Phosphazene Superbase-Mediated Regio- and Stereoselective Iodoaminocyclization of 2-(1-Alkynyl)benzamides for the Synthesis of Isoindolin-1-ones

Article abstract of DOI:10.1021/acs.joc.9b00452

Phosphazene superbase P₄-t-Bu mediated iodoaminocyclization of 2-(1-alkynyl)benzamides is reported. The reaction works under ambient conditions and instantaneously results in the synthesis of isoindolin-1-ones in 65-97% yields, in a regio- and stereoselective manner. The exclusive formation of products with Z-geometry (across the exo C?C bond) has been confirmed through X-ray crystallography. The methodology also provides an easy access to aristolactams, an important class of natural products. This has been successfully demonstrated by synthesizing two aristolactam derivatives (including Cepharanone B).

Full text of DOI:10.1021/acs.joc.9b00452

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Article
Phosphazene Superbase-mediated Regio- and
Stereoselective Iodoaminocyclization of 2-(1-
Alkynyl)benzamides for the Synthesis of Isoindolin-1-ones
Saurabh Mehta, and Dhirendra Brahmchari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00452 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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Phosphazene Superbase-mediated Regio- and
Stereoselective Iodoaminocyclization of 2-(1-
Alkynyl)benzamides for the Synthesis of
Isoindolin-1-ones
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Saurabh Mehta,* and Dhirendra Brahmchari
Department of Applied Chemistry, Delhi Technological University, Delhi, 110042 India
Abstract
O
 Easy to perform
 Fast reactions
 High yields
 Broad substrate scope
 Scalable
O
O
P4-t-Bu (1.0 equiv)
E+ (3.0 equiv)
R1
R1
NH2
NH
R1
NH
THF
25 °C, < 1min
Y
single step
Y
R2
E
R2
65-97%
 Easy access to Aristolactams
 Overall a robust methodology
Aristolactams
E = I2, ICl, Br2, NBS, NIS
R1 = H, OMe, NO2, F; R2 = H, alkyl, aryl, TMS, etc.
Y = CH, N
Phosphazene superbase P4-t-Bu mediated iodoaminocyclization of 2-(1-
alkynyl)benzamides is reported. The reaction works under ambient conditions, and
instantaneously results in the synthesis of isoindolin-1-ones in 65-97% yields, in a regio- and
stereoselective manner. The exclusive formation of products with Z-geometry (across the exo
C=C bond) has been confirmed through X-ray crystallography. The methodology also
provides an easy access to Aristolactams, an important class of natural products. This has
been successfully demonstrated by synthesizing two Aristolactam derivatives (including
Cepharanone B).
Introduction
Isoindolinones, also known as phathalimidines, are important nitrogenous
compounds. This important heterocyclic scaffold is present in many pharmacologically
important natural products such as Isoindolinomycin (Idm) (I),1 Lennoxamine (II),2
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Aristolactams (III),3 etc.4 (Figure 1). Additionally, several medicinally important synthetic
compounds containing isoindolin-1-ones scaffold are also known, such as Chlortalidone
(IV),5 Dopamine receptor ligand (S)-PD 172938 (V),6 Pagoclone (Cl-1043) (VI),7
Pazinaclone (VII),8 etc.9 (Figure 1).
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Figure 1. Selected examples of natural (I-III) and synthetic (IV-VII) biologically active
compounds with the isoindolin-1-one skeleton.
Due to the medicinally privileged nature of isoindolinone scaffold, several synthetic
organic as well as medicinal researchers have reported various interesting approaches for the
synthesis of the isoindolin-1-ones.10-16 Also, various alkyne annulation reactions, such as
metal-catalyzed annulations,17-20 base-mediated annulations,21-23 aza-conjugate additions,24,25
etc. have been extensively used for synthesizing a variety of isoindolinone derivatives.
Electrophilic cyclization reactions of functionalized alkynes have emerged as very
useful synthetic tools in organic chemistry.26-28 Over the years, we have been interested in
developing novel strategies for the synthesis of heterocyclic and polyheterocyclic compounds
through iodocyclization methodology.29,30 More particularly, we and others have studied the
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synthesis of isoindolinones and their regio-isomeric cyclic imidates, through the electrophilic
cyclization reactions of o-alkynyl benzamides.31-35 In this context, it may be noted that Amide
group (−CONH2) is known to be an ambident nucleophile.36-42 Further, it may be summarized
that the cyclization of o-alkynyl benzamides in the absence of a base (using NIS in DCM),31
or in presence of weak base (using I2/ICl with NaHCO3 in MeCN),32-34 leads to the O-
cyclization yielding the corresponding cyclic imidates (Scheme 1a). It may also be noted that
some of these cyclic imidates were mis-characterized as isoindolinones and isoquinolones
before32 and this was later corrected by us and also by Opatz et al.33,34 Furthermore, we later
accomplished the N-cyclization for o-alkynyl benzamide substrates by using a stronger base
n-BuLi with I2/ICl (Scheme 1b).35 Although the use of BuLi worked reasonably well, the
scope of the methodology was found to be limited with respect to the substrate functionality,
for example the substrates with trimethylsilyl (TMS) or bromo (-Br) groups did not yield the
desired products. Also, the reaction yields were moderate in most cases. Moreover, n-BuLi
being a highly reactive reagent, is difficult to handle, and is not a preferred choice of
synthetic/industrial chemists.
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We believe that due to the ambident nature of the amide group, it is still a synthetic
challenge to accomplish an efficient and regioselective N-cyclization for the alkynyl amides
and related substrates.39-42 Moreover, we think that there is still scope for the development of
a robust methodology for the synthesis of isoindolin-1-ones, especially one that allows
further diversification, and possible extension to natural product synthesis. Therefore, we
decided to develop a simple, straight-forward and efficient methodology for the
iodoaminocyclization of o-alkynyl benzamides. We wondered if the use of an organic, non-
nucleophilic superbase would be suitable for such iodocyclizations. One important class of
such superbases is phosphazenes, which are very strong, metal free, non-nucleophilic
bases.43-45 In this context, one member of the phosphazene superbase family, namely P4-t-Bu
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(Figure 2) is particularly established as an extremely strong (pKa = 42.7 in MeCN) and useful
5
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superbase in organic synthesis.46,47
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NMe2
Me2N P NMe2
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NMe2 N
Me2N P N P N
NMe2 N
t-Bu
Me2N P NMe2
NMe2
Figure 2. Phosphazene Superbase P4-t-Bu.
Upon a thorough search of the literature, we didn’t find any report of the use of a
superbase in iodocyclization of functionally-substituted alkynes. Although we came across a
few papers where Terada et al. reported superbase-catalyzed intramolecular cyclization of o-
alkynylphenyl ethers48 and o-alkynylbenzamides,49 however, no electrophiles (other than H+)
were explored for that methodology. Also, in many cases mixtures of E/Z stereoisomers were
obtained as a result of cyclization reaction of o-alkynylbenzamides (Scheme 1c).49 Therefore,
we decided to explore the use of P4-t-Bu in halocyclization reactions, and here we report the
results of our studies on superbase P4-t-Bu mediated stereo- and regioselective
halocyclization reactions of 2-(1-alkynyl) benzamides (Scheme 1d).
