Gold-catalyzed highly regioselective oxidation of C-C triple bonds without acid additives: Propargyl moieties as masked α,β-unsaturated carbonyls

Article abstract of DOI:10.1021/ja1072614

Gold-catalyzed intermolecular oxidations of internal alkynes have been achieved with high regioselectivities using 8-alkylquinoline N-oxides as oxidants and in the absence of acid additives. Synthetically versatile α,β-unsaturated carbonyls are obtained in good to excellent yields and with excellent E-selectivities. A range of functional groups such as THP, MOMO, N₃, OTBS, and N-Boc are tolerated. This reaction allows α,β-unsaturated carbonyls to be masked as propargyl moieties, thus offering a practical solution to compatibility issues with these functional groups likely encountered in syntheses of complex structures.

Full text of DOI:10.1021/ja1072614

Published on Web 09/20/2010
Gold-Catalyzed Highly Regioselective Oxidation of C-C Triple Bonds without
Acid Additives: Propargyl Moieties as Masked r,ꢀ-Unsaturated Carbonyls
Biao Lu, Chaoqun Li, and Liming Zhang*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received August 12, 2010; E-mail: zhang@chem.ucsb.edu
To our delight, the oxidation of symmetric 6-dodecyne indeed
afforded R,ꢀ-unsaturated ketone 2a in 77% yield, albeit a sluggish
reaction (eq 1). In contrast to cis-C-C double bonds formed in
Abstract: Gold-catalyzed intermolecular oxidations of internal
alkynes have been achieved with high regioselectivities using
8-alkylquinoline N-oxides as oxidants and in the absence of acid
additives. Synthetically versatile R,ꢀ-unsaturated carbonyls are
obtained in good to excellent yields and with excellent E-
selectivities. A range of functional groups such as THP, MOMO,
N3, OTBS, and N-Boc are tolerated. This reaction allows R,ꢀ-
unsaturated carbonyls to be masked as propargyl moieties, thus
offering a practical solution to compatibility issues with these
functional groups likely encountered in syntheses of complex
structures.
Rh-catalyzed decomposition of R-diazo carbonyl compounds,11 only
trans-2a was observed, reflecting a unique aspect of gold carbene
reactivities.
Table 1. Screening Gold Catalyst and Reaction Conditions for
High Regioselectivitya
Although alkene epoxidation is a classic and versatile reaction
in organic synthesis, epoxidation of C-C triple bonds1 with DMDO
or peracids has little synthetic utility except with electronically
biased ynamide substrates,2 as often multiple products including
R,ꢀ-unsaturated ketones were formed with little chemoselectivity
and regioselectivity. Many of the product formations could be
rationalized via an initial rearrangement of oxirene A3 into highly
reactive R-oxocarbene B (Scheme 1A). In the cases of alternative
metal-mediated/catalyzed intermolecular alkynes oxidation, further
oxidation is unavoidable,4 leading to R,ꢀ-epoxy ketones5 or 1,2-
dicarbonyl or carboxylic products;6 hence, regioselectivity has not
been studied nor achieved. Herein, we report a rare, highly
regioselectiVe single oxidation of internal alkynes via gold catalysis
under exceedingly mild conditions, and synthetically versatile R,ꢀ-
unsaturated carbonyls are directly formed from propargyl moieties
for the first time in good yields and with high to excellent
regioselectiVities.
