Au(i)-catalyzed intramolecular oxidative cyclopropanation of 1,6-enynes derived from propiolamides with diphenyl sulfoxide

Article abstract of DOI:10.1039/c2ob27394b

We have developed gold(i)-catalyzed oxidative cyclopropanation of 1,6-enynes derived from propiolamides employing diphenyl sulfoxide as an oxidant. 1,6-Enynes having a terminal alkyne and a propiolamide tether efficiently transformed into cyclopropane carboxaldehyde derivatives.

Full text of DOI:10.1039/c2ob27394b

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Au(I)-catalyzed intramolecular oxidative
cyclopropanation of 1,6-enynes derived from
Cite this: Org. Biomol. Chem., 2013, 11,
1089
propiolamides with diphenyl sulfoxide†
Received 10th December 2012,
Accepted 21st December 2012
Hyun-Suk Yeom and Seunghoon Shin*
DOI: 10.1039/c2ob27394b
www.rsc.org/obc
We have developed gold(I)-catalyzed oxidative cyclopropanation
In 2011, Zhang and coworkers reported cyclopropanation of
of 1,6-enynes derived from propiolamides employing diphenyl 1,6-enyne scaffolds employing Au(I) catalyst and pyridine-N-
sulfoxide as an oxidant. 1,6-Enynes having a terminal alkyne and oxides (quinolone-N-oxides) as oxidants (Scheme 1A).11,12 They
a propiolamide tether efficiently transformed into cyclopropane proposed that the alkyne is initially oxidized by pyridine-N-
carboxaldehyde derivatives.
oxides to form an α-oxo gold carbenoid followed by cyclopropa-
nation with the pendant olefin. Replacing pyridine-N-oxides
with Ph2SvO in this case turned out to be ineffective, presum-
ably because Ph2SvO is a weaker oxidant and/or the S–O cleav-
ing redox process is known to occur through concerted 3,3-
sigmatropic rearrangement to produce α-arylated carbonyl
compounds, as supported by DFT computational study
(Scheme 1B).8d,e Furthermore, neither the Pd(II) catalyzed
Cyclopropane rings are highly strained but nonetheless fre-
quently found in a wide range of natural products, such as ter-
penes, fatty acid metabolites and amino acids, as well as
medicinal agents.1 Due to the inherent ring strain, they also
serve as useful synthons for diverse organic reactions.2 There-
fore, there has been a large amount of effort toward efficient
synthesis of the cyclopropane unit. Traditional approaches
employing Simmons–Smith reagent (RZnCH2I)3 or sulfonium
(sulfoxonium or phosphonium) ylides,4 although effective,
have poor atom-economy and involve highly basic conditions.
Metal catalyzed decomposition of diazoacetates has been
known to generate metal carbenoids that form cyclopropanes
in the presence of olefins.5 However, the use and preparation
of non-stabilized diazo compounds involve explosion hazards,
thus limiting their widespread applications. Therefore, much
attention has been paid to the diazo-free access to metal carbe-
noids in the past decades.6
12
cyclopropanation with PhI(OAc)2 nor the Au(I) catalyzed oxi-
dative cyclopropanation by pyridine-N-oxides11 could accom-
modate terminal alkyne substrates (vide infra, eqn (1)). In
contrast to these precedents, we have found that the corres-
ponding terminal alkyne substrates underwent efficient oxi-
dative cyclopropanation with Ph2SvO oxidants (Scheme 1C)
and details of this study are presented herein.13
We recently reported that acceptor-polarized alkynes are
highly efficient substrates for intermolecular coupling reac-
tions with alkenes.14 To further probe the effect of acceptor-
substituents on alkynes, we examined the intramolecular
Recently, we have introduced a new method of generating
α-oxo gold carbenoid synthons by oxidation of alkynes with
nitrones and hydroxylamines (N–O bond oxidants),7 based on
the seminal reports by Toste and coworkers employing sulfox-
ides.8 Since then, Zhang and coworkers have introduced pyri-
dine-N-oxides as intermolecular oxidants.9 This method
provides for a convenient and benign route to α-oxo gold car-
benoids and diverse transformations have been realized,
including X–H (X = O, N) insertion,10a ylide formation/cyclo-
addition,10b C–H insertion10c and 1,2-alkyl (or H) shift.10d
Department of Chemistry, Hanyang University, Seoul, 133-791, Korea.