Scheme 1. Base-mediated Cyclizations of 2‑(1-Alkynyl)benzamides
(a) Electrophilic Cyclization of 2‑(1-Alkynyl)benzamides yielding Cyclic Imidates33
NR2
O
NR2
O
O
I2/ICl
NaHCO3
MeCN
NHR2
R3
R1
R1
R1
R3
R3
Cyclic Imidates
I
I
(b) n-Butyl Lithium-mediated Iodocyclization of 2‑(1-Alkynyl)benzamides Generating
isoindolin-1-ones35
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O
O
I2 or ICl
BuLi/THF
NH2
R1
R1
NH
0 °C, 30 min
R2
I
R2
38-94%
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isoindolin-1-ones
(c) P4-t-Bu Catalyzed Cyclization of o-Alkynylbenzamide forming isoindolinones49
O
O
P4-t-Bu
(10 mol%)
R2
N
R1
R1
N R2
R3
H
40°C
solvent, 30-60 min
R3
E/Z
(d) Present work: P4-t-Bu mediated Stereoselective Electrophilic Cyclization of o-
Alkynylbenzamides
O
O
P4-t-Bu (1.0 equiv)
E+ (3.0 equiv)
NH2
R1
R1
NH
THF
25 °C, <1 min
Y
Y
R2
E
R2
Stereoselective
Results and Discussion
The starting materials, 2-(1-alkynyl)benzamides, were prepared through a two-step
strategy (Scheme 2). It involved the reaction of commercially available o-halobenzoic acids
(1a-1e) with thionyl chloride, followed by the reaction with ammonia/primary amine,
resulting in the formation of o-halobenzamides (2a-2g), which were then subjected to
Sonogashira coupling50 with appropriate terminal alkyne (3) affording o-alkynylbenzamides
(4a-4aa) in good to excellent yields (Table 1).
Scheme 2. Strategy for the Synthesis of 2-(1-alkynyl)benzamidesa
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R2
CONHR
R2
3
CO2H
X
CONHR
(i) SOCl2
R1
Pd/Cu
Sonogashira
R1
R1
Y
(ii) NH4OH/
RNH2
Y
1
Y
2
X
coupling
4
R1 = H, OMe, NO2, etc.
R2 = alkyl, aryl, TMS, etc.
R = H, Me, Ph
X = Br, I
Y = CH, N
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Table 1. Sonogashira Coupling: Preparation of 2-(1-Alkynyl)benzamidesa
entry
product
Y
R1
R
R2
isolated
yield
1
2
3
4
5
6
CH
CH
CH
CH
CH
CH
H
H
H
H
H
H
H
H
H
H
H
H
Ph
96
96
72
69
66
77
4a
4b
4c
4d
4e
4f
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
4-OMe-C6H4
4-NMe2-
C6H4
7
CH
CH
CH
CH
H
H
H
H
H
H
H
4-F-C6H4
4-Br-C6H4
2-Br-C6H4
2-Br-C6H4
67
4g
4h
4i
8
74b
76b
95b
9
10
4,5-
(OMe)2
4j
11
12
13
14
15
16
17
CH
CH
CH
CH
CH
CH
CH
H
H
H
H
H
H
H
H
H
H
H
H
H
3-Cl-C6H4
n-hexyl
50
75
4k
4l
cyclohexyl
cyclohexenyl
TMS
83
4m
4n
4oc
4q
4r
86
94d
3-thienyl
Ph
92
4,5-
(OMe)2
91e
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CH
CH
CH
CH
CH
N
5-F
5-F
5-F
5-NO2
5-NO2
H
H
H
Ph
4-Me-C6H4
3-thienyl
Ph
94
95
93
96
94
84f
90 f
85
96
4s
4t
H
4u
4v
4w
4x
4y
4z
H
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H
4-Me-C6H4
Ph
H
N
H
H
n-hexyl
Ph
CH
CH
H
Me
Ph
H
4-Me-C6H4
4aa
aAll reactions were carried using the 0.50 mmol o-iodo/bromo amide substrate in DMF (see experimental
section for details). bThe reaction was carried out in THF:DIPA (50:1) as solvent. cThis compound 4o (2 mmol)
d
was used for preparing 4p through TMS group deprotection. This reaction was performed on a 3 mmol scale.
f
e15 mol% of catalyst was used and the reaction was carried out at 80 °C. THF was used as a solvent and the
reaction was carried out at 50 °C.
Our efforts for the superbase P4-t-Bu mediated synthesis of isoindolin-1-ones began
by taking 2-(phenylethynyl)benzamide (4a) as the substrate for the cyclization reaction. The
summary of the results of the optimization studies are compiled in Table 2.
Table 2. Optimization Studies for Halocyclization Reactiona,b
O
O
O
P4-t-Bu
electrophile
NH2
NH
NH
Ph
solvent
E
Ph
Ph
E
4a
Z
E
5a (E = I)
6a (E = Br)
5a' (E = I)
S.
base solvent temp
time
electrophile
total isolated yield
Z/E
ratio
No. equiv.
(°C)
(min)
(5a + 5a’) or (6a) (%)
(5a:5a’)
82/18
1
2
3
4
5
0.10
0.10
0.20
0.20
0.30
THF
THF
THF
THF
THF
25
25
25
25
25
30
1
I2
I2
I2
I2
I2
63c
63c
72c
72c
78c
82/18
82/18
82/18
84/16
1
30
1
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6
0.30
0.50
0.50
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
MeCN
25
25
25
25
25
0
30
1
I2
I2
78c
85
85
87
87
87
83
72c
84
82
81
71d
68d
78
73
84/16
88/12
88/12
100/0
100/0
90/10
100/0
71/29
73/27
100/0
100/0
-
7
8
30
1
I2
9
I2
10
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30
1
I2
I2
50
25
25
25
25
25
25
25
25
1
I2
1
1 I2
2 I2
ICl
NIS
Br2
NBS
I2
1
1
1
1
1
-
1
100/0
1
I2
100/0
aUnless otherwise indicated, all reactions were performed on 0.25 mmol scale using 3.0 equiv of the
b
electrophile. Unless otherwise indicated, the reactions were complete in less than 1 min, however, for the
c
uniform comparison of yields, the reactions were stopped after 1 min/30 min. Starting material was not
consumed completely. dOnly Z-isomer (6a) was obtained.
Firstly, the superbase P4-t-Bu was used as a catalyst (10%) (entry 1). We were pleased
to observe the formation of the desired N-cyclized product (5), the structure of which was
confirmed by comparing its spectroscopic data with the previously published results.35
Notably the major product (5a) was found to have Z-configuration across the exocyclic C=C
bond. The same result was obtained when the reaction was stopped after 1 minute (entry 2).
Increasing the amount of the base led to the improvement in the product yield and
stereoselectivity (entries 3-8). Nevertheless, it was observed that for all the experiments
where P4-t-Bu was used as catalyst (10-50%), the starting material was not completely
consumed and/or the E-isomer of the product (5a’) was also formed in small quantities
(entries 1-8). The best isolated yield of the exclusively formed Z-isomer (87%) was obtained
with 1 equiv of the superbase (entry 9). The same result was obtained when the reaction was
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run for 30 minutes (entry 10). The lowering of the reaction temperature led to the formation
of the E-isomer (entry 11) as minor co-product, whereas the increase in temperature resulted
in the slight reduction of the product yield (entry 12). On reducing the amount of the
electrophile (I2), the reaction either didn’t complete (starting material was remaining with 1
equiv), and/or a significant amount of E-isomer was also formed (entries 13 and 14). The
methodology also worked well with ICl, NIS (entry 15-16) as well as with bromine
electrophiles such as Br2 and NBS (entry 17-18), although the product yield was lower as
compared to reactions with I2. The use of other solvents such as DCM or MeCN (entries 19-
20) also resulted in formation of the desired product but the yield could not be further
improved. In all the cases, the product yield remained unchanged when the reaction was run
for longer durations (30 minutes). Therefore the optimized conditions involve stirring of o-
alkynylbenzamide (1.0 equiv), P4-t-Bu superbase (1.0 equiv.), I2 (3.0 equiv) in THF at
ambient temperature.
