FeCl3-Catalyzed Allylation Reactions onto 3-Hydroxy-2-oxindoles: Formal Total Syntheses of Bis-cyclotryptamine Alkaloids, (±)-Chimonanthine, and (±)-Folicanthine

Article abstract of DOI:10.1021/acs.joc.7b01232

An FeCl₃-catalyzed efficient strategy for the allylation reactions of 3-hydroxy-2-oxindoles with allyltrimethylsilane has been developed. The reaction affords a variety of 2-oxindoles having quaternary center at the pseudobenzylic position in an operationally simple and inexpensive procedure. Control experiments using enantioenriched 3-hydroxy-2-oxindole show that the reaction proceeds through in situ generated 2H-indol-2-one (8). The methodology presents an efficient and concise access to the pyrroloindoline alkaloids (±)-deoxyeseroline (1a), (±)-esermethole (1b), (±)-physostigmine (1c), (±)-phenserine (1d), and (±)-physovenine (1e). Eventually, we extrapolated the scope of this methodology to the formal total syntheses of dimeric cyclotyrptamine alkaloids (±)-chimonanthine (3a), (±)-folicanthine (3c), and (±)-calycanthine (4).

Full text of DOI:10.1021/acs.joc.7b01232

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Article
FeCl3-Catalyzed Allylation Reactions onto 3-Hydroxy 2-
Oxindoles: Formal Total Syntheses of Bis-Cyclotryptamine
Alkaloids, (±)-Chimonanthine and (±)-Folicanthine
Lakshmana Kumar KINTHADA, Sai Raghavendra Medisetty,
Amarchand Parida, K. Naresh Babu, and Alakesh Bisai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01232 • Publication Date (Web): 18 Jul 2017
Downloaded from http://pubs.acs.org on July 18, 2017
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FeCl -Catalyzed Allylation Reactions onto 3-Hydroxy 2-
3
Oxindoles: Formal Total Syntheses of Bis-Cyclotryptamine
Alkaloids, (±)-Chimonanthine and (±)-Folicanthine
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Lakshmana K. Kinthada, Sai Raghavendra Medisetty, Amarchand Parida, K. Naresh Babu,
and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Bhopal Bypass Road, Bhopal, Madhya Pradesh - 462 066, INDIA
TOC GRAPHIC
R
R
H
R1
N
R1
N
N
Me
N
O
O
O
N
10 mol% cat.
CH Cl) , rt
(
2
2
R
OH
N
up to 92%
N
6
R2
O
7
N
N
R2
N
Me
R
R H
R
+
SiMe3
R = Me, (5a)
R = Bn, (5b)
R = H, ( )-chimonanthine (3a)
R = Me, ( )-folicanthine (3c)
R = H or Me
ABSTRACT
A FeCl -Catalyzed efficient strategy for the allylation reactions of 3-hydroxy-2-oxindoles
3
with allyltrimethylsilane has been developed. The reaction affords a variety of 2-oxindoles
having quaternary center at the pseudobenzylic position in operationally simple and
inexpensive procedure. Control experiments using enantioenriched 3-hydroxy-2-oxindole
depicts that the reaction proceeds through in situ generated 2H-indol-2-one (8). The
methodology presents an efficient and concise access to the pyrroloindoline alkaloids (±)-
deoxyeseroline (1a), (±)-esermethole (1b), (±)-physostigmine (1c), (±)-phenserine (1d), and
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(
±)-physovenine (1e). Eventually, we extrapolated the scope of this methodology to the
formal total syntheses of dimeric cyclotyrptamine alkaloids (±)-chimonanthine (3a), (±)-
folicanthine (3c), and (±)-calycanthine (4).
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INTRODUCTION
1
Construction of small molecules sharing the biologically active natural product skeleton is of
crucial importance for the success of a chemical genetics/genomics-based program. In this
regard, 2-oxindoles are compounds of great interest as they are encountered in many
2
3
biologically active molecules and are also used as building blocks for pharmaceuticals.
Particularly, the construction of carbon atoms having four carbon ligands i.e. all-carbon
4
quaternary centers, is a challenging task to address owing to the resultant steric congestion.
In this regard, 2-oxindoles having all-carbon quaternary centers at the pseudobenzylic
position, of the type 2, are found to be indispensible intermediates in the total syntheses of the
naturally occurring Calabar alkaloids deoxyeseroline (1a), esermethole (1b), physostigmine
5a-c
(
1c), physovenine (1d), phenserine (1e) (Figure 1)
and many other complex
5
d-f
pyrroloindoline alkaloids. Recently, a number of elegant approaches have been reported to
address total syntheses of these alkaloids, which include Movassaghi’s Friedel-Crafts-based
method for the regioselective and directed C3 functionalization of advanced pyrroloindoline
5
d
intermediates employing a range of π-nucleophiles, Stephenson’s Ru-catalyzed visible-light
5e
mediated coupling of bromopyrroloindolines with indoles, and Li’s Ir-catalyzed radical
5
f
conjugate addition of bromopyrroloindolines with ,-unsaturated ketone.
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MeHN
O
PhHN
O
O
O
R
Me
N
Me
N
Me
N
Me
R'
N
Me
X
N
Me
O
N
R
H
H
H
Me
Me
Me
X = NMe, ( )-physostigmine (1c)
X = O, ( )-physovenine (1d)
(
2)
R = H, ( )-deoxyeseroline (1a)
R = OMe, ( )-esermethole (1b)
( )-phenserine (1e)
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Figure 1: Selected cyclotryptamine (1a-e) alkaloids.
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On the other hand, dimeric cyclotryptamine alkaloids (3a-d and 4, Figure 2) possessing a
bis-pyrrolidino-[2,3b]indoline moiety with a labile 3a-3a' -bond, constitute a large family of
7
architecturally interesting alkaloids with a wide range of biological activities. Their unique
structural arrays and impressive biological activities have led to a demand for the
development of novel strategies involving construction of vicinal all-carbon quaternary
8
centers. In this regard, C
2
-symmetric 2-oxindole, such as 5 (Figure 2), provides an excellent
9
, 10
platform to access these alkaloids.
Figure 2: Selected dimeric cyclotryptamine alkaloids (3a-d and 4).
A number of elegant approaches have been reported for synthesizing 2-oxindoles having
1
1
quaternary centres from more reactive 3-halo-2-oxindole substrates. However, in view of
the demand for efficient, economic, and environmentally friendly processes, the development
of direct catalytic carbon-carbon bond-forming reactions of 3-hydroxy-2-oxindoles with prior
unmodified substrates is an important task to pursue.
