Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-Mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides

Article abstract of DOI:10.1021/acs.joc.7b02903

A simple and straightforward synthesis of isoindolin-1-ones is reported. Exclusive N-cyclization of the amide functional group, an ambident nucleophile, was accomplished for the cyclization of 2-(1-alkynyl)benzamides using n-BuLi-I₂/ICl. The methodology works with the primary amide and affords the desired isoindolinones in yields of 38-94%. Interestingly, the isolated products exhibit a Z-stereochemistry across the C=C double bond. The reaction mechanism involving the formation of either a vinylic anion or an intimate ion pair intermediate is proposed.

Full text of DOI:10.1021/acs.joc.7b02903

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Note
Regio- and Stereoselective Synthesis of Isoindolin-1-ones through
BuLi-mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides
Dhirendra Brahmchari, Akhilesh K. Verma, and Saurabh Mehta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02903 • Publication Date (Web): 19 Feb 2018
Downloaded from http://pubs.acs.org on February 19, 2018
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Regio- and Stereoselective Synthesis of
Isoindolin-1-ones through BuLi-mediated
Iodoaminocyclization of 2-(1-Alkynyl)benzamides
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Dhirendra Brahmchari,† Akhilesh K. Verma‡ and Saurabh Mehta†,

†Department of Applied Chemistry, Delhi Technological University, Delhi, 110042 India.
‡Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of
Delhi, Delhi 110007 India
Abstract
A simple and straightforward synthesis of isoindolin-1-ones is reported. Exclusive N-
cyclization of the amide functional group, an ambident nucleophile, has been accomplished
for the cyclization of 2-(1-alkynyl)benzamides using n-BuLi-I2/ICl. The methodology works
with the primary amide and affords the desired isoindolinones in yields of 38-94%.
Interestingly, the isolated products exhibit a Z-stereochemistry across the C=C double bond.
The reaction mechanism involving the formation of either a vinylic anion or an intimate ion
pair intermediate is proposed.
Isoindolinones or phthalimidines represent an important class of nitrogen-containing
heterocycles. This benzo-fused lactam scaffold is present in several naturally occurring,
pharmacologically active substances such as alkaloids, e.g. Fumaridine, Chilenine,
Nuevamine, Lennoxamine, and Stachybotrin C, etc.1–3 Moreover, numerous molecules
containing isoindolin-1-one scaffold display a wide array of important biological activities
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such as vasodilatory,4 anti-HIV,5 antilcancer,6 antimicrobial,7 anticonvulsant,8 sedative &
hypnotic,9 etc. A few specific examples of such drugs and other medicinally important
compounds containing isoindolin-1-one scaffold include Chlortalidone,10 JM-1232,11 (S)-PD
172938,12 Pagoclone (Cl-1043),13 Pazinaclone (DN 2327), etc.14 Owing to their widespread
medicinal importance, there has been a continuous interest in developing new syntheses of
isoindolin-1-ones that improve accessibility to a broad array of structurally related analogues.
Several research groups have developed various interesting approaches (>200 research
articles in the recent literature) for the synthesis of the isoindolin-1-ones.15,16 More
particularly, alkyne annulation reactions have been used for the synthesis of isoindolinones,
e.g. through metal catalyzed, including Pd-catalyzed,17–21 Cu-catalyzed/mediated,22–26 Ru-
catalyzed;27 base-mediated annulations,28–35 etc.36,37
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The electrophilic cyclization, particularly the iodocyclization of functionalized
alkynes has emerged as a powerful method for the synthesis of a wide variety of heterocyclic
and carbocyclic compounds.38–40 These reactions have several practical advantages including
the ease of performing the reactions, fast reactions, simple workup, compatibility with most
functional groups, and importantly the fact that the products contain Iodine atom, which
provides easy handle for various metal-catalyzed coupling reactions.41 We have also studied
this methodology and have used it to make a variety of heterocyclic compounds in the
past.42,43 Moreover, efforts have been made previously by Yao et al. for the iodocyclization of
o-(1-alkynyl)benzamides for the synthesis of isoindolin-1-ones,44 however, later it was found
that the methodology resulted in the cyclization via the O-atom of the amide group leading to
the formation of the cyclic imidates rather than isoindolin-1-ones, which was later on
confirmed and corrected by us and others (Scheme 1).45,46
SCHEME 1. Previous work
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O
I
O
R2
R3
N
R2
R3
R1
R1
N
I
Reported/mischaracterized products
(isoindolinones/Isoquinolinones)
Yao et. al. J. Org. Chem. 2005, 70, 1432-1437
O
NHR2
R3
R1
I2 or ICl
NaHCO3/MeCN
R2
R2
N
N
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R1
O
O
R1
R3
R3
I
I
Actually formed products (cyclic imidates)
Mehta et al. J. Org. Chem. 2012, 77, 10938-10944
Schlemmer et al. J. Org. Chem. 2012, 77, 10118-10124
Furthermore, to the best of our knowledge, the synthesis of isoindolin-1-ones has not
been accomplished via iodocyclization, probably due to the challenge posed by the ambident
nucleophilic nature of the amide functionality (N- Vs. O-cyclization). Nonetheless, such
methodology would be synthetically useful and would lead to diverse isoindolin-1-ones with
interesting substitution patterns. Due to our continuous interest in developing new
methodologies for heterocyclic synthesis, we became interested in tuning the reactivity of
these 2-(1-alkynyl)benzamides to achieve regioselective synthesis of isoindolinones (Scheme
2), and report our findings here.
SCHEME 2. Present work
Amide group (–CONH2) is an ambident nucleophile and is known to undergo N vs O
cyclization in alkyne annulation reactions,47,48 therefore, the choice of the suitable reagents is
important for tuning the reactivity of the nucleophilic site.29 Our efforts were directed
towards the development of a suitable methodology employing I2/ICl as efficient electrophile
for the N-cyclization of 2-(1-alkynyl)benzamides to furnish isoindolin-1-ones. During a
thorough literature survey, we came across an interesting methodology developed by Fujita et
al. that involves a regiocontrolled iodoaminocyclization of the protected amide group at the
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activated double bond (eq 1).49 The authors also presented a rationale of N- Vs O-cyclization
of unsaturated amides based on HSAB theory. Furthermore, the authors achieved
regiocontrol (N-cyclization) in the iodocyclization of allyl or homoallyl carbamates, etc.
through the use of suitable base/additives, n-BuLi/LiAl(Ot-Bu)4 (eq 1). The authors
postulated that the reaction proceeds through the formation of a metal imino alkolate
intermediate and explained the achieved regiocontrol through the increased reactivity of
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amide nitrogen atom.
(i) n-BuLi
or LiAl(Ot-Bu)4
OR (ii) I2
Li
N
O
O
O
O
O
O
X
N
n
OR
eq.143
N
X
OR
H
X
I
n = 1, 2
X = O, NR', CH2
R = Et, t-Bu, Bn
n
n
62-88%
I2
Regiocontrolled
N-cyclization
Inspired by the methodology developed by Fujita et.al, we envisioned a similar
intramolecular iodoaminocyclization of 2-(1-alkynyl)benzamide derivatives. The required
alkyne substrates would be conveniently prepared from the commercially available starting
materials using the following approach (Scheme 3).