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Having optimized the reaction conditions, we then focused on studying the scope of
the iodocyclization reaction. The reactions were performed with the o-alkynyl benzamide
substrates (4a-4y) using iodine electrophile and the results are presented below (Table 3),
where the structures of the products along with the isolated yields are indicated. Additionally,
a few reactions were also performed using ICl as electrophile and where applicable, the
corresponding yields are reported in the parentheses.
Table 3. Scope for P4-t-Bu Mediated Iodocyclization Reactiona
5i
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O
O
O
5
6
NH
NH
NH
5b (R = o-methyl), 94%
7
8
9
5c (R = m-methyl), 93%
(83%)
5d (R = p-methyl), 86%
I
I
I
R
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(84%)
MeO
5a, 87%
5e, 72%
(82%)
(65%)
O
O
O
O
R1
R1
NH
NH
NH
I
NH
I
I
I
Br
F
Me2N
Br
5i (R1 = H), 86%
5j (R1 = OMe), 96%
5f, 88%
(82%)
5g, 81%
5h, 83%
(75%)
(79%)
O
O
O
O
NH
NH
NH
NH
I
I
I
I
Cl
5l, 91%
(84%)
5n, 73%
(69%)
5m, 94%
(80%)
5k, 89%
(84%)
O
O
O
O
MeO
MeO
NH
NH
I
NH
I
NH
I
I
TMS
H
S
5o, 91%
5p,c 94%
5r, 91%
(91%)
5q, 90%
(88%)
(85%)
O
O
O
F
O2N
O
F
NH
NH
NH
NH
I
N
I
I
I
S
R
R
R
5x, R = Ph, 94%
5u, 96%
5s, R = H, 90%
5t, R = Me, 96%
5v, R = H, 97%
5w, R = Me, 93%
5y, R = n-hexyl, 91%
aAll reactions were run using 0.25 mmol of o-(alkynyl)benzamide and 1.0 equiv of P4-t-Bu (0.8 M in Hexane), 3.0 equiv
I2 in dry THF at 25 °C. bThe yields in the parentheses correspond to the reactions that were performed using 3.0 equiv ICl as
the electrophile. cThis reaction was also performed at 1 mmol scale (isolated yield: 96%).
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When substrates containing the electron donating/withdrawing groups on the phenyl
ring at the distal end of the alkyne were subjected to the cyclization conditions, the desired
isoindolin-1-ones were formed (5b-5k) in good yields (Table 3). The cyclization of halogen (-
F, -Cl, -Br) containing substrates was particularly interesting, and in all these cases the
desired products (5g-5k) were isolated in good yields. It is noteworthy that the substrate
containing the bromo and chloro groups were efficiently transformed into corresponding
cyclized products in good yields and no dehalogenated product was observed in either case.
The reaction was also successful with the substrate having aliphatic chain (n-hexyl) to give
the corresponding product 5l in 91% yield. The alkyne substrate containing cyclohexyl group
was cyclized to give the desired product 5m in excellent yield (94%). Even the cyclohexenyl
group was well tolerated to give product 5n in good yield (73%). Next, the cyclization of
alkynyl substrate containing a highly labile trimethylsilyl (TMS) functional group resulted in
the formation of cyclized product 5o in 91% yield, with TMS group intact. When the terminal
alkyne (4p) was subjected to the cyclization conditions, the cyclized product 5p was formed
in excellent yield (94%). Notably the reaction with the same substrate (4p) at higher scale (1
mmol) afforded the desired product at even higher isolated yield of 96%. The substrate
containing the heterocyclic moiety (3-thienyl) also worked well under the reaction conditions
and resulted in the thienyl containing isoindolin-1-one 5q in 90% yield. The reaction also
worked for the alkynyl substrates containing various electron-donating (5r) and withdrawing
groups (5s-5w) on the benzamide ring. With fluoro (-F) substitution on the benzamide ring,
the substrates containing the phenyl, p-tolyl and even 3-thienyl groups at the alkyne-terminal
afforded the corresponding products 5s-5u in excellent yields. Substrates with electron
withdrawing nitro group on benzamide ring afforded products 5v and 5w in excellent yields,
97% and 93%, respectively. The introduction of heteroatom (nitrogen) in the benzamide ring
was also well accommodated and the reaction resulted in the isolation of the desired
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heteroatom containing isoindolinone derivatives 5x and 5y in 94% and 91% yield,
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respectively.
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As indicated above, a few reactions that were performed with ICl as the source of
electrophile also afforded the desired products; however, the yields were generally slightly
lower as compared to the reactions when iodine was used. The results indicate that iodine is
the electrophile of choice for this methodology.
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The iodocyclization of secondary amide substrates (N-methyl and N-phenyl
substituted) was also attempted (Scheme 3). Although these substrates underwent cyclization
via the nitrogen atom of the amide group to form the corresponding isoindolinones, however,
the iodine atom (C-I bond) was found to be absent in the isolated products. Also, the
geometry of the resulting products 7a and 7b was found to be different (the nitrogen atom is
trans with respect to the incoming H) as compared to the products (5a-5y) obtained from
primary amide substrates (where the nitrogen atom is cis with respect to the incoming I). This
observation is discussed in the mechanism section (Scheme 4).
Scheme 3. Cyclization of N-substituted o-alkynylbenzamides
O
O
N R
R
P4-t-Bu (1.0 equiv)
I2 (3.0 equiv)
N
H
THF, 25 °C
1 min
R1
H
R1
7a (R = Me; R1 = H) 81 %
7b (R = Ph; R1 = Me) 77 %
4z (R = Me, R1 = H)
4aa (R = Ph; R1 = Me)
Thus, the above results indicate that it is an efficient methodology for the synthesis of
isoindolin-1-ones, and it is superior to our previously reported BuLi-mediated iodocyclization
on several important criteria. These include the ease of setting up the reactions, as well as
having metal-free and ambient reaction conditions. Also, the reactions are cleaner, faster,
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generally afford better yields, and are scalable. The present methodology also has a broader
scope, as trimethylsilyl group as well as the halogens are well tolerated. The tolerance of
halogens, particularly bromo group, offers the possibility of further expansion of the present
methodology for the synthesis of more complex derivatives as well as natural products. This
type of expansion was not possible for the BuLi-mediated iodocyclization methodology, due
to the debromination of the bromo-containing substrates during the reaction. Moreover, the
present methodology also works with a secondary amide group, leading to the formation of
the desired isoindolinone (although without the incorporation of iodo group). Thus, the new
and successful substrates in this work either expand the scope of this methodology, and/or
provide insights for the possible mechanism of the reaction. Overall, we think that these
results reported here constitute a significant advancement in the area of electrophilic
cyclization of alkynes, and will further advance this interesting area of organic synthesis.