E-mail: sshin@hanyang.ac.kr; Fax: +82-2-2299-0762; Tel: +82-2-2220-0948
†Electronic supplementary information (ESI) available: Characterizations of all
new products and copies of spectra. See DOI: 10.1039/c2ob27394b
Scheme 1 Intramolecular oxidative cyclopropanation.
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Table 1 Optimization of ligands and counter-anionsa
Entry
Catalystb
5a
6a
SM(4a)
1
2
3
4
5
6
7
8
Au(PPh3)SbF6
[Au(L1)]SbF6
[Au(L2)]SbF6
[Au(L3)]SbF6
[Au(L4)]SbF6
[Au(L5)]SbF6
[Au(IMes)]SbF6
[Au(IPr)]SbF6
[AuP(C6F5)3]SbF6
AuCl3
[Au(L3)]OTf
[Au(L3)]NTf2
[Au(L3)]BF4
[Au(L3)]ClO4
[Au(L3)]OTs
—
—
84%
—
64%
—
76%
—
95%
26%
90%
65%
—
52%
10%
54%
17%
53%
—
10%
—
—
23%
57%
33%
3%
15%
12%
16%
16%
22%
—
Scheme 2 6-endo-dig or 5-exo-dig cyclization.
9
—
—
22%
17%
29%
—
10
11
12
13
14
15
reaction of 1,6-enynes having propiolamide tether.15 Chung
and coworkers proposed that the cyclization of propiol-
amide-derived 1,6-enynes proceeds with 6-endo-dig pathway to
form 1 and 2 (σ-bond reorganization) based on the experi-
mental and computational study (Path A, Scheme 2).15a In
contrast, we have found that the reaction of terminal alkyne
substrates predominantly proceed through 5-exo-dig pathway
leading to an Alder-ene type cycloisomerization 3 either
with Ag(I) or Au(I) catalyst (Path B, Scheme 2).15b Along
this line, we projected that trapping the intermediates II
with Ph2SvO might lead to oxidative intramolecular
cyclopropanation.
—
—
91%
>97%
—
—
a [Au(L)]X catalyst was generated in situ from an equimolar mixture of
Au(L)Cl (5 mol%) and AgX (5 mol%); the yields of 4a–6a are crude
yields based on 1H NMR spectra (1,3,5-tri-MeO-C6H3 as an internal
standard); the remaining mass balance was unselective
decomposition. b See below for ligand structures.
Our study commenced with the N-methallyl substrate 4a
employing various Au(I) catalysts and 3 equiv. of Ph2SO in
chloroform (0.1 M) at 60 °C (Table 1). Gratifyingly, we were
able to isolate oxidative cyclopropanation product 5a along
with a small amount of enyne metathesis product 6a. The
efficiency as well as the selectivity toward 5a was affected tre-
mendously by the catalyst used. Buchwald ligands having
ortho-biphenyl group generally performed better than NHC
ligands, while P(C6F5)3 or ligandless AuCl3 were not effective at
all (entries 1–10). From the screening of counter-anion, NTf2
anion was proved optimal for cationic Au(L3) complex (entries
11–15).
Table 2 Optimization of solvents and the amount of Ph2SOa
The selectivity between 5a and 6a was also highly depen-
dent on the solvent used: 1,4-dioxane tends to give more
metathesis product 6a and the use of 1,2-dichloroethane pre-
dominantly gave oxidative cyclopropanation product 5a,
further improving the yield to 64% in 2 h (entries 2 and 5,
Table 2). A decrease in the amount of Ph2SvO to 2 equivalent
did not affect the reaction much (entry 11), but the reactions
run at lower temperature took much longer time (entries
12–13). We also examined other oxidants (pyridine-N-oxide
derivatives, DMSO, mCPBA, H2O2, tBuOOH, oxone and air):
while DMSO (80 °C/24 h, 34% of 5a), H2O2 (60 °C/9 h, 35% of
5a), tBuOOH (60 °C/3 h, 17% of 5a) were somewhat inferior,
mCPBA (epoxidation as a side reaction), oxone and air were
completely inactive as oxidants. Importantly, 2-bromo pyri-
dine-N-oxide was incompatible with the terminal alkyne sub-
Entry
Solvent
x equiv.