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One of the most powerful methods for construction of all-carbon quaternary centers is the
Lewis acid activation of 3-hydroxy-2-oxindoles followed by reaction with a suitable
1
2
nucleophile. Towards this, recently, our group have reported efficient Lewis acid catalyzed
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activation of 3-alkyl-3-hydroxy-2-oxindole with various electron-rich substrates. These
reactions presumably go through in situ generation of reactive intermediate 2H-indol-2-one
of type 8 (Scheme 1). Herein, we report an inexpensive and environmentally benign FeCl
3
-
catalyzed allylation reaction of a variety of 3-hydroxy-2-oxindoles for the synthesis of
1
4
various 3,3-disubstituted 2-oxindoles. and its eventual application to the synthesis of
pyrroloindoline alkaloid (±)-deoxyeseroline (1a), (±)-esermethole (1b), (±)-physostigmine
(
1c), (±)-phenserine (1e), and (±)-physovenine (1d).
Scheme 1: Our hypothesis via allylation of 3-hydroxy-2-oxindoles.
The versatility of this methodology has been shown by formal total syntheses of (±)-
chimonanthine (3a), (±)-folicanthine (3c), and (±)-calycanthine (4) (Figure 2) as well, by
elaborating a key allylated intermediate 9a to dimeric 2-oxindoles having bis-allyl substrate,
1
0
such as 5a-b (Scheme 2).
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Scheme 2: Our hypothesis for synthesis of 3a,3a'-bispyrrolidino[2,3-b]indoline alkaloids (3a-
d).
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RESULTS AND DISCUSSIONS
Initial experiments were focused on finding the appropriate condition for the reaction of 3-
hydroxy-2-oxindole (6b) with allyl trimethylsilane to the corresponding 3,3-disubstituted 2-
oxindoles (9b) (Table 1). At the outset, we carried out our studies taking (6b) as the electron-
deficient partner for allylation reaction in acetonitrile at room temperature in presence of
FeCl . We found that, 20 mol%, 10 mol%, and 5 mol% of FeCl afforded product 9b in 93%,
3
3
9
3
8
1%, and 83% of isolated yields, respectively, without forming Ritter product (10) (entries 1-
15
). Along the same line, 10 mol%, and 5 mol% of FeCl
3
afforded product 9b in 86% and
1
6
1% yields, respectively, in nitromethane without forming compound 11 (entries 4-5). The
product was obtained in 62-64%, when the reaction was carried out in dichloromethane or
toluene (entries 6-7).
Table 1: Optimization studies of allylation reaction of 3-hydroxy-2-oxindole (6b).
S. No.
Lewis acid (mol%)
solvent
temp
time
%
yield % SM
a,b
a,b
(
9b)
(6b)
1
2
3
.
.
.
20 mol% FeCl
10 mol% FeCl
3
3
MeCN
MeCN
MeCN
25 ºC
25 ºC
25 ºC
4 h
4 h
6 h
93%
91%
83%
----
----
----
5 mol% FeCl
3
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6
.
.
.
10 mol% FeCl
3
MeNO
2
2
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
14 h
20 h
10 h
12 h
5 h
86%
81%
----
----
----
----
----
----
----
----
----
----
35%
42%
5 mol% FeCl
10 mol% FeCl
10 mol% FeCl
10 mol% FeCl
10 mol% AlCl
3
MeNO
c
3
3
3
3
CH
2
Cl
2
64%
62%
94%
c
e
0
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0
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0
7.
PhMe
8
9
.
.
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
2
5 h
84%
43%
1
0.
10 mol% InCl
10 mol% SnCl
5 mol% SnCl
5 mol% FeCl
2.5 mol% FeCl
3
12 h
5 h
f
11.
12.
4
92%
77%
80%
4
12 h
12 h
12 h
20 h
36 h
1
1
1
3.
4.
5.
3
c
c
c
3
MeCN
MeCN
MeCN
51%
39%
----
c
1 mol% FeCl
none
3
16.
99%
a
b
all the reactions were performed using 0.3 mmol of 6b in open reaction vessel. isolated yields after
c
d
column chromatography. decomposition of the rest of the mass balance. recovered starting materials.
e
f
1
3 4
0mol% of FeCl (condition A). 10mol% of SnCl (condition B).
Interestingly, 10 mol% of FeCl
Among various metal halides tested for this reaction (entries 9 - 11), it was observed that 10
mol% of SnCl in dichloroethane (entry 11) afforded product in 92% yield. By lowering the
catalyst loading to 5 mol%, it was observed that, product can be isolated in 77-80% yields
entries 12 - 13). However, further lowering the catalysts to 1-2.5%, the reaction became
3
in dichloroethane afforded product in 94% yield (entry 8).
4
(
sluggish, which resulted product 9b in 39-51% yields, along with 35-42% recovered starting
materials (entries 14 - 15). There was no trace of reaction without catalyst and starting
material was observed quantitatively (entry 16). Therefore, based on our exhaustive
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optimization, it was decided to carry out further substrate study using 10 mol% of FeCl
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(
condition A) and SnCl (condition B) in dichloroethane.
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H
N
H
N
H
N
H
N
O
O
O
O
Me
OMe
9b
OMe
9c
2%, 17 h (A)
45%, 17 h (B)
OMe
9
d
9e OMe
5
9
9
2%, 5 h (A)
0%, 5 h (B)
82%, 2 h (A)
85%, 2 h (B)
5
7
9%, 7 h (A)
8%, 3 h (B)
Me
N
Me
N
Bn
O
O
O
N
N
O
OMe
9
f
Br
14a OMe
14b OMe
OMe
1
4c
5
4
1%, 12 h (A)
5%, 12 h (B)
79%, 3 h (A)
82%, 2 h (B)
81%, 2 h (A)
78%, 2 h (B)
7
8
8%, 2 h (A)
2%, 3 h (B)
a
b
all the reactions were performed using 0.3 mmol of 6b-e, 13a-c in open reaction vessel. isolated
c
d
yields after column chromatography. condition A: 10 mol% FeCl ; condition B: 10 mol% SnCl
3
4
a-d
Scheme 3: Substrate scope of allylations using 3-hydroxy-2-oxindoles 6b-d, 13a-c.