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In order to explain the interesting results obtained through the superbase-mediated
electrophilic cyclization reaction, we considered various factors affecting the reaction, as well
as the various types of intermediates that may be involved. 35,51 Moreover, we came across the
literature evidence for an intimate ion pair intermediate that was reported to be isolated and
characterized through X-ray crystallography,52 for a base-mediated iodocyclization reaction
of a metallabenzene. In view of the literature evidence available in this regard, along with our
combined observations with bases BuLi as well as P4-t-Bu, we propose a similar kind of
intermediate i.e. an intimate ion pair intermediate, for the mechanism of this reaction
(Scheme 4). It appears that, the first step of the base-mediated cyclization of 2-(1-
alkynyl)benzamides involves the generation of the amide anion (I).36-38 Thereafter, in
presence of iodine, the aminocyclization of primary amide containing substrates proceeds
through the intimate ion pair (II) intermediate (path a). As far as the quantity of the base is
concerned, it seems that a stoichiometric amount of superbase is required for quick and
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complete generation of the intermediate, as well as for the cyclization reaction. It must also
be mentioned here that while we believe that involvement of an intimate ion pair is likely,
alternatively the involvement of a cationic intermediate cannot be completely ruled out.
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Scheme 4. Plausible Mechanism for iodoaminocyclization reaction
O
O
H
N
cyclization
NH
I
-I
R = H
I2
5a-5y
I
R1
II
R1
a
h
t
Intimate ion pair
a
p
O
O
O
O
I2
slow
R
R
N
NHR
R1
P4-t-Bu
-[P4-t-Bu.H]+
N
N R
R = Me/Ph
I
-I
R1
p
I
I
4
R1
a
III
t
h
R1
O
b
Does not form
fast
O
H+
N R
N R
R1
R = Me/Ph
R1
IV
7a-7b
H
vinylic anion
Furthermore, in case of the secondary amide substrates (4z and 4aa), the formation of
the corresponding intimate ion pair (III) is presumably slow due to the steric hindrance. It
appears that the cyclization proceeds through an alternate mechanism (path b), i.e. a relatively
fast anionic mechanism in this case, where the vinylic anion intermediate (IV) seems to be
quenched with H+ (presumably during the reaction work-up), leading to the isolation of the
corresponding isoindolinones (7a and 7b) without iodine incorporation. It may be noted that
when the substrate was subjected to the BuLi-mediated iodocyclization conditions, the N-
cyclization was disfavored and the reaction resulted in the isolation of the O-cyclized
product.35 The combined observations suggest that being a kinetically-controlled reaction, the
presence of a free amide group is necessary for the successful iodoaminocyclization. Any
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steric hindrance at the nitrogen atom of the amide functionality either leads to the N-cyclized
product without iodine incorporation (for P4-t-Bu mediated cyclization), or O-cyclization (for
BuLi-mediated cyclization). Finally, the nature of the base also appears to be an important
factor for the cyclization, and interestingly the use of P4-t-Bu seems to favor N-cyclization.49
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The presence of C-I bond, as well as the free –NH group in the iodocyclized products
provide easy handles for further functionalization. It has been previously demonstrated
through various metal-catalyzed transformations such as Sonogashira alkynylation, Heck
reaction, Suzuki-Miyaura coupling, etc. on iodo-containing heterocycles;53,54 as well as
through alkylation/arylation of the lactam (–NH).35 Further, we considered testing the utility
of our superbase-mediated iodocyclization methodology for the synthesis of important natural
products. As mentioned above, the isoindolinone core is prevalent in a variety of biologically
active natural products, and we believe that there is still scope for the development of new
and efficient methodologies for the synthesis of important natural products and their
analogues. One such example is Aristolactams that is an important class of naturally
occurring phenanthrene lactam alkaloids, found in the leaves and roots of several plants
families such as Aristolochiaceae, Piperaceae, etc.55,56 In East Asia, traditionally the
aristolactams have been used as folk medicines and have also displayed important biological
properties including anticancer, anti-inflammatory, antiplatelet and neuro-protective
activities.57-59 We thought of devising a new synthetic route for Aristolactams using our
iodocyclization methodology. For demonstrating this utility, we were particularly interested
in synthesizing a particular Aristolactam derivative, namely Aristolactam BII (also known as
Cepharanone B), due to its known antitumor60 and antitubercular activities.61
As indicated above, the substrates containing halogens are easily tolerated under our
iodocyclization conditions (see products 5i and 5j in Table 3). This feature of our
methodology may be used for further extension. We considered using this feature to
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synthesize Aristolactam derivatives. Using a brief retrosynthetic analysis (Scheme 5), we
envisioned that the Aristolactam derivatives could indeed be conveniently synthesized by
constructing the ‘C’ ring through an annulation reaction (such as free redical-mediated
annulation) of a suitably substituted isoindolinone derivative obtained from our
iodocyclization methodology.
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Scheme 5. Retrosynthetic Analysis for the Synthesis of Aristolactams
O
O
R
A
D
R
NH
B
A
B
NH
C
I
D
Br
In this context, the Z geometry at the exo C=C double bond of the cyclized products
(confirmed through the X-ray crystallographic studies of the cyclized product 5i (Table 3)
seems to be favorable for a subsequent annulation reaction.
Scheme 6. Synthesis of Aristolactam Derivatives
The isoindolinones containing bromo group when subjected to free radical cyclization
using tributyltin hydride and AIBN,62,63 resulted in the formation of the Aristolactam
derivative 8a and Cepharanone B/Aristolactam BII (8b) in good yields of 72% and 70%
respectively (Scheme 6). The structure of 8a was also confirmed through single crystal X-ray
crystallography (see ORTEP diagram in Scheme 6). Thus, it has been demonstrated that the
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methodology offers scope for the synthesis of novel isoindolinones as well as related natural
products and their derivatives.
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Conclusions
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In summary, we have developed a simple and robust methodology for the regio- and
stereoselective synthesis of isoindolinones. This is the first report of a superbase-mediated
electrophilic cyclization/iodocyclization reaction. The reaction is easy to perform,
accommodates a variety of sensitive functional groups (including TMS, halogens, etc.),
works with other halogen electrophiles (such as ICl, Br2, NBS, etc.), and is also scalable. It is
notable that in addition to the broader scope; the yields are generally higher (on average 15-
20%) as compared to the yields obtained through n-BuLi-mediated iodoaminocyclization.
Moreover, the suitably substituted iodocyclized products may be conveniently converted into
the corresponding Aristolactam derivatives. We believe that this methodology will be of
interest to the synthetic/medicinal chemists, and may find applications in the pharmaceutical
industry.
EXPERIMENTAL SECTION
General information
The 1H NMR and 13C NMR spectra were obtained at 400 and 100 MHz, respectively,
with Tetramethylsilane (TMS) as the internal standard, using deuterated chloroform (CDCl3)
or deuterated Dimethyl sulfoxide (DMSO-d6) as the solvent. Crystal structure analysis was
performed on single needles X-ray diffractometer. Reaction progress was monitored by thin-
layer chromatography (TLC) analysis, that was performed on commercially available silica
gel 60 F254 0.25 mm precoated aluminium foil plates and visualization was done with short
wavelength UV light (254 nm). HRMS data was recorded on an Agilent G6530A (LC-
HRMS-Q-TOF) mass spectrometer equipped with an electrospray source with a mass
accuracy > 2 ppm having HPLC pressure 600 Bar and MS pressure 10-4 to 10-5 Torr.
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Compounds purification was performed by column chromatography using commercially
available silica having mesh size 100-200, and using ethylacetate-hexane as solvent. All
melting points are uncorrected.
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Reagents and Solvents. Unless otherwise indicated, all reagents and solvents were used as
obtained commercially.
2-Halobenzoic Acids (1a-1e). Commercially available, and were used as received.
Terminal Alkynes (3). Commercially available terminal alkynes were used as received.
Superbase P4-t-Bu (0.8 M in hexane) was used as received (Sigma Aldrich, SKU 79421).
