Gold-catalyzed regioselective oxidation of propargylic carboxylates: A reliable access to α-carboxy-α,β-unsaturated ketones/aldehydes

Article abstract of DOI:10.3762/bjoc.9.227

Gold-catalyzed intermolecular oxidation of carboxylates of primary or secondary propargylic alcohols are realized with excellent regioselectivity, which is ascribed to inductive polarization of the C-C triple bond by the electron-withdrawing carboxy group

Full text of DOI:10.3762/bjoc.9.227

Gold-catalyzed regioselective oxidation of
propargylic carboxylates: a reliable access to
α-carboxy-α,β-unsaturated ketones/aldehydes
Kegong Ji, Jonathan Nelson and Liming Zhang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1925–1930.
Department of Chemistry and Biochemistry, University of California,
Santa Barbara, California, 93106, USA
doi:10.3762/bjoc.9.227
Received: 06 July 2013
Email:
Accepted: 23 August 2013
Published: 24 September 2013
Liming Zhang* - zhang@chem.ucsb.edu
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Keywords:
enone; gold catalysis; oxidation; propargyl carboxylate
Guest Editor: F. D. Toste
© 2013 Ji et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Gold-catalyzed intermolecular oxidation of carboxylates of primary or secondary propargylic alcohols are realized with excellent
regioselectivity, which is ascribed to inductive polarization of the C–C triple bond by the electron-withdrawing carboxy group. The
gold carbene intermediates thus generated undergo selective 1,2-acyloxy migration over a 1,2-C–H insertion, and the selectivities
could be dramatically improved by the use of a P,S-bidentate ligand, which is proposed to enable the formation of tris-coordinated
and hence less electrophilic gold carbene species. α-Carboxy α,β-unsaturated ketones/aldehydes can be obtained with fair to excel-
lent yields.
Introduction
We reported in 2010 [1] that α-oxo gold carbenes could be general approach by us [2,6-12] and other researchers [13-20],
conveniently generated as reactive intermediates in gold- thus making it an exciting area for further advancing gold
catalyzed intermolecular oxidation of alkynes. By using pyri- chemistry.
dine N-oxides [1] and later 8-substituted quinoline N-oxides [2]
as the external oxidants, this approach permits a safe and effi- Among various types of alkynes examined, internal alkynes,
cient access to α-oxo gold carbenes without resorting to the while without incident in the generation of the gold carbene
dediazotization strategy [3-5] using hazardous and potentially intermediates, present an additional challenge, namely how to
explosive diazo substrates (Scheme 1). Since then an array of control the regioselectivity of the oxidation. We reported previ-
versatile synthetic methods has been developed based on the ously that synthetically useful regioselectivity could be
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Beilstein J. Org. Chem. 2013, 9, 1925–1930.
Scheme 1: Generation of α-oxo gold carbenes via intermolecular oxidation of alkynes: a non-diazo approach.
achieved if the two ends of the C–C triple bond are biased by a attributed to that B adopts a preferred conformation, as detailed
steric bulk and/or via conjugation (Scheme 2). In our continued in Scheme 3, in order to avoid steric interaction between Me
effort to reveal regioselectivities of this oxidation with different and the acyl moiety. It needs to be noted that a related intramol-
types of internal alkynes, we examined propargylic carboxy- ecular version of this reaction has been previously reported
lates, which have served as a versatile platform for the develop- [24].
ment of a diverse range of gold catalysis [21]. Herein we report
our findings and the development of a reliable synthesis of An alternative mechanism for the formation of 5a-OAc is also
α-carboxy α,β-unsaturated ketones/aldehydes.