Having established a standard reaction protocol, we then probed a diverse set of 3-hydroxy-2-
oxindoles with allyltrimethylsilane (Scheme 3) to furnish various 2-oxindole moieties bearing
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an all-carbon quaternary stereocenters at 3-position. To our delight, these reactions worked
without event to generate desired allylated/methallylated products 9b, 9d-e, 14a-c in
synthetically useful yields, except in the case of substrate 6c which afforded allylated product
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c in only 45-52%. This led us to conclude that, in order to achieve better yields, the
substrates must contain electron-donating group (Scheme 3). We have also tested 3-hydroxy
3
-aryl-2-oxindole sharing a bromo group in aromatic ring, such as 6e, which afforded product
f in 45-51% isolated yields (Scheme 3). 2-Oxindoles of the type 9b, 9d-f, 14a-c are known
9
to be potential intermediates for the synthesis of C-(3a)-arylpyrroloindoline, a common
structural motif present in many complex alkaloids.
R1
R1
N
O
R
1
(
0 mol% cat
CH Cl) , rt
N
O
R
2
2
SiMe3
+
up to 92%
OR
N
R = H (12a)
N
R2
6
R2
R = Me (12b)
H
N
R
N
R
N
O
O
O
R = Me (13d)
R = Bn (13e)
R = prenyl (13f)
R = Me (15a)
R = Bn (15b)
R = allyl (15c)
HO
HO
RO
NH
NH
N
R
6
a
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a
b
all the reactions were performed using 0.3 mmol of 6, 13, 15 in open reaction vessel. isolated yields
c
d
after column chromatography. condition A: 10 mol% FeCl ; condition B: 10 mol% SnCl
3
4
a-d
Scheme 4: Substrate scope of allylations using 3-hydroxy-2-oxindoles 6, 13, 15.
We then turned our attention for synthesis of 3,3-disubstituted 2-oxindoles where one of the
substitutions is 3-indolyl unit at the pseudobenzylic position such as compounds 9a, 14d-f,
1
6a-c, 9g (Scheme 4). Towards this, we synthesized 3-hydroxy-2-oxindoles 6a, 13d-f, 15a-c
and these were reacted with allyltrimethylsilane under optimized conditions. To our delight,
we could access 9a, 14d-f, 16a-c in good yields (68-90%). We have also synthesized 2-
oxindole 9g by reaction with methallyltrimethylsilane in 61-82% yields. X-ray crystal
structure of 9g unambiguously proved the formation of quaternary center at the
pseudobenzylic position of 2-oxindoles (see, Supporting Information for details). Later, 3-
alkyloxy-2-oxindoles 15a-c were also reacted with allyltrimethylsilane to afford products
1
6a-c in 72-88% isolated yields (Scheme 5). Importantly, a gram scale reaction of compound
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a also afforded product 9a in 81-85% isolated yields, thereby showing synthetic viability of
our method (Scheme 5).
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
N
H
R
N
10 mol% cat
O
N
O
O
NaH, DMF
(CH Cl) , 25 C
2
2
2
5 C, 2-3 h
SiMe3
+
R-X
+
74 - 90%
up to 92%
HO
RO
NH
NR
RN
R = Me, 15a
R = Bn, 15b
R = allyl, 15c
6
a
16
Ph
Me
N
O
N
O
N
O
1
6b
16c
1
6a
7
7
5%, 3 h (A)
2%, 2 h (B)
82%, 1 h (A)
88%, 1 h (B)
85%, 2 h (A)
82%, 2 h (B)
MeN
N
N
H
Ph
5
mol% cat
H
N
O
N
O
(
CH Cl) , 25 C
2
2
SiMe3
81% (A)
85% (B)
+
6
a
81 - 85%
1
g scale
12a
OH
NH
9a
N
H
a
all the reactions were performed using 0.3 mmol of 15a-c in open reaction vessel unless stated
b
c
d
otherwise. isolated yields after column chromatography. conditionA: 10 mol% FeCl ; conditionB:
3
10 mol% SnCl4.
a-d
Scheme 5: Substrate scope of allylation reactions using 3-alkoxy-2-oxindoles 15a-c.
In case of 3-hydroxy-2-oxindoles, the Friedel-Crafts alkylation is known to proceed through
the formation of 2H-indol-2-one ring. Similar kind of species is also reported to be formed
under base mediated elimination of 3-halo-2-oxindoles and is well utilized in the total
11
synthesis of complex indole alkaloids via formal cycloaddition processes. Mechanistically,
we propose that FeCl
3
activates 3-hydroxy/alkyloxy-2-oxindoles to form active intermediate
2
H-indol-2-one ring (8), which then reacts with allyltrimethylsilane to form intermediate (17)
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9
(
Scheme 6). The latter can be stabilized by -effect of silicon. From this intermediate,
removal of TMSOH can afford allylated product (9) (Scheme 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6: Plausible mechanism of allylation reactions via intermediacy of (17) and (18).
If this hypothesis is true, then enantioenriched 3-hydroxy-2-oxindole should afford product in
racemic form via the intermediacy of (8). Towards this direction, we synthesized
enantioenriched 6a (91% ee) utilizing literature known organocatalytic enantioselective
addition of indole onto isatin in the presence of 10 mol% of cinchona catalyst, as described
1
7
by Chimni (Scheme 7). We have also synthesized 3-methoxy-2-oxindole (15a) from (6a) by
methylation (Scheme 7). Upon reactions of 3-hydroxy/methoxy-2-oxindole i.e. (6a) and
(
15a) in the presence of allyltrimethylsilane, we observed products (9a) and (16a) in racemic
from, thereby indicating the involvement of cataionic intermediate of type 8 (Scheme 6).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7: Control experiments using 3-hydroxy/methoxy-2-oxindoles.
We also hypothesized that in case indolyl substrates, the intermediate of type 8 can be further
stabilized by the electron donation of indole moiety to establish intermediates (20a) and
(20b) (Figure 3). Intermediate (20b) can also behave as a mask Michael acceptor and could
react with soft nucleophiles. A similar resonance stability also might operate to form
intermediates (20d-e), with 3-aryl-3-hydroxy-2-oxindoles having electron-donating groups at
aromatic ring. In fact, that also explains the comparatively less reactivity of 3-phenyl-3-
hydroxy-2-oxindole 6c (see, Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3: Plausible reaction intermediates.
Further, in order to see effect of electron-donating ability of aromatic ring at 3-position of 2-
oxindole, we synthesized compounds 21a-c having electron-withdrawing groups at nitrogen
of 2-oxindoles (Scheme 8). Gratifyingly, it was found that these 3-hydroxy-2-oxindoles were
good substrates to afford products 22a-c in 71-84% isolated yields, which probably supports
the formation of intermediates 20d-e (Figure 3).