Procedure for the synthesis of 2-Halobenzamides:
To an oven-dried round bottom flask, added corresponding 2-Halobenzoic acid 1a-1e
(1 gm) followed by the addition of 5 mL of thionyl chloride (SOCl2). The solution was
allowed to reflux for 7 hours. After the completion of the reaction, the excess of thionyl
chloride was removed under reduced pressure and the residue was cooled to 0 °C using ice-
bath. The primary amine was added dropwise while vigorously stirring the reaction mixture.
The amide (2a-2g) was formed as white solid, which were filtered in scintered flask and
washed with water several times to remove any traces of starting acid. The moist amide was
dried in a hot air oven at 50 °C for 12 hours, weighed and used as such.
2-Iodobenzamide (2a).64 This compound was prepared by performing the reaction on a 10
mmol scale. Yield: 2.42 g (98%).
5-Fluoro-2-iodobenzamide (2b).65 Yield: (976.3 mg, 98%).
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2-Bromo-5-nitrobenzamide (2c). Yield: (956.0 mg, 96%); White solid: TLC Rf = 0.18 (30%
5
6
1
EtOAc:Hexanes, UV); mp 130-132 °C; IR (KBr, cm-1) 3361, 3186, 1627, 639; H NMR
7
8
9
(400 MHz, DMSO-d6) δ 8.18-8.16 (m, 2H), 8.12 (s, 1H), 7.97 (d, J = 8.40 Hz, 1H), 7.85 (s,
1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.6, 147.0, 140.8, 135.0, 126.9, 125.5, 123.5;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C7H6BrN2O3 244.9556; Found 244.9554.
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2-Bromonicotinamide (2d). Yield: (776.1 mg, 78%); White solid: TLC Rf = 0.26 (50%
1
EtOAc:Hexanes, UV); mp 185-187 °C; IR (KBr, cm-1) 3329, 3153, 1669, 629; H NMR
(400 MHz, DMSO-d6) δ 8.45-8.44 (m, 1H), 8.05 (s, 1H), 7.90-7.88 (m, 1H), 7.78 (s, 1H),
7.49-7.46 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.4, 150.5, 146.7, 138.3, 133.9,
123.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C6H6BrN2O 200.9658; Found 200.9651.
2-Iodo-4,5-dimethoxybenzamide (2e). Yield: (966.8 mg, 97%); White solid: TLC Rf = 0.15
(40% EtOAc:Hexanes, UV); mp 186-188 °C; IR (KBr, cm-1) 3364, 319, 2964, 1638, 1256 ;
1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 6.96 (s, 1H), 3.76
(s, 3H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 170.1, 149.7, 148.3, 134.6,
121.9, 111.8, 81.8, 55.9, 55.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H11INO3
307.9778; Found 307.9780.
2-Iodo-N-methylbenzamide (2f).64 Yield: (979 mg, 93%).
2-iodo-N-phenylbenzamide (2g).35 Yield: (1.27 g, 98%).
Procedure for Sonogashira coupling for the preparation of 2-(1-Alkynyl)benzamides:
The starting bromo/iodo amide (0.50 mmol) was placed in DMF (6 mL) in an oven-
dried round bottom flask. Pd(PPh3)2Cl2 (4 mol %) and Copper iodide (2 mol %) were added
to the flask and the reaction mixture was placed under Argon atmosphere. The reaction
mixture was stirred (5 min) at room temperature, and triethylamine (4.0 equiv) was added by
a syringe. The temperature was then increased to 70 °C. The terminal alkyne (1.2 equiv)
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dissolved in DMF (2 mL) was added drop wise over 5 minutes. The reaction mixture was
allowed to stir at 70 °C for 2 hours, and the reaction was monitored by TLC to establish
completion. After the reaction was over, it was allowed to cool, and was quenched with
aqueous NH4Cl (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (3
× 20 mL). The combined organic layer was washed with brine, dried using anhydrous
Na2SO4, and was evaporated under reduced pressure. The crude product thus obtained was
purified through the column chromatography.
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Substrates 4h, 4i and 4j were synthesized using the slightly modified procedure, as
the reaction was carried at 50 °C in THF:DIPA (50:1) as the solvent, and that the terminal
alkyne in THF (2 mL) was added very slowly over a period of 30 min. Substrate 4r was
prepared as before.35 For preparing substrate 4x and 4y, the reaction was carried out at 50 °C
using THF as the solvent. The terminal alkyne 4p was prepared from 4o as before on a 2
mmol scale, as per a modified literature procedure.29,66
2-(Phenylethynyl)benzamide (4a).67 Yield: (106.1 mg, 96%).
2-(o-Tolylethynyl)benzamide (4b). Yield: (112.9 mg, 96%); White solid; TLC Rf = 0.28
(30% EtOAc:Hexanes, UV); mp 131-133 °C; IR (KBr, cm–1) 3380, 3179, 3019, 2214, 1650,
1397; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.58-7.56 (m, 2H), 7.52-7.49 (m, 1H),
13
7.46-7.38 (m, 3H), 7.28-7.27 (m, 2H), 7.22-7.16 (m, 1H), 2.43 (s, 3H); C{1H} NMR (100
MHz, DMSO-d6) δ 169.2, 139.9, 139.4, 132.5, 131.6, 129.6, 129.5, 128.8, 128.4, 127.5,
125.8, 122.2, 120.0, 91.7, 91.6, 20.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14NO
236.1070; Found 236.1081.
2-(m-Tolylethynyl)benzamide (4c).35 Yield: (84.7 mg, 72%).
2-(p-Tolylethynyl)benzamide (4d).68 Yield: (81.2 mg, 69%).
2-((4-Methoxyphenyl)ethynyl)benzamide (4e).67 Yield: (82.9 mg, 66%).
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2-((4-(Dimethylamino)phenyl)ethynyl)benzamide (4f).35 Yield: (101.8 mg, 77%).
2-((4-Fluorophenyl)ethynyl)benzamide (4g).68 Yield: (80.2 mg, 67%).
2-((4-Bromophenyl)ethynyl)benzamide (4h).35 Yield: (111.0 mg, 74%).
2-((2-Bromophenyl)ethynyl)benzamide (4i).35 Yield: (114.0 mg, 76%).
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2-((2-Bromophenyl)ethynyl)-4,5-dimethoxybenzamide (4j). Yield: (171.0 mg, 95%); Yellow
solid; TLC Rf = 0.45 (30% EtOAc:Hexanes, UV); mp 138-140 °C; IR (KBr, cm–1) 3436,
1
3150, 2961, 2202, 1671, 1263, 1067; H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.70 (s,
1H), 7.60-7.54 (m, 2H), 7.32-7.28 (m, 1H), 7.22-7.18 (m, 1H), 7.04 (s, 1H), 6.56 (s, 1H), 3.94
13
(s, 3H), 3.93 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 167.5, 150.9, 149.5, 133.4, 132.4,
130.0, 127.2, 124.9, 124.3, 115.3, 115.3, 112.8, 112.5, 93.3, 91.9, 56.0. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H14BrNO3 360.0230; Found 360.0223.
2-((3-Chlorophenyl)ethynyl)benzamide (4k).19 Yield: (63.9 mg, 50%).
2-(Oct-1-yn-1-yl)benzamide (4l).69 Yield: (86.0 mg, 75%).
2-(Cyclohexylethynyl)benzamide (4m).68 Yield: (94.3 mg, 83%).
2-(Cyclohex-1-en-1-ylethynyl)benzamide (4n).67 Yield: (96.9 mg, 86%).