SCHEME 3. Strategy for preparing 2-(1-alkynyl)benzamides
R3
O
O
O
3
R2
R3
R2
(i) SOCl2
(ii) R2-NH2
Pd/Cu
N
N
OH
R1
R1
R1
H
H
X
X
2
4
1
X = Br, I
Initially, we started our reactions (eq 2) with the cyclization of tert-butyl(2-
(phenylethynyl)benzoyl)carbamate (4a), which involves the (-CO-NH-CO-) group for the
formation of a metal imino alkolate intermediate with metallic base that makes the nitrogen
atom more nucleophilic, leading to the formation of N-cyclized product. Although the desired
product 5a was isolated, however, it was not stable enough and isolated yield (27%) was
poor.
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Li
O
O
O
O
O
N
OtBu
N
OtBu
I2
n-BuLi
H
eq.2
NBoc
6
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8
Ph
Ph
27%
Ph
5a
4a
I
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We attributed the formation of unstable product and low reaction yield to the presence
of the labile protecting group (N-Boc) and/or the sterically hindered substrate, and we
decided to use the unprotected amide group instead. We then took 2-(1-
phenylethynyl)benzamide (4b) as a model substrate for determining the optimum
reagents/conditions for the cyclization reaction, using I2/ICl as the iodine source (Table S1).
To our pleasant surprise, the use of n-BuLi as base worked and the cyclized product 5b was
isolated with a yield of 67% (eq 3). The procedure involved the addition of n-BuLi to the
alkyne substrate in THF at 0 °C, followed by the addition of I2/ICl and stirring the reaction
mixture at 0 °C. The cyclized product was thoroughly characterized using spectroscopy (IR,
1H-NMR, 13C-NMR), mass spectrometry (HRMS) as well as single crystal X-ray
crystallography (see ORTEP diagram in eq 3). It is noteworthy that the cyclized product 5b
was found to possess Z-geometrical configuration. Also, the reaction at lower temperature (-
o
78 C) resulted in a mixture of stereoisomers (E:Z 1:9). The reaction also worked with ICl,
however the yield was slightly lower (63%). It was attempted to improve the reaction yield
through the use of other bases and other reaction parameters (reaction time, temperature,
solvent, etc.) and the details are summarized in the optimization Table S1 (See
Supplementary Information).
Overall, the yield could not be improved for this substrate. Therefore, we decided to
proceed further and to study the scope and limitations of the cyclization reaction using the
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same reaction conditions (eq 3). The required alkyne substrates 4b-4t were prepared (Scheme
3) in yields ranging from 48-95% by using the palladium/copper-catalyzed Sonogashira cross
coupling50 and the results are summarized in Table S2 (See supporting information).
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Thus a variety of 2-(1-Alkynyl)benzamides were subjected to the cyclization
conditions and the results are summarized in Table 1.
TABLE 1: BuLi-mediated Cyclization of 2-(1-Alkynyl)benzamidesa
entr
y
subst R1
rate
R2
H
H
H
H
R3
I+
I2
prod yield
uct
(%)
1.
2.
3.
4.
5.
6.
7.
8.
4b
4b
4c
4c
4d
4d
4e
4e
4f
4g
4g
4h
4i
H
H
H
H
Ph
5b
67
63
71
61
89
71
52
44
67
69
67
41b,c
ICl 5b
I2
5c
ICl 5c
I2
5d
ICl 5d
I2
5e
ICl 5e
4-MePh
3-MePh
4-OMePh
9.
H
H
H
H
4-NMe2Ph I2
4-FPh
5f
5g
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
I2
ICl 5g
H
H
H
H
H
H
4-BrPh
2-BrPh
3-ClPh
I2
I2
I2
5h
5i
b,d
-
4j
5j
74
73
75
69
94
57
4j
ICl 5j
I2
5k
ICl 5k
4k
4k
4l
H
H
n-hexyl
H
H
H
H
cyclohexyl I2
cyclohexe
nyl
TMS
H
3-thienyl
Ph
5l
5m
4m
I2
e
20.
21.
22.
23.
4n
4o
4p
4q
H
H
H
3,4-
(OM
e)2
H
H
H
H
H
H
H
I2
I2
I2
I2
5n
5o
5p
5q
-
82
75
78
f
24.
25.
26.
4r
4s
4t
Me
Ph
Ph
Ph
Ph
n-hexyl
I2
I2
I2
5r
5s
5t
-
g
-
g
-
aAll reactions were run using 0.25 mmol of 2-(1-alkynyl)benzamide
in 2 mL THF and 1.2 equiv of n-BuLi (1.6 M in Hexane), stirred for
10 minutes, followed by the dropwise addition (approx.1 min) of 3.0
equiv I2/ICl in 1 mL THF and the reaction mixture was stirred at 0
°C for 20 minutes under Argon atmosphere (total reaction time 30
min). b1.0 equiv of n-BuLi (1.6
M in Hexane) was used.
ccorresponding debrominated product was also formed (yield: 9%).
donly the corresponding debrominated product was isolated (yield:
e
38%). corresponding desilylated product was isolated (yield: 75%).
fO-cyclized product was formed (yield: 47%). gcomplex reaction
mixture was obtained.
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The reaction worked well with the substrates 4b-4g containing electron donating and
withdrawing groups, e.g. Me, OMe, NMe2, F, etc. (Table 1, entries 3-11). The cyclization of
bromine containing substrates 4h and 4i resulted in the isolation of partially (entry 12) or
completely debrominated (entry 13) products. The cyclization of the substrate 4j containing
chloro group (entries 14 and 15) resulted in the formation of desired product. The substrate
4k with n-hexyl group at the distal end of the alkyne was also cyclized to give good yield
(entries 16 and 17). Even a cyclohexyl group containing substrate 4l was successfully
cyclized with an excellent yield (entry 18). Cyclization of alkyne substrate 4m with
unsaturation (cyclohexenyl group) resulted in moderate yield (entry 19). The cyclization of
the substrate 4n with TMS group resulted in the formation of desilylated product in 75%
yield (entry 20). The reaction worked well for the terminal alkyne 4o and the expected
product was isolated in 82% yield (entry 21). The methodology also worked for the substrate
4p with a heterocyclic moiety and resulted in the thienyl containing isoindolinone 5p in 75%
yield (entry 22). The substrate 4q with electron donating methoxy groups at the benzamide
ring in substrate was successfully converted to the desired product in 78% yield (entry 23).
We then attempted the cyclization of secondary amide substrates (4r-4t). The N-Me
substituted amide 4r underwent cyclization (entry 24), however, the product was found to be
the corresponding imidate (O-cyclized product) instead of the expected isoindollin-1-one.
Furthermore, the cyclization of N-phenyl substituted amides 4s and 4t (entries 25 and 26
respectively) resulted in the formation of complex mixtures that could not be resolved. These
results (entries 24-26) indicate that the steric hindrance due to the Methyl or Phenyl
substituent on the nitrogen atom of the amide group presumably disfavors the desired N-
cyclization under these reaction conditions.
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1
All the cyclized products were characterized using the spectroscopy (IR, H-NMR,
13C-NMR) and Mass Spectrometry (HRMS). The stereochemistry of the cyclized products
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was assigned by correlating the spectroscopic data with that of 5b. It is noteworthy that the
N-cyclized products were differentiated from the O-cyclized products by the presence of the
diagnostic signals in the 13C-NMR spectra of these compounds (Figure 1).