shown in Scheme 3 (the top half). Instead of initially under-
going oxidative gold carbene formation, a gold-promoted 1,2-
acetoxy migration [25] would generate a vinyl gold carbene
Results and Discussion
We began by subjecting the propargylic acetate 4a to the suit- intermediate (i.e., C), which can then be oxidized by 3 to yield
able conditions developed in our previous study, namely the product. However, this scenario is deemed unlikely by the
IPrAuNTf2 (5 mol %) and 8-methylquinoline N-oxide (3, following observations and considerations: a) propargylic
1.5 equiv) in 1,2-dichloroethane at ambient temperature. To our carboxylates of type 4a with an internal C–C triple bond typi-
delight, the reaction proceeded efficiently, yielding the cally undergo facile 3,3-rearrangements [26-30] instead of 1,2-
α-acetoxyenone 5a-OAc (Z/E >50:1) and the isomeric acyloxy migrations. The former process would eventually lead
β-acetoxyenone 5a-H in an excellent combined 92% yield along to the formation of the enones 6 [31]. Due to hydrolysis, only
with a minute amount of the enone 6 (<0.5%, Scheme 3); more- under thermal and anhydrous conditions products derived from
over, 5a-OAc is favored over 5a-H by a ratio of ~7:1. Of par- the latter processes can be predominantly formed [32]; under
ticular importance is that the anticipated isomer 5a’, accessible our conditions (at ambient temperature and without exclusion of
via the gold carbene B’ from a regioisomeric alkyne oxidation, moisture), the enone 6 was indeed detected but in a minute
was not positively detected due to the trace amount (<0.5%), amount, suggesting that the 1,2-acyloxy migration might be an
thereby revealing an exceptional level of regioselectivity in the even less meaningful event in the reaction; b) it is known that
oxidation of this type of internal alkynes. The formations of the gold carbenes of type B can be readily oxidized by Ph2S=O
5a-OAc and 5a-H are rationalized as the results of divergent [33], which, however, is an inefficient oxidant for generating
transformations of the α-oxo gold carbene B: the former is α-oxo gold carbenes of type A via alkyne oxidation [34,35];
formed via a two-step 2,3-acetoxy migration [22,23], and the when the N-oxide 3 is replaced by the sulfoxide, 5a-OAc was
latter most likely via a concerted carbene 1,2-C–H insertion[2]. formed in only 5% yield even at 60 °C after 12 h (Scheme 4);
The selective formation of the Z isomer of 5a-OAc can be moreover, the major product in the reaction was the expected
Scheme 2: Gold-catalyzed regioselective oxidation of a sterically biased internal alkyne.
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Scheme 3: Gold-catalyzed oxidation of the propargylic acetate 4a and the mechanistic rationale.
enone 6 (56% yield, 88% conversion) due to a dominant gold- former case is ~13:1, better than ~7:1 in the latter case, albeit
catalyzed 3,3-rearrangement; c) this alternative could not ratio- both lower than that by IPrAuNTf2 (>50:1, see Scheme 3). The
nalize the formation of 5a-H.
enhanced preference of AcO migration en route to the forma-
tion of 5a-OAc over the 1,2-C-H insertion is attributed to atten-
The fact that in the presence of the oxidant 3 the previously uation of the electrophilicity of the gold carbene moiety via the
observed facile transformations of propargylic carboxylates formation of a tris-coordinated gold complex (i.e., D) [11].
(i.e., 3,3-rearrangement and 1,2-acyloxy migration) are no
longer competitive with the oxidative catalysis is surprising and
suggests that this oxidation process could divert substrates from
other well established, facile gold catalysis to the formation of
distinctively different functional products in the presence of
oxidants.
The relatively low selectivity (i.e., ~7:1) of 5a-OAc over 5a-H
was drastically improved upon catalyst screening. It was even-
tually found that the ratio could reach >200:1 by using the
gold(I) catalyst derived from our previously developed bulky
P,S-bidentate ligand L1 (Figure 1) [11]. A similarly high selec-
tivity was also achieved by using the P,N-bidentate ligand Mor-
DalPhos [36,37]. However, the Z/E ratios of 5a-OAc in the
Figure 1: The impact of ligands on the ratio of 5a-OAc and 5a-H in the
gold-catalyzed oxidation of 4a (reaction conditions: 5 mol % gold cata-
lyst, 1.5 equiv of 3, DCE, rt, 3 h).
Scheme 4: A drastically different outcome by using diphenyl sulfoxide as the oxidant.
