An NHC-catalyzed in situ activation strategy to β-functionalize saturated carboxylic acid: An enantioselective formal [3+2] annulation for spirocyclic oxindolo-γ-butyrolactones

Article abstract of DOI:10.1002/chem.201500345

An in situ NHC-catalyzed activation strategy to β-functionalize saturated carboxylic acid was developed. This asymmetric formal [3+2] annulation could deliver spirocyclic oxindolo-γ-butyrolactones from saturated carboxylic acid and isatin in good yields with high to excellent enantioselectivities. The easy availability of the starting materials, direct installation of functional units at unreactive carbon atom and the convergent assembly make this protocol attractive in the field of organic synthesis. Top cat: An in situ N-heterocyclic carbene (NHC)-catalyzed activation strategy to β-functionalize saturated carboxylic acid was developed (see scheme). This asymmetric formal [3+2] annulation delivered spirocyclic oxindolo-γ-butyrolactones from saturated carboxylic acid and isatin in good yields with high to excellent enantioselectivities. The availability of the starting materials, direct installation of functional units at unreactive carbon atom and the convergent assembly make this protocol attractive for organic synthesis.

Full text of DOI:10.1002/chem.201500345

DOI: 10.1002/chem.201500345
Communication
&
Organocatalysis
An NHC-Catalyzed In Situ Activation Strategy to b-Functionalize
Saturated Carboxylic Acid: An Enantioselective Formal [3+2]
Annulation for Spirocyclic Oxindolo-g-butyrolactones
Yuanwei Xie, Chenxia Yu, Tuanjie Li, Shujiang Tu, and Changsheng Yao*[a]
ed an elegant way to set up an aryl or alkyl group at the b-po-
Abstract: An in situ NHC-catalyzed activation strategy to
b-functionalize saturated carboxylic acid was developed.
This asymmetric formal [3+2] annulation could deliver spi-
rocyclic oxindolo-g-butyrolactones from saturated carbox-
ylic acid and isatin in good yields with high to excellent
enantioselectivities. The easy availability of the starting
materials, direct installation of functional units at unreac-
tive carbon atom and the convergent assembly make this
protocol attractive in the field of organic synthesis.
sition directly through photoredox one-electron oxidation of
enamine to the b-carbon radical.[5] Even so, the direct installa-
tion of a functional group at the unreactive b-position of readi-
ly available carbonyl compounds, for example, saturated car-
boxylic acids, deserves further study.
N-heterocyclic carbenes (NHCs) have been confirmed as flex-
ible catalysts for several “umpolung” reactions,[6] such as the
benzoin condensation,[7] Stetter reaction,[8] a3–d3 umpolung
(homoenolate).[9] Moreover, NHC-catalyzed b-carbon functional-
izations of derivatives of saturated carboxylic acids including
Carbonyl compounds including
carboxylic acids, esters, ketones
and aldehydes are very useful
building
blocks
employed
widely for the synthesis of phar-
maceuticals and materials. Thus,
much effort has been devoted
to the transformation of these
important compounds. Tradi-
tionally, the conjugate addition
of a,b-unsaturated carbonyl
compounds with nucleophiles is
a powerful strategy for intro-
Scheme 1. Some strategies to generate homoenolates or their equivalents.
ducing a functional group at
the b-position of a carbonyl
group.[1] The amino-catalyzed
oxidation of saturated aldehydes to the corresponding a,b-un-
saturated iminium and subsequent reaction with nucleophilic
reagents could also functionalize b carbon atoms circuitously.[2]
However, the direct functionalization of unreactive saturated
carbon atoms remote from carbonyl group is a great challenge
for organic chemists.[3] Recently, several groups disclosed the
transition-metal, for example, palladium-catalyzed bb-function-
alization of carbonyl compounds by chelation-assisted C(sp3)À
H activation in the presence of auxiliary groups or directing
groups (Scheme 1a).[4] In addition, MacMillan’s group present-
esters and anhydrides through the generation of homoeno-
lates have been achieved successfully (Scheme 1b and c).[10] In
2014, Scheidt’s group found a facile NHC-promoted generation
of enolate from the acyl imidazole formed in situ from the car-
boxylic acid and carbonyldiimidazole (CDI), which paved a new
avenue to the direct activation of a-carbon of carboxylic acid
(Scheme 2).[11]
Later, the work of Ye et al. showed that a,b-unsaturated acyl
azoliums could be obtained readily from a,b-unsaturated car-
boxylic acids via mixed anhydrides generated in situ
(Scheme 3).[12] The activation of carboxylic acids in situ was
proved to be an efficient strategy to give rise to reactive inter-
mediates such as enolates and a,b-unsaturated acyl azoliums
under the catalysis of NHC (for the in situ activation of carbox-
ylic acids catalyzed by cinchona alkaloids or isothioureas devel-
oped by Smith and Romo, please see ref. [13]). However, as an
alternative of classical a3–d3 umpolung, a challenging approach
[a] Y. Xie, Prof. C. Yu, T. Li, Prof. Dr. S. Tu, Prof. Dr. C. Yao
School of Chemistry and Chemical Engineering
Jiangsu Key Lab of Green Synthetic Chemistry for Functional Materials
Jiangsu Normal University, Xuzhou, Jiangsu 221116 (P.R. China)
E-mail: csyao@jsnu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500345.