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NR2
O
 <155 ppm
 >162 ppm
R1
NR2
R1
O
I
I
R3
R3
FIGURE 1. 13C NMR data for the identification of N vs O-cyclized products
We think that the results of the presented methodology are quite interesting with respect
to the exclusive N-cyclization, selective 5-exo-dig cyclization, and especially the observed
stereochemistry of the cyclized products. As mentioned above, our methodology yields the
cyclized products with Z-stereochemistry and the products with E-configuration were not
o
isolated except for one case involving the model substrate at -78 C. As we attempted to
rationalise our observations from a mechanistic perspective, we considered the possibility of
the formation of a vinylic cation or an alkyne iodonium intermediate for our cyclization
reaction. Both of these species have been reported in the literature as possible intermediates
in iodocyclization reactions.51 We also considered the possibility of an anionic cyclization
(See Supporting Information).21,32,33 Moreover, we came across a study in which while using
metallaaromatic compounds, Wang et al. captured and characterized the key intermediates in
the base-mediated alkyne iodocyclization reactions.52 With the help of X-ray structural
evidence of an isolated intermediate, the authors claimed the involvement of an intimate ion
pair intermediate instead of the generally accepted iodonium ion.
In view of the evidence presented in the literature53–55 as well as our own observations
(see Supporting Information), we propose a possible mechanism (Scheme 4) where the
alkynyl amide 4 is first deprotonated by BuLi yielding the corresponding amide anion (I). We
believe that the amide anion (I) either undergoes 5-exo-dig cyclization via path A leading to
the formation of vinylic anion intermediate (II) which on reaction with iodine generates the
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iodine containing isoindolin-1-one 5. Alternatively, the amide anion (I) may react with iodine
leading to the formation of an intimate ion pair (III) via path B, followed by the
aminocyclization to yield the corresponding iodinated isoindolinone 5.
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SCHEME 4. Plausible mechanism
The resulting products contain iodine as well as a free -NH group, which are potential
sites for further structural modifications. This has been explored by us and is demonstrated in
Scheme 5. Thus, the resulting iodine containing isoindolin-1-ones are diversified via N-
benzylation (Scheme 5A), and by using conventional palladium-catalyzed transformations,
including Sonogashira alkynylation (Scheme 5B) and Suzuki-Miyaura (Scheme 5C)
reactions. All these reactions resulted in the multi-substituted isoindolin-1-ones in good
yields.
SCHEME 5: Diversification of iodine-containing isoindolin-1-ones
O
NaH, BnBr
NBn
A
6 (87%)
I
Ph
O
cat. Pd
O
NH
OMe
NH
7 (78%)
8 (86%)
B
Ph
Ph
I
OMe
Ph
5b
O
cat. Pd
(HO)2B
NH
S
C
S
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Method A (N-Benzylation): NaH (1.2 equiv), BnBr (1.1 equiv.), DMF, 0 °C, 2 h. Method B (Sonogashira coupling): 3 mol % PdCl2(PPh3)2,
2 mol % CuI, DIPA (4 equiv.), 1-ethynyl-4-methoxybenzene (1.2 equiv.), DMF, 70 °C, 2 h. Method C (Suzuki-Miyaura coupling): 5 mol %
PdCl2, Cs2CO3 (1.4 equiv.), thiophen-2-ylboronic acid (1.2 equiv.), 4:1 DMF/H2O, 80 °C, 2 h.
6
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8
9
Thus the methodology reported here represents the first successful
iodoaminocyclization of easily accessible 2-(1-alkynyl)benzamides, yielding the
corresponding isoindolin-1-ones regio- and stereoselectively. Further efforts for achieving
broader reaction scope as well as for better understanding of the reaction mechanism, are
currently underway in our laboratory.
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EXPERIMENTAL SECTION
General
1
The H NMR and 13C NMR spectra were recorded at 25 °C at 400 MHz and 100 MHz,
respectively, with Me4Si as an internal standard. The chemical shifts () and coupling
constants (J) are given ppm and in Hz, respectively. Thin layer chromatography was
performed using commercially prepared 60-100-mesh silica gel plates and visualization was
effected with short wavelength UV light (254 nm). Compounds were purified by column
chromatography. All melting points are uncorrected.
Reagents. All reagents were used directly as obtained commercially unless otherwise noted.
Solvents. All solvents were used directly as obtained commercially.
2-halobenzoic acids: 1a and 1b are commercially available and were used as received.
Terminal alkyne building blocks. Commercially available terminal alkynes (3) were used as
received.
Procedure for the preparation of 2-Halobenzamides:
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2-Halobenzoic acid (1gm) was refluxed in 5 mL SOCl2 for 7 hrs. The solvent was evaporated
under reduced pressure and the resulting yellow oil was treated with the corresponding
primary amines at 0 °C. The resulting white solid was filtered and dried overnight in hot air
oven at 50 °C. 2-bromobenzamide was commercially available and used as such.
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tert-butyl (2-iodobenzoyl)carbamate (2a): Yield: (477 mg, 34%); light yellow Solid; TLC Rf
= 0.22 (20% EtOAc:Hexanes, UV); mp 113-115 °C; 1H NMR (400 MHz, CDCl3) δ = 8.15 (s,
1H), 7.79 (d, J = 7.6 Hz, 1H), 7.37-7.33 (m, 1H), 7.28-7.26 (m, 1H), 7.10-7.05 (m, 1H), 1.37
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(s, 9H); C NMR (100 MHz, CDCl3) δ = 168.9, 149.3, 141.0, 139.1, 131.0, 127.7, 127.5,
91.9, 82.7, 27.8.
2-iodobenzamide (2b):56 Yield: (966 mg, 97%); White Solid: TLC Rf = 0.15 (30%
EtOAc:Hexanes, UV); mp 183-185 °C; 1H NMR (400 MHz, CDCl3) δ = 7.90 (d, J = 10.4
Hz, 1H), 7.48-7.46 (m, 1H), 7.41-7.37 (m, 1H), 7.14-7.10 (m, 1H), 5.88 (s, 2H).
2-bromo-4,5-dimethoxybenzamide (2c):57 Yield: (976 mg, 98%); White Solid; TLC Rf =
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0.26 (40% EtOAc:Hexanes, UV); mp 177-178 °C; H NMR (400 MHz, CDCl3) δ = 7.30 (s,
13
1H), 7.98 (s, 1H), 6.54 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H); C NMR (100 MHz, DMSO) δ =
168.6, 151.0, 148.2, 127.6, 115.8, 113.2, 110.1, 56.2, 56.0.
2-iodo-N-phenylbenzamide (2d):56 Yield: (1.211 g, 93%); White Solid; TLC Rf = 0.33 (10%
EtOAc:Hexanes, UV); mp 144-146 °C; 1H NMR (400 MHz, CDCl3) δ = 7.89 (d, J = 7.2 Hz,
1H), 7.63-7.61 (m, 3H), 7.50-7.48 (m, 1H), 7.42-7.35 (m, 3H), 7.19-7.10 (m, 2H).
2-iodo-N-methylbenzamide (2e):56 Yield: (998 mg, 95%); White Solid; TLC Rf = 0.23 (10%
EtOAc:Hexanes, UV); mp 146-148 °C (lit. mp 145-147 °C)58; 1H NMR (400 MHz, CDCl3) δ
= 7.83 (d, J = 8.0 Hz, 1H), 7.38-7.31 (m, 2H), 7.10-7.03 (m, 1H), 5.99 (s, 1H), 2.97 (d, J =
4.8 Hz, 3H).
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Representative Sonogashira procedure: To a solution of the appropriate iodo/bromo
starting material (0.25 mmol) in DMF (2 mL) were added PdCl2(PPh3)2 (4 mol %) and CuI (2
mol %). The reaction vial was flushed with Ar and the reaction mixture was stirred for 5 min
at room temperature. TEA (4.0 equiv) was added by a syringe. The reaction mixture was then
heated to 70 °C. A solution of the corresponding terminal alkyne (1.2 equiv) in DMF (1 mL)
was added dropwise over 5 min, and the mixture was allowed to stir at 70 °C for 2 h (the
reaction progress was monitored by TLC). After completion, the reaction mixture was
cooled, diluted with EtOAc, and washed with satd. aq. NH4Cl and water. The organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude
product, which was purified by column chromatography on silica gel using Hexanes-EtOAc
as the eluent.