N-oxide MsOH
(equiv) (equiv)
reaction
conditions
yield %
(% 1b left)b 2b/4
entry
catalyst
1
2
3
4
5
6
7
8
9
Ph3PAuNTf2 3a (2)
Ph3PAuNTf2 3b (2)
Ph3PAuNTf2 3c (2)
Ph3PAuNTf2 3d (2)
Ph3PAuNTf2 3e (2)
Ph3PAuNTf2 3f (2)
1.2 DCE, rt, 12 h
1.2 DCE, rt, 12 h
1.2 DCE, rt, 18 h
1.2 DCE, rt, 40 min
1.2 DCE, rt, 40 min
1.2 DCE, rt, 40 min
45 (50)
53 (37)
46 (20)
88
82
85
87
71
83
85
2.1
2.6
2.3
2.8
3.1
3.4
3.2
3.8
3.1
6.4
9.1
Ph3PAuNTf2 3f (1.2) no
Et3PAuNTf2 3f (1.2) no
DCE, rt, 40 min
DCE, rt, 40 min
DCE, rt, 40 min
DCE, rt, 15 min
DCE, -20 °C, 14 h
toluene, -20 °C, 14 h 80
THF, -20 °C, 14 h
c
3f (1.2) no
3f (1.2) no
3f (1.2) no
3f (1.2) no
3f (1.2) no
LAuNTf2
10 IPrAuNTf2
11 IPrAuNTf2
12 IPrAuNTf2
13 IPrAuNTf2
89
12
13
d
90
a In vial; [1b] ) 0.1 M. b Estimated by 1H NMR using diethyl
phthalate as internal reference. c L ) (4-CF3Ph)3P. d 83% isolated yield.
Scheme 1. Oxidation of C-C Triple Bonds: Conversion of a
Propargyl Moiety into an R,ꢀ-Unsaturated Carbonyl Moiety
With this encouraging result, we then chose nonsymmetric
aliphatic alkyne 1b to study regioselectivity by tuning the steric
and electronic properties of gold catalysts and N-oxides. Table 1
shows some of the results. Several trends can be readily concluded:
(1) the oxygen atom was selectively delivered to the less hindered
alkyne end, suggesting that the oxidant approach was the regio-
determining event; (2) the bulkier the N-oxide was, the more
selective the oxidation (comparing entries 1, 2 and entries 3-6);
(3) 8-alkylquinoline N-oxides (i.e., 3d-f) oxidized alkynes much
more rapidly than the unsubstituted one (i.e., 3c) and pyridine
N-oxides; and (4) the less Lewis acidic the gold catalyst was, the
better the selectivity (comparing entries 8-11). To our surprise,
no acid was needed when 3f12 was used as the oxidant, and the
reaction rate was not affected at all! This is a major improvement
over the conditions used in our previous studies,8 and as a result,
acid-labile groups could be completely tolerated (vide infra). With
only a slight excess of 3f (1.2 equiv) and 5 mol % of IPrAuNTf2,
We have recently reported that terminal alkynes or alkynoates
can be oxidized intermolecularly into R-oxo gold carbene C,7 which
could be trapped efficiently by tethered OH groups.8 We envisioned
such a gold carbene intermediate, if generated from internal alkynes,
might undergo facile 1,2-C-H insertions, thus avoiding further
oxidation and forming highly valuable R,ꢀ-unsaturated carbonyls
(Scheme 1B). This gold catalysis would make a propargyl moiety
a masked R,ꢀ-unsaturated carbonyl;9 however, the challenge is how
to achieve high regioselectivities10 without much bias in the sub-
strate structure.
9
14070 J. AM. CHEM. SOC. 2010, 132, 14070–14072
10.1021/ja1072614  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Reaction Scope Studies of Conjugated Alkynesa b
,
a high selectivity was achieved when the reaction was run at -20
°C in THF (entry 13), and the isolated yield was 83%.
With the optimized, exceedingly mild reaction conditions (Table
1, entry 13) in hand, we then examined a range of aliphatic alkynes,
and the results are shown in Table 2. All the alkynes were oxidized
efficiently and without any observable overoxidation; importantly,
regioselectivities were high with nonsymmetric substrates (g10:
1), and the oxygen was always selectively delivered to the less
hindered end of the C-C triple bond. A range of sensitive functional
groups (entries 4-9) were allowed, and without acid additive the
reaction conditions were so mild that even THP (entry 9) was
tolerated. Notably, 6-exo-dig cyclizations in the cases of entries 8
and 9 did not compete. Somewhat to our surprise, cyclopentylalkyne
1k led mostly to ring enlargement, presumably due to the release
of the cyclopentane ring strain (6.2 kcal/mol,13 entry 10).
