Base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one

Article abstract of DOI:10.1016/j.tetlet.2013.11.118

The base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one yields Morita-Baylis-Hillman (MBH) adducts instead of the expected aldol products in good to high yields (up to 97%). Various organic and inorganic bases are efficient catalysts for this reaction. Our study excluded the Morita-Baylis-Hillman mechanism for the formation of the MBH-type products. The MBH products are most likely formed as a result of the subsequent isomerization of the original aldol products between isatins and N-Boc-3-pyrrolin-2-one.

Full text of DOI:10.1016/j.tetlet.2013.11.118

Tetrahedron Letters 55 (2014) 706–709
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one
⇑
Naresh Ramireddy, John C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one yields Morita–Baylis–Hillman
(MBH) adducts instead of the expected aldol products in good to high yields (up to 97%). Various organic
and inorganic bases are efficient catalysts for this reaction. Our study excluded the Morita–Baylis–Hillman
mechanism for the formation of the MBH-type products. The MBH products are most likely formed
Received 9 October 2013
Revised 28 November 2013
Accepted 30 November 2013
Available online 6 December 2013
as
a result of the subsequent isomerization of the original aldol products between isatins and
N-Boc-3-pyrrolin-2-one.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Isatin
3-Pyrrolin-2-one
Catalysis
Mechanism
Morita–Baylis–Hillman reaction
Polyfunctional MBH adducts are considered privileged sub-
strates in modern organic chemistry. As a matter of fact, the
MBH adducts are widely used in target-oriented synthesis1 be-
cause they may be successfully transformed into molecules of bio-
logical interest or natural products using a variety of strategies.2
Moreover, some of the MBH adducts themselves exhibit antimalar-
ial, molluscicide, leishmanicidal, antichagasic, antitumoral, anti-
fungal, antibacterial, and herbicide activities.3 Traditionally, MBH
sioned that the N-Boc-3-pyrrolin-2-one (1, Scheme 1) should be a
good substrate for the aldol reaction with isatins (2, Scheme 1). The
C5 protons in 1 should be acidic enough for enolization since the
formed carbanion will be in conjugation with the a,b-unsaturated
system and substituted with an electronegative nitrogen atom.
Herein we wish to report our study on the base-catalyzed reaction
between compound 1 and isatins (2), which does not produce the
expected aldol products 3 (Scheme 1). Instead, this reaction yields
adducts are synthesized via
a
nucleophile-catalyzed reaction
the unexpected Morita–Baylis–Hillman (MBH)1 adducts
4
between an ,b-unsaturated system and an electrophile, such as
a
(Scheme 1), and provides an alternative method for the synthesis
of the MBH-type compounds. It should be pointed out that during
the progress our research, the Wang’s group reported a similar
an aldehyde, that involves a Michael addition-aldol-elimination
sequence.1
On the other hand, the 3-substituted-3-hydroxy-2-oxindole
skeleton may be found in many natural products with interesting
biological activities.4 Due to its potential biological activities, it
has become an emerging scaffold for drug discovery in recent
years.5 Accordingly, recently there were many reports on the cata-
lytic asymmetric synthesis of 3-substituted 3-hydroxyoxindole
derivatives.6–8 Most of the reported organocatalytic methods are
based on the aldol reactions between ketones/aldehydes and isa-
tins via the enamine catalysis.8,9a We are interested in developing
organocatalytic methods10 for the asymmetric synthesis of biolog-
ical active molecules.11 In this regard, we developed methods for
the synthesis of 3-substituted 3-hydroxyoxindoles9d–g on the basis
of the enolate-mediated aldol reactions,12 Since the enolate mech-
anism does not depend on the electrophilicity of the carbonyl com-
pounds, our method complements the enamine mechanism in
terms of the substrate scope.9d–g,12 During this study, we envi-
reaction of 1 with a-ketoesters and a a-ketophosphonate using
Takemoto-type thiourea catalysts.13 However, isatins were not
studied. Most importantly, our study was more focused on the
mechanistic side of the formation of these unexpected products
and demonstrated that the reaction is actually not a MBH reaction;
instead, the products are most likely the results of the isomeriza-
tion of the original aldol reaction products under the reaction
conditions.
Using N-Boc-3-pyrrolin-2-one (1) and isatin (2a) as the model
substrates and dichloromethane as the solvent, we initially
screened DABCO as the base catalyst to effect the desired aldol
reaction between 1 and 2. As shown by the data in Table 1, when
the reaction was carried out with 20 mol % of DABCO at rt for
4 h, we did not obtain the expected aldol product 3a (Scheme 1,
R1 = R2 = H). Instead, a product, which was identified to be 4a,
was isolated in 82% yield (Table 1, entry 1). Compound 4a is struc-
turally an MBH product between 1 and 2a. Some additional organic
bases were then screened. The results are summarized in Table 1.
Similar to DABCO, quinuclidine (entry 2), DBU (entry 3), Et3N
⇑
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (J.C.-G. Zhao).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.118