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Scheme 3. An in situ protocol to form a,b-unsaturated acyl azoliums.
Scheme 2. An in situ strategy for formation of enolate from carboxylic acid.
with great significance to homoenolate is the direct conversion
from carboxylic acids.
Since the coupling reagents, such as diisopropylcarbodii-
mide (DIC) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetrame-
thyluronium hexafluorophosphate (HATU), are employed
widely in peptide synthesis to activate the carboxylic acids via
intermediates including esters and anhydrides,[14] we envisaged
that these intermediates could be produced in situ and their
reaction with NHC could also deliver homoenolate in the pres-
Scheme 4. Our proposal for NHC-catalyzed generation of homoenolate.
ence
of
base
effectively
(Scheme 4). To continue our in-
terest in the cascade synthesis
of heterocycles and NHC cataly-
sis,[15] herein we report our pre-
liminary results of NHC-cata-
lyzed asymmetric annulation for
the synthesis of spirocyclic oxin-
Table 1. Optimization of the reaction conditions.[a]
dolo-g-butyrolactones,
are of biological interest, from
saturated carboxylic acid
which
through in situ activation strat-
egy in the presence of coupling
reagents.[9a,b,16]
Entry
NHC cat.
Base
PCR[b]
Solvent
Yield [%][c]
d.r.[d]
ee [%][e]
We commenced our study
from the optimization of reac-
tion conditions, which are sum-
marized in Table 1. The NHC-cat-
alyzed formal [3+2] cyclization
of 3-(4-bromophenyl)propanoic
acid (1a) and 1-benzylindoline-
2,3-dione (2a) was tested as
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4b
4c
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CDI
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH2Cl2
THF
–
67
55
–
83
–
85
trace
80
79
–
–
4:1
4:1
–
3:1
–
7:1
–
1.5:1
–
89
89
–
93
–
95
–
93
97
–
DCC/HOBt
DIC/HOBt
BOP-Cl
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
HATU
[j]
9
6
a
model reaction. Firstly, we
10
11
12
13
14
15
16
17
18
19
20
21
4c
4c
4c
4c
4c
4c
4c
4c
4c[f]
4c[g]
4c[h]
4c[i]
5:1
–
–
DBU
evaluated the reaction condi-
tions by screening the peptide
coupling reagents. CDI and BOP-
Cl did not work for this reaction
(Table 1, entries 1 and 4). Gratify-
ingly, the desired [3+2] annula-
tion product 3a could be ob-
tained with 89% ee by DCC/
HOBt and DIC/HOBt. When
HATU was investigated, much
better performance was ob-
served (83% yield, 3:1 d.r. and
93% ee). Next, we explored the
DABCO
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
–
–
–
–
74
72
69
85
80
83
80
78
3:1
4:1
2:1
6:1
5:1
5:1
6:1
6:1
94
96
79
98
77
79
93
91
toluene
DME
DME
DME
DME
DME
[a] Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), NHC cat. (0.03 mmol), base (0.3 mmol), PCR (0.3 mmol),
solvent (4 mL), 208C, 12 h. [b] PCR=peptide coupling reagent. [c] Isolated yields. [d] Diastereomeric ratio deter-
mined by 1H NMR spectroscopy. [e] The ee values were determined by HPLC. [f] 10 mol% of NHC. [g] 20 mol%
of NHC. [h] 08C. [i] 408C. [j] 2.5 equiv.
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influence of catalysts; in contrast to the NHC precursor 4a and
6, precatalyst 4c gave the product in good yield, diastereo-
and enantioselectivity (Table 1, entries 5, 7 and 9), whereas the
catalyst 4b and 5 failed to give the desired annulation product
(Table 1, entries 6 and 8). A catalyst loading test indicated that
15 mol% of 4c would be better. Decreasing or increasing load-
ing of the catalyst showed lower enantioselectivity (Table 1, en-
tries 18 and 19). Then, K2CO3, Cs2CO3, DABCO (1,4-diazabicyclo
[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and
NaOAc were deployed to assess the scope of the base. The re-
sults demonstrated that inorganic bases are more effective
than organic bases; screening of inorganic bases revealed that
Cs2CO3 was the best choice (Table 1, entries 10–13). Subse-
quently, the influence of different solvents on the reaction of
1a and 2a were examined to optimize the conditions (Table 1,
entries 14–17); we found that DME is better than 1,4-dioxane,
CH2Cl2, THF and toluene. Temperature screening showed that
208C should be optimal (Table 1,
provide the corresponding cascade product (3m) with moder-
ate d.r. and high e.r. values, albeit with moderate yield. These
results highlighted the wide application scope of this NHC-cat-
alyzed [3+2] reaction.