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19
20
21
22
23
24
25
26
27
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52
53
54
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59
60
a
all the reactions were performed using 0.3 mmol of 21 in open reaction vessel unless stated
b
c
d
otherwise. isolated yields after column chromatography. condition A: 10 mol% FeCl
3
; condition B:
1
0 mol% SnCl
4
a-d
Scheme 8: Substrate scope of allylation reactions using 21a-c.
Later, few 3-hydroxy-2-oxindoles having alkyl functionalities such as 7a and 23a-c were
tested under optimized conditions. However, to our disappointment, not even a trace amount
3
of product was observed even after running the reaction with 20 mol% FeCl for 24 h at room
temperature and starting material was isolated in 89-97% after column purification. In the
latter case the reaction was sluggish even under heating (at 80 ºC) conditions.
Figure 4: Substrates 7a, 23a-c, 24a unsuitable for allylation reaction.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
However little improvement was found by heating the reaction mixture at 80 ºC in
dichloroethane with the substrate (24a) and maximum of 28% of isolated yield of (2a) was
observed (Table 2). These results indicate that 3-hydroxy-2-oxindoles (6) can stabilize the
intermediate 20d (Figure 3) when there is an aromatic ring for the allylation reaction, which
goes through a stable dibenzylic cationic intermediate. The electronic effect in case of 3-
hydroxy/methoxy-2-oxindoles 7a, 23a-c, 24a (Figure 4) having an alkyl group is probably
not enough for efficient allylation reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a-c
Table 2: Optimization of allylation of 24a in presence of Lewis acids.
a, b
S.N
1
Lewis acid
solvent
temp.
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
time
12 h
12 h
12 h
12 h
12 h
12 h
yield
28%
NR
FeCl
3
(20 mol%)
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
2
2
Sc(OTf)
3
(20 mol%)
(20 mol%)
(20 mol%)
(20 mol%)
(20 mol%)
3
In(OTf)
Bi(OTf)
3
22%
24%
18%
15%
4
3
5
Cu(OTf)
Sn(OTf)
2
6
2
a
reactions were carried out on a 0.5 mmol (1 equiv.) of 24a with 1.5 mmol of allyltrimehtylsilane (3
b
c
equiv) in 3 mL of solvent. isolated yields after column purification. starting material was recovered
for the rest of the mass balance.
The unsuccessful attempts for the allylation reactions of 7a, 23a-c, 24a led us to think of
activating the -OH group to acetate group such as substrate 25a-f (Figure 5). We
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hypothesized that Lewis acid can activate both carbonyls of 25a-f to form a transition state
similar to 26 (Figure 5), which then may undergo substitution reaction to afford 2-oxindoles
having an all-carbon quaternary center.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5: 3-Acetoxy-2-oxindole derivatives 25a-f and proposed Lewis acid coordination.
At the outset, we carried out allylation studies taking 3-acetoxy 2-oxindole (25a) with allyl
trimethylsilane in different solvents in the presence of 20 mol% of Lewis acid (Table 3). We
have screened a several Lewis acids including various metal triflates and metal halides. After
exhaustive optimization, we found that, allylation can be efficiently carried out in refluxing
dichloroethane to afford products in 88-92% isolated yields (entries 12 and entries 13). Based
on our optimization, a two sets of conditions viz 20 mol% FeCl
SnCl (condition B) were chosen for further substrate scope.
3
(condition A) and 20 mol%
4
a-f
Table 3: Selected optimization studies of allylation of acetate 25a.
a,b
entry
1.
Lewis acid
solvent
temp
25 ºC
80 ºC
80 ºC
time
24 h
9 h
Yield
0%
20 mol% Bi(OTf)
20 mol% Bi(OTf)
3
(CH
(CH
(CH
2
2
2
Cl)
Cl)
Cl)
2
2
2
c
2
3
.
.
3
81%
20 mol% Sn(OTf)
2
7 h
81%
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
5
6
.
.
.
20 mol% Cu(OTf)
2
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
2
2
2
2
2
2
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
80 ºC
40 ºC
40 ºC
40 ºC
7 h
14 h
9 h
84%
52%
20 mol% Yb(OTf)
3
d
20 mol% In(OTf)
3
79%
43%
73%
60%
68%
73%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.
20 mol% Zn(OTf)
19 h
12 h
12 h
7 h
2
8
9
.
.
10 mol% Bi(OTf)
10 mol% In(OTf)
20 mol% BiCl
20 mol% InCl
20 mol% FeCl
20 mol% SnCl
10 mol% FeCl
20 mol% Bi(OTf)
20 mol% In(OTf)
20 mol% FeCl
3
3
1
0.
3
11.
12.
3
7 h
e
3
11 h
12 h
12 h
12 h
12 h
12 h
92%
f
1
1
1
3.
4.
5.
4
86%
3
73%
75%
74%
76%
3
Cl
Cl
Cl
2
2
2
16.
7.
3
CH
1
3
CH
a
reactions were carried out on a 0.5 mmol (1 equiv.) of 25a with 1.5 mmol of allyltrimehtylsilane (3
b
c
equiv.) in 3 mL of solvent. isolated yields after column purification. decomposition of the rest of the
d
e
f
mass balance. recovered starting materials. 10mol% of FeCl (condition A). 10mol% of SnCl
3
4
(condition B).
With the optimized condition in hand, a variety of 3-acetoxy-3-methyl-2-oxindoles (25a-d)
were synthesized. As per scheme 9, isatins 19a-c were reacted with alkyl halides to form N-
alkylated isatins 27a-d, which upon treatment with MeMgBr afforded 3-alkyl-3-hydroxy-2-
oxindoles 23a, 23d, 23e, and 23f in high yields over 2 steps. Finally, O-acetylations were
carried out with acetic anhydride in the presence of NaH in DMF to afford electron-deficient
partners 25a-d (Scheme 9).
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Me
Me
NaH, MeI, DMF
Me
MeMgX, THF
C - rt, 1 h
O
NaH, Ac2O
DMF, 0 C-rt
N
O
H
N
N
N
O
0
C - rt, 12 h
0
O
O
OH
62 - 71%
O
Me
8
6 - 92%
62 - 67%
Me
Me
X
O
X
O
X
X
X = H, 25a, 62%
X = OMe, 25b, 63%
X = Cl, 25c, 71%
X = H, (19a)
X = OMe, (19b)
X = Cl, (19c)
X = H, (27a), 92%
X = OMe, (27b), 91%
X = Cl, (27c), 86%
X = H, 23a, 64%
X = OMe, 23d, 67%
X = Cl, 23e, 65%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
NaH, BnBr, DMF
C - rt, 12 h
Bn
MeMgX, THF
Bn
NaH, Ac2O
DMF, 0 C-rt
Bn
N
O
N
O
N
O
N
O
0
C - rt, 1 h
0
O
9
2%
88%
OH
91%
O
Me
O
O
Me
Me
25d
(
19a)
(27d)
2
3f
(
Scheme 9: Synthesis of N-methyl protected 3-acetoxy-2-oxindoles.