2-((Trimethylsilyl)ethynyl)benzamide (4o).67 This reaction was performed on a 3 mmol scale.
Yield: (612.7 mg, 94%).
2-Ethynylbenzamide (4p).67 This reaction was performed on a 2 mmol scale. Yield: (278.6
mg, 96%).
2-(Thiophen-3-ylethynyl)benzamide (4q).67 Yield: (104.6 mg, 92%).
4,5-Dimethoxy-2-(phenylethynyl)benzamide (4r).35 Yield: (127.9 mg, 91%).
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5-Fluoro-2-(phenylethynyl)benzamide (4s).67 Yield: (112.4 mg, 94%); White solid; TLC Rf
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= 0.54 (30% EtOAc:Hexanes, UV); mp 160-162 °C; H NMR (400 MHz, CDCl3) δ 7.87-
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7.84 (m, 1H), 7.63-7.60 (m, 1H), 7.53-7.51 (m, 2H), 7.41-7.37 (m, 4H), 7.21-7.17 (m, 1H),
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6.35 (s, 1H); C{1H} NMR (100 MHz, CDCl3) δ 166.8, 163.7, 137.0, 135.5, 131.5, 129.3,
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128.6, 121.7, 117.7, 117.3, 116.2, 95.6, 86.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H11FNO 240.0819; Found 240.0827.
5-Fluoro-2-(p-tolylethynyl)benzamide (4t). Yield: (120.2 mg, 95%); Light yellow solid; TLC
Rf = 0.47 (30% EtOAc:Hexanes, UV); mp 191-193 °C; IR (KBr, cm–1) 3367, 3167, 2957,
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2213, 1644, 1376; H NMR (400 MHz, CDCl3) δ 7.87-7.84 (m, 1H), 7.62-7.58 (m, 2H),
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7.42-7.40 (m, 2H), 7.20-7.15 (m, 3H), 6.31 (s, 1H), 2.38 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 166.7, 163.6, 139.7, 135.5, 135.4, 131.3, 129.3, 118.6, 117.6, 117.3, 116.5, 95.9,
86.0, 21.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H13FNO 254.0976; Found
254.0994.
5-Fluoro-2-(thiophen-3-ylethynyl)benzamide (4u). Yield: (114.0 mg, 93%); Yellow solid;
TLC Rf = 0.41 (30% EtOAc:Hexanes, UV); mp 105-107 °C; IR (KBr, cm–1) 3353, 3175,
2204, 1651, 1384;1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.80-7.79 (m, 1H), 7.64 (s,
1H), 7.63-7.58 (m, 2H), 7.36-7.28 (m, 2H), 7.18-7.17 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 167.7, 162.5, 141.6, 134.9, 134.8, 129.9, 129.5, 127.0, 121.2, 117.0, 115.0, 88.0,
86.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H9FNOS 246.0383; Found 246.0352.
5-Nitro-2-(phenylethynyl)benzamide (4v). Yield: (127.8 mg, 96%); Yellow solid; TLC Rf =
0.59 (30% EtOAc:Hexanes, UV); mp 176-177 °C; IR (KBr, cm–1) 3368, 3186, 2209, 1650,
1342; 1H NMR (400 MHz, DMSO-d6) δ 8.32-8.29 (m, 2H), 8.13 (s, 1H), 7.92-7.86 (m, 2H),
13
7.62-7.56 (m, 2H), 7.48-7.45 (m, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 167.5, 146.8,
141.1, 134.4, 132.1, 130.3, 129.4, 127.0, 124.8, 123.1, 122.0, 98.0, 87.2; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H11N2O3 267.0764; Found 267.0779.
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5-Nitro-2-(p-tolylethynyl)benzamide (4w). Yield: (131.7 mg, 94%); Yellow solid; TLC Rf =
0.55 (30% EtOAc:Hexanes, UV); mp 217-219 °C; IR (KBr, cm–1) 3373, 3203, 2925, 2209,
1641, 1350; 1H NMR (400 MHz, DMSO-d6) δ 8.34-8.28 (m, 2H), 8.12 (s, 1H), 7.86-7.84 (m,
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2H), 7.51-7.42 (m, 2H), 7.30-7.28 (m, 2H), 2.35 (s, 3H); C{1H} NMR (100 MHz, DMSO-
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d6) δ 167.6, 146.7, 140.8, 140.3, 134.0, 131.9, 130.0, 127.3, 124.5, 122.5, 118.5, 98.4, 86.4,
21.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H13N2O3 281.0921; Found 281.0928.
2-(Phenylethynyl)nicotinamide (4x). Yield: (93.4 mg, 84%); White solid; TLC Rf = 0.27
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(50% EtOAc:Hexanes, UV); mp 201-202 °C; IR (KBr, cm–1) 3370, 3173, 2223, 1648; H
NMR (400 MHz, DMSO-d6) δ 8.63-8.61 (m, 1H), 8.03 (s, 1H), 7.91-7.88 (m, 1H), 7.74 (s,
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1H), 7.57-7.51 (m, 2H), 7.47-7.43 (m, 4H); C{1H} NMR (100 MHz, DMSO-d6) δ 168.0,
150.5, 139.0, 136.0, 135.4, 131.6, 129.5, 128.8, 123.1, 121.6, 91.5, 87.8; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H11N2O 223.0866; Found 223.0872.
2-(Oct-1-yn-1-yl)nicotinamide (4y). Yield: (103.6 mg, 90.0%); Yellow viscous liquid; TLC
Rf = 0.20 (30% EtOAc:Hexanes, UV); IR (KBr, cm–1) 3370, 3174, 2957, 2924, 2232, 1650;
1H NMR (400 MHz, CDCl3) δ = 8.65-8.63 (m, 1H), 8.42-8.40 (m, 1H), 7.74 (s, 1H), 7.35-
7.32 (m, 1H), 6.51 (s, 1H), 2.54-2.50 (m, 2H), 1.69-1.62 (m, 2H), 1.48-1.40 (m, 2H), 1.31-
1.27 (m, 4H), 0.89-0.86 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 166.6, 151.8, 139.9,
138.3, 130.3, 122.7, 98.1, 79.6, 31.2, 28.7, 27.9, 22.4, 19.5, 13.9; HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C14H19N2O 231.1492; Found 231.1495.
N-Methyl-2-(phenylethynyl)benzamide (4z).33 Yield: (100.0 mg, 85%).
N-Phenyl-2-(p-tolylethynyl)benzamide (4aa).70 Yield: (149.4 mg, 96%).
Procedure for Iodocyclization Reaction:
To an oven dried round bottom flask, the appropriate alkyne substrate 4 (0.25 mmol)
was taken in 2 mL of THF at 25 °C, and flushed with Argon. 1.0 equiv of P4-t-Bu (0.8 M in
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Hexane) superbase was added by a syringe. Iodine (3 equiv)/[ICl (3 equiv; 1.0 molar in
THF)] dissolved in 1 ml THF, was added by a syringe and the reaction was stirred for 1
minute (since the addition of superbase). The reaction was quenched by the addition of
saturated aq. NH4Cl (3 ml), followed by the addition of satd. aq. Na2S2O3 (3 ml). Water (10
ml) was added and the product was extracted with ethyl acetate (3 × 10 ml). The combined
organic layer was dried using anhydrous Na2SO4, evaporated under reduced pressure, and the
residue was purified by column chromatography (using hexane-EtOAc as eluent) to afford
the pure isoindolin-1-one product 5.
