One-step synthesis of methanesulfonyloxymethyl ketones via gold-catalyzed oxidation of terminal alkynes: A combination of ligand and counter anion enables high efficiency and a one-pot synthesis of 2,4-disubstituted thiazoles

Article abstract of DOI:10.1002/adsc.201300855

By using Mor-DalPhos as the P,N-bidentate ligand and mesylate as the counter ion, the resulting gold(I) complex catalyzes efficient oxidative transformations of various terminal alkynes into synthetically versatile methanesulfonyloxymethyl ketones. The mild reaction conditions and high efficiency permit the one-pot synthesis of a range of valuable 2,4-disubstituted thiazoles by subjecting the resulting reaction mixture to a further condensation with thioamides under mild conditions.

Full text of DOI:10.1002/adsc.201300855

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DOI: 10.1002/adsc.201300855
One-Step Synthesis of Methanesulfonyloxymethyl Ketones via
Gold-Catalyzed Oxidation of Terminal Alkynes: A Combination
of Ligand and Counter Anion Enables High Efficiency and
a One-Pot Synthesis of 2,4-Disubstituted Thiazoles
Gongde Wu,a,b Renhua Zheng,a Jonathan Nelson,a and Liming Zhanga,*
a
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
Fax : (+1)-805-893-4120; e-mail: zhang@chem.ucsb.edu
Current address: Nanjing Institute of Technology, Nanjing, 211167, Peopleꢀs Republic of China
b
Received: September 23, 2013; Revised: January 24, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300855.
Abstract: By using Mor-DalPhos as the P,N-biden-
tate ligand and mesylate as the counter ion, the re-
sulting gold(I) complex catalyzes efficient oxidative
transformations of various terminal alkynes into
synthetically versatile methanesulfonyloxymethyl
ketones. The mild reaction conditions and high effi-
ciency permit the one-pot synthesis of a range of
valuable 2,4-disubstituted thiazoles by subjecting
the resulting reaction mixture to a further conden-
sation with thioamides under mild conditions.
formed in only 5% yield. While the reaction offers
a useful access to ketones with good a-leaving groups
(e.g., 2a-Cl and 2a), the yields are moderate (ꢀ70%).
Moreover, 2-chloroethyl mesylate, also an alkylating
reagent,[4] was formed as a by-product in a theoretical-
ly equal amount to 2a-Cl. Consequently, one-pot
strategies using in situ-generated 2a-Cl as the alkylat-
ing agent can be problematic.
More recently we reported that the high electrophi-
licity of the in situ-generated a-oxo gold carbene
could be attenuated via the formation of a tricoordi-
nated gold center (as in A), which is enabled by
Keywords: carbenes; catalysis; gold; oxidation;
thiazoles
a
P,N-bidentate ligand (Scheme 2).[3h,i] As such,
weakly nucleophilic carboxamides[3h] and carboxylic
acids[3i] were capable of trapping it with good efficien-
cy (Scheme 2). To expand the scope of trapping nucle-
ophiles and, moreover, to provide a facile and highly
Aliphatic ketones with good a-leaving groups are ver- efficient access to aliphatic ketones with good a-leav-
satile substrates for a diverse range of organic trans- ing groups, we turned our attention to MsOH, as its
formations. However, their schematically straightfor- conjugate base is a good leaving group. The anticipat-
ward one-step preparations from aliphatic ketones, es- ed products, mesylated ketones (e.g., 2a), are of high
pecially unsymmetrical linear ones, can be plagued by synthetic value.[5] Herein, we disclose an efficient syn-
low or moderate regioselectivity[1] and by overreac- thesis of methanesulfonyloxymethyl ketones via
tion.[2] It is fair to state there is still a lack of a general- MsOH trapping of in-situ generated a-oxo gold car-
ly efficient synthesis of this important class of com-
pounds from simple substrates.
A couple of years ago we developed a strategy for
generating a-oxo gold carbenes via gold-catalyzed ox-
idation of alkynes,[3] which circumvents the use of
hazardous diazo carbonyl compounds (see Scheme 2).
In one of the studies,[3f] we showed that the carbene
intermediate thus generated is so electrophilic that it
can abstract a chloride from the reaction solvent di-
chloroethane, eventually yielding an a-chloromethyl
ketone (i.e., 2a-Cl, Scheme 1). Interestingly, a compet-
ing trapping of the gold carbene by the acid additive,
MsOH, was a minor process, as the mesylate 2a was Scheme 1. Previous work.
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Gongde Wu et al.
Scheme 2. Trapping of in-situ generated a-oxo gold carbenes by external nucleophiles.
benes[6] and the application of this chemistry in an ef-
ficient one-pot synthesis of 2,4-disubstituted thiazoles.