Under the optimized conditions A and B, we found that 3-acetoxy-2-oxindole (25a) is good
substrate for allylation reaction with allyltrimethylsilane, which afforded products (2a) in up
to 92% yields. Agreeably, we found that 3-acetoxy-2-oxindoles having an electron-donating
group such as (25b) and a halogen functionality such as (25c) were also good substrates for
allylation reaction that afforded products (2b) and (2c) in up to 95% yields (Figure 6). Then,
we turned our attention for 3-acetoxy-2-oxindole having allyl group such as (25e), which
afforded bis-allylated product (2e) in 83-89% yields. 3-Acetoxy-2-oxindole having N-
phthalimido protected aminoethyl group such as (25f), which afforded allylated product (2f)
in 75-92% yields. Later, methallyltrimethylsilane was used as nucleophile, which afforded
products (2g-k) in up to 95% yield (Figure 6).
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1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
all the reactions were performed using 0.3 mmol of 25a-f in open reaction vessel unless stated
b
c
d
otherwise. isolated yields after column chromatography. condition A: 20 mol% FeCl ; condition B:
3
20 mol% SnCl4
a-d
Figure 6: Substrate scope of allylation of acetates 25a-f.
To illustrate the synthetic utility of this methodology, we undertook the formal synthesis of
several pyrroloindoline alkaloids (Scheme 10). Towards this end, we have elaborated 2b to
the synthesis of a variety of advanced intermediates required for formal total synthesis of
cyclotryptamine alkaloids. The olefin functionality was oxidized to afford aldehyde 28 in 2
4
steps, which was then reduced with NaBH , to synthesize 29 in 3 steps in 90% overall yield.
The aldehyde 28 was directly converted to furoindoline intermediate ±-30 in 82% overall
yield in 3 steps (Scheme 10). In another sequence, aldehyde 28 was reacted with
4
methylamine hydrochloride followed by reduction using LiAlH to complete total synthesis
of naturally occurring alkaloid (±)-esermethole 1b in 79% overall yield. Since, total syntheses
of (±)-physostigmine (1c), (±)-phenserine (1e), and (±)-physovenine (1d) is known from (±)-
esermethole 1b and intermediate ±-30, this effort culminated in the formal total syntheses of
1
8, 19
all these alkaloids (Scheme 10).
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MeO
Me
(a) OsO (cat.), NMO MeO
Me
MeO
4
O Et N, MeNH .HCl
Me
N
3
2
(
b) NaIO , THF:H O
4
2
then LiAlH , THF
4
N
O
O
N
N
7
9% over 3 steps
Me
H
2b Me
28
Me
Me
( )-esermethole (1b)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
LiAlH , THF, rt, 40 min
4
NaBH , EtOH, rt, 1h
4
8
2% (over 3 steps)
9
0% (over 3 steps)
2
steps4a
MeO
(
MeO
Me
OH
Me
N
(
)-physostigmine (1c)
( )--phenserine (1e)
( )-physovenine (1d)
O
O
N
H
)-30
29
Me
Me
Scheme 10: Total synthesis of (±)-esermethole (1b) and related structures.
Later, we were interested for formal total syntheses of bis-cyclotryptamine alkaloids (±)-
folicanthine (3c), and (±)-chimonanthine (3a) (Figure 2). Towards this end, we converted 2-
oxindoles (16a-b) to diastereomeric mixture of bis-2-oxindole derivatives 31a-b in the
presence of DMSO/HCl in AcOH (Scheme 11). The latter were then reacted with
allylbromide in the presence of NaH to afford C
upto 3.1:1 dr. Intermediates 5a-b were then converted to C
intermediates in 93-95% yields via OsO treatment followed by periodate cleavage, which
were then reduced with NaBH in MeOH to furnish C -symmetric bis-diols 32a-b in 67-70%
2
-symmetric bis-allylated products 4a-b in
2
-symmetric bis-aldehyde
4
4
2
yields. As, total syntheses of (±)-folicanthine (3c) and (±)-chimonanthine (3a) is already
reported from intermediate 32, our efforts in this direction culminated in formal total
9c, 20
syntheses of these alkaloids as well.
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 11: Formal total syntheses of chimonanthine (±)-3a and folicanthine (±)-3c.
CONCLUSIONS
In summary, we developed an efficient FeCl -catalyzed allylation onto 3-hydroxy-2-
3
oxindoles. The current allylation strategy relies on the utility of the 2H-indol-2-one ring (8),
formed in the presence of Lewis acids, to afford oxindole derivatives possessing an all-carbon
quaternary center at the C(3a)-position. Allylations using enantioenriched 3-hydroxy-2-
oxindole (+)-6a and 3-methoxy-2-oxindole (+)-15a suggest that the reaction involves the
intermediacy of a carbocataion intermediate which is responsible for the formation of 2H-
indol-2-one ring system (20a) (Figure 4). Utilizing aforementioned strategy, we have shown
synthesis of pyrroloindoline alkaloids esermethole and related structures. Further synthetic
viability is shown by constructing dimeric C2-symmetric 2-oxindole structures 5a, an
advanced intermediate for the concise and efficient access of a variety of naturally occurring
dimeric pyrroloindoline alkaloids (±)-chimonanthine (3a), (±)-folianthine (3c) and (±)-
calycanthine (4).
EXPERIMENTAL SECTION
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Materials and Methods. Unless otherwise stated, reactions were carried out using oven
dried glass ware fitted with rubber septa under inert atmosphere (nitrogen or argon).Teflon-
coated magnetic stirring bars were used to stir the reactions. Syringe was used to transfer the
solvents and liquid reagents using standard Schlenk techniques. Tetrahydrofuran (THF), and
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60
diethyl ether (Et O) were distilled over sodium/benzophenone ketyl. Dichloromethane
2
2 2
(CH Cl ) was distilled over calcium hydride. All other solvents like nitromethane, MeOH,
EtOAc, DMF, dichloroethane (DCE) and reagents were used as received unless otherwise
noted. Reaction temperatures above 25 °C considered as oil bath temperature. Thin layer
chromatography (TLC) analysis was performed using silicagel precoated plates (0.25 mm) 60
(
F-254), visualized by UV irradiation, yellow dip stain and other stains. Silicagel of particle
size 230-400 and 100-200 mesh were used to perform flash chromatography. Digital melting
1
point apparatus was used to record the melting points and are uncorrected. H NMR spectra
13
was recorded by using 400, 500 MHz spectrometers, C NMR operating frequencies are 100,
1
25 MHz, respectively. Chemical shifts (δ) are reported in ppm relative to the residual
1
13
3
solvent (CDCl ) signal (δ = 7.24 for H NMR and δ = 77.0 for C NMR) and DMSO-d6.