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Sonogashira Coupling Procedure for the Preparation of 4h and 4i: Both 4h and 4i were
synthesised using the slightly modified procedure as the reaction was performed at 50 °C and
the corresponding terminal alkyne (1.2 equiv) in THF (1 mL) was added dropwise over 30
min.
Procedure for the synthesis of terminal alkyne 4o: A modified literature procedure was
used.59 To a solution of compound 4n (0.25 mmol) in methanol (5 mL), KF·2H2O (6 equiv)
was added and the reaction mixture was stirred for 30 min at 25 °C. After the reaction was
over, methanol was removed under vacuum and the residue was extracted with EtOAc (3 x
25 mL), washed with 0.1M HCl and brine, dried (anhydrous Na2SO4), filtered, and the
solvent removed under vacuum. Purification by flash chromatography afforded the product.60
Sonogashira Coupling Procedure for the Preparation of 4q: This compound was
synthesised using the slightly modified procedure using PdCl2(PPh3)2 (15 mol %) and the
reaction was carried at 80 °C.
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Sonogashira Coupling Procedure for the Preparation of 4s-4t: General Sonogashira was
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followed with the difference that DCE was used as solvent.
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tert-butyl (2-(phenylethynyl)benzoyl)carbamate (4a): Yield: (14.4 mg, 18%); Yellow Solid;
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TLC Rf = 0.5 (20% EtOAc:Hexanes, UV); mp 108-110 °C; IR (CHCl3, cm–1) 3265, 2978,
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1761, 1693, 1220; H NMR (400 MHz, CDCl3) δ = 9.28 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H),
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7.62-7.59 (m, 3H), 7.52-7.42 (m, 2H), 7.40-7.34 (m, 3H), 1.45 (s, 9H); C NMR (100 MHz,
CDCl3) δ = 164.9, 149.3, 139.3, 133.2, 131.6, 131.4, 130.4, 129.2, 128.9, 128.3, 121.7, 119.8,
86.5, 82.5, 67.4, 27.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H20NO3 322.1438;
Found 322.1449.
2-(phenylethynyl)benzamide (4b):61 Yield: (51.3 mg, 95%); Yellow Solid; TLC Rf = 0.26
(30% EtOAc:Hexanes, UV); mp 146-148 °C; 1H NMR (400 MHz, DMSO) δ = 7.82 (s, 1H),
7.62-7.60 (m, 2H), 7.58-7.55 (m, 1H), 7.54-7.52 (m, 2H), 7.49-7.47 (m, 2H), 7.46-7.45 (m,
1H), 7.44-7.43 (m, 2H); 13C NMR (100 MHz, DMSO) δ = 169.5, 139.9, 132.9, 131.7, 130.0,
129.3, 129.1, 129.0, 128.1, 122.9, 120.2, 93.2, 88.5; MS (m/z) 222 (M+H)+.
2-(p-tolylethynyl)benzamide (4c):62 Yield: (38.2 mg, 65%); Yellow Solid; TLC Rf = 0.30
(30% EtOAc:Hexanes, UV); mp 142-144 °C; 1H NMR (400 MHz, DMSO) δ = 7.82 (s, 1H),
7.59-7.54 (m, 3H), 7.47-7.40 (m, 4H), 7.26 (d, J = 7.88 Hz, 2H), 2.34 (s, 3H); 13C NMR (100
MHz, DMSO) δ = 169.5, 139.7, 139.1, 132.8, 131.6, 130.0, 129.8, 128.8, 128.1, 120.3, 119.9,
93.4, 87.9, 21.5; MS (m/z) 236 (M+H)+.
2-(m-tolylethynyl)benzamide (4d): Yield: (40.6 mg, 69%); Yellow Solid; TLC Rf = 0.30
(30% EtOAc:Hexanes, UV); mp 128-129 °C; IR (CHCl3, cm–1) 3374, 3177, 2902, 2208,
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1644; H NMR (400 MHz, DMSO) δ = 7.83 (s, 1H), 7.61-7.56 (m, 3H), 7.50-7.43 (m, 2H),
7.35-7.32 (m, 3H), 7.26-7.24 (m, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSO) δ = 169.5,
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139.9, 138.4, 132.8, 132.1, 130.0, 130.0, 129.0, 128.9, 128.8, 128.1, 122.8, 120.2, 93.3, 88.2,
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21.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14NO 236.1070; Found 236.1068.
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2-((4-methoxyphenyl)ethynyl)benzamide (4e):61 Yield: (39.6 mg, 63%); Yellow Solid; TLC
Rf = 0.23 (30% EtOAc:Hexanes, UV); mp 123-124 °C; 1H NMR (400 MHz, DMSO) δ = 7.82
(s, 1H), 7.58-7.55 (m, 3H), 7.48-7.44 (m, 4H), 7.02-6.99 (m, 2H), 3.80 (s, 3H); 13C NMR
(100 MHz, DMSO) δ = 169.5, 160.1, 139.6, 138.5, 133.3, 132.7, 130.0, 128.5, 128.2, 120.6,
114.8, 93.5, 87.2, 55.7; MS (m/z) 252 (M+H)+.
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2-((4-(dimethylamino)phenyl)ethynyl)benzamide (4f): Yield: (49.6 mg, 75%); Brown yellow
Solid; TLC Rf = 0.22 (30% EtOAc:Hexanes, UV); mp 151-153 °C; IR (CHCl3, cm–1) 3025,
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2940, 2204, 1662, 1218; H NMR (400 MHz, DMSO) δ = 7.79 (s, 1H), 7.58-7.52 (m, 3H),
7.44-7.32 (m, 4H), 6.73-6.71 (m, 2H), 2.96 (s, 6H); 13C NMR (100 MHz, DMSO) δ = 169.6,
150.7, 138.9, 132.8, 132.5, 130.0, 128.2, 128.0, 121.1, 112.2, 108.9, 95.3, 86.5, 40.1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H17N2O 265.1335; Found 265.1345.
2-((4-fluorophenyl)ethynyl)benzamide (4g):62 Yield: (39.4 mg, 66%); Yellow Solid; TLC Rf
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= 0.21 (30% EtOAc:Hexanes, UV); mp 159-160 °C; H NMR (400 MHz, DMSO) δ = 7.84
(s, 1H), 7.60-7.54 (m, 5H), 7.47-7.30 (m, 2H), 7.28-7.26 (m, 2H); 13C NMR (100 MHz,
DMSO) δ = 169.5, 163.7, 161.3, 139.9, 134.1, 134.0, 132.8, 130.0, 129.0, 128.2, 120.1,
119.4, 119.4, 116.5, 116.3, 92.1, 88.3; MS (m/z) 240 (M+H)+.
2-((4-bromophenyl)ethynyl)benzamide (4h): Yield: (54.7 mg, 73%); Brown yellow Solid;
TLC Rf = 0.25 (30% EtOAc:Hexanes, UV); mp 178-180 °C; IR (CHCl3, cm–1) 3455, 3177,
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2890, 2217, 1652; H NMR (400 MHz, DMSO) δ =7.89 (s, 1H), 7.71-7.69 (m, 2H), 7.67-
7.65 (m, 1H), 7.62-7.60 (m, 2H), 7.54-7.50 (m, 4H); 13C NMR (100 MHz, DMSO) δ = 169.4,
139.9, 133.6, 132.9, 132.2, 130.1, 129.2, 128.2, 122.7, 122.2, 119.9, 92.0, 89.8; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H11BrNO 300.0019; Found 300.0002.