Table 1 shows the reaction discovery and subse-
quent optimization of the reaction conditions. As ex-
pected, ligands frequently used in homogeneous gold
catalysis such as Ph3P (entry 1) and the bulky elec-
tron-rich ligands such as BrettPhos (entry 2) were in-
effective, resulting in poor yields of 2a. On the other
hand, a 28% yield of the desired product was detect-
ed by using Me-DalPhosAuNTf2 as the catalyst
(entry 3). Moreover, Mor-DalPhosAuNTf2 was found
to be an even better catalyst, forming 2a in a 54%
Scheme 3. Structures of the ligands.
yield (Scheme 3). These encouraging results are con-
Table 1. Screening for gold catalysts and reaction conditions.[a]
Entry
[Au]
MsOH/3 (equiv.)
Conversion [%]
Yield [%][b]
1
2
3
4
5
6
7
8
Ph3PAuNTf2
1.2/1.3
1.2/1.3
1.2/1.3
1.2/1.3
1.2/1.3
1.2/1.3
1.2/1.3
1.2/1.3
1.4/1.2
1.1/1.2
1.2/1.5
53
86
83
83
89
72
100
100
<10
100
100
8[c]
12[c]
28
54
26
BrettPhosAuNTf2
Me-DalPhosAuNTf2
Mor-DalPhosAuNTf2
L1AuNTf2
L2AuNTf2
38
Mor-DalPhosAuOMs
Mor-DalPhosAuOMs
Mor-DalPhosAuOMs
Mor-DalPhosAuOMs
Mor-DalPhosAuOMs
80
90[d]
0
9
10
11
75
77
[a]
A mixture of MsOH and 3 in DCM was introduced into the reaction mixture in a septum-capped vial via a syringe
pump; the nominal final concentration of 1a was 0.05M.
Estimated by H NMR using the methyl group at 0.89 ppm as the internal standard.
2a-Cl is also formed.
The nominal final concentration of 1a was 0.25M, and the isolated yield was 89%.
[b]
[c]
[d]
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One-Step Synthesis of Methanesulfonyloxymethyl Ketones
Table 2. The reaction scope for the synthesis of methanesul-
sistent with our previous works on intermolecular
trapping of the in-situ generated a-oxo gold carbene
intermediates[3h,i] and lend further support to our
notion that P,N-bidentate ligands such as Me-DalPhos
and Mor-DalPhos[7] can attenuate the strong electro-
phility of the a-oxo gold carbene via the formation of
a tricoordinated metal center. The ligands L1 and L2
with conformationally more rigid N-heterocycles,
however, led to unexpectedly lower yields (entries 5
and 6). To further improve this reaction, we reasoned
that a more efficient trapping of the a-oxo gold car-
bene by MsOH, which is likely in the form of MsOÀ
in the presence of basic 8-methylquinoline and its N-
oxide, could be realized Àif the catalystꢀs counter anion
is MsOÀ instead of NTf2 due to spatial proximity. Al-
though MsOÀ has seldom[8] been used as the counter
anion in Au(I) catalysis due to its comparably better
coordination capacity, to our delight, when Mor-Dal-
PhosAuOMs was used as the catalyst, the reaction
yield jumped to 80% (entry 7), and an even better
yield was realized when the nominal final concentra-
tion of 1a was five times higher (entry 8). It is note-
worthy that all the above reactions were run with the
oxidant, 8-methylquinoline N-oxide (i.e., 3), in slight
fonyloxymethyl ketones.[a]
[a]
Isolated yields.
excess to MsOH which, in turn, was 1.2 equiv. to the ylene groups (entry 8), the expected mesylated was
alkyne substrate. When MsOH was used in excess to isolated in 75% yield, notably with little interference
3, no oxidation occurred (entry 9). This surprising from a Friedel–Crafts-type cyclization.
result, however, could be rationalized by supposing
With the facile formation of mesylates 2 from read-
that the oxidant is fully protonated by the excess acid ily available terminal alkynes under mild conditions,
and thereby no longer capable of participating in the we envisioned that these synthetically versatile prod-
gold-catalyzed alkyne oxidation. The reaction yield ucts can be channelled to further transformations
also dropped to some extent if the amount of 3 was without isolation. To demonstrate the feasibility of
decreased (entry 10) or increased (entry 11). It must this approach and to enhance the synthetic utility of
be pointed out that in these reactions a mixture of the gold catalyst, we examined the reaction of these
MsOH and 3 was added to the reaction vessel via sy- products with thioamides.[11] In order to establish the
ringe pump in order to avoid over-oxidation. In the proper reaction conditions, we first reacted isolated
absence of the gold catalyst, no reaction was detect- 2a with thioacetamide. To our delight, the 2,4-disub-
ed.[9]
stituted thiazole 4a was formed in 96% isolated yield
With the optimized conditions (i.e., Table 1, upon stirring them together in dichloromethane at
entry 8) in hand, we applied the reaction to various 408C for 6 h.