1
Data for H NMR spectra are reported as follows: chemical shift (multiplicity, coupling
constants, and number of hydrogen). Abbreviations are as follows: s (singlet), d (doublet), t
(
triplet), q (quartet), m (multiplet), br (broad). IR spectra were recorded on a FT-IR system
-1
(Spectrum BX) and are reported in frequency of absorption (cm ). Only selected IR
absorbencies are reported. High-Resolution Mass Spectrometry (HRMS) and Low-Resolution
Mass Spectrometry (LRMS) data were recorded on MicrOTOF-Q-II mass spectrometer using
methanol as solvent. Enantiomeric excess was determined by chiral HPLC analysis
performed on HPLC system.
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6
General procedure for the synthesis of 3-hydroxy-3-substituted-2-oxindole: As described
1
3b
in reference isatin derivative (10 mmol; 1.0 equiv) was taken in an oven-dried round-
bottom flask under nitrogen atmosphere in THF (40 mL) at 0 °C. Aryl magnesium bromide
0
1
2
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6
7
8
9
0
1
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0
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8
9
0
1
2
3
4
5
6
7
8
9
0
(
22.0 mmol, 2.2 equiv) was added dropwise over a period of 10 minutes to that reaction
mixture and allowed to stir it for 3 h (TLC showed complete consumption of the starting
materials). Then the reaction mixture was quenched by careful addition of saturated aqueous
ammonium chloride solution (10 mL) and diluted with EtOAc (50 mL). The organic layer
was separated, dried over anhydrous sodium sulphate and concentrated under reduced
pressure. The crude product was purified through column chromatography using a hexane–
EtOAc system as the eluent to afford the desired product.
For characterization of compounds 6b-d, 13a see reference 13b.
Synthesis of 3-hydroxy-2-oxindole 33: 4-Bromophenol (1.3 g; 7.4 mmol; 1.1 equiv.) was
taken in anhydrous THF (10 mL) and cooled the reaction mixture at 0 ºC. i-PrMgCl (2 M in
THF) (3.7 mL; 7.4 mmol; 1.1 equiv.) was added to this solution over a period of 2 min. The
resultant white suspension was concentrated by rotary evaporation to dryness and
immediately dissolved in anhydrous methylene chloride (10 mL). To this solution isatin (1 g;
6.8 mmol; 1.0 equiv.) was added portion wise over a period of 2 min and stirring continued
for 20 h (TLC showed complete consumption of starting materials under UV light and I
stain). After completion of the reaction, it was quenched with 1 N HCl (5 mL). The organic
layer was separated, dried with Na SO and the crude material was purified through flash
2
2
4
column chromatography using hexane-EtOAc mixture as eluent to afford compound 33.
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3
-(4-Bromo-2-hydroxyphenyl)-3-hydroxyindolin-2-one 33: The product was obtained as a
1
orange solid (1.5 g; 69% yield); R = 0.45 (50% EtOAc in hexane); H-NMR (400 MHz,
f
DMSO-D6) δ 10.24 (s, 1H), 9.88 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.14 - 7.10 (m, 1H), 7.03
10
11
12
13
14
15
16
17
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33
34
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41
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(
d, J = 8.3 Hz, 1H), 6.79 - 6.75 (m, 4H), 6.49 (s, 1H); C-NMR (100 MHz, CDCl ) δ 178.37,
3
155.12, 143.52, 132.95, 129.39, 129.27, 128.21, 124.13, 121.69, 121.58, 120.94, 117.82,
1
1
09.63, 75.45; IR (film) υmax 3509, 3490, 3025, 2279, 1725, 1624, 1493, 1406, 1261, 1122,
-1
+
006, 800, 729, 530 cm ; MP 125 - 127 ºC; HRMS (ESI) m/z: [M + Na] Calcd for
+
[C14
H
10BrNO
3
+ Na] 341.9736; Found 341.9721.
Synthesis of compound 6e: Compound 33 (1.7 g, 5.3 mmol, 1.0 equiv) was taken in an oven
dried round-bottom flask at room temperature. To this solution, NaH (60% suspension in
mineral oil) (705 mg, 17.6 mmol, 3.3 equiv) was added over a period of 5 minutes. After 5
minutes of stirring at same temperature, MeI (1.1 mL, 17.6 mmol, 3.3 equiv.) was added
drop-wise and starring continued for 1 h. After completion of the reaction, (TLC analysis
showed complete consumption of starting materials under U.V. light and ceric ammonium
2
molybdate stain), the reaction mixture was quenched by careful addition of H O (30 mL) and
diluted with EtOAc (50 mL). The organic layer was separated and dried over anhydrous
sodium sulphate and concentrated under reduced pressure. The crude product was purified
through flash column chromatography using hexane-EtOAc mixture as eluent to afford the
desired product.
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-(4-Bromo-2-methoxyphenyl)-3-methoxy-1-methylindolin-2-one 6e: The product was
1
obtained as a colourless solid (1.7 g; 89%); R = 0.5 (40% EtOAc in hexane); H-NMR (400
f
MHz, CDCl
3
) δ 7.80 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
6
.99 - 6.92 (m, 2H), 6.85 - 6.83 (m, 2H), 3.43 (s, 3H), 3.28 (s, 3H), 3.13 (s, 3H); C-NMR
(100 MHz, CDCl
3
) δ 174.9, 154.6, 145.1, 131.7, 130.6, 130.2, 129.9, 127.3, 124.6, 122.9,
1
1
13.6, 113.2, 107.7, 80.3, 56.2, 51.7, 26.3; IR (film) υmax 3284, 3109, 2905, 1711, 1624,
-1
611, 1523, 1426, 1214, 1172, 1017, 890, 790, 630, 520, 399 cm ; MP 165 - 167 ºC; HRMS
+
+
3
(ESI) m/z: [M + Na] Calcd for [C17H16BrNO + Na] 384.0206; Found 384.0229.
1-Benzyl-3-hydroxy-3-(4-methoxyphenyl)indolin-2-one 13b: The reaction was carried out
with N-benzyl isatin (2.4 g, 10.0 mmol) following a general procedure as shown above.