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2-((2-bromophenyl)ethynyl)benzamide (4i): Yield: (55.5 mg, 74%); White Solid; TLC Rf =
0.25 (30% EtOAc:Hexanes, UV); mp 177-179°C; IR (CHCl3, cm–1) 3446, 3161, 2926, 1669;
1H NMR (400 MHz, CDCl3) δ = 8.16-8.13 (m, 1H), 7.69-7.67 (m, 1H), 7.64-7.57 (m, 2H),
7.50-7.48 (m, 3H), 7.35-7.32 (m, 1H), 7.26-7.22 (m, 2H, including solvent protons), 6.20 (s,
1H); 13C NMR (100 MHz, CDCl3) δ = 167.8, 134.3, 133.8, 133.6, 132.5, 131.0, 130.4, 130.3,
129.2, 127.2, 125.1, 124.3, 119.7, 94.2, 91.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H11BrNO 300.0019; Found 300.0002.
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2-((3-chlorophenyl)ethynyl)benzamide (4j):58 Yield: (30.7 mg, 48%); Brown yellowish
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Solid; TLC Rf = 0.24 (30% EtOAc:Hexanes, UV); mp 139-141 °C; H NMR (400 MHz,
DMSO) δ = 7.87 (s, 1H), 7.63-7.57 (m, 4H), 7.50-7.48(m, 5H); 13C NMR (100 MHz, DMSO)
δ = 169.4, 140.1, 133.7, 133.0, 131.1, 131.1, 130.3, 130.1, 129.4, 129.3, 128.2, 124.9, 119.7,
91.5, 89.9; MS (m/z) 256 (M+H)+, 258.
2-(oct-1-yn-1-yl)benzamide (4k):63 Yield: (41.8 mg, 73%); Yellow Solid; TLC Rf = 0.32
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(30% EtOAc:Hexanes, UV); mp 88-89 °C; H NMR (400 MHz, DMSO) δ = 7.68 (s, 1H),
7.53-7.51 (m, 2H), 7.42-7.37 (m, 3H), 2.44-2.40 (m, 2H), 1.55-1.52 (m, 2H), 1.44-1.41 (m,
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2H), 1.30-1.29 (m, 4H), 0.90-0.87 (m, 3H); C NMR (100 MHz, DMSO) δ = 169.4, 139.3,
133.1, 129.9, 128.1, 128.0, 121.0, 95.2, 79.5, 31.2, 28.4, 28.4, 22.4, 19.3, 14.3; MS (m/z) 230
(M+H)+.
2-(cyclohexylethynyl)benzamide (4l):62 Yield: (46.6 mg, 82%); White Solid; TLC Rf = 0.31
(30% EtOAc:Hexanes, UV); mp 119-121 °C; 1H NMR (400 MHz, CDCl3 ) δ = 8.14-8.11 (m,
1H), 7.75 (s, 1H), 7.50-7.48 (m, 1H), 7.41-7.38 (m, 2H), 6.44 (s, 1H), 2.70-2.63 (m, 1H),
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1.92-1.89 (m, 2H), 1.77-1.71 (m, 2H), 1.56-1.53 (m, 2H), 1.39-1.35 (m, 4H); C NMR (100
MHz, CDCl3) δ = 168.2, 133.8, 133.6, 130.8, 130.2, 128.0, 120.9, 101.7, 79.6, 32.2, 29.8,
25.6, 24.8.
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2-(cyclohex-1-en-1-ylethynyl)benzamide (4m):61 Yield: (47.8 mg, 85%); White Solid; TLC
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Rf = 0.28 (30% EtOAc:Hexanes, UV); mp 133-135 °C; H NMR (400 MHz, CDCl3) δ =
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6.25 (m, 1H), 2.22-2.19 (m, 2H), 2.17-2.14 (m, 2H), 1.69-1.60 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ = 168.3, 137.0, 133.9, 133.3, 130.8, 130.2, 128.2, 120.6, 119.9, 97.9, 85.2, 28.7,
25.7, 22.0, 21.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H16NO 226.1226; Found
226.1214.
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2-((trimethylsilyl)ethynyl)benzamide (4n):61 Yield: (50 mg, 93%); White Solid; Rf = 0.55
(30% EtOAc:Hexanes); mp 148-150 °C; 1H NMR (400 MHz, CDCl3): δ =8.13-8.11 (m, 1H),
7.70 (s, 1H), 7.55-7.52 (m, 1H), 7.42-7.40 (m, 2H), 6.46 (s,1H), 0.26 (s, 9H).
2-ethynylbenzamide (4o):61 Yield: (34.8 mg, 95%); Yellow Solid; TLC Rf = 0.16 (30%
EtOAc:Hexanes, UV); mp 146-148 °C (lit. mp 145- 147 °C). 1H NMR (400 MHz, CDCl3): δ
= 8.08-8.06 (m, 1H), 7.60-7.58 (m, 1H), 7.49-7.43 (m, 2H), 7.34 (s, 1H), 6.30 (s, 1H), 3.52 (s,
1H).
2-(thiophen-3-ylethynyl)benzamide (4p):61 Yield: (52.8 mg, 93%); White Solid; TLC Rf =
0.24 (30% EtOAc:Hexanes, UV); mp 111-113 °C; 1H NMR (400 MHz, CDCl3) δ = 7.99-7.84
(m, 2H), 7.51-7.44 (m, 2H), 7.37-7.18 (m, 3H), 7.14-7.04 (m, 1H), 6.70 (d, J = 21.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ = 168.5, 139.9, 134.5, 133.3, 131.8, 130.8, 129.9, 129.6,
129.4, 128.6, 125.8, 90.8, 87.0.
4,5-dimethoxy-2-(phenylethynyl)benzamide (4q): Yield: (65.4 mg, 93%); Brown Solid; TLC
Rf = 0.20 (50% EtOAc:Hexanes, UV); mp 148-150 °C; IR (CHCl3, cm–1) 3445, 3170, 2995,
1666,1216, 1069; 1H NMR (400 MHz, CDCl3) δ = 7.72 (s, 1H), 7.68-7.63 (m, 1H), 7.53-7.51
(m, 2H), 7.47-7.43 (m, 1H), 7.39-7.37 (m, 2H), 7.04 (s, 1H), 6.10 (s, 1H), 3.96 (s, 3H), 3.95
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(s, 3H); C NMR (100 MHz, CDCl3) δ = 167.5, 150.9, 149.5, 132.1, 132.0, 131.4, 129.1,
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C17H16NO3 282.1125; Found 282.1120.
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N-methyl-2-(phenylethynyl)benzamide (4r):45 Yield: (48 mg, 82%); White Solid; TLC Rf =
0.23 (10% EtOAc:Hexanes, UV); mp 105-106 °C (lit. mp 103-105 °C). 1H NMR (400 MHz,
CDCl3): δ =8.02-8.00 (m, 1H), 7.59-7.56 (m, 1H), 7.52-7.50 (m, 2H), 7.43-7.30 (m, 5H), 3.06
(d, J = 4.8 Hz, 3H).