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The scope of this alkyne oxidation/acetoxy migration reaction is isolated with fair to excellent yields. While the bulky catalyst
outlined in Table 1. Acetates derived from primary/secondary Me4t-BuXPhosAuNTf2 [38] was used in entry 1 to obtain a
propargylic alcohols with various substitution patterns and better oxidation regioselectivity (28/1), it did not lead to a good
containing different functional groups were all allowed, ratio in the case of 4h (entry 7), where the oxidation regio-
although the tertiary counterpart underwent gold-catalyzed 3,3- isomer of type 5a’ was formed in 23% yield. This outcome is
rearrangement preferentially [21] and hence was not a viable rationalized in the next paragraph. In the case of pivalate 3c
substrate. Except entry 7, the gold-catalyzed oxidations with a terminal alkyne (entry 2), the use of this bulky acyl
proceeded with excellent regioselectivities (>25:1), and the group instead of acetyl is to curtail the hydrolytic formation of
desired α-acyloxy α,β-unsaturated ketones/aldehyde were the corresponding α-ketoaldehyde. In many cases the ratios of
Table 1: Reaction scope studies for the formation of α-acetoxyenones from propargyl acetates.a
yieldb
ratioc
time
yieldb
ratioc
entry
1d
4
5
entry
7d
4
5
80%
14/1
3 h
62%
21/1h
5 h
74%e
>100:1
2.5 h
60%
>200/1
6.5 h
2
3
8f
9f
86%
>50/1
12 h
75%
>100/1
2.5 h
85%
>50/1
9 h
90%
>20/1
10 h
4
10
11
75%
>200/1
2.5 h
84%
>35/1
5 h
5f,g
76%
33/1
7 h
85%
>20/1
10 h
6
12
a[4] = 0.05 M. bIsolated yield of 5-OAc. c5-OAc/5-H. dMe4t-BuXPhosAuNTf2 was used as the catalyst. eIPrAuCl/AgSbF6 as the catalyst, 3,5-
dicholoropyridine N-oxide (2 equiv) as the oxidant, and DCM as the solvent. fL1AuCl/AgNTf2 used as catalyst. g10 mol % catalyst. hThe oxidation
regioisomer of type 5a’ was formed in a 23% yield.
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Beilstein J. Org. Chem. 2013, 9, 1925–1930.
5-OAc and 5-H were high with IPrAuNTf2 as the catalyst; for Conclusion
the ones with low selectivities, L1AuNTf2 offered again We have realized a gold-catalyzed, highly regioselective oxi-
dramatic improvements (entries 5, 8 and 9) although at the dation of carboxylates of primary and secondary propargylic
expense of the geometric selectivities of the major product. alcohols by utilizing inductive polarization of the C-C triple
bond by the electron-withdrawing carboxy moiety. The α-oxo
The excellent regioselectivities of gold-catalyzed oxidations of gold carbene intermediates generated can selectively undergo
propargylic carboxylates, albeit unexpected, could be readily 1,2-acyloxy migrations over 1,2-C–H insertion. This inherent
rationalized by invoking inductive polarization of the C–C triple selectivity can be much enhanced by the use of our previously
bond by the electronegative carboxy group. Such polarization developed P,S-bidentate ligand, which enables the generation of
could be revealed by calculated natural charges via natural tri-coordinated and less electrophilic gold carbene species.
population analysis [39] and corroborated by experimentally α-Acyloxy α,β-unsaturated ketones/aldehydes can be obtained
detectable properties such as pKa [40] and 13C NMR [41]. We with fair to excellent yields.
calculated the natural charges at the sp-hybridized carbons in 4a
using the Density Functional Theory (B3LYP/6-31G*,
Supporting Information
Spartan06). The NC is 0.230 for the C(sp) distal to the carboxy
group and −0.081 for the proximal C(sp), revealing a strong
Supporting Information File 1
inductive effect that leads to a more electron-defficient distal
alkyne end (Figure 2). This revelation is consistent with the 13C
NMR chemical shifts of the alkynyl carbons. The observed
regioselectivity can be ascribed to a selective attack of the
nucleophilic oxidant to the more electrophilic distal C(sp).
Notably, a recently published Pt-catalyzed hydrosilylation on a
similar substrate showed a 3.7:1 regioselectivity [42]. This
unexpectedly high selectivity with gold catalysis is attributed to
the augmentation of the electronic bias of the C–C triple bond
via the gold activation. The decreased regioselectivity with 4h
(entry 7) is due to the counter polarization of the C–C triple
bond by the propargylic BnO group. The better result with 4i
also containing a similarly positioned BnO group (entry 8) is
attributed to the synergistic effect of the steric bias [2].
Experimental procedure, compound characterization, and
NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-227-S1.pdf]
Acknowledgements
The authors are grateful for the financial support from NSF
(CHE-1301343).
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