5a
6a
SM (4a)
1
2
3
4
5
6
7
8
CH2Cl2
1,2-DCE
CH3CN
CH3NO2
1,4-Dioxane
Toluene
DME
3
3
3
3
3
3
3
3
38%
64%
5%
51%
30%
50%
38%
—
37%
45%
59%
50%
12%
8%
10%
—
48%
—
93%
—
—
—
35%
>97%
27%
15%
—
—
62%
14%
43%
11%
13%
—
11%
11%
13%
6%
DMF
9
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1
10
11
12
13
1.5
2
2b
2c
—
a [Au(SPhos)]NTf2 catalyst was generated in situ; the yields of 4a–6a are
crude yields based on 1H NMR spectra (1,3,5-tri-MeO-C6H3 as an
internal standard); the remaining mass balance was unselective
strate 4a and predominantly gave conjugate addition adduct decomposition. b 24 h at 40 °C. c 72 h at rt.
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(crude 1H NMR) along with only a small amount of 5a (8%) Finally, for the aryl substituted enyne 4j, the efficiency toward
(eqn (1)).
oxidative cyclopropanation 5j was significantly diminished, in
contrast to the reactions with pyridine-N-oxide derivatives.11
Based on the regioselectivity of propiolamide-derived 1,6-
enynes in the cyclization by Au(I) catalysts (Scheme 2), a plaus-
ible mechanism of the gold-catalyzed oxidative cyclopropana-
tion may involve initial formation of cyclopropyl gold
carbenoid II/II′ (Path B, Scheme 2) followed by rapid trapping
ð1Þ
Employing the above optimized conditions (Au(SPhos)NTf2 of the resulting highly reactive carbenoid by sulfoxides.8g–i In
(5 mol%) and Ph2SvO (2 equiv.) in 1,2-DCE at 60 °C), we next the alternative scenario, 4 could evolve through initial oxi-
investigated the scope of this transformation as in Table 3. dation of the alkyne to form gold carbenoids (Scheme 1A)
Except for a few cases where a small amount of competitive followed by intramolecular cyclopropanation. The latter
formation of metathesis product 6 (entries 1 and 3) is seen, possibility seems less likely for Ph2SO mediated oxidation,
most 1,6-enynes with a terminal alkyne provided oxidative considering that the sulfoxide redox tends to occur through a
cyclopropanation products 5 as the major respective products. 3,3-sigmatropic rearrangement pathway to afford α-aryl carbo-
A notable feature of this transformation is that diverse substi- nyl compounds rather than through a gold carbenoid.
tutions on the allyl unit could be accommodated. For example,
In summary, we have developed intramolecular oxidative
methallyl (entries 1, 2, 7 and 8), allyl (entries 3 and 6), crotyl cyclopropanation of 1,6-enynes having propiolamide tethers.
(entry 4) and cinnamyl (entry 9) substrates all provided the cor- Substrates with terminal alkyne were first employed in the oxi-
responding 5’s as exclusive products. Of particular relevance is dative cyclopropanation to afford cyclopropane carboxalde-
substrate 4e with electron-rich tri-substituted olefin, since this hydes that would have distinct applications due to aldehyde
substrate was known to undergo Alder-ene type cycloisomeriza- functionality.11,12 For this type of substrate, diphenyl sulfoxide,
tion leading to 7e exclusively both under Au(I) or Ag(I) cataly- rather than pyridine-N-oxides, performed as an excellent
sis.15b,16 Intriguingly, 4e afforded predominant formation of 5e oxidant and thus a wide generality in terms of alkenes has
(55%) under the current optimized conditions, along with only been demonstrated.
a small amount of 7e (17%). Thus, the examples in Table 3
We thank the National Research Foundation of Korea
exemplify the excellent generality, especially considering that (NRF-2011-0023686 and NRF-2012-015662) and also nano
the reaction manifolds of 1,6-enyne cycloisomerization depend material
technology
development
program
highly on the subtle structural variations on the allyl unit.16 (NRF-2012M3A7B4049653) for support.
Table 3 The scope of oxidative cyclopropanationa
Entry
1
Substrate
Productb
Entry
6
Substrate
Productb
2
7c
3c
8c
4
5
9c
10
a [Au(SPhos)]Cl (5 mol%) and AgNTf2 (5 mol%) were mixed in 1,2-dichloroethane followed by addition of substrate 4 (0.1 M in DCE) and 2 equiv.
of Ph2SvO; the reaction mixture was stirred at 60 °C for 2–8 h. b Isolated yields after chromatographic separation. c The products were
inseparable with excess Ph2SvO; in this case, the crude reaction mixture was treated with 2 equiv. of NaBH4 in MeOH before isolation.
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