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N-phenyl-2-(phenylethynyl)benzamide (4s):45 Yield: (62.4 mg, 84%); White Solid; TLC Rf =
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0.60 (20% EtOAc:Hexanes, UV); mp 150-152 °C; H NMR (400 MHz, CDCl3) δ = 9.22 (s,
1H), 8.13-8.11 (m, 1H), 7.68-7.63 (m, 3H), 7.50-7.44 (m, 4H), 7.41-7.32 (m, 5H), 7.16-7.12
(m, 1H).
2-(oct-1-yn-1-yl)-N-phenylbenzamide (4t):45 Yield: (68 mg, 89%); Brownish semi-solid;
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TLC Rf = 0.64 (20% EtOAc:Hexanes, UV); H NMR (400 MHz, CDCl3) δ = 9.43 (s, 1H),
8.09-8.07 (m, 1H), 7.69-7.67 (m, 2H), 7.50-7.48 (m, 1H), 7.40-7.34 (m, 4H), 7.16-7.12 (m,
1H), 2.51-2.47 (m, 2H), 1.62-1.55 (m, 2H), 1.44-1.36 (m, 2H), 1.28-1.21 (m, 4H), 0.89-0.85
(m, 3H).
Representative procedure for the cyclization reaction: All cyclization reactions have been
performed using the appropriate alkyne starting material (0.25 mmol) in 2 mL of THF placed
in an ice bath at 0 °C and flushed with Argon. 1.2 equiv n-BuLi (1.6 M in Hexane) was added
dropwise (approx. 1 min). After 10 min, I2 (3 equiv)/ [ICl (1.0 molar in THF)] (3 equiv),
dissolved in 1 ml THF, was added dropwise (approx. 1 min) and the reaction was stirred in
ice bath for 20 minutes (total reaction time 30 min). After the reaction was over, the reaction
mixture was quenched with satd. aq. NH4Cl solution, diluted with 10 mL of EtOAc, washed
with 25 mL of satd. aq. Na2S2O3 and dried (anhydrous Na2SO4). The solvent was evaporated
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under reduced pressure and the product was isolated by chromatography on a silica gel
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(E)-tert-butyl 1-(iodo(phenyl)methylene)-3-oxoisoindoline-2-carboxylate (5a): Yield:
(30.2 mg, 27%); Yellow Solid; TLC Rf = 0.5 (10% EtOAc:Hexanes, UV); mp 171-173 °C. IR
(CHCl3, cm–1) 2925, 2854, 1816, 1710, 1470, 1216. 1H NMR (400 MHz, CDCl3): δ = 9.08 (d,
J = 7.6 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.62-7.59 (m, 1H), 7.45-7.42
(m, 2H), 7.36-7.32 (m, 2H), 7.24-7.21 (m, 1H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
= 165.2, 148.1, 144.3, 137.9, 133.8, 133.1, 130.2, 129.9, 129.2, 128.6, 128.3, 124.8, 124.0,
84.5, 84.0, 27.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H19INO3 448.0404; Found
448.0416.
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(Z)-3-(iodo(phenyl)methylene)isoindolin-1-one (5b): Yield: (58.2 mg, 67%); Yellow Solid;
TLC Rf = 0.62 (30% EtOAc:Hexanes, UV); mp 165-167 °C; IR (CHCl3, cm–1) 3184, 3068,
2965, 1703, 1469; 1H NMR (400 MHz, DMSO) δ = 10.26 (s, 1H), 7.70 (d, J = 7.48 Hz, 1H),
7.52-7.40 (m, 6H), 7.33-7.29 (m, 1H), 6.29 (d, J = 7.96 Hz, 1H); 13C NMR (100 MHz,
DMSO) δ = 167.9, 142.6, 139.0, 135.1, 132.5, 131.8, 129.7, 129.6, 129.6, 129.4, 123.5,
123.1, 78.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H11INO 347.9880; Found
347.9869.
(E)-3-(iodo(phenyl)methylene)isoindolin-1-one (5b’): Yellow Solid; TLC Rf = 0.60 (30%
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EtOAc:Hexanes, UV); mp 172-173 °C; IR (CHCl3, cm–1) 3257, 3059, 2961, 1705, 1470; H
NMR (400 MHz, CDCl3) δ = 8.95 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.76-7.74 (m,
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1H), 7.63-7.61 (m, 1H), 7.59 (s, 1H), 7.44-7.40 (m, 4H), 7.37-7.33 (m, 1H); C NMR (100
MHz, CDCl3) δ = 166.0, 141.9, 136.1, 135.4, 132.0, 131.0, 130.1, 129.2, 129.1, 128.9, 123.8,
123.7, 72.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H11INO 347.9880; Found
347.9869.
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(Z)-3-(iodo(p-tolyl)methylene)isoindolin-1-one (5c): Yield: (64.1 mg, 71%); White Solid;
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TLC Rf = 0.66 (30% EtOAc:Hexanes, UV); mp 192-194 °C; IR (CHCl3, cm–1) 3189, 2956,
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2925, 1704, 1469; H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H),
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7.43-7.39 (m, 1H), 7.34-7.32 (m, 2H), 7.28-7.25 (m, 3H), 6.60 (d, J = 8.4 Hz, 1H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 167.2, 139.4, 138.0, 137.4, 134.5, 132.1, 131.7, 129.8,
129.3, 129.2, 123.7, 123.2, 79.4, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H13INO 362.0036; Found 362.0025.
(Z)-3-(iodo(m-tolyl)methylene)isoindolin-1-one (5d): Yield: (80.4 mg, 89%); White Solid;
TLC Rf = 0.65 (30% EtOAc:Hexanes, UV); mp 146-148 °C; IR (CHCl3, cm–1) 3175, 3060,
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2891, 1703, 1469; H NMR (400 MHz, CDCl3) δ = 7.78-7.76 (m, 2H), 7.41-7.38 (m, 1H),
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7.35-7.31 (m, 1H), 7.26-7.21(m, 3H), 6.53 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H); C NMR (100
MHz, CDCl3) δ = 167.2, 140.7, 138.9, 137.4, 134.5, 132.1, 131.7, 130.0, 130.0, 129.2, 128.9,
126.4, 123.7, 123.2, 79.1, 21.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H13INO
362.0036; Found 362.0065.
(Z)-3-(iodo(4-methoxyphenyl)methylene)isoindolin-1-one (5e): Yield: (49 mg, 52%);
Brown Solid; TLC Rf = 0.58 (30% EtOAc:Hexanes, UV); mp 175-177 °C; IR (CHCl3, cm–1)
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3196, 2917, 2849, 1708, 1471, 1250; H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.0 Hz,
1H), 7.70 (s, 1H), 7.43-7.36 (m, 4H), 6.98-6.96 (m, 2H), 6.62 (d, J = 7.6 Hz, 1H), 3.89 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 167.2, 160.1, 137.4, 134.5, 133.2, 132.2, 131.7, 131.0,
129.2, 123.7, 123.1, 114.4, 79.4, 55.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H13INO2 377.9985; Found 377.9978.
(Z)-3-((4-(dimethylamino)phenyl)iodomethylene)isoindolin-1-one (5f): Yield: (65.4 mg,
67%); Brown Solid; TLC Rf = 0.57 (30% EtOAc:Hexanes, UV); mp 192-193 °C; IR (CHCl3,
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cm–1) 3019, 2917, 2850, 1707, 1466, 1364, 1216; H NMR (400 MHz, CDCl3) δ = 9.39 (s,
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1H), 8.35-8.33 (m, 1H), 7.99-7.97 (m, 1H), 7.76-7.71 (m, 1H), 7.51-7.47 (m, 1H), 7.41-7.39
(m, 3H), 6.76 (d, J = 8.4 Hz, 1H), 3.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ = 162.5,
150.9, 143.1, 139.1, 133.7, 131.5, 130.2, 127.6, 126.9, 125.3, 124.5, 111.2, 75.2, 40.1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16IN2O 391.0302; Found 391.0325.