N. Ramireddy, J. C.-G. Zhao / Tetrahedron Letters 55 (2014) 706–709
707
O
conditions. The results are summarized in Table 2. As shown in
Table 2, besides isatin (2a, entry 1), substituted isatins are also
good substrates for this reaction. An electron-withdrawing group
at the fifth position of the isatin ring enhances the reaction rate
slightly (entries 2–5). High yields of the expected products were
obtained for these substrates, except for 5-nitroisatin, which led
to a much inferior yield (entry 5). A poor yield was also obtained
for 5-methoxyisatin (2f, entry 6). It should be pointed out that,
due to the low solubility of 2f in water, the reaction between com-
pound 1 and 2f was carried out in a mixture of THF and water (3/1
v/v) as the solvent (entry 6). The reaction went to completion in 5 h
and the MBH product 4f was obtained in 62% yield (entry 6). Sim-
ilarly, 5-methyl-, 4-bromo-, 6-bromo-, and 7-bromoisatins were
also barely soluble in water and therefore, the THF/H2O mixture
was used as the solvent for their reactions with compound 1 (en-
tries 7–10), and excellent yields were obtained for the correspond-
ing MBH products (entries 7–10). An N-methyl protected isatin (2l)
was also applied under these conditions, and the desired MBH
product 4l was obtained in a high yield, although the reaction took
7 h for completion (entry 11).
Boc
N
HO
R2
O
O
N
R1
N5
Boc
Base
+ R2
O
3
O
N
R1
Boc
O
N
HO
1
2
R2
O
N
R1
4
Scheme 1. Base-catalyzed reaction between N-Boc-3-pyrrolin-2-one and isatins.
Table 1
Screening of the catalyst and solventa
Boc
O
Besides isatins, we found that a-ketophosphonate may also be
O
used as the substrate.13 For example, when compound 1 was
reacted with diethyl benzoylphosphonate (5) using K2CO3 as the
catalyst, the expected MBH product 6 was obtained in 66%
yield (Eq. 1).
N
HO
Catalyst
O
O
+
N
Boc
Solvent, rt
N
O
H
N
H
1
2a
4a
O
Ph OH
O
O
O
K2CO3
Entry
Catalyst
DABCO
Quinuclidine
DBU
Et3N
TMG
K2CO3
NaHCO3
PPh3
TMG
TMG
Solvent
Time (h)
Yieldb (%)
O
+
(1)
N
Boc
P
EtO
Ph
P
Boc
N
OEt
THF-H2O
24 h, 66%
1
2
3
4
5
6
7
8
9
10
11
12
13
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
4
4
4
4
4
82
86
86
85
88
74
0c
OEt
EtO
6
1
5
4
24
24
4
4
4
On the basis of the facts that Ph3P, which is a good nucleophilic cat-
alyst for the MBH reaction,14 fails to catalyze the reaction between
compound 1 and isatin (Table 1, entry 8), while a non-nucleophilic
base CO32À is a good catalyst (Table 1, entry 12) for this reaction, we
do not believe that the MBH products obtained in our study were
0c
90
86
83
94
88
Ether
Toluene
H2O
TMG
K2CO3
Cs2CO3
4
4
H2O
a
All reactions were carried out with 1 (0.20 mmol), isatin (2a, 0.1 0 mmol), and
the catalyst (0.020 mmol, 20 mol %) in the specified solvent (2.0 mL) at room
temperature.
Table 2
Substrate scope of the base-catalyzed formal MBH reactiona
b
Yield of the isolated product 4a after column chromatography.
c
No formation of 4a was observed in the 1H NMR of the crude product.
Boc
O
O
N
HO
K2CO3
H2O, rt
+ R2
O
O
N
Boc
(entry 4), and TMG (entry 5) can also catalyze this reaction and
produce 4a in similar high yields. An inorganic base K2CO3 can also
catalyze the reaction, albeit in slightly lower efficiency (entry 6).
However, a much weaker base NaHCO3 does not catalyze this reac-
tion (entry 7). Triphenylphosphine is a very good nucleophile and,
therefore, a good catalyst for the MBH reaction.14 Nonetheless, no
product 4a was obtained when triphenylphosphine was used as
the catalyst (entry 8). Further screening of the solvents using
TMG showed that high yields of product 4a can be obtained from
all the organic solvents screened (entries 9–11), although a slightly
higher yield (90%) was obtained in THF (entry 9).
As mentioned above, slightly lowered yield was obtained with
K2CO3 in dichloromethane (entry 6). We speculated that this was
due to poor solubility of the base in the organic solvent. Thus, we
conducted the reaction again using water as the solvent. Indeed,
a much higher yield of 94% was obtained in 4 h (entry 12). Under
similar conditions, another inorganic base Cs2CO3 (entry 13) gave
product 4a in a slightly lower yield of 88%.
R2
N
R1
O
N
R1
1
2
4
Entry
R1
R2
4
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
Me
H
a
b
c
d
e
f
g
h
i
4
97
96
96
97
5-F
5-Cl
5-Br
5-NO2
5-OMe
5-Me
4-Br
6-Br
7-Br
H
3.5
3.5
3.5
3.5
5
5
4
2
2
66
62c
88c
94c
93c
94c
90c
10
11
j
k
7
a
Unless otherwise indicated, all reactions were carried out using isatin
(0.10 mmol), 1 (0.20 mmol), and K2CO3 (0.020 mmol, 20 mol %) in H2O (2.0 mL) at
room temperature.
2
b
Since K2CO3 in water yields the best yield of 4a (Table 1, entry
12), we then evaluated the scope of this reaction using these
Yield of isolated product 4 after column chromatography.
A mixture of THF/H2O (1.5 mL/0.5 mL) was used as the solvent.
c

