2
C.C. Black, A.E.V. Gorden / Tetrahedron Letters xxx (2018) xxx–xxx
entry 13). Using this aqueous system, we can reduce or eliminate
the use of volatile organic solvents which has the potential to
increase the hazards in large scale oxidation reactions.30,31 Doing
these reactions in water provides a much greener and safer
approach without sacrificing yields. It also greatly increases the
ease of product isolation because the reaction is done in an ‘‘on
water” fashion..32 Subsequent to oxidation – once the stirring has
stopped, the substrate separates from the water and can easily
be removed from the catalyst/aqueous solution by means of a sep-
aratory funnel.
A series of differently functionalized substrates were oxidized
using the conditions previously optimized with 1-phenyl-1-pen-
tyne. The results of these are given in Table 2 as isolated yields.
Shortening the length of the R group suffers a slight decrease in
isolated yield (Table 2 entry 2). Substrate 3c gives an example that
this reaction works in the absence of aromatic compounds while
also producing a good isolated yield. However, terminal alkynes
3d and 3f produced lower yields even when the time was increased
to 16 h or 20 h. Previous reports also demonstrated low yields and
longer reaction times when oxidizing these types of terminal
alkynes.8–11,33 This could be due to competition from a Glaser cou-
pling reaction in the presence of the copper catalyst.34
To overcome the potential competing Glaser coupling reaction,
terminal alkynes can be protected with TMS following standard
procedures (3g).35 With the protected substrates, we were able
to decrease the reaction time from 16 h to 4 h while also signifi-
cantly increasing the overall yield (3g). Allowing the reaction to
proceed for 16 h in order to compare to the terminal alkyne, leads
to an overall yield more than double the unprotected terminal
alkyne (57%).
Fig. 1. Complex 1 (left) Cu(II) 2-quinoxalinol salen (Salqu) catalyst. Complex 2
(right) sulfonated 2-quinoxalinol salen (sulfosalqu) catalyst.
ities of TBHP, the use of Tetrabutylammonium iodide (TBAI) as
cooxidant has also been employed, but this was also found to result
in a significant decrease in overall yield (Table 1 entry 4).28 Reduc-
ing the temperature also gave a lower yield (Table 1 entry 5). When
the heat added to the reaction was reduced, only a trace amount of
the desired product was produced (Table 1 entry 6).
In exploring the use of different solvents, using dichloro-
methane (DCM) led to a much lower yield, even when running
the reaction for 24 h (entries 7 and 8). Acetonitrile likely gives
the highest yield due to having a high oxygen solubility (8.1
mM).29 Previous studies with catalyst 1 have shown the important
role of molecular oxygen in the allylic oxidations. Employing a sim-
ple Cu(II) salts (entries 10–12), under comparable conditions even
in higher catalyst loading (10%), resulted in only a modest yields
(17–31%) after 4–6 h. Also, the absent any metal catalyst resulted
in only 8% yield, indicating the important role of copper (Table 1
entry 9). Throughout the optimization experiments, entry 1 – using
acetonitrile at 70 °C, 1 mol% catalyst, and 4 equivalents of TBHP –
produced the best overall yield within a reaction time of 4 h.
In order to demonstrate the potential utility of these reactions
in water, our model substrate (3a) was tested using a water soluble
sulfonated version of catalyst 1, catalyst 2. Complex 2 (1 mol%) was
also able to oxidize 3a in just 4 h resulting in a yield of 64% (Table 1
Entry 5 shows an example possessing a CAH position that is
both benzylic and propargylic activated resulting in oxidation with
an isolated yield of 77%. Because our catalyst has been shown to
oxidize benzylic positions, we would expect a higher yield with
the added functional group; however, the added bulk of the aro-
matic compound can hinder the reactive site of the molecule yield-
ing a smaller yield then desired. For the symmetrical alkyne (entry
3) we only observed oxidation on one side of the alkyne without
Table 1
Optimization of the reaction conditions.
Entry
Catalysta
Solvent
T °C
Time
Additiveb
Yield (%)c
1
2
3
4
5
6
7
8
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
Complex 1
None
Cu(OAc)2 10 mol%
Cu(acac)2 10 mol%
Cu(NO3)2 10 mol%
Complex 2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH3CN
H2O
70
50
50
50
50
RT
40
40
70
80
80
80
80
4 h
1 h
24 h
4 h
4 h
24 h
4 h
24 h
4 h
6 h
4 h
4 h
4 h
78
26
15
4
47
trace
17
45
8
26
31
17
64
K2CO3
K2CO3
TBAI
9
10
11
12
13
H2O
H2O
H2O
a
b
c
1 mol% unless otherwise stated.
50 mol%.
GC yields using internal standard method.