Synthesis of 1,3-Diynes via Cadiot-Chodkiewicz Coupling of Volatile, in Situ Generated Bromoalkynes

Article abstract of DOI:10.1021/acs.orglett.8b02975

A convenient Cadiot-Chodkiewicz protocol that facilitates the use of low molecular weight alkyne coupling partners is described. The method entails an in situ elimination from a dibromoolefin precursor and immediate subjection to copper-catalyzed conditions, circumventing the hazards of volatile brominated alkynes. The scope of this method is described, and the internal 1,3-diyne products are preliminarily evaluated in ruthenium-catalyzed azide-alkyne cycloadditions.

Full text of DOI:10.1021/acs.orglett.8b02975

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 1,3-Diynes via Cadiot−Chodkiewicz Coupling of
Volatile, in Situ Generated Bromoalkynes
Phil C. Knutson, Haleigh E. Fredericks,† and Eric M. Ferreira*
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
S
* Supporting Information
ABSTRACT: A convenient Cadiot−Chodkiewicz protocol
that facilitates the use of low molecular weight alkyne coupling
partners is described. The method entails an in situ
elimination from a dibromoolefin precursor and immediate
subjection to copper-catalyzed conditions, circumventing the
hazards of volatile brominated alkynes. The scope of this
method is described, and the internal 1,3-diyne products are
preliminarily evaluated in ruthenium-catalyzed azide-alkyne
cycloadditions.
n organic synthesis, 1,3-diynes have been attractive targets
I
for several decades.1 The structural motif appears in many
natural products,1b bioactive molecules,2 intriguing materials,3
and supramolecular tools,1a,4 and it has been exploited as a
central functionality in several complexity-generating hexahy-
dro-Diels−Alder cycloadditions.5,6 The Glaser−Eglinton−Hay
coupling represents a straightforward synthesis of homo-
coupled 1,3-diynes,7 but producing cross-coupled diynes is
more complicated. Among methods for accessing the cross-
coupled variant, the Cadiot−Chodkiewicz coupling8 stands out
as the most widely employed, exemplified by its use in a
number of natural product syntheses.9 Recent examples
utilizing this coupling include polyyne natural products
ivorenolide A9a,b and 4,8-dihydroxy-3,4-dihydrovernoniyne
(Figure 1).9c This coupling strategy has also been employed
to provide important intermediates en route to natural
products, such as toward the selaginpulvilins9d and the
dictyodendrins.9e
Figure 2. 1,3-Diynes from volatile bromoalkynes: synthetic strategy.
ideal for accessing this unsymmetrical diyne, although we were
wary of potential issues. Namely, it is well appreciated that
homocoupling can complicate these transformations, partic-
ularly in cases where the reactants have similar electronic
characteristics (e.g., aryl−aryl, alkyl−alkyl).1a,b,11 We consid-
ered two possible sets of coupling precursors (Figure 2a). In
Case 1, a bromoalkyne would be coupled with propyne, but we
anticipated this strategy would be complicated by the latter’s
low boiling point (−23 °C).12 Case 2, where we switch the
bromination of the coupling partners, appeared more attractive
from this perspective. Indeed, 1-bromopropyne is known, but
previous reports13 indicated serious hazardous properties.14 To
circumvent the handling of this compound, we conceived of an
in situ approach involving direct elimination from a
dibromoolefin and immediate coupling (Figure 2b). In several
copper- and palladium-catalyzed reactions, 1,1-dibromo-1-
alkenes have been used to generate alkynyl electrophiles,
During the course of our synthesis of gelsenicine,10 our
strategy evolved to utilize a diene−diyne as a key precursor
(Figure 2). The Cadiot−Chodkiewicz reaction appeared to be
Received: September 17, 2018
Figure 1. 1,3-Diynes in natural product synthesis.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02975
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Reaction Optimization
a
b
Elimination conditions: NaH: THF, 0 to 23 °C, 24 h; TBAF·3H2O: DMF, 60 °C, 3 h; LiHMDS: THF, −78 to 0 °C, 1.5 h. Bromoalkyne
c
intermediate 2a was not observed; coupling was not attempted. Et3N used as base instead of n-BuNH2.
suggesting promise for this strategy.15,16 Herein, we report the
development of this elimination/coupling procedure, used
successfully in our total synthesis effort,10 and we demonstrate
its viability as a method to directly couple volatile alkyne
substrates. We also describe preliminary reactivity of these
diyne compounds in Ru-catalyzed azide−alkyne cycloaddi-
tions, highlighting that 1,2,3-triazoles can be obtained from
these diynes in a chemo- and regioselective fashion.