Table 2. Reaction Scope Studies of Aliphatic Alkynesa b
,
a In vial; [alkyne] ) 0.1 M. Oxidant, 3b (1.2 equiv); catalyst,
[(2,4-tBu2PhO)3P]AuNTf2 (5 mol %); solvent, THF. b Isolated yields; the
regioselectivity (defined as 2/diketone) is shown in parentheses, and the
bold bonds are the original C-C triple bonds. d Oxidant, 3e; catalyst,
IPrAuNTf2. e Oxidant, 3f; catalyst, IPrAuNTf2.
Divinyl ketones are highly useful compounds. While they could
be prepared via Pd/Ni-catalyzed carbonylative Stille or Nigishi
reaction,16 the use of toxic alkenylstannanes or reactive alkenylzincs
is synthetically limiting. This intermolecular alkyne oxidation
reaction would provide an exceedingly mild and safe approach to
this important class of compounds from easily available enynes.
For example, divinyl ketone 2t was obtained in 81% yield and with
a 10:1 regioselectivity (entry 9). With cyclohexene as the ene part,
the reactions proceeded to completion in 1 h, and the desired
products were obtained in high yields and without the detection of
any diketone isomer14 (entries 10, 11); notably, the N-Boc group
was readily tolerated. Surprisingly, enyne 1w (entry 12) did not
work well, indicating that the alkene internal end needs to be fully
substituted in order to achieve efficient reactions.
a In vial; [alkyne] ) 0.1 M. Oxidant, 3f (1.2 equiv); catalyst, IPrAuNTf2
(5 mol %); solvent, THF. b Isolated yields; the regioselectivity (defined as
2/4) is shown in parentheses, and the bold bond is the original C-C triple
bond.
For arylalkyne substrates, the combination of IPrAuNTf2 and
3f, however, led to poor regioselectivity,14 which was expected
as in these cases the resonance stabilization by the aryl group
worked against the expected regio preference (assuming aryl is
n
bigger than Bu). Catalyst and oxidant screening led to [(2,4-
tBu2PhO)3P]AuNTf2 and 3b as the optimal combination, and the
regioselectivities were opposite to those of alphatic alkynes.
Apparently, resonance stabilization became the controlling factor
with arylalkynes, and more Lewis acidic [(2,4-tBu2PhO)3P]AuNTf2
led to better regioselectivities. As shown in Table 3, entries 1-6,
activated benzene rings (entries 2, 3) led to better regioselectivities
over the parent benzene ring, in line with the electronic effect. While
a slight deactivation (entry 4) did not diminish the selectivity, strong
deactivation proved to be detrimental (e.g., 4-MeO2CPh, 3.5:114).
Notably, when electronics and sterics worked in sync, an excellent
selectivity was observed (entry 6). Again, no acid additive was
needed in these reactions.12
In conclusion, a rare single oxidation of internal alkynes with
high to excellent regioselectivity was achieved via gold catalysis,
leading to synthetically versatile R,ꢀ-unsaturated carbonyls in good
to excellent yields and with excellent E-selectivities. The exceed-
ingly mild reaction conditions (mostly room temperature or below,
no N2 protection, no acid additive, and mild oxidants) readily
tolerate a range of sensitive functional groups. This reaction
provides an efficient masking of R,ꢀ-unsaturated carbonyls as
propargyl moieties, offering a practical solution to compatibility
issues involving R,ꢀ-unsaturated carbonyls, which are likely
encountered in many multistep syntheses. Moreover, the identifica-
tion of 8-alkylqinoline N-oxides as facile oxidants and the abolish-
ment of acid additives should unveil many exciting opportunities
to apply this mild alkyne oxidation to the development of various
novel synthetic methods.
For other types of conjugated alkynes, the regioselectivity is again
dictated by resonance stabilization.15 For example, R,ꢀ-unsaturated
N-acyloxazolidinone 2r was obtained from the corresponding
ynamide in 92% yield in 1 h (entry 7); notably, the regioselectivity
was opposite to those observed upon DMDO oxidation.2 The
combination of IPrAuNTf2 and 3e worked the best in this case.
Under similar conditions (oxidant, 3f, entry 8), cyclopropyl enone
2s was obtained in 83% yield.
Acknowledgment. We thank NSF (CAREER award CHE-
0969157), NIGMS (R01 GM084254), and UCSB for generous
financial support.
9
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C O M M U N I C A T I O N S
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