Copper-Mediated Nucleophilic Addition/Cascade Cyclization of Aryl Diynes

Article abstract of DOI:10.1021/acs.orglett.6b03787

Treatment of diyne substrates with sulfinate salts under the action of copper(II) triflate results in a cascade cyclization reaction. The reaction involves nucleophilic addition of the sulfinate and formation of two new C-C bonds with concomitant cleavage of an aryl C-H bond. The reaction proceeds in good yields with a range of diyne precursors and sulfinate salts. Preliminary mechanistic analysis reveals a rare example of an operative ionic mechanism in contrast to other related cyclizations.

Full text of DOI:10.1021/acs.orglett.6b03787

Letter
pubs.acs.org/OrgLett
Copper-Mediated Nucleophilic Addition/Cascade Cyclization of Aryl
Diynes
Geoffrey S. Sinclair, Tianyu Yang, Sunmeng Wang, Wei H. Chen, and Derek J. Schipper*
Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
S
* Supporting Information
ABSTRACT: Treatment of diyne substrates with sulfinate salts under the action of copper(II) triflate results in a cascade
cyclization reaction. The reaction involves nucleophilic addition of the sulfinate and formation of two new C−C bonds with
concomitant cleavage of an aryl C−H bond. The reaction proceeds in good yields with a range of diyne precursors and sulfinate
salts. Preliminary mechanistic analysis reveals a rare example of an operative ionic mechanism in contrast to other related
cyclizations.
apid and efficient construction of complex molecular
Scheme 1. Cyclization of Aryl Diynes
R
structures has become an increasingly important goal in
organic chemistry. This ever-demanding need stems from the
desire to limit the number of synthetic steps and hence reduce
the costs associated with a synthesis.1 A typical class of
reactions that fit these needs are tandem or domino reactions.
With these methods, a significant increase in molecular
complexity can be afforded through multiple steps occurring
in a cascade solely due to the reactivity installed in the initial
steps.2 In more recent years, the functionalization of carbon−
hydrogen bonds by transition metals has become a linchpin in
the development of efficient synthetic pathways.3 The
associated efficiency is gained by activating and functionalizing
previously nonfunctionalized components of organic substrates.
Therefore, approaches that combine C−H functionalization
with tandem reactions are highly desired because they allow for
increased efficiency in the elaboration of molecular architec-
tures. Additionally, exploring mechanistically distinct pathways
opens the door to developing new, increasingly efficient
methods.
proceed through such as the turnover-requisite proto-
demetalation and thiol radical-producing silver salt precursors.
As such, there is currently a paucity of synthetic methods that
can enable incorporation of additional functionality, such as
nucleophiles.
Herein, we describe a novel synthetic method in which an
ionic nucleophilic addition occurs in tandem with a cyclization.
This method is technically simple and proceeds via a
mechanistically distinct pathway where the incorporation of
the nucleophile facilitates transition-metal mediated C−C bond
formation and C−H bond functionalization (Scheme 1, eq 3).
The copper-mediated tandem reaction was first discovered
using aryl 1,6-diyne 1a with Cu(II) triflate and nucleophilic
sulfinate salt 2a, which yielded a mixture of products 3a and 4
While C−H functionalization and tandem reactions have
been studied in detail, instances of their combination are rare.4
In a seminal example, Liu and co-workers report the formal [3
+ 2] cyclization of aryl diynes where C−H functionalization is
coupled with the tandem formation of an additional C−C bond
to yield a tricylic ring product (Scheme 1, eq 1).5 The
cyclization mechanism is suggested to proceed through the
formation of a nine-membered cationic ring that is closed by a
5-exo-dig cyclization and the catalytic cycle turned over by a
proto-demetalation event. More recently, Liang and co-workers
have demonstrated the ability to also install new functionality
such as radical thiol incorporation during the formation of
formal [3 + 2] cyclization products (Scheme 1, eq 2).6 These
noteworthy examples, while enlightening, have limitations in
scope and functionality due the mechanistic pathway they
Received: December 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03787
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Letter
after a reaction time of 16 h (Table 1). The product 3a was
identified and characterized by single-crystal X-ray crystallog-
a
Table 1. Optimization of Conditions
a
entry
solvent
temp (°C)
copper (equiv)
% yield of 3a/4
b
1
2
3
4
5
6
DCM
DCE
DCE
DCE
DCE
DCE
DCE
rt
rt
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.0)
16:15
b
20:10
b
100
100
100
100
100
42:0
e
b
Cu(OAc)2 (1.0)
33:0
e
b
CuSO4 (1.0)
36:0
e
b
Cu(BF4)2 (1.0)
28:0
c
d
7
Cu(OTf)2 (2.0)
83:0
a
Conditions: sodium p-toluenesulfinate hydrate (2 equiv), aryl diyne
(1 equiv), and Cu(II) reagent in solvent (0.025 M) with stirring at the
Figure 1. Scope of copper-mediated C−S bond formation via cascade
cyclization. Conditions: aryl diyne (1 equiv), sulfinate salt (2 equiv),
Cu(OTf)2 (2 equiv), in DCE (0.025 M) at 100 °C for 16 h. Isolated
yields.
