile decarboxylation of
the former (Scheme 3, entry 4). A satisfactory result was again
available by Au(I)-catalyzed cycloisomerization of 4a (Scheme
3, entry 5). 2,5-Disubstituted furans 25 and 26 were also easily
prepared from 4c and 15 under similar conditions.
(7) (a) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727. (b) Miller, S. I.; Ziegler, G. R.;
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In addition to the aforementioned preparation of substituted
furans, 1,4-diketones are readily accessible from γ-alkynones by
employing wet toluene, as exemplified by the synthesis of 27
(Scheme 4). 1,4-Diketones have been utilized as a useful
precursor to a number of structural motifs.6b A common
intermediate is presumed to be involved in the formation of
furans and 1,4-diketones.
In conclusion, a convenient cross-coupling reaction between
cyclopropanols and 1-bromo-1-alkynes offers a versatile
method for preparing attractively functionalized alk-4-yn-1-
ones. Segment coupling is particularly useful for building a
rapid increase in molecular complexity due to an expedient
bond connection under mild conditions and with operational
simplicity. Synthetic applications of chiral γ-alkynones, which
capitalize on directing effects of resident stereocenters, are
currently in progress.
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Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (b) Zhang, X.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
(11) For a review, see: Brand, J. P.; Waser. Chem. Soc. Rev. 2012, 41,
4165.
Experimental procedures and spectroscopic data for key
intermediates. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01789.
(12) The presence of a β-keto group reduces the nucleophilicity of
the presumed homoenolate species. Consequently, it is not clear
whether many commonly used electrophiles could be employed
successfully for the C−C bond formation. For example, the coupling
reaction between cyclopropanols and aldehydes has so far failed under
various conditions.
AUTHOR INFORMATION
■
Corresponding Author
(13) For reviews, see: (a) Furstner, A.; Davies, P. W. Angew. Chem.,
̈
Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180. (c) Arcadi, A. Chem. Rev. 2008, 108, 3266. (d) Shen, H. C.
*E-mail: jcha@chem.wayne.edu.
Notes
Tetrahedron 2008, 64, 3885. (e) Jimen
Chem. Commun. 2007, 333.
́
ez-Nunez, E.; Echavarren, A. M.
́
̃
The authors declare no competing financial interest.
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(b) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
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ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1265843) for generous financial
support.
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DOI: 10.1021/acs.orglett.5b01789
Org. Lett. XXXX, XXX, XXX−XXX