Product 13b was obtained as yellow solid (2.9 g, 86% yield) after column chromatography,
1
R
f
= 0.45 (50% EtOAc in hexane). H NMR (400 MHz, 0.5 mL CDCl
3
) δ 7.37-7.23 (m, 8H),
7
1
0
1
1
.21 (t, J = 7.7 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 7.8 Hz,
1
3
H), 5.01 (d, J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 3.77 (s, 1H); C NMR (100 MHz,
.5 mL CDCl ) δ 177.7, 159.7, 142.6, 135.5, 132.2, 131.6, 129.7, 128.9, 127.8, 127.2, 126.8,
3
25.0, 123.5, 114.1, 109.7, 77.6, 55.3, 44.0; IR (film) υmax 3462, 2104, 1699, 1611, 1512,
-1
472, 1368, 1300, 1248, 1177, 1109, 1026, 928 cm ; MP 132-137 ºC.
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1
-allyl-3-hydroxy-3-(4-methoxyphenyl)indolin-2-one 13c: The reaction was carried out
with N-allyl isatin (1.9 g, 10.0 mmol) following a general procedure as shown above. Product
1
3b was obtained as yellow solid (2.6 g, 90% yield) after column chromatography; R = 0.42
f
10
11
12
13
14
15
16
17
18
19
20
21
22
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33
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(
50% EtOAc in hexane). H NMR (100 MHz, CDCl ) δ 7.36-7.31 (m, 4H), 7.10 (td, J = 7.6,
3
0.9 Hz, 1H), 6.92- 6.90 (m, J = 7.5 Hz, 1H), 6.89-6.86 (m, 2H), 5.91-5.84 (m, 1H), 5.30-5.25
13
(
m, 2H), 4.48-4.43 (m, 1H), 4.30-4.25 (m, 1H), 3.80 (s, 3H), 3.63 (s, 1H); C NMR (100
MHz, CDCl ) δ 177.4, 159.6, 142.6, 132.3, 131.7, 131.1, 129.7, 126.8, 125.0, 123.4, 117.9,
3
114.0, 109.6, 77.6, 55.3, 42.5; IR (film) υmax 3404, 2041, 1715, 1611, 1512, 1364, 1254,
-1
1
182, 1103, 1032, 934, 824, 752 cm ; MP 100-105 °C.
1
3c
Procedure for the synthesis of 6a and 13d-f: As described in reference, isatin derivative
(
18 mmol; 1.0 equiv) was taken in MeOH at 25 °C. To this solution was added indole (21.6
mmol; 1.2 equiv). Afterward (3.6 mmol; 0.2 equiv) of KOH was added and stirring was
continued for 7 h. Upon completion of the reaction confirmed by TLC, the reaction mixture
was quenched with H
collected, dried over anhydrous magnesium sulphate and concentrated under reduced
pressure. The crude product was washed with Et O to remove excess indole from the desired
product 6a, 13. For the charecterization of compound 6a please see the reference13c.
2
O (80 mL) and diluted with EtOAc (80 mL). The organic layer was
2
19a
3-Hydroxy-3-(1H-indol-3-yl)-1-methylindolin-2-one 13d: The reaction was carried out
with N-methyl isatin (2.9 g, 18.0 mmol) following a general procedure as shown above.
Product 13d was obtained as yellow solid (4.1 g, 82% yield) after column chromatography;
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2
2
2
2
2
3
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3
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6
1
R
f
= 0.40 (40% EtOAc in hexane); H-NMR (400 MHz, DMSO-D6) δ 10.97 (brs, 1H), 7.32-
7
3
1
.27, (m, 4H), 7.05-7.01 (m, 4H), 6.85 (d, J = 3.6 Hz, 1H), 6.41 (d, J = 3.4 Hz, 1H), 3.13 (s,
1
3
H); C-NMR (100 MHz, DMSO-D6) δ 177.1, 143.6, 137.3, 133.2, 129.7, 125.3, 124.7,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
24.1, 122.1, 121.6, 120.8, 119.0, 115.6, 111.9, 108.9, 75.1, 26.4; IR (film) υmax 3410, 3210,
-1
2835, 2165, 2140, 1660, 1480, 1320, 1290, 1228, 1100, 950, 750 cm ; MP 155 - 160 ºC.
14
1
-Benzyl-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one 13e: The reaction was carried out
with N-benzyl isatin (4.3 g, 18.0 mmol) following a general procedure as shown above.
Product 13e was obtained as brown solid (6.0 g, 95% yield) after column chromatography; R
f
1
=
0.35 (40% EtOAc in hexane); H-NMR (400 MHz, CDCl
3
) δ 8.23 (brs, 1H), 7.50 (d, J =
6
2
4
.2 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.31-7.20 (m, 7H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 (d, J =
.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 2H), 6.79 (d, J = 7.82 Hz, 1H), 5.03 (d, J = 15.6 Hz, 1H),
13
.83 (d, J = 15.7 Hz, 1H), 3.54 (brs, 1H); C-NMR (100 MHz, CDCl
3
) δ 177.3, 142.4,
136.9, 135.5, 131.1, 129.7, 128.8, 127.7, 127.4, 125.0,124.8, 123.3, 123.2, 122.5, 120.5,
1
1
20.1, 115.5, 111.5, 109.6, 75.7, 44.1; IR (film) υmax 3400, 3180, 2901, 2260, 2105, 1640,
-1
450, 1319, 1227, 1109, 1056, 990, 914, 760 cm ; MP 150 - 155 ºC.
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3
-Hydroxy-3-(1H-indol-3-yl)-1-(3-methylbut-2-en-1-yl)indolin-2-one 13f: The reaction
was carried out with N-prenyl isatin (3.9 g, 18.0 mmol) following a general procedure as
shown above. Product 13f was obtained as yellow solid (5.2 g, 88% yield) after column
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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48
49
50
51
52
53
54
55
56
57
58
59
60
1
chromatography; R = 0.43 (50% EtOAc in hexane). H NMR (400 MHz, CDCl ) δ 8.41 (s,
f
3
1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.23 (d, J =
6
.9 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.03-6.95 (m, 3H), 6.87 (d, J = 7.8 Hz, 1H), 5.22 (t, J =
.6 Hz, 1H), 4.40 (dd, J = 15.4, 6.6 Hz, 1H), 4.26 (dd, J = 15.4, 6.7 Hz, 1H), 3.81 (s, 1H),
6
13
1.95-1.83 (m, 1H), 1.80 (s, 3H), 1.71 (s, 3H); C NMR (100 MHz, CDCl ) δ 176.8, 142.6,
3
1
1
1
37.2, 137.0, 131.4, 129.7, 125.0, 124.7, 123.3, 123.2, 122.3, 120.2, 119.9, 118.0, 115.4,
11.6, 109.3, 77.4, 77.1, 76.7, 75.7, 38.4, 25.7, 18.2; IR (film) υmax 3410, 1705, 1616, 1466,
-1
+
368, 1368, 1165, 1099, 912, 756 cm ; MP 104 - 109 ºC; HRMS (ESI) m/z [M + Na] Calcd
+
for [C21
H
20
N
2
O
2
+ Na] 355.1407; Found 355.1417.