The optical rotation data and HPLC analysis data of spirocy-
clic oxindolo-g-butyrolactone 3b were found to be in good
agreement with those reported in the literature; thus, the ab-
solute configuration could be determined by comparison.[17]
A plausible catalytic cycle of this NHC-catalyzed [3+2] annu-
lation of saturated carboxylic acid is illustrated in Scheme 5.
The addition of NHC to the ester substrate, which was generat-
ed in situ from the saturated carboxylic acid, gave the corre-
sponding NHC-bounded intermediate A. It could undergo de-
protonation to form the enolate intermediate B, which was
transformed into intermediate C through b-sp3-H shift similar
to the formation of homoenolate in the NHC-catalyzed reac-
tions of derivatives of carboxylic acids.[10] Then intermediate C
entries 20 and 21). Based on the
Table 2. Scope with saturated carboxylic acids 1 and the isatin derivatives 2.[a]
above results, it was clear that
the formation of spirocyclic ox-
indolo-g-butyrolactones in high
yield with good to excellent
enantioselectivity and diastereo-
selectivity is facilitated by the
combination of triazole carbene
precursor 4c and Cs2CO3 in DME
as the solvent at 208C.
With the optimized reaction
conditions in hand, we turned
our attention to the scope of
substrates by the variation of sa-
turated carboxylic acids 1 and
the isatin derivatives 2. It was
found that both electron-defi-
cient (Cl, Br, NO2) and electron-
rich (CH3) moieties are tolerated
well on the aryl group (3a–3e).
The scope of the isatins 2 was
then studied. It was found that
isatins with both electron-with-
drawing groups (5-F, 5-Cl and 5-
Br) and electron-donating group
(5-Me) are compatible with the
reaction conditions. When isa-
tins with the electron-donating
group (Me) at the 5-position
were engaged in this reaction,
both electron-withdrawing and
electron-donating groups on
the carboxylic acids worked well
to afford the corresponding
products in high yields and ex-
cellent enantioselectivities (93–
98% ee). To our pleasure, satu-
rated carboxylic acids with an
alkyl group reacted with 2a to
[a] Reaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), 4c (0.03 mmol), Cs2CO3 (0.3 mmol), HATU (0.3 mmol), DME
(4 mL), 208C, 12 h; d.r. determined by H NMR spectroscopy; the ee values were determined by HPLC.
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Keywords: annulation · beta-functionalization · N-heterocyclic
carbine · organocatalysis · spirocyclic oxindole
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Scheme 5. Plausible catalytic cycle.
reacted with isatin derivatives 2 through nucleophilic addition
giving the zwitterionic intermediate E. The catalyst could then
be regenerated by the release of the final cycloadduct 3.
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tion. The present NHC-catalyzed asymmetric process provides
an efficient access to spirocyclic oxindolo-g-butyrolactones in
good to high yields with excellent enantioselectivity. Further
studies aimed at the expansion of the reaction scope and the
further development of analogous cyclization of saturated car-
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General procedure for the preparation of compounds 3a–
3m
An oven-dried 10 mL Schlenk tube equipped with a magnetic stir
bar was charged with triazolium salt 4c (12.6 mg, 0.03 mmol),
Cs2CO3 (97.5 mg, 0.30 mmol), saturated carboxylic acid
1 (0.24 mmol), isatin 2 (0.2 mmol) and HATU (114.0 mg, 0.3 mmol).
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nitrogen. To this mixture was added freshly distilled DME (4 mL)
with a syringe. Then the mixture was stirred at 08C until comple-
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Received: January 27, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organocatalysis
Y. Xie, C. Yu, T. Li, S. Tu, C. Yao*
&& – &&
An NHC-Catalyzed In Situ Activation
Strategy to b-Functionalize Saturated
Carboxylic Acid: An Enantioselective
Formal [3+2] Annulation for
Top cat: An in situ NHC-catalyzed acti-
vation strategy to b-functionalize satu-
rated carboxylic acid was developed
(see scheme). This asymmetric formal
[3+2] annulation delivered spirocyclic
oxindolo-g-butyrolactones from saturat-
ed carboxylic acid and isatin in good
yields with high to excellent enantiose-
lectivities. The availability of the starting
materials, direct installation of function-
al units at unreactive carbon atom and
the convergent assembly make this pro-
tocol attractive for organic synthesis.
Spirocyclic Oxindolo-g-butyrolactones
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!