Angewandte
Communications
Chemie
Table 1: Synthesis of methylene oxindoles: Optimization of reaction conditions. Reactions were
performed on a 0.2 mmol scale. NMR yields and isomeric ratios determined using CH2Br2 as internal
standard. Isolated yield given in parenthesis.
aniline core was also investigated
(2i–2o), and the corresponding
products were obtained in yields
ranging from 86% to 97% yield.
Products containing a variety
of alkyne substitutions were syn-
thesized (2p–2w). The acidity of
HFIP may also be responsible for
O-TBS cleavage in product 2s,
resulting in diminished yields.
Complementary to known meth-
ods for the synthesis of (E)-3-
(chloromethylene)oxindoles,[6c,7]
products containing aryl substitu-
ents at the alkene were obtained in
excellent yields and good selectiv-
ities. Product 2u, encompassing an
unsubstituted phenyl group, was
formed in 80% yield, and 7:1 E/Z
ratio. Excellent yield and stereose-
lectivity was obtained when 1v was
employed, containing an electron-
rich -OMe substituent. Product 2w,
containing a p-fluoride on the aryl
Entry
Solvent (0.2 m)
Temp. (8C)
Additive
Yield 2a (%)
E/Z ratio
1
2
3
4
5
6
7
8
TFE
100
100
80
None
None
None
HFIP (8 equiv)
HFIP (3 equiv)
iPrOH (8 equiv)
None
None
None
TFA (8 equiv)
AcOH (8 equiv)
BzOH (8 equiv)
TfOH (8 equiv)
52
71
27
96 (94)
34
11
N. D.
10
N. D.
61
N. D.
N. D.
N. D.
20:1
>20:1
2.2:1
HFIP
HFIP
PhMe
PhMe
PhMe
PhMe
MeCN
NMP
PhMe
PhMe
PhMe
PhMe
100
100
100
100
100
150
100
100
100
100
>20:1
>20:1
N. D.
N. D.
>20:1
N. D.
>20:1
N. D.
N. D.
N. D.
9[a]
10
11
12
13[a]
N. D.=Not detected. [a] Complete decomposition of starting material.
attributed to the distinct physical properties of their fluori-
nated counterparts. These include increased acidity and
hydrogen bond-donating ability, reduced nucleophilicity,
and the ability to stabilize cationic species.[12] With this
observation, an improved yield of 71% and > 20:1 E/Z
selectivity was observed when HFIP was employed as the
solvent (entry 2).
Decreased yield and stereoselectivity was obtained at
a lower temperature (entry 3). The loss in stereoselectivity
suggests that higher temperatures lead to preferential for-
mation of the more stable isomer (vide infra). Ultimately,
8 equivalents of HFIP in toluene solvent gave the product in
96% yield and > 20:1 E/Z (entry 4). The product was formed
in lower yield when 3 equivalents of HFIP were used
(entry 5). Interestingly, we observed product formation in
11% yield using a PhMe/iPrOH solvent system (entry 6).
Complete recovery of starting material was observed in the
absence of HFIP (entry 7). The product was formed in low
yields by heating 1a in acetonitrile (entry 8), while heating the
substrate in NMP at 1508C resulted in decomposition of the
starting material (entry 9). TFA was an effective reagent,
generating the product in 61% yield and > 20:1 E/Z
(entry 10). However, other protic acids were inefficient in
this process (entries 11–13).
The generality of this process was evaluated (Scheme 2).
Apart from products 2u and 2w, which displayed decreased
E/Z ratios, all products were furnished with complete E-
selectivity. Initially, we examined the effect of substitutions at
the nitrogen atom (entries 2a–2h). The corresponding prod-
ucts were obtained in good to excellent yields. The acidic
nature of HFIP is responsible for the decreased yields in 2d,
resulting from PMB-group cleavage. Increased HFIP loadings
and longer reaction times were required for complete
conversion in the presence of electron-withdrawing function-
alities (2e and 2 f). The effect of various substituents on the
moiety, was formed in 84% yield and 11:1 E/Z. X-ray
crystallographic analysis of 2w[26] served to confirm the E-
1
stereochemistry of the products, while H NMR analysis was
applied for all other examples using characteristic chemical
shifts. Chlorinated methylene pyrrolidone 2x was isolated in
84% yield. In contrast to the oxindole products, the 2-
pyrrolidone scaffold was obtained with complete Z-selectivity
as determined by X-ray crystallographic analysis.[26] The
synthesis of this class of compounds has not been achieved
by previous metal-catalyzed alkyne chloroacylation
reports.[6c,7,8,11a]
We sought to determine the substrate limitations of this
reaction. Unreacted starting material was observed when
substrate 1b-TIPS was subjected to the reaction conditions.
The bulky TIPS substituent likely hinders addition of the
chloride to the alkyne moiety. Similarly, no reaction took
place with substrate 1y, containing a bromide substituent
ortho to the carbamoyl functionality which may impact its
conformation. In addition, substrate 1z, containing an acid-
sensitive alkyl carbonate on the alkyne, led to complete
decomposition of the starting material.
The chloroacylation of 1a was successfully performed on
a 2 mmol scale, forming product 2a in 90% yield and
complete E-selectivity (Scheme 3). The synthetic utility of
the chlorinated methylene oxindole products was determined
by carrying out various transformations. Nucleophilic sub-
stitution with p-anisidine resulted in generation of Z-3 in 96%
yield and complete Z-selectivity. When benzyl mercaptan was
used as a nucleophile, product E-4 was furnished in 87%
yield.[11a] Employing dimethyl malonate as the nucleophile
generated product Z-5 in 83% yield and > 20:1 Z/E ratio. The
stereoselective formation of products Z-3, E-4, and Z-5 is
likely resulting from a stereoselective addition/elimination
mechanism to form the more stable isomer. This phenomenon
has been reported by Meyer and Cossy, who observed a shift
Angew. Chem. Int. Ed. 2021, 60, 18478 –18483
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