General procedure for the synthesis of compound 15a-c: In an oven dried round bottom
flask under nitrogen atmosphere was charged with compound 6a (1.5 g, 5.68 mmol, 1.0
equiv) at 25 °C. To that solution NaH (60% suspension in mineral oil) 681 mg, 17.0 mmol,
3
.0 equiv) was added in pinch-wise over a period of 5 minutes. After 5 minutes of stirring at
same temperature alkyl halide (17.0 mmol, 3.0 equiv.) was added drop-wise and starring was
continued for 2 h (TLC analysis showed most of the starting materials being consumed).The
reaction mixture was quenched by careful addition of H
2
O (100 mL) and diluted with EtOAc
(
100 mL). The organic layer was separated and dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The crude product was purified through flash column
chromatography using hexane-EtOAc mixture as eluent to afford the desired product.
For the charecterization of compound 15a, see the reference 13c.
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0
1-Benzyl-3-(1-benzyl-1H-indol-3-yl)-3-(benzyloxy)indolin-2-one 15b: The reaction was
carried out with 6a (1.5 g, 5.7 mmol) following a general procedure as shown above. Product
1
f
5b was obtained as brown gel (2.5 g, 84% yield) after column chromatography; R = 0.52
1
(20% EtOAc in hexane); H-NMR (400 MHz, CDCl
3
) δ 7.86 (d, J = 7.9 Hz, 1H), 7.53 (d, J =
7
6
.1 Hz, 1H), 7.36 (m, 2H), 7.23-7.32 (m, 12H), 7.18 (m, 1H), 7.05-7.15 (m, 5H), 6.95 (s, 1H),
.80 (d, J = 7.8 Hz, 1H), 5.23 (s, 2H), 4.94 (m, 2H), 4.57 (d, J = 10.3 Hz, 1H), 4.39 (d, J =
1
3
10.3 Hz, 1H); C-NMR (100 MHz, CDCl ) δ 175.2, 143.2, 137.9, 137.5, 137.2, 135.8,
3
1
1
3
29.9, 128.8, 128.7, 128.5, 128.3, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 126.7, 126.3,
25.7, 123.1, 122.3, 122.1, 120.0, 113.3, 109.9, 109.6, 81.3, 67.3, 50.2, 43.9; IR (film) υmax
-1
404, 2928, 2845, 1711, 1694, 1616, 1503, 1466, 1254, 1182, 1026, 430 cm ; HRMS (ESI)
+
+
m/z [M + Na] Calcd for [C37
30 2 2
H N O + Na] 557.2214; Found 557.2199.
.
N
O
O
N
15c
1
-Allyl-3-(1-allyl-1H-indol-3-yl)-3-(allyloxy)indolin-2-one 15c: The reaction was carried
out with 6a (1.5 g, 5.7 mmol) following a general procedure as shown above. Product 15c
was obtained as red gel (1.96 g, 90% yield) after column chromatography; R = 0.61 (30%
f
1
EtOAc in hexane); H-NMR (400 MHz, CDCl ) δ 7.82 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.2
3
Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.12-7.07
(
(
m, 2H); 6.90 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.01-5.79 (m, 3H), 5.28-5.06 (m, 6H), 4.61
1
3
d, J = 5.4 Hz, 2H), 4.36 (t, J = 5.58 Hz, 2H), 4.03-3.91 (m, 2H); C NMR (100 MHz,
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Page 29 of 66
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CDCl
3
) δ 174.8, 143.1, 137.2, 134.6, 133.2, 131.4, 129.8, 128.6, 127.5, 126.2, 125.6, 122.9,
122.1, 121.9, 119.9, 117.7, 117.6, 116.9, 112.8, 109.8, 109.4, 80.8, 66.2, 38.9, 42.4; IR (film)
υmax 3110, 2970, 2300, 2110, 1690, 1655, 1620, 1490, 1340, 1210, 1150, 1065, 1010, 980,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
36
37
38
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41
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46
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48
49
50
51
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54
55
56
57
58
59
60
-1
+
+
8
50, 720 cm ; HRMS (ESI) m/z [M + Na] Calcd for [C H N O + Na] 407.1742; Found
25 24 2 2
407.1730.
General Procedure for Lewis acid catalyzed synthesis of compounds 9a-f, 14a-f: 3-
Hydroxy 2-oxindole (6 or 13 or 15) (1 equiv) was dissolved in 1,2-dichloroethane (CH ) Cl
2
2
2
in an oven dried round bottom flask at 25 ºC. To this reaction mixture, Lewis acid (10 mol%,
.1 equiv) was added and stirred it for 5 minutes. Afterwards, allyl trimethyl silane (3 equiv)
0
was added drop wise by a syringe to the solution. Then the reaction mixture was allowed to
stir for 12 h at 25 ºC. Upon completion of reaction (monitored by TLC), the reaction mixture
was quenched with water and diluted with 10 mL of CH
2
Cl
2
. The organic layer was separated
SO , concentrated in a rotary
with a separatory funnel and dried over anhydrous Na
2
4
evaporator. The crude product was purified by flash chromatography to afford required
products. For the characterization of compound 9c, see the reference 14.
14
3
-Allyl-3-(4-methoxyphenyl)indolin-2-one 9b: The product was obtained as yellow solid
(
0.12 mmol scale; 30 mg, 92% yield in Condition A; 0.12 mmol scale; 29 mg, 90% yield in
1
Condition B), R
f
= 0.55 (30% EtOAc in hexane); H NMR (400 MHz, CDCl
3
) δ 9.02 (brs,
1
2
H), 7.29-7.17 (m, 4H), 7.05 (t, J = 7.4 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.9,
H), 5.50-5.40 (m, 1H), 5.04 (d, J = 17 Hz, 1H), 4.92 (d, J = 10.1 Hz, 1H), 3.75 (s, 3H),
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