b
indicated temperature for 16 h. 1H NMR yield of the major product
c
using 1,3,5-trimethoxybenzene as an internal standard. Anhydrous
d
sodium p-toluenesulfinate (2.0 equiv) is applied. Separated yield.
e
Hydrous copper reagent.
(3i,m,o), and acetyl- (3j) groups where yields ranging from
41% to 90% were obtained. Diynes 1b and 1o were further
applied to investigate the scope of various nucleophiles which
include the methyl (2b) as well as phenyl (2c) sulfinate salts.
The yields of products obtained for these reactions (3p,q) were
lower than with the comparable p-tolyl sodium sulfinate salt.
However, halogen substitution on the sulfinate salt (2d,e) was
also tolerated, giving chloro- and bromo-substituted products
3r and 3s in 62% and 65%, respectively. In addition, electron-
rich aromatics (1k,l) as well as asymmetric substrates
containing a single alkylated or terminal alkyne only provided
trace amounts of cyclized product.
Specifically for diyne substrates with electron-donating
substituents on the aromatic ring (1k,l), it is possible to
attribute these diminished yields to either the low activity of
electron rich aromatics or, alternatively, poisoning of the
copper(II) reagent. To test this hypothesis, a poisoning
experiment was carried out in which two reactions were
performed on substrate 1h, one containing an additive of 1
equiv of 1k and the other with no additive (Scheme 2). The
raphy. We then continued with a series of reactions to optimize
conditions to maximize the yield of product 3a while
eliminating the unwanted side product 4. An initial solvent
screen revealed that chlorinated solvents such as dichloro-
methane (DCM) (Table 1, entry 1) produced the target
compound, while nonchlorinated solvents showed no sign of
product formation.7
Switching the solvent to 1,2-dichloroethane (DCE) (Table 1,
entry 2) gave slightly better results while also allowing higher
reaction temperatures to be examined. Increasing the reaction
temperature from room temperature to 100 °C afforded a rise
in yield of product 3a while eliminating side product 4 (Table
1, entry 3), although further temperature increases resulted in
starting material decomposition. While a diverse range of
copper(II) reagents were shown to be capable of producing
product 3a, the most effective reagent in facilitating this
reaction was Cu(OTf)2 (Table 1, entry 4−6). Finally, applying
2 equiv of Cu(OTf)2 to the reaction mixture offered a
significant increase to 83% yield of desired product (Table 1,
entry 7) and led us to establish the optimal conditions.
With optimized conditions in hand, we proceeded to explore
the substrate scope of the reaction, the results of which are
outlined in Figure 1. After identifying the reaction with a
nitrogen-based tether (1a), carbon- (1b,c) and oxygen-based
(1d) tethers were synthesized and employed as substrates to
deliver products 3b−d. The dimethyl malonate substrate gave
an isolated yield of 85% of product 3b. A range of substrates
with electron-withdrawing group substituted aromatics (1e−o)
were also synthesized and tested. These include trifluorometh-
yl- (3e and 3n), chloro- (3f), nitro- (3g), nitrile- (3h), fluoro-
Scheme 2. Poisoning Experiment
B
DOI: 10.1021/acs.orglett.6b03787
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reaction without additive resulted in a 79% yield of the desired
product, while the reaction with 1k as additive resulted in only
trace amounts of product 3h. This indicated that it was, in fact,
a poisoning of the copper reagent that was responsible for the
diminished yields obtained by electron-rich aromatic substrates,
as the reaction of substrate 1h to product 3h was also inhibited
by the presence of 1k.