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(Z)-3-((4-fluorophenyl)iodomethylene)isoindolin-1-one (5g): Yield: (63 mg, 69%); Yellow
Solid; TLC Rf = 0.55 (30% EtOAc:Hexanes, UV); mp 145-147 °C; IR (CHCl3, cm–1) 3193,
3068, 1708, 1471, 1229; 1H NMR (400 MHz, DMSO) δ = 10.27 (s, 1H), 7.70 (d, J = 7.44 Hz,
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1H), 7.49-7.46 (m, 3H), 7.39-7.31 (m, 3H), 6.35 (d, J = 7.88 Hz, 1H); C NMR (100 MHz,
DMSO) δ = 167.9, 163.7, 139.4, 139.1, 139.1, 135.0, 132.7, 132.0, 131.9, 129.8, 123.5,
123.1, 116.8, 116.5, 77.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H10FINO 365.9786;
Found 365.9809.
(Z)-3-((4-bromophenyl)iodomethylene)isoindolin-1-one (5h): Yield: (43.6 mg, 41%);
Yellow Solid; TLC Rf = 0.60 (30% EtOAc:Hexanes, UV); mp 164-166 °C; IR (CHCl3, cm–1)
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3204, 3015, 1708, 1470; H NMR (400 MHz, CDCl3) δ = 7.80-7.78 (m, 1H), 7.74 (s, 1H),
7.60-7.56 (m, 2H), 7.45-7.42 (m, 1H), 7.33-7.28 (m, 3H), 6.60 (d, J = 8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ = 167.1, 139.9, 138.0, 134.2, 132.4, 131.7, 131.2, 130.7, 129.5, 123.9,
123.5, 123.1, 86.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H10BrINO 425.8985;
Found 425.8978.
(Z)-3-((3-chlorophenyl)iodomethylene)isoindolin-1-one (5j): Yield: (70.6 mg, 74%); Brown
Solid; TLC Rf = 0.59 (30% EtOAc:Hexanes, UV); mp 148-150 °C; IR (CHCl3, cm–1) 3192,
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2961, 1709, 1471; H NMR (400 MHz, CDCl3) δ = 7.80-7.77 (m, 2H), 7.46-7.44 (m, 2H),
7.42-7.40 (m, 2H), 7.34-7.29 (m, 2H), 6.57 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ = 167.2, 142.5, 138.3, 134.7, 134.2, 132.4, 131.7, 130.4, 129.7, 129.5, 129.4, 127.8, 123.9,
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123.1, 75.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H10ClINO 381.9490; Found
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381.9475.
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(Z)-3-(1-iodoheptylidene)isoindolin-1-one (5k): Yield: (66.6 mg, 75%); Yellow Solid; TLC
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Rf = 0.69 (30% EtOAc:Hexanes, UV); mp 88-89 °C; IR (CHCl3, cm–1) 3191, 2955, 2927,
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2856, 1700, 1471; H NMR (400 MHz, CDCl3) δ = 7.86-7.84 (m, 1H), 7.80-7.78 (m, 1H),
7.68 (s, 1H), 7.66-7.60 (m, 1H), 7.55-7.51 (m, 1H), 1.75-1.67 (m, 2H), 1.46-1.43 (m, 2H),
1.36-1.34 (m, 6H), 0.92-0.88 (m, 3H); 13C NMR (100 MHz, CDCl3) δ = 166.8, 135.9, 134.0,
132.5, 132.2, 129.0, 124.2, 123.0, 89.9, 40.1, 31.5, 29.5, 28.3, 22.5, 14.0; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C15H19INO 356.0506; Found 356.0541.
(Z)-3-(cyclohexyliodomethylene)isoindolin-1-one (5l): Yield: (83 mg, 94%); White Solid;
TLC Rf = 0.66 (30% EtOAc:Hexanes, UV); mp 118-119 °C; IR (CHCl3, cm–1) 3186, 2927,
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2853, 1697, 1471; H NMR (400 MHz, CDCl3) δ = 7.87-7.79 (m, 3H), 7.65-7.58 (m, 1H),
7.54-7.50 (m, 1H), 2.76-2.72 (m, 1H), 1.90-1.88 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.48 (m,
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4H), 1.29-1.24 (m, 2H); C NMR (100 MHz, CDCl3) δ = 166.8, 134.7, 134.1, 132.5, 132.3,
129.1, 124.3, 123.0, 102.1, 42.7, 34.5, 25.8, 25.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H17INO 354.0349; Found 354.0371.
(Z)-3-(cyclohex-1-en-1-yliodomethylene)isoindolin-1-one (5m): Yield: (50 mg, 57%);
White Solid; TLC Rf = 0.65 (30% EtOAc:Hexanes, UV); mp 165-167 °C; IR (CHCl3, cm–1)
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3159, 3015, 2932, 2854, 1711, 1652, 1465; H NMR (400 MHz, CDCl3) δ = 10.8 (s, 1H),
8.35-8.33 (m, 1H), 7.93-7.91 (m, 1H), 7.74-7.70 (m, 1H), 7.51-7.47 (m, 1H), 5.96-5.94 (m,
1H), 2.34-2.32 (m, 2H), 2.26-2.24 (m, 2H), 1.88-1.83 (m, 2H), 1.78-1.72 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ = 163.4, 145.3, 138.9, 136.6, 133.6, 132.5, 131.2, 127.4, 126.9, 124.6,
74.5, 27.6, 25.0, 22.4, 21.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H15INO
352.0193; Found 352.0175.
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(Z)-3-(iodomethylene)isoindolin-1-one (5o): Yield: (56 mg, 82%); White Solid; TLC Rf =
0.33 (10% EtOAc:Hexanes, UV); mp 191-193 °C; IR (CHCl3, cm–1) 3019, 2880, 1709, 1467;
1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.84-7.79 (m, 1H),
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7.68-7.64 (m, 1H), 7.61-7.56 (m, 1H), 6.22 (s, 1H); C NMR (100 MHz, CDCl3) δ = 165.8,
140.7, 135.3, 132.5, 132.3, 130.2, 124.3, 123.8, 54.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C9H7INO 271.9567; Found 271.9563.
(Z)-3-(iodo(thiophen-3-yl)methylene)isoindolin-1-one (5p): Yield: (66.3 mg, 75%); Yellow
Solid; TLC Rf = 0.58 (30% EtOAc:Hexanes, UV); mp 162-164 °C; IR (CHCl3, cm–1) 3208,
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2928, 1708, 1471; H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 4.0 Hz, 1H), 7.72 (s, 1H),
7.48-7.42 (m, 3H), 7.34-7.30 (m, 1H), 7.15 (d, J = 4.8 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ = 167.0, 140.7, 138.4, 134.6, 132.3, 131.4, 129.4, 128.3, 126.8,
125.8, 123.8, 122.9, 72.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H9INOS 353.9444;
Found 353.9426.