There have been a few reports using 1,1-dibromoalkenes to
generate 1-bromo-1-alkynes in situ as precursors for 1,3-
diynes.16a−c Unfortunately, these strategies require excess
terminal alkyne or elevated temperature (70−100 °C), and
none utilized a volatile haloalkyne intermediate. These cases
contrasted with conditional stipulations in our desired
coupling. First, the terminal alkyne needed to be used as the
limiting reagent, chiefly because that coupling component had
already been advanced multiple steps in our total synthesis
campaign. Second, the temperature needed to be kept low so
as to maximize the quantity of volatile alkyne in solution.
Although we would consider all options, we felt that in general
we wanted to steer away from Pd-based conditions that could
result in byproduct formation from enyne reactivity.
(i.e., TLC). NaH17 did not induce the elimination (entry 1),
while TBAF·3H2O in DMF18 was incompatible with the
coupling. We found that LiHMDS in THF19 could induce the
elimination at the desired lower temperature, and the desired
1,3-diyne product was observed in low yield when this was
subjected to Cu(I) coupling conditions (CuCl, NH2OH·HCl,
DMF,20 entry 3). Palladium/copper mixed systems11c,21 were
not as effective (entries 4 and 5). However, we found that
using aqueous conditions with Cu(I)1d in the coupling process
were ultimately the most promising (entries 7 and 8).
With this lead, we then switched to the volatile 1-
bromopropyne (Table 1, entries 9−13). Because the
dibromoolefin is also relatively volatile, we found that the
simplest protocol was to synthesize this directly from
acetaldehyde using the zinc-based dibromoolefination con-
ditions originally described by Corey and Fuchs (eq 1).22,23
Simply passing the reaction mixture through a plug of silica
gel to remove the phosphine byproducts and removing the
volatiles afforded the crude dibromoolefin in sufficient purity
to be advanced directly. Testing this compound in the above
optimized conditions showed they were not as effective. We
Our optimization studies are presented in Table 1. Our
strategy here involved first testing with hydrocinnamaldehyde-
based dibromoolefin 2a, whose in situ elimination would be
more straightforward to monitor by conventional methods
B
DOI: 10.1021/acs.orglett.8b02975
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Letter
hypothesized that using a significant excess of the in situ
generated bromopropyne was not advantageous, and even-
tually, we found that 1.5 equiv was the optimal amount to
employ with an increased loading of CuCl/NH2OH·HCl to
ensure efficient reaction completion.
Scheme 2. Coupling of in Situ Generated 1-Bromobutyne
With this protocol fully optimized, we proceed to evaluate
this coupling of in situ generated 1-bromopropyne with a range
of terminal alkynes (Scheme 1). Aryl alkynes were generally
Scheme 1. Coupling of in Situ Generated 1-Bromopropyne
coupled effectively to afford products 8d-− in excellent yields.
Benzyl ether 8g was also formed, albeit in diminished yield
compared to the related propynyl example.
1,3-Diynes have been shown to be precursors to thiophenes
and pyrroles, among other transformations.1c Toward further
expanding the potential applications of these compounds, we
sought to investigate 1,3-diyne reactivity in metal-catalyzed
azide−alkyne cycloadditions.26 While a few cases using other
catalyst systems for intermolecular azide−alkyne cycloaddi-
tions with internal alkynes have been reported,27 ruthenium-
catalyzed systems have been by far the most prominent.28
Internal 1,3-diynes can pose intriguing questions regarding
cycloaddition reactivity, with respect to both chemoselectivity
and regioselectivity.29 In a standard 1,3-diyne cycloaddition,
there can be up to eight possible products. Selective reactivity
has been successfully addressed to some extent with terminal
1,3-diynes using Cu catalysis via acetylide formation,30 but that
mechanistic strategy cannot be extended to internal alkynes.
Other selectivity modes, however, may be achievable.31
When propargylic alcohol 7o was subjected to Ru-catalyzed
conditions as described by Fokin, an approximately 5:1 ratio of
triazole products 9 and 10 were observed (Scheme 3). Cu-
a
CH2Cl2 was added to the coupling reaction to solubilize the
b
c
reactants. Coupling stirred 4 h at 0 °C and 2 h at 23 °C. Gram scale.