Scheme 5. Internal Competition Experiments
To understand the observed reactivity, we began our
investigation into the reaction mechanism with radical-
inhibition experiments to determine if the reaction proceeded
by a radical mechanism (Scheme 3). The reaction on substrate
Scheme 3. Radical-Trapping Experiments
evaluate reaction kinetics and probe the C−H bond cleavage
step. Deuterated asymmetric substrate 7 was first synthesized
and subjected to the optimal reaction conditions. The two
products 8a and 8b were produced in a 1:1 ratio,14 and no
significant isotopic effect on the reaction was observed. This
may seem to indicate that the reaction proceeds by an SEAr-
type pathway, but these results could also be explained by an
irreversible step prior to C−H functionalization.15 Following
this experiment, symmetric substrate 9 was prepared and under
optimal conditions yielded products 10a and 10b in a 1:1
ratio.14 Since this experiment showed no sign of kinetic isotope
effect, it is probable that the mechanism proceeds though an
SEAr-type pathway. To gain additional evidence, asymmetric
substrate 11 was prepared containing an electron-poor ring and
a phenyl ring. The results of this reaction under optimal
conditions led to a 1:2.3 ratio14 of products 12a and 12b,
revealing that the more electron-rich phenyl ring was favored
for C−H functionalization, which is also consistent with SEAr-
type reactivity.
1b was performed with either no additive or with 1.5 equiv of
radical-trapping reagents such as benzoquinone, dibutylhydrox-
ytoluene (BHT),8 or 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO).9 In all cases, product 3b was observed in equivalent
or slightly diminished yields when compared to no additive. If
the mechanism proceeded by a radical pathway, we would
expect only trace amounts of product to be observed. This
indicates that the reaction mechanism likely does not generate
radical intermediates, and it is, therefore, likely to proceed by an
ionic mechanistic pathway.
Given that the mechanism proceeds via an ionic pathway, it is
likely that the copper center is intimately involved in the C−H
bond-cleavage step. We hypothesized that the C−H bond-
cleavage step could be proceeding through one of two
pathways: concerted metalation−deprotonation (CMD)10 or
electrophilic aromatic substitution (SEAr).11 In the case of
CMD, we would expect a significant deuterium isotope
effect.10a,b,12 Conversely, for SEAr, we would likely see a lack
of any deuterium isotope effect.13 Therefore, we devised a
kinetic isotope experiment to shed light on the nature of the
C−H bond-cleavage step as well as to help determine the rate-
limiting step. First, the relative rate of product formation for
deuterated substrate 5 was compared to the nondeuterated
substrate (3b, Scheme 4) in separate parallel reactions. The
Based on these observations, a plausible mechanism
consistent with experimental evidence is proposed (Scheme
6). The reaction is initiated by coordination of the copper to
the alkyne functional groups, rendering them electrophilic.16
Nucleophilic attack by the sulfinate salt onto an activated
alkyne17 can be followed by migratory insertion of the
remaining alkyne in the carbon−copper bond, which furnishes
Scheme 4. Kinetic Isotope Effect
Scheme 6. Proposed Reaction Mechanism
KH/KD was determined to be 1, which indicates that the C−H
bond-cleavage step of the reaction is a non-rate-limiting step.
Also, since the C−H bond cleavage is not rate limiting, this
experiment or others on substrate 5 would not be effective in
revealing more information about the C−H bond-cleavage step.
We next turned our attention to asymmetric substrates for
use in internal competition experiments (Scheme 5) to further
C
DOI: 10.1021/acs.orglett.6b03787
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(4) (a) Gericke, K. M.; Chai, D. I.; Bieler, N.; Lautens, M. Angew.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03787.
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Crystallographic data for 3a (CIF)
Experimental procedures and characterization data for
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dschipper@uwaterloo.ca.
ORCID
(11) Galabov, B.; Nalbantova, D.; Schleyer, P. V. R.; Schaefer, H. F.
Acc. Chem. Res. 2016, 49, 1191−1199.
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(a) García-Cuadrado, D.; De Mendoza, P.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880−6886.
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(14) These products were not separable by standard chromatog-
raphy, and consequently, the ratios have been assigned by NMR
analysis.
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Derek J. Schipper: 0000-0003-4854-531X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSERC, the University of Waterloo, and the Canada
Research Chairs Program (CRC-Tier II, D.J.S.) for financial
support. S.W. thanks NSERC for an undergraduate research
award. Jalil Assoud (University of Waterloo) is gratefully
acknowledged for assistance in obtaining and solving the crystal
structure of 3a.
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D
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