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(Z)-3-(Iodo(phenyl)methylene)isoindolin-1-one (5a).35 Yield: (75.5 mg, 87%).
(E)-3-(Iodo(phenyl)methylene)isoindolin-1-one (5a’).35 Yield: (10 mg, 12%).
(Z)-3-(Iodo(o-tolyl)methylene)isoindolin-1-one (5b). Yield: (84.6 mg, 94%); Light yellow
solid; TLC Rf = 0.36 (30% EtOAc:Hexanes, UV); mp 144-145 °C; IR (KBr, cm–1) 3170,
2959, 1708, 1467; 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H),
7.45-7.41 (m, 1H), 7.37-7.28 (m, 4H), 7.26-7.21 (m, 1H), 6.02 (d, J = 8.0 Hz, 1H), 2.10 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.4, 140.8, 138.5, 135.6, 134.6, 132.4, 131.2,
130.8, 129.4, 129.3, 129.1, 127.0, 123.1, 122.0, 77.4, 18.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C16H13INO 362.0036; Found 362.0047.
(Z)-3-(Iodo(m-tolyl)methylene)isoindolin-1-one (5c).35 Yield: (83.9 mg, 93%).
(Z)-3-(Iodo(p-tolyl)methylene)isoindolin-1-one (5d).35 Yield: (77.6 mg, 86%).
(Z)-3-(Iodo(4-methoxyphenyl)methylene)isoindolin-1-one (5e).35 Yield: (67.9 mg, 72%).
(Z)-3-((4-(Dimethylamino)phenyl)iodomethylene)isoindolin-1-one (5f).35 Yield: (85.8 mg,
88%).
(Z)-3-((4-Fluorophenyl)iodomethylene)isoindolin-1-one (5g).35 Yield: (73.9 mg, 81%).
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(Z)-3-((4-Bromophenyl)iodomethylene)isoindolin-1-one (5h).35 Yield: (88.4 mg, 83%).
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(Z)-3-((2-Bromophenyl)iodomethylene)isoindolin-1-one (5i). Yield: (91.6 mg, 86%);
Yellow solid; TLC Rf = 0.54 (30% EtOAc:Hexanes, UV); mp 172-174 °C; IR (KBr, cm–1)
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3219, 3058, 1707, 1471; H NMR (400 MHz, CDCl3) δ 7.80-7.78 (m, 2H), 7.73-7.71 (m,
1H), 7.44-7.40 (m, 4H), 7.35-7.28 (m, 1H), 6.27 (d, J = 8.4 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 167.2, 140.4, 138.8, 134.2, 133.8, 132.6, 131.6, 131.3, 130.8, 129.5, 128.4,
124.1, 123.9, 122.7, 76.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H10BrINO
425.8985; Found 425.8978.
(Z)-3-((2-Bromophenyl)iodomethylene)-5,6-dimethoxyisoindolin-1-one (5j). Yield: (116.6
mg, 96%); Yellow solid; TLC Rf = 0.43 (50% EtOAc:Hexanes, UV); mp 174-175 °C; IR
(KBr, cm–1) 3198, 2913, 1710, 1463, 1356; 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H),
7.67-7.65 (m, 1H), 7.61-7.59 (m, 2H), 7.41-7.39 (m, 1H), 7.19 (s, 1H), 6.60 (s, 1H), 3.91 (s,
3H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 169.0, 153.0, 150.8, 135.1, 134.8,
132.5, 131.6, 131.3, 128.8, 127.9, 123.3, 121.4, 104.2, 103.1, 72.0, 56.2, 55.8; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C17H14BrINO3 485.9196; Found 485.9212.
(Z)-3-((3-Chlorophenyl)iodomethylene)isoindolin-1-one (5k).35 Yield: (84.9 mg, 89%).
(Z)-3-(1-Iodoheptylidene)isoindolin-1-one (5l).35 Yield: (80.8 mg, 91%).
(Z)-3-(Cyclohexyliodomethylene)isoindolin-1-one (5m).35 Yield: (83.0 mg, 94%).
(Z)-3-(Cyclohex-1-en-1-yliodomethylene)isoindolin-1-one (5n).35 Yield: (64.0 mg, 73%).
(Z)-3-(Iodo(trimethylsilyl)methylene)isoindolin-1-one (5o). Yield: (78.0 mg, 91%); Yellow
solid; TLC Rf = 0.37 (20% EtOAc:Hexanes, UV); mp 157-159 °C; IR (KBr, cm-1) 3180,
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2917, 1708, 1467; H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.51-7.48 (m, 2H), 7.45-7.43
(m, 2H), 0.23 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.3, 140.0, 135.4, 135.1, 132.2,
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131.0, 123.9, 123.9, 71.8, 0.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H15INOSi
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343.9962; Found 343.9978.
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(Z)-3-(Iodomethylene)isoindolin-1-one (5p).35 Yield: (63.7 mg, 94%), Yield at 1 mmol
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scale: 260.0 mg, 96%.
(Z)-3-(Iodo(thiophen-3-yl)methylene)isoindolin-1-one (5q).35 Yield: (79.4 mg, 90%).
(Z)-3-(Iodo(phenyl)methylene)-5,6-dimethoxyisoindolin-1-one (5r).35 Yield: (92.6 mg,
91%).
(Z)-6-Fluoro-3-(iodo(phenyl)methylene)isoindolin-1-one (5s). Yield: (82.1 mg, 90%);
White solid; TLC Rf = 0.42 (30% EtOAc:Hexanes, UV); mp 176-178 °C; IR (KBr, cm–1)
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3342, 1706, 1478, 1362; H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.49-7.41 (m, 6H),
6.95-6.90 (m, 1H), 6.47-6.43 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 164.2,
140.7, 136.8, 134.0, 133.9, 130.4, 129.4, 129.2, 125.2, 119.9, 119.7, 78.5; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H10FINO 365.9786; Found 365.9781.
(Z)-6-Fluoro-3-(iodo(p-tolyl)methylene)isoindolin-1-one (5t). Yield: (91.0 mg, 96%); White
solid; TLC Rf = 0.38 (30% EtOAc:Hexanes, UV); mp 202-204 °C; IR (KBr, cm–1) 3174,
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2957, 2957, 1707, 1478, 1367; H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.43-7.41 (m,
1H), 7.33-7.31 (m, 2H), 7.27-7.21 (m, 3H, including solvent proton), 6.97-6.92 (m, 1H),
6.56-6.52 (m, 1H), 2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 164.2, 139.6,
137.8, 136.6, 133.9, 130.4, 129.9, 129.3, 125.2, 119.9, 119.6, 79.2, 24.6; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C16H12FINO 379.9942; Found 379.9936.
((Z)-6-Fluoro-3-(iodo(thiophen-3-yl)methylene)isoindolin-1-one (5u). Yield: (89.0 mg,
96%); White solid; TLC Rf = 0.33 (30% EtOAc:Hexanes, UV); mp 182-183 °C; IR (KBr,
cm–1) 3205, 1709, 1466, 1364; H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.76-7.74
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(m, 1H), 7.69-7.68 (m, 1H), 7.48-7.46 (m, 1H), 7.32-7.27 (m, 1H), 7.15-7.14 (m, 1H), 6.50-
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6.47 (m, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.2, 163.6, 141.7, 138.3, 133.6,
130.9, 128.2, 127.8, 125.9, 124.8, 120.0, 109.7, 72.0; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C13H8FINOS 371.9350; Found 371.9367.