other terminal alkynes. As shown in Table 2, the reac-
By combining the gold catalysis and the thiazole
tion worked smoothly with substrates containing formation in a one-pot process,[12] 4a was isolated in
remote functional groups such as chloro (entry 1) and an excellent yield (Table 3, entry 1). It is worth point-
silyl ether (entry 2) as well as the one with a propar- ing out that the 2,4-disubstituted thiazole ring can be
gylic methyl ether (entry 9), affording the correspond- found in the structures of many bioactive natural
ing mesylates in good yields. In the case of a homopro- products and pharmaceuticals such as epothilones[13]
pargylic alkoxy group, the yield was low (<20%), and mycothiazole.[14] Various other thioamides were
which we attributed to intramolecular trapping of the readily accommodated, giving the corresponding thia-
gold carbene center by the ether oxygen.[3b,10] Cyclo- zole products, including interesting biheteroaryls such
propylacetylene participated in the reaction without as 4f (entry 6) and 4g (entry 7), in mostly good yields
incident (entry 3), so did the sterically more demand- (entries 2–8). By varying the terminal alkyne, 2-phe-
ing cyclohexylacetylene (entry 4). Enynes reacted nylthiazoles containing different substituents at the 4-
smoothly, delivering alkenyl methanesulfonyloxy- position were isolated in mostly good yields (en-
methyl ketones in excellent yields (entries 5 and 6). tries 9–17). Notably, the chloride in entry 10 and the
Similarly, phenylacetylene, also a conjugated acety- conjugated enone intermediates in entries 15 and 16
lene, was readily allowed (entry 7). When the phenyl did not appear to interfere with the thiazole forma-
group and the acetylene were separated by two meth- tion.
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Gongde Wu et al.
Table 3. One-pot synthesis of 2,4-disubstituted thiazoles.[a]
[a]
Isolated yields.
All the examples in Table 3 were run by using we subjected 30 times that amount of 1-dodecyne
0.25 mmol of alkyne substrates. To demonstrate the (1.e., 7.5 mmol, 1.245 g) to the one-pot protocol
applicability of the chemistry on a much larger scale, (Scheme 4). To our delight, with a much lower cata-
lyst loading (1 mol% instead of 5 mol% in Table 3),
the reaction still proceeded smoothly, albeit expected-
ly slower, and the thiazole product 4a was isolated in
83% yield, which is only marginally lower than that
of the 0.25-mmol scale reaction (see Table 3, entry 1).
In summary, we have developed a novel and effi-
cient access to methanesulfonyloxymethyl ketones via
gold-catalyzed oxidation of terminal alkynes. This
chemistry has a good substrate scope and is facilitated
by the use of Mor-DalPhos, a P,N-bidentate phos-
Scheme 4. One-pot preparation of 2,4-disubstituted thiazole
4a on a gram scale.
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One-Step Synthesis of Methanesulfonyloxymethyl Ketones
phine as the ligand and the use of MsOÀ as the coun- Acknowledgements
ter anion in the gold catalyst. This mild method gives
We are grateful of the financial support by NSF (CHE-
access to reactive a-functionalized methyl ketones
without the often problematic regioselectivity issue
and paves the way for a one-pot synthesis of 2,4-dis-
ubstituted thiazoles with good efficiency and under
mild conditions. We anticipate that this gold catalysis
could be stringed together with a diverse range of
other transformations based on methyl ketones with
a-leaving groups into step-economic and efficient
one-pot reactions. Further studies along this line will
be reported in due course.
1301343 and CHE-0969157). GW thanks the fellowship from
the Government of Jiangsu, China and the support of NSFC
(21003073).
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General Procedure for the Synthesis of Mesylates 2
To a 3-dram vial containing 0.50 mL of dichloromethane
were added a terminal alkyne 1 (0.25 mmol), followed by
Mor-DalPhosAuOMs (9.4 mg, 0.0125 mmol, 5.0 mol%).
While the reaction mixture was stirred at room temperature,
a
solution of 8-methylquinoline N-oxide (3a; 52.0 mg,
0.325 mmol) and MsOH (28.1 mg, 0.300 mmol) in 0.50 mL
of dichloromethane was added via a syringe pump over 5 h.
The reaction mixture was further stirred for 1 h at room
temperature before concentration under vacuum. The re-
sulting residue was purified by silica gel flash chromatogra-
phy to afford 2.
General Procedure for the One-Pot Synthesis of 2,4-
Disubstituted Thiazoles 4
To a 3-dram vial containing 0.50 mL of dichloromethane
were added a terminal alkyne 1 (0.25 mmol), followed by
Mor-DalPhosAuOMs (9.4 mg, 0.0125 mmol, 5.0 mol%).
While the mixture was stirred at room temperature, a solu-
tion of 8-methylquinoline N-oxide (52.0 mg, 0.325 mmol)
and MsOH (28.1 mg, 0.300 mmol) in 0.50 mL of dichlorome-
thane was added to the reaction mixture via a syringe pump
over 5 h. The reaction mixture was further stirred for 1 h
before the addition of thioamide (0.30 mmol). The resulting
mixture was then heated to 408C for 6 h, before concentra-
tion under vacuum. The resulting crude reaction mixture
was purified by silica gel flash chromatography to afford 4.
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One-Step Synthesis of Methanesulfonyloxymethyl Ketones
via Gold-Catalyzed Oxidation of Terminal Alkynes: A
Combination of Ligand and Counter Anion Enables High
Efficiency and a One-Pot Synthesis of 2,4-Disubstituted
Thiazoles
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Gongde Wu, Renhua Zheng, Jonathan Nelson,
Liming Zhang*
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