Scheme 3. 1,3-Diynes in Azide−Alkyne Cycloadditions
effective. Electron-neutral aryl alkyne coupling partners
afforded the 1,3-diyne product in good yields (7a,b).
Comparatively, terminal alkynes with more electron-rich
arenes were lower yielding (7d,e), while electron-deficient
arenes were tolerated unless the withdrawing functionality was
sensitive to reduction (i.e., 7f). Ortho-substituted aryl bromide
7j could be obtained, a compound with a convenient coupling
handle for potential further manipulations.
Pyridine 7k was formed in 69% yield, and enynes were also
effective (7l). Alcohols and ethers were successful alkyne
coupling partners, where the products could be formed in
generally good yields. Notably, the transformation also
performs reasonably consistent upon scaleup; ether 7p was
formed in 76% yield on gram-scale.24 Propiolates and
silylalkynes were ineffective in this coupling procedure
(7t,u).25
We also evaluated our coupling procedure using in situ
generated 1-bromobutyne. 1-Bromobutyne is relatively volatile
(bp = 90−91 °C), but it is not reported to have hazardous
properties similar to those of 1-bromopropyne. However, the
method can serve as a useful strategy to circumvent handling 1-
butyne (bp = 8 °C). Scheme 2 illustrates examples of couplings
originating from 1,1-dibromobutene. Aryl and heteroaryl
alkynes were again successful. Propargylic alcohols were
catalyzed cycloaddition attempts using this diyne were
unsuccessful.29a Interestingly, in the Ru case only the
alcohol-adjacent alkyne was reactive; the other alkyne
remained intact. Our observation matched hypotheses
regarding cycloaddition regioselectivity for internal alkynes
with Ru catalysis,32,33 where hydrogen bond donors are
presumed to enable catalyst coordination with the ligating
C
DOI: 10.1021/acs.orglett.8b02975
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Letter
chloride to favor the regioselectivity outcome for the observed
triazole isomer (intermediate 11). Notably, the alcohol
imparting chemoselectivity between two alkynes has not been
observed in this transformation. When benzyl ether diyne 7q
was utilized, which lacks this hydrogen bond donor, even
better regioselectivity was observed (12). The alkyne chemo-
selectivity was somewhat compromised, however, in that the
second alkyne became competitive in cycloaddition as triazole
12 was being formed. Regioselectivities for both additions were
excellent (>19:1); origins of these effects are presently unclear.
Mechanistically, the most nucleophilic carbon of an alkyne
precursor is expected to become C-4 in the triazole,34 but
assessments of relative nucleophilicities of the alkyne carbons
were inconclusive.35 To our knowledge, ethereal groups have
not been invoked as catalyst directing moieties in these
cycloadditions, but they could be influential here. In this
preliminary study, it appears that synthetically useful levels of
selectivity can be attained; factors that impact chemo- and
regioselectivity in these azide−alkyne cycloadditions appear to
be somewhat interconnected and merit further investigation.
In summary, we have developed a useful addition to the
Cadiot−Chodkiewicz alkyne−alkyne cross coupling. The in
situ generation of the reportedly hazardous 1-bromo-1-
propyne intermediate allows an efficient and convenient
workaround to using volatile unit alkynes as coupling partners.
We have also showed that this method can be readily scaled for
applications in complex molecule synthesis. Preliminary studies
in azide−alkyne cycloadditions demonstrate that synthetically
useful chemo- and regioselectivities can be achieved. Further
investigations of the synthetic utility of these 1,3-diynes are
currently underway.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02975.
Experimental procedures, compound characterization
data, and spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: emferr@uga.edu.
ORCID
Eric M. Ferreira: 0000-0001-9412-0713
Present Address
†(H.E.F.) Medical College of Georgia, Augusta University,
Augusta, GA 30912
Notes
The authors declare no competing financial interest.
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The National Institutes of Health (NIGMS, R01GM110560)
is gratefully acknowledged. H.E.F. was supported by the
National Science Foundation and Environmental Protection
Agency (CHE-1339674: NSMDS). Mass spectrometry data
were acquired on an instrument supported by the NIH
(S10RR028859).
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DOI: 10.1021/acs.orglett.8b02975
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