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(Z)-3-(Iodo(phenyl)methylene)-6-nitroisoindolin-1-one (5v). Yield: (95.0 mg, 97%); Light
yellow solid; TLC Rf = 0.45 (30% EtOAc:Hexanes, UV); mp 190-192 °C; IR (KBr, cm–1)
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3172, 1705, 1463, 1342; H NMR (400 MHz, CDCl3) δ 8.61-8.60 (m, 1H), 8.25 (s, 1H),
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8.11-8.08 (m, 1H), 7.51-7.42 (m, 5H), 6.62 (d, J = 8.8 Hz, 1H); C{1H} NMR (100 MHz,
CDCl3) δ 165.0, 147.9, 140.3, 138.3, 136.6, 133.0, 130.0, 129.4, 129.1, 127.0, 124.2, 119.4,
84.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H10IN2O3 392.9731; Found 392.9722.
(Z)-3-(Iodo(p-tolyl)methylene)-6-nitroisoindolin-1-one (5w). Yield: (94.4 mg, 93%); Yellow
solid; TLC Rf = 0.41 (30% EtOAc:Hexanes, UV); mp 235-237 °C; IR (KBr, cm–1) 3167,
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2924, 1704, 1342; H NMR (400 MHz, CDCl3) δ 8.60-8.60 (m, 1H), 8.13-8.10 (m, 2H),
7.33-7.28 (m, 4H), 6.71 (d, J = 8.8 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-
d6) δ 166.1, 148.0, 139.6, 139.4, 137.9, 132.9, 130.4, 129.7, 129.4, 127.6, 124.5, 118.6, 79.7,
21.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H12IN2O3 406.9887; Found 406.9858.
(Z)-7-(Iodo(phenyl)methylene)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (5x). Yield:
(81.8 mg, 94%); Light yellow solid; TLC Rf = 0.38 (50% EtOAc:Hexanes, UV); mp 221-223
°C; IR (KBr, cm–1) 3427, 1702, 1466; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 9.05-9.04
(m, 1H), 8.58-8.55 (m, 1H), 7.58-7.52 (m, 5H), 7.47-7.44 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 161.8, 155.2, 152.4, 147.7, 137.5, 135.5, 129.5, 128.1, 122.5, 120.4, 79.2 (1
peak missing due to overlap); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H10IN2O
348.9832; Found 348.9820.
(Z)-7-(1-Iodoheptylidene)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (5y). Yield: (162.0
mg, 91.0%); Light yellow solid; TLC Rf = 0.20 (30% EtOAc:Hexanes, UV); mp 142-144 °C;
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IR (KBr, cm–1) 3310, 2958, 2924, 1707, 1459; 1H NMR (400 MHz, CDCl3) δ 11.71 (s, 1H),
9.01-9.00 (m, 1H), 8.61-8.59 (m, 1H), 7.43-7.40 (m, 1H), 1.81-1.74 (m, 2H), 1.54-1.47 (m,
2H), 1.37-1.33 (m, 2H), 1.27-1.23 (m, 4H), 0.91-0.88 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.0, 155.3, 153.2, 148.2, 136.1, 121.5, 119.8, 79.5, 38.7, 31.4, 28.9, 28.3, 22.5,
14.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18IN2O 357.0458; Found 357.0464.
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(Z)-3-(Bromo(phenyl)methylene)isoindolin-1-one (6a).71 Yield: (53.2 mg, 71%); Light
yellow solid; TLC Rf = 0.37 (30% EtOAc:Hexanes, UV); mp 214-216 °C; IR (KBr, cm–1)
3171, 1704, 1469; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.83-7.81 (d, J = 7.6 Hz, 1H),
7.51-7.47 (m, 5H), 7.44-7.40 (m,1H), 7.29-7.25 (m, 1H), 6.65-6.63 (d, J = 8.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 167.2, 137.4, 135.0, 135.4, 132.2, 130.9, 130.1, 129.8,
129.2, 129.1, 123.8, 122.7, 103.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H11BrNO
300.0019; Found 300.0016.
(Z)-3-Benzylidene-2-methylisoindolin-1-one (7a).72 This reaction was performed twice.
Yield: (47.6 mg, 81%); Light yellow solid; TLC Rf = 0.48 (30% EtOAc:Hexanes, UV); mp
182-183 °C; 1H NMR (400 MHz, CDCl3) δ 7.86-7.84 (m, 1H), 7.75-7.73 (m, 1H), 7.59-7.57
(m, 1H), 7.50-7.47 (m, 1H), 7.40-7.31 (m, 5H), 6.78 (s, 1H), 3.03 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.8, 137.9, 136.1, 134.6, 131.7, 129.5, 128.9, 128.4, 128.0, 127.4,
123.1, 119.2, 106.4, 30.4.
(Z)-3-(4-methylbenzylidene)-2-phenylisoindolin-1-one (7b).73 Yield: (60.0 mg, 77%). Light
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yellow Solid; TLC Rf = 0.28 (10% EtOAc:Hexanes, UV); H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.55-7.51 (m, 1H),
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7.11-7.08 (m, 5H), 6.80 (s, 1H), 6.76-6.71 (m, 4H), 2.19 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 167.9, 136.4, 135.9, 133.6, 132.3, 130.5, 129.0, 128.9, 127.8, 127.6, 127.2, 127.0,
126.7, 123.8, 119.2, 107.9, 21.1.
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The Journal of Organic Chemistry
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Procedure for the Synthesis of Aristolactam Derivatives:63
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The isoindolin-1-one derivative (5i or 5j) was dissolved (0.25 mmol) in dry, degassed
benzene (20 mL), and the solution was heated at reflux under Argon atmosphere. A solution
of nBu3SnH (2.2 equiv, 0.55 mmol) and AIBN (1.0 equiv, 0.25 mmol) in dry, degassed
benzene (4 mL) was added by syringe over 30 minutes. Once the addition was complete, the
reaction mixture was refluxed for 12 hours. Benzene was evaporated under reduced pressure,
and the residue was dissolved in CH3CN (10 mL). The solution was washed with hexane
(3×50 mL) and concentrated in vacuum to give the crude product, which was purified by
column chromatography using Hexanes-EtOAc as the eluent.
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Dibenzo[cd,f]indol-4(5H)-one (8a). Yield: (39.5 mg, 72%); Light yellow solid; TLC Rf =
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0.61 (30% EtOAc:Hexanes, UV); mp 154-156 °C; IR (KBr, cm–1) 3414, 1707; H NMR
(400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.69 (d, J = 7.2 Hz, 1H),
8.04-8.02 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.92-7.88 (m, 1H), 7.61-7.54 (m, 2H), 7.24 (s,
1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.9, 135.6, 134.9, 134.2, 131.7, 129.4, 129.2,
129.0, 128.6, 127.7, 126.9, 125.3, 123.5, 123.4, 105.5. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H10NO 220.0757; Found 220.0774.
1,2-Dimethoxydibenzo[cd,f]indol-4(5H)-one (8b).74 Yield: (48.9 mg, 70%); Light yellow
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solid; TLC Rf = 0.14 (30% EtOAc:Hexanes, UV); mp 250-251°C; H NMR (400 MHz,
DMSO-d6) δ 10.84 (s, 1H), 9.12-9.09 (m, 1H), 7.95-7.93 (m, 1H), 7.85 (s, 1H), 7.60-7.54 (m,
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2H), 7.13 (s 1H), 4.04 (s, 3H), 4.02 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 168.4,
154.2, 150.4, 135.1, 134.8, 129.1, 127.5, 126.9, 125.9, 125.4, 123.3, 121.6, 119.9, 109.9,
104.6, 59.9, 56.9.
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