2
Tetrahedron Letters
bIsolated yield.
Figure 1. Synthesis of the rhodium catalyst.
cUnder air.
d10 equiv of water was added.
2.3. Substrates scope
With the optimization conditions in hand, we started to
investigate the substrate scope with respect to acetylenes (Figure
2). The reaction of N-benzyl isatin (2a) with a wide range of
acetylenes 3 with different functional groups were examined by a
treatment with catalyst Rh-Cat (2-4 mol%) and Hunig's Base
(0.2 equiv) in DMF (0.5 M) at 50 C for 16 hours. Aromatic
acetylenes with either electron-donating groups (4b-4f) or
electro-withdrawing groups (4g-4i) afforded excellent yields of
the desired propargylic alcohols. The ortho-position substituent
on the benzyl acetylene gave a lower yield (4d, 72%). It could be
resulted from the hindrance during the activation of the acetylene
by the catalyst, which was in need of a higher catalyst loading (4
mol%) and a longer reaction time. It is also noteworthy that
functional groups, including methoxy group (4f), halides (4g-4i),
hetero-aromatic (4j), alkene (4h), cyclopropanyl (4m) and TMS
(4n), were all well tolerated under these mild conditions. When
ethynyltrimethylsilane was introduced into this reaction, a
slightly lower yield was observed (4n, 79%). Substituents in the
aromatic ring of the isatin derivatives were also investigated.
Electro-withdrawing groups (4o, 98%) afforded a better yield and
electro-donating groups afforded a lower yield (4p, 74%). When
the Bn group (2a) was changed to a methyl group, the yield of 4q
reached 84% with a longer reaction time of 48 hours. When the
Bn group (2a) was changed to a Boc group, the yield of 4r was
increased to 99% under the standard condition, which indicated
that the substituent on the N-atom of the isatins strongly
influenced the reactivity of isatin derivatives.
Figure 2. The crystal structure of Rh-Cat (CCDC 2032843)
2.2. Initial experiments
With the new rhodium catalyst in hand, its catalytic activities
were then investigated focusing on the direct alkynylation of
substrates with electrophilic functions. After several trials, it was
found out that the alkynylation of N-benzyl of isatin could be
carried out smoothly. Therefore, phenylacetylene and N-benzyl
isatin were selected as the standard substrates for the
optimization of reaction conditions by treatment of N-benzyl
isatin with phenylacetylene (3.0 equiv), Rh-Cat (5 mol%) and
Hunig base (0.2 equiv) in THF at 50 ºC for 24 hours. The
corresponding propargylic alcohols were generated in 81% yield
(Table 1, entry 1). As the activation of the terminal alkyne is
affected by the solvent used, six different solvents were
evaluated, most of which were observed to give high yields
(Table 1, entries 1-6). Among these solvents, the highest yield
was achieved by DMF at a relatively shorter time (Table 1, entry
7). Encouragingly, the catalyst loading can be reduced down to 2
mol% without any loss in yield when the reaction time was
extended to 18 hours (Table 1, entry 8). Further decrease of the
catalyst loading to 1 mol% led to a significantly reduced yield of
84% even with a longer reaction time (Table 1, entry 9).
Pleasingly, the reaction rate was not sensitive to the presence of
air or water (Table 1, entries 10 and 11), disclosing the wide
applicability of the proposed method, such as in the large scale
synthesis26. Control experiments showed that both of the catalyst
and the base were indispensable in this reaction (Table 1, entries
12 and 13).
2.4. A plausible mechanism for the alkynylation.
As both of the Rh-Cat and the Hunig's Base were only needed
in catalytic amounts in this reaction, a plausible mechanism of
the alkynylation of isatin derivatives was depicted in Figure 4.
Firstly, one of the labile acetonitriles in the Rh-Cat was
exchanged by the Hunig's Base to form M1, which activated the
terminal alkyne by forming the Rh-alkyne intermediate M2 along
with the concomitant loss of the DIPEA•hexafluorophosphate
(V) salt (i-Pr2NEt•HPF6). The reaction of species M2 and N-
benzyl isatin led to the formation of an unstable alkoxide
intermediate M3. The latter was then protonated by i-
Pr2NEt•HPF6. The product was liberated and M1 was regenerated
afterwards.
3. Conclusion
In summary, we developed a new octahedron rhodium
catalyst, which could be applied for the direct activation of
terminal alkynes and alkynylation of isatins derivatives. The
alkynylation produced various 3-alkynyl-3-hydroxyoxindoles in
high yields. Notably, the rhodium complex enabled the direct
catalytic alkynylation of isatin derivatives under mild conditions
with excellent yield at low catalyst loadings. Intriguingly, the
alkynylation processes were insensitive to water and air. Further
investigations on the alkynylation of different electronphilic
reagents and asymmetric catalyzation by using the optical
octahedron rhodium catalyst are in progress in our laboratory.
Table 1. Initial catalysis experimentsa.
Catalyst loading Base
( mol%) (0.2 eq)
Time
(h)
24
24
24
24
24
24
12
18
24
18
18
18
18
Yield
(%)b
81
88
72
86
90
90
95
95
84
95
95
0
Entry
Solvent
1
2
3
4
5
6
7
8
5
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
-
THF
CH3CN
DCE
EtOAc
Dioxane
i-PrOH
DMF
DMF
DMF
DMF
DMF
5
5
5
5
5
5
2
1
2
2
2
0
Acknowledgments
This work was supported by the Young Scholar Supporting
Plan of Changzhou Institute of Technology, the National Natural
Science Foundation of China (No. 21703187) and the SKL of
Xiamen University (No. 201919).
9
10 c
11 c,d
12
13
DMF
DMF
DIPEA
0
aConditions: 0.2 mmol isatin derivatives, 0.6 mmol phenylacetylene, 0.04
mmol DIPEA (N,N-Diisopropylethylamine), 0.4 mL solvent (0.5 M), 50 C.
Wu, Ze-ying