708
N. Ramireddy, J. C.-G. Zhao / Tetrahedron Letters 55 (2014) 706–709
formed through the MBH mechanism.15 Instead, we propose a tan-
dem enolization-aldol-proton transfer reaction to account for the
formation of products 4 and 6 in our reaction.13 As shown in
Scheme 2, when compound 1 is treated with a base, one of the C5
protons is deprotonated to generate the carbanion intermediate
9a, which has two other resonance forms 9b and 9c. This tridentate
nucleophile attacks isatin 2a using its C3 site to give the deproto-
nated aldol product 10.16 The C3 site is more nucleophilic probably
because it is less hindered as the large Boc group is away from the
reaction site. However, electronic effects may also be at play for
favoring the C3 attack. Although the O1 site is also less hindered,
it cannot form a stable product with isatin. An intramolecular pro-
ton-transfer within compound 10 leads to the intermediate 11a,
which is also stabilized through two additional resonance forms
11b and 11c. The protonation of this intermediate by the conjugate
acid of the base yields the more stable MBH-type product 4a, regen-
erates the base catalyst, and completes the catalytic cycle.
formation of the MBH-type products is actually a result of a tan-
dem enolization-aldol-proton transfer reaction.
Boc
O
O
N
HO
DABCO
THF, rt
O
O
+
(2)
(3)
N
Boc
O
N
O
H
N
H
7
2a
12
Boc
O
O
N
H(D)
5
HO
K2CO3
D2O, rt
+
H(D)
N
O
N
O
Boc
50% D
H
N
H
1
2a
4a
76% D 49% D
The MBH product 4a is obtained also because it is thermody-
namically more stable than the original aldol product (i.e., the pro-
tonated 10).17 Nevertheless, although the aldol product 10 was
proposed as the primary product of this reaction, it was never ob-
served in the crude reaction product. Similarly, the formation of
compound 3 was not observed, either.
O
(D)H
O
H(D)
H(D)
K2CO3
THF, rt
+
O
5
N
H
N
H(D)
Boc
80% D
To distinguish between the mechanism proposed in Scheme 2
and the MBH mechanism, 5,5-dimethylated N-Boc-3-pyrrolin-
2-one (7) was synthesized as a probe. We then conducted the
reaction between 7 and 2a using DABCO as the catalyst. DABCO
is a good catalyst for the MBH reaction Eq. (2)1,15 and, therefore,
if the reaction does go through the MBH mechanism, we should
obtain the expected MBH product 12. However, if the reaction
works through our proposed mechanism, no product should be
obtained because compound 7 cannot be deprotonated by DBACO
due to the lack of an acidic proton. Indeed, there was not any
reaction at all even after 24 h at rt Eq. (2). In addition, we also con-
ducted the reaction of 1 and 2a in the presence of D2O Eq. (3), and
an incorporation of 50% D into the C5 position of product 4a was
observed. Similarly, the reaction of deuterated 1, which has an
enrichment of 80% D at the C5 position, and 2a in THF yielded
the product 4a with only 63% D remaining at that location
Eq. (4). These results are consistent with the ionization mecha-
nism. Thus, the above results support our mechanism that the
1
2a
Boc
O
N
H(D)
H(D)
5
HO
(4)
O
63% D
N
H
4a
In summary, we demonstrated that both organic and inorganic
bases are good catalysts for the reaction of isatins and N-Boc-
3-pyrrolin-2-one, which leads to the formation of the MBH-type
of products. Using potassium carbonate as the catalyst, the corre-
sponding MBH products were obtained in good to excellent yields.
The reaction can also be applied to a-ketophosphonates, which is in
agreement with a similar reported cinchona alkaloid-catalyzed
reaction. A tandem enolization-aldol-proton transfer reaction was
proposed to account for the formation of these MBH products,
which is supported by the results of our mechanistic probes.
B:
Acknowledgment
O
O
O
O
N
N
N
N
Boc
Boc
Boc
Boc
BH
This research was supported by the Welch Foundation (Grant
No. AX-1953), for which we are very grateful.
1
9a
9b
9c
Boc
N
Boc
N
O
O
Supplementary data
O
HO
2a
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.11.118.
O
O
N
N
H
H
11a
10
References and notes
Boc
N
Boc
N
O
O
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Scheme 2. Proposed mechanism for the formation of the MBH product 4a.

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