(Z)-3-(iodo(phenyl)methylene)-5,6-dimethoxyisoindolin-1-one (5q): Yield: (79.4 mg, 78%);
Yellow Solid; TLC Rf = 0.48 (50% EtOAc:Hexanes, UV); mp 206-207 °C; IR (CHCl3, cm–1)
3220, 3019, 2838, 1701, 1496, 1217; 1H NMR (400 MHz, CDCl3) δ = 7.61 (s, 1H), 7.46-7.45
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(m, 4H), 7.41-7.39 (m, 1H), 7.17 (s, 1H), 5.86 (s, 1H), 3.88 (s, 3H), 3.38 (s, 3H); C NMR
(100 MHz, CDCl3) δ = 167.5, 152.3, 150.5, 141.1, 137.8, 129.7, 129.1, 129.0, 128.5, 124.6,
105.2, 104.7, 76.0, 56.1, 55.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H15INO3
408.0091; Found 408.0079.
N-((E)-3-(iodo(phenyl)methylene)isobenzofuran-1(3H)-ylidene)methanamine (5r):45 Yield:
(42.4 mg, 47%); White Solid; TLC Rf = 0.27 (30% EtOAc:Hexanes, UV); mp 121-124 °C;
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Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.58-7.53 (m, 3H), 7.49-7.45 (m, 1H), 7.33-7.29 (m, 1H),
7.22-7.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ = 154.7, 147.1, 140.5, 135.9, 131.6, 131.1,
130.5, 130.1, 128.2, 127.9, 124.9, 122.9, 73.4, 34.9.
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Procedure for the Synthesis of (Z)-2-benzyl-3-(iodo(phenyl)methylene)isoindolin-1-one
(6): To the ice cooled suspension of NaH (60 % dispersion in oil) (1.2 equiv) in DMF was
added 5b (0.25 mmol). After 15 min, Benzyl bromide (1.1 equiv) was added slowly. Reaction
was stirred for 2 h. After completion, 1 mL methanol was added and the reaction mixture was
diluted with EtOAc, and washed with satd. aq. NH4Cl and water. The organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product,
which was purified by column chromatography on silica gel using Hexanes-EtOAc as the
eluent. Yield: (92.2 mg, 87%); White Solid; TLC Rf = 0.66 (30% EtOAc:Hexanes, UV);
mp150-152°C; IR (CHCl3, cm–1) 3068, 3029, 2928, 1709, 1470; 1H NMR (400 MHz, CDCl3)
δ = 7.76-7.74 (m, 1H), 7.31-7.05 (m, 13H)(solvent peak included), 5.89 (d, J = 8.0 Hz, 1H),
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5.61 (d, J = 6.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ =169.5, 145.0, 139.4, 137.6, 137.4,
132.1, 129.3, 129.1, 129.0, 128.9, 128.4, 128.1, 126.9, 126.4, 123.8, 122.9, 87.1, 44.5;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H17INO 438.0349; Found 438.0363.
Procedure for the Synthesis of (Z)-3-(3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-
ylidene)isoindolin-1-one (7): To a solution of the 5b (0.25 mmol) in DMF (2 mL) were
added PdCl2(PPh3)2 (4 mol %) and CuI (3 mol %). The reaction vial was flushed with Ar and
the reaction mixture was stirred for 5 min at room temperature. TEA (4.0 equiv) was added
by a syringe. The reaction mixture was heated to 80 °C. A solution of the 4-Ethynylanisole
(1.2 equiv) in DMF (1 mL) was added dropwise over 5 min, and the mixture was allowed to
stir at 80 °C for 2 h (the reaction progress was monitored by TLC). After cooling, the reaction
mixture was diluted with EtOAc, and washed with satd. aq. NH4Cl and water. The organic
layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude
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product, which was purified by column chromatography on silica gel using Hexane-EtOAc as
the eluent. Yield: (68.5 mg, 78%); Yellow Solid; TLC Rf = 0.67 (30% EtOAc:Hexanes, UV);
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mp 194-195°C; IR (CHCl3, cm–1) 3183, 3019, 2928, 2184, 1703, 1471, 1249; H NMR (400
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MHz, CDCl3) δ = 8.74(s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.58-7.55 (m, 2H), 7.51-7.46 (m,
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5H), 7.42-7.38 (m, 1H), 7.30-7.27 (m, 1H), 6.90-6.86 (m, 3H), 3.82 (s, 3H); C NMR (100
MHz, CDCl3) δ = 167.2, 160.0, 138.0, 135.7, 135.0, 133.2, 131.8, 130.6, 129.7, 129.2, 128.9,
128.6, 123.6, 114.6, 114.1, 105.4, 99.7, 86.5, 55.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C22H18NO2 328.1332; Found 328.1355.
Procedure for the Synthesis of (Z)-3-(phenyl(thiophen-2-yl)methylene)isoindolin-1-one
(8): To a suspension of 5b (0.25 mmol) and thiophen-2-ylboronic acid (1.2 equiv) in
DMF:H2O (4:1) 2 ml was added PdCl2 (5 mol %) and Cs2CO3 (1.4 equiv). The reaction was
heated to 80°C for 2 h (the reaction progress was monitored by TLC). After cooling, the
reaction mixture was diluted with EtOAc, and washed with satd. aq. NH4Cl and water. The
organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the
crude product, which was purified by column chromatography on silica gel using Hexanes-
EtOAc as the eluent. Yield: (65.2 mg, 86%); White Solid; TLC Rf = 0.47 (30%
EtOAc:Hexanes, UV); mp 158-160 °C; IR (CHCl3, cm–1) 3196, 3081, 1700, 1607, 1472,
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1216; H NMR (400 MHz, CDCl3) δ = 8.27 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.50-7.47(m,
3H), 7.41-7.35 (m, 4H), 7.24-7.20 (m, 1H), 7.08-7.06 (m, 1H), 7.03-7.02 (m, 1H), 6.35 (d, J
13
= 7.6 Hz, 1H); C NMR (100 MHz, CDCl3) δ = 167.9, 142.8, 138.8, 136.8, 131.9, 131.7,
130.4, 130.1, 129.0, 128.8, 128.6, 128.3, 127.7, 127.2, 123.7, 123.4, 117.3; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C19H14NOS 304.0791; Found 304.0810.
ACKNOWLEDGMENTS
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This paper is dedicated to Professor Richard C. Larock on the occasion of his 73rd birthday
and also for his mentorship on the wonderful opportunities in Palladium as well as Iodine
chemistry. We gratefully acknowledge the Delhi Technological University for financially
supporting this work, DST and the SAIF at IIT Madras for the SC-XRD analysis, USIC-CIF
University of Delhi for NMR data, Instrumentation facility at DTU for IR analysis, and AIRF
at Jawaharlal Nehru University for Mass analysis. AKV gratefully acknowledges the SERB
(SB/S1/OC-84/2013) for financial support. We are also thankful to Ph.D. candidate Mr.
Mange Ram Mangyan for his support in experimental work and also for proofreading the
manuscript. The authors also thank the reviewers of the paper for their observations and
suggestions regarding the proposed mechanism of the cyclization reaction.
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ASSOCIATED CONTENT
Supporting information
Supplementary data including the Table S1 (Aminocyclization of 2-Phenylethynyl-
benzamide: Optimization Studies) and Table S2 (Preparation of 2-(1-alkynyl)benzamides),
NMR spectra, and analytical data (for compounds 4a-4t and 5a-5t, 6-8) is available free of
charge via the Internet or from the author. Also, the crystallographic data for the structures
reported in this paper have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-1561244. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (+44)1223
33603; e-mail: deposit@ccdc.cam.ac. uk).
AUTHOR INFORMATION
Corresponding Author
Tel.: +91-8800665868; E-mail: saurabh.mehta@dtu.ac.in
Notes
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The authors declare no competing financial interest.
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